# AMR-English alignment release (generated on Mon Mar 14, 2016 at 23:18:32) # ::id a_pmid_2094_2929.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 1 @- RT @-@ PCR and western blot analyses confirmed the strong up @-@ regulation of serpinE2 expression and secretion by IECs expressing oncogenic MEK , Ras or BRAF . # ::alignments 0-1.1 2-1.2.1.1.1.1 4-1.2.1.1.1.1 5-1.2 6-1.2.2 7-1.2.2 8-1.2.1 9-1 11-1.3.1.2 12-1.3.1 13-1.3.1 14-1.3.1 15-1.3.1.1.r 16-1.3.1.1.1.1.1 17-1.3.1.1 18-1.3 19-1.3.2 20-1.3.2.1.r 21-1.3.2.1.1.1 22-1.3.2.1.2 23-1.3.2.1.2.1.4 23-1.3.2.1.2.1.4.1.2.1 24-1.3.2.1.2.1.1.1.1 26-1.3.2.1.2.1.2.1.1 27-1.3.2.1.2.1 28-1.3.2.1.2.1.3.1.1 (c / confirm-01~e.9 :li 1~e.0 :ARG0 (a / and~e.5 :op1 (a2 / analyze-01~e.8 :instrument (t / thing :name (n4 / name :op1 "RT-PCR"~e.2,4))) :op2 (i / immunoblot-01~e.6,7)) :ARG1 (a4 / and~e.18 :op1 (u / upregulate-01~e.12,13,14 :ARG1~e.15 (e3 / express-03~e.17 :ARG2 (p / protein :name (n6 / name :op1 "serpinE2"~e.16))) :ARG1-of (s / strong-02~e.11)) :op2 (s2 / secrete-01~e.19 :ARG0~e.20 (c2 / cell :name (n7 / name :op1 "IEC"~e.21) :ARG3-of (e4 / express-03~e.22 :ARG2 (o2 / or~e.27 :op1 (e / enzyme :name (n2 / name :op1 "MEK"~e.24)) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.26)) :op3 (e5 / enzyme :name (n8 / name :op1 "BRAF"~e.28)) :ARG0-of (c3 / cause-01~e.23 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.23)))))) :ARG1 p))) # ::id a_pmid_2094_2929.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 2 @- Interestingly , serpinE2 mRNA and protein were also markedly enhanced in human CRC cells exhibiting mutation in KRAS @ and BRAF @ . # ::alignments 0-1.1 2-1.6 2-1.6.r 4-1.2.2.1.1 5-1.2.1.1.1 6-1.2 7-1.2.2 9-1.4 10-1.3 10-1.3.r 11-1 12-1.5.r 13-1.5.2 14-1.5.3.1.1 15-1.5 16-1.5.1 17-1.5.1.1 20-1.5.1.1.1.1.1.1 22-1.5.1.1.1 24-1.5.1.1.1.2.1.1 (e / enhance-01~e.11 :li 2~e.0 :ARG1 (a3 / and~e.6 :op1 (n6 / nucleic-acid :name (n / name :op1 "mRNA"~e.5) :ARG0-of (e2 / encode-01 :ARG1 p)) :op2 (p / protein~e.7 :name (n2 / name :op1 "serpinE2"~e.4))) :manner~e.10 (m / marked~e.10) :mod (a2 / also~e.9) :location~e.12 (c / cell~e.15 :ARG0-of (e3 / exhibit-01~e.16 :ARG1 (m2 / mutate-01~e.17 :ARG1 (a4 / and~e.22 :op1 (g / gene :name (n4 / name :op1 "KRAS"~e.20)) :op2 (g2 / gene :name (n5 / name :op1 "BRAF"~e.24))))) :mod (h / human~e.13) :mod (d / disease :name (n3 / name :op1 "CRC"~e.14))) :manner~e.2 (i / interesting~e.2)) # ::id a_pmid_2094_2929.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 3 @- RNAi directed against serpinE2 in caMEK @-@ transformed rat IECs or in human CRC cell lines HCT116 and LoVo markedly decreased foci formation , anchorage @-@ independent growth in soft agarose , cell migration and tumor formation in nude mice . # ::alignments 0-1.1 3-1.2.2 4-1.2.2.1 5-1.2.2.1.1.1.1.1 5-1.2.2.1.1.2.1.1 9-1.2.2.1.1.1.2.3 10-1.2.2.1.1.1.2.2 11-1.2.2.1.1.1.2.1.1 12-1.2.2.1.1 13-1.2.2.1.1.r 14-1.2.2.1.1.2.2.2 15-1.2.2.1.1.2.2.3.1.1 16-1.2.2.1.1.2.2 17-1.2.2.1.1.2.2.1.1.1 17-1.2.2.1.1.2.2.1.1.2 18-1.2.2.1.1.2.2.1.1.1.1.1 19-1.2.2.1.1.2.2.1.1 20-1.2.2.1.1.2.2.1.1.2.1.1 21-1.4 21-1.4.r 22-1 23-1.3.1.1 24-1.3.1 26-1.3.2.1.2 28-1.3.2.1 28-1.3.2.1.1 28-1.3.2.1.1.r 29-1.3.2 30-1.3.2.2.r 31-1.3.2.2.1 32-1.3.2.2 34-1.3.3.1 35-1.3.3 36-1.3 37-1.3.4.1 38-1.3.4 39-1.3.4.2.r 40-1.3.4.2.1 41-1.3.4.2 (d / decrease-01~e.22 :li 3~e.0 :ARG0 (i2 / interfere-01 :ARG1 (n / nucleic-acid :name (n11 / name :op1 "RNA")) :ARG1-of (d2 / direct-01~e.3 :ARG2 (o2 / oppose-01~e.4 :ARG1~e.13 (o / or~e.12 :op1 (p / protein :name (n2 / name :op1 "serpinE2"~e.5) :location (c / cell :name (n3 / name :op1 "IEC"~e.11) :mod (r / rat~e.10) :ARG1-of (t / transform-01~e.9 :ARG0 (e / enzyme :name (n4 / name :op1 "MEK") :ARG2-of (m5 / mutate-01) :mod (c3 / constitutive) :ARG1-of (a4 / activate-01))))) :op2 (p2 / protein :name (n5 / name :op1 "serpinE2"~e.5) :location (c6 / cell~e.16 :ARG2-of (i / include-91 :ARG1 (a3 / and~e.19 :op1 (c2 / cell-line~e.17 :name (n6 / name :op1 "HCT116"~e.18)) :op2 (c4 / cell-line~e.17 :name (n8 / name :op1 "LoVo"~e.20)))) :mod (h / human~e.14) :mod (d4 / disease :name (n10 / name :op1 "CRC"~e.15)))))))) :ARG1 (a / and~e.36 :op1 (f / form-01~e.24 :ARG1 (f2 / focus~e.23)) :op2 (g / grow-01~e.29 :ARG1-of (d3 / depend-01~e.28 :polarity~e.28 -~e.28 :ARG0 (a2 / anchorage~e.26)) :location~e.30 (a5 / agarose~e.32 :ARG1-of (s / soft-02~e.31))) :op3 (m3 / migrate-01~e.35 :ARG0 (c5 / cell~e.34)) :op4 (f3 / form-01~e.38 :ARG1 (t2 / tumor~e.37) :location~e.39 (m4 / mouse~e.41 :mod (n9 / nude~e.40)))) :manner~e.21 (m2 / marked~e.21)) # ::id a_pmid_2094_2929.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 4 @- Treatment of CRC cell lines with U0126 markedly reduced serpinE2 @ mRNA levels , indicating that expression of serpinE2 @ is likely dependent of ERK activity . # ::alignments 0-1.1 2-1.2 3-1.2.1.r 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1 7-1.2.2.r 8-1.2.2.1.1 9-1.4 9-1.4.r 10-1 12-1.3.1.2.1.1.1 14-1.3.1.1.1 15-1.3 17-1.5 18-1.5.1.r 19-1.5.1.1.1 22-1.5.1.1.1.1 25-1.5.1 26-1.5.1.1 27-1.5.1.1.2.r 28-1.5.1.1.2.1.1.1 29-1.5.1.1.2 (r / reduce-01~e.10 :li 4~e.0 :ARG0 (t / treat-04~e.2 :ARG1~e.3 (c / cell-line~e.5,6 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.4))) :ARG2~e.7 (s / small-molecule :name (n / name :op1 "U0126"~e.8))) :ARG1 (l / level~e.15 :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.14) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n5 / name :op1 "serpinE2"~e.12))))) :manner~e.9 (m / marked~e.9) :ARG0-of (i / indicate-01~e.17 :ARG1~e.18 (l2 / likely-01~e.25 :ARG1 (d / depend-01~e.26 :ARG0 (e3 / express-03~e.19 :ARG2 p~e.22) :ARG1~e.27 (a / activity-06~e.29 :ARG0 (e / enzyme :name (n2 / name :op1 "ERK"~e.28))))))) # ::id a_pmid_2094_2929.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 5 @- Finally , Q @-@ PCR analyses demonstrated that mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues and in colorectal tumors , regardless of tumor stage and grade . # ::alignments 0-1.1 2-1.1.r 2-1.2 2-1.2.r 4-1.3.1.1.1 6-1.3.1.1.1 7-1.3 8-1 9-1.4.r 10-1.4.1.1.1.1 11-1.4.1 13-1.4.1.1.2.1.1.1 15-1.4.4 15-1.4.4.r 16-1.4 17-1.4.2.r 18-1.4.2.1.1 19-1.4.2.1 21-1.4.5.r 23-1.4.5.2 24-1.4.5.1 25-1.4.5 26-1.4.2 28-1.4.2.2.1 29-1.4.2.2 31-1.4.3 33-1.4.3.1.1.1.1 34-1.4.3.1.1 34-1.4.3.1.1.1 34-1.4.3.1.1.1.r 35-1.4.3.1 36-1.4.3.1.2 (d / demonstrate-01~e.8 :li~e.2 5~e.0 :li~e.2 -1~e.2 :ARG0 (a / analyze-01~e.7 :mod (t / thing :name (n / name :op1 "Q-PCR"~e.4,6))) :ARG1~e.9 (i / increase-01~e.16 :ARG1 (l / level~e.11 :quant-of (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.10) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2"~e.13))))) :location~e.17 (a2 / and~e.26 :op1 (a3 / adenomas~e.19 :mod (h / human~e.18)) :op2 (t3 / tumor~e.29 :mod (c / colon~e.28))) :ARG1-of (r / regardless-91~e.31 :ARG2 (a5 / and~e.35 :op1 (t5 / thing~e.34 :ARG2-of~e.34 (s / stage-02~e.34 :ARG1 (t4 / tumor~e.33))) :op2 (g / grade~e.36 :mod t4))) :manner~e.15 (m / marked~e.15) :compared-to~e.21 (t2 / tissue~e.25 :mod (a4 / adjacent~e.24) :mod (h2 / healthy~e.23)))) # ::id a_pmid_2094_2929.39 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SerpinE2 is overexpressed in intestinal epithelial cells transformed by activated MEK1 and oncogenic RAS and BRAF # ::alignments 2-1 3-1.2.r 4-1.2.2 5-1.2.1 6-1.2 7-1.2.3 8-1.2.3.1.r 9-1.2.3.1.1.2 10-1.2.3.1.1.1.1 11-1.2.3.1 12-1.2.3.1.2 12-1.2.3.1.2.2 12-1.2.3.1.2.2.1.2.1 12-1.2.3.1.2.2.r 13-1.2.3.1.2.1.1 14-1.2.3.1 15-1.2.3.1.3.1.1 (o / overexpress-01~e.2 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2")) :location~e.3 (c / cell~e.6 :mod (e2 / epithelium~e.5) :part-of (i / intestine~e.4) :ARG1-of (t / transform-01~e.7 :ARG0~e.8 (a / and~e.11,14 :op1 (e3 / enzyme :name (n3 / name :op1 "MEK1"~e.10) :ARG1-of (a2 / activate-01~e.9)) :op2 (e4 / enzyme~e.12 :name (n4 / name :op1 "RAS"~e.13) :ARG0-of~e.12 (c2 / cause-01~e.12 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.12)))) :op3 (e / enzyme :name (n5 / name :op1 "BRAF"~e.15) :ARG0-of c2))))) # ::id a_pmid_2094_2929.40 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the most harmful of all genetic abnormalities that appear in CRC development are mutations of KRAS and its downstream effector BRAF as they result in abnormal ERK signaling . # ::alignments 0-1 2-1.2.4.1 3-1.2.4 5-1.2.3 6-1.2.2 9-1.2.5 11-1.2.5.1.1.1.1.1 12-1.2.5.1 14-1.1.1 15-1.1.1.1.r 16-1.1.1.1.1.1 17-1.1 18-1.1.2.3 18-1.1.2.3.r 19-1.1.2.1 20-1.1.2 21-1.1.2.2.1.1 22-1.2.5.1.r 24-1.1.3 26-1.1.3.1.2 26-1.1.3.1.2.1 26-1.1.3.1.2.1.r 26-1.2 26-1.2.1 26-1.2.1.r 27-1.1.3.1.1.1.1 28-1.1.3.1 (i / include-91~e.0 :ARG1 (a4 / and~e.17 :op1 (m2 / mutate-01~e.14 :ARG1~e.15 (e4 / enzyme :name (n3 / name :op1 "KRAS"~e.16))) :op2 (e2 / effector~e.20 :mod (d2 / downstream~e.19) :mod (e3 / enzyme :name (n4 / name :op1 "BRAF"~e.21)) :poss~e.18 e4~e.18) :ARG1-of (r / result-01~e.24 :ARG2 (s / signal-07~e.28 :ARG0 (e / enzyme :name (n / name :op1 "ERK"~e.27)) :ARG1-of (n6 / normal-02~e.26 :polarity~e.26 -~e.26)))) :ARG2 (n5 / normal-02~e.26 :polarity~e.26 -~e.26 :ARG2 (g / genetics~e.6) :mod (a2 / all~e.5) :ARG0-of (h / harmful-02~e.3 :degree (m / most~e.2)) :ARG1-of (a3 / appear-01~e.9 :time~e.22 (d / develop-02~e.12 :ARG1 (c / cell :mod (d3 / disease :name (n2 / name :op1 "CRC"~e.11))))))) # ::id a_pmid_2094_2929.41 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a previous report , we had shown that expression of a constitutive active mutant of MEK1 ( caMEK ) in the intestinal epithelial cell line IEC @-@ 6 induced morphological transformation and growth in soft agar ; in marked contrast , wtMEK overexpression had no effect on IEC @-@ 6 phenotype [ @ 3 @ ] . # ::alignments 2-1.1.3.1 3-1.1.3 5-1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.1 10-1.1.2.1.1.r 12-1.1.2.1.1.2 13-1.1.2.1.1.3 14-1.1.2.1.1 15-1.1.2.1.1.1.r 16-1.1.2.1.1.1.1.1 20-1.1.2.1.2.r 22-1.1.2.1.2.2.1 23-1.1.2.1.2.2 24-1.1.2.1.2 25-1.1.2.1.2 25-1.2.3.1 26-1.1.2.1.2.1.1 28-1.1.2.1.2.1.1 29-1.1.2 30-1.1.2.2.1.1 31-1.1.2.2.1 32-1.1.2.2 33-1.1.2.2.2 34-1.1.2.2.2.1.r 35-1.1.2.2.2.1.1 36-1.1.2.2.2.1 39-1.2.5.1 40-1.2.5 43-1.2.2 45-1.2.1 45-1.2.1.r 46-1.2 47-1.2.3.r 48-1.2.3.1.1.1 50-1.2.3.1.1.1 51-1.2.3 54-1.2.4.1.1.1 (a / and :op1 (s / show-01~e.7 :ARG0 (w / we~e.5) :ARG1~e.8 (i / induce-01~e.29 :ARG0 (e / express-03~e.9 :ARG2~e.10 (m / mutate-01~e.14 :ARG2~e.15 (e2 / enzyme :name (n / name :op1 "MEK1"~e.16)) :mod (c / constitutive~e.12) :ARG0-of (a2 / activity-06~e.13)) :ARG3~e.20 (c2 / cell-line~e.24,25 :name (n3 / name :op1 "IEC-6"~e.26,28) :mod (e4 / epithelium~e.23 :part-of (i2 / intestine~e.22)))) :ARG2 (a3 / and~e.32 :op1 (t / transform-01~e.31 :mod (m3 / morphological~e.30)) :op2 (g / grow-01~e.33 :location~e.34 (a4 / agar~e.36 :ARG1-of (s2 / soft-02~e.35))))) :medium (r / report~e.3 :time (p / previous~e.2))) :op2 (a5 / affect-01~e.46 :polarity~e.45 -~e.45 :ARG0 (o / overexpress-01~e.43 :ARG1 (e5 / enzyme :name (n4 / name :op1 "MEK") :mod (w2 / wild-type))) :ARG1~e.47 (p2 / phenotype~e.51 :mod (c3 / cell-line~e.25 :name (n5 / name :op1 "IEC-6"~e.48,50))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 3~e.54))) :ARG2-of (c5 / contrast-01~e.40 :ARG1-of (m4 / mark-01~e.39)))) # ::id a_pmid_2094_2929.42 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to understand the mechanisms by which activated MEK1 induces intestinal cell tumorigenesis , the pattern of gene expression was analyzed by microarray in IEC @-@ 6 cells overexpressing activated MEK1 . # ::alignments 0-1.4.r 1-1.4.r 2-1.4.r 3-1.4 5-1.4.1 8-1.4.1.1.1.2 9-1.4.1.1.1.1.1 10-1.4.1.1 11-1.4.1.1.2.1.1.1 12-1.4.1.1.2.1.1 13-1.4.1.1.2 13-1.4.1.1.2.1 13-1.4.1.1.2.1.r 16-1.2 17-1.2.1.r 18-1.2.1.1 19-1.2.1 21-1 22-1.1.r 23-1.1 24-1.3.r 25-1.3.1.1 27-1.3.1.1 28-1.3 29-1.3.2 30-1.3.2.1 31-1.3.2.1 (a3 / analyze-01~e.21 :ARG0~e.22 (m2 / microarray~e.23) :ARG1 (p / pattern-01~e.16 :ARG1~e.17 (e2 / express-03~e.19 :ARG2 (g / gene~e.18))) :location~e.24 (c2 / cell-line~e.28 :name (n2 / name :op1 "IEC-6"~e.25,27) :ARG0-of (o / overexpress-01~e.29 :ARG1 e~e.30,31)) :purpose~e.0,1,2 (u / understand-01~e.3 :ARG1 (m / mechanism~e.5 :instrument-of (i / induce-01~e.10 :ARG0 (e / enzyme :name (n / name :op1 "MEK1"~e.9) :ARG1-of (a / activate-01~e.8)) :ARG2 (c3 / create-01~e.13 :ARG1~e.13 (t / tumor~e.13 :mod (c / cell~e.12 :part-of (i2 / intestine~e.11)))))))) # ::id a_pmid_2094_2929.43 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results from microarrays comparing control ( wtMEK ) to caMEK @-@ expressing IEC @-@ 6 cells identified the Serpin clade E member 2 @ ( serpinE2 @ or PN @-@ 1 ) gene as a potential target of activated MEK1 . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.2.r 2-1.1.2 3-1.1.2.1 4-1.1.2.1.1 11-1.1.2.1.2.2 12-1.1.2.1.2.1.1 14-1.1.2.1.2.1.1 15-1.1.2.1.2 16-1 19-1.2.1.1 20-1.2.1.2 21-1.2.1.3 22-1.2.1.4 23-1.2.1.5 27-1.2.2.1.1.1.1 31-1.2.2.1.2.1.1 33-1.2.2.1.2.1.1 36-1.2 36-1.2.2.1.1 36-1.2.2.1.2 37-1.3.r 39-1.3.3 40-1.3 42-1.1.2.1.2.2.1.4 42-1.3.1.2 43-1.3.1.1.1 (i / identify-01~e.16 :ARG0 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0) :source~e.1 (m / microarray~e.2 :ARG0-of (c / compare-01~e.3 :ARG1 (c2 / control~e.4 :ARG1-of (m2 / mean-01 :ARG2 (e / enzyme :name (n / name :op1 "MEK") :mod (w / wild-type)))) :ARG2 (c3 / cell-line~e.15 :name (n2 / name :op1 "IEC-6"~e.12,14) :ARG3-of (e2 / express-03~e.11 :ARG2 (e3 / enzyme :name (n3 / name :op1 "MEK") :ARG2-of (m4 / mutate-01) :mod (c4 / constitutive) :ARG1-of (a4 / activate-01~e.42))))))) :ARG1 (g / gene~e.36 :name (n4 / name :op1 "Serpin"~e.19 :op2 "clade"~e.20 :op3 "E"~e.21 :op4 "member"~e.22 :op5 2~e.23) :ARG1-of (m3 / mean-01 :ARG2 (a / and :op1 (g2 / gene~e.36 :name (n5 / name :op1 "serpinE2"~e.27)) :op2 (g3 / gene~e.36 :name (n6 / name :op1 "PN-1"~e.31,33))))) :ARG2~e.37 (t2 / target-01~e.40 :ARG0 (e4 / enzyme :name (n7 / name :op1 "MEK1"~e.43) :ARG1-of (a2 / activate-01~e.42)) :ARG1 g :mod (p / potential~e.39))) # ::id a_pmid_2094_2929.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , serpinE2 @ expression was significantly induced by more that 28 @-@ fold ( p < 0.05 ) in cells overexpressing activated MEK1 in comparison to cells expressing wtMEK ( data not shown ) . # ::alignments 0-1.2 3-1.1.1.1.1 5-1.1 7-1.3 8-1 9-1.7.r 10-1.7 12-1.7.1.1 14-1.7.1 16-1.8 17-1.8.1 18-1.8.1.1 20-1.4.r 21-1.4 22-1.4.1 23-1.4.1.1.2 24-1.4.1.1.1.1 26-1.5.r 28-1.5 29-1.5.1 32-1.6.1 33-1.6.1.1.1 33-1.6.1.1.1.r 34-1.6.1.1 (i / induce-01~e.8 :ARG2 (e / express-03~e.5 :ARG1 (g / gene :name (n / name :op1 "serpinE2"~e.3))) :mod (i2 / indeed~e.0) :ARG1-of (s / significant-02~e.7) :location~e.20 (c / cell~e.21 :location-of (o / overexpress-01~e.22 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1"~e.24) :ARG1-of (a / activate-01~e.23)))) :compared-to~e.26 (c2 / cell~e.28 :ARG3-of (e3 / express-03~e.29 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MEK") :mod (w / wild-type)))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.32 :ARG1-of (s2 / show-01~e.34 :polarity~e.33 -~e.33))) :quant~e.9 (m2 / more-than~e.10 :op1 (p / product-of~e.14 :op1 28~e.12)) :ARG1-of (s3 / statistical-test-91~e.16 :ARG2 (l / less-than~e.17 :op1 0.05~e.18))) # ::id a_pmid_2094_2929.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of serpinE2 @ in caMEK @-@ expressing IECs was furthermore confirmed following RT @-@ PCR analysis as shown in Figure 1A @ . # ::alignments 0-1.1.1 3-1.1.1.1.1.1 8-1.1.1.2.2 9-1.1.1.2.1.1 11-1 12-1.1 13-1.1.2 14-1.1.2.1.1.1.1 16-1.1.2.1.1.1.1 17-1.1.2.1 18-1.1.2.r 19-1.2 20-1.2.1.r 21-1.2.1 23-1.2.1.1 (a / and~e.11 :op2 (c / confirm-01~e.12 :ARG1 (o / overexpress-01~e.0 :ARG1 (g / gene :name (n / name :op1 "serpinE2"~e.3)) :location (c2 / cell :name (n2 / name :op1 "IEC"~e.9) :ARG3-of (e / express-03~e.8 :ARG2 (e2 / enzyme :name (n3 / name :op1 "MEK") :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01))))) :time~e.18 (f / follow-01~e.13 :ARG2 (a2 / analyze-01~e.17 :mod (t / thing :name (n4 / name :op1 "RT-PCR"~e.14,16))))) :ARG1-of (s / show-01~e.19 :ARG0~e.20 (f2 / figure~e.21 :mod "1A"~e.23))) # ::id a_pmid_2094_2929.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SerpinE2 expression was also markedly enhanced in IEC @-@ 6 cells transformed by oncogenic RAS ( 26 @-@ fold ) or BRAF ( 12 @-@ fold after 12 h of 4 @-@ hydroxytamoxifen ( 4 @-@ OHT ) ( Figure 1B and 1C ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1.4 4-1.1.3 4-1.1.3.r 5-1.1 5-1.2 7-1.1.5.1.1 7-1.2.4.1.1 9-1.1.5.1.1 10-1.1.5 10-1.2.4 11-1.1.5.2 11-1.2.4.2 12-1.1.5.2.1.r 13-1.1.5.2.1 13-1.1.5.2.1.2 13-1.1.5.2.1.2.1.2.1 13-1.1.5.2.1.2.r 14-1.1.5.2.1.1.1 16-1.1.2.1 18-1.1.2 20-1 21-1.2.4.2.1.1.1 23-1.2.2.1 25-1.2.2 26-1.2.3 27-1.2.3.2.1 28-1.2.3.2.2 30-1.2.3.1.1.1.1 32-1.2.3.1.1.1.1 34-1.2.3.1.1.1.1 39-1.3.1.1 39-1.3.1.2 41-1.3.1.1.1 43-1.3.1 45-1.3.1.2.1 (o / or~e.20 :op1 (e2 / enhance-01~e.5 :ARG1 (e3 / express-03~e.1 :ARG2 (p / protein :name (n2 / name :op1 "SerpinE2"~e.0))) :ARG3 (p2 / product-of~e.18 :op1 26~e.16) :manner~e.4 (m / marked~e.4) :mod (a / also~e.3) :location (c / cell-line~e.10 :name (n3 / name :op1 "IEC-6"~e.7,9) :ARG1-of (t / transform-01~e.11 :ARG0~e.12 (e / enzyme~e.13 :name (n / name :op1 "Ras"~e.14) :ARG0-of~e.13 (c2 / cause-01~e.13 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.13))))))) :op2 (e4 / enhance-01~e.5 :ARG1 e3 :ARG3 (p4 / product-of~e.25 :op1 12~e.23) :time (a2 / after~e.26 :op1 (s / stimulate-01 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "4-hydroxytamoxifen"~e.30,32,34))) :quant (t2 / temporal-quantity :quant 12~e.27 :unit (h / hour~e.28))) :location (c4 / cell-line~e.10 :name (n7 / name :op1 "IEC-6"~e.7) :ARG1-of (t3 / transform-01~e.11 :ARG0 (e5 / enzyme :name (n4 / name :op1 "BRAF"~e.21) :ARG0-of c2)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.43 :op1 (f / figure~e.39 :mod "1B"~e.41) :op2 (f2 / figure~e.39 :mod "1C"~e.45)))) # ::id a_pmid_2094_2929.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of note , the induction of serpinE2 was induced within 1 h following ERK activation as observed in cells expressing the inducible BRAF : ER fusion protein stimulated with 4 @-@ OHT ( Figure 1C ) . # ::alignments 1-1 4-1.1 6-1.1.1.1.1.1 8-1.1 9-1.1.2 9-1.1.2.2 9-1.1.2.2.1.1.r 9-1.1.2.2.r 10-1.1.2.2.1.1 11-1.1.2.2.1.2 12-1.1.2 12-1.1.3 13-1.1.2.1.1.1.1 14-1.1.2.1 15-1.1.2.r 15-1.1.4.r 16-1.1.4 17-1.1.4.1.r 18-1.1.4.1 19-1.1.4.1.1 21-1.1.1 21-1.1.4.1.1.1.2 22-1.1.4.1.1.1.1.1 24-1.1.4.1.1.1.1.1 25-1.1.4.1.1.1.1.2 26-1.1.1.1 26-1.1.4.1.1.1 27-1.1.4.1.1.1.3 28-1.1.4.1.1.1.3.1.r 29-1.1.4.1.1.1.3.1.1.1 31-1.1.4.1.1.1.3.1.1.1 33-1.2.1 35-1.2.1.1 (n2 / note-02~e.1 :ARG1 (i / induce-01~e.4,8 :ARG2 (i2 / induce-01~e.21 :ARG2 (p / protein~e.26 :name (n3 / name :op1 "serpinE2"~e.6))) :time~e.15 (a / after~e.9,12 :op1 (a2 / activate-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.13))) :quant~e.9 (u / up-to~e.9 :op1 (t / temporal-quantity :quant~e.9 1~e.10 :unit (h / hour~e.11)))) :ARG1-of (f / follow-01~e.12) :ARG1-of~e.15 (o / observe-01~e.16 :location~e.17 (c / cell~e.18 :ARG3-of (e2 / express-03~e.19 :ARG2 (p3 / protein~e.26 :name (n5 / name :op1 "BRAF:ER"~e.22,24 :op2 "fusion"~e.25) :ARG1-of (i3 / induce-01~e.21 :ARG1-of (p2 / possible-01)) :ARG1-of (s / stimulate-01~e.27 :ARG2~e.28 (s2 / small-molecule :name (n4 / name :op1 "4-OHT"~e.29,31)))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.33 :mod "1C"~e.35))) # ::id a_pmid_2094_2929.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with the MEK @-@ inhibitor U0126 completely abrogated serpinE2 gene expression induced by oncogenic MEK1 ( Figure 1A ) and BRAF ( Figure 1C ) , indicating that induction of serpinE2 is an early and direct event occurring following the activation of ERK signaling . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1.2.1.1.1 5-1.2.1 5-1.2.1.2 5-1.2.1.2.r 6-1.2.1.1.1 7-1.3 8-1 9-1.1.1.1.1 10-1.1.1 11-1.1 12-1.1.2 12-1.1.3 13-1.1.2.1.r 14-1.1.2.1 14-1.1.2.1.2 14-1.1.2.1.2.1.2.1 14-1.1.2.1.2.r 15-1.1.2.1.1.1 17-1.1.2.2.1 19-1.1.2.2.1.1 23-1.1.3.1.1.1 25-1.1.3.2.1 27-1.1.3.2.1.1 31-1.4 32-1.4.1.r 33-1.4.1.3 34-1.4.1.3.1.r 35-1.4.1.3.1 36-1.4.1.3.r 38-1.4.1.1 40-1.4.1.2 41-1.4.1 43-1.4.1.4 45-1.4.1.4.1 46-1.4.1.4.1.1.r 47-1.4.1.4.1.1.1.1.1 48-1.4.1.4.1.1 (a / abrogate-01~e.8 :ARG1 (e3 / express-03~e.11 :ARG2 (g / gene~e.10 :name (n5 / name :op1 "serpinE2"~e.9)) :ARG2-of (i2 / induce-01~e.12 :ARG0~e.13 (e4 / enzyme~e.14 :name (n6 / name :op1 "MEK1"~e.15) :ARG0-of~e.14 (c2 / cause-01~e.14 :ARG1 (d4 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.14)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod "1A"~e.19))) :ARG2-of (i3 / induce-01~e.12 :ARG0 (e7 / enzyme :name (n7 / name :op1 "BRAF"~e.23) :ARG0-of c2) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.25 :mod "1C"~e.27)))) :ARG2 (t / treat-04~e.0 :ARG2~e.1 (s2 / small-molecule~e.5 :name (n3 / name :op1 "U0126"~e.6) :ARG0-of~e.5 (i / inhibit-01~e.5 :ARG1 (p2 / protein-family :name (n4 / name :op1 "MEK"~e.3))))) :ARG1-of (c / complete-02~e.7) :ARG0-of (i4 / indicate-01~e.31 :ARG1~e.32 (e5 / event~e.41 :mod (e6 / early~e.38) :ARG1-of (d3 / direct-02~e.40) :domain~e.36 (i5 / induce-01~e.33 :ARG1~e.34 g~e.35) :ARG1-of (f3 / follow-01~e.43 :ARG2 (a2 / activate-01~e.45 :ARG1~e.46 (s3 / signal-07~e.48 :ARG0 (p / protein-family :name (n2 / name :op1 "ERK"~e.47)))))))) # ::id a_pmid_2094_2929.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since serpinE2 protein is known to be secreted [ @ 22 , 33 @ ] , we easily confirmed its presence in conditioned culture medium of caMEK @-@ expressing IECs whereas no serpinE2 protein was detected in the culture medium of wtMEK @-@ expressing or parental IECs ( Figure 1D ) . # ::alignments 0-1.5 1-1.2.1.1.1 2-1.2.1 4-1.5.1 7-1.5.1.1 10-1.5.2.1.1.1.1 14-1.5.2.1.1.1.2 18-1.1 19-1.4 20-1 22-1.2 23-1.2.2.r 24-1.2.2.2 25-1.2.2.1 26-1.2.2 30-1.2.2.3.2 31-1.2.2.3.1.1 32-1.6 33-1.6.1.1 33-1.6.1.1.r 34-1.6.1.2 35-1.6.1.2 37-1.6.1 38-1.6.1.3.r 40-1.6.1.3.1.1 40-1.6.1.3.2.1 41-1.6.1.3.1 41-1.6.1.3.2 45-1.6.1.3.1.2.2 46-1.6.1.3 47-1.6.1.3.2.2.2 48-1.6.1.3.1.2.1.1 48-1.6.1.3.2.2.1.1 50-1.3.1 52-1.3.1.1 (c / confirm-01~e.20 :ARG0 (w2 / we~e.18) :ARG1 (p / present-02~e.22 :ARG1 (p2 / protein~e.2 :name (n / name :op1 "serpinE2"~e.1)) :ARG2~e.23 (m / medium~e.26 :mod (c3 / culture~e.25) :ARG1-of (c4 / condition-01~e.24) :poss (c7 / cell :name (n4 / name :op1 "IEC"~e.31) :ARG3-of (e2 / express-03~e.30 :ARG2 (e / enzyme :name (n3 / name :op1 "MEK") :ARG2-of (m2 / mutate-01) :mod (c6 / constitutive) :ARG1-of (a3 / activate-01)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.50 :mod "1D"~e.52)) :ARG1-of (e5 / easy-05~e.19) :ARG0-of (c10 / cause-01~e.0 :ARG1 (k / know-01~e.4 :ARG1 (s2 / secrete-01~e.7 :ARG1 p2)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c9 / cite-01 :ARG2 (a2 / and :op1 22~e.10 :op2 33~e.14))))) :ARG1-of (c2 / contrast-01~e.32 :ARG2 (d / detect-01~e.37 :polarity~e.33 -~e.33 :ARG1 p2~e.34,35 :location~e.38 (o / or~e.46 :op1 (m3 / medium~e.41 :mod (c5 / culture-01~e.40) :poss (c12 / cell :name (n2 / name :op1 "IEC"~e.48) :ARG3-of (e4 / express-03~e.45 :ARG2 (e3 / enzyme :name (n5 / name :op1 "MEK") :mod (w / wild-type))))) :op2 (m4 / medium~e.41 :mod (c11 / culture-01~e.40) :poss (c8 / cell :name (n6 / name :op1 "IEC"~e.48) :mod (p4 / parent~e.47))))))) # ::id a_pmid_2094_2929.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Again , treatment with the MEK @-@ inhibitor U0126 completely abrogated serpinE2 secretion ( Figure 1D ) . # ::alignments 0-1.3 2-1.2 3-1.2.1.r 5-1.2.1.2.1.1.1 7-1.2.1 7-1.2.1.2 7-1.2.1.2.r 8-1.2.1.1.1 9-1.5 10-1 11-1.1.1.1.1 12-1.1 14-1.4.1 16-1.4.1.1 (a / abrogate-01~e.10 :ARG1 (s2 / secrete-01~e.12 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2"~e.11))) :ARG2 (t / treat-04~e.2 :ARG2~e.3 (s / small-molecule~e.7 :name (n / name :op1 "U0126"~e.8) :ARG0-of~e.7 (i / inhibit-01~e.7 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.5))))) :mod (a2 / again~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "1D"~e.16)) :ARG1-of (c / complete-02~e.9)) # ::id a_pmid_2094_2929.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , serpinE2 protein was difficult to detect in total cell lysates ( Figure 1E , lane 2 ) . # ::alignments 0-1.2 2-1.3.1.1.1 3-1.3.1 4-1.3.r 5-1 7-1.3 8-1.3.2.r 9-1.3.2.2 10-1.3.2.1 11-1.3.2 13-1.1.1.1 15-1.1.1.1.1 18-1.1.1.1.2 19-1.1.1.1.2.1 (d / difficult~e.5 :ARG1-of (d3 / describe-01 :ARG0 (a / and :op1 (f / figure~e.13 :mod "1E"~e.15 :part (l2 / lane~e.18 :mod 2~e.19)))) :mod (i / interesting~e.0) :domain~e.4 (d2 / detect-01~e.7 :ARG1 (p / protein~e.3 :name (n / name :op1 "serpinE2"~e.2)) :location~e.8 (l / lysate~e.11 :mod (c / cell~e.10) :mod (t / total~e.9)))) # ::id a_pmid_2094_2929.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , serpinE2 was easily observed in lysates prepared from foci of post @-@ confluent caMEK @-@ expressing cells ( Figure 1E , lane 4 ) , while it was not detectable in the surrounding monolayer ( Figure 1E , lane 3 ) . # ::alignments 0-1 0-1.1 0-1.1.r 2-1.1.1.1.1.1 3-1.1.1.3.1.1.1.1.1.1.r 4-1.1.1.2 5-1.1.1 6-1.1.1.3.r 7-1.1.1.3 8-1.1.1.3.1 9-1.1.1.3.1.1.r 10-1.1.1.3.1.1 11-1.1.1.3.1.1.1.r 12-1.1.1.3.1.1.1.1 14-1.1.1.3.1.1.1.1.1 17-1.1.1.3.1.1.1.2 18-1.1.1.3.1.1.1 20-1.1.1.4.1.1 22-1.1.1.4.1.1.1 25-1.1.1.4.1.1.2 26-1.1.1.4.1.1.2.1 29-1.1.1.3.1.1.1.1.r 30-1.1.2.1.2 31-1.1.1.3.1.1.1.1.1.1.r 32-1.1.2.1.1 32-1.1.2.1.1.r 33-1.1.2.1 34-1.1.2.1.3.r 36-1.1.2.1.3.1 37-1.1.2.1.3 39-1.1.2.1.4.1.1 41-1.1.2.1.4.1.1.1 44-1.1.2.1.4.1.1.2 45-1.1.2.1.4.1.1.2.1 (h / have-concession-91~e.0 :ARG1~e.0 (c / contrast-01~e.0 :ARG1 (o / observe-01~e.5 :ARG1 (p / protein :name (n / name :op1 "serpinE2"~e.2)) :ARG1-of (e / easy-05~e.4) :location~e.6 (l / lysate~e.7 :ARG1-of (p2 / prepare-01~e.8 :ARG2~e.9 (f / focus~e.10 :part-of~e.11 (c2 / cell~e.18 :time~e.29 (a / after~e.12 :op1 (c4 / confluent~e.14 :domain~e.3,31 c2)) :ARG3-of (e3 / express-03~e.17 :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEK") :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure~e.20 :mod "1E"~e.22 :part (l2 / lane~e.25 :mod 4~e.26))))) :ARG2 (p4 / possible-01 :ARG1 (d2 / detect-01~e.33 :polarity~e.32 -~e.32 :ARG1 p~e.30 :location~e.34 (m2 / monolayer~e.37 :ARG1-of (s / surround-01~e.36)) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f3 / figure~e.39 :mod "1E"~e.41 :part (l3 / lane~e.44 :mod 3~e.45)))))))) # ::id a_pmid_2094_2929.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This indicates a stronger expression of serpinE2 protein by the transformed IECs forming the foci . # ::alignments 0-1.1 1-1 3-1.2.3 3-1.2.3.1 3-1.2.3.1.r 4-1.2 5-1.2.1.r 6-1.2.1.1.1 7-1.2.1 8-1.2.2.r 10-1.2.2.2 11-1.2.2.1.1 12-1.2.2.3 14-1.2.2.3.1 (i / indicate-01~e.1 :ARG0 (t / this~e.0) :ARG1 (e / express-03~e.4 :ARG2~e.5 (p / protein~e.7 :name (n / name :op1 "serpinE2"~e.6)) :ARG3~e.8 (c / cell :name (n2 / name :op1 "IEC"~e.11) :ARG1-of (t2 / transform-01~e.10) :ARG0-of (f / form-01~e.12 :ARG1 (f2 / focus~e.14))) :ARG1-of (s / strong-02~e.3 :degree~e.3 (m / more~e.3)))) # ::id a_pmid_2094_2929.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Gene silencing of serpinE2 decreases foci formation , growth in soft agarose and migration induced by activated MEK # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1 5-1.2.1.1 6-1.2.1 8-1.2.2 9-1.2.2.1.r 10-1.2.2.1.1 11-1.2.2.1 12-1.2 13-1.2.3 14-1.2.3.1 15-1.2.3.1.1.r 16-1.2.3.1.1.2 17-1.2.3.1.1.1.1 (d / decrease-01~e.4 :ARG0 (s / silence-01~e.1 :ARG1~e.2 (p / protein :name (n2 / name :op1 "serpinE2"~e.3)) :mod (g / gene~e.0)) :ARG1 (a / and~e.12 :op1 (f / form-01~e.6 :ARG1 (f2 / focus~e.5)) :op2 (g2 / grow-01~e.8 :location~e.9 (a3 / agarose~e.11 :ARG1-of (s2 / soft-02~e.10))) :op3 (m2 / migrate-01~e.13 :ARG2-of (i / induce-01~e.14 :ARG0~e.15 (e2 / enzyme :name (n4 / name :op1 "MEK"~e.17) :ARG1-of (a2 / activate-01~e.16)))))) # ::id a_pmid_2094_2929.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to determine the contribution of serpinE2 in intestinal transformation induced by activated MEK , foci from post @-@ confluent caMEK @-@ expressing IECs were retrieved by aspiration with a pipette and pooled as one caMEK @-@ expressing cell population . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 5-1.3.1 6-1.3.1.1.r 7-1.3.1.1.1.1 8-1.3.1.2.r 9-1.3.1.2.1 10-1.3.1.2 11-1.3.1.2.2 13-1.1.2.2.1.4 13-1.3.1.2.2.1.2 14-1.1.2.2.1.1.1 14-1.3.1.2.2.1.1.1 16-1.1.1 18-1.1.2.3 20-1.1.2.3.1 23-1.1.2.2 24-1.1.2.1.1 25-1.1.2.3.1.1.r 26-1.1 27-1.1.3.r 28-1.1.3 29-1.1.3.3.r 31-1.1.3.3 32-1 33-1.2 34-1.1.2.3.r 38-1.2.2.1.1 39-1.2.2.1 40-1.2.2 (a5 / and~e.32 :op1 (r / retrieve-01~e.26 :ARG1 (f / focus~e.16) :ARG2 (c2 / cell :name (n3 / name :op1 "IEC"~e.24) :ARG3-of (e2 / express-03~e.23 :ARG2 (e3 / enzyme :name (n4 / name :op1 "MEK"~e.14) :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01~e.13))) :time~e.34 (a2 / after~e.18 :op1 (c5 / confluent~e.20 :domain~e.25 c2))) :manner~e.27 (a3 / aspirate-101~e.28 :ARG1 f :ARG2 c2 :instrument~e.29 (p3 / pipette~e.31))) :op2 (p4 / pool-01~e.33 :ARG1 f :ARG2 (p5 / population~e.40 :mod (c4 / cell~e.39 :ARG3-of (e4 / express-03~e.38 :ARG2 e3)))) :purpose~e.0,1,2 (d / determine-01~e.3 :ARG1 (c / contribute-01~e.5 :ARG0~e.6 (p / protein :name (n2 / name :op1 "serpinE2"~e.7)) :ARG2~e.8 (t / transform-01~e.10 :mod (i / intestine~e.9) :ARG2-of (i2 / induce-01~e.11 :ARG0 (e / enzyme :name (n / name :op1 "MEK"~e.14) :ARG1-of (a / activate-01~e.13))))))) # ::id a_pmid_2094_2929.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All further experiments were performed with this previously characterized caMEK @-@ expressing IEC population [ @ 14 @ ] and compared with wtMEK @-@ expressing cell populations . # ::alignments 0-1.1.1.3 1-1.1.1.2 2-1.1.1 4-1.1 5-1.1.1.1.r 6-1.1.1.1.3 7-1.1.1.1.1.1 8-1.1.1.1.1 11-1.1.1.1.2.2 12-1.1.1.1.2.1.1 13-1.1.1.1 16-1.1.2.1.1.1 19-1 20-1.2 24-1.2.2.1.1 25-1.2.2.1 26-1.2.2 (a3 / and~e.19 :op1 (p / perform-02~e.4 :ARG1 (e / experiment-01~e.2 :ARG1~e.5 (p2 / population~e.13 :ARG1-of (c / characterize-01~e.8 :time (p3 / previous~e.7)) :mod (c2 / cell :name (n / name :op1 "IEC"~e.12) :ARG3-of (e2 / express-03~e.11 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK") :mod (c3 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a4 / activate-01)))) :mod (t / this~e.6)) :degree (f / further~e.1) :mod (a / all~e.0)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 14~e.16)))) :op2 (c5 / compare-01~e.20 :ARG1 e :ARG2 (p5 / population~e.26 :mod (c6 / cell~e.25 :ARG3-of (e4 / express-03~e.24 :ARG2 (e5 / enzyme :name (n3 / name :op1 "MEK") :mod (w / wild-type))))))) # ::id a_pmid_2094_2929.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recombinant lentiviruses encoding anti @- @ serpinE2 @ short hairpin RNA ( shRNA ) were therefore developed to stably suppress serpinE2 levels in these cells . # ::alignments 0-1.1.1.1 2-1.1.1.2 2-1.1.1.2.1.2 3-1.1.1.2.1.2.1.1 6-1.1.1.2.1.2.1.1.1.1.1 8-1.1.1.2.1.1.1 9-1.1.1.2.1.1.2 10-1.1.1.2.1 10-1.1.1.2.1.3.1 12-1.1.1.2.1.3.1.1.1 15-1 16-1.1 18-1.1.2.2 19-1.1.2 20-1.1.2.1.1 21-1.1.2.1 22-1.1.2.3.r 23-1.1.2.3.1 24-1.1.2.3 (c / cause-01~e.15 :ARG1 (d / develop-02~e.16 :ARG1 (l / lentivirus :ARG3-of (r / recombine-01~e.0) :ARG0-of (e / encode-01~e.2 :ARG1 (n4 / nucleic-acid~e.10 :name (n / name :op1 "short"~e.8 :op2 "hairpin"~e.9) :ARG0-of (e2 / encode-01~e.2 :ARG1 (a / antibody :ARG0-of (o / oppose-01~e.3 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"~e.6))))) :ARG1-of (m / mean-01 :ARG2 (n5 / nucleic-acid~e.10 :name (n3 / name :op1 "shRNA"~e.12)))))) :ARG4 (s / suppress-01~e.19 :ARG1 (l2 / level~e.21 :quant-of p~e.20) :ARG1-of (s2 / stable-03~e.18) :location~e.22 (c2 / cell~e.24 :mod (t / this~e.23))))) # ::id a_pmid_2094_2929.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several lentiviral constructs were generated and tested for their ability to knock down serpinE2 protein . # ::alignments 0-1.1.1.2 1-1.1.1.1 2-1.1.1 4-1.1 5-1 6-1.2 9-1.2.2 10-1.2.2.2.r 11-1.2.2.2 12-1.2.2.2 13-1.2.2.2.2.1.1 14-1.2.2.2.2 (a / and~e.5 :op1 (g / generate-01~e.4 :ARG1 (c / construct-01~e.2 :ARG1 (l / lentiviral~e.1) :quant (s / several~e.0))) :op2 (t / test-01~e.6 :ARG1 c :ARG2 (c2 / capable-01~e.9 :ARG1 c :ARG2~e.10 (k / knock-down-02~e.11,12 :ARG0 c :ARG1 (p / protein~e.14 :name (n / name :op1 "serpinE2"~e.13)))))) # ::id a_pmid_2094_2929.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One of these viral shRNAs was selected and designated as shSerpinE2 . # ::alignments 2-1.1.1.1.1.3 3-1.1.1.1.1.2 4-1.1.1.1.1.1.1 4-1.2.2.1.1 6-1.1 7-1 8-1.2 (a / and~e.7 :op1 (s / select-01~e.6 :ARG1 (n6 / nucleic-acid :ARG1-of (i / include-91 :ARG2 (n4 / nucleic-acid :name (n / name :op1 "shRNA"~e.4) :mod (v / virus~e.3) :mod (t / this~e.2))))) :op2 (d / designate-01~e.8 :ARG1 n6 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "shRNA"~e.4) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2")))))) # ::id a_pmid_2094_2929.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok caMEK @-@ expressing cells were henceforth infected with shSerpinE2 lentiviruses or with lentiviruses expressing a control shRNA ( shScrambled ) . # ::alignments 2-1.1.1 3-1.1 5-1.3 6-1 10-1.2 13-1.2.2.1 15-1.2.2.1.1 15-1.2.2.1.1.2 15-1.2.2.1.1.2.r 16-1.2.1.1.1.1 16-1.2.2.1.1.1.1 18-1.2.2.1.1.3.1.1.1 (i / infect-01~e.6 :ARG1 (c / cell~e.3 :ARG3-of (e / express-03~e.2 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK") :mod (c2 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a2 / activate-01)))) :ARG2 (o / or~e.10 :op1 (l / lentivirus :mod (n6 / nucleic-acid :name (n2 / name :op1 "shRNA"~e.16) :ARG0-of (e3 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "serpinE2"))))) :op2 (l2 / lentivirus :ARG1-of (e4 / express-03~e.13 :ARG2 (n7 / nucleic-acid~e.15 :name (n4 / name :op1 "shRNA"~e.16) :ARG0-of~e.15 (c3 / control-01~e.15) :ARG1-of (m2 / mean-01 :ARG2 (n8 / nucleic-acid :name (n5 / name :op1 "shScrambled"~e.18))))))) :time (h / henceforth~e.5)) # ::id a_pmid_2094_2929.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Secretion of serpinE2 protein was analyzed 14 days after selection with blasticidin S in these populations . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1 5-1 6-1.2.2.1 7-1.2.2.2 8-1.2 9-1.2.1 10-1.2.1.2.r 11-1.2.1.2.1.1 12-1.2.1.2.1.2 13-1.2.1.1.r 14-1.2.1.1.1 15-1.2.1.1 (a / analyze-01~e.5 :ARG1 (s / secrete-01~e.0 :ARG1~e.1 (p / protein~e.3 :name (n / name :op1 "serpinE2"~e.2))) :time (a2 / after~e.8 :op1 (s2 / select-01~e.9 :ARG2~e.13 (p2 / population~e.15 :mod (t2 / this~e.14)) :instrument~e.10 (s3 / small-molecule :name (n2 / name :op1 "blasticidin"~e.11 :op2 "S"~e.12))) :quant (t / temporal-quantity :quant 14~e.6 :unit (d2 / day~e.7)))) # ::id a_pmid_2094_2929.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 2A , secreted serpinE2 levels were markedly reduced (> 60 %) in cells @-@ expressing shSerpinE2 ; in contrast , shScrambled had no effect on the secretion of serpinE2 ( data not shown ) . # ::alignments 1-1.1.5 2-1.1.5.1.r 3-1.1.5.1 5-1.1.5.1.1 8-1.1.1.2 9-1.1.1.1.1.1 10-1.1.1 12-1.1.3 12-1.1.3.r 13-1.1 15-1.1.2.1.1 17-1.1.4.r 18-1.1.4 20-1.1.4.1 24-1.2 26-1.2.1.2.1.1 28-1.2.1.1 28-1.2.1.1.r 29-1.2.1 30-1.2.1.3.r 32-1.2.1.3 33-1.2.1.3.1.r 34-1.2.1.3.1 36-1.2.2.1 37-1.2.2.1.1.1 37-1.2.2.1.1.1.r 38-1.2.2.1.1 (a / and :op1 (r / reduce-01~e.13 :ARG1 (l / level~e.10 :quant-of (p2 / protein :name (n / name :op1 "serpinE2"~e.9)) :ARG1-of (s / secrete-01~e.8)) :ARG2 (m2 / more-than :op1 (p / percentage-entity :value 60~e.15)) :manner~e.12 (m / marked~e.12) :location~e.17 (c / cell~e.18 :ARG3-of (e2 / express-03~e.20 :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG0-of (e / encode-01 :ARG1 p2)))) :ARG1-of (s3 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "2A"~e.5))) :op2 (c2 / contrast-01~e.24 :ARG2 (a2 / affect-01~e.29 :polarity~e.28 -~e.28 :ARG0 (n5 / nucleic-acid :name (n3 / name :op1 "shScrambled"~e.26)) :ARG1~e.30 (s2 / secrete-01~e.32 :ARG1~e.33 p2~e.34)) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.36 :ARG1-of (s4 / show-01~e.38 :polarity~e.37 -~e.37))))) # ::id a_pmid_2094_2929.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine the functional role of serpinE2 in caMEK @-@ expressing cells , the proliferation rate of these cell populations was assessed when cultured on plastic . # ::alignments 1-1.3 3-1.3.1.2 4-1.3.1 5-1.3.1.1.r 6-1.3.1.1.1.1 10-1.3.1.3.1 11-1.3.1.3 14-1.1.1 15-1.1 16-1.1.1.1.r 17-1.1.1.1.2 18-1.1.1.1.1 19-1.1.1.1 21-1 22-1.2.r 23-1.2 24-1.2.2.r 25-1.2.2 (a3 / assess-01~e.21 :ARG1 (r2 / rate~e.15 :degree-of (p2 / proliferate-01~e.14 :ARG0~e.16 (p3 / population~e.19 :mod (c3 / cell~e.18) :mod (t / this~e.17)))) :time~e.22 (c4 / culture-01~e.23 :ARG1 p3 :manner~e.24 (p4 / plastic~e.25)) :purpose (d / determine-01~e.1 :ARG1 (r / role~e.4 :topic~e.5 (p / protein :name (n / name :op1 "serpinE2"~e.6)) :ARG1-of (f / function-01~e.3) :location (c / cell~e.11 :ARG3-of (e / express-03~e.10 :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEK") :mod (c2 / constitutive) :ARG2-of (m / mutate-01) :ARG1-of (a2 / activate-01))))))) # ::id a_pmid_2094_2929.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No difference was observed in the proliferation rate of subconfluent caMEK @-@ expressing cells when serpinE2 expression was downregulated ( Figure 2B ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.1.2.r 6-1.1.2.1 7-1.1.2 8-1.1.2.1.1.r 9-1.1.2.1.1.2 10-1.1.2.1.1.1.1.1.1 12-1.1.2.1.1.1 13-1.1.2.1.1 14-1.2.r 15-1.2.1.1.1.1 16-1.2.1 18-1.2 20-1.3.1 22-1.3.1.1 (o / observe-01~e.3 :ARG1 (d / differ-02~e.1 :polarity~e.0,1 -~e.0,1 :ARG1~e.4 (r / rate~e.7 :degree-of (p / proliferate-01~e.6 :ARG0~e.8 (c / cell~e.13 :ARG3-of (e / express-03~e.12 :ARG2 (e2 / enzyme :name (n / name :op1 "caMEK"~e.10))) :mod (s / subconfluent~e.9))))) :time~e.14 (d2 / downregulate-01~e.18 :ARG1 (e3 / express-03~e.16 :ARG2 (p2 / protein :name (n2 / name :op1 "serpinE2"~e.15)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.20 :mod "2B"~e.22))) # ::id a_pmid_2094_2929.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a previous study , we had shown that expression of activated MEK in intestinal epithelial cells resulted in loss of cell @-@ cell contact growth inhibition and produced colonies or multilayered domes which grew to increased saturation density and formed tumors when transplanted into nude mice [ @ 14 @ ] . # ::alignments 2-1.3.1 3-1.3 5-1.1 7-1 8-1.2.r 9-1.2.1.1 10-1.2.1.1.1.r 11-1.2.1.1.1.2 12-1.2.1.1.1.1.1 13-1.2.1.1.2.r 14-1.2.1.1.2.1.1 15-1.2.1.1.2.1 16-1.2.1.1.2 17-1.2.1 18-1.2.1.2.r 19-1.2.1.2 20-1.2.1.2.1.r 21-1.2.1.2.1.1.1 23-1.2.1.2.1.1.1 23-1.2.1.2.1.1.2 24-1.2.1.2.1.1 25-1.2.1.2.1.2 26-1.2.1.2.1 27-1.2 28-1.2.2 29-1.2.2.2.1 30-1.2.2.2 31-1.2.2.2.2.1 32-1.2.2.2.2 34-1.2.2.2.3 35-1.2.2.2.3.1.r 36-1.2.2.2.3.1.2 37-1.2.2.2.3.1.1 38-1.2.2.2.3.1 40-1.2.2.2.4 41-1.2.2.2.4.1 42-1.2.2.2.4.2.r 43-1.2.2.2.4.2 44-1.2.2.2.4.2.2.r 45-1.2.2.2.4.2.2.1 46-1.2.2.2.4.2.2 49-1.4.1.1.1 (s / show-01~e.7 :ARG0 (w / we~e.5) :ARG1~e.8 (a2 / and~e.27 :op1 (r / result-01~e.17 :ARG1 (e / express-03~e.9 :ARG2~e.10 (e2 / enzyme :name (n / name :op1 "MEK"~e.12) :ARG1-of (a / activate-01~e.11)) :ARG3~e.13 (c / cell~e.16 :source (e3 / epithelium~e.15 :part-of (i / intestine~e.14)))) :ARG2~e.18 (l / lose-02~e.19 :ARG1~e.20 (i2 / inhibit-01~e.26 :ARG0 (c2 / contact-01~e.24 :ARG0 (c4 / cell~e.21,23) :ARG1 (c3 / cell~e.23)) :ARG1 (g / grow-01~e.25)))) :op2 (p / produce-01~e.28 :ARG0 e :ARG1 (o / or~e.30 :op1 (c5 / colony~e.29) :op2 (d / dome~e.32 :mod (m / multilayered~e.31)) :ARG1-of (g2 / grow-01~e.34 :ARG4~e.35 (d2 / density~e.38 :mod (s2 / saturate-01~e.37) :ARG1-of (i3 / increase-01~e.36))) :ARG0-of (f / form-01~e.40 :ARG1 (t / tumor~e.41) :time~e.42 (t2 / transplant-01~e.43 :ARG1 o :ARG2~e.44 (m2 / mouse~e.46 :mod (n2 / nude~e.45))))))) :medium (s3 / study-01~e.3 :time (p2 / previous~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 14~e.49)))) # ::id a_pmid_2094_2929.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of note , focus formation assays performed herein revealed that initially , there was little difference in the number of foci obtained between control cells and serpinE2 @-@ depleted cells ( data not shown ) . # ::alignments 1-1.3 3-1.1.1.1 4-1.1.1 5-1.1 6-1.1.2 7-1.1.2.1 8-1 9-1.2.r 10-1.2.5 14-1.2.4 15-1.2 16-1.2.3.r 18-1.2.3 19-1.2.3.1.r 20-1.2.3.1 21-1.2.3.2 23-1.2.1.1 24-1.2.1 26-1.2.2.1.1.1.1 28-1.2.2.1 29-1.2.2 31-1.4.1 32-1.4.1.1.1 32-1.4.1.1.1.r 33-1.4.1.1 (r / reveal-01~e.8 :ARG0 (a / assay-01~e.5 :ARG1 (f2 / form-01~e.4 :ARG1 (f3 / focus~e.3)) :ARG1-of (p / perform-02~e.6 :medium (h / herein~e.7))) :ARG1~e.9 (d / differ-02~e.15 :ARG1 (c / cell~e.24 :mod (c2 / control~e.23)) :ARG2 (c3 / cell~e.29 :ARG1-of (d2 / deplete-01~e.28 :ARG2 (p2 / protein :name (n3 / name :op1 "serpinE2"~e.26)))) :ARG3~e.16 (n2 / number~e.18 :quant-of~e.19 (f / focus~e.20) :ARG1-of (o / obtain-01~e.21)) :degree (l / little~e.14) :time (i / initial~e.10)) :ARG1-of (n4 / note-02~e.1) :ARG1-of (d3 / describe-01 :ARG0 (d4 / data~e.31 :ARG1-of (s / show-01~e.33 :polarity~e.32 -~e.32)))) # ::id a_pmid_2094_2929.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , serpinE2 @ silencing markedly reduced the size of foci ( Figure 2C ) suggesting a reduced capacity of these foci to grow . # ::alignments 0-1 3-1.1.1.1.1.1 5-1.1.1 6-1.1.3 6-1.1.3.r 7-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1 13-1.1.4.1 15-1.1.4.1.1 18-1.1.5 20-1.1.5.1.3 21-1.1.5.1 24-1.1.5.1.2.1 26-1.1.5.1.2 (c2 / contrast-01~e.0 :ARG2 (r / reduce-01~e.7 :ARG0 (s / silence-01~e.5 :ARG1 (g2 / gene :name (n / name :op1 "serpinE2"~e.3))) :ARG1 (s2 / size~e.9 :poss~e.10 (f / focus~e.11)) :manner~e.6 (m / marked~e.6) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.13 :mod "2C"~e.15)) :ARG0-of (s3 / suggest-01~e.18 :ARG1 (c / capable-01~e.21 :ARG1 f :ARG2 (g / grow-01~e.26 :ARG1 f~e.24) :ARG1-of (r2 / reduce-01~e.20))))) # ::id a_pmid_2094_2929.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , phase @-@ contrast microscopy revealed that the colonies were smaller when serpinE2 was downregulated ( Figure 2D ) . # ::alignments 0-1.4 2-1.1.1.1 4-1.1.1.1 5-1.1.1.2 6-1 7-1.2.r 9-1.2.2 10-1.2.2.r 11-1.2 11-1.2.1 11-1.2.1.r 12-1.2.3.r 13-1.2.3.1.1.1 15-1.2.3 17-1.3.1 19-1.3.1.1 (r / reveal-01~e.6 :ARG0 (t / thing :name (n / name :op1 "phase-contrast"~e.2,4 :op2 "microscopy"~e.5)) :ARG1~e.7 (s / small~e.11 :degree~e.11 (m / more~e.11) :domain~e.10 (c / colony~e.9) :time~e.12 (d / downregulate-01~e.15 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"~e.13)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod "2D"~e.19)) :mod (i / indeed~e.0)) # ::id a_pmid_2094_2929.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , expression of shSerpinE2 led to a significant decrease in the ability of caMEK @-@ expressing cells to grow under anchorage @-@ independent conditions in soft agarose ( Figure 2E ) . # ::alignments 0-1.1 0-1.1.r 2-1.2 3-1.2.1.r 4-1.2.1.1.1 5-1 8-1.3.2 9-1.3 10-1.3.1.r 12-1.3.1 13-1.3.1.1.r 14-1.3.1.1.1.1.1.1 16-1.3.1.1.1 17-1.3.1.1 19-1.3.1.2 21-1.3.1.2.3.3 23-1.3.1.2.3 23-1.3.1.2.3.1 23-1.3.1.2.3.1.r 24-1.3.1.2.3.r 25-1.3.1.2.2.r 26-1.3.1.2.2.1 27-1.3.1.2.2 29-1.4.1 31-1.4.1.1 (l / lead-03~e.5 :li~e.0 -1~e.0 :ARG0 (e / express-03~e.2 :ARG2~e.3 (p / protein :name (n / name :op1 "shSerpinE2"~e.4))) :ARG1 (d / decrease-01~e.9 :ARG1~e.10 (c / capable-01~e.12 :ARG1~e.13 (c2 / cell~e.17 :ARG3-of (e2 / express-03~e.16 :ARG2 (e3 / enzyme :name (n2 / name :op1 "caMEK"~e.14)))) :ARG2 (g / grow-01~e.19 :ARG1 c2 :location~e.25 (a2 / agarose~e.27 :ARG1-of (s2 / soft-02~e.26)) :condition~e.24 (d2 / depend-01~e.23 :polarity~e.23 -~e.23 :ARG0 g :ARG1 (a / anchorage~e.21)))) :ARG2 (s / significant-02~e.8)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.29 :mod "2E"~e.31))) # ::id a_pmid_2094_2929.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell migration is an important process of tumorigenesis and metastasis . # ::alignments 0-1.1.1 1-1.1 4-1.2 5-1 6-1.3.r 7-1.3.1 7-1.3.1.1 7-1.3.1.1.r 8-1.3 9-1.3.2 (p / process-02~e.5 :ARG1 (m / migrate-01~e.1 :ARG0 (c / cell~e.0)) :mod (i / important~e.4) :subevent-of~e.6 (a / and~e.8 :op1 (c2 / create-01~e.7 :ARG1~e.7 (t / tumor~e.7)) :op2 (m2 / metastasis~e.9))) # ::id a_pmid_2094_2929.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , we recently reported that intestinal epithelial cells expressing activated MEK1 clearly acquire an increased capacity to migrate as compared to wtMEK @-@ expressing cells [ @ 14 @ ] . # ::alignments 0-1 2-1.1.1 3-1.1.3 4-1.1 5-1.1.2.r 6-1.1.2.1.1.1 7-1.1.2.1.1 8-1.1.2.1 8-1.1.2.2.4.1 9-1.1.2.1.2 9-1.1.2.2.4.1.1 10-1.1.2.1.2.1.2 11-1.1.2.1.2.1.1.1 12-1.1.2.3 13-1.1.2 15-1.1.2.2.3 16-1.1.2.2 16-1.1.2.2.4 18-1.1.2.2.2 19-1.1.3.r 20-1.1.2.2.4.r 24-1.1.2.2.1 25-1.1.2.2.1 28-1.2.1.1.1 (a / and~e.0 :op2 (r / report-01~e.4 :ARG0 (w / we~e.2) :ARG1~e.5 (a2 / acquire-01~e.13 :ARG0 (c2 / cell~e.8 :source (e / epithelium~e.7 :part-of (i / intestine~e.6)) :ARG3-of (e2 / express-03~e.9 :ARG2 (e3 / enzyme :name (n / name :op1 "MEK1"~e.11) :ARG1-of (a3 / activate-01~e.10)))) :ARG1 (c3 / capable-01~e.16 :ARG1 c2~e.24,25 :ARG2 (m / migrate-01~e.18 :ARG0 c2) :ARG1-of (i2 / increase-01~e.15) :compared-to~e.20 (c4 / capable-01~e.16 :ARG1 (c5 / cell~e.8 :ARG3-of (e4 / express-03~e.9 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MEK") :mod (w2 / wild-type)))) :ARG2 m)) :ARG1-of (c / clear-06~e.12)) :time~e.19 (r2 / recent~e.3)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c6 / cite-01 :ARG2 14~e.28)))) # ::id a_pmid_2094_2929.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Herein , in an in vitro @ transwell migration assay , serpinE2 deficiency significantly reduced caMEK @-@ expressing IEC migration to the undersurface of the polycarbonate membrane of Boyden chambers coated with fibronectin or vitronectin ( Figure 2F ) , two extracellular matrix proteins which can interact with serpinE2 [ @ 34 , 35 @ ] . # ::alignments 0-1.4 2-1.6.2 5-1.6.2 6-1.6.2 8-1.6.1.1 9-1.6.1 10-1.6 12-1.1.1.1.1 14-1.3 15-1 16-1.2.1.2.1.1.1 18-1.2.1.2 19-1.2.1.1.1 20-1.2 21-1.2.2.r 23-1.2.2 24-1.2.2.1.r 26-1.2.2.1.1 27-1.2.2.1 28-1.2.2.1.2.r 29-1.2.2.1.2.1.1 30-1.2.2.1.2.1.2 31-1.2.2.2 32-1.2.2.2.1.r 33-1.2.2.2.1.1.1.1 34-1.2.2.2.1 35-1.2.2.2.1.2.1.1 37-1.5.1 39-1.5.1.1 43-1.2.2.2.1.3.1.1 44-1.2.2.2.1.3.1.4.1 45-1.2.2.2.1.3.1.4 46-1.2.2.2.1.3.1 48-1.2.2.2.1.3.1.3.2 49-1.2.2.2.1.3.1.3 50-1.2.2.2.1.3.1.3.1.r 51-1.2.2.2.1.3.1.3.1 54-1.2.2.2.1.3.1.2.1.1.1.1 58-1.2.2.2.1.3.1.2.1.1.1.2 (r / reduce-01~e.15 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2"~e.12))) :ARG1 (m / migrate-01~e.20 :ARG0 (c / cell :name (n2 / name :op1 "IEC"~e.19) :ARG3-of (e / express-03~e.18 :ARG2 (e2 / enzyme :name (n3 / name :op1 "caMEK"~e.16)))) :ARG1~e.21 (u / undersurface~e.23 :part-of~e.24 (m2 / membrane~e.27 :consist-of (p2 / polycarbonate~e.26) :poss~e.28 (t / thing :name (n4 / name :op1 "Boyden"~e.29 :op2 "chamber"~e.30))) :ARG1-of (c2 / coat-01~e.31 :ARG2~e.32 (o / or~e.34 :op1 (p3 / protein :name (n5 / name :op1 "fibronectin"~e.33)) :op2 (p4 / protein :name (n6 / name :op1 "vitronectin"~e.35)) :ARG1-of (m3 / mean-01 :ARG2 (p5 / protein~e.46 :quant 2~e.43 :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 34~e.54 :op2 35~e.58)))) :ARG0-of (i / interact-01~e.49 :ARG1~e.50 p~e.51 :ARG1-of (p6 / possible-01~e.48)) :mod (m4 / matrix~e.45 :mod (e3 / extracellular~e.44)))))))) :ARG2 (s / significant-02~e.14) :medium (h / herein~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.37 :mod "2F"~e.39)) :condition (a2 / assay-01~e.10 :ARG1 (m5 / migrate-01~e.9 :mod (t3 / transwell~e.8)) :manner (i2 / in-vitro~e.2,5,6))) # ::id a_pmid_2094_2929.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these results support a role of serpinE2 in MEK1 @-@ induced transformation whereby serpinE2 activates anchorage @-@ independent growth and cell migration . # ::alignments 0-1.2 1-1.2.2 3-1.1.1.1 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 5-1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.1 10-1.1.2.2.r 11-1.1.2.2.1.1.1.1 13-1.1.2.2.1 14-1.1.2.2 16-1.1.2.2.2.1 17-1.1.2.2.2 18-1.1.2.2.2.2.1.2.2 20-1.1.2.2.2.2.1.2 20-1.1.2.2.2.2.1.2.1 20-1.1.2.2.2.2.1.2.1.r 21-1.1.2.2.2.2.1 23-1.1.2.2.2.2.1.1 24-1.1.2.2.2.2.2 (h / have-condition-91 :ARG1 (s / support-01~e.5 :ARG0 (t / thing~e.4 :mod (t2 / this~e.3) :ARG2-of~e.4 (r / result-01~e.4)) :ARG1 (r2 / role~e.7 :poss~e.8 (p / protein :name (n / name :op1 "serpinE2"~e.9)) :purpose~e.10 (t3 / transform-01~e.14 :ARG2-of (i / induce-01~e.13 :ARG0 (e / enzyme :name (n2 / name :op1 "MEK1"~e.11))) :subevent (a / activate-01~e.17 :ARG0 p~e.16 :ARG1 (a2 / and :op1 (g / grow-01~e.21 :ARG1 (c2 / cell~e.23) :ARG0-of (d / depend-01~e.20 :polarity~e.20 -~e.20 :ARG1 (a3 / anchorage~e.18))) :op2 (m / migrate-01~e.24 :ARG0 c2)))))) :ARG2 (t4 / take-01~e.0 :ARG1 t :mod (t5 / together~e.1))) # ::id a_pmid_2094_2929.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of serpinE2 in colorectal cancer cells is dependent on MEK @/@ ERK activity # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 4-1.1.2.1.1.1 5-1.1.2.1.1.2 6-1.1.2 8-1 9-1.2.r 10-1.2.1.1.1 12-1.2.1.1.1 13-1.2 (d / depend-01~e.8 :ARG0 (e / express-03~e.0 :ARG2~e.1 (p / protein :name (n / name :op1 "serpinE2"~e.2)) :ARG3~e.3 (c / cell~e.6 :source (d2 / disease :name (n3 / name :op1 "colorectal"~e.4 :op2 "cancer"~e.5)))) :ARG1~e.9 (a / activity-06~e.13 :ARG0 (p2 / pathway :name (n2 / name :op1 "MEK/ERK"~e.10,12)))) # ::id a_pmid_2094_2929.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the contribution of serpinE2 in human colorectal cancer , serpinE2 expression was first examined in various CRC cell lines including Caco @-@ 2 @/@ 15 as well as others exhibiting mutation in KRAS @ ( HCT @-@ 116 , DLD @-@ 1 , LoVo , SW480 , T84 ) or BRAF @ ( Colo @-@ 205 , HT @-@ 29 ) [ @ 36 @ ] . # ::alignments 1-1.5 3-1.5.1 4-1.5.1.1.r 5-1.5.1.1 6-1.5.1.2.r 7-1.5.1.2.2 8-1.5.1.2.1.1 9-1.5.1.2.1.2 11-1.1.1.1.1 12-1.1 14-1.2 15-1 16-1.3.r 17-1.3.1 18-1.3.3.1.1 19-1.3 20-1.3 20-1.3.2.1.2 20-1.3.2.1.3 21-1.3.2 22-1.3.2.1.1.1.1 24-1.3.2.1.1.1.1 26-1.3.2.1.1.1.1 27-1.3.2.1 27-1.3.2.1.2.3.1 27-1.3.2.1.3.3.1 28-1.3.2.1.2.3.1 29-1.3.2.1.2.1.r 29-1.3.2.1.2.3.1 30-1.3.2.1.2.1 31-1.3.2.1.2.2 31-1.3.2.1.3.1 32-1.3.2.1.2.2.1 32-1.3.2.1.3.1.1 35-1.3.2.1.2.2.1.1.1.1 38-1.3.2.1.2.3.1.1.1.1 40-1.3.2.1.2.3.1.1.1.1 42-1.3.2.1.2.3.1.2.1.1 44-1.3.2.1.2.3.1.2.1.1 46-1.3.2.1.2.3.1.3.1.1 48-1.3.2.1.2.3.1.4.1.1 50-1.3.2.1.2.3.1.5.1.1 54-1.3.2.1.3.1.1.1.1.1 57-1.3.2.1.3.3.1.1.1.1 59-1.3.2.1.3.3.1.1.1.1 61-1.3.2.1.3.3.1.2.1.1 63-1.3.2.1.3.3.1.2.1.1 67-1.4.1.1.1 (e / examine-01~e.15 :ARG1 (e2 / express-03~e.12 :ARG2 (p / protein :name (n / name :op1 "serpinE2"~e.11))) :time (f / first~e.14) :location~e.16 (c / cell-line~e.19,20 :mod (v / various~e.17) :ARG2-of (i / include-01~e.21 :ARG1 (a / and~e.27 :op1 (c2 / cell-line :name (n3 / name :op1 "Caco-2/15"~e.22,24,26)) :op2 (c3 / cell-line~e.20 :mod~e.29 (o / other~e.30) :ARG0-of (e3 / exhibit-01~e.31 :ARG1 (m / mutate-01~e.32 :ARG1 (g / gene :name (n4 / name :op1 "KRAS"~e.35)))) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and~e.27,28,29 :op1 (c5 / cell-line :name (n6 / name :op1 "HCT-116"~e.38,40)) :op2 (c6 / cell-line :name (n7 / name :op1 "DLD-1"~e.42,44)) :op3 (c7 / cell-line :name (n8 / name :op1 "LoVo"~e.46)) :op4 (c8 / cell-line :name (n9 / name :op1 "SW480"~e.48)) :op5 (c9 / cell-line :name (n10 / name :op1 "T84"~e.50))))) :op3 (c4 / cell-line~e.20 :ARG0-of (e4 / exhibit-01~e.31 :ARG1 (m2 / mutate-01~e.32 :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF"~e.54)))) :mod o :ARG1-of (m4 / mean-01 :ARG2 (a3 / and~e.27 :op1 (c10 / cell-line :name (n11 / name :op1 "Colo-205"~e.57,59)) :op2 (c11 / cell-line :name (n12 / name :op1 "HT-29"~e.61,63))))))) :mod (d3 / disease :name (n2 / name :op1 "CRC"~e.18))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c12 / cite-01 :ARG2 36~e.67))) :purpose (a4 / assess-01~e.1 :ARG1 (c13 / contribute-01~e.3 :ARG0~e.4 p~e.5 :ARG2~e.6 (d2 / disease :name (n13 / name :op1 "colorectal"~e.8 :op2 "cancer"~e.9) :mod (h / human~e.7))))) # ::id a_pmid_2094_2929.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 3A , serpinE2 @ mRNA levels were barely detectable in the Caco @-@ 2 @/@ 15 cell line while being markedly expressed in all other CRC cell lines tested . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 5-1.3.1.1 9-1.1.1.1.1.2.1.1.1 11-1.1.1.1.1.1.1 12-1.1.1.1 14-1.1.1.2 15-1.1.1 16-1.1.1.3.r 18-1.1.1.3.1.1 20-1.1.1.3.1.1 22-1.1.1.3.1.1 23-1.2.2 24-1.2.2 25-1 27-1.2.3 27-1.2.3.r 28-1.2 30-1.2.2.1 31-1.2.2.2 32-1.2.2.4.1.1 33-1.2.2 34-1.2.2 35-1.2.2.3 (c / contrast-01~e.25 :ARG1 (p / possible-01 :ARG1 (d / detect-01~e.15 :ARG1 (l / level~e.12 :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.11) :ARG0-of (e / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "serpinE2"~e.9))))) :degree (b / bare~e.14) :location~e.16 (c2 / cell-line :name (n3 / name :op1 "Caco-2/15"~e.18,20,22)))) :ARG2 (e2 / express-03~e.28 :ARG1 n5 :ARG3 (c3 / cell-line~e.23,24,33,34 :mod (a / all~e.30) :mod (o / other~e.31) :ARG1-of (t / test-01~e.35) :mod (d2 / disease :name (n4 / name :op1 "CRC"~e.32))) :manner~e.27 (m / marked~e.27)) :ARG1-of (s / show-01~e.1 :medium~e.2 (f / figure~e.3 :mod "3A"~e.5))) # ::id a_pmid_2094_2929.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two human CRC cell lines , namely HCT116 and LoVo , which have an activating mutation in the KRAS @ gene resulting in elevated MEK @/@ ERK activities [ @ 37 @ ] , were thereby chosen to further analyze the regulation and role of serpinE2 expression in human colorectal cancer cells . # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1.1.1.5.1.1 3-1.1.1 4-1.1.1 6-1.1.1.4 7-1.1.1.4.1.1.1.1 8-1.1.1.4.1 9-1.1.1.4.1.2.1.1 14-1.1.1.3.3 15-1.1.1.3 19-1.1.1.3.1.1.1 21-1.1.1.3.1 22-1.1.1.3.2 23-1.1.1.3.2.1.r 24-1.1.1.3.2.1.2 25-1.1.1.3.2.1.1.1.1 27-1.1.1.3.2.1.1.1.1 28-1.1.1.3.2.1 31-1.1.1.3.4.1.1.1 37-1.1 39-1.1.2.2 40-1.1.2 42-1.1.2.1.1 43-1.1.2.1 44-1.1.2.1.2 45-1.1.2.1.1.1.r 46-1.1.2.1.1.1.1.1.1 47-1.1.2.1.1.1 49-1.1.2.1.1.1.2.1.2 50-1.1.2.1.1.1.2.1.1.1 51-1.1.2.1.1.1.2.1.1.2 52-1.1.1 52-1.1.2.1.1.1.2 (c9 / cause-01 :ARG1 (c / choose-01~e.37 :ARG1 (c2 / cell-line~e.3,4,52 :quant 2~e.0 :mod (h / human~e.1) :location-of (m2 / mutate-01~e.15 :ARG1 (g / gene~e.21 :name (n4 / name :op1 "KRAS"~e.19)) :ARG1-of (r / result-01~e.22 :ARG2~e.23 (a3 / act-02~e.28 :ARG0 (p3 / pathway :name (n8 / name :op1 "MEK/ERK"~e.25,27)) :ARG1-of (e / elevate-01~e.24))) :ARG0-of (a2 / activate-01~e.14) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 37~e.31)))) :ARG1-of (m / mean-01~e.6 :ARG2 (a / and~e.8 :op1 (c3 / cell-line :name (n2 / name :op1 "HCT116"~e.7)) :op2 (c4 / cell-line :name (n3 / name :op1 "LoVo"~e.9)))) :mod (d3 / disease :name (n / name :op1 "CRC"~e.2))) :purpose (a4 / analyze-01~e.40 :ARG1 (a5 / and~e.43 :op1 (r2 / regulate-01~e.42 :ARG1~e.45 (e4 / express-03~e.47 :ARG2 (p2 / protein :name (n7 / name :op1 "serpinE2"~e.46)) :ARG3 (c6 / cell~e.52 :source (d2 / disease :name (n5 / name :op1 "colorectal"~e.50 :op2 "cancer"~e.51) :mod (h2 / human~e.49))))) :op2 (r3 / role~e.44 :poss e4)) :degree (f / further~e.39)))) # ::id a_pmid_2094_2929.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , the impact of U0126 treatment was also investigated to evaluate the contribution of endogenous MEK @/@ ERK activities in serpinE2 expression in human cell models . # ::alignments 0-1 1-1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1.1 7-1.1.1.1 9-1.1.3 10-1.1 12-1.1.2 14-1.1.2.1 15-1.1.2.1.1.r 16-1.1.2.1.1.1.2 17-1.1.2.1.1.1.1.1 19-1.1.2.1.1.1.1.1 20-1.1.2.1.1 21-1.1.2.1.2.r 22-1.1.2.1.2.1.1.1 23-1.1.2.1.2 24-1.1.2.1.2.2.r 25-1.1.2.1.2.2.1.1 26-1.1.2.1.2.2.1 27-1.1.2.1.2.2 (a / and~e.0,1 :op2 (i2 / investigate-01~e.10 :ARG1 (i / impact-01~e.4 :ARG0~e.5 (t / treat-04~e.7 :ARG2 (s / small-molecule :name (n / name :op1 "U0126"~e.6)))) :ARG2 (e / evaluate-01~e.12 :ARG1 (c / contribute-01~e.14 :ARG0~e.15 (a3 / act-02~e.20 :ARG0 (p / pathway :name (n2 / name :op1 "MEK/ERK"~e.17,19) :mod (e2 / endogenous~e.16))) :ARG2~e.21 (e3 / express-03~e.23 :ARG2 (p2 / protein :name (n4 / name :op1 "serpinE2"~e.22)) :ARG3~e.24 (m / model~e.27 :mod (c2 / cell~e.26 :mod (h / human~e.25)))))) :mod (a2 / also~e.9))) # ::id a_pmid_2094_2929.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Forty @-@ eight @-@ hour treatment of HCT116 and LoVo cell lines with U0126 efficiently blocked endogenous MEK activity as confirmed by the marked inhibition of ERK1 @/@ 2 phosphorylation ( data not shown ) [ @ 14 @ ] . # ::alignments 4-1.1.3.2 5-1.1 6-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.1.1 10-1.1.1.1 10-1.1.1.2 11-1.1.1.1 12-1.1.2.r 13-1.1.2.1.1 14-1.3 15-1 16-1.2.1.2 17-1.2.1.1.1 18-1.2 19-1.4.r 20-1.4 21-1.4.1.r 23-1.4.1.2 24-1.4.1 25-1.4.1.1.r 26-1.4.1.1.1.1.1.1 27-1.4.1.1.1 29-1.4.1.1 31-1.5.1.1 32-1.5.1.1.1.1 32-1.5.1.1.1.1.r 33-1.5.1.1.1 37-1.5.1.2.1.1 (b2 / block-01~e.15 :ARG0 (t2 / treat-04~e.5 :ARG1~e.6 (a / and~e.8 :op1 (c / cell-line~e.10,11 :name (n3 / name :op1 "HCT116"~e.7)) :op2 (c2 / cell-line~e.10 :name (n4 / name :op1 "LoVo"~e.9))) :ARG2~e.12 (s / small-molecule :name (n / name :op1 "U0126"~e.13)) :duration (t / temporal-quantity :quant 48 :unit (h / hour~e.4))) :ARG1 (a2 / activity-06~e.18 :ARG0 (e / enzyme :name (n2 / name :op1 "MEK"~e.17) :mod (e3 / endogenous~e.16))) :ARG2-of (e2 / efficient-01~e.14) :ARG1-of~e.19 (c3 / confirm-01~e.20 :ARG0~e.21 (i / inhibit-01~e.24 :ARG1~e.25 (p / phosphorylate-01~e.29 :ARG1 (s2 / slash~e.27 :op1 (e4 / enzyme :name (n5 / name :op1 "ERK1"~e.26)) :op2 (e5 / enzyme :name (n6 / name :op1 "ERK2")))) :mod (m / marked~e.23))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (d2 / data~e.31 :ARG1-of (s3 / show-01~e.33 :polarity~e.32 -~e.32)) :op2 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 14~e.37))))) # ::id a_pmid_2094_2929.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 3B , treatment of these CRC cell lines with U0126 markedly and significantly reduced serpinE2 @ mRNA levels , indicating that expression of serpinE2 @ is likely dependent of ERK activity in these cell lines . # ::alignments 1-1.5 2-1.5.1.r 3-1.5.1 5-1.5.1.1 8-1.1 9-1.1.1.r 10-1.1.1.1 11-1.1.1.2.1.1 12-1.1.1 13-1.1.1 14-1.1.2.r 15-1.1.2.1.1 16-1.3.1 17-1.3 18-1.3.2 19-1 21-1.2.1.2.1.1.1 23-1.2.1.1.1 24-1.2 26-1.4 27-1.4.1.r 28-1.4.1.1.1 31-1.4.1.1.1.1 34-1.4.1 35-1.4.1.1 36-1.4.1.1.2.r 37-1.4.1.1.2.1.1.1 38-1.4.1.1.2 40-1.1.1.1 41-1.1.1 42-1.1.1 (r / reduce-01~e.19 :ARG0 (t / treat-04~e.8 :ARG1~e.9 (c / cell-line~e.12,13,41,42 :mod (t2 / this~e.10,40) :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.11))) :ARG2~e.14 (s / small-molecule :name (n / name :op1 "U0126"~e.15))) :ARG1 (l / level~e.24 :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.23) :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n5 / name :op1 "serpinE2"~e.21))))) :ARG2 (a / and~e.17 :op1 (m / marked~e.16) :op2 (s2 / significant-02~e.18)) :ARG0-of (i / indicate-01~e.26 :ARG1~e.27 (l2 / likely-01~e.34 :ARG1 (d / depend-01~e.35 :ARG0 (e3 / express-03~e.28 :ARG1 g~e.31 :ARG3 c) :ARG1~e.36 (a2 / activity-06~e.38 :ARG0 (p / protein-family :name (n2 / name :op1 "ERK"~e.37)))))) :ARG1-of (s3 / show-01~e.1 :medium~e.2 (f / figure~e.3 :mod "3B"~e.5))) # ::id a_pmid_2094_2929.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Down @-@ regulation of serpinE2 expression in human colorectal cancer cells inhibits soft agarose colony formation , migration and tumor growth in nude mice # ::alignments 0-1.1 1-1.1 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.r 7-1.1.1.2.1.2 8-1.1.1.2.1.1.1 9-1.1.1.2.1.1.2 10-1.1.1.2 11-1 12-1.2.1.2.1 13-1.2.1.2 14-1.2.1.1 15-1.2.1 17-1.2.2 18-1.2 19-1.2.3.1 20-1.2.3 21-1.3.r 22-1.3.1 23-1.3 (i / inhibit-01~e.11 :ARG0 (d / downregulate-01~e.0,1,2 :ARG1~e.3 (e / express-03~e.5 :ARG2 (p / protein :name (n / name :op1 "serpinE2"~e.4)) :ARG3~e.6 (c / cell~e.10 :source (d2 / disease :name (n3 / name :op1 "colorectal"~e.8 :op2 "cancer"~e.9) :mod (h / human~e.7))))) :ARG1 (a / and~e.18 :op1 (f / form-01~e.15 :ARG1 (c4 / colony~e.14) :location (a2 / agarose~e.13 :ARG1-of (s / soft-02~e.12))) :op2 (m / migrate-01~e.17) :op3 (g / grow-01~e.20 :ARG1 (t / tumor~e.19))) :location~e.21 (m2 / mouse~e.23 :mod (n2 / nude~e.22))) # ::id a_pmid_2094_2929.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next investigated the effect of serpinE2 knockdown on anchorage independent growth and cell migration after downregulation of serpinE2 @ gene expression by RNA interference in HCT116 and LoVo cells . # ::alignments 0-1.1 1-1.3 1-1.4 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1 7-1.2.1 8-1.2.2.r 9-1.2.2.1.1.2 10-1.2.2.1.1 10-1.2.2.1.1.1 10-1.2.2.1.1.1.r 11-1.2.2.1 12-1.2.2 13-1.2.2.2.1 14-1.2.2.2 15-1.4 16-1.4.1 19-1.4.1.1.1.1.1 21-1.4.1.1.1 22-1.4.1.1 23-1.4.1.2.r 24-1.4.1.2.1.1.1 25-1.4.1.2 26-1.4.1.1.2.r 27-1.4.1.1.2.1.1.1 28-1.4.1.1.2 29-1.4.1.1.2.2.1.1 30-1.4.1.1.2.1 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / affect-01~e.4 :ARG0~e.5 (k / knock-down-02~e.7 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"~e.6))) :ARG1~e.8 (a2 / and~e.12 :op1 (g / grow-01~e.11 :ARG0-of (d / depend-01~e.10 :polarity~e.10 -~e.10 :ARG1 (a3 / anchorage~e.9))) :op2 (m / migrate-01~e.14 :ARG0 (c / cell~e.13)))) :time (n / next~e.1) :time (a4 / after~e.1,15 :op1 (d2 / downregulate-01~e.16 :ARG1 (e / express-03~e.22 :ARG1 (g2 / gene~e.21 :name (n3 / name :op1 "serpinE2"~e.19)) :ARG3~e.26 (a5 / and~e.28 :op1 (c2 / cell-line~e.30 :name (n4 / name :op1 "HCT116"~e.27)) :op2 (c3 / cell-line :name (n5 / name :op1 "LoVo"~e.29)))) :ARG2~e.23 (i2 / interfere-01~e.25 :ARG0 (n6 / nucleic-acid :name (n7 / name :op1 "RNA"~e.24)))))) # ::id a_pmid_2094_2929.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 4A , serpinE2 @ mRNA were significantly reduced by respectively 37 % and 88 % in LoVo cells expressing shSerpinE2(#15 ) or shSerpinE2(#16 ) and by 77 % and 92 % in HCT116 expressing shSerpinE2(#15 ) or shSerpinE2(#16 ) ; conversely , expression of the control shRNA ( shTGFP ) had no effect on endogenous serpinE2 @ expression ( data not shown ) . # ::alignments 1-1.1.5 2-1.1.5.1.r 3-1.1.5.1 5-1.1.5.1.1 9-1.1.1.1.2.1.1.1 11-1.1.1.1.1.1 13-1.1.1.3 14-1.1.1 14-1.1.2 14-1.1.3 14-1.1.4 17-1.1.1.2.1 18-1.1.1.2 19-1.1 20-1.1.2.2.1 21-1.1.2.2 23-1.1.1.4.1.1 23-1.1.2.3.1.1 24-1.1.1.4 24-1.1.2.3 24-1.1.3.3 24-1.1.4.4 25-1.1.1.4.2 25-1.1.2.3.2 31-1.1 32-1.1.3.2.r 33-1.1.3.2.1 34-1.1.3.2 35-1.1 36-1.1.4.2.1 37-1.1.4.2 39-1.1.3.3.1.1 39-1.1.4.4.1.1 40-1.1.1.4.2 49-1.2.1.2 52-1.2.1.2.1.2 53-1.2.1.2.1.1.1 55-1.2.1.2.1.3.1.1.1 58-1.2.1.1 58-1.2.1.1.r 59-1.2.1 61-1.2.1.3.1.2 63-1.2.1.3.1.1.1 65-1.2.1.2 65-1.2.1.3 67-1.2.2.1 68-1.2.2.1.1.1 68-1.2.2.1.1.1.r 69-1.2.2.1.1 (c5 / contrast-01 :ARG1 (a5 / and~e.19,31,35 :op1 (r / reduce-01~e.14 :ARG1 (n12 / nucleic-acid :name (n / name :op1 "mRNA"~e.11) :ARG0-of (e / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "serpinE2"~e.9)))) :ARG2 (p / percentage-entity~e.18 :value 37~e.17) :ARG1-of (s / significant-02~e.13) :location (c / cell-line~e.24 :name (n3 / name :op1 "LoVo"~e.23) :ARG3-of (e2 / express-03~e.25,40 :ARG2 (p5 / protein :name (n5 / name :op1 "shSerpinE2") :ARG1-of (l / label-01 :ARG2 15))))) :op2 (r8 / reduce-01~e.14 :ARG1 n12 :ARG2 (p2 / percentage-entity~e.21 :value 88~e.20) :location (c6 / cell-line~e.24 :name (n10 / name :op1 "LoVo"~e.23) :ARG3-of (e6 / express-03~e.25 :ARG2 (p6 / protein :name (n4 / name :op1 "shSerpinE2") :ARG1-of (l2 / label-01 :ARG2 16)))) :ARG1-of s) :op3 (r9 / reduce-01~e.14 :ARG1 n12 :ARG2~e.32 (p3 / percentage-entity~e.34 :value 77~e.33) :location (c2 / cell-line~e.24 :name (n6 / name :op1 "HCT116"~e.39) :ARG3-of e2) :ARG1-of s) :op4 (r10 / reduce-01~e.14 :ARG1 n12 :ARG2 (p4 / percentage-entity~e.37 :value 92~e.36) :ARG1-of s :location (c7 / cell-line~e.24 :name (n11 / name :op1 "HCT116"~e.39) :ARG3-of e6)) :ARG1-of (s3 / show-01~e.1 :medium~e.2 (f / figure~e.3 :mod "4A"~e.5))) :ARG2 (c3 / contrast-01 :ARG1 (a4 / affect-01~e.59 :polarity~e.58 -~e.58 :ARG0 (e3 / express-03~e.49,65 :ARG2 (n15 / nucleic-acid :name (n7 / name :op1 "shRNA"~e.53) :mod (c4 / control~e.52) :ARG1-of (d / describe-01 :ARG2 (p7 / protein :name (n8 / name :op1 "shTGFP"~e.55))))) :ARG1 (e4 / express-03~e.65 :ARG1 (g2 / gene :name (n9 / name :op1 "serpinE2"~e.63) :mod (e5 / endogenous~e.61)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.67 :ARG1-of (s2 / show-01~e.69 :polarity~e.68 -~e.68))))) # ::id a_pmid_2094_2929.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Again , the proliferation rate of these cell populations was assessed when cultured on plastic . # ::alignments 0-1.3 3-1.1.1 4-1.1 5-1.1.1.1.r 6-1.1.1.1.1 7-1.1.1.1.2 8-1.1.1.1 10-1 11-1.2.r 12-1.2 13-1.2.2.r 14-1.2.2 (a / assess-01~e.10 :ARG1 (r / rate~e.4 :degree-of (p / proliferate-01~e.3 :ARG0~e.5 (p2 / population~e.8 :mod (t / this~e.6) :mod (c / cell~e.7)))) :time~e.11 (c2 / culture-01~e.12 :ARG1 p2 :location~e.13 (p3 / plastic~e.14)) :mod (a2 / again~e.0)) # ::id a_pmid_2094_2929.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No difference was observed in the proliferation rate of subconfluent cells when serpinE2 expression was downregulated ( Figure 4B ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.1.2.r 6-1.1.2.1 7-1.1.2 8-1.1.2.1.1.r 9-1.1.2.1.1.1 10-1.1.2.1.1 11-1.2.r 12-1.2.1.1.1.1 13-1.2.1 15-1.2 17-1.3.1 19-1.3.1.1 (o / observe-01~e.3 :ARG1 (d / differ-02~e.1 :polarity~e.0,1 -~e.0,1 :ARG1~e.4 (r / rate~e.7 :degree-of (p / proliferate-01~e.6 :ARG0~e.8 (c / cell~e.10 :mod (s / subconfluent~e.9))))) :time~e.11 (d2 / downregulate-01~e.15 :ARG1 (e / express-03~e.13 :ARG2 (p2 / protein :name (n / name :op1 "serpinE2"~e.12)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.17 :mod "4B"~e.19))) # ::id a_pmid_2094_2929.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We then verified whether the reduction in serpinE2 @ expression alters the ability of colon cancer cells to form colonies in soft agarose . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.1.r 5-1.2.2 8-1.2.2.1.1.1.1 10-1.2.2.1 11-1.2 13-1.2.3 14-1.2.3.1.r 15-1.2.3.1.1.1.1 16-1.2.3.1.1.1.2 17-1.2.3.1 19-1.2.3.2 20-1.2.3.2.2 21-1.2.3.2.3.r 22-1.2.3.2.3.1 23-1.2.3.2.3 (v / verify-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / alter-01~e.11 :mode~e.3 interrogative~e.3 :ARG0 (r / reduce-01~e.5 :ARG1 (e / express-03~e.10 :ARG1 (g / gene :name (n / name :op1 "serpinE2"~e.8)))) :ARG1 (c / capable-01~e.13 :ARG1~e.14 (c2 / cell~e.17 :source (d / disease :name (n2 / name :op1 "colon"~e.15 :op2 "cancer"~e.16))) :ARG2 (f / form-01~e.19 :ARG0 c2 :ARG1 (c5 / colony~e.20) :location~e.21 (a2 / agarose~e.23 :ARG1-of (s / soft-02~e.22))))) :time (t / then~e.1)) # ::id a_pmid_2094_2929.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 4C , expression of both shRNA against SerpinE2 (#15 and #16 ) decreased the ability of HCT116 and LoVo cells to form colonies in soft agarose . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 5-1.3.1.1 8-1.1 9-1.1.1.r 10-1.1.1.2 11-1.1.1.1.1 12-1.1.1 12-1.1.1.3 12-1.1.1.3.r 13-1.1.1.3.1.1.1 13-1.1.1.3.1.2.1.1.1.1 13-1.1.1.3.1.2.1.2.1.1 15-1.1.1.3.1.2.1 18-1 20-1.2 21-1.2.1.r 22-1.2.1.1.1.1 23-1.2.1 24-1.2.1.2.1.1 25-1.2.1.1 25-1.2.1.2 27-1.2.2 28-1.2.2.2 29-1.2.2.3.r 30-1.2.2.3.1 31-1.2.2.3 (d / decrease-01~e.18 :ARG0 (e / express-03~e.8 :ARG2~e.9 (n7 / nucleic-acid~e.12 :name (n / name :op1 "shRNA"~e.11) :mod (b / both~e.10) :ARG0-of~e.12 (c / counter-01~e.12 :ARG1 (p / protein :name (n2 / name :op1 "SerpinE2"~e.13) :ARG1-of (m / mean-01 :ARG2 (a / and~e.15 :op1 (p2 / protein :name (n3 / name :op1 "SerpinE2"~e.13) :ARG1-of (l / label-01 :ARG2 15)) :op2 (p3 / protein :name (n4 / name :op1 "SerpinE2"~e.13) :ARG1-of (l2 / label-01 :ARG2 16)))))))) :ARG1 (c2 / capable-01~e.20 :ARG1~e.21 (a2 / and~e.23 :op1 (c3 / cell-line~e.25 :name (n5 / name :op1 "HCT116"~e.22)) :op2 (c4 / cell-line~e.25 :name (n6 / name :op1 "LoVo"~e.24))) :ARG2 (f / form-01~e.27 :ARG0 a2 :ARG1 (c5 / colony~e.28) :location~e.29 (a3 / agarose~e.31 :ARG1-of (s / soft-02~e.30)))) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f2 / figure~e.3 :mod "4C"~e.5))) # ::id a_pmid_2094_2929.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of note , shSerpinE2(#15 ) which was less efficient than the shRNA (#16 ) to reduce serpinE2 @ gene expression ( Figure 4A ) was also less efficient to reduce colony formation . # ::alignments 1-1.1.4 7-1.1.2.2 8-1.1 8-1.1.2 8-1.1.2.r 9-1.1.2.4.r 11-1.1.2.4.1.1 15-1.1.2.1 17-1.1.2.1.2.1.1.1 19-1.1.2.1.2.1 20-1.1.2.1.2 22-1.1.2.3.1 24-1.1.2.3.1.1 28-1.3 29-1.4 30-1 30-1.1 30-1.1.2 30-1.1.2.r 30-1.1.r 32-1.2 33-1.2.2.1 34-1.2.2 (e / efficient-01~e.30 :ARG1~e.30 (p / protein~e.8,30 :name (n / name :op1 "shSerpinE2") :ARG1-of~e.8,30 (e2 / efficient-01~e.8,30 :ARG2 (r4 / reduce-01~e.15 :ARG0 p :ARG1 (e3 / express-03~e.20 :ARG1 (g / gene~e.19 :name (n3 / name :op1 "serpinE2"~e.17)))) :degree (l / less~e.7) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.22 :mod "4A"~e.24)) :compared-to~e.9 (n6 / nucleic-acid :name (n2 / name :op1 "shRNA"~e.11) :ARG1-of (l3 / label-01 :ARG2 16))) :ARG1-of (l2 / label-01 :ARG2 15) :ARG1-of (n4 / note-02~e.1)) :ARG2 (r / reduce-01~e.32 :ARG0 p :ARG1 (f / form-01~e.34 :ARG1 (c / colony~e.33))) :mod (a / also~e.28) :degree l~e.29) # ::id a_pmid_2094_2929.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This indicates that serpinE2 controls anchorage @-@ independent growth of human colon carcinoma cells . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1 4-1.2 5-1.2.2.2.2 7-1.2.2.2 7-1.2.2.2.1 7-1.2.2.2.1.r 8-1.2.2 9-1.2.2.1.r 10-1.2.2.1.1.1 11-1.2.2.1.1.2 12-1.2.2.1.1 13-1.2.2.1 (i / indicate-01~e.1 :ARG0 (t / this~e.0) :ARG1~e.2 (c / control-01~e.4 :ARG0 (p / protein :name (n / name :op1 "serpinE2"~e.3)) :ARG1 (g / grow-01~e.8 :ARG1~e.9 (c2 / cell~e.13 :source (c3 / carcinoma~e.12 :mod (h / human~e.10) :mod (c4 / colon~e.11))) :ARG0-of (d / depend-01~e.7 :polarity~e.7 -~e.7 :ARG1 (a / anchorage~e.5))))) # ::id a_pmid_2094_2929.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , as observed in caMEK @-@ expressing IECs , the size of foci formed at post @-@ confluency was significantly decreased in serpinE2 @-@ depleted LoVo cells ( Figure 4D ) . # ::alignments 0-1 2-1.1.1.1.1.1.r 3-1.1.4 5-1.1.4.1.2.1.1.1 7-1.1.4.1.2 8-1.1.4.1.1.1 11-1.1.1 13-1.1.1.1 14-1.1.1.1.1 16-1.1.1.1.1.1 18-1.1.1.1.1.1.1 20-1.1.2 21-1.1 23-1.1.3.2.1.1.1 25-1.1.3.2 26-1.1.3.1.1 27-1.1.3 27-1.1.4.1 29-1.2.1 31-1.2.1.1 (a / and~e.0 :op2 (d / decrease-01~e.21 :ARG1 (s2 / size~e.11 :poss (f / focus~e.13 :ARG1-of (f2 / form-01~e.14 :time~e.2 (a2 / after~e.16 :op1 (c3 / confluency~e.18))))) :ARG2 (s / significant-02~e.20) :location (c / cell-line~e.27 :name (n / name :op1 "LoVo"~e.26) :ARG1-of (d2 / deplete-01~e.25 :ARG2 (p2 / protein :name (n2 / name :op1 "serpinE2"~e.23)))) :ARG1-of (o / observe-01~e.3 :location (c2 / cell~e.27 :name (n3 / name :op1 "IEC"~e.8) :ARG3-of (e / express-03~e.7 :ARG2 (e2 / enzyme :name (n4 / name :op1 "caMEK"~e.5)))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.29 :mod "4D"~e.31))) # ::id a_pmid_2094_2929.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The tumorigenicity of colorectal cell lines was next assessed after subcutaneous ( s.c.) injection into the flank of nude mice . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.2 1-1.1.1.2.r 1-1.1.1.r 2-1.1.1.1.r 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1.1 7-1.2 7-1.3 8-1 9-1.3 10-1.3.1.2 13-1.3.1 14-1.3.1.1.r 16-1.3.1.1 17-1.3.1.1.1.r 18-1.3.1.1.1.1 19-1.3.1.1.1 (a / assess-01~e.8 :ARG1 (p / possible-01~e.1 :ARG1~e.1 (c3 / create-01~e.1 :ARG0~e.2 (c / cell-line~e.4,5 :source (c2 / colorectal~e.3)) :ARG1~e.1 (t / tumor~e.1))) :time (n / next~e.7) :time (a2 / after~e.7,9 :op1 (i / inject-01~e.13 :ARG2~e.14 (f / flank~e.16 :poss~e.17 (m / mouse~e.19 :mod (n2 / nude~e.18))) :mod (s / subcutaneous~e.10)))) # ::id a_pmid_2094_2929.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 5A and 5B , HCT116 and LoVo cell lines induced palpable tumors with a short latency period of respectively 15 and 10 days after their injection . # ::alignments 0-1.2.2.3.r 1-1.3 2-1.3.1.r 3-1.3.1.1 3-1.3.1.2 5-1.3.1.1.1 7-1.3.1 9-1.3.1.2.1 12-1.1.1.1.1 13-1.1 14-1.1.2.1.1 15-1.1.1 15-1.1.2 16-1.1.1 17-1 18-1.2.1 19-1.2 22-1.2.2.2 23-1.2.2.1 24-1.2.2 26-1.2.2.3.2.3 27-1.2.2.3.2.1.1 28-1.2.2.3.2 29-1.2.2.3.2.2.1 30-1.2.2.3.2.1.2 30-1.2.2.3.2.2.2 31-1.2.2.3 32-1.2.2.3.1.1 32-1.2.2.3.1.1.r 33-1.2.2.3.1 (i / induce-01~e.17 :ARG0 (a / and~e.13 :op1 (c / cell-line~e.15,16 :name (n / name :op1 "HCT116"~e.12)) :op2 (c2 / cell-line~e.15 :name (n2 / name :op1 "LoVo"~e.14))) :ARG2 (t2 / tumor~e.19 :mod (p / palpable~e.18) :mod (p2 / period~e.24 :mod (l / latency~e.23) :ARG1-of (s / short-07~e.22) :time~e.0 (a3 / after~e.31 :op1 (i2 / inject-01~e.33 :ARG1~e.32 a~e.32) :quant (a2 / and~e.28 :op1 (t3 / temporal-quantity :quant 15~e.27 :unit (d2 / day~e.30)) :op2 (t4 / temporal-quantity :quant 10~e.29 :unit (d / day~e.30)) :mod (r / respective~e.26))))) :ARG1-of (s2 / show-01~e.1 :medium~e.2 (a4 / and~e.7 :op1 (f / figure~e.3 :mod "5A"~e.5) :op2 (f2 / figure~e.3 :mod "5B"~e.9)))) # ::id a_pmid_2094_2929.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More importantly , downregulation of serpinE2 expression with shSerpinE2(#16 ) in these cell lines severely impaired their capacity to grow as tumors in nude mice . # ::alignments 0-1.4.1 1-1.4 3-1.1 4-1.1.1.r 5-1.1.1.1.1.1 6-1.1.1 10-1.1.1.2.r 11-1.1.1.2.1 12-1.1.1.2 13-1.1.1.2 14-1.3 14-1.3.r 15-1 16-1.2.1 16-1.2.1.r 17-1.2 19-1.2.2 20-1.2.2.2.r 21-1.2.2.2 22-1.2.2.3.r 23-1.2.2.3.1 24-1.2.2.3 (i / impair-01~e.15 :ARG0 (d / downregulate-01~e.3 :ARG1~e.4 (e / express-03~e.6 :ARG2 (p / protein :name (n / name :op1 "serpinE2"~e.5)) :ARG3~e.10 (c / cell-line~e.12,13 :mod (t / this~e.11))) :ARG2 (p2 / protein :name (n2 / name :op1 "shSerpinE2") :ARG1-of (l / label-01 :ARG2 16))) :ARG1 (c2 / capable-01~e.17 :ARG1~e.16 c~e.16 :ARG2 (g / grow-02~e.19 :ARG1 c :ARG2~e.20 (t2 / tumor~e.21) :location~e.22 (m / mouse~e.24 :mod (n3 / nude~e.23)))) :manner~e.14 (s / severe~e.14) :mod (i2 / important~e.1 :degree (m2 / more~e.0))) # ::id a_pmid_2094_2929.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , in vitro @ transwell migration assays were performed to verify the importance of serpinE2 in colon carcinoma cell migration . # ::alignments 0-1.1 0-1.1.r 3-1.2.2 4-1.2.2 6-1.2.1.1 7-1.2.1 8-1.2 10-1 12-1.3 14-1.3.1 15-1.3.1.1.r 16-1.3.1.1.1.1 17-1.2.2 17-1.3.1.2.r 18-1.3.1.2.1.1.1 19-1.3.1.2.1.1 20-1.3.1.2.1 21-1.3.1.2 (p / perform-02~e.10 :li~e.0 -1~e.0 :ARG1 (a / assay-01~e.8 :ARG1 (m2 / migrate-01~e.7 :mod (t2 / transwell~e.6)) :manner (i / in-vitro~e.3,4,17)) :purpose (v / verify-01~e.12 :ARG1 (i2 / important~e.14 :domain~e.15 (p2 / protein :name (n2 / name :op1 "serpinE2"~e.16)) :purpose~e.17 (m / migrate-01~e.21 :ARG0 (c / cell~e.20 :source (c2 / carcinoma~e.19 :mod (c3 / colon~e.18))))))) # ::id a_pmid_2094_2929.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As illustrated in Figure 6A , serpinE2 deficiency significantly reduced HCT116 ( not shown ) and LoVo cell migration to the undersurface of the membrane coated or not with fibronectin or vitronectin ( data not shown ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 5-1.4.1.1 8-1.1.1.1.1 10-1.3 11-1 12-1.2.1.1.1.1 14-1.2.1.1.2.1 14-1.2.1.1.2.1.r 15-1.2.1.1.2 17-1.2.1 18-1.2.1.2.1.1 19-1.2.1.1 19-1.2.1.2 20-1.2 21-1.2.2.r 23-1.2.2 24-1.2.2.1.r 26-1.2.2.1 27-1.2.2.2 27-1.2.2.2.2.1 28-1.2.2.2.1 28-1.2.2.2.2 29-1.2.2.2.2.1.1 29-1.2.2.2.2.1.1.r 30-1.2.2.2.1.r 31-1.2.2.2.1.1.1.1 32-1.2.2.2.1 33-1.2.2.2.1.2.1.1 35-1.5.1 36-1.5.1.1 37-1.5.1.1 (r / reduce-01~e.11 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "serpinE2"~e.8))) :ARG1 (m / migrate-01~e.20 :ARG0 (a / and~e.17 :op1 (c2 / cell-line~e.19 :name (n2 / name :op1 "HCT116"~e.12) :ARG1-of (s2 / show-01~e.15 :polarity~e.14 -~e.14)) :op2 (c4 / cell-line~e.19 :name (n3 / name :op1 "LoVo"~e.18))) :ARG2~e.21 (u / undersurface~e.23 :part-of~e.24 (m2 / membrane~e.26) :ARG1-of (c5 / coat-01~e.27 :ARG2~e.30 (o / or~e.28,32 :op1 (p2 / protein :name (n4 / name :op1 "fibronectin"~e.31)) :op2 (p3 / protein :name (n5 / name :op1 "vitronectin"~e.33))) :op1-of (o2 / or~e.28 :op2 (c6 / coat-01~e.27 :polarity~e.29 -~e.29 :ARG1 u :ARG2 o))))) :ARG2 (s / significant-02~e.10) :ARG1-of (i / illustrate-01~e.1 :medium~e.2 (f / figure~e.3 :mod "6A"~e.5)) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.35 :ARG1-of s2~e.36,37))) # ::id a_pmid_2094_2929.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The net effect of serpinE2 knockdown was also determined on invasion by using BD Biocoat Matrigel invasion chambers , in presence of hydroxyurea . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 7-1.2 8-1 9-1.3.r 10-1.3 11-1.4.r 12-1.4 13-1.4.1.1.1 14-1.4.1.1.2 15-1.4.1.1.3 16-1.4.1.1.4 17-1.4.1.1.5 19-1.5.r 20-1.5 21-1.5.1.r 22-1.5.1.1.1 (d / determine-01~e.8 :ARG1 (a / affect-01~e.2 :ARG0~e.3 (k / knock-down-02~e.5 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"~e.4))) :mod (n / net~e.1)) :mod (a2 / also~e.7) :time~e.9 (i / invade-01~e.10) :manner~e.11 (u / use-01~e.12 :ARG1 (t / thing :name (n3 / name :op1 "BD"~e.13 :op2 "Biocoat"~e.14 :op3 "Matrigel"~e.15 :op4 "invasion"~e.16 :op5 "chamber"~e.17))) :condition~e.19 (p2 / present-02~e.20 :ARG1~e.21 (s / small-molecule :name (n4 / name :op1 "hydroxyurea"~e.22)))) # ::id a_pmid_2094_2929.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 6B , the capacity of LoVo cells to invade Matrigel was also altered by serpinE2 silencing # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 5-1.4.1.1 9-1.2 10-1.2.1.r 11-1.2.1.1.1 12-1.2.1 14-1.2.2 15-1.2.2.2.1.1 17-1.3 18-1 19-1.1.r 20-1.1.1.1.1 21-1.1 (a / alter-01~e.18 :ARG0~e.19 (s / silence-01~e.21 :ARG1 (p2 / protein :name (n3 / name :op1 "serpinE2"~e.20))) :ARG1 (c / capable-01~e.9 :ARG1~e.10 (c2 / cell-line~e.12 :name (n / name :op1 "LoVo"~e.11)) :ARG2 (i / invade-01~e.14 :ARG0 c2 :ARG1 (p / protein :name (n2 / name :op1 "Matrigel"~e.15)))) :mod (a2 / also~e.17) :ARG1-of (s2 / show-01~e.1 :medium~e.2 (f / figure~e.3 :mod "6B"~e.5))) # ::id a_pmid_2094_2929.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test the hypothesis that this altered migration and invasion capacity could result from a defect in cell adhesion , adhesion strength to the substrate was examined for control and shSerpinE2(#16 ) - expressing LoVo cells . # ::alignments 1-1.2 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.1.2.3 6-1.2.1.1.1.2.2 7-1.2.1.1.1.2.1.1 8-1.2.1.1.1.2.1 9-1.2.1.1.1.2.1.2 10-1.2.1.1.1.2 11-1.2.1.1 12-1.2.1.1.1 13-1.2.1.1.1.1.r 15-1.2.1.1.1.1 16-1.2.1.1.1.1.1.r 17-1.2.1.1.1.1.1.1 18-1.2.1.1.1.1.1 20-1.1.1 21-1.1 22-1.1.1.2.r 24-1.1.1.2 26-1 27-1.1.1.1.r 28-1.1.1.1.1.2 29-1.1.1.1 33-1.1.1.1.2.2 34-1.1.1.1.1.1.1 34-1.1.1.1.2.1.1 35-1.1.1.1.1 35-1.1.1.1.2 (e / examine-01~e.26 :ARG1 (s / strong-02~e.21 :degree-of (a / adhere-01~e.20 :ARG1~e.27 (a2 / and~e.29 :op1 (c / cell-line~e.35 :name (n / name :op1 "LoVo"~e.34) :mod (c2 / control~e.28)) :op2 (c3 / cell-line~e.35 :name (n2 / name :op1 "LoVo"~e.34) :ARG3-of (e2 / express-03~e.33 :ARG2 (p2 / protein :name (n3 / name :op1 "shSerpinE2") :ARG1-of (l / label-01 :ARG2 16))))) :ARG2~e.22 (s2 / substrate~e.24))) :ARG2 (t2 / test-01~e.1 :ARG1 (h / hypothesize-01~e.3 :ARG1~e.4 (p / possible-01~e.11 :ARG1 (r2 / result-01~e.12 :ARG1~e.13 (d / defect~e.15 :topic~e.16 (a5 / adhere-01~e.18 :ARG1 (c5 / cell~e.17))) :ARG2 (c4 / capable-01~e.10 :ARG2 (a3 / and~e.8 :op1 (m / migrate-01~e.7) :op2 (i / invade-01~e.9)) :ARG1-of (a4 / alter-01~e.6) :mod (t3 / this~e.5))))))) # ::id a_pmid_2094_2929.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using a trypsin @-@ mediated de @-@ adhesion assay , downregulation of serpinE2 significantly delayed LoVo cell detachment after trypsinization ( Figure 6C ) , suggesting that serpinE2 expression decreases adhesion of colorectal carcinoma cells to the substrate . # ::alignments 0-1.5 2-1.5.1.2.1.1.1 4-1.5.1.2 7-1.5.1.1 8-1.5.1 10-1.1 11-1.1.1.r 12-1.1.1.1.1 13-1.3 14-1 15-1.2.1.1.1 16-1.2.1 17-1.2 18-1.4 21-1.6.1 23-1.6.1.1 27-1.7 28-1.7.1.r 29-1.7.1.1.1 30-1.7.1.1 31-1.7.1 32-1.7.1.2 33-1.7.1.2.1.r 34-1.7.1.2.1.1.1 35-1.7.1.2.1.1 36-1.7.1.2.1 37-1.7.1.2.2.r 39-1.7.1.2.2 (d / delay-01~e.14 :ARG0 (d2 / downregulate-01~e.10 :ARG1~e.11 (p / protein :name (n / name :op1 "serpinE2"~e.12))) :ARG1 (d3 / detach-01~e.17 :ARG1 (c / cell-line~e.16 :name (n2 / name :op1 "LoVo"~e.15))) :ARG2 (s / significant-02~e.13) :time (a / after~e.18 :op1 (t / trypsinize-00)) :manner (u / use-01~e.0 :ARG1 (a2 / assay-01~e.8 :ARG1 (a3 / adhere-01~e.7 :polarity -) :ARG1-of (m / mediate-01~e.4 :ARG0 (e / enzyme :name (n4 / name :op1 "trypsin"~e.2))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.21 :mod "6C"~e.23)) :ARG0-of (s2 / suggest-01~e.27 :ARG1~e.28 (d5 / decrease-01~e.31 :ARG0 (e2 / express-03~e.30 :ARG2 p~e.29) :ARG1 (a4 / adhere-01~e.32 :ARG1~e.33 (c2 / cell~e.36 :source (c3 / carcinoma~e.35 :mod (c4 / colorectal~e.34))) :ARG2~e.37 (s3 / substrate~e.39))))) # ::id a_pmid_2094_2929.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SerpinE2 @ gene expression is up @-@ regulated in human colorectal cancers # ::alignments 3-1.1.1 4-1.1 9-1.1.2.r 10-1.1.2.3 11-1.1.2.4 12-1.1.2.2.1 (u / upregulate-01 :ARG1 (e / express-03~e.4 :ARG1 (g / gene~e.3 :name (n / name :op1 "serpinE2")) :ARG3~e.9 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.12) :mod (h / human~e.10) :mod (c2 / colorectal~e.11)))) # ::id a_pmid_2094_2929.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next analyzed serpinE2 @ gene expression in a series of human paired specimens ( resection margins and primary tumors ) by Q @-@ PCR analysis . # ::alignments 0-1.1 1-1.3 2-1 2-1.4.1.2 4-1.2.1.1.1 6-1.2.1 7-1.2 8-1.2.2.r 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.1 13-1.2.2.1.2 14-1.2.2.1 16-1.2.2.1.3.1.1.1 17-1.2.2.1.3.1.1 18-1.2.2.1.3.1 19-1.2.2.1.3.1.2.1 20-1.2.2.1.3.1.2 23-1.4.1.1 25-1.4.1.1 26-1 26-1.4.1.2 (a / analyze-01~e.2,26 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.7 :ARG1 (g / gene~e.6 :name (n2 / name :op1 "serpinE2"~e.4)) :ARG3~e.8 (s / series~e.10 :consist-of~e.11 (s2 / specimen~e.14 :mod (h / human~e.12) :ARG1-of (p / pair-01~e.13) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.18 :op1 (m2 / margin~e.17 :mod (r / resection~e.16)) :op2 (t / tumor~e.20 :mod (p2 / primary~e.19))))))) :time (n / next~e.1) :manner (t2 / thing :name (n3 / name :op1 "Q-PCR"~e.23,25 :op2 "analysis"~e.2,26))) # ::id a_pmid_2094_2929.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 7 , mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 5-1.3.1.1 8-1.1.1.1.1 9-1.1 9-1.4 11-1.1.1.2.1.1.1 13-1.2 13-1.2.r 14-1 15-1.5.r 16-1.5.2 17-1.5.1.1 19-1.4.r 20-1.4.1.r 21-1.4.1.1 22-1.4.1.2 23-1.4.1 (i / increase-01~e.14 :ARG1 (l / level~e.9 :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.8) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"~e.11))))) :manner~e.13 (m / marked~e.13) :ARG1-of (s / show-01~e.1 :medium~e.2 (f / figure~e.3 :mod 7~e.5)) :compared-to~e.19 (l2 / level~e.9 :location~e.20 (t / tissue~e.23 :mod (h2 / healthy~e.21) :mod (a2 / adjacent~e.22)) :quant-of n4) :location~e.15 (m2 / medical-condition :name (n3 / name :op1 "adenoma"~e.17) :mod (h / human~e.16))) # ::id a_pmid_2094_2929.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , serpinE2 expression was also significantly enhanced in colorectal tumors , regardless of tumor stage and grade . # ::alignments 0-1 2-1.1.1.1.1.1 3-1.1.1 5-1.1.3 6-1.1.2 7-1.1 8-1.1.1.2.r 9-1.1.1.2.1 10-1.1.1.2 12-1.1.4 14-1.1.4.1.1.1.1 15-1.1.4.1.1 15-1.1.4.1.1.1 15-1.1.4.1.1.1.r 16-1.1.4.1 17-1.1.4.1.2 (a / and~e.0 :op2 (e / enhance-01~e.7 :ARG1 (e2 / express-03~e.3 :ARG2 (p / protein :name (n / name :op1 "serpinE2"~e.2)) :ARG3~e.8 (t / tumor~e.10 :mod (c / colorectal~e.9))) :ARG3 (s / significant-02~e.6) :mod (a2 / also~e.5) :ARG1-of (r / regardless-91~e.12 :ARG2 (a3 / and~e.16 :op1 (t2 / thing~e.15 :ARG2-of~e.15 (s2 / stage-02~e.15 :ARG1 t~e.14)) :op2 (g / grade~e.17 :mod t))))) # ::id a_pmid_2139_2397.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The average level of phosphorylation of YB @-@ 1 in the breast cancer cell lines SKBr3 , MCF @-@ 7 , HBL100 and MDA @-@ MB @-@ 231 was significantly higher than that in normal cells . # ::alignments 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 8-1.1.2.1.1.1 9-1.1.3.r 11-1.1.3.5.2.1 12-1.1.3.5.2.2 13-1.1.3.1 14-1.1.3.1 14-1.1.3.2 14-1.1.3.3 14-1.1.3.4 15-1.1.3.1.1.1 17-1.1.3.2.1.1 19-1.1.3.2.1.1 21-1.1.3.3.1.1 22-1.1.3 23-1.1.3.4.1.1 25-1.1.3.4.1.1 27-1.1.3.4.1.1 29-1.3 30-1 30-1.2 30-1.2.r 31-1.4.r 34-1.4.1 35-1.4 (h / high-02~e.30 :ARG1 (l / level~e.2 :ARG1-of (a / average-04~e.1) :degree-of~e.3 (p / phosphorylate-01~e.4 :ARG1~e.5 (p2 / protein :name (n / name :op1 "YB-1"~e.6,8))) :location~e.9 (a2 / and~e.22 :op1 (c3 / cell-line~e.13,14 :name (n3 / name :op1 "SKBr3"~e.15)) :op2 (c4 / cell-line~e.14 :name (n4 / name :op1 "MCF-7"~e.17,19)) :op3 (c5 / cell-line~e.14 :name (n5 / name :op1 "HBL100"~e.21)) :op4 (c6 / cell-line~e.14 :name (n6 / name :op1 "MDA-MB-231"~e.23,25,27)) :mod (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast"~e.11 :op2 "cancer"~e.12)))) :degree~e.30 (m / more~e.30) :ARG1-of (s / significant-02~e.29) :compared-to~e.31 (c7 / cell~e.35 :ARG1-of (n7 / normal-02~e.34))) # ::id a_pmid_2139_2397.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exposure to IR and stimulation with erbB1 ligands resulted in phosphorylation of YB @-@ 1 in K @-@ RAS @ _wt@ SKBr3 , MCF @-@ 7 and HBL100 cells , which was shown to be K @-@ Ras @-@ independent . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 2-1.1.1.1.1 2-1.1.1.1.1.r 3-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 7-1.1.2.1 8-1 9-1.2.r 10-1.2 11-1.2.1.r 12-1.2.1.1.1 14-1.2.1.1.1 17-1.2.2.4.1.1 22-1.2.2.4.2 24-1.2.2.1.1.1 26-1.2.2.2.1.1 28-1.2.2.2.1.1 29-1.2.2 30-1.2.2.3.1.1 31-1.2.2.1 31-1.2.2.2 31-1.2.2.3 35-1.2.3.3 38-1.2.3.2 39-1.2.3.2 40-1.2.3.2 42-1.2.3 42-1.2.3.1 42-1.2.3.1.r (r / result-01~e.8 :ARG1 (a / and~e.3 :op1 (e / expose-01~e.0 :ARG2~e.1 (r2 / radiate-01~e.2 :ARG0-of~e.2 (i / ionize-01~e.2))) :op2 (s / stimulate-01~e.4 :ARG2~e.5 (l / ligand~e.7 :name (n2 / name :op1 "erbB1"~e.6)))) :ARG2~e.9 (p / phosphorylate-01~e.10 :ARG1~e.11 (p2 / protein :name (n3 / name :op1 "YB-1"~e.12,14)) :location (a2 / and~e.29 :op1 (c / cell-line~e.31 :name (n4 / name :op1 "SKBr3"~e.24)) :op2 (c2 / cell-line~e.31 :name (n5 / name :op1 "MCF-7"~e.26,28)) :op3 (c3 / cell-line~e.31 :name (n6 / name :op1 "HBL100"~e.30)) :mod (g / gene :name (n7 / name :op1 "K-Ras"~e.17) :mod (w / wild-type~e.22))) :ARG1-of (d / depend-01~e.42 :polarity~e.42 -~e.42 :ARG0 g~e.38,39,40 :ARG1-of (s2 / show-01~e.35)))) # ::id a_pmid_2139_2397.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , lack of YB @-@ 1 phosphorylation after stimulation with either IR or erbB1 ligands was observed in K @-@ RAS @ _mt@ MDA @-@ MB @-@ 231 cells . # ::alignments 1-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1 7-1.1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.2 10-1.1.1.2.1 13-1.1.1.2.1.1.1 13-1.1.1.2.1.1.1.1 13-1.1.1.2.1.1.1.1.r 14-1.1.1.2.1.1 15-1.1.1.2.1.1.2.1.1 16-1.1.1.2.1.1.2 18-1.1 21-1.1.2.2.1.1 23-1.1.2.2.1.1 28-1.1.2.1.1 30-1.1.2.1.1 32-1.1.2.1.1 33-1.1.2 (c / contrast-01~e.1 :ARG2 (o / observe-01~e.18 :ARG1 (l / lack-01~e.3 :ARG1~e.4 (p / phosphorylate-01~e.8 :ARG1 (p2 / protein :name (n / name :op1 "YB-1"~e.5,7))) :time (a / after~e.9 :op1 (s / stimulate-01~e.10 :ARG2 (o2 / or~e.14 :op1 (r / radiate-01~e.13 :ARG0-of~e.13 (i / ionize-01~e.13)) :op2 (l3 / ligand~e.16 :name (n3 / name :op1 "erbB1"~e.15)))))) :location (c2 / cell-line~e.33 :name (n4 / name :op1 "MDA-MB-231"~e.28,30,32) :mod (g / gene :name (n5 / name :op1 "K-RAS"~e.21,23) :ARG2-of (m / mutate-01))))) # ::id a_pmid_2139_2397.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly to MDA @-@ MB @-@ 231 cells , YB @-@ 1 became constitutively phosphorylated in K @-@ RAS @ _wt@ cells following the overexpression of mutated K @-@ RAS , and its phosphorylation was not further enhanced by IR. # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1.1 4-1.3.1.1.1 6-1.3.1.1.1 7-1.3.1 9-1.1.1.1.1 11-1.1.1.1.1 12-1.1 13-1.1.2.2 14-1.1.2 17-1.1.2.3.1.1.1 19-1.1.2.3.1.1.1 22-1.1.2.3.1.2 24-1.1.2.3 25-1.1.3 27-1.1.3.1 28-1.1.3.1.1.r 29-1.1.3.1.1.2 31-1.1.3.1.1.1.1 33-1.1.3.1.1.1.1 37-1.1.2.1 37-1.1.2.1.r 38-1.1.2 40-1.2.1 40-1.2.1.r 41-1.2.4 42-1.2 (a / and :op1 (b / become-01~e.12 :ARG1 (p / protein :name (n / name :op1 "YB-1"~e.9,11)) :ARG2 (p2 / phosphorylate-01~e.14,38 :ARG1~e.37 p~e.37 :mod (c / constitutive~e.13) :location (c2 / cell~e.24 :mod (g2 / gene :name (n2 / name :op1 "K-RAS"~e.17,19) :mod (w / wild-type~e.22)))) :ARG2-of (f / follow-01~e.25 :ARG1 (o / overexpress-01~e.27 :ARG1~e.28 (g / gene :name (n3 / name :op1 "K-RAS"~e.31,33) :ARG2-of (m / mutate-01~e.29))))) :op2 (e3 / enhance-01~e.42 :polarity~e.40 -~e.40 :ARG1 p2 :ARG2 (r2 / radiate-01 :ARG0-of (i / ionize-01)) :degree (f2 / further~e.41)) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (c3 / cell-line~e.7 :name (n5 / name :op1 "MDA-MB-231"~e.2,4,6)))) # ::id a_pmid_2139_2397.16 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of YB @-@ 1 as a result of irradiation or K @-@ RAS @ mutation was dependent on erbB1 and its downstream pathways , PI3K and MAPK/ERK . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1.2.r 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1 12-1.1.2.1.2.1.1.1 14-1.1.2.1.2.1.1.1 16-1.1.2.1.2 18-1 19-1.2.r 20-1.2.1.1.1 21-1.2 22-1.2.2.3 22-1.2.2.3.r 23-1.2.2.1 24-1.2.2 26-1.2.2.2.1.1.1.1 27-1.2.2.2.1 28-1.2.2.2.1.2.1.1 (d / depend-01~e.18 :ARG0 (p2 / phosphorylate-01~e.0 :ARG1~e.1 (p3 / protein :name (n2 / name :op1 "YB-1"~e.2,4)) :ARG2-of~e.5 (r / result-01~e.7 :ARG1~e.8 (a / and :op1 (i / irradiate-01~e.9) :op2 (m / mutate-01~e.16 :ARG1 (g / gene :name (n3 / name :op1 "K-RAS"~e.12,14)))))) :ARG1~e.19 (a3 / and~e.21 :op1 (p / protein :name (n6 / name :op1 "erbB1"~e.20)) :op2 (p4 / pathway~e.24 :mod (d2 / downstream~e.23) :ARG2-of (i2 / include-91 :ARG1 (a2 / and~e.27 :op1 (p5 / pathway :name (n4 / name :op1 "PI3K"~e.26)) :op2 (p6 / pathway :name (n5 / name :op1 "MAPK/ERK"~e.28)))) :poss~e.22 p~e.22))) # ::id a_pmid_2139_2397.17 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In K @-@ RAS @ _mt@ cells K @-@ RAS @ siRNA as well as YB @-@ 1 siRNA blocked repair of DNA @-@ DSB . # ::alignments 2-1.1.1.2.1.1.1 2-1.3.1.1.1 4-1.3.1.1.1 9-1.3 11-1.3.1.1.1 13-1.3.1.1.1 15-1.1.1.1.1 15-1.1.2.1.1 16-1.1 17-1.1 18-1.1 19-1.1.2.2.1.1.1 21-1.1.2.2.1.1.1 22-1.1.1.1.1 22-1.1.2.1.1 23-1 24-1.2 25-1.2.1.r 26-1.2.1.1.1 28-1.2.1.1.1 (b / block-01~e.23 :ARG0 (a / and~e.16,17,18 :op1 (n7 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.15,22) :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras"~e.2)))) :op2 (n8 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.15,22) :ARG0-of (e3 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "YB-1"~e.19,21))))) :ARG1 (r3 / repair-01~e.24 :ARG1~e.25 (t / thing :name (n5 / name :op1 "DNA-DSB"~e.26,28))) :location (c / cell~e.9 :mod (g2 / gene :name (n6 / name :op1 "K-RAS"~e.2,4,11,13) :ARG2-of (m / mutate-01)))) # ::id a_pmid_2139_2397.18 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , YB @-@ 1 siRNA increased radiation sensitivity . # ::alignments 0-1.3 2-1.1.2.1.1.1 4-1.1.2.1.1.1 5-1.1.1.1 6-1 7-1.2.1 8-1.2 (i / increase-01~e.6 :ARG0 (n3 / nucleic-acid :name (n / name :op1 "siRNA"~e.5) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "YB-1"~e.2,4)))) :ARG1 (s / sensitive-03~e.8 :ARG1 (r2 / radiate-01~e.7)) :manner (l / likewise~e.0)) # ::id a_pmid_2139_2397.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stimulation of YB @-@ 1 phosphorylation in breast cancer cells by IR and exposure to erbB1 ligands # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1.1 4-1.1.2.1.1.1 5-1.1.2 6-1.1.3.r 7-1.1.3.1.2.1 8-1.1.3.1.2.2 9-1.1.3 10-1.1.1.r 11-1.1.1 11-1.1.1.1 11-1.1.1.1.r 12-1 13-1.2 14-1.2.1.r 15-1.2.1.1.1 16-1.2.1 (a / and~e.12 :op1 (s / stimulate-01~e.0 :ARG0~e.10 (r / radiate-01~e.11 :ARG0-of~e.11 (i / ionize-01~e.11)) :ARG1~e.1 (p2 / phosphorylate-01~e.5 :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1"~e.2,4))) :location~e.6 (c / cell~e.9 :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast"~e.7 :op2 "cancer"~e.8)))) :op2 (e / expose-01~e.13 :ARG1~e.14 (l / ligand~e.16 :name (n4 / name :op1 "erbB1"~e.15)))) # ::id a_pmid_2139_2397.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The level of basal YB @-@ 1 phosphorylation at S102 in a panel of breast cancer cells ( MDA @-@ MB @-@ 231 , MCF @-@ 7 , HBL100 and SKBr3 ) was compared to the level of YB @-@ 1 phosphorylation in normal cells , that is , human skin and lung fibroblasts ( HSF1 , HSF7 and HFL ) as well as normal mammary epithelial cells ( MCF @-@ 10A ) ( Figures 1A and 1B ) . # ::alignments 1-1.1 3-1.1.1.3 4-1.1.1.1.3.1.1 6-1.1.1.1.3.1.1 7-1.1.1 10-1.1.1.2.r 12-1.1.1.2 13-1.1.1.2.1.r 14-1.1.1.2.1.2.2.1 15-1.1.1.2.1.2.2.2 16-1.1.1.2.1 18-1.1.1.2.1.1.1.1.1.1 20-1.1.1.2.1.1.1.1.1.1 22-1.1.1.2.1.1.1.1.1.1 24-1.1.1.2.1.1.1.2.1.1 26-1.1.1.2.1.1.1.2.1.1 28-1.1.1.2.1.1.1.3.1.1 29-1.1.1.2.1.1.1 30-1.1.1.2.1.1.1.4.1.1 33-1 36-1.1 36-1.2 37-1.2.1.r 38-1.2.1.1 39-1.2.1.1 40-1.2.1.1 41-1.2.1 42-1.2.1.2.r 43-1.2.1.2.1 44-1.2.1.2 49-1.2.1.2.2.1.1.1 50-1.2.1.2.2.1.1 51-1.2.1.2.2.1 52-1.2.1.2.2.1.2.1 53-1.2.1.2.2.1.2 55-1.2.1.2.2.1.4.1.1.1.1 57-1.2.1.2.2.1.4.1.2.1.1 59-1.2.1.2.2.1.4.1.3.1.1 61-1.1.1.2.1.1.1 62-1.1.1.2.1.1.1 63-1.1.1.2.1.1.1 63-1.2.1.2.2.1.4.1 64-1.2.1.2.2.1.3.4 65-1.2.1.2.2.1.3.2 66-1.2.1.2.2.1.3.1 67-1.2.1.2.2.1.3 69-1.2.1.2.2.1.3.3.1.1.1 71-1.2.1.2.2.1.3.3.1.1.1 74-1.3.1.1 74-1.3.1.2 76-1.3.1.1.1 78-1.3.1 80-1.3.1.2.1 (c / compare-01~e.33 :ARG1 (l / level~e.1,36 :degree-of (p / phosphorylate-01~e.7 :ARG1 (a / amino-acid :mod 102 :name (n2 / name :op1 "serine") :part-of (p2 / protein :name (n3 / name :op1 "YB-1"~e.4,6))) :location~e.10 (p3 / panel~e.12 :consist-of~e.13 (c2 / cell-line~e.16 :ARG2-of (i / include-91 :ARG1 (a2 / and~e.29,61,62,63 :op1 (c4 / cell-line :name (n4 / name :op1 "MDA-MB-231"~e.18,20,22)) :op2 (c5 / cell-line :name (n5 / name :op1 "MCF-7"~e.24,26)) :op3 (c6 / cell-line :name (n6 / name :op1 "HBL100"~e.28)) :op4 (c7 / cell-line :name (n7 / name :op1 "SKBr3"~e.30)))) :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast"~e.14 :op2 "cancer"~e.15)))) :mod (b2 / basal~e.3))) :ARG2 (l2 / level~e.36 :degree-of~e.37 (p4 / phosphorylate-01~e.41 :ARG1 p2~e.38,39,40 :location~e.42 (c8 / cell-line~e.44 :ARG1-of (n8 / normal-02~e.43) :ARG2-of (m3 / mean-01 :ARG1 (a4 / and~e.51 :op1 (s / skin~e.50 :mod (h / human~e.49)) :op2 (f / fibroblast~e.53 :mod (l3 / lung~e.52)) :op3 (c12 / cell~e.67 :mod (e / epithelium~e.66) :mod (m / mammary~e.65) :ARG1-of (m2 / mean-01 :ARG2 (c13 / cell-line :name (n14 / name :op1 "MCF-10A"~e.69,71))) :ARG1-of n8~e.64) :ARG2-of (i3 / include-91 :ARG1 (a3 / and~e.63 :op1 (c10 / cell-line :name (n10 / name :op1 "HSF1"~e.55)) :op2 (c9 / cell-line :name (n11 / name :op1 "HSF7"~e.57)) :op3 (c11 / cell-line :name (n12 / name :op1 "HFL"~e.59))))))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.78 :op1 (f2 / figure~e.74 :mod "1A"~e.76) :op2 (f3 / figure~e.74 :mod "1B"~e.80)))) # ::id a_pmid_2139_2397.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 1C , the ratio of P @-@ YB @-@ 1/YB @-@ 1 is significantly higher in tumor cells than in fibroblasts . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1 5-1.2.1.1 9-1.1 10-1.1 11-1.1.1.2 13-1.1.1.1.1 13-1.1.2.1.1 17-1.1.1.1.1 17-1.1.2.1.1 18-1.1.r 19-1.1.3.2 20-1 20-1.1.3 20-1.1.3.1 20-1.1.3.1.r 21-1.1.4.r 22-1.1.4.1 23-1.1.4 24-1.1.5.r 26-1.1.5 (h2 / high~e.20 :domain~e.18 (r / ratio-of~e.9,10 :op1 (p2 / protein :name (n / name :op1 "YB-1"~e.13,17) :ARG3-of (p / phosphorylate-01~e.11)) :op2 (p3 / protein :name (n2 / name :op1 "YB-1"~e.13,17)) :ARG1-of (h / high-02~e.20 :degree~e.20 (m / more~e.20) :ARG1-of (s2 / significant-02~e.19)) :location~e.21 (c / cell~e.23 :mod (t / tumor~e.22)) :compared-to~e.24 (f2 / fibroblast~e.26)) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "1C"~e.5))) # ::id a_pmid_2139_2397.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The comparisons of the ratio of P @-@ YB @-@ 1/YB @-@ 1 in tumor cells and normal mammary epithelial cells indicated an even stronger significant difference as tested for MDA @-@ MB @-@ 231 and MCF @-@ 10A cells ( Figures 1B and 1C ) . # ::alignments 1-1.1 2-1.1.1 4-1.1.1 5-1.1.1 6-1.1.1.1.2 8-1.1.1.1.1.1 8-1.1.1.2.1.1 12-1.1.1.1.1.1 12-1.1.1.2.1.1 13-1.1.2.r 14-1.1.2.1.1 15-1.1.2.1 15-1.1.2.2 16-1.1.2 17-1.1.2.2.3 18-1.1.2.2.2 19-1.1.2.2.1 20-1.1.2.2 21-1 23-1.2.1.2 24-1.2.1 24-1.2.1.1 24-1.2.1.1.r 25-1.2.2 26-1.2 27-1.2.3.r 28-1.2.3 29-1.2.3.1.r 30-1.2.3.1.1.1.1 32-1.2.3.1.1.1.1 34-1.2.3.1.1.1.1 35-1.2.3.1 36-1.2.3.1.2.1.1 38-1.2.3.1.2.1.1 39-1.2.3.1.1 41-1.3.1.1 41-1.3.1.2 43-1.3.1.1.1 45-1.3.1 47-1.3.1.2.1 (i / indicate-01~e.21 :ARG0 (c / compare-01~e.1 :ARG2 (r / ratio-of~e.2,4,5 :op1 (p2 / protein :name (n / name :op1 "YB-1"~e.8,12) :ARG3-of (p / phosphorylate-01~e.6)) :op2 (p3 / protein :name (n2 / name :op1 "YB-1"~e.8,12))) :location~e.13 (a3 / and~e.16 :op1 (c2 / cell~e.15 :mod (t / tumor~e.14)) :op2 (c3 / cell~e.15,20 :mod (e / epithelium~e.19) :mod (m / mammary~e.18) :ARG1-of (n5 / normal-02~e.17)))) :ARG1 (d / differ-02~e.26 :mod (s / strong~e.24 :degree~e.24 (m2 / more~e.24) :mod (e2 / even~e.23)) :ARG1-of (s2 / significant-02~e.25) :ARG1-of~e.27 (t2 / test-01~e.28 :ARG2~e.29 (a / and~e.35 :op1 (c4 / cell-line~e.39 :name (n3 / name :op1 "MDA-MB-231"~e.30,32,34)) :op2 (c5 / cell-line :name (n4 / name :op1 "MCF-10A"~e.36,38))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.45 :op1 (f / figure~e.41 :mod "1B"~e.43) :op2 (f2 / figure~e.41 :mod "1C"~e.47)))) # ::id a_pmid_2139_2397.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok YB @-@ 1 has been identified as a direct substrate of Akt [ @ 12 , 35 @ ] . # ::alignments 0-1.1.1.1 2-1.1.1.1 5-1 6-1.2.r 8-1.2.2 9-1.2 10-1.2.1.r 11-1.2.1.1.1 14-1.3.1.1.1.1 18-1.3.1.1.1.2 (i / identify-01~e.5 :ARG1 (p / protein :name (n / name :op1 "YB-1"~e.0,2)) :ARG2~e.6 (s / substrate~e.9 :mod~e.10 (e / enzyme :name (n2 / name :op1 "Akt"~e.11)) :ARG1-of (d / direct-02~e.8)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 12~e.14 :op2 35~e.18))))) # ::id a_pmid_2139_2397.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As previously reported , IR can activate the Akt ligand independently [ @ 30 , 36 @ ] . # ::alignments 0-1.3.1.r 1-1.3.1 2-1.3 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1 6-1.1 8-1.1.2.1.1.1 9-1.1.2 10-1.1.3.1 13-1.2.1.1.1.1 17-1.2.1.1.1.2 (p / possible-01~e.5 :ARG1 (a / activate-01~e.6 :ARG0 (r2 / radiate-01~e.4 :ARG0-of~e.4 (i / ionize-01~e.4)) :ARG1 (l / ligand~e.9 :mod (e / enzyme :name (n3 / name :op1 "Akt"~e.8))) :manner (d2 / depend-01 :polarity -~e.10)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 30~e.13 :op2 36~e.17)))) :ARG1-of (r / report-01~e.2 :time~e.0 (p2 / previous~e.1))) # ::id a_pmid_2139_2397.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we asked whether IR could induce YB @-@ 1 phosphorylation as well . # ::alignments 0-1 2-1.1.2 3-1.1 4-1.1.1 4-1.1.1.r 5-1.1.3.1.1 5-1.1.3.1.1.1 5-1.1.3.1.1.1.r 6-1.1.3 7-1.1.3.1 8-1.1.3.1.2.1.1.1 10-1.1.3.1.2.1.1.1 11-1.1.3.1.2 12-1.1.3.1.3 13-1.1.3.1.3 (c / cause-01~e.0 :ARG1 (a / ask-01~e.3 :mode~e.4 interrogative~e.4 :ARG0 (w / we~e.2) :ARG1 (p3 / possible-01~e.6 :ARG1 (i / induce-01~e.7 :ARG0 (r / radiate-01~e.5 :ARG0-of~e.5 (i2 / ionize-01~e.5)) :ARG2 (p2 / phosphorylate-01~e.11 :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1"~e.8,10))) :mod (a2 / as-well~e.12,13))))) # ::id a_pmid_2139_2397.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 1D , IR induces YB @-@ 1 phosphorylation differentially . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 5-1.3.1.1 8-1.1 8-1.1.1 8-1.1.1.r 9-1 10-1.2.1.1.1 12-1.2.1.1.1 13-1.2 14-1.4 14-1.4.r (i / induce-01~e.9 :ARG0 (r / radiate-01~e.8 :ARG0-of~e.8 (i2 / ionize-01~e.8)) :ARG2 (p / phosphorylate-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"~e.10,12))) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "1D"~e.5)) :manner~e.14 (d / differential~e.14)) # ::id a_pmid_2139_2397.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A strong phosphorylation signal was observed in SKBr3 , whereas HBL100 showed moderate phosphorylation of YB @-@ 1 and phosphorylation in MCF @-@ 7 was weak . # ::alignments 1-1.1.1.2 2-1.1.1.1 3-1.1.1 5-1.1 6-1.1.1.3.r 7-1.1.1.3.1.1 9-1 10-1.2.1.1.1.1 11-1.2.1 12-1.2.1.2.2 13-1.2.1.2 14-1.2.1.2.1.r 15-1.2.1.2.1.1.1 17-1.2.1.2.1.1.1 18-1.2 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.1.1 23-1.2.2.1.1.1 25-1.2.2.2 (c / contrast-01~e.9 :ARG1 (o / observe-01~e.5 :ARG1 (s / signal-07~e.3 :ARG1 (p / phosphorylate-01~e.2) :mod (s2 / strong~e.1) :location~e.6 (c2 / cell-line :name (n / name :op1 "SKBr3"~e.7)))) :ARG2 (a / and~e.18 :op1 (s3 / show-01~e.11 :ARG0 (c3 / cell-line :name (n2 / name :op1 "HBL100"~e.10)) :ARG1 (p2 / phosphorylate-01~e.13 :ARG1~e.14 (p3 / protein :name (n3 / name :op1 "YB-1"~e.15,17)) :ARG1-of (m / moderate-03~e.12))) :op2 (p4 / phosphorylate-01~e.19 :location~e.20 (c4 / cell-line :name (n4 / name :op1 "MCF-7"~e.21,23)) :ARG1-of (w / weak-02~e.25)))) # ::id a_pmid_2139_2397.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in MDA @-@ MB @-@ 231 cells , a lack of IR @-@ induced YB @-@ 1 phosphorylation was observed . # ::alignments 0-1 3-1.1.1.2.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 8-1.1.1.2 11-1.1.1 12-1.1.1.1.r 13-1.1.1.1.2.1 13-1.1.1.1.2.1.1 13-1.1.1.1.2.1.1.r 15-1.1.1.1.2 16-1.1.1.1.1.1.1 18-1.1.1.1.1.1.1 19-1.1.1.1 21-1.1 (h / have-concession-91~e.0 :ARG1 (o / observe-01~e.21 :ARG1 (l / lack-01~e.11 :ARG1~e.12 (p / phosphorylate-01~e.19 :ARG1 (p2 / protein :name (n / name :op1 "YB-1"~e.16,18)) :ARG2-of (i / induce-01~e.15 :ARG0 (r / radiate-01~e.13 :ARG0-of~e.13 (i2 / ionize-01~e.13)))) :location (c / cell-line~e.8 :name (n3 / name :op1 "MDA-MB-231"~e.3,5,7))))) # ::id a_pmid_2139_2397.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this cell line , stimulation with the erbB1 ligand EGF , AREG or TGFα did not induce YB @-@ 1 phosphorylation , whereas strong phosphorylation at the indicated times after stimulation was observed in the cell lines SKBr3 , HBL100 and MCF @-@ 7 ( Figure 1D ) . # ::alignments 1-1.1.4.1 2-1.1.4 3-1.1.4 5-1.1.2 6-1.1.2.1.r 8-1.1.2.1.1.1 9-1.1.2.1 10-1.1.2.1.2.1.1.1.1 12-1.1.2.1.2.1.2.1.1 14-1.1.2.1.2.1.3.1.1 16-1.1.1 16-1.1.1.r 17-1.1 18-1.1.3.1.1.1 20-1.1.3.1.1.1 21-1.1.3 21-1.2.1 23-1 24-1.2.1.1 25-1.2.1 28-1.2.1.2.1 29-1.2.1.2 29-1.2.1.2.r 29-1.2.1.3.r 30-1.2.1.3 31-1.2.1.3.1 33-1.2 34-1.2.2.r 36-1.2.2.1 37-1.2.2.1 37-1.2.2.2 37-1.2.2.3 38-1.2.2.1.1.1 40-1.2.2.2.1.1 41-1.2.2 42-1.2.2.3.1.1 44-1.2.2.3.1.1 46-1.3.1 48-1.3.1.1 (c / contrast-01~e.23 :ARG1 (i / induce-01~e.17 :polarity~e.16 -~e.16 :ARG0 (s / stimulate-01~e.5 :ARG2~e.6 (l / ligand~e.9 :name (n / name :op1 "erbB1"~e.8) :ARG2-of (i2 / include-91 :ARG1 (a / and :op1 (p6 / protein :name (n2 / name :op1 "EGF"~e.10)) :op2 (p2 / protein :name (n3 / name :op1 "AREG"~e.12)) :op3 (p3 / protein :name (n4 / name :op1 "TGFα"~e.14)))))) :ARG2 (p / phosphorylate-01~e.21 :ARG1 (p4 / protein :name (n5 / name :op1 "YB-1"~e.18,20))) :location (c5 / cell-line~e.2,3 :mod (t2 / this~e.1))) :ARG2 (o / observe-01~e.33 :ARG1 (p5 / phosphorylate-01~e.21,25 :mod (s3 / strong~e.24) :time~e.29 (t / time~e.29 :ARG1-of (i3 / indicate-01~e.28)) :time~e.29 (a2 / after~e.30 :op1 s~e.31)) :location~e.34 (a3 / and~e.41 :op1 (c2 / cell-line~e.36,37 :name (n6 / name :op1 "SKBr3"~e.38)) :op2 (c3 / cell-line~e.37 :name (n7 / name :op1 "HBL100"~e.40)) :op3 (c4 / cell-line~e.37 :name (n8 / name :op1 "MCF-7"~e.42,44)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.46 :mod "1D"~e.48))) # ::id a_pmid_2139_2397.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the MCF @-@ 7 and HBL100 cell lines have K @-@ RAS @ _wt@ status , these cells presented high basal YB @-@ 1 phosphorylation . # ::alignments 0-1 2-1.2.1.1.1.1 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1.2.1.1 7-1.2.1.1 7-1.2.1.2 8-1.2.1.1 9-1.2 11-1.2.2.1.1.1 13-1.2.2.1.1.1 16-1.2.2.1.2 18-1.2.2 21-1.2.1.1 22-1.1 23-1.1.2.2 24-1.1.2.3 25-1.1.2.1.1.1 27-1.1.2.1.1.1 28-1.1.2 (h / have-concession-91~e.0 :ARG1 (p2 / present-01~e.22 :ARG0 a :ARG1 (p / phosphorylate-01~e.28 :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1"~e.25,27)) :ARG1-of (h3 / high-02~e.23) :mod (b / basal~e.24))) :ARG2 (h2 / have-03~e.9 :ARG0 (a / and~e.5 :op1 (c / cell-line~e.7,8,21 :name (n2 / name :op1 "MCF-7"~e.2,4)) :op2 (c2 / cell-line~e.7 :name (n3 / name :op1 "HBL100"~e.6))) :ARG1 (s / status~e.18 :mod (g / gene :name (n / name :op1 "K-RAS"~e.11,13) :mod (w / wild-type~e.16))))) # ::id a_pmid_2139_2397.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To prove whether the high basal phosphorylation status of YB @-@ 1 was due to stimulation by growth factors in the culture medium , P @-@ YB @-@ 1 was compared under serum supplementation and serum depletion in MCF @-@ 7 cells . # ::alignments 0-1.3.1 1-1.3 2-1.3.1.1 2-1.3.1.1.r 4-1.3.1.3.1.2 5-1.3.1.3.1.3 6-1.3.1.3.1 7-1.3.1.3 8-1.3.1.3.1.1.r 9-1.3.1.3.1.1.1.1 11-1.3.1.3.1.1.1.1 13-1.3.1 14-1.3.1 15-1.3.1.2 16-1.3.1.2.1.r 17-1.3.1.2.1 18-1.3.1.2.1 19-1.3.1.2.2.r 21-1.3.1.2.2.1 22-1.3.1.2.2 24-1.2.2 26-1.2.1.1 28-1.2.1.1 30-1 32-1.1.1.1 33-1.1.1 35-1.1.1.1 36-1.1.2 37-1.1.r 38-1.1.3.1.1 40-1.1.3.1.1 41-1.1.3 (c5 / compare-01~e.30 :ARG0~e.37 (a / and :op1 (s4 / supplement-01~e.33 :ARG1 (s5 / serum~e.32,35)) :op2 (d / deplete-01~e.36 :ARG1 s5) :location (c4 / cell-line~e.41 :name (n3 / name :op1 "MCF-7"~e.38,40))) :ARG1 (p4 / protein :name (n4 / name :op1 "YB-1"~e.26,28) :ARG3-of (p5 / phosphorylate-01~e.24)) :purpose (p2 / prove-01~e.1 :ARG1 (c / cause-01~e.0,13,14 :mode~e.2 interrogative~e.2 :ARG0 (s2 / stimulate-01~e.15 :ARG0~e.16 (g / growth-factor~e.17,18) :location~e.19 (m / medium~e.22 :mod (c2 / culture~e.21))) :ARG1 (s / status~e.7 :mod (p / phosphorylate-01~e.6 :ARG1~e.8 (p3 / protein :name (n / name :op1 "YB-1"~e.9,11)) :degree (h / high-02~e.4) :mod (b / basal~e.5)))))) # ::id a_pmid_2139_2397.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 1F , P @-@ YB @-@ 1 was markedly reduced when cells were incubated in serum @-@ free medium for 24 hours . # ::alignments 0-1.3.r 1-1.4 2-1.4.1.r 3-1.4.1 5-1.4.1.1 8-1.1.2 10-1.1.1.1 12-1.1.1.1 14-1.2 14-1.2.r 15-1 16-1.3.r 17-1.3.1 19-1.3 20-1.3.2.r 21-1.3.2.1.1 23-1.3.2.1 24-1.3.2 25-1.3.3.r 26-1.3.3.1 27-1.3.3.2 (r / reduce-01~e.15 :ARG1 (p / protein :name (n / name :op1 "YB-1"~e.10,12) :ARG3-of (p2 / phosphorylate-01~e.8)) :manner~e.14 (m / marked~e.14) :time~e.0,16 (i / incubate-01~e.19 :ARG1 (c / cell~e.17) :ARG2~e.20 (m2 / medium~e.24 :ARG1-of (f / free-04~e.23 :ARG2 (s / serum~e.21))) :duration~e.25 (t2 / temporal-quantity :quant 24~e.26 :unit (h2 / hour~e.27))) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f2 / figure~e.3 :mod "1F"~e.5))) # ::id a_pmid_2139_2397.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , serum depletion did not reduce basal YB @-@ 1 phosphorylation in K @-@ RAS @ _mt@ MDA @-@ MB @-@ 231 cells ( Figure 1F ) . # ::alignments 1-1 3-1.1.2.1 4-1.1.2 6-1.1.1 6-1.1.1.r 7-1.1 8-1.1.3.2 9-1.1.3.1.1.1 11-1.1.3.1.1.1 12-1.1.3 15-1.1.4.2.1.1 17-1.1.4.2.1.1 22-1.1.4.1.1 24-1.1.4.1.1 26-1.1.4.1.1 27-1.1.4 29-1.2.1 31-1.2.1.1 (c / contrast-01~e.1 :ARG2 (r / reduce-01~e.7 :polarity~e.6 -~e.6 :ARG0 (d / deplete-01~e.4 :ARG1 (s / serum~e.3)) :ARG1 (p / phosphorylate-01~e.12 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"~e.9,11)) :mod (b / basal~e.8)) :location (c2 / cell-line~e.27 :name (n3 / name :op1 "MDA-MB-231"~e.22,24,26) :mod (g / gene :name (n / name :op1 "K-RAS"~e.15,17) :ARG2-of (m / mutate-01)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod "1F"~e.31))) # ::id a_pmid_2139_2397.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutive phosphorylation of YB @-@ 1 in MDA @-@ MB @-@ 231 cells is K @-@ Ras @-@ dependent # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.3.r 7-1.1.3.1.1 9-1.1.3.1.1 11-1.1.3.1.1 12-1.1.3 14-1.2.1.1 16-1.2.1.1 18-1 (d / depend-01~e.18 :ARG0 (p / phosphorylate-01~e.1 :ARG1~e.2 (p2 / protein :name (n / name :op1 "YB-1"~e.3,5)) :mod (c / constitutive~e.0) :location~e.6 (c2 / cell-line~e.12 :name (n2 / name :op1 "MDA-MB-231"~e.7,9,11))) :ARG1 (e / enzyme :name (n3 / name :op1 "K-Ras"~e.14,16))) # ::id a_pmid_2139_2397.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MDA @-@ MB @-@ 231 cells are characterized by a point mutation at codon 13 in the K @-@ RAS @ gene [ @ 37 @ ] . # ::alignments 0-1.2.1.1 2-1.2.1.1 4-1.2.1.1 5-1.2 7-1 8-1.1.r 10-1.1.2 11-1.1 12-1.1.1.r 13-1.1.1 14-1.1.1.1 18-1.1.1.2.1.1 20-1.1.1.2.1.1 22-1.1.1.2 25-1.3.1.1.1 (c / characterize-01~e.7 :ARG0~e.8 (m / mutate-01~e.11 :ARG1~e.12 (c3 / codon~e.13 :mod 13~e.14 :part-of (g / gene~e.22 :name (n3 / name :op1 "K-RAS"~e.18,20))) :mod (p / point~e.10)) :ARG1 (c2 / cell-line~e.5 :name (n2 / name :op1 "MDA-MB-231"~e.0,2,4)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 37~e.25)))) # ::id a_pmid_2139_2397.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This mutation is responsible for the constitutive phosphorylation of ERK1 @/@ 2 [ @ 30 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 6-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.1.1 11-1.2.1.1.1 14-1.3.1.1.1 (r / responsible-01~e.3 :ARG0 (m / mutate-01~e.1 :mod (t / this~e.0)) :ARG1~e.4 (p / phosphorylate-01~e.7 :ARG1~e.8 (e / enzyme :name (n / name :op1 "ERK1/2"~e.9,11)) :mod (c / constitutive~e.6)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 30~e.14)))) # ::id a_pmid_2139_2397.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to ERK1 @/@ 2 phosphorylation , these cells also present a constitutive phosphorylation of YB @-@ 1 , which is not further modified after exposure to IR or stimulation with erbB1 ligands ( Figures 1D and 1E ) . # ::alignments 0-1.5.1 1-1.4 3-1.4.1.1.1.1 5-1.4.1.1.1.1 6-1.2 6-1.4.1 8-1.1.1 9-1.1 10-1.3 11-1 13-1.2.2 14-1.2 15-1.2.1.r 16-1.2.1.1.1 18-1.2.1.1.1 22-1.2.3.1 22-1.2.3.1.r 23-1.2.3.3 24-1.2.3 26-1.2.3.2.1 27-1.2.3.2.1.2.r 28-1.2.3.2.1.2 28-1.2.3.2.1.2.1 28-1.2.3.2.1.2.1.r 29-1.2.3.2 30-1.2.3.2.2 31-1.2.3.2.2.2.r 32-1.2.3.2.2.2.1.1 33-1.2.3.2.2.2 35-1.5.1.1 35-1.5.1.2 37-1.5.1.1.1 39-1.5.1 41-1.5.1.2.1 (p5 / present-01~e.11 :ARG0 (c / cell~e.9 :mod (t / this~e.8)) :ARG1 (p3 / phosphorylate-01~e.6,14 :ARG1~e.15 (p4 / protein :name (n2 / name :op1 "YB-1"~e.16,18)) :mod (c2 / constitutive~e.13) :ARG1-of (m / modify-01~e.24 :polarity~e.22 -~e.22 :ARG0 (o / or~e.29 :op1 (e2 / expose-01~e.26 :ARG1 c :ARG2~e.27 (r / radiate-01~e.28 :ARG0-of~e.28 (i / ionize-01~e.28))) :op2 (s / stimulate-01~e.30 :ARG1 c :ARG2~e.31 (l / ligand~e.33 :name (n4 / name :op1 "erbB1"~e.32)))) :degree (f3 / further~e.23))) :mod (a2 / also~e.10) :ARG1-of (a4 / add-02~e.1 :ARG2 (p / phosphorylate-01~e.6 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.3,5)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.0,39 :op1 (f / figure~e.35 :mod "1D"~e.37) :op2 (f2 / figure~e.35 :mod "1E"~e.41)))) # ::id a_pmid_2139_2397.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , we investigated whether the constitutive phosphorylation of YB @-@ 1 in MDA @-@ MB @-@ 231 cells is due to the described endogenous expression of mutated K @-@ RAS @ [ @ 37 @ ] . # ::alignments 0-1.1.2 2-1.1.1 3-1.1 4-1.1.2.1 4-1.1.2.1.r 6-1.1.2.3.3 7-1.1.2.3 8-1.1.2.3.1.r 9-1.1.2.3.1.1.1 11-1.1.2.3.1.1.1 12-1.1.2.3.2.r 13-1.1.2.3.2.1.1 15-1.1.2.3.2.1.1 17-1.1.2.3.2.1.1 18-1.1.2.3.2 20-1 21-1 23-1.1.2.2.2 23-1.2 24-1.1.2.2.3 25-1.1.2.2 26-1.1.2.2.1.r 27-1.1.2.2.1.2 29-1.1.2.2.1.1.1 31-1.1.2.2.1.1.1 35-1.2.1.1.1 (c / cause-01~e.20,21 :ARG1 (i / investigate-01~e.3 :ARG0 (w / we~e.2) :ARG1 (c2 / cause-01~e.0 :mode~e.4 interrogative~e.4 :ARG0 (e2 / express-03~e.25 :ARG2~e.26 (g / gene :name (n / name :op1 "K-RAS"~e.29,31) :ARG2-of (m2 / mutate-01~e.27)) :ARG1-of (d / describe-01~e.23) :mod (m / monocot~e.24)) :ARG1 (p / phosphorylate-01~e.7 :ARG1~e.8 (p2 / protein :name (n2 / name :op1 "YB-1"~e.9,11)) :location~e.12 (c3 / cell-line~e.18 :name (n3 / name :op1 "MDA-MB-231"~e.13,15,17)) :mod (c4 / constitutive~e.6)))) :ARG1-of (d2 / describe-01~e.23 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 37~e.35)))) # ::id a_pmid_2139_2397.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , K @-@ Ras expression was downregulated by siRNA , and the level of P @-@ YB @-@ 1 was investigated . # ::alignments 0-1 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1 7-1.1.1 8-1.1.1.2.r 9-1.1.1.2.1.1 11-1.1 13-1.1.2.1 14-1.1.2.1.1.r 15-1.1.2.1.1.2 17-1.1.2.1.1.1.1 19-1.1.2.1.1.1.1 21-1.1.2 (c / cause-01~e.0 :ARG1 (a / and~e.11 :op1 (d / downregulate-01~e.7 :ARG1 (e2 / express-03~e.5 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras"~e.2,4))) :ARG2~e.8 (n4 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.9))) :op2 (i / investigate-01~e.21 :ARG1 (l / level~e.13 :quant-of~e.14 (p / protein :name (n3 / name :op1 "YB-1"~e.17,19) :ARG3-of (p2 / phosphorylate-01~e.15)))))) # ::id a_pmid_2139_2397.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using a similar approach , we analyzed the effect of ERK1 on YB @-@ 1 phosphorylation downstream of mutated K @-@ Ras . # ::alignments 0-1.3 2-1.3.1.1 3-1.3.1 5-1.1 6-1 8-1.2 9-1.2.1.r 10-1.2.1.1.1 11-1.2.2.r 12-1.2.2.1.1.1 14-1.2.2.1.1.1 15-1.2.2 16-1.2.2.2.2 18-1.2.2.2.1.2 19-1.2.2.2.1.1.1 21-1.2.2.2.1.1.1 (a4 / analyze-01~e.6 :ARG0 (w / we~e.5) :ARG1 (a3 / affect-01~e.8 :ARG0~e.9 (e2 / enzyme :name (n2 / name :op1 "ERK1"~e.10)) :ARG1~e.11 (p / phosphorylate-01~e.15 :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1"~e.12,14)) :location (r2 / relative-position :op1 (e / enzyme :name (n / name :op1 "K-Ras"~e.19,21) :ARG2-of (m / mutate-01~e.18)) :direction (d / downstream~e.16)))) :manner (u / use-01~e.0 :ARG1 (a / approach-02~e.3 :ARG1-of (r / resemble-01~e.2)))) # ::id a_pmid_2139_2397.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 2A , K @-@ RAS @ siRNA led to a strong reduction in P @-@ ERK1 @/@ 2 and P @-@ YB @-@ 1 ( Figure 2A ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 5-1.3.1.1 9-1.1.2.1.1.1 13-1.1.1.1 14-1 15-1.2.r 17-1.2.2 18-1.2 19-1.2.1.r 20-1.2.1.1 20-1.2.1.1.2 20-1.2.1.1.2.r 20-1.2.1.2.2 22-1.2.1.1.1.1 24-1.2.1.1.1.1 25-1.2.1 26-1.2.1.1 26-1.2.1.1.2 26-1.2.1.1.2.r 26-1.2.1.2.2 28-1.2.1.2.1.1 30-1.2.1.2.1.1 32-1.3.1 34-1.3.1.1 (l / lead-03~e.14 :ARG0 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.13) :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n / name :op1 "K-Ras"~e.9)))) :ARG2~e.15 (r2 / reduce-01~e.18 :ARG1~e.19 (a / and~e.25 :op1 (e3 / enzyme~e.20,26 :name (n3 / name :op1 "ERK1/2"~e.22,24) :ARG1-of~e.20,26 (p / phosphorylate-01~e.20,26)) :op2 (p2 / protein :name (n4 / name :op1 "YB-1"~e.28,30) :ARG3-of (p3 / phosphorylate-01~e.20,26))) :mod (s / strong~e.17)) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f / figure~e.3,32 :mod "2A"~e.5,34))) # ::id a_pmid_2139_2397.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Yet , ERK1 @/@ 2 and YB @-@ 1 protein levels were not affected . # ::alignments 2-1.1.2.1.1.1.1 4-1.1.2.1.1.1.1 5-1.1.2 6-1.1.2.2.1.1.1 8-1.1.2.2.1.1.1 9-1.1.2.2.1 10-1.1.2.1 10-1.1.2.2 12-1.1.1 12-1.1.1.r 13-1.1 (h / have-concession-91 :ARG1 (a / affect-01~e.13 :polarity~e.12 -~e.12 :ARG1 (a2 / and~e.5 :op1 (l / level~e.10 :quant-of (e / enzyme :name (n / name :op1 "ERK1/2"~e.2,4))) :op2 (l2 / level~e.10 :quant-of (p / protein~e.9 :name (n2 / name :op1 "YB-1"~e.6,8)))))) # ::id a_pmid_2139_2397.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , a marked reduction of P @-@ YB @-@ 1 was observed when ERK1 was targeted with siRNA . # ::alignments 0-1.2 3-1.1.3 4-1.1 5-1.1.1.r 6-1.1.1.2 8-1.1.1.1.1 10-1.1.1.1.1 12-1 13-1.1.2.r 14-1.1.2.1.1.1 16-1.1.2 17-1.1.2.2.r 18-1.1.2.2.1.1 (o / observe-01~e.12 :ARG1 (r / reduce-01~e.4 :ARG1~e.5 (p / protein :name (n / name :op1 "YB-1"~e.8,10) :ARG3-of (p2 / phosphorylate-01~e.6)) :time~e.13 (t / target-01~e.16 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1"~e.14)) :ARG2~e.17 (n4 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.18))) :degree (m / marked~e.3)) :manner (l / likewise~e.0)) # ::id a_pmid_2139_2397.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The role of stimulated ERK1 @/@ 2 phosphorylation on YB @-@ 1 phosphorylation was further supported by the results when a MEK inhibitor was used . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.2 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1 7-1.2.2 8-1.2.2.1.r 9-1.2.2.1.1.1 11-1.2.2.1.1.1 12-1.2.1 14-1.3 15-1 16-1.1.r 18-1.1 18-1.1.1 18-1.1.1.r 19-1.4.r 21-1.4.1.1.1.1.1 22-1.4.1 22-1.4.1.1 22-1.4.1.1.r 24-1.4 (s / support-01~e.15 :ARG0~e.16 (t2 / thing~e.18 :ARG2-of~e.18 (r2 / result-01~e.18)) :ARG1 (r / role~e.1 :poss~e.2 (p / phosphorylate-01~e.7,12 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.4,6)) :ARG1-of (s2 / stimulate-01~e.3)) :topic (p2 / phosphorylate-01~e.7 :ARG1~e.8 (p3 / protein :name (n3 / name :op1 "YB-1"~e.9,11)))) :degree (f / further~e.14) :time~e.19 (u / use-01~e.24 :ARG1 (m / molecular-physical-entity~e.22 :ARG0-of~e.22 (i / inhibit-01~e.22 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"~e.21)))))) # ::id a_pmid_2139_2397.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 2B , pretreatment of MDA @-@ MB @-@ 231 cells with the MEK inhibitor PD98059 markedly blocked YB @-@ 1 phosphorylation . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 5-1.4.1.1 8-1.1 9-1.1.1.r 10-1.1.1.1.1 12-1.1.1.1.1 14-1.1.1.1.1 15-1.1.1 16-1.1.2.r 18-1.1.2.2.1.1.1 19-1.1.2 19-1.1.2.2 19-1.1.2.2.r 20-1.1.2.1.1 21-1.3 22-1 23-1.2.1.1.1 25-1.2.1.1.1 26-1.2 (b / block-01~e.22 :ARG0 (p2 / pretreat-01~e.8 :ARG1~e.9 (c / cell-line~e.15 :name (n2 / name :op1 "MDA-MB-231"~e.10,12,14)) :ARG3~e.16 (s2 / small-molecule~e.19 :name (n3 / name :op1 "PD98059"~e.20) :ARG0-of~e.19 (i2 / inhibit-01~e.19 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"~e.18))))) :ARG1 (p / phosphorylate-01~e.26 :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1"~e.23,25))) :degree (m2 / marked~e.21) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "2B"~e.5))) # ::id a_pmid_2139_2397.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to the data shown in Figure 1D , exposure to IR did not induce YB @-@ 1 phosphorylation . # ::alignments 0-1.4 1-1.4.1.r 3-1.4.1 4-1.5 5-1.5.1.r 6-1.5.1 8-1.5.1.1 11-1.2 12-1.2.1.r 13-1.2.1 13-1.2.1.1 13-1.2.1.1.r 15-1.1 15-1.1.r 16-1 17-1.3.1.1.1 19-1.3.1.1.1 20-1.3 (i2 / induce-01~e.16 :polarity~e.15 -~e.15 :ARG0 (e / expose-01~e.11 :ARG2~e.12 (r2 / radiate-01~e.13 :ARG0-of~e.13 (i / ionize-01~e.13))) :ARG2 (p / phosphorylate-01~e.20 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"~e.17,19))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (d / data~e.3)) :ARG1-of (s / show-01~e.4 :ARG0~e.5 (f / figure~e.6 :mod "1D"~e.8))) # ::id a_pmid_2139_2397.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicates that the constitutive YB @-@ 1 phosphorylation in MDA @-@ MB @-@ 231 cells is a consequence of mutated K @-@ Ras @-@ mediated ERK1 @/@ 2 phosphorylation . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1.2 6-1.2.1.1.2.1 8-1.2.1.1.2.1 9-1.2.1 10-1.2.1.3.r 11-1.2.1.3.2.1 13-1.2.1.3.2.1 15-1.2.1.3.2.1 16-1.2.1.3 17-1.2.1.r 19-1.2 19-1.2.2 19-1.2.2.r 20-1.2.2.1.r 21-1.2.2.1.2.1.3 22-1.2.2.1.2.1.2.1 24-1.2.2.1.2.1.2.1 26-1.2.2.1.2 27-1.2.2.1.1.2.1 29-1.2.2.1.1.2.1 30-1.2.2.1 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (c / consequence~e.19 :domain~e.17 (p / phosphorylate-01~e.9 :ARG1 (p2 / protein :wiki "Y_box_binding_protein_1" :name (n / name :op1 "YB-1"~e.6,8)) :mod (c2 / constitutive~e.5) :location~e.10 (c3 / cell-line~e.16 :wiki - :name (n2 / name :op1 "MDA-MB-231"~e.11,13,15))) :ARG1-of~e.19 (c4 / cause-01~e.19 :ARG0~e.20 (p3 / phosphorylate-01~e.30 :ARG1 (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n3 / name :op1 "ERK1/2"~e.27,29)) :ARG1-of (m / mediate-01~e.26 :ARG0 (e2 / enzyme :wiki "KRAS" :name (n4 / name :op1 "K-Ras"~e.22,24) :ARG2-of (m2 / mutate-01~e.21))))))) # ::id a_pmid_2139_2397.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of mutated K @-@ RAS @ ^V12@ enhances basal YB @-@ 1 phosphorylation # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 4-1.1.1.1.1 6-1.1.1.1.1 9-1.1.1.2.1 11-1 12-1.2.2 13-1.2.1.1.1 15-1.2.1.1.1 16-1.2 (e2 / enhance-01~e.11 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (g / gene :name (n / name :op1 "K-RAS"~e.4,6) :ARG2-of (m / mutate-01~e.2 :value "V12"~e.9))) :ARG1 (p / phosphorylate-01~e.16 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"~e.13,15)) :mod (b / basal~e.12))) # ::id a_pmid_2139_2397.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the role of K @-@ Ras in the constitutive phosphorylation of YB @-@ 1 , we further analyzed the status of K @-@ RAS @ in SKBr3 , MCF @-@ 7 and HBL100 cells . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.2.r 5-1.4.2.2.1.1 7-1.4.2.2.1.1 8-1.4.2.1.r 10-1.4.2.1.2 11-1.4.2.1 12-1.4.2.1.1.r 13-1.4.2.1.1.1.1 15-1.4.2.1.1.1.1 17-1.1 18-1.3 19-1 21-1.2 24-1.2.2.1.1 26-1.2.2.1.1 28-1.2.1.r 29-1.2.1.1.1.1 31-1.2.1.2.1.1 33-1.2.1.2.1.1 34-1.2.1 35-1.2.1.3.1.1 36-1.2.1.1 36-1.2.1.2 36-1.2.1.3 (a / analyze-01~e.19 :ARG0 (w / we~e.17) :ARG1 (s / status~e.21 :location~e.28 (a2 / and~e.34 :op1 (c / cell-line~e.36 :name (n2 / name :op1 "SKBr3"~e.29)) :op2 (c2 / cell-line~e.36 :name (n3 / name :op1 "MCF-7"~e.31,33)) :op3 (c3 / cell-line~e.36 :name (n4 / name :op1 "HBL100"~e.35))) :poss (g / gene :name (n6 / name :op1 "K-RAS"~e.24,26))) :degree (f / further~e.18) :purpose (i / investigate-01~e.1 :ARG0 w :ARG1 (r / role~e.3 :topic~e.8 (p / phosphorylate-01~e.11 :ARG1~e.12 (p2 / protein :name (n5 / name :op1 "YB-1"~e.13,15)) :mod (c4 / constitutive~e.10)) :poss~e.4 (e / enzyme :name (n / name :op1 "K-Ras"~e.5,7))))) # ::id a_pmid_2139_2397.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sequencing of the K @-@ RAS @ gene revealed that none of these cell lines presents a K @-@ RAS @ point mutation in codon 12 , codon 13 or 61 . # ::alignments 0-1.1 4-1.1.1.1.1 6-1.1.1.1.1 8-1.1.1 9-1 10-1.2.r 11-1.2.1.1 12-1.2.1.1.r 13-1.2.1.2 14-1.2.1 15-1.2.1 16-1.2 19-1.2.2.1 20-1.2.2.1 21-1.2.2.1 23-1.2.2.2 24-1.2.2 25-1.2.2.3.r 26-1.2.2.3.1 27-1.2.2.3.1.1 29-1.2.2.3.2 29-1.2.2.3.3 30-1.2.2.3.2.1 31-1.2.2.3 32-1.2.2.3.3.1 (r / reveal-01~e.9 :ARG0 (s / sequence-01~e.0 :ARG1 (g / gene~e.8 :name (n2 / name :op1 "K-RAS"~e.4,6))) :ARG1~e.10 (p / present-01~e.16 :ARG0 (c / cell-line~e.14,15 :quant~e.12 (n3 / none~e.11) :mod (t / this~e.13)) :ARG1 (m / mutate-01~e.24 :ARG1 g~e.19,20,21 :mod (p2 / point~e.23) :location~e.25 (o / or~e.31 :op1 (c2 / codon~e.26 :mod 12~e.27) :op2 (c3 / codon~e.29 :mod 13~e.30) :op3 (c4 / codon~e.29 :mod 61~e.32))))) # ::id a_pmid_2139_2397.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate whether mutated K @-@ RAS @ ^V12@ could upregulate YB @-@ 1 phosphorylation , we introduced mutated K @-@ RAS @ into K @-@ RAS @ _wt , SKBr3 and MCF @-@ 7 cells . # ::alignments 1-1.4 2-1.4.2.1 2-1.4.2.1.r 3-1.4.2.2.2.2 5-1.4.2.2.2.1.1 7-1.4.2.2.2.1.1 10-1.4.2.2.2.2.1 12-1.4.2 13-1.4.2.2 14-1.4.2.2.1.1.1.1 16-1.4.2.2.1.1.1.1 17-1.4.2.2.1 19-1.1 20-1 21-1.2 23-1.3.3.1.1 23-1.4.2.2.2.1.1 25-1.3.3.1.1 25-1.4.2.2.2.1.1 29-1.3.3.1.1 29-1.4.2.2.2.1.1 31-1.3.3.1.1 31-1.4.2.2.2.1.1 34-1.3.3.2 37-1.3.1.1.1 38-1.3 39-1.3.2.1.1 41-1.3.2.1.1 42-1.3.1 42-1.3.2 (i / introduce-02~e.20 :ARG0 (w / we~e.19) :ARG1 g~e.21 :ARG2 (a / and~e.38 :op1 (c / cell-line~e.42 :name (n4 / name :op1 "SKBr3"~e.37)) :op2 (c2 / cell-line~e.42 :name (n5 / name :op1 "MCF-7"~e.39,41)) :mod (g2 / gene :name (n3 / name :op1 "K-RAS"~e.23,25,29,31) :mod (w2 / wild-type~e.34))) :purpose (i2 / investigate-01~e.1 :ARG0 w :ARG1 (p3 / possible-01~e.12 :mode~e.2 interrogative~e.2 :ARG1 (u / upregulate-01~e.13 :ARG1 (p2 / phosphorylate-01~e.17 :ARG1 (p / protein :name (n2 / name :op1 "YB-1"~e.14,16))) :ARG2 (g / gene :name (n / name :op1 "K-RAS"~e.5,7,23,25,29,31) :ARG2-of (m / mutate-01~e.3 :value "V12"~e.10)))))) # ::id a_pmid_2139_2397.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were transiently transfected with either a control pEGFP @-@ C1 vector ( indicated as con . @-@ vector ) or a vector expressing mutated K @-@ RAS , pEGFP @-@ C1/ @ K @-@ RAS @ ^V12@ ( indicated as K @-@ RAS @ ^V12 ) . # ::alignments 0-1.1 2-1.3 3-1 7-1.2.1.2 8-1.2.1.1.1 8-1.2.2.1.1 10-1.2.1.1.1 10-1.2.2.1.1 11-1.2.1 11-1.2.1.3.1 11-1.2.1.3.1.1.1 11-1.2.2.3.1 13-1.2.1.3 13-1.2.2.3 18-1.2.1.3.1.1.1 18-1.2.2 20-1.2 22-1.2.1.3.1.1.1 22-1.2.2 23-1.2.2.2 24-1.2.2.2.1.2 26-1.2.2.2.1.1.1 28-1.2.2.2.1.1.1 31-1.2.2.1.1 35-1.2.2.1.1 35-1.2.2.2.1.1.1 35-1.2.2.3.1.1.1 37-1.2.2.2.1.1.1 43-1.2.1.3 46-1.2.2.1.1 46-1.2.2.2.1.1.1 46-1.2.2.3.1.1.1 48-1.2.2.2.1.1.1 (t / transfect-01~e.3 :ARG1 (c / cell~e.0) :ARG2 (o / or~e.20 :op1 (v / vector~e.11 :name (n2 / name :op1 "pEGFP-C1"~e.8,10) :mod (c2 / control~e.7) :ARG1-of (i / indicate-01~e.13,43 :ARG0 (v4 / vector~e.11 :name (n5 / name :op1 "con.-vector"~e.11,18,22)))) :op2 (v2 / vector~e.18,22 :name (n4 / name :op1 "pEGFP-C1/K-RASV12"~e.8,10,31,35,46) :ARG3-of (e2 / express-03~e.23 :ARG1 (g / gene :name (n / name :op1 "K-RAS"~e.26,28,35,37,46,48) :ARG2-of (m / mutate-01~e.24))) :ARG1-of (i2 / indicate-01~e.13 :ARG0 (v3 / vector~e.11 :name (n3 / name :op1 "K-RASV12"~e.35,46))))) :ARG1-of (t2 / transient-02~e.2)) # ::id a_pmid_2139_2397.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fluorescence images of living cells transfected with con . @-@ vector and K @-@ RAS @ ^V12@ revealed that GFP in K @-@ RAS @ ^V12@ vector @-@ transfected cells was localized to the plasma membrane , but that in con . @-@ vector @-@ transfected cells it was not ( Figure 3A ) . # ::alignments 0-1.3 1-1.1 3-1.1.1.1.1 4-1.1.1.1 4-1.1.1.2 4-1.2.1.3 5-1.1.1.2.2 10-1.1.1.2.2.1 13-1.1.1.2.2.1.1.1 20-1 21-1.2.r 22-1.2.1.1.1.1 25-1.1.1.2.2.1.1.1 32-1.2.2.3.1 33-1.2.2.3.1 34-1.2.2.3.1 35-1.2.2.3 37-1.2.1 37-1.2.2 38-1.2.1.2.r 40-1.2.1.2.1 41-1.2.1.2 43-1.2 49-1.2.2.3.1 50-1.2.2.3.1 51-1.2.2.3.1 52-1.2.2.3 55-1.2.2.1 55-1.2.2.1.r 57-1.4.1 59-1.4.1.1 (r / reveal-01~e.20 :ARG0 (i / image-101~e.1 :ARG1 (a / and :op1 (c / cell~e.4 :ARG0-of (l / live-01~e.3) :ARG1-of (t / transfect-01 :ARG2 (v / vector :name (n2 / name :op1 "con.-vector")))) :op2 (c3 / cell~e.4 :ARG0-of l :ARG1-of (t2 / transfect-01~e.5 :ARG2 (v2 / vector~e.10 :name (n / name :op1 "K-RASV12"~e.13,25)))))) :ARG1~e.21 (c2 / contrast-01~e.43 :ARG1 (l2 / localize-01~e.37 :ARG1 (p / protein :name (n3 / name :op1 "GFP"~e.22)) :location~e.38 (m / membrane~e.41 :mod (p2 / plasma~e.40)) :location (c4 / cell~e.4 :ARG2-of t2)) :ARG2 (l3 / localize-01~e.37 :polarity~e.55 -~e.55 :ARG1 p :location (c5 / cell~e.35,52 :ARG2-of t~e.32,33,34,49,50,51) :location m)) :mod (f / fluorescence~e.0) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.57 :mod "3A"~e.59))) # ::id a_pmid_2139_2397.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is due to posttranslational modification and membrane association of K @-@ Ras ( Figure 3A ) . # ::alignments 0-1.2 2-1 3-1 4-1.1.1.1.1.1.r 4-1.1.1.2 4-1.1.1.2.1 4-1.1.1.2.1.r 4-1.1.1.r 5-1.1.1 6-1.1 7-1.1.2.2 8-1.1.2 9-1.1.1.1.r 10-1.1.1.1.1.1 12-1.1.1.1.1.1 14-1.3.1 16-1.3.1.1 (c / cause-01~e.2,3 :ARG0 (a / and~e.6 :op1~e.4 (m / modify-01~e.5 :ARG1~e.9 (e / enzyme :name (n / name :op1~e.4 "K-Ras"~e.10,12)) :time (a2 / after~e.4 :op1~e.4 (t2 / translate-02~e.4 :ARG1 e))) :op2 (a3 / associate-01~e.8 :ARG1 e :ARG2 (m2 / membrane~e.7))) :ARG1 (t / this~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "3A"~e.16))) # ::id a_pmid_2139_2397.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In con . @-@ vector @-@ transfected cells , GFP expression was not accumulated at the cell membrane , but rather it was equally distributed throughout the cytoplasm . # ::alignments 4-1.2.3.2.1.1 4-1.2.3.2.1.1.1.1 6-1.2.3.2.1 7-1.2.3.2 9-1.2.3.1.1.1 10-1.2.3 12-1.2.1 12-1.2.1.r 13-1.2 14-1.2.2.r 16-1.2.2.1 17-1.2.2 20-1 20-1.1.3 21-1.1.1 23-1.1.4 24-1.1 27-1.1.2 (i / instead-of-91~e.20 :ARG1 (d / distribute-01~e.24 :ARG1 e~e.21 :location (c / cytoplasm~e.27) :mod (r / rather~e.20) :ARG1-of (e2 / equal-01~e.23)) :ARG2 (a / accumulate-01~e.13 :polarity~e.12 -~e.12 :ARG0~e.14 (m / membrane~e.17 :part-of c2~e.16) :ARG1 (e / express-03~e.10 :ARG2 (p / protein :name (n / name :op1 "GFP"~e.9)) :ARG3 (c2 / cell~e.7 :ARG1-of (t / transfect-01~e.6 :ARG2 (v / vector~e.4 :name (n2 / name :op1 "con.-vector"~e.4))))))) # ::id a_pmid_2139_2397.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The efficiency of transfection was verified by immunoblotting as well ( Figure 3B ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 5-1 6-1.4.r 7-1.4 8-1.2 9-1.2 11-1.3.1 13-1.3.1.1 (v / verify-01~e.5 :ARG1 (e / efficient-01~e.1 :ARG1~e.2 (t / transfect-01~e.3)) :mod (a / as-well~e.8,9) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "3B"~e.13)) :manner~e.6 (i / immunoblot-01~e.7)) # ::id a_pmid_2139_2397.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In cells transfected with K @-@ RAS @ ^V12@ vector , the expression of K @-@ Ras ( 21 kDa ) resulted in a shift of GFP from 27 kDa to 48 kDa ( Figure 3B ) . # ::alignments 1-1.1.2 2-1.1.2.1 5-1.1.2.1.1.1.1 12-1.1.2.1.1 15-1.1 17-1.1.1.1.1 17-1.1.2.1.1.1.1 19-1.1.1.1.1 21-1.1.1.2.1 22-1.1.1.2.2 24-1 25-1.2.r 27-1.2 28-1.2.1.r 29-1.2.1.1.1 30-1.2.3.r 31-1.2.3.1 32-1.1.1.2.2 33-1.2.2.r 34-1.2.2.1 35-1.2.2.2 37-1.3.1 39-1.3.1.1 (r / result-01~e.24 :ARG1 (e2 / express-03~e.15 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras"~e.17,19) :quant (m2 / mass-quantity :quant 21~e.21 :unit (k / kilodalton~e.22,32))) :ARG3 (c / cell~e.1 :ARG1-of (t / transfect-01~e.2 :ARG2 (v / vector~e.12 :name (n2 / name :op1 "K-RASV12"~e.5,17))))) :ARG2~e.25 (s / shift-01~e.27 :ARG1~e.28 (p / protein :name (n3 / name :op1 "GFP"~e.29)) :ARG2~e.33 (m4 / mass-quantity :quant 48~e.34 :unit k~e.35) :ARG3~e.30 (m3 / mass-quantity :quant 27~e.31 :unit k)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.37 :mod "3B"~e.39))) # ::id a_pmid_2139_2397.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression of GFP @-@ tagged K @-@ Ras with a molecular weight of 48 kDa was further confirmed by stripping the anti @-@ GFP antibody from the membrane and reincubating the blots with a K @-@ Ras antibody . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2.1.1.1 5-1.1.1.2 6-1.1.1.1.1 8-1.1.1.1.1 11-1.1.1.3.1 12-1.1.1.3 13-1.1.1.3.2.r 14-1.1.1.3.2.1 15-1.1.1.3.2.2 17-1.2 18-1 19-1.3.r 20-1.3.1 22-1.3.1.1.1 22-1.3.2.2.1 24-1.1.1.2.1.1.1 25-1.3.1.1 25-1.3.2.2 26-1.3.1.2.r 28-1.3.1.2 29-1.3 32-1.3.2.1 35-1.1.1.1.1 37-1.1.1.1.1 38-1.3.1.1 (c / confirm-01~e.18 :ARG1 (e2 / express-03~e.1 :ARG2~e.2 (e / enzyme :name (n / name :op1 "K-Ras"~e.6,8,35,37) :ARG1-of (t / tag-01~e.5 :ARG2 (p / protein :name (n2 / name :op1 "GFP"~e.3,24))) :mod (w / weight~e.12 :mod (m / molecule~e.11) :quant~e.13 (m2 / mass-quantity :quant 48~e.14 :unit (k / kilodalton~e.15))))) :degree (f / further~e.17) :manner~e.19 (a2 / and~e.29 :op1 (s / strip-01~e.20 :ARG1 (a3 / antibody~e.25,38 :ARG0-of (c2 / counter-01~e.22 :ARG1 p)) :ARG2~e.26 (m3 / membrane~e.28)) :op2 (i / incubate-01 :ARG1 (b / blot~e.32) :ARG2 (a4 / antibody~e.25 :ARG0-of (c3 / counter-01~e.22 :ARG1 e)) :mod (a5 / again)))) # ::id a_pmid_2139_2397.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In line with our observations of MDA @-@ MB @-@ 231 cells , exogenous expression of K @-@ RAS @ ^V12@ in K @-@ RAS @ _wt , SKBr3 and MCF @-@ 7 cells resulted in markedly enhanced basal phosphorylation of YB @-@ 1 at S102 ( Figure 3B ) , which prevents further enhancement of phosphorylation by IR ( Figure 3C ) . # ::alignments 1-1.3.1.2 3-1.3.1.1 3-1.3.1.1.r 4-1.3.1 6-1.3.1.2.1.1 8-1.3.1.2.1.1 10-1.3.1.2.1.1 11-1.3.1.2 13-1.1.3 14-1.1 17-1.1.1.1.1 17-1.1.2.3.1.1 19-1.1.1.1.1 19-1.1.2.3.1.1 22-1.1.1.2.1 26-1.1.1.1.1 26-1.1.2.3.1.1 28-1.1.1.1.1 28-1.1.2.3.1.1 31-1.1.2.3.2 34-1.1.2.1.1.1 35-1.1.2 36-1.1.2.2.1.1 38-1.1.2.2.1.1 39-1.1.2.1 39-1.1.2.2 40-1 41-1.2.r 42-1.2.3.1 42-1.2.3.1.r 43-1.2.3 44-1.2.2 45-1.2 47-1.2.1.3.1.1 49-1.2.1.3.1.1 53-1.4.1 55-1.4.1.1 60-1.2.4 61-1.2.4.1.3 62-1.2.4.1 64-1.2 65-1.2.4.1.2.r 66-1.2.4.1.2 66-1.2.4.1.2.1 66-1.2.4.1.2.1.r 68-1.2.4.2.1 70-1.2.4.2.1.1 (r / result-01~e.40 :ARG1 (e2 / express-03~e.14 :ARG1 (g / gene :name (n / name :op1 "K-RAS"~e.17,19,26,28) :ARG2-of (m / mutate-01 :value "V12"~e.22)) :ARG3 (a / and~e.35 :op1 (c / cell-line~e.39 :name (n3 / name :op1 "SKBr3"~e.34)) :op2 (c2 / cell-line~e.39 :name (n4 / name :op1 "MCF-7"~e.36,38)) :mod (g2 / gene :name (n2 / name :op1 "K-RAS"~e.17,19,26,28) :mod (w / wild-type~e.31))) :mod (e3 / exogenous~e.13)) :ARG2~e.41 (p / phosphorylate-01~e.45,64 :ARG1 (a2 / amino-acid :mod 102 :name (n5 / name :op1 "serine") :part-of (p2 / protein :name (n6 / name :op1 "YB-1"~e.47,49))) :mod (b / basal~e.44) :ARG1-of (e5 / enhance-01~e.43 :manner~e.42 (m2 / marked~e.42)) :ARG0-of (p3 / prevent-01~e.60 :ARG1 (e6 / enhance-01~e.62 :ARG1 p :ARG2~e.65 (r3 / radiate-01~e.66 :ARG0-of~e.66 (i / ionize-01~e.66)) :degree (f2 / further~e.61)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.68 :mod "3C"~e.70)))) :ARG1-of (r2 / resemble-01 :ARG2 (o / observe-01~e.4 :ARG0~e.3 (w2 / we~e.3) :ARG1 (c3 / cell-line~e.1,11 :name (n7 / name :op1 "MDA-MB-231"~e.6,8,10)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.53 :mod "3B"~e.55))) # ::id a_pmid_2139_2397.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , these data support the hypothesis that in cells expressing mutated K @-@ RAS , the basal phosphorylation of YB @-@ 1 is constitutively enhanced and cannot be further stimulated by IR. # ::alignments 2-1.1.1.1 3-1.1.1 4-1.1 6-1.1.2 8-1.1.2.1.r 9-1.1.2.1.3 10-1.1.2.1.3.1 11-1.1.2.1.3.1.1.2 13-1.1.2.1.3.1.1.1.1 15-1.1.2.1.3.1.1.1.1 19-1.1.2.1.1.1.2 20-1.1.2.1.1.1 21-1.1.2.1.1.1.1.r 22-1.1.2.1.1.1.1.1.1 24-1.1.2.1.1.1.1.1.1 26-1.1.2.1.1.2 27-1.1.2.1.1 28-1.1.2.1 29-1.1.2.1.2 29-1.1.2.1.2.1 29-1.1.2.1.2.1.r 31-1.1.2.1.2.2.3 32-1.1.2.1.2.2 (i / infer-01 :ARG1 (s / support-01~e.4 :ARG0 (d / data~e.3 :mod (t2 / this~e.2)) :ARG1 (h2 / hypothesize-01~e.6 :ARG1~e.8 (a / and~e.28 :op1 (e2 / enhance-01~e.27 :ARG1 (p / phosphorylate-01~e.20 :ARG1~e.21 (p3 / protein :name (n2 / name :op1 "YB-1"~e.22,24)) :mod (b / basal~e.19)) :mod (c / constitutive~e.26)) :op2 (p2 / possible-01~e.29 :polarity~e.29 -~e.29 :ARG1 (s2 / stimulate-01~e.32 :ARG1 p :ARG2 (r / radiate-01 :ARG0-of (i2 / ionize-01)) :degree (f / further~e.31))) :location (c2 / cell~e.9 :ARG3-of (e3 / express-03~e.10 :ARG1 (g / gene :name (n / name :op1 "K-RAS"~e.13,15) :ARG2-of (m / mutate-01~e.11)))))))) # ::id a_pmid_2139_2397.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IR @-@ induced YB @-@ 1 phosphorylation is mediated by erbB1 @-@ dependent PI3K @/@ Akt and MAPK @/@ ERK pathways # ::alignments 0-1.2.2.1 0-1.2.2.1.1 0-1.2.2.1.1.r 2-1.2.2 3-1.2.1.1.1 5-1.2.1.1.1 6-1.2 8-1 9-1.1.r 10-1.1.3.1.1.1 12-1.1.3 13-1.1.1.1.1 16-1.1 17-1.1.2.1.1 19-1.1.2.1.1 20-1.1.1 20-1.1.2 (m / mediate-01~e.8 :ARG0~e.9 (a / and~e.16 :op1 (p2 / pathway~e.20 :name (n / name :op1 "PI3K/AKT"~e.13)) :op2 (p4 / pathway~e.20 :name (n4 / name :op1 "MAPK/ERK"~e.17,19)) :ARG0-of (d / depend-01~e.12 :ARG1 (p5 / protein :name (n5 / name :op1 "erbB1"~e.10)))) :ARG1 (p / phosphorylate-01~e.6 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"~e.3,5)) :ARG2-of (i / induce-01~e.2 :ARG0 (r / radiate-01~e.0 :ARG0-of~e.0 (i2 / ionize-01~e.0))))) # ::id a_pmid_2139_2397.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The phosphorylation of YB @-@ 1 at S102 in response to stimulation with EGF has been described as being dependent on p90 ribosomal S6 kinase [ @ 11 @ ] . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.3.1.1 5-1.1.1.3.1.1 8-1.1.2.r 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1 12-1.1.2.1.2.r 13-1.1.2.1.2.1.1 16-1 16-1.3 16-1.3.r 19-1.2 20-1.2.2.r 21-1.2.2.1.1 22-1.2.2.1.2 23-1.2.2.1.3 24-1.2.2.1.4 27-1.3.1.1.1 (d / describe-01~e.16 :ARG1 (p / phosphorylate-01~e.1 :ARG1~e.2 (a / amino-acid :mod 102 :name (n2 / name :op1 "serine") :part-of (p2 / protein :name (n / name :op1 "YB-1"~e.3,5))) :ARG2-of~e.8 (r / respond-01~e.9 :ARG1~e.10 (s / stimulate-01~e.11 :ARG1 p2 :ARG2~e.12 (p4 / protein :name (n3 / name :op1 "EGF"~e.13))))) :ARG2 (d2 / depend-01~e.19 :ARG0 p :ARG1~e.20 (e / enzyme :name (n5 / name :op1 "p90"~e.21 :op2 "ribosomal"~e.22 :op3 "S6"~e.23 :op4 "kinase"~e.24))) :ARG1-of~e.16 (d3 / describe-01~e.16 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 11~e.27)))) # ::id a_pmid_2139_2397.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In that study [ @ 11 @ ] , Stratford et al @ . showed that the stimulation of SUM149 breast cancer cells with serum , EGF and phorbol 12 @-@ myristate 13 @-@ acetate ( PMA ) leads to phosphorylation of YB @-@ 1 at S102 , which is dependent on the MAP kinase pathway [ @ 11 @ ] . # ::alignments 1-1.3.1 2-1.3 5-1.3.2.1.1.1 9-1.1.1.1.1 11-1.1 12-1.1.2.1 15-1 16-1.2.r 16-1.3.1 18-1.2.1 19-1.2.1.1.r 20-1.2.1.1.1.1 21-1.2.1.1.2.2.1 22-1.2.1.1.2.2.2 23-1.2.1.1 24-1.2.1.2.r 25-1.2.1.2.1 27-1.2.1.2.2.1.1 28-1.2.1.2 29-1.2.1.2.3.1.1 30-1.2.1.2.3.1.2 32-1.2.1.2.3.1.2 33-1.2.1.2.3.1.3 35-1.2.1.2.3.1.3 37-1.2.1.2.3.2.1.1.1 39-1.2 40-1.2.2.r 41-1.2.2 42-1.2.2.1.r 43-1.2.2.1.3.1.1 45-1.2.2.1.3.1.1 51-1.2.2.2 52-1.2.2.2.1.r 54-1.2.2.2.1.1.1 55-1.2.2.2.1.1.2 56-1.2.2.2.1 59-1.4 (s / show-01~e.15 :ARG0 (a / and~e.11 :op1 (p2 / person :name (n2 / name :op1 "Stratford"~e.9)) :op2 (p3 / person :mod (o / other~e.12))) :ARG1~e.16 (l / lead-03~e.39 :ARG0 (s2 / stimulate-01~e.18 :ARG1~e.19 (c / cell-line~e.23 :name (n3 / name :op1 "SUM149"~e.20) :source (d4 / disease :wiki "Breast_cancer" :name (n9 / name :op1 "breast"~e.21 :op2 "cancer"~e.22))) :ARG2~e.24 (a2 / and~e.28 :op1 (s3 / serum~e.25) :op2 (p7 / protein :name (n4 / name :op1 "EGF"~e.27)) :op3 (s5 / small-molecule :name (n5 / name :op1 "phorbol"~e.29 :op2 "12-myristate"~e.30,32 :op3 "13-acetate"~e.33,35) :ARG1-of (d2 / describe-01 :ARG2 (s6 / small-molecule :name (n6 / name :op1 "PMA"~e.37)))))) :ARG2~e.40 (p / phosphorylate-01~e.41 :ARG1~e.42 (a3 / amino-acid :mod 102 :name (n7 / name :op1 "serine") :part-of (p4 / protein :name (n / name :op1 "YB-1"~e.43,45))) :ARG0-of (d / depend-01~e.51 :ARG1~e.52 (p5 / pathway~e.56 :name (n8 / name :op1 "MAP"~e.54 :op2 "kinase"~e.55))))) :medium (s7 / study-01~e.2 :mod (t / that~e.1,16) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 11~e.5)))) :ARG1-of d3~e.59) # ::id a_pmid_2139_2397.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because we and others have shown that IR induces activation of erbB1 in a ligand @-@ independent manner [ @ 24 , 25 @ ] , we tested whether the IR @-@ induced YB @-@ 1 phosphorylation shown in Figure 1D could be blocked by erbB1 tyrosine kinase inhibitors . # ::alignments 0-1.3 1-1.3.1.1.1 2-1.3.1.1 3-1.3.1.1.2.1 5-1.3.1 7-1.2.2.1.2.1 7-1.2.2.1.2.1.1 7-1.2.2.1.2.1.1.r 8-1.2.2.1.2 8-1.3.1.2 9-1.3.1.2.2 14-1.3.1.2.3.3 16-1.3.1.2.3 16-1.3.1.2.3.1 16-1.3.1.2.3.1.r 17-1.3.1.2.3.r 20-1.3.1.3.1.1.1.1 24-1.3.1.3.1.2.1.1 28-1.1 29-1 30-1.2.1 30-1.2.1.r 32-1.2.2.1.2.1 32-1.2.2.1.2.1.1 32-1.2.2.1.2.1.1.r 34-1.2.2.1.2 35-1.2.2.1.1.1.1 37-1.2.2.1.1.1.1 38-1.2.2.1 39-1.2.2.1.3 40-1.2.2.1.3.1.r 41-1.2.2.1.3.1 43-1.2.2.1.3.1.1 45-1.2 47-1.2.2 50-1.2.2.2.1.1.1.2 51-1.2.2.2.1.1.1.3 52-1.2.2.2 52-1.2.2.2.1 52-1.2.2.2.1.r (t2 / test-01~e.29 :ARG0 (w / we~e.28) :ARG1 (p2 / possible-01~e.45 :mode~e.30 interrogative~e.30 :ARG1 (b / block-01~e.47 :ARG1 (p / phosphorylate-01~e.38 :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1"~e.35,37)) :ARG2-of (i2 / induce-01~e.8,34 :ARG0 (r / radiate-01~e.7,32 :ARG0-of~e.7,32 (i4 / ionize-01~e.7,32))) :ARG1-of (s / show-01~e.39 :medium~e.40 (f / figure~e.41 :mod "1D"~e.43))) :ARG3 (m3 / molecular-physical-entity~e.52 :ARG0-of~e.52 (i / inhibit-01~e.52 :ARG1 (e / enzyme :name (n4 / name :op1 "erB1" :op2 "tyrosine"~e.50 :op3 "kinase"~e.51)))))) :ARG1-of (c / cause-01~e.0 :ARG0 (s2 / show-01~e.5 :ARG0 (a / and~e.2 :op1 (w2 / we~e.1) :op2 (p5 / person :mod (o / other~e.3))) :ARG1 (i3 / induce-01~e.8 :ARG0 r :ARG2 (a2 / activate-01~e.9 :ARG1 e) :manner~e.17 (d / depend-01~e.16 :polarity~e.16 -~e.16 :ARG0 a2 :ARG1 (l / ligand~e.14))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 24~e.20)) :op2 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 25~e.24))))))) # ::id a_pmid_2139_2397.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this hypothesis , the effect of the erbB1 @-@ RTK inhibitor erlotinib on YB @-@ 1 phosphorylation was analyzed in whole cell extracts as well as in cytoplasmic and nuclear fractions . # ::alignments 1-1.3 2-1.3.1.2 3-1.3.1 3-1.3.1.1 3-1.3.1.1.r 6-1.1 7-1.1.1.r 9-1.1.1.2.1.1.1 11-1.1.1.2.1.1.1 12-1.1.1 12-1.1.1.2 12-1.1.1.2.r 13-1.1.1.1.1 14-1.1.2.r 15-1.1.2.1.1.1 17-1.1.2.1.1.1 18-1.1.2 20-1 21-1.2.r 22-1.2.1.1.1 23-1.2.1.1 24-1.2.1 25-1.2 26-1.2 27-1.2 29-1.2.2.1 30-1.2 31-1.2.3.1 32-1.2.2 32-1.2.3 (a / analyze-01~e.20 :ARG1 (a2 / affect-01~e.6 :ARG0~e.7 (s / small-molecule~e.12 :name (n / name :op1 "erlotinib"~e.13) :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (p3 / pathway :name (n4 / name :op1 "erbB1-RTK"~e.9,11)))) :ARG1~e.14 (p / phosphorylate-01~e.18 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"~e.15,17)))) :location~e.21 (a3 / and~e.25,26,27,30 :op1 (e / extract-01~e.24 :ARG1 (c / cell~e.23 :mod (w / whole~e.22))) :op2 (f / fraction~e.32 :part-of (c2 / cytoplasm~e.29)) :op3 (f2 / fraction~e.32 :part-of (n3 / nucleus~e.31))) :purpose (t3 / test-01~e.1 :ARG1 (t / thing~e.3 :ARG1-of~e.3 (h / hypothesize-01~e.3) :mod (t4 / this~e.2)))) # ::id a_pmid_2139_2397.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pretreatment of SKBr3 cells with erlotinib resulted in complete inhibition of YB @-@ 1 phosphorylation in whole cell extract ( Figure 4A ) as well as in cytoplasmic and nuclear fractions ( Figure 4B ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1 4-1.1.2.r 5-1.1.2.1.1 6-1 7-1.2.r 8-1.2.2 9-1.2 10-1.2.1.r 11-1.2.1.1.1.1 13-1.2.1.1.1.1 14-1.2.1 15-1.2.3.r 16-1.2.3.1.1.1 17-1.2.3.1.1 18-1.2.3.1 20-1.2.3.1.2.1 22-1.2.3.1.2.1.1 25-1.2.3 25-1.2.3.2 25-1.2.3.2.r 26-1.2.3.2 27-1.2.3.2 29-1.2.3.2.1.1 30-1.2.3.2 31-1.2.3.2.2.1 32-1.2.3.2.1 32-1.2.3.2.2 34-1.2.3.2.3.1 36-1.2.3.2.3.1.1 (r / result-01~e.6 :ARG1 (p3 / pretreat-01~e.0 :ARG1~e.1 (c / cell-line~e.3 :name (n / name :op1 "SKBr3"~e.2)) :ARG3~e.4 (s / small-molecule :name (n2 / name :op1 "erlotinib"~e.5))) :ARG2~e.7 (i / inhibit-01~e.9 :ARG1~e.10 (p / phosphorylate-01~e.14 :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1"~e.11,13))) :ARG1-of (c2 / complete-02~e.8) :location~e.15 (a / and~e.25 :op1 (e / extract-01~e.18 :ARG1 (c3 / cell~e.17 :mod (w / whole~e.16)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "4A"~e.22))) :op2~e.25 (a2 / and~e.25,26,27,30 :op1 (f2 / fraction~e.32 :part-of (c4 / cytoplasm~e.29)) :op2 (f3 / fraction~e.32 :part-of (n4 / nucleus~e.31)) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure~e.34 :mod "4B"~e.36)))))) # ::id a_pmid_2139_2397.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , erlotinib also blocked basal @- and radiation @-@ induced P @-@ Akt and P @-@ ERK1 @/@ 2 in these cells ( Figure 4A ) . # ::alignments 1-1.4 3-1.1.1.1 4-1.6 5-1 6-1.2.1.3 8-1.2.1 9-1.2.2.4.1 11-1.2.2.4 12-1.2.1.4 14-1.2.1.1.1.1 15-1.2.1 16-1.2.1.4 18-1.2.1.2.1.1.1 19-1.2.1.2 21-1.3.r 22-1.3.1 23-1.3 25-1.5.1 27-1.5.1.1 (b / block-01~e.5 :ARG0 (s / small-molecule :name (n / name :op1 "erlotinib"~e.3)) :ARG1 (a / and :op1 (a3 / and~e.8,15 :op1 (e / enzyme :name (n2 / name :op1 "Akt"~e.14)) :op2 (s2 / slash~e.19 :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1"~e.18)) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2"))) :mod (b2 / basal~e.6) :ARG1-of (p / phosphorylate-01~e.12,16)) :op2 (a4 / and :op1 e :op2 s2 :ARG1-of p :ARG2-of (i / induce-01~e.11 :ARG0 (r / radiate-01~e.9)))) :location~e.21 (c / cell~e.23 :mod (t / this~e.22)) :ARG1-of (e4 / expect-01~e.1) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "4A"~e.27)) :mod (a2 / also~e.4)) # ::id a_pmid_2139_2397.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To rule out off @-@ target effects of erlotinib , the efficacy of the highly specific erbB1 @-@ RTK inhibitor BIBX1382BS [ @ 38 @ ] on radiation @-@ induced YB @-@ 1 phosphorylation was tested in cytoplasmic and nuclear fractions . # ::alignments 1-1.3 2-1.3 3-1.3.1.2 5-1.3.1.2 6-1.3.1 7-1.3.1.1.r 8-1.3.1.1.2.1 14-1.1.1.5.1 15-1.1.1.5 16-1.1.1.3.1.2.1 18-1.1.1.3.1.2.1 19-1.1.1 19-1.1.1.3 19-1.1.1.3.r 20-1.1.1.2.1 23-1.1.1.4.1.1.1 27-1.1.2.2.1 29-1.1.2.2 30-1.1.2.1.2.1 32-1.1.2.1.2.1 33-1.1.2 35-1 36-1.2.r 37-1.2.1.1 38-1.2 39-1.2.2.1 40-1.2.1 40-1.2.2 (t2 / test-01~e.35 :ARG1 (e / efficient-01 :ARG1 (s3 / small-molecule~e.19 :wiki - :name (n2 / name :op1 "BIBX1382BS"~e.20) :ARG0-of~e.19 (i / inhibit-01~e.19 :ARG1 (e2 / enzyme :wiki - :name (n5 / name :op1 "erbB1-RTK"~e.16,18))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 38~e.23))) :ARG1-of (s / specific-02~e.15 :ARG1-of (h / high-02~e.14))) :ARG2 (p / phosphorylate-01~e.33 :ARG1 (p2 / protein :wiki "Y_box_binding_protein_1" :name (n / name :op1 "YB-1"~e.30,32)) :ARG2-of (i2 / induce-01~e.29 :ARG0 (r / radiate-01~e.27)))) :location~e.36 (a2 / and~e.38 :op1 (f / fraction~e.40 :part-of (c2 / cytoplasm~e.37)) :op2 (f2 / fraction~e.40 :mod (n3 / nucleus~e.39))) :purpose (r2 / rule-out-02~e.1,2 :ARG1 (a3 / affect-01~e.6 :ARG0~e.7 (s2 / small-molecule :wiki "Erlotinib" :name (n4 / name :op1 "erlotinib"~e.8)) :mod (o / off-target~e.3,5)))) # ::id a_pmid_2139_2397.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF was included as positive control . # ::alignments 0-1.1.1.1 2-1 3-1.2.r 4-1.2.1 5-1.2 (i / include-01~e.2 :ARG1 (p2 / protein :name (n / name :op1 "EGF"~e.0)) :condition~e.3 (c / control~e.5 :mod (p / positive~e.4))) # ::id a_pmid_2139_2397.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown at the bottom of Figure 4B , in both cytoplasmic and nuclear protein fractions treatment with BIBX1382BS resulted in a marked reduction of YB @-@ 1 phosphorylation stimulated by IR as well as EGF treatment . # ::alignments 1-1.3 2-1.3.1.r 4-1.3.1 5-1.3.1.1.r 6-1.3.1.1 8-1.3.1.1.1 12-1.4.3 13-1.4.1.1.1 14-1.4 15-1.4.2.1.1 16-1.4.1.1 16-1.4.2.1 17-1.4.1 17-1.4.2 18-1.1 19-1.1.1.r 20-1.1.1.1.1 21-1 22-1.2.r 24-1.2.2 25-1.2 26-1.2.1.r 27-1.2.1.1.1.1 29-1.2.1.1.1.1 30-1.2.1 31-1.2.3 32-1.2.3.1.r 33-1.2.3.1.1 33-1.2.3.1.1.1 33-1.2.3.1.1.1.r 34-1.2.3.1 35-1.2.3.1 36-1.2.3.1 37-1.2.3.1.2.1.1.1 38-1.2.3.1.2 (r / result-01~e.21 :ARG1 (t / treat-04~e.18 :ARG2~e.19 (s2 / small-molecule :name (n / name :op1 "BIBX1382BS"~e.20))) :ARG2~e.22 (r2 / reduce-01~e.25 :ARG1~e.26 (p / phosphorylate-01~e.30 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"~e.27,29))) :mod (m2 / marked~e.24) :ARG1-of (s / stimulate-01~e.31 :ARG0~e.32 (a / and~e.34,35,36 :op1 (r3 / radiate-01~e.33 :ARG0-of~e.33 (i / ionize-01~e.33)) :op2 (t2 / treat-04~e.38 :ARG2 (p5 / protein :name (n4 / name :op1 "EGF"~e.37)))))) :ARG1-of (s4 / show-01~e.1 :medium~e.2 (b / bottom~e.4 :mod~e.5 (f / figure~e.6 :mod "4B"~e.8))) :location (a2 / and~e.14 :op1 (f2 / fraction~e.17 :part-of (p3 / protein~e.16 :mod (c / cytoplasm~e.13))) :op2 (f3 / fraction~e.17 :part-of (p4 / protein~e.16 :mod (n5 / nucleus~e.15))) :mod (b2 / both~e.12))) # ::id a_pmid_2139_2397.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data indicate that erbB1 @-@ RTK activity is necessary for radiation @-@ induced YB @-@ 1 phosphorylation , and this is most likely due to activation of the PI3K @/@ Akt and MAPK @/@ ERK pathways . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.2.1.1.1 6-1.1.2.2.1.1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.2.1 13-1.1.2.1.2 14-1.1.2.1.1.1.1 16-1.1.2.1.1.1.1 17-1.1.2.1 20-1.1.1.1 22-1.2.2 23-1.2 24-1.2.1 25-1.2.1 26-1.1.2.2 26-1.2.1.1 27-1.2.1.1.1.r 29-1.2.1.1.1.1.1.1 32-1.2.1.1.1 33-1.2.1.1.1.2.1.1 35-1.2.1.1.1.2.1.1 36-1.1.2.2.1 36-1.2.1.1.1.1 36-1.2.1.1.1.2 (a2 / and :op1 (i / indicate-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0,20)) :ARG1~e.3 (n / need-01~e.9 :ARG0~e.10 (p / phosphorylate-01~e.17 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"~e.14,16)) :ARG2-of (i2 / induce-01~e.13 :ARG0 (r / radiate-01~e.11))) :ARG1 (a / activate-01~e.26 :ARG1 (p5 / pathway~e.36 :name (n5 / name :op1 "erbB1-RTK"~e.4,6))))) :op2 (l / likely-01~e.23 :ARG1 (c / cause-01~e.24,25 :ARG0 (a3 / activate-01~e.26 :ARG1~e.27 (a4 / and~e.32 :op1 (p2 / pathway~e.36 :name (n2 / name :op1 "PI3K/AKT"~e.29)) :op2 (p4 / pathway~e.36 :name (n4 / name :op1 "MAPK/ERK"~e.33,35)))) :ARG1 n) :degree (m / most~e.22))) # ::id a_pmid_2139_2397.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test the function of PI3K @/@ Akt and MAPK @/@ ERK pathways in YB @-@ 1 phosphorylation , we further investigated whether the inhibitors of PI3K , Akt and MAPK affect YB @-@ 1 phosphorylation in irradiated cells . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.1.r 5-1.4.2.1.1.1.1 7-1.4.2.1.1.1.1 8-1.4.2.1 9-1.4.2.1.2.1.1 11-1.4.2.1.2.1.1 12-1.4.2.1.1 12-1.4.2.1.2 13-1.4.2.2.r 14-1.4.2.2 15-1.4.2.2 16-1.4.2.2 17-1.4.2.2 19-1.1 20-1.3 21-1 22-1.2.1 22-1.2.1.r 24-1.2.2.1 24-1.2.2.1.1 24-1.2.2.1.1.r 24-1.2.2.2 24-1.2.2.2.1 24-1.2.2.2.1.r 24-1.2.2.3 24-1.2.2.3.1 24-1.2.2.3.1.r 25-1.2.2.1.1.1.r 26-1.2.2.1.1.1.1.1 28-1.2.2.2.1.1.1.1 29-1.2.2 30-1.2.2.3.1.1.1.1 31-1.2 32-1.2.3.1.1.1 34-1.2.3.1.1.1 35-1.2.3 36-1.2.4.r 37-1.2.4.1 38-1.2.4 (i2 / investigate-01~e.21 :ARG0 (w / we~e.19) :ARG1 (a / affect-01~e.31 :mode~e.22 interrogative~e.22 :ARG0 (a4 / and~e.29 :op1 (m / molecular-physical-entity~e.24 :ARG0-of~e.24 (i / inhibit-01~e.24 :ARG1~e.25 (e / enzyme :name (n3 / name :op1 "PI3K"~e.26)))) :op2 (m2 / molecular-physical-entity~e.24 :ARG0-of~e.24 (i4 / inhibit-01~e.24 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Akt"~e.28)))) :op3 (m3 / molecular-physical-entity~e.24 :ARG0-of~e.24 (i5 / inhibit-01~e.24 :ARG1 (p5 / protein-family :name (n5 / name :op1 "MAPK"~e.30))))) :ARG1 (p2 / phosphorylate-01~e.35 :ARG1 (p4 / protein :name (n6 / name :op1 "YB-1"~e.32,34))) :location~e.36 (c / cell~e.38 :ARG1-of (i3 / irradiate-01~e.37))) :degree (f / further~e.20) :purpose (t / test-01~e.1 :ARG0 w :ARG1 (f2 / function-01~e.3 :ARG0~e.4 (a3 / and~e.8 :op1 (p / pathway~e.12 :name (n / name :op1 "PI3K/Akt"~e.5,7)) :op2 (p3 / pathway~e.12 :name (n2 / name :op1 "MAPK/ERK"~e.9,11))) :ARG1~e.13 p2~e.14,15,16,17))) # ::id a_pmid_2139_2397.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The data shown in Figures 4C and 4D indicate that treatment with either of the inhibitors markedly reduced the phosphorylation of YB @-@ 1 at S102 . # ::alignments 1-1.1 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1 4-1.1.1.1.2 6-1.1.1.1.1.1 8-1.1.1.1 10-1.1.1.1.2.1 12-1 13-1.2.r 14-1.2.1 15-1.2.1.1.r 16-1.2.1.1.1 19-1.2.1.1 19-1.2.1.1.2 19-1.2.1.1.2.r 20-1.2.3 20-1.2.3.r 21-1.2 23-1.2.2 24-1.2.2.1.r 25-1.2.2.1.3.1.1 27-1.2.2.1.3.1.1 (i2 / indicate-01~e.12 :ARG0 (d / data~e.1 :ARG1-of (s2 / show-01~e.2 :medium~e.3 (a / and~e.8 :op1 (f / figure~e.4 :mod "4C"~e.6) :op2 (f2 / figure~e.4 :mod "4D"~e.10)))) :ARG1~e.13 (r / reduce-01~e.21 :ARG0 (t / treat-04~e.14 :ARG2~e.15 (m2 / molecular-physical-entity~e.19 :mod (e / either~e.16) :ARG0-of~e.19 (i / inhibit-01~e.19))) :ARG1 (p / phosphorylate-01~e.23 :ARG1~e.24 (a2 / amino-acid :mod 102 :name (n / name :op1 "serine") :part-of (p2 / protein :name (n2 / name :op1 "YB-1"~e.25,27)))) :manner~e.20 (m / marked~e.20))) # ::id a_pmid_2139_2397.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , optimal inhibition was observed when cells were treated with a combination of PI3K and MEK inhibitors . # ::alignments 0-1 2-1.1.1.1 3-1.1.1 3-1.1.2.2.1 3-1.1.2.2.1.1 3-1.1.2.2.1.1.r 5-1.1 6-1.1.2.r 7-1.1.2.1 9-1.1.2 10-1.1.2.2.r 12-1.1.2.2 13-1.1.2.2.1.1.1.r 14-1.1.2.2.1.1.1.1.1 16-1.1.2.2.2.1.1.1.1 17-1.1.1 17-1.1.2.2.2 17-1.1.2.2.2.1 17-1.1.2.2.2.1.r (h / have-concession-91~e.0 :ARG1 (o / observe-01~e.5 :ARG1 (i / inhibit-01~e.3,17 :mod (o2 / optimal~e.2)) :time~e.6 (t2 / treat-04~e.9 :ARG1 (c / cell~e.7) :ARG2~e.10 (c2 / combine-01~e.12 :ARG1 (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (i2 / inhibit-01~e.3 :ARG1~e.13 (p / protein-family :name (n2 / name :op1 "PI3K"~e.14)))) :ARG2 (m2 / molecular-physical-entity~e.17 :ARG0-of~e.17 (i3 / inhibit-01~e.17 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.16)))))))) # ::id a_pmid_2139_2397.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutive YB @-@ 1 phosphorylation due to K @-@ RAS @ mutation depends on erbB1 and downstream PI3K @/@ Akt and MAPK @/@ ERK pathways # ::alignments 0-1.1.2 1-1.1.1.1.1 3-1.1.1.1.1 4-1.1 5-1.1.3 6-1.1.3 8-1.1.3.1.1.1.1 10-1.1.3.1.1.1.1 12-1.1.3.1 13-1 14-1.2.r 15-1.2.1.1.1 16-1.2 17-1.2.2.2 18-1.2.2.1.1 21-1.2 22-1.2.3.1.1 24-1.2.3.1.1 25-1.2.2 25-1.2.3 (d / depend-01~e.13 :ARG0 (p / phosphorylate-01~e.4 :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"~e.1,3)) :mod (c / constitutive~e.0) :ARG1-of (c2 / cause-01~e.5,6 :ARG0 (m / mutate-01~e.12 :ARG1 (g / gene :name (n4 / name :op1 "K-RAS"~e.8,10))))) :ARG1~e.14 (a / and~e.16,21 :op1 (p4 / protein :name (n5 / name :op1 "erbB1"~e.15)) :op2 (p2 / pathway~e.25 :name (n2 / name :op1 "PI3K/AKT"~e.18) :location (d2 / downstream~e.17)) :op3 (p5 / pathway~e.25 :name (n6 / name :op1 "MAPK/ERK"~e.22,24) :location d2))) # ::id a_pmid_2139_2397.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As IR @-@ induced YB @-@ 1 phosphorylation was shown to be dependent on erbB1 , PI3K @/@ Akt and MAPK/ERK , we further investigated whether K @-@ RAS @ _mt@ -@ dependent constitutive phosphorylation of YB @-@ 1 might be sensitive to the inhibition of erbB1 , PI3K and MEK . # ::alignments 1-1.4.1.1.1.2.1 1-1.4.1.1.1.2.1.1 1-1.4.1.1.1.2.1.1.r 3-1.4.1.1.1.2 4-1.4.1.1.1.1 5-1.4.1.1.1.1 6-1.4.1.1.1.1 7-1.4.1.1.1 9-1.4.1 12-1.4.1.1 14-1.2.2.2.1.1.1.1 16-1.2.2.2.1.2.1.1 18-1.4.1.1.2.2.1.1 19-1.4.1.1.2 20-1.4.1.1.2.3.1.1 22-1.1 23-1.3 24-1 25-1.2.1 25-1.2.1.r 27-1.2.2.1.3.1.1.1 29-1.2.2.1.3.1.1.1 35-1.2.2.1.3 36-1.2.2.1.2 37-1.2.2.1 38-1.2.2.1.1.r 39-1.2.2.1.1.1.1 41-1.2.2.1.1.1.1 42-1.2 44-1.2.2 47-1.2.2.2 49-1.2.2.2.1.1.1.1 51-1.2.2.2.1.2.1.1 52-1.2.2.2.1 53-1.2.2.2.1.3.1.1 (i / investigate-01~e.24 :ARG0 (w / we~e.22) :ARG1 (p3 / possible-01~e.42 :mode~e.25 interrogative~e.25 :ARG1 (s / sensitive-03~e.44 :ARG0 (p / phosphorylate-01~e.37 :ARG1~e.38 (p4 / protein :name (n4 / name :op1 "YB-1"~e.39,41)) :mod (c / constitutive~e.36) :ARG0-of (d / depend-01~e.35 :ARG1 (g / gene :name (n2 / name :op1 "K-RAS"~e.27,29) :ARG1-of (m / mutate-01)))) :ARG1 (i2 / inhibit-01~e.47 :ARG1 (a / and~e.52 :op1 (p5 / protein :name (n5 / name :op1 "erbB1"~e.14,49)) :op2 (e / enzyme :name (n6 / name :op1 "PI3K"~e.16,51)) :op3 (e2 / enzyme :name (n3 / name :op1 "MEK"~e.53)))))) :degree (f / further~e.23) :ARG1-of (c2 / cause-01 :ARG0 (s2 / show-01~e.9 :ARG1 (d2 / depend-01~e.12 :ARG0 (p6 / phosphorylate-01~e.7 :ARG1 p4~e.4,5,6 :ARG2-of (i3 / induce-01~e.3 :ARG0 (r / radiate-01~e.1 :ARG0-of~e.1 (i4 / ionize-01~e.1)))) :ARG1 (a2 / and~e.19 :op1 p5 :op2 (p2 / pathway :name (n / name :op1 "PI3K/Akt"~e.18)) :op3 (p7 / pathway :name (n8 / name :op1 "MAPK/ERK"~e.20))))))) # ::id a_pmid_2139_2397.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To this end , K @-@ RAS @ _wt@ MCF @-@ 7 cells were transiently transfected with con . @-@ vector or K @-@ RAS @ ^V12@ vector , and 48 hours after transfection the cells were treated with the erbB1 inhibitor erlotinib , the PI3K inhibitor LY294002 or the MEK inhibitor PD98059 for 2 hours . # ::alignments 1-1.3 5-1.2.3.1 6-1.2.3.1 7-1.2.3.1 8-1.2.3.1 9-1.2.3.1 10-1.2.3.1 11-1.2.3.1 12-1.2.3.1 13-1.2.3.1 14-1.2.3.1 15-1.2.3.1 16-1.2.3.1 17-1.2.3.1 18-1.2.3.1 19-1.2.3.1 20-1.2.3.1 21-1.2.3.1 22-1.2.3.1 23-1.2.3.1 24-1.2.3.1 25-1.2.3.1 26-1.2.3.1 27-1.2.3.1 28-1.2.3.1 29-1.2.3.1 30-1.2.3.1 31-1.2.3.1 32-1.2.3.1 33-1.2.3.1 35-1 36-1.2.3.2.1 37-1.2.3.2.2 38-1.2.3 39-1.1 41-1.1.1 43-1.2 44-1.2.2.r 46-1.2.2.1.2.1.1.1 47-1.2.2.1 47-1.2.2.1.2 47-1.2.2.1.2.r 48-1.2.2.1.1.1 51-1.2.2.2.2.1.1.1 52-1.2.2.2 52-1.2.2.2.2 52-1.2.2.2.2.r 53-1.2.2.2.1.1 54-1.1.2 56-1.2.2.3.2.1.1.1 57-1.2.2.3 57-1.2.2.3.2 57-1.2.2.3.2.r 58-1.2.2.3.1.1 59-1.2.4.r 60-1.2.4.1 61-1.2.4.2 (a / and~e.35 :op1 (t4 / transfect-01~e.39 :ARG1 (c / cell-line~e.41 :name (n3 / name :op1 "MCF-7") :mod (g / gene :name (n / name :op1 "K-RAS") :mod (w / wild-type))) :ARG2 (o / or~e.54 :op1 (v2 / vector :name (n2 / name :op1 "con.-vector")) :op2 (v / vector :name (n4 / name :op1 "K-RASV12"))) :ARG1-of (t5 / transient-02)) :op2 (t / treat-04~e.43 :ARG1 c :ARG2~e.44 (a2 / and :op1 (s / small-molecule~e.47 :name (n5 / name :op1 "erlotinib"~e.48) :ARG0-of~e.47 (i / inhibit-01~e.47 :ARG1 (p / protein :name (n6 / name :op1 "erbB1"~e.46)))) :op2 (s3 / small-molecule~e.52 :name (n7 / name :op1 "LY294002"~e.53) :ARG0-of~e.52 (i2 / inhibit-01~e.52 :ARG1 (p2 / protein-family :name (n9 / name :op1 "PI3K"~e.51)))) :op3 (s2 / small-molecule~e.57 :name (n8 / name :op1 "PD98059"~e.58) :ARG0-of~e.57 (i3 / inhibit-01~e.57 :ARG1 (p3 / protein-family :name (n10 / name :op1 "MEK"~e.56))))) :time (a3 / after~e.38 :op1 t4~e.5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33 :quant (t2 / temporal-quantity :quant 48~e.36 :unit (h / hour~e.37))) :duration~e.59 (t3 / temporal-quantity :quant 2~e.60 :unit h~e.61)) :purpose (t6 / this~e.1)) # ::id a_pmid_2139_2397.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to the results shown in Figure 3 , overexpression of K @-@ RAS @ ^V12@ resulted in an about 2.5 @-@ fold stimulation of YB @-@ 1 phosphorylation . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1.1 4-1.3.1 4-1.3.1.2 4-1.3.1.2.r 5-1.3.1.2.1.r 6-1.3.1.2.1 8-1.3.1.2.1.1 11-1.1 14-1.1.1.1.1 16-1.1.1.1.1 19-1.1.1.2.1 21-1 21-1.3.1.1 22-1.2.r 24-1.2.2 25-1.2.2.1.1 27-1.2.2.1 28-1.2 29-1.2.1.r 29-1.2.2.1 30-1.2.1.1.1.1 32-1.2.1.1.1.1 33-1.2.1 (r2 / result-01~e.21 :ARG1 (o / overexpress-01~e.11 :ARG1 (g / gene :name (n2 / name :op1 "K-RAS"~e.14,16) :ARG2-of (m / mutate-01 :value "V12"~e.19))) :ARG2~e.22 (s / stimulate-01~e.28 :ARG1~e.29 (p / phosphorylate-01~e.33 :ARG1 (p2 / protein :name (n / name :op1 "YB-1"~e.30,32))) :degree (a / about~e.24 :op1 (p3 / product-of~e.27,29 :op1 2.5~e.25))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (t / thing~e.4 :ARG2-of (r3 / result-01~e.3,21) :ARG1-of~e.4 (s2 / show-01~e.4 :medium~e.5 (f / figure~e.6 :mod 3~e.8))))) # ::id a_pmid_2139_2397.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Erlotinib reduced mutated K @-@ RAS @ ^V12@ -@ induced YB @-@ 1 phosphorylation by about 50 % , while the PI3K inhibitor and the MEK inhibitor reduced K @-@ RAS @ ^V12@ -@ induced YB @-@ 1 phosphorylation to the control level . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.2.1.2 4-1.1.2.2.1.1.1 6-1.1.2.2.1.1.1 9-1.1.2.2.1.2.1 12-1.1.2.2 13-1.1.2.1.1.1 15-1.1.2.1.1.1 16-1.1.2 19-1.1.3.1 20-1.1.3 22-1 24-1.2.1.1.1.1.1.1 25-1.2.1.1 25-1.2.1.1.1 25-1.2.1.1.1.r 25-1.2.1.2 25-1.2.1.2.1 25-1.2.1.2.1.r 26-1.2.1 28-1.2.1.2.1.1.1.1 29-1.2.1.1 29-1.2.1.1.1 29-1.2.1.1.1.r 29-1.2.1.2 29-1.2.1.2.1 29-1.2.1.2.1.r 30-1.1 30-1.2 32-1.2.2 33-1.2.2 34-1.2.2 35-1.2.2 36-1.2.2 37-1.2.2 38-1.2.2 39-1.2.2 40-1.2.2 41-1.2.2 42-1.2.2 43-1.2.2 44-1.2.2 45-1.2.3.r 47-1.2.3.1 48-1.2.3 (c / contrast-01~e.22 :ARG1 (r / reduce-01~e.1,30 :ARG0 (s / small-molecule :name (n3 / name :op1 "erlotinib"~e.0)) :ARG1 (p2 / phosphorylate-01~e.16 :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1"~e.13,15)) :ARG2-of (i2 / induce-01~e.12 :ARG0 (g / gene :name (n / name :op1 "K-RAS"~e.4,6) :ARG2-of (m / mutate-01~e.2 :value "V12"~e.9)))) :ARG2 (p4 / percentage-entity~e.20 :value 50~e.19)) :ARG2 (r2 / reduce-01~e.30 :ARG0 (a / and~e.26 :op1 (m2 / molecular-physical-entity~e.25,29 :ARG0-of~e.25,29 (i / inhibit-01~e.25,29 :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K"~e.24)))) :op2 (m3 / molecular-physical-entity~e.25,29 :ARG0-of~e.25,29 (i3 / inhibit-01~e.25,29 :ARG1 (p5 / protein-family :name (n2 / name :op1 "MEK"~e.28))))) :ARG1 p2~e.32,33,34,35,36,37,38,39,40,41,42,43,44 :ARG4~e.45 (l / level~e.48 :mod (c2 / control~e.47)))) # ::id a_pmid_2139_2397.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the combination of PD98059 and LY294002 ( PD/LY ) blocked basal and K @-@ RAS @ ^V12@ -@ induced YB @-@ 1 phosphorylation completely ( Figure 5A ) . # ::alignments 0-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1.1.2.1.1 11-1.1 12-1.1.2.1.2 13-1.1.2 15-1.1.2.2.2.1.1.1 17-1.1.2.2.2.1.1.1 20-1.1.2.2.2.1.2.1 23-1.1.2.2.2 24-1.1.2.1.1.1.1 26-1.1.2.1.1.1.1 27-1.1.2.1 27-1.1.2.2 28-1.1.3 30-1.2.1 32-1.2.1.1 (h / have-concession-91~e.0 :ARG1 (b / block-01~e.11 :ARG0 (c / combine-01~e.3 :ARG1~e.4 (s / small-molecule :name (n2 / name :op1 "PD98059"~e.5)) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "LY294002"~e.7))) :ARG1 (a / and~e.13 :op1 (p / phosphorylate-01~e.27 :ARG1 (p2 / protein :name (n4 / name :op1 "YB-1"~e.24,26)) :mod (b2 / basal~e.12)) :op2 (p3 / phosphorylate-01~e.27 :ARG1 p2 :ARG2-of (i / induce-01~e.23 :ARG0 (g / gene :name (n / name :op1 "K-RAS"~e.15,17) :ARG2-of (m3 / mutate-01 :value "V12"~e.20))))) :ARG1-of (c2 / complete-02~e.28)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.30 :mod "5A"~e.32))) # ::id a_pmid_2139_2397.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data indicate that phosphorylation of YB @-@ 1 due to mutation of K @-@ RAS @ in part depends on activation of erbB1 . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1 5-1.2.1.1.r 6-1.2.1.1.1.1 8-1.2.1.1.1.1 9-1.2.1.2 10-1.2.1.2 11-1.2.1.2.1 14-1.2.1.2.1.1.1.1 16-1.2.1.2.1.1.1.1 18-1.2.3.r 19-1.2.3 19-1.2.3.r 20-1.2 21-1.2.2.r 22-1.2.2 23-1.2.2.1.r 24-1.2.2.1.1.1 (i / indicate-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (d2 / depend-01~e.20 :ARG0 (p / phosphorylate-01~e.4 :ARG1~e.5 (p2 / protein :name (n2 / name :op1 "YB-1"~e.6,8)) :ARG1-of (c / cause-01~e.9,10 :ARG0 (m / mutate-01~e.11 :ARG1 (g / gene :name (n / name :op1 "K-RAS"~e.14,16))))) :ARG1~e.21 (a / activate-01~e.22 :ARG1~e.23 (p3 / protein :name (n3 / name :op1 "erbB1"~e.24))) :degree~e.18,19 (p4 / part~e.19))) # ::id a_pmid_2139_2397.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is most likely mediated by autocrine production of ligands and is in part independent of erbB1 , but it is dependent on activation of the PI3K @/@ Akt and MAPK @/@ ERK pathways . # ::alignments 0-1.1.1.1.2 2-1.1.1.2 3-1.1.1 4-1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.2 7-1.1.1.1.1 8-1.1.1.1.1.1.r 9-1.1.1.1.1.1 10-1.1 12-1.1.2.4.r 13-1.1.2.4 13-1.1.2.4.r 14-1.1.2 14-1.1.2.1 14-1.1.2.1.r 15-1.1.2.3.r 16-1.1.2.3.1.1 18-1 19-1.2.1 21-1.2 22-1.2.2.r 23-1.2.2 24-1.2.2.1.r 26-1.2.2.1.1.1.1 28-1.2.2.1.1.1.1 29-1.2.2.1 30-1.2.2.1.2.1.1 32-1.2.2.1.2.1.1 33-1.2.2.1.1 33-1.2.2.1.2 (c / contrast-01~e.18 :ARG1 (a / and~e.10 :op1 (l / likely-01~e.3 :ARG1 (m2 / mediate-01~e.4 :ARG0~e.5 (p2 / produce-01~e.7 :ARG1~e.8 (l2 / ligand~e.9) :mod (a2 / autocrine~e.6)) :ARG1 (t / this~e.0)) :degree (m / most~e.2)) :op2 (d / depend-01~e.14 :polarity~e.14 -~e.14 :ARG0 t :ARG1~e.15 (p3 / protein :name (n2 / name :op1 "erbB1"~e.16)) :degree~e.12,13 (p5 / part~e.13))) :ARG2 (d2 / depend-01~e.21 :ARG0 t~e.19 :ARG1~e.22 (a3 / activate-01~e.23 :ARG1~e.24 (a4 / and~e.29 :op1 (p / pathway~e.33 :name (n / name :op1 "PI3K/Akt"~e.26,28)) :op2 (p4 / pathway~e.33 :name (n3 / name :op1 "MAPK/ERK"~e.30,32)))))) # ::id a_pmid_2139_2397.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because K @-@ Ras strongly induces YB @-@ 1 phosphorylation when it is mutated ( Figures 3 and 5A ) , we next analyzed whether phosphorylation of YB @-@ 1 in K @-@ RAS @ _wt@ cells after irradiation or stimulation with EGF depends on K @-@ Ras expression . # ::alignments 0-1.4 1-1.4.1.1 2-1.4.1.1 3-1.4.1.1 4-1.4.1.4 4-1.4.1.4.r 5-1.4.1 6-1.4.1.2 7-1.4.1.2 8-1.4.1.2 9-1.4.1.2 10-1.2.4.r 10-1.3.r 13-1.4.1.3 15-1.4.2.1.1 15-1.4.2.1.2 17-1.4.2.1.1.1 19-1.4.2.1 21-1.4.2.1.2.1 25-1.1 26-1.3 27-1 28-1.2.1 28-1.2.1.r 29-1.2.2 30-1.2.2.1.r 31-1.2.2.1.1.1 33-1.2.2.1.1.1 36-1.2.2.2.1.1.1 38-1.2.2.2.1.1.1 41-1.2.2.2.1.2 43-1.2.2.2 44-1.2.4 45-1.2.4.1.1 46-1.2.4.1 47-1.2.4.1.2 48-1.2.4.1.2.2.r 49-1.2.4.1.2.2.1.1 50-1.2 51-1.2.3.r 52-1.2.3.1.1.1 54-1.2.3.1.1.1 55-1.2.3 (a / analyze-01~e.27 :ARG0 (w / we~e.25) :ARG1 (d / depend-01~e.50 :mode~e.28 interrogative~e.28 :ARG0 (p / phosphorylate-01~e.29 :ARG1~e.30 (p2 / protein :name (n2 / name :op1 "YB-1"~e.31,33)) :location (c / cell~e.43 :mod (g / gene :name (n3 / name :op1 "K-RAS"~e.36,38) :mod (w2 / wild-type~e.41)))) :ARG1~e.51 (e2 / express-03~e.55 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras"~e.52,54))) :time~e.10 (a2 / after~e.44 :op1 (o / or~e.46 :op1 (i / irradiate-01~e.45 :ARG1 c) :op2 (s / stimulate-01~e.47 :ARG1 c :ARG2~e.48 (p3 / protein :name (n7 / name :op1 "EGF"~e.49)))))) :time~e.10 (n5 / next~e.26) :ARG1-of (c2 / cause-01~e.0 :ARG0 (i2 / induce-01~e.5 :ARG0 e~e.1,2,3 :ARG2 p~e.6,7,8,9 :condition (m / mutate-01~e.13 :ARG2 e) :manner~e.4 (s3 / strong~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.19 :op1 (f / figure~e.15 :mod 3~e.17) :op2 (f2 / figure~e.15 :mod "5A"~e.21))))) # ::id a_pmid_2139_2397.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , following downregulation of K @-@ Ras by siRNA , SKBr3 cells were irradiated or stimulated with EGF . # ::alignments 0-1 2-1.1.3 3-1.1.3.1 4-1.1.3.1.1.r 5-1.1.3.1.1.1.1 7-1.1.3.1.1.1.1 8-1.1.3.1.2.r 9-1.1.3.1.2.1.1 11-1.1.1.1.1.1 12-1.1.1.1 14-1.1.1 15-1.1 16-1.1.2 17-1.1.2.2.r 18-1.1.2.2.1.1 (i / infer-01~e.0 :ARG1 (o / or~e.15 :op1 (i2 / irradiate-01~e.14 :ARG1 (c / cell-line~e.12 :name (n2 / name :op1 "SKBr3"~e.11))) :op2 (s / stimulate-01~e.16 :ARG1 c :ARG2~e.17 (p / protein :name (n3 / name :op1 "EGF"~e.18))) :ARG1-of (f / follow-01~e.2 :ARG2 (d / downregulate-01~e.3 :ARG1~e.4 (e / enzyme :name (n / name :op1 "K-Ras"~e.5,7)) :ARG2~e.8 (n5 / nucleic-acid :name (n4 / name :op1 "siRNA"~e.9)))))) # ::id a_pmid_2139_2397.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 5B , downregulation of K @-@ Ras did not affect either IR @- or EGF @-@ induced YB @-@ 1 phosphorylation . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 5-1.4.1.1 8-1.2 9-1.2.1.r 10-1.2.1.1.1 12-1.2.1.1.1 14-1.1 14-1.1.r 15-1 17-1.3.1.2.1 17-1.3.1.2.1.1 17-1.3.1.2.1.1.r 19-1.3 20-1.3.2.2.1.1.1 22-1.3.1.2 22-1.3.2.2 23-1.3.1.1.1.1 25-1.3.1.1.1.1 26-1.3.1 26-1.3.2 (a / affect-01~e.15 :polarity~e.14 -~e.14 :ARG0 (d / downregulate-01~e.8 :ARG1~e.9 (e / enzyme :name (n / name :op1 "K-Ras"~e.10,12))) :ARG1 (o / or~e.19 :op1 (p / phosphorylate-01~e.26 :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"~e.23,25)) :ARG2-of (i / induce-01~e.22 :ARG0 (r / radiate-01~e.17 :ARG0-of~e.17 (i3 / ionize-01~e.17)))) :op2 (p3 / phosphorylate-01~e.26 :ARG1 p2 :ARG2-of (i2 / induce-01~e.22 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF"~e.20))))) :ARG1-of (s3 / show-01~e.1 :medium~e.2 (f / figure~e.3 :mod "5B"~e.5))) # ::id a_pmid_2139_2397.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A lack of effect of K @-@ RAS @ -@ siRNA on P @-@ ERK1 @/@ 2 was observed as well ( Figure 5B ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 6-1.1.1.1.2.1.1 8-1.1.1.1.2.1.1 11-1.1.1.1.1.1 12-1.1.1.2.r 13-1.1.1.2.3 15-1.1.1.2.1.1.1 16-1.1.1.2 19-1 20-1.2 21-1.2 23-1.3.1 25-1.3.1.1 (o / observe-01~e.19 :ARG1 (l / lack-01~e.1 :ARG1~e.2 (a / affect-01~e.3 :ARG0 (n / nucleic-acid :name (n2 / name :op1 "siRNA"~e.11) :mod (g / gene :name (n3 / name :op1 "K-RAS"~e.6,8))) :ARG1~e.12 (s / slash~e.16 :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1"~e.15)) :op2 (e4 / enzyme :name (n5 / name :op1 "ERK2")) :ARG1-of (p / phosphorylate-01~e.13)))) :manner (a2 / as-well~e.20,21) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "5B"~e.25))) # ::id a_pmid_2139_2397.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok YB @-@ 1 regulates repair of IR @-@ induced DNA @-@ DSB and postirradiation survival # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2.1 5-1.2.1.1.r 6-1.2.1.1.3.1 6-1.2.1.1.3.1.1 6-1.2.1.1.3.1.1.r 8-1.2.1.1.3 9-1.2.1.1.2.2.1 11-1.2.1.1.1.1 12-1.2 14-1.2.2 (r / regulate-01~e.3 :ARG0 (p / protein :name (n / name :op1 "YB-1"~e.0,2)) :ARG1 (a / and~e.12 :op1 (r2 / repair-01~e.4 :ARG1~e.5 (e / event :name (n2 / name :op1 "DSB"~e.11) :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.9)) :ARG2-of (i / induce-01~e.8 :ARG0 (r3 / radiate-01~e.6 :ARG0-of~e.6 (i3 / ionize-01~e.6))))) :op2 (s2 / survive-01~e.14 :time (a2 / after :op1 (i2 / irradiate-01))))) # ::id a_pmid_2139_2397.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to its function as a transcription factor , YB @-@ 1 is also involved in DNA repair , that is , base excision repair and mismatch repair [ @ 39 @ ] . # ::alignments 0-1.2.2.1 1-1.2.2.1 1-1.4 3-1.4.1.1 3-1.4.1.1.r 4-1.4.1 5-1.4.1.2.r 7-1.4.1.2.1 8-1.4.1.2 10-1.1.1.1 12-1.1.1.1 14-1.3 15-1 17-1.2.1.2.1 18-1.2 23-1.2.2.1.1.1.1 24-1.2.2.1.1.1.2 25-1.2.2.1.1.1.3 26-1.2.2.1 27-1.2.2.1.2.1.1 28-1.2.2.1.2.1.2 31-1.5.1.1.1 (i / involve-01~e.15 :ARG1 (p / protein :name (n / name :op1 "YB-1"~e.10,12)) :ARG2 (r / repair-01~e.18 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.17)) :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.0,1,26 :op1 (e / event :name (n2 / name :op1 "base"~e.23 :op2 "excision"~e.24 :op3 "repair"~e.25)) :op2 (e2 / event :name (n3 / name :op1 "mismatch"~e.27 :op2 "repair"~e.28))))) :mod (a / also~e.14) :ARG1-of (a2 / add-02~e.1 :ARG2 (f / function-01~e.4 :ARG0~e.3 p~e.3 :ARG1~e.5 (f2 / factor~e.8 :ARG0-of (t / transcribe-01~e.7)))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 39~e.31)))) # ::id a_pmid_2139_2397.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In line with this function , it has been demonstrated that YB @-@ 1 binds to double @-@ stranded , single @-@ stranded and DNA @-@ containing abasic sites [ @ 40 @ ] . # ::alignments 3-1.3.1.1 4-1.3.1 9-1 10-1.1.r 11-1.1.1.1.1 13-1.1.1.1.1 14-1.1 15-1.1.2.r 16-1.1.2.1.3.1 18-1.1.2.1.3 20-1.1.2.2.3.1 22-1.1.2.1.3 22-1.1.2.2.3 23-1.1.2 24-1.1.2.1.2.1 24-1.1.2.2.2.1 24-1.1.2.3.2.1.2.1 26-1.1.2.3.2 27-1.1.2.3.1.1 28-1.1.2.3.1.2 31-1.2.1.1.1 (d / demonstrate-01~e.9 :ARG1~e.10 (b / bind-01~e.14 :ARG1 (p / protein :name (n / name :op1 "YB-1"~e.11,13)) :ARG2~e.15 (a / and~e.23 :op1 (n2 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.24) :mod (s / strand~e.18,22 :mod (d3 / double~e.16))) :op2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.24) :mod (s2 / strand~e.22 :ARG1-of (s3 / single-02~e.20))) :op3 (d2 / dna-sequence :name (n3 / name :op1 "abasic"~e.27 :op2 "site"~e.28) :ARG0-of (c / contain-01~e.26 :ARG1 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA"~e.24)))))) :ARG1-of (d7 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 40~e.31))) :ARG1-of (r / resemble-01 :ARG2 (f / function~e.4 :mod (t / this~e.3)))) # ::id a_pmid_2139_2397.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok So far , however , no data demonstrating the function of YB @-@ 1 in repair of IR @-@ induced DNA @-@ DSB and postirradiation survival exist . # ::alignments 0-1.2 1-1.2 3-1 5-1.1.1.1 5-1.1.1.1.r 6-1.1.1 7-1.1.1.2 9-1.1.1.2.1 10-1.1.1.2.1.1.r 11-1.1.1.2.1.1.1.1 13-1.1.1.2.1.1.1.1 14-1.1.1.2.1.2.r 15-1.1.1.2.1.2.1 16-1.1.1.2.1.2.1.2.r 17-1.1.1.2.1.2.1.2.1 17-1.1.1.2.1.2.1.2.1.1 17-1.1.1.2.1.2.1.2.1.1.r 19-1.1.1.2.1.2.1.2 20-1.1.1.2.1.2.1.1.2.2.1 22-1.1.1.2.1.2.1.1.1.1 23-1.1.1.2.1.2 25-1.1.1.2.1.2.2 26-1.1 (h / have-concession-91~e.3 :ARG1 (e / exist-01~e.26 :ARG1 (d / data~e.6 :polarity~e.5 -~e.5 :ARG0-of (d2 / demonstrate-01~e.7 :ARG1 (f / function-01~e.9 :ARG0~e.10 (p / protein :name (n / name :op1 "YB-1"~e.11,13)) :ARG1~e.14 (a / and~e.23 :op1 (r / repair-01~e.15 :ARG1 (e2 / event :name (n2 / name :op1 "DSB"~e.22) :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.20))) :ARG2-of~e.16 (i / induce-01~e.19 :ARG0 (r2 / radiate-01~e.17 :ARG0-of~e.17 (i3 / ionize-01~e.17)))) :op2 (s3 / survive-01~e.25 :time (a2 / after :op1 (i2 / irradiate-01)))))))) :time (s / so-far~e.0,1)) # ::id a_pmid_2139_2397.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The function of erbB1 and its downstream pathways and the impact of mutated K @-@ RAS @ on repair of DNA @-@ DSB have been demonstrated previously [ @ 15 , 34 , 41 , 42 @ ] . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.1 5-1.1.1.1.2.1.r 6-1.1.1.1.2.2 7-1.1.1.1.2 8-1.1 8-1.1.1.1 10-1.1.2 12-1.1.2.1.2 14-1.1.2.1.1.1 16-1.1.2.1.1.1 19-1.1.2.2 20-1.1.2.2.1.r 21-1.1.2.2.1.2.2.1 23-1.1.2.2.1.1.1 24-1.1.2 26-1 27-1.2 30-1.3.1.1.1.1 34-1.3.1.2.1.1 38-1.3.1.3.1.1 42-1.3.1.4.1.1 (d / demonstrate-01~e.26 :ARG1 (a / and~e.8 :op1 (f / function-01~e.1 :ARG0~e.2 (a2 / and~e.4,8 :op1 (p2 / protein :name (n2 / name :op1 "erbB1"~e.3)) :op2 (p3 / pathway~e.7 :poss~e.5 p2~e.5 :location (d2 / downstream~e.6)))) :op2 (i / impact-01~e.10,24 :ARG0 (g / gene :name (n / name :op1 "K-RAS"~e.14,16) :ARG2-of (m / mutate-01~e.12)) :ARG1 (r / repair-01~e.19 :ARG1~e.20 (e / event :name (n3 / name :op1 "DSB"~e.23) :mod (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.21)))))) :time (p / previous~e.27) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and :op1 (p4 / publication :ARG1-of (c / cite-01 :ARG2 15~e.30)) :op2 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 34~e.34)) :op3 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 41~e.38)) :op4 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 42~e.42))))) # ::id a_pmid_2139_2397.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we next asked whether the cells presenting a differential pattern of basal @- and radiation @-@ induced YB @-@ 1 phosphorylation additionally exert a differential sensitivity to IR. # ::alignments 0-1 2-1.1.1 3-1.1.3 4-1.1 5-1.1.2.1 5-1.1.2.1.r 7-1.1.2.2 8-1.1.2.2.1 10-1.1.2.2.1.1.1 11-1.1.2.2.1.1 13-1.1.2.2.1.1.2.1.2 15-1.1.2.2.1.1.2 16-1.1.2.2.1.1.2.2.2.1 16-1.1.2.3.2 18-1.1.2.2.1.1.2.2.2 19-1.1.2.2.1.1.2.1.1.1.1 21-1.1.2.2.1.1.2.1.1.1.1 22-1.1.2.2.1.1.2.1 22-1.1.2.2.1.1.2.2 23-1.1.2.2.1.1.2 23-1.1.2.4 23-1.1.2.4.r 24-1.1.2 26-1.1.2.3.3 27-1.1.2.3 28-1 (c2 / cause-01~e.0,28 :ARG1 (a / ask-01~e.4 :ARG0 (w / we~e.2) :ARG1 (e / exert-01~e.24 :mode~e.5 interrogative~e.5 :ARG0 (c / cell~e.7 :ARG0-of (p2 / present-01~e.8 :ARG1 (p3 / pattern~e.11 :mod (d / differential~e.10) :topic (a3 / and~e.15,23 :op1 (p / phosphorylate-01~e.22 :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1"~e.19,21)) :mod (b / basal~e.13)) :op2 (p5 / phosphorylate-01~e.22 :ARG1 p4 :ARG2-of (i2 / induce-01~e.18 :ARG0 (r / radiate-01~e.16))))))) :ARG1 (s / sensitive-03~e.27 :ARG0 c :ARG1 (r2 / radiate-01~e.16 :ARG0-of (i / ionize-01)) :mod d~e.26) :manner~e.23 (a2 / additional~e.23)) :time (n / next~e.3))) # ::id a_pmid_2139_2397.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results obtained by clonogenic assay indicate a differential response in terms of postirradiation survival of the cell lines analyzed . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1 5-1.1.2.1 6-1 8-1.2.2 9-1.2 14-1.2.1 15-1.2.1.1.r 17-1.2.1.1 18-1.2.1.1 19-1.2.1.1.1 (i / indicate-01~e.6 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :ARG1-of (o / obtain-01~e.2 :manner~e.3 (a3 / assay-01~e.5 :mod (c2 / clonogenic~e.4)))) :ARG1 (r2 / respond-01~e.9 :ARG2 (s / survive-01~e.14 :ARG0~e.15 (c / cell-line~e.17,18 :ARG1-of (a2 / analyze-01~e.19)) :time (a / after :op1 (i2 / irradiate-01))) :ARG1-of (d / differ-02~e.8))) # ::id a_pmid_2139_2397.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The radiation dose , D @₃₇ , which is required to reduce cell survival to 37 % , is 1.95 Gy for SKBr3 , 1.65 Gy for MDA @-@ MB @-@ 23 , 1.35 Gy for MCF @-@ 7 and 1.10 Gy for HBL100 cells . # ::alignments 1-1.1.1 1-1.2.1 1-1.2.2 1-1.2.3 1-1.2.4 2-1.1 6-1.1.2.1.2.1 11-1.1.2 13-1.1.2.1 14-1.2.2.3 14-1.2.3.3 14-1.2.4.3 15-1.1.2.1.1 17-1.1.2.1.2.1 18-1.1.2.1.2 21-1.2.1.1 23-1.2.1.3.r 24-1.2.1.3.1.1 26-1.2.2.1 29-1.2.2.3.1.1 31-1.2.2.3.1.1 33-1.2.2.3.1.1 35-1.2.3.1 38-1.2.3.3.1.1 40-1.2.3.3.1.1 41-1.2 42-1.2.4.1 45-1.2.4.3.1.1 46-1.2.1.3 (e / equal-01 :ARG1 (d / dose-01~e.2 :ARG1 (r5 / radiate-01~e.1) :ARG1-of (r6 / require-01~e.11 :ARG0 (r7 / reduce-01~e.13 :ARG1 (s / survive-01~e.15 :ARG0 c) :ARG4 (p2 / percentage-entity~e.18 :value 37~e.6,17))) :ARG1-of (l / label-01 :ARG2 (s2 / string-entity :value "D37"))) :ARG2 (a / and~e.41 :op1 (r / radiation-quantity~e.1 :quant 1.95~e.21 :unit (g / gray) :location~e.23 (c / cell-line~e.46 :name (n / name :op1 "SKBr3"~e.24))) :op2 (r2 / radiation-quantity~e.1 :quant 1.65~e.26 :unit g :location (c2 / cell-line~e.14 :name (n2 / name :op1 "MDA-MB-23"~e.29,31,33))) :op3 (r3 / radiation-quantity~e.1 :quant 1.35~e.35 :unit g :location (c3 / cell-line~e.14 :name (n3 / name :op1 "MCF-7"~e.38,40))) :op4 (r4 / radiation-quantity~e.1 :quant 1.10~e.42 :unit g :location (c4 / cell-line~e.14 :name (n4 / name :op1 "HBL100"~e.45))))) # ::id a_pmid_2139_2397.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We further investigated whether YB @-@ 1 activity is involved in the process of DNA @-@ DSB repair and postirradiation survival . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.1.r 4-1.2.2.1.1.1 6-1.2.2.1.1.1 7-1.2.2 9-1.2 10-1.2.3.r 12-1.2.3.1 13-1.2.3.1.1.r 14-1.2.3.1.1.1.2.2.1 16-1.2.3.1.1.1.1.1 17-1.2.3.1.1 18-1.2.3 20-1.2.3.2 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (i2 / involve-01~e.9 :mode~e.3 interrogative~e.3 :ARG1 (a / activity-06~e.7 :ARG0 (p / protein :name (n / name :op1 "YB-1"~e.4,6))) :ARG2~e.10 (a2 / and~e.18 :op1 (p2 / process-02~e.12 :ARG1~e.13 (r / repair-01~e.17 :ARG1 (e / event :name (n2 / name :op1 "DSB"~e.16) :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.14))))) :op2 (s / survive-01~e.20 :time (a3 / after :op1 (i3 / irradiate-01))))) :degree (f / further~e.1)) # ::id a_pmid_2139_2397.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For this purpose , a siRNA approach was used . # ::alignments 1-1.2 2-1.2.r 5-1.1.1.1.1 6-1.1 8-1 8-1.2.r (u / use-01~e.8 :ARG1 (a / approach-02~e.6 :mod (n2 / nucleic-acid :name (n / name :op1 "siRNA"~e.5))) :purpose~e.2,8 (t / this~e.1)) # ::id a_pmid_2139_2397.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 6 , downregulation of YB @-@ 1 by siRNA , either in K @-@ RAS @ _mt@ MDA @-@ MB @-@ 231 or in K @-@ RAS @ _wt@ SKBr3 cells , resulted in impaired repair of DNA @-@ DSB as shown by enhanced residual γ-H2AX foci 24 hours after irradiation . # ::alignments 0-1.4.2.r 1-1.3 2-1.3.1.r 3-1.3.1 5-1.3.1.1 8-1.1 9-1.1.1.r 10-1.1.1.1.1 12-1.1.1.1.1 13-1.1.2.r 14-1.1.2.1.1 19-1.1.3.1.2.1.1 19-1.1.3.2.2.1.1 21-1.1.3.1.2.1.1 21-1.1.3.2.2.1.1 26-1.1.3.1.1.1 28-1.1.3.1.1.1 30-1.1.3.1.1.1 31-1.1.3 34-1.1.3.1.2.1.1 34-1.1.3.2.2.1.1 36-1.1.3.1.2.1.1 36-1.1.3.2.2.1.1 39-1.1.3.2.2.2 41-1.1.3.2.1.1 42-1.1.3.1 42-1.1.3.2 44-1 45-1.2.r 46-1.2.2 47-1.2 48-1.2.1.r 49-1.2.1.2.2.1 51-1.2.1.1.1 52-1.4.2.r 53-1.4 54-1.4.1.r 55-1.4.1.3 56-1.4.1.2 57-1.4.1.1.1.1 58-1.4.1 59-1.4.2.2.1 60-1.4.2.2.2 61-1.4.2 62-1.4.2.1 (r / result-01~e.44 :ARG1 (d / downregulate-01~e.8 :ARG1~e.9 (p / protein :name (n2 / name :op1 "YB-1"~e.10,12)) :ARG2~e.13 (n11 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.14)) :location (o / or~e.31 :op1 (c / cell-line~e.42 :name (n4 / name :op1 "MDA-MB-231"~e.26,28,30) :mod (g / gene :name (n6 / name :op1 "K-RAS"~e.19,21,34,36) :ARG2-of (m / mutate-01))) :op2 (c2 / cell-line~e.42 :name (n5 / name :op1 "SKBr3"~e.41) :mod (g2 / gene :name (n7 / name :op1 "K-RAS"~e.19,21,34,36) :mod (w / wild-type~e.39))))) :ARG2~e.45 (r4 / repair-01~e.47 :ARG1~e.48 (e2 / event :name (n8 / name :op1 "DSB"~e.51) :mod (n / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA"~e.49))) :ARG1-of (i / impair-01~e.46)) :ARG1-of (s2 / show-01~e.1 :medium~e.2 (f2 / figure~e.3 :mod 6~e.5)) :ARG1-of (s / show-01~e.53 :ARG0~e.54 (f / focus~e.58 :mod (p2 / protein :name (n9 / name :op1 "γ-H2AX"~e.57)) :mod (r3 / residual~e.56) :ARG1-of (e3 / enhance-01~e.55)) :time~e.0,52 (a / after~e.61 :op1 (i2 / irradiate-01~e.62) :quant (t / temporal-quantity :quant 24~e.59 :unit (h / hour~e.60))))) # ::id a_pmid_2139_2397.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , downregulating K @-@ Ras resulted in enhanced frequency of residual DSB to the level observed with YB @-@ 1 siRNA . # ::alignments 0-1.3 2-1.1 3-1.1.1.1.1 5-1.1.1.1.1 6-1 8-1.2.2 9-1.2 11-1.2.1.2 12-1.2.1.1.1 13-1.2.2.1.r 15-1.2.2.1 16-1.2.2.1.1 17-1.2.2.1.1.1.r 18-1.2.2.1.1.1.2.1.1 20-1.2.2.1.1.1.2.1.1 21-1.2.2.1.1.1.1.1 (r / result-01~e.6 :ARG1 (d / downregulate-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.3,5))) :ARG2 (h / have-frequency-91~e.9 :ARG1 (e3 / event :name (n2 / name :op1 "DSB"~e.12) :mod (r3 / residual~e.11)) :ARG1-of (e2 / enhance-01~e.8 :ARG3~e.13 (l / level~e.15 :ARG1-of (o / observe-01~e.16 :location~e.17 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.21) :mod (p / protein :name (n4 / name :op1 "YB-1"~e.18,20))))))) :ARG2-of (i / interest-01~e.0)) # ::id a_pmid_2139_2397.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , siRNA targeting of YB @-@ 1 increased radiation sensitivity tested in MDA @-@ MB @-@ 231 cells . # ::alignments 2-1.1.1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1 7-1.1.2.1.1 8-1 9-1.2.1 10-1.2 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1 15-1.2.2.1.1.1 17-1.2.2.1.1.1 18-1.2.2.1 (i / increase-01~e.8 :ARG0 (t / target-01~e.3 :ARG0 (n4 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.2)) :ARG1~e.4 (p / protein :name (n / name :op1 "YB-1"~e.5,7))) :ARG1 (s / sensitive-03~e.10 :ARG1 (r / radiate-01~e.9) :ARG2-of (t2 / test-01~e.11 :ARG1~e.12 (c / cell-line~e.18 :name (n3 / name :op1 "MDA-MB-231"~e.13,15,17)))) :ARG1-of (r3 / resemble-01)) # ::id a_pmid_2169_9731.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Primary macrophages from both naïve and lung @-@ tumor bearing mice stimulated epithelial cell proliferation . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 4-1.1.2.1.1 5-1.1.2 6-1.1.2.2.1.1.1 8-1.1.2.2.1.1 9-1.1.2.2.1 10-1.1.2.1 10-1.1.2.2 11-1 12-1.2.1.1 13-1.2.1 14-1.2 (s / stimulate-01~e.11 :ARG0 (m / macrophage~e.1 :mod (p2 / primary~e.0) :source~e.2 (a / and~e.5 :op1 (m2 / mouse~e.10 :mod (n / naive~e.4)) :op2 (m3 / mouse~e.10 :ARG0-of (b / bear-01~e.9 :ARG1 (t / tumor~e.8 :mod (l / lung~e.6)))))) :ARG1 (p / proliferate-01~e.14 :ARG0 (c / cell~e.13 :mod (e / epithelium~e.12)))) # ::id a_pmid_2169_9731.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lungs of tumor @-@ bearing mice contained 3.5 @-@ times more IGF @-@ 1 than naïve littermates , and media conditioned by freshly isolated tumor @-@ educated macrophages contained more IGF @-@ 1 than media conditioned by naïve macrophages ; IL @-@ 4 stimulated IGF @-@ 1 production by both macrophage subsets . # ::alignments 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1.1.1 7-1.1.1 8-1.1.1.4.1.1 10-1.1.1.4.1 11-1.1.1.4 12-1.1.1.2.1.1 14-1.1.1.2.1.1 15-1.1.1.3.r 16-1.1.1.3.1 17-1.1.1.3 19-1.1 20-1.1.2.1 21-1.1.2.1.1 22-1.1.2.1.1.1.r 23-1.1.2.1.1.1.2.1 24-1.1.2.1.1.1.2 25-1.1.2.1.1.1.1.1 27-1.1.2.1.1.1.1 28-1.1.2.1.1.1 29-1.1.1 29-1.1.2 30-1.1.2.4 31-1.1.2.2 32-1.1.2.2 33-1.1.2.2 34-1.1.2.3.r 35-1.1.2.3 36-1.1.2.3.1 37-1.1.2.3.1.1.r 38-1.1.2.3.1.1.1 39-1.1.2.3.1.1 41-1.2.1.1.1 43-1.2.1.1.1 44-1.2 45-1.2.2.2.1.1 47-1.2.2.2.1.1 48-1.2.2 49-1.2.2.1.r 50-1.2.2.1.2 51-1.2.2.1.1 52-1.2.2.1 (m / multi-sentence :snt1 (a / and~e.19 :op1 (c / contain-01~e.7,29 :ARG0 (l / lung~e.1 :part-of~e.2 (m2 / mouse~e.6 :ARG0-of (b / bear-01~e.5 :ARG1 (t / tumor~e.3)))) :ARG1 (p2 / protein :name (n / name :op1 "IGF-1"~e.12,14)) :compared-to~e.15 (l2 / littermate~e.17 :mod (n2 / naive~e.16)) :quant (m3 / more~e.11 :degree (p / product-of~e.10 :op1 3.5~e.8))) :op2 (c2 / contain-01~e.29 :ARG0 (m4 / medium~e.20 :ARG1-of (c3 / condition-01~e.21 :ARG0~e.22 (m5 / macrophage~e.28 :ARG1-of (e / educate-01~e.27 :ARG0 (t2 / tumor~e.25)) :ARG1-of (i / isolate-01~e.24 :ARG1-of (f / fresh-04~e.23))))) :ARG1 p2~e.31,32,33 :compared-to~e.34 (m6 / medium~e.35 :ARG1-of (c4 / condition-01~e.36 :ARG0~e.37 (m7 / macrophage~e.39 :mod (n3 / naive~e.38)))) :quant (m9 / more~e.30))) :snt2 (s / stimulate-01~e.44 :ARG0 (p3 / protein :name (n4 / name :op1 "IL-4"~e.41,43)) :ARG1 (p5 / produce-01~e.48 :ARG0~e.49 (s2 / subset~e.52 :part-of (m8 / macrophage~e.51) :mod (b2 / both~e.50)) :ARG1 (p4 / protein :name (n5 / name :op1 "IGF-1"~e.45,47))))) # ::id a_pmid_2169_9731.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The ability of macrophage conditioned media to stimulate neoplastic proliferation correlated with media IGF @-@ 1 levels , and recombinant IGF @-@ 1 alone was sufficient to induce epithelial proliferation in all cell lines evaluated . # ::alignments 1-1.1 2-1.1.2.r 3-1.1.2.1.1.1 4-1.1.2.1.1 5-1.1.2.1 7-1.1.2 9-1.1.2.2 10-1.1.2.2.2 11-1.1.2.2.2.1.r 12-1.1.2.2.2.1.1.1.2 13-1.1.2.2.2.1.1.1.1.1 13-1.1.2.2.2.1.2.1.1 15-1.1.2.2.2.1.1.1.1.1 15-1.1.2.2.2.1.2.1.1 16-1.1.2.2.2.1.1 18-1.1.2.2.2.1 19-1.1.2.2.2.1.2.3 20-1.1.2.2.2.1.2.1.1 22-1.1.2.2.2.1.2.1.1 23-1.1.2.2.2.1.2.2 25-1 27-1.2 28-1.2.2.1 29-1.2.2 30-1.2.3.r 31-1.2.3.2 32-1.2.3 33-1.2.3 34-1.2.3.1 (s / suffice-01~e.25 :ARG0 (c4 / capable-01~e.1 :ARG1 m :ARG2~e.2 (s2 / stimulate-01~e.7 :ARG0 (m / medium~e.5 :ARG1-of (c / condition-01~e.4 :ARG0 (m2 / macrophage~e.3))) :ARG1 (p2 / proliferate-01~e.9 :ARG0 (t / tumor) :ARG1-of (c2 / correlate-01~e.10 :ARG2~e.11 (a / and~e.18 :op1 (l / level~e.16 :quant-of (p3 / protein :name (n2 / name :op1 "IGF-1"~e.13,15) :mod (m3 / medium~e.12))) :op2 (p4 / protein :name (n3 / name :op1 "IGF-1"~e.13,15,20,22) :mod (a2 / alone~e.23) :ARG3-of (r2 / recombine-01~e.19))))))) :ARG1 (i / induce-01~e.27 :ARG0 c4 :ARG2 (p5 / proliferate-01~e.29 :ARG0 (e / epithelium~e.28)) :location~e.30 (c5 / cell-line~e.32,33 :ARG1-of (e2 / evaluate-01~e.34) :mod (a3 / all~e.31)))) # ::id a_pmid_2169_9731.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophage @-@ conditioned media and IGF @-@ 1 stimulated lung tumor cell growth in an additive manner , while EGF had no effect . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1 3-1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 8-1.1 9-1.1.2.1.1.1 10-1.1.2.1.1 11-1.1.2.1 12-1.1.2 15-1.1.3 16-1.1.3.r 18-1 19-1.2.2.1.1 21-1.2.1 21-1.2.1.r 22-1.2 (c3 / contrast-01~e.18 :ARG1 (s / stimulate-01~e.8 :ARG0 (a / and~e.4 :op1 (m / medium~e.3 :ARG1-of (c / condition-01~e.2 :ARG0 (m2 / macrophage~e.0))) :op2 (p / protein :name (n / name :op1 "IGF-1"~e.5,7))) :ARG1 (g / grow-01~e.12 :ARG1 (c2 / cell~e.11 :mod (t / tumor~e.10 :mod (l / lung~e.9)))) :manner~e.16 (a2 / additive~e.15)) :ARG2 (a3 / affect-01~e.22 :polarity~e.21 -~e.21 :ARG0 (p2 / protein :name (n2 / name :op1 "EGF"~e.19)) :ARG1 g)) # ::id a_pmid_2169_9731.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophage @-@ derived factors increased p @-@ Erk1 @/@ 2 , p @-@ Akt and cyclin D1 levels in neoplastic cells , and the combined inhibition of both MEK and PI3K ablated macrophage @-@ mediated increases in epithelial growth . # ::alignments 0-1.1.1.1.1 2-1.1.1.1 3-1.1.1 4-1.1 5-1.1.2.1.1.2 7-1.1.2.1.1.1.1 9-1.1.2.1.1.1.1 11-1.1.2.1.1.2 13-1.1.2.2.1.1.1 14-1.1.2 15-1.1.2.3.1.1.1 16-1.1.2.3.1.1.2 17-1.1.2.1 17-1.1.2.2 17-1.1.2.3 20-1.1.3 22-1.1.2 24-1.2.2.2 25-1.2.2 28-1.2.2.1.1.1.1 30-1.2.2.1.2.1.1 31-1.2 32-1.2.1.2.1 34-1.2.1.2 35-1.2.1 36-1.2.1.1.r 37-1.2.1.1.1 38-1.2.1.1 (a / and :op1 (i / increase-01~e.4 :ARG0 (f / factor~e.3 :ARG1-of (d / derive-01~e.2 :ARG2 (m3 / macrophage~e.0))) :ARG1 (a2 / and~e.14,22 :op1 (l / level~e.17 :quant-of (e4 / enzyme :name (n / name :op1 "Erk1/2"~e.7,9) :ARG3-of (p / phosphorylate-01~e.5,11))) :op2 (l2 / level~e.17 :quant-of (e5 / enzyme :name (n2 / name :op1 "Akt"~e.13) :ARG3-of p)) :op3 (l3 / level~e.17 :quant-of (p3 / protein :name (n3 / name :op1 "cyclin"~e.15 :op2 "D1"~e.16)))) :location (c / cell~e.20 :mod (t / tumor))) :op2 (a3 / ablate-01~e.31 :ARG1 (i3 / increase-01~e.35 :ARG1~e.36 (g / grow-01~e.38 :ARG1 (e3 / epithelium~e.37)) :ARG1-of (m / mediate-01~e.34 :ARG0 m3~e.32)) :ARG3 (i2 / inhibit-01~e.25 :ARG1 (a4 / and :op1 (e / enzyme :name (n5 / name :op1 "MEK"~e.28)) :op2 (e2 / enzyme :name (n6 / name :op1 "PI3K"~e.30))) :ARG1-of (c2 / combine-01~e.24)))) # ::id a_pmid_2169_9731.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophage conditioned media profoundly stimulates the anchorage @-@ independent growth of lung tumor cells # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.3 3-1.3.r 4-1 6-1.2.2.2 8-1.2.2 8-1.2.2.1 8-1.2.2.1.r 9-1.2 10-1.2.1.r 11-1.2.1.1.1 12-1.2.1.1 13-1.2.1 (s / stimulate-01~e.4 :ARG0 (m / medium~e.2 :ARG1-of (c2 / condition-01~e.1 :ARG0 (m2 / macrophage~e.0))) :ARG1 (g / grow-01~e.9 :ARG1~e.10 (c / cell~e.13 :mod (t / tumor~e.12 :mod (l / lung~e.11))) :ARG0-of (d / depend-01~e.8 :polarity~e.8 -~e.8 :ARG1 (a / anchorage~e.6))) :manner~e.3 (p / profound~e.3)) # ::id a_pmid_2169_9731.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the correlation between lung macrophage content and lung tumor growth , the direct contribution of alveolar macrophages to lung tumor growth is unclear [ @ 6 , 7 , 13 @ ] . # ::alignments 0-1.4.r 2-1.4 4-1.4.1.1.1 5-1.4.1.1 6-1.4.1 7-1.3.1.1.1 8-1.2.2.1.1 9-1.2.2.1 10-1.2.2 13-1.2.3 14-1.2 15-1.2.1.r 16-1.2.1.1 17-1.2.1 19-1.2.2.1.1 20-1.2.2.1 21-1.2.2 23-1 23-1.1 23-1.1.r 26-1.3.1.1.1.1 30-1.3.1.1.1.2 34-1.3.1.1.1.3 (c / clear-06~e.23 :polarity~e.23 -~e.23 :ARG1 (c2 / contribute-01~e.14 :ARG0~e.15 (m / macrophage~e.17 :mod (a / alveolus~e.16)) :ARG2 (g / grow-01~e.10,21 :ARG1 (t / tumor~e.9,20 :mod (l / lung~e.8,19))) :ARG1-of (d / direct-02~e.13)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 (a2 / and~e.7 :op1 6~e.26 :op2 7~e.30 :op3 13~e.34)))) :concession~e.0 (c3 / correlate-01~e.2 :ARG1 (c4 / content~e.6 :mod (m2 / macrophage~e.5 :mod (l2 / lung~e.4))) :ARG2 g)) # ::id a_pmid_2169_9731.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Media conditioned by an immortalized lung macrophage cell line , MH @-@ S , has been previously reported to stimulate the migration of lung epithelial cells harboring Kras @ mutations [ @ 18 @ ] . # ::alignments 0-1.1.1 1-1.1.1.1 2-1.1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.1.1.3.1 6-1.1.1.1.1.3 7-1.1.1.1.1 8-1.1.1.1.1 10-1.1.1.1.1.2.1.1.1 12-1.1.1.1.1.2.1.1.1 16-1.2 17-1 19-1.1 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1.3 24-1.1.2.1.1 25-1.1.2.1 26-1.1.2.1.2 28-1.1.2.1.2.1.1.1.1 30-1.1.2.1.2.1 33-1.3.1.1.1 (r / report-01~e.17 :ARG1 (s / stimulate-01~e.19 :ARG0 (m3 / medium~e.0 :ARG1-of (c2 / condition-01~e.1 :ARG0~e.2 (c6 / cell-line~e.7,8 :ARG1-of (i / immortalize-03~e.4) :ARG1-of (m5 / mean-01 :ARG2 (c4 / cell-line :name (n2 / name :op1 "MH-S"~e.10,12))) :mod (m4 / macrophage~e.6 :mod (l / lung~e.5))))) :ARG1 (m / migrate-01~e.21 :ARG0~e.22 (c / cell~e.25 :mod (e / epithelium~e.24) :ARG0-of (h / harbor-01~e.26 :ARG1 (m2 / mutate-01~e.30 :ARG1 (g / gene :name (n / name :op1 "Kras"~e.28)))) :mod l~e.23))) :time (p / previous~e.16) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 18~e.33)))) # ::id a_pmid_2169_9731.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if MH @-@ S conditioned media directly stimulates neoplastic growth , we first evaluated neoplastic colony formation and cell number after long @-@ term conditioned media exposure . # ::alignments 1-1.5 3-1.5.2.1.2.1.1 5-1.5.2.1.2.1.1 6-1.5.2.1.1 7-1.5.2.1 8-1.5.2.3 9-1.5.2 11-1.5.2.2 13-1.1 14-1.3 14-1.3.1 14-1.3.1.r 15-1 17-1.2.1.1 18-1.2.1 19-1.2 20-1.2.2.1 21-1.2.2 22-1.4 23-1.4.1.2 23-1.4.1.2.r 25-1.4.1.2.r 26-1.4.1.1.1 27-1.4.1.1 28-1.4.1 (e / evaluate-01~e.15 :ARG0 (w / we~e.13) :ARG1 (a / and~e.19 :op1 (f / form-01~e.18 :ARG1 (c / colony~e.17 :mod (t / tumor))) :op2 (n2 / number~e.21 :quant-of (c2 / cell~e.20))) :ord (o / ordinal-entity~e.14 :value~e.14 1~e.14) :time (a2 / after~e.22 :op1 (e2 / expose-01~e.28 :ARG2 (m / medium~e.27 :ARG1-of (c3 / condition-01~e.26)) :duration~e.23,25 (l / long-03~e.23))) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (s / stimulate-01~e.9 :ARG0 (m2 / medium~e.7 :ARG1-of (c4 / condition-01~e.6) :mod (c5 / cell-line :name (n4 / name :op1 "MH-S"~e.3,5))) :ARG1 (g / grow-01~e.11 :mod t) :ARG1-of (d2 / direct-02~e.8)))) # ::id a_pmid_2169_9731.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In both the classic model of anchorage @-@ independent neoplastic growth on soft agar ( Figure 1A @-@ C ) , and colonization on new ultra @-@ low adherence , neutrally @-@ charged plastic ( Figure 1D @-@ F ) , macrophage @-@ conditioned media potently stimulated the proliferation of two Kras @ mutant lung tumor @-@ derived cell lines ( LM2 and JF32 ) . # ::alignments 3-1.4.1.1 4-1.4.1 5-1.4.1.2.r 6-1.4.1.2.2.2 8-1.4.1.2.2 8-1.4.1.2.2.1 8-1.4.1.2.2.1.r 10-1.4.1.2 11-1.4.1.2.1.r 12-1.4.1.2.1.1 13-1.4.1.2.1 15-1.4.1.3.1.1 15-1.4.1.3.1.2 15-1.4.1.3.1.3 15-1.4.2.3.1.2 15-1.4.2.3.1.3 17-1.4.1.3.1.1.1 23-1.4 23-1.4.1.3.1 24-1.4.2 25-1.4.2.2.r 26-1.4.2.2.2.1 27-1.4.2.2.2.2.1 29-1.4.2.2.2.2 34-1.4.2.2.1 35-1.4.2.2 37-1.4.2.3.1.1 39-1.4.2.3.1.1.1 45-1.1.1.1 47-1.1.1 48-1.1 49-1.3 49-1.3.r 50-1 52-1.2 53-1.2.1.r 54-1.2.1.1 56-1.2.1.5.1.1 58-1.2.1.2 59-1.2.1.4.1.1 60-1.2.1.4.1 60-1.4.1.2.3 62-1.2.1.4 63-1.2.1 64-1.2.1 66-1.2.1.3.1.1.1.1 67-1.2.1.3.1 68-1.2.1.3.1.2.1.1 (s / stimulate-01~e.50 :ARG0 (m / medium~e.48 :ARG1-of (c / condition-01~e.47 :ARG0 (m2 / macrophage~e.45))) :ARG1 (p2 / proliferate-01~e.52 :ARG0~e.53 (c2 / cell-line~e.63,64 :quant 2~e.54 :ARG1-of (m3 / mutate-01~e.58) :ARG2-of (m5 / mean-01 :ARG1 (a / and~e.67 :op1 (c3 / cell-line :name (n2 / name :op1 "LM2"~e.66)) :op2 (c4 / cell-line :name (n3 / name :op1 "JF32"~e.68)))) :ARG1-of (d / derive-01~e.62 :ARG2 (t / tumor~e.60 :mod (l / lung~e.59))) :mod (e / enzyme :name (n / name :op1 "Kras"~e.56)))) :manner~e.49 (p / potent~e.49) :location (a2 / and~e.23 :op1 (m4 / model~e.4 :mod (c5 / classic~e.3) :topic~e.5 (g / grow-01~e.10 :location~e.11 (a3 / agar~e.13 :ARG1-of (s2 / soft-02~e.12)) :ARG0-of (d2 / depend-01~e.8 :polarity~e.8 -~e.8 :ARG1 (a4 / anchorage~e.6)) :mod (t2 / tumor~e.60)) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and~e.23 :op1 (f / figure~e.15 :mod "1A"~e.17) :op2 (f5 / figure~e.15 :mod "1B") :op3 (f6 / figure~e.15 :mod "1C")))) :op2 (c6 / colonize-01~e.24 :ARG0 c2 :location~e.25 (p3 / plastic~e.35 :ARG1-of (c7 / charge-03~e.34 :ARG0-of (n4 / neutral-02)) :ARG1-of (a5 / adhere-01 :ARG1-of (n5 / new-01~e.26) :ARG1-of (l2 / low-04~e.29 :degree (u / ultra~e.27)))) :ARG1-of (d4 / describe-01 :ARG0 (a6 / and :op1 (f2 / figure~e.37 :mod "1D"~e.39) :op2 (f3 / figure~e.15 :mod "1E") :op3 (f4 / figure~e.15 :mod "1F")))))) # ::id a_pmid_2169_9731.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , macrophages secrete soluble molecules capable of greatly stimulating neoplastic colony formation and proliferation in vitro , which may shed light on the role of macrophage recruitment to lung cancer in vivo @ . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2 6-1.1.2.1 7-1.1.2.1.1.r 8-1.1.2.1.1.4 8-1.1.2.1.1.4.r 9-1.1.2.1.1 11-1.1.2.1.1.2.1.1 12-1.1.2.1.1.2.1 13-1.1.2.1.1.2 14-1.1.2.1.1.2.2 16-1.1.2.1.1.3 17-1.1.2.1.1.3 21-1.1.2.2.1 22-1.1.3 23-1.1.3.1 24-1.1.3.2.r 26-1.1.3.2 27-1.1.3.2.1.r 28-1.1.3.2.1.1 29-1.1.3.2.1 30-1.1.3.2.1.2.r 31-1.1.3.2.1.2.2.1 32-1.1.3.2.1.2.2.2 34-1.1.3.2.1.3 35-1.1.3.2.1.3 (c / cause-01~e.0 :ARG1 (s / secrete-01~e.3 :ARG0 (m / macrophage~e.2) :ARG1 (m2 / molecule~e.5 :ARG1-of (c2 / capable-01~e.6 :ARG2~e.7 (s2 / stimulate-01~e.9 :ARG0 m2 :ARG1 (a / and~e.13 :op1 (f / form-01~e.12 :ARG1 (c3 / colony~e.11 :mod (t / tumor))) :op2 (p / proliferate-01~e.14 :ARG0 c3)) :manner (i / in-vitro~e.16,17) :manner~e.8 (g / great~e.8))) :ARG1-of (d / dissolve-01 :ARG1-of (p3 / possible-01~e.21))) :ARG0-of (s3 / shed-03~e.22 :ARG1 (l / light~e.23) :ARG2~e.24 (r / role~e.26 :topic~e.27 (r2 / recruit-01~e.29 :ARG1 m~e.28 :ARG2~e.30 (d2 / disease :wiki "Lung_cancer" :name (n / name :op1 "lung"~e.31 :op2 "cancer"~e.32)) :manner (i2 / in-vivo~e.34,35))) :ARG1-of p3))) # ::id a_pmid_2169_9731.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Naïve and tumor @-@ educated primary macrophage co @-@ culture stimulates the proliferation of neoplastic and non @-@ neoplastic pulmonary epithelial cells # ::alignments 0-1.1.1.1 1-1.1 2-1.1.2.2.1.1 2-1.2.1.2.3 4-1.1.2.2.1 5-1.1.1.2 6-1.1.1.3 6-1.1.2.2 7-1.1.1 7-1.1.2 9-1.1.1 10-1 12-1.2 15-1.2.1 16-1.2.1.2.3.1 16-1.2.1.2.3.1.r 20-1.2.1.1.1 21-1.2.1.1 21-1.2.1.2 (s / stimulate-01~e.10 :ARG0 (a / and~e.1 :op1 (c / co-culture~e.7,9 :mod (n / naive~e.0) :mod (p / primary~e.5) :mod (m / macrophage~e.6)) :op2 (c2 / co-culture~e.7 :mod p :mod (m2 / macrophage~e.6 :ARG1-of (e / educate-01~e.4 :ARG0 (t / tumor~e.2))))) :ARG1 (p2 / proliferate-01~e.12 :ARG0 (a2 / and~e.15 :op1 (c3 / cell~e.21 :mod (e2 / epithelium~e.20) :mod (l / lung) :mod t) :op2 (c4 / cell~e.21 :mod e2 :mod l :mod (t2 / tumor~e.2 :polarity~e.16 -~e.16))))) # ::id a_pmid_2169_9731.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The relative ability of naïve vs. tumor @-@ educated alveolar macrophages to directly stimulate lung epithelial cell proliferation not been reported . # ::alignments 1-1.2.3 2-1.2 4-1.2.1.1 5-1.2.4.r 6-1.2.4.1.1 8-1.2.4.1 9-1.2.1.2 10-1.2.1 10-1.2.4 12-1.2.2.3 13-1.2.2 14-1.2.2.2.1.2 15-1.2.2.2.1.1 16-1.2.2.2.1 17-1.2.2.2 18-1.1 18-1.1.r 20-1 (r / report-01~e.20 :polarity~e.18 -~e.18 :ARG1 (c2 / capable-01~e.2 :ARG1 (m / macrophage~e.10 :mod (n / naive~e.4) :mod (a / alveolus~e.9)) :ARG2 (s / stimulate-01~e.13 :ARG0 m :ARG1 (p2 / proliferate-01~e.17 :ARG0 (c / cell~e.16 :mod (e2 / epithelium~e.15) :mod (l / lung~e.14))) :ARG1-of (d / direct-02~e.12)) :ARG2-of (r2 / relative-05~e.1) :compared-to~e.5 (m2 / macrophage~e.10 :ARG1-of (e / educate-01~e.8 :ARG0 (t / tumor~e.6)) :mod a))) # ::id a_pmid_2169_9731.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if macrophages from the lungs of tumor @-@ bearing mice could directly stimulate neoplastic cell growth in a co @-@ culture system , neoplastic LM2 cells were co @-@ cultured with bronchoalveolar lavage ( BAL ) macrophages ( MØ) isolated from tumor @-@ bearing mice , and monolayer growth was assessed ( Figure 2A ) . # ::alignments 1-1.3 3-1.3.1.1.1 4-1.3.1.1.1.1.r 6-1.3.1.1.1.1 7-1.3.1.1.1.1.1.r 8-1.3.1.1.1.1.1 9-1.3.1.1.1.1.1 10-1.3.1.1.1.1.1 11-1.3.1.1.1.1.1 12-1.3.1 12-1.3.1.1.3 13-1.3.1.1.4 14-1.3.1.1 15-1.3.1.1.2.1.1 16-1.3.1.1.2.1 17-1.3.1.1.2 18-1.3.1.1.2.2.r 20-1.3.1.1.2.2.1 22-1.3.1.1.2.2.1 23-1.3.1.1.2.2 25-1.1.1.1.2 26-1.1.1.1.1.1 27-1.1.1.1 29-1.3.1.1.2.2.1 31-1.1 31-1.3.1.1.2.2.1 32-1.1.1.r 33-1.1.1.2.1 34-1.1.1.2.1.1 36-1.1.1.2.1.1 38-1.1.1.2 41-1.1.1.2.2 42-1.3.1.1.1.1.r 43-1.3.1.1.1.1.1 44-1.3.1.1.1.1.1 45-1.3.1.1.1.1.1 46-1.3.1.1.1.1.1 48-1 48-1.1.1 50-1.2.1 52-1.2 54-1.4.1 56-1.4.1.1 (a2 / and~e.48 :op1 (c / culture-01~e.31 :ARG1~e.32 (a / and~e.48 :op1 (c2 / cell-line~e.27 :name (n / name :op1 "LM2"~e.26) :mod (n2 / neoplastic~e.25)) :op2 (m / macrophage~e.38 :mod (b / bronchoalveolar~e.33 :mod (l / lavage~e.34,36)) :ARG1-of (i / isolate-01~e.41 :ARG2 (m2 / mouse :ARG0-of (b2 / bear-01 :ARG1 (t / tumor))))))) :op2 (a3 / assess-01~e.52 :ARG1 (g / grow-01~e.50 :ARG1 (l2 / layer :quant 1))) :purpose (d / determine-01~e.1 :ARG1 (p2 / possible-01~e.12 :ARG1 (s / stimulate-01~e.14 :ARG0 (m3 / macrophage~e.3 :source~e.4,42 (l3 / lung~e.6 :part-of~e.7 m2~e.8,9,10,11,43,44,45,46)) :ARG1 (g2 / grow-01~e.17 :mod (c3 / cell~e.16 :mod (n3 / neoplastic~e.15)) :location~e.18 (s2 / system~e.23 :mod (c4 / co-culture~e.20,22,29,31))) :ARG1-of (p / possible-01~e.12) :ARG1-of (d3 / direct-02~e.13)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.54 :mod "2A"~e.56))) # ::id a_pmid_2169_9731.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Growth in standard tissue culture conditions measures proliferation per se , and not cell motility or the requirement for solid support , and permits the evaluation of non @-@ neoplastic epithelial cells which do not proliferate in anchorage @-@ independent systems . # ::alignments 0-1.1.1.1 1-1.1.1.1.1.r 2-1.1.1.1.1.1.1 3-1.1.1.1.1.1 4-1.1.1.1.1 6-1.1.1 6-1.1.2 7-1.1.1.2 9-1.1.1.3 10-1.1.1.3 14-1.1.2.1 14-1.1.2.1.r 15-1.1.2.3.1.1 16-1.1.2.3.1 17-1.1.2.3 19-1.1.2.3.2 20-1.1.2.3.2.1.r 21-1.1.2.3.2.1.1 22-1.1.2.3.2.1 24-1 25-1.2 27-1.2.2 28-1.2.2.1.r 29-1.2.2.1.2.1 29-1.2.2.1.2.1.r 32-1.2.2.1.1 33-1.2.2.1 36-1.2.2.1.2.1 36-1.2.2.1.2.1.r 36-1.2.2.1.3.1 36-1.2.2.1.3.1.r 37-1.2.2.1.3 38-1.2.2.1.3.2.r 39-1.2.2.1.3.2.1.2 41-1.2.2.1.3.2.1 41-1.2.2.1.3.2.1.1 41-1.2.2.1.3.2.1.1.r 42-1.2.2.1.3.2 (a / and~e.24 :op1 (c2 / contrast-01 :ARG1 (m / measure-01~e.6 :ARG0 (g / grow-01~e.0 :ARG1~e.1 (c / culture-01~e.4 :ARG1 (t / tissue~e.3 :ARG1-of (s / standard-02~e.2)))) :ARG1 (p4 / proliferate-01~e.7) :manner (p / per-se~e.9,10)) :ARG2 (m2 / measure-01~e.6 :polarity~e.14 -~e.14 :ARG0 g :ARG1 (o / or~e.17 :op1 (m3 / motility~e.16 :mod (c3 / cell~e.15)) :op2 (r / require-01~e.19 :ARG1~e.20 (s2 / support-01~e.22 :ARG1-of (s3 / solid-02~e.21)))))) :op2 (p2 / permit-01~e.25 :ARG0 g :ARG1 (e / evaluate-01~e.27 :ARG1~e.28 (c4 / cell~e.33 :mod (e2 / epithelium~e.32) :mod (t2 / tumor :polarity~e.29,36 -~e.29,36) :ARG0-of (p3 / proliferate-01~e.37 :polarity~e.36 -~e.36 :location~e.38 (s4 / system~e.42 :ARG0-of (d / depend-01~e.41 :polarity~e.41 -~e.41 :ARG1 (a2 / anchorage~e.39)))))))) # ::id a_pmid_2169_9731.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LM2 cell number significantly increased with BAL macrophage co @-@ culture at 48 ( 2.3 vs. 4.1 @-@ fold ) and 72 hrs ( 3.5 vs. 7.5 @-@ fold ) ( Figure 2A ) . # ::alignments 0-1.1.2.1.1.1 1-1.1.2.1 2-1.1.2 3-1.1.3 4-1.1 4-1.2 5-1.1.1.r 6-1.1.1.1.1 6-1.1.1.1.1.1 6-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1.r 6-1.1.1.1.1.1.r 7-1.1.1.1 8-1.1.1 10-1.1.1 12-1.1.6.1.1 14-1.1.4.1 16-1.1.5.1 18-1.1.4 18-1.1.5 20-1 21-1.2.6.1.1 22-1.1.6.1.2 22-1.2.6.1.2 24-1.2.4.1 26-1.2.5.1 28-1.2.4 28-1.2.5 31-1.3.1 33-1.3.1.1 (a / and~e.20 :op1 (i / increase-01~e.4 :ARG0~e.5 (c / co-culture~e.8,10 :mod (m / macrophage~e.7 :mod (l / lavage~e.6 :mod~e.6 (a4 / alveolus~e.6 :mod~e.6 (b / bronchus~e.6))))) :ARG1 (n2 / number~e.2 :quant-of (c2 / cell-line~e.1 :name (n3 / name :op1 "LM2"~e.0))) :ARG2 (s / significant-02~e.3) :ARG3 (p / product-of~e.18 :op1 2.3~e.14) :ARG4 (p2 / product-of~e.18 :op1 4.1~e.16) :time (a2 / after :op1 (t2 / temporal-quantity :quant 48~e.12 :unit (h / hour~e.22)))) :op2 (i2 / increase-01~e.4 :ARG0 c :ARG1 n2 :ARG2 s :ARG3 (p3 / product-of~e.28 :op1 3.5~e.24) :ARG4 (p4 / product-of~e.28 :op1 7.5~e.26) :time (a3 / after :op1 (t3 / temporal-quantity :quant 72~e.21 :unit (h2 / hour~e.22)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "2A"~e.33))) # ::id a_pmid_2169_9731.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As 72 hrs of macrophage co @-@ culture resulted in ≥ 2 @-@ times more tumor cells , this time point was used in subsequent experiments . # ::alignments 0-1.2.1.r 1-1.3.1.1.2.1 2-1.3.1.1.2.2 4-1.3.1.1.1 5-1.3.1.1 7-1.3.1.1 8-1.3.1 11-1.3.1.2.2.1.1.1.1 11-1.3.1.2.2.1.2.1 13-1.3.1.1.2 13-1.3.1.2.2.1.2 14-1.3.1.2.2 14-1.3.1.2.2.1.1 15-1.3.1.2.1 16-1.3.1.2 18-1.1.2 19-1.1.1 20-1.1 22-1 24-1.2.1 24-1.2.1.r 25-1.2 (u / use-01~e.22 :ARG0 (p / point~e.20 :mod (t / time~e.19) :mod (t4 / this~e.18)) :ARG1 (e / experiment-01~e.25 :time~e.0,24 (s / subsequent~e.24)) :ARG1-of (c / cause-01 :ARG0 (r / result-01~e.8 :ARG1 (c2 / co-culture~e.5,7 :mod (m / macrophage~e.4) :duration (t2 / temporal-quantity~e.13 :quant 72~e.1 :unit (h / hour~e.2))) :ARG2 (c3 / cell~e.16 :mod (t3 / tumor~e.15) :quant (m2 / more~e.14 :degree (v / value-interval :op1 (m3 / more-than~e.14 :op1 (p2 / product-of :op1 2~e.11)) :op2 (p3 / product-of~e.13 :op1 2~e.11))))))) # ::id a_pmid_2169_9731.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if tumor @-@ educated macrophages stimulated neoplastic growth more effectively than naïve , BAL macrophages from either naïve or tumor @-@ bearing mice were co @-@ cultured with neoplastic LM2 ( Figure 2B ) and JF32 ( Figure 2C ) cells . # ::alignments 1-1.2 3-1.2.1.2.1.1 5-1.2.1.2.1 6-1.2.1.2 7-1.2.1 9-1.2.1.3 10-1.2.1.4.1 11-1.2.1.4 12-1.2.1.4.2.r 13-1.2.1.4.2.1 15-1.1.1.2 15-1.1.1.2.1 15-1.1.1.2.1.1 15-1.1.1.2.1.1.r 15-1.1.1.2.1.r 16-1.1.1 16-1.2.1.4.2 17-1.1.1.1.r 19-1.1.1.1.1.1 20-1.1.1.1 21-1.1.1.1.2.1.1 23-1.1.1.1.2.1 24-1.1.1.1.1 24-1.1.1.1.2 28-1 31-1.1.2.1.1 33-1.1.2.2.1 35-1.1.2.2.1.1 38-1.1 39-1.1.3.1.1 41-1.1.3.2.1 43-1.1.3.2.1.1 46-1.1.2 46-1.1.3 (c / culture-01~e.28 :ARG1 (a / and~e.38 :op1 (m / macrophage~e.16 :source~e.17 (o / or~e.20 :op1 (m2 / mouse~e.24 :mod (n / naive~e.19)) :op2 (m3 / mouse~e.24 :ARG0-of (b / bear-01~e.23 :ARG1 (t / tumor~e.21)))) :mod (l / lavage~e.15 :mod~e.15 (a2 / alveolus~e.15 :mod~e.15 (b2 / bronchus~e.15)))) :op2 (c2 / cell-line~e.46 :name (n2 / name :op1 "LM2"~e.31) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.33 :mod "2B"~e.35)) :mod t) :op3 (c3 / cell-line~e.46 :name (n3 / name :op1 "JF32"~e.39) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.41 :mod "2C"~e.43)) :mod t)) :purpose (d3 / determine-01~e.1 :ARG1 (s / stimulate-01~e.7 :mode interrogative :ARG0 (m4 / macrophage~e.6 :ARG1-of (e / educate-01~e.5 :ARG0 t~e.3)) :ARG1 (g / grow-01~e.9 :ARG1 t) :ARG1-of (e2 / effective-04~e.11 :degree (m5 / more~e.10) :compared-to~e.12 (m6 / macrophage~e.16 :mod (n6 / naive~e.13)))))) # ::id a_pmid_2169_9731.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LM2 growth was equally stimulated by both naïve and tumor @-@ educated BAL macrophages , while the growth of JF32 cells was enhanced slightly upon co @-@ culture with tumor @-@ educated BAL macrophages ( Figure 2C ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1.3 4-1.1 7-1.1.2.1.1 8-1.1.2 9-1.1.2.2.1.1 11-1.1.2.2.1 12-1.1.2.1.2 12-1.1.2.1.2.1 12-1.1.2.1.2.1.1 12-1.1.2.1.2.1.1.r 12-1.1.2.1.2.1.r 13-1.1.2.1 13-1.1.2.2 15-1 17-1.1.1 17-1.2.1 18-1.2.r 19-1.2.1.1.1.1 20-1.1.1.1 20-1.2.1.1 22-1.2 23-1.2.2 23-1.2.2.r 27-1.2.3.1 28-1.2.3.1.1.r 29-1.2.3.1.1.2 30-1.2.3.1.1.2 31-1.2.3.1.1.2 32-1.1.2.1.2 32-1.1.2.1.2.1 32-1.1.2.1.2.1.1 32-1.1.2.1.2.1.1.r 32-1.1.2.1.2.1.r 33-1.1.2.1 35-1.3.1 37-1.3.1.1 (c / contrast-01~e.15 :ARG1 (s / stimulate-01~e.4 :ARG0 (g / grow-01~e.1,17 :ARG1 (c2 / cell-line~e.20 :name (n2 / name :op1 "LM2"~e.0))) :ARG1 (a / and~e.8 :op1 (m / macrophage~e.13,33 :mod (n / naive~e.7) :mod (l / lavage~e.12,32 :mod~e.12,32 (a4 / alveolus~e.12,32 :mod~e.12,32 (b / bronchus~e.12,32)))) :op2 (m2 / macrophage~e.13 :ARG1-of (e / educate-01~e.11 :ARG0 (t / tumor~e.9)))) :ARG1-of (e2 / equal-01~e.3)) :ARG2~e.18 (e3 / enhance-01~e.22 :ARG1 (g2 / grow-01~e.17 :ARG1 (c3 / cell-line~e.20 :name (n3 / name :op1 "JF32"~e.19))) :manner~e.23 (s2 / slight~e.23) :time (a3 / after :op1 (c4 / culture-01~e.27 :ARG1~e.28 (a2 / and :op1 c3 :op2 m2~e.29,30,31)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "2C"~e.37))) # ::id a_pmid_2169_9731.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if primary alveolar macrophages also stimulated the proliferation of non @-@ tumor cells , the non @-@ neoplastic E10 cell line was co @-@ cultured with naïve and tumor @-@ educated BAL macrophages . # ::alignments 1-1.2 3-1.2.1.2.1 4-1.2.1.2.2 5-1.2.1.2 6-1.2.1.4 7-1.2.1 9-1.2.1.3 11-1.1.1.2.1 11-1.1.1.2.1.r 13-1.1.1.2 14-1.2.1.3.1 17-1.1.1.2.1.r 20-1.1.1.1.1 21-1.1.1 22-1.1.1 26-1 28-1.1.2.1 29-1.1 30-1.1.3.1.1 32-1.1.3.1 33-1.1.3.2 33-1.1.3.2.1 33-1.1.3.2.1.1 33-1.1.3.2.1.1.r 33-1.1.3.2.1.r 34-1.1.2 34-1.1.3 (c / culture-01~e.26 :ARG1 (a / and~e.29 :op1 (c2 / cell-line~e.21,22 :name (n / name :op1 "E10"~e.20) :mod (t3 / tumor~e.13 :polarity~e.11,17 -~e.11)) :op2 (m / macrophage~e.34 :mod (n2 / naive~e.28)) :op3 (m2 / macrophage~e.34 :ARG1-of (e / educate-01~e.32 :ARG0 (t / tumor~e.30)) :mod (l / lavage~e.33 :mod~e.33 (a4 / alveolus~e.33 :mod~e.33 (b / bronchus~e.33))))) :purpose (d / determine-01~e.1 :ARG1 (s / stimulate-01~e.7 :mode interrogative :ARG0 (m3 / macrophage~e.5 :mod (p2 / primary~e.3) :mod (a2 / alveolus~e.4)) :ARG1 (p / proliferate-01~e.9 :ARG0 (c3 / cell~e.14 :mod t3)) :mod (a3 / also~e.6)))) # ::id a_pmid_2169_9731.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both macrophage types increased E10 cell number 3.5 @-@ fold ( Figure 2D ) when maintained in serum @-@ free conditions ; only tumor @-@ educated macrophages stimulated E10 proliferation when cultured in the presence of serum ( Figure 2E ) . # ::alignments 0-1.1.1.2 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.1.1.1 5-1.1.2.1 5-1.2.2.1 6-1.1.2 7-1.1.3.1 9-1.1.3 11-1.1.4.1 13-1.1.2.1.r 13-1.1.4.1.1 16-1.1.5.r 17-1.1.5 18-1.1.5.2.r 19-1.1.5.2.1.1 21-1.1.5.2.1 22-1.1.5.2 24-1.2.1.2 25-1.2.1.1.1 27-1.2.1.1 28-1.2.1 29-1.2 30-1.2.2.1.1.1 31-1.2.2 32-1.2.3.r 33-1.2.3 34-1.2.4.r 36-1.2.4 37-1.2.4.1.r 38-1.2.4.1 40-1.2.5.1 42-1.2.5.1.1 (m / multi-sentence :snt1 (i / increase-01~e.3 :ARG0 (t / type-03~e.2 :ARG1 (m2 / macrophage~e.1) :mod (b / both~e.0)) :ARG1 (n / number~e.6 :quant-of~e.13 (c / cell-line~e.5 :name (n2 / name :op1 "E10"~e.4))) :ARG2 (p / product-of~e.9 :op1 3.5~e.7) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "2D"~e.13)) :time~e.16 (m3 / maintain-01~e.17 :ARG1 t :ARG2~e.18 (c2 / condition~e.22 :ARG1-of (f2 / free-04~e.21 :ARG2 (s / serum~e.19))))) :snt2 (s2 / stimulate-01~e.29 :ARG0 (m4 / macrophage~e.28 :ARG1-of (e / educate-01~e.27 :ARG0 (t2 / tumor~e.25)) :mod (o / only~e.24)) :ARG1 (p2 / proliferate-01~e.31 :ARG0 (c3 / cell-line~e.5 :name (n3 / name :op1 "E10"~e.30))) :time~e.32 (c4 / culture-01~e.33 :ARG1 c3) :condition~e.34 (p3 / present-02~e.36 :ARG1~e.37 (s3 / serum~e.38)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.40 :mod "2E"~e.42)))) # ::id a_pmid_2169_9731.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both types of primary macrophages equally stimulated LM2 proliferation in the presence of serum , though the magnitude was reduced when compared to serum @-@ free co @-@ culture ( data not shown ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1.3 6-1 7-1.2.1.1.1 8-1.2 9-1.4.r 11-1.4 12-1.4.1.r 13-1.4.1 15-1.6.r 17-1.6.1 19-1.6 20-1.6.2.r 21-1.6.2 22-1.6.2.2.r 23-1.6.2.2.1.1 25-1.6.2.2.1 26-1.6.2.2 28-1.6.2.2 30-1.5.1 31-1.5.1.1.1 31-1.5.1.1.1.r 32-1.5.1.1 (s / stimulate-01~e.6 :ARG0 (t / type-03~e.1 :ARG1~e.2 (m / macrophage~e.4 :mod (p3 / primary~e.3)) :mod (b / both~e.0)) :ARG1 (p / proliferate-01~e.8 :ARG0 (c / cell-line :name (n / name :op1 "LM2"~e.7))) :ARG1-of (e / equal-01~e.5) :condition~e.9 (p2 / present-02~e.11 :ARG1~e.12 (s2 / serum~e.13)) :ARG1-of (d / describe-01 :ARG0 (d3 / data~e.30 :ARG1-of (s3 / show-01~e.32 :polarity~e.31 -~e.31))) :concession~e.15 (r / reduce-01~e.19 :ARG1 (m2 / magnitude~e.17) :time~e.20 (c2 / compare-01~e.21 :ARG1 m2 :ARG2~e.22 (c3 / co-culture~e.26,28 :ARG1-of (f / free-04~e.25 :ARG2 s2~e.23))))) # ::id a_pmid_2169_9731.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if MH @-@ S macrophages could recapitulate the effects of primary alveolar macrophages in this in vitro @ model , we co @-@ cultured MH @-@ S macrophages with both neoplastic and non @-@ neoplastic lung epithelial cells . # ::alignments 1-1.3 3-1.2.1.1.1.1 5-1.2.1.1.1.1 6-1.2.1 7-1.3.2 8-1.3.2.1 10-1.3.2.1.2 11-1.3.2.1.2.1.r 12-1.3.2.1.2.1.2 13-1.3.2.1.2.1.1 14-1.3.2.1.2.1 15-1.3.2.1.3.1 16-1.3.2.1.3.2 18-1.3.2.1.3.1 19-1.3.2.1.3.1 21-1.3.2.1.3 23-1.1 26-1 27-1.2.1.1.1.1 29-1.2.1.1.1.1 30-1.2.1 33-1.2.3.2 35-1.2.3.2.1 35-1.2.3.2.1.r 37-1.2.3.2 38-1.2.2.1 39-1.2.2.2 40-1.2.2 40-1.2.3 (c / culture-01~e.26 :ARG0 (w / we~e.23) :ARG1 (a / and :op1 (m / macrophage~e.6,30 :mod (c2 / cell-line :name (n / name :op1 "MH-S"~e.3,5,27,29))) :op2 (c3 / cell~e.40 :mod (l / lung~e.38) :mod (e / epithelium~e.39) :mod (t2 / tumor)) :op3 (c4 / cell~e.40 :mod l :mod (n3 / neoplastic~e.33,37 :polarity~e.35 -~e.35) :mod t2)) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (p / possible-01~e.7 :ARG1 (r / recapitulate-01~e.8 :ARG0 m :ARG1 (a2 / affect-01~e.10 :ARG0~e.11 (m2 / macrophage~e.14 :mod (a3 / alveolar~e.13) :mod (p2 / primary~e.12))) :location (m3 / model~e.21 :mod (i / in-vitro~e.15,18,19) :mod (t / this~e.16)))))) # ::id a_pmid_2169_9731.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MH @-@ S co @-@ culture increased the growth rate of all pulmonary epithelial cell lines similar to co @-@ culture with tumor @-@ educated BAL macrophages ( Figure 2B @-@ E ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 5-1.1 6-1 8-1.2.1 9-1.2 10-1.2.1.1.r 11-1.2.1.1.1 13-1.2.1.1.2 14-1.2.1.1 15-1.2.1.1 16-1.2.1.1.4 18-1.1 20-1.2.1.1.4.1 21-1.2.1.1.4.1.1.r 22-1.2.1.1.4.1.1.1.1 24-1.2.1.1.4.1.1.1 25-1.2.1.1.4.1.1.2 25-1.2.1.1.4.1.1.2.1 25-1.2.1.1.4.1.1.2.1.1 25-1.2.1.1.4.1.1.2.1.1.r 25-1.2.1.1.4.1.1.2.1.r 26-1.2.1.1.4.1.1 28-1.3.1.1 28-1.3.1.2 28-1.3.1.3 28-1.3.1.4 30-1.3.1.1.1 (i / increase-01~e.6 :ARG0 (c / co-culture~e.3,5,18 :mod (c2 / cell-line :name (n / name :op1 "MH-S"~e.0,2))) :ARG1 (r / rate~e.9 :degree-of (g / grow-01~e.8 :ARG1~e.10 (c3 / cell-line~e.14,15 :mod (a / all~e.11) :mod (e / epithelium~e.13) :mod (l / lung) :ARG1-of (r2 / resemble-01~e.16 :ARG2 (c4 / culture-01~e.20 :ARG1~e.21 (m / macrophage~e.26 :ARG1-of (e2 / educate-01~e.24 :ARG0 (t / tumor~e.22)) :mod (l2 / lavage~e.25 :mod~e.25 (a3 / alveolus~e.25 :mod~e.25 (b / bronchus~e.25))))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.28 :mod "2B"~e.30) :op2 (f2 / figure~e.28 :mod "2C") :op3 (f3 / figure~e.28 :mod "2D") :op4 (f4 / figure~e.28 :mod "2E")))) # ::id a_pmid_2169_9731.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that primary lung macrophages produce diffusible signals which can augment the proliferation of both non @-@ neoplastic and neoplastic cells in vitro @ . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1 5-1.2.1.2 6-1.2.1 7-1.2 9-1.2.2 11-1.2.2.1.1 12-1.2.2.2 14-1.2.2.2.1 17-1.2.2.2.1.1.1.1.1 17-1.2.2.2.1.1.1.1.1.r 19-1.2.2.2.1.1.2.1 21-1.2.2.2.1.1.2.1 22-1.2.2.2.1.1.1 22-1.2.2.2.1.1.2 24-1.2.2.2.1.2 25-1.2.2.2.1.2 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (p / produce-01~e.7 :ARG0 (m / macrophage~e.6 :mod (p4 / primary~e.4) :mod (l / lung~e.5)) :ARG1 (s / signal-07~e.9 :ARG1-of (d / diffuse-01 :ARG1-of (p2 / possible-01~e.11)) :ARG0-of (a / augment-01~e.12 :ARG1 (p3 / proliferate-01~e.14 :ARG0 (a2 / and :op1 (c / cell~e.22 :mod (t3 / tumor :polarity~e.17 -~e.17)) :op2 (c2 / cell~e.22 :mod (n2 / neoplastic~e.19,21))) :manner (i2 / in-vitro~e.24,25)) :ARG1-of p2)))) # ::id a_pmid_2169_9731.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further , we observed that in vivo @ tumor education of primary lung macrophages slightly enhances this ability to stimulate epithelial proliferation , an effect similar to co @-@ culture with MH @-@ S macrophages . # ::alignments 0-1.3 2-1.1 3-1 6-1.2.1.3 7-1.2.1.3 9-1.2.1.1 10-1.2.1 12-1.2.1.2.2 13-1.2.1.2.1 14-1.2.1.2 15-1.2.2 15-1.2.2.r 16-1.2 18-1.2.3 20-1.2.3.1 21-1.2.3.1.1.1 22-1.2.3.1.1 25-1.2.4 26-1.2.4.2 30-1.2.4.2.1 32-1.2.4.2.1.1.2.1.1.1 34-1.2.4.2.1.1.2.1.1.1 35-1.2.1.2 35-1.2.4.2.1.1.2 (o / observe-01~e.3 :ARG0 (w / we~e.2) :ARG1 (e / enhance-01~e.16 :ARG0 (e2 / educate-01~e.10 :ARG0 (t / tumor~e.9) :ARG1 (m / macrophage~e.14,35 :mod (l / lung~e.13) :mod (p / primary~e.12)) :manner (i / in-vivo~e.6,7)) :manner~e.15 (s / slight~e.15) :ARG1-of (c / capable-01~e.18 :ARG2 (s2 / stimulate-01~e.20 :ARG1 (p2 / proliferate-01~e.22 :ARG0 (e3 / epithelium~e.21)))) :ARG2-of (a / affect-01~e.25 :ARG1 c :ARG1-of (r / resemble-01~e.26 :ARG2 (c2 / culture-01~e.30 :ARG1 (a2 / and :op1 m :op2 (m2 / macrophage~e.35 :mod (c3 / cell-line :name (n / name :op1 "MH-S"~e.32,34)))))))) :mod (f / further~e.0)) # ::id a_pmid_2169_9731.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophage co @-@ culture stimulates epithelial proliferation through kinase activation # ::alignments 0-1.1.1 1-1.1 2-1.1 3-1.1 4-1 5-1.2.1 6-1.2 8-1.3.1 9-1.3 (s / stimulate-01~e.4 :ARG0 (c / coculture-01~e.1,2,3 :ARG1 (m / macrophage~e.0)) :ARG1 (p / proliferate-01~e.6 :ARG0 (e / epithelium~e.5)) :ARG2 (a / activate-01~e.9 :ARG1 (k / kinase~e.8))) # ::id a_pmid_2169_9731.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since MH @-@ S macrophages and tumor @-@ educated primary macrophages stimulated epithelial proliferation to a similar degree , MH @-@ S macrophages were used to elucidate the mechanisms of increased epithelial proliferation . # ::alignments 0-1.3 1-1.3.1.1.1 2-1.3.1.1.1 3-1.3.1.1.1 4-1.3.1.1.1 5-1.3.1.1 6-1.3.1.1.2.2.1 8-1.3.1.1.2.2 9-1.3.1.1.2.1 10-1.3.1.1.2 11-1.3.1 12-1.3.1.2 13-1.3.1.2 14-1.3 16-1.3.1.3 17-1.3.1.3.r 19-1.1.1.1.1 21-1.1.1.1.1 22-1.1 24-1 25-1.3 26-1.2 28-1.2.2 29-1.2.2.1.r 30-1.2.2.1.2 31-1.2.2.1.1 32-1.2.2.1 (u / use-01~e.24 :ARG1 (m2 / macrophage~e.22 :mod (c2 / cell-line :name (n / name :op1 "MH-S"~e.19,21))) :ARG2 (e / elucidate-01~e.26 :ARG0 m2 :ARG1 (m / mechanism~e.28 :poss~e.29 (p / proliferate-01~e.32 :ARG0 (e2 / epithelium~e.31) :ARG1-of (i / increase-01~e.30)))) :ARG1-of (c / cause-01~e.0,14,25 :ARG0 (s / stimulate-01~e.11 :ARG0 (a / and~e.5 :op1 m2~e.1,2,3,4 :op2 (m3 / macrophage~e.10 :mod (p2 / primary~e.9) :ARG1-of (e3 / educate-01~e.8 :ARG0 (t / tumor~e.6)))) :ARG1 p~e.12,13 :degree~e.17 (r / resemble-01~e.16)))) # ::id a_pmid_2169_9731.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because Kras pathways are commonly hyper @-@ activated in lung tumorigenesis [ @ 22 , 23 @ ] , and the tumorigenic lines examined herein contain Kras @ mutations , activities of downstream mediators Erk and Akt were examined . # ::alignments 0-1.2 2-1.2.1.1.1 4-1.2.1.1.5 4-1.2.1.1.5.r 5-1.2.1.1.2 7-1.2.1.1 8-1.2.1.1.3.r 9-1.2.1.1.3.1.1 10-1.2.1.1.3 10-1.2.1.1.3.1 10-1.2.1.1.3.1.r 13-1.2.1.1.4.1.1.1.1 17-1.2.1.1.4.1.1.1.2 21-1.2.1 21-1.2.1.1.4.1.1.1 23-1.2.1.2.1.2 23-1.2.1.2.1.2.1 23-1.2.1.2.1.2.1.r 23-1.2.1.2.1.2.2 23-1.2.1.2.1.2.2.r 24-1.2.1.2.1 25-1.2.1.2.1.1 26-1.2.1.2.1.1.1 27-1.2.1.2 31-1.2.1.2.2 33-1.1 34-1.1.1.r 35-1.1.1.3.1 36-1.1.1.3 37-1.1.1.1.1.1 38-1.1.1 39-1.1.1.2.1.1 41-1 (e / examine-01~e.41 :ARG1 (a / act-02~e.33 :ARG0~e.34 (a2 / and~e.38 :op1 (e2 / enzyme :name (n / name :op1 "Erk"~e.37)) :op2 (e3 / enzyme :name (n2 / name :op1 "Akt"~e.39)) :ARG0-of (m / mediate-01~e.36 :direction (d / downstream~e.35)))) :ARG1-of (c / cause-01~e.0 :ARG0 (a3 / and~e.21 :op1 (a4 / activate-01~e.7 :ARG1 (p / pathway~e.2 :name (n3 / name :op1 "K-Ras")) :degree (h / hyper~e.5) :time~e.8 (c2 / create-01~e.10 :ARG1~e.10 (t / tumor~e.10 :mod (l / lung~e.9))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a5 / and~e.21 :op1 22~e.13 :op2 23~e.17)))) :manner~e.4 (c4 / common~e.4)) :op2 (c5 / contain-01~e.27 :ARG0 (l2 / line~e.24 :ARG1-of (e5 / examine-01~e.25 :medium (h2 / herein~e.26)) :ARG0-of (c6 / create-01~e.23 :ARG1~e.23 (t2 / tumor~e.23) :ARG1-of~e.23 (p3 / possible-01~e.23))) :ARG1 (m2 / mutate-01~e.31 :ARG2 (g / gene :name (n4 / name :op1 "K-Ras"))))))) # ::id a_pmid_2169_9731.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytosolic Raf functionally links the Erk and Akt pathways ; activated Akt can phosphorylate cRaf at S259 , placing Erk regulation downstream of Akt activation [ @ 32 , 33 @ ] . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 2-1.1.3 3-1.1 5-1.1.2.1.1.1 6-1 6-1.1.2 7-1.1.2.2.1.1 7-1.2.1.2.1.1 8-1.1.2.1 8-1.1.2.2 8-1.2.1.2 10-1.2.1.2.2 11-1.2.1.2.1.1 12-1.2 13-1.2.1 18-1.2.1.3.1 19-1.2.1.3.1.1.1 20-1.2.1.3.1.1 21-1.2.1.3.1.2.2 23-1.2.1.3.1.2.1 24-1.2.1.3.1.2.1 27-1.2.2.1.1.1.1 31-1.2.2.1.1.1.2 (a / and~e.6 :op1 (l / link-01~e.3 :ARG0 (e / enzyme :name (n / name :op1 "Raf"~e.1) :location (c / cytosol~e.0)) :ARG1 (a2 / and~e.6 :op1 (p2 / pathway~e.8 :name (n2 / name :op1 "Erk"~e.5)) :op2 (p3 / pathway~e.8 :name (n3 / name :op1 "Akt"~e.7))) :ARG0-of (f / function-01~e.2)) :op2 (p4 / possible-01~e.12 :ARG1 (p / phosphorylate-01~e.13 :ARG1 (a4 / amino-acid :mod 259 :name (n6 / name :op1 "serine") :part-of (e2 / enzyme :name (n4 / name :op1 "C-Raf"))) :ARG2 (p7 / pathway~e.8 :name (n5 / name :op1 "Akt"~e.7,11) :ARG1-of (a3 / activate-01~e.10)) :ARG0-of (c2 / cause-01 :ARG1 (p5 / place-01~e.18 :ARG1 (r / regulate-01~e.20 :ARG1 p2~e.19) :ARG2 (r3 / relative-position :op1 p7~e.23,24 :direction (d / downstream~e.21))))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 32~e.27 :op2 33~e.31)))))) # ::id a_pmid_2169_9731.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MH @-@ S co @-@ culture stimulated cRaf phosphorylation at S259 in all three cell lines , resulting in significantly higher levels of p @-@ cRaf ( Figure 3A @-@ C ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1 4-1.1 5-1.1 6-1 8-1.2 8-1.3.2.2 11-1.4.r 12-1.4.2 13-1.4.1 14-1.4 15-1.4 18-1.3.r 19-1.3.1.2 20-1.3.1 20-1.3.1.1 20-1.3.1.1.r 21-1.3 23-1.2 23-1.3.2.2 27-1.5.1.1 27-1.5.1.2 27-1.5.1.3 29-1.5.1.1.1 31-1.2.1.3.1.1 31-1.3.2.1.1 (s / stimulate-01~e.6 :ARG0 (c / coculture-01~e.3,4,5 :ARG1 (m / macrophage :mod (c3 / cell-line :name (n / name :op1 "MH-S"~e.0,2)))) :ARG1 (p / phosphorylate-01~e.8,23 :ARG1 (a / amino-acid :mod 259 :name (n2 / name :op1 "serine") :part-of (e / enzyme :name (n3 / name :op1 "C-Raf"~e.31)))) :ARG3~e.18 (l / level~e.21 :ARG1-of (h / high-02~e.20 :degree~e.20 (m2 / more~e.20) :ARG1-of (s2 / significant-02~e.19)) :quant-of (e2 / enzyme :name (n4 / name :op1 "C-Raf"~e.31) :ARG3-of (p2 / phosphorylate-01~e.8,23))) :location~e.11 (c2 / cell-line~e.14,15 :quant 3~e.13 :mod (a2 / all~e.12)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.27 :mod "3A"~e.29) :op2 (f2 / figure~e.27 :mod "3B") :op3 (f3 / figure~e.27 :mod "3C")))) # ::id a_pmid_2169_9731.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The smaller (~ 74 kDa ) p @-@ cRaf isoform was most highly abundant and its phosphorylation significantly increased with macrophage co @-@ culture in the LM2 and E10 cells , but a larger (~ 100 kDa ) isoform was heavily phosphorylated at the expense of the 74 kDa isoform in neoplastic JF32 cells ( Figure 3A ) . # ::alignments 1-1.1.1.1.3 1-1.1.1.1.3.1 1-1.1.1.1.3.1.r 3-1.1.1.1.2.1.1.1 4-1.1.1.1.2.1.1.2 6-1.1.1.1.1.2 9-1.1.1.1 10-1.1.1.1.r 11-1.1.1.2.1 12-1.1.1.2 13-1.1.1 14-1.1 16-1.1.1.1.1.2 16-1.1.2.1 17-1.1.2.2 18-1.1.2 19-1.1.2.3.r 20-1.1.2.3.1 21-1.1.2.3 22-1.1.2.3 23-1.1.2.3 24-1.1.2.3.2.r 26-1.1.2.3.2.1.1.1 27-1.1.2.3.2 28-1.1.2.3.2.2.1.1 29-1.1.2.3.2.1 29-1.1.2.3.2.2 31-1 33-1.2.1.1 33-1.2.1.1.1 33-1.2.1.1.1.r 35-1.2.1.2.1.1.1 36-1.2.1.2.1.1.2 38-1.2.1 40-1.2.2 40-1.2.2.r 41-1.2 42-1.2.3.r 44-1.2.3 45-1.2.3 47-1.2.3.1.1 48-1.2.3.1.1 49-1.2.3.1 50-1.2.4.r 51-1.2.4.2 52-1.2.4.1.1 53-1.2.4 55-1.3.1 57-1.3.1.1 (c / contrast-01~e.31 :ARG1 (a / and~e.14 :op1 (a2 / abundant~e.13 :domain~e.10 (i / isoform~e.9 :mod (e / enzyme :name (n / name :op1 "C-Raf") :ARG3-of (p2 / phosphorylate-01~e.6,16)) :ARG1-of (e2 / equal-01 :ARG2 (a4 / approximately :op1 (m2 / mass-quantity :quant 74~e.3 :unit (k / kilodalton~e.4)))) :mod (s / small~e.1 :degree~e.1 (m3 / more~e.1))) :ARG1-of (h / high-02~e.12 :degree (m / most~e.11))) :op2 (i2 / increase-01~e.18 :ARG1 (p3 / phosphorylate-01~e.16 :ARG1 e) :ARG2 (s2 / significant-02~e.17) :instrument~e.19 (c2 / coculture-01~e.21,22,23 :ARG1 (m4 / macrophage~e.20) :location~e.24 (a3 / and~e.27 :op1 (c3 / cell-line~e.29 :name (n2 / name :op1 "LM2"~e.26)) :op2 (c4 / cell-line~e.29 :name (n3 / name :op1 "E10"~e.28)))))) :ARG2 (p / phosphorylate-01~e.41 :ARG1 (i3 / isoform~e.38 :mod (l / large~e.33 :degree~e.33 (m5 / more~e.33)) :ARG1-of (e3 / equal-01 :ARG2 (a5 / approximately :op1 (m6 / mass-quantity :quant 100~e.35 :unit (k2 / kilodalton~e.36))))) :manner~e.40 (h2 / heavy~e.40) :ARG0-of~e.42 (c5 / compromise-02~e.44,45 :ARG1 (i4 / isoform~e.49 :quant m2~e.47,48)) :location~e.50 (c6 / cell-line~e.53 :name (n5 / name :op1 "JF32"~e.52) :mod (n6 / neoplastic~e.51))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.55 :mod "3A"~e.57))) # ::id a_pmid_2169_9731.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The 74 kDa isoform was the most abundant in total cRaf immunoblots from all three cell lines . # ::alignments 1-1.3.1.1 2-1.3.1.2 3-1.3 4-1.3.r 6-1.1 7-1 9-1.2.3 13-1.2.2.2 14-1.2.2.1 15-1.2.2 16-1.2.2 (a / abundant~e.7 :degree (m / most~e.6) :location (i2 / immunoblot-01 :ARG1 (e / enzyme :name (n2 / name :op1 "C-Raf")) :ARG2 (c / cell-line~e.15,16 :quant 3~e.14 :mod (a2 / all~e.13)) :mod (t / total~e.9)) :domain~e.4 (i / isoform~e.3 :quant (m2 / mass-quantity :quant 74~e.1 :unit (k / kilodalton~e.2)))) # ::id a_pmid_2169_9731.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MH @-@ S co @-@ culture significantly increased the levels of active Erk1 @/@ 2 ( p @-@ Erk ) in LM2 and JF32 cells , as well as non @-@ neoplastic E10 cells , when normalized either to total Erk ( panErk ) or β-actin levels ( Figure 3A , D and 3E ) , which correlates with the observed increases in proliferation ( Figure 2 ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1 4-1.1 5-1.1 6-1.3 7-1 9-1.2 10-1.2.1.r 11-1.2.1.3 12-1.2.1.1.1.1 13-1.2.1 14-1.7.2.1.1 16-1.2.1.4.1.2 18-1.2.1.4.1.1.1 20-1.4.r 21-1.4.1.1.1 22-1.4 23-1.4.2.1.1 24-1.4.1 24-1.4.2 24-1.4.3 26-1.4 27-1.4 28-1.4 29-1.4.3.2.1 29-1.4.3.2.1.r 31-1.4.3.2 32-1.4.3.1.1 33-1.1.1.1 33-1.4.3 36-1.5 38-1.5.2 39-1.5.2.1.1.1.2 40-1.5.2.1.1.1.1.1 40-1.5.2.1.1.1.3.1.1.1 44-1.5.2.1 45-1.5.2.1.2.1.1.1 46-1.5.2.1.1 46-1.5.2.1.2 48-1.6.1.1 48-1.6.1.2 48-1.6.1.3 50-1.6.1.1.1 54-1.6.1 56-1.6.1.3.1 61-1.7 62-1.7.1.r 64-1.7.1.2 65-1.7.1 66-1.7.1.1.r 67-1.7.1.1 69-1.7.2.1 71-1.7.2.1.1 (i / increase-01~e.7 :ARG0 (c / coculture-01~e.3,4,5 :ARG1 (m / macrophage :mod (c7 / cell-line~e.33 :name (n / name :op1 "MH-S"~e.0,2)))) :ARG1 (l / level~e.9 :quant-of~e.10 (s2 / slash~e.13 :op1 (e3 / enzyme :name (n10 / name :op1 "Erk1"~e.12)) :op2 (e4 / enzyme :name (n11 / name :op1 "Erk2")) :ARG0-of (a / activity-06~e.11) :ARG1-of (m2 / mean-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Erk"~e.18) :ARG3-of (p3 / phosphorylate-01~e.16))))) :ARG2 (s / significant-02~e.6) :location~e.20 (a2 / and~e.22,26,27,28 :op1 (c2 / cell-line~e.24 :name (n3 / name :op1 "LM2"~e.21)) :op2 (c3 / cell-line~e.24 :name (n4 / name :op1 "JF32"~e.23)) :op3 (c4 / cell-line~e.24,33 :name (n5 / name :op1 "E10"~e.32) :mod (n6 / neoplastic~e.31 :polarity~e.29 -~e.29))) :condition (n7 / normalize-01~e.36 :ARG1 s2 :ARG1-of (c6 / conform-01~e.38 :ARG2 (o / or~e.44 :op1 (l3 / level~e.46 :quant-of (e2 / enzyme :name (n8 / name :op1 "Erk"~e.40) :mod (t / total~e.39) :ARG1-of (m3 / mean-01 :ARG2 (e5 / enzyme :name (n12 / name :op1 "Erk"~e.40) :mod (p4 / pan))))) :op2 (l2 / level~e.46 :quant-of (p / protein :name (n9 / name :op1 "β-actin"~e.45)))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.54 :op1 (f / figure~e.48 :mod "3A"~e.50) :op2 (f2 / figure~e.48 :mod "3D") :op3 (f3 / figure~e.48 :mod "3E"~e.56))) :ARG1-of (c5 / correlate-01~e.61 :ARG2~e.62 (i2 / increase-01~e.65 :ARG1~e.66 (p2 / proliferate-01~e.67) :ARG1-of (o2 / observe-01~e.64)) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure~e.69 :mod 2~e.14,71)))) # ::id a_pmid_2169_9731.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E10 cells expressed lower basal p @-@ Erk @/@ panErk vs. the neoplastic cell lines , consistent with previous observations [ @ 21 @ ] . # ::alignments 0-1.2.1.1 1-1.2 2-1 2-1.3.1 3-1.1.4 3-1.1.4.1 3-1.1.4.1.r 4-1.1.3 5-1.1.1.2 7-1.1.1.1.1 7-1.1.2.1.1 8-1.1 10-1.3 12-1.3.1.2.1 13-1.3.1.2 14-1.3.1.2 16-1.4 17-1.4.1.r 18-1.4.1.1 19-1.4.1 22-1.5.1.1.1 (e / express-03~e.2 :ARG2 (s / slash~e.8 :op1 (e3 / enzyme :name (n4 / name :op1 "Erk"~e.7) :ARG3-of (p4 / phosphorylate-01~e.5)) :op2 (e4 / enzyme :name (n5 / name :op1 "Erk"~e.7) :mod (p5 / pan)) :mod (b / basal~e.4) :ARG1-of (l / low-04~e.3 :degree~e.3 (m / more~e.3))) :ARG3 (c / cell-line~e.1 :name (n / name :op1 "E10"~e.0)) :ARG1-of (c2 / contrast-01~e.10 :ARG2 (e2 / express-03~e.2 :ARG2 s :ARG3 (c3 / cell-line~e.13,14 :mod (n3 / neoplastic~e.12)))) :ARG1-of (c4 / consistent-01~e.16 :ARG2~e.17 (o / observe-01~e.19 :time (p2 / previous~e.18))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c5 / cite-01 :ARG2 21~e.22)))) # ::id a_pmid_2169_9731.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total Erk remained unchanged in both neoplastic cell lines , while macrophage co @-@ culture caused Erk2 ( 42 kDa ) to nearly disappear in the E10 cells , with little effect on Erk1 ( Figure 3A , D and 3E ) . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 2-1.1 3-1.1.2 3-1.1.2.1 3-1.1.2.1.r 4-1.1.2.3.r 5-1.1.2.3.1 6-1.1.2.3.2 7-1.1.2.3 8-1.1.2.3 10-1 11-1.2.1.1 12-1.2.1 13-1.2.1 14-1.2.1 15-1.2 16-1.2.2.2.1.1 22-1.2.2.3 23-1.2.2 24-1.2.2.4.r 26-1.2.2.4.1.1 27-1.2.2.4 29-1.2.3.r 30-1.2.3.2 31-1.2.3 32-1.2.3.1.r 33-1.2.3.1.1.1 35-1.3.1.1 35-1.3.1.2 35-1.3.1.3 37-1.3.1.1.1 41-1.3.1 43-1.3.1.3.1 (c / contrast-01~e.10 :ARG1 (r / remain-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "Erk"~e.1) :mod (t / total~e.0)) :ARG3 (c2 / change-01~e.3 :polarity~e.3 -~e.3 :ARG1 e :location~e.4 (c6 / cell-line~e.7,8 :mod (b / both~e.5) :mod (n6 / neoplastic~e.6)))) :ARG2 (c3 / cause-01~e.15 :ARG0 (c4 / coculture-01~e.12,13,14 :ARG1 (m / macrophage~e.11)) :ARG1 (d / disappear-01~e.23 :ARG0 c4 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk2"~e.16)) :mod (n3 / near~e.22) :location~e.24 (c5 / cell-line~e.27 :name (n4 / name :op1 "E10"~e.26))) :ARG0-of~e.29 (a / affect-01~e.31 :ARG1~e.32 (e3 / enzyme :name (n5 / name :op1 "Erk1"~e.33)) :degree (l / little~e.30))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.41 :op1 (f / figure~e.35 :mod "3A"~e.37) :op2 (f2 / figure~e.35 :mod "3D") :op3 (f3 / figure~e.35 :mod "3E"~e.43)))) # ::id a_pmid_2169_9731.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated Akt ( p @-@ Akt ) levels rose significantly in both neoplastic cell lines when normalized to either total Akt ( panAkt ) or β-actin , but macrophage co @-@ culture caused both p @-@ Akt and panAkt levels to rise to similar extents in E10 cells ( Figure 3A and 3F ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1.1 1-1.1.1.1.3.1.1.1 3-1.1.1.1.3.1.2 5-1.1.1.1.1.1 5-1.1.1.1.3.1.1.1 7-1.1.1 8-1.1 9-1.1.2 10-1.1.3.r 11-1.1.3.1 12-1.1.3.2 13-1.1.3 14-1.1.3 16-1.1.4 17-1.1.4.2 19-1.1.4.2.1.1.2 20-1.1.4.2.1.1.1.1 24-1.1.4.2.1 25-1.1.4.2.1.2.1.1 27-1 28-1.2.1.1 29-1.2.1 30-1.2.1 31-1.2.1 32-1.2 33-1.1.3.1 34-1.2.2.2.1.1 35-1.2.2.2.1.1 36-1.2.2.2.1.1 37-1.2.2.2.1 39-1.2.2.2 41-1.2.2 42-1.2.2.3.r 43-1.2.2.3.1 44-1.2.2.3 47-1.2.2.4 49-1.3.1.1 49-1.3.1.2 51-1.3.1.1.1 53-1.3.1 55-1.3.1.2.1 (c / contrast-01~e.27 :ARG1 (r / rise-01~e.8 :ARG1 (l / level~e.7 :quant-of (e / enzyme :name (n / name :op1 "Akt"~e.1,5) :ARG1-of (a / activate-01~e.0) :ARG1-of (m2 / mean-01 :ARG2 (e3 / enzyme :name (n6 / name :op1 "Akt"~e.1,5) :ARG3-of (p2 / phosphorylate-01~e.3))))) :ARG2 (s / significant-02~e.9) :location~e.10 (c3 / cell-line~e.13,14 :mod (b / both~e.11,33) :mod (n2 / neoplastic~e.12)) :condition (n3 / normalize-01~e.16 :ARG1 e :ARG1-of (c5 / conform-01~e.17 :ARG2 (o / or~e.24 :op1 (e2 / enzyme :name (n4 / name :op1 "Akt"~e.20) :mod (t / total~e.19)) :op2 (p / protein :name (n5 / name :op1 "β-actin"~e.25)))))) :ARG2 (c2 / cause-01~e.32 :ARG0 (c4 / coculture-01~e.29,30,31 :ARG1 (m / macrophage~e.28)) :ARG1 (r3 / rise-01~e.41 :ARG0 c4 :ARG1 (l2 / level~e.39 :quant-of (a2 / and~e.37 :op1 e~e.34,35,36 :op2 e2)) :ARG2~e.42 (e4 / extent~e.44 :ARG1-of (r4 / resemble-01~e.43 :ARG2 l)) :location c3~e.47)) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.53 :op1 (f / figure~e.49 :mod "3A"~e.51) :op2 (f2 / figure~e.49 :mod "3F"~e.55)))) # ::id a_pmid_2169_9731.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When p @-@ Akt was normalized to panAkt expression , there was no change in E10 cells with MH @-@ S co @-@ culture ( Figure 3F ) . # ::alignments 0-1.3.r 1-1.3.1.2 3-1.3.1.1.1 3-1.3.2.1.1.1 5-1.3 6-1.3.2 8-1.3.2.1 8-1.3.2.1.3 8-1.3.2.1.3.r 12-1.1 12-1.1.r 13-1 14-1.2.r 15-1.2.1.1 16-1.2 16-1.2.2.1.1.1 18-1.2.2.1.1.1.1.1 20-1.2.2.1.1.1.1.1 21-1.2.2.1 22-1.2.2.1 23-1.2.2.1 25-1.4.1 27-1.4.1.1 (c / change-01~e.13 :polarity~e.12 -~e.12 :ARG1~e.14 (c2 / cell-line~e.16 :name (n / name :op1 "E10"~e.15) :ARG0-of (c3 / contain-01 :ARG1 (c4 / coculture-01~e.21,22,23 :ARG1 (m / macrophage :mod (c6 / cell-line~e.16 :name (n2 / name :op1 "MH-S"~e.18,20)))))) :time~e.0 (n3 / normalize-01~e.5 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Akt"~e.3) :ARG3-of (p / phosphorylate-01~e.1)) :ARG1-of (c5 / conform-01~e.6 :ARG2 (e3 / enzyme~e.8 :name (n6 / name :op1 "Akt"~e.3) :mod (p3 / pan) :ARG2-of~e.8 (e / express-03~e.8)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "3F"~e.27))) # ::id a_pmid_2169_9731.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total Akt expression increased slightly in LM2 cells but decreased in JF32 cells ( Figure 3A ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1.1 2-1.1.1 3-1.1 4-1.1.2 5-1.1.3.r 6-1.1.3.1.1 7-1.1.3 8-1 9-1.2 10-1.2.2.r 11-1.2.2.1.1 12-1.2.2 14-1.3.1 16-1.3.1.1 (c / contrast-01~e.8 :ARG1 (i2 / increase-01~e.3 :ARG1 (e / express-03~e.2 :ARG2 (e2 / enzyme :name (n / name :op1 "Akt"~e.1) :mod (t / total~e.0))) :ARG2 (s / slight~e.4) :location~e.5 (c2 / cell-line~e.7 :name (n2 / name :op1 "LM2"~e.6))) :ARG2 (d / decrease-01~e.9 :ARG1 e :location~e.10 (c3 / cell-line~e.12 :name (n3 / name :op1 "JF32"~e.11))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.14 :mod "3A"~e.16))) # ::id a_pmid_2169_9731.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When normalized to β-actin , p @-@ Akt levels significantly increased upon MH @-@ S co @-@ culture in all three cell lines ( Figure 3A and 3G ) . # ::alignments 1-1.4 2-1.4.2 3-1.4.2.1.1.1 5-1.2.1.2 7-1.2.1.1.1 8-1.2 9-1.3 10-1 12-1.1.1.1.1.1 14-1.1.1.1.1.1 15-1.1 16-1.1 17-1.1 18-1.5.r 19-1.5.2 20-1.5.1 21-1.5 22-1.5 24-1.6.1.1 24-1.6.1.2 26-1.6.1.1.1 28-1.6.1 30-1.6.1.2.1 (i / increase-01~e.10 :ARG0 (c / coculture-01~e.15,16,17 :ARG1 (m / macrophage :mod (c4 / cell-line :name (n4 / name :op1 "MH-S"~e.12,14)))) :ARG1 (l / level~e.8 :quant-of (e / enzyme :name (n3 / name :op1 "Akt"~e.7) :ARG3-of (p2 / phosphorylate-01~e.5))) :ARG2 (s / significant-02~e.9) :condition (n / normalize-01~e.1 :ARG1 e :ARG1-of (c3 / conform-01~e.2 :ARG2 (p / protein :name (n2 / name :op1 "β-actin"~e.3)))) :location~e.18 (c2 / cell-line~e.21,22 :quant 3~e.20 :mod (a / all~e.19)) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.28 :op1 (f / figure~e.24 :mod "3A"~e.26) :op2 (f2 / figure~e.24 :mod "3G"~e.30)))) # ::id a_pmid_2169_9731.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Increased p @-@ S473 Akt content suggests increased enzymatic activity , which can be confirmed by enhanced phosphorylation of downstream substrates . # ::alignments 0-1.1.2 1-1.1.1.2 1-1.1.1.2.3 1-1.1.1.2.3.r 4-1.1.1.1.1 5-1.1 6-1 7-1.1.2 8-1.2.1 9-1.2 12-1.2.3.2 14-1.2.3 15-1.2.3.1.r 16-1.2.3.1.2 17-1.2.3.1 18-1.2.3.1.1.r 19-1.2.3.1.1.1 20-1.2.3.1.1 (s / suggest-01~e.6 :ARG0 (c / contain-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "Akt"~e.4) :part (a / amino-acid~e.1 :mod 473 :name (n2 / name :op1 "serine") :ARG1-of~e.1 (p / phosphorylate-01~e.1))) :ARG1-of (i / increase-01~e.0,7)) :ARG1 (a2 / activity-06~e.9 :ARG0 (e2 / enzyme~e.8) :ARG1-of i :ARG1-of (c2 / confirm-01~e.14 :ARG0~e.15 (p3 / phosphorylate-01~e.17 :ARG1~e.18 (s2 / substrate~e.20 :direction (d / downstream~e.19)) :ARG1-of (e3 / enhance-01~e.16)) :ARG1-of (p2 / possible-01~e.12)))) # ::id a_pmid_2169_9731.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if macrophage co @-@ culture increases Akt activity , we measured levels of p @-@ GSK @-@ 3β, a known target of Akt [ @ 32 @ ] . # ::alignments 1-1.3 3-1.3.2.1.1 4-1.3.2.1 5-1.3.2.1 6-1.3.2.1 7-1.3.2 8-1.3.2.2.1.1.1 9-1.3.2.2 11-1.1 12-1 13-1.2 14-1.2.1.r 15-1.2.1.3 17-1.2.1.1.1 21-1.2.1.2.2 22-1.2.1 22-1.2.1.2 22-1.2.1.2.r 23-1.2.1.2.1.r 24-1.2.1.2.1 27-1.4.1.1.1 (m / measure-01~e.12 :ARG0 (w / we~e.11) :ARG1 (l / level~e.13 :quant-of~e.14 (e2 / enzyme~e.22 :name (n2 / name :op1 "GSK-3β"~e.17) :ARG1-of~e.22 (t / target-01~e.22 :ARG0~e.23 e~e.24 :ARG1-of (k / know-01~e.21)) :ARG3-of (p / phosphorylate-01~e.15))) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (i / increase-01~e.7 :ARG0 (c / coculture-01~e.4,5,6 :ARG1 (m2 / macrophage~e.3)) :ARG1 (a / activity-06~e.9 :ARG0 (e / enzyme :name (n / name :op1 "Akt"~e.8))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 32~e.27)))) # ::id a_pmid_2169_9731.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the elevation in p @-@ Akt , MH @-@ S co @-@ culture significantly increased p @-@ GSK @-@ 3β in both LM2 and E10 cells and trended towards an increase in JF32 cells ( Figure 3A and 3H ) ; panGSK @-@ 3β levels were unchanged ( data not shown ) . # ::alignments 0-1.2.3 1-1.2.3.1.r 3-1.2.3.1 4-1.2.3.1.1.r 5-1.2.3.1.1.2 7-1.2.3.1.1.1.1 9-1.2.2.2 10-1.2.2.2 11-1.2.2.2 12-1.2.2.2 13-1.2.2.2 14-1.2.2.2 15-1.2.2.2 16-1.2.2.2 17-1.2.2.2 18-1.2.2.2 19-1.2.2.2 20-1.2.2.2 21-1.2.2.2 22-1.2.2.2 23-1.2.2.2 24-1.2.2.2 25-1.2.2.2 26-1.2.2.2 27-1.2.2.2 28-1.2 28-1.2.1.4 29-1.2.2 32-1.2.2.2 34-1.2.2.3.1.1 35-1.2.1.1.1.1 35-1.2.2.3 37-1.2.4.1.1 37-1.2.4.1.2 39-1.2.4.1.1.1 41-1.2.4.1 43-1.2.4.1.2.1 49-1.1.2.1.1.1 50-1.1.2 52-1.1 52-1.1.1 52-1.1.1.r 54-1.1.3.1 55-1.1.3.1.1.1 55-1.1.3.1.1.1.r 56-1.1.3.1.1 (m / multi-sentence :snt2 (c / change-01~e.52 :polarity~e.52 -~e.52 :ARG1 (l / level~e.50 :quant-of (e2 / enzyme :name (n6 / name :op1 "GSK-3β"~e.49) :mod (p2 / pan))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.54 :ARG1-of (s2 / show-01~e.56 :polarity~e.55 -~e.55)))) :snt1 (a2 / and~e.28 :op1 (i / increase-01 :ARG0 (c2 / coculture-01 :ARG1 (m2 / macrophage :mod (c7 / cell-line~e.35 :name (n / name :op1 "MH-S")))) :ARG1 (e / enzyme :name (n2 / name :op1 "GSK-3β") :ARG3-of (p / phosphorylate-01)) :ARG2 (s / significant-02) :location (a / and~e.28 :op1 (c3 / cell-line :name (n3 / name :op1 "LM2")) :op2 (c4 / cell-line :name (n4 / name :op1 "E10")))) :op2 (t / trend-01~e.29 :ARG1 c2 :ARG2 i~e.9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,32 :location (c5 / cell-line~e.35 :name (n5 / name :op1 "JF32"~e.34))) :ARG1-of (c6 / consistent-01~e.0 :ARG2~e.1 (e3 / elevate-01~e.3 :ARG1~e.4 (e4 / enzyme :name (n7 / name :op1 "Akt"~e.7) :ARG3-of p~e.5))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.41 :op1 (f / figure~e.37 :mod "3A"~e.39) :op2 (f2 / figure~e.37 :mod "3H"~e.43))))) # ::id a_pmid_2169_9731.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phospho @-@ S259 cRaf is another measure of Akt activity , and p @-@ cRaf levels increased in all three cell lines with macrophage co @-@ culture ( Figure 3A @-@ C ) . # ::alignments 0-1.1.1.2.3 5-1.1.3 6-1.1 7-1.1.2.r 8-1.1.2.1.1.1 9-1.1.2 12-1.1.1.2.3 15-1.2.1 16-1.2 17-1.2.2.r 18-1.2.2.2 19-1.2.2.1 20-1.2.2 21-1.2.2 23-1.2.2.3.1.1 24-1.2.2.3.1 25-1.2.2.3.1 26-1.2.2.3.1 28-1.3.1.1 28-1.3.1.2 30-1.3.1.1.1 32-1.1.1.1.1 (a / and :op1 (m / measure-01~e.6 :ARG0 (e / enzyme :name (n / name :op1 "C-Raf"~e.32) :part (a2 / amino-acid :mod 259 :name (n2 / name :op1 "serine") :ARG3-of (p / phosphorylate-01~e.0,12))) :ARG1~e.7 (a3 / activity-06~e.9 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Akt"~e.8))) :mod (a4 / another~e.5)) :op2 (i / increase-01~e.16 :ARG1 (l / level~e.15 :quant-of e) :location~e.17 (c / cell-line~e.20,21 :quant 3~e.19 :mod (a5 / all~e.18) :ARG0-of (c2 / contain-01 :ARG1 (c3 / coculture-01~e.24,25,26 :ARG1 (m2 / macrophage~e.23))))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.28 :mod "3A"~e.30) :op2 (f2 / figure~e.28 :mod "3C")))) # ::id a_pmid_2169_9731.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , the observed increases in epithelial proliferation and the known roles for Erk and Akt in neoplastic lung cell division suggest that macrophage co @-@ culture stimulates lung cell proliferation through increased Erk and Akt activity [ @ 34 @ ] . # ::alignments 0-1.1.3 3-1.1.1.2 4-1.1.1 6-1.1.1.1.1 7-1.1.1.1 8-1.1 10-1.1.2.1 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2.1.1.1 15-1.1.2.2.2.1.1 16-1.1.2.3.r 17-1.1.2.3.1.2 18-1.1.2.3.1.1 19-1.1.2.3.1 20-1.1.2.3 21-1 22-1.2.r 23-1.2.1.1 24-1.2.1 25-1.2.1 26-1.2.1 27-1.2 28-1.2.2.1.1 29-1.2.2.1 30-1.2.2 32-1.1.1 32-1.2.3.2 33-1.2.3.1 34-1.2.3.1 35-1.2.3.1 36-1.2.3 39-1.3.1.1.1 (s / suggest-01~e.21 :ARG0 (a / and~e.8 :op1 (i / increase-01~e.4,32 :ARG1 (p / proliferate-01~e.7 :ARG0 (e / epithelium~e.6)) :ARG1-of (o / observe-01~e.3)) :op2 (r / role~e.11 :ARG1-of (k / know-01~e.10) :poss~e.12 (a3 / and :op1 (e2 / enzyme :name (n / name :op1 "Erk"~e.13)) :op2 (e3 / enzyme :name (n2 / name :op1 "Akt"~e.15))) :topic~e.16 (d / divide-02~e.20 :ARG1 (c / cell~e.19 :mod (l / lung~e.18) :mod (n3 / neoplasm~e.17)))) :mod (t / together~e.0)) :ARG1~e.22 (s2 / stimulate-01~e.27 :ARG0 (c2 / coculture-01~e.24,25,26 :ARG1 (m / macrophage~e.23)) :ARG1 (p2 / proliferate-01~e.30 :ARG0 (c4 / cell~e.29 :mod l~e.28)) :manner (a2 / activity-06~e.36 :ARG0 a3~e.33,34,35 :ARG1-of (i2 / increase-01~e.32))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 34~e.39)))) # ::id a_pmid_2169_9731.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combined inhibition of MEK and PI3K abrogates macrophage stimulation of neoplastic growth # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1 7-1.2.1 8-1.2 9-1.2.2.r 10-1.2.2.1 11-1.2.2 (a / abrogate-01~e.6 :ARG0 (i / inhibit-01~e.1 :ARG1~e.2 (a2 / and~e.4 :op1 (e / enzyme :name (n / name :op1 "MEK"~e.3)) :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K"~e.5))) :ARG3-of (c / combine-01~e.0)) :ARG1 (s / stimulate-01~e.8 :ARG0 (m / macrophage~e.7) :ARG1~e.9 (g / grow-01~e.11 :ARG1 (n3 / neoplasm~e.10)))) # ::id a_pmid_2169_9731.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Erk and Akt regulate both proliferation and resistance to apoptotic cell death , are more active in lung tumors than in normal tissue [ @ 21 , 35 @ ] , and were activated with macrophage co @-@ culture . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.2 8-1.1.2.2.1.r 9-1.1.2.2.1.2 10-1.1.2.2.1.1 11-1.1.2.2.1 14-1.2.2 15-1.2 16-1.2.4.r 17-1.2.4.1 18-1.2.4 19-1.2.4.2.r 21-1.2.4.2.1 22-1.2.4.2 25-1.2.3.1.1.1.1 29-1.2.3.1.1.1.2 33-1 33-1.2.3.1.1.1 35-1.3 36-1.3.1.r 37-1.3.1.1 38-1.3.1 39-1.3.1 40-1.3.1 (a / and~e.33 :op1 (r / regulate-01~e.3 :ARG0 (a4 / and~e.1 :op1 (e / enzyme :name (n / name :op1 "Erk"~e.0)) :op2 (e2 / enzyme :name (n2 / name :op1 "Akt"~e.2))) :ARG1 (a5 / and~e.6 :op1 (p / proliferate-01~e.5) :op2 (r2 / resist-01~e.7 :ARG1~e.8 (d / die-01~e.11 :ARG1 (c / cell~e.10) :mod (a6 / apoptosis~e.9))))) :op2 (a2 / activity-06~e.15 :ARG0 a4 :degree (m / more~e.14) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a7 / and~e.33 :op1 21~e.25 :op2 35~e.29)))) :location~e.16 (t / tumor~e.18 :mod (l / lung~e.17) :compared-to~e.19 (t2 / tissue~e.22 :ARG1-of (n3 / normal-02~e.21)))) :op3 (a3 / activate-01~e.35 :ARG0~e.36 (c2 / coculture-01~e.38,39,40 :ARG1 (m2 / macrophage~e.37)) :ARG1 a4)) # ::id a_pmid_2169_9731.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since combined MEK and PI3K inhibition slowed mutant Kras @- @ driven lung tumor growth in vivo @ [ @ 25 @ ] , we determined whether selective inhibition of MEK and PI3K affected macrophage @-@ stimulated proliferation in these Kras @ mutant lung tumor cell lines . # ::alignments 0-1.3 1-1.3.1.1.1 2-1.2.2.1.1.1.1 3-1.2.2.1 4-1.2.2.1.2.1.1 5-1.3.1.1 6-1.3.1 7-1.3.1.2.1.2.1 12-1.3.1.2.1.2 13-1.3.1.2.1.1 14-1.3.1.2.1 15-1.3.1.2 17-1.3.1.2.2 18-1.3.1.2.2 22-1.3.1.3.1.1.1 26-1.1 27-1 28-1.2.1 28-1.2.1.r 29-1.2.2.2 30-1.2.2 32-1.2.2.1.1.1.1 33-1.2.2.1 34-1.2.2.1.2.1.1 35-1.2 36-1.2.3.1.1 38-1.2.3.1 39-1.2.3 40-1.3.1.2.2 45-1.2.3.2.1 45-1.2.3.2.1.2 45-1.2.3.2.1.2.r 46-1.2.3.2.3 47-1.2.3.2.2 48-1.2.3.2 49-1.2.3.2 (d / determine-01~e.27 :ARG0 (w / we~e.26) :ARG1 (a / affect-01~e.35 :mode~e.28 interrogative~e.28 :ARG0 (i / inhibit-01~e.30 :ARG1 (a2 / and~e.3,33 :op1 (e / enzyme :name (n / name :op1 "MEK"~e.2,32)) :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K"~e.4,34))) :manner (s / selective~e.29)) :ARG1 (p / proliferate-01~e.39 :ARG1-of (s2 / stimulate-01~e.38 :ARG0 (m / macrophage~e.36)) :location (c / cell-line~e.48,49 :mod (g2 / gene~e.45 :name (n3 / name :op1 "K-Ras") :ARG2-of~e.45 (m2 / mutate-01~e.45)) :mod (t / tumor~e.47) :mod (l / lung~e.46)))) :ARG1-of (c2 / cause-01~e.0 :ARG0 (s3 / slow-01~e.6 :ARG0 (i4 / inhibit-01~e.5 :ARG3-of (c4 / combine-01~e.1)) :ARG1 (g / grow-01~e.15 :ARG1 (t2 / tumor~e.14 :mod (l2 / lung~e.13) :ARG1-of (d2 / drive-02~e.12 :ARG0 g2~e.7)) :manner (i2 / in-vivo~e.17,18,40)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 25~e.22)))))) # ::id a_pmid_2169_9731.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Selective inhibition of either MEK ( by U0126 ) or PI3K ( by LY294002 ) significantly decreased basal proliferation , and blocked growth stimulated by macrophage co @-@ culture to different extents in LM2 and JF32 cells ( Figure 4A and 4B , respectively ) . # ::alignments 0-1.1.1.3 1-1.1.1.1 1-1.1.1.2 4-1.1.1.1.2.1.1 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1 9-1.1.1 10-1.1.1.2.2.1.1 12-1.1.1.2.1.r 13-1.1.1.2.1.1.1 15-1.1.3 16-1.1 17-1.1.2.1 18-1.1.2 20-1 21-1.2 22-1.2.2 23-1.2.2.1 24-1.2.2.1.1.r 25-1.2.2.1.1.1 26-1.2.2.1.1 27-1.2.2.1.1 28-1.2.2.1.1 29-1.2.2.1.2.r 30-1.2.2.1.2.1 31-1.2.2.1.2 32-1.2.3.r 33-1.2.3.1.1.1 34-1.2.3 35-1.2.3.2.1.1 36-1.2.3.1 36-1.2.3.2 38-1.3.1.1 38-1.3.1.2 40-1.3.1.1.1 42-1.3.1 44-1.3.1.2.1 47-1.3.2 (a / and~e.20 :op1 (d / decrease-01~e.16 :ARG0 (o2 / or~e.9 :op1 (i2 / inhibit-01~e.1 :ARG0~e.6 (s2 / small-molecule :name (n3 / name :op1 "U0126"~e.7)) :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.4))) :op2 (i3 / inhibit-01~e.1 :ARG0~e.12 (s3 / small-molecule :name (n4 / name :op1 "LY294002"~e.13)) :ARG1 (e2 / enzyme :name (n2 / name :op1 "PI3K"~e.10))) :manner (s / selective~e.0)) :ARG1 (p / proliferate-01~e.18 :mod (b2 / basal~e.17)) :ARG2 (s4 / significant-02~e.15)) :op2 (b / block-01~e.21 :ARG0 o2 :ARG1 (g / grow-01~e.22 :ARG1-of (s5 / stimulate-01~e.23 :ARG0~e.24 (c / coculture-01~e.26,27,28 :ARG1 (m / macrophage~e.25)) :degree~e.29 (e3 / extent~e.31 :ARG1-of (d2 / differ-02~e.30)))) :location~e.32 (a2 / and~e.34 :op1 (c2 / cell-line~e.36 :name (n5 / name :op1 "LM2"~e.33)) :op2 (c3 / cell-line~e.36 :name (n6 / name :op1 "JF32"~e.35)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.42 :op1 (f / figure~e.38 :mod "4A"~e.40) :op2 (f2 / figure~e.38 :mod "4B"~e.44)) :mod (r / respective~e.47))) # ::id a_pmid_2169_9731.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only the combined inhibition of both kinases ablated the stimulatory effect of macrophage co @-@ culture on neoplastic proliferation ( U0 + LY , Figure 4 ) . # ::alignments 0-1.2.4 2-1.2.3 3-1.2 4-1.2.2.r 5-1.2.2.1 6-1.2.2 7-1 10-1.1 11-1.1.1.r 12-1.1.1.1 13-1.1.1 14-1.1.1 15-1.1.1 16-1.1.2.r 17-1.1.2.1 18-1.1.2 20-1.2.3.1.1.1.1.1 21-1.2.3.1.1 22-1.2.3.1.1.2.1.1 24-1.2.3.1.2.1 26-1.2.3.1.2.1.1 (a / ablate-01~e.7 :ARG1 (a2 / affect-01~e.10 :ARG0~e.11 (c / coculture-01~e.13,14,15 :ARG1 (m / macrophage~e.12)) :ARG1~e.16 (p / proliferate-01~e.18 :ARG0 (n / neoplasm~e.17)) :ARG2 (s / stimulate-01)) :ARG3 (i / inhibit-01~e.3 :ARG0 a3 :ARG1~e.4 (k / kinase~e.6 :mod (b / both~e.5)) :ARG3-of (c2 / combine-01~e.2 :ARG1-of (m2 / mean-01 :ARG2 (a3 / and~e.21 :op1 (s3 / small-molecule :name (n2 / name :op1 "U0"~e.20)) :op2 (s4 / small-molecule :name (n3 / name :op1 "LY"~e.22))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod 4~e.26)))) :mod (o / only~e.0))) # ::id a_pmid_2169_9731.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Kinase inhibitors were applied at concentrations reported to be cytostatic and not cytotoxic [ @ 34 , 36 , 37 @ ] , and none of these treatments significantly increased LM2 or JF32 cell death ( data not shown ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1.1 1-1.1.1.1.1 1-1.1.1.1.1.r 3-1.1 5-1.1.1 6-1.1.1.2 9-1.1.1.3 11-1.1.1.4.1 11-1.1.1.4.1.r 12-1.1.1.4 15-1.1.2.1.1.1.1 19-1.1.2.1.1.1.2 23-1.1.2.1.1.1.3 27-1 27-1.1.2.1.1.1 28-1.2.1.2 29-1.2.1.2.r 30-1.2.1.1 31-1.2.1 32-1.2.3 33-1.2 34-1.2.2.1.1.1.1 35-1.2.2.1 36-1.2.2.1.2.1.1 37-1.2.2.1.1 37-1.2.2.1.2 38-1.2.2 40-1.3.1 41-1.3.1.1.1 41-1.3.1.1.1.r 42-1.3.1.1 (a / and~e.27 :op1 (a2 / apply-02~e.3 :ARG1 (c / concentrate-02~e.5 :ARG1 (m / molecular-physical-entity~e.1 :ARG0-of~e.1 (i2 / inhibit-01~e.1 :ARG1 (k / kinase~e.0))) :ARG1-of (r / report-01~e.6) :mod (c2 / cytostatic~e.9) :mod (c3 / cytotoxic~e.12 :polarity~e.11 -~e.11)) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c6 / cite-01 :ARG2 (a3 / and~e.27 :op1 34~e.15 :op2 36~e.19 :op3 37~e.23))))) :op2 (i / increase-01~e.33 :ARG0 (t / treatment~e.31 :mod (t2 / this~e.30) :quant~e.29 (n / none~e.28)) :ARG1 (d3 / die-01~e.38 :ARG1 (o / or~e.35 :op1 (c4 / cell-line~e.37 :name (n2 / name :op1 "LM2"~e.34)) :op2 (c5 / cell-line~e.37 :name (n3 / name :op1 "JF32"~e.36)))) :ARG2 (s2 / significant-02~e.32)) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.40 :ARG1-of (s / show-01~e.42 :polarity~e.41 -~e.41)))) # ::id a_pmid_2169_9731.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that both the MEK and PI3K pathways must be blocked to effectively inhibit macrophage @-@ stimulated neoplastic growth . # ::alignments 0-1.3.1.2 1-1.3.1 1-1.3.1.1 1-1.3.1.1.r 2-1.3 6-1.1.1.1.1 7-1.1 8-1.1.2.1.1 9-1.1.1 9-1.1.2 10-1 12-1.2 14-1.2.2.3 15-1.2.2 16-1.2.2.2.2.1 18-1.2.2.2.2 19-1.2.2.2.1 20-1.2.2.2 (o / obligate-01~e.10 :ARG1 (a / and~e.7 :op1 (p / pathway~e.9 :name (n / name :op1 "MEK"~e.6)) :op2 (p2 / pathway~e.9 :name (n2 / name :op1 "PI3K"~e.8))) :ARG2 (b / block-01~e.12 :ARG1 a :purpose (i / inhibit-01~e.15 :ARG0 a :ARG1 (g / grow-01~e.20 :ARG1 (n3 / neoplasm~e.19) :ARG1-of (s2 / stimulate-01~e.18 :ARG0 (m / macrophage~e.16))) :ARG1-of (e / effective-04~e.14))) :ARG1-of (s / suggest-01~e.2 :ARG0 (t2 / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t / this~e.0)))) # ::id a_pmid_2169_9731.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophage conditioned media contains 3 @-@ 10 kDa factors which stimulate neoplastic proliferation # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.2.1.1 6-1.2.2.2.1 7-1.2.2.1.2 7-1.2.2.2.2 8-1.2 10-1.2.1 11-1.2.1.1.1 12-1.2.1.1 (c / contain-01~e.3 :ARG0 (m / medium~e.2 :ARG1-of (c2 / condition-01~e.1 :ARG2 (m2 / macrophage~e.0))) :ARG1 (f / factor~e.8 :ARG0-of (s / stimulate-01~e.10 :ARG1 (p / proliferate-01~e.12 :ARG0 (n / neoplasm~e.11))) :quant (b / between :op1 (m3 / mass-quantity :quant 3~e.4 :unit (k3 / kilodalton~e.7)) :op2 (m4 / mass-quantity :quant 10~e.6 :unit (k4 / kilodalton~e.7))))) # ::id a_pmid_2169_9731.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophages produce numerous cytokines , eicosanoids and other soluble factors depending upon tissue location and environmental stimuli [ @ 4 , 18 @ ] , any number of which could be responsible for the observed neoplastic growth stimulation described above . # ::alignments 0-1.1 1-1 2-1.2.1.1 3-1.2.1 6-1.2 7-1.2.3.2 8-1.2.3.1 9-1.2.3 10-1.3 12-1.3.1.1.1 13-1.3.1.1 14-1.3.1 15-1.3.1.2.1 16-1.3.1.2 19-1.4.1.1.1.1 23-1.4.1.1.1.2 27-1.2.5.1 28-1.2.5 31-1.2.4.2 33-1.2.4 34-1.2.4.1.r 36-1.2.4.1.1.2 37-1.2.4.1.1.1 38-1.2.4.1.1 39-1.2.4.1 40-1.2.4.1.2 40-1.4 41-1.2.4.1.2.1 (p / produce-01~e.1 :ARG0 (m / macrophage~e.0) :ARG1 (a / and~e.6 :op1 (c / cytokine~e.3 :quant (n / numerous~e.2)) :op2 (e / eicosanoid) :op3 (f / factor~e.9 :mod (s / soluble~e.8) :mod (o / other~e.7)) :ARG0-of (r / responsible-01~e.33 :ARG1~e.34 (s3 / stimulate-01~e.39 :ARG1 (g / grow-01~e.38 :ARG1 (n2 / neoplasm~e.37) :ARG1-of (o2 / observe-01~e.36)) :ARG1-of (d2 / describe-01~e.40 :location (a4 / above~e.41))) :ARG1-of (p2 / possible-01~e.31)) :quant (n3 / number~e.28 :mod (a3 / any~e.27))) :ARG0-of (d / depend-01~e.10 :ARG1 (a2 / and~e.14 :op1 (l / location~e.13 :mod (t / tissue~e.12)) :op2 (s2 / stimulus~e.16 :mod (e2 / environment~e.15)))) :ARG1-of (d3 / describe-01~e.40 :ARG0 (p3 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 4~e.19 :op2 18~e.23))))) # ::id a_pmid_2169_9731.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Media conditioned by primary BAL macrophages ( MØCM ) stimulated the proliferation of LM2 cells , albeit to a lesser extent than primary macrophage co @-@ culture ( Figure 5 " Total " vs. Figure 2B ) . # ::alignments 0-1.1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2 4-1.1.1.1.1 4-1.1.1.1.1.1 4-1.1.1.1.1.1.r 5-1.1.1.1 9-1 9-1.4 9-1.4.r 11-1.2 12-1.2.1.r 13-1.2.1.1.1 14-1.2.1 17-1.4.3.r 19-1.4.3 19-1.4.3.1 19-1.4.3.1.r 21-1.4.5.r 22-1.4.5.1.1 23-1.4.5.1 24-1.4.5 25-1.4.5 26-1.4.5 28-1.3.1 30-1.3.1.1 33-1.3.2 35-1.4.5.r 36-1.4.4.1 38-1.4.4.1.1 (s / stimulate-01~e.9 :ARG0 (m / medium~e.0 :ARG1-of (c / condition-01~e.1 :ARG0~e.2 (m2 / macrophage~e.5 :source (a / alveolus~e.4 :mod~e.4 (b / bronchus~e.4)) :mod (p / primary~e.3)))) :ARG1 (p2 / proliferate-01~e.11 :ARG0~e.12 (c2 / cell-line~e.14 :name (n2 / name :op1 "LM2"~e.13))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod 5~e.30) :ARG2 (t / total~e.33)) :concession~e.9 (s2 / stimulate-01~e.9 :ARG0 m :ARG1 p2 :degree~e.17 (l / less~e.19 :degree~e.19 (m4 / more~e.19)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.36 :mod "2B"~e.38)) :compared-to~e.21,35 (c3 / coculture-01~e.24,25,26 :ARG1 (m5 / macrophage~e.23 :mod (p3 / primary~e.22))))) # ::id a_pmid_2169_9731.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When size @-@ fractionated MØCM was added to LM2 cells , molecules between 3 and 10 kDa stimulated LM2 growth to the greatest extent ( Figure 5 ) . # ::alignments 1-1.4.1.1.1 3-1.4.1.1 6-1.4 7-1.4.2.r 8-1.4.2 9-1.4.2 11-1.1 12-1.1.1.1 13-1.1.1.1.1 14-1.1.1.1 15-1.1.1.1.2 16-1.1.1.2 17-1 18-1.2.1.1.1 19-1.2 20-1.3.r 22-1.3 22-1.3.1 22-1.3.1.r 25-1.5.1 27-1.5.1.1 (s / stimulate-01~e.17 :ARG0 (m2 / molecule~e.11 :mod (m3 / mass-quantity :quant (b / between~e.12,14 :op1 3~e.13 :op2 10~e.15) :unit (k / kilodalton~e.16))) :ARG1 (g2 / grow-01~e.19 :ARG1 (c / cell-line :name (n / name :op1 "LM2"~e.18))) :degree~e.20 (g / great~e.22 :degree~e.22 (m / most~e.22)) :condition (a / add-02~e.6 :ARG1 (m4 / medium :ARG1-of (f / fractionate-00~e.3 :mod (s2 / size~e.1)) :ARG1-of (c2 / condition-01 :ARG0 (m5 / macrophage))) :ARG2~e.7 c~e.8,9) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.25 :mod 5~e.27))) # ::id a_pmid_2169_9731.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , factors of this size mediated the majority of MØCM effects on LM2 growth . # ::alignments 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1 5-1.1.1.1 6-1.1 8-1.1.2.3 9-1.1.2.3.r 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2.1.1.1 14-1.1.2.2 (i / infer-01 :ARG1 (m / mediate-01~e.6 :ARG0 (f / factor~e.2 :mod~e.3 (s / size~e.5 :mod (t / this~e.4))) :ARG1 (a / affect-01~e.11 :ARG0 (m3 / medium :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage))) :ARG1~e.12 (g / grow-01~e.14 :ARG0 (c / cell-line :name (n2 / name :op1 "LM2"~e.13))) :quant~e.9 (m2 / majority~e.8)))) # ::id a_pmid_2169_9731.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alveolar macrophages produce numerous growth factors in this size range , including IGF @-@ 1 , GM @-@ CSF and EGF [ @ 11 , 18 @ ] . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.2 4-1.2 5-1.2 6-1.3.r 7-1.3.2 8-1.3.1 9-1.3 11-1.2.1 12-1.2.1.1.1.1.1 14-1.2.1.1.1.1.1 16-1.2.1.1.2.1.1 18-1.2.1.1.2.1.1 19-1.2.1.1 20-1.2.1.1.3.1.1 23-1.4.1.1.1.1 27-1.4.1.1.1.2 (p / produce-01~e.2 :ARG0 (m / macrophage~e.1 :mod (a / alveolus~e.0)) :ARG1 (g / growth-factor~e.4,5 :ARG2-of (i / include-01~e.11 :ARG1 (a2 / and~e.19 :op1 (p5 / protein :name (n2 / name :op1 "IGF-1"~e.12,14)) :op2 (p4 / protein :name (n3 / name :op1 "GM-CSF"~e.16,18)) :op3 (p3 / protein :name (n4 / name :op1 "EGF"~e.20)))) :quant (n5 / numerous~e.3)) :prep-in~e.6 (r / range~e.9 :mod (s2 / size~e.8) :mod (t / this~e.7)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 11~e.23 :op2 18~e.27))))) # ::id a_pmid_2169_9731.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further narrow down the list of possible candidates , an in silico @ analysis was performed for each fraction size as described in Materials and Methods . # ::alignments 1-1.2.2 2-1.2 3-1.2 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.1 8-1.2.1.1 12-1.1.2 13-1.1.2 15-1.1 17-1 18-1.1.1.r 19-1.1.1.2 20-1.1.1.1 21-1.1.1 22-1.3.r 23-1.3 24-1.1.2 25-1.3.1.1.1 26-1.3.1.1.2 27-1.3.1.1.3 (p / perform-02~e.17 :ARG1 (a / analyze-01~e.15 :ARG1~e.18 (s / size~e.21 :mod (f / fraction~e.20) :mod (e / each~e.19)) :manner (i / in-silico~e.12,13,24)) :purpose (n / narrow-down-03~e.2,3 :ARG1 (l / list~e.5 :consist-of~e.6 (c / candidate~e.8 :ARG1-of (p2 / possible-01~e.7))) :degree (f2 / further~e.1)) :ARG1-of~e.22 (d / describe-01~e.23 :ARG0 (s2 / section :name (n2 / name :op1 "Materials"~e.25 :op2 "and"~e.26 :op3 "Methods"~e.27)))) # ::id a_pmid_2169_9731.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The resulting data points were separately fit for each fraction size to the general equation y @ = y @ ₀@ + a @ ( 1 @- @ e @^{-@ bx}@ ) as described , with regression r @²@ = 0.997 , 0.842 and 0.918 for the > 3 , > 10 and > 30 kDa fractions , respectively . # ::alignments 1-1.1.2 2-1.1.1 3-1.1 5-1.3 6-1 7-1.4.r 8-1.4.2 9-1.4.1 10-1.4 11-1.2.r 13-1.2.1 14-1.2 25-1.5 33-1.2.2.1 40-1.6.r 41-1.6 50-1.5.1.1 52-1.5.2.1 53-1.5 54-1.5.3.1 57-1.5.1.2.1 58-1.5.1.2.1.1.1 60-1.5.1.2.1 61-1.5.2.2.1.1.1 62-1.5 63-1.5.1.2.1 63-1.5.2.2.1 63-1.5.3.2.1 64-1.5.3.2.1.1.1 65-1.5.1.2.1.1.2 65-1.5.2.2.1.1.2 65-1.5.3.2.1.1.2 66-1.5.1.2 66-1.5.2.2 66-1.5.3.2 (f / fit-06~e.6 :ARG1 (p / point~e.3 :mod (d / data~e.2) :ARG1-of (r / result-01~e.1)) :ARG2~e.11 (e2 / equation~e.14 :ARG1-of (g / general-02~e.13) :mod (s6 / string-entity :value "y=y0+a(1-e-bx)"~e.33)) :manner (s / separate-02~e.5) :beneficiary~e.7 (s2 / size~e.10 :mod (f2 / fraction~e.9) :mod (e / each~e.8)) :condition (a / and~e.25,53,62 :op1 (s3 / statistical-test-91 :ARG3 0.997~e.50 :ARG1 (f3 / fraction~e.66 :mod (m4 / more-than~e.57,60,63 :op1 (m / mass-quantity :quant 3~e.58 :unit (k / kilodalton~e.65))))) :op2 (s4 / statistical-test-91 :ARG3 0.842~e.52 :ARG1 (f4 / fraction~e.66 :mod (m5 / more-than~e.63 :op1 (m2 / mass-quantity :quant 10~e.61 :unit (k2 / kilodalton~e.65))))) :op3 (s5 / statistical-test-91 :ARG3 0.918~e.54 :ARG1 (f5 / fraction~e.66 :mod (m6 / more-than~e.63 :op1 (m3 / mass-quantity :quant 30~e.64 :unit (k3 / kilodalton~e.65)))))) :ARG1-of~e.40 (d2 / describe-01~e.41)) # ::id a_pmid_2169_9731.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok From regression analysis , the responsible factor( s ) appeared to be 7.23 @-@ 10.8 kDa in size , suggesting that growth factors such as IGF @-@ 1 ( 7.5 kDa ) may be responsible for the MØCM @-@ stimulated neoplastic proliferation . # ::alignments 2-1.2.1 5-1.1.3.1.1 9-1 12-1.1.2.1.2.1 14-1.1.2.1.2.2 15-1.1.2.1.1 17-1.1.2 19-1.1.3 21-1.1.3.1.1.1 22-1.1.1 22-1.1.3.1.1.1 23-1.1.3.1.1.1.1.r 24-1.1.3.1.1.1.1.r 25-1.1.3.1.1.1.1.1.1 27-1.1.3.1.1.1.1.1.1 29-1.1.3.1.1.1.1.2.1 30-1.1.3.1.1.1.1.2.2 32-1.1.3.1 34-1.1.1.1 34-1.1.3.1.1 39-1.1.3.1.1.2.2 41-1.1.3.1.1.2 (a / appear-02~e.9 :ARG1 (h / have-03 :ARG0 (f / factor~e.22 :ARG0-of (r / responsible-01~e.34)) :ARG1 (s / size~e.17 :mod (m / mass-quantity :unit (k / kilodalton~e.15) :quant (b / between :op1 7.23~e.12 :op2 10.8~e.14))) :ARG0-of (s2 / suggest-01~e.19 :ARG1 (p / possible-01~e.32 :ARG1 (r3 / responsible-01~e.5,34 :ARG0 (g / growth-factor~e.21,22 :example~e.23,24 (p3 / protein :name (n2 / name :op1 "IGF-1"~e.25,27) :mod (m2 / mass-quantity :quant 7.5~e.29 :unit (k2 / kilodalton~e.30)))) :ARG1 (p2 / proliferate-01~e.41 :ARG0 (t / tumor) :ARG1-of (s4 / stimulate-01~e.39 :ARG0 (m3 / medium :ARG1-of (c / condition-01 :ARG0 (m4 / macrophage))))))))) :ARG1-of (d2 / deduce-01 :ARG2 (a2 / analysis~e.2 :mod (r2 / regress-01)))) # ::id a_pmid_2169_9731.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophage @-@ conditioned media IGF @-@ 1 levels correlate to effects on neoplastic proliferation # ::alignments 0-1.1.2.1.1 2-1.1.2.1 3-1.1.2 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1 8-1 9-1.2.r 10-1.2 13-1.2.1 (c / correlate-01~e.8 :ARG1 (l / level~e.7 :quant-of (p2 / protein :name (n / name :op1 "IGF-1"~e.4,6)) :source (m / medium~e.3 :ARG1-of (c2 / condition-01~e.2 :ARG0 (m2 / macrophage~e.0)))) :ARG2~e.9 (a / affect-01~e.10 :ARG1 (p / proliferate-01~e.13 :ARG0 (t / tumor)))) # ::id a_pmid_2169_9731.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IGF @-@ 1 has a well @-@ established role in the metastasis of cancer cells in vivo , as well as stimulating growth in vitro @ [ @ 27 @ ] , and alveolar macrophages produce high levels of IGF @-@ 1 in response to quartz dust @-@ induced lung injury [ @ 30 @ ] . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 5-1.1.2.1.1 7-1.1.2.1 8-1.1.2 9-1.1.2.2.r 11-1.1.2.2.1 12-1.1.2.2.1.1.r 13-1.1.2.2.1.1.1.2.1 14-1.1.2.2.1.1 16-1.1.2.2.1.2.r 16-1.1.2.2.r 17-1.1.2.2.1.2 20-1.1.2.2 21-1.1.2.2 22-1.1.2.2 23-1.1.2.2.2 24-1.1.2.2.2.2 26-1.1.2.2.2.3 27-1.1.2.2.2.3 31-1.1.2.3.1.1.1 35-1 36-1.2.1.1 37-1.2.1 38-1.2 39-1.2.2.1 40-1.2.2 41-1.2.2.2.r 42-1.2.2.2 43-1.2.2.2 44-1.2.2.2 45-1.1.2.2.r 45-1.2.4.r 46-1.2.4 47-1.2.4.1.r 48-1.2.4.1.2.1.1.1 49-1.2.4.1.2.1.1.2 51-1.2.4.1.2 52-1.2.4.1.1 53-1.2.4.1 56-1.2.3.1.1.1 (a / and~e.35 :op1 (h / have-03~e.3 :ARG0 (p4 / protein :name (n2 / name :op1 "IGF-1"~e.0,2)) :ARG1 (r / role~e.8 :ARG1-of (e2 / establish-01~e.7 :mod (w / well~e.5)) :prep-in~e.9,16,45 (a2 / and~e.20,21,22 :op1 (m / metastasize-101~e.11 :ARG1~e.12 (c / cell~e.14 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.13))) :manner~e.16 (i / in-vivo~e.17)) :op2 (s / stimulate-01~e.23 :ARG0 p4 :ARG1 (g / grow-01~e.24) :manner (i2 / in-vitro~e.26,27))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 27~e.31))))) :op2 (p2 / produce-01~e.38 :ARG0 (m2 / macrophage~e.37 :mod (a3 / alveolus~e.36)) :ARG1 (l / level~e.40 :ARG1-of (h2 / high-02~e.39) :quant-of~e.41 p4~e.42,43,44) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 30~e.56))) :ARG2-of~e.45 (r2 / respond-01~e.46 :ARG1~e.47 (i3 / injure-01~e.53 :ARG1 (l2 / lung~e.52) :ARG2-of (i4 / induce-01~e.51 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "quartz"~e.48 :op2 "dust"~e.49))))))) # ::id a_pmid_2169_9731.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While alveolar macrophages are an important component of the chronic inflammatory milieu responsible for promoting lung tumorigenesis , IGF @-@ 1 has not been examined as a possible connection between macrophage recruitment and lung cancer progression . # ::alignments 0-1 1-1.2.3.1 2-1.2.3 3-1.2.3.r 5-1.2.1 6-1.2 9-1.2.2.1.1 10-1.2.2.1.2 11-1.2.2.1 12-1.2.2.1.3 13-1.2.2.1.3.1.r 14-1.2.2.1.3.1 15-1.2.2.1.3.1.1.1.1 16-1.2.2.1.3.1.1 16-1.2.2.1.3.1.1.1 16-1.2.2.1.3.1.1.1.r 18-1.1.2.1.1 20-1.1.2.1.1 22-1.1.1 22-1.1.1.r 24-1.1 25-1.1.3.r 27-1.1.3.4 28-1.1.3 30-1.1.3.2.1 31-1.1.3.2 33-1.1.3.3.1.2.1 34-1.1.3.3.1.2.2 35-1.1.3.3 (c / contrast-01~e.0 :ARG1 (e / examine-01~e.24 :polarity~e.22 -~e.22 :ARG1 (p / protein :name (n2 / name :op1 "IGF-1"~e.18,20)) :ARG2~e.25 (c2 / connect-01~e.28 :ARG0 p :ARG1 (r / recruit-01~e.31 :ARG1 (m / macrophage~e.30)) :ARG1 (p3 / progress-01~e.35 :ARG1 (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung"~e.33 :op2 "cancer"~e.34))) :ARG1-of (p2 / possible-01~e.27))) :ARG2 (c4 / component~e.6 :mod (i3 / important~e.5) :ARG1-of (i / include-91 :ARG2 (m3 / milieu~e.11 :mod (c3 / chronic~e.9) :mod (i2 / inflame-01~e.10) :ARG0-of (r2 / responsible-01~e.12 :ARG1~e.13 (p4 / promote-01~e.14 :ARG1 (c5 / create-01~e.16 :ARG1~e.16 (t2 / tumor~e.16 :mod (l / lung~e.15))))))) :domain~e.3 (m2 / macrophage~e.2 :mod (a / alveolus~e.1)))) # ::id a_pmid_2169_9731.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BALF from tumor @-@ bearing lungs contained 3.5 @-@ times more IGF @-@ 1 than BALF from naïve mice , while EGF levels were unchanged ( Figure 6A ) . # ::alignments 0-1.1.1 0-1.1.3.2.1 0-1.1.3.2.1.1 0-1.1.3.2.1.1.r 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1 5-1.1.1.1 6-1.1 7-1.1.2.2.1.1 9-1.1.2.2.1 10-1.1.2.2 11-1.1.2.1.1 13-1.1.2.1.1 14-1.1.3.r 15-1.1.3 15-1.1.3.2 15-1.1.3.2.1 15-1.1.3.2.1.1 15-1.1.3.2.1.1.r 15-1.1.3.2.1.r 15-1.1.3.2.r 16-1.1.1.1.r 16-1.1.3.1.r 17-1.1.3.1.1 18-1.1.3.1 20-1 21-1.2.2.1.1.1 22-1.2.2 24-1.2 24-1.2.1 24-1.2.1.r 26-1.3.1 28-1.3.1.1 (c / contrast-01~e.20 :ARG1 (c3 / contain-01~e.6 :ARG0 (f3 / fluid~e.0 :source~e.1,16 (l2 / lung~e.5 :ARG0-of (b / bear-01~e.4 :ARG1 (t / tumor~e.2))) :mod l3) :ARG1 (p2 / protein :name (n3 / name :op1 "IGF-1"~e.11,13) :quant (m2 / more~e.10 :degree (p3 / product-of~e.9 :op1 3.5~e.7))) :compared-to~e.14 (f2 / fluid~e.15 :part-of~e.16 (m4 / mouse~e.18 :mod (n5 / naive~e.17)) :mod~e.15 (l3 / lavage~e.15 :mod~e.15 (a / alveolus~e.0,15 :mod~e.0,15 (b2 / bronchus~e.0,15))))) :ARG2 (c2 / change-01~e.24 :polarity~e.24 -~e.24 :ARG1 (l / level~e.22 :quant-of (p / protein :name (n / name :op1 "EGF"~e.21)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "6A"~e.28))) # ::id a_pmid_2169_9731.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Even after normalizing to total BALF protein levels , BALF IGF @-@ 1 was significantly higher in tumor @-@ bearing animals than naïve controls ( 1.81 ± 0.33 vs. 0.95 ± 0.36 pg IGF @-@ 1/ug BALF protein , respectively , P @ < 0.01 , mean ± SD ) , suggesting that more IGF @-@ 1 is produced in the lungs of tumor @-@ bearing mice . # ::alignments 2-1.7 3-1.7.2.r 4-1.7.2.2 5-1.1.1.2 5-1.1.1.2.1 5-1.1.1.2.1.1 5-1.1.1.2.1.1.1 5-1.1.1.2.1.1.1.r 5-1.1.1.2.1.1.r 5-1.1.1.2.1.r 6-1.7.2.1 7-1.1 7-1.2 7-1.7.2 9-1.1.1.2.1.1 9-1.1.1.2.1.1.1 9-1.1.1.2.1.1.1.r 10-1.1.1.1.1 12-1.1.1.1.1 14-1.6 15-1 15-1.5 15-1.5.r 16-1.3.r 17-1.3.1.1 19-1.3.1 20-1.3 21-1.2.r 22-1.2.1.2.1 23-1.2.1.2 25-1.1.2.1.2.1.2 25-1.1.2.1.2.2.2 27-1.1.2.1.2.1.1 27-1.1.2.1.2.2.1 28-1.2.r 29-1.2.2.1.2.1.2 29-1.2.2.1.2.2.2 31-1.2.2.1.2.1.1 31-1.2.2.1.2.2.1 33-1.1.1.1.1 36-1.1.1.2 36-1.1.1.2.1 36-1.1.1.2.1.1 36-1.1.1.2.1.1.1 36-1.1.1.2.1.1.1.r 36-1.1.1.2.1.1.r 36-1.1.1.2.1.r 37-1.1.1 42-1.1.2.2.1 44-1.1.2.2.1.1 45-1.1.2.2.1.1.1 47-1.1.2.2.2.1 52-1.4 54-1.4.1.2 54-1.5 55-1.2.1.1.1 57-1.2.1.1.1 59-1.4.1 60-1.4.1.3.r 62-1.4.1.3 63-1.1.2.1.1 63-1.4.1.3.1.r 64-1.4.1.3.1.1 65-1.4.1.3.1.1 66-1.4.1.3.1.1 67-1.4.1.3.1 (h / high-02~e.15 :ARG1 (l3 / level~e.7 :quant-of (p / protein~e.37 :name (n / name :op1 "IGF-1"~e.10,12,33) :source (f / fluid~e.5,36 :mod~e.5,36 (l5 / lavage~e.5,36 :mod~e.5,36 (a3 / alveolus~e.5,9,36 :mod~e.5,9,36 (b2 / bronchus~e.5,9,36))))) :ARG1-of (e2 / equal-01 :ARG2 (m4 / mass-quantity :unit (r / ratio-of~e.63 :op1 (p5 / picogram :mod p) :op2 (m6 / microgram :mod f)) :quant (v / value-interval :op1 (s4 / subtract-01 :ARG1 0.33~e.27 :ARG2 1.81~e.25) :op2 (a4 / add-02 :ARG1 0.33~e.27 :ARG2 1.81~e.25))) :condition (a2 / and :op1 (s6 / statistical-test-91~e.42 :ARG2 (l6 / less-than~e.44 :op1 0.01~e.45)) :op2 (d / deviate-01 :mod (m8 / mean~e.47) :ARG1-of (s3 / standard-02))))) :compared-to~e.21,28 (l4 / level~e.7 :quant-of (p4 / protein :name (n5 / name :op1 "IGF-1"~e.55,57) :source (c / control~e.23 :mod (n3 / naive~e.22))) :ARG1-of (e3 / equal-01 :ARG2 (m7 / mass-quantity :unit r :quant (v2 / value-interval :op1 (s5 / subtract-01 :ARG1 0.36~e.31 :ARG2 0.95~e.29) :op2 (a5 / add-02 :ARG1 0.36~e.31 :ARG2 0.95~e.29))) :condition a2)) :location~e.16 (a / animal~e.20 :ARG0-of (b / bear-01~e.19 :ARG1 (t / tumor~e.17))) :ARG0-of (s2 / suggest-01~e.52 :ARG1 (p3 / produce-01~e.59 :ARG1 p :quant (m2 / more~e.54) :location~e.60 (l2 / lung~e.62 :part-of~e.63 (m3 / mouse~e.67 :ARG0-of b~e.64,65,66)))) :degree~e.15 (m5 / more~e.15,54) :ARG1-of (s / significant-02~e.14) :concession (n4 / normalize-01~e.2 :ARG1 p :prep-to~e.3 (l / level~e.7 :quant-of (p2 / protein~e.6 :mod f) :mod (t2 / total~e.4)))) # ::id a_pmid_2169_9731.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Measurement of IGF @-@ 1 levels in MØCM from primary naïve and tumor @-@ educated BAL macrophages showed that tumor @-@ educated macrophages produced significantly more IGF @-@ 1 than naïve macrophages ( Figure 6B , grey bars ) . # ::alignments 0-1.1 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1 5-1.2.2 8-1.1.2.1.r 9-1.1.2.1.4 10-1.1.2.1.1.1 11-1.1.2.1 12-1.1.2.1.2.1.1 14-1.1.2.1.2.1 15-1.1.2.1.3.1 15-1.1.2.1.3.1.1 15-1.1.2.1.3.1.1.r 16-1.1.2.1.2 16-1.1.2.2.1 17-1 19-1.1.2.1.2.1.1 21-1.1.2.1.2.1 22-1.1.2.1.1 22-1.1.2.1.2 22-1.1.2.2.1 23-1.2 24-1.2.2.2.1 25-1.2.2.2 26-1.2.2.1 27-1.2.2.1 28-1.2.2.1 29-1.2.3.r 30-1.2.3 31-1.1.2.1.1 31-1.1.2.2.1 33-1.3.1 35-1.3.1.1 38-1.3.2.1 39-1.3.2 (s / show-01~e.17 :ARG0 (m / measure-01~e.0 :ARG1 (l / level~e.5 :quant-of (p / protein :name (n / name :op1 "IGF-1"~e.2,4))) :location (m2 / medium :source~e.8 (a / and~e.11 :op1 (m3 / macrophage~e.22,31 :mod (n4 / naive~e.10)) :op2 (m5 / macrophage~e.16,22 :ARG1-of (e / educate-01~e.14,21 :ARG0 (t / tumor~e.12,19))) :mod (f2 / fluid :mod (a2 / alveolus~e.15 :mod~e.15 (b2 / bronchus~e.15))) :mod (p2 / primary~e.9)) :ARG1-of (c / condition-01 :ARG0 (m7 / macrophage~e.16,22,31)))) :ARG1 (p3 / produce-01~e.23 :ARG0 m5 :ARG1 (l2 / level~e.5 :quant-of p~e.26,27,28 :quant (m6 / more~e.25 :ARG1-of (s2 / significant-02~e.24))) :compared-to~e.29 m3~e.30) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.33 :mod "6B"~e.35) :ARG2 (b / bar~e.39 :ARG1-of (g / gray-02~e.38)))) # ::id a_pmid_2169_9731.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 4 potently stimulates alternative macrophage activation , and is more abundant in tumor @-@ bearing lungs than naïve [ @ 38 @ ] . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1.3 3-1.1.3.r 4-1.1 5-1.1.2.2 6-1.1.2.1 7-1.1.2 9-1 10-1.2.1.r 11-1.2.2 12-1.2 13-1.2.3.r 14-1.2.3.1.1 16-1.2.3.1 17-1.2.3 18-1.2.4.r 19-1.2.4 22-1.3.1.1.1 (a / and~e.9 :op1 (s / stimulate-01~e.4 :ARG0 (p2 / protein :name (n / name :op1 "IL-4"~e.0,2)) :ARG1 (a2 / activate-01~e.7 :ARG1 (m / macrophage~e.6) :mod (a3 / alternative~e.5)) :manner~e.3 (p / potent~e.3)) :op2 (a4 / abundant~e.12 :domain~e.10 p2 :degree (m2 / more~e.11) :location~e.13 (l / lung~e.17 :ARG0-of (b / bear-01~e.16 :ARG1 (t / tumor~e.14))) :compared-to~e.18 (n2 / naive~e.19)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 38~e.22)))) # ::id a_pmid_2169_9731.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternative macrophage polarization is associated with tumorigenesis [ @ 6 @ ] and increased macrophage IGF @-@ 1 production [ @ 39 @ ] . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1 6-1.2.1.1 6-1.2.1.1.r 9-1.2.1.2.1.1.1 12-1.2 13-1.2.2.3 14-1.2.2.1 15-1.2.2.2.1.1 17-1.2.2.2.1.1 18-1.2.2 21-1.2.2.4.1.1.1 (a / associate-01~e.4 :ARG1 (p / polarize-01~e.2 :ARG1 (m / macrophage~e.1) :mod (a2 / alternative~e.0)) :ARG2~e.5 (a3 / and~e.12 :op1 (c3 / create-01~e.6 :ARG1~e.6 (t / tumor~e.6) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 6~e.9)))) :op2 (p3 / produce-01~e.18 :ARG0 m~e.14 :ARG1 (p4 / protein :name (n / name :op1 "IGF-1"~e.15,17)) :ARG1-of (i / increase-01~e.13) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 39~e.21)))))) # ::id a_pmid_2169_9731.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , IL @-@ 4 was added to wells containing primary naïve and tumor @-@ educated BAL macrophages to determine if alternative activation could increase IGF @-@ 1 production in either macrophage group . # ::alignments 0-1 2-1.1.1.1.1 4-1.1.1.1.1 6-1.1 7-1.1.2.r 8-1.1.2 9-1.1.2.1 10-1.1.2.1.1.3 11-1.1.2.1.1.1.1 12-1.1.2.1.1 13-1.1.2.1.1.2.1.1 15-1.1.2.1.1.2.1 17-1.1.2.1.1.1 17-1.1.2.1.1.2 17-1.1.2.1.1.4.1.1 19-1.1.3 21-1.1.3.1.1.1.1 22-1.1.3.1.1.1 23-1.1.3.1 24-1.1.3.1.1 28-1.1.3.1.1.2 31-1.1.3.1.1.3 (c / cause-01~e.0 :ARG1 (a / add-02~e.6 :ARG1 (p2 / protein :name (n / name :op1 "IL-4"~e.2,4)) :ARG2~e.7 (w / well~e.8 :ARG0-of (c2 / contain-01~e.9 :ARG1 (a2 / and~e.12 :op1 (m2 / macrophage~e.17 :mod (n3 / naive~e.11)) :op2 (m3 / macrophage~e.17 :ARG1-of (e / educate-01~e.15 :ARG0 (t / tumor~e.13))) :mod (p3 / primary~e.10) :mod (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m4 / macrophage~e.17)))))) :purpose (d / determine-01~e.19 :ARG1 (p4 / possible-01~e.23 :ARG1 (i / increase-01~e.24 :ARG0 (a3 / activate-01~e.22 :mod (a4 / alternative~e.21)) :ARG1 (p5 / produce-01~e.28 :ARG1 p2) :location a2~e.31))))) # ::id a_pmid_2169_9731.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both naïve and tumor @-@ educated macrophages produced significantly more IGF @-@ 1 after IL @-@ 4 treatment ; tumor @-@ educated macrophages more than doubled IGF @-@ 1 output compared to naïve samples ( Figure 6B , green bars ) . # ::alignments 1-1.1.1.1.1 2-1.1.1 3-1.1.1.2.1.1 5-1.1.1.2.1 6-1.1.1.1 6-1.1.1.2 7-1.1 8-1.1.2.2.1 9-1.1.2.2 10-1.1.2.1.1 12-1.1.2.1.1 14-1.1.3.1.1.1 16-1.1.3.1.1.1 17-1.1.3 19-1.2.1.1.1 21-1.2.1.1 22-1.2.1 23-1.2.3 24-1.2.3 24-1.2.4.r 25-1.2 26-1.2.2.1.1.1 28-1.2.2.1.1.1 29-1.2.2 30-1.2.4.r 32-1.2.4.1 33-1.2.4 33-1.2.4.2 33-1.2.4.2.r 35-1.3.1 37-1.3.1.1 40-1.3.2.1 41-1.3.2 (m / multi-sentence :snt1 (p / produce-01~e.7 :ARG0 (a / and~e.2 :op1 (m2 / macrophage~e.6 :mod (n / naive~e.1)) :op2 (m3 / macrophage~e.6 :ARG1-of (e / educate-01~e.5 :ARG0 (t / tumor~e.3)))) :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1"~e.10,12) :quant (m4 / more~e.9 :degree (s / significant~e.8))) :condition (t2 / treat-04~e.17 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-4"~e.14,16)))) :snt2 (d / double-01~e.25 :ARG0 (m6 / macrophage~e.22 :ARG1-of (e2 / educate-01~e.21 :ARG0 (t3 / tumor~e.19))) :ARG1 (o / output~e.29 :mod (p4 / protein :name (n4 / name :op1 "IGF-1"~e.26,28))) :degree (m5 / more-than~e.23,24) :compared-to~e.24,30 (t4 / thing~e.33 :mod (n5 / naive~e.32) :ARG1-of~e.33 (s2 / sample-01~e.33))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.35 :mod "6B"~e.37) :ARG2 (b / bar~e.41 :ARG1-of (g / green-02~e.40)))) # ::id a_pmid_2169_9731.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MH @-@ S macrophages produced 20 @-@ times more IGF @-@ 1 than either non @-@ neoplastic or neoplastic lung cell lines , and all three cell lines produced only trace amounts (< 2 pg/mL ) of EGF ( Figure 6E ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1 5-1.1.2.2.1.1 7-1.1.2.2.1 8-1.1.2.2 9-1.1.2.1.1 11-1.1.2.1.1 12-1.1.3.r 12-1.2.2.3.1 14-1.1.3.1.1.1 14-1.1.3.1.1.1.r 17-1.1.3 19-1.1.3.3 20-1.1.3.1 21-1.1.3.1 21-1.1.3.2 26-1.1.3.1 27-1.1.3.1 28-1.2 29-1.2.2.4 30-1.2.2.1 31-1.2.2 33-1.2.2.3.1.1.1 36-1.2.2.2.r 37-1.2.2.2.1.1 39-1.3.1 41-1.3.1.1 (a / and :op1 (p / produce-01~e.4 :ARG0 (m / macrophage~e.3 :source (c / cell-line :name (n / name :op1 "MH-S"~e.0,2))) :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1"~e.9,11) :quant (m2 / more~e.8 :degree (p3 / product-of~e.7 :op1 20~e.5))) :compared-to~e.12 (o / or~e.17 :op1 (c5 / cell-line~e.20,21,26,27 :mod (t / tumor :polarity~e.14 -~e.14)) :op2 (c6 / cell-line~e.21 :mod (t2 / tumor)) :source (l2 / lung~e.19))) :op2 (p4 / produce-01~e.28 :ARG0 (a2 / and :op1 m :op2 c5 :op3 c6) :ARG1 (a3 / amount~e.31 :mod (t3 / trace~e.30) :mod~e.36 (p5 / protein :name (n3 / name :op1 "EGF"~e.37)) :ARG1-of (e / equal-01 :ARG2 (l5 / less-than~e.12 :op1 (c4 / concentration-quantity :quant 2~e.33 :unit (p6 / picogram-per-milliliter)))) :mod (o2 / only~e.29))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod "6E"~e.41))) # ::id a_pmid_2169_9731.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to determine whether the growth effects of MØCM from samples generated in Figure 6B correlated with their IGF @-@ 1 content , MØCM was added to neoplastic LM2 cells . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 4-1.3.1.1 4-1.3.1.1.r 6-1.3.1.2.2 7-1.3.1.2 10-1.3.1.2.3.r 11-1.3.1.2.3 11-1.3.1.2.3.1 11-1.3.1.2.3.1.r 12-1.3.1.2.4 13-1.3.1.2.4.1.r 14-1.3.1.2.4.1 16-1.3.1.2.4.1.1 18-1.3.1 19-1.3.1.3.r 20-1.3.1.3.1 20-1.3.1.3.1.r 21-1.3.1.3.2.1.1 23-1.3.1.3.2.1.1 24-1.3.1.3 28-1 31-1.2.1.1 32-1.2 (a / add-02~e.28 :ARG1 (m / medium :ARG1-of (c4 / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (c / cell-line~e.32 :name (n2 / name :op1 "LM2"~e.31) :mod (t / tumor)) :purpose~e.0,1,2 (d / determine-01~e.3 :ARG1 (c2 / correlate-01~e.18 :mode~e.4 interrogative~e.4 :ARG1 (a2 / affect-01~e.7 :ARG0 m :ARG1 (g / grow-01~e.6) :location~e.10 (t2 / thing~e.11 :ARG1-of~e.11 (s / sample-01~e.11)) :ARG1-of (g2 / generate-01~e.12 :location~e.13 (f / figure~e.14 :mod "6B"~e.16))) :ARG2~e.19 (c3 / contain-01~e.24 :ARG0~e.20 t2~e.20 :ARG1 (p / protein :name (n3 / name :op1 "IGF-1"~e.21,23)))))) # ::id a_pmid_2169_9731.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 4 stimulated naïve and tumor @-@ educated MØCM significantly augmented LM2 proliferation ( Figure 6C , green bars ) , with IL @-@ 4 treated tumor @-@ educated MØCM being the most potent . # ::alignments 0-1.1.1.3.1.1.1 2-1.1.1.3.1.1.1 3-1.1.1.3 4-1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 8-1.1.1.2.1 10-1.1.3 11-1.1 12-1.1.2.1.1.1 13-1.1.2 15-1.1.4.1 17-1.1.4.1.1 20-1.1.4.2.1 21-1.1.4.2 25-1.1.1.3.1.1.1 27-1.1.1.3.1.1.1 29-1.1.1.2.1.1 31-1.1.1.2.1 33-1.2.2.r 35-1.2.1 36-1.2 (a / and :op1 (a2 / augment-01~e.11 :ARG0 (a3 / and~e.5 :op1 (m / medium :mod (n3 / naive~e.4) :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage))) :op2 (m2 / medium :ARG1-of (e / educate-01~e.8,31 :ARG0 (t / tumor~e.6,29)) :ARG1-of c2) :ARG1-of (s / stimulate-01~e.3 :ARG0 (p / protein :name (n4 / name :op1 "IL-4"~e.0,2,25,27)))) :ARG1 (p2 / proliferate-01~e.13 :ARG0 (c / cell-line :name (n5 / name :op1 "LM2"~e.12))) :ARG1-of (s2 / significant-02~e.10) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod "6C"~e.17) :ARG2 (b / bar~e.21 :ARG1-of (g / green-02~e.20)))) :op2 (p3 / potent~e.36 :degree (m3 / most~e.35) :domain~e.33 m2)) # ::id a_pmid_2169_9731.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MØCM from untreated tumor @-@ educated macrophages did not stimulate LM2 growth significantly more than untreated naïve MØCM ( Figure 6C , grey bars ) , corresponding to previous co @-@ culture results ( Figure 2B ) . # ::alignments 1-1.2.1.r 2-1.2.1.1 2-1.2.1.1.1 3-1.2.1.2.1 5-1.2.1.2 6-1.2.1 6-1.7.3.1 8-1.1 8-1.1.r 8-1.2.1.1.1.r 9-1 10-1.3.1.1.1 11-1.3 12-1.4.1 13-1.4 14-1.7.r 15-1.7.1 16-1.7.2 19-1.5.1 21-1.5.1.1 24-1.5.2.1 25-1.5.2 28-1.6 29-1.6.1.r 30-1.6.1.1.2 31-1.6.1.1.1 33-1.6.1.1.1 34-1.6.1 34-1.6.1.1 34-1.6.1.1.r 36-1.6.1.1.3.1 38-1.6.1.1.3.1.1 (s / stimulate-01~e.9 :polarity~e.8 -~e.8 :ARG0 (m / medium :source~e.1 (m2 / macrophage~e.6 :ARG1-of (t / treat-04~e.2 :polarity~e.8 -~e.2) :ARG1-of (e / educate-01~e.5 :ARG0 (t2 / tumor~e.3))) :ARG1-of c4) :ARG1 (g / grow-01~e.11 :ARG1 (c / cell-line :name (n2 / name :op1 "LM2"~e.10))) :degree (m3 / more~e.13 :degree (s2 / significant~e.12)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "6C"~e.21) :ARG2 (b / bar~e.25 :ARG1-of (g2 / gray-02~e.24))) :ARG1-of (c2 / correspond-02~e.28 :ARG2~e.29 (t3 / thing~e.34 :ARG2-of~e.34 (r / result-01~e.34 :ARG1 (c3 / co-culture~e.31,33) :time (p / previous~e.30) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.36 :mod "2B"~e.38))))) :compared-to~e.14 (m4 / medium :ARG1-of t~e.15 :mod (n4 / naive~e.16) :ARG1-of (c4 / condition-01 :ARG0 (m5 / macrophage~e.6)))) # ::id a_pmid_2169_9731.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As the growth @-@ stimulating ability of MØCM appeared to correlate to media IGF @-@ 1 levels , the levels of IGF @-@ 1 present were plotted against the fold @-@ change in LM2 cell number after MØCM addition ( Figure 6D ) . # ::alignments 2-1.3.1.1.1.2.2 4-1.3.1.1.1.2 5-1.3.1.1.1 8-1.3.1 10-1.3.1.1 11-1.3 12-1.2.2.1 13-1.1.1.1.1 15-1.1.1.1.1 16-1.1 19-1.1 21-1.1.1.1.1 23-1.1.1.1.1 24-1.1.2 26-1 29-1.2.3 31-1.2 32-1.2.1.r 33-1.2.1.1.1.1 34-1.2.1.1 35-1.2.1 38-1.2.2 40-1.4.1 42-1.4.1.1 (p / plot-01~e.26 :ARG1 (l / level~e.16,19 :quant-of (p2 / protein :name (n / name :op1 "IGF-1"~e.13,15,21,23) :location m) :ARG1-of (p4 / present-02~e.24)) :ARG2 (c / change-01~e.31 :ARG1~e.32 (n2 / number~e.35 :quant-of (c2 / cell-line~e.34 :name (n3 / name :op1 "LM2"~e.33))) :condition (a / add-02~e.38 :ARG1 (m / medium~e.12 :ARG1-of (c6 / condition-01 :ARG0 (m3 / macrophage)))) :mod (p3 / product-of~e.29)) :ARG1-of (c3 / cause-01~e.11 :ARG0 (a2 / appear-02~e.8 :ARG1 (c4 / correlate-01~e.10 :ARG1 (c5 / capable-01~e.5 :ARG1 m :ARG2 (s / stimulate-01~e.4 :ARG0 m :ARG1 (g / grow-01~e.2))) :ARG2 l))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.40 :mod "6D"~e.42))) # ::id a_pmid_2169_9731.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The correlation between IGF @-@ 1 levels and neoplastic growth stimulation was highly significant ( p < 0.001 ) , indicating that MØCM IGF @-@ 1 levels were directly related to the ability of MØCM to stimulate neoplastic proliferation . # ::alignments 1-1.1 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1 9-1.1.2.1 10-1.1.2 12-1.2 13-1 16-1.4.1 17-1.4.1.1 20-1.3 23-1.3.1.1.1 24-1.3.1.1.1 25-1.3.1.1.1 26-1.3.1.1 28-1.3.1.3 29-1.3.1 30-1.3.1.2.r 32-1.3.1.2 36-1.3.1.2.2 38-1.3.1.2.2.2 (s / significant-02~e.13 :ARG1 (c / correlate-01~e.1 :ARG1 (l / level~e.6 :quant-of (p / protein :name (n / name :op1 "IGF-1"~e.3,5))) :ARG2 (s2 / stimulate-01~e.10 :ARG1 (g / grow-01~e.9 :ARG1 (t / tumor)))) :ARG1-of (h / high-02~e.12) :ARG0-of (i / indicate-01~e.20 :ARG1 (r / relate-01~e.29 :ARG1 (l2 / level~e.26 :quant-of p~e.23,24,25 :location (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m3 / macrophage)))) :ARG2~e.30 (c2 / capable-01~e.32 :ARG1 m :ARG2 (s3 / stimulate-01~e.36 :ARG0 m :ARG1 (p2 / proliferate-01~e.38 :ARG0 t))) :ARG1-of (d / direct-02~e.28))) :ARG1-of (m2 / mean-01 :ARG2 (l4 / less-than~e.16 :op1 0.001~e.17))) # ::id a_pmid_2169_9731.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IGF @-@ 1 stimulates lung epithelial cell proliferation and is additive with MØCM # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1 4-1.2.1.1 5-1.2.1.2 6-1.2.1 7-1.2 8-1.1 (s / stimulate-01~e.3 :ARG0 (a / and~e.8 :op1 (p / protein :name (n / name :op1 "IGF-1"~e.0,2)) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (p2 / proliferate-01~e.7 :ARG0 (c / cell~e.6 :source (l / lung~e.4) :mod (e / epithelium~e.5)))) # ::id a_pmid_2169_9731.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While IGF @-@ 1 levels correlated strongly with the ability of MØCM to stimulate neoplastic growth , IGF @-@ 1 induced proliferation of these non @-@ neoplastic and neoplastic mouse lung cell lines has not been demonstrated . # ::alignments 0-1 1-1.2.1.1 2-1.2.1.1 3-1.2.1.1 4-1.2.1 5-1.2 6-1.2.3 7-1.2.2.r 9-1.2.2 13-1.2.2.2 15-1.2.2.2.2 17-1.1.2.2.1.1.1 19-1.1.2.2.1.1.1 20-1.1.2.2 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1.4 24-1.1.2.1.1.1.1 24-1.1.2.1.1.1.1.r 27-1.1.2.1 29-1.1.2.1.3.1 30-1.1.2.1.3 31-1.1.2.1.1 31-1.1.2.1.2 32-1.1.2.1.1 34-1.1.1 34-1.1.1.r 36-1.1 (c3 / contrast-01~e.0 :ARG1 (d / demonstrate-01~e.36 :polarity~e.34 -~e.34 :ARG1 (p / proliferate-01~e.21 :ARG0~e.22 (a / and~e.27 :op1 (c / cell-line~e.31,32 :mod (t / tumor :polarity~e.24 -~e.24)) :op2 (c2 / cell-line~e.31 :mod (t2 / tumor)) :source (l / lung~e.30 :part-of (m / mouse~e.29)) :mod (t3 / this~e.23)) :ARG2-of (i / induce-01~e.20 :ARG0 (p2 / protein :name (n / name :op1 "IGF-1"~e.17,19))))) :ARG2 (c4 / correlate-01~e.5 :ARG1 (l2 / level~e.4 :quant-of p2~e.1,2,3) :ARG2~e.7 (c5 / capable-01~e.9 :ARG1 (m2 / medium :ARG1-of (c6 / condition-01 :ARG0 (m3 / macrophage))) :ARG2 (s2 / stimulate-01~e.13 :ARG0 m2 :ARG1 (g / grow-01~e.15 :ARG1 t2))) :ARG1-of (s / strong-02~e.6))) # ::id a_pmid_2169_9731.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recombinant mouse IGF @-@ 1 or MH @-@ S macrophage @-@ conditioned media was sufficient to stimulate the proliferation of neoplastic LM2 , JF32 and E9 cells and non @-@ neoplastic E10 cells ( Figure 7A @-@ D ) . # ::alignments 0-1.1.1.1.1.3 1-1.1.1.1.1.2 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 5-1.1 6-1.1.2.1.1.1.1.1 8-1.1.2.1.1.1.1.1 9-1.1.2.1.1 11-1.1.1.1 11-1.1.2.1 12-1.1.1 12-1.1.2 14-1 16-1.2 18-1.2.2 21-1.2.2.1.1.1.1.1 23-1.2.2.1.1.2.1.1 24-1.2.2.1.1 25-1.2.2.1.1.3.1.1 26-1.1.2.1.1.1 26-1.2.2.1.1.1 26-1.2.2.1.1.2 26-1.2.2.1.1.3 26-1.2.2.1.2 27-1.2.2.1 27-1.2.2.1.1 27-1.2.2.1.1.r 28-1.2.2.1.2.2.1 28-1.2.2.1.2.2.1.r 31-1.2.2.1.2.1.1 32-1.2.2.1.1.1 34-1.3.1.1 34-1.3.1.2 34-1.3.1.3 34-1.3.1.4 36-1.3.1.1.1 (s / suffice-01~e.14 :ARG0 (o / or~e.5 :op1 (m3 / medium~e.12 :ARG1-of (c3 / condition-01~e.11 :ARG0 (p / protein :name (n2 / name :op1 "IGF-1"~e.2,4) :source (m4 / mouse~e.1) :ARG3-of (r / recombine-01~e.0)))) :op2 (m / medium~e.12 :ARG1-of (c / condition-01~e.11 :ARG0 (m2 / macrophage~e.9 :source (c2 / cell-line~e.26 :name (n / name :op1 "MH-S"~e.6,8)))))) :ARG1 (s2 / stimulate-01~e.16 :ARG0 o :ARG1 (p2 / proliferate-01~e.18 :ARG0 (a / and~e.27 :op1~e.27 (a2 / and~e.24,27 :op1 (c4 / cell-line~e.26,32 :name (n3 / name :op1 "LM2"~e.21)) :op2 (c5 / cell-line~e.26 :name (n4 / name :op1 "JF32"~e.23)) :op3 (c6 / cell-line~e.26 :name (n5 / name :op1 "E9"~e.25)) :mod (t / tumor)) :op2 (c7 / cell-line~e.26 :name (n6 / name :op1 "E10"~e.31) :mod (t2 / tumor :polarity~e.28 -~e.28))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.34 :mod "7A"~e.36) :op2 (f2 / figure~e.34 :mod "7B") :op3 (f3 / figure~e.34 :mod "7C") :op4 (f4 / figure~e.34 :mod "7D")))) # ::id a_pmid_2169_9731.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The degree of growth stimulated by 50 ng @/@ mL IGF @-@ 1 was similar to that of MØCM in each line ( Figure 7A @-@ D ) . # ::alignments 3-1.1 3-1.2 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.2.1 7-1.1.1.1.2.2 9-1.1.1.1.2.2 10-1.1.1.1.1.1 12-1.1.1.1.1.1 14-1 19-1.3.r 20-1.3.1 21-1.3 23-1.4.1.1 23-1.4.1.2 23-1.4.1.3 23-1.4.1.4 25-1.4.1.1.1 (r / resemble-01~e.14 :ARG1 (g / grow-01~e.3 :ARG1-of (s / stimulate-01~e.4 :ARG0~e.5 (p / protein :name (n / name :op1 "IGF-1"~e.10,12) :quant (c / concentration-quantity :quant 50~e.6 :unit (n2 / nanogram-per-milliliter~e.7,9))))) :ARG2 (g2 / grow-01~e.3 :ARG1 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :location~e.19 (l / line~e.21 :mod (e / each~e.20)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.23 :mod "7A"~e.25) :op2 (f2 / figure~e.23 :mod "7B") :op3 (f3 / figure~e.23 :mod "7C") :op4 (f4 / figure~e.23 :mod "7D")))) # ::id a_pmid_2169_9731.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results confirm that IGF @-@ 1 alone can stimulate the growth of long @-@ established neoplastic and non @-@ neoplastic cell lines , as well as cells isolated more recently from primary mouse lung tumors ( JF32 ) , consistent with previous reports on human cancer cell lines [ @ 27 @ ] . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1.1.2 8-1.2 9-1.2.1 11-1.2.1.2 12-1.2.1.2.1.r 13-1.2.1.2.1.1.3.1 15-1.2.1.2.1.1.3 17-1.2.1.2.1.1 18-1.2.1.2.1.1.2.1.1 18-1.2.1.2.1.1.2.1.1.r 21-1.2.1.2.1.2 22-1.2.1.2.1.1.1 24-1.2.1.2.1.1 25-1.2.1.2.1.1 26-1.2.1.2.1 26-1.2.1.2.1.1 26-1.2.1.2.1.1.r 27-1.2.1.2.1.1.1 27-1.2.1.2.1.1.2 27-1.2.1.2.1.2 28-1.2.1.2.1.2.1 29-1.2.1.2.1.2.1.2.1 30-1.2.1.2.1.2.1.2 31-1.1.1.1.1.3.1.r 31-1.2.1.2.1.2.1.1.r 32-1.2.1.2.1.2.1.1.2 33-1.2.1.2.1.2.1.1.1.1 34-1.2.1.2.1.2.1.1.1 35-1.2.1.2.1.1.1.1 35-1.2.1.2.1.1.2.1 35-1.2.1.2.1.2.1.1 37-1.2.1.2.1.2.1.1.3.1.1.1 40-1.1.1.1 42-1.1.1.1.1.2 43-1.1.1.1.1 43-1.1.1.1.1.1 43-1.1.1.1.1.1.r 45-1.1.1.1.1.3.1.3 46-1.1.1.1.1.3.1.2.1 47-1.1.1.1.1.3 48-1.1.1.1.1.3 51-1.1.1.1.1.4.1.1.1 (c / confirm-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (r / result-01~e.1 :ARG1-of (c6 / consistent-01~e.40 :ARG2 (t6 / thing~e.43 :ARG1-of~e.43 (r3 / report-01~e.43) :time (p4 / previous~e.42) :topic (c7 / cell-line~e.47,48 :source~e.31 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.46) :mod (h / human~e.45))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c9 / cite-01 :ARG2 27~e.51)))))) :mod (t2 / this~e.0)) :ARG1~e.3 (p / possible-01~e.8 :ARG1 (s / stimulate-01~e.9 :ARG0 (p2 / protein :name (n2 / name :op1 "IGF-1"~e.4,6) :mod (a / alone~e.7)) :ARG1 (g / grow-01~e.11 :ARG1~e.12 (a2 / and~e.26 :op1~e.26 (a3 / and~e.17,24,25,26 :op1 (c2 / cell-line~e.22,27 :mod (t3 / tumor~e.35)) :op2 (c3 / cell-line~e.27 :mod (t4 / tumor~e.35 :polarity~e.18 -~e.18)) :ARG1-of (e / establish-01~e.15 :ARG1-of (l / long-03~e.13))) :op2 (c4 / cell~e.21,27 :ARG1-of (i / isolate-01~e.28 :ARG2~e.31 (t5 / tumor~e.35 :mod (l2 / lung~e.34 :part-of (m2 / mouse~e.33)) :mod (p3 / primary~e.32) :ARG1-of (m3 / mean-01 :ARG2 (c5 / cell-line :name (n3 / name :op1 "JF32"~e.37)))) :time (r2 / recent~e.30 :degree (m / more~e.29))))))))) # ::id a_pmid_2169_9731.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to determine any relevant role of EGFR in mediating macrophage @-@ stimulated tumor cell proliferation in these cell lines , recombinant mouse EGF was added at 2 ng/mL . # ::alignments 0-1.2.r 1-1.2.r 2-1.2.r 3-1.2 5-1.2.1 6-1.2.1.1 7-1.2.1.1.1.r 8-1.2.1.1.1.1.1 9-1.2.1.2.r 10-1.2.1.2 11-1.2.1.2.2.2.1 13-1.2.1.2.2.2 14-1.2.1.2.2.1.1 15-1.2.1.2.2.1 15-1.2.1.2.2.3 16-1.2.1.2.2 18-1.2.1.2.2.3.1 19-1.2.1.2.2.3 20-1.2.1.2.2.3 22-1.2.1.2.1 23-1.2.1.2.1 24-1.2.1.2.1 26-1 27-1.1.r 28-1.1.2.1 (a / add-02~e.26 :ARG1~e.27 (p / protein :name (n2 / name :op1 "EGF") :quant (c / concentration-quantity :quant 2~e.28 :unit (n3 / nanogram-per-milliliter)) :source (m / mouse) :ARG3-of (r / recombine-01)) :purpose~e.0,1,2 (d / determine-01~e.3 :ARG1 (r3 / relevant-01~e.5 :ARG1 (r4 / role~e.6 :poss~e.7 (e / enzyme :name (n / name :op1 "EGFR"~e.8))) :ARG2~e.9 (m2 / mediate-01~e.10 :ARG0 p~e.22,23,24 :ARG1 (p2 / proliferate-01~e.16 :ARG0 (c2 / cell~e.15 :mod (t / tumor~e.14)) :ARG1-of (s / stimulate-01~e.13 :ARG0 (m3 / macrophage~e.11)) :location (c3 / cell-line~e.15,19,20 :mod (t2 / this~e.18))))))) # ::id a_pmid_2169_9731.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is roughly 500 @-@ times the reported EC @₅₀@ for growth stimulation and 20 @-@ times higher than levels found in the BALF from tumor @-@ bearing animals ( Figure 6A ) . # ::alignments 0-1.1.1 2-1.1.2 2-1.2.2 3-1.1.2.1.1 5-1.1.2.1 7-1.1.2.1.2.2 10-1.1.2.1.2.1.1 13-1.1.2.1.2.1.2.1 14-1.1.2.1.2.1.2 15-1 16-1.2.2.1.3.1 18-1.2.2.1.3 19-1.2.2.1 19-1.2.2.1.2 19-1.2.2.1.2.r 20-1.2.2.1.4.r 21-1.2.2.1.4 22-1.2.2.1.4.1 23-1.2.2.1.4.1.1.r 25-1.2.2.1.4.1.1 25-1.2.2.1.4.1.1.1 25-1.2.2.1.4.1.1.1.1 25-1.2.2.1.4.1.1.1.1.1 25-1.2.2.1.4.1.1.1.1.1.r 25-1.2.2.1.4.1.1.1.1.r 25-1.2.2.1.4.1.1.1.r 26-1.2.2.1.4.1.1.2.r 27-1.2.2.1.4.1.1.2.1.1 29-1.2.2.1.4.1.1.2.1 30-1.2.2.1.4.1.1.2 32-1.3.1 34-1.3.1.1 (a / and~e.15 :op1 (e / equal-01 :ARG1 (t / this~e.0) :ARG2 (r2 / roughly~e.2 :op1 (p / product-of~e.5 :op1 500~e.3 :op2 (c / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-effective-concentration-01 :ARG2 50~e.10 :ARG3 (s / stimulate-01~e.14 :ARG1 (g / grow-01~e.13))) :ARG1-of (r / report-01~e.7))))) :op2 (e2 / equal-01 :ARG1 t :ARG2 (r3 / roughly~e.2 :op1 (h / high-02~e.19 :ARG1 t :degree~e.19 (m / more~e.19) :degree (p2 / product-of~e.18 :op1 20~e.16) :compared-to~e.20 (l / level~e.21 :ARG1-of (f / find-01~e.22 :location~e.23 (f3 / fluid~e.25 :mod~e.25 (l2 / lavage~e.25 :mod~e.25 (a3 / alveolus~e.25 :mod~e.25 (b2 / bronchus~e.25))) :source~e.26 (a2 / animal~e.30 :ARG0-of (b / bear-01~e.29 :ARG1 (t3 / tumor~e.27))))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.32 :mod "6A"~e.34))) # ::id a_pmid_2169_9731.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF had no significant effect on tumor cell proliferation when added alone , and did not significantly affect the ability of either IGF @-@ 1 or MØCM to stimulate neoplastic growth ( Figure 7E , F ) . # ::alignments 0-1.1.2.1.1 2-1.1.1 2-1.1.1.r 3-1.1.4 4-1.1 5-1.1.3.r 6-1.1.3.1.1 7-1.1.3.1 8-1.1.3 10-1.1.5 11-1.1.5.2 13-1 13-1.3.1 15-1.2.1 15-1.2.1.r 16-1.2.4 17-1.2 19-1.2.3 22-1.2.3.2.1.1.1.1 24-1.2.3.2.1.1.1.1 25-1.2.3.2.1 28-1.2.3.2 29-1.2.3.2.2.1 30-1.2.3.2.2 32-1.3.1.1 32-1.3.1.2 34-1.3.1.1.1 (a4 / and~e.13 :op1 (a / affect-01~e.4 :polarity~e.2 -~e.2 :ARG0 (p / protein :name (n / name :op1 "EGF"~e.0)) :ARG1~e.5 (p2 / proliferate-01~e.8 :ARG0 (c / cell~e.7 :mod (t / tumor~e.6))) :ARG1-of (s / significant-02~e.3) :condition (a2 / add-02~e.10 :ARG1 p :manner (a3 / alone~e.11))) :op2 (a5 / affect-01~e.17 :polarity~e.15 -~e.15 :ARG0 p :ARG1 (c3 / capable-01~e.19 :ARG1 o :ARG2 (s3 / stimulate-01~e.28 :ARG0 (o / or~e.25 :op1 (p4 / protein :name (n3 / name :op1 "IGF-1"~e.22,24)) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (g / grow-01~e.30 :ARG1 (n2 / neoplasm~e.29)))) :ARG1-of s~e.16) :ARG1-of (d / describe-01 :ARG0 (a6 / and~e.13 :op1 (f / figure~e.32 :mod "7E"~e.34) :op2 (f2 / figure~e.32 :mod "7F")))) # ::id a_pmid_2169_9731.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is not surprising in view of recent studies showing that EGFR inhibitors do not inhibit growth of lung cells with KRAS @ mutations [ @ 40 @ ] . # ::alignments 0-1.2 2-1.1 2-1.1.r 3-1 4-1.4.r 5-1.4 6-1.4.1.r 7-1.4.1.1.1 8-1.4.1.1 9-1.4.1 10-1.4.1.2.r 11-1.4.1.2.2.1.1.1.1 12-1.4.1.2 12-1.4.1.2.2 12-1.4.1.2.2.1 12-1.4.1.2.2.1.r 12-1.4.1.2.2.r 13-1.4.1.1 14-1.4.1.2.1 14-1.4.1.2.1.r 15-1.4.1.2 15-1.4.1.2.2 15-1.4.1.2.2.1 15-1.4.1.2.2.1.r 15-1.4.1.2.2.r 16-1.4.1.2.3 17-1.4.1.2.3.1.r 18-1.4.1.2.3.1.1 19-1.4.1.2.3.1 22-1.4.1.2.3.1.2.1.1 24-1.4.1.2.3.1.2 24-1.4.1.2.3.1.2.2 24-1.4.1.2.3.1.2.2.r 27-1.3.1.1.1 (s / surprise-01~e.3 :polarity~e.2 -~e.2 :ARG0 (t2 / this~e.0) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 40~e.27))) :ARG2-of~e.4 (v / view-02~e.5 :ARG1~e.6 (s2 / show-01~e.9 :ARG0 (s3 / study-01~e.8,13 :time (r / recent~e.7)) :ARG1~e.10 (i2 / inhibit-01~e.12,15 :polarity~e.14 -~e.14 :ARG0~e.12,15 (m / molecular-physical-entity~e.12,15 :ARG0-of~e.12,15 (i3 / inhibit-01~e.12,15 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.11)))) :ARG1 (g / grow-01~e.16 :ARG1~e.17 (c2 / cell~e.19 :mod (l / lung~e.18) :mod (g2 / gene~e.24 :name (n2 / name :op1 "KRAS"~e.22) :ARG2-of~e.24 (m2 / mutate-01~e.24)))))))) # ::id a_pmid_2169_9731.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As IGF @-@ 1 was sufficient to induce neoplastic proliferation , we determined whether the IGF @-@ 1 and MØCM growth effects were additive . # ::alignments 1-1.3.1.1 2-1.3.1.1 3-1.3.1.1 5-1.3.1 7-1.3.1.2 8-1.3.1.2.2.1 9-1.3.1.2.2 11-1.1 12-1 13-1.2.1 13-1.2.1.r 15-1.2.2.1.1.1.1 17-1.2.2.1.1.1.1 20-1.2.2.1.2 21-1.2.2.1 21-1.2.2.2 23-1.2 (d / determine-01~e.12 :ARG0 (w / we~e.11) :ARG1 (a / add-02~e.23 :mode~e.13 interrogative~e.13 :ARG1 (a5 / and :op1 (a2 / affect-01~e.21 :ARG0 (p / protein :name (n / name :op1 "IGF-1"~e.15,17)) :ARG2 (g / grow-01~e.20)) :op2 (a3 / affect-01~e.21 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG2 g))) :ARG1-of (c2 / cause-01 :ARG0 (s / suffice-01~e.5 :ARG0 p~e.1,2,3 :ARG1 (i / induce-01~e.7 :ARG0 p :ARG2 (p2 / proliferate-01~e.9 :ARG0 (n3 / neoplasm~e.8)))))) # ::id a_pmid_2169_9731.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A dose of 50 ng @/@ ml IGF @-@ 1 stimulated neoplastic growth to a similar extent as MØCM ( Figure 7A @-@ D ) ; 2 ng @/@ mL IGF is the reported EC @₅₀@ for IGF @-@ 1 stimulated proliferation in vitro @ as well as the concentration detected in the BALF of tumor @-@ bearing mice in vivo @ ( Figure 6A ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2.1 4-1.1.1.1.2.2 6-1.1.1.1.2.2 7-1.1.1.1.1.1 9-1.1.1.1.1.1 10-1.1 10-1.1.3.1.1 11-1.1.2.1 12-1.1.2 13-1.1.3.r 15-1.1.3.1 16-1.1.3 20-1.1.4.1.1 22-1.1.4.1.1.1 28-1.2.2.1 29-1.2.2.2 30-1.2.2.2 31-1.2.2.2 32-1.2.1.1 35-1.2.3.1.1.2 38-1.2.3.1.1.1 41-1.2.1.1 43-1.2.4.1.1.1.1 44-1.2.4.1 45-1.2.4 47-1.2.4.2 48-1.2.4.2 50-1 50-1.2.3.1 51-1.2.3.1 52-1.1.4.1 52-1.2.3.1 54-1.1.1.1.2 54-1.2.2 54-1.2.3.1.1 54-1.2.3.1.2 55-1.2.3.1.2.2 56-1.2.3.1.2.1.r 56-1.2.3.1.2.3 58-1.2.3.1.2.1 58-1.2.3.1.2.1.1 58-1.2.3.1.2.1.1.1 58-1.2.3.1.2.1.1.1.1 58-1.2.3.1.2.1.1.1.1.r 58-1.2.3.1.2.1.1.1.r 58-1.2.3.1.2.1.1.r 59-1.2.3.1.2.1.2.r 60-1.2.3.1.2.1.2.1.1 62-1.2.3.1.2.1.2.1 63-1.2.3.1.2.1.2 65-1.2.3.1.2.3 66-1.2.3.1.2.3 69-1.1.4.1.2 69-1.1.4.1.3 69-1.1.4.1.4 69-1.3.1 71-1.3.1.1 (a2 / and~e.50 :op1 (s / stimulate-01~e.10 :ARG0 (d / dose-01~e.1 :ARG2~e.2 (p / protein :name (n / name :op1 "IGF-1"~e.7,9) :quant (c / concentration-quantity~e.54 :quant 50~e.3 :unit (n5 / nanogram-per-milliliter~e.4,6)))) :ARG1 (g / grow-01~e.12 :ARG1 (n2 / neoplasm~e.11)) :ARG3~e.13 (e / extent~e.16 :ARG1-of (r2 / resemble-01~e.15 :ARG2 (s2 / stimulate-01~e.10 :ARG0 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage))) :ARG1 g))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.52 :op1 (f / figure~e.20 :mod "7A"~e.22) :op2 (f3 / figure~e.69 :mod "7B") :op3 (f4 / figure~e.69 :mod "7C") :op4 (f5 / figure~e.69 :mod "7D")))) :op2 (p2 / protein :name (n4 / name :op1 "IGF"~e.32,41) :quant (c3 / concentration-quantity~e.54 :quant 2~e.28 :unit n5~e.29,30,31) :ARG1-of (e2 / equal-01 :ARG2 (a / and~e.50,51,52 :op1 (h / have-percentage-maximal-effective-concentration-01~e.54 :ARG2 50~e.38 :ARG1-of (r3 / report-01~e.35)) :op2 (c4 / concentrate-02~e.54 :ARG1~e.56 (f6 / fluid~e.58 :mod~e.58 (l / lavage~e.58 :mod~e.58 (a4 / alveolus~e.58 :mod~e.58 (b2 / bronchus~e.58))) :source~e.59 (m2 / mouse~e.63 :ARG0-of (b / bear-01~e.62 :ARG1 (t / tumor~e.60)))) :ARG1-of (d3 / detect-01~e.55) :manner (i2 / in-vivo~e.56,65,66)))) :condition (p3 / proliferate-01~e.45 :ARG1-of (s3 / stimulate-01~e.44 :ARG0 (p5 / protein :name (n6 / name :op1 "IGF-1"~e.43))) :manner (i / in-vitro~e.47,48))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.69 :mod "6A"~e.71))) # ::id a_pmid_2169_9731.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IGF @-@ 1 dose @-@ dependently stimulated the proliferation of both LM2 and JF32 cells , and augmented the growth @-@ stimulating effects of MØCM when added in combination . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1.3.1 5-1.1.3 6-1.1 8-1.1.2 11-1.1.2.1.1.1.1 12-1.1.2.1 13-1.1.2.1.2.1.1 14-1.1.2.1.1 14-1.1.2.1.2 16-1 17-1.2 19-1.2.2.2.1 21-1.2.2.2 22-1.2.2 26-1.2.3 27-1.2.3.2.r 28-1.2.3.2 (a / and~e.16 :op1 (s / stimulate-01~e.6 :ARG0 (p / protein :name (n / name :op1 "IGF-1"~e.0,2)) :ARG1 (p2 / proliferate-01~e.8 :ARG0 (a3 / and~e.12 :op1 (c / cell-line~e.14 :name (n2 / name :op1 "LM2"~e.11)) :op2 (c2 / cell-line~e.14 :name (n3 / name :op1 "JF32"~e.13)))) :ARG0-of (d2 / depend-01~e.5 :ARG1 (d3 / dose~e.3))) :op2 (a2 / augment-01~e.17 :ARG0 p :ARG1 (a5 / affect-01~e.22 :ARG0 (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (s2 / stimulate-01~e.21 :ARG1 (g / grow-01~e.19))) :condition (a4 / add-02~e.26 :ARG1 p :ARG2~e.27 (c4 / combine-01~e.28)))) # ::id a_pmid_2169_9731.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if IGF @-@ 1R signaling mediates both IGF @-@ 1 and MØCM stimulation , lung cancer cells were pre @-@ treated with vehicle or 5 μM NVP @-@ AEW541 (- or +, respectively ) , and cell numbers determined as indicated . # ::alignments 1-1.3 3-1.3.1.2.1.1.1 3-1.3.1.3.1.1.1.1 5-1.3.1.2.1.1.1 6-1.3.1.2 7-1.3.1 9-1.3.1.3.1.1.1.1 11-1.3.1.3.1.1.1.1 12-1.3.1.3.1 14-1.3.1.3 16-1.1.1.1.2.1 17-1.1.1.1.2.2 18-1.1.1 24-1.1.2.1 25-1.1.2 26-1.1.2.2.2.1 27-1.1.2.2.2.2 28-1.1.2.2.1.1 30-1.1.2.2.1.1 32-1.1.2 37-1 38-1.2.1.1 39-1.2.1 40-1.2 41-1.2.2.r 42-1.2.2 (a / and~e.37 :op1 (p3 / pretreat-01 :ARG1 (c / cell~e.18 :source (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung"~e.16 :op2 "cancer"~e.17))) :ARG3 (o / or~e.25,32 :op1 (v / vehicle~e.24) :op2 (s3 / small-molecule :name (n2 / name :op1 "NVP-AEW541"~e.28,30) :quant (c3 / concentration-quantity :quant 5~e.26 :unit (m / micromolar~e.27))))) :op2 (d2 / determine-01~e.40 :ARG1 (n3 / number~e.39 :quant-of (c4 / cell~e.38)) :ARG1-of~e.41 (i / indicate-01~e.42)) :purpose (d3 / determine-01~e.1 :ARG1 (m2 / mediate-01~e.7 :mode interrogative :ARG0 (s / signal-07~e.6 :ARG0 (p / protein :name (n4 / name :op1 "IGF-1R"~e.3,5))) :ARG1 (s2 / stimulate-01~e.14 :ARG1 (a2 / and~e.12 :op1 (p2 / protein :name (n5 / name :op1 "IGF-1"~e.3,9,11)) :op2 (m3 / medium :ARG1-of (c2 / condition-01 :ARG0 (m4 / macrophage)))))))) # ::id a_pmid_2169_9731.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IGF @-@ 1 and MØCM each significantly increased cell numbers after 48 and 72 hrs , while pharmacological inhibition of IGF @-@ 1R signaling blocked IGF @-@ 1 and MØCM growth effects in both neoplastic lines ( Figure 7G , H ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 6-1.1.3 7-1.1 8-1.1.2.1 9-1.1.2 10-1.1.4 11-1.1.4.1.1.1 12-1.1.4.1 13-1.1.4.1.2.1 14-1.1.4.1.1.2 16-1 16-1.1.4.r 17-1.2.1.2 18-1.2.1 19-1.2.1.1.r 20-1.2.1.1.1.1.1 22-1.2.1.1.1.1.1 23-1.2.1.1 24-1.2 25-1.2.2.1.1.1 26-1.2.2.1.1.1 27-1.2.2.1.1.1 28-1.2.2.1.1 28-1.3.1 30-1.2.2.1 31-1.2.2 32-1.2.3.r 33-1.2.3.2 34-1.2.3.1 35-1.2.3 37-1.3.1.1 37-1.3.1.2 39-1.3.1.1.1 (c / contrast-01~e.16 :ARG1 (i / increase-01~e.7 :ARG0 (a / and~e.3 :op1 (p / protein :name (n / name :op1 "IGF-1"~e.0,2)) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (n3 / number~e.9 :quant-of (c3 / cell~e.8)) :ARG1-of (s / significant-02~e.6) :time~e.16 (a2 / after~e.10 :quant (a3 / and~e.12 :op1 (t / temporal-quantity :quant 48~e.11 :unit (h / hour~e.14)) :op2 (t2 / temporal-quantity :quant 72~e.13 :unit h)))) :ARG2 (b / block-01~e.24 :ARG0 (i2 / inhibit-01~e.18 :ARG1~e.19 (s2 / signal-07~e.23 :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1R"~e.20,22))) :mod (p2 / pharmacology~e.17)) :ARG1 (a6 / affect-01~e.31 :ARG2 (g / grow-01~e.30 :ARG0 (a4 / and~e.28 :op1 p~e.25,26,27 :op2 m))) :location~e.32 (l / line~e.35 :mod (n5 / neoplasm~e.34) :mod (b2 / both~e.33))) :ARG1-of (d / describe-01 :ARG0 (a5 / and~e.28 :op1 (f / figure~e.37 :mod "7G"~e.39) :op2 (f2 / figure~e.37 :mod "7H")))) # ::id a_pmid_2169_9731.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Parallel comparison of MTS values indicated a highly significant correlation between live cell numbers and relative MTS scores ( r @²@ = 0.7912 and 0.8201 for LM2 and JF32 , respectively , p < 0.0001 , data not shown ) . # ::alignments 0-1.1.3 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1 7-1.2.3.1 8-1.2.3 9-1.2 11-1.2.1.1.1 12-1.2.1.1 13-1.2.1 14-1.2.2.3.1 15-1.2.2.2 16-1.2.2.1 17-1.2.2 24-1.2.2.3.1.1.1 25-1.2.2.3.1 26-1.2.2.3.1.2.1 28-1.2.2.3.1.1.2.1.1 29-1.2.2.3.1 30-1.2.2.3.1.2.2.1.1 34-1.2.2.3.1.1 34-1.2.2.3.1.2 34-1.2.2.3.1.3 35-1.2.2.3.1.3.1 36-1.2.2.3.1.3.1.1 38-1.2.2.3.2.1 39-1.2.2.3.2.1.1.1 39-1.2.2.3.2.1.1.1.r 40-1.2.2.3.2.1.1 (i / indicate-01~e.5 :ARG0 (c / compare-01~e.1 :ARG1~e.2 (v / value~e.4 :mod (t / thing :name (n / name :op1 "MTS"~e.3))) :ARG2 v :manner (p / parallel~e.0)) :ARG1 (c2 / correlate-01~e.9 :ARG1 (n3 / number~e.13 :quant-of (c3 / cell~e.12 :ARG0-of (l / live-01~e.11))) :ARG2 (s / score-01~e.17 :ARG1 t~e.16 :ARG1-of (r / relative-05~e.15) :ARG1-of (m / mean-01 :ARG2 (a / and~e.14,25,29 :op1 (s4 / statistical-test-91~e.34 :ARG3 0.7912~e.24 :ARG1 (c4 / cell-line :name (n5 / name :op1 "LM2"~e.28))) :op2 (s5 / statistical-test-91~e.34 :ARG3 0.8201~e.26 :ARG1 (c5 / cell-line :name (n6 / name :op1 "JF32"~e.30))) :op3 (s6 / statistical-test-91~e.34 :ARG2 (l2 / less-than~e.35 :quant 0.0001~e.36))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.38 :ARG1-of (s3 / show-01~e.40 :polarity~e.39 -~e.39))))) :ARG1-of (s2 / significant-02~e.8 :ARG1-of (h / high-02~e.7)))) # ::id a_pmid_2169_9731.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , both IGF @-@ 1 and MØCM increased the fraction of BrdU @⁺@ LM2 cells 12 @-@ 24 hrs after treatment , corresponding with significantly increased cell numbers ( data not shown ) . # ::alignments 0-1 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1 8-1.1 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1.2.1.1 14-1 16-1.1.2.1.1.1 17-1.1.2.1 18-1.1.3.2.1.1 20-1.1.3.2.1.2 21-1.1.3.2.2 22-1.1.3 23-1.1.3.1 25-1.1.4 26-1.1.4.1.r 27-1.1.4.1.2.1 28-1.1.4.1.2 29-1.1.4.1.1 30-1.1.4.1 32-1.2.1 33-1.2.1.1.1 33-1.2.1.1.1.r 34-1.2.1.1 (a / and~e.0,14 :op2 (i / increase-01~e.8 :ARG0 (a2 / and~e.6 :op1 (p / protein :name (n / name :op1 "IGF-1"~e.3,5)) :op2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage)))) :ARG1 (f / fraction~e.10 :quant-of~e.11 (c / cell-line~e.17 :name (n4 / name :op1 "LM2"~e.16) :mod (s3 / small-molecule :name (n3 / name :op1 "BrdU"~e.12) :mod (w / wild-type)))) :time (a3 / after~e.22 :op1 (t / treat-04~e.23) :quant (t2 / temporal-quantity :quant (v / value-interval :op1 12~e.18 :op2 24~e.20) :unit (h / hour~e.21))) :ARG1-of (c3 / correspond-02~e.25 :ARG2~e.26 (n5 / number~e.30 :quant-of (c4 / cell~e.29) :ARG1-of (i2 / increase-01~e.28 :ARG2 (s / significant-02~e.27))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.32 :ARG1-of (s2 / show-01~e.34 :polarity~e.33 -~e.33)))) # ::id a_pmid_2169_9731.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These observations suggest that IGF @-@ 1 , but not EGF , plays a major role in macrophage stimulated neoplastic growth in vitro , consistent with the elevated IGF @-@ 1 levels observed in lung @-@ tumor bearing animals in vivo @ . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1.1 6-1.2.1.1.1.1 8-1.2 9-1.2.2.1 9-1.2.2.1.r 10-1.2.2.2.1.1 12-1.2.1 12-1.2.2 14-1.2.1.4 16-1.2.1.2.r 16-1.2.1.3 17-1.2.1.2.1.1.1 18-1.2.1.2.1.1 19-1.2.1.2.1 20-1.2.1.2 22-1.2.1.3 23-1.2.1.3 26-1.3 27-1.3.1.r 29-1.3.1.2 30-1.3.1.3 31-1.3.1.3 32-1.3.1.3 33-1.3.1 34-1.3.1.1 35-1.3.1.1.1 35-1.3.1.1.2.r 36-1.3.1.1.2.1.1.1 38-1.3.1.1.2.1.1 39-1.3.1.1.2.1 40-1.3.1.1.2 42-1.3.1.1.1 43-1.3.1.1.1 (s / suggest-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1~e.3 (c / contrast-01~e.8 :ARG1 (p / play-08~e.12 :ARG0 (p2 / protein :name (n / name :op1 "IGF-1"~e.4,6)) :ARG1~e.16 (g / grow-01~e.20 :ARG1 (n2 / neoplasm~e.19 :ARG1-of (s2 / stimulate-01~e.18 :ARG0 (m2 / macrophage~e.17)))) :manner (i / in-vitro~e.16,22,23) :ARG1-of (m / major-02~e.14)) :ARG2 (p3 / play-08~e.12 :polarity~e.9 -~e.9 :ARG0 (p4 / protein :name (n3 / name :op1 "EGF"~e.10)))) :ARG1-of (c2 / consistent-01~e.26 :ARG2~e.27 (l / level~e.33 :ARG1-of (o2 / observe-01~e.34 :manner (i2 / in-vivo~e.35,42,43) :location~e.35 (a / animal~e.40 :ARG0-of (b / bear-01~e.39 :ARG1 (t2 / tumor~e.38 :mod (l2 / lung~e.36))))) :ARG1-of (e / elevate-01~e.29) :quant-of p2~e.30,31,32))) # ::id a_pmid_2169_9731.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MØCM stimulation of neoplastic growth is diminished when IGF @-@ 1 content is decreased # ::alignments 1-1.1 2-1.1.2.r 3-1.1.2.1 4-1.1.2 6-1 7-1.2.r 8-1.2.1.1.1.1 10-1.2.1.1.1.1 11-1.2.1 13-1.2 (d / diminish-01~e.6 :ARG1 (s / stimulate-01~e.1 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG1~e.2 (g / grow-01~e.4 :ARG1 (n2 / neoplasm~e.3))) :time~e.7 (d2 / decrease-01~e.13 :ARG1 (c2 / content~e.11 :quant-of (p / protein :name (n3 / name :op1 "IGF-1"~e.8,10))))) # ::id a_pmid_2169_9731.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to determine if IGF @-@ 1 was a molecular mediator directly responsible for growth stimulated by MØCM , we decreased MØCM IGF @-@ 1 content through two independent avenues : immuno @-@ depletion and siRNA interference . # ::alignments 0-1.4.r 1-1.4.r 2-1.4.r 3-1.4 5-1.4.2.2.1.1 7-1.4.2.2.1.1 10-1.4.2.2.3 11-1.4.2.2 11-1.4.2.2.2 11-1.4.2.2.2.r 12-1.4.2.4 13-1.4.2 14-1.4.2.3.r 15-1.4.2.3 16-1.4.2.3.1 20-1.1 20-1.4.1 21-1 23-1.2.2 24-1.2.2 25-1.2.2 26-1.2 28-1.3.1 29-1.3.2 29-1.3.2.1 29-1.3.2.1.r 30-1.3 35-1.3.3.1 36-1.3.3.1.2.1.1.1 37-1.3.3.1.2 (d / decrease-01~e.21 :ARG0 (w / we~e.20) :ARG1 (c / contain-01~e.26 :ARG0 m4 :ARG1 p3~e.23,24,25) :instrument (a2 / avenue~e.30 :quant 2~e.28 :ARG0-of (d2 / depend-01~e.29 :polarity~e.29 -~e.29) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and~e.35 :op1 (i / immunodeplete-00) :op2 (i2 / interfere-01~e.37 :ARG1 (n / nucleic-acid :name (n3 / name :op1 "siRNA"~e.36)))))) :purpose~e.0,1,2 (d3 / determine-01~e.3 :ARG0 (w2 / we~e.20) :ARG1 (r2 / responsible-01~e.13 :mode interrogative :ARG0 (p3 / protein~e.11 :name (n4 / name :op1 "IGF-1"~e.5,7) :ARG0-of~e.11 (m / mediate-01~e.11) :mod (m3 / molecule~e.10)) :ARG1~e.14 (g / grow-01~e.15 :ARG1-of (s / stimulate-01~e.16 :ARG0 (m4 / medium :ARG1-of (c2 / condition-01 :ARG0 (m5 / macrophage))))) :ARG1-of (d4 / direct-02~e.12)))) # ::id a_pmid_2169_9731.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MØCM was concentrated to contain ~ 3.5 ng @/@ mL IGF @-@ 1 , and then incubated with control IgG ( Con IgG ) or α-IGF @-@ 1 IgG coated resin , as described [ @ 39 @ ] . # ::alignments 2-1.1 2-1.1.2.2.2.1 4-1.1.2 5-1.1.2.2.2 6-1.1.2.2.2.1.1 7-1.1.2.2.2.1.2 9-1.1.2.2.2.1.2 10-1.1.2.2.1.1 12-1.1.2.2.1.1 14-1 15-1.2.3 16-1.2 17-1.2.2.r 18-1.2.2.1 18-1.2.2.1.2 18-1.2.2.1.2.r 19-1.2.2.1.1.1 22-1.2.2.1.1.1 24-1.2.2 27-1.2.2.2.1.1.1.1.1 28-1.2.2.2.1.1.2 29-1.2.2.2.1 30-1.2.2.2 32-1.2.3.r 33-1.3.1.1 36-1.3.1.1.1.1.1 (a / and~e.14 :op1 (c / concentrate-02~e.2 :ARG1 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage))) :purpose (c3 / contain-01~e.4 :ARG0 m :ARG1 (p4 / protein :name (n5 / name :op1 "IGF-1"~e.10,12) :quant (a3 / approximately~e.5 :op1 (c4 / concentration-quantity~e.2 :quant 3.5~e.6 :unit (n6 / nanogram-per-milliliter~e.7,9)))))) :op2 (i / incubate-01~e.16 :ARG1 m :ARG2~e.17 (o / or~e.24 :op1 (p / protein~e.18 :name (n2 / name :op1 "IgG"~e.19,22) :ARG0-of~e.18 (c5 / control-01~e.18)) :op2 (r2 / resin~e.30 :ARG1-of (c6 / coat-01~e.29 :ARG2 (a2 / and :op1 (p2 / protein :name (n4 / name :op1 "α-IGF-1"~e.27)) :op2 p~e.28)))) :time~e.32 (t / then~e.15)) :ARG1-of (r / resemble-01 :ARG2 (t2 / thing :ARG1-of (d / describe-01~e.33 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 39~e.36)))))) # ::id a_pmid_2169_9731.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This procedure successfully decreased MØCM IGF @-@ 1 levels to 40 @-@ 50 % of control ( Figure 8A ) . # ::alignments 0-1.1.1 1-1.1 2-1.5 3-1 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2 9-1.3.r 10-1.3.1.1.1 12-1.3.1.1.2 13-1.3.1 14-1.3.1.r 15-1.3 17-1.4.1 19-1.4.1.1 (d / decrease-01~e.3 :ARG0 (p2 / procedure~e.1 :mod (t / this~e.0)) :ARG1 (l / level~e.8 :quant-of (p3 / protein :name (n2 / name :op1 "IGF-1"~e.5,7) :mod (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))))) :ARG4~e.9 (c3 / control~e.15 :quant~e.14 (p4 / percentage-entity~e.13 :value (v / value-interval :op1 40~e.10 :op2 50~e.12))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod "8A"~e.19)) :ARG1-of (s / succeed-01~e.2)) # ::id a_pmid_2169_9731.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When this IGF @-@ 1 depleted media was added to LM2 and JF32 cells , growth stimulation was significantly decreased compared to untreated MØCM or IgG controls , which were identical ( Figure 8B ) . # ::alignments 0-1.3.r 1-1.3.1.2 2-1.3.1.1.1.1.1 4-1.3.1.1.1.1.1 5-1.3.1.1 6-1.3.1 6-1.4.1.1 8-1.3 9-1.3.2.r 10-1.3.2.1.1.1 11-1.3.2 12-1.3.2.2.1.1 13-1.3.2.1 13-1.3.2.2 15-1.1.1 16-1.1 18-1.2 19-1 20-1.4.r 21-1.4.1.1.1.r 22-1.4.1.1.1 22-1.4.1.1.1.1 22-1.4.1.1.1.1.r 24-1.4.1 25-1.4.1.2.1.1 26-1.4 30-1.4.1.2 30-1.4.1.2.2 30-1.4.1.2.2.r 32-1.5.1 34-1.5.1.1 (d4 / decrease-01~e.19 :ARG1 (s / stimulate-01~e.16 :ARG1 (g / grow-01~e.15)) :ARG2 (s2 / significant-02~e.18) :time~e.0 (a / add-02~e.8 :ARG1 (m / media~e.6 :ARG1-of (d2 / deplete-01~e.5 :ARG2 (p2 / protein :name (n3 / name :op1 "IGF-1"~e.2,4))) :mod (t2 / this~e.1)) :ARG2~e.9 (a2 / and~e.11 :op1 (c / cell-line~e.13 :name (n4 / name :op1 "LM2"~e.10)) :op2 (c4 / cell-line~e.13 :name (n5 / name :op1 "JF32"~e.12)))) :compared-to~e.20 (c3 / control-01~e.26 :ARG0 (o / or~e.24 :op1 (m2 / medium~e.6 :ARG1-of~e.21 (t / treat-04~e.22 :polarity~e.22 -~e.22) :ARG1-of (c2 / condition-01 :ARG0 (m3 / macrophage))) :op2 (p / protein~e.30 :name (n2 / name :op1 "IgG"~e.25) :ARG1-of~e.30 (i / identical-01~e.30 :ARG2 m2) :ARG1-of t))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.32 :mod "8B"~e.34))) # ::id a_pmid_2169_9731.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , MH @-@ S macrophage IGF @-@ 1 secretion was interrupted by transfection with scrambled control ( scr siRNA ) or siRNA constructs designed against mouse IGF @-@ 1 (α-IGF siRNA ) . # ::alignments 0-1 1-1 3-1.1.2.1.1.1.1 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1.2.2.1.1 9-1.1.2.2.1.1 10-1.1.2 12-1.1 13-1.1.1.r 14-1.1.1 15-1.1.1.1.r 16-1.1.1.1.1.1 17-1.1.1.1.1 20-1.1.1.1.1.2.1.1.1 20-1.1.1.1.2.1.1.1 22-1.1.1.1 23-1.1.1.1.1.2.1.1.1 23-1.1.1.1.2.1.1.1 24-1.1.1.1.2 25-1.1.1.1.2.2 26-1.1.1.1.2.2.1 27-1.1.1.1.2.2.1.1.2 28-1.1.1.1.2.2.1.1.1.1 28-1.1.1.1.2.2.1.1.3.1.2.1.1 30-1.1.1.1.2.2.1.1.1.1 32-1.1.1.1.1.2.1.1.1 32-1.1.1.1.2.1.1.1 32-1.1.1.1.2.2.1.1.3.1.1.1 (a / and~e.0,1 :op2 (i / interrupt-01~e.12 :ARG0~e.13 (t / transfect-01~e.14 :ARG2~e.15 (o / or~e.22 :op1 (c / control~e.17 :ARG1-of (s2 / scramble-02~e.16) :ARG1-of (m4 / mean-01 :ARG2 (n8 / nucleic-acid :name (n7 / name :op1 "siRNA"~e.20,23,32) :ARG1-of s2))) :op2 (c2 / construct~e.24 :mod (n9 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.20,23,32)) :ARG1-of (d / design-01~e.25 :purpose (o2 / oppose-01~e.26 :ARG1 (p2 / protein :name (n4 / name :op1 "IGF-1"~e.28,30) :source (m2 / mouse~e.27) :ARG1-of (m3 / mean-01 :ARG2 (n10 / nucleic-acid :name (n5 / name :op1 "siRNA"~e.32) :mod (p3 / protein :name (n6 / name :op1 "α-IGF"~e.28)))))))))) :ARG1 (s / secrete-01~e.10 :ARG0 (m / macrophage~e.6 :mod (c3 / cell-line :name (n / name :op1 "MH-S"~e.3,5))) :ARG1 (p / protein :name (n2 / name :op1 "IGF-1"~e.7,9))))) # ::id a_pmid_2169_9731.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One α-IGF siRNA construct was more effective than the scr siRNA , and significantly decreased MØCM IGF @-@ 1 levels to 25 % of control ( Figure 8C ) . # ::alignments 0-1.1.1.1 1-1.1.1.2.2.1.1 2-1.1.1.2.1.1 3-1.1.1 5-1.1.2 6-1.1 7-1.1.3.r 10-1.1.3.1.1 12-1 13-1.2.2 14-1.2 16-1.2.1.1.1.1 18-1.2.1.1.1.1 19-1.2.1 20-1.2.3.r 21-1.2.3.1.1 22-1.2.3.1 23-1.2.3.1.r 24-1.2.3 26-1.3.1 28-1.3.1.1 (a / and~e.12 :op1 (e / effective-04~e.6 :ARG0 (c / construct-01~e.3 :quant 1~e.0 :ARG2 (n6 / nucleic-acid :name (n / name :op1 "siRNA"~e.2) :mod (p2 / protein :name (n2 / name :op1 "α-IGF"~e.1)))) :degree (m / more~e.5) :compared-to~e.7 (n7 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.10) :ARG1-of (s / scramble-02))) :op2 (d / decrease-01~e.14 :ARG1 (l / level~e.19 :quant-of (p3 / protein :name (n4 / name :op1 "IGF-1"~e.16,18) :mod (m2 / medium :ARG1-of (c2 / condition-01 :ARG0 (m3 / macrophage))))) :ARG2 (s2 / significant-02~e.13) :ARG4~e.20 (c3 / control~e.24 :quant~e.23 (p / percentage-entity~e.22 :value 25~e.21))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26 :mod "8C"~e.28))) # ::id a_pmid_2169_9731.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The scr siRNA construct decreased macrophage IGF @-@ 1 secretion to a lesser extent ( Figure 8C ) . # ::alignments 2-1.1.1.1.1 3-1.1 4-1 5-1.2.1 6-1.2.2.1.1 8-1.2.2.1.1 9-1.2 10-1.3.r 12-1.3.1 13-1.3 15-1.4.1 17-1.4.1.1 (d / decrease-01~e.4 :ARG0 (c / construct~e.3 :topic (n3 / nucleic-acid :name (n / name :op1 "siRNA"~e.2) :ARG1-of (s / scramble-02))) :ARG1 (s2 / secrete-01~e.9 :ARG0 (m / macrophage~e.5) :ARG1 (p / protein :name (n2 / name :op1 "IGF-1"~e.6,8))) :ARG4~e.10 (e / extent~e.13 :degree (l / less~e.12)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.15 :mod "8C"~e.17))) # ::id a_pmid_2169_9731.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transfection reagents and conditions were chosen to minimize cellular toxicity , and media IGF @-@ 1 content significantly decreased when normalized to MH @-@ S viability ( media IGF @-@ 1/MTS relative viability , data not shown ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1 2-1.1.1 3-1.1.1.2 5-1.1 7-1.1.2 8-1.1.2.2.1 9-1.1.2.2 11-1.1.1 12-1.2.1.1.2 13-1.2.1.1.1.1 15-1.2.1.1.1.1 16-1.2.1 17-1.2.2 18-1.2 19-1.2.3.r 20-1.2.3 22-1.2.3.2.1.1.1.1 24-1.2.3.2.1.1.1.1 27-1.2.3.2.2.1.1 28-1.2.3.2.2.1.1 31-1.2.3.2.2.1.2.1 34-1.2.3.2.2.1.3.2 35-1.2.3.2.2.1.3.1 35-1.2.3.2.2.1.3.1.r 36-1.2.3.2.2.1.3 (a / and :op1 (c / choose-01~e.5 :ARG1 (a2 / and~e.2,11 :op1 (r / reagent~e.1 :ARG2-of (t / transfect-01~e.0)) :op2 (c2 / condition~e.3 :mod t)) :purpose (m / minimize-01~e.7 :ARG0 a2 :ARG1 (t2 / toxicity~e.9 :mod (c3 / cell~e.8)))) :op2 (d / decrease-01~e.18 :ARG1 (c4 / content~e.16 :quant-of (p / protein :name (n / name :op1 "IGF-1"~e.13,15) :mod (m2 / media~e.12))) :ARG2 (s / significant-02~e.17) :time~e.19 (n2 / normalize-01~e.20 :ARG1 c4 :topic (v / viable :domain (m3 / macrophage :mod (c5 / cell-line :name (n3 / name :op1 "MH-S"~e.22,24))) :ARG1-of (m4 / mean-01 :ARG2 (s2 / slash :op1 p~e.27,28 :op2 (v2 / viable :ARG2-of (r2 / relative-05~e.31)) :ARG1-of (s3 / show-01~e.36 :polarity~e.35 -~e.35 :ARG0 (d2 / data~e.34)))))))) # ::id a_pmid_2169_9731.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neoplastic growth reflected the level of IGF @-@ 1 in the media conditioned by siRNA @-@ treated macrophages , with all three groups differing significantly in JF32 cells ( Figure 8D ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 8-1.1.2.1.1.1 9-1.1.3.r 11-1.1.3 12-1.1.3.1 13-1.1.3.1.1.r 14-1.1.3.1.1.1.1.1.1 16-1.1.3.1.1.1 17-1.1.3.1.1 20-1.2.1.2 21-1.2.1.1 22-1.2.1 23-1.2 24-1.2.2 25-1.2.3.r 26-1.2.3.1.1 27-1.2.3 29-1.1.4.1 31-1.1.4.1.1 (a / and :op1 (r / reflect-01~e.2 :ARG1 (g / grow-01~e.1 :ARG1 (n / neoplasm~e.0)) :ARG2 (l / level~e.4 :quant-of~e.5 (p / protein :name (n2 / name :op1 "IGF-1"~e.6,8))) :location~e.9 (m / media~e.11 :ARG1-of (c / condition-01~e.12 :ARG0~e.13 (m2 / macrophage~e.17 :ARG1-of (t / treat-04~e.16 :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.14)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod "8D"~e.31))) :op2 (d / differ-02~e.23 :ARG1 (g2 / group~e.22 :quant 3~e.21 :mod (a2 / all~e.20)) :ARG1-of (s / significant-02~e.24) :location~e.25 (c2 / cell~e.27 :name (n4 / name :op1 "JF32"~e.26)))) # ::id a_pmid_2169_9731.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While scr siRNA @-@ treated media did not significantly lower LM2 cell growth , the correlation of media IGF @-@ 1 levels vs. LM2 proliferation was highly significant , as in JF32 cells ( Figure 8D @-@ F ) . # ::alignments 0-1 2-1.1.2.1.1.1.1 4-1.1.2.1 5-1.1.2 7-1.1.1 7-1.1.1.r 8-1.1.4 9-1.1 10-1.1.3.1.1.1 11-1.1.3.1 12-1.1.3 15-1.2 16-1.2.1.r 17-1.2.1.1.2 18-1.2.1.1.1.1 20-1.2.1.1.1.1 21-1.2.1 22-1 23-1.1.3.1.1.1 24-1.2.2 24-1.2.4.1 26-1.2.3.1 27-1.2.3 31-1.2.4.1.1.1.1 32-1.1.3.1 32-1.2.4.1.1 34-1.3.1.1 34-1.3.1.2 34-1.3.1.3 36-1.3.1.1.1 (c / contrast-01~e.0,22 :ARG1 (l2 / lower-05~e.9 :polarity~e.7 -~e.7 :ARG0 (m2 / medium~e.5 :ARG1-of (t / treat-04~e.4 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "siRNA"~e.2) :ARG1-of (s2 / scramble-02)))) :ARG1 (g / grow-01~e.12 :ARG1 (c2 / cell-line~e.11,32 :name (n2 / name :op1 "LM2"~e.10,23))) :ARG1-of (s / significant-02~e.8)) :ARG2 (c3 / correlate-01~e.15 :ARG1~e.16 (l3 / level~e.21 :quant-of (p / protein :name (n3 / name :op1 "IGF-1"~e.18,20) :mod (m / medium~e.17))) :ARG2 (p2 / proliferate-01~e.24 :ARG0 c2) :ARG1-of (s3 / significant-02~e.27 :ARG1-of (h / high-02~e.26)) :ARG1-of (r2 / resemble-01 :ARG2 (p3 / proliferate-01~e.24 :ARG0 (c4 / cell-line~e.32 :name (n4 / name :op1 "JF32"~e.31))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.34 :mod "8D"~e.36) :op2 (f2 / figure~e.34 :mod "8E") :op3 (f3 / figure~e.34 :mod "8F")))) # ::id a_pmid_2169_9731.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these experiments demonstrate that IGF @-@ 1 is responsible for the majority of neoplastic growth stimulated by MØCM . # ::alignments 0-1 1-1.2 3-1.1.2 4-1.1 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1.1 9-1.1.1.1.1.1.1 11-1.1.1.1 12-1.1.1.1.2.r 14-1.1.1.1.2.2 16-1.1.1.1.2.1 17-1.1.1.1.2 18-1.1.1.1.2.3 (t / take-01~e.0 :ARG1 (e / experiment-01~e.4 :ARG0-of (d / demonstrate-01~e.5 :ARG1~e.6 (r / responsible-01~e.11 :ARG0 (p / protein :name (n / name :op1 "IGF-1"~e.7,9)) :ARG1~e.12 (g / grow-01~e.17 :ARG1 (n2 / neoplasm~e.16) :mod (m / majority~e.14) :ARG1-of (s / stimulate-01~e.18 :ARG0 (m2 / medium :ARG1-of (c / condition-01 :ARG0 (m3 / macrophage))))))) :mod (t3 / this~e.3)) :mod (t2 / together~e.1)) # ::id a_pmid_2169_9731.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combined MEK and PI3K inhibition blocks IGF @-@ 1 and MØCM induced neoplastic proliferation by decreasing cyclin D1 expression # ::alignments 0-1.1.1 1-1.1.1.1.1.1.1 3-1.1.1.2.1.1.1 4-1.1.1.1 4-1.1.1.2 5-1.1 6-1.1.2.1.1 8-1.1.2.1.1 9-1 11-1.2 12-1.2.2.1 13-1.2.2 14-1.2.3.r 15-1.2.3 16-1.2.3.1.1.1.1 17-1.2.3.1.1.1.1 18-1.2.3.1 (a / and~e.9 :op1 (b / block-01~e.5 :ARG0 (c / combine-01~e.0 :ARG1 (i2 / inhibit-01~e.4 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK"~e.1))) :ARG2 (i3 / inhibit-01~e.4 :ARG1 (e3 / enzyme :name (n3 / name :op1 "PI3K"~e.3)))) :ARG1 (p / protein :name (n4 / name :op1 "IGF-1"~e.6,8))) :op2 (i / induce-01~e.11 :ARG0 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (p2 / proliferate-01~e.13 :ARG0 (n6 / neoplasm~e.12)) :instrument~e.14 (d / decrease-01~e.15 :ARG1 (e4 / express-03~e.18 :ARG2 (p3 / protein :name (n7 / name :op1 "cyclin-D1"~e.16,17)))))) # ::id a_pmid_2169_9731.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IGF @-@ 1 stimulated neoplastic proliferation and mediated a significant portion of macrophage @-@ induced tumor cell growth in culture . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 6-1 7-1.2 9-1.2.2.2 10-1.2.2 12-1.2.2.1.1.2.1 14-1.2.2.1.1.2 15-1.2.2.1.1.1.1 16-1.2.2.1.1.1 17-1.2.2.1.1 18-1.2.3.r 19-1.2.3 (a / and~e.6 :op1 (s / stimulate-01~e.3 :ARG0 (p / protein :name (n / name :op1 "IGF-1"~e.0,2)) :ARG1 (p2 / proliferate-01~e.5 :ARG0 (n2 / neoplasm~e.4))) :op2 (m / mediate-01~e.7 :ARG0 p :ARG1 (p3 / portion~e.10 :ARG1-of (i / include-01 :ARG2 (g2 / grow-01~e.17 :ARG1 (c2 / cell~e.16 :mod (t2 / tumor~e.15)) :ARG2-of (i3 / induce-01~e.14 :ARG0 (m3 / macrophage~e.12)))) :ARG1-of (s2 / significant-02~e.9)) :location~e.18 (c3 / culture~e.19))) # ::id a_pmid_2169_9731.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if MØCM and @/@ or IGF @-@ 1 were similarly blocked by MEK and PI3K inhibition , LM2 and JF32 cells were treated with combinations of MEK and @/@ or PI3K inhibitors , in the presence of IGF @-@ 1 or MØCM . # ::alignments 1-1.4 2-1.3.r 4-1.4.1.2 6-1.4.1.2 7-1.4.1.2.2 8-1.4.1.2.2 9-1.4.1.2.2 11-1.4.1.3 12-1.4.1 14-1.2.1.1.1.1.1.1 16-1.2.1.2.1.1.1.1 17-1.2.1.1 17-1.2.1.1.1 17-1.2.1.1.1.r 17-1.2.1.2 17-1.2.1.2.1 17-1.2.1.2.1.r 17-1.4.1.1 19-1.1.1.1.1 20-1.1 21-1.1.2.1.1 22-1.1.1 22-1.1.2 24-1 26-1.2 28-1.2.1.1.1.1.1.1 29-1.2.1 31-1.2.1 32-1.2.1.2.1.1.1.1 33-1.2.1.2 33-1.2.1.2.1 33-1.2.1.2.1.r 33-1.4.1.1 37-1.3 38-1.3.1.r 39-1.3.1.1.1.1 41-1.3.1.1.1.1 42-1.3.1 (t / treat-04~e.24 :ARG1 (a / and~e.20 :op1 (c / cell-line~e.22 :name (n2 / name :op1 "LM2"~e.19)) :op2 (c2 / cell-line~e.22 :name (n3 / name :op1 "JF32"~e.21))) :ARG2 (c3 / combine-01~e.26 :ARG1 (a4 / and-or~e.29,31 :op1 (m / molecular-physical-entity~e.17 :ARG0-of~e.17 (i / inhibit-01~e.17 :ARG1 (e / enzyme :name (n7 / name :op1 "MEK"~e.14,28)))) :op2 (m3 / molecular-physical-entity~e.17,33 :ARG0-of~e.17,33 (i2 / inhibit-01~e.17,33 :ARG1 (e2 / enzyme :name (n8 / name :op1 "PI3K"~e.16,32)))))) :condition~e.2 (p / present-02~e.37 :ARG1~e.38 (o / or~e.42 :op1 (p2 / protein :name (n5 / name :op1 "IGF-1"~e.39,41)) :op2 (m2 / medium :ARG1-of (c4 / condition-01 :ARG0 (m4 / macrophage))))) :purpose (d / determine-01~e.1 :ARG1 (b / block-01~e.12 :ARG0 (i3 / inhibit-01~e.17,33 :ARG1 (a3 / and :op1 e :op2 e2)) :ARG1 (a2 / and-or~e.4,6 :op1 m2 :op2 p2~e.7,8,9) :ARG1-of (r / resemble-01~e.11)))) # ::id a_pmid_2169_9731.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analogous to previous results with macrophage co @-@ culture , growth stimulated by either IGF @-@ 1 or MØCM was blocked by combined inhibition of MEK and PI3K , to a greater extent than either pathway by itself ( Figure 9A , B ) . # ::alignments 0-1.5 1-1.5.1.r 2-1.5.1.1.2 3-1.5.1 3-1.5.1.1 3-1.5.1.1.r 5-1.2.1.1.2.1.1 5-1.5.1.1.1.1 6-1.5.1.1.1 8-1.5.1.1.1 10-1.2 10-1.4.2.1 11-1.2.1 11-1.4.2.1.1 14-1.2.1.1.1.1.1 16-1.2.1.1.1.1.1 17-1.2.1.1 17-1.4.2.1.1.1 20-1 20-1.4.2 21-1.1.r 22-1.1.1 23-1.1 25-1.1.1.1.1.1 27-1.1.1.2.1.1 29-1.4.r 31-1.4 31-1.4.1 31-1.4.1.r 33-1.4.2.r 35-1.1.1.1 35-1.1.1.2 39-1.3.1.1 39-1.3.1.2 41-1.3.1.1.1 (b3 / block-01~e.20 :ARG0~e.21 (i / inhibit-01~e.23 :ARG3-of (c2 / combine-01~e.22 :ARG1 (p2 / pathway~e.35 :name (n / name :op1 "MEK"~e.25)) :ARG2 (p3 / pathway~e.35 :name (n4 / name :op1 "PI3K"~e.27)))) :ARG1 (g2 / grow-01~e.10 :ARG1-of (s / stimulate-01~e.11 :ARG0 (o / or~e.17 :op1 (p / protein :name (n2 / name :op1 "IGF-1"~e.14,16)) :op2 (m3 / medium :ARG1-of (c / condition-01 :ARG0 (m4 / macrophage~e.5)))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.39 :mod "9A"~e.41) :op2 (f2 / figure~e.39 :mod "9B"))) :degree~e.29 (g / great~e.31 :degree~e.31 (m / more~e.31) :compared-to~e.33 (b2 / block-01~e.20 :ARG1 (g3 / grow-01~e.10 :ARG1-of (s2 / stimulate-01~e.11 :ARG0 (o2 / or~e.17 :op1 p :op2 m3))))) :mod (a2 / analogous~e.0 :topic~e.1 (t / thing~e.3 :ARG2-of~e.3 (r2 / result-01~e.3 :ARG1 (c3 / co-culture~e.6,8 :mod (m2 / macrophage~e.5)) :mod (p4 / previous~e.2))))) # ::id a_pmid_2169_9731.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the proliferation results , cyclin D1 content ( a biochemical correlate of lung cell proliferation [ @ 41 @ ]) was reduced by these inhibitors ( Figure 9C @-@ E ) . # ::alignments 0-1 1-1.2.r 3-1.2.1.1 4-1.2 4-1.2.1 4-1.2.1.r 6-1.1.2.1.1.1 7-1.1.2.1.1.1 8-1.1.2 11-1.1.2.1.2.1.2 12-1.1.2.1.2.1 12-1.1.2.1.2.1.1 12-1.1.2.1.2.1.1.r 13-1.1.2.1.2.1.1.1.r 14-1.1.2.1.2.1.1.1.1.1 15-1.1.2.1.2.1.1.1.1 16-1.1.2.1.2.1.1.1 19-1.1.2.1.2.1.1.2.1.1.1 23-1.1 24-1.1.1.r 25-1.1.1.2 26-1.1.1 26-1.1.1.1 26-1.1.1.1.r 28-1.3.1.1 28-1.3.1.2 28-1.3.1.3 30-1.3.1.1.1 (c / consistent-01~e.0 :ARG1 (r2 / reduce-01~e.23 :ARG0~e.24 (m / molecular-physical-entity~e.26 :ARG0-of~e.26 (i / inhibit-01~e.26) :mod (t / this~e.25)) :ARG1 (c2 / content~e.8 :quant-of (p2 / protein :name (n / name :op1 "cyclin-D1"~e.6,7) :ARG1-of (m2 / mean-01 :ARG2 (t3 / thing~e.12 :ARG1-of~e.12 (c3 / correlate-01~e.12 :ARG2~e.13 (p3 / proliferate-01~e.16 :ARG0 (c4 / cell~e.15 :mod (l / lung~e.14))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 41~e.19)))) :mod (b / biochemistry~e.11)))))) :ARG2~e.1 (t2 / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4 :mod (p / proliferate-01~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure~e.28 :mod "9C"~e.30) :op2 (f2 / figure~e.28 :mod "9D") :op3 (f3 / figure~e.28 :mod "9E")))) # ::id a_pmid_2169_9731.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MØCM induced early increases in cRaf , Akt and GSK @-@ 3β phosphorylation , and Erk1 @/@ 2 phosphorylation peaked at 24 hrs ( Figure 9C , D ) . # ::alignments 1-1.1 2-1.1.2.2 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1.1.1 7-1.1.2.1.1.2.1.1 8-1.1.2.1.1 9-1.1.2.1.1.3.1.1 11-1.1.2.1.1.3.1.1 12-1.1.2.1 14-1 14-1.3.1 15-1.2.1.1.1.1.1 16-1.2.1.1 18-1.2.1 19-1.2 21-1.2.2.1.1 22-1.2.2.1.2 24-1.3.1.1 24-1.3.1.2 26-1.3.1.1.1 (a / and~e.14 :op1 (i / induce-01~e.1 :ARG0 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage))) :ARG2 (i2 / increase-01~e.3 :ARG1~e.4 (p / phosphorylate-01~e.12 :ARG1 (a2 / and~e.8 :op1 (e2 / enzyme :name (n2 / name :op1 "cRaf"~e.5)) :op2 (e3 / enzyme :name (n3 / name :op1 "Akt"~e.7)) :op3 (e4 / enzyme :name (n4 / name :op1 "GSK-3β"~e.9,11)))) :time (e / early~e.2))) :op2 (p2 / peak-01~e.19 :ARG1 (p3 / phosphorylate-01~e.18 :ARG1 (s / slash~e.16 :op1 (e5 / enzyme :name (n5 / name :op1 "Erk1"~e.15)) :op2 (e6 / enzyme :name (n6 / name :op1 "Erk2")))) :time (a3 / after :quant (t / temporal-quantity :quant 24~e.21 :unit (h / hour~e.22)))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.14 :op1 (f / figure~e.24 :mod "9C"~e.26) :op2 (f2 / figure~e.24 :mod "9D")))) # ::id a_pmid_2169_9731.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In both LM2 and JF32 cells , increased Akt phosphorylation corresponded to more phosphorylation of the Akt substrate , pGSK @-@ 3β ( Figure 9H and 9I ) . # ::alignments 2-1.3.1.1.1 3-1.3 4-1.3.2.1.1 5-1.3.1 5-1.3.2 7-1.1.2 8-1.1.1.1.1 9-1.1 10-1 11-1.2.r 12-1.2.2 13-1.2 13-1.2.1.2.1.2 14-1.2.1.r 16-1.2.1.1 17-1.2.1 21-1.2.1.2.1.1.1 23-1.4.1.1 23-1.4.1.2 25-1.4.1.1.1 27-1.4.1 29-1.4.1.2.1 (c / correspond-02~e.10 :ARG1 (p / phosphorylate-01~e.9 :ARG1 (e / enzyme :name (n / name :op1 "Akt"~e.8)) :ARG1-of (i / increase-01~e.7)) :ARG2~e.11 (p2 / phosphorylate-01~e.13 :ARG1~e.14 (s / substrate~e.17 :poss e~e.16 :ARG1-of (m2 / mean-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "GSK-3β"~e.21) :ARG3-of (p3 / phosphorylate-01~e.13)))) :degree (m / more~e.12)) :location (a / and~e.3 :op1 (c2 / cell-line~e.5 :name (n3 / name :op1 "LM2"~e.2)) :op2 (c3 / cell-line~e.5 :name (n4 / name :op1 "JF32"~e.4))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.27 :op1 (f / figure~e.23 :mod "9H"~e.25) :op2 (f2 / figure~e.23 :mod "9I"~e.29)))) # ::id a_pmid_2169_9731.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phospho @-@ cRaf levels , another marker of Akt activity , also increased in concert with heightened increased Akt activity from 4 @-@ 24 hrs ; although p @-@ cRaf abruptly dropped at 48 hrs , pAkt and pGSK @-@ 3β levels remained highly elevated ( Figure 9F , H and 9I ) . # ::alignments 0-1.1.1.1.2 2-1.1.1.1.1.1 3-1.1.1 5-1.1.1.1.3.1.2 6-1.1.1.1.3.1 7-1.1.1.1.3.1.1.r 8-1.1.1.1.3.1.1.1.1.1 9-1.1.1.1.3.1.1 11-1.1.2 12-1.1 13-1.1.3 14-1.1.3 15-1.1.3.2.r 16-1.1.3.2.2 17-1.1.3.2.3 18-1.1.3.2.1 19-1.1.3.2 21-1.1.4.1.1 23-1.1.4.2.1 24-1.2.2.3.1.2 26-1.2 27-1.1.1.1.2 29-1.1.1.1.1.1 30-1.2.2.2 30-1.2.2.2.r 31-1.2.2 33-1.2.2.3.1.1 34-1.1.4.1.2 34-1.2.2.3.1.2 36-1.2.1.1.1.1.1.1 37-1.2.1.1 40-1.2.1.1.2.1.1.1 41-1.2.1.1.1 41-1.2.1.1.2 42-1.2.1 43-1.2.1.2.1 44-1.2.1.2 46-1.3.1.1 46-1.3.1.2 46-1.3.1.3 48-1.3.1.1.1 52-1.3.1 54-1.3.1.3.1 (a9 / and :op1 (i / increase-01~e.12 :ARG1 (l / level~e.3 :quant-of (e / enzyme :name (n / name :op1 "cRaf"~e.2,29) :ARG3-of (p / phosphorylate-01~e.0,27) :ARG1-of (m2 / mean-01 :ARG2 (m3 / marker~e.6 :mod~e.7 (a / activity-06~e.9 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Akt"~e.8))) :mod (a2 / another~e.5))))) :mod (a3 / also~e.11) :manner (i2 / in-concert~e.13,14 :op1 i :op2~e.15 (a5 / activity-06~e.19 :ARG0 e2~e.18 :ARG1-of (h / heighten-01~e.16) :ARG1-of (i3 / increase-01~e.17))) :time (b / between :op1 (t / temporal-quantity :quant 4~e.21 :unit (h6 / hour~e.34)) :op2 (t4 / temporal-quantity :quant 24~e.23 :unit h6))) :op2 (h2 / have-concession-91~e.26 :ARG1 (r / remain-01~e.42 :ARG1 (a8 / and~e.37 :op1 (l2 / level~e.41 :quant-of (e3 / enzyme :name (n3 / name :op1 "Akt"~e.36) :ARG3-of p)) :op2 (l3 / level~e.41 :quant-of (e4 / enzyme :name (n4 / name :op1 "GSK-3β"~e.40) :ARG3-of p))) :ARG3 (e5 / elevate-01~e.44 :ARG1-of (h4 / high-02~e.43))) :ARG2 (d / drop-01~e.31 :ARG1 e :manner~e.30 (a6 / abrupt~e.30) :time (a7 / after :quant (t2 / temporal-quantity :quant 48~e.33 :unit (h3 / hour~e.24,34))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.52 :op1 (f / figure~e.46 :mod "9F"~e.48) :op2 (f2 / figure~e.46 :mod "9H") :op3 (f3 / figure~e.46 :mod "9I"~e.54)))) # ::id a_pmid_2169_9731.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We observed reciprocal changes in the Erk and Akt pathways in response to their respective enzyme inhibitors . # ::alignments 0-1.1 1-1 2-1.2.2 3-1.2 6-1.2.1.1.1.1 6-1.2.3.1.1.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1 8-1.2.3.1.1.1.2.1.1 9-1.2.1.1 9-1.2.1.2 10-1.2.3.r 11-1.2.3 14-1.2.3.1.2 15-1.2.3.1.1.1.1 15-1.2.3.1.1.1.2 16-1.2.3.1 16-1.2.3.1.1 16-1.2.3.1.1.r (o / observe-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / change-01~e.3 :ARG1 (a / and~e.7 :op1 (p / pathway~e.9 :name (n2 / name :op1 "Erk"~e.6)) :op2 (p2 / pathway~e.9 :name (n3 / name :op1 "Akt"~e.8))) :mod (r / reciprocal~e.2) :ARG2-of~e.10 (r2 / respond-01~e.11 :ARG1 (t / thing~e.16 :ARG0-of~e.16 (i / inhibit-01~e.16 :ARG1 (a2 / and :op1 (p3 / protein-family~e.15 :name (n4 / name :op1 "Erk"~e.6)) :op2 (p4 / protein-family~e.15 :name (n5 / name :op1 "Akt"~e.8)))) :mod (r3 / respective~e.14))))) # ::id a_pmid_2169_9731.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In LM2 cells , MEK inhibition ( by U0126 ) suppressed early Erk1 @/@ 2 phosphorylation while p @-@ Akt levels increased . # ::alignments 1-1.3.1.1 2-1.3 4-1.1.1.2.1.1 5-1.1.1 7-1.1.1.1.r 8-1.1.1.1.1.1 10-1.1 11-1.1.2.2 12-1.1.2.1.1.1.1 13-1.1.2.1 15-1.1.2 15-1.2.1.1 15-1.2.1.1.2 15-1.2.1.1.2.r 16-1 17-1.1.2 17-1.2.1.1 17-1.2.1.1.2 17-1.2.1.1.2.r 19-1.2.1.1.1.1 20-1.2.1 21-1.2 (c / contrast-01~e.16 :ARG1 (s2 / suppress-01~e.10 :ARG0 (i / inhibit-01~e.5 :ARG0~e.7 (s / small-molecule :name (n2 / name :op1 "U0126"~e.8)) :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.4))) :ARG1 (p2 / phosphorylate-01~e.15,17 :ARG1 (s3 / slash~e.13 :op1 (e3 / enzyme :name (n3 / name :op1 "Erk1"~e.12)) :op2 (e4 / enzyme :name (n4 / name :op1 "Erk2"))) :time (e2 / early~e.11))) :ARG2 (i2 / increase-01~e.21 :ARG1 (l / level~e.20 :quant-of (e5 / enzyme~e.15,17 :name (n5 / name :op1 "Akt"~e.19) :ARG1-of~e.15,17 (p / phosphorylate-01~e.15,17)))) :location (c2 / cell-line~e.2 :name (n6 / name :op1 "LM2"~e.1))) # ::id a_pmid_2169_9731.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , PI3K inhibition ( by LY294002 ) increased basal p @-@ Erk1 @/@ 2 levels at the expense of p @-@ Akt ( 4 hrs time point ; Figure 9C ) . # ::alignments 2-1.1.1.2.1.1 3-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1.1 9-1.1.2.2 10-1.1.2.1.1.2 12-1.1.2.1.1.1.1 13-1.1.2.1 15-1.1.2 16-1.1.3.r 18-1.1.3 19-1.1.3 20-1.1.3.1.2 22-1.1.3.1.1.1 24-1.2.1.1 24-1.2.1.2 26-1.2.1 26-1.2.r 29-1.3.1 31-1.3.1.1 (c / contrast-01 :ARG2 (i / increase-01~e.8 :ARG0 (i2 / inhibit-01~e.3 :ARG0~e.5 (s / small-molecule :name (n2 / name :op1 "LY294002"~e.6)) :ARG1 (e2 / enzyme :name (n / name :op1 "PI3K"~e.2))) :ARG1 (l / level~e.15 :quant-of (s2 / slash~e.13 :op1 (e3 / enzyme :name (n3 / name :op1 "Erk1"~e.12) :ARG3-of (p / phosphorylate-01~e.10)) :op2 (e4 / enzyme :name (n4 / name :op1 "Erk2") :ARG3-of p)) :mod (b / basal~e.9)) :ARG0-of~e.16 (c2 / compromise-02~e.18,19 :ARG1 (e5 / enzyme :name (n5 / name :op1 "Akt"~e.22) :ARG3-of p~e.20))) :time~e.26 (a / after :quant (t2 / temporal-quantity~e.26 :quant 4~e.24 :unit 4~e.24)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "9C"~e.31))) # ::id a_pmid_2169_9731.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK inhibition raised p @-@ Erk1 @/@ 2 and total Erk1 @/@ 2 levels at 24 and 48 hrs , while PI3K inhibition caused a compensatory increase in cellular p @-@ Akt levels from 24 @-@ 48 hrs . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.1.1.1.2 3-1.1.2.1.2.1.2 5-1.1.2.1.1.1.1.1 5-1.1.2.2.1.1.1.1 6-1.1.2.2 9-1.1.2.2.3 10-1.1.2.2.1.1.1.1 11-1.1.2.2 13-1.1.2.1.1 13-1.1.2.1.2 13-1.1.2.2.1 13-1.1.2.2.2 15-1.1.3.1.1.1 16-1.1.2.1 17-1.1.3.2.1.1 18-1.1.3.1.1.2 18-1.1.3.2.1.2 20-1 20-1.1.3.r 21-1.2.1.1.1.1 22-1.2.1 23-1.2 26-1.2.2 27-1.2.2.1.r 28-1.2.2.1.1.2 29-1.1.2.1.1.1.2 29-1.1.2.1.2.1.2 31-1.2.2.1.1.1.1 32-1.2.2.1 34-1.1.3.1.1.1 34-1.2.2.3.1.1 36-1.1.3.2.1.1 37-1.1.3.1.1.2 37-1.1.3.2.1.2 37-1.2.2.3.1.2 (c / contrast-01~e.20 :ARG1 (r / raise-01~e.2 :ARG0 (i / inhibit-01~e.1 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK"~e.0))) :ARG1 (a2 / and :op1 (a / and~e.16 :op1 (l / level~e.13 :quant-of (e3 / enzyme :name (n3 / name :op1 "Erk1"~e.5) :ARG3-of (p / phosphorylate-01~e.3,29))) :op2 (l2 / level~e.13 :quant-of (e4 / enzyme :name (n4 / name :op1 "Erk2") :ARG3-of (p2 / phosphorylate-01~e.3,29)))) :op2 (s / slash~e.6,11 :op1 (l3 / level~e.13 :quant-of (e5 / enzyme :name (n5 / name :op1 "Erk1"~e.5,10))) :op2 (l4 / level~e.13 :quant-of (e6 / enzyme :name (n6 / name :op1 "Erk2"))) :mod (t / total~e.9))) :time~e.20 (a4 / and :op1 (a5 / after :quant (t2 / temporal-quantity :quant 24~e.15,34 :unit (h / hour~e.18,37))) :op2 (a6 / after :quant (t3 / temporal-quantity :quant 48~e.17,36 :unit (h2 / hour~e.18,37))))) :ARG2 (c2 / cause-01~e.23 :ARG0 (i2 / inhibit-01~e.22 :ARG1 (e7 / enzyme :name (n7 / name :op1 "PI3K"~e.21))) :ARG1 (i3 / increase-01~e.26 :ARG1~e.27 (l5 / level~e.32 :quant-of (e8 / enzyme :name (n8 / name :op1 "Akt"~e.31) :mod (c4 / cell~e.28) :ARG3-of p)) :ARG0-of (c3 / compensate-01) :time (b / between :op1 (t5 / temporal-quantity :quant 24~e.34 :unit (h4 / hour~e.37)) :op2 (t6 / temporal-quantity :quant 28 :unit h4))))) # ::id a_pmid_2169_9731.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok JF32 cell growth was also suppressed by each drug ; although MEK inhibition did not affect p @-@ Erk1 @/@ 2 levels at 4 hrs , p @-@ Erk1 @/@ 2 levels decreased at 48 hrs ( Figure 9D ) . # ::alignments 0-1.1.2.1.1.1 1-1.1.2.1 2-1.1.2 4-1.1.3 5-1.1 6-1.1.1.r 7-1.1.1.1 8-1.1.1 10-1.2 11-1.2.2.2.1.1.1 12-1.2.2.2 14-1.2.2.1 14-1.2.2.1.r 15-1.2.2 16-1.2.2.3.1.1.2 18-1.2.2.3.1.1.1.1 19-1.2.2.3 21-1.2.2.3.1 21-1.2.2.3.2 23-1.2.2.4.1.1 24-1.2.2.4.1.2 26-1.2.2.3.1.1.2 28-1.2.2.3.1.1.1.1 29-1.2.2.3 31-1.2.2.3.1 31-1.2.2.3.2 32-1.2.1 34-1.2.1.2.1.1 35-1.2.1.2.1.2 37-1.3.1 39-1.3.1.1 (a5 / and :op1 (s / suppress-01~e.5 :ARG0~e.6 (d / drug~e.8 :mod (e2 / each~e.7)) :ARG1 (g / grow-01~e.2 :ARG1 (c / cell-line~e.1 :name (n2 / name :op1 "JF32"~e.0))) :mod (a / also~e.4)) :op2 (h / have-concession-91~e.10 :ARG1 (d2 / decrease-01~e.32 :ARG1 s2 :time (a4 / after :quant (t2 / temporal-quantity :quant 48~e.34 :unit (h3 / hour~e.35)))) :ARG2 (a2 / affect-01~e.15 :polarity~e.14 -~e.14 :ARG0 (i / inhibit-01~e.12 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK"~e.11))) :ARG1 (s2 / slash~e.19,29 :op1 (l / level~e.21,31 :quant-of (e4 / enzyme :name (n4 / name :op1 "Erk1"~e.18,28) :ARG3-of (p / phosphorylate-01~e.16,26))) :op2 (l2 / level~e.21,31 :quant-of (e5 / enzyme :name (n5 / name :op1 "Erk2") :ARG3-of p))) :time (a3 / after :quant (t / temporal-quantity :quant 4~e.23 :unit (h2 / hour~e.24))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.37 :mod "9D"~e.39))) # ::id a_pmid_2169_9731.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PI3K inhibition stimulated Erk1 @/@ 2 phosphorylation from 4 @-@ 24 hrs , and increased Akt phosphorylation throughout the treatment time @-@ course ( Figure 9G , H ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.1.1.1.1 4-1.1.2.1 6-1.1.2 8-1.1.3.1.1 10-1.1.3.2.1 11-1.1.3.1.2 13-1 13-1.1.3 13-1.3.1 14-1.2 15-1.2.1.1.1.1 16-1.2.1 19-1.2.2 20-1.1.3.1 20-1.1.3.2 20-1.1.3.r 20-1.2.2.r 24-1.3.1.1 24-1.3.1.2 26-1.3.1.1.1 (a / and~e.13 :op1 (s / stimulate-01~e.2 :ARG0 (i2 / inhibit-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "PI3K"~e.0))) :ARG1 (p2 / phosphorylate-01~e.6 :ARG1 (s2 / slash~e.4 :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1"~e.3)) :op2 (e3 / enzyme :name (n3 / name :op1 "Erk2")))) :time~e.20 (b / between~e.13 :op1 (t3 / temporal-quantity~e.20 :quant 4~e.8 :unit (h2 / hour~e.11)) :op2 (t4 / temporal-quantity~e.20 :quant 24~e.10 :unit h2))) :op2 (i / increase-01~e.14 :ARG1 (p3 / phosphorylate-01~e.16 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Akt"~e.15))) :time~e.20 (t2 / treat-04~e.19)) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.13 :op1 (f / figure~e.24 :mod "9G"~e.26) :op2 (f2 / figure~e.24 :mod "9H")))) # ::id a_pmid_2169_9731.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While each inhibitor decreased basal proliferation rates ( Figure 9A , B ) , combinations of kinase inhibitors and MØCM increased cRaf , Erk1 @/@ 2 , Akt and GSK @-@ 3β phosphorylation in an additive manner , with the highest levels observed in cells treated with both kinase inhibitors and MØCM (" U+L +", Figure 9C @-@ I ) . # ::alignments 0-1 1-1.1.1.2 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 3-1.1 4-1.1.2.2 5-1.1.2.1 6-1.1.2 8-1.1.3.1.1 10-1.1.3.1.1.1 16-1.2.1 17-1.2.1.1.r 18-1.2.1.1.1.1 19-1.2.1.1 19-1.2.1.1.1 19-1.2.1.1.1.r 22-1.2 23-1.2.2.1.1.1.1 25-1.2.2.1.2.1.1.1 26-1.2.2.1.2 29-1.2.2.1.3.1.1 30-1.2.2.1 31-1.2.2.1.4.1.1 33-1.2.2.1.4.1.1 34-1.2.2 35-1.2.3.r 37-1.2.3 38-1.2.4.r 42-1.2.4.1.1 42-1.2.4.1.1.1 42-1.2.4.1.1.1.r 43-1.2.4.1 44-1.2.4 45-1.2.4.2.r 46-1.2.4.2 47-1.2.4.2.1 50-1.2.4.2.1.1.1 51-1.2.4.2.1.1.1 52-1.1.3.1 52-1.3.1 57-1.1.3.1.2 57-1.3.1.1 57-1.3.1.2 57-1.3.1.3 57-1.3.1.4 57-1.3.1.5 57-1.3.1.6 57-1.3.1.7 59-1.3.1.1.1 (c / contrast-01~e.0 :ARG1 (d / decrease-01~e.3 :ARG0 (m2 / molecular-physical-entity~e.2 :ARG0-of~e.2 (i2 / inhibit-01~e.2) :mod (e / each~e.1)) :ARG1 (r / rate~e.6 :mod (p2 / proliferate-01~e.5) :mod (b / basal~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.52 :op1 (f / figure~e.8 :mod "9A"~e.10) :op2 (f2 / figure~e.57 :mod "9B")))) :ARG2 (i3 / increase-01~e.22 :ARG0 (c2 / combine-01~e.16 :ARG1~e.17 (m3 / molecular-physical-entity~e.19 :ARG0-of~e.19 (i4 / inhibit-01~e.19 :ARG1 (k / kinase~e.18))) :ARG2 (m / medium :ARG1-of (c3 / condition-01 :ARG0 (m4 / macrophage)))) :ARG1 (p3 / phosphorylate-01~e.34 :ARG1 (a2 / and~e.30 :op1 (e3 / enzyme :name (n3 / name :op1 "cRaf"~e.23)) :op2 (s / slash~e.26 :op1 (e4 / enzyme :name (n4 / name :op1 "Erk1"~e.25)) :op2 (e5 / enzyme :name (n5 / name :op1 "Erk2"))) :op3 (e6 / enzyme :name (n6 / name :op1 "Akt"~e.29)) :op4 (e7 / enzyme :name (n7 / name :op1 "GSK-3β"~e.31,33)))) :manner~e.35 (a3 / add-02~e.37) :manner~e.38 (o / observe-01~e.44 :ARG1 (l / level~e.43 :ARG1-of (h / high-02~e.42 :degree~e.42 (m5 / most~e.42))) :location~e.45 (c4 / cell~e.46 :ARG1-of (t / treat-04~e.47 :ARG2 (a4 / and :op1 m3~e.50,51 :op2 m))))) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and~e.52 :op1 (f3 / figure~e.57 :mod "9C"~e.59) :op2 (f4 / figure~e.57 :mod "9D") :op3 (f5 / figure~e.57 :mod "9E") :op4 (f6 / figure~e.57 :mod "9F") :op5 (f7 / figure~e.57 :mod "9G") :op6 (f8 / figure~e.57 :mod "9H") :op7 (f9 / figure~e.57 :mod "9I")))) # ::id a_pmid_2169_9731.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total and p @-@ cRaf , p @-@ Akt and p @-@ GSK @-@ 3β were each significantly higher after 4 @-@ 24 hrs of treatment in all groups receiving any combination of drug and MØCM , and p @-@ Erk1 @/@ 2 levels spiked after 24 hrs of treatment ( Figure 9F @-@ I ) . # ::alignments 0-1.1.1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 1-1.1.1.2 1-1.1.1.2.r 2-1.1.1.2.1.2 4-1.1.1.1.1.1.1 4-1.1.1.2.1.1.1 6-1.1.1.2.1.2 8-1.1.1.1.2.1.1 8-1.1.1.2.2.1.1 9-1.1.1.2 10-1.1.1.2.1.2 12-1.1.1.1.3.1.1 12-1.1.1.2.3.1.1 14-1.1.1.1.3.1.1 14-1.1.1.2.3.1.1 17-1.1.3 18-1.1 18-1.1.2 18-1.1.2.r 19-1.1.4 20-1.1.4.2.1.1 22-1.1.4.2.1.2 23-1.1.4.2.2 24-1.1.4.1.r 25-1.1.4.1 26-1.1.5.r 27-1.1.5.1 28-1.1.5 29-1.1.5.2 30-1.1.5.2.1.3 31-1.1.5.2.1 32-1.1.5.2.1.1.r 33-1.1.5.2.1.1 34-1.1.1 34-1.1.1.1 34-1.1.1.1.r 34-1.1.1.2 34-1.1.1.2.r 37-1.1.1 37-1.1.1.1 37-1.1.1.1.r 37-1.1.1.2 37-1.1.1.2.r 38-1.1.1.2.1.2 40-1.2.1.1.1.1.1 41-1.2.1.1 43-1.2.1 44-1.2 45-1.2.2 46-1.2.2.2.1 47-1.2.2.2.2 48-1.2.2.1.r 49-1.2.2.1 51-1.3.1.1 51-1.3.1.2 51-1.3.1.3 51-1.3.1.4 53-1.3.1.1.1 (a6 / and :op1 (h / high-02~e.18 :ARG1 (a / and~e.1,34,37 :op1~e.1,34,37 (a2 / and~e.1,34,37 :op1 (e / enzyme :name (n / name :op1 "cRaf"~e.4) :mod (t / total~e.0)) :op2 (e2 / enzyme :name (n2 / name :op1 "Akt"~e.8) :mod t) :op3 (e3 / enzyme :name (n3 / name :op1 "GSK-3β"~e.12,14) :mod t)) :op2~e.1,34,37 (a3 / and~e.1,9,34,37 :op1 (e4 / enzyme :name (n4 / name :op1 "cRaf"~e.4) :ARG3-of (p / phosphorylate-01~e.2,6,10,38)) :op2 (e5 / enzyme :name (n5 / name :op1 "Akt"~e.8) :ARG3-of p) :op3 (e6 / enzyme :name (n6 / name :op1 "GSK-3β"~e.12,14) :ARG3-of p))) :degree~e.18 (m2 / more~e.18) :ARG1-of (s / significant-02~e.17) :time (a4 / after~e.19 :op1~e.24 (t3 / treat-04~e.25) :quant (t2 / temporal-quantity :quant (v / value-interval :op1 4~e.20 :op2 24~e.22) :unit (h3 / hour~e.23))) :location~e.26 (g / group~e.28 :mod (a5 / all~e.27) :ARG0-of (r / receive-01~e.29 :ARG1 (c / combine-01~e.31 :ARG1~e.32 (d / drug~e.33) :ARG2 (m / medium :ARG1-of (c2 / condition-01 :ARG0 (m3 / macrophage))) :mod (a8 / any~e.30))))) :op2 (s2 / spike-04~e.44 :ARG1 (l / level~e.43 :quant-of (s3 / slash~e.41 :op1 (e7 / enzyme :name (n8 / name :op1 "Erk1"~e.40)) :op2 (e8 / enzyme :name (n9 / name :op1 "Erk2")))) :time (a7 / after~e.45 :op1~e.48 (t4 / treat-04~e.49) :quant (t5 / temporal-quantity :quant 24~e.46 :unit (h4 / hour~e.47)))) :ARG1-of (d2 / describe-01 :ARG0 (a9 / and :op1 (f / figure~e.51 :mod "9F"~e.53) :op2 (f2 / figure~e.51 :mod "9G") :op3 (f3 / figure~e.51 :mod "9H") :op4 (f4 / figure~e.51 :mod "9I")))) # ::id a_pmid_2169_9731.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Either inhibitor alone partially prevented the increase in cyclin D1 in cells treated with MØCM ; cells receiving both inhibitors had the lowest cyclin D1 levels and were unresponsive to MØCM @-@ induced growth ( Figure 9E ) . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1.1.3 3-1.1.3 3-1.1.3.r 4-1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1 9-1.1.2.1.1.1 10-1.1.2.2.r 11-1.1.2.2 12-1.1.2.2.1 16-1.2.1.1 17-1.2.1.1.1 18-1.2.1.1.1.1.2 19-1.2.1.1.1.1.1 20-1.2.1 22-1.2.1.2.2 22-1.2.1.2.2.1 22-1.2.1.2.2.1.r 23-1.2.1.2.1 24-1.2.1.2.1 25-1.2.1.2 26-1.2 28-1.2.2 28-1.2.2.1 28-1.2.2.1.r 32-1.2.2.3.1 33-1.2.2.3 35-1.3.1 37-1.3.1.1 (a / and :op1 (p / prevent-01~e.4 :ARG0 (m / molecular-physical-entity~e.1 :ARG0-of~e.1 (i2 / inhibit-01~e.1) :mod (e / either~e.0) :mod (a3 / alone~e.2)) :ARG1 (i3 / increase-01~e.6 :ARG1~e.7 (p3 / protein :name (n / name :op1 "cyclin-D1"~e.8,9)) :location~e.10 (c / cell~e.11 :ARG1-of (t / treat-04~e.12 :ARG2 (m4 / medium :ARG1-of (c2 / condition-01 :ARG0 (m5 / macrophage)))))) :degree~e.3 (p2 / part~e.3)) :op2 (a2 / and~e.26 :op1 (h / have-03~e.20 :ARG0 (c3 / cell~e.16 :ARG0-of (r / receive-01~e.17 :ARG1 (m3 / molecular-physical-entity :ARG0-of i2~e.19 :mod (b / both~e.18)))) :ARG1 (l / level~e.25 :quant-of p3~e.23,24 :ARG1-of (l2 / low-04~e.22 :degree~e.22 (m2 / most~e.22)))) :op2 (r2 / respond-01~e.28 :polarity~e.28 -~e.28 :ARG0 c3 :ARG1 (g / grow-01~e.33 :ARG2-of (i4 / induce-01~e.32 :ARG0 m4)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "9E"~e.37))) # ::id a_pmid_2169_9731.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , MØCM @-@ induced neoplastic Akt and Erk1 @/@ 2 phosphorylation was magnified several @-@ fold by inhibitor treatment , dissociating kinase activity from proliferation in drug @-@ treated cells ; however , cyclin D1 levels were suppressed by either drug alone , which corresponded to decreased cell proliferation . # ::alignments 0-1.2.1.3 1-1.2.1.3.1 5-1.2.3 6-1.2.2 7-1.2.1.1.1.1 8-1.2.1 9-1.2.1.2.1.1.1 10-1.2.1.2 12-1.2 14-1 15-1.4.1 17-1.4 18-1.1.r 19-1.1.1 19-1.1.1.1 19-1.1.1.1.r 20-1.1 22-1.2.4 23-1.2.4.1.1 24-1.2.4.1 26-1.2.4.2 28-1.2.4.2.2.1.1 30-1.2.4.2.2.1 31-1.2.4.2.2 33-1.3 35-1.3.1.2.1.1.1 36-1.3.1.2.1.1.1 37-1.3.1.2 39-1.3.1 40-1.3.1.1.r 41-1.3.1.1.1 42-1.3.1.1 43-1.3.1.1.2 46-1.3.1.3 48-1.3.1.3.1.2 49-1.2.4.2.2 49-1.3.1.3.1.1 50-1.2.4.2 50-1.3.1.3.1 (m2 / magnify-01~e.14 :ARG0~e.18 (t / treat-04~e.20 :ARG2 (m / molecular-physical-entity~e.19 :ARG0-of~e.19 (i4 / inhibit-01~e.19))) :ARG1 (p2 / phosphorylate-01~e.12 :ARG1 (a / and~e.8 :op1 (e / enzyme :name (n / name :op1 "Akt"~e.7)) :op2 (s / slash~e.10 :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1"~e.9)) :op2 (e3 / enzyme :name (n3 / name :op1 "Erk2"))) :ARG1-of (t2 / take-01~e.0 :mod (t3 / together~e.1))) :mod (n4 / neoplasm~e.6) :ARG2-of (i2 / induce-01~e.5 :ARG0 (m3 / medium :ARG1-of (c / condition-01 :ARG0 (m4 / macrophage)))) :ARG0-of (d / dissociate-01~e.22 :ARG1 (a2 / activity-06~e.24 :ARG0 (k / kinase~e.23)) :ARG2 (p5 / proliferate-01~e.26,50 :ARG0 (p4 / protein) :location (c2 / cell~e.31,49 :ARG1-of (t5 / treat-03~e.30 :ARG3 (d2 / drug~e.28)))))) :ARG1-of (c5 / contrast-01~e.33 :ARG2 (s3 / suppress-01~e.39 :ARG0~e.40 (d4 / drug~e.42 :mod (e4 / either~e.41) :mod (a3 / alone~e.43)) :ARG1 (l / level~e.37 :quant-of (p6 / protein :name (n7 / name :op1 "cyclin-D1"~e.35,36))) :ARG1-of (c3 / correspond-02~e.46 :ARG2 (p7 / proliferate-01~e.50 :ARG0 (c4 / cell~e.49) :ARG1-of (d3 / decrease-01~e.48))))) :quant (p3 / product-of~e.17 :op1 (s2 / several~e.15))) # ::id a_pmid_2169_9731.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As with MØCM , IGF @-@ 1 stimulated both Akt and Erk1 @/@ 2 activities . # ::alignments 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1 9-1.1.2.1.1.1.1 10-1.1.2.1 11-1.1.2.1.2.1.1.1 12-1.1.2.1.2 14-1.1.2 (r / resemble-01 :ARG1 (s / stimulate-01~e.7 :ARG0 (p / protein :name (n2 / name :op1 "IGF-1"~e.4,6)) :ARG1 (a / act-02~e.14 :ARG0 (a2 / and~e.10 :op1 (e / enzyme :name (n3 / name :op1 "Akt"~e.9)) :op2 (s2 / slash~e.12 :op1 (e2 / enzyme :name (n4 / name :op1 "Erk1"~e.11)) :op2 (e3 / enzyme :name (n5 / name :op1 "Erk2")))))) :ARG2 (m / medium :ARG1-of (c / condition-01 :ARG0 (m2 / macrophage)))) # ::id a_pmid_2169_9731.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Kinase activation was greatest within 4 hrs of treatment , and remained elevated 48 hrs later , corresponding with increased cyclin D1 expression ( Figure 10A @-@ E ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.r 3-1.1 3-1.1.2 3-1.1.2.r 4-1.1.3 4-1.1.3.2 4-1.1.3.2.1.1.r 4-1.1.3.2.r 4-1.2.3 5-1.1.3.2.1.1 6-1.1.3.2.1.2 7-1.1.3.1.r 8-1.1.3.1 10-1 10-1.3.1 11-1.2 12-1.2.2 13-1.2.3.1.1 14-1.2.3.1.2 17-1.2.4 18-1.2.4.1.r 19-1.2.4.1.2 20-1.2.4.1.1.1.1 21-1.2.4.1.1.1.1 22-1.2.4.1 24-1.3.1.1 24-1.3.1.2 24-1.3.1.3 24-1.3.1.4 24-1.3.1.5 26-1.3.1.1.1 (a / and~e.10 :op1 (g2 / great~e.3 :domain~e.2 (a2 / activate-01~e.1 :ARG1 (k / kinase~e.0)) :degree~e.3 (m / most~e.3) :time (a3 / after~e.4 :op1~e.7 (t / treat-03~e.8) :quant~e.4 (u / up-to~e.4 :op1 (t2 / temporal-quantity :quant~e.4 4~e.5 :unit (h / hour~e.6))))) :op2 (r / remain-01~e.11 :ARG1 a2 :ARG3 (e2 / elevate-01~e.12 :ARG1 a2) :time (a4 / after~e.4 :quant (t3 / temporal-quantity :quant 48~e.13 :unit (h2 / hour~e.14))) :ARG1-of (c / correspond-02~e.17 :ARG2~e.18 (e3 / express-03~e.22 :ARG2 (p / protein :name (n2 / name :op1 "cyclin-D1"~e.20,21)) :ARG1-of (i / increase-01~e.19)))) :ARG1-of (d / describe-01 :ARG0 (a5 / and~e.10 :op1 (f / figure~e.24 :mod "10A"~e.26) :op2 (f2 / figure~e.24 :mod "10B") :op3 (f3 / figure~e.24 :mod "10C") :op4 (f4 / figure~e.24 :mod "10D") :op5 (f5 / figure~e.24 :mod "10E")))) # ::id a_pmid_2169_9731.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When treated with 2 ng @/@ mL EGF , a concentration 1,000 @-@ times higher than the amount of EGF in cell @-@ conditioned media and 40 @-@ times higher than what is detected in BAL fluid , Erk1 @/@ 2 activity was not significantly elevated and Akt levels were unaffected ( Figure 10C , D ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.2.1 4-1.3.1.2.2 5-1.1.2.1 6-1.3.1.2.2 7-1.3.1.1.1 10-1.3.1.2 10-1.3.1.3.1 11-1.3.1.3.1.2.1.1.1 13-1.3.1.3.1.2.1.1 14-1.3.1.3.1.2 14-1.3.1.3.1.2.1 14-1.3.1.3.1.2.1.r 15-1.3.1.3.1.2.2.r 17-1.3.1.3.1.2.2.1 18-1.3.1.3.1.2.1.1 19-1.3.1.1.1 20-1.3.1.3.1.2.2.1.2.r 21-1.3.1.3.1.2.2.1.2.1.1 23-1.3.1.3.1.2.2.1.2.1 24-1.3.1.3.1.2.2.1.2 25-1.3.1.3.1.2.2 26-1.3.1.3.1.3.1.1.1 28-1.3.1.3.1.3.1.1 29-1.3.1.3.1.3 29-1.3.1.3.1.3.1 29-1.3.1.3.1.3.1.r 30-1.3.1.3.1.3.2.r 31-1.3.1.3.1.3.2 33-1.3.1.3.1.3.2.1 34-1.3.1.3.1.3.2.1.1.r 35-1.3.1.3.1.3.2.1.1.1 35-1.3.1.3.1.3.2.1.1.1.1 35-1.3.1.3.1.3.2.1.1.1.1.1 35-1.3.1.3.1.3.2.1.1.1.1.1.r 35-1.3.1.3.1.3.2.1.1.1.1.r 36-1.3.1.3.1.3.2.1.1 38-1.1.2.1.1.1.1 39-1.1.2.1 40-1.3.1.2.1 41-1.1.2 43-1.1.1 43-1.1.1.r 44-1.1.3 45-1.1 46-1 46-1.4.1 47-1.2.2.1.1.1 48-1.2.2 50-1.2 50-1.2.1 50-1.2.1.r 52-1.4.1.1 52-1.4.1.2 54-1.4.1.1.1 (a2 / and~e.46 :op1 (e / elevate-01~e.45 :polarity~e.43 -~e.43 :ARG1 (a / activity-06~e.41 :ARG0 (s / slash~e.5,39 :op1 (e2 / enzyme :name (n / name :op1 "Erk1"~e.38)) :op2 (e3 / enzyme :name (n2 / name :op1 "Erk2")))) :ARG1-of (s2 / significant-02~e.44)) :op2 (a3 / affect-01~e.50 :polarity~e.50 -~e.50 :ARG1 (l / level~e.48 :quant-of (e4 / enzyme :name (n3 / name :op1 "Akt"~e.47)))) :condition (t / treat-04~e.1 :ARG2~e.2 (p / protein :name (n4 / name :op1 "EGF"~e.7,19) :quant (c / concentration-quantity~e.10 :quant 2~e.3,40 :unit (n6 / nanogram-per-milliliter~e.4,6)) :ARG1-of (e5 / equal-01 :ARG2 (c2 / concentrate-02~e.10 :ARG1 p :ARG1-of (h / high-02~e.14 :degree~e.14 (m2 / more~e.14 :quant (p2 / product-of~e.13,18 :op1 1000~e.11)) :compared-to~e.15 (a4 / and~e.25 :op1 (a5 / amount~e.17 :quant-of p :location~e.20 (m3 / media~e.24 :ARG1-of (c3 / condition-01~e.23 :ARG2 (c4 / cell~e.21)))))) :ARG1-of (h2 / high-02~e.29 :degree~e.29 (m4 / more~e.29 :quant (p3 / product-of~e.28 :op1 40~e.26)) :compared-to~e.30 (t2 / thing~e.31 :ARG1-of (d2 / detect-01~e.33 :location~e.34 (f / fluid~e.36 :mod (l2 / lavage~e.35 :mod~e.35 (a7 / alveolus~e.35 :mod~e.35 (b / bronchus~e.35))))))))))) :ARG1-of (d / describe-01 :ARG0 (a6 / and~e.46 :op1 (f2 / figure~e.52 :mod "10C"~e.54) :op2 (f3 / figure~e.52 :mod "10D")))) # ::id a_pmid_2169_9731.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF may partially stimulate Erk1 @/@ 2 activity at supra @-@ physiological levels , but this was not sufficient to stimulate cellular growth . # ::alignments 0-1.1.1.1.1.1 1-1.1 2-1.1.1.3 2-1.1.1.3.r 2-1.1.1.4.1.1.r 3-1.1.1 4-1.1.1.2.1.1.1.1 5-1.1.1.2.1 7-1.1.1.2 8-1.1.1.4.r 9-1.1.1.4.1.1 11-1.1.1.4.1 12-1.1.1.4 14-1 15-1.2.2 17-1.2.1 17-1.2.1.r 18-1.2 20-1.2.3 21-1.2.3.2.1 22-1.2.3.2 (c / contrast-01~e.14 :ARG1 (p / possible-01~e.1 :ARG1 (s / stimulate-01~e.3 :ARG0 (p2 / protein :name (n / name :op1 "EGF"~e.0)) :ARG1 (a / activity-06~e.7 :ARG0 (s2 / slash~e.5 :op1 (e / enzyme :name (n2 / name :op1 "Erk1"~e.4)) :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2")))) :degree~e.2 (p3 / part~e.2) :location~e.8 (l / level~e.12 :mod (p4 / physiological~e.11 :degree~e.2 (s3 / supra~e.9))))) :ARG2 (s4 / suffice-01~e.18 :polarity~e.17 -~e.17 :ARG0 (t / this~e.15) :ARG1 (s5 / stimulate-01~e.20 :ARG0 t :ARG1 (g / grow-01~e.22 :ARG1 (c2 / cell~e.21))))) # ::id a_pmid_2169_9731.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When administered at cell @-@ and tissue @-@ relevant levels , IGF @-@ 1 stimulated both Erk1 @/@ 2 and Akt activation , elevated cellular cyclin D1 content , and induced neoplastic proliferation . # ::alignments 1-1.4 3-1.2.2.1.2 5-1.4.2 6-1.4.2.2.1 8-1.4.2.1.2 9-1.4.2.1 9-1.4.2.2 11-1.1.1.1.1 13-1.1.1.1.1 14-1.1 16-1.1.2.1.1.1.1.1 17-1.1.2.1.1 19-1.1.2 20-1.1.2.2.1.1.1 21-1.1.2.1 21-1.1.2.2 23-1.2 24-1.2.2.1.2 25-1.2.2.1.1.1 26-1.2.2.1.1.1 27-1.2.2 29-1 30-1.3 31-1.3.2.1 32-1.3.2 (a4 / and~e.29 :op1 (s / stimulate-01~e.14 :ARG0 (p / protein :name (n / name :op1 "IGF-1"~e.11,13)) :ARG1 (a / and~e.19 :op1 (a2 / activate-01~e.21 :ARG1 (s2 / slash~e.17 :op1 (e / enzyme :name (n2 / name :op1 "Erk1"~e.16)) :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2")))) :op2 (a3 / activate-01~e.21 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Akt"~e.20))))) :op2 (e4 / elevate-01~e.23 :ARG0 p :ARG1 (c / content~e.27 :quant-of (p2 / protein :name (n5 / name :op1 "cyclin-D1"~e.25,26) :source (c2 / cell~e.3,24)))) :op3 (i / induce-01~e.30 :ARG0 p :ARG2 (p3 / proliferate-01~e.32 :ARG0 (n6 / neoplasm~e.31))) :condition (a5 / administer-01~e.1 :ARG1 p :location (a6 / and~e.5 :op1 (l / level~e.9 :mod c2 :ARG1-of (r / relevant-01~e.8)) :op2 (l2 / level~e.9 :mod (t / tissue~e.6) :ARG1-of r)))) # ::id a_pmid_2194_3101.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Evidence presented here indicate that BRAF @^V600E@ significantly induces cell migration and invasion properties in vitro @ in colon cancer cells , at least in part through activation of RhoA GTPase . # ::alignments 0-1.1 1-1.1.1 2-1.1.1.1 3-1 4-1.2.r 5-1.2.1.1.1 7-1.2.1.2.1 9-1.2.3 10-1.2 11-1.2.2.4 12-1.2.2.1.1 13-1.2.2 14-1.2.2.2.1 15-1.2.2.1 15-1.2.2.2 17-1.2.2.3 18-1.2.2.3 20-1.2.2.3 20-1.2.2.4.1.r 21-1.2.2.4.1.3 22-1.2.2.4.1.2.1 23-1.2.2.1.1.1 25-1.2.4.3 26-1.2.4.3 27-1.2.4.3.1 27-1.2.4.3.r 28-1.2.4.3.r 30-1.2.4 31-1.2.4.2.r 32-1.2.4.2.1.1 33-1.2.4.2.1.2 (i / indicate-01~e.3 :ARG0 (e / evidence~e.0 :ARG1-of (p / present-01~e.1 :medium (h / here~e.2))) :ARG1~e.4 (i2 / induce-01~e.10 :ARG0 (e3 / enzyme :name (n / name :op1 "BRAF"~e.5) :ARG1-of (m / mutate-01 :value "V600E"~e.7)) :ARG2 (a / and~e.13 :op1 (p2 / property~e.15 :mod (m2 / migrate-01~e.12 :ARG0 (c / cell~e.23))) :op2 (p3 / property~e.15 :mod (i3 / invade-01~e.14 :ARG0 c)) :manner (i4 / in-vitro~e.17,18,20) :location (c2 / cell~e.11 :mod~e.20 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.22) :mod (c3 / colon~e.21)))) :ARG1-of (s / significant-02~e.9) :manner (a2 / activate-01~e.30 :ARG0 e3 :ARG1~e.31 (p5 / pathway :name (n3 / name :op1 "RhoA"~e.32 :op2 "GTPase"~e.33)) :degree~e.27,28 (a3 / at-least~e.25,26 :op1 (p4 / part~e.27))))) # ::id a_pmid_2194_3101.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The relationship established between BRAF @^V600E@ and RhoA activation is mediated by the MEK @-@ ERK pathway . # ::alignments 1-1.2 2-1.2.3 4-1.2.1.1.1.1 6-1.2.1.1.2.1 9-1.2.2.1.1.1 10-1.2.1 10-1.2.2 12-1 13-1.1.r 15-1.1.1.1 17-1.1.1.1 18-1.1 (m / mediate-01~e.12 :ARG0~e.13 (p / pathway~e.18 :name (n / name :op1 "MEK-ERK"~e.15,17)) :ARG1 (r / relation-03~e.1 :ARG0 (a / activate-01~e.10 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.4) :ARG1-of (m2 / mutate-01 :value "V600E"~e.6))) :ARG2 (a2 / activate-01~e.10 :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA"~e.9))) :ARG1-of (e / establish-01~e.2))) # ::id a_pmid_2194_3101.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In parallel , KRAS @^G12V@ enhances the ability of colon adenocarcinoma cells Caco @-@ 2 to migrate and invade through filopodia formation and PI3K @-@ dependent Cdc42 activation . # ::alignments 1-1.3 3-1.1.1.1 5-1.1.2.1 7-1 9-1.2 10-1.2.1.r 11-1.2.1.2.1 12-1.2.1.2 13-1.2.1 14-1.2.1.1.1 16-1.2.1.1.1 17-1.2.2.r 18-1.2.2.1 19-1.2.2 20-1.2.2.2 22-1.2.2.3.1.2 23-1.2.2.3.1 24-1.2.2.3 25-1.2.2.3.2.3.1.1.1 27-1.2.2.3.2.3 28-1.2.2.3.2.2.1.1 29-1.2.2.3.2 (e / enhance-01~e.7 :ARG0 (e2 / enzyme :name (n / name :op1 "KRAS"~e.3) :ARG1-of (m / mutate-01 :value "G12V"~e.5)) :ARG1 (c / capable-01~e.9 :ARG1~e.10 (c2 / cell-line~e.13 :name (n2 / name :op1 "Caco-2"~e.14,16) :source (a / adenocarcinoma~e.12 :part-of (c3 / colon~e.11))) :ARG2~e.17 (a2 / and~e.19 :op1 (m2 / migrate-01~e.18 :ARG0 c2) :op2 (i / invade-01~e.20 :ARG0 c2) :manner (a3 / and~e.24 :op1 (f / form-01~e.23 :ARG0 c2 :ARG1 (f2 / filopodia~e.22)) :op2 (a4 / activate-01~e.29 :ARG0 c2 :ARG1 (p2 / protein :name (n3 / name :op1 "Cdc42"~e.28)) :ARG0-of (d / depend-01~e.27 :ARG1 (e3 / enzyme :name (n4 / name :op1 "PI3K"~e.25))))))) :mod (p / parallel~e.1)) # ::id a_pmid_2194_3101.16 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ultimately increased cell migration and invasion , mediated by Rac1 , along with the mesenchymal morphology obtained through the Epithelial @-@ Mesenchymal Transition ( EMT ) were the main characteristics rendered by HRAS @^G12V@ in Caco @-@ 2 cells . # ::alignments 0-1.1.5.1 0-1.1.5.1.r 1-1.1.5 2-1.1.1.1 3-1.1.1 4-1.1 5-1.1.2 7-1.1.4 8-1.1.4.1.r 9-1.1.4.1.1.1 14-1.1.3.1 15-1.1.3 16-1.1.3.2 19-1.1.3.2.1.2 21-1.1.3.2.1.1 22-1.1.3.2.1 24-1.1.3.2.1 28-1.2 29-1 30-1.3 31-1.3.1.r 32-1.3.1.1.1 34-1.3.1.2.1 36-1.3.2.r 37-1.3.2.1.1 39-1.3.2.1.1 40-1.3.2 (c / characteristic-02~e.29 :ARG2 (a / and~e.4 :op1 (m4 / migrate-01~e.3 :ARG0 (c3 / cell~e.2)) :op2 (i2 / invade-01~e.5 :ARG0 c3) :op3 (m5 / morphology~e.15 :mod (m6 / mesenchyme~e.14) :ARG1-of (o / obtain-01~e.16 :ARG2 (t / transition-01~e.22,24 :ARG2 (m7 / mesenchyme~e.21) :ARG3 (e / epithelium~e.19)))) :ARG1-of (m3 / mediate-01~e.7 :ARG0~e.8 (p / protein :name (n3 / name :op1 "Rac1"~e.9))) :ARG1-of (i / increase-01~e.1 :manner~e.0 (u / ultimate~e.0))) :mod (m2 / main~e.28) :ARG1-of (r / render-01~e.30 :ARG0~e.31 (g / gene :name (n / name :op1 "HRAS"~e.32) :ARG1-of (m / mutate-01 :value "G12V"~e.34)) :location~e.36 (c2 / cell-line~e.40 :name (n2 / name :op1 "Caco-2"~e.37,39)))) # ::id a_pmid_2194_3101.17 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , BRAF and KRAS oncogenes are shown to cooperate with the TGFβ-1 pathway to provide cells with additional transforming properties . # ::alignments 0-1.1.1.1 2-1.1.1.1.1.1.1 3-1.1.1.1 4-1.1.1.1.2.1.1 7-1.1 8-1.1.1.1.3 9-1.1.1 10-1.1.1.2.r 12-1.1.1.2.1.1 13-1.1.1.2 14-1.1.1.1.3 15-1.1.1.3 16-1.1.1.3.3 17-1.1.1.3.2.r 18-1.1.1.3.2.2 19-1.1.1.3.2.1 20-1.1.1.3.2 (a / and :op2 (s / show-01~e.7 :ARG1 (c / cooperate-01~e.9 :ARG0 (a2 / and~e.0,3 :op1 (g / gene :name (n / name :op1 "BRAF"~e.2)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS"~e.4)) :ARG0-of (c3 / cause-01~e.8,14 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :ARG1~e.10 (p2 / pathway~e.13 :name (n3 / name :op1 "TGFβ-1"~e.12)) :ARG2 (p / provide-01~e.15 :ARG0 (a4 / and :op1 a2 :op2 p2) :ARG1~e.17 (p3 / property~e.20 :mod (t / transform-01~e.19) :mod (a3 / additional~e.18)) :ARG2 (c2 / cell~e.16))))) # ::id a_pmid_2194_3101.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @^V600E@ induces distinct morphological changes in colon adenocarcinoma cells as compared to KRAS @^G12V@ and loss of their epithelial architecture in 3D culture # ::alignments 0-1.1.1.1 2-1.1.2.1 4-1 5-1.2.1.4 6-1.2.1.3 7-1.2.1 8-1.2.1.2.r 9-1.2.1.2.1.1 10-1.2.1.2.1 11-1.2.1.2 13-1.2.1.5.r 15-1.2.1.5.1.1 17-1.2.1.5.2.1 19-1.2 20-1.2.2 21-1.2.2.1.r 22-1.2.2.1 23-1.2.2.2.1 24-1.2.2.2 25-1.2.2.2.2.r 26-1.2.2.2.2.1 26-1.2.2.2.2.1.1 26-1.2.2.2.2.1.1.r 27-1.2.2.2.2 (i / induce-01~e.4 :ARG0 (e2 / enzyme :name (n / name :op1 "BRAF"~e.0) :ARG1-of (m / mutate-01 :value "V600E"~e.2)) :ARG2 (a4 / and~e.19 :op1 (c / change-01~e.7 :ARG0 e2 :ARG1~e.8 (c2 / cell~e.11 :source (a / adenocarcinoma~e.10 :mod (c3 / colon~e.9))) :mod (m2 / morphology~e.6) :mod (d / distinct~e.5) :compared-to~e.13 (e3 / enzyme :name (n2 / name :op1 "KRAS"~e.15) :ARG1-of (m3 / mutate-01 :value "G12V"~e.17))) :op2 (l / lose-02~e.20 :ARG0~e.21 c2~e.22 :ARG1 (a3 / architecture~e.24 :mod (e / epithelium~e.23) :location~e.25 (c4 / culture~e.27 :mod (d2 / dimension~e.26 :quant~e.26 3~e.26)))))) # ::id a_pmid_2194_3101.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previously established Caco @-@ BR cells have adopted a substantially different morphology when compared to the parental Caco @-@ 2 cells [ @ 21 @ ] . # ::alignments 0-1.1.2.1 1-1.1.2 2-1.1.1.1 4-1.1.1.1 5-1.1 7-1 9-1.2.1.1 10-1.2.1 11-1.2 12-1.4.r 13-1.4 14-1.4.2.r 16-1.4.2.2 17-1.4.2.1.1 19-1.4.2.1.1 20-1.4.2 23-1.3.1.1.1 (a / adopt-01~e.7 :ARG0 (c2 / cell-line~e.5 :name (n / name :op1 "Caco-BR"~e.2,4) :ARG1-of (e / establish-01~e.1 :time (p2 / previous~e.0))) :ARG1 (m / morphology~e.11 :ARG1-of (d2 / differ-02~e.10 :degree (s / substantial~e.9))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 21~e.23))) :time~e.12 (c3 / compare-01~e.13 :ARG1 c2 :ARG2~e.14 (c4 / cell-line~e.20 :name (n2 / name :op1 "Caco-2"~e.17,19) :mod (p3 / parent~e.16)))) # ::id a_pmid_2194_3101.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The elongated morphology acquired by Caco @-@ BR cells was characterized by long membrane protrusions ( Figure 1A , Additional Figure 1 ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1.1 10-1 11-1.2.r 12-1.2.2 13-1.2.1 14-1.2 16-1.3.1.1 18-1.3.1.1.1 21-1.3.1.2.2 22-1.3.1.2 24-1.3.1.2.1 (c / characterize-01~e.10 :ARG1 (m / morphology~e.2 :ARG1-of (a3 / acquire-01~e.3 :ARG0~e.4 (c2 / cell-line~e.8 :name (n / name :op1 "Caco-BR"~e.5,7))) :ARG1-of (e / elongate-01~e.1)) :ARG2~e.11 (p / protrude-01~e.14 :ARG1 (m2 / membrane~e.13) :ARG1-of (l / long-03~e.12)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.16 :mod "1A"~e.18) :op2 (f2 / figure~e.22 :mod 1~e.24 :mod (a2 / additional~e.21))))) # ::id a_pmid_2194_3101.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We present evidence that the morphology of Caco @-@ BR13 cells show properties of both Caco @-@ 2 epithelial nature and of the mesenchymal phenotype of Caco @-@ H2 cells . # ::alignments 0-1.1 1-1 2-1.2 3-1.2.1.r 5-1.2.1.1 7-1.2.1.1.1.1.1 9-1.2.1.1.1.1.1 10-1.2.1.1.1 10-1.2.1.2.1.1.2 11-1.2.1 12-1.2.1.2.1 12-1.2.1.2.2 15-1.2.1.2.1.1.2.1.1 17-1.2.1.2.1.1.2.1.1 18-1.2.1.2.1.1.1 19-1.2.1.2.1.1 20-1.2.1.2 21-1.2.1.2.2.1.r 23-1.2.1.2.2.1.1 24-1.2.1.2.2.1 25-1.2.1.2.2.1.2.r 26-1.2.1.2.2.1.2.1.1 28-1.2.1.2.2.1.2.1.1 29-1.2.1.2.2.1.2 (p / present-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / evidence-01~e.2 :ARG1~e.3 (s / show-01~e.11 :ARG0 (m / morphology~e.5 :poss (c / cell-line~e.10 :name (n / name :op1 "Caco-BR13"~e.7,9))) :ARG1 (a / and~e.20 :op1 (p2 / property~e.12 :poss (n2 / nature~e.19 :mod (e2 / epithelium~e.18) :poss (c2 / cell-line~e.10 :name (n3 / name :op1 "Caco-2"~e.15,17)))) :op2 (p3 / property~e.12 :poss~e.21 (p4 / phenotype~e.24 :mod (m2 / mesenchyme~e.23) :poss~e.25 (c3 / cell-line~e.29 :name (n4 / name :op1 "Caco-H2"~e.26,28)))))))) # ::id a_pmid_2194_3101.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , Caco @-@ K15 cells , which overexpress KRAS @^G12V , have retained the overall parental morphology of Caco @-@ 2 cells . # ::alignments 5-1.1.1.1.1 7-1.1.1.1.1 8-1.1.1 11-1.1.1.2 12-1.1.1.2.1.1.1 14-1.1.1.2.1.2.1 18-1.1 20-1.1.2.1 21-1.1.2.2 22-1.1.2 23-1.1.2.3.r 24-1.1.2.3.1.1 26-1.1.2.3.1.1 27-1.1.2.3 (c3 / contrast-01 :ARG2 (r2 / retain-01~e.18 :ARG0 (c / cell-line~e.8 :name (n / name :op1 "Caco-K15"~e.5,7) :location-of (o / overexpress-01~e.11 :ARG1 (g / gene :name (n2 / name :op1 "KRAS"~e.12) :ARG1-of (m / mutate-01 :value "G12V"~e.14)))) :ARG1 (m2 / morphology~e.22 :mod (o2 / overall~e.20) :mod (p / parent~e.21) :poss~e.23 (c2 / cell-line~e.27 :name (n3 / name :op1 "Caco-2"~e.24,26))))) # ::id a_pmid_2194_3101.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For comparison , established adenocarcinoma cell lines HT29 and DLD @-@ 1 , bearing mutant BRAF @^V600E@ @ and KRAS @^G13D@ @ respectively , have also been analyzed in the present study . # ::alignments 1-1.2 3-1.1.4 4-1.1.3 5-1.1.1 6-1.1.1 6-1.1.2 7-1.1.1.1.1 8-1.1 9-1.1.2.1.1 11-1.1.2.1.1 13-1.1.1.2 13-1.1.2.2 14-1.1.1.2.1 14-1.1.1.2.1.2 14-1.1.1.2.1.2.r 14-1.1.2.2.1 14-1.1.2.2.1.2 14-1.1.2.2.1.2.r 16-1.1.1.2.1.1.1 18-1.1.1.2.1.2.1 21-1.1 23-1.1.2.2.1.1.1 25-1.1.2.2.1.2.1 28-1.1.5 31-1.4 33-1 34-1.3.r 36-1.3.1 37-1.3 (a / analyze-01~e.33 :ARG1 (a3 / and~e.8,21 :op1 (c2 / cell-line~e.5,6 :name (n / name :op1 "HT29"~e.7) :ARG0-of (b / bear-01~e.13 :ARG1 (g / gene~e.14 :name (n3 / name :op1 "BRAF"~e.16) :ARG1-of~e.14 (m / mutate-01~e.14 :value "V600E"~e.18)))) :op2 (c3 / cell-line~e.6 :name (n2 / name :op1 "DLD-1"~e.9,11) :ARG0-of (b2 / bear-01~e.13 :ARG1 (g2 / gene~e.14 :name (n4 / name :op1 "KRAS"~e.23) :ARG1-of~e.14 (m2 / mutate-01~e.14 :value "G13D"~e.25)))) :mod (a4 / adenocarcinoma~e.4) :ARG1-of (e / establish-01~e.3) :mod (r / respective~e.28)) :purpose (c / compare-01~e.1) :medium~e.34 (s / study-01~e.37 :time (p / present~e.36)) :mod (a2 / also~e.31)) # ::id a_pmid_2194_3101.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is of interest that the phenotype of Caco @-@ BR cells resembles that of DLD @-@ 1 cells ( KRAS @^G13D ) , especially since both of these cell types share high levels of p @-@ BRAF ( later analyzed ) . # ::alignments 3-1 6-1.1.1 6-1.1.2 7-1.1.1.1.r 8-1.1.1.1.1.1 10-1.1.1.1.1.1 11-1.1.1.1 11-1.1.2.1 12-1.1 15-1.1.2.1.1.1 17-1.1.2.1.1.1 18-1.1.1.1 20-1.1.2.1.2.1.1 22-1.1.2.1.2.2.1 26-1.2.2 27-1.2 31-1.1.1.1 33-1.2.1 34-1.2.1.2.1 35-1.2.1.2 36-1.2.1.2.2.r 37-1.2.1.2.2.2 39-1.2.1.2.2.1.1 41-1.2.1.2.2.3.1 41-1.2.1.2.2.3.1.1 41-1.2.1.2.2.3.1.1.r 42-1.2.1.2.2.3 (i / interest-01~e.3 :ARG0 (r / resemble-01~e.12 :ARG1 (p / phenotype~e.6 :poss~e.7 (c2 / cell-line~e.11,18,31 :name (n / name :op1 "Caco-BR"~e.8,10))) :ARG2 (p2 / phenotype~e.6 :poss (c3 / cell-line~e.11 :name (n2 / name :op1 "DLD-1"~e.15,17) :mod (e3 / enzyme :name (n3 / name :op1 "KRAS"~e.20) :ARG1-of (m2 / mutate-01 :value "G13D"~e.22))))) :ARG1-of (c / cause-01~e.27 :ARG0 (s / share-01~e.33 :ARG0 (a / and :op1 c2 :op2 c3) :ARG1 (l / level~e.35 :ARG1-of (h / high-02~e.34) :quant-of~e.36 (e2 / enzyme :name (n4 / name :op1 "BRAF"~e.39) :ARG3-of (p4 / phosphorylate-01~e.37) :ARG1-of (a2 / analyze-01~e.42 :time (l2 / late~e.41 :degree~e.41 (m3 / more~e.41)))))) :mod (e / especially~e.26))) # ::id a_pmid_2194_3101.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our previous study shows important similarities between Caco @-@ BR and DLD @-@ 1 cells regarding their tumourigenic properties and signaling pathways , suggesting that their transformation process occurs mainly through the constitutive activation of the MAPK ( Mitogen @-@ Activated Protein Kinase ) pathway [ @ 21 @ ] . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1 3-1 4-1.2.4 5-1.2 7-1.2.1.1.1 9-1.2.1.1.1 11-1.2.2.1.1 13-1.2.2.1.1 14-1.2.1 14-1.2.2 15-1.2.3.r 17-1.2.3.1 17-1.2.3.1.1 17-1.2.3.1.1.1 17-1.2.3.1.1.1.r 17-1.2.3.1.1.r 19-1.2.3 20-1.2.3.2.1 21-1.2.3.2 23-1.3 26-1.3.1.1 27-1.3.1 32-1.3.2.2 33-1.3.2 34-1.3.2.1.r 36-1.3.2.1.1.1 38-1.3.2.1.2.1.1.1 40-1.3.2.1.2.1.1.1 41-1.3.2.1.2.1.1.2 42-1.3.2.1.2.1.1.3 44-1.3.2.1 44-1.3.2.1.2.1 47-1.4.1.1.1 (s / show-01~e.3 :ARG0 (s2 / study-01~e.2 :ARG0~e.0 (w / we~e.0) :time (p / previous~e.1)) :ARG1 (r / resemble-01~e.5 :ARG1 (c / cell-line~e.14 :name (n / name :op1 "Caco-BR"~e.7,9)) :ARG2 (c2 / cell-line~e.14 :name (n2 / name :op1 "DLD-1"~e.11,13)) :topic~e.15 (a / and~e.19 :op1 (p2 / possible-01~e.17 :ARG1~e.17 (c5 / create-01~e.17 :ARG1~e.17 (t / tumor~e.17))) :op2 (p3 / pathway~e.21 :ARG0-of (s3 / signal-07~e.20))) :mod (i / important~e.4)) :ARG0-of (s4 / suggest-01~e.23 :ARG1 (p4 / process-02~e.27 :ARG1 (t2 / transform-01~e.26 :ARG1 (a3 / and :op1 c :op2 c2))) :manner (a4 / activate-01~e.33 :ARG1~e.34 (p5 / pathway~e.44 :name (n3 / name :op1 "MAPK"~e.36) :ARG1-of (m / mean-01 :ARG2 (p6 / pathway~e.44 :name (n4 / name :op1 "Mitogen-Activated"~e.38,40 :op2 "Protein"~e.41 :op3 "Kinase"~e.42)))) :mod (c3 / constitutive~e.32))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 21~e.47)))) # ::id a_pmid_2194_3101.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Staining with phalloidin resolved the morphological differences within the cell line panel indicating major actin cytoskeleton changes ( Figure 1A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1 5-1.2.2 6-1.2 9-1.2.1.1 10-1.2.1.1 11-1.2.1 12-1.2.1.2 13-1.2.1.2.1.2 14-1.2.1.2.1.1.1.1.1 15-1.2.1.2.1.1 16-1.2.1.2.1 18-1.3.1 20-1.3.1.1 (r / resolve-01~e.3 :ARG0 (s / stain-01~e.0 :ARG2~e.1 (s2 / small-molecule :name (n / name :op1 "phalloidin"~e.2))) :ARG1 (d2 / differ-02~e.6 :ARG1 (p / panel~e.11 :mod (c / cell-line~e.9,10) :ARG0-of (i / indicate-01~e.12 :ARG1 (c2 / change-01~e.16 :ARG1 (c3 / cytoskeleton~e.15 :mod (p2 / protein :name (n2 / name :op1 "actin"~e.14))) :ARG1-of (m3 / major-02~e.13)))) :mod (m2 / morphology~e.5)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "1A"~e.20))) # ::id a_pmid_2194_3101.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More specifically , in Caco @-@ BR13 cells the formation of stress fibers was enhanced , whereas formation of filopodia @-@ membrane protrusions enriched with actin @- is evident in Caco @-@ K15 cells ( Figure 1A @-@ ii , arrow ) . # ::alignments 0-1.4.1 1-1.4 4-1.1.2.1.1 6-1.1.2.1.1 7-1.1.2 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.1 12-1.1.1.1 14-1.1 16-1 17-1.2.1 18-1.2.1.1.r 19-1.2.1.1.1.1 21-1.2.1.1.1 22-1.2.1.1 23-1.2.1.1.2 24-1.2.1.1.2.1.r 25-1.2.1.1.2.1.1.1 27-1.2.1.r 28-1.2 29-1.2.2.r 30-1.2.2.1.1 32-1.2.2.1.1 33-1.2.2 35-1.3.1.1 42-1.3.1.2 (c / contrast-01~e.16 :ARG1 (e / enhance-01~e.14 :ARG1 (f4 / form-01~e.9 :ARG1~e.10 (f5 / fiber~e.12 :mod (s2 / stress~e.11))) :location (c3 / cell-line~e.7 :name (n3 / name :op1 "Caco-BR13"~e.4,6))) :ARG2 (e2 / evident~e.28 :domain~e.27 (f / form-01~e.17 :ARG1~e.18 (p / protrusion~e.22 :mod (m2 / membrane~e.21 :mod (f2 / filopodia~e.19)) :ARG1-of (e3 / enrich-01~e.23 :ARG2~e.24 (p2 / protein :name (n / name :op1 "actin"~e.25))))) :location~e.29 (c2 / cell-line~e.33 :name (n2 / name :op1 "Caco-K15"~e.30,32))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f3 / figure~e.35 :mod "1A.ii") :op2 (a2 / arrow~e.42))) :ARG1-of (s / specific-02~e.1 :degree (m / more~e.0))) # ::id a_pmid_2194_3101.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to study in depth the morphology and architecture of the different cell lines under conditions that resemble the real tissue microenvironment , the three @-@ dimensional ( 3D ) culture system was adopted . # ::alignments 0-1.2.r 1-1.2.r 2-1.2.r 3-1.2 4-1.2.2.r 5-1.2.2 7-1.2.1.1 8-1.2.1 9-1.2.1.2 10-1.2.1.1.1.r 12-1.2.1.1.1.1 13-1.2.1.1.1 14-1.2.1.1.1 16-1.1.2 16-1.1.2.r 18-1.1.2.1 20-1.1.2.1.1.1.1 21-1.1.2.1.1.1 22-1.1.2.1.1 25-1.1.1.1.1 27-1.1.1.1 29-1.1.1.1 29-1.1.1.1.1 29-1.1.1.1.1.r 31-1.1.1 32-1.1 34-1 (a / adopt-01~e.34 :ARG1 (s / system~e.32 :mod (c / culture~e.31 :mod (d3 / dimension~e.27,29 :quant~e.29 3~e.25,29)) :condition~e.16 (c4 / condition~e.16 :ARG1-of (r2 / resemble-01~e.18 :ARG2 (m3 / microenvironment~e.22 :mod (t2 / tissue~e.21 :ARG1-of (r / real-04~e.20)))))) :purpose~e.0,1,2 (s2 / study-01~e.3 :ARG1 (a2 / and~e.8 :op1 (m2 / morphology~e.7 :poss~e.10 (c2 / cell-line~e.13,14 :ARG1-of (d2 / differ-02~e.12))) :op2 (a3 / architecture~e.9 :poss c2)) :ARG1-of~e.4 (d / deep-03~e.5))) # ::id a_pmid_2194_3101.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As also previously shown [ @ 22 @ ] , Caco @-@ 2 cells were organized into cyst @-@ like structures that resemble normal colon cell architecture following their growth in Matrigel for about 12 days ( Figure 1B ) . # ::alignments 0-1.2.r 1-1.3 2-1.2 3-1 6-1.4.1.1.1 10-1.1.1.1.1 12-1.1.1.1.1 13-1.1.1 15-1.1 16-1.1.2.r 17-1.1.2.1.1 19-1.1.2.1 19-1.1.2.2 20-1.1.2 22-1.1.2.2 23-1.1.2.2.1.1.1.1 24-1.1.2.2.1.1.1 25-1.1.2.2.1.1 26-1.1.2.2.1 27-1.1.3 28-1.1.3.1.1 28-1.1.3.1.1.r 29-1.1.3.1 30-1.1.3.1.2.r 31-1.1.3.1.2.1.1 32-1.1.3.1.3.r 33-1.1.3.1.3 34-1.1.3.1.3.1.1 35-1.1.3.1.3.1.2 37-1.1.4.1 39-1.1.4.1.1 (s / show-01~e.3 :ARG1 (o / organize-01~e.15 :ARG1 (c2 / cell-line~e.13 :name (n2 / name :op1 "Caco-2"~e.10,12)) :ARG4~e.16 (s2 / structure~e.20 :ARG1-of (r / resemble-01~e.19 :ARG2 (c3 / cyst~e.17)) :ARG1-of (r2 / resemble-01~e.19,22 :ARG2 (a3 / architecture~e.26 :mod (c4 / cell~e.25 :source (c5 / colon~e.24 :ARG1-of (n3 / normal-02~e.23)))))) :ARG1-of (f / follow-01~e.27 :ARG2 (g / grow-03~e.29 :ARG1~e.28 c2~e.28 :medium~e.30 (p3 / protein :name (n / name :op1 "Matrigel"~e.31)) :duration~e.32 (a / about~e.33 :op1 (t / temporal-quantity :quant 12~e.34 :unit (d / day~e.35))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.37 :mod "1B"~e.39))) :time~e.0 (p / previous~e.2) :mod (a2 / also~e.1) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 22~e.6)))) # ::id a_pmid_2194_3101.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , Caco @-@ H cells ( EMT model ) formed invasive masses with elongated protrusions , an architecture not shared by Caco @-@ BR13 and Caco @-@ K15 cells ( Figure 1B , upper panel , black arrow ) . # ::alignments 1-1 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.1 8-1.1.1.2 11-1.1 12-1.1.2.1 13-1.1.2 14-1.1.2.2.r 15-1.1.2.2.1 16-1.1.2.2 19-1.1.2.2.2 20-1.1.2.2.2.1.1 20-1.1.2.2.2.1.1.r 21-1.1.2.2.2.1 22-1.1.2.2.2.1.2.r 23-1.1.2.2.2.1.2.1.1.1 25-1.1.2.2.2.1.2.1.1.1 26-1.1.2.2.2.1.2 27-1.1.2.2.2.1.2.1.1.1 27-1.1.2.2.2.1.2.2.1.1 29-1.1.2.2.2.1.2.2.1.1 30-1.1.2.2.2.1.2.1 30-1.1.2.2.2.1.2.2 32-1.2.1.1 34-1.2.1.1.1 37-1.2.1.2.1 38-1.2.1.2 40-1.2.1.3.1 41-1.2.1.3 (c / contrast-01~e.1 :ARG2 (f / form-01~e.11 :ARG0 (c2 / cell-line~e.6 :name (n / name :op1 "Caco-H"~e.3,5) :mod (t / transition-01~e.8 :ARG2 (m2 / mesenchyme) :ARG3 (e2 / epithelium))) :ARG1 (m / mass~e.13 :ARG0-of (i / invade-01~e.12) :ARG1-of~e.14 (p / protrude-01~e.16 :ARG1-of (e / elongate-01~e.15) :mod (a / architecture~e.19 :ARG1-of (s / share-01~e.21 :polarity~e.20 -~e.20 :ARG0~e.22 (a2 / and~e.26 :op1 (c3 / cell-line~e.30 :name (n2 / name :op1 "Caco-BR13"~e.23,25,27)) :op2 (c4 / cell-line~e.30 :name (n3 / name :op1 "Caco-K15"~e.27,29)))))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f2 / figure~e.32 :mod "1B"~e.34) :op2 (p2 / panel~e.38 :mod (u / upper~e.37)) :op3 (a4 / arrow~e.41 :ARG1-of (b / black-04~e.40))))) # ::id a_pmid_2194_3101.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok During 3D culture conditions , normal epithelial cells are organized into spheroids presenting a characteristic centrally @-@ localized hollow lumen and distinct polarization of cells surrounding this lumen . # ::alignments 1-1.3.1 1-1.3.1.1 1-1.3.1.1.r 2-1.3 3-1.3.r 5-1.1.1 6-1.1.2 7-1.1 9-1 10-1.2.r 11-1.2 12-1.2.1 14-1.2.1.1.1.3 15-1.2.1.1.1.2 18-1.2.1.1.1.1 19-1.2.1.1.1 20-1.2.1.1 21-1.2.1.1.2.2 22-1.2.1.1.2 23-1.2.1.1.2.1.r 24-1.2.1.1.2.1 25-1.2.1.1.2.1.1 27-1.2.1.1.2.1.1.1 (o2 / organize-01~e.9 :ARG1 (c3 / cell~e.7 :ARG1-of (n / normal-02~e.5) :source (e / epithelium~e.6)) :ARG4~e.10 (s / spheroid~e.11 :ARG0-of (p / present-01~e.12 :ARG1 (a / and~e.20 :op1 (l / lumen~e.19 :ARG1-of (h / hollow-02~e.18) :location (c / center~e.15) :ARG1-of (c6 / characteristic-02~e.14)) :op2 (p2 / polarize-01~e.22 :ARG1~e.23 (c4 / cell~e.24 :ARG1-of (s2 / surround-01~e.25 :ARG2 l~e.27)) :mod (d / distinct~e.21))))) :condition~e.3 (c2 / culture~e.2 :mod (d2 / dimension~e.1 :quant~e.1 3~e.1))) # ::id a_pmid_2194_3101.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Epithelial cancer cells do not form such structures ; instead they develop non @-@ polarized clusters with limited differentiation [ @ 23 , 24 @ ] . # ::alignments 0-1.3.1.1.2 1-1.3.1.1.1.2.1 2-1.3.1.1 4-1.2.1.1.r 5-1.3.1 6-1.3.1.2.1 7-1.3.1.2 9-1.3 11-1 12-1.2.1.1 12-1.2.1.1.r 14-1.2.1 15-1.2 16-1.2.2.r 17-1.2.2.1 18-1.2.2 21-1.4.1.1.1.1 25-1.4.1.2.1.1 (d / develop-02~e.11 :ARG0 c :ARG1 (c2 / cluster~e.15 :ARG1-of (p / polarize-01~e.14 :polarity~e.4,12 -~e.12) :mod~e.16 (d3 / differentiate-01~e.18 :ARG1-of (l / limit-01~e.17))) :ARG1-of (i / instead-of-91~e.9 :ARG2 (f / form-01~e.5 :ARG0 (c / cell~e.2 :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.1)) :mod (e / epithelium~e.0)) :ARG1 (s / structure~e.7 :degree (s2 / such~e.6)))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 23~e.21)) :op2 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 24~e.25))))) # ::id a_pmid_2194_3101.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following staining with Hoechst and phalloidin the ability of Caco @-@ 2 cells to form spheroids with lumen was observed , a property also retained by Caco @-@ K15 cells but completely absent in Caco @-@ BR13 and Caco @-@ H2 cells ( Figure 1B , lower panel ) . # ::alignments 0-1.2 1-1.2.1 2-1.2.1.1.r 3-1.2.1.1.1.1.1 4-1.2.1.1 5-1.2.1.1.2.1.1 7-1.1 8-1.1.1.r 9-1.1.1.1.1 11-1.1.1.1.1 12-1.1.1 14-1.1.2 15-1.1.2.2 16-1.1.2.2.1.r 17-1.1.2.2.1 19-1 22-1.1.3.1 23-1.1.3.1.1.2 24-1.1.3.1.1 25-1.1.3.1.1.1.r 26-1.1.3.1.1.1.1.1 28-1.1.3.1.1.1.1.1 29-1.1.3.1.1.1 31-1.1.3.1.2.2 32-1.1.3.1.2 33-1.1.3.1.2.1.r 34-1.1.3.1.2.1.1.1.1 36-1.1.3.1.2.1.1.1.1 37-1.1.3.1.2.1 38-1.1.3.1.2.1.1.1.1 38-1.1.3.1.2.1.2.1.1 40-1.1.3.1.2.1.2.1.1 41-1.1.3.1.2.1.1 41-1.1.3.1.2.1.2 43-1.3.1.1 45-1.3.1.1.1 48-1.3.1.2.1 48-1.3.1.2.1.1 48-1.3.1.2.1.1.r 49-1.3.1.2 (o / observe-01~e.19 :ARG1 (c / capable-01~e.7 :ARG1~e.8 (c2 / cell-line~e.12 :name (n3 / name :op1 "Caco-2"~e.9,11)) :ARG2 (f3 / form-01~e.14 :ARG0 c2 :ARG1 (s2 / spheroid~e.15 :mod~e.16 (l / lumen~e.17))) :ARG1-of (m4 / mean-01 :ARG2 (p2 / property~e.22 :ARG1-of (r / retain-01~e.24 :ARG0~e.25 (c3 / cell-line~e.29 :name (n4 / name :op1 "Caco-K15"~e.26,28)) :mod (a2 / also~e.23)) :ARG1-of (a3 / absent-01~e.32 :ARG2~e.33 (a4 / and~e.37 :op1 (c4 / cell-line~e.41 :name (n5 / name :op1 "Caco-BR13"~e.34,36,38)) :op2 (c6 / cell-line~e.41 :name (n6 / name :op1 "Caco-H2"~e.38,40))) :ARG1-of (c5 / complete-02~e.31))))) :ARG2-of (f / follow-01~e.0 :ARG1 (s / stain-01~e.1 :ARG2~e.2 (a / and~e.4 :op1 (s4 / small-molecule :name (n / name :op1 "Hoechst"~e.3)) :op2 (s3 / small-molecule :name (n2 / name :op1 "phalloidin"~e.5))))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f2 / figure~e.43 :mod "1B"~e.45) :op2 (p / panel~e.49 :ARG1-of (l2 / low-04~e.48 :degree~e.48 (m3 / more~e.48)))))) # ::id a_pmid_2194_3101.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significantly enlarged and more compact spheroids without lumen were formed by Caco @-@ BR13 cells as compared to Caco @-@ 2 cells . # ::alignments 0-1.2.1.1 1-1.2.1 3-1.2.2.1 4-1.2.2 5-1.2 6-1.2.3.1 6-1.2.3.1.r 7-1.2.3.2 9-1 10-1.1.r 11-1.1.1.1 13-1.1.1.1 14-1.1 14-1.3 16-1.3.r 18-1.3.1.1 20-1.3.1.1 21-1.1 (f / form-01~e.9 :ARG0~e.10 (c2 / cell-line~e.14,21 :name (n / name :op1 "Caco-BR13"~e.11,13)) :ARG1 (s / spheroid~e.5 :ARG1-of (e / enlarge-01~e.1 :ARG2 (s2 / significant-02~e.0)) :ARG1-of (c / compact-01~e.4 :degree (m / more~e.3)) :ARG0-of (h / have-03 :polarity~e.6 -~e.6 :ARG1 (l2 / lumen~e.7))) :compared-to~e.16 (c3 / cell-line~e.14 :name (n2 / name :op1 "Caco-2"~e.18,20))) # ::id a_pmid_2194_3101.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the case of Caco @-@ H2 cells , no typical spheroids were formed , instead large masses with non @-@ canonical shape were observed , typical of cancer cells . # ::alignments 3-1.2 4-1.3.1.1 6-1.3.1.1 7-1.3 9-1.1.2.1.r 10-1.2.1.1.1 11-1.2.1.1 13-1.2.1 15-1.2 16-1.1.1 17-1.1 19-1.1.2.1 19-1.1.2.1.r 21-1.1.2.2 22-1.1.2 24-1 26-1.2.1.1.1 27-1.2 28-1.1.3.1.1.2.1 29-1.1.3.1 (o / observe-01~e.24 :ARG1 (m / mass~e.17 :mod (l / large~e.16) :ARG1-of (s2 / shape-01~e.22 :polarity~e.9,19 -~e.19 :ARG2 (c3 / canonical~e.21)) :ARG0-of (t2 / typify-01 :ARG1 (c4 / cell~e.29 :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.28))))) :ARG1-of (i / instead-of-91~e.3,15,27 :ARG2 (f / form-01~e.13 :ARG1 (s / spheroid~e.11 :ARG1-of (t / typical-02~e.10,26)))) :topic (c2 / cell-line~e.7 :name (n / name :op1 "Caco-H2"~e.4,6))) # ::id a_pmid_2194_3101.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , under 2D as well as 3D culture conditions BRAF @^V600E@ overexpression managed to alter the morphology of colon adenocarcinoma cells , rendering them a more mesenchymal @-@ like phenotype , while KRAS @^G12V@ conserved the epithelial architecture of Caco @-@ 2 cells in general . # ::alignments 0-1 3-1.1.3.1.1.1 3-1.1.3.1.1.1.r 4-1.1.3 5-1.1.3 6-1.1.3 7-1.1.3.1.1 7-1.1.3.2.1 7-1.1.3.2.1.1 7-1.1.3.2.1.1.r 8-1.1.3.1 8-1.1.3.2 9-1.1.3.r 10-1.1.1.1.1.1.1 12-1.1.1.1.1.2.1 14-1.1.1.1 15-1.1.1 17-1.1.1.1.2 19-1.1.1.1.2.1 20-1.1.1.1.2.1.1.r 21-1.1.1.1.2.1.1.1.1 22-1.1.1.1.2.1.1.1 23-1.1.1.1.2.1.1 25-1.1.1.2 26-1.1.1.2.2 28-1.1.1.2.1.1.1.1.1 29-1.1.1.2.1.1.1.1 31-1.1.1.2.1.1 32-1.1.1.2.1 32-1.1.1.2.1.1.1 34-1.1 35-1.1.2.1.1.1 37-1.1.2.1.2.1 39-1.1.2 41-1.1.2.2.1 42-1.1.2.2 43-1.1.2.2.2.r 44-1.1.2.2.2.1.1 46-1.1.2.2.2.1.1 47-1.1.2.2.2 48-1.1.2.3.r 49-1.1.2.3 (c / cause-01~e.0 :ARG1 (c10 / contrast-01~e.34 :ARG1 (m / manage-02~e.15 :ARG0 (o / overexpress-01~e.14 :ARG1 (e3 / enzyme :name (n3 / name :op1 "BRAF"~e.10) :ARG1-of (m3 / mutate-01 :value "V600E"~e.12)) :ARG0-of (a2 / alter-01~e.17 :ARG1 (m4 / morphology~e.19 :poss~e.20 (c5 / cell~e.23 :source (a3 / adenocarcinoma~e.22 :part-of (c6 / colon~e.21)))))) :ARG0-of (r / render-02~e.25 :ARG1 (p / phenotype~e.32 :ARG1-of (r2 / resemble-01~e.31 :ARG2 (p2 / phenotype~e.32 :mod (m5 / mesenchyme~e.29 :degree (m6 / more~e.28))))) :ARG2 c5~e.26)) :ARG2 (c2 / conserve-01~e.39 :ARG0 (e2 / enzyme :name (n / name :op1 "KRAS"~e.35) :ARG1-of (m2 / mutate-01 :value "G12V"~e.37)) :ARG1 (a / architecture~e.42 :mod (e / epithelium~e.41) :source~e.43 (c3 / cell-line~e.47 :name (n2 / name :op1 "Caco-2"~e.44,46))) :ARG1-of~e.48 (g2 / general-02~e.49)) :condition~e.9 (a4 / and~e.4,5,6 :op1 (c8 / culture~e.8 :mod (d / dimension~e.7 :quant~e.3 2~e.3)) :op2 (c9 / culture~e.8 :mod (d2 / dimension~e.7 :quant~e.7 3~e.7))))) # ::id a_pmid_2194_3101.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @^V600E@ downregulates E @-@ cadherin at the mRNA level and impairs its distribution in human colon adenocarcinoma cells # ::alignments 0-1.1.2.1.1 2-1.1.2.2.1 4-1.1 5-1.1.1.1.1 7-1.1.1.1.1 8-1.1.3.r 10-1.1.3.1.1.1 11-1.1.3 12-1 13-1.2 15-1.2.2 16-1.2.2.2.r 17-1.2.2.2.1.1.1 18-1.2.2.2.1.1 19-1.2.2.2.1 20-1.2.2.2 (a / and~e.12 :op1 (d / downregulate-01~e.4 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin"~e.5,7)) :ARG2 (e / enzyme :name (n / name :op1 "BRAF"~e.0) :ARG1-of (m / mutate-01 :value "V600E"~e.2)) :location~e.8 (l / level~e.11 :quant-of (n4 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.10)))) :op2 (i / impair-01~e.13 :ARG0 e :ARG1 (d2 / distribute-01~e.15 :ARG1 p :location~e.16 (c / cell~e.20 :source (a2 / adenocarcinoma~e.19 :mod (c2 / colon~e.18 :mod (h / human~e.17))))))) # ::id a_pmid_2194_3101.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been previously shown that HRAS @^G12V@ converts Caco @-@ 2 epithelial into mesenchymal cells by inducing loss of E @-@ cadherin and overexpression of vimentin [ @ 25 @ ] . # ::alignments 3-1.3 4-1 5-1.1.r 6-1.1.1.1.1 8-1.1.1.2.1 10-1.1 11-1.1.2.1.1 13-1.1.2.1.1 14-1.1.2.2 15-1.1.3.r 16-1.1.3.1 17-1.1.3 18-1.1.4.r 19-1.1.4 20-1.1.4.2.1 21-1.1.4.2.1.1.r 22-1.1.4.2.1.1.1.1 24-1.1.4.2.1.1.1.1 25-1.1.4.2 26-1.1.4.2.2 27-1.1.4.2.2.1.r 28-1.1.4.2.2.1.1.1 31-1.2.1.1.1 (s / show-01~e.4 :ARG1~e.5 (c2 / convert-01~e.10 :ARG0 (g / gene :name (n3 / name :op1 "HRAS"~e.6) :ARG1-of (m / mutate-01 :value "G12V"~e.8)) :ARG1 (c3 / cell-line :name (n4 / name :op1 "Caco-2"~e.11,13) :mod (e / epithelium~e.14)) :ARG2~e.15 (c4 / cell~e.17 :location (m2 / mesenchyme~e.16)) :manner~e.18 (i / induce-01~e.19 :ARG0 g :ARG2 (a / and~e.25 :op1 (l / lose-02~e.20 :ARG1~e.21 (p4 / protein :name (n2 / name :op1 "E-cadherin"~e.22,24))) :op2 (o / overexpress-01~e.26 :ARG1~e.27 (p3 / protein :name (n / name :op1 "vimentin"~e.28)))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 25~e.31))) :time (p2 / previous~e.3)) # ::id a_pmid_2194_3101.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to examine whether BRAF @^V600E@ had a similar effect on Caco @-@ 2 cells , the expression and localization of E @-@ cadherin was analyzed ( Figure 2A , B ) . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 4-1.3.1.1 4-1.3.1.1.r 5-1.3.1.2.1.1.1 7-1.3.1.2.1.2.1 11-1.3.1.2.3 12-1.3.1.2 13-1.3.1.2.2.r 14-1.3.1.2.2.1.1 16-1.3.1.2.2.1.1 17-1.3.1.2.2 20-1.1.1 21-1.1 22-1.1.2 24-1.1.2.1.1.1 26-1.1.2.1.1.1 27-1.1.2 28-1 30-1.2.1.1 30-1.2.1.2 32-1.2.1.1.1 (a / analyze-01~e.28 :ARG1 (a3 / and~e.21 :op1 (e / express-03~e.20 :ARG2 p) :op2 (b / be-located-at-91~e.22,27 :ARG2 (p / protein :name (n / name :op1 "E-cadherin"~e.24,26)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.30 :mod "2A"~e.32) :op2 (f2 / figure~e.30 :mod "2B"))) :purpose~e.0,1,2 (e2 / examine-01~e.3 :ARG1 (p2 / possible-01 :mode~e.4 interrogative~e.4 :ARG1 (a4 / affect-01~e.12 :ARG0 (e3 / enzyme :name (n2 / name :op1 "BRAF"~e.5) :ARG1-of (m / mutate-01 :value "V600E"~e.7)) :ARG1~e.13 (c / cell-line~e.17 :name (n3 / name :op1 "Caco-2"~e.14,16)) :ARG1-of (r / resemble-01~e.11))))) # ::id a_pmid_2194_3101.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transformation of Caco @-@ 2 cells with BRAF @^V600E@ led to a significant decrease in the mRNA levels of E @-@ cadherin but had no significant effect on the actual protein expression ( Figure 2A ) . # ::alignments 0-1.1.1 1-1.1.1.2.r 2-1.1.1.2.1.1 4-1.1.1.2.1.1 5-1.1.1.2 6-1.1.1.1.r 7-1.1.1.1.1.1 9-1.1.1.1.2.1 11-1.1 14-1.1.2.2 15-1.1.2 16-1.1.2.1.r 18-1.1.2.1.1.1.1 19-1.1.2.1 21-1.1.2.1.1.2.1.1 23-1.1.2.1.1.2.1.1 24-1 26-1.2.1 26-1.2.1.r 27-1.2.4 28-1.2 29-1.2.3.r 31-1.2.3.2 32-1.2.3.1 33-1.2.3 35-1.3.1 37-1.3.1.1 (c / contrast-01~e.24 :ARG1 (l / lead-03~e.11 :ARG0 (t / transform-01~e.0 :ARG0~e.6 (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.7) :ARG1-of (m / mutate-01 :value "V600E"~e.9)) :ARG1~e.1 (c2 / cell-line~e.5 :name (n / name :op1 "Caco-2"~e.2,4))) :ARG1 (d / decrease-01~e.15 :ARG1~e.16 (l2 / level~e.19 :quant-of (n5 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.18) :mod (p / protein :name (n4 / name :op1 "E-cadherin"~e.21,23)))) :ARG2 (s / significant-02~e.14))) :ARG2 (a / affect-01~e.28 :polarity~e.26 -~e.26 :ARG0 t :ARG1~e.29 (e / express-03~e.33 :ARG2 p~e.32 :ARG1-of (a2 / actual-02~e.31)) :ARG1-of s~e.27) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.35 :mod "2A"~e.37))) # ::id a_pmid_2194_3101.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , in Caco @-@ BR cells reduced intensity for E @-@ cadherin was observed mostly in lower molecular weight protein bands representing the mature protein at 120 kDa ( Figure 2A @ -@ lower panel , high exposure ) , whereas the decrease in the actual precursors at 135 kDa ( Figure 2A @ -@ lower panel , low exposure ) , is considerably less . # ::alignments 0-1.3 3-1.1.4.1.1 5-1.1.4.1.1 6-1.1.4 7-1.1.1.1 8-1.1.1 9-1.1.1.2.r 10-1.1.1.2.1.1 12-1.1.1.2.1.1 12-1.1.2.2.1.1.1 14-1.1 15-1.1.3 16-1.1.2.r 17-1.1.2.1.1 17-1.1.2.1.1.2 17-1.1.2.1.1.2.r 18-1.1.2.1.1.1.1 19-1.1.2.1.1.1 20-1.1.2.1 21-1.1.2 22-1.1.2.2 24-1.1.2.2.1.2 25-1.1.2.2.1 26-1.1.2.2.1.3.r 27-1.1.2.2.1.3.1 28-1.1.2.2.1.3.2 30-1.1.5.1.1 30-1.2.3.1.1 32-1.1.5.1.1.1 32-1.2.3.1.1.1 35-1.1.5.1.2.1 35-1.1.5.1.2.1.1 35-1.1.5.1.2.1.1.r 35-1.2.3.1.2.1 35-1.2.3.1.2.1.1 35-1.2.3.1.2.1.1.r 36-1.1.5.1.2 36-1.2.3.1.2 38-1.1.5.1.3.1 39-1.1.5.1.3 42-1 44-1.2 45-1.2.1.r 47-1.2.1.1 48-1.2.1 49-1.2.1.2.r 50-1.2.1.2.1 51-1.2.1.2.2 53-1.2.3.1.1 55-1.2.3.1.1.1 58-1.2.3.1.2.1 58-1.2.3.1.2.1.1 58-1.2.3.1.2.1.1.r 59-1.2.3.1.2 61-1.2.3.1.3.1 62-1.2.3.1.3 66-1.2.2.1 67-1.2.2 (c / contrast-01~e.42 :ARG1 (o / observe-01~e.14 :ARG1 (i / intensity~e.8 :ARG1-of (r2 / reduce-01~e.7) :poss~e.9 (p5 / protein :name (n4 / name :op1 "E-cadherin"~e.10,12))) :location~e.16 (b / band~e.21 :mod (p3 / protein~e.20 :ARG1-of (l4 / low-04~e.17 :ARG2 (w / weight-01~e.19 :ARG1 (m4 / molecule~e.18)) :degree~e.17 (m5 / more~e.17))) :ARG0-of (r / represent-01~e.22 :ARG1 (p4 / protein~e.25 :name (n2 / name :op1 "E-cadherin"~e.12) :ARG1-of (m / mature-02~e.24) :quant~e.26 (m7 / mass-quantity :quant 120~e.27 :unit k~e.28)))) :degree (m3 / most~e.15) :location (c3 / cell-line~e.6 :name (n3 / name :op1 "Caco-BR"~e.3,5)) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure~e.30 :mod "2A"~e.32) :op2 (p6 / panel~e.36 :ARG1-of (l5 / low-04~e.35 :degree~e.35 (m8 / more~e.35))) :op3 (e2 / expose-01~e.39 :ARG1-of (h / high-02~e.38))))) :ARG2 (d / decrease-01~e.44 :ARG1~e.45 (p / precursor~e.48 :ARG1-of (a / actual-02~e.47) :quant~e.49 (m9 / mass-quantity :quant 135~e.50 :unit (k / kilodalton~e.51))) :ARG2 (l6 / less~e.67 :degree (c2 / considerable~e.66)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.30,53 :mod "2A"~e.32,55) :op2 (p2 / panel~e.36,59 :ARG1-of (l / low-04~e.35,58 :degree~e.35,58 (m2 / more~e.35,58))) :op3 (e / exposure~e.62 :ARG1-of (l2 / low-04~e.61))))) :ARG1-of (n / notable-04~e.0)) # ::id a_pmid_2194_3101.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It appears that mutant BRAF @^V600E@ but not upstream KRAS @^G12V@ activation is able to suppress the mature E @-@ cadherin , while the precursor remained mostly unaffected . # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1 3-1.1.1.1.1.2 3-1.1.1.1.1.2.r 3-1.1.1.1.2.1.1 3-1.1.1.1.2.1.1.2 3-1.1.1.1.2.1.1.2.r 4-1.1.1.1.1.1.1 6-1.1.1.1.1.2.1 8-1.1.1.1.2 9-1.1.1.1.2.1.2.1 9-1.1.1.1.2.1.2.1.r 10-1.1.1.1.2.1.3 11-1.1.1.1.2.1.1.1.1 13-1.1.1.1.2.1.1.2.1 15-1.1.1.1 15-1.1.1.1.2.1 17-1.1.1 17-1.1.1.1.2.1.2 19-1.1.1.2 21-1.1.1.2.1 21-1.1.1.2.1.2 21-1.1.1.2.1.2.r 22-1.1.1.2.1.1.1 24-1.1.1.2.1.1.1 26-1.1 28-1.1.2.1 29-1.1.2 30-1.1.2.2.2 31-1.1.2.2 31-1.1.2.2.1 31-1.1.2.2.1.r (a / appear-01~e.1 :ARG1~e.2 (c3 / contrast-01~e.26 :ARG1 (c2 / capable-01~e.17 :ARG1 (a3 / activate-01~e.15 :ARG1 (e / enzyme~e.3 :name (n / name :op1 "BRAF"~e.4) :ARG1-of~e.3 (m / mutate-01~e.3 :value "V600E"~e.6)) :ARG1-of (c / contrast-01~e.8 :ARG2 (a4 / activate-01~e.15 :ARG1 (e2 / enzyme~e.3 :name (n2 / name :op1 "KRAS"~e.11) :ARG1-of~e.3 (m2 / mutate-01~e.3 :value "G12V"~e.13)) :ARG1-of (c4 / capable-01~e.17 :polarity~e.9 -~e.9 :ARG2 s) :location (u / upstream~e.10)))) :ARG2 (s / suppress-01~e.19 :ARG1 (p / protein~e.21 :name (n3 / name :op1 "E-cadherin"~e.22,24) :ARG1-of~e.21 (m3 / mature-02~e.21)))) :ARG2 (r / remain-01~e.29 :ARG1 (p2 / precursor~e.28) :ARG3 (a2 / affect-01~e.31 :polarity~e.31 -~e.31 :degree (m4 / most~e.30))))) # ::id a_pmid_2194_3101.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nevertheless , immunostaining with E @-@ cadherin revealed a significant impairment of its distribution at the cell @-@ cell boundaries since staining appeared discontinuous at the adherent junctions ( Figure 2B , upper panel magnification ) . # ::alignments 0-1 2-1.1.2.1 3-1.1.2.1.1.r 4-1.1.2.1.1.1.1 6-1.1.2.1.1.1.1 7-1.1.2 9-1.1.2.2.2 10-1.1.2.2 11-1.1.2.2.1.r 12-1.1.2.2.1.1 12-1.1.2.2.1.1.r 13-1.1.2.2.1 14-1.1.2.2.1.2.r 16-1.1.2.2.1.2.1.2 18-1.1.2.2.1.2.1.2 19-1.1.2.2.1.2 20-1.1 21-1.1.1.1.2 22-1.1.1 23-1.1.1.1 23-1.1.1.1.1 23-1.1.1.1.1.r 24-1.1.1.2.r 26-1.1.1.2.1.1 27-1.1.1.2.1.2 29-1.2.1.1 31-1.2.1.1.1 34-1.2.1.2.1.1 35-1.2.1.2.1 36-1.2.1.2 (h / have-concession-91~e.0 :ARG1 (c2 / cause-01~e.20 :ARG0 (a / appear-01~e.22 :ARG1 (c / continue-01~e.23 :polarity~e.23 -~e.23 :ARG1 (s / stain-01~e.21)) :location~e.24 (m3 / macro-molecular-complex :name (n2 / name :op1 "adherent"~e.26 :op2 "junction"~e.27))) :ARG1 (r / reveal-01~e.7 :ARG0 (i / immunostain-01~e.2 :ARG2~e.3 (p / protein :name (n / name :op1 "E-cadherin"~e.4,6))) :ARG1 (i2 / impair-01~e.10 :ARG1~e.11 (d2 / distribute-01~e.13 :ARG1~e.12 p~e.12 :ARG2~e.14 (b / boundary~e.19 :mod (b2 / between :op1 c3 :op2 (c3 / cell~e.16,18)))) :ARG1-of (s2 / significant-02~e.9)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.29 :mod "2B"~e.31) :op2 (m / magnify-01~e.36 :ARG1 (p2 / panel~e.35 :mod (u / upper~e.34)))))) # ::id a_pmid_2194_3101.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of E @-@ cadherin in the Caco @-@ BR grown in 3D spheroids was found significantly downregulated with diffused distribution ( Figure 2B , lower panel ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1.2.r 7-1.1.1.2.1.1 9-1.1.1.2.1.1 10-1.1.1.2 10-1.1.1.2.2 10-1.1.1.2.2.r 11-1.1.1.2.2.1.r 12-1.1.1.2.2.1.1 12-1.1.1.2.2.1.1.1 12-1.1.1.2.2.1.1.1.r 13-1.1.1.2.2.1 15-1 16-1.1.3 17-1.1 18-1.1.2.r 19-1.1.2.1 20-1.1.2 22-1.2.1.1 24-1.2.1.1.1 27-1.2.1.2.1 27-1.2.1.2.1.1 27-1.2.1.2.1.1.r 28-1.2.1.2 (f / find-01~e.15 :ARG1 (d2 / downregulate-01~e.17 :ARG1 (e / express-03~e.0 :ARG2~e.1 (p2 / protein :name (n / name :op1 "E-cadherin"~e.2,4)) :ARG3~e.5 (c / cell-line~e.10 :name (n2 / name :op1 "Caco-BR"~e.7,9) :ARG1-of~e.10 (g / grow-03~e.10 :location~e.11 (s / spheroid~e.13 :mod (d5 / dimension~e.12 :quant~e.12 3~e.12))))) :manner~e.18 (d3 / distribute-01~e.20 :ARG1-of (d4 / diffuse-01~e.19)) :ARG1-of (s2 / significant-02~e.16)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure~e.22 :mod "2B"~e.24) :op2 (p / panel~e.28 :ARG1-of (l / low-04~e.27 :degree~e.27 (m / more~e.27)))))) # ::id a_pmid_2194_3101.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the epithelial marker E @-@ cadherin was normally localized at the cell @-@ cell junctions of Caco @-@ 2 and Caco @-@ K15 cells ( Figure 2B , lower panel magnification ) . # ::alignments 1-1 4-1.1.1.2 5-1.1.1 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1 10-1.1.3 11-1.1 12-1.1 14-1.1.2.1.1 16-1.1.2.1.1 17-1.1.2 19-1.1.2.1.1.1.1 19-1.1.2.1.2.1.1 21-1.1.2.1.1.1.1 22-1.1.2.1 23-1.1.2.1.1.1.1 23-1.1.2.1.2.1.1 25-1.1.2.1.2.1.1 26-1.1.2.1.1 26-1.1.2.1.2 28-1.2.1.1 30-1.2.1.1.1 33-1.2.1.2.1.1 34-1.2.1.2.1 35-1.2.1.2 (c / contrast-01~e.1 :ARG2 (b / be-located-at-91~e.9,11,12 :ARG1 (m3 / marker~e.5 :name (n2 / name :op1 "E-cadherin"~e.6,8) :mod (e / epithelium~e.4)) :ARG2 (j3 / junction~e.17 :mod (b2 / between~e.22 :op1 (c2 / cell-line~e.14,16,26 :name (n3 / name :op1 "Caco-2"~e.19,21,23)) :op2 (c3 / cell-line~e.26 :name (n4 / name :op1 "Caco-K15"~e.19,23,25)))) :ARG1-of (n / normal-02~e.10)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.28 :mod "2B"~e.30) :op2 (m / magnify-01~e.35 :ARG1 (p / panel~e.34 :ARG1-of (l2 / low-04~e.33)))))) # ::id a_pmid_2194_3101.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to determine whether Caco @-@ BR cells have acquired more mesenchymal characteristics , RNA and protein levels of the mesenchymal marker Vimentin were examined ( Figure 2C ) . # ::alignments 0-1.2.r 1-1.2.r 2-1.2.r 3-1.2 4-1.2.1.1 4-1.2.1.1.r 5-1.2.1.2.1.1 7-1.2.1.2.1.1 8-1.2.1.2 10-1.2.1 11-1.2.1.3.1 12-1.2.1.3.2.1 13-1.2.1.3 13-1.2.1.3.2 13-1.2.1.3.2.r 15-1.1.1.1.1.1 16-1.1 17-1.1.2.1 18-1.1.1 18-1.1.2 21-1.1.3.2 22-1.1.3 23-1.1.3.1.1 25-1 27-1.3.1 29-1.3.1.1 (e / examine-01~e.25 :ARG1 (a / and~e.16 :op1 (l / level~e.18 :quant-of (n3 / nucleic-acid :name (n4 / name :op1 "RNA"~e.15))) :op2 (l2 / level~e.18 :quant-of (p / protein~e.17)) :poss (m4 / marker~e.22 :name (n / name :op1 "Vimentin"~e.23) :mod (m / mesenchyme~e.21))) :purpose~e.0,1,2 (d / determine-01~e.3 :ARG1 (a2 / acquire-01~e.10 :mode~e.4 interrogative~e.4 :ARG0 (c / cell-line~e.8 :name (n2 / name :op1 "Caco-BR"~e.5,7)) :ARG1 (t / thing~e.13 :quant (m3 / more~e.11) :ARG2-of~e.13 (c2 / characteristic-02~e.13 :ARG1 m~e.12)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.27 :mod "2C"~e.29))) # ::id a_pmid_2194_3101.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok An increase of about 3 @-@ fold was observed at the protein level , while confocal images did not show significant difference , as compared to Caco @-@ 2 ( Figure 2D ) , since it is known that some cancer epithelial cells abnormally express N @-@ cadherin which has been shown to promote motility and invasion [ @ 26 , 27 @ ] , N @-@ cadherin expression was examined ( Figure 2E ) . # ::alignments 1-1.1.1.1 2-1.1.1.1.2.1.1 3-1.1.1.1.2 3-1.1.1.1.2.1 3-1.1.1.1.2.1.r 4-1.1.1.1.2.1.1.1 6-1.1.1.1.2.1.1 8-1.1.1 9-1.1.1.1.1.r 11-1.1.1.1.1.1 12-1.1.1.1.1 14-1.1 15-1.1.2.2.1 16-1.1.2.2 18-1.1.2.1 18-1.1.2.1.r 19-1.1.2 20-1.1.2.3.1 21-1.1.2.3 24-1.1.2.4.r 26-1.1.2.4.1.1 28-1.1.2.4.1.1 30-1.1.2.5.1 32-1.1.2.5.1.1 36-1.2 39-1.2.1 40-1.2.1.1.r 41-1.2.1.1.2.1 42-1.2.1.1.2.3.2.1 43-1.2.1.1.2.2 44-1.2.1.1.2 45-1.2.1.1.3 45-1.2.1.1.3.r 46-1.2.1.1 47-1.2.1.1.1.1.1 49-1.2.1.1.1.1.1 53-1.2.1.1.1.2.2 55-1.2.1.1.1 55-1.2.1.1.1.2 55-1.2.1.1.1.2.r 56-1.2.1.1.1.2.1.1 57-1.2.1.1.1.2.1 58-1.2.1.1.1.2.1.2 61-1.2.1.1.1.2.2.1.1.1.1 65-1.2.1.1.1.2.2.1.2.1.1 69-1.2.1.1.1.1.1 71-1.2.1.1.1.1.1 72-1.2.1.1 74-1.2.2 76-1.2.2.2.1 78-1.2.2.2.1.1 (a5 / and :op1 (c2 / contrast-01~e.14 :ARG1 (o / observe-01~e.8 :ARG1 (i2 / increase-01~e.1 :ARG1~e.9 (l / level~e.12 :quant-of (p5 / protein~e.11)) :ARG3 (a6 / about~e.3 :quant~e.3 (a4 / about~e.3 :op1 (p6 / product-of~e.2,6 :op1 3~e.4))))) :ARG2 (s / show-01~e.19 :polarity~e.18 -~e.18 :ARG0 (i3 / image~e.16 :mod (c8 / confocal~e.15)) :ARG1 (d4 / differ-02~e.21 :ARG1-of (s4 / significant-02~e.20)) :compared-to~e.24 (c / cell-line :name (n3 / name :op1 "Caco-2"~e.26,28)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "2D"~e.32)))) :op2 (c9 / cause-01~e.36 :ARG0 (k / know-01~e.39 :ARG1~e.40 (e2 / express-03~e.46,72 :ARG2 (p / protein~e.55 :name (n2 / name :op1 "N-cadherin"~e.47,49,69,71) :ARG0-of~e.55 (p2 / promote-01~e.55 :ARG1 (a2 / and~e.57 :op1 (m / motility~e.56) :op2 (i / invade-01~e.58)) :ARG1-of (s3 / show-01~e.53 :ARG0 (a3 / and :op1 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 26~e.61)) :op2 (p4 / publication :ARG1-of (c7 / cite-01 :ARG2 27~e.65)))))) :ARG3 (c5 / cell~e.44 :quant (s2 / some~e.41) :source (e3 / epithelium~e.43) :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.42))) :manner~e.45 (a / abnormal~e.45))) :ARG1 (e / examine-01~e.74 :ARG1 e2 :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.76 :mod "2E"~e.78))))) # ::id a_pmid_2194_3101.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In Caco @-@ BR cells N @-@ cadherin expression is increased about 2 @-@ fold both at mRNA and protein levels , as compared to Caco @-@ 2 cells . # ::alignments 1-1.1.2.1.1 1-1.4.1.1 3-1.1.2.1.1 4-1.1.2 5-1.1.1.1.1 7-1.1.1.1.1 8-1.1 10-1 11-1.2 12-1.4.1.1 14-1.2.1 16-1.3.r 17-1.3.1.1.1.1 18-1.3 19-1.3.2.1 20-1.3.1 20-1.3.2 23-1.4.r 25-1.4.1.1 27-1.4.1.1 28-1.4 (i / increase-01~e.10 :ARG1 (e / express-03~e.8 :ARG2 (p / protein :name (n2 / name :op1 "N-cadherin"~e.5,7)) :ARG3 (c2 / cell-line~e.4 :name (n3 / name :op1 "Caco-BR"~e.1,3))) :ARG2 (a2 / about~e.11 :op1 (p2 / product-of~e.14 :op1 12)) :prep-at~e.16 (a / and~e.18 :op1 (l2 / level~e.20 :mod (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.17))) :op2 (l / level~e.20 :mod (p3 / protein~e.19))) :compared-to~e.23 (c / cell-line~e.28 :name (n / name :op1 "Caco-2"~e.1,12,25,27))) # ::id a_pmid_2194_3101.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Confocal images confirmed this increase , as shown in Figure 2F @ . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1 4-1.2 6-1.3.r 7-1.3 8-1.3.1.r 9-1.3.1 11-1.3.1.1 (c / confirm-01~e.2 :ARG0 (i / images~e.1 :mod (c2 / confocal~e.0)) :ARG1 (i2 / increase-01~e.4 :mod (t / this~e.3)) :ARG1-of~e.6 (s / show-01~e.7 :ARG0~e.8 (f / figure~e.9 :mod "2F"~e.11))) # ::id a_pmid_2194_3101.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together these data suggest that BRAF @^V600E@ overexpression failed to induce an integrated EMT phenotype , which is the case with HRAS @^G12V@ overexpression [ @ 25 @ ] , but managed to transform Caco @-@ 2 cells through the loss of some important epithelial characteristics . # ::alignments 0-1.1.2 1-1.1.2.1 2-1.1.1 3-1.1 4-1 5-1.2.r 6-1.2.1.1.1.1.1 8-1.2.1.1.1.2.1 10-1.2.1.1 11-1.2.1 13-1.2.1.2 15-1.2.1.2.2.2 16-1.2.1.2.2.1 17-1.2.1.2.2 24-1.2.1.3.1.1.1.1 26-1.2.1.3.1.1.2.1 28-1.2.1.3.1 31-1.2.1.3.1.2.1.1.1 35-1.2 35-1.2.1.3 36-1.2.2 38-1.2.2.2 39-1.2.2.2.2.1.1 41-1.2.2.2.2.1.1 42-1.2.2.2.2 45-1.2.2.3 46-1.2.2.3.2.r 47-1.2.2.3.2.2.2 48-1.2.2.3.2.1 49-1.2.1.2.2.1.2 49-1.2.2.3.2.2.1 50-1.2.2.3.2 50-1.2.2.3.2.2 50-1.2.2.3.2.2.r (s / suggest-01~e.4 :ARG0 (d / data~e.3 :mod (t2 / this~e.2) :ARG1-of (t / take-01~e.0 :mod (t3 / together~e.1))) :ARG1~e.5 (c4 / contrast-01~e.35 :ARG1 (f / fail-01~e.11 :ARG1 (o / overexpress-01~e.10 :ARG1 (e3 / enzyme :name (n / name :op1 "BRAF"~e.6) :ARG1-of (m / mutate-01 :value "V600E"~e.8))) :ARG2 (i / induce-01~e.13 :ARG0 o :ARG2 (p / phenotype~e.17 :mod (t5 / transition-01~e.16 :ARG2 (m4 / mesenchyme) :ARG3 (e4 / epithelium~e.49)) :ARG1-of (i2 / integrate-01~e.15))) :ARG2-of (c5 / contrast-01~e.35 :ARG1 (o2 / overexpress-01~e.28 :ARG1 (e2 / enzyme :name (n3 / name :op1 "HRAS"~e.24) :ARG1-of (m2 / mutate-01 :value "G12V"~e.26)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 25~e.31)))))) :ARG2 (m3 / manage-02~e.36 :ARG0 o :ARG1 (t4 / transform-01~e.38 :ARG0 o :ARG1 (c2 / cell-line~e.42 :name (n4 / name :op1 "Caco-2"~e.39,41))) :manner (l / lose-02~e.45 :ARG0 c2 :ARG1~e.46 (t6 / thing~e.50 :mod (i3 / important~e.48) :ARG2-of~e.50 (c3 / characteristic-02~e.50 :ARG1 (e / epithelium~e.49) :quant (s2 / some~e.47))))))) # ::id a_pmid_2194_3101.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Differential BRAF @^V600E , KRAS @^G12V@ and HRAS @^G12V@ effect on the migration and invasion ability of Caco @-@ 2 cells in vitro # ::alignments 0-1.1.4 1-1.1.1.1.1 3-1.1.1.2.1 6-1.1.2.1.1 8-1.1.2.2.1 8-1.1.3.2.1 11-1.1.3.1.1 13-1.1.2.2.1 13-1.1.3.2.1 15-1 16-1.2.r 18-1.2.1.2 19-1.2 20-1.2.2.2 21-1.2.1 21-1.2.2 22-1.2.1.1.r 23-1.2.1.1.1.1 25-1.2.1.1.1.1 26-1.2.1.1 28-1.2.3 29-1.2.3 (a / affect-01~e.15 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "BRAF"~e.1) :ARG1-of (m / mutate-01 :value "V600E"~e.3)) :op2 (e2 / enzyme :name (n2 / name :op1 "KRAS"~e.6) :ARG1-of (m2 / mutate-01 :value "G12V"~e.8,13)) :op3 (e3 / enzyme :name (n3 / name :op1 "HRAS"~e.11) :ARG1-of (m3 / mutate-01 :value "G12V"~e.8,13)) :ARG1-of (d / differ-02~e.0)) :ARG1~e.16 (a3 / and~e.19 :op1 (c / capable-01~e.21 :ARG1~e.22 (c3 / cell-line~e.26 :name (n4 / name :op1 "Caco-2"~e.23,25)) :ARG2 (m4 / migrate-01~e.18 :ARG0 c3)) :op2 (c2 / capable-01~e.21 :ARG1 c3 :ARG2 (i / invade-01~e.20 :ARG0 c3)) :manner (i2 / in-vitro~e.28,29))) # ::id a_pmid_2194_3101.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further explore oncogenic effects on the cell cytoskeleton with regard to oncogenic transformation , the invasive and migratory properties of the previously established oncogenic cell models and in colon cancer cell lines HT29 and DLD @-@ 1 were analyzed . # ::alignments 1-1.2.3 2-1.2 4-1.2.1 5-1.2.1.2.r 7-1.2.1.2.1 8-1.2.1.2 13-1.2.2 16-1.1.1.1 17-1.1 17-1.1.1.2 18-1.1.2.1 19-1.1.1 19-1.1.2 20-1.1.1.2.r 22-1.1.1.2.1.1.1 23-1.1.1.2.1.1 25-1.1.1.2.1.3 26-1.1.1.2.1 27-1.1.1.2 29-1.1.1.2.2.2.3 30-1.1.1.2.2.2.2.1 31-1.1.1.2.2 32-1.1.1.2.2 33-1.1.1.2.2.1.1 34-1.1.1.2 35-1.1.1.2.3.1.1 37-1.1.1.2.3.1.1 39-1 (a / analyze-01~e.39 :ARG1 (a3 / and~e.17 :op1 (p / property~e.19 :mod (i / invade-01~e.16) :poss~e.20 (a4 / and~e.17,27,34 :op1 (m2 / model~e.26 :ARG1-of (e2 / establish-01~e.23 :time (p3 / previous~e.22)) :mod o :mod (c7 / cell~e.25)) :op2 (c4 / cell-line~e.31,32 :name (n / name :op1 "HT29"~e.33) :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.30) :mod (c6 / colon~e.29))) :op3 (c5 / cell-line :name (n2 / name :op1 "DLD-1"~e.35,37) :mod d))) :op2 (p2 / property~e.19 :mod (m / migrate-01~e.18) :poss a4)) :purpose (e / explore-01~e.2 :ARG1 (a2 / affect-01~e.4 :ARG0 (o / oncogene) :ARG1~e.5 (c / cytoskeleton~e.8 :part-of (c2 / cell~e.7))) :ARG2 (t / transform-01~e.13 :mod o) :degree (f / further~e.1))) # ::id a_pmid_2194_3101.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transformation induced by each of the three oncogenes KRAS @^G12V@ @ ( Caco @-@ K cells ) , BRAF @^V600E@ @ ( Caco @-@ BR cells ) and HRAS @^G12V@ @ ( Caco @-@ H cells ) managed to increase the ability of Caco @-@ 2 cells to migrate and invade in vitro , independently of their proliferating ability , which has been previously analyzed in [ @ 21 @ ] . # ::alignments 0-1.1 1-1.1.1 9-1.1.1.1.1.1.1 15-1.1.1.1.1.2.1.1 17-1.1.1.1.1.2.1.1 18-1.1.1.1.1.2 22-1.1.1.1.2.1.1 28-1.1.1.1.2.2.1.1 30-1.1.1.1.2.2.1.1 31-1.1.1.1.1.2 35-1.1.1.1.3.1.1 41-1.1.1.1.3.2.1.1 43-1.1.1.1.3.2.1.1 44-1.1.1.1.1.2 44-1.1.1.1.3.2 46-1 47-1.1.1.1.4 48-1.2 50-1.2.2 52-1.2.2.1.1.1 54-1.2.2.1.1.1 55-1.1.1.1.2.2 55-1.2.2.1 56-1.2.2.2.r 57-1.2.2.2.1 58-1.2.2.2 59-1.2.2.2.2 61-1.2.2.2.3 62-1.2.2.2.3 65-1.2.2.2.4 65-1.2.2.2.4.r 68-1.2.2.2.4.1.2 69-1.2.2.2.4.1 74-1.1.1.1.2.2.2 75-1.2.2.2.4.1.3 76-1.2.2.2.3 79-1.2.2.2.4.1.3.1.1.1 (m / manage-01~e.46 :ARG0 (t / transform-01~e.0 :ARG2-of (i / induce-01~e.1 :ARG0 (a / and :op1 (g / gene :name (n4 / name :op1 "KRAS"~e.9) :location-of (c2 / cell~e.18,31,44 :name (n / name :op1 "Caco-K"~e.15,17))) :op2 (g2 / gene :name (n5 / name :op1 "BRAF"~e.22) :location-of (c3 / cell-line~e.55 :name (n2 / name :op1 "Caco-BR"~e.28,30) :time (p3 / previous~e.74))) :op3 (g3 / gene :name (n6 / name :op1 "HRAS"~e.35) :location-of (c4 / cell-line~e.44 :name (n3 / name :op1 "Caco-H"~e.41,43))) :ARG0-of (c8 / cause-01~e.47 :ARG1 (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))) :ARG1 (i2 / increase-01~e.48 :ARG0 t :ARG1 (c5 / capable-01~e.50 :ARG1 (c6 / cell-line~e.55 :name (n7 / name :op1 "Caco-2"~e.52,54)) :ARG2~e.56 (a2 / and~e.58 :op1 (m2 / migrate-01~e.57 :ARG0 c6) :op2 (i3 / invade-01~e.59 :ARG0 c6) :manner (i4 / in-vitro~e.61,62,76) :manner~e.65 (i5 / independent~e.65 :topic (c7 / capable-01~e.69 :ARG1 c6 :ARG2 (p2 / proliferate-01~e.68 :ARG0 c6) :ARG1-of (a3 / analyze-01~e.75 :medium (p / publication :ARG1-of (c / cite-01 :ARG2 21~e.79))))))))) # ::id a_pmid_2194_3101.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More specifically , BRAF @^V600E@ @ and HRAS @^G12V@ @ provided Caco @-@ 2 cells with highly migrating and invasive properties , some similar to those in DLD @-@ 1 cells ( Figure 3A , B ) , which is compatible with their more elongated morphology described earlier ( Figure 1 ) . # ::alignments 0-1.5.1 1-1.5 4-1.1.1.1.1 6-1.1.1.2.1 9-1.1 11-1.1.2.1.1 13-1.1.2.2.1 16-1 17-1.3.1.1 19-1.3.1.1 20-1.3 21-1.2.r 21-1.4.1.r 22-1.2.1.1 23-1.2.2 25-1.2.1 26-1.2 26-1.2.3.1 28-1.2.3.1.2 29-1.2.3 32-1.2.3.1.1.r 33-1.2.3.1.1.1.1 35-1.2.3.1.1.1.1 36-1.2.3.1.1 38-1.2.3.2.1.1 38-1.2.3.2.1.2 40-1.2.3.2.1.1.1 48-1.4 49-1.4.1.r 51-1.4.1.2.1 52-1.4.1.2 53-1.4.1 54-1.2.3.2 54-1.4.1.3 55-1.4.1.3.2 57-1.4.1.3.1 59-1.4.1.3.1.1 (p / provide-01~e.16 :ARG0 (a / and~e.9 :op1 (g / gene :name (n / name :op1 "BRAF"~e.4) :ARG2-of (m / mutate-01 :value "V600E"~e.6)) :op2 (g2 / gene :name (n2 / name :op1 "HRAS"~e.11) :ARG2-of (m2 / mutate-01 :value "G12V"~e.13))) :ARG1~e.21 (p2 / property~e.26 :mod (i / invade-01~e.25 :ARG1-of (h / high-02~e.22)) :mod (m3 / migrate-01~e.23 :degree h) :ARG1-of (r / resemble-01~e.29 :ARG2 (p3 / property~e.26 :location~e.32 (c / cell-line~e.36 :name (n3 / name :op1 "DLD-1"~e.33,35)) :quant (s / some~e.28)) :ARG1-of (d / describe-01~e.54 :ARG0 (a2 / and :op1 (f / figure~e.38 :mod "3A"~e.40) :op2 (f2 / figure~e.38 :mod "3B"))))) :ARG2 (c2 / cell-line~e.20 :name (n4 / name :op1 "Caco-2"~e.17,19)) :mod (c3 / compatible~e.48 :prep-with~e.21,49 (m4 / morphology~e.53 :poss c2 :ARG1-of (e3 / elongate-01~e.52 :degree (m5 / more~e.51)) :ARG1-of (d2 / describe-01~e.54 :ARG0 (f3 / figure~e.57 :mod 1~e.59) :time (e4 / early~e.55 :degree m5)))) :ARG1-of (s2 / specific-02~e.1 :degree m5~e.0)) # ::id a_pmid_2194_3101.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , Caco @-@ K cells , that retained typical epithelial morphology of Caco @-@ 2 parental cells also presented enhanced migrating and invasive properties , but to a lesser extent . # ::alignments 0-1 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1.1 8-1.1.1.2 9-1.1.1.2.1.2 10-1.1.1.2.1.1 11-1.1.1.2.1 13-1.1.1.2.1.3.1.1 15-1.1.1.2.1.3.1.1 16-1.1.1.2.1.3.2 17-1.1.1 17-1.1.1.2.1.3 18-1.1.3 19-1.1 19-1.1.4.1 20-1.1.2.3 21-1.1.2.2 23-1.1.2.1 24-1.1.2 26-1.1.4 27-1.1.4.1.3.r 29-1.1.4.1.3 (a / and~e.0 :op2 (p / present-01~e.19 :ARG0 (c / cell~e.5,17 :name (n / name :op1 "Caco-K"~e.2,4) :ARG0-of (r / retain-01~e.8 :ARG1 (m / morphology~e.11 :mod (e / epithelium~e.10) :ARG1-of (t / typical-02~e.9) :poss (c2 / cell-line~e.17 :name (n2 / name :op1 "Caco-2"~e.13,15) :mod (p2 / parent~e.16))))) :ARG1 (p3 / property~e.24 :mod (i / invade-01~e.23) :mod (m2 / migrate-01~e.21) :ARG1-of (e2 / enhance-01~e.20)) :mod (a2 / also~e.18) :ARG1-of (c3 / contrast-01~e.26 :ARG2 (p4 / present-01~e.19 :ARG0 c :ARG1 p3 :degree~e.27 (l / less~e.29))))) # ::id a_pmid_2194_3101.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , morphological properties induced by either BRAF @^V600E@ @ or KRAS @^G12V@ @ oncogene affected the ability of Caco @-@ 2 cells to migrate and invade in vitro , but were not sufficient to fully reverse their epithelial phenotype . # ::alignments 0-1.3 1-1.3.1 3-1.1.1.1 4-1.1.1 5-1.1.1.2 9-1.1.1.2.1.1.1.1 11-1.1.1.2.1.1.2.1 14-1.1.1.2.1 16-1.1.1.2.1.2.1.1 18-1.1.1.2.1.2.2.1 22-1.1 26-1.1.2.1.1.1.1.1 28-1.1.2.1.1.1.1.1 29-1.1.2.1.1.1 31-1.1.2.1.1 32-1.1.2.1 33-1.1.2.1.2 35-1.1.2.1.3 36-1.1.2.1.3 39-1 41-1.2.1 41-1.2.1.r 42-1.2 44-1.2.3.3 45-1.2.3 46-1.2.3.2.2 46-1.2.3.2.2.r 47-1.2.3.2.1 48-1.2.3.2 (c / contrast-01~e.39 :ARG1 (a / affect-01~e.22 :ARG0 (p / property~e.4 :mod (m / morphological~e.3) :ARG2-of (i / induce-01~e.5 :ARG0 (o / or~e.14 :op1 (g / gene :name (n / name :op1 "BRAF"~e.9) :ARG2-of (m2 / mutate-01 :value "V600E"~e.11)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS"~e.16) :ARG2-of (m3 / mutate-01 :value "G12V"~e.18)) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))) :ARG1 (p2 / possible-01 :ARG1 (a2 / and~e.32 :op1 (m4 / migrate-01~e.31 :ARG0 (c2 / cell-line~e.29 :name (n3 / name :op1 "Caco-2"~e.26,28))) :op2 (i2 / invade-01~e.33 :ARG0 c2) :manner (i3 / in-vitro~e.35,36)))) :ARG2 (s / suffice-01~e.42 :polarity~e.41 -~e.41 :ARG0 p :ARG1 (r / reverse-01~e.45 :ARG0 p :ARG1 (p3 / phenotype~e.48 :mod (e / epithelium~e.47) :poss~e.46 c2~e.46) :degree (f / full~e.44))) :ARG1-of (t / take-01~e.0 :mod (t2 / together~e.1))) # ::id a_pmid_2194_3101.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The role of BRAF @ and KRAS @ oncogenes in altering cytoskeletal properties was further emphasized following depletion of BRAF @^V600E@ by shRNA in HT29 cells , where migration ability of HT @-@ ShBR3 cells , with downregulated expression of mt @ BRAF @ gene , was significantly impaired as compared to the empty vector control HT @-@ ps cells . # ::alignments 1-1.1 4-1.1.1.1.1.1 6-1.1.1 8-1.1.1.2.1.1 11-1.1.2.r 12-1.1.2 14-1.1.2.2 16-1.2 17-1 18-1.3 19-1.3.1 20-1.3.1.2.r 21-1.3.1.2.1.1 23-1.3.1.2.2.1 25-1.3.1.1.r 26-1.3.1.1.1.1 27-1.3.1.3.r 28-1.3.1.3.1.1 29-1.3.1.3 31-1.3.1.3.2.r 32-1.3.1.3.2.1.1 34-1.3.1.3.2.1.1.1.r 35-1.3.1.3.2.1.1.1.1.1 37-1.3.1.3.2.1.1.1.1.1 38-1.3.1.3.2.1.1.1 40-1.3.1.3.2.1.2.r 41-1.3.1.3.2.1.2.2 42-1.3.1.3.2.1.2 46-1.3.1.3.2.1.2.1.1.1 48-1.1.1.1 48-1.1.1.2 48-1.3.1.3.2.1.2.1 51-1.3.1.3.2.2 52-1.3.1.3.2 53-1.3.1.3.2.3.r 54-1.3.1.3.2.3 55-1.3.1.3.2.3.1.r 57-1.3.1.3.2.3.1.2.1.1 58-1.3.1.3.2.3.1.2.1 59-1.3.1.3.2.3.1.2 60-1.3.1.3.2.3.1.1.1 62-1.3.1.3.2.3.1.1.1 63-1.3.1.3.2.3.1 (e / emphasize-01~e.17 :ARG1 (r / role~e.1 :poss (a / and~e.6 :op1 (g2 / gene~e.48 :name (n / name :op1 "BRAF"~e.4)) :op2 (g3 / gene~e.48 :name (n2 / name :op1 "KRAS"~e.8)) :ARG0-of (c7 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n10 / name :op1 "cancer")))) :topic~e.11 (a2 / alter-01~e.12 :ARG0 a :ARG1 (p / property~e.14 :mod (c / cytoskeleton)))) :degree (f / further~e.16) :ARG1-of (f2 / follow-01~e.18 :ARG2 (d / deplete-01~e.19 :ARG0~e.25 (n9 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.26)) :ARG1~e.20 (e2 / enzyme :name (n4 / name :op1 "BRAF"~e.21) :ARG2-of (m / mutate-01 :value "V600E"~e.23)) :location~e.27 (c2 / cell-line~e.29 :name (n5 / name :op1 "HT29"~e.28) :location-of~e.31 (i / impair-01~e.52 :ARG1 (p2 / possible-01 :ARG1 (m2 / migrate-01~e.32 :ARG0~e.34 (c3 / cell-line~e.38 :name (n6 / name :op1 "HT-ShBR3"~e.35,37))) :accompanier~e.40 (e3 / express-03~e.42 :ARG1 (g / gene~e.48 :name (n7 / name :op1 "BRAF"~e.46) :ARG2-of (m3 / mutate-01)) :ARG1-of (d2 / downregulate-01~e.41))) :ARG1-of (s / significant-02~e.51) :ARG1-of~e.53 (c4 / compare-01~e.54 :ARG2~e.55 (c5 / cell-line~e.63 :name (n8 / name :op1 "HT-ps"~e.60,62) :ARG2-of (c6 / control-01~e.59 :ARG0 (v / vector~e.58 :ARG1-of (e4 / empty-02~e.57)))))))))) # ::id a_pmid_2194_3101.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , knock out of KRAS @^G13D@ in DLD @-@ 1 cells ( DKO @-@ 4 ) [ @ 28 @ ] significantly reverted the migration ability of DLD @-@ 1 cells ( Figure 3C ) . # ::alignments 0-1.4 2-1.1 3-1.1 4-1.1.1.r 5-1.1.1.1.1 7-1.1.1.2.1 9-1.1.2.r 10-1.1.2 11-1.1.2 12-1.1.2 13-1.1.3.1 13-1.2.1.1 15-1.1.3.1.1.1 17-1.1.3.1.1.1 21-1.1.4.1.1.1 24-1.3 25-1 27-1.2.1 30-1.2.1.1.1.1 32-1.2.1.1.1.1 33-1.2.1.1 35-1.5.1 37-1.5.1.1 (r / revert-01~e.25 :ARG0 (k / knock-out-03~e.2,3 :ARG1~e.4 (e / enzyme :name (n2 / name :op1 "KRAS"~e.5) :ARG2-of (m2 / mutate-01 :value "G13D"~e.7)) :location~e.9 c~e.10,11,12 :ARG1-of (d / describe-01 :ARG0 (c2 / cell-line~e.13 :name (n3 / name :op1 "DKO-4"~e.15,17))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 28~e.21)))) :ARG1 (p / possible-01 :ARG1 (m / migrate-01~e.27 :ARG0 (c / cell-line~e.13,33 :name (n / name :op1 "DLD-1"~e.30,32)))) :ARG1-of (s / significant-02~e.24) :mod (l / likewise~e.0) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.35 :mod "3C"~e.37))) # ::id a_pmid_2194_3101.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @^V600E@ enhances the ability of Caco @-@ 2 cells to migrate and invade in vitro @ through RhoA activation # ::alignments 0-1.1.1.1 2-1.1.2.1 4-1 8-1.2.1.1.1.1.1 10-1.2.1.1.1.1.1 11-1.2.1.1.1 13-1.2.1.1 14-1.2.1 15-1.2.1.2 17-1.2.1.3 18-1.2.1.3 21-1.3.1.1.1 22-1.3 (e / enhance-01~e.4 :ARG0 (e2 / enzyme :name (n / name :op1 "BRAF"~e.0) :ARG2-of (m / mutate-01 :value "V600E"~e.2)) :ARG1 (p / possible-01 :ARG1 (a / and~e.14 :op1 (m2 / migrate-01~e.13 :ARG0 (c / cell-line~e.11 :name (n2 / name :op1 "Caco-2"~e.8,10))) :op2 (i / invade-01~e.15 :ARG0 c) :manner (i2 / in-vitro~e.17,18))) :manner (a2 / activate-01~e.22 :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA"~e.21)))) # ::id a_pmid_2194_3101.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of BRAF @^V600E@ in Caco @-@ 2 cells had a profound effect on the RAS effector protein RhoA ( Figure 4 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 4-1.1.1.2.1 6-1.1.2.r 7-1.1.2.1.1 9-1.1.2.1.1 10-1.1.2 13-1.3 14-1 15-1.2.r 17-1.2.2.1.1.1 18-1.2.2 19-1.2 19-1.2.2.1 20-1.2.1.1 22-1.4.1 24-1.4.1.1 (a / affect-01~e.14 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "BRAF"~e.2) :ARG2-of (m / mutate-01 :value "V600E"~e.4)) :location~e.6 (c / cell-line~e.10 :name (n2 / name :op1 "Caco-2"~e.7,9))) :ARG1~e.15 (p / protein~e.19 :name (n3 / name :op1 "RhoA"~e.20) :mod (e2 / effector~e.18 :mod (p3 / protein-family~e.19 :name (n4 / name :op1 "RAS"~e.17)))) :degree (p2 / profound~e.13) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.22 :mod 4~e.24))) # ::id a_pmid_2194_3101.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In Caco @-@ BR cells activation of RhoA is increased ( Figure 4A ) as well as phosphorylation of its downstream target Cofilin , a protein that is related to stress fibre formation ( Figure 4B ) . # ::alignments 1-1.1.2.1.2.1.1.1 3-1.1.2.1.2.1.1.1 4-1.1.2.1.2.1 5-1.1.1 7-1.1.1.1.1.1 9-1 11-1.1.1.2.1 13-1.1.1.2.1.1 16-1.1 17-1.1 18-1.1 19-1.1.2 22-1.1.2.1.2.2 23-1.1.2.1.2 24-1.1.2.1.1.1 27-1.1.1.1 27-1.1.2.1 30-1.1.2.1.3 31-1.1.2.1.3.1.r 32-1.1.2.1.3.1.1.1 34-1.1.2.1.3.1 36-1.1.2.2.1 38-1.1.2.2.1.1 (i / increase-01~e.9 :ARG1 (a / and~e.16,17,18 :op1 (a2 / activate-01~e.5 :ARG1 (p / protein~e.27 :name (n / name :op1 "RhoA"~e.7)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "4A"~e.13))) :op2 (p2 / phosphorylate-01~e.19 :ARG1 (p3 / protein~e.27 :name (n2 / name :op1 "Cofilin"~e.24) :ARG1-of (t / target-01~e.23 :ARG0 (c / cell-line~e.4 :name (n3 / name :op1 "Caco-BR"~e.1,3)) :location (d2 / downstream~e.22)) :ARG1-of (r / relate-01~e.30 :ARG2~e.31 (f2 / form-01~e.34 :ARG1 (f3 / fiber :mod (s / stress~e.32))))) :ARG1-of (d3 / describe-01 :ARG0 (f4 / figure~e.36 :mod "4B"~e.38)))) :location c) # ::id a_pmid_2194_3101.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings are closely related to the observation regarding increased stress fibre formation indicated by phalloidin staining in Caco @-@ BR13 cells ( Figure 1 ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1.3 4-1 5-1.2.r 7-1.2 8-1.2.1 9-1.2.1.1.2 10-1.2.1.1.1.1 12-1.2.1.1 13-1.2.1.1.3 14-1.2.1.1.3.1.r 15-1.2.1.1.3.1.1.1.1 16-1.2.1.1.3.1 17-1.2.1.1.3.1.2.r 18-1.2.1.1.3.1.2.1.1 20-1.2.1.1.3.1.2.1.1 21-1.2.1.1.3.1.2 23-1.4.1 25-1.4.1.1 (r / relate-01~e.4 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :mod (t2 / this~e.0)) :ARG2~e.5 (o / observe-01~e.7 :ARG0-of (r2 / regard-01~e.8 :ARG1 (f2 / form-01~e.12 :ARG1 (f3 / fiber :mod (s / stress~e.10)) :ARG1-of (i / increase-01~e.9) :ARG1-of (i2 / indicate-01~e.13 :ARG0~e.14 (s2 / stain-01~e.16 :ARG2 (s3 / small-molecule :name (n / name :op1 "phalloidin"~e.15)) :location~e.17 (c / cell-line~e.21 :name (n2 / name :op1 "Caco-BR13"~e.18,20))))))) :ARG1-of (c2 / close-10~e.3) :ARG1-of (d / describe-01 :ARG0 (f4 / figure~e.23 :mod 1~e.25))) # ::id a_pmid_2194_3101.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , an extra band of lower molecular weight is detected for RhoA in Caco @-@ BR and DLD @-@ 1 cells , which potentially represents the main active GTPase form ( Figure 4A ) . # ::alignments 0-1.3 3-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.2 6-1.1.2.2.1 6-1.1.2.2.1.r 7-1.1.2.1 8-1.1.2 10-1 11-1.1.3.r 12-1.1.3.1.1 13-1.2.r 14-1.2.1.1.1 16-1.2.1.1.1 17-1.2 18-1.2.2.1.1 20-1.2.2.1.1 21-1.2.1 21-1.2.2 24-1.1.4.2 25-1.1.4 27-1.1.4.1.3 29-1.1.4.1.1.1.1 30-1.1.4.1 32-1.4.1 34-1.4.1.1 (d / detect-01~e.10 :ARG1 (b / band~e.4 :mod (e / extra~e.3) :ARG1-of~e.5 (w / weight-01~e.8 :mod (m / molecule~e.7) :ARG1-of (l / low-04~e.6 :degree~e.6 (m2 / more~e.6))) :mod~e.11 (p / protein :name (n / name :op1 "RhoA"~e.12)) :ARG0-of (r / represent-01~e.25 :ARG1 (f / form~e.30 :mod (e2 / enzyme :name (n4 / name :op1 "GTPase"~e.29)) :ARG1-of (a / activate-01) :mod (m3 / main~e.27)) :mod (p2 / potential~e.24))) :location~e.13 (a2 / and~e.17 :op1 (c / cell-line~e.21 :name (n2 / name :op1 "Caco-BR"~e.14,16)) :op2 (c2 / cell-line~e.21 :name (n3 / name :op1 "DLD-1"~e.18,20))) :ARG1-of (n5 / notable-04~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.32 :mod "4A"~e.34))) # ::id a_pmid_2194_3101.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A variant of lower molecular weight for RhoA protein has previously been reported both in colon and breast tissues [ @ 7 @ ] . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 3-1.1.1.2.1 3-1.1.1.2.1.r 4-1.1.1.1 5-1.1.1 6-1.1.2.r 7-1.1.2.1.1 8-1.1.2 10-1.2 12-1 14-1.3.r 15-1.3.1.1 16-1.3 17-1.3.2.1 18-1.3.1 18-1.3.2 21-1.4.1.1.1 (r / report-01~e.12 :ARG1 (v / variant~e.1 :ARG1-of~e.2 (w / weight-01~e.5 :mod (m / molecule~e.4) :ARG1-of (l / low-04~e.3 :degree~e.3 (m2 / more~e.3))) :poss~e.6 (p / protein~e.8 :name (n / name :op1 "RhoA"~e.7))) :time (p2 / previous~e.10) :location~e.14 (a / and~e.16 :op1 (t / tissue~e.18 :part-of (c / colon~e.15)) :op2 (t2 / tissue~e.18 :part-of (b / breast~e.17))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 7~e.21)))) # ::id a_pmid_2194_3101.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , RT @-@ PCR analysis and treatment with the proteasome inhibitor MG @-@ 132 , both in Caco @-@ BR and DLD @-@ 1 cells , suggested no association of this faster migrating RhoA band with alternative splicing or proteasomal degradation ( data not shown ) . # ::alignments 0-1 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1 6-1.1.1.3 6-1.1.1.3.r 7-1.1.1.2 8-1.1.1.1.1.r 8-1.1.1.2.1.r 10-1.1.1.2.1.2.1.1.1 11-1.1.1.2.1 11-1.1.1.2.1.2 11-1.1.1.2.1.2.r 12-1.1.1.2.1.1.1 14-1.1.1.2.1.1.1 18-1.1.1.3.1.1.1 20-1.1.1.3.1.1.1 21-1.1.1.3 22-1.1.1.3.2.1.1 24-1.1.1.3.2.1.1 25-1.1.1.3.1 25-1.1.1.3.2 27-1.1 28-1.1.2.1 28-1.1.2.1.r 29-1.1.2 30-1.1.2.2.r 31-1.1.2.2.3 32-1.1.2.2.2.1 32-1.1.2.2.2.1.1 32-1.1.2.2.2.1.1.r 33-1.1.2.2.2 34-1.1.2.2.1.1.1 35-1.1.2.2 36-1.1.1.1.1.r 38-1.1.2.3.1 39-1.1.2.3 41-1.1.2.3.2 43-1.2.1 44-1.2.1.1.1 44-1.2.1.1.1.r 45-1.2.1.1 (h / have-concession-91~e.0 :ARG1 (s / suggest-01~e.27 :ARG0 (a / and~e.6 :op1 (a2 / analyze-01~e.5 :instrument~e.8,36 (t3 / thing :name (n / name :op1 "RT-PCR"~e.2,4))) :op2 (t / treat-04~e.7 :ARG2~e.8 (s2 / small-molecule~e.11 :name (n2 / name :op1 "MG-132"~e.12,14) :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1 (e / enzyme :name (n3 / name :op1 "proteasome"~e.10))))) :location~e.6 (a3 / and~e.6,21 :op1 (c / cell-line~e.25 :name (n4 / name :op1 "Caco-BR"~e.18,20)) :op2 (c2 / cell-line~e.25 :name (n5 / name :op1 "DLD-1"~e.22,24)))) :ARG1 (a4 / associate-01~e.29 :polarity~e.28 -~e.28 :ARG1~e.30 (b / band~e.35 :mod (p2 / protein :name (n6 / name :op1 "RhoA"~e.34)) :ARG0-of (m / migrate-01~e.33 :ARG1-of (f / fast-02~e.32 :degree~e.32 (m2 / more~e.32))) :mod (t2 / this~e.31)) :ARG2 (o / or~e.39 :op1 (s3 / splice-01~e.38 :ARG1-of (a5 / alternate-01)) :op2 (d / degrade-01~e.41 :ARG1 e)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.43 :ARG1-of (s4 / show-01~e.45 :polarity~e.44 -~e.44)))) # ::id a_pmid_2194_3101.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggested that the additional band potentially represents a post @-@ translational modification of RhoA protein . # ::alignments 0-1.1.1 1-1.1 2-1 6-1.2.1 7-1.2.3 8-1.2 10-1.2.2.2 12-1.2.2.2.1 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.1.1 16-1.2.2.1 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1 (r / represent-01~e.8 :ARG0 (b / band~e.6 :ARG1-of (a / add-02)) :ARG1 (m / modify-01~e.13 :ARG1~e.14 (p / protein~e.16 :name (n / name :op1 "RhoA"~e.15)) :time (a2 / after~e.10 :op1 (t2 / translate-02~e.12))) :mod (p3 / potential~e.7))) # ::id a_pmid_2194_3101.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further explore the role of BRAF @^V600E@ in the activation of the RhoA pathway , transient transfection of the oncogene in Caco @-@ 2 cells was performed ( Additional Figure 2 ) . # ::alignments 1-1.2.2 2-1.2 4-1.2.1 5-1.2.1.1.r 6-1.2.1.1.1.1 8-1.2.1.1.2.1 10-1.2.1.2.r 12-1.2.1.2 13-1.2.1.2.1.r 15-1.2.1.2.1.1.1 16-1.2.1.2.1 18-1.1.3 19-1.1 20-1.1.2.r 22-1.1.2 23-1.1.1.r 24-1.1.1.1.1 26-1.1.1.1.1 27-1.1.1 29-1 32-1.3.1 34-1.3.1.1 (p / perform-02~e.29 :ARG1 (t / transfect-01~e.19 :ARG1~e.23 (c / cell-line~e.27 :name (n / name :op1 "Caco-2"~e.24,26)) :ARG2~e.20 (o / oncogene~e.22) :ARG1-of (t2 / transient-02~e.18)) :purpose (e / explore-01~e.2 :ARG1 (r / role~e.4 :poss~e.5 (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.6) :ARG2-of (m / mutate-01 :value "V600E"~e.8)) :topic~e.10 (a / activate-01~e.12 :ARG1~e.13 (p2 / pathway~e.16 :name (n3 / name :op1 "RhoA"~e.15)))) :degree (f / further~e.1)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.32 :mod 2~e.34 :ARG1-of (a2 / add-02)))) # ::id a_pmid_2194_3101.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Subsequent analysis of the migration and invasion properties showed that moderate RhoA activation induced a partial cell migration and cell invasion response ( Addition Figure 2A , B ) . # ::alignments 0-1.1.2 0-1.1.2.r 1-1.1 2-1.1.1.r 4-1.1.1.2 6-1.1.1.1 7-1.1.1 8-1 9-1.2.r 10-1.2.1.2 11-1.2.1.1.1.1 12-1.2.1 13-1.2 15-1.2.2.3 15-1.2.2.3.r 16-1.2.2.1.1.1 17-1.2.2.1.1 19-1.2.2.1.1.1 20-1.2.2.2.1 21-1.2.2.1 21-1.2.2.2 23-1.3.1.3 24-1.3.1.1 24-1.3.1.2 26-1.3.1.1.1 (s / show-01~e.8 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (p / property~e.7 :mod (i / invade-01~e.6) :mod (m / migrate-01~e.4)) :time~e.0 (s2 / subsequent~e.0)) :ARG1~e.9 (i2 / induce-01~e.13 :ARG0 (a2 / activate-01~e.12 :ARG1 (p2 / protein :name (n / name :op1 "RhoA"~e.11)) :ARG1-of (m2 / moderate-03~e.10)) :ARG2 (a3 / and :op1 (r / respond-01~e.21 :ARG2 (m3 / migrate-01~e.17 :ARG0 (c / cell~e.16,19))) :op2 (r2 / respond-01~e.21 :ARG2 (i3 / invade-01~e.20 :ARG0 c)) :degree~e.15 (p3 / part~e.15))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.24 :mod "2A"~e.26) :op2 (f2 / figure~e.24 :mod "2B") :ARG1-of (a5 / add-02~e.23)))) # ::id a_pmid_2194_3101.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably in the invasion assay cell phenotype became slightly altered and resembled that of the stable Caco @-@ BR clones ( Additional Figure 2C ) , suggesting that a stable expression of BRAF @^V600E@ is required to achieve complete cell transformation and extensive RhoA activation . # ::alignments 0-1.3 3-1.4.1 4-1.4 5-1.2.2.1.1 6-1.1.1 6-1.2.2 7-1.1 8-1.1.2.2 9-1.1.2 10-1 11-1.2 15-1.2.2.1.2 16-1.2.2.1.1.1.1 18-1.2.2.1.1.1.1 19-1.2.2.1 22-1.5.1 24-1.5.1.1 28-1.6 29-1.6.1.r 31-1.6.1.2.2 32-1.6.1.2 33-1.6.1.2.1.r 34-1.6.1.2.1.1.1 36-1.6.1.2.1.2.1 39-1.6.1 41-1.6.1.1 42-1.6.1.1.1.1.2 43-1.1.1.1 44-1.6.1.1.1.1 45-1.6.1.1.1 46-1.6.1.1.1.2.2 47-1.6.1.1.1.2.1.1.1 48-1.6.1.1.1.2 (a / and~e.10 :op1 (b / become-01~e.7 :ARG1 (p / phenotype~e.6 :mod (c / cell~e.43)) :ARG2 (a2 / alter-01~e.9 :ARG1 p :degree (s / slight~e.8))) :op2 (r / resemble-01~e.11 :ARG1 p :ARG2 (p2 / phenotype~e.6 :poss (c2 / clone-01~e.19 :ARG1 (c3 / cell-line~e.5 :name (n / name :op1 "Caco-BR"~e.16,18)) :ARG1-of (s2 / stable-03~e.15)))) :ARG1-of (n2 / notable-04~e.0) :time (a3 / assay-01~e.4 :ARG1 (i / invade-01~e.3)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.22 :mod "2C"~e.24 :ARG1-of (a4 / add-02))) :ARG0-of (s3 / suggest-01~e.28 :ARG1~e.29 (r2 / require-01~e.39 :ARG0 (a5 / achieve-01~e.41 :ARG1 (a6 / and~e.45 :op1 (t / transform-01~e.44 :ARG1 c :ARG1-of (c4 / complete-02~e.42)) :op2 (a7 / activate-01~e.48 :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA"~e.47)) :ARG1-of (e / extensive-03~e.46)))) :ARG1 (e2 / express-03~e.32 :ARG2~e.33 (e3 / enzyme :name (n4 / name :op1 "BRAF"~e.34) :ARG2-of (m / mutate-01 :value "V600E"~e.36)) :ARG1-of s2~e.31)))) # ::id a_pmid_2194_3101.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regarding the importance of RhoA activation in the induced cell migration and invasion observed in Caco @-@ BR cells , siRNA against RhoA was performed leading to significant protein depletion in both Caco @-@ 2 and Caco @-@ BR13 cells ( Figure 5A ) . # ::alignments 0-1.2.r 2-1.2 4-1.2.1.1 5-1.2.1 6-1.2.1.2.r 8-1.2.1.2.3 9-1.2.1.2.4.1 9-1.3.1.3.2 10-1.2.1.2.1 11-1.2.1.2 12-1.2.1.2.2 13-1.2.1.2.4 15-1.2.1.2.4.1.1.1 17-1.2.1.2.4.1.1.1 18-1.2.1.2.1.1 20-1.1.1.1 21-1.1 21-1.1.2 21-1.1.2.r 22-1.1.2.1.1.1 23-1.2.1.r 24-1 25-1.3 26-1.3.1.r 27-1.3.1.2 28-1.3.1.1 29-1.3.1 32-1.3.1.3.1.1.1 34-1.3.1.3.1.1.1 35-1.3.1.3 36-1.3.1.3.1.1.1 36-1.3.1.3.2.1.1 38-1.3.1.3.2.1.1 39-1.3.1.3.1 41-1.4.1 43-1.4.1.1 (p / perform-02~e.24 :ARG1 (n6 / nucleic-acid~e.21 :name (n / name :op1 "siRNA"~e.20) :ARG0-of~e.21 (o / oppose-01~e.21 :ARG1 (p2 / protein :name (n2 / name :op1 "RhoA"~e.22)))) :topic~e.0 (i / important~e.2 :domain~e.23 (a / activate-01~e.5 :ARG1 p2~e.4 :location~e.6 (a2 / and~e.11 :op1 (m / migrate-01~e.10 :ARG0 (c / cell~e.18)) :op2 (i2 / invade-01~e.12 :ARG0 c) :ARG2-of (i3 / induce-01~e.8) :ARG1-of (o2 / observe-01~e.13 :location (c2 / cell-line~e.9 :name (n3 / name :op1 "Caco-BR"~e.15,17)))))) :ARG0-of (l / lead-03~e.25 :ARG2~e.26 (d / deplete-01~e.29 :ARG1 (p3 / protein~e.28) :ARG1-of (s / significant-02~e.27) :location (a3 / and~e.35 :op1 (c3 / cell-line~e.39 :name (n4 / name :op1 "Caco-2"~e.32,34,36)) :op2 (c4 / cell-line~e.9 :name (n5 / name :op1 "Caco-BR13"~e.36,38))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.41 :mod "5A"~e.43))) # ::id a_pmid_2194_3101.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Depletion of RhoA substantially impaired both acquired properties with more profound effect in Caco @-@ BR13 cells , further illustrating its central role in the BRAF @^V600E@ oncogene @-@ induced transformation of colon adenocarcinoma cells ( Figure 5B ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.3 4-1 5-1.2.2 6-1.2.1 7-1.2 8-1.4.r 9-1.4.1.1 10-1.4.1 11-1.4 12-1.4.2.r 13-1.4.2.1.1 15-1.4.2.1.1 16-1.4.2 18-1.5.2 19-1.5 20-1.5.1.1 20-1.5.1.1.r 21-1.5.1.3 22-1.5.1 23-1.5.1.2.r 25-1.5.1.2.2.1.1.1 27-1.5.1.2.2.1.2.1 31-1.5.1.2.2 32-1.5.1.2 33-1.5.1.2.1.r 34-1.5.1.2.1.1.1 35-1.5.1.2.1.1 36-1.5.1.2.1 38-1.6.1 40-1.6.1.1 (i / impair-01~e.4 :ARG0 (d / deplete-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "RhoA"~e.2))) :ARG1 (p2 / property~e.7 :ARG1-of (a / acquire-01~e.6) :mod (b / both~e.5)) :degree (s / substantial~e.3) :ARG0-of~e.8 (a2 / affect-01~e.11 :degree (p3 / profound~e.10 :degree (m / more~e.9)) :location~e.12 (c / cell-line~e.16 :name (n2 / name :op1 "Caco-BR13"~e.13,15))) :ARG0-of (i2 / illustrate-01~e.19 :ARG1 (r / role~e.22 :poss~e.20 d~e.20 :topic~e.23 (t / transform-01~e.32 :ARG1~e.33 (c2 / cell~e.36 :mod (a3 / adenocarcinoma~e.35 :mod (c3 / colon~e.34))) :ARG2-of (i3 / induce-01~e.31 :ARG0 (g / gene :name (n3 / name :op1 "BRAF"~e.25) :ARG2-of (m2 / mutate-01 :value "V600E"~e.27) :ARG0-of (c5 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))) :mod (c4 / central~e.21)) :mod (f / further~e.18)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.38 :mod "5B"~e.40))) # ::id a_pmid_2194_3101.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , following RhoA depletion in Caco @-@ 2 cells , the number and size of stress fibres were notably reduced as compared to Caco @-@ BR cells , where no such alteration was observed ( data not shown ) . # ::alignments 0-1.1.1 2-1.1.4 3-1.1.4.1.1.1.1 4-1.1.4.1 5-1.1.4.1.2.r 6-1.1.4.1.2.1.1 8-1.1.4.1.2.1.1 9-1.1.4.1.2 12-1.1.1.1 13-1.1.1 14-1.1.1.2 16-1.1.1.3.1 19-1.1.2 20-1.1 22-1.1.3.r 24-1.1.3.1.1 26-1.1.3.1.1 27-1.1.3 29-1.1.3.2.r 30-1.1.3.2.1.1 30-1.1.3.2.1.1.r 31-1.1.3.2.1.2 32-1.1.3.2.1 34-1.1.3.2 36-1.2.1 37-1.2.1.1.1 37-1.2.1.1.1.r 38-1.2.1.1 (a / and :op2 (r / reduce-01~e.20 :ARG1 (a2 / and~e.0,13 :op1 (n / number~e.12) :op2 (s / size~e.14) :quant-of (f / fiber :mod (s2 / stress~e.16))) :ARG2 (n3 / notable-04~e.19) :compared-to~e.22 (c / cell-line~e.27 :name (n2 / name :op1 "Caco-BR"~e.24,26) :location-of~e.29 (o / observe-01~e.34 :ARG1 (a3 / alter-01~e.32 :polarity~e.30 -~e.30 :mod (s3 / such~e.31)))) :ARG1-of (f2 / follow-01~e.2 :ARG2 (d / deplete-01~e.4 :ARG1 (p / protein :name (n4 / name :op1 "RhoA"~e.3)) :location~e.5 (c2 / cell-line~e.9 :name (n5 / name :op1 "Caco-2"~e.6,8))))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.36 :ARG1-of (s4 / show-01~e.38 :polarity~e.37 -~e.37)))) # ::id a_pmid_2194_3101.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to study further the impact of RhoA GTPase on cell migration , silencing of RhoA was performed in DLD @-@ 1 and HT29 cells . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 4-1.3.2 6-1.3.1 7-1.3.1.1.r 8-1.3.1.1.1.1 9-1.3.1.1.1.2 10-1.3.1.2.r 11-1.3.1.2.1 12-1.3.1.2 14-1.1 15-1.1.1.r 16-1.1.1.1.1 18-1 19-1.2.r 20-1.2.1.1.1 22-1.2.1.1.1 23-1.2 24-1.2.2.1.1 25-1.2.1 25-1.2.2 (p / perform-02~e.18 :ARG1 (s / silence-01~e.14 :ARG1~e.15 (p2 / protein :name (n / name :op1 "RhoA"~e.16))) :location~e.19 (a / and~e.23 :op1 (c / cell-line~e.25 :name (n2 / name :op1 "DLD-1"~e.20,22)) :op2 (c2 / cell-line~e.25 :name (n3 / name :op1 "HT29"~e.24))) :purpose~e.0,1,2 (s2 / study-01~e.3 :ARG1 (i / impact-01~e.6 :ARG0~e.7 (p3 / pathway :name (n4 / name :op1 "RhoA"~e.8 :op2 "GTPase"~e.9)) :ARG1~e.10 (m / migrate-01~e.12 :ARG0 (c3 / cell~e.11))) :degree (f / further~e.4))) # ::id a_pmid_2194_3101.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Considering that these cell lines bear mutation in KRAS @^G13D@ and BRAF @^V600E@ respectively , RhoA depletion was also performed in selected clones where KRAS @^G13D@ ( DKO4 ) or BRAF @^V600E@ ( HTshBR3 ) was knocked out or down regulated via shRNA respectively . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.1.1 3-1.4.1.1 4-1.4.1.1 5-1.4.1 6-1.3.1.1 6-1.3.1.1.2 6-1.3.1.1.2.r 6-1.3.2.1 6-1.3.2.1.2 6-1.3.2.1.2.r 6-1.4.1.2 8-1.3.1.1.1.1 10-1.3.1.1.2.1 13-1.3.2.1.1.1 15-1.3.2.1.2.1 17-1.3.3.2 19-1.1.1.1.1 20-1.1 22-1.2 23-1 25-1.3.1.2 26-1.3.1 26-1.3.2 27-1.3.r 28-1.3.1.1.1.1 30-1.3.1.1.2.1 33-1.3.1.1.3.1.1.1 35-1.3 36-1.3.2.1.1.1 38-1.3.2.1.2.1 41-1.3.2.1.3.1.1.1 44-1.3.3 45-1.3.3 46-1.3 50-1.3.3.1.1.1 51-1.3.3.2 (p / perform-02~e.23 :ARG1 (d / deplete-01~e.20 :ARG1 (p2 / protein :name (n / name :op1 "RhoA"~e.19))) :mod (a / also~e.22) :location~e.27 (o / or~e.35,46 :op1 (c / clone-01~e.26 :ARG1 (e / enzyme~e.6 :name (n2 / name :op1 "KRAS"~e.8,28) :ARG2-of~e.6 (m / mutate-01~e.6 :value "G13D"~e.10,30) :ARG1-of (d2 / describe-01 :ARG0 (c2 / cell :name (n3 / name :op1 "DKO4"~e.33)))) :ARG1-of (s / select-01~e.25)) :op2 (c3 / clone-01~e.26 :ARG1 (e2 / enzyme~e.6 :name (n4 / name :op1 "BRAF"~e.13,36) :ARG2-of~e.6 (m2 / mutate-01~e.6 :value "V600E"~e.15,38) :ARG1-of (d3 / describe-01 :ARG0 (c4 / cell :name (n5 / name :op1 "HTshBR3"~e.41)))) :ARG1-of s) :ARG1-of (k / knock-out-03~e.44,45 :ARG2 (n7 / nucleic-acid :name (n6 / name :op1 "shRNA"~e.50)) :mod (r2 / respective~e.17,51)) :ARG1-of (d4 / downregulate-01 :mod r2 :instrument n7)) :ARG2-of (c5 / consider-02~e.0 :ARG1~e.1 (b / bear-01~e.5 :ARG0 (c6 / cell-line~e.3,4 :mod (t / this~e.2)) :ARG1 (m3 / mutate-01~e.6) :location (a2 / and :op1 e :op2 e2 :mod r2)))) # ::id a_pmid_2194_3101.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This approach can implement the connection between each oncogene and the small GTPase . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 3-1.1 5-1.1.2 7-1.1.2.1.1 8-1.1.2.1 11-1.1.2.2.2 12-1.1.2.2.1.1 (p / possible-01~e.2 :ARG1 (i / implement-01~e.3 :ARG0 (a / approach-02~e.1 :mod (t / this~e.0)) :ARG1 (c / connect-01~e.5 :ARG1 (o / oncogene~e.8 :mod (e / each~e.7)) :ARG1 (p2 / protein-family :name (n / name :op1 "GTPase"~e.12) :mod (s / small~e.11))))) # ::id a_pmid_2194_3101.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After silencing of RhoA , cell migration was significantly reduced in DLD @-@ 1 , while no reduction was observed in DKO4 cells , where mutant KRAS @^G13D@ is knocked out , ( Figure 5C ) . # ::alignments 0-1.3 1-1.3.1 2-1.3.1.1.r 3-1.3.1.1.1.1 5-1.1.1.1 6-1.1.1 8-1.1.2 9-1.1 10-1.1.3.r 11-1.1.3.1.1 13-1.1.3.1.1 15-1 15-1.3.r 16-1.2.1.1 16-1.2.1.1.r 17-1.2.1 19-1.2 20-1.2.2.r 21-1.2.2.1.1 22-1.2.2 24-1.2.2.2.r 25-1.2.2.2.1 25-1.2.2.2.1.2 25-1.2.2.2.1.2.r 26-1.2.2.2.1.1.1 28-1.2.2.2.1.2.1 31-1.2.2.2 32-1.2.2.2 35-1.4.1 37-1.4.1.1 (c / contrast-01~e.15 :ARG1 (r / reduce-01~e.9 :ARG1 (m / migrate-01~e.6 :ARG0 (c2 / cell~e.5)) :ARG2 (s / significant-02~e.8) :location~e.10 (c3 / cell-line :name (n / name :op1 "DLD-1"~e.11,13))) :ARG2 (o / observe-01~e.19 :ARG1 (r2 / reduce-01~e.17 :polarity~e.16 -~e.16) :location~e.20 (c4 / cell-line~e.22 :name (n2 / name :op1 "DKO4"~e.21) :location-of~e.24 (k / knock-out-03~e.31,32 :ARG1 (e / enzyme~e.25 :name (n3 / name :op1 "KRAS"~e.26) :ARG2-of~e.25 (m2 / mutate-01~e.25 :value "G13D"~e.28))))) :time~e.15 (a / after~e.0 :op1 (s2 / silence-01~e.1 :ARG1~e.2 (p / protein :name (n4 / name :op1 "RhoA"~e.3)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "5C"~e.37))) # ::id a_pmid_2194_3101.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Depletion of RhoA in HTshBR3 ( transfected with shRNA pSUPER BRAF @^V600E ) cells with suppressed BRAF @^V600E@ activity did not reverse the ability of HT29 cell to migrate , while in HTps ( HT29 cells transfected with empty vector pSUPER ) a moderate reduction in cell migration was observed ( Figure 5D ) . # ::alignments 0-1.1.2 1-1.1.2.1.r 2-1.1.2.1.1.1 4-1.1.2.2.1.1 6-1.2.1.3.2.1.2 8-1.1.2.2.2.1.4.1.1.1 9-1.1.2.2.2.1.3.1.1 10-1.1.2.2.2.1.1.1 12-1.1.2.2.2.1.2.1 15-1.2.1.3.2.1 17-1.1.2.2.3.1.2 18-1.1.2.2.3.1.1 19-1.1.2.2.3.1.1 20-1.1.2.2.3.1.1 22-1.1.2.2.3.1 24-1.1.1 24-1.1.1.r 25-1.1 29-1.1.3.1.1.1.1 29-1.2.1.3.2.1.1.1 30-1.2.1.1.1 32-1.2.1.1 34-1 36-1.2.1.3.1.1 38-1.2.1.3.2.1.1.1 39-1.1.2.2 39-1.2.1.3.2.1 40-1.1.2.2.2 40-1.2.1.3.2.1.2 41-1.2.1.3.2.1.2.1.r 42-1.2.1.3.2.1.2.1.2 43-1.1.2.2.2.1.3 43-1.2.1.3.2.1.2.1 44-1.2.1.3.2.1.2.1.1.1 47-1.2.1.2 48-1.2.1 50-1.1.3.1.1 50-1.2.1.3 51-1.1.3.1 53-1.2 55-1.3.1 57-1.3.1.1 (c / contrast-01~e.34 :ARG1 (r / reverse-01~e.25 :polarity~e.24 -~e.24 :ARG0 (d / deplete-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "RhoA"~e.2)) :location (c2 / cell~e.39 :name (n2 / name :op1 "HTshBR3"~e.4) :ARG1-of (t / transfect-01~e.40 :ARG2 (e / enzyme :name (n3 / name :op1 "BRAF"~e.10) :ARG2-of (m / mutate-01 :value "V600E"~e.12) :mod (v / vector~e.43 :name (n4 / name :op1 "pSUPER"~e.9)) :ARG1-of (e2 / encode-01 :ARG0 (n10 / nucleic-acid :name (n5 / name :op1 "shRNA"~e.8))))) :ARG0-of (h / have-03 :ARG1 (a / activity-06~e.22 :ARG0 e~e.18,19,20 :ARG1-of (s / suppress-01~e.17))))) :ARG1 (p2 / possible-01 :ARG1 (m2 / migrate-01~e.51 :ARG0 (c3 / cell-line~e.50 :name (n6 / name :op1 "HT29"~e.29))))) :ARG2 (o / observe-01~e.53 :ARG1 (r3 / reduce-01~e.48 :ARG1 (m3 / migrate-01~e.32 :ARG0 (c4 / cell~e.30)) :ARG1-of (m4 / moderate-03~e.47) :location (c5 / cell-line~e.50 :name (n7 / name :op1 "HTps"~e.36) :ARG1-of (d2 / describe-01 :ARG0 (c6 / cell-line~e.15,39 :name (n8 / name :op1 "HT29"~e.29,38) :ARG1-of (t2 / transfect-01~e.6,40 :ARG2~e.41 (v2 / vector~e.43 :name (n9 / name :op1 "pSUPER"~e.44) :ARG1-of (e3 / empty-02~e.42)))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.55 :mod "5D"~e.57))) # ::id a_pmid_2194_3101.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these results indicate that both BRAF @ and KRAS @ oncogenes utilize RhoA activation to promote cell migration . # ::alignments 0-1.3 1-1.3.1 3-1.1.2 4-1.1 4-1.1.1 4-1.1.1.r 5-1 9-1.2.1.1.1.1 11-1.2.1 13-1.2.1.2.1.1 16-1.2 17-1.2.2.1.1.1 18-1.2.2 19-1.2.1.3 20-1.2.3 21-1.2.3.2.1 22-1.2.3.2 (i / indicate-01~e.5 :ARG0 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :mod (t2 / this~e.3)) :ARG1 (u / utilize-01~e.16 :ARG0 (a / and~e.11 :op1 (g / gene :name (n / name :op1 "BRAF"~e.9)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS"~e.13)) :ARG0-of (c2 / cause-01~e.19 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :ARG1 (a2 / activate-01~e.18 :ARG1 (p / protein :name (n3 / name :op1 "RhoA"~e.17))) :purpose (p2 / promote-01~e.20 :ARG0 a :ARG1 (m / migrate-01~e.22 :ARG0 (c / cell~e.21)))) :ARG1-of (t3 / take-01~e.0 :mod (t4 / together~e.1))) # ::id a_pmid_2194_3101.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a different approach , inhibition of RhoA downstream signalling was achieved via treatment of cells with UO126 , a MEK ( mitogen @-@ activated protein kinase @/@ extracellular signal @-@ regulated kinase kinase ) inhibitor targeting the MAPK pathway , which is active in Caco @-@ BR cells [ @ 21 @ ] . # ::alignments 2-1.3.1 3-1.3 5-1.1 6-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1.2 9-1.1.1 11-1 13-1.2 14-1.2.1.r 15-1.2.1 16-1.2.2.r 17-1.2.2.1.1 20-1.2.2.2.1.1.1 22-1.2.2.2.1.2.1.1.1.1 24-1.2.2.2.1.2.1.1.1.1 24-1.2.2.3.1.2 25-1.2.2.2.1.2.1.1.1.2 26-1.2.2.2.1.2.1.1.1.3 26-1.2.2.2.1.2.1.2.1.3 28-1.2.2.2.1.2.1.2.1.1 29-1.2.2.2.1.2.1.2.1.2 31-1.2.2.2.1.2.1.2.1.2 32-1.2.2.2.1.2.1.1.1.3 32-1.2.2.2.1.2.1.2.1.3 33-1.2.2.2.1.2.1.1.1.3 33-1.2.2.2.1.2.1.2.1.3 35-1.2.2 35-1.2.2.2 35-1.2.2.2.r 36-1.2.2.3 38-1.2.2.3.1.1.1 39-1.2.2.3.1 44-1.2.2.3.1.2.1.r 45-1.2.2.3.1.2.1.1.1 47-1.2.2.3.1.2.1.1.1 48-1.2.2.3.1.2.1 51-1.4.1.1.1 (a / achieve-01~e.11 :ARG1 (i / inhibit-01~e.5 :ARG1~e.6 (s / signal-07~e.9 :ARG0 (p / protein :name (n / name :op1 "RhoA"~e.7)) :location (d / downstream~e.8))) :manner (t / treat-04~e.13 :ARG1~e.14 (c / cell~e.15) :ARG2~e.16 (s2 / small-molecule~e.35 :name (n2 / name :op1 "UO126"~e.17) :ARG0-of~e.35 (i2 / inhibit-01~e.35 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK"~e.20) :ARG1-of (m / mean-01 :ARG2 (o / or :op1 (p5 / protein-family :name (n4 / name :op1 "mitogen-activated"~e.22,24 :op2 "protein"~e.25 :op3 "kinase"~e.26,32,33)) :op2 (p6 / protein-family :name (n5 / name :op1 "extracellular"~e.28 :op2 "signal-regulated"~e.29,31 :op3 "kinase"~e.26,32,33)))))) :ARG0-of (t2 / target-01~e.36 :ARG1 (p2 / pathway~e.39 :name (n6 / name :op1 "MAPK"~e.38) :ARG1-of (a2 / activate-01~e.24 :location~e.44 (c2 / cell-line~e.48 :name (n7 / name :op1 "Caco-BR"~e.45,47))))))) :ARG1-of (a3 / approach-02~e.3 :ARG1-of (d2 / differ-02~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 21~e.51)))) # ::id a_pmid_2194_3101.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with UO126 , at the most optimal treatment condition ( Additional Figure 3 ) , resulted in the decreased activation of RhoA illustrating that mutant BRAF @^V600E@ utilises the MAPK pathway to activate RhoA ( Figure 5E , upper panel ) . # ::alignments 0-1.1 2-1.1.1.1.1 6-1.1.2.1 7-1.1.2 8-1.1 9-1.1.2.r 12-1.1.3.1 14-1.1.3.1.1 18-1 19-1.2.r 21-1.2.3 22-1.2 24-1.2.2.1.1 25-1.3 27-1.3.1.1 27-1.3.1.1.2 27-1.3.1.1.2.r 28-1.3.1.1.1.1 30-1.3.1.1.2.1 34-1.3.1.2.1.1 35-1.3.1.2 37-1.2 37-1.3.1.3 38-1.2.2.1.1 40-1.4.1.1 42-1.4.1.1.1 45-1.4.1.1.2.1 46-1.4.1.1.2 (r / result-01~e.18 :ARG1 (t / treat-04~e.0,8 :ARG2 (s / small-molecule :name (n / name :op1 "UO126"~e.2)) :condition~e.9 (o / optimal~e.7 :degree (m / most~e.6)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.12 :mod 3~e.14 :ARG1-of (a / add-02)))) :ARG2~e.19 (a2 / activate-01~e.22,37 :ARG0 t :ARG1 (p / protein :name (n2 / name :op1 "RhoA"~e.24,38)) :ARG1-of (d2 / decrease-01~e.21)) :ARG0-of (i / illustrate-01~e.25 :ARG1 (u / utilize-01 :ARG0 (e / enzyme~e.27 :name (n3 / name :op1 "BRAF"~e.28) :ARG2-of~e.27 (m2 / mutate-01~e.27 :value "V600E"~e.30)) :ARG1 (p2 / pathway~e.35 :name (n4 / name :op1 "MAPK"~e.34)) :purpose (a3 / activate-01~e.37 :ARG0 e :ARG1 p))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (f2 / figure~e.40 :mod "5E"~e.42 :part (p3 / panel~e.46 :mod (u2 / upper~e.45)))))) # ::id a_pmid_2194_3101.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternative regulation of RhoA through the PI3K pathway was analysed in Caco @-@ BR cells , and a mild effect on RhoA downstream components like p @-@ Cofilin and p @-@ Myl was observed ( Figure 5E , lower panel ) . # ::alignments 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 6-1.1.1.1.1.1 7-1.1.1.1 9-1.1 10-1.1.2.r 11-1.1.2.1.1 13-1.1.2.1.1 14-1.1.2 16-1 18-1.2.1.2 19-1.2.1 20-1.2.1.1.r 21-1.2.1.1.2 22-1.2.1.1.1 23-1.2.1.1 24-1.2.1.1.3.r 25-1.2.1.1.3.1 25-1.2.1.1.3.1.2 25-1.2.1.1.3.1.2.r 27-1.2.1.1.3.1.1.1 29-1.2.1.1.3.1 29-1.2.1.1.3.1.2 29-1.2.1.1.3.1.2.r 31-1.2.1.1.3.2.1.1 33-1.2 35-1.3.1.1 37-1.3.1.1.1 40-1.3.1.1.2.1 40-1.3.1.1.2.1.1 40-1.3.1.1.2.1.1.r 41-1.3.1.1.2 (a / and~e.16 :op1 (a2 / analyze-01~e.9 :ARG1 (r / regulate-01~e.1 :ARG0 (p / pathway~e.7 :name (n / name :op1 "PI3K"~e.6)) :ARG1~e.2 (p2 / protein :name (n2 / name :op1 "RhoA"~e.3)) :ARG1-of (a3 / alternate-01)) :location~e.10 (c / cell-line~e.14 :name (n3 / name :op1 "Caco-BR"~e.11,13))) :op2 (o / observe-01~e.33 :ARG1 (a4 / affect-01~e.19 :ARG1~e.20 (c2 / component~e.23 :location (d / downstream~e.22) :part-of p2~e.21 :example~e.24 (a5 / and :op1 (p3 / protein~e.25,29 :name (n4 / name :op1 "Cofilin"~e.27) :ARG1-of~e.25,29 (p4 / phosphorylate-01~e.25,29)) :op2 (p5 / protein :name (n5 / name :op1 "Myl"~e.31) :ARG1-of p4))) :degree (m / mild~e.18))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f / figure~e.35 :mod "5E"~e.37 :part (p6 / panel~e.41 :ARG1-of (l / low-04~e.40 :degree~e.40 (m2 / more~e.40))))))) # ::id a_pmid_2194_3101.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of RhoA @-@ ROCK axis # ::alignments 0-1 1-1.1.r 2-1.1.1.1 4-1.1.1.1 5-1.1 (a / analyze-01~e.0 :ARG1~e.1 (a2 / axis~e.5 :name (n / name :op1 "RhoA-ROCK"~e.2,4))) # ::id a_pmid_2194_3101.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since RhoA appears to be essential for the attained migration in Caco @-@ BR13 cells , RhoA @-@ Rho kinase signalling was inhibited using the selective ROCK ( Rho @-@ associated coiled coil forming protein serine @/@ threonine kinase ) inhibitor Y @-@ 27632 aiming to inhibit cell migration . # ::alignments 0-1 1-1.2.2.1.1.1 2-1.1 3-1.1.1.r 4-1.1.1.1.r 5-1.1.1 6-1.1.1.2.r 8-1.1.1.2.1 9-1.1.1.2 10-1.1.1.2.2.r 11-1.1.1.2.2.1.1 13-1.1.1.2.2.1.1 14-1.1.1.2.2 16-1.1.1.1.1.1 18-1.2.2.1.1.1 19-1.2.2.1 20-1.2.2 22-1.2 22-1.2.1.2 23-1.2.3.r 26-1.2.1.2.1.1.1 28-1.2.2.1.1.1 34-1.1.1.1 38-1.2.2.1 40-1.2 40-1.2.1.2 41-1.2.1.1.1 43-1.2.1.1.1 44-1.2.3 46-1.2.3.1 47-1.2.3.1.1.1 48-1.2.3.1.1 (c / cause-01~e.0 :ARG0 (a / appear-02~e.2 :ARG1~e.3 (e / essential~e.5 :domain~e.4 (p / protein~e.34 :name (n / name :op1 "RhoA"~e.16)) :purpose~e.6 (m / migrate-01~e.9 :ARG1-of (a2 / attain-01~e.8) :location~e.10 (c2 / cell-line~e.14 :name (n2 / name :op1 "Caco-BR13"~e.11,13))))) :ARG1 (i / inhibit-01~e.22,40 :ARG0 (s / small-molecule :name (n4 / name :op1 "Y-27632"~e.41,43) :ARG0-of (i2 / inhibit-01~e.22,40 :ARG1 (e2 / enzyme :name (n5 / name :op1 "ROCK"~e.26))) :ARG0-of (s2 / select-01)) :ARG1 (s3 / signal-07~e.20 :ARG0 (k / kinase~e.19,38 :name (n6 / name :op1 "RhoA-Rho"~e.1,18,28))) :purpose~e.23 (a3 / aim-01~e.44 :ARG1 (i3 / inhibit-01~e.46 :ARG1 (m2 / migrate-01~e.48 :ARG0 (c3 / cell~e.47)))))) # ::id a_pmid_2194_3101.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of Caco @-@ 2 and Caco @-@ BR13 cells with the ROCK inhibitor had a moderate effect on downstream target p @-@ Cofilin , while cell motility was found significantly increased in both cell lines ( Figure 6A @-@ B ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.2.1 2-1.1.1.1.2.2.1 4-1.1.1.1.1.2.1 5-1.1.1.1 6-1.1.1.1.1.2.1 6-1.1.1.1.2.2.1 8-1.1.1.1.2.2.1 9-1.1.1.1.1 9-1.1.1.1.2 10-1.1.1.2.r 12-1.1.1.2.1.1.2.1 13-1.1.1.2 13-1.1.1.2.1 13-1.1.1.2.1.r 16-1.1.3 17-1.1 18-1.1.2.r 19-1.1.2.4.1 20-1.1.2.4 21-1.1.2 21-1.1.2.3 21-1.1.2.3.r 23-1.1.2.2.1 25-1 26-1.2.1.1.1 27-1.2.1.1 29-1.2 30-1.2.1.2 31-1.2.1 34-1.2.1.1.1 35-1.2.2 37-1.3.1.1 37-1.3.1.2 39-1.3.1.1.1 (c / contrast-01~e.25 :ARG1 (a / affect-01~e.17 :ARG0 (t / treat-04~e.0 :ARG1~e.1 (a2 / and~e.5 :op1 (c2 / cell-line~e.9 :wiki "Caco-2" :name (n / name :op1 "Caco-2"~e.2,4,6)) :op2 (c3 / cell-line~e.9 :wiki - :name (n2 / name :op1 "Caco-BR13"~e.2,6,8))) :ARG2~e.10 (m / molecular-physical-entity~e.13 :ARG0-of~e.13 (i / inhibit-01~e.13 :ARG1 (e / enzyme :wiki "ROCK1" :name (n3 / name :op1 "ROCK"~e.12))))) :ARG1~e.18 (p / protein~e.21 :wiki "Cofilin" :name (n4 / name :op1 "Cofilin"~e.23) :ARG1-of~e.21 (p2 / phosphorylate-01~e.21) :ARG1-of (t3 / target-01~e.20 :location (d / downstream~e.19))) :ARG1-of (m2 / moderate-03~e.16)) :ARG2 (f / find-01~e.29 :ARG1 (i2 / increase-01~e.31 :ARG1 (m3 / motility~e.27 :mod (c4 / cell~e.26,34)) :ARG2 (s / significant-02~e.30)) :location a2~e.35) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure~e.37 :mod "6A"~e.39) :op2 (f3 / figure~e.37 :mod "6B")))) # ::id a_pmid_2194_3101.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To exclude the possibility of this observation being the non @-@ specific effect of the inhibitor targeting several other kinases , siRNA against both ROCK isoforms ( ROCK1 and ROCK2 ) was applied to both Caco @-@ BR clones and parental Caco @-@ 2 cells ( Figure 6C ) . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.2 6-1.3.1.1 9-1.3.1.1.1.2.1 9-1.3.1.1.1.2.1.r 11-1.3.1.1.1.2 12-1.3.1.1.1 13-1.3.1.1.1.1.r 15-1.3.1.1.1.1 15-1.3.1.1.1.1.1 15-1.3.1.1.1.1.1.r 16-1.3.1.1.1.1.2 17-1.3.1.1.1.1.2.1.2 18-1.3.1.1.1.1.2.1.1 19-1.3.1.1.1.1.2.1 21-1.1.1.1 22-1.1 22-1.1.2 22-1.1.2.r 25-1.1.2.1.1 25-1.1.2.1.2 27-1.1.2.1.1.1.1 28-1.1.2.1 29-1.1.2.1.2.1.1 32-1 35-1.2.1.1.1.1 37-1.2.1.1.1.1 38-1.2.1 39-1.2 40-1.2.2.2 41-1.2.2.1.1 43-1.2.2.1.1 44-1.2.1.1 44-1.2.2 46-1.4.1 48-1.4.1.1 (a / apply-02~e.32 :ARG1 (n4 / nucleic-acid~e.22 :name (n / name :op1 "siRNA"~e.21) :ARG0-of~e.22 (o / oppose-01~e.22 :ARG1 (a2 / and~e.28 :op1 (i / isoform~e.25 :name (n2 / name :op1 "ROCK1"~e.27)) :op2 (i2 / isoform~e.25 :name (n3 / name :op1 "ROCK2"~e.29))))) :ARG2 (a3 / and~e.39 :op1 (c / clone-01~e.38 :ARG1 (c2 / cell-line~e.44 :name (n5 / name :op1 "Caco-BR"~e.35,37))) :op2 (c3 / cell-line~e.44 :name (n6 / name :op1 "Caco-2"~e.41,43) :mod (p / parent~e.40))) :purpose (e2 / exclude-01~e.1 :ARG1 (p2 / possible-01~e.3 :ARG1~e.4 (o2 / observe-01~e.6 :ARG1 (a4 / affect-01~e.12 :ARG0~e.13 (m2 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i3 / inhibit-01~e.15) :ARG0-of (t2 / target-01~e.16 :ARG1 (k / kinase~e.19 :mod (o3 / other~e.18) :quant (s / several~e.17)))) :ARG1-of (s2 / specific-02~e.11 :polarity~e.9 -~e.9)) :mod (t / this~e.5)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.46 :mod "6C"~e.48))) # ::id a_pmid_2194_3101.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Besides , the use of siRNA to deplete a protein and especially a small GTPase can prove more promising since the specific protein sequence is targeted . # ::alignments 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1.1.1 7-1.1.1.1.2 9-1.1.1.1.2.2.1 10-1.1.1.1.2.2 11-1.1.1.1.2.2.2.3 13-1.1.1.1.2.2.2.2 14-1.1.1.1.2.2.2.1.1 15-1.1 16-1.1.1 17-1.1.1.2.1 18-1.1.1.2 19-1.1.2 21-1.1.2.1.1.1 22-1.1.2.1.1.2 23-1.1.2.1.1 25-1.1.2.1 (a / and :op2 (p / possible-01~e.15 :ARG1 (p2 / prove-01~e.16 :ARG0 (u / use-01~e.3 :ARG1~e.4 (n3 / nucleic-acid :name (n / name :op1 "siRNA"~e.5)) :ARG2 (d / deplete-01~e.7 :ARG0 n3 :ARG1 (a2 / and~e.10 :op1 (p3 / protein~e.9) :op2 (e / enzyme :name (n2 / name :op1 "GTPase"~e.14) :mod (s / small~e.13) :mod (e2 / especially~e.11))))) :ARG1 (p4 / promise-01~e.18 :degree (m / more~e.17))) :ARG1-of (c / cause-01~e.19 :ARG0 (t / target-01~e.25 :ARG1 (s3 / sequence~e.23 :ARG1-of (s2 / specific-02~e.21) :part-of (p5 / protein~e.22)))))) # ::id a_pmid_2194_3101.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In several reported studies , treatment with a selective inhibitor may produce more adverse effect through interaction with other ( associated ) components . # ::alignments 1-1.2.2 2-1.2.1 3-1.2 5-1.1.1 9-1.1.1.1 9-1.1.1.1.1 9-1.1.1.1.1.r 10-1 11-1.1 12-1.1.2.1.1 13-1.1.2.1 14-1.1.2 16-1.1.3 17-1.1.3.2.r 18-1.1.3.2.1 20-1.1.3.2.2 22-1.1.3.2 (p / possible-01~e.10 :ARG1 (p2 / produce-01~e.11 :ARG0 (t / treat-04~e.5 :ARG2 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (i / inhibit-01~e.9) :ARG0-of (s / select-01))) :ARG1 (a / affect-01~e.14 :mod (a2 / adverse~e.13 :degree (m2 / more~e.12))) :manner (i2 / interact-01~e.16 :ARG0 m :ARG1~e.17 (c / component~e.22 :mod (o / other~e.18) :ARG1-of (a3 / associate-01~e.20)))) :medium (s2 / study-01~e.3 :ARG1-of (r / report-01~e.2) :quant (s3 / several~e.1))) # ::id a_pmid_2194_3101.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regardless efficient ROCK depletion , no inhibition in cell migration or invasion was observed in BRAF @^V600E@ transformed cells ( Figure 6D ) . # ::alignments 0-1.3.r 1-1.3.2 2-1.3.1.1.1 3-1.3 5-1.1.1 5-1.1.1.r 6-1.1 7-1.1.2.r 8-1.1.2.1.1 9-1.1.2.1 10-1.1.2 11-1.1.2.2 13-1 14-1.2.r 15-1.2.1.1.1.1 17-1.2.1.1.2.1 19-1.2.1 20-1.2 22-1.4.1 24-1.4.1.1 (o / observe-01~e.13 :ARG1 (i / inhibit-01~e.6 :polarity~e.5 -~e.5 :ARG1~e.7 (o2 / or~e.10 :op1 (m / migrate-01~e.9 :ARG0 (c / cell~e.8)) :op2 (i2 / invade-01~e.11 :ARG0 c))) :location~e.14 (c2 / cell~e.20 :ARG1-of (t / transform-01~e.19 :ARG0 (e / enzyme :name (n / name :op1 "BRAF"~e.15) :ARG2-of (m2 / mutate-01 :value "V600E"~e.17)))) :concession~e.0 (d / deplete-01~e.3 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ROCK"~e.2)) :ARG1-of (e3 / efficient-01~e.1)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.22 :mod "6D"~e.24))) # ::id a_pmid_2194_3101.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nevertheless increase motility was recorded in Caco @-@ 2 cells suggesting that Rac1 activation may be taking a lead role in the absence of the RhoA @-@ Rho kinase signalling . # ::alignments 0-1 1-1.1.1 2-1.1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.1 8-1.1.2.1.1 9-1.1.2 10-1.1.3 11-1.1.3.1.r 12-1.1.3.1.1.1.1.1.1 13-1.1.3.1.1.1 14-1.1.3.1 16-1.1.3.1.1 18-1.1.3.1.1.2.1 19-1.1.3.1.1.2 20-1.1.3.1.1.3.r 22-1.1.3.1.1.3 23-1.1.3.1.1.3.1.r 25-1.1.3.1.1.3.1.1.1.1 27-1.1.3.1.1.3.1.1.1.1 28-1.1.3.1.1.3.1.1 29-1.1.3.1.1.3.1 (h / have-concession-91~e.0 :ARG1 (r / record-01~e.4 :ARG1 (i / increase-01~e.1 :ARG1 (m / motility~e.2)) :location~e.5 (c / cell-line~e.9 :name (n / name :op1 "Caco-2"~e.6,8)) :ARG0-of (s / suggest-01~e.10 :ARG1~e.11 (p / possible-01~e.14 :ARG1 (t / take-01~e.16 :ARG0 (a / activate-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "Rac1"~e.12))) :ARG1 (r2 / role~e.19 :purpose (l / lead-02~e.18)) :condition~e.20 (a2 / absent-01~e.22 :ARG1~e.23 (s2 / signal-07~e.29 :ARG0 (k / kinase~e.28 :name (n4 / name :op1 "RhoA-Rho"~e.25,27))))))))) # ::id a_pmid_2194_3101.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KRAS @^G12V@ induces Cdc42 @-@ dependent migration ability and filopodia formation in Caco @-@ 2 cells , partially dependent on PI3K pathway # ::alignments 0-1.1.2.1.1 2-1.1.1 4-1 5-1.2.1.1.2.1.1.1 7-1.2.1.1.2 8-1.2.1.1 10-1.2 12-1.2.2 13-1.2.2.2.r 14-1.2.2.2.1.1 16-1.2.2.2.1.1 17-1.2.2.2 19-1.1.3.2 19-1.1.3.2.r 20-1.1.3 21-1.1.3.1.r 22-1.1.3.1.1.1 23-1.1.3.1 (i / induce-01~e.4 :ARG0 (m2 / mutate-01 :value "G12V"~e.2 :ARG1 (g / gene :name (n4 / name :op1 "KRAS"~e.0)) :ARG0-of (d3 / depend-01~e.20 :ARG1~e.21 (p4 / pathway~e.23 :name (n7 / name :op1 "PI3K"~e.22)) :degree~e.19 (p2 / part~e.19))) :ARG2 (a / and~e.10 :op1 (p3 / possible-01 :ARG1 (m / migrate-01~e.8 :ARG0 n2 :condition (d / depend-01~e.7 :ARG1 (p / protein :name (n / name :op1 "Cdc42"~e.5))))) :op2 (f / form-01~e.12 :ARG1 (f2 / filopodium) :location~e.13 (c / cell-line~e.17 :name (n2 / name :op1 "Caco-2"~e.14,16))))) # ::id a_pmid_2194_3101.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previous studies have indicated that RhoA , Rac1 and Cdc42 signalling is essential for oncogenic Ras transforming capacity [ @ 29 , 30 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.1.1.1.1.1 7-1.2.1.1.2.1.1 8-1.2.1.1 9-1.2.1.1.3.1.1 10-1.2.1 11-1.2.1.r 12-1.2 13-1.2.2.r 14-1.2.2.1 14-1.2.2.1.2 14-1.2.2.1.2.1.2.1 14-1.2.2.1.2.r 15-1.2.2.1.1.1 16-1.2.2.2 17-1.2.2 20-1.3.1.1.1 24-1.3.1.1.2 (i / indicate-01~e.3 :ARG0 (s / study-01~e.1 :time (p / previous~e.0)) :ARG1~e.4 (e / essential~e.12 :domain~e.11 (s2 / signal-07~e.10 :ARG0 (a / and~e.8 :op1 (p2 / protein :name (n / name :op1 "RhoA"~e.5)) :op2 (p3 / protein :name (n2 / name :op1 "Rac1"~e.7)) :op3 (p4 / protein :name (n3 / name :op1 "Cdc42"~e.9)))) :purpose~e.13 (c3 / capable-01~e.17 :ARG1 (e2 / enzyme~e.14 :name (n4 / name :op1 "Ras"~e.15) :ARG0-of~e.14 (c / cause-01~e.14 :ARG1 (d2 / disease :wiki "Disease" :name (n5 / name :op1 "Cancer"~e.14)))) :ARG2 (t / transform-01~e.16 :ARG1 e2))) :ARG1-of (d / describe-01 :ARG0 (c2 / cite-01 :ARG1 (a2 / and :op1 29~e.20 :op2 30~e.24)))) # ::id a_pmid_2194_3101.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the present study , Caco @-@ 2 cells overexpressing mutant KRAS @^G12V@ ( Caco @-@ K ) , selective activation for Cdc42 was detected ( Figure 7A ) . # ::alignments 2-1.2.2 3-1.2 5-1.2.1.2.1.1 5-1.2.1.3.1.1.1 7-1.2.1.2.1.1 8-1.2.1.2 8-1.2.1.3.1 9-1.2.1 10-1.2.1.1 11-1.2.1.1.2.1.1 13-1.2.1.1.1 16-1.2.1.2.1.1 16-1.2.1.3.1.1.1 18-1.2.1.3.1.1.1 21-1.1.2 22-1.1 23-1.1.1.r 24-1.1.1.1.1 26-1 28-1.3.1 30-1.3.1.1 (d / detect-01~e.26 :ARG1 (a / activate-01~e.22 :ARG1~e.23 (p / protein :name (n / name :op1 "Cdc42"~e.24)) :manner (s / selective~e.21)) :location (s2 / study-01~e.3 :ARG1 (o2 / overexpress-01~e.9 :ARG1 (m / mutate-01~e.10 :value "G12V"~e.13 :ARG1 (g / gene :name (n3 / name :op1 "KRAS"~e.11))) :location (c / cell-line~e.8 :name (n2 / name :op1 "Caco-2"~e.5,7,16)) :ARG1-of (m2 / mean-01 :ARG2 (c2 / cell-line~e.8 :name (n4 / name :op1 "Caco-K"~e.5,16,18)))) :time (p2 / present~e.2)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.28 :mod "7A"~e.30))) # ::id a_pmid_2194_3101.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The formation of filopodia in these cells , earlier described , was in agreement with the high Cdc42 activity and is illustrated here by staining with antibody against Fascin , a filopodia marker ( Figure 7B , upper panel ) . # ::alignments 1-1.1.1 4-1.1.1.2.r 5-1.1.1.2.1 6-1.1.1.2 8-1.3.2 8-1.3.2.1 8-1.3.2.1.r 9-1.3 13-1.1 14-1.1.2.r 16-1.1.2.2 17-1.1.2.1.1.1 18-1.1.2 19-1 21-1.2 22-1.2.3 23-1.2.2.r 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1 27-1.2.2.1.1 28-1.2.2.1.1.1.1.1 32-1.2.2.1.1.1 34-1.3.1.2 36-1.3.1.2.1 39-1.3.1.1 40-1.3.1 (a / and~e.19 :op1 (a2 / agree-01~e.13 :ARG1 (f / form-01~e.1 :ARG1 (f2 / filopodium) :location~e.4 (c / cell~e.6 :mod (t / this~e.5))) :ARG2~e.14 (a3 / activity-06~e.18 :ARG0 (p / protein :name (n / name :op1 "Cdc42"~e.17)) :ARG1-of (h / high-02~e.16))) :op2 (i / illustrate-01~e.21 :ARG1 f :ARG0-of~e.23 (s / stain-01~e.24 :ARG2~e.25 (a4 / antibody~e.26 :ARG0-of (c2 / counter-01~e.27 :ARG1 (m / marker~e.32 :name (n2 / name :op1 "Fascin"~e.28) :mod (f3 / filopodium))))) :medium (h2 / here~e.22)) :ARG1-of (d / describe-01~e.9 :ARG0 (p2 / panel~e.40 :location (u / upper~e.39) :part-of (f4 / figure~e.34 :mod "7B"~e.36)) :mod (e / early~e.8 :degree~e.8 (m3 / more~e.8)))) # ::id a_pmid_2194_3101.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A large number of relatively short filopodia distributed almost exclusively at the cell periphery was evident in Caco @-@ K cells , while Caco @-@ BR and Caco @-@ H cells formed less but longer structures with a rather polarized shape potentially pointing towards the direction of cell migration ( Figure 7B , upper panel ) . # ::alignments 1-1.1.1.2.1 2-1.1.1.2 4-1.1.1.1.1 5-1.1.1.1 7-1.1.1.3 8-1.1.1.3.2.1 9-1.1.1.3.2 10-1.1.1.3.1.r 12-1.1.1.3.1.1 13-1.1.1.3.1 14-1.1.1.3.1.1.r 14-1.1.1.r 15-1.1 16-1.1.2.r 17-1.1.2.1.1 19-1.1.2.1.1 20-1.1.2 22-1 23-1.2.1.1.1.1 25-1.2.1.1.1.1 26-1.2.1 27-1.2.1.1.1.1 27-1.2.1.2.1.1 29-1.2.1.2.1.1 30-1.2.1.1 30-1.2.1.2 31-1.2 32-1.2.2.2 33-1.2.2.2.1 34-1.2.2.2.1.1 34-1.2.2.2.1.1.2 34-1.2.2.2.1.1.2.r 35-1.2.2 38-1.2.2.1.1.1.1 39-1.2.2.1.1.1 40-1.2.2.1.1 41-1.2.2.1.1.2.2 42-1.2.2.1.1.2 43-1.2.2.1.1.2.1.1.r 45-1.2.2.1.1.2.1 45-1.2.2.1.1.2.1.1.r 47-1.2.2.1.1.2.1.1.1 48-1.2.2.1.1.2.1.1 50-1.3.1.2 52-1.3.1.2.1 55-1.3.1.1 56-1.3.1 (c / contrast-01~e.22 :ARG1 (e3 / evident~e.15 :domain~e.14 (f / filopodium :ARG1-of (s / short-07~e.5 :ARG2-of (r / relative-05~e.4)) :quant (n2 / number~e.2 :mod (l2 / large~e.1)) :ARG1-of (d / distribute-01~e.7 :location~e.10 (p6 / periphery~e.13 :domain~e.14 (c7 / cell~e.12)) :ARG0-of (e / exclusive-02~e.9 :degree (a3 / almost~e.8)))) :location~e.16 (c2 / cell~e.20 :name (n / name :op1 "Caco-K"~e.17,19))) :ARG2 (f2 / form-01~e.31 :ARG0 (a2 / and~e.26 :op1 (c4 / cell-line~e.30 :name (n3 / name :op1 "Caco-BR"~e.23,25,27)) :op2 (c5 / cell-line~e.30 :name (n4 / name :op1 "Caco-H"~e.27,29))) :ARG1 (s2 / structure~e.35 :ARG0-of (h / have-03 :ARG1 (s4 / shape~e.40 :ARG1-of (p / polarize-01~e.39 :degree (r3 / rather~e.38)) :ARG0-of (p7 / point-01~e.42 :ARG2 (d4 / direction~e.45 :direction-of~e.43,45 (m2 / migrate-01~e.48 :ARG0 (c3 / cell~e.47))) :mod (p8 / potential~e.41)))) :quant (l4 / less~e.32 :ARG1-of (c6 / contrast-01~e.33 :ARG2 (l / long-03~e.34 :ARG1 s :degree~e.34 (m / more~e.34)) :compared-to f)))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / panel~e.56 :location (u / upper~e.55) :part-of (f3 / figure~e.50 :mod "7B"~e.52)))) # ::id a_pmid_2194_3101.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nevertheless , no changes in Fascin protein expression were recorded in the different cell lines , ( Figure 7B , lower panel ) . # ::alignments 0-1 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1 4-1.1.1.2.r 5-1.1.1.2.1.1.1 6-1.1.1.2.1 7-1.1.1.2 9-1.1 10-1.1.2.r 12-1.1.2.1 13-1.1.2 14-1.1.2 17-1.2.1.2 19-1.2.1.2.1 22-1.2.1.1 22-1.2.1.1.1 22-1.2.1.1.1.r 23-1.2.1 (h / have-concession-91~e.0 :ARG2 (r / record-01~e.9 :ARG1 (c / change-01~e.3 :polarity~e.2 -~e.2 :ARG1~e.4 (e / express-03~e.7 :ARG2 (p / protein~e.6 :name (n / name :op1 "Fascin"~e.5)))) :location~e.10 (c2 / cell-line~e.13,14 :ARG1-of (d / differ-02~e.12))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / panel~e.23 :ARG1-of (l / low-04~e.22 :degree~e.22 (m2 / more~e.22)) :part-of (f / figure~e.17 :mod "7B"~e.19)))) # ::id a_pmid_2194_3101.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Increased migration ability in Caco @-@ BR and Caco @-@ H cells may be indicative for the length and the location of filopodia . # ::alignments 0-1.1.1 1-1.1.1.1.1 3-1.1.1.1.1.1.r 4-1.1.1.1.1.1.1.1.1 4-1.1.1.1.1.1.2.1.1 6-1.1.1.1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1.1.1.1.1.1.1 8-1.1.1.1.1.1.2.1.1 10-1.1.1.1.1.1.2.1.1 11-1.1.1.1.1.1.1 11-1.1.1.1.1.1.2 12-1 12-1.1.1.1 17-1.1.2.1 18-1.1.2 20-1.1.2.2 20-1.1.2.2.1.r (p / possible-01~e.12 :ARG1 (i / indicate-01 :ARG0 (i2 / increase-01~e.0 :ARG1 (p2 / possible-01~e.12 :ARG1 (m / migrate-01~e.1 :location~e.3 (a2 / and~e.7 :op1 (c / cell-line~e.11 :name (n / name :op1 "Caco-BR"~e.4,6,8)) :op2 (c2 / cell-line~e.11 :name (n2 / name :op1 "Caco-H"~e.4,8,10)))))) :ARG1 (a3 / and~e.18 :op1 (l / length~e.17 :mod (f / filopodium)) :op2 (l2 / location~e.20 :location-of~e.20 f)))) # ::id a_pmid_2194_3101.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been previously shown that in CHO @-@ K1 cells ( Chinese hamster ovary fibroblast @- like cells ) RhoA expression down @-@ regulates Cdc42 and Rac1 activity in order to regulate membrane protrusions and cell polarity . # ::alignments 3-1.2 4-1 7-1.1.1.2.1.1 9-1.1.1.2.1.1 10-1.1.1.2.2.1.2.1 12-1.1.1.2.2.1.1.1.1.1.2.1 13-1.1.1.2.2.1.1.1.1 14-1.1.1.2.2.1.1 15-1.1.1.2.2.1 17-1.1.1.2.2.1.2 18-1.1.1.2 20-1.1.1.1.1.1 21-1.1.1 24-1.1.3 25-1.1.2.1.1.1.1 26-1.1.2.1 27-1.1.2.1.2.1.1 28-1.1.2 29-1.1.3.r 30-1.1.3.r 31-1.1.3.r 32-1.1.3 33-1.1.3.2.1.1 34-1.1.3.2.1 35-1.1.3.2 36-1.1.3.2.2.1 37-1.1.3.2.2 (s / show-01~e.4 :ARG1 (d / downregulate-01 :ARG0 (e / express-03~e.21 :ARG2 (p2 / protein :name (n3 / name :op1 "RhoA"~e.20)) :location (c2 / cell-line~e.18 :name (n6 / name :op1 "CHO-K1"~e.7,9) :ARG1-of (m2 / mean-01 :ARG2 (f2 / fibroblast~e.15 :location (o2 / ovary~e.14 :part-of (a5 / animal :mod (h2 / hamster~e.13 :mod (c5 / country :wiki "China" :name (n / name :op1 "China"~e.12))))) :ARG1-of (r3 / resemble-01~e.17 :ARG2 (c6 / cell~e.10)))))) :ARG1 (a / activity-06~e.28 :ARG0 (a2 / and~e.26 :op1 (p3 / protein :name (n4 / name :op1 "Cdc42"~e.25)) :op2 (p4 / protein :name (n5 / name :op1 "Rac1"~e.27)))) :purpose~e.29,30,31 (r2 / regulate-01~e.24,32 :ARG0 e :ARG1 (a4 / and~e.35 :op1 (p5 / protrude-01~e.34 :ARG1 (m / membrane~e.33)) :op2 (p6 / polarity~e.37 :mod (c4 / cell~e.36))))) :time (p / previous~e.3)) # ::id a_pmid_2194_3101.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , Rac1 activity may down @-@ regulate Cdc42 activity and promote the formation of stabilized rather than transient protrusions [ @ 31 @ ] . # ::alignments 0-1.1.1 1-1 1-1.1.1 3-1.1.1.1.1.1.1.1 4-1.1.1.1.1 4-1.1.1.1.2 5-1.1 9-1.1.1.1.2.1.1.1 10-1.1.1.1.1 10-1.1.1.1.2 11-1.1.1 12-1.1.1.2 14-1.1.1.2.1 15-1.1.1.2.1.2 16-1.1.1.2.1.1.1 17-1.1.1.2.1.2 19-1.1.1.2.1.2.1.1 20-1.1.1.2.1.1 20-1.1.1.2.1.2.1 23-1.2.1 (a / and~e.1 :op2 (p / possible-01~e.5 :ARG1 (a2 / and~e.0,1,11 :op1 (d2 / downregulate-01 :ARG0 (a3 / activity-06~e.4,10 :ARG0 (p2 / protein :name (n / name :op1 "Rac1"~e.3))) :ARG1 (a4 / activity-06~e.4,10 :ARG0 (p3 / protein :name (n2 / name :op1 "Cdc42"~e.9)))) :op2 (p4 / promote-02~e.12 :ARG1 (f / form-01~e.14 :ARG1 (p5 / protrude-01~e.20 :ARG1-of (s / stabilize-01~e.16)) :ARG1-of (i / instead-of-91~e.15,17 :ARG2 (p6 / protrude-01~e.20 :ARG1-of (t / transient-02~e.19))))))) :ARG1-of (c / cite-01 :ARG2 31~e.23)) # ::id a_pmid_2194_3101.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , low Cdc42 activity was recorded in Caco @-@ BR and Caco @-@ H cells where RhoA signaling is activated . # ::alignments 0-1.3 2-1.1.2 3-1.1.1.1.1 4-1.1 6-1 7-1.2.r 8-1.2.1.1.1 8-1.2.2.1.1 10-1.2.1.1.1 11-1.2 12-1.2.1.1.1 12-1.2.2.1.1 14-1.2.2.1.1 15-1.2.1 15-1.2.2 16-1.2.3.r 17-1.2.3.1.1.1.1 18-1.2.3.1 20-1.2.3 (r / record-01~e.6 :ARG1 (a / activity-06~e.4 :ARG0 (p / protein :name (n / name :op1 "Cdc42"~e.3)) :ARG1-of (l / low-04~e.2)) :location~e.7 (a2 / and~e.11 :op1 (c / cell-line~e.15 :name (n2 / name :op1 "Caco-BR"~e.8,10,12)) :op2 (c2 / cell-line~e.15 :name (n3 / name :op1 "Caco-H"~e.8,12,14)) :location-of~e.16 (a4 / activate-01~e.20 :ARG1 (s2 / signal-07~e.18 :ARG0 (p3 / protein :name (n5 / name :op1 "RhoA"~e.17))))) :mod (i / indeed~e.0)) # ::id a_pmid_2194_3101.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To explore the role of Cdc42 in mutant KRAS @^G12V@ induced cell transformation , Caco @-@ 2 and Caco @-@ K15 cells were treated with siRNA against this small GTPase . # ::alignments 1-1.2 3-1.2.1.1.2 5-1.2.1.1.1.1 7-1.2.1.3.1 8-1.2.1.3.1.2.1.1 10-1.2.1.3.1.1 12-1.2.1.3 13-1.2.1.2 14-1.2.1 16-1.1.1.1.1.1 16-1.1.1.2.1.1 18-1.1.1.1.1.1 19-1.1.1 20-1.1.1.1.1.1 20-1.1.1.2.1.1 22-1.1.1.2.1.1 23-1.1.1.1 23-1.1.1.2 25-1.1 30-1.1.2.1.1 30-1.1.3.2.2 31-1.1.3.2.1.1 (h / have-purpose-91 :ARG1 (t / treat-04~e.25 :ARG1 (a / and~e.19 :op1 (c / cell-line~e.23 :name (n2 / name :op1 "Caco-2"~e.16,18,20)) :op2 (c2 / cell-line~e.23 :name (n3 / name :op1 "Caco-K15"~e.16,20,22))) :ARG2 (n7 / nucleic-acid :name (n4 / name :op1 "small"~e.30 :op2 "interfering" :op3 "RNA")) :purpose (d / defend-01 :ARG2 n7 :ARG3 (e2 / enzyme :name (n5 / name :op1 "GTPase"~e.31) :mod (s / small~e.30)))) :ARG2 (e / explore-01~e.1 :ARG1 (t2 / transform-01~e.14 :ARG0 (p / protein :name (n / name :op1 "Cdc42"~e.5) :domain (r / role~e.3)) :ARG1 (c3 / cell~e.13) :ARG2-of (i / induce-01~e.12 :ARG0 (m / mutate-01~e.7 :value "G12V"~e.10 :ARG1 (g / gene :name (n6 / name :op1 "KRAS"~e.8))))))) # ::id a_pmid_2194_3101.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significant downregulation of Cdc42 at the protein level was observed in both cell lines ( Figure 7C @ -@ upper panel ) , that caused a significant decrease of cell migration and invasion ability of Caco @-@ K15 and of Caco @-@ 2 cells but to a lesser extent ( Figure 7C @ -@ lower panel ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.3.r 6-1.1.3.1 7-1.1.3 9-1.1.4 10-1.1.4.1.r 11-1.1.4.1.1 12-1.1.4.1 13-1.1.4.1 15-1.1.5.1 17-1.1.5.1.1 20-1.1.5.1.2.1 21-1.1.5.1.2 25-1 27-1.2.3 28-1.2 29-1.2.2.r 30-1.2.2.1.1.1 30-1.2.2.2.1.1 31-1.2.2.1.1 31-1.2.2.2.1 32-1.2.2 32-1.2.2.1 32-1.2.2.1.r 32-1.2.2.2 32-1.2.2.2.r 33-1.2.2.1.2.1 33-1.2.2.2.2 36-1.2.2.1.1.1.1.1 36-1.2.2.2.1.1.1.1 38-1.2.2.1.1.1.1.1 39-1.2.2.1 41-1.2.2.1.1.1.1.1 41-1.2.2.2.1.1.1.1 43-1.2.2.2.1.1.1.1 44-1.2.2.1.1.1 45-1.2.2.1.3 46-1.2.2.1.3.2.r 48-1.2.2.1.3.2.1 49-1.2.2.1.3.2 51-1.2.4.1 53-1.2.4.1.1 56-1.2.4.1.2.1 56-1.2.4.1.2.1.1 56-1.2.4.1.2.1.1.r 57-1.2.4.1.2 (c / cause-01~e.25 :ARG0 (d / downregulate-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "Cdc42"~e.3)) :ARG1-of (s / significant-02~e.0) :prep-at~e.4 (l2 / level~e.7 :mod (p2 / protein~e.6)) :ARG1-of (o / observe-01~e.9 :location~e.10 (c2 / cell-line~e.12,13 :mod (b / both~e.11))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.15 :mod "7C"~e.17 :part-of (p3 / panel~e.21 :mod (u / upper~e.20))))) :ARG1 (d3 / decrease-01~e.28 :ARG0 d :ARG1~e.29 (a / and~e.32 :op1~e.32 (a2 / and~e.32,39 :op1 (m3 / migrate-01~e.31 :ARG0 (c3 / cell-line~e.30,44 :name (n2 / name :op1 "Caco-K15"~e.36,38,41))) :op2 (p5 / possible-01 :ARG1 (i3 / invade-01~e.33 :ARG0 c3)) :ARG1-of (c6 / contrast-01~e.45 :ARG2 a4 :mod~e.46 (e / extent~e.49 :degree (l / less~e.48)))) :op2~e.32 (a4 / and~e.32 :op1 (m4 / migrate-01~e.31 :ARG0 (c4 / cell-line~e.30 :name (n3 / name :op1 "Caco-2"~e.36,41,43))) :op2 (i2 / invade-01~e.33 :ARG0 c4))) :ARG2 (s2 / significant-02~e.27) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.51 :mod "7C"~e.53 :part-of (p4 / panel~e.57 :ARG1-of (l3 / low-04~e.56 :degree~e.56 (m5 / more~e.56))))))) # ::id a_pmid_2194_3101.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Depletion of Cdc42 also affected the filopodia formation , when Caco @-@ K cells were treated with siRNA against Cdc42 acquired rounded cell membrane lacking filapodia protrusion suggesting that filopodia formation in Caco @-@ K cells is Cdc42 @-@ dependent ( Figure 7D ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.3 4-1.1 7-1.1.2 10-1.1.4.2.1.1 11-1.1.4.2.1.1 12-1.1.4.2.1.1 13-1.1.4.2.1.1 15-1.1.4.2.1 18-1.1.4.2.1.3 19-1.1.4.2.1.3.1 20-1.1.4 20-1.1.4.2.2.1 21-1.1.4.2.2.1.2.1 22-1.1.4.2.2.1.2.2 23-1.1.4.2.2.1.2 24-1.1.4.2.2.1.2.3 26-1.1.4.2.2.1.2.3.1 27-1 30-1.2.1 31-1.2.1.2.r 32-1.2.1.2 33-1.2.1.2 34-1.2.1.2 35-1.2.1.2 37-1.2.2 39-1.2 41-1.3.1 43-1.3.1.1 (s / suggest-01~e.27 :ARG0 (a / affect-01~e.4 :ARG0 (d / deplete-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "Cdc42"~e.2))) :ARG1 (f / form-01~e.7 :ARG1 (f2 / filopodium)) :mod (a2 / also~e.3) :condition (a3 / acquire-01~e.20 :ARG0 (c2 / cell :name (n4 / name :op1 "Caco-K")) :ARG1-of (c3 / condition-01 :ARG0 (t / treat-04~e.15 :ARG1 c2~e.10,11,12,13 :ARG2 (n2 / nucleic-acid :name (n5 / name :op1 "small" :op2 "interfere" :op3 "RNA")) :ARG0-of (c4 / counter-01~e.18 :ARG1 p~e.19)) :ARG1-of (r2 / result-01 :ARG2 (a4 / acquire-01~e.20 :ARG0 c2 :ARG1 (m / membrane~e.23 :ARG1-of (r / round-04~e.21) :mod (c5 / cell~e.22) :ARG0-of (l / lack-01~e.24 :ARG1 (p2 / protrude-01~e.26 :ARG1 (f5 / filopodium))))))))) :ARG2 (d2 / depend-01~e.39 :ARG0 (f3 / form-01~e.30 :ARG1 (f4 / filopodium) :location~e.31 c2~e.32,33,34,35) :ARG1 p~e.37) :ARG1-of (d3 / describe-01 :ARG0 (f6 / figure~e.41 :mod "7D"~e.43))) # ::id a_pmid_2194_3101.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings suggest that KRAS @^G12V@ regulates motility and invasiveness of colon cancer cells through the Cdc42 GTPase . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1 3-1.2.r 4-1.2.1.2.1.1 6-1.2.1.1 8-1.2 9-1.2.2.1 12-1.2.2.1.1.r 13-1.2.2.1.1.1.2 14-1.2.2.1.1.1.1.1 15-1.2.2.1.1 18-1.2.3.1.1 19-1.2.3.1.2 (s / suggest-01~e.2 :ARG0 (t2 / thing~e.1 :mod (t / this~e.0) :ARG1-of~e.1 (f / find-01~e.1)) :ARG1~e.3 (r / regulate-01~e.8 :ARG0 (m / mutate-01 :value "G12V"~e.6 :ARG1 (g / gene :name (n3 / name :op1 "KRAS"~e.4))) :ARG1 (a3 / and :op1 (m2 / motility~e.9 :mod~e.12 (c2 / cell~e.15 :mod (d / disease :name (n / name :op1 "Cancer"~e.14) :location (c / colon~e.13)))) :op2 (i / invade-01 :ARG0 c2)) :manner (p / protein :name (n4 / name :op1 "Cdc42"~e.18 :op2 "GTPase"~e.19)))) # ::id a_pmid_2194_3101.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Considering that the PI3K pathway is also a KRAS effector pathway , the possibility of a cross @-@ talk between the PI3K signalling pathway and Cdc42 was explored [ @ 16 , 21 @ ] . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1.2 4-1.2.1 5-1.2.1.2.r 6-1.2.2 8-1.2.1.1.1.1.1 9-1.2.1.1 10-1.2.1 13-1.1 21-1.1.1.1.1.1.1.1 22-1.1.1.1.1 23-1.1.1.1 25-1.1.1.2.1.1 26-1.2.1.2.r 27-1 30-1.3.1.1 34-1.3.1.2 (e / explore-01~e.27 :ARG1 (p / possible-01~e.13 :ARG1 (i / interfere-01 :ARG0 (p2 / pathway~e.23 :ARG1-of (s / signal-07~e.22 :ARG0 (p3 / pathway :name (n / name :op1 "PI3K"~e.21)))) :ARG1 (p4 / protein :name (n2 / name :op1 "Cdc42"~e.25)))) :condition (c / consider-01~e.0 :ARG1~e.1 (p5 / pathway~e.4,10 :mod (e2 / effector~e.9 :mod (g / gene :name (n3 / name :op1 "KRAS"~e.8))) :domain~e.5,26 p3~e.3) :mod (a / also~e.6)) :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 16~e.30 :op2 21~e.34))) # ::id a_pmid_2194_3101.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following treatment with wortmanin at the most optimal treatment condition , as retrieved from inhibition of the active PI3K pathway in Caco @-@ H2 cells that show high p @-@ AKT levels ( Additional Figure 4 ) , resulted in reduced Cdc42 activity . # ::alignments 0-1.2.1 1-1.2.1 2-1.2.1 3-1.2.1 4-1.2.1 5-1.2.1 6-1.2.1 7-1.2.1 8-1.2.1 9-1.2.1 10-1.2.1 11-1.2.1 12-1.2.1 13-1.2.1 14-1.2.1 17-1.2.2 18-1.1.2.1.1.1 19-1.1.2.1 21-1.1.2.3.1.1 23-1.1.2.3.1.1 24-1.1.2.3 26-1.1.2.3.2 27-1.1.2.3.2.1.1 28-1.1.2.3.2.1.2.2 30-1.1.2.3.2.1.2.1.1 31-1.1.2.3.2.1 33-1.1.3.1.2 34-1.1.3.1 36-1.1.3.1.1 40-1 42-1.2 43-1.2.2.1.1.1 44-1.2.2 (r / result-01~e.40 :ARG1 (f3 / follow-01 :ARG2 (t / treat-04 :ARG2 (w2 / wortmanin)) :example (i / inhibit-01 :ARG1 (p2 / pathway~e.19 :name (n2 / name :op1 "PI3K"~e.18) :ARG1-of (a2 / activate-01)) :ARG1-of (r3 / retrieve-01) :location (c / cell-line~e.24 :name (n3 / name :op1 "Caco-H2"~e.21,23) :ARG0-of (s / show-01~e.26 :ARG1 (l / level~e.31 :ARG1-of (h / high-02~e.27) :quant-of (e / enzyme :name (n4 / name :op1 "AKT"~e.30) :ARG3-of (p3 / phosphorylate-01~e.28)))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.34 :mod 4~e.36 :mod (a4 / additional~e.33))) :condition (t3 / treat-04 :mod (o2 / optimal :degree (m3 / most)))) :ARG2 (r2 / reduce-01~e.42 :ARG0 f3~e.0,1,2,3,4,5,6,7,8,9,10,11,12,13,14 :ARG1 (a / activity-06~e.17,44 :ARG0 (p / protein :name (n / name :op1 "Cdc42"~e.43))))) # ::id a_pmid_2194_3101.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This illustrates how Cdc42 activation in response to the KRAS @^G12V@ -@ PI3K signalling pathway can be potentially essential for Cdc42 @-@ dependent cell migration and invasion properties ( Figure 7E ) . # ::alignments 0-1.1 1-1 2-1.2.1.r 3-1.2.1.1.1.1.1.1 4-1.2.1.1.1 5-1.2.1.1.1.2.r 6-1.2.1.1.1.2 14-1.2.1.1.1.2.1.1.1 15-1.2.1.1.1.2.1.2 16-1.2.1.1.1.2.1 17-1.2.1 18-1.2.1.1.1.r 20-1.2.1.1 21-1.2.1.1.2.r 22-1.2.1.1.2.1.1.1.1 24-1.2.1.1.2.1.1.1 25-1.2.1.1.2.1.1 26-1.2.1.1.2.1 27-1.2.1.1.2 28-1.2.1.1.2.2.1 29-1.2.1.1.2.2 31-1.3.1 33-1.3.1.1 (i / illustrate-01~e.1 :ARG0 (t / this~e.0) :ARG1 (t2 / thing :manner-of~e.2 (p4 / possible-01~e.17 :ARG1 (e2 / essential~e.20 :domain~e.18 (a2 / activate-01~e.4 :ARG1 (p6 / protein :name (n3 / name :op1 "Cdc42"~e.3)) :ARG2-of~e.5 (r2 / respond-01~e.6 :ARG1 (p7 / pathway~e.16 :name (n4 / name :op1 "KRASG12V-PI3K"~e.14) :ARG1-of (s2 / signal-07~e.15)))) :purpose~e.21 (a3 / and~e.27 :op1 (m / migrate-01~e.26 :ARG0 (c / cell~e.25 :ARG0-of (d3 / depend-01~e.24 :ARG1 p6~e.22))) :op2 (p8 / property~e.29 :mod (i2 / invade-01~e.28 :ARG0 c)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "7E"~e.33))) # ::id a_pmid_2194_3101.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HRAS @^G12V@ induces high cell migration and invasion properties mediated by Rac1 associated with acquired EMT # ::alignments 0-1.1.2.1.1 2-1.1.1 4-1 5-1.2.1.2 6-1.2.1.1 7-1.2.1 8-1.2 9-1.2.2.1 10-1.2.2 11-1.2.2.1.1 12-1.2.2.1.1.1.r 13-1.2.2.1.1.1.1.1.1 14-1.2.2.1.1.1 15-1.2.2.1.1.1.2.r 16-1.2.2.1.1.1.2.3 17-1.2.2.1.1.1.2.2.2 (i / induce-01~e.4 :ARG0 (m / mutate-01 :value "G12V"~e.2 :ARG1 (g / gene :name (n / name :op1 "HRAS"~e.0))) :ARG2 (a3 / and~e.8 :op1 (m2 / migrate-01~e.7 :ARG0 (c2 / cell~e.6) :ARG1-of (h / high-02~e.5)) :op2 (p3 / property~e.10 :mod (i2 / invade-01~e.9 :ARG1-of (m3 / mediate-01~e.11 :ARG0~e.12 (a4 / associate-01~e.14 :ARG1 (p2 / protein :name (n4 / name :op1 "Rac1"~e.13)) :ARG2~e.15 (e / event :wiki "Epithelial–mesenchymal_transition" :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.17) :ARG1-of (a6 / acquire-01~e.16)))))))) # ::id a_pmid_2194_3101.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of Rac1 , another RAS effector protein , was found slightly increased in Caco @-@ H2 cells with EMT characteristics [ @ 15 , 25 @ ] ( Figure 8A ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.2 5-1.1.1.1.3.1.1.1 6-1.1.1.1.3 7-1.1.1.1 7-1.1.1.1.3.1 9-1.1.1.1.3.r 10-1 11-1.1.2 12-1.1 13-1.1.3.r 14-1.1.3.1.1 16-1.1.3.1.1 17-1.1.3 18-1.1.3.2.r 19-1.1.3.2.1.1.2 20-1.1.3.2 23-1.2.1.1.1.1.1 27-1.2.1.1.1.1.2 31-1.2.1.2 33-1.2.1.2.1 (f / find-01~e.10 :ARG1 (i3 / increase-01~e.12 :ARG1 (a / activate-01~e.0 :ARG1~e.1 (p / protein~e.7 :name (n2 / name :op1 "Rac1"~e.2) :mod (a6 / another~e.4) :domain~e.9 (e2 / effector~e.6 :mod (p2 / protein-family~e.7 :name (n3 / name :op1 "Ras"~e.5))))) :ARG2 (s2 / slight~e.11) :location~e.13 (c / cell-line~e.17 :name (n5 / name :op1 "Caco-H2"~e.14,16) :ARG1-of~e.18 (c6 / characteristic-02~e.20 :ARG2 (e / event :name (n / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.19))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 (a5 / and :op1 15~e.23 :op2 25~e.27))) :op2 (f2 / figure~e.31 :mod "8A"~e.33)))) # ::id a_pmid_2194_3101.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of Rac1 in Caco @-@ H2 cells is in agreement with previous studies that correlate Rac1 with EMT and the inhibition of E @-@ cadherin in mammary epithelial and pancreatic carcinoma cells respectively [ @ 32 @ ] . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 4-1.1.1.2.1.1 6-1.1.1.2.1.1 7-1.1.1.2 10-1 11-1.2.r 12-1.2.2 13-1.2 15-1.2.1 16-1.2.1.1 17-1.2.1.2.r 18-1.2.1.2.1.1.2 19-1.2.1.2 21-1.2.1.2.2 22-1.2.1.2.2.1.r 23-1.2.1.2.2.1.1.1 25-1.2.1.2.2.1.1.1 27-1.2.1.2.2.1.2.1.2 28-1.2.1.2.2.1.2.1.1 29-1.2.1.2.2.1.2 30-1.2.1.2.2.1.2.2.1 31-1.2.1.2.2.1.2.2.2 32-1.2.1.2.2.1.2.1 32-1.2.1.2.2.1.2.2 33-1.2.1.2.2.1.2.3 36-1.3.1.1.1 (a / agree-01~e.10 :ARG0 (a2 / activate-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "Rac1"~e.2) :location (c / cell-line~e.7 :name (n2 / name :op1 "Caco-H2"~e.4,6)))) :ARG2~e.11 (s / study-01~e.13 :ARG0-of (c2 / correlate-01~e.15 :ARG1 p~e.16 :ARG2~e.17 (a3 / and~e.19 :op1 (e3 / event :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.18)) :op2 (i / inhibit-01~e.21 :ARG1~e.22 (p2 / protein :name (n4 / name :op1 "E-cadherin"~e.23,25) :location (a4 / and~e.29 :op1 (c3 / cell~e.32 :mod (e / epithelium~e.28) :mod (m / mammary~e.27)) :op2 (c4 / cell~e.32 :mod (p3 / pancreas~e.30) :mod (c5 / carcinoma~e.31)) :mod (r / respective~e.33)))))) :time (p5 / previous~e.12)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 32~e.36)))) # ::id a_pmid_2194_3101.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , a weak effect on Rac1 GTPase was recorded in Caco @-@ BR cells ( Figure 8A ) and could be explained by the known antagonistic effect that exists between RhoA and Rac1 [ @ 33 @ ] . # ::alignments 1-1 4-1.1.1.1.2 5-1.1.1.1 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1 8-1.1.1.1.1.1.2 10-1.1.1 11-1.1.1.2.r 12-1.1.1.2.1.1 14-1.1.1.2.1.1 15-1.1.1.2 17-1.1.1.3.1 19-1.1.1.3.1.1 22-1.1 23-1.1.2 25-1.1.2.1 26-1.1.2.1.1.r 28-1.1.2.1.1.2 30-1.1.2.1.1 34-1.1.2.1.1.1.1.1.1 35-1.1 36-1.1.2.1.1.1.2.1.1 39-1.2.1.1.1 (c / contrast-01~e.1 :ARG2 (a / and~e.22,35 :op1 (r / record-01~e.10 :ARG1 (a2 / affect-01~e.5 :ARG1~e.6 (p2 / protein :name (n / name :op1 "Rac1"~e.7 :op2 "GTPase"~e.8)) :ARG1-of (w / weak-02~e.4)) :location~e.11 (c2 / cell-line~e.15 :name (n2 / name :op1 "Caco-BR"~e.12,14)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod "8A"~e.19))) :op2 (p / possible-01~e.23 :ARG1 (e / explain-01~e.25 :ARG0~e.26 (a3 / affect-01~e.30 :ARG2 (a4 / antagonize-02 :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA"~e.34)) :ARG2 (p4 / protein :name (n4 / name :op1 "Rac1"~e.36))) :ARG1-of (k / know-01~e.28)) :ARG1 a2))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 33~e.39)))) # ::id a_pmid_2194_3101.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As described earlier , HRAS @^G12V@ -@ transfected Caco @-@ 2 cells ( Caco @-@ H2 ) have undergone EMT , followed by the dramatic reduction of E @-@ cadherin expression [ @ 16 @ ] . # ::alignments 0-1.4.1.r 1-1.4 1-1.5 2-1.4.1 2-1.4.1.1 2-1.4.1.1.r 4-1.1.2.1.1.1 6-1.1.2.1.2.1 9-1.1.2 10-1.1.1.1 12-1.1.1.1 13-1.1 15-1.1.1.1 20-1 21-1.2.1.2 23-1.3 24-1.3.1.r 26-1.3.1.2 27-1.3.1 28-1.3.1.1.r 29-1.3.1.1.1.1.1 31-1.3.1.1.1.1.1 32-1.3.1.1 35-1.5.1.1.1 (u / undergo-28~e.20 :ARG1 (c / cell-line~e.13 :name (n / name :op1 "Caco-2"~e.10,12,15) :ARG1-of (t / transfect-01~e.9 :ARG2 (e3 / enzyme :name (n2 / name :op1 "HRAS"~e.4) :ARG2-of (m / mutate-01 :value "G12V"~e.6)))) :ARG2 (e4 / event :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.21)) :ARG2-of (f / follow-01~e.23 :ARG1~e.24 (r / reduce-01~e.27 :ARG1~e.28 (e / express-03~e.32 :ARG2 (p2 / protein :name (n4 / name :op1 "E-cadherin"~e.29,31))) :manner (d / dramatic~e.26))) :ARG1-of (d2 / describe-01~e.1 :time~e.0 (e2 / early~e.2 :degree~e.2 (m2 / more~e.2))) :ARG1-of (d3 / describe-01~e.1 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 16~e.35)))) # ::id a_pmid_2194_3101.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following PI3K pathway depletion using the specific inhibitor wortmanin at the most optimal treatment condition ( Additional Figure 4 ) , Rac1 activity was successfully inhibited only in Caco @-@ 2 cells , leaving Caco @-@ H2 cells unaffected ( Figure 8B , upper panel ) . # ::alignments 0-1.4 1-1.4.1.1.1.1 2-1.4.1.1 3-1.4.1 4-1.4.1.2 6-1.4.1.2.1.3 7-1.4.1.2.1 7-1.4.1.2.1.2 7-1.4.1.2.1.2.r 8-1.4.1.2.1.1.1 11-1.4.1.2.2.1.1 13-1.4.1.2.2 14-1.4.1.2.2.r 17-1.4.1.3.1 19-1.4.1.3.1.1 23-1.1.1.1.1 24-1.1 26-1.2 27-1 28-1.3.2 30-1.3.1.1 32-1.3.1.1 33-1.3 35-1.1.1.2 36-1.1.1.2.1.2.1.1 38-1.1.1.2.1.2.1.1 39-1.1.1.2.1.2 40-1.1.1.2.1 40-1.1.1.2.1.1 40-1.1.1.2.1.1.r 42-1.5.1 44-1.5.1.1 47-1.5.1.2.1 48-1.5.1.2 (i / inhibit-01~e.27 :ARG1 (a / activity-06~e.24 :ARG0 (p / protein :name (n / name :op1 "Rac1"~e.23) :ARG0-of (l / leave-13~e.35 :ARG1 (a2 / affect-01~e.40 :polarity~e.40 -~e.40 :ARG1 (c2 / cell-line~e.39 :name (n3 / name :op1 "Caco-H2"~e.36,38)))))) :ARG1-of (s / succeed-01~e.26) :location (c / cell-line~e.33 :name (n2 / name :op1 "Caco-2"~e.30,32) :mod (o / only~e.28)) :ARG2-of (f / follow-01~e.0 :ARG1 (d / deplete-01~e.3 :ARG1 (p2 / pathway~e.2 :name (n4 / name :op1 "PI3K"~e.1)) :ARG0-of (u / use-01~e.4 :ARG1 (s2 / small-molecule~e.7 :name (n5 / name :op1 "wortmanin"~e.8) :ARG0-of~e.7 (i2 / inhibit-01~e.7) :ARG1-of (s3 / specific-02~e.6)) :condition~e.14 (t2 / treat-04~e.13 :mod (o2 / optimum :degree (m2 / most~e.11)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.17 :mod 4~e.19 :ARG1-of (a3 / add-02))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.42 :mod "8B"~e.44 :location (p3 / panel~e.48 :mod (u2 / upper~e.47))))) # ::id a_pmid_2194_3101.226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , under the same treatment conditions RhoA activity was found to be slightly increased , suggesting an involvement of the PI3K pathway in RhoA regulation ( Figure 8B , lower panel ) . # ::alignments 0-1.4 4-1.2.1 5-1.2 6-1.2.r 7-1.1.1.1.2.1 8-1.1.1 10-1 13-1.1.2 14-1.1 16-1.1.3 18-1.1.3.1 19-1.1.3.1.1.r 21-1.1.3.1.1.2.1 22-1.1.3.1.1 23-1.1.3.1.2.r 24-1.1.3.1.2.1 25-1.1.3.1.2 27-1.3.1 29-1.3.1.1 32-1.3.1.2.1 32-1.3.1.2.1.1 32-1.3.1.2.1.1.r 33-1.3.1.2 (f / find-02~e.10 :ARG1 (i / increase-01~e.14 :ARG1 (a / activity-06~e.8 :ARG0 (p / protein :wiki "RHOA" :name (n / name :op1 "RhoA"~e.7))) :ARG2 (s / slight~e.13) :ARG0-of (s3 / suggest-01~e.16 :ARG1 (i2 / involve-01~e.18 :ARG1~e.19 (p2 / pathway~e.22 :wiki - :name (n2 / name :op1 "PI3K"~e.21)) :ARG2~e.23 (r / regulate-01~e.25 :ARG1 p~e.24)))) :condition~e.6 (t / treat-04~e.5 :ARG1-of (s2 / same-01~e.4)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.27 :mod "8B"~e.29 :location (p3 / panel~e.33 :ARG1-of (l / low-04~e.32 :degree~e.32 (m / more~e.32))))) :ARG1-of (n3 / notable-04~e.0)) # ::id a_pmid_2194_3101.227 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is therefore concluded that in Caco @-@ H2 cells , HRAS @^G12V@ deregulates PI3K @-@ dependent activation of Rac1 as well as mediates RhoA inhibition . # ::alignments 2-1 3-1.1 5-1.1.1.r 6-1.1.1.1.3.1.1 8-1.1.1.1.3.1.1 9-1.1.1.1.3 11-1.1.1.1.1.1.1 13-1.1.1.1.1.2.1 15-1.1.1.1 16-1.1.1.1.2.1.2.1.1.1 18-1.1.1.1.2.1 18-1.1.1.1.2.1.2 18-1.1.1.1.2.1.2.r 19-1.1.1.1.2 21-1.1.1.1.2.1.1.1 22-1.1.1 23-1.1.1 24-1.1.1 25-1.1.1.2 26-1.1.1.2.2.1.1.1 27-1.1.1.2.2 (c2 / cause-01~e.2 :ARG1 (c / conclude-01~e.3 :ARG1~e.5 (a2 / and~e.22,23,24 :op1 (d / deregulate-01~e.15 :ARG0 (e2 / enzyme :name (n / name :op1 "HRAS"~e.11) :ARG2-of (m / mutate-01 :value "G12V"~e.13)) :ARG1 (a / activate-01~e.19 :ARG1 (p2 / protein~e.18 :name (n2 / name :op1 "Rac1"~e.21) :ARG0-of~e.18 (d2 / depend-01~e.18 :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K"~e.16))))) :location (c3 / cell-line~e.9 :name (n5 / name :op1 "Caco-H2"~e.6,8))) :op2 (m2 / mediate-01~e.25 :ARG0 e2 :ARG1 (i / inhibit-01~e.27 :ARG1 (p3 / protein :name (n4 / name :op1 "RhoA"~e.26))))))) # ::id a_pmid_2194_3101.228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further explore the involvement of Rac1 activation in the transforming ability of HRAS @^G12V@ in Caco @-@ 2 cells , pharmacological inhibition of Rac1 was established using the selective inhibitor NSC23766 ( Figure 8C ) [ @ 34 @ ] . # ::alignments 1-1.3.2 2-1.3 4-1.3.1 5-1.3.1.1.r 6-1.3.1.1.1 7-1.3.1.1 8-1.3.1.2.r 10-1.3.1.2.2 11-1.3.1.2 12-1.3.1.2.1.r 13-1.3.1.2.1.1.1 15-1.3.1.2.1.2.1 17-1.3.1.2.2.2.r 18-1.3.1.2.2.2.1.1 20-1.3.1.2.2.2.1.1 21-1.3.1.2.2.2 24-1.1 24-1.2.1 24-1.2.1.2 24-1.2.1.2.r 25-1.1.1.r 26-1.1.1.1.1 28-1 29-1.2 29-1.3.r 31-1.2.1.3 32-1.2.1 32-1.2.1.2 32-1.2.1.2.r 33-1.2.1.1.1 35-1.4.1.1 37-1.4.1.1.1 42-1.4.1.2.1.1 (e / establish-01~e.28 :ARG1 (i / inhibit-01~e.24 :ARG1~e.25 (p / protein :name (n / name :op1 "Rac1"~e.26)) :mod (p2 / pharmacologic)) :ARG2-of (u / use-01~e.29 :ARG1 (s2 / small-molecule~e.24,32 :name (n2 / name :op1 "NSC23766"~e.33) :ARG0-of~e.24,32 (i2 / inhibit-01~e.24,32) :mod (s / selective~e.31))) :purpose~e.29 (e2 / explore-01~e.2 :ARG1 (i3 / involve-01~e.4 :ARG1~e.5 (a / activate-01~e.7 :ARG1 p~e.6) :ARG2~e.8 (c / capable-01~e.11 :ARG1~e.12 (e3 / enzyme :name (n3 / name :op1 "HRAS"~e.13) :ARG2-of (m2 / mutate-01 :value "G12V"~e.15)) :ARG2 (t / transform-01~e.10 :ARG0 e3 :location~e.17 (c2 / cell-line~e.21 :name (n4 / name :op1 "Caco-2"~e.18,20))))) :degree (f / further~e.1)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure~e.35 :mod "8C"~e.37) :op2 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 34~e.42))))) # ::id a_pmid_2194_3101.229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibition of Rac1 not only managed to suppress Rac1 activation but also to abolish cell migration and invasion properties in a dose dependent manner ( Figure 8D ) , indicating the critical role of Rac1 in EMT cell properties of Caco @-@ H cells . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 5-1 7-1.2.1 8-1.2.1.2.1 9-1.2.1.2 11-1.2.2.3 13-1.2.2 14-1.2.2.2.1.1 15-1.2.2.2.1.1.1 16-1.2.2.2 17-1.2.2.2.2.1.1 18-1.2.2.2.1 21-1.2.2.4.1 22-1.2.2.4 23-1.2.2.4.r 25-1.3.1 27-1.3.1.1 31-1.4 33-1.4.1.1 34-1.4.1 36-1.1.1.1.1 37-1.4.1.1.1.r 38-1.4.1.1.1.2.1.2 39-1.4.1.1.1.1 40-1.2.2.2.2 40-1.4.1.1.1 42-1.4.1.1.1.1.1.1 44-1.4.1.1.1.1.1.1 45-1.2.2.2.2.1 (m / manage-01~e.5 :ARG0 (i / inhibit-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "Rac1"~e.2,36))) :ARG1 (a / and :op1 (s / suppress-01~e.7 :ARG0 i :ARG1 (a2 / activate-01~e.9 :ARG1 p~e.8)) :op2 (a3 / abolish-01~e.13 :ARG0 i :ARG1 (a4 / and~e.16 :op1 (p2 / property~e.18 :mod (c / cell~e.14 :ARG0-of (m2 / migrate-01~e.15))) :op2 (p3 / property~e.40 :mod (c5 / cell~e.45 :ARG0-of (i2 / invade-01~e.17)))) :mod (a5 / also~e.11) :manner~e.23 (d / depend-01~e.22 :ARG1 (d2 / dose~e.21)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.25 :mod "8D"~e.27)) :ARG0-of (i3 / indicate-01~e.31 :ARG1 (r / role~e.34 :ARG1-of (c2 / critical-02~e.33 :ARG2~e.37 (p4 / property~e.40 :poss (c3 / cell-line~e.39 :name (n3 / name :op1 "Caco-H"~e.42,44)) :mod (e / event :name (n2 / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.38)))) :poss p))) # ::id a_pmid_2194_3101.230 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGFβ-1 co @-@ operates with BRAF @^V600E@ @ and KRAS @^G12V@ @ oncogenes to provide Caco @-@ 2 cells with enhanced transformation properties # ::alignments 0-1.1.1.1 6-1.2.1.1.1 8-1.2.1.2.1 11-1.2 13-1.2.2.1.1 15-1.2.2.2.1 19-1.2.3 20-1.3 21-1.3.3.1.1 23-1.3.3.1.1 24-1.3.3 25-1.3.2.r 26-1.3.2.2 27-1.3.2.1 28-1.3.2 (c / cooperate-01 :ARG0 (p / protein :name (n / name :op1 "TGFβ-1"~e.0)) :ARG1 (a / and~e.11 :op1 (g / gene :name (n2 / name :op1 "BRAF"~e.6) :ARG2-of (m / mutate-01 :value "V600E"~e.8)) :op2 (g2 / gene :name (n3 / name :op1 "KRAS"~e.13) :ARG2-of (m2 / mutate-01 :value "G12V"~e.15)) :ARG0-of (c2 / cause-01~e.19 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG2 (p2 / provide-01~e.20 :ARG0 p :ARG1~e.25 (p3 / property~e.28 :ARG0-of (t / transform-01~e.27) :ARG1-of (e / enhance-01~e.26)) :ARG2 (c3 / cell-line~e.24 :name (n4 / name :op1 "Caco-2"~e.21,23)))) # ::id a_pmid_2194_3101.231 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since BRAF @^V600E@ @ and KRAS @^G12V@ @ oncogenes did not manage to fully transform Caco @-@ 2 cells nor induced an EMT phenotype , as HRAS @^G12V@ @ did , it was further investigated whether co @-@ operation of oncogene @-@ growth factor can produce synergistic effect . # ::alignments 0-1.1.1.2.1.1 0-1.3 2-1.3.1.1.2.1.1.1 4-1.3.1.1.2.1.2.1 7-1.3.1.1.2 9-1.3.1.1.2.2.1.1 11-1.3.1.1.2.2.2.1 16-1.3.1.1.1 16-1.3.1.1.1.r 17-1.3.1.1 19-1.3.1.1.3.3 20-1.3.1.1.3 21-1.3.1.1.3.2.1.1 23-1.3.1.1.3.2.1.1 24-1.3.1.1.3.2 25-1.3.1.2.1 25-1.3.1.2.1.r 26-1.3.1.2 28-1.3.1.2.3.1.1.2 29-1.3.1.2.3 33-1.3.1.3.1.1.1 35-1.3.1.3.1.2.1 42-1.2 43-1 44-1.1.1.1 44-1.1.1.1.r 51-1.1.1.2.1 52-1.1.1.2.1 53-1.1 54-1.1.1 55-1.1.1.3.1 56-1.1.1.3 (i / investigate-01~e.43 :ARG1 (p2 / possible-01~e.53 :ARG1 (p / produce-01~e.54 :mode~e.44 interrogative~e.44 :ARG0 (c / cooperate-01 :ARG0 (g4 / growth-factor~e.51,52 :ARG0-of (c2 / cause-01~e.0 :ARG1 (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))) :ARG1 (a / affect-01~e.56 :ARG2 (s / synergize-01~e.55)))) :degree (f / further~e.42) :ARG1-of (c4 / cause-01~e.0 :ARG0 (a2 / and :op1 (m / manage-01~e.17 :polarity~e.16 -~e.16 :ARG0 (a3 / and~e.7 :op1 (g / gene :name (n2 / name :op1 "BRAF"~e.2) :ARG2-of (m2 / mutate-01 :value "V600E"~e.4)) :op2 (g2 / gene :name (n3 / name :op1 "KRAS"~e.9) :ARG2-of (m3 / mutate-01 :value "G12V"~e.11)) :ARG0-of c2) :ARG1 (t / transform-01~e.20 :ARG0 a3 :ARG1 (c3 / cell-line~e.24 :name (n4 / name :op1 "Caco-2"~e.21,23)) :degree (f2 / full~e.19))) :op2 (i2 / induce-01~e.26 :polarity~e.25 -~e.25 :ARG0 a3 :ARG2 (p4 / phenotype~e.29 :mod (e / event :name (n5 / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.28)))) :ARG1-of (c8 / contrast-01 :ARG2 (g3 / gene :name (n6 / name :op1 "HRAS"~e.33) :ARG2-of (m4 / mutate-01 :value "G12V"~e.35)))))) # ::id a_pmid_2194_3101.232 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The previously established oncogenic models of BRAF @^V600E@ and KRAS @^G12V@ along with the parental Caco @-@ 2 cells were treated with Transforming Growth Factor beta @-@ 1 ( TGFβ-1 ) for 14 days . # ::alignments 1-1.1.1.3.1 2-1.1.1.3 3-1.1.1.2 3-1.1.1.2.1.2.1 4-1.1.1 4-1.1.2 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1.1.1.1.2.1 10-1.1 11-1.1.2.1.1.1 13-1.1.2.1.2.1 18-1.1.3.2 19-1.1.3.1.1 21-1.1.3.1.1 22-1.1.3 24-1 25-1.2.r 26-1.2.1.1 27-1.2.1.2 28-1.2.1.3 29-1.2.1.4 31-1.2.1.4 35-1.3.r 36-1.3.1 37-1.3.2 (t / treat-04~e.24 :ARG1 (a / and~e.10 :op1 (m / model~e.4 :poss~e.5 (g / gene :name (n2 / name :op1 "BRAF"~e.6) :ARG2-of (m2 / mutate-01 :value "V600E"~e.8)) :ARG0-of (c / cause-01~e.3 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.3))) :ARG1-of (e / establish-01~e.2 :time (p3 / previous~e.1))) :op2 (m3 / model~e.4 :poss (g2 / gene :name (n3 / name :op1 "KRAS"~e.11) :ARG2-of (m4 / mutate-01 :value "G12V"~e.13)) :ARG1-of e :ARG0-of c) :op3 (c2 / cell-line~e.22 :name (n4 / name :op1 "Caco-2"~e.19,21) :mod (p2 / parent~e.18))) :ARG2~e.25 (p / protein :name (n / name :op1 "Transforming"~e.26 :op2 "Growth"~e.27 :op3 "Factor"~e.28 :op4 "beta-1"~e.29,31)) :duration~e.35 (t2 / temporal-quantity :quant 14~e.36 :unit (d / day~e.37))) # ::id a_pmid_2194_3101.233 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Staining with phalloidin revealed significant morphological changes in TGFβ-1 treated Caco @-@ K15 cells that were not observed in Caco @-@ 2 cells following treatment with TGFβ-1 , while no morphological changes were recorded in TGFβ-1 treated Caco @-@ BR13 cells ( Figure 9A ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1 4-1.1.2.4 5-1.1.2.2 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.2.1.1.1 9-1.1.2.1.2 10-1.1.2.1.1.1 12-1.1.2.1.1.1 13-1.1.2.1 13-1.1.2.3.2 16-1.1.2.3.1 16-1.1.2.3.1.r 17-1.1.2.3 19-1.1.2.3.2.1.1 21-1.1.2.3.2.1.1 22-1.1.2.1 23-1.1.2.3.3 24-1.1.2.3.3.1 25-1.1.2.3.3.1 26-1.1.2.3.3.1 28-1 29-1.2.1.1 29-1.2.1.1.r 30-1.2.1.3 31-1.2.1 33-1.2 34-1.2.1.2.r 35-1.2.1.2.2 36-1.2.1.2.2 37-1.2.1.2.1.1 39-1.2.1.2.1.1 40-1.2.1.2 42-1.3.1 44-1.3.1.1 (c4 / contrast-01~e.28 :ARG1 (r / reveal-01~e.3 :ARG0 (s / stain-01~e.0 :ARG2~e.1 (s3 / small-molecule :name (n / name :op1 "phalloidin"~e.2))) :ARG1 (c / change-01~e.6 :ARG1~e.7 (c2 / cell-line~e.13,22 :name (n2 / name :op1 "Caco-K15"~e.10,12) :ARG1-of (t / treat-04~e.9 :ARG2 (p / protein :name (n3 / name :op1 "TGFβ-1"~e.8)))) :mod (m2 / morphological~e.5) :ARG1-of (o / observe-01~e.17 :polarity~e.16 -~e.16 :location (c3 / cell-line~e.13 :name (n4 / name :op1 "Caco-2"~e.19,21)) :ARG1-of (f / follow-01~e.23 :ARG2 t~e.24,25,26)) :ARG1-of (s2 / significant-02~e.4))) :ARG2 (r2 / record-01~e.33 :ARG1 (c5 / change-01~e.31 :polarity~e.29 -~e.29 :ARG1~e.34 (c6 / cell-line~e.40 :name (n5 / name :op1 "Caco-BR13"~e.37,39) :ARG1-of t~e.35,36) :mod m2~e.30)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.42 :mod "9A"~e.44))) # ::id a_pmid_2194_3101.234 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein analysis for E @-@ cadherin , in fractionized soluble ( intracellular ) and insoluble ( bound @-@ membrane E @-@ cadherin ) extracts indicated a reduction of E @-@ cadherin in the insoluble fraction in Caco @-@ 2 and Caco @-@ K15 cells to a greater extend ( Figure 9B , upper panel ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.3.r 3-1.1.3.1.1 5-1.1.3.1.1 9-1.1.1.2.1 11-1.1.1.1.2 13-1.1.1 14-1.1.1.1.1 14-1.1.1.2.1 14-1.1.1.2.1.1 14-1.1.1.2.1.1.r 16-1.1.1.2.2.1.2.1 18-1.1.1.2.2.1.2 19-1.1.1.2.2.1.1.1 21-1.1.1.2.2.1.1.1 23-1.1.1.1 23-1.1.1.2 24-1 26-1.2 28-1.1.1.2.2.1.1.1 28-1.1.3.1.1 30-1.1.1.2.2.1.1.1 30-1.1.3.1.1 33-1.1.1.2.1 33-1.1.1.2.1.1 33-1.1.1.2.1.1.r 34-1.1.1.3 34-1.2.3.1 34-1.2.3.2 35-1.2.3.r 36-1.2.3.1.1.1.1 36-1.2.3.2.1.1.1 38-1.2.3.1.1.1.1 39-1.2.3 40-1.2.3.1.1.1.1 40-1.2.3.2.1.1.1 42-1.2.3.2.1.1.1 43-1.2.3.1.1 43-1.2.3.2.1 44-1.2.2.r 46-1.2.2 46-1.2.2.1 46-1.2.2.1.r 49-1.3.1 51-1.3.1.1 54-1.3.1.2.1 55-1.3.1.2 (i / indicate-01~e.24 :ARG0 (a / analyze-01~e.1 :ARG1 (a2 / and~e.13 :op1 (e / extract~e.23 :mod (s / soluble~e.14) :location (c / cell~e.11)) :op2 (e2 / extract~e.23 :mod (s2 / soluble~e.9,14,33 :polarity~e.14,33 -~e.14,33) :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n / name :op1 "E-cadherin"~e.19,21,28,30) :mod (m2 / membrane~e.18 :ARG1-of (b / bind-01~e.16))))) :ARG1-of (f / fraction-01~e.34)) :mod (p / protein~e.0) :purpose~e.2 (p3 / protein :name (n2 / name :op1 "E-cadherin"~e.3,5,28,30))) :ARG1 (r / reduce-01~e.26 :ARG1 p3 :ARG2~e.44 (g / great~e.46 :degree~e.46 (m3 / more~e.46)) :location~e.35 (a3 / and~e.39 :op1 (f2 / fraction~e.34 :part-of (c2 / cell-line~e.43 :name (n3 / name :op1 "Caco-2"~e.36,38,40)) :mod s2) :op2 (f3 / fraction~e.34 :part-of (c3 / cell-line~e.43 :name (n4 / name :op1 "Caco-K15"~e.36,40,42)) :mod s2))) :ARG1-of (d / describe-01 :ARG0 (f4 / figure~e.49 :mod "9B"~e.51 :location (p4 / panel~e.55 :mod (u / upper~e.54))))) # ::id a_pmid_2194_3101.235 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , even though levels of E @-@ cadherin were not altered in Caco @-@ BR13 cells , confocal images clearly presented disrupted cell @-@ cell contacts and discontinuous staining which weakens cell junctions allowing cell migration ( Figure 9B , lower panel @-@ arrows ) . # ::alignments 0-1.5 0-1.5.r 2-1.8.r 3-1.8.r 4-1.8.2 5-1.8.2.1.r 6-1.8.2.1.1.1 8-1.8.2.1.1.1 10-1.8.1 10-1.8.1.r 11-1.8 12-1.8.3.r 13-1.8.3.1.1 15-1.8.3.1.1 16-1.8.3 18-1.1.1 19-1.1 20-1.7 21-1 22-1.2.1.3 23-1.2.1.1 25-1.2.1.1 26-1.2.1 27-1.2 28-1.2.2.1 28-1.2.2.1.1 28-1.2.2.1.1.r 29-1.2.2 31-1.3 32-1.3.1.1 33-1.3.1 34-1.4 35-1.4.1.1 36-1.4.1 38-1.6.1 40-1.6.1.1 43-1.6.1.2.1 43-1.6.1.2.1.1 43-1.6.1.2.1.1.r 44-1.6.1.2 46-1.6.1.2 (p / present-102~e.21 :ARG0 (i / image~e.19 :mod (c / confocal~e.18)) :ARG1 (a / and~e.27 :op1 (c2 / contact-01~e.26 :ARG0 (c3 / cell~e.23,25) :ARG1 c3 :ARG1-of (d / disrupt-01~e.22)) :op2 (s / stain-01~e.29 :ARG1-of (c4 / continue-01~e.28 :polarity~e.28 -~e.28))) :ARG0-of (w / weaken-01~e.31 :ARG1 (j / junction~e.33 :mod c3~e.32)) :ARG0-of (a2 / allow-01~e.34 :ARG1 (m / migrate-01~e.36 :ARG0 c3~e.35)) :manner~e.0 (i2 / interesting~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.38 :mod "9B"~e.40 :location (p3 / panel-arrow~e.44,46 :ARG1-of (l2 / low-04~e.43 :degree~e.43 (m2 / more~e.43))))) :ARG1-of (c5 / clear-06~e.20) :concession~e.2,3 (a3 / alter-01~e.11 :polarity~e.10 -~e.10 :ARG1 (l / level~e.4 :quant-of~e.5 (p2 / protein :name (n / name :op1 "E-cadherin"~e.6,8))) :location~e.12 (c6 / cell-line~e.16 :name (n2 / name :op1 "Caco-BR13"~e.13,15)))) # ::id a_pmid_2194_3101.236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Altered localization of E @-@ cadherin is an important mechanism contributing to cell metastasis [ @ 35 @ ] . # ::alignments 0-1.3.2 1-1.3 2-1.3.1.r 3-1.3.1.1.1 5-1.3.1.1.1 6-1.3.r 8-1.1 9-1 10-1.2 11-1.2.1.r 12-1.2.1.1 13-1.2.1 16-1.4.1.1.1 (m / mechanism~e.9 :mod (i / important~e.8) :ARG0-of (c / contribute-01~e.10 :ARG2~e.11 (m2 / metastasize-101~e.13 :ARG1 (c2 / cell~e.12))) :domain~e.6 (l / localize-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "E-cadherin"~e.3,5)) :ARG1-of (a / alter-01~e.0)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 35~e.16)))) # ::id a_pmid_2194_3101.237 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGFβ-1 was also investigated for its potential effect on cell migration and invasion . # ::alignments 0-1.1.1.1 2-1.3 3-1 4-1.2.r 5-1.2.1 5-1.2.1.r 6-1.2.3 7-1.2 8-1.2.2.r 9-1.2.2.1.1 10-1.2.2.1 11-1.2.2 12-1.2.2.2 (i / investigate-01~e.3 :ARG1 (p / protein :name (n / name :op1 "TGFβ-1"~e.0)) :ARG2~e.4 (a / affect-01~e.7 :ARG0~e.5 p~e.5 :ARG1~e.8 (a2 / and~e.11 :op1 (m / migrate-01~e.10 :ARG0 (c / cell~e.9)) :op2 (i2 / invade-01~e.12 :ARG0 c)) :mod (p2 / potential~e.6)) :mod (a3 / also~e.2)) # ::id a_pmid_2194_3101.238 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with TGFβ-1 increased the capacity of Caco @-@ BR13 cells to invade in vitro , while no effect in the migrating ability of these cells was recorded ( Figure 9C ) . # ::alignments 0-1.1.1 1-1.1.1.2.r 2-1.1.1.2.1.1 3-1.1 5-1.1.2 6-1.1.2.2.r 7-1.1.2.2.1 8-1.1.2.2.1 9-1.1.2.2.1 10-1.1.2.2.1 12-1.1.2.2 14-1.1.2.2.2 15-1.1.2.2.2 18-1 19-1.2.1.1 19-1.2.1.1.r 20-1.2.1 21-1.1.2.2.2 21-1.2.1.2.r 23-1.2.1.2.2 24-1.2.1.2 27-1.2.1.2.1 29-1.2 31-1.3.1 33-1.3.1.1 (c / contrast-01~e.18 :ARG1 (i / increase-01~e.3 :ARG0 (t / treat-04~e.0 :ARG1 c3 :ARG2~e.1 (p / protein :name (n / name :op1 "TGFβ-1"~e.2))) :ARG1 (c2 / capable-01~e.5 :ARG1 (c3 / cell-line :name (n2 / name :op1 "Caco-BR13")) :ARG2~e.6 (i2 / invade-01~e.12 :ARG0 c3~e.7,8,9,10 :manner (i3 / in-vitro~e.14,15,21)))) :ARG2 (r / record-01~e.29 :ARG1 (a / affect-01~e.20 :polarity~e.19 -~e.19 :ARG1~e.21 (c4 / capable-01~e.24 :ARG1 c3~e.27 :ARG2 (m / migrate-01~e.23 :ARG0 c3)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "9C"~e.33))) # ::id a_pmid_2194_3101.239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This enhanced invasive capacity of Caco @-@ BR13 cells is independent of their cell proliferation ( Additional Figure 5 ) . # ::alignments 0-1.2.4 1-1.2.3 2-1.2.2 3-1.2 4-1.2.1.r 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2.1 10-1 10-1.1 10-1.1.r 13-1.3.1 14-1.3 17-1.4.1 19-1.4.1.1 (d / depend-01~e.10 :polarity~e.10 -~e.10 :ARG0 (c / capable-01~e.3 :ARG1~e.4 (c2 / cell-line~e.8 :name (n / name :op1 "Caco-BR13"~e.5,7)) :ARG2 (i / invade-01~e.2 :ARG0 c2) :ARG1-of (e / enhance-01~e.1) :mod (t / this~e.0)) :ARG1 (p / proliferate-01~e.14 :ARG0 c2~e.13) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod 5~e.19 :ARG1-of (a / add-02)))) # ::id a_pmid_2194_3101.240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , cell migration and invasion of Caco @-@ 2 and Caco @-@ K15 cells were not affected by TGFβ-1 treatment , although KRAS @^G12V@ -@ transfected cells acquired a more elongated morphology and slightly downregulated E @-@ cadherin . # ::alignments 1-1 3-1.1.3.1.1.1 3-1.1.3.1.1.2 4-1.1.3.1 5-1.1.3 5-1.1.3.1.1 6-1.1.3.2 7-1.1.3.2.1.r 8-1.1.3.2.1 9-1.1.3.2.1 10-1.1.3.2.1 11-1.1.3.2.1 12-1.1.3.2.1 13-1.1.3.2.1 14-1.1.3.2.1 15-1.1.3.2.1 17-1.1.1 17-1.1.1.r 18-1.1 19-1.1.2.r 20-1.1.2.1.1.1 21-1.1.2 23-1.1.4.r 24-1.1.4.1.1.1.1.1.1 26-1.1.4.1.1.1.1.2.1 29-1.1.4.1.1.1 30-1.1.4.1.1 31-1.1.4.1 33-1.1.4.1.2.1.1 34-1.1.4.1.2.1 35-1.1.4.1.2 36-1.1.4 37-1.1.4.2.3 38-1.1.4.2 39-1.1.4.2.1.1.1 41-1.1.4.2.1.1.1 (c / contrast-01~e.1 :ARG2 (a / affect-01~e.18 :polarity~e.17 -~e.17 :ARG0~e.19 (t3 / treat-04~e.21 :ARG2 (p3 / protein :name (n6 / name :op1 "TGFβ-1"~e.20))) :ARG1 (a2 / and~e.5 :op1 (m / migrate-01~e.4 :ARG0 (a3 / and~e.5 :op1 (c2 / cell-line~e.3 :name (n / name :op1 "Caco-2")) :op2 (c3 / cell-line~e.3 :name (n2 / name :op1 "Caco-K15")))) :op2 (i / invade-01~e.6 :ARG0~e.7 a3~e.8,9,10,11,12,13,14,15)) :concession~e.23 (a5 / and~e.36 :op1 (a6 / acquire-01~e.31 :ARG0 (c4 / cell~e.30 :ARG1-of (t / transfect-01~e.29 :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS"~e.24) :ARG2-of (m2 / mutate-01 :value "G12V"~e.26)))) :ARG1 (m3 / morphology~e.35 :ARG1-of (e / elongate-01~e.34 :degree (m4 / more~e.33)))) :op2 (d / downregulate-01~e.38 :ARG1 (p2 / protein :name (n5 / name :op1 "E-cadherin"~e.39,41)) :ARG2 c4 :degree (s / slight~e.37))))) # ::id a_pmid_2194_3101.241 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these results suggest that TGFβ-1 can synergise with KRAS @^G12V@ and BRAF @^V600E@ oncogenes to provide Caco @-@ 2 cells with a more transforming phenotype . # ::alignments 0-1.1.3 1-1.1.3.1 3-1.1.2 4-1.1 4-1.1.1 4-1.1.1.r 5-1 6-1.2.r 7-1.2.1.1.1.1 8-1.2 11-1.2.1.2.1.1.1 13-1.2.1.2.1.2.1 15-1.2.1.2 16-1.2.1.2.2.1.1 18-1.2.1.2.2.2.1 21-1.2.1.2.3 22-1.2.1.3 23-1.2.1.3.3.1.1 25-1.2.1.3.3.1.1 26-1.2.1.3.3 27-1.2.1.3.2.r 29-1.2.1.3.2.1.1 30-1.2.1.3.2.1 31-1.2.1.3.2 (s / suggest-01~e.5 :ARG0 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :mod (t2 / this~e.3) :ARG1-of (t4 / take-01~e.0 :mod (t5 / together~e.1))) :ARG1~e.6 (p3 / possible-01~e.8 :ARG1 (s2 / synergize-01 :ARG0 (g / gene :name (n / name :op1 "TGFβ-1"~e.7)) :ARG1 (a / and~e.15 :op1 (g2 / gene :name (n2 / name :op1 "KRAS"~e.11) :ARG2-of (m / mutate-01 :value "G12V"~e.13)) :op2 (g3 / gene :name (n3 / name :op1 "BRAF"~e.16) :ARG2-of (m2 / mutate-01 :value "V600E"~e.18)) :ARG0-of (c / cause-01~e.21 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG2 (p / provide-01~e.22 :ARG0 g :ARG1~e.27 (p2 / phenotype~e.31 :ARG1-of (t3 / transform-01~e.30 :degree (m3 / more~e.29))) :ARG2 (c2 / cell-line~e.26 :name (n4 / name :op1 "Caco-2"~e.23,25)))))) # ::id a_pmid_2194_3101.242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok According to previous studies , the mutation in the C @-@ terminal domain of Smad4 , D351H , that is present in Caco @-@ 2 cells , results in complete Smad4 inactivation [ @ 36 @ ] . # ::alignments 0-1.3 1-1.3 2-1.3.1.1 3-1.3.1 3-1.3.1.2 3-1.3.1.2.r 6-1.1 7-1.1.2.r 9-1.1.2.1.1 11-1.1.2.1.1 14-1.1.2.2.1.1 16-1.1.1 21-1.1.3.r 22-1.1.3.1.1 24-1.1.3.1.1 25-1.1.3 27-1 28-1.2.r 29-1.2.2 30-1.1.2.2.1.1 31-1.2 31-1.2.1 31-1.2.1.r 34-1.4.1.1.1 (r / result-01~e.27 :ARG1 (m / mutate-01~e.6 :value "D351H"~e.16 :ARG1~e.7 (p / protein-segment :name (n / name :op1 "C-terminus"~e.9,11) :part-of (p2 / protein :name (n2 / name :op1 "Smad4"~e.14,30))) :location~e.21 (c2 / cell-line~e.25 :name (n4 / name :op1 "Caco-2"~e.22,24))) :ARG2~e.28 (a / activate-01~e.31 :polarity~e.31 -~e.31 :ARG1-of (c / complete-02~e.29)) :ARG1-of (s / say-01~e.0,1 :ARG0 (t / thing~e.3 :time (p3 / previous~e.2) :ARG1-of~e.3 (s2 / study-01~e.3))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 36~e.34)))) # ::id a_pmid_2194_3101.243 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , TGFβ-1 has been shown to act through alternative non @-@ Smad pathways , such as Rho GTPases and MAPK [ @ 37 @ - @ 39 @ ] . # ::alignments 0-1 2-1.1.1.1.1.1 5-1.1 7-1.1.1 9-1.1.1.2.3 10-1.1.1.2.1 10-1.1.1.2.1.r 12-1.1.1.2.2.1 13-1.1.1.2 13-1.1.1.2.4.1 13-1.1.1.2.4.2 15-1.1.1.2.4.r 16-1.1.1.2.4.r 17-1.1.1.2.4.1.1.1 19-1.1.1.2.4 20-1.1.1.2.4.2.1.1 23-1.1.2.1.1.1.1 27-1.1.2.1.1.1.2 (h / have-concession-91~e.0 :ARG1 (s / show-01~e.5 :ARG1 (a / act-01~e.7 :ARG0 (p / protein :name (n / name :op1 "TGFβ-1"~e.2)) :manner (p7 / pathway~e.13 :polarity~e.10 -~e.10 :name (n5 / name :op1 "Smad"~e.12) :mod (a3 / alternative~e.9) :example~e.15,16 (a2 / and~e.19 :op1 (p4 / pathway~e.13 :name (n3 / name :op1 "Rho"~e.17 :op2 "GTPase")) :op2 (p5 / pathway~e.13 :name (n4 / name :op1 "MAPK"~e.20))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 37~e.23 :op2 39~e.27)))))) # ::id a_pmid_2194_3101.244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , following TGFβ-1 treatment , enhanced activity for RhoA GTPase as well as pERK1 @/@ 2 was recorded in Caco @-@ 2 , Caco @-@ K15 and Caco @-@ BR13 cells . # ::alignments 0-1.4 2-1.3 3-1.3.1.1.1.1 4-1.3.1 6-1.1.2 7-1.1 8-1.1.1.r 9-1.1.1.1.1.1 10-1.1.1.1.1.2 11-1.1.1 12-1.1.1 13-1.2 16-1.1.1.2.1.1 16-1.2.1.1.1 18-1 20-1.2.1.1.1 20-1.2.2.1.1 20-1.2.3.1.1 22-1.2.1.1.1 24-1.2.1.1.1 24-1.2.2.1.1 24-1.2.3.1.1 26-1.2.2.1.1 27-1.2 28-1.2.1.1.1 28-1.2.2.1.1 28-1.2.3.1.1 30-1.2.3.1.1 31-1.2.1 31-1.2.2 31-1.2.3 (r / record-01~e.18 :ARG1 (a / activity-06~e.7 :ARG0~e.8 (a2 / and~e.11,12 :op1 (p / pathway :name (n / name :op1 "RhoA"~e.9 :op2 "GTPase"~e.10)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.16) :ARG3-of (p3 / phosphorylate-01))) :ARG1-of (e / enhance-01~e.6)) :location (a3 / and~e.13,27 :op1 (c / cell-line~e.31 :name (n3 / name :op1 "Caco-2"~e.16,20,22,24,28)) :op2 (c2 / cell-line~e.31 :name (n4 / name :op1 "Caco-K15"~e.20,24,26,28)) :op3 (c3 / cell-line~e.31 :name (n5 / name :op1 "Caco-BR13"~e.20,24,28,30))) :ARG1-of (f / follow-01~e.2 :ARG2 (t / treat-04~e.4 :ARG2 (p2 / protein :name (n6 / name :op1 "TGFβ-1"~e.3)))) :mod (i / indeed~e.0)) # ::id a_pmid_2194_3101.245 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Based on these observations other than non @-@ Smad signaling like RhoA GTPase and pERK1 @/@ 2 pathways can be regulated by TGF @-@ beta , to induce the morphological changes observed in the Caco @-@ 2 transformed and parental cells ( Figure 9D ) . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1 3-1.3.1 6-1.1.2.1.1.1 6-1.1.2.1.1.1.r 8-1.1.2.1.1.2.1 9-1.1.2.1.1.3 10-1.1.2.1.1.4.r 11-1.1.2.1.1.4.1.1.1 12-1.1.2.1.1.4.1.1.2 13-1.1.2.1.1.4 14-1.1.2.1.1.4.2.1.1 16-1.1.2.1.1.4.2.1.1 17-1.1.2 18-1 20-1.1 21-1.1.1.r 22-1.1.1.1.1 24-1.1.1.1.1 27-1.1.3 29-1.1.3.2.2 30-1.1.3.2 31-1.1.3.2.1 32-1.1.3.2.1.1.r 34-1.1.3.2.1.1.1.1.1 34-1.1.3.2.1.1.2.1.1 36-1.1.3.2.1.1.1.1.1 36-1.1.3.2.1.1.2.1.1 37-1.1.3.2.1.1.1.2 38-1.1.3.2.1.1 39-1.1.3.2.1.1.2.2 40-1.1.3.2.1.1.1 40-1.1.3.2.1.1.2 42-1.2.1 44-1.2.1.1 (p / possible-01~e.18 :ARG1 (r / regulate-01~e.20 :ARG0~e.21 (p2 / protein :name (n / name :op1 "TGF-beta"~e.22,24)) :ARG1 (p7 / pathway~e.17 :ARG2-of (e / except-01 :ARG1 (p4 / pathway :polarity~e.6 -~e.6 :name (n4 / name :op1 "Smad"~e.8) :ARG0-of (s / signal-07~e.9) :example~e.10 (a2 / and~e.13 :op1 (p5 / pathway :name (n5 / name :op1 "RhoA"~e.11 :op2 "GTPase"~e.12)) :op2 (p6 / pathway :name (n6 / name :op1 "pERK1/2"~e.14,16)))))) :purpose (i / induce-01~e.27 :ARG0 r :ARG2 (c / change-01~e.30 :ARG1-of (o / observe-01~e.31 :location~e.32 (a / and~e.38 :op1 (c2 / cell-line~e.40 :name (n2 / name :op1 "Caco-2"~e.34,36) :ARG1-of (t / transform-01~e.37)) :op2 (c3 / cell-line~e.40 :name (n3 / name :op1 "Caco-2"~e.34,36) :mod (p3 / parent~e.39)))) :mod (m / morphological~e.29)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.42 :mod "9D"~e.44)) :ARG1-of (b / base-02~e.0 :ARG2~e.1 (o2 / observe-01~e.3 :mod (t2 / this~e.2)))) # ::id a_pmid_2256_9000.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In @-@ vitro inhibition of cell proliferation by selumetinib treatment in NSCLC and CRC cell lines # ::alignments 1-1.4 3-1.4 5-1 6-1.2.r 7-1.2.1 8-1.2 9-1.1.r 10-1.1.1.1.1 11-1.1 12-1.3.r 12-1.4 13-1.3.1.1.1.1 14-1.3 15-1.3.2.1.1.1 16-1.3.1 16-1.3.2 17-1.3.1 (i / inhibit-01~e.5 :ARG0~e.9 (t / treat-04~e.11 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib"~e.10))) :ARG1~e.6 (p / proliferate-01~e.8 :ARG0 (c / cell~e.7)) :location~e.12 (a / and~e.14 :op1 (c2 / cell-line~e.16,17 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.13))) :op2 (c3 / cell-line~e.16 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.15)))) :manner (i2 / in-vitro~e.1,3,12)) # ::id a_pmid_2256_9000.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We first evaluated the sensitivity to the selective MEK1 @/@ 2 inhibitor , selumetinib , in a panel of five NSCLC ( GLC82 , H460 , A549 , H1299 , Calu3 ) and six CRC ( GEO , HCT15 , HCT116 , SW480 , SW620 , LS174T ) cell lines by using the MTT assay . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 8-1.2.1.2.1.1.1 10-1.2.1.2.1.1.1 11-1.2.1 11-1.2.1.2 11-1.2.1.2.r 13-1.2.1.1.1 15-1.4.r 17-1.4 18-1.4.1.r 19-1.4.1.1.1 20-1.4.1.1.3.1.1 22-1.4.1.1.2.1.1.1.1 24-1.4.1.1.2.1.2.1.1 26-1.4.1.1.2.1.3.1.1 28-1.4.1.1.2.1.4.1.1 30-1.4.1.1.2.1.5.1.1 32-1.4.1 32-1.4.1.1.2.1 33-1.4.1.2.1 34-1.4.1.2.3.1.1 36-1.4.1.2.2.1.1.1.1 38-1.4.1.2.2.1.2.1.1 40-1.4.1.2.2.1.3.1.1 42-1.4.1.2.2.1.4.1.1 44-1.4.1.2.2.1.5.1.1 46-1.4.1.2.2.1.6.1.1 48-1.4.1.1 48-1.4.1.2 49-1.4.1.2 50-1.5.r 51-1.5 53-1.5.2.1.1.1 54-1.5.2 (e / evaluate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (s / sensitive-03~e.4 :ARG1 (s2 / small-molecule~e.11 :name (n / name :op1 "selumetinib"~e.13) :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1/2"~e.8,10))) :ARG0-of (s3 / select-01))) :mod (f / first~e.1) :location~e.15 (p / panel~e.17 :consist-of~e.18 (a / and~e.32 :op1 (c / cell-line~e.48 :quant 5~e.19 :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.32 :op1 (c2 / cell-line :name (n4 / name :op1 "GLC82"~e.22)) :op2 (c3 / cell-line :name (n5 / name :op1 "H460"~e.24)) :op3 (c4 / cell-line :name (n6 / name :op1 "A549"~e.26)) :op4 (c5 / cell-line :name (n7 / name :op1 "H1299"~e.28)) :op5 (c6 / cell-line :name (n8 / name :op1 "Calu3"~e.30)))) :mod (d / disease :name (n3 / name :op1 "NSCLC"~e.20))) :op2 (c7 / cell-line~e.48,49 :quant 6~e.33 :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (c8 / cell-line :name (n10 / name :op1 "GEO"~e.36)) :op2 (c9 / cell-line :name (n11 / name :op1 "HCT15"~e.38)) :op3 (c10 / cell-line :name (n12 / name :op1 "HCT116"~e.40)) :op4 (c11 / cell-line :name (n13 / name :op1 "SW480"~e.42)) :op5 (c12 / cell-line :name (n14 / name :op1 "SW620"~e.44)) :op6 (c13 / cell-line :name (n15 / name :op1 "LS174T"~e.46)))) :mod (d2 / disease :name (n9 / name :op1 "CRC"~e.34))))) :manner~e.50 (u / use-01~e.51 :ARG0 w :ARG1 (a4 / assay-01~e.54 :instrument (s4 / small-molecule :name (n16 / name :op1 "MTT"~e.53))))) # ::id a_pmid_2256_9000.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cancer cells were treated with selumetinib at concentrations ranging from 0.01 to 10 μ @ ℳ for 48 , 72 , and 96 h . # ::alignments 0-1.1.1.2.1 1-1.1 3-1 4-1.2.r 5-1.2.1.1 7-1.2.2 7-1.2.2.1.1 7-1.2.2.1.2 8-1.2.2.1 10-1.2.2.1.1.1 12-1.2.2.1.2.1 17-1.3.r 18-1.3.1.1 20-1.3.1.2 22-1.3.1 23-1.3.1.3 24-1.3.2 (t / treat-04~e.3 :ARG1 (c / cell~e.1 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.0))) :ARG2~e.4 (s / small-molecule :name (n2 / name :op1 "selumetinib"~e.5) :quant (c2 / concentration~e.7 :ARG1-of (r / range-01~e.8 :ARG3 (c3 / concentration-quantity~e.7 :quant 0.01~e.10 :unit (m2 / micromolar)) :ARG4 (c4 / concentration-quantity~e.7 :quant 10~e.12 :unit m2)))) :duration~e.17 (t2 / temporal-quantity :quant (a / and~e.22 :op1 48~e.18 :op2 72~e.20 :op3 96~e.23) :unit (h / hour~e.24))) # ::id a_pmid_2256_9000.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 1 , there was a wide range of sensitivity , with IC @₅₀ values varying between 0.01 and > 10 μ @ ℳ. # ::alignments 1-1.2 4-1.2.1 5-1.2.1.1 11-1.1.1 12-1.1 14-1 17-1.1.2.1.1.1 19-1.1.2.1.1.1.1 21-1.1.2.1.1 22-1.1.2.1 24-1.1.2.1.2.1 26-1.1.2.1.3 27-1.1.2.1.3.1.1 (s / sensitive-03~e.14 :ARG1-of (r / range-01~e.12 :ARG1-of (w / wide-02~e.11) :ARG1-of (m / mean-01 :ARG2 (v / vary-01~e.22 :ARG1 (v2 / value~e.21 :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01~e.17 :ARG2 50~e.19)) :ARG3 (c / concentration-quantity :quant 0.01~e.24 :unit (m2 / micromolar)) :ARG4 (m3 / more-than~e.26 :op1 (c2 / concentration-quantity :quant 10~e.27 :unit (m4 / micromolar)))))) :ARG1-of (s2 / show-01~e.1 :ARG0 (f / figure~e.4 :mod 1~e.5))) # ::id a_pmid_2256_9000.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We classified as sensitive ( S ) or resistant ( R ) the cancer cell lines according to selumetinib IC @₅₀ at 96 h ⩽ 1 or > 1 μ @ ℳ, respectively . # ::alignments 0-1.1.1 1-1.1 1-1.2 2-1.1.3.r 3-1.1.3 7-1.1.4.3 8-1.2.3 13-1.1.2.1.2.1 14-1.1.2 15-1.1.2 18-1.1.4.2.1.1 19-1.1.4 19-1.2.4 21-1.1.4.1 21-1.2.4.1 24-1.1.4.4.1.1 25-1.1.4.4.1.2 27-1.1.4.3.1.1 27-1.1.4.3.2.1.1 28-1.1.4.3 29-1.2.4.3 30-1.1.4.3.1.1 30-1.1.4.3.2.1.1 30-1.2.4.3.1.1 (a / and :op1 (c / classify-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c2 / cell-line~e.14,15 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.13))) :ARG2~e.2 (s / sensitive-03~e.3 :ARG0 c2) :condition (h2 / have-percentage-maximal-inhibitory-concentration-01~e.19 :ARG2 50~e.21 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib"~e.18)) :ARG4 (o / or~e.7,28 :op1 (c3 / concentration-quantity :quant 1~e.27,30 :unit (m3 / micromolar)) :op2 (l / less-than :op1 (c4 / concentration-quantity :quant 1~e.27,30 :unit (m / micromolar)))) :time (a2 / after :op1 (t2 / temporal-quantity :quant 96~e.24 :unit (h / hour~e.25))))) :op2 (c5 / classify-01~e.1 :ARG0 w :ARG1 c2 :ARG2 (r / resist-01~e.8 :ARG0 c2) :condition (h3 / have-percentage-maximal-inhibitory-concentration-01~e.19 :ARG2 50~e.21 :ARG1 s2 :ARG4 (m2 / more-than~e.29 :op1 (c7 / concentration-quantity :quant 1~e.30 :unit (m4 / micromolar))) :time a2))) # ::id a_pmid_2256_9000.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This concentration was chosen based on the data from phase I studies , which indicated that 1 μ @ ℳ was within the average plasma concentrations of selumetinib achieved in patients at the maximum tolerated dose for this agent ( Adjei et al , 2008 ) . # ::alignments 0-1.1.1 1-1.1 1-1.2.1.2.1.1 3-1 4-1.2 5-1.2.1.r 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1 10-1.2.1.1.1.1.1 11-1.2.1.1 14-1.2.1.2 16-1.2.1.2.1.1.1 22-1.2.1.2.1.1.1.r 24-1.2.1.2.1.2.3 25-1.2.1.2.1.2.2 26-1.2.1.2.1.2 27-1.2.1.2.1.2.1.r 28-1.2.1.2.1.2.1.1.1 29-1.2.1.2.1.2.4 30-1.2.1.2.1.2.4.1.r 31-1.2.1.2.1.2.4.1 32-1.2.1.2.1.2.5.r 34-1.2.1.2.1.2.5.1 35-1.2.1.2.1.2.5.2 36-1.2.1.2.1.2.5 37-1.2.1.2.1.2.5.2.1.r 38-1.2.1.2.1.2.5.2.1.1 39-1.2.1.2.1.2.5.2.1 42-1.3.1.1.1.1.1 44-1.3.1.1 45-1.3.1.1.2.1 48-1.3.1.2.1 (c / choose-01~e.3 :ARG1 (c2 / concentrate-02~e.1 :mod (t / this~e.0)) :ARG1-of (b / base-02~e.4 :ARG2~e.5 (d / data~e.7 :source~e.8 (s / study-01~e.11 :mod (p / phase~e.9 :ord (o / ordinal-entity :value 1~e.10))) :ARG0-of (i / indicate-01~e.14 :ARG1 (i2 / include-01 :ARG1 (c3 / concentration-quantity~e.1 :quant~e.22 1~e.16 :unit (m / micromolar)) :ARG2 (c4 / concentrate-02~e.26 :ARG1~e.27 (s2 / small-molecule :name (n / name :op1 "selumetinib"~e.28)) :location (p2 / plasma~e.25) :ARG1-of (a / average-04~e.24) :ARG1-of (a2 / achieve-01~e.29 :location~e.30 (p3 / patient~e.31)) :quant~e.32 (d2 / dose~e.36 :quant (m2 / maximum~e.34) :ARG1-of (t2 / tolerate-01~e.35 :topic~e.37 (a3 / agent~e.39 :mod (t3 / this~e.38))))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and~e.44 :op1 (p5 / person :name (n2 / name :op1 "Adjei"~e.42)) :op2 (p6 / person :mod (o2 / other~e.45))) :time (d4 / date-entity :year 2008~e.48)))) # ::id a_pmid_2256_9000.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overall , 67 % ( four of six ) CRC and 40 % ( two of five ) NSCLC cell lines had a selumetinib IC @₅₀ of ⩽ 1 μ @ ℳ. # ::alignments 0-1.3 2-1.1.1.2.2.1 3-1.1.1.2.2 5-1.1.1.1 7-1.1.1.2.1.1 9-1.1.1.2.1.2.1.1 10-1.1 11-1.1.2.2.2.1 12-1.1.2.2.2 14-1.1.2.1 16-1.1.2.2.1.1 18-1.1.2.2.1.2.1.1 19-1.1.1 19-1.1.1.2.1 19-1.1.2 19-1.1.2.2.1 20-1.1.2.2.1 21-1 23-1.2.1.1 24-1.2 24-1.2.2 24-1.2.2.r 26-1.2.2.1 30-1.2.2.2.1.2.1 30-1.2.2.2.1.1 (h / have-03~e.21 :ARG0 (a / and~e.10 :op1 (c / cell-line~e.19 :quant 4~e.5 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.19 :quant 6~e.7 :mod (d2 / disease :name (n / name :op1 "CRC"~e.9))) :ARG3 (p / percentage-entity~e.3 :value 67~e.2))) :op2 (c3 / cell-line~e.19 :quant 2~e.14 :ARG1-of (i2 / include-91 :ARG2 (c4 / cell-line~e.19,20 :quant 5~e.16 :mod (d / disease :name (n3 / name :op1 "NSCLC"~e.18))) :ARG3 (p2 / percentage-entity~e.12 :value 40~e.11)))) :ARG1 (s / small-molecule~e.24 :name (n6 / name :op1 "selumetinib"~e.23) :ARG1-of~e.24 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.24 :ARG2 50~e.26 :ARG4 (c5 / concentration-quantity :quant (o / or :op2 1~e.30 :op1 (l / less-than :op1 1~e.30)) :unit (m / micromolar)))) :mod (o2 / overall~e.0)) # ::id a_pmid_2256_9000.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In particular , among the sensitive cancer cell lines there were four , two NSCLC ( Calu3 and H1299 ) and two CRC ( HCT116 and SW620 ) , extremely sensitive to selumetinib with an IC @₅₀ of ⩽ 0.01 μ @ ℳ ( Figure 1A and B ) . # ::alignments 1-1.3 3-1 3-1.1.4 5-1.1.3 6-1.1.2.2.1 7-1.1 7-1.2 8-1.1 8-1.1.4.1.1 8-1.1.4.1.2 11-1.1.1 13-1.1.4.1.2.1 14-1.1.4.1.1.3.1.1 16-1.1.4.1.1.2.1.1.1.1 17-1.1.4.1.1.2.1 18-1.1.4.1.1.2.1.2.1.1 21-1.1.4.1.1.1 22-1.1.4.1.2.3.1.1 24-1.1.4.1.2.2.1.1.1.1 26-1.1.4.1.2.2.1.2.1.1 29-1.1.4.1.3.2 30-1.1.4.1.3 31-1.1.4.1.3.1.r 32-1.1.4.1.3.1.1.1 35-1.1.4.1.3.1 35-1.1.4.1.3.1.2 35-1.1.4.1.3.1.2.r 37-1.1.4.1.3.1.2.1 41-1.1.4.1.3.1.2.2.1.2.1 41-1.1.4.1.3.1.2.2.1.1 48-1.4.1.1 48-1.4.1.2 49-1.4.1.1.1 50-1.4.1 (i / include-91~e.3 :ARG1 (c / cell-line~e.7,8 :quant 4~e.11 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.6)) :ARG0-of (s / sensitive-03~e.5) :ARG2-of (i2 / include-91~e.3 :ARG1 (a / and :op1 (c2 / cell-line~e.8 :quant 2~e.21 :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.17 :op1 (c3 / cell-line :name (n3 / name :op1 "Calu3"~e.16)) :op2 (c4 / cell-line :name (n4 / name :op1 "H1299"~e.18)))) :mod (d3 / disease :name (n2 / name :op1 "NSCLC"~e.14))) :op2 (c5 / cell-line~e.8 :quant 2~e.13 :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (c6 / cell-line :name (n6 / name :op1 "HCT116"~e.24)) :op2 (c7 / cell-line :name (n7 / name :op1 "SW620"~e.26)))) :mod (d4 / disease :name (n5 / name :op1 "CRC"~e.22))) :ARG0-of (s2 / sensitive-03~e.30 :ARG1~e.31 (s3 / small-molecule~e.35 :name (n8 / name :op1 "selumetinib"~e.32) :ARG1-of~e.35 (h / have-percentage-maximal-inhibitory-concentration-01~e.35 :ARG2 50~e.37 :ARG4 (c8 / concentration-quantity :quant (o / or :op2 0.01~e.41 :op1 (l / less-than :op1 0.01~e.41)) :unit (m3 / micromolar)))) :degree (e2 / extreme~e.29))))) :ARG2 (c9 / cell-line~e.7 :mod d :ARG0-of s) :mod (p / particular~e.1) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.50 :op1 (f / figure~e.48 :mod "1A"~e.49) :op2 (f2 / figure~e.48 :mod "1B")))) # ::id a_pmid_2256_9000.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the mechanisms underlying the different sensitivities to the drug , we conducted experiments on a group of four cancer cell lines representing both selumetinib @-@ sensitive ( HCT116 and Calu3 ) and selumetinib @-@ resistant ( HCT15 and H460 ) models . # ::alignments 1-1.3 3-1.3.2 4-1.3.2.1 6-1.3.2.1.1.2 7-1.3.2.1.1 8-1.3.2.1.1.1.r 10-1.3.2.1.1.1 12-1.1 13-1 14-1.2 15-1.2.2.r 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1.1 20-1.2.2.1.2.2.1 21-1.2.2.1 22-1.2.2.1 23-1.2.2.1.3 25-1.2.2.1.3.1.1.1.1.1.1 27-1.2.2.1.3.1.1.1 29-1.2.2.1.3.1.1.2.1.1.1.1 30-1.2.2.1.3.1.1.2.1 31-1.2.2.1.3.1.1.2.1.2.1.1 34-1.2.2.1.3.1.2.1.1 36-1.2.2.1.3.1.2.1 38-1.2.2.1.3.1.2.2.1.1.1.1 40-1.2.2.1.3.1.2.2.1.2.1.1 42-1.2.2.1.3.1.1 42-1.2.2.1.3.1.2 (c / conduct-01~e.13 :ARG0 (w / we~e.12) :ARG1 (e / experiment-01~e.14 :ARG0 w :ARG1~e.15 (g / group~e.17 :consist-of~e.18 (c2 / cell-line~e.21,22 :quant 4~e.19 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.20)) :ARG0-of (r / represent-01~e.23 :ARG1 (a / and :op1 (m / model-01~e.42 :ARG0-of (s / sensitive-03~e.27 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib"~e.25))) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.30 :op1 (c3 / cell-line :name (n3 / name :op1 "HCT116"~e.29)) :op2 (c4 / cell-line :name (n4 / name :op1 "Calu3"~e.31))))) :op2 (m3 / model-01~e.42 :ARG0-of (r2 / resist-01~e.36 :ARG1 s2~e.34) :ARG1-of (m4 / mean-01 :ARG2 (a3 / and :op1 (c5 / cell-line :name (n5 / name :op1 "HCT15"~e.38)) :op2 (c6 / cell-line :name (n6 / name :op1 "H460"~e.40)))))))))) :purpose (i / investigate-01~e.1 :ARG0 w :ARG1 (m5 / mechanism~e.3 :ARG0-of (u / underlie-01~e.4 :ARG1 (s3 / sensitive-03~e.7 :ARG1~e.8 (d2 / drug~e.10) :ARG1-of (d3 / differ-02~e.6)))))) # ::id a_pmid_2256_9000.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of selumetinib treatment on cell @-@ cycle distribution in NSCLC and CRC cell lines # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1 3-1.1 4-1.2.r 5-1.2.1.1 7-1.2.1 8-1.2 9-1.3.r 10-1.3.1.1.1.1 11-1.3 12-1.3.2.1.1.1 13-1.3.1 13-1.3.2 14-1.3.1 (a / affect-01~e.0 :ARG0~e.1 (t / treat-04~e.3 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib"~e.2))) :ARG1~e.4 (d / distribute-01~e.8 :ARG1 (c / cycle-02~e.7 :ARG1 (c2 / cell~e.5))) :location~e.9 (a2 / and~e.11 :op1 (c3 / cell-line~e.13,14 :mod (d2 / disease :name (n2 / name :op1 "NSCLC"~e.10))) :op2 (c4 / cell-line~e.13 :mod (d3 / disease :name (n3 / name :op1 "CRC"~e.12))))) # ::id a_pmid_2256_9000.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We conducted flow cytometric analysis to compare the cell @-@ cycle distribution following treatment of the selumetinib @-@ sensitive HCT116 and Calu3 cancer cell lines and of the selumetinib @-@ resistant HCT15 and H460 cancer cell lines . # ::alignments 0-1.1 1-1 2-1.2.1.1 4-1.2 6-1.3 8-1.3.2.1.1 10-1.3.2.1 11-1.3.2 12-1.3.2.2 13-1.3.2.2.1 14-1.3.2.2.1.1.r 16-1.3.2.2.1.1.1.4.1.1.1 18-1.3.2.2.1.1.1.4 19-1.3.2.2.1.1.1.1.1.1 20-1.3.2.2.1.1.1 21-1.3.2.2.1.1.1.2.1.1 22-1.3.2.2.1.1.1.3.2.1 23-1.3.2.2.1.1.1.1 24-1.3.2.2.1.1.1.1 24-1.3.2.2.1.1.1.2 24-1.3.2.2.1.1.2.2 25-1.3.2.2.1.1.1 28-1.3.2.2.1.1.2.4.1 30-1.3.2.2.1.1.2.4 31-1.3.2.2.1.1.2.1.1.1 32-1.3.2.2.1.1.2 33-1.3.2.2.1.1.2.2.1.1 34-1.3.2.2.1.1.1.3.2.1 35-1.3.2.2.1.1.2.1 36-1.3.2.2.1.1.2.1 (c / conduct-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / analyze-01~e.4 :manner (c9 / cytometry :mod (f2 / flow~e.2))) :purpose (c2 / compare-01~e.6 :ARG0 w :ARG1 (d / distribute-01~e.11 :ARG1 (c3 / cycle-02~e.10 :ARG1 (c4 / cell~e.8)) :ARG1-of (f / follow-01~e.12 :ARG2 (t / treat-04~e.13 :ARG1~e.14 (a2 / and :op1 (a3 / and~e.20,25 :op1 (c5 / cell-line~e.23,24 :name (n2 / name :op1 "HCT116"~e.19)) :op2 (c6 / cell-line~e.24 :name (n3 / name :op1 "Calu3"~e.21)) :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.22,34)) :ARG0-of (s / sensitive-03~e.18 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "selumetinib"~e.16)))) :op2 (a4 / and~e.32 :op1 (c7 / cell-line~e.35,36 :name (n6 / name :op1 "HCT15"~e.31)) :op2 (c8 / cell-line~e.24 :name (n7 / name :op1 "H460"~e.33)) :mod d2 :ARG0-of (r / resist-01~e.30 :ARG1 s2~e.28)))))))) # ::id a_pmid_2256_9000.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cancer cells were treated with selumetinib at the IC @₅₀ values for inhibition of cell proliferation for 24 , 48 , and 72 h . # ::alignments 0-1.1.1.2.1 1-1.1 3-1 4-1.2.r 5-1.2.1.1 8-1.2 8-1.2.2 8-1.2.2.r 10-1.2.2.1 13-1.2.2.2.r 14-1.2.2.2 15-1.2.2.2.1.r 16-1.2.2.2.1.1 17-1.2.2.2.1 18-1.3.r 19-1.3.1.1 21-1.3.1.2 23-1.3.1 24-1.3.1.3 25-1.3.2 (t / treat-04~e.3 :ARG1 (c / cell~e.1 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.0))) :ARG2~e.4 (s / small-molecule~e.8 :name (n2 / name :op1 "selumetinib"~e.5) :ARG1-of~e.8 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.8 :ARG2 50~e.10 :ARG3~e.13 (i / inhibit-01~e.14 :ARG1~e.15 (p / proliferate-01~e.17 :ARG0 (c2 / cell~e.16))))) :duration~e.18 (t3 / temporal-quantity :quant (a / and~e.23 :op1 24~e.19 :op2 48~e.21 :op3 72~e.24) :unit (h / hour~e.25))) # ::id a_pmid_2256_9000.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Twenty @-@ four hours selumetinib treatment caused cell accumulation in the G1 phase and concomitant reduction in the S phase as compared with controls in selumetinib @-@ sensitive cancer cell lines ( Figure 2A ) . # ::alignments 3-1.1.2.2 4-1.1.1.1.1 5-1.1 6-1 7-1.2.1.1 8-1.2.1 9-1.2.1.2.r 11-1.2.1.2.1.1 12-1.2.1.2 13-1.2 14-1.2.2.2 15-1.2.2 18-1.2.2.3.1.1 19-1.2.2.3 20-1.2.2.3.r 20-1.2.r 21-1.2.3.r 23-1.2.3 23-1.2.3.1 23-1.2.3.1.r 24-1.2.3.2.r 25-1.2.3.2.2.1 27-1.2.3.2.2 28-1.2.3.2.1.2.1 29-1.2.3.2 30-1.2.3.2 33-1.3.1 34-1.3.1.1 (c / cause-01~e.6 :ARG0 (t / treat-04~e.5 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib"~e.4)) :duration (t2 / temporal-quantity :quant 24 :unit (h / hour~e.3))) :ARG1~e.20 (a / and~e.13 :op1 (a2 / accumulate-01~e.8 :ARG1 (c2 / cell~e.7) :time~e.9 (p / phase~e.12 :name (n2 / name :op1 "G1"~e.11))) :op2 (r / reduce-01~e.15 :ARG1 c2 :mod (c3 / concomitant~e.14) :time~e.20 (p2 / phase~e.19 :name (n3 / name :op1 "S"~e.18))) :compared-to~e.21 (m / molecular-physical-entity~e.23 :ARG2-of~e.23 (c4 / control-01~e.23) :location~e.24 (c5 / cell-line~e.29,30 :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.28)) :ARG0-of (s2 / sensitive-03~e.27 :ARG1 s~e.25)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.33 :mod "2A"~e.34))) # ::id a_pmid_2256_9000.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The arrest in the G1 phase was significantly increased with longer ( 48 and 72 h ) treatment with selumetinib in both HCT116 and Calu3 cells . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.1.1 5-1.1.1 7-1.2 8-1 9-1.3.r 10-1.3.2 10-1.3.2.1 10-1.3.2.1.r 12-1.3.2.2.1.1.1 13-1.3.2.2.1 14-1.3.2.2.1.2.1 15-1.3.2.2.1.1.2 15-1.3.2.2.1.2.2 17-1.3 18-1.3.1.r 18-1.3.r 19-1.3.1.1.1 22-1.4.1.1.1 23-1.4 24-1.4.2.1.1 25-1.4.1 25-1.4.2 (i / increase-01~e.8 :ARG1 (a / arrest-02~e.1 :time~e.2 (p / phase~e.5 :name (n / name :op1 "G1"~e.4))) :ARG2 (s / significant-02~e.7) :instrument~e.9,18 (t / treat-04~e.17 :ARG2~e.18 (s2 / small-molecule :name (n2 / name :op1 "selumetinib"~e.19)) :ARG1-of (l / long-03~e.10 :degree~e.10 (m / more~e.10) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and~e.13 :op1 (t2 / temporal-quantity :quant 48~e.12 :unit (h / hour~e.15)) :op2 (t3 / temporal-quantity :quant 72~e.14 :unit (h2 / hour~e.15)))))) :location (a3 / and~e.23 :op1 (c / cell-line~e.25 :name (n3 / name :op1 "HCT116"~e.22)) :op2 (c2 / cell-line~e.25 :name (n4 / name :op1 "Calu3"~e.24)))) # ::id a_pmid_2256_9000.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This effect was also paralleled by a time @-@ dependent reduction in the S phase in both selumetinib @-@ sensitive cancer cell lines ( Figure 2A ) . # ::alignments 0-1.1.1 1-1.1 3-1.3 4-1 5-1.2.r 7-1.2.1.1 9-1.2.1 10-1.2 11-1.2.2.r 13-1.2.2.1.1 14-1.2.2 15-1.2.3.r 16-1.2.3.3 17-1.2.3.2.1.1.1 19-1.2.3.2 20-1.2.3.1.2.1 21-1.2.3 22-1.2.3 25-1.4.1 26-1.4.1.1 (p / parallel-01~e.4 :ARG0 (a / affect-01~e.1 :mod (t / this~e.0)) :ARG1~e.5 (r / reduce-01~e.10 :ARG0-of (d / depend-01~e.9 :ARG1 (t2 / time~e.7)) :time~e.11 (p2 / phase~e.14 :name (n / name :op1 "S"~e.13)) :location~e.15 (c / cell-line~e.21,22 :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.20)) :ARG0-of (s / sensitive-03~e.19 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib"~e.17))) :mod (b / both~e.16))) :mod (a2 / also~e.3) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.25 :mod "2A"~e.26))) # ::id a_pmid_2256_9000.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , no effect was observed on cell @-@ cycle distribution in the two selumetinib @-@ resistant HCT15 and H460 cells ( Figure 2A ) . # ::alignments 1-1 3-1.1.1.1 3-1.1.1.1.r 4-1.1.1 6-1.1 7-1.1.1.2.r 8-1.1.1.2.1.1 10-1.1.1.2.1 11-1.1.1.2 12-1.1.2.r 14-1.1.2.1 15-1.1.2.4.1.1.1 17-1.1.2.4 18-1.1.2.2.1.1 19-1.1.2 20-1.1.2.3.1.1 21-1.1.2.2 21-1.1.2.3 24-1.2.1 25-1.2.1.1 (c / contrast-01~e.1 :ARG2 (o / observe-01~e.6 :ARG1 (a / affect-01~e.4 :polarity~e.3 -~e.3 :ARG1~e.7 (d / distribute-01~e.11 :ARG1 (c2 / cycle-02~e.10 :ARG1 (c3 / cell~e.8)))) :location~e.12 (a2 / and~e.19 :quant 2~e.14 :op1 (c4 / cell-line~e.21 :name (n / name :op1 "HCT15"~e.18)) :op2 (c5 / cell-line~e.21 :name (n2 / name :op1 "H460"~e.20)) :ARG0-of (r / resist-01~e.17 :ARG1 (s / small-molecule :name (n3 / name :op1 "selumetinib"~e.15))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "2A"~e.25))) # ::id a_pmid_2256_9000.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results were supported also by Garon et al ( 2010 ) , in which the block in G1 phase inducted by selumetinib is evident only in sensitive cell lines . # ::alignments 0-1.2.2 1-1.2 1-1.2.1 1-1.2.1.r 3-1 4-1.3 7-1.1.1.1.1.1 9-1.1.1 10-1.1.1.2.1 13-1.1.2.1 20-1.1.3.1 21-1.1.3.1.1.r 22-1.1.3.1.1.1.1 23-1.1.3.1.1 26-1.1.3.1.2.1.1.1 27-1.1.3.1.r 28-1.1.3 29-1.1.3.2.2 31-1.1.3.2.1 32-1.1.3.2 33-1.1.3.2 (s / support-01~e.3 :ARG0 (p / publication-91 :ARG0 (a / and~e.9 :op1 (p2 / person :name (n / name :op1 "Garon"~e.7)) :op2 (p3 / person :mod (o / other~e.10))) :time (d / date-entity :year 2010~e.13) :location-of (e / evident~e.28 :domain~e.27 (b / block-01~e.20 :time~e.21 (p4 / phase~e.23 :name (n2 / name :op1 "G1"~e.22)) :ARG2-of (i / induce-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "selumetinib"~e.26)))) :location (c / cell-line~e.32,33 :ARG0-of (s3 / sensitive-03~e.31) :mod (o2 / only~e.29)))) :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :mod (a2 / also~e.4)) # ::id a_pmid_2256_9000.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of selumetinib treatment on the induction of apoptosis in NSCLC and CRC cell lines # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1 3-1.1 4-1.2.r 6-1.2 7-1.2.1.r 8-1.2.1 9-1.3.r 10-1.3.1.1.1.1 11-1.3 12-1.3.2.1.1.1 13-1.3.1 13-1.3.2 14-1.3.1 (a / affect-01~e.0 :ARG0~e.1 (t / treat-04~e.3 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib"~e.2))) :ARG1~e.4 (i / induce-01~e.6 :ARG2~e.7 (a2 / apoptosis~e.8)) :location~e.9 (a3 / and~e.11 :op1 (c / cell-line~e.13,14 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.10))) :op2 (c2 / cell-line~e.13 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.12))))) # ::id a_pmid_2256_9000.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several preclinical models have demonstrated that selumetinib act as a cytotoxic drug rather than cytostatic by inducing proapoptotic activity ( Huynh et al , 2007a ; Huynh et al , 2007b ; Meng et al , 2009 ; Meng et al , 2010 ) . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2 8-1.2.2.r 8-1.3.1.1.2.r 8-1.3.1.2.2.r 8-1.3.1.4.2.r 10-1.2.2.1 11-1.2.2 11-1.2.2.2.1 12-1.2.2.2 14-1.2.2.2.1.1 15-1.2.3.r 16-1.2.3 18-1.2.3.1 21-1.3.1.1.1.1.1.1 23-1.3.1.1.1 24-1.3.1.1.1.2.1 31-1.3.1.1.1.1.1.1 33-1.3.1.1.1 34-1.3.1.1.1.2.1 41-1.3.1.3.1.1.1.1 43-1.3.1 43-1.3.1.1.1 43-1.3.1.3.1 44-1.3.1.1.1.2.1 47-1.3.1.3.2.1 51-1.3.1.3.1.1.1.1 53-1.3.1 53-1.3.1.1.1 53-1.3.1.3.1 54-1.3.1.1.1.2.1 57-1.3.1.4.2.1 (d / demonstrate-01~e.4 :ARG0 (m / model-01~e.2 :mod (p / preclinical~e.1) :quant (s / several~e.0)) :ARG1~e.5 (a / act-01~e.7 :ARG0 (s2 / small-molecule :name (n / name :op1 "selumetinib"~e.6)) :ARG1~e.8 (d2 / drug~e.11 :mod (c / cytotoxic~e.10) :ARG1-of (i / instead-of-91~e.12 :ARG2 (d3 / drug~e.11 :mod (c2 / cytostatic~e.14)))) :manner~e.15 (i2 / induce-01~e.16 :ARG2 (a2 / activity-06~e.18 :ARG0-of (f / favor-01 :ARG1 (a3 / apoptosis))))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and~e.43,53 :op1 (p2 / publication-91 :ARG0 (a5 / and~e.23,33,43,53 :op1 (p3 / person :name (n2 / name :op1 "Huynh"~e.21,31)) :op2 (p4 / person :mod (o / other~e.24,34,44,54))) :time~e.8 (d5 / date-entity :year 2007)) :op2 (p5 / publication-91 :ARG0 a5 :time~e.8 d5) :op3 (p6 / publication-91 :ARG0 (a6 / and~e.43,53 :op1 (p7 / person :name (n3 / name :op1 "Meng"~e.41,51)) :op2 p4) :time (d6 / date-entity :year 2009~e.47)) :op4 (p8 / publication-91 :ARG0 a6 :time~e.8 (d7 / date-entity :year 2010~e.57))))) # ::id a_pmid_2256_9000.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm this effect , the induction of apoptosis was evaluated using an FACS @-@ based assay for Annexin V and PI staining . # ::alignments 1-1.3 2-1.3.1.1 3-1.3.1 6-1.1 7-1.1.1.r 8-1.1.1 10-1 11-1.2 11-1.3.r 13-1.2.1.1.1.1.1 15-1.2.1.1 16-1.2.1 17-1.2.2.r 18-1.2.2.1.1.1.1 19-1.2.2.1.1.1.2 20-1.2.2.1 21-1.2.2.1.2.1.1 22-1.2.2 (e / evaluate-01~e.10 :ARG1 (i / induce-01~e.6 :ARG2~e.7 (a / apoptosis~e.8)) :manner (u / use-01~e.11 :ARG1 (a2 / assay-01~e.16 :ARG1-of (b / base-02~e.15 :ARG2 (t / thing :name (n / name :op1 "FACS"~e.13)))) :purpose~e.17 (s / stain-01~e.22 :ARG1 (a3 / and~e.20 :op1 (p / protein :name (n2 / name :op1 "Annexin"~e.18 :op2 "V"~e.19)) :op2 (s2 / small-molecule :name (n3 / name :op1 "PI"~e.21))))) :purpose~e.11 (c / confirm-01~e.1 :ARG1 (a4 / affect-01~e.3 :mod (t2 / this~e.2)))) # ::id a_pmid_2256_9000.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 24 h of selumetinib treatment , a significant induction of apoptosis was detected in the sensitive HCT116 and Calu3 cancer cell lines , which was maximal following 72 h of treatment ( Figure 2B ) . # ::alignments 0-1.3 1-1.3.1.2.1 2-1.3.1.2.2 4-1.1.4.1.1.1.1 5-1.3.1 8-1.1.2 9-1.1 10-1.1.1.r 11-1.1.1 13-1 14-1.2.r 16-1.2.3 17-1.2.1.1.1 18-1.2 19-1.2.2.1.1 20-1.2.4.2.1 21-1.2.1 21-1.2.2 22-1.2.1 26-1.1.3 27-1.1.4 28-1.1.4.1.2.1 29-1.1.4.1.2.2 31-1.1.4.1 31-1.3.1 34-1.4.1 35-1.4.1.1 (d / detect-01~e.13 :ARG1 (i / induce-01~e.9 :ARG2~e.10 (a / apoptosis~e.11) :ARG1-of (s / significant-02~e.8) :mod (m / maximal~e.26) :ARG1-of (f / follow-01~e.27 :ARG2 (t / treat-04~e.31 :ARG2 (s2 / small-molecule :name (n / name :op1 "selumetinib"~e.4)) :duration (t2 / temporal-quantity :quant 72~e.28 :unit (h / hour~e.29))))) :location~e.14 (a2 / and~e.18 :op1 (c / cell-line~e.21,22 :name (n2 / name :op1 "HCT116"~e.17)) :op2 (c2 / cell-line~e.21 :name (n3 / name :op1 "Calu3"~e.19)) :ARG0-of (s3 / sensitive-03~e.16) :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.20))) :time (a3 / after~e.0 :op1 (t3 / treat-04~e.5,31 :ARG2 s2 :duration (t4 / temporal-quantity :quant 24~e.1 :unit h~e.2))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.34 :mod "2B"~e.35))) # ::id a_pmid_2256_9000.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , apoptosis was not detectable following treatment with selumetinib in the two resistant HCT15 and H460 cancer cell lines ( Figure 2B ) . # ::alignments 0-1 2-1.1.2.1 4-1.1.1 4-1.1.1.r 5-1.1.2 6-1.1.3 7-1.1.3.1 8-1.1.3.1.1.r 9-1.1.3.1.1.1.1 10-1.1.2.2.r 12-1.1.2.2.1 13-1.1.2.2.4 14-1.1.2.2.2.1.1 15-1.1.2.2 16-1.1.2.2.3.1.1 17-1.1.2.2.5.2.1 18-1.1.2.2.2 18-1.1.2.2.3 19-1.1.2.2.2 22-1.2.1 23-1.2.1.1 (a / and~e.0 :op2 (p / possible-01 :polarity~e.4 -~e.4 :ARG1 (d / detect-01~e.5 :ARG1 (a2 / apoptosis~e.2) :location~e.10 (a3 / and~e.15 :quant 2~e.12 :op1 (c / cell-line~e.18,19 :name (n / name :op1 "HCT15"~e.14)) :op2 (c2 / cell-line~e.18 :name (n2 / name :op1 "H460"~e.16)) :ARG0-of (r / resist-01~e.13) :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.17)))) :ARG1-of (f / follow-01~e.6 :ARG2 (t / treat-04~e.7 :ARG2~e.8 (s / small-molecule :name (n4 / name :op1 "selumetinib"~e.9))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.22 :mod "2B"~e.23))) # ::id a_pmid_2256_9000.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of selumetinib treatment on intracellular signalling in NSCLC and CRC cell lines # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1 3-1.1 4-1.2.r 5-1.2.1 6-1.2 7-1.3.r 8-1.3.1.1.1.1 9-1.3 10-1.3.2.1.1.1 11-1.3.1 11-1.3.2 12-1.3.1 (a / affect-01~e.0 :ARG0~e.1 (t / treat-04~e.3 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib"~e.2))) :ARG1~e.4 (s2 / signal-07~e.6 :mod (i / intracellular~e.5)) :location~e.7 (a2 / and~e.9 :op1 (c / cell-line~e.11,12 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.8))) :op2 (c2 / cell-line~e.11 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.10))))) # ::id a_pmid_2256_9000.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the effects of selumetinib treatment on key intracellular downstream signalling pathways , western blots were performed to assess total and phosphorylated EGFR and downstream effectors ( total MEK1 @/@ 2 , phospho @-@ MEK1 @/@ 2 , total MAPK , phospho @-@ MAPK , total AKT , phospho @-@ AKT , total 4EBP1 , and phosho @-@ 4EBP1 ) . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1.1 6-1.3.1.1 7-1.3.1.2.r 8-1.3.1.2.3 9-1.3.1.2.2 10-1.3.1.2.1.1 11-1.3.1.2.1 12-1.3.1.2 14-1.1 15-1.1 17-1 19-1.2 19-1.3 20-1.2.1.1.2 21-1.2.1 22-1.2.1.2.2 23-1.2.1.1.1.1 23-1.2.1.2.1.1 24-1.2.1 25-1.2.1.3.1 26-1.2.1.3 28-1.2.1.1.2 29-1.2.1.3.2.1.1.1.1 29-1.2.1.3.2.1.2.1.1 31-1.2.1.3.2.1.1.1.1 31-1.2.1.3.2.1.2.1.1 33-1.2.1.2.2 35-1.2.1.3.2.1.1.1.1 35-1.2.1.3.2.1.2.1.1 37-1.2.1.3.2.1.1.1.1 37-1.2.1.3.2.1.2.1.1 39-1.2.1.1.2 40-1.2.1.3.2.1.3.1.1 40-1.2.1.3.2.1.4.1.1 42-1.2.1.2.2 44-1.2.1.3.2.1.3.1.1 44-1.2.1.3.2.1.4.1.1 46-1.2.1.1.2 47-1.2.1.3.2.1.5.1.1 47-1.2.1.3.2.1.6.1.1 49-1.2.1.2.2 51-1.2.1.3.2.1.5.1.1 51-1.2.1.3.2.1.6.1.1 53-1.2.1.1.2 54-1.2.1.3.2.1.7.1.1 54-1.2.1.3.2.1.8.1.1 56-1.2.1.3.2.1 59-1.2.1.3.2.1.7.1.1 59-1.2.1.3.2.1.8.1.1 (p / perform-01~e.17 :ARG1 (i2 / immunoblot-01~e.14,15) :purpose (a / assess-01~e.19 :ARG1 (a2 / and~e.21,24 :op1 (e / enzyme :name (n2 / name :op1 "EGFR"~e.23) :mod (t2 / total-01~e.20,28,39,46,53)) :op2 (e2 / enzyme :name (n3 / name :op1 "EGFR"~e.23) :ARG3-of (p2 / phosphorylate-01~e.22,33,42,49)) :op3 (e3 / effector~e.26 :location (d / downstream~e.25) :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.56 :op1 (e4 / enzyme :name (n4 / name :op1 "MEK1/2"~e.29,31,35,37) :mod t2) :op2 (e5 / enzyme :name (n5 / name :op1 "MEK1/2"~e.29,31,35,37) :ARG3-of p2) :op3 (e6 / enzyme :name (n6 / name :op1 "MAPK"~e.40,44) :mod t2) :op4 (e7 / enzyme :name (n7 / name :op1 "MAPK"~e.40,44) :ARG3-of p2) :op5 (e8 / enzyme :name (n8 / name :op1 "AKT"~e.47,51) :mod t2) :op6 (e9 / enzyme :name (n9 / name :op1 "AKT"~e.47,51) :ARG3-of p2) :op7 (p3 / protein :name (n10 / name :op1 "4EBP1"~e.54,59) :mod t2) :op8 (p4 / protein :name (n11 / name :op1 "4EBP1"~e.54,59) :ARG3-of p2)))))) :purpose (a4 / assess-01~e.1,19 :ARG1 (a5 / affect-01~e.3 :ARG0~e.4 (t3 / treat-04~e.6 :ARG2 (s / small-molecule :name (n12 / name :op1 "selumetinib"~e.5))) :ARG1~e.7 (p5 / pathway~e.12 :ARG0-of (s2 / signal-07~e.11 :direction (d2 / downstream~e.10)) :mod (i / intracellular~e.9) :ARG1-of (k / key-02~e.8))))) # ::id a_pmid_2256_9000.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cancer cells were evaluated at baseline and at different time points after treatment with selumetinib at 0.05 μ @ ℳ. # ::alignments 0-1.1.1.2.1 1-1.1 3-1 4-1.2.r 5-1.2.1 6-1.2 8-1.2.2.2 9-1.2.2.1 10-1.2.2 11-1.3 12-1.3.1 13-1.3.1.1.r 14-1.3.1.1.1.1 16-1.3.1.1.2.1 (e / evaluate-01~e.3 :ARG1 (c / cell~e.1 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.0))) :manner~e.4 (a / and~e.6 :op1 (b / baseline~e.5) :op2 (p / point~e.10 :mod (t / time~e.9) :ARG1-of (d2 / differ-02~e.8))) :time (a2 / after~e.11 :op1 (t2 / treat-04~e.12 :ARG2~e.13 (s / small-molecule :name (n2 / name :op1 "selumetinib"~e.14) :quant (c2 / concentration-quantity :quant 0.05~e.16 :unit (m / micromolar)))))) # ::id a_pmid_2256_9000.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No change in total and phosphorylated EGFR expression was observed in both selumetinib @-@ sensitive and selumetinib @-@ resistant cancer cell lines ( Figure 3A @–@ D ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1.1.2.r 3-1.1.2.1.1.2 4-1.1.2.1 5-1.1.2.1.2.2 6-1.1.2.1.1.1.1 6-1.1.2.1.2.1.1 7-1.1.2 9-1 12-1.2.1.1.1.1.1 14-1.2.1.1 16-1.2.1.1.1.1.1 18-1.2.2.1 19-1.2.3.2.1 20-1.2.1 20-1.2.2 21-1.2.2 24-1.3.1.1 24-1.3.1.2 24-1.3.1.3 24-1.3.1.4 25-1.3.1.1.1 (o / observe-01~e.9 :ARG1 (c / change-01~e.1 :polarity~e.0 -~e.0 :ARG1~e.2 (e / express-03~e.7 :ARG2 (a / and~e.4 :op1 (e2 / enzyme :name (n / name :op1 "EGFR"~e.6) :mod (t / total-01~e.3)) :op2 (e3 / enzyme :name (n2 / name :op1 "EGFR"~e.6) :ARG3-of (p / phosphorylate-01~e.5))))) :location (a2 / and :op1 (c2 / cell-line~e.20 :ARG0-of (s / sensitive-03~e.14 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib"~e.12,16)))) :op2 (c3 / cell-line~e.20,21 :ARG0-of (r / resist-01~e.18 :ARG1 s2)) :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.19))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.24 :mod "3A"~e.25) :op2 (f2 / figure~e.24 :mod "3B") :op3 (f3 / figure~e.24 :mod "3C") :op4 (f4 / figure~e.24 :mod "3D")))) # ::id a_pmid_2256_9000.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with selumetinib caused a time @-@ dependent inhibition in phospho @-@ MEK1 @/@ 2 with a complete signal suppression within 60 or 15 min of treatment in HCT116 and Calu3 cells , respectively ( Figure 3A and B ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1 5-1.2.1.1.1 5-1.2.2.3.1.2.1 5-1.2.3.3.2.1 5-1.2.3.3.r 7-1.2.1.1 8-1.2.1 9-1.3.r 10-1.3.2 12-1.3.1.1 14-1.3.1.1 15-1.2.r 17-1.2.2.2 18-1.2.2.1 19-1.2.2 19-1.2.3 20-1.2.2.3 20-1.2.2.3.1.2 20-1.2.2.3.1.2.1.1.r 20-1.2.3.3 20-1.2.3.3.2 20-1.2.3.3.2.r 21-1.2.2.3.1.2.1.1 23-1.2.3.3.2.1.1 24-1.2.2.3.1.2.1.2 25-1.2.2.3.1.2.r 26-1.2.2.3.1 26-1.2.3.3.1 28-1.2.2.4.1.1 29-1.2 30-1.2.3.4.1.1 31-1.2.2.4 31-1.2.3.4 36-1.4.1.1 36-1.4.1.2 37-1.4.1.1.1 38-1.4.1 (c / cause-01~e.3 :ARG0 (t / treat-04~e.0 :ARG2~e.1 (s / small-molecule :name (n / name :op1 "selumetinib"~e.2))) :ARG1~e.15 (a4 / and~e.29 :op1 (i / inhibit-01~e.8 :ARG0-of (d / depend-01~e.7 :ARG1 (t2 / time~e.5))) :op2 (s2 / suppress-01~e.19 :ARG1 (s3 / signal-07~e.18) :degree (c2 / complete-01~e.17) :time (a / after~e.20 :op1 (t3 / treat-04~e.26 :ARG2 s :quant~e.25 (u / up-to~e.20 :op1 (t4 / temporal-quantity~e.5 :quant~e.20 60~e.21 :unit (m / minute~e.24))))) :location (c3 / cell-line~e.31 :name (n2 / name :op1 "HCT116"~e.28))) :op3 (s4 / suppress-01~e.19 :ARG1 s3 :degree c2 :time~e.5 (a2 / after~e.20 :op1 (t5 / treat-04~e.26 :ARG2 s) :quant~e.20 (u2 / up-to~e.20 :op1 (t6 / temporal-quantity~e.5 :quant 15~e.23 :unit m))) :location (c4 / cell-line~e.31 :name (n3 / name :op1 "Calu3"~e.30)))) :location~e.9 (e / enzyme :name (n4 / name :op1 "MEK1/2"~e.12,14) :ARG3-of (p / phosphorylate-01~e.10)) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.38 :op1 (f / figure~e.36 :mod "3A"~e.37) :op2 (f2 / figure~e.36 :mod "3B")))) # ::id a_pmid_2256_9000.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This inhibition was sustained for 24 h of selumetinib treatment in both cancer cell lines . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.2.1 6-1.2.2.2 8-1.2.1.1.1 9-1.2 10-1.3.r 11-1.3.2 12-1.3.1.2.1 13-1.3 14-1.3 (s / sustain-01~e.3 :ARG1 (i / inhibit-01~e.1 :mod (t / this~e.0)) :duration~e.4 (t2 / treat-04~e.9 :ARG2 (s2 / small-molecule :name (n / name :op1 "selumetinib"~e.8)) :duration (t3 / temporal-quantity :quant 24~e.5 :unit (h / hour~e.6))) :location~e.10 (c / cell-line~e.13,14 :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.12)) :mod (b / both~e.11))) # ::id a_pmid_2256_9000.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , MEK1 @/@ 2 inhibition of protein phosphorylation was less effective with only a slight reduction in pospho @-@ MEK1 @/@ 2 in the two selumetinib @-@ resistant HCT15 and H460 cancer cell lines ( Figure 3C and D ) . # ::alignments 1-1 3-1.1.1.1.1.1 3-1.1.2.1.1.1 5-1.1.1.1.1.1 5-1.1.2.1.1.1 6-1.1.1 8-1.1.1.2.1 9-1.1.1.2 9-1.1.2.1.2 11-1.1.3 12-1.1 13-1.1.2.r 14-1.1.2.3 16-1.1.2.2 17-1.1.2 21-1.1.2.1.1.1 23-1.1.2.1.1.1 23-1.1.2.4.1 26-1.1.2.1.1.1 26-1.1.2.4.1 27-1.1.2.4.5.1.1.1 29-1.1.2.4.5 30-1.1.2.4.2.1.1 31-1.1.2.4 32-1.1.2.4.3.1.1 33-1.1.2.4.4.2.1 34-1.1.2.4.2 34-1.1.2.4.3 35-1.1.2.4.2 38-1.2.1.1 38-1.2.1.2 39-1.2.1.1.1 40-1.2.1 (c / contrast-01~e.1 :ARG2 (e / effective-04~e.12 :ARG0 (i / inhibit-01~e.6 :ARG0 (e3 / enzyme :name (n6 / name :op1 "MEK1/2"~e.3,5)) :ARG1 (p2 / phosphorylate-01~e.9 :ARG1 (p3 / protein~e.8))) :ARG1~e.13 (r / reduce-01~e.17 :ARG1 (e2 / enzyme :name (n / name :op1 "MEK1/2"~e.3,5,21,23,26) :ARG3-of (p / phosphorylate-01~e.9)) :ARG2 (s / slight~e.16) :mod (o / only~e.14) :location (a / and~e.31 :quant 2~e.23,26 :op1 (c2 / cell-line~e.34,35 :name (n2 / name :op1 "HCT15"~e.30)) :op2 (c3 / cell-line~e.34 :name (n3 / name :op1 "H460"~e.32)) :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.33)) :ARG0-of (r2 / resist-01~e.29 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "selumetinib"~e.27))))) :degree (l / less~e.11)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.40 :op1 (f / figure~e.38 :mod "3C"~e.39) :op2 (f2 / figure~e.38 :mod "3D")))) # ::id a_pmid_2256_9000.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , MAPK phosphorylation was completely blocked following selumetinib treatment in HCT116 and Calu3 . # ::alignments 0-1 2-1.1.1.1.1.1 3-1.1.1 5-1.1.2 6-1.1 7-1.1.3 8-1.1.3.1.1.1.1 9-1.1.3.1 10-1.1.4.r 11-1.1.4.1.1.1 12-1.1.4 13-1.1.4.2.1.1 (a / and~e.0 :op2 (b / block-01~e.6 :ARG1 (p / phosphorylate-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "MAPK"~e.2))) :degree (c / complete-01~e.5) :ARG1-of (f / follow-01~e.7 :ARG2 (t / treat-04~e.9 :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib"~e.8)))) :location~e.10 (a2 / and~e.12 :op1 (c2 / cell-line :name (n3 / name :op1 "HCT116"~e.11)) :op2 (c3 / cell-line :name (n4 / name :op1 "Calu3"~e.13))))) # ::id a_pmid_2256_9000.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , in the two selumetinib @-@ resistant HCT15 and H460 cells MAPK phosphorylation was only reduced but never completely abrogated ( Figure 3C and D ) . # ::alignments 1-1 1-1.1 3-1.1.r 5-1.1.3.1 6-1.1.3.4.1.1.1 8-1.1.3.4 9-1.1.3.2.1.1 10-1.1.3 11-1.1.3.3.1.1 12-1.1.3.2 12-1.1.3.3 13-1.1.1.1.1.1.1 14-1.1.1.1 16-1.1.1.2 17-1.1.1 18-1.1 19-1.1.2.3 19-1.1.2.3.1 19-1.1.2.3.1.r 20-1.1.2.2 21-1.1.2 24-1.2.1.1 24-1.2.1.2 25-1.2.1.1.1 26-1.2.1 (c / contrast-01~e.1 :ARG2~e.3 (c2 / contrast-01~e.1,18 :ARG1 (r / reduce-01~e.17 :ARG1 (p / phosphorylate-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "MAPK"~e.13))) :mod (o / only~e.16)) :ARG2 (a2 / abrogate-01~e.21 :ARG1 p :degree (c3 / complete-01~e.20) :time (e2 / ever~e.19 :polarity~e.19 -~e.19)) :location (a / and~e.10 :quant 2~e.5 :op1 (c4 / cell-line~e.12 :name (n2 / name :op1 "HCT15"~e.9)) :op2 (c5 / cell-line~e.12 :name (n3 / name :op1 "H460"~e.11)) :ARG0-of (r2 / resist-01~e.8 :ARG1 (s / small-molecule :name (n4 / name :op1 "selumetinib"~e.6))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.26 :op1 (f / figure~e.24 :mod "3C"~e.25) :op2 (f2 / figure~e.24 :mod "3D")))) # ::id a_pmid_2256_9000.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next assessed the levels of AKT , phosphor @-@ AKT , 4EBP1 and poshospho @-@ 4EBP1 , which are downstream effectors of the PI3 kinase ( PI3K ) pathway . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.1 4-1.2.2 4-1.2.3 4-1.2.4 6-1.2.1.1.1.1 6-1.2.2.1.1.1 10-1.2.1.1.1.1 10-1.2.2.1.1.1 12-1.2.3.1.1.1 12-1.2.4.1.1.1 13-1.2 16-1.2.3.1.1.1 16-1.2.4.1.1.1 20-1.4.2 24-1.4.1.1.1 25-1.4.1.1.2 29-1.4.1 (a / assess-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a2 / and~e.13 :op1 (l / level~e.4 :quant-of (e / enzyme :name (n2 / name :op1 "AKT"~e.6,10))) :op2 (l2 / level~e.4 :quant-of (e2 / enzyme :name (n3 / name :op1 "AKT"~e.6,10) :ARG3-of (p / phosphorylate-01))) :op3 (l3 / level~e.4 :quant-of (p2 / protein :name (n4 / name :op1 "4EBP1"~e.12,16))) :op4 (l4 / level~e.4 :quant-of (p3 / protein :name (n5 / name :op1 "4EBP1"~e.12,16) :ARG3-of p))) :time (n / next~e.1) :ARG0-of (a3 / affect-01 :ARG1 (p5 / pathway~e.29 :name (n6 / name :op1 "PI3"~e.24 :op2 "kinase"~e.25)) :mod (d / downstream~e.20))) # ::id a_pmid_2256_9000.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previous reports have suggested that resistance to selumetinib treatment in CRC and NSCLC cell lines was associated with baseline increased PI3K signalling ( Balmanno et al , 2009 ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.2.r 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.1.1.1 8-1.2.1.1 9-1.2.1.2.r 10-1.2.1.2.1.1.1.1 11-1.2.1.2 12-1.2.1.2.2.1.1.1 13-1.2.1.2.1 13-1.2.1.2.2 14-1.2.1.2.1 16-1.2 17-1.2.2.r 18-1.2.2.1.3 19-1.2.2.1.2 20-1.2.2.1.1.1 21-1.2.2 24-1.3.1.1.1.1.1 26-1.3.1.1 27-1.3.1.1.2.1 30-1.3.1.2.1 (s / suggest-01~e.3 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (r / report-01~e.1) :time (p / previous~e.0)) :ARG1~e.4 (a2 / associate-01~e.16 :ARG1 (r2 / resist-01~e.5 :ARG1~e.6 (t2 / treat-04~e.8 :ARG2 (s4 / small-molecule :name (n5 / name :op1 "selumetinib"~e.7))) :location~e.9 (a / and~e.11 :op1 (c / cell-line~e.13,14 :mod (d4 / disease :name (n / name :op1 "CRC"~e.10))) :op2 (c2 / cell-line~e.13 :mod (d3 / disease :name (n2 / name :op1 "NSCLC"~e.12))))) :ARG2~e.17 (s3 / signal-07~e.21 :ARG0 (p2 / pathway :name (n3 / name :op1 "PI3K"~e.20) :ARG1-of (i / increase-01~e.19) :mod (b / baseline~e.18)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.26 :op1 (p4 / person :name (n4 / name :op1 "Balmanno"~e.24)) :op2 (p5 / person :mod (o / other~e.27))) :time (d / date-entity :year 2009~e.30)))) # ::id a_pmid_2256_9000.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , as depicted in Figure 3E @–@ H , we failed to segregate the panel of 11 NSCLC and CRC cell lines into selumetinib @-@ sensitive and selumetinib @-@ resistant groups , by using the PI3K pathway . # ::alignments 0-1 3-1.2 6-1.2.1.1 6-1.2.1.2 7-1.2.1.1.1 12-1.1.1 13-1.1 15-1.1.2 17-1.1.2.2 18-1.1.2.2.1.r 19-1.1.2.2.1.1 20-1.1.2.2.1.2.1.1.1 21-1.1.2.2.1 22-1.1.2.2.1.3.1.1.1 23-1.1.2.2.1.2 23-1.1.2.2.1.3 24-1.1.2.2.1.2 26-1.1.2.3.1.1.1.1.1 28-1.1.2.3.1.1 30-1.1.2.3.1.1.1.1.1 32-1.1.2.3.2.1 33-1.1.2.3.1 33-1.1.2.3.2 35-1.1.2.4.r 36-1.1.2.4 38-1.1.2.4.1.1.1 39-1.1.2.4.1 (h / have-concession-91~e.0 :ARG1 (f / fail-01~e.13 :ARG1 (w / we~e.12) :ARG2 (s / segregate-01~e.15 :ARG0 w :ARG1 (p / panel~e.17 :consist-of~e.18 (a3 / and~e.21 :quant 11~e.19 :op1 (c / cell-line~e.23,24 :mod (d2 / disease :name (n / name :op1 "NSCLC"~e.20))) :op2 (c2 / cell-line~e.23 :mod (d3 / disease :name (n2 / name :op1 "CRC"~e.22))))) :ARG2 (a2 / and :op1 (g / group~e.33 :ARG0-of (s2 / sensitive-03~e.28 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "selumetinib"~e.26,30)))) :op2 (g2 / group~e.33 :ARG0-of (r / resist-01~e.32 :ARG1 s4))) :manner~e.35 (u / use-01~e.36 :ARG1 (p3 / pathway~e.39 :name (n3 / name :op1 "PI3K"~e.38))))) :ARG1-of (d / depict-01~e.3 :ARG0 (v / value-interval :op1 (f2 / figure~e.6 :mod "3E"~e.7) :op2 (f3 / figure~e.6 :mod "3H")))) # ::id a_pmid_2256_9000.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of selumetinib treatment on NSCLC and CRC tumour xenografts in nude mice # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1 3-1.1 4-1.2.r 5-1.2.1.1.1.1.1 6-1.2 7-1.2.2.1.1.1.1 8-1.2.1.1 8-1.2.2.1 9-1.2.1 9-1.2.2 10-1.3.r 11-1.3.1 12-1.3 (a / affect-01~e.0 :ARG0~e.1 (t / treat-04~e.3 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib"~e.2))) :ARG1~e.4 (a2 / and~e.6 :op1 (x3 / xenograft~e.9 :source (t2 / tumor~e.8 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.5)))) :op2 (x / xenograft~e.9 :source (t3 / tumor~e.8 :mod (d2 / disease :name (n / name :op1 "CRC"~e.7))))) :location~e.10 (m / mouse~e.12 :mod (n3 / nude~e.11))) # ::id a_pmid_2256_9000.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 4A and B , HCT116 and Calu3 xenograft growth was significantly inhibited by selumetinib treatment in a dose @-@ dependent manner . # ::alignments 1-1.5 4-1.5.1.1 4-1.5.1.2 5-1.5.1.1.1 6-1.5.1 10-1.2.1.1.1.1.1 11-1.2.1 12-1.2.1.2.1.1.1 13-1.2.1.1 13-1.2.1.2 14-1.2 17-1 18-1.1.r 19-1.1.1.1.1 20-1.1 23-1.4.2 25-1.4 26-1.4.r (i / inhibit-01~e.17 :ARG0~e.18 (t / treat-04~e.20 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "selumetinib"~e.19))) :ARG1 (g / grow-01~e.14 :ARG1 (a / and~e.11 :op1 (x3 / xenograft~e.13 :source (c / cell-line :name (n / name :op1 "HCT116"~e.10))) :op2 (x2 / xenograft~e.13 :source (c2 / cell-line :name (n4 / name :op1 "Calu3"~e.12))))) :ARG1-of (s / signify-01) :manner~e.26 (d / depend-01~e.25 :ARG0 g :ARG1 (d2 / dose~e.23)) :ARG1-of (s3 / show-01~e.1 :ARG0 (a2 / and~e.6 :op1 (f / figure~e.4 :mod "4A"~e.5) :op2 (f2 / figure~e.4 :mod "4B")))) # ::id a_pmid_2256_9000.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As an example , at day 50 from the injection of cancer cells , the mean tumour volume in mice bearing HCT116 tumour xenografts and treated with selumetinib , 25 or 50 mg kg @⁻¹ were 40 % and 15 % , respectively , as compared with control untreated mice . # ::alignments 0-1.3.r 2-1.6 5-1.3.2.2 6-1.3.2.1 7-1.1.3.1.1.1.r 9-1.3.1 10-1.3.1.1.r 11-1.3.1.1.1.2.1 12-1.3.1.1 16-1.1.1.1 17-1.1.1 19-1.1.3 20-1.1.3.1 21-1.1.3.1.1.1.1.1.1 22-1.1.3.1.1.1 23-1.1.3.1.1 24-1 25-1.2.3.1 26-1.2.3.1.1.r 27-1.2.3.1.1.1.1 29-1.2.3.1.1.2.1.1 30-1.2.3.1.1.2 31-1.2.3.1.1.2.2.1 32-1.2.3.1.1.2.1.2 32-1.2.3.1.1.2.2.2 33-1.2.3.1.1.2.1.2 33-1.2.3.1.1.2.2.2 38-1.1.2.1 39-1.1.2 40-1 41-1.2.2.1 42-1.2.2 44-1.4 46-1.3.r 47-1.5.r 49-1.5.2 50-1.5.1 50-1.5.1.1 50-1.5.1.1.r 51-1.2.3 51-1.5 (a4 / and~e.24,40 :op1 (a / average-01 :ARG1 (v / volume~e.17 :mod (t / tumor~e.16)) :ARG2 (p / percentage-entity~e.39 :value 40~e.38) :location (m2 / mouse~e.19 :ARG0-of (b / bear-01~e.20 :ARG1 (x2 / xenograft~e.23 :source~e.7 (t3 / tumor~e.22 :mod (c / cell-line :name (n / name :op1 "HCT116"~e.21))))))) :op2 (a5 / average-01 :ARG1 v :ARG2 (p2 / percentage-entity~e.42 :value 15~e.41) :location (m4 / mouse~e.51 :ARG1-of (t4 / treat-04~e.25 :ARG2~e.26 (s2 / small-molecule :name (n4 / name :op1 "selumetinib"~e.27) :quant (o / or~e.30 :op1 (c3 / concentration-quantity :quant 25~e.29 :unit (m / milligram-per-kilogram~e.32,33)) :op2 (c2 / concentration-quantity :quant 50~e.31 :unit (m3 / milligram-per-kilogram~e.32,33))))))) :time~e.0,46 (a2 / after :op1 (i / inject-01~e.9 :ARG2~e.10 (c4 / cell~e.12 :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.11)))) :quant (t5 / temporal-quantity :quant 50~e.6 :unit (d2 / day~e.5))) :mod (r / respective~e.44) :compared-to~e.47 (m5 / mouse~e.51 :ARG1-of (t6 / treat-04~e.50 :polarity~e.50 -~e.50) :mod (c6 / control~e.49)) :ARG0-of (e / exemplify-01~e.2)) # ::id a_pmid_2256_9000.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , at day 50 from the injection of cancer cells , the mean tumour volume in mice bearing Calu3 tumour xenografts and treated with selumetinib , 25 or 50 mg kg @⁻¹ were 22 % and 8 % , respectively , as compared with control untreated mice . # ::alignments 0-1.5 3-1.6.2.2 4-1.6.2.1 5-1.1.3.1.1.1.r 7-1.6.1 9-1.6.1.1.1.2.1 10-1.1.3.1.1.1.1.1.1 10-1.6.1.1 14-1.1.1.1 15-1.1.1 17-1.1.3 18-1.1.3.1 19-1.1.3.1.1.1.1.1.2 20-1.1.3.1.1.1 21-1.1.3.1.1 22-1 23-1.2.3.1 24-1.2.3.1.1.r 25-1.2.3.1.1.1.1 27-1.2.3.1.1.2.1.1 28-1.2.3.1.1.2 29-1.2.3.1.1.2.2.1 30-1.2.3.1.1.2.1.2 30-1.2.3.1.1.2.2.2 31-1.2.3.1.1.2.1.2 31-1.2.3.1.1.2.2.2 36-1.1.2.1 37-1.1.2 38-1 39-1.2.2.1 40-1.2.2 42-1.3 44-1.6.r 45-1.4.r 47-1.4.2 48-1.4.1 48-1.4.1.1 48-1.4.1.1.r 49-1.2.3 49-1.4 (a / and~e.22,38 :op1 (a2 / average-01 :ARG1 (v / volume~e.15 :mod (t / tumor~e.14)) :ARG2 (p / percentage-entity~e.37 :value 22~e.36) :location (m / mouse~e.17 :ARG0-of (b / bear-01~e.18 :ARG1 (x2 / xenograft~e.21 :source~e.5 (t6 / tumor~e.20 :mod (d3 / disease :name (n / name :op1 "cell-line"~e.10 :op2 "Calu3"~e.19))))))) :op2 (a3 / average-01 :ARG1 v :ARG2 (p2 / percentage-entity~e.40 :value 8~e.39) :location (m2 / mouse~e.49 :ARG1-of (t3 / treat-04~e.23 :ARG2~e.24 (s / small-molecule :name (n3 / name :op1 "selumetinib"~e.25) :quant (o / or~e.28 :op1 (c2 / concentration-quantity :quant 25~e.27 :unit (m3 / milligram-per-kilogram~e.30,31)) :op2 (c3 / concentration-quantity :quant 50~e.29 :unit (m4 / milligram-per-kilogram~e.30,31))))))) :mod (r / respective~e.42) :compared-to~e.45 (m5 / mouse~e.49 :ARG1-of (t2 / treat-04~e.48 :polarity~e.48 -~e.48) :mod (c4 / control~e.47)) :ARG1-of (r2 / resemble-01~e.0) :time~e.44 (a4 / after :op1 (i / inject-01~e.7 :ARG2 (c5 / cell~e.10 :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.9)))) :quant (t5 / temporal-quantity :quant 50~e.4 :unit (d / day~e.3)))) # ::id a_pmid_2256_9000.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , selumetinib treatment was unable to affect tumour growth in both HCT15 and H460 tumour xenografts ( Figure 4C and D ) . # ::alignments 1-1 3-1.1.2.1.1.1 4-1.1.2 6-1.1.1 8-1.1.3 9-1.1.3.2.1 10-1.1.3.2 13-1.1.3.2.2.1.1.1.1.1 14-1.1.3.2.2 15-1.1.3.2.2.2.1.1.1.1 16-1.1.3.2.2.1.1 16-1.1.3.2.2.2.1 17-1.1.3.2.2.1 17-1.1.3.2.2.2 20-1.2.1.1 20-1.2.1.2 21-1.2.1.1.1 22-1.2.1 (c / contrast-01~e.1 :ARG2 (c2 / capable-01 :polarity -~e.6 :ARG1 (t / treat-04~e.4 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib"~e.3))) :ARG2 (a / affect-01~e.8 :ARG0 t :ARG1 (g / grow-01~e.10 :ARG1 (t2 / tumor~e.9) :location (a2 / and~e.14 :op1 (x3 / xenograft~e.17 :source (t3 / tumor~e.16 :mod (c4 / cell-line :name (n3 / name :op1 "HCT15"~e.13)))) :op2 (x / xenograft~e.17 :source (t4 / tumor~e.16 :mod (c3 / cell-line :name (n2 / name :op1 "H460"~e.15)))))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.22 :op1 (f / figure~e.20 :mod "4C"~e.21) :op2 (f2 / figure~e.20 :mod "4D")))) # ::id a_pmid_2256_9000.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGFR , RAS , MEK , and AKT protein expression and selumetinib sensitivity in NSCLC and CRC cell lines # ::alignments 0-1.1.1.1.1.1 2-1.1.1.2.1.1 4-1.1.1.3.1.1 7-1.1.1.4.1.1 9-1.1 10-1 11-1.2.1.1.1 12-1.2 13-1.2.2.r 14-1.2.2.1.1.1.1 15-1.2.2 16-1.2.2.2.1.1.1 17-1.2.2.1 17-1.2.2.2 18-1.2.2.1 (a / and~e.10 :op1 (e4 / express-03~e.9 :ARG2 (a2 / and :op1 (e8 / enzyme :name (n4 / name :op1 "EGFR"~e.0)) :op2 (e5 / enzyme :name (n5 / name :op1 "RAS"~e.2)) :op3 (e6 / enzyme :name (n6 / name :op1 "MEK"~e.4)) :op4 (e7 / enzyme :name (n7 / name :op1 "AKT"~e.7))) :ARG3 a3) :op2 (s / sensitive-03~e.12 :ARG1 (s2 / small-molecule :name (n8 / name :op1 "selumetinib"~e.11)) :location~e.13 (a3 / and~e.15 :op1 (c / cell-line~e.17,18 :mod (d / disease :name (n / name :op1 "NSCLC"~e.14))) :op2 (c2 / cell-line~e.17 :mod (d2 / disease :name (n2 / name :op1 "CRC"~e.16)))))) # ::id a_pmid_2256_9000.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Identification of predictive biomarkers is becoming a fundamental aspect in the development of targeted agents . # ::alignments 0-1.1 2-1.1.1.1 5-1 7-1.2.2 8-1.2 9-1.2.1.r 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1 14-1.2.1.1 (b / become-01~e.5 :ARG1 (i / identify-01~e.0 :ARG1 (b2 / biomarker :ARG0-of (p / predict-01~e.2))) :ARG2 (a / aspect~e.8 :topic~e.9 (d / develop-02~e.11 :ARG1~e.12 (a2 / agent~e.14 :ARG1-of (t / target-01~e.13))) :mod (f / fundamental~e.7))) # ::id a_pmid_2256_9000.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok So far , several preclinical studies have been published trying to address this aspect for the sensitivity to MEK inhibitors , but , since different results have been reported , no univocal interpretation could be made ( Balmanno et al , 2009 ; Dry et al , 2010 ; Garon et al , 2010 ; Tendler et al , 2010 ) @ . # ::alignments 0-1.1.2 1-1.1.2 3-1.1.1.2 4-1.1.1.1 5-1.1.1 8-1.1 8-1.3.1.1 8-1.3.1.2 8-1.3.1.3 8-1.3.1.4 9-1.1.1.3 11-1.1.1.3.1 12-1.1.1.3.1.2.1 13-1.1.1.3.1.2 14-1.1.1.3.1.2.2.r 16-1.1.1.3.1.2.2 17-1.1.1.3.1.2.2.1.r 18-1.1.1.3.1.2.2.1.1.1.1.1 19-1.1.1.3.1.2.2.1 19-1.1.1.3.1.2.2.1.1 19-1.1.1.3.1.2.2.1.1.r 21-1 23-1.2.2 24-1.2.2.1.1.2 25-1.2.2.1.1 25-1.2.2.1.1.1 25-1.2.2.1.1.1.r 28-1.2.2.1 30-1.2.1.1 30-1.2.1.1.r 31-1.2.1.2 32-1.2.1 33-1.2 35-1.2.2.1 38-1.3.1.1.1.1.1.1 40-1.3.1.1.1 40-1.3.1.2.1 40-1.3.1.3.1 40-1.3.1.4.1 41-1.3.1.1.1.2.1 44-1.3.1.1.2.1 48-1.3.1.2.1.1.1.1 50-1.3.1 51-1.3.1.1.1.2.1 54-1.3.1.3.2 58-1.3.1.3.1.1.1.1 60-1.3.1 61-1.3.1.1.1.2.1 64-1.3.1.4.2 68-1.3.1.4.1.1.1.1 70-1.3.1 71-1.3.1.1.1.2.1 74-1.3.1.2.2.1 (c / contrast-01~e.21 :ARG1 (p2 / publish-01~e.8 :ARG1 (s2 / study-01~e.5 :mod (p3 / preclinical~e.4) :quant (s3 / several~e.3) :ARG0-of (t2 / try-01~e.9 :ARG1 (a / address-02~e.11 :ARG0 s2 :ARG1 (a2 / aspect~e.13 :mod (t3 / this~e.12) :topic~e.14 (s4 / sensitive-03~e.16 :ARG1~e.17 (m / molecular-physical-entity~e.19 :ARG0-of~e.19 (i / inhibit-01~e.19 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.18))))))))) :time (s / so-far~e.0,1)) :ARG2 (p4 / possible-01~e.33 :ARG1 (i2 / interpret-01~e.32 :polarity~e.30 -~e.30 :mod (u / univocal~e.31)) :ARG1-of (c2 / cause-01~e.23 :ARG0 (r / report-01~e.28,35 :ARG1 (t4 / thing~e.25 :ARG2-of~e.25 (r2 / result-01~e.25) :ARG1-of (d4 / differ-02~e.24))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.50,60,70 :op1 (p5 / publication-91~e.8 :ARG0 (a4 / and~e.40 :op1 (p6 / person :name (n2 / name :op1 "Balmanno"~e.38)) :op2 (p7 / person :mod (o / other~e.41,51,61,71))) :time (d / date-entity :year 2009~e.44)) :op2 (p8 / publication-91~e.8 :ARG0 (a5 / and~e.40 :op1 (p9 / person :name (n3 / name :op1 "Dry"~e.48)) :op2 p7) :time (d2 / date-entity :year 2010~e.74)) :op3 (p11 / publication-91~e.8 :ARG0 (a6 / and~e.40 :op1 (p12 / person :name (n4 / name :op1 "Garon"~e.58)) :op2 p7) :time d2~e.54) :op4 (p14 / publication-91~e.8 :ARG0 (a7 / and~e.40 :op1 (p15 / person :name (n5 / name :op1 "Tendler"~e.68)) :op2 p7) :time d2~e.64)))) # ::id a_pmid_2256_9000.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To identify specific profiles , which could allow identifying different molecular patterns of sensitivity or resistance to MEK inhibition , we first screened the intracellular signalling status of each cell lines . # ::alignments 1-1.3 2-1.3.2.1 3-1.3.2 6-1.3.2.2.2 7-1.3.2.2 8-1.3.2.2.1 9-1.3.2.2.1.1.3 10-1.3.2.2.1.1.1.1.1.2 10-1.3.2.2.1.1.2 11-1.3.2.2.1.1 11-1.3.2.2.1.1.1.1.1 12-1.3.2.2.1.1.1.r 13-1.3.2.2.1.1.1.1 14-1.3.2.2.1.1.1 15-1.3.2.2.1.1.1.2 16-1.3.2.2.1.1.1.1.1.1.r 17-1.3.2.2.1.1.1.1.1.1.1.1.1 18-1.3.2.2.1.1.1.1.1.1 20-1.1 21-1.4 22-1 24-1.2.1.1 24-1.2.1.2 25-1.2.1 26-1.2 28-1.2.1.1.1 29-1.2.1.1 30-1.2.1.1 (s / screen-01~e.22 :ARG0 (w / we~e.20) :ARG1 (s2 / status~e.26 :mod (s3 / signal-07~e.25 :ARG1 (c / cell-line~e.24,29,30 :mod (e2 / each~e.28)) :mod (i4 / intracellular~e.24))) :purpose (i / identify-01~e.1 :ARG0 w :ARG1 (p2 / profile~e.3 :ARG1-of (s4 / specific-02~e.2) :ARG0-of (a / allow-01~e.7 :ARG1 (i2 / identify-01~e.8 :ARG1 (p3 / pattern-01~e.11 :ARG1~e.12 (o3 / or~e.14 :op1 (s5 / sensitive-03~e.13 :ARG1 (p / pattern~e.11 :ARG0-of~e.16 (i3 / inhibit-01~e.18 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.17))) :mod (m2 / molecule~e.10))) :op2 (r2 / resist-01~e.15 :ARG1 p)) :mod (m / molecule~e.10) :ARG1-of (d / differ-02~e.9))) :ARG1-of (p4 / possible-01~e.6)))) :time (f / first~e.21)) # ::id a_pmid_2256_9000.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As depicted in Supplementary Figure 1A , the NCSLC and CRC cell lines displayed highly variable basal levels of total and phosphorylated EGFR , RAS , MEK , and AKT . # ::alignments 1-1.3 4-1.3.1.2 5-1.3.1 6-1.3.1.1 10-1.1.1.1.1.1 11-1.1 12-1.1.2.1.1.1 13-1.1.1 13-1.1.2 14-1.1.1 15-1 16-1.2.9.1 18-1.2.10 19-1.2.1 19-1.2.2 19-1.2.3 19-1.2.4 19-1.2.5 19-1.2.6 19-1.2.7 19-1.2.8 20-1.2.1.1.r 21-1.2.1.1.2 22-1.2 23-1.2.2.1.2 24-1.2.1.1.1.1 24-1.2.2.1.1.1 26-1.2.3.1.1.1 26-1.2.4.1.1.1 28-1.2.5.1.1.1 28-1.2.6.1.1.1 30-1.2 31-1.2.7.1.1.1 31-1.2.8.1.1.1 (d / display-01~e.15 :ARG0 (a / and~e.11 :op1 (c / cell-line~e.13,14 :mod (d4 / disease :name (n4 / name :op1 "NCSLC"~e.10))) :op2 (c2 / cell-line~e.13 :mod (d3 / disease :name (n5 / name :op1 "CRC"~e.12)))) :ARG1 (a2 / and~e.22,30 :op1 (l5 / level~e.19 :quant-of~e.20 (e2 / enzyme :name (n2 / name :op1 "EGFR"~e.24) :mod (t2 / total~e.21))) :op2 (l / level~e.19 :quant-of (e / enzyme :name (n / name :op1 "EGFR"~e.24) :ARG3-of (p / phosphorylate-01~e.23))) :op3 (l6 / level~e.19 :quant-of (e3 / enzyme :name (n3 / name :op1 "RAS"~e.26) :mod t2)) :op4 (l2 / level~e.19 :quant-of (e4 / enzyme :name (n6 / name :op1 "RAS"~e.26) :ARG3-of p)) :op5 (l3 / level~e.19 :quant-of (e5 / enzyme :name (n7 / name :op1 "MEK"~e.28) :mod t2)) :op6 (l7 / level~e.19 :quant-of (e7 / enzyme :name (n9 / name :op1 "MEK"~e.28) :ARG2-of p)) :op7 (l4 / level~e.19 :quant-of (e6 / enzyme :name (n8 / name :op1 "AKT"~e.31) :mod t2)) :op8 (l8 / level~e.19 :quant-of (e8 / enzyme :name (n10 / name :op1 "AKT"~e.31) :ARG3-of p)) :ARG1-of (v / vary-01 :ARG2 (h / high-02~e.16)) :mod (b / basal~e.18)) :ARG1-of (d2 / depict-01~e.1 :ARG0 (f / figure~e.5 :mod "1A"~e.6 :ARG2-of (s / supplement-01~e.4)))) # ::id a_pmid_2256_9000.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As illustrated in Supplementary Figure 1B , there was no apparent correlation between basal levels of total and phosphorylated proteins listed above in both tumour types . # ::alignments 1-1.5 4-1.5.1.2 5-1.5.1 6-1.5.1.1 11-1.1 11-1.1.r 12-1.4 13-1 15-1.2.2 16-1.2 16-1.3 17-1.2.1.r 18-1.2.1.1 20-1.3.1 21-1.2.1 22-1.2.3 23-1.2.3.1 24-1.2.4.r 25-1.2.4.2 26-1.2.4.1 27-1.2.4 (c2 / correlate-01~e.13 :polarity~e.11 -~e.11 :ARG1 (l / level~e.16 :quant-of~e.17 (p / protein~e.21 :mod (t / total~e.18)) :mod (b / basal~e.15) :ARG1-of (l3 / list-01~e.22 :location (a2 / above~e.23)) :location~e.24 (t2 / type-03~e.27 :ARG1 (t3 / tumor~e.26) :mod (b2 / both~e.25))) :ARG2 (l2 / level~e.16 :ARG3-of (p3 / phosphorylate-01~e.20) :ARG1-of l3 :mod b :location t2) :mod (a / apparent~e.12) :ARG1-of (i / illustrate-01~e.1 :ARG0 (f / figure~e.5 :mod "1B"~e.6 :ARG2-of (s / supplement-01~e.4)))) # ::id a_pmid_2256_9000.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Gene mutations and selumetinib sensitivity in NSCLC and CRC cell lines # ::alignments 0-1.1.1 1-1.1 2-1 2-1.3 3-1.2.1.1.1 4-1.2 5-1.3.r 6-1.3.1.1.1.1 7-1.3 8-1.3.2.1.1.1 9-1.3.1 9-1.3.2 10-1.3.1 (a / and~e.2 :op1 (m / mutate-01~e.1 :ARG2 (g / gene~e.0)) :op2 (s / sensitive-03~e.4 :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib"~e.3))) :location~e.5 (a2 / and~e.2,7 :op1 (c / cell-line~e.9,10 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.6))) :op2 (c2 / cell-line~e.9 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.8))))) # ::id a_pmid_2256_9000.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of the classic MAPK cascade ( RAS @-@ RAF @-@ MEK @-@ ERK ) is a common event in colorectal and lung cancer . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1.2 4-1.3.1.1.1 7-1.3.1.3.1.1.1.1 9-1.3.1.3.1.2.1.1 11-1.3.1.3.1.3.1.1 13-1.3.1.3.1.4.1.1 15-1.3.r 17-1.1 18-1 19-1.2.r 20-1.2.1.2.1 21-1.2 23-1.2.2.2.1 (e / event~e.18 :mod (c / common~e.17) :location~e.19 (a / and~e.21 :op1 (d / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon"~e.20 :op2 "cancer")) :op2 (d2 / disease :wiki "Lung_cancer" :name (n7 / name :op1 "cancer"~e.23))) :domain~e.15 (a2 / activate-01~e.0 :ARG1~e.1 (p / pathway :name (n / name :op1 "MAPK"~e.4) :mod (c6 / classic~e.3) :ARG1-of (m / mean-01 :ARG2 (m2 / macro-molecular-complex :part (e5 / enzyme :name (n3 / name :op1 "RAS"~e.7)) :part (e2 / enzyme :name (n4 / name :op1 "RAF"~e.9)) :part (e4 / enzyme :name (n5 / name :op1 "MEK"~e.11)) :part (e3 / enzyme :name (n6 / name :op1 "ERK"~e.13))))))) # ::id a_pmid_2256_9000.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Some genes within this pathway are mutated or aberrantly expressed . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.2.1.1 4-1.1.1.2.1 6-1.1 7-1 9-1.2 (o / or~e.7 :op1 (m / mutate-01~e.6 :ARG1 (g / gene~e.1 :quant~e.2 (s / some~e.0) :ARG1-of (i / include-91 :ARG2 (p / pathway~e.4 :mod (t / this~e.3))))) :op2 (e / express-03~e.9 :ARG2 g :manner (a / aberrant))) # ::id a_pmid_2256_9000.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the MAPK pathway can be indirectly activated by mutations of genes encoding for PI3K/PTEN/AKT and p53 . # ::alignments 0-1 3-1.1.1.2.1.1 4-1.1.1.1.1.1.1.1 4-1.1.1.2 5-1.1 7-1.1.1.3 7-1.1.1.3.1 7-1.1.1.3.1.r 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1 11-1.1.1.1.1.r 12-1.1.1.1.1 13-1.1.1.1.1.1 14-1.1.1.1.1.1.1.r 15-1.1.1.1.1.1.1.1.1.1 16-1.1.1.1.1.1.1 17-1.1.1.1.1.1.1.2.1.1 (a / and~e.0 :op2 (p2 / possible-01~e.5 :ARG1 (a2 / activate-01~e.8 :ARG0~e.9 (m / mutate-01~e.10 :ARG1~e.11 (g / gene~e.12 :ARG0-of (e / encode-01~e.13 :ARG1~e.14 (a3 / and~e.16 :op1 (p3 / pathway~e.4 :name (n2 / name :op1 "PI3K/PTEN/AKT"~e.15)) :op2 (p4 / protein :name (n3 / name :op1 "p53"~e.17)))))) :ARG1 (p / pathway~e.4 :name (n / name :op1 "MAPK"~e.3)) :ARG1-of (d / direct-02~e.7 :polarity~e.7 -~e.7)))) # ::id a_pmid_2256_9000.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have screened the panel of 11 NSCLC and CRC cell lines for mutations in KRAS , NRAS , BRAF , PIK3CA , p53 , PTEN , MEK1 @/@ 2 , AKT , EGFR ( Table 1 ; Supplementary Table 1A @–@ F ) . # ::alignments 0-1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1.2.1.1.1 8-1.2.1 9-1.2.1.3.1.1.1 10-1.2.1.2 10-1.2.1.3 11-1.2.1.2 12-1.3.r 13-1.3 16-1.3.1.1.1.1 18-1.3.1.2.1.1 20-1.3.1.3.1.1 22-1.3.1.4.1.1 24-1.3.1.5.1.1 26-1.3.1.6.1.1 28-1.3.1.7.1.1 30-1.3.1.7.1.1 32-1.3.1.8.1.1 34-1.3.1.9.1.1 38-1.4.1.1 38-1.4.1.2.2 39-1.4.1.1.1 43-1.4.1.2.3 44-1.4.1.2.1 44-1.4.1.2.2 45-1.4.1.2.1.1 (s / screen-01~e.2 :ARG0 (w2 / we~e.0) :ARG1 (p / panel~e.4 :consist-of~e.5 (a4 / and~e.8 :quant 11~e.6 :op1 (c / cell-line~e.10,11 :mod (d2 / disease :name (n / name :op1 "NSCLC"~e.7))) :op2 (c2 / cell-line~e.10 :mod (d3 / disease :name (n2 / name :op1 "CRC"~e.9))))) :ARG2~e.12 (m / mutate-01~e.13 :ARG1 (a2 / and :op1 (g2 / gene :name (n5 / name :op1 "KRAS"~e.16)) :op2 (g3 / gene :name (n6 / name :op1 "NRAS"~e.18)) :op3 (g4 / gene :name (n7 / name :op1 "BRAF"~e.20)) :op4 (g5 / gene :name (n8 / name :op1 "PIK3CA"~e.22)) :op5 (g6 / gene :name (n9 / name :op1 "p53"~e.24)) :op6 (g7 / gene :name (n10 / name :op1 "PTEN"~e.26)) :op7 (g8 / gene :name (n11 / name :op1 "MEK1/2"~e.28,30)) :op8 (g9 / gene :name (n12 / name :op1 "AKT"~e.32)) :op9 (g10 / gene :name (n13 / name :op1 "EGFR"~e.34)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (t / table~e.38 :mod 1~e.39) :op2 (v / value-interval :op1 (t2 / table~e.44 :mod "1A"~e.45) :op2 (t3 / table~e.38,44 :mod "1F") :ARG2-of (s2 / supplement-01~e.43))))) # ::id a_pmid_2256_9000.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In NSCLC cell lines , two out of five ( 40 %) harboured a KRAS mutation , which was located in codon 12 or 13 . # ::alignments 1-1.3.1.1.1 2-1.1 3-1.1 3-1.1.2.1 3-1.3 5-1.1.1 8-1.1.2.1.1 10-1.1.2.2.1 12-1 15-1.2.1.1.1 17-1.2 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1 23-1.2.2.1.2 24-1.2.2.1.1.1 25-1.2.2.1 26-1.2.2.1.2.1 (h / harbor-01~e.12 :ARG0 (c4 / cell-line~e.2,3 :quant 2~e.5 :ARG1-of (i / include-91 :ARG2 (c5 / cell-line~e.3 :quant 5~e.8) :ARG3 (p / percentage-entity :value 40~e.10))) :ARG1 (m / mutate-01~e.17 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.15)) :ARG1-of (l / locate-01~e.21 :location~e.22 (o / or~e.25 :op1 (c / codon~e.23 :mod 12~e.24) :op2 (c2 / codon~e.23 :mod 13~e.26)))) :location (c3 / cell-line~e.3 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.1)))) # ::id a_pmid_2256_9000.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , three out of five ( 60 %) of NSCLC cells harboured a PI3KCA mutation , which were located in exon 9 or 20 . # ::alignments 0-1 2-1.1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.2.1 10-1.1.1.2.1.2.1.1 11-1.1.1 11-1.1.1.2.1 12-1.1 15-1.1.2.1.1.1 17-1.1.2 21-1.1.2.2 22-1.1.2.2.1.r 23-1.1.2.2.1.1 23-1.1.2.2.1.2 24-1.1.2.2.1.1.1 25-1.1.2.2.1 26-1.1.2.2.1.2.1 (a / and~e.0 :op2 (h / harbor-01~e.12 :ARG0 (c / cell-line~e.11 :quant 3~e.2 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.11 :quant 5~e.5 :mod (d / disease :name (n / name :op1 "NSCLC"~e.10))) :ARG3 (p / percentage-entity :value 60~e.7))) :ARG1 (m / mutate-01~e.17 :ARG1 (g / gene :name (n3 / name :op1 "PI3KCA"~e.15)) :ARG1-of (l / locate-01~e.21 :location~e.22 (o / or~e.25 :op1 (e / exon~e.23 :mod 9~e.24) :op2 (e2 / exon~e.23 :mod 20~e.26)))))) # ::id a_pmid_2256_9000.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A concomitant mutation in KRAS and PI3KCA gene was found in two out of five ( 40 %) NSCLC . # ::alignments 1-1.1.2 2-1.1 5-1.1.1.1.1.1 7-1.1.1 9-1.1.1.2.1.1 11-1.1.1.1 11-1.1.1.2 13-1 14-1.2.r 15-1.2.1 18-1.2.2.1.1 20-1.2.2.2.1 22-1.2.2.1.2.1.1 (f / find-01~e.13 :ARG1 (m / mutate-01~e.2 :ARG1 (a / and~e.7 :op1 (g / gene~e.11 :name (n / name :op1 "KRAS"~e.5)) :op2 (g2 / gene~e.11 :name (n2 / name :op1 "PI3KCA"~e.9))) :mod (c / concomitant~e.1)) :location~e.14 (c2 / cell-line :quant 2~e.15 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant 5~e.18 :mod (d / disease :name (n3 / name :op1 "NSCLC"~e.22))) :ARG3 (p / percentage-entity :value 40~e.20)))) # ::id a_pmid_2256_9000.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One NSCLC cell line had an NRAS mutation ( Table 1 ; Supplementary Table 1A @–@ F ) . # ::alignments 0-1.1.1 1-1.1.2.1.1 2-1.1 3-1.1 4-1 7-1.2.1.1.1 9-1.2 12-1.3.1.1 12-1.3.1.2.2 13-1.3.1.1.1 17-1.3.1.2.3 18-1.3.1.2.1 18-1.3.1.2.2 19-1.3.1.2.1.1 (h / have-03~e.4 :ARG0 (c / cell-line~e.2,3 :quant 1~e.0 :mod (d2 / disease :name (n / name :op1 "NSCLC"~e.1))) :ARG1 (m / mutate-01~e.9 :ARG1 (g / gene :name (n2 / name :op1 "NRAS"~e.7))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (t / table~e.12 :mod 1~e.13) :op2 (v / value-interval :op1 (t2 / table~e.18 :mod "1A"~e.19) :op2 (t3 / table~e.12,18 :mod "1F") :ARG2-of (s / supplement-01~e.17))))) # ::id a_pmid_2256_9000.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the panel of six CRC cell lines , all of them harboured a KRAS gene mutation that was located in codon 12 or 13 . # ::alignments 2-1.3 3-1.3.1.r 4-1.3.1.1 5-1.3.1.2.1.1 6-1.3.1 7-1.3.1 11-1.1 12-1 15-1.2.1.1.1 17-1.2.1 18-1.2 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1 23-1.2.2.1.2 24-1.2.2.1.1.1 25-1.2.2.1 26-1.2.2.1.2.1 (h / harbor-01~e.12 :ARG0 c3~e.11 :ARG1 (m / mutate-01~e.18 :ARG1 (g / gene~e.17 :name (n / name :op1 "KRAS"~e.15)) :ARG1-of (l / locate-01~e.21 :location~e.22 (o / or~e.25 :op1 (c / codon~e.23 :mod 12~e.24) :op2 (c2 / codon~e.23 :mod 13~e.26)))) :location (p / panel~e.2 :consist-of~e.3 (c3 / cell-line~e.6,7 :quant 6~e.4 :mod (d / disease :name (n2 / name :op1 "CRC"~e.5))))) # ::id a_pmid_2256_9000.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , half of CRC cell lines had both a PI3KCA mutation in exon 9 or 20 and a KRAS mutation . # ::alignments 0-1 2-1.1.1.1 4-1.1.1.2.1.1.1.1 5-1.1.1 5-1.1.1.2.1 6-1.1.1 6-1.1.1.2.1 7-1.1 11-1.1.2.1.1.1.1 13-1.1.2.1 15-1.1.2.1.2.1 15-1.1.2.1.2.2 16-1.1.2.1.2.1.1 18-1.1.2.1.2.2.1 19-1.1.2 19-1.1.2.1.2 22-1.1.2.2.1.1.1 24-1.1.2.1 24-1.1.2.2 (a / and~e.0 :op2 (h / have-03~e.7 :ARG0 (c / cell-line~e.5,6 :quant "1/2"~e.2 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.5,6 :mod (d / disease :name (n / name :op1 "CRC"~e.4))))) :ARG1 (a2 / and~e.19 :op1 (m / mutate-01~e.13,24 :ARG1 (g / gene :name (n3 / name :op1 "PI3KCA"~e.11)) :location (a3 / and~e.19 :op1 (e / exon~e.15 :mod 9~e.16) :op2 (e2 / exon~e.15 :mod 20~e.18))) :op2 (m2 / mutate-01~e.24 :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS"~e.22)))))) # ::id a_pmid_2256_9000.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok None of the CRC cells had an NRAS mutation . # ::alignments 0-1.1.1 1-1.1.1.r 3-1.1.2.1.1 4-1.1 5-1 8-1.2.1.1.1 10-1.2 (h / have-03~e.5 :ARG0 (c / cell-line~e.4 :quant~e.1 (n2 / none~e.0) :mod (d / disease :name (n / name :op1 "CRC"~e.3))) :ARG1 (m / mutate-01~e.10 :ARG1 (g / gene :name (n3 / name :op1 "NRAS"~e.8)))) # ::id a_pmid_2256_9000.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No BRAF mutations were observed in the whole panel of NSCLC and CRC cells . # ::alignments 0-1.1.1 0-1.1.1.r 2-1.1.2.1.1 4-1.1 6-1 7-1.2.r 9-1.2.1 10-1.2 11-1.2.2.r 12-1.2.2.1.1.1.1 13-1.2.2 14-1.2.2.2.1.1.1 15-1.2.2.1 15-1.2.2.2 (o / observe-01~e.6 :ARG1 (m / mutate-01~e.4 :polarity~e.0 -~e.0 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.2))) :location~e.7 (p / panel~e.10 :mod (w / whole~e.9) :consist-of~e.11 (a2 / and~e.13 :op1 (c / cell-line~e.15 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.12))) :op2 (c2 / cell-line~e.15 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.14)))))) # ::id a_pmid_2256_9000.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As reported in Supplementary Table 1E and F , no other gene mutations were found in both NSCLC and CRC cell lines . # ::alignments 1-1.3 4-1.3.1.3 5-1.3.1.1 5-1.3.1.2 6-1.3.1.1.1 7-1.3.1 11-1.1.1 11-1.1.1.r 12-1.1.2.1 13-1.1.2 14-1.1 16-1 19-1.2.1.1.1.1 20-1.2 21-1.2.2.1.1.1 22-1.2.1 22-1.2.2 23-1.2.1 (f / find-01~e.16 :ARG1 (m / mutate-01~e.14 :polarity~e.11 -~e.11 :ARG1 (g / gene~e.13 :mod (o / other~e.12))) :location (a / and~e.20 :op1 (c / cell-line~e.22,23 :mod (d2 / disease :name (n / name :op1 "NSCLC"~e.19))) :op2 (c2 / cell-line~e.22 :mod (d / disease :name (n2 / name :op1 "CRC"~e.21)))) :ARG1-of (r / report-01~e.1 :ARG0 (a2 / and~e.7 :op1 (t / table~e.5 :mod "1E"~e.6) :op2 (t2 / table~e.5 :mod "1F") :ARG2-of (s / supplement-01~e.4)))) # ::id a_pmid_2256_9000.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After this screening , we tried to correlate the mutational status with selumetinib sensitivity . # ::alignments 0-1.3 1-1.3.1.1 2-1.3.1 4-1.1 5-1 7-1.2 9-1.2.2.1 10-1.2.2 11-1.2.3.r 12-1.2.3.1.1.1 13-1.2.3 (t / try-01~e.5 :ARG0 (w / we~e.4) :ARG1 (c / correlate-01~e.7 :ARG0 w :ARG1 (s / status~e.10 :mod (m / mutate-01~e.9)) :ARG2~e.11 (s2 / sensitive-03~e.13 :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib"~e.12)))) :time (a / after~e.0 :op1 (s4 / screen-01~e.2 :mod (t2 / this~e.1)))) # ::id a_pmid_2256_9000.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The analysis was made either considering separately the two sets of cell lines ( data not shown ) or all together ( Supplementary Figure 2A and B ) . # ::alignments 1-1 5-1.1 6-1.1.1.1.3 8-1.1.1.1.1 8-1.1.1.2.1 9-1.1.1.1 9-1.1.1.2 10-1.1.1.1.2.r 11-1.1.1.1.2 12-1.1.1.1.2 14-1.1.1.1.4.1 15-1.1.1.1.4.1.1.1 15-1.1.1.1.4.1.1.1.r 16-1.1.1.1.4.1.1 18-1.1.1 20-1.1.1.2.3 23-1.1.1.2.4.1.3 24-1.1.1.2.4.1.1 24-1.1.1.2.4.1.2 25-1.1.1.2.4.1.1.1 26-1.1.1.2.4.1 (a4 / analyze-01~e.1 :manner (c / consider-01~e.5 :ARG1 (o / or~e.18 :op1 (s / set~e.9 :quant 2~e.8 :consist-of~e.10 (c2 / cell-line~e.11,12) :ARG1-of (s2 / separate-02~e.6) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.14 :ARG1-of (s3 / show-01~e.16 :polarity~e.15 -~e.15)))) :op2 (s5 / set~e.9 :quant 2~e.8 :consist-of c2 :mod (t2 / together~e.20) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.26 :op1 (f / figure~e.24 :mod "2A"~e.25) :op2 (f2 / figure~e.24 :mod "2B") :ARG2-of (s4 / supplement-01~e.23))))))) # ::id a_pmid_2256_9000.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity to selumetinib did not seem to correlate with any specific gene mutations in this panel of NSCLC and CRC cell lines . # ::alignments 0-1.2.1 1-1.2.1.1.r 2-1.2.1.1.1.1 4-1.1 4-1.1.r 5-1 7-1.2 8-1.2.2.r 9-1.2.2.3 10-1.2.2.2 11-1.2.2.1 12-1.2.2 13-1.2.3.r 14-1.2.3.2 15-1.2.3 16-1.2.3.1.r 17-1.2.3.1.1.1.1.1 18-1.2.3.1 19-1.2.3.1.2.1.1.1 20-1.2.3.1.1 20-1.2.3.1.2 21-1.2.3.1.1 (s / seem-01~e.5 :polarity~e.4 -~e.4 :ARG1 (c / correlate-01~e.7 :ARG1 (s2 / sensitive-03~e.0 :ARG1~e.1 (s3 / small-molecule :name (n / name :op1 "selumetinib"~e.2))) :ARG2~e.8 (m / mutate-01~e.12 :ARG1 (g / gene~e.11) :ARG1-of (s4 / specific-02~e.10) :mod (a / any~e.9)) :location~e.13 (p / panel~e.15 :consist-of~e.16 (a3 / and~e.18 :op1 (c2 / cell-line~e.20,21 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.17))) :op2 (c3 / cell-line~e.20 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.19)))) :mod (t / this~e.14)))) # ::id a_pmid_2256_9000.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Identification of gene expression profiles that could be predictive of response to selumetinib in NSCLC and CRC cell lines # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.1.1 4-1.1 6-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.1 13-1.3.r 14-1.3.1.1.1.1 15-1.3 16-1.3.2.1.1.1 17-1.3.1 17-1.3.2 18-1.3.1 (i2 / identify-01~e.0 :ARG1~e.1 (p / profile~e.4 :topic (e / express-03~e.3 :ARG2 (g / gene~e.2))) :ARG0-of (p5 / predict-01~e.8 :ARG1~e.9 (r / respond-01~e.10 :ARG1~e.11 (s / small-molecule :name (n / name :op1 "selumetinib"~e.12))) :ARG1-of (p2 / possible-01~e.6)) :location~e.13 (a / and~e.15 :op1 (c / cell-line~e.17,18 :mod (d / disease :name (n2 / name :op1 "NSCLC"~e.14))) :op2 (c2 / cell-line~e.17 :mod (d2 / disease :name (n3 / name :op1 "CRC"~e.16))))) # ::id a_pmid_2256_9000.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RNAs from the 11 cancer cell lines were extracted and used for microarray gene expression analysis . # ::alignments 1-1.1.1.2.r 3-1.1.1.2.1 4-1.1.1.2.2.2.1 5-1.1.1.2 6-1.1.1.2 8-1.1 9-1 10-1.2 11-1.2.2.r 12-1.2.2.1 13-1.2.2.2.1 14-1.2.2.2 15-1.2.2 (a / and~e.9 :op1 (e / extract-01~e.8 :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "RNA") :source~e.1 (c / cell-line~e.5,6 :quant 11~e.3 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.4))))) :op2 (u / use-01~e.10 :ARG1 n3 :ARG2~e.11 (a2 / analyze-01~e.15 :ARG0 (m / microarray~e.12) :ARG1 (e2 / express-03~e.14 :ARG2 (g / gene~e.13))))) # ::id a_pmid_2256_9000.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using Student 's t @ -@ test with Benjamini @–@ Hochberg multiple test correction , 21 and 18 genes were identified as upregulated or downregulated , respectively , in selumetinib @-@ resistant cancer cell lines ( t @ -@ test , P @ < 0.05 ) ( Supplementary Figure 3 ) . # ::alignments 1-1.4.2.2.1 2-1.4.2.2.1 4-1.4.2.2.2 7-1.4.2.2.2 9-1.4.2.3.2.1.1.1.1 11-1.4.2.3.2.1.2.1.1 12-1.4.2.3.1.1 13-1.4.2.3.1 14-1.4.2.3 16-1.1.1.1 17-1 18-1.2.1.1 19-1.1.1 19-1.2.1 21-1.1 21-1.2 22-1.1.2.r 23-1.1.2 25-1.2.2 30-1.3.2.1.1.1 32-1.3.2 33-1.3.1.2.1 34-1.3 35-1.3 38-1.4.2.2.2 41-1.4 41-1.4.2.2.2 44-1.4 46-1.4.1 47-1.4.1.1 51-1.5.1.2 52-1.5.1 53-1.5.1.1 (a2 / and~e.17 :op1 (i / identify-01~e.21 :ARG1 (g / gene~e.19 :quant 21~e.16) :ARG2~e.22 (u / upregulate-01~e.23)) :op2 (i2 / identify-01~e.21 :ARG1 (g2 / gene~e.19 :quant 18~e.18) :ARG2 (d2 / downregulate-01~e.25)) :location (c / cell-line~e.34,35 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.33)) :ARG0-of (r2 / resist-01~e.32 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib"~e.30)))) :ARG1-of (s / statistical-test-91~e.41,44 :ARG2 (l / less-than~e.46 :op1 0.05~e.47) :ARG4 (t / thing :wiki "Student's_t-test" :name (n3 / name :op1 "Student's"~e.1,2 :op2 "t-test"~e.4,7,38,41) :mod (c2 / correct-01~e.14 :mod (t2 / test-01~e.13 :quant (m / multiple~e.12)) :ARG1-of (a3 / accord-02 :ARG2 (a4 / and :op1 (p / person :name (n5 / name :op1 "Benjamini"~e.9)) :op2 (p2 / person :name (n6 / name :op1 "Hochberg"~e.11))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.52 :mod 3~e.53 :ARG2-of (s3 / supplement-01~e.51)))) # ::id a_pmid_2256_9000.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 2 lists the differentially expressed genes in selumetinib @-@ resistant cancer cell lines . # ::alignments 1-1.1 2-1.1.1 4-1 6-1.2.1.2 6-1.2.1.2.r 7-1.2.1 8-1.2 9-1.2.1.1.r 10-1.2.1.1.1.1.1.1 12-1.2.1.1.1 13-1.2.1.1.2.2.1 14-1.2.1.1 15-1.2.1.1 (l / list-01~e.4 :ARG0 (t / table~e.1 :mod 2~e.2) :ARG1 (g / gene~e.8 :ARG2-of (e / express-03~e.7 :ARG3~e.9 (c / cell-line~e.14,15 :ARG0-of (r / resist-01~e.12 :ARG1 (s / small-molecule :name (n2 / name :op1 "selumetinib"~e.10))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.13))) :manner~e.6 (d2 / differential~e.6)))) # ::id a_pmid_2256_9000.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the 21 genes that were upregulated in selumetinib @-@ resistant cancer cell lines , we identified two genes , ADCY7 and AKAP13 , which are involved in the cAMP @-@ dependent protein kinase ( PKA ) pathway ( Table 2A ; Supplementary Figure 3 ) . # ::alignments 0-1.2.4 2-1.2.4.1.1 3-1.2.4.1 6-1.2.4.1.2 7-1.2.4.1.2.1.r 8-1.2.4.1.2.1.1.1.1.1 10-1.2.4.1.2.1.1 11-1.2.4.1.2.1.2.2.1 12-1.2.4.1.2.1 13-1.2.4.1.2.1 15-1.1 16-1 18-1.2.1 18-1.2.2 21-1.2.1.1.1 23-1.2 25-1.2.2.1.1 30-1.2.3 31-1.2.3.1.r 33-1.2.3.1.1.1 35-1.2.3.1.1.1 36-1.2.3.1.1.2 37-1.2.3.1.1.3 41-1.2.3.1 44-1.3.1.1 45-1.3.1.1.1 49-1.3.1.2.2 50-1.3.1.2 51-1.3.1.2.1 (i / identify-01~e.16 :ARG0 (w / we~e.15) :ARG1 (a / and~e.23 :op1 (g / gene~e.18 :name (n / name :op1 "ADCY7"~e.21)) :op2 (g2 / gene~e.18 :name (n2 / name :op1 "AKAP13"~e.25)) :ARG1-of (i2 / involve-01~e.30 :ARG2~e.31 (p / pathway~e.41 :name (n3 / name :op1 "cAMP-dependent"~e.33,35 :op2 "protein"~e.36 :op3 "kinase"~e.37))) :ARG1-of (i3 / include-91~e.0 :ARG2 (g3 / gene~e.3 :quant 21~e.2 :ARG1-of (u / upregulate-01~e.6 :location~e.7 (c / cell-line~e.12,13 :ARG0-of (r / resist-01~e.10 :ARG1 (s / small-molecule :name (n4 / name :op1 "selumetinib"~e.8))) :mod (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.11))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (t / table~e.44 :mod "2A"~e.45) :op2 (f / figure~e.50 :mod 3~e.51 :ARG2-of (s2 / supplement-01~e.49))))) # ::id a_pmid_2256_9000.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The ADCY7 gene encodes a membrane @-@ bound adenylatecyclase that convert ATP into 3 ', 5 ' @-@ adenosine monophosphate ( cAMP ) and pyrophosphate ( Supplementary Figure 4 ) . # ::alignments 2-1.1.1.1 4-1.1 5-1 7-1.2.2.1 9-1.2 9-1.2.2 9-1.2.2.r 10-1.2.1.1 12-1.2.3 13-1.2.3.1.1.1 14-1.2.3.2.r 15-1.2.3.2.1.1.1 17-1.2.3.2.1.1.2 18-1.2.3.2.1.1.1 18-1.2.3.2.1.1.2 20-1.2.3.2.1.1.3 21-1.2.3.2.1.1.4 25-1.2.3.2 26-1.2.3.2.2.1.1 29-1.3.1.2 30-1.3.1 31-1.3.1.1 (e / encode-01~e.5 :ARG0 (g / gene~e.4 :name (n / name :op1 "ADCY7"~e.2)) :ARG1 (e2 / enzyme~e.9 :name (n2 / name :op1 "adenylatecyclase"~e.10) :ARG1-of~e.9 (b / bind-01~e.9 :ARG2 (m2 / membrane~e.7)) :ARG0-of (c / convert-01~e.12 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP"~e.13)) :ARG2~e.14 (a / and~e.25 :op1 (s2 / small-molecule :name (n4 / name :op1 "3'"~e.15,18 :op2 "5'"~e.17,18 :op3 "adenosine"~e.20 :op4 "monophosphate"~e.21)) :op2 (s3 / small-molecule :name (n5 / name :op1 "pyrophosphate"~e.26))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod 4~e.31 :ARG2-of (s4 / supplement-01~e.29)))) # ::id a_pmid_2256_9000.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cAMP is a second messenger that has a key role in intracellular signalling transduction . # ::alignments 1-1.1.1.1.1 2-1.1.1.r 4-1.1.2 4-1.1.2.1 4-1.1.2.1.r 5-1.1 7-1 9-1.2.1 10-1.2 11-1.2.2.r 12-1.2.2.1.1 13-1.2.2.1 14-1.2.2 (h / have-03~e.7 :ARG0 (m / messenger~e.5 :domain~e.2 (s3 / small-molecule :name (n / name :op1 "cAMP"~e.1)) :ord (o / ordinal-entity~e.4 :value~e.4 2~e.4)) :ARG1 (r / role~e.10 :ARG1-of (k / key-02~e.9) :prep-in~e.11 (t / transduce-01~e.14 :ARG1 (s2 / signal-07~e.13 :mod (i / intracellular~e.12))))) # ::id a_pmid_2256_9000.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A major function in mammalian cells is the activation of the PKA ( Tasken et al , 1997 ) . # ::alignments 1-1.2 2-1 3-1.3.r 4-1.3.1.1.1 5-1.3 8-1.1 9-1.1.1.r 11-1.1.1.1.1 14-1.4.1.1.1.1.1 16-1.4.1.1 17-1.4.1.1.2.1 20-1.4.1.2.1 (f / function-01~e.2 :ARG1 (a / activate-01~e.8 :ARG1~e.9 (e / enzyme :name (n / name :op1 "PKA"~e.11))) :ARG1-of (m / major-02~e.1) :location~e.3 (c / cell~e.5 :part-of (a2 / animal :name (n2 / name :op1 "Mammalia"~e.4))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and~e.16 :op1 (p3 / person :name (n3 / name :op1 "Tasken"~e.14)) :op2 (p2 / person :mod (o / other~e.17))) :time (d2 / date-entity :year 1997~e.20)))) # ::id a_pmid_2256_9000.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The AKAP13 gene encodes the A @-@ kinase anchor protein 13 that has the function of binding to the regulatory subunits of PKA ( Supplementary Figure 4 ) . # ::alignments 2-1.1.1.1 4-1.1 5-1 7-1.2.1.1 9-1.2.1.1 10-1.2.1.2 11-1.2.1.3 12-1.2.1.4 16-1.2 16-1.2.2 16-1.2.2.r 17-1.2.2.1.r 18-1.2.2.1 19-1.2.2.1.2.r 21-1.2.2.1.2.1 22-1.2.2.1.2 23-1.2.2.1.2.2.r 24-1.2.2.1.2.2.1.1 27-1.3.1.2 28-1.3.1 29-1.3.1.1 (e / encode-01~e.5 :ARG0 (g / gene~e.4 :name (n / name :op1 "AKAP13"~e.2)) :ARG1 (e2 / enzyme~e.16 :name (n2 / name :op1 "A-kinase"~e.7,9 :op2 "anchor"~e.10 :op3 "protein"~e.11 :op4 13~e.12) :ARG0-of~e.16 (f / function-01~e.16 :ARG1~e.17 (b / bind-01~e.18 :ARG1 e2 :ARG2~e.19 (s / subunit~e.22 :ARG0-of (r / regulate-01~e.21) :part-of~e.23 (e3 / enzyme :name (n3 / name :op1 "PKA"~e.24)))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.28 :mod 4~e.29 :ARG2-of (s2 / supplement-01~e.27)))) # ::id a_pmid_2256_9000.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , four genes ( NCOA3 , TAF3 , NR1H2 , and RXRA ) , which are upregulated in selumetinib @-@ resistant cancer cell lines , belong to the retinoic acid pathway , which is also activated by PKA ( Altucci et al , 2007 ) . # ::alignments 0-1.1.3.1.1 2-1.1.1.1 3-1.1.1 6-1.1.1.2.1.1.1.1 8-1.1.1.2.1.2.1.1 10-1.1.1.2.1.3.1.1 13-1.1.1.2.1 15-1.1.1.2.1.4.1.1 21-1.1.1.3 22-1.1.1.3.1.r 23-1.1.1.3.1.1.1.1.1 25-1.1.1.3.1.1 26-1.1.1.3.1.2.2.1 27-1.1.1.3.1 28-1.1.1.3.1 30-1.1 31-1.1.2.r 33-1.1.2.1.1 34-1.1.2.1.2 35-1.1.2 39-1.1.2.2.2 40-1.1.2.2 41-1.1.2.2.1.r 42-1.1.2.2.1.1.1 45-1.1.3.1.1.1.1.1 47-1 47-1.1.3.1.1 48-1.1.3.1.1.2.1 51-1.1.3.1.2.1 (a / and~e.47 :op2 (b / belong-01~e.30 :ARG0 (g5 / gene~e.3 :quant 4~e.2 :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.13 :op1 (g / gene :name (n / name :op1 "NCOA3"~e.6)) :op2 (g2 / gene :name (n2 / name :op1 "TAF3"~e.8)) :op3 (g3 / gene :name (n3 / name :op1 "NR1H2"~e.10)) :op4 (g4 / gene :name (n4 / name :op1 "RXRA"~e.15)))) :ARG1-of (u / upregulate-01~e.21 :location~e.22 (c / cell-line~e.27,28 :ARG0-of (r / resist-01~e.25 :ARG1 (s / small-molecule :name (n5 / name :op1 "selumetinib"~e.23))) :mod (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer"~e.26))))) :ARG1~e.31 (p / pathway~e.35 :name (n6 / name :op1 "retinoic"~e.33 :op2 "acid"~e.34) :ARG1-of (a3 / activate-01~e.40 :ARG0~e.41 (e / enzyme :name (n7 / name :op1 "PKA"~e.42)) :mod (a4 / also~e.39))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a5 / and~e.0,47 :op1 (p3 / person :name (n8 / name :op1 "Altucci"~e.45)) :op2 (p4 / person :mod (o / other~e.48))) :time (d2 / date-entity :year 2007~e.51))))) # ::id a_pmid_2256_9000.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with selective PKA inhibitors sensitises selumetinib @-@ resistant cancer cell lines to selumetinib # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 3-1.1.1.1.1.1.1 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 6-1.2.1.1.1.1 8-1.2.1 9-1.2.2.2.1 10-1.2 11-1.2 13-1.3 (s / sensitize-01 :ARG0 (t / treat-04~e.0 :ARG2~e.1 (m / molecular-physical-entity~e.4 :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (p / protein-family :name (n / name :op1 "PKA"~e.3))) :mod (s2 / selective~e.2))) :ARG1 (c / cell-line~e.10,11 :ARG0-of (r / resist-01~e.8 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "selumetinib"~e.6))) :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.9))) :ARG2 s3~e.13) # ::id a_pmid_2256_9000.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To functionally evaluate if the cAMP @-@ dependent PKA could mediate resistance to MEK inhibitor treatment , we have treated the panel of NSCLC and CRC with 8 @-@ Cl @-@ cAMP , a site @-@ selective cAMP analogue , which specifically inhibits PKAI , the PKA isoform that is directly involved in mitogenic signalling and the transformed phenotype ( Tortora and Ciardiello , 2000 ; Naviglio et al , 2009 ) . # ::alignments 1-1.4.3 1-1.4.3.r 2-1.4 5-1.3.2.1.1.1 7-1.4.2.2.1 7-1.4.2.2.1.2 7-1.4.2.2.1.2.r 8-1.4.2.2.1.1.1 9-1.4.2 10-1.4.2.2 11-1.4.2.2.2 13-1.4.2.2.2.1.1.1.1.1.1 14-1.3 14-1.3.3 14-1.3.3.r 14-1.4.2.2.2.1.1 14-1.4.2.2.2.1.1.1 14-1.4.2.2.2.1.1.1.r 15-1 15-1.4.2.2.2.1 17-1.1 19-1 21-1.2 22-1.2.1.r 23-1.2.1.1.1.1 25-1.2.2.1.1.1 27-1.3.1.1 29-1.3.1.1 31-1.3.2.1.1.1 34-1.3.2.2.1 36-1.3.2.2 37-1.3.2.1.1.1 38-1.3.2 41-1.3.3.2 42-1.3 42-1.3.3 42-1.3.3.r 43-1.3.3.1.1.1 46-1.3.3.1.2.1.1.1 47-1.3.3.1.2 50-1.3.3.1.2.2.2 51-1.3.3.1.2.2 52-1.3.3.1.2.2.1.r 53-1.3.3.1.2.2.1.1.1 54-1.3.3.1.2.2.1.1 55-1.3.3.1.2.2.1 57-1.3.3.1.2.2.1.2.1 58-1.3.3.1.2.2.1.2 61-1.5.1.1.1.1.1.1 62-1.5.1.1.1 63-1.5.1.1.1.2.1.1 65-1.5.1.1.2.1 69-1.5.1.2.1.1.1.1 71-1.5.1 71-1.5.1.2.1 72-1.5.1.2.1.2.1 75-1.5.1.2.2.1 (t / treat-04~e.15,19 :ARG0 (w / we~e.17) :ARG1 (p / panel~e.21 :part~e.22 (c / cell-line :mod (d6 / disease :name (n / name :op1 "NSCLC"~e.23))) :part (c2 / cell-line :mod (d7 / disease :name (n2 / name :op1 "CRC"~e.25)))) :ARG2 (s / small-molecule~e.14,42 :name (n3 / name :op1 "8-Cl-cAMP"~e.27,29) :mod (a2 / analogue~e.38 :poss (s2 / small-molecule :name (n4 / name :op1 "cAMP"~e.5,31,37)) :mod (s3 / selective~e.36 :mod (s4 / site~e.34))) :ARG0-of~e.14,42 (i / inhibit-01~e.14,42 :ARG1 (e / enzyme :name (n5 / name :op1 "PKAI"~e.43) :mod (i2 / isoform~e.47 :poss (e2 / enzyme :name (n6 / name :op1 "PKA"~e.46)) :ARG1-of (i3 / involve-01~e.51 :ARG2~e.52 (a3 / and~e.55 :op1 (s6 / signal-07~e.54 :mod (m / mitogenic~e.53)) :op2 (p2 / phenotype~e.58 :ARG1-of (t2 / transform-01~e.57))) :ARG1-of (d / direct-02~e.50)))) :ARG1-of (s5 / specific-02~e.41))) :purpose (e3 / evaluate-01~e.2 :ARG0 w :ARG1 (p3 / possible-01~e.9 :mode interrogative :ARG1 (m2 / mediate-01~e.10 :ARG0 (e4 / enzyme~e.7 :name (n7 / name :op1 "PKA"~e.8) :ARG0-of~e.7 (d2 / depend-01~e.7 :ARG1 s2)) :ARG1 (r / resist-01~e.11 :ARG1 (t3 / treat-04~e.15 :ARG2 (m3 / molecular-physical-entity~e.14 :ARG0-of~e.14 (i4 / inhibit-01~e.14 :ARG1 (p10 / protein-family :name (n8 / name :op1 "MEK"~e.13)))))))) :manner~e.1 (f / functional~e.1)) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.71 :op1 (p4 / publication-91 :ARG0 (a5 / and~e.62 :op1 (p5 / person :name (n9 / name :op1 "Tortora"~e.61)) :op2 (p6 / person :name (n10 / name :op1 "Ciardiello"~e.63))) :time (d4 / date-entity :year 2000~e.65)) :op2 (p7 / publication-91 :ARG0 (a6 / and~e.71 :op1 (p8 / person :name (n11 / name :op1 "Naviglio"~e.69)) :op2 (p9 / person :mod (o / other~e.72))) :time (d5 / date-entity :year 2009~e.75))))) # ::id a_pmid_2256_9000.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A dose @-@ dependent inhibition of growth was observed in all cancer cell lines with a different degree of sensitivity , as illustrated in Figure 5A @ . # ::alignments 1-1.1.2.1 3-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1 8-1 9-1.2.r 10-1.2.2 11-1.2.3.2.1 12-1.2 13-1.2 16-1.2.1.1 16-1.2.1.1.2 16-1.2.1.1.2.r 17-1.2.1.1.1.r 19-1.2.1.1.1 21-1.3.r 22-1.3 25-1.3.1 26-1.3.1.1 (o / observe-01~e.8 :ARG1 (i / inhibit-01~e.4 :ARG1~e.5 (g / grow-01~e.6) :ARG0-of (d / depend-01~e.3 :ARG1 (d2 / dose~e.1))) :location~e.9 (c / cell-line~e.12,13 :ARG0-of (h / have-03 :ARG1 (t / thing~e.16 :degree-of~e.17 (s / sensitive-03~e.19) :ARG1-of~e.16 (d4 / differ-02~e.16))) :mod (a / all~e.10) :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.11))) :ARG1-of~e.21 (i2 / illustrate-01~e.22 :ARG0 (f / figure~e.25 :mod "5A"~e.26))) # ::id a_pmid_2256_9000.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To evaluate the interaction between selumetinib and 8 @-@ Cl @-@ cAMP , combination analyses were done . # ::alignments 1-1.2 3-1.2.1 5-1.2.1.1.1.1 7-1.2.1.2.1.1 9-1.2.1.2.1.1 11-1.2.1.2.1.1 13-1.1 14-1 (a / analyze-01~e.14 :mod (c / combine-01~e.13) :purpose (e / evaluate-01~e.1 :ARG1 (i / interact-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "selumetinib"~e.5)) :ARG1 (s2 / small-molecule :name (n2 / name :op1 "8-Cl-cAMP"~e.7,9,11))))) # ::id a_pmid_2256_9000.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The CRC and NSCLC cancer cells were treated with different concentrations of selumetinib ( range , 0.01 @–@ 10 μ @ ℳ) and 8 @-@ Cl @-@ cAMP ( range , 0.01 @–@ 5 μ @ ℳ) each day , for a total of 3 days at a fixed drug ratio selumetinib to 8 @-@ Cl @-@ cAMP of 1 : 1 . # ::alignments 1-1.1.2.1.1.1 2-1.1 3-1.1.1.1.1.1 4-1.1.3.2.1 5-1.1.1 5-1.1.2 7-1 9-1.2.1.2.3 9-1.2.2.2.1 10-1.2.1.2 10-1.2.2.2 11-1.2.r 12-1.2.1.1.1 16-1.2.1.2.1.1 18-1.2.1.2.1.2 24-1.2.2.1.1 26-1.2.2.1.1 28-1.2.2.1.1 32-1.2.2.2.2.1 34-1.2.2.2.2.2 40-1.3.1.2 40-1.5.2 42-1.5.r 44-1.5.3 46-1.5.1 47-1.3.1.2 47-1.5.2 50-1.4.1.3 52-1.4.1 53-1.4.1.1 55-1.2.2.1.1 57-1.2.2.1.1 59-1.2.2.1.1 60-1.4.2 61-1.3.1.1 61-1.4.2.1 61-1.4.2.2 63-1.3.1.1 63-1.4.2.1 (t / treat-04~e.7 :ARG1 (a / and~e.2 :op1 (c / cell-line~e.5 :mod (d6 / disease :name (n / name :op1 "NSCLC"~e.3))) :op2 (c2 / cell-line~e.5 :mod (d7 / disease :name (n2 / name :op1 "CRC"~e.1))) :mod (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.4))) :ARG2~e.11 (a2 / and :op1 (s / small-molecule :name (n3 / name :op1 "selumetinib"~e.12) :mod (c4 / concentration-quantity~e.10 :quant (v / value-interval :op1 0.01~e.16 :op2 10~e.18) :unit (m / micromolar) :ARG1-of (d3 / differ-02~e.9))) :op2 (s2 / small-molecule :name (n4 / name :op1 "8-Cl-cAMP"~e.24,26,28,55,57,59) :mod (c5 / concentration-quantity~e.10 :ARG1-of (d4 / differ-02~e.9) :quant (v2 / value-interval :op1 0.01~e.32 :op2 5~e.34) :unit m))) :frequency (r2 / rate-entity-91 :ARG3 (t2 / temporal-quantity :quant 1~e.61,63 :unit (d / day~e.40,47))) :condition (e / equal-01 :ARG1 (r3 / ratio-of~e.52 :op1 s~e.53 :op2 s2 :ARG1-of (f / fix-03~e.50)) :ARG2 (r4 / ratio-of~e.60 :op1 1~e.61,63 :op2 1~e.61)) :duration~e.42 (t3 / temporal-quantity :quant 3~e.46 :unit (d2 / day~e.40,47) :mod (t4 / total~e.44))) # ::id a_pmid_2256_9000.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In all selumetinib @-@ resistant cancer cell lines , the combination treatment caused synergistic growth inhibitory effects . # ::alignments 1-1.3.2 2-1.3.1.1.1.1 4-1.3.1 5-1.3.3.2.1 6-1.3 7-1.3 10-1.1.1 11-1.1 12-1 13-1.2.2 14-1.2.1.1 15-1.2.1 16-1.2 (c / cause-01~e.12 :ARG0 (t / treat-04~e.11 :mod (c2 / combine-01~e.10)) :ARG1 (a / affect-01~e.16 :ARG2 (i / inhibit-01~e.15 :ARG1 (g / grow-01~e.14)) :ARG0-of (s2 / synergize-01~e.13)) :location (c3 / cell-line~e.6,7 :ARG0-of (r / resist-01~e.4 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib"~e.2))) :mod (a2 / all~e.1) :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.5)))) # ::id a_pmid_2256_9000.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In fact , the CI values for the combinations treatments ranged between 0.013 and 0.350 . # ::alignments 0-1.4 1-1.4 4-1.3.1 4-1.3.1.1 4-1.3.1.1.r 5-1.3 6-1.3.2.r 8-1.3.2.1 9-1.3.2 10-1 12-1.1 14-1.2 (r / range-01~e.10 :ARG3 0.013~e.12 :ARG4 0.350~e.14 :ARG1 (v / value~e.5 :mod (i / interval~e.4 :mod~e.4 (c / confidence~e.4)) :poss~e.6 (t / treat-04~e.9 :mod (c2 / combine-01~e.8))) :mod (i2 / in-fact~e.0,1)) # ::id a_pmid_2256_9000.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was significantly different in the selumetinib @-@ sensitive cancer cells in which the combination treatment was clearly antagonistic with CI between 1.3 and 3.6 ( Figure 5B ) . # ::alignments 0-1.1 2-1.4 3-1 4-1.2.r 6-1.2.1.1.1.1 8-1.2.1 9-1.2.4.2.1 10-1.2 14-1.2.2.1.1 15-1.2.2.1 17-1.2.2.2 20-1.2.3.1 20-1.2.3.1.1 20-1.2.3.1.1.r 20-1.2.3.1.2 20-1.2.3.1.2.r 22-1.2.3.1.2.1 24-1.2.3.1.2.2 27-1.3.1 28-1.3.1.1 (d2 / differ-02~e.3 :ARG1 (t / this~e.0) :location~e.4 (c / cell-line~e.10 :ARG0-of (s2 / sensitive-03~e.8 :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib"~e.6))) :location-of (a / antagonize-02 :ARG1 (t2 / treat-04~e.15 :mod (c3 / combine-01~e.14)) :ARG1-of (c2 / clear-06~e.17)) :ARG0-of (h / have-03 :ARG1 (i / interval~e.20 :mod~e.20 (c4 / confidence~e.20) :mod~e.20 (v / value-interval~e.20 :op1 1.3~e.22 :op2 3.6~e.24))) :mod (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.9))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "5B"~e.28)) :ARG1-of (s4 / significant-02~e.2)) # ::id a_pmid_2256_9000.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next assessed the phosphorylation state of MEK and MAPK following treatment with selumetinib , 8 @-@ Cl @-@ cAMP as single agents or in combination with HCT15 and H460 cancer cell lines . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.1 5-1.2 6-1.2.1.1.r 7-1.2.1.1.1.1.1 8-1.2.1.1 9-1.2.1.1.2.1.1 10-1.2.2 11-1.2.2.1 13-1.2.2.1.1.1.1.1.1 15-1.2.2.1.1.1.2.1.1 17-1.2.2.1.1.1.2.1.1 19-1.2.2.1.1.1.2.1.1 21-1.2.2.1.1.1.3.1.1 22-1.2.2.1.1.1.3.1 23-1.2.2.1.1 23-1.2.2.1.1.1 23-1.2.2.1.1.1.r 24-1.2.2.1.1.r 25-1.2.2.1.1.2 26-1.2.2.1.1.2.2.r 27-1.2.2.1.1.2.2.1.1.1 28-1.2.2.1.1.2.2 29-1.2.2.1.1.2.2.2.1.1 30-1.2.2.1.1.2.2.3.2.1 31-1.2.2.1.1.2.2.1 31-1.2.2.1.1.2.2.2 32-1.2.2.1.1.2.2.1 (a / assess-01~e.2 :ARG0 (w / we~e.0) :ARG1 (s / state~e.5 :mod (p / phosphorylate-01~e.4 :ARG1~e.6 (a2 / and~e.8 :op1 (e / enzyme :name (n2 / name :op1 "MEK"~e.7)) :op2 (e2 / enzyme :name (n3 / name :op1 "MAPK"~e.9)))) :ARG1-of (f / follow-01~e.10 :ARG2 (t / treat-04~e.11 :ARG2~e.24 (o / or~e.23 :op1~e.23 (o2 / or~e.23 :op1 (s2 / small-molecule :name (n4 / name :op1 "selumetinib"~e.13)) :op2 (s3 / small-molecule :name (n5 / name :op1 "8-Cl-cAMP"~e.15,17,19)) :ARG0-of (a3 / act-01 :ARG1 (a4 / agent~e.22 :ARG1-of (s4 / single-02~e.21)))) :op2 (c / combine-01~e.25 :ARG1 (a5 / and :op1 s2 :op2 s3) :ARG2~e.26 (a6 / and~e.28 :op1 (c2 / cell-line~e.31,32 :name (n6 / name :op1 "HCT15"~e.27)) :op2 (c3 / cell-line~e.31 :name (n7 / name :op1 "H460"~e.29)) :mod (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.30)))))))) :mod (n / next~e.1)) # ::id a_pmid_2256_9000.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 3C , single agent selumetinib or 8 @-@ Cl @-@ cAMP slightly inhibited p @-@ MEK and p @-@ MAPK , whereas the combination induced a significant inhibition of both phosphorylated proteins . # ::alignments 1-1.3 4-1.3.1 5-1.3.1.1 8-1.1.1.3.1.1 9-1.1.1.3.1 10-1.1.1.1.1.1 11-1.1.1 12-1.1.1.2.1.1 14-1.1.1.2.1.1 16-1.1.1.2.1.1 17-1.1.3 18-1.1 19-1.1.2.1.2 21-1.1.2.1.1.1 23-1.1.2.1.2 25-1.1.2.2.1.1 27-1 29-1.2.1 30-1.2 32-1.2.2.2 33-1.2.2 36-1.2.2.1 (c / contrast-01~e.27 :ARG1 (i / inhibit-01~e.18 :ARG0 (o / or~e.11 :op1 (s2 / small-molecule :name (n / name :op1 "selumetinib"~e.10)) :op2 (s3 / small-molecule :name (n2 / name :op1 "8-Cl-cAMP"~e.12,14,16)) :ARG0-of (a / act-01 :ARG1 (a2 / agent~e.9 :ARG1-of (s4 / single-02~e.8)))) :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "MEK"~e.21) :ARG3-of (p5 / phosphorylate-01~e.19,23)) :op2 (e2 / enzyme :name (n4 / name :op1 "MAPK"~e.25) :ARG3-of p5)) :degree (s / slight~e.17)) :ARG2 (i2 / induce-01~e.30 :ARG0 (c2 / combine-01~e.29 :ARG1 s2 :ARG2 s3) :ARG1 (i3 / inhibit-01~e.33 :ARG1 a3~e.36 :ARG1-of (s7 / significant-02~e.32))) :ARG1-of (s6 / show-01~e.1 :ARG0 (f / figure~e.4 :mod "3C"~e.5))) # ::id a_pmid_2256_9000.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A genetic approach to inhibiting PKAI expression was developed by the use of phosphorothioate antisense oligonucleotides targeting the synthesis of the PKAI regulatory subunit RI @ α @ . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1 5-1.1.1.1.1.1.1 6-1.1.1.1 8-1 9-1.2.r 11-1.2 12-1.2.1.r 13-1.2.1.3 15-1.2.1 16-1.2.1.1 18-1.2.1.1.1 19-1.2.1.1.1.1.r 21-1.2.1.1.1.1.2 22-1.2.1.1.1.1 22-1.2.1.1.1.1.3 22-1.2.1.1.1.1.3.r (d / develop-02~e.8 :ARG1 (a / approach-02~e.2 :ARG1~e.3 (i / inhibit-01~e.4 :ARG1 (e / express-03~e.6 :ARG2 (e2 / enzyme :name (n / name :op1 "PKAI"~e.5)))) :mod (g / genetics~e.1)) :manner~e.9 (u / use-01~e.11 :ARG1~e.12 (o / oligonucleotide~e.15 :ARG0-of (t / target-01~e.16 :ARG1 (s / synthesize-01~e.18 :ARG1~e.19 (p / protein-segment~e.22 :name (n3 / name :op1 "RIα") :part-of e2~e.21 :ARG0-of~e.22 (r / regulate-01~e.22)))) :ARG0-of (c / counter-01 :ARG1 (s2 / sense-01)) :mod (p2 / phosphorothioate~e.13)))) # ::id a_pmid_2256_9000.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These oligonucleotides inhibit growth of several human cancer cell lines in vitro and in vivo ( Yokozaki et al , 1993 ; Nesterova and Cho @-@ Chung , 1995 ; Tortora et al , 1997a ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2 4-1.2.1.r 5-1.2.1.2 6-1.2.1.1 7-1.2.1.3.2.1 8-1.2.1 9-1.2.1 11-1.3.1 12-1.3.1 14-1.3 16-1.3.1 16-1.3.2 17-1.3.2 21-1.4.1.1.1.1.1.1 23-1.4.1.1.1 24-1.4.1.1.1.2.1 27-1.4.1.1.2.1 31-1.4.1.2.1.1.1.1 32-1.4.1.2.1 33-1.4.1.2.1.2.1.1 35-1.4.1.2.1.2.1.1 37-1.4.1.2.2.1 41-1.4.1.3.2.1.1.1 43-1.4.1 43-1.4.1.1.1 43-1.4.1.3.2 44-1.4.1.1.1.2.1 (i / inhibit-01~e.2 :ARG0 (o / oligonucleotide~e.1 :mod (t / this~e.0)) :ARG1 (g / grow-01~e.3 :ARG1~e.4 (c / cell-line~e.8,9 :mod (h / human~e.6) :quant (s / several~e.5) :mod (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.7)))) :manner (a / and~e.14 :op1 (i2 / in-vitro~e.11,12,16) :op2 (i3 / in-vivo~e.16,17)) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.43 :op1 (p / publication-91 :ARG0 (a3 / and~e.23,43 :op1 (p4 / person :name (n / name :op1 "Yokozaki"~e.21)) :op2 (p5 / person :mod (o2 / other~e.24,44))) :time (d2 / date-entity :year 1993~e.27)) :op2 (p2 / publication-91 :ARG0 (a4 / and~e.32 :op1 (p6 / person :name (n2 / name :op1 "Nesterova"~e.31)) :op2 (p7 / person :name (n3 / name :op1 "Cho-Chung"~e.33,35))) :time (d3 / date-entity :year 1995~e.37)) :op3 (p3 / publication-91 :li "a" :ARG0 (a5 / and~e.43 :op1 (p8 / person :name (n4 / name :op1 "Tortora"~e.41)) :op2 p5) :time (d4 / date-entity :year 1997))))) # ::id a_pmid_2256_9000.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , HYB 190 , an 18 @-@ mer MBO antisense to the N @-@ terminal 8 @–@ 13 codons of the RI @ α subunit of PKAI , and the control HYB 239 , containing four mismatched bases , were tested to study the effect on the growth of NSCLC and CRC cell lines . # ::alignments 0-1 2-1.1.1.1.1.1 3-1.1.1.1.1.2 6-1.1.1.1.4.1.1 10-1.1.1.1.3 11-1.1.1.1.3.1.r 13-1.1.1.1.3.1.2.1.1 15-1.1.1.1.3.1.2.1.1 16-1.1.1.1.3.1.1.1 18-1.1.1.1.3.1.1.2 19-1.1.1.1.3.1 27-1.1.1.1.3.1.3.r 28-1.1.1.1.3.1.3.2.1.1 30-1.1.1 32-1.1.1.2 32-1.1.1.2.3 32-1.1.1.2.3.r 33-1.1.1.2.1.1 34-1.1.1.2.1.2 36-1.1.1.2.2 37-1.1.1.2.2.1.1 38-1.1.1.2.2.1.2 39-1.1.1.2.2.1 42-1.1 44-1.1.2 46-1.1.2.1 47-1.1.2.1.1.r 49-1.1.2.1.1 50-1.1.2.1.1.1.r 51-1.1.2.1.1.1.1.1.1.1 52-1.1.2.1.1.1 53-1.1.2.1.1.1.2.1.1.1 54-1.1.2.1.1.1.1 54-1.1.2.1.1.1.2 55-1.1.2.1.1.1.1 (c3 / cause-01~e.0 :ARG1 (t / test-01~e.42 :ARG1 (a3 / and~e.30 :op1 (o / oligonucleotide :name (n3 / name :op1 "HYB"~e.2 :op2 190~e.3) :mod (b2 / backbone :ARG3-of (m / mix-01)) :mod (a4 / antisense~e.10 :prep-to~e.11 (c4 / codon~e.19 :mod (v / value-interval :op1 8~e.16 :op2 13~e.18) :part-of (p / protein-segment :name (n4 / name :op1 "N-terminus"~e.13,15)) :part-of~e.27 (p2 / protein-segment :name (n5 / name :op1 "RIα") :part-of (e2 / enzyme :name (n6 / name :op1 "PKAI"~e.28))))) :mod (p3 / polymer :ARG1-of (l / long-03 :ARG2 18~e.6))) :op2 (s2 / small-molecule~e.32 :name (n7 / name :op1 "HYB"~e.33 :op2 239~e.34) :ARG0-of (c6 / contain-01~e.36 :ARG1 (b / base~e.39 :quant 4~e.37 :mod (m4 / mismatch~e.38))) :ARG0-of~e.32 (c5 / control-01~e.32))) :purpose (s / study-01~e.44 :ARG1 (a / affect-01~e.46 :ARG1~e.47 (g / grow-01~e.49 :ARG1~e.50 (a2 / and~e.52 :op1 (c / cell-line~e.54,55 :mod (d / disease :name (n / name :op1 "NSCLC"~e.51))) :op2 (c2 / cell-line~e.54 :mod (d2 / disease :name (n2 / name :op1 "CRC"~e.53))))))))) # ::id a_pmid_2256_9000.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All cancer cell lines treated with HBY 190 displayed a dose @-@ dependent inhibition of growth by MTT assay ( Figure 6A ) . # ::alignments 0-1.1.2 1-1.1.3.2.1 2-1.1 3-1.1 4-1.1.1 5-1.4.1.r 7-1.1.1.1.1.2 8-1 10-1.2.2.1 12-1.2.2 13-1.2 14-1.2.1.r 15-1.2.1 17-1.4.1.1.1 18-1.4 21-1.3.1 22-1.3.1.1 (d2 / display-01~e.8 :ARG0 (c / cell-line~e.2,3 :ARG1-of (t / treat-04~e.4 :ARG2 (s / small-molecule :name (n2 / name :op1 "HYB" :op2 190~e.7))) :mod (a / all~e.0) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.1))) :ARG1 (i / inhibit-01~e.13 :ARG1~e.14 (g / grow-01~e.15) :ARG0-of (d3 / depend-01~e.12 :ARG1 (d4 / dose~e.10))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure~e.21 :mod "6A"~e.22)) :manner (a2 / assay-01~e.18 :instrument~e.5 (s2 / small-molecule :name (n3 / name :op1 "MTT"~e.17)))) # ::id a_pmid_2256_9000.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Growth inhibition was more pronounced in selumetinib @-@ resistant cancer cell lines ( IC @₅₀ between 0.25 and 1 μ @ ℳ) , while the IC @₅₀ values were > 5 μ @ ℳ in the selumetinib @-@ sensitive cancer cells . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1.2 4-1.1 5-1.1.3.r 6-1.1.3.1.1.1.1 8-1.1.3.1 9-1.1.3.2.2.1 10-1.1.3 11-1.2.3 13-1.1.3.1.1 13-1.1.3.1.1.2 13-1.1.3.1.1.2.r 13-1.2 15-1.1.3.1.1.2.1 15-1.2.1 18-1.1.3.1.1.2.2.2.1 20-1.1.3.1.1.2.2.2.2 26-1 28-1.1.3.1.1 28-1.1.3.1.1.2 28-1.1.3.1.1.2.r 28-1.2 30-1.1.3.1.1.2.1 30-1.2.1 32-1.1.3.1.1.2.2.2 34-1.2.2 35-1.2.2.1.1 42-1.2.3.1.1 44-1.2.3.1 45-1.2.3.2 46-1.2.3 (c / contrast-01~e.26 :ARG1 (p / pronounced-02~e.4 :ARG1 (i / inhibit-01~e.1 :ARG1 (g / grow-01~e.0)) :degree (m / more~e.3) :location~e.5 (c2 / cell-line~e.10 :ARG0-of (r / resist-01~e.8 :ARG1 (s / small-molecule~e.13,28 :name (n2 / name :op1 "selumetinib"~e.6) :ARG1-of~e.13,28 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.13,28 :ARG2 50~e.15,30 :ARG4 (c4 / concentration-quantity :unit (m3 / micromolar) :quant (v / value-interval~e.32 :op1 0.25~e.18 :op2 1~e.20))))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.9)))) :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.13,28 :ARG2 50~e.15,30 :ARG4 (m5 / more-than~e.34 :op1 (c7 / concentration-quantity :quant 5~e.35 :unit m3)) :location (c5 / cell-line~e.11,46 :ARG0-of (s2 / sensitive-03~e.44 :ARG1 s~e.42) :mod d~e.45))) # ::id a_pmid_2256_9000.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the control oligonucleotide , HYB 239 , at doses up to 5 μ @ ℳ, showed only 5 @–@ 15 % growth inhibition among all of the cell lines tested ( Figure 6A ) . # ::alignments 1-1 4-1.1.1.3 5-1.1.1 7-1.1.1.2.1 8-1.1.1.2.2 11-1.1.3 12-1.1.3.1 13-1.1.3.1 14-1.1.3.1.1.1 19-1.1 20-1.1.2.2.2 21-1.1.2.2.1.1 23-1.1.2.2.1.2 24-1.1.2.2 25-1.1.2.1 26-1.1.2 28-1.1.4.1 31-1.1.4 32-1.1.4 33-1.1.4.2 36-1.2.1 37-1.2.1.1 (c / contrast-01~e.1 :ARG2 (s / show-01~e.19 :ARG0 (o / oligonucleotide~e.5 :wiki - :name (n / name :op1 "HYB"~e.7 :op2 239~e.8) :ARG0-of (c2 / control-01~e.4)) :ARG1 (i / inhibit-01~e.26 :ARG1 (g / grow-01~e.25) :mod (p / percentage-entity~e.24 :value (v / value-interval :op1 5~e.21 :op2 15~e.23) :mod (o2 / only~e.20))) :condition (d / dose~e.11 :quant (u / up-to~e.12,13 :op1 (c4 / concentration-quantity :quant 5~e.14 :unit (m / micromolar)))) :location (c3 / cell-line~e.31,32 :mod (a / all~e.28) :ARG1-of (t / test-01~e.33))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.36 :mod "6A"~e.37))) # ::id a_pmid_2256_9000.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether a combination of selumetinib and oligonucleotide HYB 190 could enhance the antiproliferative effect compared with either agent alone , selumetinib @-@ resistant cells were treated with different combinations of the two agents at a fixed drug ratio of 1 : 1 . # ::alignments 1-1.3 2-1.3.1.1 2-1.3.1.1.r 4-1.3.1.2.1 5-1.3.1.2.1.1.r 6-1.3.1.2.1.1.1.1 8-1.3.1.2.1.2 9-1.3.1.2.1.2.1.1 10-1.3.1.2.1.2.1.2 11-1.3.1 12-1.3.1.2 12-1.3.1.2.3.1 12-1.3.1.2.3.2 14-1.3.1.2.2.1 14-1.3.1.2.2.1.1 14-1.3.1.2.2.1.1.r 15-1.3.1.2.2 16-1.3.1.2.3.r 22-1.1.1.1 24-1.1.1 25-1.1 27-1 28-1.2.r 29-1.2.3 30-1.2 31-1.4.2 37-1.4.1.2 38-1.4.1.1 39-1.4.1 40-1.4.2 41-1.4.2.1 41-1.4.2.2 43-1.4.2.1 (t / treat-04~e.27 :ARG1 (c4 / cell~e.25 :ARG0-of (r3 / resist-01~e.24 :ARG1 s~e.22)) :ARG2~e.28 (c / combine-01~e.30 :ARG1 s :ARG2 o :ARG1-of (d3 / differ-02~e.29)) :purpose (d / determine-01~e.1 :ARG1 (p2 / possible-01~e.11 :mode~e.2 interrogative~e.2 :ARG1 (e / enhance-01~e.12 :ARG0 (c2 / combine-01~e.4 :ARG1~e.5 (s / small-molecule :name (n / name :op1 "selumetinib"~e.6)) :ARG2 (o / oligonucleotide~e.8 :name (n2 / name :op1 "HYB"~e.9 :op2 190~e.10))) :ARG1 (a / affect-01~e.15 :ARG2 (c3 / counter-01~e.14 :ARG1~e.14 (p3 / proliferate-01~e.14))) :compared-to~e.16 (o2 / or :op1 (e2 / enhance-01~e.12 :ARG0 s :ARG1 a) :op2 (e3 / enhance-01~e.12 :ARG0 o :ARG1 a))))) :condition (e4 / equal-01 :ARG1 (r2 / ratio~e.39 :mod (d2 / drug~e.38) :ARG1-of (f / fix-03~e.37)) :ARG2 (r4 / ratio-of~e.31,40 :op1 1~e.41,43 :op2 1~e.41))) # ::id a_pmid_2256_9000.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 6B , the combination treatment caused synergistic growth inhibitory effects . # ::alignments 1-1.3 4-1.3.1 5-1.3.1.1 9-1.1.1 10-1.1 11-1 13-1.2.1.1 14-1.2.1 15-1.2 (c / cause-01~e.11 :ARG0 (t / treat-04~e.10 :mod (c2 / combine-01~e.9)) :ARG1 (a / affect-01~e.15 :ARG2 (i / inhibit-01~e.14 :ARG1 (g / grow-01~e.13))) :ARG1-of (s / show-01~e.1 :ARG0 (f / figure~e.4 :mod "6B"~e.5))) # ::id a_pmid_2256_9000.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether the growth inhibitory effect of oligonucleotide HYB 190 correlated with a reduction in RI @ α protein levels , we performed protein blots on total cell extracts prepared from H460 cells treated with oligonucleotide HYB 190 , oligonucleotide HYB 239 , selumetinib , and combinations . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 4-1.3.2.2.2.2 5-1.3.2.2.2 6-1.3.2.2 8-1.2.2.3.1.2.1.2 8-1.3.2.2.1 9-1.3.2.2.1.1.1 10-1.3.2.2.1.1.2 11-1.3.2 12-1.3.2.3.r 14-1.3.2.3 20-1.3.2.3.1.1 21-1.3.2.3.1 23-1.1 24-1 25-1.2.1 28-1.2.2.2 29-1.2.2.1.1 30-1.2.2 30-1.2.2.1 30-1.2.2.1.r 31-1.2.2.3 32-1.2.2.3.1.r 33-1.2.2.3.1.1.1 34-1.2.2.3.1 35-1.2.2.3.1.2 36-1.2.2.3.1.2.1.r 37-1.2.2.3.1.2.1.1 38-1.2.2.3.1.2.1.1 39-1.2.2.3.1.2.1.1 40-1.2.2.3.1.2.1.1 41-1.2.2.3.1.2.1.1 42-1.2.2.3.1.2.1.2.1.1 43-1.2.2.3.1.2.1.2.1.2 45-1.2.2.3.1.2.1.3.1.1 48-1.2.2.3.1.2.1.4 (p / perform-01~e.24 :ARG0 (w / we~e.23) :ARG1 (i2 / immunoblot-01 :ARG1 (p2 / protein~e.25) :ARG2 (m / molecular-physical-entity~e.30 :ARG1-of~e.30 (e / extract-01~e.30 :ARG2 (c2 / cell~e.29)) :mod (t / total~e.28) :ARG1-of (p4 / prepare-01~e.31 :ARG2~e.32 (c3 / cell-line~e.34 :name (n3 / name :op1 "H460"~e.33) :ARG1-of (t2 / treat-04~e.35 :ARG2~e.36 (o2 / or :op1 o~e.37,38,39,40,41 :op2 (o3 / oligonucleotide~e.8 :name (n4 / name :op1 "HYB"~e.42 :op2 239~e.43)) :op3 (s / small-molecule :name (n5 / name :op1 "selumetinib"~e.45)) :op4 (c4 / combine-01~e.48))))))) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (c / correlate-01~e.11 :mode~e.2 interrogative~e.2 :ARG1 (a / affect-01~e.6 :ARG0 (o / oligonucleotide~e.8 :name (n / name :op1 "HYB"~e.9 :op2 190~e.10)) :ARG2 (i / inhibit-01~e.5 :ARG0 o3 :ARG1 (g / grow-01~e.4))) :ARG2~e.12 (r / reduce-01~e.14 :ARG1 (l / level~e.21 :quant-of (p3 / protein-segment~e.20 :name (n2 / name :op1 "RIα"))))))) # ::id a_pmid_2256_9000.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Compared with untreated H460 cells , RI @ α levels were substantially unchanged , even in cells treated with a higher dose of the control oligonucleotide HYB 239 ( 1 μ @ ℳ) and selumetinib ( 5 μ @ ℳ) . # ::alignments 0-1.2.2.r 2-1.2.2.2 2-1.2.2.2.1 2-1.2.2.2.1.r 3-1.2.2.1.1 4-1.2.2 10-1.2 12-1.3 13-1 13-1.1 13-1.1.r 16-1.4.r 17-1.4.1 18-1.4 19-1.4.2.r 21-1.4.2.1.1 21-1.4.2.1.1.1 21-1.4.2.1.1.1.r 22-1.4.2.1 22-1.4.2.2 23-1.4.2.1.2.r 25-1.4.2.1.2.2 26-1.4.2.1.2 27-1.4.2.1.2.1.1 28-1.4.2.1.2.1.2 30-1.4.2.1.3.1.1 35-1.4.2 36-1.4.2.2.2.1.1 38-1.4.2.2.3.1.1 (c / change-01~e.13 :polarity~e.13 -~e.13 :ARG1 (l / level~e.10 :quant-of (p / protein-segment :name (n / name :op1 "RIα")) :compared-to~e.0 (c2 / cell-line~e.4 :name (n2 / name :op1 "H460"~e.3) :ARG1-of (t / treat-04~e.2 :polarity~e.2 -~e.2))) :degree (s / substantial~e.12) :concession~e.16 (t2 / treat-04~e.18 :ARG1 (c3 / cell~e.17) :ARG2~e.19 (a / and~e.35 :op1 (d / dose~e.22 :ARG1-of (h / high-02~e.21 :degree~e.21 (m / more~e.21)) :quant-of~e.23 (o / oligonucleotide~e.26 :name (n3 / name :op1 "HYB"~e.27 :op2 239~e.28) :ARG0-of (c4 / control-01~e.25)) :ARG1-of (m2 / mean-01 :ARG2 (c5 / concentration-quantity :quant 1~e.30 :unit (m3 / micromolar)))) :op1 (d2 / dose~e.22 :ARG1-of h :quant-of (s2 / small-molecule :name (n4 / name :op1 "selumetinib"~e.36)) :ARG1-of (m5 / mean-01 :ARG2 (m6 / mass-quantity :quant 5~e.38 :unit m3)))))) # ::id a_pmid_2256_9000.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , reduction of RI @ α expression was seen when H460 cells were treated with oligonucleotide HYB 190 ( Figure 6C ) . # ::alignments 0-1 2-1.1.1 8-1.1.1.1 10-1.1 12-1.1.2.1.1.1 13-1.1.2.1 15-1.1.2 16-1.1.2.2.r 17-1.1.2.2 18-1.1.2.2.1.1 19-1.1.2.2.1.2 22-1.1.3.1 23-1.1.3.1.1 (c2 / contrast-01~e.0 :ARG2 (s / see-01~e.10 :ARG1 (r / reduce-01~e.2 :ARG1 (e / express-03~e.8 :ARG2 (p / protein-segment :name (n / name :op1 "RIα")))) :condition (t / treat-04~e.15 :ARG1 (c / cell-line~e.13 :name (n2 / name :op1 "H460"~e.12)) :ARG2~e.16 (o / oligonucleotide~e.17 :name (n3 / name :op1 "HYB"~e.18 :op2 190~e.19))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.22 :mod "6C"~e.23)))) # ::id a_pmid_2256_9000.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , a complete inhibition of RI @ α expression was seen in the combination treatment ( Figure 6C ) . # ::alignments 0-1 3-1.1.1.2 4-1.1.1 10-1.1.1.1 12-1.1 13-1.1.2.r 15-1.1.2.1 16-1.1.2 19-1.1.3.1 20-1.1.3.1.1 (a / and~e.0 :op2 (s / see-01~e.12 :ARG1 (i / inhibit-01~e.4 :ARG1 (e / express-03~e.10 :ARG2 (p / protein-segment :name (n / name :op1 "RIα"))) :degree (c / complete-02~e.3)) :condition~e.13 (t / treat-04~e.16 :mod (c2 / combine-01~e.15)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "6C"~e.20)))) # ::id a_pmid_2256_9000.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We finally evaluated whether the combined inhibition of both PKA and MEK pathways would have antitumour activity in vivo in selumetinib @-@ resistant HCT15 and H460 xenografts ( Figure 7 ) . # ::alignments 0-1.2 1-1.1 1-1.1.r 2-1 3-1.3.1 3-1.3.1.r 5-1.3.2.2 6-1.3.2 9-1.3.2.1.1.1.1 10-1.3.2.1 11-1.3.2.1.2.1.1 12-1.3.2.1.1 12-1.3.2.1.2 16-1.3 18-1.3.4 19-1.3.4 21-1.3.4 21-1.3.5.r 22-1.3.5.3.1.1.1 24-1.3.5.3 25-1.3.5.1.1.1.1 26-1.3.5 27-1.3.5.2.1.1.1 28-1.3.5.1 28-1.3.5.2 31-1.4.1 32-1.4.1.1 (e2 / evaluate-01~e.2 :li~e.1 -1~e.1 :ARG0 (w2 / we~e.0) :ARG1 (a / activity-06~e.16 :mode~e.3 interrogative~e.3 :ARG0 (i / inhibit-01~e.6 :ARG1 (a2 / and~e.10 :op1 (p / pathway~e.12 :name (n2 / name :op1 "PKA"~e.9)) :op2 (p2 / pathway~e.12 :name (n3 / name :op1 "MEK"~e.11))) :ARG1-of (c / combine-01~e.5)) :ARG1 (c2 / counter-01 :ARG1 (t / tumor)) :manner (i2 / in-vivo~e.18,19,21) :location~e.21 (a3 / and~e.26 :op1 (x / xenograft~e.28 :source (c3 / cell-line :name (n / name :op1 "HCT15"~e.25))) :op2 (x2 / xenograft~e.28 :source (c4 / cell-line :name (n4 / name :op1 "H460"~e.27))) :ARG0-of (r / resist-01~e.24 :ARG1 (s / small-molecule :name (n6 / name :op1 "selumetinib"~e.22))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.31 :mod 7~e.32))) # ::id a_pmid_2256_9000.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At day 50 from cancer cell injection , the mean tumour volume in mice bearing HCT15 and H460 tumour xenografts and treated with selumetinib , 25 mg kg @⁻¹ , and 8 @-@ Cl @-@ cAMP , 0.5 mg kg @⁻¹ , were 20 % and 16 % , respectively , as compared with control untreated mice . # ::alignments 1-1.3.2.2 2-1.3.2.1 3-1.1.3.1.1.1.1.r 3-1.1.3.1.1.2.1.r 4-1.3.1.1.1.2.1 5-1.3.1.1 6-1.3.1 9-1.1.1.2 10-1.1.1.1 11-1.1.1 13-1.1.3 14-1.1.3.1 15-1.1.3.1.1.1.1.1.1.1 16-1.1.3.1.1 17-1.1.3.1.1.2.1.1.1.1 18-1.1.3.1.1.1.1 18-1.1.3.1.1.2.1 19-1.1.3.1.1.1 19-1.1.3.1.1.2 20-1.1.3.1.1 21-1.1.3.2 22-1.1.3.2.1.r 23-1.1.3.2.1.1.1 25-1.1.3.2.1.2.1 26-1.1.3.2.1.2.2 27-1.1.3.2.1.2.2 32-1.1.3.1.1 33-1.2.3.2.1.1.1 35-1.2.3.2.1.1.1 37-1.2.3.2.1.1.1 39-1.2.3.2.1.2.1 40-1.2.3.2.1.2.2 41-1.2.3.2.1.2.2 47-1.1.2.1 48-1.1.2 49-1 50-1.2.2.1 51-1.2.2 55-1.3.r 56-1.4.r 58-1.4.1 59-1.2.3.2 59-1.4.2 59-1.4.2.1 59-1.4.2.1.r 60-1.2.3 60-1.4 (a / and~e.49 :op1 (e / equal-01 :ARG1 (v / volume~e.11 :mod (t / tumor~e.10) :mod (m / mean~e.9)) :ARG2 (p / percentage-entity~e.48 :value 20~e.47) :location (m2 / mouse~e.13 :ARG0-of (b / bear-01~e.14 :ARG1 (a2 / and~e.16,20,32 :op1 (x / xenograft~e.19 :source~e.3 (t2 / tumor~e.18 :mod (c6 / cell-line :name (n / name :op1 "HCT15"~e.15)))) :op2 (x2 / xenograft~e.19 :source~e.3 (t3 / tumor~e.18 :mod (c4 / cell-line :name (n2 / name :op1 "H460"~e.17)))))) :ARG1-of (t4 / treat-04~e.21 :ARG2~e.22 (s / small-molecule :name (n4 / name :op1 "selumetinib"~e.23) :mod (c / concentration-quantity :quant 25~e.25 :unit (m3 / milligram-per-kilogram~e.26,27)))))) :op2 (e2 / equal-01 :ARG1 v :ARG2 (p2 / percentage-entity~e.51 :value 16~e.50) :location (m4 / mouse~e.60 :ARG0-of b :ARG1-of (t5 / treat-04~e.59 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "8-Cl-cAMP"~e.33,35,37) :mod (c2 / concentration-quantity :quant 0.5~e.39 :unit (m5 / milligram-per-kilogram~e.40,41)))))) :time~e.55 (a3 / after :op1 (i / inject-01~e.6 :ARG1 (c3 / cell~e.5 :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.4)))) :quant (t6 / temporal-quantity :quant 50~e.2 :unit (d2 / day~e.1))) :compared-to~e.56 (m6 / mouse~e.60 :ARG0-of (c5 / control-01~e.58) :ARG1-of (t7 / treat-04~e.59 :polarity~e.59 -~e.59))) # ::id a_pmid_2458_8908.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a cohort of 144 metastatic melanoma patients we found that patients with N @-@ RAS mutant melanoma had a worse prognosis . # ::alignments 2-1.2.1.3.1 3-1.2.1.3.1.1.r 4-1.2.1.3.1.1.1 5-1.2.1.3.1.1.2.1.2 6-1.2.1.1.1.1.1 6-1.2.1.3.1.1.2.1.1.1 7-1.2.1.2.1 8-1.1 9-1 11-1.2.1.2.1 11-1.2.1.3.1.1.3.1 13-1.2.1.1.1.2.1.1 15-1.2.1.1.1.2.1.1 16-1.2.1.1.1.2 16-1.2.1.1.1.2.2 16-1.2.1.1.1.2.2.r 17-1.2.1.1.1.1.1 17-1.2.1.3.1.1.2.1.1.1 18-1.2 20-1.2.2.1 20-1.2.2.1.1 20-1.2.2.1.1.r 21-1.2.2 (f / find-01~e.9 :ARG0 (w / we~e.8) :ARG1 (h / have-03~e.18 :ARG0 (p / person :ARG0-of (h2 / have-03 :ARG1 (m5 / medical-condition :name (n / name :op1 "melanoma"~e.6,17) :mod (e / enzyme~e.16 :name (n2 / name :op1 "N-RAS"~e.13,15) :ARG2-of~e.16 (m / mutate-01~e.16)))) :ARG0-of (h4 / have-rel-role-91 :ARG2 (p4 / patient~e.7,11)) :ARG1-of (i / include-91 :ARG2 (c / cohort~e.2 :consist-of~e.3 (p3 / person :quant 144~e.4 :ARG0-of (h3 / have-03 :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma"~e.6,17) :ARG1-of (m3 / metastasize-101~e.5))) :ARG0-of (h5 / have-rel-role-91 :ARG2 (p5 / patient~e.11)))))) :ARG1 (p2 / prognosis~e.21 :ARG1-of (b / bad-07~e.20 :degree~e.20 (m2 / more~e.20))))) # ::id a_pmid_2458_8908.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These patients were more likely to have brain metastases at the time of presentation with metastatic disease than their N @-@ RAS @-@ wild @-@ type counterparts . # ::alignments 0-1.1.1.1 1-1.1.1.3.1 3-1.2 4-1 6-1.1 6-1.1.1.3 7-1.1.2.1 8-1.1.2 11-1.1.3.r 13-1.1.3 14-1.1.3.2.r 15-1.1.3.2.1 16-1.1.3.2 17-1.1.3.1 18-1.1.3.1 19-1.1.3.1 20-1.1.3.1 21-1.1.3.1 22-1.1.3.1 23-1.1.3.1 24-1.1.3.1 25-1.1.3.1 26-1.1.3.1 (l / likely-01~e.4 :ARG1 (h / have-03~e.6 :ARG0 (p / person :mod (t / this~e.0) :compared-to (c / counterpart :mod (e / enzyme :name (n / name :op1 "N-RAS") :mod (w / wild-type))) :ARG0-of (h2 / have-rel-role-91~e.6 :ARG2 (p3 / patient~e.1))) :ARG1 (m / metastasize-101~e.8 :ARG2 (b / brain~e.7)) :time~e.11 (p2 / present-102~e.13 :ARG0 p~e.17,18,19,20,21,22,23,24,25,26 :ARG1~e.14 (d / disease~e.16 :ARG1-of (m2 / metastasize-101~e.15)))) :degree (m3 / more~e.3)) # ::id a_pmid_2458_8908.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All N @-@ RAS mutant melanoma cultures tested in our study ( n = 7 ) were sensitive to MEK inhibition162 . # ::alignments 0-1.1.4 1-1.1.2.2.1.1 3-1.1.2.2.1.1 4-1.1.2.2 4-1.1.2.2.2 4-1.1.2.2.2.r 5-1.1.2.1.1 6-1.1 7-1.1.3 8-1.1.3.1.r 9-1.1.3.1.1 9-1.1.3.1.1.r 10-1.1.3.1 14-1.1.1 17-1 19-1.2.1.1.1 (s / sensitive-03~e.17 :ARG0 (c / culture-01~e.6 :quant 7~e.14 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma"~e.5) :mod (e / enzyme~e.4 :name (n4 / name :op1 "N-RAS"~e.1,3) :ARG2-of~e.4 (m / mutate-01~e.4))) :ARG1-of (t / test-01~e.7 :medium~e.8 (s2 / study-01~e.10 :ARG0~e.9 (w / we~e.9))) :mod (a / all~e.0)) :ARG1 (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "MEK"~e.19 :op2 162)))) # ::id a_pmid_2458_8908.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exposure to MEK162 reduced ERK1 @/@ 2 phosphorylation , and induced apoptosis . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1 4-1.1.2.1.1.1 6-1.1.2.1.1.1 7-1.1.2 9-1 10-1.2 11-1.2.2 (a / and~e.9 :op1 (r2 / reduce-01~e.3 :ARG0 (e2 / expose-01~e.0 :ARG2~e.1 (s2 / small-molecule :name (n3 / name :op1 "MEK162"~e.2))) :ARG1 (p / phosphorylate-01~e.7 :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK1/2"~e.4,6)))) :op2 (i2 / induce-01~e.10 :ARG0 e2 :ARG2 (a3 / apoptosis~e.11))) # ::id a_pmid_2458_8908.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Clonogenic survival was significantly reduced in sensitive melanoma cell cultures . # ::alignments 1-1.1 3-1.2 4-1 5-1.3.r 6-1.3.1.1 7-1.3.1.2.1.1 8-1.3.1 9-1.3 (r / reduce-01~e.4 :ARG1 (s2 / survive-01~e.1 :mod (c / clonogen)) :ARG2 (s / significant-02~e.3) :location~e.5 (c2 / culture-01~e.9 :ARG1 (c3 / cell~e.8 :ARG0-of (s3 / sensitive-03~e.6) :mod (m / medical-condition :name (n / name :op1 "melanoma"~e.7))))) # ::id a_pmid_2458_8908.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Clinical profiles of patients whose tumors harbor N @-@ RAS and B @-@ RAF mutations # ::alignments 0-1.2 1-1 2-1.1.r 3-1.1.2.1 5-1.1.1.1 6-1.1.1.1.1 7-1.1.1.1.1.1.1.1.1.1 9-1.1.1.1.1.1.1.1.1.1 10-1.1.1.1.1.1.1 11-1.1.1.1.1.1.1.2.1.1 13-1.1.1.1.1.1.1.2.1.1 14-1.1.1.1.1.1 (p / profile-01~e.1 :ARG1~e.2 (p2 / person :ARG0-of (h2 / have-03 :ARG1 (t / tumor~e.5 :ARG0-of (h / harbor-01~e.6 :ARG1 (m / mutate-01~e.14 :ARG1 (a / and~e.10 :op1 (e / enzyme :name (n3 / name :op1 "N-RAS"~e.7,9)) :op2 (e2 / enzyme :name (n4 / name :op1 "B-RAF"~e.11,13))))))) :ARG0-of (h3 / have-rel-role-91 :ARG2 (p3 / patient~e.3))) :mod (c / clinical~e.0)) # ::id a_pmid_2458_8908.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Characteristics of our cohort of 144 patients with stage IV melanoma are shown in Table 1 @ . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.4.1.1 2-1.2.1.4.1.1.r 3-1.2.1.4.1 5-1.2.1.1 6-1.2.1.3.1 8-1.2.1.2.1 8-1.2.1.2.1.2 8-1.2.1.2.1.2.r 9-1.2.1.2.1.2.1 10-1.2.1.2.1.1.1 12-1 13-1.1.r 14-1.1 16-1.1.1 (s / show-01~e.12 :ARG0~e.13 (t / table~e.14 :mod 1~e.16) :ARG1 (c / characteristic-02~e.0 :ARG1~e.1 (p / person :quant 144~e.5 :ARG0-of (h / have-03 :ARG1 (m / medical-condition~e.8 :name (n / name :op1 "melanoma"~e.10) :ARG1-of~e.8 (s2 / stage-02~e.8 :ARG2 "IV"~e.9))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.6)) :ARG1-of (i / include-91 :ARG2 (c2 / cohort~e.3 :poss~e.2 (w / we~e.2)))))) # ::id a_pmid_2458_8908.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutations were found in B @-@ RAF in 43.7 % , N @-@ RAS in 27.7 % , and 28.4 % were wild type ( WT ) for both . # ::alignments 0-1.1 2-1 3-1.1.1.r 4-1.1.1.1.1.1 6-1.1.1.1.1.1 8-1.1.1.1.2.1 9-1.1.1.1.2 11-1.1.1.2.1.1 13-1.1.1.2.1.1 15-1.1.1.2.2.1 16-1.1.1.2.2 18-1.1.1 19-1.1.1.3.2.1 20-1.1.1.3.2 22-1.1.1.3.1.1 23-1.1.1.3.1.1 25-1.1.1.3.1.1 (f / find-01~e.2 :ARG1 (m / mutate-01~e.0 :ARG1~e.3 (a2 / and~e.18 :op1 (e / enzyme :name (n3 / name :op1 "B-RAF"~e.4,6) :quant (p4 / percentage-entity~e.9 :value 43.7~e.8)) :op2 (e2 / enzyme :name (n4 / name :op1 "N-RAS"~e.11,13) :quant (p5 / percentage-entity~e.16 :value 27.7~e.15)) :ARG2-of (i / include-91 :ARG1 (e3 / enzyme :mod (w2 / wild-type~e.22,23,25)) :ARG3 (p6 / percentage-entity~e.20 :value 28.4~e.19))))) # ::id a_pmid_2458_8908.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The majority of B @-@ RAF mutations were represented by substitution of valine at position 600 to glutamic acid ( 74.6 % were B @-@ RAF @^V600E ) or to lysine ( 19 % were B @-@ RAF @^V600K ) . # ::alignments 1-1.1.2.1.2 3-1.1.2.1.1.1.1.1 5-1.1.2.1.1.1.1.1 6-1.1.2 6-1.1.2.1.1 6-1.1.2.2.1 6-1.2.2 6-1.2.2.2.1 8-1.1 8-1.2 10-1.1.1 10-1.2.1 11-1.1.1.2.r 12-1.1.1.2.2.1 15-1.1.1.2.1 16-1.1.1.1.r 17-1.1.1.1.1.1 18-1.1.1.1.1.2 20-1.1.2.2.2.1 21-1.1.2.2.2 23-1.1.2.2.1.2 24-1.1.2.2.1.2 25-1.1.2.2.1.2 27-1.1.2.2.1.1 30-1 31-1.2.1.1.r 32-1.2.1.1.1.1 34-1.2.2.2.2.1 35-1.2.2.2.2 37-1.2.2.2.1.2 38-1.2.2.2.1.2 39-1.2.2.2.1.2 41-1.2.2.2.1.1 (o2 / or~e.30 :op1 (r / represent-01~e.8 :ARG0 (s / substitute-01~e.10 :ARG1~e.16 (a / amino-acid :name (n2 / name :op1 "glutamic"~e.17 :op2 "acid"~e.18)) :ARG2~e.11 (a2 / amino-acid :mod 600~e.15 :name (n5 / name :op1 "valine"~e.12))) :ARG1 (m / mutate-01~e.6 :ARG1-of (i / include-91 :ARG2 (m5 / mutate-01~e.6 :ARG2 (e2 / enzyme :name (n / name :op1 "B-RAF"~e.3,5))) :ARG3 (m2 / majority~e.1)) :ARG2-of (i2 / include-91 :ARG1 (m3 / mutate-01~e.6 :value "V600E"~e.27 :ARG2 e2~e.23,24,25) :ARG3 (p / percentage-entity~e.21 :value 74.6~e.20)))) :op2 (r2 / represent-01~e.8 :ARG0 (s2 / substitute-01~e.10 :ARG1~e.31 (a4 / amino-acid :name (n7 / name :op1 "lysine"~e.32)) :ARG2 a2) :ARG1 (m6 / mutate-01~e.6 :ARG1-of i :ARG2-of (i3 / include-91 :ARG1 (m4 / mutate-01~e.6 :value "V600K"~e.41 :ARG2 e2~e.37,38,39) :ARG3 (p2 / percentage-entity~e.35 :value 19~e.34))))) # ::id a_pmid_2458_8908.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Substitutions of glutamine 61 accounted for 95 % of N @-@ RAS mutations ( most frequently Q61R/K/L/H ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2.1 3-1.1.1.1 4-1 5-1.2.r 6-1.2.3.2.1 7-1.2.3.2 9-1.2.1.1.1 11-1.2.1.1.1 12-1.2 12-1.2.2.1.1 12-1.2.2.1.2 12-1.2.2.1.3 12-1.2.2.1.4 12-1.2.3.1 14-1.2.2.2.1 15-1.2.2.2 (a / account-01~e.4 :ARG0 (s / substitute-01~e.0 :ARG2~e.1 (a2 / amino-acid :mod 61~e.3 :name (n / name :op1 "glutamine"~e.2))) :ARG2~e.5 (m / mutate-01~e.12 :ARG1 (e / enzyme :name (n2 / name :op1 "N-RAS"~e.9,11)) :ARG2-of (i / include-91 :ARG1 (a3 / and :op1 (m2 / mutate-01~e.12 :value "Q61R") :op2 (m5 / mutate-01~e.12 :value "Q61K") :op3 (m6 / mutate-01~e.12 :value "Q61L") :op4 (m7 / mutate-01~e.12 :value "Q61H")) :ARG1-of (f / frequent-02~e.15 :degree (m3 / most~e.14))) :ARG1-of (i2 / include-91 :ARG2 (m4 / mutate-01~e.12 :ARG1 e) :ARG3 (p2 / percentage-entity~e.7 :value 95~e.6)))) # ::id a_pmid_2458_8908.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The slightly higher percentage of N @-@ RAS mutant melanomas in our population than what is commonly reported may be a result of the relatively small sample size or a reflection of local demographics . # ::alignments 1-1.1.1.2.1.1.1 2-1.1.1.2.1 2-1.1.1.2.1.1 2-1.1.1.2.1.1.r 3-1.1.1.2 4-1.1.1.2.2.r 5-1.1.1.2.2.2.1.1 7-1.1.1.2.2.2.1.1 8-1.1.1.2.2.2 8-1.1.1.2.2.2.2 8-1.1.1.2.2.2.2.r 9-1.1.1.2.2.1.1 10-1.1.1.2.3.r 11-1.1.1.2.3.1 11-1.1.1.2.3.1.r 12-1.1.1.2.3 13-1.1.1.2.4.r 14-1.1.1.1.1 14-1.1.1.2.4 16-1.1.1.2.4.1.1 17-1.1.1.2.4.1 18-1 21-1.1.1 22-1.1.1.1.r 24-1.1.1.1.2.1 25-1.1.1.1.2 26-1.1.1.1.1.1 27-1.1.1.1 28-1.1 30-1.1.2 31-1.1.2.2.r 32-1.1.2.2.1 33-1.1.2.2 (p / possible-01~e.18 :ARG1 (o2 / or~e.28 :op1 (r / result-01~e.21 :ARG1~e.22 (s2 / size-01~e.27 :ARG1 (t2 / thing~e.14 :ARG1-of (s3 / sample-01~e.26)) :ARG2 (s4 / small~e.25 :ARG2-of (r4 / relative-05~e.24))) :ARG2 (p2 / percentage~e.3 :ARG1-of (h / high-02~e.2 :degree~e.2 (m2 / more~e.2 :degree (s / slight~e.1))) :quant-of~e.4 (m / medical-condition :name (n / name :op1 "melanoma"~e.9) :mod (e / enzyme~e.8 :name (n2 / name :op1 "N-RAS"~e.5,7) :ARG2-of~e.8 (m3 / mutate-01~e.8))) :location~e.10 (p3 / population~e.12 :poss~e.11 (w / we~e.11)) :compared-to~e.13 (t / thing~e.14 :ARG1-of (r2 / report-01~e.17 :mod (c / common~e.16))))) :op2 (r3 / reflect-01~e.30 :ARG1 p2 :ARG2~e.31 (d / demographics~e.33 :ARG1-of (l / local-02~e.32))))) # ::id a_pmid_2458_8908.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Clinical and pathological characteristics # ::alignments 0-1.1 2-1.2 3-1 (c / characteristic-02~e.3 :mod (c2 / clinical~e.0) :mod (p / pathology~e.2)) # ::id a_pmid_2458_8908.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with B @-@ RAF mutations tended to be younger ; median age at initial diagnosis of melanoma was 57.6 in patients with B @-@ RAF mutations , 68.2 in patients with N @-@ RAS mutations and 66.3 years in patients wild @-@ type for both ( P < 0.0001 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.1.1.r 2-1.1.1.1.1.1.1.1 4-1.1.1.1.1.1.1.1 5-1.1.1.1.1.1 5-1.1.1.1.1.1.2 5-1.1.1.1.1.1.2.r 6-1.1 9-1.1.2.1 9-1.1.2.1.1 9-1.1.2.1.1.r 11-1.2.4 12-1.2.1 12-1.2.2 12-1.2.3 14-1.2.5.2 17-1.2.5.1.1.1 19-1.2.1.2.1 20-1.2.1.1.r 21-1.2.1.1 22-1.2.1.1 23-1.2.1.1 24-1.2.1.1 25-1.2.1.1 26-1.2.1.1 28-1.2.2.2.1 29-1.2.2.1.r 30-1.2.2.1.1.1 31-1.2.2.1.1.1.1.r 32-1.2.2.1.1.1.1.1.1 34-1.2.2.1.1.1.1.1.1 35-1.2.2.1.1.1.1 35-1.2.2.1.1.1.1.2 35-1.2.2.1.1.1.1.2.r 36-1.2 37-1.2.3.2.1 38-1.2.1.2.2 38-1.2.2.2.2 38-1.2.3.2.2 39-1.2.3.1.r 40-1.2.3.1.1.1 41-1.2.3.1.1.1.3 43-1.2.3.1.1.1.3 48-1.2.6.1 49-1.2.6.1.1 (a3 / and :op1 (t / tend-02~e.6 :ARG1 (p / person :ARG0-of (h4 / have-rel-role-91 :ARG2 (p3 / patient~e.0 :mod~e.1 (e3 / enzyme~e.5 :name (n / name :op1 "B-RAF"~e.2,4) :ARG2-of~e.5 (m / mutate-01~e.5))))) :ARG2 (p2 / person :mod (y / young~e.9 :degree~e.9 (m3 / more~e.9)))) :op2 (a / and~e.36 :op1 (a4 / age-01~e.12 :ARG1~e.20 p~e.21,22,23,24,25,26 :ARG2 (t2 / temporal-quantity :quant 57.6~e.19 :unit (y2 / year~e.38))) :op2 (a5 / age-01~e.12 :ARG1~e.29 (p4 / person :ARG0-of (h6 / have-rel-role-91 :ARG2 (p7 / patient~e.30 :mod~e.31 (e / enzyme~e.35 :name (n4 / name :op1 "N-RAS"~e.32,34) :ARG2-of~e.35 (m6 / mutate-01~e.35))))) :ARG2 (t3 / temporal-quantity :quant 68.2~e.28 :unit (y3 / year~e.38))) :op3 (a6 / age-01~e.12 :ARG1~e.39 (p5 / person :ARG0-of (h7 / have-rel-role-91 :ARG2 (p8 / patient~e.40 :mod e :mod e3 :mod (w / wild-type~e.41,43)))) :ARG2 (t4 / temporal-quantity :quant 66.3~e.37 :unit (y4 / year~e.38))) :mod (m4 / median~e.11) :time (d / diagnose-01 :ARG2 (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.17)) :mod (i / initial~e.14)) :ARG1-of (p6 / possible-01 :quant (l / less-than~e.48 :value 0.0001~e.49)))) # ::id a_pmid_2458_8908.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our cohort included 22 patients who received either dabrafenib ( N = 1 ) , vemurafenib ( N = 19 ) , a pan @-@ RAF inhibitor ( N = 1 ) or a pan @-@ RAF inhibitor and vemurafenib ( N = 1 ) . # ::alignments 0-1.2.1 0-1.2.1.r 1-1.2 2-1 2-1.1.2.1.1 3-1.1.1 4-1.1.2.1 4-1.1.2.1.1.1.1.2.1 6-1.1.2.1.1.1.1.3 6-1.1.2.1.1.1.2.3 6-1.1.2.1.1.1.3.3 6-1.1.2.1.1.1.4.3 8-1.1.2.1.1.1.1.3.1.1.1 12-1.1.2.1.1.1.1.1 12-1.1.2.1.1.1.3.1 12-1.1.2.1.1.1.4.1 15-1.1.2.1.1.1.2.3.1.1.1 19-1.1.2.1.1.1.2.1 23-1.1.2.1.1.1.3.3.1.1.1.1.1 25-1.1.2.1.1.1.3.3.1.1.1.1.1 26-1.1.2.1.1.1.3.3.1 26-1.1.2.1.1.1.3.3.1.1 26-1.1.2.1.1.1.3.3.1.1.r 30-1.1.2.1.1.1.3.1 34-1.1.2.1.1.1.3.3.1.1.1.1.1 36-1.1.2.1.1.1.3.3.1.1.1.1.1 37-1.1.2.1.1.1.3.3.1 37-1.1.2.1.1.1.3.3.1.1 37-1.1.2.1.1.1.3.3.1.1.r 38-1.1.2.1.1.1 38-1.1.2.1.1.1.4.3.1 39-1.1.2.1.1.1.2.3.1.1.1 43-1.1.2.1.1.1.1.1 43-1.1.2.1.1.1.3.1 43-1.1.2.1.1.1.4.1 (i2 / include-01~e.2 :ARG1 (p / person :quant 22~e.3 :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient~e.4 :ARG2-of (i7 / include-91~e.2 :ARG1 (a2 / and~e.38 :op1 (p2 / person :quant 1~e.12,43 :ARG0-of (h2 / have-rel-role-91 :ARG2 (p7 / patient~e.4)) :ARG0-of (r2 / receive-01~e.6 :ARG1 (s / small-molecule :name (n / name :op1 "dabrafenib"~e.8)))) :op2 (p3 / person :quant 19~e.19 :ARG0-of h2 :ARG0-of (r3 / receive-01~e.6 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib"~e.15,39)))) :op3 (p4 / person :quant 1~e.12,30,43 :ARG0-of h2 :ARG0-of (r4 / receive-01~e.6 :ARG1 (m / molecular-physical-entity~e.26,37 :ARG0-of~e.26,37 (i / inhibit-01~e.26,37 :ARG1 (e / enzyme :name (n4 / name :op1 "pan-RAF"~e.23,25,34,36)))))) :op4 (p5 / person :quant 1~e.12,43 :ARG0-of h2 :ARG0-of (r5 / receive-01~e.6 :ARG2 (a3 / and~e.38 :op1 m :op2 s2)))))))) :ARG2 (c / cohort~e.1 :poss~e.0 (w / we~e.0))) # ::id a_pmid_2458_8908.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with N @-@ RAS mutated melanomas appear to have an increased rate of skin and soft tissue involvement ( 70 %) compared to B @-@ RAF mutated counterparts and WT patients ( 37 % and 41 % respectively , P = 0.0025 ) . # ::alignments 0-1.1.3.1.2.2.1.1 2-1.1.2.1.1.1.2.1.1 4-1.1.2.1.1.1.2.1.1 5-1.1.2.1.1.1.2.2 6-1.1.2.1.1.1.1.1 7-1 9-1.1.2 9-1.1.2.1 9-1.1.2.1.1 9-1.1.2.1.1.r 9-1.1.2.1.2 9-1.1.2.1.2.r 9-1.1.2.1.r 11-1.1 12-1.1.1 12-1.1.3.1.1 12-1.1.3.1.2 13-1.1.1.1.r 14-1.1.1.1.1.1 15-1.1.1.1.1 16-1.1.1.1.1.2.1 17-1.1.1.1.1.2 18-1.1.1.1 20-1.1.1.2.1 22-1.1.3 24-1.1.3.1.1.2.1.1.1 24-1.1.3.1.2.2.1.1.1.1.1 26-1.1.3.1.1.2.1.1.1 26-1.1.3.1.2.2.1.1.1.1.1 27-1.1.3.1.1.2.1.2 28-1.1.3.1.1.2 29-1.1.3.1 30-1.1.3.1.2.2.1.1.1.2 31-1.1.2.1.2.1 33-1.1.3.1.1.3.1 34-1.1.1.2 34-1.1.3.1.1.3 35-1.1.3.1 36-1.1.3.1.2.3.1 37-1.1.3.1.2.3 38-1.1.3.1.3 42-1.2.1 (a / appear-01~e.7 :ARG1 (i / increase-01~e.11 :ARG1 (r / rate~e.12 :degree-of~e.13 (i2 / involve-01~e.18 :ARG1 (a2 / and~e.15 :op1 (s / skin~e.14) :op2 (t / tissue~e.17 :ARG1-of (s2 / soft-02~e.16)))) :mod (p6 / percentage-entity~e.34 :value 70~e.20)) :ARG1-of (h / have-03~e.9 :ARG0~e.9 (p2 / person~e.9 :ARG0-of~e.9 (h2 / have-03~e.9 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma"~e.6) :mod (e / enzyme :name (n4 / name :op1 "N-RAS"~e.2,4) :ARG2-of (m / mutate-01~e.5)))) :ARG0-of~e.9 (h3 / have-rel-role-91~e.9 :ARG2 (p3 / patient~e.31)))) :ARG1-of (c / compare-01~e.22 :ARG2 (a3 / and~e.29,35 :op1 (r3 / rate~e.12 :degree-of i2 :mod (c3 / counterpart~e.28 :mod (e2 / enzyme :name (n5 / name :op1 "B-RAF"~e.24,26) :ARG2-of (m3 / mutate-01~e.27))) :mod (p7 / percentage-entity~e.34 :value 37~e.33)) :op2 (r4 / rate~e.12 :degree-of i2 :mod (p4 / person :ARG0-of (h4 / have-rel-role-91 :ARG2 (p5 / patient~e.0 :mod (e3 / enzyme :name (n / name :op1 "B-RAF"~e.24,26) :mod (w2 / wild-type~e.30))))) :mod (p8 / percentage-entity~e.37 :value 41~e.36)) :mod (r2 / respective~e.38)))) :ARG1-of (p / possible-01 :value 0.0025~e.42)) # ::id a_pmid_2458_8908.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The rate of lymph node metastasis was also noted to be higher in patients with N @-@ RAS mutations ( 75 %) compared to B @-@ RAF mutant and WT patients ( 46 % and 61 % , respectively ) ( P = 0.01 ) . # ::alignments 1-1.1 1-1.1.5.1.1 1-1.1.5.1.2 2-1.1.3.r 3-1.1.3.1.1 4-1.1.3.1 5-1.1.3 7-1.3 8-1 11-1.1.2 11-1.1.2.1 11-1.1.2.1.r 12-1.1.4.r 13-1.1.4.1.1 14-1.1.4.1.1.1.r 15-1.1.4.1.1.1.1.1 17-1.1.4.1.1.1.1.1 18-1.1.4.1.1.1 18-1.1.4.1.1.1.2 18-1.1.4.1.1.1.2.r 20-1.1.1.1 22-1.1.5 23-1.1.5.1.1.1.r 23-1.1.5.1.r 24-1.1.5.1.1.1.2.1.1 26-1.1.5.1.1.1.2.1.1 27-1.1.5.1.1.1.2 27-1.1.5.1.1.1.2.2 27-1.1.5.1.1.1.2.2.r 28-1.1.5.1 29-1.1.5.1.2.1.2 30-1.1.5.1.1.1.1.1 32-1.1.5.1.1.2.1 33-1.1.1 33-1.1.5.1.1.2 34-1.1.5.1 35-1.1.5.1.2.2.1 36-1.1.5.1.2.2 43-1.2.1 (n3 / note-02~e.8 :ARG1 (r / rate~e.1 :mod (p4 / percentage-entity~e.33 :value 75~e.20) :ARG1-of (h2 / high-02~e.11 :degree~e.11 (m3 / more~e.11)) :mod~e.2 (m / metastasize-101~e.5 :ARG2 (n4 / node~e.4 :mod (l / lymph~e.3))) :condition~e.12 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.13 :mod~e.14 (e / enzyme~e.18 :name (n5 / name :op1 "N-RAS"~e.15,17) :ARG2-of~e.18 (m4 / mutate-01~e.18))))) :ARG1-of (c / compare-01~e.22 :ARG2~e.23 (a / and~e.28,34 :op1 (r3 / rate~e.1 :mod~e.23 (p3 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p5 / patient~e.30)) :mod (e2 / enzyme~e.27 :name (n6 / name :op1 "B-RAF"~e.24,26) :ARG2-of~e.27 (m5 / mutate-01~e.27))) :mod (p7 / percentage-entity~e.33 :value 46~e.32)) :op2 (r2 / rate~e.1 :mod (p6 / person :ARG0-of h3 :mod (w / wild-type~e.29)) :mod (p8 / percentage-entity~e.36 :value 61~e.35))))) :ARG1-of (p9 / possible-01 :value 0.01~e.43) :mod (a2 / also~e.7)) # ::id a_pmid_2458_8908.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No statistically significant difference was seen between the genotypes and other clinical characteristics , such as M stage and LDH levels.Seeing that B @-@ RAF inhibitors can affect survival in patients with B @-@ RAF mutant melanomas , this group of patients was removed from the survival analysis . # ::alignments 0-1.1.1.r 2-1.1.2.3 3-1.1.1 3-1.1.1.r 3-1.1.2 5-1.1 5-1.2 8-1.1.2.1 9-1.1.2.2.1 10-1.1.2.2.3 11-1.1.2.2.2 12-1.1.2.2 15-1.1.2.2.1.r 16-1.1.2.2.1.1.1.1 17-1.1.2.2.1.1.1.2 18-1.1.2.2.1 19-1.1.2.2.1.2.1.1.1 21-1.2.1.r 22-1.2.1.1.1.1.1.1.1 24-1.2.1.1.1.1.1.1.1 25-1.2.1.1.1 25-1.2.1.1.1.1 25-1.2.1.1.1.1.r 26-1.2.1 27-1.2.1.1 28-1.2.1.1.2 29-1.2.1.1.2.1.r 30-1.2.1.1.2.1.2.1 32-1.2.1.1.2.1.1.1.2.1.1 34-1.2.1.1.2.1.1.1.2.1.1 35-1.2.1.1.2.1.1.1.2 35-1.2.1.1.2.1.1.1.2.2 35-1.2.1.1.2.1.1.1.2.2.r 36-1.2.1.1.2.1.1.1.1.1 38-1.2.2.1.1.1 39-1.2.2.1.1 41-1.2.1.1.2.1.2.1 43-1.2.2.1 44-1.2.2.1.2.r 46-1.2.2.1.2.1 47-1.2.2.1.2 (m / multi-sentence :snt1 (s / see-01~e.5 :polarity~e.0,3 -~e.3 :ARG1 (d / differ-02~e.3 :ARG1 (g / genotype~e.8) :ARG2 (c / characteristic-02~e.12 :ARG2~e.15 (a / and~e.9,18 :op1 (e5 / event :name (n4 / name :op1 "M"~e.16 :op2 "stage"~e.17)) :op2 (l / level :quant-of (e3 / enzyme :name (n3 / name :op1 "LDH"~e.19))) :ARG1-of (e / exemplify-01)) :mod (c2 / clinic~e.11) :mod (o / other~e.10)) :ARG1-of (s2 / significant-02~e.2 :mod (s3 / statistic)))) :snt2 (s7 / see-01~e.5 :ARG1~e.21 (p / possible-01~e.26 :ARG1 (a2 / affect-01~e.27 :ARG0 (m3 / molecular-physical-entity~e.25 :ARG0-of~e.25 (i2 / inhibit-01~e.25 :ARG1 (e4 / enzyme :name (n / name :op1 "B-RAF"~e.22,24)))) :ARG1 (s5 / survive-01~e.28 :ARG0~e.29 (p2 / person :ARG0-of (h / have-03 :ARG1 (m2 / medical-condition :name (n5 / name :op1 "melanoma"~e.36) :mod (e2 / enzyme~e.35 :name (n2 / name :op1 "B-RAF"~e.32,34) :ARG2-of~e.35 (m4 / mutate-01~e.35)))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient~e.30,41)))))) :ARG0-of (c4 / cause-01 :ARG1 (r / remove-01~e.43 :ARG1 (g2 / group~e.39 :mod (t / this~e.38) :ARG2-of (i / include-91 :ARG1 p2)) :ARG2~e.44 (a3 / analyze-01~e.47 :ARG1 (s6 / survive-01~e.46)))))) # ::id a_pmid_2458_8908.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By Cox univariate analysis we found a trend towards shorter survival in the N @-@ RAS mutant population , compared to the B @-@ RAF and WT groups combined ( p = 0.12 ) . # ::alignments 1-1.4.1.1 2-1.4.2 3-1.4 4-1.1 5-1 7-1.2 9-1.2.1.2 9-1.2.1.2.1 9-1.2.1.2.1.r 10-1.2.1 11-1.2.1.1.r 13-1.2.1.1.1.1.1.1 15-1.2.1.1.1.1.1.1 16-1.2.1.1.1.1 16-1.2.1.1.1.1.2 16-1.2.1.1.1.1.2.r 17-1.2.1.1 19-1.2.1.3 20-1.2.1.3.1.r 22-1.2.1.3.1.1.1.1.1 24-1.2.1.3.1.1.1.1.1 25-1.2.1.3.1 26-1.2.1.3.1.2.1 27-1.2.1.3.1.1 27-1.2.1.3.1.2 28-1.2.1.3.1.3 32-1.3.1 (f / find-01~e.5 :ARG0 (w / we~e.4) :ARG1 (t / trend-01~e.7 :ARG2 (s / survive-01~e.10 :ARG1~e.11 (p / population~e.17 :ARG0-of (h / have-03 :ARG1 (e3 / enzyme~e.16 :name (n3 / name :op1 "N-RAS"~e.13,15) :ARG2-of~e.16 (m / mutate-01~e.16)))) :ARG1-of (s2 / short-07~e.9 :degree~e.9 (m2 / more~e.9)) :ARG1-of (c / compare-01~e.19 :ARG2~e.20 (a / and~e.25 :op1 (g / group~e.27 :mod (e4 / enzyme :name (n4 / name :op1 "B-RAF"~e.22,24))) :op2 (g2 / group~e.27 :mod (w2 / wild-type~e.26)) :ARG1-of (c3 / combine-01~e.28))))) :ARG1-of (p2 / possible-01 :value 0.12~e.32) :manner (a3 / analyze-01~e.3 :name (n / name :op1 "Cox"~e.1) :mod (u / univariate~e.2))) # ::id a_pmid_2458_8908.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The median survival was 13 and 19.6 months , respectively . # ::alignments 1-1.1 2-1 4-1.2.1.1 5-1.2 6-1.2.2.1 7-1.2.1.2 9-1.2.3 (s / survive-01~e.2 :mod (m2 / median~e.1) :duration (a / and~e.5 :op1 (t / temporal-quantity :quant 13~e.4 :unit (m / month~e.7)) :op2 (t4 / temporal-quantity :quant 19.6~e.6 :unit m) :mod (r / respective~e.9))) # ::id a_pmid_2458_8908.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Kaplan @-@ Meier survival curves are shown in Figure 1 @ a for the three groups of patients ( BRAF or NRAS mutant or WT for both ) and Figure 1 @ b for the two groups ( NRAS compared to BRAF mutant and WT combined ) to visually demonstrate the differences between the groups . # ::alignments 0-1.2.1.1 2-1.2.1.1 3-1.2.2 4-1.2 6-1 7-1.1.r 8-1.1.1 15-1.1.1.2.1 16-1.1.1.2 17-1.1.1.2.2.r 18-1.1.1.2.2.1.1 20-1.1.1.2.2.2.1.1.1 20-1.1.1.2.2.2.2.1.1 21-1.1.1.2.2.2 22-1.1.1.2.2.2.3.1.1 22-1.1.1.2.2.2.4.1.1 23-1.1.1.2.2.2.1 23-1.1.1.2.2.2.1.2 23-1.1.1.2.2.2.1.2.r 23-1.1.1.2.2.2.3 23-1.1.1.2.2.2.3.2 23-1.1.1.2.2.2.3.2.r 24-1.1.1.2.2.2 25-1.1.1.2.2.2.2.2 25-1.1.1.2.2.2.4.2 29-1.1 30-1.1.1 30-1.1.2 35-1.1.2.2.r 37-1.1.2.2.1 38-1.1.2.2 40-1.1.2.2.2.1.1.1 41-1.1.2.2.2 43-1.1.1.2.2.2.1.1.1 43-1.1.1.2.2.2.2.1.1 44-1.1.1.2.2.2.1 44-1.1.1.2.2.2.1.2 44-1.1.1.2.2.2.1.2.r 44-1.1.1.2.2.2.3 44-1.1.1.2.2.2.3.2 44-1.1.1.2.2.2.3.2.r 46-1.1.1.2.2.2.2.2 46-1.1.1.2.2.2.4.2 47-1.1.2.2.2.2 50-1.3.2 51-1.3 53-1.3.1 56-1.3.1.2 (s / show-01~e.6 :ARG0~e.7 (a / and~e.29 :op1 (f / figure~e.8,30 :mod "1a" :beneficiary (g / group-01~e.16 :quant 3~e.15 :ARG1~e.17 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.18)) :mod (o2 / or~e.21,24 :op1 (e / enzyme~e.23,44 :name (n / name :op1 "BRAF"~e.20,43) :ARG2-of~e.23,44 (m4 / mutate-01~e.23,44)) :op2 (e3 / enzyme :name (n4 / name :op1 "BRAF"~e.20,43) :mod (w2 / wild-type~e.25,46)) :op3 (e2 / enzyme~e.23,44 :name (n2 / name :op1 "NRAS"~e.22) :ARG2-of~e.23,44 (m5 / mutate-01~e.23,44)) :op4 (e4 / enzyme :name (n5 / name :op1 "NRAS"~e.22) :mod (w3 / wild-type~e.25,46)))))) :op2 (f2 / figure~e.30 :mod "1b" :beneficiary~e.35 (g2 / group-01~e.38 :quant 2~e.37 :mod (c / compare-01~e.41 :ARG1 (e5 / enzyme :name (n3 / name :op1 "NRAS"~e.40)) :ARG2 (c2 / combine-01~e.47 :ARG1 e :ARG2 e3))))) :ARG1 (c4 / curve~e.4 :name (n6 / name :op1 "Kaplan-Meier"~e.0,2) :mod (s2 / survive-01~e.3)) :purpose (d / demonstrate-01~e.51 :ARG1 (d2 / differ-02~e.53 :ARG1 g :ARG2 g2~e.56) :mod (v / visual~e.50))) # ::id a_pmid_2458_8908.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , analysis of anatomic sites at the time of initial diagnosis of stage IV disease revealed a higher rate of brain involvement among B @-@ RAF ( 16 %) and N @-@ RAS ( 15 %) mutant melanoma patients , compared with patients with WT disease ( 2.5 %) ( P = 0.04 ) . # ::alignments 0-1.3 2-1.1 3-1.1.1.r 4-1.1.1.1 5-1.1.1 8-1.1.2.r 10-1.1.2.2 13-1.1.2.1.1 14-1.1.2.1.1.1 15-1.1.2.1 16-1 18-1.2.3 18-1.2.3.1 18-1.2.3.1.r 19-1.2.1 19-1.2.2 19-1.2.4.1 20-1.2.1.1.r 21-1.2.1.1.1 22-1.2.1.1 22-1.2.2.1 22-1.2.4.1.1 23-1.2.1.1.2.r 24-1.2.1.1.2.1.1.1.2.1.1 26-1.2.1.1.2.1.1.1.2.1.1 28-1.2.1.2.1 30-1.2 31-1.2.2.1.2.1.1.1.2.1.1 33-1.2.2.1.2.1.1.1.2.1.1 35-1.2.2.2.1 37-1.2.1.1.2.1.1.1.2 37-1.2.1.1.2.1.1.1.2.2 37-1.2.1.1.2.1.1.1.2.2.r 37-1.2.2.1.2.1.1.1.2 37-1.2.2.1.2.1.1.1.2.2 37-1.2.2.1.2.1.1.1.2.2.r 38-1.2.1.1.2.1.1.1.1.1 38-1.2.2.1.2.1.1.1.1.1 39-1.2.4.1.2.1.1 41-1.2.4 43-1.2.1.1.2.1.1 43-1.2.2.1.2.1.1 43-1.2.4.1.2.1.1 44-1.2.4.1.2.1.1.1.r 45-1.2.4.1.2.1.1.1.1 46-1.2.4.1.2.1.1.1 48-1.2.4.1.3.1 53-1.4.1 (r / reveal-01~e.16 :ARG0 (a / analyze-01~e.2 :ARG1~e.3 (s / site~e.5 :mod (a2 / anatomy~e.4)) :time~e.8 (d / diagnose-01 :ARG2 (d2 / disease~e.15 :ARG1-of (s2 / stage-02~e.13 :ARG2 "IV"~e.14)) :mod (i / initial~e.10))) :ARG1 (a4 / and~e.30 :op1 (r3 / rate~e.19 :mod~e.20 (i4 / involve-01~e.22 :ARG1 (b / brain~e.21) :prep-among~e.23 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p8 / patient~e.43 :mod (m3 / medical-condition :name (n5 / name :op1 "melanoma"~e.38) :mod (e / enzyme~e.37 :name (n / name :op1 "B-RAF"~e.24,26) :ARG2-of~e.37 (m / mutate-01~e.37))))))) :mod (p4 / percentage-entity :value 16~e.28)) :op2 (r4 / rate~e.19 :mod (i5 / involve-01~e.22 :ARG1 b :prep-among (p9 / person :ARG0-of (h5 / have-rel-role-91 :ARG2 (p10 / patient~e.43 :mod (m5 / medical-condition :name (n2 / name :op1 "melanoma"~e.38) :mod (e2 / enzyme~e.37 :name (n6 / name :op1 "N-RAS"~e.31,33) :ARG2-of~e.37 (m4 / mutate-01~e.37))))))) :mod (p5 / percentage-entity :value 15~e.35)) :ARG1-of (h2 / high-02~e.18 :degree~e.18 (m2 / more~e.18)) :ARG1-of (c / compare-01~e.41 :ARG2 (r2 / rate~e.19 :mod (i3 / involve-01~e.22 :ARG1 b) :condition (p6 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p7 / patient~e.39,43 :mod~e.44 (d6 / disease~e.46 :mod (w2 / wild-type~e.45))))) :mod (p / percentage-entity :value 2.5~e.48)))) :ARG2-of (i2 / interest-01~e.0) :ARG1-of (p2 / possible-01 :value 0.04~e.53)) # ::id a_pmid_2458_8908.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With longitudinal follow @-@ up , however , the rate of development of brain metastases did not differ among the three groups , possibly because the WT groups lived longer and thus developed brain metastases over time . # ::alignments 1-1.2.1.1 2-1.2.1 4-1.2.1 6-1 9-1.1.3 10-1.1.3.1.r 11-1.1.3.1 12-1.1.3.1.1.r 13-1.1.3.1.1.1 14-1.1.3.1.1 16-1.1.1 16-1.1.1.r 17-1.1 20-1.1.2.1 21-1.1.2 23-1.1.4.2 24-1.1.4 26-1.1.4.1.1.1.1 27-1.1.4.1.1.1 28-1.1.4.1.1 29-1.1.4.1.1.2 29-1.1.4.1.1.2.1 29-1.1.4.1.1.2.1.r 30-1.1.4.1 31-1.1.4.1.2.3 32-1.1.4.1.2 33-1.1.4.1.2.1 34-1.1.4.1.2.1 35-1.1.4.1.2.2 36-1.1.4.1.2.2.1 (c3 / contrast-01~e.6 :ARG2 (d / differ-02~e.17 :polarity~e.16 -~e.16 :ARG1 (g / group~e.21 :quant 3~e.20) :ARG3 (r / rate~e.9 :mod~e.10 (d2 / develop-01~e.11 :ARG2~e.12 (m / metastasize-101~e.14 :ARG2 (b / brain~e.13)))) :ARG1-of (c2 / cause-01~e.24 :ARG0 (a2 / and~e.30 :op1 (l2 / live-01~e.28 :ARG0 (g2 / group~e.27 :mod (w / wild-type~e.26)) :ARG1-of (l3 / long-03~e.29 :degree~e.29 (m2 / more~e.29))) :op2 (d3 / develop-01~e.32 :ARG2 m~e.33,34 :duration (o / over~e.35 :mod (t / time~e.36)) :ARG1-of (c4 / cause-01~e.31 :ARG0 l2))) :ARG1-of (p / possible-01~e.23))) :ARG1-of (c / condition-01 :ARG2 (f / follow-up-03~e.2,4 :mod (l / longitude~e.1)))) # ::id a_pmid_2458_8908.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro activity of B @-@ RAF and MEK inhibitors in a large panel of melanoma cultures # ::alignments 1-1.2 2-1.2 4-1 5-1.1.r 6-1.1.1.1.1.1.1 8-1.1.1.1.1.1.1 9-1.1 10-1.1.2.1.1.1.1 11-1.1.1 11-1.1.1.1 11-1.1.1.1.r 11-1.1.2 11-1.1.2.1 11-1.1.2.1.r 12-1.2 12-1.3.r 14-1.3.1 15-1.3 16-1.3.2.r 17-1.3.2.1.1.1 18-1.3.2 (a / activity-06~e.4 :ARG0~e.5 (a2 / and~e.9 :op1 (m2 / molecular-physical-entity~e.11 :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "B-RAF"~e.6,8)))) :op2 (m3 / molecular-physical-entity~e.11 :ARG0-of~e.11 (i3 / inhibit-01~e.11 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.10))))) :manner (i2 / in-vitro~e.1,2,12) :location~e.12 (p / panel~e.15 :mod (l / large~e.14) :consist-of~e.16 (c / culture~e.18 :mod (m / medical-condition :name (n3 / name :op1 "melanoma"~e.17))))) # ::id a_pmid_2458_8908.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the effect of B @-@ RAF and MEK inhibition in melanoma cultures , we used RAF265 ( a pan @-@ RAF inhibitor ) , MEK162 ( a MEK1 @/@ 2 inhibitor ) and the MEK inhibitor trametinib . # ::alignments 1-1.3 3-1.3.2 5-1.3.2.1.1.1.2.1 7-1.3.2.1.1.1.2.1 8-1.2 8-1.3.2.1.1 9-1.3.2.1.1.2 10-1.2.3 10-1.2.3.3 10-1.2.3.3.r 10-1.3.2.1 11-1.3.2.2.r 12-1.3.2.2.1.2.1 13-1.3.2.2 15-1.1 16-1 17-1.2.1.2.1 20-1.2.1.3.1.2.1 22-1.2.1.3.1.2.1 23-1.2.1 23-1.2.1.3 23-1.2.1.3.r 23-1.2.3 23-1.2.3.3 23-1.2.3.3.r 26-1.2.2.2.1 29-1.2.2.3.1.2.1 31-1.2.2.3.1.2.1 32-1.2.1 32-1.2.1.3 32-1.2.1.3.r 32-1.2.2 32-1.2.2.3 32-1.2.2.3.r 32-1.2.3 32-1.2.3.3 32-1.2.3.3.r 36-1.2.3.3.1.2.1 37-1.2.3 37-1.2.3.3 37-1.2.3.3.r 38-1.2.3.2.1 (u / use-01~e.16 :ARG0 (w / we~e.15) :ARG1 (a / and~e.8 :op1 (s2 / small-molecule~e.23,32 :wiki - :name (n4 / name :op1 "RAF265"~e.17) :ARG0-of~e.23,32 (i2 / inhibit-01~e.23,32 :ARG1 (e / enzyme :wiki - :name (n5 / name :op1 "pan-RAF"~e.20,22)))) :op2 (s3 / small-molecule~e.32 :wiki "Binimetinib" :name (n6 / name :op1 "MEK162"~e.26) :ARG0-of~e.32 (i3 / inhibit-01~e.32 :ARG1 (e7 / enzyme :wiki "Mitogen-activated_protein_kinase_kinase" :name (n7 / name :op1 "MEK1/2"~e.29,31)))) :op3 (s / small-molecule~e.10,23,32,37 :wiki "Trametinib" :name (n8 / name :op1 "trametinib"~e.38) :ARG0-of~e.10,23,32,37 (i4 / inhibit-01~e.10,23,32,37 :ARG1 (p / protein-family :wiki "Mitogen-activated_protein_kinase_kinase" :name (n9 / name :op1 "MEK"~e.36))))) :ARG2 (i5 / investigate-01~e.1 :ARG0 w :ARG1 (a2 / affect-01~e.3 :ARG0 (i6 / inhibit-01~e.10 :ARG0 (a3 / and~e.8 :op1 (e9 / enzyme :wiki - :name (n10 / name :op1 "B-RAF"~e.5,7)) :op2 p~e.9)) :ARG1~e.11 (c / culture~e.13 :mod (m / medical-condition :wiki "Melanoma" :name (n12 / name :op1 "melanoma"~e.12)))))) # ::id a_pmid_2458_8908.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A panel of 22 patient @-@ derived melanoma cultures was used ; the IC @₅₀ for RAF265 and MEK162 are shown in Table 2 @ . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1 4-1.1.1.1.3.1.1.1 6-1.1.1.1.3 7-1.1.1.1.2.1.1 8-1.1.1.1 10-1.1 13-1.2.2.1 15-1.2.2.1.1 17-1.2.2.1.2.r 18-1.2.2.1.2.1.1.1 19-1.2.2.1.2 20-1.2.2.1.2.2.1.1 22-1.2 23-1.2.1.r 24-1.2.1 (m / multi-sentence :snt1 (u / use-01~e.10 :ARG1 (p / panel~e.1 :consist-of~e.2 (c / culture-01~e.8 :quant 22~e.3 :ARG1 (m2 / medical-condition :name (n / name :op1 "melanoma"~e.7)) :ARG1-of (d / derive-01~e.6 :ARG2 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.4))))))) :snt2 (s / show-01~e.22 :ARG0~e.23 (t2 / table~e.24 :mod 1) :ARG1 (c2 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01~e.13 :ARG2 50~e.15 :ARG1~e.17 (a / and~e.19 :op1 (s2 / small-molecule :name (n3 / name :op1 "RAF265"~e.18)) :op2 (s3 / small-molecule :name (n4 / name :op1 "MEK162"~e.20))))))) # ::id a_pmid_2458_8908.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was compared to the IC @₅₀ for trametinib ( Additional file 1 @ : Table S1 ) . # ::alignments 0-1.1 2-1 3-1.2.r 5-1.2 7-1.2.1 9-1.2.2.r 10-1.2.2.1.1 12-1.3.1.2.2 13-1.3.1.2 15-1.3.1.2.1 18-1.3.1 19-1.3.1.1 (c / compare-01~e.2 :ARG1 (t / this~e.0) :ARG2~e.3 (h / have-percentage-maximal-inhibitory-concentration-01~e.5 :ARG2 50~e.7 :ARG1~e.9 (s / small-molecule :name (n2 / name :op1 "trametinib"~e.10))) :ARG1-of (d / describe-01 :ARG0 (t3 / table~e.18 :mod "S1"~e.19 :location (f / file~e.13 :mod 1~e.15 :mod (a / additional~e.12))))) # ::id a_pmid_2458_8908.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patient @-@ derived melanoma cultures with their B @-@ RAF/N @-@ RAS mutational status and sensitivity to RAF265 and MEK162 # ::alignments 0-1.2.1.1 2-1 3-1.1.1.1.1 4-1.1 5-1.3.r 6-1.3.1.2 6-1.3.1.2.r 7-1.3.1.1.1.1.1.1 11-1.3.1.1.1.2.1.1 12-1.3.1.1 13-1.3.1 14-1.3 15-1.3.2 16-1.3.2.2.r 17-1.3.2.2.1.1.1 19-1.3.2.2.2.1.1 (d / derive-01~e.2 :ARG1 (c / culture-01~e.4 :ARG1 (m2 / medical-condition :name (n / name :op1 "melanoma"~e.3))) :ARG2 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0))) :accompanier~e.5 (a / and~e.14 :op1 (s / status~e.13 :mod (m / mutate-01~e.12 :ARG1 (s5 / slash :op1 (e / enzyme :name (n5 / name :op1 "B-RAF"~e.7)) :op2 (e2 / enzyme :name (n6 / name :op1 "N-RAS"~e.11)))) :poss~e.6 c~e.6) :op2 (s2 / sensitive-03~e.15 :ARG0 c :ARG1~e.16 (a2 / and :op1 (s3 / small-molecule :name (n3 / name :op1 "RAF265"~e.17)) :op2 (s4 / small-molecule :name (n4 / name :op1 "MEK162"~e.19)))))) # ::id a_pmid_2458_8908.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were treated with each drug individually at concentrations ranging from 1 nM to 1000 nM and analyzed three days later . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.2 5-1.1.2 6-1.1.3 6-1.1.3.r 7-1.1.2.1.r 8-1.1.2.1 8-1.1.2.1.1.1 8-1.1.2.1.1.2 9-1.1.2.1.1 11-1.1.2.1.1.1.1 12-1.1.2.1.1.1.2 14-1.1.2.1.1.2.1 15-1.1.2.1.1.2.2 16-1 17-1.2 18-1.2.2.1.1 19-1.2.2.1.2 20-1.2.2 20-1.2.2.2 20-1.2.2.2.r (a / and~e.16 :op1 (t / treat-04~e.2 :ARG1 (c / cell~e.0) :ARG2~e.3 (d / drug~e.5 :mod~e.7 (c2 / concentration~e.8 :ARG1-of (r / range-01~e.9 :ARG3 (c3 / concentration-quantity~e.8 :quant 1~e.11 :unit (n / nanomolar~e.12)) :ARG4 (c4 / concentration-quantity~e.8 :quant 1000~e.14 :unit n~e.15))) :mod (e / each~e.4)) :manner~e.6 (i / individual~e.6)) :op2 (a2 / analyze-01~e.17 :ARG1 c :time (l3 / late~e.20 :op1 (t3 / temporal-quantity :quant 3~e.18 :unit (d3 / day~e.19)) :degree~e.20 (m4 / more~e.20)))) # ::id a_pmid_2458_8908.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Table 2 , the IC @₅₀ for RAF265 ranged from 24 to > 10000 nM , 4 to 2004 nM , and 62 to 2082 nM for WT , B @-@ RAF mutant and N @-@ RAS mutant cultures , respectively . # ::alignments 1-1 2-1.1.r 3-1.1 5-1.1.1 9-1.2.1.1.1 9-1.2.2.1.1 9-1.2.3.1.1 11-1.2.1.1.1.1 11-1.2.2.1.1.1 11-1.2.3.1.1.1 13-1.2.1.1.1.2.r 13-1.2.r 14-1.2.1.1.1.2.1.1 15-1.2.1 15-1.2.2 15-1.2.3 16-1.2.1.2.r 17-1.2.1.2.1 18-1.2.1.3.r 19-1.2.1.3 20-1.2.1.3.1.1 21-1.2.1.2.2 23-1.2.2.2.1 24-1.2.2.3.r 25-1.2.2.3.1 26-1.2.1.2.2 28-1.2 29-1.2.3.2.1 30-1.2.3.3.r 31-1.2.3.3.1 32-1.2.3.3.2 34-1.2.1.4.1 36-1.2.2.4.1.1.1.1 38-1.2.2.4.1.1.1.1 39-1.2.2.4.1 40-1.2 41-1.2.3.4.1.1.1.1 43-1.2.3.4.1.1.1.1 44-1.2.2.4.1 44-1.2.3.4.1 45-1.2.1.4 45-1.2.2.4 45-1.2.3.4 47-1.2.4 (s / show-01~e.1 :ARG0~e.2 (t / table~e.3 :mod 2~e.5) :ARG1~e.13 (a / and~e.28,40 :op1 (r / range-01~e.15 :ARG1 (c10 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01~e.9 :ARG2 50~e.11 :ARG1~e.13 (s2 / small-molecule :name (n / name :op1 "RAF265"~e.14)))) :ARG3~e.16 (c4 / concentration-quantity :quant 24~e.17 :unit (n5 / nanomolar~e.21,26)) :ARG4~e.18 (m / more-than~e.19 :op1 (c5 / concentration-quantity :quant 10000~e.20 :unit n5)) :location (c / culture-01~e.45 :mod (w / wild-type~e.34))) :op2 (r2 / range-01~e.15 :ARG1 (c11 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01~e.9 :ARG2 50~e.11 :ARG1 s2)) :ARG3 (c6 / concentration-quantity :quant 4~e.23 :unit n5) :ARG4~e.24 (c7 / concentration-quantity :quant 2004~e.25 :unit n5) :location (c2 / culture-01~e.45 :mod (m2 / mutate-01~e.39,44 :ARG2 (e / enzyme :name (n2 / name :op1 "B-RAF"~e.36,38))))) :op3 (r3 / range-01~e.15 :ARG1 (c12 / concentration-quantity :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01~e.9 :ARG2 50~e.11 :ARG1 s2)) :ARG3 (c8 / concentration-quantity :quant 62~e.29 :unit n5) :ARG4~e.30 (c9 / concentration-quantity :quant 2082~e.31 :unit n5~e.32) :location (c3 / culture-01~e.45 :mod (m3 / mutate-01~e.44 :ARG2 (e2 / enzyme :name (n3 / name :op1 "N-RAS"~e.41,43))))) :mod (r4 / respective~e.47))) # ::id a_pmid_2458_8908.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The IC @₅₀ for MEK162 ranged from 10 to > 10000 nM , < 1 to 150 nM , and 4 to 13 nM for WT , B @-@ RAF mutant and N @-@ RAS mutant melanoma cultures , respectively . # ::alignments 1-1.1.1.1 1-1.2.1.1 1-1.3.1.1 3-1.1.1.1.1 3-1.2.1.1.1 3-1.3.1.1.1 5-1.1.1.1.2.r 6-1.1.1.1.2.1.1 7-1.1 7-1.2 7-1.3 8-1.1.2.r 9-1.1.2.1 10-1.1.3.r 11-1.1.3 12-1.1.3.1.1 13-1.1.3.1.2 15-1.2.2 16-1.2.2.1.1 17-1.2.3.r 18-1.2.3.1 19-1.1.2.2 21-1 22-1.3.2.1 23-1.3.3.r 24-1.3.3.1 25-1.3.3.2 27-1.1.1.2.1 29-1.2.1.2.1.2.1.1 31-1.2.1.2.1.2.1.1 32-1.2.1.2.1.2 32-1.2.1.2.1.2.2 32-1.2.1.2.1.2.2.r 32-1.3.1.2.1.2 32-1.3.1.2.1.2.2 32-1.3.1.2.1.2.2.r 33-1 34-1.3.1.2.1.2.1.1 36-1.3.1.2.1.2.1.1 37-1.2.1.2.1.2 37-1.2.1.2.1.2.2 37-1.2.1.2.1.2.2.r 37-1.3.1.2.1.2 37-1.3.1.2.1.2.2 37-1.3.1.2.1.2.2.r 38-1.2.1.2.1.1.1 39-1.1.1.2 39-1.2.1.2 39-1.3.1.2 41-1.4 (a / and~e.21,33 :op1 (r / range-01~e.7 :ARG1 (c10 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01~e.1 :ARG2 50~e.3 :ARG1~e.5 (s / small-molecule :name (n3 / name :op1 "MEK162"~e.6))) :location (c / culture-01~e.39 :mod (w / wild-type~e.27))) :ARG3~e.8 (c4 / concentration-quantity :quant 10~e.9 :unit (n2 / nanomolar~e.19)) :ARG4~e.10 (m / more-than~e.11 :op1 (c5 / concentration-quantity :quant 10000~e.12 :unit n2~e.13))) :op2 (r2 / range-01~e.7 :ARG1 (c11 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01~e.1 :ARG2 50~e.3 :ARG1 s) :location (c2 / culture-01~e.39 :mod (m2 / medical-condition :name (n5 / name :op1 "melanoma"~e.38) :mod (e2 / enzyme~e.32,37 :name (n6 / name :op1 "B-RAF"~e.29,31) :ARG2-of~e.32,37 (m3 / mutate-01~e.32,37))))) :ARG3 (l / less-than~e.15 :op1 (c6 / concentration-quantity :quant 1~e.16 :unit n2)) :ARG4~e.17 (c7 / concentration-quantity :quant 150~e.18 :unit n2)) :op3 (r3 / range-01~e.7 :ARG1 (c12 / concentration-quantity :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01~e.1 :ARG2 50~e.3 :ARG1 s) :location (c3 / culture-01~e.39 :mod (m5 / medical-condition :name n5 :mod (e / enzyme~e.32,37 :name (n9 / name :op1 "N-RAS"~e.34,36) :ARG2-of~e.32,37 (m4 / mutate-01~e.32,37))))) :ARG3 (c8 / concentration-quantity :quant 4~e.22 :unit n2) :ARG4~e.23 (c9 / concentration-quantity :quant 13~e.24 :unit n2~e.25)) :mod (r4 / respective~e.41)) # ::id a_pmid_2458_8908.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The sensitivity to RAF265 in wild type ( 2 out of 5 ) and N @-@ RAS ( 2 out of 7 ) melanoma cultures was low . # ::alignments 1-1 2-1.2.r 3-1.2.1.1 4-1.1.r 5-1.1.1.2.2 6-1.1.1.2.2 8-1.1.1.1 11-1.1.1.3.1.1 13-1.1 14-1.1.2.2.2.1.1 16-1.1.2.2.2.1.1 18-1.1.2.1 21-1.1.2.3.1.1 23-1.1.1.2.1.1 23-1.1.2.2.1.1 24-1.1.1 24-1.1.1.3.1 24-1.1.2 24-1.1.2.3.1 26-1.3 (s / sensitive-03~e.1 :ARG0~e.4 (a2 / and~e.13 :op1 (c2 / culture-01~e.24 :quant 2~e.8 :ARG1 (m / medical-condition :name (n4 / name :op1 "melanoma"~e.23) :mod (w2 / wild-type~e.5,6)) :ARG1-of (i3 / include-91 :ARG2 (c / culture-01~e.24 :quant 5~e.11))) :op2 (c3 / culture-01~e.24 :quant 2~e.18 :ARG1 (m2 / medical-condition :name (n5 / name :op1 "melanoma"~e.23) :mod (e / enzyme :name (n6 / name :op1 "N-RAS"~e.14,16))) :ARG1-of (i4 / include-91 :ARG2 (c4 / culture-01~e.24 :quant 7~e.21)))) :ARG1~e.2 (s2 / small-molecule :name (n / name :op1 "RAF265"~e.3)) :ARG1-of (l / low-04~e.26)) # ::id a_pmid_2458_8908.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two wild type cultures ( YUROB and YUSOC ) are sensitive to both RAF265 and MEK162 . # ::alignments 0-1.1.1 1-1.1.2 2-1.1.2 3-1.1 5-1.1.3.1.1.1.1 6-1.1.3.1 7-1.1.3.1.2.1.1 10-1 11-1.2.r 12-1.2.3 13-1.2.1.1.1 14-1.2 15-1.2.2.1.1 (s / sensitive-03~e.10 :ARG0 (c / culture-01~e.3 :quant 2~e.0 :mod (w / wild-type~e.1,2) :ARG1-of (m / mean-01 :ARG2 (a / and~e.6 :op1 (c2 / cell-line :name (n / name :op1 "YUROB"~e.5)) :op2 (c3 / cell-line :name (n2 / name :op1 "YUSOC"~e.7))))) :ARG1~e.11 (a2 / and~e.14 :op1 (s2 / small-molecule :name (n3 / name :op1 "RAF265"~e.13)) :op2 (s3 / small-molecule :name (n4 / name :op1 "MEK162"~e.15)) :mod (b / both~e.12))) # ::id a_pmid_2458_8908.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Six of ten B @-@ RAF mutant cultures were sensitive to RAF265 , and seven out of ten were sensitive to MEK162 . # ::alignments 0-1.1.1.1 2-1.1.1.3.1.1 3-1.1.1.2.1.1.1 5-1.1.1.2.1.1.1 6-1.1.1.2 7-1.1.1 7-1.1.1.3.1 7-1.2.1 9-1.1 9-1.2 11-1.1.2.1.1 13-1 14-1.2.1.1 17-1.1.1.3.1.1 19-1.1 20-1.2.2.r 21-1.2.2.1.1 (a / and~e.13 :op1 (s / sensitive-03~e.9,19 :ARG0 (c / culture-01~e.7 :quant 6~e.0 :mod (m / mutate-01~e.6 :ARG2 (e3 / enzyme :name (n3 / name :op1 "B-RAF"~e.3,5))) :ARG1-of (i3 / include-91 :ARG2 (c2 / culture-01~e.7 :quant 10~e.2,17))) :ARG1 (s3 / small-molecule :name (n4 / name :op1 "RAF265"~e.11))) :op2 (s2 / sensitive-03~e.9 :ARG0 (c3 / culture-01~e.7 :quant 7~e.14 :ARG1-of (i / include-91 :ARG2 c2) :mod m) :ARG1~e.20 (s4 / small-molecule :name (n5 / name :op1 "MEK162"~e.21)))) # ::id a_pmid_2458_8908.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In N @-@ RAS mutant melanoma cultures , 2 out of 7 were sensitive to RAF265 and , strikingly , all were sensitive to MEK162 . # ::alignments 1-1.1.1.3.1.1.1 3-1.1.1.3.1.1.1 4-1.1.1.3 5-1.1.1.2.1.1 6-1.1.1 6-1.1.1.4.1 8-1.1.1.1 11-1.1.1.4.1.1 13-1.1 14-1.1.2.r 15-1.1.2.1.1 16-1 18-1.2.3 20-1.2.1 22-1.2 23-1.2.2.r 24-1.2.2.1.1 (a / and~e.16 :op1 (s / sensitive-03~e.13 :ARG0 (c / culture-01~e.6 :quant 2~e.8 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma"~e.5)) :mod (m / mutate-01~e.4 :ARG1 (e3 / enzyme :name (n4 / name :op1 "N-RAS"~e.1,3))) :ARG1-of (i2 / include-91 :ARG2 (c2 / culture-01~e.6 :quant 7~e.11))) :ARG1~e.14 (s4 / small-molecule :name (n / name :op1 "RAF265"~e.15))) :op2 (s2 / sensitive-03~e.22 :ARG0 (a2 / all~e.20) :ARG1~e.23 (s5 / small-molecule :name (n2 / name :op1 "MEK162"~e.24)) :ARG1-of (s3 / strike-04~e.18))) # ::id a_pmid_2458_8908.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the 7 N @-@ RAS mutant cultures , 5 were sensitive to trametinib . # ::alignments 2-1.1.3.1.1 3-1.1.2.1.1.1 5-1.1.2.1.1.1 6-1.1.2 7-1.1 7-1.1.3.1 9-1.1.1 11-1 12-1.2.r 13-1.2.1.1 (s / sensitive-03~e.11 :ARG0 (c / culture-01~e.7 :quant 5~e.9 :mod (m / mutate-01~e.6 :ARG2 (e / enzyme :name (n2 / name :op1 "N-RAS"~e.3,5))) :ARG1-of (i / include-91 :ARG2 (c2 / culture-01~e.7 :quant 7~e.2))) :ARG1~e.12 (s2 / small-molecule :name (n / name :op1 "trametinib"~e.13))) # ::id a_pmid_2458_8908.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok YUFIC and YUTICA were more resistant . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 4-1.2 5-1 (r / resist-01~e.5 :ARG0 (a / and~e.1 :op1 (c / cell-line :name (n / name :op1 "YUFIC"~e.0)) :op2 (c2 / cell-line :name (n2 / name :op1 "YUTICA"~e.2))) :degree (m / more~e.4)) # ::id a_pmid_2458_8908.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Molecular effects of MEK162 # ::alignments 0-1.2 1-1 2-1.1.r 3-1.1.1.1 (a / affect-01~e.1 :ARG0~e.2 (s / small-molecule :name (n / name :op1 "MEK162"~e.3)) :ARG1 (m / molecule~e.0)) # ::id a_pmid_2458_8908.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Due to the striking sensitivity patterns of MEK162 , we conducted additional studies to verify target down @-@ regulation in the sensitive and resistant cultures . # ::alignments 0-1 1-1 3-1.1.2 4-1.1.1 5-1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 9-1.2.1 10-1.2 11-1.2.2.2 12-1.2.2 14-1.2.3 15-1.2.3.2.1 16-1.2.3.2 17-1.2.3.2 18-1.2.3.2 19-1.2.3.2.2.r 21-1.2.3.2.2.1.1 22-1.2.3.2.2 23-1.2.3.2.2.2.1 24-1.2.3.2.2.1 24-1.2.3.2.2.2 (c / cause-01~e.0,1 :ARG0 (p / pattern-01~e.5 :ARG1 (s / sensitive-03~e.4 :ARG1~e.6 (s5 / small-molecule :name (n / name :op1 "MEK162"~e.7))) :ARG1-of (s2 / strike-04~e.3)) :ARG1 (c2 / conduct-01~e.10 :ARG0 (w / we~e.9) :ARG1 (s3 / study-01~e.12 :ARG0 w :mod (a / additional~e.11)) :purpose (v / verify-01~e.14 :ARG0 w :ARG1 (d / downregulate-01~e.16,17,18 :ARG1 (t / target-01~e.15) :location~e.19 (a2 / and~e.22 :op1 (c3 / culture-01~e.24 :ARG0-of (s6 / sensitive-03~e.21)) :op2 (c4 / culture-01~e.24 :ARG0-of (r2 / resist-01~e.23))))))) # ::id a_pmid_2458_8908.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK1 @/@ 2 isoforms are the immediate downstream substrates and best studied effectors of dual specificity kinases MEK1 @/@ 2 . # ::alignments 0-1.3.1.1.1 2-1.3.1.1.1 3-1.3 4-1.3.r 6-1.1.2 7-1.1.1 8-1.1 9-1 10-1.2.1.1 10-1.2.1.1.1 10-1.2.1.1.1.r 11-1.2.1 12-1.2 13-1.2.2.r 14-1.2.2.2.1 15-1.2.2.2 16-1.2.2 17-1.2.2.1.1 19-1.2.2.1.1 (a2 / and~e.9 :op1 (s / substrate~e.8 :location (d / downstream~e.7) :mod (i2 / immediacy~e.6)) :op2 (e3 / effector~e.12 :ARG1-of (s4 / study-01~e.11 :ARG1-of (g / good-02~e.10 :degree~e.10 (m / most~e.10))) :poss~e.13 (k / kinase~e.16 :name (n2 / name :op1 "MEK1/2"~e.17,19) :mod (s3 / specificity~e.15 :mod (d2 / dual~e.14)))) :domain~e.4 (i / isoform~e.3 :mod (e2 / enzyme :name (n / name :op1 "ERK1/2"~e.0,2)))) # ::id a_pmid_2458_8908.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the effect of MEK1 @/@ 2 inhibition on ERK1 @/@ 2 activation state ( phosphorylation at T202 @/@ Y204 sites ) , melanoma cultures were treated with MEK162 and compared with untreated controls . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1.1 6-1.3.1.3.1.1 7-1.3.1.1.1.1.1 7-1.3.1.2.1.1.1.1 8-1.3.1.1 9-1.3.1.2.r 10-1.3.1.2.1.1.1.1 11-1.3.1.3.1.1 12-1.3.1.2.1.1.1.1 13-1.3.1.2.1 14-1.3.1.2 16-1.3.1.3.1 19-1.3.1.3.1.1 24-1.1.1.1.1.1 25-1.1.1 27-1.1 28-1.1.2.r 29-1.1.2.1.1 30-1 31-1.2 32-1.2.2.r 33-1.2.2.1 33-1.2.2.1.1 33-1.2.2.1.1.r 34-1.2.2 (a / and~e.30 :op1 (t / treat-04~e.27 :ARG1 (c2 / culture-01~e.25 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma"~e.24))) :ARG2~e.28 (s3 / small-molecule :name (n4 / name :op1 "MEK162"~e.29))) :op2 (c / compare-01~e.31 :ARG1 c2 :ARG2~e.32 (c3 / control~e.34 :ARG1-of (t2 / treat-04~e.33 :polarity~e.33 -~e.33))) :purpose (a2 / assess-01~e.1 :ARG1 (a3 / affect-01~e.3 :ARG0~e.4 (i / inhibit-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2"~e.5,7))) :ARG1~e.9 (s / state~e.14 :mod (a4 / activate-01~e.13 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.7,10,12)))) :ARG2-of (m / mean-01 :ARG1 (p2 / phosphorylate-01~e.16 :ARG1 (s4 / slash~e.6,11,19 :op1 (a5 / amino-acid :mod 202 :name (n6 / name :op1 "threonine")) :op2 (a6 / amino-acid :mod 204 :name (n7 / name :op1 "tyrosine")))))))) # ::id a_pmid_2458_8908.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We selected one sensitive and one resistant culture in the WT and B @-@ RAF mutant categories . # ::alignments 0-1.1 1-1 2-1.2.1.1 3-1.2.1.2 4-1.2 5-1.2.2.1 6-1.2.2.2 7-1.2.1 7-1.2.2 10-1.3.1.1 12-1.3.2.1.1.2.1 14-1.3.2.1.1.2.1 15-1.3.2.1 16-1.3.1 16-1.3.2 (s / select-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a3 / and~e.4 :op1 (c3 / culture-01~e.7 :quant 1~e.2 :ARG0-of (s3 / sensitive-03~e.3)) :op2 (c4 / culture-01~e.7 :quant 1~e.5 :ARG0-of (r2 / resist-01~e.6))) :ARG2 (a / and :op1 (c / category~e.16 :mod (w4 / wild-type~e.10)) :op2 (c5 / category~e.16 :mod (m / mutate-01~e.15 :ARG2 (e3 / enzyme :wiki - :name (n3 / name :op1 "B-RAF"~e.12,14)))))) # ::id a_pmid_2458_8908.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Seeing that all N @-@ RAS mutant cultures were sensitive to MEK162 , we selected two sensitive cultures for these studies . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.2 3-1.1.1.1.1.1.1.1 5-1.1.1.1.1.1.1.1 6-1.1.1.1.1 7-1.1.1.1 9-1.1.1 10-1.1.1.2.r 11-1.1.1.2.1.1 13-1.2.1 14-1.2 15-1.2.2.1 16-1.2.2.2 17-1.2.2 18-1.2.3.r 19-1.2.3.1 20-1.2.3 (c / cause-01 :ARG0 (s / see-01~e.0 :ARG1~e.1 (s3 / sensitive-03~e.9 :ARG0 (c2 / culture-01~e.7 :mod (m / mutate-01~e.6 :ARG2 (e / enzyme :name (n / name :op1 "N-RAS"~e.3,5))) :mod (a / all~e.2)) :ARG1~e.10 (s6 / small-molecule :name (n2 / name :op1 "MEK162"~e.11)))) :ARG1 (s2 / select-01~e.14 :ARG0 (w / we~e.13) :ARG1 (c3 / culture-01~e.17 :quant 2~e.15 :ARG0-of (s4 / sensitive-03~e.16)) :ARG3~e.18 (s5 / study-01~e.20 :mod (t / this~e.19)))) # ::id a_pmid_2458_8908.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok WT ( YUVON and YUROB ) , B @-@ RAF mutant ( YUKSI and YUMAC ) and N @-@ RAS mutant ( YUDOSO and YUKIM ) cells were treated with increasing doses ( 10 @-@ 1000 nM ) of MEK162 or left untreated for 4 and 24 hours . # ::alignments 0-1.1.1.1.3 2-1.1.1.1.1.1.1 3-1.1.1.1 4-1.1.1.1.2.1.1 7-1.1.1.2.3.1.1 9-1.1.1.2.3.1.1 10-1.1.1.2.3 10-1.1.1.2.3.2 10-1.1.1.2.3.2.r 12-1.1.1.2.1.1.1 14-1.1.1.2.2.1.1 16-1.1.1 17-1.1.1.3.3.1.1 19-1.1.1.3.3.1.1 20-1.1.1.3.3 20-1.1.1.3.3.2 20-1.1.1.3.3.2.r 22-1.1.1.3.1.1.1 23-1.1.1.3 24-1.1.1.3.2.1.1 26-1.1.1.1.1 26-1.1.1.1.2 26-1.1.1.2.1 26-1.1.1.2.2 26-1.1.1.3.1 26-1.1.1.3.2 28-1.2.1 30-1.1.2.2.2 31-1.1.2.2 33-1.1.2.2.1.1.1 35-1.1.2.2.1.2.1 36-1.1.2.2.1.1.2 39-1.1.2.1.1 40-1 41-1.2 42-1.1 42-1.2.1.1 43-1.3.r 44-1.3.1.1 45-1.3 46-1.3.2.1 47-1.3.1.2 (o / or~e.40 :op1 (t2 / treat-04~e.42 :ARG1 (a6 / and~e.16 :op1 (a7 / and~e.3 :op1 (c2 / cell-line~e.26 :name (n / name :op1 "YUVON"~e.2)) :op2 (c3 / cell-line~e.26 :name (n2 / name :op1 "YUROB"~e.4)) :mod (w2 / wild-type~e.0)) :op2 (a2 / and :op1 (c4 / cell-line~e.26 :name (n6 / name :op1 "YUKSI"~e.12)) :op2 (c5 / cell-line~e.26 :name (n7 / name :op1 "YUMAC"~e.14)) :mod (e / enzyme~e.10 :name (n8 / name :op1 "B-RAF"~e.7,9) :ARG2-of~e.10 (m3 / mutate-01~e.10))) :op3 (a3 / and~e.23 :op1 (c6 / cell-line~e.26 :name (n3 / name :op1 "YUDOSO"~e.22)) :op3 (c7 / cell-line~e.26 :name (n9 / name :op1 "YUKIM"~e.24)) :mod (e2 / enzyme~e.20 :name (n10 / name :op1 "N-RAS"~e.17,19) :ARG2-of~e.20 (m / mutate-01~e.20)))) :ARG2 (s / small-molecule :name (n5 / name :op1 "MEK162"~e.39) :quant (d / dose~e.31 :quant (b / between :op1 (c8 / concentration-quantity :quant 10~e.33 :unit (n4 / nanomolar~e.36)) :op2 (c9 / concentration-quantity :quant 1000~e.35 :unit n4)) :ARG1-of (i / increase-01~e.30)))) :op2 (l / leave-14~e.41 :ARG1 (t3 / treat-04~e.28 :polarity -~e.42 :ARG1 a6)) :duration~e.43 (a5 / and~e.45 :op1 (t / temporal-quantity :quant 4~e.44 :unit (h / hour~e.47)) :op2 (t4 / temporal-quantity :quant 24~e.46 :unit h))) # ::id a_pmid_2458_8908.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis was performed using phospho @-@ ERK1 @/@ 2 , total ERK1 @/@ 2 and β-actin antibodies , and results are shown in Figure 2 @ A.In the MEK162 resistant melanoma cultures ( YUVON and YUKSI ) , the baseline level of phospho @-@ ERK1 @/@ 2 and the ratio of phospho @-@ ERK1 @/@ 2 to total ERK1 @/@ 2 was lower compared to sensitive cultures ( YUROB , YUMAC , YUDOSO , YUKIM ) . # ::alignments 0-1.1.1.1 1-1.1.1.1 4-1.1.1 6-1.1.1.2.1.2 8-1.1.1.2.1.1.1 8-1.1.1.2.2.1.1 10-1.1.1.2.1.1.1 10-1.1.1.2.2.1.1 12-1.1.1.2.2.2 13-1.1.1.2.1.1.1 13-1.1.1.2.2.1.1 15-1.1.1.2.1.1.1 15-1.1.1.2.2.1.1 16-1.1.1.2 17-1.1.1.2.3.1.1.1.1 18-1.1.1.2.3 20-1.1 20-1.1.1.2 21-1.1.2.2 21-1.1.2.2.1 21-1.1.2.2.1.r 23-1.1.2 24-1.1.2.1.r 25-1.1.2.1 27-1.2.1.2.2.1.1 31-1.2.3.2.1.1.1 32-1.2.3.2 33-1.2.3.1.1.1 34-1.2.3 36-1.2.3.3.1.1.1.1 37-1.2.3.3.1 38-1.2.3.3.1.2.1.1 42-1.2.1.1.1 43-1.2.1.1 44-1.2.1.1.2.r 44-1.2.1.2 45-1.2.1.1.2.2 47-1.2.1.1.2.1.1 47-1.2.1.2.2.1.1 49-1.2.1.1.2.1.1 49-1.2.1.2.2.1.1 50-1.2.1 52-1.2.1.2 53-1.2.1.2 54-1.2.1.1.2.2 56-1.2.1.1.2.1.1 56-1.2.1.2.2.1.1 58-1.2.1.1.2.1.1 58-1.2.1.2.2.1.1 60-1.2.1.2.2.2 61-1.2.1.1.2.1.1 61-1.2.1.2.2.1.1 63-1.2.1.1.2.1.1 63-1.2.1.2.2.1.1 65-1.2 65-1.2.2 65-1.2.2.r 66-1.2.1.3 67-1.2.1.3.1.r 68-1.2.1.3.1.1 69-1.2.1.3.1 71-1.2.1.3.1.2.1.1.1.1 73-1.2.1.3.1.2.1.2.1.1 75-1.2.1.3.1.2.1.3.1.1 77-1.2.1.3.1.2.1.4.1.1 (m2 / multi-sentence :snt1 (a / and~e.20 :op1 (p / perform-01~e.4 :ARG1 (i / immunoblot-01~e.0,1) :ARG2 (a3 / and~e.16,20 :op1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"~e.8,10,13,15) :ARG3-of (p2 / phosphorylate-01~e.6)) :op2 (e4 / enzyme :name (n3 / name :op1 "ERK1/2"~e.8,10,13,15) :mod (t / total~e.12)) :op3 (a4 / antibody~e.18 :ARG0-of (c4 / counter-01 :ARG2 (p7 / protein :name (n4 / name :op1 "β-actin"~e.17)))))) :op2 (s / show-01~e.23 :ARG0~e.24 (f / figure~e.25 :mod "2A") :ARG1 (t2 / thing~e.21 :ARG2-of~e.21 (r / result-01~e.21)))) :snt2 (l2 / low-04~e.65 :ARG1 (a5 / and~e.50 :op1 (l3 / level~e.43 :domain (b2 / baseline~e.42) :quant-of~e.44 (e / enzyme :name (n8 / name :op1 "ERK1/2"~e.47,49,56,58,61,63) :ARG3-of (p8 / phosphorylate-01~e.45,54))) :op2 (r2 / ratio-of~e.44,52,53 :op1 e :op2 (e2 / enzyme :name (n9 / name :op1 "ERK1/2"~e.27,47,49,56,58,61,63) :mod (t3 / total~e.60))) :ARG1-of (c2 / compare-01~e.66 :ARG2~e.67 (c3 / culture-01~e.69 :ARG0-of (s3 / sensitive-03~e.68) :ARG1-of (m4 / mean-01 :ARG2 (a6 / and :op1 (c7 / cell-line :name (n11 / name :op1 "YUROB"~e.71)) :op2 (c8 / cell-line :name (n12 / name :op1 "YUMAC"~e.73)) :op3 (c9 / cell-line :name (n13 / name :op1 "YUDOSO"~e.75)) :op4 (c10 / cell-line :name (n14 / name :op1 "YUKIM"~e.77))))))) :degree~e.65 (m3 / more~e.65) :location (c / culture-01~e.34 :ARG1 (m5 / medical-condition :name (n6 / name :op1 "melanoma"~e.33)) :ARG0-of (r3 / resist-01~e.32 :ARG1 (s2 / small-molecule :name (n7 / name :op1 "MEK162"~e.31))) :ARG1-of (m / mean-01 :ARG2 (a8 / and~e.37 :op1 (c5 / cell-line :name (n5 / name :op1 "YUVON"~e.36)) :op2 (c6 / cell-line :name (n10 / name :op1 "YUKSI"~e.38))))))) # ::id a_pmid_2458_8908.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In MEK162 @-@ sensitive melanomas exposure to MEK162 resulted in a significant decrease in the level of ERK1 @/@ 2 phosphorylation ( Figure 2 @ A ) . # ::alignments 1-1.1.1.2.1.1.1 3-1.1.1 3-1.1.1.2 3-1.1.1.2.r 4-1.1.1.1.1 5-1.1 6-1.1.2.r 7-1.1.2 8-1 9-1.2.r 11-1.2.3 12-1.2 13-1.2.2.r 15-1.2.2 16-1.2.2.1.r 17-1.2.2.1.1.1.1 19-1.2.2.1.1.1.1 20-1.2.2.1 22-1.3.1 24-1.2.2.1.1.1.1 (r / result-01~e.8 :ARG1 (e / expose-01~e.5 :ARG1 (m / medical-condition~e.3 :name (n / name :op1 "melanoma"~e.4) :ARG0-of~e.3 (s / sensitive-03~e.3 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "MEK162"~e.1)))) :ARG2~e.6 s4~e.7) :ARG2~e.9 (d2 / decrease-01~e.12 :ARG0 e :ARG1~e.13 (l / level~e.15 :degree-of~e.16 (p2 / phosphorylate-01~e.20 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"~e.17,19,24)))) :ARG2 (s2 / significant-02~e.11)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.22 :mod "2A"))) # ::id a_pmid_2514_2146.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity fell into three groups : sensitive , 50 % inhibitory concentration ( IC @₅₀ ) < 1 μM ; intermediately sensitive , IC @₅₀ 1 @-@ 2 μM ; and resistant , > 2 μM . Fifteen of 21 ( 71 %) BRAF mutants , including 4 with innate vemurafenib resistance , were sensitive to SCH772984 . # ::alignments 0-1.1.1 0-1.2 1-1.1 2-1.1.2.r 3-1.1.2.1 4-1.1.2 6-1.1.1 8-1.1.2.2.1.2.2.1.1 9-1.2.1.4.2 10-1.1.2.2.1.2.2.1 11-1.1.2.2.1.1.1.1.2.1 11-1.1.2.2.1.2.2.1 11-1.1.2.2.1.2.2.1.2 11-1.1.2.2.1.2.2.1.2.r 11-1.1.2.2.1.3.1.1.2.1 13-1.1.2.2.1.1.1.1 13-1.1.2.2.1.2.2.1 15-1.1.2.2.1.1.1.1.1 15-1.1.2.2.1.2.2.1.1 18-1.1.2.2.1.1.1.1.2 19-1.1.2.2.1.1.1.1.2.1.1 20-1.1.2.2.1.1.1.1.2.1.2 22-1.1.2.2.1.2.1 23-1.1.2.2.1.1 23-1.1.2.2.1.2 25-1.1.2.2.1.1.1.1 25-1.1.2.2.1.3.1.1 27-1.1.2.2.1.1.1.1.1 27-1.1.2.2.1.3.1.1.1 29-1.1.2.2.1.2.2.1.2.1.1 31-1.1.2.2.1.2.2.1.2.1.2 31-1.1.2.2.1.3.1.1.2.1.1 32-1.1.2.2.1.1.1.1.2.1.2 34-1.1.2.2.1 34-1.1.2.2.1.2.2.1.2.1 35-1.1.2.2.1.3 37-1.1.2.2.1.3.1.1.2 38-1.1.2.2.1.2.2.1.2.1.2 39-1.1.2.2.1.2.2.1.2.2 41-1.2.1.1 43-1.2.1.4.1.1 45-1.2.1.4.2.1 48-1.2.1.2.1 48-1.2.1.4.1.2.1 48-1.2.1.5.1.2.1 50-1.2.1 50-1.2.1.3 50-1.2.1.3.r 52-1.2.1.4 52-1.2.1.5 53-1.2.1.5.1.1 55-1.2.1.5.1.3.2 56-1.2.1.5.1.3.1.1.1 57-1.2.1.5.1 57-1.2.1.5.1.3 57-1.2.1.5.1.3.r 60-1.2 61-1.2.2.r 62-1.2.2.1.1 (m6 / multi-sentence :snt1 (f / fall-04~e.1 :ARG1 (s / sensitive-03~e.0,6) :ARG2~e.2 (g / group~e.4 :quant 3~e.3 :ARG1-of (m9 / mean-01 :ARG2 (a / and~e.34 :op1 (s2 / sensitive-03~e.23 :ARG1-of (m / mean-01 :ARG2 (h / have-percentage-maximal-inhibitory-concentration-01~e.13,25 :ARG2 50~e.15,27 :ARG4 (l / less-than~e.18 :op1 (c / concentration-quantity~e.11 :quant 1~e.19 :unit (m2 / micromolar~e.20,32)))))) :op2 (s3 / sensitive-03~e.23 :mod (i / intermediate~e.22) :ARG1-of (m3 / mean-01 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.10,11,13 :ARG2 50~e.8,15 :ARG4~e.11 (c3 / concentration-quantity~e.11 :quant (b / between~e.34 :op1 1~e.29 :op2 2~e.31,38) :unit m2~e.39)))) :op3 (r / resist-01~e.35 :ARG1-of (m4 / mean-01 :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.25 :ARG2 50~e.27 :ARG4 (m5 / more-than~e.37 :op1 (c2 / concentration-quantity~e.11 :quant 2~e.31 :unit m2))))))))) :snt2 (s4 / sensitive-03~e.0,60 :ARG0 (g2 / gene~e.50 :quant 15~e.41 :name (n4 / name :op1 "BRAF"~e.48) :ARG2-of~e.50 (m7 / mutate-01~e.50) :ARG1-of (i2 / include-91~e.52 :ARG2 (g3 / gene :quant 21~e.43 :name (n5 / name :op1 "BRAF"~e.48) :ARG2-of m7) :ARG3 (p / percentage-entity~e.9 :value 71~e.45)) :ARG2-of (i3 / include-01~e.52 :ARG1 (g4 / gene~e.57 :quant 4~e.53 :name (n6 / name :op1 "BRAF"~e.48) :ARG0-of~e.57 (r2 / resist-01~e.57 :ARG1 (s5 / small-molecule :name (n7 / name :op1 "vemurafenib"~e.56)) :mod (i4 / innate~e.55)) :ARG2-of m7))) :ARG1~e.61 (s6 / small-molecule :name (n8 / name :op1 "SCH772984"~e.62)))) # ::id a_pmid_2514_2146.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All three ( 100 %) BRAF @/@ NRAS double mutants , 11 of 14 ( 78 %) NRAS mutants and 5 of 7 ( 71 %) wild @-@ type melanomas were sensitive . # ::alignments 0-1.1.1.5 1-1.1.1.1.1 3-1.1.1.4.1.1 6-1.1.1.1.2.1 7-1.1.1 8-1.1.1.2.1.1 8-1.1.2.4.1.2.1 10-1.1.1.3.1 11-1.1.1.3 11-1.1.2 11-1.1.2.3 11-1.1.2.3.r 13-1.1.2.1 15-1.1.2.4.1.1 17-1.1.2.4.2.1 20-1.1.1.2.1.1 20-1.1.2.2.1 22-1.1.1.3 22-1.1.2 22-1.1.2.3 22-1.1.2.3.r 23-1.1 24-1.1.3.1 26-1.1.3.4.1.1 28-1.1.3.4.2.1 30-1.1.3.3 32-1.1.3.3 33-1.1.3.2.1 33-1.1.3.4.1.2.1 35-1 (s / sensitive-03~e.35 :ARG0 (a / and~e.23 :op1 (s2 / slash~e.7 :op1 (g / gene :quant 3~e.1 :name (n / name :op1 "BRAF"~e.6)) :op2 (g4 / gene :name (n6 / name :op1 "NRAS"~e.8,20)) :ARG2-of (m / mutate-01~e.11,22 :mod (d / double~e.10)) :ARG1-of (i3 / include-91 :ARG3 (p / percentage-entity :value 100~e.3)) :mod (a2 / all~e.0)) :op2 (g2 / gene~e.11,22 :quant 11~e.13 :name (n2 / name :op1 "NRAS"~e.20) :ARG2-of~e.11,22 (m2 / mutate-01~e.11,22) :ARG1-of (i / include-91 :ARG2 (g3 / gene :quant 14~e.15 :name (n3 / name :op1 "NRAS"~e.8) :ARG2-of m2) :ARG3 (p2 / percentage-entity :value 78~e.17))) :op2 (m4 / medical-condition :quant 5~e.24 :name (n4 / name :op1 "melanoma"~e.33) :mod (w / wild-type~e.30,32) :ARG1-of (i2 / include-91 :ARG2 (m3 / medical-condition :quant 7~e.26 :name (n5 / name :op1 "melanoma"~e.33)) :ARG3 (p3 / percentage-entity :value 71~e.28))))) # ::id a_pmid_2514_2146.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among BRAF @ ^{V600 @} mutants with in vitro acquired resistance to vemurafenib , those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984 . # ::alignments 0-1.1.5 2-1.1.2.1 2-1.1.5.1.2.1 6-1.1.3.1 9-1.1 9-1.1.3 9-1.1.3.r 12-1.1.5.1.4.2.2 13-1.1.5.1.4.2.2 15-1.1.5.1.4.2 16-1.1.5.1 16-1.1.5.1.4 16-1.1.5.1.4.r 17-1.1.5.1.4.1.r 18-1.1.5.1.4.1.2.1 21-1.1.4.r 22-1.1.4.1.2.1 23-1.1.4.1 24-1.1.4 27-1.1.4.2.1 28-1.1.4.2.1.1.r 29-1.1.4.2.1.1 31-1 32-1.2.r 33-1.2.2.1 (s / sensitive-03~e.31 :ARG0 (g2 / gene~e.9 :wiki "BRAF_(gene)" :name (n3 / name :op1 "BRAF"~e.2) :ARG2-of~e.9 (m2 / mutate-01~e.9 :value "V600"~e.6) :ARG0-of~e.21 (r2 / reactivate-01~e.24 :ARG1 (p / pathway~e.23 :wiki "MAPK/ERK_pathway" :name (n4 / name :op1 "MAPK"~e.22)) :ARG1-of (m3 / mean-01 :ARG2 (m4 / mechanism~e.27 :mod~e.28 (r3 / resist-01~e.29)))) :ARG1-of (i2 / include-91~e.0 :ARG2 (g / gene~e.16 :wiki "BRAF_(gene)" :name (n / name :op1 "BRAF"~e.2) :ARG2-of m2 :ARG0-of~e.16 (r / resist-01~e.16 :ARG1~e.17 (s2 / small-molecule :wiki "Vemurafenib" :name (n2 / name :op1 "vemurafenib"~e.18)) :ARG1-of (a / acquire-01~e.15 :ARG0 g :manner (i / in-vitro~e.12,13)))))) :ARG1~e.32 (s3 / small-molecule :wiki - :name (n5 / name :op1 "SCH772984"~e.33))) # ::id a_pmid_2514_2146.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SCH772984 caused G1 arrest and induced apoptosis . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1.1 3-1.1.2 4-1 5-1.2 6-1.2.2 (a / and~e.4 :op1 (c / cause-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "SCH772984"~e.0)) :ARG1 (a2 / arrest-02~e.3 :ARG1 (t / thing :name (n2 / name :op1 "G1"~e.2)))) :op2 (i / induce-01~e.5 :ARG0 s :ARG2 (a3 / apoptosis~e.6))) # ::id a_pmid_2514_2146.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @-@ mutant melanoma cell lines are sensitive to ERK inhibition # ::alignments 0-1.1.2.1.1 2-1.1.2 2-1.1.2.2 2-1.1.2.2.r 3-1.1.1.1.1 4-1.1 5-1.1 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2 (s / sensitive-03~e.7 :ARG0 (c / cell-line~e.4,5 :mod (m / medical-condition :name (n3 / name :op1 "melanoma"~e.3)) :mod (e / enzyme~e.2 :name (n / name :op1 "BRAF"~e.0) :ARG2-of~e.2 (m2 / mutate-01~e.2))) :ARG1~e.8 (i / inhibit-01~e.10 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.9)))) # ::id a_pmid_2514_2146.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Twenty @-@ one melanoma cell lines containing mutations in the BRAF gene were evaluated to determine sensitivity to SCH772984 ( ERKi ) . # ::alignments 3-1.1.3.1.1 4-1.1 5-1.1 6-1.1.2 7-1.1.2.1 11-1.1.2.1.1.1.1 13-1.1.2.1.1 15-1 17-1.2 18-1.2.1 19-1.2.1.2.r 20-1.2.1.2.1.1 (e / evaluate-01~e.15 :ARG1 (c / cell-line~e.4,5 :quant 21 :ARG0-of (c2 / contain-01~e.6 :ARG1 (m2 / mutate-01~e.7 :ARG1 (g / gene~e.13 :name (n / name :op1 "BRAF"~e.11)))) :mod (m / medical-condition :name (n4 / name :op1 "melanoma"~e.3))) :purpose (d / determine-01~e.17 :ARG1 (s / sensitive-03~e.18 :ARG0 c :ARG1~e.19 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"~e.20) :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "ERK"))))))) # ::id a_pmid_2514_2146.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a comparison , sensitivity to vemurafenib was also determined . # ::alignments 2-1.3 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.2 9-1 (d / determine-01~e.9 :ARG1 (s / sensitive-03~e.4 :ARG1~e.5 (s2 / small-molecule :name (n / name :op1 "vemurafenib"~e.6))) :mod (a / also~e.8) :ARG1-of (c / compare-01~e.2)) # ::id a_pmid_2514_2146.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @ ^{V600E @} was the most frequently observed BRAF mutation , present in 17 of 21 cell lines . # ::alignments 1-1.1.1.1 1-1.4.1.1 5-1.4.2.1 8-1.4.r 10-1.2.1.1 11-1.2.1 12-1.2 13-1.1.1.1 13-1.4.1.1 14-1 14-1.4 14-1.4.2 14-1.4.2.r 16-1.3 17-1.3.1.r 18-1.3.1.1 20-1.3.1.2.1.1 21-1.3.1 21-1.3.1.2.1 22-1.3.1.2.1 (m4 / mutate-01~e.14 :ARG2 (g3 / gene :name (n3 / name :op1 "BRAF"~e.1,13)) :ARG1-of (o / observe-01~e.12 :ARG1-of (f / frequent-02~e.11 :degree (m2 / most~e.10))) :ARG1-of (p / present-02~e.16 :ARG2~e.17 (c / cell-line~e.21 :quant 17~e.18 :ARG1-of (i2 / include-91 :ARG2 (c2 / cell-line~e.21,22 :quant 21~e.20)))) :domain~e.8 (g / gene~e.14 :name (n2 / name :op1 "BRAF"~e.1,13) :ARG2-of~e.14 (m / mutate-01~e.14 :value "V600E"~e.5))) # ::id a_pmid_2514_2146.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M381 contains BRAF @ ^{V600R @} substitution , M414 contains BRAF @ ^{V600K @} , M417 contains BRAF @ ^{G466E @} and M420 contains BRAF @ ^{L597S @} mutation . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2.1.1.1 7-1.1.2.1.2.1 10-1.1.2 12-1.2.1.1.1 13-1.1 15-1.2.2.2 19-1.2.2.1 23-1.3.1.1.1 24-1.1 26-1.3.2.2 30-1.3.2.1 33-1 34-1.4.1.1.1 35-1.1 35-1.2 35-1.3 35-1.4 37-1.4.2.2 41-1.4.2.1 44-1.1.2.1 44-1.1.2.1.2 44-1.1.2.1.2.r 44-1.2.2 44-1.3.2 44-1.4.2 (a / and~e.33 :op1 (c / contain-01~e.1,13,24,35 :ARG0 (c2 / cell-line :name (n / name :op1 "M381"~e.0)) :ARG1 (s / substitute-01~e.10 :ARG2 (g / gene~e.44 :name (n2 / name :op1 "BRAF"~e.3) :ARG2-of~e.44 (m2 / mutate-01~e.44 :value "V600R"~e.7)))) :op2 (c3 / contain-01~e.35 :ARG0 (c4 / cell-line :name (n3 / name :op1 "M414"~e.12)) :ARG1 (m3 / mutate-01~e.44 :value "V600K"~e.19 :ARG1 g~e.15)) :op3 (c5 / contain-01~e.35 :ARG0 (c6 / cell-line :name (n4 / name :op1 "M417"~e.23)) :ARG1 (m4 / mutate-01~e.44 :value "G466E"~e.30 :ARG1 g~e.26)) :op4 (c7 / contain-01~e.35 :ARG0 (c8 / cell-line :name (n5 / name :op1 "M420"~e.34)) :ARG1 (m5 / mutate-01~e.44 :value "L597S"~e.41 :ARG1 g~e.37))) # ::id a_pmid_2514_2146.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the 21 cell lines , sensitivity to vemurafenib or SCH @-@ 772984 fell into 3 groups : highly sensitive ( 50 % inhibitory concentration , IC @₅₀ < 1 μM ) , intermediate sensitivity ( IC @₅₀ 1 @–@ 2 μM ) and resistant ( IC @₅₀ > 2 μM ) . # ::alignments 2-1.1.1.1 3-1.1.1 4-1.1.1 6-1.1 7-1.1.2.r 8-1.1.2.1.1.1 9-1.1.2 10-1.1.2.2.1.1 12-1.1.2.2.1.1 13-1 14-1.2.r 15-1.2.1 16-1.2 18-1.2.2.1.1.1 19-1.2.2.1.1 21-1.2.2.1.2.2.1.1 23-1.2.2.1.2.2.1 24-1.2.2.1.1.2.1.2.1 24-1.2.2.1.2.2.1 24-1.2.2.1.2.2.1.2 24-1.2.2.1.2.2.1.2.r 24-1.2.2.1.3.1.1.2.1 26-1.2.2.1.1.2.1 26-1.2.2.1.2.2.1 28-1.2.2.1.2.2.1.1 30-1.2.2.1.1.2.1.2 31-1.2.2.1.1.2.1.2.1.1 32-1.2.2.1.1.2.1.2.1.2 35-1.2.2.1.2.1 36-1.2.2.1.2 38-1.2.2.1.1.2.1 40-1.2.2.1.1.2.1.1 42-1.2.2.1.2.2.1.2.1.1 44-1.2.2.1.2.2.1.2.1.2 44-1.2.2.1.3.1.1.2.1.1 45-1.2.2.1.1.2.1.2.1.2 47-1.2.2.1 47-1.2.2.1.2.2.1.2.1 48-1.2.2.1.3 50-1.2.2.1.3.1.1 52-1.2.2.1.3.1.1.1 54-1.2.2.1.3.1.1.2 55-1.2.2.1.2.2.1.2.1.2 56-1.2.2.1.2.2.1.2.2 (f / fall-04~e.13 :ARG1 (s / sensitive-03~e.6 :ARG0 (c2 / cell-line~e.3,4 :quant 21~e.2) :ARG1~e.7 (o / or~e.9 :op1 (s2 / small-molecule :name (n / name :op1 "vemurafenib"~e.8)) :op2 (s3 / small-molecule :name (n2 / name :op1 "SCH-772984"~e.10,12)))) :ARG2~e.14 (g / group~e.16 :quant 3~e.15 :ARG1-of (m6 / mean-01 :ARG2 (a / and~e.47 :op1 (s4 / sensitive-03~e.19 :ARG1-of (h / high-02~e.18) :ARG1-of (m / mean-01 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.26,38 :ARG2 50~e.40 :ARG4 (l / less-than~e.30 :op1 (c / concentration-quantity~e.24 :quant 1~e.31 :unit (m2 / micromolar~e.32,45)))))) :op2 (s5 / sensitive-03~e.36 :mod (i2 / intermediate~e.35) :ARG1-of (m3 / mean-01 :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.23,24,26 :ARG2 50~e.21,28 :ARG4~e.24 (c3 / concentration-quantity~e.24 :quant (b / between~e.47 :op1 1~e.42 :op2 2~e.44,55) :unit m2~e.56)))) :op3 (r / resist-01~e.48 :ARG1-of (m4 / mean-01 :ARG2 (h4 / have-percentage-maximal-inhibitory-concentration-01~e.50 :ARG2 50~e.52 :ARG4 (m5 / more-than~e.54 :op1 (c4 / concentration-quantity~e.24 :quant 2~e.44 :unit m2))))))))) # ::id a_pmid_2514_2146.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 15 cell lines were highly sensitive to SCH @-@ 772984 with IC @₅₀ less than or equal to 1 μM . Of the 12 cell lines highly sensitive to vemurafenib , all contain BRAF @ ^{V600E @} and were also sensitive to SCH @-@ 772984 . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1 4-1.1.3 5-1.1 6-1.1.2.r 7-1.1.2.1.1 9-1.1.2.1.1 11-1.1.2 11-1.1.2.2 11-1.1.2.2.r 13-1.1.2.2.1 19-1.1.2.2.2.r 20-1.1.2.2.2.1 21-1.1.2.2.2.2 25-1.2.1.1.1 26-1.2.1.1 27-1.2.1.1 28-1.2.1.1.3.2 29-1.2.1.1.3 30-1.2.1.1.3.1.r 31-1.2.1.1.3.1.1.1 33-1.2.1.1.2 34-1.2.1 36-1.2.1.2.1.1 40-1.2.1.2.2.1 43-1.2 45-1.2.2.3 46-1.2.2 47-1.2.2.2.r 48-1.2.2.2.1.1 50-1.2.2.2.1.1 (m / multi-sentence :snt1 (s / sensitive-03~e.5 :ARG0 (c / cell-line~e.1,2 :quant 15~e.0) :ARG1~e.6 (s2 / small-molecule~e.11 :name (n / name :op1 "SCH-772984"~e.7,9) :ARG1-of~e.11 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.11 :ARG2 50~e.13 :ARG4~e.19 (c4 / concentration-quantity :quant 1~e.20 :unit (m2 / micromolar~e.21)))) :ARG1-of (h / high-02~e.4)) :snt2 (a / and~e.43 :op1 (c2 / contain-01~e.34 :ARG0 (c3 / cell-line~e.26,27 :quant 12~e.25 :mod (a2 / all~e.33) :ARG0-of (s3 / sensitive-03~e.29 :ARG1~e.30 (s4 / small-molecule :name (n2 / name :op1 "vemurafenib"~e.31)) :ARG1-of h~e.28)) :ARG1 (g / gene :name (n3 / name :op1 "BRAF"~e.36) :ARG2-of (m5 / mutate-01 :value "V600E"~e.40))) :op2 (s5 / sensitive-03~e.46 :ARG0 c3 :ARG1~e.47 (s6 / small-molecule :name (n4 / name :op1 "SCH-772984"~e.48,50)) :mod (a3 / also~e.45)))) # ::id a_pmid_2514_2146.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , M399 , M414 , M308 , and M409 were sensitive to SCH @-@ 772984 but only intermediately sensitive ( M399 , M409 and M414 ) or resistant ( M308 ) to vemurafenib . # ::alignments 0-1.4 2-1.1.1.1.1 4-1.1.2.1.1 6-1.1.3.1.1 8-1.1 9-1.1.4.1.1 11-1 12-1.2.r 13-1.2.1.1 15-1.2.1.1 16-1.3 17-1.3.1.1.3.1 18-1.3.1.1.3 19-1.3.1.1 21-1.1.1.1.1 23-1.1.4.1.1 25-1.1.2.1.1 27-1.3.1 28-1.3.1.2 30-1.3.1.2.1 32-1.3.1.1.2.r 33-1.3.1.1.2.1.1 (s / sensitive-03~e.11 :ARG0 (a / and~e.8 :op1 (c / cell-line :name (n / name :op1 "M399"~e.2,21)) :op2 (c2 / cell-line :name (n2 / name :op1 "M414"~e.4,25)) :op3 (c3 / cell-line :name (n3 / name :op1 "M308"~e.6)) :op4 (c5 / cell-line :name (n6 / name :op1 "M409"~e.9,23))) :ARG1~e.12 (s2 / small-molecule :name (n4 / name :op1 "SCH-772984"~e.13,15)) :ARG1-of (c4 / contrast-01~e.16 :ARG2 (o / or~e.27 :op1 (s3 / sensitive-03~e.19 :ARG0 (a3 / and :op1 c :op2 c5 :op3 c2) :ARG1~e.32 (s4 / small-molecule :name (n5 / name :op1 "vemurafenib"~e.33)) :mod (i2 / intermediate~e.18 :mod (o2 / only~e.17))) :op2 (r / resist-01~e.28 :ARG0 c3~e.30 :ARG1 s4))) :mod (i / interesting~e.0)) # ::id a_pmid_2514_2146.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With the exception of M414 , all non @-@ V600E mutants were resistant to both vemurafenib and SCH772984 ( Figure 1 @ A ) . # ::alignments 2-1.1.4 3-1.1.4.1.r 4-1.1.4.1.1.1 6-1.1.3 7-1.1.2 7-1.1.2.r 9-1.1.1 10-1.1 12-1 15-1.2.1.1.1 16-1.2 17-1.2.2.1.1 19-1.3.1 (r / resist-01~e.12 :ARG0 (m / mutate-01~e.10 :value "V600E"~e.9 :polarity~e.7 -~e.7 :mod (a2 / all~e.6) :ARG2-of (e / except-01~e.2 :ARG1~e.3 (c / cell-line :name (n3 / name :op1 "M414"~e.4)))) :ARG1 (a / and~e.16 :op1 (s / small-molecule :name (n / name :op1 "vemurafenib"~e.15)) :op2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"~e.17))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "1A"))) # ::id a_pmid_2514_2146.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a comparison , sensitivity to the MEKi trametinib segregated all cell lines into three different groups : highly sensitive ( IC @₅₀ < 2 nM ) , intermediately sensitive ( IC @₅₀ 2 @-@ 30 nM ) and resistant ( IC @₅₀ > 30 nM ) ( Additional file 1 @ : Figure S1 ) . # ::alignments 2-1.5 4-1.1 8-1.1.1.1.1 9-1 10-1.2.1 11-1.2 12-1.2 13-1.3.r 14-1.3.1 15-1.3.2 16-1.3 18-1.3.3.1.1.1 19-1.3.3.1.1 21-1.3.3.1.1.2.1 23-1.3.3.1.1.2.1.1 25-1.3.3.1.1.2.1.2 26-1.3.3.1.1.2.1.2.1.1 27-1.3.3.1.1.2.1.2.1.2 30-1.3.3.1.2.1 30-1.3.3.1.2.1.r 31-1.3.3.1.2 33-1.3.3.1.1.2.1 33-1.3.3.1.2.2.1 35-1.3.3.1.1.2.1.1 35-1.3.3.1.2.2.1.1 37-1.3.3.1.1.2.1.2.1.1 37-1.3.3.1.2.2.1.2.1.1 39-1.3.3.1.2.2.1.2.1.2 40-1.3.3.1.2.2.1.2.2 42-1.3.3.1 42-1.3.3.1.2.2.1.2.1 43-1.3.3.1.3 45-1.3.3.1.3.1.1 47-1.3.3.1.3.1.1.1 49-1.3.3.1.3.1.1.2 50-1.3.3.1.2.2.1.2.1.2 50-1.3.3.1.3.1.1.2.1.1 51-1.3.3.1.1.2.1.2.1.2 55-1.4.1 57-1.4.1.1 60-1.4.1.3.1 61-1.4.1.3.1.1 (s / segregate-01~e.9 :ARG0 (s2 / sensitive-03~e.4 :ARG1 (s3 / small-molecule :name (n / name :op1 "trametinib"~e.8) :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK"))))) :ARG1 (c2 / cell-line~e.11,12 :mod (a / all~e.10)) :ARG2~e.13 (g / group~e.16 :quant 3~e.14 :ARG1-of (d / differ-02~e.15) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and~e.42 :op1 (s4 / sensitive-03~e.19 :ARG1-of (h / high-02~e.18) :ARG1-of (m / mean-01 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.21,33 :ARG2 50~e.23,35 :ARG4 (l / less-than~e.25 :op1 (c3 / concentration-quantity :quant 2~e.26,37 :unit (n3 / nanomolar~e.27,51)))))) :op2 (s5 / sensitive-03~e.31 :manner~e.30 (i2 / intermediate~e.30) :ARG1-of (m2 / mean-01 :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.33 :ARG2 50~e.35 :ARG4 (c4 / concentration-quantity :quant (b / between~e.42 :op1 2~e.37 :op2 30~e.39,50) :unit n3~e.40)))) :op3 (r / resist-01~e.43 :ARG1-of (m3 / mean-01 :ARG2 (h4 / have-percentage-maximal-inhibitory-concentration-01~e.45 :ARG2 50~e.47 :ARG4 (m4 / more-than~e.49 :op1 (c5 / concentration-quantity :quant 30~e.50 :unit n3)))))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / file~e.55 :mod 1~e.57 :ARG1-of (a4 / add-02) :ARG1-of (m6 / mean-01 :ARG2 (f2 / figure~e.60 :mod "S1"~e.61)))) :ARG1-of (c / compare-01~e.2)) # ::id a_pmid_2514_2146.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In general , cell lines sensitive to SCH772984 were also sensitive to trametinib . @ Figure 1 @

Effect of SCH @-@ 722984 on BRAF @-@ mutant melanoma cell lines . # ::alignments 1-1.1.3 3-1.1.1 4-1.1.1 5-1.1.1.1 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1 9-1.1.4 10-1.1 11-1.1.2.r 12-1.1.2.1.1 16-1.2 17-1.2.1 22-1.2.2.1 23-1.2.2.1.1.r 24-1.2.2.1.1.1.1 26-1.2.2.1.1.1.1 27-1.2.2.1.2.r 28-1.2.2.1.2.2.1.1 30-1.2.2.1.2.2 30-1.2.2.1.2.2.2 30-1.2.2.1.2.2.2.r 31-1.2.2.1.2.1.1.1 32-1.2.2.1.2 33-1.2.2.1.2 (m / multi-sentence :snt1 (s / sensitive-03~e.10 :ARG0 (c / cell-line~e.3,4 :ARG0-of (s3 / sensitive-03~e.5 :ARG1~e.6 (s4 / small-molecule :name (n2 / name :op1 "SCH772984"~e.7)))) :ARG1~e.11 (s2 / small-molecule :name (n / name :op1 "trametinib"~e.12)) :ARG1-of (g / general-02~e.1) :mod (a / also~e.9)) :snt2 (f2 / figure~e.16 :mod 1~e.17 :ARG1-of (d2 / describe-01 :ARG2 (a2 / affect-01~e.22 :ARG0~e.23 (s5 / small-molecule :name (n3 / name :op1 "SCH-722984"~e.24,26)) :ARG1~e.27 (c2 / cell-line~e.32,33 :mod (m2 / medical-condition :name (n5 / name :op1 "melanoma"~e.31)) :mod (e / enzyme~e.30 :name (n4 / name :op1 "BRAF"~e.28) :ARG2-of~e.30 (m3 / mutate-01~e.30))))))) # ::id a_pmid_2514_2146.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A @ . # ::alignments 0-1.1 (h / have-li-91 :ARG2 "A"~e.0) # ::id a_pmid_2514_2146.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IC @₅₀ ( nM ) . # ::alignments 0-1 2-1.1 5-1.2.1 (h / have-percentage-maximal-inhibitory-concentration-01~e.0 :ARG2 50~e.2 :ARG4 (c / concentration-quantity :unit (n / nanomolar~e.5))) # ::id a_pmid_2514_2146.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 21 BRAF @-@ mutant melanoma cell lines were exposed to 0 @–@ 10 μM SCH @-@ 722984 ( black bars ) or vemurafenib ( grey bars ) and cell viability determined by ATP @-@ based bioluminescence assay . # ::alignments 0-1.1.1.1 1-1.1.1.3.1.1 3-1.1.1.3 3-1.1.1.3.2 3-1.1.1.3.2.r 4-1.1.1.2.1.1 5-1.1.1 6-1.1.1 8-1.1 9-1.1.2.r 10-1.1.2.1.2.1.1 12-1.1.2.1.2.1.2 13-1.1.2.1.2.2 14-1.1.2.1.1.1 16-1.1.2.1.1.1 18-1.1.2.1.3.1.1 19-1.1.2.1.3.1 21-1.1.2 22-1.1.2.2.1.1 24-1.1.2.2.3.1.1 25-1.1.2.2.3.1 28-1.1.1 29-1.2.1 30-1.2 31-1.2.2.r 32-1.2.2.2.1.1.1 34-1.2.2.2 35-1.2.2.1 36-1.2.2 (a / and :op1 (e / expose-01~e.8 :ARG1 (c / cell-line~e.5,6,28 :quant 21~e.0 :mod (m3 / medical-condition :name (n5 / name :op1 "melanoma"~e.4)) :mod (e2 / enzyme~e.3 :name (n / name :op1 "BRAF"~e.1) :ARG2-of~e.3 (m2 / mutate-01~e.3))) :ARG2~e.9 (o / or~e.21 :op1 (s / small-molecule :name (n2 / name :op1 "SCH-722984"~e.14,16) :quant (c2 / concentration-quantity :quant (b / between :op1 0~e.10 :op2 10~e.12) :unit (m / micromolar~e.13)) :ARG1-of (d / describe-01 :ARG0 (b2 / bar~e.19 :ARG1-of (b3 / black-04~e.18)))) :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.22) :quant c2 :ARG1-of (d4 / describe-01 :ARG0 (b4 / bar~e.25 :ARG1-of (g2 / gray-02~e.24)))))) :op2 (d2 / determine-01~e.30 :ARG1 (v / viability~e.29 :mod c) :instrument~e.31 (a2 / assay-01~e.36 :ARG1 (b5 / bioluminescence~e.35) :ARG1-of (b6 / base-02~e.34 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "ATP"~e.32)))))) # ::id a_pmid_2514_2146.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results are the mean of three experiments , performed in duplicates ( n = 6 ) . # ::alignments 0-1 3-1.1 4-1.1.1.r 5-1.1.1.1 6-1.1.1 8-1.1.1.2 9-1.1.1.2.1.r 10-1.1.1.2.1 14-1.1.1.2.1.1 (r / result-01~e.0 :ARG2 (m / mean~e.3 :poss~e.4 (e / experiment-01~e.6 :quant 3~e.5 :ARG1-of (p / perform-01~e.8 :manner~e.9 (d / duplicate~e.10 :quant 6~e.14))))) # ::id a_pmid_2514_2146.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Error bars are standard deviation . # ::alignments 0-1.2.1 1-1.2 2-1.2.r 3-1.1 4-1 (d / deviate-01~e.4 :ARG1-of (s / standard-02~e.3) :domain~e.2 (b / bar~e.1 :mod (e / error~e.0))) # ::id a_pmid_2514_2146.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Non @-@ V600E substitutions are denoted in the bar graph for each corresponding cell line ( M420 , BRAF @^L597S ; M381 , BRAF @^V600R , M417 , BRAF @^G466E , M414 , BRAF @^V600K ) . # ::alignments 0-1.1.1.2 0-1.1.1.2.r 2-1.1.1.1 3-1.1 5-1 6-1.2.r 8-1.2.1 9-1.2 12-1.1.2 12-1.3.1.1 12-1.3.1.2 12-1.3.1.3 12-1.3.1.4 13-1.1.2.1 14-1.1.2.1 16-1.3.1.1.1.1.1 18-1.3.1.1.2.1.1 20-1.3.1.1.2.2.1 23-1.3.1.2.1.1.1 25-1.3.1.2.2.1.1 27-1.3.1.2.2.2.1 30-1.3.1.3.1.1.1 32-1.3.1.3.2.1.1 34-1.3.1.3.2.2.1 37-1.3.1.4.1.1.1 39-1.3.1.4.2.1.1 41-1.3.1.4.2.2.1 (d / denote-01~e.5 :ARG1 (s / substitute-01~e.3 :ARG2 (m / mutate-01 :value "V600E"~e.2 :polarity~e.0 -~e.0) :ARG1-of (c / correspond-02~e.12 :ARG2 (c2 / cell-line~e.13,14))) :location~e.6 (g / graph~e.9 :mod (b / bar~e.8)) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c3 / correspond-02~e.12 :ARG1 (c4 / cell-line :name (n / name :op1 "M420"~e.16)) :ARG2 (e / enzyme :name (n5 / name :op1 "BRAF"~e.18) :ARG2-of (m3 / mutate-01 :value "L597S"~e.20))) :op2 (c5 / correspond-02~e.12 :ARG1 (c8 / cell-line :name (n2 / name :op1 "M381"~e.23)) :ARG2 (e2 / enzyme :name (n6 / name :op1 "BRAF"~e.25) :ARG2-of (m4 / mutate-01 :value "V600R"~e.27))) :op3 (c6 / correspond-02~e.12 :ARG1 (c9 / cell-line :name (n3 / name :op1 "M417"~e.30)) :ARG2 (e3 / enzyme :name (n7 / name :op1 "BRAF"~e.32) :ARG2-of (m5 / mutate-01 :value "G466E"~e.34))) :op4 (c7 / correspond-02~e.12 :ARG1 (c10 / cell-line :name (n4 / name :op1 "M414"~e.37)) :ARG2 (e4 / enzyme :name (n8 / name :op1 "BRAF"~e.39) :ARG2-of (m6 / mutate-01 :value "V600K"~e.41)))))) # ::id a_pmid_2514_2146.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bar at 1 μM denotes threshold between sensitive and intermediate . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.2 4-1 5-1.2 6-1.2.1 7-1.2.1.1 8-1.2.1 9-1.2.1.2 (d / denote-01~e.4 :ARG0 (b / bar~e.0 :quant~e.1 (c / concentration-quantity :quant 1~e.2 :unit (m / micromolar~e.3))) :ARG1 (t / threshold~e.5 :topic (b2 / between~e.6,8 :op1 (s / sensitive-03~e.7) :op2 (i / intermediate~e.9)))) # ::id a_pmid_2514_2146.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Resistant cell lines have IC @₅₀ higher than 2 μM . # ::alignments 0-1.2.1 1-1.2 2-1.2 3-1 4-1 6-1.1 9-1.3 10-1.3.1.1 11-1.3.1.2 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.3,4 :ARG2 50~e.6 :ARG1 (c / cell-line~e.1,2 :ARG0-of (r / resist-01~e.0)) :ARG4 (m / more-than~e.9 :op1 (c2 / concentration-quantity :quant 2~e.10 :unit (m2 / micromolar~e.11)))) # ::id a_pmid_2514_2146.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "B"~e.1) # ::id a_pmid_2514_2146.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Timecourse effects of SCH722984 on the MAPK signaling . # ::alignments 0-1.3 1-1 2-1.1.r 3-1.1.1.1 4-1.2.r 6-1.2.1.1.1 7-1.2 (a / affect-01~e.1 :ARG0~e.2 (s / small-molecule :name (n / name :op1 "SCH722984"~e.3)) :ARG1~e.4 (s2 / signal-07~e.7 :ARG0 (p / pathway :name (n2 / name :op1 "MAPK"~e.6))) :mod (t / timecourse~e.0)) # ::id a_pmid_2514_2146.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SCH722984 @-@ sensitive M238 , SCH722984 @-@ resistant M233 , were treated in a timecourse manner with 500 nM SCH722984 at 1 , 2 , 6 , 12 , 24 and 48 hours compared to DMSO as solvent control ( C ) @ . # ::alignments 0-1.1.1.2.1.1.1 0-1.2.1.1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 3-1.1.1.1.1 5-1.2.1.1 7-1.1.2 7-1.1.2.2 7-1.1.2.2.r 8-1.1.2.1.1 11-1 14-1.4 15-1.4.r 17-1.2.2.1 18-1.2.2.2 19-1.2.1.1 21-1.3.1.1.1 23-1.3.1.2.1 25-1.3.1.3.1 27-1.3.1.4.1 29-1.3.1.5.1 30-1.3.1 31-1.3.1.6.1 32-1.3.1.1.2 33-1.2.3 34-1.2.3.1.r 35-1.2.3.1.1.1 36-1.3.r 38-1.2.3.1 38-1.2.3.1.2 38-1.2.3.1.2.r (t / treat-04~e.11 :ARG1 (a / and :op1 (c / cell-line~e.2 :name (n / name :op1 "M238"~e.3) :ARG0-of~e.2 (s2 / sensitive-03~e.2 :ARG1 (s / small-molecule :name (n2 / name :op1 "SCH722984"~e.0)))) :op2 (c2 / cell-line~e.7 :name (n3 / name :op1 "M233"~e.8) :ARG0-of~e.7 (r / resist-01~e.7 :ARG1 s))) :ARG2 (s3 / small-molecule :name (n4 / name :op1 "SCH722984"~e.0,5,19) :quant (c5 / concentration-quantity :quant 500~e.17 :unit (n5 / nanomolar~e.18)) :ARG1-of (c3 / compare-01~e.33 :ARG2~e.34 (s5 / small-molecule~e.38 :name (n6 / name :op1 "DMSO"~e.35) :ARG0-of~e.38 (c4 / control-01~e.38 :ARG1 (d / dissolve-01))))) :time~e.36 (a2 / after :op1 (a3 / and~e.30 :op1 (t2 / temporal-quantity :quant 1~e.21 :unit (h / hour~e.32)) :op2 (t3 / temporal-quantity :quant 2~e.23 :unit h) :op3 (t4 / temporal-quantity :quant 6~e.25 :unit h) :op4 (t5 / temporal-quantity :quant 12~e.27 :unit h) :op5 (t6 / temporal-quantity :quant 24~e.29 :unit h) :op6 (t7 / temporal-quantity :quant 48~e.31 :unit h))) :manner~e.15 (t8 / timecourse~e.14)) # ::id a_pmid_2514_2146.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylated or total MEK , ERK1 @/@ 2 , RSK , AKT , or beta @-@ actin as loading control were determined by western blot analysis . # ::alignments 0-1.1.1.1.2 1-1.1 2-1.1.2.1.2 3-1.1.1.1.1.1 3-1.1.2.1.1.1 5-1.1.1.2.1.1 5-1.1.2.2.1.1 7-1.1.1.2.1.1 7-1.1.2.2.1.1 9-1.1.1.3.1.1 9-1.1.2.3.1.1 11-1.1.1.4.1.1 11-1.1.2.4.1.1 13-1.1 14-1.1.3.1.1 16-1.1.3.1.1 18-1.1.3.2.1 19-1.1.3 19-1.1.3.2 19-1.1.3.2.r 21-1 22-1.2.r 23-1.2.1 24-1.2.1 25-1.2 (d / determine-01~e.21 :ARG1 (o / or~e.1,13 :op1 (a / and :op1 (e / enzyme :name (n / name :op1 "MEK"~e.3) :ARG3-of (p / phosphorylate-01~e.0)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.5,7) :ARG3-of p) :op3 (e3 / enzyme :name (n3 / name :op1 "RSK"~e.9) :ARG3-of p) :op4 (e4 / enzyme :name (n4 / name :op1 "AKT"~e.11) :ARG3-of p)) :op2 (a2 / and :op1 (e8 / enzyme :name (n8 / name :op1 "MEK"~e.3) :mod (t / total~e.2)) :op2 (e7 / enzyme :name (n7 / name :op1 "ERK1/2"~e.5,7) :mod t) :op3 (e6 / enzyme :name (n6 / name :op1 "RSK"~e.9) :mod t) :op4 (e5 / enzyme :name (n5 / name :op1 "AKT"~e.11) :mod t)) :op3 (p2 / protein~e.19 :name (n9 / name :op1 "beta-actin"~e.14,16) :ARG0-of~e.19 (c / control-01~e.19 :ARG1 (l / load-01~e.18)))) :manner~e.22 (a3 / analyze-01~e.25 :manner (i / immunoblot-01~e.23,24))) # ::id a_pmid_2514_2146.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "C"~e.1) # ::id a_pmid_2514_2146.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of SCH722984 on the MAPK signaling at 24 hours . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 5-1.2.1.1.1 6-1.2 8-1.3.1.1 9-1.3.1.2 (a2 / affect-01~e.0 :ARG0~e.1 (s / small-molecule :name (n / name :op1 "SCH722984"~e.2)) :ARG1~e.3 (s2 / signal-07~e.6 :ARG0 (p / pathway :name (n2 / name :op1 "MAPK"~e.5))) :time (a / after :quant (t / temporal-quantity :quant 24~e.8 :unit (h / hour~e.9)))) # ::id a_pmid_2514_2146.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SCH722984 @-@ sensitive M262 , SCH722984 @-@ resistant M381 , SCH722984 @-@ intermediately sensitive M409 cells were treated for 24 h with DMSO as solvent control (-) or 500 nM SCH722984 (+) .

@ @ @ # ::alignments 0-1.2.2.1.1 2-1.1.3.2 3-1.1.1.1.1 5-1.1.2.2.1 7-1.1.2.2 8-1.1.2.1.1 10-1.1.3.2.1 12-1.1.3.2.2 13-1.1.1.2 13-1.1.3.2 14-1.1.3.1.1 15-1.1.1 15-1.1.2 15-1.1.3 17-1 18-1.3.r 19-1.3.1 20-1.3.2 21-1.2.r 22-1.2.1.1.1 25-1.2.1 25-1.2.1.2 25-1.2.1.2.r 27-1.2 28-1.2.2.2.1 29-1.2.2.2.2 30-1.2.2.1.1 (t / treat-04~e.17 :ARG1 (a / and :op1 (c / cell-line~e.15 :name (n / name :op1 "M262"~e.3) :ARG0-of (s / sensitive-03~e.13 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "SCH722984")))) :op2 (c2 / cell-line~e.15 :name (n3 / name :op1 "M381"~e.8) :ARG0-of (r / resist-01~e.7 :ARG1 s2~e.5)) :op3 (c3 / cell-line~e.15 :name (n4 / name :op1 "M409"~e.14) :ARG0-of (s3 / sensitive-03~e.2,13 :ARG1 s2~e.10 :mod (i / intermediate~e.12)))) :ARG2~e.21 (o / or~e.27 :op1 (s4 / small-molecule~e.25 :name (n5 / name :op1 "DMSO"~e.22) :ARG0-of~e.25 (c4 / control-01~e.25 :ARG1 (d / dissolve-01))) :op2 (s5 / small-molecule :name (n6 / name :op1 "SCH722984"~e.0,30) :quant (c5 / concentration-quantity :quant 500~e.28 :unit (n7 / nanomolar~e.29)))) :duration~e.18 (t2 / temporal-quantity :quant 24~e.19 :unit (h / hour~e.20))) # ::id a_pmid_2514_2146.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next determined a time @-@ course of SCH772984 on MAPK and PI3K @/@ AKT pathway signaling for M238 , a SCH772984 @-@ sensitive BRAF @ ^{V600E @}@ -@ mutant melanoma cell line and M233 , a SCH772984 @-@ resistant BRAF @ ^{V600E @}@ -@ mutant melanoma cell line ( Figure 1 @ B ) . # ::alignments 0-1.1 1-1.3 2-1 4-1.3.r 8-1.2.1.1.1 10-1.2.1.2.1.1.1.1 11-1.2.1.2.1 12-1.2.1.2.1.2.1.1 14-1.2.1.2.1.2.1.1 15-1.2.1.2.1.1 15-1.2.1.2.1.2 16-1.2.1.2.1.1.2 18-1.2.2.1.1.1 21-1.2.2.1.2.1.1.1 23-1.2.2.1.2.1.1 25-1.2.2.1.2.1.2.1.1 29-1.2.2.1.2.1.2.2.1 33-1.2.2.1.2.1.2 33-1.2.2.1.2.1.2.2 33-1.2.2.1.2.1.2.2.r 34-1.2.2.1.2.1.3.1.1 35-1.2.2.1.2.1 36-1.2.2.1 36-1.2.2.2 37-1.2.2 38-1.2.2.2.1.1 41-1.2.2.2.2.1.1.1 43-1.2.2.2.2.1.1 45-1.2.2.2.2.1.3 46-1.2.2.2.2.1.3 47-1.2.2.2.2.1.3 48-1.2.2.2.2.1.3 49-1.2.2.2.2.1.3 50-1.2.2.2.2.1.3 51-1.2.2.2.2.1.3 52-1.2.2.2.2.1.3 53-1.2.2.2.2.1.3 54-1.2.2.1.2.1.3.1.1 55-1.2.2.2.2.1 56-1.2.2.2.2.1 58-1.4.1 (d / determine-01~e.2 :ARG0 (w / we~e.0) :ARG1 (t / timecourse :poss (s / small-molecule :name (n2 / name :op1 "SCH772984"~e.8) :ARG2-of (t2 / treat-04 :ARG1 (a / and~e.11 :op1 (p / pathway~e.15 :name (n4 / name :op1 "MAPK"~e.10) :ARG0-of (s2 / signal-07~e.16)) :op2 (p2 / pathway~e.15 :name (n5 / name :op1 "PI3K/AKT"~e.12,14) :ARG0-of s2)))) :beneficiary (a2 / and~e.37 :op1 (c2 / cell-line~e.36 :name (n6 / name :op1 "M238"~e.18) :ARG2-of (m / mean-01 :ARG1 (c3 / cell-line~e.35 :ARG0-of (s3 / sensitive-03~e.23 :ARG1 s~e.21) :mod (g / gene~e.33 :name (n7 / name :op1 "BRAF"~e.25) :ARG2-of~e.33 (m3 / mutate-01~e.33 :value "V600E"~e.29)) :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma"~e.34,54))))) :op2 (c5 / cell-line~e.36 :name (n8 / name :op1 "M233"~e.38) :ARG1-of (m4 / mean-01 :ARG2 (c4 / cell-line~e.55,56 :ARG0-of (r / resist-01~e.43 :ARG1 s~e.41) :mod m2 :mod g~e.45,46,47,48,49,50,51,52,53))))) :time~e.4 (n / next~e.1) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.58 :mod "1B"))) # ::id a_pmid_2514_2146.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For both M233 and M238 , treatment with 500 nM SCH772984 inhibited pRSK , a known ERK1 @/@ 2 downstream target , as well as pERK1 @/@ 2 itself . # ::alignments 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 6-1.1 7-1.1.2.r 8-1.1.2.2.1 9-1.1.2.2.2 10-1.1.2.1.1 11-1 12-1.2.1.1.1 12-1.2.1.2 15-1.2.1.3.2 16-1.2.1.3.1.1.1 18-1.2.1.3.1.1.1 19-1.2.1.3.3 20-1.2.1 20-1.2.1.3 20-1.2.1.3.r 22-1.2 23-1.2 24-1.2 27-1.2.1.3.1.1.1 27-1.2.2.1.1 (i / inhibit-01~e.11 :ARG0 (t / treat-04~e.6 :ARG1 (a / and~e.3 :op1 (c / cell-line :name (n2 / name :op1 "M233"~e.2)) :op2 (c2 / cell-line :name (n3 / name :op1 "M238"~e.4))) :ARG2~e.7 (s / small-molecule :name (n / name :op1 "SCH772984"~e.10) :quant (c3 / concentration-quantity :quant 500~e.8 :unit (n4 / nanomolar~e.9)))) :ARG1 (a2 / and~e.22,23,24 :op1 (e / enzyme~e.20 :name (n5 / name :op1 "RSK"~e.12) :ARG3-of (p / phosphorylate-01~e.12) :ARG1-of~e.20 (t2 / target-01~e.20 :ARG0 (e3 / enzyme :name (n7 / name :op1 "ERK1/2"~e.16,18,27)) :ARG1-of (k / know-01~e.15) :location (d / downstream~e.19))) :op2 (e2 / enzyme :name (n6 / name :op1 "ERK1/2"~e.27) :ARG3-of p))) # ::id a_pmid_2514_2146.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For the resistant M233 , the MAPK inhibition was strong as early as 1 hour post treatment , with decreased pERK and near @-@ complete disappearance of pRSK . # ::alignments 2-1.1.1.1.2 2-1.1.1.1.2.2 2-1.1.1.1.2.2.r 3-1.1.1.1.2.1.1 6-1.1.1.1.1.1 7-1.1.1 8-1.1.1.r 9-1.1 10-1.1.2.r 12-1.1.2.r 13-1.1.2.2.1 14-1.1.2.2.2 15-1.1.2 16-1.1.2.1 19-1.2 20-1.2.1.1.1 20-1.2.1.2 21-1 22-1.3.2.1 24-1.3.2 25-1.3 27-1.2.1.2 27-1.3.1.1.1 (a2 / and~e.21 :op1 (s / strong~e.9 :domain~e.8 (i / inhibit-01~e.7 :ARG1 (p / protein-family :name (n / name :op1 "MAPK"~e.6) :part-of (c / cell-line~e.2 :name (n2 / name :op1 "M233"~e.3) :ARG0-of~e.2 (r / resist-01~e.2)))) :time~e.10,12 (a / after~e.15 :op1 (t / treat-04~e.16) :quant (t2 / temporal-quantity :quant 1~e.13 :unit (h / hour~e.14)))) :op2 (d / decrease-01~e.19 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"~e.20) :ARG3-of (p2 / phosphorylate-01~e.20,27) :part-of c)) :op3 (d2 / disappear-01~e.25 :ARG1 (e2 / enzyme :name (n5 / name :op1 "RSK"~e.27) :ARG3-of p2 :part-of c) :ARG1-of (c2 / complete-01~e.24 :degree (n4 / near~e.22)))) # ::id a_pmid_2514_2146.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , between 12 and 24 hours we observe a rebound in the pathway with a return to baseline pERK1 @/@ 2 levels and an induction in pMEK above baseline levels by 24 hours . # ::alignments 0-1 2-1.1.3 3-1.1.3.1.1 4-1.1.3 5-1.1.3.2.1 6-1.1.3.1.2 7-1.1.1 8-1.1 10-1.1.2 11-1.1.2.1.r 13-1.1.2.1 16-1.1.2.2.1.1 18-1.1.2.2.1.1.1.2 21-1.1.2.2.1.1.1.1.1.1 22-1.1.2.2.1.1.1 23-1.1.2.2.1 25-1.1.2.2.1.2 28-1.1.2.2.1.2.2 29-1.1.2.2.1.2.2.1.2 30-1.1.2.2.1.1.1 30-1.1.2.2.1.2.2.1 32-1.1.2.2.1.3.1.1 32-1.1.3.2.1 33-1.1.2.2.1.3.1.2 (h3 / have-concession-91~e.0 :ARG2 (o / observe-01~e.8 :ARG0 (w / we~e.7) :ARG1 (r / rebound-01~e.10 :ARG1~e.11 (p / pathway~e.13) :ARG0-of (c2 / cause-01 :ARG1 (a / and~e.23 :op1 (r2 / return-01~e.16 :ARG1 (l / level~e.22,30 :quant-of (e / enzyme :name (n / name :op1 "ERK1/2"~e.21) :ARG3-of (p2 / phosphorylate-01)) :mod (b2 / baseline~e.18))) :op2 (i / induce-01~e.25 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of p2) :ARG2 (a2 / above~e.28 :op1 (l2 / level~e.30 :quant-of e2 :mod b2~e.29))) :time (a3 / after :quant (t3 / temporal-quantity :quant 24~e.32 :unit (h2 / hour~e.33)))))) :time (b / between~e.2,4 :op1 (t / temporal-quantity :quant 12~e.3 :unit (h / hour~e.6)) :op2 (t2 / temporal-quantity :quant 24~e.5,32 :unit h)))) # ::id a_pmid_2514_2146.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Little change in pAKT was seen at any timepoint up to 24 hours , though a mild induction was seen at 48 hours . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 3-1.1.1.2 5-1 6-1.2.r 7-1.2.1 8-1.2 9-1.2.2 10-1.2.2 11-1.2.2.1.1 12-1.2.2.1.2 14-1.3.r 16-1.3.1.2 17-1.3.1 19-1.3 21-1.3.2.1.1 22-1.3.2.1.2 (s / see-01~e.5 :ARG1 (c / change-01~e.1 :ARG1~e.2 (e / enzyme :name (n / name :op1 "AKT"~e.3) :ARG3-of (p / phosphorylate-01~e.3)) :mod (l / little~e.0)) :time~e.6 (t / timepoint~e.8 :mod (a / any~e.7) :quant (u / up-to~e.9,10 :op1 (t2 / temporal-quantity :quant 24~e.11 :unit (h / hour~e.12)))) :concession~e.14 (s2 / see-01~e.19 :ARG1 (i / induce-01~e.17 :ARG2 e :degree (m / mild~e.16)) :time (a2 / after :op1 (t3 / temporal-quantity :quant 48~e.21 :unit h~e.22)))) # ::id a_pmid_2514_2146.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For the sensitive M238 , pRSK levels also decreased as early as 1 hour and levels continued to decrease thereafter . # ::alignments 2-1.1.1.1.3 2-1.1.1.1.3.2 2-1.1.1.1.3.2.r 3-1.1.1.1.3.1.1 5-1.1.1.1.1.1 5-1.1.1.1.2 6-1.1.1 7-1.1.2 8-1.1 9-1.1.3.r 11-1.1.3.r 12-1.1.3.1.1 13-1.1.3.1.2 15-1.1.1 16-1.2 18-1.2.1 19-1.2.2 (a / and :op1 (d / decrease-01~e.8 :ARG1 (l / level~e.6,15 :quant-of (e / enzyme :name (n / name :op1 "RSK"~e.5) :ARG3-of (p / phosphorylate-01~e.5) :part-of (c / cell-line~e.2 :name (n2 / name :op1 "M238"~e.3) :ARG0-of~e.2 (s / sensitive-03~e.2)))) :mod (a2 / also~e.7) :time~e.9,11 (a3 / after :op1 (t / temporal-quantity :quant 1~e.12 :unit (h / hour~e.13)))) :op2 (c2 / continue-01~e.16 :ARG1 (d2 / decrease-01~e.18 :ARG1 l) :time (t2 / thereafter~e.19))) # ::id a_pmid_2514_2146.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Meanwhile , pERK1 @/@ 2 remained suppressed through 24 hours . # ::alignments 0-1.4 4-1.1.1.1 5-1 6-1.2 8-1.3.1 9-1.3.2 (r / remain-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.4) :ARG3-of (p / phosphorylate-01)) :ARG3 (s / suppress-01~e.6 :ARG1 e) :duration (t / temporal-quantity :quant 24~e.8 :unit (h / hour~e.9)) :time (m / meanwhile~e.0)) # ::id a_pmid_2514_2146.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By 48 hours , pERK1 @/@ 2 levels increased , though at reduced levels compared to baseline . # ::alignments 1-1.2.1.1 2-1.2.1.2 6-1.1.1.1.1 7-1.1 7-1.3 8-1 10-1.3.r 12-1.3.1 13-1.3 14-1.3.1.1 15-1.3.1.1.1.r 16-1.3.1.1.1 (i / increase-01~e.8 :ARG1 (l / level~e.7 :quant-of (e / enzyme :name (n / name :op1 "ERK1/2"~e.6) :ARG3-of (p / phosphorylate-01))) :time (a / after :op1 (t / temporal-quantity :quant 48~e.1 :unit (h / hour~e.2))) :concession~e.10 (l2 / level~e.7,13 :ARG1-of (r / reduce-01~e.12 :ARG1-of (c / compare-01~e.14 :ARG2~e.15 (b / baseline~e.16))))) # ::id a_pmid_2514_2146.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concomitant with this , pMEK levels remained unchanged until 24 hours and increased further by 48 hours . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1 5-1.1.1 6-1.1 7-1.1.2 7-1.1.2.1 7-1.1.2.1.r 8-1.1.3 9-1.1.3.1.1 10-1.1.3.1.2 11-1 12-1.2 13-1.2.3 15-1.2.2.1.1 16-1.2.2.1.2 (a / and~e.11 :op1 (r / remain-01~e.6 :ARG1 (l / level~e.5 :quant-of (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01))) :ARG3 (c / change-01~e.7 :polarity~e.7 -~e.7 :ARG1 l) :time (u / until~e.8 :op1 (t / temporal-quantity :quant 24~e.9 :unit (h / hour~e.10)))) :op2 (i / increase-01~e.12 :ARG1 l :time (a2 / after :op1 (t2 / temporal-quantity :quant 48~e.15 :unit h~e.16)) :degree (f / further~e.13)) :manner (c2 / concomitant~e.0 :prep-with~e.1 (t3 / this~e.2))) # ::id a_pmid_2514_2146.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regarding pAKT , an early induction at 1 hour occurred , followed by decreases thereafter though never becoming completely suppressed even at 48 hours . # ::alignments 1-1.1.1.1 1-1.1.2 4-1.2 5-1 7-1.3.1.1 8-1.3.1.2 11-1.3 11-1.4 11-1.4.1.3.3.2 12-1.4.1.r 13-1.4.1 14-1.4.1.2 15-1.4.1.3.r 16-1.4.1.3.1 16-1.4.1.3.1.r 16-1.4.1.3.4 17-1.4.1.3 18-1.4.1.3.3.4 19-1.4.1.3.3 20-1.4.1.3.3.3 21-1.4.1.3.3.2.1.r 22-1.4.1.3.3.2.1.1 23-1.4.1.3.3.2.1.2 (i / induce-01~e.5 :ARG2 (e2 / enzyme :name (n / name :op1 "AKT"~e.1) :ARG3-of (p / phosphorylate-01~e.1)) :time (e / early~e.4) :time (a / after~e.11 :op1 (t / temporal-quantity :quant 1~e.7 :unit (h / hour~e.8))) :ARG2-of (f / follow-01~e.11 :ARG1~e.12 (d / decrease-01~e.13 :ARG1 e :time (t2 / thereafter~e.14) :concession~e.15 (b / become-01~e.17 :polarity~e.16 -~e.16 :ARG1 e2 :ARG2 (s / suppress-01~e.19 :ARG1 e2 :time (a2 / after~e.11 :op1~e.21 (t3 / temporal-quantity :quant 48~e.22 :unit h~e.23)) :mod (e4 / even~e.20) :degree (c / complete~e.18)) :time (e3 / ever~e.16))))) # ::id a_pmid_2514_2146.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In both cell lines , pRSK remained blocked at all timepoints , demonstrating ongoing , potent inhibition of ERK1 @/@ 2 activity by SCH772984 . # ::alignments 1-1.3.1 2-1.3 3-1.3 5-1.1.1.1 6-1 7-1.2 8-1.2.2.r 9-1.2.2.2.1 12-1.2.2 13-1.2.2.1.3 15-1.2.2.1.4 16-1.2.2.1 17-1.2.2.1.2.r 18-1.2.2.1.2.1.1.1 20-1.2.2.1.2.1.1.1 21-1.2.2.1.2 22-1.2.2.1.1.r 23-1.2.2.1.1.1.1 (r / remain-01~e.6 :ARG1 (p / protein :name (n / name :op1 "pRSK"~e.5)) :ARG3 (b / block-01~e.7 :ARG1 p :ARG0-of~e.8 (d / demonstrate-01~e.12 :ARG1 (i / inhibit-01~e.16 :ARG0~e.22 (s / small-molecule :name (n3 / name :op1 "SCH772984"~e.23)) :ARG1~e.17 (a2 / activity-06~e.21 :ARG0 (e / enzyme :name (n2 / name :op1 "ERK1/2"~e.18,20))) :ARG1-of (g / go-on-15~e.13) :mod (p2 / potent~e.15)) :time (t / timepoint :mod (a / all~e.9)))) :location (c2 / cell-line~e.2,3 :mod (b2 / both~e.1))) # ::id a_pmid_2514_2146.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data supports that the distinction between sensitive and resistant cell lines could be best made based on pERK recovery at 24 hours , as recovery of the feedback loop that restores MAPK activity occurred by 24 hours in the resistant cell line whereas the sensitive cell line required longer than 24 hours . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.1.1 7-1.2.1.1.1.1 7-1.2.1.1.1.1.1 7-1.2.1.1.1.1.1.r 8-1.2.1.1.1 9-1.2.1.1.1.2.1 10-1.2.1.1.1.2 11-1.2.1.1.1.2 12-1.2 14-1.2.1.3 14-1.2.1.3.1 14-1.2.1.3.1.r 16-1.2.1 17-1.2.1.2.r 18-1.2.1.2.1.1.1 18-1.2.1.2.1.2 19-1.2.1.2 21-1.2.1.2.2.1.1 22-1.2.1.2.2.1.2 24-1.2.1.2.2.r 25-1.2.1.2.3.1 26-1.2.1.2.3.1.1.r 28-1.2.1.2.3.1.1.1 29-1.2.1.2.3.1.1 31-1.2.1.2.3.1.1.2 32-1.2.1.2.3.1.1.2.1.1.1.1 33-1.2.1.2.3.1.1.2.1 35-1.2.1.2.3.1.1.2.4.r 36-1.2.1.2.3.1.1.2.4 37-1.2.1.2.3.1.1.2.4 38-1.2.1.2.3.1.1.2.2.r 40-1.2.1.2.3.1.1.2.2 41-1.2.1.2.3.1.1.2.2 42-1.2.1.2.3.1.1.2.2 43-1.2.1.2.3.1.1.2.3 45-1.2.1.2.3.1.1.2.3.1.1 46-1.2.1.2.3.1.1.2.3.1.1 47-1.2.1.2.3.1.1.2.3.1.1 48-1.2.1.2.3.1.1.2.3.1 49-1.2.1.2.3.1.1.2.3.1.2 49-1.2.1.2.3.1.1.2.3.1.2.2 49-1.2.1.2.3.1.1.2.3.1.2.2.r 51-1.2.1.2.3.1.1.2.3.1.2.1 52-1.2.1.2.3.1.1.2.3.1.2.1 (s / support-01~e.2 :ARG0 (d2 / data~e.1 :mod (t2 / this~e.0)) :ARG1~e.3 (p / possible-01~e.12 :ARG1 (b / base-02~e.16 :ARG1 (d / distinguish-01~e.5 :ARG1 (a / and~e.8 :op1 (c / cell-line~e.7 :ARG0-of~e.7 (s2 / sensitive-03~e.7)) :op2 (c2 / cell-line~e.10,11 :ARG0-of (r / resist-01~e.9)))) :ARG2~e.17 (r2 / recover-02~e.19 :ARG0 (e / enzyme :name (n2 / name :op1 "ERK"~e.18) :ARG3-of (p3 / phosphorylate-01~e.18)) :time~e.24 (a3 / after :op1 (t / temporal-quantity :quant 24~e.21 :unit (h / hour~e.22))) :ARG1-of (m3 / mean-01 :ARG2 (r5 / recover-02~e.25 :ARG0~e.26 (l / loop~e.29 :mod (f / feedback~e.28) :ARG0-of (r3 / restore-01~e.31 :ARG1 (a2 / activity-06~e.33 :ARG0 (p2 / pathway :name (n / name :op1 "MAPK"~e.32))) :location~e.38 c2~e.40,41,42 :ARG1-of (c3 / contrast-01~e.43 :ARG2 (r4 / require-01~e.48 :ARG0 c~e.45,46,47 :ARG1 (l2 / long-03~e.49 :ARG2 t~e.51,52 :degree~e.49 (m2 / more~e.49)))) :time~e.35 a3~e.36,37))))) :ARG1-of (g / good-02~e.14 :degree~e.14 (m / most~e.14))))) # ::id a_pmid_2514_2146.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , for subsequent analyses , we selected 24 hours as the optimal timepoint to compare signaling in our cell lines . # ::alignments 0-1 2-1.1.r 3-1.1.5.2 3-1.1.5.2.r 4-1.1.5 6-1.1.1 7-1.1 8-1.1.2.1 9-1.1.2.2 10-1.1.3.r 10-1.1.5.2.r 12-1.1.3.1 13-1.1.3 15-1.1.4 16-1.1.4.2 17-1.1.4.2.1.r 18-1.1.4.2.1.1 18-1.1.4.2.1.1.r 19-1.1.4.2.1 20-1.1.4.2.1 (c / cause-01~e.0 :ARG1~e.2 (s / select-01~e.7 :ARG0 (w / we~e.6) :ARG1 (t / temporal-quantity :quant 24~e.8 :unit (h / hour~e.9)) :ARG3~e.10 (t2 / timepoint~e.13 :mod (o / optimal~e.12)) :purpose (c2 / compare-01~e.15 :ARG0 w :ARG1 (s2 / signal-07~e.16 :location~e.17 (c3 / cell-line~e.19,20 :poss~e.18 w~e.18))) :purpose (a / analyze-01~e.4 :ARG0 w :time~e.3,10 (s3 / subsequent~e.3)))) # ::id a_pmid_2514_2146.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 1 @ C , three BRAF mutant cell lines representative of the different sensitivity groups to SCH772984 were profiled in terms of downstream signaling inhibition at 24 hours : a highly sensitive cell line ( M262 , BRAF @ ^{V600E @} ) , an intermediately sensitive cell line ( M409 , BRAF @ ^{V600E @} ) , and a resistant cell line ( M381 , BRAF @ ^{V600R @} ) . # ::alignments 0-1.2.2.r 1-1.3 2-1.3.1.r 3-1.3.1 9-1.1.1 11-1.1.4.1.1 13-1.1.3.1.1.2.1.2 13-1.1.3.1.1.2.1.2.2 13-1.1.3.1.1.2.1.2.2.r 13-1.1.3.1.3.2.1.2 13-1.1.3.1.3.2.1.2.2 13-1.1.3.1.3.2.1.2.2.r 13-1.1.4 13-1.1.4.2 13-1.1.4.2.r 14-1.1 15-1.1 16-1.1.2 17-1.1.2.1.r 19-1.1.2.1.1 20-1.1.2.1.2 21-1.1.2.1 22-1.1.2.1.2.1.r 23-1.1.2.1.2.1.1.1 25-1 29-1.2.1.1 30-1.2.1 31-1.2 33-1.2.2.1.1 34-1.2.2.1.2 37-1.1.3.1.1.1.1 38-1.1.3.1.1.1 39-1.1.3.1.1 40-1.1.3.1.1 42-1.1.3.1.1.2.1.1.1 45-1.1.3.1.1.2.1.2.1.1 49-1.1.3.1.1.2.1.2.2.1 55-1.1.3.1.2.1.1 56-1.1.3.1.2.1 57-1.1.3.1.2 58-1.1.3.1.2 60-1.1.3.1.2.2.1.1.1 63-1.1.3.1.2.2.1.2 64-1.1.3.1.2.2.1.2 65-1.1.3.1.2.2.1.2 66-1.1.3.1.2.2.1.2 67-1.1.3.1.2.2.1.2 72-1.1.3.1 74-1.1.3.1.3.1 75-1.1.3.1.3 76-1.1.3.1.3 78-1.1.3.1.3.2.1.1.1 81-1.1.3.1.3.2.1.2.1.1 85-1.1.3.1.3.2.1.2.2.1 (p2 / profile-01~e.25 :ARG1 (c / cell-line~e.14,15 :quant 3~e.9 :ARG0-of (r2 / represent-01~e.16 :ARG1~e.17 (g / group~e.21 :ARG1-of (d2 / differ-02~e.19) :ARG0-of (s / sensitive-03~e.20 :ARG1~e.22 (s6 / small-molecule :name (n2 / name :op1 "SCH772984"~e.23))))) :ARG1-of (m7 / mean-01 :ARG2 (a / and~e.72 :op1 (c3 / cell-line~e.39,40 :ARG0-of (s3 / sensitive-03~e.38 :ARG1-of (h2 / high-02~e.37)) :ARG1-of (m2 / mean-01 :ARG2 (c4 / cell-line :name (n3 / name :op1 "M262"~e.42) :mod (g2 / gene~e.13 :name (n4 / name :op1 "BRAF"~e.45) :ARG2-of~e.13 (m3 / mutate-01~e.13 :value "V600E"~e.49))))) :op2 (c5 / cell-line~e.57,58 :ARG0-of (s4 / sensitive-03~e.56 :mod (i2 / intermediate~e.55)) :ARG1-of (m4 / mean-01 :ARG2 (c6 / cell-line :name (n5 / name :op1 "M409"~e.60) :mod g2~e.63,64,65,66,67))) :op3 (c7 / cell-line~e.75,76 :ARG0-of (r4 / resist-01~e.74) :ARG1-of (m5 / mean-01 :ARG2 (c8 / cell-line :name (n6 / name :op1 "M381"~e.78) :mod (g4 / gene~e.13 :name (n7 / name :op1 "BRAF"~e.81) :ARG2-of~e.13 (m6 / mutate-01~e.13 :value "V600R"~e.85))))))) :mod (g3 / gene~e.13 :name (n / name :op1 "BRAF"~e.11) :ARG2-of~e.13 (m / mutate-01~e.13))) :topic (i / inhibit-01~e.31 :ARG1 (s2 / signal-07~e.30 :location (d / downstream~e.29)) :time~e.0 (a2 / after :op1 (t / temporal-quantity :quant 24~e.33 :unit (h / hour~e.34)))) :ARG1-of (s5 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "1C"))) # ::id a_pmid_2514_2146.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For M262 , treatment with SCH772984 resulted in disappearance of pRSK , disappearance of pERK1 @/@ 2 , decrease in pAKT , and slight induction of pMEK at 24 hours . # ::alignments 1-1.1.1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1 6-1 7-1.2.r 8-1.2.1 10-1.2.1.1.1.1 10-1.2.1.1.2 12-1.2.1 12-1.2.2 16-1.2.2.1.1.1 18-1.2.3 20-1.2.1.1.2 20-1.2.3.1.1.1 22-1.2 23-1.2.4.2 24-1.2.4 28-1.2.5.1.1 29-1.2.5.1.2 (r / result-01~e.6 :ARG1 (t2 / treat-04~e.3 :ARG1 (c / cell-line :name (n / name :op1 "M262"~e.1)) :ARG2~e.4 (s / small-molecule :name (n2 / name :op1 "SCH772984"~e.5))) :ARG2~e.7 (a / and~e.22 :op1 (d / disappear-01~e.8,12 :ARG1 (e4 / enzyme :name (n3 / name :op1 "RSK"~e.10) :ARG3-of (p2 / phosphorylate-01~e.10,20))) :op2 (d2 / disappear-01~e.12 :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2"~e.16) :ARG3-of p2)) :op3 (d3 / decrease-01~e.18 :ARG1 (e2 / enzyme :name (n5 / name :op1 "AKT"~e.20) :ARG3-of p2)) :op4 (i / induce-01~e.24 :ARG2 (e3 / enzyme :name (n6 / name :op1 "MEK") :ARG3-of p2) :degree (s2 / slight~e.23)) :time (a2 / after :op1 (t / temporal-quantity :quant 24~e.28 :unit (h / hour~e.29))))) # ::id a_pmid_2514_2146.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M409 had a similar cell signaling profile as M262 , consistent with its modest sensitivity . # ::alignments 0-1.1.1.1 1-1 3-1.2.2 4-1.2.1.1 5-1.2.1 6-1.2 7-1.2.2.1.r 8-1.2.2.1.1.1 10-1.2.3 11-1.2.3.1.r 12-1.2.3.1.1 12-1.2.3.1.1.r 13-1.2.3.1.2 14-1.2.3.1 (h / have-03~e.1 :ARG0 (c / cell-line :name (n / name :op1 "M409"~e.0)) :ARG1 (p / profile-01~e.6 :ARG0-of (s / signal-07~e.5 :ARG1 (c2 / cell~e.4)) :ARG1-of (r / resemble-01~e.3 :ARG2~e.7 (c3 / cell-line :name (n2 / name :op1 "M262"~e.8))) :ARG1-of (c4 / consistent-01~e.10 :ARG2~e.11 (s2 / sensitive-03~e.14 :ARG0~e.12 p~e.12 :mod (m / modest~e.13))))) # ::id a_pmid_2514_2146.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For M381 induction of pMEK and pERK1 @/@ 2 were seen with no change in pRSK at 24 h . # ::alignments 1-1.1.2.1.1 2-1.1 5-1.1.1 8-1.1.1.2.1.1 10-1 11-1.2.r 12-1.2.1 12-1.2.1.r 13-1.2 15-1.1.1.1.2 15-1.2.2.1.1 17-1.3.1.1 18-1.3.1.2 (s / see-01~e.10 :ARG1 (i / induce-01~e.2 :ARG2 (a2 / and~e.5 :op1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01~e.15)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.8) :ARG3-of p)) :location (c2 / cell-line :name (n4 / name :op1 "M381"~e.1))) :ARG2~e.11 (c / change-01~e.13 :polarity~e.12 -~e.12 :ARG1 (e3 / enzyme :name (n3 / name :op1 "RSK"~e.15) :ARG3-of p)) :time (a / after :op1 (t / temporal-quantity :quant 24~e.17 :unit (h / hour~e.18)))) # ::id a_pmid_2514_2146.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine the effect of SCH772984 on the PI3K @/@ AKT pathway , we first evaluated the baseline pAKT levels for a group of cell lines ( Additional file 2 @ : Figure S2 ) . # ::alignments 1-1.3 3-1.3.2 4-1.3.2.1.r 5-1.3.2.1.1.1 6-1.3.2.2.r 8-1.3.2.2.1.1 10-1.3.2.2.1.1 11-1.3.2.2 13-1.1 14-1.5 15-1 17-1.2.2 18-1.2.1.1.1 18-1.2.1.2 19-1.2 22-1.2.1.3 23-1.2.1.3.1.r 24-1.2.1.3.1 25-1.2.1.3.1 28-1.4.1 30-1.4.1.1 33-1.4.1.2.1 34-1.4.1.2.1.1 (e / evaluate-01~e.15 :ARG0 (w / we~e.13) :ARG1 (l / level~e.19 :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT"~e.18) :ARG3-of (p2 / phosphorylate-01~e.18) :part-of (g / group~e.22 :consist-of~e.23 (c / cell-line~e.24,25))) :mod (b / baseline~e.17)) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (a / affect-01~e.3 :ARG0~e.4 (s / small-molecule :name (n3 / name :op1 "SCH772984"~e.5)) :ARG1~e.6 (p / pathway~e.11 :name (n / name :op1 "PI3K/AKT"~e.8,10)))) :ARG1-of (d2 / describe-01 :ARG0 (f / file~e.28 :mod 2~e.30 :ARG1-of (m / mean-01 :ARG2 (f2 / figure~e.33 :mod "S2"~e.34)) :ARG1-of (a3 / add-02))) :time (f3 / first~e.14)) # ::id a_pmid_2514_2146.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found a weak correlation with the activity of the PI3K @/@ AKT pathway and sensitivity to SCH772984 for BRAF mutants . # ::alignments 0-1.1 1-1 3-1.2.1.3 4-1.2.1 5-1.2.1.2.r 7-1.2.1.2 8-1.2.1.2.1.r 10-1.2.1.2.1.1.1 12-1.2.1.2.1.1.1 13-1.2.1.2.1 14-1.2 15-1.2.2 16-1.2.2.2.r 17-1.2.2.2.1.1 18-1.2.2.1.r 19-1.2.2.1.1.1 20-1.2.2.1 20-1.2.2.1.2 20-1.2.2.1.2.r (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a2 / and~e.14 :op1 (c / correlate-01~e.4 :ARG1 e :ARG2~e.5 (a / activity-06~e.7 :ARG0~e.8 (p / pathway~e.13 :name (n / name :op1 "PI3K/AKT"~e.10,12))) :ARG1-of (w2 / weak-02~e.3)) :op2 (s / sensitive-03~e.15 :ARG0~e.18 (e / enzyme~e.20 :name (n2 / name :op1 "BRAF"~e.19) :ARG2-of~e.20 (m / mutate-01~e.20)) :ARG1~e.16 (s2 / small-molecule :name (n3 / name :op1 "SCH772984"~e.17))))) # ::id a_pmid_2514_2146.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , M238 and M409 are two clear examples of cell lines with low levels of pAKT related to sensitivity to SCH772984 . # ::alignments 0-1.3 1-1.3 1-1.5 3-1.1.1.1 4-1 5-1.2.1.1 7-1.3.1 8-1.3.3 9-1.3 10-1.3.2.r 11-1.3.2 12-1.3.2 14-1.3.2.1.1.2 15-1.3.2.1.1 16-1.3.2.1.1.1.r 17-1.3.2.1.1.1.1.1 17-1.3.2.1.1.1.2 18-1.4 19-1.4.1.r 20-1.4.1 21-1.4.1.1.r 22-1.4.1.1.1.1 (a2 / and~e.4 :op1 (c / cell-line :name (n / name :op1 "M238"~e.3)) :op2 (c2 / cell-line :name (n2 / name :op1 "M409"~e.5)) :ARG0-of (e2 / exemplify-01~e.0,1,9 :quant 2~e.7 :ARG1~e.10 (c3 / cell-line~e.11,12 :ARG0-of (h / have-03 :ARG1 (l / level~e.15 :quant-of~e.16 (e3 / enzyme :name (n3 / name :op1 "AKT"~e.17) :ARG3-of (p / phosphorylate-01~e.17)) :ARG1-of (l2 / low-04~e.14)))) :ARG1-of (c4 / clear-06~e.8)) :ARG1-of (r / relate-01~e.18 :ARG2~e.19 (s / sensitive-03~e.20 :ARG1~e.21 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"~e.22)))) :ARG0-of (e / exemplify-01~e.1)) # ::id a_pmid_2514_2146.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For both of them , ERK inhibition with SCH772984 was accompanied by an upregulation of pAKT levels even at 24 hours treatment ( Figure 1 @ B ) . # ::alignments 1-1.4.1 3-1.4 5-1.2.2.1.1 6-1.2 7-1.2.1.r 8-1.2.1.1.1 10-1 11-1.1.r 13-1.1 14-1.1.1.r 15-1.1.1.1.1.1 15-1.1.1.1.2 16-1.1.1 17-1.3.2 19-1.3.3.1 20-1.3.3.2 21-1.3.1 23-1.5.1 (a / accompany-01~e.10 :ARG0~e.11 (u / upregulate-01~e.13 :ARG1~e.14 (l / level~e.16 :quant-of (e3 / enzyme :name (n4 / name :op1 "AKT"~e.15) :ARG3-of (p / phosphorylate-01~e.15)))) :ARG1 (i / inhibit-01~e.6 :ARG0~e.7 (s / small-molecule :name (n3 / name :op1 "SCH772984"~e.8)) :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.5))) :time (a2 / after :op1 (t2 / treat-04~e.21) :mod (e / even~e.17) :quant (t / temporal-quantity :quant 24~e.19 :unit (h / hour~e.20))) :beneficiary (t3 / they~e.3 :mod (b / both~e.1)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "1B"))) # ::id a_pmid_2514_2146.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M233 was among the resistant BRAF @ ^{V600E @} melanoma cell lines , which appeared to have increased pAKT at baseline compared to other BRAF mutant cell lines . # ::alignments 0-1.1.1 2-1.3 4-1.4 6-1.3.1.1.1.1 10-1.3.1.1.2.1 13-1.3.1.2.1.1 14-1.3.1 15-1 18-1.2.2 20-1.2 21-1.2.1.3 22-1.2.1.1.1 22-1.2.1.2 23-1.2.1.3.1.r 24-1.2.1.3.1 25-1.2.1.3.2.r 27-1.2.1.3.2.2 29-1.2.1.3.2.1.1.1 31-1.2.1.3.2.1 31-1.2.1.3.2.1.2 31-1.2.1.3.2.1.2.r 31-1.3.1.1 31-1.3.1.1.2 31-1.3.1.1.2.r 32-1.2.1.3.2 33-1.2.1.3.2 (c4 / cell-line~e.15 :name (n5 / name :op1 "M233"~e.0) :ARG0-of (h / have-03~e.20 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT"~e.22) :ARG3-of (p / phosphorylate-01~e.22) :ARG1-of (i2 / increase-01~e.21 :location~e.23 (b / baseline~e.24) :compared-to~e.25 (c3 / cell-line~e.32,33 :mod (g2 / gene~e.31 :name (n4 / name :op1 "BRAF"~e.29) :ARG2-of~e.31 (m3 / mutate-01~e.31)) :mod (o / other~e.27)))) :ARG1-of (a / appear-01~e.18)) :ARG1-of (i / include-91~e.2 :ARG2 (c2 / cell-line~e.14 :mod (g / gene~e.31 :name (n2 / name :op1 "BRAF"~e.6) :ARG2-of~e.31 (m2 / mutate-01~e.31 :value "V600E"~e.10)) :mod (m4 / medical-condition :name (n / name :op1 "melanoma"~e.13)))) :ARG0-of (r / resist-01~e.4)) # ::id a_pmid_2514_2146.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with this , M233 is a PTEN null cell line and has a concomitant AKT1 amplification [ @ 31 @ ] . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1 4-1.1.3.1.1 5-1.1.3.r 7-1.1.2.1.1 8-1.1.1 9-1.1 10-1.1 11-1 12-1.2 14-1.2.2.2 16-1.2.2.1.1.1 18-1.2.2 21-1.4.1.1.1 (a / and~e.11 :op1 (c2 / cell-line~e.9,10 :mod (n2 / null~e.8) :mod (p / protein :name (n3 / name :op1 "PTEN"~e.7)) :domain~e.5 (c / cell-line :name (n / name :op1 "M233"~e.4))) :op2 (h / have-03~e.12 :ARG0 c :ARG1 (a2 / amplify-01~e.18 :ARG1 (g / gene :name (n4 / name :op1 "AKT1"~e.16)) :mod (c3 / concomitant~e.14))) :ARG1-of (c4 / consistent-01~e.0 :ARG2~e.1 (t / this~e.2)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 31~e.21)))) # ::id a_pmid_2514_2146.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After treatment with SCH772984 ( Figure 1 @ B ) , these levels stay constant , indicating that dual inhibition with SCH772984 and AKT @/@ mTOR inhibitors may be a useful strategy . # ::alignments 0-1.4 1-1.4.1 2-1.4.1.1.r 3-1.4.1.1 5-1.4.2.1 12-1.1.1 13-1.1 14-1 15-1.2 17-1.3 18-1.3.1.r 19-1.3.1.1.1.2 20-1.3.1.1.1 22-1.3.1.1.1.1.1.1 23-1.3.1.1 24-1.3.1.1.2.1.1.1.1 26-1.3.1.1.2.1.1.1.1 27-1.3.1.1.1 27-1.3.1.1.2 27-1.3.1.1.2.1 27-1.3.1.1.2.1.r 28-1.3.1.3 29-1.3.1.1.r 31-1.3.1.2 32-1.3.1 (s / stay-01~e.14 :ARG1 (l / level~e.13 :mod (t2 / this~e.12)) :ARG3 (c / constant~e.15) :ARG0-of (i2 / indicate-01~e.17 :ARG1~e.18 (s2 / strategy~e.32 :domain~e.29 (a / and~e.23 :op1 (i3 / inhibit-01~e.20,27 :ARG0 (s3 / small-molecule :name (n / name :op1 "SCH772984"~e.22)) :mod (d2 / dual~e.19)) :op2 (m / molecular-physical-entity~e.27 :ARG0-of~e.27 (i / inhibit-01~e.27 :ARG1 (p2 / pathway :name (n2 / name :op1 "AKT/mTOR"~e.24,26))))) :ARG1-of (u / useful-05~e.31) :ARG1-of (p / possible-01~e.28))) :time (a2 / after~e.0 :op1 (t3 / treat-04~e.1 :ARG2~e.2 s3~e.3) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.5 :mod "1B")))) # ::id a_pmid_2514_2146.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , M262 is an AKT1 amplified cell line [ @ 31 @ ] with high sensitivity to SCH772984 and vemurafenib . # ::alignments 1-1 3-1.1.2.1.1 4-1.1.2.r 7-1.1.1.1.1.1 9-1.1.1 10-1.1 11-1.1 14-1.1.3.1.1.1 18-1.1.2.2.2 19-1.1.2 19-1.1.2.2 19-1.1.2.2.r 20-1.1.2.2.1.r 21-1.1.2.2.1.1.1.1 22-1.1.2.2.1 23-1.1.2.2.1.2.1.1 (c / contrast-01~e.1 :ARG2 (c2 / cell-line~e.10,11 :ARG1-of (a / amplify-01~e.9 :ARG0 (g / gene :name (n / name :op1 "AKT1"~e.7))) :domain~e.4 (c3 / cell-line~e.19 :name (n2 / name :op1 "M262"~e.3) :ARG0-of~e.19 (s / sensitive-03~e.19 :ARG1~e.20 (a2 / and~e.22 :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984"~e.21)) :op2 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib"~e.23))) :ARG1-of (h / high-02~e.18))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 31~e.14))))) # ::id a_pmid_2514_2146.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of M262 with SCH772984 reduced both pERK1 @/@ 2 and pAKT levels , indicating blockade of the MAPK pathway and PI3K @/@ AKT pathway at the same time ( Figure 1 @ C ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 4-1.1.2.1.1 5-1 9-1.2.1.1.1.1 10-1.2 11-1.2.1.1.2 11-1.2.2.1.1.1 12-1.2.1 12-1.2.2 14-1.3 15-1.3.1 16-1.3.1.1.r 18-1.3.1.1.1.1.1 19-1.3.1.1.1 19-1.3.1.1.2 20-1.3.1.1 21-1.3.1.1.2.1.1 23-1.3.1.1.2.1.1 24-1.3.1.1.1 25-1.3.1.2.r 27-1.3.1.2.1 28-1.3.1.2 30-1.4.1 (r / reduce-01~e.5 :ARG0 (t2 / treat-04~e.0 :ARG1~e.1 (c / cell-line :name (n3 / name :op1 "M262"~e.2)) :ARG2~e.3 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"~e.4))) :ARG1 (a / and~e.10 :op1 (l / level~e.12 :quant-of (e / enzyme :name (n5 / name :op1 "ERK1/2"~e.9) :ARG3-of (p3 / phosphorylate-01~e.11))) :op2 (l2 / level~e.12 :quant-of (e2 / enzyme :name (n6 / name :op1 "AKT"~e.11) :ARG3-of p3))) :ARG0-of (i / indicate-01~e.14 :ARG1 (b / blockade-01~e.15 :ARG1~e.16 (a2 / and~e.20 :op1 (p / pathway~e.19,24 :name (n / name :op1 "MAPK"~e.18)) :op2 (p2 / pathway~e.19 :name (n2 / name :op1 "PI3K/AKT"~e.21,23))) :time~e.25 (t3 / time~e.28 :ARG1-of (s3 / same-01~e.27)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "1C"))) # ::id a_pmid_2514_2146.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In general , the presence of AKT1 or AKT2 amplification did not preclude sensitivity to SCH772984 , as three of five such cell lines were highly sensitive to SCH772984 ( M229 , M249 , and M262 ) , one was intermediately sensitive ( M255 ) , and M233 and M308 were resistant ( Figure 1 @ A ) . # ::alignments 1-1.6 7-1.2.1.1.1.1 11-1.2.1.2.1.1 13-1.2 15-1.1 15-1.1.r 16-1 17-1.3 18-1.3.1.r 19-1.3.1.1.1 21-1.4.r 22-1.4.1.1.1.1 24-1.4.1.1.1.2.1.1 26-1.4.1.1.1.2.1 27-1.4.1.1.1 27-1.4.1.2 29-1.4.1.1.3 30-1.4.1.1 31-1.4 32-1.3.1.1.1 34-1.4.1.1.1.3.1.1.1.1 36-1.4.1.1.1.3.1.2.1.1 38-1.4.1.1.1.3.1 39-1.4.1.1.1.3.1.3.1.1 42-1.4.1.2.1 44-1.4.1.2.2.2 45-1.4.1.2.2 47-1.4.1.2.3.1.1.1 50-1.4.1 50-1.4.1.3 50-1.4.1.3.r 51-1.4.1.3.1.1.1 52-1.4.1.3 53-1.4.1.3.2.1.1 55-1.4.1.3.3 57-1.5.1 59-1.4.1.2.1 (p / preclude-01~e.16 :polarity~e.15 -~e.15 :ARG0 (a / amplify-01~e.13 :ARG1 (a2 / and :op1 (g2 / gene :name (n / name :op1 "AKT1"~e.7)) :op2 (g3 / gene :name (n2 / name :op1 "AKT2"~e.11)))) :ARG1 (s / sensitive-03~e.17 :ARG1~e.18 (s2 / small-molecule :name (n3 / name :op1 "SCH772984"~e.19,32))) :ARG1-of~e.21 (c / cause-01~e.31 :ARG0 (a3 / and~e.50 :op1 (s3 / sensitive-03~e.30 :ARG0 (c2 / cell-line~e.27 :quant 3~e.22 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.26 :quant 5~e.24)) :ARG1-of (m / mean-01 :ARG2 (a4 / and~e.38 :op1 (c4 / cell-line :name (n5 / name :op1 "M229"~e.34)) :op2 (c5 / cell-line :name (n6 / name :op1 "M249"~e.36)) :op3 (c6 / cell-line :name (n7 / name :op1 "M262"~e.39))))) :ARG1 s2 :ARG1-of (h / high-02~e.29)) :op2 (c7 / cell-line~e.27 :quant 1~e.42,59 :ARG0-of (s5 / sensitive-03~e.45 :ARG1 s2 :mod (i2 / intermediate~e.44)) :ARG1-of (m2 / mean-01 :ARG2 (c8 / cell-line :name (n8 / name :op1 "M255"~e.47)))) :op3~e.50 (a5 / and~e.50,52 :op1 (c9 / cell-line :name (n9 / name :op1 "M233"~e.51)) :op2 (c10 / cell-line :name (n10 / name :op1 "M308"~e.53)) :ARG0-of (r / resist-01~e.55 :ARG1 s2)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.57 :mod "1A")) :ARG1-of (g / general-02~e.1)) # ::id a_pmid_2514_2146.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given high baseline pAKT levels were seen in some cells resistant to ERK inhibition ( Additional file 2 @ : Figure S2 ) and the persistence of pAKT activity with SCH722984 treatment , we evaluated the effect of SCH772984 in combination with the AKT inhibitor MK @-@ 2206 or the mTOR inhibitor MK @-@ 8669 . # ::alignments 1-1.1.1.1.3 2-1.1.1.1.2 3-1.1.1.1.1.1.1 3-1.1.1.1.1.2 3-1.1.2.1.1.2 4-1.1.1.1 6-1.1.1 7-1.1.1.2.r 8-1.1.1.2.1 9-1.1.1.2 10-1.1.1.2.2 11-1.1.1.2.2.1.r 12-1.1.1.2.2.1.1.1.1 13-1.1.1.2.2.1 16-1.1.1.3.1 18-1.1.1.3.1.1 21-1.1.1.3.1.2.1 22-1.1.1.3.1.2.1.1 24-1.1 26-1.1.2 28-1.2.2.1.2.1.1.2.1.1.1 29-1.1.2.1 30-1.1.2.1.1.r 31-1.1.2.1.1.3.1.1.1 32-1.1.2.1.1 32-1.1.2.1.1.3 32-1.1.2.1.1.3.r 34-1.2.1 35-1.2 37-1.2.2 39-1.2.2.1.1.1 41-1.2.2.1 41-1.2.2.1.2 41-1.2.2.1.2.r 44-1.1.2.1.1.1.1 45-1.2.2.1.2.1.2 45-1.2.2.1.2.1.2.2 45-1.2.2.1.2.1.2.2.r 46-1.2.2.1.2.1.1.1.1 48-1.2.2.1.2.1.1.1.1 49-1.2.2.1.2.1 51-1.2.2.1.2.1.2.2.1.1.1 52-1.2.2.1.2.1.1 52-1.2.2.1.2.1.1.2 52-1.2.2.1.2.1.1.2.r 52-1.2.2.1.2.1.2 52-1.2.2.1.2.1.2.2 52-1.2.2.1.2.1.2.2.r 53-1.2.2.1.2.1.2.1.1 55-1.2.2.1.2.1.2.1.1 (c / cause-01 :ARG0 (a / and~e.24 :op1 (s / see-01~e.6 :ARG1 (l / level~e.4 :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT"~e.3) :ARG3-of (p / phosphorylate-01~e.3)) :mod (b / baseline~e.2) :ARG1-of (h / high-02~e.1)) :location~e.7 (c2 / cell~e.9 :quant (s2 / some~e.8) :ARG0-of (r / resist-01~e.10 :ARG1~e.11 (i2 / inhibit-01~e.13 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"~e.12))))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.16 :mod 2~e.18 :ARG1-of (m / mean-01 :ARG2 (f2 / figure~e.21 :mod "S2"~e.22)) :ARG1-of (a5 / add-02)))) :op2 (p2 / persist-01~e.26 :ARG1 (a2 / activity-06~e.29 :ARG0~e.30 (e4 / enzyme~e.32 :name (n4 / name :op1 "AKT"~e.44) :ARG3-of (p3 / phosphorylate-01~e.3) :ARG1-of~e.32 (t2 / treat-04~e.32 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "SCH722984"~e.31))))))) :ARG1 (e5 / evaluate-01~e.35 :ARG0 (w / we~e.34) :ARG1 (a4 / affect-01~e.37 :ARG0 (s4 / small-molecule~e.41 :name (n6 / name :op1 "SCH772984"~e.39) :ARG1-of~e.41 (c3 / combine-01~e.41 :ARG2 (o / or~e.49 :op1 (s6 / small-molecule~e.52 :name (n7 / name :op1 "MK-2206"~e.46,48) :ARG0-of~e.52 (i3 / inhibit-01~e.52 :ARG1 (e6 / enzyme :name (n8 / name :op1 "AKT"~e.28)))) :op2 (s5 / small-molecule~e.45,52 :name (n9 / name :op1 "MK-8669"~e.53,55) :ARG0-of~e.45,52 (i4 / inhibit-01~e.45,52 :ARG1 (p4 / protein :name (n10 / name :op1 "mTOR"~e.51)))))))))) # ::id a_pmid_2514_2146.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The addition of either the AKTi or mTORi always resulted in more potent cell growth inhibition compared to ERKi alone ( Additional file 3 @ : Figures S3A and 3B ) . # ::alignments 1-1.1 1-1.4.1.3 6-1.1.1 8-1.3 9-1 10-1.2.r 11-1.2.2.1 12-1.2.2 13-1.2.1.1 14-1.2.1 15-1.1.1.1 15-1.1.1.1.1 15-1.1.1.1.1.r 15-1.1.1.2 15-1.1.1.2.1 15-1.1.1.2.1.r 15-1.2 15-1.2.3 15-1.2.3.1 15-1.2.3.1.r 16-1.2.3.r 19-1.2.3.1.1.2 22-1.4.1 24-1.4.1.1 27-1.4.1.2.1.1 27-1.4.1.2.1.2 28-1.4.1.2.1.1.1 29-1.4.1.2.1 (r / result-01~e.9 :ARG1 (a / add-02~e.1 :ARG1 (o / or~e.6 :op1 (m3 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1 (p3 / protein-family :name (n / name :op1 "AKT")))) :op2 (m4 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i2 / inhibit-01~e.15 :ARG1 (p / protein :name (n2 / name :op1 "mTOR")))))) :ARG2~e.10 (i3 / inhibit-01~e.15 :ARG1 (g / grow-01~e.14 :ARG1 (c / cell~e.13)) :mod (p2 / potent~e.12 :mod (m / more~e.11)) :compared-to~e.16 (m5 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i4 / inhibit-01~e.15 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK") :mod (a3 / alone~e.19))))) :time (a2 / always~e.8) :ARG1-of (d / describe-01 :ARG0 (f / file~e.22 :mod 3~e.24 :ARG1-of (m2 / mean-01 :ARG2 (a5 / and~e.29 :op1 (f2 / figure~e.27 :mod "S3A"~e.28) :op2 (f3 / figure~e.27 :mod "S3B"))) :ARG1-of (a6 / add-02~e.1)))) # ::id a_pmid_2514_2146.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combining SCH772984 with the mTOR inhibitor MK @-@ 8669 was particularly synergistic . # ::alignments 0-1.1 1-1.1.1.1.1 2-1.1.2.r 4-1.1.2.2.1.1.1 5-1.1.2 5-1.1.2.2 5-1.1.2.2.r 6-1.1.2.1.1 8-1.1.2.1.1 10-1.2 11-1 (s2 / synergize-01~e.11 :ARG0 (c / combine-01~e.0 :ARG1 (s / small-molecule :name (n / name :op1 "SCH772984"~e.1)) :ARG2~e.2 (s3 / small-molecule~e.5 :name (n2 / name :op1 "MK-8669"~e.6,8) :ARG0-of~e.5 (i2 / inhibit-01~e.5 :ARG1 (p / protein :name (n3 / name :op1 "mTOR"~e.4))))) :mod (p2 / particular~e.10)) # ::id a_pmid_2514_2146.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For BRAF @-@ mutant cell line M233 , both combinations resulted in more complete decrease in pERK compared to treatment with SCH772984 alone . # ::alignments 1-1.3.2.1.1 3-1.3.2 3-1.3.2.2 3-1.3.2.2.r 4-1.3 5-1.3 6-1.3.1.1 8-1.1.1 9-1.1 10-1 11-1.2.r 12-1.2.2.1 13-1.2.2 14-1.2 15-1.2.1.r 16-1.2.1.1.1 16-1.2.1.2 17-1.2.3.r 19-1.2.3 20-1.2.3.1.r 21-1.2.3.1.1.1 22-1.2.3.1.2 (r / result-01~e.10 :ARG1 (c / combine-01~e.9 :mod (b / both~e.8)) :ARG2~e.11 (d / decrease-01~e.14 :ARG1~e.15 (e / enzyme :name (n / name :op1 "ERK"~e.16) :ARG3-of (p / phosphorylate-01~e.16)) :degree (c2 / complete~e.13 :mod (m / more~e.12)) :compared-to~e.17 (t / treat-04~e.19 :ARG2~e.20 (s / small-molecule :name (n2 / name :op1 "SCH772984"~e.21) :mod (a / alone~e.22)))) :beneficiary (c3 / cell-line~e.4,5 :name (n3 / name :op1 "M233"~e.6) :mod (e2 / enzyme~e.3 :name (n4 / name :op1 "BRAF"~e.1) :ARG2-of~e.3 (m2 / mutate-01~e.3)))) # ::id a_pmid_2514_2146.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the improved inhibition of the MAPK pathway , the levels of pAKT were largely unaffected by the addition of MK @-@ 2206 or MK @-@ 8669 ( Additional file 3 @ : Figure S3C ) . # ::alignments 0-1 2-1.2.2 3-1.2 4-1.2.1.r 6-1.2.1.1.1 7-1.2.1 10-1.1.3 11-1.1.3.1.r 12-1.1.3.1.1.1 12-1.1.3.1.2 14-1.1.4 15-1.1 15-1.1.1 15-1.1.1.r 18-1.1.2 18-1.3.1.3 19-1.1.2.1.r 20-1.1.2.1.1.1.1 20-1.1.2.1.2.1.1 22-1.1.2.1.1.1.1 23-1.1.2.1 24-1.1.2.1.1.1.1 24-1.1.2.1.2.1.1 26-1.1.2.1.2.1.1 29-1.3.1 31-1.3.1.1 34-1.3.1.2.1 35-1.3.1.2.1.1 (h / have-concession-91~e.0 :ARG1 (a / affect-01~e.15 :polarity~e.15 -~e.15 :ARG0 (a2 / add-02~e.18 :ARG1~e.19 (o / or~e.23 :op1 (s / small-molecule :name (n3 / name :op1 "MK-2206"~e.20,22,24)) :op2 (s2 / small-molecule :name (n4 / name :op1 "MK-8669"~e.20,24,26)))) :ARG1 (l / level~e.10 :quant-of~e.11 (e / enzyme :name (n2 / name :op1 "AKT"~e.12) :ARG3-of (p2 / phosphorylate-01~e.12))) :degree (l2 / large~e.14)) :ARG2 (i / inhibit-01~e.3 :ARG1~e.4 (p / pathway~e.7 :name (n / name :op1 "MAPK"~e.6)) :ARG1-of (i2 / improve-01~e.2)) :ARG1-of (d / describe-01 :ARG0 (f / file~e.29 :mod 3~e.31 :ARG1-of (m3 / mean-01 :ARG2 (f2 / figure~e.34 :mod "S3C"~e.35)) :ARG1-of (a4 / add-02~e.18)))) # ::id a_pmid_2514_2146.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Potent SCH772984 @-@ mediated ERK inhibition in BRAF @ -@ wild type melanoma cell lines # ::alignments 0-1.3 1-1.2.1.1.1 3-1.2 4-1.1.1.1 5-1 8-1.2.2.1.1.1.1 11-1.2.2.1.1.2 12-1.2.2.1.1.2 13-1.2.2.1 14-1.2.2 15-1.2.2 (i2 / inhibit-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.4)) :ARG1-of (m / mediate-01~e.3 :ARG0 (s / small-molecule :name (n2 / name :op1 "SCH772984"~e.1)) :location (c / cell-line~e.14,15 :mod (m2 / melanoma~e.13 :mod (g / gene :name (n3 / name :op1 "BRAF"~e.8) :mod (w / wild-type~e.11,12))))) :mod (p / potent~e.0)) # ::id a_pmid_2514_2146.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Currently , there is no effective targeted therapy for BRAF wild @-@ type melanoma , which comprises 50 % of all melanomas . # ::alignments 0-1.5 4-1.1 4-1.1.r 6-1.3 7-1 10-1.6.2.1.1 12-1.6.2.2 14-1.6.2.2 15-1.6.1.1 18-1.4 19-1.4.1.2.2.1 20-1.4.1.2.2 22-1.4.1.2.1.2 23-1.4.1.1.1 23-1.4.1.2.1.1.1 (t3 / therapy~e.7 :polarity~e.4 -~e.4 :ARG0-of (a / affect-01) :ARG1-of (t2 / target-01~e.6) :ARG1-of (c2 / comprise-01~e.18 :ARG2 (m / medical-condition :name (n3 / name :op1 "melanoma"~e.23) :ARG1-of (i / include-91 :ARG2 (m2 / medical-condition :name (n4 / name :op1 "melanoma"~e.23) :mod (a2 / all~e.22)) :ARG3 (p / percentage-entity~e.20 :value 50~e.19)))) :time (c / current~e.0) :beneficiary (m4 / medical-condition :name (n2 / name :op1 "melanoma"~e.15) :mod (g / gene :name (n / name :op1 "BRAF"~e.10) :mod (w / wild-type~e.12,14)))) # ::id a_pmid_2514_2146.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fourteen NRAS mutant melanoma and seven cells lines with wild @-@ type BRA @ F and NRAS were evaluated for SCH772984 sensitivity . # ::alignments 0-1.1.1.1 2-1.1.1.3.1.1 4-1.1.1.3 4-1.1.1.3.2 4-1.1.1.3.2.r 5-1.1.1.2.1 6-1.1 7-1.1.2.1 8-1.1.2 9-1.1.2 11-1.1.2.2.1.1.2 13-1.1.2.2.1.1.2 18-1.1 18-1.1.2.2.1 20-1.1.2.2.1.2.1.1 23-1 24-1.2.r 25-1.2.2.1.1 26-1.2 (e / evaluate-01~e.23 :ARG1 (a / and~e.6,18 :op1 (m3 / medical-condition :quant 14~e.0 :name (n5 / name :op1 "melanoma"~e.5) :mod (e2 / enzyme~e.4 :name (n / name :op1 "NRAS"~e.2) :ARG2-of~e.4 (m2 / mutate-01~e.4))) :op2 (c / cell-line~e.8,9 :quant 7~e.7 :ARG0-of (h / have-03 :ARG1 (a2 / and~e.18 :op1 (g / gene :name (n2 / name :op1 "BRAF") :mod (w / wild-type~e.11,13)) :op2 (g2 / gene :name (n3 / name :op1 "NRAS"~e.20) :mod w))))) :purpose~e.24 (s / sensitive-03~e.26 :ARG0 a :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"~e.25)))) # ::id a_pmid_2514_2146.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 2 @ A , while all NRAS @ -@ mutant cell lines were resistant to vemurafenib , 11 of 14 were highly sensitive to SCH772984 ( IC @₅₀ < 1 μM ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 9-1 10-1.1.1.1 12-1.1.1.2.1.1 15-1.1.1.2 15-1.1.1.2.2 15-1.1.1.2.2.r 16-1.2.1.2.1 17-1.1.1 17-1.2.1 19-1.1 20-1.1.2.r 21-1.1.2.1.1 23-1.2.1.1 25-1.2.1.2.1.1 27-1.2.3 28-1.2 29-1.2.2.r 30-1.2.2.1.1 32-1.2.2 32-1.2.2.2 32-1.2.2.2.r 34-1.2.2.2.1 36-1.2.2.2.2 37-1.2.2.2.2.1.1 38-1.2.2.2.2.1.2 (c / contrast-01~e.9 :ARG1 (r / resist-01~e.19 :ARG0 (c2 / cell-line~e.17 :mod (a / all~e.10) :mod (g / gene~e.15 :name (n / name :op1 "NRAS"~e.12) :ARG2-of~e.15 (m / mutate-01~e.15))) :ARG1~e.20 (s / small-molecule :name (n2 / name :op1 "vemurafenib"~e.21))) :ARG2 (s2 / sensitive-03~e.28 :ARG0 (c3 / cell-line~e.17 :quant 11~e.23 :ARG1-of (i / include-91 :ARG2 (c4 / cell-line~e.16 :quant 14~e.25 :mod m))) :ARG1~e.29 (s3 / small-molecule~e.32 :name (n3 / name :op1 "SCH772984"~e.30) :ARG1-of~e.32 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.32 :ARG2 50~e.34 :ARG4 (l / less-than~e.36 :op1 (c5 / concentration-quantity :quant 1~e.37 :unit (m3 / micromolar~e.38))))) :ARG1-of (h / high-02~e.27)) :ARG1-of (s4 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "2A"))) # ::id a_pmid_2514_2146.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Across the 11 NRAS sensitive cell lines , two of them were Q61L ( M296 and M311 ) , four were Q61K ( M408 , Sbcl2 , WM1366 , M245 and M244 ) , one was Q61H ( M243 ) and three were Q61R ( SKMEL173 , M296 and M412a ) . # ::alignments 2-1.5.1.1 3-1.5.1.3.1.1 4-1.5.1.2 5-1.5.1 6-1.1 6-1.2 6-1.3 6-1.4 6-1.5.1 8-1.1.1 12-1.1.2.1 14-1.1.3.1.1.1.1 15-1.1.3.1 16-1.1.3.1.2.1.1 21-1.2.2.1 23-1.2.3.1.1.1.1 25-1.2.3.1.2.1.1 27-1.2.3.1.3.1.1 29-1.2.3.1.4.1.1 30-1.2.3.1 31-1.2.3.1.5.1.1 34-1.3.1 36-1.3.2.1 38-1.3.3.1.1.1 40-1.2.3.1 41-1.4.1 43-1.4.2.1 45-1.4.3.1.1.1.1 47-1.4.3.1.2 48-1.2.3.1 49-1.4.3.1.3.1.1 (a2 / and :op1 (c3 / cell-line~e.6 :quant 2~e.8 :ARG1-of (m / mutate-01 :value "Q61L"~e.12) :ARG1-of (m5 / mean-01 :ARG2 (a3 / and~e.15 :op1 (c5 / cell-line :name (n3 / name :op1 "M296"~e.14)) :op2 (c6 / cell-line :name (n4 / name :op1 "M311"~e.16))))) :op2 (c7 / cell-line~e.6 :quant 5 :ARG1-of (m2 / mutate-01 :value "Q61K"~e.21) :ARG1-of (m6 / mean-01 :ARG2 (a4 / and~e.30,40,48 :op1 (c8 / cell-line :name (n5 / name :op1 "M408"~e.23)) :op2 (c9 / cell-line :name (n6 / name :op1 "Sbcl2"~e.25)) :op3 (c10 / cell-line :name (n7 / name :op1 "WM1366"~e.27)) :op4 (c11 / cell-line :name (n8 / name :op1 "M245"~e.29)) :op5 (c12 / cell-line :name (n9 / name :op1 "M244"~e.31))))) :op3 (c13 / cell-line~e.6 :quant 1~e.34 :ARG1-of (m3 / mutate-01 :value "Q61H"~e.36) :ARG1-of (m7 / mean-01 :ARG2 (c14 / cell-line :name (n10 / name :op1 "M243"~e.38)))) :op4 (c15 / cell-line~e.6 :quant 3~e.41 :ARG1-of (m4 / mutate-01 :value "Q61R"~e.43) :ARG1-of (m8 / mean-01 :ARG2 (a5 / and :op1 (c16 / cell-line :name (n11 / name :op1 "SKMEL173"~e.45)) :op2 c5~e.47 :op3 (c18 / cell-line :name (n13 / name :op1 "M412a"~e.49))))) :ARG1-of (i2 / include-91 :ARG2 (c4 / cell-line~e.5,6 :quant 11~e.2 :ARG0-of (s2 / sensitive-03~e.4) :mod (e2 / enzyme :name (n2 / name :op1 "NRAS"~e.3))))) # ::id a_pmid_2514_2146.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the three cell lines with IC50 > 1 uM ( M202 , M207 and M318 ) were exclusively NRAS Q61L mutated . # ::alignments 0-1.4 3-1.2.2.1 4-1.2.2 5-1.2.2 8-1.2.2.2.1.1 9-1.2.2.2.1.1.1.1 12-1.2.2.3.1.1.1.1 14-1.2.2.3.1.2.1.1 15-1.2.2.3.1 16-1.2.2.3.1.3.1.1 19-1.3 20-1.2.1.1 21-1.1 22-1 (m / mutate-01~e.22 :value "Q61L"~e.21 :ARG2 (e2 / enzyme :name (n / name :op1 "NRAS"~e.20) :part-of (c / cell-line~e.4,5 :quant 3~e.3 :ARG0-of (h / have-03 :ARG1 (c6 / concentrate-02 :quant (m2 / more-than~e.8 :op1 (c2 / concentration-quantity :quant 1~e.9 :unit (m3 / micromolar))) :mod (i2 / inhibit-01 :degree (p / percentage-entity :value 50)))) :ARG1-of (m4 / mean-01 :ARG2 (a / and~e.15 :op1 (c3 / cell-line :name (n3 / name :op1 "M202"~e.12)) :op2 (c4 / cell-line :name (n4 / name :op1 "M207"~e.14)) :op3 (c5 / cell-line :name (n5 / name :op1 "M318"~e.16)))))) :ARG0-of (e / exclusive-02~e.19) :ARG2-of (i / interest-01~e.0)) # ::id a_pmid_2514_2146.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity to trametinib are shown in Additional file 4 @ : Figures S4A and 4B for NRAS @-@ mutant and wild @-@ type melanoma cell lines , respectively . # ::alignments 0-1.2 1-1.2.2.r 2-1.2.2.1.1 4-1 7-1.1 9-1.1.1 12-1.1.2.1.1 12-1.1.2.1.2 13-1.1.2.1.1.1 14-1.1.2.1 16-1.2.1.r 17-1.2.1.1.1.1.1 19-1.2.1.1.1 19-1.2.1.1.1.2 19-1.2.1.1.1.2.r 20-1.2.1 21-1.2.1.2.1.2 23-1.2.1.2.1.2 24-1.2.1.2.1.1.1 25-1.2.1.1 25-1.2.1.2 26-1.2.1.1 28-1.2.1.3 (s / show-01~e.4 :ARG0 (f / file~e.7 :mod 4~e.9 :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.14 :op1 (f2 / figure~e.12 :mod "S4A"~e.13) :op2 (f3 / figure~e.12 :mod "S4B"))) :ARG1-of (a4 / add-02)) :ARG1 (s2 / sensitive-03~e.0 :ARG0~e.16 (a3 / and~e.20 :op1 (c2 / cell-line~e.25,26 :mod (e / enzyme~e.19 :name (n2 / name :op1 "NRAS"~e.17) :ARG2-of~e.19 (m3 / mutate-01~e.19))) :op2 (c / cell-line~e.25 :mod (m4 / medical-condition :name (n3 / name :op1 "melanoma"~e.24) :mod (w / wild-type~e.21,23))) :mod (r / respective~e.28)) :ARG1~e.1 (s3 / small-molecule :name (n / name :op1 "trametinib"~e.2)))) # ::id a_pmid_2514_2146.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the profile for sensitive cell lines , treatment with SCH772984 for the sensitive M408 resulted in decreased pRSK , disappearance of pERK1 @/@ 2 , and slight induction of pMEK , with no change in total RSK , MEK , ERK 1 @/@ 2 , or AKT . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1 6-1.3.1.1 7-1.1.1 9-1.1 10-1.1.2.r 11-1.1.2.1.1 12-1.1.1.2.r 14-1.1.1.2 15-1.1.1.1.1 16-1 17-1.2.r 18-1.2.1 19-1.2.1.1.1.1 19-1.2.1.1.2 19-1.2.2.1.2 19-1.2.3.1.2 21-1.2.2 25-1.2.2.1.1.1 27-1.2 28-1.2.3.2 29-1.2.3 34-1.2.4.1 34-1.2.4.1.r 35-1.2.4 36-1.2.4.2.r 37-1.2.4.2.1.2 38-1.2.4.2.1.1.1 40-1.2.3.1.1.1 40-1.2.4.2.2.1.1 45-1.2.4.2.3.1.1 48-1.2.4.2.4.1.1 (r / result-01~e.16 :ARG1 (t / treat-04~e.9 :ARG1 (c / cell-line~e.7 :name (n3 / name :op1 "M408"~e.15) :ARG0-of~e.12 (s / sensitive-03~e.14)) :ARG2~e.10 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"~e.11))) :ARG2~e.17 (a / and~e.27 :op1 (d / decrease-01~e.18 :ARG1 (e3 / enzyme :name (n5 / name :op1 "RSK"~e.19) :ARG3-of (p / phosphorylate-01~e.19))) :op2 (d2 / disappear-01~e.21 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.25) :ARG3-of (p4 / phosphorylate-01~e.19))) :op3 (i / induce-01~e.29 :ARG2 (e4 / enzyme :name (n6 / name :op1 "MEK"~e.40) :ARG3-of (p2 / phosphorylate-01~e.19)) :degree (s3 / slight~e.28)) :ARG0-of (c2 / change-01~e.35 :polarity~e.34 -~e.34 :ARG1~e.36 (a2 / and :op1 (e5 / enzyme :name (n7 / name :op1 "RSK"~e.38) :mod (t2 / total~e.37)) :op2 (e6 / enzyme :name (n8 / name :op1 "MEK"~e.40) :mod t2) :op3 (e7 / enzyme :name (n9 / name :op1 "ERK1/2"~e.45) :mod t2) :op4 (e8 / enzyme :name (n10 / name :op1 "AKT"~e.48) :mod t2)))) :ARG1-of (c3 / consistent-01~e.0 :ARG2~e.1 (p3 / profile-01~e.3 :beneficiary~e.4 (c4 / cell-line~e.6 :ARG0-of (s4 / sensitive-03~e.5))))) # ::id a_pmid_2514_2146.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For the resistant M202 , a modest induction of pMEK with some decrease in pERK and pRSK was observed at 24 hours ( Figure 2 @ B ) . # ::alignments 2-1.3 2-1.3.2 2-1.3.2.r 3-1.3.1.1 6-1.1.1.2 7-1.1.1 11-1.1.2.2 12-1.1.2 14-1.1.1.1.2 14-1.1.2.1.1.1.1 15-1.1 15-1.1.2.1 16-1.1.1.1.2 16-1.1.2.1.2.1.1 18-1 20-1.2.1.1 21-1.2.1.2 23-1.4.1 (o / observe-01~e.18 :ARG1 (a / and~e.15 :op1 (i / induce-01~e.7 :ARG2 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01~e.14,16)) :mod (m / modest~e.6)) :op2 (d / decrease-01~e.12 :ARG1 (a2 / and~e.15 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.14)) :op2 (e3 / enzyme :name (n3 / name :op1 "RSK"~e.16)) :ARG3-of p) :ARG2 (s / some~e.11))) :time (a3 / after :quant (t / temporal-quantity :quant 24~e.20 :unit (h / hour~e.21))) :location (c / cell-line~e.2 :name (n4 / name :op1 "M202"~e.3) :ARG0-of~e.2 (r / resist-01~e.2)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.23 :mod "2B"))) # ::id a_pmid_2514_2146.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with SCH772984 resulted in upregulation of pAKT levels for M408 and WM1366 ( Additional file 3 @ : Figure S3C ) . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1 3-1 4-1.2.r 5-1.2 6-1.2.1.r 7-1.2.1.1.1.1 7-1.2.1.1.2 8-1.2.1 9-1.1.1.r 10-1.1.1.1.1.1 11-1.1.1 12-1.1.1.2.1.1 14-1.3.1.3 15-1.3.1 17-1.3.1.1 20-1.3.1.2 21-1.3.1.2.1 (r / result-01~e.3 :ARG1 (t / treat-04~e.0 :ARG1~e.9 (a / and~e.11 :op1 (c / cell-line :name (n3 / name :op1 "M408"~e.10)) :op2 (c2 / cell-line :name (n4 / name :op1 "WM1366"~e.12))) :ARG2~e.1 (s / small-molecule :name (n / name :op1 "SCH772984"~e.2))) :ARG2~e.4 (u / upregulate-01~e.5 :ARG1~e.6 (l / level~e.8 :quant-of (e / enzyme :name (n2 / name :op1 "AKT"~e.7) :ARG3-of (p / phosphorylate-01~e.7)))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.15 :mod 3~e.17 :mod (f2 / figure~e.20 :mod "S3C"~e.21) :mod (a2 / additional~e.14)))) # ::id a_pmid_2514_2146.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the synergistic growth inhibition seen with combining SCH772984 and either MK @-@ 2206 or MK @-@ 8669 , pAKT levels were abrogated with the addition of MK @-@ 2206 ( AKT inhibitor ) and MK @-@ 8669 ( mTOR inhibitor ) ( Additional file 3 @ : Figure S3A @-@ C ) . @ Figure 2 @

Susceptibility of NRAS @-@ mutant melanoma cell lines to SCH @-@ 722984 . # ::alignments 0-1.1 1-1.1.2.r 3-1.1.2.2 4-1.1.2.1 5-1.1.2 6-1.1.2.3 7-1.1.2.3.1.r 8-1.1.2.3.1 9-1.1.2.3.1.1.1.1 10-1.1.1.2.1 12-1.1.1.2.1.1.1.1 12-1.1.1.2.1.2.1.1 14-1.1.1.2.1.1.1.1 15-1.1.2.3.1.2 16-1.1.1.2.1.1.1.1 16-1.1.1.2.1.2.1.1 18-1.1.1.2.1.2.1.1 20-1.1.1.1.1.2 21-1.1.1.1 23-1.1.1 26-1.1.1.2 28-1.1.1.2.1.1.1.1 28-1.1.1.2.1.2.1.1 30-1.1.1.2.1.1.1.1 32-1.1.1.1.1.1.1 33-1.1.1.2.1.1 33-1.1.1.2.1.1.2 33-1.1.1.2.1.1.2.r 33-1.1.1.2.1.2 33-1.1.1.2.1.2.2 33-1.1.1.2.1.2.2.r 35-1.1.1.2.1 36-1.1.1.2.1.1.1.1 36-1.1.1.2.1.2.1.1 38-1.1.1.2.1.2.1.1 40-1.1.1.2.1.2.2.1.1.1 41-1.1.1.2.1.2 41-1.1.1.2.1.2.2 41-1.1.1.2.1.2.2.r 41-1.1.2 44-1.1.3.1.2 45-1.1.3.1 47-1.1.3.1.1 50-1.1.3.1.3 50-1.1.3.1.4 50-1.1.3.1.5 51-1.1.3.1.3.1 58-1.2.3.1 59-1.2.3.1.1 64-1.2 65-1.2.1.r 66-1.2.1.1.1.1 68-1.2.1.1 68-1.2.1.1.2 68-1.2.1.1.2.r 69-1.2.1.2.1.1 70-1.2.1 71-1.2.1 (m / multi-sentence :snt1 (c / consistent-01~e.0 :ARG1 (a / abrogate-01~e.23 :ARG1 (l / level~e.21 :quant-of (e / enzyme :name (n / name :op1 "AKT"~e.32) :ARG3-of (p / phosphorylate-01~e.20))) :ARG2 (a2 / add-02~e.26 :ARG1 (a3 / and~e.10,35 :op1 (s6 / small-molecule~e.33 :name (n2 / name :op1 "MK-2206"~e.12,14,16,28,30,36) :ARG0-of~e.33 (i2 / inhibit-01~e.33 :ARG1 e)) :op2 (s7 / small-molecule~e.33,41 :name (n3 / name :op1 "MK-8669"~e.12,16,18,28,36,38) :ARG0-of~e.33,41 (i3 / inhibit-01~e.33,41 :ARG1 (p2 / protein :name (n4 / name :op1 "mTOR"~e.40))))))) :ARG2~e.1 (i / inhibit-01~e.5,41 :ARG1 (g / grow-01~e.4) :ARG0-of (s / synergize-01~e.3) :ARG1-of (s2 / see-01~e.6 :manner~e.7 (c2 / combine-01~e.8 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "SCH772984"~e.9)) :ARG2 (o / or~e.15 :op1 s6 :op2 s7)))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.45 :mod 3~e.47 :mod (a4 / additional~e.44) :part (f2 / figure~e.50 :mod "S3A"~e.51) :part (f4 / figure~e.50 :mod "S3B") :part (f5 / figure~e.50 :mod "S3C")))) :snt2 (s4 / susceptibility~e.64 :mod~e.65 (c3 / cell-line~e.70,71 :mod (e3 / enzyme~e.68 :name (n8 / name :op1 "NRAS"~e.66) :ARG2-of~e.68 (m7 / mutate-01~e.68)) :source (m2 / medical-condition :name (n6 / name :op1 "melanoma"~e.69))) :ARG2-of (r / respond-01 :ARG1 (s5 / small-molecule :name (n9 / name :op1 "SCH722984"))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.58 :mod 2~e.59)))) # ::id a_pmid_2514_2146.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A @ . # ::alignments 0-1.1 (s / string-entity :value "A"~e.0) # ::id a_pmid_2514_2146.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IC @₅₀ ( nM ) . # ::alignments 0-1 2-1.1 5-1.2.1 (h / have-percentage-maximal-inhibitory-concentration-01~e.0 :ARG2 50~e.2 :ARG4 (c / concentration-quantity :unit (n / nanomolar~e.5))) # ::id a_pmid_2514_2146.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Melanoma cell lines containing mutations in NRAS were exposed to 0 @–@ 10 μM SCH @-@ 722984 ( black bars ) or vemurafenib ( grey bars ) , and the cell viability determined . # ::alignments 0-1.1.1.2.1.1 1-1.1.1 2-1.1.1 3-1.1.1.1 4-1.1.1.1.1 7-1.1.1.1.1.1.1.1 10-1.1 11-1.1.2.r 12-1.1.2.3.1.1 14-1.1.2.3.1.2 15-1.1.2.3.2 20-1.1.2.1.2.1.1 21-1.1.2.1.2.1 23-1.1.2 24-1.1.2.2.1.1 26-1.1.2.2.2.1.1 27-1.1.2.2.2.1 32-1.1.1 33-1.2.1 34-1.2 (a / and :op1 (e / expose-01~e.10 :ARG1 (c / cell-line~e.1,2,32 :ARG0-of (c2 / contain-01~e.3 :ARG1 (m2 / mutate-01~e.4 :ARG1 (g / gene :name (n / name :op1 "NRAS"~e.7)))) :source (m3 / medical-condition :name (n4 / name :op1 "melanoma"~e.0))) :ARG2~e.11 (o / or~e.23 :op1 (s / small-molecule :name (n2 / name :op1 "SCH722984") :ARG1-of (d / describe-01 :ARG2 (b / bar~e.21 :ARG1-of (b2 / black-04~e.20)))) :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.24) :ARG1-of (d2 / describe-01 :ARG2 (b3 / bar~e.27 :ARG1-of (g2 / gray-02~e.26)))) :mod (c3 / concentration-quantity :quant (v / value-interval :op1 0~e.12 :op2 10~e.14) :unit (m / micromolar~e.15)))) :op2 (d3 / determine-01~e.34 :ARG1 (v2 / viability~e.33 :poss c))) # ::id a_pmid_2514_2146.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results are the mean of three experiments , performed in duplicate ( n = 6 ) . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.r 3-1 3-1.2.3 4-1.2.2.1 5-1.2.1 6-1.2 8-1.2.2 14-1.2.3.1.1 (m / mean~e.3 :domain~e.1 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) :mod (e / experiment-01~e.6 :quant 3~e.5 :ARG1-of (p / perform-01~e.8 :frequency (p2 / product-of~e.4 :op1 2)) :ARG1-of (m2 / mean-01~e.3 :ARG2 (e2 / equal-01 :ARG2 6~e.14 :ARG1 e)))) # ::id a_pmid_2514_2146.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Error bars are standard deviation . # ::alignments 0-1.2.1.1 1-1.2.1 3-1.1 4-1 (d / deviate-01~e.4 :ARG1-of (s / standard-02~e.3) :ARG1-of (d2 / describe-01 :ARG0 (b / bar~e.1 :mod (e / error~e.0)))) # ::id a_pmid_2514_2146.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bar at 1 μM denotes threshold between sensitive and intermediate . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.2 4-1 5-1.2 6-1.2.1 7-1.2.1.1 8-1.2.1 9-1.2.1.2 (d / denote-01~e.4 :ARG0 (b / bar~e.0 :location~e.1 (c / concentration-quantity :quant 1~e.2 :unit (m / micromolar~e.3))) :ARG1 (t / threshold~e.5 :location (b2 / between~e.6,8 :op1 (s / sensitive-03~e.7) :op2 (i / intermediate~e.9)))) # ::id a_pmid_2514_2146.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Resistant cell lines have IC @₅₀ higher than 2 μM . # ::alignments 0-1.2.1 1-1.2 2-1.2 3-1 4-1 6-1.1 9-1.3 10-1.3.1.1 11-1.3.1.2 (h / have-percentage-maximal-inhibitory-concentration-01~e.3,4 :ARG2 50~e.6 :ARG1 (c / cell-line~e.1,2 :ARG0-of (r / resist-01~e.0)) :ARG4 (m2 / more-than~e.9 :op1 (c2 / concentration-quantity :quant 2~e.10 :unit (m / micromolar~e.11)))) # ::id a_pmid_2514_2146.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B @ . # ::alignments 1-1.1 (f / figure :mod "B"~e.1) # ::id a_pmid_2514_2146.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of SCH722984 on MAPK signaling . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 4-1.2.1.1.1 5-1.2 (a / affect-01~e.0 :ARG0~e.1 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"~e.2)) :ARG1~e.3 (s / signal-07~e.5 :ARG0 (p / pathway :name (n / name :op1 "MAPK"~e.4)))) # ::id a_pmid_2514_2146.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SCH722984 @-@ resistant M202 and SCH722984 @-@ sensitive M408 were treated for 24 h with DMSO as solvent control (-) or 500 nM SCH722984 (+) . # ::alignments 0-1.1.1.2.1 1-1.2.1.3.1.1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 3-1.1.1.1.1 4-1.1 5-1.1.2.2.1 6-1.2.1.3.1.1 7-1.1.2 7-1.1.2.2 7-1.1.2.2.r 8-1.1.2.1.1 10-1 11-1.3.r 12-1.3.1 13-1.3.2 14-1.2.r 15-1.2.1.1.1 17-1.2.1.2.1 18-1.2.1.2 20-1.2 21-1.2.2.2.1 22-1.2.2.2.2 23-1.2.2.1.1 (t / treat-04~e.10 :ARG1 (a / and~e.4 :op1 (c / cell-line~e.2 :name (n / name :op1 "M202"~e.3) :ARG0-of~e.2 (r / resist-01~e.2 :ARG1 s5~e.0)) :op2 (c2 / cell-line~e.7 :name (n2 / name :op1 "M408"~e.8) :ARG0-of~e.7 (s / sensitive-03~e.7 :ARG1 s5~e.5))) :ARG2~e.14 (o / or~e.20 :op1 (s2 / small-molecule :name (n4 / name :op1 "DMSO"~e.15) :mod (c3 / control~e.18 :mod (s3 / solvent~e.17)) :ARG1-of (l / label-01 :ARG2 (s4 / string-entity :value -~e.1,6))) :op2 (s5 / small-molecule :name (n5 / name :op1 "SCH722984"~e.23) :quant (c4 / concentration-quantity :quant 500~e.21 :unit (n3 / nanomolar~e.22)) :ARG1-of (l2 / label-01 :ARG2 (s6 / string-entity :value +)))) :duration~e.11 (t2 / temporal-quantity :quant 24~e.12 :unit (h / hour~e.13))) # ::id a_pmid_2514_2146.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylated or total MEK , ERK 1 @/@ 2 , RSK , AKT or beta @-@ actin as loading control were determined by western blot analysis .

Susceptibility of BRAF @/@ NRAS wild @-@ type melanoma to SCH @-@ 722984 . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.1.1.1 5-1.1.2 7-1.1.2.1 8-1.1.2.1.2 10-1.1.2.1.2.2.3 11-1.1.2.1.2.2.3.r 13-1.1.2.1.2.2.1.1.1 15-1.1.2.1.2.2.1.2 17-1.1.2.1.2.2.1.2 18-1.1.2.1.2.2 19-1.1.2.1.2.2 19-1.1.2.1.2.2.2.1.1 20-1.1.2.1.2.2.2 22-1.1.2.1.2.2.2.1.1.1.1.1 24-1.1.2.1.2.2.2.1.1.1 24-1.1.2.1.2.2.2.1.1.1.2 24-1.1.2.1.2.2.2.1.1.1.2.r 25-1.1.2.1.2.2.2.1 27-1.1.2.1.2.2.2.1.2.1.1 28-1.1.2.1.2.2.2.1.2.1 32-1.1.2.1.2.2.2.1.2.1.1 33-1.1.2.1.2.2.2.1.2.1.1 34-1.1.2.1.2.2.2.1.2.1.1 35-1.1.2.1.2.2.2.1.4.1.1 36-1.1.2.1.2.2.2.1.2 37-1.1.2.1.2.2.2.1.2 39-1.1.2.1.2.2.2.1.3 40-1.1.2.1.2.2.2.1.3.1 41-1.1.2.1.2.2.2.1.3.1.2.r 43-1.1.2.1.2.2.2.1.3.1.2.1.1 44-1.1.2.1.2.2.2.1.3.1.2 45-1.1.2.1.2.2.2.1.3.1.3.r 46-1.1.2.1.2.2.2.1.3.1.3.2 47-1.1.2.1.2.2.2.1.3.1.3 51-1.2.2.1 52-1.2.2.1.1 57-1.2 58-1.2.3.r 59-1.2.3.2.1.1.1 60-1.2.3.2 61-1.1.2.1.2.2.2.1.2.1.2.1.1 61-1.2.3.2.2.1.1 62-1.1.2.1.2.2.1.2 62-1.2.3.2.3 64-1.1.2.1.2.2.1.2 64-1.2.3.2.3 65-1.1.2.1.2.2.2.1.4.1.1 65-1.2.3.1.1 (m / multi-sentence :snt1 (i / indicate-01~e.2 :ARG0 (d2 / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (p2 / possible-01~e.5 :ARG1 (e / effective-04~e.7 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "SCH772984"~e.4)) :ARG1 (c / counter-01~e.8 :ARG0 s4 :ARG1 (c2 / cell-line~e.18,19 :mod (g / gene :name (n3 / name :op1 "BRAF"~e.13) :mod (w / wild-type~e.15,17,62,64)) :ARG2-of (i2 / include-01~e.20 :ARG1 (a / and~e.25 :op1 (c3 / cell-line~e.19 :mod (g2 / gene~e.24 :name (n4 / name :op1 "NRAS"~e.22) :ARG2-of~e.24 (m4 / mutate-01~e.24))) :op2 (c4 / cell-line~e.36,37 :mod (s / slash~e.28 :op1 g~e.27,32,33,34 :op2 (g6 / gene :name (n10 / name :op1 "NRAS"~e.61) :mod w))) :ARG1-of (r / remain-01~e.39 :ARG3 (d3 / depend-01~e.40 :ARG0 a :ARG1~e.41 (p / pathway~e.44 :name (n / name :op1 "MAPK"~e.43)) :purpose~e.45 (g3 / grow-01~e.47 :ARG1 a :ARG1-of (c5 / continue-01~e.46)))) :source (m3 / medical-condition :name (n8 / name :op1 "melanoma"~e.35,65)))) :quant~e.11 (m2 / majority~e.10)))))) :snt2 (s2 / susceptibility~e.57 :ARG2-of (r2 / respond-01 :ARG1 (s5 / small-molecule :name (n7 / name :op1 "SCH722984"))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.51 :mod 3~e.52)) :mod~e.58 (m5 / medical-condition :name (n9 / name :op1 "melanoma"~e.65) :mod (s3 / slash~e.60 :op1 (g4 / gene :name (n5 / name :op1 "BRAF"~e.59)) :op2 (g5 / gene :name (n6 / name :op1 "NRAS"~e.61)) :mod (w2 / wild-type~e.62,64))))) # ::id a_pmid_2514_2146.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IC @₅₀ ( nM ) . # ::alignments 0-1 2-1.1 5-1.2.1 (h / have-percentage-maximal-inhibitory-concentration-01~e.0 :ARG2 50~e.2 :ARG4 (c2 / concentration-quantity :unit (n / nanomolar~e.5))) # ::id a_pmid_2514_2146.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were treated with 0 @–@ 10 μM SCH @-@ 722984 ( black bars ) or vemurafenib ( grey bars ) and cell viability determined by ATP @-@ based bioluminescence assay . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.3.1.1 6-1.1.2.3.1.2 7-1.1.2.3.2 12-1.1.2.1.2.1.1 13-1.1.2.1.2.1 15-1.1.2 16-1.1.2.2.1.1 18-1.1.2.2.2.1.1 19-1.1.2.2.2.1 22-1.1.1 23-1.2.1 24-1.2 25-1.2.2.r 26-1.2.2.2.1.1.1 28-1.2.2.2 29-1.2.2.1 30-1.2.2 (a / and :op1 (t / treat-04~e.2 :ARG1 (c / cell~e.0,22) :ARG2~e.3 (o / or~e.15 :op1 (s2 / small-molecule :name (n / name :op1 "SCH722984") :ARG1-of (d / describe-01 :ARG0 (b / bar~e.13 :ARG1-of (b2 / black-04~e.12)))) :op2 (s3 / small-molecule :name (n2 / name :op1 "vemurafenib"~e.16) :ARG1-of (d2 / describe-01 :ARG0 (b3 / bar~e.19 :ARG1-of (g / gray-02~e.18)))) :mod (c2 / concentration-quantity :quant (v / value-interval :op1 0~e.4 :op2 10~e.6) :unit (m / micromolar~e.7)))) :op2 (d3 / determine-01~e.24 :ARG1 (v2 / viability~e.23 :poss c) :manner~e.25 (a2 / assay-01~e.30 :ARG1 (b4 / bioluminescence~e.29) :ARG1-of (b5 / base-02~e.28 :ARG2 (s / small-molecule :name (n3 / name :op1 "ATP"~e.26)))))) # ::id a_pmid_2514_2146.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results are the mean of duplicate experiments , performed in triplicate ( n = 6 ) . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.r 3-1 3-1.2.3 4-1.2.1.1 4-1.2.2 6-1.2 8-1.2.1 14-1.2.3.1.1 (m / mean~e.3 :domain~e.1 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) :mod (e / experiment-01~e.6 :ARG1-of (p / perform-01~e.8 :frequency (p3 / product-of~e.4 :op1 3)) :frequency (p2 / product-of~e.4 :op1 2) :ARG1-of (m2 / mean-01~e.3 :ARG2 (e2 / equal-01 :ARG2 6~e.14 :ARG1 e)))) # ::id a_pmid_2514_2146.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Error bars are standard deviation . # ::alignments 0-1.2.1.1 1-1.2.1 3-1.1 4-1 (d / deviate-01~e.4 :ARG1-of (s / standard-02~e.3) :ARG1-of (d2 / describe-01 :ARG0 (b / bar~e.1 :mod (e / error~e.0)))) # ::id a_pmid_2514_2146.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bar at 1 μM denotes threshold between sensitive and intermediate . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.2 4-1 5-1.2 6-1.2.1 7-1.2.1.1 8-1.2.1 9-1.2.1.2 (d / denote-01~e.4 :ARG0 (b / bar~e.0 :location~e.1 (c / concentration-quantity :quant 1~e.2 :unit (m / micromolar~e.3))) :ARG1 (t / threshold~e.5 :location (b2 / between~e.6,8 :op1 (s / sensitive-03~e.7) :op2 (i / intermediate~e.9)))) # ::id a_pmid_2514_2146.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Resistant cell lines have IC @₅₀ higher than 2 μM . # ::alignments 0-1.2.1 1-1.2 2-1.2 3-1 4-1 6-1.1 9-1.3 10-1.3.1.1 11-1.3.1.2 (h / have-percentage-maximal-inhibitory-concentration-01~e.3,4 :ARG2 50~e.6 :ARG1 (c / cell-line~e.1,2 :ARG0-of (r / resist-01~e.0)) :ARG4 (m2 / more-than~e.9 :op1 (c2 / concentration-quantity :quant 2~e.10 :unit (m / micromolar~e.11)))) # ::id a_pmid_2514_2146.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of SCH722984 on MAPK signaling . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 4-1.2.1.1.1 5-1.2 (a / affect-01~e.0 :ARG0~e.1 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"~e.2)) :ARG1~e.3 (s / signal-07~e.5 :ARG0 (p / pathway :name (n / name :op1 "MAPK"~e.4)))) # ::id a_pmid_2514_2146.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SCH @-@ 722984 @-@ resistant M257 and SCH @-@ 722984 @-@ sensitive M285 , were treated for 24 h with DMSO (-) or 500 nM SCH722984 (+) . # ::alignments 1-1.2.1.2.1.1 3-1.2.1.2.1.1 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 5-1.1.1.1.1 6-1.1 11-1.1.2 11-1.1.2.2 11-1.1.2.2.r 12-1.1.2.1.1 15-1 16-1.3.r 17-1.3.1 18-1.3.2 20-1.2.1.1.1 22-1.2 23-1.2.2.2.1 24-1.2.2.2.2 25-1.2.2.1.1 (t / treat-04~e.15 :ARG1 (a / and~e.6 :op1 (c / cell-line~e.4 :name (n / name :op1 "M257"~e.5) :ARG0-of~e.4 (r / resist-01~e.4 :ARG1 s4)) :op2 (c2 / cell-line~e.11 :name (n2 / name :op1 "M285"~e.12) :ARG0-of~e.11 (s / sensitive-03~e.11 :ARG1 s4))) :ARG2 (o / or~e.22 :op1 (s2 / small-molecule :name (n4 / name :op1 "DMSO"~e.20) :ARG1-of (l / label-01 :ARG2 (s3 / string-entity :value -~e.1,3))) :op2 (s4 / small-molecule :name (n5 / name :op1 "SCH722984"~e.25) :quant (c3 / concentration-quantity :quant 500~e.23 :unit (n3 / nanomolar~e.24)) :ARG1-of (l2 / label-01 :ARG2 (s5 / string-entity :value +)))) :duration~e.16 (t2 / temporal-quantity :quant 24~e.17 :unit (h / hour~e.18))) # ::id a_pmid_2514_2146.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylated or total MEK , ERK 1 @/@ 2 , RSK , AKT or beta @-@ actin as loading control were determined by western blot analysis .

@ @ @ # ::alignments 0-1.1.1.6 1-1.1 1-1.1.1 1-1.1.1.r 1-1.1.2 1-1.1.2.r 2-1.1.2.6 3-1.1.1.1.1.1 3-1.1.2.1.1.1 7-1.1.1.2 7-1.1.2.2 10-1.1.1.3.1.1 10-1.1.2.3.1.1 12-1.1.1.4.1.1 12-1.1.2.4.1.1 13-1.1 14-1.1.1.5.1.1 14-1.1.2.5.1.1 16-1.1.1.5.1.1 16-1.1.2.5.1.1 18-1.1.3.1 19-1.1.3 21-1 22-1.2.r 23-1.2.1 24-1.2.1 25-1.2 (d / determine-01~e.21 :ARG1 (o / or~e.1,13 :op1~e.1 (o2 / or~e.1 :op1 (e / enzyme :name (n / name :op1 "MEK"~e.3)) :op2 (s / slash~e.7 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2"))) :op3 (e4 / enzyme :name (n5 / name :op1 "RSK"~e.10)) :op4 (e5 / enzyme :name (n6 / name :op1 "AKT"~e.12)) :op5 (p / protein :name (n7 / name :op1 "beta-actin"~e.14,16)) :ARG1-of (p2 / phosphorylate-01~e.0)) :op2~e.1 (o3 / or~e.1 :op1 (e6 / enzyme :name (n8 / name :op1 "MEK"~e.3)) :op2 (s2 / slash~e.7 :op1 e2 :op2 e3) :op3 (e9 / enzyme :name (n11 / name :op1 "RSK"~e.10)) :op4 (e10 / enzyme :name (n12 / name :op1 "AKT"~e.12)) :op5 (p3 / protein :name (n13 / name :op1 "beta-actin"~e.14,16)) :mod (t / total~e.2)) :mod (c / control-01~e.19 :ARG1 (l / load-01~e.18))) :manner~e.22 (a / analyze-01~e.25 :manner (i / immunoblot-01~e.23,24))) # ::id a_pmid_2514_2146.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SCH722984 is effective in BRAF @ -@ mutant melanoma with acquired vemurafenib @-@ resistance # ::alignments 0-1.1.1.1 2-1 5-1.2.2.1.1 8-1.2.2 8-1.2.2.2 8-1.2.2.2.r 9-1.2.1.1 11-1.2.3 12-1.2.3.1.2.1.1 14-1.2.3.1 (e / effective-04~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "SCH722984"~e.0)) :location (m / medical-condition :name (n4 / name :op1 "melanoma"~e.9) :mod (g / gene~e.8 :name (n2 / name :op1 "BRAF"~e.5) :ARG2-of~e.8 (m3 / mutate-01~e.8)) :ARG0-of (a / acquire-01~e.11 :ARG1 (r / resist-01~e.14 :ARG0 m :ARG1 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.12)))))) # ::id a_pmid_2514_2146.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The IC @₅₀ of SCH722984 or vemurafenib was next determined in eight BRAF @ -@ mutant vemurafenib @-@ resistant melanoma cell lines ( Figure 4 @ A ) . # ::alignments 1-1.1.1 3-1.1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1.1 7-1.1.1.2 8-1.1.1.2.2.1.1 10-1.2 11-1 12-1.3.r 13-1.3.1 15-1.3.2.1.1 18-1.3.2 18-1.3.2.2 18-1.3.2.2.r 19-1.3.3.1 21-1.3.3 22-1.3.4.1.1 23-1.3 24-1.3 26-1.4.1 (d / determine-01~e.11 :ARG1 (c3 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01~e.1 :ARG2 50~e.3 :ARG1~e.5 (o / or~e.7 :op1 (s / small-molecule :name (n2 / name :op1 "SCH722984"~e.6)) :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.8))))) :time (n4 / next~e.10) :location~e.12 (c / cell-line~e.23,24 :quant 8~e.13 :mod (g / gene~e.18 :name (n5 / name :op1 "BRAF"~e.15) :ARG2-of~e.18 (m5 / mutate-01~e.18)) :ARG0-of (r / resist-01~e.21 :ARG1 s2~e.19) :source (m / medical-condition :name (n / name :op1 "melanoma"~e.22))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26 :mod "4A"))) # ::id a_pmid_2514_2146.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M376 and M398 , two BRAF @/@ NRAS double mutant cell lines derived from the same patient tumors , were highly sensitive to SCH722984 , despite high resistance to vemurafenib . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 4-1.1.3.1.1 6-1.1.3.1.2.1.1.1 7-1.1.3.1.2 8-1.1.3.1.2.2.1.1 10-1.1.3.1.2.3.1 11-1.1.3.1.2.3 12-1.1.3.1 13-1.1.3.1 14-1.1.3.1.3 15-1.1.3.1.3.1.r 17-1.1.3.1.3.1.2 18-1.1.3.1.3.1.1.1.1 19-1.1.3.1.3.1 22-1.3 23-1 24-1.2.r 25-1.2.1.1 27-1.4.r 28-1.3 29-1.4 30-1.4.2.r 31-1.4.2.1.1 (s / sensitive-03~e.23 :ARG0 (a / and~e.1 :op1 (c / cell-line :name (n / name :op1 "M376"~e.0)) :op2 (c2 / cell-line :name (n2 / name :op1 "M398"~e.2)) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line~e.12,13 :quant 2~e.4 :mod (s2 / slash~e.7 :op1 (g / gene :name (n4 / name :op1 "BRAF"~e.6)) :op2 (g2 / gene :name (n5 / name :op1 "NRAS"~e.8)) :ARG2-of (m2 / mutate-01~e.11 :mod (d / double~e.10))) :ARG1-of (d2 / derive-01~e.14 :ARG2~e.15 (t / tumor~e.19 :poss (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.18))) :ARG1-of (s3 / same-01~e.17 :ARG3 p)))))) :ARG1~e.24 (s4 / small-molecule :name (n3 / name :op1 "SCH722984"~e.25)) :ARG1-of (h / high-02~e.22,28) :concession~e.27 (r / resist-01~e.29 :ARG0 a :ARG1~e.30 (s5 / small-molecule :name (n6 / name :op1 "vemurafenib"~e.31) :ARG1-of h))) # ::id a_pmid_2514_2146.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M376 is a spontaneously arising double mutant , whereas M398 was established from tumor from the same patient upon progression on vemurafenib . # ::alignments 0-1.1.1.1.1 3-1.1.1.2.1 3-1.1.1.2.1.r 4-1.1.1.2 5-1.1.2 6-1.1 8-1 9-1.2.2.1.1 11-1.2 12-1.2.3.r 13-1.2.3 14-1.2.3.1.r 14-1.2.3.r 16-1.2.3.1 16-1.2.3.1.2 16-1.2.3.1.2.r 17-1.2.3.1.1.1 19-1.2.1 20-1.2.1.1.r 21-1.2.1.1.1.1 (c / contrast-01~e.8 :ARG1 (m / mutate-01~e.6 :ARG2 (c2 / cell-line :name (n / name :op1 "M376"~e.0) :ARG1-of (a / arise-02~e.4 :manner~e.3 (s / spontaneous~e.3))) :mod (d / double~e.5)) :ARG2 (e / establish-01~e.11 :ARG0 (p3 / progress-01~e.19 :ARG1~e.20 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.21))) :ARG1 (c3 / cell-line :name (n2 / name :op1 "M398"~e.9)) :source~e.12,14 (t / tumor~e.13 :source~e.14 (p / person~e.16 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.17)) :ARG1-of~e.16 (s2 / same-01~e.16))))) # ::id a_pmid_2514_2146.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to their isogenic parental cell lines , potent growth inhibition with SCH772984 was also seen for three BRAF @ ^{V600E @} mutant melanoma cell lines with in vitro @ -@ derived vemurafenib resistance ( polyclonal population ) : M395AR , M397AR , and M249AR4 . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.1 2-1.4.1.1.r 3-1.4.1.2 4-1.4.1.3 5-1.4.1 6-1.4.1 8-1.1.3 9-1.1.2 10-1.1 11-1.1.1.r 12-1.1.1.1.1 14-1.2 15-1 16-1.3.r 17-1.3.1 19-1.3.2.1.1 23-1.3.2.2.1 26-1.3.2 26-1.3.2.2 26-1.3.2.2.r 27-1.3.5.1.1 28-1.3 29-1.3 32-1.3.3.2.1 33-1.3.3.2.1 36-1.3.3.2 37-1.3.3.1.1.1 38-1.3.3 41-1.3.6.1 44-1.3.4.1.1.1.1 46-1.3.4.1.2.1.1 48-1.3.4.1 49-1.3.4.1.3.1.1 (s / see-01~e.15 :ARG1 (i / inhibit-01~e.10 :ARG0~e.11 (s2 / small-molecule :name (n / name :op1 "SCH772984"~e.12)) :ARG1 (g / grow-01~e.9) :mod (p / potent~e.8)) :mod (a / also~e.14) :location~e.16 (c / cell-line~e.28,29 :quant 3~e.17 :mod (g2 / gene~e.26 :name (n2 / name :op1 "BRAF"~e.19) :ARG2-of~e.26 (m3 / mutate-01~e.26 :value "V600E"~e.23)) :ARG0-of (r2 / resist-01~e.38 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.37)) :ARG1-of (d / derive-01~e.36 :ARG2 (i2 / in-vitro~e.32,33))) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and~e.48 :op1 (c3 / cell-line :name (n4 / name :op1 "M395AR"~e.44)) :op2 (c4 / cell-line :name (n5 / name :op1 "M397AR"~e.46)) :op3 (c5 / cell-line :name (n6 / name :op1 "M249AR4"~e.49)))) :source (m / medical-condition :name (n7 / name :op1 "melanoma"~e.27)) :ARG1-of (d3 / describe-01 :ARG2 (p3 / population~e.41 :mod (p4 / polyclone)))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (c2 / cell-line~e.5,6 :poss~e.2 (t / they~e.2) :mod (i3 / isogenic~e.3) :mod (p2 / parental~e.4)))) # ::id a_pmid_2514_2146.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previously data demonstrated that these cell lines reactivate the MAPK pathway via generation of BRAF splice variants ( M395AR and M397AR ) [ @ 7 , 24 @ ] , or via secondary NRAS mutation ( M249AR4 ) [ @ 6 @ ] . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1 5-1.2.1 6-1.2.1 7-1.2 9-1.2.2.1.1 10-1.2.2 12-1.2.3.1 13-1.2.3.1.1.r 14-1.2.3.1.1.1.1.1.1.1 15-1.2.3.1.1.1.1 16-1.2.3.1.1 18-1.2.3.1.3.1.1.1.1 19-1.2.3.1.3.1 20-1.2.3.1.3.1.2.1.1 24-1.2.3.1.2.1.1.1.1 28-1.2.3.1.2.1.2.1.1 32-1.2.3 34-1.2.3.2.2 36-1.2.3.2.1.1.1 38-1.2.3.2 40-1.2.3.2.4.1.1.1 44-1.2.3.2.3.1.1.1 (d / demonstrate-01~e.2 :ARG0 (d2 / data~e.1 :mod (p2 / previous~e.0)) :ARG1~e.3 (r / reactivate-01~e.7 :ARG0 (c / cell-line~e.5,6 :mod (t / this~e.4)) :ARG1 (p / pathway~e.10 :name (n / name :op1 "MAPK"~e.9)) :manner (o / or~e.32 :op1 (g / generate-01~e.12 :ARG1~e.13 (v / variant~e.16 :ARG2-of (r2 / result-01 :ARG1 (s / splice-01~e.15 :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF"~e.14))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 7~e.24)) :op2 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 24~e.28)))) :ARG1-of (m / mean-01 :ARG2 (a / and~e.19 :op1 (c5 / cell-line :name (n3 / name :op1 "M395AR"~e.18)) :op2 (c6 / cell-line :name (n4 / name :op1 "M397AR"~e.20))))) :op2 (m2 / mutate-01~e.38 :ARG1 (g2 / gene :name (n5 / name :op1 "NRAS"~e.36)) :mod (s2 / secondary~e.34) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 6~e.44))) :ARG1-of (m3 / mean-01 :ARG2 (c7 / cell-line :name (n6 / name :op1 "M249AR4"~e.40))))))) # ::id a_pmid_2514_2146.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , M229AR9 , M238AR2 and M409AR1 remained highly resistant to SCH722984 with IC50 s > 2 uM . # ::alignments 1-1 3-1.1.1.1.1.1 5-1.1.1.2.1.1 6-1.1.1 7-1.1.1.3.1.1 8-1.1 9-1.1.2.3 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2.1.1 16-1.1.2.2.2.2 17-1.1.2.2.2.2.1.1 (c / contrast-01~e.1 :ARG2 (r / remain-01~e.8 :ARG1 (a / and~e.6 :op1 (c2 / cell-line :name (n / name :op1 "M229AR9"~e.3)) :op2 (c3 / cell-line :name (n2 / name :op1 "M238AR2"~e.5)) :op3 (c4 / cell-line :name (n3 / name :op1 "M409AR1"~e.7))) :ARG3 (r2 / resist-01~e.10 :ARG0 a :ARG1~e.11 (s / small-molecule :name (n4 / name :op1 "SCH722984"~e.12) :ARG1-of (c6 / concentrate-02 :mod (i / inhibit-01 :degree (p / percentage-entity :value 50)) :quant (m2 / more-than~e.16 :op1 (c5 / concentration-quantity :quant 2~e.17 :unit (m / micromolar))))) :ARG1-of (h / high-02~e.9)))) # ::id a_pmid_2514_2146.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For M229AR9 and M238AR2 upregulation of RTK is the mechanism of vemurafenib resistance [ @ 6 @ ] . # ::alignments 1-1.2.1.1.1.1 2-1.2.1 3-1.2.1.2.1.1 4-1.1 5-1.1.1.r 6-1.1.1.1.1 7-1.1.r 9-1 11-1.2.2.1.1 12-1.2 15-1.3.1.1.1 (m / mechanism~e.9 :domain~e.7 (u / upregulate-01~e.4 :ARG1~e.5 (e / enzyme :name (n / name :op1 "RTK"~e.6))) :mod (r / resist-01~e.12 :ARG0 (a / and~e.2 :op1 (c / cell-line :name (n2 / name :op1 "M229AR9"~e.1)) :op2 (c2 / cell-line :name (n3 / name :op1 "M238AR2"~e.3))) :ARG1 (s / small-molecule :name (n4 / name :op1 "vemurafenib"~e.11))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 6~e.15)))) # ::id a_pmid_2514_2146.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mechanism of resistance for M409AR is unknown at this time , and studies are ongoing to delineate the mechanism underlying BRAFi @-@ resistance . @ Figure 4 @

SCH722984 in BRAF @-@ mutant melanoma cell lines with vemurafenib @-@ acquired resistance . # ::alignments 1-1.1.1.2 2-1.1.1.2.1.r 3-1.1.1.2.1 4-1.1.1.2.1.1.r 5-1.1.1.2.1.1.1.1 7-1.1.1 7-1.1.1.1 7-1.1.1.1.r 9-1.1.1.3 10-1.1.1.3.r 12-1.1 13-1.1.2.1 15-1.1.2 17-1.1.2.2 19-1.1.2.2.2 20-1.1.2.2.2.1 23-1.1.2.2.2.1.1 27-1.2.3.1 28-1.2.3.1.1 33-1.2.1.1 35-1.1.2.2.2.1.1.1.1.1.1.1 35-1.2.2.1.1.1 37-1.2.2.1 37-1.2.2.1.2 37-1.2.2.1.2.r 38-1.2.2.2.1.1 39-1.2.2 40-1.2.2 41-1.2.2.3.r 42-1.2.2.3.1.1.1 44-1.2.2.3.2 45-1.2.2.3 (m / multi-sentence :snt1 (a / and~e.12 :op1 (k / know-01~e.7 :polarity~e.7 -~e.7 :ARG1 (m2 / mechanism~e.1 :mod~e.2 (r / resist-01~e.3 :ARG0~e.4 (c / cell-line :name (n / name :op1 "M409AR"~e.5)))) :time~e.10 (t / this~e.9)) :op2 (g / go-on-15~e.15 :ARG1 (s / study-01~e.13) :purpose (d / delineate-01~e.17 :ARG0 s :ARG1 (m3 / mechanism~e.19 :ARG0-of (u / underlie-01~e.20 :ARG1 (r2 / resist-01~e.23 :ARG1 (m4 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF"~e.35)))))))))) :snt2 (s2 / small-molecule :name (n3 / name :op1 "SCH722984"~e.33) :location (c2 / cell-line~e.39,40 :mod (g2 / gene~e.37 :name (n4 / name :op1 "BRAF"~e.35) :ARG2-of~e.37 (m5 / mutate-01~e.37)) :source (m6 / medical-condition :name (n5 / name :op1 "melanoma"~e.38)) :ARG0-of~e.41 (r3 / resist-01~e.45 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"~e.42)) :ARG1-of (a2 / acquire-01~e.44))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.27 :mod 4~e.28)))) # ::id a_pmid_2514_2146.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IC @₅₀ ( nM ) to SCH @-@ 722984 or vemurafenib . # ::alignments 0-1 2-1.1 5-1.3.1 11-1.2 12-1.2.2.1.1 (h / have-percentage-maximal-inhibitory-concentration-01~e.0 :ARG2 50~e.2 :ARG1 (o / or~e.11 :op1 (s / small-molecule :name (n / name :op1 "SCH722984")) :op2 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib"~e.12))) :ARG4 (c2 / concentration-quantity :unit (n3 / nanomolar~e.5))) # ::id a_pmid_2514_2146.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M398 and M376 , two melanoma cell lines established from tumors progressing on vemurafenib , as well as six parental BRAF mutant melanoma cell lines and their paired in vitro derived vemurafenib @-@ acquired resistance sublines ( AR ) were grown in the presence of 0 @–@ 10 μM SCH @-@ 722984 ( black bars ) or vemurafenib ( grey bars ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 4-1.1.1.3.1.1 5-1.1.1.3.1.3.1.1 6-1.1.1.3.1 7-1.1.1.3.1 8-1.1.1.3.1.2 9-1.1.1.3.1.2.1.r 10-1.1.1.3.1.2.1 11-1.1.1.3.1.2.1.1 13-1.1.1.3.1.2.1.1.1.1 15-1.1.1 16-1.1.1 17-1.1.1 18-1.1.2.1 19-1.1.2.2 21-1.1.2.3.1.1 23-1.1.2.3 23-1.1.2.3.2 23-1.1.2.3.2.r 24-1.1.2.4 25-1.1.2 26-1.1.2 27-1.1 27-1.1.1 27-1.1.1.r 28-1.1.3.1 28-1.1.3.1.r 29-1.1.3.2 31-1.1.3.3.1.3.1 32-1.1.3.3.1.3.1 34-1.1.3.3.1.3 35-1.2.2.1.1.1 37-1.1.3.3 38-1.1.3.3.1 44-1 45-1.1.3.3.1.3.1 47-1.2.1 47-1.2.2 48-1.2.1.1.r 49-1.2.1.1.2.1.1 51-1.2.1.1.2.1.2 52-1.2.1.1.2.2 57-1.2.1.2.1.1 58-1.2.1.2.1 60-1.2 61-1.2.2.1.1.1 63-1.2.2.2.1.1 64-1.2.2.2.1 (g / grow-03~e.44 :ARG1 (a / and~e.27 :op1~e.27 (a2 / and~e.1,15,16,17,27 :op1 (c / cell-line :name (n / name :op1 "M398"~e.0)) :op2 (c2 / cell-line :name (n2 / name :op1 "M376"~e.2)) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line~e.6,7 :quant 2~e.4 :ARG1-of (e / establish-01~e.8 :source~e.9 (t / tumor~e.10 :ARG1-of (p / progress-01~e.11 :ARG1-of (c4 / cause-01 :ARG0 s2~e.13)))) :source (m4 / medical-condition :name (n6 / name :op1 "melanoma"~e.5))))) :op2 (c5 / cell-line~e.25,26 :quant 6~e.18 :mod (p2 / parental~e.19) :mod (g2 / gene~e.23 :name (n4 / name :op1 "BRAF"~e.21) :ARG2-of~e.23 (m3 / mutate-01~e.23)) :source m4~e.24) :op3 (s / subline :poss~e.28 c5~e.28 :ARG1-of (p3 / pair-01~e.29) :ARG0-of (a3 / acquire-01~e.37 :ARG1 (r / resist-01~e.38 :ARG0 s :ARG1 s2 :ARG1-of (d / derive-01~e.34 :ARG2 (i / in-vitro~e.31,32,45)))))) :condition (o / or~e.60 :op1 (p4 / present-02~e.47 :ARG1~e.48 (s3 / small-molecule :name (n5 / name :op1 "SCH722984") :mod (c6 / concentration-quantity :quant (v / value-interval :op1 0~e.49 :op2 10~e.51) :unit (m2 / micromolar~e.52))) :ARG1-of (d2 / describe-01 :ARG0 (b / bar~e.58 :ARG1-of (b2 / black-04~e.57)))) :op2 (p5 / present-02~e.47 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.35,61) :quant v) :ARG1-of (d3 / describe-01 :ARG0 (b3 / bar~e.64 :ARG1-of (g3 / gray-02~e.63)))))) # ::id a_pmid_2514_2146.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Values are mean of three experiments , performed in duplicate ( n = 6 ) . # ::alignments 0-1.1 1-1.1.r 2-1 2-1.2.3 3-1.2.2.1 4-1.2.1 5-1.2 7-1.2.2 13-1.2.3.1.1 (m / mean~e.2 :domain~e.1 (v / value~e.0) :mod (e / experiment-01~e.5 :quant 3~e.4 :ARG1-of (p / perform-01~e.7 :frequency (p2 / product-of~e.3 :op1 2)) :ARG1-of (m2 / mean-01~e.2 :ARG2 (e2 / equal-01 :ARG2 6~e.13 :ARG1 e)))) # ::id a_pmid_2514_2146.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Error bars are standard deviation . # ::alignments 0-1.2.1.1 1-1.2.1 3-1.1 4-1 (d / deviate-01~e.4 :ARG1-of (s / standard-02~e.3) :ARG1-of (d2 / describe-01 :ARG0 (b / bar~e.1 :mod (e / error~e.0)))) # ::id a_pmid_2514_2146.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bar at 1 μM denotes threshold between sensitive and intermediate . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.2 4-1 5-1.2 6-1.2.1 7-1.2.1.1 8-1.2.1 9-1.2.1.2 (d / denote-01~e.4 :ARG0 (b / bar~e.0 :location~e.1 (c / concentration-quantity :quant 1~e.2 :unit (m / micromolar~e.3))) :ARG1 (t / threshold~e.5 :location (b2 / between~e.6,8 :op1 (s / sensitive-03~e.7) :op2 (i / intermediate~e.9)))) # ::id a_pmid_2514_2146.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Resistant cell lines have IC @₅₀ higher than 2 μM . # ::alignments 0-1.2.1 1-1.2 2-1.2 3-1 4-1 6-1.1 9-1.3 10-1.3.1.1 11-1.3.1.2 (h / have-percentage-maximal-inhibitory-concentration-01~e.3,4 :ARG2 50~e.6 :ARG1 (c3 / cell-line~e.1,2 :ARG0-of (r / resist-01~e.0)) :ARG4 (m / more-than~e.9 :op1 (c2 / concentration-quantity :quant 2~e.10 :unit (m2 / micromolar~e.11)))) # ::id a_pmid_2514_2146.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok *: BRAF @/@ NRAS double mutant , **: BRAF @-@ splice variant , §: Receptor tyrosine kinase upreguation , +: resistance mechanism unknown . # ::alignments 1-1.1.1.1.1 1-1.2.1.1.1.1.1 2-1.1 3-1.1.2.1.1 4-1.1.3.1 5-1.1.3 8-1.1.1.1.1 8-1.2.1.1.1.1.1 10-1.2.1.1 11-1.2 14-1.3.1.1.1 15-1.3.1.1.2 16-1.3.1.1.3 20-1.4.2 21-1.4 22-1.4.1 22-1.4.1.1 22-1.4.1.1.r (m / multi-sentence :snt1 (s / slash~e.2 :op1 (e2 / enzyme :name (n / name :op1 "BRAF"~e.1,8)) :op2 (e3 / enzyme :name (n2 / name :op1 "NRAS"~e.3)) :ARG2-of (m2 / mutate-01~e.5 :mod (d / double~e.4))) :snt2 (v / variant~e.11 :ARG2-of (r / result-01 :ARG1 (s2 / splice-01~e.10 :ARG1 (e4 / enzyme :name (n3 / name :op1 "BRAF"~e.1,8))))) :snt3 (u / upregulate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "receptor"~e.14 :op2 "tyrosine"~e.15 :op3 "kinase"~e.16))) :snt4 (m3 / mechanism~e.21 :ARG1-of (k2 / know-01~e.22 :polarity~e.22 -~e.22) :mod (r2 / resist-01~e.20))) # ::id a_pmid_2514_2146.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effect of SCH722984 on MAPK signaling . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 4-1.2.1.1.1 5-1.2 (a / affect-01~e.0 :ARG0~e.1 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"~e.2)) :ARG1~e.3 (s / signal-07~e.5 :ARG0 (p / pathway :name (n / name :op1 "MAPK"~e.4)))) # ::id a_pmid_2514_2146.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis was performed to evaluate the effect of 24 hour exposure to 500 nM SCH&22984 (+) or DMSO (-) on phospho @- or total MEK , ERK 1 @/@ 2 , RSK , AKT or beta @-@ actin as loading control .

@ @ @ # ::alignments 0-1.1.1 1-1.1.1 2-1.1 4-1 6-1.2 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.3.1 11-1.2.1.1.3.2 12-1.2.1.1 13-1.2.1.1.2.r 14-1.2.1.1.2.1.2.1 15-1.2.1.1.2.1.2.2 18-1.2.1.1.2 19-1.2.1.1.2.2.1.1 22-1.2.1.1.1.1.6 23-1.2.1.1.2.2.2.1.1 24-1.2.1.1.1 24-1.2.1.1.1.1 24-1.2.1.1.1.1.r 24-1.2.1.1.1.2 24-1.2.1.1.1.2.r 25-1.2.1.1.1.2.6 26-1.2.1.1.1.1.1.1.1 26-1.2.1.1.1.2.1.1.1 30-1.2.1.1.1.1.2 30-1.2.1.1.1.2.2 33-1.2.1.1.1.1.3.1.1 33-1.2.1.1.1.2.3.1.1 35-1.2.1.1.1.1.4.1.1 35-1.2.1.1.1.2.4.1.1 36-1.2.1.1.1 37-1.2.1.1.1.1.5.1.1 37-1.2.1.1.1.2.5.1.1 39-1.2.1.1.1.1.5.1.1 39-1.2.1.1.1.2.5.1.1 40-1.2.1.1.1.r 41-1.2.1.1.1.3.1 42-1.2.1.1.1.3 (p / perform-01~e.4 :ARG1 (a2 / analyze-01~e.2 :manner (i / immunoblot-01~e.0,1)) :purpose (e3 / evaluate-01~e.6 :ARG1 (a / affect-01~e.8 :ARG0~e.9 (e4 / expose-01~e.12 :ARG1~e.40 (o2 / or~e.24,36 :op1~e.24 (o3 / or~e.24 :op1 (e / enzyme :name (n2 / name :op1 "MEK"~e.26)) :op2 (s2 / slash~e.30 :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1")) :op2 (e5 / enzyme :name (n7 / name :op1 "ERK2"))) :op3 (e6 / enzyme :name (n8 / name :op1 "RSK"~e.33)) :op4 (e7 / enzyme :name (n9 / name :op1 "AKT"~e.35)) :op5 (p2 / protein :name (n10 / name :op1 "beta-actin"~e.37,39)) :ARG3-of (p3 / phosphorylate-01~e.22)) :op2~e.24 (o4 / or~e.24 :op1 (e10 / enzyme :name (n14 / name :op1 "MEK"~e.26)) :op2 (s3 / slash~e.30 :op1 e2 :op2 e5) :op3 (e9 / enzyme :name (n13 / name :op1 "RSK"~e.33)) :op4 (e8 / enzyme :name (n12 / name :op1 "AKT"~e.35)) :op5 (p4 / protein :name (n11 / name :op1 "beta-actin"~e.37,39)) :mod (t / total~e.25)) :manner (c2 / control-01~e.42 :ARG1 (l / load-01~e.41))) :ARG2~e.13 (o / or~e.18 :op1 (s4 / small-molecule :name (n / name :op1 "SCH722984") :quant (c / concentration-quantity :quant 500~e.14 :unit (n4 / nanomolar~e.15)) :ARG1-of (l2 / label-01 :ARG2 (s5 / string-entity :value +))) :op2 (s / small-molecule :name (n6 / name :op1 "DMSO"~e.19) :ARG1-of (l3 / label-01 :ARG2 (s6 / string-entity :value -~e.23)))) :duration (t3 / temporal-quantity :quant 24~e.10 :unit (h2 / hour~e.11)))))) # ::id a_pmid_2514_2146.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the signaling for other sensitive cell lines , all three BRAF @/@ NRAS double mutants ( M376 , M398 , M249AR4 ) displayed decreased pRSK and pERK1 @/@ 2 at 24 hours with no detectable change in pMEK . # ::alignments 0-1 1-1.2.r 3-1.2 5-1.2.1.1 6-1.2.1.2 7-1.2.1 8-1.1.1 8-1.2.1 10-1.1.1.4 11-1.1.1.1 13-1.1.1.2.1.1.1 14-1.1.1.2 15-1.1.1.2.2.1.1 17-1.1.1.2.3.1 18-1.1.1.2.3 20-1.1.1.3.1.1.1.1 22-1.1.1.3.1.2.1.1 24-1.1.1.3.1.3.1.1 26-1.1 27-1.1.2.1.4 28-1.1.2.1.1.1.1 28-1.1.2.1.3 29-1.1.2.1 31-1.1.2.1.2 34-1.1.2.1.5.1.1 35-1.1.2.1.5.1.2 37-1.1.2.2.1 37-1.1.2.2.1.r 38-1.1.2.2.2 39-1.1.2.2.2.1 (c / consistent-01~e.0 :ARG1 (d / display-01~e.26 :ARG0 (c3 / cell-line~e.8 :quant 3~e.11 :mod (s3 / slash~e.14 :op1 (g / gene :name (n / name :op1 "BRAF"~e.13)) :op2 (g2 / gene :name (n2 / name :op1 "NRAS"~e.15)) :ARG2-of (m / mutate-01~e.18 :mod (d2 / double~e.17))) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c4 / cell-line :name (n3 / name :op1 "M376"~e.20)) :op2 (c5 / cell-line :name (n4 / name :op1 "M398"~e.22)) :op3 (c6 / cell-line :name (n5 / name :op1 "M249AR4"~e.24)))) :mod (a2 / all~e.10)) :ARG1 (a5 / and :op1 (a3 / and~e.29 :op1 (e / enzyme :name (n6 / name :op1 "RSK"~e.28)) :op2 (s4 / slash~e.31 :op1 (e2 / enzyme :name (n7 / name :op1 "ERK1")) :op2 (e3 / enzyme :name (n8 / name :op1 "ERK2"))) :ARG3-of (p / phosphorylate-01~e.28) :ARG1-of (d3 / decrease-01~e.27) :time (a4 / after :op1 (t / temporal-quantity :quant 24~e.34 :unit (h / hour~e.35)))) :op2 (p2 / possible-01 :polarity~e.37 -~e.37 :ARG1 (d4 / detect-01~e.38 :ARG1 (c7 / change-01~e.39 :ARG1 (e4 / enzyme :name (n9 / name :op1 "MEK") :ARG3-of p)))))) :ARG2~e.1 (s / signal-07~e.3 :ARG1 (c2 / cell-line~e.7,8 :mod (o / other~e.5) :ARG0-of (s2 / sensitive-03~e.6)))) # ::id a_pmid_2514_2146.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the paired parental and acquired @-@ resistance cell lines , treatment of the parental cell lines ( M397 , M249 , M229 , M238 and M409 ) with SCH722984 resulted in disappearance of pRSK , decrease in pERK1 @/@ 2 . # ::alignments 2-1.3.3 3-1.1.1.6 4-1.1.1 4-1.3 5-1.3.2.1 7-1.3.2.1.1 8-1.3.2 9-1.3.2 11-1.1 14-1.3.1.1 15-1.3.1 16-1.3.1 18-1.1.1.1.1.1 20-1.1.1.2.1.1 22-1.1.1.3.1.1 24-1.1.1.4.1.1 26-1.1.1.5.1.1 28-1.1.2.r 29-1.1.2.1.1 30-1 31-1.2.r 32-1.2.1 33-1.2.1.1.r 34-1.2.1.1.1.1 34-1.2.1.1.2 36-1.2.2 39-1.2.2.1 (r / result-01~e.30 :ARG1 (t / treat-04~e.11 :ARG1 (a / and~e.4 :op1 (c / cell-line :name (n / name :op1 "M397"~e.18)) :op2 (c2 / cell-line :name (n2 / name :op1 "M249"~e.20)) :op3 (c3 / cell-line :name (n3 / name :op1 "M229"~e.22)) :op4 (c4 / cell-line :name (n4 / name :op1 "M238"~e.24)) :op5 (c5 / cell-line :name (n5 / name :op1 "M409"~e.26)) :mod (p / parental~e.3)) :ARG2~e.28 (s2 / small-molecule :name (n9 / name :op1 "SCH722984"~e.29))) :ARG2~e.31 (a2 / and :op1 (d / disappear-01~e.32 :ARG1~e.33 (e / enzyme :name (n6 / name :op1 "RSK"~e.34) :ARG3-of (p2 / phosphorylate-01~e.34))) :op2 (d2 / decrease-01~e.36 :ARG1 (s / slash~e.39 :op1 (e2 / enzyme :name (n7 / name :op1 "ERK1")) :op2 (e3 / enzyme :name (n8 / name :op1 "ERK2")) :ARG3-of p2))) :location (a3 / and~e.4 :op1 (c6 / cell-line~e.15,16 :mod p~e.14) :op2 (c7 / cell-line~e.8,9 :ARG0-of (a4 / acquire-01~e.5 :ARG1 (r2 / resist-01~e.7))) :ARG1-of (p3 / pair-01~e.2))) # ::id a_pmid_2514_2146.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , we observed again upregulation of pAKT levels after treatment with SCH772984 in M398 , M376 , M397AR , M249AR4 , and M409AR1 , suggesting a rapid upregulation of the PI3K/AKT/mTOR pathway . # ::alignments 0-1.6 2-1.1 3-1 4-1.3 5-1.2 6-1.2.1.r 7-1.2.1.1.1.1 7-1.2.1.1.2 8-1.2.1 9-1.4 10-1.4.1 11-1.4.1.2.r 12-1.4.1.2.1.1 13-1.4.1.1.r 14-1.4.1.1.1.1.1 16-1.4.1.1.2.1.1 18-1.4.1.1.3.1.1 20-1.4.1.1.4.1.1 22-1.4.1.1 23-1.4.1.1.5.1.1 25-1.5 27-1.5.1.2 28-1.5.1 29-1.5.1.1.r 31-1.5.1.1.1.1 32-1.5.1.1 (o / observe-01~e.3 :ARG0 (w / we~e.2) :ARG1 (u / upregulate-01~e.5 :ARG1~e.6 (l / level~e.8 :quant-of (e / enzyme :name (n / name :op1 "AKT"~e.7) :ARG3-of (p / phosphorylate-01~e.7)))) :mod (a / again~e.4) :time (a2 / after~e.9 :op1 (t / treat-04~e.10 :ARG1~e.13 (a3 / and~e.22 :op1 (c / cell-line :name (n3 / name :op1 "M398"~e.14)) :op2 (c2 / cell-line :name (n4 / name :op1 "M376"~e.16)) :op3 (c3 / cell-line :name (n5 / name :op1 "M397AR"~e.18)) :op4 (c4 / cell-line :name (n6 / name :op1 "M249AR4"~e.20)) :op5 (c5 / cell-line :name (n7 / name :op1 "M409AR1"~e.23))) :ARG2~e.11 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"~e.12)))) :ARG0-of (s / suggest-01~e.25 :ARG1 (u2 / upregulate-01~e.28 :ARG1~e.29 (p2 / pathway~e.32 :name (n8 / name :op1 "PI3K/AKT/mTOR"~e.31)) :mod (r / rapid~e.27))) :ARG2-of (i / interest-01~e.0)) # ::id a_pmid_2514_2146.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This suggests that dual inhibition with SCH772984 and an AKT or mTOR inhibitor may result in more potent growth inhibition . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.2 4-1.2.1.1 5-1.2.1.1.1.r 6-1.2.1.1.1.1.1.1 7-1.2.1.1.1 9-1.2.1.1.1.2.1.1.1.1.1 10-1.2.1.1.1.2.1.1 11-1.2.1.1.1.2.1.1.2.1.1 12-1.2.1.1.1.2 12-1.2.1.1.1.2.1 12-1.2.1.1.1.2.1.r 12-1.2.1.2 13-1.2 14-1.2.1 16-1.2.1.2.2.1 17-1.2.1.2.2 18-1.2.1.2.1 19-1.2.1.2 (s / suggest-01~e.1 :ARG0 (t / this~e.0) :ARG1~e.2 (p / possible-01~e.13 :ARG1 (r / result-01~e.14 :ARG1 (i / inhibit-01~e.4 :ARG0~e.5 (a / and~e.7 :op1 (s2 / small-molecule :name (n / name :op1 "SCH772984"~e.6)) :op2 (m2 / molecular-physical-entity~e.12 :ARG0-of~e.12 (i3 / inhibit-01~e.12 :ARG1 (o / or~e.10 :op1 (p2 / protein-family :name (n2 / name :op1 "AKT"~e.9)) :op2 (p4 / protein :name (n3 / name :op1 "mTOR"~e.11)))))) :mod (d / dual~e.3)) :ARG2 (i2 / inhibit-01~e.12,19 :ARG1 (g / grow-01~e.18) :mod (p3 / potent~e.17 :degree (m / more~e.16)))))) # ::id a_pmid_2514_2146.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For M397AR and M249AR4 , the disappearance of pERK was robust . # ::alignments 1-1.2.1.1.1 2-1.2 3-1.2.2.1.1 6-1.1 7-1.1.1.r 8-1.1.1.1.1 8-1.1.1.2 9-1.1.r 10-1 (r / robust~e.10 :domain~e.9 (d / disappear-01~e.6 :ARG1~e.7 (e / enzyme :name (n3 / name :op1 "ERK"~e.8) :ARG3-of (p / phosphorylate-01~e.8))) :location (a / and~e.2 :op1 (c / cell-line :name (n / name :op1 "M397AR"~e.1)) :op2 (c2 / cell-line :name (n2 / name :op1 "M249AR4"~e.3)))) # ::id a_pmid_2514_2146.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , for the resistant M229AR9 , M238AR2 and M409AR1 , though treatment with SCH772984 resulted in disappearance of pRSK , pMEK appeared to be induced and pERK1 @/@ 2 remained almost unchanged ( Figure 4 @ B ) . # ::alignments 1-1 1-1.1 1-1.1.r 6-1.1.1.1.1.1.1.1 8-1.1.1.1.1.2.1.1 9-1.1.1.1.1 10-1.1.1.1.1.3.1.1 13-1.1.1.1 14-1.1.1.1.2.r 15-1.1.1.1.2.1.1 16-1.1.1 17-1.1.1.2.r 18-1.1.1.2 20-1.1.1.2.1.1.2 20-1.1.1.2.1.2.1.1 23-1.1.2 26-1.1.2.1.1 27-1.1.2.1 30-1.1.2.1.2.1.2.1.1 31-1.1.2.1.2 32-1.1.2.1.2.1.3 33-1.1.2.1.2.1 33-1.1.2.1.2.1.1 33-1.1.2.1.2.1.1.r 35-1.2.1 (c / contrast-01~e.1 :ARG2~e.1 (c2 / contrast-01~e.1 :ARG1 (r2 / result-01~e.16 :ARG1 (t / treat-04~e.13 :ARG1 (a4 / and~e.9 :op1 (c5 / cell-line :name (n4 / name :op1 "M229AR9"~e.6)) :op2 (c6 / cell-line :name (n5 / name :op1 "M238AR2"~e.8)) :op3 (c7 / cell-line :name (n6 / name :op1 "M409AR1"~e.10))) :ARG2~e.14 (s / small-molecule :name (n3 / name :op1 "SCH772984"~e.15))) :ARG2~e.17 (d2 / disappear-01~e.18 :ARG1 (a5 / and :op1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01~e.20)) :op2 (e3 / enzyme :name (n7 / name :op1 "RSK"~e.20) :ARG3-of p)))) :ARG2 (a / appear-02~e.23 :ARG1 (a2 / and~e.27 :op1 (i / induce-01~e.26 :ARG2 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG3-of p)) :op2 (r / remain-01~e.31 :ARG3 (c3 / change-01~e.33 :polarity~e.33 -~e.33 :ARG1 (e4 / enzyme :name (n8 / name :op1 "ERK1/2"~e.30) :ARG3-of p) :degree (a3 / almost~e.32)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "4B"))) # ::id a_pmid_2514_2146.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Synergistic inhibition with combination BRAF and ERK inhibition # ::alignments 0-1.1 1-1 1-1.2.1 1-1.2.2 3-1.2 4-1.2.1.1.1.1 6-1.2.2.1.1.1 7-1 (i3 / inhibit-01~e.1,7 :ARG0-of (s / synergize-01~e.0) :manner (c / combine-01~e.3 :ARG1 (i / inhibit-01~e.1 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.4))) :ARG2 (i2 / inhibit-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.6))))) # ::id a_pmid_2514_2146.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next determined whether combining BRAF and ERK inhibition could result in synergistic inhibition by dual MAPK pathway inhibition . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.1.r 4-1.2.2.1 5-1.2.2.1.1.1.1.1.1 6-1.2.2.1.1 7-1.2.2.1.1.2.1.1.1 8-1.2.2.1.1.1 8-1.2.2.1.1.2 8-1.2.2.2 9-1.2 10-1.2.2 11-1.2.2.2.r 12-1.2.2.2.1 13-1.2.2.2 14-1.2.2.3.r 15-1.2.2.3.2 16-1.2.2.3.1.1.1 17-1.2.2.3.1 18-1.2.2.3 (d / determine-01~e.2 :ARG0 (w / we~e.0) :ARG1 (p3 / possible-01~e.9 :mode~e.3 interrogative~e.3 :ARG1 (r / result-01~e.10 :ARG1 (c / combine-01~e.4 :ARG1 (a / and~e.6 :op1 (i / inhibit-01~e.8 :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF"~e.5))) :op2 (i2 / inhibit-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.7))))) :ARG2~e.11 (i3 / inhibit-01~e.8,13 :ARG0-of (s / synergize-01~e.12)) :manner~e.14 (i4 / inhibit-01~e.18 :ARG1 (p2 / pathway~e.17 :name (n2 / name :op1 "MAPK"~e.16)) :mod (d2 / dual~e.15)))) :mod (n3 / next~e.1)) # ::id a_pmid_2514_2146.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of M238 and M792 , two BRAF @ ^{V600E @}@ -@ mutant melanoma cell lines highly sensitive to singular treatment with vemurafenib and SCH772984 , with equimolar concentrations of combined vemurafenib and SCH772984 treatment resulted in potent synergistic growth inhibition with IC @₅₀ of 10 nM ( Figure 5 @ A , 5 @ B ) . # ::alignments 0-1.1.1.3.1.3.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 6-1.1.1.3.1.1 8-1.1.1.3.1.2.1.1 12-1.1.1.3.1.2.2.1 16-1.1.1.3.1.2 16-1.1.1.3.1.2.2 16-1.1.1.3.1.2.2.r 17-1.1.1.3.1.5.1.1 18-1.1.1.3.1 19-1.1.1.3.1 20-1.1.1.3.1.3.2 21-1.1.1.3.1.3 24-1.1.1.3.1.3.1 25-1.1.1.3.1.4.r 26-1.1.1.3.1.3.1.2.1.1.1 28-1.1.1.3.1.3.1.2.2.1.1 30-1.1.1.3.1.4.r 31-1.1.1.3.1.4.2 32-1.1.1.3.1.4 32-1.2.4.2 34-1.1.1.3.1.4.1.2 35-1.1.1.3.1.3.1.2.1.1.1 36-1.1.1.3.1.3.1.2 37-1.1.1.3.1.3.1.2.2.1.1 38-1.1 38-1.1.1.3.1.3.1 38-1.1.1.3.1.4.1 39-1 40-1.2.r 41-1.2.2 42-1.2.3 43-1.2.1 44-1.2 45-1.1.1.3.1.4.r 45-1.2.4.r 46-1.2.4 48-1.2.4.1 51-1.2.4.2.1 52-1.2.4.2.2 54-1.3.1.1 54-1.3.1.2 (r / result-01~e.39 :ARG1 (t / treat-04~e.38 :ARG1 (a / and~e.3 :op1 (c / cell-line :name (n / name :op1 "M238"~e.2)) :op2 (c2 / cell-line :name (n2 / name :op1 "M792"~e.4)) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line~e.18,19 :quant 2~e.6 :mod (g / gene~e.16 :name (n3 / name :op1 "BRAF"~e.8) :ARG1-of~e.16 (m2 / mutate-01~e.16 :value "V600E"~e.12)) :ARG0-of (s / sensitive-03~e.21 :ARG1 (t2 / treat-04~e.0,24,38 :ARG1 a :ARG2 (a2 / and~e.36 :op1 (s4 / small-molecule :name (n6 / name :op1 "vemurafenib"~e.26,35)) :op2 (s3 / small-molecule :name (n4 / name :op1 "SCH772984"~e.28,37)))) :ARG1-of (h / high-02~e.20)) :prep-with~e.25,30,45 (c5 / concentrate-02~e.32 :ARG1 (t3 / treat-04~e.38 :ARG2 (a3 / and :op1 s4 :op2 s3) :ARG1-of (c6 / combine-01~e.34)) :mod (e / equimolar~e.31)) :part-of (m3 / medical-condition :name (n7 / name :op1 "melanoma"~e.17)))))) :ARG2~e.40 (i / inhibit-01~e.44 :ARG1 (g2 / grow-03~e.43) :mod (p / potent~e.41) :ARG0-of (s2 / synergize-01~e.42) :ARG3-of~e.45 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.46 :ARG2 50~e.48 :ARG4 (c7 / concentration-quantity~e.32 :quant 10~e.51 :unit (n5 / nanomolar~e.52)))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.54 :mod "5A") :op2 (f2 / figure~e.54 :mod "5B")))) # ::id a_pmid_2514_2146.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combining vemurafenib with SCH772984 resulted in a more profound decrease in pRSK and pERK for the highly sensitive M262 and M792 lines compared to untreated controls or treatment with either agent alone . # ::alignments 0-1.1 1-1.1.1.1.1 2-1.1.2.r 3-1.1.2.1.1 4-1 5-1.2.r 7-1.2.3.1 8-1.2.3 9-1.2 10-1.2.1.r 11-1.2.1.1.1.1 11-1.2.1.1.2 12-1.2.1 13-1.2.1.1.2 13-1.2.1.2.1.1 14-1.2.2.r 16-1.2.2.3.1 17-1.2.2.3 18-1.2.2.1.1.1 19-1.2.2 20-1.2.2.2.1.1 21-1.2.2.1 21-1.2.2.2 22-1.2.4.r 24-1.2.4.1.1 24-1.2.4.1.1.1 24-1.2.4.1.1.1.r 25-1.2.4.1 26-1.2.4 27-1.2.4.2 28-1.2.4.2.1.r 29-1.2.4.2.1.2 30-1.2.4.2.1 31-1.2.4.2.1.1 (r / result-01~e.4 :ARG1 (c / combine-01~e.0 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"~e.1)) :ARG2~e.2 (s2 / small-molecule :name (n / name :op1 "SCH772984"~e.3))) :ARG2~e.5 (d / decrease-01~e.9 :ARG1~e.10 (a / and~e.12 :op1 (e / enzyme :name (n2 / name :op1 "RSK"~e.11) :ARG3-of (p2 / phosphorylate-01~e.11,13)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK"~e.13) :ARG3-of p2)) :location~e.14 (a2 / and~e.19 :op1 (c3 / cell-line~e.21 :name (n4 / name :op1 "M262"~e.18)) :op2 (c4 / cell-line~e.21 :name (n5 / name :op1 "M792"~e.20)) :ARG0-of (s / sensitive-03~e.17 :ARG1-of (h / high-02~e.16))) :mod (p / profound~e.8 :degree (m / more~e.7)) :compared-to~e.22 (o / or~e.26 :op1 (c5 / control~e.25 :ARG1-of (t2 / treat-04~e.24 :polarity~e.24 -~e.24)) :op2 (t / treat-04~e.27 :ARG2~e.28 (a3 / agent~e.30 :mod (a4 / alone~e.31) :mod (e3 / either~e.29)))))) # ::id a_pmid_2514_2146.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M262 resulted in decreased pAKT levels after all three treatments . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1 4-1.2.2.1.1 4-1.2.2.2 5-1.2 6-1.3 7-1.3.1.2 8-1.3.1.1 9-1.3.1 (r / result-01~e.1 :ARG1 (c / cell-line :name (n / name :op1 "M262"~e.0)) :ARG2~e.2 (l / level~e.5 :ARG1-of (d / decrease-01~e.3) :quant-of (e / enzyme :name (n2 / name :op1 "AKT"~e.4) :ARG3-of (p2 / phosphorylate-01~e.4))) :time (a / after~e.6 :op1 (t / treat-04~e.9 :quant 3~e.8 :mod (a2 / all~e.7)))) # ::id a_pmid_2514_2146.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For M308 , which is resistant to vemurafenib and sensitive to SCH772984 , as pRSK was already completely absent with treatment with SCH772984 alone , no additional effect of the combination was apparent ( Figure 5 @ C ) . # ::alignments 1-1.2.2.2.1.1 5-1.2.2.2 5-1.2.2.2.2 5-1.2.2.2.2.r 6-1.2.2.2.2.1.r 7-1.2.2.2.2.1.1.1 9-1.2.2.2.3 10-1 10-1.2.2.2.3.1.r 11-1.2.2.2.3.1.1.1 13-1.1.4.r 14-1.1.1.1.1 14-1.1.1.2 16-1.1.4 17-1.1.2 17-1.1.2.r 18-1.1 20-1.1.3.1 22-1.1.3.1.1.1.1 22-1.2.2.2.3.1.1.1 23-1.2.2.2.3.1.2 25-1.2.1 25-1.2.1.r 26-1.2.2.3 27-1.2.2 28-1.2.2.1.r 30-1.2.2.1 34-1.3.1 (c / cause-01~e.10 :ARG0 (a / absent-01~e.18 :ARG1 (e / enzyme :name (n / name :op1 "RSK"~e.14) :ARG3-of (p / phosphorylate-01~e.14)) :manner~e.17 (c2 / complete~e.17) :ARG1-of (c3 / cause-01 :ARG0 (t / treat-04~e.20 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"~e.22)))) :time~e.13 (a3 / already~e.16)) :ARG1 (a4 / appear-01 :polarity~e.25 -~e.25 :ARG1 (a5 / affect-01~e.27 :ARG0~e.28 (c5 / combine-01~e.30) :ARG1 (c6 / cell-line~e.5 :name (n3 / name :op1 "M308"~e.1) :ARG0-of~e.5 (r / resist-01~e.5 :ARG1~e.6 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib"~e.7))) :ARG0-of (s / sensitive-03~e.9 :ARG1~e.10 (s4 / small-molecule :name (n5 / name :op1 "SCH772984"~e.11,22) :mod (a2 / alone~e.23)))) :mod (a6 / additional~e.26))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "5C"))) # ::id a_pmid_2514_2146.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , at 24 hours post treatment , induction of pMEK and pERK was already seen , indicating rapid feedback recovery for M308 , despite its sensitivity to SCH772984 . # ::alignments 0-1.2 0-1.2.r 3-1.3.2.1 4-1.3.2.2 5-1.3 6-1.3.1 8-1.1 11-1.1.1 12-1.1.1.1.2 12-1.1.1.2.1.1 14-1.4 15-1 17-1.5 18-1.5.1.3 19-1.5.1.2 20-1.5.1 21-1.5.1.1.r 22-1.5.1.1.1.1 24-1.5.1.4.r 25-1.5.1.4.1 25-1.5.1.4.1.r 26-1.5.1.4 27-1.5.1.4.2.r 28-1.5.1.4.2.1.1 (s / see-01~e.15 :ARG1 (i2 / induce-01~e.8 :ARG2 (a / and~e.11 :op1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01~e.12)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.12) :ARG3-of p2))) :manner~e.0 (i / interesting~e.0) :time (a3 / after~e.5 :op1 (t3 / treat-04~e.6) :quant (t2 / temporal-quantity :quant 24~e.3 :unit (h2 / hour~e.4))) :time (a2 / already~e.14) :ARG0-of (i3 / indicate-01~e.17 :ARG1 (r / recover-02~e.20 :ARG0~e.21 (c2 / cell-line :name (n3 / name :op1 "M308"~e.22)) :ARG1 (f / feedback~e.19) :mod (r2 / rapid~e.18) :concession~e.24 (s2 / sensitive-03~e.26 :ARG0~e.25 c2~e.25 :ARG1~e.27 (s3 / small-molecule :name (n4 / name :op1 "SCH772984"~e.28)))))) # ::id a_pmid_2514_2146.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A slight decrease in pERK1 @/@ 2 was seen with SCH772984 treatment , with a compensatory increase in pMEK . # ::alignments 1-1.1.1.2 2-1.1.1 6-1.1.1.1.1.1 8-1 10-1.1.1.3.1.1.1.1 11-1.1.1.3.1 16-1.1.2 (s / see-01~e.8 :ARG1 (a / and :op1 (d / decrease-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.6) :ARG3-of p) :ARG2 (s2 / slight~e.1) :ARG1-of (c / cause-01 :ARG0 (t / treat-04~e.11 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "SCH772984"~e.10))))) :op2 (i / increase-01~e.16 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK") :ARG3-of (p / phosphorylate-01)) :ARG0-of (c2 / compensate-01)))) # ::id a_pmid_2514_2146.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The generally more resistant M308 and M370 lines , in contrast to the generally more sensitive M262 and M792 lines , did not show a decrease in pMEK when combining the two drugs , which seems to be due to the lack of activity of vemurafenib in these resistant cells . # ::alignments 1-1.2.3.2 2-1.2.3.1 3-1.2.3 4-1.2.1.1.1 5-1.2 6-1.2.2.1.1 7-1.2.1 7-1.2.2 10-1.2.5 11-1.2.4 13-1.2.3.2 14-1.2.3.1 15-1.2.5.1.3 16-1.2.5.1.1.1.1 17-1.2.5.1 18-1.2.5.1.2.1.1 19-1.2.5.1.1 19-1.2.5.1.2 22-1.1 22-1.1.r 23-1 25-1.3 28-1.4.r 29-1.4 31-1.4.1.1 32-1.4.1 35-1.2.4.2 36-1.2.4 38-1.2.4 39-1.2.4 41-1.2.4.1 42-1.2.4.1.2.r 43-1.2.4.1.2 44-1.2.4.1.2.1.r 45-1.2.4.1.2.1.1.1 48-1.2.3 49-1.2.1 (s / show-01~e.23 :polarity~e.22 -~e.22 :ARG0 (a2 / and~e.5 :op1 (c5 / cell-line~e.7,49 :name (n2 / name :op1 "M308"~e.4)) :op2 (c6 / cell-line~e.7 :name (n3 / name :op1 "M370"~e.6)) :ARG0-of (r2 / resist-01~e.3,48 :degree (m / more~e.2,14) :ARG1-of (g / general-02~e.1,13)) :ARG1-of (c3 / cause-01~e.11,36,38,39 :ARG0 (l / lack-01~e.41 :ARG0 a2 :ARG1~e.42 (a / activity-06~e.43 :ARG0~e.44 (s4 / small-molecule :name (n6 / name :op1 "vemurafenib"~e.45)))) :ARG1-of (s2 / seem-01~e.35)) :ARG1-of (c / contrast-01~e.10 :ARG2 (a3 / and~e.17 :op1 (c7 / cell-line~e.19 :name (n4 / name :op1 "M262"~e.16)) :op2 (c8 / cell-line~e.19 :name (n5 / name :op1 "M792"~e.18)) :ARG0-of (s3 / sensitive-03~e.15 :degree m :ARG1-of g)))) :ARG1 (d / decrease-01~e.25 :ARG1 (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01))) :time~e.28 (c2 / combine-01~e.29 :ARG1 (d2 / drug~e.32 :quant 2~e.31))) # ::id a_pmid_2514_2146.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No additive effect from the dual upstream blockade could be noticed in the immediate downstream targets , indicating that the pathway remained active ( Figure 5 @ C ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2.2 2-1.1.2 3-1.1.2.1.r 5-1.1.2.1.2 6-1.1.2.1.1 7-1.1.2.1 8-1 10-1.1 11-1.1.3.r 13-1.1.3.1.1 14-1.1.3.1 15-1.1.3 17-1.1.4 18-1.1.4.1.r 20-1.1.4.1.1 21-1.1.4.1 22-1.1.4.1.2 24-1.2.1 (p2 / possible-01~e.8 :ARG1 (n / notice-01~e.10 :polarity~e.0 -~e.0 :ARG1 (a2 / affect-01~e.2 :ARG0~e.3 (b / blockade-01~e.7 :location (u / upstream~e.6) :mod (d2 / dual~e.5)) :ARG1-of (a3 / add-02~e.1)) :location~e.11 (t / target~e.15 :location (d3 / downstream~e.14 :mod (i2 / immediacy~e.13))) :ARG0-of (i / indicate-01~e.17 :ARG1~e.18 (r / remain-01~e.21 :ARG1 (p / pathway~e.20) :ARG3 (a / active~e.22)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "5C"))) # ::id a_pmid_2514_2146.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All cell lines sensitive to BRAFi were also sensitive to the combination . # ::alignments 0-1.1.1 1-1.1 2-1.1 3-1 3-1.1.2 7-1.3 8-1 9-1.2.r 11-1.2 (s / sensitive-03~e.3,8 :ARG0 (c / cell-line~e.1,2 :mod (a / all~e.0) :ARG0-of (s2 / sensitive-03~e.3 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF")))))) :ARG1~e.9 (c2 / combine-01~e.11) :mod (a2 / also~e.7)) # ::id a_pmid_2514_2146.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Four intermediately sensitive cell lines to BRAFi became highly sensitive to the combination , with improved pathway inhibition compared to ERK inhibition alone in all cases . # ::alignments 0-1.1.1 1-1.1.2.2 2-1.1.2 3-1.1 4-1.1 7-1 8-1.2.3 9-1.2 10-1.2.2.r 12-1.2.2 14-1.3.r 15-1.3.2 16-1.3.1 17-1.3 18-1.3.3.r 20-1.3.3.1.1.1 21-1.1.2.1 21-1.1.2.1.1 21-1.1.2.1.1.r 21-1.3.3 22-1.3.3.2 23-1.3.3.3.r 24-1.3.3.3.1 25-1.3.3.3 (b / become-01~e.7 :ARG1 (c / cell-line~e.3,4 :quant 4~e.0 :ARG0-of (s / sensitive-03~e.2 :ARG1 (m / molecular-physical-entity~e.21 :ARG0-of~e.21 (i5 / inhibit-01~e.21 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF")))) :degree (i / intermediate~e.1))) :ARG2 (s2 / sensitive-03~e.9 :ARG0 c :ARG1~e.10 (c2 / combine-01~e.12) :ARG1-of (h / high-02~e.8)) :prep-with~e.14 (i2 / inhibit-01~e.17 :ARG1 (p / pathway~e.16) :ARG1-of (i3 / improve-01~e.15) :compared-to~e.18 (i4 / inhibit-01~e.21 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.20)) :mod (a / alone~e.22) :prep-in~e.23 (c3 / case-04~e.25 :mod (a2 / all~e.24))))) # ::id a_pmid_2514_2146.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More importantly , highly resistant cell lines to BRAFi became sensitive ( M420 , M308 , M410 ) or intermediately sensitive ( M417 , M370 , M229AR , M409AR1 ) to the combination . # ::alignments 0-1.3.1 1-1.3 1-1.3.r 3-1.1.1.2 4-1.1.1 5-1.1 6-1.1 9-1 10-1.2.2 12-1.2.1.1.1.1.1 14-1.2.1.1.2.1.1 16-1.2.1.1.3.1.1 18-1.2 19-1.2.2.3 20-1.2.1 20-1.2.2 22-1.2.2.1.1.1.1 24-1.2.2.1.2.1.1 26-1.2.2.1.3.1.1 28-1.2.2.1.4.1.1 30-1.2.1.2.r 32-1.2.1.2 (b / become-01~e.9 :ARG1 (c / cell-line~e.5,6 :ARG0-of (r / resist-01~e.4 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF")))) :ARG1-of (h / high-02~e.3))) :ARG2 (o / or~e.18 :op1 (s / sensitive-03~e.20 :ARG0 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "M420"~e.12)) :op2 (c3 / cell-line :name (n3 / name :op1 "M308"~e.14)) :op3 (c4 / cell-line :name (n4 / name :op1 "M410"~e.16))) :ARG1~e.30 (c5 / combine-01~e.32)) :op2 (s2 / sensitive-03~e.10,20 :ARG0 (a2 / and :op1 (c6 / cell-line :name (n5 / name :op1 "M417"~e.22)) :op2 (c7 / cell-line :name (n6 / name :op1 "M370"~e.24)) :op3 (c8 / cell-line :name (n7 / name :op1 "M229AR"~e.26)) :op4 (c9 / cell-line :name (n8 / name :op1 "M409AR1"~e.28))) :ARG1 c5 :degree (i / intermediate~e.19))) :manner~e.1 (i2 / important~e.1 :degree (m / more~e.0))) # ::id a_pmid_2514_2146.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Three remained resistant but with a slightly improved IC @_{50 .} C.I.s demonstrated synergy with combined BRAF and ERK inhibition for all cell lines except M308 , in which dual treatment with vemurafenib and SCH772984 is only additive ( Figure 5 @ D ) . @ Figure 5 @

Susceptibility of @ BRAF @ @ mutant melanoma cell lines to MAPK inhibitors . # ::alignments 0-1.3.1.1 1-1.3 2-1.3.2 3-1.3.2.2 7-1.3.2.2.1.3 8-1.3.2.2.1 10-1.3.2.2.1.1 14-1.1 15-1.1.2 17-1.1.1.1 18-1.1.2.2.1.1.1.1 19-1.1.2.2.1 20-1.1.2.2.1.2.1.1 21-1.1.2.2 23-1.1.2.2.2.1 24-1.1.2.2.2 24-1.3.1 25-1.1.2.2.2 26-1.1.2.2.2.2 27-1.1.2.2.2.2.1.1.1 31-1.1.2.2.2.2.1.2.1.2 32-1.1.2.2.2.2.1.2.1 33-1.1.2.2.2.2.1.2.1.1.r 34-1.1.2.2.2.2.1.2.1.1.1.1.1 35-1.1.2.2.2.2.1.2.1.1 36-1.1.2.2.2.2.1.2.1.1.2.1.1 38-1.1.2.2.2.2.1.2.2 39-1.1.2.2.2.2.1.2 41-1.1.3.1 41-1.2.3.1 43-1.2.3.1.1 50-1.2.3.1 51-1.2.3.1.1 61-1.2.1.1.2.1.1 65-1.2.1.1.2 65-1.2.1.1.2.2 65-1.2.1.1.2.2.r 66-1.2.1.1.1.1 67-1.2.1 68-1.2.1 69-1.2.2.r 70-1.2.2.1.1.1.1 71-1.1.2.2 71-1.2.2 71-1.2.2.1 71-1.2.2.1.r (m / multi-sentence :snt2 (d / demonstrate-01~e.14 :ARG0 (i3 / index :mod (c3 / combine-01~e.17)) :ARG1 (s / synergize-01~e.15 :ARG0 i3 :ARG1 (i4 / inhibit-01~e.21,71 :ARG1 (a3 / and~e.19 :op1 (e4 / enzyme :name (n3 / name :op1 "BRAF"~e.18)) :op2 (e / enzyme :name (n / name :op1 "ERK"~e.20))) :location (c7 / cell-line~e.24,25 :mod (a / all~e.23) :ARG2-of (e2 / except-01~e.26 :ARG1 (c8 / cell-line :name (n4 / name :op1 "M308"~e.27) :location-of (a2 / add-02~e.39 :ARG1 (t2 / treat-04~e.32 :ARG2~e.33 (a4 / and~e.35 :op1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"~e.34)) :op2 (s4 / small-molecule :name (n9 / name :op1 "SCH772984"~e.36))) :mod (d2 / dual~e.31)) :mod (o / only~e.38))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.41 :mod "5D"))) :snt3 (s2 / susceptible :domain (c9 / cell-line~e.67,68 :part-of (m6 / medical-condition :name (n8 / name :op1 "melanoma"~e.66) :mod (e3 / enzyme~e.65 :name (n5 / name :op1 "BRAF"~e.61) :ARG2-of~e.65 (m3 / mutate-01~e.65)))) :prep-to~e.69 (m4 / molecular-physical-entity~e.71 :ARG0-of~e.71 (i / inhibit-01~e.71 :ARG1 (p / protein-family :name (n2 / name :op1 "MAPK"~e.70)))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.41,50 :mod 5~e.43,51))) :snt1 (r3 / remain-01~e.1 :ARG1 (c2 / cell-line~e.24 :quant 3~e.0) :ARG3 (r / resist-01~e.2 :ARG0 c2 :ARG1-of (c / contrast-01~e.3 :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.8 :ARG2 50~e.10 :ARG1 c2 :ARG1-of (i2 / improve-01~e.7)))))) # ::id a_pmid_2514_2146.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Percent growth inhibition of ( A ) M238 and ( B ) M792 . # ::alignments 0-1.1.2 1-1.1 2-1 9-1.1.1.1.1.1 10-1.1.1 16-1.1.1.2.1.1 (i / inhibit-01~e.2 :ARG1 (g / grow-01~e.1 :ARG1 (a / and~e.10 :op1 (c / cell-line :name (n / name :op1 "M238"~e.9) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) :op2 (c2 / cell-line :name (n2 / name :op1 "M792"~e.16) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5B")))) :quant (p / percent~e.0))) # ::id a_pmid_2514_2146.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 120 hours treatment with 0 @–@ 10 μM vemurafenib ( V , squares ) , SCH722984 ( E , circles ) , or the combination ( V + E , triangles ) , cell viability was determined by bioluminescence assay . # ::alignments 0-1.3 1-1.3.1.2.1 2-1.3.1.2.2 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.3.1.1 7-1.3.1.1.1.3.2.1 8-1.3.1.1.1.3.1.2 9-1.3.1.1.1.1.1 11-1.3.1.1.1.2.1.1.1 13-1.3.1.1.1.2.1.2 16-1.3.1.1.2.1.1 18-1.3.1.1.2.2.1.1.1 20-1.3.1.1.2.2.1.2 23-1.3.1.1 25-1.3.1.1.3 27-1.3.1.1.3.1 28-1.3.1.1.1.2.1 28-1.3.1.1.2.2.1 28-1.3.1.1.3.3.1 29-1.3.1.1.3.2 31-1.3.1.1.3.3.1.2 34-1.1.1 35-1.1 37-1 38-1.2.r 39-1.2.1 40-1.2 (d / determine-01~e.37 :ARG1 (v / viability~e.35 :poss (c / cell~e.34)) :ARG2~e.38 (a / assay-01~e.40 :ARG1 (b / bioluminescence~e.39)) :time (a2 / after~e.0 :op1 (t2 / treat-04~e.3 :ARG2~e.4 (o / or~e.23 :op1 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib"~e.9) :ARG1-of (l / label-01 :ARG0 (a4 / and~e.28 :op2 (s / string-entity :value "V"~e.11) :op2 (s4 / square~e.13))) :quant (v2 / value-interval :op1 (c4 / concentration-quantity :quant 0~e.5 :unit (m / micromolar~e.8)) :op2 (c5 / concentration-quantity :quant 10~e.7 :unit m))) :op2 (s2 / small-molecule :name (n / name :op1 "SCH722984"~e.16) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and~e.28 :op1 (s5 / string-entity :value "E"~e.18) :op2 (c2 / circle~e.20)))) :op3 (c3 / combine-01~e.25 :ARG1 s3~e.27 :ARG2 s2~e.29 :ARG1-of (d4 / describe-01 :ARG0 (a6 / and~e.28 :op1 (s6 / string-entity :value "V+E") :op2 (t4 / triangle~e.31))))) :duration (t / temporal-quantity :quant 120~e.1 :unit (h / hour~e.2))))) # ::id a_pmid_2514_2146.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results are representative data in duplicate from three independent experiments ( n = 6 ) . # ::alignments 0-1.3 0-1.3.1 0-1.3.1.r 1-1.3.r 2-1.1 3-1 4-1.2.r 5-1.2 7-1.2.1.1 8-1.2.1.2 8-1.2.1.2.1 8-1.2.1.2.1.r 9-1.2.1 9-1.2.2.1 13-1.2.2.1.1 (d / data~e.3 :ARG0-of (r / represent-01~e.2) :ARG0-of~e.4 (d2 / duplicate-01~e.5 :ARG1 (e / experiment-01~e.9 :quant 3~e.7 :ARG0-of (d3 / depend-01~e.8 :polarity~e.8 -~e.8)) :ARG1-of (m / mean-01 :ARG2 (e2 / experiment-01~e.9 :quant 6~e.13))) :domain~e.1 (t / thing~e.0 :ARG2-of~e.0 (r2 / result-01~e.0))) # ::id a_pmid_2514_2146.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C @ . # ::alignments (f / figure :mod "5C") # ::id a_pmid_2514_2146.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effect of BRAF-, ERK @- inhibition or the combination on MAPK signaling . # ::alignments 0-1 3-1.1.2.1.1.1 5-1.1.1 5-1.1.2 6-1.1 8-1.1.3 9-1.2.r 10-1.2.1.1.1 11-1.2 (a / affect-01~e.0 :ARG0 (o2 / or~e.6 :op1 (i / inhibit-01~e.5 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF"))) :op2 (i2 / inhibit-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.3))) :op3 (c / combine-01~e.8 :ARG1 i :ARG2 i2)) :ARG1~e.9 (s / signal-07~e.11 :ARG0 (p / pathway :name (n2 / name :op1 "MAPK"~e.10)))) # ::id a_pmid_2514_2146.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell lines were treated with DMSO ( control , C ) , 500 nM Vemurafenib ( BRAFi , B ) , 500 nM SCH722984 ( ERKi , E ) or the combination of vemurafenib and SCH722984 ( B + E ) for 24 hours . # ::alignments 0-1.1 1-1.1 3-1 4-1.2.r 5-1.2.1.1.1 7-1.2.1.2.1 12-1.2.2.2.1 12-1.2.3.2.1 13-1.2.2.2.2 13-1.2.3.2.2 14-1.2.2.1.1 21-1.2.2.2.1 21-1.2.3.2.1 22-1.2.2.2.2 22-1.2.3.2.2 23-1.2.3.1.1 29-1.2 31-1.2.4 32-1.2.4.1.r 33-1.2.4.1 35-1.2.3.1.1 41-1.3.r 42-1.3.1 43-1.3.2 (t2 / treat-04~e.3 :ARG1 (c / cell-line~e.0,1) :ARG2~e.4 (o / or~e.29 :op1 (s4 / small-molecule :name (n5 / name :op1 "DMSO"~e.5) :ARG1-of (l / label-01 :ARG2 (c2 / control~e.7))) :op2 (s2 / small-molecule :name (n4 / name :op1 "vemurafenib"~e.14) :quant (c4 / concentration-quantity :quant 500~e.12,21 :unit (n2 / nanomolar~e.13,22)) :ARG1-of (l2 / label-01 :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "BRAF")))))) :op3 (s / small-molecule :name (n / name :op1 "SCH722984"~e.23,35) :quant (c5 / concentration-quantity :quant 500~e.12,21 :unit (n3 / nanomolar~e.13,22)) :ARG1-of (l3 / label-01 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n6 / name :op1 "ERK")))))) :op4 (c3 / combine-01~e.31 :ARG1~e.32 s2~e.33 :ARG2 s :ARG1-of (l4 / label-01 :ARG2 (s3 / string-entity :value "B+E")))) :duration~e.41 (t3 / temporal-quantity :quant 24~e.42 :unit (h2 / hour~e.43))) # ::id a_pmid_2514_2146.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blots analyzed for phospho @- and total MEK , ERK1 @/@ 2 , RSK , AKT and actin as loading control . # ::alignments 0-1.2 1-1.2 2-1 3-1.1.r 4-1.1.1.6 6-1.1 6-1.1.1 6-1.1.1.r 6-1.1.2 6-1.1.2.r 7-1.1.2.6 8-1.1.1.1.1.1 10-1.1.1.2.1.1 12-1.1.1.2.1.1 14-1.1.1.3.1.1 16-1.1.1.4.1.1 17-1.1 18-1.1.2.5.1.1 20-1.1.3.1 21-1.1.3 (a7 / analyze-01~e.2 :purpose~e.3 (a3 / and~e.6,17 :op1~e.6 (a4 / and~e.6 :op1 (e2 / enzyme :name (n / name :op1 "MEK"~e.8)) :op2 (e / enzyme :name (n2 / name :op1 "ERK1/2"~e.10,12)) :op3 (e3 / enzyme :name (n4 / name :op1 "RSK"~e.14)) :op4 (e4 / enzyme :name (n5 / name :op1 "AKT"~e.16)) :op5 p2 :ARG3-of (p / phosphorylate-01~e.4)) :op2~e.6 (a5 / and~e.6 :op1 e2 :op2 e :op3 e3 :op4 e4 :op5 (p2 / protein :name (n6 / name :op1 "actin"~e.18)) :mod (t / total~e.7)) :ARG0-of (c / control-01~e.21 :ARG1 (l / load-01~e.20))) :manner (i / immunoblot-01~e.0,1)) # ::id a_pmid_2514_2146.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok D @ . # ::alignments 1-1.1 (s / string-entity :value "D"~e.1) # ::id a_pmid_2514_2146.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IC @₅₀ ( nM ) to MAPK inhibitors and synergistic effect . # ::alignments 0-1.1 2-1.1.1 5-1.1.3.1 7-1.1.2.r 8-1.1.2.1.1.2.1 9-1.1.2 9-1.1.2.1 9-1.1.2.1.r 10-1 11-1.2.1 12-1.2 (a / and~e.10 :op1 (h / have-percentage-maximal-inhibitory-concentration-01~e.0 :ARG2 50~e.2 :ARG1~e.7 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (i2 / inhibit-01~e.9 :ARG1 (p / protein-family :wiki "Mitogen-activated_protein_kinase" :name (n / name :op1 "MAPK"~e.8)))) :ARG4 (c / concentration-quantity :unit (n2 / nanomolar~e.5))) :op2 (a2 / affect-01~e.12 :ARG2 (s / synergize-01~e.11))) # ::id a_pmid_2514_2146.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @-@ mutant melanoma cell lines were treated with 0 @–@ 10 μM vemurafenib ( BRAFi ) or SCH722984 ( ERKi ) , the combination ( B + E ) or 0 @–@ 1 μM trametinib ( MEKi ) . # ::alignments 0-1.1.1.2.1.1 0-1.2.1.3.1.1.1 2-1.1.1.2 2-1.1.1.2.2 2-1.1.1.2.2.r 3-1.1.1.1.1 4-1.1 5-1.1 7-1 8-1.2.r 9-1.2.4.3.2.1 11-1.2.1.2.2.2 12-1.2.1.2.1 13-1.2.1.1.1 17-1.2 18-1.2.2.1.1 24-1.2.3 30-1.2 31-1.2.4.3.2.1 33-1.2.1.2.2.1 33-1.2.4.3.2.2 34-1.2.4.3.1 35-1.2.4.1.1 (t / treat-04~e.7 :ARG1 (c / cell-line~e.4,5 :part-of (m5 / medical-condition :name (n4 / name :op1 "melanoma"~e.3) :mod (e3 / enzyme~e.2 :name (n / name :op1 "BRAF"~e.0) :ARG2-of~e.2 (m2 / mutate-01~e.2)))) :ARG2~e.8 (o / or~e.17,30 :op1 (s2 / small-molecule :name (n7 / name :op1 "vemurafenib"~e.13) :quant (c2 / concentration-quantity :unit (m3 / micromolar~e.12) :quant (v / value-interval :op1 1~e.33 :op2 10~e.11)) :ARG0-of (i2 / inhibit-01 :ARG1 (e4 / enzyme :name (n9 / name :op1 "BRAF"~e.0)))) :op2 (s / small-molecule :name (n2 / name :op1 "SCH722984"~e.18) :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "ERK")))) :op3 (c3 / combine-01~e.24 :ARG1 s2 :ARG2 s :ARG1-of (l / label-01 :ARG2 (s4 / string-entity :value "B+E"))) :op4 (s3 / small-molecule :name (n8 / name :op1 "trametinib"~e.35) :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "MEK"))) :quant (c4 / concentration-quantity :unit (m4 / micromolar~e.34) :quant (b2 / between :op1 0~e.9,31 :op2 1~e.33))))) # ::id a_pmid_2514_2146.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Green indicates sensitivity , yellow intermediately sensitive , and red for resistant . # ::alignments 0-1.1.1 1-1.1 1-1.2 1-1.3 2-1.1.2 4-1.2.1 5-1.2.2.1 6-1.2.2 8-1 9-1.3.1 10-1.3.2.r 11-1.3.2 (a / and~e.8 :op1 (i / indicate-01~e.1 :ARG0 (g / green-02~e.0) :ARG1 (s / sensitive-03~e.2)) :op2 (i2 / indicate-01~e.1 :ARG0 (y / yellow-02~e.4) :ARG1 (s2 / sensitive-03~e.6 :degree (i4 / intermediate~e.5))) :op3 (i3 / indicate-01~e.1 :ARG0 (r / red-02~e.9) :ARG1~e.10 (r2 / resist-01~e.11))) # ::id a_pmid_2514_2146.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The CI column indicates the combination index of vemurafenib and SCH722984 .

@ @ @ # ::alignments 1-1.1.1.1 2-1.1 3-1 5-1.2.1 6-1.2 7-1.2.1.1.r 8-1.2.1.1.1.1 10-1.2.1.2.1.1 (i / indicate-01~e.3 :ARG0 (c / column~e.2 :mod (s3 / string-entity :value "CI"~e.1)) :ARG1 (i2 / index~e.6 :mod (c2 / combine-01~e.5 :ARG1~e.7 (s / small-molecule :name (n3 / name :op1 "vemurafenib"~e.8)) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"~e.10))))) # ::id a_pmid_2514_2146.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next examined whether cells inherently resistant to BRAFi could be sensitive to a MEK inhibitor ( MEKi ) or ERKi . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.1.r 4-1.2.2.1 5-1.2.2.1.1.2 6-1.2.2.1.1 9-1.2 11-1.2.2 12-1.2.2.2.r 14-1.2.2.2.1.1.1.1.1 15-1.2.2.1.1.1 15-1.2.2.1.1.1.1 15-1.2.2.1.1.1.1.r 15-1.2.2.2.1 15-1.2.2.2.1.1 15-1.2.2.2.1.1.r 15-1.2.2.2.2 15-1.2.2.2.2.1 15-1.2.2.2.2.1.r 19-1.2.2.2 (e2 / examine-01~e.2 :ARG0 (w / we~e.0) :ARG1 (p / possible-01~e.9 :mode~e.3 interrogative~e.3 :ARG1 (s / sensitive-03~e.11 :ARG0 (c / cell~e.4 :ARG0-of (r / resist-01~e.6 :ARG1 (m3 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i3 / inhibit-01~e.15 :ARG1 (e4 / enzyme :name (n3 / name :op1 "BRAF")))) :mod (i4 / inherent~e.5))) :ARG1~e.12 (o / or~e.19 :op1 (m / molecular-physical-entity~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.14)))) :op2 (m2 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i2 / inhibit-01~e.15 :ARG1 (p2 / protein-family :name (n4 / name :op1 "ERK"))))))) :mod (n2 / next~e.1)) # ::id a_pmid_2514_2146.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity of BRAF mutant melanoma cell lines to BRAFi predicted sensitivity to MEK and ERK inhibitors . # ::alignments 0-1.1 3-1.1.1.1.1.1 3-1.1.2.1.1.1.1 5-1.1.1.1 5-1.1.1.1.2 5-1.1.1.1.2.r 6-1.1.1.2.1.1 7-1.1.1 8-1.1.1 11-1 12-1.1 12-1.2 13-1.2.1.r 14-1.2.1.1.1.1.1.1 15-1.2.1 16-1.2.1.2.1.1.1.1 17-1.1.2 17-1.1.2.1 17-1.1.2.1.r 17-1.2.1.1 17-1.2.1.1.1 17-1.2.1.1.1.r 17-1.2.1.2 17-1.2.1.2.1 17-1.2.1.2.1.r (p / predict-01~e.11 :ARG0 (s2 / sensitive-03~e.0,12 :ARG0 (c / cell-line~e.7,8 :mod (g / gene~e.5 :name (n / name :op1 "BRAF"~e.3) :ARG2-of~e.5 (m2 / mutate-01~e.5)) :part-of (m / medical-condition :name (n5 / name :op1 "melanoma"~e.6))) :ARG1 (m5 / molecular-physical-entity~e.17 :ARG0-of~e.17 (i / inhibit-01~e.17 :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.3))))) :ARG1 (s / sensitive-03~e.12 :ARG1~e.13 (a / and~e.15 :op1 (m3 / molecular-physical-entity~e.17 :ARG0-of~e.17 (i2 / inhibit-01~e.17 :ARG1 (p3 / protein-family :name (n3 / name :op1 "MEK"~e.14)))) :op2 (m4 / molecular-physical-entity~e.17 :ARG0-of~e.17 (i3 / inhibit-01~e.17 :ARG1 (p2 / protein-family :name (n4 / name :op1 "ERK"~e.16))))))) # ::id a_pmid_2514_2146.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , 10 cell lines inherently resistant to BRAFi were often sensitive to MEK and ERK inhibition , and cell lines resistant to BRAFi or MEKi were relatively more sensitive to SCH722984 . # ::alignments 0-1.1 2-1.1.1.1.1 3-1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.2 5-1.1.1.1.2.2.r 6-1.1.1.1.2 10-1.1.1.3 11-1.1.1 12-1.1.1.2.r 13-1.1.1.2.1.1.1.1 14-1.1.1.2.1 15-1.1.1.2.1.2.1.1 16-1.1.1.1.2.1 16-1.1.1.1.2.1.1 16-1.1.1.1.2.1.1.r 16-1.1.1.2 16-1.2.1.1.1.2 16-1.2.1.1.1.2.1 16-1.2.1.1.1.2.1.r 18-1.1.1.2.1 19-1.1.1.1 20-1.2.1 21-1.2.1.1 24-1.2.1.1.1 27-1.2.4 28-1.2.3 29-1.2 30-1.2.2.r 31-1.2.2.1.1 (a / and :op2 (a2 / and~e.0 :op1 (s / sensitive-03~e.11 :ARG0 (c / cell-line~e.3,4,19 :quant 10~e.2 :ARG0-of (r / resist-01~e.6 :ARG1 (m2 / molecular-physical-entity~e.16 :ARG0-of~e.16 (i3 / inhibit-01~e.16 :ARG1 (e / enzyme :name (n3 / name :op1 "BRAF")))) :manner~e.5 (i / inherent~e.5))) :ARG1~e.12 (i2 / inhibit-01~e.16 :ARG1 (a3 / and~e.14,18 :op1 (e3 / enzyme :name (n4 / name :op1 "MEK"~e.13)) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK"~e.15)))) :frequency (o / often~e.10))) :op2 (s2 / sensitive-03~e.29 :ARG0 (c2 / cell-line~e.20 :ARG0-of (r3 / resist-01~e.21 :ARG1 (o2 / or~e.24 :op1 m2 :op2 (m3 / molecular-physical-entity~e.16 :ARG0-of~e.16 (i4 / inhibit-01~e.16 :ARG1 e3))))) :ARG1~e.30 (s3 / small-molecule :name (n / name :op1 "SCH722984"~e.31)) :degree (m / more~e.28) :ARG2-of (r2 / relative-05~e.27))) # ::id a_pmid_2514_2146.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , combining BRAF with ERK inhibition potently decreased the equimolar IC @₅₀ of all cell lines and resulted in synergy in all but one case ( M308 ) , including M255 , M399 and M420 , which are completely resistant to individual inhibitors ( Figure 5 @ D ) . # ::alignments 0-1.4 2-1.1.1 3-1.1.1.1.1.1.1 5-1.1.1.2.1.1.1 6-1.1.1.1 6-1.1.1.2 7-1.1.3 7-1.1.3.r 8-1.1 10-1.1.2.3 11-1.1.2 13-1.1.2.1 15-1.1.2.2.r 16-1.1.2.2.1 17-1.1.2.2 18-1.2.3.1.1.1 18-1.2.3.1.1.2 18-1.2.3.1.1.3 18-1.2.3.3.1 20-1.2 21-1.2.2.r 21-1.2.3.r 22-1.2.2 23-1.2.3.r 24-1.2.3.2 25-1.2.3.3 27-1.2.3 29-1.2.3.3.1.1.1 32-1.2.3.1 33-1.2.3.1.1.1.1.1 35-1.2.3.1.1.2.1.1 36-1.2.3.1.1 37-1.2.3.1.1.3.1.1 42-1.2.3.1.1.4 43-1.2.3.1.1.4.1.r 44-1.2.3.1.1.4.1.1 45-1.2.3.1.1.4.1 45-1.2.3.1.1.4.1.2 45-1.2.3.1.1.4.1.2.r 47-1.3.1 (a / and :op1 (d / decrease-01~e.8 :ARG0 (c2 / combine-01~e.2 :ARG1 (i5 / inhibit-01~e.6 :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF"~e.3))) :ARG2 (i / inhibit-01~e.6 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.5)))) :ARG1 (h / have-percentage-maximal-inhibitory-concentration-01~e.11 :ARG2 50~e.13 :ARG1~e.15 (c3 / cell-line~e.17 :mod (a3 / all~e.16)) :mod (e4 / equimolar~e.10)) :manner~e.7 (p / potent~e.7)) :op2 (r / result-01~e.20 :ARG1 c2 :ARG2~e.21 (s / synergize-01~e.22) :prep-in~e.21,23 (c / case-04~e.27 :ARG1-of (i2 / include-91~e.32 :ARG2 (a4 / and~e.36 :op1 (c6 / cell-line~e.18 :name (n5 / name :op1 "M255"~e.33)) :op2 (c7 / cell-line~e.18 :name (n6 / name :op1 "M399"~e.35)) :op3 (c8 / cell-line~e.18 :name (n7 / name :op1 "M420"~e.37)) :ARG0-of (r2 / resist-01~e.42 :ARG1~e.43 (m2 / molecular-physical-entity~e.45 :mod (i3 / individual~e.44) :ARG0-of~e.45 (i4 / inhibit-01~e.45))))) :mod a3~e.24 :ARG2-of (e3 / except-01~e.25 :ARG1 (c5 / cell-line~e.18 :name (n4 / name :op1 "M308"~e.29))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.47 :mod "5D")) :mod (i6 / indeed~e.0)) # ::id a_pmid_2514_2146.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because the combination on BRAF combined with MEK inhibition is currently FDA approved for BRAF @ ^{V600 @} mutant melanoma , we also determined the IC @₅₀ for the combination of vemurafenib and trametinib . # ::alignments 0-1 2-1.1.2.1.2 4-1.1.2.1.1.1 5-1.1.2 5-1.1.2.1.2 6-1.1.2.1.2.1.r 7-1.1.2.1.2.1.1.1.1 8-1.1.2.1.2.1 10-1.1.3 11-1.1.1.1.1 12-1.1 15-1.1.2.1.1.1 15-1.1.4.2.1.1 19-1.1.4.2.2.1 22-1.1.4.2 22-1.1.4.2.2 22-1.1.4.2.2.r 23-1.1.4.1.1 25-1.2.1 26-1.2.3 27-1.2 29-1.2.2 31-1.2.2.1 33-1.2.2.2.r 35-1.2.2.2 36-1.2.2.2.1.r 37-1.2.2.2.1.1.1 39-1.2.2.2.2.1.1 (c / cause-01~e.0 :ARG0 (a2 / approve-01~e.12 :ARG0 (o / organization :name (n4 / name :op1 "FDA"~e.11)) :ARG1 (c3 / combine-01~e.5 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF"~e.4,15) :ARG1-of (c4 / combine-01~e.2,5 :ARG2~e.6 (i / inhibit-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.7)))))) :time (c5 / current~e.10) :purpose (m3 / medical-condition :name (n2 / name :op1 "melanoma"~e.23) :mod (g / gene~e.22 :name (n5 / name :op1 "BRAF"~e.15) :ARG2-of~e.22 (m2 / mutate-01~e.22 :value "V600"~e.19)))) :ARG1 (d / determine-01~e.27 :ARG0 (w / we~e.25) :ARG1 (h / have-percentage-maximal-inhibitory-concentration-01~e.29 :ARG2 50~e.31 :ARG1~e.33 (c2 / combine-01~e.35 :ARG1~e.36 (s / small-molecule :name (n6 / name :op1 "vemurafenib"~e.37)) :ARG2 (s2 / small-molecule :name (n7 / name :op1 "trametinib"~e.39)))) :mod (a / also~e.26))) # ::id a_pmid_2514_2146.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed potent growth inhibition and synergy in all cell lines . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.1.2 4-1.2.1.1 5-1.2.1 6-1.2 7-1.2.2 8-1.2.r 9-1.2.3.1 10-1.2.3 11-1.2.3 (s / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.8 (a / and~e.6 :op1 (i / inhibit-01~e.5 :ARG1 (g / grow-01~e.4) :mod (p / potent~e.3)) :op2 (s2 / synergize-01~e.7) :location (c / cell-line~e.10,11 :mod (a2 / all~e.9)))) # ::id a_pmid_2514_2146.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity to the vemurafenib + trametinib combination generally overlapped with sensitivity to the vemurafenib + SCH722984 combination ( Figure 5 @ D ) , consistent with the idea that both combinations cause dual MAPK blockade . # ::alignments 0-1.1 3-1.1.1.1.1.1.1 4-1.5.1.1.1 5-1.5.1.1.1.1 6-1.1.1.1 6-1.2.1.1 7-1.3 8-1 10-1.1 10-1.2 11-1.5.1.1 13-1.5.1.1.1.1 14-1.5.1.1.1 15-1.2.1.1.2.1.1 16-1.1.1.1 16-1.2.1.1 18-1.4.1 25-1.5 28-1.5.1 31-1.1.1.1 31-1.2.1.1 32-1.5.1.1 33-1.5.1.1.2.2 34-1.5.1.1.2.1.1.1 35-1.5.1.1.2 (o / overlap-01~e.8 :ARG0 (s / sensitive-03~e.0,10 :ARG1 (t / thing :ARG3-of (c / combine-01~e.6,16,31 :ARG1 (s4 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.3)) :ARG2 (s5 / small-molecule :name (n4 / name :op1 "trametinib"))))) :ARG1 (s2 / sensitive-03~e.10 :ARG1 (t2 / thing :ARG3-of (c2 / combine-01~e.6,16,31 :ARG1 s4 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "SCH722984"~e.15))))) :ARG1-of (g / general-02~e.7) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "5D")) :ARG1-of (c4 / consistent-01~e.25 :ARG2 (i / idea~e.28 :topic (c5 / cause-01~e.11,32 :ARG0 (a / and~e.4,14 :op1 t~e.5,13 :op2 t2) :ARG1 (b / blockade-01~e.35 :ARG1 (p / pathway :name (n / name :op1 "MAPK"~e.34)) :mod (d2 / dual~e.33)))))) # ::id a_pmid_2514_2146.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The growth curves for the vemurafenib + trametinib combinations are shown in Additional file 5 @ : Figure S5 . # ::alignments 1-1.2.1 2-1.2 3-1.2.1.1.r 5-1.2.1.1.1.1.1 7-1.2.1.1.2.1.1 8-1.2.1.1 10-1 11-1.1.r 12-1.1.2 13-1.1 15-1.1.1 18-1.1.3.1 19-1.1.3.1.1 (s / show-01~e.10 :ARG0~e.11 (f / file~e.13 :mod 5~e.15 :mod (a / additional~e.12) :ARG1-of (m / mean-01 :ARG2 (f2 / figure~e.18 :mod "S5"~e.19))) :ARG1 (c / curve~e.2 :topic (g / grow-01~e.1 :ARG1~e.3 (c2 / combine-01~e.8 :ARG1 (s2 / small-molecule :name (n / name :op1 "vemurafenib"~e.5)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "trametinib"~e.7)))))) # ::id a_pmid_2514_2146.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of MAPK pathway inhibition on cell cycle progression and apoptosis # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1 3-1.1.1 4-1.1 5-1.2.r 6-1.2.1.1.1 7-1.2.1.1 8-1.2.1 9-1.2 10-1.2.2 (a / affect-01~e.0 :ARG0~e.1 (i / inhibit-01~e.4 :ARG0 (p / pathway~e.3 :name (n / name :op1 "MAPK"~e.2))) :ARG1~e.5 (a2 / and~e.9 :op1 (p2 / progress-01~e.8 :ARG1 (c / cycle-02~e.7 :ARG1 (c2 / cell~e.6))) :op2 (a3 / apoptosis~e.10))) # ::id a_pmid_2514_2146.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine the effect of BRAF or ERK inhibition on cell cycle progression and apoptosis , cells were treated with SCH772984 , alone or in combination with vemurafenib for 48 hours then stained with DAPI and intracellularly for cleaved PARP and analyzed by flow cytometry . # ::alignments 1-1.4 3-1.4.1 4-1.4.1.1.r 5-1.4.1.1.1.1.1.1 6-1.4.1.1.1 7-1.4.1.1.1.2.1.1 8-1.4.1.1 9-1.4.1.2.r 10-1.4.1.2.1.1.1 11-1.4.1.2.1.1 12-1.4.1.2.1 13-1.4.1.2 14-1.4.1.2.2 16-1.1.1 18-1.1 19-1.1.2.r 20-1.1.2.1.1.1 22-1.1.2.1.2 23-1.1.2 25-1.1.2.2 26-1.1.2.2.2.r 27-1.1.2.2.2.1.1 28-1.1.3.r 29-1.1.3.1 30-1.1.3.2 31-1.2.5 32-1.2 33-1.2.2.r 34-1.2.2.1.1 37-1.2.4.r 38-1.2.4.2 39-1.2.4.1.1 40-1 41-1.3 42-1.3.2.r 43-1.3.2.1 44-1.3.2 (a / and~e.40 :op1 (t2 / treat-04~e.18 :ARG1 (c6 / cell-line~e.16) :ARG2~e.19 (o2 / or~e.23 :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984"~e.20) :mod (a5 / alone~e.22)) :op2 (c4 / combine-01~e.25 :ARG1 s2 :ARG2~e.26 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"~e.27)))) :duration~e.28 (t / temporal-quantity :quant 48~e.29 :unit (h / hour~e.30))) :op2 (s / stain-01~e.32 :ARG1 c6 :ARG2~e.33 (s4 / small-molecule :name (n4 / name :op1 "DAPI"~e.34)) :manner (i3 / intracellular) :purpose~e.37 (p2 / protein :name (n5 / name :op1 "PARP"~e.39) :ARG1-of (c3 / cleave-01~e.38)) :time (t3 / then~e.31)) :op3 (a6 / analyze-01~e.41 :ARG1 c6 :manner~e.42 (c5 / cytometry~e.44 :mod (f / flow~e.43))) :purpose (d / determine-01~e.1 :ARG1 (a2 / affect-01~e.3 :ARG0~e.4 (i / inhibit-01~e.8 :ARG1 (o3 / or~e.6 :op1 (e2 / enzyme :name (n / name :op1 "BRAF"~e.5)) :op2 (e / enzyme :name (n2 / name :op1 "ERK"~e.7)))) :ARG1~e.9 (a3 / and~e.13 :op1 (p / progress-01~e.12 :ARG1 (c / cycle-02~e.11 :ARG1 (c2 / cell~e.10))) :op2 (a4 / apoptosis~e.14))))) # ::id a_pmid_2514_2146.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with either of these two inhibitors resulted in an increase in the sub @-@ G0 population , the G1 population , as well as an increase in cleaved PARP levels which indicates apoptotic cells ( Figure 6 @ A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.3 4-1.1.1.2.1.2 5-1.1.1.2.1.1 6-1.1.1 6-1.1.1.1 6-1.1.1.1.r 7-1 8-1.2.r 10-1.2 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1 16-1.2.1.1 19-1.2.1.2.1.1.1 20-1.2.1.1 20-1.2.1.2 22-1.2.1 23-1.2.1 24-1.2.1 26-1.2 27-1.2.1.r 28-1.2.1.3.2 29-1.2.1.3.1.1.1 30-1.2.1.3 32-1.2.1.4 33-1.2.1.4.1.1 34-1.2.1.4.1 36-1.3.1 (r / result-01~e.7 :ARG1 (t2 / treat-04~e.0 :ARG1~e.1 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6) :ARG1-of (i4 / include-91 :ARG2 (m2 / molecular-physical-entity :quant 2~e.5 :mod (t3 / this~e.4))) :mod (e / either~e.2))) :ARG2~e.8 (i2 / increase-01~e.10,26 :ARG1~e.27 (a / and~e.22,23,24 :op1 (p / population~e.16,20 :mod (e2 / event :name (n / name :op1 "sub-G0"~e.13,15))) :op2 (p4 / population~e.20 :mod (e3 / event :name (n3 / name :op1 "G1"~e.19))) :op3 (l / level~e.30 :quant-of (p3 / protein :name (n2 / name :op1 "PARP"~e.29)) :ARG1-of (c2 / cleave-01~e.28)) :ARG0-of (i3 / indicate-01~e.32 :ARG1 (c / cell~e.34 :mod (a2 / apoptosis~e.33))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "6A"))) # ::id a_pmid_2514_2146.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A modest increase of 3 @-@ 10 % was seen in the sub @-@ G0 population for all cell lines treated with vemurafenib , SCH772984 or the combination . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1 6-1.1.1.2.1 7-1.1.1.1 7-1.1.1.2 9-1 10-1.2.r 12-1.2.2.1.1 15-1.2 16-1.2.1.r 17-1.2.1.1 18-1.2.1 19-1.2.1 20-1.2.1.2 21-1.2.1.2.1.r 22-1.2.1.2.1.1.1.1 24-1.2.1.2.1.2.1.1 25-1.2.1.2.1 27-1.2.1.2.1.3 (s / see-01~e.9 :ARG1 (i / increase-01~e.2 :ARG2~e.3 (v / value-interval :op1 (p2 / percentage-entity~e.7 :value 3~e.4) :op2 (p / percentage-entity~e.7 :value 10~e.6)) :mod (m / modest~e.1)) :location~e.10 (p3 / populate-01~e.15 :ARG1~e.16 (c / cell-line~e.18,19 :mod (a / all~e.17) :ARG1-of (t / treat-04~e.20 :ARG2~e.21 (o / or~e.25 :op1 (s3 / small-molecule :name (n2 / name :op1 "vemurafenib"~e.22)) :op2 (s2 / small-molecule :name (n / name :op1 "SCH772984"~e.24)) :op3 (c3 / combine-01~e.27 :ARG1 s3 :ARG2 s2)))) :time (e / event :name (n3 / name :op1 "sub-GO"~e.12)))) # ::id a_pmid_2514_2146.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The amount of subG1 increase did not correlate with sensitivity or resistance to the MAPK pathway inhibitors . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1.1.1 4-1.2.1 6-1.1 6-1.1.r 7-1 8-1.3.r 9-1.3.1 10-1.3 11-1.3.2 12-1.3.1.1.r 14-1.3.1.1.1.1.1.1 15-1.3.1.1.1.1 16-1.3.1.1 16-1.3.1.1.1 16-1.3.1.1.1.r (c / correlate-01~e.7 :polarity~e.6 -~e.6 :ARG1 (a / amount-01~e.1 :ARG1~e.2 (i2 / increase-01~e.4 :time (e / event :name (n2 / name :op1 "subG1"~e.3)))) :ARG2~e.8 (o / or~e.10 :op1 (s / sensitive-03~e.9 :ARG1~e.12 (m / molecular-physical-entity~e.16 :ARG0-of~e.16 (i3 / inhibit-01~e.16 :ARG1 (p2 / pathway~e.15 :name (n3 / name :op1 "MAPK"~e.14))))) :op2 (r / resist-01~e.11 :ARG1 m))) # ::id a_pmid_2514_2146.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , for the G0 @-@ G1 populations , there was a correlation with sensitivity , with an up to 40 % increase in G0 @-@ G1 population seen in the sensitive cell lines M238 and M792 , while the resistant cell lines M233 and M299 demonstrated only a 10 % increase in the G0 @-@ G1 population for the combination treatment . # ::alignments 1-1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1 13-1.1 14-1.1.2.r 14-1.1.3.r 15-1.1.2 17-1.1.3.r 19-1.1.3 19-1.1.3.2 19-1.1.3.2.r 20-1.1.3.2 21-1.1.3.2.1.1 22-1.1.3.2.1 23-1.1.3 24-1.1.3.1.r 25-1.1.3.1 26-1.1.3.1 27-1.1.3.1 28-1.1.3.1 29-1.1.3.3 30-1.1.3.3.1.r 32-1.1.3.3.1.3 33-1.1.3.3.1.1 34-1.1.3.3.1.1 34-1.1.3.3.1.2 35-1.1.3.3.1.1.1.1 36-1.1.3.3.1 37-1.1.3.3.1.2.1.1 39-1 41-1.2.1.4 42-1.1.3.3.1.1 43-1.2.1.1 43-1.2.1.2 44-1.2.1.1.1.1 45-1.2.1 46-1.2.1.2.1.1 47-1.2 50-1.2.2.2.1 51-1.2.2.2 52-1.2.2 53-1.2.2.1.r 55-1.2.2.1 56-1.2.2.1 57-1.2.2.1 58-1.2.2.1 59-1.2.1.r 61-1.2.1.3.1 62-1.2.1.3 (c / contrast-01~e.1,39 :ARG1 (c2 / correlate-01~e.13 :ARG1 (p / population~e.8 :mod (e / event :name (n3 / name :op1 "G0-G1"~e.5,7))) :ARG2~e.14 (s3 / sensitive-03~e.15) :prep-with~e.14,17 (i / increase-01~e.19,23 :ARG1~e.24 p~e.25,26,27,28 :ARG2~e.19 (u / up-to~e.19,20 :op1 (p3 / percentage-entity~e.22 :value 40~e.21)) :ARG1-of (s / see-01~e.29 :location~e.30 (a / and~e.36 :op1 (c3 / cell-line~e.33,34,42 :name (n / name :op1 "M238"~e.35)) :op2 (c4 / cell-line~e.34 :name (n2 / name :op1 "M792"~e.37)) :ARG0-of (s2 / sensitive-03~e.32))))) :ARG2 (d / demonstrate-01~e.47 :ARG0~e.59 (a2 / and~e.45 :op1 (c5 / cell-line~e.43 :name (n4 / name :op1 "M233"~e.44)) :op2 (c6 / cell-line~e.43 :name (n5 / name :op1 "M299"~e.46)) :ARG1-of (t / treat-04~e.62 :ARG2 (c7 / combine-01~e.61)) :ARG0-of (r / resist-01~e.41)) :ARG1 (i2 / increase-01~e.52 :ARG1~e.53 p~e.55,56,57,58 :ARG2 (p4 / percentage-entity~e.51 :value 10~e.50)))) # ::id a_pmid_2514_2146.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concomitant with the increase in G0 @-@ G1 , a decreased proportion of cells were observed in S @-@ phase , with the largest decreases of over 20 % seen in the sensitive cell lines M792 and M238 ( Figure 6 @ B ) . # ::alignments 0-1.3 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1 7-1.1.2.1.1.1 10-1.1.1.2 11-1.1.1 12-1.1.1.1.r 13-1.1.1.1 15-1 16-1.1.1.2.1.r 17-1.1.1.2.1.1.1 19-1.1.1.2.1.1.1 21-1.1.r 23-1.1.3.2 23-1.1.3.2.1 23-1.1.3.2.1.r 24-1.1.3 25-1.1.3.1.r 26-1.1.3.1 27-1.1.3.1.1.1 28-1.1.3.1.1 29-1.1.3.3 30-1.1.3.3.1.r 32-1.1.3.3.1.3 33-1.1.3.3.1.1 34-1.1.3.3.1.1 34-1.1.3.3.1.2 35-1.1.3.3.1.1.1.1 36-1.1.3.3.1 37-1.1.3.3.1.2.1.1 39-1.2.1 (o / observe-01~e.15 :ARG1~e.21 (a2 / and :op1 (p3 / proportion-01~e.11 :ARG1~e.12 (c / cell~e.13) :ARG1-of (d2 / decrease-01~e.10 :time~e.16 (e / event :name (n5 / name :op1 "S-phase"~e.17,19)))) :op2 (i / increase-01~e.3 :time~e.4 (e2 / event :name (n / name :op1 "G0-G1"~e.5,7))) :op3 (d3 / decrease-01~e.24 :ARG2~e.25 (o2 / over~e.26 :op1 (p5 / percentage-entity~e.28 :value 20~e.27)) :mod (l2 / large~e.23 :degree~e.23 (m2 / most~e.23)) :ARG1-of (s / see-01~e.29 :location~e.30 (a / and~e.36 :op1 (c2 / cell-line~e.33,34 :name (n3 / name :op1 "M792"~e.35)) :op2 (c3 / cell-line~e.34 :name (n4 / name :op1 "M238"~e.37)) :ARG0-of (s2 / sensitive-03~e.32))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod "6B")) :mod (c4 / concomitant~e.0)) # ::id a_pmid_2514_2146.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of the sensitive cell lines , M238 and M792 , with SCH772984 alone or in combination with vemurafenib resulted in a dramatic increase in cleaved PARP reaching induced percentages around 40 @-@ 50 % . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.3 4-1.1.1.1 5-1.1.1.1 5-1.1.1.2 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.1.1 11-1.1.2.r 12-1.1.2.1.1.1 13-1.1.2.1.2 14-1.1.2 16-1.1.2.2 17-1.1.2.2.2.r 18-1.1.2.2.2.1.1 19-1 20-1.2.r 22-1.2.2 23-1.2 24-1.2.1.r 25-1.2.1.2 26-1.2.1.1.1 27-1.2.1.3 28-1.2.1.3.1.1 29-1.2.1.3.1 29-1.2.1.3.1.2.1.1.1 30-1.2.1.3.1.2.1 30-1.2.1.3.1.2.1.1.3 31-1.2.1.3.1.2.1.1.1.1 33-1.2.1.3.1.2.1.1.2.1 34-1.2.1.3.1.2.1.1.2 (r / result-01~e.19 :ARG1 (t / treat-04~e.0 :ARG1~e.1 (a2 / and~e.8 :op1 (c2 / cell-line~e.4,5 :name (n / name :op1 "M238"~e.7)) :op2 (c3 / cell-line~e.5 :name (n2 / name :op1 "M792"~e.9)) :ARG0-of (s / sensitive-03~e.3)) :ARG2~e.11 (o / or~e.14 :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984"~e.12) :mod (a3 / alone~e.13)) :op2 (c / combine-01~e.16 :ARG1 s2 :ARG2~e.17 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib"~e.18))))) :ARG2~e.20 (i / increase-01~e.23 :ARG1~e.24 (p2 / protein :name (n5 / name :op1 "PARP"~e.26) :ARG1-of (c4 / cleave-01~e.25) :ARG0-of (r2 / reach-01~e.27 :ARG1 (p3 / percentage~e.29 :ARG2-of (i2 / induce-01~e.28) :ARG1-of (e2 / equal-01 :ARG2 (a4 / around~e.30 :op1 (v / value-interval :op1 (p4 / percentage-entity~e.29 :value 40~e.31) :op2 (p5 / percentage-entity~e.34 :value 50~e.33) :mod (a / around~e.30))))))) :degree (d / dramatic~e.22))) # ::id a_pmid_2514_2146.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In comparison , the resistant cell lines ( M233 and M299 ) had cleaved PARP at 20 @-@ 25 % ( Figure 6 @ C ) . # ::alignments 1-1 4-1.1.1.3 5-1.1.1.1 6-1.1.1.1 6-1.1.1.2 8-1.1.1.1.1.1 9-1.1.1 10-1.1.1.2.1.1 12-1.1 13-1.1.2.2 14-1.1.2.1.1 16-1.1.2.3.1.1 18-1.1.2.3.2.1 19-1.1.2.3.1 19-1.1.2.3.2 21-1.2.1 (c / compare-01~e.1 :ARG2 (h / have-03~e.12 :ARG0 (a / and~e.9 :op1 (c3 / cell-line~e.5,6 :name (n / name :op1 "M233"~e.8)) :op2 (c4 / cell-line~e.6 :name (n2 / name :op1 "M299"~e.10)) :ARG0-of (r / resist-01~e.4)) :ARG1 (p2 / protein :name (n3 / name :op1 "PARP"~e.14) :ARG1-of (c2 / cleave-01~e.13) :quant (v / value-interval :op1 (p / percentage-entity~e.19 :value 20~e.16) :op2 (p3 / percentage-entity~e.19 :value 25~e.18)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "6C"))) # ::id a_pmid_2514_2146.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With the exception of M299 , a statistically significant increase in cleaved PARP was seen in all cell lines treated with SCH772984 , or the combination of SCH772984 and vemurafenib , compared to vemurafenib alone . # ::alignments 2-1.1.3.2 3-1.1.3.2.1.r 4-1.1.3.2.1.1.1 7-1.1.2.1 8-1.1.2 9-1.1 10-1.1.1.r 11-1.1.1.2 12-1.1.1.1.1 14-1 16-1.1.3.3 17-1.1.3 18-1.1.3 19-1.1.3.1 19-1.1.4 20-1.1.3.1.1.r 21-1.1.3.1.1.1.1.1 23-1.1.3.1.1 25-1.1.3.1.1.2 26-1.1.3.1.1.2.1.r 27-1.1.3.1.1.2.1 29-1.1.4.1 31-1.1.4.r 33-1.1.4.1 34-1.1.4.2 (s / see-01~e.14 :ARG1 (i / increase-01~e.9 :ARG1~e.10 (p / protein :name (n / name :op1 "PARP"~e.12) :ARG1-of (c / cleave-01~e.11)) :ARG2 (s2 / significant-02~e.8 :mod (s3 / statistics~e.7)) :location (c2 / cell-line~e.17,18 :ARG1-of (t / treat-04~e.19 :ARG2~e.20 (o / or~e.23 :op1 (s4 / small-molecule :name (n2 / name :op1 "SCH772984"~e.21)) :op2 (c3 / combine-01~e.25 :ARG1~e.26 s4~e.27 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "vemurafenib"))))) :ARG2-of (e3 / except-01~e.2 :ARG1~e.3 (c4 / cell-line :name (n5 / name :op1 "M299"~e.4))) :mod (a2 / all~e.16)) :compared-to~e.31 (t2 / treat-04~e.19 :ARG2 s5~e.29,33 :mod (a / alone~e.34)))) # ::id a_pmid_2514_2146.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combinatorial treatment offered a statistically significant increase in cleaved PARP compared to vemurafenib alone in all cell lines ( 20 % increase in sensitive cell lines and 10 % increase in resistant cell lines compared to vemurafenib alone ) . # ::alignments 1-1.1 1-1.2.3.1 2-1 2-1.2.3 4-1.2.2.1 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.2 9-1.2.1.1.1 10-1.2.3.r 11-1.2.3.1.1.r 12-1.2.3.1.1.1.1 13-1.2.3.1.1.2 14-1.2.4.r 15-1.2.4.1 16-1.2.4 17-1.2.4 19-1.2.5.1.1.1.1 20-1.2.5.1.1.1 21-1.2.5.1.1 22-1.2.5.1.1.2.r 23-1.2.5.1.1.2.1 24-1.2.5.1.1.2 25-1.2.5.1.1.2 26-1.2.5.1 27-1.2.5.1.2.1.1 28-1.2.5.1.2.1 29-1.2.5.1.2 30-1.2.5.1.2.2.r 31-1.2.5.1.2.2.1 32-1.2.5.1.2.2 33-1.2.5.1.2.2 34-1.2.3.r 36-1.2.3.1.1.1.1 37-1.2.3.1.1.2 (o / offer-01~e.2 :ARG0 (t / treat-04~e.1 :mod (c / combine-01)) :ARG1 (i / increase-01~e.6 :ARG1~e.7 (p3 / protein :name (n / name :op1 "PARP"~e.9) :ARG1-of (c2 / cleave-01~e.8)) :ARG2 (s / significant-02~e.5 :mod (s2 / statistics~e.4)) :compared-to~e.10,34 (o2 / offer-01~e.2 :ARG0 (t2 / treat-04~e.1 :ARG2~e.11 (s4 / small-molecule :name (n2 / name :op1 "vemurafenib"~e.12,36) :mod (a2 / alone~e.13,37)))) :location~e.14 (c3 / cell-line~e.16,17 :mod (a / all~e.15)) :ARG1-of (e2 / equal-01 :ARG2 (a3 / and~e.26 :op1 (i3 / increase-01~e.21 :ARG2 (p4 / percentage-entity~e.20 :value 20~e.19) :location~e.22 (c4 / cell-line~e.24,25 :ARG1-of (s3 / sensitive-03~e.23))) :op2 (i4 / increase-01~e.29 :ARG2 (p5 / percentage-entity~e.28 :value 10~e.27) :location~e.30 (c5 / cell-line~e.32,33 :ARG0-of (r / resist-01~e.31))))))) # ::id a_pmid_2514_2146.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However only a trend towards increased cleaved PARP fractions was observed comparing combinatorial treatment with SCH772984 alone without reaching statistical significance . @ Figure 6 @

Effect of SCH722984 , vemurafenib or the combination on cell cycle progression and apoptosis in BRAF @-@ mutant melanoma cell lines . # ::alignments 0-1.1 1-1.1.1.1.2 3-1.1.1.1 5-1.1.1.1.1.2 6-1.1.1.1.1.1.2 7-1.1.1.1.1.1.1.1 8-1.1.1.1.1 10-1.1.1 11-1.1.1.2 13-1.1.1.2.1 13-1.1.1.2.2 14-1.1.1.2.2.1.r 15-1.1.1.2.2.1.1.1 16-1.1.1.2.2.1.2 17-1.1.1.1.1.2.1.1 17-1.1.1.1.1.2.1.1.r 18-1.1.1.1.1.2.1 19-1.1.1.1.1.2.1.2.1 20-1.1.1.1.1.2.1.2 24-1.2.4.1 25-1.2.4.1.1 30-1.2 31-1.2.1.r 32-1.2.1.1.1.1 34-1.2.1.2.1.1 35-1.2.1 37-1.1.1.2.1.1 37-1.2.1.3 38-1.2.3.r 39-1.2.3 40-1.2.2.1.1 41-1.2.2.1 42-1.2.2 43-1.2.2.2 45-1.2.3.1.2.1.1 47-1.2.3.1.2 47-1.2.3.1.2.2 47-1.2.3.1.2.2.r 48-1.2.3.1.1.1 49-1.2.2.1.1.1 50-1.2.3 (m / multi-sentence :snt1 (c8 / contrast-01~e.0 :ARG2 (o / observe-01~e.10 :ARG1 (t / trend-01~e.3 :ARG2 (f / fraction-01~e.8 :ARG1 (p / protein :name (n / name :op1 "PARP"~e.7) :ARG1-of (c / cleave-01~e.6)) :ARG1-of (i / increase-01~e.5 :ARG0-of (r / reach-01~e.18 :polarity~e.17 -~e.17 :ARG1 (s2 / significant-02~e.20 :mod (s3 / statistics~e.19))))) :mod (o3 / only~e.1)) :condition (c2 / compare-01~e.11 :ARG1 (t2 / treat-04~e.13 :mod (c3 / combine-01~e.37)) :ARG2 (t3 / treat-04~e.13 :ARG2~e.14 (s / small-molecule :name (n2 / name :op1 "SCH772984"~e.15) :mod (a3 / alone~e.16)))))) :snt2 (a / affect-01~e.30 :ARG0~e.31 (o2 / or~e.35 :op1 (s4 / small-molecule :name (n3 / name :op1 "SCH722984"~e.32)) :op2 (s5 / small-molecule :name (n4 / name :op1 "vemurafenib"~e.34)) :op3 (c4 / combine-01~e.37 :ARG1 s4 :ARG2 s5)) :ARG1 (a2 / and~e.42 :op1 (p2 / progress-01~e.41 :ARG1 (c5 / cycle-02~e.40 :ARG1 (c6 / cell~e.49))) :op2 (a4 / apoptosis~e.43)) :location~e.38 (c7 / cell-line~e.39,50 :mod (m3 / medical-condition :name (n6 / name :op1 "melanoma"~e.48) :mod (e2 / enzyme~e.47 :name (n7 / name :op1 "BRAF"~e.45) :ARG2-of~e.47 (m2 / mutate-01~e.47)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.24 :mod 6~e.25)))) # ::id a_pmid_2514_2146.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two sensitive cell lines ( M238 and M792 ) and two resistant cell lines ( M233 and M299 ) were exposed to DMSO as vehicle control ( Unst , control unstained : Control , control stained ) , 1 μM vemurafenib ( Vem ) , SCH722984 ( ERKi ) , the combination ( V + E ) or 1 μM staurosporine for 48 hours . # ::alignments 1-1.1.1.3 2-1.1.1.1 3-1.1.1.1 3-1.1.1.2 5-1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1 9-1.2.1 11-1.2.1.3 12-1.2.1.1 12-1.2.1.2 13-1.2.1.1 13-1.2.1.2 15-1.2.1.1.1.1 16-1.2.1 17-1.2.1.2.1.1 20-1.1 20-1.2 21-1.1.2.r 22-1.1.2.1.1.1 24-1.1.2.1.2.1 25-1.1.2.1 25-1.1.2.1.2 25-1.1.2.1.2.r 29-1.1.2.1 29-1.1.2.1.2 29-1.1.2.1.2.r 32-1.1.2.1 32-1.1.2.1.2 32-1.1.2.1.2.r 34-1.1.2.1 34-1.1.2.1.2 34-1.1.2.1.2.r 35-1.1.2.1.2.2.1.1 35-1.1.2.1.2.2.1.2 38-1.1.2.2.2.1 38-1.1.2.5.2.1 39-1.1.2.2.2.2 39-1.1.2.5.2.2 40-1.1.2.2.1.1 45-1.1.2.3.1.1 51-1.1.2.4 54-1.1.2.1.2.2.1 57-1.1.2 57-1.2.2 58-1.1.2.2.2.1 58-1.1.2.5.2.1 59-1.1.2.2.2.2 59-1.1.2.5.2.2 60-1.1.2.5.1.1 61-1.1.3.r 62-1.1.3.1 63-1.1.3.2 (a4 / and :op1 (e / expose-01~e.20 :ARG1 (a / and~e.6 :op1 (c2 / cell-line~e.2,3 :name (n / name :op1 "M238"~e.5)) :op2 (c3 / cell-line~e.3 :name (n2 / name :op1 "M792"~e.7)) :ARG0-of (s / sensitive-03~e.1)) :ARG2~e.21 (o / or~e.57 :op1 (s2 / small-molecule~e.25,29,32,34 :name (n5 / name :op1 "DMSO"~e.22) :ARG0-of~e.25,29,32,34 (c5 / control-01~e.25,29,32,34 :ARG1 (v / vehicle~e.24) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.54 :op1 (s3 / stain-01~e.35 :ARG1 c5) :op2 (s8 / stain-01~e.35 :polarity - :ARG1 c5))))) :op2 (s4 / small-molecule :name (n7 / name :op1 "vemurafenib"~e.40) :quant (c7 / concentration-quantity :quant 1~e.38,58 :unit (m2 / micromolar~e.39,59))) :op3 (s6 / small-molecule :name (n9 / name :op1 "SCH722984"~e.45) :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n6 / name :op1 "ERK")))) :op4 (c8 / combine-01~e.51 :ARG1 s4 :ARG2 s6 :ARG1-of (l / label-01 :ARG2 (s5 / string-entity :value "V+E"))) :op5 (s7 / small-molecule :name (n10 / name :op1 "staurosporine"~e.60) :quant (c9 / concentration-quantity :quant 1~e.38,58 :unit (m3 / micromolar~e.39,59)))) :duration~e.61 (t2 / temporal-quantity :quant 48~e.62 :unit (h2 / hour~e.63))) :op2 (e3 / expose-01~e.20 :ARG1 (a3 / and~e.9,16 :op1 (c / cell-line~e.12,13 :name (n3 / name :op1 "M233"~e.15)) :op2 (c4 / cell-line~e.12,13 :name (n4 / name :op1 "M299"~e.17)) :ARG0-of (r / resist-01~e.11)) :ARG2 (o2 / or~e.57 :op1 s2 :op2 s4 :op3 s6 :op4 c8 :op5 s7) :duration t2)) # ::id a_pmid_2514_2146.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "A"~e.1) # ::id a_pmid_2514_2146.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell cycle progression was tested by DAPI staining solution and induced apoptosis by cleaved PARP ( PARP @-@ Ax700 ) . # ::alignments 0-1.1.2.1.1 1-1.1.2.1 2-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1 9-1 10-1.2 11-1.2.2 12-1.2.3.r 13-1.2.3.2 14-1.2.3.1.1 14-1.2.3.3.1.1.1 16-1.2.3.1.1 16-1.2.3.3.1.1.1 18-1.2.3.3.1.2.1.1 (a / and~e.9 :op1 (t / test-01~e.4 :ARG0~e.5 (s / solution~e.8 :mod (s2 / stain-01~e.7 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "DAPI"~e.6)))) :ARG1 (p / progress-01~e.2 :ARG1 (c / cycle-02~e.1 :ARG1 (c2 / cell~e.0)))) :op2 (i / induce-01~e.10 :ARG0 p :ARG2 (a2 / apoptosis~e.11) :instrument~e.12 (p2 / protein :name (n2 / name :op1 "PARP"~e.14,16) :ARG1-of (c3 / cleave-01~e.13) :ARG1-of (e / equal-01 :ARG2 (p3 / protein :name (n3 / name :op1 "PARP"~e.14,16) :mod (s4 / small-molecule :name (n5 / name :op1 "Ax700"~e.18))))))) # ::id a_pmid_2514_2146.226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figures are representative of triplicate experiments . # ::alignments 0-1.1 2-1 5-1.2 (r2 / represent-01~e.2 :ARG0 (f / figure~e.0) :ARG1 (e / experiment~e.5 :quant 3)) # ::id a_pmid_2514_2146.227 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "B"~e.1) # ::id a_pmid_2514_2146.228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Quantitative analysis of the cell cycle progression by DAPI staining using flow cytometry shows the percentage of cells in sub @-@ G0 ( blue ) , G0 @/@ G1 ( red ) , S phase ( yellow ) , or G2/M ( green ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 4-1.1.1.1.1 5-1.1.1.1 6-1.1.1 7-1.1.1.2.r 8-1.1.1.2.1.1.1 9-1.1.1.2 10-1.1.1.2.2 11-1.1.1.2.2.1.1 12-1.1.1.2.2.1 13-1 15-1.2.1 15-1.2.2 15-1.2.3 15-1.2.4 17-1.2.1.1 17-1.2.2.1 17-1.2.3.1 17-1.2.4.1 18-1.2.1.1.2.r 19-1.2.1.1.2.1.1 21-1.2.1.1.2.1.1 23-1.2.1.1.1.1 26-1.2.2.1.2.1.1.1 27-1.2.2.1.2 27-1.2.4.1.2 28-1.2.2.1.2.2.1.1 30-1.2.2.1.1.1 33-1.2.3.1.2.1.1 34-1.2.3.1.2.1.2 36-1.2.3.1.1.1 39-1.2 42-1.2.4.1.1.1 (s / show-01~e.13 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (p / progress-01~e.6 :ARG1 (c / cycle-02~e.5 :ARG1 (c2 / cell~e.4)) :instrument~e.7 (s2 / stain-01~e.9 :ARG2 (s5 / small-molecule :name (n / name :op1 "DAPI"~e.8)) :ARG0-of (u / use-01~e.10 :ARG1 (c3 / cytometry~e.12 :mod (f / flow~e.11))))) :mod (q / quantitative~e.0)) :ARG1 (o / or~e.39 :op1 (p2 / percentage~e.15 :quant-of (c4 / cell~e.17 :ARG1-of (c5 / color-01 :ARG2 (b / blue~e.23)) :mod~e.18 (e / event :name (n2 / name :op1 "sub-G0"~e.19,21)))) :op2 (p3 / percentage~e.15 :quant-of (c6 / cell~e.17 :ARG1-of (c7 / color-01 :ARG2 (r / red-02~e.30)) :mod (s3 / slash~e.27 :op1 (e2 / event :name (n6 / name :op1 "G0"~e.26)) :op2 (e3 / event :name (n7 / name :op1 "G1"~e.28))))) :op3 (p4 / percentage~e.15 :quant-of (c8 / cell~e.17 :ARG1-of (c9 / color-01 :ARG2 (y / yellow-02~e.36)) :mod (e4 / event :name (n5 / name :op1 "S"~e.33 :op2 "phase"~e.34)))) :op4 (p5 / percentage~e.15 :quant-of (c10 / cell~e.17 :ARG1-of (c11 / color-01 :ARG2 (g / green-02~e.42)) :mod (s4 / slash~e.27 :op1 (e5 / event :name (n3 / name :op1 "G2")) :op2 (e6 / event :name (n8 / name :op1 "M"))))))) # ::id a_pmid_2514_2146.229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Numbers on the bar graph represent percentage of cells in G0/G1 . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1 6-1.2 7-1.2.1.r 8-1.2.1 (r / represent-01~e.5 :ARG0 (n / number~e.0 :mod~e.1 (g / graph~e.4 :mod (b / bar~e.3))) :ARG1 (p / percentage~e.6 :quant-of~e.7 (c / cell~e.8) :mod (s / slash :op1 (e / event :name (n2 / name :op1 "G0")) :op2 (e2 / event :name (n3 / name :op1 "G1"))))) # ::id a_pmid_2514_2146.230 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Columns represent mean values of three independent experiments ( n = 3 ) ; bars , SEM . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.1 2-1.1.3 2-1.3 3-1.1.2 4-1.1.2.2.r 5-1.1.2.2.1 6-1.1.2.2.2 6-1.1.2.2.2.1 6-1.1.2.2.2.1.r 7-1.1.2.2 9-1.1.3.1.2.1.1 11-1.1.2.2.1 11-1.1.3.1.1 14-1.2 (a / and :op1 (r / represent-01~e.1 :ARG0 (c / column~e.0) :ARG1 (v / value~e.3 :mod (m / mean~e.2) :poss~e.4 (e / experiment~e.7 :quant 3~e.5,11 :ARG0-of (d / depend-01~e.6 :polarity~e.6 -~e.6))) :ARG1-of (m2 / mean-01~e.2 :ARG2 (e2 / equal-01 :ARG2 3~e.11 :ARG1 (v2 / variable :name (n / name :op1 "n"~e.9))))) :op2 (b / bar~e.14) :op3 (m3 / mean~e.2 :mod (e3 / error :ARG1-of (s / standard-02)))) # ::id a_pmid_2514_2146.231 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C @ . # ::alignments 1-1.1 (s / string-entity :value "C"~e.1) # ::id a_pmid_2514_2146.232 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Apoptosis in response to MAPK inhibitors . # ::alignments 0-1.2 2-1 3-1.1.r 4-1.1.1.1.1.1 5-1.1 5-1.1.1 5-1.1.1.r (r / respond-01~e.2 :ARG1~e.3 (m / molecular-physical-entity~e.5 :ARG0-of~e.5 (i / inhibit-01~e.5 :ARG1 (p / protein-family :name (n3 / name :op1 "MAPK"~e.4)))) :ARG2 (a / apoptosis~e.0)) # ::id a_pmid_2514_2146.233 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Percentage of apoptotic cells positive for cleaved PARP ( PARP @-@ Ax700 ) in this four melanoma cell lines . # ::alignments 0-1 1-1.1.r 2-1.1.2 3-1.1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.2 7-1.1.1.1.1.1 7-1.1.1.1.2.1.1.1 9-1.1.1.1.2.1.1.1 11-1.1.1.1.2.1.2.1.1 13-1.2.r 14-1.2.3 15-1.2.1 16-1.2.2.1.1 17-1.2 18-1.2 (p6 / percentage~e.0 :quant-of~e.1 (c / cell~e.3 :mod (p5 / positive~e.4 :topic~e.5 (p3 / protein :name (n2 / name :op1 "PARP"~e.7) :ARG1-of (c2 / cleave-01~e.6 :ARG2 (p4 / protein :name (n3 / name :op1 "PARP"~e.7,9) :mod (s / small-molecule :name (n5 / name :op1 "Ax700"~e.11)))))) :mod (a / apoptosis~e.2)) :location~e.13 (c3 / cell-line~e.17,18 :quant 4~e.15 :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma"~e.16)) :mod (t2 / this~e.14))) # ::id a_pmid_2514_2146.234 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Columns represent mean values of three independent experiments ( n = 3 ) ; bars , SEM ; *, P < 0.05 .

@ @ @ # ::alignments 0-1.1.1 1-1.1 2-1.1.2.1 2-1.3 3-1.1.2 4-1.1.2.2.r 5-1.1.2.2.1 6-1.1.2.2.2 6-1.1.2.2.2.1 6-1.1.2.2.2.1.r 7-1.1.2.2 11-1.1.2.2.1 14-1.2 19-1.4 20-1.4.1 21-1.4.1.1 (a / and :op1 (r / represent-01~e.1 :ARG0 (c / column~e.0) :ARG1 (v / value~e.3 :mod (m / mean~e.2) :poss~e.4 (e / experiment~e.7 :quant 3~e.5,11 :ARG0-of (d / depend-01~e.6 :polarity~e.6 -~e.6)))) :op2 (b / bar~e.14) :op3 (m2 / mean-01~e.2 :mod (e2 / error :ARG1-of (s / standard-02))) :op3 (s2 / statistical-test-91~e.19 :ARG2 (l / less-than~e.20 :op1 0.05~e.21))) # ::id a_pmid_2514_2146.235 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To address whether there are differences in MEK inhibition or ERK inhibition on apoptosis , we performed cell cycle analysis on three melanoma cell lines with distinct sensitivity profile to SCH772984 : M263 ( sensitive ) , M255 ( intermediately sensitive ) and M370 ( resistant ) . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 5-1.3.2 6-1.3.2.2.r 7-1.3.2.2.1.1.1 8-1.3.2.2 8-1.3.2.3 10-1.3.2.3.1.1.1 11-1.3.2.2 12-1.3.2.4.r 13-1.3.2.4 15-1.1 16-1 17-1.2.2.1 18-1.2.2 19-1.2 20-1.2.3.r 21-1.2.3.1 22-1.2.3.2.1.1 23-1.2.3 24-1.2.3 26-1.2.3.3.1.1.3 27-1.2.3.3.1.1 27-1.2.3.4.1.1 27-1.2.3.4.1.1.2 27-1.2.3.4.1.1.2.r 28-1.2.3.3.1 30-1.2.3.3.1.1.2.1.1 32-1.2.3.4.1.1.1.1 34-1.2.3.3.1.1 37-1.2.3.4.1.2.1.1 39-1.2.3.4.1.2.2.2 40-1.2.3.4.1.2 40-1.2.3.4.1.2.2 40-1.2.3.4.1.2.2.r 42-1.2.3.4.1 43-1.2.3.4.1.3.1.1 45-1.2.3.4.1.3 45-1.2.3.4.1.3.2 45-1.2.3.4.1.3.2.r (p / perform-01~e.16 :ARG0 (w / we~e.15) :ARG1 (a / analyze-01~e.19 :ARG0 w :ARG1 (c / cycle-02~e.18 :ARG1 (c2 / cell~e.17)) :location~e.20 (c3 / cell-line~e.23,24 :quant 3~e.21 :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma"~e.22)) :ARG0-of (h / have-03 :ARG1 (p2 / profile-01~e.28 :ARG1 (s / sensitive-03~e.27,34 :ARG0 c3 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"~e.30)) :mod (d2 / distinct~e.26)))) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.42 :op1 (c4 / cell-line~e.27 :name (n5 / name :op1 "M263"~e.32) :ARG0-of~e.27 (s3 / sensitive-03~e.27 :ARG1 s2)) :op2 (c5 / cell-line~e.40 :name (n6 / name :op1 "M255"~e.37) :ARG0-of~e.40 (s4 / sensitive-03~e.40 :ARG1 s2 :mod (i / intermediate~e.39))) :op3 (c6 / cell-line~e.45 :name (n7 / name :op1 "M370"~e.43) :ARG0-of~e.45 (r / resist-01~e.45 :ARG1 s2)))))) :purpose (a3 / address-02~e.1 :ARG0 w :ARG1 (d3 / differ-02~e.5 :mode~e.2 interrogative~e.2 :ARG1~e.6 (i2 / inhibit-01~e.8,11 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.7))) :ARG2 (i3 / inhibit-01~e.8 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.10))) :ARG3~e.12 (a4 / apoptosis~e.13)))) # ::id a_pmid_2514_2146.236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All three cell lines demonstrated good synergy for the combination of vemurafenib and SCH772984 . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 3-1.1 4-1 5-1.2.1 6-1.2 7-1.3.r 9-1.3 10-1.3.1.r 11-1.3.1.1.1 13-1.3.2.1.1 (d / demonstrate-01~e.4 :ARG0 (c / cell-line~e.2,3 :quant 3~e.1 :mod (a / all~e.0)) :ARG1 (s / synergize-01~e.6 :ARG1-of (g / good-02~e.5)) :condition~e.7 (c2 / combine-01~e.9 :ARG1~e.10 (s3 / small-molecule :name (n / name :op1 "vemurafenib"~e.11)) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"~e.13)))) # ::id a_pmid_2514_2146.237 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell lines treated with SCH772984 or the combination of vemurafenib + SCH772984 had the highest levels of cleaved PARP . # ::alignments 0-1.1 1-1.1 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1 7-1.1.1.1.2 8-1.1.1.1.2.1.r 9-1.1.1.1.2.1.1.1 11-1.1.1.1.2.2 12-1 14-1.2.1 14-1.2.1.1 14-1.2.1.1.r 15-1.2 16-1.2.2.r 17-1.2.2.2 18-1.2.2.1.1 (h2 / have-03~e.12 :ARG0 (c / cell-line~e.0,1 :ARG1-of (t / treat-04~e.2 :ARG2~e.3 (o / or~e.5 :op1 (s / small-molecule :name (n / name :op1 "SCH772984"~e.4)) :op2 (c2 / combine-01~e.7 :ARG1~e.8 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib"~e.9)) :ARG2 s~e.11)))) :ARG1 (l / level~e.15 :ARG1-of (h / high-02~e.14 :degree~e.14 (m / most~e.14)) :quant-of~e.16 (p / protein :name (n3 / name :op1 "PARP"~e.18) :ARG1-of (c3 / cleave-01~e.17)))) # ::id a_pmid_2514_2146.238 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In comparison , trametinib , did not induce the same levels of apoptosis in any case . # ::alignments 0-1.1.4.r 1-1 3-1.1.2.1.1 6-1.1.1 6-1.1.1.r 7-1.1 9-1.1.3.1 10-1.1.3 11-1.1.3.2.r 12-1.1.3.2 13-1.1.4.r 14-1.1.4.1 15-1.1.4 (c / compare-01~e.1 :ARG2 (i / induce-01~e.7 :polarity~e.6 -~e.6 :ARG0 (s2 / small-molecule :name (n / name :op1 "trametinib"~e.3)) :ARG2 (l / level~e.10 :ARG2-of (s / same-01~e.9) :degree-of~e.11 (a2 / apoptosis~e.12)) :prep-in~e.0,13 (c2 / case-04~e.15 :mod (a / any~e.14)))) # ::id a_pmid_2514_2146.239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In terms of effects on the cell cycle , G0 @-@ G1 arrest was maximally induced by ERK inhibition also ( Additional file 6 @ : Figure S6 ) . # ::alignments 3-1 4-1.1.r 6-1.1.1 7-1.1 9-1.2.2.1.1.1.1 11-1.2.2.1.2.1.1 12-1.2.2 14-1.2.4 14-1.2.4.r 15-1.2 16-1.2.1.r 17-1.2.1.1.1.1 18-1.2.1 19-1.2.3 22-1.3.1.2 24-1.3.1.2.1 27-1.3.1 28-1.3.1.1 (a3 / affect-01~e.3 :ARG1~e.4 (c / cycle-02~e.7 :ARG1 (c2 / cell~e.6)) :ARG2 (i / induce-01~e.15 :ARG0~e.16 (i2 / inhibit-01~e.18 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.17))) :ARG2 (a / arrest-02~e.12 :time (v / value-interval :op1 (e2 / event :name (n2 / name :op1 "G0"~e.9)) :op2 (e3 / event :name (n3 / name :op1 "G1"~e.11)))) :mod (a2 / also~e.19) :manner~e.14 (m / maximal~e.14)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "S6"~e.28 :location (f2 / file~e.22 :mod 6~e.24 :ARG1-of (a4 / add-02))))) # ::id a_pmid_2514_2146.240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This data support the potent activity of SCH772984 both as a single agent and in combination . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1.1.1 11-1.2.1.1.2.1 12-1.2.1.1.2 13-1.2.1 15-1.2.1.2 (s / support-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1 (a / activity-06~e.5 :ARG0~e.6 (a2 / and~e.13 :op1 (s2 / small-molecule :name (n / name :op1 "SCH772984"~e.7) :mod (a3 / agent~e.12 :ARG1-of (s3 / single-02~e.11))) :op2 (c / combine-01~e.15 :ARG1 s2)) :mod (p / potent~e.4))) # ::id a_pmid_2514_2146.241 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combining BRAF and ERK inhibition delays the development of resistance # ::alignments 0-1.1 1-1.1.1.1.1.1 3-1.1.2.1.1.1 4-1.1.1 4-1.1.2 5-1 7-1.2 8-1.2.1.r 9-1.2.1 (d / delay-01~e.5 :ARG0 (c / combine-01~e.0 :ARG1 (i / inhibit-01~e.4 :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF"~e.1))) :ARG2 (i2 / inhibit-01~e.4 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK"~e.3)))) :ARG1 (d2 / develop-01~e.7 :ARG2~e.8 (r / resist-01~e.9))) # ::id a_pmid_2514_2146.242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given the potent synergistic inhibition seen when combining vemurafenib and SCH772984 , we hypothesized that chronic exposure to dual inhibition would significantly delay the development of resistance compared to either single agent alone . # ::alignments 2-1.3.1.2 3-1.3.1.1 4-1.3.1 5-1.3.1.3 6-1.3.1.3.1.r 7-1.3.1.3.1 8-1.3.1.3.1.1.1.1 10-1.3.1.3.1.2.1.1 12-1.1 13-1 14-1.2.r 15-1.2.1.2 16-1.2.1 17-1.2.1.1.r 18-1.2.1.1.1 19-1.2.1.1 21-1.2.3 22-1.2 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1 27-1.2.3.1.r 29-1.2.3.1.1 30-1.2.3.1.2 31-1.2.3.1 (h / hypothesize-01~e.13 :ARG0 (w / we~e.12) :ARG1~e.14 (d2 / delay-01~e.22 :ARG0 (e / expose-01~e.16 :ARG2~e.17 (i / inhibit-01~e.19 :mod (d / dual~e.18)) :mod (c / chronic~e.15)) :ARG1 (d3 / develop-01~e.24 :ARG2~e.25 (r / resist-01~e.26)) :ARG1-of (s / significant-02~e.21 :compared-to~e.27 (a / agent~e.31 :mod (e3 / either~e.29) :ARG1-of (s5 / single-02~e.30)))) :ARG1-of (c2 / cause-01 :ARG0 (i2 / inhibit-01~e.4 :ARG0-of (s2 / synergize-01~e.3) :mod (p / potent~e.2) :ARG1-of (s3 / see-01~e.5 :time~e.6 (c3 / combine-01~e.7 :ARG1 (s6 / small-molecule :name (n / name :op1 "vemurafenib"~e.8)) :ARG2 (s4 / small-molecule :name (n2 / name :op1 "SCH772984"~e.10))))))) # ::id a_pmid_2514_2146.243 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this hypothesis , long term cultures were established in 96 @-@ well plates to allow both qualitative and quantitative assessment of the effect of each drug alone or their combination on M238 and M792 , which are highly sensitive to both inhibitors and for which dual therapy was highly synergistic ( Figure 7 @ A ) . # ::alignments 1-1.4 2-1.4.1.1 3-1.4.1 5-1.1.1 7-1.1 9-1 10-1.2.r 11-1.2.1 13-1.2.2 14-1.2 16-1.3 17-1.3.1.1.1.2.3.1.2 18-1.3.1.1.2 19-1.3.1 20-1.3.1.2.2 21-1.3.1.1 21-1.3.1.2 24-1.3.1.1.1 25-1.3.1.1.1.1.r 26-1.3.1.1.1.1.1.1 27-1.3.1.1.1.1.1 28-1.3.1.1.1.1.1.2 29-1.3.1.1.1.1 31-1.3.1.1.1.1.2 32-1.3.1.1.1.2.r 33-1.3.1.1.1.2.1.1.1 34-1.3.1.1.1.2 35-1.3.1.1.1.2.2.1.1 39-1.3.1.1.1.2.4.1.2.1 40-1.3.1.1.1.2.3 42-1.3.1.1.1.2.3.1.2 43-1.3.1.1.1.2.3.1 43-1.3.1.1.1.2.3.1.1 43-1.3.1.1.1.2.3.1.1.r 44-1.3.1.1.1.2 47-1.3.1.1.1.2.4.1.1 48-1.3.1.1.1.2.4.1 50-1.3.1.1.1.2.4.1.2.1 51-1.3.1.1.1.2.4.1.2 53-1.5.1 (e / establish-01~e.9 :ARG1 (c / culture~e.7 :ARG1-of (l / long-03~e.5)) :location~e.10 (p / plate~e.14 :quant 96~e.11 :mod (w / well~e.13)) :purpose (a / allow-01~e.16 :ARG1 (a8 / and~e.19 :op1 (a2 / assess-01~e.21 :ARG1 (a4 / affect-01~e.24 :ARG0~e.25 (o / or~e.29 :op1 (d / drug~e.27 :mod (e2 / each~e.26) :mod (a5 / alone~e.28)) :op2 (c2 / combine-01~e.31 :ARG1 d :ARG2 d)) :ARG1~e.32 (a6 / and~e.34,44 :op1 (c3 / cell-line :name (n / name :op1 "M238"~e.33)) :op2 (c4 / cell-line :name (n2 / name :op1 "M792"~e.35)) :ARG0-of (s / sensitive-03~e.40 :ARG1 (m / molecular-physical-entity~e.43 :ARG0-of~e.43 (i2 / inhibit-01~e.43) :mod (b / both~e.17,42))) :ARG0-of (h2 / have-03 :ARG1 (t3 / therapy~e.48 :mod (d2 / dual~e.47) :ARG0-of (s2 / synergize-01~e.51 :ARG1-of (h3 / high-02~e.39,50)))))) :mod (q / qualitative~e.18)) :op2 (a9 / assess-01~e.21 :ARG1 a4 :mod (q2 / quantitative~e.20)))) :purpose (t4 / test-01~e.1 :ARG1 (h / hypothesize-01~e.3 :mod (t5 / this~e.2))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.53 :mod "7A"))) # ::id a_pmid_2514_2146.244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with 500 nM vemurafenib initially suppressed growth of M238 and M792 , however , by 42 days of treatment , several wells were confluent and cells had normal morphology , indicating development of BRAFi @-@ resistance . # ::alignments 0-1.1.4.1 0-1.2.1 1-1.2.1.1.r 2-1.2.1.1.2.1 3-1.2.1.1.2.2 4-1.2.1.1.1.1 5-1.2.3 6-1.2 7-1.2.2 8-1.2.2.1.r 9-1.2.2.1.1.1.1 11-1.2.2.1.2.1.1 13-1 16-1.1.4.2.1 17-1.1.4.2.2 19-1.1.4.1 21-1.1.1.1.1 22-1.1.1.1 23-1.1.1.1.r 24-1.1.1 25-1.1 26-1.1.2.1 27-1.1.2 28-1.1.2.2.1 29-1.1.2.2 31-1.1.3 32-1.1.3.1 36-1.1.3.1.1 (h / have-concession-91~e.13 :ARG1 (a2 / and~e.25 :op1 (c4 / confluent~e.24 :domain~e.23 (w / well~e.22 :quant (s2 / several~e.21))) :op2 (h2 / have-03~e.27 :ARG0 (c5 / cell~e.26) :ARG1 (m / morphology~e.29 :ARG1-of (n5 / normal-02~e.28))) :ARG0-of (i2 / indicate-01~e.31 :ARG1 (d2 / develop-01~e.32 :ARG2 (r / resist-01~e.36 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n6 / name :op1 "BRAF"))))))) :time (a3 / after :op1 (t4 / treat-04~e.0,19) :quant (t3 / temporal-quantity :quant 42~e.16 :unit (d3 / day~e.17)))) :ARG2 (s / suppress-01~e.6 :ARG0 (t2 / treat-04~e.0 :ARG2~e.1 (s3 / small-molecule :name (n / name :op1 "vemurafenib"~e.4) :quant (c / concentration-quantity :quant 500~e.2 :unit (n2 / nanomolar~e.3)))) :ARG1 (g / grow-01~e.7 :ARG1~e.8 (a / and :op1 (c2 / cell-line :name (n3 / name :op1 "M238"~e.9)) :op2 (c3 / cell-line :name (n4 / name :op1 "M792"~e.11)))) :time (i / initial~e.5))) # ::id a_pmid_2514_2146.245 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , very few cells were seen in plates treated with ERKi alone or in combination at 42 days ( Figure 7 @ B ) . # ::alignments 1-1 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1 7-1.1 8-1.1.2.r 9-1.1.2 10-1.1.2.1 13-1.1.2.1.1.1.1 14-1.1.2.1.1 15-1.1.2.1.1.r 16-1.1.2.1.1.2 18-1.1.3.1.1 19-1.1.3.1.2 21-1.2.1 (c / contrast-01~e.1 :ARG2 (s / see-01~e.7 :ARG1 (c2 / cell~e.5 :mod (f / few~e.4 :mod (v / very~e.3))) :location~e.8 (p / plate~e.9 :ARG1-of (t2 / treat-04~e.10 :ARG2~e.15 (o / or~e.14 :op1 (m / molecular-physical-entity :mod (a / alone~e.13) :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "ERK")))) :op2 (c3 / combine-01~e.16 :ARG1 m)))) :time (a2 / after :quant (t3 / temporal-quantity :quant 42~e.18 :unit (d2 / day~e.19)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.21 :mod "7B"))) # ::id a_pmid_2514_2146.246 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For ERKi @-@ treated M792 plates , confluent wells were not seen until 84 days . # ::alignments 1-1.4.2.1.1.1 3-1.4.2 4-1.4.1.1.1 5-1.4 7-1.2.1 8-1.2 10-1.1 10-1.1.r 11-1 12-1.3 13-1.3.1.1 14-1.3.1.2 (s / see-01~e.11 :polarity~e.10 -~e.10 :ARG1 (w / well~e.8 :mod (c / confluent~e.7)) :time (u / until~e.12 :quant (t2 / temporal-quantity :quant 84~e.13 :unit (d2 / day~e.14))) :location (p / plate~e.5 :part (c2 / cell-line :name (n / name :op1 "M792"~e.4)) :ARG1-of (t3 / treat-04~e.3 :ARG2 (e / enzyme :name (n2 / name :op1 "ERKi"~e.1))))) # ::id a_pmid_2514_2146.247 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When cell viability was quantified at day 44 for BRAFi @-@ treated cells , over 90 % of the wells had > 10,000 viable cells . # ::alignments 0-1.3.2.r 0-1.3.r 1-1.3.3 3-1.3.1.1.r 4-1.3 6-1.3.2.1.2 7-1.3.2.1.1 11-1.3.3.1 12-1.3.3 14-1.1.2 15-1.1.2.1.1 16-1.1.2.1 17-1.1.2.r 19-1.1 19-1.1.1.1 20-1 21-1.2.2 22-1.2.2.1 23-1.2.1 23-1.3.1 24-1.2 24-1.3.1.1 (h / have-03~e.20 :ARG0 (w / well~e.19 :ARG1-of (i / include-91 :ARG2 (w2 / well~e.19)) :quant~e.17 (o2 / over~e.14 :op1 (p / percentage-entity~e.16 :value 90~e.15))) :ARG1 (c / cell~e.24 :mod (v / viable~e.23) :quant (m / more-than~e.21 :op1 10000~e.22)) :time~e.0 (q / quantify-01~e.4 :ARG1 (v2 / viable~e.23 :domain~e.3 (c2 / cell~e.24)) :time~e.0 (a / after :quant (t / temporal-quantity :quant 44~e.7 :unit (d / day~e.6))) :beneficiary (c3 / cell~e.1,12 :ARG1-of (t2 / treat-04~e.11 :ARG2 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "BRAF")))))))) # ::id a_pmid_2514_2146.248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , many fewer viable cells were seen for M792 treated with ERKi alone or in combination with BRAFi measured at day 84 . # ::alignments 1-1 3-1.1.1.1.2 4-1.1.1.1 5-1.1.1.2 6-1.1.1 8-1.1 9-1.1.2.r 10-1.1.2.1.1 11-1.1.2.2 12-1.1.2.2.1.r 13-1.1.2.2.1.1.1.1 14-1.1.2.2.1.1.2 15-1.1.2.2.1 17-1.1.2.2.1.2 20-1.1.2.3 22-1.1.2.3.1.1.2 23-1.1.2.3.1.1.1 (c / contrast-01~e.1 :ARG2 (s / see-01~e.8 :ARG1 (c2 / cell~e.6 :mod (f / few~e.4 :mod (m / more) :mod (m2 / many~e.3)) :mod (v / viable~e.5)) :location~e.9 (c3 / cell-line :name (n / name :op1 "M792"~e.10) :ARG1-of (t / treat-04~e.11 :ARG2~e.12 (o / or~e.15 :op1 (e / enzyme :name (n2 / name :op1 "ERKi"~e.13) :mod (a / alone~e.14)) :op2 (c4 / combine-01~e.17 :ARG1 e :ARG2 (m4 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF"))))))) :ARG1-of (m3 / measure-01~e.20 :time (a2 / after :quant (t2 / temporal-quantity :quant 84~e.23 :unit (d / day~e.22))))))) # ::id a_pmid_2514_2146.249 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only 20 % of the wells treated with ERKi alone and < 5 % of wells treated with the combination had > 10,000 cells ( Figure 7 @ C ) . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 2-1.1.1.1 2-1.1.2.1.1 5-1.1.1 5-1.1.1.1.2.1 5-1.1.2 5-1.1.2.2.1 6-1.1.1.1.2.1.1 6-1.1.2.2.1.1 7-1.1.1.1.2.1.1.1.r 8-1.1.1.1.2.1.1.1.1.1 9-1.1.1.1.2.1.1.1.2 10-1.1 12-1.2.1.1 13-1.2 15-1.3.1 (h / have-03 :ARG0 (a / and~e.10 :op1 (w / well~e.5 :quant (p2 / percentage-entity~e.2 :value 20~e.1 :ARG1-of (i / include-91 :ARG2 (w2 / well~e.5 :ARG1-of (t / treat-04~e.6 :ARG2~e.7 (e / enzyme :name (n / name :op1 "ERKi"~e.8) :mod (a2 / alone~e.9)))))) :mod (o2 / only~e.0)) :op2 (w3 / well~e.5 :quant (l / less-than :op1 (p3 / percentage-entity~e.2 :value 5)) :ARG1-of (i2 / include-91 :ARG2 (w4 / well~e.5 :ARG1-of (t2 / treat-04~e.6 :ARG2 (c / combine-01 :ARG1 e)))))) :ARG1 (c2 / cell~e.13 :quant (m / more-than :op1 10000~e.12)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod "7C"))) # ::id a_pmid_2514_2146.250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For M238 , similar data were seen , though in this case , treatment with 500 nM ERKi alone delayed the development of resistance until 140 days . # ::alignments 1-1.2.1.1 3-1.1.1 4-1.1 6-1 8-1.3.r 10-1.3.4.1 11-1.3.4 13-1.3.1 14-1.3.1.1.r 15-1.3.1.1.2.1 16-1.3.1.1.2.2 17-1.3.1.1.1.1 18-1.3.1.1.3 19-1.3 21-1.3.2 22-1.3.2.1.r 23-1.3.2.1 24-1.3.3 25-1.3.3.1.1 26-1.3.3.1.2 (s / see-01~e.6 :ARG1 (d / data~e.4 :ARG2-of (r2 / resemble-01~e.3)) :location (c / cell-line :name (n / name :op1 "M238"~e.1)) :concession~e.8 (d3 / delay-01~e.19 :ARG0 (t2 / treat-04~e.13 :ARG2~e.14 (e / enzyme :name (n2 / name :op1 "ERKi"~e.17) :quant (c2 / concentration-quantity :quant 500~e.15 :unit (n3 / nanomolar~e.16)) :mod (a / alone~e.18))) :ARG1 (d4 / develop-01~e.21 :ARG2~e.22 (r3 / resist-01~e.23)) :ARG2 (u / until~e.24 :quant (t3 / temporal-quantity :quant 140~e.25 :unit (d5 / day~e.26))) :condition (c3 / case-04~e.11 :ARG1 (t4 / this~e.10)))) # ::id a_pmid_2514_2146.251 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Most strikingly , for M238 , 280 days , twice that for SCH772984 alone , were required for resistance to the combination of vemurafenib and SCH772984 to develop ( Figure 7 @ D ) . # ::alignments 0-1.3.1 1-1.3 4-1.1.1.1.1 6-1.2.1 7-1.2.2 9-1.2.3.1.1 12-1.2.3.1.2.1.1.1.1 13-1.2.3.1.2.1.1.2 16-1 16-1.2.3.1.2.1 18-1.1.2 19-1.1.2.1.r 21-1.1.2.1 22-1.1.2.1.1.r 23-1.1.2.1.1.1.1 25-1.1.2.1.2 27-1.1 29-1.4.1 (r / require-01~e.16 :ARG0 (d3 / develop-01~e.27 :ARG1 (c / cell-line :name (n / name :op1 "M238"~e.4)) :ARG2 (r3 / resist-01~e.18 :ARG1~e.19 (c2 / combine-01~e.21 :ARG1~e.22 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib"~e.23)) :ARG2 s~e.25))) :ARG1 (t2 / temporal-quantity :quant 280~e.6 :unit (d2 / day~e.7) :ARG1-of (e / equal-01 :ARG2 (p / product-of :op1 2~e.9 :op2 (t / temporal-quantity :ARG1-of (r2 / require-01~e.16 :ARG0 (s / small-molecule :name (n2 / name :op1 "SCH772984"~e.12) :mod (a / alone~e.13))))))) :ARG1-of (s2 / strike-04~e.1 :degree (m2 / most~e.0)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.29 :mod "7D"))) # ::id a_pmid_2514_2146.252 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these data provide preliminary in vitro evidence that SCH772984 may more potently and more durably inhibit BRAF @ -@ mutant melanoma compared to single agent vemurafenib , and that the combination of BRAF and ERK inhibition results in better inhibition than either alone . # ::alignments 0-1.1.2 1-1.1.2.1 3-1.1.1 4-1.1 5-1 6-1.2.2 8-1.2.3 9-1.2.3 11-1.2 12-1.2.1.r 13-1.2.1.1.1.1.1.1 14-1.2.1.1 15-1.2.1.1.1.3.1 15-1.2.1.1.1.4.1 16-1.2.1.1.1.3 18-1.2.1.1.1.3.1 18-1.2.1.1.1.4.1 20-1.2.1.1.1 20-1.2.1.1.1.3.2 22-1.2.1.1.1.2.2.1.1 25-1.2.1.1.1.2.2 25-1.2.1.1.1.2.2.2 25-1.2.1.1.1.2.2.2.r 26-1.2.1.1.1.2.1.1 27-1.2.1.1.1.3.2.r 28-1.2.1.1.1.3.2.1.r 29-1.2.1.1.1.3.2.1 29-1.2.1.1.1.3.2.1.2 29-1.2.1.1.1.3.2.1.2.r 30-1.2.1.1.1.3.2.1.3 31-1.2.1.1.1.3.2.1.1.1 33-1.2.1 34-1.2.1.r 36-1.2.1.2.1 38-1.2.1.2.1.1.1.1.1 40-1.2.1.2.1.2.1.1.1 41-1.2.1.2.1.1 41-1.2.1.2.1.2 41-1.2.1.2.2 42-1.2.1.2 43-1.2.3 44-1.2.1.1.1.3.1.r 44-1.2.1.1.1.4.1 44-1.2.1.1.1.4.1.r 44-1.2.1.2.2.1 44-1.2.1.2.2.1.1 44-1.2.1.2.2.1.1.r 45-1.2.1.2.2 45-1.2.1.2.2.1.2 46-1.2.1.2.2.1.2.r 48-1.2.1.2.2.1.2.2 (p / provide-01~e.5 :ARG0 (d2 / data~e.4 :mod (t / this~e.3) :ARG1-of (t2 / take-01~e.0 :manner (t3 / together~e.1))) :ARG1 (e2 / evidence-01~e.11 :ARG1~e.12,34 (a2 / and~e.33 :op1 (p3 / possible-01~e.14 :ARG1 (i2 / inhibit-01~e.20 :ARG0 (s3 / small-molecule :name (n / name :op1 "SCH772984"~e.13)) :ARG1 (m5 / medical-condition :name (n2 / name :op1 "melanoma"~e.26) :mod (g2 / gene~e.25 :name (n3 / name :op1 "BRAF"~e.22) :ARG2-of~e.25 (m4 / mutate-01~e.25))) :mod (p4 / potent~e.16 :degree~e.44 (m2 / more~e.15,18) :compared-to~e.27 (i3 / inhibit-01~e.20 :ARG0~e.28 (s2 / small-molecule~e.29 :name (n4 / name :op1 "vemurafenib"~e.31) :ARG1-of~e.29 (s / single-02~e.29) :mod (a / agent~e.30)))) :mod (d3 / durable :degree~e.44 (m3 / more~e.15,18,44)))) :op2 (r / result-01~e.42 :ARG1 (c / combine-01~e.36 :ARG1 (i4 / inhibit-01~e.41 :ARG1 (e / enzyme :name (n5 / name :op1 "BRAF"~e.38))) :ARG2 (i5 / inhibit-01~e.41 :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK"~e.40)))) :ARG2 (i6 / inhibit-01~e.41,45 :ARG1-of (g / good-02~e.44 :degree~e.44 (m / more~e.44) :compared-to~e.46 (i7 / inhibit-01~e.45 :ARG0 (o / or :op1 e :op2 e3) :mod (a3 / alone~e.48)))))) :mod (p2 / preliminary~e.6) :mod (i / in-vitro~e.8,9,43))) # ::id a_pmid_2514_2146.253 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data are intriguing and should be further validated in vivo @ . @ Figure 7 @

Effect of combined MAPK inhibition on long @-@ term melanoma cultures . # ::alignments 0-1.1.1.1.1 1-1.1.1.1 3-1.1.1 4-1.1 5-1.1.2 7-1.1.2.1.2 8-1.1.2.1 10-1.1.2.1.3 11-1.1.2.1.3 16-1.1.3.1 17-1.1.3.1.1 22-1.2 23-1.2.1.r 24-1.2.1.2 25-1.2.1.1.1.1 26-1.2.1 27-1.2.2.r 28-1.2.2.2 31-1.2.2.1.1.1 32-1.2.2 (m / multi-sentence :snt1 (a / and~e.4 :op1 (i / intrigue-01~e.3 :ARG0 (d / data~e.1 :mod (t / this~e.0))) :op2 (r2 / recommend-01~e.5 :ARG1 (v / validate-01~e.8 :ARG1 d :manner (f / further~e.7) :manner (i2 / in-vivo~e.10,11))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.16 :mod 7~e.17))) :snt2 (a2 / affect-01~e.22 :ARG0~e.23 (i3 / inhibit-01~e.26 :ARG1 (p / pathway :name (n / name :op1 "MAPK"~e.25)) :ARG1-of (c / combine-01~e.24)) :ARG1~e.27 (c2 / culture-01~e.32 :ARG1 (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.31)) :ARG1-of (l / long-03~e.28)))) # ::id a_pmid_2514_2146.254 ::amr-annotator SDL-AMR-09 ::preferred # ::tok M238 and M792 , two MAPK inhibitor @-@ sensitive cell lines , were chronically exposed to 500 nM of Vemurafenib ( V ) , SCH722984 ( E ) or combination ( V + E ) in 96 @-@ well plates . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 5-1.1.3.1.1.1.1.1 6-1.1.3.1 6-1.1.3.1.1 6-1.1.3.1.1.r 8-1.1.3 9-1.1.1 9-1.1.2 10-1.1.1 13-1.3 14-1 15-1.2.r 16-1.2.1.2.1 17-1.2.1.2.2 18-1.2.1.2.r 19-1.2.1.1.1 24-1.2.2.1.1 28-1.2 29-1.2.3 32-1.1 35-1.4.r 36-1.4.1 38-1.4.2 39-1.4 (e / expose-01~e.14 :ARG1 (a / and~e.1,32 :op1 (c2 / cell-line~e.9,10 :name (n2 / name :op1 "M238"~e.0)) :op2 (c3 / cell-line~e.9 :name (n3 / name :op1 "M792"~e.2)) :ARG0-of (s / sensitive-03~e.8 :ARG1 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6 :ARG1 (p / protein-family :name (n / name :op1 "MAPK"~e.5)))))) :ARG2~e.15 (o / or~e.28 :op1 (s3 / small-molecule :name (n4 / name :op1 "Vemurafenib"~e.19) :quant~e.18 (c4 / concentration-quantity :quant 500~e.16 :unit (n5 / nanomolar~e.17))) :op2 (s2 / small-molecule :name (n6 / name :op1 "SCH722984"~e.24)) :op3 (c5 / combine-01~e.29 :ARG1 s3 :ARG2 s2)) :manner (c / chronic~e.13) :location~e.35 (p2 / plate~e.39 :quant 96~e.36 :mod (w / well~e.38))) # ::id a_pmid_2514_2146.255 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "A"~e.1) # ::id a_pmid_2514_2146.256 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Schematic . # ::alignments 0-1 (s / schematic~e.0) # ::id a_pmid_2514_2146.257 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For each cell line , 20,000 cells @/@ well were plated on 96 @-@ well plates . # ::alignments 1-1.2.1 2-1.2 3-1.2 5-1.1.1.1 5-1.1.2.1 6-1.1.1 8-1.1.2 10-1 10-1.3 10-1.3.r 12-1.3.1 14-1.3.2 15-1.3 (p / plate-00~e.10 :ARG1 (o / or :op1 (c / cell~e.6 :quant 20000~e.5) :op2 (w / well~e.8 :quant 20000~e.5)) :condition (c2 / cell-line~e.2,3 :mod (e / each~e.1)) :location~e.10 (p2 / plate~e.10,15 :quant 96~e.12 :mod (w2 / well~e.14))) # ::id a_pmid_2514_2146.258 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The following day , all cells on the plate were treated with 500 nM of each drug or combination . # ::alignments 1-1.3.1 2-1.3 4-1.1.2 5-1.1 6-1.1.1.r 8-1.1.1 10-1 11-1.2.r 12-1.2.1.2.1 13-1.2.1.2.2 14-1.2.1.2.r 15-1.2.1.1 16-1.2.1 17-1.2 18-1.2.2 (t / treat-04~e.10 :ARG1 (c / cell~e.5 :location~e.6 (p / plate~e.8) :mod (a / all~e.4)) :ARG2~e.11 (o / or~e.17 :op1 (d / drug~e.16 :mod (e / each~e.15) :quant~e.14 (c2 / concentration-quantity :quant 500~e.12 :unit (n / nanomolar~e.13))) :op2 (c3 / combine-01~e.18 :ARG1 d)) :time (d2 / day~e.2 :ARG1-of (f / follow-01~e.1))) # ::id a_pmid_2514_2146.259 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fresh media containing the appropriate inhibitor( s ) was added weekly . # ::alignments 0-1.1.1 1-1.1 2-1.1.2 4-1.1.2.1 4-1.1.2.1.2 4-1.1.2.1.2.r 9-1 10-1.2 10-1.2.1 10-1.2.1.r 10-1.2.2.1 10-1.2.2.2 (a / add-02~e.9 :ARG1 (m / medium~e.1 :ARG1-of (f / fresh-04~e.0) :ARG0-of (c / contain-01~e.2 :ARG1 (m2 / molecular-physical-entity~e.4 :ARG0-of (i / inhibit-01) :ARG1-of~e.4 (a2 / appropriate-02~e.4)))) :frequency (r / rate-entity-91~e.10 :ARG1~e.10 1~e.10 :ARG2 (t / temporal-quantity :quant 1~e.10 :unit (w / week~e.10)))) # ::id a_pmid_2514_2146.260 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When cells in several wells were confluent , viable cells were quantified by MTS assay and cell numbers were determined by comparing with a standard curve of known cell numbers . # ::alignments 0-1.3.r 1-1.3.1 2-1.3.1.1.r 3-1.3.1.1.1 4-1.3.1.1 5-1.3.1.r 6-1.3 8-1.1.2.1 9-1.1.2 11-1.1 12-1.1.1.r 13-1.1.1.1.1.1 14-1.1.1 15-1 16-1.2.1.1 17-1.2.1 19-1.2 20-1.2.2.r 21-1.2.2 22-1.2.2.2.r 24-1.2.2.2.1 25-1.2.2.2 26-1.2.2.2.2.r 27-1.2.2.2.2.2 28-1.2.2.2.2.1 29-1.2.2.2.2 (a2 / and~e.15 :op1 (q / quantify-01~e.11 :ARG0~e.12 (a / assay-01~e.14 :instrument (s3 / small-molecule :name (n / name :op1 "MTS"~e.13))) :ARG1 (c / cell~e.9 :mod (v / viable~e.8))) :op2 (d / determine-01~e.19 :ARG1 (n2 / number~e.17 :quant-of (c2 / cell~e.16)) :instrument~e.20 (c3 / compare-01~e.21 :ARG1 n2 :ARG2~e.22 (c4 / curve~e.25 :ARG1-of (s / standard-02~e.24) :quant-of~e.26 (n3 / number~e.29 :mod (c5 / cell~e.28) :ARG1-of (k / know-01~e.27))))) :time~e.0 (c6 / confluent~e.6 :domain~e.5 (c7 / cell~e.1 :location~e.2 (w / well~e.4 :quant (s2 / several~e.3))))) # ::id a_pmid_2514_2146.261 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "B"~e.1) # ::id a_pmid_2514_2146.262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Microscopic imaging of treated M238 cells photographed at 14 days ( top ) or 44 days ( bottom ) of treatment . # ::alignments 0-1.2 1-1 3-1.1.1.2 3-1.1.1.3.1.1 3-1.1.2.3.1.1 4-1.1.1.1.1 4-1.1.2.1.1 5-1.1.1 5-1.1.2 6-1.1.1.3 6-1.1.2.3 8-1.1.1.3.1.2.1 9-1.1.1.3.1.2.2 11-1.1.1.4 14-1.1.2.3.1.2.1 15-1.1.2.3.1.2.2 17-1.1.2.4 19-1.1.1.2.r 20-1.1.1.2 (i / image-101~e.1 :ARG1 (a3 / and :op1 (c / cell-line~e.5 :name (n / name :op1 "M238"~e.4) :ARG1-of~e.19 (t3 / treat-04~e.3,20) :ARG1-of (p / photograph-01~e.6 :time (a / after :op1 (t7 / treat-04~e.3) :quant (t4 / temporal-quantity :quant 14~e.8 :unit (d3 / day~e.9)))) :location (t5 / top~e.11)) :op2 (c2 / cell-line~e.5 :name (n2 / name :op1 "M238"~e.4) :ARG1-of t3 :ARG1-of (p2 / photograph-01~e.6 :time (a2 / after :op1 (t / treat-04~e.3) :quant (t6 / temporal-quantity :quant 44~e.14 :unit (d4 / day~e.15)))) :location (b / bottom~e.17))) :mod (m / microscopic~e.0)) # ::id a_pmid_2514_2146.263 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "C"~e.1) # ::id a_pmid_2514_2146.264 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Quantitative analysis of viable cells for M792 at 44 days ( V ) or 84 days ( E and V + E ) . # ::alignments 0-1.2 0-1.3.1.2.2 0-1.3.2.2.2 1-1 2-1.1.r 3-1.1.1 4-1.1 6-1.3.1.1.1 6-1.3.2.1.1 7-1.3.r 8-1.3.1.2.2.1 9-1.3.1.2.2.2 9-1.3.2.2.2.2 14-1.3.2.2.2.1 15-1.3.1.2.2.2 18-1.3 18-1.3.2.2.1 20-1.3 20-1.3.2.2.1 (a / analyze-01~e.1 :ARG1~e.2 (c / cell~e.4 :mod (v / viable~e.3)) :mod (q / quantitative~e.0) :purpose~e.7 (a5 / and~e.18,20 :op1 (c2 / cell-line :name (n / name :op1 "M792"~e.6) :ARG1-of (e / expose-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Vemurafenib")) :duration (t3 / temporal-quantity~e.0 :quant 44~e.8 :unit (d3 / day~e.9,15)))) :op1 (c4 / cell-line :name (n4 / name :op1 "M792"~e.6) :ARG1-of (e3 / expose-01 :ARG2 (a3 / and~e.18,20 :op1 (s / small-molecule :name (n3 / name :op1 "SCH722984")) :op2 (c3 / combine-01 :ARG1 s2 :ARG2 s)) :duration (t4 / temporal-quantity~e.0 :quant 84~e.14 :unit (d4 / day~e.9)))))) # ::id a_pmid_2514_2146.265 ::amr-annotator SDL-AMR-09 ::preferred # ::tok D @ . # ::alignments 1-1.1 (h / have-li-91 :ARG2 "D"~e.1) # ::id a_pmid_2514_2146.266 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Quantitative analysis of viable cells for M238 at 44 days ( V ) , 140 days ( E ) or 280 days ( V + E ) . # ::alignments 0-1.2 0-1.3.1.2.2 0-1.3.2.2.2 0-1.3.3.2.2 1-1 2-1.1.r 3-1.1.1.1 4-1.1.1 6-1.3.1.1.1 6-1.3.2.1.1 6-1.3.3.1.1 7-1.3.r 8-1.3.1.2.2.1 9-1.3.1.2.2.2 9-1.3.2.2.2.2 9-1.3.3.2.2.2 14-1.3.2.2.2.1 15-1.3.1.2.2.2 19-1.1 20-1.3.3.2.2.1 21-1.3.1.2.2.2 24-1.3 24-1.3.3.2.1 (a3 / analyze-01~e.1 :ARG1~e.2 (o2 / or~e.19 :op1 (c / cell~e.4 :mod (v / viable~e.3))) :mod (q / quantitative~e.0) :purpose~e.7 (a / and~e.24 :op1 (c2 / cell-line :name (n / name :op1 "M238"~e.6) :ARG1-of (e / expose-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Vemurafenib")) :duration (t4 / temporal-quantity~e.0 :quant 44~e.8 :unit (d4 / day~e.9,15,21)))) :op2 (c3 / cell-line :name (n6 / name :op1 "M238"~e.6) :ARG1-of (e3 / expose-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "SCH722984")) :duration (t5 / temporal-quantity~e.0 :quant 140~e.14 :unit (d5 / day~e.9)))) :op3 (c6 / cell-line :name (n7 / name :op1 "M238"~e.6) :ARG1-of (e4 / expose-01 :ARG2 (a6 / and~e.24 :op1 s2 :op2 s) :duration (t6 / temporal-quantity~e.0 :quant 280~e.20 :unit (d6 / day~e.9)))))) # ::id a_pmid_2514_2146.267 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The percentage of wells with 1 @–@ 1,000 ( white ) , 2,000 @-@ 3,999 ( tan ) , 4,000 @-@ 5,999 ( yellow ) , 6,000 @-@ 7,999 ( orange ) , 8,000 @-@ 9,999 ( red ) and > 10,000 ( brown ) viable cells are shown . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 5-1.1.1.1.1.1.2.1 7-1.1.1.1.1.1.2.2 9-1.1.1.1.1.1.3.1 12-1.1.1.1.1.2.2.1 14-1.1.1.1.1.2.2.2 16-1.1.1.1.1.2.3.1 19-1.1.1.1.1.3.2.1 21-1.1.1.1.1.3.2.2 23-1.1.1.1.1.3.3.1 26-1.1.1.1.1.4.2.1 28-1.1.1.1.1.4.2.2 30-1.1.1.1.1.4.3.1 33-1.1.1.1.1.5.2.1 35-1.1.1.1.1.5.2.2 37-1.1.1.1.1.5.3.1 39-1.1.1.1.1 40-1.1.1.1.1.6.2 41-1.1.1.1.1.6.2.1 43-1.1.1.1.1.6.3.1 45-1.1.1.1.1.1.1 46-1.1.1.1.1.1 46-1.1.1.1.1.2 46-1.1.1.1.1.3 46-1.1.1.1.1.4 46-1.1.1.1.1.5 46-1.1.1.1.1.6 48-1 (s / show-01~e.48 :ARG1 (p2 / percentage~e.1 :quant-of~e.2 (w / well~e.3 :ARG0-of (h / have-03 :ARG1 (a / and~e.39 :op1 (c / cell~e.46 :mod (v / viable~e.45) :quant (v2 / value-interval :op1 1~e.5 :op2 1000~e.7) :ARG1-of (c2 / color-01 :ARG2 (w2 / white-03~e.9))) :op2 (c3 / cell~e.46 :mod v :quant (v3 / value-interval :op1 2000~e.12 :op2 3999~e.14) :ARG1-of (c4 / color-01 :ARG2 (t / tan~e.16))) :op3 (c5 / cell~e.46 :mod v :quant (v4 / value-interval :op1 4000~e.19 :op2 5999~e.21) :ARG1-of (c6 / color-01 :ARG2 (y / yellow-02~e.23))) :op4 (c7 / cell~e.46 :mod v :quant (v5 / value-interval :op1 6000~e.26 :op2 7999~e.28) :ARG1-of (c8 / color-01 :ARG2 (o / orange~e.30))) :op5 (c9 / cell~e.46 :mod v :quant (v6 / value-interval :op1 8000~e.33 :op2 9999~e.35) :ARG1-of (c10 / color-01 :ARG2 (r / red-02~e.37))) :op6 (c11 / cell~e.46 :mod v :quant (m / more-than~e.40 :op1 10000~e.41) :ARG1-of (c12 / color-01 :ARG2 (b4 / brown~e.43)))))))) # ::id a_pmid_2514_2146.268 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Data are representative of triplicate independent experiments .

@ @ @ # ::alignments 0-1.1 2-1 5-1.2.2 5-1.2.2.1 5-1.2.2.1.r 6-1.2 (r2 / represent-01~e.2 :ARG0 (d / data~e.0) :ARG1 (e / experiment~e.6 :quant 3 :ARG0-of (d2 / depend-01~e.5 :polarity~e.5 -~e.5))) # ::id bel_pmid_1088_2715.4484 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GEF activity of Ras @-@ GRF1 toward Ha @-@ Ras , as defined by in vitro GDP binding and release assays , was augmented after tyrosine phosphorylation by ACK1 . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2.1.1 3-1.1.3.1.1 5-1.1.2.1.1 7-1.1.3.1.1 9-1.1.2.1.1 9-1.1.3.1.1 11-1.1.4.r 11-1.2.r 12-1.1.4 13-1.1.4.1.r 14-1.1.4.1.1.2 15-1.1.4.1.1.2 16-1.1.4.1.1.1.1.1 17-1.1.4.1.1 18-1.1.4.1 19-1.1.4.1.2.1 20-1.1.4.1.2 23-1 24-1.2 25-1.2.1.1.1.1 26-1.2.1 27-1.2.1.2.r 28-1.2.1.2.1.1 (a / augment-01~e.23 :ARG1 (a3 / activity-06~e.1 :ARG0 (p3 / protein :name (n3 / name :op1 "GEF"~e.0)) :ARG1 (p2 / protein :name (n4 / name :op1 "Ras-GRF1"~e.3,5,9)) :beneficiary (e2 / enzyme :name (n5 / name :op1 "Ha-Ras"~e.3,7,9)) :manner~e.11 (d / define-01~e.12 :ARG0~e.13 (a4 / and~e.18 :op1 (b / bind-01~e.17 :ARG1 (s2 / small-molecule :name (n6 / name :op1 "GDP"~e.16)) :manner (i / in-vitro~e.14,15)) :op2 (a5 / assay-01~e.20 :ARG1 (r / release-01~e.19))) :ARG1 a3)) :time~e.11 (a6 / after~e.24 :op1 (p / phosphorylate-01~e.26 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine"~e.25)) :ARG2~e.27 (e / enzyme :name (n / name :op1 "ACK1"~e.28))))) # ::id bel_pmid_1088_2715.4486 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras @-@ GRF1 acts as a GEF for Rac when tyrosine @-@ phosphorylated following G protein @-@ coupled receptor stimulation . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.3.r 6-1.2.1.1 7-1.5.r 8-1.5.1.1 9-1.3.r 10-1.3.1.1.1 12-1.3 13-1.4 14-1.4.1.1.1.1.1.1 15-1.1 15-1.2 15-1.4.1.1.1.1 17-1.4.1.1.1 18-1.4.1.1 19-1.4.1 (a / act-01~e.3 :ARG0 (p / protein~e.15 :name (n / name :op1 "Ras-GRF1"~e.0,2)) :ARG1 (p2 / protein~e.15 :name (n2 / name :op1 "GEF"~e.6)) :time~e.4,9 (p3 / phosphorylate-01~e.12 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine"~e.10) :part-of p)) :ARG1-of (f / follow-01~e.13 :ARG2 (s2 / stimulate-01~e.19 :ARG1 (r / receptor~e.18 :ARG1-of (c / couple-01~e.17 :ARG2 (p4 / protein~e.15 :name (n5 / name :op1 "G"~e.14)))))) :beneficiary~e.7 (e / enzyme :name (n3 / name :op1 "Rac"~e.8))) # ::id bel_pmid_1088_2715.21490 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We show here that activated ACK1 , a nonreceptor tyrosine kinase that belongs to the focal adhesion kinase family , causes tyrosine phosphorylation of Ras @-@ GRF1 . # ::alignments 0-1.1 1-1 2-1.3 3-1.2.r 4-1.2.1.4 5-1.2.1.1.1 8-1.2.1 9-1.2.1 10-1.2.1 12-1.2.1.2 13-1.2.1.2.1.r 15-1.2.1.2.1.1.1 16-1.2.1.2.1.1.2 17-1.2.1.2.1.1.3 18-1.2.1.2.1 20-1.2 21-1.2.2.1.1.1 22-1.2.2 24-1.2.2.1.2.1.1 26-1.2.2.1.2.1.1 (s / show-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.3 (c / cause-01~e.20 :ARG0 (n5 / nonreceptor-tyrosine-kinase~e.8,9,10 :name (n4 / name :op1 "ACK1"~e.5) :ARG0-of (b / belong-01~e.12 :ARG1~e.13 (p3 / protein-family~e.18 :name (n3 / name :op1 "focal"~e.15 :op2 "adhesion"~e.16 :op3 "kinase"~e.17))) :ARG0-of (r / receive-01 :polarity -) :ARG1-of (a2 / activate-01~e.4)) :ARG1 (p / phosphorylate-01~e.22 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.21) :part-of (p2 / protein :name (n2 / name :op1 "Ras-GRF1"~e.24,26))))) :location (h / here~e.2)) # ::id bel_pmid_1090_3731.2472 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stimulation by IL @-@ 18 strongly enhanced tyrosine phosphorylation of STAT3 and of the mitogen @-@ activated protein kinases ( MAPK ) p44 erk @-@ 1 and p42 erk @-@ 2 . # ::alignments 0-1.1 2-1.1.1.1.1 4-1.1.1.1.1 5-1.3 6-1 7-1.2.1.1.1.1 7-1.2.1.2.1.1.1 8-1.2 9-1.2.1.r 10-1.2.1.1.2.1.1 11-1.2.1 11-1.2.1.2 11-1.2.1.2.1.2 11-1.2.1.2.r 17-1.1.1 17-1.2.1.1.2 17-1.2.1.2.1.2.3.1 20-1.2.1.2.1.2.3.1.1.1 22-1.2.1.2.1.2.1.1.1 22-1.2.1.2.1.2.2.1.1 25-1.2.1.2.1.2.1.1.2 26-1.2.1.2.1.2 30-1.2.1.2.1.2.2.1.2 (e / enhance-01~e.6 :ARG0 (s2 / stimulate-01~e.0 :ARG2 (p5 / protein~e.17 :name (n4 / name :op1 "IL-18"~e.2,4))) :ARG1 (p / phosphorylate-01~e.8 :ARG1~e.9 (a / and~e.11 :op1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine"~e.7) :part-of (p6 / protein~e.17 :name (n5 / name :op1 "STAT3"~e.10))) :op2~e.11 (a2 / and~e.11 :op1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine"~e.7) :part-of (a6 / and~e.11,26 :op1 (e3 / enzyme :name (n / name :op1 "p44"~e.22 :op2 "ERK-1"~e.25)) :op2 (e4 / enzyme :name (n2 / name :op1 "p44"~e.22 :op2 "ERK-2"~e.30)) :ARG1-of (m3 / mean-01 :ARG2 (p2 / protein-family~e.17 :name (n8 / name :op1 "MAPK"~e.20)))))))) :ARG1-of (s / strong-02~e.5)) # ::id bel_pmid_1090_3731.37032 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MAPK activation appears to play a prominent role in IL @-@ 18 signaling , being involved in transcription and translation of IL @-@ 18 @-@ induced IFN @-@ gamma mRNA and IL @-@ 18 @-@ induced cytolytic effects . # ::alignments 0-1.2.1.1.1.1.1 1-1.2.1.1 2-1.2 4-1.2.1 6-1.2.1.2.1 7-1.2.1.2 8-1.2.1.3.r 9-1.2.1.3.1.1.1 11-1.2.1.3.1.1.1 12-1.2.1.3 15-1.1 16-1.1.2.r 17-1.1.2.1 18-1.1.2 19-1.1.2.2 20-1.1.2.1.2.r 21-1.1.2.1.2.3.1 22-1.1.2.1.2.3.1 23-1.1.2.1.2.3.1 25-1.1.2.1.2.3 26-1.1.2.1.2.2.1.1 28-1.1.2.1.2.2.1.1 29-1.1.2.1.2.1.1 30-1.1.2 31-1.1.2.1.2.3.1 32-1.1.2.1.2.3.1 33-1.1.2.1.2.3.1 35-1.1.2.3.2 36-1.1.2.3.1 37-1.1.2.3 (c / cause-01 :ARG0 (i / involve-01~e.15 :ARG1 a2 :ARG2~e.16 (a3 / and~e.18,30 :op1 (t / transcribe-01~e.17 :ARG0 a2 :ARG1~e.20 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.29) :mod (p5 / protein :name (n4 / name :op1 "IFN-gamma"~e.26,28)) :ARG2-of (i2 / induce-01~e.25 :ARG0 p4~e.21,22,23,31,32,33))) :op2 (t2 / translate-01~e.19 :ARG0 a2 :ARG1 n5) :op3 (a4 / affect-01~e.37 :ARG2 (c2 / cytolysis~e.36) :ARG1-of i2~e.35))) :ARG1 (a / appear-01~e.2 :ARG1 (p2 / play-02~e.4 :ARG0 (a2 / activate-01~e.1 :ARG0 (p / pathway :name (n / name :op1 "MAPK"~e.0))) :ARG1 (r / role~e.7 :mod (p3 / prominent~e.6)) :topic~e.8 (s / signal-07~e.12 :ARG0 (p4 / protein :name (n2 / name :op1 "IL-18"~e.9,11)))))) # ::id bel_pmid_1090_3734.4380 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , cord blood T cells cultured with IGF @-@ 1 and PHA had a higher resistance to anti @-@ Fas @-@ induced apoptosis as compared with PHA @-@ activated cord blood T cells . IGF @-@ 1 also significantly inhibited PHA @-@ induced Fas expression on cord blood T cells # ::alignments 0-1.1.1.1.2.1 2-1.2.2.2.2.1 3-1.2.2.2.2 4-1.1.1.1.1.1 4-1.1.1.3.1.1 4-1.2.2.2.1.1 5-1.1.1.1 6-1.1.1.1.2 7-1.1.1.1.2.1.r 8-1.1.1.1.2.1.1.1.1 10-1.1.1.1.2.1.1.1.1 11-1.1.1.1.2.1 12-1.1.1.1.2.1.2.1.1 15-1.1.1.4 15-1.1.1.4.1 15-1.1.1.4.1.r 16-1.1.1 17-1.1.1.2.r 18-1.1.1.2.1 20-1.1.1.2.1.1 22-1.1.1.2.2 23-1.1.1.2 25-1.1.1.3.r 27-1.1.1.3.2.1 29-1.1.1.3.2 30-1.1.1.1.2.2.1 31-1.1.1.1.2.2 32-1.1.1.1.1.1 32-1.1.1.3.1.1 33-1.1.1.3 35-1.2.1.1.1 37-1.2.1.1.1 38-1.2.3 39-1.2.4 40-1.2 41-1.2.2.3.1.1.1 43-1.2.2.3 44-1.2.2.1.1.1 45-1.2.2 47-1.2.2.2.2.1 48-1.2.2.2.2 49-1.2.2.2.1.1 50-1.2.2.2 (m / multi-sentence :snt1 (a2 / and :op2 (r / resist-01~e.16 :ARG0 (c4 / cell~e.5 :name (n4 / name :op1 "T"~e.4,32) :ARG1-of (c3 / culture-01~e.6 :ARG0~e.7 (a6 / and~e.0,11 :op1 (p2 / protein :name (n5 / name :op1 "IGF-1"~e.8,10)) :op2 (p3 / protein :name (n6 / name :op1 "PHA"~e.12))) :mod (b2 / blood~e.31 :location (c5 / cord~e.30)))) :ARG1~e.17 (a4 / apoptosis~e.23 :ARG0-of (c6 / counter-01~e.18 :ARG1 p5~e.20) :ARG2-of (i3 / induce-01~e.22)) :compared-to~e.25 (c7 / cell~e.33 :name (n7 / name :op1 "T"~e.4,32) :ARG1-of (a5 / activate-01~e.29 :ARG0 p3~e.27) :mod b2) :ARG1-of (h / high-02~e.15 :degree~e.15 (m2 / more~e.15)))) :snt2 (i / inhibit-01~e.40 :ARG0 (p4 / protein :name (n8 / name :op1 "IGF-1"~e.35,37)) :ARG1 (e / express-03~e.45 :ARG1 (p5 / protein :name (n2 / name :op1 "Fas"~e.44)) :ARG3 (c / cell~e.50 :name (n3 / name :op1 "T"~e.4,49) :mod (b / blood~e.3,48 :location (c2 / cord~e.2,47))) :ARG2-of (i2 / induce-01~e.43 :ARG0 (p / protein :name (n / name :op1 "PHA"~e.41)))) :mod (a / also~e.38) :ARG1-of (s / significant-02~e.39))) # ::id bel_pmid_1090_3734.23408 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our previous study indicated that IGF @-@ 1 could significantly increase IL @-@ 6 mRNA expression and protein production in PHA @- activated cord blood MNC ( 12 ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1.1 7-1.2.1.1.1.1 8-1.2 9-1.2.1.3 10-1.2.1 11-1.2.1.2.1.1.2.1.1 13-1.2.1.2.1.1.2.1.1 14-1.2.1.2.1.1.1.1 15-1.2.1.2.1 16-1.2.1.2 17-1.2.1.2.2.1 18-1.2.1.2.2 19-1.2.1.2.2.2.r 20-1.2.1.2.2.2.2.1.1.1 22-1.2.1.2.2.2.2 23-1.2.1.2.2.2.3.1 24-1.2.1.2.2.2.3 25-1.2.1.2.2.2.1.1 27-1.3.1.1.1 (i / indicate-01~e.3 :ARG0 (s / study-01~e.2 :ARG0~e.0 (w / we~e.0) :time (p / previous~e.1)) :ARG1~e.4 (p5 / possible-01~e.8 :ARG1 (i2 / increase-01~e.10 :ARG0 (p2 / protein :name (n3 / name :op1 "IGF-1"~e.5,7)) :ARG1 (a / and~e.16 :op1 (e / express-03~e.15 :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.14) :mod (p4 / protein :name (n / name :op1 "IL-6"~e.11,13)))) :op2 (p3 / produce-01~e.18 :ARG1 (p6 / protein~e.17) :ARG3~e.19 (c3 / cell :name (n4 / name :op1 "MNC"~e.25) :ARG1-of (a2 / activate-01~e.22 :ARG0 (p7 / protein :name (n5 / name :op1 "PHA"~e.20))) :mod (b / blood~e.24 :location (c / cord~e.23))))) :ARG2 (s2 / significant-02~e.9))) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 12~e.27)))) # ::id bel_pmid_1091_2795.5930 ::amr-annotator SDL-AMR-09 ::preferred # ::tok constitutively active kinases within the ERK1 @/@ 2 pathway ( MEKK1 , MEK1 ) or the p38 pathway ( ASK1 , MEKK1 , MKK3 ) are potent activators of the MMP @-@ 1 promoter # ::alignments 0-1.1.1.1.1 0-1.1.1.1.1.r 1-1.1.1.1 2-1.1.1 5-1.1.1.2.1.1.1 7-1.1.1.2.1.1.1 8-1.1.1.2.1 10-1.1.1.2.1.2.1.1.1.1 12-1.1.1.2.1.2.1.2.1.1 14-1.1 14-1.1.1.2 16-1.1.1.2.2.1.1 17-1.1.1.2.2 19-1.1.1.2.2.2.1.1.1.1 21-1.1.1.2.2.2.1.2 23-1.1.1.2.2.2.1.3.1.1 26-1.3 27-1 28-1.2.r 30-1.2.1.1.1.1 32-1.2.1.1.1.1 33-1.2 33-1.2.1 33-1.2.1.r (a / activate-01~e.27 :ARG0 (o / or~e.14 :op1 (k / kinase~e.2 :ARG0-of (a2 / activity-06~e.1 :manner~e.0 (c / constitutive~e.0)) :location (o2 / or~e.14 :op1 (p4 / pathway~e.8 :name (n3 / name :op1 "ERK1/2"~e.5,7) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (e5 / enzyme :name (n5 / name :op1 "MEKK1"~e.10)) :op2 (e6 / enzyme :name (n6 / name :op1 "MEK1"~e.12))))) :op2 (p3 / pathway~e.17 :name (n2 / name :op1 "p38"~e.16) :ARG1-of (m3 / mean-01 :ARG2 (a4 / and :op1 (e2 / enzyme :name (n7 / name :op1 "ASK1"~e.19)) :op2 e5~e.21 :op3 (e4 / enzyme :name (n9 / name :op1 "MKK3"~e.23)))))))) :ARG1~e.28 (m / molecular-physical-entity~e.33 :ARG0-of~e.33 (p2 / promote-01~e.33 :ARG1 (e / enzyme :name (n / name :op1 "MMP-1"~e.30,32)))) :mod (p / potent~e.26)) # ::id bel_pmid_1092_5306.24430 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGF @-@ b1 also stimulates H2O2 production in bovine pulmonary artery endothelial cells ( 22 ) , vascular endothelial cells ( 23 ) , mouse osteoblastic cells ( 24 ) , and human lung fibroblast ( HLF ) cells ( 25 , 26 ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1.3 4-1 5-1.2.1.1.1 6-1.2 7-1.4.r 8-1.4.1.3.2 10-1.4.1.3 11-1.4.1.2 12-1.4.1 14-1.4.1.1.1.1.1 17-1.4.2.3 18-1.4.2.2 19-1.4.2 21-1.4.2.1.1.1.1 24-1.4.3.3 26-1.4.3 28-1.4.3.1.1.1.1 31-1.4 32-1.4.4.2.1 33-1.4.1.3.1 33-1.4.4.2 34-1.4.4.3 38-1.4.4 40-1.4.4.1.1.1.1.1 42-1.4.4.1.1.1.1.2 (s / stimulate-01~e.4 :ARG0 (p5 / protein :name (n / name :op1 "TGF-b1"~e.0,2)) :ARG1 (p / produce-01~e.6 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "H2O2"~e.5))) :mod (a / also~e.3) :location~e.7 (a2 / and~e.31 :op1 (c / cell~e.12 :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c8 / cite-01 :ARG2 22~e.14))) :mod (e / endothelium~e.11) :part-of (a3 / artery~e.10 :mod (l2 / lung~e.33) :mod (c9 / cattle~e.8))) :op2 (c2 / cell~e.19 :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 23~e.21))) :mod e~e.18 :part-of (v / vessel~e.17)) :op3 (c3 / cell~e.26 :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 24~e.28))) :mod (o / osteoblast) :part-of (m3 / mouse~e.24)) :op4 (c4 / cell~e.38 :ARG1-of (d5 / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 (a4 / and :op1 25~e.40 :op2 26~e.42)))) :part-of (l / lung~e.33 :mod (h / human~e.32)) :mod (f / fibroblast~e.34)))) # ::id bel_pmid_1092_5306.24432 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGF @-@ b1 ( 1 ng/ml ) - induced intracellular ROS levels in HLF cells were measured with DCFH @-@ DA and laser @-@ scanning confocal microscopy ... As shown in Fig. 1 , A and B , DCF fluorescence displayed a rapid increase with maximal intensity at 5 min after treatment and was followed by a decline in fluorescence to the basal level by 20 min . # ::alignments 0-1.1.1.4.1.1.1 2-1.1.1.4.1.1.1 4-1.1.1.4.1.2.1 8-1.1.1.4 9-1.1.1.3 10-1.1.1.1.1.1 11-1.1.1 12-1.1.1.2.r 13-1.1.1.2.1.1 14-1.1.1.2 16-1.1 17-1.1.2.r 18-1.1.2.1.1.1 20-1.1.2.1.1.1 21-1.1.2 22-1.1.2.2.2.1 24-1.1.2.2.2 25-1.1.2.2.1 29-1.2.3 31-1.2.3.1.1 31-1.2.3.1.2 32-1.1.1.4.1.2.1 35-1.2.3.1 38-1.2.1.1.1.1.1.1 40-1.2.1 42-1.2.1.1.2 43-1.2.1.1 44-1.2.1.1.3.r 45-1.2.1.1.3.1 46-1.2.1.1.3 48-1.2.1.1.4.2.1 49-1.2.1.1.4.2.2 50-1.2.1.1.4 50-1.2.2.1.3 51-1.2.1.1.4.1 51-1.2.2.1.3.1 52-1.2 54-1.2.2 55-1.2.2.1.r 57-1.2.2.1 60-1.2.2.1.2.r 62-1.2.2.1.2.1 63-1.2.2.1.2 64-1.2.2.1.3.2.r 65-1.2.2.1.3.2.1 66-1.2.1.1.4.2.2 66-1.2.2.1.3.2.2 (m / multi-sentence :snt1 (m2 / measure-01~e.16 :ARG1 (l / level~e.11 :quant-of (s3 / small-molecule :name (n / name :op1 "ROS"~e.10)) :location~e.12 (c / cell~e.14 :name (n2 / name :op1 "HLF"~e.13)) :mod (i / intracellular~e.9) :ARG2-of (i2 / induce-01~e.8 :ARG0 (p / protein :name (n3 / name :op1 "TGF-b1"~e.0,2) :quant (c2 / concentration-quantity :quant 1~e.4,32 :unit (n4 / nanogram-per-milliliter))))) :ARG2~e.17 (a / and~e.21 :op1 (s4 / small-molecule :name (n5 / name :op1 "DCFH-DA"~e.18,20)) :op2 (m6 / microscope :mod (c3 / confocal~e.25) :ARG2-of (s / scan-01~e.24 :ARG0 (l2 / laser~e.22))))) :snt2 (a2 / and~e.52 :op1 (d / display-01~e.40 :ARG1 (i3 / increase-01~e.43 :ARG1 (f4 / fluoresce-01 :ARG1 (s5 / small-molecule :name (n6 / name :op1 "DCF"~e.38))) :mod (r / rapid~e.42) :ARG1-of~e.44 (i4 / intense-02~e.46 :degree (m8 / maximal~e.45)) :time (a4 / after~e.50 :op1 (t2 / treat-04~e.51 :ARG1 f4 :ARG2 s5) :quant (t / temporal-quantity :quant 5~e.48 :unit (m4 / minute~e.49,66))))) :op2 (f / follow-01~e.54 :ARG1~e.55 (d3 / decline-01~e.57 :ARG1 (f5 / fluoresce-01) :degree~e.60 (l3 / level~e.63 :mod (b / basal~e.62)) :time (a5 / after~e.50 :op1 (t3 / treat-04~e.51) :quant~e.64 (t4 / temporal-quantity :quant 20~e.65 :unit (m3 / minute~e.66)))) :ARG2 f4) :ARG1-of (s2 / show-01~e.29 :ARG0 (a3 / and~e.35 :op1 (f2 / figure~e.31 :mod "1A") :op2 (f3 / figure~e.31 :mod "1B"))))) # ::id bel_pmid_1092_5306.24450 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Also , stimulation with TGF @-@ b1 ( 1 ng/ml ) caused a time @-@ dependent increase in IL @-@ 6 protein accumulation in the culture supernatants ( Fig . 2C ) . # ::alignments 0-1.4 2-1.1 4-1.1.1.1.1 6-1.1.1.1.1 8-1.1.1.2.1 11-1 13-1.2.2.1 15-1.2.2 16-1.2 17-1.2.1.r 18-1.2.1.1.1.1 20-1.2.1.1.1.1 21-1.1.1 21-1.2.1.1 22-1.2.1 23-1.2.3.r 25-1.2.3.1 26-1.2.3 28-1.3.1 30-1.3.1.1 (c / cause-01~e.11 :ARG0 (s / stimulate-01~e.2 :ARG2 (p2 / protein~e.21 :name (n / name :op1 "TGF-b1"~e.4,6) :quant (c2 / concentration-quantity :quant 1~e.8 :unit (n2 / nanogram-per-milliliter)))) :ARG1 (i / increase-01~e.16 :ARG1~e.17 (a2 / accumulate-01~e.22 :ARG0 (p / protein~e.21 :name (n3 / name :op1 "IL-6"~e.18,20))) :ARG0-of (d2 / depend-01~e.15 :ARG1 (t / time~e.13)) :location~e.23 (s2 / supernatant~e.26 :mod (c3 / culture~e.25))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod "2C"~e.30)) :mod (a / also~e.0)) # ::id bel_pmid_1092_5306.24464 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The amount of 1 ng @/@ ml TGF @-@ b1 was sufficient to induce the IL @-@ 6 mRNA ( Fig . 2A ) . TGF @-@ b1 ( 1 ng/ml ) treatment produced a progressive increase in IL @-@ 6 mRNA concentrations , beginning as early as 30 min , peaking at 12 h , and decreasing after 24 h ( Fig . 2B ) . # ::alignments 1-1.1.1 3-1.1.1.2.1 4-1.1.1.2.2 6-1.1.1.2.2 6-1.2.1.1.2.2 7-1.1.1.1.1.1 9-1.1.1.1.1.1 11-1.1 13-1.1.2 15-1.1.2.2.2.1.1 17-1.1.2.2.2.1.1 18-1.1.2.2.1.1 20-1.1.3.1 22-1.1.3.1.1 25-1.2.1.1.1.1 27-1.2.1.1.1.1 29-1.2.1.1.2.1 32-1.2.1 33-1.2 36-1.2.2 38-1.2.2.1.1.2.1.1 40-1.2.2.1.1.2.1.1 41-1.2.2.1.1.1.1 42-1.1.1.2 42-1.2.1.1.2 42-1.2.2.1 44-1.2.2.2 45-1.2.2.2.1.r 46-1.2.2.2.1 47-1.2.2.2.1.1.r 47-1.2.2.2.1.r 48-1.2.2.2.1.1.1 49-1.2.2.2.1.1.2 51-1.2.2.3 53-1.2.2.3.1.1.1 54-1.2.2.3.1.1.2 57-1.2.2.4 58-1.2.2.3.1 58-1.2.2.4.1 59-1.2.2.4.1.1.1 60-1.2.2.3.1.1.2 60-1.2.2.4.1.1.2 62-1.2.3.1 64-1.2.3.1.1 (m / multi-sentence :snt1 (s / suffice-01~e.11 :ARG0 (a / amount-01~e.1 :ARG1 (p6 / protein :name (n / name :op1 "TGF-b1"~e.7,9)) :ARG2 (c / concentration-quantity~e.42 :quant 1~e.3 :unit (n2 / nanogram-per-milliliter~e.4,6))) :ARG1 (i / induce-01~e.13 :ARG0 a :ARG2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.18) :mod (p / protein :name (n3 / name :op1 "IL-6"~e.15,17)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "2A"~e.22))) :snt2 (p2 / produce-01~e.33 :ARG0 (t / treat-04~e.32 :ARG2 (p7 / protein :name (n6 / name :op1 "TGF-b1"~e.25,27) :quant (c2 / concentration-quantity~e.42 :quant 1~e.29 :unit (n5 / nanogram-per-milliliter~e.6)))) :ARG1 (i2 / increase-01~e.36 :ARG1 (c3 / concentrate-02~e.42 :ARG1 (n10 / nucleic-acid :name (n7 / name :op1 "mRNA"~e.41) :mod (p3 / protein :name (n8 / name :op1 "IL-6"~e.38,40)))) :ARG0-of (b / begin-01~e.44 :time~e.45,47 (e / early~e.46 :op1~e.47 (t2 / temporal-quantity :quant 30~e.48 :unit (m4 / minute~e.49)))) :ARG1-of (p4 / peak-01~e.51 :time (a3 / after~e.58 :op1 (t3 / temporal-quantity :quant 12~e.53 :unit (h / hour~e.54,60)))) :ARG1-of (d3 / decrease-01~e.57 :time (a2 / after~e.58 :op1 (t4 / temporal-quantity :quant 24~e.59 :unit (h2 / hour~e.60)))) :ARG1-of (p5 / progress-01)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.62 :mod "2B"~e.64)))) # ::id bel_pmid_1093_8266.21268 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB @-@ 2 by Jak2 , provides docking sites for Grb2 and stimulates Ras @-@ MAP kinase cascade , thereby causing unrestricted cellular proliferation . # ::alignments 0-1.1.2 0-1.1.2.r 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2.1.1 6-1.2.1.1.2.r 7-1.2.1.1.2.1.1 8-1.2.1 9-1.2.1.2.1.1.1 10-1.2.1.2 12-1.2.1.2.1.2.1.1 14-1.2.1.2.1.2.1.1 15-1.2.1.2.2.r 16-1.2.1.2.2.1.1 18-1.2.2 19-1.2.2.2.1 20-1.2.2.2 21-1.2.2.3.r 22-1.2.2.3.1.1 23-1.2 24-1.2.1 24-1.2.3 25-1.2.3.2.1.1 27-1.2.3.2.1.1 28-1.2.3.2.1.2 32-1.2.4 33-1.2.4.1.2 33-1.2.4.1.2.1 33-1.2.4.1.2.1.r 34-1.2.4.1.1 35-1.2.4.1 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :poss~e.0 (w / we~e.0)) :ARG1~e.3 (a / and~e.23 :op1 (s / stimulate-01~e.8,24 :ARG0 (s3 / secrete-01~e.5 :ARG0 (a2 / autocrine~e.4) :ARG1~e.6 (p4 / protein :name (n / name :op1 "PRL"~e.7))) :ARG1 (p3 / phosphorylate-01~e.10 :ARG1 (a3 / amino-acid :name (n2 / name :op1 "tyrosine"~e.9) :part-of (e2 / enzyme :name (n3 / name :op1 "ErbB-2"~e.12,14))) :ARG2~e.15 (e / enzyme :name (n4 / name :op1 "Jak2"~e.16)))) :op2 (p / provide-01~e.18 :ARG0 a2 :ARG1 (s4 / site~e.20 :ARG0-of (d / dock-01~e.19)) :ARG2~e.21 (p7 / protein :name (n5 / name :op1 "Grb2"~e.22))) :op3 (s2 / stimulate-01~e.24 :ARG0 a2 :ARG1 (p6 / pathway :name (n7 / name :op1 "Ras-MAP"~e.25,27 :op2 "kinase"~e.28))) :ARG0-of (c / cause-01~e.32 :ARG1 (p2 / proliferate-01~e.35 :ARG0 (c2 / cell~e.34) :ARG1-of (r2 / restrict-01~e.33 :polarity~e.33 -~e.33))))) # ::id bel_pmid_1094_3842.21324 ::amr-annotator SDL-AMR-09 ::preferred # ::tok inhibition of MAPK14 activity also interfered with stabilization of EPO mRNA in human hepatoma cells undergoing hypoxic stress # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.3 5-1 6-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.2.1.1 10-1.2.1.1.1 11-1.2.2.r 12-1.2.2.2 13-1.2.2.1 14-1.2.2 17-1.2.2.3 (i / interfere-01~e.5 :ARG0 (i2 / inhibit-01~e.0 :ARG1~e.1 (a / activity-06~e.3 :ARG0 (e / enzyme :name (n / name :op1 "MAPK14"~e.2)))) :ARG1~e.6 (s / stabilize-01~e.7 :ARG1~e.8 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.10) :mod (s3 / small-molecule :name (n3 / name :op1 "EPO"~e.9))) :location~e.11 (c / cell~e.14 :mod (h / hepatoma~e.13) :mod (h2 / human~e.12) :ARG1-of (s2 / stress-02~e.17 :ARG0 (h3 / hypoxia)))) :mod (a2 / also~e.4)) # ::id bel_pmid_1094_5974.21384 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the earlier results , p42 @/@ 44 MAPK and its upstream kinase MEK1 @/@ 2 were activated in a time @-@ dependent manner by the induction of Pak1 ( Fig . 3C ) . # ::alignments 0-1.4 1-1.4.1.r 3-1.4.1.1.1 3-1.4.1.1.1.1 3-1.4.1.1.1.1.r 4-1.4.1 4-1.4.1.1 4-1.4.1.1.r 6-1.2.1.1.1.1 7-1.2.1 9-1.2.1.1.1.2 9-1.2.1.2.1.2 10-1.2 11-1.2.2.4 11-1.2.2.4.r 12-1.2.2.3 13-1.2.2.1 13-1.2.2.2 14-1.2.2.1.1.1 15-1.2.2 18-1 21-1.3.1 23-1.3 24-1.3.r 25-1.1.r 27-1.1 28-1.1.1.r 29-1.1.1.1.1 31-1.4.2.1 33-1.4.2.1.1 (a3 / activate-01~e.18 :ARG0~e.25 (i / induce-01~e.27 :ARG2~e.28 (e2 / enzyme :name (n / name :op1 "Pak1"~e.29))) :ARG1 (a2 / and~e.10 :op1 (s / slash~e.7 :op1 (e3 / enzyme :name (n3 / name :op1 "p42"~e.6 :op2 "MAPK"~e.9)) :op2 (e4 / enzyme :name (n4 / name :op1 "p44" :op2 "MAPK"~e.9))) :op2 (s2 / slash~e.15 :op1 (k5 / kinase~e.13 :name (n2 / name :op1 "MEK1"~e.14)) :op2 (k6 / kinase~e.13 :name (n6 / name :op1 "MEK2")) :location (u / upstream~e.12) :poss~e.11 s~e.11)) :manner~e.24 (d / depend-01~e.23 :ARG1 (t2 / time~e.21)) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4 :time (e / early~e.3 :degree~e.3 (m / more~e.3)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "3C"~e.33)))) # ::id bel_pmid_1097_1465.18050 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Jaffe et al. [ 22,23 ] reported IL @-@ 5 and IL @-@ 13 production from human lung mast cells following IgE @-@ mediated activation . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.3.1.1.1 2-1.1.2.1 6-1 7-1.2.1.1.1.1 7-1.2.1.2.1.1 9-1.2.1.1.1.1 10-1.2.1 11-1.2.1.1.1.1 11-1.2.1.2.1.1 13-1.2.1.2.1.1 14-1.2 15-1.2.2.r 16-1.2.2.2.1 17-1.2.2.2 18-1.2.2.1 19-1.2.2 20-1.2.3 21-1.2.3.1.1.1.1.1 23-1.2.3.1.1 24-1.2.3.1 (r / report-01~e.6 :ARG0 (a / and~e.1 :op1 (p / person :name (n / name :op1 "Jaffe"~e.0)) :op2 (p2 / person :mod (o / other~e.2))) :ARG1 (p4 / produce-01~e.14 :ARG1 (a3 / and~e.10 :op1 (p5 / protein :name (n2 / name :op1 "IL-5"~e.7,9,11)) :op2 (p6 / protein :name (n3 / name :op1 "IL-13"~e.7,11,13))) :ARG2~e.15 (c2 / cell~e.19 :mod (m / mast~e.18) :part-of (l / lung~e.17 :mod (h / human~e.16))) :ARG1-of (f / follow-01~e.20 :ARG2 (a4 / activate-01~e.24 :ARG1-of (m2 / mediate-01~e.23 :ARG0 (s / small-molecule :name (n4 / name :op1 "IgE"~e.21)))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and~e.1 :op1 22 :op2 23))))) # ::id bel_pmid_1097_1465.18052 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using immunocytochemistry , Bradding et al. [ 1± 4 ] reported that interleukin ( IL ) - 4 , IL @-@ 5 , IL @-@ 6 , and tumour necrosis factor ( TNF ) - a were present within mast cells in nasal and bronchial mucosa taken from both normal subjects and patients with allergic perennial rhinitis , # ::alignments 0-1.1 1-1.1.2 3-1.2.1.1.1.1 4-1.1.3.1.1.1.2 4-1.2.1 5-1.2.1.2.1 8-1.1.3.1.1.1.2.2 8-1.2.2.1.1.1.1 10-1.2 14-1.2.2.1.1.1.1 14-1.2.2.1.2.1.1 14-1.2.2.1.3.1.1 17-1.2.2.1.1.1.1 19-1.2.2.1.1.1.1 19-1.2.2.1.2.1.1 19-1.2.2.1.3.1.1 21-1.2.2.1.2.1.1 23-1.2.2.1.1.1.1 23-1.2.2.1.2.1.1 23-1.2.2.1.3.1.1 25-1.2.2.1.3.1.1 28-1.2.2.1.4.1.1 29-1.2.2.1.4.1.2 30-1.2.2.1.4.1.3 35-1.2.2.1.4.1.3 37-1.2.2 39-1.2.2.2.1 40-1.2.2.2 43-1.2.2.2.1.1 44-1.2.2.2.1.1.2.1 45-1.2.2.2.1.1.1 45-1.2.2.2.1.1.2 46-1.2.2.2.1.1.3 49-1.2.2.2.1.1.3.1.1.1 50-1.2.2.2.1.1.3.1.1 51-1.2.2.2.1.1.3.1 52-1.2.2.2.1.1.3.1.2 53-1.2.2.2.1.1.3.1.2.1.r 54-1.2.2.2.1.1.3.1.2.1 55-1.2.2.2.1.1.3.1.2.1.1.1.1 56-1.2.2.2.1.1.3.1.2.1.1.1.2 (c / cause-01 :ARG0 (u / use-01~e.0 :ARG0 a :ARG1 (i / immunocytochemistry~e.1) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 (o2 / or :op1 1 :op2 (a6 / and~e.4 :op1 1 :op2 4~e.8)))))) :ARG1 (r / report-01~e.10 :ARG0 (a / and~e.4 :op1 (p / person :name (n / name :op1 "Bradding"~e.3)) :op2 (p2 / person :mod (o / other~e.5))) :ARG1 (p9 / present-02~e.37 :ARG1 (a2 / and :op1 (p4 / protein :name (n4 / name :op1 "IL-4"~e.8,14,17,19,23)) :op2 (p5 / protein :name (n5 / name :op1 "IL-5"~e.14,19,21,23)) :op3 (p6 / protein :name (n6 / name :op1 "IL-6"~e.14,19,23,25)) :op4 (p7 / protein :name (n7 / name :op1 "tumour"~e.28 :op2 "necrosis"~e.29 :op3 "factor-a"~e.30,35))) :ARG2 (c2 / cell~e.40 :mod (m / mast~e.39 :location (a4 / and~e.43 :op1 (m2 / mucosa~e.45 :mod (n8 / nose)) :op2 (m3 / mucosa~e.45 :mod (b3 / bronchus~e.44)) :ARG1-of (t / take-01~e.46 :ARG2 (a3 / and~e.51 :op1 (s / subject~e.50 :ARG1-of (n2 / normal-02~e.49)) :op2 (p3 / patient~e.52 :ARG1-of~e.53 (a5 / allergic-01~e.54 :ARG2 (m4 / medical-condition :name (n3 / name :op1 "perennial"~e.55 :op2 "rhinitis"~e.56)))))))))))) # ::id bel_pmid_1099_3906.5890 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAM2 is downstream of the Jak family of kinases since coexpression of STAM2 with Jak1 or Jak2 but not an unrelated Tec family kinase , Etk , resulted in its tyrosine phosphorylation . # ::alignments 0-1.2.1 1-1.2 2-1.2.2.2 5-1.2.2.1.1.1 6-1.2.2.1 8-1.1.2.2 9-1 12-1.1.1.1.1.1.1.1 14-1.1.1.1.1.2.1.1.1 15-1.1.1.1.1.2 16-1.1.1.1.1.2.2.1.1 17-1.1 18-1.1.2.1.r 18-1.1.2.2.2.1.r 20-1.1.2.1 20-1.1.2.2.2 20-1.1.2.2.2.1 21-1.1.2.2.3.1.1.1 22-1.1.2.2.3.1 23-1.1.2.2 25-1.1.2.2.1.1 27-1.1.1 27-1.1.2 28-1.1.1.2.r 29-1.1.1.2.1.2 29-1.1.1.2.1.2.r 30-1.1.1.2.1.1.1 31-1.1.1.2 (c4 / cause-01~e.9 :ARG0 (c5 / contrast-01~e.17 :ARG1 (r / result-01~e.27 :ARG1 (e3 / express-03 :ARG2 (a2 / and :op1 (p5 / protein :name (n3 / name :op1 "STAM2"~e.12)) :op2 (o / or~e.15 :op1 (e / enzyme :name (n / name :op1 "Jak1"~e.14)) :op2 (e2 / enzyme :name (n2 / name :op1 "Jak2"~e.16))))) :ARG2~e.28 (p4 / phosphorylate-01~e.31 :ARG1 (a / amino-acid :name (n5 / name :op1 "tyrosine"~e.30) :part-of~e.29 p5~e.29))) :ARG2 (r2 / result-01~e.27 :polarity~e.18 -~e.20 :ARG1 (k2 / kinase~e.8,23 :name (n7 / name :op1 "Etk"~e.25) :ARG1-of (r3 / relate-01~e.20 :polarity~e.18 -~e.20) :ARG1-of (i / include-91 :ARG2 (p2 / protein-family~e.22 :name (n6 / name :op1 "Tec"~e.21)))) :ARG2 p4)) :ARG1 (b / be-located-at-91~e.1 :ARG1 p5~e.0 :ARG2 (r4 / relative-position :op1 (p / protein-family~e.6 :name (n4 / name :op1 "Jak"~e.5)) :direction (d / downstream~e.2)))) # ::id bel_pmid_1099_3906.6852 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tyrosine phosphorylation of STAM2 is induced by growth factors such as epidermal growth factor and platelet @-@ derived growth factor as well as by cytokines like IL @-@ 3 . # ::alignments 0-1.2.1.1.1 1-1.2 3-1.2.1.2.1.1 5-1 6-1.1.r 7-1.1 8-1.1 9-1.1.1.r 10-1.1.1.r 11-1.1.1.1.1.1 12-1.1.1.1.1.2 13-1.1.1.1.1.3 14-1.1.1 15-1.1.1.2.1.1 17-1.1.1.2.1.1 18-1.1.1.2.1.2 19-1.1.1.2.1.3 20-1.1.1 21-1.1.1 22-1.1.1 24-1.1.1.3.1.1 25-1.1.1.3.2.r 26-1.1.1.3.2.1.1 28-1.1.1.3.2.1.1 (i / induce-01~e.5 :ARG0~e.6 (g / growth-factor~e.7,8 :example~e.9,10 (a2 / and~e.14,20,21,22 :op1 (p3 / protein :name (n7 / name :op1 "epidermal"~e.11 :op2 "growth"~e.12 :op3 "factor"~e.13)) :op2 (p4 / protein :name (n6 / name :op1 "platelet-derived"~e.15,17 :op2 "growth"~e.18 :op3 "factor"~e.19)) :op2 (p5 / protein :name (n5 / name :op1 "cytokine"~e.24) :example~e.25 (p6 / protein :name (n4 / name :op1 "IL-3"~e.26,28))))) :ARG2 (p8 / phosphorylate-01~e.1 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.0) :part-of (p / protein :name (n2 / name :op1 "STAM2"~e.3))))) # ::id bel_pmid_1099_3906.7612 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , overexpression of wild type STAM2 led to an increase in IL @-@ 2 @-@ mediated induction of c @-@ Myc promoter activation indicating that it potentiates cytokine receptor signaling . # ::alignments 0-1.1 0-1.1.r 2-1.2 3-1.2.1.r 4-1.2.1.2 5-1.2.1.2 6-1.2.1.1.1 7-1 10-1.3 11-1.3.1.r 12-1.3.1.2.1.1.1 14-1.3.1.2.1.1.1 16-1.3.1.2 17-1.3.1 18-1.3.1.1.r 19-1.3.1.1.1.1.1.1.1 21-1.3.1.1.1.1.1.1.1 22-1.3.1.1.1 22-1.3.1.1.1.1 22-1.3.1.1.1.1.r 23-1.3.1.1 24-1.4 25-1.4.1.r 26-1.4.1.2 27-1.4.1 28-1.4.1.1.1.1.1.1 29-1.4.1.1.1 30-1.4.1.1 (l / lead-03~e.7 :li~e.0 -1~e.0 :ARG0 (o / overexpress-01~e.2 :ARG1~e.3 (p5 / protein :name (n / name :op1 "STAM2"~e.6) :mod (w / wild-type~e.4,5))) :ARG2 (i / increase-01~e.10 :ARG1~e.11 (i2 / induce-01~e.17 :ARG2~e.18 (a / activate-01~e.23 :ARG1 (m2 / molecular-physical-entity~e.22 :ARG0-of~e.22 (p2 / promote-01~e.22 :ARG1 (p6 / protein :name (n3 / name :op1 "c-Myc"~e.19,21))))) :ARG1-of (m / mediate-01~e.16 :ARG0 (p / protein :name (n2 / name :op1 "IL-2"~e.12,14))))) :ARG0-of (i3 / indicate-01~e.24 :ARG1~e.25 (p3 / potentiate-01~e.27 :ARG1 (s / signal-07~e.30 :ARG0 (r / receptor~e.29 :mod (p4 / protein :name (n4 / name :op1 "cytokine"~e.28)))) :ARG2 o~e.26))) # ::id bel_pmid_1101_5448.8236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , T cells from CCR2(-/)- immunized mice showed decreased antigen @-@ induced proliferation and production of IFN @-@ gamma compared with wild @-@ type immunized controls , suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE . # ::alignments 0-1.1.2 2-1.1.1.1.1 3-1.1.1 4-1.1.1.2.r 6-1.1.1.2.1 7-1.1.1.2 7-1.1.2.3.1.1 8-1.1 9-1.1.2.3 10-1.1.2.1.1.1 12-1.1.2.1.1 13-1.1.2.1 14-1.1.2 15-1.1.2.2 16-1.1.2.2.1.r 17-1.1.2.2.1.1.1 19-1.1.2.2.1.1.1 20-1.1.2.3.1 21-1.1.2.3.1.1.3.r 22-1.1.2.3.1.1.3 24-1.1.2.3.1.2.1.2.1.2 25-1.1.2.3.1.1.2 26-1.1.2.3.1.1.1 28-1.1.2.3.1.2 30-1.1.1.2.2.1.1 31-1.1.2.3.1.2.1 33-1.1.2.3.1.2.1.2.1.1.1 34-1.1.2.3.1.2.1.2.1.1.1 35-1.1.2.3.1.2.1.2.1 36-1.1.2.3.1.2.1.2.1.2 38-1.1.2.3.1.2.1.2.2 39-1.1.2.3.1.2.1.2 (a / and :op2 (s / show-01~e.8 :ARG0 (c / cell~e.3 :name (n / name :op1 "T"~e.2) :source~e.4 (m / mouse~e.7 :ARG1-of (i / immunize-01~e.6) :mod (p / protein :name (n2 / name :op1 "CCR2"~e.30) :ARG2-of (m2 / mutate-01 :mod "-/-")))) :ARG1 (a2 / and~e.0,14 :op1 (p2 / proliferate-01~e.13 :ARG2-of (i2 / induce-01~e.12 :ARG0 (a3 / antigen~e.10))) :op2 (p3 / produce-01~e.15 :ARG1~e.16 (p4 / protein :name (n3 / name :op1 "IFN-gamma"~e.17,19))) :ARG1-of (d / decrease-01~e.9 :ARG1-of (c2 / compare-01~e.20 :ARG2 (m3 / mouse~e.7 :ARG2-of (c3 / control-01~e.26) :ARG1-of i~e.25 :mod~e.21 (w / wild-type~e.22)) :ARG0-of (s2 / suggest-01~e.28 :ARG1 (e / enhance-01~e.31 :ARG0 p :ARG1 (r / respond-01~e.39 :ARG0 (c4 / cell~e.35 :name (n4 / name :op1 "T-helper"~e.33,34) :ARG1-of (t2 / type-03~e.24,36)) :ARG1-of (i3 / immune-02~e.38 :ARG2 (d2 / disease :name (n6 / name :op1 "experimental" :op2 "autoimmune" :op3 "encephalomyelitis"))))))))))) # ::id bel_pmid_1101_5448.18896 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At days 8 , 11 , 20 , 23 , and 26 after disease induction , splenocytes from CCR2 @-@ deficient mice also proliferated less robustly to Ag and secreted lower levels of IFN-{gamma} and IL @-@ 6 than splenocytes from wild @-@ type controls # ::alignments 1-1.3.2.1.2 1-1.3.2.2.2 1-1.3.2.3.2 1-1.3.2.4.2 1-1.3.2.5.2 2-1.3.2.1.1 4-1.3.2.2.1 6-1.3.2.3.1 8-1.3.2.4.1 10-1.3.2 11-1.3.2.5.1 12-1.3 13-1.3.1.1 14-1.3.1 16-1.1.1.1.1 17-1.1.1.2.r 18-1.1.1.2.1.1.1 20-1.1.1.2.1 20-1.1.1.2.1.2 20-1.1.1.2.1.2.1 20-1.1.1.2.1.2.1.r 20-1.1.1.2.1.2.r 21-1.1.1.2 21-1.2.2.1.2.2.2 22-1.1.3 23-1.1 24-1.1.2.1 25-1.1.2 25-1.1.2.r 27-1.1.4.1.1.1 28-1 29-1.2 30-1.2.2.1.2 30-1.2.2.1.2.1 30-1.2.2.1.2.1.r 31-1.2.2.1 31-1.2.2.2 34-1.2.2 35-1.2.2.2.1.1.1 37-1.2.2.2.1.1.1 38-1.2.2.2.2 39-1.1.1.1.1 39-1.2.2.1.2.2.1.1 40-1.1.1.2.r 40-1.2.2.1.2.2.2.2.r 40-1.2.2.1.2.2.r 41-1.2.2.1.2.2.2.2 43-1.2.2.1.2.2.2.2 44-1.2.2.1.2.2.2.1 (a / and~e.28 :op1 (p / proliferate-01~e.23 :ARG0 (c / cell :name (n / name :op1 "splenocyte"~e.16,39) :source~e.17,40 (m / mouse~e.21 :mod (p2 / protein~e.20 :name (n2 / name :op1 "CCR2"~e.18) :ARG2-of~e.20 (m2 / mutate-01~e.20 :mod~e.20 "-/-"~e.20)))) :manner~e.25 (r / robust~e.25 :degree (l / less~e.24)) :mod (a2 / also~e.22) :ARG1-of (r2 / result-01 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "Ag"~e.27)))) :op2 (s / secrete-01~e.29 :ARG0 c :ARG1 (a4 / and~e.34 :op1 (l2 / level~e.31 :quant-of (p3 / protein :name (n3 / name :op1 "IFN-γ")) :ARG1-of (l3 / low-04~e.30 :degree~e.30 (m4 / more~e.30) :compared-to~e.40 (c2 / cell :name (n6 / name :op1 "splenocyte"~e.39) :source (m5 / mouse~e.21 :mod (c3 / control~e.44) :mod~e.40 (w / wild-type~e.41,43))))) :op2 (l4 / level~e.31 :quant-of (p4 / protein :name (n4 / name :op1 "IL-6"~e.35,37)) :ARG1-of l3~e.38))) :time (a5 / after~e.12 :op1 (i / induce-01~e.14 :ARG2 (d2 / disease~e.13)) :quant (a3 / and~e.10 :op1 (t / temporal-quantity :quant 8~e.2 :unit (d3 / day~e.1)) :op2 (t2 / temporal-quantity :quant 11~e.4 :unit (d4 / day~e.1)) :op3 (t3 / temporal-quantity :quant 20~e.6 :unit (d5 / day~e.1)) :op4 (t4 / temporal-quantity :quant 23~e.8 :unit (d6 / day~e.1)) :op5 (t5 / temporal-quantity :quant 26~e.11 :unit (d7 / day~e.1))))) # ::id bel_pmid_1102_9459.7644 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The wild @-@ type Ki @-@ ras transfectants lack functional TGF @-@ beta receptors , whereas all three Ki @-@ ras( G12V ) transfectants expressed functional TGF @-@ beta receptors that bound ( 125 ) I @-@ TGF @-@ beta1 . # ::alignments 1-1.1.1.1.1.2 3-1.1.1.1.1.2 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 7-1.1.1 7-1.1.1.1 7-1.1.1.1.r 8-1.1 9-1.1.2.2 10-1.1.2.1.1 13-1.1.2.1.2 15-1 16-1.2.2.3 17-1.2.2.1 18-1.2.2.2.1.1.1 21-1.2.2.2.1.2.1 23-1.2.2 23-1.2.2.2 23-1.2.2.2.r 24-1.2 25-1.1.2.2 26-1.1.2.1.1 26-1.2.1.1.1 26-1.2.1.3.1.1.1 29-1.1.2.1.2 29-1.2.1.1.2 31-1.2.1 31-1.2.1.3 31-1.2.1.3.r 35-1.2.1.2 37-1.1.2.1.1 37-1.2.1.1.1 37-1.2.1.3.1.1.1 (c / contrast-01~e.15 :ARG1 (l / lack-01~e.8 :ARG0 (c2 / cell~e.7 :ARG1-of~e.7 (t / transfect-01~e.7 :ARG2 (p / protein :name (n / name :op1 "Ki-ras"~e.4,6) :mod (w / wild-type~e.1,3)))) :ARG1 (p4 / protein :name (n6 / name :op1 "TGF-β"~e.10,26,37 :op2 "receptor"~e.13,29) :mod (f / function-01~e.9,25))) :ARG2 (e / express-03~e.24 :ARG2 (p5 / protein~e.31 :name (n2 / name :op1 "TGF-β"~e.26,37 :op2 "receptor"~e.29) :mod f~e.35 :ARG1-of~e.31 (b / bind-01~e.31 :ARG2 (p2 / protein :name (n4 / name :op1 "(125)I-TGF-β1"~e.26,37)))) :ARG3 (c3 / cell~e.23 :quant 3~e.17 :ARG1-of~e.23 (t2 / transfect-01~e.23 :ARG2 (p3 / protein :name (n5 / name :op1 "Ki-ras"~e.18) :ARG2-of (m / mutate-01 :value "G12V"~e.21))) :mod (a / all~e.16)))) # ::id bel_pmid_1102_9459.20858 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GnT @-@ V transcription was stimulated by several oncogenes including src , her -@ 2/ neu , H @- ras , and v @- sis ( 9 , 10 , 11 ) , and this overexpression was regulated through the ras @-@ raf @-@ ets pathways . # ::alignments 0-1.1.2.1.1.1 2-1.1.2.1.1.1 3-1.1.2 5-1.1 6-1.1.1.r 7-1.1.1.1 8-1.1.1 9-1.1.1.2 10-1.1.1.2.1.1.1.1 12-1.1.1.2.1.2.1.1 15-1.1.1.2.1.2.1.1 17-1.1.1.2.1.3.1.1 19-1.1.1.2.1.3.1.1 21-1.1.1.2.1 22-1.1.1.2.1.4.1.1 24-1.1.1.2.1.4.1.1 26-1.1.3.1.1.1 28-1.1.3.1.2.1 30-1.1.3.1.3.1 33-1 33-1.1.3.1 34-1.2.2.1 35-1.2.2 37-1.2 40-1.2.1.1.1 42-1.2.1.1.1 44-1.2.1.1.1 45-1.2.1 (a / and~e.33 :op1 (s / stimulate-01~e.5 :ARG0~e.6 (o / oncogene~e.8 :mod (s2 / several~e.7) :ARG2-of (i / include-91~e.9 :ARG1 (a2 / and~e.21 :op1 (g / gene :name (n / name :op1 "src"~e.10)) :op2 (g2 / gene :name (n2 / name :op1 "her-2/neu"~e.12,15)) :op3 (g3 / gene :name (n3 / name :op1 "H-ras"~e.17,19)) :op4 (g4 / gene :name (n4 / name :op1 "v-sis"~e.22,24)) :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))))) :ARG1 (t / transcribe-01~e.3 :ARG1 (e / enzyme :name (n5 / name :op1 "GnT-V"~e.0,2))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.33 :op1 (f / figure :mod 9~e.26) :op2 (f2 / figure :mod 10~e.28) :op3 (f3 / figure :mod 11~e.30)))) :op2 (r / regulate-01~e.37 :ARG0 (p / pathway~e.45 :name (n6 / name :op1 "ras-raf-ets"~e.40,42,44)) :ARG1 (o2 / overexpress-01~e.35 :mod (t2 / this~e.34)))) # ::id bel_pmid_1102_9459.21486 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Each of three Ki @-@ ras( G12V ) transfectants responded to TGF @-@ beta1 by an increase in proliferation and by decreasing the abundance of the Cdk inhibitor p21 and the tumor suppressor PTEN , whereas each of three wild @-@ type Ki @-@ ras transfectants remained unresponsive to TGF @-@ beta1 . # ::alignments 0-1.1.1.3 0-1.2.1.3 2-1.1.1.1 2-1.2.1.1 3-1.1.1.2.1.1.1 3-1.2.1.2.1.1.1 6-1.1.1.2.1.2.1 8-1.1.1 8-1.1.1.2 8-1.1.1.2.r 9-1.1 10-1.1.2.r 11-1.1.2.1.1 14-1.1.3.r 16-1.1.3.1 17-1.1.3.1.1.r 18-1.1.3.1.1 19-1.1.3 21-1.1.3.2 23-1.1.3.2.1 24-1.1.3.2.1.1.r 26-1.1.3.2.1.1.1.2.1.1.1 27-1.1.3.2.1.1.1 27-1.1.3.2.1.1.1.2 27-1.1.3.2.1.1.1.2.r 28-1.1.3.2.1.1.1.1.1 29-1.1.3.2.1.1 31-1.1.3.2.1.1.2.2 32-1.1.3.2.1.1.2 33-1.1.3.2.1.1.2.1.1.1 35-1 36-1.1.1.3 36-1.2.1.3 38-1.1.1.1 38-1.2.1.1 39-1.2.1.4 41-1.2.1.4 42-1.2.1.2.1.1.1 44-1.2.1.2.1.1.1 45-1.2.1 45-1.2.1.2 45-1.2.1.2.r 46-1.2 47-1.2.2 47-1.2.2.1 47-1.2.2.1.r 48-1.2.2.3.r 49-1.2.2.3 (c / contrast-01~e.35 :ARG1 (r / respond-01~e.9 :ARG0 (c2 / cell~e.8 :quant 3~e.2,38 :ARG1-of~e.8 (t / transfect-01~e.8 :ARG2 (e5 / enzyme :name (n / name :op1 "Ki-ras"~e.3) :ARG2-of (m / mutate-01 :value "G12V"~e.6))) :mod (e / each~e.0,36)) :ARG1~e.10 (p2 / protein :name (n3 / name :op1 "TGF-β1"~e.11)) :ARG2~e.14 (a / and~e.19 :op1 (i / increase-01~e.16 :ARG1~e.17 (p3 / proliferate-01~e.18)) :op2 (d / decrease-01~e.21 :ARG1 (a2 / abound-01~e.23 :ARG1~e.24 (a3 / and~e.29 :op1 (p4 / protein~e.27 :name (n4 / name :op1 "p21"~e.28) :ARG0-of~e.27 (i2 / inhibit-01~e.27 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Cdk"~e.26)))) :op2 (s / suppress-01~e.32 :ARG0 (g / gene :name (n6 / name :op1 "PTEN"~e.33)) :ARG1 (t2 / tumor~e.31))))))) :ARG2 (r2 / remain-01~e.46 :ARG1 (c3 / cell~e.45 :quant 3~e.2,38 :ARG1-of~e.45 (t3 / transfect-01~e.45 :ARG2 (e4 / enzyme :name (n7 / name :op1 "Ki-ras"~e.3,42,44))) :mod (e3 / each~e.0,36) :mod (w / wild-type~e.39,41)) :ARG3 (r3 / respond-01~e.47 :polarity~e.47 -~e.47 :ARG0 c3 :ARG1~e.48 p2~e.49))) # ::id bel_pmid_1103_6942.20042 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SIRP is a transmembrane protein that is now known to bind to integrin @-@ associated protein . It appears to bind directly to JAK2 by a process that does not require tyrosyl phosphorylation , although is itself highly phosphorylated on tyrosines in response to GH . The phosphorylated SIRP recruits one or more molecules of the tyrosine phosphatase SHP2 that , in turn , de @-@ phosphorylates SIRP and most likely JAK2 . # ::alignments 0-1.1.1.1.1.1 0-1.3.1.1.1 3-1.1.1.1.2 4-1.1.1.1 7-1.1.2 8-1.1 10-1.1.1 11-1.1.1.2.r 12-1.1.1.2.1.1.1.1 14-1.1.1.2.1 15-1.1.1.2 18-1.2 20-1.2.1 21-1.2.1.3 22-1.2.1.2.r 23-1.2.1.2.1.1 24-1.2.1.4.r 26-1.2.1.4 29-1.2.1.4.1.1 29-1.2.1.4.1.1.r 30-1.2.1.4.1 32-1.2.1.4.1.2 32-1.3.1 32-1.3.1.2 32-1.3.1.2.r 34-1.2.2.r 37-1.2.2.2 38-1.2.2 40-1.2.1.4.1.2.1.1.1 40-1.2.2.1.1.1 40-1.3.2.1 41-1.3.2.1.2.1.3 42-1.2.2.3 42-1.3.2.1.2 43-1.2.2.3.1.r 44-1.2.2.3.1.1.1 47-1.2.2 48-1.2.1.1.1.1 48-1.3.1.1.1 49-1.3 50-1.3.2.2.1 51-1.3.2.2 52-1.3.2.2 53-1.3.2 56-1.3.2.1 57-1.3.2.1 58-1.3.2.1.1.1 61-1.3.2.1.2.1.3 62-1.3.2.1.2.1.3 66-1.2.2 67-1.3.1.1.1 68-1.3.2.1.2.1.2 69-1.3.2.1.2.1.2.2.2.1 70-1.3.2.1.2.1.2.2 70-1.3.2.1.2.1.2.2.2 70-1.3.2.1.2.1.2.2.2.r 71-1.3.2.1.2.1.2.2.1.1 (m / multi-sentence :snt1 (k / know-01~e.8 :ARG1 (b / bind-01~e.10 :ARG1 (p / protein~e.4 :name (n / name :op1 "SIRP"~e.0) :mod (t / transmembrane~e.3)) :ARG2~e.11 (p2 / protein~e.15 :ARG1-of (a / associate-01~e.14 :ARG2 (p3 / protein :name (n2 / name :op1 "integrin"~e.12))))) :time (n3 / now~e.7)) :snt2 (a2 / appear-02~e.18 :ARG1 (b2 / bind-01~e.20 :ARG1 (p4 / protein :name (n5 / name :op1 "SIRP"~e.48)) :ARG2~e.22 (e / enzyme :name (n4 / name :op1 "JAK2"~e.23)) :ARG1-of (d / direct-02~e.21) :ARG1-of~e.24 (p5 / process-02~e.26 :ARG0-of (r / require-01~e.30 :polarity~e.29 -~e.29 :ARG1 (p6 / phosphorylate-01~e.32 :ARG1 (a6 / amino-acid :name (n6 / name :op1 "tyrosine"~e.40)))))) :concession~e.34 (p7 / phosphorylate-01~e.38,47,66 :ARG1 (a3 / amino-acid :name (n7 / name :op1 "tyrosine"~e.40) :part-of p4) :ARG1-of (h / high-02~e.37) :ARG2-of (r2 / respond-01~e.42 :ARG1~e.43 (p10 / protein :name (n8 / name :op1 "GH"~e.44))))) :snt3 (r3 / recruit-01~e.49 :ARG0 (p8 / protein~e.32 :name (n9 / name :op1 "SIRP"~e.0,48,67) :ARG1-of~e.32 (p9 / phosphorylate-01~e.32)) :ARG1 (m4 / molecule~e.53 :mod (t2 / tyrosine-phosphatase~e.40,56,57 :name (n10 / name :op1 "SHP2"~e.58) :ARG1-of (r4 / respond-01~e.42 :ARG2 (d2 / dephosphorylate-01 :ARG0 t2 :ARG1 (a4 / and~e.68 :op1 p8 :op2 (e3 / enzyme~e.70 :name (n11 / name :op1 "JAK2"~e.71) :ARG1-of~e.70 (l / likely-01~e.70 :degree (m5 / most~e.69)))) :mod (i / in-turn~e.41,61,62)))) :quant (a5 / at-least~e.51,52 :op1 1~e.50)))) # ::id bel_pmid_1104_3579.5226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with acting through a G protein @-@ coupled receptor , estradiol signaling to Erk @-@ 1/-2 occurred via a Gbetagamma @-@ dependent , pertussis toxin @-@ sensitive pathway that required Src @-@ related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein . # ::alignments 0-1.4 1-1.4.1.1.r 2-1.4.1 5-1.4.1.1.1.1.1.1 6-1.4.1.1.1.1 8-1.4.1.1.1 9-1.4.1.1 11-1.1.1.1 12-1 13-1.2.r 14-1.2.1.1 22-1.3.1 24-1.3.2.1.1.1 25-1.3.2.1.1.2 27-1.3.2 28-1.3 30-1.3.3 31-1.3.3.1.1.2.1.1.1 33-1.3.3.1.1.2 34-1.3.3.1.1.1.1.1 35-1.3.3.1.1.1.1.2 36-1.3.3.1.1 37-1.3.3.1 38-1.3.3.1.2.1.2.1 39-1.3.3.1.2 41-1.3.3.1.2.1.2.1 42-1.3.3.1.2.1.1 45-1.3.3.1.2.1.3.1.1 46-1.3.3.1.2.1.3.1.2 47-1.3.1.1.1 47-1.3.1.1.2 47-1.3.3.1.1.2.1 47-1.3.3.1.2.1.3 (s / signal-07~e.12 :ARG0 (s3 / small-molecule :name (n / name :op1 "estradiol"~e.11)) :ARG2~e.13 (e / enzyme :name (n2 / name :op1 "Erk-1/-2"~e.14)) :manner (p / pathway~e.28 :ARG0-of (d / depend-01~e.22 :ARG1 (m2 / macro-molecular-complex :part (p2 / protein~e.47 :name (n3 / name :op1 "Gβ")) :part (p3 / protein~e.47 :name (n4 / name :op1 "Gγ")))) :ARG0-of (s2 / sensitive-03~e.27 :ARG1 (s4 / small-molecule :name (n5 / name :op1 "pertussis"~e.24 :op2 "toxin"~e.25))) :ARG0-of (r / require-01~e.30 :ARG1 (a / and~e.37 :op1 (a2 / activity-06~e.36 :ARG0 (e2 / enzyme :name (n6 / name :op1 "tyrosine"~e.34 :op2 "kinase"~e.35)) :ARG1-of (r2 / relate-01~e.33 :ARG2 (p4 / protein~e.47 :name (n7 / name :op1 "Src"~e.31)))) :op2 (p5 / phosphorylate-01~e.39 :ARG1 (a3 / amino-acid :mod 317~e.42 :name (n8 / name :op1 "tyrosine"~e.38,41) :part-of (p6 / protein~e.47 :name (n9 / name :op1 "Shc"~e.45 :op2 "adapter"~e.46))))))) :ARG1-of (c / consistent-01~e.0 :ARG2 (a4 / act-01~e.2 :instrument~e.1 (r3 / receptor~e.9 :ARG1-of (c2 / couple-01~e.8 :ARG2 (p7 / protein~e.6 :name (n10 / name :op1 "G"~e.5))))))) # ::id bel_pmid_1104_3579.5228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reinforcing this idea , estradiol signaling to Erk @-@ 1/-2 was dependent upon trans @-@ activation of the epidermal growth factor ( EGF ) receptor via release of heparan @-@ bound EGF ( HB @-@ EGF ) . # ::alignments 0-1.3 1-1.3.1.1 2-1.3.1 4-1.1.1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.1.1 11-1 13-1.2.2 15-1.2 16-1.2.1.r 18-1.2.1.1.1 19-1.2.1.1.2 20-1.2.1.1.3 22-1.2.3.1.3.1.1.1 24-1.2.1.1.4 24-1.2.3.1.1 26-1.2.3 30-1.2.3.1 31-1.2.3.1.3.1.1.1 33-1.2.3.1.3.1.1.1 35-1.2.3.1.3.1.1.1 (d / depend-01~e.11 :ARG0 (s / signal-07~e.5 :ARG0 (s2 / small-molecule :name (n / name :op1 "estradiol"~e.4)) :ARG2~e.6 (e / enzyme :name (n2 / name :op1 "Erk-1/-2"~e.7))) :ARG1 (a / activate-01~e.15 :ARG1~e.16 (p2 / protein :name (n4 / name :op1 "epidermal"~e.18 :op2 "growth"~e.19 :op3 "factor"~e.20 :op4 "receptor"~e.24)) :mod (t / trans~e.13) :manner (r3 / release-01~e.26 :ARG1 (b / bind-01~e.30 :ARG1 (r2 / receptor~e.24) :ARG2 (h / heparin) :ARG1-of (d3 / describe-01 :ARG0 (p / protein :name (n5 / name :op1 "HB-EGF"~e.22,31,33,35)))))) :ARG2-of (r4 / reinforce-01~e.0 :ARG1 (i / idea~e.2 :mod (t2 / this~e.1)))) # ::id bel_pmid_1104_3579.19856 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Estrogen rapidly activates the mitogen @-@ activated protein kinases , Erk @-@ 1 and Erk @-@ 2 , via an as yet unknown mechanism . requires the expression of the G protein @-@ coupled receptor homolog , GPR30 . We show that 17 beta @-@ estradiol activates Erk @-@ 1/-2 not only in MCF @-@ 7 cells , which express both estrogen receptor alpha ( ER alpha ) and ER beta , but # ::alignments 0-1.1.1 1-1.1.3 1-1.1.3.r 2-1.1 2-1.1.2.3.2 4-1.1.2.3.2.1 6-1.1.2.3.2 7-1.1.2.3.1.1 8-1.1.2.3.1.2 10-1.1.2.1.1.1 10-1.1.2.2.1.1 12-1.1.2.1.1.1 13-1.1.2 14-1.1.2.1.1.1 14-1.1.2.2.1.1 16-1.1.2.2.1.1 20-1.1.4.r 21-1.1.4.1.2 22-1.1.4.1 22-1.1.4.1.1 22-1.1.4.1.1.r 23-1.1.4 25-1.2 27-1.2.1 28-1.2.1.1.r 30-1.2.1.1.1.1 31-1.2.1.1.1.2 33-1.2.1.1.1.2 34-1.2.1.1.1.3 35-1.2.1.1.1.4 37-1.2.1.1.2.1.1.1 39-1.3.1 40-1.3 45-1.3.2.1.1.1 46-1.3.2 47-1.3.2.2.1.1 50-1.3.2.3.2.1 50-1.3.2.3.2.1.r 51-1.3.2.3.2 53-1.3.2.3.1.1 55-1.3.2.3.1.1 56-1.3.2.3 59-1.3.2.3.3 61-1.3.2.3.3.1.1.1.1 62-1.3.2.3.3.1.1.1.2 68-1.3.2.3.3.1 (m / multi-sentence :snt1 (a / activate-01~e.2 :ARG0 (e / estrogen~e.0) :ARG1 (a2 / and~e.13 :op1 (e2 / enzyme :name (n / name :op1 "Erk-1"~e.10,12,14)) :op2 (e3 / enzyme :name (n2 / name :op1 "Erk-2"~e.10,14,16)) :domain (e4 / enzyme :name (n3 / name :op1 "protein"~e.7 :op2 "kinase"~e.8) :ARG1-of (a3 / activate-01~e.2,6 :ARG0 (m2 / mitogen~e.4)))) :manner~e.1 (r / rapid~e.1) :manner~e.20 (m3 / mechanism~e.23 :ARG1-of (k / know-01~e.22 :polarity~e.22 -~e.22 :mod (y / yet~e.21)))) :snt2 (r2 / require-01~e.25 :ARG1 (e5 / express-03~e.27 :ARG2~e.28 (p / protein :name (n4 / name :op1 "G"~e.30 :op2 "protein-coupled"~e.31,33 :op3 "receptor"~e.34 :op4 "homolog"~e.35) :ARG1-of (d / describe-01 :ARG0 (p2 / protein :name (n5 / name :op1 "GPR30"~e.37)))))) :snt3 (s / show-01~e.40 :ARG0 (w / we~e.39) :ARG1 (a4 / activate-01~e.46 :ARG0 (s2 / small-molecule :name (n6 / name :op1 "17β-estradiol"~e.45)) :ARG1 (e6 / enzyme :name (n7 / name :op1 "Erk-1/-2"~e.47)) :location (c / cell-line~e.56 :name (n8 / name :op1 "MCF-7"~e.53,55) :mod (o / only~e.51 :polarity~e.50 -~e.50) :ARG2-of (e7 / express-03~e.59 :ARG1 (a5 / and~e.68 :op1 (p3 / protein :name (n9 / name :op1 "estrogen"~e.61 :op2 "receptor"~e.62 :op3 "α") :ARG1-of (d2 / describe-01 :ARG0 (p4 / protein :name (n10 / name :op1 "ERα")))) :op2 (p5 / protein :name (n11 / name :op1 "ERβ")))))))) # ::id bel_pmid_1106_2502.20878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Correspondingly , in vitro kinase assays showed that N17Rac1 inhibited the kinase activities of MEK1 @/@ 2 and ERK1 @/@ 2 stimulated by target signals ( Fig . 4b ) . # ::alignments 0-1.3 2-1.1.2 3-1.1.2 4-1.1.1 5-1.1 6-1 7-1.2.r 8-1.2.1.1.1 9-1.2 11-1.2.2.2 12-1.2.2 13-1.2.2.1.r 14-1.2.2.1.1.1.1 16-1.2.2.1.1.1.1 16-1.2.2.1.2.1.1 17-1.2.2.1 18-1.2.2.1.2.1.1 20-1.2.2.1.1.1.1 20-1.2.2.1.2.1.1 21-1.2.2.3 22-1.2.2.3.1.r 23-1.2.2.3.1.1 24-1.2.2.3.1 26-1.4.1 28-1.4.1.1 (s / show-01~e.6 :ARG0 (a / assay-01~e.5 :ARG1 (k / kinase~e.4) :manner (i / in-vitro~e.2,3)) :ARG1~e.7 (i2 / inhibit-01~e.9 :ARG0 (e3 / enzyme :name (n / name :op1 "N17Rac1"~e.8)) :ARG1 (a2 / activity-06~e.12 :ARG0~e.13 (a3 / and~e.17 :op1 (e / enzyme :name (n2 / name :op1 "MEK1/2"~e.14,16,20)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"~e.16,18,20))) :ARG1 k~e.11 :ARG1-of (s2 / stimulate-01~e.21 :ARG0~e.22 (s3 / signal-07~e.24 :ARG1-of (t / target-01~e.23))))) :ARG1-of (c / correspond-02~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "4b"~e.28))) # ::id bel_pmid_1106_2502.20880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Introduction of N17Rac1 into NK92 cells totally blocked PAK1 activation triggered by target ligation , whereas introduction of V12Rac1 strongly stimulated PAK1 activity even in the absence of target cells ( Fig . 7d ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.2.r 4-1.1.1.2.1.1 5-1.1.1.2 6-1.1.3 7-1.1 8-1.1.2.1.1.1 9-1.1.2 10-1.1.2.2 11-1.1.2.2.1.r 12-1.1.2.2.1.1 13-1.1.2.2.1 15-1 16-1.2.1 17-1.2.1.1.r 18-1.2.1.1.1.1 19-1.2.3 20-1.2 21-1.2.2.1 22-1.2.2 24-1.2.4.r 26-1.2.4 27-1.2.4.1.r 28-1.2.4.1.1 29-1.2.4.1 31-1.3.1 33-1.3.1.1 (c / contrast-01~e.15 :ARG1 (b / block-01~e.7 :ARG0 (i / introduce-02~e.0 :ARG1~e.1 (e3 / enzyme :name (n / name :op1 "N17Rac1"~e.2)) :ARG2~e.3 (c2 / cell~e.5 :name (n2 / name :op1 "NK92"~e.4))) :ARG1 (a / activate-01~e.9 :ARG1 (e / enzyme :name (n3 / name :op1 "PAK1"~e.8)) :ARG1-of (t / trigger-01~e.10 :ARG0~e.11 (l / ligate-01~e.13 :ARG1 (t2 / target-01~e.12)))) :degree (t3 / total~e.6)) :ARG2 (s / stimulate-01~e.20 :ARG0 (i2 / introduce-02~e.16 :ARG1~e.17 (e2 / enzyme :name (n4 / name :op1 "V12Rac1"~e.18)) :ARG2 c2) :ARG1 (a2 / activity-06~e.22 :ARG1 e~e.21) :ARG1-of (s2 / strong-02~e.19) :concession~e.24 (a3 / absent-01~e.26 :ARG1~e.27 (c3 / cell~e.29 :ARG1-of (t4 / target-01~e.28)) :ARG2 s)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "7d"~e.33))) # ::id bel_pmid_1106_2502.21386 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Examination of whole cell lysates from the same NK92 cells showed that kinase @-@ deficient ( KD ) PAK1 , unlike control CD56 , also effectively suppressed MEK and ERK activation by target ligation ( Fig . 7b ) . Thus , PAK1 is upstream of both MEK and ERK in the NK lytic process . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.3 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.r 7-1.1.1.1.2.2 8-1.1.1.1.2.1.1 9-1.1.1.1.2 10-1.1 12-1.1.2.1.1.2 14-1.1.2.1.1.2.1 14-1.1.2.1.1.2.1.1 14-1.1.2.1.1.2.1.1.r 18-1.1.2.1.1.1.1 20-1.1.2.2.1 21-1.1.2.2.2 21-1.1.2.2.2.2 21-1.1.2.2.2.2.r 22-1.1.2.2.2.1.1 24-1.1.2.1.3 25-1.1.2.1.4 26-1.1.2.1 26-1.1.2.2 27-1.1.2.1.2.2.1.1.1 28-1.1.2.1.2.2 29-1.1.2.1.2.2.2.1.1 30-1.1.2.1.2 31-1.1.2.1.2.1.r 32-1.1.2.1.2.1.1 33-1.1.2.1.2.1 35-1.1.3.1 37-1.1.3.1.1 40-1.2 42-1.2.1.1.1.1 43-1.2.1 44-1.2.1.2.2 47-1.2.1.2.1.1.1.1 48-1.2.1.2.1 49-1.2.1.2.1.2.1.1 52-1.2.1.3.1.1.1.1 54-1.2.1.3 (m / multi-sentence :snt1 (s / show-01~e.10 :ARG0 (e / examine-01~e.0 :ARG1~e.1 (l / lysate~e.4 :mod (c / cell~e.3) :source~e.5 (c2 / cell~e.9 :name (n / name :op1 "NK92"~e.8) :ARG1-of (s2 / same-01~e.7)) :mod (w / whole~e.2))) :ARG1 (c3 / contrast-01 :ARG1 (s3 / suppress-01~e.26 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PAK1"~e.18) :mod (k / kinase~e.12 :ARG2-of (m2 / mutate-01~e.14 :mod~e.14 "-/-"~e.14))) :ARG1 (a / activate-01~e.30 :ARG0~e.31 (l2 / ligate-01~e.33 :ARG1 (t / target-01~e.32)) :ARG1 (a2 / and~e.28 :op1 (e3 / enzyme :name (n3 / name :op1 "MEK"~e.27)) :op2 (e4 / enzyme :name (n4 / name :op1 "ERK"~e.29)))) :mod (a3 / also~e.24) :manner (e5 / effective-04~e.25)) :ARG2 (s4 / suppress-01~e.26 :polarity -~e.20 :ARG0 (p / protein~e.21 :name (n5 / name :op1 "CD56"~e.22) :ARG2-of~e.21 (c4 / control-01~e.21)) :ARG1 a)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "7b"~e.37))) :snt2 (c5 / cause-01~e.40 :ARG1 (b / be-located-at-91~e.43 :ARG1 (e6 / enzyme :name (n6 / name :op1 "PAK1"~e.42)) :ARG2 (r / relative-position :op1 (a4 / and~e.48 :op1 (e7 / enzyme :name (n7 / name :op1 "MEK"~e.47)) :op2 (e8 / enzyme :name (n8 / name :op1 "ERK"~e.49))) :direction (u / upstream~e.44)) :time (p2 / process-02~e.54 :ARG1 (l3 / lyse-00 :ARG1 (c6 / cell :name (n9 / name :op1 "NK"~e.52))))))) # ::id bel_pmid_1111_7534.6206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PRL enhanced tyrosine phosphorylation of NKCC1 , and this effect was attenuated by the JAK2 inhibitor AG490 . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1.1 3-1.1.2 5-1.1.2.1.2.1.1 9-1.1.3 11-1.2 12-1.2.1.r 14-1.2.1.2.1.1.1 15-1.2.1 15-1.2.1.2 15-1.2.1.2.r 16-1.2.1.1.1 (a / and :op1 (e / enhance-01~e.1 :ARG0 (p3 / protein :name (n / name :op1 "PRL"~e.0)) :ARG1 (p / phosphorylate-01~e.3 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine"~e.2) :part-of (p2 / protein :name (n3 / name :op1 "NKCC1"~e.5)))) :ARG2-of (a4 / affect-01~e.9)) :op2 (a3 / attenuate-01~e.11 :ARG0~e.12 (s / small-molecule~e.15 :name (n4 / name :op1 "AG490"~e.16) :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1 (e2 / enzyme :name (n5 / name :op1 "JAK2"~e.14)))) :ARG1 e)) # ::id bel_pmid_1111_7534.6208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PRL treatment of HC11 cells increased phosphorylation of STAT5 . The JAK2 inhibitor AG490 blocked phosphorylation of STAT5 and PRL @-@ induced , but not PGE1 @-@ induced , Cl @- transport # ::alignments 0-1.1.1.2.1.1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1.1.1 5-1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1 11-1.2.1.2.1.1.1 12-1.2.1 12-1.2.1.2 12-1.2.1.2.r 13-1.2.1.1.1 14-1.2 14-1.2.2.2.3.1 15-1.2.2.1 16-1.2.2.1.1.r 17-1.2.2.1.1.1.1 18-1.2.2 19-1.2.2.2.2.1.1.1 21-1.2.2.2.2 23-1.2.2.2.3 24-1.2.2.2.3.1.1 24-1.2.2.2.3.1.1.r 25-1.2.2.2.3.1.2.2.1.1.1 27-1.2.2.2.2 27-1.2.2.2.3.1.2.2 29-1.2.2.2.1.1.1 31-1.2.2.2 31-1.2.2.2.3.1.2 (m / multi-sentence :snt1 (i / increase-01~e.5 :ARG0 (t / treat-04~e.1 :ARG1~e.2 (c / cell~e.4 :name (n / name :op1 "HC11"~e.3)) :ARG2 (p5 / protein :name (n2 / name :op1 "PRL"~e.0))) :ARG1 (p / phosphorylate-01~e.6 :ARG1~e.7 (p2 / protein :name (n3 / name :op1 "STAT5"~e.8)))) :snt2 (b / block-01~e.14 :ARG0 (s2 / small-molecule~e.12 :name (n4 / name :op1 "AG490"~e.13) :ARG0-of~e.12 (i2 / inhibit-01~e.12 :ARG1 (e / enzyme :name (n5 / name :op1 "JAK2"~e.11)))) :ARG1 (a / and~e.18 :op1 (p3 / phosphorylate-01~e.15 :ARG1~e.16 (p4 / protein :name (n6 / name :op1 "STAT5"~e.17))) :op2 (t2 / transport-01~e.31 :ARG1 (s3 / small-molecule :name (n7 / name :op1 "Cl"~e.29)) :ARG2-of (i3 / induce-01~e.21,27 :ARG0 (s4 / small-molecule :name (n8 / name :op1 "PRL"~e.19))) :ARG1-of (c2 / contrast-01~e.23 :ARG2 (b2 / block-01~e.14 :polarity~e.24 -~e.24 :ARG1 (t3 / transport-01~e.31 :ARG1 s3 :ARG2-of (i4 / induce-01~e.27 :ARG0 (s / small-molecule :name (n10 / name :op1 "PGE1"~e.25)))))))))) # ::id bel_pmid_1112_3332.21962 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that ERK2 has a regulatory role in activating CREB in vivo in lung neutrophils after hemorrhage or endotoxemia . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 7-1.2.1 8-1.2 9-1.2.1.2.2 10-1.2.1.2 11-1.2.1.2.1.1.1 12-1.2.1.2.2 13-1.2.1.2.2 14-1.2.1.2.2 14-1.2.1.2.3.r 15-1.2.1.2.3.2 16-1.2.1.2.3.1.1 17-1.2.1.2.4 18-1.2.1.2.4.1.1 19-1.2.1.2.4.1 20-1.2.1.2.4.1.2 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (r2 / role~e.8 :topic (r3 / regulate-01~e.7 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK2"~e.4)) :ARG1 (a / activate-01~e.10 :ARG1 (p / protein :name (n / name :op1 "CREB"~e.11)) :manner (i / in-vivo~e.9,12,13,14) :location~e.14 (c / cell :name (n2 / name :op1 "neutrophil"~e.16) :part-of (l / lung~e.15)) :time (a2 / after~e.17 :mod (o / or~e.19 :op1 (h / hemorrhage-01~e.18) :op2 (e2 / endotoxemia~e.20))))) :poss e)) # ::id bel_pmid_1112_3332.37042 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that ERK2 has a regulatory role in activating CREB in vivo in lung neutrophils after hemorrhage or endotoxemia . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 7-1.2.1 8-1.2 9-1.2.1.2.2 10-1.2.1.2 11-1.2.1.2.1.1.1 12-1.2.1.2.2 13-1.2.1.2.2 14-1.2.1.2.2 14-1.2.1.2.3.r 15-1.2.1.2.3.2 16-1.2.1.2.3.1.1 17-1.2.1.2.4 18-1.2.1.2.4.1.1 19-1.2.1.2.4.1 20-1.2.1.2.4.1.2 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (r2 / role~e.8 :topic (r3 / regulate-01~e.7 :ARG0 (e / enzyme :name (n / name :op1 "ERK2"~e.4)) :ARG1 (a / activate-01~e.10 :ARG1 (p / protein :name (n2 / name :op1 "CREB"~e.11)) :manner (i / in-vivo~e.9,12,13,14) :location~e.14 (c / cell :name (n3 / name :op1 "neutrophil"~e.16) :part-of (l / lung~e.15)) :time (a2 / after~e.17 :mod (o / or~e.19 :op1 (h / hemorrhage-01~e.18) :op2 (e2 / endotoxemia~e.20))))) :poss e)) # ::id bel_pmid_1112_7821.23468 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tyrosine phosphorylation of JAK1 was detected at a very low concentration of IL @-@ 4 ( 1 ng/ml ) , while IL @-@ 13 induced phosphorylation only at concentrations of 50 ng @/@ ml and above , both in normal ( Figure 2a , b, upper blots ) and tumor lung myo®broblasts ( Figure 2c , d, upper blots ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1.1.1.2.1.1 5-1.1 5-1.2 6-1.1.2.r 7-1.1.2.2.1 8-1.1.2.2.3.1 9-1.1.2.2.3 10-1.1.2.2 12-1.1.2.1.1 14-1.1.2.1.1 16-1.1.2.2.1 20-1 21-1.1.2.1.1 21-1.2.2.1.1 23-1.2.1.1.1 24-1.2.1.1 25-1.2.1 26-1.2.2.2.3 28-1.2.2.2.1 30-1.2.2.2.1.1 31-1.1.2.2.2 33-1.1.2.2.2 34-1.2.2.2 34-1.3 35-1.2.2.2.2 39-1.3.1.2 41-1.3.1.3.1.1 42-1.3.1.3.1.1.1 45-1.3.1.3.1.3.1 46-1.3.1.3.1.3 48-1.3.1.3.1 49-1.3.2.2 50-1.3.1.1 53-1.3.1.3.1.2 53-1.3.2.3.1.1 53-1.3.2.3.1.2 54-1.3.2.3.1.1.1 57-1.3.2.3.1.3 58-1.3.2.3.1.3 (c / contrast-01~e.20 :ARG1 (d / detect-01~e.5 :ARG1 (p / phosphorylate-01~e.1 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.0) :part-of (e / enzyme :name (n2 / name :op1 "JAK1"~e.3)))) :condition~e.6 (p2 / protein :name (n3 / name :op1 "IL-4"~e.12,14,21) :quant (c2 / concentration-quantity~e.10 :quant 1~e.7,16 :unit (n4 / nanogram-per-milliliter~e.31,33) :ARG1-of (l / low-04~e.9 :degree (v / very~e.8))))) :ARG2 (d2 / detect-01~e.5 :ARG1 (p3 / phosphorylate-01~e.25 :ARG2-of (i / induce-01~e.24 :ARG0 p4~e.23)) :condition (p4 / protein :name (n5 / name :op1 "IL-13"~e.21) :quant (a2 / and~e.34 :op1 (c3 / concentration-quantity~e.28 :quant 50~e.30 :unit n4) :op2 (a3 / above~e.35 :op1 c3) :mod (o / only~e.26)))) :location (a4 / and~e.34 :op1 (m / myofibroblast :part-of (l2 / lung~e.50) :ARG1-of (n6 / normal-02~e.39) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and~e.48 :op1 (f / figure~e.41 :mod "2a"~e.42) :op2 (f2 / figure~e.53 :mod "2b") :op3 (b / blot~e.46 :mod (u / upper~e.45))))) :op2 (m2 / myofibroblast :part-of l2 :mod (t / tumor~e.49) :ARG1-of (d4 / describe-01 :ARG0 (a6 / and :op1 (f3 / figure~e.53 :mod "2c"~e.54) :op2 (f4 / figure~e.53 :mod "2d") :op3 b~e.57,58))))) # ::id bel_pmid_1112_7821.23470 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the constitutive phosphorylation of STAT3 was observed repeatedly in tumor myo®bro @- blasts ( Figure 6f ) , but only occasionally in normal ®broblasts ( Figure 6e ) . In the latter cells , IL @-@ 4 and IL @- 13 induced ( Figure 6d ) or increased ( Figure 6e ) the tyrosine phosphorylation of STAT3 , whereas in tumor myo®broblasts the two cytokines only caused an increase in the phosphorylation of STAT3 ( Figure 6f ) . # ::alignments 2-1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1 6-1.1.2 7-1.1.1.2 9-1.1.1.3.1 14-1.1.1.4.1 15-1.1.1.4.1.1 18-1.1 19-1.1.2.2.1 20-1.1.2.2 22-1.1.2.3.1 25-1.1.2.4.1 26-1.1.2.4.1.1 31-1.2.1.3.1 32-1.2.1.3 34-1.2.1.1.1.1.1.1 34-1.2.1.1.1.2.1.1 36-1.2.1.1.1.1.1.1 37-1.2.1.1.1 38-1.2.1.1.1.1.1.1 38-1.2.1.1.1.2.1.1 40-1.2.1.1.1.2.1.1 41-1.2.1.1 43-1.2.1.1.3.1 44-1.2.1.1.3.1.1 46-1.2.1 47-1.2.1.2 49-1.2.1.2.3.1 50-1.2.1.2.3.1.1 53-1.2.1.2.2 54-1.2.1.2.2 55-1.2.1.2.2 56-1.2.1.2.2 58-1.2 59-1.2.2.r 60-1.2.2.4.1 64-1.2.2.1 65-1.2.2.3 66-1.2.2 68-1.2.2.2 69-1.2.2.2.2.r 71-1.2.2.2.2 72-1.2.2.2.2 73-1.2.2.2.2 75-1.2.2.5.1 76-1.2.2.5.1.1 (m / multi-sentence :snt1 (c / contrast-01~e.18 :ARG1 (o / observe-01~e.6 :ARG1 (p / phosphorylate-01~e.2 :ARG1~e.3 (p2 / protein :name (n / name :op1 "STAT3"~e.4)) :mod (c2 / constitute-01)) :ARG1-of (r / repeat-01~e.7) :location (m2 / myofibroblast :mod (t / tumor~e.9)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "6f"~e.15))) :ARG2 (o2 / observe-01~e.6 :ARG1 p :frequency (o3 / occasional~e.20 :mod (o4 / only~e.19)) :location (f2 / fibroblast :ARG1-of (n2 / normal-02~e.22)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.25 :mod "6e"~e.26)))) :snt2 (c3 / contrast-01~e.58 :ARG1 (o5 / or~e.46 :op1 (i / induce-01~e.41 :ARG0 (a / and~e.37 :op1 (c4 / cytokine :name (n3 / name :op1 "IL-4"~e.34,36,38)) :op2 (c5 / cytokine :name (n4 / name :op1 "IL-13"~e.34,38,40))) :ARG2 (p3 / phosphorylate-01 :ARG0 (a2 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (p4 / protein :name (n5 / name :op1 "STAT3")))) :ARG1-of (d3 / describe-01 :ARG0 (f4 / figure~e.43 :mod "6d"~e.44))) :op2 (i2 / increase-01~e.47 :ARG0 a :ARG1 p3~e.53,54,55,56 :ARG1-of (d4 / describe-01 :ARG0 (f5 / figure~e.49 :mod "6e"~e.50))) :location (c6 / cell~e.32 :mod (l / latter~e.31))) :ARG2~e.59 (c7 / cause-01~e.66 :ARG0 a~e.64 :ARG1 (i3 / increase-01~e.68 :ARG0 a :ARG1~e.69 p3~e.71,72,73) :mod (o6 / only~e.65) :location (m3 / myofibroblast :mod (t2 / tumor~e.60)) :ARG1-of (d5 / describe-01 :ARG0 (f6 / figure~e.75 :mod "6f"~e.76))))) # ::id bel_pmid_1112_7821.23472 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In normal lung ®broblasts and in tumor myo®broblasts , STAT6 was indeed phosphorylated on tyrosine residues in response to IL @-@ 4 and IL @-@ 13 ( Figure 4a , b, upper blots ) . # ::alignments 1-1.1.3.1.1 2-1.1.3.1.2 4-1.1.3 6-1.1.3.2.1 9-1.1.2.1.1 11-1.3 12-1 14-1.1.1.1.1 15-1.1 16-1.2.r 17-1.2 18-1.2.1.r 19-1.2.1.1.1.1 19-1.2.1.2.1.1 21-1.2.1.1.1.1 22-1.2.1 23-1.2.1.1.1.1 23-1.2.1.2.1.1 25-1.2.1.2.1.1 27-1.4.1.1 27-1.4.1.2 28-1.4.1.1.1 31-1.4.1.3.1 32-1.4.1.3 (p / phosphorylate-01~e.12 :ARG1 (r / residue~e.15 :mod (a / amino-acid :name (n / name :op1 "tyrosine"~e.14)) :part-of (p2 / protein :name (n2 / name :op1 "STAT6"~e.9)) :location (a2 / and~e.4 :op1 (f / fibroblast :ARG1-of (n3 / normal-02~e.1) :part-of (l / lung~e.2)) :op2 (m / myofibroblast :mod (t / tumor~e.6)))) :ARG2-of~e.16 (r2 / respond-01~e.17 :ARG1~e.18 (a3 / and~e.22 :op1 (p3 / protein :name (n4 / name :op1 "IL-4"~e.19,21,23)) :op2 (p4 / protein :name (n5 / name :op1 "IL-13"~e.19,23,25)))) :mod (i / indeed~e.11) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f2 / figure~e.27 :mod "4a"~e.28) :op2 (f3 / figure~e.27 :mod "4b") :op3 (b / blot~e.32 :mod (u / upper~e.31))))) # ::id bel_pmid_1112_7821.23474 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , Tyk2 , the fourth member of the JAK family , was found to be constitutively tyrosine @-@ phosphorylated in these cells . However , IL @-@ 4 and IL @-@ 13 increased its phosphorylation level in lung myo®broblasts ( Figure 2j ) , but not in normal cells , where both cytokines appear to slightly decrease its extent of phosphoryla @- tion ( Figure 2i ) . # ::alignments 0-1.1.1 0-1.1.1.r 2-1.1.2.1.2.1.1 5-1.1.2.1.2.2.1.1 5-1.1.2.1.2.2.1.1.1 5-1.1.2.1.2.2.1.1.1.r 6-1.1.2.1.2.2.1 9-1.1.2.1.2.2.1.2.1.1.1 10-1.1.2.1.2.2.1.2.1 13-1.1 16-1.1.2.2 16-1.1.2.2.r 17-1.1.2.1.1.1 17-1.2.1.2.1.1.1.1 19-1.1.2 20-1.1.2.3.r 21-1.1.2.3.1 22-1.1.2.3 24-1.2 26-1.2.1.1.1.1.1 26-1.2.1.1.2.1.1 28-1.2.1.1.1.1.1 29-1.2.1.1 30-1.2.1.1.1.1.1 30-1.2.1.1.2.1.1 32-1.2.1.1.2.1.1 33-1.2.1 33-1.2.2 35-1.2.1.2.1 36-1.2.1.2 38-1.2.1.3.1 41-1.2.1.4.1 42-1.2.1.4.1.1 45-1.2 46-1.2.2.1 46-1.2.2.1.r 47-1.2.2.4.r 48-1.2.2.4.1 49-1.2.2.4 51-1.2.1.3.r 51-1.2.2.4.2.r 53-1.2.2.4.2.1 54-1.2.2.4.2.3 56-1.2.2.4.2.4 57-1.2.2.4.2 59-1.2.2.4.2.2 65-1.2.2.5.1 66-1.2.2.5.1.1 (m / multi-sentence :snt1 (f / find-01~e.13 :li~e.0 -1~e.0 :ARG1 (p / phosphorylate-01~e.19 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.17) :part-of (e / enzyme :name (n2 / name :op1 "Tyk2"~e.2) :ARG1-of (m2 / mean-01 :ARG2 (m3 / member~e.6 :ord (o / ordinal-entity~e.5 :value~e.5 4~e.5) :ARG1-of (i / include-91 :ARG2 (p3 / protein-family~e.10 :name (n3 / name :op1 "JAK"~e.9))))))) :manner~e.16 (c / constitutive~e.16) :location~e.20 (c2 / cell~e.22 :mod (t / this~e.21)))) :snt2 (c3 / contrast-01~e.24,45 :ARG1 (i2 / increase-01~e.33 :ARG0 (a2 / and~e.29 :op1 (c4 / cytokine :name (n4 / name :op1 "IL-4"~e.26,28,30)) :op2 (c5 / cytokine :name (n5 / name :op1 "IL-13"~e.26,30,32))) :ARG1 (l / level~e.36 :degree-of (p2 / phosphorylate-01~e.35 :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine"~e.17)))) :location~e.51 (m4 / myofibroblast :part-of (l2 / lung~e.38)) :ARG1-of (d / describe-01 :ARG0 (f4 / figure~e.41 :mod "2j"~e.42))) :ARG2 (i3 / increase-01~e.33 :polarity~e.46 -~e.46 :ARG0 a2 :ARG1 l :location~e.47 (c6 / cell~e.49 :ARG1-of (n7 / normal-02~e.48) :location-of~e.51 (d2 / decrease-01~e.57 :ARG0 a2~e.53 :ARG1 (e3 / extent~e.59 :degree-of p2) :ARG1-of (a4 / appear-02~e.54) :degree (s / slight~e.56))) :ARG1-of (d3 / describe-01 :ARG0 (f5 / figure~e.65 :mod "2i"~e.66))))) # ::id bel_pmid_1112_7821.23486 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 4 and IL @-@ 13 induced tyrosine phosphorylation of STAT6 ( green cytoplasmic staining ) but probably also nuclear translocation of some phosphorylated STAT6 mole @- cules , accounting for the yellow signal detected . Similar results were obtained with normal lung ®broblasts . # ::alignments 0-1.1.1.1.1.1 0-1.1.1.2.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.1.1.1 4-1.1.1.2.1.1 6-1.1.1.2.1.1 7-1.1 8-1.1.2.1.1.1.1 9-1.1.2.1 11-1.1.2.1.1.2.1.1 13-1.1.2.1.2.1.2 14-1.1.2.1.2.1.1 15-1.1.2.1.2.1 18-1.1.2.2.3 19-1.1.2.2.4 20-1.1.2.2.2 21-1.1.2.2 23-1.1.2.2.1.3 24-1.1.2.2.1.2 25-1.1.2.2.1.2 30-1.1.2.2.5 31-1.1.2.2.5.1.r 33-1.1.2.2.5.1.2 34-1.1.2.2.5.1 35-1.1.2.2.5.1.1 37-1.2.1.2 38-1.2.1 38-1.2.1.1 38-1.2.1.1.r 40-1.2 42-1.2.2.2 43-1.2.2.1 (m / multi-sentence :snt1 (i / induce-01~e.7 :ARG0 (a / and~e.3 :op1 (p / protein :name (n / name :op1 "IL-4"~e.0,2,4)) :op2 (p2 / protein :name (n2 / name :op1 "IL-13"~e.0,4,6))) :ARG2 (a2 / and :op1 (p3 / phosphorylate-01~e.9 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine"~e.8) :part-of (p4 / protein :name (n4 / name :op1 "STAT6"~e.11))) :ARG1-of (d / describe-01 :ARG0 (s / stain-01~e.15 :ARG2 (c / cytoplasm~e.14) :ARG1-of (g / green-02~e.13)))) :op2 (t / translocate-01~e.21 :ARG1 (m2 / molecule :mod p4 :ARG1-of p3~e.24,25 :quant (s2 / some~e.23)) :ARG2 (n5 / nucleus~e.20) :mod (p5 / probable~e.18) :mod (a4 / also~e.19) :ARG2-of (a5 / account-01~e.30 :ARG1~e.31 (s3 / signal-07~e.34 :ARG1-of (d2 / detect-01~e.35) :ARG1-of (y / yellow-02~e.33)))))) :snt2 (o / obtain-01~e.40 :ARG1 (t2 / thing~e.38 :ARG2-of~e.38 (r / result-01~e.38) :ARG1-of (r2 / resemble-01~e.37)) :ARG2 (f / fibroblast :part-of (l / lung~e.43) :ARG1-of (n6 / normal-02~e.42)))) # ::id bel_pmid_1113_4016.21280 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using purified wild @-@ type and mutant c @-@ Raf @-@ 1 proteins , we demonstrate that Thr( 269 ) is the major c @-@ Raf @-@ 1 site phosphorylated by KSR in vitro and that phosphorylation of this site is essential for c @-@ Raf @-@ 1 activation by KSR . # ::alignments 0-1.3 1-1.3.2.1.2 2-1.3.2.1.1 4-1.3.2.1.1 5-1.3.2 6-1.3.2.2 6-1.3.2.2.2 6-1.3.2.2.2.r 7-1.3.2.2.1.1 9-1.3.2.2.1.1 11-1.3.2.2.1.1 12-1.3.2.1 14-1.1 15-1 18-1.2.1.2.1 20-1.2.1.2.r 22-1.2.1.3 23-1.2.1.1.1.1 25-1.2.1.1.1.1 27-1.2.1.1.1.1 28-1.2.1 29-1.2.1.4 31-1.2.1.4.1.1.1 32-1.2.1.4.2 33-1.2.1.4.2 36-1.2.1.4 36-1.2.2.1 39-1.2.1 40-1.2.1.2.r 41-1.2.2 41-1.2.2.1.2 42-1.2.2.1.3.r 43-1.2.2.1.3.2 44-1.2.2.1.3.2 45-1.2.2.1.3.2 46-1.2.2.1.3.2 47-1.2.2.1.3.2 48-1.2.2.1.3 49-1.2.2.1.3.1.r 50-1.2.2.1.3.1 (d / demonstrate-01~e.15 :ARG0 (w / we~e.14) :ARG1 (a / and :op1 (p2 / protein-segment~e.28,39 :part-of (e5 / enzyme :name (n2 / name :op1 "c-Raf-1"~e.23,25,27)) :domain~e.20,40 (a2 / amino-acid :mod 269~e.18 :name (n / name :op1 "threonine")) :ARG1-of (m / major-02~e.22) :ARG1-of (p / phosphorylate-01~e.29,36 :ARG2 (e2 / enzyme :name (n3 / name :op1 "KSR"~e.31)) :manner (i / in-vitro~e.32,33))) :op1 (e3 / essential~e.41 :domain (p5 / phosphorylate-01~e.36 :ARG1 a2 :mod (e / essential~e.41) :purpose~e.42 (a3 / activate-01~e.48 :ARG0~e.49 e2~e.50 :ARG1 e5~e.43,44,45,46,47) :mod a2))) :manner (u / use-01~e.0 :ARG0 w :ARG1 (a4 / and~e.5 :op1 (p6 / protein~e.12 :mod (w2 / wild-type~e.2,4) :ARG1-of (p8 / purify-01~e.1)) :op2 (e4 / enzyme~e.6 :name (n4 / name :op1 "c-Raf-1"~e.7,9,11) :ARG2-of~e.6 (m2 / mutate-01~e.6))))) # ::id bel_pmid_1113_4016.22950 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vivo , low physiologic doses of EGF ( 0.001 @-@ 0.1 ng/ml ) stimulated KSR activation and induced Thr( 269 ) phosphorylation and activation of c @-@ Raf @-@ 1 . # ::alignments 0-1.3 1-1.3 3-1.1.1.2.1 5-1.1.1.2 6-1.1.1.2.r 7-1.1.1.1.1 9-1.1.1.3.1 11-1.1.1.3.2 14-1.1 15-1.1.2.1.1.1 16-1.1.2 17-1 18-1.2 20-1.2.2.1.1.1 22-1.2.2.1 23-1.2.2 24-1.2.2.2 25-1.2.2.1.2.r 26-1.2.2.1.2.1.1 28-1.2.2.1.2.1.1 30-1.2.2.1.2.1.1 (a / and~e.17 :op1 (s / stimulate-01~e.14 :ARG0 (p / protein :name (n / name :op1 "EGF"~e.7) :quant~e.6 (d / dose~e.5 :ARG1-of (l / low-04~e.3) :mod (p2 / physiology)) :quant (v / value-interval :op1 0.001~e.9 :op1 0.1~e.11 :unit (n3 / nanogram-per-milliliter))) :ARG1 (a2 / activate-01~e.16 :ARG1 (e / enzyme :name (n2 / name :op1 "KSR"~e.15)))) :op2 (i / induce-01~e.18 :ARG0 p :ARG2 (a3 / and~e.23 :op1 (p4 / phosphorylate-01~e.22 :ARG1 (a4 / amino-acid :mod 269~e.20 :name (n5 / name :op1 "threonine")) :part-of~e.25 (e2 / enzyme :name (n4 / name :op1 "c-Raf-1"~e.26,28,30))) :op2 (a5 / activate-01~e.24 :ARG1 e2))) :manner (i2 / in-vivo~e.0,1)) # ::id bel_pmid_1114_5587.7292 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In conclusion , our results show that IL @-@ 6 stimulates hepatic IGFBP @-@ 4 gene expression and production in vitro and in vivo , thereby suggesting another mechanism by which cytokines could control IGF @-@ I action . # ::alignments 0-1.2.2.2.3.1 1-1 3-1.2.1.2 3-1.2.1.2.r 4-1.2.1 4-1.2.1.1 4-1.2.1.1.r 5-1.2 7-1.2.2.1.1.1 9-1.2.2.1.1.1 10-1.2.2 11-1.2.2.2.1.1.2 12-1.2.2.2.1.1.1.1 14-1.2.2.2.1.1.1.1 15-1.2.2.2.1.1 16-1.2.2.2.1 17-1.2.2.2 18-1.2.2.2.2 19-1.2.2.2.3.1 20-1.2.2.2.3.1 21-1.2.2.2.3 22-1.2.2.2.3.1 22-1.2.2.2.3.2 23-1.2.2.2.3.2 25-1.2.2.2.3.r 26-1.2.3 27-1.2.3.1.1.3.1 28-1.2.3.1.1.3 31-1.2.3.1.1.1 32-1.2.3.1 33-1.2.3.1.1 34-1.2.3.1.1.2.1.1.1 36-1.2.3.1.1.2.1.1.1 37-1.2.3.1.1.2 (c / conclude-02~e.1 :ARG0 w :ARG1 (s / show-01~e.5 :ARG0 (t / thing~e.4 :ARG1-of~e.4 (r / result-01~e.4) :poss~e.3 (w / we~e.3)) :ARG1 (s2 / stimulate-01~e.10 :ARG0 (p / protein :name (n / name :op1 "IL-6"~e.7,9)) :ARG1 (a / and~e.17 :op1 (e / express-03~e.16 :ARG1 (g / gene~e.15 :name (n2 / name :op1 "IGFBP-4"~e.12,14) :mod (h / hepatic~e.11))) :op2 (p2 / produce-01~e.18 :ARG1 g) :manner~e.25 (a2 / and~e.21 :op1 (i / in-vitro~e.0,19,20,22) :op2 (i2 / in-vivo~e.22,23)))) :ARG0-of (s3 / suggest-01~e.26 :ARG1 (p5 / possible-01~e.32 :ARG1 (c2 / control-01~e.33 :ARG0 (c3 / cytokine~e.31) :ARG1 (a3 / act-02~e.37 :ARG0 (p4 / protein :name (n4 / name :op1 "IGF-I"~e.34,36))) :manner (m / mechanism~e.28 :mod (a4 / another~e.27))))))) # ::id bel_pmid_1115_4060.8844 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GAGA box of the rat serine protease inhibitor 2 ( spi 2 ) genes not only acts as a basal promoter element , but also mediates transcriptional activation by growth hormone and interleukin @-@ 6 . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 4-1.1.1.2.2 5-1.1.1.2.1.1 6-1.1.1.2.1.2 7-1.1.1.2.1.3 8-1.1.1.2.1.4 13-1.1.1.2 16-1.1 17-1.1.2.r 19-1.1.2.1.1 20-1.1.2.1 21-1.1.2 24-1.2.3 25-1.2 26-1.2.2.2 27-1.2.2 28-1.2.2.1.r 29-1.2.2.1.1.1 30-1.2.2.1.1 31-1.2.2.1 32-1.2.2.1.2.1.1 34-1.2.2.1.2.1.1 (a / and :op1 (a2 / act-02~e.16 :ARG0 (d2 / dna-sequence :name (n3 / name :op1 "GAGA"~e.0 :op2 "box"~e.1) :part-of (g2 / gene~e.13 :name (n / name :op1 "serine"~e.5 :op2 "protease"~e.6 :op3 "inhibitor"~e.7 :op4 2~e.8) :mod (r / rat~e.4))) :ARG1~e.17 (e2 / element~e.21 :ARG0-of (p / promote-01~e.20 :mod (b2 / basal~e.19)))) :op2 (m / mediate-01~e.25 :ARG0 d2 :ARG1 (a3 / activate-01~e.27 :ARG0~e.28 (a4 / and~e.31 :op1 (h / hormone~e.30 :ARG0-of (g / grow-01~e.29)) :op2 (p2 / protein :name (n2 / name :op1 "interleukin-6"~e.32,34))) :mod (t / transcribe-01~e.26)) :mod (a5 / also~e.24))) # ::id bel_pmid_1116_0334.6798 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SDF @-@ 1 alpha treatment induced expression of the chemokines monocyte chemoattractant protein @-@ 1 , IL @-@ 8 , and IFN @-@ gamma @-@ inducible protein @-@ 10 . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1.1.1.2 4-1.1 5-1 6-1.2 7-1.2.1.r 9-1.2.1.4.1.1 10-1.2.1.1.1.1 11-1.2.1.1.1.2 12-1.2.1.1.1.3 14-1.2.1.1.1.3 16-1.2.1.2.1.1 18-1.2.1.2.1.1 20-1.2.1 21-1.2.1.3.1.1 23-1.2.1.3.1.1 25-1.2.1.3.1.1 26-1.2.1.3.1.2 28-1.2.1.3.1.2 (i / induce-01~e.5 :ARG0 (t / treat-04~e.4 :ARG2 (p / protein :name (n / name :op1 "SDF-1"~e.0,2 :op2 "alpha"~e.3))) :ARG2 (e / express-03~e.6 :ARG2~e.7 (a / and~e.20 :op1 (p2 / protein :name (n2 / name :op1 "monocyte"~e.10 :op2 "chemoattractant"~e.11 :op3 "protein-1"~e.12,14)) :op2 (p3 / protein :name (n4 / name :op1 "IL-8"~e.16,18)) :op3 (p4 / protein :name (n3 / name :op1 "IFN-gamma-inducible"~e.21,23,25 :op2 "protein-10"~e.26,28)) :mod (p5 / protein :name (n5 / name :op1 "chemokine"~e.9))))) # ::id bel_pmid_1116_0334.7176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CXCR4 protein expression was also enhanced upon treatment with TNF @-@ alpha and IL @-@ 1 beta ( 2 @- to 3 @-@ fold ) . # ::alignments 0-1.1.1.1.1 1-1.1.1 1-1.3.1.1 1-1.3.1.2 2-1.1 4-1.2 5-1 7-1.3 8-1.3.1.r 9-1.3.1.1.1.1 11-1.3.1.1.1.1 12-1.3.1 13-1.3.1.2.1.1 18-1.3.1.3.1.1 21-1.3.1.3.1.2 23-1.3.1.3 (e / enhance-01~e.5 :ARG1 (e2 / express-03~e.2 :ARG2 (p / protein~e.1 :name (n / name :op1 "CXCR4"~e.0))) :mod (a / also~e.4) :condition (t / treat-04~e.7 :ARG2~e.8 (a2 / and~e.12 :op1 (p2 / protein~e.1 :name (n2 / name :op1 "TNF-alpha"~e.9,11)) :op2 (p3 / protein~e.1 :name (n3 / name :op1 "IL-1beta"~e.13)) :quant (p4 / product-of~e.23 :op1 (v / value-interval :op1 2~e.18 :op2 3~e.21))))) # ::id bel_pmid_1116_0334.7194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Enhancement of CXC chemokine receptor 4 ( CXCR4 ) mRNA expression was observed upon treatment with the cytokines TNF @-@ alpha and IL @-@ 1 beta . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2.1.1 3-1.1.1.2.1.2 4-1.1.1.2.1.3 5-1.1.1.2.1.4 7-1.1.1.2.2.1.1.1 9-1.1.1.1.1.1 10-1.1.1 12-1 14-1.2 15-1.2.1.r 17-1.2.1.1 17-1.2.1.2 18-1.2.1.1.1.1 20-1.2.1.1.1.1 21-1.2.1 22-1.2.1.2.1.1 (o / observe-01~e.12 :ARG1 (e / enhance-01~e.0 :ARG1~e.1 (e2 / express-03~e.10 :ARG1 (n6 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.9)) :ARG2 (p / protein :name (n / name :op1 "CXC"~e.2 :op2 "chemokine"~e.3 :op3 "receptor"~e.4 :op4 4~e.5) :ARG1-of (d / describe-01 :ARG2 (p2 / protein :name (n4 / name :op1 "CXCR4"~e.7)))))) :condition (t / treat-04~e.14 :ARG2~e.15 (a / and~e.21 :op1 (c / cytokine~e.17 :name (n2 / name :op1 "TNF-alpha"~e.18,20)) :op2 (c2 / cytokine~e.17 :name (n3 / name :op1 "IL-1beta"~e.22))))) # ::id bel_pmid_1116_0334.22876 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stimulation of cells with the ligand for CXCR4 , stromal cell @-@ derived factor @-@ 1 alpha ( SDF @-@ 1 alpha ) , resulted in an elevation in intracellular Ca( 2+) concentration # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2 6-1.1.1.r 7-1.1.1.2.1.1.1 9-1.1.1.1.1 10-1.1.1.1.2 12-1.1.1.1.2 13-1.1.1.1.3 24-1 25-1.2.r 27-1.2 28-1.2.1.r 29-1.2.1.1.1 32-1.2.1 (r / result-01~e.24 :ARG1 (s / stimulate-01~e.0 :ARG0~e.6 (p2 / protein :name (n / name :op1 "stromal"~e.9 :op2 "cell-derived"~e.10,12 :op3 "factor-1alpha"~e.13) :ARG1-of (b / bind-01 :ARG2 (p / protein :name (n2 / name :op1 "CXCR4"~e.7)))) :ARG1~e.1 (c / cell~e.2)) :ARG2~e.25 (e / elevate-01~e.27 :ARG1~e.28 (c2 / concentrate-02~e.32 :ARG1 (c3 / calcium :mod (i / intracellular~e.29) :ARG1-of (i2 / ionize-01 :value "2+"))))) # ::id bel_pmid_1116_0334.22880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok resulted in an elevation in intracellular Ca( 2+) concentration and activation of the mitogen @-@ activated protein kinase cascade , specifically , extracellular signal @-@ regulated kinase 2 ( ERK2 ) mitogen @-@ activated protein kinase . # ::alignments 0-1 1-1.1.r 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 8-1.1.1.1 9-1.1 10-1.1.2 11-1.1.2.1.r 13-1.1.2.1.1.1.1 15-1.1.2.1.1.1.1 16-1.1.2.1.1.1.2 17-1.1.2.1.1.1.3 18-1.1.2.1 20-1.1.2.1.1.2.2 22-1.1.2.1.1.2.1.1.1 23-1.1.2.1.1.2.1.1.2 25-1.1.2.1.1.2.1.1.2 26-1.1.2.1.1.2.1.1.3 26-1.1.2.1.1.2.1.1.7 27-1.1.2.1.1.2.1.1.4 31-1.1.2.1.1.1.1 31-1.1.2.1.1.2.1.1.5 33-1.1.2.1.1.1.1 33-1.1.2.1.1.2.1.1.5 34-1.1.2.1.1.1.2 34-1.1.2.1.1.2.1.1.6 35-1.1.2.1.1.1.3 35-1.1.2.1.1.2.1.1.3 35-1.1.2.1.1.2.1.1.7 (r / result-01~e.0 :ARG1~e.1 (a3 / and~e.9 :op1 (e / elevate-01~e.3 :ARG1~e.4 (c2 / concentrate-02~e.8 :ARG1 (c / calcium :mod (i / intracellular~e.5) :ARG1-of (i2 / ionize-01 :value "2+")))) :op2 (a2 / activate-01~e.10 :ARG1~e.11 (c3 / cascade~e.18 :mod (p / pathway :name (n / name :op1 "mitogen-activated"~e.13,15,31,33 :op2 "protein"~e.16,34 :op3 "kinase"~e.17,35) :ARG1-of (m / mean-01 :ARG2 (p2 / pathway :name (n2 / name :op1 "extracellular"~e.22 :op2 "signal-regulated"~e.23,25 :op3 "kinase"~e.26,35 :op4 2~e.27 :op5 "mitogen-activated"~e.31,33 :op6 "protein"~e.34 :op7 "kinase"~e.26,35)) :ARG1-of (s / specific-02~e.20))))))) # ::id bel_pmid_1116_0334.23556 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 1 beta stimulation also enhanced CXCR4 expression ( 28.8 % for CRT @-@ J and 41.6 % for U87 @-@ MG cells ) . # ::alignments 0-1.1.1.1 4-1 5-1.2.2 6-1.2 7-1.2.1.1.1.1 8-1.2.1 10-1.2.1.1.2.1.1.2.1 11-1.2.1.1.2.1.1.2 13-1.2.1.1.2.1.1.1.1 15-1.2.1.1.2.1.1.1.1 16-1.2.1.1.2.1 17-1.2.1.1.2.1.2.2.1 18-1.2.1.1.2.1.2.2 20-1.2.1.1.2.1.2.1.1 22-1.2.1.1.2.1.2.1.1 23-1.2.1.1.2.1.1 23-1.2.1.1.2.1.2 (s / stimulate-01~e.4 :ARG0 (p / protein :name (n / name :op1 "IL-1beta"~e.0)) :ARG0-of (e / enhance-01~e.6 :ARG1 (e2 / express-03~e.8 :ARG2 (p2 / protein :name (n2 / name :op1 "CXCR4"~e.7) :ARG0-of (m / mean-01 :ARG1 (a / and~e.16 :op1 (c / cell~e.23 :name (n3 / name :op1 "CRT-J"~e.13,15) :mod (p3 / percentage-entity~e.11 :value 28.8~e.10)) :op2 (c2 / cell~e.23 :name (n5 / name :op1 "U87-MG"~e.20,22) :mod (p4 / percentage-entity~e.18 :value 41.6~e.17)))))) :mod (a2 / also~e.5))) # ::id bel_pmid_1116_0334.37038 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SDF @-@ 1 alpha @-@ induced chemokine expression was abrogated upon inclusion of U0126 , a pharmacological inhibitor of ERK1 @/@ 2 , indicating that the ERK signaling cascade is involved in this response . # ::alignments 0-1.1.2.1.1.1 2-1.1.2.1.1.1 3-1.1.2.1.1.2 5-1.1.2 6-1.1.1 7-1.1 9-1 11-1.2 12-1.2.1.r 13-1.2.1.1.1 16-1.2.1.2.2 17-1.2.1 17-1.2.1.2 17-1.2.1.2.r 18-1.2.1.2.1.r 19-1.2.1.2.1.1.1.1 20-1.2.1.2.1 23-1.3 24-1.3.1.r 26-1.3.1.1.1.1 27-1.3.1.1.2 30-1.3.1 31-1.3.1.2.r 32-1.3.1.2.1 33-1.3.1.2 (a / abrogate-01~e.9 :ARG1 (e / express-03~e.7 :ARG2 (c / chemokine~e.6) :ARG2-of (i / induce-01~e.5 :ARG0 (p / protein :name (n / name :op1 "SDF-1"~e.0,2 :op2 "alpha"~e.3)))) :time (i2 / include-01~e.11 :ARG1~e.12 (s3 / small-molecule~e.17 :name (n5 / name :op1 "U0126"~e.13) :ARG0-of~e.17 (i3 / inhibit-01~e.17 :ARG1~e.18 (s / slash~e.20 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"~e.19)) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2"))) :mod (p2 / pharmacology~e.16)))) :ARG0-of (i4 / indicate-01~e.23 :ARG1~e.24 (i5 / involve-01~e.30 :ARG1 (p3 / pathway :name (n4 / name :op1 "ERK"~e.26) :ARG0-of (s2 / signal-07~e.27)) :ARG2~e.31 (r / respond-01~e.33 :mod (t / this~e.32))))) # ::id bel_pmid_1119_6191.2576 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In T47D cells , IL @-@ 6 stimulated the activation of Janus @-@ activated kinase 1 tyrosine kinase and signal transducers and activators of transcription ( STAT ) 1 and STAT3 transcription factors . Expression of dominant negative STAT3 in the cells strongly reduced IL @-@ 6 @-@ mediated growth inhibition but did not prevent IL @-@ 6 @-@ induced cell migration . # ::alignments 1-1.1.3.1.1 2-1.1.3 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1 13-1.1.2.1.1.1.1 14-1.1.2.1.1.1.2 14-1.1.2.1.1.1.5 15-1.1.2.1.1.1.3 16-1.1.2.1.1.1.4 17-1.1.2.1.1.1.2 17-1.1.2.1.1.1.5 18-1.1.2.1 19-1.1.2.1.2.1.1 20-1.1.2.1.2.1.2 21-1.1.2.1 22-1.1.2.1.2.1.3 24-1.1.2.1.2.1.4 28-1.1.2.1.1.1.3 29-1.1.2.1 30-1.1.2.1.3.1.1 31-1.1.2.1.3.1.2 32-1.1.2.1.3.1.3 34-1.2.1.1 35-1.2.1.1.1.r 36-1.2.1.1.1 36-1.2.1.1.1.3 36-1.2.1.1.1.3.r 38-1.2.1.1.1.1.1 39-1.2.1.1.2.r 41-1.2.1.1.2 42-1.2.1.3 43-1.2.1 44-1.2.1.2.2.1 45-1.2.1.2.2.1 46-1.2.1.2.2.1 48-1.2.1.2.2 49-1.2.1.2.1 50-1.2.1.2 51-1.2 53-1.2.2.1 53-1.2.2.1.r 54-1.2.2 55-1.2.2.3.2.1 56-1.2.2.3.2.1 57-1.2.2.3.2.1 59-1.2.2.3.2 60-1.2.2.3.1 61-1.2.2.3 (m / multi-sentence :snt1 (s / stimulate-01~e.7 :ARG0 (p / protein :name (n / name :op1 "IL-6"~e.4,6)) :ARG1 (a / activate-01~e.9 :ARG1~e.10 (a2 / and~e.18,21,29 :op1 (e / enzyme :name (n2 / name :op1 "Janus-activated"~e.11,13 :op2 "kinase"~e.14,17 :op3 1~e.15,28 :op4 "tyrosine"~e.16 :op5 "kinase"~e.14,17)) :op2 (p2 / protein :name (n3 / name :op1 "signal"~e.19 :op2 "transducers"~e.20 :op3 "activator"~e.22 :op4 "transcription"~e.24)) :op3 (e2 / enzyme :name (n4 / name :op1 "STAT3"~e.30 :op2 "transcription"~e.31 :op3 "factors"~e.32)))) :location (c4 / cell~e.2 :name (n8 / name :op1 "T47D"~e.1))) :snt2 (c / contrast-01~e.51 :ARG1 (r / reduce-01~e.43 :ARG0 (e3 / express-03~e.34 :ARG2~e.35 (p3 / protein~e.36 :name (n5 / name :op1 "STAT3"~e.38) :ARG2-of (m4 / mutate-01 :mod "-/-") :ARG0-of~e.36 (d / dominate-01~e.36)) :location~e.39 (c2 / cell~e.41)) :ARG1 (i / inhibit-01~e.50 :ARG1 (g / grow-01~e.49) :ARG1-of (m2 / mediate-01~e.48 :ARG0 p~e.44,45,46)) :ARG1-of (s2 / strong-02~e.42)) :ARG2 (p4 / prevent-01~e.54 :polarity~e.53 -~e.53 :ARG0 e3 :ARG1 (m3 / migrate-01~e.61 :ARG0 (c3 / cell~e.60) :ARG2-of (i2 / induce-01~e.59 :ARG0 p~e.55,56,57))))) # ::id bel_pmid_1119_6191.23672 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The IL @-@ 6 @-@ type cytokines , IL @-@ 6 and oncostatin M , simultaneously inhibited cell proliferation and increased cell migration # ::alignments 1-1.1.1.1.1 1-1.1.2.1.1 3-1.1.1.1.1 3-1.1.2.1.1 5-1.1.1.1.1 6-1.1.1.1.2 8-1.1.2.1.1 10-1.1.2.1.1 12-1.1.3.1.1 13-1.1.3.1.2 15-1.3 15-1.3.r 16-1 17-1.2.1.1 18-1.2.1 19-1.2 20-1.2.2 21-1.2.2.1.1 22-1.2.2.1 (i / inhibit-01~e.16 :ARG0 (a / and :op1 (p2 / protein :name (n3 / name :op1 "IL-6-type"~e.1,3,5 :op2 "cytokine"~e.6)) :op2 (p3 / protein :name (n4 / name :op1 "IL-6"~e.1,3,8,10)) :op3 (p4 / protein :name (n5 / name :op1 "oncostatin"~e.12 :op2 "M"~e.13))) :ARG1 (a2 / and~e.19 :op1 (p / proliferate-01~e.18 :ARG0 (c3 / cell~e.17)) :op2 (i2 / increase-01~e.20 :ARG1 (m / migrate-01~e.22 :ARG0 (c4 / cell~e.21)))) :manner~e.15 (s / simultaneous~e.15)) # ::id bel_pmid_1119_6191.38528 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pretreatment of cells with EGF receptor specific inhibitor CGP59326 or with the bispecific EGF receptor @/@ ERBB2 inhibitor PD153035 , diminished IL6 induced MAPK activation . Even the PKB phosphorylation was also affected by these two inhibitors . # ::alignments 0-1.1.1.1 0-1.1.1.2 1-1.1.1.1.1.r 2-1.1.1.1.1 3-1.1.1.1.2.r 4-1.1.1.1.2.3.1.1.1 5-1.1.1.1.2.3.1.1.2 6-1.1.1.1.2.3 7-1.1.1.1.2 7-1.1.1.1.2.2 7-1.1.1.1.2.2.r 8-1.1.1.1.2.1.1 9-1.1.1 10-1.1.1.2.2.r 12-1.1.1.2.2.3 13-1.1.1.2.2.3.1.1 14-1.1.1.2.2.3.1.1 15-1.1.1.2.2.3.1 16-1.1.1.2.2.3.1.2.1.1 17-1.1.1.2.2 17-1.1.1.2.2.2 17-1.1.1.2.2.2.r 18-1.1.1.2.2.1.1 20-1.1 21-1.1.2.2.1.1.1 22-1.1.2.2 23-1.1.2.1.1.1 24-1.1.2 28-1.2.1.1.1.1 29-1.2.1 31-1.2.3 32-1.2 33-1.2.2.r 34-1.2.2.3 35-1.2.2.1 36-1.2.2 36-1.2.2.2 36-1.2.2.2.r (m / multi-sentence :snt1 (d / diminish-01~e.20 :ARG0 (o / or~e.9 :op1 (p / pretreat-01~e.0 :ARG1~e.1 (c / cell~e.2) :ARG3~e.3 (s4 / small-molecule~e.7 :name (n / name :op1 "CGP59326"~e.8) :ARG0-of~e.7 (i / inhibit-01~e.7) :ARG1-of (s / specific-02~e.6 :ARG2 (e2 / enzyme :name (n7 / name :op1 "EGF"~e.4 :op2 "receptor"~e.5))))) :op2 (p3 / pretreat-01~e.0 :ARG1 c :ARG3~e.10 (s3 / small-molecule~e.17 :name (n3 / name :op1 "PD153035"~e.18) :ARG0-of~e.17 (i2 / inhibit-01~e.17) :mod (b / bispecific~e.12 :prep-to (s2 / slash~e.15 :op1 e2~e.13,14 :op2 (p2 / protein :name (n2 / name :op1 "ERBB2"~e.16))))))) :ARG1 (a / activate-01~e.24 :ARG1 (e / enzyme :name (n4 / name :op1 "MAPK"~e.23)) :ARG2-of (i3 / induce-01~e.22 :ARG0 (p5 / protein :name (n5 / name :op1 "il6"~e.21))))) :snt2 (a2 / affect-01~e.32 :ARG1 (p6 / phosphorylate-01~e.29 :ARG1 (e3 / enzyme :name (n6 / name :op1 "PKB"~e.28))) :ARG2~e.33 (t / thing~e.36 :quant 2~e.35 :ARG0-of~e.36 (i4 / inhibit-01~e.36) :mod (t2 / this~e.34)) :mod (a3 / also~e.31))) # ::id bel_pmid_1120_8678.16854 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tissue factor ( TF ) can be induced in monocytes by external signals such as growth factors , inflammatory cytokines ( interleukin [ IL]-1b and tumor necrosis factor [ TNF]-a ) , oxidized LDLs , and endotoxin . 2 # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 5-1 7-1.1 8-1.1.2.r 9-1.1.2 10-1.1.3.r 11-1.1.3.1 12-1.1.3 13-1.1.3.2.r 14-1.1.3.2.r 15-1.1.3.2.1 16-1.1.3.2.1 18-1.1.3.2.2.1 19-1.1.3.2.2 21-1.1.3.2.2.2.1.1.1.1 24-1.1.3.2.2.2.1 25-1.1.3.2.2.2.1.2.1.1 26-1.1.3.2.2.2.1.2.1.2 27-1.1.3.2.2.2.1.2.1.3 32-1.1.3.2.3.2 35-1.1.3.2 35-1.1.3.2.2.2.1 36-1.1.3.2.4.1.1 38-1.1.4.1.1.1 (p6 / possible-01~e.5 :ARG1 (i / induce-01~e.7 :ARG2 (p5 / protein :name (n6 / name :op1 "tissue"~e.0 :op2 "factor"~e.1)) :location~e.8 (m / monocyte~e.9) :manner~e.10 (s / signal-07~e.12 :mod (e / external~e.11) :example~e.13,14 (a / and~e.35 :op1 (g / growth-factor~e.15,16) :op2 (c / cytokine~e.19 :ARG1-of (i2 / inflame-01~e.18) :ARG0-of (m2 / mean-01 :ARG1 (a2 / and~e.24,35 :op1 (p / protein :name (n2 / name :op1 "interleukin"~e.21 :op2 "IL-1b")) :op2 (p4 / protein :name (n3 / name :op1 "tumor"~e.25 :op2 "necrosis"~e.26 :op3 "factor"~e.27))))) :op3 (p2 / protein :name (n4 / name :op1 "LDL") :ARG1-of (o / oxidize-01~e.32)) :op4 (s2 / small-molecule :name (n5 / name :op1 "endotoxin"~e.36)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 2~e.38))))) # ::id bel_pmid_1120_8678.23564 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Incubation of monocytes with LPS or IL @-@ 1b resulted in a 10 @- and 5 @-@ fold increase of TF activity , respectively . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1 3-1.1.2.r 4-1.1.2.1 5-1.1.2 6-1.1.2.2.1.1 8-1.1.2.2.1.1 9-1 10-1.2.r 12-1.2.2.1 15-1.2.2.2 17-1.2.2 18-1.2 19-1.2.1.r 19-1.2.2 20-1.2.1.1.1.1 21-1.2.1 (r / result-01~e.9 :ARG1 (i / incubate-01~e.0 :ARG1~e.1 (m / monocyte~e.2) :ARG2~e.3 (o / or~e.5 :op1 (l / lipopolysaccharide~e.4) :op2 (p / protein :name (n2 / name :op1 "IL-1b"~e.6,8)))) :ARG2~e.10 (i2 / increase-01~e.18 :ARG1~e.19 (a / activity-06~e.21 :ARG0 (p3 / protein :name (n3 / name :op1 "TF"~e.20))) :ARG2 (p2 / product-of~e.17,19 :op1 10~e.12 :op2 5~e.15))) # ::id bel_pmid_1120_8678.24148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In human aortic smooth muscle cells , fibrates inhibit the IL @-@ 1b ? induced expression of cyclooxygenase ( COX ) - 2 and IL @-@ 6 by inhibiting the NF @-@ kB and AP @-@ 1 signaling pathway.9,10 # ::alignments 1-1.4.2.1 2-1.4.2 3-1.4.1.1 4-1.4.1 5-1.4 8-1 8-1.3 10-1.2.2.1.1.1 12-1.2.2.1.1.1 14-1.2.2 15-1.2 16-1.2.1.r 17-1.2.1.1.1.1 22-1.2.1.1.1.2 23-1.2.1 24-1.2.1.2.1.1 26-1.2.1.2.1.1 27-1.3.r 28-1.3 30-1.3.1.1.1.1 32-1.3.1.1.1.1 33-1.3.1 34-1.3.1.2.1.1 36-1.3.1.2.1.1 37-1.3.1.2.2 (i / inhibit-01~e.8 :ARG0 (f / fibrate) :ARG1 (e / express-03~e.15 :ARG2~e.16 (a / and~e.23 :op1 (e2 / enzyme :name (n / name :op1 "cyclooxygenase"~e.17 :op2 2~e.22)) :op2 (p2 / protein :name (n3 / name :op1 "IL-6"~e.24,26))) :ARG2-of (i2 / induce-01~e.14 :ARG0 (p / protein :name (n2 / name :op1 "IL-1b"~e.10,12)))) :manner~e.27 (i3 / inhibit-01~e.8,28 :ARG1 (a2 / and~e.33 :op1 (p3 / protein :name (n4 / name :op1 "NF-kB"~e.30,32)) :op2 (p4 / pathway :name (n5 / name :op1 "AP-1"~e.34,36) :ARG0-of (s / signal-07~e.37)))) :location (c / cell~e.5 :mod (m / muscle~e.4 :ARG1-of (s2 / smooth-06~e.3)) :mod (a3 / aortic~e.2 :mod (h / human~e.1))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG0-of (c2 / cite-01 :ARG2 (a4 / and :op1 9 :op2 10))))) # ::id bel_pmid_1120_8678.24150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PPARa activators prevent TNF @-@ a ? induced VCAM @-@ 1 expression in human saphenous vein endothelial cells , partly via inhibition of the NF @-@ kB pathway.14 # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2.2.1.1.1 5-1.2.2.1.1.1 7-1.2.2 8-1.2.1.1.1 10-1.2.1.1.1 11-1.2 12-1.3.r 13-1.3.3 14-1.3.2.1 15-1.3.2 16-1.3.1 17-1.3 19-1.4 19-1.4.r 21-1.5 22-1.5.1.r 24-1.5.1.1.1 26-1.5.1.1.1 (p / prevent-01~e.2 :ARG0 (a / activate-01~e.1 :ARG1 (p2 / protein :name (n / name :op1 "PPARa"~e.0))) :ARG1 (e / express-03~e.11 :ARG2 (p3 / protein :name (n2 / name :op1 "VCAM-1"~e.8,10)) :ARG2-of (i / induce-01~e.7 :ARG0 (p4 / protein :name (n3 / name :op1 "TNF-a"~e.3,5)))) :location~e.12 (c / cell~e.17 :mod (e2 / endothelium~e.16) :mod (v / vein~e.15 :mod (s / saphenous~e.14)) :mod (h / human~e.13)) :degree~e.19 (p5 / part~e.19) :manner (i2 / inhibit-01~e.21 :ARG1~e.22 (p6 / pathway :name (n5 / name :op1 "NF-kB"~e.24,26))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 14)))) # ::id bel_pmid_1120_8678.24166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In human vascular endothelial cells , PPARa inhibits the thrombin @-@ mediated activation of endothelin @-@ 1 via negative interference with the AP @-@ 1 signaling pathway.13 # ::alignments 1-1.4.1.1 2-1.4.1.2 3-1.4.1.3 4-1.4 6-1.1.1.1 7-1 9-1.2.2.1.1.1 11-1.2.2 12-1.2 13-1.2.1.r 14-1.2.1.1.1 16-1.2.1.1.1 18-1.3.3 19-1.3 20-1.3.2.r 22-1.3.2.1.1 24-1.3.2.1.1 25-1.3.2.2 (i / inhibit-01~e.7 :ARG0 (p / protein :name (n / name :op1 "PPARa"~e.6)) :ARG1 (a / activate-01~e.12 :ARG1~e.13 (p2 / protein :name (n2 / name :op1 "endothelin-1"~e.14,16)) :ARG1-of (m / mediate-01~e.11 :ARG0 (e / enzyme :name (n3 / name :op1 "thrombin"~e.9)))) :manner (i2 / interfere-01~e.19 :ARG0 p :ARG1~e.20 (p3 / pathway :name (n5 / name :op1 "AP-1"~e.22,24) :ARG0-of (s / signal-07~e.25)) :ARG0-of (n4 / negative-02~e.18)) :location (c / cell~e.4 :name (n6 / name :op1 "human"~e.1 :op2 "vascular"~e.2 :op3 "endothelial"~e.3)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 13)))) # ::id bel_pmid_1120_8678.24170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Incubation of THP @-@ 1 cells with PPARa activators 1 hour before LPS stimulation for 2 hours resulted in a decreased level of TF mRNA compared with cells incubated with only LPS ( Figure 2A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1.1 6-1.1.2.r 7-1.1.2.1.1.1 8-1.1.2 9-1.1.3.2.1 10-1.1.3.2.2 11-1.1.3 12-1.1.3.1.1 13-1.1.3.1 14-1.1.3.1.2.r 15-1.1.3.1.2.1 16-1.1.3.1.2.2 16-1.1.3.2.2 17-1 18-1.2.r 20-1.2 21-1.2.1 22-1.2.1.1.r 23-1.2.1.1.2.1.1.1 24-1.2.1.1.1.1 25-1.2.2.r 27-1.2.2 28-1.2.2.1 29-1.2.2.1.2.r 30-1.2.2.1.2 31-1.2.2.1.1 33-1.3.1 34-1.3.1.1 (r / result-01~e.17 :ARG1 (i / incubate-01~e.0 :ARG1~e.1 (c / cell~e.5 :name (n / name :op1 "THP-1"~e.2,4)) :ARG2~e.6 (a / activate-01~e.8 :ARG1 (p / protein :name (n2 / name :op1 "PPARa"~e.7))) :time (b / before~e.11 :op1 (s / stimulate-01~e.13 :ARG1 (l2 / lipopolysaccharide~e.12) :duration~e.14 (t2 / temporal-quantity :quant 2~e.15 :unit (h2 / hour~e.16))) :quant (t / temporal-quantity :quant 1~e.9 :unit (h / hour~e.10,16)))) :ARG2~e.18 (d / decrease-01~e.20 :ARG1 (l / level~e.21 :quant-of~e.22 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.24) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n6 / name :op1 "TF"~e.23))))) :compared-to~e.25 (c2 / cell~e.27 :ARG1-of (i2 / incubate-01~e.28 :ARG2 l2~e.31 :mod~e.29 (o / only~e.30)))) :ARG1-of (d2 / describe-01 :ARG2 (f / figure~e.33 :mod "2A"~e.34))) # ::id bel_pmid_1123_1577.20122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bag1 , a co @-@ chaperone for heat @-@ shock protein 70 ( Hsp70 ) , coordinates signals for cell growth in response to cell stress , by downregulating the activity of Raf @-@ 1 kinase . Raf @-@ 1 and Hsp70 compete for binding to Bag1 , such that Bag1 binds to and activates Raf @-@ 1 , subsequently activating the downstream extracellular signal @-@ related kinases # ::alignments 0-1.1.1.1.1 3-1.1.1.2.1.1.1 5-1.1.1.2.1.1.1 7-1.1.1.2.1.2.1.1 9-1.1.1.2.1.2.1.1 10-1.1.1 10-1.1.1.2.1 10-1.1.1.2.1.2 10-1.1.1.2.1.2.r 10-1.2.2 10-1.2.3.1 11-1.1.1.2.1.2.2.1 13-1.2.2.1.1 16-1.1 17-1.1.2 18-1.1.2.1.r 19-1.1.2.1.1 20-1.1.2.1 21-1.1.2.2.r 22-1.1.2.2 24-1.1.2.2.1.1 25-1.1.2.2.1 27-1.1.3.r 28-1.1.3 30-1.1.3.1 32-1.1.3.1.1.1.1 32-1.2.1.1.1 34-1.1.3.1.1.1.1 34-1.2.1.1.1 35-1.2.5.1.1.1.3 37-1.2.1.1.1 39-1.2.1.1.1 40-1.2.4.1 41-1.2.2.1.1 42-1.2 43-1.2.3.r 44-1.2.3 45-1.2.4 46-1.2.3.1.1.1 50-1.2.3.1.1.1 51-1.2.4.1.1 53-1.2.4.1 54-1.2.4.1.2 55-1.2.4.1.2.2 56-1.2.4.1.2.2 57-1.2.4.1.2.2 59-1.2.5 59-1.2.5.r 60-1.2.5.1 62-1.2.5.1.1.2 63-1.2.5.1.1.1.1 64-1.2.5.1.1.1.2 66-1.2.5.1.1.1.2 67-1.2.5.1.1.1.3 (m / multi-sentence :snt1 (c / coordinate-01~e.16 :ARG1 (p / protein~e.10 :name (n / name :op1 "Bag1"~e.0) :ARG0-of (m2 / mean-01 :ARG1 (p2 / protein~e.10 :name (n2 / name :op1 "co-chaperone"~e.3,5) :beneficiary~e.10 (p3 / protein~e.10 :name (n3 / name :op1 "heat-shock"~e.7,9) :mod (m3 / molecular-mass :mod 70~e.11))))) :ARG2 (s / signal-07~e.17 :beneficiary~e.18 (g / grow-01~e.20 :ARG1 (c2 / cell~e.19)) :ARG0-of~e.21 (r / respond-01~e.22 :ARG1 (s2 / stress-02~e.25 :ARG1 (c3 / cell~e.24)))) :manner~e.27 (d / downregulate-01~e.28 :ARG1 (a / activity-06~e.30 :ARG0 (e3 / enzyme :name (n4 / name :op1 "Raf-1"~e.32,34))))) :snt2 (c4 / compete-01~e.42 :ARG0 (e / enzyme :name (n5 / name :op1 "Raf-1"~e.32,34,37,39)) :ARG1 (p4 / protein~e.10 :name (n6 / name :op1 "Hsp70"~e.13,41)) :ARG2~e.43 (b / bind-01~e.44 :ARG1 (p5 / protein~e.10 :name (n7 / name :op1 "Bag1"~e.46,50))) :ARG1-of (c5 / cause-01~e.45 :ARG0 (a3 / and~e.40,53 :op1 (b2 / bind-01~e.51 :ARG0 p5 :ARG1 e) :op2 (a4 / activate-01~e.54 :ARG0 p5 :ARG1 e~e.55,56,57))) :time~e.59 (s3 / subsequent~e.59 :op1 (a5 / activate-01~e.60 :ARG1 (e2 / enzyme :name (n8 / name :op1 "extracellular"~e.63 :op2 "signal-related"~e.64,66 :op3 "kinase"~e.35,67) :mod (d2 / downstream~e.62)))))) # ::id bel_pmid_1123_9409.20136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of Shc produces its binding to the adaptor protein Grb2 , causing activation of the protooncogene ras , which is also upstream of the MAP kinase pathway . # ::alignments 0-1.1.1 2-1.1.1.1.1.1 3-1.1 4-1.1.2.1 4-1.1.2.1.r 5-1.1.2 6-1.1.2.2.r 8-1.1.2.2.2 9-1.1.1.1 9-1.1.2.2 10-1.1.2.2.1.1 12-1 13-1.2 14-1.2.1.r 16-1.2.1 17-1.2.1.1.1 20-1.2.1.2 21-1.2.1.2.3 22-1.2.1.2.2 25-1.2.1.2.1.1.1 26-1.2.1.2.1.1.2 27-1.2.1.2.1 (c / cause-01~e.12 :ARG0 (p / produce-01~e.3 :ARG0 (p2 / phosphorylate-01~e.0 :ARG1 (p3 / protein~e.9 :name (n / name :op1 "shc"~e.2))) :ARG1 (b / bind-01~e.5 :ARG1~e.4 p3~e.4 :ARG2~e.6 (p4 / protein~e.9 :name (n2 / name :op1 "grb2"~e.10) :mod (a / adaptor~e.8)))) :ARG1 (a2 / activate-01~e.13 :ARG1~e.14 (p5 / protooncogene~e.16 :name (n3 / name :op1 "ras"~e.17) :ARG1-of (b2 / be-located-at-91~e.20 :ARG2 (p6 / pathway~e.27 :name (n4 / name :op1 "MAP"~e.25 :op2 "kinase"~e.26)) :direction (u / upstream~e.22) :mod (a3 / also~e.21))))) # ::id bel_pmid_1123_9409.21258 ::amr-annotator SDL-AMR-09 ::preferred # ::tok insulin receptor phosphorylates a number of intracellular substrates on tyrosine including members of the insulin receptor substrate family ( IRS1 @/@ 2/3 @/@ 4 ) , the Shc adaptor ... # ::alignments 0-1.2.1 1-1.2 2-1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1 7-1.1.1.1 8-1.3.r 9-1.3.1.1 10-1.1.2 11-1.1.2.1 12-1.1.2.2.r 14-1.1.2.2.1.1 15-1.1.2.2.1.2 16-1.1.2.2.1.3 17-1.1.2.2 19-1.1.2.1.1.1.1.1.1 20-1.1.2.1.1.1 22-1.1.2.1.1.1 27-1.1.3.1.1 28-1.1.3.1.2 (p / phosphorylate-01~e.2 :ARG1 (a2 / and :op1 (n / number~e.4 :quant-of~e.5 (s / substrate~e.7 :mod (i2 / intracellular~e.6))) :op2 (i4 / include-01~e.10 :ARG1 (m / member~e.11 :ARG1-of (m2 / mean-01 :ARG2 (s2 / slash~e.20,22 :op1 (p4 / protein :name (n5 / name :op1 "IRS1"~e.19)) :op2 (p5 / protein :name (n6 / name :op1 "IRS2")) :op3 (p6 / protein :name (n7 / name :op1 "IRS3")) :op4 (p7 / protein :name (n8 / name :op1 "IRS4"))))) :ARG2~e.12 (p2 / protein-family~e.17 :name (n3 / name :op1 "insulin"~e.14 :op2 "receptor"~e.15 :op3 "substrate"~e.16))) :op3 (p3 / protein :name (n4 / name :op1 "Shc"~e.27 :op2 "adaptor"~e.28))) :ARG2 (r / receptor~e.1 :mod (i / insulin~e.0)) :location~e.8 (a / amino-acid :name (n2 / name :op1 "tyrosine"~e.9))) # ::id bel_pmid_1123_9409.23154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Insulin stimulates the tyrosine kinase activity of its receptor , leading to the phosphorylation of a number of cellular substrates , including Gab1 , Shc , IRS 1 - 4 , and Cbl . Gab1 appears to interact with the SH2 containing tyrosine phosphatase SHP2 , leading to the activation of the MAP kinase pathway . # ::alignments 0-1.1.1 1-1.1 3-1.1.2.2.1.1 4-1.1.2.2.1.2 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1 7-1.1.2.1.1.r 8-1.1.2.1 10-1.1.3 11-1.1.3.1.r 13-1.1.3.1 14-1.1.3.1.1.r 16-1.1.3.1.1 17-1.1.3.1.1.1.r 18-1.1.3.1.1.1.1 19-1.1.3.1.1.1 21-1.1.3.1.1.1.2 22-1.1.3.1.1.1.2.1.1.1.1 24-1.1.3.1.1.1.2.1.2.1.1 26-1.1.3.1.1.1.2.1.3.1.1 27-1.1.3.1.1.1.2.1.3.2.1 29-1.1.3.1.1.1.2.1.3.2.2 31-1.1.3.1.1.1.2.1 32-1.1.3.1.1.1.2.1.4.1.1 34-1.1.3.1.1.1.2.1.1.1.1 34-1.2.1.1.1 35-1.2 37-1.2.2 38-1.2.2.2.r 40-1.2.2.2.2.1.1.1 41-1.2.2.2.2 42-1.2.2.2 43-1.2.2.2 44-1.2.2.2.1.1 46-1.2.2.3 47-1.2.2.3.1.r 49-1.2.2.3.1 50-1.2.2.3.1.1.r 52-1.2.2.3.1.1.1.1 53-1.2.2.3.1.1.1.2 54-1.2.2.3.1.1 (m / multi-sentence :snt1 (s / stimulate-01~e.1 :ARG0 (i / insulin~e.0) :ARG1 (a / activity-06~e.5 :ARG0~e.6 (r / receptor~e.8 :poss~e.7 i~e.7) :ARG1 (e / enzyme :name (n / name :op1 "tyrosine"~e.3 :op2 "kinase"~e.4))) :ARG0-of (l / lead-03~e.10 :ARG2~e.11 (p / phosphorylate-01~e.13 :ARG1~e.14 (n2 / number~e.16 :quant-of~e.17 (s2 / substrate~e.19 :mod (c / cell~e.18) :ARG2-of (i2 / include-01~e.21 :ARG1 (a2 / and~e.31 :op1 (p2 / protein :name (n3 / name :op1 "Gab1"~e.22,34)) :op2 (p3 / protein :name (n4 / name :op1 "Shc"~e.24)) :op3 (p4 / protein :name (n5 / name :op1 "IRS"~e.26) :mod (v / value-interval :op1 1~e.27 :op2 4~e.29)) :op4 (p5 / protein :name (n6 / name :op1 "Cbl"~e.32))))))))) :snt2 (a3 / appear-02~e.35 :ARG1 (p6 / protein :name (n7 / name :op1 "Gab1"~e.34)) :ARG2 (i3 / interact-01~e.37 :ARG0 p6 :ARG1~e.38 (t / tyrosine-phosphatase~e.42,43 :name (n8 / name :op1 "SHP2"~e.44) :ARG1-of (c2 / contain-01~e.41 :ARG0 (p8 / protein :name (n9 / name :op1 "Sh2"~e.40)))) :ARG0-of (l2 / lead-03~e.46 :ARG2~e.47 (a4 / activate-01~e.49 :ARG1~e.50 (p9 / pathway~e.54 :name (n10 / name :op1 "MAP"~e.52 :op2 "kinase"~e.53))))))) # ::id bel_pmid_1123_9409.24744 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of these enzymes [ LAR and PTP1B ] in cultured cells prevents insulin receptor kinase activation . # ::alignments 0-1.1 3-1.1.1.1 3-1.1.1.2 3-1.2.1 5-1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1 9-1.1.2.r 10-1.1.2.1 11-1.1.2 12-1 13-1.2.1.1.1 14-1.2.1.1.2 15-1.2.1.1.3 16-1.2 (p / prevent-01~e.12 :ARG0 (o / overexpress-01~e.0 :ARG1 (a / and~e.6 :op1 (e / enzyme~e.3 :name (n / name :op1 "LAR"~e.5)) :op2 (e2 / enzyme~e.3 :name (n2 / name :op1 "PTP1B"~e.7))) :location~e.9 (c / cell~e.11 :ARG1-of (c2 / culture-01~e.10))) :ARG1 (a2 / activate-01~e.16 :ARG1 (p2 / protein~e.3 :name (n3 / name :op1 "insulin"~e.13 :op2 "receptor"~e.14 :op3 "kinase"~e.15)))) # ::id bel_pmid_1123_9409.32116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The translocation of phosphorylated cbl recruits additional signaling proteins to the lipid raft , resulting in the activation of the G protein TC10 . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 4-1.1.1.1.1 5-1 6-1.2.2 7-1.2.1 8-1.2 9-1.3.r 11-1.3.1 12-1.3 14-1.4 15-1.4.1.r 17-1.4.1 18-1.4.1.1.r 20-1.4.1.1.1.1 21-1.4.1.1 22-1.4.1.1.1.2 (r / recruit-01~e.5 :ARG0 (t / translocate-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "cbl"~e.4) :ARG1-of (p2 / phosphorylate-01~e.3))) :ARG1 (p3 / protein~e.8 :ARG0-of (s / signal-07~e.7) :mod (a / additional~e.6)) :ARG2~e.9 (r2 / raft~e.12 :mod (l / lipid~e.11)) :ARG2-of (r3 / result-01~e.14 :ARG1~e.15 (a2 / activate-01~e.17 :ARG1~e.18 (p4 / protein~e.21 :name (n2 / name :op1 "G"~e.20 :op2 "TC10"~e.22))))) # ::id bel_pmid_1125_0916.23582 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Contrary to the hypothesis , both IL @-@ 1 beta and IL @-@ 6 treatment resulted in a significant decrease in OT receptor messenger RNA measured by ribonuclease protection analysis . # ::alignments 3-1.3.1 3-1.3.1.1 3-1.3.1.1.r 6-1.1.1.1.1.1 6-1.1.1.2.1.1 10-1.1.1 11-1.1.1.1.1.1 11-1.1.1.2.1.1 13-1.1.1.2.1.1 14-1.1 15-1 16-1.2.r 18-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1.2.1.1.1 22-1.2.1.2.1 24-1.2.1.1.2 25-1.2.3 26-1.2.3.1.r 27-1.2.3.1.1.1 28-1.2.3.1.1 29-1.2.3.1 (r / result-01~e.15 :ARG1 (t / treat-04~e.14 :ARG1 (a / and~e.10 :op1 (p / protein :name (n / name :op1 "IL-1beta"~e.6,11)) :op2 (p2 / protein :name (n2 / name :op1 "IL-6"~e.6,11,13)))) :ARG2~e.16 (d / decrease-01~e.19 :ARG1~e.20 (n5 / nucleic-acid :name (n3 / name :op1 "messeger" :op2 "RNA"~e.24) :ARG0-of (e / encode-01 :ARG1 (r5 / receptor~e.22 :name (n4 / name :op1 "OT"~e.21)))) :ARG2 (s / significant-02~e.18) :ARG1-of (m / measure-01~e.25 :manner~e.26 (a2 / analyze-01~e.29 :ARG1 (p3 / protection~e.28 :mod (r3 / ribonuclease~e.27))))) :ARG0-of (c / counter-01 :ARG1 (t2 / thing~e.3 :ARG1-of~e.3 (h / hypothesize-01~e.3)))) # ::id bel_pmid_1125_2722.32494 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We demonstrated that ROR alpha is expressed in human primary smooth @-@ muscle cells and that ectopic expression of ROR alpha1 inhibits TNFalpha @-@ induced IL @-@ 6 , IL @-@ 8 and COX @-@ 2 expression in these cells . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 4-1.2.1.1.1.2 6-1.2.1 8-1.2.1.2.2 9-1.2.1.2.1.1.1 10-1.2.1.2.1.1 12-1.2.1.2.1 13-1.2.1.2 14-1.2 15-1.2.r 16-1.2.2.1.2 17-1.2.2.1 17-1.2.2.2.3 18-1.2.2.1.1.r 19-1.2.2.1.1.1.1 20-1.2.2.1.1.1.2 21-1.2.2 22-1.2.2.2.1.2.1.1.1 24-1.2.2.2.1.2 25-1.2.2.2.1.1.1 27-1.2.2.2.1.1.1 29-1.2.2.2.1.1.1 29-1.2.2.2.2.1.1 31-1.2.2.2.2.1.1 33-1.2.2.2.3.1.1.1 35-1.2.2.2.3.1.1.1 36-1.2.1 37-1.2.2.3.r 38-1.2.2.3.1 39-1.2.2.3 (d / demonstrate-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2,15 (a / and~e.14 :op1 (e / express-03~e.6,36 :ARG2 (p4 / protein :name (n2 / name :op1 "ROR"~e.3 :op2 "alpha"~e.4 :op3 "receptor")) :location (c / cell~e.13 :mod (m / muscle~e.12 :ARG1-of (s / smooth-06~e.10 :mod (p / primary~e.9))) :mod (h / human~e.8))) :op2 (i / inhibit-01~e.21 :ARG0 (e2 / express-03~e.17 :ARG2~e.18 (p2 / protein :name (n7 / name :op1 "ROR"~e.19 :op2 "alpha1"~e.20 :op3 "receptor")) :manner (e3 / ectopic~e.16)) :ARG1 (a2 / and :op1 (p5 / protein :name (n3 / name :op1 "IL-6"~e.25,27,29) :ARG2-of (i2 / induce-01~e.24 :ARG0 (p3 / protein :name (n4 / name :op1 "TNFalpha"~e.22)))) :op2 (p6 / protein :name (n5 / name :op1 "IL-8"~e.29,31)) :op3 (e4 / express-03~e.17 :ARG2 (e5 / enzyme :name (n6 / name :op1 "COX-2"~e.33,35)))) :location~e.37 (c4 / cell~e.39 :mod (t / this~e.38))))) # ::id bel_pmid_1127_9172.6266 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SB203580 , a specific p38 MAPK inhibitor , attenuated these effects , further confirming that both MMK6 and MMK3 act via p38 MAPK , whereas they had no effect on the increase in glucose transport induced by a constitutively active MAPK kinase 1 ( MEK1 ) mutant or by myristoylated Akt . # ::alignments 0-1.1.1.1 3-1.1.3 4-1.1.2.1.1.1 5-1.1.2.1.1.2 6-1.1 6-1.1.2 6-1.1.2.r 8-1 9-1.2.1 10-1.2 12-1.3.2 13-1.3 17-1.3.1.1 19-1.3.1 21-1.3.1.2 22-1.3.1.2 24-1.3.1.3 25-1.3.1.3.1.2 27-1.3.1.3.1.1 27-1.3.1.3.1.1.r 28-1.3.1.3.1 29-1.3.1.3.1.3.r 31-1.3.1.3.1.3 32-1.3.1.3.1.3.1.r 33-1.3.1.3.1.3.1.1 34-1.3.1.3.1.3.1 35-1.3.1.3.1.3.2 36-1.3.1.3.1.3.2.1.r 38-1.3.1.3.1.3.2.1.1.3.1 39-1.3.1.3.1.3.2.1.1.3 40-1.3.1.3.1.3.2.1.1.1.1 41-1.3.1.3.1.3.2.1.1.1.2 42-1.3.1.3.1.3.2.1.1.1.3 46-1.3.1.3.1.3.2.1.1 46-1.3.1.3.1.3.2.1.1.2 46-1.3.1.3.1.3.2.1.1.2.r 47-1.3.1.3.1.3.2.1 50-1.3.1.3.1.3.2.1.2.1.1 (a6 / attenuate-01~e.8 :ARG0 (s2 / small-molecule~e.6 :name (n / name :op1 "SB203580"~e.0) :ARG0-of~e.6 (i2 / inhibit-01~e.6 :ARG1 (p / protein-family :name (n2 / name :op1 "p38"~e.4 :op2 "MAPK"~e.5))) :ARG1-of (s / specific-02~e.3)) :ARG1 (a2 / affect-01~e.10 :mod (t / this~e.9)) :ARG0-of (c / confirm-01~e.13 :ARG1 (a4 / act-01~e.19 :ARG0 (a7 / and~e.17 :op1 (e / enzyme :name (n3 / name :op1 "MKK6")) :op2 (e2 / enzyme :name (n4 / name :op1 "MKK3"))) :manner p~e.21,22 :ARG1-of (c2 / contrast-01~e.24 :ARG2 (a3 / affect-01~e.28 :polarity~e.27 -~e.27 :ARG0 a7~e.25 :ARG1~e.29 (i3 / increase-01~e.31 :ARG1~e.32 (t2 / transport-01~e.34 :ARG1 (g / glucose~e.33)) :ARG2-of (i4 / induce-01~e.35 :ARG0~e.36 (o / or~e.47 :op1 (e4 / enzyme~e.46 :name (n5 / name :op1 "MAPK"~e.40 :op2 "kinase"~e.41 :op3 1~e.42) :ARG2-of~e.46 (m3 / mutate-01~e.46) :ARG0-of (a / activity-06~e.39 :mod (c3 / constitutive~e.38))) :op2 (e5 / enzyme :name (n6 / name :op1 "Akt"~e.50) :ARG1-of (m5 / myristoylate-00)))))))) :degree (f / further~e.12))) # ::id bel_pmid_1127_9172.21850 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutively active MKK6 @/@ 3 mutants up @-@ regulated GLUT1 expression and down @-@ regulated GLUT4 expression , thereby significantly increasing basal glucose transport but diminishing transport induced by insulin . # ::alignments 0-1.1.1.2.1.2.1 1-1.1.1.2.1 1-1.1.1.2.1.2 1-1.1.1.2.1.2.r 2-1.1.1.2.1.1.1 3-1.1.1.2 5-1.1.1.2.3 6-1.2.1 9-1.1.1.1.1.1.1 10-1.1.1.1 10-1.1.2.1 11-1.1 15-1.1.2.1.1.1.1 16-1.1.1.1 16-1.1.2.1 19-1.2.1.2 20-1.2.1 21-1.2.1.1.1.1 22-1.2.1.1.1 23-1.2.1.1 24-1.2 25-1.2.2 26-1.2.2.1 27-1.2.2.1.1 28-1.2.2.1.1.1.r 29-1.2.2.1.1.1.1.1 (c / cause-01 :ARG0 (a / and~e.11 :op1 (u / upregulate-01 :ARG1 (e2 / express-03~e.10,16 :ARG2 (p / protein :name (n2 / name :op1 "GLUT1"~e.9))) :ARG2 (s2 / slash~e.3 :op1 (e4 / enzyme~e.1 :name (n5 / name :op1 "MKK6"~e.2) :ARG0-of~e.1 (a2 / activity-06~e.1 :mod (c2 / constitutive~e.0))) :op2 (e5 / enzyme :name (n6 / name :op1 "MKK3") :ARG1-of a2) :ARG2-of (m / mutate-01~e.5))) :op2 (d / downregulate-01 :ARG1 (e3 / express-03~e.10,16 :ARG2 (p2 / protein :name (n3 / name :op1 "GLUT4"~e.15))) :ARG2 m)) :ARG1 (c3 / contrast-01~e.24 :ARG1 (i / increase-01~e.6,20 :ARG1 (t / transport-01~e.23 :ARG1 (g / glucose~e.22 :mod (b / basal~e.21))) :ARG2 (s / significant-02~e.19)) :ARG2 (d2 / diminish-01~e.25 :ARG1 (t2 / transport-01~e.26 :ARG2-of (i2 / induce-01~e.27 :ARG0~e.28 (p3 / protein :name (n4 / name :op1 "insulin"~e.29))))))) # ::id bel_pmid_1128_2560.28384 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A similar 24P3 induction was observed in other T cell lymphomas ( EL4 and TH201 ) in response to IL @-@ 9 , as well as in EL4 cells stimulated with IL @-@ 6 or IL @-@ 1 . # ::alignments 1-1.1.2 2-1.1.1.1.1 3-1.1 5-1 6-1.2.r 7-1.2.1.2 8-1.2.1.4.1.1 9-1.2.1.4 10-1.2.1 12-1.2.1.1.1.1.1 14-1.2.1.1.2.1.1 16-1.2.1.3.r 17-1.2.1.3 18-1.2.1.3.1.r 19-1.2.1.3.1.1.1 21-1.2.1.3.1.1.1 23-1.2.1.1 24-1.2.1.1 25-1.2.1.1 27-1.2.1.1.1.1.1 27-1.2.2.1.1 28-1.2.1.1.1 28-1.2.1.1.2 28-1.2.2 29-1.2.2.2 30-1.2.2.2.1.r 31-1.2.2.2.1.1.1.1 33-1.2.2.2.1.1.1.1 34-1.2.2.2.1 35-1.2.2.2.1.1.1.1 35-1.2.2.2.1.2.1.1 37-1.2.2.2.1.2.1.1 (o / observe-01~e.5 :ARG1 (i / induce-01~e.3 :ARG2 (p / protein :name (n / name :op1 "24P3"~e.2)) :ARG1-of (r / resemble-01~e.1)) :location~e.6 (a2 / and :op1 (l / lymphoma~e.10 :example (a / and~e.23,24,25 :op1 (c2 / cell~e.28 :name (n3 / name :op1 "EL4"~e.12,27)) :op2 (c3 / cell~e.28 :name (n4 / name :op1 "TH201"~e.14))) :mod (o2 / other~e.7) :ARG2-of~e.16 (r2 / respond-01~e.17 :ARG1~e.18 (p2 / protein :name (n5 / name :op1 "IL-9"~e.19,21))) :mod (c5 / cell~e.9 :name (n9 / name :op1 "T"~e.8))) :op2 (c4 / cell~e.28 :name (n6 / name :op1 "EL4"~e.27) :ARG1-of (s / stimulate-01~e.29 :ARG0~e.30 (o3 / or~e.34 :op1 (p3 / protein :name (n7 / name :op1 "IL-6"~e.31,33,35)) :op2 (p4 / protein :name (n8 / name :op1 "IL-1"~e.35,37))))))) # ::id bel_pmid_1128_2560.28446 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Searching for genes specifically modulated by IL @-@ 9 , we observed that the 24P3 mRNA is strongly upregulated in BW5147 T lymphoma cells upon IL @-@ 9 stimulation . # ::alignments 0-1.3 1-1.3.2.r 2-1.3.2 3-1.3.2.1.2 4-1.3.2.1 5-1.3.2.1.1.r 6-1.3.2.1.1 7-1.3.2.1.1 8-1.3.2.1.1 10-1.1 11-1 14-1.2.1.1.2.1.1.1 15-1.2.1.1.1.1 17-1.2.1.3 18-1.2.1 19-1.2.1.2.r 20-1.2.1.2.1.1 21-1.2.1.2.1.2 22-1.2.1.2.2 23-1.2.1.2 25-1.2.2.1.1.1 27-1.2.2.1.1.1 28-1.2.2 (o / observe-01~e.11 :ARG0 (w / we~e.10) :ARG1 (h / have-condition-91 :ARG1 (u / upregulate-01~e.18 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.15) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n / name :op1 "24P3"~e.14)))) :location~e.19 (c / cell~e.23 :name (n2 / name :op1 "BW5147"~e.20 :op2 "T"~e.21) :mod (l / lymphoma~e.22)) :ARG1-of (s2 / strong-02~e.17)) :ARG2 (s / stimulate-01~e.28 :ARG0 (p2 / protein :name (n3 / name :op1 "IL-9"~e.25,27)))) :time (s3 / search-01~e.0 :ARG0 w :ARG1~e.1 (g / gene~e.2 :ARG1-of (m2 / modulate-01~e.4 :ARG0~e.5 p2~e.6,7,8 :ARG1-of (s4 / specific-02~e.3))))) # ::id bel_pmid_1128_7618.22858 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ResnetDB sentence : Gadd45 gamma expression is induced by several cytokines , including IL @-@ 3 , IL @-@ 6 , and GM @-@ CSF ( 20 ) . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.2.2.1.1.1 4-1.2.2.1.1.2 5-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.2 10-1.2.1 12-1.2.1.1 13-1.2.1.1.1.1.1.1 13-1.2.1.1.1.2.1.1 15-1.2.1.1.1.1.1.1 17-1.2.1.1.1.1.1.1 17-1.2.1.1.1.2.1.1 19-1.2.1.1.1.2.1.1 21-1.2.1.1.1 22-1.2.1.1.1.3.1.1 24-1.2.1.1.1.3.1.1 26-1.3.1.1.1 (d / describe-01 :ARG0 (s / sentence~e.1 :mod (t / thing :name (n / name :op1 "ResnetDB"~e.0))) :ARG1 (i / induce-01~e.7 :ARG0~e.8 (c / cytokine~e.10 :ARG2-of (i2 / include-91~e.12 :ARG1 (a / and~e.21 :op1 (p2 / protein :name (n2 / name :op1 "IL-3"~e.13,15,17)) :op2 (p3 / protein :name (n3 / name :op1 "IL-6"~e.13,17,19)) :op3 (p4 / protein :name (n4 / name :op1 "GM-CSF"~e.22,24)))) :quant (s2 / several~e.9)) :ARG2 (e / express-03~e.5 :ARG2 (p7 / protein :name (n6 / name :op1 "Gadd45"~e.3 :op2 "gamma"~e.4)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 20~e.26)))) # ::id bel_pmid_1128_7618.23626 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Gadd45 gamma , a family member of the growth arrest and DNA damage @-@ inducible gene family 45 ( Gadd45 ) , is strongly induced by interleukin @-@ 2 ( IL @-@ 2 ) in peripheral T cells . # ::alignments 4-1.2.2.1 8-1.2.2.1.1.1 9-1.2.2.1.1.2 10-1.2.2.1.1.3 11-1.2.2.1.1.4 12-1.2.2.1.1.5 14-1.2.2.1.1.5 15-1.2.2.1.1.6 16-1.2.2.1 17-1.2.2.1.1.7 23-1.4 24-1 25-1.1.r 26-1.1.1.1 28-1.1.1.1 32-1.1.1.1 34-1.3.r 35-1.3.2 36-1.3.1.1 37-1.3 (i / induce-01~e.24 :ARG0~e.25 (p2 / protein :name (n3 / name :op1 "interleukin-2"~e.26,28,32)) :ARG2 (p / protein :name (n / name :op1 "Gadd45gamma") :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family~e.4,16 :name (n2 / name :op1 "growth"~e.8 :op2 "arrest"~e.9 :op3 "and"~e.10 :op4 "DNA"~e.11 :op5 "damage-inducible"~e.12,14 :op6 "gene"~e.15 :op7 45~e.17)))) :location~e.34 (c / cell~e.37 :name (n4 / name :op1 "T"~e.36) :mod (p3 / peripheral~e.35)) :ARG1-of (s / strong-02~e.23)) # ::id bel_pmid_1128_9146.5754 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras @-@ mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1 . # ::alignments 0-1.2.2.1.1.1 2-1.2.2.1.1.1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1.2.1.1.1 8-1.2.1.1.2.1.1.2 9-1.2.1.1.1.1 10-1.2.1 11-1 12-1.1 13-1.1.1.r 15-1.1.1.1.1 16-1.1.1.1.2 17-1.1.1.1.3 (i2 / involve-01~e.11 :ARG1 (a / activate-01~e.12 :ARG1~e.13 (e4 / enzyme :name (n3 / name :op1 "protein"~e.15 :op2 "kinase"~e.16 :op3 "B1"~e.17))) :ARG2 (i / increase-01~e.5 :ARG1~e.6 (s / stability~e.10 :mod (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.9) :ARG0-of (e2 / encode-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "cyclooxygenase"~e.7 :op2 2~e.8))))) :ARG1-of (m / mediate-01~e.4 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras"~e.0,2))))) # ::id bel_pmid_1128_9146.7350 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , Akt @/@ PKB activity is involved in K @-@ Ras @-@ induced expression of COX @-@ 2 and stabilization of COX @-@ 2 mRNA largely depends on the activation of Akt/PKB . # ::alignments 0-1 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1 7-1.1.1 8-1.1.1.2.r 9-1.1.1.2.2.1.1.1 11-1.1.1.2.2.1.1.1 13-1.1.1.2.2 14-1.1.1.2 15-1.1.1.2.1.r 16-1.1.1.2.1.1.1 18-1.1.1.2.1.1.1 19-1.1 20-1.1.2.1 22-1.1.1.2.1.1.1 24-1.1.1.2.1.1.1 25-1.1.2.1.1.1.1 26-1.1.2.3 27-1.1.2 28-1.1.2.2.r 30-1.1.2.2 31-1.1.2.2.1.r 32-1.1.2.2.1 (c / cause-01~e.0 :ARG1 (a / and~e.19 :op1 (i / involve-01~e.7 :ARG1 (a2 / activity-06~e.5 :ARG0 (p / pathway :name (n / name :op1 "Akt/PKB"~e.2,4))) :ARG2~e.8 (e3 / express-03~e.14 :ARG2~e.15 (e4 / enzyme :name (n3 / name :op1 "COX-2"~e.16,18,22,24)) :ARG2-of (i2 / induce-01~e.13 :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.9,11))))) :op2 (d / depend-01~e.27 :ARG0 (s / stabilize-01~e.20 :ARG2 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.25) :ARG0-of (e5 / encode-01 :ARG1 e4))) :ARG1~e.28 (a3 / activate-01~e.30 :ARG1~e.31 p~e.32) :degree (l / large~e.26)))) # ::id bel_pmid_1129_4897.21214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Addition of a single tyrosine residue , Y724 , restored its [ Fgfr3 ] ability to stimulate cellular transformation , phosphatidylinositol 3 @-@ kinase activation , and phosphorylation of Shp2 , MAPK , Stat1 , and Stat3 . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.2 4-1.1.1.1.2.1 5-1.1.1 9-1 12-1.2.1.1.1 14-1.2 16-1.2.2 17-1.2.2.2.1.1 18-1.2.2.2.1 20-1.2.2.2.2.1.1.1 21-1.2.2.2.2.1.1.2 23-1.2.2.2.2.1.1.2 24-1.2.2.2.2 26-1.2.2.2 27-1.2.2.2.3 28-1.2.2.2.3.1.r 29-1.2.2.2.3.1.1.1.1 31-1.2.2.2.3.1.2.1.1 33-1.2.2.2.3.1.3.1.1 36-1.2.2.2.3.1.4.1.1 (r3 / restore-01~e.9 :ARG0 (a / add-02~e.0 :ARG1~e.1 (r / residue~e.5 :mod (a2 / amino-acid :mod 724 :name (n / name :op1 "tyrosine"~e.4)) :ARG1-of (s / single-02~e.3))) :ARG1 (c / capable-01~e.14 :ARG1 (p / protein :name (n3 / name :op1 "Fgfr3"~e.12)) :ARG2 (s2 / stimulate-01~e.16 :ARG0 p :ARG1 (a4 / and~e.26 :op1 (t / transform-01~e.18 :mod (c2 / cell~e.17)) :op2 (a5 / activate-01~e.24 :ARG1 (e / enzyme :name (n4 / name :op1 "phosphatidylinositol"~e.20 :op2 "3-kinase"~e.21,23))) :op3 (p2 / phosphorylate-01~e.27 :ARG1~e.28 (a6 / and :op1 (e2 / enzyme :name (n5 / name :op1 "Shp2"~e.29)) :op2 (e3 / enzyme :name (n6 / name :op1 "MAPK"~e.31)) :op3 (p3 / protein :name (n7 / name :op1 "Stat1"~e.33)) :op4 (p4 / protein :name (n8 / name :op1 "Stat3"~e.36)))))))) # ::id bel_pmid_1129_4897.23128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also found that Y770 may function as a negative regulatory site for FGFR3 @-@ stimulated transformation and PI 3 @-@ kinase activation . # ::alignments 0-1.1 1-1.3 2-1 5-1.2 6-1.2.1 7-1.2.1.2.r 9-1.2.1.2.1 10-1.2.1.2.1 11-1.2.1.2 12-1.2.1.2.1.1.r 13-1.2.1.2.1.1.1.1.1.1.1 15-1.2.1.2.1.1.1.1 16-1.2.1.2.1.1.1 17-1.2.1.2.1.1 18-1.2.1.2.1.1.2.1.1.1 19-1.2.1.2.1.1.2.1.1.2 21-1.2.1.2.1.1.2.1.1.2 22-1.2.1.2.1.1.2 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1 (p / possible-01~e.5 :ARG1 (f2 / function-01~e.6 :ARG0 (a / amino-acid :mod 770 :name (n / name :op1 "tyrosine")) :ARG1~e.7 (p3 / protein-segment~e.11 :ARG2-of (d / downregulate-01~e.9,10 :ARG1~e.12 (a2 / and~e.17 :op1 (t / transform-01~e.16 :ARG1-of (s2 / stimulate-01~e.15 :ARG0 (p2 / protein :name (n2 / name :op1 "FGFR3"~e.13)))) :op2 (a3 / activate-01~e.22 :ARG1 (e / enzyme :name (n3 / name :op1 "PI"~e.18 :op2 "3-kinase"~e.19,21)))))))) :mod (a4 / also~e.1)) # ::id bel_pmid_1129_7520.6398 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The reintroduction of wild @-@ type LKB1 into a cancer cell line that lacks LKB1 suppressed growth , but mutants of LKB1 in which Ser( 431 ) was mutated to Ala to prevent phosphorylation of LKB1 were ineffective in inhibiting growth . # ::alignments 3-1.1.1.1.2 5-1.1.1.1.2 6-1.1.1.1.1.1 9-1.1.1.2.2.2.1 10-1.1.1.2 11-1.1.1.2 13-1.1.1.2.1 14-1.1.1.2.1.1.1.1 15-1.1 16-1.1.2 18-1 19-1.2.2 19-1.2.2.3 19-1.2.2.3.r 21-1.2.2.1.1 25-1.2.2.2.1 28-1.2.2.2.3 29-1.2.2.2.3.1.r 30-1.2.2.2.3.1.1.1 32-1.2.2.2.3.2 33-1.2.2.2.3.2.1 35-1.2.2.1.1 37-1.2 37-1.2.1 37-1.2.1.r 38-1.2.3.r 39-1.2.3 40-1.2.3.2 (c / contrast-01~e.18 :ARG1 (s / suppress-01~e.15 :ARG0 (r / reintroduce-01 :ARG1 (e / enzyme :name (n / name :op1 "LKB1"~e.6) :mod (w / wild-type~e.3,5)) :ARG2 (c4 / cell-line~e.10,11 :ARG0-of (l2 / lack-01~e.13 :ARG1 (e3 / enzyme :name (n4 / name :op1 "LKB1"~e.14))) :mod (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.9)))) :ARG1 (g / grow-01~e.16)) :ARG2 (e2 / effective-04~e.37 :polarity~e.37 -~e.37 :ARG0 (e4 / enzyme~e.19 :name (n5 / name :op1 "LKB1"~e.21,35) :part (a / amino-acid :mod 431~e.25 :name (n2 / name :op1 "serine") :ARG1-of (m2 / mutate-01~e.28 :ARG2~e.29 (a2 / amino-acid :name (n3 / name :op1 "Ala"~e.30)) :ARG0-of (p / prevent-01~e.32 :ARG1 (p2 / phosphorylate-01~e.33 :ARG1 e)))) :ARG1-of~e.19 (m / mutate-01~e.19)) :ARG1~e.38 (i / inhibit-01~e.39 :ARG0 e4 :ARG1 g~e.40))) # ::id bel_pmid_1129_7520.22158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We present pharmacological and genetic evidence that p90( RSK ) mediated this phosphorylation in response to agonists that activate ERK1 @/@ 2 and that cAMP @-@ dependent protein kinase mediated this phosphorylation in response to agonists that activate adenylate cyclase # ::alignments 0-1.1 1-1 2-1.2.3 3-1.2.1 4-1.2.2 5-1.2 8-1.2.1.1.1.1.2 10-1.2.1.1 11-1.2.1.1.2.1 12-1.2.1.1.2 14-1.2.1.1.3 18-1.2.1.1.3.1.1 19-1.2.1.1.3.1.1.1.1.1 21-1.2.1.1.3.1.1.1.1.1 22-1.2.1 23-1.2.1.r 24-1.2.1.2.1.2.1.1.1 26-1.2.1.2.1 26-1.2.1.2.1.2 26-1.2.1.2.1.2.r 27-1.2.1.2.1.1.1 28-1.2.1.2.1.1.2 29-1.2.1.1 29-1.2.1.2 30-1.2.1.2.2 31-1.2.1.2.2 32-1.2.1.2.3.r 33-1.2.1.2.3 37-1.2.1.2.3.1.1 38-1.2.1.2.3.1.1.1.1.1 39-1.2.1.2.3.1.1.1.1.2 (p / present-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / evidence-01~e.5 :ARG1~e.23 (a / and~e.3,22 :op1 (m / mediate-01~e.10,29 :ARG0 (p7 / protein :name (n8 / name :op1 "p90" :op2 "RSK"~e.8)) :ARG1 (p4 / phosphorylate-01~e.12 :mod (t / this~e.11)) :ARG2-of (r / respond-01~e.14 :ARG1 (a5 / agonist :ARG0-of (a2 / activate-01~e.18 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"~e.19,21)))))) :op2 (m3 / mediate-01~e.29 :ARG0 (e3 / enzyme~e.26 :name (n4 / name :op1 "protein"~e.27 :op2 "kinase"~e.28) :ARG0-of~e.26 (d / depend-01~e.26 :ARG1 (s / small-molecule :name (n / name :op1 "cAMP"~e.24)))) :ARG1 p4~e.30,31 :ARG2-of~e.32 (r2 / respond-01~e.33 :ARG1 (a4 / agonist :ARG0-of (a3 / activate-01~e.37 :ARG1 (e4 / enzyme :name (n6 / name :op1 "adenylate"~e.38 :op2 "cyclase"~e.39))))))) :mod (g / genetics~e.4) :mod (p2 / pharmacology~e.2))) # ::id bel_pmid_1129_7530.22688 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblot analysis of extracts from control and HT15 cells showed an increase in the activated forms of ERK1 @/@ 2 in the Sod2 @-@ overexpressing cells that was reversed upon coexpression of catalase ( Fig . 5A ) . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1 3-1.1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.1.r 5-1.1.1.1.1.1 6-1.1 7-1.1.2.1.1 8-1.1.2 9-1 11-1.2 12-1.2.1.r 14-1.2.1.2 17-1.2.1.1.1 19-1.2.1.1.1 20-1.2.2.r 22-1.2.2.1.1.1.1 24-1.2.2.1 25-1.2.2 28-1.2.3 32-1.2.3.1.1.1.1 34-1.3.1 36-1.3.1.1 (s / show-01~e.9 :ARG0 (a / and~e.6 :op1 (a2 / analyze-01~e.1 :ARG1~e.2 (t / thing~e.3 :ARG1-of~e.3 (e / extract-01~e.3 :ARG2~e.4 (c / control~e.5))) :manner (i / immunoblot-01~e.0)) :op2 (c2 / cell-line~e.8 :name (n / name :op1 "HT15"~e.7))) :ARG1 (i2 / increase-01~e.11 :ARG1~e.12 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.17,19) :ARG1-of (a3 / activate-01~e.14)) :location~e.20 (c3 / cell~e.25 :location-of (o / overexpress-01~e.24 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Sod2"~e.22)))) :ARG1-of (r / reverse-01~e.28 :ARG0 (c4 / coexpress-01 :ARG2 (e4 / enzyme :name (n4 / name :op1 "catalase"~e.32))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.34 :mod "5A"~e.36))) # ::id bel_pmid_1129_7530.22690 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of IL @-@ 1a levels in Sod2 @-@ overexpressing cells showed a 3 @-@ fold increase in basal IL @-@ 1a levels that was reversed when catalase was coexpressed in these cell lines ( Fig . 2A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1 6-1.1.2.r 7-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2 11-1 13-1.2.2.1 15-1.2.2 16-1.2 17-1.2.1.r 18-1.2.1.1 19-1.2.1.2 20-1.2.1.2 21-1.2.1.2 22-1.2.1 25-1.2.3 26-1.2.3.1.r 27-1.2.3.1.1.1.1 31-1.2.3.1.2.1 32-1.2.3.1.2 33-1.2.3.1.2 35-1.3.1 37-1.3.1.1 (s / show-01~e.11 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (l / level~e.5 :quant-of (p / protein :name (n / name :op1 "IL-1a"~e.2,4))) :location~e.6 (c / cell~e.10 :location-of (o / overexpress-01~e.9 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Sod2"~e.7))))) :ARG1 (i / increase-01~e.16 :ARG1~e.17 (l2 / level~e.22 :mod (b / basal~e.18) :quant-of p~e.19,20,21) :ARG2 (p3 / product-of~e.15 :op1 3~e.13) :ARG1-of (r / reverse-01~e.25 :time~e.26 (c2 / coexpress-01 :ARG2 (e / enzyme :name (n4 / name :op1 "catalase"~e.27)) :ARG3 (c4 / cell-line~e.32,33 :mod (t / this~e.31))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "2A"~e.37))) # ::id bel_pmid_1129_7530.24362 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , a 15 @-@ fold increase in Sod2 levels , which is well within the range of activity observed in response to cytokines and growth factors , can enhance MMP @-@ 1 expression in an H2O2 @-@ dependent fashion . # ::alignments 0-1 3-1.1.1.1.2.1 5-1.1.1.1.2 6-1.1.1.1 7-1.1.1.1.1.r 8-1.1.1.1.1.1.1.1 9-1.1.1.1.1 13-1.1.1.1.3.3 14-1.1.1.1.1.1.r 16-1.1.1.1.3 17-1.1.1.1.3.1.r 18-1.1.1.1.3.1 19-1.1.1.1.3.2 20-1.1.1.1.3.2.1.r 21-1.1.1.1.3.2.1 22-1.1.1.1.3.2.1.1.r 23-1.1.1.1.3.2.1.1.1 24-1.1.1.1.3.2.1.1 25-1.1.1.1.3.2.1.1.2 26-1.1.1.1.3.2.1.1.2 28-1.1 29-1.1.1 30-1.1.1.2.1.1.1 32-1.1.1.2.1.1.1 33-1.1.1.2 34-1.1.1.3.r 36-1.1.1.3.2.1.1 38-1.1.1.3 (c / cause-01~e.0 :ARG1 (p / possible-01~e.28 :ARG1 (e / enhance-01~e.29 :ARG0 (i / increase-01~e.6 :ARG1~e.7 (l / level~e.9 :quant-of~e.14 (e2 / enzyme :name (n / name :op1 "Sod2"~e.8))) :ARG2 (p2 / product-of~e.5 :op1 15~e.3) :part-of (r / range-01~e.16 :ARG1~e.17 (a / activity-06~e.18) :ARG1-of (o / observe-01~e.19 :ARG2-of~e.20 (r2 / respond-01~e.21 :ARG1~e.22 (a2 / and~e.24 :op1 (c2 / cytokine~e.23) :op2 (g / growth-factor~e.25,26)))) :degree (w / well~e.13))) :ARG1 (e3 / express-03~e.33 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MMP-1"~e.30,32))) :manner~e.34 (d / depend-01~e.38 :ARG0 e3 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "H2O2"~e.36)))))) # ::id bel_pmid_1129_7530.24364 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In support of this hypothesis , the gelatinolytic activity of MMP @-@ 2 and the mRNA levels of MMP @-@ 3 and MMP @-@ 7 were increased in the Sod2 overexpressors compared with control cell lines ( Fig . 5C , left panel ) . # ::alignments 1-1 2-1.2.r 3-1.2.1 4-1.2 8-1.1.1.1 9-1.1.1.1.1.r 10-1.1.1.1.1.1.1 12-1.1.1.1.1.1.1 13-1.1.1 15-1.1.1.2.1.1.1 16-1.1.1.2 18-1.1.1.2.1.2.1.1.1.1 20-1.1.1.2.1.2.1.1.1.1 21-1.1.1.2.1.2.1 22-1.1.1.2.1.2.1.1.1.1 22-1.1.1.2.1.2.1.2.1.1 24-1.1.1.2.1.2.1.2.1.1 26-1.1 27-1.1.2.r 29-1.1.2.1.1.1.1 31-1.1.2.2.r 33-1.1.2.2.1 34-1.1.2 34-1.1.2.2 35-1.1.2.2 37-1.3.1 39-1.3.1.1 41-1.3.1.2.1 42-1.3.1.2 (s / support-01~e.1 :ARG0 (i / increase-01~e.26 :ARG1 (a / and~e.13 :op1 (a2 / activity-06~e.8 :ARG0~e.9 (e / enzyme :name (n / name :op1 "MMP-2"~e.10,12)) :ARG1 (g / gelatinolysis)) :op2 (l / level~e.16 :quant-of (n6 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.15) :ARG0-of (e4 / encode-01 :ARG1 (a3 / and~e.21 :op1 (e2 / enzyme :name (n2 / name :op1 "MMP-3"~e.18,20,22)) :op2 (e3 / enzyme :name (n3 / name :op1 "MMP-7"~e.22,24))))))) :location~e.27 (c3 / cell-line~e.34 :location-of (o / overexpress-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "Sod2"~e.29))) :compared-to~e.31 (c4 / cell-line~e.34,35 :ARG2-of (c2 / control-01~e.33)))) :ARG1~e.2 (h / hypothesize-01~e.4 :mod (t / this~e.3)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.37 :mod "5C"~e.39 :location (p / panel~e.42 :ARG1-of (l2 / left-20~e.41))))) # ::id bel_pmid_1129_7530.24366 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The observed decline in MMP @-@ 9 activity in the HT15 cell line may represent a negative regulatory aspect of Sod2 in MMP expression . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.2.r 10-1.1.1.1.2.1.1 11-1.1.1.1.2 12-1.1.1.1.2 13-1 14-1.1 16-1.1.2.1 17-1.1.2.1 18-1.1.2 19-1.1.2.1.1.r 20-1.1.2.1.1.1.1 21-1.1.2.1.2.r 22-1.1.2.1.2.1.1.1 23-1.1.2.1.2 (p / possible-01~e.13 :ARG1 (r / represent-01~e.14 :ARG0 (d / decline-01~e.2 :ARG1~e.3 (a / activity-06~e.7 :ARG0 (e / enzyme :name (n / name :op1 "MMP-9"~e.4,6)) :location~e.8 (c2 / cell-line~e.11,12 :name (n5 / name :op1 "HT15"~e.10))) :ARG1-of (o / observe-01~e.1)) :ARG1 (a2 / aspect~e.18 :ARG0-of (d2 / downregulate-01~e.16,17 :ARG2~e.19 (e2 / enzyme :name (n3 / name :op1 "Sod2"~e.20)) :topic~e.21 (e3 / express-03~e.23 :ARG2 (e4 / enzyme :name (n4 / name :op1 "MMP"~e.22))))))) # ::id bel_pmid_1129_7530.28094 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The induction of MMP @-@ 13 by IL @-@ 1a and phorbol myristate acetate was severely impaired in the Sod2-/+ fibroblasts compared with the Sod2+/+ fibroblasts ( Fig . 3 , A and B ) . # ::alignments 1-1.1 2-1.1.2.r 3-1.1.2.1.1 5-1.1.2.1.1 6-1.1.1.r 7-1.1.1.1.1.1 9-1.1.1.1.1.1 10-1.1.1 11-1.1.1.2.1.1 12-1.1.1.2.1.2 13-1.1.1.2.1.3 15-1.4 16-1 20-1.2 20-1.5 21-1.5.r 25-1.2 27-1.3.1.1 27-1.3.1.2 32-1.3.1 (i / impair-01~e.16 :ARG1 (i2 / induce-01~e.1 :ARG0~e.6 (a / and~e.10 :op1 (p / protein :name (n2 / name :op1 "IL-1a"~e.7,9)) :op2 (s2 / small-molecule :name (n3 / name :op1 "phorbol"~e.11 :op2 "myristate"~e.12 :op3 "acetate"~e.13))) :ARG2~e.2 (e / enzyme :name (n / name :op1 "MMP-13"~e.3,5))) :location (f / fibroblast~e.20,25 :mod (e2 / enzyme :name (n4 / name :op1 "Sod2") :ARG2-of (m2 / mutate-01 :mod "-/+"))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.32 :op1 (f3 / figure~e.27 :mod "3A") :op2 (f4 / figure~e.27 :mod "3B"))) :degree (s / severe~e.15) :compared-to~e.21 (f2 / fibroblast~e.20 :mod (e3 / enzyme :name (n5 / name :op1 "Sod2") :mod (w / wild-type)))) # ::id bel_pmid_1129_7530.30812 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the wild @-@ type MEFs responded to the induction of MMP @-@ 13 by TNF , whereas the heterozygotes did not . # ::alignments 1-1.1.1.2 3-1.1.1.2 4-1.1.1.1.1 5-1.1 5-1.2 6-1.1.2.r 8-1.1.2 9-1.1.2.2.r 10-1.1.2.2.1.1 12-1.1.2.2.1.1 13-1.1.2.1.r 14-1.1.2.1.1.1 16-1 20-1.2.1 20-1.2.1.r (c / contrast-01~e.16 :ARG1 (r / respond-01~e.5 :ARG0 (c2 / cell :name (n / name :op1 "MEF"~e.4) :mod (w / wild-type~e.1,3)) :ARG1~e.6 (i / induce-01~e.8 :ARG0~e.13 (p2 / protein :name (n3 / name :op1 "TNF"~e.14)) :ARG2~e.9 (e / enzyme :name (n2 / name :op1 "MMP-13"~e.10,12)))) :ARG2 (r2 / respond-01~e.5 :polarity~e.20 -~e.20 :ARG0 (h / heterozygote) :ARG1 i)) # ::id bel_pmid_1129_7548.19988 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the growth factors epidermal growth factor ( EGF ) and neuregulin ( NRG ) 1 similarly stimulated Erk1 @/@ 2 in MDA @-@ MB @-@ 361 cells , EGF acting through an EGF receptor @/@ ErbB2 heterodimer preferentially stimulated protein kinase C , and NRG1 beta acting through an ErbB2 @/@ ErbB3 heterodimer preferentially stimulated Akt . # ::alignments 0-1 2-1.2.1 3-1.2.1 4-1.2.1.1.1.1.1 5-1.2.1.1.1.1.2 6-1.2.1.1.1.1.3 8-1.1.1.1.1.1 10-1.2.1.1 11-1.2.1.1.2.1.1 15-1.2.1.1.2.1.2 16-1.2.3 17-1.2 18-1.2.2.1.1 20-1.2.2.1.1 21-1.2.4.r 22-1.2.4.1.1 24-1.2.4.1.1 26-1.2.4.1.1 27-1.2.4 29-1.1.1.1.1.1 30-1.1.1.1.2 33-1.1.1.1.1.1 36-1.1.1.1.2.1.1.1.1 37-1.1.1.1.2.1 38-1.1.1.3 39-1.1.1 39-1.1.2 40-1.1.1.2.1.1 41-1.1.1.2.1.2 42-1.1.1.2.1.3 47-1.1.1.1.2 47-1.1.2.1.2 50-1.1.2.1.2.1.3 52-1.1.2.1.2.1.2.1.1 53-1.1.2.1.2.1.1.1 54-1.1.1.3 55-1.1.1 56-1.1.2.2.1.1 (h / have-concession-91~e.0 :ARG1 (a2 / and :op1 (s2 / stimulate-01~e.39,55 :ARG0 (p3 / protein :name (n5 / name :op1 "EGF"~e.8,29,33) :ARG0-of (a3 / act-01~e.30,47 :instrument (h2 / heterodimer~e.37 :part (p4 / protein :name (n7 / name :op1 "ErbB2"~e.36))))) :ARG1 (e2 / enzyme :name (n8 / name :op1 "protein"~e.40 :op2 "kinase"~e.41 :op3 "C"~e.42)) :ARG1-of (p5 / prefer-01~e.38,54)) :op2 (s3 / stimulate-01~e.39 :ARG0 (p6 / protein :name (n9 / name :op1 "NRG1beta") :ARG0-of (a4 / act-01~e.47 :instrument (m / macro-molecular-complex :name (n13 / name :op1 "heterodimer"~e.53) :part (p8 / protein :name (n11 / name :op1 "ErbB3"~e.52)) :part p4~e.50))) :ARG1 (e3 / enzyme :name (n14 / name :op1 "Akt"~e.56)) :ARG1-of p5)) :ARG2 (s / stimulate-01~e.17 :ARG0 (g / growth-factor~e.2,3 :example (a / and~e.10 :op1 (p / protein :name (n / name :op1 "epidermal"~e.4 :op2 "growth"~e.5 :op3 "factor"~e.6)) :op2 (p2 / protein :name (n2 / name :op1 "neuregulin"~e.11 :op2 1~e.15)))) :ARG1 (e / enzyme :name (n3 / name :op1 "Erk1/2"~e.18,20)) :manner (r / resemble-01~e.16) :location~e.21 (c / cell~e.27 :name (n4 / name :op1 "MDA-MB-361"~e.22,24,26)))) # ::id bel_pmid_1129_7548.24054 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In MDA @-@ MB @-@ 453 cells , NRG1 beta acting through an ErbB2 @/@ ErbB3 heterodimer stimulated prolonged signaling of all pathways examined relative to NRG2 beta acting through the same heterodimeric receptor species . Surprisingly , NRG1 beta and NRG2 beta also regulated partially overlapping but distinct sets of genes in these cells . # ::alignments 1-1.1.4.1.1 3-1.1.4.1.1 5-1.1.4.1.1 6-1.1.4 10-1.1.1.2 13-1.1.1.2.1.1.1.1 15-1.1.1.2.1.2.1.1 16-1.1.1.2.1 16-1.1.3.1.2.1.1.2 17-1.1 18-1.1.2.2 19-1.1.2 20-1.1.2.1.r 21-1.1.2.1.1 22-1.1.2.1 23-1.1.2.1.2 24-1.1.3 28-1.1.3.1.2 31-1.1.3.1.2.1.1.1 33-1.1.3.1.2.1.1 34-1.1.3.1.2.1 36-1.2.4 40-1.2.1 43-1.2.5 44-1.2 45-1.2.2.2.1 45-1.2.2.2.1.r 46-1.2.2.2 47-1.2.2.2.2 48-1.2.2.2.2.1 49-1.2.2 50-1.2.2.1.r 51-1.2.2.1 52-1.2.3.r 53-1.2.3.1 54-1.2.3 (m / multi-sentence :snt1 (s / stimulate-01~e.17 :ARG0 (p / protein :name (n / name :op1 "NRG1beta") :ARG0-of (a / act-01~e.10 :instrument (h / heterodimer~e.16 :part (p2 / protein :name (n3 / name :op1 "ErbB2"~e.13)) :part (p3 / protein :name (n4 / name :op1 "ErbB3"~e.15))))) :ARG1 (s2 / signal-07~e.19 :ARG0~e.20 (p5 / pathway~e.22 :mod (a2 / all~e.21) :ARG1-of (e / examine-01~e.23)) :ARG1-of (p4 / prolong-01~e.18)) :ARG1-of (r / relative-05~e.24 :ARG3 (p6 / protein :name (n5 / name :op1 "NRG2beta") :ARG0-of (a3 / act-01~e.28 :instrument (s3 / specie~e.34 :mod (r2 / receptor~e.33 :ARG1-of (s5 / same-01~e.31) :mod (h2 / heterodimer~e.16)))))) :location (c / cell~e.6 :name (n7 / name :op1 "MDA-MB-453"~e.1,3,5))) :snt2 (r3 / regulate-01~e.44 :ARG0 (a4 / and~e.40 :op1 (p7 / protein :name (n8 / name :op1 "NRG1beta")) :op2 (p8 / protein :name (n9 / name :op1 "NRG2beta"))) :ARG1 (s4 / set~e.49 :mod~e.50 (g / gene~e.51) :ARG0-of (o / overlap-01~e.46 :degree~e.45 (p9 / part~e.45) :ARG1-of (c3 / contrast-01~e.47 :ARG2 (d / distinct~e.48 :domain s4)))) :location~e.52 (c2 / cell~e.54 :mod (t / this~e.53)) :ARG0-of (s6 / surprise-01~e.36) :mod (a5 / also~e.43))) # ::id bel_pmid_1129_7548.24056 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , EGF preferentially stimulated the recruitment of the adaptor protein Grb2 to EGF receptor whereas NRG1 beta preferentially stimulated the recruitment of this protein to ErbB3 . NRG1 beta also preferentially stimulated the association of p85 , the 85 @-@ kDa subunit of PI3K , with ErbB3 , as demonstrated previously ( 40 ) . # ::alignments 0-1.2.5.1.r 1-1.1.3 3-1.1.1.1.1.1 4-1.1.1.3 5-1.1.1 7-1.1.1.2 8-1.1.1.2.1.r 10-1.1.1.2.1.2 11-1.1.1.2.1 12-1.1.1.2.1.1.1 13-1.1.1.2.2.r 14-1.1.1.2.2.1.1 15-1.1.1.2.2.1.2 16-1.1 19-1.1.1.3 20-1.1.1 20-1.1.2 22-1.1.2.2 25-1.1.1.1 25-1.1.2.1 25-1.1.2.2.2 25-1.2.1 25-1.2.2.1 25-1.2.2.2 27-1.1.2.2.2.1.1 27-1.2.2.2.1.1 31-1.2.3 32-1.2.4 33-1.2 35-1.2.2 37-1.2.2.1.1.1 40-1.2.2.1.2.1.2.1 42-1.2.2.1.2.1.2.2 45-1.2.2.1.2.1.1.1 48-1.2.2.2.1.1 50-1.2.5.1.r 51-1.2.5 52-1.2.5.1 54-1.2.6.1.1.1 (m / multi-sentence :snt1 (c / contrast-01~e.16 :ARG1 (s / stimulate-01~e.5,20 :ARG0 (p / protein~e.25 :name (n / name :op1 "EGF"~e.3)) :ARG1 (r / recruit-01~e.7 :ARG1~e.8 (p4 / protein~e.11 :name (n2 / name :op1 "Grb2"~e.12) :mod (a / adaptor~e.10)) :ARG2~e.13 (e3 / enzyme :name (n8 / name :op1 "EGF"~e.14 :op2 "receptor"~e.15))) :ARG1-of (p2 / prefer-01~e.4,19)) :ARG2 (s2 / stimulate-01~e.20 :ARG0 (p3 / protein~e.25 :name (n4 / name :op1 "NRG1beta")) :ARG1 (r3 / recruit-01~e.22 :ARG1 p4 :ARG2 (p5 / protein~e.25 :name (n5 / name :op1 "ErbB3"~e.27))) :ARG1-of p2) :ARG1-of (e / expect-01~e.1)) :snt2 (s3 / stimulate-01~e.33 :ARG0 (p7 / protein~e.25 :name (n6 / name :op1 "NRG1beta")) :ARG1 (a3 / associate-01~e.35 :ARG1 (p8 / protein-segment~e.25 :name (n7 / name :op1 "p85"~e.37) :ARG1-of (m2 / mean-01 :ARG2 (e2 / enzyme :name (n9 / name :op1 "PI3K"~e.45) :quant (m3 / mass-quantity :quant 85~e.40 :unit (k / kilodalton~e.42))))) :ARG2 (p11 / protein~e.25 :name (n10 / name :op1 "ErbB3"~e.27,48))) :mod (a2 / also~e.31) :ARG1-of (p6 / prefer-01~e.32) :ARG1-of (d / demonstrate-01~e.51 :time~e.0,50 (p12 / previous~e.52)) :ARG1-of (d2 / describe-01 :ARG0 (p13 / publication :ARG1-of (c2 / cite-01 :ARG2 40~e.54))))) # ::id bel_pmid_1129_7548.38074 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the growth factors epidermal growth factor ( EGF ) and neuregulin ( NRG ) 1 similarly stimulated Erk1 @/@ 2 in MDA @-@ MB @-@ 361 cells , EGF acting through an EGF receptor @/@ ErbB2 heterodimer preferentially stimulated protein kinase C , and NRG1 beta acting through an ErbB2 @/@ ErbB3 heterodimer preferentially stimulated Akt . # ::alignments 0-1 2-1.2.1 3-1.2.1 4-1.2.1.1.1.1.1 5-1.2.1.1.1.1.2 6-1.2.1.1.1.1.3 8-1.1.1.1.1.1 10-1.2.1.1 11-1.2.1.1.2.1.1 15-1.2.1.1.2.1.2 16-1.2.3 17-1.2 18-1.2.2.1.1 20-1.2.2.1.1 21-1.2.4.r 22-1.2.4.1.1 24-1.2.4.1.1 26-1.2.4.1.1 27-1.2.4 29-1.1.1.1.1.1 30-1.1.1.1.2 33-1.1.1.1.1.1 33-1.1.1.1.2.1.2.1.1 34-1.1.1.1.2.1.2.1.2 36-1.1.1.1.2.1.1.1.1 37-1.1.1.1.2.1 37-1.1.2.1.2.1 38-1.1.1.3 39-1.1.1 39-1.1.2 40-1.1.1.2.1.1 41-1.1.1.2.1.2 42-1.1.1.2.1.3 47-1.1.1.1.2 47-1.1.2.1.2 50-1.1.2.1.2.1.2 52-1.1.2.1.2.1.1.1.1 53-1.1.1.1.2.1 54-1.1.1.3 55-1.1.1 56-1.1.2.2.1.1 (h / have-concession-91~e.0 :ARG1 (a / and :op1 (s / stimulate-01~e.39,55 :ARG0 (p / protein :name (n / name :op1 "EGF"~e.8,29,33) :ARG0-of (a2 / act-01~e.30,47 :instrument (h2 / heterodimer~e.37,53 :part (p2 / protein :name (n4 / name :op1 "ErbB2"~e.36)) :part (p7 / protein :name (n3 / name :op1 "EGF"~e.33 :op2 "receptor"~e.34))))) :ARG1 (e / enzyme :name (n5 / name :op1 "protein"~e.40 :op2 "kinase"~e.41 :op3 "C"~e.42)) :ARG1-of (p3 / prefer-01~e.38,54)) :op2 (s2 / stimulate-01~e.39 :ARG0 (p4 / protein :name (n6 / name :op1 "NRG1beta") :ARG0-of (a3 / act-01~e.47 :instrument (h3 / heterodimer~e.37 :part (p6 / protein :name (n9 / name :op1 "ErbB3"~e.52)) :part p2~e.50))) :ARG1 (e2 / enzyme :name (n10 / name :op1 "Akt"~e.56)) :ARG1-of p3)) :ARG2 (s3 / stimulate-01~e.17 :ARG0 (g / growth-factor~e.2,3 :example (a4 / and~e.10 :op1 (p8 / protein :name (n11 / name :op1 "epidermal"~e.4 :op2 "growth"~e.5 :op3 "factor"~e.6)) :op2 (p9 / protein :name (n12 / name :op1 "neuregulin"~e.11 :op2 1~e.15)))) :ARG1 (e3 / enzyme :name (n13 / name :op1 "Erk1/2"~e.18,20)) :manner (r2 / resemble-01~e.16) :location~e.21 (c / cell~e.27 :name (n14 / name :op1 "MDA-MB-361"~e.22,24,26)))) # ::id bel_pmid_1131_3931.5286 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We find that Cdk10 binds full length Ets2 in vitro and in vivo and inhibits Ets2 transactivation in mammalian cells . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 4-1.2.1 5-1.2.1.2.2 6-1.2.1.2 7-1.2.1.2.1.1.1 8-1.2.1.3.1 9-1.2.1.3.1 10-1.2.1.3 11-1.2.1.3.1 11-1.2.1.3.2 12-1.2.1.3.2 13-1.2 13-1.2.1.3 14-1.2.2 15-1.2.2.2.1 16-1.2.2.2 17-1.2.1.3.1 17-1.2.2.2.2.r 18-1.2.2.2.2.1 19-1.2.2.2.2 (f3 / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (a3 / and~e.13 :op1 (b / bind-01~e.4 :ARG0 (e / enzyme :name (n / name :op1 "Cdk10"~e.3)) :ARG1 (l / length~e.6 :poss (p / protein :name (n2 / name :op1 "Ets2"~e.7)) :degree (f2 / full~e.5)) :manner (a2 / and~e.10,13 :op1 (i / in-vitro~e.8,9,11,17) :op2 (i2 / in-vivo~e.11,12))) :op2 (i3 / inhibit-01~e.14 :ARG0 e :ARG1 (t / transactivate-01~e.16 :ARG1 p~e.15 :location~e.17 (c / cell~e.19 :mod (m / mammal~e.18)))))) # ::id bel_pmid_1132_3411.1008 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistently , substrate @-@ trapping experiments with a SHP2 catalytic inactive mutant suggested that Gab1 was a SHP2 PTPase substrate in the cells . Therefore , Gab1 not only is a SHP2 activator but also is a target of its PTPase . # ::alignments 0-1.1.3 2-1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1.1 8-1.1.1.1.1.1.1.1.1 8-1.2.1.1.2.1.1 9-1.1.1.1.1.1.1.3.2 10-1.1.1.1.1.1.1.3.1 11-1.1.1.1.1.1.1 11-1.1.1.1.1.1.1.2 11-1.1.1.1.1.1.1.2.r 12-1.1 13-1.1.2.r 14-1.1.2.1.1.1 15-1.1.2.1.r 17-1.1.2.2.1.1 18-1.1.2.2.1.2 19-1.1.2 20-1.1.2.3.r 22-1.1.2.3 24-1.2 26-1.1.2.1.1.1 26-1.2.1.1.1.1.1 27-1.1.1.1.1.1.1.3.1 27-1.1.1.1.1.1.1.3.1.r 29-1.1.2.1.r 31-1.1.1.1.1.1.1.1.1 32-1.1.1.1.1.1.1.3 32-1.2.1.1 35-1.1.2.1.r 37-1.2.1.2 38-1.2.1.2.2.r 39-1.2.1.2.2 40-1.2.1.2.1.1.1 (m / multi-sentence :snt1 (s / suggest-01~e.12 :ARG0 (a / and :op1 (e / experiment-01~e.5 :ARG1 (s2 / substrate~e.2 :ARG1-of (t / trap-01~e.4 :ARG0 (e2 / enzyme~e.11 :name (n / name :op1 "SHP2"~e.8,31) :ARG2-of~e.11 (m2 / mutate-01~e.11) :ARG1-of (a2 / activate-01~e.32 :polarity~e.27 -~e.10,27 :mod (c / catalysis~e.9))))))) :ARG1~e.13 (s3 / substrate~e.19 :domain~e.15,29,35 (p / protein :name (n2 / name :op1 "Gab1"~e.14,26)) :mod (e3 / enzyme :name (n3 / name :op1 "SHP2"~e.17 :op2 "PTPase"~e.18)) :location~e.20 (c2 / cell~e.22)) :manner (c4 / consistent-02~e.0)) :snt2 (c3 / cause-01~e.24 :ARG1 (a3 / and :op1 (a4 / activate-01~e.32 :ARG0 (p2 / protein :name (n5 / name :op1 "Gab1"~e.26)) :ARG1 (e4 / enzyme :name (n4 / name :op1 "SHP2"~e.8))) :op2 (t2 / target-01~e.37 :ARG0 (e5 / enzyme :name (n6 / name :op1 "PTPase"~e.40) :part-of e4) :ARG1~e.38 p2~e.39)))) # ::id bel_pmid_1132_3411.6960 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that both Tyr @-@ 627 and Tyr @-@ 659 of Gab1 were required for SHP2 binding to Gab1 and for ERK2 activation by EGF . # ::alignments 0-1.1 1-1 4-1.2.2.1.2.1 4-1.2.2.2.2.1 6-1.2.2.1.1 8-1.2.2.1.2.1 8-1.2.2.2.2.1 10-1.2.2.2.1 12-1.2.2.2.3 14-1.2 15-1.2.1.r 16-1.2.1.1.1.1.1 17-1.2.1.1 18-1.2.1.1.2.r 19-1.2.1.1.2.1.1 20-1.2.1 22-1.2.1.2.2.1.1 23-1.2.1.2 24-1.2.1.2.1.r 25-1.2.1.2.1.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (r / require-01~e.14 :ARG0~e.15 (a4 / and~e.20 :op1 (b / bind-01~e.17 :ARG1 (e / enzyme :name (n4 / name :op1 "SHP2"~e.16)) :ARG2~e.18 (p2 / protein :name (n5 / name :op1 "Gab1"~e.19))) :op2 (a5 / activate-01~e.23 :ARG0~e.24 (p3 / protein :name (n6 / name :op1 "EGF"~e.25)) :ARG1 (e2 / enzyme :name (n7 / name :op1 "ERK2"~e.22)))) :ARG1 (a / and :op1 (a2 / amino-acid :mod 627~e.6 :name (n / name :op1 "tyrosine"~e.4,8) :part-of p2) :op2 (a3 / amino-acid :mod 659~e.10 :name (n3 / name :op1 "tyrosine"~e.4,8) :part-of p2~e.12)))) # ::id bel_pmid_1134_1776.3378 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We demonstrated that lung myofibroblasts , incubated in the presence of E2 , showed a rapid phosphorylation on serine @-@ 259 of Raf1 and tyrosine @-@ 204 of ERK1 @/@ 2 MAP kinase at 15 min , by approximately 3 @- and 5 @-@ fold , respectively # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1 6-1.2.1.2 7-1.2.1.2.1.r 9-1.2.1.2.1 10-1.2.1.2.1.1.r 11-1.2.1.2.1.1.1.1 13-1.2 15-1.2.2.1.3 16-1.2.2.1 16-1.2.2.2 17-1.2.2.1.1.r 18-1.2.2.1.1.2.1 20-1.2.2.1.1.1 21-1.2.2.1.2.r 21-1.2.2.1.4.1 22-1.2.2.1.2.1.1 23-1.2.2 24-1.2.2.2.1.2.1 26-1.2.2.2.1.1 27-1.2.2.2.2.r 28-1.2.2.2.2.1.1 30-1.2.2.2.2.1.1 31-1.2.2.2.2.1.2 32-1.2.2.2.2.1.3 34-1.2.2.4.1.1 35-1.2.2.4.1.2 38-1.2.2.1.4 38-1.2.2.2.3 39-1.2.2.1.4.1.1 41-1.2.2 42-1.2.2.2.3.1.1 44-1.2.2.1.4.1 44-1.2.2.2.3.1 46-1.2.2.3 (d / demonstrate-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (s / show-01~e.13 :ARG0 (m2 / myofibroblast :mod (l / lung~e.3) :ARG1-of (i / incubate-01~e.6 :condition~e.7 (p / present-02~e.9 :ARG1~e.10 (e / enzyme :name (n3 / name :op1 "E2"~e.11))))) :ARG1 (a / and~e.23,41 :op1 (p2 / phosphorylate-01~e.16 :ARG0~e.17 (a2 / amino-acid :mod 259~e.20 :name (n4 / name :op1 "serine"~e.18)) :ARG1~e.21 (e2 / enzyme :name (n5 / name :op1 "Raf1"~e.22)) :mod (r2 / rapid~e.15) :quant (a4 / approximately~e.38 :op1 (p4 / product-of~e.21,44 :op1 3~e.39))) :op2 (p3 / phosphorylate-01~e.16 :ARG0 (a3 / amino-acid :mod 204~e.26 :name (n6 / name :op1 "tyrosine"~e.24)) :ARG1~e.27 (e3 / enzyme :name (n7 / name :op1 "ERK1/2"~e.28,30 :op2 "MAP"~e.31 :op3 "kinase"~e.32)) :quant (a5 / approximately~e.38 :op1 (p5 / product-of~e.44 :op1 5~e.42))) :mod (r / respective~e.46) :time (a6 / after :quant (t / temporal-quantity :quant 15~e.34 :unit (m / minute~e.35)))))) # ::id bel_pmid_1135_0938.21662 ::amr-annotator SDL-AMR-09 ::preferred # ::tok since in PKR @-@ null MEFs there is a marked defect in Erk1 and Erk2 activation by PDGF ( Figure1D ) , it appears that PKR is involved in serine phosphorylation of Stat3 through the activation of Erks . # ::alignments 0-1.2 1-1.2.1.1.r 2-1.2.1.4.2.1.1.1 4-1.2.1.4.2.1 4-1.2.1.4.2.1.2 4-1.2.1.4.2.1.2.1 4-1.2.1.4.2.1.2.1.r 4-1.2.1.4.2.1.2.r 5-1.2.1.4.1.1 9-1.2.1.2 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.2.1.1.1 13-1.2.1.1.2 14-1.2.1.1.2.2.1.1 15-1.2.1.1 16-1.2.1.1.1.r 17-1.2.1.1.1.1.1 23-1 24-1.1.r 25-1.1.1.1.1 27-1.1 28-1.1.2.r 28-1.2.1.1.r 29-1.1.2.1.1.1 30-1.1.2 32-1.1.2.1.2.1.1 35-1.1.2.2 (a / appear-02~e.23 :ARG1~e.24 (i / involve-01~e.27 :ARG0 (e / enzyme :name (n / name :op1 "PKR"~e.25)) :ARG2~e.28 (p / phosphorylate-01~e.30 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "serine"~e.29) :part-of (p2 / protein :name (n2 / name :op1 "Stat3"~e.32))) :ARG2 (a2 / activate-01~e.35 :ARG1 a5))) :ARG1-of (c / cause-01~e.0 :ARG0 (d / defect~e.10 :prep-in~e.1,11,28 (a4 / activate-01~e.15 :ARG0~e.16 (p3 / protein :name (n5 / name :op1 "PDGF"~e.17)) :ARG1 (a5 / and~e.13 :op1 (e3 / enzyme :name (n6 / name :op1 "Erk1"~e.12)) :op2 (e4 / enzyme :name (n7 / name :op1 "Erk2"~e.14)))) :mod (m2 / marked~e.9) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "1D")) :location (c2 / cell :name (n8 / name :op1 "MEF"~e.5) :ARG3-of (e6 / express-03 :ARG2 (e5 / enzyme~e.4 :name (n9 / name :op1 "PKR"~e.2) :ARG2-of~e.4 (m / mutate-01~e.4 :mod~e.4 "-/-"~e.4))))))) # ::id bel_pmid_1135_0938.21664 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whereas PKR+/+ cells exhibited a clear induction in phospho @-@ Ser727 Stat3 , PKR @-@ null cells were defective in this process ( Figure1B ) # ::alignments 0-1 2-1.1.2 2-1.2.1 3-1.1 3-1.2 5-1.2.2.2 6-1.1.3 6-1.2.2 8-1.1.3.1 8-1.2.2.1 11-1.2.2.1.1.3.1.1 13-1.1.2.1.1.1.1 13-1.2.1.1.1.1.1 15-1.1.2.1.1 15-1.1.2.1.1.2 15-1.1.2.1.1.2.1 15-1.1.2.1.1.2.1.r 15-1.1.2.1.1.2.r 16-1.1.2 (c / contrast-01~e.0 :ARG1 (e3 / exhibit-01~e.3 :polarity - :ARG0 (c4 / cell~e.2,16 :ARG3-of (e5 / express-03 :ARG2 (e4 / enzyme~e.15 :name (n4 / name :op1 "PKR"~e.13) :ARG2-of~e.15 (m / mutate-01~e.15 :mod~e.15 "-/-"~e.15)))) :ARG1 (i2 / induce-01~e.6 :ARG2 (p3 / phosphorylate-01~e.8 :ARG1 a))) :ARG2 (e / exhibit-01~e.3 :ARG0 (c2 / cell~e.2 :ARG3-of (e6 / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "PKR"~e.13) :mod (w / wild-type)))) :ARG1 (i / induce-01~e.6 :ARG2 (p / phosphorylate-01~e.8 :ARG1 (a / amino-acid :mod 727 :name (n2 / name :op1 "serine") :part-of (p2 / protein :name (n3 / name :op1 "Stat3"~e.11)))) :ARG1-of (c3 / clear-06~e.5))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id bel_pmid_1135_0938.21666 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Accordingly , nuclear extracts prepared from PDGF @-@ treated PKR @- null cells were severely deficient in Stat3 containing DNA @-@ binding complexes compared with wild @-@ type MEFs ( data not shown ) . Taken together , we conclude that PDGF @-@ induced activation of Stat3 DNA binding is PKR dependent . # ::alignments 0-1.1.5 2-1.1.1.1 3-1.1.1 4-1.1.1.2 5-1.1.1.2.1.r 6-1.1.1.2.1.1.1.1.1 8-1.1.1.2.1.1 9-1.1.1.2.1.2.1.1.1 11-1.1.1.2.1.2.1 11-1.1.1.2.1.2.1.2 11-1.1.1.2.1.2.1.2.1 11-1.1.1.2.1.2.1.2.1.r 11-1.1.1.2.1.2.1.2.r 12-1.1.1.2.1 14-1.1.4 15-1.1.1.2.1.2.1 15-1.1.1.2.1.2.1.2 15-1.1.1.2.1.2.1.2.1 15-1.1.1.2.1.2.1.2.1.r 15-1.1.1.2.1.2.1.2.r 17-1.1.2.2.1.1.1 18-1.1.2.2 19-1.1.2.1.1.2.1 21-1.1.2.1 22-1.1.2 23-1.1.6.r 25-1.1.6.2 27-1.1.6.2 28-1.1.6.1.1 31-1.1.3.1 31-1.1.3.1.r 32-1.1.3 35-1.2.3 36-1.2.3.1 38-1.2.1 39-1.2 40-1.2.2.r 41-1.2.2.1.1.1.1 44-1.2.2.1 45-1.2.2.1.2.r 46-1.2.2.1.2.1.3.1.1 47-1.2.2.1.2.1.2.1 48-1.2.2.1.2 50-1.2.2.2.1.1 51-1.2.2 (m / multi-sentence :snt1 (l / lack-01 :ARG0 (e / extract~e.3 :mod (n / nucleus~e.2) :ARG1-of (p / prepare-01~e.4 :ARG2~e.5 (c / cell~e.12 :ARG1-of (t / treat-04~e.8 :ARG2 (p2 / protein :name (n2 / name :op1 "PDGF"~e.6))) :ARG2-of (e5 / express-03 :ARG1 (e2 / enzyme~e.11,15 :name (n3 / name :op1 "PKR"~e.9) :ARG2-of~e.11,15 (m4 / mutate-01~e.11,15 :mod~e.11,15 "-/-"~e.11,15)))))) :ARG1 (m3 / macro-molecular-complex~e.22 :ARG0-of (b / bind-01~e.21 :ARG1 (n9 / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA"~e.19))) :ARG0-of (c3 / contain-01~e.18 :ARG1 (p3 / protein :name (n4 / name :op1 "Stat3"~e.17)))) :ARG1-of (s / show-01~e.32 :polarity~e.31 -~e.31) :degree (s2 / severe~e.14) :manner (a2 / accordingly~e.0) :compared-to~e.23 (c2 / cell :name (n8 / name :op1 "MEF"~e.28) :mod (w2 / wild-type~e.25,27))) :snt2 (c4 / conclude-01~e.39 :ARG0 (w / we~e.38) :ARG1~e.40 (d2 / depend-01~e.51 :ARG0 (a / activate-01~e.44 :ARG0 (p4 / protein :name (n6 / name :op1 "PDGF"~e.41)) :ARG1~e.45 (b2 / bind-01~e.48 :ARG1 (n11 / nucleic-acid :wiki "DNA" :name (n12 / name :op1 "DNA"~e.47) :mod (p5 / protein :name (n7 / name :op1 "Stat3"~e.46))))) :ARG1 (e3 / enzyme :name (n5 / name :op1 "PKR"~e.50))) :ARG1-of (t2 / take-01~e.35 :mod (t3 / together~e.36)))) # ::id bel_pmid_1135_0938.26648 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PDGF treatment induced two Tyr705 @-@ phosphorylated forms of Stat3 in PKR+/+ cells , a faster migrating species termed Stat3 fm and a slower migrating species termed Stat3 sm ( Figure1A ) ..... Importantly , PDGF treatment did not induce either form of tyrosine @-@ phosphorylated Stat3 in PKR @-@ null cells ( Figure1A ) , implicating a requirement for PKR in both tyrosine and serine phosphorylation of Stat3 . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1 2-1.2 3-1.2.3.1 6-1.1.2.1.4.3 6-1.2.3.2.2.2 7-1.2.3 9-1.1.2.1.1.1 9-1.2.3.2.1.1 12-1.1.3 12-1.2.4 15-1.1.2.1.2.1 15-1.1.2.1.2.1.1 15-1.1.2.1.2.1.1.r 16-1.1.2.1.2 18-1.1.2.1.3 18-1.1.2.2.3 19-1.1.2.1.1.1 19-1.1.2.2.1.1 21-1.1.2 23-1.1.2.2.2.1 24-1.1.2.2.2 26-1.1.2.1.3 26-1.1.2.2.3 27-1.2.3.2.1.1 33-1.2.7 35-1.2.2.1.1.1 36-1.2.2 38-1.2.1 38-1.2.1.r 39-1.2 40-1.2.3.3 41-1.2.3 43-1.2.3.2.2.1.1 45-1.2.3.2.2.2 46-1.2.3.2.1.1 48-1.2.4.1.1.1.1 50-1.2.4.1.1 50-1.2.4.1.1.2 50-1.2.4.1.1.2.1 50-1.2.4.1.1.2.1.r 50-1.2.4.1.1.2.r 51-1.2.4 58-1.2.6.1 60-1.1.3.1.1.1.1 63-1.1.2.1.4.2.1 63-1.2.3.2.2.1.1 63-1.2.6.1.1.1.1.1.1 64-1.2.6.1.1.1 65-1.2.6.1.1.1.2.1.1 66-1.2.6.1.1 67-1.2.6.1.1.1.r 68-1.2.6.1.1.1.1.2.1.1 (m2 / multi-sentence :snt1 (i / induce-01~e.2 :ARG0 (t / treat-04~e.1 :ARG1 (p2 / protein :name (n2 / name :op1 "PDGF"~e.0))) :ARG2 (a2 / and~e.21 :op1 (p4 / protein :name (n5 / name :op1 "Stat3"~e.9,19) :ARG0-of (m3 / migrate-01~e.16 :ARG1-of (f2 / fast-02~e.15 :degree~e.15 (m4 / more~e.15))) :ARG1-of (t2 / term-01~e.18,26 :ARG3 (s2 / string-entity :value "Stat3fm")) :part (a3 / amino-acid :mod 705 :name (n4 / name :op1 "tyrosine"~e.63) :ARG1-of (p3 / phosphorylate-01~e.6))) :op2 (p5 / protein :name (n6 / name :op1 "Stat3"~e.19) :ARG0-of (m5 / migrate-01~e.24 :ARG1-of (s3 / slow-05~e.23 :degree (l / less))) :ARG1-of (t3 / term-01~e.18,26 :ARG3 (s / string-entity :value "Stat3sm")) :part a3)) :location (c / cell~e.12 :ARG2-of (e4 / express-03 :ARG1 (e / enzyme :name (n3 / name :op1 "PKR"~e.60) :mod (w / wild-type)))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "1A"))) :snt2 (i2 / induce-01~e.2,39 :polarity~e.38 -~e.38 :ARG0 (t4 / treat-04~e.36 :ARG1 (p6 / protein :name (n7 / name :op1 "PDGF"~e.35))) :ARG2 (f / form~e.7,41 :quant 2~e.3 :mod (p7 / protein :name (n8 / name :op1 "Stat3"~e.9,27,46) :part (a4 / amino-acid :name (n9 / name :op1 "tyrosine"~e.43,63) :ARG1-of (p8 / phosphorylate-01~e.6,45))) :mod (e2 / either~e.40)) :location (c2 / cell~e.12,51 :ARG2-of (e5 / express-03 :ARG1 (e3 / enzyme~e.50 :name (n10 / name :op1 "PKR"~e.48) :ARG2-of~e.50 (m / mutate-01~e.50 :mod~e.50 "-/-"~e.50)))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure :mod "1A")) :ARG0-of (i3 / imply-01 :ARG1 (r / require-01~e.58 :ARG0 (p9 / phosphorylate-01~e.66 :ARG1~e.67 (a / and~e.64 :op1 (a5 / amino-acid :name (n11 / name :op1 "tyrosine"~e.63) :part-of (p10 / protein :name (n13 / name :op1 "Stat3"~e.68))) :op2 (a6 / amino-acid :name (n12 / name :op1 "serine"~e.65) :part-of p10))) :ARG1 e3)) :mod (i4 / important~e.33))) # ::id bel_pmid_1135_0938.26650 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results ( Figure4A and B ) showed a 16 @-@ fold induction in PKR wild @-@ type cells in contrast to a 0.8 @-@ fold induction in c @-@ fos message in PKR @-@ null cells at 15 min of PDGF treatment # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 4-1.1.1.1.1 7-1 9-1.2.1.2.1 11-1.2.1.2 12-1.2.1 13-1.2.1.1.r 14-1.2.1.1.1.1.1.1 15-1.2.1.1.1.1.2 17-1.2.1.1.1.1.2 18-1.2.1.1 20-1.2 21-1.2.2.r 23-1.2.2.3.1 25-1.2.2.3 26-1.2.2 28-1.2.2.1.1.1.1 30-1.2.2.1.1.1.1 32-1.2.2.2.r 33-1.2.2.2.1.1.1.1 35-1.2.2.2.1.1 35-1.2.2.2.1.1.2 35-1.2.2.2.1.1.2.1 35-1.2.2.2.1.1.2.1.r 35-1.2.2.2.1.1.2.r 36-1.2.2.2 38-1.2.3.2.1 39-1.2.3.2.2 41-1.2.3.1.1.1.1 42-1.2.3.1 (s / show-01~e.7 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (r / result-01~e.1 :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.4 :op1 (f / figure :mod "4A") :op2 (f2 / figure :mod "4B"))))) :ARG1 (c / contrast-01~e.20 :ARG1 (i / induce-01~e.12 :location~e.13 (c2 / cell~e.18 :ARG3-of (e5 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "PKR"~e.14) :mod (w / wild-type~e.15,17)))) :mod (p2 / product-of~e.11 :op1 16~e.9)) :ARG2~e.21 (i2 / induce-01~e.26 :ARG1 (e4 / express-03 :ARG1 (g / gene :name (n4 / name :op1 "c-fos"~e.28,30))) :location~e.32 (c3 / cell~e.36 :ARG2-of (e3 / express-03 :ARG1 (e2 / enzyme~e.35 :name (n2 / name :op1 "PKR"~e.33) :ARG2-of~e.35 (m4 / mutate-01~e.35 :mod~e.35 "-/-"~e.35)))) :mod (p3 / product-of~e.25 :op1 0.8~e.23)) :time (a / after :op1 (t2 / treat-04~e.42 :ARG2 (p / protein :name (n3 / name :op1 "PDGF"~e.41))) :quant (t3 / temporal-quantity :quant 15~e.38 :unit (m2 / minute~e.39))))) # ::id bel_pmid_1135_0938.29866 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblotting with anti @-@ Stat3 as well as anti @-@ PKR anti bodies ( Figure2E ) showed an increase in interaction within 5 @-@ 15 min of treatment with the growth factor , followed by a decrease to below basal level at later time points . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 2-1.1.1.2.1 4-1.1.1.1.1.1.1.1 5-1.1.1 6-1.1.1 7-1.1.1 8-1.1.1.1.1 8-1.1.1.2.1 10-1.1.1.2.1.1.1.1 11-1.1.1.1.1 11-1.1.1.2.1 16-1 18-1.2 19-1.2.1.r 20-1.2.1 21-1.2.2 21-1.2.2.2.1.r 21-1.2.2.2.r 22-1.2.2.2.1.1 24-1.2.2.2.1.2 25-1.2.2.2.2 26-1.2.2.1.r 27-1.2.2.1 28-1.2.2.1.1.r 30-1.2.2.1.1 31-1.2.2.1.1 33-1.2.3 34-1.2.3.1.r 36-1.2.3.1 37-1.2.3.1.1.r 38-1.2.3.1.1 39-1.2.3.1.1.1.1 40-1.2.3.1.1.1 41-1.2.3.1.2.r 42-1.2.3.1.2 42-1.2.3.1.2.1 42-1.2.3.1.2.1.r 43-1.2.2.2 (s2 / show-01~e.16 :ARG0 (i / immunoblot-01~e.0 :ARG3~e.1 (a / and~e.5,6,7 :op1 (a2 / antibody :ARG0-of (c / counter-01~e.2,8,11 :ARG1 (p / protein :name (n2 / name :op1 "Stat3"~e.4)))) :op2 (a3 / antibody :ARG0-of (c2 / counter-01~e.2,8,11 :ARG1 (e / enzyme :name (n3 / name :op1 "PKR"~e.10))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2E"))) :ARG1 (i2 / increase-01~e.18 :ARG1~e.19 (i3 / interact-01~e.20) :time (a4 / after~e.21 :op1~e.26 (t / treat-04~e.27 :ARG2~e.28 (g / growth-factor~e.30,31)) :quant~e.21 (t2 / temporal-quantity~e.43 :quant~e.21 (b / between :op1 5~e.22 :op2 15~e.24) :unit (m2 / minute~e.25))) :ARG2-of (f2 / follow-01~e.33 :ARG1~e.34 (d2 / decrease-01~e.36 :ARG4~e.37 (b3 / below~e.38 :op1 (l2 / level~e.40 :mod (b2 / basal~e.39))) :time~e.41 (l / late~e.42 :degree~e.42 (m / more~e.42)))))) # ::id bel_pmid_1140_4390.9676 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The induction of TNF @-@ alpha production by NGF was blocked by K252a , an inhibitor of the TrkA receptor . # ::alignments 1-1.2 2-1.2.2.r 3-1.2.2.1.1.1 5-1.2.2.1.1.1 6-1.2.2 7-1.2.1.r 8-1.2.1.1.1 10-1 11-1.1.r 12-1.1.1.1 15-1.1 15-1.1.2 15-1.1.2.r 16-1.1.2.1.r 18-1.1.2.1.1.1 19-1.1.2.1 (b / block-01~e.10 :ARG0~e.11 (s / small-molecule~e.15 :name (n3 / name :op1 "K252a"~e.12) :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1~e.16 (r / receptor~e.19 :name (n4 / name :op1 "TrkA"~e.18)))) :ARG1 (i2 / induce-01~e.1 :ARG0~e.7 (p / protein :name (n / name :op1 "NGF"~e.8)) :ARG2~e.2 (p2 / produce-01~e.6 :ARG1 (p3 / protein :name (n2 / name :op1 "TNF-alpha"~e.3,5))))) # ::id bel_pmid_1140_4390.22028 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the role of TrkA in NGF 's effects , we used K252a , which inhibits the tyrosine kinase activity of this receptor . Pretreatment of the cells with K252a ( 50 ng/mL ) inhibited the production of TNF @-@ a by NGF # ::alignments 1-1.1.3 3-1.1.3.2 5-1.1.3.2.1.1.1 6-1.1.3.2.2.r 7-1.1.3.2.2.1.1.1.1 8-1.1.3.2.2.1.1.r 9-1.1.3.2.2 9-1.1.3.2.2.1 9-1.1.3.2.2.1.r 11-1.1.1 12-1.1 13-1.1.2.1.1 16-1.1.2 16-1.1.2.2 16-1.1.2.2.r 18-1.1.2.2.1.2.1.1 19-1.1.2.2.1.2.1.2 20-1.1.2.2.1 23-1.1.2.2.1.1 25-1.2.1 26-1.2.1.1.r 28-1.2.1.1 29-1.2.1.2.r 30-1.2.1.2.1.1 32-1.2.1.2.2.1 35-1.2 37-1.2.2 38-1.2.2.2.r 39-1.2.2.2.1.1 41-1.2.2.2.1.1 42-1.2.2.1.r 43-1.2.2.1.1.1 (m / multi-sentence :snt1 (u / use-01~e.12 :ARG0 (w / we~e.11) :ARG1 (s / small-molecule~e.16 :name (n / name :op1 "K252a"~e.13) :ARG0-of~e.16 (i / inhibit-01~e.16 :ARG1 (a / activity-06~e.20 :ARG0 r2~e.23 :ARG1 (e2 / enzyme :name (n9 / name :op1 "tyrosine"~e.18 :op2 "kinase"~e.19))))) :ARG2 (e / examine-01~e.1 :ARG0 w :ARG1 (r / role~e.3 :poss (r2 / receptor :name (n2 / name :op1 "TrkA"~e.5)) :topic~e.6 (t / thing~e.9 :ARG2-of~e.9 (a2 / affect-01~e.9 :ARG0~e.8 (p2 / protein :name (n3 / name :op1 "NGF"~e.7))))))) :snt2 (i2 / inhibit-01~e.35 :ARG0 (p / pretreat-01~e.25 :ARG1~e.26 (c / cell~e.28) :ARG3~e.29 (s2 / small-molecule :name (n5 / name :op1 "K252a"~e.30) :quant (m2 / mass-quantity :quant 50~e.32 :unit (n8 / nanogram-per-milliliter)))) :ARG1 (p3 / produce-01~e.37 :ARG0~e.42 (p4 / protein :name (n6 / name :op1 "NGF"~e.43)) :ARG1~e.38 (p5 / protein :name (n7 / name :op1 "TNF-a"~e.39,41))))) # ::id bel_pmid_1140_4390.29562 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NGF activates Erk1 @/@ Erk2 and JNK but not p38MAPK in J774 cells ... NGF also induced phosphorylation of JNK # ::alignments 0-1.2.1.1.1 1-1.1.1 1-1.1.2 2-1.1.1.2.1.1.1 4-1.1.1.2.2.1.1 5-1.1.1.2 6-1.1.1.2.3.1.1 7-1.1 8-1.1.2.1 8-1.1.2.1.r 9-1.1.2.3.1.1 10-1.1.1.3.r 11-1.1.1.3.1.1 12-1.1.1.3 14-1.1.1.1.1.1 14-1.2.1.1.1 15-1.2.3 16-1.2 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1.1.1 (m / multi-sentence :snt1 (c / contrast-01~e.7 :ARG1 (a / activate-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "NGF"~e.14)) :ARG1 (a3 / and~e.5 :op1 (e / enzyme :name (n2 / name :op1 "Erk1"~e.2)) :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2"~e.4)) :op3 (e3 / enzyme :name (n4 / name :op1 "JNK"~e.6))) :location~e.10 (c2 / cell-line~e.12 :name (n6 / name :op1 "J774"~e.11))) :ARG2 (a2 / activate-01~e.1 :polarity~e.8 -~e.8 :ARG0 p2 :ARG1 (e4 / enzyme :name (n5 / name :op1 "p38MAPK"~e.9)) :location c2)) :snt2 (i / induce-01~e.16 :ARG0 (p3 / protein :name (n7 / name :op1 "NGF"~e.0,14)) :ARG2 (p4 / phosphorylate-01~e.17 :ARG1~e.18 (e5 / enzyme :name (n8 / name :op1 "JNK"~e.19))) :mod (a4 / also~e.15))) # ::id bel_pmid_1140_4390.29566 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MAP kinase @-@ Erk kinase ( MEK ) inhibitor PD 098059 inhibits the production of TNF @-@ alpha induced by NGF # ::alignments 1-1.1.2.1.1.1.1 2-1.1.2.1.1.1.2 4-1.1.2.1.2.1.1 9-1 9-1.1 9-1.1.2 9-1.1.2.r 9-1.1.r 12-1 12-1.1 12-1.1.2 12-1.1.2.r 12-1.1.r 14-1.2 15-1.2.1.r 16-1.2.1.1.1 18-1.2.1.1.1 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.1.1 (i2 / inhibit-01~e.9,12 :ARG0~e.9,12 (s / small-molecule~e.9,12 :name (n4 / name :op1 "PD098059") :ARG0-of~e.9,12 (i / inhibit-01~e.9,12 :ARG1 (a / and :op1 (p4 / protein-family :name (n6 / name :op1 "MAP"~e.1 :op2 "kinase"~e.2)) :op2 (p5 / protein-family :name (n3 / name :op1 "Erk"~e.4))))) :ARG1 (p / produce-01~e.14 :ARG1~e.15 (p2 / protein :name (n5 / name :op1 "TNF-alpha"~e.16,18)) :ARG2-of (i3 / induce-01~e.19 :ARG0~e.20 (p3 / protein :name (n / name :op1 "NGF"~e.21))))) # ::id bel_pmid_1140_8560.1760 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both early passage and immortalized MEF cells from GSTpi(-/-) animals expressed significantly elevated activity of extracellular signal @-@ regulated kinases ERK1/ERK2 , kinases linked to cell proliferation pathways # ::alignments 1-1.1.1.1.1 2-1.1.1.1 3-1.1 4-1.1.2.1 5-1.1.1.2.1.1 6-1.1.1 6-1.1.2 7-1.1.1.2.r 10-1.1.1.2.2 11-1.2.2.1 12-1.2.2 13-1.2 14-1.2.1.r 15-1.2.1.1.3.1.1.1 16-1.2.1.1.3.1.1.2 18-1.2.1.1.3.1.1.2 19-1.2.1.1.3.1.1.3 22-1.2.1.1.3.1.1.3 23-1.2.1.1.2 24-1.2.1.1.2.1.r 25-1.2.1.1.2.1.1.1 26-1.2.1.1.2.1.1 27-1.2.1.1.2.1 (e / exhibit-01 :ARG0 (a / and~e.3 :op1 (c / cell~e.6 :mod (p / passage~e.2 :mod (e2 / early~e.1)) :source~e.7 (c4 / cell :name (n4 / name :op1 "MEF"~e.5) :ARG3-of (e4 / express-03~e.10 :ARG2 (p2 / protein :name (n3 / name :op1 "GSTpi") :ARG2-of (m2 / mutate-01 :mod "-/-"))))) :op2 (c2 / cell~e.6 :ARG1-of (i / immortalize-03~e.4) :source c4)) :ARG1 (a2 / activity-06~e.13 :ARG0~e.14 (a3 / and :op1 (e3 / enzyme :name (n / name :op1 "ERK1") :ARG1-of (l / link-01~e.23 :ARG2~e.24 (p3 / pathway~e.27 :mod (p4 / proliferate-01~e.26 :ARG0 (c3 / cell~e.25)))) :ARG1-of (i2 / include-91 :ARG2 (p5 / protein-family :name (n5 / name :op1 "extracellular"~e.15 :op2 "signal-regulated"~e.16,18 :op3 "kinase"~e.19,22)))) :op2 (e6 / enzyme :name (n2 / name :op1 "ERK2") :ARG1-of l :ARG1-of i2)) :ARG1-of (e5 / elevate-01~e.12 :ARG1-of (s / significant-02~e.11)))) # ::id bel_pmid_1143_8543.2568 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A tetrameric Stat3 complex was found to be essential in transfection experiments for maximal interleukin @-@ 6 @-@ inducible activation of alpha2 @-@ macroglobulin gene promoter . # ::alignments 1-1.1.1.1 2-1.1.1.2.1.1 3-1.1.1 4-1.1.1.r 5-1 7-1.1.1.r 8-1.1 9-1.1.3.r 10-1.1.3.1 11-1.1.3 12-1.1.2.r 13-1.1.2.2 14-1.1.2.3.1.1.1 16-1.1.2.3.1.1.1 18-1.1.2.3 19-1.1.2 20-1.1.2.1.r 21-1.1.2.1.1.1.1.1.1.1 23-1.1.2.1.1.1.1.1.1.1 24-1.1.2.1.1.1 25-1.1.2.1 25-1.1.2.1.1 25-1.1.2.1.1.r (f / find-01~e.5 :ARG1 (e / essential~e.8 :domain~e.4,7 (m3 / macro-molecular-complex~e.3 :mod (t / tetrameric~e.1) :mod (p / protein :name (n / name :op1 "Stat3"~e.2))) :purpose~e.12 (a / activate-01~e.19 :ARG1~e.20 (m2 / molecular-physical-entity~e.25 :ARG0-of~e.25 (p4 / promote-01~e.25 :ARG1 (g / gene~e.24 :ARG0-of (e3 / encode-01 :ARG1 (p5 / protein :name (n3 / name :op1 "alpha2-macroglobulin"~e.21,23)))))) :degree (m / maximum~e.13) :ARG2-of (i / induce-01~e.18 :ARG0 (p3 / protein :name (n2 / name :op1 "interleukin-6"~e.14,16)) :ARG1-of (p2 / possible-01))) :prep-in~e.9 (e2 / experiment-01~e.11 :ARG2 (t2 / transfect-01~e.10)))) # ::id bel_pmid_1144_7289.27070 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have previously demonstrated that complex formation between the SH2 domain of Grb2 and FRS2a is mediated via Y196-, Y306-, Y349-, and Y392 @-@ designated Grb2 binding sites ( 4 , 5 ) . # ::alignments 0-1.1 2-1.3 3-1 4-1.2.r 5-1.2.2.2 6-1.2.2 9-1.2.2.1.1.1.1 10-1.2.2.1.1.1.2 12-1.2.2.1.1.2.1.1 13-1.2.2.1 14-1.2.2.1.2.1.1 16-1.2 21-1.2.1.1 21-1.2.2.1 25-1.2.2.1.1.2.1.1 26-1.2.1 27-1.2.2.1.1 29-1.4.1.1.1.1 31-1.4.1.1.1.2 (d / demonstrate-01~e.3 :ARG0 (w2 / we~e.0) :ARG1~e.4 (m / mediate-01~e.16 :ARG0 (b / bind-01~e.26 :ARG2 (a2 / and~e.21 :op1 (a4 / amino-acid :mod 196 :name (n8 / name :op1 "tyrosine") :part-of p2) :op2 (a5 / amino-acid :mod 306 :name (n9 / name :op1 "tyrosine") :part-of p2) :op3 (a6 / amino-acid :mod 349 :name (n10 / name :op1 "tyrosine") :part-of p2))) :ARG1 (f / form-01~e.6 :ARG0 (a / and~e.13,21 :op1 (p4 / protein-segment~e.27 :name (n4 / name :op1 "SH2"~e.9 :op2 "domain"~e.10) :part-of (p2 / protein :name (n2 / name :op1 "Grb2"~e.12,25))) :op2 (p3 / protein :name (n3 / name :op1 "FRS2a"~e.14))) :ARG1 (m2 / macro-molecular-complex~e.5))) :time (p / previous~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 4~e.29 :op2 5~e.31))))) # ::id bel_pmid_1144_7289.27072 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , FRS2a recruits Grb2 indirectly by means of two binding sites for the SH2 domains of the protein tyrosine phosphatase Shp2 at Y436 @- and Y471 @-@ designated Shp2 binding sites ( 5 ) . # ::alignments 0-1 1-1 1-1.1.6 3-1.1.1.1.1 4-1.1 5-1.1.2.1.1 6-1.1.3 6-1.1.3.1 6-1.1.3.1.r 11-1.1.4 12-1.1.6.1.3 15-1.1.6.1.3.1.1 16-1.1.6.1.3.1.2 19-1.1.1 19-1.1.2 19-1.1.6.1.3 19-1.1.6.1.3.2 19-1.1.6.1.3.2.r 20-1.1.6.1.2.1 20-1.1.6.2.2.1 21-1.1.6.1.3.2 22-1.1.6.1.3.2.1.1 30-1.1.6.1.3.2.1.1 31-1.1.6.1.3.3 32-1.1.6.1.3 34-1.1.5.1.1.1 (a / and~e.0,1 :op2 (r / recruit-01~e.4 :ARG0 (p / protein~e.19 :name (n / name :op1 "FRS2a"~e.3)) :ARG1 (p2 / protein~e.19 :name (n2 / name :op1 "Grb2"~e.5)) :ARG1-of (d / direct-02~e.6 :polarity~e.6 -~e.6) :manner (b / bind-01~e.11) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 5~e.34))) :instrument (a3 / and~e.1 :op1 (a4 / amino-acid :mod 436 :name (n7 / name :op1 "tyrosine"~e.20) :part-of (p3 / protein-segment~e.12,19,32 :name (n5 / name :op1 "SH2"~e.15 :op2 "domain"~e.16) :part-of~e.19 (p4 / protein-tyrosine-phosphatase~e.19,21 :name (n6 / name :op1 "Shp2"~e.22,30)) :ARG1-of (b2 / bind-01~e.31))) :op2 (a5 / amino-acid :mod 471 :name (n8 / name :op1 "tyrosine"~e.20) :part-of p3)))) # ::id bel_pmid_1149_0023.3486 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Serum amyloid A @-@ activating factor @-@ 1 ( SAF @-@ 1 ) is a zinc finger transcription factor that is activated by many mediators of inflammation including IL @-@ 1 , IL @-@ 6 , and bacterial LPS . # ::alignments 0-1.2.1.1 1-1.2.1.2 2-1.2.1.3 4-1.2.1.3 5-1.2.1.4 7-1.2.1.4 11-1.2.1.4 15-1.2.2.1.1.1 16-1.2.2.1.1.2 17-1.2 17-1.2.2 17-1.2.2.r 18-1.2.1.4 21-1 22-1.1.r 23-1.1.2 24-1.1 24-1.1.1 24-1.1.1.r 25-1.1.1.1.r 26-1.1.1.1 27-1.1.3 28-1.1.3.1.1.1.1 28-1.1.3.1.2.1.1 30-1.1.3.1.1.1.1 32-1.1.3.1.1.1.1 32-1.1.3.1.2.1.1 34-1.1.3.1.2.1.1 36-1.1.3.1 37-1.1.3.1.3.1 38-1.1.3.1.3 (a / activate-01~e.21 :ARG0~e.22 (m2 / molecular-physical-entity~e.24 :ARG0-of~e.24 (m3 / mediate-01~e.24 :ARG1~e.25 (i / inflame-01~e.26)) :quant (m4 / many~e.23) :ARG2-of (i2 / include-01~e.27 :ARG1 (a2 / and~e.36 :op1 (p2 / protein :name (n2 / name :op1 "IL-1"~e.28,30,32)) :op2 (p3 / protein :name (n3 / name :op1 "IL-6"~e.28,32,34)) :op3 (l / lipopolysaccharide~e.38 :mod (b / bacteria~e.37))))) :ARG1 (p / protein~e.17 :name (n / name :op1 "serum"~e.0 :op2 "amyloid"~e.1 :op3 "A-activating"~e.2,4 :op4 "factor-1"~e.5,7,11,18) :ARG0-of~e.17 (t / transcribe-01~e.17 :ARG1 (p4 / protein :name (n5 / name :op1 "zinc"~e.15 :op2 "finger"~e.16))))) # ::id bel_pmid_1149_0023.22070 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We further show that SAF @-@ 1 is phosphorylated in vitro by PKA @-@ Calpha and that addition of cAMP markedly induces in vivo phosphorylation of SAF @-@ 1 and transcription of SAF @-@ regulated reporter genes . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 3-1.1.2.r 4-1.1.2.1.1.1.1 6-1.1.2.1.1.1.1 8-1.1.2.1 9-1.1.2.1.3 10-1.1.2.1.3 11-1.1.2.1.2.r 12-1.1.2.1.2.1.1 14-1.1.2.1.2.1.1 15-1.1.2 16-1.1.2.r 17-1.1.2.2.1 18-1.1.2.2.1.1.r 19-1.1.2.2.1.1.1.1 20-1.1.2.2.3 20-1.1.2.2.3.r 21-1.1.2.2 22-1.1.2.2.2.1.2 23-1.1.2.2.2.1.2 24-1.1.2.2.2.1 25-1.1.2.2.2.1.1.r 26-1.1.2.2.2.1.1 27-1.1.2.2.2.1.1 28-1.1.2.2.2.1.1 29-1.1.2.2.2 30-1.1.2.2.2.2 31-1.1.2.2.2.2.1.r 32-1.1.2.2.2.2.1.1.1 34-1.1.2.2.2.2.1.1 35-1.1.2.2.2.2.1.2 36-1.1.2.2.2.2.1 (a / and :op2 (s / show-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3,16 (a2 / and~e.15 :op1 (p3 / phosphorylate-01~e.8 :ARG1 (p4 / protein :name (n / name :op1 "SAF-1"~e.4,6)) :ARG2~e.11 (e / enzyme :name (n2 / name :op1 "PKA-Calpha"~e.12,14)) :manner (i2 / in-vitro~e.9,10)) :op2 (i / induce-01~e.21 :ARG0 (a3 / add-02~e.17 :ARG1~e.18 (s2 / small-molecule :name (n3 / name :op1 "cAMP"~e.19))) :ARG2 (a4 / and~e.29 :op1 (p5 / phosphorylate-01~e.24 :ARG1~e.25 p4~e.26,27,28 :manner (i3 / in-vivo~e.22,23)) :op2 (t / transcribe-01~e.30 :ARG1~e.31 (g / gene~e.36 :ARG1-of (r2 / regulate-01~e.34 :ARG0 p4~e.32) :ARG0-of (r3 / report-01~e.35)) :manner i3)) :manner~e.20 (m / marked~e.20))) :mod (f / further~e.1))) # ::id bel_pmid_1149_3654.6262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibition of p38 MAPK by SB203580 in differentiating C2C12 myoblasts blocks MyoD expression , SHPS @-@ 1 tyrosyl phosphorylation and the association of SHPS @-@ 1 with SHP @-@ 2 . # ::alignments 0-1.1 4-1.1.1.r 5-1.1.1.1.1 7-1.1.3.1.2 8-1.1.3.1.1.1 10-1 11-1.2.1.1.1.1 12-1.2.1 14-1.2.2.1.2.1.1 16-1.2.2.1.2.1.1 18-1.2.2 19-1.2 21-1.2.3 22-1.2.3.1.r 23-1.2.3.1 24-1.2.3.1 25-1.2.3.1 26-1.2.3.2.r 27-1.2.3.2.1.1 29-1.2.3.2.1.1 (b / block-01~e.10 :ARG0 (i / inhibit-01~e.0 :ARG0~e.4 (s / small-molecule :name (n2 / name :op1 "SB203580"~e.5)) :ARG1 (e / enzyme :name (n3 / name :op1 "p38MAPK")) :location (m / myoblast :part-of (c / cell-line :name (n4 / name :op1 "C2C12"~e.8) :ARG1-of (d / differentiate-101~e.7)))) :ARG1 (a / and~e.19 :op1 (e2 / express-03~e.12 :ARG2 (p4 / protein :name (n5 / name :op1 "MyoD"~e.11))) :op2 (p3 / phosphorylate-01~e.18 :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (p5 / protein :name (n7 / name :op1 "SHPS-1"~e.14,16)))) :op3 (a2 / associate-01~e.21 :ARG1~e.22 p5~e.23,24,25 :ARG2~e.26 (p6 / protein :name (n8 / name :op1 "SHP-2"~e.27,29))))) # ::id bel_pmid_1149_3654.11578 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Either constitutive expression or inducible activation of MyoD in 10T( 1 @/@ 2 ) fibroblasts promotes SHPS @-@ 1 tyrosyl phosphorylation and its association with SHP @-@ 2 . # ::alignments 1-1.1.1.3 2-1.1.1 4-1.1.2.2 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1 10-1.2.2.1 12-1.2.2.2.1.1 14-1.1.1.2 15-1 16-1.2.1.1.2.1.1 18-1.2.1.1.2.1.1 20-1.2.1 21-1.2 23-1.2.2 25-1.2.2.2.1.1 27-1.2.2.2.1.1 (p2 / promote-01~e.15 :ARG0 (a / and :op1 (e / express-03~e.2 :ARG2 p :ARG3 (f / fibroblast~e.14 :part-of (c2 / cell-line :name (n2 / name :op1 "10T(1/2)"))) :mod (c / constitutive~e.1)) :op2 (a2 / activate-01~e.5 :ARG1~e.6 (p / protein :name (n / name :op1 "MyoD"~e.7)) :ARG2-of (i / induce-01~e.4 :ARG1-of (p3 / possible-01)) :location f)) :ARG1 (a3 / and~e.21 :op1 (p5 / phosphorylate-01~e.20 :ARG1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (p6 / protein :name (n4 / name :op1 "SHPS-1"~e.16,18)))) :op2 (a5 / associate-01~e.23 :ARG1 p6~e.10 :ARG2 (p7 / protein :name (n5 / name :op1 "SHP-2"~e.12,25,27))))) # ::id bel_pmid_1149_3654.30640 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have identified that the 120 kDa complex consists of the SHP @-@ 2 substrate @-@ 1 ( SHPS @-@ 1 ) and the Grb2 @-@ associated binder @-@ 1 ( Gab @-@ 1 ) . SHPS @-@ 1 , but not Gab @-@ 1 , undergoes tyrosyl phosphorylation and association with SHP @-@ 2 during myogenesis , # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 5-1.1.2.1.1.1.1 6-1.1.2.1.1.1.2 7-1.1.2.1 8-1.1.2 9-1.1.2.2.r 11-1.1.2.2.1.1.1 13-1.1.2.2.1.1.1 14-1.1.2.2.1.1.2 16-1.1.2.2.1.1.2 16-1.1.2.2.2.1.2 20-1.1.2.2.1.1.2 20-1.1.2.2.2.1.2 22-1.1.2.2 24-1.1.2.2.2.1.1 26-1.1.2.2.2.1.1 26-1.2.2.1.2.2.1.1 27-1.1.2.2.2.1.2 29-1.1.2.2.1.1.2 29-1.1.2.2.2.1.2 33-1.1.2.2.1.1.2 33-1.1.2.2.2.1.2 38-1.1.2.2.1.1.2 38-1.1.2.2.2.1.2 40-1.2 41-1.2.2.1.1 41-1.2.2.1.1.r 44-1.2.1.1.1.2.1.2 44-1.2.2.1.2.2.1.2 48-1.2.1.1 48-1.2.2.1 49-1.2.1 49-1.2.2 50-1.2.1.2 50-1.2.2.2 52-1.2.1.1.1.2.1.1 52-1.2.1.2.2.1.1 54-1.2.1.1.1.2.1.1 54-1.2.1.2.2.1.1 55-1.2.1.1.2.r 55-1.2.1.2.3.r 55-1.2.2.1.3.r 55-1.2.2.2.3.r 56-1.2.1.1.2 (m / multi-sentence :snt1 (i / identify-01~e.2 :ARG0 (w2 / we~e.0) :ARG1~e.3 (c / consist-01~e.8 :ARG1 (m4 / macro-molecular-complex~e.7 :ARG1-of (e / equal-01 :ARG2 (m2 / mass-quantity :quant 120~e.5 :unit (k / kilodalton~e.6)))) :ARG2~e.9 (a / and~e.22 :op1 (p2 / protein :name (n / name :op1 "SHP-2"~e.11,13 :op2 "substrate-1"~e.14,16,20,29,33,38)) :op2 (p3 / protein :name (n2 / name :op1 "Grb2-associated"~e.24,26 :op2 "binder-1"~e.16,20,27,29,33,38))))) :snt2 (c3 / contrast-01~e.40 :ARG1 (a3 / and~e.49 :op1 (p4 / phosphorylate-01~e.48 :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (p / protein :name (n6 / name :op1 "SHP-2"~e.52,54 :op2 "substrate-1"~e.44))) :time~e.55 (m3 / myogenesis~e.56)) :op2 (a4 / associate-01~e.50 :ARG1 p :ARG2 (p5 / protein :name (n4 / name :op1 "SHP-2"~e.52,54)) :time~e.55 m3)) :ARG2 (a5 / and~e.49 :op1 (p6 / phosphorylate-01~e.48 :polarity~e.41 -~e.41 :ARG1 (a6 / amino-acid :name (n5 / name :op1 "tyrosine") :part-of (p7 / protein :name (n7 / name :op1 "Grb2-associated"~e.26 :op2 "binder-1"~e.44))) :time~e.55 m3) :op2 (a7 / associate-01~e.50 :ARG1 p7 :ARG2 p5 :time~e.55 m3)))) # ::id bel_pmid_1150_0506.8864 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression and activity of the protein @-@ tyrosine phosphatase 1B ( PTP1B ) , but not protein @-@ tyrosine phosphatases SHP @-@ 1 , SHP @-@ 2 , and LAR , were constitutively decreased in tissues expressing the Q205L Galpha( i2 ) . # ::alignments 1-1.2.2.1 2-1.2.2 2-1.2.2.1.1 3-1.1.1.2 3-1.2.2.2 6-1.1.1.1.1.1.1 6-1.2.2.1.1.1 6-1.2.2.1.1.3 8-1.2.2.1.1.1 9-1.1.1.1.1.1.3 9-1.2.2.1.1.2 10-1.1.1.1.1.1.4 15-1 16-1.2.1 16-1.2.1.r 17-1.1.1.1.2.1.1 17-1.2.2.1.1.1 19-1.2.2.1.1.1 20-1.2.2.1.1.2 21-1.2.2.1.1.1.1.1 21-1.2.2.1.1.2.1.1 23-1.2.2.1.1.1.1.1 25-1.2.2.1.1.1.1.1 25-1.2.2.1.1.2.1.1 27-1.2.2.1.1.2.1.1 30-1.2.2.1.1.3.1.1 33-1.1.2 34-1.1 34-1.2 36-1.1.1.1.2 37-1.1.1.1 37-1.1.1.1.2.1 39-1.1.1.1.2.1.1.2.1 (c2 / contrast-01~e.15 :ARG1 (d / decrease-01~e.34 :ARG1 (a / and :op1 (e / express-03~e.37 :ARG2 (e4 / enzyme :name (n6 / name :op1 "protein"~e.6 :op2 "tyrosyne" :op3 "phosphatase"~e.9 :op4 "1B"~e.10)) :ARG3 (t / tissue~e.36 :ARG3-of (e2 / express-03~e.37 :ARG2 (p2 / protein~e.17 :name (n2 / name :op1 "Galpha(i2)") :ARG1-of (m / mutate-01 :value "Q205L"~e.39))))) :op2 (a2 / activity-06~e.3 :ARG0 e4 :location t)) :mod (c / constitutive~e.33)) :ARG2 (d2 / decrease-01~e.34 :polarity~e.16 -~e.16 :ARG1 (a3 / and~e.2 :op1 (e3 / express-03~e.1 :ARG2 (a4 / and~e.2 :op1 (p3 / protein-tyrosine-phophatase~e.6,8,17,19 :name (n3 / name :op1 "SHP-1"~e.21,23,25)) :op2 (p4 / protein-tyrosine-phosphatase~e.9,20 :name (n4 / name :op1 "SHP-2"~e.21,25,27)) :op3 (p5 / protein-tyrosine-phosphatase~e.6 :name (n5 / name :op1 "LAR"~e.30))) :ARG3 t) :op2 (a5 / activity-06~e.3 :ARG0 a4 :location t)))) # ::id bel_pmid_1153_6047.16526 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 6 induced STAT3 transactivation was reduced from sixfold to 2.5 @-@ fold when cells were pre @-@ treated with the JAK2 inhibitor ( Figure 2b ) . # ::alignments 0-1.1.2.1.1.1 2-1.1.2.1.1.1 2-1.2.1 3-1.1.2 4-1.1.1.1.1 5-1.1 7-1 11-1.3.1 13-1.2 13-1.3 14-1.4.3.r 15-1.4.1 22-1.4.2.1.1.1.1 23-1.4.2 23-1.4.2.1 23-1.4.2.1.r 25-1.5.1 26-1.5.1.1 (r / reduce-01~e.7 :ARG1 (t / transactivate-01~e.5 :ARG1 (p / protein :name (n / name :op1 "STAT3"~e.4)) :ARG2-of (i2 / induce-01~e.3 :ARG0 (p2 / protein :name (n2 / name :op1 "IL-6"~e.0,2)))) :ARG3 (p4 / product-of~e.13 :op1 6~e.2) :ARG4 (p5 / product-of~e.13 :op1 2.5~e.11) :condition (p3 / pretreat-01 :ARG1 (c / cell~e.15) :ARG3 (m3 / molecular-physical-entity~e.23 :ARG0-of~e.23 (i / inhibit-01~e.23 :ARG1 (e / enzyme :name (n4 / name :op1 "JAK2"~e.22)))) :time~e.14 (b / before)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "2b"~e.26))) # ::id bel_pmid_1153_6047.22124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of both MEN2A @-@ RET and STAT3 strongly enhanced reporter activation , indicating that MEN2A @-@ RET induces cyclin @-@ D1 gene expression via STAT3 ( Figure 4a ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.3 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1 8-1.3 9-1 10-1.2.1.1 11-1.2 13-1.4 14-1.4.1.r 15-1.4.1.1 16-1.4.1.1 17-1.4.1.1 18-1.4.1 19-1.4.1.2.1.1.1 21-1.4.1.2.1.1.1 22-1.2.1 23-1.4.1.2 25-1.4.1.3 27-1.5.1 28-1.5.1.1 (e / enhance-01~e.9 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (a / and~e.6 :op1 (p2 / protein :name (n / name :op1 "MEN2A-RET"~e.3,5)) :op2 (p3 / protein :name (n2 / name :op1 "STAT3"~e.7)) :mod (b / both~e.2))) :ARG1 (a2 / activate-01~e.11 :ARG1 (g / gene~e.22 :ARG0-of (r2 / report-01~e.10))) :ARG1-of (s / strong-02~e.8) :ARG0-of (i / indicate-01~e.13 :ARG1~e.14 (i2 / induce-01~e.18 :ARG0 p2~e.15,16,17 :ARG2 (e2 / express-03~e.23 :ARG1 (g2 / gene :name (n3 / name :op1 "cyclin-D1"~e.19,21))) :instrument p3~e.25)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "4a"~e.28))) # ::id bel_pmid_1153_6047.22126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data indicate that MEN2A @-@ RET enhances proliferation via STAT3 , and that a full length STAT3 is required to mediate the MEN2A @-@ RET induced proliferation . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2 10-1.2.1.3.1.1 10-1.2.2.2.1.1 12-1.2 13-1.2.r 15-1.2.2.2.2.1 16-1.2.2.2 16-1.2.2.2.2 16-1.2.2.2.2.r 17-1.2.2.2.1.1 19-1.2.2 21-1.2.2.1 23-1.2.2.1.2.1.1 24-1.2.2.1.2.1.1 25-1.2.2.1.2.1.1 26-1.2.2.1.2.1 27-1.2.2.1.2 (i / indicate-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3,13 (a / and~e.12 :op1 (e / enhance-01~e.7 :ARG0 (p / protein :name (n / name :op1 "MEN2A-RET"~e.4,6)) :ARG1 (p2 / proliferate-01~e.8) :ARG2 (p3 / protein :name (n2 / name :op1 "STAT3"~e.10))) :op2 (r / require-01~e.19 :ARG0 (m / mediate-01~e.21 :ARG0 p4 :ARG1 (p5 / proliferate-01~e.27 :ARG2-of (i2 / induce-01~e.26 :ARG0 p~e.23,24,25))) :ARG1 (p4 / protein~e.16 :name (n3 / name :op1 "STAT3"~e.10,17) :ARG1-of~e.16 (l / long-03~e.16 :degree (f / full~e.15)))))) # ::id bel_pmid_1153_6047.30396 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Over @-@ expression of MEN2A @-@ RET mutants reduced STAT3 ser727 phosphorylation to basal levels , suggesting that STAT3 tyr705 phosphorylation is a prerequisite for maximal MEN2A @-@ RET induced STAT3 ser727 phosphorylation ( Figure 3b ) . # ::alignments 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1.1 7-1.1.1.2 7-1.1.1.2.r 8-1 11-1.2 12-1.3.r 13-1.3.1 14-1.3 16-1.4 20-1.4.1.1 20-1.4.1.2 25-1.4.1.1.2 26-1.4.1.1.3.1 27-1.4.1.1.3.1 28-1.4.1.1.3.1 29-1.4.1.1.3 32-1.4.1.1 32-1.4.1.2 34-1.5.1 35-1.5.1.1 (r / reduce-01~e.8 :ARG0 (o / overexpress-01 :ARG1 (p3 / protein~e.7 :name (n / name :op1 "MEN2A-RET"~e.4,6) :ARG2-of~e.7 (m / mutate-01~e.7))) :ARG1 (p2 / phosphorylate-01~e.11 :ARG1 (a / amino-acid :mod 727 :name (n2 / name :op1 "serine") :part-of (p4 / protein :name (n3 / name :op1 "STAT-3")))) :ARG4~e.12 (l / level~e.14 :mod (b / basal~e.13)) :ARG0-of (s / suggest-01~e.16 :ARG1 (r2 / require-01 :ARG0 (p5 / phosphorylate-01~e.20,32 :ARG1 a :degree (m2 / maximum~e.25) :ARG2-of (i / induce-01~e.29 :ARG0 p3~e.26,27,28)) :ARG1 (p / phosphorylate-01~e.20,32 :ARG1 (a3 / amino-acid :mod 705 :name (n6 / name :op1 "tyrosine") :part-of p4)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "3b"~e.35))) # ::id bel_pmid_1153_6047.30398 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAT3 tyr705 phosphorylation was reduced when the MEN2A @-@ RET single mutants tyr752 phe or tyr928 phe were overexpressed , while no STAT3 tyr705 phosphorylation was observed in the presence of the MEN2A @-@ RET double mutant ( Figure 3b ) . # ::alignments 0-1.1.1.1.3.1.1 2-1.1.1 4-1.1 7-1.1.2.1.1.1.1 7-1.1.2.1.2.1.1 9-1.1.2.1.1.1.1 9-1.1.2.1.2.1.1 10-1.1.2.1.1.3 11-1.1.2.1.1 11-1.1.2.1.1.2 11-1.1.2.1.1.2.r 11-1.1.2.1.2 11-1.1.2.1.2.2 11-1.1.2.1.2.2.r 14-1.1.2.1 18-1.1.2 20-1 21-1.2.1 21-1.2.1.r 22-1.2.2 23-1.2.2 24-1.2.2 26-1.2 27-1.2.3.r 29-1.2.3 30-1.2.3.1.r 32-1.2.3.1.1.1 34-1.2.3.1.1.1 35-1.2.3.1.2.1 36-1.2.3.1 36-1.2.3.1.2 36-1.2.3.1.2.r 38-1.3.1 39-1.3.1.1 (c / contrast-01~e.20 :ARG1 (r / reduce-01~e.4 :ARG1 (p2 / phosphorylate-01~e.2 :ARG1 (a / amino-acid :mod 705 :name (n / name :op1 "tyrosine") :part-of (p3 / protein :name (n2 / name :op1 "STAT3"~e.0)))) :condition (o / overexpress-01~e.18 :ARG1 (o2 / or~e.14 :op1 (p / protein~e.11 :name (n4 / name :op1 "MEN2A-RET"~e.7,9) :ARG2-of~e.11 (m2 / mutate-01~e.11 :value "tyr752phe") :ARG1-of (s / single-02~e.10)) :op2 (p5 / protein~e.11 :name (n9 / name :op1 "MEN2A-RET"~e.7,9) :ARG2-of~e.11 (m5 / mutate-01~e.11 :value "tyr928phe") :ARG1-of s)))) :ARG2 (o3 / observe-01~e.26 :polarity~e.21 -~e.21 :ARG1 p2~e.22,23,24 :condition~e.27 (p4 / present-02~e.29 :ARG1~e.30 (p7 / protein~e.36 :name (n5 / name :op1 "MEN2A-RET"~e.32,34) :ARG1-of~e.36 (m3 / mutate-01~e.36 :mod (d / double~e.35))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.38 :mod "3b"~e.39))) # ::id bel_pmid_1153_6047.30400 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As depicted in Figure 3a , mutation of tyr928 ( RET ) reduced STAT3 transactivation approximately 1.5 @-@ fold , indicating that other STAT3 docking sites must be present in MEN2A @-@ RET as well . # ::alignments 0-1.4.1.1.3 1-1.5 2-1.5.1.r 3-1.5.1 4-1.5.1.1 6-1.1 7-1.3 10-1.1.1.3.1.1 12-1 13-1.2.1.1.1 14-1.2 15-1.3.2 16-1.3.1 18-1.3 20-1.4 22-1.4.1.1.1.2 23-1.4.1.1.1.1.1 24-1.4.1.1.1.1 25-1.4.1.1.1 26-1.4.1 28-1.4.1.1 29-1.4.1.1.2.r 30-1.4.1.1.2.1.1 32-1.4.1.1.2.1.1 33-1.4.1.1.3 34-1.4.1.1.3 (r / reduce-01~e.12 :ARG0 (m / mutate-01~e.6 :ARG1 (a / amino-acid :mod 928 :name (n / name :op1 "tyrosine") :part-of (p / protein :name (n2 / name :op1 "RET"~e.10)))) :ARG1 (t / transactivate-01~e.14 :ARG1 (p2 / protein :name (n3 / name :op1 "STAT3"~e.13))) :ARG2 (p5 / product-of~e.7,18 :op1 1.5~e.16 :mod (a3 / approximate~e.15)) :ARG0-of (i / indicate-01~e.20 :ARG1 (o / obligate-01~e.26 :ARG2 (p6 / present-02~e.28 :ARG1 (p4 / protein-segment~e.25 :ARG2-of (d / dock-01~e.24 :ARG1 p2~e.23) :mod (o2 / other~e.22)) :ARG2~e.29 (p3 / protein :name (n4 / name :op1 "MEN2A-RET"~e.30,32)) :mod (a2 / as-well~e.0,33,34)))) :ARG1-of (d2 / depict-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "3a"~e.4))) # ::id bel_pmid_1153_6047.30402 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As depicted in Figure 1a , b, over @-@ expression of both MEN2A @-@ RET and STAT3 strongly enhanced IRE transactivation , while overexpression of STAT3 alone did not affect reporter activation . # ::alignments 1-1.3 3-1.3.1.1 3-1.3.1.2 4-1.3.1.1.1 12-1.1.1.1.1.1.1 14-1.1.1.1.1.1.1 15-1.1.1.1 16-1.1.1.1.2.1.1 17-1.1.3 18-1.1 19-1.1.2.1.1.1 20-1.1.2 22-1 23-1.1.1 23-1.2.2 25-1.1.1.1.2.1.1 28-1.2.1 28-1.2.1.r 29-1.2 30-1.2.3.1 30-1.2.3.1.1 30-1.2.3.1.1.r 31-1.2.3 (c / contrast-01~e.22 :ARG1 (e / enhance-01~e.18 :ARG0 (o / overexpress-01~e.23 :ARG1 (a / and~e.15 :op1 (p2 / protein :name (n / name :op1 "MEN2A-RET"~e.12,14)) :op2 (p3 / protein :name (n2 / name :op1 "STAT3"~e.16,25)))) :ARG1 (t / transactivate-01~e.20 :ARG1 (p4 / protein-segment :name (n3 / name :op1 "IRE"~e.19))) :ARG1-of (s / strong-02~e.17)) :ARG2 (a2 / affect-01~e.29 :polarity~e.28 -~e.28 :ARG0 (o2 / overexpress-01~e.23 :ARG1 p3) :ARG1 (a4 / activate-01~e.31 :ARG1 (g / gene~e.30 :ARG0-of~e.30 (r2 / report-01~e.30)))) :ARG1-of (d / depict-01~e.1 :ARG0 (a5 / and :op1 (f / figure~e.3 :mod "1a"~e.4) :op2 (f2 / figure~e.3 :mod "1b")))) # ::id bel_pmid_1155_7580.38186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After bFGF was added to pulmonary fibroblasts , the kinase activities of p44 @/@ p42 ERK1 @/@ 2 were determined by an in @-@ gel assay at various times after exposure ( Fig . 1 ) . The data demonstrate that the addition of bFGF results in activation of ERK1 @/@ 2 within 5 min , with the highest activity at 30 min , followed by a lower level of activity that persists for 8 @-@ 12 h . # ::alignments 0-1.1.3 1-1.1.3.1.1.1.1 3-1.1.3.1 6-1.1.3.1.2 9-1.1.1.1.1 9-1.1.1.2.1 10-1.1.1.1 10-1.1.1.2 12-1.1.1.1.1.1.1 14-1.1.1.2.1.1.1 15-1.2.2.2.1.1.1.1 19-1.1 20-1.1.2.r 22-1.1.2.1 24-1.1.2.1 25-1.1.2 26-1.1.5.r 27-1.1.5 28-1.1.5.1.r 28-1.2.2.2.1.3.1.1.3.1.1 28-1.2.2.2.1.3.1.1.3.1.2 28-1.2.2.2.1.3.2.2.2 28-1.2.2.2.2.2.1 29-1.1.5.1 29-1.2.2.2.1.3.2.2 30-1.1.5.1.1 32-1.1.4.1 34-1.1.4.1.1 38-1.2.1 39-1.2 42-1.2.2.1 43-1.2.2.1.1.r 44-1.2.2.1.1.1.1 45-1.2.2 46-1.1.2.1 47-1.2.2.2 49-1.2.2.2.1.1.1.1 52-1.2.2.2.2 52-1.2.2.2.2.2 52-1.2.2.2.2.2.1.1.r 52-1.2.2.2.2.2.r 53-1.2.2.2.2.2.1.1 54-1.2.2.2.2.2.1.2 56-1.2.2.2.1.r 58-1.2.2.2.1.3.2 58-1.2.2.2.1.3.2.1 58-1.2.2.2.1.3.2.1.r 59-1.2.2.2.1.3 61-1.2.2.2.1.3.2.2.2.1 62-1.2.2.2.1.3.2.2.2.2 64-1.2.2.2.1.3.1 65-1.2.2.2.1.3.1.1.r 67-1.2.2.2.1.3.1.1.2 67-1.2.2.2.1.3.1.1.2.1 67-1.2.2.2.1.3.1.1.2.1.r 70-1.2.2.2.1.3.1.1 72-1.2.2.2.1.3.1.1.3 74-1.2.2.2.1.3.1.1.3.1.1.1 76-1.2.2.2.1.3.1.1.3.1.2.1 77-1.2.2.2.1.3.1.1.3.1.1.2 77-1.2.2.2.1.3.1.1.3.1.2.2 (m3 / multi-sentence :snt1 (d / determine-01~e.19 :ARG1 (a14 / and :op1 (a / activity-06~e.10 :ARG0 (k2 / kinase~e.9 :name (n / name :op1 "p44"~e.12 :op2 "ERK1"))) :op2 (a13 / activity-06~e.10 :ARG0 (k3 / kinase~e.9 :name (n3 / name :op1 "p42"~e.14 :op2 "ERK2")))) :manner~e.20 (a3 / assay-01~e.25 :manner (i / in-gel~e.22,24,46)) :time (a5 / after~e.0 :op1 (a6 / add-02~e.3 :ARG1 (p3 / protein :name (n2 / name :op1 "bFGF"~e.1)) :ARG2 (f3 / fibroblast~e.6 :part-of (l3 / lung)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.32 :mod 1~e.34)) :frequency~e.26 (v / various~e.27 :time~e.28 (a4 / after~e.29 :op1 (e2 / expose-01~e.30)))) :snt2 (d3 / demonstrate-01~e.39 :ARG0 (d4 / data~e.38) :ARG1 (r / result-01~e.45 :ARG1 (a7 / add-02~e.42 :ARG1~e.43 (p / protein :name (n5 / name :op1 "bFGF"~e.44))) :ARG2 (a8 / activate-01~e.47 :ARG1~e.56 (a9 / and :op1 (e4 / enzyme :name (n6 / name :op1 "ERK1"~e.15,49)) :op2 (e5 / enzyme :name (n7 / name :op1 "ERK2")) :ARG0-of (a2 / activity-06~e.59 :ARG2-of (f2 / follow-01~e.64 :ARG1~e.65 (a12 / activity-06~e.70 :ARG0 a9 :ARG1-of (l / low-04~e.67 :degree~e.67 (m2 / more~e.67)) :ARG1-of (p2 / persist-01~e.72 :duration (b2 / between :op1 (t4 / temporal-quantity~e.28 :quant 8~e.74 :unit (h3 / hour~e.77)) :op2 (t5 / temporal-quantity~e.28 :quant 12~e.76 :unit (h4 / hour~e.77)))))) :ARG1-of (h / high-02~e.58 :degree~e.58 (m / most~e.58) :time (a11 / after~e.29 :op1 a7 :quant (t2 / temporal-quantity~e.28 :quant 30~e.61 :unit m4~e.62))))) :time (a10 / after~e.52 :op1 a7 :quant~e.52 (u / up-to~e.52 :op1 (t / temporal-quantity~e.28 :quant~e.52 5~e.53 :unit (m4 / minute~e.54)))))))) # ::id bel_pmid_1155_7774.11824 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PPARalpha ( NR1C1 ) controls lipid oxidation and clearance in hepatocytes and PPARgamma ( NR1C3 ) promotes preadipocyte differentiation and lipogenesis . # ::alignments 0-1.1.1.1.1 2-1.1.1.2.1.1.1 4-1.1 5-1.1.2.1.1 7-1.1.2 8-1.1.2.2 9-1.1.3.r 10-1.1.3 11-1.1.2 12-1.2.1.1.1 14-1.2.1.2.1.1.1 16-1.2 17-1.2.2.1.1 18-1.2.2.1 19-1.2.2 20-1.2.2.2 (a / and :op1 (c / control-01~e.4 :ARG0 (p / protein :name (n / name :op1 "PPARalpha"~e.0) :ARG1-of (d2 / describe-01 :ARG2 (p4 / protein :name (n5 / name :op1 "NR1C1"~e.2)))) :ARG1 (a2 / and~e.7,11 :op1 (o / oxidize-01 :ARG1 (l / lipid~e.5)) :op2 (c2 / clear-01~e.8 :ARG2 l)) :location~e.9 (h / hepatocyte~e.10)) :op2 (p2 / promote-02~e.16 :ARG0 (p3 / protein :name (n3 / name :op1 "PPARgamma"~e.12) :ARG1-of (d3 / describe-01 :ARG2 (p5 / protein :name (n6 / name :op1 "NR1C3"~e.14)))) :ARG1 (a3 / and~e.19 :op1 (d / differentiate-01~e.18 :ARG1 (p6 / preadipocyte~e.17)) :op2 (l2 / lipogenesis~e.20 :location p6)))) # ::id bel_pmid_1155_7774.16262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , it has been shown that activation of PPARg by the thiozolidinedione , rosiglitazaone , decreased scavenger receptor class A expresion . # ::alignments 0-1 5-1.1 6-1.1.1.r 7-1.1.1.1 16-1.1.1 17-1.1.1.2.1.1.1 18-1.1.1.2.1.1.2 19-1.1.1.2.1.1.3 20-1.1.1.2.1.1.4 (a / and~e.0 :op2 (s / show-01~e.5 :ARG1~e.6 (d / decrease-01~e.16 :ARG0 (a2 / activate-01~e.7 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "rosiglitazone") :ARG1-of (i / include-91 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "thiazolidinedione")))) :ARG1 (p / protein :name (n / name :op1 "PPARgamma"))) :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n4 / name :op1 "scavenger"~e.17 :op2 "receptor"~e.18 :op3 "class"~e.19 :op4 "A"~e.20)))))) # ::id bel_pmid_1155_7774.16418 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pparg , which is activated by 15 @-@ deoxy @-@ D12,14 @-@ prostaglandin J2 and the thiazolidione class of insulin @-@ sensitizing drugs , ... Among its known target genes are adipocyte factty @-@ acid binidng protein and fatty acid synthase , which are efeeectors of lipid accumulaiton during adipogeesis . # ::alignments 4-1.1 5-1.1.1.r 6-1.1.1.1.1.1 8-1.1.1.1.1.1 12-1.1.1.1.1.2 13-1.1.1.1.1.3 14-1.1.1 16-1.1.1.2.1.1.1 17-1.1.1.2 19-1.1.1.2.2.1.1.1.1.1 21-1.1.1.2.2.1.1 22-1.1.1.2.2.1 25-1.1.1.2.2 25-1.2 27-1.2.2.2 28-1.2.2.1 29-1.2.1.1 29-1.2.1.2 29-1.2.2 31-1.2.1.1.1.1.1.1 31-1.2.1.4 34-1.2.1.1.1.1.1.2 36-1.2.1.1.1.1.1.4 37-1.2.1 38-1.2.1.2.1.1.1.1 39-1.2.1.2.1.1.1.2 40-1.2.1.2.1.1.1.3 46-1.2.1.3.1.1.1 48-1.2.1.3.1.2.r (m / multi-sentence :snt1 (a / activate-01~e.4 :ARG0~e.5 (a2 / and~e.14 :op1 (s / small-molecule :name (n2 / name :op1 "15-deoxy-D12"~e.6,8 :op2 "14-prostaglandin"~e.12 :op3 "J2"~e.13)) :op2 (c / class~e.17 :mod (s2 / small-molecule :name (n3 / name :op1 "thiazolidione"~e.16)) :ARG1-of (i / include-91~e.25 :ARG2 (d / drug~e.22 :ARG0-of (s3 / sensitize-01~e.21 :ARG2 (p4 / protein :name (n4 / name :op1 "insulin"~e.19))))))) :ARG1 (p / protein :name (n / name :op1 "PPAR-gamma"))) :snt2 (i2 / include-91~e.25 :ARG1 (a3 / and~e.37 :op1 (g2 / gene~e.29 :ARG0-of (e3 / encode-01 :ARG1 (p5 / protein :name (n8 / name :op1 "adipocyte"~e.31 :op2 "fatty-acid"~e.34 :op3 "biniding" :op4 "protein"~e.36)))) :op2 (g3 / gene~e.29 :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n7 / name :op1 "fatty"~e.38 :op2 "acid"~e.39 :op3 "synthase"~e.40)))) :mod (e2 / effector :ARG0-of (c2 / cause-01 :ARG1 (a4 / accumulate-01 :ARG1 (l / lipid~e.46)) :time~e.48 (a5 / adipogenesis))) :part-of (a6 / adipocyte~e.31)) :ARG2 (g / gene~e.29 :ARG1-of (t / target-01~e.28 :ARG2 (p2 / protein :name (n5 / name :op1 "PPARgamma"))) :ARG1-of (k / know-01~e.27)))) # ::id bel_pmid_1155_7774.30036 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore the profound repression of CYP27 and apoE expressoin by activatoin or overexpression of PPARd might contribute to the lipid accumulation observed in these cells in culture # ::alignments 0-1 2-1.1.1.1.3 3-1.1.1.1 5-1.1.1.1.2.1.1.1.1 6-1.1.1.1.2.1 7-1.1.1.1.2.1.2.1.1 11-1.1.1.1.1 12-1.1.1.1.1.2 15-1.1 16-1.1.1 17-1.1.1.2.r 19-1.1.1.2.1 20-1.1.1.2 21-1.1.1.2.2 22-1.1.1.2.2.1.r 22-1.1.1.2.2.2 23-1.1.1.2.2.1.1 24-1.1.1.2.2.1 25-1.1.1.2.2.2 26-1.1.1.2.2.2 (i / infer-01~e.0 :ARG1 (p / possible-01~e.15 :ARG1 (c / contribute-01~e.16 :ARG0 (r / repress-01~e.3 :ARG0 (o / or~e.11 :op1 (a3 / activate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "PPARdelta"))) :op2 (o2 / overexpress-01~e.12 :ARG1 p2)) :ARG1 (e / express-03 :ARG1 (a2 / and~e.6 :op1 (g / gene :name (n / name :op1 "CYP27"~e.5)) :op2 (g2 / gene :name (n2 / name :op1 "apoE"~e.7)))) :mod (p3 / profound~e.2)) :ARG2~e.17 (a / accumulate-01~e.20 :ARG1 (l / lipid~e.19) :ARG1-of (o3 / observe-01~e.21 :location~e.22 (c2 / cell~e.24 :mod (t / this~e.23)) :manner (i2 / in-culture~e.22,25,26)))))) # ::id bel_pmid_1155_7774.33822 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , plaque formation is also appreciated to be an inflammoratory response and it has been shown that activators of Pparg inhibit the production of inflammoratory cytokines such as TNFa , Il6 and Il1b . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1.1 5-1.1.1.3 7-1.1.1 11-1.1.1.2 12-1.1 16-1.1.2 17-1.1.2.1.r 18-1.1.2.1.1 18-1.1.2.1.1.1 18-1.1.2.1.1.1.r 21-1.1.2.1 23-1.1.2.1.2 26-1.1.2.1.2.1 27-1.1.2.1.2.1.1.r 28-1.1.2.1.2.1.1.r 29-1.1.2.1.2.1.1.1.1.1 31-1.1.2.1.2.1.1.2.1.1 32-1.1.2.1.2.1.1 (c2 / contrast-01~e.0 :ARG2 (a2 / and~e.12 :op1 (u / understand-01~e.7 :ARG1 (f / form-01~e.3 :ARG1 (p / plaque~e.2)) :ARG2 (r / respond-01~e.11 :ARG2 (i / inflame-01)) :mod (a4 / also~e.5)) :op2 (s / show-01~e.16 :ARG1~e.17 (i2 / inhibit-01~e.21 :ARG0 (t / thing~e.18 :ARG0-of~e.18 (a / activate-01~e.18 :ARG1 (p2 / protein :name (n / name :op1 "PPARgamma")))) :ARG1 (p3 / produce-01~e.23 :ARG1 (c / cytokine~e.26 :example~e.27,28 (a3 / and~e.32 :op1 (p5 / protein :name (n3 / name :op1 "TNFa"~e.29)) :op2 (p6 / protein :name (n4 / name :op1 "Il6"~e.31)) :op3 (p7 / protein :name (n5 / name :op1 "Il6b"))) :ARG0-of i)))))) # ::id bel_pmid_1155_7774.33878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These studies started with the observation that Pparg up @-@ regulates CD36 ( savenger receptor calss @-@ B ) expression in macrophages . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2 11-1.2.1.1.1.1.1 13-1.2.1.1.1.2.1.1.1 14-1.2.1.1.1.2.1.1.2 17-1.2.1.1.1.2.1.1.4 19-1.2.1.1 20-1.2.1.1.2.r 21-1.2.1.1.2 (s / start-01~e.2 :ARG1 (s2 / study-01~e.1 :mod (t / this~e.0)) :ARG2~e.3 (o / observe-02~e.5 :ARG1 (u / upregulate-01 :ARG1 (e / express-03~e.19 :ARG2 (p2 / protein :name (n2 / name :op1 "CD36"~e.11) :ARG1-of (d / describe-01 :ARG2 (p3 / protein :name (n3 / name :op1 "savenger"~e.13 :op2 "receptor"~e.14 :op3 "class" :op4 "B"~e.17)))) :ARG3~e.20 (m / macrophage~e.21)) :ARG2 (p / protein :name (n / name :op1 "PPARgamma"))))) # ::id bel_pmid_1158_3971.7986 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exogenous ANXA1 but not ANXA5 , administered to IL @-@ 6 KO mice before LPS challenge inhibited TNF @-@ alpha release . # ::alignments 0-1.1.2 1-1.1.1.1 2-1.1 2-1.1.3 2-1.1.3.r 4-1.1.3.1.1.1 6-1.1.4 7-1.1.4.1.r 8-1.1.4.1.1.1.1 10-1.1.4.1.1.1.1 12-1.1.4.1 13-1.1.4.2 14-1.1.4.2.1.1 15-1.1.4.2.1 16-1 17-1.2.1.1.1 19-1.2.1.1.1 20-1.2 (i / inhibit-01~e.16 :ARG0 (p / protein~e.2 :name (n / name :op1 "ANXA1"~e.1) :mod (e / exogenous~e.0) :ARG1-of~e.2 (c / contrast-01~e.2 :ARG2 (p2 / protein :name (n2 / name :op1 "ANXA5"~e.4))) :ARG1-of (a / administer-01~e.6 :ARG2~e.7 (m / mouse~e.12 :mod (p3 / protein :name (n3 / name :op1 "IL-6"~e.8,10) :ARG2-of (m2 / mutate-01 :mod "-/+"))) :time (b / before~e.13 :op1 (c2 / challenge-01~e.15 :ARG2 (l / lipopolysaccharide~e.14))))) :ARG1 (r / release-01~e.20 :ARG1 (p4 / protein :name (n5 / name :op1 "TNF-alpha"~e.17,19)))) # ::id bel_pmid_1158_3971.9278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok recombinant IL @-@ 6 to IL @-@ 6 KO animals before LPS or TNF @-@ alpha challenge , replenished ANXA1 liver synthesis to that of WT animals . # ::alignments 0-1.1 0-1.1.2 0-1.1.2.r 1-1.1.1.1 1-1.1.3.1.1.1.1 3-1.1.1.1 3-1.1.3.1.1.1.1 5-1.1.1.1 5-1.1.3.1.1.1.1 7-1.1.1.1 7-1.1.3.1.1.1.1 9-1.1.3.1 10-1.1.3.2 11-1.1.3.2.1.1.1 12-1.1.3.2.1.1 13-1.1.3.2.1.1.2.1.1 15-1.1.3.2.1.1.2.1.1 16-1.1.3.2.1 18-1 19-1.2.2.1.1 20-1.2.1 20-1.3.1 21-1.2 21-1.3 25-1.3.1.1.1 26-1.1.3.1 26-1.3.1.1 (r / replenish-01~e.18 :ARG0 (p / protein~e.0 :name (n / name :op1 "IL-6"~e.1,3,5,7) :ARG1-of~e.0 (r2 / recombine-01~e.0) :ARG1-of (a / administer-01 :ARG2 (a2 / animal~e.9,26 :mod (p4 / protein :name (n5 / name :op1 "IL-6"~e.1,3,5,7) :ARG2-of (m / mutate-01 :mod "-/+"))) :time (b / before~e.10 :op1 (c / challenge-01~e.16 :ARG2 (o / or~e.12 :op1 (l3 / lipopolysaccharide~e.11) :op2 (p2 / protein :name (n3 / name :op1 "TNF-alpha"~e.13,15))))))) :ARG1 (s2 / synthesize-01~e.21 :ARG0 (l / liver~e.20) :ARG1 (p3 / protein :name (n4 / name :op1 "ANXA1"~e.19))) :extent (s3 / synthesize-01~e.21 :ARG0 (l2 / liver~e.20 :part-of (a3 / animal~e.26 :mod (w / wild-type~e.25))) :ARG1 p3)) # ::id bel_pmid_1159_1769.19228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here we show that IL @-@ 10 directly affects progenitor myeloid cells by protecting them from death following the removal of growth factors . # ::alignments 0-1.3 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1 6-1.2.1.1.1 7-1.2.4 8-1.2 9-1.2.2.1 10-1.2.2.2 11-1.2.2 12-1.2.3.r 13-1.2.3 15-1.2.3.3.r 16-1.2.3.3 17-1.2.3.3.1 19-1.2.3.3.1.1 20-1.2.3.3.1.1.1.r 21-1.2.3.3.1.1.1 22-1.2.3.3.1.1.1 (s / show-01~e.2 :ARG0 (w / we~e.1) :ARG1~e.3 (a / affect-01~e.8 :ARG0 (p2 / protein :name (n / name :op1 "IL-10"~e.4,6)) :ARG1 (c / cell~e.11 :mod (p3 / progenitor~e.9) :mod (m / myeloid~e.10)) :ARG2~e.12 (p4 / protect-01~e.13 :ARG0 p2 :ARG1 c :ARG2~e.15 (d / die-01~e.16 :ARG1-of (f / follow-01~e.17 :ARG2 (r / remove-01~e.19 :ARG1~e.20 (g / growth-factor~e.21,22))))) :ARG1-of (d2 / direct-02~e.7)) :medium (h / here~e.0)) # ::id bel_pmid_1159_1769.21788 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following ligand binding to the IL @-@ 10R , Jak1 and Tyk2 , which are constitutively associated with IL @-@ 10R1 and IL @-@ 10R2 , respectively ( 3 , 14 ) , are phosphorylated on tyrosine The phosphorylated IL @-@ 10R/Jak1/Tyk2 complex serves as a docking site for the transcription factors Stat @-@ 1 and Stat @-@ 3 Jak1 , which is required for the biological activity of IL @-@ 10 ( 20 ) , also tyrosine phosphorylates the insulin receptor substrate @-@ 1 ( IRS @-@ 1 ) # ::alignments 0-1.1.2 1-1.1.2.1.1 2-1.1.2.1 5-1.1.2.1.2.1.1 7-1.1.2.1.2.1.1 9-1.3.2.1.1 11-1.1.1.2.2.1.1 11-1.2.1.3.1.1 15-1.1.1.1.2.2.2 15-1.1.1.1.2.2.2.r 16-1.1.1.1.2.2 16-1.1.1.2.2.2 18-1.1.1.1.2.2.1.1.1 20-1.1.1.1.2.2.1.1.1 21-1.1.1 21-1.1.1.1.2.2.4.1.1.1 22-1.1.1.1.2.2.1.1.1 22-1.1.1.2.2.2.1.1.1 24-1.1.1.2.2.2.1.1.1 26-1.1.1.1.2.2.3 26-1.1.1.1.2.2.3.r 28-1.1.1.1.2.2.4.1.1.1.1 30-1.1.1.1.2.2.4.1.1.1.2 34-1.1 34-1.2.1.4 36-1.1.1.1.1.1 38-1.2.1.4 39-1.2.1.1.1.1 42-1.2.1 43-1.2 44-1.2.2.r 46-1.2.2.1 47-1.2.2 48-1.2.2.1.1.r 50-1.2.2.1.1.3.1 51-1.2.2.1.1.3 52-1.2.2.1.1.1.1.1 52-1.2.2.1.1.2.1.1 54-1.2.2.1.1.1.1.1 55-1.2.2.1.1 56-1.2.2.1.1.1.1.1 56-1.2.2.1.1.2.1.1 58-1.1.1.1.2.2.4.1.1.1.1 58-1.2.2.1.1.2.1.1 59-1.1.1.1.2.1.1 59-1.2.1.2.1.1 59-1.3.2.1.1 63-1.3.2.2 64-1.3.2.2.1.r 66-1.3.2.2.1.2 67-1.3.2.2.1 68-1.3.2.2.1.1.r 69-1.3.2.2.1.1.1.1 71-1.3.2.2.1.1.1.1 73-1.3.2.2.2.1.1.1 76-1.3.3 77-1.1.1.2.1.1 77-1.3.1.1.1 78-1.3 80-1.3.1.2.1.1 81-1.1.1.1.2.2.1 81-1.1.1.2.2.2.1 81-1.1.2.1.2 81-1.2.1.1 81-1.3.1.2.1.2 82-1.3.1.2.1.3 84-1.3.1.2.1.4 84-1.3.1.2.2.1.1.1 86-1.3.1.2.2.1.1.1 88-1.2.2.1.1.1.1.1 88-1.3.1.2.2.1.1.1 (m / multi-sentence :snt1 (p / phosphorylate-01~e.34 :ARG1 (a / and~e.21 :op1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine"~e.36) :part-of (e / enzyme :name (n / name :op1 "Jak1"~e.59) :ARG1-of (a4 / associate-01~e.16 :ARG2 (r2 / receptor~e.81 :name (n6 / name :op1 "IL-10R1"~e.18,20,22)) :manner~e.15 (c / constitutive~e.15) :manner~e.26 (r4 / respective~e.26) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and~e.21 :op1 3~e.28,58 :op2 14~e.30))))))) :op2 (a3 / amino-acid :name (n4 / name :op1 "tyrosine"~e.77) :part-of (e2 / enzyme :name (n2 / name :op1 "Tyk2"~e.11) :ARG1-of (a5 / associate-01~e.16 :ARG2 (r3 / receptor~e.81 :name (n7 / name :op1 "IL-10R2"~e.22,24)) :manner c :ARG1-of d :manner r4)))) :ARG1-of (f / follow-01~e.0 :ARG2 (b / bind-01~e.2 :ARG1 (l / ligand~e.1) :ARG2 (r / receptor~e.81 :name (n5 / name :op1 "IL-10R"~e.5,7))))) :snt2 (s / serve-01~e.43 :ARG0 (m2 / macro-molecular-complex~e.42 :part (r5 / receptor~e.81 :name (n8 / name :op1 "IL-10R"~e.39)) :part (e3 / enzyme :name (n9 / name :op1 "Jak1"~e.59)) :part (e4 / enzyme :name (n10 / name :op1 "Tyk2"~e.11)) :ARG1-of (p3 / phosphorylate-01~e.34,38)) :ARG1~e.44 (s2 / site~e.47 :ARG2-of (d2 / dock-01~e.46 :ARG1~e.48 (a7 / and~e.55 :op1 (p4 / protein :name (n11 / name :op1 "Stat-1"~e.52,54,56,88)) :op2 (p5 / protein :name (n12 / name :op1 "Stat-3"~e.52,56,58)) :mod (f2 / factor~e.51 :ARG0-of (t / transcribe-01~e.50)))))) :snt3 (p6 / phosphorylate-01~e.78 :ARG1 (a9 / amino-acid :name (n14 / name :op1 "tyrosine"~e.77) :part-of (p7 / protein :name (n15 / name :op1 "insulin"~e.80 :op2 "receptor"~e.81 :op3 "substrate"~e.82 :op4 1~e.84) :ARG1-of (d3 / describe-01 :ARG2 (p8 / protein :name (n16 / name :op1 "IRS-1"~e.84,86,88))))) :ARG2 (e5 / enzyme :name (n13 / name :op1 "Jak1"~e.9,59) :ARG1-of (r6 / require-01~e.63 :ARG0~e.64 (a10 / activity-06~e.67 :ARG0~e.68 (p9 / protein :name (n17 / name :op1 "IL-10"~e.69,71)) :mod (b2 / biology~e.66)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication :ARG1-of (c3 / cite-01 :ARG2 20~e.73))))) :mod (a8 / also~e.76))) # ::id bel_pmid_1159_1769.27658 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We and others have shown that activation of IL @-@ 4 ( 23 ) and IFN-{alpha} receptors stimulates tyrosyl phosphorylation of IRS docking proteins , which depends upon Jak , # ::alignments 0-1.1.1 1-1.1 2-1.1.2.1 4-1 5-1.2.r 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.1.1.1 10-1.2.1.1.1.1.1 12-1.2.1.1.1.2.1.1.1 14-1.2.1.1 16-1.2.1.1.2 17-1.2 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.2.1.1 22-1.2.2.1.2.2 23-1.2.1.1.1 23-1.2.2.1.2 26-1.2.2.2 28-1.2.2.2.1.1.1 (s / show-01~e.4 :ARG0 (a / and~e.1 :op1 (w / we~e.0) :op2 (p2 / person :mod (o / other~e.2))) :ARG1~e.5 (s2 / stimulate-01~e.17 :ARG0 (a2 / activate-01~e.6 :ARG1~e.7 (a3 / and~e.14 :op1 (p3 / protein~e.23 :name (n / name :op1 "IL-4"~e.8,10) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 23~e.12)))) :op2 (r / receptor~e.16 :name (n2 / name :op1 "IFN-alpha")))) :ARG1 (p / phosphorylate-01~e.19 :ARG1~e.20 (a4 / amino-acid :name (n3 / name :op1 "tyrosine") :part-of (p5 / protein~e.23 :name (n4 / name :op1 "IRS"~e.21) :ARG1-of (d2 / dock-01~e.22))) :ARG0-of (d3 / depend-01~e.26 :ARG1 (e / enzyme :name (n5 / name :op1 "Jak"~e.28)))))) # ::id bel_pmid_1159_1769.27854 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 10 can directly promote the death of inflammatory cells , including activated macrophages ( 4 ) , neutrophils ( 5 ) , and T cells # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1 4-1.1.3 5-1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1 10-1.1.2.1 12-1.1.2.1.2 13-1.1.2.1.2.1.1.1 14-1.1.2.1.2.1.1 16-1.1.2.1.2.1.1.2.1.1.1 19-1.1.2.1.2.1.2 21-1.1.2.1.2.1.2.1.1.1.1 24-1.1.2.1.2.1 25-1.1.2.1.2.1.3.1.1 26-1.1.2.1.2.1.3 (p / possible-01~e.3 :ARG1 (p2 / promote-02~e.5 :ARG0 (p3 / protein :name (n / name :op1 "IL-10"~e.0,2)) :ARG1 (d2 / die-01~e.7 :ARG1~e.8 (c / cell~e.10 :ARG0-of (i / inflame-01~e.9) :ARG2-of (i2 / include-01~e.12 :ARG1 (a / and~e.24 :op1 (m / macrophage~e.14 :ARG1-of (a2 / activate-01~e.13) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.16)))) :op2 (n2 / neutrophil~e.19 :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 5~e.21)))) :op3 (c4 / cell~e.26 :name (n3 / name :op1 "T"~e.25)))))) :ARG1-of (d / direct-02~e.4))) # ::id bel_pmid_1159_1769.27880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , IL @-@ 10 increases the survival of some types of human cancer cells , such as Burkitt lymphoma ( 7 ) . Non @-@ Hodgkin s lymphoma cells secrete IL @-@ 10 , and inhibition of this autocrine IL @-@ 10 has recently been shown to promote cell death and reduce expression of the anti @-@ apoptotic protein Bcl @-@ 2 # ::alignments 1-1.1 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1 8-1.1.1.2 9-1.1.1.2.1.r 10-1.1.1.2.1.1.1 11-1.1.1.2.1.1 13-1.1.1.2.1.2.3 14-1.1.1.2.1.2.2.1 15-1.1.1.2.1 18-1.2.2.2.r 19-1.1.1.2.1.2.4.1.1 20-1.1.1.2.1.2.4.1.2 22-1.1.2.1.1.1 25-1.2.1.1.1.1.1 27-1.2.1.1.1.1.1 29-1.2.1.1.1.1.2 30-1.2.1.1 31-1.2.1 32-1.2.1.2.1.1 34-1.2.1.2.1.1 36-1.2 37-1.2.2.1.1.1 40-1.2.2.1.1.1.1 41-1.2.2.1.1.1.1 42-1.2.2.1.1.1.1 43-1.2.2.1.1.1.1 45-1.2.2.2 47-1.2.2 49-1.2.2.1.1 50-1.2.2.1.1.2.1 51-1.2.2.1.1.2 52-1.2.2.1 53-1.2.2.1.2 54-1.2.2.1.2.2 55-1.2.2.1.2.2.1.r 57-1.2.2.1.2.2.1.2 59-1.2.2.1.2.2.1.2.1 60-1.1.1.1 60-1.2.1.2 60-1.2.2.1.2.2.1 61-1.2.2.1.2.2.1.1.1 63-1.2.2.1.2.2.1.1.1 (m / multi-sentence :snt1 (c / contrast-01~e.1 :ARG2 (i / increase-01~e.6 :ARG0 (p / protein~e.60 :name (n2 / name :op1 "IL-10"~e.3,5)) :ARG1 (s / survive-01~e.8 :ARG0~e.9 (c2 / cell~e.15 :ARG1-of (t / type-03~e.11 :quant (s2 / some~e.10)) :mod (d5 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.14) :mod (h / human~e.13) :mod (d / disease :name (n / name :op1 "Burkitt"~e.19 :op2 "lymphoma"~e.20)))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 7~e.22)))) :snt2 (a / and~e.36 :op1 (s3 / secrete-01~e.31 :ARG0 (c5 / cell~e.30 :mod (d4 / disease :name (n4 / name :op1 "non-Hodgkin"~e.25,27 :op2 "lymphoma"~e.29))) :ARG1 (p3 / protein~e.60 :name (n3 / name :op1 "IL-10"~e.32,34) :mod (a3 / autocrine))) :op2 (s4 / show-01~e.47 :ARG1 (a2 / and~e.52 :op1 (p4 / promote-01~e.49 :ARG0 (i2 / inhibit-01~e.37 :ARG1 p3~e.40,41,42,43) :ARG1 (d3 / die-01~e.51 :ARG1 (c6 / cell~e.50))) :op2 (r / reduce-01~e.53 :ARG0 i2 :ARG1 (e / express-03~e.54 :ARG2~e.55 (p5 / protein~e.60 :name (n5 / name :op1 "Bcl-2"~e.61,63) :ARG0-of (c7 / counter-01~e.57 :ARG1 (a4 / apoptosis~e.59)))))) :time~e.18 (r2 / recent~e.45)))) # ::id bel_pmid_1159_1769.27882 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , IL @-@ 10 increases the expression of Bcl @-@ xL in thyrocytes from patients with Graves disease # ::alignments 0-1.3 2-1.1.1.1 4-1.1.1.1 5-1 7-1.2 8-1.2.1.r 9-1.2.1.1.1 11-1.2.1.1.1 14-1.2.2.1.r 15-1.2.2.1.2.1 17-1.2.2.1.1.1.1.1 18-1.2.2.1.1.1 (i / increase-01~e.5 :ARG0 (p / protein :name (n / name :op1 "IL-10"~e.2,4)) :ARG1 (e / express-03~e.7 :ARG2~e.8 (p2 / protein :name (n2 / name :op1 "Bcl-xL"~e.9,11)) :ARG3 (t / thyrocyte :source~e.14 (p3 / person :ARG0-of (s / suffer-01 :ARG1 (d / disease~e.18 :name (n5 / name :op1 "Graves"~e.17))) :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.15))))) :ARG1-of (r / resemble-01~e.0)) # ::id bel_pmid_1160_6453.38354 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LDL , in pathophysiological concentrations , affect the IGF @-@ I signaling pathway at multiple levels : 1 ) they induce phosphorylation of IGF @-@ I receptor beta and IRS @-@ 1 in a time @- and dose @-@ dependent manner ; 2 ) they up @-@ regulate IRS @-@ 1 @-@ associated PI3 kinase @/@ Akt activation in response to IGF @-@ I at early times ; and 3 ) they show additive effects with IGF @-@ I on extracellular signal @-@ regulated MAPK 1 @/@ 2 phosphorylation . # ::alignments 0-1.1.1.1 4-1.1.2 6-1 8-1.2.1.1 10-1.2.1.1 11-1.2.2 12-1.2 12-1.3.2.1.2.2.1 13-1.3.r 14-1.3.1 15-1.3 17-1.3.2.1.1.1 19-1.3.2.1.1.2 20-1.3.2.1.1 21-1.3.2.1.1.3 22-1.3.2.1.1.3.1.r 23-1.3.2.1.1.3.1.1.1.1 25-1.3.2.1.1.3.1.1.1.1 26-1.3.2.1.1.3.1.1.1.2 27-1.3.2.1.1.3.1.1.1.3 28-1.3.2.1.1.3.1 29-1.3.2.1.1.3.1.2.1.1 31-1.3.2.1.1.1 31-1.3.2.1.1.3.1.2.1.1 34-1.3.2.1.1.4.2.1 36-1.3.2.1.1.4.2 37-1.3.2.1.1.4.2.2 39-1.3.2.1.1.4 40-1.3.2.1.1.4.r 42-1.3.2.1.2.1 47-1.3.2.1.3.3.2.2 48-1.3.2.1.1.3.1.2.1.1 50-1.3.2.1.1.1 50-1.3.2.1.1.3.1.2.1.1 52-1.3.2.1.2.2.2 53-1.3.2.1.2.2.1.1.1 54-1.3.2.1.2.2.1.1.1 56-1.3.2.1.2.2.1.1.1 57-1.3.2.1.2.2 59-1.3.2.1.2.4 61-1.3.2.1.1.3.1.1.1.1 63-1.3.2.1.1.1 63-1.3.2.1.1.3.1.2.1.1 65-1.3.2.1.2.5 66-1.3.2.1.2.5.r 68-1.3.2.1 68-1.3.2.1.3.3.2.1 69-1.3.2.1.3.1 72-1.3.2.1.3 73-1.3.2.1.3.3.3 74-1.3.2.1.3.3 76-1.3.2.1.1.3.1.1.1.1 78-1.3.2.1.1.1 78-1.3.2.1.1.3.1.2.1.1 80-1.3.2.1.3.3.2.2.1.1 81-1.3.2.1.3.3.2.2.1 83-1.3.2.1.3.3.2.2 85-1.3.2.1.1.1 85-1.3.2.1.1.3.1.2.1.1 87-1.3.2.1.2.1 88-1.3.2.1.3.3.2 (a / affect-01~e.6 :ARG0 (p6 / protein :name (n2 / name :op1 "LDL"~e.0) :quant (c / concentration~e.4 :mod (p2 / pathophysiology))) :ARG1 (p4 / pathway~e.12 :name (n3 / name :op1 "IGF-I"~e.8,10) :ARG0-of (s2 / signal-07~e.11)) :manner~e.13 (l / level~e.15 :quant (m / multiple~e.14) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.68 :op1 (i / induce-01~e.20 :li 1~e.17,31,50,63,78,85 :ARG0 p6~e.19 :ARG2 (p / phosphorylate-01~e.21 :ARG2~e.22 (a3 / and~e.28 :op1 (p3 / protein :name (n4 / name :op1 "IGF-I"~e.23,25,61,76 :op2 "receptor"~e.26 :op3 "beta"~e.27)) :op2 (p7 / protein :name (n5 / name :op1 "IRS-1"~e.29,31,48,50,63,78,85)))) :manner~e.40 (d / depend-01~e.39 :ARG0 p :ARG1 (a4 / and~e.36 :op1 (t / time~e.34) :op2 (d2 / dose~e.37)))) :op2 (u / upregulate-01 :li 2~e.42,87 :ARG1 (a5 / activate-01~e.57 :ARG1 (p8 / pathway~e.12 :name (n6 / name :op1 "PI3-kinase/Akt"~e.53,54,56)) :ARG1-of (a6 / associate-01~e.52 :ARG2 p7)) :ARG2 p6 :ARG2-of (r / respond-01~e.59 :ARG1 (p5 / protein)) :time~e.66 (e / early~e.65)) :op3 (s3 / show-01~e.72 :li 3~e.69 :ARG0 p6 :ARG1 (a7 / affect-01~e.74 :ARG0 p6 :ARG1 (p9 / phosphorylate-01~e.88 :ARG1 (a9 / and~e.68 :op1 (e3 / enzyme :name (n / name :op1 "MAPK1")) :op2 (e4 / enzyme :name (n7 / name :op1 "MAPK2"))) :ARG1-of (r2 / regulate-01~e.47,83 :ARG0 (s4 / signal-07~e.81 :mod (e2 / extracellular~e.80)))) :ARG1-of (a8 / add-02~e.73 :ARG2 p5))))))) # ::id bel_pmid_1168_9697.19254 ::amr-annotator SDL-AMR-09 ::preferred # ::tok identification of an acidic domain of gp130 as a binding region for Hck , which mediates proliferative signaling the deletion of this region of gp130 resulted in a significant reduction of Hck kinase activity and cell proliferation upon stimulation of gp130 compared to wild @-@ type gp130 # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1 6-1.1.1.2.1.1 7-1.1.2.r 9-1.1.2.1 10-1.1.2 12-1.1.2.1.1.1.1 15-1.1.2.2 17-1.1.2.2.1 19-1.2.1 20-1.2.1.1.r 21-1.2.1.1.1 22-1.1.2 24-1.2.1.1.2.1.1 25-1.2 26-1.2.2.r 28-1.2.2.2 29-1.2.2 30-1.2.2.1.r 31-1.2.2.1.1.1.1.1 32-1.1.2.1.1 32-1.2.2.1.1.1 33-1.2.2.1.1 34-1.2.2.1 35-1.2.2.1.2.1 36-1.1.2.2.1.1 36-1.2.2.1.2 38-1.2.2.4 40-1.2.2.3.1.1 41-1.2.2.3.r 43-1.2.2.3.2 45-1.2.2.3.2 46-1.2.2.3.1.1 (m / multi-sentence :snt1 (i / identify-01~e.0 :ARG1~e.1 (p / protein-segment :mod (a / acid~e.3) :part-of (p2 / protein :name (n / name :op1 "gp130"~e.6))) :ARG2~e.7 (r / region~e.10,22 :ARG2-of (b / bind-01~e.9 :ARG1 (k2 / kinase~e.32 :name (n2 / name :op1 "Hck"~e.12))) :ARG0-of (m2 / mediate-01~e.15 :ARG1 (s / signal-07~e.17 :mod (p3 / proliferate-01~e.36))))) :snt2 (r2 / result-01~e.25 :ARG1 (d / delete-01~e.19 :ARG1~e.20 (p4 / protein-segment :mod (t / this~e.21) :part-of (p5 / protein :name (n3 / name :op1 "gp130"~e.24)))) :ARG2~e.26 (r3 / reduce-01~e.29 :ARG1~e.30 (a4 / and~e.34 :op1 (a2 / activity-06~e.33 :ARG0 (k3 / kinase~e.32 :name (n4 / name :op1 "Hck"~e.31))) :op2 (p6 / proliferate-01~e.36 :ARG0 (c / cell~e.35))) :ARG2 (s2 / significant-02~e.28) :compared-to~e.41 (p7 / protein :name (n5 / name :op1 "gp130"~e.40,46) :mod (w / wild-type~e.43,45)) :condition (s3 / stimulate-01~e.38 :ARG1 p5)))) # ::id bel_pmid_1168_9697.28350 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Il6 induces the activation of the Src family kinase Hck , which is associated with the Il6 receptor beta @-@ chain , gp130 # ::alignments 1-1 3-1.2 4-1.2.1.r 6-1.2.1.2.1.1.1 7-1.2.1.2.1 8-1.2.1 9-1.2.1.1.1 13-1.2.1.3 17-1.2.1.3.1.1.2 18-1.2.1.3.1.1.3 20-1.2.1.3.1.1.3 22-1.2.1.3.1.2.1.1.1 (i / induce-01~e.1 :ARG0 (p / protein :name (n / name :op1 "IL-6")) :ARG2 (a / activate-01~e.3 :ARG1~e.4 (k2 / kinase~e.8 :name (n2 / name :op1 "Hck"~e.9) :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family~e.7 :name (n3 / name :op1 "Src"~e.6))) :ARG1-of (a2 / associate-01~e.13 :ARG2 (p3 / protein :name (n4 / name :op1 "IL-6" :op2 "receptor"~e.17 :op3 "beta-chain"~e.18,20) :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n5 / name :op1 "gp130"~e.22)))))))) # ::id bel_pmid_1168_9697.28396 ::amr-annotator SDL-AMR-09 ::preferred # ::tok this acidic domain of gp130 is responsible for the activation of Hck , Erk , Pyk2 and signals cell proliferation upon growth factor stimulation # ::alignments 0-1.1.1.3 1-1.1.1.1 4-1.1.1.2.1.1 6-1.1 7-1.1.2.r 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1 13-1.1.2.1.2.1.1 15-1.1.2.1.3.1.1 16-1 16-1.1.2.1 17-1.2 18-1.2.2.1 19-1.2.2 21-1.2.3.1 22-1.2.3.1 23-1.2.3 (a / and~e.16 :op1 (r / responsible-01~e.6 :ARG0 (p / protein-segment :mod (a3 / acid~e.1) :part-of (p2 / protein :name (n3 / name :op1 "gp130"~e.4)) :mod (t / this~e.0)) :ARG1~e.7 (a2 / activate-01~e.9 :ARG1~e.10 (a4 / and~e.16 :op1 (e2 / enzyme :name (n4 / name :op1 "Hck"~e.11)) :op2 (e3 / enzyme :name (n5 / name :op1 "Erk"~e.13)) :op3 (e4 / enzyme :name (n6 / name :op1 "Pyk2"~e.15))))) :op2 (s2 / signal-07~e.17 :ARG0 p :ARG1 (p3 / proliferate-01~e.19 :ARG0 (c / cell~e.18)) :condition (s3 / stimulate-01~e.23 :ARG2 (g / growth-factor~e.21,22)))) # ::id bel_pmid_1169_8287.20332 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It hasrecently been reported that a cytosolic isoform of PTPepsilon ( PTPepsilonC ) whenover @-@ expressed in murine M1 myeloid cells inhibits interleukin @-@ 6 ( IL @-@ 6 )- and leukemia inhibitory factor @-@ induced activation of Janus kinases ( JAKs ) , thereby suppressing STAT3 tyrosine phosphorylation and STAT3 signaling . # ::alignments 3-1 4-1.1.r 6-1.1.1.1 7-1.1.1 8-1.1.1.2.r 9-1.1.1.2.1.1 11-1.1.1.3.1.1.1 18-1.1.3.2.1.1 19-1.1.3.2.2 20-1.1.3.2 21-1.1 22-1.1.2.2.1.1.1.1 24-1.1.2.2.1.1.1.1 24-1.1.2.2.1.1.2.1.1.1 26-1.1.2.2.1.1.2.1.1.1 28-1.1.2.2.1.1.1.1 28-1.1.2.2.1.1.2.1.1.1 30-1.1.2.2.1 31-1.1.2.2.1.2.1.1 32-1.1.2.2.1.2.1.2 33-1.1.2.2.1.2.1.3 35-1.1.2.2 36-1.1.2 37-1.1.2.1.r 38-1.1.2.1.1.1 39-1.1.2.1.1.2 45-1.1.4.1 46-1.1.4.1.2.1.1.2.1.1 47-1.1.4.1.2.1.1.1.1 48-1.1.4.1.2.1 50-1.1.4.1.2.2.1 51-1.1.4.1.2.2 (r / report-01~e.3 :ARG1~e.4 (i / inhibit-01~e.21 :ARG0 (i2 / isoform~e.7 :part-of (c / cytosol~e.6) :mod~e.8 (e / enzyme :name (n2 / name :op1 "PTPepsilon"~e.9)) :ARG1-of (d2 / describe-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "PTPepsilonC"~e.11)))) :ARG1 (a / activate-01~e.36 :ARG1~e.37 (e3 / enzyme :name (n6 / name :op1 "Janus"~e.38 :op2 "kinase"~e.39)) :ARG2-of (i3 / induce-01~e.35 :ARG0 (a3 / and~e.30 :op1 (p2 / protein :name (n7 / name :op1 "interleukin-6"~e.22,24,28) :ARG1-of (d4 / describe-01 :ARG2 (p3 / protein :name (n8 / name :op1 "IL-6"~e.24,26,28)))) :op2 (p5 / protein :name (n / name :op1 "leukemia"~e.31 :op2 "inhibitory"~e.32 :op3 "factor"~e.33))))) :condition (o / overexpress-01 :ARG1 i2 :location (c2 / cell-line~e.20 :name (n4 / name :op1 "M1"~e.18) :mod (m / myeloid~e.19) :part-of (m2 / mouse))) :ARG0-of (c3 / cause-01 :ARG1 (s / suppress-01~e.45 :ARG0 i2 :ARG1 (a5 / and :op1 (p / phosphorylate-01~e.48 :ARG1 (a2 / amino-acid :name (n11 / name :op1 "tyrosine"~e.47) :part-of (p4 / protein :name (n10 / name :op1 "STAT3"~e.46)))) :op2 (s2 / signal-07~e.51 :ARG2 p4~e.50))))) :time (r2 / recent)) # ::id bel_pmid_1174_2412.20342 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Others are themselves enzymes , including the phosphotyrosine phosphatase SHP2 and the cytoplasmic tyrosine kinase Fyn . # ::alignments 3-1 5-1.1 8-1.1.1.1 9-1.1.1.1.1.1 10-1.1.1 12-1.1.1.2.2 13-1.1.1.2 14-1.1.1.2 15-1.1.1.2.1.1 (e / enzyme~e.3 :ARG2-of (i / include-01~e.5 :ARG1 (a / and~e.10 :op1 (t2 / tyrosine-phosphatase~e.8 :name (n3 / name :op1 "SHP2"~e.9) :ARG3-of (p / phosphorylate-01)) :op2 (t3 / tyrosine-kinase~e.13,14 :name (n4 / name :op1 "Fyn"~e.15) :part-of (c / cytoplasm~e.12))))) # ::id bel_pmid_1174_2412.25070 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Blockade of the pathway with dominant negative mutants or pharmacological inhibitors prevents the stimulation of cell growth by insulin , but has no effect on the metabolic actions of the hormone deletion of Akt2 produces hepatic insulin resistance in mice # ::alignments 3-1.1.1.1.1 5-1.1.1.1.2.1.2 7-1.1.1.1.2.1 7-1.1.1.1.2.1.1 7-1.1.1.1.2.1.1.r 8-1.1.1.1.2 9-1.1.1.1.2.2.2 10-1.1.1.1.2.2 10-1.1.1.1.2.2.1 10-1.1.1.1.2.2.1.r 11-1.1.1 13-1.1.1.2 14-1.1.1.2.1.r 15-1.1.1.2.1.1 16-1.1.1.2.1 17-1.1.1.2.2.r 18-1.1.1.2.2.1.1 20-1.1 22-1.1.2.1 22-1.1.2.1.r 23-1.1.2 27-1.1.2.3 28-1.1.2.3.1.r 30-1.1.2.3.1 31-1.2.1 32-1.2.1.1.r 33-1.2.1.1.1.1 34-1.2 35-1.2.2.1 36-1.2.2.2.1.1 37-1.2.2 38-1.2.3.r 39-1.2.3 (m2 / multi-sentence :snt1 (c / contrast-01~e.20 :ARG1 (p / prevent-01~e.11 :ARG0 (b / block-01 :ARG1 (p2 / pathway~e.3) :ARG3 (o / or~e.8 :op1 (g2 / gene~e.7 :ARG2-of~e.7 (m / mutate-01~e.7 :mod "-/-") :ARG0-of (d / dominate-01~e.5)) :op2 (m5 / molecular-physical-entity~e.10 :ARG0-of~e.10 (i / inhibit-01~e.10) :mod (p3 / pharmacological~e.9)))) :ARG1 (s / stimulate-01~e.13 :ARG1~e.14 (g / grow-01~e.16 :ARG1 (c2 / cell~e.15)) :ARG2~e.17 (p6 / protein :name (n / name :op1 "insulin"~e.18)))) :ARG2 (a / affect-01~e.23 :polarity~e.22 -~e.22 :ARG0 b :ARG1 (a2 / act-01~e.27 :ARG0~e.28 (h / hormone~e.30 :ARG1-of (m6 / mean-01 :ARG2 p6)) :ARG1 (m3 / metabolize-01)))) :snt2 (p4 / produce-01~e.34 :ARG0 (d2 / delete-01~e.31 :ARG1~e.32 (e / enzyme :name (n2 / name :op1 "Akt2"~e.33))) :ARG1 (r / resist-01~e.37 :ARG0 (l / liver~e.35) :ARG1 (p5 / protein :name (n3 / name :op1 "insulin"~e.36))) :location~e.38 (m4 / mouse~e.39))) # ::id bel_pmid_1174_2412.38246 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upon its activation downstream of PI( 3 ) K , Akt phosphorylates and inactivates GSK @-@ 3 , decreasing the rate of phosphorylation of glycogen synthase , thus increasing its activity state59 . # ::alignments 1-1.4.1 1-1.4.1.r 2-1.4 3-1.4.2.2 6-1.1.1.1.1 10-1.1.2.1.1 11-1.1 12-1 13-1.2 14-1.2.2 15-1.2.2 16-1.2.2 18-1.3.1 20-1.3.1.1 21-1.3.1.1.1.r 22-1.3.1.1.1 23-1.3.1.1.1.1.r 24-1.3.1.1.1.1.1.1 25-1.3.1.1.1.1.1.2 27-1.3 27-1.3.1.2 28-1.3.1.2.1 29-1.3.1.2.1.1.1.1 29-1.3.1.2.1.1.1.1.r 30-1.3.1.2.1.1.1 (a / and~e.12 :op1 (p / phosphorylate-01~e.11 :ARG1 (e4 / enzyme :name (n2 / name :op1 "GSK-3"~e.6)) :ARG2 (e / enzyme :name (n / name :op1 "Akt"~e.10))) :op2 (i / inactivate-00~e.13 :ARG0 e :ARG1 e4~e.14,15,16) :ARG0-of (c / cause-01~e.27 :ARG1 (d / decrease-01~e.18 :ARG1 (r / rate~e.20 :degree-of~e.21 (p2 / phosphorylate-01~e.22 :ARG1~e.23 (e2 / enzyme :name (n3 / name :op1 "glycogen"~e.24 :op2 "synthase"~e.25)))) :ARG0-of (c2 / cause-01~e.27 :ARG1 (i2 / increase-01~e.28 :ARG1 (s / state :mod (a2 / activity-06~e.30 :ARG0~e.29 e2~e.29)))))) :condition (a3 / activate-01~e.2 :ARG1~e.1 e~e.1 :location (r2 / relative-position :op1 (e3 / enzyme :name (n4 / name :op1 "PI(3)K")) :direction (d2 / downstream~e.3))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 59)))) # ::id bel_pmid_1175_3615.28390 ::amr-annotator SDL-AMR-09 ::preferred # ::tok interleukin @-@ 6 ( IL @-@ 6 ) or leukemia inhibitory factor ( LIF ) - induced differentiation of the myeloid cell line M1 was associated with a rapid increase in the level of mRNA encoding the signaling adaptor protein , SKAP55R # ::alignments 0-1.1.2.1.1.1.1 2-1.1.2.1.1.1.1 2-1.1.2.1.1.2.1.1.1 4-1.1.2.1.1.2.1.1.1 6-1.1.2.1.1.1.1 6-1.1.2.1.1.2.1.1.1 8-1.1.2.1 9-1.1.2.1.2.1.1 10-1.1.2.1.2.1.2 11-1.1.2.1.2.1.3 13-1.1.2.1.2.2.1.1.1 16-1.1.2 17-1.1 18-1.1.1.r 20-1.1.1.2 21-1.1.1 22-1.1.1 23-1.1.1.1.1 25-1 26-1.2.r 28-1.2.2 29-1.2 30-1.2.1.r 32-1.2.1 33-1.2.1.1.r 34-1.2.1.1.1.1 35-1.2.1.1.2 37-1.2.1.1.2.1.3 38-1.2.1.1.2.1.2 39-1.1.2.1.1 39-1.1.2.1.1.2.1 39-1.1.2.1.2 39-1.1.2.1.2.2.1 39-1.2.1.1.2.1 41-1.2.1.1.2.1.1.1 (a / associate-01~e.25 :ARG1 (d2 / differentiate-01~e.17 :ARG1~e.18 (c / cell-line~e.21,22 :name (n2 / name :op1 "M1"~e.23) :mod (m / myeloid~e.20)) :ARG2-of (i / induce-01~e.16 :ARG0 (o / or~e.8 :op1 (p / protein~e.39 :name (n3 / name :op1 "interleukin-6"~e.0,2,6) :ARG1-of (d3 / describe-01 :ARG2 (p2 / protein~e.39 :name (n4 / name :op1 "IL-6"~e.2,4,6)))) :op2 (p5 / protein~e.39 :name (n5 / name :op1 "leukemia"~e.9 :op2 "inhibitory"~e.10 :op3 "factor"~e.11) :ARG1-of (d4 / describe-01 :ARG2 (p3 / protein~e.39 :name (n6 / name :op1 "LIF"~e.13))))))) :ARG2~e.26 (i2 / increase-01~e.29 :ARG1~e.30 (l / level~e.32 :quant-of~e.33 (n / nucleic-acid :name (n7 / name :op1 "mRNA"~e.34) :ARG0-of (e / encode-01~e.35 :ARG1 (p4 / protein~e.39 :name (n9 / name :op1 "SKAP55R"~e.41) :mod (a2 / adaptor~e.38) :ARG0-of (s3 / signal-07~e.37))))) :mod (r / rapid~e.28))) # ::id bel_pmid_1177_9161.28386 ::amr-annotator SDL-AMR-09 ::preferred # ::tok inflammatory cytokines , notably Tnf @-@ alpha , and Il6 , induce the expression of Cox2 and the secretion of Pge2 in human prostate cancer cell lines # ::alignments 0-1.1.2 1-1.1 3-1.1.1.1.3 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2.1.1 11-1 13-1.2.1 14-1.2.1.1.r 15-1.2.1.1.1.1 16-1.2 18-1.2.2 19-1.2.2.1.r 20-1.2.2.1.1.1 21-1.2.r 22-1.2.3.1 23-1.2.3.2.2.1 24-1.2.3.2.2.2 25-1.2.3 26-1.2.3 (i / induce-01~e.11 :ARG0 (c3 / cytokine~e.1 :ARG2-of (i2 / include-91 :ARG1 (a2 / and~e.8 :op1 (p2 / protein :name (n2 / name :op1 "Tnf-alpha"~e.4,6)) :op2 (p3 / protein :name (n4 / name :op1 "Il6"~e.9)) :ARG1-of (n / notable-04~e.3))) :ARG0-of (i3 / inflame-01~e.0)) :ARG2~e.21 (a / and~e.16 :op1 (e / express-03~e.13 :ARG2~e.14 (e2 / enzyme :name (n5 / name :op1 "Cox2"~e.15))) :op2 (s / secrete-01~e.18 :ARG1~e.19 (s2 / small-molecule :name (n6 / name :op1 "Pge2"~e.20))) :location (c / cell-line~e.25,26 :mod (h / human~e.22) :mod (d / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate"~e.23 :op2 "cancer"~e.24))))) # ::id bel_pmid_1177_9161.28388 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the human COx2 gene contains a putative NF @-@ IL @-@ 6 element in the 5 ' @-@ flanking promoter region which can be activated by Il6 # ::alignments 1-1.1.2 2-1.1.1.1 3-1.1 4-1 6-1.2.2 7-1.2.1.1.1 9-1.2.1.1.1 11-1.2.1.1.1 12-1.2 18-1.3.1.1.1 19-1.3.2 20-1.3 22-1.2.3 22-1.2.4.2 24-1.2.4 25-1.2.4.1.r 26-1.2.4.1.1.1 (c / contain-01~e.4 :ARG0 (g / gene~e.3 :name (n / name :op1 "COx2"~e.2) :mod (h / human~e.1)) :ARG1 (e2 / element~e.12 :mod (p / protein :name (n2 / name :op1 "NF-IL-6"~e.7,9,11)) :ARG1-of (t / think-01~e.6) :ARG1-of (p3 / possible-01~e.22) :ARG1-of (a2 / activate-01~e.24 :ARG0~e.25 (p5 / protein :name (n4 / name :op1 "Il6"~e.26)) :ARG1-of (p4 / possible-01~e.22))) :location (r / region~e.20 :mod (d / dna-sequence :name (n3 / name :op1 "5'-flanking"~e.18)) :ARG0-of (p2 / promote-01~e.19))) # ::id bel_pmid_1177_9161.34138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok events lead to activation of Stat signaling and result in the induction of proteins , such as bcl @-@ 2 and cMyc , both of which are critical regulators of cell cycle progression and apoptosis # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1 8-1.2 9-1.2.2.r 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1 15-1.2.2.1.1.r 16-1.2.2.1.1.r 17-1.2.2.1.1.1.1.1 19-1.2.2.1.1.1.1.1 20-1.2.2.1.1 21-1.2.2.1.1.2.1.1 23-1.2.2.1.1.3.2 27-1.2.2.1.1.4 28-1.2.2.1.1.3 29-1.2.2.1.1.3.1.r 30-1.2.2.1.1.3.1.1.1.1 31-1.2.2.1.1.3.1.1.1 32-1.2.2.1.1.3.1.1 33-1.2.2.1.1.3.1 34-1.2.2.1.1.3.1.2 (a / and~e.7 :op1 (l / lead-03~e.1 :ARG0 (e / event~e.0) :ARG2~e.2 (a2 / activate-01~e.3 :ARG1~e.4 (s / signal-07~e.6 :ARG0 (p / protein :name (n / name :op1 "Stat"~e.5))))) :op2 (r / result-01~e.8 :ARG1 e :ARG2~e.9 (i / induce-01~e.11 :ARG2~e.12 (p2 / protein~e.13 :example~e.15,16 (a3 / and~e.20 :op1 (p3 / protein :name (n2 / name :op1 "bcl-2"~e.17,19)) :op2 (p4 / protein :name (n3 / name :op1 "cMyc"~e.21)) :ARG0-of (r2 / regulate-01~e.28 :ARG1~e.29 (a4 / and~e.33 :op1 (p5 / progress-01~e.32 :ARG1 (c2 / cycle-02~e.31 :ARG1 (c3 / cell~e.30))) :op2 (a5 / apoptosis~e.34 :mod c2)) :mod (b / both~e.23)) :ARG1-of (c / critical-02~e.27)))))) # ::id bel_pmid_1179_0801.20476 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further work revealed that TGF @-@ R signaling ( Massague and Wotton , 2000 ) was required for EMT , invasion in vitro , and metastasis in vivo , # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.2.1.1.1 6-1.2.2.1.1.1 7-1.2.2 9-1.3.1.1.1.1.1 10-1.3.1.1 11-1.3.1.1.2.1.1 13-1.3.1.2.1 16-1.2 17-1.2.1.r 18-1.2.1.1.1.2 20-1.2.1.2 21-1.2.1.2.1 22-1.2.1.2.1 24-1.2.1 25-1.2.1.3 26-1.2.1.3.1 27-1.2.1.3.1 (r / reveal-01~e.2 :ARG0 (w / work-01~e.1 :degree (f / further~e.0)) :ARG1~e.3 (r2 / require-01~e.16 :ARG0~e.17 (a2 / and~e.24 :op1 (e / event :name (n4 / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.18)) :op2 (i / invade-01~e.20 :manner (i2 / in-vitro~e.21,22)) :op3 (m / metastasis~e.25 :manner (i3 / in-vivo~e.26,27))) :ARG1 (s / signal-07~e.7 :ARG1 (p / pathway :name (n / name :op1 "TGF-R"~e.4,6)))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and~e.10 :op1 (p3 / person :name (n2 / name :op1 "Massague"~e.9)) :op2 (p4 / person :name (n3 / name :op1 "Wotton"~e.11))) :time (d2 / date-entity :year 2000~e.13)))) # ::id bel_pmid_1179_0801.21076 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Raf @/@ mitogen @-@ activated protein kinase ( MAPK ) is required for EMT , whereas activation of phosphatidylinositol 3 @-@ kinase ( PI3K ) causes scattering and protects from TGFbeta @-@ induced apoptosis . # ::alignments 0-1.2.1.1 4-1.3.1.2.1 5-1.3.1.2.2.1.1 6-1.3.1.1.1.1.1.2 8-1.2.1.1 11-1 12-1.1.r 13-1.1.1.2 15-1.3 16-1.3.1.1.1 18-1.3.1.1.1.1.1.1 19-1.3.1.1.1.1.1.2 21-1.3.1.1.1.1.1.2 25-1.3.1.1 26-1.3.1.1.2 27-1.3.1 28-1.3.1.2 29-1.3.1.2.2.r 30-1.3.1.2.2.1.1.1.1 32-1.3.1.2.2.1 33-1.3.1.2.2 (r / require-01~e.11 :ARG0~e.12 (e2 / event :name (n / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.13)) :ARG1 (p3 / pathway :name (n6 / name :op1 "Raf/MAPK"~e.0,8)) :ARG1-of (c / contrast-01~e.15 :ARG2 (a2 / and~e.27 :op1 (c2 / cause-01~e.25 :ARG0 (a3 / activate-01~e.16 :ARG1 (e / enzyme :name (n4 / name :op1 "phosphatidylinositol"~e.18 :op2 "3-kinase"~e.6,19,21))) :ARG1 (s / scatter-01~e.26)) :op2 (p5 / protect-01~e.28 :ARG0 a3~e.4 :ARG2~e.29 (a4 / apoptosis~e.33 :ARG2-of (i / induce-01~e.32 :ARG0 (p6 / protein~e.5 :name (n5 / name :op1 "TGFbeta"~e.30)))))))) # ::id bel_pmid_1179_0801.26880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to oncogenic Ras ( Oft et al. , 1996 ) , hepatocyte growth factor ( HGF ) / scatter factor ( SF ) , fibroblast growth factor ( FGF ) , and TGF alone induce mesenchymal features in diverse epithelial cell systems ( Brinkmann et al. , 1995 ; Piek et al. , 1999 ; Thiery and Chopin , 1999 ) . # ::alignments 0-1.1 0-1.4.1 0-1.4.1.1.1 1-1.1 1-1.4.1 1-1.4.1.1.1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 3-1.1.1 3-1.1.1.2 3-1.1.1.2.1.2.1 3-1.1.1.2.r 4-1.1.1.1.1 6-1.1.1.3.1.1.1.1.1 7-1.1.1.3.1.1 8-1.1.1.3.1.1.2.1 10-1.1.1.3.1.2.1 13-1.1.2.1.1.1 14-1.1.2.1.1.2 15-1.1.2.1.1.3 19-1.1.2 20-1.1.3.1.1 21-1.1.3.1.2 26-1.1.4.1.1 27-1.1.4.1.2 28-1.1.4.1.3 33-1.1 34-1.1.5.1.1 35-1.1.5.2 36-1 37-1.2.1 38-1.2 39-1.3.r 40-1.3.2 41-1.3.1.1 42-1.3.1 43-1.3 45-1.4.1.1.1.1.1.1 46-1.4.1.1.1 47-1.4.1.1.1.2.1 49-1.4.1.1.1.3.1 51-1.4.1.2.1.1.1.1 52-1.4.1.2.1 53-1.4.1.2.1.2.1 55-1.4.1.2.1.3.1 57-1.4.1.3.1.1.1.1 58-1.4.1.3.1 59-1.4.1.3.1.2.1.1 61-1.4.1.3.2 (i / induce-01~e.36 :ARG0 (a / and~e.0,1,33 :op1 (e2 / enzyme~e.2,3 :name (n / name :op1 "Ras"~e.4) :ARG0-of~e.2,3 (c / cause-01~e.2,3 :ARG1 (d7 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"~e.3))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.7 :op1 (p3 / person :name (n3 / name :op1 "Oft"~e.6)) :op2 (p4 / person :mod (o / other~e.8))) :time (d2 / date-entity :year 1996~e.10)))) :op2 (s / slash~e.19 :op1 (s4 / small-molecule :name (n2 / name :op1 "hepatocyte"~e.13 :op2 "growth"~e.14 :op3 "factor"~e.15))) :op3 (s2 / small-molecule :name (n5 / name :op1 "scatter"~e.20 :op2 "factor"~e.21) :ARG1-of d3) :op4 (p13 / protein-family :name (n8 / name :op1 "fibroblast"~e.26 :op2 "growth"~e.27 :op3 "factor"~e.28)) :op5 (p12 / protein :name (n6 / name :op1 "TGF"~e.34) :mod (a3 / alone~e.35))) :ARG2 (f / feature~e.38 :mod (m4 / mesenchyme~e.37)) :location~e.39 (s5 / system~e.43 :consist-of (c6 / cell~e.42 :mod (e / epithelium~e.41)) :mod (d6 / diverse~e.40)) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.0,1 :op1 (p5 / publication-91 :ARG0 (a5 / and~e.0,1,46 :op1 (p6 / person :name (n9 / name :op1 "Brinkmann"~e.45)) :op2 (p14 / person :mod (o2 / other~e.47)) :time (d4 / date-entity :year 1995~e.49))) :op2 (p7 / publication-91 :ARG0 (a6 / and~e.52 :op1 (p8 / person :name (n11 / name :op1 "Piek"~e.51)) :op2 (p15 / person :mod (o3 / other~e.53)) :time (d5 / date-entity :year 1999~e.55))) :op3 (p9 / publication-91 :ARG0 (a7 / and~e.58 :op1 (p10 / person :name (n13 / name :op1 "Thiery"~e.57)) :op2 (p11 / person :name (n10 / name :op1 "Chopin"~e.59))) :time d5~e.61)))) # ::id bel_pmid_1179_0801.27514 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ha @-@ Ras cooperates with transforming growth factor beta ( TGFbeta ) to cause epithelial mesenchymal transition ( EMT ) characterized by spindle @-@ like cell morphology , loss of epithelial markers , and induction of mesenchymal markers . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2.r 5-1.2.1.1 6-1.2.1.2 7-1.2.1.3 8-1.2.1.4 12-1.3 13-1.3 14-1.3.2.2 15-1.3.2.3.1.3.1.1 16-1.3.2 18-1.3.2 20-1.3.2.3 21-1.3.2.3.1.r 22-1.3.2.3.1.1.2.1 24-1.3.2.3.1.1.2 25-1.3.2.3.1.1.1 26-1.3.2.3.1.1 28-1.3.2.3.1.2 29-1.3.2.3.1.2.1.r 30-1.3.2.3.1.2.1.1 31-1.3.2.3.1.2.1 33-1.3.2.3.1 34-1.3.2.3.1.3 36-1.3.2.3.1.3.1.1 37-1.3.2.3.1.3.1 (c / cooperate-01~e.3 :ARG0 (e2 / enzyme :name (n / name :op1 "Ha-Ras"~e.0,2)) :ARG1~e.4 (p / protein :name (n3 / name :op1 "transforming"~e.5 :op2 "growth"~e.6 :op3 "factor"~e.7 :op4 "beta"~e.8)) :ARG2 (c2 / cause-01~e.12,13 :ARG0 (a2 / and :op1 e2 :op2 p) :ARG1 (t2 / transition-01~e.16,18 :ARG2 m4 :ARG3 e~e.14 :ARG1-of (c3 / characterize-01~e.20 :ARG2~e.21 (a / and~e.33 :op1 (m / morphology~e.26 :mod (c4 / cell~e.25) :ARG1-of (r / resemble-01~e.24 :ARG2 (s / spindle~e.22))) :op2 (l / lose-02~e.28 :ARG1~e.29 (m2 / marker~e.31 :mod (e / epithelium~e.30))) :op3 (i / induce-01~e.34 :ARG2 (m3 / marker~e.37 :mod (m4 / mesenchyme~e.15,36)))))))) # ::id bel_pmid_1179_0801.31150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the spindle @-@ like phenotype induced by TGF treatment ( Fig . 1 A , inset ) persisted after factor removal ( Fig . 1 B , inset ) and involved loss of E @-@ cadherin/4 @-@ integrin , whereas vimentin was strongly induced # ::alignments 1-1.1.1.1.1 3-1.1.1.1 4-1.1.1 5-1.1.1.2 6-1.1.1.2.1.r 7-1.1.1.2.1.1.1.1 8-1.1.1.2.1 10-1.1.1.2.2.1 15-1.1.1.2.2.1.2 17-1.1 18-1.1.2 20-1.1.2.1 22-1.1.1.2.2.1 22-1.1.2.1.2.1 27-1.1.1.2.2.1.2 29-1 30-1.2 31-1.2.2 33-1.2.2.1.1.1.1 37-1.2.2.1.2.1.1 39-1.3 40-1.3.1.1.1.1 42-1.3.1.2 43-1.3.1 (a / and~e.29 :op1 (p / persist-01~e.17 :ARG1 (p2 / phenotype~e.4 :ARG1-of (r / resemble-01~e.3 :ARG2 (s / spindle~e.1)) :ARG1-of (i2 / induce-01~e.5 :ARG0~e.6 (t / treat-04~e.8 :ARG2 (p5 / protein :name (n3 / name :op1 "TGF"~e.7))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.10,22 :mod "1A" :location (i3 / inset~e.15,27))))) :time (a2 / after~e.18 :op1 (r2 / remove-01~e.20 :ARG1 p5 :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.22 :mod "1B" :location i3))))) :op2 (i / involve-01~e.30 :ARG0 p2 :ARG1 (l / lose-02~e.31 :ARG1 (s2 / slash :op1 (p3 / protein :name (n / name :op1 "E-cadherin"~e.33)) :op2 (p4 / protein :name (n2 / name :op1 "4-integrin"~e.37))))) :ARG1-of (c / contrast-01~e.39 :ARG2 (i4 / induce-01~e.43 :ARG2 (p6 / protein :name (n4 / name :op1 "vimentin"~e.40)) :ARG1-of (s3 / strong-02~e.42)))) # ::id bel_pmid_1179_8191.15678 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two peroxisome proliferator @-@ activated receptor a agonsists : Wy @-@ 14643 and a marketed fribrate drug , fenofibrate # ::alignments 0-1.3.1 1-1.3.2.1.1 2-1.3.2.1.2 4-1.3.2.1.2 5-1.3.2.1.3 9-1.1.1.1 11-1.1.1.1 12-1 14-1.2.2.1 16-1.2.2 18-1.2.1.1 (a / and~e.12 :op1 (s / small-molecule :name (n / name :op1 "Wy-14643"~e.9,11)) :op3 (s2 / small-molecule :name (n2 / name :op1 "fenofibrate"~e.18) :domain (d / drug~e.16 :ARG1-of (m / market-01~e.14) :mod (f / fibrate))) :domain (a2 / agonist :quant 2~e.0 :mod (p / protein :name (n3 / name :op1 "peroxisome"~e.1 :op2 "proliferator-activated"~e.2,4 :op3 "receptor"~e.5 :op4 "alpha")))) # ::id bel_pmid_1179_8191.28334 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several pro @-@ inflammatory mediators up @-@ regulate SAA transcription , including Il1 , Il6 , TNFalpha , and Lif . # ::alignments 0-1.1.1.1 0-1.1.4 1-1.1.2 3-1.1.2.1 4-1.1 4-1.1.1 4-1.1.1.r 8-1.2.1.1.1 9-1.2 11-1.1.3 12-1.1.3.1.1.1.1 14-1.1.3.1.2.1.1 16-1.1.3.1.3.1.1 18-1.1.3.1 19-1.1.3.1.4.1.1 (u / upregulate-01 :ARG0 (m2 / molecular-physical-entity~e.4 :ARG0-of~e.4 (m / mediate-01~e.4 :quant (s / several~e.0)) :ARG0-of (f / favor-01~e.1 :ARG1 (i / inflame-01~e.3)) :ARG2-of (i2 / include-91~e.11 :ARG1 (a / and~e.18 :op1 (p / protein :name (n2 / name :op1 "Il1"~e.12)) :op2 (p2 / protein :name (n3 / name :op1 "Il6"~e.14)) :op3 (p3 / protein :name (n4 / name :op1 "TNFalpha"~e.16)) :op4 (p4 / protein :name (n5 / name :op1 "Lif"~e.19)))) :quant (s2 / several~e.0)) :ARG1 (t / transcribe-01~e.9 :ARG1 (g / gene :name (n / name :op1 "SAA"~e.8)))) # ::id bel_pmid_1179_8191.33678 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fibrates induce the peroxisomal b @-@ oxidation system of fatty acids in rodents , resulting in proliferation of peroxisomes , hepatomegaly and eventually hepatocarcinoma . # ::alignments 1-1 7-1.2 10-1.2.1.1 11-1.4.r 12-1.4 14-1.3 15-1.3.1.r 16-1.3.1.1 20-1.3.1.2 21-1.3.1 22-1.3.1.3.1 23-1.3.1.3 (i / induce-01~e.1 :ARG0 (f / fibrate) :ARG2 (s / system~e.7 :mod (o / oxidize-01 :ARG1 (a / acid~e.10 :ARG1-of (f2 / fat-03)) :mod (b / beta) :mod (p / peroxisome))) :ARG1-of (r / result-01~e.14 :ARG2~e.15 (a2 / and~e.21 :op1 (p2 / proliferate-01~e.16 :ARG0 p) :op2 (h / hepatomegaly~e.20) :op3 (h2 / hepatocarcinoma~e.23 :time (e / eventual~e.22)))) :location~e.11 (r2 / rodent~e.12)) # ::id bel_pmid_1180_3570.9290 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We note a marked and differential increase in Itih @-@ 4 labeling in proliferating hepatocytes , compared with bile duct cells in liver explant cultures treated with interleukin @-@ 6 ( IL @-@ 6 ) # ::alignments 0-1.1 1-1 3-1.2.4 5-1.2.5 6-1.2 7-1.2.1.r 8-1.2.1.1.1.1 10-1.2.1.1.1.1 11-1.2.1 12-1.2.2.r 13-1.2.2.1 14-1.2.2 16-1.2.3.r 18-1.2.3.1.1 19-1.2.3.1 20-1.2.3 21-1.2.3.2.r 22-1.2.3.2.2 23-1.2.3.2.1 24-1.2.3.2 25-1.2.3.2.3 26-1.2.3.2.3.1.r 27-1.2.3.2.3.1.1.1 29-1.2.3.2.3.1.1.1 33-1.2.3.2.3.1.1.1 (n / note-01~e.1 :ARG1 (w / we~e.0) :ARG2 (i / increase-01~e.6 :ARG1~e.7 (l / label-01~e.11 :ARG1 (p / protein :name (n2 / name :op1 "Itih-4"~e.8,10))) :location~e.12 (h / hepatocyte~e.14 :ARG0-of (p2 / proliferate-01~e.13)) :compared-to~e.16 (c2 / cell~e.20 :mod (d2 / duct~e.19 :mod (b / bile~e.18)) :location~e.21 (c3 / culture~e.24 :mod (e / explant~e.23) :mod (l2 / liver~e.22) :ARG1-of (t / treat-04~e.25 :ARG2~e.26 (p3 / protein :name (n4 / name :op1 "interleukin-6"~e.27,29,33))))) :ARG2-of (m / mark-02~e.3) :ARG1-of (d / differ-02~e.5))) # ::id bel_pmid_1180_3570.9376 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inter @-@ alpha @-@ trypsin inhibitor @-@ 4 ( Itih @-@ 4 ) is a liver @-@ restricted member of the serine protease inhibitor family with diverse functions as an anti @-@ apoptotic and matrix stabilizing molecule that are important throughout development . # ::alignments 0-1.1.1.1 2-1.1.1.1 4-1.1.1.1 5-1.1.1.2 7-1.1.1.2 11-1.1.1.2 15-1.1.2.1 17-1.1.2 21-1.2.1.1 22-1.2.1.2 23-1.2.1.3 24-1.2 26-1.1.3.3 27-1.1 27-1.1.3 27-1.1.3.r 28-1.1.3.1.r 28-1.1.3.2.1.r 30-1.1.3.1.1 32-1.1.3.1.1.1 33-1.1.3.1 34-1.1.3.1.2.2 35-1.1.3.1.2 36-1.1.3.1.2.1 39-1.1.3.2 41-1.1.3.2.1 (i / include-91 :ARG1 (p2 / protein~e.27 :name (n4 / name :op1 "Inter-alpha-trypsin"~e.0,2,4 :op2 "inhibitor-4"~e.5,7,11) :ARG1-of (r / restrict-01~e.17 :ARG2 (l / liver~e.15)) :ARG0-of~e.27 (f2 / function-01~e.27 :ARG1~e.28 (a2 / and~e.33 :op1 (c / counter-01~e.30 :ARG1 (a3 / apoptosis~e.32)) :op2 (s / stabilize-01~e.35 :ARG0 (m / molecule~e.36) :ARG1 (m2 / matrix~e.34))) :mod (i3 / important~e.39 :time~e.28 (d / develop-01~e.41)) :mod (d2 / diverse~e.26))) :ARG2 (p3 / protein-family~e.24 :name (n3 / name :op1 "serine"~e.21 :op2 "protease"~e.22 :op3 "inhibitor"~e.23))) # ::id bel_pmid_1182_0727.27898 ::amr-annotator SDL-AMR-09 ::preferred # ::tok tryosine phosphorylation of gp130 was observed in fibroblasts after stimulation with all the cytokines # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2.1.1 5-1 6-1.2.r 7-1.2 8-1.3 9-1.3.1 10-1.3.1.1.r 11-1.3.1.1.1 13-1.3.1.1 (o / observe-01~e.5 :ARG1 (p / phosphorylate-01~e.1 :ARG1~e.2 (a / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (p2 / protein :name (n / name :op1 "gp130"~e.3)))) :location~e.6 (f / fibroblast~e.7) :time (a2 / after~e.8 :op1 (s / stimulate-01~e.9 :ARG2~e.10 (c / cytokine~e.13 :mod (a3 / all~e.11))))) # ::id bel_pmid_1183_2424.8080 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have previously shown that B cell lymphoma @/@ leukemia @-@ 2 ( bcl @-@ 2 ) -/- mice develop cystic kidneys and exhibit sustained phosphorylation of FAK and paxillin . # ::alignments 0-1.1 2-1.3 3-1 11-1.2.1.1.1.1.1 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1 17-1.2.1.1.1.2.1 18-1.2.1.1 19-1.2.1 20-1.2.1.2.1 21-1.2.1.2 22-1.2 23-1.2.2 24-1.2.2.2.2 25-1.2.2.2 26-1.2.2.2.1.r 27-1.2.2.2.1.1.1.1 28-1.2.2.2.1 29-1.2.2.2.1.2.1.1 (s / show-01~e.3 :ARG0 (w / we~e.0) :ARG1 (a / and~e.22 :op1 (d / develop-01~e.19 :ARG1 (m / mouse~e.18 :mod (p5 / protein :name (n3 / name :op1 "bcl-2"~e.11,13,15) :ARG2-of (m3 / mutate-01 :mod "-/-"~e.17))) :ARG2 (k2 / kidney~e.21 :mod (c / cyst~e.20))) :op2 (e / exhibit-01~e.23 :ARG0 m :ARG1 (p / phosphorylate-01~e.25 :ARG1~e.26 (a2 / and~e.28 :op1 (e2 / enzyme :name (n / name :op1 "FAK"~e.27)) :op2 (p3 / protein :name (n2 / name :op1 "paxillin"~e.29))) :ARG1-of (s2 / sustain-01~e.24)))) :time (p4 / previous~e.2)) # ::id bel_pmid_1183_2424.8082 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cystic kidneys from postnatal day 20 bcl @-@ 2 -/- mice demonstrate a reduced expression , sixfold decrease in activity , and altered distribution of SHP @-@ 2 and PTP 1B # ::alignments 0-1.1.1 1-1.1 2-1.1.3.r 3-1.1.3.1.1.1.r 3-1.1.4 3-1.1.4.1 3-1.1.4.1.r 4-1.1.2 5-1.1.2.1 6-1.1.3.1.1.1 8-1.1.3.1.1.1 9-1.1.3.1.2.1 10-1.1.3 11-1 13-1.2.1 14-1.2.1.1 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1 21-1.2 22-1.2.3.2 23-1.2.3 24-1.2.3.1.r 25-1.2.3.1.1.1.1 27-1.2.3.1.1.1.1 29-1.2.3.1.2.1.1 30-1.2.3.1.2.1.2 (d / demonstrate-01~e.11 :ARG0 (k / kidney~e.1 :mod (c / cyst~e.0) :time (d2 / day~e.4 :value 20~e.5) :source~e.2 (m / mouse~e.10 :mod (p2 / protein :name (n / name :op1~e.3 "bcl-2"~e.6,8) :ARG2-of (m2 / mutate-01 :mod "-/-"~e.9))) :time (a5 / after~e.3 :op1~e.3 (b / bear-02~e.3))) :ARG1 (a / and~e.21 :op1 (r2 / reduce-01~e.13 :ARG1-of (e / express-03~e.14)) :op2 (d3 / decrease-01~e.17 :ARG1~e.18 (a2 / activity-06~e.19) :ARG2 (p / product-of :op1 6)) :op3 (d4 / distribute-01~e.23 :ARG1~e.24 (a3 / and :op1 (p3 / protein :name (n2 / name :op1 "SHP-2"~e.25,27)) :op2 (e2 / enzyme :name (n3 / name :op1 "PTP"~e.29 :op2 "1B"~e.30))) :ARG1-of (a4 / alter-01~e.22)))) # ::id bel_pmid_1183_2424.8084 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cystic kidneys from postnatal day 20 bcl @-@ 2 -/- mice demonstrate a reduced expression , sixfold decrease in activity , and altered distribution of SHP @-@ 2 and PTP 1B . # ::alignments 0-1.1.1 1-1.1 2-1.1.3.r 3-1.1.3.1.1.1.r 3-1.1.4 3-1.1.4.1 3-1.1.4.1.r 4-1.1.2 5-1.1.2.1 6-1.1.3.1.1.1 8-1.1.3.1.1.1 9-1.1.3.1.2.1 10-1.1.3 11-1 13-1.2.1 14-1.2.1.1 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1 21-1.2 22-1.2.3.2 23-1.2.3 24-1.2.3.1.r 25-1.2.3.1.1.1.1 27-1.2.3.1.1.1.1 29-1.2.3.1.2.1.1 30-1.2.3.1.2.1.2 (d / demonstrate-01~e.11 :ARG0 (k / kidney~e.1 :mod (c / cyst~e.0) :time (d2 / day~e.4 :value 20~e.5) :source~e.2 (m / mouse~e.10 :mod (p2 / protein :name (n / name :op1~e.3 "bcl-2"~e.6,8) :ARG0-of (m2 / mutate-01 :mod "-/-"~e.9))) :time (a5 / after~e.3 :op1~e.3 (b / bear-02~e.3))) :ARG1 (a / and~e.21 :op1 (r / reduce-01~e.13 :ARG1 (e / express-03~e.14)) :op2 (d3 / decrease-01~e.17 :ARG1~e.18 (a2 / activity-06~e.19) :ARG2 (p / product-of :op1 6)) :op3 (d4 / distribute-01~e.23 :ARG1~e.24 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "SHP-2"~e.25,27)) :op2 (e2 / enzyme :name (n2 / name :op1 "PTP"~e.29 :op2 "1B"~e.30))) :ARG1-of (a4 / alter-01~e.22)))) # ::id bel_pmid_1190_2577.36732 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The primary substrates of CDK4 @/@ 6 and CDK2 in G1 progression are the members of the retinoblastoma protein family RB , p107 and p130 The activity of the RB proteins is modulated by sequential phosphorylation by CDK4 @/@ 6 cyclinD and CDK2 cyclinE complexes # ::alignments 1-1.1.1.3 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.2.1.1 9-1.1.1.2.r 10-1.1.1.2.1.1.1 11-1.1.1.2 17-1.1.2.1.1 18-1.1.2 18-1.1.2.2.1.1 18-1.1.2.2.1.2 18-1.1.2.2.1.3 19-1.1.2 20-1.1.2.2.1.1.1.1 22-1.1.2.2.1.2.1.1 23-1.1.2.2.1 24-1.1.2.2.1.3.1.1 26-1.2.2 29-1.2.2.1.1.1 30-1.2.1.1.1.2 30-1.2.1.1.2.2 30-1.2.2.1 32-1.2 33-1.2.1.r 34-1.2.1.2 35-1.2.1 36-1.2.1.1.r 37-1.2.1.1.1.1.1.1 39-1.2.1.1.1.1.1.1 40-1.2.1.1.1.2.1.1 41-1.2.1.1 42-1.2.1.1.2.1.1.1 43-1.2.1.1.2.2.1.1 44-1.2.1.1.1 44-1.2.1.1.2 (m / multi-sentence :snt1 (i / include-91 :ARG1 (s5 / substrate~e.2 :poss~e.3 (a5 / and~e.7 :op1 (e3 / enzyme :name (n9 / name :op1 "CDK4/6"~e.4,6)) :op2 (e4 / enzyme :name (n10 / name :op1 "CDK2"~e.8))) :time~e.9 (p9 / progress-01~e.11 :ARG1 (e5 / event :name (n12 / name :op1 "G1"~e.10))) :mod (p10 / primary~e.1)) :ARG2 (p / protein-family~e.18,19 :name (n / name :op1 "retinoblastoma"~e.17) :ARG1-of (m2 / mean-01 :ARG2 (a / and~e.23 :op1 (p2 / protein~e.18 :name (n2 / name :op1 "RB"~e.20)) :op2 (p3 / protein~e.18 :name (n3 / name :op1 "p107"~e.22)) :op2 (p4 / protein~e.18 :name (n4 / name :op1 "p130"~e.24)))))) :snt2 (m3 / modulate-01~e.32 :ARG0~e.33 (p5 / phosphorylate-01~e.35 :ARG2~e.36 (a2 / and~e.41 :op1 (m4 / macro-molecular-complex~e.44 :op1 (e / enzyme :name (n5 / name :op1 "CDK4/6"~e.37,39)) :op2 (p7 / protein~e.30 :name (n7 / name :op1 "cyclinD"~e.40))) :op2 (m5 / macro-molecular-complex~e.44 :op1 (e2 / enzyme :name (n11 / name :op1 "CDK2"~e.42)) :op2 (p8 / protein~e.30 :name (n8 / name :op1 "cyclinE"~e.43)))) :mod (s3 / sequence~e.34)) :ARG1 (a3 / activity-06~e.26 :ARG0 (p6 / protein~e.30 :name (n6 / name :op1 "RB"~e.29))))) # ::id bel_pmid_1190_2577.37122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibitory phosphorylation of adjacent threonine and tyrosine residues ( T14/Y15 in CDK1 ) is mediated by dualspecificity kinases ( such as WEE1 and MYT1 ) . This inhibition is relieved when the CDC25 phosphatases ( CDC25A , CDC25B and CDC25C ) dephosphorylate these residues , which triggers entry into mitosis # ::alignments 0-1.1.2.2 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1.3 4-1.1.2.1.1.1.1.1 5-1.1.2.1 6-1.1.2.1.2.1.1.1 7-1.1.2.1.1 7-1.1.2.1.2 11-1.1.2.1.1.1.2.1.1 14-1.1 15-1.1.1.r 16-1.1.1.1 17-1.1.1 17-1.1.1.2.1 17-1.1.1.2.2 19-1.1.1.2.r 20-1.1.1.2.r 21-1.1.1.2.1.1.1 22-1.1.1.2 23-1.1.1.2.2.1.1 26-1.2.1.1 27-1.2.1 29-1.2 30-1.2.2.r 32-1.2.2.2.1.1 33-1.2.2.2 35-1.2.2.2.2.1.1.1.1 37-1.2.2.2.2.1.2.1.1 38-1.2.2.2.2.1 39-1.2.2.2.2.1.3.1.1 41-1.2.2 42-1.2.2.1.1 43-1.2.2.1 46-1.2.2.3 47-1.2.2.3.1 48-1.2.2.3.1.1.r 49-1.2.2.3.1.1 (m / multi-sentence :snt1 (m2 / mediate-01~e.14 :ARG0~e.15 (k / kinase~e.17 :mod (d / dualspecificity~e.16) :example~e.19,20 (a5 / and~e.22 :op1 (k2 / kinase~e.17 :name (n4 / name :op1 "WEE1"~e.21)) :op2 (k3 / kinase~e.17 :name (n5 / name :op1 "MYT1"~e.23)))) :ARG1 (p / phosphorylate-01~e.1 :ARG1~e.2 (a7 / and~e.5 :op1 (r / residue~e.7 :mod (a / amino-acid :name (n / name :op1 "threonine"~e.4) :part-of (e5 / enzyme :name (n3 / name :op1 "CDK1"~e.11)))) :op2 (r3 / residue~e.7 :mod (a2 / amino-acid :name (n2 / name :op1 "tyrosine"~e.6) :part-of e5)) :mod (a4 / adjacent~e.3)) :ARG0-of (i / inhibit-01~e.0))) :snt2 (r2 / relieve-01~e.29 :ARG1 (i2 / inhibit-01~e.27 :mod (t / this~e.26)) :time~e.30 (d2 / dephosphorylate-01~e.41 :ARG1 (r4 / residue~e.43 :mod (t2 / this~e.42)) :ARG2 (p3 / phosphatase~e.33 :name (n6 / name :op1 "CDC25"~e.32) :ARG2-of (i3 / include-91 :ARG1 (a3 / and~e.38 :op1 (e / enzyme :name (n7 / name :op1 "CDC25A"~e.35)) :op2 (e2 / enzyme :name (n8 / name :op1 "CDC25B"~e.37)) :op3 (e3 / enzyme :name (n9 / name :op1 "CDC25C"~e.39))))) :ARG0-of (t4 / trigger-01~e.46 :ARG1 (e4 / enter-01~e.47 :ARG1~e.48 (m4 / mitosis~e.49)))))) # ::id bel_pmid_1190_2577.37858 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CDK2 is sequentially activated by the E @-@ type cyclins cyclin E1 and E2 during the G1/S transition , and the A @-@ type cyclins cyclin A1 and A2 during S phase # ::alignments 0-1.2.1.1 2-1.3 3-1 4-1.1.r 6-1.1.1.1.2 8-1.1.1 8-1.1.1.3 8-1.1.1.3.r 9-1.1.1.1.1 10-1.1.1.3.1.1.1.1 11-1.1.1.3.1.1.1.2 12-1.1.1.3.1 13-1.1.1.3.1.2.1.2 14-1.1.1.2.r 17-1.1.1.2 19-1.1.1.3.1 21-1.1.2.1.2 23-1.1.2 23-1.1.2.2 23-1.1.2.2.r 24-1.1.2.1.1 25-1.1.2.2.1.1.1.1 26-1.1.2.2.1.1.1.2 27-1.1.2.2.1 28-1.1.2.2.1.2.1.2 29-1.1.1.2.r 29-1.1.2.3.r 30-1.1.1.2.1.1.1 (a / activate-01~e.3 :ARG0~e.4 (a2 / and :op1 (p5 / protein~e.8 :name (n4 / name :op1 "cyclin"~e.9 :op2 "E"~e.6) :time~e.14,29 (t / transition-01~e.17 :ARG2 (e3 / event :name (n9 / name :op1 "S"~e.30)) :ARG3 (e / event :name (n7 / name :op1 "G1"))) :ARG2-of~e.8 (t4 / type-03~e.8 :ARG1 (a3 / and~e.12,19 :op1 (p7 / protein :name (n11 / name :op1 "cyclin"~e.10 :op2 "E1"~e.11)) :op2 (p8 / protein :name (n12 / name :op1 "cyclin" :op2 "E2"~e.13))))) :op2 (p / protein~e.23 :name (n2 / name :op1 "cyclin"~e.24 :op2 "A"~e.21) :ARG2-of~e.23 (t2 / type-03~e.23 :ARG1 (a4 / and~e.27 :op1 (p2 / protein :name (n / name :op1 "cyclin"~e.25 :op2 "A1"~e.26)) :op2 (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "A2"~e.28)))) :time~e.29 e3)) :ARG1 (e2 / enzyme :name (n8 / name :op1 "CDK2"~e.0)) :manner (s / sequence~e.2)) # ::id bel_pmid_1190_2577.37928 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CKIs are of two types( reviewed in REF . 17 ) . The four members of the INK4 family INK4A ( also known as p16 ) ,INK4B( also known as p15 ) ,INK4C ( also known as p18 ) and INK4D ( also known as p19 ) exert their inhibitory activity by binding to the CDK4 and CDK6 kinases and preventing their association with D @-@ type cyclins # ::alignments 3-1.2.1 5-1.2.3 6-1.2.3.1.r 7-1.2.3.1 9-1.2.3.1.1 17-1.1.1.5.1.1.1 18-1.1.1.4.2.1 19-1.1.1.1.1.1 21-1.1.1.1.2.2 22-1.1.1.1 22-1.1.1.1.2 22-1.1.1.1.2.1.1.r 22-1.1.1.1.2.r 23-1.1.1.1.2.1.1.r 24-1.1.1.1.2.1.1.1 27-1.1.1.1.2.2 28-1.1.1.1 28-1.1.1.1.1.r 28-1.1.1.1.2 28-1.1.1.1.2.1.1.r 28-1.1.1.1.2.r 28-1.1.1.2 28-1.1.1.2.1.r 28-1.1.1.2.2 28-1.1.1.2.2.1.1.r 28-1.1.1.2.2.r 28-1.1.1.3 28-1.1.1.3.1.r 28-1.1.1.3.2 28-1.1.1.3.2.1.1.r 28-1.1.1.3.2.r 28-1.1.1.4 28-1.1.1.4.1.r 28-1.1.1.4.2 28-1.1.1.4.2.r 28-1.1.1.5.1.1.r 29-1.1.1.1.1.r 29-1.1.1.1.2.1.1.r 29-1.1.1.2.1.r 29-1.1.1.2.2.1.1.r 29-1.1.1.3.1.r 29-1.1.1.3.2.1.1.r 29-1.1.1.4.1.r 29-1.1.1.4.2.1.1.r 29-1.1.1.5.1.1.r 30-1.1.1.2.2.1.1.1 34-1.1.1.2.2.2 35-1.1.1.1 35-1.1.1.1.1.r 35-1.1.1.1.2 35-1.1.1.1.2.1.1.r 35-1.1.1.1.2.r 35-1.1.1.2 35-1.1.1.2.1.r 35-1.1.1.2.2 35-1.1.1.2.2.1.1.r 35-1.1.1.2.2.r 35-1.1.1.3 35-1.1.1.3.1.r 35-1.1.1.3.2 35-1.1.1.3.2.1.1.r 35-1.1.1.3.2.r 35-1.1.1.4 35-1.1.1.4.1.r 35-1.1.1.4.2 35-1.1.1.4.2.r 35-1.1.1.5.1.1.r 36-1.1.1.1.1.r 36-1.1.1.1.2.1.1.r 36-1.1.1.2.1.r 36-1.1.1.2.2.1.1.r 36-1.1.1.3.1.r 36-1.1.1.3.2.1.1.r 36-1.1.1.4.1.r 36-1.1.1.4.2.1.1.r 36-1.1.1.5.1.1.r 37-1.1.1.3.2.1.1.1 39-1.1.1 40-1.1.1.4.1.1 42-1.1.1.1.2.2 43-1.1.1.1 43-1.1.1.1.2 43-1.1.1.1.2.r 43-1.1.1.2 43-1.1.1.2.1.r 43-1.1.1.2.2 43-1.1.1.2.2.1.1.r 43-1.1.1.2.2.r 43-1.1.1.3 43-1.1.1.3.1.r 43-1.1.1.3.2 43-1.1.1.3.2.1.1.r 43-1.1.1.3.2.r 43-1.1.1.4 43-1.1.1.4.1.r 43-1.1.1.4.2 43-1.1.1.4.2.r 43-1.1.1.5.1.1.r 44-1.1.1.2.1.r 44-1.1.1.2.2.1.1.r 44-1.1.1.3.1.r 44-1.1.1.3.2.1.1.r 44-1.1.1.4.1.r 44-1.1.1.5.1.1.r 45-1.1.1.4.2.1.1.1 47-1.1 49-1.1.2.2 50-1.1.2 51-1.1.3.r 52-1.1.3.1 55-1.1.3.1.1.1.1.1 56-1.1.3.1.1 57-1.1.3.1.1.2.1.1 58-1.1.3.1.1.1 58-1.1.3.1.1.2 59-1.1.3 59-1.1.3.1.1 60-1.1.3.2 61-1.1.3.2.1.1 61-1.1.3.2.1.1.r 62-1.1.3.2.1 63-1.1.3.2.1.2.r 64-1.1.3.2.1.2.1.2 66-1.2 67-1.1.3.2.1.2.1.1 (m / multi-sentence :snt2 (e2 / exert-01~e.47 :ARG0 (a / and~e.39 :op1 (p / protein~e.22,28,35,43 :name~e.28,29,35,36 (n2 / name :op1 "INK4A"~e.19) :ARG1-of~e.22,28,35,43 (k / know-02~e.22,28,35,43 :ARG2 (p5 / protein :name~e.22,23,28,29,35,36 (n6 / name :op1 "p16"~e.24)) :mod (a5 / also~e.21,27,42))) :op2 (p2 / protein~e.28,35,43 :name~e.28,29,35,36,43,44 (n3 / name :op1 "INK4B") :ARG1-of~e.28,35,43 (k2 / know-02~e.28,35,43 :ARG2 (p6 / protein :name~e.28,29,35,36,43,44 (n7 / name :op1 "p15"~e.30)) :mod a5~e.34)) :op3 (p3 / protein~e.28,35,43 :name~e.28,29,35,36,43,44 (n4 / name :op1 "INK4C") :ARG1-of~e.28,35,43 (k3 / know-02~e.28,35,43 :ARG2 (p7 / protein :name~e.28,29,35,36,43,44 (n8 / name :op1 "p18"~e.37)) :mod a5)) :op4 (p4 / protein~e.28,35,43 :name~e.28,29,35,36,43,44 (n5 / name :op1 "INK4D"~e.40) :ARG1-of~e.28,35,43 (k4 / know-02~e.28,35,43 :ARG2 (p8 / protein-family~e.18 :name~e.29,36 (n9 / name :op1 "p19"~e.45)) :mod a5)) :ARG1-of (i2 / include-91 :ARG2 (p10 / protein :name~e.28,29,35,36,43,44 (n12 / name :op1 "INK4"~e.17)))) :ARG1 (a3 / activity-06~e.50 :ARG0 a :ARG1 (i / inhibit-01~e.49 :ARG0 a)) :manner~e.51 (a4 / and~e.59 :op1 (b / bind-01~e.52 :ARG1 (a2 / and~e.56,59 :op1 (k5 / kinase~e.58 :name (n10 / name :op1 "CDK4"~e.55)) :op2 (k6 / kinase~e.58 :name (n11 / name :op1 "CDK6"~e.57)))) :op2 (p9 / prevent-01~e.60 :ARG1 (a6 / associate-01~e.62 :ARG1~e.61 a2~e.61 :ARG2~e.63 (p13 / protein :name (n13 / name :op1 "cyclin"~e.67 :op2 "D"~e.64)))))) :snt1 (t / type-03~e.66 :quant 2~e.3 :ARG1 (e / enzyme :name (n / name :op1 "CKI")) :ARG1-of (r / review-02~e.5 :medium~e.6 (r2 / ref~e.7 :mod 17~e.9)))) # ::id bel_pmid_1190_9529.24784 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cotransfection of JAK1 or JAK3 with TCPTP @-@ WT resulted in substantial dephosphorylation of the kinases # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1.1 3-1.1.1.1 4-1.1.1.1.2.1.1 6-1.1.1.2.1.1 8-1.1.1.2.2 9-1 10-1.2.r 11-1.2.2 12-1.2 (r / result-01~e.9 :ARG1 (c / cotransfect-01~e.0 :ARG2~e.1 (a / and :op1 (o / or~e.3 :op1 (e2 / enzyme :name (n / name :op1 "JAK1"~e.2)) :op2 (e / enzyme :name (n2 / name :op1 "JAK3"~e.4))) :op2 (p3 / protein :name (n3 / name :op1 "TCPTP"~e.6) :mod (w / wild-type~e.8)))) :ARG2~e.10 (d / dephosphorylate-01~e.12 :ARG1 o :degree (s / substantial~e.11))) # ::id bel_pmid_1190_9529.30256 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblotting with a phospho @-@ STAT1 antibody revealed an increase in STAT1 phosphorylation in TCPTP @-@ deficient thymocytes # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.1.2 5-1.1.1.1.1.1.1 6-1.1.1 7-1 9-1.2 11-1.1.1.1.1.1.1 12-1.1.1.1.1.2 12-1.2.1 13-1.2.2.r 14-1.2.2.2.1.1.1 (r / reveal-01~e.7 :ARG0 (i / immunoblot-01~e.0 :ARG3~e.1 (a / antibody~e.6 :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n / name :op1 "STAT1"~e.5,11) :ARG3-of (p5 / phosphorylate-01~e.3,12))))) :ARG1 (i2 / increase-01~e.9 :ARG1 (p2 / phosphorylate-01~e.12 :ARG1 p) :location~e.13 (c2 / cell :name (n4 / name :op1 "thymocyte") :ARG0-of (l2 / lack-01 :ARG1 (p4 / protein :name (n3 / name :op1 "TCPTP"~e.14)))))) # ::id bel_pmid_1197_1957.1966 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PKA also decreased Raf @-@ 1 serine 338 phosphorylation of Raf @-@ 1 , previously shown to be required for Raf @-@ 1 activation . # ::alignments 0-1.1.1.1 1-1.3 2-1 3-1.2.1.3.1.1 5-1.2.1.3.1.1 6-1.2.1.2.1 7-1.2.1.1 8-1.2 10-1.2.1.3.1.1 12-1.2.1.3.1.1 14-1.2.3.2.1 15-1.2.3.2 18-1.2.3 19-1.2.3.1.r 20-1.2.3.1.1 21-1.2.3.1.1 22-1.2.3.1.1 23-1.2.3.1 (d / decrease-01~e.2 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA"~e.0)) :ARG1 (p / phosphorylate-01~e.8 :ARG1 (a / amino-acid :mod 338~e.7 :name (n3 / name :op1 "serine"~e.6) :part-of (e / enzyme :name (n / name :op1 "Raf-1"~e.3,5,10,12))) :ARG2 e :ARG1-of (r / require-01~e.18 :purpose~e.19 (a4 / activate-01~e.23 :ARG1 e~e.20,21,22) :ARG1-of (s2 / show-01~e.15 :time (p2 / previous~e.14)))) :mod (a2 / also~e.1)) # ::id bel_pmid_1197_1957.37446 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cyclic AMP ( cAMP ) - dependent protein kinase ( PKA ) can inhibit Raf @-@ 1 by direct phosphorylation . We have mapped all cAMP @-@ induced phosphorylation sites in Raf @-@ 1 , showing that serines 43 , 259 , and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo . # ::alignments 4-1.1.1.1.2.1 7-1.1.1.1 7-1.1.1.1.2 7-1.1.1.1.2.r 8-1.1.1.1.1.1 9-1.1.1.1.1.2 11-1.2.3.1.2.1.2.1.1 13-1.1 14-1.1.1 15-1.1.1.2.1.1 17-1.1.1.2.1.1 18-1.1.1.3.r 19-1.1.1.3.1 20-1.1.1.3 22-1.2.1 24-1.2 25-1.2.2.4 26-1.2.2.3.1.1.1 28-1.2.2.3 29-1.2.2.2 30-1.2.2 31-1.2.2.1.r 31-1.2.3.1.2.1.3 32-1.2.2.1.1.1 34-1.2.2.1.1.1 36-1.2.3.1 38-1.2.3.1.2.1.1.1.2.1 38-1.2.3.1.2.1.1.2.2.1 38-1.2.3.1.2.1.1.3.2.1 39-1.2.3.1.2.1.1.1.1 41-1.2.3.1.2.1.1.2.1 44-1.2.3.1.2.1.1.3.1 46-1.2.3.1.2.1 48-1.2.3.1.2.1.2.1.1 49-1.2.3.1.2.1.3 50-1.2.3.1.2.1.3 51-1.2.3.1.2 52-1.2.3.1.2.2 53-1.2.3.1.2.2.1.r 54-1.2.3.1.2.2.1 55-1.2.3.1.2.2.3 56-1.2.3.1.2.2.3 (m / multi-sentence :snt1 (p2 / possible-01~e.13 :ARG1 (i / inhibit-01~e.14 :ARG0 (e5 / enzyme~e.7 :name (n5 / name :op1 "protein"~e.8 :op2 "kinase"~e.9) :ARG0-of~e.7 (d2 / depend-01~e.7 :ARG1 s~e.4)) :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"~e.15,17)) :manner~e.18 (p4 / phosphorylate-01~e.20 :ARG1-of (d / direct-02~e.19)))) :snt2 (m3 / map-01~e.24 :ARG0 (w / we~e.22) :ARG1 (p3 / protein-segment~e.30 :location~e.31 (e2 / enzyme :name (n4 / name :op1 "Raf-1"~e.32,34)) :ARG1-of (p / phosphorylate-01~e.29) :ARG2-of (i2 / induce-01~e.28 :ARG0 (s / small-molecule :name (n10 / name :op1 "cAMP"~e.26))) :mod (a / all~e.25)) :ARG0-of (c2 / cause-01 :ARG1 (s2 / show-01~e.36 :ARG0 w :ARG1 (a7 / and~e.51 :op1 (p6 / phosphorylate-01~e.46 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod 43~e.39 :name (n6 / name :op1 "serine"~e.38)) :op2 (a4 / amino-acid :mod 259~e.41 :name (n7 / name :op1 "serine"~e.38)) :op3 (a5 / amino-acid :mod 621~e.44 :name (n8 / name :op1 "serine"~e.38))) :ARG2 (e3 / enzyme :name (n9 / name :op1 "PKA"~e.11,48)) :manner (i3 / in-vitro~e.31,49,50)) :op2 (i4 / induce-01~e.52 :ARG0~e.53 s~e.54 :ARG2 a2 :manner (i5 / in-vivo~e.55,56))))))) # ::id bel_pmid_1202_1251.10412 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , LPS from Escherichia coli stimulated mast cells in a TLR4 @-@ dependent manner to produce TNF @-@ alpha , IL @-@ 1 beta , IL @-@ 6 , and IL @-@ 13 , but not IL @-@ 4 nor IL @-@ 5 . # ::alignments 1-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.1.1.2 7-1.1 8-1.1.2.1 9-1.1.2 12-1.1.3.1.1.1 14-1.1.3 15-1.1.3.r 16-1.1.4.r 17-1.1.4.1 17-1.1.4.2 18-1.1.4.1.2.1.1.1 20-1.1.4.1.2.1.1.1 22-1.1.4.1.2.2.1.1 22-1.1.4.1.2.3.1.1 22-1.1.4.1.2.4.1.1 27-1.1.4.1.2.2.1.1 27-1.1.4.1.2.3.1.1 27-1.1.4.1.2.4.1.1 29-1.1.4.1.2.3.1.1 31-1.1.4.1.2 32-1.1.4.1.2.2.1.1 32-1.1.4.1.2.3.1.1 32-1.1.4.1.2.4.1.1 34-1.1.4.1.2.4.1.1 36-1.1.4 37-1.1.4.2.1 37-1.1.4.2.1.r 38-1.1.4.2.3.1.1.1 40-1.1.4.2.3.1.1.1 41-1.1.4.2.1.r 42-1.1.4.2.3.1.1.1 42-1.1.4.2.3.2.1.1 44-1.1.4.2.3.2.1.1 (c / contrast-01~e.1 :ARG2 (s / stimulate-01~e.7 :ARG0 (l / lipopolysaccharide~e.3 :source~e.4 (o / organism :name (n2 / name :op1 "Escherichia"~e.5 :op2 "coli"~e.6))) :ARG1 (c3 / cell~e.9 :mod (m2 / mast~e.8)) :manner~e.15 (d / depend-01~e.14 :ARG1 (p / protein :name (n3 / name :op1 "TLR4"~e.12))) :purpose~e.16 (c4 / contrast-01~e.36 :ARG1 (p8 / produce-01~e.17 :ARG0 c3 :ARG1 (a / and~e.31 :op1 (p2 / protein :name (n4 / name :op1 "TNF-alpha"~e.18,20)) :op2 (p3 / protein :name (n5 / name :op1 "IL-1beta"~e.22,27,32)) :op3 (p4 / protein :name (n6 / name :op1 "IL-6"~e.22,27,29,32)) :op4 (p5 / protein :name (n7 / name :op1 "IL-13"~e.22,27,32,34)))) :ARG2 (p9 / produce-01~e.17 :polarity~e.37,41 -~e.37 :ARG0 c3 :ARG1 (a2 / and :op1 (p6 / protein :name (n8 / name :op1 "IL-4"~e.38,40,42)) :op2 (p7 / protein :name (n9 / name :op1 "IL-5"~e.42,44))))))) # ::id bel_pmid_1202_3369.1246 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like IL @-@ 12 , IL @-@ 23 binds to the IL @-@ 12R subunit IL @-@ 12Rbeta1 . # ::alignments 0-1.1 0-1.1.2 0-1.1.2.r 1-1.1.2.1.1.1 3-1.1.2.1.1.1 5-1.1.1.1 5-1.1.2.1.1.1 7-1.1.1.1 8-1 11-1.1.1.1 11-1.2.2.1.1.1 13-1.2.2.1.1.1 15-1.2.1.1 15-1.2.2.1.1.1 17-1.2.1.1 (b / bind-01~e.8 :ARG1 (p / protein~e.0 :name (n2 / name :op1 "IL-23"~e.5,7,11) :ARG1-of~e.0 (r / resemble-01~e.0 :ARG2 (p2 / protein :name (n / name :op1 "IL-12"~e.1,3,5)))) :ARG2 (p4 / protein :name (n3 / name :op1 "IL-12Rbeta1"~e.15,17) :ARG1-of (i / include-91 :ARG2 (p3 / protein :name (n4 / name :op1 "IL-12R"~e.11,13,15))))) # ::id bel_pmid_1202_3369.35656 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 23 activates the same Jak @-@ stat signaling molecules as IL @-@ 12 : Jak2 , Tyk2 , and stat1 , -@ 3 , -@ 4 , and -@ 5 , but stat4 activation is substantially weaker and different DNA @-@ binding stat complexes form in response to IL @-@ 23 compared with IL @-@ 12 . IL @-@ 23R associates constitutively with Jak2 and in a ligand @-@ dependent manner with stat3 . # ::alignments 0-1.1.1.2.2.1.1.1 0-1.2.1.1.1.1 2-1.1.2.1 3-1.1.2 3-1.1.2.2.3.1.1 5-1.1.2.2.4 6-1.1.2.2.1.1.1.1 8-1.1.2.2.1.1.1.1 9-1.1.2.2.1 10-1.1.2.2 10-1.1.2.2.3.1 12-1.1.1.2.2.1.1.1 12-1.1.1.2.3.1.1 14-1.1.1.2.3.1.1 16-1.1.2.2.2.1.1.1.1 18-1.1.2.2.2.1.2.1.1 20-1.1.2.2.2.1 21-1.1.2.2.2.1.3.1.1 29-1.1.1 29-1.1.2.2.2.1 33-1.1 34-1.1.2.2.2.1.5.1.1 35-1.1.1.1.1 35-1.1.2 37-1.1.1.1.3 38-1.1.1.1 38-1.1.1.1.2 38-1.1.1.1.2.r 39-1.1.1 40-1.1.1.2.1.3 40-1.1.2.2.3 41-1.1.1.2.1.1.1.2.1 43-1.1.1.2.1.1 44-1.1.1.2.1.2.1.1 45-1.1.1.2.1 46-1.1.1.2 47-1.1.1.2.2.r 48-1.1.1.2.2 49-1.1.1.2.2.1.r 50-1.1.1.2.2.1.1.1 52-1.1.1.2.2.1.1.1 53-1.1.1.2.3.r 55-1.1.1.2.3.1.1 57-1.1.1.2.3.1.1 59-1.1.1.2.3.1.1 59-1.2.1.1.1.1 61-1.2.1.1.1.1 62-1.2.1 62-1.2.2 63-1.2.1.3 64-1.2.1.2.r 65-1.2.1.2.1.1 66-1.2 67-1.2.2.3.r 69-1.2.2.3.1 71-1.2.2.3 72-1.2.1.3.r 74-1.1.2.2.2.1.4.1.1 74-1.2.2.2.1.1 (m / multi-sentence :snt1 (h / have-concession-91~e.33 :ARG1 (a3 / and~e.29,39 :op1 (w / weak-02~e.38 :ARG1 (a4 / activate-01~e.35 :ARG1 p12) :degree~e.38 (m2 / more~e.38) :degree (s / substantial~e.37)) :op2 (f / form-01~e.46 :ARG1 (m3 / macro-molecular-complex~e.45 :ARG1-of (b / bind-01~e.43 :ARG2 (n14 / nucleic-acid :wiki "DNA" :name (n15 / name :op1 "DNA"~e.41))) :mod (p7 / protein :name (n13 / name :op1 "stat"~e.44)) :ARG1-of (d3 / differ-02~e.40)) :ARG2-of~e.47 (r2 / respond-01~e.48 :ARG1~e.49 (p5 / protein :name (n5 / name :op1 "IL-23"~e.0,12,50,52))) :compared-to~e.53 (p6 / protein :name (n6 / name :op1 "IL-12"~e.12,14,55,57,59)))) :ARG2 (a2 / activate-01~e.3,35 :ARG0 p5~e.2 :ARG1 (m4 / molecule~e.10 :ARG0-of (s3 / signal-07~e.9 :ARG1 (p4 / pathway :name (n7 / name :op1 "Jak-stat"~e.6,8))) :ARG1-of (m5 / mean-01 :ARG2 (a5 / and~e.20,29 :op1 (e2 / enzyme :name (n4 / name :op1 "Jak2"~e.16)) :op2 (e3 / enzyme :name (n12 / name :op1 "Tyk2"~e.18)) :op3 (p10 / protein :name (n8 / name :op1 "stat1"~e.21)) :op4 (p11 / protein :name (n9 / name :op1 "stat3"~e.74)) :op5 (p12 / protein :name (n10 / name :op1 "stat4"~e.34)) :op6 (p13 / protein :name (n11 / name :op1 "stat5")))) :ARG1-of (r3 / resemble-01~e.40 :ARG2 (m6 / molecule~e.10 :ARG1-of (a8 / activate-01~e.3 :ARG0 p6))) :ARG1-of (s2 / same-01~e.5)))) :snt2 (a / and~e.66 :op1 (a6 / associate-01~e.62 :ARG1 (p / protein :name (n / name :op1 "IL-23R"~e.0,59,61)) :ARG2~e.64 (e / enzyme :name (n2 / name :op1 "Jak2"~e.65)) :manner~e.72 (c / constitutive~e.63)) :op2 (a7 / associate-01~e.62 :ARG1 p :ARG2 (p3 / protein :name (n3 / name :op1 "stat3"~e.74)) :manner~e.67 (d / depend-01~e.71 :ARG0 (l / ligand~e.69))))) # ::id bel_pmid_1207_7275.28056 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At day 7 following infection , lung tissue from mice given hIL @-@ 17F Ad showed substantial increases in the mRNA for inflammatory cytokines and chemokines , including IL @-@ 6 , IFN @-@ g , inflammatory protein 10 , and monokine induced by IFN @-@ g ( Fig . 3 ) . # ::alignments 1-1.4.2.2 2-1.4.2.1 3-1.4 4-1.4.1 6-1.1.1 7-1.1 8-1.1.2.r 9-1.1.2 10-1.1.2.1 11-1.1.2.1.1.2.1.1.1 13-1.1.2.1.1.2.1.1.1 14-1.1.2.1.1.1.1 15-1 16-1.2.2 17-1.2 18-1.2.1.r 20-1.2.1.1.1.1 22-1.2.1.1.2.3 23-1.2.1.1.2.1 24-1.2.1.1.2 25-1.2.1.1.2.2 27-1.2.1.1.2.4 28-1.2.1.1.2.4.1.1.1.1 30-1.2.1.1.2.4.1.1.1.1 32-1.2.1.1.2.4.1.2.1.1 34-1.2.1.1.2.4.1.2.1.1 36-1.2.1.1.2.4.1.3.1.1 37-1.2.1.1.2.4.1.3.1.2 38-1.2.1.1.2.4.1.3.1.3 40-1.2.1.1.2.4.1 41-1.2.1.1.2.4.1.4 42-1.2.1.1.2.4.1.4.1 43-1.2.1.1.2.4.1.4.1.1.r 44-1.2.1.1.2.4.1.4.1.1 45-1.2.1.1.2.4.1.4.1.1 46-1.2.1.1.2.4.1.4.1.1 48-1.3.1 50-1.3.1.1 (s / show-01~e.15 :ARG0 (t / tissue~e.7 :location (l / lung~e.6) :source~e.8 (m / mouse~e.9 :ARG2-of (g / give-01~e.10 :ARG1 (g2 / gene :name (n / name :op1 "Ad"~e.14) :ARG3-of (e / express-03 :ARG2 (p6 / protein :name (n8 / name :op1 "hil-17F"~e.11,13))))))) :ARG1 (i2 / increase-01~e.17 :ARG1~e.18 (a2 / and :op1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.20) :purpose (a3 / and~e.24 :op1 (c / cytokine~e.23) :op2 (c2 / chemokine~e.25) :ARG0-of (i3 / inflame-01~e.22) :ARG2-of (i4 / include-91~e.27 :ARG1 (a4 / and~e.40 :op1 (p3 / protein :name (n5 / name :op1 "IL-6"~e.28,30)) :op2 (p4 / protein :name (n6 / name :op1 "IFN-g"~e.32,34)) :op3 (p5 / protein :name (n7 / name :op1 "inflammatory"~e.36 :op2 "protein"~e.37 :op3 10~e.38)) :op4 (m2 / monokine~e.41 :ARG2-of (i5 / induce-01~e.42 :ARG0~e.43 p4~e.44,45,46))))))) :degree (s2 / substantial~e.16)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.48 :mod 3~e.50)) :time (a / after~e.3 :op1 (i / infect-01~e.4 :ARG1 t) :quant (t2 / temporal-quantity :quant 7~e.2 :unit (d / day~e.1)))) # ::id bel_pmid_1207_7275.28070 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We cultured sorted mast cells and basophils with IL @-@ 25 , IL @-@ 18 , or IL @-@ 25 IL @-@ 18 and detected both IL @-@ 5 and IL @-@ 13 from IL @-@ 18 cultured cell supernatants # ::alignments 0-1.1.1 1-1.1 2-1.1.3.1.2 3-1.1.3.1.1 4-1.1.3.1 5-1.1.3 6-1.1.3.2.1.1 7-1.1.2.r 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 12-1.1.2.1.1.1.1 12-1.1.2.1.2.1.1 14-1.1.2.1.2.1.1 16-1.1.2 17-1.1.2.1.1.1.1 17-1.1.2.1.2.1.1 19-1.1.2.1.1.1.1 20-1.1.2.1.1.1.1 20-1.1.2.1.2.1.1 22-1.1.2.1.2.1.1 23-1 23-1.1.2.1 23-1.1.2.2 24-1.2 26-1.2.2.1.1.1 28-1.2.2.1.1.1 29-1.2.2 30-1.2.2.1.1.1 30-1.2.2.2.1.1 32-1.2.2.2.1.1 33-1.2.2.3.r 34-1.1.2.1.1.1.1 34-1.1.2.1.2.1.1 34-1.2.2.1.1.1 34-1.2.2.2.1.1 36-1.2.2.3.2.2 37-1.2.2.3.2 38-1.2.2.3.1 39-1.2.2.3 (a / and~e.23 :op1 (c / culture-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.7 (o / or~e.16 :op1 (a3 / and~e.23 :op1 (p / protein :name (n / name :op1 "IL-25"~e.8,10,12,17,19,20,34)) :op2 (p2 / protein :name (n2 / name :op1 "IL-18"~e.12,14,17,20,22,34))) :op2 (a4 / and~e.23 :op1 p :op2 p2)) :location (a2 / and~e.5 :op1 (c2 / cell~e.4 :mod (m / mast~e.3) :ARG1-of (s2 / sort-01~e.2)) :op2 (c5 / cell :name (n3 / name :op1 "basophil"~e.6)))) :op2 (d / detect-01~e.24 :ARG0 w :ARG1 (a5 / and~e.29 :op1 (p3 / protein :name (n4 / name :op1 "IL-5"~e.26,28,30,34)) :op2 (p4 / protein :name (n5 / name :op1 "IL-13"~e.30,32,34)) :source~e.33 (s / supernatant~e.39 :mod (c3 / cell~e.38) :location-of (c4 / culture-01~e.37 :ARG0 w :ARG1 p2~e.36))))) # ::id bel_pmid_1208_2107.1700 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The dual phosphorylation of Thr @-@ 183 and Tyr @-@ 185 in ERK2 is catalyzed by MAPK @/@ ERK kinase 1 ( MEK1 ) . # ::alignments 1-1.2.2 2-1.2 6-1.2.1.1.1 7-1.2.1 8-1.2.1.2.2.1 10-1.2.1.2.1 12-1.2.1.1.3.1.1 14-1 15-1.1.r 16-1.1.1.1 18-1.1.1.1 19-1.1.1.2 20-1.1.1.3 (c / catalyze-01~e.14 :ARG0~e.15 (e2 / enzyme :name (n / name :op1 "MAPK/ERK"~e.16,18 :op2 "kinase"~e.19 :op3 1~e.20)) :ARG1 (p2 / phosphorylate-01~e.2 :ARG1 (a / and~e.7 :op1 (a2 / amino-acid :mod 183~e.6 :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n4 / name :op1 "ERK2"~e.12))) :op2 (a3 / amino-acid :mod 185~e.10 :name (n3 / name :op1 "tyrosine"~e.8) :part-of e)) :mod (d / dual~e.1))) # ::id bel_pmid_1208_7097.38812 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the phosphorylation of Raf @-@ 1 on Ser @-@ 259 induced by paclitaxel he region surrounding Ser @-@ 259 in Raf @-@ 1 conforms to a consensus sequence for phosphorylation by Akt # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.3.1.1 5-1.1.1.3.1.1 7-1.1.1.2.1 9-1.1.1.1 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1 14-1.1.2.1.1 15-1.1.2.1.1.1 16-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 18-1.1.2.1.1.1.1 19-1.1.2.1.1.1.1 20-1.1.2.1.1.1.1 21-1.1.2.1.1.1.1 22-1.1.2.1.1.1.1 23-1 24-1 26-1.2.1 27-1.2 28-1.2.2.r 29-1.2.2 30-1.2.2.1.r 31-1.2.2.1.1.1 (c / conform-01~e.23,24 :ARG1 (p / phosphorylate-01~e.1 :ARG2~e.2 (a / amino-acid :mod 259~e.9 :name (n2 / name :op1 "serine"~e.7) :part-of (e2 / enzyme :name (n3 / name :op1 "Raf-1"~e.3,5))) :ARG2-of (i / induce-01~e.10 :ARG0~e.11 (p3 / paclitaxel~e.12 :location (r / region~e.14 :ARG0-of (s2 / surround-01~e.15 :ARG1 a~e.16,17,18,19,20,21,22))))) :ARG2 (s / sequence~e.27 :mod (c2 / consensus~e.26) :purpose~e.28 (p2 / phosphorylate-01~e.29 :ARG2~e.30 (e / enzyme :name (n / name :op1 "Akt"~e.31))))) # ::id bel_pmid_1208_9357.6280 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MAPK kinase inhibitors did not affect Nur77 and Nurr1 mRNA induction but blocked CRH or cAMP @-@ stimulated Nur transcriptional activity . # ::alignments 1-1.1.2.1.1.1.1 2-1.1.2.1.1.1.2 3-1.1.2 3-1.1.2.1 3-1.1.2.1.r 5-1.1.1 5-1.1.1.r 6-1.1 7-1.1.3.1.1.2.1.1.1 8-1.1.3.1 9-1.1.3.1.2.2.1.1.1 10-1.1.3.1.1.1.1 10-1.1.3.1.2.1.1 11-1.1.3 12-1 13-1.2 14-1.2.2.3.1.1.1.1 15-1.2.2.3.1 16-1.2.2.3.1.2.1.1 18-1.2.2.3 19-1.2.2.1.1.1 20-1.2.2.2 21-1.2.2 (c / contrast-01~e.12 :ARG1 (a / affect-01~e.6 :polarity~e.5 -~e.5 :ARG0 (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (i3 / inhibit-01~e.3 :ARG1 (p3 / protein-family :name (n8 / name :op1 "MAPK"~e.1 :op2 "kinase"~e.2)))) :ARG1 (i / induce-01~e.11 :ARG2 (a2 / and~e.8 :op1 (n9 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.10) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n / name :op1 "Nur77"~e.7)))) :op2 (n10 / nucleic-acid :name (n7 / name :op1 "mRNA"~e.10) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Nurr1"~e.9))))))) :ARG2 (b / block-01~e.13 :ARG0 m :ARG1 (a3 / activity-06~e.21 :ARG0 (p6 / protein :name (n5 / name :op1 "Nur"~e.19)) :ARG1 (t2 / transcribe-01~e.20) :ARG1-of (s / stimulate-01~e.18 :ARG0 (o / or~e.15 :op1 (s2 / small-molecule :name (n3 / name :op1 "CRH"~e.14)) :op2 (s3 / small-molecule :name (n4 / name :op1 "cAMP"~e.16))))))) # ::id bel_pmid_1208_9357.19824 ::amr-annotator SDL-AMR-09 ::preferred # ::tok calcium @-@ independent pathways are accounted for in part by MAPK activation ( Rap1/B @-@ Raf @/@ MAPK @-@ ERK kinase @/@ ERK1 @/@ 2 ) AtT @-@ 20 corticotrophs express B @-@ Raf , as do other cells in which cAMP stimulates MAPK . CRH @/@ cAMP stimulated ERK2 ( Mapk1 ) activity and increased transcriptional activity of a Gal4 @-@ Elk1 protein , which was blocked by overexpression of dominant negative mutants and kinase inhibitors and stimulated by expression of B @-@ Raf . # ::alignments 0-1.1.1.1.2 2-1.1.1.1 2-1.1.1.1.1 2-1.1.1.1.1.r 3-1.1.1 5-1.1 7-1.1.3 7-1.1.3.r 8-1.1.3.r 9-1.1.2.r 10-1.1.2.1.1.1 11-1.1.2 15-1.1.1.2.1.1 15-1.2.2.1.1 16-1.3.1.1 17-1.1.2.1.1.1 19-1.1.1.2.1.1 20-1.1.1.2.1.1 21-1.3.1.1 22-1.1.1.2.1.1 23-1.3.1.1 24-1.1.1.2.1.1 26-1.2.1.1.1 28-1.2.1.1.1 30-1.2 30-1.2.3.1 31-1.2.2.1.1 33-1.2.2.1.1 37-1.2.3.1.1.1 38-1.2.3.1.1 41-1.2.3.1.1.2.1.1.1 41-1.3.1.1.2.1.1 42-1.2.3.1.1.2 42-1.3.1 43-1.2.3.1.1.2.2.1.1 45-1.3.1.1.1.1.1 46-1.3.1.1 47-1.3.1.1.2.1.1 48-1.3.1 49-1.3.1.2.1.1.1 53-1.3.1.2 54-1.3 55-1.3.2 56-1.3.2.2.2 57-1.3.2.2 58-1.3.2.2.1.r 60-1.3.2.2.1.1.1 62-1.3.2.2.1.1.1 63-1.3.2.2.1.2.1.1.1 67-1.3.2.2.1.2 69-1.3.2.2.1.2.1.1 73-1.3.2.2.1.2.1.1.1.1 74-1.3.2.2.1.2.1 75-1.3.2.2.1.2.1.2.1.1 76-1.3.2.2.1.2.1.2 76-1.3.2.2.1.2.1.2.1 76-1.3.2.2.1.2.1.2.1.r 77-1.3 78-1.3.1 78-1.3.2.2.1.3 80-1.2 80-1.3.2.2.1.3.1 82-1.1.1.2.1.1 82-1.2.2.1.1 84-1.1.1.2.1.1 84-1.2.2.1.1 84-1.3.2.2.1.3.1.1.1.1 (m / multi-sentence :snt1 (a5 / account-01~e.5 :ARG1 (p / pathway~e.3 :ARG0-of (d2 / depend-01~e.2 :polarity~e.2 -~e.2 :ARG1 (c / calcium~e.0)) :example (p4 / pathway :name (n16 / name :op1 "Rap1/B-Raf/MAPK-ERK-kinase/ERK1/2"~e.15,19,20,22,24,82,84))) :ARG2~e.9 (a6 / activate-01~e.11 :ARG1 (e7 / enzyme :name (n3 / name :op1 "MAPK"~e.10,17))) :degree~e.7,8 (p3 / part~e.7)) :snt2 (e / express-03~e.30,80 :ARG1 (c2 / corticotroph :name (n / name :op1 "AtT-20"~e.26,28)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "B-Raf"~e.15,31,33,82,84)) :ARG1-of (r / resemble-01 :ARG2 (e11 / express-03~e.30 :ARG1 (c3 / cell~e.38 :mod (o2 / other~e.37) :location-of (s4 / stimulate-01~e.42 :ARG0 (s6 / small-molecule :name (n10 / name :op1 "cAMP"~e.41)) :ARG1 (e4 / enzyme :name (n14 / name :op1 "MAPK"~e.43))))))) :snt3 (a / and~e.54,77 :op1 (s / stimulate-01~e.42,48,78 :ARG0 (s2 / slash~e.16,21,23,46 :op1 (s7 / small-molecule :name (n4 / name :op1 "CRH"~e.45)) :op2 (s5 / small-molecule :name (n5 / name :op1 "cAMP"~e.41,47))) :ARG1 (a2 / activity-06~e.53 :ARG0 (e3 / enzyme :name (n6 / name :op1 "ERK2"~e.49)))) :op2 (i2 / increase-01~e.55 :ARG0 s2 :ARG1 (a3 / activity-06~e.57 :ARG0~e.58 (p5 / protein :name (n8 / name :op1 "Gal4-Elk1"~e.60,62) :ARG1-of (b / block-01~e.67 :ARG0 (a4 / and~e.74 :op1 (o / overexpress-01~e.69 :ARG1 (p6 / protein~e.63 :ARG2-of (m3 / mutate-01~e.73 :mod "-/-"))) :op2 (m2 / molecular-physical-entity~e.76 :ARG0-of~e.76 (i3 / inhibit-01~e.76 :ARG1 (k / kinase~e.75))))) :ARG1-of (s3 / stimulate-01~e.78 :ARG0 (e5 / express-03~e.80 :ARG2 (e6 / enzyme :name (n9 / name :op1 "B-Raf"~e.84))))) :ARG1 (t2 / transcribe-01~e.56))))) # ::id bel_pmid_1208_9357.26116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CRH and cAMP induce Nur77 and Nurr1 expression and transcription at the NurRE site by protein kinase A ( PKA ) and calcium @-@ dependent and -@ independent mechanisms . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1 4-1.2.1.1.1.1.1 6-1.2.1.1.2.1.1 7-1.2.1 8-1.2 9-1.2.2 10-1.2.2.3.r 12-1.2.2.3.1.1 13-1.2.2.3 14-1.2.2.1.r 15-1.2.2.1.1.1.1 16-1.2.2.1.1.1.2 17-1.2.2.1.1.1.3 22-1.2.2.1.2.1.1 22-1.2.2.1.3.1.2 24-1.2.2.1.3.1 25-1.2.2.1 27-1.2.2.1.2.1 27-1.2.2.1.3.1 27-1.2.2.1.3.1.1 27-1.2.2.1.3.1.1.r 28-1.2.2.1.2 28-1.2.2.1.3 (i / induce-01~e.3 :ARG0 (a / and~e.1 :op1 (s / small-molecule :name (n / name :op1 "CRH"~e.0)) :op2 (s2 / small-molecule :name (n2 / name :op1 "cAMP"~e.2))) :ARG2 (a4 / and~e.8 :op1 (e / express-03~e.7 :ARG2 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "Nur77"~e.4)) :op2 (p4 / protein :name (n4 / name :op1 "Nurr1"~e.6)))) :op2 (t / transcribe-01~e.9 :ARG0~e.14 (a3 / and~e.25 :op1 (e2 / enzyme :name (n6 / name :op1 "protein"~e.15 :op2 "kinase"~e.16 :op3 "A"~e.17)) :op2 (m / mechanism~e.28 :ARG0-of (d / depend-01~e.27 :ARG1 (c / calcium~e.22))) :op3 (m2 / mechanism~e.28 :ARG0-of (d2 / depend-01~e.24,27 :polarity~e.27 -~e.27 :ARG1 (c2 / calcium~e.22)))) :ARG1 a2 :location~e.10 (p / protein-segment~e.13 :name (n5 / name :op1 "NurRE"~e.12))))) # ::id bel_pmid_1210_1242.29522 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of collagen alpha1 ( I ) , alpha1 ( III ) , and fibronectin mRNAs were reduced in 1 @-@ day wounds of Nrf2 knockout mice compared to control littermates . # ::alignments 1-1.1.1 1-1.1.2 1-1.1.3 2-1.1.1.1.r 3-1.1.1.1.1.1 6-1.2.2.1 14-1.1 15-1.1.3.1.2 16-1.1.3.1.1.1 18-1 20-1.2.2.1 22-1.2.2.2 23-1.2 24-1.2.1.r 25-1.2.1.1.1.1.1 26-1.2.1.1 27-1.2.1 28-1.2.3.r 30-1.2.3.1 31-1.2.3 (r / reduce-01~e.18 :ARG1 (a / and~e.14 :op1 (l2 / level~e.1 :quant-of~e.2 (p2 / protein :name (n3 / name :op1 "collagen"~e.3 :op2 "alpha1(I)"))) :op2 (l3 / level~e.1 :quant-of (p3 / protein :name (n / name :op1 "alpha1(III)"))) :op3 (l4 / level~e.1 :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.16) :mod (f / fibronectin~e.15)))) :location (w / wound-01~e.23 :ARG1~e.24 (m / mouse~e.27 :ARG1-of (k / knock-out-03~e.26 :ARG0 (p / protein :name (n2 / name :op1 "Nrf2"~e.25)))) :age (t / temporal-quantity :quant 1~e.6,20 :unit (d / day~e.22)) :compared-to~e.28 (l / littermate~e.31 :ARG1-of (c / control-01~e.30)))) # ::id bel_pmid_1210_1242.29526 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the normally observed induction of IL @-@ 1 beta and TNF @-@ alpha expression ( 22 ) was delayed in the knockout mice . The levels of IL @-@ 1 beta mRNA were 50 % lower in the 1 @-@ day wounds of Nrf2-/- mice than for control littermates . # ::alignments 0-1.1.2 3-1.1.1.2.1 4-1.1.1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1.1.1 9-1.2.4.2.1 11-1.1.1.1.1 12-1.1.1.1.1.2.1.1 14-1.1.1.1.1.2.1.1 15-1.1.1.1 17-1.1.1.3.1.1.1 20-1.1 23-1.2.4.1.1 24-1.1.3 24-1.2.4.1 27-1.2.1 28-1.2.1.1.r 29-1.2.1.1.2.1.1 31-1.2.4.2.1 33-1.2.1.1.1.1 35-1.2.3.1 36-1.2.3 37-1.2 37-1.2.2 37-1.2.2.r 40-1.2.4.2.1 42-1.2.4.2.2 43-1.2.4 46-1.2.4.1 47-1.2.5.r 49-1.2.5.1 50-1.2.5 (m2 / multi-sentence :snt1 (d2 / delay-01~e.20 :ARG1 (i / induce-01~e.5 :ARG2~e.6 (e / express-03~e.15 :ARG2 (a / and~e.11 :op1 (p4 / protein :name (n5 / name :op1 "IL-1beta"~e.7)) :op2 (p5 / protein :name (n6 / name :op1 "TNF-alpha"~e.12,14)))) :ARG1-of (o / observe-01~e.4 :ARG1-of (n4 / normal-02~e.3)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 22~e.17)))) :ARG2-of (i2 / interest-01~e.0) :location (m5 / mouse~e.24 :ARG2-of (m6 / mutate-01 :mod "+/-"))) :snt2 (l2 / low-04~e.37 :ARG1 (l / level~e.27 :quant-of~e.28 (n7 / nucleic-acid :name (n / name :op1 "mRNA"~e.33) :mod (p2 / protein :name (n2 / name :op1 "IL-1beta"~e.29)))) :degree~e.37 (m / more~e.37) :quant (p / percentage-entity~e.36 :value 50~e.35) :location (w / wound-01~e.43 :ARG1 (m3 / mouse~e.24,46 :ARG1-of (k / knock-out-03~e.23 :ARG0 (p3 / protein :name (n3 / name :op1 "Nrf2")))) :age (t / temporal-quantity :quant 1~e.9,31,40 :unit (d / day~e.42))) :compared-to~e.47 (l3 / littermate~e.50 :ARG1-of (c / control-01~e.49)))) # ::id bel_pmid_1210_1242.29528 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of IL @-@ 6 was also lower in 1 @-@ day wounds of Nrf2 null mice , but in contrast to IL @-@ 1 beta the mRNA of this cytokine was no longer detectable at later stages of repair . # ::alignments 0-1.2.1 1-1.2.1.1.r 2-1.2.1.1.1.1 4-1.2.1.1.1.1 6-1.2.3 7-1.2 7-1.2.2 7-1.2.2.r 8-1.2.4.r 9-1.2.4.2.1 11-1.2.4.2.2 12-1.2.4 13-1.2.4.1.r 14-1.2.4.1.1.1.1 15-1.2.4.1.1 15-1.2.4.1.1.2 15-1.2.4.1.1.2.1 15-1.2.4.1.1.2.1.r 15-1.2.4.1.1.2.r 16-1.2.4.1 18-1 18-1.1 18-1.1.r 20-1.1 22-1.2.1.1.1.1 24-1.2.4.2.1 25-1.1.1.1.1 27-1.1.2.1.1.1.1 32-1.1.2.1.2 33-1.1.2.1.2 34-1.1.2.1 35-1.1.2.1.3.r 36-1.1.2.1.3.1 36-1.1.2.1.3.1.1 36-1.1.2.1.3.1.1.r 37-1.1.2.1.3 38-1.1.2.1.3.2.r 39-1.1.2.1.3.2 (h / have-concession-91~e.18 :ARG1~e.18 (c2 / contrast-01~e.18,20 :ARG1 (p3 / protein :name (n3 / name :op1 "IL1-beta"~e.25)) :ARG2 (p4 / possible-01 :ARG1 (d2 / detect-01~e.34 :ARG1 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.27) :poss p) :time (n6 / no-longer~e.32,33) :time~e.35 (s / stage~e.37 :mod (l / late~e.36 :degree~e.36 (m3 / more~e.36)) :subevent-of~e.38 (r2 / repair-01~e.39))))) :ARG2 (l2 / low-04~e.7 :ARG1 (e / express-03~e.0 :ARG2~e.1 (p / protein :name (n / name :op1 "IL-6"~e.2,4,22))) :degree~e.7 (m / more~e.7) :mod (a / also~e.6) :location~e.8 (w / wound-01~e.12 :ARG1~e.13 (m2 / mouse~e.16 :mod (p2 / protein~e.15 :name (n2 / name :op1 "Nrf2"~e.14) :ARG2-of~e.15 (m4 / mutate-01~e.15 :mod~e.15 "-/-"~e.15))) :age (t / temporal-quantity :quant 1~e.9,24 :unit (d / day~e.11))))) # ::id bel_pmid_1210_1242.29532 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , TGF @-@ beta1 mRNA was present at lower levels in unwounded back skin and in 1 @-@ day wounds of Nrf2-/- mice ( Fig.7 ) . # ::alignments 0-1.4 2-1.1.2.1.1 4-1.1.2.1.1 5-1.1.1.1 7-1 9-1.1.3.1 9-1.1.3.1.1 9-1.1.3.1.1.r 10-1.1.3 11-1.2.r 12-1.2.1.2.1 13-1.2.1.1 14-1.2.1 15-1.2 17-1.2.2.1.2.1 19-1.2.2.1.2.2 20-1.2.1.2 20-1.2.2 23-1.2.2.1 (p3 / present-02~e.7 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.5) :mod (p / protein :name (n3 / name :op1 "TGF-beta1"~e.2,4)) :quant (l / level~e.10 :ARG1-of (l2 / low-04~e.9 :degree~e.9 (m / more~e.9)))) :ARG2~e.11 (a2 / and~e.15 :op1 (s / skin~e.14 :location (b2 / back~e.13) :ARG1-of (w / wound-01~e.20 :polarity -~e.12)) :op2 (w2 / wound-01~e.20 :ARG1 (m2 / mouse~e.23 :mod (p2 / protein :name (n / name :op1 "Nrf2") :ARG2-of (m3 / mutate-01 :mod "-/-")) :age (t / temporal-quantity :quant 1~e.17 :unit (d / day~e.19))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod 7)) :mod (i / indeed~e.0)) # ::id bel_pmid_1210_1242.29534 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of VEGF , a major regulator of angiogenesis , was also reduced in nonwounded skin and in 1 @-@ day wounds of Nrf2 null mice ( Fig.7 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 5-1.1.1.2.2 6-1.1.1 6-1.1.1.2 6-1.1.1.2.r 7-1.1.1.2.1.r 8-1.1.1.2.1 11-1.2 12-1 15-1.3.1 16-1.3 17-1.3.r 18-1.3.2.2.1 20-1.3.2.2.2 21-1.3.1.1 23-1.3.2.1.1.1 24-1.3.2.1 24-1.3.2.1.2 24-1.3.2.1.2.1 24-1.3.2.1.2.1.r 24-1.3.2.1.2.r 25-1.3.2 (r2 / reduce-01~e.12 :ARG1 (e / express-03~e.0 :ARG2~e.1 (p / protein~e.6 :name (n2 / name :op1 "VEGF"~e.2) :ARG0-of~e.6 (r / regulate-01~e.6 :ARG1~e.7 (a4 / angiogenesis~e.8) :ARG1-of (m3 / major-02~e.5)))) :mod (a2 / also~e.11) :location~e.17 (a3 / and~e.16 :op1 (s / skin~e.15 :ARG1-of (w / wound-01~e.21 :polarity -)) :op2 (m / mouse~e.25 :mod (p2 / protein~e.24 :name (n3 / name :op1 "Nrf2"~e.23) :ARG2-of~e.24 (m2 / mutate-01~e.24 :mod~e.24 "-/-"~e.24)) :age (t / temporal-quantity :quant 1~e.18 :unit (d / day~e.20)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod 7))) # ::id bel_pmid_1211_0143.268 ::amr-annotator SDL-AMR-09 ::preferred # ::tok binding of Il6 to Il6R induces homodimerization ofgp130 , activating JAK associated with gp130 at Box1 . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 4-1.1.2.1.1 5-1 6-1.2 9-1.3 10-1.3.1.1.1 11-1.3.1.2 12-1.2.1.r 13-1.2.1.1.1 14-1.3.1.2.2.r 15-1.3.1.2.2.1.1 (i / induce-01~e.5 :ARG0 (b / bind-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "Il6"~e.2)) :ARG2~e.3 (p2 / protein :name (n2 / name :op1 "Il6R"~e.4))) :ARG2 (h2 / homodimerize-01~e.6 :ARG1~e.12 (p3 / protein :name (n3 / name :op1 "gp130"~e.13))) :ARG0-of (a / activate-01~e.9 :ARG1 (e / enzyme :name (n4 / name :op1 "JAK"~e.10) :ARG1-of (a2 / associate-01~e.11 :ARG2 p3 :location~e.14 (p5 / protein-segment :name (n5 / name :op1 "Box1"~e.15) :part-of p3))))) # ::id bel_pmid_1211_0143.20340 ::amr-annotator SDL-AMR-09 ::preferred # ::tok in Il6 signal cascade , the SHP2 interaction site of gp130 has also been shown to be a Socs3 contact site so that Socs3 may compete for the SHP2 @-@ gp130 interaction site # ::alignments 2-1.2.1 3-1.2 6-1.1.1.1.1.1 7-1.1.1 8-1.1 10-1.1.3.1.1 12-1.3 13-1.1.2.r 14-1 16-1.1.2.r 18-1.1.2.1.1.1.1 19-1.1.2.1 20-1.1.2 21-1.1.2.1.1.2.r 22-1.1.2.1.1.2.r 23-1.1.2.1.1.1.1 24-1.1.2.1.1.2 25-1.1.2.1.1.2.1 28-1.1.1.1.1.1 30-1.1.3.1.1 31-1.1.1 32-1.1 (s / show-01~e.14 :ARG1 (p5 / protein-segment~e.8,32 :location-of (i / interact-01~e.7,31 :ARG1 (e / enzyme :name (n / name :op1 "SHP2"~e.6,28))) :domain~e.13,16 (p6 / protein-segment~e.20 :ARG0-of (c / contact-01~e.19 :ARG1 (p2 / protein :name (n3 / name :op1 "Socs3"~e.18,23) :purpose~e.21,22 (p3 / possible-01~e.24 :ARG1 (c2 / compete-01~e.25 :ARG0 p2 :ARG1 p5))))) :part-of (p / protein :name (n2 / name :op1 "gp130"~e.10,30))) :location (c3 / cascade~e.3 :mod (s2 / signal-07~e.2 :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6")))) :mod (a / also~e.12)) # ::id bel_pmid_1211_0143.28372 ::amr-annotator SDL-AMR-09 ::preferred # ::tok nonreceptor tyrosine kinases , such as Btk , Tec , Fes , and Hck are activated through the Il6R receptor # ::alignments 0-1.2.1.1 1-1.2.1.2 2-1.2.1.3 2-1.2.2.1 2-1.2.2.2 2-1.2.2.3 2-1.2.2.4 4-1.2.2.r 5-1.2.2.r 6-1.2.2.1.1.1 8-1.2.2.2.1.1 10-1.2.2.3.1.1 12-1.2.2 13-1.2.2.4.1.1 15-1 19-1.1 (a / activate-01~e.15 :ARG0 (r / receptor~e.19 :name (n / name :op1 "IL-6R")) :ARG1 (e5 / enzyme :name (n2 / name :op1 "nonreceptor"~e.0 :op2 "tyrosine"~e.1 :op3 "kinase"~e.2) :example~e.4,5 (a3 / and~e.12 :op1 (k / kinase~e.2 :name (n3 / name :op1 "Btk"~e.6)) :op2 (k2 / kinase~e.2 :name (n4 / name :op1 "Tec"~e.8)) :op3 (k3 / kinase~e.2 :name (n5 / name :op1 "Fes"~e.10)) :op4 (k4 / kinase~e.2 :name (n6 / name :op1 "Hck"~e.13))))) # ::id bel_pmid_1211_0143.28412 ::amr-annotator SDL-AMR-09 ::preferred # ::tok tyrosine phosphorylation of SHP2 , a phosphotyrosine phosphatase , and that of STAT3 depend on the second tyrosine residue Y2 from the membrane in gp130 # ::alignments 0-1.2.2.1.1 1-1.1.1 1-1.1.2 2-1.1.1.1.r 3-1.1.1.1.2.1.1 6-1.1.1.1.2.2.1.1 7-1.1.1.1.2.2.1 9-1.1 11-1.1.2.1.r 12-1.1.2.1.2.1.1 13-1 16-1.2.3 16-1.2.3.1 16-1.2.3.1.r 17-1.1.1.1.1.1 17-1.1.2.1.1.1 17-1.2.2.1.1 18-1.2 19-1.2.1.1 20-1.2.4.r 22-1.2.4 23-1.2.4.1.r 24-1.2.4.1.1.1 (d / depend-01~e.13 :ARG0 (a / and~e.9 :op1 (p / phosphorylate-01~e.1 :ARG1~e.2 (a3 / amino-acid :name (n6 / name :op1 "tyrosine"~e.17) :part-of (e / enzyme :name (n4 / name :op1 "SHP2"~e.3) :ARG1-of (m / mean-01 :ARG2 (p3 / phosphatase~e.7 :mod (p5 / phosphotyrosine~e.6)))))) :op2 (p4 / phosphorylate-01~e.1 :ARG1~e.11 (a4 / amino-acid :name (n7 / name :op1 "tyrosine"~e.17) :part-of (p6 / protein :name (n5 / name :op1 "STAT3"~e.12))))) :ARG1 (r / residue~e.18 :name (n2 / name :op1 "Y2"~e.19) :mod (a2 / amino-acid :name (n / name :op1 "tyrosine"~e.0,17)) :mod (o / ordinal-entity~e.16 :value~e.16 2~e.16) :location~e.20 (m2 / membrane~e.22 :part-of~e.23 (p2 / protein :name (n3 / name :op1 "gp130"~e.24))))) # ::id bel_pmid_1211_0143.32746 ::amr-annotator SDL-AMR-09 ::preferred # ::tok presence of type 1 Il6R , which is a binding site for NF @-@ IL @-@ 6 , IL @-@ 6DBP , and CEBPbeta has been confirmed in the genes for CRP , hemoplexin A and haptoglobin binding activity of NF @-@ IL @-@ 6 is probably induced by Il6 through the increased expression of the NF @-@ IL @-@ 6 gene # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 2-1.1.1.1.2 2-1.1.1.1.2.r 3-1.1.1.1.2.1 7-1.1.1.1.3.r 9-1.1.1.1.3.1 10-1.1.1.1.3 11-1.1.1.1.3.1.1.r 12-1.1.1.1.3.1.1.1.1.1 14-1.1.1.1.3.1.1.1.1.1 14-1.1.1.1.3.1.1.2.1.1 16-1.1.1.1.3.1.1.1.1.1 18-1.1.1.1.3.1.1.1.1.1 18-1.1.1.1.3.1.1.2.1.1 20-1.1.1.1.3.1.1.2.1.1 22-1.1.1.1.3.1.1 23-1.1.1.1.3.1.1.3.1.1 25-1.1.1.1.3.r 26-1.1 27-1.1.3.r 29-1.1.3 30-1.1.2.r 31-1.1.2.1.1.1 33-1.1.2.2.1.1 34-1.1.2.2.1.2 35-1.1.2 36-1.1.2.3.1.1 37-1.2.2.2 38-1.2.2 39-1.2.2.1.r 40-1.2.2.1.1.1 42-1.2.2.1.1.1 44-1.2.2.1.1.1 46-1.2.3 47-1.2 48-1.2.1.r 49-1.2.1.1.1 52-1.2.4.2 53-1.2.4 54-1.2.4.1.r 56-1.2.4.1.1.1 57-1.2.4.1.1.1 58-1.2.4.1.1.1 59-1.2.4.1.1.1 60-1.2.4.1.1.1 61-1.2.4.1 (m / multi-sentence :snt1 (c / confirm-01~e.26 :ARG1 (p3 / present-02~e.0 :ARG1~e.1 (p4 / protein~e.2 :name (n3 / name :op1 "IL-6R") :ARG1-of~e.2 (t / type-03~e.2 :mod 1~e.3) :domain~e.7,25 (p8 / protein-segment~e.10 :ARG1-of (b2 / bind-01~e.9 :ARG2~e.11 (a3 / and~e.22 :op1 (p5 / protein :name (n / name :op1 "NF-IL-6"~e.12,14,16,18)) :op2 (p6 / protein :name (n4 / name :op1 "IL-6DBP"~e.14,18,20)) :op3 (p7 / protein :name (n5 / name :op1 "CEBPbeta"~e.23))))))) :ARG2~e.30 (a / and~e.35 :op1 (p9 / protein :name (n6 / name :op1 "CRP"~e.31)) :op2 (p10 / protein :name (n7 / name :op1 "hemoplexin"~e.33 :op2 "A"~e.34)) :op3 (p11 / protein :name (n9 / name :op1 "haptoglobin"~e.36))) :location~e.27 (g2 / gene~e.29)) :snt2 (i / induce-01~e.47 :ARG0~e.48 (p2 / protein :name (n10 / name :op1 "Il6"~e.49)) :ARG2 (a2 / activity-06~e.38 :ARG0~e.39 (p12 / protein :name (n8 / name :op1 "NF-IL-6"~e.40,42,44)) :ARG1 (b / bind-01~e.37)) :mod (p / probable~e.46) :manner (e / express-03~e.53 :ARG2~e.54 (g / gene~e.61 :ARG0-of (e2 / encode-01 :ARG1 p12~e.56,57,58,59,60)) :ARG1-of (i2 / increase-01~e.52)))) # ::id bel_pmid_1211_0143.35664 ::amr-annotator SDL-AMR-09 ::preferred # ::tok binding of Il6 to Il6R induces homodimerization ofgp130 , activating JAK associated with gp130 at Box1 ....... Our group and others found that JAK1 , JAK2 , and Tky @-@ 2 are activated and are tyrosine @-@ phosphorylated in response to IL @-@ 6 , CNTF , LIF , and OSM [ 14 ] # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.2.r 4-1.1.1.2.1.1 5-1.1 6-1.1.2 9-1.1.3 10-1.1.3.1.1.1 11-1.1.3.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1 14-1.1.3.1.2.2.r 15-1.1.3.1.2.2.1.1 17-1.2.1.1.1 17-1.2.1.1.1.r 18-1.2.1.1 18-1.2.1.2 19-1.2.1 20-1.2.1.2.1 21-1.2 22-1.2.2.r 23-1.2.2.1.1.1.1.1 25-1.2.2.1.1.2.1.1 27-1.2.2 28-1.2.2.2.1.3.2.1.1 30-1.2.2.2.1.3.2.1.1 32-1.2.2.1 33-1.2.2 33-1.2.2.2.1 35-1.2.2.2.1.1.1.1 35-1.2.2.2.1.2.1.1 35-1.2.2.2.1.3.1.1 37-1.2.2.2 38-1.2.2.2.2.r 39-1.2.2.2.2 40-1.2.2.2.2.1.r 41-1.2.2.2.2.1.1.1.1 43-1.2.2.2.2.1.1.1.1 45-1.2.2.2.2.1.2.1.1 47-1.2.2.2.2.1.3.1.1 50-1.2.2.2.2.1.4.1.1 52-1.2.3.1.1.1 (m / multi-sentence :snt1 (i / induce-01~e.5 :ARG0 (b / bind-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "Il6"~e.2)) :ARG2~e.3 (p2 / protein :name (n2 / name :op1 "Il6R"~e.4))) :ARG2 (h / homodimerize-01~e.6 :ARG1~e.12 (p3 / protein :name (n3 / name :op1 "gp130"~e.13))) :ARG0-of (a / activate-01~e.9 :ARG1 (e2 / enzyme :name (n4 / name :op1 "JAK"~e.10) :ARG1-of (a2 / associate-01~e.11 :ARG2 p3 :location~e.14 (p5 / protein-segment :name (n5 / name :op1 "Box1"~e.15)))))) :snt2 (f / find-01~e.21 :ARG0 (a3 / and~e.19 :op1 (g / group~e.18 :poss~e.17 (w / we~e.17)) :op2 (g2 / group~e.18 :mod (o / other~e.20))) :ARG1~e.22 (a4 / and~e.27,33 :op1 (a5 / activate-01~e.32 :ARG1 (a6 / and :op1 (e3 / enzyme :name (n6 / name :op1 "JAK1"~e.23)) :op2 (e4 / enzyme :name (n7 / name :op1 "JAK2"~e.25)) :op3 (p9 / protein :name (n8 / name :op1 "Tky2")))) :op2 (p6 / phosphorylate-01~e.37 :ARG1 (a9 / and~e.33 :op1 (a7 / amino-acid :name (n9 / name :op1 "tyrosine"~e.35) :part-of e3) :op2 (a10 / amino-acid :name (n14 / name :op1 "tyrosine"~e.35) :part-of e4) :op3 (a11 / amino-acid :name (n15 / name :op1 "tyrosine"~e.35) :part-of (e / enzyme :name (n16 / name :op1 "Tky-2"~e.28,30)))) :ARG2-of~e.38 (r / respond-01~e.39 :ARG1~e.40 (a8 / and :op1 (p10 / protein :name (n10 / name :op1 "IL-6"~e.41,43)) :op2 (p11 / protein :name (n11 / name :op1 "CNTF"~e.45)) :op3 (p12 / protein :name (n12 / name :op1 "LIF"~e.47)) :op4 (p7 / protein :name (n13 / name :op1 "OSM"~e.50)))))) :ARG1-of (d2 / describe-01 :ARG0 (p14 / publication :ARG1-of (c2 / cite-01 :ARG2 14~e.52))))) # ::id bel_pmid_1211_0143.38318 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Socs1 is essential for inhibition of IFN @-@ gamma @-@ induced inhibition of STAT6 # ::alignments 0-1.1.1.1 1-1.1.r 2-1 3-1.2.r 4-1.2 5-1.2.1.r 6-1.2.1.2.1.1.1 8-1.2.1.2.1.1.1 10-1.2.1.2 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1.1 (e / essential~e.2 :domain~e.1 (p / protein :name (n / name :op1 "Socs1"~e.0)) :purpose~e.3 (i / inhibit-01~e.4 :ARG1~e.5 (i2 / inhibit-01~e.11 :ARG1~e.12 (p3 / protein :name (n3 / name :op1 "STAT6"~e.13)) :ARG2-of (i3 / induce-01~e.10 :ARG0 (p2 / protein :name (n2 / name :op1 "IFN-gamma"~e.6,8)))))) # ::id bel_pmid_1211_0143.38516 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Socs1 inhibits activation of STAT6 by Il4 stimulation # ::alignments 0-1.1.1.1 1-1 2-1.2 3-1.2.2.r 4-1.2.2.1.1 7-1.2.1 (i / inhibit-01~e.1 :ARG0 (p3 / protein :name (n / name :op1 "Socs1"~e.0)) :ARG1 (a / activate-01~e.2 :ARG0 (s / stimulate-01~e.7 :ARG1 (p2 / protein :name (n3 / name :op1 "IL-4"))) :ARG1~e.3 (p / protein :name (n2 / name :op1 "STAT6"~e.4)))) # ::id bel_pmid_1211_0143.38548 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Il6 activates STAT1 and STAT5 in addition to STAT3 # ::alignments 1-1 2-1.2.1.1.1 3-1.2 4-1.2.2.1.1 5-1.2 6-1.2 7-1.2.r 8-1.2.3.1.1 (a / activate-01~e.1 :ARG0 (p / protein :name (n5 / name :op1 "IL-6")) :ARG1~e.7 (a2 / and~e.3,5,6 :op1 (p2 / protein :name (n2 / name :op1 "STAT1"~e.2)) :op2 (p3 / protein :name (n3 / name :op1 "STAT5"~e.4)) :op3 (p4 / protein :name (n4 / name :op1 "STAT3"~e.8)))) # ::id bel_pmid_1214_7685.34134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the down @-@ regulation of D1 and D2 cyclins by OSM was mediated by STAT3 but not by SHP2 @/@ Ras STAT3 activation is necessary and sufficient for down @-@ regulation of D1 and D2 cyclins in fetal hepatocytes # ::alignments 1-1.1.1.2 2-1.1.1.2 3-1.1.1.2 4-1.1.1.2.1.r 5-1.1.1.2.1.1.1.1 6-1.1.1.2.1 7-1.1.1.2.1.2.1.1 8-1.1.1.2.1.1.1.2 8-1.1.1.2.1.2.1.2 9-1.1.1.2.2.r 10-1.1.1.2.2.1.1 12-1.1.1 12-1.1.2 13-1.1.1.1.r 14-1.1.1.1.1.1 15-1.1 16-1.1.2.1 16-1.1.2.1.r 17-1.1.2.2.r 18-1.1.2.2.1.1 20-1.1.2.2.1.1 21-1.2.1.2.1.1.1 22-1.2.1.2 24-1.2.1 25-1.2 26-1.2.2 27-1.2.1.1.r 28-1.2.1.1 29-1.2.1.1 30-1.2.1.1 31-1.2.1.1.1.r 32-1.2.1.1.1.1.1.1 33-1.2.1.1.1 34-1.2.1.1.1.2.1.1 35-1.2.1.1.1.1.1.2 35-1.2.1.1.1.2.1.2 37-1.2.1.1.1.3.1 38-1.2.1.1.1.3 (m3 / multi-sentence :snt1 (c4 / contrast-01~e.15 :ARG1 (m / mediate-01~e.12 :ARG0~e.13 (p7 / protein :name (n10 / name :op1 "STAT3"~e.14)) :ARG1 (d2 / downregulate-01~e.1,2,3 :ARG1~e.4 (a5 / and~e.6 :op1 (p5 / protein :name (n8 / name :op1 "D1"~e.5 :op2 "cyclin"~e.8)) :op2 (p6 / protein :name (n9 / name :op1 "D2"~e.7 :op2 "cyclin"~e.8))) :ARG2~e.9 (e / enzyme :name (n4 / name :op1 "OSM"~e.10)))) :ARG2 (m2 / mediate-01~e.12 :polarity~e.16 -~e.16 :ARG0~e.17 (p4 / pathway :name (n7 / name :op1 "SHP2/Ras"~e.18,20)) :ARG1 d2)) :snt2 (a / and~e.25 :op1 (n / need-01~e.24 :ARG0~e.27 (d / downregulate-01~e.28,29,30 :ARG1~e.31 (a2 / and~e.33 :op1 (p2 / protein :name (n2 / name :op1 "D1"~e.32 :op2 "cyclin"~e.35)) :op2 (p3 / protein :name (n3 / name :op1 "D2"~e.34 :op2 "cyclin"~e.35)) :location (h / hepatocyte~e.38 :mod (f / fetus~e.37)))) :ARG1 (a4 / activate-01~e.22 :ARG1 (p / protein :name (n6 / name :op1 "STAT3"~e.21)))) :op2 (s / suffice-01~e.26 :ARG0 a2 :ARG1 d))) # ::id bel_pmid_1217_7059.29876 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Substitution of Arg @-@ 238 , equivalent to conserved Arg in the 14 @-@ 3 @-@ 3 binding motif , with Glu ( R238E ) decreased 14 @-@ 3 @-@ 3 theta binding to PDK1 ( Fig . 3 C , upper panel , lane 4 ) . In contrast , substitution of Val @-@ 243 with Pro ( V243P ) , a residue conserved in many 14 @-@ 3 @-@ 3 targets , such as Raf @-@ 1 and Bad ( Fig.3 A ) , dramatically increased the amount of 14 @-@ 3 @-@ 3 theta bound to PDK1 # ::alignments 0-1.1.1 4-1.1.1.3.1 6-1.1.1.3 6-1.1.1.3.3 6-1.1.1.3.3.r 7-1.1.1.3.3.1.r 8-1.1.1.3.3.1.2 10-1.1.1.3.3.1.2.1.r 12-1.1.1.3.3.1.2.1.1.1.1.1 14-1.1.1.3.3.1.2.1.1.1.1.1 16-1.1.1.3.3.1.2.1.1.1.1.1 17-1.1.1.3.3.1.2.1.1 18-1.1.1.3.3.1.2.1 23-1.1.1.1 25-1.1 26-1.1.2.1.1.1 28-1.1.2.1.1.1 30-1.1.2.1.1.1 32-1.1.2 34-1.1.2.2.1.1 36-1.1.3.1 36-1.2.1.1.3.3.1.2.1 38-1.1.2.1.1.1 41-1.1.3.2.2.1 42-1.1.3.2.2 44-1.1.3.2 45-1.1.3.2.1 49-1.2 51-1.2.1.1 55-1.2.1.1.3.1 59-1.2.1.1.1 63-1.2.1.1.3.3.1 64-1.2.1.1.3.3.1.1 65-1.2.1.1.3.3.1.1.1.r 66-1.2.1.1.3.3.1.1.1.3 67-1.2.1.1.3.3.1.1.1.1.1.1.1 69-1.2.1.1.3.3.1.1.1.1.1.1.1 71-1.2.1.1.3.3.1.1.1.1.1.1.1 72-1.2.1.1.3.3.1.1.1 72-1.2.1.1.3.3.1.1.1.1 72-1.2.1.1.3.3.1.1.1.1.r 74-1.2.1.1.3.3.1.1.1.2.r 75-1.2.1.1.3.3.1.1.1.2.r 76-1.2.1.1.3.3.1.1.1.2.1.1.1 78-1.2.1.1.3.3.1.1.1.2.1.1.1 79-1.2.1.1.3.3.1.1.1.2 80-1.2.1.1.3.3.1.1.1.2.2.1.1 86-1.2.1.3 87-1.2.1 89-1.2.1.2 91-1.1.2.1.1.1 91-1.2.1.2.1.1.1 93-1.1.2.1.1.1 93-1.2.1.2.1.1.1 95-1.1.2.1.1.1 95-1.2.1.2.1.1.1 97-1.1.2 97-1.2.1.2.1 97-1.2.1.2.1.2 97-1.2.1.2.1.2.r 99-1.1.2.2.1.1 99-1.2.1.2.1.2.1.1.1 (m / multi-sentence :snt1 (d / decrease-01~e.25 :ARG0 (s / substitute-01~e.0 :value "R238E"~e.23 :ARG1 (a8 / amino-acid :name (n14 / name :op1 "glutamic" :op2 "acid")) :ARG3 (a / amino-acid~e.6 :mod 238~e.4 :name (n2 / name :op1 "arginine") :ARG1-of~e.6 (e / equal-01~e.6 :ARG2~e.7 (a2 / amino-acid :name (n3 / name :op1 "arginine") :ARG1-of (c / conserve-01~e.8 :location~e.10 (p9 / protein-segment~e.18 :ARG1-of (b2 / bind-01~e.17 :ARG2 (p / protein :name (n / name :op1 "14-3-3"~e.12,14,16))))))))) :ARG1 (b3 / bind-01~e.32,97 :ARG1 (p2 / protein :name (n5 / name :op1 "14-3-3theta"~e.26,28,30,38,91,93,95)) :ARG2 (e3 / enzyme :name (n6 / name :op1 "PDK1"~e.34,99))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.36 :mod "3C") :location (l / lane~e.44 :mod 4~e.45 :location (p8 / panel~e.42 :mod (u2 / upper~e.41))))) :snt2 (c2 / contrast-01~e.49 :ARG2 (i / increase-01~e.87 :ARG0 (s2 / substitute-01~e.51 :value "V243P"~e.59 :ARG1 (a4 / amino-acid :name (n7 / name :op1 "proline")) :ARG2 (a5 / amino-acid :mod 243~e.55 :name (n8 / name :op1 "valine") :ARG1-of (m3 / mean-01 :ARG2 (r / residue~e.63 :ARG1-of (c3 / conserve-01~e.64 :location~e.65 (m2 / molecular-physical-entity~e.72 :ARG1-of~e.72 (t / target-01~e.72 :ARG0 (p4 / protein :name (n9 / name :op1 "14-3-3"~e.67,69,71))) :example~e.74,75 (a6 / and~e.79 :op1 (e2 / enzyme :name (n10 / name :op1 "Raf-1"~e.76,78)) :op2 (p5 / protein :name (n11 / name :op1 "Bad"~e.80))) :quant (m4 / many~e.66))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.36 :mod "3A")))))) :ARG1 (a7 / amount~e.89 :quant-of (p6 / protein~e.97 :name (n12 / name :op1 "14-3-3theta"~e.91,93,95) :ARG1-of~e.97 (b4 / bind-01~e.97 :ARG2 (e4 / enzyme :name (n13 / name :op1 "PDK1"~e.99))))) :manner (d4 / dramatic~e.86)))) # ::id bel_pmid_1217_7059.29878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Co @-@ immunoprecipitation analysis indicated that mutation at Ser @-@ 241 impairs the PDK1 binding ability for 14 @-@ 3 @-@ 3 theta and 14 @-@ 3 @-@ 3 eta ( Fig . 3 B , upper panel , lane 3 , and data not shown ) . # ::alignments 3-1.1 4-1 5-1.2.r 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.2.1 10-1.2.1.1.1 11-1.2 13-1.2.2.1.1.1 14-1.2.2.2 15-1.2.2 16-1.2.2.2.2.r 17-1.2.2.2.2.1.1.1 17-1.2.2.2.2.2.1.1 19-1.2.2.2.2.1.1.1 19-1.2.2.2.2.2.1.1 21-1.2.2.2.2.1.1.1 21-1.2.2.2.2.2.1.1 23-1.2.2.2.2 24-1.2.2.2.2.1.1.1 24-1.2.2.2.2.2.1.1 26-1.2.2.2.2.1.1.1 26-1.2.2.2.2.2.1.1 28-1.2.2.2.2.1.1.1 28-1.2.2.2.2.2.1.1 31-1.3.1.1 33-1.3.1.1.2.1 36-1.3.1.1.2.2.1 37-1.3.1.1.2.2 39-1.3.1.1.2 40-1.3.1.1.2.1 42-1.3.1 43-1.3.1.2 44-1.3.1.2.1.1 44-1.3.1.2.1.1.r 45-1.3.1.2.1 (i / indicate-01~e.4 :ARG0 (a / analyze-01~e.3 :manner (c / coimmunoprecipitate-01)) :ARG1~e.5 (i2 / impair-01~e.11 :ARG0 (m / mutate-01~e.6 :ARG1~e.7 (a2 / amino-acid :mod 241~e.10 :name (n2 / name :op1 "serine"~e.8))) :ARG1 (c2 / capable-01~e.15 :ARG1 (e / enzyme :name (n3 / name :op1 "PDK1"~e.13)) :ARG2 (b2 / bind-01~e.14 :ARG1 e :ARG2~e.16 (a3 / and~e.23 :op1 (p3 / protein :name (n4 / name :op1 "14-3-3theta"~e.17,19,21,24,26,28)) :op2 (p4 / protein :name (n5 / name :op1 "14-3-3eta"~e.17,19,21,24,26,28)))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.42 :op1 (f / figure~e.31 :mod "3B" :location (l / lane~e.39 :mod 3~e.33,40 :location (p5 / panel~e.37 :mod (u2 / upper~e.36)))) :op2 (d2 / data~e.43 :ARG1-of (s / show-01~e.45 :polarity~e.44 -~e.44))))) # ::id bel_pmid_1219_8646.11798 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hepatic expression of Ccnd1 , cMyc , IL @-@ 1r1 , and IL @-@ 6r was induced in wild @-@ type mice , but not Pparalpha @-@ null mice , after acute exposure to the potent Pparalpha agonist Wy @-@ 14,643 , indicating a role for Pparalpha in regulating the expression of these genes . # ::alignments 0-1.1.2 1-1.1 1-1.2.2.1.2 2-1.1.1.r 3-1.1.1.1.1.1 5-1.1.1.2.1.1 7-1.1.1.3.1.1 7-1.1.1.4.1.1 9-1.1.1.3.1.1 11-1.1.1 12-1.1.1.3.1.1 12-1.1.1.4.1.1 14-1.1.1.4.1.1 16-1 17-1.2.r 18-1.2.1 20-1.2.1 21-1.2 23-1.2.2 24-1.2.2.1.1 24-1.2.2.1.1.r 25-1.2.2.1.2.1.1.1 27-1.2.2.1.2.1 27-1.2.2.1.2.1.2 27-1.2.2.1.2.1.2.1 27-1.2.2.1.2.1.2.1.r 27-1.2.2.1.2.1.2.r 28-1.2.2.1 30-1.3 31-1.3.1.2 32-1.3.1 33-1.3.1.1.r 35-1.3.1.1.2 36-1.3.1.1.3.1.1 37-1.3.1.1 38-1.3.1.1.1.1 40-1.3.1.1.1.1 42-1.3.1.3 44-1.3.1.3.1 45-1.3.1.3.1.1.r 46-1.3.1.3.1.1.1 48-1.3.1.3.1.1 50-1.3.1.3.1.1.2 53-1.3.1.3.1.1.2.1 (i / induce-01~e.16 :ARG2 (e / express-03~e.1 :ARG2~e.2 (a / and~e.11 :op1 (g / gene :name (n / name :op1 "Ccnd1"~e.3)) :op2 (g2 / gene :name (n2 / name :op1 "cMyc"~e.5)) :op3 (g3 / gene :name (n3 / name :op1 "IL-1r1"~e.7,9,12)) :op4 (g4 / gene :name (n4 / name :op1 "IL-6r"~e.7,12,14))) :mod (h / hepatic~e.0)) :location~e.17 (m / mouse~e.21 :mod (w / wild-type~e.18,20) :ARG1-of (c / contrast-01~e.23 :ARG2 (m2 / mouse~e.28 :polarity~e.24 -~e.24 :ARG3-of (e4 / express-03~e.1 :ARG2 (p5 / protein~e.27 :name (n6 / name :op1 "Pparalpha"~e.25) :ARG2-of~e.27 (m3 / mutate-01~e.27 :mod~e.27 "-/-"~e.27)))))) :time (a2 / after~e.30 :op1 (e2 / expose-01~e.32 :ARG2~e.33 (a4 / agonist~e.37 :name (n7 / name :op1 "Wy-14,643"~e.38,40) :mod (p6 / potent~e.35) :mod (p7 / protein :name (n8 / name :op1 "Pparalpha"~e.36))) :mod (a3 / acute~e.31) :ARG0-of (i2 / indicate-01~e.42 :ARG1 (r / role~e.44 :topic~e.45 (r2 / regulate-01~e.48 :ARG0 p7~e.46 :ARG1 (e3 / express-03~e.50 :ARG2 a~e.53))))))) # ::id bel_pmid_1220_4103.24772 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Jak1 phosphorylation was reduced in wildtype indivduals after Il13 treatement , implying that SHP @-@ 2 is responsible for this effect . # ::alignments 0-1.1.1.1.1 1-1.1 3-1 5-1.2.1 7-1.3 8-1.3.1.1.1.1 11-1.4 12-1.4.1.r 13-1.4.1.1.1.1 15-1.4.1.1.1.1 17-1.4.1 20-1.4.1.2 (r / reduce-01~e.3 :ARG1 (p / phosphorylate-01~e.1 :ARG1 (e3 / enzyme :name (n / name :op1 "Jak1"~e.0))) :location (i / individual :mod (w / wild-type~e.5)) :time (a / after~e.7 :op1 (t / treat-04 :ARG2 (p3 / protein :name (n2 / name :op1 "Il13"~e.8)))) :ARG0-of (i2 / imply-01~e.11 :ARG1~e.12 (r2 / responsible-01~e.17 :ARG0 (p2 / protein :name (n3 / name :op1 "SHP-2"~e.13,15)) :ARG1 (a2 / affect-01~e.20 :ARG0 p2 :ARG2 r)))) # ::id bel_pmid_1220_4103.27950 ::amr-annotator SDL-AMR-09 ::preferred # ::tok as for Jak1 , the phosphoryaltions of Tyk2 and IRS @-@ 2 were reduced after IL13 stimulaiton in wildtype cells . # ::alignments 0-1.3.r 2-1.2.1.1 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.1.1 11-1.1.1.2.1.1 13-1 14-1.3 15-1.3.1.1.1.1 18-1.3.1.2.1 19-1.3.1.2 (r / reduce-01~e.13 :ARG1 (p / phosphorylate-01 :ARG1 (a / and~e.8 :op1 (e / enzyme :name (n / name :op1 "Tyk2"~e.7)) :op2 (p2 / protein :name (n2 / name :op1 "IRS-2"~e.9,11)))) :topic (e2 / enzyme :name (n3 / name :op1 "Jak1"~e.2)) :time~e.0 (a2 / after~e.14 :op1 (s / stimulate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "IL13"~e.15)) :location (c / cell~e.19 :mod (w / wild-type~e.18))))) # ::id bel_pmid_1220_4103.27958 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results In cytoplasmic extracts , phosphoryalation of the p85 alpha subunit of PI3 @-@ kinase was markedly increased after stimulation with Il13 in both groups of probands . # ::alignments 0-1.4 2-1.5.1.1 3-1.5 3-1.5.1 3-1.5.1.r 12-1.1.1.2.1.1 14-1.1.1.2.1.1 16-1.2 16-1.2.r 17-1 18-1.3 19-1.3.1 20-1.3.1.1.r 21-1.3.1.1.1.1 22-1.3.1.2.r 23-1.3.1.2.1 24-1.3.1.2 (i / increase-01~e.17 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :name (n / name :op1 "p85alpha") :part-of (e / enzyme :name (n2 / name :op1 "PI3-kinase"~e.12,14)))) :manner~e.16 (m / marked~e.16) :time (a / after~e.18 :op1 (s / stimulate-01~e.19 :ARG2~e.20 (p3 / protein :name (n3 / name :op1 "Il13"~e.21)) :location~e.22 (g / group~e.24 :mod (b / both~e.23) :ARG2-of (i2 / include-91 :ARG1 (p4 / proband))))) :ARG2-of (r / result-01~e.0) :location (m2 / molecular-physical-entity~e.3 :ARG1-of~e.3 (e2 / extract-01~e.3 :ARG2 (c / cytoplasm~e.2)))) # ::id bel_pmid_1221_8157.20330 ::amr-annotator SDL-AMR-09 ::preferred # ::tok when Il6 and Il6R were combined , significant stimulation of both mineral and matrix release from bone explants was noted # ::alignments 0-1.2.r 1-1.2.1.1.1 3-1.2.2.1.1 5-1.2 7-1.1.2 8-1.1 11-1.1.1.1.1 12-1.1.1.1 13-1.1.1.1.2 14-1.1.1 16-1.1.1.2.1 19-1 (n / note-02~e.19 :ARG1 (s / stimulate-01~e.8 :ARG1 (r / release-01~e.14 :ARG1 (a / and~e.12 :op1 (m / mineral~e.11) :op2 (m2 / matrix~e.13)) :ARG2 (e / explant :mod (b / bone~e.16))) :ARG1-of (s2 / significant-02~e.7)) :time~e.0 (c / combine-01~e.5 :ARG1 (p / protein :name (n2 / name :op1 "Il6"~e.1)) :ARG2 (p2 / protein :name (n3 / name :op1 "Il6R"~e.3)))) # ::id bel_pmid_1221_8157.20336 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Il6 plus Il6R enhanced the expression of RANKL and OPG in calvarial bones , but decreased RANK expression # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1.1 8-1.1.2.1 9-1.1.2.1.2.1.1 10-1.1.3.r 11-1.1.3.1 12-1.1.3 14-1 15-1.2 16-1.2.2.1.1.1 17-1.2.2 (c / contrast-01~e.14 :ARG1 (e / enhance-01~e.3 :ARG0 (a / and~e.1 :op1 (p / protein :name (n / name :op1 "Il6"~e.0)) :op2 (p2 / protein :name (n2 / name :op1 "Il6R"~e.2))) :ARG1 (e2 / express-03~e.5 :ARG2~e.6 (a2 / and~e.8 :op1 (p3 / protein :name (n3 / name :op1 "RANKL"~e.7)) :op2 (p4 / protein :name (n4 / name :op1 "OPG"~e.9)))) :location~e.10 (b / bone~e.12 :mod (c2 / calvarial~e.11))) :ARG2 (d / decrease-01~e.15 :ARG0 a :ARG1 (e3 / express-03~e.17 :ARG2 (p5 / protein :name (n5 / name :op1 "RANK"~e.16))))) # ::id bel_pmid_1221_8157.28344 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Il6 , leukemia inhibitory factor [ LIF}, and oncostatin M [ OSM ] are Il6 @-@ type cytokines that stimulate osteoclast formation and function # ::alignments 0-1.1.1.1.1 2-1.1.2.1.1 3-1.1.2.1.2 4-1.1.2.1.3 8-1.1.3.1.1 9-1.1.3.1.2 14-1.1.1.1.1 16-1 17-1.2 19-1.2.1 20-1.2.1.1.1.1 21-1.2.1.1.1 22-1.2.1.1 23-1.2.1.1.2 (t2 / type-03~e.16 :ARG1 (a3 / and :op1 (p / protein :name (n2 / name :op1 "Il6"~e.0,14)) :op2 (p2 / protein :name (n3 / name :op1 "leukemia"~e.2 :op2 "inhibitory"~e.3 :op3 "factor"~e.4)) :op3 (p3 / protein :name (n4 / name :op1 "oncostatin"~e.8 :op2 "M"~e.9))) :ARG2 (c / cytokine~e.17 :ARG0-of (s / stimulate-01~e.19 :ARG1 (a2 / and~e.22 :op1 (f / form-01~e.21 :ARG1 (o / osteoclast~e.20)) :op2 (f2 / function-01~e.23 :ARG0 o))) :mod p)) # ::id bel_pmid_1221_8157.29756 ::amr-annotator SDL-AMR-09 ::preferred # ::tok OSM also stimulated Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calcaria , but have no effect on the expression of RANK # ::alignments 0-1.1.1.1.1.1 1-1.1.1.3 2-1.1.1 4-1.1.1.2 5-1.1 6-1.1.2 8-1.1.2.2.1.1.1 9-1.1.2.2 10-1.1.2.2.2.r 11-1.1.2.2.2.1.1.1 12-1.1.2.2.2 13-1.1.2.2.2.2.1.1 14-1.1.2.2.3.r 15-1.1.2.2.3.1 16-1.1.2.2.3 18-1 20-1.2.1 20-1.2.1.r 21-1.2 22-1.2.3.r 24-1.2.3 25-1.2.3.1.r 26-1.2.3.1.1.1 (c / contrast-01~e.18 :ARG1 (a / and~e.5 :op1 (s2 / stimulate-01~e.2 :ARG0 (p / protein :name (n2 / name :op1 "OSM"~e.0)) :ARG1 (r / release-01~e.4 :ARG1 (c3 / calcium)) :mod (a2 / also~e.1)) :op2 (e / enhance-01~e.6 :ARG0 p :ARG1 (e2 / express-03~e.9 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "mRNA"~e.8)) :ARG2~e.10 (a3 / and~e.12 :op1 (p2 / protein :name (n4 / name :op1 "RANKL"~e.11)) :op2 (p3 / protein :name (n5 / name :op1 "OPG"~e.13))) :ARG3~e.14 (c2 / calcaria~e.16 :mod (m2 / mouse~e.15))))) :ARG2 (a4 / affect-01~e.21 :polarity~e.20 -~e.20 :ARG0 p :ARG1~e.22 (e3 / express-03~e.24 :ARG2~e.25 (p4 / protein :name (n6 / name :op1 "RANK"~e.26))))) # ::id bel_pmid_1221_9085.28406 ::amr-annotator SDL-AMR-09 ::preferred # ::tok functions of the 2 major signaling pathways , the signal transducers and activators of transcription 1 and 3 [ STAT1 @/@ 3 ] and the Src @-@ homology tyrosine phosphatase 2 [ SHP2]-Ras @-@ ERK [ Ptpn11 ] , emanating from the common signal transducer , gp130 , in the gastrointestinal tract # ::alignments 0-1 1-1.1.r 3-1.1.1 4-1.1.3 5-1.1.2 6-1.1 9-1.1.2 10-1.1.4.1.1.1.2 10-1.1.4.1.2.1.2 11-1.1.4.1 11-1.1.4.1.1.1.3 11-1.1.4.1.2.1.3 12-1.1.4.1.1.1.4 12-1.1.4.1.2.1.4 13-1.1.4.1.1.1.5 13-1.1.4.1.2.1.5 14-1.1.4.1.1.1.6 14-1.1.4.1.2.1.6 15-1.1.4.1.1.1.7 16-1.1.4.1.1.1.3 16-1.1.4.1.2.1.3 17-1.1.4.1.2.1.7 21-1.1.4.1.2.1.7 23-1.1.4 23-1.1.4.1.1.1.3 23-1.1.4.1.2.1.3 25-1.1.4.2.1.1 27-1.1.4.2.1.1 28-1.1.4.2.1.2 29-1.1.4.2.1.3 30-1.1.4.2.1.4 34-1.1.4.2.1.4 39-1.2 40-1.2.1.r 42-1.2.1.2 43-1.1.2 43-1.1.4.1.1.1.1 43-1.1.4.1.2.1.1 43-1.2.1.1.1 44-1.1.4.1.1.1.2 44-1.1.4.1.2.1.2 46-1.2.1.1.2.1.1.1 48-1.2.2.r 50-1.2.2.1 51-1.2.2 (f2 / function-01~e.0 :ARG0~e.1 (p / pathway~e.6 :quant 2~e.3 :ARG0-of (s / signal-07~e.5,9,43) :ARG1-of (m / major-02~e.4) :example (a2 / and~e.23 :op1 (a / and~e.11 :op1 (p3 / pathway :name (n2 / name :op1 "signal"~e.43 :op2 "transducer"~e.10,44 :op3 "and"~e.11,16,23 :op4 "activator"~e.12 :op5 "of"~e.13 :op6 "transcription"~e.14 :op7 1~e.15)) :op2 (p6 / pathway :name (n5 / name :op1 "signal"~e.43 :op2 "transducer"~e.10,44 :op3 "and"~e.11,16,23 :op4 "activator"~e.12 :op5 "of"~e.13 :op6 "transcription"~e.14 :op7 3~e.17,21))) :op2 (p4 / pathway :name (n3 / name :op1 "Src-homology"~e.25,27 :op2 "tyrosine"~e.28 :op3 "phosphatase"~e.29 :op4 "2-Ras-ERK"~e.30,34)))) :ARG1-of (e / emanate-01~e.39 :ARG2~e.40 (m3 / molecular-physical-entity :ARG2-of (t / transduce-01 :ARG1 (s2 / signal-07~e.43) :ARG1-of (m2 / mean-01 :ARG2 (p2 / protein :name (n / name :op1 "gp130"~e.46)))) :mod (c / common~e.42)) :location~e.48 (t3 / tract~e.51 :mod (g / gastrointestinal~e.50)))) # ::id bel_pmid_1222_0517.8134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sp1 @-@ mediated transcription is one of the mechanisms , which is responsible for BMP2 @-@ induced up @-@ regulation of Erk2 expression . # ::alignments 0-1.1.1.1.1 2-1.1 3-1 8-1.2.1 12-1.3 13-1.3.1.r 14-1.3.1.1.2.1.1.1 16-1.3.1.1.2 17-1.3.1.1 18-1.3.1.1 19-1.3.1.1 20-1.3.1.1.1.r 21-1.3.1.1.1.1.1 22-1.3.1 (t2 / transcribe-01~e.3 :ARG1-of (m / mediate-01~e.2 :ARG0 (p / protein :name (n / name :op1 "Sp1"~e.0))) :ARG1-of (i / include-91 :ARG2 (m2 / mechanism~e.8)) :ARG0-of (r / responsible-01~e.12 :ARG1~e.13 (e / express-03~e.22 :ARG2 (u / upregulate-01~e.17,18,19 :ARG1~e.20 (e2 / enzyme :name (n3 / name :op1 "Erk2"~e.21)) :ARG2-of (i2 / induce-01~e.16 :ARG0 (p2 / protein :name (n2 / name :op1 "BMP2"~e.14))))))) # ::id bel_pmid_1222_0517.25504 ::amr-annotator SDL-AMR-09 ::preferred # ::tok increased Erk2 protein level under BMP2 inducement comes from BMP2 @-@ up @-@ regulated Erk2 mRNA expression . # ::alignments 0-1.1.2 1-1.1.1.1.1 2-1.1.3.1 3-1.1 5-1.1.3.1.1.1 6-1.1.3 7-1 8-1.2.r 9-1.1.3.1.1.1 11-1.1.2 14-1.1.1.1.1 15-1.2.1.1.1 16-1.2 (c / come-01~e.7 :ARG1 (l / level~e.3 :quant-of (e3 / enzyme :name (n / name :op1 "Erk2"~e.1,14)) :ARG1-of (i / increase-01~e.0,11) :ARG2-of (i2 / induce-01~e.6 :ARG0 (p2 / protein~e.2 :name (n2 / name :op1 "BMP2"~e.5,9)))) :ARG3~e.8 (e / express-03~e.16 :ARG2 (n3 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.15) :ARG1-of (u / upregulate-01 :ARG2 p2) :ARG0-of (e2 / encode-01 :ARG1 e3)))) # ::id bel_pmid_1222_6756.17890 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NIH3T3 cells expressing either Raf :ER @-@ DD or Raf : ER @-@ YY synthesized RALT upon stimulation with Tamoxifen for 4 ± 8 h in serum @-@ deprived medium ( Figure 4b ) . The effect of tamoxifen was as strong as serum stimulation and was reverted by the administra @- tion of U0126 ( Figure 4b ) # ::alignments 0-1.1.1.1.1 1-1.1.1 2-1.1.1.2 4-1.1.1.2.1.1.1.1 4-1.1.1.2.1.2.1.1 7-1.1.1.2.1.1.1.1 8-1.1.1.2.1 9-1.1.1.2.1.1.1.1 9-1.1.1.2.1.2.1.1 11-1.1.1.2.1.1.1.1 11-1.1.1.2.1.2.1.1 13-1.1.1.2.1.2.1.1 14-1.1 15-1.1.2.1.1 17-1.1.3 18-1.1.3.1.r 19-1.1.3.1.1.1 21-1.1.3.2.1.1 23-1.1.3.2.2.1 24-1.1.3.2.1.2 24-1.1.3.2.2.2 25-1.1.3.3.r 26-1.1.3.3.1.1 28-1.1.3.3.1 29-1.1.3.3 31-1.1.4.1 31-1.2.3.1 32-1.1.4.1.1 32-1.2.3.1.1 36-1.2.1.1 38-1.1.3.1.1.1 38-1.2.1.1.1.1.1 40-1.1.3.r 41-1.2.1 42-1.1.3.r 42-1.2.1.3.r 43-1.2.1.3.1 44-1.2.1.3 45-1.2 47-1.2.2 54-1.2.2.1.1.1.1 56-1.1.4.1 56-1.2.3.1 57-1.1.4.1.1 57-1.2.3.1.1 (m / multi-sentence :snt1 (s2 / synthesize-01~e.14 :ARG0 (c / cell-line~e.1 :name (n3 / name :op1 "NIH3T3"~e.0) :ARG3-of (e2 / express-03~e.2 :ARG2 (o / or~e.8 :op1 (p2 / protein :name (n / name :op1 "Raf:ER-DD"~e.4,7,9,11)) :op2 (p3 / protein :name (n4 / name :op1 "Raf:ER-YY"~e.4,9,11,13))))) :ARG1 (p / protein :name (n8 / name :op1 "RALT"~e.15)) :time~e.40,42 (s3 / stimulate-01~e.17 :ARG2~e.18 (s9 / small-molecule :name (n9 / name :op1 "tamoxifen"~e.19,38)) :duration (b / between :op1 (t / temporal-quantity :quant 4~e.21 :unit (h / hour~e.24)) :op2 (t2 / temporal-quantity :quant 8~e.23 :unit (h2 / hour~e.24))) :location~e.25 (m5 / medium~e.29 :ARG1-of (d / deprive-01~e.28 :ARG2 (s4 / serum~e.26)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31,56 :mod "4b"~e.32,57))) :snt2 (a / and~e.45 :op1 (s5 / strong-02~e.41 :ARG1 (a2 / affect-01~e.36 :ARG0 (s7 / small-molecule :name (n10 / name :op1 "tamoxifen"~e.38))) :degree (e3 / equal) :compared-to~e.42 (s6 / stimulate-01~e.44 :ARG0 (s8 / serum~e.43))) :op2 (r / revert-01~e.47 :ARG0 (a3 / administrate-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "U0126"~e.54))) :ARG1 a2) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.31,56 :mod "4b"~e.32,57)))) # ::id bel_pmid_1222_6756.17894 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ablation of RALT expression by MEK @- 1 inhibitors is caused by suppression of RALT transcription , as indicated by the Northern blot analysis presented in Figure 3 . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1.1.1 3-1.2.1 4-1.2.2.r 5-1.2.2.1.1.1.1 7-1.2.2.1.1.1.1 8-1.2.2 8-1.2.2.1 8-1.2.2.1.r 10-1 11-1.1.r 12-1.1 13-1.1.1.r 14-1.1.1.1 15-1.1.1 17-1.3.r 18-1.3 19-1.3.1.r 21-1.3.1.1.1.1 22-1.3.1.1.1.2 23-1.3.1 24-1.3.1.2 25-1.3.1.2.1.r 26-1.3.1.2.1 27-1.3.1.2.1.1 (c2 / cause-01~e.10 :ARG0~e.11 (s / suppress-01~e.12 :ARG1~e.13 (t2 / transcribe-01~e.15 :ARG1 p~e.14)) :ARG1 (a / ablate-01~e.0 :ARG1~e.1 (e3 / express-03~e.3 :ARG2 (p / protein :name (n3 / name :op1 "RALT"~e.2))) :ARG3~e.4 (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (i2 / inhibit-01~e.8 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK-1"~e.5,7))))) :ARG1-of~e.17 (i3 / indicate-01~e.18 :ARG0~e.19 (a2 / analyze-01~e.23 :instrument (t3 / thing :name (n4 / name :op1 "Northern"~e.21 :op2 "blot"~e.22)) :ARG1-of (p2 / present-01~e.24 :location~e.25 (f / figure~e.26 :mod 3~e.27))))) # ::id bel_pmid_1222_6756.26554 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upon stimulation with EGF ( 0.3 ng/ml ) or bFGF ( 0.3 ng/ml ) about 20 % of uninjected EGFR @/@ ErbB @-@ 2 cells entered S phase ( data not shown ) . We observed a similar rate of entrance into S phase when counting cells microinjected with a control antiserum ( RAM , Figure 1e ) . Cells micro @- injected with anti @-@ RALT antibodies and stimulated with EGF progressed to S phase at a frequency which was 2.8 @-@ fold higher than control cells . # ::alignments 1-1.1.3 2-1.1.3.1.r 3-1.1.3.1.1.1.1 5-1.1.3.1.1.2.1 5-1.1.3.1.2.2.1 8-1.1.3.1 9-1.1.3.1.2.1.1 11-1.1.3.1.1.2.1 11-1.1.3.1.2.2.1 14-1.1.1 15-1.1.1.1.1 16-1.1.1.1 19-1.1.1.1.2.2.1.1.1 20-1.1.1.1.2.2 21-1.1.1.1.2.2.2.1.1 23-1.1.1.1.2.2.2.1.1 24-1.1.1.1.2 25-1.1 26-1.1.2.1.1 27-1.1.2.1.2 29-1.1.4.1 30-1.1.1.1.2.1.1 30-1.1.4.1.1.1 30-1.1.4.1.1.1.r 31-1.1.4.1.1 34-1.2.1 35-1.2 37-1.2.2.2 38-1.2.2 39-1.2.2.1.r 40-1.2.2.1 41-1.2.2.1.1.r 42-1.2.2.1.1.1.1 43-1.2.2.1.1.1.2 44-1.2.3.r 45-1.2.3 46-1.2.3.1 46-1.3.1.1.2 47-1.2.3.1.1 47-1.3.1.1 48-1.2.3.1.1.1.r 50-1.2.3.1.1.1.1 51-1.2.3.1.1.1 53-1.2.3.1.1.1.2.1.1 55-1.2.4.1 56-1.2.4.1.1 59-1.1.1.1.2 62-1.1.1.1.2.1 63-1.3.1.1.1.r 64-1.3.1.1.1.1 66-1.3.1.1.1.1.1.1.1 67-1.3.1.1.1 68-1.3.1 69-1.3.1.2 70-1.3.1.2.2.r 71-1.3.1.2.2.1.1 72-1.3 73-1.3.2.r 74-1.3.2.1.1 75-1.3.2.1.2 78-1.3.3 81-1.3.3.1.1 83-1.3.3.1 84-1.3.3.2 85-1.3.3.3.r 86-1.3.3.3.1 87-1.3.3.3 (m / multi-sentence :snt1 (e / enter-01~e.25 :ARG0 (a / about~e.14 :op1 (p2 / percentage-entity~e.16 :value 20~e.15 :quant-of (c3 / cell~e.24,59 :ARG2-of (i / inject-01~e.62 :polarity -~e.30) :mod (s4 / slash~e.20 :op1 (e6 / enzyme :name (n8 / name :op1 "EGFR"~e.19)) :op2 (e7 / enzyme :name (n9 / name :op1 "ErbB-2"~e.21,23)))))) :ARG1 (e4 / event :name (n10 / name :op1 "S"~e.26 :op2 "phase"~e.27)) :time (s / stimulate-01~e.1 :ARG2~e.2 (o / or~e.8 :op1 (p3 / protein :name (n / name :op1 "EGF"~e.3) :quant (c / concentration-quantity :quant 0.3~e.5,11 :unit (n2 / nanogram-per-milliliter))) :op2 (p5 / protein :name (n3 / name :op1 "bFGF"~e.9) :quant (c2 / concentration-quantity :quant 0.3~e.5,11 :unit (n4 / nanogram-per-milliliter))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.29 :ARG1-of (s2 / show-01~e.31 :polarity~e.30 -~e.30)))) :snt2 (o2 / observe-01~e.35 :ARG0 (w / we~e.34) :ARG1 (r / rate~e.38 :degree-of~e.39 (e2 / enter-01~e.40 :ARG1~e.41 (e5 / event :name (n11 / name :op1 "S"~e.42 :op2 "phase"~e.43))) :ARG1-of (r2 / resemble-01~e.37)) :time~e.44 (c4 / count-01~e.45 :ARG1 (c5 / cell~e.46 :ARG2-of (m2 / microinject-01~e.47 :ARG1~e.48 (a2 / antiserum~e.51 :mod (c6 / control-01~e.50) :ARG1-of (l / label-01 :ARG2 (s5 / string-entity :value "RAM"~e.53)))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.55 :mod "1e"~e.56))) :snt3 (p4 / progress-01~e.72 :ARG1 (a4 / and~e.68 :op1 (m3 / microinject-01~e.47 :ARG1~e.63 (a5 / antibody~e.67 :ARG0-of (c10 / counter-01~e.64 :ARG1 (p9 / protein :name (n5 / name :op1 "RALT"~e.66)))) :ARG2 (c7 / cell~e.46)) :op2 (s3 / stimulate-01~e.69 :ARG1 c7 :ARG2~e.70 (p / protein :name (n7 / name :op1 "EGF"~e.71)))) :ARG4~e.73 (e3 / event :name (n6 / name :op1 "S"~e.74 :op2 "phase"~e.75)) :ARG1-of (h2 / have-frequency-91~e.78 :ARG2 (p6 / product-of~e.83 :op1 2.8~e.81) :ARG1-of (h / high-02~e.84) :compared-to~e.85 (c8 / cell~e.87 :mod (c9 / control-01~e.86))))) # ::id bel_pmid_1222_6756.26768 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We conclude that endogenous RALT protein behaves as a bonafide feedback inhibitor of the ErbB @-@ 2 kinase . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.2 4-1.2.1.1.1 5-1.2.1 6-1.2 7-1.2.2.r 9-1.2.2.1.2.1 10-1.2.2.1.2 11-1.2.2 11-1.2.2.1 11-1.2.2.1.r 12-1.2.2.1.1.r 14-1.2.2.1.1.1.1 16-1.2.2.1.1.1.1 17-1.2.2.1.1.1.2 (c / conclude-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (b / behave-01~e.6 :ARG0 (p / protein~e.5 :name (n / name :op1 "RALT"~e.4) :mod (m / monocot~e.3)) :ARG1~e.7 (m2 / molecular-physical-entity~e.11 :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1~e.12 (e / enzyme :name (n2 / name :op1 "ErbB-2"~e.14,16 :op2 "kinase"~e.17)) :mod (f / feedback~e.10 :mod (b2 / bonafide~e.9)))))) # ::id bel_pmid_1222_6756.29724 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These observations were extended to HC @-@ 11 cells , a murine cell line derived from breast epithelium . In these cells TGF @-@ a , an activator of EGFR , and HRG @- 1b , which triggers ErbB @-@ 2/ErbB @-@ 3 dimers ( Marte et al. , 1995a , b ) , are able to induce RALT expression ( Fiorentino et al. , 2000 ) . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 3-1.1 4-1.1.2.r 5-1.1.2.1.1 7-1.1.2.1.1 8-1.1.2 10-1.2.1.1.1.1.1 11-1.1.2.2.1.1.1.1 12-1.1.2.2.1 13-1.1.2.2.1 14-1.1.2.2.1.2 15-1.1.2.2.1.2.1.r 16-1.1.2.2.1.2.1.1 17-1.1.2.2.1.2.1 20-1.2.1.4.1 21-1.2.1.4 22-1.2.1.1.1.1.1 24-1.2.1.1.1.1.1 24-1.2.1.1.3.2.1.1.1 27-1.2.1.1.1 27-1.2.1.1.1.2 27-1.2.1.1.1.2.r 28-1.2.1.1.1.2.1.r 29-1.2.1.1.1.2.1.1.1 31-1.2.1.1 32-1.2.1.1.2.1.1 34-1.2.1.1.2.1.1 37-1.2.1.1.3 38-1.2.1.1.3.1.1.1.1 38-1.2.1.1.3.1.2.1.1 42-1.2.1.1.3.1.2.1.1 45-1.2.1.1.3.2.1.1.2.1.1.1 46-1.2.1.1.3.2.1 46-1.2.1.1.3.2.1.1.2 47-1.2.1.1.3.2.1.1.2.2.1 51-1.2.1.1.3.2.1.2.1 55-1.2 57-1.2.1 58-1.2.1.2.1.1.1 59-1.2.1.2 61-1.2.1.3.1.1.1.1.1 62-1.2.1.3.1.1 63-1.2.1.3.1.1.2.1 65-1.2.1.3.1.2.1 (m / multi-sentence :snt1 (e2 / extend-01~e.3 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (o / observe-01~e.1) :mod (t2 / this~e.0)) :ARG4~e.4 (c / cell~e.8 :name (n2 / name :op1 "HC-11"~e.5,7) :ARG1-of (m2 / mean-01 :ARG2 (c3 / cell-line~e.12,13 :mod (o4 / organism :name (n / name :op1 "Muridae"~e.11)) :ARG1-of (d3 / derive-01~e.14 :ARG2~e.15 (e3 / epithelium~e.17 :mod (b / breast~e.16))))))) :snt2 (p / possible-01~e.55 :ARG1 (i / induce-01~e.57 :ARG0 (a2 / and~e.31 :op1 (p2 / protein~e.27 :name (n3 / name :op1 "TGF-a"~e.10,22,24) :ARG0-of~e.27 (a3 / activate-01~e.27 :ARG1~e.28 (e4 / enzyme :name (n4 / name :op1 "EGFR"~e.29)))) :op2 (p3 / protein :name (n5 / name :op1 "HRG-1b"~e.32,34)) :ARG0-of (t3 / trigger-01~e.37 :ARG1 (a6 / and :op1 (e / enzyme :name (n10 / name :op1 "ErbB-2"~e.38)) :op2 (e6 / enzyme :name (n11 / name :op1 "ErbB-3"~e.38,42)) :ARG3-of (d4 / dimerize-01)) :ARG1-of (d5 / describe-01 :ARG0 (a7 / and~e.46 :op1 (p4 / publication-91 :li "a"~e.24 :ARG0 (a4 / and~e.46 :op1 (p5 / person :name (n7 / name :op1 "Marte"~e.45)) :op2 (p6 / person :mod (o2 / other~e.47)))) :op2 (p12 / publication-91 :li "b"~e.51 :ARG0 a4) :time (d / date-entity :year 1995))))) :ARG2 (e5 / express-03~e.59 :ARG2 (p7 / protein :name (n8 / name :op1 "RALT"~e.58))) :ARG1-of (d6 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a5 / and~e.62 :op1 (p9 / person :name (n9 / name :op1 "Fiorentino"~e.61)) :op2 (p10 / person :mod (o3 / other~e.63))) :time (d2 / date-entity :year 2000~e.65))) :location (c2 / cell~e.21 :mod (t4 / this~e.20))))) # ::id bel_pmid_1223_7173.1150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We tested if human coronary artery endothelial cells ( HCAEC ) may become a source of cytokine and adhesion molecule expression when stimulated with bacterial lipopolysaccharide ( LPS ) . Analysis of HCAEC supernatants by ELISA identified enhanced secretion of IL @-@ 6 , IL @-@ 8 , and MCP @-@ 1 while # ::alignments 0-1.1.1 1-1.1 3-1.1.2.1.2.3 4-1.1.2.1.2.2.1 5-1.1.2.1.2.2 6-1.1.2.1.2.1 7-1.1.2.1.2 9-1.2.1.1.1.1.1 11-1.1.2 12-1.1.2.1 14-1.1.2.1.3 15-1.1.2.1.3.1.r 16-1.1.2.1.3.1.1.1 17-1.1.2.1.3.1.1 18-1.1.2.1.3.1.1.2.1.1 19-1.1.2.1.3.1.1.2.1.2 20-1.1.2.1.3.1 21-1.1.2.1.4.r 22-1.1.2.1.4 23-1.1.2.1.4.2.r 23-1.2.1.2.r 24-1.1.2.1.4.2.1 25-1.1.2.1.4.2 27-1.1.2.1.4.2 30-1.2.1 32-1.2.1.1.1.1.1 33-1.2.1.1 35-1.2.1.2.1.1 36-1.2 37-1.2.2.2 38-1.2.2 39-1.2.2.1.r 40-1.2.2.1.1.1.1 40-1.2.2.1.2.1.1 42-1.2.2.1.1.1.1 44-1.2.2.1.1.1.1 44-1.2.2.1.2.1.1 46-1.2.2.1.2.1.1 48-1.2.2.1 49-1.2.2.1.3.1.1 51-1.2.2.1.3.1.1 52-1.1.2.1.4.r (m / multi-sentence :snt1 (t / test-01~e.1 :ARG0 (w / we~e.0) :ARG1 (p / possible-01~e.11 :ARG1 (b / become-01~e.12 :mode interrogative :ARG1 (c / cell~e.7 :mod (e3 / endothelium~e.6) :mod (a / artery~e.5 :mod (c4 / coronary~e.4)) :mod (h / human~e.3)) :ARG2 (s / source-02~e.14 :ARG1~e.15 (e / express-03~e.20 :ARG2 (a5 / and~e.17 :op1 (c2 / cytokine~e.16) :op2 (p5 / protein :name (n8 / name :op1 "adhesion"~e.18 :op2 "molecule"~e.19))))) :time~e.21,52 (s2 / stimulate-01~e.22 :ARG1 c :ARG2~e.23 (l / lipopolysaccharide~e.25,27 :mod (b2 / bacteria~e.24)))))) :snt2 (i / identify-01~e.36 :ARG1 (a3 / analyze-01~e.30 :ARG1 (s3 / supernatant~e.33 :mod (c3 / cell :name (n3 / name :op1 "HCAEC"~e.9,32))) :instrument~e.23 (t2 / thing :name (n4 / name :op1 "ELISA"~e.35))) :ARG2 (s4 / secrete-01~e.38 :ARG1~e.39 (a4 / and~e.48 :op1 (p2 / protein :name (n5 / name :op1 "IL-6"~e.40,42,44)) :op2 (p3 / protein :name (n6 / name :op1 "IL-8"~e.40,44,46)) :op3 (p4 / protein :name (n7 / name :op1 "MCP-1"~e.49,51))) :ARG1-of (e2 / enhance-01~e.37)))) # ::id bel_pmid_1223_7173.1152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 1 beta and TNF @-@ alpha but not IL @-@ 10 . FACS analysis showed an LPS @-@ induced upregulation of ICAM @-@ 1 , VCAM , and ELAM @-@ 1 . # ::alignments 0-1.1.1.1.1.1 2-1.2.2.1.1.1.1 2-1.2.2.1.3.1.1 4-1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 8-1.1 9-1.1.2.1 9-1.1.2.1.r 10-1.1.2.2.1 12-1.1.2.2.1 14-1.2.1.1.1.1 15-1.2.1 16-1.2 18-1.2.2.2.1 20-1.2.2.2 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1.1.1 25-1.2.2.1.1.1.1 25-1.2.2.1.3.1.1 27-1.2.2.1.2.1.1 29-1.2.2.1 30-1.2.2.1.3.1.1 32-1.2.2.1.1.1.1 32-1.2.2.1.3.1.1 (m / multi-sentence :snt1 (c / contrast-01~e.8 :ARG1 (a / and~e.4 :op1 (p / protein :name (n / name :op1 "IL-1beta"~e.0)) :op2 (p2 / protein :name (n2 / name :op1 "TNF-alpha"~e.5,7))) :ARG2 (p3 / protein :polarity~e.9 -~e.9 :name (n3 / name :op1 "IL-10"~e.10,12))) :snt2 (s / show-01~e.16 :ARG0 (a2 / analyze-01~e.15 :instrument (t / thing :name (n4 / name :op1 "FACS"~e.14))) :ARG1 (u / upregulate-01~e.21 :ARG1~e.22 (a3 / and~e.29 :op1 (p4 / protein :name (n6 / name :op1 "ICAM-1"~e.2,23,25,32)) :op2 (p5 / protein :name (n7 / name :op1 "VCAM"~e.27)) :op3 (p6 / protein :name (n8 / name :op1 "ELAM-1"~e.2,25,30,32))) :ARG2-of (i / induce-01~e.20 :ARG0 (l / lipopolysaccharide~e.18))))) # ::id bel_pmid_1227_0932.7862 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SHP @-@ 2 is a dual @-@ specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1.1.r 5-1.3.1 8-1 9-1.2 10-1.2.1.r 11-1.2.1.1.3.1.1 12-1.2.1 15-1.2.1.1.1.1.1.1 16-1.2.1.1 17-1.2.1.1.2.1.1.1 18-1.2.1.1.1 18-1.2.1.1.2 19-1.2.1.2.r 20-1.2.1.2 (p3 / phosphatase~e.8 :domain~e.3 (p / protein :name (n2 / name :op1 "SHP-2"~e.0,2)) :ARG1-of (i / involve-01~e.9 :ARG2~e.10 (d2 / dephosphorylate-01~e.12 :ARG1 (a2 / and~e.16 :op1 (r2 / residue~e.18 :mod (a3 / amino-acid :name (n4 / name :op1 "tyrosine"~e.15))) :op2 (r3 / residue~e.18 :mod (a / amino-acid :name (n / name :op1 "serine"~e.17))) :part-of (p2 / protein :name (n3 / name :op1 "Stat1"~e.11))) :location~e.19 (n5 / nucleus~e.20))) :ARG1-of (s / specific-02 :mod (d / dual~e.5))) # ::id bel_pmid_1227_0932.9942 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In SHP @-@ 2-/- mouse fibroblast cells , Stat1 phosphorylation at both the tyrosine residue Tyr( 701 ) and the serine residue Ser( 727 ) by IFNgamma was enhanced and prolonged . # ::alignments 1-1.3.3.1.1 4-1.3.2 5-1.3.1.1 6-1.3 8-1.1.1.1.3.1.1 9-1.1.1 13-1.1.1.1.1.1.2.1 14-1.1.1.1.1 16-1.1.1.1.1.1.1 18-1.1.1.1 20-1.1.1.1.2.1.2.1 21-1.1.1.1.2 23-1.1.1.1.2.1.1 25-1.1.1.2.r 26-1.1.1.2.1.1 28-1.1 29-1 30-1.2 (a2 / and~e.29 :op1 (e / enhance-01~e.28 :ARG1 (p / phosphorylate-01~e.9 :ARG1 (a3 / and~e.18 :op1 (r / residue~e.14 :mod (a4 / amino-acid :mod 701~e.16 :name (n3 / name :op1 "tyrosine"~e.13))) :op2 (r2 / residue~e.21 :mod (a / amino-acid :mod 727~e.23 :name (n / name :op1 "serine"~e.20))) :part-of (p2 / protein :name (n2 / name :op1 "Stat1"~e.8))) :ARG2~e.25 (p3 / protein :name (n4 / name :op1 "IFNgamma"~e.26)))) :op2 (p4 / prolong-01~e.30 :ARG1 p) :location (c2 / cell~e.6 :name (n5 / name :op1 "fibroblast"~e.5) :mod (m / mouse~e.4) :mod (p5 / protein :name (n6 / name :op1 "SHP-2"~e.1) :ARG2-of (m2 / mutate-01 :mod "-/-")))) # ::id bel_pmid_1227_0932.39476 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistently , purified GST @-@ SHP @-@ 2 dephosphorylated Stat1 at both tyrosine and serine residues when immunoprecipitated phospho @-@ Stat1 or a peptide corresponding to the sequence surrounding Tyr( P )( 701 ) or Ser( P )( 727 ) of Stat1 was used as the substrate . # ::alignments 0-1.4 2-1.2.2 3-1.2.1.1 5-1.2.1.1 7-1.2.1.1 8-1 9-1.1.3.1.1 12-1.1.1.1.1.1 12-1.3.1.2.1.1.1.1.1.2.1 13-1.1 14-1.1.2.1.1.1 14-1.3.1.2.1.1.1.1.2.2.1 15-1.1.1 15-1.1.2 16-1.3.r 17-1.3.1.1.2 18-1.3.1.1.3 20-1.3.1.1.1.1 21-1.3.1 23-1.3.1.2 24-1.3.1.2.1 25-1.3.1.2.1.1.r 27-1.3.1.2.1.1 28-1.3.1.2.1.1.1 30-1.3.1.2.1.1.1.1.1.4 32-1.3.1.2.1.1.1.1.1.1 34-1.3.1.2.1.1.1.1 36-1.3.1.2.1.1.1.1.2.4 38-1.3.1.2.1.1.1.1.2.1 41-1.3.1.1.1.1 43-1.3 44-1.3.2.r 44-1.3.r 46-1.3.2 (d / dephosphorylate-01~e.8 :ARG1 (a2 / and~e.13 :op1 (r / residue~e.15 :mod (a3 / amino-acid :name (n3 / name :op1 "tyrosine"~e.12))) :op2 (r2 / residue~e.15 :mod (a4 / amino-acid :name (n4 / name :op1 "serine"~e.14))) :part-of (p2 / protein :name (n5 / name :op1 "Stat1"~e.9))) :ARG2 (e / enzyme :name (n2 / name :op1 "GST-SHP-2"~e.3,5,7) :ARG1-of (p / purify-01~e.2)) :time~e.16,44 (u / use-01~e.43 :ARG1 (o / or~e.21 :op1 (p3 / protein :name (n6 / name :op1 "Stat1"~e.20,41) :ARG1-of (i / immunoprecipitate-01~e.17) :ARG3-of (p4 / phosphorylate-01~e.18)) :op2 (p5 / peptide~e.23 :ARG1-of (c / correspond-02~e.24 :ARG2~e.25 (s / sequence~e.27 :ARG1-of (s2 / surround-01~e.28 :ARG2 (o2 / or~e.34 :op1 (a5 / amino-acid :mod 701~e.32 :name (n7 / name :op1 "tyrosine"~e.12) :part-of p2 :ARG3-of p4~e.30) :op2 (a6 / amino-acid :mod 727~e.38 :name (n8 / name :op1 "serine"~e.14) :part-of p2 :ARG3-of p4~e.36))))))) :ARG2~e.44 (s3 / substrate~e.46)) :manner (c2 / consistent-02~e.0)) # ::id bel_pmid_1240_2043.4190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here we show that after stimulation by growth factors Spry1 and Spry2 translocate to the plasma membrane and become phosphorylated on a conserved tyrosine . # ::alignments 0-1.3 1-1.1 2-1 3-1.2.r 4-1.2.3 5-1.2.3.1 6-1.2.3.1.1.r 7-1.2.3.1.1 8-1.2.3.1.1 9-1.2.1.1.1.1.1 11-1.2.1.1.2.1.1 12-1.2.1 13-1.2.1.2.r 15-1.2.1.2.1 16-1.2.1.2 17-1.2 18-1.2.2 19-1.2.2.2 20-1.2.2.2.1.r 22-1.2.2.2.1.2 23-1.2.2.2.1.1.1 (s / show-01~e.2 :ARG0 (w / we~e.1) :ARG1~e.3 (a / and~e.17 :op1 (t / translocate-01~e.12 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "Spry1"~e.9)) :op2 (p2 / protein :name (n2 / name :op1 "Spry2"~e.11))) :ARG2~e.13 (m / membrane~e.16 :mod (p3 / plasma~e.15))) :op2 (b / become-01~e.18 :ARG1 a2 :ARG2 (p4 / phosphorylate-01~e.19 :ARG1~e.20 (a3 / amino-acid :name (n3 / name :op1 "tyrosine"~e.23) :ARG1-of (c / conserve-01~e.22) :part-of a2))) :time (a4 / after~e.4 :op1 (s2 / stimulate-01~e.5 :ARG0~e.6 (g / growth-factor~e.7,8) :ARG1 a2))) :location (h / here~e.0)) # ::id bel_pmid_1240_2043.10224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Next , they bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2 @-@ Sos complex either to the fibroblast growth factor receptor ( FGFR ) docking adaptor protein FRS2 or to Shp2 . Membrane translocation of Spry is necessary for its phosphorylation , which is essential for its inhibitor activity . # ::alignments 0-1.1.3 2-1.1.1.1 3-1.1.1 4-1.1.1.2.r 6-1.1.1.2.1.1 7-1.1.1.2.1.2 8-1.1.1.2.1.3 9-1.1 10-1.1.2 12-1.1.2.2 13-1.1.2.2.1.r 15-1.1.2.2.1.1.1.1 17-1.1.2.2.1.2.1.1 18-1.1.2.2.1 20-1.1.2.3.r 22-1.1.2.3.1.1.1 23-1.1.2.3.1.1.2 24-1.1.2.3.1.1.3 25-1.1.2.3.1.1.4 29-1.1.2.3.1.2 30-1.1.2.3.1.2.1.1.1 31-1.1.2.3.1.2.1.1.2 32-1.1.2.3.1.2.1.1.3 33-1.1.2.3 35-1.1.2.3.2.1.1 37-1.2.1.2 38-1.2.1 39-1.2.1.1.r 40-1.2.1.1.1.1 42-1.2 43-1.2.2.r 44-1.2.2.1 44-1.2.2.1.r 45-1.2.2 49-1.2.2.2 50-1.2.2.3.r 51-1.2.2.3.1 51-1.2.2.3.1.r 52-1.2.2.3.2 53-1.2.2.3 (m / multi-sentence :snt1 (a / and~e.9 :op1 (b / bind-01~e.3 :ARG1 (t2 / they~e.2) :ARG2~e.4 (p2 / protein :name (n3 / name :op1 "adaptor"~e.6 :op2 "protein"~e.7 :op3 "Grb2"~e.8))) :op2 (i2 / inhibit-01~e.10 :ARG0 t2 :ARG1 (r / recruit-01~e.12 :ARG1~e.13 (m2 / macro-molecular-complex~e.18 :part (p3 / protein :name (n4 / name :op1 "Grb2"~e.15)) :part (p4 / protein :name (n5 / name :op1 "Sos"~e.17)))) :location~e.20 (o / or~e.33 :op1 (p5 / protein :name (n6 / name :op1 "fibroblast"~e.22 :op2 "growth"~e.23 :op3 "factor"~e.24 :op4 "receptor"~e.25) :ARG0-of (d / dock-01~e.29 :ARG1 (p6 / protein :name (n7 / name :op1 "adaptor"~e.30 :op2 "protein"~e.31 :op3 "FRS2"~e.32)))) :op2 (e2 / enzyme :name (n8 / name :op1 "Shp2"~e.35)))) :time (n / next~e.0)) :snt2 (n2 / need-01~e.42 :ARG0 (t / translocate-01~e.38 :ARG1~e.39 (p8 / protein :name (n9 / name :op1 "Spry"~e.40)) :ARG2 (m3 / membrane~e.37)) :ARG1~e.43 (p9 / phosphorylate-01~e.45 :ARG1~e.44 p8~e.44 :mod (e / essential~e.49) :purpose~e.50 (a2 / activity-06~e.53 :ARG0~e.51 p8~e.51 :ARG1 (i3 / inhibit-01~e.52))))) # ::id bel_pmid_1240_2043.26582 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using an antibody against Spry2 , we showed that endogenous Spry2 becomes phosphorylated on tyrosine in response to EGF or FGF stimulation in C2C12 cells ( Fig . 4b , left ) and in COS7 cells ( Fig . 4b , right ) . # ::alignments 0-1.3 2-1.3.1 3-1.3.1.1 4-1.2.1.1.1 4-1.3.1.1.1.1.1 6-1.1 7-1 8-1.2.r 9-1.2.1.2 10-1.2.1.1.1 11-1.2 12-1.2.2 13-1.2.2.1.r 14-1.2.2.1.1.1 15-1.2.2.2.r 16-1.2.2.2 17-1.2.2.2.1.r 18-1.2.2.2.1.2.1.1.1 19-1.2.2.2.1.2 20-1.2.2.2.1.2.2.1.1 21-1.2.2.2.1 22-1.2.2.2.1.3.r 23-1.2.2.2.1.3.1.1.1 24-1.2.2.2.1.3.1 26-1.2.2.2.1.3.1.2.1 28-1.2.2.2.1.3.1.2.1.1 30-1.2.2.2.1.3.1.2.1.2 32-1.2.2.2.1.3 34-1.2.2.2.1.3.2.1.1 35-1.2.2.2.1.3.2 37-1.2.2.2.1.3.2.2.1 39-1.2.2.2.1.3.2.2.1.1 41-1.2.2.2.1.3.2.2.1.2 (s / show-01~e.7 :ARG0 (w / we~e.6) :ARG1~e.8 (b / become-01~e.11 :ARG1 (p / protein :name (n / name :op1 "Spry2"~e.4,10) :mod (m / monocot~e.9)) :ARG2 (p2 / phosphorylate-01~e.12 :ARG1~e.13 (a / amino-acid :name (n2 / name :op1 "tyrosine"~e.14) :part-of p) :ARG2-of~e.15 (r / respond-01~e.16 :ARG1~e.17 (s2 / stimulate-01~e.21 :ARG1 p :ARG2 (o / or~e.19 :op1 (p3 / protein :name (n3 / name :op1 "EGF"~e.18)) :op2 (p4 / protein :name (n4 / name :op1 "FGF"~e.20))) :location~e.22 (a2 / and~e.32 :op1 (c / cell-line~e.24 :name (n5 / name :op1 "C2C12"~e.23) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "4b"~e.28 :ARG1-of (l / left-20~e.30)))) :op2 (c2 / cell~e.35 :name (n6 / name :op1 "COS7"~e.34) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.37 :mod "4b"~e.39 :ARG1-of (r2 / right-04~e.41))))))))) :manner (u / use-01~e.0 :ARG1 (a3 / antibody~e.2 :ARG0-of (c3 / counter-01~e.3 :ARG1 (p5 / protein :name (n7 / name :op1 "Spry2"~e.4)))))) # ::id bel_pmid_1240_2043.26584 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , neither xSpry1Y53F nor mSpry2Y55F was tyrosine phosphorylated in cells stimulated with EGF ( data not shown ) . # ::alignments 0-1 1-1 1-1.1.2 3-1.1.1.r 4-1.1.2.1.2.1.1 5-1.1.1 5-1.1.1.r 6-1.1.2.2.2.1.1 8-1.1.2.1.1.1 8-1.1.2.2.1.1 9-1.1 10-1.1.3.r 11-1.1.3 12-1.1.3.1 13-1.1.3.1.1.r 14-1.1.3.1.1.1.1 16-1.2.1 17-1.2.1.1.1 17-1.2.1.1.1.r 18-1.2.1.1 (a / and~e.0,1 :op2 (p / phosphorylate-01~e.9 :polarity~e.3,5 -~e.5 :ARG1 (a6 / and~e.1 :op1 (a5 / amino-acid :name (n5 / name :op1 "tyrosine"~e.8) :part-of (p4 / protein :name (n7 / name :op1 "xSpry1Y53F"~e.4))) :op2 (a7 / amino-acid :name (n8 / name :op1 "tyrosine"~e.8) :part-of (p5 / protein :name (n9 / name :op1 "mSpry2Y55F"~e.6)))) :location~e.10 (c / cell~e.11 :ARG1-of (s / stimulate-01~e.12 :ARG0~e.13 (p2 / protein :name (n6 / name :op1 "EGF"~e.14))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.16 :ARG1-of (s3 / show-01~e.18 :polarity~e.17 -~e.17)))) # ::id bel_pmid_1240_2043.26602 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When Myc @-@ tagged mSpry2 and haemagluttinin A ( HA )- tagged Grb2 were expressed in cultured cells , both molecules translocated to the ruffling membrane region in response to stimulation with FGF or EGF and colocalized there ( Fig . 1c ) . # ::alignments 0-1.3.r 1-1.3.1.1.3.1.2.1 3-1.3.1.1.3 3-1.3.1.2.3 5-1.3.1 6-1.3.1.2.3.1.2.1 7-1.3.1.2.3.1.2.2 11-1.3.1.2.3 12-1.3.1.2.2.1 14-1.3 15-1.3.2.r 16-1.3.2.1 17-1.3.2 21-1.1 22-1.1.2.r 24-1.1.2.2 25-1.1.2.1 26-1.1.2 27-1.1.3.r 28-1.1.3 29-1.1.3.1.r 30-1.1.3.1 31-1.1.3.1.1.r 32-1.1.3.1.1.1.2.1 33-1.1.3.1.1 34-1.1.3.1.1.2.2.1 35-1 36-1.2 39-1.4.1 41-1.4.1.1 (a5 / and~e.35 :op1 (t3 / translocate-01~e.21 :ARG1 a2 :ARG2~e.22 (r / region~e.26 :part-of (m / membrane~e.25) :ARG0-of (r2 / ruffle-02~e.24)) :ARG2-of~e.27 (r3 / respond-01~e.28 :ARG1~e.29 (s / stimulate-01~e.30 :ARG0~e.31 (o / or~e.33 :op1 (p5 / protein :wiki "Fibroblast_growth_factor" :name (n5 / name :op1 "FGF"~e.32)) :op2 (p6 / protein :wiki "Epidermal_growth_factor" :name (n6 / name :op1 "EGF"~e.34)))))) :op2 (c3 / colocalize-01~e.36 :ARG1 a2 :ARG2 r) :time~e.0 (e / express-03~e.14 :ARG2 (a2 / and~e.5 :op1 (p2 / protein :wiki "SPRY2" :name (n2 / name :op1 "Spry2") :ARG1-of (t / tag-01~e.3 :ARG2 (p / protein :wiki - :name (n / name :op1 "Myc"~e.1))) :mod (m2 / mouse)) :op2 (p4 / protein :wiki "GRB2" :name (n4 / name :op1 "Grb2"~e.12) :ARG1-of (t2 / tag-01~e.3,11 :ARG0 (p3 / protein :wiki - :name (n3 / name :op1 "haemagluttinin"~e.6 :op2 "A"~e.7))))) :ARG3~e.15 (c / cell~e.17 :ARG1-of (c2 / culture-01~e.16))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod "1c"~e.41))) # ::id bel_pmid_1240_2043.30896 ::amr-annotator SDL-AMR-09 ::preferred # ::tok both xSpry1Y53F and mSpry2Y55F were unable to inhibit the binding of Grb2 to FRS2 or Shp2 in response to FGF stimulation ( Fig . 2a , b ) or the recruitment of Grb2 @–@ Sos complex to FRS2 ( Fig . 2c ) . # ::alignments 2-1.2.1 5-1 5-1.1 5-1.1.r 7-1.2 9-1.2.2.1 10-1.2.2.1.1.r 11-1.2.2.1.1.1.1 12-1.2.2.1.2.r 13-1.2.2.1.2.1.1.1 14-1.2.2.1.2 15-1.2.2.1.2.2.1.1 16-1.2.2.1.3.r 17-1.2.2.1.3 18-1.2.2.1.3.1.r 19-1.2.2.1.3.1.1.1.1.1 20-1.2.2.1.3.1.1 22-1.2.2.1.3.1.1.2.1.1 22-1.2.2.1.3.1.1.2.1.2 24-1.2.2.1.3.1.1.2.1.1.1 28-1.2.2.1.3.1 30-1.2.2.2 31-1.2.2.2.1.r 32-1.2.2.2.1.1 34-1.2.2.2.1.2.1.1 35-1.2.2.2.1 36-1.2.2.2.2.r 37-1.2.2.2.2 39-1.2.2.2.3.1 41-1.2.2.2.3.1.1 (p / possible-01~e.5 :polarity~e.5 -~e.5 :ARG1 (i / inhibit-01~e.7 :ARG0 (a / and~e.2 :op1 (p3 / protein :name (n12 / name :op1 "xSpry1") :ARG2-of (m2 / mutate-01 :value "Y53F")) :op2 (p8 / protein :name (n / name :op1 "Spry2") :ARG1-of (t / tag-01 :ARG2 (p10 / protein :name (n3 / name :op1 "myc"))) :ARG2-of (m3 / mutate-01 :value "Y55F"))) :ARG1 (a5 / and :op1 (b / bind-01~e.9 :ARG1~e.10 (p4 / protein :name (n5 / name :op1 "Grb2"~e.11)) :ARG2~e.12 (o / or~e.14 :op1 (p5 / protein :name (n6 / name :op1 "FRS2"~e.13)) :op2 (e / enzyme :name (n7 / name :op1 "Shp2"~e.15))) :ARG2-of~e.16 (r / respond-01~e.17 :ARG1~e.18 (o2 / or~e.28 :op1 (s / stimulate-01~e.20 :ARG0 (p7 / protein :name (n8 / name :op1 "FGF"~e.19)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.22 :mod "2a"~e.24) :op2 (f2 / figure~e.22 :mod "2b"))))))) :op2 (r2 / recruit-01~e.30 :ARG1~e.31 (m / macro-molecular-complex~e.35 :part p4~e.32 :part (p9 / protein :name (n10 / name :op1 "Sos"~e.34))) :ARG2~e.36 p5~e.37 :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.39 :mod "2c"~e.41)))))) # ::id bel_pmid_1240_2043.30898 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We investigated the ability of the Spry mutants to bind to Grb2 . Both xSpry1Y53F and mSpry2Y55F failed to bind to Grb2 in response to FGF stimulation ( Fig . 5c ) . # ::alignments 0-1.1.1 1-1.1 3-1.1.2 6-1.1.2.1.1.1 7-1.1.2.1 7-1.1.2.1.2 7-1.1.2.1.2.r 7-1.2.1.1 7-1.2.1.1.2 7-1.2.1.1.2.r 7-1.2.1.2 7-1.2.1.2.2 7-1.2.1.2.2.r 9-1.1.2.2 10-1.1.2.2.2.r 11-1.1.2.2.2.1.1 15-1.2.1 17-1.2 19-1.2.2 20-1.2.2.2.r 21-1.2.2.2.1.1 22-1.2.2.3.r 23-1.2.2.3 24-1.2.2.3.1.r 25-1.2.2.3.1.1.1.1 26-1.2.2.3.1 28-1.2.3.1 30-1.2.3.1.1 (m / multi-sentence :snt1 (i / investigate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / capable-01~e.3 :ARG1 (p / protein~e.7 :name (n / name :op1 "Spry"~e.6) :ARG2-of~e.7 (m2 / mutate-01~e.7)) :ARG2 (b / bind-01~e.9 :ARG1 p :ARG2~e.10 (p2 / protein :name (n2 / name :op1 "Grb2"~e.11))))) :snt2 (f / fail-01~e.17 :ARG1 (a / and~e.15 :op1 (p4 / protein~e.7 :name (n9 / name :op1 "xSpry1") :ARG2-of~e.7 (m3 / mutate-01~e.7 :value "Y53F")) :op2 (p7 / protein~e.7 :name (n3 / name :op1 "Spry2") :ARG2-of~e.7 (m4 / mutate-01~e.7 :value "Y55F") :ARG1-of (t / tag-01 :ARG2 (p3 / protein :name (n5 / name :op1 "myc"))))) :ARG2 (b2 / bind-01~e.19 :ARG1 a :ARG2~e.20 (p5 / protein :name (n7 / name :op1 "Grb2"~e.21)) :ARG2-of~e.22 (r / respond-01~e.23 :ARG1~e.24 (s / stimulate-01~e.26 :ARG0 (p6 / protein :name (n8 / name :op1 "FGF"~e.25))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.28 :mod "5c"~e.30)))) # ::id bel_pmid_1240_2043.30900 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also found that the tyrosine @- phosphorylated , endogenous Spry2 binds to endogenous Grb2 in a manner dependent on FGF stimulation ( Fig . 4c ) . # ::alignments 0-1.1 1-1.4 2-1 3-1.2.r 5-1.2.1.1.1 7-1.2.1.2 9-1.2.1.3.2 10-1.2.1.3.1.1 11-1.2 12-1.2.2.r 13-1.2.2.2 14-1.2.2.1.1 17-1.2.3.r 18-1.2.3 19-1.2.3.1.r 20-1.2.3.1.1.1.1 21-1.2.3.1 23-1.3.1 25-1.3.1.1 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (b / bind-01~e.11 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.5) :ARG1-of (p / phosphorylate-01~e.7) :part-of (p2 / protein :name (n2 / name :op1 "Spry2"~e.10) :mod (m / monocot~e.9))) :ARG2~e.12 (p3 / protein :name (n3 / name :op1 "Grb2"~e.14) :mod m~e.13) :manner~e.17 (d / depend-01~e.18 :ARG1~e.19 (s / stimulate-01~e.21 :ARG0 (p4 / protein :name (n4 / name :op1 "FGF"~e.20))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.23 :mod "4c"~e.25)) :mod (a2 / also~e.1)) # ::id bel_pmid_1242_3677.2596 ::amr-annotator SDL-AMR-09 ::preferred # ::tok gp130 @-@ mediated Stat1 @/@ 3 activation is required to maintain the normal balance of hematopoietic progenitors during fetal and adult hematopoiesis # ::alignments 0-1.2.2.1.1.1 2-1.2.2 3-1.2.1.1.1 5-1.2.1.1.1 6-1.2 8-1 10-1.1 12-1.1.1.2 13-1.1.1 16-1.1.1.1 17-1.3.r 18-1.3.1.1 19-1.3 20-1.3.2.1 21-1.1.1.1.1 21-1.3.1 21-1.3.2 (r / require-01~e.8 :ARG0 (m / maintain-01~e.10 :ARG1 (b / balance-01~e.13 :ARG1 (p / progenitor~e.16 :mod (h / hematopoiesis~e.21)) :ARG1-of (n2 / normal-02~e.12))) :ARG1 (a / activate-01~e.6 :ARG1 (p2 / protein :name (n / name :op1 "Stat1/3"~e.3,5)) :ARG1-of (m2 / mediate-01~e.2 :ARG0 (p3 / protein :name (n3 / name :op1 "gp130"~e.0)))) :time~e.17 (a2 / and~e.19 :op1 (h2 / hematopoiesis~e.21 :mod (f / fetus~e.18)) :op2 (h3 / hematopoiesis~e.21 :mod (a3 / adult~e.20)))) # ::id bel_pmid_1244_4555.28358 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblots using antibodies to BATF detected an increase in BATF protein in response to LIF @/@ IL @-@ 6 stimulation . # ::alignments 1-1.1.1 2-1.1.1.1 4-1.1.1.1.1.1.1.1 5-1 7-1.2 8-1.2.1.r 9-1.2.1 10-1.1.1.1.1.1 10-1.2.2.1.1 11-1.2.2.r 12-1.2.2 13-1.2.2.1.r 14-1.2.2.1.1.1.1 16-1.2.2.1.1.1.1 18-1.2.2.1.1.1.1 19-1.2.2.1 (d / detect-01~e.5 :ARG0 (i / immunoblot-01 :ARG0-of (u / use-01~e.1 :ARG1 (a / antibody~e.2 :ARG0-of (c / counter-01 :ARG1 (p / protein~e.10 :name (n / name :op1 "BATF"~e.4)))))) :ARG1 (i2 / increase-01~e.7 :ARG1~e.8 p~e.9 :ARG2-of~e.11 (r / respond-01~e.12 :ARG1~e.13 (s / stimulate-01~e.19 :ARG2 (p2 / protein~e.10 :name (n2 / name :op1 "LIF/IL-6"~e.14,16,18)))))) # ::id bel_pmid_1247_9220.29758 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data demonstrate that OSM induces up @-@ regulation of C/EBPdelta via a Stat3 @-@ dependent pathway in mammary epithelial cells and that the growth inhibition induced by OSM depends on the presence of C/EBPdelta . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1.2 7-1.2.1.2 8-1.2.1.2 13-1.2.1.3.1.1.1.1 15-1.2.1.3.1 16-1.2.1.3 17-1.2.1.4.r 18-1.2.1.4.1.1 19-1.2.1.4.1 20-1.2.1.4 21-1.2 22-1.2.r 24-1.2.2.1.1 25-1.2.2.1 26-1.2.2.1.2 27-1.2.2.1.2.1.r 28-1.2.2.1.2.1 29-1.2.2 30-1.2.2.2.r 32-1.2.2.2 (d / demonstrate-01~e.2 :ARG0 (d2 / data~e.1 :mod (t / this~e.0)) :ARG1~e.3,22 (a / and~e.21 :op1 (i / induce-01~e.5 :ARG0 (p / protein :name (n / name :op1 "OSM"~e.4)) :ARG2 (u / upregulate-01~e.6,7,8 :ARG1 (p2 / protein :name (n2 / name :op1 "C/EBPδ"))) :instrument (p3 / pathway~e.16 :ARG0-of (d3 / depend-01~e.15 :ARG1 (p4 / protein :name (n3 / name :op1 "Stat3"~e.13)))) :location~e.17 (c / cell~e.20 :mod (e / epithelium~e.19 :mod (m / mammary~e.18)))) :op2 (d4 / depend-01~e.29 :ARG0 (i2 / inhibit-01~e.25 :ARG1 (g / grow-01~e.24) :ARG2-of (i3 / induce-01~e.26 :ARG0~e.27 p~e.28)) :ARG1~e.30 (p5 / present-02~e.32 :ARG1 p2)))) # ::id bel_pmid_1247_9220.29764 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncostatin M ( OSM ) , an interleukin 6 @-@ type cytokine , induces sustained up @-@ regulation of CCAAT @/@ enhancer @-@ binding protein ( C/EBP ) delta mRNA and protein # ::alignments 0-1.1.1.1 1-1.1.1.2 7-1.1.2.1.1.1 8-1.1.2.1.1.2 10-1.1.2.1.1.2 11-1.1.2.1.1.3 13-1 14-1.2.2 15-1.2 16-1.2 17-1.2 18-1.2.1.r 19-1.2.1.1.2.1.1.1 21-1.2.1.1.2.1.1.1 23-1.2.1.1.2.1.1.1 24-1.2.1.1.2.1.1.2 29-1.2.1.1.1.1 30-1.2.1 31-1.1.2.1 (i / induce-01~e.13 :ARG0 (p / protein :name (n / name :op1 "Oncostatin"~e.0 :op2 "M"~e.1) :ARG1-of (m / mean-01 :ARG2 (p3 / protein~e.31 :name (n2 / name :op1 "interleukin"~e.7 :op2 "6-type"~e.8,10 :op3 "cytokine"~e.11)))) :ARG2 (u / upregulate-01~e.15,16,17 :ARG1~e.18 (a / and~e.30 :op1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.29) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "CCAAT/enhancer-binding"~e.19,21,23 :op2 "protein"~e.24 :op3 "δ")))) :op2 p2) :ARG1-of (s / sustain-01~e.14))) # ::id bel_pmid_1247_9220.29772 ::amr-annotator SDL-AMR-09 ::preferred # ::tok % Oncostatin M ( OSM ) , an interleukin 6 @-@ type cytokine , induces sustained up @-@ regulation of CCAAT @/@ enhancer @-@ binding protein ( C/EBP ) delta mRNA and protein in nonneoplastic HC11 mouse mammary epithelial cells . # ::alignments 1-1.1.1.1 2-1.1.1.2 8-1.1.2.1.1.1 9-1.1.2.1.1.2 11-1.1.2.1.1.2 12-1.1.2.1.1.3 14-1 15-1.2.2 16-1.2 17-1.2 18-1.2 19-1.2.1.r 20-1.2.1.1.2.1.1.1 22-1.2.1.1.2.1.1.1 24-1.2.1.1.2.1.1.1 25-1.2.1.1.2.1.1.2 30-1.2.1.1.1.1 31-1.2.1 32-1.1.2.1 35-1.3.1.1 36-1.3.2.1.1 37-1.3.2.1 38-1.3.2 39-1.3 (i / induce-01~e.14 :ARG0 (p / protein :name (n / name :op1 "Oncostatin"~e.1 :op2 "M"~e.2) :ARG1-of (m / mean-01 :ARG2 (p3 / protein~e.32 :name (n2 / name :op1 "interleukin"~e.8 :op2 "6-type"~e.9,11 :op3 "cytokine"~e.12)))) :ARG2 (u / upregulate-01~e.16,17,18 :ARG1~e.19 (a / and~e.31 :op1 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.30) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "CCAAT/enhancer-binding"~e.20,22,24 :op2 "protein"~e.25 :op3 "δ")))) :op2 p2) :ARG1-of (s / sustain-01~e.15)) :location (c2 / cell~e.39 :name (n5 / name :op1 "HC11"~e.35) :mod (e2 / epithelium~e.38 :mod (m2 / mammary~e.37 :part-of (m3 / mouse~e.36))) :mod (n6 / neoplasm :polarity -))) # ::id bel_pmid_1247_9220.29776 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This up @-@ regulation is dependent on signaling by phospho @-@ Stat3 ( signal transducers and activators of transcription ) . # ::alignments 0-1.1.1 1-1.1 2-1.1 3-1.1 5-1 6-1.2.r 7-1.2 7-1.2.1.3.1 8-1.2.1.r 9-1.2.1.2 11-1.2.1.1.1 13-1.2.1.3.1 16-1.2.1 16-1.2.1.4 16-1.2.1.4.r 17-1.2.1.4.1.r 18-1.2.1.4.1 (d / depend-01~e.5 :ARG0 (u / upregulate-01~e.1,2,3 :mod (t / this~e.0)) :ARG1~e.6 (s / signal-07~e.7 :ARG0~e.8 (p / protein~e.16 :name (n / name :op1 "Stat3"~e.11) :ARG3-of (p2 / phosphorylate-01~e.9) :ARG2-of (t2 / transduce-01 :ARG1 (s2 / signal-07~e.7,13)) :ARG0-of~e.16 (a / activate-01~e.16 :ARG1~e.17 (t3 / transcribe-01~e.18))))) # ::id bel_pmid_1249_6442.9810 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recombinant murine OSM stimulated eotaxin protein production and mRNA levels in the NIH 3T3 fibroblast cell line # ::alignments 0-1.1.3 1-1.1.2.1.1 2-1.1.1.1 3-1 4-1.2.1.1.1.1 5-1.1 5-1.2.1.1 6-1.2.1 7-1.2 8-1.2.2.1.1.1 9-1.2.2 10-1.3.r 12-1.3.1.1 13-1.3.1.1 14-1.3.2 15-1.3 16-1.3 (s / stimulate-01~e.3 :ARG0 (p / protein~e.5 :name (n / name :op1 "OSM"~e.2) :part-of (o / organism :name (n2 / name :op1 "Muridae"~e.1)) :ARG3-of (r / recombine-01~e.0)) :ARG1 (a / and~e.7 :op1 (p2 / produce-01~e.6 :ARG1 (p3 / protein~e.5 :name (n3 / name :op1 "eotaxin"~e.4))) :op2 (l / level~e.9 :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.8)))) :location~e.10 (c / cell-line~e.15,16 :name (n5 / name :op1 "NIH-3T3"~e.12,13) :mod (f / fibroblast~e.14))) # ::id bel_pmid_1249_6442.19422 ::amr-annotator SDL-AMR-09 ::preferred # ::tok overexpression of Osm in lungs of mice resulted in a vigorous inflammatory response strongly supports a role of Osm in lung inflammatory responses that involve eosinophil infiltration # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.2.r 4-1.1.1.2 5-1.1.1.2.1.r 6-1.1.1.2.1 7-1.1 8-1.1.2.r 10-1.1.2.2 11-1.1.2.1 12-1.1.2 13-1.2.2 14-1.2 16-1.2.1 17-1.2.1.1.r 18-1.2.1.1.1.1 19-1.2.1.2.r 20-1.2.1.2.1.1 21-1.2.1.2.1 22-1.2.1.2 24-1.2.1.2.2 25-1.2.1.2.2.1.1.1.1 26-1.2.1.2.2.1 (m / multi-sentence :snt1 (r / result-01~e.7 :ARG1 (o / overexpress-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "OSM"~e.2)) :location~e.3 (l / lung~e.4 :part-of~e.5 (m2 / mouse~e.6))) :ARG2~e.8 (r2 / respond-01~e.12 :ARG0-of (i / inflame-01~e.11) :mod (v / vigorous~e.10))) :snt2 (s / support-01~e.14 :ARG1 (r3 / role~e.16 :poss~e.17 (p2 / protein :name (n2 / name :op1 "OSM"~e.18)) :topic~e.19 (r4 / respond-01~e.22 :ARG0-of (i2 / inflame-01~e.21 :ARG1 (l2 / lung~e.20)) :ARG2-of (i3 / involve-01~e.24 :ARG1 (i4 / infiltrate-01~e.26 :ARG0 (c / cell :name (n3 / name :op1 "eosinophil"~e.25)))))) :ARG1-of (s2 / strong-02~e.13))) # ::id bel_pmid_1249_6442.19424 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Osm stimluated eotaxin protein prudction and mRNA levels in fibroblasts Il6 could regulate a small induction of eotaxin , but other Il6 @/@ Lif cytokines [ Lif , cariotrophin @-@ 1 ] had no effect # ::alignments 0-1.1.1.1.1 2-1.1.2.1.1.1.1 3-1.1.1 3-1.1.2.1.1 3-1.2.1.1.1 3-1.2.1.1.2.1 3-1.2.2.2.3.1.1 3-1.2.2.2.3.1.2 5-1.1.2 6-1.1.2.2.1.1.1 7-1.1.2.2 9-1.1.3 10-1.2.2.2.1.1 11-1.2.1 12-1.2.1.1 14-1.2.1.1.2.2 15-1.2.1.1.2 17-1.2.1.1.2.1.1.1 19-1.2 20-1.2.2.2.2 21-1.2.1.1.1.1.1 23-1.2.2.2.3.1.1.1.1 24-1.2.2.2 26-1.2.2.2.3.1.1.1.1 28-1.2.2.2.3.1.2.1.1 30-1.2.2.2.3.1.2.1.1 33-1.2.2.1 33-1.2.2.1.r 34-1.2.2 (m / multi-sentence :snt1 (s / stimulate-01 :ARG0 (p / protein~e.3 :name (n / name :op1 "OSM"~e.0)) :ARG1 (a / and~e.5 :op1 (p2 / produce-01 :ARG1 (p3 / protein~e.3 :name (n2 / name :op1 "eotaxin"~e.2))) :op2 (l / level~e.7 :quant-of (n9 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.6)))) :location (f / fibroblast~e.9)) :snt2 (c / contrast-01~e.19 :ARG1 (p4 / possible-01~e.11 :ARG1 (r2 / regulate-01~e.12 :ARG0 (p5 / protein~e.3 :name (n4 / name :op1 "Il6"~e.21)) :ARG1 (i / induce-01~e.15 :ARG2 (p6 / protein~e.3 :name (n5 / name :op1 "eotaxin"~e.17)) :degree (s2 / small~e.14)))) :ARG2 (a2 / affect-01~e.34 :polarity~e.33 -~e.33 :ARG0 (c2 / cytokine~e.24 :name (n6 / name :op1 "Il6/Lif"~e.10) :mod (o / other~e.20) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (p7 / protein~e.3 :name (n7 / name :op1 "Lif"~e.23,26)) :op2 (p8 / protein~e.3 :name (n8 / name :op1 "cariotrophin-1"~e.28,30)))))))) # ::id bel_pmid_1249_6958.18008 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GSK3 @-@ beta is also phosphorylated in response to hormonal stimuli not involving mechanical stress , such as insulin28 ; this pathway , however , was unaffected in the melusin @-@ null background . # ::alignments 4-1.2 5-1 6-1.3.r 7-1.3 8-1.3.1.r 9-1.3.1.1 10-1.3.1 11-1.3.1.2.1 11-1.3.1.2.1.r 12-1.3.1.2 13-1.3.1.2.2.1 14-1.3.1.2.2 16-1.3.1.1.1.r 17-1.3.1.1.1.r 21-1.1 23-1.4 26-1.4.1 26-1.4.1.1 26-1.4.1.1.r 27-1.4.1.3.r 29-1.4.1.3.1.1.1 31-1.4.1.3.1 31-1.4.1.3.1.2 31-1.4.1.3.1.2.1 31-1.4.1.3.1.2.1.r 31-1.4.1.3.1.2.r 32-1.4.1.3 (p / phosphorylate-01~e.5 :ARG1 (p2 / pathway~e.21 :name (n / name :op1 "GSK-3β")) :mod (a / also~e.4) :ARG2-of~e.6 (r / respond-01~e.7 :ARG1~e.8 (s / stimulate-01~e.10 :ARG0 (h / hormone~e.9 :example~e.16,17 (p3 / protein :name (n2 / name :op1 "insulin"))) :ARG2-of (i / involve-01~e.12 :polarity~e.11 -~e.11 :ARG1 (s2 / stress-02~e.14 :mod (m / mechanics~e.13))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 28))))) :ARG1-of (c / contrast-01~e.23 :ARG2 (a2 / affect-01~e.26 :polarity~e.26 -~e.26 :ARG1 p2 :location~e.27 (b / background~e.32 :mod (p4 / protein~e.31 :name (n3 / name :op1 "melusin"~e.29) :ARG2-of~e.31 (m2 / mutate-01~e.31 :mod~e.31 "-/-"~e.31)))))) # ::id bel_pmid_1249_6958.19264 ::amr-annotator SDL-AMR-09 ::preferred # ::tok but did not substantially affect phosphorylation of p38 and ERK 1 @/@ 2 . In addition , phosphorylation of AKT was greatly impaired in aortic @-@ banded heart of melusin @-@ null mice . # ::alignments 0-1.1 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1.3 4-1.1.1 5-1.1.1.2 7-1.1.1.2.1.1.1.1 8-1.1.1.2.1 12-1.1.1.2.1.2.1.1 14-1.1.1.2.1 15-1.1.1.2.1 15-1.2 17-1.1.1.2 17-1.2.1.1 18-1.2.1.1.1.r 19-1.2.1.1.1.1.1 21-1.2.1.3 22-1.2.1 26-1.2.1.2.1 27-1.2.1.2 28-1.2.1.2.2.r 29-1.2.1.2.2.1.1.1 31-1.2.1.2.2.1 31-1.2.1.2.2.1.2 31-1.2.1.2.2.1.2.1 31-1.2.1.2.2.1.2.1.r 31-1.2.1.2.2.1.2.r 32-1.2.1.2.2 (m / multi-sentence :snt1 (c / contrast-01~e.0 :ARG2 (a / affect-01~e.4 :polarity~e.2 -~e.2 :ARG1 (p / phosphorylate-01~e.5,17 :ARG1 (a2 / and~e.8,14,15 :op1 (e / enzyme :name (n / name :op1 "p38"~e.7)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.12)))) :degree (s / substantial~e.3))) :snt2 (a3 / and~e.15 :op2 (i / impair-01~e.22 :ARG1 (p2 / phosphorylate-01~e.17 :ARG1~e.18 (e3 / enzyme :name (n3 / name :op1 "AKT"~e.19))) :location (h / heart~e.27 :ARG1-of (b / band-01~e.26 :ARG2 (a4 / aorta)) :part-of~e.28 (m2 / mouse~e.32 :mod (p3 / protein~e.31 :name (n4 / name :op1 "melusin"~e.29) :ARG2-of~e.31 (m3 / mutate-01~e.31 :mod~e.31 "-/-"~e.31)))) :degree (g / great~e.21)))) # ::id bel_pmid_1249_6958.19266 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase @-@ 3 beta ( GSK @-@ 3 beta ) was specifically blunted in melusin @-@ null hearts . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 3-1.1.1.1 4-1.1.1 5-1.1.1.3 6-1.1.1.3.1.r 7-1.1.1.3.1.1 8-1.1.1.3.1 9-1 10-1.2.r 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1.1 14-1.2.1.1.1.2 15-1.2.1.1.1.3 26-1.2.3 27-1.2 28-1.2.2.r 29-1.2.2.1.1.1 31-1.2.2.1 31-1.2.2.1.2 31-1.2.2.1.2.1 31-1.2.2.1.2.1.r 31-1.2.2.1.2.r 32-1.2.2 (i / indicate-01~e.9 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (e / event~e.4 :mod (s / signal-07~e.3) :mod (i2 / intracellular~e.2) :ARG2-of (i3 / induce-01~e.5 :ARG0~e.6 (o / overload-01~e.8 :ARG2 (p / pressure-01~e.7))))) :ARG1~e.10 (b / blunt-01~e.27 :ARG1 (p2 / phosphorylate-01~e.11 :ARG1~e.12 (e2 / enzyme :name (n / name :op1 "glycogen"~e.13 :op2 "synthase"~e.14 :op3 "kinase-3β"~e.15))) :location~e.28 (h / heart~e.32 :mod (p3 / protein~e.31 :name (n2 / name :op1 "melusin"~e.29) :ARG2-of~e.31 (m / mutate-01~e.31 :mod~e.31 "-/-"~e.31))) :ARG1-of (s2 / specific-02~e.26))) # ::id bel_pmid_1252_4227.38280 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HGF induced activation of ERK1 and ERK2 was shown to be dependent on the presence of HS moieties . # ::alignments 0-1.1.1.2.1.1.1 1-1.1.1.2 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1 8-1 11-1.1 12-1.1.2.r 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1.1.1 17-1.1.2.1 (s / show-01~e.8 :ARG1 (d / depend-01~e.11 :ARG0 (a / activate-01~e.2 :ARG1~e.3 (a2 / and~e.5 :op1 (e / enzyme :name (n / name :op1 "ERK1"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"~e.6))) :ARG2-of (i / induce-01~e.1 :ARG0 (p / protein :name (n3 / name :op1 "HGF"~e.0)))) :ARG1~e.12 (p2 / present-02~e.14 :ARG1~e.15 (m / moiety~e.17 :mod (s2 / small-molecule :name (n4 / name :op1 "HS"~e.16)))))) # ::id bel_pmid_1254_0842.9294 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAP @-@ 2 mRNA was strongly induced in the liver in response to lipopolysaccharide and in isolated hepatocytes in response to interleukin @-@ 6 . # ::alignments 0-1.1.1.2.1.1.1 2-1.1.1.2.1.1.1 3-1.1.1.1.1 5-1.1.3 6-1.1 6-1.2 7-1.1.2.r 9-1.1.2 11-1.1.4 11-1.2.4 13-1.1.4.1.1.1 14-1 15-1.2.3.r 16-1.2.3.1 17-1.2.3 19-1.1.4 20-1.2.4.1.r 21-1.2.4.1.1.1 23-1.2.4.1.1.1 (a / and~e.14 :op1 (i / induce-01~e.6 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.3) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "STAP-2"~e.0,2)))) :location~e.7 (l / liver~e.9) :ARG1-of (s / strong-02~e.5) :ARG0-of (r2 / respond-01~e.11,19 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "lipopolysaccharide"~e.13)))) :op2 (i2 / induce-01~e.6 :ARG2 n5 :degree s :location~e.15 (h / hepatocyte~e.17 :ARG1-of (i3 / isolate-01~e.16)) :ARG0-of (r3 / respond-01~e.11 :ARG1~e.20 (p2 / protein :name (n4 / name :op1 "interleukin-6"~e.21,23))))) # ::id bel_pmid_1254_0842.10250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest that STAP @-@ 2 is a new class of adaptor molecule that modulates STAT3 activity through its YXXQ motif . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1 6-1.2.1.1 7-1.2.2.r 9-1.2.2.2 10-1.2.2 13-1.2.2.1 15-1.2 15-1.2.3 15-1.2.3.r 16-1.2.3.1.1.1.1 17-1.2.3.1 19-1.2.3.2.2 19-1.2.3.2.2.r 20-1.2.3.2.1.1 21-1.2.3.2 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (p / protein~e.15 :name (n / name :op1 "STAP-2"~e.4,6) :domain~e.7 (c / class~e.10 :mod (m / molecule~e.13 :ARG0-of (a / adapt-01)) :ARG1-of (n2 / new-01~e.9)) :ARG0-of~e.15 (m2 / modulate-01~e.15 :ARG1 (a2 / activity-06~e.17 :ARG0 (p2 / protein :name (n3 / name :op1 "STAT3"~e.16))) :instrument (m3 / motif~e.21 :name (n4 / name :op1 "YXXQ"~e.20) :part-of~e.19 p2~e.19)))) # ::id bel_pmid_1254_0842.28154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because STAP @-@ 2 expression is induced by proinflammatory cytokines such as IL @-@ 6 or IL @-@ 1 beta , STAP @-@ 2 may play a role in the regulation of inflammation . # ::alignments 0-1 1-1.1.2.1.1.1 3-1.1.2.1.1.1 4-1.1.2 6-1.1 7-1.1.1.r 8-1.1.1.1 8-1.1.1.1.1 9-1.1.1 9-1.1.1.2.1 9-1.1.1.2.2 10-1.1.1.2.r 11-1.1.1.2.r 12-1.1.1.2.1.1.1 12-1.1.1.2.2.1.1 14-1.1.1.2.1.1.1 15-1.1.1.2 16-1.1.1.2.1.1.1 16-1.1.1.2.2.1.1 21-1.1.2.1.1.1 23-1.1.2.1.1.1 24-1.2 25-1.2.1 28-1.2.1.2.r 30-1.2.1.2 31-1.1.1.1.1.r 32-1.1.1.1.1 (c / cause-01~e.0 :ARG0 (i / induce-01~e.6 :ARG0~e.7 (c2 / cytokine~e.9 :ARG0-of (f / favor-01~e.8 :ARG1~e.31 (i2 / inflame-01~e.8,32)) :example~e.10,11 (o / or~e.15 :op1 (c3 / cytokine~e.9 :name (n / name :op1 "IL-6"~e.12,14,16)) :op2 (c4 / cytokine~e.9 :name (n2 / name :op1 "IL-1β"~e.12,16)))) :ARG2 (e / express-03~e.4 :ARG2 (p / protein :name (n3 / name :op1 "STAP-2"~e.1,3,21,23)))) :ARG1 (p2 / possible-01~e.24 :ARG1 (p3 / play-08~e.25 :ARG0 p :ARG1~e.28 (r / regulate-01~e.30 :ARG1 i2)))) # ::id bel_pmid_1258_6835.2750 ::amr-annotator SDL-AMR-09 ::preferred # ::tok conditional inactivation of Cdc2 reduces phosphorylation of S6K1 at S/TP sites while simultaneously increasing phosphorylation of Thr( 389 ) and of the S6K1 substrate , RPS6 . # ::alignments 0-1.1.1.3 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1.1.2.r 3-1.1.1.2.1.1 4-1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.2.1.1 9-1.1.2.1.1.1 10-1.1.2.1 11-1 12-1.2.3 12-1.2.3.r 13-1.2 14-1.2.2 17-1.2.2.1.1.1 19-1.2.2.1 20-1.2.2.1.r 22-1.2.2.1.2.2 23-1.2.2.1.2 25-1.2.2.1.2.1.1 (c / contrast-01~e.11 :ARG1 (r / reduce-01~e.4 :ARG0 (a / activate-01~e.1 :polarity~e.1 -~e.1 :ARG1~e.2 (e / enzyme :name (n / name :op1 "Cdc2"~e.3)) :mod (c2 / conditional~e.0)) :ARG1 (p / phosphorylate-01~e.5 :ARG1~e.6 (p2 / protein-segment~e.10 :name (n2 / name :op1 "S/TP"~e.9) :part-of (e2 / enzyme :name (n3 / name :op1 "S6K1"~e.7))))) :ARG2 (i / increase-01~e.13 :ARG0 a :ARG1 (p3 / phosphorylate-01~e.14 :ARG1~e.20 (a2 / and~e.19 :op1 (a3 / amino-acid :mod 389~e.17 :name (n4 / name :op1 "threonine")) :op2 (s / substrate~e.23 :name (n5 / name :op1 "RPS6"~e.25) :part-of e2~e.22))) :manner~e.12 (s2 / simultaneous~e.12))) # ::id bel_pmid_1259_5539.28136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok iNOS protein was undetectable at 1 h but was increased after 2 , 4 , and 24 h of incubation with IL @-@ 6 . The iNOS expression induced by a 2 @-@ h incubation with 10 ng @/@ ml IL @-@ 1 beta , a well known inducer of iNOS in cardiac myocytes ( 38 ) , was used as a positive control in these experiments . # ::alignments 0-1.1.1.2.1.1.1 0-1.2.1.1.1.1 1-1.1.2.2.1.1 1-1.2.1.2.1.1 3-1.1.1.1 3-1.1.1.2 5-1.1.1.3.1.1 6-1.1.1.3.1.2 7-1.1 9-1.1.2 10-1.1.1.3 10-1.1.2.2 11-1.1.2.2.1.2.1.1 13-1.1.2.2.1.2.1.2 15-1.1.2.2.1.2.1 16-1.1.2.2.1.2.1.3 17-1.1.2.2.1.2.2 19-1.1.2.2.1 21-1.1.2.2.1.1.1.1 23-1.1.2.2.1.1.1.1 26-1.1.1.2.1.1.1 26-1.2.1.1.1.1 27-1.2.1 28-1.2.1.2 28-1.2.1.2.1.1.3 29-1.2.1.2.1.r 31-1.2.1.2.1.2.1 33-1.2.1.2.1.2.2 34-1.2.1.2.1 35-1.2.1.2.1.1.2.r 36-1.2.1.2.1.1.2.1 37-1.2.1.2.1.1.2.2 39-1.2.1.2.1.1.2.2 40-1.1.2.2.1.1.1.1 40-1.2.1.2.1.1.1.1 42-1.1.1.3.1.1 46-1.2.1.2.1.1.3.3.1 47-1.2.1.2.1.1.3.3 49-1.2.1.1.r 50-1.2.1.1.1.1 52-1.2.1.2.1.1.3.2.1 55-1.2.1.2.1.1.3.4.1.1.1 59-1.2 60-1.1.1.3.r 60-1.1.2.2.r 60-1.2.2.r 62-1.2.2.1 63-1.2.2 64-1.2.3.r 65-1.2.3.1 66-1.2.3 (m / multi-sentence :snt1 (c / contrast-01~e.7 :ARG1 (p / possible-01 :polarity -~e.3 :ARG1 (d / detect-01~e.3 :ARG1 (e3 / enzyme :name (n / name :op1 "iNOS"~e.0,26))) :time~e.60 (a / after~e.10 :op1 (t / temporal-quantity :quant 1~e.5,42 :unit (h / hour~e.6)))) :ARG2 (i / increase-01~e.9 :ARG1 e3 :time~e.60 (a2 / after~e.10 :op1 (i2 / incubate-01~e.19 :ARG2 (p3 / protein~e.1 :name (n2 / name :op1 "IL-6"~e.21,23,40)) :duration (t2 / temporal-quantity :quant (a3 / and~e.15 :op1 2~e.11 :op2 4~e.13 :op3 24~e.16) :unit h~e.17))))) :snt2 (u / use-01~e.59 :ARG1 (e / express-03~e.27 :ARG2~e.49 (e4 / enzyme :name (n3 / name :op1 "iNOS"~e.0,26,50)) :ARG2-of (i3 / induce-01~e.28 :ARG0~e.29 (i4 / incubate-01~e.34 :ARG2 (p5 / protein~e.1 :name (n4 / name :op1 "IL-1β"~e.40) :quant~e.35 (c2 / concentration-quantity :quant 10~e.36 :unit (n5 / nanogram-per-milliliter~e.37,39)) :ARG0-of (i5 / induce-01~e.28 :ARG1 e4 :location (m2 / myocyte :part-of (h2 / heart~e.52)) :ARG1-of (k / know-02~e.47 :degree (w / well~e.46)) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 38~e.55))))) :duration (t3 / temporal-quantity :quant 2~e.31 :unit (h3 / hour~e.33))))) :ARG2~e.60 (c4 / control-01~e.63 :mod (p7 / positive~e.62)) :location~e.64 (e2 / experiment-01~e.66 :mod (t4 / this~e.65)))) # ::id bel_pmid_1259_5539.28352 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fig.3 A shows that an increase in phosphorylation of ERK2 at Tyr204 was detected after 5 min of exposure to 10 ng @/@ ml IL @-@ 6 ; this effect peaked at 30 min and was followed by a decline to basal levels by 2 h . # ::alignments 2-1.1 3-1.1.2.r 5-1.1.2.1 6-1.1.2.1.1.r 7-1.1.2.1.1 8-1.1.2.1.1.1.r 9-1.1.2.1.1.1.3.1.1 13-1.1.2 14-1.1.2.2 15-1.1.2.2.1.2.1 16-1.1.2.2.1.2.2 18-1.1.2.2.1 19-1.1.2.2.1.1.r 20-1.1.2.2.1.1.2.1 21-1.1.2.2.1.1.2.2 23-1.1.2.2.1.1.2.2 24-1.1.2.2.1.1.1.1 26-1.1.2.2.1.1.1.1 28-1.2.1.1.1 29-1.2.1.1 30-1.2.1 32-1.2.1.2.1.1 33-1.2.1.2.1.2 34-1.2 36-1.2.1.2 36-1.2.2 36-1.2.2.1.2 37-1.2.2.1.r 39-1.2.2.1 40-1.2.2.1.1.r 40-1.2.2.1.2.1 41-1.2.2.1.1.1 42-1.2.2.1.1 43-1.2.2.1.2.1.1.r 44-1.2.2.1.2.1.1.1 45-1.2.2.1.2.1.1.2 (m / multi-sentence :snt1 (s / show-01~e.2 :ARG0 (f / figure :mod "3A") :ARG1~e.3 (d / detect-01~e.13 :ARG1 (i / increase-01~e.5 :ARG1~e.6 (p / phosphorylate-01~e.7 :ARG1~e.8 (a / amino-acid :mod 204 :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "ERK2"~e.9))))) :time (a2 / after~e.14 :op1 (e2 / expose-01~e.18 :ARG2~e.19 (p2 / protein :name (n3 / name :op1 "IL-6"~e.24,26) :quant (c / concentration-quantity :quant 10~e.20 :unit (n4 / nanogram-per-milliliter~e.21,23))) :duration (t / temporal-quantity :quant 5~e.15 :unit (m2 / minute~e.16)))))) :snt2 (a3 / and~e.34 :op1 (p3 / peak-01~e.30 :ARG1 (a4 / affect-01~e.29 :mod (t2 / this~e.28)) :time (a5 / after~e.36 :quant (t3 / temporal-quantity :quant 30~e.32 :unit m2~e.33))) :op2 (f2 / follow-01~e.36 :ARG1~e.37 (d2 / decline-01~e.39 :ARG4~e.40 (l / level~e.42 :mod (b / basal~e.41)) :time (a6 / after~e.36 :quant (u / up-to~e.40 :op1~e.43 (t4 / temporal-quantity :quant 2~e.44 :unit (h / hour~e.45))))) :ARG2 a4))) # ::id bel_pmid_1259_5539.28364 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 6 increased phosphorylation of STAT3 ( at Tyr( 705 )) and ERK1 @/@ 2 ( at Tyr( 204 )) within 5 min that peaked at 15 @-@ 30 min and returned to basal levels at 2 h # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2 5-1.2.1.r 6-1.2.1.1.3.1.1 10-1.2.1.1.1 12-1.2.1 13-1.2.1.2.3.1.1 15-1.2.1.2.3.1.1 19-1.2.1.2.1 21-1.3 21-1.3.1 21-1.3.1.1.1.r 21-1.3.1.r 21-1.4.1 21-1.5.2 22-1.3.1.1.1 23-1.3.1.1.2 25-1.4 26-1.4.1.1.r 27-1.4.1.1.1.1 29-1.4.1.1.1.2 30-1.4.1.1.2 31-1.2.1 32-1.5 33-1.5.1.r 34-1.5.1.1 35-1.5.1 36-1.5.2.1.r 37-1.5.2.1.1 38-1.5.2.1.2 (i / increase-01~e.3 :ARG0 (p / protein :name (n / name :op1 "IL-6"~e.0,2)) :ARG1 (p2 / phosphorylate-01~e.4 :ARG1~e.5 (a / and~e.12,31 :op1 (a2 / amino-acid :mod 705~e.10 :name (n2 / name :op1 "tyrosine") :part-of (p3 / protein :name (n3 / name :op1 "STAT3"~e.6))) :op2 (a3 / amino-acid :mod 204~e.19 :name (n4 / name :op1 "tyrosine") :part-of (e / enzyme :name (n5 / name :op1 "ERK1/2"~e.13,15))))) :time (a4 / after~e.21 :quant~e.21 (u / up-to~e.21 :op1 (t / temporal-quantity :quant~e.21 5~e.22 :unit (m / minute~e.23)))) :ARG1-of (p4 / peak-01~e.25 :time (a5 / after~e.21 :quant~e.26 (t2 / temporal-quantity :quant (v / value-interval :op1 15~e.27 :op2 30~e.29) :unit m~e.30))) :ARG1-of (r / return-01~e.32 :ARG4~e.33 (l / level~e.35 :mod (b / basal~e.34)) :time (a6 / after~e.21 :quant~e.36 (t3 / temporal-quantity :quant 2~e.37 :unit (h / hour~e.38))))) # ::id bel_pmid_1259_5539.28368 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fig. 1 Ashows that phosphorylation of STAT3 at Tyr705 was detected after 5 min of exposure to 10 ng @/@ ml IL @-@ 6 , reached a maximum at 15 min , and then declined within 1 h . These results demonstrate that IL @-@ 6 activates a STAT3 signaling in adult rat ventricular myocytes . # ::alignments 0-1.1.1 1-1.1.2.3.2.1.1.1 4-1.1.2.1.1 5-1.1.2.1.1.1.r 6-1.1.2.1.1.1.3.1.1 10-1.1.2.1 11-1.1.2.1.2 12-1.1.2.1.2.1.2.1 13-1.1.2.1.2.1.2.2 15-1.1.2.1.2.1 16-1.1.2.1.2.1.1.r 17-1.1.2.1.2.1.1.2.1 18-1.1.2.1.2.1.1.2.2 20-1.1.2.1.2.1.1.2.2 21-1.1.2.1.2.1.1.1.1 23-1.1.2.1.2.1.1.1.1 25-1.1.2.2 27-1.1.2.2.2 29-1.1.2.2.3.1.1 30-1.1.2.2.3.1.2 32-1.1.2 33-1.1.2.3.3 34-1.1.2.3 35-1.1.2.2.3 35-1.1.2.3.2 35-1.1.2.3.2.1 35-1.1.2.3.2.1.1.1.r 35-1.1.2.3.2.1.r 36-1.1.2.3.2.1.1.1 37-1.1.2.3.2.1.1.2 39-1.2.1.2 40-1.2.1 40-1.2.1.1 40-1.2.1.1.r 41-1.2 42-1.2.2.r 43-1.2.2.1.1.1 45-1.2.2.1.1.1 46-1.2.2 48-1.2.2.2.1.1.1 49-1.2.2.2 51-1.2.2.3.2.1 52-1.2.2.3.2 53-1.2.2.3.1 (m / multi-sentence :snt1 (s / show-01 :ARG0 (f / figure~e.0 :mod "1A") :ARG1 (a / and~e.32 :op1 (d / detect-01~e.10 :ARG1 (p / phosphorylate-01~e.4 :ARG1~e.5 (a2 / amino-acid :mod 705 :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "STAT3"~e.6)))) :time (a3 / after~e.11 :op1 (e / expose-01~e.15 :ARG2~e.16 (p3 / protein :name (n3 / name :op1 "IL-6"~e.21,23) :quant (c / concentration-quantity :quant 10~e.17 :unit (n4 / nanogram-per-milliliter~e.18,20))) :duration (t / temporal-quantity :quant 5~e.12 :unit (m2 / minute~e.13))))) :op2 (r / reach-01~e.25 :ARG0 p :ARG1 (m3 / maximum~e.27) :time (a4 / after~e.35 :quant (t2 / temporal-quantity :quant 15~e.29 :unit m2~e.30))) :op3 (d2 / decline-01~e.34 :ARG1 p :time (a5 / after~e.35 :quant~e.35 (u / up-to~e.35 :op1 (t3 / temporal-quantity :quant~e.35 1~e.1,36 :unit (h / hour~e.37)))) :mod (t4 / then~e.33)))) :snt2 (d3 / demonstrate-01~e.41 :ARG0 (t5 / thing~e.40 :ARG2-of~e.40 (r2 / result-01~e.40) :mod (t6 / this~e.39)) :ARG1~e.42 (a6 / activate-01~e.46 :ARG0 (p4 / protein :name (n5 / name :op1 "IL-6"~e.43,45)) :ARG1 (s2 / signal-07~e.49 :ARG0 (p5 / protein :name (n6 / name :op1 "STAT3"~e.48))) :location (m4 / myocyte :mod (v / ventricle~e.53) :part-of (r3 / rat~e.52 :mod (a7 / adult~e.51)))))) # ::id bel_pmid_1259_5539.38542 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fig. 1 Ashows that phosphorylation of STAT3 at Tyr705 was detected after 5 min of exposure to 10 ng @/@ ml IL @-@ 6 , reached a maximum at 15 min , and then declined within 1 h . These results demonstrate that IL @-@ 6 activates a STAT3 signaling in adult rat ventricular myocytes . # ::alignments 0-1.1.1 1-1.1.2.3.2.1.1.1 4-1.1.2.1.1 5-1.1.2.1.1.1.r 6-1.1.2.1.1.1.3.1.1 10-1.1.2.1 11-1.1.2.1.2 12-1.1.2.1.2.1.2.1 13-1.1.2.1.2.1.2.2 15-1.1.2.1.2.1 16-1.1.2.1.2.1.1.r 17-1.1.2.1.2.1.1.2.1 18-1.1.2.1.2.1.1.2.2 20-1.1.2.1.2.1.1.2.2 21-1.1.2.1.2.1.1.1.1 23-1.1.2.1.2.1.1.1.1 25-1.1.2.2 27-1.1.2.2.2 29-1.1.2.2.3.1.1 30-1.1.2.2.3.1.2 32-1.1.2 33-1.1.2.3.3 34-1.1.2.3 35-1.1.2.2.3 35-1.1.2.3.2 35-1.1.2.3.2.1 35-1.1.2.3.2.1.1.1.r 35-1.1.2.3.2.1.r 36-1.1.2.3.2.1.1.1 37-1.1.2.3.2.1.1.2 39-1.2.1.2 40-1.2.1 40-1.2.1.1 40-1.2.1.1.r 41-1.2 42-1.2.2.r 43-1.2.2.1.1.1 45-1.2.2.1.1.1 46-1.2.2 48-1.2.2.2.1.1.1 49-1.2.2.2 51-1.2.2.3.2.1 52-1.2.2.3.2 53-1.2.2.3.1 (m / multi-sentence :snt1 (s / show-01 :ARG0 (f / figure~e.0 :mod "1A") :ARG1 (a / and~e.32 :op1 (d / detect-01~e.10 :ARG1 (p / phosphorylate-01~e.4 :ARG1~e.5 (a2 / amino-acid :mod 705 :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "STAT3"~e.6)))) :time (a3 / after~e.11 :op1 (e / expose-01~e.15 :ARG2~e.16 (p3 / protein :name (n3 / name :op1 "IL-6"~e.21,23) :quant (c / concentration-quantity :quant 10~e.17 :unit (n4 / nanogram-per-milliliter~e.18,20))) :duration (t / temporal-quantity :quant 5~e.12 :unit (m2 / minute~e.13))))) :op2 (r / reach-01~e.25 :ARG0 p :ARG1 (m3 / maximum~e.27) :time (a4 / after~e.35 :op1 (t2 / temporal-quantity :quant 15~e.29 :unit m2~e.30))) :op3 (d2 / decline-01~e.34 :ARG1 p :time (a5 / after~e.35 :op1~e.35 (u / up-to~e.35 :op1 (t3 / temporal-quantity :quant~e.35 1~e.1,36 :unit (h / hour~e.37)))) :mod (t4 / then~e.33)))) :snt2 (d3 / demonstrate-01~e.41 :ARG0 (t5 / thing~e.40 :ARG2-of~e.40 (r2 / result-01~e.40) :mod (t6 / this~e.39)) :ARG1~e.42 (a6 / activate-01~e.46 :ARG0 (p4 / protein :name (n5 / name :op1 "IL-6"~e.43,45)) :ARG1 (s2 / signal-07~e.49 :ARG0 (p5 / protein :name (n6 / name :op1 "STAT3"~e.48))) :location (m4 / myocyte :mod (v / ventricle~e.53) :part-of (r3 / rat~e.52 :mod (a7 / adult~e.51)))))) # ::id bel_pmid_1260_4616.9184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of mSef in NIH3T3 cells results in a decrease in FGF @-@ induced cell proliferation associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2 . As a consequence , there is a reduction in the phosphorylation of Raf @-@ 1 at Ser( 338 ) , MEK1 @/@ 2 at Ser( 217 ) and Ser( 221 ) , and ERK1 @/@ 2 at Thr( 202 ) and Tyr( 204 ) . # ::alignments 0-1.1.1 3-1.1.1.2.r 4-1.1.1.2.1.1 5-1.1.1.2 6-1.1 7-1.1.2.r 9-1.1.2.1 11-1.1.2.1.1.2.1.1.1 13-1.1.2.1.1.2 14-1.1.2.1.1.1 15-1.1.2.1.1 16-1.1.2 19-1.1.2.1 19-1.1.2.2 21-1.1.2.2.1.1.1.1.1 21-1.1.2.2.1.1.2.1.1 21-1.2.1.1.1.5.2.1 22-1.1.2.2.1 23-1.1.2.2.1.1.r 24-1.1.2.2.1.1.1.2.1.1 25-1.1.2.2.1.1 26-1.1.2.2.1.1.2.2.1.1 28-1.2 29-1.2 30-1.2 35-1.2.1 36-1.2.1.1.r 38-1.2.1.1 39-1.2.1.1.1.r 40-1.2.1.1.1.1.3.1.1 42-1.2.1.1.1.1.3.1.1 45-1.2.1.1.1.1.1 48-1.2.1.1.1.2.3.1.1 50-1.2.1.1.1.2.3.1.1 53-1.2.1.1.1.2.1 55-1.2.1.1.1 57-1.2.1.1.1.3.1 60-1.2.1.1.1 61-1.2.1.1.1.4.3.1.1 63-1.2.1.1.1.4.3.1.1 66-1.2.1.1.1.4.1 68-1.2.1.1.1 70-1.2.1.1.1.5.1 (m / multi-sentence :snt1 (r / result-01~e.6 :ARG1 (o / overexpress-01~e.0 :ARG1 (p / protein :name (n / name :op1 "Sef") :part-of (m2 / mouse)) :location~e.3 (c / cell-line~e.5 :name (n2 / name :op1 "NIH3T3"~e.4))) :ARG2~e.7 (a / associate-01~e.16 :ARG1 (d / decrease-01~e.9,19 :ARG1 (p2 / proliferate-01~e.15 :ARG0 (c2 / cell~e.14) :ARG2-of (i / induce-01~e.13 :ARG0 (p3 / protein :name (n3 / name :op1 "FGF"~e.11))))) :ARG2 (d2 / decrease-01~e.19 :ARG1 (p4 / phosphorylate-01~e.22 :ARG1~e.23 (a2 / and~e.25 :op1 (a3 / amino-acid :name (n4 / name :op1 "tyrosine"~e.21) :part-of (e4 / enzyme :name (n5 / name :op1 "FGFR1"~e.24))) :op2 (a4 / amino-acid :name (n6 / name :op1 "tyrosine"~e.21) :part-of (p6 / protein :name (n7 / name :op1 "FRS2"~e.26)))))))) :snt2 (c3 / cause-01~e.28,29,30 :ARG1 (r2 / reduce-01~e.35 :ARG1~e.36 (p7 / phosphorylate-01~e.38 :ARG1~e.39 (a5 / and~e.55,60,68 :op1 (a6 / amino-acid :mod 338~e.45 :name (n8 / name :op1 "serine") :part-of (e / enzyme :name (n9 / name :op1 "Raf-1"~e.40,42))) :op2 (a7 / amino-acid :mod 217~e.53 :name (n10 / name :op1 "serine") :part-of (e2 / enzyme :name (n11 / name :op1 "MEK1/2"~e.48,50))) :op3 (a8 / amino-acid :mod 221~e.57 :name (n12 / name :op1 "serine") :part-of e2) :op4 (a9 / amino-acid :mod 202~e.66 :name (n13 / name :op1 "threonine") :part-of (e3 / enzyme :name (n14 / name :op1 "ERK1/2"~e.61,63))) :op5 (a10 / amino-acid :mod 204~e.70 :name (n15 / name :op1 "tyrosine"~e.21) :part-of e3)))))) # ::id bel_pmid_1260_4616.26900 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data indicate that adenovirus @-@ mediated expression of mSef reduced FGF @-@ induced tyrosine phosphorylation of FGFR without affecting the overall level of FGFR expression ( Fig.4 A ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.2.1 6-1.2.1.2 7-1.2.1 10-1.2 11-1.2.2.2.1.1.1 13-1.2.2.2 14-1.2.2.1.1.1 15-1.2.2 17-1.2.2.1.2.1.1 18-1.2.3.1 18-1.2.3.1.r 19-1.2.3 21-1.2.3.2.2 22-1.2.3.2 23-1.2.3.2.1.r 24-1.2.3.2.1.1 25-1.2.3.2.1 (i / indicate-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (r / reduce-01~e.10 :ARG0 (e / express-03~e.7 :ARG2 (p / protein :name (n / name :op1 "Sef") :part-of (m / mouse)) :ARG1-of (m2 / mediate-01~e.6 :ARG0 (a / adenovirus~e.4))) :ARG1 (p2 / phosphorylate-01~e.15 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine"~e.14) :part-of (p3 / protein :name (n3 / name :op1 "FGFR"~e.17))) :ARG2-of (i2 / induce-01~e.13 :ARG0 (p4 / protein :name (n4 / name :op1 "FGF"~e.11)))) :manner (a3 / affect-01~e.19 :polarity~e.18 -~e.18 :ARG1 (l / level~e.22 :quant-of~e.23 (e2 / express-03~e.25 :ARG2 p3~e.24) :mod (o / overall~e.21)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4A"))) # ::id bel_pmid_1260_4616.28060 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Adenovirus @-@ mediated expression of mSef but not GFP resulted in a reduction in the levels of activated ERK1 @/@ 2 , whereas overall levels of ERK1 @/@ 2 were unaffected ( Fig . 2 A ) . # ::alignments 0-1.1.1.1.2.1 2-1.1.1.1.2 3-1.1.1.1 3-1.1.1.2 6-1.1.1 7-1.1.1.2.1 7-1.1.1.2.1.r 8-1.1.1.2.2.1.1 9-1.1 10-1.1.2.r 12-1.1.2 13-1.1.2.1.r 15-1.1.2.1 16-1.1.2.1.1.r 17-1.1.2.1.1.2 18-1.1.2.1.1.1.1 18-1.2.2.1.1.1 20-1.1.2.1.1.1.1 20-1.2.2.1.1.1 22-1 23-1.2.2.2 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1.1.1 28-1.2.2.1.1.1 30-1.2 30-1.2.1 30-1.2.1.r 32-1.3.1 34-1.1.2.1.1.1.1 (c / contrast-01~e.22 :ARG1 (r / result-01~e.9 :ARG1 (c2 / contrast-01~e.6 :ARG1 (e / express-03~e.3 :ARG2 (p / protein :name (n / name :op1 "Sef") :part-of (m / mouse)) :ARG1-of (m2 / mediate-01~e.2 :ARG0 (a / adenovirus~e.0))) :ARG2 (e2 / express-03~e.3 :polarity~e.7 -~e.7 :ARG2 (p2 / protein :name (n2 / name :op1 "GFP"~e.8)) :ARG1-of m2)) :ARG2~e.10 (r2 / reduce-01~e.12 :ARG1~e.13 (l / level~e.15 :quant-of~e.16 (e3 / enzyme :name (n3 / name :op1 "ERK1/2"~e.18,20,34) :ARG1-of (a2 / activate-01~e.17))))) :ARG2 (a3 / affect-01~e.30 :polarity~e.30 -~e.30 :ARG1 (l2 / level~e.24 :quant-of~e.25 (e4 / enzyme :name (n4 / name :op1 "ERK1/2"~e.18,20,26,28)) :mod (o / overall~e.23))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "2A"))) # ::id bel_pmid_1261_2908.9036 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that liver from ICAM @-@ 1 @-@ deficient mice exhibited impaired regeneration after partial hepatectomy . This finding is associated with dramatic decrease in leukocyte recruitment and tissue TNF @-@ alpha and IL @-@ 6 levels . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1 4-1.1.2.1.1.r 5-1.1.2.1.1.1.1.1 7-1.1.2.1.1.1.1.1 9-1.1.2.1.1.1 9-1.1.2.1.1.1.2 9-1.1.2.1.1.1.2.1 9-1.1.2.1.1.1.2.1.r 9-1.1.2.1.1.1.2.r 10-1.1.2.1.1 11-1.1.2 12-1.1.2.2.1 13-1.1.2.2 14-1.1.2.3 15-1.1.2.3.1.1 15-1.1.2.3.1.1.r 16-1.1.2.3.1 18-1.2.1.1 19-1.2.1 21-1.2 22-1.2.2.r 23-1.2.2.2 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1.1.1.1.1 27-1.2.2.1.1 28-1.2.2.1 28-1.2.2.1.2.1 29-1.2.2.1.2.1.3 30-1.2.2.1.2.1.1.1.1 33-1.2.2.1.2.1 34-1.2.2.1.2.1.2.1.1 36-1.2.2.1.2.1.2.1.1 37-1.2.2.1.2 (m / multi-sentence :snt1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (e / exhibit-01~e.11 :ARG0 (l / liver~e.3 :source~e.4 (m2 / mouse~e.10 :mod (p / protein~e.9 :name (n / name :op1 "ICAM-1"~e.5,7) :ARG2-of~e.9 (m3 / mutate-01~e.9 :mod~e.9 "-/-"~e.9)))) :ARG1 (r / regenerate-01~e.13 :ARG1-of (i / impair-01~e.12)) :time (a / after~e.14 :op1 (h / hepatectomy~e.16 :degree~e.15 (p2 / part~e.15))))) :snt2 (a2 / associate-01~e.21 :ARG1 (f2 / find-01~e.19 :mod (t / this~e.18)) :ARG2~e.22 (d / decrease-01~e.24 :ARG1~e.25 (a3 / and~e.28 :op1 (r2 / recruit-01~e.27 :ARG1 (c / cell :name (n2 / name :op1 "leukocyte"~e.26))) :op2 (l2 / level~e.37 :quant-of (a4 / and~e.28,33 :op1 (p3 / protein :name (n3 / name :op1 "TNF-α"~e.30)) :op2 (p4 / protein :name (n4 / name :op1 "IL-6"~e.34,36)) :mod (t2 / tissue~e.29)))) :degree (d2 / dramatic~e.23)))) # ::id bel_pmid_1261_8892.1630 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The treatment of NCI @-@ N87 cells with EGF resulted in increases in phosphorylation of Erk1 @/@ 2 , Akt , and P38 . Blockade of the Erk , phosphatidylinositol @-@ 3 kinase/Akt , or P38 pathways in this cell line # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.2.r 8-1.1.1.2.1.1 9-1.1 10-1.1.2.r 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2 14-1.1.2.2.1.r 15-1.1.2.2.1.1.1.1 17-1.1.2.2.1.1.1.1 19-1.1.2.2.1.2.1.1 21-1.1.2.2.1 22-1.1.2.2.1.3.1.1 24-1.2 25-1.2.1.r 27-1.2.1.1.1.1 29-1.2.1.2.1.1 31-1.2.1.2.1.1 34-1.2.1 35-1.2.1.3.1.1 36-1.2.1.1 36-1.2.1.2 36-1.2.1.3 37-1.2.2.r 38-1.2.2.1 39-1.2.2 40-1.2.2 (m / multi-sentence :snt1 (r / result-01~e.9 :ARG1 (t / treat-04~e.1 :ARG1~e.2 (c / cell~e.6 :name (n / name :op1 "NCI-N87"~e.3,5)) :ARG2~e.7 (p / protein :name (n2 / name :op1 "EGF"~e.8))) :ARG2~e.10 (i / increase-01~e.11 :ARG0 t :ARG1~e.12 (p2 / phosphorylate-01~e.13 :ARG1~e.14 (a / and~e.21 :op1 (e / enzyme :name (n3 / name :op1 "Erk1/2"~e.15,17)) :op2 (e2 / enzyme :name (n4 / name :op1 "Akt"~e.19)) :op3 (e3 / enzyme :name (n5 / name :op1 "P38"~e.22)))))) :snt2 (b / blockade-01~e.24 :ARG1~e.25 (o / or~e.34 :op1 (p3 / pathway~e.36 :name (n6 / name :op1 "Erk"~e.27)) :op2 (p4 / pathway~e.36 :name (n7 / name :op1 "phosphatidylinositol-3-kinase/Akt"~e.29,31)) :op3 (p5 / pathway~e.36 :name (n8 / name :op1 "P38"~e.35))) :location~e.37 (c2 / cell-line~e.39,40 :mod (t2 / this~e.38)))) # ::id bel_pmid_1262_9177.8352 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ciliary neurotrophic factor , CNTF , activation of gp130 in NSCs rapidly increased Notch1 expression # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1.1.1.3 6-1.1 7-1.1.2.r 8-1.1.2.1.1 11-1.3 11-1.3.r 12-1 13-1.2.1.1.1 14-1.2 (i / increase-01~e.12 :ARG0 (a / activate-01~e.6 :ARG0 (p / protein :name (n / name :op1 "ciliary"~e.0 :op2 "neurotrophic"~e.1 :op3 "factor"~e.2)) :ARG1~e.7 (p2 / protein :name (n2 / name :op1 "gp130"~e.8)) :location (c / cell :name (n3 / name :op1 "NSC"))) :ARG1 (e / express-03~e.14 :ARG2 (p3 / protein :name (n4 / name :op1 "Notch1"~e.13))) :manner~e.11 (r / rapid~e.11)) # ::id bel_pmid_1262_9177.26086 ::amr-annotator SDL-AMR-09 ::preferred # ::tok infusion of EGF and CNTF into adult forebrain lateral ventricles increased periventricular NOTCH1 compared with EGF alone # ::alignments 0-1.1 0-1.3 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 5-1.1.2.r 6-1.1.2.2.1 7-1.1.2.2 8-1.1.2.1 9-1.1.2 10-1 11-1.2.2 12-1.2.1.1 13-1.3.r 14-1.3.1.r 15-1.3.1 (i / increase-01~e.10 :ARG0 (i2 / infuse-01~e.0 :ARG1~e.1 (a / and~e.3 :op1 (p / protein :name (n / name :op1 "EGF"~e.2)) :op2 (p2 / protein :name (n2 / name :op1 "CNTF"~e.4))) :ARG2~e.5 (v / ventricle~e.9 :location (l / lateral~e.8) :part-of (f / forebrain~e.7 :mod (a2 / adult~e.6)))) :ARG1 (p3 / protein :name (n3 / name :op1 "NOTCH1"~e.12) :location (p4 / periventricular~e.11)) :compared-to~e.13 (i3 / infuse-01~e.0 :ARG1~e.14 p~e.15 :ARG2 v)) # ::id bel_pmid_1262_9177.28408 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NOTCH1 activation , indicated by tumor necrosis factor alpha @-@ converting enzyme , TACE [ Adam17 ] , and presenilin @-@ mediated processing , also increased # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1.1 6-1.1.2.1.1.1.2 7-1.1.2.1.1.1.3 8-1.1.2.1.1.1.4 10-1.1.2.1.1.1.4 11-1.1.2.1.1.1.5 18-1.1.2.1 19-1.1.2.1.2.1.1.1.1 21-1.1.2.1.2.1 22-1.1.2.1.2 24-1.2 25-1 (i / increase-01~e.25 :ARG1 (a / activate-01~e.1 :ARG1 (p / protein :name (n / name :op1 "NOTCH1"~e.0)) :ARG1-of (i2 / indicate-01~e.3 :ARG0~e.4 (a2 / and~e.18 :op1 (e / enzyme :name (n2 / name :op1 "tumor"~e.5 :op2 "necrosis"~e.6 :op3 "factor"~e.7 :op4 "alpha-converting"~e.8,10 :op5 "enzyme"~e.11)) :op2 (p2 / process-01~e.22 :ARG1-of (m / mediate-01~e.21 :ARG0 (p3 / protein :name (n3 / name :op1 "presenilin"~e.19))))))) :mod (a4 / also~e.24)) # ::id bel_pmid_1268_6512.15962 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We used a murine macrophage @-@ like cell line , RAW264.7 , to demonstrate that Janus kinase ( JAK ) 2 is tyrosine phosphorylated immediately after LPS stimulation . Anti @-@ Toll @-@ like receptor ( TLR ) 4 neutralization antibody inhibits the phosphorylation of JAK2 and the c @-@ Jun NH2 @-@ terminal protein kinase ( JNK ) . # ::alignments 0-1.1.1 1-1.1 3-1.1.2.3.1.1 4-1.1.2.2.1.1.1 6-1.1.2.2 7-1.1.2 7-1.1.2.2.1 8-1.1.2 10-1.1.2.1.1 13-1.1.3 14-1.1.3.2.r 15-1.1.3.2.1.2.1.1 16-1.1.3.2.1.2.1.2 20-1.1.3.2.1.2.1.3 22-1.1.3.2.1.1.1 23-1.1.3.2 24-1.1.3.2.2.2 25-1.1.3.2.2 26-1.1.3.2.2.1.1 27-1.1.3.2.2.1 31-1.2.1.1.1.1.1 33-1.2.1.1.1.1.1 34-1.2.1.1.1.1.2 38-1.2.1.1.1.1.3 39-1.2.1.1 40-1.2.1 41-1.2 43-1.2.2 44-1.2.2.1.r 45-1.2.2.1.1.1.1 46-1.2.2.1 48-1.2.2.1.2.1.1 50-1.2.2.1.2.1.1 51-1.2.2.1.2.1.2 53-1.2.2.1.2.1.2 54-1.2.2.1.2.1.3 55-1.2.2.1.2.1.4 (m / multi-sentence :snt1 (u / use-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / cell-line~e.7,8 :name (n / name :op1 "RAW264.7"~e.10) :ARG1-of (r / resemble-01~e.6 :ARG2 (c2 / cell~e.7 :name (n2 / name :op1 "macrophage"~e.4))) :part-of (o / organism :name (n3 / name :op1 "Muridae"~e.3))) :ARG2 (d / demonstrate-01~e.13 :ARG0 w :ARG1~e.14 (p / phosphorylate-01~e.23 :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine"~e.22) :part-of (e / enzyme :name (n5 / name :op1 "Janus"~e.15 :op2 "kinase"~e.16 :op3 2~e.20))) :time (a2 / after~e.25 :op1 (s / stimulate-01~e.27 :ARG0 (l / lipopolysaccharide~e.26) :ARG1 e) :mod (i / immediate~e.24))))) :snt2 (i2 / inhibit-01~e.41 :ARG0 (a3 / antibody~e.40 :ARG0-of (n7 / neutralize-01~e.39 :ARG1 (p2 / protein :name (n8 / name :op1 "Toll-like"~e.31,33 :op2 "receptor"~e.34 :op3 4~e.38)))) :ARG1 (p3 / phosphorylate-01~e.43 :ARG1~e.44 (a4 / and~e.46 :op1 (e2 / enzyme :name (n9 / name :op1 "JAK2"~e.45)) :op2 (e3 / enzyme :name (n10 / name :op1 "c-Jun"~e.48,50 :op2 "NH2-terminal"~e.51,53 :op3 "protein"~e.54 :op4 "kinase"~e.55)))))) # ::id bel_pmid_1268_7404.28336 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Il6 can elicit proinflammatory or anti @-@ inflammatory effects , depending on the in vivo environmental circumstances # ::alignments 0-1.1.1.1.1 1-1 2-1.1 3-1.1.2.1.1 3-1.1.2.1.1.1 3-1.1.2.1.1.1.r 5-1.1.2.2.1 7-1.1.2.1.1.1 8-1.1.2.1 8-1.1.2.2 10-1.2 11-1.2.1.r 13-1.2.1.1 14-1.2.1.1 15-1.2.1.2 16-1.2.1 (p / possible-01~e.1 :ARG1 (e / elicit-01~e.2 :ARG0 (p2 / protein :name (n / name :op1 "Il6"~e.0)) :ARG1 (a / and :op1 (a2 / affect-01~e.8 :ARG0-of (f / favor-01~e.3 :ARG1~e.3 (i / inflame-01~e.3,7))) :op2 (a3 / affect-01~e.8 :ARG0-of (c / counter-01~e.5 :ARG1 i)))) :ARG0-of (d / depend-01~e.10 :ARG1~e.11 (c2 / circumstance~e.16 :manner (i2 / in-vivo~e.13,14) :mod (e4 / environment~e.15)))) # ::id bel_pmid_1268_7404.38564 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Il6 promotes the growth arrest and differentiation of M1 cells through gp130 @-@ mediated Stat3 activation , whereas the Y759 @/@ SHP @-@ 2 @-@ mediated cascade by gp130 stimulation has growth @-@ enhancing effects # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2.1.1 4-1.1.2.1 5-1.1.2 6-1.1.2.2 7-1.1.2.1.1.1.r 8-1.1.2.1.1.1.1.1 9-1.1.2.1.1.1 11-1.1.3.2.1.1.1 13-1.1.3.2 14-1.1.3.1.1.1 15-1.1.3 17-1 21-1.2.1.1.1.3.1.1 23-1.2.1.1.1.3.1.1 25-1.2.1.1 26-1.2.1 28-1.2.1.2.1 29-1.2.2.1 31-1.2.2.2 33-1.2.2 34-1.2 (c / contrast-01~e.17 :ARG1 (p / promote-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "Il6"~e.0)) :ARG1 (a / and~e.5 :op1 (a2 / arrest-02~e.4 :ARG1 (g / grow-01~e.3 :ARG1~e.7 (c2 / cell~e.9 :name (n2 / name :op1 "M1"~e.8)))) :op2 (d / differentiate-01~e.6 :ARG1 c2)) :manner (a3 / activate-01~e.15 :ARG1 (p3 / protein :name (n3 / name :op1 "Stat3"~e.14)) :ARG1-of (m / mediate-01~e.13 :ARG0 (p4 / protein :name (n4 / name :op1 "gp130"~e.11))))) :ARG2 (a5 / affect-01~e.34 :ARG0 (c3 / cascade~e.26 :ARG1-of (m2 / mediate-01~e.25 :ARG0 (a4 / amino-acid :mod 759 :name (n5 / name :op1 "tyrosine") :part-of (p5 / protein :name (n6 / name :op1 "SHP-2"~e.21,23)))) :ARG1-of (s / stimulate-01 :ARG0 p4~e.28)) :ARG2 (e3 / enhance-01~e.33 :ARG0 c3~e.29 :ARG1 (g2 / grow-01~e.31)))) # ::id bel_pmid_1276_9686.36092 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutational inactivation of the MYCantagonist Mxi @-@ 1 in prostate carcinoma may be another mechanism of MYC activation [ 54 ] . Mxi @-@ 1 inactivation would presumably shift the equilibrium between Mxi @-@ 1/MAX and c @-@ MYC @/@ MAX in prostate cells towards c @- MYC @/@ MAX hetero @-@ dimers , and therefore lead to elevated expression of c @-@ MYC @-@ target genes . # ::alignments 0-1.1.3.3 1-1.1.3 1-1.1.3.1 1-1.1.3.1.r 5-1.1.3.2.1.1 7-1.1.3.2.1.1 9-1.1.3.4.2 10-1.1.3.4.1.1 11-1.1.1 12-1.1.3.r 13-1.1.4 14-1.1 16-1.1.2.1.1.1 17-1.1.2 17-1.1.3 19-1.1.5.1.1.1 22-1.2.1.1.2.1.1 24-1.2.1.1.2.1.1 25-1.2.1.1 25-1.2.1.1.1 25-1.2.1.1.1.r 27-1.2.1.5 28-1.2.1 30-1.2.1.2 31-1.2.1.2.1 32-1.2.1.1.2.1.1 35-1.2.1.2.1 36-1.2.1.2.1.2.1.1.1 38-1.2.1.2.1.2.1.1.1 40-1.2.1.2.1.1.2.1.1 41-1.2.1.4.r 42-1.2.1.4.1 43-1.2.1.4 45-1.2.1.2.1.2.1.1.1 47-1.2.1.2.1.2.1.1.1 49-1.2.1.2.1.2.2 54-1.2 55-1.2.2 56-1.2.2.2 57-1.2.2.2.1.r 58-1.2.2.2.1.2 59-1.2.2.2.1 60-1.2.2.2.1.1.r 61-1.2.2.2.1.1.1.1 63-1.2.2.2.1.1.1.1 65-1.2.2.2.1.1 65-1.2.2.2.1.1.2 65-1.2.2.2.1.1.2.r (m / multi-sentence :snt1 (m2 / mechanism~e.14 :ARG1-of (p / possible-01~e.11) :ARG0-of (a / activate-01~e.17 :ARG1 (p10 / protein :name (n / name :op1 "MYC"~e.16))) :domain~e.12 (a2 / activate-01~e.1,17 :polarity~e.1 -~e.1 :ARG1 (p11 / protein :name (n2 / name :op1 "Mxi-1"~e.5,7) :ARG1-of (a3 / antagonize-02 :ARG2 p10)) :ARG1-of (m3 / mutate-01~e.0) :location (m6 / medical-condition :name (n3 / name :op1 "carcinoma"~e.10) :location (p2 / prostate~e.9))) :mod (a4 / another~e.13) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 54~e.19)))) :snt2 (a5 / and~e.54 :op1 (s / shift-01~e.28 :ARG0 (a6 / activate-01~e.25 :polarity~e.25 -~e.25 :ARG1 (p9 / protein :name (n4 / name :op1 "Mxi-1"~e.22,24,32))) :ARG1 (e / equilibrium~e.30 :mod (b / between~e.31,35 :op1 (m4 / macro-molecular-complex :part p9 :part (p4 / protein :name (n5 / name :op1 "MAX"~e.40))) :op2 (m5 / macro-molecular-complex :part (p8 / protein :name (n6 / name :op1 "c-MYC"~e.36,38,45,47)) :part p4~e.49))) :ARG2 (h / heterodimer :mod m5) :location~e.41 (c2 / cell~e.43 :part-of (p5 / prostate~e.42)) :ARG1-of (p6 / presume-01~e.27)) :op2 (c3 / cause-01~e.55 :ARG0 s :ARG1 (l / lead-03~e.56 :ARG2~e.57 (e2 / express-03~e.59 :ARG1~e.60 (p7 / protein~e.65 :name (n7 / name :op1 "c-MYC"~e.61,63) :ARG1-of~e.65 (t / target-01~e.65)) :ARG1-of (e3 / elevate-01~e.58)))))) # ::id bel_pmid_1276_9686.37908 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The encoded protein ( CDKN1A ) binds to and inhibits the activity of cyclin @-@ CDK2 or -@ CDK4 complexes # ::alignments 1-1.1.1.1 2-1.1.1 4-1.1.1.1.1.1.1 6-1.1 8-1 9-1.2 11-1.2.2 12-1.1.2.r 13-1.1.2.1.1.1.1 15-1.1.2.1.2.1.1 16-1.1.2 18-1.1.2.2.2.1.1 19-1.1.2.1 19-1.1.2.2 (a / and~e.8 :op1 (b / bind-01~e.6 :ARG1 (p / protein~e.2 :ARG1-of (e / encode-01~e.1 :ARG0 (g / gene :name (n / name :op1 "CDKN1A"~e.4)))) :ARG2~e.12 (o / or~e.16 :op1 (m / macro-molecular-complex~e.19 :part (p2 / protein :name (n2 / name :op1 "cyclin"~e.13)) :part (e2 / enzyme :name (n3 / name :op1 "CDK2"~e.15))) :op2 (m2 / macro-molecular-complex~e.19 :part p2 :part (e3 / enzyme :name (n4 / name :op1 "CDK4"~e.18))))) :op2 (i / inhibit-01~e.9 :ARG0 p :ARG1 (a2 / activity-06~e.11 :ARG0 o))) # ::id bel_pmid_1276_9686.37918 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The encoded protein binds to and prevents the activation of cyclin E @-@ CDK2 or cyclin D @-@ CDK4 complexes # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1 5-1 6-1.2 8-1.2.2 9-1.1.2.r 10-1.1.2.1.1.1.1 11-1.1.2.1.1.1.2 13-1.1.2.1.2.1.1 14-1.1.2 15-1.1.2.2.1.1.1 16-1.1.2.2.1.1.2 18-1.1.2.2.2.1.1 19-1.1.2.1 19-1.1.2.2 (a / and~e.5 :op1 (b / bind-01~e.3 :ARG1 (p / protein~e.2 :ARG1-of (e / encode-01~e.1)) :ARG2~e.9 (o / or~e.14 :op1 (m / macro-molecular-complex~e.19 :part (p2 / protein :name (n / name :op1 "cyclin"~e.10 :op2 "E"~e.11)) :part (e2 / enzyme :name (n2 / name :op1 "CDK2"~e.13))) :op2 (m2 / macro-molecular-complex~e.19 :part (p3 / protein :name (n3 / name :op1 "cyclin"~e.15 :op2 "D"~e.16)) :part (e3 / enzyme :name (n4 / name :op1 "CDK4"~e.18))))) :op2 (p4 / prevent-01~e.6 :ARG0 p :ARG1 (a2 / activate-01~e.8 :ARG1 o))) # ::id bel_pmid_1281_2976.37028 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In many cells PKA inhibits the extracellular receptor kinase ( ERK1 @/@ 2 ) cascade of the mitogen @-@ activated protein kinase ( MAPK ) pathway leading to inhibition of cell proliferation . # ::alignments 1-1.3.1 2-1.3 3-1.1.1.1 4-1 6-1.2.1.1.1 7-1.2.1.1.2 8-1.2.1.1.3 14-1.2 15-1.2.2.r 17-1.2.2.1.1 19-1.2.2.1.1 20-1.2.2.1.2 21-1.2.2.1.3 25-1.2.2 26-1.4 27-1.4.1.r 28-1.4.1 29-1.4.1.1.r 30-1.4.1.1.1 31-1.4.1.1 (i / inhibit-01~e.4 :ARG0 (e / enzyme :name (n / name :op1 "PKA"~e.3)) :ARG1 (c / cascade~e.14 :mod (e2 / enzyme :name (n2 / name :op1 "extracellular"~e.6 :op2 "receptor"~e.7 :op3 "kinase"~e.8)) :poss~e.15 (p / pathway~e.25 :name (n3 / name :op1 "mitogen-activated"~e.17,19 :op2 "protein"~e.20 :op3 "kinase"~e.21))) :location (c2 / cell~e.2 :quant (m / many~e.1)) :ARG0-of (l / lead-03~e.26 :ARG2~e.27 (i2 / inhibit-01~e.28 :ARG1~e.29 (p2 / proliferate-01~e.31 :ARG0 (c3 / cell~e.30))))) # ::id bel_pmid_1288_1425.6346 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here we demonstrate that Ser311 accounts for zetaPKC phosphorylation of RelA and that this site is phosphorylated in vivo in response to TNF @-@ alpha . # ::alignments 0-1.3 1-1.1 2-1 5-1.2.1 6-1.2.1.2.r 7-1.2.1.2.2.1.1 8-1.2.1.2 9-1.2.1.2.1.r 10-1.2.1.2.1.1.1 11-1.2 12-1.2.r 13-1.2.2.1.1 14-1.2.2.1 16-1.2.2 17-1.2.2.2 18-1.2.2.2 19-1.2.2.2 19-1.2.2.3.r 20-1.2.2.3 21-1.2.2.3.1.r 22-1.2.2.3.1.1.1 24-1.2.2.3.1.1.1 (d / demonstrate-01~e.2 :ARG0 (w / we~e.1) :ARG1~e.12 (a / and~e.11 :op1 (a2 / account-01~e.5 :ARG0 (a3 / amino-acid :mod 311 :name (n / name :op1 "serine")) :ARG1~e.6 (p / phosphorylate-01~e.8 :ARG1~e.9 (p2 / protein :name (n2 / name :op1 "RelA"~e.10)) :ARG2 (e / enzyme :name (n3 / name :op1 "zetaPKC"~e.7)))) :op2 (p3 / phosphorylate-01~e.16 :ARG1 (p4 / protein-segment~e.14 :mod (t / this~e.13)) :manner (i / in-vivo~e.17,18,19) :ARG2-of~e.19 (r / respond-01~e.20 :ARG1~e.21 (p5 / protein :name (n4 / name :op1 "TNF-alpha"~e.22,24))))) :location (h / here~e.0)) # ::id bel_pmid_1288_1425.9992 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Also , an inactivating mutation of that residue severely impairs RelA transcriptional activity , blocks its anti @-@ apoptotic function and abrogates the interaction of RelA with the co @-@ activator CBP as well as its recruitment , and that of RNA polymerase II ( Pol II ) with the interleukin @-@ 6 ( IL @-@ 6 ) promoter . # ::alignments 0-1.5 3-1.1.1.2.1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1 7-1.1.1.1 8-1.4 8-1.4.r 9-1.1 10-1.1.2.1.1.1 11-1.1.2.2 12-1.1.2 14-1.2 16-1.2.2.2 18-1.2.2.2.1 19-1.2.2 20-1 21-1.3 23-1.3.2.1 23-1.3.2.2 25-1.1.2.1.1.1 30-1.1.1.2 31-1.3.2.1.2.1.1.1 32-1.3.2.1.2 33-1.3.2.1.2 34-1.3.2.1.2 34-1.3.2.1.2.r 35-1.3.2.1.2.2.1 35-1.3.2.1.2.2.1.r 36-1.3.2.1.2.2 38-1.3.2.1.2 39-1.1.1.1.1 40-1.3.2.2.1.r 41-1.3.2.2.1.1.1 42-1.3.2.2.1.1.2 43-1.3.2.2.1.1.3 48-1.3.2.2.2.r 50-1.3.2.2.2.1.1.1.1 52-1.3.2.2.2.1.1.1.1 56-1.3.2.2.2.1.1.1.1 58-1.3.2.2.2 58-1.3.2.2.2.1 58-1.3.2.2.2.1.r (a2 / and~e.20 :op1 (i / impair-01~e.9 :ARG0 (m / mutate-01~e.4 :ARG1~e.5 (r / residue~e.7 :mod (t / that~e.6,39)) :ARG1-of (a3 / activate-01~e.30 :polarity -~e.3)) :ARG1 (a4 / activity-06~e.12 :ARG0 (p / protein :name (n / name :op1 "RelA"~e.10,25)) :ARG1 (t2 / transcribe-01~e.11))) :op2 (b / block-01~e.14 :ARG0 m :ARG1 (f / function-01~e.19 :ARG0 r :ARG1 (o / oppose-01~e.16 :ARG1 (a5 / apoptosis~e.18)))) :op3 (a6 / abrogate-01~e.21 :ARG0 m :ARG1 (a7 / and :op1 (i2 / interact-01~e.23 :ARG0 p :ARG1~e.34 (a8 / and~e.32,33,34,38 :op1 (p2 / protein :name (n2 / name :op1 "CBP"~e.31) :ARG0-of (c / coactivate-01)) :op2 (r2 / recruit-01~e.36 :ARG0~e.35 p2~e.35))) :op2 (i3 / interact-01~e.23 :ARG0~e.40 (e / enzyme :name (n3 / name :op1 "RNA"~e.41 :op2 "polymerase"~e.42 :op3 "II"~e.43)) :ARG1~e.48 (m2 / molecular-physical-entity~e.58 :ARG0-of~e.58 (p3 / promote-01~e.58 :ARG1 (p4 / protein :name (n4 / name :op1 "interleukin-6"~e.50,52,56))))))) :manner~e.8 (s / severe~e.8) :mod (a9 / also~e.0)) # ::id bel_pmid_1292_3167.9944 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblot analyses confirm that Tyr @-@ 542 and Tyr @-@ 580 are the major sites of Shp2 tyrosyl phosphorylation and that Tyr @-@ 542 is the major Grb2 binding site . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1.2.1 4-1.2.1.3.1.1.1 6-1.2.1.1.1.1 8-1.2.1.1.1.2.1 8-1.2.1.1.2.2.1 10-1.2.1.1.2.1 11-1.2.1.1.r 13-1.2.1.2 14-1.2.1 15-1.2.1.3.r 16-1.2.1.3.1.2.1.1 18-1.2.1.3 19-1.2.1.1 21-1.2.1.1.1.2.1 21-1.2.1.1.2.2.1 23-1.2.1.1.1.1 24-1.2.1.1.r 26-1.2.1.2 27-1.2.2.4.1.1 28-1.2.2.3 29-1.2.2 (c / confirm-01~e.2 :ARG0 (a / analyze-01~e.1 :manner (i / immunoblot-01~e.0)) :ARG1~e.3 (a2 / and :op1 (p / protein-segment~e.14 :domain~e.11,24 (a3 / and~e.19 :op1 (a4 / amino-acid :mod 542~e.6,23 :name (n / name :op1 "tyrosine"~e.4,8,21)) :op2 (a5 / amino-acid :mod 580~e.10 :name (n2 / name :op1 "tyrosine"~e.8,21))) :ARG1-of (m / major-02~e.13,26) :location-of~e.15 (p2 / phosphorylate-01~e.18 :ARG1 (a6 / amino-acid :name (n3 / name :op1 "tyrosine"~e.4) :part-of (e / enzyme :name (n4 / name :op1 "Shp2"~e.16))))) :op2 (p3 / protein-segment~e.29 :domain a4 :ARG1-of m :ARG1-of (b / bind-01~e.28) :part-of (p4 / protein :name (n5 / name :op1 "Grb2"~e.27))))) # ::id bel_pmid_1292_3167.29880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Y542F @-@ expressing cells exhibited an ?50 % decrease in Tyr @-@ 580 phosphorylation ( Fig . 3C , right panel ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1 3-1.1 4-1 7-1.2.2.1 8-1.2 9-1.2.1.r 10-1.2.1.1.2.1 12-1.2.1.1.1 13-1.2.1 15-1.3.1.1 17-1.3.1.1.1 19-1.3.1.1.2.1 20-1.3.1.1.2 (e / exhibit-01~e.4 :ARG0 (c / cell~e.3 :ARG3-of (e2 / express-03~e.2 :ARG2 (a / amino-acid :ARG2-of (m / mutate-01 :value "Y542F"~e.0)))) :ARG1 (d / decrease-01~e.8 :ARG1~e.9 (p / phosphorylate-01~e.13 :ARG1 (a2 / amino-acid :mod 580~e.12 :name (n / name :op1 "tyrosine"~e.10))) :quant (a3 / approximately :op1 (p2 / percentage-entity~e.7 :value 50))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.15 :mod "3C"~e.17 :part (p3 / panel~e.20 :ARG1-of (r / right-04~e.19)))))) # ::id bel_pmid_1293_4012.314 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , the cell cycle progression from S to M phase was impaired during liver regeneration in Cry @-@ deficient mice # ::alignments 0-1 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1 6-1.1.1.2.r 7-1.1.1.2.1.1 8-1.1.1.3.r 9-1.1.1.3.1.1 10-1.1.1.3.1.2 12-1.1 13-1.1.2.r 14-1.1.2.1 15-1.1.2 16-1.1.2.2.r 17-1.1.2.2.1.1.1 19-1.1.2.2.1 19-1.1.2.2.1.2 19-1.1.2.2.1.2.1 19-1.1.2.2.1.2.1.r 19-1.1.2.2.1.2.r 20-1.1.2.2 (c / cause-01~e.0 :ARG1 (i / impair-01~e.12 :ARG1 (p / progress-01~e.5 :ARG1 (c2 / cycle-02~e.4 :ARG1 (c3 / cell~e.3)) :ARG3~e.6 (e / event :name (n / name :op1 "S"~e.7 :op2 "phase")) :ARG4~e.8 (e2 / event :name (n2 / name :op1 "M"~e.9 :op2 "phase"~e.10))) :time~e.13 (r / regenerate-01~e.15 :ARG1 (l / liver~e.14) :location~e.16 (m / mouse~e.20 :mod (p2 / protein~e.19 :name (n3 / name :op1 "Cry"~e.17) :ARG2-of~e.19 (m2 / mutate-01~e.19 :mod~e.19 "-/-"~e.19)))))) # ::id bel_pmid_1293_4012.20242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - Three E @-@ box elements were found within 1.2 kb of the mouse wee1 gene 5 @-@ upstream region ( Fig . 3B ) . CLOCK and BMAL1 together , but neither of them alone , produced a major increase in transcriptional activity through this fragment in transfected NIH3T3 cells # ::alignments 0-1.3.r 1-1.3.1 2-1.3 4-1.1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 8-1.1.1 10-1.1 11-1.1.2.2.3.1.r 11-1.1.2.2.3.r 12-1.1.2.2.3.1 16-1.1.2.2.2 17-1.1.2.2.1.1 18-1.1.2.2 18-1.2.1.1.1 18-1.2.1.1.2 19-1.1.2.1.1 21-1.1.2.1 22-1.1.2 24-1.1.3.1 26-1.1.3.1.1 29-1.2.1.1.1.1.1 30-1.2.1.1 31-1.2.1.1.2.1.1 32-1.2.1.1.3 34-1.2.1 38-1.2.1.2.3 40-1.2 42-1.2.2.4 43-1.2.2 44-1.2.2.1.r 45-1.2.2.1.2 46-1.2.2.1 48-1.2.2.2.1 49-1.2.2.2 50-1.2.2.3.r 51-1.2.2.3.2 52-1.2.2.3.1.1 53-1.2.2.3 (m / multi-sentence :snt1 (f / find-01~e.10 :ARG1 (e / element~e.8 :quant 3~e.4 :mod (d / dna-sequence :name (n / name :op1 "E-box"~e.5,7))) :location (r / region~e.22 :direction (u / upstream~e.21 :mod 5~e.19) :location (g / gene~e.18 :name (n2 / name :op1 "wee1"~e.17) :part-of (m2 / mouse~e.16) :quant~e.11 (d2 / distance-quantity :quant~e.11 1.2~e.12 :unit (k / kilo-base-pair)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.24 :mod "3B"~e.26))) :snt2 (p / produce-01~e.40 :ARG0 (c / contrast-01~e.34 :ARG1 (a / and~e.30 :op1 (g2 / gene~e.18 :name (n3 / name :op1 "CLOCK"~e.29)) :op2 (g3 / gene~e.18 :name (n4 / name :op1 "BMAL1"~e.31)) :mod (t / together~e.32)) :ARG2 (o / or :op1 g2 :op2 g3 :mod (a2 / alone~e.38))) :ARG1 (i / increase-01~e.43 :ARG1~e.44 (a3 / activity-06~e.46 :ARG0 a :ARG1 (t2 / transcribe-01~e.45)) :medium (f3 / fragment~e.49 :mod (t3 / this~e.48)) :location~e.50 (c2 / cell-line~e.53 :name (n5 / name :op1 "NIH3T3"~e.52) :ARG1-of (t4 / transfect-01~e.51)) :ARG1-of (m3 / major-02~e.42))) :source~e.0 (t5 / text~e.2 :ARG1-of (f4 / full-09~e.1))) # ::id bel_pmid_1293_4012.22244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - The wee1 gene product phosphorylates Cdc2 on Tyr @-@ 15 [ p @-@ Cdc2( Tyr 15 )] and keeps it in an inactive form # ::alignments 0-1.3.r 1-1.3.1 2-1.3 5-1.1.2.1.1.1 6-1.1.2.1 7-1.1.2 8-1.1 8-1.2.2.4 9-1.1.1.3.1.1 11-1.1.1.2.1 13-1.1.1.1 15-1.1 18-1.1.1.2.1 18-1.2.2.2.1 19-1.1.1.1 19-1.2.2.1 21-1 22-1.2 24-1.2.2.r 26-1.2.2.5.1.1 27-1.2.2.5 (a / and~e.21 :op1 (p / phosphorylate-01~e.8,15 :ARG1 (a2 / amino-acid :mod 15~e.13,19 :name (n / name :op1 "tyrosine"~e.11,18) :part-of (e / enzyme :name (n2 / name :op1 "Cdc2"~e.9))) :ARG2 (p2 / product~e.7 :poss (g / gene~e.6 :name (n3 / name :op1 "wee1"~e.5)))) :op2 (k / keep-01~e.22 :ARG0 p2 :ARG1~e.24 (a4 / amino-acid :mod 15~e.19 :name (n5 / name :op1 "tyrosine"~e.18) :part-of e :ARG3-of (p3 / phosphorylate-01~e.8) :mod (f / form~e.27 :ARG1-of (a3 / activate-01 :polarity -~e.26)))) :source~e.0 (t / text~e.2 :ARG1-of (f2 / full-09~e.1))) # ::id bel_pmid_1293_4012.26132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - Furthermore , Cdc2 kinase activity was reduced ( Figs . 2B and 1C ) . Therefore , the cell cycle progression from S to M phase was impaired during liver regeneration in Cry @-@ deficient mice # ::alignments 0-1.3.r 1-1.3.1 2-1.3 4-1.1 4-1.1.2.1 6-1.1.1.1.1.1.1 7-1.1.1.1.1 8-1.1.1.1 10-1.1.1 14-1.1.2.1.1.1 15-1.1.2.1 16-1.1.2.1.2.1 19-1.2 22-1.2.1.1.1.1 23-1.2.1.1.1 24-1.2.1.1 25-1.2.1.1.2.r 25-1.3.r 26-1.2.1.1.2.1.1 27-1.2.1.1.3.r 28-1.2.1.1.3.1.1 29-1.2.1.1.3.1.2 31-1.2.1 32-1.2.1.2.r 33-1.2.1.2.1 34-1.2.1.2 35-1.2.1.2.2.r 36-1.2.1.2.2.1.1.1 38-1.2.1.2.2.1 38-1.2.1.2.2.1.2 38-1.2.1.2.2.1.2.1 38-1.2.1.2.2.1.2.1.r 38-1.2.1.2.2.1.2.r 39-1.2.1.2.2 (m / multi-sentence :snt1 (a / and~e.4 :op2 (r / reduce-01~e.10 :ARG1 (a2 / activity-06~e.8 :ARG1 (k / kinase~e.7 :name (n / name :op1 "Cdc2"~e.6)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.4,15 :op1 (f / figure :mod "2B"~e.14) :op2 (f2 / figure :mod "1C"~e.16)))) :snt2 (c / cause-01~e.19 :ARG1 (i / impair-01~e.31 :ARG1 (p / progress-01~e.24 :ARG1 (c2 / cycle-02~e.23 :ARG1 (c3 / cell~e.22)) :ARG3~e.25 (e / event :name (n2 / name :op1 "S"~e.26 :op2 "phase")) :ARG4~e.27 (e2 / event :name (n3 / name :op1 "M"~e.28 :op2 "phase"~e.29))) :time~e.32 (r2 / regenerate-01~e.34 :ARG1 (l / liver~e.33) :location~e.35 (m2 / mouse~e.39 :mod (p2 / protein~e.38 :name (n4 / name :op1 "Cry"~e.36) :ARG2-of~e.38 (m3 / mutate-01~e.38 :mod~e.38 "-/-"~e.38)))))) :source~e.0,25 (t3 / text~e.2 :ARG1-of (f3 / full-09~e.1))) # ::id bel_pmid_1293_4012.26134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - The expression profiles of cyclin D1 and wee1 transcripts were markedly different between Cry @-@ deficient and wildtype mice throughout the liver regeneration process : cyclin D1 expression decreased up to 86 % and wee1 expression increased up to 4.6 @-@ fold # ::alignments 0-1.8.r 1-1.8.1 2-1.8 5-1.3 6-1.1 6-1.2 7-1.1.1.r 8-1.1.1.1.1 9-1.1.1.1.2 10-1.5 11-1.2.1.1.1 14-1.4 15-1 16-1.5 17-1.5.1.1.1.1 19-1.5.1.1 19-1.5.1.1.2 19-1.5.1.1.2.1 19-1.5.1.1.2.1.r 19-1.5.1.1.2.r 20-1.5 21-1.5.2.1 22-1.5.1 22-1.5.2 25-1.6.1.1 26-1.6.1 27-1.6 29-1.7.1.1.1.1 30-1.7.1.1.1.1 31-1.7.1.1.1 32-1.7.1.1 33-1.7.1.1.2 34-1.7.1.1.2 35-1.7.1.1.2.1.1 36-1.7.1.1.2.1 37-1.3.1 37-1.7.1 38-1.2.1.1.1 39-1.3 39-1.7.1.2.1 40-1.7.1.2 41-1.7.1.2 42-1.7.1.2.2 43-1.7.1.2.2.1.1 45-1.7.1.2.2.1 (d / differ-02~e.15 :ARG1 (p / profile-01~e.6 :ARG1~e.7 (p2 / protein :name (n / name :op1 "cyclin"~e.8 :op2 "D1"~e.9) :ARG1-of (t / transcribe-01))) :ARG2 (p3 / profile-01~e.6 :ARG1 (p4 / protein :name (n2 / name :op1 "wee1"~e.11,38) :ARG1-of t)) :degree (e / express-03~e.5,39 :ARG2 (a / and~e.37 :op1 p2 :op2 p4)) :degree (m / marked~e.14) :location (b / between~e.10,16,20 :op1 (m2 / mouse~e.22 :mod (p5 / protein~e.19 :name (n3 / name :op1 "Cry"~e.17) :ARG2-of~e.19 (m3 / mutate-01~e.19 :mod~e.19 "-/-"~e.19))) :op2 (m4 / mouse~e.22 :mod (w / wild-type~e.21))) :time (p6 / process-02~e.27 :ARG1 (r / regenerate-01~e.26 :ARG1 (l / liver~e.25))) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and~e.37 :op1 (d2 / decrease-01~e.32 :ARG1 (e2 / express-03~e.31 :ARG1 p2~e.29,30) :ARG2 (u / up-to~e.33,34 :op1 (p7 / percentage-entity~e.36 :value 86~e.35))) :op2 (i / increase-01~e.40,41 :ARG1 (e3 / express-03~e.39 :ARG1 p4) :ARG2 (u2 / up-to~e.42 :op1 (p8 / product-of~e.45 :op1 4.6~e.43))))) :source~e.0 (t2 / text~e.2 :ARG1-of (f / full-09~e.1))) # ::id bel_pmid_1293_4012.32782 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - However , in Clock mutant ( Clock/Clock ) mice ( 26 ) , which carry dominantnegative Clock mutations ( 27 ) , wee1 expression was low at both ZTs # ::alignments 0-1.2.r 1-1.2.1 2-1.2 4-1 7-1.1.3.1.1.1 7-1.1.3.3.1.1.1 8-1.1.3.3.1 8-1.1.3.3.1.2 8-1.1.3.3.1.2.r 12-1.1.3 14-1.1.3.2.1.1.1 18-1.1.3.3 20-1.1.3.3.1.1.1 21-1.1.3.3.1 21-1.1.3.3.1.2 21-1.1.3.3.1.2.r 23-1.1.3.3.2.1.1.1 26-1.1.1.1.1.1 27-1.1.1 29-1.1 31-1.1.2.1 (h / have-concession-91~e.4 :ARG1 (l / low-04~e.29 :ARG1 (e / express-03~e.27 :ARG2 (p / protein :name (n / name :op1 "wee1"~e.26))) :time (z / zeitgeber-time :mod (b / both~e.31)) :location (m / mouse~e.12 :mod (g / gene :name (n2 / name :op1 "Clock"~e.7) :mod (w / wild-type)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 26~e.14))) :ARG0-of (c2 / carry-01~e.18 :ARG1 (g2 / gene~e.8,21 :name (n3 / name :op1 "Clock"~e.7,20) :ARG2-of~e.8,21 (m3 / mutate-01~e.8,21 :mod "-/-")) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 27~e.23)))))) :source~e.0 (t / text~e.2 :ARG1-of (f / full-09~e.1))) # ::id bel_pmid_1295_7325.25184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Studies crossing PPAR-–deficient mice with apolipoprotein E atherosclerosis @-@ prone mice and placing them on high @-@ fat diets found less atherosclerosis , despite the PPAR @- null mice having higher atherogenic lipids.101 # ::alignments 0-1.1 1-1.1.1 3-1.1.1.1.2 4-1.1.2.2.1.r 5-1.1.1.1.2.2.1.1 6-1.1.1.1.2.2.1.2 7-1.1.1.1.2.1.1.1.1 9-1.1.1.1.2.1 10-1.1.1.1.2 11-1.1.1.1 12-1.1.2 15-1.1.2.2.1.1 17-1.1.2.2.1 18-1.1.2.2 19-1 20-1.2.2 21-1.2.1.1 23-1.3.r 25-1.1.1.1.1.1.1.1 27-1.1.1.1.1.1 27-1.1.1.1.1.1.2 27-1.1.1.1.1.1.2.1 27-1.1.1.1.1.1.2.1.r 27-1.1.1.1.1.1.2.r 28-1.1.1.1.1 29-1.3 30-1.3.2.2 30-1.3.2.2.1 30-1.3.2.2.1.r 31-1.3.2.1 (f / find-01~e.19 :ARG0 (s / study-01~e.0 :ARG0-of (c / cross-01~e.1 :ARG1 (a / and~e.11 :op1 (m / mouse~e.28 :mod (p / protein~e.27 :name (n / name :op1 "PPAR"~e.25) :ARG2-of~e.27 (m2 / mutate-01~e.27 :mod~e.27 "-/-"~e.27))) :op2 (m3 / mouse~e.3,10 :ARG1-of (p2 / prone-01~e.9 :ARG2 (d / disease :name (n2 / name :op1 "atherosclerosis"~e.7))) :mod (p3 / protein :name (n3 / name :op1 "apolipoprotein"~e.5 :op2 "E"~e.6))))) :ARG0-of (p4 / place-01~e.12 :ARG1 a :ARG2 (d2 / diet~e.18 :instrument~e.4 (f2 / fat~e.17 :ARG1-of (h / high-02~e.15))))) :ARG1 (d3 / disease :name (n4 / name :op1 "atherosclerosis"~e.21) :quant (l / less~e.20)) :concession~e.23 (h3 / have-03~e.29 :ARG0 m :ARG1 (l2 / lipid :mod (a2 / atherogenic~e.31) :ARG1-of (h4 / high-02~e.30 :degree~e.30 (m4 / more~e.30)))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 101)))) # ::id bel_pmid_1295_7325.30032 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These investigators went on to demonstrate that interleukin @-@ 6 production is increased in aortic explants of PPAR-–deficient mice.95 # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1 5-1.2 6-1.2.2.r 7-1.2.2.1.1.1.1 9-1.2.2.1.1.1.1 10-1.2.2.1 12-1.2.2 (g / go-on-15~e.2,3 :ARG1 (p / person~e.1 :ARG0-of~e.1 (i / investigate-01~e.1) :mod (t / this~e.0)) :purpose (d / demonstrate-01~e.5 :ARG0 p :ARG1~e.6 (i2 / increase-01~e.12 :ARG1 (p2 / produce-01~e.10 :ARG1 (p3 / protein :name (n / name :op1 "interleukin-6"~e.7,9))) :location (e / explant :part-of (a / aorta :part-of (m / mouse :mod (p4 / protein :name (n2 / name :op1 "PPAR") :ARG2-of (m2 / mutate-01 :mod "-/-"))))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 95)))) # ::id bel_pmid_1463_5034.19774 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As demonstrated in Fig. 3A , blockade of the OX40 @/@ OX40L interaction significantly reduced the Th1 @-@ specific transcription factor T @-@ bet to 30.8 % compared with controls ( p= 0.007 ) . On the other hand , expression of IL @-@ 10 , a cytokine that was shown to be protective in chronic DSS @-@ induced colitis [ 29 ] , increased 3.6 @-@ fold ( p= 0.008 ) . # ::alignments 1-1.1.6 2-1.1.6.1.r 3-1.1.6.1 4-1.1.6.1.1 6-1.1.1 7-1.1.1.1.r 9-1.1.1.1.1.1.1 11-1.1.1.1.2.1.1 12-1.1.1.1 13-1.1.3 14-1.1 16-1.1.2.3.1.1.1 18-1.1.2.3 19-1.1.2 19-1.1.2.2 19-1.1.2.2.r 21-1.1.2.1.1 23-1.1.2.1.1 24-1.1.4.r 25-1.1.4.1 26-1.1.4 27-1.1.5 28-1.1.5.1.r 29-1.1.5.1 31-1.1.7 32-1.1.7.1 40-1.2.1.1 41-1.2.1.1.1.r 42-1.2.1.1.1.1.1 44-1.2.1.1.1.1.1 47-1.2.1.1.1.2.1 50-1.2.1.1.1.2.1.1.1 53-1.2.1.1.1.2.1.1 54-1.2.1.1.1.2.1.1.2.r 55-1.2.1.1.1.2.1.1.2.2 56-1.2.1.1.1.2.1.1.2.3.1.1.1 58-1.2.1.1.1.2.1.1.2.3 59-1.2.1.1.1.2.1.1.2.1.1 61-1.2.1.1.1.2.2.1.1.1 64-1.2.1 65-1.2.1.2.1 67-1.2.1.2 69-1.2.1.3 70-1.2.1.3.1 (m / multi-sentence :snt1 (r / reduce-01~e.14 :ARG0 (b / blockade-01~e.6 :ARG1~e.7 (i / interact-01~e.12 :ARG0 (p8 / protein :name (n / name :op1 "OX40"~e.9)) :ARG1 (p9 / protein :name (n2 / name :op1 "OX40L"~e.11)))) :ARG1 (p2 / protein~e.19 :name (n3 / name :op1 "T-bet"~e.21,23) :ARG0-of~e.19 (t / transcribe-01~e.19) :ARG1-of (s / specific-02~e.18 :ARG2 (p7 / protein :name (n4 / name :op1 "Th1"~e.16)))) :ARG2 (s2 / significant-02~e.13) :ARG4~e.24 (p / percentage-entity~e.26 :value 30.8~e.25) :ARG1-of (c2 / compare-01~e.27 :ARG2~e.28 (c3 / control-01~e.29)) :ARG1-of (d / demonstrate-01~e.1 :ARG0~e.2 (f2 / figure~e.3 :mod "3A"~e.4)) :ARG1-of (s4 / statistical-test-91~e.31 :ARG2 0.007~e.32)) :snt2 (c4 / contrast-01 :ARG2 (i2 / increase-01~e.64 :ARG1 (e / express-03~e.40 :ARG2~e.41 (p3 / protein :name (n5 / name :op1 "IL-10"~e.42,44) :ARG1-of (m4 / mean-01 :ARG2 (c5 / cytokine~e.47 :ARG0-of (p4 / protect-01~e.53 :ARG1-of (s3 / show-01~e.50) :location~e.54 (d2 / disease :name (n6 / name :op1 "colitis"~e.59) :mod (c6 / chronic~e.55) :ARG2-of (i3 / induce-01~e.58 :ARG0 (s6 / small-molecule :name (n7 / name :op1 "DSS"~e.56)))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c7 / cite-01 :ARG2 29~e.61)))))) :ARG2 (p6 / product-of~e.67 :op1 3.6~e.65) :ARG1-of (s5 / statistical-test-91~e.69 :ARG2 0.008~e.70)))) # ::id bel_pmid_1463_5034.19776 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @- 10 secretion increased 20 @-@ fold ( p X 0.0001 ) . This was accompanied by a significant , 18 @-@ fold , increase of IL @-@ 5 secretion . IFNG levels were not altered , but IL @-@ 6 secretion was reduced to 60 % compared with controls . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 3-1.2.1.1 4-1.1 5-1.1.2.1 7-1.1.2 9-1.1.3 10-1.1.1.1.1.1 11-1.1.3.1.1 14-1.2.2 16-1.2 17-1.2.1.r 19-1.2.1.3 21-1.2.1.2.1 23-1.2.1.2 25-1.2.1 26-1.2.1.1.1.r 26-1.2.1.2 27-1.2.1.1.1.1.1 29-1.2.1.1.1.1.1 30-1.1.1 33-1.3.2.2 35-1.3.2.1 35-1.3.2.1.r 36-1.3.2 38-1.3 39-1.3.1.1.1.1.1 41-1.3.1.1.1.1.1 42-1.3.1.1 44-1.3.1 45-1.3.1.2.r 46-1.3.1.2.1 47-1.3.1.2 48-1.3.1.3 49-1.3.1.3.1.r 50-1.3.1.3.1 (m / multi-sentence :snt1 (i / increase-01~e.4 :ARG1 (s / secrete-01~e.3,30 :ARG1 (p / protein :name (n / name :op1 "IL-10"~e.0,2,10))) :ARG2 (p2 / product-of~e.7 :op1 20~e.5) :ARG1-of (s5 / statistical-test-91~e.9 :ARG2 (l / less-than :op1 0.0001~e.11))) :snt2 (a / accompany-01~e.16 :ARG0~e.17 (i2 / increase-01~e.25 :ARG1 (s2 / secrete-01~e.3 :ARG1~e.26 (p4 / protein :name (n2 / name :op1 "IL-5"~e.27,29))) :ARG2 (p5 / product-of~e.23,26 :op1 18~e.21) :ARG1-of (s3 / significant-02~e.19)) :ARG1 (t / this~e.14)) :snt3 (c / contrast-01~e.38 :ARG1 (r / reduce-01~e.44 :ARG1 (s4 / secrete-01~e.42 :ARG1 (p6 / protein :name (n3 / name :op1 "IL-6"~e.39,41))) :ARG4~e.45 (p7 / percentage-entity~e.47 :value 60~e.46) :ARG1-of (c2 / compare-01~e.48 :ARG2~e.49 (c3 / control-01~e.50))) :ARG2 (a2 / alter-01~e.36 :polarity~e.35 -~e.35 :ARG1 (l2 / level~e.33 :quant-of (p8 / protein :name (n4 / name :op1 "IFN-γ")))))) # ::id bel_pmid_1465_6721.15754 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In neutrophils challenged with LPS , IkB @-@ a underwent time @-@ dependent degradation ( Fig . 8C ) . However , in neutrophils incubated with both LPS and H2O2 , no degradation of IkB @-@ a was apparent . # ::alignments 1-1.1.3.1.1 2-1.1.3.2 3-1.1.3.2.1.r 4-1.1.3.2.1 9-1.1 10-1.1.2.2.1 12-1.1.2.2 13-1.1.2 15-1.1.4.1 17-1.1.4.1.1 20-1.2 23-1.2.1.3.1.1 24-1.2.1.3.2 27-1.2.1.3.2.1.1 28-1.2.1.3.2.1 29-1.2.1.3.2.1.2.1.1 31-1.2.1.1 31-1.2.1.1.r 32-1.2.1.2 38-1.2.1 (m / multi-sentence :snt1 (u / undergo-28~e.9 :ARG1 (p / protein :name (n / name :op1 "IκB-α")) :ARG2 (d / degrade-01~e.13 :ARG1 p :ARG0-of (d2 / depend-01~e.12 :ARG1 (t / time~e.10))) :location (c / cell :name (n2 / name :op1 "neutrophil"~e.1) :ARG1-of (c2 / challenge-01~e.2 :ARG0~e.3 (l / lipopolysaccharide~e.4))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.15 :mod "8C"~e.17))) :snt2 (h / have-concession-91~e.20 :ARG1 (a / appear-02~e.38 :polarity~e.31 -~e.31 :ARG1 (d4 / degrade-01~e.32 :ARG1 (p2 / protein :name (n4 / name :op1 "IκB-α"))) :location (c3 / cell :name (n5 / name :op1 "neutrophil"~e.23) :ARG1-of (i / incubate-01~e.24 :ARG2 (a2 / and~e.28 :op1 (l2 / lipopolysaccharide~e.27) :op2 (s / small-molecule :name (n7 / name :op1 "H2O2"~e.29)))))))) # ::id bel_pmid_1465_6721.15758 ::amr-annotator SDL-AMR-09 ::preferred # ::tok neutrophils stimulated with LPS demonstrated increased TNF @-@ a secretion ( Fig . 6A ) . The response was significantly attenuated by concurrent incubation of neutrophils with H2O2 . # ::alignments 0-1.1.1.1.1 1-1.1.1.2 2-1.1.1.2.1.r 3-1.1.1.2.1.1.1 4-1.1 5-1.1.2.2 6-1.1.2.1.1.1 9-1.1.2 11-1.1.3.1 13-1.1.3.1.1 17-1.2.2 17-1.2.2.1 17-1.2.2.1.r 19-1.2.3 20-1.2 21-1.2.1.r 22-1.2.1.2 22-1.2.1.2.2 22-1.2.1.2.2.r 23-1.2.1 24-1.2.1.1.r 25-1.2.1.1.1.1 27-1.2.1.2.1.1 (m / multi-sentence :snt1 (d / demonstrate-01~e.4 :ARG0 (c / cell :name (n / name :op1 "neutrophil"~e.0) :ARG1-of (s / stimulate-01~e.1 :ARG2~e.2 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.3)))) :ARG1 (s2 / secrete-01~e.9 :ARG1 (p / protein :name (n3 / name :op1 "TNF-α"~e.6)) :ARG1-of (i / increase-01~e.5)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.11 :mod "6A"~e.13))) :snt2 (a / attenuate-01~e.20 :ARG0~e.21 (i2 / incubate-01~e.23 :ARG1~e.24 (c2 / cell :name (n4 / name :op1 "neutrophil"~e.25)) :ARG2 (s4 / small-molecule~e.22 :name (n5 / name :op1 "H2O2"~e.27) :ARG1-of~e.22 (c3 / concurrent-02~e.22))) :ARG1 (t / thing~e.17 :ARG2-of~e.17 (r / respond-01~e.17)) :ARG1-of (s3 / significant-02~e.19))) # ::id bel_pmid_1465_6721.15794 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As was the case for p38 , ERK1 @/@ 2 was both rapidly and persistently activated in neutrophils exposed to H2O2 ( Fig . 2A ) . # ::alignments 5-1.4.1.1.1 7-1.1.1.1 9-1.1.1.1 12-1.3.1 13-1.3 14-1.3.2 15-1 16-1.2.r 17-1.2.1.1 18-1.2.2 19-1.2.2.1.r 20-1.2.2.1.1.1 22-1.5.1 24-1.5.1.1 (a / activate-01~e.15 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.7,9)) :location~e.16 (c / cell :name (n2 / name :op1 "neutrophil"~e.17) :ARG1-of (e2 / expose-01~e.18 :ARG2~e.19 (s / small-molecule :name (n3 / name :op1 "H2O2"~e.20)))) :manner (a2 / and~e.13 :op1 (r / rapid~e.12) :op2 (p / persistent~e.14)) :ARG1-of (r2 / resemble-01 :ARG2 (e3 / enzyme :name (n4 / name :op1 "p38"~e.5))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.22 :mod "2A"~e.24))) # ::id bel_pmid_1465_6721.15796 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to the patterns seen with ERK1 @/@ 2 and p38 , JNK activation in neutrophils exposed to H2O2 was both rapid and persistent ( Fig . 2B ) . # ::alignments 0-1.4 1-1.4.1.r 3-1.4.1 4-1.4.1.1 5-1.4.1.2.r 6-1.4.1.2.1.1.1 8-1.4.1.2.1.1.1 9-1.4.1.2 10-1.4.1.2.2.1.1 12-1.3.1.1.1 13-1.3 14-1.3.2.r 15-1.3.2.1.1 16-1.3.2.2 17-1.3.2.2.1.r 18-1.3.2.2.1.1.1 19-1.3.r 21-1.1 22-1 23-1.2 25-1.5.1 27-1.5.1.1 (a / and~e.22 :op1 (r / rapid~e.21) :op2 (p / persistent~e.23) :domain~e.19 (a2 / activate-01~e.13 :ARG1 (e / enzyme :name (n / name :op1 "JNK"~e.12)) :location~e.14 (c / cell :name (n2 / name :op1 "neutrophil"~e.15) :ARG1-of (e2 / expose-01~e.16 :ARG2~e.17 (s2 / small-molecule :name (n3 / name :op1 "H2O2"~e.18))))) :ARG1-of (r2 / resemble-01~e.0 :ARG2~e.1 (p2 / pattern~e.3 :ARG1-of (s / see-01~e.4) :poss~e.5 (a3 / and~e.9 :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1/2"~e.6,8)) :op2 (e4 / enzyme :name (n5 / name :op1 "p38"~e.10))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "2B"~e.27))) # ::id bel_pmid_1465_6721.15930 ::amr-annotator SDL-AMR-09 ::preferred # ::tok whereas exposure of neutrophils to LPS or TNF @-@ a resulted in increased levels of the transcriptionally active serine 133 @-@ phosphorylated form of CREB # ::alignments 0-1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1.1.2.r 5-1.1.1.2.1.1.1 6-1.1.1.2 7-1.1.1.2.2.1.1 10-1.1 11-1.1.2.r 12-1.1.2.1 13-1.1.2 14-1.1.2.2.r 16-1.1.2.2.4.1 17-1.1.2.2 17-1.1.2.2.4 17-1.1.2.2.4.r 18-1.1.2.2.2.2.1 19-1.1.2.2.2.1 21-1.1.2.2.3 24-1.1.2.2.1.1 (c / contrast-01~e.0 :ARG2 (r / result-01~e.10 :ARG1 (e / expose-01~e.1 :ARG1~e.2 (c2 / cell :name (n / name :op1 "neutrophil"~e.3)) :ARG2~e.4 (o / or~e.6 :op1 (m / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.5)) :op2 (p / protein :name (n3 / name :op1 "TNF-α"~e.7)))) :ARG2~e.11 (l / level~e.13 :ARG1-of (i / increase-01~e.12) :quant-of~e.14 (p2 / protein~e.17 :name (n4 / name :op1 "CREB"~e.24) :part (a / amino-acid :mod 133~e.19 :name (n5 / name :op1 "serine"~e.18)) :ARG1-of (p3 / phosphorylate-01~e.21) :ARG0-of~e.17 (a2 / activity-06~e.17 :manner (t / transcribe-01~e.16)))))) # ::id bel_pmid_1465_6721.15966 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exposure of neutrophils to LPS resulted in persistence of p38 activation that was similar to that produced by H2O2 , but the increase in phosphorylated p38 was less rapid , rising above baseline values more than 5 min after LPS was added to the neutrophils . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.2.r 4-1.1.1.2.1.1 5-1.1 6-1.1.2.r 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.1.1 10-1.1.2.1 13-1.1.2.2 16-1.1.2.2.1 17-1.1.2.2.1.1.r 18-1.1.2.2.1.1.1.1 20-1 22-1.2.2 23-1.2.2.1.r 24-1.2.2.1.3 25-1.2.2.1.1.1 26-1.2.2.r 27-1.2.1 28-1.2 30-1.2.2.1.2 31-1.2.2.1.2.1 32-1.2.2.1.2.1.1.1 33-1.2.2.1.2.1.1 34-1.2.2.1.2.2.2 35-1.2.2.1.2.2.2 36-1.2.2.1.2.2.2.1.1 37-1.2.2.1.2.2.2.1.2 38-1.2.2.1.2.2 39-1.2.2.1.2.2.1.1 40-1.2.2.r 41-1.2.2.1.2.2.1 42-1.2.2.1.2.2.1.2.r 44-1.2.2.1.2.2.1.2 (c / contrast-01~e.20 :ARG1 (r / result-01~e.5 :ARG1 (e / expose-01~e.0 :ARG1~e.1 (c2 / cell :name (n / name :op1 "neutrophil"~e.2)) :ARG2~e.3 (m / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.4))) :ARG2~e.6 (p / persist-01~e.7 :ARG1~e.8 (a / activate-01~e.10 :ARG1 (e2 / enzyme :name (n3 / name :op1 "p38"~e.9))) :ARG1-of (r2 / resemble-01~e.13 :ARG2 (p2 / produce-01~e.16 :ARG0~e.17 (s / small-molecule :name (n4 / name :op1 "H2O2"~e.18)) :ARG1 p)))) :ARG2 (r3 / rapid~e.28 :degree (l / less~e.27) :domain~e.26,40 (i / increase-01~e.22 :ARG1~e.23 (e3 / enzyme :name (n5 / name :op1 "p38"~e.25) :ARG1-of (r4 / rise-01~e.30 :ARG4 (a2 / above~e.31 :op1 (v / value~e.33 :mod (b / baseline~e.32))) :time (a3 / after~e.38 :op1 (a4 / add-02~e.41 :ARG1 m~e.39 :ARG2~e.42 c2~e.44) :op1 (m2 / more-than~e.34,35 :op1 (t / temporal-quantity :quant 5~e.36 :unit (m3 / minute~e.37))))) :ARG3-of (p3 / phosphorylate-01~e.24))))) # ::id bel_pmid_1465_6721.15968 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of ERK1 @/@ 2 after exposure of neutrophils with LPS was only apparent after 20 @-@ min incubation and was less intense than that produced by stimulation of neutrophils with H2O2 . # ::alignments 0-1.1.1 0-1.2.3 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1.2 6-1.1.1.2.1 7-1.1.1.2.1.1.r 8-1.1.1.2.1.1.1.1 9-1.1.1.2.1.2.r 10-1.1.1.2.1.2.1.1 12-1.1.2 13-1.1 14-1.1.3 15-1.1.3.1.1.1 17-1.1.3.1.1.2 18-1.1.3.1 19-1 21-1.2.2 22-1.2 23-1.2.3.r 25-1.2.3.2 26-1.2.3.2.1.r 27-1.2.3.2.1 28-1.2.3.2.1.1.r 29-1.2.3.2.1.1 30-1.2.3.2.1.2.r 31-1.2.3.2.1.2.1.1 (a / and~e.19 :op1 (a2 / appear-02~e.13 :ARG1 (p / phosphorylate-01~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.2,4)) :time (a3 / after~e.5 :op1 (e2 / expose-01~e.6 :ARG1~e.7 (c / cell :name (n2 / name :op1 "neutrophil"~e.8)) :ARG2~e.9 (m / molecular-physical-entity :name (n3 / name :op1 "LPS"~e.10))))) :mod (o / only~e.12) :time (a4 / after~e.14 :op1 (i / incubate-01~e.18 :duration (t / temporal-quantity :quant 20~e.15 :unit (m2 / minute~e.17))))) :op2 (i2 / intense-02~e.22 :ARG1 p :degree (l / less~e.21) :compared-to~e.23 (p2 / phosphorylate-01~e.0 :ARG1 e :ARG1-of (p3 / produce-01~e.25 :ARG0~e.26 (s / stimulate-01~e.27 :ARG1~e.28 c~e.29 :ARG2~e.30 (s2 / small-molecule :name (n4 / name :op1 "H2O2"~e.31))))))) # ::id bel_pmid_1465_6721.15970 ::amr-annotator SDL-AMR-09 ::preferred # ::tok JNK activation induced by LPS only became apparent 20 min after LPS was added to the cells and was of a lesser degree than that induced by H2O2 at all time points . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 1-1.2 1-1.2.4 2-1.1.1.2 2-1.2.4.2 3-1.1.1.2.r 4-1.1.1.2.1.1.1 5-1.1.3 6-1.1 7-1.1.2 8-1.1.4.2.1 9-1.1.4.2.2 10-1.1.4 11-1.1.4.1.1 13-1.1.4.1 14-1.1.4.1.2.r 16-1.1.4.1.2 17-1 19-1.2.3.r 21-1.2.3 21-1.2.3.1 21-1.2.3.1.r 22-1.2.3.1.r 23-1.2.4.r 25-1.1.1.2 26-1.2.4.2.1.r 27-1.2.4.2.1.1.1 30-1.1.4.2 (a / and~e.17 :op1 (b / become-01~e.6 :ARG1 (a2 / activate-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "JNK"~e.0)) :ARG2-of~e.3 (i / induce-01~e.2,25 :ARG0 (m / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.4)))) :ARG2 (a3 / appear-02~e.7 :ARG1 a2) :mod (o / only~e.5) :time (a4 / after~e.10 :op1 (a5 / add-02~e.13 :ARG1 m~e.11 :ARG2~e.14 (c / cell~e.16)) :quant (t / temporal-quantity~e.30 :quant 20~e.8 :unit (m2 / minute~e.9)))) :op2 (a8 / activate-01~e.1 :ARG1 e :ARG2-of i :degree~e.19 (l / less~e.21 :degree~e.21,22 (m3 / more~e.21) :time (a7 / always)) :compared-to~e.23 (a6 / activate-01~e.1 :ARG1 e :ARG2-of (i2 / induce-01~e.2 :ARG0~e.26 (s / small-molecule :name (n3 / name :op1 "H2O2"~e.27)))))) # ::id bel_pmid_1465_7354.10332 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further , evidence is presented for TGF @-@ beta @-@ stimulated p160ROCK translocation to the nucleus and inhibitory phosphorylation of the cyclin @-@ dependent kinase @-@ activating phosphatase , Cdc25A . # ::alignments 0-1.2 2-1.1 4-1 5-1.1.1.r 6-1.1.1.1.1.2.1.1.1 8-1.1.1.1.1.2.1.1.1 10-1.1.1.1.1.2 11-1.1.1.1.1.1.1 12-1.1.1.1 13-1.1.1.1.2.r 15-1.1.1.1.2 16-1.1.1 17-1.1.1.2.3 18-1.1.1.2 19-1.1.1.2.2.r 21-1.1.1.2.2.1 23-1.1.1.2.2 24-1.1.1.2.2.1.1.1 26-1.1.1.2.2.1.1 27-1.1.1.2.1 29-1.1.1.2.1.1.1 (p / present-01~e.4 :ARG1 (e / evidence-01~e.2 :ARG1~e.5 (a / and~e.16 :op1 (t / translocate-01~e.12 :ARG1 (p2 / protein :name (n / name :op1 "p160ROCK"~e.11) :ARG1-of (s / stimulate-01~e.10 :ARG0 (p4 / protein :name (n2 / name :op1 "TGF-beta"~e.6,8)))) :ARG2~e.13 (n3 / nucleus~e.15)) :op2 (p3 / phosphorylate-01~e.18 :ARG1 (p6 / phosphatase~e.27 :name (n4 / name :op1 "Cdc25A"~e.29)) :ARG0-of~e.19 (d / depend-01~e.23 :ARG1 (c / cyclin~e.21 :ARG0-of (a2 / activate-01~e.26 :ARG1 (k / kinase~e.24)))) :ARG0-of (i / inhibit-01~e.17)))) :mod (f / further~e.0)) # ::id bel_pmid_1467_1317.33588 ::amr-annotator SDL-AMR-09 ::preferred # ::tok p57Kip2 ( Cdkn1c ) is expressed in postmitotic differentiating midbrain dopamine cells . Induction of p57Kip2 expression depends on Nurr1 , # ::alignments 0-1.1.1.1.1 0-1.2.1.1.1.1.1 2-1.1.1.2.1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.3 8-1.1.2.4 9-1.1.2.2 10-1.1.2.1 11-1.1.2 13-1.2.1 14-1.2.1.1.r 15-1.2.1.1.1.1.1 16-1.2.1.1 17-1.2 18-1.2.2.r 19-1.2.2.1.1 (m3 / multi-sentence :snt1 (e / express-03~e.5 :ARG2 (p / protein :name (n / name :op1 "p57Kip2"~e.0) :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Cdkn1c"~e.2)))) :ARG3~e.6 (c / cell~e.11 :mod (d / dopamine~e.10) :mod (m2 / midbrain~e.9) :mod (p3 / postmitotic~e.7) :ARG0-of (d2 / differentiate-01~e.8))) :snt2 (d3 / depend-01~e.17 :ARG0 (i / induce-01~e.13 :ARG2~e.14 (e2 / express-03~e.16 :ARG2 (p5 / protein :name (n4 / name :op1 "p57Kip2"~e.0,15)))) :ARG1~e.18 (p4 / protein :name (n3 / name :op1 "Nurr1"~e.19)))) # ::id bel_pmid_1475_9523.36890 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression of MUP2 is known to be stimulated by growth hormone ( GH ) , through the GH receptor ( GHR ) , Janus kinase 2 ( JAK2 ) and signal transducer and activator of transcription 5 ( STAT5 ) signal transduction pathway . # ::alignments 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1.1.1 5-1 8-1.1 9-1.1.1.r 10-1.1.1.1.1 11-1.1.1.1.2 13-1.1.3.1.1.1 18-1.1.3.1.1.1 19-1.1.3.1 24-1.1.3.2.1.1 25-1.1.3.2.1.2 26-1.1.3.2.1.3 30-1.1.3 31-1.1.3.3.1.1 32-1.1.3.3.1.2 33-1.1.3.3.1.3 34-1.1.3.3.1.4 35-1.1.3.3.1.5 36-1.1.3.3.1.6 37-1.1.3.3.1.7 41-1.1.3.3.2 42-1.1.3.3.2.1 43-1.1.3.3 (k / know-01~e.5 :ARG1 (s / stimulate-01~e.8 :ARG0~e.9 (s2 / small-molecule :name (n3 / name :op1 "growth"~e.10 :op2 "hormone"~e.11)) :ARG1 (e / express-03~e.1 :ARG2~e.2 (p / protein :name (n / name :op1 "MUP2"~e.3))) :ARG2 (a / and~e.30 :op1 (r / receptor~e.19 :name (n2 / name :op1 "GH"~e.13,18)) :op2 (e2 / enzyme :name (n4 / name :op1 "Janus"~e.24 :op2 "kinase"~e.25 :op3 2~e.26)) :op3 (p2 / pathway~e.43 :name (n5 / name :op1 "signal"~e.31 :op2 "transducer"~e.32 :op3 "and"~e.33 :op4 "activator"~e.34 :op5 "of"~e.35 :op6 "transcription"~e.36 :op7 5~e.37) :ARG0-of (s3 / signal-07~e.41 :ARG1-of (t / transduce-01~e.42)))))) # ::id bel_pmid_1496_3018.30938 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation at Ser727 in signal transducer and activator of transcription 1 ( STAT1 ) is essential for its activation and signal transduction . # ::alignments 0-1.1 3-1.1.1.r 4-1.1.1.3.1.1 5-1.1.1.3.1.2 6-1.1.1.3.1.3 7-1.1.1.3.1.4 8-1.1.1.3.1.5 9-1.1.1.3.1.6 10-1.1.1.3.1.7 14-1.1.r 15-1 16-1.2.r 17-1.2.1.1 17-1.2.1.1.r 18-1.2.1 19-1.2 20-1.2.2.1 21-1.2.2 (e / essential~e.15 :domain~e.14 (p / phosphorylate-01~e.0 :ARG1~e.3 (a / amino-acid :mod 727 :name (n / name :op1 "serine") :part-of (p2 / protein :name (n2 / name :op1 "signal"~e.4 :op2 "transducer"~e.5 :op3 "and"~e.6 :op4 "activator"~e.7 :op5 "of"~e.8 :op6 "transcription"~e.9 :op7 1~e.10)))) :purpose~e.16 (a2 / and~e.19 :op1 (a3 / activate-01~e.18 :ARG1~e.17 p2~e.17) :op2 (t / transduce-01~e.21 :ARG1 (s / signal-07~e.20)))) # ::id bel_pmid_1496_3018.37018 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S @-@ transferase pull down show that active ERK1 , JNK1 , p38 kinase , MEK1 and MSK1 stimulated phosphorylation of STAT1 ( Ser727 ) indirectly through an unidentified factor or a downstream kinase . # ::alignments 0-1.1.2 1-1.1.2 2-1.1.1 3-1.1 4-1.1.3 6-1.1.3.1.2 7-1.1.3.1.1.1 8-1.1.3.1 9-1.1.3.2.r 10-1.1.3.2 11-1.1.3.2.1.r 12-1.1.3.2.1.1 13-1.1.3.2.1 14-1.1.3.2.1.2.1.1.1 15-1.1.3.2.1.2.1.1.2 17-1.1.3.2.1.2.1.1.2 18-1.1.3.2.1.2 19-1.1.3.2.1.2 20-1 21-1.2.r 22-1.2.4 23-1.2.1.1.1.1 25-1.2.1.2.1.1 27-1.2.1.3.1.1 28-1.2.1.3.1.2 30-1.2.1.4.1.1 31-1.2.1 32-1.2.1.5.1.1 33-1.2 34-1.2.2 36-1.1.3.1.1.1 40-1.2.3 40-1.2.3.1 43-1.2.2.2.1.1 43-1.2.2.2.1.1.1 43-1.2.2.2.1.1.1.r 43-1.2.3.1.r 44-1.2.2.2.1 45-1.2.2.2 47-1.2.2.2.2.1 48-1.2.2.2.2 (s / show-01~e.20 :ARG0 (a / assay-01~e.3 :ARG1 (k / kinase~e.2) :manner (i / in-vitro~e.0,1) :ARG0-of (u / use-01~e.4 :ARG1 (p / protein~e.8 :name (n / name :op1 "STAT1"~e.7,36) :ARG3-of (c / combine-01~e.6)) :ARG2~e.9 (s2 / substrate~e.10 :source~e.11 (a2 / and~e.13 :op1 (i2 / immunoprecipitate-01~e.12) :op2 (p2 / pull-down-08~e.18,19 :ARG1 (e / enzyme :name (n2 / name :op1 "glutathione"~e.14 :op2 "S-transferase"~e.15,17))))))) :ARG1~e.21 (s3 / stimulate-01~e.33 :ARG0 (a3 / and~e.31 :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1"~e.23)) :op2 (e3 / enzyme :name (n4 / name :op1 "JNK1"~e.25)) :op3 (e6 / enzyme :name (n5 / name :op1 "p38"~e.27 :op2 "kinase"~e.28)) :op4 (e4 / enzyme :name (n6 / name :op1 "MEK1"~e.30)) :op5 (e5 / enzyme :name (n7 / name :op1 "MSK1"~e.32))) :ARG1 (p3 / phosphorylate-01~e.34 :ARG1 (a4 / amino-acid :mod 727 :name (n8 / name :op1 "serine") :part-of p) :ARG2 (o / or~e.45 :op1 (f / factor~e.44 :ARG1-of (i4 / identify-01~e.43 :polarity~e.43 -~e.43)) :op2 (k3 / kinase~e.48 :mod (d / downstream~e.47)))) :ARG1-of (d2 / direct-02~e.40 :polarity~e.43 -~e.40) :ARG0-of (a5 / activity-06~e.22))) # ::id bel_pmid_1496_6563.336 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inactivation of Icmt inhibited cell growth and K @-@ Ras @-@ induced oncogenic transformation , both in soft agar assays and in a nude mice model . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.2.r 2-1.1.2.1.1 3-1.1.3 4-1.1.3.1.1 5-1.1.3.1 6-1 6-1.1.3.2 7-1.2.2.1.1.1 9-1.2.2.1.1.1 11-1.2.2 12-1.2.3 12-1.2.3.1.2.1 13-1.2 16-1.1.3.2.r 17-1.1.3.2.1.1.1 18-1.1.3.2.1.1 19-1.1.3.2.1 20-1.1.3.2 23-1.1.3.2.2.2 24-1.1.3.2.2.1 25-1.1.3.2.2 (a2 / and~e.6 :op1 (a / activate-01~e.0 :polarity~e.0 -~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "Icmt"~e.2)) :ARG0-of (i / inhibit-01~e.3 :ARG1 (g / grow-01~e.5 :ARG1 (c / cell~e.4)) :location~e.16 (a5 / and~e.6,20 :op1 (a3 / assay-01~e.19 :ARG1 (a4 / agar~e.18 :ARG1-of (s / soft-02~e.17))) :op2 (m / model~e.25 :topic (m2 / mouse~e.24) :mod (n3 / nude~e.23))))) :op2 (t / transform-01~e.13 :ARG1 c :ARG2-of (i2 / induce-01~e.11 :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.7,9))) :ARG0-of (c2 / cause-01~e.12 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.12))))) # ::id bel_pmid_1496_6563.338 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The effect of inactivating Icmt was not limited to the inhibition of K @-@ Ras @-@ induced transformation : inactivation of Icmt blocked transformation by an oncogenic form of B @-@ Raf # ::alignments 1-1.1.2 3-1.1.1 4-1.1.2.1.2.1.1 6-1.1.1 6-1.1.1.r 6-1.1.2.1.1.r 7-1.1 8-1.1.3.r 10-1.1.3 11-1.1.3.1.r 12-1.1.3.1.1.1.1.1 14-1.1.3.1.1.1.1.1 16-1.1.3.1.1 17-1.1.3.1 19-1.2.1 20-1.2.1 21-1.2.1 22-1.2 23-1.2.2 24-1.2.3.r 26-1.2.3.1 26-1.2.3.1.1.2.1 27-1.2.3 28-1.2.3.2.r 29-1.2.3.2.1.1 31-1.2.3.2.1.1 (a3 / and :op1 (l / limit-01~e.7 :polarity~e.6 -~e.3,6 :ARG1 (a / affect-01~e.1 :ARG0 (a2 / activate-01 :polarity~e.6 - :ARG1 (e / enzyme :name (n / name :op1 "Icmt"~e.4)))) :ARG2~e.8 (i / inhibit-01~e.10 :ARG1~e.11 (t / transform-01~e.17 :ARG2-of (i2 / induce-01~e.16 :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.12,14)))))) :op2 (b / block-01~e.22 :ARG0 a2~e.19,20,21 :ARG1 (t2 / transform-01~e.23) :ARG3~e.24 (f / form~e.27 :ARG0-of (c2 / cause-01~e.26 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.26))) :mod~e.28 (e3 / enzyme :name (n3 / name :op1 "B-Raf"~e.29,31))))) # ::id bel_pmid_1496_6563.4878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the case of the Ras proteins , carboxyl methylation is important for targeting of the proteins to the plasma membrane . # ::alignments 5-1.1.2.1.1 6-1.1.1 8-1.1.1.1.1 9-1.1.1.1.2 11-1 13-1.1 16-1.1.1 16-1.1.2 17-1.1.3.r 19-1.1.3.1 20-1.1.3 (i / important~e.11 :purpose (t / target-01~e.13 :ARG0 (p / protein~e.6,16 :name (n / name :op1 "carboxyl"~e.8 :op2 "methylation"~e.9)) :ARG1 (p3 / protein-family~e.16 :name (n2 / name :op1 "Ras"~e.5)) :direction~e.17 (m / membrane~e.20 :part-of (p2 / plasma~e.19)))) # ::id bel_pmid_1496_6563.4882 ::amr-annotator SDL-AMR-09 ::preferred # ::tok levels of RhoA were greatly reduced as a consequence of accelerated protein turnover . In addition , there was a large Ras @/@ Erk1 @/@ 2 @-@ dependent increase in p21( Cip1 ) , which was probably a consequence of the reduced levels of RhoA . Deletion of p21( Cip1 ) restored the ability of K @-@ Ras @-@ Icmt( Delta/Delta ) fibroblasts to grow in soft agar . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.2 5-1.1 6-1.1.3 7-1.1.3 8-1.1.3 9-1.1.3.1.r 10-1.1.3.1.2 11-1.1.3.1.1 12-1.1.3.1 14-1.3 15-1.3 20-1.3.1.2 21-1.3.1.3.1.1.1 23-1.3.1.3.1.1.1 25-1.3.1.3.1.1.1 27-1.3.1.3 28-1.3.1 36-1.3.1.4.2 38-1.3.1.4 39-1.3.1.4.1.r 41-1.3.1.4.1 42-1.3.1.4.1.1 43-1.3.1.4.1.1.1.r 44-1.3.1.4.1.1.1.1.1 46-1.2.1 51-1.2 53-1.2.2 54-1.2.2.1.r 55-1.2.2.1.1.1.1.1 57-1.2.2.1.1.1.1.1 62-1.2.2.1 64-1.2.2.2 65-1.2.2.2.2.r 66-1.2.2.2.2.1 67-1.2.2.2.2 (m / multi-sentence :snt1 (r / reduce-01~e.5 :ARG1 (l / level~e.0 :degree-of~e.1 (p / protein :name (n / name :op1 "RhoA"~e.2))) :ARG2 (g / great~e.4) :ARG1-of (c / cause-01~e.6,7,8 :ARG0~e.9 (t / turnover~e.12 :mod (p2 / protein~e.11) :ARG1-of (a / accelerate-01~e.10)))) :snt3 (r2 / restore-01~e.51 :ARG0 (d2 / delete-01~e.46 :ARG1 (p6 / protein :name (n5 / name :op1 "p21(Cip1)"))) :ARG1 (c3 / capable-01~e.53 :ARG1~e.54 (f / fibroblast~e.62 :ARG0-of (c4 / contain-01 :ARG1 (e2 / enzyme :name (n6 / name :op1 "K-Ras-Icmt(Delta/Delta)"~e.55,57)))) :ARG2 (g2 / grow-01~e.64 :ARG1 f :location~e.65 (a3 / agar~e.67 :ARG1-of (s / soft-02~e.66))))) :snt2 (a2 / and~e.14,15 :op2 (i / increase-01~e.28 :ARG1 (p3 / protein :name (n2 / name :op1 "p21(Cip1)")) :ARG2 (l2 / large~e.20) :ARG0-of (d / depend-01~e.27 :ARG1 (p7 / pathway :name (n3 / name :op1 "Ras/Erk1/2"~e.21,23,25))) :ARG1-of (c2 / cause-01~e.38 :ARG0~e.39 (r3 / reduce-01~e.41 :ARG1 (l3 / level~e.42 :quant-of~e.43 (p5 / protein :name (n4 / name :op1 "RhoA"~e.44)))) :mod (p4 / probable~e.36))))) # ::id bel_pmid_1496_6572.18984 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The increase in IL @-@ 6 in septic DPPI(-/-) mice , which appears to protect these mice from death , may be related to reduced DPPI @-@ mediated activation of mast cell tryptase and other peptidases , which we show cleave IL @-@ 6 in vitro . # ::alignments 1-1.1.1 2-1.1.1.1.r 2-1.1.2.1.3.2 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.2.1.3.2 7-1.1.1.1.2.1 8-1.1.1.1.2.1 9-1.1.1.1.2.1 12-1.1.1.1.2.3 14-1.1.1.1 14-1.1.1.1.2 14-1.1.1.1.2.r 16-1.1.1.1.2.2.1 17-1.1.1.1.2.2.r 18-1.1.1.1.2.2 20-1 22-1.1 24-1.1.2.3 25-1.1.1.2.2.1.1 27-1.1.2.2 28-1.1.2 29-1.1.2.1.r 30-1.1.2.1.1.3 31-1.1.2.1.1.2 32-1.1.2.1.1.1.1 33-1.1.2.1 34-1.1.2.1.2.1 35-1.1.2.1.2 38-1.1.2.1.3.3.1 39-1.1.2.1.3.3 40-1.1.2.1.3 41-1.1.1.1.1.1 43-1.1.1.1.1.1 44-1.1.2.1.3.2 45-1.1.2.1.3.2 (p / possible-01~e.20 :ARG1 (r / relate-01~e.22 :ARG1 (i / increase-01~e.1 :ARG1~e.2 (p2 / protein~e.14 :name (n / name :op1 "IL-6"~e.3,5,41,43) :ARG0-of~e.14 (p3 / protect-01~e.14 :ARG1 m~e.7,8,9 :ARG2~e.17 (d / die-01~e.18 :ARG1 m~e.16) :ARG1-of (a2 / appear-02~e.12))) :location (m / mouse :mod (s / septic) :mod (e / enzyme :name (n2 / name :op1 "DPPI"~e.25) :ARG2-of (m2 / mutate-01 :mod "-/-")))) :ARG2 (a / activate-01~e.28 :ARG1~e.29 (a3 / and~e.33 :op1 (e3 / enzyme :name (n4 / name :op1 "tryptase"~e.32) :mod (c2 / cell~e.31) :mod (m4 / mast~e.30)) :op2 (p4 / peptidase~e.35 :mod (o / other~e.34)) :ARG0-of (c / cleave-01~e.40 :ARG1 p2 :manner (i2 / in-vitro~e.2,6,44,45) :ARG1-of (s2 / show-01~e.39 :ARG0 (w / we~e.38)))) :ARG1-of (m3 / mediate-01~e.27 :ARG0 e) :ARG1-of (r2 / reduce-01~e.24)))) # ::id bel_pmid_1503_9780.28646 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , over @-@ expression of c @-@ Jun rescued the defects in proliferation and premature senescence observed in mkk7-/- MEFs ( Fig . 7b @-@ d ) . # ::alignments 0-1.3 6-1.1.1.1.1 8-1.1.1.1.1 9-1 11-1.2 12-1.2.1.r 13-1.2.1.1 14-1.2.1 15-1.2.1.2.1 16-1.2.1.2 17-1.2.1.3 20-1.2.1.3.1.1.1 22-1.4.1.1 22-1.4.1.2 22-1.4.1.3 24-1.4.1.1.1 (r / rescue-01~e.9 :ARG0 (o2 / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "c-Jun"~e.6,8))) :ARG1 (d / defect~e.11 :topic~e.12 (a / and~e.14 :op1 (p2 / proliferate-01~e.13) :op2 (s / senescence~e.16 :mod (p3 / premature~e.15)) :ARG1-of (o / observe-01~e.17 :location (c / cell :name (n2 / name :op1 "MEF"~e.20) :part (e2 / enzyme :name (n3 / name :op1 "mkk7") :ARG2-of (m / mutate-01 :mod "-/-")))))) :mod (i / important~e.0) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.22 :mod "7b"~e.24) :op2 (f3 / figure~e.22 :mod "7c") :op3 (f2 / figure~e.22 :mod "7d")))) # ::id bel_pmid_1503_9780.29004 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , genetic inactivation of MKK4 in MEFs resulted in reduced proliferation doubling times and premature senescence , indicating that both MKK4 and MKK7 are essential for these cellular processes ( data not shown ) . # ::alignments 0-1.1.2 2-1.1.1.3 3-1.1.1 3-1.1.1.1 3-1.1.1.1.r 4-1.1.1.2.r 5-1.1.1.2.1.1 7-1.1.1.2.2.1.1 8-1.1 9-1.1.2.r 10-1.1.2.1.1 11-1.1.2.1.2.1 12-1.1.2.1.2 13-1.1.2.1 14-1.1.2 15-1.1.2.2.1 16-1.1.2.2 18-1.1.3 21-1.1.3.1.2.1 22-1.1.3.1.2 23-1.1.3.1.2.2.1.1 24-1.1.3.1.2.r 25-1.1.3.1 26-1.1.3.1.1.r 27-1.1.3.1.1.2 28-1.1.3.1.1.1 29-1.1.3.1.1 32-1.1.3.1.3.1 32-1.1.3.1.3.1.r 33-1.1.3.1.3 (a4 / and :op2 (r / result-01~e.8 :ARG1 (a / activate-01~e.3 :polarity~e.3 -~e.3 :ARG1~e.4 (e / enzyme :name (n / name :op1 "MKK4"~e.5) :location (c / cell :name (n2 / name :op1 "MEF"~e.7))) :mod (g / genetic~e.2) :location c) :ARG2~e.9 (a2 / and~e.0,14 :op1 (t2 / time~e.13 :ARG1-of (r2 / reduce-01~e.10) :duration-of (d / double-01~e.12 :ARG1 (p / proliferate-01~e.11 :ARG0 c))) :op2 (s / senescence~e.16 :mod (p3 / premature~e.15))) :ARG0-of (i / indicate-01~e.18 :ARG1 (e2 / essential~e.25 :purpose~e.26 (p2 / process-02~e.29 :location (c2 / cell~e.28) :mod (t / this~e.27)) :domain~e.24 (a3 / and~e.22 :op1 e~e.21 :op2 (e3 / enzyme :name (n3 / name :op1 "MKK7"~e.23))) :ARG1-of (s2 / show-01~e.33 :polarity~e.32 -~e.32))))) # ::id bel_pmid_1503_9780.29010 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , proliferation of hepatocytes was markedly impaired in E11.5 mkk7-/- embryos , as determined by BrdU in vivo labelling ( data not shown ) . # ::alignments 0-1.1.4.1.2 1-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1.2 7-1.1.2.r 8-1.1 9-1.1.4.1.2 12-1.1.3 15-1.1.4 17-1.1.4.1.1.1.1 18-1.1.4.1.2 19-1.1.4.1.2 20-1.1.4.1 23-1.1.5.1 23-1.1.5.1.r 24-1.1.5 (c2 / contrast-01~e.1 :ARG2 (i / impair-01~e.8 :ARG1 (p / proliferate-01~e.3 :ARG0~e.4 (c / cell :name (n / name :op1 "hepatocyte"~e.5))) :manner~e.7 (m / marked~e.7) :location (e / embryo~e.12 :mod (e2 / enzyme :name (n2 / name :op1 "mkk7") :ARG2-of (m2 / mutate-01 :mod "-/-")) :age (t2 / temporal-quantity :quant 11.5 :unit (d2 / day))) :ARG1-of (d / determine-01~e.15 :ARG0 (l / label-01~e.20 :instrument (s2 / small-molecule :name (n4 / name :op1 "BrdU"~e.17)) :manner (i2 / in-vivo~e.0,9,18,19))) :ARG1-of (s / show-01~e.24 :polarity~e.23 -~e.23))) # ::id bel_pmid_1503_9780.29012 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Re @-@ expression of wild @-@ type MKK7 ( Fig . 2c ) restored the reduced proliferation of mkk7 @- /- MEFs to levels observed in wild @-@ type MEFs . # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1.2 6-1.1.1.2 7-1.1.1.1.1 9-1.1.3.1 11-1.1.3.1.1 13-1 15-1.2.2 16-1.2 17-1.2.1.r 18-1.2.1.2.1.1 21-1.2.1.1.1 22-1.3.r 23-1.3 24-1.3.1 26-1.1.1.2 28-1.1.1.2 29-1.2.1.1.1 (r / restore-01~e.13 :ARG0 (e / express-03~e.2 :ARG2~e.3 (e2 / enzyme :name (n / name :op1 "MKK7"~e.7) :mod (w / wild-type~e.4,6,26,28)) :mod (a / again) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.9 :mod "2c"~e.11))) :ARG1 (p / proliferate-01~e.16 :ARG0~e.17 (c / cell :name (n2 / name :op1 "MEF"~e.21,29) :part (e3 / enzyme :name (n3 / name :op1 "mkk7"~e.18) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1-of (r2 / reduce-01~e.15)) :ARG2~e.22 (l / level~e.23 :ARG1-of (o / observe-01~e.24 :location c))) # ::id bel_pmid_1503_9780.29014 ::amr-annotator SDL-AMR-09 ::preferred # ::tok loss of MKK7 expression resulted in impaired JNK activation in MEFs at the basal level and after stimulation with tumour necrosis factor alpha ( TNF @-@ alpha ) or UV irradiation ( Fig . 2a ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1 5-1.2.r 6-1.2.2 7-1.2.1.1.1 8-1.2 9-1.2.3.r 10-1.2.3.1.1 11-1.2.4.r 13-1.2.4.1 14-1.2.4 16-1.2.5 17-1.2.5.1 18-1.2.5.1.2.r 19-1.2.5.1.2.1.1.1 20-1.2.5.1.2.1.1.2 21-1.2.5.1.2.1.1.3 22-1.2.5.1.2.1.1.4 28-1.2.5.1.2 30-1.2.5.1.2.2 32-1.3.1 34-1.3.1.1 (r / result-01~e.4 :ARG1 (l / lose-02~e.0 :ARG1~e.1 (e / express-03~e.3 :ARG2 (e2 / enzyme :name (n / name :op1 "MKK7"~e.2)))) :ARG2~e.5 (a / activate-01~e.8 :ARG1 (e3 / enzyme :name (n2 / name :op1 "JNK"~e.7)) :ARG1-of (i / impair-01~e.6) :location~e.9 (c / cell :name (n3 / name :op1 "MEF"~e.10)) :location~e.11 (l2 / level~e.14 :mod (b / basal~e.13)) :time (a2 / after~e.16 :op1 (s / stimulate-01~e.17 :ARG1 e3 :ARG2~e.18 (o / or~e.28 :op1 (p / protein :name (n4 / name :op1 "tumour"~e.19 :op2 "necrosis"~e.20 :op3 "factor"~e.21 :op4 "alpha"~e.22)) :op2 (i2 / irradiate-01~e.30 :ARG2 (l3 / light :mod (u / ultraviolet))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "2a"~e.34))) # ::id bel_pmid_1503_9780.29016 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , cyclin B1 @-@ associated CDC2 kinase activity was markedly reduced in mkk7-/- MEFs ( Fig . 4d ) , indicating that reduced CDC2 expression correlates with impaired cyclin B1 @/@ CDC2 activity . # ::alignments 0-1.2 2-1.1.1.2.1.1.1 3-1.1.1.2.1.1.2 5-1.1.1.2 6-1.1.1.1.1 7-1.1.1 8-1.1 10-1.3 10-1.3.r 11-1 14-1.4.1.1 16-1.5.1 18-1.5.1.1 21-1.6 23-1 23-1.6.1.1.2 24-1.6.1.1.1 25-1.6.1.1 26-1.6.1 27-1.6.1.2.r 28-1.6.1.2.2 29-1.6.1.2.1.1 30-1.6.1.2.1.1 31-1.6.1.2.1 32-1.6.1.2.1.2 33-1.6.1.2 (r / reduce-01~e.11,23 :ARG1 (a / activity-06~e.8 :ARG0 (k / kinase~e.7 :name (n / name :op1 "CDC2"~e.6) :ARG1-of (a2 / associate-01~e.5 :ARG2 (p / protein :name (n2 / name :op1 "cyclin"~e.2 :op2 "B1"~e.3))))) :mod (i / important~e.0) :manner~e.10 (m / marked~e.10) :location (c / cell :name (n3 / name :op1 "MEF"~e.14) :part (e / enzyme :name (n4 / name :op1 "mkk7") :ARG2-of (m2 / mutate-01 :mod "-/-"))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "4d"~e.18)) :ARG0-of (i2 / indicate-01~e.21 :ARG1 (c2 / correlate-01~e.26 :ARG1 (e2 / express-03~e.25 :ARG2 k~e.24 :ARG1-of (r2 / reduce-01~e.23)) :ARG2~e.27 (a3 / activity-06~e.33 :ARG0 (s / slash~e.31 :op1 p~e.29,30 :op2 k~e.32) :ARG1-of (i3 / impair-01~e.28))))) # ::id bel_pmid_1503_9780.29022 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly to mkk7-/- MEFs , cdc2 mRNA expression was downregulated in primary mkk7-/- hepatocytes ( Fig . 4g ) . # ::alignments 0-1.3 3-1.3.1.1.1.1 5-1.1.1.2.1.1.1 6-1.1.1.1.1 7-1.1 7-1.3.1 9-1 10-1.2.r 11-1.2.2 13-1.2.1.1 15-1.4.1 17-1.4.1.1 (d / downregulate-01~e.9 :ARG1 (e / express-03~e.7 :ARG1 (n6 / nucleic-acid :name (n / name :op1 "mRNA"~e.6) :ARG0-of (e2 / encode-01 :ARG1 (e5 / enzyme :name (n2 / name :op1 "cdc2"~e.5))))) :location~e.10 (c / cell :name (n3 / name :op1 "hepatocyte"~e.13) :mod (p2 / primary~e.11) :mod (e3 / enzyme :name (n4 / name :op1 "mkk7") :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1-of (r2 / resemble-01~e.0 :ARG2 (e4 / express-03~e.7 :ARG3 (c2 / cell :name (n5 / name :op1 "MEF"~e.3) :part e3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.15 :mod "4g"~e.17))) # ::id bel_pmid_1503_9780.29098 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are consistent with previous data showing that loss of JNK1 @/@ JNK2 in MEFs results in reduced proliferation17 and that inactivation of c @-@ Jun in MEFs results in premature senescence and impaired proliferation19 . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.2.r 5-1.2.1 6-1.2 7-1.2.2 9-1.2.2.1.1.1 10-1.2.2.1.1.1.1.r 11-1.2.2.1.1.1.1.1.1.1 12-1.2.2.1.1.1.1 13-1.2.2.1.1.1.1.2.1.1 14-1.2.2.1.1.1.1.3.r 15-1.2.2.1.1.1.1.3.1.1 16-1.2.2.1.1 18-1.2.2.1.1.1.2.1 20-1.2.2.1 22-1.2.2.1.2.1 22-1.2.2.1.2.1.1 22-1.2.2.1.2.1.1.r 23-1.2.2.1.2.1.2.r 24-1.2.2.1.2.1.2.1.1 26-1.2.2.1.2.1.2.1.1 28-1.2.2.1.2.1.2.2 29-1.2.2.1.2 30-1.2.2.1.2.2.r 31-1.2.2.1.2.2.1.1 32-1.2.2.1.2.2.1 33-1.2.2.1.2.2 34-1.2.2.1.2.2.2.1 (c / consistent-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG2~e.4 (d / data~e.6 :time (p / previous~e.5) :ARG0-of (s / show-01~e.7 :ARG2 (a / and~e.20 :op1 (r2 / result-01~e.16 :ARG1 (l / lose-02~e.9 :ARG1~e.10 (s2 / slash~e.12 :op1 (e / enzyme :name (n / name :op1 "JNK1"~e.11)) :op2 (e2 / enzyme :name (n2 / name :op1 "JNK2"~e.13)) :location~e.14 (c2 / cell :name (n3 / name :op1 "MEF"~e.15))) :ARG2 (p2 / proliferate-01 :ARG1-of (r4 / reduce-01~e.18))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 17)))) :op2 (r3 / result-01~e.29 :ARG1 (a2 / activate-01~e.22 :polarity~e.22 -~e.22 :ARG1~e.23 (p7 / protein :name (n4 / name :op1 "c-Jun"~e.24,26) :location c2~e.28)) :ARG2~e.30 (a3 / and~e.33 :op1 (s3 / senescence~e.32 :mod (p3 / premature~e.31)) :op2 (p5 / proliferate-01 :ARG1-of (i2 / impair-01~e.34))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 19)))))))) # ::id bel_pmid_1503_9780.33214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Over @-@ expression of c @-@ Jun in mkk7-/- MEFs restored CDC2 expression ( Fig . 6c ) and transactivation of the cdc2 AP @-@ 1 promoter construct to levels observed in wild @-@ type MEFs ( Fig . 6d ) . # ::alignments 2-1.2.1 4-1.1.1.1.1 6-1.1.1.1.1 9-1.1.2.1.1 10-1 11-1.2.1.1.1.1 12-1.2.1 14-1.2.1.2.1 16-1.2.1.2.1.1 18-1.2 19-1.2.2 20-1.2.2.1.r 22-1.2.2.1.1.1.1.1 23-1.2.2.1.1.1.1.2 25-1.2.2.1.1.1.1.2 26-1.2.2.1 26-1.2.2.1.1 26-1.2.2.1.1.r 27-1.2.2.1.1.1 27-1.2.2.1.1.1.2 27-1.2.2.1.1.1.2.r 28-1.3.r 29-1.3 30-1.3.1 31-1.3.1.1.r 32-1.3.1.1.2 34-1.3.1.1.2 35-1.1.2.1.1 35-1.3.1.1.1.1 37-1.2.2.2.1 39-1.2.2.2.1.1 (r / restore-01~e.10 :ARG0 (o2 / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "c-Jun"~e.4,6)) :location (c / cell :name (n2 / name :op1 "MEF"~e.9,35) :part (e2 / enzyme :name (n3 / name :op1 "mkk7") :ARG2-of (m / mutate-01 :mod "-/-")))) :ARG1 (a / and~e.18 :op1 (e3 / express-03~e.2,12 :ARG2 (e / enzyme :name (n4 / name :op1 "CDC2"~e.11)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "6c"~e.16))) :op2 (t / transactivate-01~e.19 :ARG1~e.20 (m2 / molecular-physical-entity~e.26 :ARG0-of~e.26 (p3 / promote-01~e.26 :ARG1 (p4 / protein~e.27 :name (n5 / name :op1 "cdc2"~e.22 :op2 "AP-1"~e.23,25) :ARG1-of~e.27 (c2 / construct-01~e.27)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.37 :mod "6d"~e.39)))) :ARG2~e.28 (l / level~e.29 :ARG1-of (o / observe-01~e.30 :location~e.31 (c3 / cell :name (n6 / name :op1 "MEF"~e.35) :mod (w / wild-type~e.32,34))))) # ::id bel_pmid_1511_5616.1726 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this study , we found that H @-@ Ras interacted with ASK1 to cause the inhibition of both ASK1 activity and ASK1 @-@ induced apoptosis in vivo # ::alignments 0-1.2.3.2.1.2.1.2 1-1.3.1 2-1.3 4-1.1 5-1 7-1.2.1.1.1 9-1.2.1.1.1 10-1.2 11-1.2.2.r 12-1.2.2.1.1 13-1.2.3 14-1.2.3 16-1.2.3.2 19-1.2.3.2.1.1.1 20-1.2.3.2.1.1 21-1.2.3.2.1 22-1.2.3.2.1.1.1 24-1.2.3.2.1.2.1 25-1.2.3.2.1.2 26-1.2.3.2.1.2.1.2 27-1.2.3.2.1.2.1.2 (f / find-01~e.5 :ARG0 (w / we~e.4) :ARG1 (i / interact-01~e.10 :ARG0 (e / enzyme :name (n / name :op1 "H-Ras"~e.7,9)) :ARG1~e.11 (e2 / enzyme :name (n2 / name :op1 "ASK1"~e.12)) :purpose (c / cause-01~e.13,14 :ARG0 e :ARG1 (i2 / inhibit-01~e.16 :ARG1 (a2 / and~e.21 :op1 (a / activity-06~e.20 :ARG0 e2~e.19,22) :op2 (a3 / apoptosis~e.25 :ARG2-of (i3 / induce-01~e.24 :ARG0 e2 :manner (i4 / in-vivo~e.0,26,27))))))) :medium (s / study-01~e.2 :mod (t / this~e.1))) # ::id bel_pmid_1512_8871.1604 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this report , we demonstrate that the CDC25B phosphatase , an activator of cyclin dependent kinases at mitosis , is phosphorylated both in vitro and in vivo by Aurora @-@ A on serine 353 and that this phosphorylated form of CDC25B is located at the centrosome during mitosis . # ::alignments 0-1.2.1.3.1 1-1.3.1 2-1.3 4-1.1 5-1 8-1.2.1.1.3.1.1 9-1.2.1.1.3 12-1.2.1.1.3.2 13-1.2.1.1.3.2.1.r 14-1.2.1.1.3.2.1.1.1 15-1.2.1.1.3.2.1.1 16-1.2.1.1.3.2.1 17-1.2.2 18-1.2.2.3 21-1.2.1 23-1.2.1.3.1 24-1.2.1.3.1 25-1.2.1.3 26-1.2.1.3.1 26-1.2.1.3.2 27-1.2.1.3.2 29-1.2.1.2.1.1 31-1.2.1.2.1.1 33-1.2.1.1.2.1 34-1.2.1.1.1 35-1.2 35-1.2.1.3 37-1.3.1 38-1.2.1 41-1.2.1.1.3.1.1 42-1.2.2 43-1.2.2 44-1.2.2 46-1.2.2.2 47-1.2.1.1.3.2.2.r 47-1.2.2.3.r 48-1.2.1.1.3.2.2 (d / demonstrate-01~e.5 :ARG0 (w / we~e.4) :ARG1 (a4 / and~e.35 :op1 (p / phosphorylate-01~e.21,38 :ARG1 (a2 / amino-acid :mod 353~e.34 :name (n2 / name :op1 "serine"~e.33) :part-of (p3 / phosphatase~e.9 :name (n4 / name :op1 "CDC25B"~e.8,41) :ARG0-of (a / activate-01~e.12 :ARG1~e.13 (k / kinase~e.16 :ARG0-of (d2 / depend-01~e.15 :ARG1 (c / cyclin~e.14))) :time~e.47 (m / mitosis~e.48)))) :ARG2 (e / enzyme :name (n3 / name :op1 "Aurora-A"~e.29,31)) :manner (a3 / and~e.25,35 :op1 (i / in-vitro~e.0,23,24,26) :op2 (i2 / in-vivo~e.26,27))) :op2 (b2 / be-located-at-91~e.17,42,43,44 :ARG1 (p2 / protein) :ARG2 (c2 / centrosome~e.46) :time~e.47 m~e.18)) :medium (r / report~e.2 :mod (t / this~e.1,37))) # ::id bel_pmid_1514_3158.1864 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor ( EGF ) signaling . EGF receptor phosphorylation and downstream activation of ERK 1 @/@ 2 and Elk1 @-@ dependent gene transcription are enhanced by PTPD1 . # ::alignments 0-1.1.1.1.1.1 0-1.2.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1.1.2.1.2 4-1.1.1.2.1.3 5-1.1 6-1.1.2 8-1.1.2.2.1 9-1.1.2.2 10-1.1.2.2.2 11-1.1.2.2.1.1.r 12-1.1.2.2.1.1.1.1.1 13-1.1.2.2.1.1.1.1.2 14-1.1.2.2.1.1.1.1.3 18-1.1.2.2.1.1 22-1.2.2.1 23-1.2.2 24-1.2.2.2.2 25-1.2.2.2 26-1.2.2.2.1.r 27-1.2.2.2.1.2.1.1.1.1 28-1.2.2.2.1.2.1.1.1.2 30-1.2.2.2.1.2.1.1.1.2 31-1.2.2.2.1.2.1 32-1.2.2.2.1.2.1.2.1.1 34-1.2.2.2.1.2 35-1.2.2.2.1.1 36-1.2.2.2.1 38-1.2 39-1.2.1.r 40-1.2.1.1.1 (m / multi-sentence :snt1 (a / and~e.5 :op1 (a2 / activate-01~e.1 :ARG0 (p / protein :name (n / name :op1 "PTPD1"~e.0)) :ARG1 (p2 / protein :name (n3 / name :op1 "src"~e.2 :op2 "tyrosine"~e.3 :op3 "kinase"~e.4))) :op2 (i / increase-01~e.6 :ARG0 p :ARG1 (a3 / and~e.9 :op1 (m2 / magnitude~e.8 :poss~e.11 (s / signal-07~e.18 :ARG0 (p3 / protein :name (n2 / name :op1 "epidermal"~e.12 :op2 "growth"~e.13 :op3 "factor"~e.14)))) :op2 (d / duration~e.10 :poss s)))) :snt2 (e / enhance-01~e.38 :ARG0~e.39 (p4 / protein :name (n4 / name :op1 "PTPD1"~e.0,40)) :ARG1 (a4 / and~e.23 :op1 (p5 / phosphorylate-01~e.22 :ARG1 (e3 / enzyme :name (n8 / name :op1 "EFG" :op2 "rececptor"))) :op2 (a5 / activate-01~e.25 :ARG1~e.26 (t / transcribe-01~e.36 :ARG1 (g / gene~e.35) :ARG0-of (d3 / depend-01~e.34 :ARG1 (a6 / and~e.31 :op1 (e2 / enzyme :name (n6 / name :op1 "ERK"~e.27 :op2 "1/2"~e.28,30)) :op2 (p6 / protein :name (n7 / name :op1 "Elk1"~e.32))))) :mod (d2 / downstream~e.24))))) # ::id bel_pmid_1515_6153.27354 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , expression of Myc @–@ Hes1 greatly increased the amount of endogenous JAK2 coprecipitated with endogenous STAT3 ( Fig . 4e ) , suggesting that Hes1 facilitates the interaction between JAK2 and its substrate STAT3 # ::alignments 0-1.4 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 6-1.1.1.2.1.1 7-1.3 8-1 10-1.2 11-1.2.1.r 12-1.2.1.2 13-1.2.1.1.1 16-1.2.1.3.1.2 17-1.2.1.3.1.1.1 19-1.5.1 21-1.5.1.1 24-1.6 25-1.6.1.r 26-1.6.1.1 27-1.6.1 29-1.6.1.2 31-1.6.1.2.1 32-1.6.1.2.1 33-1.6.1.2.1 34-1.6.1.2.1 35-1.6.1.2.1 (i / increase-01~e.8 :ARG0 (e / express-03~e.2 :ARG2~e.3 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Myc"~e.4)) :part (p3 / protein :name (n5 / name :op1 "Hes1"~e.6)))) :ARG1 (a / amount~e.10 :quant-of~e.11 (e2 / enzyme :name (n2 / name :op1 "JAK2"~e.13) :mod (e3 / endogenous~e.12) :op1-of (a2 / and :op2 (p2 / protein :name (n3 / name :op1 "STAT3"~e.17) :mod e3~e.16) :ARG1-of (c / coprecipitate-01)))) :ARG2 (g / great~e.7) :mod (i2 / important~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "4e"~e.21)) :ARG0-of (s / suggest-01~e.24 :ARG1~e.25 (f2 / facilitate-01~e.27 :ARG0 p3~e.26 :ARG1 (i3 / interact-01~e.29 :ARG0 e2~e.31,32,33,34,35 :ARG1 p2)))) # ::id bel_pmid_1515_6153.27358 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of either Hes1 or Hes5 significantly activated the STAT reporter gene construct in both E13 neuroepithelial cells and MNS @-@ 70 cells , # ::alignments 0-1.1 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1.3 7-1 9-1.2.1.1 10-1.2.2 11-1.2 12-1.2.3 15-1.4.1.1.1 17-1.4.1 17-1.4.2 18-1.4 19-1.4.2.1.1 21-1.4.2.1.1 22-1.4.1 (a / activate-01~e.7 :ARG0 (e / express-03~e.0 :ARG2 (o / or~e.4 :op1 (p / protein :name (n / name :op1 "Hes1"~e.3)) :op2 (p2 / protein :name (n2 / name :op1 "Hes5"~e.5)))) :ARG1 (g / gene~e.11 :name (n3 / name :op1 "STAT"~e.9) :ARG0-of (r / report-01~e.10) :ARG1-of (c / construct-01~e.12)) :ARG1-of (s / significant-02~e.6) :location (a2 / and~e.18 :op1 (c3 / cell~e.17,22 :name (n5 / name :op1 "E13"~e.15) :part-of (n4 / neuroepithelium)) :op2 (c2 / cell~e.17 :name (n6 / name :op1 "MNS-70"~e.19,21)))) # ::id bel_pmid_1515_6153.29634 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of an active form of Notch ( Notch ? E; the transmembrane and intracellular domains of mouse Notch1 , comprising residues 1,704 @–@ 2,531 ) 15 , significantly induced activation of a STAT @-@ dependent reporter gene ( APRE @-@ Luc ) 16 in mouse cortical neuroepithelial cells derived on embryonic day ( E ) 13 or in the rat neural precursor MNS @-@ 70 cells17 # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.2 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1.1.1.1.1.1 12-1.1.1.1.2.1.2.1.1.1 13-1.1.1.1.2.1.2.1 14-1.1.1.1.2.1.2.1.2.1 16-1.1.1.1.2.1.2.1.2.1.1.r 17-1.1.1.1.2.1.2.1.2.1.1 18-1.1.1.1.2.1.2.1.2.1.1 20-1.1.1.1.2.1.2.1.3 21-1.1.1.1.2.1.2.1.3.1.1 21-1.1.1.1.2.1.2.1.3.1.2 22-1.1.1.1.2.1.2.1.3.1.1.1 24-1.1.1.1.2.1.2.1.3.1.2.1 26-1.1.2.1.1.1 28-1.3 29-1 30-1.2 30-1.2.1.2.1 30-1.2.1.2.1.2 30-1.2.1.2.1.2.r 31-1.2.1.r 33-1.2.1.2.1.1.1 35-1.2.1.2 36-1.2.1.3 37-1.2.1 39-1.2.1.1.1 41-1.2.1.1.1 43-1.4.1.1.1 45-1.1.1.1.2.1.2.1.1.2.2 46-1.2.2.1.2 48-1.2.2.1 49-1.2.2.1.3 50-1.2.2.1.3.2.r 51-1.2.2.1.3.2.2 52-1.2.2.1.3.2 54-1.1.1.1.2.1.1.3 56-1.2.2.1.3.2.1.1 57-1.2.2 58-1.2.2.r 60-1.2.2.2.3 61-1.2.2.2.4 62-1.2.2.2.2 63-1.2.2.2.1.1 65-1.2.2.2.1.1 (i / induce-01~e.29 :ARG0 (e / express-03~e.0 :ARG2~e.1 (f / form~e.4 :mod~e.5 (p2 / protein :name (n3 / name :op1 "Notch"~e.6,8) :ARG1-of (m3 / mean-01 :ARG2 (p9 / protein :name (n4 / name :op1 "Notch" :op2 "Delta" :op3 "E"~e.54) :ARG1-of (m / mean-01 :ARG2 (a4 / and~e.13 :op1 (p3 / protein-segment :mod (t / transmembrane~e.12) :part-of (p5 / protein :name (n6 / name :op1 "Notch1") :mod (m2 / mouse~e.45))) :op2 (p10 / protein-segment :mod (c2 / cell~e.14 :part-of~e.16 p5~e.17,18)) :ARG1-of (c / comprise-01~e.20 :ARG2 (v2 / value-interval :op1 (r2 / residue~e.21 :mod 1704~e.22) :op2 (r4 / residue~e.21 :mod 2531~e.24)))))))) :ARG0-of (a3 / activity-06~e.3)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c6 / cite-01 :ARG2 15~e.26)))) :ARG2 (a / activate-01~e.30 :ARG1~e.31 (g / gene~e.37 :name (n / name :op1 "APRE-Luc"~e.39,41) :ARG0-of (d / depend-01~e.35 :ARG1 (p / protein~e.30 :name (n2 / name :op1 "STAT"~e.33) :ARG1-of~e.30 (a2 / activate-01~e.30))) :ARG0-of (r / report-01~e.36)) :location~e.58 (o / or~e.57 :op1 (c3 / cell~e.48 :part-of (n7 / neuroepithelium) :mod (c4 / cortex~e.46) :ARG1-of (d2 / derive-01~e.49 :ARG1-of (d6 / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c8 / cite-01 :ARG2 17))) :time~e.50 (d3 / day~e.52 :ord (o2 / ordinal-entity :value 13~e.56) :mod (e2 / embryo~e.51)))) :op2 (c5 / cell :name (n8 / name :op1 "MNS-70"~e.63,65) :mod (p6 / precursor~e.62) :mod (r3 / rat~e.60) :mod (n9 / neural~e.61)))) :ARG1-of (s / significant-02~e.28) :ARG1-of (d5 / describe-01 :ARG0 (p7 / publication-91 :ARG1-of (c7 / cite-01 :ARG2 16~e.43)))) # ::id bel_pmid_1516_6036.20904 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following depletion of both serum and Epo for 2 hours , p44 @/@ 42 ERK ( Phospho ERK1 ( Thr202/Tyr204 ) ; phospho @-@ ERK2 ( Thr185/Tyr187 )) remained active in H @-@ ras.V12 @-@ transduced cells but not in the control cells . No difference was seen in the expression of total p44 @/@ 42 ERK in the 2 populations of cells # ::alignments 0-1.1.3 1-1.1.3.1 4-1.1.3.1.1.1 5-1.1.3.1.1 6-1.1.3.1.1.2.1.1 7-1.1.3.1.2.r 8-1.1.3.1.2.1 9-1.1.3.1.2.2 12-1.1.1 12-1.1.1.3.1.1 12-1.1.1.3.1.2 16-1.1.1.3.1.1.2.4 17-1.1.1.3.1.1.2.3.1.1 22-1.1.1.3.1.1.1.4 24-1.1.1.3.1.2.2.2.1.1 28-1.1 28-1.1.2.1 29-1.1.2.1.2 29-1.1.2.2 30-1.1.2.1.3.r 31-1.1.2.1.3.2.1.1.1 35-1.1.2.1.3.2 36-1.1.2.1.3 37-1.1.2 38-1.1.2.2.1 38-1.1.2.2.1.r 39-1.1.2.2.3.r 41-1.1.2.2.3.1 42-1.1.2.2.3 44-1.2.1.1 44-1.2.1.1.r 45-1.2.1 45-1.2.1.1 45-1.2.1.1.r 47-1.2 48-1.2.1.2.r 50-1.2.1.2 51-1.2.1.2.1.r 52-1.2.1.2.1.3 54-1.2.1.2.1 57-1.2.1.2.2.r 59-1.2.1.2.2.1 60-1.2.1.2.2 61-1.2.1.2.2.2.r 62-1.2.1.2.2.2 (m3 / multi-sentence :snt1 (r / remain-01~e.28 :ARG1 (s2 / slash~e.12 :op1 (e6 / enzyme :name (n10 / name :op1 "p44ERK")) :op2 (e7 / enzyme :name (n11 / name :op1 "p42ERK")) :ARG1-of (m / mean-01 :ARG2 (a5 / and :op1 (s3 / slash~e.12 :op1 (a6 / amino-acid :mod 202 :name (n / name :op1 "threonine") :part-of e :ARG3-of (p / phosphorylate-01~e.22)) :op2 (a7 / amino-acid :mod 204 :name (n2 / name :op1 "tyrosine") :part-of (e / enzyme :name (n6 / name :op1 "ERK1"~e.17)) :ARG1-of p~e.16)) :op2 (s4 / slash~e.12 :op1 (a8 / amino-acid :mod 185 :name (n7 / name :op1 "threonine") :part-of e4 :ARG3-of p) :op2 (a9 / amino-acid :name (n8 / name :op1 "tyrosine") :part-of (e4 / enzyme :name (n9 / name :op1 "ERK2"~e.24)) :ARG3-of p))))) :ARG3 (c / contrast-01~e.37 :ARG1 (r2 / remain-01~e.28 :ARG1 s2 :ARG2 (a3 / activity-06~e.29 :ARG0 s2) :location~e.30 (c5 / cell~e.36 :ARG2-of (m2 / mutate-01 :value "V12") :ARG1-of (t / transduce-01~e.35 :ARG2 (e2 / enzyme :name (n5 / name :op1 "H-Ras"~e.31))))) :ARG2 (a4 / activity-06~e.29 :polarity~e.38 -~e.38 :ARG0 s2 :location~e.39 (c2 / cell~e.42 :ARG0-of (c3 / control-01~e.41)))) :time (a / after~e.0 :op1 (d / deplete-01~e.1 :ARG1 (a2 / and~e.5 :op1 (s / serum~e.4) :op2 (s7 / small-molecule :name (n3 / name :op1 "Epo"~e.6))) :duration~e.7 (t2 / temporal-quantity :quant 2~e.8 :unit (h2 / hour~e.9))))) :snt2 (s5 / see-01~e.47 :ARG0 (d2 / differ-02~e.45 :polarity~e.44,45 -~e.44,45 :ARG1~e.48 (e5 / express-03~e.50 :ARG2~e.51 (s6 / slash~e.54 :op1 e6 :op2 e7 :mod (t3 / total~e.52)) :ARG3~e.57 (p2 / population~e.60 :quant 2~e.59 :consist-of~e.61 (c4 / cell~e.62)))))) # ::id bel_pmid_1519_6705.1680 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , GH induced rapid , time @- and dose @-@ dependent signaling events in LNCaP cells , including phosphorylation of JAK2 tyrosine kinase , of GHR itself and of STAT5A ( JAK2 @-@ STAT5A pathway ) , of p42 @/@ p44 MAPK and of Akt/PKB . # ::alignments 0-1 2-1.1.1.1.1 3-1.1 4-1.1.2.1.2 6-1.1.2.1.1.1.1 8-1.1.2.1.1.1 9-1.1.2.1.1.1.2 11-1.1.2.1.1 12-1.1.2.1 13-1.1.2 14-1.1.2.2.r 15-1.1.2.2.1.1 16-1.1.2.2 18-1.1.2.3 19-1.1.2.3.1 20-1.1.2.3.1.1.r 21-1.1.2.3.1.1.1.1.1 22-1.1.2.3.1.1.1 23-1.1.2.3.1.1.1 26-1.1.2.3.1.1.2.1.1 28-1.1.2.3.1.1 30-1.1.2.3.1.1.3.1.1 32-1.1.2.3.1.1.1.1.1 34-1.1.2.3.1.1.3.1.1 39-1.1.2.3.1.1.4.1.1 41-1.1.2.3.1.1.4.1.1 42-1.1.2.3.1.1.4.1.2 43-1.1.2.3.1.1 45-1.1.2.3.1.1.5.1.1 (a2 / and~e.0 :op2 (i / induce-01~e.3 :ARG0 (p / protein :name (n2 / name :op1 "GH"~e.2)) :ARG2 (e / event~e.13 :mod (s / signal-07~e.12 :ARG0-of (d / depend-01~e.11 :ARG1 (a / and~e.8 :op1 (t / time~e.6) :op2 (d2 / dose~e.9))) :mod (r / rapid~e.4)) :location~e.14 (c / cell-line~e.16 :name (n3 / name :op1 "LNCaP"~e.15)) :ARG2-of (i2 / include-01~e.18 :ARG1 (p3 / phosphorylate-01~e.19 :ARG1~e.20 (a3 / and~e.28,43 :op1 (t2 / tyrosine-kinase~e.22,23 :name (n / name :op1 "JAK2"~e.21,32)) :op2 (p2 / protein :name (n5 / name :op1 "GHR"~e.26)) :op3 (p4 / protein :name (n6 / name :op1 "STAT5A"~e.30,34)) :op4 (e5 / enzyme :name (n7 / name :op1 "p42/p44"~e.39,41 :op2 "MAPK"~e.42)) :op5 (e4 / enzyme :name (n8 / name :op1 "Akt/PKB"~e.45)))))))) # ::id bel_pmid_1528_4181.1506 ::amr-annotator SDL-AMR-09 ::preferred # ::tok COX @-@ 2 protein and activity measured as prostaglandin E( 2 ) level were up @-@ regulated in cells expressing mutant K @-@ ras( V12 ) ; # ::alignments 0-1.1.2.1 1-1.1.2.1 2-1.1.2.1 4-1.1 5-1.1.2 6-1.1.2.2 7-1.1.2.2.1.r 8-1.1.2.2.1.1.1.1 10-1.1.1.1.1 12-1.1.2.2.1 18-1.2 19-1.2.1 20-1.2.1.1 20-1.2.1.1.2 20-1.2.1.1.2.r 21-1.2.1.1.1.1 24-1.2.1.1.2.1 (u / upregulate-01 :ARG1 (a / and~e.4 :op1 (e3 / enzyme :name (n / name :op1 "COX-2"~e.10)) :op2 (a2 / activity-06~e.5 :ARG0 e3~e.0,1,2 :ARG1-of (m / measure-01~e.6 :ARG3~e.7 (l / level~e.12 :quant-of (s / small-molecule :name (n2 / name :op1 "prostaglandin"~e.8 :op2 "E2")))))) :location (c / cell~e.18 :ARG1-of (e / express-03~e.19 :ARG2 (e2 / enzyme~e.20 :name (n3 / name :op1 "K-ras"~e.21) :ARG2-of~e.20 (m3 / mutate-01~e.20 :value "V12"~e.24))))) # ::id bel_pmid_1528_4181.19506 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In conclusion , the results suggest that ROS generation , through COX @-@ 2 up @-@ regulation , may contribute to the active oncogenicity of mutant K @-@ ras in the lung as a result of DNA damage # ::alignments 1-1 4-1.1 4-1.1.1 4-1.1.1.r 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1.1.1.1 8-1.1.2.1.1.1 11-1.1.2.1.1.1.2.1.1.1 13-1.1.2.1.1.1.2.1.1.1 14-1.1.2.1.1.1.2 15-1.1.2.1.1.1.2 16-1.1.2.1.1.1.2 18-1.1.2.1 19-1.1.2.1.1 23-1.1.2.1.1.2 24-1.1.2.1.1.2.2.r 25-1.1.2.1.1.2.2 25-1.1.2.1.1.2.2.2 25-1.1.2.1.1.2.2.2.r 26-1.1.2.1.1.2.2.1.1 28-1.1.2.1.1.2.2.1.1 29-1.1.2.1.1.2.3.r 31-1.1.2.1.1.2.3 32-1.1.2.1.1.2.4.r 34-1.1.2.1.1.2.4 35-1.1.2.1.1.2.4.1.r 36-1.1.2.1.1.2.4.1.1.2.1 37-1.1.2.1.1.2.4.1 (c / conclude-02~e.1 :ARG1 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :ARG0-of (s / suggest-01~e.5 :ARG1~e.6 (p / possible-01~e.18 :ARG1 (c2 / contribute-01~e.19 :ARG0 (g / generate-01~e.8 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ROS"~e.7)) :instrument (u / upregulate-01~e.14,15,16 :ARG1 (e2 / enzyme :name (n3 / name :op1 "COX-2"~e.11,13)))) :ARG2 (o / oncogenicity~e.23 :ARG0-of (a / activate-01) :poss~e.24 (e3 / enzyme~e.25 :name (n4 / name :op1 "K-ras"~e.26,28) :ARG1-of~e.25 (m2 / mutate-01~e.25)) :location~e.29 (l / lung~e.31) :ARG2-of~e.32 (r2 / result-01~e.34 :ARG1~e.35 (d2 / damage-01~e.37 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.36)))))))))) # ::id bel_pmid_1528_4181.28764 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutively active mutant K @-@ ras( V12 ) in E10 cells led to a highly significant ( P < 0.001 ) increased level of peroxides , and a corresponding increase in the amount of DNA strand @-@ break damage , compared with the parental line E10 and the vector control # ::alignments 0-1.1.2.1 0-1.1.2.1.r 1-1.1 1-1.1.2 1-1.1.2.r 2-1.1.3 3-1.1.1.1 6-1.1.3.1 9-1.2.1.1 10-1.2 11-1 12-1.3.r 14-1.3.1.2.1 15-1.3.1.2 17-1.3.1.3 18-1.3.1.3.1 19-1.3.1.3.1.1 21-1.3.1 22-1.3.1.1 23-1.3.1.1.1.r 24-1.3.1.1.1 26-1.3 28-1.3.2.2 29-1.3.2 30-1.3.2.1.r 32-1.3.2.1 33-1.3.2.1.1.r 34-1.3.2.1.1.1.1.1.1.1.1 35-1.3.2.1.1.1.1.1 37-1.3.2.1.1.1.1 38-1.3.2.1.1 40-1.4 41-1.4.1.r 43-1.4.1.1.2 44-1.4.1.1 45-1.4.1.1.1.1 46-1.4.1 48-1.4.1.2.1 49-1.4.1.2 (l / lead-03~e.11 :ARG0 (e / enzyme~e.1 :name (n / name :op1 "K-ras"~e.3) :ARG0-of~e.1 (a / activity-06~e.1 :manner~e.0 (c / constitutive~e.0)) :ARG2-of (m / mutate-01~e.2 :value "V12"~e.6)) :ARG1 (c2 / cell-line~e.10 :name (n2 / name :op1 "E10"~e.9)) :ARG2~e.12 (a2 / and~e.26 :op1 (i / increase-01~e.21 :ARG1 (l2 / level~e.22 :quant-of~e.23 (p / peroxide~e.24)) :ARG2 (s2 / significant-02~e.15 :ARG1-of (h / high-02~e.14)) :ARG1-of (s3 / statistical-test-91~e.17 :ARG2 (l3 / less-than~e.18 :op1 0.001~e.19))) :op2 (i2 / increase-01~e.29 :ARG1~e.30 (a3 / amount~e.32 :degree-of~e.33 (d / damage-01~e.38 :ARG1-of (c3 / cause-01 :ARG0 (b / break-01~e.37 :ARG1 (s / strand~e.35 :part-of (n5 / nucleic-acid :name (n3 / name :op1 "DNA"~e.34))))))) :ARG2-of (c4 / correspond-02~e.28 :ARG1 i))) :ARG1-of (c5 / compare-01~e.40 :ARG2~e.41 (a4 / and~e.46 :op1 (c6 / cell-line~e.44 :name (n4 / name :op1 "E10"~e.45) :mod (p2 / parent~e.43)) :op2 (c7 / control-01~e.49 :ARG0 (v / vector~e.48))))) # ::id bel_pmid_1528_4232.30936 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAT3 activation is much stronger and more prolonged in STAT1 @-@ null mouse embryo fibroblasts than in wild @-@ type cells . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1.2 4-1.1 5-1 6-1.1.2.1 6-1.2.2 7-1.2 8-1.1.3.r 9-1.1.3.1.1.1 11-1.1.3.1 11-1.1.3.1.2 11-1.1.3.1.2.1 11-1.1.3.1.2.1.r 11-1.1.3.1.2.r 12-1.1.3.2.1 13-1.1.3.2 14-1.1.3 17-1.3.1.1 19-1.3.1.1 20-1.3.1 (a3 / and~e.5 :op1 (s / strong-02~e.4 :ARG1 (a2 / activate-01~e.1 :ARG1 (p2 / protein :name (n / name :op1 "STAT3"~e.0))) :mod (m5 / much~e.3 :degree (m6 / more~e.6)) :location~e.8 (f / fibroblast~e.14 :mod (p3 / protein~e.11 :name (n2 / name :op1 "STAT1"~e.9) :ARG2-of~e.11 (m3 / mutate-01~e.11 :mod~e.11 "-/-"~e.11)) :part-of (e / embryo~e.13 :mod (m4 / mouse~e.12)))) :op2 (p / prolong-01~e.7 :ARG1 a2 :degree (m2 / more~e.6) :location f) :ARG1-of (c / compare-01 :ARG2 (c2 / cell~e.20 :mod (w / wild-type~e.17,19)))) # ::id bel_pmid_1528_4232.36882 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In response to IFNgamma , SRC @-@ family kinases are required to activate STAT3 ( but not STAT1 ) through tyrosine phosphorylation , whereas the receptor @-@ bound kinases JAK1 and JAK2 are required to activate both STATs . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.1.1 5-1.1.1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1.1 10-1 10-1.2.1 12-1.1.1 12-1.1.2 12-1.2.1.1 13-1.1.1.2.1.1 15-1.1 15-1.2 16-1.1.2.1 16-1.1.2.1.r 17-1.1.2.3.1.1 20-1.1.1.3.1.1.1 21-1.1.1.3 23-1.1 25-1.2.1.1.1.1.2.1 27-1.2.1.1.1.1.2 28-1.2.1.1.1.1 28-1.2.1.1.1.2 29-1.2.1.1.1.1.1.1 30-1.2.1.1.1 31-1.2.1.1.1.2.1.1 33-1.2.1 35-1.2.1.1 (r2 / require-01~e.10 :ARG1 (c / contrast-01~e.15,23 :ARG1 (a / activate-01~e.12 :ARG0 (k / kinase~e.8 :ARG1-of (i / include-91 :ARG2 (p / protein-family~e.7 :name (n7 / name :op1 "SRC"~e.5)))) :ARG1 (p5 / protein :name (n2 / name :op1 "STAT3"~e.13)) :instrument (p3 / phosphorylate-01~e.21 :ARG1 (a6 / amino-acid :name (n4 / name :op1 "tyrosine"~e.20)))) :ARG2 (a2 / activate-01~e.12 :polarity~e.16 -~e.16 :ARG0 k :ARG1 (p6 / protein :name (n3 / name :op1 "STAT1"~e.17)) :instrument p3)) :ARG1-of (c2 / contrast-01~e.15 :ARG2 (r3 / require-01~e.10,33 :ARG1 (a3 / activate-01~e.12,35 :ARG0 (a4 / and~e.30 :op1 (k4 / kinase~e.28 :name (n6 / name :op1 "JAK1"~e.29) :ARG1-of (b / bind-01~e.27 :ARG2 (r4 / receptor~e.25))) :op2 (k3 / kinase~e.28 :name (n5 / name :op1 "JAK2"~e.31) :ARG1-of b)) :ARG1 (a5 / and :op1 p5 :op2 p6)))) :ARG2-of (r / respond-01~e.1 :ARG1~e.2 (p2 / protein :name (n / name :op1 "IFNgamma"~e.3)))) # ::id bel_pmid_1529_2179.378 ::amr-annotator SDL-AMR-09 ::preferred # ::tok hyperoxia stimulated ERK @-@ 1 and ERK @-@ 2 phosphorylation # ::alignments 0-1.1 1-1 2-1.2.1.1.1.1 2-1.2.1.2.1.1 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1.1.1.1 6-1.2.1.2.1.1 8-1.2.1.2.1.1 9-1.2 (s / stimulate-01~e.1 :ARG0 (h / hyperoxia~e.0) :ARG1 (p2 / phosphorylate-01~e.9 :ARG1 (a / and~e.5 :op1 (e / enzyme :name (n / name :op1 "ERK-1"~e.2,4,6)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK-2"~e.2,6,8))))) # ::id bel_pmid_1529_2179.380 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Collectively , these results indicate that ERK @-@ 1 regulates hyperoxia @-@ stimulated Nrf2 phosphorylation and the subsequent ARE @-@ driven transcriptional response . # ::alignments 0-1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 5-1.2.r 6-1.2.1.1.1 8-1.2.1.1.1 9-1.2 10-1.2.2.1.1.2.1 12-1.2.2.1.1.2 13-1.2.2.1.1.1.1 14-1.2.2.1 15-1.2.2 17-1.2.2.2.1 18-1.2.2.2.3.1.1.1 20-1.2.2.2.3 21-1.2.2.2.2 22-1.2.2.2 (i / indicate-01~e.4 :ARG0 (t / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :mod (t3 / this~e.2)) :ARG1~e.5 (r2 / regulate-01~e.9 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK-1"~e.6,8)) :ARG1 (a / and~e.15 :op1 (p2 / phosphorylate-01~e.14 :ARG1 (p / protein :name (n / name :op1 "Nrf2"~e.13) :ARG1-of (s / stimulate-01~e.12 :ARG0 (h / hyperoxia~e.10)))) :op2 (r3 / respond-01~e.22 :mod (s2 / subsequent~e.17) :mod (t2 / transcribe-01~e.21) :ARG1-of (d / drive-02~e.20 :ARG0 (p3 / protein :name (n2 / name :op1 "ARE"~e.18)))))) :mod (c / collective~e.0)) # ::id bel_pmid_1529_2179.382 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As was seen for wild @-@ type MEFs , hyperoxia enhanced the phosphorylation of endogenous Nrf2 ( lane 6 ) when compared with room air @-@ exposed controls ( lane 5 ) . # ::alignments 2-1.4.1 2-1.4.1.1 2-1.4.1.1.r 4-1.4.1.1.1.2 6-1.4.1.1.1.2 9-1.1 10-1 12-1.2 15-1.2.1.1.1 17-1.2.1.3.1 18-1.2.1.3.1.1.1 21-1.3 22-1.3.2.r 23-1.3.2.1.1.1 24-1.3.2.1.1 26-1.3.2.1 27-1.3.2 29-1.3.2.2.1 30-1.3.2.2.1.1.1 (e5 / enhance-01~e.10 :ARG0 (h / hyperoxia~e.9) :ARG1 (p2 / phosphorylate-01~e.12 :ARG1 (p / protein :name (n / name :op1 "Nrf2"~e.15) :mod (e2 / endogene) :ARG1-of (d / describe-01 :ARG0 (l / lane~e.17 :ARG1-of (l2 / label-01 :ARG2 6~e.18))))) :condition (c3 / compare-01~e.21 :ARG1 h :ARG2~e.22 (c2 / control~e.27 :ARG1-of (e3 / expose-01~e.26 :ARG2 (a / air~e.24 :mod (r / room~e.23))) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane~e.29 :ARG1-of (l4 / label-01 :ARG2 5~e.30))))) :ARG1-of (r2 / resemble-01 :ARG2 (t / thing~e.2 :ARG1-of~e.2 (s2 / see-01~e.2 :location (f / fibroblast :part-of (e4 / embryo :mod (m / mouse)) :mod (w / wild-type~e.4,6)))))) # ::id bel_pmid_1529_2179.384 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In ERK @-@ 1+/+ MEFs , hyperoxia stimulated phosphorylation of Nrf2 ( lane 4 ) , when compared with room air @-@ exposed controls ( lane 3 ) . # ::alignments 1-1.4.2.1.1 6-1.1 7-1 8-1.2 9-1.2.1.r 10-1.2.1.1.1 12-1.3.1 13-1.3.1.1.1 17-1.5 18-1.5.2.r 19-1.5.2.1.1.1 20-1.5.2.1.1 22-1.5.2.1 23-1.5.2 25-1.5.2.2.1 26-1.5.2.2.1.1.1 (s2 / stimulate-01~e.7 :ARG0 (h / hyperoxia~e.6) :ARG1 (p2 / phosphorylate-01~e.8 :ARG1~e.9 (p / protein :name (n / name :op1 "Nrf2"~e.10))) :ARG1-of (d / describe-01 :ARG0 (l / lane~e.12 :ARG1-of (l2 / label-01 :ARG2 4~e.13))) :location (f2 / fibroblast :part-of (e / embryo :mod (m / mouse)) :mod (e3 / enzyme :name (n2 / name :op1 "ERK-1"~e.1) :mod (w / wild-type))) :condition (c / compare-01~e.17 :ARG1 s2 :ARG2~e.18 (c2 / control~e.23 :ARG1-of (e2 / expose-01~e.22 :ARG2 (a / air~e.20 :mod (r / room~e.19))) :ARG1-of (d2 / describe-01 :ARG0 (l3 / lane~e.25 :ARG1-of (l4 / label-01 :ARG2 3~e.26)))))) # ::id bel_pmid_1529_2179.386 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , a high proportion of Nrf2 accumulated in the nucleus of both cell types following the exposure of cells to hyperoxia ( Fig . 1A , right panels ) . # ::alignments 0-1 3-1.1.1.1 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1 7-1.1 8-1.1.2.r 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1.1.1 13-1.1.2.1 14-1.1.2.1.1 15-1.1.3 17-1.1.3.1 18-1.1.3.1.1.r 19-1.1.3.1.1 20-1.1.3.1.2.r 21-1.1.3.1.2 23-1.2.1 25-1.2.1.1 27-1.2.1.2.1 28-1.2.1.2 (h3 / have-concession-91~e.0 :ARG1 (a / accumulate-01~e.7 :ARG1 (p / proportion~e.4 :ARG1-of (h / high-02~e.3) :quant-of~e.5 (p3 / protein :name (n / name :op1 "Nrf2"~e.6))) :location~e.8 (n2 / nucleus~e.10 :part-of~e.11 (c2 / cell~e.13 :ARG1-of (t / type-03~e.14 :mod (b / both~e.12)))) :time (a2 / after~e.15 :op1 (e / expose-01~e.17 :ARG1~e.18 c2~e.19 :ARG2~e.20 (h2 / hyperoxia~e.21)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "1A"~e.25 :location (p2 / panel~e.28 :ARG1-of (r / right-04~e.27))))) # ::id bel_pmid_1529_2179.388 ::amr-annotator SDL-AMR-09 ::preferred # ::tok hyperoxia caused the translocation of Nrf2 from the cytoplasm to the nucleus within 30 @-@ 60 min of exposure # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1.1 6-1.2.3.r 8-1.2.3 9-1.2.2.r 11-1.2.2 12-1.2.4 12-1.2.4.2 12-1.2.4.2.1.1.1.r 12-1.2.4.2.r 13-1.2.4.2.1.1.1 15-1.2.4.2.1.2.1 16-1.2.4.2.1.1.2 16-1.2.4.2.1.2.2 17-1.2.4.1.r 18-1.2.4.1 (c / cause-01~e.1 :ARG0 (h / hyperoxia~e.0) :ARG1 (t / translocate-01~e.3 :ARG1~e.4 (p / protein :name (n / name :op1 "Nrf2"~e.5)) :ARG2~e.9 (n2 / nucleus~e.11) :ARG3~e.6 (c2 / cytoplasm~e.8) :time (a / after~e.12 :op1~e.17 (e / expose-01~e.18) :quant~e.12 (u / up-to~e.12 :op1 (v / value-interval :op1 (t2 / temporal-quantity :quant~e.12 30~e.13 :unit (m2 / minute~e.16)) :op2 (t3 / temporal-quantity :quant 60~e.15 :unit (m3 / minute~e.16))))))) # ::id bel_pmid_1529_2179.16234 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these observations strongly support a role for NADPH oxidase @-@ generated ROS in mediating hyperoxia @-@ induced Nrf2 activation in pulmonary epithelial cells . # ::alignments 0-1.3 1-1.3.2 3-1.1.3 4-1.1 4-1.1.1 4-1.1.1.r 5-1.1.2.1 6-1 6-1.1.2 8-1.2 9-1.2.2.r 10-1.2.2.2.1.2.1.1 11-1.2.2.2.1.1 13-1.2.2.2 14-1.2.2.1.1 15-1.2.1.r 16-1.2.1 17-1.2.1.1.2.1 19-1.2.1.1.2 20-1.2.1.1.1.1.1 21-1.2.1.1 24-1.2.1.1.3.1 25-1.2.1.1.3 (s4 / support-01~e.6 :ARG0 (t3 / thing~e.4 :ARG1-of~e.4 (o / observe-02~e.4) :ARG0-of (s / support-01~e.6 :ARG1-of (s2 / strong-02~e.5)) :mod (t4 / this~e.3)) :ARG1 (r / role~e.8 :topic~e.15 (m4 / mediate-01~e.16 :ARG1 (a / activate-01~e.21 :ARG1 (p / protein :name (n3 / name :op1 "Nrf2"~e.20)) :ARG2-of (i / induce-01~e.19 :ARG0 (h2 / hyperoxia~e.17)) :location (c / cell~e.25 :part-of (e2 / epithelium~e.24 :part-of (l / lung))))) :beneficiary~e.9 (s3 / small-molecule :name (n / name :op1 "ROS"~e.14) :ARG1-of (g / generate-01~e.13 :ARG0 (m2 / macro-molecular-complex :part (o2 / oxidase~e.11) :part (s5 / small-molecule :name (n4 / name :op1 "NADPH"~e.10)))))) :condition (t6 / take-01~e.0 :ARG1 t3 :mod (t2 / together~e.1))) # ::id bel_pmid_1529_2179.22402 ::amr-annotator SDL-AMR-09 ::preferred # ::tok hyperoxia stimulated ERK @-@ 1 and ERK @-@ 2 phosphorylation {SE : Canonical ERK phosphorylation leading directly to activation} # ::alignments 0-1.1.1 1-1.1 2-1.1.2.1.1.1.1 4-1.1.2.1.1.1.1 5-1.1.2.1 6-1.1.2.1.1.1.1 6-1.1.2.1.2.1.1 8-1.1.2.1.2.1.1 9-1.1.2 13-1.2.1.1.1 14-1.2 15-1.2.3 16-1.2.3.2 (m / multi-sentence :snt1 (s / stimulate-01~e.1 :ARG0 (h / hyperoxia~e.0) :ARG1 (p2 / phosphorylate-01~e.9 :ARG1 (a / and~e.5 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK-1"~e.2,4,6)) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK-2"~e.6,8))))) :snt2 (p / phosphorylate-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.13)) :mod (c2 / canon) :ARG0-of (l / lead-03~e.15 :ARG2 (a2 / activate-01) :ARG1-of (d / direct-02~e.16)))) # ::id bel_pmid_1529_2179.37048 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of the ERK @-@ 1 mutant , but not the ERK @-@ 2 mutant , significantly inhibited hyperoxia @-@ induced ARE transcription , suggesting that ERK @-@ 1 at least in part mediates Nrf2 translocation and its downstream target expression ( Fig . 7B ) . # ::alignments 0-1.1.1 0-1.2.2 1-1.1.1.1.r 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1.1 6-1.1.1.1.2 6-1.1.1.1.2.r 8-1 9-1.2.1 9-1.2.1.r 11-1.2.2.1.1.1 13-1.2.2.1.1.1 14-1.1.1.1 14-1.1.1.1.2 14-1.1.1.1.2.r 14-1.2.2.1 14-1.2.2.1.2 14-1.2.2.1.2.r 16-1.1.3 17-1.1 17-1.2 18-1.1.2.2.1 20-1.1.2.2 21-1.1.2.1.1.1 22-1.1.2 24-1.3 26-1.1.1.1.1.1 26-1.2.2.1.1.1 28-1.3.1.1 29-1.3.1.3 30-1.3.1.3 31-1.3.1.3.1 31-1.3.1.3.r 32-1.3.1.3.r 33-1.3.1 34-1.3.1.2.1.1.1.1 35-1.3.1.2.1 36-1.3.1.2 37-1.3.1.2.2.1 37-1.3.1.2.2.1.r 38-1.3.1.2.2.2 39-1.3.1.2.2.3 40-1.3.1.2.2 42-1.4.1 44-1.4.1.1 (c / contrast-01~e.8 :ARG1 (i / inhibit-01~e.17 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (e2 / enzyme~e.6,14 :name (n / name :op1 "ERK-1"~e.3,5,26) :ARG2-of~e.6,14 (m / mutate-01~e.6,14))) :ARG1 (t3 / transcribe-01~e.22 :ARG1 (p3 / protein :name (n3 / name :op1 "ARE"~e.21)) :ARG2-of (i3 / induce-01~e.20 :ARG0 (h / hyperoxia~e.18))) :ARG1-of (s2 / significant-02~e.16)) :ARG2 (i2 / inhibit-01~e.17 :polarity~e.9 -~e.9 :ARG0 (o2 / overexpress-01~e.0 :ARG1 (e4 / enzyme~e.14 :name (n2 / name :op1 "ERK-2"~e.11,13,26) :ARG1-of~e.14 (m2 / mutate-01~e.14))) :ARG1 t3) :ARG0-of (s / suggest-01~e.24 :ARG1 (m3 / mediate-01~e.33 :ARG0 e2~e.28 :ARG1 (a2 / and~e.36 :op1 (t2 / translocate-01~e.35 :ARG1 (p / protein :name (n4 / name :op1 "Nrf2"~e.34))) :op2 (e5 / express-03~e.40 :ARG2~e.37 p~e.37 :location (d / downstream~e.38) :mod (t / target-01~e.39))) :degree~e.31,32 (a / at-least~e.29,30 :op1 (p2 / part~e.31)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.42 :mod "7B"~e.44))) # ::id bel_pmid_1529_2206.19252 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The interleukin @-@ 6 ( IL6 ) family of cytokines signals through the common receptor subunit gp130 , and subsequently activates Stat3 , MAPK , and PI3K . # ::alignments 1-1.1.1.1.1 3-1.1.1.1.1 7-1.1.1 10-1.1 13-1.1.2.2.1.1 14-1.1.2.2.1 15-1.1.2.2 16-1.1.2.1.1 18-1 19-1.2.2 19-1.2.2.r 20-1.2 21-1.2.1.1.1.1 23-1.2.1.2.1.1 26-1.2.1.3.1.1 (a / and~e.18 :op1 (s / signal-07~e.10 :ARG0 (p / protein-family~e.7 :name (n2 / name :op1 "interleukin-6"~e.1,3)) :instrument (p4 / protein :name (n3 / name :op1 "gp130"~e.16) :mod (s2 / subunit~e.15 :part-of (r2 / receptor~e.14 :mod (c2 / common~e.13))))) :op2 (a2 / activate-01~e.20 :ARG1 (a3 / and :op1 (p3 / protein :name (n4 / name :op1 "Stat3"~e.21)) :op2 (e / enzyme :name (n / name :op1 "MAPK"~e.23)) :op3 (e2 / enzyme :name (n5 / name :op1 "PI3K"~e.26))) :manner~e.19 (s4 / subsequent~e.19))) # ::id bel_pmid_1529_2206.21658 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Experiments in primary mammary epithelial cells and transfected COS @-@ 7 cells revealed a p44 @/@ 42 MAPK and EGFR @-@ dependent Stat3 activation . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.2 3-1.1.1.1.3 4-1.1.1.1.1 5-1.1.1.1 6-1.1.1 7-1.1.1.2.2 8-1.1.1.2.1.1 10-1.1.1.2.1.1 11-1.1.1.2 12-1 15-1.2.2.1.2 18-1.2.2.1 19-1.2.2.1.1.1.1 21-1.2.2 22-1.2.1.1.1 23-1.2 (r / reveal-01~e.12 :ARG0 (e / experiment-01~e.0 :ARG1~e.1 (a / and~e.6 :op1 (c / cell~e.5 :part-of (e2 / epithelium~e.4) :mod (p2 / primary~e.2) :mod (m / mammary~e.3)) :op2 (c2 / cell-line~e.11 :name (n2 / name :op1 "COS-7"~e.8,10) :ARG1-of (t / transfect-01~e.7)))) :ARG1 (a2 / activate-01~e.23 :ARG1 (p / protein :name (n3 / name :op1 "Stat3"~e.22)) :ARG0-of (d / depend-01~e.21 :ARG1 (a3 / and~e.18 :op1 (e5 / enzyme :name (n4 / name :op1 "EGFR"~e.19)) :op2 (s / slash~e.15 :op1 (e3 / enzyme :name (n / name :op1 "p44MAPK")) :op2 (e4 / enzyme :name (n5 / name :op1 "p42MAPK"))))))) # ::id bel_pmid_1529_2206.28426 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution , which is partially induced by IL6 and LIF . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1 3-1.2.1 4-1.2 5-1.2.2.1 6-1.2.2 7-1.3.r 9-1.3.2 10-1.3.1 11-1.3 12-1.4.r 13-1.4 17-1.4.1.2 17-1.4.1.2.r 18-1.4.1 19-1.4.1.1.r 20-1.4.1.1.1.1.1 21-1.4.1.1 22-1.4.1.1.2.1.1 (c / control-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "Stat3"~e.0)) :ARG1 (a / and~e.4 :op1 (d / die-01~e.3 :ARG1 (c2 / cell~e.2)) :op2 (r / remodel-01~e.6 :ARG1 (t / tissue~e.5))) :location~e.7 (g2 / gland~e.11 :mod (m / mammary~e.10) :part-of (m2 / mouse~e.9)) :time~e.12 (i / involution~e.13 :ARG2-of (i2 / induce-01~e.18 :ARG0~e.19 (a2 / and~e.21 :op1 (p3 / protein :name (n2 / name :op1 "IL6"~e.20)) :op2 (p4 / protein :name (n3 / name :op1 "LIF"~e.22))) :degree~e.17 (p / part~e.17)))) # ::id bel_pmid_1532_0963.2798 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that the Tyr701 phosphorylation kinetics of Stat1 mediated by IFN stimulation was higher when cells were incubated with IFN @-@ alpha5 than when using IFN @-@ alpha2 . Similarly , Tyr( 1054 @/@ 1055 ) phosphorylation kinetics of Tyk2 were more intense after exposure to IFN @-@ alpha5 than when using IFN @-@ alpha2 . Concomitantly , Tyr705 phosphorylation of Stat3 was higher after stimulation with IFN @-@ alpha5 than with IFN @-@ alpha2 . # ::alignments 0-1.1.1 1-1.1 5-1.1.2.1.1 6-1.1.2.1 7-1.1.2.1.1.1.r 8-1.1.2.1.1.1.3.1.1 9-1.1.2.1.2 10-1.1.2.1.2.1.r 11-1.1.2.1.2.1.1.1.1 12-1.1.2.1.2.1 14-1.1.2 14-1.1.2.2 14-1.1.2.2.r 14-1.3 14-1.3.2 14-1.3.2.r 15-1.3.3.r 16-1.1.2.3.1 18-1.1.2.3 20-1.1.2.1.2.1.1.1.1 22-1.1.2.3.2.1.1 23-1.1.2.4.r 24-1.3.3.r 25-1.1.2.4 26-1.1.2.4.1.1.1 26-1.3.3.1.1.1.1 26-1.3.4.1.1.1 28-1.1.2.4.1.1.1 28-1.3.4.1.1.1 30-1.2.5 33-1.2.1.1.1.1.1 34-1.2.1.1.1 35-1.2.1.1.1.2.1 37-1.2.1.1 38-1.2.1 40-1.2.1.1.1.1.3.1.1 42-1.1.2.2 42-1.2.2 42-1.3.2 43-1.2 44-1.2.4 45-1.2.4.1 47-1.2.3.1.1.1 47-1.2.4.1.1.1.1 49-1.2.4.1.1.1.1 50-1.2.3.r 51-1.2.4.r 52-1.2.3 53-1.1.2.4.1.1.1 53-1.2.3.1.1.1 53-1.3.3.1.1.1.1 53-1.3.4.1.1.1 55-1.1.2.4.1.1.1 55-1.2.3.1.1.1 55-1.3.4.1.1.1 57-1.3.5 60-1.3.1 61-1.3.1.1.r 62-1.3.1.1.3.1.1 64-1.3 64-1.3.2 64-1.3.2.r 65-1.3.3 66-1.3.3.1 66-1.3.4 68-1.3.3.1.1.1.1 68-1.3.4.1.1.1 70-1.3.3.1.1.1.1 71-1.3.4.r 73-1.1.2.4.1.1.1 73-1.2.3.1.1.1 73-1.3.4.1.1.1 75-1.1.2.4.1.1.1 75-1.2.3.1.1.1 75-1.3.4.1.1.1 (m / multi-sentence :snt1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (h2 / high-02~e.14 :ARG1 (k / kinetics~e.6 :mod (p2 / phosphorylate-01~e.5 :ARG1~e.7 (a / amino-acid :mod 701 :name (n / name :op1 "tyrosine") :part-of (p / protein :name (n12 / name :op1 "Stat1"~e.8)))) :ARG1-of (m2 / mediate-01~e.9 :ARG0~e.10 (s / stimulate-01~e.12 :ARG0 (p3 / protein :name (n3 / name :op1 "IFN"~e.11,20))))) :degree~e.14 (m3 / more~e.14,42) :condition (i / incubate-01~e.18 :ARG1 (c / cell~e.16) :ARG2 (p4 / protein :name (n4 / name :op1 "IFN-alpha5"~e.22))) :compared-to~e.23 (u / use-01~e.25 :ARG1 (p5 / protein :name (n7 / name :op1 "IFN-alpha2"~e.26,28,53,55,73,75))))) :snt2 (i2 / intense-02~e.43 :ARG1 (k3 / kinetics~e.38 :mod (p6 / phosphorylate-01~e.37 :ARG1 (s2 / slash~e.34 :op1 (a4 / amino-acid :mod 1054~e.33 :name (n2 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n6 / name :op1 "Tyk2"~e.40))) :op2 (a5 / amino-acid :mod 1055~e.35 :name (n5 / name :op1 "tyrosine") :part-of e2)))) :degree (m4 / more~e.42) :compared-to~e.50 (u2 / use-01~e.52 :ARG1 (p7 / protein :name (n8 / name :op1 "IFN-alpha2"~e.47,53,55,73,75))) :time~e.51 (a3 / after~e.44 :op1 (e / expose-01~e.45 :ARG1 (p8 / protein :name (n9 / name :op1 "IFN-alpha5"~e.47,49)))) :ARG1-of (r / resemble-01~e.30)) :snt3 (h / high-02~e.14,64 :ARG1 (p9 / phosphorylate-01~e.60 :ARG1~e.61 (a6 / amino-acid :mod 705 :name (n13 / name :op1 "tyrosine") :part-of (p10 / protein :name (n14 / name :op1 "Stat3"~e.62)))) :degree~e.14,64 (m5 / more~e.14,42,64) :time~e.15,24 (a7 / after~e.65 :op1 (s3 / stimulate-01~e.66 :ARG0 (p11 / protein :name (n15 / name :op1 "IFN-alpha5"~e.26,53,68,70)))) :compared-to~e.71 (s4 / stimulate-01~e.66 :ARG0 (p12 / protein :name (n16 / name :op1 "IFN-alpha2"~e.26,28,53,55,68,73,75))) :mod (c2 / concomitant~e.57))) # ::id bel_pmid_1535_5339.5770 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The accumulation of the ST6Gal I transcript in response to activated Ras was accompanied by an increase of alpha2,6 @-@ sialyltransferase activity and of Neu5Acalpha2,6Gal at the cell surface . # ::alignments 1-1.2 2-1.2.1.r 4-1.2.1.1.1.1.1 5-1.2.1.1.1.1.1 7-1.2.2.r 8-1.2.2 9-1.2.2.1.r 10-1.2.2.1.2 11-1.2.2.1.1.1 13-1 14-1.1.r 16-1.1 17-1.1.1.r 18-1.1.1.1.1.1.1 20-1.1.1.1.1.1.1 21-1.1.1 22-1.1.1.1 23-1.1.1.1.r 24-1.1.1.1.2.1.1 25-1.1.1.2.r 27-1.1.1.2.1 28-1.1.1.2 (a6 / accompany-01~e.13 :ARG0~e.14 (i / increase-01~e.16 :ARG1~e.17 (a2 / activity-06~e.21 :ARG0~e.23 (a5 / and~e.22 :op1 (e3 / enzyme :name (n4 / name :op1 "alpha2,6-sialyltransferase"~e.18,20)) :op2 (e4 / enzyme :name (n5 / name :op1 "Neu5Acalpha2,6Gal"~e.24))) :location~e.25 (s / surface~e.28 :part-of (c / cell~e.27)))) :ARG1 (a / accumulate-01~e.1 :ARG1~e.2 (m / molecular-physical-entity :ARG0-of (t / transcribe-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ST6Gal-I"~e.4,5)))) :ARG2-of~e.7 (r / respond-01~e.8 :ARG1~e.9 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.11) :ARG1-of (a3 / activate-01~e.10))))) # ::id bel_pmid_1535_5339.19518 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results obtained with H @-@ RasV12 partial loss of function mutants H @-@ RasV12S35 ( Raf signal only ) , H @-@ RasV12C40 ( PI3 @-@ kinase signal only ) and H @-@ RasV12G37 ( RalGEFs signal only ) suggest that the H @-@ Ras induction of the mouse ST6Gal I gene ( Siat1 ) transcription is primarily routed through RalGEFs . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1.1.1.1 3-1.1.2.1.1.3.1.1.1 3-1.1.2.1.2.1.1 3-1.1.2.1.3.1.1 6-1.1.2.1.1.3.1.3.2 6-1.1.2.1.1.3.1.3.2.r 7-1.1.2.1.1.3.1.3 8-1.1.2.1.1.3.1.3.1.r 9-1.1.2.1.1.3.1.3.1 10-1.1.2.1.1 10-1.1.2.1.1.2 10-1.1.2.1.1.2.r 10-1.1.2.1.1.3.1 10-1.1.2.1.1.3.1.2 10-1.1.2.1.1.3.1.2.r 10-1.1.2.1.2 10-1.1.2.1.2.2 10-1.1.2.1.2.2.r 10-1.1.2.1.3 10-1.1.2.1.3.2 10-1.1.2.1.3.2.r 11-1.1.2.1.1.1.1 11-1.1.2.1.1.3.1.1.1 15-1.1.2.1.1.4.1.1.1 16-1.1.2.1.1.4 16-1.1.2.1.3.3 17-1.1.2.1.3.3.2 20-1.1.2.1.1.1.1 20-1.1.2.1.2.1.1 20-1.1.2.1.3.1.1 26-1.1.2.1.2.3.1 27-1.1.2.1.1.4 27-1.1.2.1.2.3 27-1.1.2.1.3.3 28-1.1.2.1.3.3.2 31-1.1.2.1.3.1.1 36-1.1.2.1.3.3 37-1.1.2.1.3.3.2 39-1 42-1.1.2.1.3.1.1 42-1.2.2.1.1.1 44-1.1.2.1.3.1.1 44-1.2.2.1.1.1 45-1.2.2 46-1.2.2.2.r 48-1.2.2.2.1.2 49-1.2.2.2.1.1.1 50-1.2.2.2.1.1.2 51-1.2.2.2.1 55-1.2.2.2 57-1.2.3 58-1.2 (s / suggest-01~e.39 :ARG0 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0) :ARG1-of (o / obtain-01~e.1 :instrument~e.2 (a / and :op1 (e / enzyme~e.10 :name (n3 / name :op1 "H-Ras"~e.3,11,20) :ARG2-of~e.10 (m / mutate-01~e.10 :value "V12S35") :ARG1-of (m5 / mean-01 :ARG2 (e2 / enzyme~e.10 :name (n / name :op1 "H-Ras"~e.3,11) :ARG2-of~e.10 (m6 / mutate-01~e.10 :value "V12") :ARG0-of (l2 / lose-02~e.7 :ARG1~e.8 (f2 / function~e.9) :degree~e.6 (p / part~e.6)))) :ARG1-of (s2 / signal-07~e.16,27 :ARG0 (e5 / enzyme :name (n2 / name :op1 "Raf"~e.15)))) :op2 (e3 / enzyme~e.10 :name (n4 / name :op1 "H-Ras"~e.3,20) :ARG2-of~e.10 (m2 / mutate-01~e.10 :value "V12C40") :ARG1-of (s3 / signal-07~e.27 :ARG0 (k / kinase~e.26 :name (n6 / name :op1 "P13")))) :op3 (e4 / enzyme~e.10 :name (n5 / name :op1 "H-Ras"~e.3,20,31,42,44) :ARG2-of~e.10 (m3 / mutate-01~e.10 :value "V12G37") :ARG1-of (s4 / signal-07~e.16,27,36 :ARG0 (p2 / pathway :name (n9 / name :op1 "RalGEF")) :mod (o2 / only~e.17,28,37)))))) :ARG1 (r2 / route-01~e.58 :ARG0 p2 :ARG1 (i / induce-01~e.45 :ARG0 (e6 / enzyme :name (n7 / name :op1 "H-Ras"~e.42,44)) :ARG2~e.46 (t2 / transcribe-01~e.55 :ARG1 (g / gene~e.51 :name (n8 / name :op1 "ST6Gal"~e.49 :op2 "I"~e.50) :mod (m4 / mouse~e.48)))) :mod (p3 / primary~e.57))) # ::id bel_pmid_1535_5339.20914 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transformation by human K @-@ Ras or H @-@ Ras ( S12 and V12 point mutations , respectively ) results in a 10 @-@ fold increase in ST6Gal I mRNA , but no alteration in the expression of related sialyltransferases . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.3 3-1.1.1.1.1.1 5-1.1.1.1.1.1 5-1.1.1.2.1.1 6-1.1.1 7-1.1.1.2.1.1 9-1.1.1.2.1.1 13-1.1.1.2.2.1 15-1.1.1.1 15-1.1.1.1.2 15-1.1.1.1.2.r 15-1.1.1.2 15-1.1.1.2.2 15-1.1.1.2.2.r 19-1 20-1.2.r 22-1.2.1.2.1 24-1.2.1.2 25-1.2.1 26-1.2.1.1.r 27-1.2.1.1.2.1.1.1 28-1.2.1.1.2.1.1.2 29-1.2.1.1.1.1 31-1.2 32-1.2.2.1 32-1.2.2.1.r 33-1.2.2 34-1.2.2.2.r 36-1.2.2.2 37-1.2.2.2.1.r 38-1.2.2.2.1.2 (r / result-01~e.19 :ARG1 (t / transform-01~e.0 :ARG0~e.1 (o / or~e.6 :op1 (e / enzyme~e.15 :name (n / name :op1 "K-Ras"~e.3,5) :ARG2-of~e.15 (m / mutate-01~e.15 :value "S2") :mod (h / human~e.2)) :op2 (e2 / enzyme~e.15 :name (n2 / name :op1 "H-Ras"~e.5,7,9) :ARG2-of~e.15 (m2 / mutate-01~e.15 :value "V12"~e.13) :mod h))) :ARG2~e.20 (c / contrast-01~e.31 :ARG1 (i / increase-01~e.25 :ARG1~e.26 (n6 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.29) :ARG0-of (e5 / encode-01 :ARG1 (e6 / enzyme :name (n3 / name :op1 "ST6Gal"~e.27 :op2 "I"~e.28)))) :ARG2 (p / product-of~e.24 :op1 10~e.22)) :ARG2 (a / alter-01~e.33 :polarity~e.32 -~e.32 :ARG1~e.34 (e3 / express-03~e.36 :ARG2~e.37 (e4 / enzyme :name (n5 / name :op1 "sialyltransferase") :ARG1-of (r3 / relate-01~e.38)))))) # ::id bel_pmid_1536_9798.8104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Survivin disruption by DN T34A Survivin blocked CA @-@ Ras @-@ induced IL @-@ 3 @-@ independent cell survival and proliferation ; however , it did not affect CA @-@ Ras @-@ mediated enhancement of S @-@ phase , indicating that the anti @-@ apoptotic activity of CA @-@ Ras is Survivin dependent while its S @-@ phase enhancing effect is not . # ::alignments 0-1.2.1.1.1.1 0-1.2.1.2.1.1 1-1.2.1 4-1.2.1.1.2.1 5-1.2.1.1.1.1 5-1.2.1.2.1.1 6-1.2 7-1.2.2.1.2.1.1.1 9-1.2.2.1.2.1.1.1 11-1.2.2.1.2 12-1.2.2.1.3.1.1.1 14-1.2.2.1.3.1.1.1 16-1.1.4.1.2.1 16-1.2.2.1.3 17-1.2.2.1.1 18-1.2.2.1 19-1.2.2 20-1.2.2.2 22-1 24-1.1.2 26-1.1.1 26-1.1.1.r 27-1.1 28-1.1.3.2.1 29-1.1.3.2.1 30-1.1.3.2.1 32-1.1.3.2 33-1.1.3 34-1.1.3.1.r 35-1.1.3.1.1.1 37-1.1.3.1.1.1 39-1.1.4 40-1.1.4.1.r 42-1.1.4.1.1.2 44-1.1.4.1.1.2.1 45-1.1.4.1.1 46-1.1.4.1.1.1.r 47-1.1.4.1.1.1 48-1.1.4.1.1.1 49-1.1.4.1.1.1 51-1.2.1.1.1.1 51-1.2.1.2.1.1 52-1.1.4.1.1.3 52-1.1.4.1.2 53-1.1.4.1 55-1.1.4.1.2.2.1.1 56-1.1.4.1.2.2.1.1 57-1.1.4.1.2.2.1.1 58-1.1.4.1.2.2.1 59-1.1.4.1.2.2 61-1.1.4.1.2.1.r (h / have-concession-91~e.22 :ARG1 (a2 / affect-01~e.27 :polarity~e.26 -~e.26 :ARG0 d~e.24 :ARG1 (e2 / enhance-01~e.33 :ARG1~e.34 (e5 / event :name (n / name :op1 "S-phase"~e.35,37)) :ARG1-of (m / mediate-01~e.32 :ARG0 e~e.28,29,30)) :ARG0-of (i2 / indicate-01~e.39 :ARG1~e.40 (c3 / contrast-01~e.53 :ARG1 (a3 / activity-06~e.45 :ARG0~e.46 e~e.47,48,49 :ARG1 (o / oppose-01~e.42 :ARG1 (a4 / apoptosis~e.44)) :ARG0-of (d4 / depend-01~e.52 :ARG1 p)) :ARG2 (d5 / depend-01~e.52 :polarity~e.61 -~e.16 :ARG0 (a5 / affect-01~e.59 :ARG2 (e4 / enhance-01~e.58 :ARG0 e5~e.55,56,57)) :ARG1 p2)))) :ARG2 (b / block-01~e.6 :ARG0 (d / disrupt-01~e.1 :ARG0 (p2 / protein :name (n2 / name :op1 "Survivin"~e.0,5,51) :ARG2-of (m2 / mutate-01 :value "T34A"~e.4 :mod "-/-")) :ARG1 (p / protein :name (n5 / name :op1 "Survivin"~e.0,5,51))) :ARG1 (a / and~e.19 :op1 (s / survive-01~e.18 :ARG0 (c / cell~e.17) :ARG2-of (i / induce-01~e.11 :ARG0 (e / enzyme :name (n3 / name :op1 "CA-Ras"~e.7,9))) :ARG0-of (d3 / depend-01~e.16 :ARG1 (p5 / protein :name (n4 / name :op1 "IL-3"~e.12,14)))) :op2 (p3 / proliferate-01~e.20 :ARG0 c :ARG1-of i :ARG0-of d3)))) # ::id bel_pmid_1536_9798.9254 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Survivin expression is up @-@ regulated by IL @-@ 3 in Ba @/@ F3 and CD34+ cells and inhibited by the Ras inhibitor , farnesylthiosalicylic acid . # ::alignments 0-1.1.1.1.2.1 1-1.1.1 7-1.1.2.2.1 9-1.1.2.2.1 11-1.1.3.1.2.1 13-1.1.3.1.2.1 14-1.1.3 15-1.1.3.2.2.1 16-1.1.3.1 16-1.1.3.2 17-1 17-1.1.3 18-1.2 18-1.2.1.3 19-1.2.1.r 21-1.2.1.3.1.2.1 22-1.2.1.3 24-1.2.1.2.1 25-1.2.1.2.2 (a2 / and~e.17 :op1 (u / upregulate-01 :ARG1 (e2 / express-03~e.1 :ARG2 (p / protein :wiki "Survivin" :name (n2 / name :op1 "Survivin"~e.0))) :ARG2 (p2 / protein :wiki "Interleukin_3" :name (n3 / name :op1 "IL-3"~e.7,9)) :location (a / and~e.14,17 :op1 (c2 / cell-line~e.16 :wiki - :name (n4 / name :op1 "Ba/F3"~e.11,13)) :op2 (c / cell-line~e.16 :wiki "CD34" :name (n5 / name :op1 "CD34+"~e.15)))) :op2 (i2 / inhibit-01~e.18 :ARG0~e.19 (s / small-molecule :wiki - :name (n7 / name :op1 "farnesylthiosalicylic"~e.24 :op2 "acid"~e.25) :ARG0-of (i / inhibit-01~e.18,22 :ARG1 (p3 / protein-family :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras"~e.21)))) :ARG1 e2)) # ::id bel_pmid_1536_9798.27516 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Over @-@ expression of constitutively activated H @-@ Ras ( CA @-@ Ras ) in Ba @/@ F3 cells blocked down @-@ modulation of Survivin expression , G0 @/@ G1 arrest , and apoptosis induced by IL @-@ 3 withdrawal , while dominant @-@ negative ( DN ) H @-@ Ras down @-@ regulated Survivin . # ::alignments 2-1.1.2.1.1 4-1.1.1.1.2.1 4-1.1.1.1.2.1.r 5-1.1.1.1.2 6-1.1.1.1.1.1 8-1.1.1.1.1.1 12-1.1.1.1.1.1 15-1.1.1.2.1.1 17-1.1.1.2.1.1 18-1.1.1.2 18-1.1.2.2.1 19-1.1 24-1.1.2.1.1.1.1.1 25-1.1.2.1.1 27-1.1.2.2.1.1.1 29-1.1.2.2.1.1.1 30-1.1.2.2 32-1.1.2 33-1.1.2.3 34-1.1.2.3.1 35-1.1.2.3.1.1.r 36-1.1.2.3.1.1.1.1.1 38-1.1.2.3.1.1.1.1.1 39-1.1.2.3.1.1 41-1 48-1.2.1.1.1 50-1.2.1.1.1 54-1.2.2 (c4 / contrast-01~e.41 :ARG1 (b / block-01~e.19 :ARG0 (o / overexpress-01 :ARG1 (e / enzyme :name (n / name :op1 "H-Ras"~e.6,8,12) :ARG1-of (a / activate-01~e.5 :manner~e.4 (c / constitutive~e.4))) :location (c5 / cell-line~e.18 :name (n7 / name :op1 "Ba/F3"~e.15,17))) :ARG1 (a2 / and~e.32 :op1 (d2 / downmodulate-01 :ARG1 (e3 / express-03~e.2,25 :ARG2 (p / protein :name (n3 / name :op1 "Survivin"~e.24)))) :op2 (a3 / arrest-02~e.30 :ARG1 (c3 / cell-line~e.18 :name (n4 / name :op1 "G0/G1"~e.27,29))) :op3 (a4 / apoptosis~e.33 :ARG2-of (i / induce-01~e.34 :ARG0~e.35 (w / withdraw-01~e.39 :ARG1 (p2 / protein :name (n5 / name :op1 "IL-3"~e.36,38))))))) :ARG2 (d / downregulate-01 :ARG0 (e4 / enzyme :name (n6 / name :op1 "H-Ras"~e.48,50) :ARG2-of (m / mutate-01 :mod "-/-")) :ARG1 p~e.54)) # ::id bel_pmid_1538_3658.21950 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By contrast , serum @- and glucocorticoid @-@ inducible kinase 1 ( SGK1 ) was significantly induced in a p53 @-@ dependent manner after DNA damage , and this induction was through extracellular signal @-@ regulated kinase 1 @/@ 2 @-@ mediated posttranslational regulation . # ::alignments 1-1 8-1.1 9-1.1.5.3.1.1.1.1 10-1.1.5.3.1.1.1.2 12-1.1.1.1.1 15-1.1.4 16-1.1 19-1.1.2.1.1.1 21-1.1.2 22-1.1.2.r 23-1.1.3 24-1.1.3.1.1.2.1 25-1.1.3.1 29-1.1 32-1.1.5.1 33-1.1.5.2.1 35-1.1.5.2 36-1.1.5.3.1.1.1.1 37-1.1.5.3.1.1.1.2 38-1.1.5.3.1 39-1.1.5.3.1.2.1.2 41-1.1.5.3 42-1.1.5.4 42-1.1.5.4.1 42-1.1.5.4.1.r 43-1.1.5 43-1.1.5.2 43-1.1.5.2.r (c / contrast-01~e.1 :ARG2 (i / induce-01~e.8,16,29 :ARG2 (e3 / enzyme :name (n3 / name :op1 "SGK1"~e.12)) :manner~e.22 (d / depend-01~e.21 :ARG1 (p / protein :name (n / name :op1 "p53"~e.19))) :time (a2 / after~e.23 :op1 (d2 / damage-01~e.25 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.24)))) :ARG1-of (s3 / significant-02~e.15) :instrument (r2 / regulate-01~e.43 :mod (e / extracellular~e.32) :ARG1-of~e.43 (r / regulate-01~e.35,43 :ARG0 (s / signal-07~e.33)) :ARG1-of (m / mediate-01~e.41 :ARG0 (s2 / slash~e.38 :op1 (e2 / enzyme :name (n2 / name :op1 "kinase"~e.9,36 :op2 1~e.10,37)) :op2 (e4 / enzyme :name (n4 / name :op1 "kinase" :op2 2~e.39)))) :time (a4 / after~e.42 :op1~e.42 (t / translate-02~e.42))))) # ::id bel_pmid_1538_9879.2572 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 6 family cytokines ( Interleukin @-@ 6 and Oncostatin M ( OSM )) - increase STAT3 phosphorylation ( pSTAT3 ) , increase CCAAT enhancer binding protein delta ( C/EBPdelta ) gene expression # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1.1 4-1.1 6-1.1.2.1.1.1.1 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2.1.2.1.1 11-1.1.2.1.2.1.1 16-1 17-1.2.1.1.1.1 18-1.2.1 23-1 27-1.1.2.1.1 27-1.1.2.1.2 27-1.2.1.1 30-1.2.2.1.1.1 32-1.2.2.1 33-1.2.2 (i / increase-01~e.16,23 :ARG0 (c / cytokine~e.4 :ARG1-of (i2 / include-91 :ARG2 (p3 / protein-family~e.3 :name (n7 / name :op1 "IL-6"~e.0,2))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and~e.9 :op1 (p5 / protein~e.27 :name (n8 / name :op1 "Interleukin-6"~e.6,8)) :op2 (p6 / protein~e.27 :name (n9 / name :op1 "Oncostatin-M"~e.10,11))))) :ARG1 (a2 / and :op1 (p / phosphorylate-01~e.18 :ARG1 (p2 / protein~e.27 :name (n5 / name :op1 "STAT3"~e.17))) :op2 (e / express-03~e.33 :ARG2 (g3 / gene~e.32 :name (n6 / name :op1 "C/EBPdelta"~e.30))))) # ::id bel_pmid_1550_7530.2578 ::amr-annotator SDL-AMR-09 ::preferred # ::tok results indicate that BCL @-@ 6 negatively regulates proliferation of the monocytic @/@ macrophage lineage by suppressing an autocrine IL @-@ 6/STAT3 @-@ mediated gene expression program . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1 2-1.2.r 3-1.2.1.1.1 5-1.2.1.1.1 6-1.2 7-1.2 8-1.2.2 12-1.2.2.1 12-1.2.3.1.2.1 13-1.2.2.1.2.1 14-1.2.2.1.1 14-1.2.2.1.2 15-1.2.3.r 16-1.2.3 18-1.2.3.1.3 19-1.2.3.1.2.1.1.1.1 23-1.2.3.1.2 24-1.2.3.1.1.1 25-1.2.3.1.1 26-1.2.3.1 (i / indicate-01~e.1 :ARG0 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) :ARG1~e.2 (d / downregulate-01~e.6,7 :ARG0 (p3 / protein :name (n / name :op1 "BCL-6"~e.3,5)) :ARG1 (p / proliferate-01~e.8 :ARG0 (s2 / slash~e.12 :op1 (l2 / lineage~e.14 :mod (m2 / monocyte)) :op2 (l3 / lineage~e.14 :mod (m3 / macrophage~e.13)))) :manner~e.15 (s / suppress-01~e.16 :ARG1 (p2 / program~e.26 :mod (e / express-03~e.25 :ARG2 (g2 / gene~e.24)) :ARG1-of (m / mediate-01~e.23 :ARG0 (s3 / slash~e.12 :op1 (p4 / protein :name (n3 / name :op1 "IL-6"~e.19)) :op2 (p5 / protein :name (n4 / name :op1 "STAT3")))) :mod (a / autocrine~e.18))))) # ::id bel_pmid_1550_7530.32694 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Crucial to this enhanced proliferation is spontaneous interleukin 6 ( IL @-@ 6 ) production and signal transducer and activator of transcription 3 ( STAT3 ) activation in BCL @-@ 6(-/-) macrophages . Gene expression studies demonstrate that BCL @-@ 6 binds to several sequence motifs scattered in the IL @-@ 6 locus and can repress IL @-@ 6 transcription both in 293T cells and in macrophages . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 3-1.1.1.1 4-1.1.1 5-1.1.2.r 6-1.1.2.1.2 7-1.1.2.1.1.1.1 8-1.1.2.1.1.1.1 8-1.1.2.2.2.1.1.1 8-1.2.2.1.1.1.1 8-1.2.2.1.2.3.1.1.1.1 10-1.2.2.1.2.3.1.1.1.1 12-1.1.2.1.1.1.1 12-1.1.2.2.2.1.1.1 12-1.2.2.1.1.1.1 12-1.2.2.1.2.3.1.1.1.1 14-1.1.2.1 15-1.1.2 16-1.1.2.2.1.1.1 17-1.1.2.2.1.1.2 18-1.1.2.2.1.1.3 19-1.1.2.2.1.1.4 20-1.1.2.2.1.1.5 21-1.1.2.2.1.1.6 22-1.1.2.2.1.1.7 26-1.1.2.2 28-1.1.2.2.2.1.1.1 28-1.2.2.1.1.1.1 31-1.1.2.2.2 33-1.2.1.1.1 34-1.2.1.1 35-1.2.1 36-1.2 38-1.2.2.1.1.1.1 40-1.2.2.1.1.1.1 40-1.2.2.1.2.3.1.1.1.1 41-1.2.2.1 43-1.2.2.1.2.2 44-1.2.2.1.2.1 45-1.2.2.1.2 46-1.2.2.1.2.3 49-1.2.2.1.2.3.1.1.1.1 51-1.2.2.1.2.3.1.1.1.1 52-1.2.2.1.2.3.1 53-1.2.2 54-1.2.2.2 55-1.2.2.2.1 56-1.2.2.1.2.3.1.1.1.1 58-1.2.2.1.1.1.1 58-1.2.2.1.2.3.1.1.1.1 59-1.2.2.2.1.2 61-1.2.2.2.1.3.r 62-1.2.2.2.1.3.1.1.1 63-1.2.2.2.1.3.1 63-1.2.2.2.1.3.2 64-1.2.2.2.1.3 66-1.1.2.2.2 66-1.2.2.2.1.3.2.1.1 (m3 / multi-sentence :snt1 (c / crucial~e.0 :prep-to~e.1 (p3 / proliferate-01~e.4 :ARG1-of (e / enhance-01~e.3) :mod (t2 / this~e.2)) :domain~e.5 (a2 / and~e.15 :op1 (p / produce-01~e.14 :ARG1 (p2 / protein :name (n / name :op1 "interleukin-6"~e.7,8,12)) :mod (s / spontaneous~e.6)) :op2 (a3 / activate-01~e.26 :ARG1 (p8 / protein :name (n9 / name :op1 "signal"~e.16 :op2 "transducer"~e.17 :op3 "and"~e.18 :op4 "activator"~e.19 :op5 "of"~e.20 :op6 "transcription"~e.21 :op7 3~e.22)) :location (m4 / macrophage~e.31,66 :mod (p4 / protein :name (n4 / name :op1 "BCL-6"~e.8,12,28) :ARG2-of (m / mutate-01 :mod "-/-")))))) :snt2 (d / demonstrate-01~e.36 :ARG0 (s2 / study-01~e.35 :ARG1 (e2 / express-03~e.34 :ARG2 (g2 / gene~e.33))) :ARG1 (a4 / and~e.53 :op1 (b / bind-01~e.41 :ARG0 (p7 / protein :name (n8 / name :op1 "BCL-6"~e.8,12,28,38,40,58)) :ARG1 (m2 / motif~e.45 :mod (s4 / sequence~e.44) :quant (s5 / several~e.43) :ARG1-of (s6 / scatter-01~e.46 :ARG2 (l / locus~e.52 :location-of (g3 / gene :name (n5 / name :op1 "IL-6"~e.8,10,12,40,49,51,56,58)))))) :op2 (p5 / possible-01~e.54 :ARG1 (r / repress-01~e.55 :ARG0 p7 :ARG1 (t4 / transcribe-01~e.59 :ARG1 g3) :location~e.61 (a5 / and~e.64 :op1 (c2 / cell-line~e.63 :name (n2 / name :op1 "293T"~e.62)) :op2 (c3 / cell~e.63 :name (n3 / name :op1 "macrophage"~e.66)))))))) # ::id bel_pmid_1559_0693.2660 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK1 @/@ 2 and JNK inactivation was associated with Ets @-@ like transcription factor @-@ 1 ( ELK @-@ 1 ) dephosphorylation . # ::alignments 0-1.1.2.1.1.1 3-1.1.2 4-1.1.2.3.1.1 5-1.1 5-1.1.1 5-1.1.1.r 7-1 8-1.2.r 9-1.2.1.1.1 11-1.2.1.1.1 12-1.2.1.1.2 13-1.2.1.1.3 15-1.2.1.1.3 15-1.2.1.2.1.1.1 17-1.2.1.2.1.1.1 19-1.2.1.1.3 19-1.2.1.2.1.1.1 21-1.2 (a / associate-01~e.7 :ARG1 (a3 / activate-01~e.5 :polarity~e.5 -~e.5 :ARG1 (a2 / and~e.3 :op1 (e / enzyme :name (n / name :op1 "ERK1"~e.0)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2")) :op3 (e3 / enzyme :name (n3 / name :op1 "JNK"~e.4)))) :ARG2~e.8 (d / dephosphorylate-01~e.21 :ARG1 (p2 / protein :name (n6 / name :op1 "Ets-like"~e.9,11 :op2 "transcription"~e.12 :op3 "factor-1"~e.13,15,19) :ARG1-of (d2 / describe-01 :ARG2 (p / protein :name (n5 / name :op1 "ELK-1"~e.15,17,19)))))) # ::id bel_pmid_1562_3503.11656 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rev @-@ erbbeta is an orphan nuclear receptor that selectively blocks trans @-@ activation mediated by the retinoic acid @-@ related orphan receptor @-@ alpha ( RORalpha ) # ::alignments 0-1.3.1.1 2-1.3.1.1 3-1.3.r 5-1.1 6-1.2 7-1 7-1.4.1.1.1.2.1 9-1.4.2 9-1.4.2.r 10-1.4 14-1.4.1.1 15-1.4.1.1.1.r 17-1.4.1.1.1.1.1 18-1.4.1.1.1.1.2 20-1.4.1.1.1.1.2 21-1.4.1.1.1.1.3 22-1.4.1.1.1.1.4 24-1.4.1.1.1.1.4 26-1.4.1.1.1.2.1.1.1 (r / receptor~e.7 :mod (o / orphan~e.5) :mod (n / nucleus~e.6) :domain~e.3 (p / protein :name (n2 / name :op1 "Rev-erbbeta"~e.0,2)) :ARG0-of (b / block-01~e.10 :ARG1 (t / transactivate-01 :ARG1-of (m / mediate-01~e.14 :ARG0~e.15 (p2 / protein :name (n3 / name :op1 "retinoic"~e.17 :op2 "acid-related"~e.18,20 :op3 "orphan"~e.21 :op4 "receptor-alpha"~e.22,24) :ARG1-of (d / describe-01 :ARG2 (r2 / receptor~e.7 :name (n4 / name :op1 "RORalpha"~e.26)))))) :manner~e.9 (s / selective~e.9))) # ::id bel_pmid_1562_3503.33508 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exogenous expression of a dominant negative version of mouse Rev @-@ erbbeta decreases the expression of many genes involved in fatty acid @/@ lipid absorption ( including Cd36 , and Fabp @-@ 3 and -@ 4 ) . Interestingly , we observed a robust induction ( 15 @-@ fold ) in mRNA expression of interleukin @-@ 6 # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 4-1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.r 8-1.1.1.1.2.2 9-1.1.1.1.2.1.1 11-1.1.1.1.2.1.1 12-1.1 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1 17-1.1.2.1 18-1.1.2.1.2 21-1.1.2.1.2.1.1.1 22-1.1.2.1.2.1.1 23-1.1.2.1.2.1.1.2 24-1.1.2.1.2.1 26-1.1.2.1.3 27-1.1.2.1.3.1.1.1.1 29-1.1.2.1.3.1 30-1.1.2.1.3.1.2.1.1 30-1.1.2.1.3.1.3.1.1 32-1.1.2.1.3.1.2.1.1 33-1.1.2.1.3.1 35-1.1.2.1.3.1.3.1.1 38-1.2.3 40-1.2.1 41-1.2 43-1.2.2.2 44-1.2.2 46-1.2.2.2.1.1.1 48-1.2.2.2.1.1 50-1.2.2.1.r 51-1.2.2.1.1.1.1 52-1.2.2.1 54-1.2.2.1.1.2.1.1.1 56-1.2.2.1.1.2.1.1.1 (m / multi-sentence :snt1 (d / decrease-01~e.12 :ARG0 (e / express-03~e.1 :ARG2~e.2 (v / version~e.6 :ARG0-of (d2 / dominate-01~e.4) :mod~e.7 (p / protein :name (n / name :op1 "Rev-erbbeta"~e.9,11) :source (m2 / mouse~e.8)) :ARG2-of (m5 / mutate-01 :mod "-/-")) :mod (e2 / exogenous~e.0)) :ARG1 (e3 / express-03~e.14 :ARG1~e.15 (g / gene~e.17 :quant (m3 / many~e.16) :ARG1-of (i / involve-01~e.18 :ARG2 (a / absorb-01~e.24 :ARG1 (s / slash~e.22 :op1 (a2 / acid~e.21 :ARG1-of (f / fat-03)) :op2 (l / lipid~e.23)))) :ARG2-of (i2 / include-01~e.26 :ARG1 (a4 / and~e.29,33 :op1 (g2 / gene :name (n3 / name :op1 "Cd36"~e.27)) :op2 (g3 / gene :name (n4 / name :op1 "Fabp-3"~e.30,32)) :op3 (g4 / gene :name (n5 / name :op1 "Fabp-4"~e.30,35))))))) :snt2 (o / observe-01~e.41 :ARG0 (w / we~e.40) :ARG1 (i3 / induce-01~e.44 :ARG2~e.50 (e4 / express-03~e.52 :ARG2 (n8 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.51) :ARG0-of (e5 / encode-01 :ARG1 (p3 / protein :name (n7 / name :op1 "interleukin-6"~e.54,56))))) :mod (r / robust~e.43 :ARG1-of (m4 / mean-01 :ARG2 (p2 / product-of~e.48 :op1 15~e.46)))) :ARG2-of (i4 / interest-01~e.38))) # ::id bel_pmid_1564_7320.19184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We report here that loss of Lsh specifically alters expression of the Cdkn1c gene The reactivation of the silenced paternal Cdkn1c allele correlates closely with a loss of CpG methylation at the 5 ' DMR at the Cdkn1c promoter Chromatin immunoprecipitations demonstrate a direct association of Lsh with the 5 ' DMR at the Cdkn1c promoter # ::alignments 0-1.1.1 1-1.1 2-1.1.3 3-1.1.2.r 4-1.1.2.1 5-1.1.2.1.1.r 6-1.1.2.1.1.1.1 7-1.1.2.3 8-1.1.2 9-1.1.2.2 10-1.1.2.2.1.r 12-1.1.2.2.1.1.1 13-1.1.2.2.1 13-1.2.1.1.1 13-1.3.2.2.2.1.1 15-1.2.1 16-1.2.1.1.r 18-1.2.1.1.3 19-1.2.1.1.2 20-1.2.1.1.1.1.1 21-1.2.1.1 22-1.2 23-1.2.3 24-1.2.2.r 26-1.2.2 27-1.2.2.1.r 28-1.2.2.1.1.3.1.1 29-1.2.2.1 32-1.3.2.2.1.1 33-1.3.2.2.1.1 34-1.3.2.2.1.2 37-1.1.2.2.1.1.1 39-1.3.1.1.1.1 41-1.3 43-1.3.2.3 44-1.3.2 45-1.3.2.1.r 46-1.3.2.1.1.1 49-1.3.2.2.1.1 50-1.2.2.1.1.1.1 50-1.3.2.2.1.1 51-1.2.2.1.1.1.2 51-1.3.2.2.1.2 54-1.1.2.2.1.1.1 54-1.3.2.2.2.1.1.1.1 (m / multi-sentence :snt1 (r / report-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.3 (a / alter-01~e.8 :ARG0 (l / lose-01~e.4 :ARG1~e.5 (p2 / protein :name (n / name :op1 "Lsh"~e.6))) :ARG1 (e / express-03~e.9 :ARG1~e.10 (g / gene~e.13 :name (n2 / name :op1 "Cdkn1c"~e.12,37,54))) :manner (s / specific-02~e.7)) :medium (h / here~e.2)) :snt2 (c / correlate-01~e.22 :ARG1 (r2 / reactivate-01~e.15 :ARG1~e.16 (a2 / allele~e.21 :mod (g2 / gene~e.13 :name (n3 / name :op1 "Cdkn1c"~e.20)) :mod (p3 / paternal~e.19) :ARG1-of (s2 / silence-01~e.18))) :ARG2~e.24 (l2 / lose-02~e.26 :ARG1~e.27 (m2 / methylate-01~e.29 :ARG1 (d5 / dna-sequence :name (n8 / name :op1 "5'"~e.50 :op2 "DMR"~e.51) :part-of (m4 / molecular-physical-entity :ARG0-of (p4 / promote-02 :ARG1 g2)) :part-of (d / dna-sequence :name (n4 / name :op1 "CpG"~e.28))))) :ARG1-of (c2 / close-10~e.23)) :snt3 (d3 / demonstrate-01~e.41 :ARG0 (i / immunoprecipitate-01 :ARG1 (m3 / macro-molecular-complex :name (n6 / name :op1 "chromatin"~e.39))) :ARG1 (a4 / associate-01~e.44 :ARG1~e.45 (p6 / protein :name (n7 / name :op1 "Lsh"~e.46)) :ARG2 (d6 / dna-sequence :name (n10 / name :op1 "5'"~e.32,33,49,50 :op2 "DMR"~e.34,51) :part-of (m5 / molecular-physical-entity :ARG0-of (p7 / promote-02 :ARG1 (g3 / gene~e.13 :name (n9 / name :op1 "Cdkn1c"~e.54))))) :ARG1-of (d4 / direct-02~e.43)))) # ::id bel_pmid_1564_7320.25946 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Entrez gene : Cyclin @-@ dependent kinase inhibitor 1C is a tight @-@ binding inhibitor of several G1 cyclin @/@ Cdk complexes and a negative regulator of cell proliferation . # ::alignments 0-1.3.1.1.1 1-1.3.1.1.2 3-1.1.2.1.1.1 5-1.1.1.1.1 6-1.1.1.1.2 7-1.1.1.1.3 8-1.1.1.1.4 11-1.1.1.2.1 13-1.1.1.2 14-1.1 16-1.1.2.3 17-1.1.2.4.1.1 18-1.1.2.1.1.1 20-1.1.2.2.1.1 21-1.1.2 22-1 24-1.2 25-1.2 26-1.2.1.r 27-1.2.1.1 28-1.2.1 (a / and~e.22 :op1 (i2 / inhibit-01~e.14 :ARG0 (p / protein :name (n / name :op1 "cyclin-dependent"~e.5 :op2 "kinase"~e.6 :op3 "inhibitor"~e.7 :op4 "1C"~e.8) :ARG1-of (b / bind-01~e.13 :ARG0-of (t / tight-05~e.11))) :ARG1 (m / macro-molecular-complex~e.21 :part (p2 / protein :name (n2 / name :op1 "cyclin"~e.3,18)) :part (e / enzyme :name (n3 / name :op1 "Cdk"~e.20)) :quant (s / several~e.16) :mod (e2 / event :name (n5 / name :op1 "G1"~e.17)))) :op2 (d / downregulate-01~e.24,25 :ARG1~e.26 (p3 / proliferate-01~e.28 :ARG0 (c / cell~e.27)) :ARG2 p) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG8 (n4 / name :op1 "Entrez"~e.0 :op2 "gene"~e.1)))) # ::id bel_pmid_1566_5273.5396 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CDK2 @-@ cyclin A1 @/@ E1 and CDK1 @-@ cyclin B1 phosphorylate BARD1 on its NH( 2 ) terminus in vivo and in vitro . # ::alignments 0-1.2.1.1.1.1 2-1.2.1.2.1.1 3-1.2.1.2.1.2 5-1.2.2.1.1.2 6-1.2 7-1.2.3.1.1.1 9-1.2.3.2.1.1 10-1.2.3.2.1.2 11-1 12-1.1.2.1.1 18-1.1.1.1 19-1.3.1 20-1.3.1 21-1.3 22-1.3.1 22-1.3.2 23-1.3.2 (p / phosphorylate-01~e.11 :ARG1 (p5 / protein-segment :name (n7 / name :op1 "NH2-terminus"~e.18) :part-of (p6 / protein :name (n8 / name :op1 "BARD1"~e.12))) :ARG2 (a / and~e.6 :op1 (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "CDK2"~e.0)) :part (p2 / protein :name (n3 / name :op1 "cyclin"~e.2 :op2 "A1"~e.3))) :op2 (m2 / macro-molecular-complex :part (p3 / protein :name (n4 / name :op1 "cyclin" :op2 "E1"~e.5)) :part e) :op3 (m3 / macro-molecular-complex :part (e3 / enzyme :name (n5 / name :op1 "CDK1"~e.7)) :part (p4 / protein :name (n6 / name :op1 "cyclin"~e.9 :op2 "B1"~e.10)))) :manner (a2 / and~e.21 :op1 (i / in-vivo~e.19,20,22) :op2 (i2 / in-vitro~e.22,23))) # ::id bel_pmid_1566_5823.1056 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also provide evidence that IRF @-@ 5 interacts with and is activated by MyD88 and TRAF6 # ::alignments 0-1.1 1-1.3 2-1 3-1.2 5-1.2.1.1.1.1.1 7-1.2.1.1.1.1.1 8-1.2.1.1 10-1.2.1 10-1.2.1.1.2 12-1.2.1.2 13-1.2.1.1.2.r 14-1.2.1.1.2.1.1.1 16-1.2.1.1.2.2.1.1 (p / provide-01~e.2 :ARG0 (w / we~e.0) :ARG1 (e / evidence~e.3 :topic (a2 / and~e.10 :op1 (i / interact-01~e.8 :ARG0 (p2 / protein :name (n / name :op1 "IRF-5"~e.5,7)) :ARG1~e.13 (a3 / and~e.10 :op1 (p3 / protein :name (n2 / name :op1 "MyD88"~e.14)) :op2 (p4 / protein :name (n3 / name :op1 "TRAF6"~e.16)))) :op2 (a4 / activate-01~e.12 :ARG0 a3 :ARG1 p2))) :mod (a / also~e.1)) # ::id bel_pmid_1566_5823.33196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here , we demonstrate that the transcription factor IRF @-@ 5 is generally involved downstream of the TLR @-@ MyD88 signalling pathway for gene induction of proinflammatory cytokines , such as interleukin @-@ 6 ( IL @-@ 6 ) , IL @-@ 12 and tumour @-@ necrosis factor @-@ alpha . In haematopoietic cells from mice deficient in the Irf5 gene ( Irf5-/- mice ) , the induction of these cytokines by various TLR ligands is severely impaired # ::alignments 0-1.1.3 2-1.1.1 3-1.1 4-1.1.2.r 6-1.1.2.1.2.1 7-1.1.2.1.2 8-1.1.2.1.1.1 10-1.1.2.1.1.1 12-1.1.2.2 13-1.1.2 14-1.1.2.3.2 17-1.1.2.3.1.1.1 19-1.1.2.3.1.1.1 20-1.1.2.3.1.2 21-1.1.2.3.1 22-1.1.2.3.1.2.1.r 23-1.1.2.3.1.2.1.1 24-1.1.2.3.1.2.1 26-1.1.2.3.1.2.1.1.1.1.1 26-1.1.2.3.1.2.1.1.1.1.1.1 26-1.1.2.3.1.2.1.1.1.1.1.1.r 27-1.1.2.3.1.2.1.1.1.1 29-1.1.2.3.1.2.1.1.1.1.2.r 30-1.1.2.3.1.2.1.1.1.1.2.r 31-1.1.2.3.1.2.1.1.1.1.2.1.1.1 33-1.1.2.3.1.2.1.1.1.1.2.1.1.1 33-1.1.2.3.1.2.1.1.1.1.2.1.2.1.1.1 35-1.1.2.3.1.2.1.1.1.1.2.1.2.1.1.1 37-1.1.2.3.1.2.1.1.1.1.2.1.1.1 37-1.1.2.3.1.2.1.1.1.1.2.1.2.1.1.1 40-1.1.2.3.1.2.1.1.1.1.2.1.2.1.1.1 40-1.1.2.3.1.2.1.1.1.1.2.2.1.1 42-1.1.2.3.1.2.1.1.1.1.2.2.1.1 43-1.1.2.3.1.2.1.1.1.1.2 44-1.1.2.3.1.2.1.1.1.1.2.3.1.1 46-1.1.2.3.1.2.1.1.1.1.2.3.1.1 47-1.1.2.3.1.2.1.1.1.1.2.3.1.2 49-1.1.2.3.1.2.1.1.1.1.2.3.1.2 52-1.2.3.1 53-1.2.3 54-1.2.3.2.r 55-1.2.3.2 56-1.2.3.2.2.1.1.2 56-1.2.3.2.2.1.1.2.1 56-1.2.3.2.2.1.1.2.1.r 59-1.2.3.2.1.1.1.1 59-1.2.3.2.2.1.1.1.1 60-1.2.3.2.1.1 60-1.2.3.2.2.1.1 63-1.2.3.2.2.1 67-1.2.1 68-1.2.1.2.r 69-1.2.1.2.1 70-1.2.1.2 71-1.2.1.1.r 72-1.2.1.1.2 73-1.2.1.1.1.1 74-1.2.1.1 76-1.2.2 76-1.2.2.r 77-1.2 (m / multi-sentence :snt1 (d / demonstrate-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (i / involve-01~e.13 :ARG1 (p2 / protein :name (n / name :op1 "IRF-5"~e.8,10) :mod (f / factor~e.7 :ARG0-of (t2 / transcribe-01~e.6))) :ARG1-of (g / general-02~e.12) :location (r / relative-position :op1 (p3 / pathway~e.21 :name (n2 / name :op1 "TLR-MyD88"~e.17,19) :ARG0-of (s / signal-07~e.20 :ARG1~e.22 (i2 / induce-01~e.24 :ARG2 (g2 / gene~e.23 :ARG0-of (e / encode-01 :ARG1 (c2 / cytokine~e.27 :ARG0-of (f2 / favor-01~e.26 :ARG1~e.26 (i3 / inflame-01~e.26)) :example~e.29,30 (a / and~e.43 :op1 (p5 / protein :name (n4 / name :op1 "interleukin-6"~e.31,33,37) :ARG1-of (d3 / describe-01 :ARG2 (p8 / protein :name (n7 / name :op1 "IL-6"~e.33,35,37,40)))) :op2 (p6 / protein :name (n5 / name :op1 "IL-12"~e.40,42)) :op3 (p7 / protein :name (n6 / name :op1 "tumour-necrosis"~e.44,46 :op2 "factor-alpha"~e.47,49))))))))) :direction (d2 / downstream~e.14))) :medium (h2 / here~e.0)) :snt2 (i4 / impair-01~e.77 :ARG1 (i5 / induce-01~e.67 :ARG0~e.71 (l / ligand~e.74 :name (n9 / name :op1 "TLR"~e.73) :mod (v / various~e.72)) :ARG2~e.68 (c3 / cytokine~e.70 :mod (t3 / this~e.69))) :manner~e.76 (s2 / severe~e.76) :location (c / cell~e.53 :mod (h / haematopoietic~e.52) :source~e.54 (m2 / mouse~e.55 :ARG0-of (l2 / lack-01 :ARG1 (g4 / gene~e.60 :name (n3 / name :op1 "IRF5"~e.59))) :ARG1-of (d4 / describe-01 :ARG2 (m3 / mouse~e.63 :mod (g3 / gene~e.60 :name (n10 / name :op1 "IRF5"~e.59) :ARG2-of (m4 / mutate-01~e.56 :mod~e.56 "-/-"~e.56)))))))) # ::id bel_pmid_1567_1526.28746 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stable knockdown of mutant KRAS( D12 ) in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX @-@ 2 synthesis and prostaglandin E2 production . # ::alignments 0-1.1.3 1-1.1 2-1.1.1.r 3-1.1.1 3-1.1.1.2 3-1.1.1.2.r 5-1.1.1.2.1 9-1.1.4.1.1 10-1.1.4.3.1.1 11-1.1.4 12-1.1.2.r 13-1.1.2.1.1.1 14-1.1.2 15-1 16-1.2.r 18-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1.1.1.1.1 23-1.2.1.1.1.1.1 24-1.2.1.1 25-1.2.1 26-1.2.1.2.1.1.1 27-1.2.1.2.1.1.2 28-1.2.1.2 (l / lead-03~e.15 :ARG0 (k / knock-down-02~e.1 :ARG1~e.2 (e2 / enzyme~e.3 :name (n / name :op1 "KRAS") :ARG1-of~e.3 (m / mutate-01~e.3 :value "D12"~e.5)) :ARG5~e.12 (i / interfere-01~e.14 :ARG0 (n5 / nucleic-acid :name (n6 / name :op1 "RNA"~e.13))) :ARG1-of (s / stable-03~e.0) :location (c / cell-line~e.11 :name (n4 / name :op1 "C26"~e.9) :source (m2 / mouse) :mod (d2 / disease :name (n7 / name :op1 "CRC"~e.10)))) :ARG2~e.16 (r2 / reduce-01~e.19 :ARG1~e.20 (a2 / and~e.25 :op1 (s2 / synthesize-01~e.24 :ARG1 (e / enzyme :name (n2 / name :op1 "COX-2"~e.21,23))) :op2 (p2 / produce-01~e.28 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "prostaglandin"~e.26 :op2 "E2"~e.27)))) :degree (d / dramatic~e.18))) # ::id bel_pmid_1568_5173.4092 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings indicate that lipid accumulation in the liver leads to subacute hepatic ' inflammation ' through NF @-@ kappaB activation and downstream cytokine production . This causes insulin resistance both locally in liver and systemically . # ::alignments 0-1.1.1.1 0-1.2.1 1-1.1.1 1-1.1.1.2 1-1.1.1.2.r 2-1.1 3-1.1.2.r 4-1.1.2.1.2 5-1.1.2.1 6-1.1.2.1.1.r 8-1.1.2.1.1 9-1.1.2 10-1.1.2.2.r 11-1.1.2.2.3 12-1.1.2.2.2 13-1.1.2.2.2.r 14-1.1.2.2 17-1.1.2.2.1.1.1.1.1 19-1.1.2.2.1.1.1.1.1 20-1.1.2.2.1.1 21-1.1.2.2.1 22-1.1.2.2.1.2.2 23-1.1.2.2.1.2.1 24-1.1.2.2.1.2 26-1.2.1 27-1.2 28-1.2.2.1.1.1 29-1.2.2 31-1.2.3.1 32-1.2.3.1.1.r 33-1.2.3.1.1 34-1.2.3 (m / multi-sentence :snt1 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :mod (t2 / this~e.0) :ARG1-of~e.1 (f / find-01~e.1)) :ARG1~e.3 (l / lead-03~e.9 :ARG0 (a / accumulate-01~e.5 :ARG0~e.6 (l3 / liver~e.8) :ARG1 (l2 / lipid~e.4)) :ARG1~e.10 (i2 / inflame-01~e.14 :ARG0 (a2 / and~e.21 :op1 (a3 / activate-01~e.20 :ARG1 (m2 / macro-molecular-complex :name (n / name :op1 "NF-kappaB"~e.17,19))) :op2 (p / produce-01~e.24 :ARG1 (c2 / cytokine~e.23) :location (d / downstream~e.22))) :ARG1~e.13 l3~e.12 :mod (s / subacute~e.11)))) :snt2 (c / cause-01~e.27 :ARG0 (t3 / this~e.0,26) :ARG1 (r / resist-01~e.29 :ARG1 (p2 / protein :name (n3 / name :op1 "insulin"~e.28))) :manner (a4 / and~e.34 :op1 (l4 / local-02~e.31 :ARG2~e.32 (l5 / liver~e.33)) :op2 (s2 / system)))) # ::id bel_pmid_1568_5173.6180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Insulin resistance was improved by systemic neutralization of IL @-@ 6 or salicylate inhibition of IKK @-@ beta . # ::alignments 0-1.2.1.1.1 1-1.2 3-1 6-1.1.1 7-1.1.1.1.r 8-1.1.1.1.1.1 10-1.1.1.1.1.1 11-1.1 12-1.1.2.1.1.1 13-1.1.2 14-1.1.2.2.r 15-1.1.2.2.1.1 17-1.1.2.2.1.1 (i / improve-01~e.3 :ARG0 (o / or~e.11 :op1 (n2 / neutralize-01~e.6 :ARG1~e.7 (p / protein :name (n3 / name :op1 "IL-6"~e.8,10)) :mod (s2 / system)) :op2 (i2 / inhibit-01~e.13 :ARG0 (s3 / small-molecule :name (n5 / name :op1 "salicylate"~e.12)) :ARG1~e.14 (e / enzyme :name (n4 / name :op1 "IKK-beta"~e.15,17)))) :ARG1 (r / resist-01~e.1 :ARG1 (p3 / protein :name (n / name :op1 "insulin"~e.0)))) # ::id bel_pmid_1568_8424.11152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We here report that the NFkappaB and C/EBP beta controlled gene IL6 is upregulated in DDIT3 @- and FUS @-@ DDIT3 @-@ expressing fibrosarcoma cell lines # ::alignments 0-1.1 1-1.3 2-1 6-1.2.1.2.1 7-1.2.1.2.1.2.1.1 8-1.2.1.2.1.2.1.2 9-1.2.1.2 10-1.2.1 11-1.2.1.1.1 13-1.2 14-1.2.2.r 15-1.2.2.2.1.1.1.1 17-1.2.2.2.1 18-1.2.2.2.1.2.1.1 20-1.2.2.2.1.1.1.1 22-1.2.2.2 23-1.2.2.1 24-1.2.2 25-1.2.2 (r / report-01~e.2 :ARG0 (w / we~e.0) :ARG1 (u / upregulate-01~e.13 :ARG1 (g / gene~e.10 :name (n / name :op1 "IL6"~e.11) :ARG1-of (c / control-01~e.9 :ARG0 (a / and~e.6 :op1 (m / macro-molecular-complex :name (n2 / name :op1 "NF-kappaB")) :op2 (p2 / protein :name (n3 / name :op1 "C/EBP"~e.7 :op2 "beta"~e.8))))) :location~e.14 (c2 / cell-line~e.24,25 :part-of (f / fibrosarcoma~e.23) :ARG3-of (e / express-03~e.22 :ARG1 (a2 / and~e.17 :op1 (p / protein :name (n4 / name :op1 "DDIT3"~e.15,20)) :op2 (p3 / protein :name (n5 / name :op1 "FUS-DDIT3"~e.18)))))) :medium (h / here~e.1)) # ::id bel_pmid_1568_8424.11196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Knockdown experiments using siRNA against CEBPB transcripts showed that the effect of FUS @-@ DDIT3 on IL6 expression is C/EBP beta dependent # ::alignments 0-1.1.1 1-1.1 2-1.1.2 3-1.1.2.1.1.1 4-1.1.2.1 4-1.1.2.1.2 4-1.1.2.1.2.r 5-1.1.2.1.2.1.1.1 7-1 8-1.2.r 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.1 14-1.2.1.1.1.1 15-1.2.1.2.r 16-1.2.1.2.1.1.1 17-1.2.1.2 19-1.2.2.1.1 20-1.2.2.1.2 21-1.2 (s / show-01~e.7 :ARG0 (e / experiment-01~e.1 :ARG1 (k / knock-down-02~e.0) :ARG0-of (u / use-01~e.2 :ARG1 (n2 / nucleic-acid~e.4 :name (n / name :op1 "siRNA"~e.3) :ARG0-of~e.4 (c / counter-01~e.4 :ARG1 (g / gene :name (n3 / name :op1 "CEBPB"~e.5) :ARG1-of (t / transcribe-01)))))) :ARG1~e.8 (d / depend-01~e.21 :ARG0 (a / affect-01~e.10 :ARG0~e.11 (p2 / protein :name (n6 / name :op1 "FUS-DDIT3"~e.12,14)) :ARG1~e.15 (e2 / express-03~e.17 :ARG2 (p3 / protein :name (n5 / name :op1 "IL6"~e.16)))) :ARG1 (p / protein :name (n4 / name :op1 "C/EBP"~e.19 :op2 "beta"~e.20)))) # ::id bel_pmid_1573_6430.6098 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our results suggest that Chk1 associates with BAD and phosphorylates the BAD protein at serine @-@ 155 # ::alignments 0-1.1.2 0-1.1.2.r 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1.2.r 7-1.2.1.2.1.1 8-1.2 9-1.2.2 11-1.2.2.1.3 12-1.2.2.1.3 14-1.2.2.1.2.1 16-1.2.2.1.1 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (r / result-01~e.1) :poss~e.0 (w / we~e.0)) :ARG1~e.3 (a / and~e.8 :op1 (a2 / associate-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "Chk1"~e.4)) :ARG2~e.6 (p / protein :name (n2 / name :op1 "BAD"~e.7))) :op2 (p2 / phosphorylate-01~e.9 :ARG1 (a3 / amino-acid :mod 155~e.16 :name (n3 / name :op1 "serine"~e.14) :part-of p~e.11,12) :ARG2 e))) # ::id bel_pmid_1573_6430.6100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , Chk1 also phosphorylates Cdc25A on serine 123 which accelerates its degradation through the ubiquitin @-@ proteasome pathway and arrests cells in late G2 @-@ phase after DNA damage . # ::alignments 0-1 2-1.1.2.1.1 3-1.1.5 4-1.1 5-1.1.1.3.1.1 7-1.1.1.2.1 8-1.1.1.1 10-1.1.3 11-1.1.3.1.1 11-1.1.3.1.1.r 12-1.1.3.1 15-1.1.3.1.2.1.1 17-1.1.3.1.2.1.1 18-1.1.3.1.2 20-1.1.4 21-1.1.4.1 22-1.1.4.3.r 23-1.1.4.3.2 24-1.1.4.3.1.2 26-1.1.4.3.1.1 27-1.1.4.2 28-1.1.4.2.1.1.2.1 29-1.1.4.2.1 (a2 / and~e.0 :op2 (p / phosphorylate-01~e.4 :ARG1 (a / amino-acid :mod 123~e.8 :name (n / name :op1 "serine"~e.7) :part-of (e / enzyme :name (n3 / name :op1 "Cdc25A"~e.5))) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Chk1"~e.2)) :ARG0-of (a3 / accelerate-01~e.10 :ARG1 (d / degrade-01~e.12 :ARG1~e.11 e~e.11 :ARG2 (p2 / pathway~e.18 :name (n4 / name :op1 "ubiquitin-proteasome"~e.15,17)))) :ARG0-of (a4 / arrest-02~e.20 :ARG1 (c / cell~e.21) :time (a5 / after~e.27 :op1 (d2 / damage-01~e.29 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.28)))) :time~e.22 (e3 / event :name (n7 / name :op1 "phase"~e.26 :op2 "G2"~e.24) :mod (l / late~e.23))) :mod (a6 / also~e.3))) # ::id bel_pmid_1574_9903.11636 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IkappaBNS was recruited to the IL @-@ 6 promoter , but not to the TNF @-@ alpha promoter , together with p50 . # ::alignments 0-1.1.1.1 2-1 2-1.3.1 5-1.2.1.1.1.1 7-1.2.1.1.1.1 8-1.2 8-1.2.1 8-1.2.1.r 8-1.3.1.3 8-1.3.1.3.1 10-1.3 11-1.3.1.1 11-1.3.1.1.r 12-1.3.1.3.1.1.r 14-1.3.1.3.1.1.1.1 16-1.3.1.3.1.1.1.1 17-1.3.1.3.1.r 20-1.3.1.2 21-1.3.1.2 (r / recruit-01~e.2 :ARG1 (p / protein :name (n / name :op1 "IkappaBNS"~e.0) :accompanier (p6 / protein :name (n4 / name :op1 "p50"))) :ARG2 (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (p2 / promote-01~e.8 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"~e.5,7)))) :ARG1-of (c / contrast-01~e.10 :ARG2 (r2 / recruit-01~e.2 :polarity~e.11 -~e.11 :ARG1 p~e.20,21 :ARG2 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.17 (p4 / promote-01~e.8 :ARG1~e.12 (p5 / protein :name (n3 / name :op1 "TNF-alpha"~e.14,16))))))) # ::id bel_pmid_1574_9903.11638 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IkappaBNS resulted in impaired LPS @-@ induced IL @-@ 6 production , but not TNF @-@ alpha production in the murine macrophage cell line RAW264.7 . # ::alignments 0-1.1.1.1 1-1 1-1.3.1 2-1.2.r 3-1.2.2 4-1.2.3.1.1.1 6-1.2.3 7-1.2.1.1.1 9-1.2.1.1.1 10-1.2 12-1.3 13-1.3.1.1 13-1.3.1.1.r 14-1.3.1.3.1.1.1 16-1.3.1.3.1.1.1 17-1.2 17-1.3.1.3 21-1.2.4.2 22-1.2.4 23-1.2.4 24-1.2.4.1.1 (r / result-01~e.1 :ARG1 (p / protein :name (n / name :op1 "IkappaBNS"~e.0)) :ARG2~e.2 (p2 / produce-01~e.10,17 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"~e.7,9)) :ARG1-of (i / impair-01~e.3) :ARG2-of (i2 / induce-01~e.6 :ARG0 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS"~e.4))) :location (c / cell-line~e.22,23 :name (n5 / name :op1 "RAW264.7"~e.24) :consist-of (m / macrophage~e.21 :mod (m2 / mouse)))) :ARG1-of (c2 / contrast-01~e.12 :ARG2 (r2 / result-01~e.1 :polarity~e.13 -~e.13 :ARG1 p :ARG2 (p4 / produce-01~e.17 :ARG1 (p5 / protein :name (n4 / name :op1 "TNF-alpha"~e.14,16)) :location c)))) # ::id bel_pmid_1574_9903.27884 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We compared CLPMphi gene expression profiles of wild @-@ type mice with IL @-@ 10 @-@ deficient mice , and identified genes that are selectively expressed in wild @-@ type CLPMphi . These genes included nuclear IkappaB proteins such as Bcl @-@ 3 and IkappaBNS . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.2.1.1.1.1 3-1.1.1.2.1.1 4-1.1.1.2.1 5-1.1.1.2 6-1.1.1.2.2.r 7-1.1.1.2.2.1 9-1.1.1.2.2.1 10-1.1.1.2.2 10-1.1.1.3 12-1.1.1.3.1.1.1.1 14-1.1.1.3.1.1.1.1 17-1.1.2.2.1.1 20-1.1.2 21-1.1.2.2 24-1.1.2.2.1.2 24-1.1.2.2.1.2.r 25-1.1.2.2.1 27-1.1.1.2.2.1 29-1.1.1.2.2.1 30-1.1.1.2.1.1.1.1 32-1.2.2.1 33-1.2.2 34-1.2 35-1.2.1.2 36-1.2.1.1.1 37-1.1.1.3.1.1 37-1.2.1 37-1.2.1.3.1 37-1.2.1.3.2 38-1.2.1.3.r 39-1.2.1.3.r 40-1.2.1.3.1.1.1 42-1.2.1.3.1.1.1 43-1.2.1.3 44-1.2.1.3.2.1.1 (m / multi-sentence :snt1 (a / and :op1 (c / compare-01~e.1 :ARG0 (w / we~e.0) :ARG1 (p / profile~e.5 :mod (e / express-03~e.4 :ARG1 (g / gene~e.3 :name (n / name :op1 "CLPMphi"~e.2,30))) :poss~e.6 (m2 / mouse~e.10 :mod (w2 / wild-type~e.7,9,27,29))) :ARG2 (m3 / mouse~e.10 :ARG0-of (l / lack-01 :ARG1 (p2 / protein~e.37 :name (n2 / name :op1 "IL-10"~e.12,14))))) :op2 (i / identify-01~e.20 :ARG0 w :ARG1 (g2 / gene~e.21 :ARG1-of (e2 / express-03~e.25 :ARG3 (m4 / mouse~e.17 :mod w2 :mod g) :manner~e.24 (s / selective~e.24))))) :snt2 (i2 / include-01~e.34 :ARG1 (p3 / protein~e.37 :name (n3 / name :op1 "IkappaB"~e.36) :mod (n4 / nucleus~e.35) :example~e.38,39 (a2 / and~e.43 :op1 (p4 / protein~e.37 :name (n5 / name :op1 "Bcl-3"~e.40,42)) :op2 (p5 / protein~e.37 :name (n6 / name :op1 "IkappaBNS"~e.44)))) :ARG2 (g3 / gene~e.33 :mod (t / this~e.32)))) # ::id bel_pmid_1575_7894.10588 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One of the phenotypes of mice with targeted disruption of the uncoupling protein @-@ 2 gene ( Ucp2-/-) is greater macrophage phagocytic activity and free radical production , resulting in a striking resistance to infectious microorganisms . # ::alignments 3-1.1.4 3-1.2 4-1.2.1.r 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.2 8-1.2.1.1 9-1.2.1.1.1.r 11-1.2.1.1.1.1.1 12-1.2.1.1.1.1.2 14-1.2.1.1.1.1.2 14-1.2.1.1.1.2.1.1.1 15-1.2.1.1.1 15-1.2.1.1.1.2.1 18-1.1.4.r 19-1.1.1.3 19-1.1.1.3.1 19-1.1.1.3.1.r 20-1.1.1.1 22-1.1.1 23-1.1 24-1.1.2.1.1 25-1.1.2.1 26-1.1.2 28-1.1.3 29-1.1.3.1.r 31-1.1.3.1.2 32-1.1.3.1 33-1.1.3.1.1.r 34-1.1.3.1.1.1 35-1.1.3.1.1 (i / include-91 :ARG1 (a / and~e.23 :op1 (a2 / activity-06~e.22 :ARG0 (m2 / macrophage~e.20) :ARG1 (p / phagocytosis) :mod (g / great~e.19 :degree~e.19 (m / more~e.19))) :op2 (p2 / produce-01~e.26 :ARG1 (r3 / radical~e.25 :ARG1-of (f / free-04~e.24))) :ARG1-of (r / result-01~e.28 :ARG2~e.29 (r2 / resist-01~e.32 :ARG1~e.33 (m5 / microorganism~e.35 :ARG0-of (i2 / infect-01~e.34)) :ARG1-of (s / strike-04~e.31))) :domain~e.18 (p4 / phenotype~e.3)) :ARG2 (p3 / phenotype~e.3 :poss~e.4 (m3 / mouse~e.5 :mod~e.6 (d / disrupt-01~e.8 :ARG1~e.9 (g2 / gene~e.15 :name (n2 / name :op1 "uncoupling"~e.11 :op2 "protein-2"~e.12,14) :ARG1-of (d2 / describe-01 :ARG2 (g3 / gene~e.15 :name (n3 / name :op1 "Ucp-2"~e.14) :ARG2-of (m4 / mutate-01 :mod "-/-")))) :ARG1-of (t / target-01~e.7))))) # ::id bel_pmid_1575_7894.31794 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2-/- mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2+/+ mice . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.1.1 6-1.2.1.1.1.2 7-1.2.1.2 10-1.2.1.2.1.1 11-1.2.1.2.1 12-1.2.1.2.1.2.1 13-1.2.1.2.1.2 14-1.2.1.2.1.3.r 16-1.2.1.2.1.3 16-1.2.4 18-1.2.2 19-1.2 20-1.2.3.r 21-1.2.3 24-1.2.3.1.1.1.1 25-1.2.3.1 26-1.2.4.r 28-1.2.4.1.1 29-1.2.4.1 31-1.2.4 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (e / elevate-01~e.19 :ARG1 (l / level~e.3 :quant-of~e.4 (s2 / small-molecule :name (n / name :op1 "nitric"~e.5 :op2 "oxide"~e.6)) :ARG1-of (m / measure-01~e.7 :location (o / or~e.11 :op1 (p / plasma~e.10) :op2 (m2 / macrophage~e.13 :ARG1-of (i / isolate-01~e.12)) :source~e.14 (m3 / mouse~e.16 :mod (g / gene :name (n2 / name :op1 "Ucp2") :ARG2-of (m4 / mutate-01 :mod "-/-")))))) :ARG1-of (s / significant-02~e.18) :ARG2-of~e.20 (r / respond-01~e.21 :ARG1 (c2 / challenge-01~e.25 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "lipopolysaccharide"~e.24) :mod (b / bacterium)))) :compared-to~e.26 (m5 / mouse~e.16,31 :ARG1-of (t / treat-03~e.29 :manner (r2 / resemble-01~e.28)) :mod (g2 / gene :name (n4 / name :op1 "Ucp2") :mod (w2 / wild-type))))) # ::id bel_pmid_1575_7894.31802 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein levels of iNOS and {beta}-actin were measured by Western blotting . ( increased Nos2 expression ) # ::alignments 0-1.1.2.1 1-1.1.1 1-1.1.2 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1 7-1 8-1.3.r 9-1.3 10-1.3 13-1.2.2 14-1.2.1.1.1 15-1.2 (m / measure-01~e.7 :ARG1 (a2 / and~e.4 :op1 (l / level~e.1 :quant-of~e.2 (e3 / enzyme :name (n2 / name :op1 "iNOS"~e.3))) :op2 (l2 / level~e.1 :quant-of (p2 / protein~e.0 :name (n3 / name :op1 "beta-actin")))) :ARG3 (e / express-03~e.15 :ARG2 (e2 / enzyme :name (n / name :op1 "Nos2"~e.14)) :ARG1-of (i / increase-01~e.13)) :manner~e.8 (i2 / immunoblot-01~e.9,10)) # ::id bel_pmid_1575_7894.31804 ::amr-annotator SDL-AMR-09 ::preferred # ::tok nduction of inflammatory cytokines by LPS is increased in Ucp2-/- mice . A , Northern blotting . Spleen total RNA was isolated from mice treated with 4 µg/g bw LPS or PBS . RNA for IFNg , IL1b , TNF and IL6 were elevated in Ucp2-/- mice in response to LPS . # ::alignments 2-1.1.1.2.1 3-1.1.1.2 5-1.1.1.1.1.1 7-1.1 10-1.1.2 12-1.2.2.1.1 14-1.2.1.1 15-1.2.1.2 17-1.3.1.3 18-1.3.1.2 19-1.3.1.1.1 21-1.3 22-1.3.2.r 23-1.3.2 24-1.3.2.1 25-1.3.2.1.1.r 26-1.3.2.1.1.1.2.1 29-1.3.2.1.1.1.1.1 30-1.3.2.1.1 31-1.3.2.1.1.2.1.1 33-1.4.1.1.1.1 33-1.4.1.2.1.1 33-1.4.1.3.1.1 33-1.4.1.4.1.1 35-1.4.1.1.2.1.1.1 39-1.4.1.3.2.1.1.1 40-1.4.1 43-1.4 46-1.4.2 47-1.4.3.r 48-1.4.3 49-1.4.3.1.r 50-1.4.3.1.1.1 (m / multi-sentence :snt1 (i / increase-01~e.7 :ARG1 (i2 / induce-01 :ARG0 (m8 / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.5)) :ARG2 (c4 / cytokine~e.3 :ARG0-of (i3 / inflame-01~e.2))) :location (m2 / mouse~e.10 :mod (g / gene :name (n3 / name :op1 "Ucp2") :ARG2-of (m3 / mutate-01 :mod "-/-")))) :snt2 (t / thing :name (n4 / name :op1 "Northern"~e.14 :op2 "blotting"~e.15) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"~e.12))) :snt3 (i4 / isolate-01~e.21 :ARG1 (n / nucleic-acid :name (n7 / name :op1 "RNA"~e.19) :quant (t2 / total~e.18) :mod (s2 / spleen~e.17)) :ARG2~e.22 (m4 / mouse~e.23 :ARG1-of (t3 / treat-03~e.24 :ARG3~e.25 (o / or~e.30 :op1 (m9 / molecular-physical-entity :name (n5 / name :op1 "LPS"~e.29) :quant (c2 / concentration-quantity :quant 4~e.26 :unit (m5 / microgram-per-gram) :mod (w / weight :mod (b / basis)))) :op2 (m10 / molecular-physical-entity :name (n6 / name :op1 "PBS"~e.31) :quant c2))))) :snt4 (e / elevate-01~e.43 :ARG1 (a / and~e.40 :op1 (n14 / nucleic-acid :name (n15 / name :op1 "RNA"~e.33) :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n8 / name :op1 "IFNg"~e.35)))) :op2 (n16 / nucleic-acid :name (n17 / name :op1 "RNA"~e.33) :ARG0-of (e3 / encode-01 :ARG1 (p3 / protein :name (n9 / name :op1 "IL-1b")))) :op3 (n18 / nucleic-acid :name (n19 / name :op1 "RNA"~e.33) :ARG0-of (e4 / encode-01 :ARG1 (p4 / protein :name (n10 / name :op1 "TNF"~e.39)))) :op4 (n20 / nucleic-acid :name (n21 / name :op1 "RNA"~e.33) :ARG0-of (e5 / encode-01 :ARG1 (p5 / protein :name (n11 / name :op1 "IL-6"))))) :location (m6 / mouse~e.46 :mod (g2 / gene :name (n12 / name :op1 "Ucp2") :ARG2-of (m7 / mutate-01 :mod "-/-"))) :ARG2-of~e.47 (r6 / respond-01~e.48 :ARG1~e.49 (m11 / molecular-physical-entity :name (n13 / name :op1 "LPS"~e.50))))) # ::id bel_pmid_1576_4709.2580 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Signal transducer and activator of transcription 3 ( STAT3 ) is activated by the IL @-@ 6 family of cytokines and growth factors . STAT3 requires phosphorylation on Ser @-@ 727 , in addition to tyrosine phosphorylation on Tyr @-@ 705 , to be transcriptionally active . # ::alignments 0-1.1.2.1.1 1-1.1.2.1.2 2-1.1.2.1.3 3-1.1.2.1.4 4-1.1.2.1.5 5-1.1.2.1.6 6-1.1.2.1.7 11-1.1 12-1.1.1.r 14-1.1.1.1.1.1 16-1.1.1.1.1.1 17-1.1.1.1 20-1.1.1 21-1.1.1.2 22-1.1.1.2 25-1.2 26-1.2.1 27-1.2.1.1.r 28-1.2.1.1.2.1 30-1.2.1.1.1 32-1.1.1 32-1.2.1.2.r 33-1.2.1.2 34-1.2.1.2.1.r 35-1.2.1.2.1.1.2.1 36-1.2.1.2.1 40-1.2.1.2.1.1.1 44-1.2.2.2 45-1.2.2 (m / multi-sentence :snt1 (a2 / activate-01~e.11 :ARG0~e.12 (a3 / and~e.20,32 :op1 (p4 / protein-family~e.17 :name (n4 / name :op1 "IL-6"~e.14,16)) :op2 (g / growth-factor~e.21,22)) :ARG1 (p2 / protein :name (n / name :op1 "signal"~e.0 :op2 "transducer"~e.1 :op3 "and"~e.2 :op4 "activator"~e.3 :op5 "of"~e.4 :op6 "transcription"~e.5 :op7 3~e.6) :ARG1-of (d / describe-01 :ARG2 (p3 / protein :name (n2 / name :op1 "STAT-3"))))) :snt2 (r / require-01~e.25 :ARG1 (p / phosphorylate-01~e.26 :ARG1~e.27 (a4 / amino-acid :mod 727~e.30 :name (n7 / name :op1 "serine"~e.28) :part-of (p7 / protein :name (n6 / name :op1 "STAT-3"))) :ARG1-of~e.32 (a5 / add-02~e.33 :ARG2~e.34 (p8 / phosphorylate-01~e.36 :ARG1 (a6 / amino-acid :mod 705~e.40 :name (n8 / name :op1 "tyrosine"~e.35) :part-of p7)))) :purpose (a / activity-06~e.45 :ARG0 p7 :ARG1 (t2 / transcribe-01~e.44)))) # ::id bel_pmid_1577_8365.952 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that CCR7 induced a Gi @-@ dependent activation of MAPK members ERK1 @/@ 2 , JNK , and p38 , with ERK1 @/@ 2 and p38 controlling JNK . MAPK members regulated chemotaxis , but not the migratory speed , of DCs . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1.1 4-1.1.2 6-1.1.2.2.2.1.1.1 8-1.1.2.2.2 9-1.1.2.2 11-1.1.2.2.1.5.1.1.1 11-1.2.1.1.1.1.1 12-1.2.1 13-1.1.2.2.1.1.1.1 17-1.1.2.2.1.3.1.1 19-1.1.2.2.1 20-1.1.2.2.1.4.1.1 23-1.1.2.2.1.1.1.1 27-1.1.2.2.1.4.1.1 28-1.1.2.2.3 29-1.1.2.2.3.2 31-1.1.2.2.1.5.1.1.1 31-1.2.1.1.1.1.1 32-1.2.1 33-1.2 33-1.2.3.1 34-1.2.2 36-1.2.3 37-1.2.3.1.1 37-1.2.3.1.1.r 39-1.2.3.1.3.1 40-1.2.3.1.3 (m3 / multi-sentence :snt1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (i / induce-01~e.4 :ARG0 (p2 / protein :name (n2 / name :op1 "CCR7"~e.3)) :ARG2 (a / activate-01~e.9 :ARG1 (a2 / and~e.19 :op1 (e / enzyme :name (n4 / name :op1 "ERK1"~e.13,23)) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2")) :op3 (e3 / enzyme :name (n6 / name :op1 "JNK"~e.17)) :op4 (e5 / enzyme :name (n7 / name :op1 "p38"~e.20,27)) :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n / name :op1 "MAPK"~e.11,31)))) :ARG0-of (d / depend-01~e.8 :ARG1 (p3 / protein :name (n3 / name :op1 "Gi"~e.6))) :manner (c / control-01~e.28 :ARG0 (a3 / and :op1 e :op2 e2 :op3 e5) :ARG1 e3~e.29)))) :snt2 (r / regulate-01~e.33 :ARG0 (m4 / member~e.12,32 :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family :name (n8 / name :op1 "MAPK"~e.11,31)))) :ARG1 (c2 / chemotaxis~e.34 :mod (c3 / cell :name (n9 / name :op1 "DC"))) :ARG1-of (c4 / contrast-01~e.36 :ARG2 (r2 / regulate-01~e.33 :polarity~e.37 -~e.37 :ARG0 m4 :ARG1 (s / speed~e.40 :mod (m6 / migrate-01~e.39 :ARG0 c3)))))) # ::id bel_pmid_1577_8365.1824 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs , but did not affect chemotaxis . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1.1 3-1.1.1.1 4-1.1.1.1.2.1.1 5-1.1 6-1.1.2.1.2.1.1 7-1.1.2.1 7-1.1.2.1.1 7-1.1.2.1.1.r 8-1.1.2 10-1.1.2.2.1 11-1.1.2.2 15-1 17-1.2.1 17-1.2.1.r 18-1.2 19-1.2.3 (c / contrast-01~e.15 :ARG1 (i / inhibit-01~e.5 :ARG0 (i2 / interfere-01~e.0 :ARG1~e.1 (o / or~e.3 :op1 (p / protein :name (n / name :op1 "Rho"~e.2)) :op2 (e / enzyme :name (n2 / name :op1 "Pyk2"~e.4)))) :ARG1 (a3 / and~e.8 :op1 (a2 / activate-01~e.7 :polarity~e.7 -~e.7 :ARG1 (p2 / protein :name (n3 / name :op1 "cofilin"~e.6))) :op2 (s / speed~e.11 :mod (m / migrate-01~e.10 :ARG0 (c2 / cell :name (n4 / name :op1 "DC")))))) :ARG2 (a4 / affect-01~e.18 :polarity~e.17 -~e.17 :ARG0 i2 :ARG1 (c3 / chemotaxis~e.19))) # ::id bel_pmid_1579_3228.19202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AdipoQ ( 23 ) , has been suggested to serve as an insulin @-@ sensitizing factor ( 24 ) . The mRNA level in mesenteric fat from Tg mice was markedly decreased # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.2.1.1.1 7-1.1 9-1.1.1 10-1.1.1.2.r 12-1.1.1.2.1.1.1.1 14-1.1.1.2.1 15-1.1.1.2 17-1.1.2.1.1.1 21-1.2.1.1.1.1 22-1.2.1 23-1.2.1.2.r 24-1.2.1.2.1 25-1.2.1.2 26-1.2.1.2.2.r 27-1.2.1.2.2.1 28-1.2.1.2.2 30-1.2.2 30-1.2.2.r 31-1.2 (m / multi-sentence :snt1 (s / suggest-01~e.7 :ARG1 (s2 / serve-01~e.9 :ARG0 (p / protein :name (n / name :op1 "AdipoQ"~e.0) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 23~e.2)))) :ARG1~e.10 (f / factor~e.15 :ARG0-of (s3 / sensitize-01~e.14 :ARG2 (p2 / protein :name (n2 / name :op1 "insulin"~e.12))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 24~e.17)))) :snt2 (d / decrease-01~e.31 :ARG1 (l / level~e.22 :quant-of (n4 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.21)) :location~e.23 (f2 / fat~e.25 :mod (m3 / mesentery~e.24) :source~e.26 (m4 / mouse~e.28 :mod (t / transgenic~e.27)))) :manner~e.30 (m2 / marked~e.30))) # ::id bel_pmid_1579_3228.19204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Angiotensinogen mRNA , which is up @-@ regulated by glucocorticoids ( 26 ) , was substantially increased in Tg mice . # ::alignments 0-1.1.2.1.1.1 1-1.1.1.1 5-1 9-1.1.3.1.1.1 11-1.1.3.2.1.1.1 15-1.2 16-1 17-1.3.r 18-1.3.1 19-1.3 (i / increase-01~e.5,16 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.1) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "angiotensinogen"~e.0))) :ARG1-of (u / upregulate-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "glucocorticoid"~e.9)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 26~e.11))))) :degree (s / substantial~e.15) :location~e.17 (m / mouse~e.19 :mod (t / transgenic~e.18))) # ::id bel_pmid_1579_3228.19208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mRNA for resistin , which has been suggested to be involved in glucose homeostasis ( 25 ) , was significantly decreased in Tg mice . # ::alignments 1-1.1.2.1 3-1.1.3.1.2.1 8-1.1.4.2 11-1.1.4 12-1.1.4.1.r 13-1.1.4.1.1 14-1.1.4.1 16-1.1.4.3.1.1.1 20-1.2 21-1 22-1.3.r 23-1.3.1 24-1.3 (d / decrease-01~e.21 :ARG1 (n3 / nucleic-acid :wiki "Messenger_RNA" :name (n / name :op1 "mRNA"~e.1) :ARG0-of (e / encode-01 :ARG1 (p / protein :wiki "Resistin" :name (n2 / name :op1 "resistin"~e.3))) :ARG1-of (i / involve-01~e.11 :ARG2~e.12 (h / homeostasis~e.14 :mod (g / glucose~e.13)) :ARG1-of (s / suggest-01~e.8) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 25~e.16))))) :ARG2 (s2 / significant-02~e.20) :location~e.22 (m / mouse~e.24 :mod (t / transgenic~e.23))) # ::id bel_pmid_1579_3228.19210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok model . Tumor necrosis factor @- alpha ( TNF @-@ a ) , a fat cell @- derived cytokine that can cause insulin resistance ( 3 , 22 ) , was significantly elevated in serum of Tg mice # ::alignments 0-1.1 2-1.2.1.1.1 3-1.2.1.1.2 4-1.2.1.1.3 6-1.2.1.1.4 8-1.2.1.2.1.1.1 10-1.2.1.2.1.1.1 13-1.2.1.2.1.1.1 14-1.2.1.3.1.1.1 15-1.2.1.3.1.1 17-1.2.1.3.1 18-1.2.1.3 20-1.2.1.3.2.2 21-1.2.1.3.2 22-1.2.1.3.2.1.1.1.1 23-1.2.1.3.2.1 25-1.2.1.3.3.1.1.1.1 27-1.2.1.3.3.1.1.1.2 31-1.2.2 32-1.2 33-1.2.3.r 34-1.2.3 35-1.2.3.1.r 36-1.2.3.1.1 37-1.2.3.1 (m / multi-sentence :snt1 (m2 / model~e.0) :snt2 (e / elevate-01~e.32 :ARG1 (p / protein :name (n / name :op1 "tumor"~e.2 :op2 "necrosis"~e.3 :op3 "factor"~e.4 :op4 "alpha"~e.6) :ARG1-of (d / describe-01 :ARG2 (p2 / protein :name (n2 / name :op1 "TNF-a"~e.8,10,13))) :mod (c / cytokine~e.18 :ARG1-of (d2 / derive-01~e.17 :ARG2 (c2 / cell~e.15 :mod (f / fat~e.14))) :ARG0-of (c3 / cause-01~e.21 :ARG1 (r / resist-01~e.23 :ARG1 (p4 / protein :name (n3 / name :op1 "insulin"~e.22))) :ARG1-of (p3 / possible-01~e.20)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 (a / and :op1 3~e.25 :op2 22~e.27)))))) :ARG1-of (s / significant-02~e.31) :location~e.33 (s2 / serum~e.34 :source~e.35 (m3 / mouse~e.37 :mod (t / transgenic~e.36))))) # ::id bel_pmid_1579_3228.21750 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Genetic disruption of these pathways improves insulin resistance ( 86,87 ) . Heterozygous IKKbeta+/- mice , fed with a high @-@ fat diet or crossed with obese ob @/@ ob mice , showed a significant decrease in blood glucose levels and improved insulin resistance ( 87 ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1 4-1.1.1.1 5-1.1 6-1.1.2.1.1.1 7-1.1.2 12-1.2.1.3 14-1.2.1 16-1.2.1.2 17-1.2.1.2.1.r 19-1.2.1.2.1.1.1.1 21-1.2.1.2.1.1.1 22-1.2.1.2.1 23-1.2.1.2.2 24-1.2.1.2.2.1 25-1.2.1.2.2.1.1.r 26-1.2.1.2.2.1.1.2.1 27-1.2.1.2.2.1.1.2.2 29-1.2.1.2.2.1.1.2.2 30-1.2.1.2.2.1.1.2 32-1.2 34-1.2.2.1.2 35-1.2.2.1 36-1.2.2.1.1.r 37-1.2.2.1.1.2 38-1.2.2.1.1.1 39-1.2.2.1.1 40-1.1.3.1.1.1 40-1.2.2 41-1.1 41-1.2.2.2.2 42-1.1.2.1.1.1 42-1.2.2.2.1.1.1 43-1.1.2 43-1.2.2.2 45-1.1.3.1.1.1.2 45-1.2.3.1.1.1 (m / multi-sentence :snt1 (i / improve-01~e.5,41 :ARG0 (d / disrupt-01~e.1 :ARG1~e.2 (p / pathway~e.4 :mod (t / this~e.3)) :mod (g / gene)) :ARG1 (r / resist-01~e.7,43 :ARG1 (p2 / protein :name (n / name :op1 "insulin"~e.6,42))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a / and~e.40 :op1 86 :op2 87~e.45))))) :snt2 (s / show-01~e.32 :ARG0 (m2 / mouse~e.14 :mod (p6 / protein :name (n2 / name :op1 "IKKbeta") :ARG2-of (m3 / mutate-01 :mod "+/-")) :ARG2-of (f / feed-01~e.16 :ARG1~e.17 (d5 / diet~e.22 :ARG0-of (c3 / contain-01 :ARG1 (f2 / fat~e.21 :ARG1-of (h2 / high-02~e.19)))) :op1-of (o / or~e.23 :op2 (c4 / cross-01~e.24 :ARG1~e.25 (a3 / and :op1 m2 :op2 (m4 / mouse~e.30 :mod (o2 / obese~e.26) :mod (o3 / ob-ob~e.27,29)))))) :mod (h / heterozygous~e.12)) :ARG1 (a2 / and~e.40 :op1 (d3 / decrease-01~e.35 :ARG1~e.36 (l / level~e.39 :quant-of (g3 / glucose~e.38) :location (b / blood~e.37)) :ARG2 (s2 / significant-02~e.34)) :op2 (r2 / resist-01~e.43 :ARG1 (p4 / protein :name (n3 / name :op1 "insulin"~e.42)) :ARG1-of (i2 / improve-01~e.41))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 87~e.45))))) # ::id bel_pmid_1579_3228.21980 ::amr-annotator SDL-AMR-09 ::preferred # ::tok JNK1 knockout mice gain less weight and are protected against diet @-@ induced insulin resistance or insulin resistance associated with a genetic model of obesity ( ob/ob ) ( 86 ) . # ::alignments 0-1.1.1.1.1.1.1 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 6-1 8-1.2 9-1.2.2.r 10-1.2.2.1.2.1 12-1.2.2.1.2 13-1.2.2.1.1.1.1 14-1.2.2.1 15-1.2.2 16-1.2.2.2.1 17-1.2.2.2 18-1.2.2.2.2 19-1.2.2.2.2.1.r 21-1.2.2.2.2.1.1 22-1.2.2.2.2.1 23-1.2.2.2.2.1.2.r 24-1.2.2.2.2.1.2 26-1.2.2.2.2.1.3.1.1 29-1.3.1.1.1 (a / and~e.6 :op1 (g / gain-02~e.3 :ARG0 (m / mouse~e.2 :ARG1-of (k / knock-out-03~e.1 :ARG0 (e / enzyme :name (n / name :op1 "JNK1"~e.0)))) :ARG1 (w / weight~e.5 :quant (l / less~e.4))) :op2 (p / protect-01~e.8 :ARG1 m :ARG2~e.9 (o / or~e.15 :op1 (r / resist-01~e.14 :ARG1 (p2 / protein :name (n2 / name :op1 "insulin"~e.13)) :ARG2-of (i / induce-01~e.12 :ARG0 (d / diet~e.10))) :op2 (r2 / resist-01~e.17 :ARG1 p2~e.16 :ARG1-of (a2 / associate-01~e.18 :ARG2~e.19 (m3 / model~e.22 :mod (g2 / genetic~e.21) :mod~e.23 (o2 / obesity~e.24) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :value "ob/ob"~e.26))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 86~e.29)))) # ::id bel_pmid_1579_3228.28348 ::amr-annotator SDL-AMR-09 ::preferred # ::tok and in mice , IL @-@ 6 treatment causes insulin resistance in skeletal muscle and in liver most likely due to defects in IRS @-@ 1 ( and IRS @-@ 2 , respectively ) - associated PI 3 @-@ kinase activity ( 56 ) . # ::alignments 2-1.1.1.1 4-1.1.1.2.1.1 6-1.1.1.2.1.1 7-1.1.1 8-1.1 9-1.1.2.1.1.1 10-1.1.2 13-1.1.2.3.1 14-1.1.2.3 15-1.1.2.3.r 16-1.1.2.3.2 17-1.1.2.2.2.1 18-1.1.2.2.2 19-1.1.2.2 20-1.1.2.2 21-1.1.2.2.1 22-1.1.2.2.1.1.r 23-1.1.2.2.1.1.2.1.1.1.1 23-1.1.2.2.1.1.2.1.2.1.1 25-1.1.2.2.1.1.2.1.1.1.1 27-1.1.2.2.1.1.2.1 28-1.1.2.2.1.1.2.1.1.1.1 28-1.1.2.2.1.1.2.1.2.1.1 30-1.1.2.2.1.1.2.1.2.1.1 32-1.1.2.2.1.1.2.1.3 32-1.1.2.2.1.1.2.1.3.r 35-1.1.2.2.1.1.2 36-1.1.2.2.1.1.1.1.1 37-1.1.2.2.1.1.1.1.2 39-1.1.2.2.1.1.1.1.2 40-1.1.2.2.1.1 42-1.2.1.1.1 (a / and :op2 (c / cause-01~e.8 :ARG0 (t / treat-03~e.7 :ARG1 (m2 / mouse~e.2) :ARG3 (p / protein :name (n / name :op1 "IL-6"~e.4,6))) :ARG1 (r / resist-01~e.10 :ARG1 (p2 / protein :name (n2 / name :op1 "insulin"~e.9)) :ARG1-of (c2 / cause-01~e.19,20 :ARG0 (d / defect-01~e.21 :ARG0~e.22 (a3 / activity-06~e.40 :ARG0 (e / enzyme :name (n3 / name :op1 "PI"~e.36 :op2 "3-kinase"~e.37,39)) :ARG1-of (a4 / associate-01~e.35 :ARG2 (a5 / and~e.27 :op1 (p3 / protein :name (n4 / name :op1 "IRS-1"~e.23,25,28)) :op2 (p4 / protein :name (n5 / name :op1 "IRS-2"~e.23,28,30)) :manner~e.32 (r2 / respective~e.32))))) :ARG1-of (l / likely-01~e.18 :degree (m / most~e.17))) :location~e.15 (a2 / and~e.14 :op1 (m3 / muscle~e.13 :mod (s / skeleton)) :op2 (l2 / liver~e.16)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 56~e.42)))) # ::id bel_pmid_1583_1486.36764 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As previously reported , expression of Dok @-@ R in EGF @-@ stimulated cells resulted in a dramatic decrease in the induction of Erk @-@ 2 activation as well as a delay in the activation kinetics ( Fig . 1 ) , while Dok @-@ R {Delta}PRR completely lost this Erk @-@ 2 attenuating capacity , which demonstrates that the key residues for mediating this attenuation are found within the PRR . # ::alignments 0-1.3.1.r 1-1.3.1 2-1.3 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1.1.1.1.1.1 9-1.1.1.2.r 10-1.1.1.2.1.1.1.1 12-1.1.1.2.1 13-1.1.1.2 14-1.1 15-1.1.2.r 17-1.1.2.1.2 18-1.1.2.1 19-1.1.2.1.1.r 21-1.1.2.1.1 22-1.1.2.1.1.1.r 23-1.1.2.1.1.1.1.1.1 25-1.1.2.1.1.1.1.1.1 26-1.1.2.1.1.1 27-1.1.2 28-1.1.2 29-1.1.2 31-1.1.2.2 32-1.1.2.2.1.r 34-1.1.2.2.1.1 35-1.1.2.2.1 37-1.1.3.1 39-1.1.3.1.1 42-1 43-1.1.1.1.1.1 43-1.2.1.1.1 45-1.1.1.1.1.1 45-1.2.1.1.1 47-1.2.3 48-1.2 50-1.2.2.1.1 51-1.2.2.1.1 52-1.2.2.1.1 53-1.2.2.1 54-1.2.2 57-1.2.4 58-1.2.4.1.r 60-1.2.4.1.1.1 61-1.2.4.1.1 62-1.2.4.1.1.1.1.r 63-1.2.4.1.1.1.1 65-1.2.4.1.1.1.1.1 67-1.2.4.1 70-1.2.4.1.2.1.1 (c / contrast-01~e.42 :ARG1 (r / result-01~e.14 :ARG1 (e / express-03~e.4 :ARG2~e.5 (p / protein :name (n / name :op1 "Dok-R"~e.6,8,43,45)) :ARG3~e.9 (c2 / cell~e.13 :ARG1-of (s / stimulate-01~e.12 :ARG2 (p5 / protein :name (n2 / name :op1 "EGF"~e.10))))) :ARG2~e.15 (a2 / and~e.27,28,29 :op1 (d / decrease-01~e.18 :ARG1~e.19 (i / induce-01~e.21 :ARG2~e.22 (a / activate-01~e.26 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk-2"~e.23,25)))) :degree (d2 / dramatic~e.17)) :op2 (d3 / delay-01~e.31 :ARG1~e.32 (k / kinetics~e.35 :mod (a3 / activate-01~e.34)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.37 :mod 1~e.39))) :ARG2 (l / lose-02~e.48 :ARG0 (p2 / protein :name (n4 / name :op1 "Dok-R"~e.43,45 :op2 "delta" :op3 "PRR")) :ARG1 (c5 / capable-01~e.54 :ARG2 (a4 / attenuate-01~e.53 :ARG1 e2~e.50,51,52)) :ARG1-of (c3 / complete-02~e.47) :ARG0-of (d5 / demonstrate-01~e.57 :ARG1~e.58 (f2 / find-01~e.67 :ARG1 (r2 / residue~e.61 :ARG1-of (k2 / key-02~e.60 :ARG2~e.62 (m / mediate-01~e.63 :ARG1 a4~e.65))) :location (p3 / protein :name (n5 / name :op1 "PRR"~e.70))))) :ARG1-of (r3 / report-01~e.2 :time~e.0 (p4 / previous~e.1))) # ::id bel_pmid_1584_5922.27198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The isoform SH2 @-@ Bbeta modulates JAK2 activity by binding to the phosphorylated enzyme , further increasing its activity . in an animal model of GH excess in which JAK2 is not phosphorylated , although it is increased in the membrane @-@ fraction , both the level of SH2 @-@ Bbeta , and especially its association to membranes , are augmented . # ::alignments 1-1.1.1.2 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1 6-1.1.3.2.1.1 7-1.1.2 9-1.1.3 12-1.1.3.2.2 13-1.1.1 13-1.1.3.2 13-1.2.1.1.1 13-1.2.2.2.1 13-1.2.2.3.2 15-1.1.3.3.2 16-1.1.3.3 17-1.1.3.3.1 18-1.1.3.3.1 22-1.2.2.1 23-1.2.2 24-1.2.2.2.r 25-1.2.2.2.1.1.1 26-1.2.2.2 29-1.2.2.3.2.1.1 31-1.2.2.3.1 31-1.2.2.3.1.r 32-1.2.2.3 34-1.2.2.3.3.r 35-1.2.2.3.3.1 37-1.2.2.3.3 38-1.2.2.3.3.2.r 40-1.2.2.3.3.2.1 42-1.2.2.3.3.2 46-1.2.1.1 48-1.2.1.1.1.1.1 50-1.2.1.1.1.1.1 52-1.2.1 53-1.2.1.2.3 55-1.2.1.2 56-1.2.1.2.2.r 57-1.2.1.2.2 60-1.2 (m / multi-sentence :snt1 (m2 / modulate-01~e.5 :ARG0 (p / protein~e.13 :name (n / name :op1 "SH2-Bbeta"~e.2,4) :mod (i / isoform~e.1)) :ARG1 (a / activity-06~e.7 :ARG0 e) :manner (b / bind-01~e.9 :ARG1 p :ARG2 (e / enzyme~e.13 :name (n2 / name :op1 "JAK2"~e.6) :ARG1-of (p2 / phosphorylate-01~e.12)) :ARG0-of (i2 / increase-01~e.16 :ARG1 a~e.17,18 :degree (f / further~e.15)))) :snt2 (a2 / augment-01~e.60 :ARG1 (a3 / and~e.52 :op1 (l / level~e.46 :quant-of (p3 / protein~e.13 :name (n3 / name :op1 "SH2-Bbeta"~e.48,50))) :op2 (a4 / associate-01~e.55 :ARG1 p3 :ARG2~e.56 (m3 / membrane~e.57) :mod (e3 / especially~e.53))) :location (m4 / model~e.23 :mod (a5 / animal~e.22) :mod~e.24 (e4 / exceed-01~e.26 :ARG0 (p4 / protein~e.13 :name (n4 / name :op1 "GH"~e.25))) :location-of (p5 / phosphorylate-01~e.32 :polarity~e.31 -~e.31 :ARG1 (e5 / enzyme~e.13 :name (n5 / name :op1 "JAK2"~e.29)) :concession~e.34 (i3 / increase-01~e.37 :ARG1 e5~e.35 :location~e.38 (f2 / fraction~e.42 :mod m3~e.40)))))) # ::id bel_pmid_1587_9117.18042 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In response to IFN @-@ gamma , C/EBP @-@ beta undergoes phosphorylation at a critical ERK1 @/@ 2 phosphorylation motif . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.1.1 5-1.3.1.1.1 9-1.1.1.1 10-1 11-1.2 14-1.2.1.2 15-1.2.2.1.1.1 18-1.2 19-1.2.1 (u / undergo-28~e.10 :ARG1 (p2 / protein :name (n / name :op1 "C/EBP-beta"~e.9)) :ARG2 (p / phosphorylate-01~e.11,18 :ARG1 (p4 / protein-segment~e.19 :part-of p2 :ARG1-of (c / critical-02~e.14 :ARG2 p)) :ARG2 (a / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1"~e.15)) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2")))) :ARG2-of (r / respond-01~e.1 :ARG1~e.2 (p3 / protein :name (n2 / name :op1 "IFN-gamma"~e.3,5)))) # ::id bel_pmid_1596_4826.36122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Serine @-@ 642 was identified as an Akt @-@ dependent phosphorylation site . WEE1Hu kinase activity was not affected by serine @-@ 642 phosphorylation . We revealed that serine @-@ 642 phosphorylation promoted cytoplasmic localization of WEE1Hu . The nuclear @-@ to @-@ cytoplasmic translocation was mediated by phosphorylation @-@ dependent WEE1Hu binding to 14 @-@ 3 @-@ 3 theta but not 14 @-@ 3 @-@ 3 beta or -@ sigma preventing Y15 phosphorylation of Cdc2 by WEE1 . # ::alignments 0-1.1.1.2.1 2-1.1.1.1 4-1.1 5-1.1.2.r 7-1.1.2.2.1.1.1 9-1.1.2.2 10-1.1.2.1 11-1.1.2 13-1.2.3.1.1.1 14-1.2.3.1 14-1.3.2.2.1 14-1.4.1.1 14-1.4.3.1.2 15-1.2.3 17-1.2.1 17-1.2.1.r 18-1.2 19-1.2.2.r 20-1.2.2.1.2.1 22-1.2.2.1.1 23-1.2.2 25-1.3.1 26-1.3 27-1.3.2.r 28-1.3.2.1.1.2.1 30-1.3.2.1.1.1 31-1.3.2.1 32-1.3.2 33-1.3.2.2.2 34-1.3.2.2 36-1.3.2.2.1.1.1 39-1.4.2.2 43-1.4.2.1 44-1.4.2 46-1.4 46-1.4.4.1 47-1.4.1.r 48-1.4.1.3.1 50-1.4.1.3 51-1.4.1.1.1.1 52-1.4.1 52-1.4.4.1.2 53-1.4.1.2.r 54-1.4.1.2.1.1 56-1.4.1.2.1.1 58-1.4.1.2.1.1 59-1.4.1.2.1.2 60-1.4.4 61-1.4.4.1.1 61-1.4.4.1.1.r 62-1.4.4.1.2.2.1.1.1 64-1.4.4.1.2.2.1.1.1 66-1.4.4.1.2.2.1.1.1 66-1.4.4.1.2.2.2.1.1 67-1.4.4.1.2.2.1.1.2 68-1.4.4.1.2.2 70-1.4.4.1.2.2.2.1.2 71-1.4.3 73-1.4.3.1 74-1.4.3.1.1.r 75-1.4.3.1.1.3.1.1 77-1.4.3.1.2.1.1 (m / multi-sentence :snt1 (i / identify-01~e.4 :ARG1 (a / amino-acid :mod 642~e.2 :name (n2 / name :op1 "serine"~e.0)) :ARG2~e.5 (s / site~e.11 :ARG1-of (p / phosphorylate-01~e.10) :ARG0-of (d / depend-01~e.9 :ARG1 (e / enzyme :name (n3 / name :op1 "Akt"~e.7))))) :snt2 (a2 / affect-01~e.18 :polarity~e.17 -~e.17 :ARG0~e.19 (p3 / phosphorylate-01~e.23 :ARG1 (a4 / amino-acid :mod 642~e.22 :name (n5 / name :op1 "serine"~e.20))) :ARG1 (a3 / activity-06~e.15 :ARG0 (k / kinase~e.14 :name (n4 / name :op1 "WEE1Hu"~e.13)))) :snt3 (r / reveal-01~e.26 :ARG0 (w / we~e.25) :ARG1~e.27 (p4 / promote-02~e.32 :ARG0 (p5 / phosphorylate-01~e.31 :ARG1 (a5 / amino-acid :mod 642~e.30 :name (n6 / name :op1 "serine"~e.28))) :ARG1 (b2 / be-located-at-91~e.34 :ARG1 (k2 / kinase~e.14 :name (n7 / name :op1 "WEE1Hu"~e.36)) :ARG2 (c / cytoplasm~e.33)))) :snt4 (m2 / mediate-01~e.46 :ARG0~e.47 (b / bind-01~e.52 :ARG1 (k3 / kinase~e.14 :name (n8 / name :op1 "WEE1Hu"~e.51)) :ARG2~e.53 (p6 / protein :name (n9 / name :op1 "14-3-3"~e.54,56,58 :op2 "theta"~e.59)) :ARG0-of (d2 / depend-01~e.50 :ARG1 (p2 / phosphorylate-01~e.48))) :ARG1 (t / translocate-01~e.44 :ARG2 (c2 / cytoplasm~e.43) :ARG3 (n / nucleus~e.39)) :ARG0-of (p9 / prevent-01~e.71 :ARG1 (p10 / phosphorylate-01~e.73 :ARG1~e.74 (a6 / amino-acid :mod 15 :name (n12 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n13 / name :op1 "Cdc2"~e.75))) :ARG2 (k4 / kinase~e.14 :name (n14 / name :op1 "WEE1"~e.77)))) :ARG1-of (c3 / contrast-01~e.60 :ARG2 (m3 / mediate-01~e.46 :polarity~e.61 -~e.61 :ARG0 (b3 / bind-01~e.52 :ARG1 k3 :ARG2 (o / or~e.68 :op1 (p7 / protein :name (n10 / name :op1 "14-3-3"~e.62,64,66 :op2 "beta"~e.67)) :op2 (p8 / protein :name (n11 / name :op1 "14-3-3"~e.66 :op2 "sigma"~e.70)))) :ARG1 t)))) # ::id bel_pmid_1610_2754.11486 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KLF5 accelerates mitotic entry in H @-@ Ras @-@ transformed cells by transcriptionally activating cyclin B1 and Cdc2 , which leads to an increase in cyclin B1 @/@ Cdc2 kinase activity # ::alignments 0-1.1.1.1 1-1 2-1.2.1 3-1.2 4-1.2.2.r 5-1.2.2.1.1.1.1 7-1.2.2.1.1.1.1 9-1.2.2.1 10-1.2.2 11-1.3.r 12-1.3.3 13-1.3 14-1.3.2.1.1.1 15-1.3.2.1.1.2 16-1.3.2 17-1.3.2.2.1.1 20-1.3.4 23-1.3.4.1 24-1.3.4.1.1.r 25-1.3.4.1.1.1 26-1.3.4.1.1.1 27-1.3.4.1.1.1 28-1.3.4.1.1.1 29-1.3.4.1.1.1 30-1.3.4.1.1 (a / accelerate-01~e.1 :ARG0 (p / protein :name (n / name :op1 "KLF5"~e.0)) :ARG1 (e / enter-01~e.3 :ARG0 (m / mitosis~e.2) :ARG1~e.4 (c / cell~e.10 :ARG1-of (t / transform-01~e.9 :ARG0 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.5,7))))) :manner~e.11 (a2 / activate-01~e.13 :ARG0 p :ARG1 (a3 / and~e.16 :op1 (p2 / protein :name (n3 / name :op1 "cyclin"~e.14 :op2 "B1"~e.15)) :op2 (k / kinase :name (n4 / name :op1 "Cdc2"~e.17))) :mod (t2 / transcribe-01~e.12) :ARG0-of (l / lead-03~e.20 :ARG2 (i / increase-01~e.23 :ARG1~e.24 (a4 / activity-06~e.30 :ARG0 a3~e.25,26,27,28,29))))) # ::id bel_pmid_1613_9224.21092 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We report that phosphorylation @-@ induced turnover of endogenous N @-@ myc protein in CGNPs increases during mitosis , due to increased priming phosphorylation of N @-@ myc for GSK @-@ 3 beta . The priming phosphorylation requires the Cdk1 complex , whose cyclin subunits are indirect Sonic hedgehog targets # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1.1 5-1.1.2.1.1 6-1.1.2.1 8-1.1.2.1.2.2 9-1.1.2.1.2.1.1 11-1.1.2.1.2.1.1 12-1.1.2.1.2 12-1.2.2.1 12-1.2.2.1.2.1 15-1.1.2 16-1.1.2.2.r 17-1.1.2.2 19-1.1.2.3 20-1.1.2.3 21-1.1.2.3.1.4 22-1.1.2.3.1.3 23-1.1.2.3.1 24-1.1.2.3.1.1.r 25-1.1.2.3.1.1 26-1.1.2.3.1.1 27-1.1.2.3.1.1 28-1.1.2.3.1.2.r 29-1.1.2.3.1.2.1.1 35-1.2.1.1 36-1.2.1 37-1.2 39-1.2.2.2.1.1 40-1.2.2 43-1.2.2.1.1.1 46-1.2.2.1.2.2 47-1.2.2.1.2.1.1.1 48-1.2.2.1.2.1.1.2 49-1.2.2.1.2 (m / multi-sentence :snt1 (r / report-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (i / increase-01~e.15 :ARG1 (t / turnover~e.6 :ARG2-of (i2 / induce-01~e.5 :ARG0 (p / phosphorylate-01~e.3)) :mod (p2 / protein~e.12 :name (n / name :op1 "N-myc"~e.9,11) :mod (e / endogenous~e.8)) :location (c2 / cell :name (n6 / name :op1 "CGNP"))) :time~e.16 (m2 / mitosis~e.17) :ARG1-of (c / cause-01~e.19,20 :ARG0 (p3 / phosphorylate-01~e.23 :ARG1~e.24 p2~e.25,26,27 :ARG2~e.28 (e2 / enzyme :name (n2 / name :op1 "GSK-3beta"~e.29)) :mod (p4 / priming~e.22) :ARG1-of (i3 / increase-01~e.21))))) :snt2 (r2 / require-01~e.37 :ARG0 (p5 / phosphorylate-01~e.36 :mod (p6 / priming~e.35)) :ARG1 (m3 / macro-molecular-complex~e.40 :part (p7 / protein~e.12 :name (n4 / name :op1 "cyclin"~e.43) :ARG1-of (t2 / target-01~e.49 :ARG2 (p8 / protein~e.12 :name (n5 / name :op1 "Sonic"~e.47 :op2 "hedgehog"~e.48)) :mod (i4 / indirect~e.46))) :part (e3 / enzyme :name (n3 / name :op1 "Cdk1"~e.39))))) # ::id bel_pmid_1614_1211.1764 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We conclude that TNFalpha and IGF @-@ I may additively contribute to fibrosis during intestinal inflammation . TNFR2 is a primary mediator of fibrogenic actions of TNFalpha acting through ERK1 @/@ 2 to stimulate proliferation and through STAT3 to stimulate TIMP @-@ 1 and inhibit collagen degradation . # ::alignments 0-1.1.1 1-1.1 4-1.1.2.1.1 5-1.1.2.1.1.2.1.1 7-1.1.2.1.1.2.1.1 8-1.1.2 10-1.1.2.1 11-1.1.2.1.2.r 12-1.1.2.1.2 13-1.1.2.1.4.r 14-1.1.2.1.4.1 15-1.1.2.1.4 17-1.2.1.1.1 20-1.2.3 21-1.2 24-1.2.2 27-1.2.4.1 27-1.2.4.2 28-1.2.4.1.2.r 28-1.2.4.2.2.r 29-1.2.4.1.2.1.1.1 33-1.2.4.1.3 34-1.2.4.1.3.2 35-1.2.4.1.2 36-1.2.4.1.2.r 37-1.2.4.2.2.1.1 38-1.2.4.2.3.r 39-1.2.4.2.3.1 40-1.2.4.2.3.1.2.1.1 42-1.2.4.2.3.1.2.1.1 43-1.2.4.2.3 44-1.2.4.2.3.2 45-1.2.4.2.3.2.2.1.1.1 46-1.2.4.2.3.2.2 (m2 / multi-sentence :snt1 (c / conclude-01~e.1 :ARG0 (w / we~e.0) :ARG1 (p2 / possible-01~e.8 :ARG1 (c2 / contribute-01~e.10 :ARG0 (a / and~e.4 :op1 (p3 / protein :name (n / name :op1 "TNF-alpha")) :op2 (p4 / protein :name (n2 / name :op1 "IGF-I"~e.5,7))) :ARG2~e.11 (f / fibrosis~e.12) :manner (a2 / add-02) :time~e.13 (i / inflame-01~e.15 :ARG1 (i2 / intestine~e.14))))) :snt2 (m3 / mediate-01~e.21 :ARG0 (p5 / protein :name (n3 / name :op1 "TNFR2"~e.17)) :ARG1 (a3 / act-01~e.24 :ARG0 (p7 / protein :name (n4 / name :op1 "TNF-alpha")) :ARG1 (f2 / fibrogenesis)) :mod (p6 / primary~e.20) :manner (a8 / and :op1 (a4 / act-02~e.27 :ARG0 p5 :path~e.28,36 (a5 / and~e.35 :op1 (e / enzyme :name (n5 / name :op1 "ERK1"~e.29)) :op2 (e2 / enzyme :name (n6 / name :op1 "ERK2"))) :purpose (s / stimulate-01~e.33 :ARG0 p5 :ARG1 (p8 / proliferate-01~e.34))) :op2 (a6 / act-02~e.27 :ARG0 p5 :path~e.28 (p9 / protein :name (n7 / name :op1 "STAT3"~e.37)) :purpose~e.38 (a7 / and~e.43 :op1 (s2 / stimulate-01~e.39 :ARG0 p5 :ARG1 (p10 / protein :name (n8 / name :op1 "TIMP-1"~e.40,42))) :op2 (i3 / inhibit-01~e.44 :ARG0 p5 :ARG1 (d2 / degrade-01~e.46 :ARG1 (p11 / protein :name (n9 / name :op1 "collagen"~e.45))))))))) # ::id bel_pmid_1614_1211.2914 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumor necrosis factor ( TNF ) alpha has defined proinflammatory # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1.1.1.3 4-1.1.2.1.1.1 6-1.1.1.4 8-1 9-1.2 9-1.2.2 9-1.2.2.r (d / define-01~e.8 :ARG1 (p3 / protein :name (n3 / name :op1 "tumor"~e.0 :op2 "necrosis"~e.1 :op3 "factor"~e.2 :op4 "alpha"~e.6) :ARG1-of (d2 / describe-01 :ARG2 (p2 / protein :name (n2 / name :op1 "TNF"~e.4)))) :ARG2 (f / favor-01~e.9 :ARG0 (p / protein) :ARG1~e.9 (i / inflame-01~e.9))) # ::id bel_pmid_1614_1211.10448 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TNFalpha , but not IGF @-@ I , induced tissue inhibitor of metalloproteinase @-@ 1 ( TIMP @-@ 1 ) expression and reduced matrix metalloproteinases @-@ 2 activity and collagen degradation . TNFalpha also activated ERK1 @/@ 2 . # ::alignments 2-1.1.1.1 2-1.1.1.1.2 2-1.1.1.1.2.r 4-1.1.1.1.2.1.1.1 6-1.1.1.1.2.1.1.1 6-1.1.1.2.1.1.4 8-1.1.1 9-1.1.1.2.1.1.1 10-1.1.1.2.1.1.2 11-1.1.1.2.1.1.3 12-1.1.1.2.1.1.4 14-1.1.1.2.1.1.4 14-1.1.1.2.1.2.1.1.1 16-1.1.1.2.1.2.1.1.1 18-1.1.1.2.1.1.4 18-1.1.1.2.1.2.1.1.1 20-1.1.1.2 21-1.1 22-1.1.2 23-1.1.2.2.1.1.1.1 26-1.1.2.2.1.1.1.2 27-1.1.2.2.1 28-1.1.2.2 29-1.1.2.2.2.1.1.1 30-1.1.2.2.2 33-1.2.3 34-1.2 35-1.2.2.1.1.1 37-1.1.2.2.1.1.1.2 (m / multi-sentence :snt1 (a / and~e.21 :op1 (i2 / induce-01~e.8 :ARG0 (p / protein~e.2 :name (n / name :op1 "TNF-alpha") :ARG1-of~e.2 (c / contrast-01~e.2 :ARG2 (p2 / protein :name (n2 / name :op1 "IGF-I"~e.4,6)))) :ARG2 (e / express-03~e.20 :ARG2 (p3 / protein :name (n3 / name :op1 "tissue"~e.9 :op2 "inhibitor"~e.10 :op3 "of"~e.11 :op4 "metalloproteinase-1"~e.6,12,14,18) :ARG1-of (d / describe-01 :ARG2 (p4 / protein :name (n4 / name :op1 "TIMP-1"~e.14,16,18)))))) :op2 (r / reduce-01~e.22 :ARG0 p :ARG1 (a2 / and~e.28 :op1 (a3 / activity-06~e.27 :ARG0 (e2 / enzyme :name (n5 / name :op1 "matrix"~e.23 :op2 "metalloproteinase-2"~e.26,37))) :op2 (d2 / degrade-01~e.30 :ARG1 (p5 / protein :name (n6 / name :op1 "collagen"~e.29)))))) :snt2 (a4 / activate-01~e.34 :ARG0 (p6 / protein :name (n7 / name :op1 "TNF-alpha")) :ARG1 (a6 / and :op1 (e3 / enzyme :name (n8 / name :op1 "ERK1"~e.35)) :op2 (e4 / enzyme :name (n9 / name :op1 "ERK2"))) :mod (a5 / also~e.33))) # ::id bel_pmid_1614_1211.19760 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These responses to TNFalpha were absent in TNFR2-/- and TNFR1 @/@ 2-/- myofibroblasts , whereas TNFR1-/- cells showed similar responses to WT . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 5-1.1 8-1.1.2 9-1.1.2.2.1.1.1 14-1 16-1.2.1 16-1.2.2.2.1 17-1.2 18-1.2.2.2 19-1.2.2 19-1.2.2.1 19-1.2.2.1.r 20-1.2.2.2.1.1.r 21-1.2.2.2.1.1 (c / contrast-01~e.14 :ARG1 (a3 / absent-01~e.5 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r2 / respond-01~e.1 :ARG1 (p / protein :name (n / name :op1 "TNF-alpha"))) :mod (t3 / this~e.0)) :ARG2 (a / and~e.8 :op1 (m2 / myofibroblast :mod p2) :op2 (m3 / myofibroblast :mod (p3 / protein :name (n3 / name :op1 "TNFR1"~e.9) :ARG2-of m) :mod (p2 / protein :name (n2 / name :op1 "TNFR2") :ARG2-of (m / mutate-01 :mod "-/-"))))) :ARG2 (s / show-01~e.17 :ARG0 (c2 / cell~e.16 :mod p3) :ARG1 (t2 / thing~e.19 :ARG2-of~e.19 (r3 / respond-01~e.19) :ARG1-of (r / resemble-01~e.18 :ARG2 (c3 / cell~e.16 :mod~e.20 (w / wild-type~e.21)))))) # ::id bel_pmid_1614_9052.2664 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , genistein enhanced RA @-@ induced neuronal differentiation by increasing the activation of extracellular signal @-@ related kinase 1 @/@ 2 ( ERK1 @/@ 2 ) via phosphorylation at Thr183 and Tyr185 in 3 @-@ 7 days . # ::alignments 0-1.3.1.1 2-1.1.1.1 3-1 4-1.2.2.1.1.1 6-1.2.2 8-1.2 10-1.3 12-1.3.1 14-1.3.1.1.1.1.1 14-1.3.1.1.2.1.1 15-1.3.1.1.1.1.2 15-1.3.1.1.2.1.2 17-1.3.1.1.1.1.2 17-1.3.1.1.2.1.2 18-1.3.1.1.1.1.3 18-1.3.1.1.2.1.3 19-1.3.1.1.1.1.4 21-1.3.1.1.2.1.4 23-1.3.1.1.1.2.1.1.1 25-1.3.1.1.2.1.4 28-1.3.2 31-1.3.2.1 31-1.5 33-1.5.1.r 34-1.5.1.1 36-1.5.2.1 37-1.5.1.2 37-1.5.2.2 (e / enhance-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "genistein"~e.2)) :ARG1 (d3 / differentiate-01~e.8 :ARG1 (n2 / neuron) :ARG2-of (i / induce-01~e.6 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "RA"~e.4)))) :manner (i2 / increase-01~e.10 :ARG1 (a / activate-01~e.12 :ARG1 (a2 / and~e.0 :op1 (e2 / enzyme :name (n4 / name :op1 "extracellular"~e.14 :op2 "signal-related"~e.15,17 :op3 "kinase"~e.18 :op4 1~e.19) :ARG1-of (d4 / describe-01 :ARG2 (e4 / enzyme :name (n6 / name :op1 "ERK1"~e.23)))) :op2 (e3 / enzyme :name (n5 / name :op1 "extracellular"~e.14 :op2 "signal-related"~e.15,17 :op3 "kinase"~e.18 :op4 2~e.21,25) :ARG1-of (d5 / describe-01 :ARG2 (e5 / enzyme :name (n7 / name :op1 "ERK2")))))) :manner (p / phosphorylate-01~e.28 :ARG1 (a3 / and~e.31 :op1 (a4 / amino-acid :mod 183 :name (n8 / name :op1 "tyrosine")) :op2 (a5 / amino-acid :mod 185 :name (n9 / name :op1 "tyrosine"))))) :ARG1-of (a6 / add-02) :time (b / between~e.31 :op1~e.33 (t / temporal-quantity :quant 3~e.34 :unit (d / day~e.37)) :op2 (t2 / temporal-quantity :quant 7~e.36 :unit (d2 / day~e.37)))) # ::id bel_pmid_1617_7098.35020 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK @-@ 2 , which are required for leukotriene C4 ( LTC4 ) release , and production of LTC4 was increased 3 @- to 5 @-@ fold , compared with cells transfected with vector alone . # ::alignments 1-1.1.2 2-1.1.2.2.r 3-1.1.2.2.1.1.2.1.1 4-1.1.2.2.1.1.1 5-1.1.2.2.1.1 6-1.1.2.2 6-1.1.2.2.1 6-1.1.2.2.1.r 8-1.1 9-1.1.1.r 10-1.1.1.2 11-1.1.1 12-1.1.1.1.r 13-1.1.1.1.1.1.1 14-1.1.1.1 15-1.1.1.1.2.1.1 17-1.1.1.1.2.1.1 21-1.1.1.1.3 22-1.1.1.1.3.1.r 23-1.1.1.1.3.1.1.1.1 24-1.1.1.1.3.1.1.1.2 28-1.1.1.1.3.1 30-1 31-1.2.1 32-1.2.2.1 35-1.2 36-1.2.2.1.1 39-1.2.2.2.1 41-1.2.2.2 43-1.2.3.r 45-1.2.3 46-1.2.3.1 47-1.2.3.1.1.r 48-1.2.3.1.1 49-1.2.3.1.1.1 (a / and~e.30 :op1 (a2 / accompany-01~e.8 :ARG0~e.9 (p / phosphorylate-01~e.11 :ARG1~e.12 (a3 / and~e.14 :op1 (e / enzyme :name (n / name :op1 "MEK"~e.13)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK-2"~e.15,17)) :ARG1-of (r / require-01~e.21 :ARG0~e.22 (r2 / release-01~e.28 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "leukotriene"~e.23 :op2 "C4"~e.24))))) :ARG1-of (e4 / enhance-01~e.10)) :ARG1 (s / stimulate-01~e.1 :ARG0 (a4 / antigen) :ARG1~e.2 (m / molecular-physical-entity~e.6 :ARG1-of~e.6 (t / transfect-01~e.6 :ARG2 (d / domain~e.5 :mod (u / unique~e.4) :part-of (e3 / enzyme :name (n3 / name :op1 "Lyn"~e.3))))))) :op2 (i / increase-01~e.35 :ARG1 (p2 / produce-01~e.31 :ARG1 s2) :ARG2 (v / value-interval :op1 (p3 / product-of~e.32 :op1 3~e.36) :op2 (p4 / product-of~e.41 :op1 5~e.39)) :compared-to~e.43 (c / cell~e.45 :ARG1-of (t2 / transfect-01~e.46 :ARG2~e.47 (v2 / vector~e.48 :mod (a5 / alone~e.49)))))) # ::id bel_pmid_1618_2244.3476 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our analyses using epiregulin @-@ deficient mice with mixed and inbred genetic backgrounds revealed that epiregulin deficiency results in the reduction of IL @-@ 6 production levels in both cell types upon peptidoglycan stimulation , and that the extent of this reduction is more evident under the BALB/c background compared with the C57BL @/@ 6J background . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1 1-1.1.1 1-1.1.1.r 3-1.1.1.2.1.1.1.1 6-1.1.1.2 7-1.1.1.2.r 8-1.1.1.2.2.1.1.1 11-1.1.1.2.2.1.1.2 12-1.1.1.2.2.1.1 12-1.1.1.2.2.1.2 13-1 14-1.2.r 15-1.2.1.1 17-1.2.1 18-1.2.1.2.2.r 20-1.2.1.2 21-1.2.1.2.1.r 22-1.2.1.2.1.1.1.1.1 24-1.2.1.2.1.1.1.1.1 25-1.2.1.2.1.1 26-1.2.1.2.1 27-1.2.1.2.2.r 29-1.2.2.3.1 29-1.2.2.4.1 32-1.2.2.1.1 33-1.2.2.1.1 38-1.2.2.1 41-1.2.2.1.1 42-1.2.2.1.r 43-1.2.2.2 44-1.2.2 45-1.2.2.3.r 47-1.2.2.3.1.1.1 48-1.2.2.3 48-1.2.2.4 49-1.2.2.4.r 50-1.1.1.2.r 52-1.2.2.4.1.1.1 54-1.2.2.4.1.1.1 55-1.2.2.3 (r / reveal-01~e.13 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (a / analyze-01~e.1 :ARG0~e.0 (w2 / we~e.0) :instrument~e.7,50 (m / mouse~e.6 :ARG0-of (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "epiregulin"~e.3))) :ARG0-of (h / have-03 :ARG1 (a2 / and :op1 (b / background~e.12 :ARG3-of (m2 / mix-01~e.8) :mod (g / genetic~e.11)) :op2 (b2 / background~e.12 :ARG1-of (i / inbreed-00) :mod g)))))) :ARG1~e.14 (a3 / and :op1 (r2 / result-01~e.17 :ARG1 l~e.15 :ARG2 (r3 / reduce-01~e.20 :ARG1~e.21 (l2 / level~e.26 :degree-of (p2 / produce-01~e.25 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"~e.22,24)))) :prep-in~e.18,27 a2 :condition (s / stimulate-01 :ARG1 (m3 / macro-molecular-complex :name (n3 / name :op1 "peptidoglycan"))))) :op2 (e / evident~e.44 :domain~e.42 (e2 / extent~e.38 :degree-of r3~e.32,33,41) :degree (m4 / more~e.43) :prep-under~e.45 (b3 / background~e.48,55 :mod (c / cell-line~e.29 :name (n4 / name :op1 "BALB/c"~e.47))) :compared-to~e.49 (b4 / background~e.48 :mod (c2 / cell-line~e.29 :name (n5 / name :op1 "C57BL/6J"~e.52,54)))))) # ::id bel_pmid_1618_2244.26736 ::amr-annotator SDL-AMR-09 ::preferred # ::tok rmEP reduced IL @-@ 18 expression in WT @- and EP –/–-derived keratinocytes at 8 h after stimulation , and there was no obvious difference between WT and EP –/– ( Fig . 3D ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1.1 4-1.1.2.1.1.1 5-1.1.2 5-1.1.2.2.2.1 7-1.1.2.2.1.1 9-1.1.2.2 10-1.1.2.2.2.1.1.1.1 12-1.1.2.2.1 12-1.1.2.2.2 13-1.1.3.r 14-1.1.3.2.1 15-1.1.3.2.2 16-1.1.3 17-1.1.3.1 19-1.1.2.2 22-1.2.2.1 22-1.2.2.1.r 23-1.2.2 24-1.2 26-1.2.1 27-1.2.1 28-1.2.1 31-1.3.1 33-1.3.1.1 (a / and :op1 (r / reduce-01~e.1 :ARG0 (p / protein :name (n / name :op1 "rmEP"~e.0)) :ARG1 (e / express-03~e.5 :ARG2 (p2 / protein :name (n2 / name :op1 "IL-18"~e.2,4)) :ARG3 (a2 / and~e.9,19 :op1 (k / keratinocyte~e.12 :mod (w / wild-type~e.7)) :op2 (k2 / keratinocyte~e.12 :ARG3-of (e2 / express-03~e.5 :ARG2 (p3 / protein :name (n3 / name :op1 "EP"~e.10) :ARG2-of (m / mutate-01 :mod "-/-")))))) :time~e.13 (a3 / after~e.16 :op1 (s / stimulate-01~e.17) :quant (t / temporal-quantity :quant 8~e.14 :unit (h / hour~e.15)))) :op2 (d / differ-02~e.24 :ARG1 a2~e.26,27,28 :ARG1-of (o2 / obvious-01~e.23 :polarity~e.22 -~e.22)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "3D"~e.33))) # ::id bel_pmid_1620_4059.41796 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here , we show that ras @-@ transformed cancer cells can also induce TSP @-@ 1 down @-@ regulation in their adjacent nontransformed stromal fibroblasts , but not in endothelial cells , in a paracrine and distance @-@ dependent manner . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1.1.1.1.1 7-1.2.1.1.1.1 7-1.2.1.1.2.2.2 8-1.2.1.1.1.2.2.1 9-1.2.1.1.1 10-1.2.1 10-1.2.2 11-1.2.1.1.3 12-1.2.1.1 12-1.2.2.2 13-1.2.1.1.2.1.1.1 15-1.2.1.1.2.1.1.1 16-1.2.1.1.2 16-1.2.2.2.2 17-1.2.1.1.2 18-1.2.1.1.2 19-1.2.1.1.2.2.r 20-1.2.1.1.2.2.4 20-1.2.1.1.2.2.4.r 24-1.2.1.1.2.2 26-1.2 27-1.2.1.1.2.2.2.1 27-1.2.1.1.2.2.2.1.r 27-1.2.2.1 27-1.2.2.1.r 28-1.2.2.2.2.2.r 29-1.2.2.2.2.2.1 30-1.2.2.2.2.2 34-1.2.1.1.4 36-1.2.1.1.5.1 38-1.2.1.1.5 39-1.2.1.1.4.r (s / show-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (c3 / contrast-01~e.26 :ARG1 (p / possible-01~e.10 :ARG1 (i / induce-01~e.12 :ARG0 (c / cell~e.9 :ARG1-of (t / transform-01~e.7 :ARG0 (e / enzyme :name (n / name :op1 "ras"~e.5))) :mod (d5 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.8))) :ARG2 (d / downregulate-01~e.16,17,18 :ARG1 (p3 / protein :name (n2 / name :op1 "TSP-1"~e.13,15)) :location~e.19 (f / fibroblast~e.24 :mod (s2 / stroma) :ARG1-of (t2 / transform-01~e.7 :polarity~e.27 -~e.27) :ARG2-of (b / border-01) :poss~e.20 e~e.20)) :mod (a / also~e.11) :manner~e.39 (p5 / paracrine~e.34) :ARG0-of (d3 / depend-01~e.38 :ARG1 (d4 / distance~e.36)))) :ARG2 (p4 / possible-01~e.10 :polarity~e.27 -~e.27 :ARG1 (i2 / induce-01~e.12 :ARG0 c :ARG2 (d2 / downregulate-01~e.16 :ARG1 p3 :location~e.28 (c4 / cell~e.30 :mod (e2 / endothelium~e.29)))))) :location (h / here~e.0)) # ::id bel_pmid_1620_4059.41800 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , MDF528 nontransformed dermal fibroblasts , like many other types of normal nonangiogenic cells ( 12 ) , express copious amounts of TSP @-@ 1 ( Fig . 1B , lane 1 ) , which becomes undetectable in their H @-@ ras -@ expressing counterparts ( 528 ras1 cells ; Fig. 1B , lane 2 ; refs . # ::alignments 0-1.3 2-1.2.3.1.1 4-1.2.1 7-1.5 8-1.5.1.1.3.1 9-1.5.1.1.3.2 10-1.5.1.1.3 12-1.5.1.1.2 14-1.5.1.1 16-1.5.2.1.1.1 19-1 19-1.5.1 20-1.1.1 21-1.1 22-1.1.2.r 23-1.1.2.1.1 25-1.1.2.1.1 27-1.4.1 29-1.4.1.1 31-1.4.1.2 32-1.1.2.1.1 32-1.4.1.2.1 36-1.1.2 36-1.1.2.2 36-1.1.2.2.r 37-1.1.2.2.1 37-1.1.2.2.1.2.1 37-1.2.2.1 37-1.5.1.1.1.1 38-1.1.2.2.2.r 39-1.1.2.2.2.2 39-1.1.2.2.2.2.r 40-1.1.2.2.2.1.1.1.1 42-1.1.2.2.2.1.1.1.1 44-1.1.2.2.2.1 45-1.1.2.2.2 49-1.1.2.2.2.3.2.2 51-1.1.2.2.2.3.1 52-1.1.2.2.2.3.1.1 54-1.1.2.2.2.3.1.2 55-1.1.2.2.2.3.1.2.1 (e / express-03~e.19 :ARG2 (a / amount~e.21 :mod (c3 / copious~e.20) :quant-of~e.22 (p / protein~e.36 :name (n3 / name :op1 "TSP-1"~e.23,25,32) :ARG1-of~e.36 (b / become-01~e.36 :ARG2 (d3 / detect-01~e.37 :ARG1 p :ARG1-of (p4 / possible-01 :polarity -~e.37)) :location~e.38 (c4 / counterpart~e.45 :ARG3-of (e2 / express-03~e.44 :ARG2 (e4 / enzyme :name (n4 / name :op1 "H-ras"~e.40,42))) :poss~e.39 f~e.39 :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure~e.51 :mod "1B"~e.52 :mod (l2 / lane~e.54 :mod 2~e.55)) :ARG2 (n7 / name :op1 "528ras1" :op2 "cells"~e.49)) :ARG1-of (d6 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01))))))) :ARG3 (f / fibrolast :mod (d / dermis~e.4) :ARG1-of (t / transform-01 :polarity -~e.37) :mod (c / cell-line :name (n5 / name :op1 "MDF528"~e.2))) :mod (i / indeed~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.27 :mod "1B"~e.29 :mod (l / lane~e.31 :mod 1~e.32))) :ARG1-of (r / resemble-01~e.7 :ARG2 (e3 / express-03~e.19 :ARG3 (c2 / cell~e.14 :mod (a2 / angiogenic :polarity -~e.37) :ARG1-of (n / normal-02~e.12) :ARG1-of (t2 / type-03~e.10 :mod (m / many~e.8) :mod (o / other~e.9)))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 12~e.16))))) # ::id bel_pmid_1620_4059.41802 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Down @-@ regulation of thrombospondin @-@ 1 promoter activity in nontumorigenic dermal fibroblasts exposed to tumor cell @-@ derived soluble mediator( s ) . # ::alignments 0-1.1 1-1.1 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1.1.1 6-1.1.1.1.1.1.1.1 7-1.1.1.1 7-1.1.1.1.1 7-1.1.1.1.1.r 8-1.1.1 11-1.1.1.2.1 12-1.1.1.2 13-1 14-1.1.1.2.2 15-1.1.1.2.2.2 16-1.2.2.1 18-1.2.2 19-1.2.3 (e / expose-01~e.13 :ARG1 (d / downregulate-01~e.0,1,2 :ARG1~e.3 (a / activity-06~e.8 :ARG0 (m / molecular-physical-entity~e.7 :ARG0-of~e.7 (p / promote-01~e.7 :ARG1 (p2 / protein :name (n / name :op1 "thrombospondin-1"~e.4,6)))) :location (f / fibroblast~e.12 :mod (d2 / dermis~e.11) :ARG0-of (c2 / cause-01~e.14 :polarity - :ARG1 (t / tumor~e.15))))) :ARG2 (m2 / molecular-physical-entity :ARG0-of (m3 / mediate-01) :ARG1-of (d3 / derive-01~e.18 :ARG2 (c / cell~e.16 :source t)) :mod (s / soluble~e.19))) # ::id bel_pmid_1620_4059.41804 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , exposure of MDF @-@ EGFP @/@ TSP @-@ 1 fibroblasts to conditioned medium derived rom H @-@ ras @-@ expressing 528 ras1 cancer cells ( 528 ras1 conditioned medium ) induced a near complete inhibition of GFP fluorescence as indicated by both confocal microscopy and flow cytometry ( Fig . 2C , left ) . # ::alignments 0-1.3 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 6-1.1.1.1.1.1 8-1.1.1.1.1.1 10-1.1.1.1.1.1 11-1.1.1 12-1.1.2.r 13-1.1.2.1 13-1.1.2.3.1.2 14-1.1.2 14-1.1.2.3.1.3 15-1.1.2.2 17-1.1.2.2.1.1.1.1.1 19-1.1.2.2.1.1.1.1.1 21-1.1.2.2.1.1 24-1.1.2.2.1.3.2.1 25-1.1.2.2.1 29-1.1.2.1 29-1.1.2.3.1.2 30-1.1.2 30-1.1.2.3.1.3 32-1 34-1.2.2.1 35-1.2.2 36-1.2 38-1.2.1.1.1.1 40-1.4.r 41-1.4 45-1.4.1.1 46-1.4.1 47-1.4.1.2.1 48-1.4.1.2 50-1.4.2.1 52-1.4.2.1.1 54-1.4.2.1.2 (i / induce-01~e.32 :ARG0 (e / expose-01~e.2 :ARG1~e.3 (f / fibroblast~e.11 :mod (c2 / cell-line :name (n2 / name :op1 "MDF-EGFP/TSP-1"~e.4,6,8,10))) :ARG2~e.12 (m / medium~e.14,30 :ARG1-of (c / condition-01~e.13,29) :ARG1-of (d2 / derive-01~e.15 :ARG2 (c3 / cell~e.25 :ARG3-of (e2 / express-03~e.21 :ARG2 (e3 / enzyme :name (n3 / name :op1 "H-ras"~e.17,19))) :mod (c5 / cell-line :name (n4 / name :op1 "528ras1")) :mod (d4 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.24)))) :ARG1-of (d / describe-01 :ARG2 (n9 / name :op1 "528ras1" :op2 "conditioned"~e.13,29 :op3 "medium"~e.14,30)))) :ARG2 (i3 / inhibit-01~e.36 :ARG1 (f2 / fluoresce-01 :ARG1 (p2 / protein :name (n6 / name :op1 "GFP"~e.38))) :ARG1-of (c6 / complete-02~e.35 :degree (n5 / near~e.34))) :ARG2-of (i2 / interest-01~e.0) :ARG1-of~e.40 (i4 / indicate-01~e.41 :instrument (a / and~e.46 :op1 (m2 / microscopy~e.45 :mod (c4 / cofocal)) :op2 (c7 / cytometry~e.48 :mod (f4 / flow~e.47))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.50 :mod "2C"~e.52 :ARG1-of (l / left-20~e.54))))) # ::id bel_pmid_1620_4059.41806 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Again , this effect was paralleled by comparable decreases in TSP @-@ 1 mRNA and protein expression in these cells exposed to 528 ras1 conditioned medium ( Fig . 2C ) . # ::alignments 0-1.3 2-1.1.1 3-1.1 5-1 6-1.2.r 7-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1.1.2.1.1 12-1.2.1.1.2.1.1 13-1.2.1.1.1.1.1 14-1.2.1.1 15-1.2.1.1.2 16-1.2.1 17-1.2.1.2.r 18-1.2.1.2.1 19-1.2.1.2 20-1.2.1.2.2 24-1.2.1.2.2.1.1 25-1.2.1.2.2.1 27-1.4.1 29-1.4.1.1 (p / parallel-01~e.5 :ARG0 (e / effect~e.3 :mod (t / this~e.2)) :ARG1~e.6 (d / decrease-01~e.8 :ARG1~e.9 (e2 / express-03~e.16 :ARG2 (a / and~e.14 :op1 (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.13) :ARG0-of (e4 / encode-01 :ARG1 p3)) :op2 (p3 / protein~e.15 :name (n3 / name :op1 "TSP-1"~e.10,12))) :ARG3~e.17 (c2 / cell~e.19 :mod (t2 / this~e.18) :ARG1-of (e3 / expose-01~e.20 :ARG2 (m / medium~e.25 :ARG1-of (c3 / condition-01~e.24) :mod (c4 / cell-line :name (n2 / name :op1 "528ras1")))))) :ARG1-of (c / comparable-03~e.7)) :mod (a2 / again~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.27 :mod "2C"~e.29))) # ::id bel_pmid_1620_4059.41808 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to the aforementioned paracrine properties of 528 ras1 cells , we observed that also conditioned medium of human colorectal cancer cells harboring a mutant K @-@ ras oncogene ( DLD @-@ 1 ) , but not that of a DLD @-@ 1 variant with genetically disrupted K @-@ ras allele ( DKO @-@ 3 cells ) , efficiently suppressed the activity of the TSP @-@ 1 reporter gene in MDF @-@ EGFP/ TSP @-@ 1 cells ( Fig . 4A ) . # ::alignments 0-1.2 1-1.2 2-1.2.2.1.1.2.2.1.3 5-1.2.1.1 6-1.2.1 10-1.2.1.3 12-1.1 13-1 14-1.2.r 15-1.2.2.1.1.3 16-1.2.2.1.1.1 16-1.2.2.2.2.1 17-1.2.2.1.1 17-1.2.2.2.2 18-1.2.2.1.1.2.r 19-1.2.2.1.1.2.1 20-1.2.2.1.1.2.4.2.1 21-1.2.2.1.1.2.2.1.3.1.2.1 21-1.2.2.1.1.2.4.2.2 22-1.2.2.1.1.2 23-1.2.2.1.1.2.2 25-1.2.2.1.1.2.2.1 25-1.2.2.1.1.2.2.1.2 25-1.2.2.1.1.2.2.1.2.r 26-1.2.2.1.1.2.2.1.1.1 28-1.2.2.1.1.2.2.1.1.1 31-1.2.2.1.1.2.3.1.1 33-1.2.2.1.1.2.3.1.1 33-1.2.2.1.3.1.1 36-1.2.2 37-1.2.2.2.1 37-1.2.2.2.1.r 39-1.2.2.2.2.2.r 41-1.2.2.2.2.2.1.1.1 43-1.2.2.2.2.2.1.1.1 44-1.2.2.2.2.2 46-1.2.2.2.2.2.3.1.2.1 47-1.2.2.2.2.2.3.1.2 48-1.2.2.2.2.2.3.1.1.1.1 50-1.2.2.2.2.2.3.1.1.1.1 51-1.2.2.2.2.2.3.1 53-1.2.2.2.2.2.2.1.1 55-1.2.2.2.2.2.2.1.1 56-1.2.2.2.2.2.2.1.2 59-1.2.2.1.4 60-1.2.2.1 60-1.2.2.2 62-1.2.2.1.2 63-1.2.2.1.2.1.r 65-1.2.2.1.2.1.1.1.1.1 67-1.2.2.1.2.1.1.1.1.1 68-1.2.2.1.2.1.1 69-1.2.2.1.2.1 70-1.2.2.1.3.r 71-1.2.2.1.3.1.1 74-1.2.2.1.2.1.1.1.1.1 74-1.2.2.1.3.1.1 76-1.2.2.2.2.2.1.1.1 77-1.2.2.2.2.2.2.1.2 79-1.3.1 81-1.3.1.1 (o / observe-01~e.13 :ARG0 (w / we~e.12) :ARG1~e.14 (a / and~e.0,1 :op1 (p2 / property~e.6 :mod (p3 / paracrine~e.5) :ARG1-of (m / mention-01 :time (b / before)) :poss (c2 / cell-line~e.10 :name (n3 / name :op1 "528ras1"))) :op1 (c10 / contrast-01~e.36 :ARG1 (s / suppress-01~e.60 :ARG0 (m2 / medium~e.17 :ARG1-of (c / condition-01~e.16) :mod~e.18 (c5 / cell~e.22 :source (h / human~e.19) :ARG0-of (h2 / harbor-01~e.23 :ARG1 (g4 / gene~e.25 :name (n6 / name :op1 "K-ras"~e.26,28) :ARG2-of~e.25 (m3 / mutate-01~e.25) :ARG0-of (c6 / cause-01~e.2 :ARG1 (d6 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.21))))) :ARG1-of (d4 / describe-01 :ARG2 (n12 / name :op1 "DLD-1"~e.31,33)) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal"~e.20 :op2 "cancer"~e.21))) :mod (a4 / also~e.15)) :ARG1 (a2 / activity-06~e.62 :ARG0~e.63 (g / gene~e.69 :ARG0-of (r2 / report-01~e.68 :ARG1 (p4 / protein :name (n4 / name :op1 "TSP-1"~e.65,67,74))))) :location~e.70 (c3 / cell-line :name (n5 / name :op1 "MDF-EGFP/TSP-1"~e.33,71,74)) :ARG2-of (e / efficient-01~e.59)) :ARG2 (s2 / suppress-01~e.60 :polarity~e.37 -~e.37 :ARG0 (m4 / medium~e.17 :ARG1-of (c4 / condition-01~e.16) :mod~e.39 (v / variant~e.44 :poss (c9 / cell-line :name (n7 / name :op1 "DLD-1"~e.41,43,76)) :ARG1-of (d5 / describe-01 :ARG2 (n10 / name :op1 "DKO-3"~e.53,55 :op2 "cells"~e.56,77)) :ARG0-of (h3 / have-03 :ARG1 (a5 / allele~e.51 :mod (g3 / gene :name (n2 / name :op1 "K-ras"~e.48,50)) :ARG1-of (d3 / disrupt-01~e.47 :mod (g2 / genetic~e.46)))))) :ARG1 a2 :location c3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.79 :mod "4A"~e.81))) # ::id bel_pmid_1620_4059.41810 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Once again , we observed that expression of TSP @-@ 1 by the nontransformed MDFB6 fibroblasts was precipitously down @-@ regulated when these cells were incubated with B6 ras conditioned medium ( Fig . 5A ) . # ::alignments 0-1.3.1 1-1.3 3-1.1 4-1 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.2.1 10-1.2.1.1.2.1 14-1.2.1.2.1.2.1 15-1.2.1.2 17-1.2.2 17-1.2.2.r 23-1.2.1.2.1 23-1.2.3.2.2 25-1.2.3 29-1.2.3.2.1 29-1.2.3.r 30-1.2.3.2 32-1.4.1 34-1.4.1.1 (o2 / observe-01~e.4 :ARG0 (w / we~e.3) :ARG1 (d / downregulate-01 :ARG1 (e2 / express-03~e.6 :ARG2~e.7 (p / protein :wiki "Thrombospondin_1" :name (n2 / name :op1 "TSP-1"~e.8,10)) :ARG3 (f / fibroblast~e.15 :mod (c / cell-line~e.23 :wiki - :name (n3 / name :op1 "MDFB6"~e.14)) :ARG1-of (t / transform-01 :polarity -))) :manner~e.17 (p2 / precipitous~e.17) :condition~e.29 (i / incubate-01~e.25 :ARG1 f :ARG2 (m / medium~e.30 :ARG1-of (c2 / condition-01~e.29) :mod (c3 / cell-line~e.23 :wiki - :name (n4 / name :op1 "B6ras"))))) :mod (a / again~e.1 :mod (o / once~e.0)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.32 :mod "5A"~e.34))) # ::id bel_pmid_1620_4059.41812 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A , immortalized dermal fibroblasts ( MDFB6 ) down @-@ regulate TSP @-@ 1 protein expression in the presence of conditioned medium from their H @-@ ras @-@ transformed counterparts ( B6 ras CM ) ; quantification of representative Western blot . # ::alignments 0-1.2.1.1 2-1.1.2.2 3-1.1.2.1 4-1.1.2 6-1.1.2.3.1.1 11-1.1.1.1.1.1 13-1.1.1.1.1.1 14-1.1.1.1 15-1.1.1 18-1.1.3 20-1.1.3.1.1 20-1.1.3.r 21-1.1.3.1 22-1.1.3.1.2.r 23-1.1.3.1.2.1 23-1.1.3.1.2.1.r 24-1.1.3.1.2.2.1.1.1 26-1.1.3.1.2.2.1.1.1 28-1.1.3.1.2.2 29-1.1.3.1.2 32-1.1.3.1.2.2.1.1.1 33-1.1.3.1.3.1.2 36-1.3 37-1.3.1.r 38-1.3.1.1 39-1.3.1 40-1.3.1 (m / multi-sentence :snt1 (d / downregulate-01 :ARG1 (e2 / express-03~e.15 :ARG2 (p2 / protein~e.14 :name (n3 / name :op1 "TSP-1"~e.11,13))) :location (f / fibroblast~e.4 :mod (d2 / dermis~e.3) :ARG1-of (i / immortalize-03~e.2) :ARG1-of (d3 / describe-01 :ARG2 (n5 / name :op1 "MDFB6"~e.6))) :condition~e.20 (p / present-02~e.18 :ARG1 (m2 / medium~e.21 :ARG1-of (c / condition-01~e.20) :mod~e.22 (c2 / counterpart~e.29 :poss~e.23 f~e.23 :ARG1-of (t / transform-01~e.28 :ARG0 (e / enzyme :name (n6 / name :op1 "H-ras"~e.24,26,32)))) :ARG1-of (d5 / describe-01 :ARG2 (n8 / name :op1 "B6ras" :op2 "CM"~e.33))))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "A"~e.0)) :snt2 (q / quantify-01~e.36 :ARG1~e.37 (i2 / immunoblot-01~e.39,40 :ARG0-of (r2 / represent-01~e.38)))) # ::id bel_pmid_1620_4059.41814 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B , absence of TSP @-@ 1 down @-@ regulation in Id1 @-@ deficient dermal fibroblasts exposed to conditioned medium of ras @-@ transformed ( 528 ras1 CM and B6 ras CM ) and neu @-@ transformed ( 528 neu CM ) tumor cells . # ::alignments 0-1.2.1.1 2-1 3-1.1.r 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1 8-1.1 9-1.1 10-1.1.2.r 11-1.1.2.2.1.1.1 14-1.1.2.1 15-1.1.2 16-1.1.2.3 17-1.1.2.3.1.r 18-1.1.2.3.1.1 19-1.1.2.3.1 20-1.1.2.3.1.2.r 21-1.1.2.3.1.2.2.1.1.1 23-1.1.2.3.1.2.2 30-1.1.2.3.1.2.2.1.1.1 34-1.1.2.3.1.2.3.1.1.1 36-1.1.2.3.1.2.3 39-1.1.2.3.1.2.3.1.1.1 42-1.1.2.3.1.2.1 43-1.1.2.3.1.2 (a / absent-01~e.2 :ARG1~e.3 (d2 / downregulate-01~e.7,8,9 :ARG1 (p / protein :name (n2 / name :op1 "TSP-1"~e.4,6)) :location~e.10 (f2 / fibroblast~e.15 :mod (d3 / dermis~e.14) :ARG0-of (l / lack-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Id1"~e.11))) :ARG1-of (e2 / expose-01~e.16 :ARG2~e.17 (m / medium~e.19 :ARG1-of (c / condition-01~e.18) :mod~e.20 (c2 / cell~e.43 :source (t / tumor~e.42) :ARG1-of (t2 / transform-01~e.23 :ARG0 (e / enzyme :name (n / name :op1 "ras"~e.21,30))) :ARG1-of (t3 / transform-01~e.36 :ARG0 (p3 / protein :name (n4 / name :op1 "neu"~e.34,39)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"~e.0))) # ::id bel_pmid_1620_4059.41816 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Paracrine effects of various ras @-@ driven cancer cells were detected at the level of TSP @-@ 1 protein , mRNA , and promoter activity ( Fig . 2C ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1 4-1.1.2.2.1.1.1 6-1.1.2.2 7-1.1.2.3.2.1 8-1.1.2 10-1 14-1.2.r 15-1.2.1.1.1 17-1.2.1.1.1 18-1.2.1 20-1.2.2.1.1 22-1.2 23-1.2.3.1 23-1.2.3.1.1 23-1.2.3.1.1.r 24-1.2.3 26-1.3.1 28-1.3.1.1 (d2 / detect-01~e.10 :ARG1 (e / effect~e.1 :mod (p / paracrine~e.0) :poss~e.2 (c / cell~e.8 :mod (v / various~e.3) :ARG1-of (d3 / drive-02~e.6 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ras"~e.4))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.7)))) :location~e.14 (a / and~e.22 :op1 (p3 / protein~e.18 :name (n3 / name :op1 "TSP-1"~e.15,17)) :op2 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.20) :ARG0-of (e3 / encode-01 :ARG1 p3)) :op3 (a2 / activity-06~e.24 :ARG0 (m / molecular-physical-entity~e.23 :ARG0-of~e.23 (p4 / promote-01~e.23 :ARG1 p3)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.26 :mod "2C"~e.28))) # ::id bel_pmid_1620_4059.41820 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , abrogation of TSP @-@ 1 suppression was observed ( Fig . 6C ) when MDF528 cells were incubated with dimethylsphingosine , a specific inhibitor of sphingosine kinase . # ::alignments 1-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1 7-1.1.1.1.1.1.1 8-1.1.1.1 10-1.1 12-1.1.2.1 14-1.1.2.1.1 17-1.1.1.2.1.1.1 18-1.1.1.2.1 20-1.1.1.2 21-1.1.1.2.2.r 22-1.1.1.2.2.1.1 25-1.1.1.2.2.3 26-1.1.1.2.2 26-1.1.1.2.2.2 26-1.1.1.2.2.2.r 27-1.1.1.2.2.2.1.r 28-1.1.1.2.2.2.1.1.1 29-1.1.1.2.2.2.1.1.2 (c / contrast-01~e.1 :ARG2 (o / observe-01~e.10 :ARG1 (a / abrogate-01~e.3 :ARG1~e.4 (s / suppress-01~e.8 :ARG1 (p / protein :name (n / name :op1 "TSP-1"~e.5,7))) :condition (i2 / incubate-01~e.20 :ARG1 (c2 / cell-line~e.18 :name (n2 / name :op1 "MDF528"~e.17)) :ARG2~e.21 (s2 / small-molecule~e.26 :name (n3 / name :op1 "dimethylsphingosine"~e.22) :ARG0-of~e.26 (i3 / inhibit-01~e.26 :ARG1~e.27 (e / enzyme :name (n4 / name :op1 "sphingosine"~e.28 :op2 "kinase"~e.29))) :ARG1-of (s3 / specific-02~e.25)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.12 :mod "6C"~e.14)))) # ::id bel_pmid_1620_4059.41822 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , suppression of TSP @-@ 1 promoter activity by fraction 2 of 528 ras1 conditioned medium was moderately sensitive to pertussis toxin but was completely abolished by dimethylsphingosine . # ::alignments 2-1.1.1.1 3-1.1.1.1.2.r 4-1.1.1.1.2.1.1.1.1.1 6-1.1.1.1.2.1.1.1.1.1 7-1.1.1.1.2.1 7-1.1.1.1.2.1.1 7-1.1.1.1.2.1.1.r 8-1.1.1.1.2 9-1.1.1.1.1.r 10-1.1.1.1.1 11-1.1.1.1.1.1 15-1.1.1.1.1.2.1.1 16-1.1.1.1.1.2.1 18-1.1.1.3 19-1.1.1 20-1.1.1.2.r 21-1.1.1.2.1.1 22-1.1.1.2.1.2 23-1.1 25-1.1.2.3 26-1.1.2 27-1.1.2.1.r 28-1.1.2.1.1.1 (i / infer-01 :ARG1 (c / contrast-01~e.23 :ARG1 (s / sensitive-03~e.19 :ARG0 (s2 / suppress-01~e.2 :ARG0~e.9 (f / fraction~e.10 :mod 2~e.11 :ARG1-of (i2 / include-91 :ARG2 (m2 / medium~e.16 :ARG1-of (c2 / condition-01~e.15) :mod (c3 / cell-line :name (n2 / name :op1 "528ras1"))))) :ARG1~e.3 (a2 / activity-06~e.8 :ARG0 (m / molecular-physical-entity~e.7 :ARG0-of~e.7 (p / promote-01~e.7 :ARG1 (p2 / protein :name (n / name :op1 "TSP-1"~e.4,6)))))) :ARG1~e.20 (s3 / small-molecule :name (n3 / name :op1 "pertussis"~e.21 :op2 "toxin"~e.22)) :ARG1-of (m3 / moderate-03~e.18)) :ARG2 (a / abolish-01~e.26 :ARG0~e.27 (s4 / small-molecule :name (n4 / name :op1 "dimethylsphingosine"~e.28)) :ARG1 s2 :ARG1-of (c4 / complete-02~e.25)))) # ::id bel_pmid_1625_4190.34278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 3 . Alteration of Gene Expression Specially Associated with p53 and H @-@ ras Status in Skin Tumorigenesis upregulated # ::alignments 0-1.3.1 1-1.3.1.1 3-1 4-1.1.r 5-1.1.1 6-1.1 7-1.1.2.2 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.1.1.1.1 11-1.1.2.1 12-1.1.2.1.2.1.1.1 14-1.1.2.1.2.1.1.1 15-1.1.2.1.1 15-1.1.2.1.2 16-1.2.r 17-1.2.1.1 18-1.2 18-1.2.1 18-1.2.1.r (a / alter-01~e.3 :ARG1~e.4 (e2 / express-03~e.6 :ARG1 (g / gene~e.5) :ARG1-of (a2 / associate-01~e.8 :ARG2~e.9 (a3 / and~e.11 :op1 (s / status~e.15 :mod (p / protein :name (n2 / name :op1 "p53"~e.10))) :op2 (s2 / status~e.15 :mod (e / enzyme :name (n3 / name :op1 "H-ras"~e.12,14)))) :ARG1-of (s4 / special-02~e.7))) :subevent-of~e.16 (c / create-01~e.18 :ARG1~e.18 (t / tumor~e.18 :mod (s3 / skin~e.17))) :ARG1-of (d / describe-01 :ARG0 (t2 / table~e.0 :mod 3~e.1))) # ::id bel_pmid_1628_7813.37026 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is known that there are two isoforms of ERK , ERK1 and ERK2 , and they phosphorylate and activate various transcription factors , such as Elk @-@ 1 and Elk @-@ 2 . These transcription factors regulate expression of diverse genes that relates to the proliferation and growth of the cells . # ::alignments 2-1.1 6-1.1.1.1.3.1.2.2.1.1 7-1.1.1.1.2 8-1.1.1.1.2.1.r 9-1.1.1.1.2.1.1.1 11-1.1.1.1.1.1 12-1.1.1 13-1.1.1.2.1.1 15-1.1.1.1.3.1.2 17-1.1.1.1 17-1.1.1.1.3 17-1.1.1.1.3.r 18-1.1.1.1.3.1.2 19-1.1.1.1.4 20-1.1.1.1.4.1 21-1.1.1.1.4.1 22-1.1.1.1.4.1 23-1.1.1.1.4.1 24-1.1.1.1.4.1 25-1.1.1.1.4.1 26-1.1.1.1.4.1 27-1.1.1.1.4.1 28-1.1.1.1.4.1 29-1.1.1.1.4.1 30-1.1.1.1.4.1 31-1.1.1.1.4.1 32-1.1.1.1.4.1 34-1.2.1.2 35-1.2.1.1 36-1.2.1 37-1.2 38-1.2.2 39-1.2.2.1.r 40-1.2.2.1.1 41-1.2.2.1 43-1.2.2.2 44-1.2.2.2.1.r 46-1.2.2.2.1.1 47-1.2.2.2.1 48-1.2.2.2.1.2 49-1.2.2.2.1.1.1.r 51-1.2.2.2.1.1.1 (m / multi-sentence :snt1 (k / know-01~e.2 :ARG1 (a4 / and~e.12 :op1 (e2 / enzyme~e.17 :name (n2 / name :op1 "ERK1"~e.11) :mod (i / isoform~e.7 :mod~e.8 (p5 / protein-family :name (n4 / name :op1 "ERK"~e.9))) :ARG0-of~e.17 (p / phosphorylate-01~e.17 :ARG1 (f / factor :ARG0-of (t / transcribe-01) :example (a / and~e.15,18 :op1 (p2 / protein :name (n5 / name :op1 "Elk-1")) :op2 (p3 / protein :name (n6 / name :op1 "Elk-2"~e.6))) :mod (v / various))) :ARG0-of (a3 / activate-01~e.19 :ARG1 f~e.20,21,22,23,24,25,26,27,28,29,30,31,32)) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2"~e.13) :mod i :ARG0-of p :ARG0-of a3))) :snt2 (r / regulate-01~e.37 :ARG0 (f2 / factor~e.36 :ARG0-of (t2 / transcribe-01~e.35) :mod (t3 / this~e.34)) :ARG1 (e5 / express-03~e.38 :ARG1~e.39 (g / gene~e.41 :mod (d / diverse~e.40)) :ARG1-of (r2 / relate-01~e.43 :ARG2~e.44 (a2 / and~e.47 :op1 (p4 / proliferate-01~e.46 :ARG0~e.49 (c / cell~e.51)) :op2 (g2 / grow-01~e.48 :ARG1 c)))))) # ::id bel_pmid_1632_4152.36878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 12 activates the Janus family tyrosine kinases JAK2 and Tyk2 , which in turn phosphorylate STAT4 on tyrosine 693 . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 5-1.2.4.1.1.1 6-1.2.4.1 7-1.2.1 8-1.2.1 8-1.2.2 9-1.2.1.1.1 10-1.2 11-1.2.2.1.1 14-1.2.3.2 15-1.2.3.2 16-1.2.3 17-1.2.3.1.3.1.1 19-1.2.3.1.2.1 20-1.2.3.1.1 (a / activate-01~e.3 :ARG0 (p / protein :name (n / name :op1 "IL-12"~e.0,2)) :ARG1 (a2 / and~e.10 :op1 (t / tyrosine-kinase~e.7,8 :name (n2 / name :op1 "JAK2"~e.9)) :op2 (t2 / tyrosine-kinase~e.8 :name (n3 / name :op1 "Tyk2"~e.11)) :ARG2-of (p2 / phosphorylate-01~e.16 :ARG1 (a3 / amino-acid :mod 693~e.20 :name (n4 / name :op1 "tyrosine"~e.19) :part-of (p3 / protein :name (n5 / name :op1 "STAT4"~e.17))) :mod (i / in-turn~e.14,15)) :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family~e.6 :name (n6 / name :op1 "Janus"~e.5))))) # ::id bel_pmid_1633_9523.28962 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the cytokines expressed after 4 h of Ag stimulation in BMMCs , our data show that levels of mRNA and protein for IL @-@ 4 , IL @-@ 6 , and for IL @-@ 13 are all significantly higher in Lyn-/- than in WT BMMCs . # ::alignments 0-1.2.1.7 2-1.2.1.7.1 3-1.2.1.7.1.1 3-1.2.3.2 4-1.2.1.7.1.1.1 5-1.2.1.7.1.1.1.2.1 6-1.2.1.7.1.1.1.2.2 9-1.2.1.7.1.1.1.1 13-1.1.1 13-1.1.1.r 14-1.1 15-1 17-1.2.1.1 17-1.2.1.2 17-1.2.1.3 17-1.2.1.4 17-1.2.1.5 17-1.2.1.6 19-1.2.1.4.1.1.1 19-1.2.1.5.1.1.1 19-1.2.1.6.1.1.1 20-1.2.1 21-1.2.1.1.1 21-1.2.1.2.1 21-1.2.1.3.1 23-1.2.1.1.1.1.1 23-1.2.1.2.1.1.1 23-1.2.1.3.1.1.1 25-1.2.1.1.1.1.1 27-1.2.1.1.1.1.1 27-1.2.1.2.1.1.1 27-1.2.1.3.1.1.1 29-1.2.1.2.1.1.1 31-1.2.1 33-1.2.1.1.1.1.1 33-1.2.1.2.1.1.1 33-1.2.1.3.1.1.1 35-1.2.1.3.1.1.1 38-1.2.5 39-1.2 39-1.2.2 39-1.2.2.r 42-1.2.4.r 44-1.2.4.2 (s / show-01~e.15 :ARG0 (d / data~e.14 :poss~e.13 (w / we~e.13)) :ARG1 (h / high-02~e.39 :ARG1 (a4 / and~e.20,31 :op1 (l2 / level~e.17 :quant-of (p / protein~e.21 :name (n / name :op1 "IL-4"~e.23,25,27,33))) :op2 (l3 / level~e.17 :quant-of (p2 / protein~e.21 :name (n2 / name :op1 "IL-6"~e.23,27,29,33))) :op3 (l4 / level~e.17 :quant-of (p3 / protein~e.21 :name (n3 / name :op1 "IL-13"~e.23,27,33,35))) :op4 (l5 / level~e.17 :quant-of (n11 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.19) :ARG0-of (e4 / encode-01 :ARG1 p))) :op5 (l6 / level~e.17 :quant-of (n12 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.19) :ARG0-of (e5 / encode-01 :ARG1 p2))) :op6 (l7 / level~e.17 :quant-of (n13 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.19) :ARG0-of (e6 / encode-01 :ARG1 p3))) :ARG1-of (i / include-91~e.0 :ARG2 (c / cytokine~e.2 :ARG2-of (e / express-03~e.3 :time (a2 / after~e.4 :op1 (s2 / stimulate-01~e.9 :ARG0 (a3 / antigen) :location (c2 / cell-line :name (n7 / name :op1 "BMMC"))) :quant (t / temporal-quantity :quant 4~e.5 :unit (h2 / hour~e.6))))))) :degree~e.39 (m / more~e.39) :location (c3 / cell-line :name (n8 / name :op1 "BMMC") :ARG3-of (e2 / express-03~e.3 :ARG2 (e3 / enzyme :name (n9 / name :op1 "Lyn") :ARG2-of (m2 / mutate-01 :mod "-/-")))) :compared-to~e.42 (c4 / cell-line :name (n10 / name :op1 "BMMC") :mod (w2 / wild-type~e.44)) :ARG1-of (s3 / significant-02~e.38))) # ::id bel_pmid_1633_9523.28966 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our data show that mRNA coding for at least one transcription factor , the cytoplasmic NF @-@ AT ( NF @-@ ATC , also known as NFATC1 and NFAT2 ) is induced 3 @-@ fold more in Lyn–/– BMMCs than in WT BMMCs ( Table II ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1 3-1.2.r 4-1.2.1.2.1.1 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.2 8-1.2.1.1.2 9-1.2.1.1.2.1 10-1.2.1.1.1 11-1.2.1.1 14-1.2.1.1.3.1.2 15-1.2.1.1.3.1.1.1 17-1.2.1.1.3.1.1.1 19-1.2.1.1.3.1.1.1 23-1.2.1.1.3.1.3.2 24-1.2.1.1.3.1 24-1.2.1.1.3.1.3 24-1.2.1.1.3.1.3.1.1.1.r 24-1.2.1.1.3.1.3.r 25-1.2.1.1.3.1.3.1.1.1.r 26-1.2.1.1.3.1.3.1.1.1.1 27-1.2.1.1.3.1.3.1 28-1.2.1.1.3.1.3.1.2.1.1 31-1.2 32-1.2.2.1 34-1.2.2 35-1.2.5 39-1.2.4.r 41-1.2.4.2 44-1.3.1 45-1.3.1.1 (s / show-01~e.2 :ARG0 (d / data~e.1 :poss~e.0 (w / we~e.0)) :ARG1~e.3 (i / induce-01~e.31 :ARG2 (c / code-01~e.5 :ARG1~e.6 (f / factor~e.11 :ARG0-of (t / transcribe-01~e.10) :quant (a / at-least~e.7,8 :op1 1~e.9) :ARG1-of (m / mean-01 :ARG2 (p4 / protein~e.24 :name (n2 / name :op1 "NF-AT"~e.15,17,19) :mod (c2 / cytoplasm~e.14) :ARG1-of~e.24 (k / know-02~e.24 :ARG2 (a4 / and~e.27 :op1 (p2 / protein :name~e.24,25 (n3 / name :op1 "NFATC1"~e.26)) :op2 (p3 / protein :name (n4 / name :op1 "NFAT2"~e.28))) :mod (a3 / also~e.23))))) :instrument (n8 / nucleic-acid :name (n / name :op1 "mRNA"~e.4))) :degree (p / product-of~e.34 :op1 3~e.32) :location (c3 / cell-line :name (n5 / name :op1 "BMMC") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n6 / name :op1 "Lyn") :ARG2-of (m2 / mutate-01 :mod "-/-")))) :compared-to~e.39 (c4 / cell-line :name (n7 / name :op1 "BMMC") :mod (w2 / wild-type~e.41)) :mod (m3 / more~e.35)) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table~e.44 :mod "II"~e.45))) # ::id bel_pmid_1633_9523.28968 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The 33 @-@ fold up @-@ regulation of sphingosine kinase 1 in Ag @-@ stimulated Lyn–/– BMMCs may also contribute to increased chemokine production # ::alignments 1-1.1.1.2.1 3-1.1.1.2 4-1.1.1 5-1.1.1 6-1.1.1 7-1.1.1.1.r 7-1.1.1.2 8-1.1.1.1.1.1 9-1.1.1.1.1.2 10-1.1.1.1.1.3 14-1.1.1.3.3 17-1 18-1.1.3 19-1.1 20-1.1.2.r 21-1.1.2.2 22-1.1.2.1 23-1.1.2 (p / possible-01~e.17 :ARG1 (c / contribute-01~e.19 :ARG0 (u / upregulate-01~e.4,5,6 :ARG1~e.7 (e3 / enzyme :name (n / name :op1 "sphingosine"~e.8 :op2 "kinase"~e.9 :op3 1~e.10)) :degree (p2 / product-of~e.3,7 :op1 33~e.1) :location (c2 / cell-line :name (n2 / name :op1 "BMMC") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Lyn") :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1-of (s / stimulate-01~e.14 :ARG0 (a / antigen)))) :ARG2~e.20 (p3 / produce-01~e.23 :ARG1 (c3 / chemokine~e.22) :ARG1-of (i / increase-01~e.21)) :mod (a2 / also~e.18))) # ::id bel_pmid_1637_4521.27952 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 24 hours of IL @-@ 13 induction , phosphorylation of ERK1 ( p44 ) and ERK2 ( p42 ) but not JNK1 @/@ 2 or p38 MAPK was observed ( Figure 1 ) . # ::alignments 0-1.3 1-1.3.2.1 2-1.3.2.2 3-1.3.1.r 4-1.3.1.1.1.1 6-1.3.1.1.1.1 7-1.3.1 9-1.1.1 9-1.2.2 15-1.1.1.1 20-1 21-1.2.1 21-1.2.1.r 22-1.2.2.1.1.1.1 25-1.2.2.1 29-1.1 29-1.2 31-1.4.1 32-1.4.1.1 (c / contrast-01~e.20 :ARG1 (o / observe-01~e.29 :ARG1 (p / phosphorylate-01~e.9 :ARG1 (a2 / and~e.15 :op1 (e / enzyme :name (n3 / name :op1 "p44ERK1")) :op2 (e2 / enzyme :name (n4 / name :op1 "p42ERK2"))))) :ARG2 (o2 / observe-01~e.29 :polarity~e.21 -~e.21 :ARG1 (p4 / phosphorylate-01~e.9 :ARG1 (o3 / or~e.25 :op1 (e3 / enzyme :name (n5 / name :op1 "JNK1"~e.22)) :op2 (e4 / enzyme :name (n6 / name :op1 "JNK2")) :op3 (e5 / enzyme :name (n7 / name :op1 "p38MAPK"))))) :time (a / after~e.0 :op1~e.3 (i / induce-01~e.7 :ARG2 (p3 / protein :name (n2 / name :op1 "IL-13"~e.4,6))) :quant (t / temporal-quantity :quant 24~e.1 :unit (h / hour~e.2))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod 1~e.32))) # ::id bel_pmid_1637_4521.27960 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our previous studies demonstrated that IL @-@ 13 causes MMP @- and cathepsin @-@ dependent lung remodeling and inhibits the expression of a1 @–@ AT ( 4 ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1.1 7-1.2.1.1.1.1 8-1.2.1 9-1.2.1.2.2.1.1.1.1 11-1.2.1.2.2.1 12-1.2.1.2.2.1.2.1.1 14-1.2.1.2.2 15-1.2.1.2.1 16-1.2.1.2 17-1.2 18-1.2.2 20-1.2.2.1 26-1.3.1.1.1 (d / demonstrate-01~e.3 :ARG0 (s / study-01~e.2 :ARG0~e.0 (w / we~e.0) :time (p / previous~e.1)) :ARG1~e.4 (a / and~e.17 :op1 (c / cause-01~e.8 :ARG0 (p2 / protein :name (n / name :op1 "IL-13"~e.5,7)) :ARG1 (r / remodel-01~e.16 :ARG1 (l / lung~e.15) :ARG0-of (d2 / depend-01~e.14 :ARG1 (a2 / and~e.11 :op1 (e / enzyme :name (n2 / name :op1 "MMP"~e.9)) :op2 (e2 / enzyme :name (n3 / name :op1 "cathepsin"~e.12)))))) :op2 (i / inhibit-01~e.18 :ARG1 (e3 / express-03~e.20 :ARG2 (p3 / protein :name (n4 / name :op1 "a1–AT"))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.26)))) # ::id bel_pmid_1637_4521.27968 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 13 Tg can be inducibly expressed in the adult murine lung by the administration of doxycycline @-@ containing ( dox @-@ containing ) water . As expected , increased levels of phospho @-@ STAT6 were readily detected by Western blot analysis after Tg activation ( Figure 1 ) . # ::alignments 0-1.1.1.1.1.1 0-1.2.5.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1.1.2 4-1.1 4-1.1.1.3.1 7-1.1.1 8-1.1.1.2.r 10-1.1.1.2.1.2 11-1.1.1.2.1.1.1 12-1.1.1.2 13-1.1.1.4.r 15-1.1.1.4 16-1.1.1.4.1.r 17-1.1.1.4.1.1.1.1.1 19-1.1.1.4.1.1 23-1.1.1.4.1.1 25-1.1.1.4.1 27-1.2.5.r 28-1.2.3 30-1.2.1.1 31-1.2.1 32-1.2.1.2.r 33-1.2.1.2.2 35-1.2.1.2.1.1 37-1.2.4 37-1.2.4.r 38-1.2 39-1.2.2.r 40-1.2.2.1 41-1.2.2.1 42-1.2.2 43-1.2.5 44-1.2.5.1.1.2 45-1.2.5.1 47-1.2.6.1 48-1.2.6.1.1 (m / multi-sentence :snt1 (p / possible-01~e.4 :ARG1 (e / express-03~e.7 :ARG2 (p3 / protein :name (n2 / name :op1 "IL-13"~e.0,2) :mod (t / transgenic~e.3)) :ARG3~e.8 (l / lung~e.12 :part-of (o / organism :name (n / name :op1 "Muridae"~e.11) :mod (a2 / adult~e.10))) :manner (i / induce-01 :ARG1-of (p2 / possible-01~e.4)) :instrument~e.13 (a3 / administer-01~e.15 :ARG1~e.16 (w2 / water~e.25 :ARG0-of (c / contain-01~e.19,23 :ARG1 (s / small-molecule :name (n3 / name :op1 "doxycycline"~e.17))))))) :snt2 (d / detect-01~e.38 :ARG1 (l2 / level~e.31 :ARG1-of (i2 / increase-01~e.30) :quant-of~e.32 (p4 / protein :name (n4 / name :op1 "STAT6"~e.35) :ARG3-of (p5 / phosphorylate-01~e.33))) :ARG2~e.39 (a4 / analyze-01~e.42 :manner (i3 / immunoblot-01~e.40,41)) :ARG1-of (e2 / expect-01~e.28) :manner~e.37 (r / ready~e.37) :time~e.27 (a5 / after~e.43 :op1 (a6 / activate-01~e.45 :ARG0 (p6 / protein :name (n6 / name :op1 "IL-6"~e.0) :mod (t2 / transgenic~e.44)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.47 :mod 1~e.48)))) # ::id bel_pmid_1637_4521.27988 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tg IL @-@ 13 caused increases in lung volume , alveolar size , goblet cell number , and Gob @-@ 5 , Muc @-@ 5 ac , and Muc @-@ 1 gene expression in Tg+ ERK1 @/@ 2 MAPK @-@ sufficient animals ( Figure 8 , A @–@ H ) . # ::alignments 0-1.1.2 0-1.2.2.2 1-1.1.1.1 3-1.1.1.1 4-1 5-1.2 6-1.2.1.r 7-1.2.1.1.1 8-1.2.1.1 10-1.2.1.2.1 11-1.2.1.2 13-1.2.1.3.1.1 14-1.2.1.3.1 15-1.2.1.3 17-1.2.1 18-1.2.1.4.1.1.1.1 20-1.2.1.4.1.1.1.1 22-1.2.1.4.1.2.1.1 22-1.2.1.4.1.3.1.1 24-1.2.1.4.1.1.1.1 27-1.2.1.4.1 28-1.2.1.4.1.2.1.1 28-1.2.1.4.1.3.1.1 30-1.2.1.4.1.3.1.1 31-1.2.1.4.1.1 31-1.2.1.4.1.2 31-1.2.1.4.1.3 32-1.2.1.4 35-1.2.2.1.1.1.1 37-1.2.2.1.1.1.1 38-1.2.2.1.1.1.2 40-1.2.2.1 41-1.2.2 43-1.3.1.1 43-1.3.1.2 43-1.3.1.3 43-1.3.1.4 43-1.3.1.5 43-1.3.1.6 43-1.3.1.7 43-1.3.1.8 (c / cause-01~e.4 :ARG0 (p / protein :name (n / name :op1 "IL-13"~e.1,3) :mod (t / transgenic~e.0)) :ARG1 (i / increase-01~e.5 :ARG1~e.6 (a / and~e.17 :op1 (v / volume~e.8 :mod (l / lung~e.7)) :op2 (s / size~e.11 :mod (a2 / alveolus~e.10)) :op3 (n2 / number~e.15 :quant-of (c2 / cell~e.14 :mod (g / goblet~e.13))) :op3 (e / express-03~e.32 :ARG1 (a3 / and~e.27 :op1 (g2 / gene~e.31 :name (n3 / name :op1 "Gob-5"~e.18,20,24)) :op2 (g3 / gene~e.31 :name (n4 / name :op1 "Muc-5ac"~e.22,28)) :op3 (g4 / gene~e.31 :name (n5 / name :op1 "Muc-1"~e.22,28,30))))) :location (a4 / animal~e.41 :ARG1-of (s2 / suffice-01~e.40 :ARG0 (p2 / pathway :name (n6 / name :op1 "ERK1/2"~e.35,37 :op2 "MAPK"~e.38))) :mod (t2 / transgenic~e.0 :mod (p3 / positive)))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure~e.43 :mod "8A") :op2 (f3 / figure~e.43 :mod "8B") :op3 (f4 / figure~e.43 :mod "8C") :op4 (f5 / figure~e.43 :mod "8D") :op5 (f6 / figure~e.43 :mod "8E") :op6 (f7 / figure~e.43 :mod "8F") :op7 (f8 / figure~e.43 :mod "8G") :op8 (f9 / figure~e.43 :mod "8H")))) # ::id bel_pmid_1643_0878.29026 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BMMCs from mice lacking Map3k2 showed reduced production ( 50 @-@ 60 %) of IL @-@ 6 , IL @-@ 13 , and TNF @-@ alpha after stimulation # ::alignments 1-1.1.2.r 2-1.1.2 3-1.1.2.1 4-1.1.2.1.1.1.1 5-1 6-1.2.2 7-1.2 9-1.2.2.1.1.1.1 11-1.2.2.1.1.2.1 13-1.2.1.r 14-1.2.1.1.1.1 14-1.2.1.2.1.1 16-1.2.1.1.1.1 18-1.2.1.1.1.1 18-1.2.1.2.1.1 20-1.2.1.2.1.1 22-1.2.1 23-1.2.1.3.1.1 25-1.2.1.3.1.1 26-1.3 27-1.3.1 (s / show-01~e.5 :ARG0 (c / cell-line :name (n / name :op1 "BMMC") :source~e.1 (m / mouse~e.2 :ARG0-of (l / lack-01~e.3 :ARG1 (g / gene :name (n2 / name :op1 "Map3k2"~e.4))))) :ARG1 (p2 / produce-01~e.7 :ARG1~e.13 (a / and~e.22 :op1 (p4 / protein :name (n3 / name :op1 "IL-6"~e.14,16,18)) :op2 (p5 / protein :name (n4 / name :op1 "IL-13"~e.14,18,20)) :op3 (p6 / protein :name (n5 / name :op1 "TNF-alpha"~e.23,25))) :ARG1-of (r / reduce-01~e.6 :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (p / percentage-entity :value 50~e.9) :op2 (p3 / percentage-entity :value 60~e.11))))) :time (a2 / after~e.26 :op1 (s2 / stimulate-01~e.27))) # ::id bel_pmid_1648_4683.21972 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In asbestos @-@ associated transformation of rodent mesothelial cells , the use of dominant negative ERK1 or Fra @-@ 1 constructs reverses the phenotype of mesothelioma cells to that of normal mesothelial cells ( 12 ) . Moreover , Fra @-@ 1 expression is increased in human mesotheliomas and in other tumor types . # ::alignments 0-1.1.4.r 1-1.1.4.2.1 3-1.1.4.2 4-1.1.4 6-1.1.2.1.2 8-1.1.2.1 11-1.1.1 12-1.1.1.1.r 13-1.1.1.1.1.2.2 15-1.1.1.1.1.1.1.1.1 16-1.1.1.1 17-1.1.1.1.2.1.1.1.1 19-1.1.1.1.2.1.1.1.1 20-1.1.1.1.1 20-1.1.1.1.1.1 20-1.1.1.1.1.1.r 20-1.1.1.1.2 20-1.1.1.1.2.1 20-1.1.1.1.2.1.r 21-1.1 23-1.1.2 23-1.1.3 25-1.2.1.1.2.1 26-1.1.3.1 30-1.1.3.1.1 32-1.1.3.1 34-1.1.5.1.1.1 37-1.2.1.1.2 39-1.2.1.1.1.1.1 41-1.2.1.1.1.1.1 42-1.2.1.1 44-1.2.1 45-1.1.4.r 45-1.2.1.1.2.1.1.r 46-1.2.1.1.2.1.1 48-1.2 48-1.2.1.1.2 49-1.1.4.r 49-1.2.1.1.2.r 50-1.2.1.1.2.2.1 51-1.2.1.1.2.2 (m / multi-sentence :snt1 (r / reverse-01~e.21 :ARG0 (u / use-01~e.11 :ARG1~e.12 (o / or~e.16 :op1 (m2 / molecular-physical-entity~e.20 :ARG1-of~e.20 (c / construct-01~e.20 :mod (e / enzyme :name (n / name :op1 "ERK1"~e.15))) :ARG2-of (m4 / mutate-01 :mod "-/-" :ARG0-of (d / dominate-01~e.13))) :op2 (m6 / molecular-physical-entity~e.20 :ARG1-of~e.20 (c5 / construct-01~e.20 :mod (p5 / protein :name (n2 / name :op1 "Fra-1"~e.17,19))) :mod m4))) :ARG1 (p / phenotype~e.23 :poss (c2 / cell~e.8 :mod (m3 / mesothelium) :source (r2 / rodent~e.6))) :prep-to (p2 / phenotype~e.23 :poss (c3 / cell~e.26,32 :ARG1-of (n4 / normal-02~e.30) :mod m3)) :prep-in~e.0,45,49 (t / transform-01~e.4 :ARG1 c2 :ARG1-of (a / associate-01~e.3 :ARG2 (a2 / asbestos~e.1))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 12~e.34)))) :snt2 (a3 / and~e.48 :op2 (i / increase-01~e.44 :ARG1 (e3 / express-03~e.42 :ARG2 (p4 / protein :name (n5 / name :op1 "Fra-1"~e.39,41)) :ARG3~e.49 (a4 / and~e.37,48 :op1 (m5 / mesothelioma~e.25 :source~e.45 (h / human~e.46)) :op2 (t2 / tumor~e.51 :mod (o2 / other~e.50))))))) # ::id bel_pmid_1648_4683.26962 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have used siRNA approaches to show that Fra @-@ 1 expression is critical to the expression of genes , such as cd44 and c @-@ met , that are critical to migration and autocrine growth factor production in transformation and invasion of mesotheliomas ( 13 ) . # ::alignments 0-1.1 2-1 2-1.3.r 3-1.2.1.1.1 4-1.2 6-1.3 7-1.3.2.r 8-1.3.2.1.1.1.1 10-1.3.2.1.1.1.1 11-1.3.2.1 11-1.3.2.2 13-1.3.2 16-1.3.2.2 17-1.3.2.2.1.r 18-1.3.2.2.1 20-1.3.2.2.1.2.r 21-1.3.2.2.1.2.r 22-1.3.2.2.1.2.1.1.1 23-1.3.2.2.1.2 24-1.3.2.2.1.2.2.1.1 26-1.3.2.2.1.2.2.1.1 30-1.3.2.2.1.1 31-1.3.2.2.1.1.1.r 32-1.3.2.2.1.1.1.1 33-1.3.2.2.1.1.1 34-1.3.2.2.1.1.1.2.1.1 35-1.3.2.2.1.1.1.2.1 36-1.3.2.2.1.1.1.2.1 37-1.3.2.2.1.1.1.2 38-1.3.2.2.1.1.1.3.r 39-1.3.2.2.1.1.1.3.1 40-1.3.2.2.1.1.1.3 41-1.3.2.2.1.1.1.3.2 45-1.4.1.1.1 (u / use-01~e.2 :ARG0 (w2 / we~e.0) :ARG1 (a / approach-02~e.4 :instrument (n6 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.3))) :purpose~e.2 (s2 / show-01~e.6 :ARG0 w2 :ARG1~e.7 (c / critical-02~e.13 :ARG1 (e / express-03~e.11 :ARG2 (p / protein :name (n3 / name :op1 "Fra-1"~e.8,10))) :ARG2 (e2 / express-03~e.11,16 :ARG1~e.17 (g / gene~e.18 :ARG1-of (c2 / critical-02~e.30 :ARG2~e.31 (a3 / and~e.33 :op1 (m2 / migrate-01~e.32) :op2 (p2 / produce-01~e.37 :ARG1 (g4 / growth-factor~e.35,36 :mod (a4 / autocrine~e.34))) :prep-in~e.38 (a5 / and~e.40 :op1 (t / transform-01~e.39 :ARG1 (m3 / mesothelioma)) :op2 (i / invade-01~e.41 :ARG1 m3)))) :example~e.20,21 (a2 / and~e.23 :op1 (g2 / gene :name (n4 / name :op1 "cd44"~e.22)) :op2 (g3 / gene :name (n5 / name :op1 "c-met"~e.24,26))))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 13~e.45)))) # ::id bel_pmid_1648_4683.37584 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , EGFR activation by gram @-@ positive bacteria occurred through cleavage of the transmembrane ligand HBEGF by ADAM 10 . # ::alignments 1-1 3-1.1.2.1.1 4-1.1 5-1.1.1.r 6-1.1.1.1 8-1.1.1.1 9-1.1.1 12-1.1.3 13-1.1.3.2.r 15-1.1.3.2.2 16-1.1.3.2 17-1.1.3.2.1.1 18-1.1.3.1.r 19-1.1.3.1.1.1 20-1.1.3.1.1.2 (c / contrast-01~e.1 :ARG2 (a / activate-01~e.4 :ARG0~e.5 (b / bacteria~e.9 :mod (g / gram-positive~e.6,8)) :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.3)) :manner (c2 / cleave-01~e.12 :ARG0~e.18 (p / protein :name (n3 / name :op1 "ADAM"~e.19 :op2 10~e.20)) :ARG1~e.13 (l / ligand~e.16 :name (n2 / name :op1 "HBEGF"~e.17) :mod (t / transmembrane~e.15))))) # ::id bel_pmid_1649_2667.37650 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - Furthermore , the decreased expression of either b @-@ arrestin 1 or b @-@ arrestin 2 ( via siRNA ) resulted in a decrease in ERK1 @/@ 2 activity # ::alignments 1-1.2.1.1 2-1.2.1 4-1 7-1.1.1.2 8-1.1.1 11-1.1.1.1.1.1.1 11-1.1.1.1.2.1.1 13-1.1.1.1.1.1.1 13-1.1.1.1.2.1.1 14-1.1.1.1.1.1.2 15-1.1.1.1 16-1.1.1.1.1.1.1 16-1.1.1.1.2.1.1 18-1.1.1.1.1.1.1 18-1.1.1.1.2.1.1 19-1.1.1.1.2.1.2 22-1.1.1.3.1.1 24-1.1 25-1.1.2.r 27-1.1.2 28-1.1.2.1.r 29-1.1.2.1.1.1.1 31-1.1.2.1.1.1.1 32-1.1.2.1 (a / and~e.4 :op2 (r / result-01~e.24 :ARG1 (e / express-03~e.8 :ARG2 (o / or~e.15 :op1 (p / protein :name (n / name :op1 "b-arrestin"~e.11,13,16,18 :op2 1~e.14)) :op2 (p2 / protein :name (n2 / name :op1 "b-arrestin"~e.11,13,16,18 :op2 2~e.19))) :ARG1-of (d / decrease-01~e.7) :instrument (n5 / nucleic-acid :name (n3 / name :op1 "siRNA"~e.22))) :ARG2~e.25 (d2 / decrease-01~e.27 :ARG1~e.28 (a2 / activity-06~e.32 :ARG0 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"~e.29,31))))) :ARG1-of (d3 / describe-01 :ARG0 (t / text~e.2 :ARG1-of (f / full-09~e.1)))) # ::id bel_pmid_1651_0581.41864 ::amr-annotator SDL-AMR-09 ::preferred # ::tok FBLN @-@ 3 expression in MB114 cells also prevented their activation of p38 MAPK , but not that of extracellular signal @-@ regulated kinase 1 @/@ 2 ( ERK1 @/@ 2 ) , stimulated by VEGF ( Fig . 2E ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.r 5-1.1.1.2.1.1 6-1.1.1.2 7-1.1.3 8-1.1 8-1.2 10-1.1.2 10-1.2.2 15-1 16-1.2.1 16-1.2.1.r 18-1.2.2.1.r 19-1.2.2.1.1.1 20-1.2.2.1.1.2 22-1.2.2.1.1.2 23-1.2.2.1.1.3 24-1.2.2.1.1.4 26-1.2.2.1.1.4 30-1.2.2.1.1.4 33-1.2.2.2 34-1.2.2.2.1.r 35-1.2.2.2.1.1.1 37-1.3.1 39-1.3.1.1 (c / contrast-01~e.15 :ARG1 (p2 / prevent-01~e.8 :ARG0 (e / express-03~e.3 :ARG2 (p3 / protein :name (n2 / name :op1 "FBLN-3"~e.0,2)) :ARG3~e.4 (c2 / cell-line~e.6 :name (n3 / name :op1 "MB114"~e.5))) :ARG1 (a / activate-01~e.10 :ARG0 c2 :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38MAPK"))) :mod (a2 / also~e.7)) :ARG2 (p4 / prevent-01~e.8 :polarity~e.16 -~e.16 :ARG1 (a3 / activate-01~e.10 :ARG1~e.18 (e3 / enzyme :name (n5 / name :op1 "extracellular"~e.19 :op2 "signal-regulated"~e.20,22 :op3 "kinase"~e.23 :op4 "1/2"~e.24,26,30)) :ARG1-of (s / stimulate-01~e.33 :ARG0~e.34 (p5 / protein :name (n6 / name :op1 "VEGF"~e.35))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.37 :mod "2E"~e.39))) # ::id bel_pmid_1651_0581.41866 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 3A shows that relative to control cells , FBLN @-@ 3 and FBLN @-@ 5 both decreased MB114 cell expression of MMP @-@ 2 and MMP @-@ 3 while simultaneously increasing that of the MMP antagonists , TIMP @-@ 1 and TIMP @-@ 3 . # ::alignments 0-1.1 1-1.1.1 2-1 5-1.2.r 6-1.2.3.1 7-1.2.3 9-1.2.1.1.1.1.1 9-1.2.1.1.2.1.1 11-1.2.1.1.1.1.1 13-1.2.1.1.1.1.1 13-1.2.1.1.2.1.1 15-1.2.1.1.2.1.1 17-1.2.1 18-1.2.1.2.2.1.1 19-1.2.1.2.2 20-1.2.1.2 21-1.2.1.2.1.r 22-1.2.1.2.1.1.1.1 22-1.2.1.2.1.2.1.1 24-1.2.1.2.1.1.1.1 25-1.2 25-1.2.1.2.1 26-1.2.1.2.1.1.1.1 26-1.2.1.2.1.2.1.1 28-1.2.1.2.1.2.1.1 30-1.2.2.3 30-1.2.2.3.r 31-1.2.2 33-1.2.2.2.r 35-1.2.2.2.1.2.1.1.1 38-1.2.2.2.1.1.1 38-1.2.2.2.2.1.1 40-1.2.2.2.1.1.1 42-1.2.2.2.1.1.1 42-1.2.2.2.2.1.1 44-1.2.1.2.1.2.1.1 44-1.2.2.2.2.1.1 (s / show-01~e.2 :ARG0 (f / figure~e.0 :mod "3A"~e.1) :ARG1~e.5 (a / and~e.25 :op1 (d / decrease-01~e.17 :ARG0 (a2 / and :op1 (p / protein :name (n / name :op1 "FBLN-3"~e.9,11,13)) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5"~e.9,13,15))) :ARG1 (e / express-03~e.20 :ARG2~e.21 (a3 / and~e.25 :op1 (e3 / enzyme :name (n4 / name :op1 "MMP-2"~e.22,24,26)) :op2 (e4 / enzyme :name (n5 / name :op1 "MMP-3"~e.22,26,28,44))) :ARG3 (c3 / cell-line~e.19 :name (n3 / name :op1 "MB114"~e.18)))) :op2 (i / increase-01~e.31 :ARG0 a2 :ARG2~e.33 (a4 / and :op1 (p5 / protein :name (n6 / name :op1 "TIMP-1"~e.38,40,42) :ARG1-of (a5 / antagonize-02 :ARG2 (e2 / enzyme :name (n7 / name :op1 "MMP"~e.35)))) :op2 (p7 / protein :name (n8 / name :op1 "TIMP-3"~e.38,42,44) :ARG1-of a5)) :manner~e.30 (s2 / simultaneous~e.30)) :compared-to (c / cell~e.7 :mod (c2 / control-01~e.6)))) # ::id bel_pmid_1651_0581.41868 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although MB114 cell expression of TIMP @-@ 2 was unaffected by either FBLN @-@ 3 or FBLN @-@ 5 , both FBLNs induced MB114 cell expression of the angiostatic molecule , TSP @-@ 1 ( Fig . 3A ) . # ::alignments 0-1 1-1.2.3.2 2-1.2.3.2 3-1.2.3 4-1.2.3.1.r 5-1.2.3.1.1.1 7-1.2.3.1.1.1 9-1.2 9-1.2.1 9-1.2.1.r 12-1.1.1.1.1.1 12-1.1.1.2.1.1 14-1.1.1.1.1.1 16-1.1.1.1.1.1 16-1.1.1.2.1.1 18-1.1.1.2.1.1 22-1.1 23-1.1.2.2.1.1 24-1.1.2.2 25-1.1.2 26-1.1.2.1.r 28-1.1.2.1.2 31-1.1.2.1.1.1 33-1.1.2.1.1.1 35-1.3.1 37-1.3.1.1 (h / have-concession-91~e.0 :ARG1 (i / induce-01~e.22 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "FBLN-3"~e.12,14,16)) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5"~e.12,16,18))) :ARG2 (e / express-03~e.25 :ARG2~e.26 (p3 / protein :name (n4 / name :op1 "TSP-1"~e.31,33) :mod (a2 / angiostatic~e.28)) :ARG3 (c2 / cell-line~e.24 :name (n3 / name :op1 "MB114"~e.23)))) :ARG2 (a3 / affect-01~e.9 :polarity~e.9 -~e.9 :ARG0 a :ARG1 (e2 / express-03~e.3 :ARG2~e.4 (p4 / protein :name (n5 / name :op1 "TIMP-2"~e.5,7)) :ARG3 c2~e.1,2)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "3A"~e.37))) # ::id bel_pmid_1651_0581.41870 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , although TIMP @-@ 3 expression was elevated basally in FBLN @-@ 5 @-@ expressing MB114 cells , only FBLN @-@ 3 stimulated TIMP @-@ 3 expression in tubulating MB114 cells ( Fig . 3B ) . # ::alignments 0-1.3 2-1 3-1.1.2.1.1.1 5-1.1.1.1.1 5-1.1.2.1.1.1 6-1.2.1 8-1.2 11-1.2.1.2.2.1.1.1 13-1.2.1.2.2.1.1.1 15-1.1.2 15-1.2.1 15-1.2.1.2.2 16-1.1.2.2.1.1 16-1.2.1.2.1.1 17-1.1.2.2 17-1.2.1.2 19-1.1.1.2 20-1.1.1.1.1 22-1.1.1.1.1 22-1.1.2.1.1.1 23-1.1 24-1.1.2.1.1.1 26-1.1.2.1.1.1 27-1.1.2 30-1.1.2.2.1.1 30-1.2.1.2.1.1 31-1.2.1.2 (h / have-concession-91~e.2 :ARG1 (s / stimulate-01~e.23 :ARG0 (p / protein :name (n / name :op1 "FBLN-3"~e.5,20,22) :mod (o / only~e.19)) :ARG1 (e / express-03~e.15,27 :ARG2 (p2 / protein :name (n3 / name :op1 "TIMP-3"~e.3,5,22,24,26)) :ARG3 (c2 / cell-line~e.17 :name (n2 / name :op1 "MB114"~e.16,30) :ARG0-of (t / tubulate-01)))) :ARG2 (e2 / elevate-01~e.8 :ARG1 (e3 / express-03~e.6,15 :ARG2 p2 :ARG3 (c3 / cell-line~e.17,31 :name (n4 / name :op1 "MB114"~e.16,30) :ARG3-of (e4 / express-03~e.15 :ARG2 (p3 / protein :name (n5 / name :op1 "FBLN-5"~e.11,13))))) :manner (b / basal)) :ARG2-of (i / interest-01~e.0)) # ::id bel_pmid_1651_0581.41872 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Gelatin zymography of MB114 cell conditioned medium confirmed that expression of either FBLN @-@ 3 or FBLN @-@ 5 significantly reduced MMP @-@ 2 protease activity in tubulating MB114 cells ( Fig . 3C ) . # ::alignments 0-1.3.1 1-1.3 2-1.3.2.r 3-1.3.2.2.1.1 4-1.3.2.2 5-1.3.2.1 6-1.3.2 7-1 8-1.1.r 9-1.1.1 12-1.1.1.1.1.1.1 12-1.1.1.1.2.1.1 14-1.1.1.1.1.1.1 15-1.1.1.1 16-1.1.1.1.1.1.1 16-1.1.1.1.2.1.1 18-1.1.1.1.2.1.1 19-1.1.3 20-1.1 21-1.1.2.1.1.1 23-1.1.2.1.1.1 24-1.1.2.1 25-1.1.2 28-1.1.2.2.1.1 29-1.1.2.2 31-1.2.1 33-1.2.1.1 (c / confirm-01~e.7 :ARG1~e.8 (r / reduce-01~e.20 :ARG0 (e / express-03~e.9 :ARG2 (o / or~e.15 :op1 (p / protein :name (n3 / name :op1 "FBLN-3"~e.12,14,16)) :op2 (p2 / protein :name (n4 / name :op1 "FBLN-5"~e.12,16,18)))) :ARG1 (a / activity-06~e.25 :ARG0 (p3 / protease~e.24 :name (n5 / name :op1 "MMP-2"~e.21,23)) :location (c4 / cell-line~e.29 :name (n6 / name :op1 "MB114"~e.28) :ARG0-of (t / tubulate-01))) :ARG2 (s / significant-02~e.19)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "3C"~e.33)) :mod (z / zymography~e.1 :mod (g / gelatin~e.0) :topic~e.2 (m / medium~e.6 :ARG1-of (c2 / condition-01~e.5) :mod (c3 / cell-line~e.4 :name (n2 / name :op1 "MB114"~e.3))))) # ::id bel_pmid_1651_0581.41874 ::amr-annotator SDL-AMR-09 ::preferred # ::tok FBLN @-@ 3 and FBLN @-@ 5 antagonize angiogenesis in vivo . # ::alignments 0-1.1.1.1.1 0-1.1.2.1.1 2-1.1.1.1.1 3-1.1 4-1.1.1.1.1 4-1.1.2.1.1 6-1.1.2.1.1 7-1 8-1.2 9-1.3 10-1.3 (a / antagonize-02~e.7 :ARG1 (a2 / and~e.3 :op1 (p / protein :name (n / name :op1 "FBLN-3"~e.0,2,4)) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5"~e.0,4,6))) :ARG2 (a3 / angiogenesis~e.8) :manner (i / in-vivo~e.9,10)) # ::id bel_pmid_1651_0581.41878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , recombinant FBLN @-@ 3 and FBLN @-@ 5 ( Fig . 4B ) both inhibited human HMEC @-@ 1 endothelial cell migration to fibronectin ( Fig . 4C ) , whereas FBLN @-@ 5 , but not FBLN @-@ 3 , mediated their adhesion in an RGD @-@ dependent manner ( Fig . 4D ; refs . # ::alignments 0-1.1.1.1 2-1.1.1.1.3 3-1.1.1.1.1.1.1 3-1.1.1.1.2.1.1 5-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.1.1.1 7-1.1.1.1.2.1.1 9-1.1.1.1.2.1.1 11-1.1.1.1.4.1 13-1.1.1.1.4.1.1 16-1.1.1 17-1.1.1.2.1.2 18-1.1.1.2.1.1.1 20-1.1.1.2.1.1.1 21-1.1.1.2.2 22-1.1.1.2.1 23-1.1.1.2 24-1.1.1.2.3.r 25-1.1.1.2.3.1.1 27-1.1.1.3.1 29-1.1.1.3.1.1 32-1.1 32-1.1.2 32-1.1.2.r 33-1.1.1.1.1.1.1 33-1.1.1.1.2.1.1 35-1.1.1.1.2.1.1 37-1.1.2 38-1.1.2.2.1 38-1.1.2.2.1.r 39-1.1.1.1.1.1.1 39-1.1.1.1.2.1.1 41-1.1.1.1.1.1.1 43-1.1.2.1 43-1.1.2.2 45-1.1.2.1.2 48-1.1.2.1.2.2.2.1.1 50-1.1.2.1.2.2 51-1.1.2.1.2.2.r 53-1.1.2.3.1 55-1.1.2.3.1.1 (a3 / and :op2 (c / contrast-01~e.32 :ARG1 (i / inhibit-01~e.16 :ARG0 (a / and~e.0,6 :op1 (p / protein :name (n / name :op1 "FBLN-3"~e.3,5,7,33,39,41)) :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5"~e.3,7,9,33,35,39)) :ARG3-of (r / recombine-01~e.2) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "4B"~e.13))) :ARG1 (m / migrate-01~e.23 :ARG0 (c2 / cell-line~e.22 :name (n3 / name :op1 "HMEC-1"~e.18,20) :mod (h / human~e.17)) :ARG1 (e / endothelium~e.21) :ARG2~e.24 (p3 / protein :name (n4 / name :op1 "fibronectin"~e.25))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.27 :mod "4C"~e.29))) :ARG2~e.32 (c3 / contrast-01~e.32,37 :ARG1 (m2 / mediate-01~e.43 :ARG0 p2 :ARG1 (a2 / adhere-01~e.45 :ARG1 c2 :manner~e.51 (d3 / depend-01~e.50 :ARG0 c2 :ARG1 (s / small-molecule :name (n5 / name :op1 "RGD"~e.48))))) :ARG2 (m3 / mediate-01~e.43 :polarity~e.38 -~e.38 :ARG0 p :ARG1 a2) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure~e.53 :mod "4D"~e.55)) :ARG1-of (d5 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01)))))) # ::id bel_pmid_1651_0581.41880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 5A shows that bFGF stimulated significant vascularization of implanted Matrigel plugs , which was quantified by measuring plug hemoglobin contents ( Fig . 5A ) and microvessel densities ( Fig . 5B ) . # ::alignments 0-1.1 1-1.1.1 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2 6-1.2.2.2 9-1.2.2.1.1 10-1.2.2.1.2.1.1 11-1.2.2.1 15-1.2.2.3 16-1.2.2.3.1.r 17-1.2.2.3.1 18-1.2.2.3.1.1.1.3 19-1.2.2.3.1.1.1.1 20-1.2.2.3.1.1.1 22-1.1 24-1.1.1 26-1.2.2.3.1.1 27-1.2.2.3.1.1.2.1 28-1.2.2.3.1.1.2 30-1.2.2.3.1.1.2.2.1 32-1.2.2.3.1.1.2.2.1.1 (s / show-01~e.2 :ARG0 (f / figure~e.0,22 :mod "5A"~e.1,24) :ARG1~e.3 (s2 / stimulate-01~e.5 :ARG0 (p / protein :name (n / name :op1 "bFGF"~e.4)) :ARG1 (v / vascularize-01 :ARG1 (p2 / plug~e.11 :ARG1-of (i / implant-01~e.9) :mod (p4 / protein :name (n2 / name :op1 "Matrigel"~e.10))) :ARG1-of (s3 / significant-02~e.6) :ARG1-of (q / quantify-01~e.15 :manner~e.16 (m / measure-01~e.17 :ARG1 (a / and~e.26 :op1 (c / content~e.20 :mod (h / hemoglobin~e.19) :ARG1-of (d2 / describe-01 :ARG0 f) :location (p3 / plug~e.18)) :op2 (d / density~e.28 :mod (m2 / microvessel~e.27) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.30 :mod "5B"~e.32))))))))) # ::id bel_pmid_1651_0581.41890 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More importantly , tumors derived from FBLN @-@ expressing MCA102 fibrosarcoma cells also exhibited significantly reduced blood vessel densities compared with tumors derived from control cells ( Fig . 6D ) . # ::alignments 0-1.3.1 1-1.3 3-1.1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.2.1.1.1 8-1.1.1.1.2 9-1.1.1.1.1.1 10-1.1.1.1.3 11-1.1.1.1 12-1.5 13-1 14-1.2.2.1 15-1.2.2 16-1.2.1.1 17-1.2.1 18-1.2 19-1.2.2.2.r 21-1.2.2.2 22-1.2.2.2.1 23-1.2.2.2.1.1.r 24-1.2.2.2.1.1.1 25-1.2.2.2.1.1 27-1.4.1 29-1.4.1.1 (e / exhibit-01~e.13 :ARG0 (t / tumor~e.3 :ARG1-of (d / derive-01~e.4 :ARG2~e.5 (c / cell-line~e.11 :name (n / name :op1 "MCA102"~e.9) :ARG3-of (e2 / express-03~e.8 :ARG2 (p / protein :name (n2 / name :op1 "FBLN"~e.6))) :mod (f2 / fibrosarcoma~e.10)))) :ARG1 (d2 / density~e.18 :mod (v / vessel~e.17 :mod (b / blood~e.16)) :ARG1-of (r / reduce-01~e.15 :ARG2 (s / significant-02~e.14) :compared-to~e.19 (t2 / tumor~e.21 :ARG1-of (d4 / derive-01~e.22 :ARG2~e.23 (c2 / cell~e.25 :mod (c3 / control-01~e.24)))))) :mod (i / important~e.1 :degree (m / more~e.0)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.27 :mod "6D"~e.29)) :mod (a / also~e.12)) # ::id bel_pmid_1651_0581.41892 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , FBLN @-@ 3 @-@ expressing MCA102 tumors contained significantly enlarged regions of central and peripheral necrosis that were typically absent in their control counterparts . # ::alignments 0-1.1.2.3 1-1.1.2.3 3-1.1.1.2.1.1.1 5-1.1.1.2.1.1.1 7-1.1.1.2 8-1.1.1.1.1.1 9-1.1.1 10-1.1 11-1.1.2.1.1 12-1.1.2.1 13-1.1.2 15-1.1.2.3.1.1 16-1.1.2.3 18-1.1.2.3.1 18-1.1.2.3.2 21-1.1.2.2.2 22-1.1.2.2 23-1.1.2.2.1.r 24-1.1.2.2.1.1 24-1.1.2.2.1.1.r 25-1.1.2.2.1.2 26-1.1.2.2.1 (a / and :op2 (c / contain-01~e.10 :ARG0 (t / tumor~e.9 :source (c2 / cell-line :name (n / name :op1 "MCA102"~e.8)) :ARG3-of (e / express-03~e.7 :ARG2 (p / protein :name (n2 / name :op1 "FBLN-3"~e.3,5)))) :ARG1 (r / region~e.13 :ARG1-of (e2 / enlarge-01~e.12 :ARG2 (s / significant-02~e.11)) :ARG1-of (a3 / absent-01~e.22 :ARG2~e.23 (c4 / counterpart~e.26 :poss~e.24 r~e.24 :mod (c5 / control-01~e.25)) :ARG1-of (t2 / typical-02~e.21)) :location-of (a2 / and~e.0,1,16 :op1 (n3 / necrosis~e.18 :mod (c3 / center~e.15)) :op2 (n4 / necrosis~e.18 :mod (p2 / periphery)))))) # ::id bel_pmid_1651_0838.19670 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The TLR3 agonist poly ( I : C ) significantly increased bidirectional secretion of CCL2 , IL6 , TNFA and CSF2 and basolateral secretion of CSF3 . # ::alignments 1-1.1.2.1.1 2-1.1 3-1.1.1.1 9-1.3 10-1 11-1.2.1.2 12-1.2.1 13-1.2.1.1.r 14-1.2.1.1.1.1.1 16-1.2.1.1.2.1.1 18-1.2.1.1.3.1.1 19-1.2.1.1 20-1.2.1.1.4.1.1 21-1.2 22-1.2.2.2 23-1.2.2 24-1.2.2.1.r 25-1.2.2.1.1.1 (i / increase-01~e.10 :ARG0 (a / agonist~e.2 :name (n / name :op1 "poly"~e.3 :op2 "(I:C)") :mod (p / protein :name (n2 / name :op1 "TLR3"~e.1))) :ARG1 (a3 / and~e.21 :op1 (s2 / secrete-01~e.12 :ARG1~e.13 (a2 / and~e.19 :op1 (p3 / protein :name (n4 / name :op1 "CCL2"~e.14)) :op2 (p2 / protein :name (n3 / name :op1 "IL6"~e.16)) :op3 (p4 / protein :name (n5 / name :op1 "TNFA"~e.18)) :op4 (p5 / protein :name (n6 / name :op1 "CSF2"~e.20))) :mod (b2 / bidirectional~e.11)) :op2 (s3 / secrete-01~e.23 :ARG1~e.24 (p6 / protein :name (n7 / name :op1 "CSF3"~e.25)) :mod (b / basolateral~e.22))) :ARG2 (s / significant-02~e.9)) # ::id bel_pmid_1654_7273.28276 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To verify the absence of the STAT6 @-@ signaling cascade in STAT6-/- MLF , we assessed mOSM and mIL @-@ 4 induced responses with respect to STAT3 and STAT6 activation . Fig. 6 confirms the absence of STAT6 protein and STAT6 induction in STAT6-/- MLF but equivalent activation of STAT3 in both wt and STAT6-/- MLF . # ::alignments 1-1.1.3 3-1.1.3.2 6-1.1.3.2.1.1.1.1.1 6-1.1.3.2.2.2.1.1 8-1.1.3.2.1.1 9-1.1.3.2.1 14-1.1.1 15-1.1 20-1.1.2.2.1.2.1.1 21-1.2.2.1.2 22-1.1.2 22-1.1.2.1 22-1.1.2.1.r 26-1.1.4.1.1.1.1 26-1.2.2.2.1.1.1 27-1.1.4.1 28-1.2.2.1.1.1.1.1 28-1.2.2.1.2.2.2.1.1 29-1.1.4 29-1.2.2.2 31-1.2.1 32-1.2.1.1 33-1.2 35-1.2.2.1.1 36-1.2.2.1.1.1.r 37-1.2.2.1.1.1.1.1 38-1.1.2.2.1.1 38-1.1.2.2.1.2 38-1.1.3.2.1.1.1 38-1.1.3.2.2.2 38-1.1.4.1.1 38-1.2.2.1.1.1 38-1.2.2.1.2.2.2 38-1.2.2.2.1 39-1.2.2.1 40-1.2.2.1.1.1.1.1 41-1.1.2.2 45-1.2.2 46-1.2.2.2.2 47-1.2.2.2 49-1.2.2.2.1.1.1 52-1.2.2.2.3.2.1 53-1.2.2.2.3 (m / multi-sentence :snt1 (a / assess-01~e.15 :ARG0 (w / we~e.14) :ARG1 (t / thing~e.22 :ARG2-of~e.22 (r / respond-01~e.22) :ARG2-of (i2 / induce-01~e.41 :ARG0 (a2 / and :op1 (p11 / protein~e.38 :name (n8 / name :op1 "OSM") :mod (m2 / mouse)) :op2 (p / protein~e.38 :name (n / name :op1 "IL-4"~e.20) :mod m2)))) :purpose (v / verify-01~e.1 :ARG0 w :ARG1 (a5 / absent-01~e.3 :ARG1 (c / cascade~e.9 :ARG0-of (s / signal-07~e.8 :ARG1 (p2 / protein~e.38 :name (n7 / name :op1 "STAT6"~e.6)))) :ARG2 (f2 / fibroblast :mod (l / lung :mod m2) :mod (p6 / protein~e.38 :name (n9 / name :op1 "STAT6"~e.6) :ARG2-of (m3 / mutate-01 :mod "-/-"))))) :topic (a3 / activate-01~e.29 :ARG1 (a4 / and~e.27 :op1 (p3 / protein~e.38 :name (n5 / name :op1 "STAT3"~e.26)) :op2 p2))) :snt2 (c2 / confirm-01~e.33 :ARG0 (f / figure~e.31 :mod 6~e.32) :ARG1 (c3 / contrast-01~e.45 :ARG1 (a6 / and~e.39 :op1 (a7 / absent-01~e.35 :ARG1~e.36 (p7 / protein~e.38 :name (n10 / name :op1 "STAT6"~e.28,37,40)) :ARG2 f3) :op2 (i / induce-01~e.21 :ARG2 p7 :location (f3 / fibroblast :mod (l2 / lung :mod (m11 / mouse)) :mod (p8 / protein~e.38 :name (n12 / name :op1 "STAT6"~e.28) :ARG2-of (m5 / mutate-01 :mod "-/-"))))) :ARG2 (a8 / activate-01~e.29,47 :ARG1 (p9 / protein~e.38 :name (n13 / name :op1 "STAT3"~e.26,49)) :ARG2-of (e3 / equal-01~e.46) :location (a9 / and~e.53 :op1 f3 :op2 (f5 / fibroblast :mod (w2 / wild-type~e.52) :mod l2)))))) # ::id bel_pmid_1654_7273.28294 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Twenty @-@ four hour stimulation with 25.0 ng @/@ ml mOSM induced detectable increases in eotaxin @-@ 1 expression at the mRNA and protein level in both wt and STAT6-/- MLF ( Fig . 5 , A and C ) . Stimulation of wt MLF using 10.0 ng @/@ ml mIL @-@ 4 induced eotaxin mRNA expression and protein production that was nondetectable in STAT6-/- MLF ( Fig . 5 , A and C ) # ::alignments 2-1.2.1.2.1.1.1 3-1.1.1.2.2 4-1.1.1 7-1.1.1.1.3.2 9-1.1.1.1.3.2 11-1.1 12-1.1.2.3 12-1.2.2.3 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 18-1.1.2.1 21-1.1.2.1.2.1.1.1.1 22-1.1.2.1.2 23-1.1.2.1.2.2.1 24-1.1.2.1.2.1 24-1.1.2.1.2.2 27-1.1.2.2.2.1 28-1.1.2.1.2 28-1.1.3.1 32-1.1.3.1.1 32-1.1.3.1.2 32-1.2.3.1.1 32-1.2.3.1.2 37-1.1.3.1 41-1.2.1 43-1.2.1.1.2 45-1.2.1.2 47-1.2.1.2.1.2.2 49-1.2.1.2.1.2.2 52-1.2.1.2.1.1.1 53-1.2 54-1.2.2.1.1.2.1.1.1 55-1.2.2.1.1.1.1 56-1.2.2.1 57-1.2.2 58-1.2.2.2.1 59-1.2.2.2 67-1.1.3.1.1 72-1.1.3.1 (m / multi-sentence :snt1 (i / induce-01~e.11 :ARG0 (s / stimulate-01~e.4 :ARG2 (p / protein :name (n2 / name :op1 "OSM") :mod (m5 / mouse) :quant (c / concentration-quantity :quant 25 :unit (n3 / nanogram-per-milliliter~e.7,9))) :duration (t3 / temporal-quantity :quant 24 :unit (h3 / hour~e.3))) :ARG2 (i2 / increase-01~e.13 :ARG1~e.14 (e2 / express-03~e.18 :ARG2 (p11 / protein :name (n / name :op1 "eotaxin-1"~e.15,17)) :manner (a4 / and~e.22,28 :op1 (l6 / level~e.24 :mod (n4 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.21))) :op2 (l / level~e.24 :mod (p2 / protein~e.23)))) :ARG3 (a2 / and :op1 (f5 / fibroblast :mod (l2 / lung :mod m5) :mod (p3 / protein :name (n7 / name :op1 "STAT6") :ARG2-of (m3 / mutate-01 :mod "-/-"))) :op2 (f6 / fibroblast :mod (w / wild-type~e.27) :mod l2)) :ARG1-of (d / detect-01~e.12 :ARG1-of (p4 / possible-01))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.28,37,72 :op1 (f / figure~e.32,67 :mod "5A") :op2 (f2 / figure~e.32 :mod "5C")))) :snt2 (i3 / induce-01~e.53 :ARG0 (s2 / stimulate-01~e.41 :ARG1 (f7 / fibroblast :mod (l4 / lung :mod (m4 / mouse)) :mod (w2 / wild-type~e.43)) :ARG2-of (u / use-01~e.45 :ARG1 (p5 / protein :name (n12 / name :op1 "IL-4"~e.2,52) :quant (c2 / concentration-quantity :quant 10 :unit (n13 / nanogram-per-milliliter~e.47,49)) :mod m4))) :ARG2 (a / and~e.57 :op1 (e5 / express-03~e.56 :ARG1 (n6 / nucleic-acid :name (n14 / name :op1 "mRNA"~e.55) :ARG0-of (e6 / encode-01 :ARG1 (p6 / protein :name (n15 / name :op1 "eotaxin"~e.54))))) :op2 (p7 / produce-01~e.59 :ARG1 (p8 / protein~e.58)) :ARG1-of (d3 / detect-01~e.12 :polarity - :location (f8 / fibroblast :mod (p10 / protein :name (n17 / name :op1 "STAT6") :ARG2-of (m8 / mutate-01 :mod "-/-")) :mod l4) :ARG1-of (p9 / possible-01))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure~e.32 :mod "5A") :op2 (f4 / figure~e.32 :mod "5C"))))) # ::id bel_pmid_1654_7273.29762 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We and others have shown that OSM can induce eotaxin @-@ 1 in mouse lung fibroblasts ( MLF ) ( 28 ) and lung smooth muscle cells ( 29 ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.1 4-1 5-1.2.r 6-1.2.1.1.1.1 7-1.2 8-1.2.1 9-1.2.1.2.1.1 11-1.2.1.2.1.1 12-1.2.1.3.r 13-1.2.1.3.1.1.1 14-1.2.1.3.1.1 15-1.2.1.3.1 20-1.2.1.3.1.2.1.1.1 22-1.2.1.3 23-1.2.1.3.2.1.2 24-1.2.1.3.2.1.1 25-1.2.1.3.2.1 26-1.2.1.3.2 28-1.2.1.3.2.2.1.1.1 (s / show-01~e.4 :ARG0 (a / and~e.1 :op1 (w / we~e.0) :op2 (p / person :mod (o / other~e.2))) :ARG1~e.5 (p2 / possible-01~e.7 :ARG1 (i / induce-01~e.8 :ARG0 (p3 / protein :name (n / name :op1 "OSM"~e.6)) :ARG2 (p6 / protein :name (n2 / name :op1 "eotaxin-1"~e.9,11)) :location~e.12 (a2 / and~e.22 :op1 (f / fibroblast~e.15 :mod (l / lung~e.14 :mod (m / mouse~e.13)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 28~e.20)))) :op2 (c2 / cell~e.26 :mod (m2 / muscle~e.25 :ARG1-of (s2 / smooth-06~e.24) :mod (l2 / lung~e.23)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 29~e.28)))))))) # ::id bel_pmid_1654_7273.29766 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also compared the effects of mOSM on IL @-@ 6 expression in both wt and STAT6-/- MLF ( Fig . 5 , B and D ) and show that STAT6-/- MLF respond similarly to wt MLF in IL @-@ 6 expression at both the mRNA and protein levels . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 4-1.1.2 7-1.1.2.2.r 8-1.1.2.2.1.1.1 10-1.1.2.2.1.1.1 11-1.1.2.2 14-1.1.2.2.2.1.2 15-1.1.2.2.2 15-1.1.4.1 19-1.1.4.1.1 19-1.1.4.1.2 24-1.1.4.1 27-1 28-1.2 32-1.2.2 33-1.2.2.2 34-1.2.2.2.1.r 35-1.2.2.2.1 38-1.1.2.2.1.1.1 40-1.1.2.2.1.1.1 41-1.2.2.3 45-1.2.2.3.2.1.1.1.1 46-1.2.2.3.2 47-1.2.2.3.2.2.1 48-1.2.2.3.2.1 48-1.2.2.3.2.2 (a / and~e.27 :op1 (c / compare-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a3 / affect-01~e.4 :ARG0 (p / protein :name (n2 / name :op1 "OSM") :mod (m4 / mouse)) :ARG1~e.7 (e2 / express-03~e.11 :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6"~e.8,10,38,40)) :ARG3 (a4 / and~e.15 :op1 (f3 / fibroblast :mod (l2 / lung :mod m4) :mod (w2 / wild-type~e.14)) :op2 (f4 / fibroblast :mod (p3 / protein :name (n6 / name :op1 "STAT6") :ARG2-of (m3 / mutate-01 :mod "-/-")) :mod l2)))) :mod (a2 / also~e.1) :ARG1-of (d / describe-01 :ARG0 (a5 / and~e.15,24 :op1 (f / figure~e.19 :mod "5B") :op2 (f2 / figure~e.19 :mod "5D")))) :op2 (s / show-01~e.28 :ARG0 w :ARG1 (r2 / respond-01~e.32 :ARG0 f4 :ARG1-of (r3 / resemble-01~e.33 :ARG2~e.34 f3~e.35) :condition (e3 / express-01~e.41 :ARG2 p2 :manner (a7 / and~e.46 :op1 (l3 / level~e.48 :mod (n / nucleic-acid :name (n7 / name :op1 "mRNA"~e.45))) :op2 (l / level~e.48 :mod (p5 / protein~e.47))))))) # ::id bel_pmid_1654_7273.29768 ::amr-annotator SDL-AMR-09 ::preferred # ::tok mOSM induced STAT1 ( Y701 ) , STAT3 ( Y705 ) , and STAT5 ( Y694 ) phosphorylation as reported by others ( 57 , 58 , 59 ) . # ::alignments 1-1 2-1.2.1.1.3.1.1 7-1.2.1.2.3.1.1 12-1.2.1 13-1.2.1.3.3.1.1 17-1.2 18-1.3.r 19-1.3 20-1.3.1.r 21-1.3.1.1 23-1.4.1.1.1.1 25-1.4.1.1.1.2 27-1.4.1.1.1.3 (i / induce-01~e.1 :ARG0 (p2 / protein :name (n2 / name :op1 "OSM") :mod (m / mouse)) :ARG2 (p / phosphorylate-01~e.17 :ARG1 (a / and~e.12 :op1 (a2 / amino-acid :mod 701 :name (n3 / name :op1 "tyrosine") :part-of (p3 / protein :name (n4 / name :op1 "STAT1"~e.2))) :op2 (a3 / amino-acid :mod 705 :name (n5 / name :op1 "tyrosine") :part-of (p4 / protein :name (n6 / name :op1 "STAT3"~e.7))) :op3 (a4 / amino-acid :mod 694 :name (n7 / name :op1 "tyrosine") :part-of (p5 / protein :name (n8 / name :op1 "STAT5"~e.13))))) :ARG1-of~e.18 (r2 / report-01~e.19 :ARG0~e.20 (p6 / person :mod (o / other~e.21))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 (a5 / and :op1 57~e.23 :op2 58~e.25 :op3 59~e.27))))) # ::id bel_pmid_1654_7273.29770 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Levels of VCAM @-@ 1 in STAT @-@ 6 @-@ deficient MLF were somewhat reduced compared with those observed in wt MLF , however , the ability of mOSM or mTNF-{alpha} to induce VCAM @-@ 1 was maintained ( Fig . 7B ) . # ::alignments 0-1.1.1 0-1.1.1.3.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 10-1.1.1.2.2 10-1.1.1.2.2.2 10-1.1.1.2.2.2.1 10-1.1.1.2.2.2.1.r 10-1.1.1.2.2.2.r 13-1.1.2 14-1.1 15-1.1.1.3 18-1.1.1.3.1.1 20-1.1.1.3.1.1.1.1 23-1 26-1.2.1 29-1.2.1.1 32-1.2.1.2 33-1.2.1.2.2 34-1.2.1.2.2 35-1.2.1.2.2 37-1.2 39-1.3.1 41-1.3.1.1 (h / have-concession-91~e.23 :ARG1 (r / reduce-01~e.14 :ARG1 (l / level~e.0 :quant-of~e.1 (p / protein :name (n / name :op1 "VCAM-1"~e.2,4)) :location (f / fibroblast :mod (l2 / lung :mod m4) :mod (p2 / protein~e.10 :name (n2 / name :op1 "STAT6") :ARG2-of~e.10 (m6 / mutate-01~e.10 :mod~e.10 "-/-"~e.10))) :ARG1-of (c / compare-01~e.15 :ARG2 (l3 / level~e.0 :ARG1-of (o / observe-01~e.18 :location (f2 / fibroblast :mod (w / wild-type~e.20) :mod l2)) :quant-of p))) :ARG2 (s / somewhat~e.13)) :ARG2 (m3 / maintain-01~e.37 :ARG1 (c2 / capable-01~e.26 :ARG1 (o2 / or~e.29 :op1 (p4 / protein :name (n4 / name :op1 "OSM") :mod (m4 / mouse)) :op2 (p5 / protein :name (n5 / name :op1 "TNF-{alpha}") :mod m4)) :ARG2 (i / induce-01~e.32 :ARG0 o2 :ARG2 p~e.33,34,35))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.39 :mod "7B"~e.41))) # ::id bel_pmid_1654_7273.38510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 4 has been documented to regulate the expression of eotaxin @-@ 1 ( 41 ) , eotaxin @-@ 2 ( 42 ) , and eotaxin @-@ 3 ( 34 ) in endothelial cells and fibroblasts in a STAT6 @-@ dependent manner ( 42 , 43 , 44 , 45 ) . IL @-@ 4 signal transduction includes activation of STAT6 ( 46 , 47 , 48 , 49 , 50 ) . # ::alignments 0-1.2.2.1.1.1.1 2-1.2.2.1.1.1.1 5-1.1 6-1.1.1.r 7-1.1.1 7-1.1.1.2 7-1.1.1.2.r 9-1.1.1.2.1 10-1.1.1.2.1.1.r 11-1.1.1.2.1.1.1.1.1 11-1.1.1.2.1.1.2.1.1 11-1.1.1.2.1.1.3.1.1 13-1.1.1.2.1.1.1.1.1 15-1.1.1.2.1.1.1.2.1.1.1 18-1.1.1.2.1.1.2.1.1 18-1.1.1.2.1.1.3.1.1 20-1.1.1.2.1.1.2.1.1 22-1.1.1.2.1.1.2.2.1.1.1 25-1.1.1.2.1.1 26-1.1.1.2.1.1.2.1.1 26-1.1.1.2.1.1.3.1.1 28-1.1.1.2.1.1.3.1.1 30-1.1.1.2.1.1.3.2.1.1.1 32-1.1.1.2.1.2.r 33-1.1.1.2.1.2.1.1 34-1.1.1.2.1.2.1 35-1.1.1.2.1.2 36-1.1.1.2.1.2.2 39-1.1.1.2.2.2.1.1 41-1.1.1.2.2 42-1.1.1.2.2.r 44-1.1.2.1.1.1.1 46-1.1.2.1.1.1.2 48-1.1.2.1.1.1.3 50-1.1.2.1.1.1.4 53-1.2.2.1.1.1.1 55-1.1.1.1.1 55-1.2.2.1.1.1.1 56-1.2.2.1 57-1.2.2 58-1.2 59-1.2.1 60-1.2.1.1.r 61-1.2.1.1.1.1 63-1.2.3.1.1.1.1 65-1.2.3.1.1.1.2 67-1.2.3.1.1.1.3 69-1.2.3.1.1.1.4 71-1.2.3.1.1.1.5 (m / multi-sentence :snt1 (d / document-01~e.5 :ARG1~e.6 (p / protein~e.7 :name (n / name :op1 "IL-4"~e.55) :ARG0-of~e.7 (r / regulate-01~e.7 :ARG1 (e / express-03~e.9 :ARG2~e.10 (a / and~e.25 :op1 (p2 / protein :name (n2 / name :op1 "eotaxin-1"~e.11,13) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 41~e.15)))) :op2 (p4 / protein :name (n3 / name :op1 "eotaxin-2"~e.11,18,20,26) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 42~e.22)))) :op3 (p6 / protein :name (n4 / name :op1 "eotaxin-3"~e.11,18,26,28) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 34~e.30))))) :ARG3~e.32 (a2 / and~e.35 :op1 (c4 / cell~e.34 :mod (e2 / endothelium~e.33)) :op2 (f / fibroblast~e.36))) :manner~e.42 (d5 / depend-01~e.41 :ARG0 r :ARG1 (p8 / protein :name (n5 / name :op1 "STAT6"~e.39))))) :ARG1-of (d6 / describe-01 :ARG0 (p9 / publication :ARG1-of (c5 / cite-01 :ARG2 (a3 / and :op1 42~e.44 :op2 43~e.46 :op3 44~e.48 :op4 45~e.50))))) :snt2 (i / include-01~e.58 :ARG1 (a4 / activate-01~e.59 :ARG1~e.60 (p11 / protein :name (n7 / name :op1 "STAT6"~e.61))) :ARG2 (t / transduce-01~e.57 :ARG1 (s / signal-07~e.56 :ARG0 (p10 / protein :name (n6 / name :op1 "IL-4"~e.0,2,53,55)))) :ARG1-of (d7 / describe-01 :ARG0 (p12 / publication :ARG1-of (c6 / cite-01 :ARG2 (a5 / and :op1 46~e.63 :op2 47~e.65 :op3 48~e.67 :op4 49~e.69 :op5 50~e.71)))))) # ::id bel_pmid_1654_7273.38520 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To verify the absence of the STAT6 @-@ signaling cascade in STAT6-/- MLF , we assessed mOSM and mIL @-@ 4 induced responses with respect to STAT3 and STAT6 activation . Fig. 6 confirms the absence of STAT6 protein and STAT6 induction in STAT6-/- MLF but equivalent activation of STAT3 in both wt and STAT6-/- MLF . # ::alignments 1-1.1.3 3-1.1.3.2 6-1.1.3.2.1.1.1.1.1 6-1.1.3.2.2.2.1.1 8-1.1.3.2.1.1 9-1.1.3.2.1 14-1.1.1 15-1.1 20-1.1.2.2.1.2.1.1 21-1.2.2.1.2 22-1.1.2 22-1.1.2.1 22-1.1.2.1.r 26-1.1.4.1.1.1.1 26-1.2.2.2.1.1.1 27-1.1.4.1 28-1.2.2.1.1.1.1.1 28-1.2.2.1.2.2.2.1.1 29-1.1.4 29-1.2.2.2 31-1.2.1 32-1.2.1.1 33-1.2 35-1.2.2.1.1 36-1.2.2.1.1.1.r 37-1.2.2.1.1.1.1.1 38-1.1.2.2.1.1 38-1.1.2.2.1.2 38-1.1.3.2.1.1.1 38-1.1.3.2.2.2 38-1.1.4.1.1 38-1.2.2.1.1.1 38-1.2.2.1.2.2.2 38-1.2.2.2.1 39-1.2.2.1 40-1.2.2.1.1.1.1.1 41-1.1.2.2 45-1.2.2 46-1.2.2.2.2 47-1.2.2.2 49-1.2.2.2.1.1.1 52-1.2.2.2.3.1.1 53-1.2.2.2.3 (m / multi-sentence :snt1 (a / assess-01~e.15 :ARG0 (w / we~e.14) :ARG1 (t / thing~e.22 :ARG1-of~e.22 (r / respond-01~e.22) :ARG2-of (i2 / induce-01~e.41 :ARG0 (a2 / and :op1 (p / protein~e.38 :name (n / name :op1 "OSM") :mod (m2 / mouse)) :op2 (p2 / protein~e.38 :name (n2 / name :op1 "IL-4"~e.20) :mod m2)))) :purpose (v / verify-01~e.1 :ARG0 w :ARG1 (a5 / absent-01~e.3 :ARG1 (c / cascade~e.9 :ARG0-of (s / signal-07~e.8 :ARG1 (p4 / protein~e.38 :name (n5 / name :op1 "STAT6"~e.6)))) :ARG2 (f / fibroblast :mod (l / lung :mod m2) :mod (p6 / protein~e.38 :name (n6 / name :op1 "STAT6"~e.6) :ARG2-of (m5 / mutate-01 :mod "-/-"))))) :topic (a3 / activate-01~e.29 :ARG1 (a4 / and~e.27 :op1 (p3 / protein~e.38 :name (n3 / name :op1 "STAT3"~e.26)) :op2 p4))) :snt2 (c2 / confirm-01~e.33 :ARG0 (f2 / figure~e.31 :mod 6~e.32) :ARG1 (c3 / contrast-01~e.45 :ARG1 (a6 / and~e.39 :op1 (a7 / absent-01~e.35 :ARG1~e.36 (p7 / protein~e.38 :name (n7 / name :op1 "STAT6"~e.28,37,40)) :ARG2 f3) :op2 (i / induce-01~e.21 :ARG2 p7 :location (f3 / fibroblast :mod (l2 / lung :mod (m6 / mouse)) :mod (p8 / protein~e.38 :name (n8 / name :op1 "STAT6"~e.28) :ARG2-of (m7 / mutate-01 :mod "-/-"))))) :ARG2 (a8 / activate-01~e.29,47 :ARG1 (p9 / protein~e.38 :name (n9 / name :op1 "STAT3"~e.26,49)) :ARG1-of (e / equal-01~e.46) :location (a9 / and~e.53 :op1 (f4 / fibroblast :mod (w2 / wild-type~e.52) :mod l2) :op2 f3))))) # ::id bel_pmid_1654_7273.39184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Levels of VCAM @-@ 1 in STAT @-@ 6 @-@ deficient MLF were somewhat reduced compared with those observed in wt MLF , however , the ability of mOSM or mTNF-{alpha} to induce VCAM @-@ 1 was maintained ( Fig . 7B ) . # ::alignments 0-1.1.1 0-1.1.1.3.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 6-1.1.1.2.2.1.1 8-1.1.1.2.2.1.1 10-1.1.1.2.2 10-1.1.1.2.2.2 10-1.1.1.2.2.2.1 10-1.1.1.2.2.2.1.r 10-1.1.1.2.2.2.r 13-1.1.2 14-1.1 15-1.1.1.3 18-1.1.1.3.1.1 20-1.1.1.3.1.1.1.1 23-1 26-1.2.1 29-1.2.1.1 32-1.2.1.2 33-1.2.1.2.2 34-1.2.1.2.2 35-1.2.1.2.2 37-1.2 39-1.3.1 41-1.3.1.1 (h / have-concession-91~e.23 :ARG1 (r / reduce-01~e.14 :ARG1 (l / level~e.0 :quant-of~e.1 (p / protein :name (n / name :op1 "VCAM-1"~e.2,4)) :location (f / fibroblast :mod (l2 / lung :mod m4) :mod (p2 / protein~e.10 :name (n2 / name :op1 "STAT-6"~e.6,8) :ARG2-of~e.10 (m6 / mutate-01~e.10 :mod~e.10 "-/-"~e.10))) :ARG1-of (c / compare-01~e.15 :ARG2 (l3 / level~e.0 :ARG1-of (o / observe-01~e.18 :location (f2 / fibroblast :mod (w / wild-type~e.20) :mod l2)) :quant-of p))) :ARG2 (s / somewhat~e.13)) :ARG2 (m3 / maintain-01~e.37 :ARG1 (c2 / capable-01~e.26 :ARG1 (o2 / or~e.29 :op1 (p4 / protein :name (n4 / name :op1 "OSM") :mod (m4 / mouse)) :op2 (p5 / protein :name (n5 / name :op1 "TNF-{alpha}") :mod m4)) :ARG2 (i / induce-01~e.32 :ARG0 o2 :ARG2 p~e.33,34,35))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.39 :mod "7B"~e.41))) # ::id bel_pmid_1658_5161.22112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Focus formation was consistently observed with both mutants . However , C @-@ RAF mutant proteins caused the formation of much smaller cell aggregates ( Fig . 5A ) as compared with v @-@ Raf . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1.2 4-1.1 5-1.1.3.r 6-1.1.3.2 7-1.1.3 7-1.1.3.1 7-1.1.3.1.r 9-1.2 11-1.2.1.1.1.1 13-1.2.1.1.1.1 14-1.2.1.1 14-1.2.1.1.2 14-1.2.1.1.2.r 16-1.2.1 18-1.2.1.2 19-1.2.1.2.1.r 20-1.2.1.2.1.2.1 21-1.2.1.2.1.2 22-1.2.1.2.1.1 23-1.2.1.2.1 25-1.2.1.2.2.1 27-1.2.1.2.2.1.1 30-1.2.1.2.1.2.2.r 31-1.1.3.r 34-1.2.1.2.1.2.2.1.1 (m / multi-sentence :snt1 (o / observe-01~e.4 :ARG1 (f / form-01~e.1 :ARG1 (f2 / focus~e.0)) :manner (c / consistent-02~e.3) :instrument~e.5,31 (m5 / molecular-physical-entity~e.7 :ARG2-of~e.7 (m2 / mutate-01~e.7) :mod (b / both~e.6))) :snt2 (c5 / contrast-01~e.9 :ARG2 (c2 / cause-01~e.16 :ARG0 (e / enzyme~e.14 :name (n / name :op1 "C-RAF"~e.11,13) :ARG2-of~e.14 (m3 / mutate-01~e.14)) :ARG1 (f3 / form-01~e.18 :ARG1~e.19 (a / aggregate-01~e.23 :ARG1 (c3 / cell~e.22) :mod (s2 / small~e.21 :degree (m4 / much~e.20) :compared-to~e.30 (e2 / enzyme :name (n2 / name :op1 "C-Raf"~e.34)))) :ARG1-of (d / describe-01 :ARG0 (f4 / figure~e.25 :mod "5A"~e.27)))))) # ::id bel_pmid_1658_5540.18258 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Wild @-@ type MEFs induced Ifnb , Tnfa , and Il @-@ 6 in response to poly( I : C ) {an viral mimetic activator of FADD signaling @-@ SE}, whereas the induction was severely impaired in FADD @-@ deficient MEFs as examined by RT @-@ PCR analyses ( Fig . 1A ) . # ::alignments 0-1.1.1.2 2-1.1.1.2 4-1.1 5-1.1.2.1.1.1 7-1.1.2.2.1.1 9-1.1.2 10-1.1.2.3.1.1 12-1.1.2.3.1.1 13-1.1.3.r 14-1.1.3 22-1.1.3.1.2.1.2.1 24-1.1.3.1.2.1 24-1.1.3.1.2.1.1 24-1.1.3.1.2.1.1.r 25-1.1.3.1.2.1.1.1.r 26-1.1.3.1.2.1.1.1.1.1.1 27-1.1.3.1.2.1.1.1 30-1 32-1.2.1 34-1.2.2 35-1.2 37-1.2.3.2.1.1 39-1.2.3.2 39-1.2.3.2.2 39-1.2.3.2.2.1 39-1.2.3.2.2.1.r 39-1.2.3.2.2.r 41-1.2.4.r 42-1.2.4 43-1.2.4.1.r 44-1.2.4.1.1.1.1 46-1.2.4.1.1.1.1 47-1.2.4.1 49-1.3.1 51-1.3.1.1 (c / contrast-01~e.30 :ARG1 (i / induce-01~e.4 :ARG0 (f / fibroblast :mod (e / embryo :mod (m / mouse)) :mod (w / wild-type~e.0,2)) :ARG2 (a2 / and~e.9 :op1 (p / protein :name (n / name :op1 "Ifnb"~e.5)) :op2 (p2 / protein :name (n2 / name :op1 "Tnfa"~e.7)) :op3 (p3 / protein :name (n3 / name :op1 "IL-6"~e.10,12))) :ARG2-of~e.13 (r / respond-01~e.14 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "poly(I:C)") :ARG1-of (m2 / mean-01 :ARG2 (m6 / molecular-physical-entity~e.24 :ARG0-of~e.24 (a3 / activate-01~e.24 :ARG1~e.25 (s / signal-07~e.27 :ARG0 (p4 / protein :name (n5 / name :op1 "FADD"~e.26)) :ARG1 (t3 / thing :name (n6 / name :op1 "SE")))) :ARG0-of (m3 / mimic-01 :ARG1 (v / virus~e.22))))))) :ARG2 (i2 / impair-01~e.35 :ARG1 i~e.32 :degree (s2 / severe~e.34) :location (f2 / fibroblast :mod (e2 / embryo :mod (m4 / mouse)) :mod (p5 / protein~e.39 :name (n7 / name :op1 "FADD"~e.37) :ARG2-of~e.39 (m5 / mutate-01~e.39 :mod~e.39 "-/-"~e.39))) :ARG1-of~e.41 (e3 / examine-01~e.42 :ARG0~e.43 (a4 / analyze-01~e.47 :mod (t / thing :name (n8 / name :op1 "RT-PCR"~e.44,46))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.49 :mod "1A"~e.51))) # ::id bel_pmid_1658_5540.25628 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the induction of Tnfa and Il @-@ 6 was severely impaired after 2 h of poly( I : C ) stimulation and reduced after 6 h of stimulation in caspase @-@ 8 @-@ deficient cells ( Fig . 4B ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.1.1 7-1.1.1.1.2.1.1 9-1.1.2 10-1.1 11-1.1.3 12-1.1.3.1.2.1 13-1.1.3.1.2.2 20-1.1.3.1 21-1 22-1.2 23-1.2.2 24-1.2.2.1.1.1 25-1.2.2.1.1.2 27-1.2.2.1 28-1.2.2.1.2.r 29-1.2.2.1.2.1.1.1 31-1.2.2.1.2.1.1.1 33-1.2.2.1.2.1 33-1.2.2.1.2.1.2 33-1.2.2.1.2.1.2.1 33-1.2.2.1.2.1.2.1.r 33-1.2.2.1.2.1.2.r 34-1.2.2.1.2 36-1.3.1 38-1.3.1.1 (a / and~e.21 :op1 (i / impair-01~e.10 :ARG1 (i2 / induce-01~e.1 :ARG2~e.2 (a2 / and~e.4 :op1 (p / protein :name (n / name :op1 "Tnfa"~e.3)) :op2 (p2 / protein :name (n2 / name :op1 "IL-6"~e.5,7)))) :degree (s / severe~e.9) :time (a3 / after~e.11 :op1 (s2 / stimulate-01~e.20 :ARG0 (s4 / small-molecule :name (n3 / name :op1 "poly(I:C)")) :duration (t / temporal-quantity :quant 2~e.12 :unit (h / hour~e.13))))) :op2 (r / reduce-01~e.22 :ARG1 i2 :time (a4 / after~e.23 :op1 (s3 / stimulate-01~e.27 :duration (t2 / temporal-quantity :quant 6~e.24 :unit (h2 / hour~e.25)) :location~e.28 (c / cell~e.34 :mod (p4 / protein~e.33 :name (n4 / name :op1 "caspase-8"~e.29,31) :ARG2-of~e.33 (m / mutate-01~e.33 :mod~e.33 "-/-"~e.33)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.36 :mod "4B"~e.38))) # ::id bel_pmid_1658_5540.25630 ::amr-annotator SDL-AMR-09 ::preferred # ::tok nuclear translocation of p65 , a component of NF-{kappa}B , was reduced in caspase @-@ 8 @-@ deficient cells ( Fig . 4C ) # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 8-1.1.1.2.1.1 11-1 12-1.2.r 13-1.2.1.1.1 15-1.2.1.1.1 17-1.2.1 17-1.2.1.2 17-1.2.1.2.1 17-1.2.1.2.1.r 17-1.2.1.2.r 18-1.2 20-1.3.1 22-1.3.1.1 (r / reduce-01~e.11 :ARG1 (t / translocate-01~e.1 :ARG1~e.2 (p / protein-segment :name (n / name :op1 "p65"~e.3) :part-of (p2 / protein :name (n3 / name :op1 "NF-{kappa}B"~e.8))) :ARG2 (n2 / nucleus~e.0)) :location~e.12 (c / cell~e.18 :mod (p3 / protein~e.17 :name (n4 / name :op1 "caspase-8"~e.13,15) :ARG2-of~e.17 (m / mutate-01~e.17 :mod~e.17 "-/-"~e.17))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.20 :mod "4C"~e.22))) # ::id bel_pmid_1663_6663.7850 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LMW @-@ DSP2 overexpression in 293T cells suppressed IL @-@ 6 @-@ induced phosphorylation and activation of STAT3 . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1 6-1.1.2 7-1 8-1.2.3.1.1.1 10-1.2.3.1.1.1 12-1.2.3 13-1.2.1 14-1.2 15-1.2.2 16-1.2.2.1.r 17-1.2.2.1.1.1 (s / suppress-01~e.7 :ARG0 (o / overexpress-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "LMW-DSP2"~e.0,2)) :location~e.4 (c / cell-line~e.6 :name (n2 / name :op1 "293T"~e.5))) :ARG1 (a / and~e.14 :op1 (p / phosphorylate-01~e.13 :ARG1 p3) :op2 (a2 / activate-01~e.15 :ARG1~e.16 (p3 / protein :name (n4 / name :op1 "STAT3"~e.17))) :ARG2-of (i / induce-01~e.12 :ARG0 (p2 / protein :name (n3 / name :op1 "IL-6"~e.8,10))))) # ::id bel_pmid_1663_6663.24748 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , small @-@ interfering RNA @-@ mediated reduction of LMW @-@ DSP2 expression enhanced IL @-@ 6 @-@ induced STAT3 @-@ dependent transcription . # ::alignments 1-1 3-1.1.1.2.1.1.1 5-1.1.1.2.1.1.1 6-1.1.1.2.1.1.2 8-1.1.1.2 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.1.1.1 13-1.1.1.1.1.1.1 14-1.1.1.1 15-1.1 16-1.1.2.1.1.1.1 18-1.1.2.1.1.1.1 20-1.1.2.1 21-1.1.2.2.1.1.1 23-1.1.2.2 24-1.1.2 (c / contrast-01~e.1 :ARG2 (e / enhance-01~e.15 :ARG0 (r2 / reduce-01~e.9 :ARG1~e.10 (e2 / express-03~e.14 :ARG2 (e3 / enzyme :name (n2 / name :op1 "LMW-DSP2"~e.11,13))) :ARG1-of (m / mediate-01~e.8 :ARG0 (n / nucleic-acid :name (n5 / name :op1 "small-interfering"~e.3,5 :op2 "RNA"~e.6)))) :ARG1 (t / transcribe-01~e.24 :ARG2-of (i / induce-01~e.20 :ARG0 (p / protein :name (n3 / name :op1 "IL-6"~e.16,18))) :ARG0-of (d / depend-01~e.23 :ARG1 (p2 / protein :name (n4 / name :op1 "STAT3"~e.21)))))) # ::id bel_pmid_1663_6672.36768 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of wild @-@ type ( wt ) Cbp remarkably suppressed EGF @-@ induced activation of Src , ERK1 @/@ 2 , and Akt @-@ 1 enzymes , and NIH3T3 cell transformation , as well as colony formation of a breast cancer cell line ( MDA @-@ MB @-@ 468 ) in soft agar . # ::alignments 0-1.1 2-1.1.1.2 4-1.1.1.2 6-1.1.1.2 8-1.1.1.1.1 9-1.3 10-1 11-1.2.1.2.1.1.1 13-1.2.1.2 14-1.2.1 15-1.2.1.1.r 16-1.2.1.1.1.1.1 18-1.2.1.1.2.1.1.1 19-1.2.1.1.2 22-1.2.1.1 23-1.2.1.1.3.1.1 25-1.2.1.1.3.1.1 26-1.1.1 26-1.2.1.1.1 26-1.2.1.1.2.1 26-1.2.1.1.2.2 26-1.2.1.1.3 26-1.2.1.2.1 28-1.2.1.1 29-1.2.2.1.1.1 30-1.2.2.1 31-1.2.2 33-1.2 34-1.2 35-1.2 35-1.2.r 36-1.2.3.2 37-1.2.3 38-1.2.3.1.r 40-1.2.3.1.2.2.1 41-1.2.3.1.2.2.2 42-1.2.3.1 43-1.2.3.1 45-1.2.3.1.1.1 47-1.2.3.1.1.1 49-1.2.3.1.1.1 51-1.2.3.3.r 52-1.2.3.3.1 53-1.2.3.3 (s / suppress-01~e.10 :ARG0 (e / express-03~e.0 :ARG2 (p / protein~e.26 :name (n2 / name :op1 "Cbp"~e.8) :mod (w / wild-type~e.2,4,6))) :ARG1~e.35 (a2 / and~e.33,34,35 :op1 (a4 / activate-01~e.14 :ARG1~e.15 (a / and~e.22,28 :op1 (p3 / protein~e.26 :name (n4 / name :op1 "Src"~e.16)) :op2 (s2 / slash~e.19 :op1 (e4 / enzyme~e.26 :name (n5 / name :op1 "ERK1"~e.18)) :op2 (e5 / enzyme~e.26 :name (n6 / name :op1 "ERK2"))) :op3 (e2 / enzyme~e.26 :name (n7 / name :op1 "Akt-1"~e.23,25))) :ARG2-of (i2 / induce-01~e.13 :ARG0 (p2 / protein~e.26 :name (n3 / name :op1 "EGF"~e.11)))) :op2 (t / transform-01~e.31 :ARG1 (c / cell-line~e.30 :name (n8 / name :op1 "NIH3T3"~e.29))) :op3 (f / form-01~e.37 :ARG1~e.38 (c3 / cell-line~e.42,43 :name (n9 / name :op1 "MDA-MB-468"~e.45,47,49) :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast"~e.40 :op2 "cancer"~e.41))) :mod (c2 / colony~e.36) :location~e.51 (a3 / agar~e.53 :ARG1-of (s3 / soft-02~e.52)))) :ARG1-of (r / remarkable-02~e.9)) # ::id bel_pmid_1671_3670.8846 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , 500 ng @/@ ml GH and 30 ng @/@ ml IL @-@ 6 increased PAI @-@ 1 secretion five @-@ fold and 3.6 @-@ fold , respectively . Furthermore , GH and IL @-@ 6 induced PAI @-@ 1 mRNA by up to 7.3 @-@ fold , and 3.6 @-@ fold , respectively , in a time @-@ dependent fashion with significant stimulation seen at concentrations as low as 5 ng @/@ ml GH and 10 ng @/@ ml IL @-@ 6 . # ::alignments 0-1.1.3 2-1.1.1.1.2.1 3-1.1.1.1.2.2 5-1.1.1.1.2.2 6-1.1.1.1.1.1 7-1.1 8-1.1.2.1.2.1 9-1.1.1.1.2.2 11-1.1.1.1.2.2 12-1.1.2.1.1.1 14-1.1.2.1.1.1 15-1.1.1 15-1.1.2 16-1.1.1.2.1.1.1 18-1.1.1.2.1.1.1 19-1.1.1.2 20-1.1.1.3.1 22-1.1.1.3 22-1.1.2.3 24-1.1.2.3.1 26-1.1.2.3 28-1.2.1.3 30-1.2.1 32-1.2.1.1.1.1.1 33-1.2.1 34-1.2.1.2.1.1.1 36-1.2.1.2.1.1.1 37-1.2.1.1 37-1.2.1.2 38-1.2.1.1.2.2.1.1.1 40-1.2.1.1.2.2.1.1.1 41-1.2.1.1.2.1.1 41-1.2.1.2.2.1.1 43-1.2.1.1.2.3 44-1.2.1.1.2.3 45-1.2.1.1.2.3.1.1 47-1.2.1.1.2.3.1 49-1.2.1 49-1.2.1.5 49-1.2.1.5.r 50-1.2.1.2.2.3.1.1 52-1.2.1.2.2.3.1 54-1.2.1.3 58-1.2.1.5.1.1 60-1.2.1.5.1 62-1.2.1.4.r 63-1.2.1.4.1 64-1.2.1.4 65-1.2.1.5.2 67-1.1.1.1.2 67-1.1.2.1.2 67-1.2.1.5.2.1 67-1.2.1.5.2.1.1.1.2 67-1.2.1.5.2.1.1.2.2 68-1.2.1.5.2.1.2.r 68-1.2.1.5.2.1.r 69-1.2.1.5.2.1.2 70-1.2.1.5.2.1.1.r 70-1.2.1.5.2.1.r 71-1.2.1.5.2.1.1.1.2.1 72-1.1.1.1.2.2 72-1.1.2.1.2.2 72-1.2.1.5.2.1.1.1.2.2 72-1.2.1.5.2.1.1.2.2.2 74-1.1.1.1.2.2 75-1.1.1.1.1.1 75-1.2.1.1.1.1.1 75-1.2.1.5.2.1.1.1.1.1 76-1.2 76-1.2.1 76-1.2.1.5 76-1.2.1.5.2.1.1 76-1.2.1.5.r 76-1.2.1.r 77-1.2.1.5.2.1.1.2.2.1 78-1.1.1.1.2.2 80-1.1.1.1.2.2 81-1.2.1.5.2.1.1.2.1.1 83-1.2.1.5.2.1.1.2.1.1 (m / multi-sentence :snt1 (a2 / and~e.7 :op1 (i / increase-01~e.15 :ARG0 (p / protein :name (n / name :op1 "GH"~e.6,75) :quant (c / concentration-quantity~e.67 :quant 500~e.2 :unit (n2 / nanogram-per-milliliter~e.3,5,9,11,72,74,78,80))) :ARG1 (s / secrete-01~e.19 :ARG1 (p3 / protein :name (n5 / name :op1 "PAI-1"~e.16,18))) :ARG2 (p4 / product-of~e.22 :op1 5~e.20)) :op2 (i2 / increase-01~e.15 :ARG0 (p2 / protein :name (n3 / name :op1 "IL-6"~e.12,14) :quant (c2 / concentration-quantity~e.67 :quant 30~e.8 :unit (n4 / nanogram-per-milliliter~e.72))) :ARG1 s :ARG2 (p6 / product-of~e.22,26 :op1 3.6~e.24)) :ARG2-of (i5 / interest-01~e.0)) :snt2 (a / and~e.76 :op2~e.76 (a3 / and~e.30,33,49,76 :op1 (i3 / induce-01~e.37 :ARG0 (p5 / protein :name (n6 / name :op1 "GH"~e.32,75)) :ARG2 (n15 / nucleic-acid :name (n7 / name :op1 "mRNA"~e.41) :ARG0-of (e / encode-01 :ARG1 (p7 / protein :name (n8 / name :op1 "PAI-1"~e.38,40))) :quant (u / up-to~e.43,44 :op1 (p8 / product-of~e.47 :op1 7.3~e.45)))) :op2 (i4 / induce-01~e.37 :ARG0 (p9 / protein :name (n9 / name :op1 "IL-6"~e.34,36)) :ARG2 (n16 / nucleic-acid :name (n10 / name :op1 "mRNA"~e.41) :ARG0-of (e2 / encode-01 :ARG1 p7) :quant (u2 / up-to :op1 (p10 / product-of~e.52 :op1 3.6~e.50)))) :mod (r4 / respective~e.28,54) :instrument~e.62 (s3 / stimulate-01~e.64 :ARG1-of (s2 / significant-02~e.63)) :manner~e.49,76 (a5 / and~e.49,76 :op1 (d / depend-01~e.60 :ARG1 (t / time~e.58)) :op2 (s5 / see-01~e.65 :time~e.68,70 (c3 / concentrate-02~e.67 :ARG1~e.70 (a4 / and~e.76 :op1 (p11 / protein :name (n11 / name :op1 "GH"~e.75) :quant (c4 / concentration-quantity~e.67 :quant 5~e.71 :unit (n12 / nanogram-per-milliliter~e.72))) :op2 (p12 / protein :name (n13 / name :op1 "IL-6"~e.81,83) :quant (c5 / concentration-quantity~e.67 :quant 10~e.77 :unit (n14 / nanogram-per-milliliter~e.72)))) :ARG1-of~e.68 (l / low-04~e.69))))))) # ::id bel_pmid_1679_8732.4954 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RNA interference @-@ mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate @-@ induced insulin resistance and IL @-@ 6 production . # ::alignments 0-1.1.2.1.1.1.1 1-1.1.2.1 3-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.2.1.1 9-1.1.1 10-1.1.1.2.r 11-1.1.1.2.1.1 12-1.1.1.2.2 13-1.1.1.2 14-1 15-1.2.r 17-1.2.1.2.1 18-1.2.1.2 19-1.2.1 20-1.2.1.1.r 21-1.2.1.1.2.1.1.1 23-1.2.1.1.2 24-1.2.1.1.1.1.1 25-1.2.1.1 26-1.2 27-1.2.2.1.1.1 29-1.2.2.1.1.1 30-1.2.2 (r / result-01~e.14 :ARG1 (i2 / inhibit-01~e.4 :ARG1~e.5 (e / express-03~e.9 :ARG2 (a3 / and~e.7 :op1 (p / protein :name (n / name :op1 "TLR2"~e.6)) :op2 (p2 / protein :name (n2 / name :op1 "MyD88"~e.8))) :ARG3~e.10 (c / cell~e.13 :name (n3 / name :op1 "C2C12"~e.11) :mod (m2 / muscle~e.12))) :ARG1-of (m / mediate-01~e.3 :ARG0 (i / interfere-01~e.1 :ARG0 (n8 / nucleic-acid :name (n9 / name :op1 "RNA"~e.0))))) :ARG2~e.15 (a / and~e.26 :op1 (i3 / inhibit-01~e.19 :ARG1~e.20 (r3 / resist-01~e.25 :ARG1 (p5 / protein :name (n5 / name :op1 "insulin"~e.24)) :ARG2-of (i4 / induce-01~e.23 :ARG0 (s / small-molecule :name (n6 / name :op1 "palmitate"~e.21)))) :ARG1-of (c2 / complete-02~e.18 :degree (n4 / near~e.17))) :op2 (p3 / produce-01~e.30 :ARG1 (p4 / protein :name (n7 / name :op1 "IL-6"~e.27,29))))) # ::id bel_pmid_1679_8732.19654 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When compared with an equimolar concentration of palmitate , fibroblast @-@ stimulating lipopeptide @-@ 1 , a known TLR2 ligand , was a slightly more potent activator of signal transduction and interleukin ( IL ) - 6 production . # ::alignments 1-1.1.3.2.r 4-1.1.3.2.2 5-1.1.3.2 6-1.1.3.2.1.r 7-1.1.3.2.1.1.1 9-1.1.1.1 11-1.1.1.1 12-1.1.1.2 14-1.1.1.2 17-1.1 17-1.1.2 17-1.1.2.r 18-1.1.4.1.1 19-1.1.4 23-1.1.3.1.1 24-1.1.3.1 25-1.1.3 26-1 27-1.2.r 28-1.2.1.1 29-1.2.1 30-1.2 31-1.2.2.1.1.1 36-1.2.2.1.1.1 37-1.2.2 (a2 / activate-01~e.26 :ARG0 (p / protein~e.17 :name (n / name :op1 "fibroblast-stimulating"~e.9,11 :op2 "lipopeptide-1"~e.12,14) :ARG1-of~e.17 (k / know-01~e.17) :mod (p2 / potent~e.25 :degree (m / more~e.24 :degree (s / slight~e.23)) :compared-to~e.1 (c2 / concentrate-02~e.5 :ARG1~e.6 (s3 / small-molecule :name (n4 / name :op1 "palmitate"~e.7)) :mod (e / equimolar~e.4))) :mod (l / ligand~e.19 :name (n2 / name :op1 "TLR2"~e.18))) :ARG1~e.27 (a3 / and~e.30 :op1 (t / transduce-01~e.29 :ARG1 (s2 / signal-07~e.28)) :op2 (p3 / produce-01~e.37 :ARG1 (p4 / protein :name (n3 / name :op1 "interleukin-6"~e.31,36))))) # ::id bel_pmid_167_9532.20916 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When c @-@ H @-@ ras expression was induced with heavy metal ions there was a marked reduction in the expression of two glycosylphosphatidylinositol ( GPI ) anchored proteins , TAP @/@ Ly @-@ 6A.2 and Thy @-@ 1 , on the plasma membrane of the transformed cells . # ::alignments 0-1.3.r 1-1.3.1.1.1.1 3-1.3.1.1.1.1 5-1.3.1.1.1.1 6-1.3.1 8-1.3 9-1.3.2.r 10-1.3.2.1.1 11-1.3.2.1 12-1.3.2 16-1.2 17-1 18-1.1.r 20-1.1 21-1.1.1.r 22-1.1.1.1 23-1.1.1.2.1 27-1.1.1.2.2 28-1.1.1.2.3 30-1.1.1.3.1.1.1.1 32-1.1.1.3.1.1.1.1 34-1.1.1.3.1.1.1.1 35-1.1.1.3.1 36-1.1.1.3.1.2.1.1 38-1.1.1.3.1.2.1.1 40-1.1.2.r 42-1.1.2.1 43-1.1.2 44-1.1.2.2.r 46-1.1.2.2.1 47-1.1.2.2 (r2 / reduce-01~e.17 :ARG1~e.18 (e / express-03~e.20 :ARG2~e.21 (p5 / protein :quant 2~e.22 :name (n5 / name :op1 "glycosylphosphatidylinositol"~e.23 :op2 "anchored"~e.27 :op3 "protein"~e.28) :ARG2-of (i / include-91 :ARG1 (a2 / and~e.35 :op1 (p2 / protein :name (n2 / name :op1 "TAP/Ly-6A.2"~e.30,32,34)) :op2 (p3 / protein :name (n3 / name :op1 "Thy-1"~e.36,38))))) :ARG3~e.40 (m2 / membrane~e.43 :mod (p / plasma~e.42) :part-of~e.44 (c / cell~e.47 :ARG1-of (t / transform-01~e.46)))) :ARG1-of (m / mark-01~e.16) :time~e.0 (i2 / induce-01~e.8 :ARG2 (e2 / express-03~e.6 :ARG2 (e3 / enzyme :name (n / name :op1 "c-H-ras"~e.1,3,5))) :instrument~e.9 (i3 / ion~e.12 :mod (m3 / metal~e.11 :mod (h / heavy~e.10))))) # ::id bel_pmid_1688_7332.6142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We demonstrate that siRNA targeting ULK2 in mouse P19 cells results in elevated FGFR1 mediated FRS3 and SHP2 tyrosyl phosphorylation . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 4-1.2.1 5-1.2.1.2.1.1 6-1.2.1.3.r 7-1.2.1.3.2 8-1.2.1.3.1.1 9-1.2.1.3 10-1.2 11-1.2.2.r 12-1.2.2.3 13-1.2.2.2.1.1.1 14-1.2.2.2 15-1.2.2.1.2.2.1.1 16-1.2.2.1 17-1.2.2.1.1.2.1.1 19-1.2.2 (d / demonstrate-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (r2 / result-01~e.10 :ARG1 (t / target-01~e.4 :ARG0 (n9 / nucleic-acid :name (n / name :op1 "siRNA"~e.3)) :ARG1 (e / enzyme :name (n2 / name :op1 "ULK2"~e.5)) :location~e.6 (c / cell~e.9 :name (n3 / name :op1 "P19"~e.8) :mod (m / mouse~e.7))) :ARG2~e.11 (p / phosphorylate-01~e.19 :ARG1 (a3 / and~e.16 :op1 (a2 / amino-acid :name (n6 / name :op1 "tyrosine") :part-of (e3 / enzyme :name (n7 / name :op1 "SHP2"~e.17))) :op2 (a4 / amino-acid :name (n8 / name :op1 "tyrosine") :part-of (p2 / protein :name (n4 / name :op1 "FRS3"~e.15)))) :ARG1-of (m2 / mediate-01~e.14 :ARG0 (e2 / enzyme :name (n5 / name :op1 "FGFR1"~e.13))) :ARG1-of (e4 / elevate-01~e.12 :ARG0 e2)))) # ::id bel_pmid_1692_4534.3554 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PGD( 2 ) induced a reduction in adiponectin and leptin mRNA , and the secretion of these adipokines was also inhibited , the effect being greater with leptin ( up to 10 @-@ fold ) than with adiponectin ( twofold ) . # ::alignments 1-1.3.3.2.1 3-1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.2.1.1.1 8-1.1.2.1 9-1.1.2.1.2.2.1.1.1 10-1.1.2.1.1.1.1 10-1.1.2.1.2.1.1 12-1.2.1.1 14-1.2.1 19-1.2.2 20-1.2 23-1.3.2 23-1.3.3 24-1.3.2.r 25-1.3 25-1.3.1 25-1.3.1.r 26-1.3.2.1.r 27-1.3.2.1 29-1.3.2.2 30-1.3.2.2 31-1.3.2.2.1.1 33-1.3.2.2.1 35-1.3.3.r 36-1.3.3.1.r 37-1.3.3.1 (a / and :op1 (i / induce-01~e.3 :ARG0 (s2 / small-molecule :name (n / name :op1 "PGD2")) :ARG2 (r / reduce-01~e.5 :ARG1~e.6 (a2 / and~e.8 :op1 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.10) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "adiponectin"~e.7)))) :op2 (n7 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.10) :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "leptin"~e.9))))))) :op2 (i2 / inhibit-01~e.20 :ARG1 (s / secrete-01~e.14 :ARG1 (a7 / and~e.12 :op1 p :op2 p2)) :mod (a4 / also~e.19)) :op3 (g / great~e.25 :degree~e.25 (m / more~e.25) :domain~e.24 (a3 / affect-01~e.23 :ARG1~e.26 p2~e.27 :quant (u / up-to~e.29,30 :op1 (p3 / product-of~e.33 :op1 10~e.31))) :compared-to~e.35 (a8 / affect-01~e.23 :ARG1~e.36 p~e.37 :quant (p4 / product-of :quant 2~e.1)))) # ::id bel_pmid_1692_4534.16206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , PGD( 2 ) induced a marked stimulation of IL @-@ 6 and MCP @-@ 1 expression ; with IL @-@ 6 , this was rapid , the mRNA level increasing by > 50 @-@ fold by 1 h . The rise in mRNA was accompanied by an increase in IL @-@ 6 and MCP @-@ 1 release ( up to 100 @- and 6.5 @-@ fold , respectively ) . # ::alignments 1-1.2.1 6-1.2.1.1 8-1.2.1.1.2.2 9-1.2.1.1.2 9-1.2.2.3.1 10-1.2.1.1.2.1.r 11-1.2.1.1.2.1.1.1.1.1 13-1.2.1.1.2.1.1.1.1.1 14-1.2.1.1.2.1 15-1.2.1.1.2.1.2.1.1.1 17-1.2.1.1.2.1.2.1.1.1 18-1.2.1.1.2.1.1 18-1.2.1.1.2.1.2 21-1.2.1.1.2.1.1.1.1.1 23-1.2.1.1.2.1.1.1.1.1 27-1.2.1.1.2.1.1.2 30-1.2.2.1.1.1.1 31-1.2.2.1 32-1.2.2 33-1.2.2.2.r 34-1.2.2.2 35-1.2.2.2.1.1 37-1.2.2.2.1 39-1.2.2.3.2.1.1 40-1.2.2.3.2.1.2 43-1.1.2 44-1.1.2.1.r 45-1.1.2.1.1.1 47-1.1 48-1.1.1.r 50-1.1.1.1 52-1.1.1.1.1.1.1.1 54-1.1.1.1.1.1.1.1 55-1.1.1 56-1.1.1.2.1.1.1.1 58-1.1.1.2.1.1.1.1 59-1.1.1.1.1 59-1.1.1.2.1 61-1.1.1.1 61-1.1.1.2 63-1.1.1.1.2.1 65-1.1.1 66-1.1.1.2.2.1 68-1.1.1.1.2 68-1.1.1.2.2 70-1.1.1.3 (m / multi-sentence :snt2 (a2 / accompany-01~e.47 :ARG0~e.48 (a4 / and~e.55,65 :op1 (i3 / increase-01~e.50,61 :ARG1 (r6 / release-01~e.59 :ARG1 (p4 / protein :name (n6 / name :op1 "IL-6"~e.52,54))) :ARG2 (p6 / product-of~e.68 :op1 100~e.63)) :op2 (i4 / increase-01~e.61 :ARG1 (r7 / release-01~e.59 :ARG1 (p5 / protein :name (n7 / name :op1 "MCP-1"~e.56,58))) :ARG2 (p7 / product-of~e.68 :op1 6.5~e.66)) :mod (r8 / respective~e.70)) :ARG1 (r4 / rise-01~e.43 :ARG1~e.44 (n8 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.45)))) :snt1 (a3 / and :op1 (c / contrast-01~e.1 :ARG2 (i / induce-01~e.6 :ARG0 (s3 / small-molecule :name (n / name :op1 "PGD2")) :ARG2 (s / stimulate-01~e.9 :ARG1~e.10 (a5 / and~e.14 :op1 (e3 / express-03~e.18 :ARG2 (p / protein :name (n2 / name :op1 "IL-6"~e.11,13,21,23)) :mod (r / rapid~e.27)) :op2 (e / express-03~e.18 :ARG2 (p2 / protein :name (n3 / name :op1 "MCP-1"~e.15,17)))) :ARG1-of (m3 / mark-01~e.8)))) :op2 (i2 / increase-01~e.32 :ARG1 (l / level~e.31 :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.30) :ARG0-of (e2 / encode-01 :ARG1 p))) :ARG2~e.33 (m4 / more-than~e.34 :op1 (p3 / product-of~e.37 :quant 50~e.35)) :time (a / after :op1 (s2 / stimulate-01~e.9 :ARG1 e3) :quant (u / up-to :op1 (t / temporal-quantity :quant 1~e.39 :unit (h / hour~e.40))))))) # ::id bel_pmid_1695_1379.27948 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 13 increased Egr @-@ 1 mRNA levels in a biphasic manner in Stat6/ fibroblasts ; early induction of Egr @-@ 1 mRNA was observed 30 min following exposure to IL @-@ 13 and declined after 3 @–@ 6 h ( Fig . 6A ) . Egr @-@ 1 protein was increased in Stat6/ fibroblasts as compared with Stat6/ fibroblasts from 30 min to 3 h after IL @-@ 13 treatment ( Fig . 6 , B and C ) . # ::alignments 0-1.2.1.1.1.1 2-1.2.1.1.1.1 3-1.2.1 4-1.2.1.2.1 5-1.2.1.2.1 6-1.2.1.2.1 7-1.2.1.2.1 8-1.2.1.2 11-1.2.1.3 12-1.2.1.3.r 15-1.1.2 17-1.2.2.1.1.2 18-1.2.2.1.1 19-1.2.2.1.1.1.r 20-1.2.2.1.1.1.2.1.1.1 22-1.2.2.1.1.1.2.1.1.1 23-1.2.2.1.1.1.1.1 25-1.2.2.1 26-1.2.2.1.2.1 27-1.2.2.1.2.2 28-1.2.2.1.1.3 29-1.2.2.1.1.3.1 30-1.2.2.1.1.3.1.2.r 31-1.2.2.1.1.3.1.2 32-1.2.2.1.1.3.1.2 33-1.2.2.1.1.3.1.2 34-1.2 34-1.2.2 34-1.2.2.r 35-1.2.2.2 36-1.2.2.2.2 37-1.2.2.2.2.2.1.1 39-1.2.2.2.2.2.2.1 40-1.2.2.2.2.2.1.2 40-1.2.2.2.2.2.2.2 42-1.2.2.3.1 44-1.2.2.3.1.1 47-1.2.2.1.1.1.2.1.1.1 49-1.1.1.1.1 49-1.2.2.1.1.1.2.1.1.1 50-1.1.1 50-1.1.2.1 50-1.1.2.2.1 50-1.1.3.1.2 50-1.2.1.1 50-1.2.1.4.1 50-1.2.2.1.1.1.2.1 52-1.1 52-1.2.1 55-1.1.2 55-1.1.2.2 55-1.2.1.4 56-1.2.2.2.2.r 57-1.1.2.2.r 60-1.1.2 61-1.1.3.r 62-1.1.3.2.1.1 63-1.1.3.2.1.2 65-1.1.3.2.2.1 66-1.1.3.2.2.2 67-1.1.3 68-1.1.3.1.2.1.1 70-1.1.3.1.2.1.1 71-1.1.3.1 73-1.1.4.1.1 73-1.1.4.1.2 75-1.2.2.2.2.2.2.1 78-1.1.4.1 (m / multi-sentence :snt2 (i3 / increase-01~e.52 :ARG1 (p6 / protein~e.50 :name (n8 / name :op1 "Erg-1"~e.49)) :location (f4 / fibroblast~e.15,55,60 :mod (p7 / protein~e.50 :name (n9 / name :op1 "Stat6")) :compared-to~e.57 (f5 / fibroblast~e.55 :mod (p8 / protein~e.50 :name (n10 / name :op1 "Stat6") :ARG2-of (m3 / mutate-01 :mod "-/-"))) :mod (w2 / wild-type)) :time~e.61 (a3 / after~e.67 :op1 (t6 / treat-04~e.71 :ARG1 f4 :ARG2 (p9 / protein~e.50 :name (n11 / name :op1 "IL-13"~e.68,70))) :quant (b2 / between :op1 (t4 / temporal-quantity :quant 30~e.62 :unit (m4 / minute~e.63)) :op2 (t5 / temporal-quantity :quant 3~e.65 :unit (h3 / hour~e.66)))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.78 :op1 (f6 / figure~e.73 :mod "6B") :op2 (f7 / figure~e.73 :mod "6C")))) :snt1 (a5 / and~e.34 :op1 (i / increase-01~e.3,52 :ARG0 (p / protein~e.50 :name (n / name :op1 "IL-13"~e.0,2)) :ARG1 (l / level~e.8 :quant-of n2~e.4,5,6,7) :manner~e.12 (b / biphasic~e.11) :location (f / fibroblast~e.55 :mod (p3 / protein~e.50 :name (n4 / name :op1 "Stat6")) :mod (w / wild-type))) :op2~e.34 (a / and~e.34 :op1 (o / observe-01~e.25 :ARG1 (i2 / induce-01~e.18 :ARG2~e.19 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.23) :ARG0-of (e2 / encode-01 :ARG1 (p4 / protein~e.50 :name (n6 / name :op1 "Egr-1"~e.20,22,47,49)))) :time (e3 / early~e.17) :ARG1-of (f2 / follow-01~e.28 :ARG2 (e4 / expose-01~e.29 :ARG1 f :ARG2~e.30 p~e.31,32,33))) :duration (t / temporal-quantity :quant 30~e.26 :unit (m2 / minute~e.27))) :op2 (d / decline-01~e.35 :ARG1 i2 :time~e.56 (a2 / after~e.36 :op1 e4 :quant (b3 / between :op1 (t2 / temporal-quantity :quant 3~e.37 :unit (h / hour~e.40)) :op2 (t3 / temporal-quantity :quant 6~e.39,75 :unit (h2 / hour~e.40))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.42 :mod "6A"~e.44))))) # ::id bel_pmid_1695_1379.27954 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PDGF @-@ AA immunostaining was strongly expressed in the lungs of IL @-@ 13 transgene @-@ positive mice and localized to the airway epithelium , airway smooth muscle , and interstitial cells ( Fig . 1 , B @–@ E ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 5-1.1.3 6-1.1 7-1.1.2.r 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1 13-1.1.2.1.1.1.1 16-1.1.2.1.2 17-1.1.2.1 18-1 19-1.2 22-1.2.2.1.1 23-1.2.2.1 25-1.2.2.1.1 26-1.2.2.2.1 27-1.2.2.2 29-1.2.2 30-1.2.2.3.1 31-1.2.2.3 33-1.3.1.1 33-1.3.1.2 (a / and~e.18 :op1 (e / express-03~e.6 :ARG2 (i / immunostain-01~e.3 :ARG3 (p / protein :name (n / name :op1 "PDGF-AA"~e.0,2))) :ARG3~e.7 (l / lung~e.9 :mod~e.10 (m / mouse~e.17 :mod (p3 / protein :name (n3 / name :op1 "IL-13"~e.11,13) :ARG2-of (m3 / mutate-01)) :mod (p2 / positive~e.16))) :ARG1-of (s / strong-02~e.5)) :op2 (b / be-located-at-91~e.19 :ARG1 p :ARG2 (a2 / and~e.29 :op1 (e2 / epithelium~e.23 :mod (a3 / airway~e.22,25)) :op2 (m2 / muscle~e.27 :ARG1-of (s2 / smooth-06~e.26) :mod a3) :op3 (c / cell~e.31 :mod (i2 / interstice~e.30)))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.33 :mod "1B") :op2 (f2 / figure~e.33 :mod "1E")))) # ::id bel_pmid_1695_1379.27956 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PDGF @-@ CC immunostaining was strongly expressed in the lungs of IL @-@ 13 transgene @-@ positive mice and localized to airway epithelium , type II pneumocytes , alveolar macrophages , and fibroblasts ( Fig . 1G ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 5-1.1.3 6-1.1 7-1.1.2.r 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1 13-1.1.2.1.1.1.1 16-1.1.2.1.2 17-1.1.2.1 18-1 19-1.2 21-1.2.2.1.1 22-1.2.2.1 24-1.2.2.2.1.1 25-1.2.2.2.1.2 28-1.2.2.3.2 29-1.2.2.3.1.1 31-1.2.2 32-1.2.2.4 34-1.3.1 36-1.3.1.1 (a / and~e.18 :op1 (e / express-03~e.6 :ARG2 (i / immunostain-01~e.3 :ARG3 (p / protein :name (n / name :op1 "PDGF-CC"~e.0,2))) :ARG3~e.7 (l / lung~e.9 :poss-of~e.10 (m / mouse~e.17 :mod (p3 / protein :name (n2 / name :op1 "IL-13"~e.11,13) :ARG2-of (m2 / mutate-01)) :mod (p2 / positive~e.16))) :ARG1-of (s / strong-02~e.5)) :op2 (b / be-located-at-91~e.19 :ARG1 p :ARG2 (a2 / and~e.31 :op1 (e2 / epithelium~e.22 :mod (a3 / airway~e.21)) :op2 (c / cell :name (n3 / name :op1 "type"~e.24 :op2 "II"~e.25 :op3 "pneumocyte")) :op3 (c2 / cell :name (n4 / name :op1 "macrophage"~e.29) :mod (a4 / alveolus~e.28)) :op4 (f / fibroblast~e.32))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.34 :mod "1G"~e.36))) # ::id bel_pmid_1695_1379.27964 ::amr-annotator SDL-AMR-09 ::preferred # ::tok we observed that IL @-@ 13 caused tyrosine phosphorylation of Stat1 in Stat6/ and Stat6/ fibroblasts ( Fig . 3 , A and C ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1 5-1.2.1.1.1 6-1.2 7-1.2.2.1.1.1 8-1.2.2 10-1.2.2.1.2.1.1 13-1.2.2.2 15-1.2.2.2.1 15-1.2.2.2.2 17-1.3.1.1 17-1.3.1.2 22-1.3.1 (o / observe-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (c / cause-01~e.6 :ARG0 (p2 / protein :name (n / name :op1 "IL-13"~e.3,5)) :ARG1 (p / phosphorylate-01~e.8 :ARG1 (a / amino-acid :name (n2 / name :op1 "tyrosine"~e.7) :part-of (p3 / protein :name (n3 / name :op1 "Stat1"~e.10))) :location (a2 / and~e.13 :op1 (f / fibroblast~e.15 :mod (p4 / protein :name (n4 / name :op1 "Stat6") :ARG2-of (m / mutate-01 :mod "-/-"))) :op2 (f2 / fibroblast~e.15 :mod (p5 / protein :name (n5 / name :op1 "Stat6")) :mod (w2 / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.22 :op1 (f3 / figure~e.17 :mod "3A") :op2 (f4 / figure~e.17 :mod "3C")))) # ::id bel_pmid_1695_1379.27966 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Next , we observed that Stat6 was tyrosine phosphorylated in Stat1/ and Stat1/ fibroblasts ( Fig . 3 , B and D ) . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1 7-1.2.1.2.1.1 8-1.2 11-1.2.2 13-1.2.2.1 13-1.2.2.2 15-1.4.1.1 15-1.4.1.2 20-1.4.1 (o / observe-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (p2 / phosphorylate-01~e.8 :ARG1 (p / protein :name (n / name :op1 "Stat6"~e.5) :part (a / amino-acid :name (n2 / name :op1 "tyrosine"~e.7))) :location (a2 / and~e.11 :op1 (f / fibroblast~e.13 :mod (p3 / protein :name (n3 / name :op1 "Stat1") :ARG2-of (m / mutate-01 :mod "-/-"))) :op2 (f2 / fibroblast~e.13 :mod (p4 / protein :name (n4 / name :op1 "Stat1")) :mod (w2 / wild-type)))) :time (n5 / next~e.0) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.20 :op1 (f3 / figure~e.15 :mod "3B") :op2 (f4 / figure~e.15 :mod "3D")))) # ::id bel_pmid_1695_1379.27992 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A late peak of Egr @-@ 1 mRNA occurred 12 @–@ 24 h after IL @-@ 13 treatment but was not accompanied by an increase in Egr @-@ 1 protein . # ::alignments 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.2.1.1.1 6-1.1.2.2.1.1.1 7-1.1.2.1.1 9-1.1.3.2.1.1 11-1.1.3.2.2.1 12-1.1.3.2.1.2 12-1.1.3.2.2.2 13-1.1.3 14-1.1.3.1.1.1.1 16-1.1.3.1.1.1.1 17-1.1.3.1 18-1 20-1.2.1 20-1.2.1.r 21-1.2 22-1.2.2.r 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1 27-1.2.2.1 28-1.2.2.1 29-1.2.3 (c / contrast-01~e.18 :ARG1 (p / peak~e.2 :mod (l / late~e.1) :mod~e.3 (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.7) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Egr-1"~e.4,6)))) :time (a / after~e.13 :op1 (t / treat-04~e.17 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-13"~e.14,16))) :quant (b / between :op1 (t2 / temporal-quantity :quant 12~e.9 :unit (h / hour~e.12)) :op2 (t3 / temporal-quantity :quant 24~e.11 :unit (h2 / hour~e.12))))) :ARG2 (a2 / accompany-01~e.21 :polarity~e.20 -~e.20 :ARG0~e.22 (i / increase-01~e.24 :ARG1~e.25 p2~e.26,27,28) :ARG1 p~e.29)) # ::id bel_pmid_1695_1379.28002 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 13 @-@ induced PDGF @-@ A and PDGF @-@ C mRNA levels were significantly reduced in fibroblasts isolated from the lungs of Stat6/ mice compared with fibroblasts isolated from the lungs of the wild @-@ type Stat6/ mice ( Fig . 2 , A and B ) . # ::alignments 0-1.1.3.1.2.1 2-1.1.3.1.2.1 4-1.1.3 5-1.1.1.1.3.1.2.1 5-1.1.2.1.3.1.2.1 7-1.1.1.1.3.1.2.1 8-1.1 9-1.1.1.1.3.1.2.1 9-1.1.2.1.3.1.2.1 11-1.1.2.1.3.1.2.1 12-1.1.1.1.2.1 12-1.1.2.1.2.1 13-1.1.1 13-1.1.2 15-1.2 16-1 17-1.3.r 18-1.3 18-1.3.2 19-1.3.1 19-1.3.2.1 20-1.3.2.1.1.r 22-1.3.2.1.1 25-1.3.2.1.1.1 26-1.3.2.r 28-1.3 29-1.3.1 30-1.3.1.1.r 32-1.3.1.1 33-1.3.2.1.1.1.1.r 35-1.3.2.1.1.1.1.3 37-1.3.2.1.1.1.1.3 39-1.3.1.1.1 41-1.4.1.1 41-1.4.1.2 45-1.1.1.1.3.1.2.1 46-1.4.1 (r / reduce-01~e.16 :ARG1 (a / and~e.8 :op1 (l / level~e.13 :quant-of (n8 / nucleic-acid :wiki "Messenger_RNA" :name (n2 / name :op1 "mRNA"~e.12) :ARG0-of (e / encode-01 :ARG1 (p / protein :wiki "PDGFA" :name (n / name :op1 "PDGF-A"~e.5,7,9,45))))) :op2 (l2 / level~e.13 :quant-of (n9 / nucleic-acid :wiki "Messenger_RNA" :name (n4 / name :op1 "mRNA"~e.12) :ARG0-of (e2 / encode-01 :ARG1 (p3 / protein :wiki "PDGFC" :name (n5 / name :op1 "PDGF-C"~e.5,9,11))))) :ARG2-of (i / induce-01~e.4 :ARG0 (p2 / protein :wiki "Interleukin_13" :name (n3 / name :op1 "IL-13"~e.0,2)))) :ARG2 (s / significant-02~e.15) :location~e.17 (f / fibroblast~e.18,28 :ARG1-of (i2 / isolate-01~e.19,29 :ARG2~e.30 (l3 / lung~e.32 :mod (m / mouse~e.39 :mod (p4 / protein :wiki "STAT6" :name (n6 / name :op1 "Stat6") :ARG2-of (m2 / mutate-01 :mod "-/-"))))) :compared-to~e.26 (f2 / fibroblast~e.18 :ARG1-of (i3 / isolate-01~e.19 :ARG2~e.20 (l4 / lung~e.22 :mod (m3 / mouse~e.25 :mod~e.33 (p5 / protein :wiki "STAT6" :name (n7 / name :op1 "Stat6") :mod (w / wild-type~e.35,37))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.46 :op1 (f3 / figure~e.41 :mod "2A") :op2 (f4 / figure~e.41 :mod "2B")))) # ::id bel_pmid_1695_1379.32888 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Egr @-@ 1 has been characterized as a transcriptional regulator of both PDGF @-@ A and PDGF @-@ C gene expression ( 18 , 19 ) . # ::alignments 2-1.1.1.1 5-1 6-1.2.r 8-1.2.2 9-1.2 12-1.2.1.1.1.1.1 12-1.2.1.1.2.1.1 14-1.2.1.1.1.1.1 15-1.2.1.1 16-1.2.1.1.1.1.1 16-1.2.1.1.2.1.1 18-1.2.1.1.2.1.1 19-1.2.1.1.1 19-1.2.1.1.2 20-1.2.1 22-1.3.1.1.1.1 24-1.3.1.1.1.2 (c / characterize-01~e.5 :ARG1 (p / protein :name (n / name :op1 "Erg-1"~e.2)) :ARG2~e.6 (r / regulate-01~e.9 :ARG1 (e / express-03~e.20 :ARG1 (a / and~e.15 :op1 (g / gene~e.19 :name (n2 / name :op1 "PDGF-A"~e.12,14,16)) :op2 (g2 / gene~e.19 :name (n3 / name :op1 "PDGF-C"~e.12,16,18)))) :mod (t / transcribe-01~e.8)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 18~e.22 :op2 19~e.24))))) # ::id bel_pmid_1695_1379.38388 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis demonstrated that PD98059 blocked IL @-@ 13 @-@ induced phosphorylation of ERK1 @/@ 2 ( Fig . 8A ) yet enhanced the phosphorylation of Stat6 and increased protein expression of Egr @-@ 1 in a time @-@ dependent manner after IL @-@ 13 treatment ( Fig . 8 , B and C ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1 5-1.2.1.1.1.1 6-1.2.1 7-1.2.1.2.2.1.1.1 9-1.2.1.2.2.1.1.1 11-1.2.1.2.2 12-1.2.1.2 13-1.2.1.2.1.r 14-1.2.1.2.1.1.1 16-1.2.1.2.1.1.1 18-1.2.1.3.1 20-1.2.1.3.1.1 23-1.2.2.1 25-1.2.2.1.2 27-1.2.2.1.2.1.1.1 28-1.2.2 29-1.2.2.2 30-1.2.1.2.2.1 30-1.2.2.1.2.1 30-1.2.2.2.2.1 31-1.2.2.2.2 35-1.2.2.2.2.1.1.1 38-1.2.2.2.3.r 38-1.2.2.2.4.2 40-1.2.2.2.4 41-1.2.2.2.4.r 42-1.2.2.2.3 43-1.2.2.2.3.1.1 44-1.2.2.2.3.1.1 45-1.2.2.2.3.1.1 46-1.2.2.2.3.1 48-1.2.2.3.1.1 48-1.2.2.3.1.2 53-1.2.2.3.1 (d / demonstrate-01~e.3 :ARG0 (a / analyze-01~e.2 :manner (i3 / immunoblot-01~e.0,1)) :ARG1 (c / contrast-01 :ARG1 (b / block-01~e.6 :ARG0 (s / small-molecule :name (n3 / name :op1 "PD98059"~e.5)) :ARG1 (p / phosphorylate-01~e.12 :ARG1~e.13 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"~e.14,16)) :ARG2-of (i / induce-01~e.11 :ARG0 (p4 / protein~e.30 :name (n6 / name :op1 "IL-13"~e.7,9)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.18 :mod "8A"~e.20))) :ARG2 (a2 / and~e.28 :op1 (e / enhance-01~e.23 :ARG0 s :ARG1 (p5 / phosphorylate-01~e.25 :ARG1 (p6 / protein~e.30 :name (n7 / name :op1 "Stat6"~e.27)))) :op2 (i2 / increase-01~e.29 :ARG0 s :ARG1 (e2 / express-03~e.31 :ARG2 (p7 / protein~e.30 :name (n8 / name :op1 "Erg-1"~e.35))) :time~e.38 (a3 / after~e.42 :op1 (t / treat-04~e.46 :ARG2 p4~e.43,44,45)) :manner~e.41 (d3 / depend-01~e.40 :ARG0 i2 :ARG1 (t2 / time~e.38))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and~e.53 :op1 (f2 / figure~e.48 :mod "8B") :op2 (f3 / figure~e.48 :mod "8C")))))) # ::id bel_pmid_1698_7002.500 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In cycling cells , the effects of Nox1 were dose dependent : levels of Nox1 that induced 3 @- to 10 @-@ fold increases in ROS promoted phosphorylation of ERK1 @/@ 2 and expression of cyclin D1 , # ::alignments 1-1.3.1 2-1.3 5-1.1 6-1.1.1.r 7-1.1.1.1.1 9-1.2 10-1 12-1.4.1.1 13-1.4.1.1.1.r 14-1.4.1.1.1 16-1.4.1.1.2 17-1.4.1.1.2.1.2.1.1 20-1.4.1.1.2.1.2.2.1 22-1.4.1.1.2.1.2.2 23-1.4.1.1.2.1 24-1.4.1.1.2.1.1.r 25-1.4.1.1.2.1.1.1.1 26-1.4.1 27-1.4.1.2.1 28-1.4.1.2.1.1.r 29-1.4.1.2.1.1.1.1 31-1.4.1.2.1.1.1.1 32-1.4.1.2 33-1.4.1.2.2 34-1.4.1.2.2.1.r 35-1.4.1.2.2.1.1.1 36-1.4.1.2.2.1.1.2 (d / depend-01~e.10 :ARG0 (a / affect-01~e.5 :ARG0~e.6 (e / enzyme :name (n / name :op1 "Nox1"~e.7))) :ARG1 (d2 / dose~e.9) :location (c / cell~e.2 :ARG1-of (c2 / cycle-02~e.1)) :ARG1-of (m / mean-01 :ARG2 (p / promote-01~e.26 :ARG0 (l / level~e.12 :quant-of~e.13 e~e.14 :ARG0-of (i / induce-01~e.16 :ARG2 (i2 / increase-01~e.23 :ARG1~e.24 (s / small-molecule :name (n4 / name :op1 "ROS"~e.25)) :ARG2 (b / between :op1 (p4 / product-of :op1 3~e.17) :op2 (p5 / product-of~e.22 :op1 10~e.20))))) :ARG1 (a2 / and~e.32 :op1 (p2 / phosphorylate-01~e.27 :ARG1~e.28 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"~e.29,31))) :op2 (e2 / express-03~e.33 :ARG2~e.34 (p3 / protein :name (n3 / name :op1 "cyclin"~e.35 :op2 "D1"~e.36))))))) # ::id bel_pmid_1700_8315.1518 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Induction of STAT3 Tyr705 and Ser727 phosphorylations by Galpha( s ) QL was suppressed by inhibition of protein kinase A , Janus kinase 2 @/@ 3 , Rac1 , c @-@ Jun N @-@ terminal kinase ( JNK ) , or phosphatidylinositol 3 @-@ kinase , and a similar profile was observed in response to beta2 @-@ adrenergic receptor stimulation # ::alignments 0-1.1.2 1-1.1.2.1.r 2-1.1.2.1.1.3.1.1 4-1.1.2.1.1 6-1.1.2.1 13-1.1 14-1.1.1.r 15-1.1.1 16-1.1.1.1.r 17-1.1.1.1.1.1.1 18-1.1.1.1.1.1.2 19-1.1.1.1.1.1.3 21-1.1.1.1.2.1.1 22-1.1.1.1.2.1.2 23-1.1.1.1.2.1.3 25-1.1.1.1.2.1.3 25-1.1.1.1.5.1.2 27-1.1.1.1.3.1.1 29-1.1.1.1.4.1.1 31-1.1.1.1.4.1.1 32-1.1.1.1.4.1.2 34-1.1.1.1.4.1.2 35-1.1.1.1.2.1.2 35-1.1.1.1.4.1.3 35-1.1.1.1.5.1.2 40-1.1.1.1 41-1.1.1.1.5.1.1 42-1.1.1.1.2.1.3 42-1.1.1.1.5.1.2 44-1.1.1.1.2.1.2 44-1.1.1.1.4.1.3 44-1.1.1.1.5.1.2 48-1.2.1.1 49-1.2.1 51-1.2 52-1.2.1.2.r 53-1.2.1.2 54-1.2.1.2.1.r 55-1.2.1.2.1.1.1.1 57-1.2.1.2.1.1.1.1 58-1.2.1.2.1.1.1.2 59-1.2.1.2.1 (a / and :op1 (s / suppress-01~e.13 :ARG0~e.14 (i2 / inhibit-01~e.15 :ARG1~e.16 (o2 / or~e.40 :op1 (e / enzyme :name (n5 / name :op1 "protein"~e.17 :op2 "kinase"~e.18 :op3 "A"~e.19)) :op2 (e2 / enzyme :name (n6 / name :op1 "Janus"~e.21 :op2 "kinase"~e.22,35,44 :op3 "2/3"~e.23,25,42)) :op3 (p4 / protein :name (n7 / name :op1 "Rac1"~e.27)) :op4 (e3 / enzyme :name (n8 / name :op1 "c-Jun"~e.29,31 :op2 "N-terminal"~e.32,34 :op3 "kinase"~e.35,44)) :op5 (e4 / enzyme :name (n9 / name :op1 "phosphatidylinositol"~e.41 :op2 "3-kinase"~e.25,35,42,44)))) :ARG1 (i / induce-01~e.0 :ARG2~e.1 (p / phosphorylate-01~e.6 :ARG1 (a2 / and~e.4 :op1 (a3 / amino-acid :mod 705 :name (n2 / name :op1 "tyrosine")) :op2 (a4 / amino-acid :mod 727 :name (n3 / name :op1 "serine")) :part-of (p2 / protein :name (n / name :op1 "STAT3"~e.2))) :ARG2 (p3 / protein :name (n4 / name :op1 "Galpha(s)QL"))))) :op2 (o / observe-01~e.51 :ARG1 (p5 / profile~e.49 :ARG1-of (r2 / resemble-01~e.48) :ARG2-of~e.52 (r / respond-01~e.53 :ARG1~e.54 (s3 / stimulate-01~e.59 :ARG1 (p6 / protein :name (n10 / name :op1 "beta2-adrenergic"~e.55,57 :op2 "receptor"~e.58))))))) # ::id bel_pmid_1703_0180.5428 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated KRAS is known to induce tyrosine phosphorylation of beta @-@ catenin , leading to its release from E @-@ cadherin at the adherens junction # ::alignments 0-1.1.2 1-1.1.1.1 3-1.4 5-1 6-1.2.1.1.1 7-1.2 9-1.2.1.2.1.1 11-1.2.1.2.1.1 13-1.3 15-1.3.1.1 15-1.3.1.1.r 16-1.3.1 17-1.3.1.2.r 18-1.3.1.2.1.1 20-1.3.1.2.1.1 21-1.3.1.3.r 23-1.3.1.3.1.1 24-1.3.1.3.1.2 (i / induce-01~e.5 :ARG0 (e / enzyme :name (n / name :op1 "KRAS"~e.1) :ARG1-of (a / activate-01~e.0)) :ARG2 (p2 / phosphorylate-01~e.7 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine"~e.6) :part-of (p3 / protein :name (n2 / name :op1 "beta-catenin"~e.9,11)))) :ARG1-of (l / lead-03~e.13 :ARG2 (r / release-01~e.16 :ARG1~e.15 p3~e.15 :ARG2~e.17 (p4 / protein :name (n3 / name :op1 "E-cadherin"~e.18,20)) :location~e.21 (m / macro-molecular-complex :name (n5 / name :op1 "adherens"~e.23 :op2 "junction"~e.24)))) :ARG1-of (k / know-01~e.3)) # ::id bel_pmid_1708_2637.21974 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TNF @-@ a strongly stimulated FRA @-@ 1 promoter activity in WT MEFs as compared with the erk1-/- MEFs ( Fig . 9B ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1.3 4-1 5-1.2.1.1.1.1.1 7-1.2.1.1.1.1.1 8-1.2.1 8-1.2.1.1 8-1.2.1.1.r 9-1.2 11-1.2.2.2 14-1.2.2.3 20-1.4.1 22-1.4.1.1 (s / stimulate-01~e.4 :ARG0 (p / protein :name (n / name :op1 "TNF-a"~e.0,2)) :ARG1 (a / activity-06~e.9 :ARG0 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.8 (p2 / promote-01~e.8 :ARG1 (p3 / protein :name (n2 / name :op1 "FRA-1"~e.5,7)))) :location (f2 / fibroblast :source (e / embryo :mod (m3 / mouse)) :mod (w / wild-type~e.11) :ARG2-of (c / compare-01~e.14 :ARG1 (f3 / fibroblast :source (e2 / embryo :mod (m / mouse)) :mod (e3 / enzyme :name (n3 / name :op1 "erk1") :ARG2-of (m4 / mutate-01 :mod "-/-")))))) :ARG1-of (s2 / strong-02~e.3) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "9B"~e.22))) # ::id bel_pmid_1708_2637.21978 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the recruitment of c @-@ Jun was strongly enhanced following TNF @-@ a treatment ( Fig . 10B , lanes 3 and 4 ) . In contrast , the binding of c @-@ Jun to the fra @-@ 1 promoter was significantly diminished in MEFS lacking the erk1-/- signaling ( cf lanes 7 and 8 with lanes 3 and 4 ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 5-1.1.1.1.1.1 7-1.1.4 8-1.1 9-1.1.3 10-1.1.3.1.1.1.1 12-1.1.3.1.1.1.1 13-1.1.3.1 15-1.1.2.1.3 17-1.1.2.1.3.1 19-1.1.2.1.1 19-1.1.2.1.2 19-1.2.2.1.2.1 19-1.2.2.1.2.2 20-1.1.2.1.1.1 20-1.2.2.1.2.1.1 21-1.1.2.1 21-1.2.2.1.2 22-1.2.2.1.2.2.1 26-1.2 29-1.2.1.1 30-1.2.1.1.1.r 31-1.2.1.1.1.1.1 33-1.2.1.1.1.1.1 34-1.2.1.1.2.r 36-1.2.1.1.2.1.1.1.1 38-1.2.1.1.2.1.1.1.1 39-1.2.1.1.2 39-1.2.1.1.2.1 39-1.2.1.1.2.1.r 41-1.2.1.2 42-1.2.1 45-1.2.1.3.2 48-1.2.1.3.2.1 51-1.2.2.1.1.1 51-1.2.2.1.1.2 52-1.2.2.1.1.1.1 53-1.2.2.1.1 54-1.2.2.1.1.2.1 56-1.2.2.1.1.2 56-1.2.2.1.2.1 56-1.2.2.1.2.2 57-1.2.2.1.2.1.1 58-1.2.2.1.2 59-1.2.2.1.2.2.1 (m / multi-sentence :snt1 (e2 / enhance-01~e.8 :ARG1 (r / recruit-01~e.1 :ARG1~e.2 (p5 / protein :name (n / name :op1 "c-Jun"~e.3,5))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.21 :op1 (l / lane~e.19 :mod 3~e.20) :op2 (l5 / lane~e.19 :mod 5) :part-of (f / figure~e.15 :mod "10B"~e.17))) :ARG1-of (f2 / follow-01~e.9 :ARG2 (t / treat-04~e.13 :ARG2 (p / protein :name (n2 / name :op1 "TNF-a"~e.10,12)))) :ARG1-of (s / strong-02~e.7)) :snt2 (c / contrast-01~e.26 :ARG2 (d2 / diminish-01~e.42 :ARG1 (b / bind-01~e.29 :ARG1~e.30 (p4 / protein :name (n4 / name :op1 "c-Jun"~e.31,33)) :ARG2~e.34 (m2 / molecular-physical-entity~e.39 :ARG0-of~e.39 (p2 / promote-01~e.39 :ARG1 (p3 / protein :name (n3 / name :op1 "fra-1"~e.36,38))))) :ARG2 (s2 / significant-02~e.41) :location (f3 / fibroblast :source (e4 / embryo :mod (m3 / mouse)) :ARG0-of (l2 / lack-01~e.45 :ARG1 (s3 / signal-07~e.48 :ARG0 (e5 / enzyme :name (n5 / name :op1 "erk1") :ARG2-of (m4 / mutate-01 :mod "-/-")))))) :ARG1-of (c2 / conform-01 :ARG0 (c3 / compare-01 :ARG1 (a2 / and~e.53 :op1 (l3 / lane~e.51 :mod 7~e.52) :op2 (l4 / lane~e.51,56 :mod 8~e.54)) :ARG2 (a3 / and~e.21,58 :op1 (l6 / lane~e.19,56 :mod 3~e.20,57) :op2 (l7 / lane~e.19,56 :mod 4~e.22,59)))))) # ::id bel_pmid_1708_2637.31490 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 9A , TNF @-@ a strongly stimulated both ERK1 and ERK2 phosphorylation in WT cells ( cf lanes 1 and 2 ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 4-1.4.1.1 6-1.1.1.1 8-1.1.1.1 9-1.5 10-1 11-1.2.1.3 12-1.2.1.1.1.1 13-1.2.1 14-1.2.1.2.1.1 15-1.2 16-1.2.2.r 17-1.2.2.1 18-1.2.2 21-1.3.1.1 21-1.3.1.2 22-1.3.1.1.1 24-1.3.1.2.1 (s / stimulate-01~e.10 :ARG0 (p / protein :name (n / name :op1 "TNF-a"~e.6,8)) :ARG1 (p2 / phosphorylate-01~e.15 :ARG1 (a / and~e.13 :op1 (e / enzyme :name (n2 / name :op1 "ERK1"~e.12)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2"~e.14)) :mod (b / both~e.11)) :location~e.16 (c / cell~e.18 :mod (w / wild-type~e.17))) :ARG1-of (c3 / conform-01 :ARG0 (c2 / compare-01 :ARG1 (l / lane~e.21 :mod 1~e.22) :ARG2 (l2 / lane~e.21 :mod 2~e.24))) :ARG1-of (s2 / show-01~e.1 :location~e.2 (f / figure~e.3 :mod "9A"~e.4)) :ARG1-of (s3 / strong-02~e.9)) # ::id bel_pmid_1708_2637.39256 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The -@ 318 TRE mediates c @-@ Jun @-@ dependent , TNF @-@ alpha @-@ inducible FRA @-@ 1 promoter activity ..... Consistent with this result , ectopic expression of a c @-@ Jun mutant lacking the transactivation domain greatly reduced (~ 80 %) TNF @-@ alpha @-@ stimulated promoter activity ( Fig . 2B ) .... However , TNF @-@ a induced the binding of c @-@ Jun to the promoter as early as 30 min ( Fig . 3A , lane 2 ) , and it remained high through 60 min ( Fig . 3A , lane 3 ) . # ::alignments 2-1.1.1.1 3-1.1.1.2.1 4-1.1 5-1.1.2.2.1.1.1 7-1.1.2.2.1.1.1 9-1.1.2.2 11-1.1.2.3.1.1.1 13-1.1.2.3.1.1.1 15-1.1.2.3 16-1.1.2.1.1.1.1.1 18-1.1.2.1.1.1.1.1 19-1.1.2.1 19-1.1.2.1.1 19-1.1.2.1.1.r 20-1.1.2 22-1.2.5 23-1.2.5.1.r 24-1.2.5.1.1 25-1.2.5.1 25-1.2.5.1.2 25-1.2.5.1.2.r 27-1.2.1.2 28-1.2.1 30-1.3.1.1.1.1.1 31-1.2.1.1.1.1 31-1.3.1.1.2.1.1.1 33-1.2.1.1.1.1 33-1.3.1.1.2.1.1.1 34-1.2.1.1 34-1.2.1.1.2 34-1.2.1.1.2.r 35-1.2.1.1.3 37-1.2.1.1.3.1 37-1.2.1.1.3.1.1 37-1.2.1.1.3.1.1.r 39-1.2.4 40-1.2 42-1.2.3.1.1 44-1.2.2.2.1.1.1 46-1.2.2.2.1.1.1 48-1.2.2.2 49-1.2.2.1 49-1.2.2.1.1 49-1.2.2.1.1.r 50-1.2.2 52-1.2.6.1 54-1.2.6.1.1 57-1.3 59-1.3.1.1.1.1.1 61-1.3.1.1.1.1.1 62-1.3.1.1 64-1.3.1.1.2 65-1.3.1.1.2.1.r 66-1.3.1.1.2.1.1.1 68-1.3.1.1.2.1.1.1 69-1.3.1.1.2.2.r 71-1.3.1.1.2.2 71-1.3.1.1.2.2.1 71-1.3.1.1.2.2.1.r 72-1.3.1.1.3.r 73-1.3.1.1.3.1 74-1.3.1.1.3.r 75-1.3.1.1.3.2.1 76-1.3.1.1.3.2.2 78-1.3.1.1.4.1.2 80-1.3.1.1.4.1.2.1 82-1.3.1.1.4.1 83-1.3.1.1.4.1.1 86-1.3.1 87-1.3.1.2.1 88-1.3.1.2 89-1.3.1.2.2 91-1.3.1.2.3.1 92-1.3.1.1.3.2.2 92-1.3.1.2.3.2 94-1.3.1.2.4.1.2 95-1.3.1.2.4.1.2 96-1.3.1.2.4.1.2 98-1.3.1.2.4.1 99-1.3.1.2.4.1.1 (m / multi-sentence :snt1 (m2 / mediate-01~e.4 :ARG0 (d / dna-sequence :mod -318~e.2 :name (n / name :op1 "TRE"~e.3)) :ARG1 (a / activity-06~e.20 :ARG0 (m8 / molecular-physical-entity~e.19 :ARG0-of~e.19 (p / promote-01~e.19 :ARG1 (p2 / protein :name (n2 / name :op1 "FRA-1"~e.16,18)))) :ARG0-of (d2 / depend-01~e.9 :ARG1 (p11 / protein :name (n3 / name :op1 "c-Jun"~e.5,7))) :ARG2-of (i / induce-01~e.15 :ARG0 (p4 / protein :name (n4 / name :op1 "TNF-alpha"~e.11,13)) :ARG1-of (p12 / possible-01)))) :snt2 (r / reduce-01~e.40 :ARG0 (e / express-03~e.28 :ARG2 (e4 / enzyme~e.34 :name (n5 / name :op1 "c-Jun"~e.31,33) :ARG2-of~e.34 (m3 / mutate-01~e.34) :ARG0-of (l / lack-01~e.35 :ARG1 (p7 / protein-segment~e.37 :ARG2-of~e.37 (t / transactivate-01~e.37)))) :mod (e2 / ectopic~e.27)) :ARG1 (a3 / activity-06~e.50 :ARG0 (m6 / molecular-physical-entity~e.49 :ARG0-of~e.49 (p3 / promote-01~e.49)) :ARG1-of (s / stimulate-01~e.48 :ARG0 (p8 / protein :name (n6 / name :op1 "TNF-alpha"~e.44,46)))) :ARG2 (a2 / approximately :op1 (p6 / percentage-entity :value 80~e.42)) :degree (g / great~e.39) :ARG1-of (c / consistent-01~e.22 :ARG2~e.23 (t5 / thing~e.25 :mod (t2 / this~e.24) :ARG2-of~e.25 (r2 / result-01~e.25))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.52 :mod "2B"~e.54))) :snt3 (c2 / contrast-01~e.57 :ARG2 (a4 / and~e.86 :op1 (i2 / induce-01~e.62 :ARG0 (p9 / protein :name (n7 / name :op1 "TNF-a"~e.30,59,61)) :ARG2 (b / bind-01~e.64 :ARG1~e.65 (p10 / protein :name (n8 / name :op1 "c-Jun"~e.31,33,66,68)) :ARG2~e.69 (m7 / molecular-physical-entity~e.71 :ARG0-of~e.71 (p5 / promote-01~e.71))) :time~e.72,74 (a5 / after :mod (e3 / early~e.73) :quant (t3 / temporal-quantity :quant 30~e.75 :unit (m4 / minute~e.76,92))) :ARG1-of (d5 / describe-01 :ARG0 (l2 / lane~e.82 :mod 2~e.83 :part-of (f2 / figure~e.78 :mod "3A"~e.80)))) :op2 (r3 / remain-01~e.88 :ARG1 b~e.87 :ARG3 (h / high-02~e.89 :ARG1 b) :duration (t4 / temporal-quantity :quant 60~e.91 :unit (m5 / minute~e.92)) :ARG1-of (d6 / describe-01 :ARG0 (l3 / lane~e.98 :mod 3~e.99 :part-of f2~e.94,95,96)))))) # ::id bel_pmid_1710_5652.28156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Real @-@ time RT @-@ PCR revealed that IL @-@ 1 beta induced SYN expression at the transcriptional level , because the mRNA level of SYN was upregulated by IL @-@ 1?. TNF-? had a weaker effect on SYN transcription , whereas IL @-@ 6 had no effect # ::alignments 0-1.1.1.2 2-1.1.1.2 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1 7-1.1.2.r 8-1.1.2.1.1.1 12-1.1.2 13-1.1.2.2.1.1.1 14-1.1.2.2 17-1.1.2.3.1 18-1.1.2.3 20-1.1.3 22-1.1.3.1.1.1.1 23-1.1.2.3 23-1.1.3.1.1.2 25-1.2.1.2.1.1.1 27-1.1.3.1 29-1.2.2.2.1.1 35-1.2.1.3 35-1.2.1.3.1 35-1.2.1.3.1.r 36-1.2.1 38-1.2.1.2.1.1.1 39-1.2.1.2 41-1.2 42-1.2.2.2.1.1 44-1.2.2.2.1.1 46-1.2.2.1 46-1.2.2.1.r 47-1.2.2 (m / multi-sentence :snt1 (r / reveal-01~e.6 :ARG0 (t3 / thing :name (n / name :op1 "RT-PCR"~e.3,5) :mod (r2 / real-time~e.0,2)) :ARG1~e.7 (i / induce-01~e.12 :ARG0 (p / protein :name (n2 / name :op1 "IL-1beta"~e.8)) :ARG2 (e2 / express-03~e.14 :ARG2 (e3 / enzyme :name (n3 / name :op1 "SYN"~e.13))) :mod (l / level~e.18,23 :mod (t / transcribe-01~e.17))) :ARG1-of (c / cause-01~e.20 :ARG0 (u / upregulate-01~e.27 :ARG1 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.22) :mod (l2 / level~e.23) :ARG0-of (e5 / encode-01 :ARG1 e3)) :ARG2 (p2 / protein :name (n5 / name :op1 "IL1B"))))) :snt2 (c2 / contrast-01~e.41 :ARG1 (a / affect-01~e.36 :ARG0 (p3 / protein :name (n6 / name :op1 "TNF-α")) :ARG1 (t2 / transcribe-01~e.39 :ARG1 (e4 / enzyme :name (n7 / name :op1 "SYN"~e.25,38))) :ARG1-of (w / weak-02~e.35 :degree~e.35 (m2 / more~e.35))) :ARG2 (a2 / affect-01~e.47 :polarity~e.46 -~e.46 :ARG0 (p4 / protein :name (n8 / name :op1 "IL-6"~e.29,42,44)) :ARG1 t2))) # ::id bel_pmid_1711_8707.35424 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAT3 is also able to prevent cell death through inhibition of the extrinsic apoptotic pathway . This pathway is activated upon binding of extracellular ligands such as FAS ligand ( FAS @-@ L ) to cell @-@ surface death receptors . Upon interaction with FAS @-@ L , the FAS death receptor induces cell death through caspase @-@ 8 activation and truncation of the death agonist BID . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.4 3-1.1 5-1.1.1 6-1.1.1.2.1 7-1.1.1.2 9-1.1.1.3 10-1.1.1.3.1.r 12-1.1.1.3.1.1 13-1.1.1.3.1.2 14-1.1.1.3.1 16-1.2.1.1 17-1.2.1 19-1.2 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1 24-1.2.2.1 24-1.2.2.1.2 25-1.2.2.1.2.r 26-1.2.2.1.2.r 27-1.2.2.1.2.1.1 28-1.2.2.1 28-1.2.2.1.2 30-1.3.4.1.1.1 32-1.3.4.1.1.1 34-1.2.2.2.r 35-1.2.2.2.1.1 37-1.2.2.2.1 38-1.2.2.2.2 39-1.2.2.2 42-1.3.4 44-1.3.4.1.1.1 46-1.3.4.1.1.1 49-1.3.1.1.1 50-1.3.1.1.2 51-1.3.1.1.3 52-1.3 53-1.3.2.1 54-1.3.2 56-1.3.3.1.1.1.1 58-1.3.3.1.1.1.1 59-1.3.3.1 60-1.3.3 61-1.3.3.2 62-1.3.3.2.1.r 64-1.3.3.2.1.1.1 65-1.3.3.2.1.1.2 66-1.3.3.2.1.1.3 (m / multi-sentence :snt1 (p / possible-01~e.3 :ARG1 (p2 / prevent-01~e.5 :ARG0 (p3 / protein :name (n / name :op1 "STAT3"~e.0)) :ARG1 (d / die-01~e.7 :ARG1 (c / cell~e.6)) :ARG3 (i / inhibit-01~e.9 :ARG1~e.10 (p4 / pathway~e.14 :mod (e2 / extrinsic~e.12) :mod (a5 / apoptosis~e.13))) :mod (a / also~e.2))) :snt2 (a2 / activate-01~e.19 :ARG1 (p5 / pathway~e.17 :mod (t / this~e.16)) :time (b / bind-01~e.21 :ARG1~e.22 (l / ligand~e.24,28 :mod (e / extracellular~e.23) :example~e.25,26 (l2 / ligand~e.24,28 :name (n3 / name :op1 "FAS"~e.27))) :ARG2~e.34 (r / receptor~e.39 :location (s / surface~e.37 :part-of (c2 / cell~e.35)) :ARG1-of (d2 / die-01~e.38)))) :snt3 (i2 / induce-01~e.52 :ARG0 (p6 / protein :name (n4 / name :op1 "FAS"~e.49 :op2 "death"~e.50 :op3 "receptor"~e.51)) :ARG2 (d3 / die-01~e.54 :ARG1 (c3 / cell~e.53)) :manner (a3 / and~e.60 :op1 (a4 / activate-01~e.59 :ARG1 (p7 / protein :name (n5 / name :op1 "caspase-8"~e.56,58))) :op2 (t2 / truncate-01~e.61 :ARG1~e.62 (p8 / protein :name (n6 / name :op1 "death"~e.64 :op2 "agonist"~e.65 :op3 "BID"~e.66)))) :time (i3 / interact-01~e.42 :ARG1 (p9 / protein :name (n7 / name :op1 "FAS-L"~e.30,32,44,46))))) # ::id bel_pmid_1711_8707.37686 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These genes can be divided in three classes : one that controls cell @-@ cycle arrest and senescence , one that controls apoptosis and one that regulates glucose metabolism and autophagy [ 42 ] . p53 is essentially known as a pro @-@ apoptotic transcription factor that upregulates the expression of proteins such as BCL2 @-@ associated X protein ( BAX ) , p53 upregulated modulator of apoptosis ( PUMA ) or NOXA . # ::alignments 0-1.2.1.1.1 1-1.2.1.1 2-1.2 4-1.2.1 5-1.2.1.2.r 6-1.2.1.2.1 7-1.2.1.2 7-1.2.1.2.2.1.1 7-1.2.1.2.2.1.2 7-1.2.1.2.2.1.3 11-1.2.1.2.2.1.1.1 12-1.2.1.2.2.1.1.1.1.1.1.1 14-1.2.1.2.2.1.1.1.1.1.1 15-1.2.1.2.2.1.1.1.1.1 16-1.2.1.2.2.1.1.1.1 17-1.2.1.2.2.1.1.1.1.2 21-1.2.1.2.2.1.1.1 21-1.2.1.2.2.1.2.1 22-1.2.1.2.2.1.2.1.1 23-1.2.1.2.2.1.1.1.1 26-1.2.1.2.2.1.3.1 27-1.2.1.2.2.1.3.1.1.1.1 29-1.2.1.2.2.1.3.1.1 30-1.2.1.2.2.1.3.1.1.2 32-1.2.1.3.1.1.1 35-1.1.1.1.1 37-1.1.3 37-1.1.3.r 38-1.1 39-1.1.1.1.r 39-1.1.2.r 41-1.1.2.2 43-1.1.2.2.1 44-1.1.2.1.1 45-1.1.2.1.2 47-1.1.2.3 49-1.1.2.3.1 50-1.1.2.3.1.1.r 51-1.1.2.3.1.1 52-1.1.2.3.1.1.1.r 53-1.1.2.3.1.1.1.r 56-1.1.2.3.1.1.1.1.1.1 57-1.1.2.3.1.1.1.1.1.2 58-1.1.2 58-1.1.2.3.1.1.1.1 58-1.1.2.3.1.1.1.2 58-1.1.2.3.1.1.1.3 63-1.1.2.3.1.1.1.2.1.1 64-1.1.2.3.1.1.1.2.1.2 65-1.1.2.3.1.1.1.2.1.3 66-1.1.2.3.1.1.1.2.1.4 67-1.1.2.3.1.1.1.2.1.5 71-1.1.2.3.1.1.1 72-1.1.2.3.1.1.1.3.1.1 (m / multi-sentence :snt2 (k / know-02~e.38 :ARG1 (p2 / protein :name~e.39 (n / name :op1 "p53"~e.35)) :ARG2~e.39 (p3 / protein~e.58 :name (n2 / name :op1 "transcription"~e.44 :op2 "factor"~e.45) :ARG0-of (f / favor-01~e.41 :ARG1 (a7 / apoptosis~e.43)) :ARG0-of (u / upregulate-01~e.47 :ARG1 (e / express-03~e.49 :ARG2~e.50 (p4 / protein~e.51 :example~e.52,53 (o2 / or~e.71 :op1 (p5 / protein~e.58 :name (n3 / name :op1 "Bcl-2-associated"~e.56 :op2 "X"~e.57)) :op2 (p6 / protein~e.58 :name (n4 / name :op1 "p53"~e.63 :op2 "upregulated"~e.64 :op3 "modulator"~e.65 :op4 "of"~e.66 :op5 "apoptosis"~e.67)) :op3 (p7 / protein~e.58 :name (n5 / name :op1 "NOXA"~e.72))))))) :manner~e.37 (e2 / essential~e.37)) :snt1 (p8 / possible-01~e.2 :ARG1 (d / divide-02~e.4 :ARG1 (g / gene~e.1 :mod (t / this~e.0)) :ARG2~e.5 (c / class~e.7 :quant 3~e.6 :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (c3 / class~e.7 :ARG0-of (c2 / control-01~e.11,21 :ARG1 (a2 / and~e.16,23 :op1 (a3 / arrest-02~e.15 :ARG1 (c4 / cycle-02~e.14 :ARG1 (c7 / cell~e.12))) :op2 (s / senescence~e.17)))) :op2 (c8 / class~e.7 :ARG0-of (c9 / control-01~e.21 :ARG1 (a4 / apoptosis~e.22))) :op3 (c10 / class~e.7 :ARG0-of (r / regulate-01~e.26 :ARG1 (a5 / and~e.29 :op1 (m3 / metabolize-01 :ARG1 (g2 / glucose~e.27)) :op2 (a6 / autophagy~e.30))))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 42~e.32)))))) # ::id bel_pmid_1711_8707.38556 ::amr-annotator SDL-AMR-09 ::preferred # ::tok that IL @-@ 6 and IL @-@ 10 , two cytokines that are known to activate STAT3 , confer a drug @-@ resistant phenotype in renal carcinomas , which was subsequently confirmed in different cancer cell lines such as multiple myeloma [ 72,73 ] . # ::alignments 1-1.1.1.1.1 1-1.1.2.1.1 3-1.1.1.1.1 4-1.1 5-1.1.1.1.1 5-1.1.2.1.1 7-1.1.2.1.1 10-1.1.1 10-1.1.2 13-1.1.3.2 15-1.1.3 16-1.1.3.1.1.1 18-1 20-1.2.1.1 22-1.2.1 23-1.2 24-1.4.r 25-1.4.2 26-1.4.1.1 30-1.2.2.2 30-1.2.2.2.r 31-1.2.2 32-1.2.2.1.r 33-1.2.2.1.1 34-1.2.2.1.2.2.1 35-1.2.2.1 36-1.2.2.1 37-1.2.2.1.2.3.r 38-1.2.2.1.2.3.r 39-1.2.2.1.2.3.1.1 40-1.2.2.1.2.3.1.2 (c / confer-02~e.18 :ARG0 (a / and~e.4 :op1 (c9 / cytokine~e.10 :name (n / name :op1 "IL-6"~e.1,3,5)) :op2 (c10 / cytokine~e.10 :name (n2 / name :op1 "IL-10"~e.1,5,7)) :ARG0-of (a2 / activate-01~e.15 :ARG1 (p / protein :name (n3 / name :op1 "STAT3"~e.16)) :ARG1-of (k / know-01~e.13))) :ARG1 (p4 / phenotype~e.23 :ARG0-of (r / resist-01~e.22 :ARG1 (d / drug~e.20)) :ARG1-of (c3 / confirm-01~e.31 :location~e.32 (c6 / cell-line~e.35,36 :ARG1-of (d3 / differ-02~e.33) :mod (d5 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.34) :example~e.37,38 (d4 / disease :name (n5 / name :op1 "multiple"~e.39 :op2 "myeloma"~e.40)))) :time~e.30 (s / subsequent~e.30))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c8 / cite-01 :ARG2 (a3 / and :op1 72 :op2 73)))) :location~e.24 (m / medical-condition :name (n6 / name :op1 "carcinoma"~e.26) :mod (k2 / kidney~e.25))) # ::id bel_pmid_1711_8707.39772 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , the expression of survivin correlates with STAT3 activation in breast tumors , and the inhibition of this signaling pathway induces apoptosis [ 47,48 ] . Finally , it has also been shown that AKT is a direct target gene of STAT3 , which binds directly to its promoter to enhance its expression [ 49 ] . # ::alignments 0-1.1.3 0-1.1.3.r 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.r 8-1.1.1.2.1.1.1 9-1.1.1.2 10-1.1.1.3.r 11-1.1.1.3.1 12-1.1.1.3 14-1.1 14-1.1.4.1.1.1 16-1.1.2.1 17-1.1.2.1.1.r 18-1.1.2.1.1.1 19-1.1.1.1.1 19-1.1.1.1.1.2 19-1.1.1.1.1.2.r 20-1.1.2.1.1 21-1.1.2 22-1.1.2.2 27-1.2.1 27-1.2.1.r 31-1.2.3 33-1.2 34-1.2.2.r 35-1.2.2.2.1.1 38-1.2.2.3 39-1.2.2 40-1.2.2.2 41-1.2.2.1.r 42-1.2.2.1.1.1 45-1.2.2.1 45-1.2.2.1.2 45-1.2.2.1.2.r 46-1.2.2.3 47-1.2.2.1.2.1.r 48-1.2.2.1.2.1.1.1 48-1.2.2.1.2.1.1.1.r 49-1.2.2.1.2.1 49-1.2.2.1.2.1.1 49-1.2.2.1.2.1.1.r 51-1.2.2.1.2.2 53-1.2.2.1.2.2.2 55-1.2.4.1.1.1 (m / multi-sentence :snt1 (a / and~e.14 :op1 (c / correlate-01~e.6 :ARG1 (e / express-03~e.3 :ARG2~e.4 (p5 / protein~e.19 :name (n4 / name :op1 "survivin"~e.5) :ARG0-of~e.19 (s / signal-07~e.19))) :ARG2~e.7 (a2 / activate-01~e.9 :ARG1 (p / protein :name (n / name :op1 "STAT3"~e.8))) :location~e.10 (t / tumor~e.12 :mod (b / breast~e.11))) :op2 (i / induce-01~e.21 :ARG0 (i2 / inhibit-01~e.16 :ARG1~e.17 (p7 / pathway~e.20 :mod (t2 / this~e.18) :ARG0-of s)) :ARG2 (a3 / apoptosis~e.22)) :manner~e.0 (i3 / important~e.0) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and~e.14 :op1 47 :op2 48))))) :snt2 (s3 / show-01~e.33 :li~e.27 -1~e.27 :ARG1~e.34 (t3 / target-01~e.39 :ARG0~e.41 (p4 / protein~e.45 :name (n2 / name :op1 "STAT3"~e.42) :ARG1-of~e.45 (b2 / bind-01~e.45 :ARG2~e.47 (m2 / molecular-physical-entity~e.49 :ARG0-of~e.49 (p2 / promote-01~e.49 :ARG1~e.48 g~e.48)) :purpose (e2 / enhance-01~e.51 :ARG0 p4 :ARG1 (e3 / express-03~e.53 :ARG1 g)))) :ARG1 (g / gene~e.40 :name (n3 / name :op1 "AKT"~e.35)) :ARG1-of (d2 / direct-02~e.38,46)) :mod (a5 / also~e.31) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 49~e.55))))) # ::id bel_pmid_1712_7443.3208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several transcription factors have also been implicated in megakaryopoiesis including , GATA @-@ 1 , friend of GATA @-@ 1 ( FOG @-@ 1 ) , nuclear factor @-@ erythroid 2 ( NF @-@ E2 ) , and Fli @-@ 1 . # ::alignments 0-1.1.2 1-1.1.1.1 2-1.1.1.2 4-1.3 6-1 7-1.2.r 8-1.2 9-1.1.3 11-1.1.3.1.1.1.1 11-1.1.3.1.2.1.3 13-1.1.3.1.1.1.1 13-1.1.3.1.2.1.3 13-1.1.3.1.4.1.1 15-1.1.3.1.2.1.1 16-1.1.3.1.2.1.2 17-1.1.3.1.1.1.1 17-1.1.3.1.2.1.3 19-1.1.3.1.1.1.1 19-1.1.3.1.2.1.3 19-1.1.3.1.4.1.1 23-1.1.3.1.1.1.1 23-1.1.3.1.2.1.3 23-1.1.3.1.4.1.1 26-1.1.3.1.3.1.1 27-1.1.3.1.3.1.2 29-1.1.3.1.3.1.2 30-1.1.3.1.3.1.3 37-1.1.3.1 38-1.1.3.1.4.1.1 40-1.1.3.1.1.1.1 40-1.1.3.1.2.1.3 40-1.1.3.1.4.1.1 (i / implicate-01~e.6 :ARG1 (p / protein :name (n / name :op1 "transcription"~e.1 :op2 "factor"~e.2) :quant (s / several~e.0) :ARG2-of (i2 / include-91~e.9 :ARG1 (a2 / and~e.37 :op1 (p2 / protein :name (n2 / name :op1 "GATA-1"~e.11,13,17,19,23,40)) :op2 (p3 / protein :name (n5 / name :op1 "friend"~e.15 :op2 "of"~e.16 :op3 "GATA-1"~e.11,13,17,19,23,40)) :op3 (p4 / protein :name (n3 / name :op1 "nuclear"~e.26 :op2 "factor-erythroid"~e.27,29 :op3 2~e.30)) :op4 (p5 / protein :name (n4 / name :op1 "Fli-1"~e.13,19,23,38,40))))) :ARG2~e.7 (m / megakaryopoiesis~e.8) :mod (a / also~e.4)) # ::id bel_pmid_1712_7443.21794 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tyk2 , along with JAK2 , does appear to regulate TPO receptor localization at the plasma membrane by stimulating recycling and enhancing the stability of the receptor in Ba @/@ F3 cells # ::alignments 0-1.1.1.1.1.1 4-1.1.1.2.1.1 7-1 9-1.1 10-1.1.2.1.1.1 11-1.1.2.1.1.2 12-1.1.2 13-1.1.2 15-1.1.2.2.1 16-1.1.2.2 17-1.1.3.r 18-1.1.3.1 19-1.1.3.1.2 20-1.1.3 21-1.1.3.2 23-1.1.3.2.2 24-1.1.3.2.2.1.r 26-1.1.3.2.2.1 27-1.1.3.2.2.2.r 28-1.1.3.2.2.2.1.1 30-1.1.3.2.2.2.1.1 31-1.1.3.2.2.2 (a / appear-02~e.7 :ARG1 (r / regulate-01~e.9 :ARG0 (a3 / and :op1 (e / enzyme :name (n / name :op1 "Tyk2"~e.0)) :op2 (e4 / enzyme :name (n5 / name :op1 "JAK2"~e.4))) :ARG1 (b / be-located-at-91~e.12,13 :ARG1 (p / protein :name (n3 / name :op1 "TPO"~e.10 :op2 "receptor"~e.11)) :ARG2 (m / membrane~e.16 :mod (p2 / plasma~e.15))) :manner~e.17 (a2 / and~e.20 :op1 (s / stimulate-01~e.18 :ARG0 a3 :ARG1 (r2 / recycle-01~e.19)) :op2 (e3 / enhance-01~e.21 :ARG0 a3 :ARG1 (s2 / stability~e.23 :poss~e.24 p~e.26 :location~e.27 (c / cell-line~e.31 :name (n4 / name :op1 "Ba/F3"~e.28,30))))))) # ::id bel_pmid_1712_7443.27130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other notable genes downregulated with GATA @-@ 1 knockdown are the p45 subunit of nuclear factor erythroid @-@ derived 2 ( NF @- E2 ) , JAK2 , and beta1 @-@ tubulin . # ::alignments 0-1.2.1 1-1.2.2 2-1.2 3-1.2.3 4-1.2.3.1.r 5-1.2.3.1.1.1 7-1.2.3.1.1.1 8-1.2.3.1 8-1.2.3.1.2 8-1.2.3.1.2.r 11-1.1.1.2.1.1 12-1.1.1 13-1.1.1.1.r 14-1.1.1.1.1.1 15-1.1.1.1.1.2 16-1.1.1.1.1.3 18-1.1.1.1.1.3 19-1.1.1.1.1.4 26-1.1.2.1.1 28-1.1 29-1.1.3.1.1 31-1.1.3.1.1 (i / include-91 :ARG1 (a / and~e.28 :op1 (s / subunit~e.12 :part-of~e.13 (g4 / gene :name (n4 / name :op1 "nuclear"~e.14 :op2 "factor"~e.15 :op3 "erythroid-derived"~e.16,18 :op4 2~e.19)) :mod (p2 / protein :name (n6 / name :op1 "p45"~e.11))) :op2 (g2 / gene :name (n2 / name :op1 "JAK2"~e.26)) :op3 (g3 / gene :name (n3 / name :op1 "beta1-tubulin"~e.29,31))) :ARG2 (g / gene~e.2 :mod (o / other~e.0) :ARG1-of (n / notable-04~e.1) :ARG1-of (d / downregulate-01~e.3 :ARG2~e.4 (p / protein~e.8 :name (n5 / name :op1 "GATA-1"~e.5,7) :ARG1-of~e.8 (k / knock-down-02~e.8))))) # ::id bel_pmid_1712_7443.29536 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There are two isoforms of 3 beta @- HSD expressed in wild @-@ type megakaryocytes ( I and VI ) , but neither are expressed in NF @-@ E2 null megakaryocytes . # ::alignments 2-1.2.2 3-1.2.2 4-1.2.2 5-1.2.2 6-1.2.2 7-1.2.2 8-1.2.2 9-1.2 11-1.1.2.1 13-1.1.2.1 14-1.1.2 14-1.2.3 16-1.1.1.3.1.1.1.2 17-1.1.1.3.1 21-1 22-1.2.1 22-1.2.1.r 24-1.1 24-1.2 25-1.2.3.1.r 26-1.2.3.1.1.1 28-1.2.3.1.1.1 29-1.2.3.1 29-1.2.3.1.2 29-1.2.3.1.2.1 29-1.2.3.1.2.1.r 29-1.2.3.1.2.r 30-1.1.2 (c / contrast-01~e.21 :ARG1 (e / express-03~e.24 :ARG2 (i / isoform :quant 2 :mod (e2 / enzyme :name (n / name :op1 "3beta-HSD")) :ARG1-of (m / mean-01 :ARG2 (a / and~e.17 :op1 (e4 / enzyme :name (n2 / name :op1 "3beta-HSD" :op2 "I"~e.16)) :op2 (e5 / enzyme :name (n3 / name :op1 "3beta-HSD" :op2 "IV"))))) :ARG3 (m4 / megakaryocyte~e.14,30 :mod (w / wild-type~e.11,13))) :ARG2 (e3 / express-03~e.9,24 :polarity~e.22 -~e.22 :ARG2 i~e.2,3,4,5,6,7,8 :ARG3 (m3 / megakaryocyte~e.14 :mod~e.25 (p / protein~e.29 :name (n5 / name :op1 "NF-E2"~e.26,28) :ARG1-of~e.29 (m2 / mutate-01~e.29 :mod~e.29 "-/-"~e.29))))) # ::id bel_pmid_1712_7443.31646 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TPO is necessary for megakaryocyte maturation in that TPO deficient mice display greatly reduced megakaryocyte production as well as reduced numbers of mature megakaryocytes # ::alignments 0-1.2.1.1 2-1 4-1.1.1 8-1.3.1.1.1.1 10-1.3.1.1 11-1.3.1 12-1.3.1.2.1.2.1 13-1.3.1.2.1.2 14-1.3.1.2.1.1 15-1.3.1.2.1 16-1.3.1.2 17-1.3.1.2 18-1.3.1.2 18-1.3.1.2.r 19-1.3.1.2.2.1 20-1.3.1.2.2 22-1.1 22-1.3.1.2.2.2.1 23-1.1.1 23-1.3.1.2.2.2 (n / need-01~e.2 :ARG0 (m / mature-01~e.22 :ARG1 (m4 / megakaryocyte~e.4,23)) :ARG1 (p2 / protein :name (n2 / name :op1 "TPO"~e.0)) :ARG1-of (c2 / cause-01 :ARG0 (d / display-01~e.11 :ARG0 (m2 / mouse~e.10 :ARG0-of (l / lack-01 :ARG1 p2~e.8)) :ARG1~e.18 (a / and~e.16,17,18 :op1 (p / produce-01~e.15 :ARG1 m4~e.14 :ARG1-of (r / reduce-01~e.13 :degree (g / great~e.12))) :op2 (n3 / number~e.20 :ARG1-of (r2 / reduce-01~e.19) :quant-of (m5 / megakaryocyte~e.23 :ARG1-of (m3 / mature-02~e.22))))))) # ::id bel_pmid_1712_7443.35706 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TPO to c @-@ Mpl ( a receptor tyrosine kinase ) activates both Janus Kinase 2 ( JAK2 ) and Tyk2 # ::alignments 0-1.1.1.1.1 2-1.1.2.1.1 4-1.1.2.1.1 7-1.1.2.2.1.1.1 8-1.1.2.2.1.1.2 9-1.1.2.2.1.1.3 11-1 12-1.3 13-1.2.1.1.1 14-1.2.1.1.2 15-1.2.1.1.3 19-1.2 20-1.2.2.1.1 (a / activate-01~e.11 :ARG0 (a3 / and :op1 (p / protein :name (n3 / name :op1 "TPO"~e.0)) :op2 (p3 / protein :name (n4 / name :op1 "c-Mpl"~e.2,4) :ARG1-of (m / mean-01 :ARG2 (e4 / enzyme :name (n5 / name :op1 "receptor"~e.7 :op2 "tyrosine"~e.8 :op3 "kinase"~e.9))))) :ARG1 (a2 / and~e.19 :op1 (e2 / enzyme :name (n / name :op1 "Janus"~e.13 :op2 "Kinase"~e.14 :op3 2~e.15)) :op2 (e3 / enzyme :name (n2 / name :op1 "Tyk2"~e.20))) :mod (b / both~e.12)) # ::id bel_pmid_1714_2955.38942 ::amr-annotator SDL-AMR-09 ::preferred # ::tok . Furthermore , the bFGF @-@ induced activation of ERK1 @/@ 2 seems to enhance the transcriptional activity of STAT3 . Co @-@ stimulation of KMS @-@ 11 with bFGF and IL @-@ 6 leads to marked expression of STAT3 target genes , such as c @-@ myc and bcl @-@ 2 , further suggesting the relevance of STAT3 phosphorylated at both Tyr705 and Ser727 for the full activation as a transcription factor ( Fig . 5 ) . In addition , the # ::alignments 1-1.1 4-1.1.1.1.1.2.1.1.1 6-1.1.1.1.1.2 7-1.1.1.1.1 8-1.1.1.1.1.1.r 9-1.1.1.1.1.1.1.1 11-1.1.1.1.1.1.1.1 12-1.1.1 14-1.1.1.1 16-1.1.1.1.2.2 17-1.1.1.1.2 18-1.1.1.1.2.1.r 19-1.1.1.1.2.1.1.1 23-1.2.1 24-1.2.1.1.r 25-1.2.1.1.1.1 27-1.2.1.1.1.1 28-1.2.1.2.r 29-1.2.1.2.1.1.1 30-1.2.1.2 31-1.2.1.2.2.1.1 33-1.2.1.2.2.1.1 34-1.2 35-1.2.2.r 36-1.2.2.2 37-1.2.2 38-1.2.2.1.r 39-1.2.2.1.2.1.1.1 40-1.2.2.1.2 41-1.2.2.1 45-1.2.2.1.1.1.1.1.1 47-1.2.2.1.1.1.1.1.1 48-1.2.2.1.1.1 49-1.2.2.1.1.1.2.1.1 51-1.2.2.1.1.1.2.1.1 53-1.2.3.2 54-1.2.3 56-1.2.3.1 57-1.2.3.1.1.r 58-1.2.3.1.1.3 59-1.2.3.1.1.1.2 63-1.2.3.1.1 65-1.2.3.1.2.r 67-1.2.3.1.2.2 68-1.2.3.1.2 69-1.2.3.1.2.1.r 71-1.2.3.1.2.1.1 72-1.2.3.1.2.1 74-1.2.4.1 76-1.2.4.1.1 79-1.2.3.1.1 80-1.2.3.1.1 (m / multi-sentence :snt1 (a / and~e.1 :op2 (s / seem-01~e.12 :ARG1 (e / enhance-01~e.14 :ARG0 (a3 / activate-01~e.7 :ARG1~e.8 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"~e.9,11)) :ARG2-of (i / induce-01~e.6 :ARG0 (p3 / protein :name (n3 / name :op1 "bFGF"~e.4)))) :ARG1 (a2 / activity-06~e.17 :ARG0~e.18 (p / protein :name (n / name :op1 "STAT3"~e.19)) :ARG1 (t / transcribe-01~e.16))))) :snt2 (l / lead-03~e.34 :ARG0 (s2 / stimulate-01~e.23 :ARG1~e.24 (c / cell-line :name (n4 / name :op1 "KMS-11"~e.25,27)) :ARG2~e.28 (a4 / and~e.30 :op1 (p4 / protein :name (n5 / name :op1 "bFGF"~e.29)) :op2 (p5 / protein :name (n6 / name :op1 "IL-6"~e.31,33))) :manner (j / joint)) :ARG1~e.35 (e2 / express-03~e.37 :ARG1~e.38 (g4 / gene~e.41 :ARG2-of (i2 / include-91 :ARG1 (a5 / and~e.48 :op1 (g2 / gene :name (n8 / name :op1 "c-myc"~e.45,47)) :op2 (g3 / gene :name (n9 / name :op1 "bcl-2"~e.49,51)))) :ARG1-of (t2 / target-01~e.40 :ARG0 (p2 / protein :name (n7 / name :op1 "STAT3"~e.39)))) :ARG1-of (m2 / mark-01~e.36)) :ARG0-of (s3 / suggest-01~e.54 :ARG1 (r / relevant-01~e.56 :ARG1~e.57 (a8 / and~e.63,79,80 :op1 (a6 / amino-acid :name (n11 / name :op1 "tyrosine") :ARG1-of (p7 / phosphorylate-01~e.59)) :op2 (a7 / amino-acid :name (n12 / name :op1 "serine") :ARG1-of p7) :part-of p2~e.58) :ARG2~e.65 (a9 / activate-01~e.68 :ARG1~e.69 (f3 / factor~e.72 :ARG0-of (t3 / transcribe-01~e.71)) :ARG1-of (f2 / full-09~e.67))) :degree (f / further~e.53)) :ARG1-of (d / describe-01 :ARG0 (f4 / figure~e.74 :mod 5~e.76)))) # ::id bel_pmid_1714_3332.29844 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of PGC @-@ 1?, PEPCK , and glucose @-@ 6 @-@ phosphatase mRNAs were also significantly increased in fasted KO compared with fasted WT livers ( Table 2 ) , consistent with enhanced glucose production in KO livers . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 5-1.1.1.2.1.1 7-1.1.1 8-1.1.1.3.2.1.1.1 10-1.1.1.3.2.1.1.1 12-1.1.1.3.2.1.1.1 13-1.1.1.3.1.1 15-1.5 16-1.2 17-1 18-1.3.r 19-1.3.1 21-1.3.2 23-1.3.2.1.1 24-1.3.2.1.2 25-1.3 25-1.3.2.1 27-1.3.3.1 28-1.3.3.1.1 31-1.4 32-1.4.1.r 33-1.4.1.2 34-1.4.1.1 35-1.4.1 38-1.4.1.3 (i / increase-01~e.17 :ARG1 (e / express-03~e.0 :ARG2~e.1 (a / and~e.7 :op1 (p / protein :name (n / name :op1 "PGC-1a"~e.2)) :op2 (e2 / enzyme :name (n2 / name :op1 "PEPCK"~e.5)) :op3 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.13) :ARG0-of (e3 / encode-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "glucose-6-phosphatase"~e.8,10,12)))))) :ARG2 (s / significant-02~e.16) :location~e.18 (l2 / liver~e.25 :ARG0-of (f / fast-01~e.19) :ARG1-of (c / compare-01~e.21 :ARG2 (l / liver~e.25 :ARG0-of f~e.23 :mod (w / wild-type~e.24))) :ARG1-of (d / describe-01 :ARG0 (t / table~e.27 :mod 2~e.28)) :ARG2-of (m / mutate-01 :mod "-/-")) :ARG1-of (c2 / consistent-01~e.31 :ARG2~e.32 (p2 / produce-01~e.35 :ARG1 (g / glucose~e.34) :ARG1-of (e4 / enhance-01~e.33) :location l2~e.38)) :mod (a2 / also~e.15)) # ::id bel_pmid_1714_3332.29846 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As analyzed by real @-@ time RT @-@ PCR , levels of SOCS @-@ 3 mRNA and mRNAs of proinflammatory cytokines IL @-@ 1 , IL @-@ 6 , TNF-?, and plasminogen activator inhibitor @–@ 1 ( PAI @-@ 1 ) were increased in fasted KO liver ( Table 2 ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1.2 5-1.4.1.2 6-1.4.1.1.1 8-1.4.1.1.1 10-1.1.1 10-1.1.2 11-1.1.1.1.r 12-1.1.1.1.2.1.1.1 14-1.1.1.1.2.1.1.1 15-1.1.1.1.1.1 15-1.1.2.1.1.1 16-1.1 16-1.1.2.1.2.1 18-1.1.2.1.r 19-1.1.2.1.2.1.1.2 19-1.1.2.1.2.1.1.2.1 19-1.1.2.1.2.1.1.2.1.r 20-1.1.2.1.2.1.1 21-1.1.2.1.2.1.1.1.1.1.1.1 21-1.1.2.1.2.1.1.1.1.2.1.1 23-1.1.2.1.2.1.1.1.1.1.1.1 25-1.1.2.1.2.1.1.1.1.1.1.1 25-1.1.2.1.2.1.1.1.1.2.1.1 27-1.1.2.1.2.1.1.1.1.2.1.1 30-1.1.2.1.2.1.1.1.1 31-1.1.2.1.2.1.2.1.1 32-1.1.2.1.2.1.2.1.2 35-1.1.2.1.2.1.1.1.1.1.1.1 39-1.1.2.1.2.1.1.1.1.1.1.1 42-1 43-1.2.r 44-1.2.1 46-1.2 48-1.3.1 49-1.3.1.1 (i / increase-01~e.42 :ARG1 (a / and~e.16 :op1 (l2 / level~e.10 :quant-of~e.11 (n9 / nucleic-acid :name (n / name :op1 "mRNA"~e.15) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "SOCS-3"~e.12,14))))) :op2 (l3 / level~e.10 :quant-of~e.18 (n10 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.15) :ARG0-of (e3 / encode-01 :ARG1 (a2 / and~e.16 :op1 (c / cytokine~e.20 :ARG2-of (i2 / include-91 :ARG1 (a3 / and~e.30 :op1 (p3 / protein :name (n4 / name :op1 "IL-1"~e.21,23,25,35,39)) :op2 (p4 / protein :name (n5 / name :op1 "IL-6"~e.21,25,27)) :op3 (p5 / protein :name (n7 / name :op1 "TNF-a")))) :ARG0-of (f2 / favor-01~e.19 :ARG1~e.19 (i3 / inflame-01~e.19))) :op2 (p2 / protein :name (n8 / name :op1 "plasminogen"~e.31 :op2 "activator"~e.32 :op3 "inhibitor–1"))))))) :location~e.43 (l / liver~e.46 :ARG0-of (f / fast-01~e.44) :ARG1-of (k / knock-out-03)) :ARG1-of (d / describe-01 :ARG0 (t / table~e.48 :mod 2~e.49)) :ARG1-of (a4 / analyze-01~e.1 :instrument~e.2 (t2 / thing :name (n6 / name :op1 "RT-PCR"~e.6,8) :mod (r / real-time~e.3,5)))) # ::id bel_pmid_1714_3332.29848 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , expression of tribbles 3 ( TRB3 ) protein ( Figure 8C ) and mRNA ( Table 2 ) was increased in fasted KO livers . # ::alignments 0-1.1.1.1 1-1.1.1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1 6-1.1.1.1.1.1.2 10-1.1.1.1.1 12-1.1.1.1.1.2.1 13-1.1.1.1.1.2.1.1 15-1.1.1.1 16-1.1.1.1.2.1.1 18-1.1.1.1.2.2.1 19-1.1.1.1.2.2.1.1 22-1.1 23-1.1.2.r 24-1.1.2.1 26-1.1.2 (a / and :op2 (i / increase-01~e.22 :ARG1 (e / express-03~e.3 :ARG2~e.4 (a2 / and~e.0,1,15 :op1 (p / protein~e.10 :name (n / name :op1 "tribbles"~e.5 :op2 3~e.6) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.12 :mod "8C"~e.13))) :op2 (n3 / nucleic-acid :name (n2 / name :op1 "mrna"~e.16) :ARG1-of (d2 / describe-01 :ARG0 (t / table~e.18 :mod 2~e.19))))) :location~e.23 (l / liver~e.26 :ARG0-of (f2 / fast-01~e.24) :ARG1-of (k / knock-out-03)))) # ::id bel_pmid_1720_0144.37610 ::amr-annotator SDL-AMR-09 ::preferred # ::tok mTORC2 can be activated by PI3K directly and phosphorylates Akt at S473 , which together with phosphorylation at T308 results in the full activation of Akt [ 12,13 ] . # ::alignments 0-1.1.1.2.1.1.1 1-1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.3 7-1 7-1.3.1.1.1 8-1.2 8-1.2.3 9-1.2.3.1.3 15-1.2.3.r 16-1.2 16-1.2.3 19-1.2.4 20-1.2.4.1.r 22-1.2.4.1.2 23-1.2.4.1 24-1.2.4.1.1.r 25-1.2.4.1.1 (a / and~e.7 :op1 (p / possible-01~e.1 :ARG1 (a2 / activate-01~e.3 :ARG0~e.4 (e / enzyme :name (n / name :op1 "PI3K"~e.5)) :ARG1 (m / macro-molecular-complex :part (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC2"~e.0))) :ARG1-of (d / direct-02~e.6))) :op2 (p3 / phosphorylate-01~e.8,16 :ARG1 (a3 / amino-acid :mod 473 :name (n4 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Akt"))) :ARG2 m2 :accompanier~e.15 (p5 / phosphorylate-01~e.8,16 :ARG1 (a4 / amino-acid :mod 308 :name (n5 / name :op1 "tyrosine") :part-of e2~e.9)) :ARG1-of (r / result-01~e.19 :ARG2~e.20 (a5 / activate-01~e.23 :ARG1~e.24 e2~e.25 :ARG1-of (f / full-09~e.22)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a6 / and~e.7 :op1 12 :op2 13))))) # ::id bel_pmid_1720_0144.38486 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The intracellular signaling induced by IL @-@ 4/IL @-@ 4R interactions on CD4 T cells has been characterized in great detail . The binding of IL @-@ 4 to the Type I receptor in CD4 T cells induces the activation of the nonreceptor tyrosine kinase Jak1 , which promotes the phosphorylation of STAT6 . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1.1.2 4-1.1.1.2.1.r 5-1.1.1.2.1.1.1.1 5-1.1.1.2.1.2.1.1 9-1.1.1.2.1.2.1.1 10-1.1.1.2.1 12-1.2.1.3.1.1 13-1.2.1.3.1.2 14-1.1.1.2.1.3 14-1.2.1.3 17-1.1 18-1.1.2.r 19-1.1.2.1 20-1.1.2 23-1.2.1 24-1.2.1.1.r 25-1.2.1.1.1.1 27-1.2.1.1.1.1 28-1.2.1.2.r 30-1.2.1.2.1.1 31-1.2.1.2.1.2 32-1.2.1.2.1.3 34-1.2.1.3.1.1 35-1.2.1.3.1.2 36-1.2.1.3 37-1.2 39-1.2.2 40-1.2.2.1.r 42-1.2.2.1.1.1 43-1.2.2.1.1.2 44-1.2.2.1.1.3 45-1.2.2.1.1.4 48-1.2.2.1 48-1.2.2.1.2 48-1.2.2.1.2.r 50-1.2.2.1.2.1 51-1.2.2.1.2.1.1.r 52-1.2.2.1.2.1.1.1.1 (m / multi-sentence :snt1 (c / characterize-01~e.17 :ARG1 (s / signal-07~e.2 :mod (i / intracellular~e.1) :ARG2-of (i2 / induce-01~e.3 :ARG0~e.4 (i3 / interact-01~e.10 :ARG0 (p / protein :name (n / name :op1 "IL-4"~e.5)) :ARG1 (p2 / protein :name (n2 / name :op1 "IL-4R"~e.5,9)) :location (c2 / cell~e.14 :name (n3 / name :op1 "CD4T"))))) :manner~e.18 (d / detail-01~e.20 :degree (g / great~e.19))) :snt2 (i4 / induce-01~e.37 :ARG0 (b / bind-01~e.23 :ARG1~e.24 (p3 / protein :name (n4 / name :op1 "IL-4"~e.25,27)) :ARG2~e.28 (p4 / protein :name (n5 / name :op1 "Type"~e.30 :op2 "I"~e.31 :op3 "receptor"~e.32)) :location (c3 / cell~e.14,36 :name (n6 / name :op1 "CD4"~e.12,34 :op2 "T"~e.13,35))) :ARG2 (a / activate-01~e.39 :ARG1~e.40 (e / enzyme~e.48 :name (n7 / name :op1 "nonreceptor"~e.42 :op2 "tyrosine"~e.43 :op3 "kinase"~e.44 :op4 "Jak1"~e.45) :ARG0-of~e.48 (p5 / promote-01~e.48 :ARG1 (p6 / phosphorylate-01~e.50 :ARG1~e.51 (p7 / protein :name (n8 / name :op1 "STAT6"~e.52)))))))) # ::id bel_pmid_1723_4180.3578 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Marimastat ( 100 mg/kg ) , dexamethasone ( 10 mg/kg ) and rolipram ( 0.3 mg/kg ) reduced significantly IL @-@ 6 , KC/CXCL1 , MIP @-@ 1 alpha @/@ CCL3 and MMP @-@ 9 levels in bronchoalveolar lavage fluid . # ::alignments 0-1.1.1.1.1 2-1.1.1.2.1 6-1.1.2.1.1 8-1.1.2.2.1 11-1.1 12-1.1.3.1.1 14-1.1.3.2.1 17-1 18-1.3 19-1.2.1.1.1.1 21-1.2.1.1.1.1 23-1.2.2.1.1.1 25-1.2.3.1.1.1 30-1.2.3.1.1.1 31-1.2 32-1.2.4.1.1.1 34-1.2.4.1.1.1 35-1.2.1 35-1.2.2 35-1.2.3 35-1.2.4 36-1.4.r 37-1.4.2 38-1.4.1 39-1.4 (r / reduce-01~e.17 :ARG0 (a / and~e.11 :op1 (s2 / small-molecule :name (n5 / name :op1 "marimastat"~e.0) :quant (c2 / concentration-quantity :quant 100~e.2 :unit (m / milligram-per-kilogram))) :op2 (s3 / small-molecule :name (n6 / name :op1 "dexamethasone"~e.6) :quant (c / concentration-quantity :quant 10~e.8 :unit (m2 / milligram-per-kilogram))) :op3 (s4 / small-molecule :name (n7 / name :op1 "rolipram"~e.12) :quant (c3 / concentration-quantity :quant 0.3~e.14 :unit (m3 / milligram-per-kilogram)))) :ARG1 (a2 / and~e.31 :op1 (l / level~e.35 :quant-of (p / protein :name (n / name :op1 "IL-6"~e.19,21))) :op2 (l3 / level~e.35 :quant-of (p2 / protein :name (n2 / name :op1 "KC/CXCL1"~e.23))) :op3 (l4 / level~e.35 :quant-of (p3 / protein :name (n3 / name :op1 "MIP-1alpha/CCL3"~e.25,30))) :op4 (l5 / level~e.35 :quant-of (e2 / enzyme :name (n4 / name :op1 "MMP-9"~e.32,34)))) :ARG2 (s / significant-02~e.18) :location~e.36 (f / fluid~e.39 :mod (l2 / lavage~e.38) :mod (b / bronchoalveolar~e.37))) # ::id bel_pmid_1729_2829.29076 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nox1 and Nox4 mRNAs were upregulated in H @-@ RasV12 @-@ transformed p38??/? MEFs , suggesting that these two NOX family members may be involved in H @-@ RasV12 @-@ induced ROS production in fibroblasts ( Figure S5B ) . # ::alignments 0-1.1.1.2.1.1.1 1-1.1 2-1.1.2.2.1.1.1 3-1.1.1.1.1 3-1.1.2.1.1 5-1 6-1.4.r 7-1.4.3.1 11-1.4.3 13-1.4.1.1 15-1.2 18-1.2.1.1.1.1 19-1.2.1.1.1.3.1.1.1 20-1.2.1.1.1.3.1 21-1.2.1.1.1 22-1.2.1 24-1.2.1.1 25-1.2.1.1.2.r 26-1.2.1.1.2.2.1.1.1 30-1.2.1.1.2.2 31-1.2.1.1.2.1.1.1 32-1.2.1.1.2 36-1.3.1 37-1.3.1.1 (u / upregulate-01~e.5 :ARG1 (a / and~e.1 :op1 (n10 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.3) :ARG0-of (e5 / encode-01 :ARG1 (e / enzyme :name (n6 / name :op1 "Nox1"~e.0)))) :op2 (n11 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.3) :ARG0-of (e6 / encode-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "Nox4"~e.2))))) :ARG0-of (s / suggest-01~e.15 :ARG1 (p / possible-01~e.22 :ARG1 (i / involve-01~e.24 :ARG1 (m / member~e.21 :quant 2~e.18 :ARG1-of (m4 / mean-01 :ARG2 a) :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family~e.20 :name (n / name :op1 "NOX"~e.19)))) :ARG2~e.25 (p2 / produce-01~e.32 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ROS"~e.31)) :ARG2-of (i2 / induce-01~e.30 :ARG0 (e4 / enzyme :name (n3 / name :op1 "H-Ras"~e.26) :ARG2-of (m3 / mutate-01 :value "V12"))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.36 :mod "S5B"~e.37)) :location~e.6 (c / cell :name (n8 / name :op1 "MEF"~e.13) :mod (e3 / enzyme :name (n9 / name :op1 "p38")) :ARG1-of (t2 / transform-01~e.11 :ARG0 e4~e.7))) # ::id bel_pmid_1729_9132.25542 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Papillary adenomas ( 1.2.1.2.2 ) were detected 6 @–@ 8 wk after BRafVE expression and appeared to increase in number and size . These lesions were bronchiolocentric , but did not appear to involve the terminal bronchioles . Rather , the lesions appeared to arise in alveolar ducts and expand outward and around bronchioles ( Fig . 4B ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1.1 1-1.1.2.1.1.1.1 3-1.1.1.1.3.1.1 6-1.1.1 7-1.1.1.2.2.1.1 9-1.1.1.2.2.2.1 11-1.1.1.2 13-1.1.1.2.1 14-1.1 15-1.1.2 17-1.1.2.1 18-1.1.2.1.1.r 19-1.1.2.1.1.1 20-1.1.2.1.1 21-1.1.2.1.1.2 23-1.3.1.1.1 24-1.3.1.1 25-1.3.1.1.r 26-1.3.1 28-1.3 30-1.3.2.1 30-1.3.2.1.r 31-1.3.2 33-1.3.2.2 35-1.3.2.2.1.1 36-1.3.2.2.1 38-1.4.2 41-1.4.1.1.1 42-1.4 44-1.4.1.1 45-1.4.1.1.2.r 46-1.4.1.1.2.1 47-1.4.1.1.2 48-1.4.1 49-1.4.1.2 50-1.4.1.2.2.1 51-1.4.1.2.2 52-1.4.1.2.2.2 53-1.4.1.2.2.1.1 55-1.2.1 55-1.5.1 57-1.2.1.1 57-1.5.1.1 (m / multi-sentence :snt1 (a / and~e.14 :op1 (d / detect-01~e.6 :ARG1 (m3 / medical-condition :name (n3 / name :op1 "adenoma"~e.1) :mod (p / papilla~e.0) :ARG1-of (l2 / label-01 :ARG2 (s2 / string-entity :value "1.2.1.2.2"~e.3))) :time (a4 / after~e.11 :op1 (e / express-03~e.13 :ARG2 (e2 / enzyme :name (n / name :op1 "BRaf") :ARG2-of (m2 / mutate-01 :value "VE"))) :quant (b5 / between :op1 (t / temporal-quantity :quant 6~e.7 :unit (w / week)) :op2 (t3 / temporal-quantity :quant 8~e.9 :unit (w2 / week))))) :op2 (a2 / appear-02~e.15 :ARG1 (i / increase-01~e.17 :ARG1~e.18 (a12 / and~e.20 :op1 (n2 / number~e.19 :quant-of (a3 / adenoma~e.1)) :op2 (s / size~e.21 :poss-of a3))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.55 :mod "4B"~e.57)) :snt2 (c / contrast-01~e.28 :ARG1 (b / bronchiolocentric~e.26 :domain~e.25 (l / lesion~e.24 :mod (t5 / this~e.23))) :ARG2 (a5 / appear-02~e.31 :polarity~e.30 -~e.30 :ARG1 (i2 / involve-01~e.33 :ARG1 (b3 / bronchiole~e.36 :mod (t2 / terminus~e.35)) :ARG2 l))) :snt3 (a6 / appear-02~e.42 :ARG1 (a8 / and~e.48 :op1 (a7 / arise-02~e.44 :ARG1 (l3 / lesion~e.41) :location~e.45 (d3 / duct~e.47 :part-of (a9 / alveolus~e.46))) :op2 (e3 / expand-01~e.49 :ARG1 l3 :location (a10 / and~e.51 :op1 (o / outward~e.50 :op1 (b4 / bronchiole~e.53)) :op2 (a11 / around~e.52 :op1 b4)))) :mod (r / rather~e.38)) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.55 :mod "4B"~e.57))) # ::id bel_pmid_1729_9132.25544 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At early times after induced BRafVE expression , we detected evidence of epithelial hyperplasia ( classified as 1.1.1.1 ) arising within the terminal bronchioles and within the central lung parenchyma . # ::alignments 1-1.3.1 2-1.3 2-1.3.r 2-1.4.r 3-1.4 4-1.4.1.2 5-1.4.1.1.1.1 6-1.4.1 8-1.1 9-1 10-1.2 11-1.2.1.r 12-1.2.1.1 13-1.2.1 15-1.2.1.3 16-1.2.1.3.1.r 16-1.4.r 17-1.2.1.3.1.1 19-1.2.1.2 20-1.4 22-1.2.1.2.1.1.1 23-1.2.1.2.1.1 24-1.2.1.2.1 25-1.4 27-1.2.1.2.1.2.1.1 28-1.2.1.2.1.2.1 29-1.2.1.2.1.2 (d / detect-01~e.9 :ARG0 (w / we~e.8) :ARG1 (e / evidence-01~e.10 :ARG1~e.11 (h / hyperplasia~e.13 :mod (e2 / epithelium~e.12) :ARG1-of (a / arise-02~e.19 :location (a2 / and~e.24 :op1 (b / bronchiole~e.23 :mod (t / terminal~e.22)) :op2 (p / parenchyma~e.29 :mod (l / lung~e.28 :mod (c / central~e.27))))) :ARG1-of (c2 / classify-01~e.15 :ARG2~e.16 (s / string-entity :value "1.1.1.1"~e.17)))) :time~e.2 (t2 / time~e.2 :mod (e3 / early~e.1)) :time~e.2,16 (a3 / after~e.3,20,25 :op1 (e4 / express-03~e.6 :ARG2 (e5 / enzyme :name (n / name :op1 "BRafVE"~e.5) :ARG2-of (m / mutate-01 :value "VE")) :ARG2-of (i / induce-01~e.4)))) # ::id bel_pmid_1729_9132.25548 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the majority of cells within BRafVE @-@ induced tumors expressed SP @-@ C , suggesting that they have properties of ATII pneumocytes ( Fig . 2K , L ) . # ::alignments 1-1.2.1 3-1.2 3-1.2.2.1 4-1.2.1.r 7-1.2.2.1.1.1 8-1.2.2.1.1 9-1 10-1.1.1.1 12-1.1.1.1 14-1.3 15-1.3.1.r 16-1.3.1.1 17-1.3.1 18-1.3.1.2 19-1.3.1.2.1.r 20-1.3.1.2.1.1.1 23-1.4.1.1 23-1.4.1.2 25-1.4.1.1.1 (e / express-03~e.9 :ARG2 (p5 / protein :name (n4 / name :op1 "SP-C"~e.10,12)) :ARG3 (c2 / cell~e.3 :quant~e.4 (m / majority~e.1) :ARG1-of (i / include-91 :ARG2 (c3 / cell~e.3 :location (t / tumor~e.8 :ARG2-of (i2 / induce-01~e.7 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf") :ARG2-of (m2 / mutate-01 :value "VE"))))))) :ARG0-of (s / suggest-01~e.14 :ARG1~e.15 (h / have-03~e.17 :ARG0 c2~e.16 :ARG1 (p / property~e.18 :poss~e.19 (c / cell :name (n / name :op1 "ATII"~e.20 :op2 "pneumocyte"))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.23 :mod "2K"~e.25) :op2 (f2 / figure~e.23 :mod "2L")))) # ::id bel_pmid_1729_9132.28748 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is reported that KRasG12D @-@ induced lung tumors do not routinely display elevated pERK1 @/@ 2 but display stress @-@ activated MAP kinase ( SAPK/JNK ) activation ( Lee et al. 2002 ) ... Interestingly , the major difference appears to be that expression of KRasG12D in the lung leads to more rapid and consistent progression to adenocarcinoma than that elicited by BRafVE . # ::alignments 2-1.2 6-1.2.1.1.2.2 7-1.2.1.1.2.1 8-1.2.1.1.2 10-1.2.1.1.1 10-1.2.1.1.1.r 11-1.2.1.1.4 12-1.2.1.1 13-1.2.1.1.3.2 16-1.2.1.1.3.1.1 17-1.2.1 18-1.2.1.2 19-1.2.1.2.1.1.2.1 21-1.2.1.2.1 21-1.2.1.2.1.1.2 22-1.2.1.2.1.1.1.1 23-1.2.1.2.1.1.1.2 25-1.2.1.2.1.1.3.1.1.1 27-1.2.1.2.1.1.2 29-1.2.2.1.1.1.1.1 30-1.2.2.1.1 31-1.2.2.1.1.2.1 32-1.2.2.2.1 35-1.1.2 38-1.1.1.3 39-1.1.1 40-1.1 43-1.1.1.1.r 44-1.1.1.1.1 47-1.1.1.1.1.2.r 49-1.1.1.1.1.2 50-1.1.1.1 51-1.1.1.1.2.r 52-1.1.1.1.2.2.1 53-1.1.1.1.2.2 55-1.1.1.1.2.3 56-1.1.1.1.2 56-1.1.1.2 57-1.1.1.1.2.1.r 58-1.1.1.1.2.1.1.1 61-1.1.1.2.2 (m / multi-sentence :snt2 (a / appear-01~e.40 :ARG1 (d / differ-02~e.39 :ARG1~e.43 (l2 / lead-03~e.50 :ARG0 (e2 / express-03~e.44 :ARG2 (e6 / enzyme :name (n2 / name :op1 "KRAS") :ARG2-of (m3 / mutate-01 :value "G12D")) :ARG3~e.47 (l / lung~e.49)) :ARG2~e.51 (p / progress-01~e.56 :ARG4~e.57 (m8 / medical-condition :name (n6 / name :op1 "adenocarcinoma"~e.58)) :mod (r / rapid~e.53 :degree (m5 / more~e.52)) :ARG1-of (c / consistent-02~e.55 :degree m5))) :ARG2 (p6 / progress-01~e.56 :ARG4 (a3 / adenocarcinoma) :ARG1-of (e3 / elicit-01~e.61 :ARG0 (e4 / enzyme :name (n / name :op1 "Braf") :ARG2-of (m6 / mutate-01 :value "VE")))) :ARG1-of (m2 / major-02~e.38)) :ARG2-of (i / interest-01~e.35)) :snt1 (r2 / report-01~e.2 :ARG1 (c3 / contrast-01~e.17 :ARG1 (d4 / display-01~e.12 :polarity~e.10 -~e.10 :ARG0 (t / tumor~e.8 :location (l4 / lung~e.7) :ARG2-of (i2 / induce-01~e.6 :ARG0 (e7 / enzyme :name (n4 / name :op1 "KRAS") :ARG1-of (m4 / mutate-01 :value "G12D")))) :ARG1 (e / enzyme :name (n5 / name :op1 "ERK1/2"~e.16) :ARG1-of (e5 / elevate-01~e.13) :ARG3-of (p4 / phosphorylate-01)) :mod (r3 / routine~e.11)) :ARG2 (d5 / display-01~e.18 :ARG1 (a5 / activate-01~e.21 :ARG1 (p9 / pathway :name (n8 / name :op1 "MAP"~e.22 :op2 "kinase"~e.23) :ARG1-of (a6 / activate-01~e.21,27 :ARG0 (s / stress-02~e.19)) :ARG1-of (m7 / mean-01 :ARG2 (p7 / pathway :name (n7 / name :op1 "SAPK/JNK"~e.25))))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and~e.30 :op1 (p2 / person :name (n3 / name :op1 "Lee"~e.29)) :op2 (p3 / person :mod (o / other~e.31)))) :time (d3 / date-entity :year 2002~e.32)))) # ::id bel_pmid_1730_3558.25228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - As shown in Fig. 1A , ERK1 @/@ 2 in wild @-@ type MEFs is phosphorylated after IGF @-@ 1 stimulation with a peak at 5 @–@ 10 min , after which pERK declined substantially . In b @-@ arrestin1 KO MEFs , on the other hand , ERK1 @/@ 2 remained essentially inactivated upon IGF @-@ 1 stimulation ( Fig . 1A ) . # ::alignments 0-1.2.r 1-1.2.1 2-1.2 5-1.3.1.2 7-1.1.1.3.1 7-1.3.1.2.1 8-1.1.1.3.1.1 10-1.3.1.1.1.1 12-1.3.1.1.1.1 14-1.3.1.3.2 16-1.3.1.3.2 17-1.3.1.3.1.1 19-1.3.1 20-1.3.1.4 21-1.3.1.4.1.1.1.1 23-1.3.1.4.1.1.1.1 24-1.3.1.4.1 27-1.3.1.5 29-1.3.1.5.1.1.1 31-1.3.1.5.1.2.1 32-1.3.1.5.1.1.2 32-1.3.1.5.1.2.2 34-1.3.1.4 34-1.3.2.3 36-1.3.1 36-1.3.2.1.1.1 36-1.3.2.1.2 37-1.3.2 38-1.3.2.2 41-1.1.1.4.2.1.1 43-1.1.1.4.2.1.1 45-1.1.1.4.1.1 52-1.1.1.1.2.1.1 54-1.1.1.1.2.1.1 55-1.1.1 56-1.1.1.2 56-1.1.1.2.r 57-1.1.1.1.1 59-1.1.1.1.3.1.1.1 59-1.3.1.4.1.1.1.1 61-1.1.1.1.3.1.1.1 61-1.3.1.4.1.1.1.1 62-1.1.1.1.3 62-1.3.1.4.1 64-1.3.1.2.1 66-1.3.1.2.1.1 (m / multi-sentence :snt2 (c3 / contrast-01 :ARG2 (r / remain-01~e.55 :ARG1 (a / activate-01 :polarity -~e.57 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2"~e.52,54)) :time (s / stimulate-01~e.62 :ARG0 (p3 / protein :name (n2 / name :op1 "IGF-1"~e.59,61)))) :manner~e.56 (e / essential~e.56) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.7 :mod "1A"~e.8)) :location (c / cell :name (n8 / name :op1 "MEF"~e.45) :mod (p4 / protein :name (n3 / name :op1 "b-arrestin1"~e.41,43) :ARG2-of (m4 / mutate-01 :mod "-/-"))))) :source~e.0 (t2 / text~e.2 :ARG1-of (f3 / full-09~e.1)) :snt1 (a3 / and :op1 (p / phosphorylate-01~e.19,36 :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK1/2"~e.10,12)) :ARG1-of (s2 / show-01~e.5 :ARG0 (f2 / figure~e.7,64 :mod "1A"~e.66)) :location (c2 / cell :name (n4 / name :op1 "MEF"~e.17) :mod (w / wild-type~e.14,16)) :time (a2 / after~e.20,34 :op1 (s3 / stimulate-01~e.24,62 :ARG0 (p5 / protein :name (n5 / name :op1 "IGF-1"~e.21,23,59,61)))) :ARG1-of (p6 / peak-01~e.27 :time (b / between :op1 (t / temporal-quantity :quant 5~e.29 :unit (m2 / minute~e.32)) :op2 (t3 / temporal-quantity :quant 10~e.31 :unit (m3 / minute~e.32))))) :op2 (d2 / decline-01~e.37 :ARG1 (e4 / enzyme :name (n6 / name :op1 "ERK"~e.36) :ARG3-of (p2 / phosphorylate-01~e.36)) :degree (s4 / substantial~e.38) :time (a4 / after~e.34 :op1 p6)))) # ::id bel_pmid_1730_3558.27774 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - Similarly , we find that both b @-@ arrestin1 and 2 are ubiquitinated in IGF @-@ 1 @-@ stimulated WT MEF cells . # ::alignments 0-1.4.r 1-1.4.1 2-1.4 4-1.3 6-1.1 7-1 10-1.2.1.1.1.1 10-1.2.1.2.1.1 12-1.2.1.1.1.1 13-1.2.1 16-1.2 17-1.2.2.r 18-1.2.2.3.1.1.1 20-1.2.2.3.1.1.1 22-1.2.2.3 23-1.2.2.2 24-1.2.2.1.1 25-1.2.2 (f / find-01~e.7 :ARG0 (w / we~e.6) :ARG1 (u / ubiquitinate-01~e.16 :ARG1 (a / and~e.13 :op1 (p / protein :name (n / name :op1 "b-arrestin1"~e.10,12)) :op2 (p2 / protein :name (n2 / name :op1 "b-arrestin2"~e.10))) :location~e.17 (c / cell~e.25 :name (n3 / name :op1 "MEF"~e.24) :mod (w2 / wild-type~e.23) :ARG1-of (s / stimulate-01~e.22 :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1"~e.18,20))))) :ARG1-of (r / resemble-01~e.4) :source~e.0 (t / text~e.2 :ARG1-of (f2 / full-09~e.1))) # ::id bel_pmid_1732_0860.11808 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the preincubation of RAW264.7 cells with a specific PPARalpha agonist , K @-@ 111 ( 2,2 @-@ dichloro @-@ 12-( 4 @-@ chlorophenyl ) dodecanoic acid ) . K @-@ 111 reduced both the IL @-@ 6 production and mRNA expression in RAW264.7 cells # ::alignments 3-1.1.1.1.1 4-1.1.1 7-1.1.2.3 8-1.1.2.2.1.1 9-1.1.2 9-1.2.1 11-1.1.2.1.1 11-1.2.1.1.1 13-1.1.2.1.1 13-1.2.1.1.1 15-1.2.1.2.1.1.1 17-1.2.1.2.1.1.1 25-1.2.1.2.1.1.2 28-1.2.1.1.1 30-1.2.1.1.1 31-1.2 34-1.2.2.1.1.1.1 36-1.2.2.1.1.1.1 37-1.2.2.1 38-1.2.2 39-1.2.2.2.1.1.1 40-1.2.2.2 42-1.1.1.1.1 42-1.2.2.2.2.1.1 43-1.1.1 43-1.2.2.2.2 (m / multi-sentence :snt1 (p4 / preincubate-01 :ARG1 (c / cell-line~e.4,43 :name (n / name :op1 "RAW264.7"~e.3,42)) :ARG2 (a / agonist~e.9 :name (n3 / name :op1 "K-111"~e.11,13) :mod (p / protein :name (n2 / name :op1 "PPARalpha"~e.8)) :ARG1-of (s / specific-02~e.7))) :snt2 (r / reduce-01~e.31 :ARG0 (a2 / agonist~e.9 :name (n4 / name :op1 "K-111"~e.11,13,28,30) :ARG1-of (m2 / mean-01 :ARG2 (s2 / small-molecule :name (n8 / name :op1 "2,2-dichloro-12-(4-chlorophenyl)dodecanoic"~e.15,17 :op2 "acid"~e.25)))) :ARG1 (a3 / and~e.38 :op1 (p2 / produce-01~e.37 :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6"~e.34,36))) :op2 (e / express-03~e.40 :ARG1 (n9 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.39)) :ARG3 (c2 / cell-line~e.43 :name (n7 / name :op1 "RAW264.7"~e.42)))))) # ::id bel_pmid_1732_2026.36370 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since activation of NF @-@ B in A549 cells is dependent on IKK2 , which phosphorylates serines 32 and 36 of IB as a prelude to IB degradation and activation of NF @-@ B ( Catley et al. , 2005 # ::alignments 0-1.2.2.2.r 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 7-1.1.1.2.1.1 8-1.1.1.2 10-1 12-1.2.1.1 15-1.2 15-1.2.2 15-1.2.2.r 16-1.2.2.1.1.2.1 16-1.2.2.1.2.2.1 17-1.2.2.1.1.1 18-1.2.2.1 19-1.2.2.1.2.1 20-1.2.2.1.r 21-1.2.2.1.3.1.1 22-1.3.2.r 24-1.2.2.2 25-1.2.2.2.1.r 26-1.2.2.2.1.1.1 27-1.2.2.2.1.1 28-1.2.2.2.1 29-1.2.2.2.1.2 30-1.2.2.2.1.2.1.r 31-1.2.2.2.1.2.1 32-1.2.2.2.1.2.1 33-1.2.2.2.1.2.1 35-1.3.1.1.1.1.1 36-1.3.1.1 37-1.3.1.1.2.1 39-1.3.2.1 (d / depend-01~e.10 :ARG0 (a / activate-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "NF-B"~e.3,5) :location (c / cell-line~e.8 :name (n2 / name :op1 "A549"~e.7)))) :ARG1 (e / enzyme~e.15 :name (n3 / name :op1 "IKK2"~e.12) :ARG2-of~e.15 (p3 / phosphorylate-01~e.15 :ARG1~e.20 (a2 / and~e.18 :op1 (a6 / amino-acid :mod 32~e.17 :name (n6 / name :op1 "serine"~e.16)) :op2 (a7 / amino-acid :mod 36~e.19 :name (n7 / name :op1 "serine"~e.16)) :part-of (e2 / enzyme :name (n4 / name :op1 "IB"~e.21))) :purpose~e.0 (p4 / prelude~e.24 :prep-to~e.25 (a3 / and~e.28 :op1 (d2 / degrade-01~e.27 :ARG1 e2~e.26) :op2 (a4 / activate-01~e.29 :ARG1~e.30 p~e.31,32,33))))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a5 / and~e.36 :op1 (p5 / person :name (n5 / name :op1 "Catley"~e.35)) :op2 (p6 / person :mod (o / other~e.37)))) :time~e.22 (d4 / date-entity :year 2005~e.39))) # ::id bel_pmid_1732_2026.38418 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , IL @-@ 6 release was substantially increased by both IL @-@ 1 and to a lesser extent by TNF . In each case , prior infection with the null adenovirus showed no significant effect , whereas dominant IBN reduced IL @-@ 6 release to near @-@ background levels . Likewise , the dominant @-@ negative IKK2 adenovirus prevented IL @-@ 6 release # ::alignments 0-1.3 2-1.3.1.1.2.1.1.1 4-1.3.1.1.2.1.1.1 5-1.3.1.1.2 7-1.3.1.1.3 8-1.3.1.1 8-1.3.1.2 11-1.3.1.1.1.1.1 11-1.3.1.1.2.1.1.1 13-1.3.1.1.1.1.1 14-1.3.1 15-1.3.1.2.3.r 17-1.3.1.2.3 17-1.3.1.2.3.1 17-1.3.1.2.3.1.r 19-1.3.1.2.1.r 20-1.3.1.2.1.1.1 22-1.2.1.3.r 23-1.2.1.3.1 24-1.2.1.3 26-1.2.1.1.2 27-1.2.1.1 30-1.1.1.1.3 30-1.1.1.1.3.1 30-1.1.1.1.3.1.r 30-1.2.1.1.1.1 30-1.2.1.1.1.1.1 30-1.2.1.1.1.1.1.r 31-1.2.1.1.1 32-1.2.1 33-1.2.1.2.1 33-1.2.1.2.1.r 34-1.2.1.2.2 35-1.2.1.2 37-1.2 38-1.2.2.1 38-1.2.2.1.2 38-1.2.2.1.2.r 40-1.2.2 41-1.2.2.2.1.1.1 43-1.2.2.2.1.1.1 44-1.2.2.2 45-1.2.2.3.r 46-1.2.2.3 48-1.2.2.3.1.1 49-1.2.2.3.1 51-1.1.3 54-1.1.1.1 54-1.1.1.1.2 54-1.1.1.1.2.r 57-1.1.1.1.1.1 58-1.1.1 59-1.1 60-1.1.2.1.1.1 62-1.1.2.1.1.1 63-1.1.2 (m / multi-sentence :snt3 (p / prevent-01~e.59 :ARG0 (a / adenovirus~e.58 :mod (e2 / enzyme~e.54 :name (n / name :op1 "IKK2"~e.57) :ARG0-of~e.54 (d2 / dominate-01~e.54) :ARG2-of (m2 / mutate-01~e.30 :mod~e.30 "-/-"~e.30))) :ARG1 (r / release-01~e.63 :ARG1 (p2 / protein :name (n10 / name :op1 "IL-6"~e.60,62))) :manner (l3 / likewise~e.51)) :snt2 (c2 / contrast-01~e.37 :ARG1 (s / show-01~e.32 :ARG0 (i2 / infect-01~e.27 :ARG0 (a2 / adenovirus~e.31 :ARG2-of (m3 / mutate-01~e.30 :mod~e.30 "-/-"~e.30)) :time (p3 / prior~e.26)) :ARG1 (a3 / affect-01~e.35 :polarity~e.33 -~e.33 :ARG1-of (s3 / significant-02~e.34)) :prep-in~e.22 (c / case-04~e.24 :mod (e / each~e.23))) :ARG2 (r3 / reduce-01~e.40 :ARG0 (p8 / protein~e.38 :name (n2 / name :op1 "IκBαΔN") :ARG0-of~e.38 (d / dominate-01~e.38)) :ARG1 (r4 / release-01~e.44 :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6"~e.41,43))) :ARG4~e.45 (n4 / near~e.46 :op1 (l / level~e.49 :mod (b / background~e.48))))) :snt1 (c3 / cause-01~e.0 :ARG1 (a4 / and~e.14 :op1 (i / increase-01~e.8 :ARG0 (p6 / protein :name (n6 / name :op1 "IL-1"~e.11,13)) :ARG1 (r5 / release-01~e.5 :ARG1 (p5 / protein :name (n5 / name :op1 "IL-6"~e.2,4,11))) :ARG2 (s2 / substantial~e.7)) :op2 (i3 / increase-01~e.8 :ARG0~e.19 (p7 / protein :name (n7 / name :op1 "TNF"~e.20)) :ARG1 r5 :ARG2~e.15 (l2 / less~e.17 :degree~e.17 (m4 / more~e.17)))))) # ::id bel_pmid_1732_2026.39144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar levels of RANTES and MCP @-@ 1 release were induced by IL @-@ 1 and TNF treatments . However , the induction of IL @-@ 6 , IL @-@ 8 , and GMCSF by TNF was 50 to 80 % lower than for IL @-@ 1 , whereas TNF @-@ induced GRO was some 35 @- to 40 @-@ fold lower than that for IL @-@ 1 . In all instances , preincubation with PS @-@ 1145 or ML120B resulted in a significant attenuation of cytokine release ( Fig . 6 ) . # ::alignments 0-1.1.2.1.2 1-1.1.2.1 1-1.1.2.1.2.1 2-1.1.2.1.1.r 3-1.1.2.1.1.1.1 5-1.1.2.1.2.1.1.1.1 7-1.1.1.2.1.1.1 7-1.1.2.1.2.1.1.1.1 8-1.1.2.1.2.1.1 8-1.1.2.1.2.1.1.2 8-1.1.2.1.2.1.1.2.r 10-1.1 10-1.2.1.1 11-1.1.1.r 12-1.1.1.2.1.1.1 14-1.1.1.2.1.1.1 14-1.1.2.1.2.1.1.1.1 15-1.1.1 16-1.1.1.1.1.1.1 17-1.1.1.1 17-1.1.1.2 19-1.2 19-1.2.3 19-1.2.3.r 22-1.2.2.1.2 24-1.2.1.1.2.1.1.1 24-1.2.1.1.2.2.1.1 26-1.2.1.1.2.1.1.1 28-1.2.1.1.2.1.1.1 28-1.2.1.1.2.2.1.1 30-1.2.1.1.2.2.1.1 33-1.2.1.1.2.3.1.1 34-1.2.1.1.1.r 35-1.2.1.1.1.1.1 37-1.2.1.2.1.1 39-1.2.1.2.2.1 40-1.2.1.2.1 40-1.2.1.2.2 40-1.2.2.2.1 40-1.2.2.2.2 41-1.2.1 41-1.2.2 42-1.2.1.3.r 42-1.2.2.3.r 44-1.2.1.1.2.1.1.1 44-1.2.1.3.2.1.1 46-1.2.1.3.2.1.1 48-1.2 48-1.2.3 48-1.2.3.r 49-1.2.1.1.1.1.1 51-1.2.1.3 51-1.2.2.1.2 52-1.2.2.1.1.1 55-1.2.2.2.1.1 58-1.2.2.2.2.1 61-1.2.1 62-1.2.1.3.r 65-1.1.1.2.1.1.1 65-1.2.1.3.2.1.1 67-1.1.1.2.1.1.1 67-1.2.1.3.2.1.1 69-1.3.3.r 70-1.3.3.1 71-1.3.3 75-1.3.1.1.1.1.1 77-1.3.1.1.1.1.1 78-1.3.1.1 79-1.3.1.1.2.1.1 80-1.3 81-1.3.2.r 81-1.3.3.r 83-1.3.2.2 84-1.3.2 85-1.3.2.1.r 86-1.3.2.1.1 87-1.3.2.1 89-1.4.1 91-1.4.1.1 (m2 / multi-sentence :snt1 (i / induce-01~e.10 :ARG0~e.11 (a / and~e.15 :op1 (t / treat-04~e.17 :ARG2 (p2 / protein :name (n / name :op1 "TNF"~e.16))) :op2 (t2 / treat-04~e.17 :ARG2 (p3 / protein :name (n2 / name :op1 "IL-1"~e.7,12,14,65,67)))) :ARG2 (a2 / and :op1 (l2 / level~e.1 :quant-of~e.2 (p14 / protein :name (n3 / name :op1 "RANTES"~e.3) :ARG1-of r2) :ARG1-of (r3 / resemble-01~e.0 :ARG2 (l3 / level~e.1 :quant-of (p4 / protein~e.8 :name (n4 / name :op1 "MCP-1"~e.5,7,14) :ARG1-of~e.8 (r2 / release-01~e.8))))))) :snt2 (c / contrast-01~e.19,48 :ARG1 (l / lower-05~e.41,61 :ARG1 (i2 / induce-01~e.10 :ARG0~e.34 (p9 / protein :name (n8 / name :op1 "TNF"~e.35,49)) :ARG2 (a3 / and :op1 (p6 / protein :name (n5 / name :op1 "IL-6"~e.24,26,28,44)) :op2 (p7 / protein :name (n6 / name :op1 "IL-8"~e.24,28,30)) :op3 (p8 / protein :name (n7 / name :op1 "GMCSF"~e.33)))) :ARG2 (b / between :op1 (p5 / percentage-entity~e.40 :value 50~e.37) :op2 (p / percentage-entity~e.40 :value 80~e.39)) :compared-to~e.42,62 (i4 / induce-01~e.51 :ARG0 p9 :ARG2 (p10 / protein :name (n9 / name :op1 "IL-1"~e.44,46,65,67)))) :ARG2 (l4 / lower-05~e.41 :ARG1 (p13 / protein :name (n10 / name :op1 "GRO"~e.52) :ARG2-of (i3 / induce-01~e.22,51 :ARG0 p9)) :ARG2 (b2 / between :op1 (p11 / percentage-entity~e.40 :value 35~e.55) :op2 (p12 / percentage-entity~e.40 :value 40~e.58)) :compared-to~e.42 i4) :ARG2-of~e.19,48 (c2 / contrast-01~e.19,48)) :snt3 (r / result-01~e.80 :ARG1 (p15 / preincubate-01 :ARG2 (o / or~e.78 :op1 (s3 / small-molecule :name (n11 / name :op1 "PS-1145"~e.75,77)) :op2 (s2 / small-molecule :name (n12 / name :op1 "ML120B"~e.79)))) :ARG2~e.81 (a5 / attenuate-01~e.84 :ARG1~e.85 (r4 / release-01~e.87 :ARG1 (c3 / cytokine~e.86)) :ARG1-of (s / significant-02~e.83)) :prep-in~e.69,81 (i6 / instance~e.71 :mod (a4 / all~e.70))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.89 :mod 6~e.91))) # ::id bel_pmid_1733_2487.25838 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exposure of CD40L enhanced the constitutive production of IL @-@ 6 and MCP @-@ 1 protein ( Figure 4A and 4B ) . # ::alignments 0-1.1 2-1.1.1.1.1 3-1 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.1.1.1 10-1.2.1.1.1.1 11-1.2.1 12-1.2.1.2.1.1 14-1.2.1.2.1.1 15-1.1.1 15-1.2.1.1 15-1.2.1.2 17-1.3.1.1 17-1.3.1.2 18-1.3.1.1.1.1 19-1.3.1 20-1.3.1.2.1.1 (e / enhance-01~e.3 :ARG0 (e2 / expose-01~e.0 :ARG1 (p / protein~e.15 :name (n / name :op1 "CD40L"~e.2))) :ARG1 (p2 / produce-01~e.6 :ARG1~e.7 (a / and~e.11 :op1 (p3 / protein~e.15 :name (n2 / name :op1 "IL-6"~e.8,10)) :op2 (p4 / protein~e.15 :name (n3 / name :op1 "MCP-1"~e.12,14))) :mod (c / constitutive~e.5)) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.19 :op1 (f / figure~e.17 :name (n4 / name :op1 "4A"~e.18)) :op2 (f2 / figure~e.17 :name (n5 / name :op1 "4B"~e.20))))) # ::id bel_pmid_1739_6137.31084 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 1 TRF2 ( myc @-@ tagged ) induces telomere dysfunction and cellular senescence in p53 P/P primary mouse embryonic fibroblasts . # ::alignments 0-1.4.1 1-1.4.1.1 2-1.1.1.1 4-1.1.2.1.1.1 6-1.1.2 8-1 9-1.2.1.2 11-1.2 12-1.2.2.1 13-1.2.2 16-1.3.1.1.2.2.1 17-1.3.1.1.1 18-1.3.1.1 19-1.3.1 20-1.3 (i / induce-01~e.8 :ARG0 (p / protein :name (n / name :op1 "TRF2"~e.2) :ARG1-of (t2 / tag-01~e.6 :ARG2 (p4 / protein :name (n2 / name :op1 "myc"~e.4)))) :ARG2 (a / and~e.11 :op1 (f2 / function-01 :polarity - :ARG0 (t / telomere~e.9)) :op2 (s / senescence~e.13 :mod (c2 / cell~e.12))) :location (f3 / fibroblast~e.20 :mod (e / embryo~e.19 :source (m / mouse~e.18 :mod (p2 / primary~e.17) :mod (p3 / protein :name (n3 / name :op1 "p35") :ARG2-of (m2 / mutate-01 :value "P/P"~e.16))))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure~e.0 :mod 1~e.1))) # ::id bel_pmid_1739_6137.31086 ::amr-annotator SDL-AMR-09 ::preferred # ::tok overexpression of TRF2 in p53 P/P MEFs resulted in upregulation of p21 ( Fig 1D ) . In addition , reduction of BrdU incorporation , induction of p21 level and increased number of SA @-@ beta @-@ gal @-@ positive senescent cells were also observed when oncogenic H @-@ Ras was overexpressed in p53 P/P MEFs ( Fig 1A ? C ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.2.r 4-1.1.1.2.2.1.1 5-1.1.1.2.2.2.1 6-1.1.1.2.1.1 7-1.1 8-1.1.2.r 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1 13-1.1.3.1 13-1.3.1.2 13-1.3.1.3 14-1.1.3.1.1 17-1.2.1.1 17-1.3.1 18-1.2.1.1 20-1.2.1.1.1 21-1.2.1.1.1.1.r 22-1.2.1.1.1.1.1.1.1 23-1.2.1.1.1.1 25-1.2.1.1.2 26-1.2.1.1.2.1.r 27-1.2.1.1.2.1.1.1.1 28-1.2.1.1.2.1 29-1.2.1.1 30-1.2.1.1.3.2 31-1.2.1.1.3 32-1.2.1.1.3.1.r 33-1.2.1.1.3.1.2.1.1.1 35-1.2.1.1.3.1.2.1.1.1 37-1.2.1.1.3.1.2.1.1.1 39-1.2.1.1.3.1.2 40-1.2.1.1.3.1.1 41-1.2.1.1.3.1 43-1.2.1.3 44-1.2.1 45-1.2.1.2.r 46-1.2.1.2.1.2 47-1.2.1.2.1.1.1 49-1.2.1.2.1.1.1 51-1.2.1.2 53-1.1.1.2.2.1.1 53-1.2.1.2.2.2.1.1 54-1.1.1.2.2.2.1 55-1.1.1.2.1.1 55-1.2.1.2.2.1.1 57-1.3.1.1 58-1.3.1.1.1 (m / multi-sentence :snt1 (r / result-01~e.7 :ARG1 (o / overexpress-01~e.0 :ARG1~e.1 (p / protein :name (n2 / name :op1 "TRF2"~e.2)) :location~e.3 (c / cell :name (n3 / name :op1 "MEF"~e.6,55) :mod (p2 / protein :name (n4 / name :op1 "p53"~e.4,53) :ARG2-of (m3 / mutate-01 :value "P/P"~e.5,54)))) :ARG2~e.8 (u / upregulate-01~e.9 :ARG1~e.10 (p3 / protein :name (n5 / name :op1 "p21"~e.11))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13 :mod "1D"~e.14))) :snt2 (a / and :op2 (o2 / observe-01~e.44 :ARG1 (a2 / and~e.17,18,29 :op1 (r2 / reduce-01~e.20 :ARG1~e.21 (i / incorporate-01~e.23 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"~e.22)))) :op2 (i2 / induce-01~e.25 :ARG2~e.26 (l / level~e.28 :degree-of (p6 / protein :name (n9 / name :op1 "p21"~e.27)))) :op3 (n10 / number~e.31 :quant-of~e.32 (c3 / cell~e.41 :mod (s / senescent~e.40) :mod (p7 / positive~e.39 :mod (e / enzyme :name (n11 / name :op1 "SA-beta-gal"~e.33,35,37)))) :ARG1-of (i3 / increase-01~e.30))) :time~e.45 (o3 / overexpress-01~e.51 :ARG1 (e2 / enzyme :name (n6 / name :op1 "H-Ras"~e.47,49) :mod (o4 / oncogenic~e.46)) :location (c2 / cell :name (n8 / name :op1 "MEF"~e.55) :mod (p4 / protein :name (n7 / name :op1 "p53"~e.53)))) :mod (a3 / also~e.43))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.17 :op1 (f3 / figure~e.57 :mod "1A"~e.58) :op2 (f4 / figure~e.13 :mod "1B") :op3 (f5 / figure~e.13 :mod "1C")))) # ::id bel_pmid_1740_4266.3636 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , i.p . administration of UA increased the levels of IL @-@ 1 beta secretion and MPO activity in colonic mucosa of ICR mice . # ::alignments 0-1.1.2 1-1 1-1.1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 8-1.1 10-1.1.2.1 10-1.1.2.2 11-1.1.2.1.1.r 12-1.1.2.1.1.1.1.1 16-1.1.2.1.1 17-1.1.2 18-1.1.2.2.1.1.1.1 19-1.1.2.2.1 20-1.1.2.2.1.2.r 21-1.1.2.2.1.2.1 22-1.1.2.2.1.2 23-1.1.2.2.1.2.2.r 24-1.1.2.2.1.2.2.1.1 25-1.1.2.2.1.2.2.1.2 (a2 / and~e.1 :op2 (i / increase-01~e.8 :ARG0 (a / administrate-01~e.5 :ARG1~e.6 (s2 / small-molecule :name (n / name :op1 "UA"~e.7)) :mod (i2 / injection :mod (i3 / intraperitoneal))) :ARG1 (a3 / and~e.0,1,17 :op1 (l / level~e.10 :degree-of~e.11 (s / secrete-01~e.16 :ARG1 (p / protein :name (n3 / name :op1 "IL-1beta"~e.12)))) :op2 (l2 / level~e.10 :degree-of (a4 / activity-06~e.19 :ARG0 (e / enzyme :name (n4 / name :op1 "MPO"~e.18)) :location~e.20 (m2 / mucosa~e.22 :part-of (c / colon~e.21) :source~e.23 (o / organism :name (n2 / name :op1 "ICR"~e.24 :op2 "mouse"~e.25)))))))) # ::id bel_pmid_1740_4266.3638 ::amr-annotator SDL-AMR-09 ::preferred # ::tok UA increased the protein release of IL @-@ 1 beta , IL @-@ 6 , and MIF , but not of TNF @-@ alpha , in dose @- and time @-@ dependent manners . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.2 3-1.1.2.1.1 3-1.1.2.1.2 3-1.1.2.1.3 3-1.2.3.1 4-1.1.2 4-1.2.3 5-1.1.2.1.r 6-1.1.2.1.1.1.1 6-1.1.2.1.2.1.1 11-1.1.2.1.1.1.1 11-1.1.2.1.2.1.1 13-1.1.2.1.2.1.1 15-1.1.2.1 16-1.1.2.1.3.1.1 18-1 19-1.2.1 19-1.2.1.r 21-1.2.3.1.1.1 23-1.2.3.1.1.1 26-1.3.1.2 28-1.3 29-1.3.2.2 31-1.3.1 31-1.3.2 32-1.3.r (c / contrast-01~e.18 :ARG1 (i2 / increase-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "UA"~e.0)) :ARG1 (r / release-01~e.4 :ARG1~e.5 (a / and~e.15 :op1 (p2 / protein~e.3 :name (n2 / name :op1 "IL-1beta"~e.6,11)) :op2 (p3 / protein~e.3 :name (n3 / name :op1 "IL-6"~e.6,11,13)) :op3 (p4 / protein~e.3 :name (n4 / name :op1 "MIF"~e.16))))) :ARG2 (i3 / increase-01~e.1 :polarity~e.19 -~e.19 :ARG0 s :ARG1 (r2 / release-01~e.4 :ARG1 (p5 / protein~e.3 :name (n5 / name :op1 "TNF-alpha"~e.21,23)))) :manner~e.32 (a2 / and~e.28 :op1 (d / depend-01~e.31 :ARG0 i2 :ARG1 (d3 / dose~e.26)) :op2 (d2 / depend-01~e.31 :ARG0 i2 :ARG1 (t / time~e.29)))) # ::id bel_pmid_1740_4266.16378 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 3 , A and B , IL @-@ 1B mRNA and proIL @-@ 1B protein were detected in a constitutive manner at low levels in nontreated pMphi . Those treated with 4 microM UA for 3 and 6 h were markedly up @-@ regulated , whereas , intriguingly , the levels diminished after 12 h . # ::alignments 0-1.2.2.2.r 1-1.1.2 3-1.1.2.1.1 3-1.1.2.1.2 4-1.2.1.1.1.2.1.1 7-1.1.2.1 10-1.1.1.1.2.1.1 12-1.1.1.2.1.1 13-1.1.1.1.1.1 14-1.1.1 15-1.1.1.2.1.1 17-1.1.1.2.1.1 18-1.1.1.1.2 18-1.1.1.2 20-1.1 23-1.1.3 24-1.1.3.r 25-1.1.1.r 26-1.1.1.3.1 27-1.1.1.3 30-1.1.4.1.1 33-1.1.4.2 33-1.2.1.1.1 34-1.2.1.1.1.1.r 35-1.2.1.1.1.1.2.1 37-1.2.1.1.1.1.1.1 39-1.2.1.1.1.2.1.1 40-1.2.1.1.1.2 41-1.2.1.1.1.2.2.1 42-1.2.1.1.1.2.2.2 44-1.2.1.2 44-1.2.1.2.r 49-1.2 51-1.2.2.3 54-1.2.2.1 55-1.2.2 56-1.2.2.2 57-1.2.2.2.1.1 58-1.2.1.1.1.2.1.2 58-1.2.2.2.1.2 (m / multi-sentence :snt1 (d / detect-01~e.20 :ARG1~e.25 (a4 / and~e.14 :op1 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.13) :part (p3 / protein~e.18 :name (n4 / name :op1 "IL-B1"~e.10))) :op2 (p2 / protein~e.18 :name (n2 / name :op1 "proIL-1B"~e.12,15,17)) :quant (l2 / level~e.27 :ARG1-of (l3 / low-04~e.26))) :ARG1-of (s / show-01~e.1 :ARG0 (a3 / and~e.7 :op1 (f / figure~e.3 :mod "3A") :op2 (f2 / figure~e.3 :mod "3B"))) :manner~e.24 (c3 / constitutive~e.23) :location (c4 / cell :name (n5 / name :op1 "pMphi"~e.30) :ARG1-of (t5 / treat-04~e.33 :polarity -))) :snt2 (c / contrast-01~e.49 :ARG1 (u / upregulate-01 :ARG1 (c5 / cell :ARG1-of (t / treat-04~e.33 :ARG2~e.34 (s2 / small-molecule :name (n / name :op1 "UA"~e.37) :quant (c2 / concentration-quantity :quant 4~e.35 :unit (m3 / micromolar))) :duration (a / and~e.40 :op1 (t2 / temporal-quantity :quant 3~e.4,39 :unit (h / hour~e.58)) :op2 (t3 / temporal-quantity :quant 6~e.41 :unit (h2 / hour~e.42))))) :manner~e.44 (m4 / marked~e.44)) :ARG2 (d2 / diminish-01~e.55 :ARG1 (l / level~e.54) :time~e.0 (a2 / after~e.56 :op1 (t4 / temporal-quantity :quant 12~e.57 :unit (h3 / hour~e.58))) :ARG0-of (i / intrigue-01~e.51)))) # ::id bel_pmid_1740_6055.15774 ::amr-annotator SDL-AMR-09 ::preferred # ::tok JAK @-@ 2 activation and phosphorylation have been demonstrated in response to exogenous H2O2 in fibroblasts and VSMCs , respectively ( 27,63 ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1 5-1.1.2 8-1 9-1.2.r 10-1.2 11-1.2.1.r 12-1.2.1.2 13-1.2.1.1.1 15-1.2.1.3.1 16-1.2.1.3 16-1.3.1 (d2 / demonstrate-01~e.8 :ARG1 (a / and~e.4 :op1 (a2 / activate-01~e.3 :ARG1 (e2 / enzyme :name (n / name :op1 "JAK-2"~e.0,2))) :op2 (p / phosphorylate-01~e.5 :ARG1 e2)) :ARG2-of~e.9 (r / respond-01~e.10 :ARG1~e.11 (s / small-molecule :name (n2 / name :op1 "H2O2"~e.13) :mod (e / exogenous~e.12) :location (a3 / and~e.16 :op1 (f / fibroblast~e.15) :op2 (c / cell :name (n3 / name :op1 "VSMC"))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.16 :op1 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 27)) :op2 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 63))))) # ::id bel_pmid_1740_6055.15784 ::amr-annotator SDL-AMR-09 ::preferred # ::tok in view of the ability of H2O2 to inhibit protein tyrosine phosphatases ( PTPases ) , such as PTP @-@ 1B ( 68 ) , and SH @-@ 2 domain @-@ containing tyrosine phosphatase ( SHP ) - 2 ( 69 ) , # ::alignments 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.1.2 9-1.1.2.2.1.1.1 10-1.1.2.2.1.1.2 11-1.1.2.2.1.1.3 16-1.1.2.2.1.2.r 17-1.1.2.2.1.2.r 18-1.1.2.2.1.2.1.1 20-1.1.2.2.1.2.1.1 22-1.1.2.2.1.3.1.1.1 25-1.1.2.2 26-1.1.2.2.2.2.1.1.1 28-1.1.2.2.2.2.1.1.1 29-1.1.2.2.2.2.1 31-1.1.2.2.2.2 32-1.1.2.2.2.1.1 33-1.1.2.2.2.1.2 38-1.1.2.2.2.2.1.1.1 40-1.1.2.2.2.3.1.1.1 (h / have-purpose-91 :ARG2 (c / capable-01~e.4 :ARG1~e.5 (s / small-molecule :name (n / name :op1 "H2O2"~e.6)) :ARG2 (i / inhibit-01~e.8 :ARG0 s :ARG1 (a / and~e.25 :op1 (e / enzyme :name (n2 / name :op1 "protein"~e.9 :op2 "tyrosine"~e.10 :op3 "phosphatase"~e.11) :example~e.16,17 (e2 / enzyme :name (n3 / name :op1 "PTP-1B"~e.18,20)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 68~e.22)))) :op2 (e3 / enzyme :name (n5 / name :op1 "tyrosine"~e.32 :op2 "phosphatase"~e.33) :ARG0-of (c4 / contain-01~e.31 :ARG1 (d3 / domain~e.29 :name (n4 / name :op1 "SH-2"~e.26,28,38))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 69~e.40)))))))) # ::id bel_pmid_1740_6055.34632 ::amr-annotator SDL-AMR-09 ::preferred # ::tok c @-@ Src has also been shown to be activated in response to ROS , including H2O2 , in different cell types ( 19,20 , 33,37,50 ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 4-1.3 6-1 9-1.1 10-1.1.2.r 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1 15-1.1.2.1.2 16-1.1.2.1.2.1.1.1 19-1.1.2.1.3.1.1 20-1.1.2.1.3 21-1.1.2.1.3.1 (s / show-01~e.6 :ARG1 (a2 / activate-01~e.9 :ARG1 (e / enzyme :name (n3 / name :op1 "c-Src"~e.0,2)) :ARG2-of~e.10 (r / respond-01~e.11 :ARG1~e.12 (s3 / small-molecule :name (n / name :op1 "ROS"~e.13) :ARG2-of (i / include-91~e.15 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "H2O2"~e.16))) :location (c6 / cell~e.20 :ARG1-of (t / type-03~e.21 :ARG1-of (d2 / differ-02~e.19)))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (p / publication :ARG1-of (c / cite-01 :ARG2 19)) :op2 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 20)) :op3 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 33)) :op4 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 37)) :op5 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 50)))) :mod (a3 / also~e.4)) # ::id bel_pmid_1746_8755.1748 ::amr-annotator SDL-AMR-09 ::preferred # ::tok deletion of p38 alpha mitogen @-@ activated protein ( MAP ) kinase in adult mice results in increased proliferation # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1.1.2 4-1.1.1.1.3 6-1.1.1.1.3 7-1.1.1.1.4 11-1.1.1.1.5 12-1.1.2.r 13-1.1.2.1 14-1.1.2 15-1 16-1.2.r 17-1.2.1 18-1.2 (r / result-01~e.15 :ARG1 (d / delete-01~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "p38"~e.2 :op2 "alpha"~e.3 :op3 "mitogen-activated"~e.4,6 :op4 "protein"~e.7 :op5 "kinase"~e.11)) :location~e.12 (m / mouse~e.14 :mod (a / adult~e.13))) :ARG2~e.16 (p / proliferate-01~e.18 :ARG1-of (i / increase-01~e.17))) # ::id bel_pmid_1746_8755.1750 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , p38 alpha controls self @-@ renewal of the lung stem and progenitor cell population by inhibiting proliferation @-@ inducing signals , most notably epidermal growth factor receptor # ::alignments 0-1 1-1 3-1.1.1.1.1 4-1.1.1.1.2 5-1.1 8-1.1.2 9-1.1.2.1.r 11-1.1.2.1.1.1.1.1 12-1.1.2.1.1.1.1 13-1.1.2.1 14-1.1.2.1.2.1.1 15-1.1.2.1.1.1 15-1.1.2.1.2.1 16-1.1.2.1.1 16-1.1.2.1.2 17-1.1.3.r 18-1.1.3 19-1.1.3.2.1.1 21-1.1.3.2.1 22-1.1.3.2 24-1.1.3.3.1 25-1.1.3.3 26-1.1.3.2.2.1.1.1 27-1.1.3.2.2.1.1.2 28-1.1.3.2.2.1.1.3 29-1.1.3.2.2.1.1.4 (a / and~e.0,1 :op2 (c / control-01~e.5 :ARG0 (e / enzyme :name (n2 / name :op1 "P38"~e.3 :op2 "Alpha"~e.4)) :ARG1 (r / renew-01~e.8 :ARG0~e.9 (a2 / and~e.13 :op1 (p2 / population~e.16 :consist-of (c2 / cell~e.15 :mod (s2 / stem~e.12 :source (l / lung~e.11)))) :op2 (p / population~e.16 :consist-of (c3 / cell~e.15 :mod (p4 / progenitor~e.14)))) :ARG1 a2) :ARG2~e.17 (i / inhibit-01~e.18 :ARG0 e :ARG1 (s3 / signal~e.22 :ARG0-of (i2 / induce-01~e.21 :ARG2 (p5 / proliferate-01~e.19)) :ARG2-of (i3 / include-91 :ARG1 (e2 / enzyme :name (n / name :op1 "epidermal"~e.26 :op2 "growth"~e.27 :op3 "factor"~e.28 :op4 "receptor"~e.29)))) :ARG1-of (n3 / notable-04~e.25 :degree (m / most~e.24))))) # ::id bel_pmid_1746_8755.1754 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that p38 alpha positively regulates factors such as CCAAT @/@ enhancer @-@ binding protein that are required for lung cell differentiation . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1 4-1.2.1.1.2 5-1.2.3 5-1.2.3.r 6-1.2 7-1.2.2 8-1.2.2.1.r 9-1.2.2.1.r 10-1.2.2.1.1.1 12-1.2.2.1.1.1 14-1.2.2.1.1.1 15-1.2.2.1.1.2 18-1.2.2.1.2 19-1.2.2.1.2.1.r 20-1.2.2.1.2.1.1.1 21-1.2.2.1.2.1.1 22-1.2.2.1.2.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (r / regulate-01~e.6 :ARG0 (e2 / enzyme :name (n / name :op1 "p38"~e.3 :op2 "alpha"~e.4)) :ARG1 (f2 / factor~e.7 :example~e.8,9 (p / protein :name (n3 / name :op1 "CCAAT/enhancer-binding"~e.10,12,14 :op2 "protein"~e.15) :ARG1-of (r2 / require-01~e.18 :ARG0~e.19 (d / differentiate-01~e.22 :ARG1 (c / cell~e.21 :mod (l / lung~e.20)))))) :manner~e.5 (p2 / positive~e.5))) # ::id bel_pmid_1746_8755.21936 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The reduction in C/EBPa could be accounted for by lower levels of phospho @-@ C/EBPb ( Fig . 3a ) , a known target for p38a ( refs . 12,20 ) , which in turn regulates the expression of C/EBPa ( ref . 21 ) . # ::alignments 1-1.1.1 2-1.1.2.2.3.1.2.2 3-1.1.1.1.1.1 3-1.1.2.2.1.1 4-1 6-1.1 9-1.1.2.1 9-1.1.2.1.1 9-1.1.2.1.1.r 10-1.1.2 12-1.1.2.2.2 16-1.1.3.1 18-1.1.3.1.1 22-1.1.2.2.3.3 23-1.1.2.2 23-1.1.2.2.3 23-1.1.2.2.3.r 25-1.1.2.2.3.1.1.1 33-1.1.2.2.3.1.2.2 34-1.1.2.2.3.1.2.2 35-1.1.2.2.3.1 35-1.1.2.2.3.1.2 35-1.1.2.2.3.1.2.r 37-1.1.2.2.3.1.2.1 39-1.1.2.2.1.1 43-1.1.2.2.3.1.2.3.1.1.1 (p / possible-01~e.4 :ARG1 (a / account-01~e.6 :ARG1 (r / reduce-01~e.1 :ARG1 (p2 / protein :name (n / name :op1 "C/EBPa"~e.3))) :ARG2 (l / level~e.10 :ARG1-of (l2 / low-04~e.9 :degree~e.9 (m / more~e.9)) :quant-of (p8 / protein~e.23 :name (n3 / name :op1 "C/EBPa"~e.3,39) :ARG3-of (p3 / phosphorylate-01~e.12) :ARG1-of~e.23 (t / target-01~e.23 :ARG0 (p4 / protein~e.35 :name (n2 / name :op1 "p38a"~e.25) :ARG0-of~e.35 (r2 / regulate-01~e.35 :ARG1 (e / express-03~e.37 :ARG2 p2) :manner (i / in-turn~e.2,33,34) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 21~e.43))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p5 / publication :ARG1-of (c / cite-01 :ARG2 12)) :op2 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 20)))) :ARG1-of (k / know-01~e.22)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "3a"~e.18)))) # ::id bel_pmid_1746_8755.22008 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mnk1 was also activated at lower levels in Mapk14 @-@ null mice ( Fig . 3b ) . This p38a @-@ activated protein kinase phosphorylates and stabilizes Sprouty2 ( ref . 26 ) , which in turn can negatively regulate tyrosine kinase receptor signaling in lung cells27 . # ::alignments 0-1.1.1.1.1 2-1.1.3 3-1.1 4-1.1.4.r 5-1.1.4.1 5-1.1.4.1.1 5-1.1.4.1.1.r 6-1.1.4 7-1.1.5.r 7-1.2.2.2.2.2 8-1.1.5.1.1.1 10-1.1.5.1 10-1.1.5.1.2 10-1.1.5.1.2.1 10-1.1.5.1.2.1.r 10-1.1.5.1.2.r 11-1.1.5 13-1.1.2.1 13-1.1.6.1 15-1.1.2.1.1 15-1.1.6.1.1 19-1.2.2.1.2.1.1.1 21-1.2.2.1.2 22-1.2.2.1.1 23-1.2.2.1 24-1.2.1 25-1.2 26-1.2.2 27-1.2.2.2.1.1 31-1.2.2.3.1.1.1 35-1.2.2.2.2.2 36-1.2.2.2.2.2 37-1.2.2.2.2.3 38-1.2.2.2 38-1.2.2.2.2 38-1.2.2.2.2.r 39-1.2.2.2 39-1.2.2.2.2 39-1.2.2.2.2.r 40-1.2.2.2.2.1.1.1.1 41-1.2.2.2.2.1.1.1.2 42-1.2.2.2.2.1.1.1.3 43-1.2.2.2.2.1 44-1.2.2.2.2.1.2.r 44-1.2.2.2.2.2 45-1.2.2.2.2.1.2.1 (m2 / multi-sentence :snt1 (a / activate-01~e.3 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Mnk1"~e.0)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13 :mod "3b"~e.15)) :mod (a5 / also~e.2) :degree~e.4 (l3 / level~e.6 :ARG1-of (l / low-04~e.5 :degree~e.5 (m / more~e.5))) :location~e.7 (m3 / mouse~e.11 :mod (e2 / enzyme~e.10 :name (n5 / name :op1 "Mapk14"~e.8) :ARG2-of~e.10 (m4 / mutate-01~e.10 :mod~e.10 "-/-"~e.10))) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure~e.13 :mod "3b"~e.15))) :snt2 (a2 / and~e.25 :op1 (p / phosphorylate-01~e.24 :ARG1 e :ARG2 k) :op2 (s / stabilize-01~e.26 :ARG0 (k / kinase~e.23 :mod (p6 / protein~e.22) :ARG1-of (a4 / activate-01~e.21 :ARG0 (p7 / protein :name (n4 / name :op1 "p38a"~e.19)))) :ARG1 (e / enzyme~e.38,39 :name (n / name :op1 "Sprouty2"~e.27) :ARG2-of~e.38,39 (d2 / downregulate-01~e.38,39 :ARG1 (s2 / signal-07~e.43 :ARG0 (p4 / pathway :name (n2 / name :op1 "tyrosine"~e.40 :op2 "kinase"~e.41 :op3 "receptor"~e.42)) :location~e.44 (c2 / cell :source (l2 / lung~e.45))) :mod (i / in-turn~e.7,35,36,44) :ARG1-of (p3 / possible-01~e.37) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 27))))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 26~e.31)))))) # ::id bel_pmid_1746_8755.25974 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our results indicated that the p38a @-@ deficient lungs had hyperproliferative alveolar tissue with loss of differentiation markers . A similar but more marked lung phenotype , with hyperproliferation and defective cell maturation , has been described previously in CCAAT/ enhancer @-@ binding protein ( C/EBP ) a knockout mice , which die shortly after birth because of respiratory failure16 @–@ 18 . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1 1-1.1.1.2 1-1.1.1.2.r 2-1.1 3-1.1.2.r 5-1.1.2.1.1.1.1.1 7-1.3.3.2 7-1.3.3.2.2 7-1.3.3.2.2.r 8-1.1.2.1 9-1.1.2 10-1.1.2.2.1 10-1.1.2.2.1.1 10-1.1.2.2.1.1.r 11-1.1.2.2.2 12-1.1.2.2 13-1.1.2.2.3.r 14-1.1.2.2.3 15-1.1.2.2.3.1.r 16-1.1.2.2.3.1.1 17-1.1.2.2.3.1 20-1.3.1.4 21-1.3.1.4.1 22-1.3.1.4.1.1.1 23-1.3.1.4.1.1 24-1.3.1.1 25-1.3.1 27-1.3.1.2.r 28-1.3.1.2 28-1.3.1.2.2 28-1.3.1.2.2.r 30-1.3.1.3.2 31-1.3.1.3.1 32-1.3.1.3 35-1.3.1.4.1.1.2.r 36-1.2 36-1.3 37-1.3.2 39-1.3.3.2.1.1 40-1.3.3.2.1.2 42-1.3.3.2.1.2 43-1.3.3.2.1.3 45-1.3.3.2.3.1.1.1 48-1.3.3.3 49-1.3.3 52-1.3.3.1 53-1.3.3.1.1.2 54-1.3.3.1.1 55-1.3.3.1.1.1 56-1.3.3.1.2 58-1.3.3.1.2.1.2 61-1.2.1.1.1.2 (m / multi-sentence :snt1 (i / indicate-01~e.2 :ARG0 (t3 / thing~e.1 :poss~e.0 (w / we~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (h / have-03~e.9 :ARG0 (l / lung~e.8 :ARG0-of (l2 / lack-01 :ARG1 (p8 / protein :name (n / name :op1 "p38a"~e.5)))) :ARG1 (t / tissue~e.12 :ARG0-of (p6 / proliferate-01~e.10 :degree~e.10 (h2 / hyper~e.10)) :mod (a / alveolus~e.11) :mod~e.13 (l3 / lose-02~e.14 :ARG1~e.15 (m8 / marker~e.17 :ARG1-of (d / differentiate-01~e.16)))))) :ARG1-of (d5 / describe-01~e.36 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 (v / value-interval :op1 16 :op2 18~e.61)))) :snt2 (d2 / describe-01~e.36 :ARG1 (p4 / phenotype~e.25 :mod (l4 / lung~e.24) :mod~e.27 (p5 / proliferate-01~e.28 :ARG0 c2 :degree~e.28 (h3 / hyper~e.28)) :ARG0-of (m5 / maturate-03~e.32 :ARG1 (c2 / cell~e.31) :mod (d3 / defective~e.30)) :ARG1-of (r2 / resemble-01~e.20 :ARG1-of (c6 / contrast-01~e.21 :ARG2 (m3 / marked~e.23 :degree (m4 / more~e.22) :domain~e.35 p4)))) :time (p3 / previous~e.37) :location (m6 / mouse~e.49 :ARG1-of (d4 / die-01~e.52 :time (a2 / after~e.54 :op1 (b / bear-02~e.55 :ARG1 m6) :ARG1-of (s / short-07~e.53)) :ARG1-of (c3 / cause-01~e.56 :ARG0 (f / fail-01 :ARG1 m6 :ARG2 (r3 / respiration~e.58)))) :mod (p2 / protein~e.7 :name (n4 / name :op1 "CCAAT/"~e.39 :op2 "enhancer-binding"~e.40,42 :op3 "protein"~e.43) :ARG2-of~e.7 (m7 / mutate-01~e.7 :mod "+/-") :ARG1-of (m2 / mean-01 :ARG2 (p / protein :name (n3 / name :op1 "C/EBP"~e.45)))) :ARG1-of (k / knock-out-03~e.48)))) # ::id bel_pmid_1746_8755.25986 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the amount of Tgfb1 ( TGFb ) mRNA was higher in p38a @-@ deficient lungs compared with Mapk14D/+ lungs ( Fig . 3e ) . TGFb has been found to be overexpressed in C/EBPa knockout lungs17 , so the reduced C/EBPa levels in the Mapk14 @-@ null lungs could account for the higher TGFb expression . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2.1.1 5-1.2.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1 9-1.1.2 9-1.1.2.r 11-1.1.3.1.1.1.1 13-1.2.1.1.2.1 13-1.2.1.1.2.1.2 13-1.2.1.1.2.1.2.1 13-1.2.1.1.2.1.2.1.r 13-1.2.1.1.2.1.2.r 14-1.1.3 14-1.1.3.2.1 15-1.1.3.2 18-1.1.3 18-1.2.1.1.2 20-1.1.4.1 22-1.1.4.1.1 25-1.2.1.1.1.1.1 28-1.2.1 31-1.2.1.1 33-1.2.1.1.2.1.1.1 37-1.2 39-1.2.2.1.1.1 40-1.2.2.1.1.2 41-1.2.2.1.1 42-1.2.2.1.1.3.r 44-1.2.2.1.1.3.1.1.1 46-1.1.3.2.1.1 46-1.1.3.2.1.1.2 46-1.1.3.2.1.1.2.r 46-1.2.2.1.1.3.1 46-1.2.2.1.1.3.1.2 46-1.2.2.1.1.3.1.2.1 46-1.2.2.1.1.3.1.2.1.r 46-1.2.2.1.1.3.1.2.r 47-1.2.2.1.1.3 48-1.1.3.2.1.1.2.1 48-1.2.2 49-1.2.2.1 50-1.2.2.1.2.r 52-1.2.2.1.2.2 52-1.2.2.1.2.2.1 52-1.2.2.1.2.2.1.r 53-1.2.2.1.2.1 54-1.2.2.1.2 (m2 / multi-sentence :snt1 (h / high-02~e.9 :ARG1 (a / amount~e.1 :quant-of~e.2 (n8 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.7) :part-of (p2 / protein :name (n3 / name :op1 "Tgfb1"~e.3)))) :degree~e.9 (m / more~e.9) :location (l / lung~e.14,18 :ARG0-of (l2 / lack-01 :ARG1 (p / protein :name (n / name :op1 "p38a"~e.11))) :ARG1-of (c / compare-01~e.15 :ARG2 (l3 / lung~e.14 :mod (e / enzyme~e.46 :name (n2 / name :op1 "Mapk14D") :ARG2-of~e.46 (m3 / mutate-01~e.46 :mod "-/+"~e.48))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "3e"~e.22))) :snt2 (c2 / cause-01~e.37 :ARG0 (f2 / find-01~e.28 :ARG1 (o / overexpress-01~e.31 :ARG1 (p3 / protein :name (n5 / name :op1 "Tgfb"~e.5,25)) :location (l4 / lung~e.18 :mod (p5 / protein~e.13 :name (n6 / name :op1 "C/EBPa"~e.33) :ARG2-of~e.13 (m6 / mutate-01~e.13 :mod~e.13 "-/-"~e.13))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :mod 17)))) :ARG1 (p6 / possible-01~e.48 :ARG1 (a2 / account-01~e.49 :ARG0 (l6 / level~e.41 :ARG1-of (r2 / reduce-01~e.39) :quant-of p5~e.40 :location~e.42 (l5 / lung~e.47 :mod (e2 / enzyme~e.46 :name (n7 / name :op1 "Mapk14"~e.44) :ARG2-of~e.46 (m4 / mutate-01~e.46 :mod~e.46 "-/-"~e.46)))) :ARG1~e.50 (e3 / express-03~e.54 :ARG2 p3~e.53 :ARG1-of (h2 / high-02~e.52 :degree~e.52 (m5 / more~e.52))))))) # ::id bel_pmid_1746_8755.28766 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of KrasG12V induced also a loss of epithelial markers ( as assessed by E @-@ cadherin staining , which was similar in Mapk14D/+ and Mapk14D/D alveoli ; Fig. 6c ) and an increase in SP @-@ C+ cells ( Fig . 6d ) . # ::alignments 0-1.1 3-1 4-1.3 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.1 9-1.2.1.1 11-1.2.1.2.r 12-1.2.1.2 13-1.2.1.2.1.r 14-1.2.1.2.1.1.1.1 16-1.2.1.2.1.1.1.1 17-1.2.1.2.1 21-1.2.1.2.1.2.3 25-1.2.1.2.1.2.3.1.1.1.1 26-1.2.1.2.1.2 26-1.2.1.2.1.2.3.1 28-1.2.1.2.2.1 29-1.2.1.2.2.1.1 31-1.2 33-1.2.2 38-1.2.2.1 40-1.4.1 42-1.4.1.1 (i / induce-01~e.3 :ARG0 (e / express-03~e.0 :ARG2 (e5 / enzyme :name (n / name :op1 "KRAS") :ARG2-of (m / mutate-01 :value "G12V"))) :ARG2 (a2 / and~e.31 :op1 (l / lose-02~e.6 :ARG1~e.7 (m4 / marker~e.9 :mod (e2 / epithelium~e.8)) :ARG1-of~e.11 (a3 / assess-01~e.12 :ARG0~e.13 (s / stain-01~e.17 :ARG2 (p / protein :name (n3 / name :op1 "E-cadherin"~e.14,16)) :location (a5 / alveoli~e.26 :mod (e3 / enzyme :name (n5 / name :op1 "Mapk14D")) :ARG2-of (m3 / mutate-01 :mod "+/-") :ARG1-of (r / resemble-01~e.21 :ARG2 (a6 / alveoli~e.26 :mod (e4 / enzyme :name (n4 / name :op1 "Mapk14D/D"~e.25)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.28 :mod "6c"~e.29)))) :op2 (i2 / increase-01~e.33 :location (c / cell~e.38 :mod (p2 / protein :name (n2 / name :op1 "SPC+"))))) :mod (a / also~e.4) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "6d"~e.42))) # ::id bel_pmid_1746_8755.29060 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the SP @-@ C+ cells were more numerous in the Mapk14-/- lungs ( with almost twice as many as in Mapk14-/+ lungs ; Fig. 2c ) . Notably , immunohistological staining showed reduced levels of the epithelial marker E @-@ cadherin in the alveolar cells ( Fig . 2c ) , indicating defective differentiation of these cells . # ::alignments 0-1.1 6-1.1.1.2 6-1.1.2.1 7-1.1.1.2.r 8-1.1.1.1 9-1.1.1 9-1.1.2.1.1 13-1.1.1.3 15-1.1.2.1.1.1.r 16-1.1.2.1.1.1.3 17-1.1.2.1.1.1.1 23-1.1.1.3 23-1.1.2.1.1.1.2.1 25-1.2.5.1 26-1.2.5.1.1 29-1.2.4 32-1.2.1 33-1.2 34-1.2.2.1 35-1.2.2 36-1.2.2.2.r 38-1.2.2.2.1 39-1.2.2.2 40-1.2.2.2.2.1.1 42-1.2.2.2.2.1.1 43-1.2.3.r 45-1.2.3.1.1.1 46-1.2.3.1.1 48-1.2.5.1 50-1.2.5.1.1 53-1.2.3 54-1.2.3.1.2 55-1.2.3.1 56-1.1.2.1.1.1 58-1.1.2.1.1.1.2 (m / multi-sentence :snt1 (c / contrast-01~e.0 :ARG2 (n / numerous~e.9 :degree (m2 / more~e.8) :domain~e.7 (c2 / cell~e.6 :mod (p2 / protein :name (n2 / name :op1 "SPC+"))) :location (l / lung~e.13,23 :mod (e / enzyme :name (n3 / name :op1 "Mapk14") :ARG2-of (m3 / mutate-01 :mod "-/-")))) :ARG1-of (m5 / mean-01 :ARG2 (c4 / cell~e.6 :quant (n6 / numerous~e.9 :quant~e.15 (p3 / product-of~e.56 :op1 2~e.17 :op2 (c5 / cell~e.58 :location (l3 / lung~e.23 :mod (e3 / enzyme :name (n7 / name :op1 "Mapk14") :ARG2-of (m6 / mutate-01 :mod "-/+")))) :mod (a2 / almost~e.16)))))) :snt2 (s / show-01~e.33 :ARG0 (s2 / stain-01~e.32 :mod (i2 / immunohistology)) :ARG1 (l2 / level~e.35 :ARG1-of (r / reduce-01~e.34) :quant-of~e.36 (m7 / marker~e.39 :mod (e2 / epithelium~e.38) :mod (p / protein :name (n5 / name :op1 "E-cadherin"~e.40,42) :location c3))) :ARG0-of~e.43 (i / indicate-01~e.53 :ARG1 (d / differentiate-01~e.55 :ARG1 (c3 / cell~e.46 :mod (a / alveolus~e.45)) :mod (d2 / defective~e.54))) :ARG1-of (n4 / notable-04~e.29) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.25,48 :mod "2c"~e.26,50)))) # ::id bel_pmid_1746_8755.29062 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , we found that p38a @-@ deficient lungs contained lower levels of C/EBPa and HNF3b , another transcription factor involved in lung differentiation whose expression is controlled by C/EBPa ( ref . 19 ) ( Fig . 3a and Supplementary Fig. 1a online ) . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1.1.1 8-1.2.1 9-1.2 10-1.2.2.3 10-1.2.2.3.1 10-1.2.2.3.1.r 11-1.2.2.1 11-1.2.2.2 12-1.2.2.1.1.r 13-1.2.2.1.1.1.1 14-1.2.2 15-1.2.2.2.1.1.1 17-1.2.2.2.1.2.4 18-1.2.2.2.1.2.1.1 19-1.2.2.2.1.2.1.2 20-1.2.2.2.1.2.2 21-1.2.2.2.1.2.2.1.r 22-1.2.2.2.1.2.2.1.1 23-1.2.2.2.1.2.2.1 25-1.2.2.2.1.2 25-1.2.2.2.1.2.3 25-1.2.2.2.1.2.3.r 27-1.2.2.2.1.2.3.1 28-1.2.2.2.1.2.3.1.1.r 29-1.2.2.2.1.2.3.1.1 33-1.4.1.1.1 36-1.5.1.1 38-1.5.1.1.1 39-1.5.1 40-1.5.1.2.2 41-1.5.1.2 42-1.5.1.2.1 43-1.5.1.2.3 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (c / contain-01~e.9 :ARG0 (l2 / lung~e.8 :ARG0-of (l3 / lack-01 :ARG1 (p / protein :name (n2 / name :op1 "p38a"~e.5)))) :ARG1 (a / and~e.14 :op1 (l4 / level~e.11 :quant-of~e.12 (p2 / protein :name (n3 / name :op1 "C/EBPa"~e.13))) :op2 (l5 / level~e.11 :quant-of (p3 / protein :name (n4 / name :op1 "HNF3b"~e.15) :domain (p4 / protein~e.25 :name (n5 / name :op1 "transcription"~e.18 :op2 "factor"~e.19) :ARG1-of (i / involve-01~e.20 :ARG2~e.21 (d / differentiate-01~e.23 :ARG1 (l6 / lung~e.22))) :ARG2-of~e.25 (e / express-03~e.25 :ARG1-of (c2 / control-01~e.27 :ARG0~e.28 p2~e.29)) :mod (a2 / another~e.17)))) :ARG1-of (l / low-04~e.10 :degree~e.10 (m / more~e.10)))) :ARG1-of (n / notable-04~e.0) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 19~e.33))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.39 :op1 (f2 / figure~e.36 :mod "3a"~e.38) :op2 (f3 / figure~e.41 :mod "1a"~e.42 :ARG2-of (s / supplement-01~e.40) :medium (o / online~e.43))))) # ::id bel_pmid_1746_8755.29066 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , the higher number of AT2 cells correlated with an almost fivefold increase in Ki67+ cells in Mapk14-/- lungs compared with the number of Ki67+ cells in their heterozygous Mapk14D/+ counterparts ( Fig . 2d ) . # ::alignments 0-1 3-1.1.1.2 3-1.1.1.2.1 3-1.1.1.2.1.r 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 7-1.1.1.1 8-1.1 9-1.1.2.r 11-1.1.2.2 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 16-1.1.2.1 19-1.1.2.1.3 19-1.1.2.3.1.1.2 20-1.1.2.3 21-1.1.2.3.1.r 23-1.1.2.3.1 24-1.1.2.3.1.1.r 25-1.1.2.3.1.1.1.1 26-1.1.2.3.1.1 29-1.1.2.3.1.1.2.2 33-1.2.1 35-1.2.1.1 (a / and~e.0 :op2 (c / correlate-01~e.8 :ARG1 (n / number~e.4 :quant-of~e.5 (c3 / cell~e.7 :name (n3 / name :op1 "AT2"~e.6)) :ARG1-of (h / high-02~e.3 :degree~e.3 (m / more~e.3))) :ARG2~e.9 (i / increase-01~e.13 :ARG1~e.14 (c4 / cell~e.16 :name (n4 / name :op1 "Ki67+"~e.15) :ARG2-of (m2 / mutate-01 :mod "+/-") :location (l / lung~e.19 :mod (e / enzyme :name (n5 / name :op1 "Mapk14") :ARG2-of (m3 / mutate-01 :mod "-/-")))) :ARG2 (a2 / almost~e.11 :op1 (p / product-of :op1 5)) :ARG1-of (c2 / compare-01~e.20 :ARG2~e.21 (n2 / number~e.23 :quant-of~e.24 (c5 / cell~e.26 :name (n6 / name :op1 "Ki67+"~e.25) :location (l2 / lung~e.19 :mod (e2 / enzyme :name (n7 / name :op1 "Mapk14D")) :mod (h2 / heterozygous~e.29) :ARG2-of (m4 / mutate-01 :mod "-/+"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.33 :mod "2d"~e.35))) # ::id bel_pmid_1746_8755.29068 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also detected a reduction in STAT3 protein in Mapk14D/D lungs ( Fig . 3a ) that correlated with the reduction in Il6 mRNA ( Fig . 3 ) . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 6-1.2.1.1.1 7-1.2.1 7-1.2.3.1.1.2 8-1.2.2.r 9-1.2.2.1.1.1 10-1.2.2 12-1.2.4.1 14-1.2.4.1.1 17-1.2.3 18-1.2.3.1.r 20-1.2.3.1 23-1.2.3.1.1.1.1 25-1.4.1 27-1.4.1.1 (d / detect-01~e.2 :ARG0 (w / we~e.0) :ARG1 (r / reduce-01~e.4 :ARG1 (p / protein~e.7 :name (n / name :op1 "STAT3"~e.6)) :location~e.8 (l / lung~e.10 :mod (p2 / pathway :name (n2 / name :op1 "Mapk14D/D"~e.9))) :ARG1-of (c / correlate-01~e.17 :ARG2~e.18 (r2 / reduce-01~e.20 :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.23) :part (p3 / protein~e.7 :name (n4 / name :op1 "IL-6"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.12 :mod "3a"~e.14))) :mod (a / also~e.1) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.25 :mod 3~e.27))) # ::id bel_pmid_1746_8755.29072 ::amr-annotator SDL-AMR-09 ::preferred # ::tok three times as much Egfr mRNA was present in Mapk14D/D lungs ( Fig . 3d ) compared with Mapk14D/+ lungs , suggesting that EGFR expression was transcriptionally enhanced in the absence of p38a . # ::alignments 0-1.1.2.1 1-1.1.2 4-1.1.3.1.1.1 5-1.1.1.1 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2 12-1.6.1 14-1.6.1.1 16-1.3 19-1.3.1 21-1.4 22-1.4.1.r 23-1.4.1.1.1.1.1 24-1.4.1.1 26-1.4.1.2 27-1.4.1 28-1.4.1.3.r 30-1.4.1.3 31-1.4.1.3.1.r 32-1.4.1.3.1.1.1 (p / present-02~e.7 :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "mRNA"~e.5) :quant (p3 / product-of~e.1 :quant 3~e.0) :ARG0-of (e6 / encode-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "Egfr"~e.4)))) :ARG2~e.8 (l / lung~e.10 :mod (e7 / enzyme :name (n3 / name :op1 "Mapk14D/D"~e.9))) :ARG1-of (c / compare-01~e.16 :ARG2 (l2 / lung~e.19 :mod (e8 / enzyme :name (n5 / name :op1 "Mapk14D") :ARG2-of (m / mutate-01 :mod "+/+")))) :ARG0-of (s / suggest-01~e.21 :ARG1~e.22 (e / enhance-01~e.27 :ARG1 (e2 / express-03~e.24 :ARG2 (e3 / enzyme :name (n / name :op1 "EGFR"~e.23))) :manner (t / transcribe-01~e.26) :condition~e.28 (a / absent-01~e.30 :ARG1~e.31 (p2 / protein :name (n2 / name :op1 "p38a"~e.32))))) :mod e3 :ARG1-of (d / describe-01 :ARG0 (f / figure~e.12 :mod "3d"~e.14))) # ::id bel_pmid_1746_8755.29082 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , EGFR transcription is regulated by AP @-@ 1 ( ref . 28 ) , and we observed higher levels of phospho @-@ c @-@ Jun , one of the AP @-@ 1 components , in the p38a @-@ deficient lungs ( Fig . 3c ) , suggesting that p38a downregulation might activate AP @-@ 1 . # ::alignments 0-1.1.4 2-1.1.2.1.1.1 3-1.1.2 5-1.1 6-1.1.1.r 7-1.1.1.1.1 9-1.1.1.1.1 13-1.1.3.1.1.1 16-1 17-1.2.1 18-1.2 19-1.2.2.1 19-1.2.2.1.1 19-1.2.2.1.1.r 20-1.2.2 21-1.2.2.2.r 22-1.2.2.2 22-1.2.2.2.3 22-1.2.2.2.3.r 24-1.2.2.2.1.1 26-1.2.2.2.1.1 28-1.2.2.2.2.1.1 29-1.2.2.2.2.1.1 30-1.2.2.2.2.1.1 31-1.2.2.2.2.1.1 32-1.2.2.2.2.1.1 33-1.2.2.2.2.1.1 34-1.2.2.2.2.1 36-1.2.2.3.r 38-1.2.2.3.1.1.1.1 41-1.2.2.3 43-1.2.3.1 45-1.2.3.1.1 48-1.3 49-1.3.1.r 50-1.3.1.1.1.1 51-1.3.1.1.1 52-1.3.1 53-1.3.1.1 54-1.3.1.1.2 55-1.3.1.1.2 56-1.3.1.1.2 (a / and~e.16 :op1 (r / regulate-01~e.5 :ARG0~e.6 (p3 / protein :name (n3 / name :op1 "AP-1"~e.7,9)) :ARG1 (t / transcribe-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.2))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 28~e.13))) :ARG1-of (n2 / notable-04~e.0)) :op2 (o / observe-01~e.18 :ARG0 (w / we~e.17) :ARG1 (l / level~e.20 :ARG1-of (h / high-02~e.19 :degree~e.19 (m / more~e.19)) :quant-of~e.21 (p / protein~e.22 :name (n4 / name :op1 "c-Jun"~e.24,26) :ARG1-of (i / include-91 :ARG2 (c2 / component~e.34 :poss p3~e.28,29,30,31,32,33)) :ARG1-of~e.22 (p4 / phosphorylate-01~e.22)) :location~e.36 (l2 / lung~e.41 :ARG0-of (l3 / lack-01 :ARG1 (p6 / protein :name (n5 / name :op1 "p38a"~e.38))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.43 :mod "3c"~e.45))) :ARG0-of (s / suggest-01~e.48 :ARG1~e.49 (p5 / possible-01~e.52 :ARG1 (a2 / activate-01~e.53 :ARG0 (d3 / downregulate-01~e.51 :ARG1 p6~e.50) :ARG1 p3~e.54,55,56)))) # ::id bel_pmid_1746_8757.6426 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , inactivation of JNK or c @-@ Jun suppressed the increased proliferation of Mapk14 @-@ deficient hepatocytes and tumor cells . # ::alignments 0-1 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1.2.r 4-1.1.1.2.1.1.1 5-1.1.1.2 6-1.1.1.2.2.1.1 8-1.1.1.2.2.1.1 9-1.1 11-1.1.2.2 12-1.1.2 13-1.1.2.1.r 14-1.1.2.1.1.2.1.1.1 17-1.1.2.1.1.1.1 18-1.1.2.1 19-1.1.2.1.2.1 20-1.1.2.1.2 (a / and~e.0 :op2 (s / suppress-01~e.9 :ARG0 (a2 / activate-01~e.2 :polarity~e.2 -~e.2 :ARG1~e.3 (o / or~e.5 :op1 (e / enzyme :name (n / name :op1 "JNK"~e.4)) :op2 (p / protein :name (n2 / name :op1 "c-Jun"~e.6,8)))) :ARG1 (p2 / proliferate-01~e.12 :ARG0~e.13 (a3 / and~e.18 :op1 (c / cell :name (n3 / name :op1 "hepatocyte"~e.17) :ARG0-of (l / lack-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Mapk14"~e.14)))) :op2 (c2 / cell~e.20 :mod (t / tumor~e.19))) :ARG1-of (i / increase-01~e.11)))) # ::id bel_pmid_1750_7094.5814 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upon stimulation with TLR ligands , p105 is phosphorylated by I kappa B kinase ( IKK ) complex and partially degraded , which releases TPL2 . The free TPL2 is active and stimulates the ERK pathway via MEK1 @/@ 2 . # ::alignments 1-1.1.4 2-1.1.4.1.r 3-1.1.4.1.1.1 4-1.1.4.1 6-1.1.1.1.1.1 8-1.1.1 13-1.1.1.2.1.2 18-1.1 19-1.1.2.2 19-1.1.2.2.r 20-1.1.2 23-1.1.3 24-1.1.3.1.1.1 24-1.2.1.1.1.1 27-1.2.1.1 27-1.2.1.1.2 27-1.2.1.1.2.r 28-1.2.1.1.1.1 30-1.2.1 31-1.2 32-1.2.2 34-1.2.2.2.1.1 35-1.2.2.2 37-1.2.2.3.1.1 39-1.2.2.3.1.1 (m / multi-sentence :snt1 (a / and~e.18 :op1 (p / phosphorylate-01~e.8 :ARG1 (p2 / protein :name (n / name :op1 "p105"~e.6)) :ARG2 (e4 / enzyme :name (n2 / name :op1 "IκB" :op2 "kinase"~e.13))) :op2 (d / degrade-01~e.20 :ARG1 p2 :degree~e.19 (p3 / part~e.19)) :ARG0-of (r / release-01~e.23 :ARG1 (e / enzyme :name (n3 / name :op1 "TPL2"~e.24))) :time (s / stimulate-01~e.1 :ARG2~e.2 (l / ligand~e.4 :name (n4 / name :op1 "TLR"~e.3)))) :snt2 (a2 / and~e.31 :op1 (a3 / activity-06~e.30 :ARG0 (e2 / enzyme~e.27 :name (n5 / name :op1 "TPL2"~e.24,28) :ARG1-of~e.27 (f / free-04~e.27))) :op2 (s2 / stimulate-01~e.32 :ARG0 e2 :ARG1 (p4 / pathway~e.35 :name (n6 / name :op1 "ERK"~e.34)) :ARG2 (e3 / enzyme :name (n7 / name :op1 "MEK1/2"~e.37,39))))) # ::id bel_pmid_1751_1588.20428 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Angiopoietin @-@ 1 stimulates association of SHP @-@ 2 to the phosphorylated Tie @-@ 2 receptor ( 47 ) , which in turn inhibits PI3 kinase @-@ dependent signaling pathways leading to EC migration . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2 5-1.2.2.r 6-1.2.2.1.1 8-1.2.2.1.1 9-1.2.3.r 11-1.2.3.2 12-1.2.3.1.1 14-1.2.3.1.1 15-1.2.3 17-1.3.1.1.1 21-1.2.4.3 22-1.2.4.3 23-1.2.4 24-1.2.4.1.2.1.1.1 25-1.2.4.1.2.1 27-1.2.4.1.2 28-1.2.4.1.1 29-1.2.4.1 30-1.2.4.2 31-1.2.4.2.1.r 32-1.2.4.2.1.1.1.1 33-1.2.4.2.1 (s / stimulate-01~e.3 :ARG0 (p / protein :name (n / name :op1 "angiopoietin-1"~e.0,2)) :ARG1 (a / associate-01~e.4 :ARG0 p :ARG1~e.5 (p5 / protein :name (n2 / name :op1 "SHP-2"~e.6,8)) :ARG2~e.9 (r / receptor~e.15 :name (n3 / name :op1 "Tie-2"~e.12,14) :ARG1-of (p2 / phosphorylate-01~e.11)) :ARG0-of (i / inhibit-01~e.23 :ARG1 (p3 / pathway~e.29 :ARG0-of (s2 / signal-07~e.28) :ARG0-of (d / depend-01~e.27 :ARG1 (k / kinase~e.25 :name (n4 / name :op1 "PI3"~e.24)))) :ARG0-of (l / lead-03~e.30 :ARG2~e.31 (m / migrate-01~e.33 :ARG0 (c / cell :name (n5 / name :op1 "EC"~e.32)))) :mod (i2 / in-turn~e.21,22))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 47~e.17)))) # ::id bel_pmid_1751_1588.36510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of dominant negative N17Rac1 significantly inhibits VEGF @-@ induced ROS production that is involved in VEGFR2 activation , EC migration , and proliferation ( 100 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 4-1.1.1.1.1 5-1.3 6-1 7-1.2.2.1.1.1 9-1.2.2 10-1.2.1.1.1 11-1.2 14-1.2.3 15-1.2.3.1.r 16-1.2.3.1.1.1.1.1 17-1.2.3.1.1 19-1.2.3.1.2.1.1.1.1 20-1.2.3.1.2.1 22-1.2.3.1.2 23-1.2.3.1.2.2 25-1.4.1.1.1 (i / inhibit-01~e.6 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (e / enzyme~e.2 :name (n / name :op1 "N17Rac1"~e.4) :ARG0-of~e.2 (d / dominate-01~e.2) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (p / produce-01~e.11 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "ROS"~e.10)) :ARG2-of (i2 / induce-01~e.9 :ARG0 (p2 / protein :name (n4 / name :op1 "VEGF"~e.7))) :ARG1-of (i3 / involve-01~e.14 :ARG2~e.15 (a / and :op1 (a2 / activate-01~e.17 :ARG1 (p3 / protein :name (n5 / name :op1 "VEGFR2"~e.16))) :op2 (a3 / and~e.22 :op1 (m2 / migrate-01~e.20 :ARG0 (c / cell :name (n6 / name :op1 "EC"~e.19))) :op2 (p4 / proliferate-01~e.23 :ARG0 c))))) :ARG1-of (s / significant-02~e.5) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 100~e.25)))) # ::id bel_pmid_1751_1588.36636 ::amr-annotator SDL-AMR-09 ::preferred # ::tok VEGFR2 forms a complex with VE @-@ cadherin , -@ catenin , and PI3 kinase that is required for phosphorylation of Akt , which plays an important role in EC survival ( 15 ) and migration ( 27 , 28 , 80 ) . # ::alignments 0-1.1.1.1 1-1 3-1.2 5-1.2.2.1.1 5-1.2.3.1.1 7-1.2.2.1.1 10-1.2.3.1.1 13-1.2.4.1.1 14-1.2.4 17-1.2.5 18-1.2.5.1.r 19-1.2.5.1 20-1.2.5.1.1.r 21-1.2.5.1.1.1.1 24-1.2.5.1.2 26-1.2.5.1.2.1.3 28-1.2.5.1.2.1.r 29-1.2.5.1.2.1.1.1.1.1 30-1.2.5.1.2.1.1 32-1.2.5.1.2.1.1.2.1.1.1 34-1.2.5.1.2.1 35-1.2.5.1.2.1.2 37-1.2.5.1.2.1.2.2.1.1.1.1 39-1.2.5.1.2.1.2.2.1.1.1.2 41-1.2.5.1.2.1.2.2.1.1.1.3 (f / form-01~e.1 :ARG0 (p / protein :name (n / name :op1 "VEGFR2"~e.0)) :ARG1 (m / macro-molecular-complex~e.3 :part p :part (p2 / protein :name (n2 / name :op1 "VE-cadherin"~e.5,7)) :part (p3 / protein :name (n3 / name :op1 "VE-catenin"~e.5,10)) :part (k / kinase~e.14 :name (n4 / name :op1 "PI3"~e.13)) :ARG1-of (r / require-01~e.17 :ARG0~e.18 (p4 / phosphorylate-01~e.19 :ARG2~e.20 (e / enzyme :name (n5 / name :op1 "Akt"~e.21)) :ARG0-of (p5 / play-08~e.24 :ARG1~e.28 (a / and~e.34 :op1 (s / survive-02~e.30 :ARG0 (c / cell :name (n6 / name :op1 "EC"~e.29)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 15~e.32)))) :op2 (m2 / migrate-01~e.35 :ARG0 c :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 27~e.37 :op2 28~e.39 :op3 80~e.41))))) :mod (i / important~e.26))))))) # ::id bel_pmid_1751_3865.31240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok FIGURE 9 . TGF @-@ beta1 induces snail @-@ 1 in hepatocytes in EMT state and lack of evidence for Akt @/@ Erk1 @/@ 2 activation # ::alignments 0-1.1 1-1.1.1 3-1.2.1.1.1 6-1.2 7-1.2.2.1.1 9-1.2.2.1.1 10-1.2.3.r 11-1.2.3.1.1 13-1.2.3.2.1.1.2 15-1.2.3.2 16-1.2.3.2.2 17-1.2.3.2.2.1.r 18-1.2.3.2.2.1 19-1.2.3.2.2.1.1.r 20-1.2.3.2.2.1.1.1.1.1 22-1.2.3.2.2.1.1.1.1.1 24-1.2.3.2.2.1.1.1.1.1 25-1.2.3.2.2.1.1 (d / describe-01 :ARG0 (f / figure~e.0 :mod 9~e.1) :ARG1 (i / induce-01~e.6 :ARG0 (p / protein :name (n / name :op1 "TGF-β1"~e.3)) :ARG2 (p2 / protein :name (n2 / name :op1 "snail-1"~e.7,9)) :location~e.10 (c / cell :name (n3 / name :op1 "hepatocyte"~e.11) :condition (a / and~e.15 :op1 (e2 / event :name (n4 / name :op1 "epithelial−mesenchymal" :op2 "transition"~e.13)) :op2 (l / lack-01~e.16 :ARG1~e.17 (e / evidence-01~e.18 :ARG1~e.19 (a2 / activate-01~e.25 :ARG1 (p3 / pathway :name (n5 / name :op1 "Akt/Erk1/2"~e.20,22,24))))))))) # ::id bel_pmid_1751_3865.39040 ::amr-annotator SDL-AMR-09 ::preferred # ::tok FIGURE 11 . TGF @-@ beta1 induces activation of Smad2 @/@ 3 pathway in AML12 cell line # ::alignments 0-1.1 1-1.1.1 3-1.2.1.1.1 6-1.2 7-1.2.2 8-1.2.2.2.r 9-1.2.2.2.1.1 11-1.2.2.2.1.1 12-1.2.2.2 13-1.2.2.3.r 14-1.2.2.3.1.1 15-1.2.2.3 16-1.2.2.3 (d / describe-01 :ARG0 (f / figure~e.0 :mod 11~e.1) :ARG1 (i / induce-01~e.6 :ARG0 (p / protein :name (n / name :op1 "TGF-β1"~e.3)) :ARG2 (a / activate-01~e.7 :ARG0 p :ARG1~e.8 (p2 / pathway~e.12 :name (n2 / name :op1 "Smad2/3"~e.9,11)) :location~e.13 (c / cell-line~e.15,16 :name (n3 / name :op1 "AML12"~e.14))))) # ::id bel_pmid_1764_3885.30204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Aortas from COX @-@ 2?/? mice on atherogenic diet after 3 weeks had significantly larger areas of neutral lipid content as measured by Oil Red O staining ( Fig . 1A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.r 7-1.1.1.2.1 8-1.1.1.2 9-1.3 10-1.3.1.1 11-1.3.1.2 12-1 13-1.2.1.2 14-1.2.1 14-1.2.1.1 14-1.2.1.1.r 15-1.2 16-1.2.2.r 17-1.2.2.1.1 18-1.2.2.1 19-1.2.2 20-1.2.3.r 20-1.3.r 21-1.2.3 22-1.2.3.1.r 23-1.2.3.1.1.1.1 24-1.2.3.1.1.1.2 25-1.2.3.1.1.1.3 26-1.2.3.1 28-1.4.1 30-1.4.1.1 (h / have-03~e.12 :ARG0 (a / aorta~e.0 :source~e.1 (m / mouse~e.5 :mod (e / enzyme :name (n / name :op1 "COX-2"~e.2) :ARG2-of (m2 / mutate-01 :mod "-/-")) :condition~e.6 (d / diet~e.8 :mod (a2 / atherogenic~e.7)))) :ARG1 (a3 / area~e.15 :quant (l / large~e.14 :degree~e.14 (m3 / more~e.14) :ARG1-of (s / significant-02~e.13)) :ARG0-of~e.16 (c / contain-01~e.19 :ARG1 (l2 / lipid~e.18 :ARG0-of (n2 / neutral-02~e.17))) :ARG1-of~e.20 (m4 / measure-01~e.21 :ARG2~e.22 (s2 / stain-01~e.26 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "Oil"~e.23 :op2 "Red"~e.24 :op3 "O"~e.25))))) :time~e.20 (a4 / after~e.9 :op1 (t / temporal-quantity :quant 3~e.10 :unit (w / week~e.11))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.28 :mod "1A"~e.30))) # ::id bel_pmid_1764_3885.30206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Serum TXB2 is significantly increased in COX @-@ 2?/? mice on chow compared to wild @-@ type littermates ( Fig . 4A ) . # ::alignments 0-1.1.2 1-1.1.1.1 3-1.2 4-1 5-1.3.r 6-1.3.1.1.1 9-1.3 11-1.3.2.1 12-1.4.r 14-1.4.1 16-1.4.1 17-1.4 19-1.5.1 21-1.5.1.1 (i / increase-01~e.4 :ARG1 (s3 / small-molecule :name (n / name :op1 "TXB2"~e.1) :mod (s / serum~e.0)) :ARG2 (s2 / significant-02~e.3) :location~e.5 (m2 / mouse~e.9 :mod (e / enzyme :name (n2 / name :op1 "COX-2"~e.6) :ARG2-of (m3 / mutate-01 :mod "-/-")) :mod (d / diet :mod (c / chow~e.11))) :compared-to~e.12 (l / littermate~e.17 :mod (w / wild-type~e.14,16)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.19 :mod "4A"~e.21))) # ::id bel_pmid_1764_3885.30216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , COX @-@ 2?/? mice on atherogenic diet showed more systemic inflammation with higher levels of TNF ( Fig . 5B ) and IL @-@ 6 ( Fig . 5D ) than wild @-@ type controls . Furthermore , IL @-@ 12 was significantly increased by atherogenic diet in wild @-@ type controls , while COX @-@ 2 depletion completely abolished this induction ( Fig . 5E ) . # ::alignments 0-1.1.3 0-1.1.3.r 2-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.r 7-1.1.1.2.1 8-1.1.1.2 9-1.1 10-1.1.2.1.1 10-1.1.2.2.2.1 11-1.1.2.1 12-1.1.2 13-1.1.2.2.r 14-1.1.2.2.2 14-1.1.2.2.2.1 14-1.1.2.2.2.1.r 15-1.1.2.2 16-1.1.2.2.1.r 17-1.1.2.2.1.1.1.1 19-1.1.2.2.1.1.2.1 21-1.1.2.2.1.1.2.1.1 23-1.1.2.2.1 24-1.1.2.2.1.2.1.1 26-1.1.2.2.1.2.1.1 28-1.1.2.2.1.2.2.1 30-1.1.2.2.1.2.2.1.1 32-1.1.2.2.2.2.r 33-1.1.2.2.2.2.1 35-1.1.2.2.2.2.1 36-1.1.2.2.2.2 38-1.2 40-1.2.1.1.2.1.1 42-1.2.1.1.2.1.1 44-1.2.1.1.3 45-1.2.1.1 46-1.2.1.1.1.r 47-1.2.1.1.1.1 48-1.2.1.1.1 50-1.1.2.2.2.2.1 52-1.2.1.1.4.1 53-1.2.1.1.4 55-1.2.1 56-1.2.1.2.1.1.1.1 58-1.2.1.2.1.1.1.1 59-1.2.1.2.1 60-1.2.1.2.3 61-1.2.1.2 62-1.2.1.2.2.1 63-1.2.1.2.2 65-1.2.2.1 67-1.2.2.1.1 (m / multi-sentence :snt1 (s / show-01~e.9 :ARG0 (m2 / mouse~e.5 :mod (e / enzyme :name (n / name :op1 "COX-2"~e.2) :ARG2-of (m3 / mutate-01 :mod "-/-")) :condition~e.6 (d / diet~e.8 :mod (a / atherogenic~e.7))) :ARG1 (i / inflame-01~e.12 :mod (s2 / systemic~e.11 :degree (m4 / more~e.10)) :mod~e.13 (l / level~e.15 :quant-of~e.16 (a2 / and~e.23 :op1 (p / protein :name (n2 / name :op1 "TNF"~e.17) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.19 :mod "5B"~e.21))) :op2 (p2 / protein :name (n3 / name :op1 "IL-6"~e.24,26) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.28 :mod "5D"~e.30)))) :ARG1-of (h / high-02~e.14 :degree~e.14 (m5 / more~e.10,14) :compared-to~e.32 (c / control-01~e.36 :mod (w / wild-type~e.33,35,50))))) :manner~e.0 (i2 / interesting~e.0)) :snt2 (a3 / and~e.38 :op2 (c2 / contrast-01~e.55 :ARG1 (i3 / increase-01~e.45 :ARG0~e.46 (d4 / diet~e.48 :mod (a4 / atherogenic~e.47)) :ARG1 (p3 / protein :name (n4 / name :op1 "IL-12"~e.40,42)) :ARG2 (s3 / significant-02~e.44) :location (c3 / control-01~e.53 :mod (w2 / wild-type~e.52))) :ARG2 (a5 / abolish-01~e.61 :ARG0 (d5 / deplete-01~e.59 :ARG1 (e2 / enzyme :name (n5 / name :op1 "COX-2"~e.56,58))) :ARG1 (i4 / induce-01~e.63 :mod (t / this~e.62)) :ARG1-of (c4 / complete-02~e.60))) :ARG1-of (d6 / describe-01 :ARG0 (f3 / figure~e.65 :mod "5E"~e.67)))) # ::id bel_pmid_1769_2569.37970 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 1 . Production of pro @- and anti @-@ angiogenic mediators by DCs Pro @-@ angiogenic mediators : VEGF , FGF2 , TNF @-@ a , IL @-@ 6 , TGF @-@ b , CXCL8 , CXCL5 , CXCL1 , 2 , 3 , CCL2 , GM @-@ CSF , ET @-@ 1 , OPN , Anti @-@ angiogenic mediators : IL @-@ 12 , IL @-@ 18 , IL @-@ 10 , TSP @-@ 1 , PTX3 , IFN @-@ a/b , CXCL9 , CXCL10 , CXCL13 , CCL21 # ::alignments 0-1.1 1-1.1.1 3-1.2 4-1.2.2.r 5-1.2.2.1.2 7-1.2.2 7-1.2.2.1.3.1 8-1.2.2.2 8-1.2.2.2.2 8-1.2.2.2.2.r 11-1.2.2.1 11-1.2.2.1.1 11-1.2.2.1.1.r 14-1.2.2.1.2 17-1.2.2.1 17-1.2.2.1.1 17-1.2.2.1.1.r 19-1.2.2.1.3.1.1.1.1 21-1.2.2.1.3.1.2.1.1 23-1.2.2.1.3.1.3.1.1 27-1.2.2.1.3.1.4.1.1 29-1.2.2.1.3.1.4.1.1 31-1.2.2.1.3.1.5.1.1 35-1.2.2.1.3.1.6.1.1 37-1.2.2.1.3.1.7.1.1 39-1.2.2.1.3.1.8.1.1 45-1.2.2.1.3.1.11.1.1 47-1.2.2.1.3.1.12.1.1 49-1.2.2.1.3.1.12.1.1 51-1.2.2.1.3.1 51-1.2.2.1.3.1.13.1.1 53-1.2.2.1.3.1.13.1.1 55-1.2.2.1.3.1.14.1.1 57-1.2.2.2 57-1.2.2.2.2 57-1.2.2.2.2.r 60-1.2.2.2.1 62-1.2.2.2.3.1.1.1.1 64-1.2.2.2.3.1.1.1.1 66-1.2.2.2.3.1.1.1.1 66-1.2.2.2.3.1.2.1.1 66-1.2.2.2.3.1.3.1.1 68-1.2.2.2.3.1.2.1.1 70-1.2.2.2.3.1.1.1.1 70-1.2.2.2.3.1.2.1.1 70-1.2.2.2.3.1.3.1.1 72-1.2.2.2.3.1.3.1.1 74-1.2.2.2.3.1.4.1.1 76-1.2.2.2.3.1.4.1.1 78-1.2.2.2.3.1.5.1.1 80-1.2.2.2.3.1.6.1.1 84-1.2.2.2.3.1.7.1.1 86-1.2.2.2.3.1.8.1.1 88-1.2.2.2.3.1.9.1.1 90-1.2.2.2.3.1.10.1.1 (d / describe-01 :ARG0 (t / table~e.0 :mod 1~e.1) :ARG1 (p / produce-01~e.3 :ARG0 (c / cell :name (n / name :op1 "DC")) :ARG1~e.4 (a / and~e.7 :op1 (m / molecular-physical-entity~e.11,17 :ARG0-of~e.11,17 (m2 / mediate-01~e.11,17) :ARG0-of (f / favor-01~e.5,14 :ARG1 (a2 / angiogenesis)) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and~e.7,51 :op1 (p2 / protein :name (n2 / name :op1 "VEGF"~e.19)) :op2 (p3 / protein :name (n3 / name :op1 "FGF2"~e.21)) :op3 (p4 / protein :name (n4 / name :op1 "TNF-α"~e.23)) :op4 (p5 / protein :name (n5 / name :op1 "IL-6"~e.27,29)) :op5 (p6 / protein :name (n6 / name :op1 "TGF-β"~e.31)) :op6 (p7 / protein :name (n7 / name :op1 "CXCL8"~e.35)) :op7 (p8 / protein :name (n8 / name :op1 "CXCL5"~e.37)) :op8 (p9 / protein :name (n9 / name :op1 "CXCL1"~e.39)) :op9 (p10 / protein :name (n10 / name :op1 "CXCL2")) :op10 (p11 / protein :name (n11 / name :op1 "CXCL3")) :op11 (p12 / protein :name (n12 / name :op1 "CCL2"~e.45)) :op12 (p13 / protein :name (n13 / name :op1 "GM-CSF"~e.47,49)) :op13 (p14 / protein :name (n14 / name :op1 "ET-1"~e.51,53)) :op14 (p15 / protein :name (n15 / name :op1 "OPN"~e.55))))) :op2 (m4 / molecular-physical-entity~e.8,57 :ARG0-of m2~e.60 :ARG0-of~e.8,57 (c2 / counter-01~e.8,57 :ARG1 a2) :ARG1-of (m5 / mean-01 :ARG2 (a4 / and :op1 (p16 / protein :name (n16 / name :op1 "IL-12"~e.62,64,66,70)) :op2 (p17 / protein :name (n17 / name :op1 "IL-18"~e.66,68,70)) :op3 (p18 / protein :name (n18 / name :op1 "IL-10"~e.66,70,72)) :op4 (p19 / protein :name (n19 / name :op1 "TSP-1"~e.74,76)) :op5 (p20 / protein :name (n20 / name :op1 "PTX3"~e.78)) :op6 (p21 / protein :name (n21 / name :op1 "IFN-α/β"~e.80)) :op7 (p22 / protein :name (n22 / name :op1 "CXCL9"~e.84)) :op8 (p23 / protein :name (n23 / name :op1 "CXCL10"~e.86)) :op9 (p24 / protein :name (n24 / name :op1 "CXCL13"~e.88)) :op10 (p25 / protein :name (n25 / name :op1 "CCL21"~e.90)))))))) # ::id bel_pmid_1770_9751.28596 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Flow cytometry confirmed that follicular B cells present in Itpkb ?/? and Itpkb ?/? E ? -2 @–@ 22 BCL @-@ 2 mice expressed a higher level of Bim protein . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.2.3 5-1.2.2.1.1 6-1.2.2 7-1.2.2.2 9-1.2.2.2.1.1.1.1.1 12-1.2.2.2.1.1.1.1.1 19-1.2.2.2.1.2.1.1.1 21-1.2.2.2.1.2.1.1.1 22-1.2.2.2.1.1 22-1.2.2.2.1.2 23-1.2 25-1.2.1.2 25-1.2.1.2.1 25-1.2.1.2.1.r 26-1.2.1 28-1.2.1.1.1.1 29-1.2.1.1 29-1.2.2.2.1.2.1 (c / confirm-01~e.2 :ARG0 (c3 / cytometry~e.1 :mod (f2 / flow~e.0)) :ARG1~e.3 (e / express-03~e.23 :ARG2 (l / level~e.26 :quant-of (p / protein~e.29 :name (n2 / name :op1 "Bim"~e.28)) :ARG1-of (h / high-02~e.25 :degree~e.25 (m / more~e.25))) :ARG3 (c2 / cell~e.6 :name (n3 / name :op1 "B"~e.5) :ARG1-of (p3 / present-02~e.7 :ARG2 (a / and :op1 (m2 / mouse~e.22 :mod (e2 / enzyme :name (n4 / name :op1 "Itpkb"~e.9,12) :ARG2-of (m3 / mutate-01 :mod "-/-"))) :op2 (m4 / mouse~e.22 :mod (p2 / protein~e.29 :name (n5 / name :op1 "BCL-2"~e.19,21) :mod (d / dna-sequence :name (n6 / name :op1 "Eμ-2–22") :mod e2))))) :location (f / follicle~e.4)))) # ::id bel_pmid_1770_9751.28598 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Erk1 and Erk2 were found to be much less phosphorylated in Itpkb ?/? E ? -2?22 @-@ BCL @-@ 2 B cells than in control B cells after BCR activation ( Fig . 3 b ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 4-1 7-1.1.2.1 8-1.1.2 9-1.1 10-1.1.3.r 11-1.1.3.2.2.2.1.1 17-1.1.3.2.1.1 19-1.1.3.2.1.1 20-1.1.3.1.1 20-1.1.3.3.1.1 21-1.1.3 21-1.1.3.3 22-1.1.3.3.r 24-1.1.3.3.2 25-1.1.3.3.1.1 26-1.1.3.3 27-1.2 28-1.2.1.1.1.1 29-1.2.1 31-1.3.1 34-1.1.3.1.1 34-1.1.3.3.1.1 (f / find-01~e.4 :ARG1 (p / phosphorylate-01~e.9 :ARG1 (a / and~e.1 :op1 (e / enzyme :name (n / name :op1 "Erk1"~e.0)) :op2 (e2 / enzyme :name (n2 / name :op1 "Erk2"~e.2))) :quant (l / less~e.8 :degree (m / much~e.7)) :location~e.10 (c / cell~e.21 :name (n3 / name :op1 "B"~e.20,34) :mod (p2 / protein :name (n6 / name :op1 "BCL-2"~e.17,19) :mod (d / dna-sequence :name (n4 / name :op1 "Eμ-2–22") :mod (e3 / enzyme :name (n5 / name :op1 "Itpkb"~e.11) :ARG2-of (m2 / mutate-01 :mod "-/-")))) :compared-to~e.22 (c2 / cell~e.21,26 :name (n7 / name :op1 "B"~e.20,25,34) :mod (c3 / control~e.24)))) :time (a2 / after~e.27 :op1 (a3 / activate-01~e.29 :ARG1 (p3 / protein :name (n8 / name :op1 "BCR"~e.28)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.31 :mod "3b"))) # ::id bel_pmid_1770_9751.28600 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Quantitative real @-@ time RT @-@ PCR analysis revealed a slight , but very significant , increase in Bim messenger RNA level in splenic resting follicular B cells persisting in Itpkb ?/? mice . # ::alignments 0-1.1.3 1-1.1.2 3-1.1.2 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1 8-1 10-1.2.2 12-1.2.2.1 13-1.2.2.1.1.1 14-1.2.2.1.1 16-1.2 17-1.2.1.r 18-1.2.1.1.2.1.1.1 19-1.2.1.1.1.1 20-1.2.1.1.1.2 21-1.2.1 22-1.2.3.r 23-1.2.3.3.1 24-1.2.3.3 25-1.2.3.2 26-1.2.3.1.1 27-1.2.3 28-1.2.3.4 29-1.2.3.4.1.r 30-1.2.3.4.1.1.1.1 32-1.2.3.4.1 (r / reveal-01~e.8 :ARG0 (a / analyze-01~e.7 :mod (t / thing :name (n / name :op1 "RT-PCR"~e.4,6)) :mod (r2 / real-time~e.1,3) :mod (q / quantitative~e.0)) :ARG1 (i / increase-01~e.16 :ARG1~e.17 (l / level~e.21 :quant-of (n6 / nucleic-acid :name (n2 / name :op1 "messenger"~e.19 :op2 "RNA"~e.20) :ARG1-of (e / express-03 :ARG2 (p / protein :name (n3 / name :op1 "Bim"~e.18))))) :ARG2 (s / slight~e.10 :ARG1-of (c / contrast-01~e.12 :ARG2 (s2 / significant-02~e.14 :degree (v / very~e.13)))) :location~e.22 (c2 / cell~e.27 :name (n4 / name :op1 "B"~e.26) :location (f / follicle~e.25) :ARG1-of (r4 / rest-01~e.24 :location (s3 / spleen~e.23)) :ARG1-of (p2 / persist-01~e.28 :location~e.29 (m / mouse~e.32 :mod (e2 / enzyme :name (n5 / name :op1 "Itpkb"~e.30) :ARG2-of (m2 / mutate-01 :mod "-/-"))))))) # ::id bel_pmid_1780_4750.41494 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The forkhead transcription factor Foxp3 is highly expressed in CD4+CD25+ regulatory T cells ( Treg ) and was recently identified as a key player in mediating their inhibitory functions . # ::alignments 1-1.1.1.1.1 2-1.1.1.1.2 3-1.1.1.1.3 4-1.1.1.2.1.1.1 6-1.1.3 7-1.1 10-1.1.2.4 11-1.1.2.1.1 12-1.1.2 16-1 18-1.2.3 19-1.2 20-1.2.2.r 20-1.2.3.r 22-1.2.2.2 23-1.2.2 23-1.2.2.1 23-1.2.2.1.r 24-1.2.2.2.1.r 25-1.2.2.2.1 27-1.2.2.2.1.2.2 28-1.2.2.2.1.2 (a / and~e.16 :op1 (e / express-03~e.7 :ARG2 (p / protein :name (n / name :op1 "forkhead"~e.1 :op2 "transcription"~e.2 :op3 "factor"~e.3) :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3"~e.4)))) :ARG3 (c / cell~e.12 :name (n3 / name :op1 "T"~e.11) :mod (p3 / protein :name (n4 / name :op1 "CD4")) :mod (p4 / protein :name (n5 / name :op1 "CD25")) :ARG0-of (r / regulate-01~e.10)) :ARG2-of (h / high-02~e.6)) :op2 (i / identify-01~e.19 :ARG1 p :ARG2~e.20 (m2 / molecular-physical-entity~e.23 :ARG0-of~e.23 (p5 / play-08~e.23) :ARG1-of (k / key-02~e.22 :ARG2~e.24 (m3 / mediate-01~e.25 :ARG0 p :ARG1 (f / function-01~e.28 :ARG0 c :ARG1 (i2 / inhibit-01~e.27))))) :time~e.20 (r2 / recent~e.18))) # ::id bel_pmid_1780_4750.41496 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Foxp3 expression was induced by transforming growth factor-( 32 ( TGF-( 32 ) , but not TGF-( 31 stimulation in these cells , and was partially suppressed following antibody @-@ mediated neutralization of TGF-( 32 . # ::alignments 0-1.1.1.2.1.1.1 1-1.1.1.2 3-1.1.1 3-1.1.2 5-1.1.1.1.1.1.1 6-1.1.1.1.1.1.2 14-1.1 15-1.1.2.1 15-1.1.2.1.r 18-1.1.1.1 18-1.1.2.2 19-1.1.3.r 20-1.1.3.1 21-1.1.3 23-1 25-1.2.2 25-1.2.2.r 26-1.2 27-1.2.3 28-1.2.3.1.2.1 30-1.2.3.1.2 31-1.2.3.1 (a / and~e.23 :op1 (c / contrast-01~e.14 :ARG1 (i / induce-01~e.3 :ARG0 (s / stimulate-01~e.18 :ARG1 (p / protein :name (n / name :op1 "transforming"~e.5 :op2 "growth"~e.6 :op3 "factor-β2"))) :ARG2 (e / express-03~e.1 :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3"~e.0)))) :ARG2 (i2 / induce-01~e.3 :polarity~e.15 -~e.15 :ARG0 (s2 / stimulate-01~e.18 :ARG1 (p3 / protein :name (n3 / name :op1 "TGF-β1")))) :location~e.19 (c2 / cell~e.21 :mod (t / this~e.20))) :op2 (s3 / suppress-01~e.26 :ARG1 e :degree~e.25 (p4 / part~e.25) :ARG1-of (f / follow-01~e.27 :ARG2 (n4 / neutralize-01~e.31 :ARG1 p :ARG1-of (m / mediate-01~e.30 :ARG0 (a2 / antibody~e.28)))))) # ::id bel_pmid_1780_4750.41498 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Down @-@ regulation of Foxp3 with small interfering RNA ( siRNA ) in pancreatic carcinoma cells resulted in the up @-@ regulation of interleukin 6 ( IL @-@ 6 ) and IL @-@ 8 expression , providing evidence for a negative transcriptional activity of Foxp3 also in these epithelial cells . # ::alignments 0-1.1 1-1.1 2-1.1 3-1.1.1.r 4-1.1.1.1.1 5-1.1.2.r 6-1.1.2.1.1 7-1.1.2.1.2 8-1.1.2.1.3 12-1.1.3.r 13-1.1.3.1.2 14-1.1.3.1.1.1 15-1.1.3 16-1 17-1.2.r 19-1.2 20-1.2 21-1.2 22-1.2.1.r 23-1.2.1.1.1.1.1 24-1.2.1.1.1.1.2 26-1.2.1.1.2.1.1 30-1.2.1.1 31-1.2.1.1.2.1.1 33-1.2.1.1.2.1.1 34-1.2.1 36-1.3 37-1.3.1 38-1.3.1.2.r 40-1.3.1.2.3 41-1.3.1.2.2 42-1.3.1.2 43-1.3.1.2.1.r 44-1.3.1.2.1 45-1.3.1.2.4.3 47-1.3.1.2.4.2 48-1.3.1.2.4.1 49-1.3.1.2.4 (r / result-01~e.16 :ARG1 (d / downregulate-01~e.0,1,2 :ARG1~e.3 (p / protein :name (n / name :op1 "Foxp3"~e.4)) :ARG2~e.5 (n6 / nucleic-acid :name (n2 / name :op1 "small"~e.6 :op2 "interfering"~e.7 :op3 "RNA"~e.8)) :location~e.12 (c / cell~e.15 :mod (m / medical-condition :name (n7 / name :op1 "carcinoma"~e.14) :mod (p2 / pancreas~e.13)))) :ARG2~e.17 (u / upregulate-01~e.19,20,21 :ARG1~e.22 (e / express-03~e.34 :ARG2 (a / and~e.30 :op1 (p3 / protein :name (n3 / name :op1 "interleukin"~e.23 :op2 6~e.24)) :op2 (p4 / protein :name (n4 / name :op1 "IL-8"~e.26,31,33))))) :ARG0-of (p5 / provide-01~e.36 :ARG1 (e2 / evidence-01~e.37 :ARG0 u :ARG1~e.38 (a2 / activity-06~e.42 :ARG0~e.43 p~e.44 :ARG1 (t / transcribe-01~e.41) :ARG2-of (n5 / negative-01~e.40) :location (c3 / cell~e.49 :mod (e3 / epithelium~e.48) :mod (t2 / this~e.47) :mod (a3 / also~e.45)))))) # ::id bel_pmid_1780_4750.41500 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Coculture of Foxp3 @-@ expressing tumor cells with naive T cells completely inhibited T @-@ cell proliferation , but not activation , and this antiproliferative effect was partially abrogated following specific inhibition of Foxp3 expression . # ::alignments 0-1.1.1.1 1-1.1.1.1.1.r 2-1.1.1.1.1.1.2.1.1.1 4-1.1.1.1.1.1.2 5-1.1.1.1.1.1.1 6-1.1.1.1.1.1 8-1.1.1.1.1.2.2 9-1.1.1.1.1.2.1.1 10-1.1.1.1.1.2 11-1.1.1.3 12-1.1.1 12-1.1.2 13-1.1.1.1.1.2.1.1 13-1.1.1.2.1.1.1 15-1.1.1.2.1 16-1.1.1.2 18-1.1 19-1.1.2.1 19-1.1.2.1.r 20-1.1.2.3 22-1 22-1.1.1.1.1 23-1.2.1.2 24-1.2.1.1 25-1.2.1 27-1.2.2 27-1.2.2.r 28-1.2 29-1.2.3 30-1.2.3.1.2 31-1.2.3.1 32-1.2.3.1.1.r 33-1.2.3.1.1.1 34-1.2.3.1.1 (a / and~e.22 :op1 (c / contrast-01~e.18 :ARG1 (i / inhibit-01~e.12 :ARG0 (c2 / coculture-01~e.0 :ARG1~e.1 (a5 / and~e.22 :op1 (c3 / cell~e.6 :mod (t / tumor~e.5) :ARG3-of (e / express-03~e.4 :ARG2 (p / protein :name (n / name :op1 "Foxp3"~e.2)))) :op2 (c4 / cell~e.10 :name (n2 / name :op1 "T"~e.9,13) :mod (n3 / naive~e.8)))) :ARG1 (p2 / proliferate-01~e.16 :ARG0 (c5 / cell~e.15 :name (n4 / name :op1 "T"~e.13))) :ARG1-of (c6 / complete-02~e.11)) :ARG2 (i2 / inhibit-01~e.12 :polarity~e.19 -~e.19 :ARG0 c2 :ARG1 (a2 / activate-01~e.20 :ARG0 c5))) :op2 (a3 / abrogate-01~e.28 :ARG1 (a4 / affect-01~e.25 :ARG2 i~e.24 :mod (t2 / this~e.23)) :degree~e.27 (p3 / part~e.27) :ARG1-of (f / follow-01~e.29 :ARG2 (i3 / inhibit-01~e.31 :ARG1~e.32 (e3 / express-03~e.34 :ARG2 p~e.33) :ARG1-of (s / specific-02~e.30))))) # ::id bel_pmid_1780_4750.41502 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In an initial analysis of microdissected pancreatic carcinoma tissue using Affymetrix chip technology , Foxp3 was among the up @-@ regulated genes in some tumor samples ( 26 ) ; ( Fig . 1A ) . # ::alignments 2-1.4.3 3-1.4 6-1.4.1.2.2 7-1.4.1.2.1.1 8-1.4.1 9-1.4.2 10-1.4.2.1.1.1 11-1.4.2.1.1.2 12-1.4.2.1 14-1.1.1.1 16-1 21-1.2 23-1.3.2 24-1.3 25-1.3.1 27-1.5.1.1.1 31-1.6.1 33-1.6.1.1 (i / include-91~e.16 :ARG1 (g / gene :name (n / name :op1 "Foxp3"~e.14)) :ARG2 (g2 / gene~e.21 :ARG1-of (u / upregulate-01)) :location (t / tumor~e.24 :ARG1-of (s / sample-01~e.25) :quant (s2 / some~e.23)) :time (a / analyze-01~e.3 :ARG1 (t2 / tissue~e.8 :ARG1-of (m / microdissect-00) :mod (m2 / medical-condition :name (n3 / name :op1 "carcinoma"~e.7) :mod (p / pancreas~e.6))) :ARG0-of (u2 / use-01~e.9 :ARG1 (t3 / technology~e.12 :name (n2 / name :op1 "Affymetrix"~e.10 :op2 "chip"~e.11))) :mod (i2 / initial~e.2)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 26~e.27))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "1A"~e.33))) # ::id bel_pmid_1780_4750.41504 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In accordance with the immunohistochemistry data pointing to FoxP3 expression in tumor cells ( see above ) , Foxp3 expression was clearly detectable in several pancreatic carcinoma cell lines at both mRNA ( Fig . 2A ) and protein levels ( Fig . 2B ) . # ::alignments 1-1.2 2-1.2.1.r 4-1.2.1.1 5-1.2.1 6-1.2.1.2 7-1.2.1.2.1.r 8-1.2.1.2.1.1 9-1.2.1.2.1 10-1.2.1.2.1.2.r 11-1.2.1.2.1.2.1 12-1.2.1.2.1.2 14-1.2.2 15-1.2.2.3 18-1.1.1.1.1.1 19-1.1.1 21-1.1.2 22-1.1 23-1.1.3.r 24-1.1.3.1 25-1.1.3.3.2 26-1.1.3.3.1.1 27-1.1.3 28-1.1.3 31-1.1.3.2.1.1.1.1 33-1.1.3.2.1.2.1 35-1.1.3.2.1.2.1.1 37-1.1.3.2 38-1.1.3.2.2.1 39-1.1.3.2.1 39-1.1.3.2.2 41-1.1.3.2.2.2.1 43-1.1.3.2.2.2.1.1 (p / possible-01 :ARG1 (d / detect-01~e.22 :ARG1 (e / express-03~e.19 :ARG2 (p2 / protein :name (n / name :op1 "Foxp3"~e.18))) :ARG1-of (c / clear-06~e.21) :location~e.23 (c2 / cell-line~e.27,28 :quant (s / several~e.24) :location-of (a / and~e.37 :op1 (l / level~e.39 :mod (n3 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.31)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.33 :mod "2A"~e.35))) :op2 (l2 / level~e.39 :mod (p4 / protein~e.38) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.41 :mod "2B"~e.43)))) :mod (m / medical-condition :name (n4 / name :op1 "carcinoma"~e.26) :mod (p3 / pancreas~e.25)))) :ARG1-of (a3 / accord-02~e.1 :ARG2~e.2 (d4 / data~e.5 :mod (i / immunohistochemistry~e.4) :ARG0-of (p5 / point-01~e.6 :ARG2~e.7 (e2 / express-03~e.9 :ARG2 p2~e.8 :ARG3~e.10 (c5 / cell~e.12 :mod (t / tumor~e.11))))) :ARG1-of (s2 / see-01~e.14 :mode imperative :ARG0 (y / you) :location (a2 / above~e.15)))) # ::id bel_pmid_1780_4750.41506 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of PANC @-@ 89 , Capan1 , and Panc1 cells with TGF @-@ h2 led to an up @-@ regulation of the Foxp3 protein , which was moderate for PANC @-@ 89 and Capan1 and strong for Panc1 ( Fig . 3A and D ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 6-1.1.1.2.1.1 8-1.1.1 9-1.1.1.3.1.1 10-1.1.1.1 10-1.1.1.2 10-1.1.1.3 12-1.1.2.1.1 14-1.1.2.1.1 15-1 16-1.2.r 18-1.2.1 19-1.2.1 20-1.2.1 20-1.2.2 23-1.2.1.1.1.1 24-1.1.2 24-1.2.1.1 28-1.2.1.2 30-1.1.1.1.1.1 32-1.1.1.1.1.1 34-1.1.1.2.1.1 35-1.2.1.2.1 36-1.2.2.2 37-1.2.2.2.1.r 38-1.2.2.2.1 40-1.2.1.2.2.1 40-1.2.2.2.2.1 42-1.2.1.2.2.1.1 43-1.2.1.2.1 (l / lead-03~e.15 :ARG0 (t / treat-04~e.0 :ARG1~e.1 (a / and~e.8 :op1 (c / cell-line~e.10 :name (n / name :op1 "PANC-89"~e.2,4,30,32)) :op2 (c2 / cell-line~e.10 :name (n2 / name :op1 "Capan1"~e.6,34)) :op3 (c3 / cell-line~e.10 :name (n3 / name :op1 "Panc1"~e.9))) :ARG2 (p / protein~e.24 :name (n4 / name :op1 "TGF-h2"~e.12,14))) :ARG2~e.16 (a2 / and :op1 (u / upregulate-01~e.18,19,20 :ARG1 (p2 / protein~e.24 :name (n5 / name :op1 "Foxp3"~e.23)) :ARG1-of (m / moderate-03~e.28 :beneficiary (a3 / and~e.35,43 :op1 c :op2 c2) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "3A"~e.42)))) :op2 (u2 / upregulate-01~e.20 :ARG1 p2 :ARG1-of (s / strong-02~e.36 :beneficiary~e.37 c3~e.38 :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.40 :mod "3D")))))) # ::id bel_pmid_1780_4750.41508 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RT @-@ PCR analysis detected a 13 @-@ fold ( mean value of four independent experiments ) increase of Foxp3 mRNA expression in PANC @-@ 89 cells after a 48 @-@ h stimulation with TGF @-@ h2 , whereas no such effect was evident after stimulation with TGF @-@ h1 ( Fig . 3B ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1 6-1.1.2.2.1 8-1.1.2.2 10-1.1.2.2.2.1.1 11-1.1.2.2.2.1 12-1.1.2.2.2.1.2.r 13-1.1.2.2.2.1.2.1 14-1.1.2.2.2.1.2.2 14-1.1.2.2.2.1.2.2.1 14-1.1.2.2.2.1.2.2.1.r 15-1.1.2.2.2.1.2 17-1.1.2 17-1.2.2.1 18-1.1.2.1.r 18-1.1.2.2 19-1.1.2.1.1.2.1.1 20-1.1.2.1.1.1.1 21-1.1.2.1 22-1.1.2.1.2.r 23-1.1.2.1.2.1.1 25-1.1.2.1.2.1.1 26-1.1.2.1.2 27-1.1.2.3 29-1.1.2.3.1.2.1 31-1.1.2.3.1.2.2 32-1.1.2.3.1 33-1.1.1.1.r 34-1.1.2.3.1.1.1.1 36-1.1.2.3.1.1.1.1 38-1 39-1.2.1 39-1.2.1.r 41-1.2.2 42-1.2.2.r 43-1.2 44-1.1.2.3 44-1.2.3 45-1.1.2.3.1 45-1.2.3.1 46-1.1.1.1.r 46-1.2.3.1.1.r 47-1.2.3.1.1.1.1 49-1.2.3.1.1.1.1 51-1.3.1 53-1.3.1.1 (c / contrast-01~e.38 :ARG1 (d / detect-01~e.4 :ARG0 (a / analyze-01~e.3 :instrument~e.33,46 (t2 / thing :name (n3 / name :op1 "RT-PCR"~e.0,2))) :ARG1 (i / increase-01~e.17 :ARG1~e.18 (e / express-03~e.21 :ARG1 (n7 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.20) :part (p / protein :name (n / name :op1 "Foxp3"~e.19))) :ARG3~e.22 (c2 / cell-line~e.26 :name (n4 / name :op1 "PANC-89"~e.23,25))) :ARG2 (p2 / product-of~e.8,18 :op1 13~e.6 :ARG1-of (d2 / describe-01 :ARG0 (v / value~e.11 :mod (m / mean~e.10) :quant-of~e.12 (e2 / experiment-01~e.15 :quant 4~e.13 :ARG0-of (d3 / depend-01~e.14 :polarity~e.14 -~e.14))))) :time (a2 / after~e.27,44 :op1 (s / stimulate-01~e.32,45 :ARG2 (p3 / protein :name (n5 / name :op1 "TGF-h2"~e.34,36)) :duration (t / temporal-quantity :quant 48~e.29 :unit (h / hour~e.31)))))) :ARG2 (e3 / evident~e.43 :polarity~e.39 -~e.39 :domain~e.42 (a4 / affect-01~e.41 :ARG2 (i2 / increase-01~e.17 :ARG1 e :ARG2 p2)) :time (a3 / after~e.44 :op1 (s3 / stimulate-01~e.45 :ARG2~e.46 (p4 / protein :name (n6 / name :op1 "TGF-h1"~e.47,49))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.51 :mod "3B"~e.53))) # ::id bel_pmid_1780_4750.41510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the incubation of PANC @-@ 89 and Capan1 cells with anti @-@ TGF @-@ h2 antibody for 48 h clearly suppressed the Foxp3 signal ( Fig . 3A ) , suggesting that endogenously produced TGF @-@ h2 maintains Foxp3 expression in pancreatic cancer cell cultures . # ::alignments 0-1.1.1.1 3-1.1.1 5-1.1.1.1.1.1.1 7-1.1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2.1.1 10-1.1.1.1.1 10-1.1.1.1.2 11-1.1.1.2.r 12-1.1.1.2.1 14-1.1.1.2.1.1.1.1 16-1.1.1.2.1.1.1.1 17-1.1.1.2 18-1.1.1.3.r 19-1.1.1.3.1 20-1.1.1.3.2 21-1.1.3 22-1.1 24-1.1.2.1.1.1 25-1.1.2 27-1.1.4.1 29-1.1.4.1.1 32-1.1.5 33-1.1.5.1.r 34-1.1.5.1.1.2.1 34-1.1.5.1.1.2.1.r 35-1.1.5.1.1.2 36-1.1.5.1.1.1.1 38-1.1.5.1.1.1.1 39-1.1.5.1 40-1.1.5.1.2.1 41-1.1.5.1.2 42-1.1.5.1.2.2.r 43-1.1.5.1.2.2.1.1.2.1 44-1.1.5.1.2.2.1.1.2.2 45-1.1.5.1.2.2.1 46-1.1.5.1.2.2 (a / and :op2 (s / suppress-01~e.22 :ARG0 (i / incubate-01~e.3 :ARG1 (a2 / and~e.0,8 :op1 (c / cell-line~e.10 :name (n / name :op1 "PANC-89"~e.5,7)) :op2 (c2 / cell-line~e.10 :name (n2 / name :op1 "Capan1"~e.9))) :ARG2~e.11 (a3 / antibody~e.17 :ARG0-of (c6 / counter-01~e.12 :ARG1 (p4 / protein :name (n3 / name :op1 "TGF-h2"~e.14,16)))) :duration~e.18 (t / temporal-quantity :quant 48~e.19 :unit (h / hour~e.20))) :ARG1 (s2 / signal-07~e.25 :ARG0 (p / protein :name (n4 / name :op1 "Foxp3"~e.24))) :ARG1-of (c3 / clear-06~e.21) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "3A"~e.29)) :ARG0-of (s3 / suggest-01~e.32 :ARG1~e.33 (m / maintain-01~e.39 :ARG0 (p2 / protein :name (n5 / name :op1 "TGF-h2"~e.36,38) :ARG1-of (p3 / produce-01~e.35 :manner~e.34 (e / endogenous~e.34))) :ARG1 (e2 / express-03~e.41 :ARG2 p~e.40 :ARG3~e.42 (c4 / culture~e.46 :mod (c5 / cell~e.45 :mod (d2 / disease :wiki "Pancreatic_cancer" :name (n6 / name :op1 "pancreatic"~e.43 :op2 "cancer"~e.44))))))))) # ::id bel_pmid_1780_4750.41512 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Specific down @-@ regulation of Foxp3 in pancreatic carcinoma cells results in up @-@ regulation of IL @-@ 6 and IL @-@ 8 . # ::alignments 0-1.1.3 1-1.1 2-1.1 3-1.1 4-1.1.1.r 5-1.1.1.1.1 6-1.1.2.r 7-1.1.2.1.2 8-1.1.2.1.1.1 9-1.1.2 10-1 11-1.2.r 12-1.2 13-1.2 14-1.2 15-1.2.1.r 16-1.2.1.1.1.1 16-1.2.1.2.1.1 18-1.2.1.1.1.1 19-1.2.1 20-1.2.1.1.1.1 20-1.2.1.2.1.1 22-1.2.1.2.1.1 (r / result-01~e.10 :ARG1 (d / downregulate-01~e.1,2,3 :ARG1~e.4 (p / protein :name (n / name :op1 "Foxp3"~e.5)) :location~e.6 (c / cell~e.9 :mod (m / medical-condition :name (n2 / name :op1 "carcinoma"~e.8) :mod (p2 / pancreas~e.7))) :ARG1-of (s / specific-02~e.0)) :ARG2~e.11 (u / upregulate-01~e.12,13,14 :ARG1~e.15 (a / and~e.19 :op1 (p3 / protein :name (n3 / name :op1 "IL-6"~e.16,18,20)) :op2 (p4 / protein :name (n4 / name :op1 "IL-8"~e.16,20,22))))) # ::id bel_pmid_1780_4750.41514 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A screen for changes in cytokine secretion in these cells using the Raybiotec Cytokine Array ( Hoelzel Diagnostica ) revealed an increase of IL @-@ 6 and IL @-@ 8 in the culture supernatant , whereas other cytokines remained unchanged ( data not shown ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.1.1 7-1.1.1.1.1.2.r 8-1.1.1.1.1.2.1 9-1.1.1.1.1.2 10-1.1.1.2 13-1.1.1.2.1.1.2 14-1.1.1.2.1.1.3 16-1.1.1.2.1.2.1.1 19-1.1 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1.1.1.1 23-1.1.2.1.2.1.1 25-1.1.2.1.1.1.1 26-1.1.2.1 27-1.1.2.1.1.1.1 27-1.1.2.1.2.1.1 29-1.1.2.1.2.1.1 30-1.1.2.2.r 32-1.1.2.2.1 33-1.1.2.2 35-1 36-1.2.1.1 37-1.2.1 38-1.2 39-1.2.2 39-1.2.2.1 39-1.2.2.1.r 41-1.2.3.1 42-1.2.3.1.1.1 42-1.2.3.1.1.1.r 43-1.2.3.1.1 (c / contrast-01~e.35 :ARG1 (r / reveal-01~e.19 :ARG0 (s / screen-01~e.1 :ARG2~e.2 (c2 / change-01~e.3 :ARG1~e.4 (s2 / secrete-01~e.6 :ARG1 (c3 / cytokine~e.5) :location~e.7 (c4 / cell~e.9 :mod (t / this~e.8)))) :ARG2-of (u / use-01~e.10 :ARG1 (p / product :name (n / name :op1 "Raybiotech" :op2 "Cytokine"~e.13 :op3 "Array"~e.14) :source (c5 / company :name (n2 / name :op1 "Hoelzel"~e.16 :op2 "Diagnostika"))))) :ARG1 (i / increase-01~e.21 :ARG1~e.22 (a / and~e.26 :op1 (p2 / protein :name (n3 / name :op1 "IL-6"~e.23,25,27)) :op2 (p3 / protein :name (n4 / name :op1 "IL-8"~e.23,27,29))) :location~e.30 (s3 / supernatant~e.33 :ARG1-of (c6 / culture-01~e.32)))) :ARG2 (r2 / remain-01~e.38 :ARG1 (c7 / cytokine~e.37 :mod (o / other~e.36)) :ARG3 (c8 / change-01~e.39 :polarity~e.39 -~e.39) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.41 :ARG1-of (s4 / show-01~e.43 :polarity~e.42 -~e.42))))) # ::id bel_pmid_1780_4750.41518 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the cocultures , Colo357 , PANC @-@ 89 , and PancTu1 tumor cells strongly inhibited the proliferation of anti @-@ CD3 @/@ anti @-@ CD28 @-@ stimulated T cells ( Fig . 4D ) . # ::alignments 4-1.1.1.1.1 6-1.1.2.1.1 8-1.1.2.1.1 10-1.1 11-1.1.3.1.1 12-1.1.4 13-1.4 14-1.3 15-1 17-1.2 18-1.2.1.r 19-1.2.1.2.1.1 19-1.2.1.2.1.1.1 19-1.2.1.2.1.1.1.r 19-1.2.1.2.1.2 19-1.2.1.2.1.2.1 19-1.2.1.2.1.2.1.r 21-1.2.1.2.1.1.1.1.1.1 23-1.2.1.2.1.1 23-1.2.1.2.1.1.1 23-1.2.1.2.1.1.1.r 23-1.2.1.2.1.2 23-1.2.1.2.1.2.1 23-1.2.1.2.1.2.1.r 25-1.2.1.2.1.2.1.1.1.1 27-1.2.1.2 28-1.2.1.1.1 29-1.2.1 31-1.5.1 33-1.5.1.1 (i / inhibit-01~e.15 :ARG0 (a / and~e.10 :op1 (c / cell-line :name (n / name :op1 "Colo357"~e.4)) :op2 (c2 / cell-line :name (n2 / name :op1 "PANC-89"~e.6,8)) :op3 (c3 / cell-line :name (n3 / name :op1 "PancTu1"~e.11)) :mod (t / tumor~e.12)) :ARG1 (p / proliferate-01~e.17 :ARG0~e.18 (c4 / cell~e.29 :name (n4 / name :op1 "T"~e.28) :ARG1-of (s / stimulate-01~e.27 :ARG0 (a2 / and :op1 (m / molecular-physical-entity~e.19,23 :ARG0-of~e.19,23 (c5 / counter-01~e.19,23 :ARG1 (p2 / protein :name (n5 / name :op1 "CD3"~e.21)))) :op2 (m2 / molecular-physical-entity~e.19,23 :ARG0-of~e.19,23 (c6 / counter-01~e.19,23 :ARG1 (p3 / protein :name (n6 / name :op1 "CD28"~e.25)))))))) :ARG1-of (s2 / strong-02~e.14) :location (c7 / cell~e.13 :ARG1-of (c8 / coculture-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "4D"~e.33))) # ::id bel_pmid_1780_4750.41520 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 5B , CD25 GITR and CD69 were up @-@ regulated after anti @-@ CD3 @/@ anti @-@ CD28 stimulation , irrespective of the presence or absence of tumor cells . # ::alignments 0-1.2.r 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1.1 6-1.1.1.1.1 7-1.1.2.1.1 8-1.1 9-1.1.3.1.1 14-1.2 15-1.2.1.1.1 15-1.2.1.1.1.1 15-1.2.1.1.1.1.r 15-1.2.1.1.2 15-1.2.1.1.2.1 15-1.2.1.1.2.1.r 17-1.2.1.1.1.1.1.1.1 19-1.2.1.1.1 19-1.2.1.1.1.1 19-1.2.1.1.1.1.r 19-1.2.1.1.2 19-1.2.1.1.2.1 19-1.2.1.1.2.1.r 21-1.2.1.1.2.1.1.1.1 22-1.2.1 24-1.4 27-1.4.1.1 28-1.4.1 29-1.4.1.2 30-1.4.1.1.1.r 31-1.4.1.1.1.1 32-1.4.1.1.1 (u / upregulate-01 :ARG1 (a / and~e.8 :op1 (p / protein :name (n / name :op1 "CD25"~e.6)) :op2 (p2 / protein :name (n2 / name :op1 "GITR"~e.7)) :op3 (p3 / protein :name (n3 / name :op1 "CD69"~e.9))) :time~e.0 (a2 / after~e.14 :op1 (s / stimulate-01~e.22 :ARG0 (a3 / and :op1 (m / molecular-physical-entity~e.15,19 :ARG0-of~e.15,19 (c / counter-01~e.15,19 :ARG1 (p4 / protein :name (n4 / name :op1 "CD3"~e.17)))) :op2 (m2 / molecular-physical-entity~e.15,19 :ARG0-of~e.15,19 (c2 / counter-01~e.15,19 :ARG1 (p5 / protein :name (n5 / name :op1 "CD28"~e.21))))))) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "5B"~e.4)) :ARG1-of (r / regardless-91~e.24 :ARG2 (o / or~e.28 :op1 (p6 / present-02~e.27 :ARG1~e.30 (c3 / cell~e.32 :mod (t / tumor~e.31))) :op2 (a4 / absent-01~e.29 :ARG1 c3)))) # ::id bel_pmid_1780_4750.41522 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When using these cells , we observed an ~ 45 % recovery of T @-@ cell proliferation in the coculture system ( Fig . 5A ) . # ::alignments 0-1.4.r 1-1.4 2-1.4.2.1 3-1.4.2 5-1.1 6-1 8-1.2.2 9-1.2.2.1.1 10-1.2.2.1 11-1.2 12-1.2.1.r 13-1.2.1.1.1.1 15-1.2.1.1 16-1.2.1 17-1.3.r 19-1.3.1 20-1.3 22-1.5.1 24-1.5.1.1 (o / observe-01~e.6 :ARG0 (w / we~e.5) :ARG1 (r / recover-02~e.11 :ARG1~e.12 (p / proliferate-01~e.16 :ARG0 (c / cell~e.15 :name (n / name :op1 "T"~e.13))) :quant (a / approximately~e.8 :op1 (p2 / percentage-entity~e.10 :value 45~e.9))) :location~e.17 (s / system~e.20 :consist-of (c2 / coculture-01~e.19)) :time~e.0 (u / use-01~e.1 :ARG0 w :ARG1 (c3 / cell~e.3 :mod (t / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.22 :mod "5A"~e.24))) # ::id bel_pmid_1794_2936.40216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results Tumor @-@ associated inflammation is reduced in IL @-@ 1R—/— mice . # ::alignments 0-1.3 1-1.1.1.1 3-1.1.1 4-1.1 6-1 7-1.2.r 8-1.2.1.1.1 11-1.2 (r / reduce-01~e.6 :ARG1 (i / inflame-01~e.4 :ARG1-of (a / associate-01~e.3 :ARG2 (t / tumor~e.1))) :location~e.7 (m2 / mouse~e.11 :mod (p / protein :name (n2 / name :op1 "IL-1R"~e.8) :ARG2-of (m3 / mutate-01 :mod "-/-"))) :ARG2-of (r2 / result-01~e.0)) # ::id bel_pmid_1794_2936.40218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Canonical proinflammatory cytokines , such as IL @-@ 6 , MCP @-@ 1 , TGFh , and IL @-@ 1h were significantly elevated in 4T1 tumor tissue . # ::alignments 0-1.1.1 1-1.1.2.1 2-1.1 4-1.1.3.r 5-1.1.3.r 6-1.1.3.1.1.1 6-1.1.3.4.1.1 8-1.1.3.1.1.1 10-1.1.3.2.1.1 12-1.1.3.2.1.1 14-1.1.3.3.1.1 16-1.1.3 17-1.1.3.1.1.1 17-1.1.3.4.1.1 19-1.1.3.4.1.1 21-1.2 22-1 23-1.3.r 24-1.3.1.1.1.1 25-1.3.1 26-1.3 (e / elevate-01~e.22 :ARG1 (c7 / cytokine~e.2 :mod (c2 / canonical~e.0) :ARG0-of (p / promote-01 :ARG1 (i / inflame-01~e.1)) :example~e.4,5 (a / and~e.16 :op1 (p2 / protein :name (n / name :op1 "IL-6"~e.6,8,17)) :op2 (p3 / protein :name (n2 / name :op1 "MCP-1"~e.10,12)) :op3 (p4 / protein :name (n3 / name :op1 "TGFh"~e.14)) :op4 (p5 / protein :name (n4 / name :op1 "IL-1h"~e.6,17,19)))) :ARG1-of (s / significant-02~e.21) :location~e.23 (t / tissue~e.26 :mod (t2 / tumor~e.25 :mod (c / cell-line :name (n5 / name :op1 "4T1"~e.24))))) # ::id bel_pmid_1794_2936.40222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , IL @-@ 1R—/— tumor tissue had less IL @-@ 12p70 and more TGFh and IFNg than tumor tissue from wild @-@ type BALB/c mice . # ::alignments 0-1.1.2 2-1.1.1.2.1.1 5-1.1.1.1 6-1.1.1 7-1.1 8-1.1.2.1.2 9-1.1.2.1.1.1 11-1.1.2.1.1.1 12-1.1.2 13-1.1.2.2.2 14-1.1.2.2.1.1 15-1.1.2 16-1.1.2.3.1.1 17-1.1.2.4.r 18-1.1.2.4.1 19-1.1.2.4 20-1.1.2.4.2.r 21-1.1.2.4.2.1.2 23-1.1.2.4.2.1.2 24-1.1.2.4.2.1.1.1 25-1.1.2.4.2 (a / and :op2 (h / have-03~e.7 :ARG0 (t / tissue~e.6 :part-of (t2 / tumor~e.5) :mod (p / protein :name (n / name :op1 "IL-1R"~e.2) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (a2 / and~e.0,12,15 :op1 (p2 / protein :name (n2 / name :op1 "IL-12p70"~e.9,11) :degree (l / less~e.8)) :op2 (p3 / protein :name (n3 / name :op1 "TGFh"~e.14) :degree (m3 / more~e.13)) :op3 (p4 / protein :name (n4 / name :op1 "IFNg"~e.16) :degree m3) :compared-to~e.17 (t3 / tissue~e.19 :mod (t4 / tumor~e.18) :source~e.20 (m4 / mouse~e.25 :mod (c / cell-line :name (n5 / name :op1 "BALB/c"~e.24) :mod (w / wild-type~e.21,23))))))) # ::id bel_pmid_1794_2936.40248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A potential downstream candidate is the proinflammatory cytokine , IL @-@ 6 , the production of which is reduced in IL @-@ 1R—/— tumor tissue ( Fig . 1B ) . # ::alignments 1-1.2.1 2-1.2.2 3-1.2 4-1.2.r 6-1.4.1 7-1 9-1.1.1 11-1.1.1 14-1.3 18-1.3.1 19-1.3.1.1.r 20-1.3.1.1.2.1.1 23-1.3.1.1.1 24-1.3.1.1 26-1.5.1 28-1.5.1.1 (c / cytokine~e.7 :name (n / name :op1 "IL-6"~e.9,11) :domain~e.4 (c2 / candidate~e.3 :mod (p3 / potential~e.1) :location (d / downstream~e.2)) :ARG1-of (p / produce-01~e.14 :ARG1-of (r / reduce-01~e.18 :location~e.19 (t / tissue~e.24 :part-of (t2 / tumor~e.23) :mod (p4 / protein :name (n2 / name :op1 "IL-1R"~e.20) :ARG2-of (m / mutate-01 :mod "-/-"))))) :ARG0-of (p2 / promote-01 :ARG1 (i / inflame-01~e.6)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26 :mod "1B"~e.28))) # ::id bel_pmid_1796_7787.34624 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data demonstrate that it is the hemin @-@ induced surge in cellular ROS levels , in particular the superoxide generated most likely from NADPH oxidase activity , and consequent oxidative stress which mediates Egr @-@ 1 upregulation via ERK @-@ 1 @/@ 2 activation . # ::alignments 0-1.1.1 1-1.1 2-1 7-1.2.1.2.1.1.1 9-1.2.1.2 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.2 13-1.2.1.1.1.1.1 14-1.2.1.1 16-1.2.r 17-1.2.2.2 19-1.2.2.1.1 20-1.2.2.3 21-1.2.2.3.2.1 22-1.2.2.3.2 23-1.2.2.3.1.r 24-1.2.2.3.1.1.2.1.1 25-1.2.2.3.1.1.1 26-1.2.2.3.1 28-1.2 31-1.2.3 33-1.2.4 34-1.2.4.1.1.1.1 36-1.2.4.1.1.1.1 36-1.2.4.1.2.1.1.1.1 37-1.2.4.1 39-1.2.4.1.2.1.1.1.1 39-1.2.4.1.2.1.2.1.1 41-1.2.4.1.2.1.1.1.1 42-1.2.4.1.2.1 43-1.2.4.1.2.1.2.1.1 44-1.2.4.1.2 (d3 / demonstrate-01~e.2 :ARG0 (d2 / data~e.1 :mod (t2 / this~e.0)) :ARG1~e.16 (a / and~e.28 :op1 (s / surge-01~e.10 :ARG1~e.11 (l2 / level~e.14 :quant-of (s4 / small-molecule :name (n / name :op1 "ROS"~e.13) :part-of (c / cell~e.12))) :ARG2-of (i / induce-01~e.9 :ARG0 (s5 / small-molecule :name (n2 / name :op1 "hemin"~e.7)))) :op2 (m4 / macro-molecular-complex :name (n3 / name :op1 "superoxide"~e.19) :mod (p / particular~e.17) :ARG1-of (g / generate-01~e.20 :ARG2~e.23 (a2 / activity-06~e.26 :ARG0 (m5 / macro-molecular-complex :part (o / oxidase~e.25) :part (s6 / small-molecule :name (n4 / name :op1 "NADPH"~e.24)))) :ARG1-of (l / likely-01~e.22 :degree (m / most~e.21)))) :op3 (s2 / stress-02~e.31 :ARG2-of (r / result-01 :ARG1 o)) :ARG0-of (m2 / mediate-01~e.33 :ARG1 (u / upregulate-01~e.37 :ARG1 (p2 / protein :name (n5 / name :op1 "Egr-1"~e.34,36)) :ARG2 (a3 / activate-01~e.44 :ARG1 (s3 / slash~e.42 :op1 (e / enzyme :name (n6 / name :op1 "ERK-1"~e.36,39,41)) :op2 (e2 / enzyme :name (n7 / name :op1 "ERK-2"~e.39,43)))))))) # ::id bel_pmid_1798_2092.10006 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , RELMbeta stimulated naive bone marrow @-@ derived macrophages to secrete significant amounts of TNF @-@ alpha , IL @-@ 6 , and RANTES # ::alignments 0-1 2-1.1.1.1.1 3-1.1 4-1.1.2.1.1.1.1.1 5-1.1.2.1.1.1.1 6-1.1.2.1.1.1 8-1.1.2.1.1 9-1.1.2.1 11-1.1.2 12-1.1.2.2.2 13-1.1.2.2 14-1.1.2.2.1.r 15-1.1.2.2.1.1.1.1 17-1.1.2.2.1.1.1.1 19-1.1.2.2.1.2.1.1 21-1.1.2.2.1.2.1.1 23-1.1.2.2.1 24-1.1.2.2.1.3.1.1 (h / have-concession-91~e.0 :ARG1 (s / stimulate-01~e.3 :ARG0 (s2 / small-molecule :name (n / name :op1 "RELMbeta"~e.2)) :ARG1 (s3 / secrete-01~e.11 :ARG0 (m2 / macrophage~e.9 :ARG1-of (d / derive-01~e.8 :ARG2 (m / marrow~e.6 :source (b / bone~e.5 :mod (n3 / naive~e.4))))) :ARG1 (a / amount~e.13 :quant-of~e.14 (a2 / and~e.23 :op1 (p / protein :name (n4 / name :op1 "TNF-alpha"~e.15,17)) :op2 (p2 / protein :name (n5 / name :op1 "IL-6"~e.19,21)) :op3 (p3 / protein :name (n6 / name :op1 "RANTES"~e.24))) :ARG1-of (s4 / significant-02~e.12))))) # ::id bel_pmid_1799_2263.15480 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MMP @-@ 2 ( 76 kDa ) activity was elevated only at day 11 in C57BL/6 mice but not in MyD88–/– and IL @-@ 1R1–/– mice ( Figure 4B ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 4-1.1.1.1.2.1 5-1.1.1.1.2.2 7-1.1.1 7-1.2.2 9-1.1 9-1.2 10-1.1.3 12-1.1.2.1.2 13-1.1.2.1.1 14-1.1.4.r 15-1.1.4.1.1 16-1.1.4 17-1 18-1.2.1 18-1.2.1.r 21-1.2.4 22-1.2.4.2.1.1.1 25-1.2.4.1 25-1.2.4.2 27-1.3.1 28-1.3.1.1 (c / contrast-01~e.17 :ARG1 (e / elevate-01~e.9 :ARG1 (a / activity-06~e.7 :ARG0 (e2 / enzyme :name (n / name :op1 "MMP-2"~e.0,2) :quant (m / mass-quantity :quant 76~e.4 :unit (k / kilodalton~e.5)))) :time (a2 / after :op1 (t / temporal-quantity :quant 11~e.13 :unit (d / day~e.12))) :mod (o / only~e.10) :location~e.14 (m6 / mouse~e.16 :name (n4 / name :op1 "C57BL/6"~e.15))) :ARG2 (e3 / elevate-01~e.9 :polarity~e.18 -~e.18 :ARG1 (a3 / activity-06~e.7 :ARG0 e2) :time a2 :location (a4 / and~e.21 :op1 (m2 / mouse~e.25 :mod (p / protein :name (n2 / name :op1 "MyD88") :ARG2-of (m3 / mutate-01 :mod "-/-"))) :op2 (m4 / mouse~e.25 :mod (p2 / protein :name (n3 / name :op1 "IL-1R1"~e.22) :ARG2-of (m5 / mutate-01 :mod "-/-"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.27 :mod "4B"~e.28))) # ::id bel_pmid_1799_2263.15482 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MMP @-@ 9 activity was significantly upregulated in BALF at day 1 in C57BL/6 mice but not in MyD88–/– mice , and only partially in IL @-@ 1R1–/– mice ( Figure 4A ) . # ::alignments 0-1.1.1.1.1.1.1 2-1.1.1.1.1.1.1 3-1.1.1.1 5-1.1.1.2 6-1.1.1 6-1.1.2 6-1.2 7-1.1.1.3.r 8-1.1.1.3 8-1.1.1.3.1 8-1.1.1.3.1.1 8-1.1.1.3.1.1.1 8-1.1.1.3.1.1.1.r 8-1.1.1.3.1.1.r 8-1.1.1.3.1.r 10-1.1.1.4.1.1.2 11-1.1.1.4.1.1.1 12-1.1.1.5.r 13-1.1.1.5.1.1 14-1.1.1.5 14-1.1.2.3 14-1.2.3 15-1 16-1.2.1 16-1.2.1.r 19-1.1.1.5 21-1.1 22-1.1.2.2.1 23-1.1.2.2 23-1.1.2.2.r 24-1.1.2.3.1.r 25-1.1.2.3.1.1.1 28-1.1.1.5 30-1.3.1 31-1.3.1.1 (c / contrast-01~e.15 :ARG1 (a3 / and~e.21 :op1 (u / upregulate-01~e.6 :ARG1 (a / activity-06~e.3 :ARG0 (e / enzyme :name (n / name :op1 "MMP-9"~e.0,2))) :ARG1-of (s / significant-02~e.5) :location~e.7 (f2 / fluid~e.8 :mod~e.8 (l / lavage~e.8 :mod~e.8 (a4 / alveolus~e.8 :mod~e.8 (b / bronchus~e.8)))) :time (a2 / after :quant (u2 / up-to :op1 (t2 / temporal-quantity :quant 1~e.11 :unit (d / day~e.10)))) :location~e.12 (m6 / mouse~e.14,19,28 :name (n5 / name :op1 "C57BL/6"~e.13))) :op2 (u3 / upregulate-01~e.6 :ARG1 a :degree~e.23 (p / part~e.23 :mod (o / only~e.22)) :location (m2 / mouse~e.14 :mod~e.24 (p3 / protein :name (n3 / name :op1 "IL-1R1"~e.25) :ARG2-of (m3 / mutate-01 :mod "-/-"))))) :ARG2 (u4 / upregulate-01~e.6 :polarity~e.16 -~e.16 :ARG1 a :location (m4 / mouse~e.14 :mod (p2 / protein :name (n4 / name :op1 "MyD88") :ARG2-of (m5 / mutate-01 :mod "-/-")))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.30 :mod "4A"~e.31))) # ::id bel_pmid_1799_2263.15488 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Latent TGF-?1 was detected after activation in BALF from WT mice 7 days after BLM administration , but was not detected in BALF from MyD88 @- or IL @-@ 1R1 @–@ deficient mice ( Figure 5G ) # ::alignments 0-1.1.1.2 3-1.1 4-1.1.2 4-1.1.3 5-1.1.2.1 7-1.1.2.1.1 7-1.1.2.1.1.2 7-1.1.2.1.1.2.r 7-1.2.3.1 7-1.2.3.2 8-1.1.2.1.1.1.r 9-1.1.2.1.1.1.1 10-1.1.2.1.1.1 10-1.2.3.2.1 11-1.1.3.2.1 12-1.1.3.2.2 13-1.1.3 14-1.1.3.1.1.1.1 15-1.1.3.1 17-1 19-1.2.1 19-1.2.1.r 20-1.2 21-1.1.2.1.1.2.1.r 22-1.1.2.1.1.2.1 22-1.1.2.1.1.2.1.1 22-1.1.2.1.1.2.1.1.r 23-1.2.3.1.1.r 24-1.2.3.1.1.1.1.1.1 26-1.2.3 27-1.2.3.2.1.1.1.1.1 29-1.2.3.2.1.1.1.1.1 32-1.2.3.1.1 34-1.3.1 35-1.3.1.1 (c / contrast-01~e.17 :ARG1 (d2 / detect-01~e.3 :ARG1 (p / protein :name (n / name :op1 "TGFβ-1") :mod (l / latent~e.0)) :time (a2 / after~e.4 :op1 (a3 / activate-01~e.5 :location (f2 / fluid~e.7 :source~e.8 (m / mouse~e.10 :mod (w / wild-type~e.9)) :mod~e.7 (l2 / lavage~e.7 :mod~e.21 (a / alveolus~e.22 :mod~e.22 (b / bronchus~e.22)))))) :time (a4 / after~e.4,13 :op1 (a5 / administer-01~e.15 :ARG1 (s / small-molecule :name (n3 / name :op1 "BLM"~e.14))) :quant (t3 / temporal-quantity :quant 7~e.11 :unit (d3 / day~e.12)))) :ARG2 (d4 / detect-01~e.20 :polarity~e.19 -~e.19 :ARG1 p :location (o / or~e.26 :op1 (f3 / fluid~e.7 :source~e.23 (m3 / mouse~e.32 :ARG0-of (l3 / lack-01 :ARG1 (p3 / protein :name (n5 / name :op1 "MyD88"~e.24)))) :mod l2) :op2 (f4 / fluid~e.7 :source (m4 / mouse~e.10 :ARG0-of (l4 / lack-01 :ARG1 (p4 / protein :name (n9 / name :op1 "IL-1R1"~e.27,29)))) :mod l2))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure~e.34 :mod "5G"~e.35))) # ::id bel_pmid_1799_2263.28110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 7 days of administration IL @-@ 1 ? caused tissue injury with marked tissue destruction , disruption of alveolar architecture , inflammation , and fibrosis ( although less pronounced than that obtained after BLM treatment ; Figure 7 , D and E ) that was absent in saline controls ( Figure 7C ) # ::alignments 0-1.1.2.1 1-1.1.2.2 3-1.1 4-1.1.1.1.1 8-1 9-1.2.1 9-1.2.4.2.1 10-1.2 10-1.2.4.2 11-1.2.2.r 12-1.2.2.1.2 13-1.2.1 14-1.2.2.1 16-1.2.2.2 17-1.2.2.2.1.r 18-1.2.2.2.1.1 19-1.2.2.2.1 21-1.2.2.3 23-1.2.2 24-1.2.2.4 26-1.2.3 27-1.2.4.1 28-1.2.4 29-1.2.4.2.r 31-1.2.4.2.2 33-1.2.4.2.2.1.1.1.1 34-1.2.4.2.2.1 36-1.2.4.2.2.2.1.1 36-1.2.4.2.2.2.1.2 37-1.1.2.1 40-1.2.4.2.2.2.1 45-1.2.5 46-1.2.5.1.r 47-1.2.5.1.1 48-1.2.5.1 50-1.3.1 51-1.3.1.1 (c / cause-01~e.8 :ARG0 (a2 / administer-01~e.3 :ARG1 (p / protein :name (n / name :op1 "IL-1β"~e.4)) :duration (t2 / temporal-quantity :quant 7~e.0,37 :unit (d / day~e.1))) :ARG1 (i2 / injure-01~e.10 :ARG1 (t3 / tissue~e.9,13) :accompanier~e.11 (a / and~e.23 :op1 (d2 / destroy-01~e.14 :ARG1 t3 :ARG1-of (m / mark-01~e.12)) :op2 (d4 / disrupt-01~e.16 :ARG1~e.17 (a7 / architecture~e.19 :poss (a8 / alveolus~e.18))) :op3 (i / inflame-01~e.21) :op4 (f2 / fibrosis~e.24)) :ARG2-of (h / have-concession-91~e.26) :ARG1-of (p2 / pronounced-02~e.28 :degree (l / less~e.27) :compared-to~e.29 (i4 / injure-01~e.10 :ARG1 (t4 / tissue~e.9) :ARG1-of (o / obtain-01~e.31 :ARG2 (t5 / treat-04~e.34 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "BLM"~e.33))) :ARG1-of (d5 / describe-01 :ARG0 (a9 / and~e.40 :op1 (f3 / figure~e.36 :mod "7D") :op2 (f4 / figure~e.36 :mod "7E")))))) :ARG1-of (a10 / absent-01~e.45 :ARG2~e.46 (c2 / control-01~e.48 :ARG0 (s / saline~e.47)))) :ARG1-of (d6 / describe-01 :ARG0 (f5 / figure~e.50 :mod "7C"~e.51))) # ::id bel_pmid_1799_2263.30264 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 1 ? production into the lung was attenuated in ASC–/– in comparison with ASC+/+ control littermates 24 hours after BLM administration ( Figure 9D ) . # ::alignments 0-1.1.1.2.1 4-1.1 4-1.5 5-1.1.2.r 7-1.1.2 9-1 13-1.5.r 16-1.2.2 16-1.2.2.4 16-1.2.2.4.r 16-1.5.2.2 16-1.5.2.2.4 16-1.5.2.2.4.r 17-1.2.1 17-1.5.2.1 18-1.3.2.1 19-1.3.2.2 20-1.3 21-1.3.1.1.2.1 22-1.3.1 24-1.4.1 25-1.4.1.1 (a2 / attenuate-01~e.9 :ARG1 (p / produce-01~e.4 :ARG1 (p2 / protein :wiki "IL1B" :name (n / name :op1 "IL-1β"~e.0)) :location~e.5 (l / lung~e.7)) :location (m / mouse :mod (l2 / littermate~e.17) :mod (p3 / protein~e.16 :wiki - :name (n2 / name :op1 "ASC") :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of~e.16 (c / control-01~e.16))) :time (a4 / after~e.20 :op1 (a5 / administer-01~e.22 :ARG1 (s / small-molecule :wiki "Bloom_syndrome_protein" :name (n4 / name :op1 "BLM"~e.21))) :quant (t3 / temporal-quantity :quant 24~e.18 :unit (h2 / hour~e.19))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "9D"~e.25)) :compared-to~e.13 (p4 / produce-01~e.4 :ARG1 p2 :location (m3 / mouse :mod (l3 / littermate~e.17) :mod (p5 / protein~e.16 :wiki - :name (n3 / name :op1 "ASC") :mod (w / wild-type) :ARG0-of~e.16 (c2 / control-01~e.16))))) # ::id bel_pmid_1799_2263.30266 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 6 production into the lung 24 hours after BLM treatment was attenuated in ASC–/– in comparison with ASC+/+ control littermates ( Figure 9E ) . Comparable reductions of IL @-@ 1 ? and IL @-@ 6 were obtained in the BALF # ::alignments 0-1.2.1.1.2.1.1 2-1.2.1.1.2.1.1 3-1.1.1 3-1.1.4 4-1.1.1.2.r 6-1.1.1.2 7-1.1.2.2.1 8-1.1.2.2.2 9-1.1.2 10-1.1.2.1.1.1.1 11-1.1.2.1 13-1.1 17-1.1.4.r 20-1.1.3.2 20-1.1.3.2.3 20-1.1.3.2.3.r 20-1.1.4.2.2 20-1.1.4.2.2.3 20-1.1.4.2.2.3.r 21-1.1.3.1 21-1.1.4.2.1 23-1.1.5.1 24-1.1.5.1.1 27-1.2.1.2 28-1.2.1 30-1.2.1.1.1.1.1 30-1.2.1.1.2.1.1 34-1.2.1.1 35-1.2.1.1.1.1.1 35-1.2.1.1.2.1.1 37-1.1.1.1.1.1 37-1.2.1.1.2.1.1 39-1.2 40-1.2.2.r 42-1.2.2 42-1.2.2.1 42-1.2.2.1.1 42-1.2.2.1.1.1 42-1.2.2.1.1.1.r 42-1.2.2.1.1.r 42-1.2.2.1.r (m4 / multi-sentence :snt1 (a / attenuate-01~e.13 :ARG1 (p / produce-01~e.3 :ARG1 (p2 / protein :name (n / name :op1 "IL-6"~e.37)) :location~e.4 (l / lung~e.6)) :time (a2 / after~e.9 :op1 (t2 / treat-04~e.11 :ARG2 (s / small-molecule :name (n2 / name :op1 "BLM"~e.10))) :quant (t4 / temporal-quantity :quant 24~e.7 :unit (h / hour~e.8))) :location (m / mouse :mod (l2 / littermate~e.21) :mod (p3 / protein~e.20 :name (n3 / name :op1 "ASC") :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of~e.20 (c / control-01~e.20))) :compared-to~e.17 (p4 / produce-01~e.3 :ARG1 p2 :location (m3 / mouse :mod (l3 / littermate~e.21) :mod (p5 / protein~e.20 :name (n4 / name :op1 "ASC") :mod (w / wild-type) :ARG0-of~e.20 (c2 / control-01~e.20)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "9E"~e.24))) :snt2 (o / obtain-01~e.39 :ARG1 (r / reduce-01~e.28 :ARG1 (a3 / and~e.34 :op1 (p6 / protein :name (n5 / name :op1 "IL-1β"~e.30,35)) :op2 (p7 / protein :name (n6 / name :op1 "IL-6"~e.0,2,30,35,37))) :ARG1-of (c3 / comparable-03~e.27)) :location~e.40 (f2 / fluid~e.42 :mod~e.42 (l4 / lavage~e.42 :mod~e.42 (a4 / alveolus~e.42 :mod~e.42 (b / bronchus~e.42)))))) # ::id bel_pmid_1803_2482.6302 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Studies using bone marrow @-@ derived macrophages ( BMDM ) isolated from a spontaneous mouse model of Crohn 's disease @-@ like ileitis ( SAMP1/YitFc strain ) revealed significant inhibition by CGP57380 of the proinflammatory cytokines TNF , IL @-@ 6 , and monocyte chemoattractant protein @-@ 1 at 4 and 24 h after LPS stimulation # ::alignments 0-1.1 1-1.1.1 2-1.1.1.1.1.1.1 3-1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1 10-1.1.1.1.2 11-1.1.1.1.2.1.r 13-1.1.1.1.2.1.2 14-1.1.1.1.2.1.1 15-1.1.1.1.2.1 16-1.1.1.1.2.1.3.r 17-1.1.1.1.2.1.3.2.1.2.1 18-1.1.1.1.2.1.3.2.1.2.1 19-1.1.1.1.2.1.3.2.1 21-1.1.1.1.2.1.3 21-1.1.1.1.2.1.3.2 21-1.1.1.1.2.1.3.2.r 22-1.1.1.1.2.1.3.1.1 24-1.1.1.1.2.1.4.1.1.1 25-1.1.1.1.2.1.4.1 27-1 28-1.2.3 29-1.2 30-1.2.1.r 31-1.2.1.1.1 32-1.2.2.r 34-1.2.2.1.2.1 35-1.2.2.1 35-1.2.2.2 36-1.2.2.1.1.1 38-1.2.2.2.1.1 40-1.2.2.2.1.1 42-1.2.2 43-1.2.2.3.1.1 43-1.2.2.4.1.1 44-1.2.2.3.1.1 44-1.2.2.4.1.1 45-1.2.2.3.1.1 45-1.2.2.4.1.1 47-1.2.2.3.1.1 49-1.2.2.4.1.1 50-1.2.2 51-1.3.2.1 52-1.3.2.2 53-1.3 54-1.3.1.1.1.1 55-1.3.1 (r / reveal-01~e.27 :ARG0 (s2 / study-01~e.0 :ARG0-of (u / use-01~e.1 :ARG1 (m5 / macrophage~e.6 :ARG1-of (d / derive-01~e.5 :ARG2 (m / marrow~e.3 :poss (b / bone~e.2))) :ARG1-of (i / isolate-01~e.10 :ARG2~e.11 (m2 / model~e.15 :mod (m3 / mouse~e.14) :mod (s / spontaneity~e.13) :topic~e.16 (m7 / medical-condition~e.21 :name (n2 / name :op1 "ileitis"~e.22) :ARG1-of~e.21 (r2 / resemble-01~e.21 :ARG2 (d2 / disease~e.19 :wiki "Crohn's_disease" :name (n / name :op1 "Crohn's"~e.17,18)))) :ARG1-of (m6 / mean-01 :ARG2 (s5 / strain~e.25 :name (n3 / name :op1 "SAMP1/YitFc"~e.24)))))))) :ARG1 (i2 / inhibit-01~e.29 :ARG0~e.30 (s6 / small-molecule :name (n4 / name :op1 "CGP57380"~e.31)) :ARG1~e.32 (a / and~e.42,50 :op1 (c2 / cytokine~e.35 :name (n5 / name :op1 "TNF"~e.36) :ARG0-of (p2 / promote-01 :ARG1 (i3 / inflame-01~e.34))) :op2 (c3 / cytokine~e.35 :name (n6 / name :op1 "IL-6"~e.38,40) :ARG0-of p2) :op3 (p / protein :name (n7 / name :op1 "monocyte-chemoattractant-protein-1"~e.43,44,45,47)) :op4 (p3 / protein :name (n8 / name :op1 "monocyte-chemoattractant-protein-4"~e.43,44,45,49))) :ARG1-of (s3 / significant-02~e.28)) :time (a2 / after~e.53 :op1 (s4 / stimulate-01~e.55 :ARG0 (m4 / molecular-physical-entity :name (n9 / name :op1 "LPS"~e.54))) :quant (t2 / temporal-quantity :quant 24~e.51 :unit (h / hour~e.52)))) # ::id bel_pmid_1804_8363.10226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Co @-@ immunoprecipitation studies with H @-@ Ras @-@ transformed cells revealed that Spry2 and H @-@ Ras interact and that H @-@ Ras interacts with Spry2 @-@ binding partners , c @-@ Cbl and CIN85 , in a Spry2 @-@ dependent manner . # ::alignments 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2 11-1 12-1.2.r 13-1.2.1.1.1.1 14-1.2 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 18-1.2.1 18-1.2.2 19-1.2 21-1.2.2.1 22-1.2.2.1 23-1.2.2.1 24-1.2.2 25-1.1.2.r 25-1.2.2.2.r 26-1.2.2.2.1.1.1 28-1.2.2.2.1.1 29-1.2.2.2.1 31-1.2.2.2.1.2.1.1.1.1 33-1.2.2.2.1.2.1.1.1.1 34-1.2.2.2.1.2.1 35-1.2.2.2.1.2.1.2.1.1 37-1.2.2.3.r 39-1.2.2.3.1 41-1.2.2.3 (r / reveal-01~e.11 :ARG0 (s / study-01~e.3 :ARG1 (c / coimmunoprecipitate-01) :instrument~e.4,25 (c2 / cell~e.10 :ARG1-of (t / transform-01~e.9 :ARG0 (e / enzyme :name (n / name :op1 "H-Ras"~e.5,7,15,17))))) :ARG1~e.12 (a / and~e.14,19 :op1 (i / interact-01~e.18 :ARG0 (p / protein :name (n2 / name :op1 "Spry2"~e.13)) :ARG1 e) :op2 (i2 / interact-01~e.18,24 :ARG0 e~e.21,22,23 :ARG1~e.25 (a2 / and :op1 (p2 / partner~e.29 :ARG2-of (b / bind-01~e.28 :ARG1 p~e.26) :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.34 :op1 (p4 / protein :name (n3 / name :op1 "c-Cbl"~e.31,33)) :op2 (p3 / protein :name (n4 / name :op1 "CIN85"~e.35)))))) :ARG0-of~e.37 (d / depend-01~e.41 :ARG1 p~e.39)))) # ::id bel_pmid_1804_8363.20908 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We compared human fibroblasts malignantly transformed by overexpression of H @-@ Ras( V12 ) oncogene to their nontransformed parental cells and found that the malignant cells express a high level of Spry2 . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.1 3-1.1.2 4-1.1.2.2.1.1 4-1.1.2.2.1.1.3 4-1.1.2.2.1.1.3.r 5-1.1.2.2 5-1.1.3.2 7-1.1.2.2.1 9-1.1.2.2.1.1.1.1 12-1.1.2.2.1.1.2.1 15-1.1.2.2.1.1.4 15-1.1.3.r 16-1.1.3.3 16-1.1.3.3.r 18-1.1.3.1 19-1.1.3 20-1 21-1.2 22-1.2.1.r 24-1.2.1.1.1 25-1.2.1.1 26-1.2.1 28-1.2.1.2.1 29-1.2.1.2 30-1.2.1.2.2.r 31-1.2.1.2.2.1.1 (a / and~e.20 :op1 (c / compare-01~e.1 :ARG0 (w / we~e.0) :ARG1 (f / fibroblast~e.3 :mod (h2 / human~e.2) :ARG1-of (t / transform-01~e.5 :ARG0 (o / overexpress-01~e.7 :ARG1 (g2 / gene~e.4 :name (n / name :op1 "H-Ras"~e.9) :ARG2-of (m2 / mutate-01 :value "V12"~e.12) :ARG1-of~e.4 (m / malignant-02~e.4) :ARG0-of (c4 / cause-01~e.15 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))))) :ARG2~e.15 (c2 / cell~e.19 :mod (p / parent~e.18) :ARG1-of (t2 / transform-01~e.5 :polarity -) :poss~e.16 f~e.16)) :op2 (f2 / find-01~e.21 :ARG1~e.22 (e / express-03~e.26 :ARG1 (c3 / cell~e.25 :ARG1-of (m3 / malignant-02~e.24)) :ARG2 (l / level~e.29 :ARG1-of (h / high-02~e.28) :quant-of~e.30 (p2 / protein :name (n2 / name :op1 "Spry2"~e.31)))))) # ::id bel_pmid_1804_8363.30892 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When we decreased expression of Spry2 , using a Spry2 @-@ specific shRNA , the H @-@ Ras( V12 ) - transformed fibroblasts could no longer form large colonies in agarose , grow in reduced levels of serum , or form tumors in athymic mice . The level of active H @-@ Ras in these cells remained unaltered . # ::alignments 0-1.1.4.r 0-1.1.5.r 1-1.1.4.1 2-1.1.4 3-1.1.4.2 4-1.1.4.2.1.r 5-1.1.4.2.1.1.1 9-1.1.4.2.1.1.1 11-1.1.4.3 11-1.1.4.3.2 11-1.1.4.3.2.r 12-1.1.4.3.1.1 15-1.1.1.1.1.1.1.1.1 18-1.1.1.1.1.1.1.2.1 21-1.1.1.1.1.1 22-1.1.1.1.1 23-1.1.1 23-1.1.2 23-1.1.3 24-1.1.5 25-1.1.5 26-1.1.1.1 27-1.1.1.1.2.1 28-1.1.1.1.2 29-1.1.1.1.3.r 30-1.1.1.1.3 32-1.1.2.1 33-1.1.2.1.2.r 34-1.1.2.1.2.2 35-1.1.2.1.2 36-1.1.2.1.2.1.r 37-1.1.2.1.2.1 39-1.1 40-1.1.3.1 41-1.1.3.1.2 42-1.1.3.1.3.r 43-1.1.3.1.3.1 44-1.1.3.1.3 47-1.2.1 48-1.2.1.1.r 49-1.2.1.1 49-1.2.1.1.2 49-1.2.1.1.2.r 50-1.2.1.1.1.1 52-1.2.1.1.1.1 54-1.2.3.1 55-1.2.3 56-1.2 57-1.2.2 57-1.2.2.1 57-1.2.2.1.r (m4 / multi-sentence :snt1 (o / or~e.39 :op1 (p2 / possible-01~e.23 :ARG1 (f / form-01~e.26 :ARG0 (f2 / fibroblast~e.22 :ARG1-of (t / transform-01~e.21 :ARG0 (e / enzyme :name (n2 / name :op1 "H-Ras"~e.15) :ARG2-of (m / mutate-01 :value "V12"~e.18)))) :ARG1 (c / colony~e.28 :mod (l / large~e.27)) :location~e.29 (a4 / agarose~e.30))) :op2 (p / possible-01~e.23 :ARG1 (g / grow-01~e.32 :ARG0 f2 :location~e.33 (l2 / level~e.35 :quant-of~e.36 (s / serum~e.37) :ARG1-of (r / reduce-01~e.34)))) :op3 (p3 / possible-01~e.23 :ARG1 (f3 / form-01~e.40 :ARG0 f2 :ARG1 (t2 / tumor~e.41) :location~e.42 (m3 / mouse~e.44 :mod (a / athymic~e.43)))) :time~e.0 (d / decrease-01~e.2 :ARG0 (w / we~e.1) :ARG1 (e2 / express-03~e.3 :ARG2~e.4 (p4 / protein :name (n5 / name :op1 "Spry2"~e.5,9))) :instrument (n3 / nucleic-acid~e.11 :name (n6 / name :op1 "shRNA"~e.12) :ARG1-of~e.11 (s2 / specific-02~e.11 :ARG2 p4))) :time~e.0 (n / no-longer~e.24,25)) :snt2 (r3 / remain-01~e.56 :ARG1 (l3 / level~e.47 :quant-of~e.48 (e3 / enzyme~e.49 :name (n7 / name :op1 "H-Ras"~e.50,52) :ARG0-of~e.49 (a2 / activity-06~e.49))) :ARG3 (a3 / alter-01~e.57 :polarity~e.57 -~e.57 :ARG1 l3) :location (c2 / cell~e.55 :mod (t3 / this~e.54)))) # ::id bel_pmid_1806_0032.38560 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next determined whether the ?EGFR @-@ expressing MCF @-@ 10A cells produced high levels of IL @-@ 6 , leading to activation of STAT3 , as was observed in lung adenocarcinoma @–@ derived cell lines harboring mutant EGFR . The ?EGFR @–@ MCF @-@ 10A cells were treated with P6 , gp130 , and IL @-@ 6 blocking antibodies , which inhibited STAT3 activation . # ::alignments 0-1.1.1 1-1.1.4 2-1.1 3-1.1.2.1 3-1.1.2.1.r 7-1.1.2.2.2 7-1.2.1.2 8-1.1.2.2.1.1 10-1.1.2.2.1.1 11-1.1.2.2 12-1.1.2 13-1.1.2.3.1 14-1.1.2.3 15-1.1.2.3.2.r 16-1.1.2.3.2.1.1 18-1.1.2.3.2.1.1 20-1.1.2.4 21-1.1.2.4.1.r 22-1.1.2.4.1 23-1.1.2.4.1.1.r 24-1.1.2.4.1.1.1.1 26-1.1.4.r 28-1.1.3.1 29-1.1.3.1.1.r 30-1.1.3.1.1.1.1.2 31-1.1.3.1.1.1.1.1.1 33-1.1.3.1.1.1 34-1.1.3.1.1 35-1.1.3.1.1 36-1.1.3.1.1.2 37-1.1.3.1.1.2.1 37-1.1.3.1.1.2.1.2 37-1.1.3.1.1.2.1.2.r 38-1.1.3.1.1.2.1.1.1 43-1.2.1.1.1 45-1.2.1.1.1 46-1.2.1 48-1.2 49-1.2.2.r 50-1.2.2.1.1.1 52-1.2.2.2.1.1 54-1.2.2 55-1.2.2.3.1.1.1.1 57-1.2.2.3.1.1.1.1 58-1.2.2.3.1 59-1.2.2.3 62-1.2.2.4 63-1.2.2.4.1.1.1.1 64-1.2.2.4.1 (m2 / multi-sentence :snt1 (d / determine-01~e.2 :ARG0 (w / we~e.0) :ARG1 (p / produce-01~e.12 :mode~e.3 interrogative~e.3 :ARG0 (c2 / cell-line~e.11 :name (n3 / name :op1 "MCF-10A"~e.8,10) :ARG1-of (e2 / express-03~e.7 :ARG2 (e / enzyme :name (n2 / name :op1 "ΔEGFR")))) :ARG1 (l / level~e.14 :ARG1-of (h / high-02~e.13) :quant-of~e.15 (p2 / protein :name (n4 / name :op1 "IL-6"~e.16,18))) :ARG0-of (l2 / lead-03~e.20 :ARG1~e.21 (a / activate-01~e.22 :ARG1~e.23 (p3 / protein :name (n5 / name :op1 "STAT3"~e.24))))) :ARG2-of (r / resemble-01 :ARG1 (o / observe-01~e.28 :location~e.29 (c / cell-line~e.34,35 :ARG1-of (d2 / derive-01~e.33 :ARG2 (m3 / medical-condition :name (n6 / name :op1 "adenocarcinoma"~e.31) :mod (l3 / lung~e.30))) :ARG0-of (h2 / harbor-01~e.36 :ARG1 (e4 / enzyme~e.37 :name (n7 / name :op1 "EGFR"~e.38) :ARG2-of~e.37 (m / mutate-01~e.37)))))) :time~e.26 (n / next~e.1)) :snt2 (t / treat-04~e.48 :ARG1 (c3 / cell-line~e.46 :name (n8 / name :op1 "MCF-10A"~e.43,45) :ARG1-of (e5 / express-03~e.7 :ARG2 (e3 / enzyme :name (n9 / name :op1 "ΔEGFR")))) :ARG2~e.49 (a2 / and~e.54 :op1 (p4 / protein :name (n10 / name :op1 "P6"~e.50)) :op2 (p5 / protein :name (n11 / name :op1 "gp130"~e.52)) :op3 (a3 / antibody~e.59 :ARG0-of (b / block-01~e.58 :ARG1 (p7 / protein :name (n13 / name :op1 "IL-6"~e.55,57)))) :ARG0-of (i / inhibit-01~e.62 :ARG1 (a4 / activate-01~e.64 :ARG1 (p6 / protein :name (n12 / name :op1 "STAT3"~e.63))))))) # ::id bel_pmid_1806_0035.1688 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , enhanced thrombopoietin signaling , conferred by enforced expression of constitutively active JAK2 or c @-@ MPL , induced phosphorylation of STAT3 and STAT5 , but not STAT1 , and failed to rescue megakaryocyte maturation . # ::alignments 1-1.1.1.2.2 3-1.1.1.1.2 4-1.1.1.1.1.1.1 5-1.1.1.1 7-1.1.1.1.3 8-1.1.1.1.3.1.r 9-1.1.1.1.3.1.2 10-1.1.1.1.3.1 11-1.1.1.1.3.1.1.r 12-1.1.1.1.3.1.1.1.2.1 13-1.1.1.1.3.1.1.1 13-1.1.1.1.3.1.1.1.2 13-1.1.1.1.3.1.1.1.2.r 14-1.1.1.1.3.1.1.1.1.1 15-1.1.1.1.3.1.1 16-1.1.1.1.3.1.1.2.1.1 18-1.1.1.1.3.1.1.2.1.1 20-1.1.1 20-1.1.1.2.2.1 21-1.1.1.2 21-1.1.1.2.2.1.3 22-1.1.1.2.1.r 23-1.1.1.2.1.1.1.1 24-1.1.1.2.1 25-1.1.1.2.1.2.1.1 27-1 27-1.1.1.2.2 28-1.1.1.2.2.1.1 28-1.1.1.2.2.1.1.r 29-1.1.1.2.2.1.3.1.1.1 31-1.1 32-1.1.2 34-1.1.2.2 35-1.1.2.2.2.1 36-1.1.2.2.2 (c / contrast-01~e.27 :ARG2 (a2 / and~e.31 :op1 (i / induce-01~e.20 :ARG0 (s / signal-07~e.5 :ARG1 (p2 / protein :name (n / name :op1 "thrombopoietin"~e.4)) :ARG1-of (e / enhance-01~e.3) :ARG1-of (c2 / confer-02~e.7 :ARG0~e.8 (e2 / express-03~e.10 :ARG2~e.11 (o / or~e.15 :op1 (e4 / enzyme~e.13 :name (n2 / name :op1 "JAK2"~e.14) :ARG0-of~e.13 (a3 / activity-06~e.13 :mod (c5 / constitutive~e.12))) :op2 (p8 / protein :name (n3 / name :op1 "c-MPL"~e.16,18))) :ARG1-of (e3 / enforce-01~e.9)))) :ARG2 (p / phosphorylate-01~e.21 :ARG1~e.22 (a / and~e.24 :op1 (p3 / protein :name (n4 / name :op1 "STAT3"~e.23)) :op2 (p4 / protein :name (n5 / name :op1 "STAT5"~e.25))) :ARG1-of (c3 / contrast-01~e.1,27 :ARG2 (i2 / induce-01~e.20 :polarity~e.28 -~e.28 :ARG0 s :ARG2 (p5 / phosphorylate-01~e.21 :ARG1 (p6 / protein :name (n6 / name :op1 "STAT1"~e.29))))))) :op2 (f / fail-01~e.32 :ARG0 s :ARG1 (r / rescue-01~e.34 :ARG0 s :ARG1 (m / maturate-03~e.36 :ARG1 (m2 / megakaryocyte~e.35)))))) # ::id bel_pmid_1806_0035.28492 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We show that ectopic expression of STAT1 or its downstream transcriptional target IRF @-@ 1 promotes features of megakaryocytic differentiation of G1ME cells , a Gata1 @-@ null erythromegakaryocytic cell line ( 25 ) , # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.2 4-1.2.1.1 4-1.2.2.1.2.2.1.1 5-1.2.1.1.1.r 6-1.2.1.1.1.1.1 7-1.2.1 8-1.2.1.2.2 8-1.2.1.2.2.r 9-1.2.1.2.3 10-1.2.1.2 10-1.2.1.2.4 10-1.2.1.2.4.r 11-1.2.1.2.5 12-1.2.1.2.1.1 14-1.2.1.2.1.1 15-1.2 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1.1 18-1.2.2.1.2.2.1.2 19-1.2.2.1 20-1.2.2.1.2.r 21-1.2.2.1.2.1.1 22-1.2.2.1.2.2.1 25-1.2.2.1.2.2.1.1.1.1.1 27-1.2.2.1.2.2.1.1.1 27-1.2.2.1.2.2.1.1.1.2 27-1.2.2.1.2.2.1.1.1.2.1 27-1.2.2.1.2.2.1.1.1.2.1.r 27-1.2.2.1.2.2.1.1.1.2.r 29-1.2.2.1.2 30-1.2.2.1.2.2.1 32-1.2.3.1.1.1 (s2 / show-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (p / promote-01~e.15 :ARG0 (o / or~e.7 :op1 (e / express-03~e.4 :ARG2~e.5 (p2 / protein :name (n / name :op1 "STAT1"~e.6)) :mod (e2 / ectopic~e.3)) :op2 (p4 / protein~e.10 :name (n2 / name :op1 "IRF-1"~e.12,14) :poss~e.8 p2~e.8 :location (d / downstream~e.9) :ARG0-of~e.10 (t / transcribe-01~e.10) :ARG1-of (t2 / target-01~e.11))) :ARG1 (f / feature~e.16 :topic~e.17 (d2 / differentiate-01~e.19 :ARG0 (m5 / megakaryocyte~e.18) :ARG1~e.20 (c / cell-line~e.29 :name (n4 / name :op1 "G1ME"~e.21) :ARG1-of (m4 / mean-01 :ARG2 (c3 / cell-line~e.22,30 :ARG3-of (e3 / express-03~e.4 :ARG2 (p5 / protein~e.27 :name (n5 / name :op1 "Gata1"~e.25) :ARG2-of~e.27 (m / mutate-01~e.27 :mod~e.27 "-/-"~e.27))) :mod (m2 / megakaryocyte~e.18) :mod (e4 / erythroid)))))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 25~e.32))))) # ::id bel_pmid_1806_0035.31648 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In most cell types , STAT1 is primarily triggered by interferon signaling ( 21 ) . However , TPO signaling phosphorylates STAT1 in WT megakaryocytes ( 10 ) . # ::alignments 1-1.1.5.1.1 2-1.1.5 3-1.1.5.1 5-1.1.2.1.1 7-1.1.3 7-1.1.3.r 8-1.1 9-1.1.1.r 10-1.1.1.1.1.1 11-1.1.1 13-1.1.4.1.1.1 16-1.2 18-1.2.1.2.1.1.1 19-1.2.1.2 20-1.2.1 21-1.2.1.1.1.1 22-1.2.1.3.r 23-1.2.1.3.1 24-1.2.1.3 26-1.2.1.4.1.1.1 (m2 / multi-sentence :snt1 (t / trigger-01~e.8 :ARG0~e.9 (s / signal-07~e.11 :ARG1 (p3 / protein :name (n2 / name :op1 "interferon"~e.10))) :ARG1 (p / protein :name (n / name :op1 "STAT1"~e.5)) :manner~e.7 (p2 / primary~e.7) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 21~e.13))) :location (c / cell~e.2 :ARG1-of (t2 / type-03~e.3 :mod (m / most~e.1)))) :snt2 (h / have-concession-91~e.16 :ARG1 (p5 / phosphorylate-01~e.20 :ARG1 (p6 / protein :name (n4 / name :op1 "STAT1"~e.21)) :ARG2 (s2 / signal-07~e.19 :ARG1 (p8 / protein :name (n3 / name :op1 "TPO"~e.18))) :location~e.22 (m3 / megakaryocyte~e.24 :mod (w / wild-type~e.23)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 10~e.26)))))) # ::id bel_pmid_1806_0035.33056 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , GATA @-@ 1 transactivated the Stat1 promoter in luciferase reporter assays ( Supplemental Figure 1 ) . STAT1 and IRF @-@ 1 reciprocally activated each other ’s transcription , as previously reported ( Figure ?( Figure1D1D and Supplemental Table 1 ; also reviewed in ref . 26 ) . # ::alignments 0-1.1 2-1.1.1.2.1.1 4-1.1.1.2.1.1 4-1.1.1.4.1.1 5-1.1.1 7-1.1.1.1.1.1.1.1 8-1.1.1.1 8-1.1.1.1.1 8-1.1.1.1.1.r 9-1.1.1.3.r 10-1.1.1.3.1.1.1.1 11-1.1.1.3.1 12-1.1.1.3 14-1.1.1.4.1.2 15-1.1.1.4.1 16-1.1.1.4.1.1 19-1.2.1.1.1.1 20-1.2 21-1.2.1.2.1.1.1 23-1.2.1.2.1.1.1 25-1.2.1 25-1.2.2 29-1.2.1.2 29-1.2.2.2 31-1.2.3.1.r 32-1.2.3.1 33-1.2.3 35-1.2.4.1.1 38-1.2.4.1 39-1.2.4.1.2.2 40-1.2.4.1.2 41-1.2.1.2.1.1.1 41-1.2.4.1.2.1 43-1.2.5.2 44-1.2.5 48-1.2.5.1.1.1 (m / multi-sentence :snt1 (a / and~e.0 :op2 (t / transactivate-01~e.5 :ARG1 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.8 (p2 / promote-01~e.8 :ARG1 (p3 / protein :name (n2 / name :op1 "Stat1"~e.7)))) :ARG2 (p / protein :name (n / name :op1 "GATA-1"~e.2,4)) :time~e.9 (a2 / assay-01~e.12 :ARG0-of (r2 / report-01~e.11 :ARG1 (e / enzyme :name (n3 / name :op1 "luciferase"~e.10)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod 1~e.4,16 :ARG2-of (s / supplement-01~e.14))))) :snt2 (a5 / and~e.20 :op1 (a3 / activate-01~e.25 :ARG0 (p4 / protein :name (n4 / name :op1 "STAT1"~e.19)) :ARG1 (t3 / transcribe-01~e.29 :ARG1 (p7 / protein :name (n5 / name :op1 "IRF-1"~e.21,23,41)))) :op2 (a4 / activate-01~e.25 :ARG0 p7 :ARG1 (t4 / transcribe-01~e.29 :ARG1 p4)) :ARG1-of (r3 / report-01~e.33 :time~e.31 (p5 / previous~e.32)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and~e.38 :op1 (f2 / figure~e.35 :mod "1D") :op2 (t5 / table~e.40 :mod 1~e.41 :ARG2-of (s2 / supplement-01~e.39)))) :ARG1-of (r / review-02~e.44 :ARG2 (p6 / publication :ARG1-of (c / cite-01 :ARG2 26~e.48)) :mod (a7 / also~e.43)))) # ::id bel_pmid_1806_0035.33182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , STAT1 or IRF @-@ 1 induced the expression of CD42 , a late marker of megakaryocyte maturation , albeit to a much lesser extent than GATA @-@ 1 ( Figure ?( Figure1C ) .1C ) . # ::alignments 0-1 1-1 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 8-1.1 8-1.2 10-1.1.2 10-1.2.4 11-1.1.2.1.r 12-1.1.2.1.1.1 15-1.1.2.1.3 18-1.1.2.1.2.1.1 19-1.1.2.1.2.1 24-1.2.3.1.1 25-1.2.3 25-1.2.3.1 25-1.2.3.1.r 26-1.2.3.r 27-1.2.4.r 28-1.2.4.1.1.1 30-1.2.4.1.1.1 32-1.3.1 (a / and~e.0,1 :op2 (i / induce-01~e.8 :ARG0 (o / or~e.4 :op1 (p / protein :name (n / name :op1 "STAT1"~e.3)) :op2 (p3 / protein :name (n2 / name :op1 "IRF-1"~e.5,7))) :ARG2 (e / express-03~e.10 :ARG2~e.11 (p2 / protein :name (n3 / name :op1 "CD42"~e.12) :ARG0-of (m / mark-02 :ARG1 (m2 / maturate-03~e.19 :ARG1 (m4 / megakaryocyte~e.18))) :mod (l3 / late~e.15)))) :concession (i2 / induce-01~e.8 :ARG0 o :ARG2 e :extent~e.26 (l / less~e.25 :degree~e.25 (m3 / more~e.25 :degree (m5 / much~e.24))) :compared-to~e.27 (e2 / express-03~e.10 :ARG2 (p4 / protein :name (n5 / name :op1 "GATA-1"~e.28,30)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "1C"))) # ::id bel_pmid_1806_0035.34122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok enforced STAT1 expression promoted several features of megakaryocytic differentiation of G1ME cells , as evidenced by increased cell size ( forward scatter ) and increased DNA content , reflecting polyploidization ( Figure ?( Figure1,1 , A and B ) . Similar effects were produced by enforced expression of IRF @-@ 1 , a major STAT1 effector ( reviewed in ref . 26 ) . # ::alignments 0-1.1.1.2 1-1.1.1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 6-1.1.2.2.r 7-1.1.2.2.1 8-1.1.2.2 9-1.1.2.2.2.r 10-1.1.2.2.2.1.1 11-1.1.2.2.2 13-1.1.3.r 14-1.1.3 15-1.1.3.1.r 16-1.1.3.1.1.2 17-1.1.3.1.1.1 18-1.1.3.1.1 20-1.1.3.1.1.3.1.1 21-1.1.3.1.1.3.1 23-1.1.3.1 24-1.1.3.1.2.1.3 25-1.1.3.1.2.1.2.1 26-1.1.3.1.2 28-1.1.4 31-1.1.5.1.1 31-1.1.5.1.2 36-1.1.5.1 40-1.2.2.1 41-1.2.1.1 41-1.2.1.1.2 41-1.2.1.1.2.r 41-1.2.2 43-1.2 44-1.2.1.r 45-1.2.1.2 46-1.2.1 48-1.2.1.1.1.1 50-1.2.1.1.1.1 53-1.2.1.1.2.2 54-1.2.1.1.2.1.1.1 61-1.2.3.1.1.1 (m / multi-sentence :snt1 (p / promote-01~e.3 :ARG0 (e / express-03~e.2 :ARG2 (p2 / protein :name (n / name :op1 "STAT1"~e.1)) :ARG1-of (e2 / enforce-01~e.0)) :ARG1 (f / feature~e.5 :quant (s / several~e.4) :topic~e.6 (d / differentiate-01~e.8 :ARG0 (m3 / megakaryocyte~e.7) :ARG1~e.9 (c2 / cell-line~e.11 :name (n3 / name :op1 "G1ME"~e.10)))) :ARG1-of~e.13 (e3 / evidence-01~e.14 :ARG0~e.15 (a2 / and~e.23 :op1 (s2 / size~e.18 :poss (c3 / cell~e.17) :ARG1-of (i / increase-01~e.16) :ARG1-of (s3 / show-01 :ARG0 (s4 / scatter-01~e.21 :direction (f4 / forward~e.20)))) :op2 (c4 / contain-01~e.26 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.25) :ARG1-of (i2 / increase-01~e.24))))) :ARG1-of (r2 / reflect-01~e.28 :ARG2 (p3 / polyploidize-01)) :ARG1-of (d3 / describe-01 :ARG0 (a / and~e.36 :op1 (f2 / figure~e.31 :mod "1.1.A") :op2 (f3 / figure~e.31 :mod "1.1.B")))) :snt2 (p4 / produce-01~e.43 :ARG0~e.44 (e5 / express-03~e.46 :ARG2 (p6 / protein~e.41 :name (n4 / name :op1 "IRF-1"~e.48,50) :ARG0-of~e.41 (a4 / affect-01~e.41 :ARG1 (p5 / protein :name (n5 / name :op1 "STAT1"~e.54)) :ARG1-of (m2 / major-02~e.53))) :ARG1-of (e6 / enforce-01~e.45)) :ARG1 (a3 / affect-01~e.41 :ARG1-of (r3 / resemble-01~e.40)) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 26~e.61))))) # ::id bel_pmid_1806_0035.34154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Second , mice deficient for both STAT5A and STAT5B are thrombocytopenic , likely due to a reduction in functional hematopoietic progenitors ( 18 ) . # ::alignments 0-1.3 0-1.3.1 0-1.3.1.r 2-1.1 7-1.1.1.1 9-1.1.r 10-1 12-1.2.2 13-1.2 14-1.2 16-1.2.1 17-1.2.1.1.r 18-1.2.1.1.2 19-1.2.1.1.1 20-1.2.1.1 22-1.4.1.1.1 (t / thrombocytopenic~e.10 :domain~e.9 (m / mouse~e.2 :ARG0-of (l / lack-01 :ARG1 (a / and~e.7 :op1 (g / gene :name (n / name :op1 "STAT1A")) :op2 (g2 / gene :name (n2 / name :op1 "STAT1B"))))) :ARG1-of (c / cause-01~e.13,14 :ARG0 (r / reduce-01~e.16 :ARG1~e.17 (p / progenitor~e.20 :mod (h / hematopoietic~e.19) :ARG0-of (f / function-01~e.18))) :ARG1-of (l2 / likely-01~e.12)) :mod (o / ordinal-entity~e.0 :value~e.0 2~e.0) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 18~e.22)))) # ::id bel_pmid_1806_0035.39068 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TPO functions through binding its receptor , c @-@ Mpl , to activate JAK2 , STAT1 , STAT3 , and STAT5 in megakaryocytes and other hematopoietic cells ( 10 @–@ 12 ) . # ::alignments 0-1.1.1.1 1-1 3-1.2 4-1.2.1.2 4-1.2.1.2.r 5-1.2.1.1.2 7-1.2.1.1.1 9-1.2.1.1.1 12-1.2.3 13-1.2.3.2.1.1.1 15-1.2.3.2.2.1.1 17-1.2.3.2.3.1.1 19-1.2.3.2 20-1.2.3.2.4.1.1 21-1.2.3.3.r 22-1.2.3.3.1 23-1.2.3.3 24-1.2.3.3.2.2 25-1.2.3.3.2.1 26-1.2.3.3.2 28-1.3.1.1.1.1 30-1.3.1.1.1.2 (f / function-01~e.1 :ARG0 (p5 / protein :name (n / name :op1 "TPO"~e.0)) :instrument (b / bind-01~e.3 :ARG1 (p6 / protein :name (n7 / name :op1 "c-Mpl"~e.7,9 :op2 "receptor"~e.5) :poss~e.4 p5~e.4) :ARG2 p5 :purpose (a / activate-01~e.12 :ARG0 p5 :ARG1 (a2 / and~e.19 :op1 (e / enzyme :name (n3 / name :op1 "JAK2"~e.13)) :op2 (p / protein :name (n4 / name :op1 "STAT1"~e.15)) :op3 (p2 / protein :name (n5 / name :op1 "STAT3"~e.17)) :op4 (p3 / protein :name (n6 / name :op1 "STAT5"~e.20))) :location~e.21 (a3 / and~e.23 :op1 (m / megakaryocyte~e.22) :op2 (c2 / cell~e.26 :mod (h / hematopoietic~e.25) :mod (o / other~e.24))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 10~e.28 :op2 12~e.30))))) # ::id bel_pmid_1806_0035.39758 ::amr-annotator SDL-AMR-09 ::preferred # ::tok enforced STAT1 expression promoted several features of megakaryocytic differentiation of G1ME cells , as evidenced by increased cell size ( forward scatter ) and increased DNA content , reflecting polyploidization ( Figure ?( Figure1,1 , A and B ) . Similar effects were produced by enforced expression of IRF @-@ 1 , a major STAT1 effector ( reviewed in ref . 26 ) . # ::alignments 0-1.1.1.2 1-1.1.1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 6-1.1.2.2.r 7-1.1.2.2.1 8-1.1.2.2 9-1.1.2.2.2.r 10-1.1.2.2.2.1.1 11-1.1.2.2.2 13-1.1.3.r 14-1.1.3 15-1.1.3.1.r 16-1.1.3.1.1.2 17-1.1.3.1.1.1 18-1.1.3.1.1 20-1.1.3.1.1.3.1.1 21-1.1.3.1.1.3.1 23-1.1.3.1 24-1.1.3.1.2.1.3 25-1.1.3.1.2.1.2.1 26-1.1.3.1.2 28-1.1.4 31-1.1.5.1.1 31-1.1.5.1.2 36-1.1.5.1 40-1.2.2.1 41-1.2.1.1 41-1.2.1.1.2 41-1.2.1.1.2.r 41-1.2.2 43-1.2 44-1.2.1.r 45-1.2.1.2 46-1.2.1 48-1.2.1.1.1.1 50-1.2.1.1.1.1 53-1.2.1.1.2.2 54-1.2.1.1.2.1.1.1 61-1.2.3.1.1.1 (m / multi-sentence :snt1 (p / promote-01~e.3 :ARG0 (e / express-03~e.2 :ARG2 (p2 / protein :name (n / name :op1 "STAT1"~e.1)) :ARG1-of (e2 / enforce-01~e.0)) :ARG1 (f / feature~e.5 :quant (s / several~e.4) :topic~e.6 (d / differentiate-01~e.8 :ARG0 (m3 / megakaryocyte~e.7) :ARG1~e.9 (c2 / cell-line~e.11 :name (n3 / name :op1 "G1ME"~e.10)))) :ARG1-of~e.13 (e3 / evidence-01~e.14 :ARG0~e.15 (a / and~e.23 :op1 (s2 / size~e.18 :poss (c3 / cell~e.17) :ARG1-of (i / increase-01~e.16) :ARG1-of (s3 / show-01 :ARG0 (s4 / scatter-01~e.21 :direction (f4 / forward~e.20)))) :op2 (c4 / contain-01~e.26 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.25) :ARG1-of (i2 / increase-01~e.24))))) :ARG1-of (r2 / reflect-01~e.28 :ARG2 (p3 / polyploidize-01)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.36 :op1 (f2 / figure~e.31 :mod "1.1.A") :op2 (f3 / figure~e.31 :mod "1.1.B")))) :snt2 (p4 / produce-01~e.43 :ARG0~e.44 (e4 / express-03~e.46 :ARG2 (p6 / protein~e.41 :name (n4 / name :op1 "IRF-1"~e.48,50) :ARG0-of~e.41 (a4 / affect-01~e.41 :ARG1 (p5 / protein :name (n5 / name :op1 "STAT1"~e.54)) :ARG1-of (m2 / major-02~e.53))) :ARG1-of (e6 / enforce-01~e.45)) :ARG1 (a3 / affect-01~e.41 :ARG1-of (r3 / resemble-01~e.40)) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 26~e.61))))) # ::id bel_pmid_1807_7438.4108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although inhibitors of PKC had no effect on this suppression , MAPK inhibitors completely prevented the TPA effect . RasGRP1 activates the MAPK pathway through activation of the small G protein H @-@ Ras . # ::alignments 0-1.1.4.r 1-1.1.4.2 1-1.1.4.2.1 1-1.1.4.2.1.r 2-1.1.4.2.1.1.r 3-1.1.4.2.1.1.1.1 5-1.1.4.1 5-1.1.4.1.r 6-1.1.4 9-1.1.4.3 11-1.1.1.1.1.1.1 12-1.1.1 12-1.1.1.1 12-1.1.1.1.r 13-1.1.3 14-1.1 16-1.1.2.1.1.1 17-1.1.2 19-1.2.1.1.1 20-1.2 22-1.2.2.1.1 23-1.1.1.1.1 23-1.2.2 25-1.2 25-1.2.3 25-1.2.3.r 26-1.2.3.2.r 28-1.2.3.2.2.1.1 29-1.2.3.2.2.1.2 30-1.2.3.2.2.1.3 31-1.2.3.2.1.1 33-1.2.3.2.1.1 (m / multi-sentence :snt1 (p / prevent-01~e.14 :ARG0 (m2 / molecular-physical-entity~e.12 :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (p2 / pathway~e.23 :name (n / name :op1 "MAPK"~e.11)))) :ARG1 (a / affect-01~e.17 :ARG0 (s / small-molecule :name (n2 / name :op1 "TPA"~e.16))) :ARG1-of (c / complete-02~e.13) :concession~e.0 (a2 / affect-01~e.6 :polarity~e.5 -~e.5 :ARG0 (m3 / molecular-physical-entity~e.1 :ARG0-of~e.1 (i2 / inhibit-01~e.1 :ARG1~e.2 (e2 / enzyme :name (n3 / name :op1 "PKC"~e.3)))) :ARG1 (s3 / suppress-01~e.9 :ARG1 a))) :snt2 (a3 / activate-01~e.20,25 :ARG0 (p3 / protein :name (n4 / name :op1 "RasGRP1"~e.19)) :ARG1 (p4 / pathway~e.23 :name (n5 / name :op1 "MAPK"~e.22)) :manner~e.25 (a4 / activate-01~e.25 :ARG0 p3 :ARG1~e.26 (e3 / enzyme :name (n7 / name :op1 "H-Ras"~e.31,33) :mod (e4 / enzyme :name (n6 / name :op1 "small"~e.28 :op2 "G"~e.29 :op3 "protein"~e.30)))))) # ::id bel_pmid_1807_7438.32114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Functional assessment of NCC by using thiazide @-@ sensitive ( 22 ) Na(+) uptakes revealed that TPA completely suppresses NCC function . Biotinylation experiments demonstrated that this result was primarily because of decreased surface expression of NCC . # ::alignments 0-1.1.1.2 1-1.1.1 3-1.2.2.1.1.1.1.1 4-1.1.1.3.r 5-1.1.1.3 6-1.1.1.3.1.2.1.1.1 13-1.1.1.3.1 14-1.1 15-1.1.2.r 16-1.1.2.1.1.1 17-1.1.2.3 18-1.1.2 19-1.1.2.2.1.1.1 20-1.1.2.2 23-1.2.1 24-1.2 26-1.2.2.2.2 27-1.2.2.2 27-1.2.2.2.1 27-1.2.2.2.1.r 29-1.2.2.3 30-1.2.2 32-1.2.2.1 33-1.2.2.1.1.2 34-1.2.2.1.1 36-1.1.2.2.1.1.1 36-1.2.2.1.1.1.1.1 (m / multi-sentence :snt1 (r / reveal-01~e.14 :ARG0 (a / assess-01~e.1 :ARG1 p2 :mod (f2 / function-01~e.0) :manner~e.4 (u / use-01~e.5 :ARG1 (u2 / uptake~e.13 :mod (s5 / small-molecule :name (n3 / name :op1 "22Na+")) :ARG1-of (s2 / sensitize-01 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "thiazide"~e.6)))))) :ARG1~e.15 (s / suppress-01~e.18 :ARG0 (s6 / small-molecule :name (n / name :op1 "TPA"~e.16)) :ARG1 (f / function-01~e.20 :ARG0 (p2 / protein :name (n2 / name :op1 "NCC"~e.19,36))) :ARG1-of (c / complete-02~e.17))) :snt2 (d / demonstrate-01~e.24 :ARG0 (e / experiment-01~e.23 :ARG1 (b / biotinylate-01)) :ARG1 (c2 / cause-01~e.30 :ARG0 (d2 / decrease-01~e.32 :ARG1 (e2 / express-03~e.34 :ARG2 (p5 / protein :name (n5 / name :op1 "NCC"~e.3,36)) :ARG3 (s4 / surface~e.33))) :ARG1 (t / thing~e.27 :ARG2-of~e.27 (r2 / result-01~e.27) :mod (t2 / this~e.26)) :mod (p4 / primary~e.29)))) # ::id bel_pmid_1820_0061.27886 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of all proinflammatory @/@ profibrotic mediators as assessed by reverse transcriptase @-@ PCR and densitometry was less in Lenti @-@ IL @-@ 10 @-@ injected wounds compared with Lenti @-@ GFP @-@ injected wounds , with the difference in the expression of IL @-@ 6 , MCP @-@ 1 , and HSP47 reaching statistical significance ( Figure 5 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.3 3-1.1.1.1 3-1.1.1.1.1 3-1.1.1.1.1.1 3-1.1.1.1.1.1.r 3-1.1.1.1.1.r 3-1.1.1.2 3-1.1.1.2.2 3-1.1.1.2.2.r 6-1.1.1.1.2 7-1.1.5.r 8-1.1.5 10-1.1.5.1.1.3.1 11-1.1.5.1.1.3 13-1.1.5.1.1 13-1.1.5.1.1.1 13-1.1.5.1.1.1.r 13-1.1.5.1.1.2 13-1.1.5.1.1.2.r 14-1.1.5.1 15-1.1.5.1.2 17-1.1.3 19-1.1.2.1.1.1.1 21-1.1.2.1.1.1.1 23-1.1.2.1.1.1.1 25-1.1.2.1 26-1.1.2 27-1.1.4.r 28-1.1.5.1.r 29-1.1.4.2.1.1.1.1 31-1.1.4.2.1.1.1.1 33-1.1.4.2.1 34-1.1.2 34-1.1.4.2 36-1.1.5.1.r 38-1.2.1 41-1.1.4 41-1.2.1.1.1 41-1.2.1.1.2 41-1.2.1.1.3 42-1.2.1.1.1.1.r 42-1.2.1.1.r 43-1.2.1.1.1.1.1.1 45-1.2.1.1.1.1.1.1 47-1.2.1.1.2.1.1.1 49-1.2.1.1.2.1.1.1 51-1.2.1.1 52-1.2.1.1.3.1.1.1 53-1.2 54-1.2.2.1 57-1.3.1 58-1.3.1.1 (a6 / and :op1 (e / express-03~e.0 :ARG2~e.1 (a / and :op1 (m2 / molecular-physical-entity~e.3 :ARG0-of~e.3 (f / favor-01~e.3 :ARG1~e.3 (i / inflame-01~e.3)) :ARG0-of (m / mediate-01~e.6)) :op2 (m3 / molecular-physical-entity~e.3 :ARG0-of m :ARG0-of~e.3 (f2 / favor-01~e.3 :ARG1 (f3 / fibrosis))) :mod (a2 / all~e.2)) :ARG3 (w / wound-01~e.26,34 :ARG2-of (i2 / inject-01~e.25 :ARG1 (p / protein :name (n / name :op1 "Lenti-IL-10"~e.19,21,23)))) :mod (l / less~e.17) :compared-to~e.27 (e5 / express-03~e.41 :ARG2 a :ARG3 (w2 / wound-01~e.34 :ARG2-of (i3 / inject-01~e.33 :ARG1 (p2 / protein :name (n2 / name :op1 "Lenti-GFP"~e.29,31))))) :ARG1-of~e.7 (a4 / assess-01~e.8 :instrument~e.28,36 (a5 / and~e.14 :op1 (r2 / react-01~e.13 :ARG0~e.13 (p6 / polymerase~e.13) :ARG1-of~e.13 (c / chain-01~e.13) :mod (t2 / transcriptase~e.11 :ARG1-of (r3 / reverse-01~e.10))) :op2 (d3 / densitometry~e.15)))) :op2 (r / reach-01~e.53 :ARG0 (d / differ-02~e.38 :ARG1~e.42 (a3 / and~e.51 :op1 (e2 / express-03~e.41 :ARG2~e.42 (p3 / protein :name (n3 / name :op1 "IL-6"~e.43,45))) :op2 (e3 / express-03~e.41 :ARG2 (p4 / protein :name (n4 / name :op1 "MCP-1"~e.47,49))) :op3 (e4 / express-03~e.41 :ARG2 (p5 / protein :name (n5 / name :op1 "HSP47"~e.52))))) :ARG1 (s3 / signify-01 :mod (s / statistics~e.54))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure~e.57 :mod 5~e.58))) # ::id bel_pmid_1826_8536.21638 ::amr-annotator SDL-AMR-09 ::preferred # ::tok observations that inhibition of PI3K or EGF @-@ R is sufficient to prevent terminal differentiation in keratinocytes in suspension ( Rodeck et al. , 1997 ; Nikolopoulos et al. , 2005 ) , and that function disrupting antibodies to E @-@ cadherin abrogate Akt phosphorylation inducing growth arrest and terminal differentiation in conventional submerged mouse keratinocyte cultures at confluency ( Calautti et al. , 2005 ) . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1.1.2.1.1 8-1.1.1.1.1.2.1.1 10-1.1.1 12-1.1.1.2 13-1.1.1.2.2.2 14-1.1.1.2.2 15-1.1.1.2.2.1.r 16-1.1.1.2.2.1.1.1 18-1.1.1.2.2.1 18-1.1.1.2.2.1.2 18-1.1.1.2.2.1.2.r 20-1.1.1.3.1.1.1.1.1.1 21-1.1.1.3.1.1.1 22-1.1.1.3.1.1.1.2.1 24-1.1.1.3.1.1.2.1 26-1.1.1.3.1.2.1.1.1.1 27-1.1 27-1.1.1.3.1 27-1.1.1.3.1.2.1 28-1.1.1.3.1.2.1.2.1 30-1.1.1.3.1.2.2 33-1.1.2.4.1.1 35-1.1.2.1.1.1 36-1.1.2.1.1 37-1.1.2.1 39-1.1.2.1.2.1.1.1 41-1.1.2.1.2.1.1.1 42-1.1.2 43-1.1.2.2.1.1.1 44-1.1.2.2 45-1.1.2.3 46-1.1.2.3.1.1.1 47-1.1.2.3.1.1 48-1.1 48-1.1.1.3.1 48-1.1.1.3.1.2.1 48-1.1.2.3.1 48-1.1.2.4.1.1 49-1.1.2.3.1.2.2 50-1.1.2.3.1.2 51-1.1.2.3.1.2.1.r 52-1.1.2.3.1.2.1.3.1 53-1.1.2.3.1.2.1.3 54-1.1.2.3.1.2.1.1 55-1.1.2.3.1.2.1.2 56-1.1.2.3.1.2.1 57-1.1.2.3.2.r 58-1.1.2.3.2 60-1.1.2.4.1.1.1.1.1 61-1.1.2.4.1.1 62-1.1.2.4.1.1.2.1 64-1.1.2.4.1.2.1 (o / observe-02~e.0 :ARG1~e.1 (a / and~e.27,48 :op1 (s / suffice-01~e.10 :ARG0 (i / inhibit-01~e.2 :ARG1~e.3 (o2 / or~e.5 :op1 (e2 / enzyme :name (n2 / name :op1 "PI3K"~e.4)) :op2 (e / enzyme :name (n / name :op1 "EGF-R"~e.6,8)))) :ARG1 (p / prevent-01~e.12 :ARG0 i :ARG1 (d / differentiate-01~e.14 :ARG1~e.15 (c / cell~e.18 :name (n3 / name :op1 "keratinocyte"~e.16) :ARG1-of~e.18 (s2 / suspend-02~e.18)) :mod (t / terminal~e.13))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.27,48 :op1 (p2 / publication-91 :ARG0 (a3 / and~e.21 :op1 (p3 / person :name (n4 / name :op1 "Rodeck"~e.20)) :op2 (p4 / person :mod (o3 / other~e.22))) :time (d7 / date-entity :year 1997~e.24)) :op2 (p5 / publication-91 :ARG0 (a4 / and~e.27,48 :op1 (p6 / person :name (n5 / name :op1 "Nikolopoulos"~e.26)) :op2 (p7 / person :mod (o4 / other~e.28))) :time d6~e.30)))) :op2 (a5 / abrogate-01~e.42 :ARG0 (a6 / antibody~e.37 :ARG0-of (d3 / disrupt-01~e.36 :ARG1 (f / function-01~e.35)) :ARG0-of (c2 / counter-01 :ARG1 (p8 / protein :name (n6 / name :op1 "E-cadherin"~e.39,41)))) :ARG1 (p9 / phosphorylate-01~e.44 :ARG1 (e3 / enzyme :name (n7 / name :op1 "Akt"~e.43))) :ARG0-of (i2 / induce-01~e.45 :ARG2 (a7 / and~e.48 :op1 (a8 / arrest-02~e.47 :ARG1 (g / grow-01~e.46 :ARG1 c3)) :op2 (d4 / differentiate-01~e.50 :ARG1~e.51 (c3 / culture~e.56 :source (m / mouse~e.54) :mod c~e.55 :ARG1-of (s3 / submerge-01~e.53 :manner (c4 / conventional~e.52))) :mod t~e.49)) :manner~e.57 (c5 / confluency~e.58)) :ARG1-of (d5 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a9 / and~e.33,48,61 :op1 (p11 / person :name (n8 / name :op1 "Calautti"~e.60)) :op2 (p12 / person :mod (o5 / other~e.62))) :time (d6 / date-entity :year 2005~e.64)))))) # ::id bel_pmid_1826_8536.21660 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vivo , b4 @-@ integrin amplifies proproliferative signals in basal epidermal keratinocytes ( Nikolopoulos et al. , 2005 ) , where STAT3 is expressed and can be activated by EGF @/@ EGF @-@ R ( Nishio et al. , 2001 ; Chan et al. , 2004 ; Li et al. , 2007 ) # ::alignments 0-1.4 1-1.4 3-1.1.1.1 5-1.1.1.1 6-1 8-1.2 9-1.3.r 9-1.4 10-1.3.2 12-1.3.1.1 14-1.5.1.1.1.1.1 15-1.5.1.1 16-1.5.1.1.2.1 18-1.5.1.2.1 21-1.3.5.r 22-1.3.4.1.1.1 24-1.3.4 26-1.3.5 28-1.3.5.1 29-1.3.5.1.1.r 30-1.3.5.1.1.1.1.1 31-1.3.5.1.1 32-1.3.5.1.1.1.1.1 34-1.3.5.1.1.2.1.1 36-1.3.5.2.1.1.1.1.1.1 37-1.3.5.2.1.1.1 38-1.3.5.2.1.1.1.2.1 40-1.3.5.2.1.1.2.1 42-1.3.5.2.1.2.1.1.1.1 43-1.3.5.2.1.2.1 44-1.3.5.2.1.2.1.2.1 46-1.3.5.2.1.2.2.1 48-1.3.5.2.1.3.1.1.1.1 49-1.3.5.2.1 49-1.3.5.2.1.3.1 50-1.3.5.2.1.3.1.2.1 52-1.3.5.2.1.3.2.1 (a / amplify-01~e.6 :ARG0 (p / protein :name (n / name :op1 "b4-integrin"~e.3,5)) :ARG1 (s / signal-07~e.8 :mod (p2 / proliferate-01)) :location~e.9 (c / cell :name (n2 / name :op1 "keratinocyte"~e.12) :mod (b / basal~e.10) :part-of (e / epidermis) :ARG3-of (e2 / express-03~e.24 :ARG2 (p6 / protein :name (n4 / name :op1 "STAT3"~e.22))) :location-of~e.21 (p7 / possible-01~e.26 :ARG1 (a3 / activate-01~e.28 :ARG0~e.29 (s3 / slash~e.31 :op1 (p17 / protein :name (n5 / name :op1 "EGF"~e.30,32)) :op2 (e4 / enzyme :name (n6 / name :op1 "EGF-R"~e.34))) :ARG1 p6) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.49 :op1 (p8 / publication-91 :ARG0 (a6 / and~e.37 :op1 (p9 / person :name (n7 / name :op1 "Nishio"~e.36)) :op2 (p10 / person :mod (o2 / other~e.38))) :time (d3 / date-entity :year 2001~e.40)) :op2 (p11 / publication-91 :ARG0 (a7 / and~e.43 :op1 (p12 / person :name (n8 / name :op1 "Chan"~e.42)) :op2 (p13 / person :mod (o3 / other~e.44))) :time (d4 / date-entity :year 2004~e.46)) :op3 (p14 / publication-91 :ARG0 (a8 / and~e.49 :op1 (p15 / person :name (n9 / name :op1 "Li"~e.48)) :op2 (p16 / person :mod (o4 / other~e.50))) :time (d5 / date-entity :year 2007~e.52)))))) :manner (i / in-vivo~e.0,1,9) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and~e.15 :op1 (p4 / person :name (n3 / name :op1 "Nikolopoulos"~e.14)) :op2 (p5 / person :mod (o / other~e.16))) :time (d6 / date-entity :year 2005~e.18)))) # ::id bel_pmid_1826_8536.22176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Src @-@ family kinases then phosphorylate the plaque proteins b @-@ catenin , plakoglobin , p120 cnt , and acatenin , which is required for their association with the E @-@ cadherin tail ( Calautti et al. , 1998 , 2005 ) . # ::alignments 0-1.2.1.1.1.1 2-1.2.1.1 3-1.2 4-1.3 5-1 7-1.1.5 8-1.5.1.2 9-1.1.1.1.1 11-1.1.1.1.1 13-1.1.2.1.1 18-1.1 19-1.1.4.1.1 23-1.5 25-1.5.1.1 25-1.5.1.1.r 26-1.5.1 27-1.5.1.2.1.r 29-1.5.1.2.1.1.1 31-1.5.1.2.1.1.1 34-1.4.1.1.1.1.1.1 35-1.4.1 35-1.4.1.1.1 36-1.4.1.1.1.2.1 38-1.4.1.1.2.1 40-1.4.1.2.2.1 (p / phosphorylate-01~e.5 :ARG1 (a / and~e.18 :op1 (p2 / protein :name (n2 / name :op1 "b-catenin"~e.9,11)) :op2 (p3 / protein :name (n3 / name :op1 "plakoglobin"~e.13)) :op3 (p4 / protein :name (n4 / name :op1 "p120cnt")) :op4 (p5 / protein :name (n5 / name :op1 "acatenin"~e.19)) :part-of (p6 / plaque~e.7)) :ARG2 (k / kinase~e.3 :ARG1-of (i / include-91 :ARG2 (p13 / protein-family~e.2 :name (n / name :op1 "Src"~e.0)))) :time (t / then~e.4) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.35 :op1 (p9 / publication-91 :ARG0 (a3 / and~e.35 :op1 (p10 / person :name (n7 / name :op1 "Calautti"~e.34)) :op2 (p11 / person :mod (o / other~e.36))) :time (d2 / date-entity :year 1998~e.38)) :op2 (p12 / publication-91 :ARG0 a3 :time (d3 / date-entity :year 2005~e.40)))) :ARG1-of (r / require-01~e.23 :purpose (a2 / associate-01~e.26 :ARG1~e.25 a~e.25 :ARG2 (p7 / protein-segment~e.8 :part-of~e.27 (p8 / protein :name (n6 / name :op1 "E-cadherin"~e.29,31)))))) # ::id bel_pmid_1826_8536.22182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok JNK2 might potentially be activated via Src kinasemediated phosphorylation of EGF @-@ R on Tyr920 ( Calautti et al. , 2005 ) , # ::alignments 0-1.1.2.1.1 1-1 2-1.2 2-1.2.r 4-1.1 6-1.1.1.2.1.1.1 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1.3.1.1 12-1.1.1.1.3.1.1 16-1.3.1.1.1.1.1 17-1.3.1.1 18-1.3.1.1.2.1 20-1.3.1.2.1 (p / possible-01~e.1 :ARG1 (a / activate-01~e.4 :ARG0 (p2 / phosphorylate-01~e.8 :ARG1~e.9 (a3 / amino-acid :mod 920 :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n4 / name :op1 "EGF-R"~e.10,12))) :ARG1-of (m / mediate-01 :ARG0 (k / kinase :name (n2 / name :op1 "Src"~e.6)))) :ARG1 (e / enzyme :name (n / name :op1 "JNK2"~e.0))) :manner~e.2 (p3 / potential~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and~e.17 :op1 (p6 / person :name (n5 / name :op1 "Calautti"~e.16)) :op2 (p7 / person :mod (o / other~e.18))) :time (d / date-entity :year 2005~e.20)))) # ::id bel_pmid_1826_8536.22186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok b1 @-@ integrin phosphorylation by Src results in EGF @-@ R activation ( Miranti and Brugge , 2002 ) , and b1 @-@ integrin expression is required for the initiation of mouse mammary tumors expressing the polyoma virus middle T antigen ( White et al. , 2004 ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.r 5-1.1.1.2.1.1 6-1.1 7-1.1.2.r 8-1.1.2.1.1.1 10-1.1.2.1.1.1 11-1.1.2 13-1.1.3.1.1.1.1.1 14-1.1.3.1.1 15-1.1.3.1.1.2.1.1 17-1.1.3.1.2.1 21-1.2.2.1 22-1.2.2.1 23-1.2.2.1 24-1.2.2 26-1.2 27-1.2.1.r 29-1.2.1 30-1.2.1.1.r 31-1.2.1.1.2 32-1.2.1.1.1 33-1.2.1.1 34-1.2.1.1.3 36-1.2.1.1.3.1.1.1 37-1.2.1.1.3.1.1.2 38-1.2.1.1.3.1.1.3 39-1.2.1.1.3.1.1.4 40-1.2.1.1.3.1.1.5 42-1.2.3.1.1.1.1.1 43-1 43-1.2.3.1.1 44-1.2.3.1.1.2.1 46-1.2.3.1.2.1 (a / and~e.43 :op1 (r / result-01~e.6 :ARG1 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein :name (n / name :op1 "b1-integrin"~e.0,2)) :ARG2~e.4 (p10 / protein :name (n2 / name :op1 "Src"~e.5))) :ARG2~e.7 (a2 / activate-01~e.11 :ARG1 (e / enzyme :name (n3 / name :op1 "EGF-R"~e.8,10))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.14 :op1 (p4 / person :name (n4 / name :op1 "Miranti"~e.13)) :op2 (p5 / person :name (n5 / name :op1 "Brugge"~e.15))) :time (d / date-entity :year 2002~e.17)))) :op2 (r2 / require-01~e.26 :ARG0~e.27 (i / initiate-01~e.29 :ARG1~e.30 (t / tumor~e.33 :mod (m / mammary~e.32) :location (m2 / mouse~e.31) :ARG3-of (e3 / express-03~e.34 :ARG2 (p6 / protein :name (n6 / name :op1 "polyoma"~e.36 :op2 "virus"~e.37 :op3 "middle"~e.38 :op4 "T"~e.39 :op5 "antigen"~e.40))))) :ARG1 (e2 / express-03~e.24 :ARG2 p2~e.21,22,23) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and~e.43 :op1 (p8 / person :name (n7 / name :op1 "White"~e.42)) :op2 (p9 / person :mod (o / other~e.44))) :time (d2 / date-entity :year 2004~e.46))))) # ::id bel_pmid_1826_8536.25888 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E @-@ cadherin gene deletion , which results in some hyperproliferation in the epidermis ( Young et al. , 2003 ; Tinkle et al. , 2004 ; Tunggal et al. , 2005 ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1 4-1 7-1.2 8-1.2.1.r 9-1.2.1.2 10-1.2.1 10-1.2.1.3 10-1.2.1.3.r 11-1.2.1.1.r 13-1.2.1.1 15-1.3.1.1.1.1.1.1 16-1.3.1.1.1 17-1.3.1.1.1.2.1 19-1.3.1.1.2.1 21-1.3.1.2.1.1.1.1 22-1.3.1.2.1 23-1.3.1.2.1.2.1 25-1.3.1.2.2.1 27-1.3.1.3.1.1.1.1 28-1.3.1 28-1.3.1.3.1 29-1.3.1.3.1.2.1 31-1.3.1.3.2.1 (d6 / delete-01~e.4 :ARG1 (g / gene~e.3 :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n / name :op1 "E-cadherin"~e.0,2)))) :ARG1-of (r / result-01~e.7 :ARG2~e.8 (p11 / proliferate-01~e.10 :location~e.11 (e2 / epidermis~e.13) :mod (s / some~e.9) :degree~e.10 (h / hyper~e.10))) :ARG1-of (d5 / describe-01 :ARG0 (a / and~e.28 :op1 (p2 / publication-91 :ARG0 (a2 / and~e.16 :op1 (p3 / person :name (n2 / name :op1 "Young"~e.15)) :op2 (p4 / person :mod (o / other~e.17))) :time (d / date-entity :year 2003~e.19)) :op2 (p5 / publication-91 :ARG0 (a3 / and~e.22 :op1 (p6 / person :name (n3 / name :op1 "Tinkle"~e.21)) :op2 (p7 / person :mod (o2 / other~e.23))) :time (d2 / date-entity :year 2004~e.25)) :op3 (p8 / publication-91 :ARG0 (a4 / and~e.28 :op1 (p9 / person :name (n4 / name :op1 "Tunggal"~e.27)) :op2 (p10 / person :mod (o3 / other~e.29))) :time (d3 / date-entity :year 2005~e.31))))) # ::id bel_pmid_1826_8536.25890 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E @-@ cadherinknockout epidermis displays some hyperproliferation , which however appears to be limited due to compensatory upregulation of P @-@ cadherin ( Young et al. , 2003 ; Tinkle et al. , 2004 ; Tunggal et al. , 2005 ) # ::alignments 0-1.1.1.1.2.1 3-1.1.1 4-1.1 5-1.1.2.1 6-1.1.2 6-1.1.2.2 6-1.1.2.2.r 6-1.2.1 9-1 10-1.2 13-1.2.1.1 17-1.2.1.1.1 18-1.2.1.1.1.1.r 19-1.2.1.1.1.1.2.1 21-1.2.1.1.1.1.2.1 23-1.3.1.1.1.1.2.1 24-1.3.1.1.1 25-1.3.1.1.1.2.1 27-1.3.1.1.2.1 29-1.3.1.2.1.1.2.1 30-1.3.1.2.1 31-1.3.1.2.1.2.1 33-1.3.1.2.2.1 35-1.3.1.3.1.1.2.1 36-1.3.1 36-1.3.1.3.1 37-1.3.1.3.1.2.1 39-1.3.1.3.2.1 (c2 / contrast-01~e.9 :ARG1 (d4 / display-01~e.4 :ARG0 (e / epidermis~e.3 :mod (p / protein :wiki "CDH1_(gene)" :name (n / name :op1 "E-cadherin"~e.0) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (p12 / proliferate-01~e.6 :mod (s / some~e.5) :degree~e.6 (h / hyper~e.6))) :ARG2 (a / appear-02~e.10 :ARG1 (p13 / proliferate-01~e.6 :ARG1-of (l / limit-01~e.13 :ARG0 (u / upregulate-01~e.17 :ARG1~e.18 (p2 / protein :wiki "CDH3_(gene)" :name (n2 / name :op1 "P-cadherin"~e.19,21)) :ARG0-of (c / compensate-01))) :degree h)) :ARG1-of (d5 / describe-01 :ARG0 (a2 / and~e.36 :op1 (p3 / publication-91 :ARG0 (a3 / and~e.24 :op1 (p4 / person :wiki - :name (n3 / name :op1 "Young"~e.23)) :op2 (p5 / person :mod (o / other~e.25))) :time (d / date-entity :year 2003~e.27)) :op2 (p6 / publication-91 :ARG0 (a4 / and~e.30 :op1 (p7 / person :wiki - :name (n4 / name :op1 "Tinkle"~e.29)) :op2 (p8 / person :mod (o2 / other~e.31))) :time (d2 / date-entity :year 2004~e.33)) :op3 (p9 / publication-91 :ARG0 (a5 / and~e.36 :op1 (p10 / person :wiki - :name (n5 / name :op1 "Tunggal"~e.35)) :op2 (p11 / person :mod (o3 / other~e.37))) :time (d3 / date-entity :year 2005~e.39))))) # ::id bel_pmid_1826_8536.25892 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recently reported in A431 cells , this can occur through E @-@ cadherin @-@ mediated inhibition of transphosphorylation on Tyr845EGF @-@ R ( Perrais et al. , 2007 ) , the site , which catalyzes EGF @-@ induced mitogenesis ( Ishizawar and Parsons , 2004 ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 4-1.1.1.2 6-1.1 7-1 10-1.2.2.1.1.1 12-1.2.2.1.1.1 14-1.2.2 15-1.2 21-1.2.1.1.3.1.1 23-1.3.1.1.1.1.1 24-1.3.1.1 25-1.3.1.1.2.1 27-1.3.1.2.1 34-1.2.1.1 34-1.2.1.1.4 34-1.2.1.1.4.r 35-1.2.1.1.4.1.1.1.1.1 37-1.2.1.1.4.1.1 38-1.2.1.1.4.1 40-1.2.1.1.4.2.1.1.1.1.1 41-1.2.1.1.4.2.1.1 42-1.2.1.1.4.2.1.1.2.1.1 44-1.2.1.1.4.2.1.2.1 (p / possible-01~e.7 :ARG1 (t / this~e.6 :ARG1-of (r / report-01~e.1 :time (r2 / recent~e.0) :location~e.2 (c2 / cell-line~e.4 :name (n8 / name :op1 "A431"~e.3)))) :manner (i / inhibit-01~e.15 :ARG1 (t2 / transphosphorylate-01 :ARG1 (a3 / amino-acid~e.34 :mod 845 :name (n3 / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "EGF-R"~e.21)) :ARG0-of~e.34 (c / catalyze-01~e.34 :ARG1 (m2 / mitogenesis~e.38 :ARG2-of (i2 / induce-01~e.37 :ARG0 (p3 / protein :name (n4 / name :op1 "EGF"~e.35)))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and~e.41 :op1 (p6 / person :name (n5 / name :op1 "Ishizawar"~e.40)) :op2 (p7 / person :name (n6 / name :op1 "Parsons"~e.42))) :time (d2 / date-entity :year 2004~e.44)))))) :ARG1-of (m / mediate-01~e.14 :ARG0 (p2 / protein :name (n / name :op1 "E-cadherin"~e.10,12)))) :ARG1-of (d4 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a2 / and~e.24 :op1 (p9 / person :name (n7 / name :op1 "Perrais"~e.23)) :op2 (p10 / person :mod (o2 / other~e.25))) :time (d / date-entity :year 2007~e.27)))) # ::id bel_pmid_1826_8536.26244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In mouse keratinocytes , Src kinase @-@ mediated phosphorylation was found to generate a docking site for PI3K ( p85 ) on plakoglobin in an EGF @-@ R @-@ dependent manner , to a minor extent on p120 cnt , but not on b @-@ catenin , which apparently lacks a PI3K ( p85 ) - docking motive ( Calautti et al. , 2005 ) . # ::alignments 1-1.2.2 2-1.2.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1.1 7-1.1.1.1 8-1.1.1 10-1 12-1.1 14-1.1.2.1 15-1.1.2 16-1.1.2.1.1.r 17-1.1.2.1.1.2.1.1 19-1.1.2.1.1.1.1 21-1.1.2.2.r 22-1.1.2.2.1.1.1 25-1.1.3.1.1.1 27-1.1.3.1.1.1 29-1.1.3 30-1.1.3.r 34-1.1.2.2.2.2 35-1.1.2.2.2.2.r 40-1.1.2.2.3 42-1.1.2.2.3.1.r 43-1.1.2.2.3.1.1.1 45-1.1.2.2.3.1.1.1 48-1.1.2.2.3.1.2.2 49-1.1.2.2.3.1 49-1.1.2.2.3.1.2 49-1.1.2.2.3.1.2.r 51-1.1.2.2.3.1.2.1.1 52-1.1.2.2.3.1.2.1.1 53-1.1.2.2.3.1.2.1.1 54-1.1.2.2.3.1.2.1.1 55-1.1.2.2.3.1.2.1.1 56-1.1.2.2.3.1.2.1.1 57-1.1.2.2.3.1.2.1 59-1.3.1.1.1.1.1 60-1.1.2.2 60-1.3.1.1 61-1.3.1.1.2.1 63-1.3.1.2.1 (f / find-01~e.10 :ARG1 (g / generate-01~e.12 :ARG0 (p / phosphorylate-01~e.8 :ARG1-of (m2 / mediate-01~e.7 :ARG0 (k / kinase~e.5 :name (n2 / name :op1 "Src"~e.4)))) :ARG1 (s / site~e.15 :ARG2-of (d2 / dock-01~e.14 :ARG1~e.16 (p2 / protein-segment :name (n4 / name :op1 "p85"~e.19) :part-of (e / enzyme :name (n3 / name :op1 "PI3K"~e.17)))) :location~e.21 (a / and~e.60 :op1 (p3 / protein :name (n5 / name :op1 "plakoglobin"~e.22)) :op2 (p5 / protein :name (n7 / name :op1 "p120cnt") :extent~e.35 (m3 / minor~e.34)) :ARG1-of (c2 / contrast-01~e.40 :ARG2~e.42 (p6 / protein~e.49 :name (n8 / name :op1 "b-catenin"~e.43,45) :ARG0-of~e.49 (l / lack-01~e.49 :ARG1 (m4 / motive~e.57 :ARG2-of d2~e.51,52,53,54,55,56) :ARG1-of (a2 / appear-02~e.48)))))) :manner~e.30 (d3 / depend-01~e.29 :ARG1 (e2 / enzyme :name (n6 / name :op1 "EGF-R"~e.25,27)))) :location (c / cell :name (n / name :op1 "keratinocyte"~e.2) :source (m / mouse~e.1)) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a3 / and~e.60 :op1 (p8 / person :name (n9 / name :op1 "Calautti"~e.59)) :op2 (p9 / person :mod (o / other~e.61))) :time (d / date-entity :year 2005~e.63)))) # ::id bel_pmid_1826_8536.28578 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transgenic mice ( both newborn and adult ) expressing the signalingdefective b4 @-@ integrin mutant showed a twofold decrease in the epidermal proliferative index , confirming that b4 @-@ integrin actually contributes to proliferation ( Nikolopoulos et al. , 2005 ) . # ::alignments 0-1.1.1.1 1-1.1.1 1-1.1.2 5-1.1 6-1.1.2.2 8-1.1.2.3 9-1.1.2.3 10-1.1.2.3 11-1.1.2.3 12-1.1.2.3 13-1.1.2.3 14-1.1.2.3 15-1 18-1.2 23-1.2.1 25-1.3 26-1.3.1.r 27-1.3.1.1 28-1.3.1.1 29-1.3.1.1 30-1.3.1.3 31-1.3.1 32-1.2.1.1.r 33-1.2.1.1 35-1.4.1.1.1.1.1 36-1.4.1.1 37-1.4.1.1.2.1 39-1.4.1.2.1 (s / show-01~e.15 :ARG0 (a4 / and~e.5 :op1 (m / mouse~e.1 :mod (t / transgenic~e.0) :ARG1-of (b / bear-02 :time (n / new-01)) :ARG3-of (e / express-03 :ARG2 (p / protein :name (n2 / name :op1 "b4-integrin") :ARG2-of (m2 / mutate-01) :ARG0-of (d2 / defect-01 :ARG1 (s2 / signal-07))))) :op2 (m3 / mouse~e.1 :mod t :mod (a / adult~e.6) :ARG3-of e~e.8,9,10,11,12,13,14)) :ARG1 (d3 / decrease-01~e.18 :ARG1 (i / index~e.23 :mod~e.32 (p3 / proliferate-01~e.33 :ARG0 (e2 / epidermis))) :ARG2 (p2 / product-of :op1 2)) :ARG0-of (c / confirm-01~e.25 :ARG1~e.26 (c2 / contribute-01~e.31 :ARG0 p~e.27,28,29 :ARG2 p3 :ARG1-of (a2 / actual-02~e.30))) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.36 :op1 (p5 / person :name (n3 / name :op1 "Nikolopoulos"~e.35)) :op2 (p6 / person :mod (o / other~e.37))) :time (d / date-entity :year 2005~e.39)))) # ::id bel_pmid_1826_8536.28582 ::amr-annotator SDL-AMR-09 ::preferred # ::tok b4 @-@ integrin mediates the phosphorylation of ErbB2 on Tyr877 by a Src @-@ family kinase .... ( Ishizawar and Parsons , 2004 ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 5-1.2 6-1.2.1.r 7-1.2.1.3.1.1 10-1.2.2.r 12-1.2.2.1.1.1.1 14-1.2.2.1.1 15-1.2.2 18-1.3.1.1.1.1.1 19-1.3.1.1 20-1.3.1.1.2.1.1 22-1.3.1.2.1 (m / mediate-01~e.3 :ARG0 (p2 / protein :name (n / name :op1 "b4-integrin"~e.0,2)) :ARG1 (p / phosphorylate-01~e.5 :ARG1~e.6 (a2 / amino-acid :mod 877 :name (n2 / name :op1 "tyrosine") :part-of (p4 / protein :name (n3 / name :op1 "ErbB2"~e.7))) :ARG2~e.10 (k / kinase~e.15 :ARG1-of (i / include-91 :ARG2 (p3 / protein-family~e.14 :name (n4 / name :op1 "Src"~e.12))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and~e.19 :op1 (p6 / person :name (n5 / name :op1 "Ishizawar"~e.18)) :op2 (p7 / person :name (n6 / name :op1 "Parsons"~e.20))) :time (d / date-entity :year 2004~e.22)))) # ::id bel_pmid_1826_8536.28586 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In parallel to JNK , two other MAPKs , ERK1 and ERK2 , were also found to be targeted to the nucleus in a b4 @-@ integrindependent manner in keratinocytes ( Nikolopoulos et al. , 2005 ) . # ::alignments 1-1.1.2.4 2-1.1.2.4.1.r 3-1.1.2.4.1.1.1 6-1.3.1.1.2.1 9-1.1.2.1.1.1 10-1.1.2 11-1.1.2.2.1.1 14-1.2 15-1 18-1.1 19-1.1.1.r 21-1.1.1 24-1.1.3.1.1.1 27-1.1.3.r 28-1.1.4.r 29-1.1.4.1.1 31-1.3.1.1.1.1.1 32-1.3.1.1 33-1.3.1.1.2.1 35-1.3.1.2.1 (f / find-01~e.15 :ARG1 (t / target-01~e.18 :ARG0~e.19 (n4 / nucleus~e.21) :ARG1 (a / and~e.10 :op1 (e / enzyme :name (n / name :op1 "ERK1"~e.9)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"~e.11)) :ARG1-of (i / include-91 :ARG2 (p6 / protein-family :name (n3 / name :op1 "MAPK"))) :ARG0-of (p2 / parallel-01~e.1 :ARG1~e.2 (e4 / enzyme :name (n7 / name :op1 "JNK"~e.3)))) :manner~e.27 (d2 / depend-01 :ARG1 (p / protein :name (n5 / name :op1 "b4-integrin"~e.24))) :location~e.28 (c / cell :name (n6 / name :op1 "keratinocyte"~e.29))) :mod (a2 / also~e.14) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.32 :op1 (p4 / person :name (n8 / name :op1 "Nikolopoulos"~e.31)) :op2 (p5 / person :mod (o2 / other~e.6,33))) :time (d / date-entity :year 2005~e.35)))) # ::id bel_pmid_1826_8536.28670 ::amr-annotator SDL-AMR-09 ::preferred # ::tok plakoglobin @-@ mediated suppression of the pro @-@ proliferative proto @-@ oncogene c @-@ Myc , which is critical for growth inhibition in these cells ( Arnold and Watt , 2001 ; Waikel et al. , 2001 ; Kolly et al. , 2005 ; Figure 2 ) . # ::alignments 0-1.1.2.1.1.1 2-1.1.2 3-1.1 4-1.1.1.r 6-1.1.1 6-1.1.1.2 6-1.1.1.2.r 9-1.1.1.3 12-1.1.1.1.1 14-1.1.1.1.1 18-1 19-1.2.r 20-1.2.1 21-1.2 22-1.2.2.r 23-1.2.2.1 24-1.2.2 26-1.3.1.1.1.1.1.1 27-1.3.1.1.1 28-1.3.1.1.1.2.1.1 30-1.3.1.1.2.1 32-1.3.1.2.1.1.1.1 33-1.3.1 33-1.3.1.1.1 33-1.3.1.2.1 33-1.3.1.3.1 34-1.3.1.2.1.2.1 34-1.3.1.3.1.2.1 36-1.3.1.1.2.1 38-1.3.1.3.1.1.1.1 39-1.3.1.3.1 40-1.3.1.3.1.2.1 42-1.3.1.3.2.1 44-1.3.1.4 45-1.3.1.4.1 (c / critical-02~e.18 :ARG1 (s / suppress-01~e.3 :ARG1~e.4 (g2 / gene~e.6 :name (n2 / name :op1 "c-Myc"~e.12,14) :ARG0-of~e.6 (f / favor-01~e.6 :ARG1 (p2 / proliferate-01)) :mod (p3 / proto~e.9) :ARG0-of (c3 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))) :ARG1-of (m / mediate-01~e.2 :ARG0 (p / protein :name (n / name :op1 "plakoglobin"~e.0)))) :ARG3~e.19 (i / inhibit-01~e.21 :ARG1 (g / grow-01~e.20) :location~e.22 (c2 / cell~e.24 :mod (t / this~e.23))) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.33 :op1 (p4 / publication-91 :ARG0 (a2 / and~e.27,33 :op1 (p7 / person :name (n3 / name :op1 "Arnold"~e.26)) :op2 (p8 / person :name (n4 / name :op1 "Watt"~e.28))) :time (d / date-entity :year 2001~e.30,36)) :op2 (p5 / publication-91 :ARG0 (a3 / and~e.33 :op1 (p9 / person :name (n5 / name :op1 "Waikel"~e.32)) :op2 (p10 / person :mod (o2 / other~e.34))) :time d) :op3 (p6 / publication-91 :ARG0 (a4 / and~e.33,39 :op1 (p11 / person :name (n6 / name :op1 "Kolly"~e.38)) :op2 (p12 / person :mod (o3 / other~e.34,40))) :time (d3 / date-entity :year 2005~e.42)) :op4 (f2 / figure~e.44 :mod 2~e.45)))) # ::id bel_pmid_1826_8536.29114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok JNK2 was found to be necessary for cell @-@ cycle arrest in keratinocytes , as exemplified by hyperproliferation of JNK2 @-@ knockout epidermis ( Sabapathy and Wagner , 2004 ; Weston et al. , 2004 ) . # ::alignments 0-1.1.2.1.1 2-1 5-1.1 6-1.1.1.r 7-1.1.1.1.1 9-1.1.1.1 10-1.1.1 11-1.1.1.2.r 12-1.1.1.2.1.1 14-1.3.1.2.2.r 16-1.2.r 17-1.2 17-1.2.2 17-1.2.2.r 18-1.2.1.r 19-1.2.1.1.1.1 21-1.2.1.1 21-1.2.1.1.2 21-1.2.1.1.2.r 22-1.2.1 24-1.3.1.1.1.1.1.1 25-1.3.1.1.1 26-1.3.1.1.1.2.1.1 28-1.3.1.1.2.1 30-1.3.1.2.1.1.1.1 31-1.3.1 31-1.3.1.2.1 32-1.3.1.2.1.2.1 34-1.3.1.2.2 (f / find-01~e.2 :ARG1 (n3 / need-01~e.5 :ARG0~e.6 (a / arrest-02~e.10 :ARG1 (c / cycle-02~e.9 :ARG1 (c2 / cell~e.7)) :location~e.11 (c3 / cell :name (n4 / name :op1 "keratinocyte"~e.12))) :ARG1 (e / enzyme :name (n2 / name :op1 "JNK2"~e.0))) :example~e.16 (p7 / proliferate-01~e.17 :ARG0~e.18 (e3 / epidermis~e.22 :mod (e4 / enzyme~e.21 :name (n5 / name :op1 "JNK2"~e.19) :ARG1-of~e.21 (k / knock-out-03~e.21))) :degree~e.17 (h / hyper~e.17)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.31 :op1 (p / publication-91 :ARG0 (a3 / and~e.25 :op1 (p2 / person :name (n / name :op1 "Sabapathy"~e.24)) :op2 (p3 / person :name (n6 / name :op1 "Wagner"~e.26))) :time (d / date-entity :year 2004~e.28)) :op2 (p4 / publication-91 :ARG0 (a4 / and~e.31 :op1 (p5 / person :name (n7 / name :op1 "Weston"~e.30)) :op2 (p6 / person :mod (o / other~e.32))) :time~e.14 d~e.34)))) # ::id bel_pmid_1826_8536.32064 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In mouse keratinocytes , it was however shown to result in Src kinase @-@ mediated phosphorylation of EGF @-@ R , presumably on Tyr920 ( Calautti et al. , 2005 ) . # ::alignments 1-1.1.2.2 2-1.1.2.1.1 4-1.1.1.1 6-1 7-1.1 9-1.1.1 10-1.1.1.2.r 11-1.1.1.2.2.1.1.1 12-1.1.1.2.2.1 14-1.1.1.2.2 15-1.1.1.2 16-1.1.1.2.1.r 17-1.1.1.2.1.4.1.1 19-1.1.1.2.1.4.1.1 21-1.1.1.2.1 21-1.1.1.2.1.3 21-1.1.1.2.1.3.r 25-1.2.1.1.1.1.1 26-1.2.1.1 27-1.2.1.1.2.1 29-1.2.1.2.1 (c / contrast-01~e.6 :ARG2 (s / show-01~e.7 :ARG1 (r / result-01~e.9 :ARG1 (i / it~e.4) :ARG2~e.10 (p / phosphorylate-01~e.15 :ARG1~e.16 (a2 / amino-acid~e.21 :mod 920 :name (n2 / name :op1 "tyrosine") :ARG1-of~e.21 (p3 / presume-01~e.21) :part-of (e / enzyme :name (n3 / name :op1 "EGF-R"~e.17,19))) :ARG1-of (m / mediate-01~e.14 :ARG0 (k / kinase~e.12 :name (n / name :op1 "Src"~e.11))))) :location (c2 / cell :name (n5 / name :op1 "keratinocyte"~e.2) :source (m2 / mouse~e.1))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and~e.26 :op1 (p6 / person :name (n4 / name :op1 "Calautti"~e.25)) :op2 (p7 / person :mod (o / other~e.27))) :time (d / date-entity :year 2005~e.29)))) # ::id bel_pmid_1826_8536.36030 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In human HaCaT keratinocytes for instance , ERK1 @/@ 2 phosphorylation increases in dependence of EGF @-@ R recruitment to transadhering E @-@ cadherin , and E @-@ cadherin @-@ mediated activation of MAPK was also reported in intestinal epithelial cells ( Pece and Gutkind , 2000 ; Laprise et al. , 2004 ) . # ::alignments 1-1.1.3.3 2-1.1.3.1.1 3-1.1.3.4.1.1 4-1.1.3 4-1.1.3.2 4-1.1.3.2.r 5-1.1.3 5-1.1.3.2 5-1.1.3.2.r 7-1.1.1.1.1.1.1 8-1.1.1.1 10-1.1.1 11-1.1 12-1.1.2.r 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 18-1.1.2.1 21-1.1.2.1.2.1.1 23-1.1.2.1.2.1.1 26-1.1.2.1.2.1.1 28-1.1.2.1.2.1.1 30-1.2.1.2 31-1.2.1 32-1.2.1.1.r 33-1.2.1.1.1.1 35-1.2.2 36-1.2 37-1.2.3.r 38-1.2.3.1.1 39-1.2.3.1 40-1.2.3 42-1.3.1.1.1.1.1.1 43-1.3.1.1.1 44-1.3.1.1.1.2.1.1 46-1.3.1.1.2.1 48-1.3.1.2.1.1.1.1 49-1 49-1.3.1 49-1.3.1.2.1 50-1.3.1.2.1.2.1 52-1.3.1.2.2.1 (a / and~e.49 :op1 (i / increase-01~e.11 :ARG1 (p / phosphorylate-01~e.10 :ARG1 (s / slash~e.8 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"~e.7)) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2")))) :ARG0-of~e.12 (d3 / depend-01~e.13 :ARG1~e.14 (r / recruit-01~e.18 :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGF-R"~e.15,17)) :ARG2 (p3 / protein :name (n5 / name :op1 "E-cadherin"~e.21,23,26,28) :ARG0-of (t / transadhere-00)))) :location (c / cell-line~e.4,5 :name (n6 / name :op1 "HaCaT"~e.2) :ARG0-of~e.4,5 (e / exemplify-01~e.4,5) :mod (h / human~e.1) :part-of (c3 / cell :name (n10 / name :op1 "keratinocyte"~e.3)))) :op2 (r2 / report-01~e.36 :ARG1 (a4 / activate-01~e.31 :ARG1~e.32 (e6 / enzyme :name (n / name :op1 "MAPK"~e.33)) :ARG1-of (m / mediate-01~e.30 :ARG0 p3)) :mod (a3 / also~e.35) :location~e.37 (c2 / cell~e.40 :part-of (e5 / epithelium~e.39 :part-of (i2 / intestine~e.38)))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and~e.49 :op1 (p4 / publication-91 :ARG0 (a6 / and~e.43 :op1 (p5 / person :name (n7 / name :op1 "Pece"~e.42)) :op2 (p6 / person :name (n8 / name :op1 "Gutkind"~e.44))) :time (d / date-entity :year 2000~e.46)) :op2 (p7 / publication-91 :ARG0 (a7 / and~e.49 :op1 (p8 / person :name (n9 / name :op1 "Laprise"~e.48)) :op2 (p9 / person :mod (o / other~e.50))) :time (d2 / date-entity :year 2004~e.52))))) # ::id bel_pmid_1828_5820.25080 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to AlkB , ABH2 and ABH3 have the ability to repair 1 meA and 3 meC residues . However , whereas ABH2 prefers double @-@ stranded DNA , ABH3 and AlkB favour single @-@ stranded DNA and RNA ( Aas et al , 2003 ; Falnes et al , 2004 ) . # ::alignments 0-1.1.1.3 1-1.1.1.3.1.r 2-1.1.1.3.1.1.1 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 9-1.1 11-1.1.2 14-1.1.2.2 19-1.2 19-1.2.1 19-1.2.1.r 21-1.2.1 22-1.2.1.1.1.1.1 23-1.2.1.1 24-1.2.1.1.2.3.1 26-1.2.1.1.2.3 27-1.2.1.1.2.2.1 29-1.2.1.2.1.1.1.1 30-1.2.1.2.1 30-1.2.1.3.1 30-1.2.1.3.1.1.1 31-1.2.1.2.1.2.1.1 32-1.2.1.2 33-1.2.1.2.2.1.3.1 35-1.2.1.2.2.1.3 36-1.2.1.2.2.1.2.1 37-1.2.1.2.2 38-1.2.1.2.2.2.1.1 40-1.2.1.3.1.1.1.1.1.1 41-1.2.1.3.1.1.1 42-1.2.1.3.1.1.1.2.1 44-1.2.1.3.1.1.2.1 46-1.2.1.3.1.2.1.1.1.1 47-1.2.1.3.1.2.1 48-1.2.1.3.1.2.1.2.1 50-1.2.1.3.1.2.2.1 (m / multi-sentence :snt1 (c / capable-01~e.9 :ARG1 (a / and~e.5 :op1 (p / protein :name (n / name :op1 "ABH2"~e.4)) :op2 (p2 / protein :name (n2 / name :op1 "ABH3"~e.6)) :ARG1-of (r3 / resemble-01~e.0 :ARG2~e.1 (p5 / protein :name (n5 / name :op1 "AlkB"~e.2)))) :ARG2 (r2 / repair-01~e.11 :ARG0 a :ARG1 (a2 / and~e.14 :op1 (p3 / protein-segment :name (n3 / name :op1 "1meA")) :op2 (p4 / protein-segment :name (n4 / name :op1 "3meC"))))) :snt2 (h / have-concession-91~e.19 :ARG1~e.19 (c2 / contrast-01~e.19,21 :ARG1 (p6 / prefer-01~e.23 :ARG0 (p7 / protein :name (n6 / name :op1 "ABH2"~e.22)) :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n13 / name :op1 "DNA"~e.27) :mod (s3 / strand~e.26 :mod (d4 / double~e.24)))) :ARG2 (f / favor-01~e.32 :ARG0 (a3 / and~e.30 :op1 (p8 / protein :name (n7 / name :op1 "ABH3"~e.29)) :op2 (p9 / protein :name (n8 / name :op1 "AlkB"~e.31))) :ARG1 (a4 / and~e.37 :op1 (n14 / nucleic-acid :wiki "DNA" :name (n15 / name :op1 "DNA"~e.36) :mod (s / strand~e.35 :ARG1-of (s2 / single-02~e.33))) :op2 (n16 / nucleic-acid :name (n11 / name :op1 "RNA"~e.38) :mod s))) :ARG1-of (d6 / describe-01 :ARG0 (a5 / and~e.30 :op1 (p10 / publication-91 :ARG0 (a6 / and~e.30,41 :op1 (p11 / person :name (n9 / name :op1 "Aas"~e.40)) :op2 (p12 / person :mod (o / other~e.42))) :time (d / date-entity :year 2003~e.44)) :op2 (p13 / publication-91 :ARG0 (a7 / and~e.47 :op1 (p14 / person :name (n10 / name :op1 "Falnes"~e.46)) :op2 (p15 / person :mod (o2 / other~e.48))) :time (d2 / date-entity :year 2004~e.50))))))) # ::id bel_pmid_1828_5820.25550 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A targeted Brca1 @-@ null mutation to the T @-@ cell lineage resulted in increased genomic instability , apoptosis , cell @-@ cycle arrest , and a drastic depletion of the T @-@ cell lineage ( Mak et al , 2000 ) . # ::alignments 1-1.1.3 2-1.1.2.1.1 4-1.1 4-1.1.1 4-1.1.1.r 5-1.1 8-1.1.2.2.1.1 10-1.1.2.2.1.1 12-1 13-1.2.r 14-1.2.1 15-1.2.1.1.1 16-1.2.1.1 18-1.2.2 20-1.2.3.1.1 22-1.2.3.1 23-1.2.3 25-1.2 27-1.2.4.2 28-1.2.4 29-1.2.4.1.r 31-1.2.4.1 32-1.2.4.1 33-1.2.4.1 36-1.3.1.1.1.1.1 37-1.3.1.1 38-1.3.1.1.2.1 40-1.3.1.2.1 (r / result-01~e.12 :ARG1 (m / mutate-01~e.4,5 :mod~e.4 "-/-"~e.4 :ARG1 (p / protein :name (n / name :op1 "Brca1"~e.2) :part-of (c / cell :name (n2 / name :op1 "T-cell"~e.8,10))) :ARG1-of (t / target-01~e.1)) :ARG2~e.13 (a / and~e.25 :op1 (i / increase-01~e.14 :ARG1 (i2 / instability~e.16 :mod (g / genome~e.15))) :op2 (a2 / apoptosis~e.18) :op3 (a3 / arrest-02~e.23 :ARG1 (c2 / cycle-02~e.22 :ARG1 (c3 / cell~e.20))) :op4 (d2 / deplete-01~e.28 :ARG2~e.29 c~e.31,32,33 :degree (d3 / drastic~e.27))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a4 / and~e.37 :op1 (p3 / person :name (n3 / name :op1 "Mak"~e.36)) :op2 (p4 / person :mod (o / other~e.38))) :time (d / date-entity :year 2000~e.40)))) # ::id bel_pmid_1828_5820.25554 ::amr-annotator SDL-AMR-09 ::preferred # ::tok null mutations for Brca2 result in early mouse embryonic lethality and impaired HR ( Ludwig et al , 1997 ; Suzuki et al , 1997 ; Moynahan et al , 2001 ) . Furthermore , loss of Brca2 in murine cells resulted in increased genomic instability and activation of p53 . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.2 7-1.1.2.1.1.1 8-1.1.2.1.1 10-1.1.2 11-1.1.2.2 12-1.1.2.2.1.1.1 14-1.1.3.1.1.1.1.1.1 15-1.1.3.1.1.1 16-1.1.3.1.1.1.2.1 18-1.1.3.1.1.2.1 20-1.1.3.1.2.1.1.1.1 21-1.1.3.1 21-1.1.3.1.1.1 21-1.1.3.1.2.1 21-1.1.3.1.3.1 22-1.1.3.1.1.1.2.1 22-1.1.3.1.2.1.2.1 22-1.1.3.1.3.1.2.1 24-1.1.3.1.1.2.1 26-1.1.3.1.3.1.1.1.1 27-1.1.3.1.3.1 28-1.1.3.1.3.1.2.1 30-1.1.3.1.3.2.1 33-1.1.3.1 35-1.2.1.1 36-1.2.1.1.1.r 37-1.2.1.1.1.1.1 40-1.2.1.1.2 41-1.2.1 42-1.2.1.2.r 43-1.2.1.2.1 44-1.2.1.2.1.1.1 45-1.2.1.2.1.1 46-1.2.1.2 47-1.2.1.2.2 48-1.2.1.2.2.1.r 49-1.2.1.2.2.1.1.1 (m / multi-sentence :snt1 (r / result-01~e.4 :ARG1 (m2 / mutate-01~e.0,1 :mod~e.0 "-/-"~e.0 :ARG1~e.2 (p / protein :name (n / name :op1 "Brca2"~e.3))) :ARG2~e.5 (a / and~e.10 :op1 (d2 / die-01 :ARG1 (e / embryo~e.8 :mod (m3 / mouse~e.7)) :time (e2 / early~e.6)) :op2 (i / impair-01~e.11 :ARG1 (t / thing :name (n2 / name :op1 "HR"~e.12)))) :ARG1-of (d4 / describe-01 :ARG0 (a2 / and~e.21,33 :op1 (p2 / publication-91 :ARG0 (a3 / and~e.15,21 :op1 (p3 / person :name (n3 / name :op1 "Ludwig"~e.14)) :op2 (p4 / person :mod (o / other~e.16,22))) :time (d / date-entity :year 1997~e.18,24)) :op2 (p5 / publication-91 :ARG0 (a4 / and~e.21 :op1 (p6 / person :name (n4 / name :op1 "Suzuki"~e.20)) :op2 (p7 / person :mod (o2 / other~e.22))) :time d) :op3 (p8 / publication-91 :ARG0 (a5 / and~e.21,27 :op1 (p9 / person :name (n5 / name :op1 "Moynahan"~e.26)) :op2 (p10 / person :mod (o3 / other~e.22,28))) :time (d3 / date-entity :year 2001~e.30))))) :snt2 (a6 / and :op2 (r2 / result-01~e.41 :ARG1 (l / lose-02~e.35 :ARG1~e.36 (p11 / protein :name (n6 / name :op1 "Brca2"~e.37)) :location (c / cell~e.40 :part-of (o4 / organism :name (n8 / name :op1 "Murinae")))) :ARG2~e.42 (a7 / and~e.46 :op1 (i2 / increase-01~e.43 :ARG1 (i3 / instability~e.45 :mod (g / genome~e.44))) :op2 (a8 / activate-01~e.47 :ARG1~e.48 (p12 / protein :name (n7 / name :op1 "p53"~e.49))))))) # ::id bel_pmid_1828_5820.25556 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRCA2 functions in the loading of the HR protein RAD51 during filament formation . It directly binds to RAD51 and its phosphorylation on Ser3291 inhibits this binding ( Esashi et al , 2005 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.r 4-1.1.2 5-1.1.2.1.r 7-1.1.2.1.2.1.1.1 8-1.1.1 8-1.1.2.1 8-1.2.1.2 9-1.1.2.1.1.1 10-1.1.3.r 11-1.1.3.1 12-1.1.3 14-1.2.2.2 15-1.2.2.2 16-1.2.2.2 17-1.2.2.2 18-1.2.2.2 19-1.2.2.2 20-1.2.2.2 21-1.2.2.1 24-1.2.2 26-1.2.2.2 28-1.2.3.1.1.1.1.1 29-1.2 29-1.2.3.1.1 30-1.2.3.1.1.2.1 32-1.2.3.1.2.1 (m / multi-sentence :snt1 (f / function-01~e.1 :ARG0 (p2 / protein~e.8 :name (n / name :op1 "BRCA2"~e.0)) :ARG1~e.2 (l / load-01~e.4 :ARG2~e.5 (p3 / protein~e.8 :name (n2 / name :op1 "RAD51"~e.9) :ARG0-of (c / cause-01 :ARG1 (t / thing :name (n3 / name :op1 "HR"~e.7))))) :time~e.10 (f2 / form-01~e.12 :ARG1 (f3 / filament~e.11))) :snt2 (a / and~e.29 :op1 (b / bind-01 :ARG1 (i2 / it) :ARG2 (p5 / protein~e.8 :name (n5 / name :op1 "RAD51")) :ARG1-of (d2 / direct-02)) :op2 (i / inhibit-01~e.24 :ARG0 (p / phosphorylate-01~e.21 :ARG1 (a3 / amino-acid :mod 3291 :name (n6 / name :op1 "serine") :part-of i2)) :ARG1 b~e.14,15,16,17,18,19,20,26) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a2 / and~e.29 :op1 (p8 / person :name (n7 / name :op1 "Esashi"~e.28)) :op2 (p9 / person :mod (o / other~e.30))) :time (d / date-entity :year 2005~e.32))))) # ::id bel_pmid_1828_5820.28866 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The death of mutants such as Xrcc1/, LigIII/ and Polb/ was preceded by elevated levels of apoptosis ( Gu et al , 1994 ; Tebbs et al , 1999 ; Sugo et al , 2000 ; Puebla @-@ Osorio et al , 2006 ) . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1 3-1.2.1.1 3-1.2.1.1.r 4-1.2.1.2.r 5-1.2.1.2.r 8-1.2.1.2 8-1.3.1 8-1.3.1.1.1 11-1 12-1.1.r 13-1.1.1 14-1.1 15-1.1.2.r 16-1.1.2 18-1.3.1.1.1.1.1.1 19-1.3.1.1.1 20-1.3.1.1.1.2.1 22-1.3.1.1.2.1 24-1.3.1.2.1.1.1.1 25-1.3.1.2.1 26-1.3.1.2.1.2.1 28-1.3.1.2.2.1 30-1.3.1.3.1.1.1.1 31-1.3.1.3.1 32-1.3.1.3.1.2.1 34-1.3.1.3.2.1 36-1.3.1.4.1.1.1.1 38-1.3.1.4.1.1.1.1 39-1.3.1.4.1 40-1.3.1.4.1.2.1 42-1.3.1.4.2.1 (p / precede-01~e.11 :ARG1~e.12 (l / level~e.14 :ARG1-of (e / elevate-01~e.13) :degree-of~e.15 (a2 / apoptosis~e.16)) :ARG2 (d5 / die-01~e.1 :ARG1~e.2 (p2 / protein~e.3 :ARG2-of~e.3 (m / mutate-01~e.3) :example~e.4,5 (a / and~e.8 :op1 (p3 / protein :name (n / name :op1 "Xrcc1")) :op2 (p4 / protein :name (n2 / name :op1 "LigIII")) :op3 (p5 / protein :name (n3 / name :op1 "Polb"))))) :ARG1-of (d6 / describe-01 :ARG0 (a3 / and~e.8 :op1 (p6 / publication-91 :ARG0 (a4 / and~e.8,19 :op1 (p10 / person :name (n4 / name :op1 "Gu"~e.18)) :op2 (p11 / person :mod (o / other~e.20))) :time (d / date-entity :year 1994~e.22)) :op2 (p7 / publication-91 :ARG0 (a5 / and~e.25 :op1 (p12 / person :name (n5 / name :op1 "Tebbs"~e.24)) :op2 (p13 / person :mod (o2 / other~e.26))) :time (d2 / date-entity :year 1999~e.28)) :op3 (p8 / publication-91 :ARG0 (a6 / and~e.31 :op1 (p14 / person :name (n6 / name :op1 "Sugo"~e.30)) :op2 (p15 / person :mod (o3 / other~e.32))) :time (d3 / date-entity :year 2000~e.34)) :op4 (p9 / publication-91 :ARG0 (a7 / and~e.39 :op1 (p16 / person :name (n7 / name :op1 "Puebla-Osorio"~e.36,38)) :op2 (p17 / person :mod (o4 / other~e.40))) :time (d4 / date-entity :year 2006~e.42))))) # ::id bel_pmid_1828_5820.29340 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( McPherson et al , 2004a ) . Heterozygous and homozygous Mus81 mutants show cancer predisposition , particularly to T @- and B @-@ cell lymphomas . # ::alignments 1-1.3.1.2.1.1.1 2-1.3.1.2 3-1.3.1.2.2.1 8-1.1.1.3 9-1.1 10-1.1.2.3 11-1.1.1.1.1 11-1.1.2.1.1 12-1.1.1 12-1.1.1.2 12-1.1.1.2.r 13-1 14-1.2.1.2.2.1 15-1.2.1 15-1.2.2 17-1.2.2.3 18-1.2.2.2.r 19-1.2.2.2.1.1.1.1 21-1.2.2.2 22-1.2.2.2.2.1.1.1 24-1.2.2.2.1.1.1.1 24-1.2.2.2.2.1.1.1 25-1.2.2.2.1 25-1.2.2.2.2 (s / show-01~e.13 :ARG0 (a / and~e.9 :op1 (e / enzyme~e.12 :name (n2 / name :op1 "Mus81"~e.11) :ARG2-of~e.12 (m / mutate-01~e.12) :mod (h / heterozygous~e.8)) :op2 (e2 / enzyme :name (n3 / name :op1 "Mus81"~e.11) :ARG2-of m :mod (h2 / homozygous~e.10))) :ARG1 (a2 / and :op1 (p / predispose-01~e.15 :ARG1 a :ARG2 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.14))) :op2 (p2 / predispose-01~e.15 :ARG1 a :ARG2~e.18 (a3 / and~e.21 :op1 (l / lymphoma~e.25 :mod (c2 / cell :name (n4 / name :op1 "T-cell"~e.19,24))) :op2 (l2 / lymphoma~e.25 :mod (c3 / cell :name (n5 / name :op1 "B-cell"~e.22,24)))) :mod (p6 / particular~e.17))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :li "a" :ARG0 (a4 / and~e.2 :op1 (p4 / person :name (n6 / name :op1 "McPherson"~e.1)) :op2 (p5 / person :mod (o / other~e.3))) :time (d / date-entity :year 2004)))) # ::id bel_pmid_1828_5820.29342 ::amr-annotator SDL-AMR-09 ::preferred # ::tok after a long latency , Ung/ and Mutyh/ mice developed B @-@ cell lymphomas and intestinal tumors , respectively ( Nilsen et al , 2003 ; Sakamoto et al , 2007 ) . # ::alignments 0-1.4 2-1.4.1.1 3-1.4.1 6-1 6-1.5.1 6-1.5.1.1.1 8-1.1.1 8-1.2.1 9-1.1 9-1.2 10-1.1.2.1.1.1 12-1.1.2.1.1.1 13-1.1.2 14-1 14-1.5.1 14-1.5.1.1.1 15-1.2.2.1 16-1.2.2 18-1.3 18-1.3.r 20-1.5.1.1.1.1.1.1 21-1.5.1.1.1 22-1.5.1.1.1.2.1 24-1.5.1.1.2.1 26-1.5.1.2.1.1.1.1 27-1.5.1.2.1 28-1.5.1.2.1.2.1 30-1.5.1.2.2.1 (a / and~e.6,14 :op1 (d3 / develop-01~e.9 :ARG1 (m / mouse~e.8 :mod (g / gene :name (n / name :op1 "Ung"))) :ARG2 (l / lymphoma~e.13 :mod (c / cell :name (n3 / name :op1 "B-cell"~e.10,12)))) :op2 (d4 / develop-01~e.9 :ARG1 (m2 / mouse~e.8 :mod (g2 / gene :name (n2 / name :op1 "Mutyh"))) :ARG2 (t / tumor~e.16 :mod (i / intestine~e.15))) :manner~e.18 (r / respective~e.18) :time (a2 / after~e.0 :op1 (l2 / latency~e.3 :ARG1-of (l3 / long-03~e.2))) :ARG1-of (d5 / describe-01 :ARG0 (a3 / and~e.6,14 :op1 (p / publication-91 :ARG0 (a4 / and~e.6,14,21 :op1 (p3 / person :name (n4 / name :op1 "Nilsen"~e.20)) :op2 (p4 / person :mod (o / other~e.22))) :time (d / date-entity :year 2003~e.24)) :op2 (p2 / publication-91 :ARG0 (a5 / and~e.27 :op1 (p5 / person :name (n5 / name :op1 "Sakamoto"~e.26)) :op2 (p6 / person :mod (o2 / other~e.28))) :time (d2 / date-entity :year 2007~e.30))))) # ::id bel_pmid_1828_5820.31706 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Increased apoptosis and proliferative arrest of pro @-@ B cells in Ku80/ mice were rescued by a p53 @-@ null background ( Difilippantonio et al , 2000 ) . # ::alignments 0-1.2.1.1 1-1.2.1 2-1.2 4-1.2.2 5-1.2.2.1.r 6-1.2.2.1.3 8-1.2.2.1.1.1 9-1.2.2.1 12-1.2.2.1.2 14-1 15-1.1.r 17-1.1.1.1.1 19-1.1.1 19-1.1.1.2 19-1.1.1.2.1 19-1.1.1.2.1.r 19-1.1.1.2.r 20-1.1 22-1.3.1.1.1.1.1 23-1.3.1.1 24-1.3.1.1.2.1 26-1.3.1.2.1 (r / rescue-01~e.14 :ARG0~e.15 (b / background~e.20 :mod (p3 / protein~e.19 :name (n3 / name :op1 "p53"~e.17) :ARG2-of~e.19 (m2 / mutate-01~e.19 :mod~e.19 "-/-"~e.19))) :ARG1 (a / and~e.2 :op1 (a2 / apoptosis~e.1 :ARG1-of (i / increase-01~e.0)) :op2 (a3 / arrest-02~e.4 :ARG1~e.5 (c / cell~e.9 :name (n / name :op1 "B"~e.8) :part-of (m / mouse~e.12 :mod (p2 / protein :name (n2 / name :op1 "Ku80"))) :time (p7 / pro~e.6)) :ARG0-of (p / proliferate-01))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and~e.23 :op1 (p5 / person :name (n4 / name :op1 "Difilippantonio"~e.22)) :op2 (p6 / person :mod (o / other~e.24))) :time (d / date-entity :year 2000~e.26)))) # ::id bel_pmid_1828_5820.36136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The consequential loss of CDC25A results in G1/S arrest , due to the inefficient loading of CDC45 at the origin of replication . In addition , activated ATM , ATR , DNA @–@ PK , Chk2 , and Chk1 all aid in the phosphorylation and activation of p53 , a key player in DNA @-@ damage checkpoints . Activated p53 transactivates p21 , which inhibits two G1/S @-@ promoting cyclin @-@ dependent kinases ( CDKs ) , CDK2 and CDK4 . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.1.1.1 8-1.1.2 10-1.1.2.2 11-1.1.2.2 13-1.1.2.2.1.2 13-1.1.2.2.1.2.1 13-1.1.2.2.1.2.1.r 14-1.1.2.2.1 15-1.1.2.2.1.1.r 16-1.1.2.2.1.1.1.1 17-1.1.2.2.1.3.r 19-1.1.2.2.1.3 20-1.1.2.2.1.3.1.r 21-1.1.2.2.1.3.1 23-1.2.1.1 24-1.2.1.1 26-1.2.1.1.7 26-1.3.2.2 27-1.2.1.1.1.1.1 29-1.2.1.1.2.1.1 31-1.2.1.2.1.1.2.1.1.1.1.2.1 35-1.2.1.1.4.1.1 37-1.2.1.1 38-1.2.1.1.5.1.1 39-1.2.1.1.6 40-1.2.1 43-1.2.1.2.1 44-1.2.1.2 45-1.2.1.2.2 46-1.2.1.2.2.1.r 47-1.2.1.2.2.1 48-1.2.1.2.2.1 49-1.2.1.2.2.1 50-1.2.1.2.2.1 51-1.2.1.2.2.1 52-1.2.1.2.2.1 53-1.2.1.2.2.1 54-1.2.1.2.2.1 55-1.2.1.2.2.1 56-1.2.1.2.2.1 58-1.3.2.2 59-1.2.1.2.1.1.1.1 59-1.3.2.1.1 60-1.3 61-1.3.1.1.1 64-1.3.1 64-1.3.1.2 64-1.3.1.2.r 65-1.3.1.2.1.1 66-1.3.1.2.1.2.1.1.1 68-1.3.1.2.1.2 69-1.3.1.2.1.4.1.1.1 71-1.3.1.2.1.4 72-1.3.1.2.1 77-1.3.1.2.1.3.1.1.1.1 78-1.3.1.2.1.3.1 79-1.3.1.2.1.3.1.2.1.1 (m / multi-sentence :snt1 (r / result-01~e.5 :ARG1 (l / lose-02~e.2 :ARG1~e.3 (e11 / enzyme :name (n / name :op1 "CDC25A"~e.4)) :mod (c / consequential~e.1)) :ARG2~e.6 (a / arrest-02~e.8 :ARG1 (e6 / event :name (n15 / name :op1 "G1/S"~e.7)) :ARG1-of (c2 / cause-01~e.10,11 :ARG0 (l2 / load-01~e.14 :ARG2~e.15 (e10 / enzyme :name (n2 / name :op1 "CDC45"~e.16)) :ARG1-of (e / efficient-01~e.13 :polarity~e.13 -~e.13) :time~e.17 (o / origin~e.19 :mod~e.20 (r2 / replicate-01~e.21)))))) :snt2 (a3 / and :op2 (a4 / aid-01~e.40 :ARG0 (a5 / and~e.23,24,37 :op1 (e2 / enzyme :name (n3 / name :op1 "ATM"~e.27)) :op2 (e12 / enzyme :name (n4 / name :op1 "ATR"~e.29)) :op3 (e3 / enzyme :name (n5 / name :op1 "DNA–PK")) :op4 (e4 / enzyme :name (n6 / name :op1 "Chk2"~e.35)) :op5 (e5 / enzyme :name (n7 / name :op1 "Chk1"~e.38)) :mod (a6 / all~e.39) :ARG1-of (a2 / activate-01~e.26)) :ARG1 (a7 / and~e.44 :op1 (p / phosphorylate-01~e.43 :ARG1 (p7 / protein :name (n8 / name :op1 "p53"~e.59) :ARG0-of (p2 / play-08 :ARG1-of (k / key-02 :ARG2 (c3 / checkpoint :mod (d / damage-01 :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n17 / name :op1 "DNA"~e.31)))))))) :op2 (a8 / activate-01~e.45 :ARG1~e.46 p7~e.47,48,49,50,51,52,53,54,55,56)))) :snt3 (t / transactivate-01~e.60 :ARG1 (p9 / protein~e.64 :name (n10 / name :op1 "p21"~e.61) :ARG0-of~e.64 (i / inhibit-01~e.64 :ARG1 (k2 / kinase~e.72 :quant 2~e.65 :ARG0-of (p10 / promote-02~e.68 :ARG1 (e7 / event :name (n16 / name :op1 "G1/S"~e.66))) :ARG1-of (m2 / mean-01 :ARG2 (a11 / and~e.78 :op1 (e8 / enzyme :name (n13 / name :op1 "CDK2"~e.77)) :op2 (e9 / enzyme :name (n14 / name :op1 "CDK4"~e.79)))) :ARG0-of (d2 / depend-01~e.71 :ARG1 (p3 / protein :name (n11 / name :op1 "cyclin"~e.69)))))) :ARG2 (p8 / protein :name (n9 / name :op1 "p53"~e.59) :ARG1-of (a9 / activate-01~e.26,58)))) # ::id bel_pmid_1828_5820.36694 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated ATM and ATR mediate the phosphorylation and subsequent activation of Chk2 and Chk1 , respectively ; this process is necessary in the induction of phosphorylation of CDC25A , marking it for proteosomal degradation ( Su , 2006 ) . # ::alignments 0-1.1.1.1.2 0-1.1.1.2.2 1-1.1.1.1.1.1 2-1.1 2-1.1.1.2 3-1.1.2.1.1.1 4-1.1.1 4-1.1.2 6-1.1.1.2.1 6-1.1.2.2.1 7-1.1.1.2 7-1.1.2.2 8-1.1.1.2.2.2 9-1.1.1.1.2 9-1.1.1.2.2 9-1.1.2.2.2 10-1.1.1.2.1.1.r 11-1.1.1.2.1.1.1.1 12-1.1.1.2 13-1.1.2.2.1.1.1.1 15-1.1.3 15-1.1.3.r 17-1.2.2.1 18-1.2.2 20-1.2 21-1.2.1.r 23-1.2.1 24-1.2.1.1.r 25-1.2.1.1 26-1.2.1.1.1.r 27-1.2.1.1.1.1.1 29-1.2.1.1.2 33-1.2.1.1.2.2 35-1.2.3.1.1.1.1 37-1.2.3.1.2.1 (m / multi-sentence :snt1 (a5 / and~e.2 :op1 (m2 / mediate-01~e.4 :ARG0 (e / enzyme :name (n2 / name :op1 "ATM"~e.1) :ARG1-of (a / activate-01~e.0,9)) :ARG1 (a2 / and~e.2,7,12 :op1 (p / phosphorylate-01~e.6 :ARG1~e.10 (e2 / enzyme :name (n4 / name :op1 "Chk2"~e.11))) :op2 (a3 / activate-01~e.0,9 :ARG1 e2 :mod (s / subsequent~e.8)))) :op2 (m3 / mediate-01~e.4 :ARG0 (e5 / enzyme :name (n3 / name :op1 "ATR"~e.3) :ARG1-of a) :ARG1 (a6 / and~e.7 :op1 (p3 / phosphorylate-01~e.6 :ARG1 (e3 / enzyme :name (n5 / name :op1 "Chk1"~e.13))) :op2 (a7 / activate-01~e.9 :ARG1 e3 :mod s))) :manner~e.15 (r / respective~e.15)) :snt2 (n / need-01~e.20 :ARG0~e.21 (i / induce-01~e.23 :ARG2~e.24 (p5 / phosphorylate-01~e.25 :ARG1~e.26 (e4 / enzyme :name (n6 / name :op1 "CDC25A"~e.27)) :ARG0-of (m4 / mark-02~e.29 :ARG1 e4 :purpose (d3 / degrade-01~e.33 :ARG1 e4 :ARG2 (p8 / protein :name (n8 / name :op1 "proteosome")))))) :ARG1 (p4 / process-02~e.18 :mod (t / this~e.17)) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (p7 / person :name (n7 / name :op1 "Su"~e.35)) :time (d / date-entity :year 2006~e.37))))) # ::id bel_pmid_1831_7950.3272 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of 4E @-@ BP1 , S6k1( Thr( 389 )) , and Erk 1 @/@ 2 was reduced 2 h following IP injection of alcohol . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 8-1.1.1.2.1 11-1.1.1 15-1.2.2.1 17-1 18-1.2.2.1 19-1.2.2.2 20-1.2 22-1.2.1 23-1.2.1.1.r 24-1.2.1.1 (r / reduce-01~e.17 :ARG1 (p / phosphorylate-01~e.0 :ARG1~e.1 (a / and~e.11 :op1 (p2 / protein :name (n2 / name :op1 "4E-BP1"~e.2,4)) :op2 (a4 / amino-acid :mod 389~e.8 :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n4 / name :op1 "S6k1"))) :op3 (e3 / enzyme :name (n5 / name :op1 "Erk1")) :op4 (e4 / enzyme :name (n6 / name :op1 "Erk2")))) :time (a2 / after~e.20 :op1 (i / inject-01~e.22 :ARG1~e.23 (a3 / alcohol~e.24) :ARG2 (p3 / peritoneum)) :quant (t / temporal-quantity :quant 2~e.15,18 :unit (h / hour~e.19)))) # ::id bel_pmid_1836_8049.20310 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGF @-@ beta @-@ induced Foxp3 expression is inhibited by IL @-@ 6 ( ref . 17 ) , IL @-@ 21 ( ref . 10 ) and IL @-@ 23 ( Supplementary Fig. 8 ) . # ::alignments 0-1.2.2.1.1.1 2-1.2.2.1.1.1 4-1.2.2 5-1.2.1.1.1 6-1.2 8-1 9-1.1.r 10-1.1.1.1.1 10-1.1.2.1.1 10-1.1.3.1.1 12-1.1.1.1.1 16-1.1.1.2.1.1.1 19-1.1.2.1.1 19-1.1.3.1.1 21-1.1.2.1.1 25-1.1.2.2.1.1.1 27-1.1 28-1.1.3.1.1 30-1.1.3.1.1 32-1.1.3.2.1.2 33-1.1.3.2.1 34-1.1.3.2.1.1 (i / inhibit-01~e.8 :ARG0~e.9 (a / and~e.27 :op1 (p3 / protein :name (n3 / name :op1 "IL-6"~e.10,12) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 17~e.16)))) :op2 (p4 / protein :name (n4 / name :op1 "IL-21"~e.10,19,21) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 10~e.25)))) :op3 (p5 / protein :name (n5 / name :op1 "IL-23"~e.10,19,28,30) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.33 :mod 8~e.34 :ARG2-of (s / supplement-01~e.32))))) :ARG1 (e / express-03~e.6 :ARG2 (p / protein :name (n / name :op1 "Foxp3"~e.5)) :ARG2-of (i2 / induce-01~e.4 :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-beta"~e.0,2))))) # ::id bel_pmid_1836_8049.27060 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Forced expression of wild @-@ type mouse Foxp3 inhibited IL @-@ 6/IL @-@ 21 @-@ induced Il23r expression , whereas Foxp3DeltaEx2 had less inhibitory activity ( Fig . 4a ) # ::alignments 0-1.1.1.3 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1 5-1.1.1.2.1 6-1.1.1.2 7-1.1.1.1.1.1 8-1.1 9-1.1.2.1.1.1 9-1.1.2.2.1.1.1.1 9-1.1.2.2.1.2.1.1 13-1.1.2.2.1.2.1.1 15-1.1.2.2 17-1.1.2 19-1 22-1.2.3 23-1.2.2 24-1.2 26-1.3.1 28-1.3.1.1 (c / contrast-01~e.19 :ARG1 (i / inhibit-01~e.8 :ARG0 (e / express-03~e.1 :ARG2 (p / protein :name (n / name :op1 "Foxp3"~e.7)) :ARG3~e.2 (m / mouse~e.6 :mod (w / wild-type~e.3,5)) :ARG1-of (f / force-02~e.0)) :ARG1 (e2 / express-03~e.17 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-23-R"~e.9)) :ARG2-of (i2 / induce-01~e.15 :ARG0 (s / slash :op1 (p3 / protein :name (n3 / name :op1 "IL-6"~e.9)) :op2 (p4 / protein :name (n4 / name :op1 "IL-21"~e.9,13)))))) :ARG2 (a / activity-06~e.24 :ARG0 (p5 / protein :name (n5 / name :op1 "Foxp3ΔEx2")) :ARG1 (i3 / inhibit-01~e.23) :degree (l / less~e.22)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.26 :mod "4a"~e.28))) # ::id bel_pmid_1836_8049.27066 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both mouse and human Foxp3 blocked RORgammat @-@ directed IL @-@ 17 expression , but full suppression required the presence of the exon 2 @-@ encoded sequence in Foxp3 , suggesting that the interaction between Foxp3 and RORgammat is essential ( Fig . 3c and Supplementary Fig. 5 ) . # ::alignments 1-1.1.1.1.2 2-1.1.1 3-1.1.1.2.2 4-1.1.1.1.1.1 4-1.1.1.2.1.1 5-1.1 6-1.1.2.2.1.1.1 8-1.1.2.2 9-1.1.2.1.1.1 11-1.1.2.1.1.1 12-1.1.2 14-1 15-1.2.1.2 16-1.2.1 17-1.2 19-1.2.2 20-1.2.2.1.r 22-1.2.2.1.1.1 23-1.2.2.1.1.2 25-1.2.2.1.2 28-1.2.2.1.3.1.1 30-1.2.3 31-1.2.3.1.r 33-1.2.3.1.1 35-1.1.1.2.1.1 35-1.2.2.1.3.1.1 36-1.3.1 37-1.1.2.2.1.1.1 38-1.2.3.1.1.r 39-1.2.3.1 41-1.3.1.1 43-1.3.1.1.1 44-1.3.1 45-1.3.1.2.2 46-1.3.1.2 47-1.3.1.2.1 (c / contrast-01~e.14 :ARG1 (b / block-01~e.5 :ARG0 (a / and~e.2 :op1 (p / protein :name (n / name :op1 "Foxp3"~e.4) :mod (m / mouse~e.1)) :op2 (p2 / protein :name (n2 / name :op1 "Foxp3"~e.4,35) :mod (h / human~e.3))) :ARG1 (e / express-03~e.12 :ARG2 (p3 / protein :name (n3 / name :op1 "IL-17"~e.9,11)) :ARG1-of (d / direct-01~e.8 :ARG0 (p4 / protein :name (n4 / name :op1 "RORgammat"~e.6,37))))) :ARG2 (r / require-01~e.17 :ARG0 (s / suppress-01~e.16 :ARG1 e :ARG1-of (f / full-09~e.15)) :ARG1 (p7 / present-02~e.19 :ARG1~e.20 (p5 / protein-segment :name (n5 / name :op1 "exon"~e.22 :op2 2~e.23) :ARG1-of (e2 / encode-01~e.25) :part-of (p6 / protein :name (n6 / name :op1 "Foxp3"~e.28,35)))) :ARG0-of (s3 / suggest-01~e.30 :ARG1~e.31 (e3 / essential~e.39 :domain~e.38 (i / interact-01~e.33 :ARG0 p6 :ARG1 p4)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.36,44 :op1 (f2 / figure~e.41 :mod "3c"~e.43) :op2 (f3 / figure~e.46 :mod 5~e.47 :ARG2-of (s4 / supplement-01~e.45))))) # ::id bel_pmid_1836_8049.33032 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Examination of IL @-@ 17 expression in heterozygous RORgammat @–@ GFP knock @-@ in mice revealed that RORgammat+Foxp3+ lamina propria T cells produced much less IL @-@ 17 than RORgammat+Foxp3 @- cells , suggesting that Foxp3 may interfere with the ability of RORgammat to induce IL @-@ 17 ( Fig . 1c ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.1 4-1.1.1.1 5-1.1.1 5-1.1.1.2.2 6-1.1.1.2.r 7-1.1.1.2.1 8-1.1.1.2.2.1.1.1.1 10-1.1.1.2.2.1.2.1.1 14-1.1.1.2 15-1 18-1.2.1.2 19-1.2.1.2 20-1.2.1.1.1 21-1.2.3 22-1.2 23-1.2.2.2.1 24-1.2.2.2 25-1.2.2.1.1 27-1.2.2.1.1 28-1.2.3.r 31-1.2.1 33-1.3 34-1.3.1.r 35-1.3.1.1.1.1.1 36-1.3.1 37-1.3.1.1 38-1.3.1.1.2.r 40-1.3.1.1.2 41-1.3.1.1.2.2.r 42-1.3.1.1.2.2.1 44-1.3.1.1.2.2 45-1.3.1.1.2.2.2 46-1.3.1.1.2.2.2 47-1.3.1.1.2.2.2 49-1.4.1 51-1.4.1.1 (r / reveal-01~e.15 :ARG0 (e / examine-01~e.0 :ARG1~e.1 (e2 / express-03~e.5 :ARG2 p~e.2,3,4 :ARG3~e.6 (m / mouse~e.14 :mod (h / heterozygous~e.7) :ARG3-of (e3 / express-03~e.5 :ARG2 (a / and :op1 (p2 / protein :name (n2 / name :op1 "RORgammat"~e.8)) :op2 (p3 / protein :name (n3 / name :op1 "GFP"~e.10))))))) :ARG1 (p4 / produce-01~e.22 :ARG0 (c / cell~e.31 :name (n4 / name :op1 "T"~e.20) :part-of (l / lamina-propria~e.18,19) :mod (p5 / protein :name (n5 / name :op1 "RORgammat+")) :mod (p6 / protein :name (n6 / name :op1 "Foxp3+"))) :ARG1 (p / protein :name (n / name :op1 "IL-17"~e.25,27) :quant (l2 / less~e.24 :degree (m2 / much~e.23))) :compared-to~e.28 (c2 / cell~e.21 :mod (p7 / protein :name (n7 / name :op1 "Foxp3-")) :mod p5)) :ARG0-of (s / suggest-01~e.33 :ARG1~e.34 (p8 / possible-01~e.36 :ARG1 (i / interfere-01~e.37 :ARG0 (p9 / protein :name (n8 / name :op1 "Foxp3"~e.35)) :ARG1~e.38 (c3 / capable-01~e.40 :ARG1 p2 :ARG2~e.41 (i2 / induce-01~e.44 :ARG0 p2~e.42 :ARG2 p~e.45,46,47))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.49 :mod "1c"~e.51))) # ::id bel_pmid_1842_3196.15956 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A ) Increase in IL @-@ 6 production from baseline in WT , tlr4/, myd88/, and trif/ alveolar macrophages treated with LPS , BAL fluid from normal control , or BAL fluid from acid @-@ treated WT mice . **p < 0.01 . Data are from four separate experiments . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.1.1 6-1.1.2.1.1.1 7-1.1.2 8-1.1.3.1.1.r 9-1.1.3.1 11-1.1.3.1.1.1 17-1.1.3.1.1.2 18-1.1.3.1.1 18-1.1.3.2 18-1.1.3.3 18-1.1.3.4 19-1.1.3.5 20-1.1.3.5.1.r 21-1.1.3.5.1.1.1.1 23-1.1.3.5.1.2.2 23-1.1.3.5.1.2.2.1 23-1.1.3.5.1.2.2.1.1 23-1.1.3.5.1.2.2.1.1.r 23-1.1.3.5.1.2.2.1.r 24-1.1.3.5.1.2 25-1.1.3.5.1.2.1.r 26-1.1.3.5.1.2.1.1 27-1.1.3.5.1.2.1 29-1.1.3.5.1 30-1.1.3.5.1.2.2 30-1.1.3.5.1.2.2.1 30-1.1.3.5.1.2.2.1.1 30-1.1.3.5.1.2.2.1.1.r 30-1.1.3.5.1.2.2.1.r 31-1.1.3.5.1.2 31-1.1.3.5.1.3 32-1.1.3.5.1.3.1.r 33-1.1.3.5.1.3.1.2.1 35-1.1.3.5.1.3.1.2 36-1.1.3.5.1.3.1.1 37-1.1.3.5.1.3.1 40-1.1.4.1 41-1.1.4.1.1 43-1.2 45-1.2.1.r 46-1.2.1.1 47-1.2.1.2 48-1.2.1 (m / multi-sentence :snt1 (i / increase-01~e.2 :li "A"~e.0 :ARG1~e.3 (p / produce-01~e.7 :ARG1 (p2 / protein :name (n / name :op1 "IL-6"~e.4,6))) :location (a / and :op1 (b / baseline~e.9 :source~e.8 (m2 / macrophage~e.18 :mod (w / wild-type~e.11) :mod (a2 / alveolus~e.17))) :op2 (m3 / macrophage~e.18 :mod a2 :mod (p3 / protein :name (n2 / name :op1 "tlr4") :ARG2-of (m4 / mutate-01 :mod "-/-"))) :op3 (m5 / macrophage~e.18 :mod a2 :mod (p4 / protein :name (n3 / name :op1 "myd88") :ARG2-of m4)) :op4 (m6 / macrophage~e.18 :mod a2 :mod (p5 / protein :name (n4 / name :op1 "trif") :ARG2-of m4)) :ARG1-of (t / treat-03~e.19 :ARG3~e.20 (o / or~e.29 :op1 (m7 / molecular-physical-entity :name (n5 / name :op1 "LPS"~e.21)) :op2 (f / fluid~e.24,31 :source~e.25 (c / control~e.27 :ARG1-of (n7 / normal-02~e.26)) :mod (l2 / lavage~e.23,30 :mod~e.23,30 (a4 / alveolus~e.23,30 :mod~e.23,30 (b2 / bronchus~e.23,30)))) :op3 (f2 / fluid~e.31 :source~e.32 (m10 / mouse~e.37 :mod w~e.36 :ARG1-of (t2 / treat-03~e.35 :ARG3 (a3 / acid~e.33))) :mod l2)))) :ARG1-of (s2 / statistical-test-91 :ARG2 (l / less-than~e.40 :op1 0.01~e.41))) :snt2 (d / data~e.43 :source~e.45 (e / experiment~e.48 :quant 4~e.46 :ARG1-of (s / separate-02~e.47)))) # ::id bel_pmid_1842_3196.15958 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By contrast , LPS @-@ induced IL @-@ 6 production in alveolar macrophages was dependent on TLR4 , MyD88 , and TRIF ( Figure 3A ) . # ::alignments 1-1 3-1.1.1.2.1.1.1 5-1.1.1.2 6-1.1.1.1.1.1 8-1.1.1.1.1.1 9-1.1.1 10-1.1.1.3.r 11-1.1.1.3.1 12-1.1.1.3 14-1.1 15-1.1.2.r 16-1.1.2.1.1.1 18-1.1.2.2.1.1 20-1.1.2 21-1.1.2.3.1.1 23-1.2.1 24-1.2.1.1 (c / contrast-01~e.1 :ARG2 (d / depend-01~e.14 :ARG0 (p / produce-01~e.9 :ARG1 (p2 / protein :name (n / name :op1 "IL-6"~e.6,8)) :ARG2-of (i / induce-01~e.5 :ARG0 (m / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.3))) :location~e.10 (m2 / macrophage~e.12 :mod (a / alveolus~e.11))) :ARG1~e.15 (a2 / and~e.20 :op1 (p3 / protein :name (n3 / name :op1 "TLR4"~e.16)) :op2 (p4 / protein :name (n4 / name :op1 "MyD88"~e.18)) :op3 (p5 / protein :name (n5 / name :op1 "TRIF"~e.21)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.23 :mod "3A"~e.24))) # ::id bel_pmid_1843_4325.28378 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 6 reduced the expression levels of Foxp3 at 48 @–@ 72 h . This is probably a direct effect of IL @-@ 6 on the Foxp3 promoter because IL @-@ 6 suppressed TGF-?1 @-@ mediated Foxp3 promoter activity in primary T cells ( data not shown ) . # ::alignments 0-1.1.1.1.1 0-1.2.1.1.1.1 2-1.1.1.1.1 2-1.2.1.1.1.1 3-1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.1.1.r 8-1.1.2.1.1.1.1 10-1.1.3.1.1 12-1.1.3.2.1 13-1.1.3.1.2 15-1.2.1.4 16-1.2.1.4.r 16-1.2.1.r 17-1.2 19-1.2.1.3 20-1.2.1 21-1.2.1.1.r 22-1.2.1.1.1.1 24-1.2.1.1.1.1 25-1.2.1.2.r 27-1.2.1.2.1.1.1.1 28-1.2.1.2.1.r 29-1.2.1.5 30-1.2.1.5.1.1 31-1.2.1.5.1.1 32-1.2.1.5.1.1 33-1.2.1.5.1 36-1.2.1.5.1.2.2 37-1.2.1.5.1.2.1 38-1.2.1.5.1.2.1 39-1.2.1.5.1.2 40-1.2.1.5.1.3.r 41-1.2.1.5.1.3.2 42-1.2.1.5.1.3.1.1 43-1.2.1.5.1.3 45-1.2.1.6.1 46-1.2.1.6.1.1.1 46-1.2.1.6.1.1.1.r 47-1.2.1.6.1.1 (m / multi-sentence :snt1 (r / reduce-01~e.3 :ARG0 (p / protein :name (n / name :op1 "IL-6"~e.0,2)) :ARG1 (l / level~e.6 :degree-of (e / express-03~e.5 :ARG2~e.7 (p2 / protein :name (n2 / name :op1 "Foxp3"~e.8)))) :time (b / between :op1 (t / temporal-quantity :quant 48~e.10 :unit (h / hour~e.13)) :op2 (t2 / temporal-quantity :quant 72~e.12 :unit h))) :snt2 (p8 / probable~e.17 :domain~e.16 (a / affect-01~e.20 :ARG0~e.21 (p3 / protein :name (n3 / name :op1 "IL-6"~e.0,2,22,24)) :ARG1~e.25 (m3 / molecular-physical-entity :ARG0-of~e.28 (p9 / promote-01 :ARG1 (p5 / protein :name (n4 / name :op1 "Foxp3"~e.27)))) :ARG1-of (d / direct-02~e.19) :domain~e.16 (t3 / this~e.15) :ARG1-of (c / cause-01~e.29 :ARG0 (s2 / suppress-01~e.33 :ARG0 p3~e.30,31,32 :ARG1 (a2 / activity-06~e.39 :ARG0 m3~e.37,38 :ARG1-of (m2 / mediate-01~e.36 :ARG0 (p6 / protein :name (n5 / name :op1 "TGF-beta1")))) :location~e.40 (c2 / cell~e.43 :name (n6 / name :op1 "T"~e.42) :mod (p7 / primary~e.41)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.45 :ARG1-of (s3 / show-01~e.47 :polarity~e.46 -~e.46)))))) # ::id bel_pmid_1843_4325.33034 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 4C , transient overexpression of WT Foxp3 , but not {Delta}2 or {Delta}FKH , inhibited induction of IL @-@ 17A transcription ( Fig . 4C ) . Taken together , these observations suggest that Foxp3 interacts with ROR{gamma}t in the exon 2 region and that the FKH domain plays a critical role in the suppression of ROR{gamma}t @-@ mediated IL @-@ 17A transcription . # ::alignments 1-1.1.3 2-1.1.3.1.r 3-1.1.3.1 4-1.1.3.1.1 6-1.1.1.1.2 7-1.1.1.1 7-1.1.2.2 8-1.1.1.1.1.r 9-1.1.1.1.1.2 10-1.1.1.1.1.1.1 12-1.1 13-1.1.2.1 13-1.1.2.1.r 15-1.1.2.2.1 18-1.1.1 18-1.1.2 19-1.1.1.2 20-1.1.1.2.1.r 21-1.1.1.2.1.1.1.1 23-1.1.1.2.1.1.1.1 24-1.1.1.2.1 26-1.1.3.1 28-1.1.3.1.1 34-1.2.1.1.2 35-1.2.1.1 35-1.2.1.1.1 35-1.2.1.1.1.r 36-1.2.1 37-1.2.1.2.r 38-1.2.1.2.1.1.2.1.1 39-1.2.1.2.1 44-1.2.1.2.1.1.1.1 45-1.2.1.2.1.1.1.2 47-1.2.1.2 48-1.2.1.2.r 50-1.2.1.2.2.1.1.1 52-1.2.1.2.2 54-1.2.1.2.2.3 56-1.2.1.2.2.2.r 58-1.2.1.2.2.2 62-1.2.1.2.2.2.1.2 63-1.2.1.2.2.2.1.1.1.1 65-1.2.1.2.2.2.1.1.1.1 66-1.2.1.2.2.2.1 (m / multi-sentence :snt1 (c / contrast-01~e.12 :ARG1 (i / inhibit-01~e.18 :ARG0 (o / overexpress-01~e.7 :ARG1~e.8 (p / protein :name (n / name :op1 "Foxp3"~e.10) :mod (w / wild-type~e.9)) :ARG1-of (t / transient-02~e.6)) :ARG1 (i2 / induce-01~e.19 :ARG2~e.20 (t2 / transcribe-01~e.24 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-17A"~e.21,23))))) :ARG2 (i3 / inhibit-01~e.18 :polarity~e.13 -~e.13 :ARG0 (o2 / overexpress-01~e.7 :ARG1 (o3 / or~e.15 :op1 (p3 / protein :name (n3 / name :op1 "Foxp3Δ2")) :op2 (p4 / protein :name (n4 / name :op1 "Foxp3ΔFNK"))) :ARG2 t) :ARG1 i2) :ARG1-of (s / show-01~e.1 :medium~e.2 (f / figure~e.3,26 :mod "4C"~e.4,28)) :ARG1-of (d / describe-01 :ARG0 f)) :snt2 (h / have-condition-91 :ARG1 (s2 / suggest-01~e.36 :ARG0 (t3 / thing~e.35 :ARG1-of~e.35 (o4 / observe-02~e.35) :mod (t4 / this~e.34)) :ARG1~e.37,48 (a / and~e.47 :op1 (i4 / interact-01~e.39 :ARG0 (p7 / protein-segment :name (n7 / name :op1 "exon"~e.44 :op2 2~e.45) :part-of (p5 / protein :name (n5 / name :op1 "Foxp3"~e.38))) :ARG1 (p6 / protein :name (n6 / name :op1 "RORgammat"))) :op2 (p8 / play-08~e.52 :ARG0 (p9 / protein-segment :name (n8 / name :op1 "FKH"~e.50) :part-of p5) :ARG1~e.56 (s3 / suppress-01~e.58 :ARG1 (t5 / transcribe-01~e.66 :ARG1 (p10 / protein :name (n9 / name :op1 "IL-17A"~e.63,65)) :ARG1-of (m2 / mediate-01~e.62 :ARG0 p6))) :ARG1-of (c2 / critical-02~e.54 :ARG2 s3)))))) # ::id bel_pmid_1843_4325.33936 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Then , IL @-@ 17A promoter activity was examined with or without an ROR{gamma}t expression vector in the HEK 293T cells in which ROR{gamma}t was not expressed . In the presence of ROR{gamma}t , the promoter activity was significantly increased ( Fig . 2A ) . # ::alignments 0-1.1.4 2-1.1.1.1.1.1.1.1 4-1.1.1.1.1.1.1.1 5-1.1.1.1 5-1.1.1.1.1 5-1.1.1.1.1.r 6-1.1.1 8-1.1 9-1.1.2.r 10-1.1.2 11-1.1.2.2.1 11-1.1.2.2.1.r 14-1.1.2.1.1 15-1.1.2.1 15-1.1.2.2 16-1.1.3.r 18-1.1.3.1.1 19-1.1.3.1.2 20-1.1.3 25-1.1.3.2.1 25-1.1.3.2.1.r 26-1.1.3.2 30-1.2.3 35-1.2.1.1 35-1.2.1.1.1 35-1.2.1.1.1.r 36-1.2.1 38-1.2.2 39-1.2 41-1.2.4.1 43-1.2.4.1.1 (m / multi-sentence :snt1 (e / examine-01~e.8 :ARG1 (a / activity-06~e.6 :ARG0 (m2 / molecular-physical-entity~e.5 :ARG0-of~e.5 (p / promote-01~e.5 :ARG1 (p2 / protein :name (n / name :op1 "IL-17A"~e.2,4))))) :manner~e.9 (o / or~e.10 :op1 (v / vector~e.15 :mod (e2 / express-03~e.14 :ARG2 (p3 / protein :name (n2 / name :op1 "RORgammat")))) :op2 (v2 / vector~e.15 :polarity~e.11 -~e.11 :mod e2)) :location~e.16 (c / cell-line~e.20 :name (n3 / name :op1 "HEK"~e.18 :op2 "293T"~e.19) :ARG3-of (e3 / express-03~e.26 :polarity~e.25 -~e.25 :ARG2 p3)) :time (t / then~e.0)) :snt2 (i / increase-01~e.39 :ARG1 (a2 / activity-06~e.36 :ARG0 (m3 / molecular-physical-entity~e.35 :ARG0-of~e.35 (p4 / promote-01~e.35))) :ARG2 (s / significant-02~e.38) :condition (p6 / present-02~e.30 :ARG1 (p5 / protein :name (n4 / name :op1 "RORgammat"))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.41 :mod "2A"~e.43)))) # ::id bel_pmid_1848_3625.9006 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Germline expression of the endogenous H @-@ RasG12V oncogene , even in homozygosis , resulted in hyperplasia of the mammary gland . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 4-1.1.1.3 5-1.1.1.1.1 10-1.3.1 12-1.3 14-1 15-1.2.r 16-1.2 17-1.2.1.r 19-1.2.1.1 20-1.2.1 (r / result-01~e.14 :ARG1 (e / express-03~e.1 :ARG1~e.2 (g3 / gene :name (n2 / name :op1 "H-Ras"~e.5) :ARG2-of (m / mutate-01 :value "G12V") :mod (e2 / endogenous~e.4) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :ARG3 (g2 / germline~e.0)) :ARG2~e.15 (h / hyperplasia~e.16 :mod~e.17 (g / gland~e.20 :mod (m2 / mammary~e.19))) :location (h2 / homozygosis~e.12 :mod (e3 / even~e.10))) # ::id bel_pmid_1855_5587.7928 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We investigated whether globular adiponectin ( gAd ) affects the expression of inflammation @-@ related genes in murine macrophages ( RAW264 cells ) . DNA microarray analysis indicated that granulocyte colony @-@ stimulating factor ( G @-@ CSF ) showed the largest increase in expression in gAd @-@ stimulated RAW264 cells . The gAd @-@ induced secretion of G @-@ CSF increased in a time @- and dose @-@ dependent manner . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.1 2-1.1.2.1.r 3-1.1.2.2.1.1 4-1.1.2.2.1.2 6-1.3.1.2.1.1.1 8-1.1.2 10-1.1.2.3 11-1.1.2.3.1.r 12-1.1.2.3.1.1.1 14-1.1.2.3.1.1 15-1.1.2.3.1 18-1.1.2.3.2 20-1.1.2.3.2.1.1.1.1 21-1.1.2.3.2.1.1 24-1.2.1.1.1.2.1 25-1.2.1.1 26-1.2.1 27-1.2 28-1.2.2.r 29-1.2.2.1.1.1 30-1.2.2.1.1.2 32-1.2.2.1.1.2 33-1.2.2.1.1.3 35-1.3.1.1.1.1 37-1.3.1.1.1.1 39-1.2.2 41-1.2.2.2.2 41-1.2.2.2.2.1 41-1.2.2.2.2.1.r 42-1.2.2.2 43-1.2.2.2.1.r 44-1.2.2.2.1 46-1.2.2.2.1.1.2.1.1.1 48-1.2.2.2.1.1.2 49-1.1.2.3.2.1.1.1.1 49-1.2.2.2.1.1.1.1 50-1.1.2.3.2.1.1 50-1.2.2.2.1.1 53-1.2.2.2.1.1.2.1.1.1 53-1.3.1.2.1.1.1 55-1.3.1.2 56-1.3.1 58-1.3.1.1.1.1 60-1.3.1.1.1.1 61-1.3 64-1.3.2.1.1 66-1.3.2.1 67-1.3.2.1.2 69-1.3.2 70-1.3.2.r (m2 / multi-sentence :snt1 (i / investigate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / affect-01~e.8 :mode~e.2 interrogative~e.2 :ARG0 (p / protein :name (n / name :op1 "globular"~e.3 :op2 "adiponectin"~e.4)) :ARG1 (e / express-03~e.10 :ARG1~e.11 (g / gene~e.15 :ARG1-of (r / relate-01~e.14 :ARG2 (i2 / inflame-01~e.12))) :ARG3 (m3 / macrophage~e.18 :ARG1-of (m5 / mean-01 :ARG2 (c / cell~e.21,50 :name (n3 / name :op1 "RAW264"~e.20,49))) :part-of (o / organism :name (n2 / name :op1 "Murinae")))))) :snt2 (i3 / indicate-01~e.27 :ARG0 (a3 / analyze-01~e.26 :instrument (m4 / microarray~e.25 :mod (n6 / nucleic-acid :wiki "DNA" :name (n11 / name :op1 "DNA"~e.24)))) :ARG1~e.28 (s / show-01~e.39 :ARG0 (p3 / protein :name (n5 / name :op1 "granulocyte"~e.29 :op2 "colony-stimulating"~e.30,32 :op3 "factor"~e.33)) :ARG1 (i4 / increase-01~e.42 :ARG1~e.43 (e2 / express-03~e.44 :ARG3 (c2 / cell~e.50 :name (n7 / name :op1 "RAW264"~e.49) :ARG1-of (s2 / stimulate-01~e.48 :ARG2 (p5 / protein :name (n8 / name :op1 "gAd"~e.46,53))))) :ARG2 (l / large~e.41 :degree~e.41 (m / most~e.41))))) :snt3 (i5 / increase-01~e.61 :ARG1 (s3 / secrete-01~e.56 :ARG1 (p7 / protein :name (n10 / name :op1 "G-CSF"~e.35,37,58,60)) :ARG2-of (i6 / induce-01~e.55 :ARG0 (p6 / protein :name (n9 / name :op1 "gAd"~e.6,53)))) :manner~e.70 (d3 / depend-01~e.69 :ARG1 (a2 / and~e.66 :op1 (t2 / time~e.64) :op2 (d4 / dose~e.67))))) # ::id bel_pmid_1855_5587.24926 ::amr-annotator SDL-AMR-09 ::preferred # ::tok gAd induced the phosphorylation of MEK1 @/@ 2 and ERK1 @/@ 2 in RAW264 cells . In addition , the gAd @-@ induced phosphorylation of MEK1 @/@ 2 and ERK1 @/@ 2 was dramatically reduced by PD98059 and U0126 , respectively . # ::alignments 0-1.1.1.1.1 0-1.2.1.2.2.1.1.1 1-1.2.1.2.2 3-1.2.1.2 5-1.2.1.2.1.1.1.1 8-1.2.1.2.1 9-1.2.1.2.1.3.1.1 13-1.1.3.1.1 14-1.1.3 16-1.1.2.1 17-1.1.2.1 20-1.1.1.1.1 22-1.1 23-1.1.2 23-1.2.1.2 25-1.1.2.1.1.1.1 25-1.2.1.2.1.1.1.1 28-1.1.2.1 28-1.2.1.2.1 29-1.1.2.1.3.1.1 29-1.2.1.2.1.3.1.1 33-1.2.1.3 34-1.2.1 35-1.2.1.1.r 36-1.2.1.1.1.1.1 37-1.2.1.1 38-1.2.1.1.2.1.1 40-1.2.1.1.3 40-1.2.1.1.3.r (m / multi-sentence :snt1 (i / induce-01~e.22 :ARG0 (p2 / protein :name (n2 / name :op1 "gAd"~e.0,20)) :ARG2 (p / phosphorylate-01~e.23 :ARG1 (a / and~e.16,17,28 :op1 (e / enzyme :name (n3 / name :op1 "MEK1"~e.25)) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2")) :op3 (e3 / enzyme :name (n5 / name :op1 "ERK1"~e.29)) :op4 (e4 / enzyme :name (n6 / name :op1 "ERK2")))) :location (c / cell~e.14 :name (n7 / name :op1 "RAW264"~e.13))) :snt2 (a2 / and :op2 (r / reduce-01~e.34 :ARG0~e.35 (a3 / and~e.37 :op1 (s2 / small-molecule :name (n8 / name :op1 "PD98059"~e.36)) :op2 (s / small-molecule :name (n / name :op1 "U0126"~e.38)) :manner~e.40 (r2 / respective~e.40)) :ARG1 (p3 / phosphorylate-01~e.3,23 :ARG1 (a4 / and~e.8,28 :op1 (e5 / enzyme :name (n9 / name :op1 "MEK1"~e.5,25)) :op2 (e6 / enzyme :name (n10 / name :op1 "MEK2")) :op3 (e7 / enzyme :name (n11 / name :op1 "ERK1"~e.9,29)) :op4 (e8 / enzyme :name (n12 / name :op1 "ERK2"))) :ARG2-of (i2 / induce-01~e.1 :ARG0 (p4 / protein :name (n13 / name :op1 "gAd"~e.0)))) :manner (d / dramatic~e.33)))) # ::id bel_pmid_1866_6314.27860 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - An inactivation of IL @-@ 10 in mice results in an increased production of IL @-@ 12 and IFN @-@ gamma [ 42,43 ] . Inflamed tissues and granulomas of CD show low IL @-@ 10[44 ] . Melgar et al[45 ] reported a highly significant increase in IL @-@ 10 mRNA levels in T lymphocytes and in IL @-@ 10 @-@ positive cells in the colons of UC patients . # ::alignments 0-1.1.4.r 1-1.1.4.1 2-1.1.4 5-1.1.1 5-1.1.1.1 5-1.1.1.1.r 6-1.1.1.2.r 7-1.1.1.2.1.1 9-1.1.1.2.1.1 10-1.1.1.3.r 11-1.1.1.3 12-1.1 15-1.3.2 16-1.1.2 17-1.1.2.1.r 18-1.1.2.1.1.1.1 20-1.1.2.1.1.1.1 21-1.1.2.1 22-1.1.2.1.2.1.1 24-1.1.2.1.2.1.1 29-1.2.1.4 30-1.2.1.1 31-1.2.1 34-1.2.1.3.1.1 35-1.2 36-1.2.2 36-1.2.2.2 36-1.2.2.2.r 37-1.2.2.1.1 37-1.3.2.1.1.2.1.1 42-1.3.1.1.1.1 43-1.3.1 46-1.3 48-1.3.2.2.1 49-1.3.2.2 50-1.3.2 51-1.3.2.1.r 52-1.3.2.1.1.2.1.1 54-1.3.2.1.1.2.1.1 55-1.3.2.1.1.1.1 56-1.3.2.1 57-1.3.2.3.r 58-1.3.2.3.1.1.1 59-1.3.2.3.1.1.2 60-1.3.2.3 62-1.3.2.1.1.2.1.1 64-1.3.2.1.1.2.1.1 66-1.3.2.3.2.1 67-1.3.2.3.2 70-1.3.2.3.3 71-1.3.2.3.3.1.r 72-1.3.2.3.3.1.1.1.1 73-1.3.2.3.3.1 (m / multi-sentence :snt1 (r / result-01~e.12 :ARG1 (a / activate-01~e.5 :polarity~e.5 -~e.5 :ARG1~e.6 (p14 / protein :name (n / name :op1 "IL-10"~e.7,9)) :location~e.10 (m2 / mouse~e.11)) :ARG2 (p / produce-01~e.16 :ARG1~e.17 (a2 / and~e.21 :op1 (p2 / protein :name (n3 / name :op1 "IL-12"~e.18,20)) :op2 (p3 / protein :name (n4 / name :op1 "IFN-gamma"~e.22,24)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 42 :op2 43)))) :source~e.0 (t2 / text~e.2 :ARG1-of (f / full-09~e.1))) :snt2 (s / show-01~e.35 :ARG0 (a4 / and~e.31 :op1 (t / tissue~e.30) :op2 (g2 / granuloma) :part-of (d2 / disease :name (n5 / name :op1 "CD"~e.34)) :ARG1-of (i / inflame-01~e.29)) :ARG1 (p11 / protein~e.36 :name (n6 / name :op1 "IL-10"~e.37) :ARG1-of~e.36 (l / low-04~e.36)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 44)))) :snt3 (r2 / report-01~e.46 :ARG0 (a5 / and~e.43 :op1 (p6 / person :name (n7 / name :op1 "Melgar"~e.42)) :op2 (p7 / person :mod (o2 / other))) :ARG1 (i2 / increase-01~e.15,50 :ARG1~e.51 (l2 / level~e.56 :quant-of (n8 / nucleic-acid :name (n9 / name :op1 "mRNA"~e.55) :location (p13 / protein :name (n13 / name :op1 "IL-10"~e.37,52,54,62,64)))) :ARG2 (s2 / significant-02~e.49 :ARG1-of (h / high-02~e.48)) :location~e.57 (a6 / and~e.60 :op1 (c3 / cell :name (n10 / name :op1 "T"~e.58 :op2 "lymphocyte"~e.59)) :op2 (c4 / cell~e.67 :mod (p10 / positive~e.66 :mod (p12 / protein :name (n12 / name :op1 "IL10")))) :location (c5 / colon~e.70 :part-of~e.71 (p8 / patient~e.73 :mod (d4 / disease :name (n11 / name :op1 "UC"~e.72)))))) :ARG1-of (d5 / describe-01 :ARG0 (p9 / publication :ARG1-of (c6 / cite-01 :ARG2 45))))) # ::id bel_pmid_1866_6314.28188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - in a murine model of UC , Sugimoto et al demonstrated a novel protective role for IL @-@ 22 , in which IL @-@ 22 attenuates in the intestine inflammation # ::alignments 0-1.4.r 1-1.4.1 2-1.4 6-1.3.1.1.1 7-1.3 11-1.1.1.1.1 12-1.1 13-1.1.2.1 14-1 16-1.2.3 17-1.2 19-1.2.1.r 20-1.2.1.1.1 22-1.2.1.1.1 26-1.2.1.1.1 28-1.2.1.1.1 29-1.2.2.1 30-1.2.2.1.2.r 32-1.2.2.1.2.1 33-1.2.2.1.2 (d / demonstrate-01~e.14 :ARG0 (a / and~e.12 :op1 (p / person :name (n / name :op1 "Sugimoto"~e.11)) :op2 (p2 / person :mod (o2 / other~e.13))) :ARG1 (p3 / protect-01~e.17 :ARG0~e.19 (p4 / protein :name (n6 / name :op1 "IL-22"~e.20,22,26,28)) :ARG0-of (m2 / mean-01 :ARG2 (a3 / attenuate-01~e.29 :ARG0 p4 :location~e.30 (i / inflame-01~e.33 :ARG1 (i2 / intestine~e.32)))) :mod (n3 / novel~e.16)) :medium (m / model~e.7 :mod (o / organism :name (n4 / name :op1 "Muridae"~e.6)) :mod (d2 / disease :name (n2 / name :op1 "ulcerative" :op2 "colitis"))) :source~e.0 (t / text~e.2 :ARG1-of (f / full-09~e.1))) # ::id bel_pmid_1866_6314.28300 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - T @-@ cell receptor alpha chain @-@ deficient mice ( TCR -/-) treated with anti @-@ IL @-@ 4 monoclonal antibody showed a decrease in Th2 @-@ type mRNA cytokine production and an increase in expression of IFN @-@ gamma , suggesting that IL @-@ 4 plays a major role in inducing Th2 @-@ type CD4+ cells in the gut to shift towards a Th1 response[51 ] . # ::alignments 0-1.4.r 1-1.4.1 2-1.4 4-1.1.1.1.1.1.1.1 6-1.1.1.1.1.1.1.1 7-1.1.1.1.1.1.1.2 8-1.1.1.1.1.2 9-1.1.1.1.1 11-1.1.1.1 11-1.1.1.3.1 11-1.1.1.3.1.2 11-1.1.1.3.1.2.r 12-1.1.1 14-1.1.1.3.1.1.1 16-1.1.1.2 17-1.1.1.2.1.r 18-1.1.1.2.1.2 20-1.1.1.2.1.2.1 21-1.1.1.2.1.2.1 22-1.1.1.2.1.2.1 23-1.1.1.2.1.1 24-1.1.1.2.1 25-1.1 27-1.1.2.1 28-1.1.2.1.1.r 29-1.1.2.1.1.2.2.1.1 32-1.1.2.1.1.2.1.1 33-1.1.2.1.1.1 34-1.1.2.1.1 35-1.1.2 37-1.1.2.2 38-1.1.2.2.1.r 39-1.1.2.2.1 40-1.1.2.2.1.1.r 41-1.1.2.2.1.1.1.1 43-1.1.2.2.1.1.1.1 45-1.2 46-1.2.1.r 47-1.2.1.1.1.1 49-1.2.1.1.1.1 50-1.2.1 52-1.2.1.3 54-1.2.1.2.r 55-1.2.1.2 56-1.2.1.2.1.1.1.1 59-1.2.1.2.1.1.3.1.1 60-1.1.1.1.1.1.1.1 63-1.2.1.2.1.1.2 65-1.2.1.2.1 68-1.2.1.2.1.2.1.1.1 (a / and :op1 (s / show-01~e.25 :ARG0 (m5 / mouse~e.12 :mod (d / deficient~e.11 :mod (c / chain~e.9 :mod (p / protein :name (n2 / name :op1 "T-cell"~e.4,6,60 :op2 "receptor"~e.7)) :mod (a2 / alpha~e.8))) :ARG1-of (t / treat-04~e.16 :ARG2~e.17 (a4 / antibody~e.24 :mod (m2 / monoclonal~e.23) :ARG0-of (c4 / counter-01~e.18 :ARG1 p7~e.20,21,22))) :ARG1-of (m4 / mean-01 :ARG2 (p2 / protein~e.11 :name (n3 / name :op1 "TCR"~e.14) :ARG2-of~e.11 (m / mutate-01~e.11 :mod "−/−")))) :ARG1 (a3 / and~e.35 :op1 (d2 / decrease-01~e.27 :ARG1~e.28 (p4 / produce-01~e.34 :ARG1 (c5 / cytokine~e.33) :ARG2 (n11 / nucleic-acid :name (n10 / name :op1 "mRNA"~e.32) :mod (p11 / protein :name (n6 / name :op1 "Th2"~e.29))))) :op2 (i / increase-01~e.37 :ARG1~e.38 (e / express-03~e.39 :ARG2~e.40 (p5 / protein :name (n5 / name :op1 "IFN-gamma"~e.41,43)))))) :op2 (s2 / suggest-01~e.45 :ARG1~e.46 (p6 / play-08~e.50 :ARG0 (p7 / protein :name (n7 / name :op1 "IL-4"~e.47,49)) :ARG1~e.54 (i2 / induce-01~e.55 :ARG2 (s3 / shift-01~e.65 :ARG1 (p9 / protein :name (n8 / name :op1 "Th2"~e.56) :location (g / gut~e.63) :mod (p3 / protein :name (n4 / name :op1 "CD4+"~e.59))) :ARG2 (r / respond-01 :ARG0 (p8 / protein :name (n9 / name :op1 "Th1"~e.68))))) :ARG1-of (m3 / major-02~e.52))) :ARG1-of (d3 / describe-01 :ARG0 (p10 / publication :ARG1-of (c2 / cite-01 :ARG2 51))) :source~e.0 (t2 / text~e.2 :ARG1-of (f / full-09~e.1))) # ::id bel_pmid_1866_6314.28380 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - anti @-@ IL @-@ 6 receptor monoclonal antibody to a murine colitis model and found that the treatment with this antibody reduced IFN @-@ gamma , TNF @-@ alpha , and IL @-@ 1 beta mRNA , and suppressed expression of several intracellular adhesion molecules in the colonic vascular endothelium . # ::alignments 0-1.3.r 1-1.3.1 2-1.3 4-1.1.2.2 6-1.1.2.2.1.1.1 8-1.1.2.2.1.1.1 9-1.1.2.2.1 10-1.1.2.1 11-1.1.2 14-1.1.3.1.2.1.1 15-1.1.3.1.1.1 16-1.1.3 17-1 17-1.1.1 18-1.2 19-1.2.1.r 21-1.2.1.1.1 22-1.2.1.1.1.1.r 23-1.2.1.1.1.1.1 24-1.2.1.1.1.1 25-1.2.1.1 26-1.2.1.1.2.2.1.1.1.1 28-1.2.1.1.2.2.1.1.1.1 30-1.2.1.1.2.2.1.2.1.1 32-1.2.1.1.2.2.1.2.1.1 34-1.2.1.1.2.2.1 35-1.2.1.1.2.2.1.3.1.1 39-1.2.1.1.2.1.1 41-1.2.1 42-1.2.1.2 43-1.2.1.2.2 44-1.2.1.2.2.1.r 45-1.2.1.2.2.1.2 46-1.2.1.2.2.1.1.1 47-1.2.1.2.2.1.1.2 48-1.2.1.2.2.1.1.3 49-1.2.1.2.3.r 51-1.2.1.2.3.1.1 53-1.2.1.2.3 (a / and~e.17 :op1 (i / introduce-02 :ARG0 (a5 / and~e.17 :op1 (p2 / person :name (n5 / name :op1 "Yamamoto")) :op2 (p3 / person :mod (o / other)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (p5 / person :name (n9 / name :op1 "Kallen" :op2 "KJ")) :ARG1-of (c2 / cite-01 :ARG2 25)))) :ARG1 (a6 / antibody~e.11 :mod (m / monoclonal~e.10) :ARG0-of (c3 / counter-01~e.4 :ARG1 (r5 / receptor~e.9 :name (n10 / name :op1 "IL-6"~e.6,8)))) :ARG2 (m2 / model~e.16 :topic (d / disease :name (n8 / name :op1 "colitis"~e.15) :mod (o2 / organism :name (n7 / name :op1 "Muridae"~e.14))))) :op2 (f / find-01~e.18 :ARG1~e.19 (a3 / and~e.41 :op1 (r / reduce-01~e.25 :ARG0 (t / treat-04~e.21 :ARG2~e.22 (a2 / antibody~e.24 :mod (t2 / this~e.23))) :ARG1 (n / nucleic-acid :name (n6 / name :op1 "mRNA"~e.39) :ARG0-of (e3 / encode-01 :ARG1 (a7 / and~e.34 :op1 (p6 / protein :name (n11 / name :op1 "IFN-gamma"~e.26,28)) :op2 (p7 / protein :name (n12 / name :op1 "TNF-alpha"~e.30,32)) :op3 (p8 / protein :name (n13 / name :op1 "IL-1beta"~e.35))))) :location e2) :op2 (s / suppress-01~e.42 :ARG0 t :ARG1 (e / express-03~e.43 :ARG2~e.44 (p / protein :name (n4 / name :op1 "intracellular"~e.46 :op2 "adhesion"~e.47 :op3 "molecule"~e.48) :quant (s2 / several~e.45))) :location~e.49 (e2 / endothelium~e.53 :part-of (v / vesel :part-of (c / colon~e.51)))))) :source~e.0 (t3 / text~e.2 :ARG1-of (f2 / full-09~e.1))) # ::id bel_pmid_1866_6314.35398 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - STAT @-@ 3 itself induces the anti @-@ apoptotic factors Bcl @-@ 2 and Bcl @-@ xL # ::alignments 0-1.3.r 1-1.3.1 2-1.3 4-1.1.1.1 6-1.1.1.1 7-1.1.2 8-1 10-1.2.2 12-1.2.2.1 13-1.2 14-1.2.1.1.1.1 14-1.2.1.2.1.1 16-1.2.1.1.1.1 17-1.2.1 18-1.2.1.1.1.1 18-1.2.1.2.1.1 20-1.2.1.2.1.1 (i / induce-01~e.8 :ARG0 (p / protein :name (n / name :op1 "STAT-3"~e.4,6) :mod (i2 / it~e.7)) :ARG2 (f / factor~e.13 :example (a / and~e.17 :op1 (p2 / protein :name (n2 / name :op1 "Bcl-2"~e.14,16,18)) :op2 (p3 / protein :name (n3 / name :op1 "Bcl-xL"~e.14,18,20))) :ARG0-of (c / counter-01~e.10 :ARG1 (a2 / apoptosis~e.12))) :source~e.0 (t / text~e.2 :ARG1-of (f2 / full-09~e.1))) # ::id bel_pmid_1866_6314.35432 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - Increased levels of IL @-@ 1 in IBD may be result of stimulation of colonic macrophages that can activate interleukin ( IL ) - 1 converting enzyme ( ICE ) and hence release mature IL @-@ 1 beta into the colonic mucosa[20 ] . # ::alignments 0-1.4.r 1-1.4.1 2-1.4 4-1.1.2.2 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1 9-1.1.2.1.1.1 12-1 14-1.1 15-1.1.1.r 16-1.1.1 17-1.1.1.1.r 18-1.1.1.1.2 19-1.1.1.1.1.1 21-1.1.1.1.3.2 22-1.1.1.1.3 23-1.1.1.1.3.1.1.1 25-1.1.2.1.1.1 28-1.1.1.1.3.1.1.1 29-1.1.1.1.3.1.1.2 30-1.1.1.1.3.1.1.3 36-1.1.1.1.3.3 37-1.1.1.1.3.3.1 37-1.1.1.1.3.3.1.2 37-1.1.1.1.3.3.1.2.r 38-1.1.1.1.3.3.1.1.1 40-1.1.1.1.3.3.1.1.1 41-1.1.1.1.3.3.1.1.2 42-1.1.1.1.3.3.2.r 44-1.1.1.1.2 44-1.1.1.1.3.3.2.1 (p / possible-01~e.12 :ARG1 (r / result-01~e.14 :ARG1~e.15 (s / stimulate-01~e.16 :ARG1~e.17 (c / cell :name (n / name :op1 "macrophage"~e.19) :mod (c2 / colon~e.18,44) :ARG0-of (a3 / activate-01~e.22 :ARG1 (e / enzyme :name (n4 / name :op1 "interleukin-1"~e.23,28 :op2 "converting"~e.29 :op3 "enzyme"~e.30)) :ARG1-of (p3 / possible-01~e.21) :ARG0-of (r2 / release-01~e.36 :ARG1 (p4 / protein~e.37 :name (n5 / name :op1 "IL-1"~e.38,40 :op2 "beta"~e.41) :ARG1-of~e.37 (m / mature-02~e.37)) :destination~e.42 (m2 / mucosa :mod (c4 / colon~e.44)))))) :ARG2 (l / level~e.5 :quant-of~e.6 (p2 / protein :name (n2 / name :op1 "IL-1"~e.7,9,25)) :ARG1-of (i / increase-01~e.4))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 20))) :topic (d / disease :name (n3 / name :op1 "inflammatory" :op2 "bowel" :op3 "disease")) :source~e.0 (t / text~e.2 :ARG1-of (f / full-09~e.1))) # ::id bel_pmid_1866_6314.36060 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - Both cytokines ( IL @-@ 12 and IL @-@ 23 ) activate TYK2 and JAK2 as well as STAT1 , STAT3 , STAT4 , and STAT5 [ 60 ] . # ::alignments 0-1.4.r 1-1.4.1 2-1.4 4-1.1.3 5-1.1.1.1 7-1.1.2.1.1.1.1 7-1.1.2.1.2.1.1 9-1.1.2.1.1.1.1 10-1.1.2.1 11-1.1.2.1.1.1.1 11-1.1.2.1.2.1.1 13-1.1.2.1.2.1.1 15-1 16-1.2.1.1.1 17-1.2 18-1.2.2.1.1 19-1.2 20-1.2 21-1.2 21-1.2.r 22-1.2.3.1.1 24-1.2.4.1.1 26-1.2.5.1.1 28-1.2 29-1.2.6.1.1 31-1.3.1.1.1 (a / activate-01~e.15 :ARG0 (p / protein :name (n / name :op1 "cytokine"~e.5) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.10 :op1 (p2 / protein :name (n2 / name :op1 "IL-12"~e.7,9,11)) :op2 (p3 / protein :name (n3 / name :op1 "IL-23"~e.7,11,13)))) :mod (b / both~e.4)) :ARG1~e.21 (a3 / and~e.17,19,20,21,28 :op1 (e / enzyme :name (n4 / name :op1 "TYK2"~e.16)) :op2 (e2 / enzyme :name (n5 / name :op1 "JAK2"~e.18)) :op3 (p5 / protein :name (n6 / name :op1 "STAT1"~e.22)) :op4 (p6 / protein :name (n7 / name :op1 "STAT3"~e.24)) :op5 (p7 / protein :name (n8 / name :op1 "STAT4"~e.26)) :op6 (p8 / protein :name (n9 / name :op1 "STAT5"~e.29))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 60~e.31))) :source~e.0 (t / text~e.2 :ARG1-of (f / full-09~e.1))) # ::id bel_pmid_1866_6314.38544 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - IL @-@ 6 signalling through signal transducer and activator of transcription @- 3 ( STAT3 ) # ::alignments 0-1.3.r 1-1.3.1 2-1.3 4-1.1.1.1 6-1.1.1.1 7-1 8-1.2.r 9-1.2.1.1 10-1.2.1.2 11-1.2.1.3 12-1.2.1.4 13-1.2.1.5 14-1.2.1.6 16-1.2.1.6 18-1.2.2.1.1.1 (s / signal-07~e.7 :ARG0 (p / protein :name (n / name :op1 "IL-6"~e.4,6)) :path~e.8 (p3 / protein :name (n3 / name :op1 "signal"~e.9 :op2 "transducer"~e.10 :op3 "and"~e.11 :op4 "activator"~e.12 :op5 "of"~e.13 :op6 "transcription-3"~e.14,16) :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "STAT3"~e.18)))) :source~e.0 (t / text~e.2 :ARG1-of (f / full-09~e.1))) # ::id bel_pmid_1866_6314.39148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - TNF @-@ alpha exerts its pro @-@ inflammatory effects through increased production of IL @-@ 1 beta and IL @-@ 6 , expression of adhesion molecules , proliferation of fibroblasts and procoagulant factors , as well as initiation of cytotoxic , apoptotic , acute @-@ phase responses , and inhibition of apoptosis [ 8,9 ] . # ::alignments 0-1.5.r 1-1.5.1 2-1.5 4-1.1.1.1 6-1.1.1.1 9-1.2 9-1.3.3.1.2.1 11-1.2.1 12-1 14-1.3.1.2 15-1.3.1 16-1.3.1.1.r 17-1.3.1.1.1.1.1 17-1.3.1.1.2.1.1 21-1.3.1.1 22-1.3.1.1.1.1.1 22-1.3.1.1.2.1.1 24-1.3.1.1.2.1.1 26-1.3.2 27-1.3.2.1.r 28-1.3.2.1.1 29-1.3.2.1 31-1.3.3 32-1.3.3.1.r 33-1.3.3.1.1 34-1.3.3.1 36-1.3.3.1.2 38-1.3.3.1 39-1.3 40-1.3 40-1.3.4.1 40-1.3.r 41-1.3.4 43-1.3.4.1.1.1 45-1.3.4.1.2.1 47-1.3.4.1.3.1.1 49-1.3.4.1.3.1 50-1.3.4.1.1 50-1.3.4.1.2 50-1.3.4.1.3 52-1.3 53-1.3.5 54-1.3.5.1.r 55-1.3.5.1 (a9 / affect-01~e.12 :ARG0 (p / protein :name (n / name :op1 "TNF-alpha"~e.4,6)) :ARG0-of (f2 / favor-01~e.9 :ARG1 (i / inflame-01~e.11)) :manner~e.40 (a / and~e.39,40,52 :op1 (p3 / produce-01~e.15 :ARG1~e.16 (a2 / and~e.21 :op1 (p4 / protein :name (n2 / name :op1 "IL-1beta"~e.17,22)) :op2 (p5 / protein :name (n3 / name :op1 "IL-6"~e.17,22,24))) :ARG1-of (i2 / increase-01~e.14)) :op2 (e3 / express-03~e.26 :ARG2~e.27 (m / molecule~e.29 :ARG0-of (a3 / adhere-01~e.28))) :op3 (p6 / proliferate-01~e.31 :ARG0~e.32 (a4 / and~e.34,38 :op1 (f / fibroblast~e.33) :op2 (f4 / factor~e.36 :ARG0-of (f3 / favor-01~e.9 :ARG1 (c / coagulate-01))))) :op4 (i3 / initiate-01~e.41 :ARG1 (a10 / and~e.40 :op1 (r / respond-01~e.50 :mod (c2 / cytotoxic~e.43)) :op2 (r2 / respond-01~e.50 :mod (a5 / apoptosis~e.45)) :op3 (r3 / respond-01~e.50 :mod (p2 / phase~e.49 :mod (a6 / acute~e.47))))) :op5 (i4 / inhibit-01~e.53 :ARG1~e.54 a5~e.55)) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 (a8 / and :op1 8 :op2 9)))) :source~e.0 (t / text~e.2 :ARG1-of (f5 / full-09~e.1))) # ::id bel_pmid_1866_6314.39746 ::amr-annotator SDL-AMR-09 ::preferred # ::tok from full text - Defective transforming growth factor TGF @-@ beta1 signaling due to high levels of Smad7 is a feature of IBD[55 ] . UC patients have exhibited increased production of TGF @-@ beta1 by LPMC as compared with both CD patients and controls # ::alignments 4-1.1.1.2 5-1.1.1.1.1.1 6-1.1.1.1.1.2 7-1.1.1.1.1.3 8-1.2.2.1.2.1.1 10-1.1.1.1.1.4 10-1.2.2.1.2.1.1 11-1.1.1 12-1.1.1.3 13-1.1.1.3 14-1.1.1.3.1.1 15-1.1.1.3.1 16-1.1.1.3.1.2.r 17-1.1.1.3.1.2.1.1 18-1.1.1.r 20-1.1 26-1.2.1 28-1.2 29-1.2.2 30-1.2.2.1 32-1.2.2.1.2.1.1 34-1.2.2.1.2.1.1 35-1.2.2.1.1.r 36-1.2.2.1.1.1.1 38-1.2.2.2.r 42-1.2.2.2.1 43-1.2.2.2 44-1.2.2.2.2 (m / multi-sentence :snt1 (f / feature~e.20 :domain~e.18 (s2 / signal-07~e.11 :ARG0 (p6 / protein :name (n2 / name :op1 "transforming"~e.5 :op2 "growth"~e.6 :op3 "factor"~e.7 :op4 "beta1"~e.10)) :mod (d / defective~e.4) :ARG1-of (c4 / cause-01~e.12,13 :ARG0 (l / level~e.15 :ARG1-of (h / high-02~e.14) :quant-of~e.16 (p5 / protein :name (n / name :op1 "Smad7"~e.17))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 55))) :poss (d2 / disease :name (n3 / name :op1 "IBD"))) :snt2 (e / exhibit-01~e.28 :ARG0 (p2 / patient~e.26 :mod (d5 / disease :name (n4 / name :op1 "ulcerative" :op2 "colitis"))) :ARG1 (i / increase-01~e.29 :ARG1 (p3 / produce-01~e.30 :ARG0~e.35 (c2 / cell :name (n5 / name :op1 "LPMC"~e.36)) :ARG1 (p7 / protein :name (n6 / name :op1 "TGF-beta1"~e.8,10,32,34))) :compared-to~e.38 (a / and~e.43 :op1 (p4 / patient~e.42 :mod (d4 / disease :name (n7 / name :op1 "coeliac" :op2 "disease"))) :op2 (c3 / control~e.44))))) # ::id bel_pmid_1876_9721.19816 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if XIAP enhanced proinflammatory gene expression in vivo , we performed qRT @-@ PCR analysis on splenic RNA from WT and XIAP knockout mice . RNA was isolated from splenocytes harvested from uninfected animals or animals infected with L. monocytogenes for 48 h ( Figure 6 ) {to activate XIAP}. The expression of il6 and ifng mRNAs were significantly enhanced in the presence of XIAP during infection . # ::alignments 1-1.3.3 2-1.2.3.r 3-1.2.3.1.1.1 3-1.3.3.2.1.1.1 4-1.3.3.2 5-1.3.3.2.2.3 5-1.3.3.2.2.3.1 5-1.3.3.2.2.3.1.r 6-1.3.3.2.2.1 7-1.3.2.3.2.1 7-1.3.3.2.2 8-1.3.3.2.2.2 9-1.3.3.2.2.2 11-1.3.1 13-1.3.4.1.1 15-1.3.4.1.1 16-1.3 17-1.3.2.r 18-1.3.2.2 19-1.3.2.1.1 20-1.3.2.3.r 21-1.3.2.3.1.1 22-1.3.2.3 23-1.3.2.3.2.1.1.1.1 24-1.3.2.3.2.1.1 24-1.3.2.3.2.1.1.2 24-1.3.2.3.2.1.1.2.r 25-1.3.2.3.1 25-1.3.2.3.2 27-1.1.1.1.1 27-1.3.2.1.1 29-1.1 30-1.1.2.r 31-1.1.2.1.1 32-1.1.2.2 33-1.1.2.2.1.r 34-1.1.2.2.1.1.1 34-1.1.2.2.1.1.1.1 34-1.1.2.2.1.1.1.1.r 34-1.1.2.2.1.2.1 35-1.1.2.2.1.1 35-1.1.2.2.1.2 36-1.1.2.2.1 37-1.1.2.2.1.1 37-1.1.2.2.1.2 38-1.1.2.2.1.1.1 38-1.1.2.2.1.2.1 39-1.1.2.2.1.2.1.1.r 39-1.3.4.r 40-1.1.2.2.1.2.1.1.1.1 42-1.1.2.2.1.2.1.2.r 43-1.1.2.2.1.2.1.2.1 44-1.1.2.2.1.2.1.2.2 46-1.1.4.1 47-1.1.4.1.1 50-1.1.3 53-1.2.1 54-1.2.1.1.r 55-1.2.1.1.2.1.1.1.1 56-1.2.1.1.2.1 57-1.2.1.1.2.1.2.1.1 58-1.2.1.1.1.1 60-1.2.2 61-1.2 62-1.3.3.2.2.2 64-1.2.3 66-1.1.3.1.1.1 66-1.2.3.1.1.1 67-1.2.4.r 68-1.2.4 (m / multi-sentence :snt2 (i3 / isolate-01~e.29 :ARG1 (n4 / nucleic-acid :name (n10 / name :op1 "RNA"~e.27)) :source~e.30 (c / cell :name (n7 / name :op1 "splenocyte"~e.31) :ARG1-of (h / harvest-01~e.32 :source~e.33 (o3 / or~e.36 :op1 (a3 / animal~e.35,37 :ARG1-of (i4 / infect-01~e.34,38 :polarity~e.34 -~e.34)) :op2 (a4 / animal~e.35,37 :ARG1-of (i5 / infect-01~e.34,38 :ARG2~e.39 (o / organism :name (n8 / name :op1 "L."~e.40 :op2 "monocytogene")) :duration~e.42 (t2 / temporal-quantity :quant 48~e.43 :unit (h2 / hour~e.44))))))) :purpose (a5 / activate-01~e.50 :ARG1 (p4 / protein :name (n9 / name :op1 "XIAP"~e.66))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.46 :mod 6~e.47))) :snt3 (e3 / enhance-01~e.61 :ARG1 (e4 / express-03~e.53 :ARG1~e.54 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.58) :ARG0-of (e6 / encode-01 :ARG1 (a7 / and~e.56 :op1 (p / protein :name (n6 / name :op1 "IL6"~e.55)) :op2 (p7 / protein :name (n13 / name :op1 "IFNG"~e.57)))))) :ARG3 (s2 / significant-02~e.60) :condition~e.2 (p2 / present-02~e.64 :ARG1 (p5 / protein :name (n12 / name :op1 "XIAP"~e.3,66))) :time~e.67 (i6 / infect-01~e.68)) :snt1 (a / analyze-01~e.16 :ARG0 (w / we~e.11) :ARG1~e.17 (n11 / nucleic-acid :name (n14 / name :op1 "RNA"~e.19,27) :mod (s / spleen~e.18) :source~e.20 (a2 / and~e.22 :op1 (m3 / mouse~e.25 :mod (w2 / wild-type~e.21)) :op2 (m4 / mouse~e.25 :ARG3-of (e5 / express-03~e.7 :ARG2 (p3 / protein~e.24 :name (n5 / name :op1 "XIAP"~e.23) :ARG1-of~e.24 (k / knock-out-03~e.24)))))) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (e / enhance-01~e.4 :ARG0 (p6 / protein :name (n / name :op1 "XIAP"~e.3)) :ARG1 (e2 / express-03~e.7 :ARG1 (g2 / gene~e.6) :manner (i2 / in-vivo~e.8,9,62) :ARG0-of (f / favor-01~e.5 :ARG1~e.5 (i / inflame-01~e.5))))) :instrument~e.39 (t / thing :name (n15 / name :op1 "qRT-PCR"~e.13,15)))) # ::id bel_pmid_1897_5310.25820 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , the hydroxyproline content was significantly reduced in the anti @-@ CD154 mAb @–@ treated group compared with the control IgG– treated group ( Figure 5c ) . # ::alignments 0-1 3-1.1.1.1.1.1 4-1.1.1 6-1.1.2 7-1.1 8-1.1.3.r 10-1.1.3.1.1.1 12-1.1.3.1.1.1.1.1.1 15-1.1.3.1 15-1.1.4.1 16-1.1.3 16-1.1.4 17-1.1.4.r 22-1.1.3.1 23-1.1.3 25-1.2.1 26-1.2.1.1 (a / and~e.0 :op2 (r / reduce-01~e.7 :ARG1 (c / contain-01~e.4 :ARG1 (a2 / amino-acid :name (n / name :op1 "hydroxyproline"~e.3))) :ARG2 (s / significant-02~e.6) :location~e.8 (g / group~e.16,23 :ARG1-of (t / treat-03~e.15,22 :ARG3 (a3 / antibody :ARG0-of (c2 / counter-01~e.10 :ARG1 (p / protein :name (n2 / name :op1 "CD154"~e.12))) :mod (m / monoclone)))) :compared-to~e.17 (g2 / group~e.16 :ARG1-of (t2 / treat-03~e.15 :ARG3 (p2 / protein :name (n3 / name :op1 "IgG"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "5c"~e.26))) # ::id bel_pmid_1897_5310.25824 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the number of BrdU @-@ positive proliferating dermal fibroblasts at 1 week was significantly reduced in the anti @-@ CD154 mAb @–@ treated group compared with the control IgG @–@ treated group # ::alignments 1-1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.3.1.1.1 8-1.1.1.1.3 9-1.1.1.1.2 10-1.1.1.1.1 11-1.1.1.1 13-1.1.5.2.1 14-1.1.5.2.2 16-1.1.2 17-1.1 20-1.1.3.1.1.2 22-1.1.3.1.1.2.1.1.1 25-1.1.3.1 26-1.1.3 26-1.1.4 27-1.1.4.r 30-1.1.4.1 31-1.1.4.2.1.1.1 33-1.1.4.2 34-1.1.4 (c / contrast-01~e.1 :ARG2 (r / reduce-01~e.17 :ARG1 (n / number~e.4 :quant-of~e.5 (f / fibroblast~e.11 :mod (d / dermis~e.10) :ARG0-of (p / proliferate-01~e.9) :mod (p2 / positive~e.8 :mod (s2 / small-molecule :name (n2 / name :op1 "BrdU"~e.6))))) :ARG2 (s / significant-02~e.16) :location (g / group~e.26 :ARG1-of (t2 / treat-03~e.25 :ARG3 (a / antibody :mod (m / monoclonal) :ARG0-of (c3 / counter-01~e.20 :ARG1 (p4 / protein :name (n3 / name :op1 "CD154"~e.22)))))) :compared-to~e.27 (g2 / group~e.26,34 :mod (c2 / control~e.30) :ARG1-of (t3 / treat-03~e.33 :ARG3 (p5 / protein :name (n4 / name :op1 "IgG"~e.31)))) :time (a2 / after :op1 (a3 / and :op1 t2 :op2 t3) :quant (t / temporal-quantity :quant 1~e.13 :unit (w / week~e.14))))) # ::id bel_pmid_1897_5310.25836 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , the anti @-@ CD154 mAb treatment suppressed the up @-@ regulated expression of COL1A1 , RANTES , and MCP @-@ 1 mRNA ( Figure 5g ) . # ::alignments 0-1 1-1 4-1.1.1.1.2 6-1.1.1.1.2.1.1.1 8-1.1.1 9-1.1 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.2.1.1.1.1 18-1.1.2.1.2.1.2.1.1 20-1.1.2.1.2.1 21-1.1.2.1.2.1.3.1.1 23-1.1.2.1.2.1.3.1.1 24-1.1.2.1.1.1 26-1.1.3.1 27-1.1.3.1.1 (a / and~e.0,1 :op2 (s / suppress-01~e.9 :ARG0 (t / treat-04~e.8 :ARG2 (a3 / antibody :mod (m / monoclonal) :ARG0-of (c / counter-01~e.4 :ARG1 (p / protein :name (n / name :op1 "CD154"~e.6))))) :ARG1 (e / express-03~e.14 :ARG1~e.15 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.24) :ARG0-of (e2 / encode-01 :ARG1 (a5 / and~e.20 :op1 (p2 / protein :name (n6 / name :op1 "COL1A1"~e.16)) :op2 (p3 / protein :name (n7 / name :op1 "RANTES"~e.18)) :op3 (p4 / protein :name (n8 / name :op1 "MCP-1"~e.21,23))))) :ARG1-of (u / upregulate-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "5g"~e.27)))) # ::id bel_pmid_1897_5310.36028 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upon stimulation with soluble CD154 , cultured fibroblasts induced to express CD40 by adenoviral gene transfer proliferated and showed up @-@ regulation of the genes for intercellular adhesion molecule 1 , interleukin @-@ 6 ( IL @-@ 6 ) , IL @-@ 8 , monocyte chemoattractant protein 1 ( MCP @-@ 1 ) , and RANTES , as well as up @-@ regulation of their proteins . # ::alignments 1-1.3 2-1.3.2.r 3-1.3.2.2 4-1.3.2.1.1 6-1.1.1.1 7-1.1.1 8-1.1.1.2 10-1.1.1.2.1 11-1.1.1.2.1.1.1.1 12-1.1.1.2.1.3.r 13-1.1.1.2.1.3.1.1 14-1.1.1.2.1.3.1 15-1.1.1.2.1.3 16-1.1 17-1 18-1.2 19-1.2.2.1 20-1.2.2.1 21-1.2.2.1 24-1.2.2.1.1 26-1.2.2.1.1.1.1.1.1.1 27-1.2.2.1.1.1.1.1.1.2 28-1.2.2.1.1.1.1.1.1.3 29-1.2.2.1.1.1.1.1.1.4 31-1.2.2.1.1.1.1.2.1.1 33-1.2.2.1.1.1.1.2.1.1 37-1.2.2.1.1.1.1.2.1.1 44-1.2.2.1.1.1.1.3.1.1 45-1.2.2.1.1.1.1.3.1.2 46-1.2.2.1.1.1.1.3.1.3 54-1.2.2.1.1.1.1 55-1.2.2.1.1.1.1.4.1.1 57-1.2.2 58-1.2.2 59-1.2.2 59-1.2.2.1.1.1.1 60-1.2.2.1 60-1.2.2.2 61-1.2.2.2 62-1.2.2.2 63-1.2.2.2.1.r 64-1.2.2.2.1 65-1.2.2.1.1.1.1.1 65-1.2.2.1.1.1.1.2 65-1.2.2.1.1.1.1.3 65-1.2.2.1.1.1.1.4 (a / and~e.17 :op1 (p / proliferate-01~e.16 :ARG0 (f / fibroblast~e.7 :mod (c / cultured~e.6) :ARG1-of (i / induce-01~e.8 :ARG2 (e / express-03~e.10 :ARG2 (p2 / protein :name (n / name :op1 "CD40"~e.11)) :ARG3 f :manner~e.12 (t / transfer-01~e.15 :ARG1 (g / gene~e.14 :mod (a2 / adenoviral~e.13))))))) :op2 (s3 / show-01~e.18 :ARG0 f :ARG1 (a3 / and~e.57,58,59 :op1 (u / upregulate-01~e.19,20,21,60 :ARG1 (g2 / gene~e.24 :ARG0-of (e2 / encode-01 :ARG1 (a4 / and~e.54,59 :op1 (p4 / protein~e.65 :name (n3 / name :op1 "intercellular"~e.26 :op2 "adhesion"~e.27 :op3 "molecule"~e.28 :op4 1~e.29)) :op2 (p5 / protein~e.65 :name (n4 / name :op1 "interleukin-6"~e.31,33,37)) :op3 (p6 / protein~e.65 :name (n5 / name :op1 "monocyte"~e.44 :op2 "chemoattractant"~e.45 :op3 "protein"~e.46)) :op4 (p7 / protein~e.65 :name (n6 / name :op1 "RANTES"~e.55)))))) :op2 (u2 / upregulate-01~e.60,61,62 :ARG1~e.63 a4~e.64))) :condition (s / stimulate-01~e.1 :ARG1 f :ARG2~e.2 (p3 / protein :name (n2 / name :op1 "CD154"~e.4) :mod (s2 / soluble~e.3)))) # ::id bel_pmid_1903_3457.27030 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with diminished numbers of squamous type I cells in epFoxm1-/- lungs , mRNA levels of T1 @-@ alpha and aquaporin 5 were significantly decreased as demonstrated by quantitative real @-@ time ( RT @-@ PCR ) ( qRT @-@ PCR ) analysis ( Fig . 3B ) . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.2 3-1.4.1 4-1.4.1.1.r 5-1.4.1.1.1.1 6-1.4.1.1.1.2 7-1.4.1.1.1.3 8-1.4.1.1.1.4 11-1.4.1.1.2 13-1.1.1.1.1 14-1.1 16-1.1.1.2.1.1.1.1 18-1.1.1.2.1.1.1.1 19-1.1.1.2.1 20-1.1.1.2.1.2.1.1 21-1.1.1.2.1.2.1.2 23-1.2 24-1 25-1.3.r 26-1.3 27-1.3.1.r 28-1.3.1.1 29-1.3.1.2 31-1.3.1.2 33-1.3.1.3.1.1.1 35-1.3.1.3.1.1.1 40-1.3.1.3.1.1.1 42-1.3.1 44-1.5.1 46-1.5.1.1 (d / decrease-01~e.24 :ARG1 (l / level~e.14 :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.13) :ARG0-of (e / encode-01 :ARG1 (a / and~e.19 :op1 (p / protein :name (n2 / name :op1 "T1-alpha"~e.16,18)) :op2 (p2 / protein :name (n3 / name :op1 "aquaporin"~e.20 :op2 5~e.21)))))) :ARG2 (s / significant-02~e.23) :ARG1-of~e.25 (d2 / demonstrate-01~e.26 :ARG0~e.27 (a2 / analyze-01~e.42 :mod (q / quantity~e.28) :mod (r2 / real-time~e.29,31) :ARG1-of (m / mean-01 :ARG2 (t / thing :name (n5 / name :op1 "RT-PCR"~e.33,35,40))))) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (n7 / number~e.3 :quant-of~e.4 (c2 / cell :name (n6 / name :op1 "squamous"~e.5 :op2 "type"~e.6 :op3 "I"~e.7 :op4 "cell"~e.8) :location (l2 / lung~e.11 :mod (p3 / protein :name (n8 / name :op1 "epFoxm1") :ARG2-of (m3 / mutate-01 :mod "−/−")))) :ARG1-of (d4 / diminish-01~e.2))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.44 :mod "3B"~e.46))) # ::id bel_pmid_1903_3457.27038 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significantly decreased mRNA levels of M @-@ phase @-@ promoting Cdc25B phosphatase ( Fig . 3B ) , a known transcriptional target of Foxm1 ( 15 ) , were observed in the lungs of epFoxm1-/- mice . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.1.1.1 3-1.1.1 5-1.1.1.1.2.1.3.1.1.1 7-1.1.1.1.2.1.3.1.1.1 9-1.1.1.1.2.1.3 10-1.1.1.1.2.1.1.1 11-1.1.1.1.2.1.1.2 13-1.1.3.1 15-1.1.3.1.1 19-1.1.1.1.2.1.2.2 20-1.1.1.1.2.1.2.3 21-1.1.1.1.2.1 21-1.1.1.1.2.1.2 21-1.1.1.1.2.1.2.r 23-1.1.1.1.2.1.2.1.1.1 23-1.2.1.1.1.1 25-1.1.1.1.2.1.2.4.1.1.1 29-1 30-1.2.r 32-1.2 35-1.2.1 (o / observe-01~e.29 :ARG1 (d / decrease-01~e.1 :ARG1 (l / level~e.3 :quant-of (n6 / nucleic-acid :name (n / name :op1 "mRNA"~e.2) :ARG0-of (e / encode-01 :ARG1 (e2 / enzyme~e.21 :name (n4 / name :op1 "Cdc25B"~e.10 :op2 "phosphatase"~e.11) :ARG1-of~e.21 (t / target-01~e.21 :ARG0 (p2 / protein :name (n3 / name :op1 "Foxm1"~e.23)) :ARG1-of (k / know-01~e.19) :purpose (t2 / transcribe-01~e.20) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 15~e.25)))) :ARG0-of (p4 / promote-01~e.9 :ARG1 (e3 / event :name (n7 / name :op1 "M-phase"~e.5,7))))))) :ARG2 (s / significant-02~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.13 :mod "3B"~e.15))) :location~e.30 (l2 / lung~e.32 :part-of (m2 / mouse~e.35 :mod (p3 / protein :name (n5 / name :op1 "Foxm1"~e.23) :ARG2-of (m / mutate-01 :mod "−/−"))))) # ::id bel_pmid_1905_2556.19692 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The authors demonstrate that HMGB1 binds to TLR4 and that HMGB1 , which is released by chemotherapy @-@ induced cell death , can activate TLR4 and induce anti @-@ tumour T @-@ cell immunity79 . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1.2.r 7-1.2.1.2.1.1 10-1.2.1.1.1.1 14-1.2.1.1.2 15-1.2.1.1.2.1.r 16-1.2.1.1.2.1.2.1 18-1.2.1.1.2.1.2 19-1.2.1.1.2.1.1 20-1.2.1.1.2.1 22-1.2.2 23-1.2.2.1.1 24-1.2.2.1.1.2 25-1.2.2.1 26-1.2.2.1.2 27-1.2.2.1.2.2.2 29-1.2.2.1.2.2.2.1 30-1.2.2.1.2.2.1.1.1 32-1.2.2.1.2.2.1.1.1 (d / demonstrate-01~e.2 :ARG0 (p5 / person~e.1 :ARG0-of~e.1 (a / author-01~e.1)) :ARG1~e.3 (a2 / and :op1 (b / bind-01~e.5 :ARG1 (p / protein :name (n / name :op1 "HMGB1"~e.4,10) :ARG1-of (r / release-01~e.14 :ARG0~e.15 (d2 / die-01~e.20 :ARG1 (c / cell~e.19) :ARG2-of (i2 / induce-01~e.18 :ARG0 (c2 / chemotherapy~e.16))))) :ARG2~e.6 (p3 / protein :name (n2 / name :op1 "TLR4"~e.7))) :op2 (p2 / possible-01~e.22 :ARG1 (a3 / and~e.25 :op1 (a4 / activate-01~e.23 :ARG0 p :ARG1 p3~e.24) :op2 (i / induce-01~e.26 :ARG0 p :ARG2 (i3 / immune-02 :ARG1 (c3 / cell :name (n3 / name :op1 "T-cell"~e.30,32)) :ARG0-of (c4 / counter-01~e.27 :ARG1 (t / tumor~e.29))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 79)))) # ::id bel_pmid_1905_2556.29386 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In response to hepatocyte cell death , MyD88 signalling was responsible for the activation of NF-?B and for the production of factors such as IL @-@ 6 ( ReF . 122 ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.1.1.1 4-1.3.1.1 5-1.3.1 7-1.1.1.1.1 8-1.1 10-1 11-1.2.r 13-1.2.1 16-1.2 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1 22-1.2.2.1.1.r 23-1.2.2.1.1.r 24-1.2.2.1.1.1.1 26-1.2.2.1.1.1.1 30-1.4.1.1.1 (r / responsible-01~e.10 :ARG0 (s / signal-07~e.8 :ARG0 (p / protein :name (n / name :op1 "MyD88"~e.7))) :ARG1~e.11 (a / and~e.16 :op1 (a2 / activate-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "NF-kB"))) :op2 (p3 / produce-01~e.19 :ARG1~e.20 (f / factor~e.21 :example~e.22,23 (p4 / protein :name (n3 / name :op1 "IL-6"~e.24,26))))) :ARG2-of (r2 / respond-01~e.1 :ARG1~e.2 (d / die-01~e.5 :ARG1 (c / cell~e.4 :name (n4 / name :op1 "hepatocyte"~e.3)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 122~e.30)))) # ::id bel_pmid_1905_2556.35940 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All TLRs ( except for TLR3 ) and IL @-@ 1 receptor family members signal through MyD88 . # ::alignments 0-1.1.1.2 3-1.1.1 3-1.1.1.3 3-1.1.1.3.r 4-1.1.1.3.1.r 5-1.1.1.3.1.1.1 7-1.1 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 12-1.1.2.1.1 13-1.1.2 14-1 16-1.2.1.1 (s / signal-07~e.14 :ARG0 (a2 / and~e.7 :op1 (p / protein~e.3 :name (n5 / name :op1 "TLR") :mod (a / all~e.0) :ARG2-of~e.3 (e / except-01~e.3 :ARG1~e.4 (p2 / protein :name (n2 / name :op1 "TLR3"~e.5)))) :op2 (m / member~e.13 :ARG1-of (i2 / include-91 :ARG2 (p3 / protein-family~e.12 :name (n3 / name :op1 "IL-1"~e.8,10))))) :manner (p4 / protein :name (n4 / name :op1 "MyD88"~e.16))) # ::id bel_pmid_1905_3174.34990 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We veri ? ed the secretion levels of several SASP proteins by ELISAs ( Figure S1 and Text S1 ) . Further , because secretion increased greater than 10 @-@ fold for some SASP factors , we could verify up @-@ regulation by intracellular immunostaining . For example , IL @-@ 6 and IL @-@ 8 were barely visible in PRE cells but clearly detectable in SEN cells ( Figure 1B , Figure S2 , and Text S1 ) . # ::alignments 0-1.1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.1.1.r 8-1.1.2.1.1.1 9-1.1.2.1.1.2.1.1 10-1.1.2.1.1 14-1.1.4.1.1 15-1.1.4.1.1.1 16-1.1.4.1 17-1.1.4.1.2 18-1.1.4.1.2.1 21-1.2.2 23-1.2.1.3 24-1.2.1.3.1.1 25-1.2.1.3.1 27-1.2.1.3.1.2 28-1.2.1.3.1.2.1.1 30-1.2.1.3.1.2.1 31-1.2.1.3.1.1.1.r 32-1.2.1.3.1.1.1.2 33-1.2.1.3.1.1.1.1.1.1 34-1.2.1.3.1.1.1 36-1.2.1.1 37-1.2 37-1.3.1.1 37-1.3.1.2 38-1.1 38-1.2.1 39-1.2.1.2 40-1.2.1.2 41-1.2.1.2 42-1.2.1.4.r 43-1.2.1.4.1 44-1.2.1.4 46-1.3 47-1.3 49-1.3.1.1.1.1.1.1.1 49-1.3.1.1.1.1.2.1.1 51-1.3.1.1.1.1.1.1.1 52-1.3.1.1.1.1 53-1.3.1.1.1.1.1.1.1 53-1.3.1.1.1.1.2.1.1 55-1.3.1.1.1.1.2.1.1 57-1.3.1.1.1.2 58-1.3.1.1.1 61-1.3.1.1.1.3 62-1.3.1 63-1.3.1.2.1.2 64-1.3.1.2.1 67-1.3.1.2.1.3 69-1.3.2.1.1 70-1.3.2.1.1.1 72-1.3.2.1.2 73-1.3.2.1.2.1 75-1.3.2.1 76-1.3.2.1.3 77-1.3.2.1.3.1 (m / multi-sentence :snt1 (v / verify-01~e.38 :ARG0 (w / we~e.0) :ARG1 (l / level~e.6 :degree-of (s / secrete-01~e.5 :ARG1~e.7 (p / protein~e.10 :quant (s2 / several~e.8) :mod (t5 / thing :name (n2 / name :op1 "SASP"~e.9))))) :instrument (t / thing :name (n / name :op1 "ELISA")) :ARG1-of (d / describe-01 :ARG0 (a / and~e.16 :op1 (f / figure~e.14 :mod "S1"~e.15) :op2 (t2 / text~e.17 :mod "S1"~e.18)))) :snt2 (p2 / possible-01~e.37 :ARG1 (v2 / verify-01~e.38 :ARG0 (w2 / we~e.36) :ARG1 (u / upregulate-01~e.39,40,41) :ARG1-of (c / cause-01~e.23 :ARG0 (i / increase-01~e.25 :ARG1 (s3 / secrete-01~e.24 :ARG1~e.31 (f2 / factor~e.34 :mod (t3 / thing :name (n3 / name :op1 "SASP"~e.33)) :mod (s4 / some~e.32))) :ARG2 (m2 / more-than~e.27 :mod (p4 / product-of~e.30 :op1 10~e.28)))) :manner~e.42 (i2 / immunostain-01~e.44 :manner (i3 / intracellular~e.43))) :mod (f5 / further~e.21)) :snt3 (e / exemplify-01~e.46,47 :ARG0 (c2 / contrast-01~e.62 :ARG1 (p5 / possible-01~e.37 :ARG1 (s5 / see-01~e.58 :ARG1 (a2 / and~e.52 :op1 (p6 / protein :name (n5 / name :op1 "IL-6"~e.49,51,53)) :op2 (p7 / protein :name (n6 / name :op1 "IL-8"~e.49,53,55))) :degree (b / bare~e.57) :location (c3 / cell~e.61 :mod (p8 / presenescent)))) :ARG2 (p9 / possible-01~e.37 :ARG1 (d2 / detect-01~e.64 :ARG1 a2 :ARG1-of (c4 / clear-06~e.63) :location (c5 / cell~e.67 :mod (s6 / senescent))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.75 :op1 (f3 / figure~e.69 :mod "1B"~e.70) :op2 (f4 / figure~e.72 :mod "S2"~e.73) :op3 (t4 / text~e.76 :mod "S1"~e.77))))) # ::id bel_pmid_1905_3174.35034 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SASP components included inflammatory and immune @-@ modulatory cytokines and chemokines ( e.g . , IL @-@ 6 , ?7 , and ?8 , MCP @-@ 2 , and MIP @-@ 3a ) . They also included growth factors ( e.g . , GRO , HGF , and IGFBPs ) , shed cell surface molecules ( e.g . , ICAMs , uPAR , and TNF receptors ) , and survival factors ( Figure 1A and Table S2 ) # ::alignments 0-1.1.2.1.1.1 1-1.1.2 2-1.1 3-1.1.1.3 4-1.1.1 5-1.1.1.4.1 8-1.1.1.1 8-1.1.1.5.1 8-1.1.1.5.2 9-1.1.1 9-1.1.1.5 9-1.1.1.5.r 10-1.1.1.2 10-1.1.1.5.3 10-1.1.1.5.4 10-1.1.1.5.5 15-1.1.1.5.1.1.1 15-1.1.1.5.2.1.1 15-1.1.1.5.3.1.1 17-1.1.1.5.1.1.1 21-1.1.1.5 24-1.1.1.5.4.1.1 26-1.1.1.5.4.1.1 29-1.1.1.5.5.1.1 31-1.1.1.5.5.1.1 34-1.2.2 35-1.2.3 36-1.2 37-1.2.1.1 38-1.2.1.1 43-1.2.1.1.1.1.1.1 45-1.2.1.1.1.2.1.1 47-1.2.1.2.3 51-1.2.1.2.2.1 52-1.2.1.2.2 53-1.2.1.2.1 54-1.2.1.2 61-1.2.1.2.3.2.1.1 64-1.2.1.2.3.3.1.1 65-1.2.1.2.3.3.1.2 68-1.2.1 68-1.2.1.1.1 69-1.2.1.3.1 70-1.2.1.1 70-1.2.1.1.1.1 70-1.2.1.1.1.2 70-1.2.1.1.1.3 70-1.2.1.3 72-1.3.1.1 73-1.3.1.1.1 74-1.3.1 75-1.3.1.2 76-1.3.1.2.1 (m / multi-sentence :snt1 (i / include-01~e.2 :ARG1 (a / and~e.4,9 :op1 (c2 / cytokine~e.8) :op2 (c3 / chemokine~e.10) :ARG0-of (i4 / inflame-01~e.3) :ARG0-of (m2 / modulate-01 :ARG1-of (i2 / immune-02~e.5)) :example~e.9 (a2 / and~e.9,21 :op1 (c4 / cytokine~e.8 :name (n2 / name :op1 "IL-6"~e.15,17)) :op2 (c5 / cytokine~e.8 :name (n3 / name :op1 "IL-7"~e.15)) :op3 (c6 / chemokine~e.10 :name (n4 / name :op1 "IL-8"~e.15)) :op4 (c7 / chemokine~e.10 :name (n5 / name :op1 "MCP-2"~e.24,26)) :op5 (c8 / chemokine~e.10 :name (n6 / name :op1 "MIP-3a"~e.29,31)))) :ARG2 (c / component~e.1 :mod (t / thing :name (n / name :op1 "SASP"~e.0)))) :snt2 (i3 / include-01~e.36 :ARG1 (a3 / and~e.68 :op1 (g / growth-factor~e.37,38,70 :example (a4 / and~e.68 :op1 (g2 / growth-factor~e.70 :name (n7 / name :op1 "GRO"~e.43)) :op2 (g3 / growth-factor~e.70 :name (n8 / name :op1 "HGF"~e.45)) :op3 (g4 / growth-factor~e.70 :name (n9 / name :op1 "IGFBP")))) :op2 (m3 / molecule~e.54 :mod (s / surface~e.53) :source (c9 / cell~e.52 :ARG1-of (s2 / shed-01~e.51)) :example (a5 / and~e.47 :op1 (p / protein :name (n10 / name :op1 "ICAM")) :op2 (p3 / protein :name (n11 / name :op1 "uPAR"~e.61)) :op3 (p2 / protein :name (n12 / name :op1 "TNF"~e.64 :op2 "receptor"~e.65)))) :op3 (f2 / factor~e.70 :mod (s3 / survive-01~e.69))) :ARG2 (t2 / they~e.34) :mod (a6 / also~e.35)) :ARG1-of (d / describe-01 :ARG0 (a7 / and~e.74 :op1 (f3 / figure~e.72 :mod "1A"~e.73) :op2 (t3 / table~e.75 :mod "S2"~e.76)))) # ::id bel_pmid_1917_3740.18146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hypoxia exposure of IL @-@ 6+/+ mice led to marked increases in IL @-@ 6 mRNA and protein levels within the first week , with positive IL @-@ 6 immunostaining in the pulmonary vessel walls ... In vitro studies of cultured human pulmonary @-@ artery smooth @-@ muscle @-@ cells ( PA @-@ SMCs ) and microvascular endothelial cells revealed prominent synthesis of IL @-@ 6 by PA @-@ SMCs , with further stimulation by hypoxia . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.2 10-1.1.2 11-1.2.1.2 12-1.1.1.1.1.1.1 12-1.1.2.1.1.1.2.1.1.1 12-1.2.2.2.1.1 14-1.1.1.1.1.1.1 14-1.1.2.1.1.1.2.1.1.1 14-1.2.2.2.1.1 15-1.1.2.1.1.1.1.1 16-1.1.2.1 17-1.1.1.1.1 17-1.1.2.1.1.1.2.1 17-1.2.2.2 18-1.1.2.1.1 18-1.1.2.1.2 19-1.1.2.1.1.1.r 19-1.1.2.1.2.1.r 21-1.1.2.3.1 21-1.1.2.3.1.1 21-1.1.2.3.1.1.r 22-1.1.2.3 24-1.1.3.r 25-1.1.3.3 26-1.1.1.1.1.1.1 28-1.1.1.1.1.1.1 29-1.1.3 30-1.1.3.1.r 30-1.2.1.2 32-1.1.3.1.1.1 33-1.1.3.1.1 34-1.1.3.1 36-1.2.1.2 37-1.2.1.2 38-1.2.1 39-1.2.1.1.r 40-1.2.1.1.1.4 41-1.2.1.1.1.3 42-1.1.3.1.1.1 44-1.2.1.1.1.2 45-1.2.1.1.1.1.1 49-1.2.1.1.1 55-1.2.1.1 56-1.2.1.1.2.1.1 57-1.2.1.1.2.1 58-1.2.1.1.1 58-1.2.1.1.2 59-1.2 60-1.2.2.3 61-1.2.2 63-1.1.1.1.1.1.1 63-1.2.2.2.1.1 65-1.1.1.1.1.1.1 65-1.2.2.2.1.1 71-1.1.3.r 71-1.2.2.4.r 72-1.2.2.4.2 73-1.2.2.4 74-1.2.2.4.1.r 75-1.2.2.4.1 (m / multi-sentence :snt1 (l / lead-03~e.7 :ARG0 (e / expose-01~e.1 :ARG1~e.2 (m2 / mouse~e.6 :mod (p / protein~e.17 :name (n / name :op1 "IL-6"~e.3,12,14,26,28,63,65) :mod (w / wild-type))) :ARG2 (h / hypoxia~e.0)) :ARG2~e.8 (i / increase-01~e.10 :ARG1 (a / and~e.16 :op1 (l2 / level~e.18 :quant-of~e.19 (n7 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.15) :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein~e.17 :name (n3 / name :op1 "IL-6"~e.12,14))))) :op2 (l3 / level~e.18 :quant-of~e.19 p2)) :ARG1-of (m3 / mark-01~e.9) :time (w2 / week~e.22 :ord (o / ordinal-entity~e.21 :value~e.21 1~e.21))) :accompanier~e.24,71 (i2 / immunostain-01~e.29 :ARG1~e.30 (w3 / wall~e.34 :mod (v / vessel~e.33 :mod (p4 / pulmonary~e.32,42))) :ARG3 p2 :mod (p3 / positive~e.25))) :snt2 (r2 / reveal-01~e.59 :ARG0 (s / study-01~e.38 :ARG1~e.39 (a2 / and~e.55 :op1 (c4 / cell~e.49,58 :mod (m4 / mucle :ARG1-of (s4 / smooth-06~e.45)) :mod (a3 / artery~e.44 :mod (l4 / lung)) :mod (h3 / human~e.41) :ARG1-of (c2 / culture-01~e.40)) :op2 (c5 / cell~e.58 :mod (e3 / endothelium~e.57 :mod (m5 / microvascular~e.56)))) :manner (i3 / in-vitro~e.11,30,36,37)) :ARG1 (s2 / synthesize-01~e.61 :ARG0 c4 :ARG1 (p5 / protein~e.17 :name (n6 / name :op1 "IL-6"~e.12,14,63,65)) :mod (p6 / prominent~e.60) :ARG1-of~e.71 (s3 / stimulate-01~e.73 :ARG0~e.74 (h2 / hypoxia~e.75) :mod (f / further~e.72))))) # ::id bel_pmid_1922_8664.9182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In CIA synoviocytes , IL @-@ 17 increased the expression of TLR @-@ 2 , 4 , and 9 , and this effect was significantly alleviated by neutralizing antibodies to IL @-@ 17 , IL @-@ 1 beta , and IL @-@ 6 . # ::alignments 4-1.2.2 5-1.2.2 6-1.2.2 7-1.2.2 8-1.2.2 9-1.2.2 10-1.2.2 11-1.2.2 12-1.2.2 13-1.2.2 14-1.2.2 15-1.2.2 16-1.2.2 17-1.2.2 18-1.2.2 20-1 24-1.2.3 25-1.2 26-1.2.1.r 27-1.2.1 28-1.2.1.1.1 28-1.2.1.1.2 28-1.2.1.1.3 30-1.1.1.1.1 30-1.2.1.1.2.1.1.1.1 30-1.2.1.1.3.1.1.1.1 32-1.1.1.1.1 34-1.1.1.1.1 34-1.2.1.1.2.1.1.1.1 34-1.2.1.1.3.1.1.1.1 39-1.2.1.1 40-1.2.1.1.2.1.1.1.1 40-1.2.1.1.3.1.1.1.1 42-1.2.1.1.3.1.1.1.1 (a / and~e.20 :op1 (i / increase-01 :ARG0 (p / protein :name (n / name :op1 "IL-17"~e.30,32,34)) :ARG1 (e / express-03 :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "TLR-2")) :op2 (p3 / protein :name (n3 / name :op1 "TLR-4")) :op3 (p4 / protein :name (n4 / name :op1 "TLR-9")))) :location (c5 / cell :name (n9 / name :op1 "synoviocyte") :mod (d / disease :name (n10 / name :op1 "collagen-induced" :op2 "arthritis")))) :op2 (a3 / alleviate-01~e.25 :ARG0~e.26 (n6 / neutralize-01~e.27 :ARG0 (a4 / and~e.39 :op1 (a5 / antibody~e.28 :ARG0-of (c2 / counter-01 :ARG1 p)) :op2 (a6 / antibody~e.28 :ARG0-of (c3 / counter-01 :ARG1 (p5 / protein :name (n7 / name :op1 "IL-1beta"~e.30,34,40)))) :op3 (a7 / antibody~e.28 :ARG0-of (c4 / counter-01 :ARG1 (p6 / protein :name (n8 / name :op1 "IL-6"~e.30,34,40,42)))))) :ARG1 i~e.4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 :ARG1-of (s2 / significant-02~e.24))) # ::id bel_pmid_1923_8385.18998 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CX3CR1 may also be of importance as it confers a survival signal , which prevents cell death of monocytes and foam cells [ 52 ] . # ::alignments 0-1.1.1.1.1 1-1 2-1.1.2 3-1.1.1.r 5-1.1 7-1.2.1.1 8-1.2.1 10-1.2.1.2.1 11-1.2.1.2 14-1.2.1.2.2 15-1.2.1.2.2.1.1.2 16-1.2.1.2.2.1 17-1.2.1.2.2.1.1.r 18-1.2.1.2.2.1.1.1 19-1.2.1.2.2.1.1 20-1.2.1.2.2.1.1.2.1 21-1.2.1.2.2.1.1.2 23-1.3.1.1.1 (p / possible-01~e.1 :ARG1 (i / important~e.5 :domain~e.3 (p2 / protein :name (n / name :op1 "CX3CR1"~e.0)) :mod (a2 / also~e.2)) :ARG1-of (c / cause-01 :ARG0 (c2 / confer-02~e.8 :ARG0 p2~e.7 :ARG1 (s / signal~e.11 :mod (s2 / survive-01~e.10) :ARG0-of (p3 / prevent-01~e.14 :ARG1 (d / die-01~e.16 :ARG1~e.17 (a / and~e.19 :op1 (m / monocyte~e.18) :op2 (c3 / cell~e.15,21 :mod (f / foam~e.20)))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 52~e.23)))) # ::id bel_pmid_1923_8385.27652 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The same group demonstrated just recently that mast cells actively participate in the formation of aortic aneurysms by release of IL @-@ 6 and IFN ? , which induced apoptosis of smooth muscle cells and protease expression [ 111 ] . # ::alignments 1-1.1.1 2-1.1 3-1 4-1.3.1 5-1.3 6-1.2.r 7-1.2.1.1 8-1.2.1 9-1.2.3 10-1.2 11-1.2.2.r 13-1.2.2 16-1.2.2.1 17-1.2.4.r 18-1.2.4 19-1.2.4.1.r 20-1.2.4.1.1.1.1 22-1.2.4.1.1.1.1 23-1.2.4.1 24-1.2.4.1.2.1.1 28-1.2.4.1.3 29-1.2.4.1.3.1.1 30-1.2.4.1.3.1.1.1.r 31-1.2.4.1.3.1.1.1.1.1 32-1.2.4.1.3.1.1.1.1 33-1.2.4.1.3.1.1.1 34-1.2.4.1.3.1 35-1.2.4.1.3.1.2.1.1.1 36-1.2.4.1.3.1.2 38-1.4.1.1.1 (d / demonstrate-01~e.3 :ARG0 (g / group~e.2 :ARG1-of (s / same-01~e.1)) :ARG1~e.6 (p / participate-01~e.10 :ARG0 (c / cell~e.8 :mod (m / mast~e.7)) :ARG1~e.11 (f / form-01~e.13 :ARG1 (a2 / aneurysm~e.16 :mod (a3 / aorta))) :ARG1-of (a / activity-06~e.9 :ARG0 c) :manner~e.17 (r / release-01~e.18 :ARG1~e.19 (a4 / and~e.23 :op1 (p2 / protein :name (n / name :op1 "IL-6"~e.20,22)) :op2 (p3 / protein :name (n2 / name :op1 "IFN-γ"~e.24)) :ARG0-of (i / induce-01~e.28 :ARG2 (a6 / and~e.34 :op1 (a5 / apoptosis~e.29 :mod~e.30 (c2 / cell~e.33 :part-of (m2 / muscle~e.32 :ARG1-of (s2 / smooth-06~e.31)))) :op2 (e / express-03~e.36 :ARG2 (e2 / enzyme :name (n3 / name :op1 "protease"~e.35)))))))) :time (r2 / recent~e.5 :mod (j / just~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 111~e.38)))) # ::id bel_pmid_1927_3391.16158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several receptor tyrosine kinases exhibit stimulated activity upon peroxynitrite exposure , triggering downstream phosphotyrosine @-@ dependent signalling , as shown for the platelet @-@ derived growth factor receptor ( PDGFR ) and the receptor for brain @-@ derived neurotrophic factor ( TrkB ) in murine fibroblasts ( 24,25 ) , as well as the Epidermal Growth Factor Receptor ( EGFR ) in rat lung myofibroblasts ( 26 ) . # ::alignments 0-1.1.2 1-1.1.1.1 2-1.1.3.1.2.1.1.1 3-1.1.1.3 4-1 5-1.2.1 6-1.2 8-1.3.1.1.1 9-1.3 11-1.1.3 12-1.1.3.1.1 15-1.1.3.1.2 16-1.1.3.1 19-1.1.3.2 19-1.1.3.3 20-1.1.3.2.1.r 22-1.1.3.2.1.1.1.1 24-1.1.3.2.1.1.1.1 24-1.1.3.2.1.2.1.1 25-1.1.3.2.1.1.1.2 26-1.1.3.2.1.1.1.3 26-1.1.3.2.1.2.1.3 27-1.1.3.2.1.1.1.4 27-1.1.3.2.1.2.1.4 31-1.1.3.2.1 33-1.1.3.2.1.1.1.4 33-1.1.3.2.1.2.1.4 35-1.1.3.2.1.2.1.1 37-1.1.3.2.1.1.1.1 37-1.1.3.2.1.2.1.1 43-1.1.3.2.2.r 44-1.1.3.2.2.1.1.1 45-1.1.3.2.2 50-1.1.3.2.1 50-1.1.3.2.3.1.1.1 51-1.1.3.2.1 51-1.1.3.2.3.1.1.1 52-1.1.3.2.1 52-1.1.3.2.3.1.1.1 52-1.1.3.3.1.r 54-1.1.3.3.1.1.1 55-1.1.3.3.1.1.2 56-1.1.3.3.1.1.3 57-1.1.3.3.1.1.4 62-1.1.3.3.2.1.1 63-1.1.3.3.2.1 66-1.1.3.3.3.1.1.1 (e2 / exhibit-01~e.4 :ARG0 (p / protein :name (n3 / name :op1 "receptor"~e.1 :op2 "tyrosine" :op3 "kinase"~e.3) :quant (s2 / several~e.0) :ARG0-of (t / trigger-01~e.11 :ARG1 (s / signal-07~e.16 :location (d / downstream~e.12) :ARG0-of (d2 / depend-01~e.15 :ARG1 (a2 / amino-acid :name (n5 / name :op1 "tyrosine"~e.2) :ARG3-of (p2 / phosphorylate-01)))) :ARG1-of (s6 / show-01~e.19 :topic~e.20 (a3 / and~e.31,50,51,52 :op1 (p3 / protein :name (n6 / name :op1 "platelet-derived"~e.22,24,37 :op2 "growth"~e.25 :op3 "factor"~e.26 :op4 "receptor"~e.27,33)) :op2 (p4 / protein :name (n7 / name :op1 "brain-derived"~e.24,35,37 :op2 "neutrophic" :op3 "factor"~e.26 :op4 "receptor"~e.27,33))) :location~e.43 (f / fibroblast~e.45 :part-of (o / organism :name (n8 / name :op1 "Muridae"~e.44))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a5 / and~e.50,51,52 :op1 24 :op2 25))))) :ARG1-of (s7 / show-01~e.19 :topic~e.52 (e / enzyme :name (n9 / name :op1 "Epidermal"~e.54 :op2 "Growth"~e.55 :op3 "Factor"~e.56 :op4 "Receptor"~e.57)) :location (m / myofibroblast :source (l / lung~e.63 :part-of (r / rat~e.62))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 26~e.66)))))) :ARG1 (a / activity-06~e.6 :ARG1-of (s3 / stimulate-01~e.5)) :condition (e3 / expose-01~e.9 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "peroxynitrite"~e.8)))) # ::id bel_pmid_1927_3391.16160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Peroxynitrite @-@ mediated JNK activation has been associated with apoptotic cell death in murine alveolar C10 cells , in which JNK was activated upon the oxidation of the death receptor Fas . # ::alignments 0-1.1.2.1.1.1 2-1.1.2 3-1.1.1.1.1 4-1.1 7-1 8-1.2.r 9-1.2.2 10-1.2.1 11-1.2 12-1.3.r 13-1.3.3.1.1 14-1.3.2 15-1.3.1.1 16-1.3 20-1.3.4.1 22-1.3.4 28-1.3.4.2.1.1.1 29-1.3.4.2.1.1.2 30-1.3.4.2.1.1.3 (a / associate-01~e.7 :ARG1 (a2 / activate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "JNK"~e.3)) :ARG1-of (m / mediate-01~e.2 :ARG0 (s / small-molecule :name (n2 / name :op1 "peroxynitrite"~e.0)))) :ARG2~e.8 (d / die-01~e.11 :ARG1 (c / cell~e.10) :mod (a3 / apoptosis~e.9)) :location~e.12 (c2 / cell-line~e.16 :name (n3 / name :op1 "C10"~e.15) :mod (a4 / alveolus~e.14) :part-of (o2 / organism :name (n4 / name :op1 "Muridae"~e.13)) :location-of (a6 / activate-01~e.22 :ARG1 e~e.20 :condition (o / oxidize-01 :ARG1 (p / protein :name (n6 / name :op1 "death"~e.28 :op2 "receptor"~e.29 :op3 "Fas"~e.30)))))) # ::id bel_pmid_1927_3391.16162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nomiyama et al , who reported that peroxynitrite inhibited insulin @-@ stimulated glucose uptake in preadipocyte @-@ derived 3T3 @-@ L1 cells by reducing insulin receptor substrate @-@ 1 ( IRS @-@ 1 ) protein levels and associated PI3K activity , upstream of Akt @/@ PKB ( 122 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1 5-1 6-1.2.r 7-1.2.1.1.1 8-1.2 9-1.2.2.2.1.1.1 11-1.2.2.2 12-1.2.2.1.1.1 14-1.2.3.r 15-1.2.3.2.1 17-1.2.3.2 18-1.2.3.1.1 20-1.2.3.1.1 21-1.2.3 22-1.2.4.r 23-1.2.4 24-1.2.4.2.1.1.1.1 25-1.2.4.2.1.1.1.2 26-1.2.4.2.1.1.1.3 28-1.2.4.2.1.1.1.3 32-1.2.4.2.1.1.1.3 34-1.2.2.2.1 34-1.2.4.2.1.1 35-1.2.4.2.1 36-1.2.4.2 37-1.2.4.2.2.2 38-1.2.4.2.2.1.1.1 39-1.2.4.2.2 41-1.2.4.3.2 43-1.2.4.3.1.1.1 45-1.2.4.3.1.1.1 47-1.3.1.1.1 (r / report-01~e.5 :ARG0 (a / and~e.1 :op1 (p2 / person :name (n2 / name :op1 "Nomiyama"~e.0)) :op2 (p / person :mod (o2 / other~e.2))) :ARG1~e.6 (i / inhibit-01~e.8 :ARG0 (s / small-molecule :name (n3 / name :op1 "peroxynitrite"~e.7)) :ARG1 (t / take-up-13 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "glucose"~e.12)) :ARG1-of (s3 / stimulate-01~e.11 :ARG0 (p7 / protein~e.34 :name (n5 / name :op1 "insulin"~e.9)))) :location~e.14 (c / cell-line~e.21 :name (n6 / name :op1 "3T3-L1"~e.18,20) :ARG1-of (d / derive-01~e.17 :ARG2 (p3 / preadipocyte~e.15))) :manner~e.22 (r2 / reduce-01~e.23 :ARG0 s :ARG1 (a2 / and~e.36 :op1 (l / level~e.35 :quant-of (p4 / protein~e.34 :name (n7 / name :op1 "insulin"~e.24 :op2 "receptor"~e.25 :op3 "substrate-1"~e.26,28,32))) :op2 (a3 / activity-06~e.39 :ARG0 (e / enzyme :name (n8 / name :op1 "PI3K"~e.38)) :ARG1-of (a4 / associate-01~e.37))) :location (r3 / relative-position :op1 (p5 / pathway :name (n9 / name :op1 "Akt/PKB"~e.43,45)) :direction (u2 / upstream~e.41)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 122~e.47)))) # ::id bel_pmid_1927_3391.30174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Administration of PTEN @-@ specific siRNA reversed PKB @/@ Akt inhibition and mitigated apoptosis in diabetic mouse aortas . These findings therefore suggest that hyperglycaemia may promote apoptosis in endothelial cells through PKB @/@ Akt downregulation , via a peroxynitrite @-@ mediated , LKB1 @-@ dependent PTEN activation ( 46 ) . # ::alignments 0-1.1.1.1 1-1.1.1.1.1.r 2-1.1.1.1.1.2.1.1.1 4-1.1.1.1.1 4-1.1.1.1.1.2 4-1.1.1.1.1.2.r 5-1.1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1.1 9-1.1.1.2.1.1.1 10-1.1.1.2 11-1.1 12-1.1.2 13-1.1.2.2 15-1.1.3.1.1 16-1.1.3.1 17-1.1.3 19-1.2.1.1.2 20-1.2.1.1 20-1.2.1.1.1 20-1.2.1.1.1.r 21-1.2 22-1.2.1 23-1.2.1.2.r 24-1.2.1.2.1.1 25-1.2.1.2 26-1.2.1.2.1 27-1.2.1.2.1.2 28-1.2.1.2.1.3.r 29-1.2.1.2.1.3.1 30-1.2.1.2.1.3 32-1.2.1.2.1.4.1.1.1 34-1.2.1.2.1.4.1.1.1 35-1.2.1.2.1.4 39-1.2.1.2.1.4.2.2.1.1.1 41-1.2.1.2.1.4.2.2 43-1.2.1.2.1.4.2.3.1.1.1 45-1.2.1.2.1.4.2.3 46-1.2.1.2.1.4.2.1.1.1 47-1.2.1.2.1.4.2 49-1.2.2.1.1.1 (m / multi-sentence :snt1 (a2 / and~e.11 :op1 (r / reverse-01~e.6 :ARG0 (a3 / administer-01~e.0 :ARG1~e.1 (n8 / nucleic-acid~e.4 :name (n / name :op1 "siRNA"~e.5) :ARG1-of~e.4 (s / specific-02~e.4 :ARG2 (p / protein :name (n2 / name :op1 "PTEN"~e.2))))) :ARG1 (i / inhibit-01~e.10 :ARG1 (p2 / pathway :name (n3 / name :op1 "PKB/Akt"~e.7,9)))) :op2 (m2 / mitigate-01~e.12 :ARG0 a3 :ARG1 (a4 / apoptosis~e.13)) :location (a5 / aorta~e.17 :part-of (m3 / mouse~e.16 :mod (d2 / diabetes~e.15)))) :snt2 (i2 / infer-01~e.21 :ARG1 (s2 / suggest-01~e.22 :ARG0 (t2 / thing~e.20 :ARG1-of~e.20 (f / find-01~e.20) :mod (t / this~e.19)) :ARG1~e.23 (p3 / possible-01~e.25 :ARG1 (p4 / promote-01~e.26 :ARG0 (h / hyperglycaemia~e.24) :ARG1 (a6 / apoptosis~e.27) :location~e.28 (c / cell~e.30 :mod (e / endothelium~e.29)) :manner (d3 / downregulate-01~e.35 :ARG1 (p5 / pathway :name (n4 / name :op1 "PKB/Akt"~e.32,34)) :manner (a7 / activate-01~e.47 :ARG1 (p6 / protein :name (n5 / name :op1 "PTEN"~e.46)) :ARG1-of (m4 / mediate-01~e.41 :ARG0 (s3 / small-molecule :name (n7 / name :op1 "peroxynitrite"~e.39))) :ARG0-of (d4 / depend-01~e.45 :ARG1 (e2 / enzyme :name (n6 / name :op1 "LKB1"~e.43)))))))) :ARG1-of (d5 / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 46~e.49))))) # ::id bel_pmid_1927_3391.36758 ::amr-annotator SDL-AMR-09 ::preferred # ::tok activation of ERK depended on EGFR , Src tyrosine kinase and calcium calmodulin in PC12 cells ( 31 ) , while requiring ras @/@ Raf @-@ 1/MEK activation in human neutrophils ( 58 ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1 7-1.1.2.2.1.1 8-1.1.2.2 9-1.1.2.2 10-1.1.2 11-1.1.2.3.1.1 12-1.1.2.3.1.2 13-1.1.3.r 14-1.1.3.1.1 15-1.1.3 17-1.1.4.1.1.1 20-1 21-1.2 22-1.2.2.1.1.1 24-1.2.2.1.1.1 27-1.2.2 28-1.2.3.r 29-1.2.3.1 30-1.2.3 32-1.2.4.1.1.1 (c / contrast-01~e.20 :ARG1 (d / depend-01~e.3 :ARG0 (a / activate-01~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "ERK"~e.2))) :ARG1~e.4 (a2 / and~e.10 :op1 (e2 / enzyme :name (n2 / name :op1 "EGFR"~e.5)) :op2 (t / tyrosine-kinase~e.8,9 :name (n3 / name :op1 "Src"~e.7)) :op3 (p / protein :name (n4 / name :op1 "calcium"~e.11 :op2 "calmodulin"~e.12))) :location~e.13 (c2 / cell-line~e.15 :name (n5 / name :op1 "PC12"~e.14)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 31~e.17)))) :ARG2 (r / require-01~e.21 :ARG0 a :ARG1 (a3 / activate-01~e.27 :ARG1 (p2 / pathway :name (n6 / name :op1 "ras/Raf-1/MEK"~e.22,24))) :location~e.28 (n7 / neutrophil~e.30 :mod (h / human~e.29)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 58~e.32))))) # ::id bel_pmid_1927_3391.37186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok we reported in H9C2 cardiomyocytes that peroxynitritemediated activation of ERK , although dependent on Raf @-@ 1 and MEK , was not due to upstream activation of p21 ras ( 63 ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.3.3.1.1.1 7-1.2.3 9-1.2.3.1.1.1 11-1.2.4.r 12-1.2.4 13-1.2.4.2.r 14-1.2.4.2.1.1.1 16-1.2.4.2.1.1.1 17-1.2.4.2 18-1.2.4.2.2.1.1 21-1.2.1 21-1.2.1.r 22-1.2 23-1.2 24-1.2.2.2 25-1.2.2 25-1.2.3 30-1.3.1.1.1 (r / report-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (c3 / cause-01~e.22,23 :polarity~e.21 -~e.21 :ARG0 (a3 / activate-01~e.25 :ARG1 (p2 / protein :name (n7 / name :op1 "p21ras")) :location (u / upstream~e.24)) :ARG1 (a / activate-01~e.7,25 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.9)) :ARG1-of (m / mediate-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "peroxynitrite"))) :location (c / cardiomyocyte :source (c2 / cell-line :name (n6 / name :op1 "H9C2"~e.3)))) :concession~e.11 (d / depend-01~e.12 :ARG0 a :ARG1~e.13 (a2 / and~e.17 :op1 (e3 / enzyme :name (n5 / name :op1 "Raf-1"~e.14,16)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK"~e.18))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 63~e.30)))) # ::id bel_pmid_1934_2884.19318 ::amr-annotator SDL-AMR-09 ::preferred # ::tok we found that IL6 effectively inhibited LIF signalling , repressing transcription of the LIF receptor gp190 , and strongly inducing axotrophin @/@ MARCH @-@ 7 , a novel E3 ubitquitin ligase that we discovered to be active in degradation of gp190 protein . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1 4-1.2.4 5-1.2 6-1.2.2.1.1.1 7-1.2.2 9-1.2.3.1 10-1.2.3.1.1 13-1.2.3.1.1.1.2 15-1.2.3.1.1.1.1.1 17-1.2.3 18-1.2.3.2.2 19-1.2.3.2 20-1.2.3.2.1.1.1 22-1.2.3.2.1.1.1 24-1.2.3.2.1.1.1 27-1.2.3.2.1.2.1.2 28-1.2.3.2.1.2.1.1.1 30-1.2.3.2.1.2.1.1.3 32-1.2.3.2.1.3.2.1 33-1.2.3.2.1.3.2 36-1.2.3.2.1.3 37-1.2.3.2.1.3.1.r 38-1.2.3.2.1.3.1 39-1.2.3.2.1.3.1.1.r 40-1.2.3.2.1.3.1.1 41-1.2.1 41-1.2.2.1 41-1.2.3.1.1.1 41-1.2.3.2.1 41-1.2.3.2.1.2.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (i / inhibit-01~e.5 :ARG0 (p / protein~e.41 :name (n / name :op1 "IL6"~e.3)) :ARG1 (s / signal-07~e.7 :ARG0 (p2 / protein~e.41 :name (n2 / name :op1 "LIF"~e.6))) :manner (a2 / and~e.17 :op1 (r / repress-01~e.9 :ARG1 (t / transcribe-01~e.10 :ARG1 (p3 / protein~e.41 :name (n3 / name :op1 "gp190"~e.15) :mod p2~e.13))) :op2 (i2 / induce-01~e.19 :ARG2 (p4 / protein~e.41 :name (n6 / name :op1 "axotrophin/MARCH-7"~e.20,22,24) :ARG1-of (m / mean-01 :ARG2 (p5 / protein~e.41 :name (n7 / name :op1 "E3"~e.28 :op2 "ubiquitin" :op3 "ligase"~e.30) :mod (n4 / novel~e.27))) :ARG0-of (a / activity-06~e.36 :ARG1~e.37 (d / degrade-01~e.38 :ARG1~e.39 p3~e.40) :ARG1-of (d2 / discover-01~e.33 :ARG0 (w2 / we~e.32)))) :ARG1-of (s2 / strong-02~e.18))) :ARG1-of (e / effective-04~e.4))) # ::id bel_pmid_1934_2884.27058 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Unlike IL6 , LIF supported expression of Foxp3 , the Treg lineage transcription factor , and LIF opposed IL6 by suppressing IL @-@ 6 @-@ induced IL @-@ 17A protein release . # ::alignments 0-1.1.3 0-1.1.3.1 0-1.1.3.1.r 3-1.1.1.1.1 4-1.1 5-1.1.2 7-1.1.2.1.1.1 10-1.1.2.1.2.1.1.1.1.1.1 11-1.1.2.1.2.1.1.1 12-1.1.2.1.2.1.1 13-1.1.2.1.2.1 16-1.1.1.1.1 17-1.2 19-1.2.3.r 20-1.2.3 21-1.2.2.1.1 23-1.2.2.1.1 25-1.2.3.1.2 26-1.2.3.1.1.1.1 28-1.2.3.1.1.1.1 29-1.1.1 29-1.1.2.1 29-1.2.2 29-1.2.3.1.1 30-1.2.3.1 (a / and :op1 (s / support-01~e.4 :ARG0 (p2 / protein~e.29 :name (n3 / name :op1 "LIF"~e.3,16)) :ARG1 (e / express-03~e.5 :ARG2 (p / protein~e.29 :name (n / name :op1 "Foxp3"~e.7) :ARG1-of (m / mean-01 :ARG2 (f / factor~e.13 :ARG0-of (t / transcribe-01~e.12 :ARG1 (l / lineage~e.11 :mod (c / cell :name (n2 / name :op1 "Treg"~e.10)))))))) :ARG1-of (r / resemble-01~e.0 :polarity~e.0 -~e.0 :ARG2 p3)) :op2 (o / oppose-01~e.17 :ARG0 p2 :ARG1 (p3 / protein~e.29 :name (n4 / name :op1 "IL-6"~e.21,23)) :manner~e.19 (s2 / suppress-01~e.20 :ARG1 (r2 / release-01~e.30 :ARG1 (p4 / protein~e.29 :name (n5 / name :op1 "IL-17A"~e.26,28)) :ARG2-of (i / induce-01~e.25 :ARG0 p3))))) # ::id bel_pmid_1935_9600.29984 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macrophages from PC Tg mice can express high level of human PON2 besides intrinsic mouse PON2 and PON3 ... PC Tg macrophages maintained significantly lower levels of ROS for at least 2 hours than macrophages from Wt mice ... Inflammatory factors such as TNF @-@ alpha and IL @-@ 6 are expressed at lower levels in PC Tg MPMs compared with Wt MPMs . # ::alignments 0-1.1.1.2 1-1.1.1.2.1.r 3-1.1.1.2.1.1.3 4-1.1.1.2.1 5-1.1 6-1.1.1 7-1.1.1.1.1.2 8-1.1.1.1.1 9-1.1.1.1.1.1.r 10-1.1.1.1.1.1.3 11-1.1.1.1.1.1.2.1 11-1.1.1.1.2.2.1 13-1.1.1.1.2.3 14-1.1.1.1.2.4 15-1.1.1.1.1.1.2.1 15-1.1.1.1.2.2.1 16-1.1.1.1 17-1.1.1.1.3.2.1 20-1.2.1.1.3 20-1.3.2.3.3 21-1.2.1 22-1.2 23-1.2.2.2.2 24-1.2.2.2 24-1.2.2.2.1 24-1.2.2.2.1.r 25-1.2.2 26-1.2.2.1.r 27-1.2.2.1.2.1 28-1.2.3.r 29-1.2.3 30-1.2.3 31-1.2.3.1.1 32-1.2.3.1.2 33-1.2.2.2.3.r 34-1.2.2.2.3 35-1.2.2.2.3.1.r 37-1.2.2.2.3.1 39-1.3.1.1 40-1.3.1 41-1.3.1.2.r 42-1.3.1.2.r 43-1.3.1.2.1.2.1 45-1.3.1.2.1.2.1 46-1.3.1.2 47-1.3.1.2.2.2.1 49-1.3.1.2.2.2.1 51-1.3 52-1.2.3 52-1.3.3.r 53-1.3.3.1 53-1.3.3.1.1 53-1.3.3.1.1.r 54-1.3.3 57-1.3.2.3.3 59-1.3.3.1.2.r (m2 / multi-sentence :snt1 (p / possible-01~e.5 :ARG1 (e / express-03~e.6 :ARG2 (a3 / and~e.16 :op1 (l / level~e.8 :quant-of~e.9 (p2 / protein :wiki "PON2" :name (n2 / name :op1 "PON2"~e.11,15) :mod (h3 / human~e.10)) :ARG1-of (h2 / high-02~e.7)) :op2 (p3 / protein :wiki "PON2" :name (n3 / name :op1 "PON2"~e.11,15) :mod (i / intrinsic~e.13) :mod (m7 / mouse~e.14)) :op3 (p4 / protein :wiki "PON3" :name (n4 / name :op1 "PON3"~e.17) :mod i :mod m7)) :ARG3 (m3 / macrophage~e.0 :source~e.1 (m4 / mouse~e.4 :mod (s3 / small-molecule :wiki "Phosphocholine" :name (n / name :op1 "phosphocholine") :mod (t2 / transgenic~e.3)))))) :snt2 (m8 / maintain-01~e.22 :ARG0 (m9 / macrophage~e.21 :mod (s4 / small-molecule :wiki "Phosphocholine" :name (n5 / name :op1 "phosphocholine") :mod (t3 / transgenic~e.20))) :ARG1 (l3 / level~e.25 :quant-of~e.26 (s / small-molecule :wiki "Reactive_oxygen_species" :name (n6 / name :op1 "ROS"~e.27)) :ARG1-of (l2 / low-04~e.24 :degree~e.24 (m / more~e.24) :ARG1-of (s2 / significant-02~e.23) :compared-to~e.33 (m5 / macrophage~e.34 :source~e.35 (m10 / mouse~e.37 :mod (w / wild-type))))) :duration~e.28 (a / at-least~e.29,30,52 :op1 (t / temporal-quantity :quant 2~e.31 :unit (h / hour~e.32)))) :snt3 (e2 / express-03~e.51 :ARG2 (f / factor~e.40 :ARG0-of (i2 / inflame-01~e.39) :example~e.41,42 (a4 / and~e.46 :op1 (p5 / protein :wiki "Tumor_necrosis_factor_alpha" :name (n7 / name :op1 "TNF-alpha"~e.43,45)) :op2 (p6 / protein :wiki "Interleukin_6" :name (n8 / name :op1 "IL-6"~e.47,49)))) :ARG3 (m14 / medical-condition :wiki - :name (n12 / name :op1 "malignant" :op2 "pleural" :op3 "mesothelioma") :mod (s5 / small-molecule :wiki "Phosphocholine" :name (n10 / name :op1 "phosphocholine") :mod (t4 / transgenic~e.20,57))) :degree~e.52 (l4 / level~e.54 :ARG1-of (l5 / low-04~e.53 :degree~e.53 (m11 / more~e.53) :compared-to~e.59 (m15 / medical-condition :wiki - :name (n9 / name :op1 "malignant" :op2 "pleural" :op3 "mesothelioma") :mod (w2 / wild-type)))))) # ::id bel_pmid_1938_6603.36754 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ATP @-@ mediated ADAM17 activation was also suppressed by the EGFR kinase inhibitor AG1478 and , to a lesser extent , by preincubation with ?-EGFR antibody ( Fig . 6B ) , indicating a role for EGFR in ADAM17 activation . # ::alignments 0-1.1.2.2.1.1.1 2-1.1.2.2 3-1.1.2.1.1.1 4-1.1.2 6-1.1.3 7-1.1 7-1.2 8-1.1.1.r 10-1.1.1.2.1.1.1 11-1.1.1.2.1 12-1.1.1 12-1.1.1.2 12-1.1.1.2.r 13-1.1.1.1.1 14-1 18-1.2.1.2 18-1.2.3 18-1.2.3.1 18-1.2.3.1.r 25-1.2.1.1 27-1.4.1 29-1.4.1.1 32-1.3 34-1.3.1 35-1.3.1.1.r 36-1.3.1.1 37-1.3.1.2.r 38-1.3.1.2.1 39-1.3.1.2 (a6 / and~e.14 :op1 (s / suppress-01~e.7 :ARG0~e.8 (s3 / small-molecule~e.12 :name (n4 / name :op1 "AG1478"~e.13) :ARG0-of~e.12 (i3 / inhibit-01~e.12 :ARG1 (k / kinase~e.11 :name (n5 / name :op1 "EGFR"~e.10)))) :ARG1 (a / activate-01~e.4 :ARG1 (p / protein :name (n2 / name :op1 "ADAM17"~e.3)) :ARG1-of (m / mediate-01~e.2 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ATP"~e.0)))) :mod (a2 / also~e.6)) :op2 (s4 / suppress-01~e.7 :ARG0 (p2 / preincubate-01 :ARG2 (a4 / antibody~e.25 :ARG0-of (c / counter-01 :ARG1 k)) :degree (l / less~e.18 :mod (m2 / more))) :ARG1 a :degree (l2 / less~e.18 :degree~e.18 (m3 / more~e.18))) :ARG0-of (i5 / indicate-01~e.32 :ARG1 (r / role~e.34 :mod~e.35 k~e.36 :prep-in~e.37 (a5 / activate-01~e.39 :ARG1 p~e.38))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "6B"~e.29))) # ::id bel_pmid_1938_6603.36760 ::amr-annotator SDL-AMR-09 ::preferred # ::tok addition of AG1478 also suppressed ATP @-@ mediated phosphorylation of ERK1 @/@ 2 and I-?B ? ( Fig . 4A ) , indicating the involvement of EGFR activation in these signaling events . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.3 4-1 5-1.2.2.1.1.1 7-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1.1.1.1 12-1.2.1.1.1.1 13-1.2.1 17-1.4.1 19-1.4.1.1 22-1.5 24-1.5.1 25-1.5.1.1.r 26-1.5.1.1.1.1.1 27-1.5.1.1 28-1.5.1.2.r 29-1.5.1.2.1 30-1.5.1.2.2 31-1.5.1.2 (s / suppress-01~e.4 :ARG0 (a / add-02~e.0 :ARG1~e.1 (s2 / small-molecule :name (n2 / name :op1 "AG1478"~e.2))) :ARG1 (p2 / phosphorylate-01~e.8 :ARG1~e.9 (a3 / and~e.13 :op1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2"~e.10,12)) :op2 (p4 / protein :name (n4 / name :op1 "I-κBα"))) :ARG1-of (m / mediate-01~e.7 :ARG0 (s3 / small-molecule :name (n5 / name :op1 "ATP"~e.5)))) :mod (a2 / also~e.3) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod "4A"~e.19)) :ARG0-of (i / indicate-01~e.22 :ARG1 (i2 / involve-01~e.24 :ARG1~e.25 (a4 / activate-01~e.27 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.26))) :ARG2~e.28 (e2 / event~e.31 :mod (t / this~e.29) :mod (s4 / signal-07~e.30))))) # ::id bel_pmid_1938_6603.38056 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 6A , both ATP and ?-ASGM1 indeed resulted in enhanced ADAM17 activity , measured by increased cleavage of a fluorogenic ADAM17 substrate , and this was attenuated after siRNA silencing of DUOX1 ( Fig . 6A # ::alignments 0-1.2.2.r 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1.1 7-1.1.1.1.1.1 8-1.1.1 10-1.1.3 11-1.1 12-1.1.2.r 13-1.1.2.2 14-1.1.2.1.1.1 15-1.1.2 17-1.1.2.3 18-1.1.2.3.1.r 19-1.1.2.3.1.2 20-1.1.2.3.1 21-1.1.2.3.1.1.r 23-1.1.2.3.1.1.2 24-1.1.2.3.1.1.1 25-1.1.2.3.1.1 27-1 30-1.2 31-1.2.2 32-1.2.2.1.1.1.1 33-1.2.2.1 34-1.2.2.1.2.r 35-1.2.2.1.2.1.1 37-1.3.1 39-1.3.1.1 (a / and~e.27 :op1 (r / result-01~e.11 :ARG1 (a2 / and~e.8 :op1 (s2 / small-molecule :name (n / name :op1 "ATP"~e.7)) :op2 (a3 / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n2 / name :op1 "ASGM1"))))) :ARG2~e.12 (a4 / activity-06~e.15 :ARG0 (p2 / protein :name (n3 / name :op1 "ADAM17"~e.14)) :ARG1-of (e / enhance-01~e.13) :ARG1-of (m / measure-01~e.17 :ARG2~e.18 (c2 / cleave-01~e.20 :ARG1~e.21 (s3 / substrate~e.25 :mod p2~e.24 :mod (f2 / fluorogenic~e.23)) :ARG1-of (i / increase-01~e.19)))) :mod (i2 / indeed~e.10)) :op2 (a5 / attenuate-01~e.30 :ARG1 a4 :time~e.0 (a6 / after~e.31 :op1 (s4 / silence-01~e.33 :ARG0 (n6 / nucleic-acid :name (n5 / name :op1 "siRNA"~e.32)) :ARG1~e.34 (e2 / enzyme :name (n4 / name :op1 "DUOX1"~e.35))))) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3,37 :mod "6A"~e.4,39))) # ::id bel_pmid_1938_6603.38058 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Silencing of DUOX1 attenuated the ATP @- and ?-ASGM1 @-@ induced TGF-? production observed in the presence of EGFR mAb ( Fig . 5B ) , indicating the involvement of DUOX1 activation in ATP @-@ induced TGF-? production and EGFR activation . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1 5-1.2.2.1.1.1.1 7-1.2.2.1 10-1.2.2 12-1.2 13-1.2.3 14-1.2.3.1.r 16-1.2.3.1 18-1.2.3.1.1.2.1.1.1 21-1.3.1 23-1.3.1.1 26-1.4 28-1.4.1 29-1.4.1.1.r 30-1.4.1.1.1 31-1.4.1.1 32-1.4.1.2.r 33-1.4.1.2.1.2.1 35-1.4.1.2.1.2 37-1.4.1.2.1 38-1.4.1.2 39-1.4.1.2.2.1 40-1.4.1.2.2 (a / attenuate-01~e.3 :ARG0 (s / silence-01~e.0 :ARG1~e.1 (e2 / enzyme :name (n2 / name :op1 "DUOX1"~e.2))) :ARG1 (p2 / produce-01~e.12 :ARG1 (p3 / protein :name (n4 / name :op1 "TGF-α")) :ARG1-of (i / induce-01~e.10 :ARG0 (a7 / and~e.7 :op1 (s2 / small-molecule :name (n5 / name :op1 "ATP"~e.5)) :op2 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p / protein :name (n3 / name :op1 "ASGM1")))))) :ARG1-of (o / observe-01~e.13 :condition~e.14 (p4 / present-02~e.16 :ARG1 (a3 / antibody :mod (m / monoclonal) :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.18))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "5B"~e.23)) :ARG0-of (i2 / indicate-01~e.26 :ARG1 (i3 / involve-01~e.28 :ARG1~e.29 (a4 / activate-01~e.31 :ARG1 e2~e.30) :ARG2~e.32 (a5 / and~e.38 :op1 (p5 / produce-01~e.37 :ARG1 p3 :ARG2-of (i4 / induce-01~e.35 :ARG0 s2~e.33)) :op2 (a6 / activate-01~e.40 :ARG1 e~e.39))))) # ::id bel_pmid_1943_9223.25342 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 1A , the HO @-@ 1 level in Bach1-/- mouse lungs was significantly higher than that of WT mice even before hyperoxic exposure , and the time @-@ dependent increase in HO @-@ 1 expression in Bach1-/- mouse lungs was much greater than that ofWT mice during hyperoxic exposure . # ::alignments 0-1.2.1.4.r 1-1 2-1.1.r 3-1.1 4-1.1.1 7-1.2.1.1.1.1.1 9-1.2.1.1.1.1.1 10-1.2.1.1 13-1.2.1.1.2.1 14-1.2.1.1.2 16-1.2.1.3 17-1.2.1 17-1.2.1.2 17-1.2.1.2.r 18-1.2.1.5.r 21-1.2.1.5.1 22-1.2.1.5 23-1.2.1.4.2 24-1.2.1.4 26-1.2.1.4.1 28-1.2 30-1.2.1.4.r 30-1.2.2.2.2.1 32-1.2.2.2.2 33-1.2.2.2 33-1.2.2.3 35-1.2.1.1.1.1.1 37-1.2.1.1.1.1.1 38-1.2.1.1.2.1.1 38-1.2.2.2.1 38-1.2.2.3.1 41-1.2.1.1.2.1 42-1.2.1.1.2 43-1.2.2.2.r 44-1.2.2.1.1 45-1.2.2 45-1.2.2.1 45-1.2.2.1.r 46-1.2.2.3.r 49-1.2.1.1.2.1 50-1.2.2.3.2.r 52-1.2.2.3.2 (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "1A"~e.4) :ARG1 (a / and~e.28 :op1 (h / high-02~e.17 :ARG1 (l / level~e.10 :quant-of (p / protein :name (n / name :op1 "HO-1"~e.7,9,35,37)) :location (l2 / lung~e.14,42 :part-of (m3 / mouse~e.13,41,49 :ARG3-of (e / express-03~e.38 :ARG1 (g3 / gene :name (n2 / name :op1 "Bach1") :ARG2-of (m4 / mutate-01 :mod "-/-")))))) :degree~e.17 (m / more~e.17) :ARG1-of (s2 / significant-02~e.16) :time~e.0,30 (b / before~e.24 :op1 (e3 / expose-01~e.26 :ARG2 (h2 / hyperoxia)) :mod (e2 / even~e.23)) :compared-to~e.18 (m5 / mouse~e.22 :mod (w / wild-type~e.21))) :op2 (g / great~e.45 :degree~e.45 (m2 / more~e.45 :degree (m6 / much~e.44)) :domain~e.43 (i / increase-01~e.33 :ARG1 (e4 / express-03~e.38 :ARG1 p :ARG3 l2) :ARG0-of (d / depend-01~e.32 :ARG1 (t / time~e.30))) :compared-to~e.46 (i2 / increase-01~e.33 :ARG1 (e5 / express-03~e.38 :ARG2 p :ARG3 m5) :time~e.50 e3~e.52)))) # ::id bel_pmid_1943_9223.32684 ::amr-annotator SDL-AMR-09 ::preferred # ::tok unexpectedly , however , the levels of IL @-@ 6 in bronchoalveolar lavage ( BAL ) fluid from Bach1(-/-) mice were significantly higher than those of WT mice . ..... In addition , a chromatin immunoprecipitation analysis revealed the binding of Bach1 to the IL @-@ 6 promoter and its detachment after oxidative stress . # ::alignments 0-1.2.1.4.1 2-1.2 5-1.2.1.1 5-1.2.1.5 6-1.2.1.1.1.r 7-1.2.1.1.1.1.1 9-1.2.1.1.1.1.1 12-1.2.1.1.2.2 14-1.2.1.1.2.2 14-1.2.1.1.2.2.1 14-1.2.1.1.2.2.1.1 14-1.2.1.1.2.2.1.1.r 14-1.2.1.1.2.2.1.r 16-1.2.1.1.2 17-1.2.1.1.2.1.r 19-1.2.1.1.2.1 21-1.2.1.3 22-1.2.1 22-1.2.1.2 22-1.2.1.2.r 23-1.2.1.5.r 25-1.2.1.5.1.r 26-1.2.1.5.1.1 27-1.2.1.5.1 30-1.1.1.2 31-1.1 31-1.1.1.2 34-1.1.1.1.1.1.1.1 35-1.1.1.1.1 36-1.1.1.1 37-1.1.1 39-1.1.1.2.1 41-1.1.1.2.1.1.1.1 41-1.2.1.1.2.1.1.1.1.1 42-1.1.1.2.1.2.r 44-1.1.1.2.1.2.1.1.1.1 46-1.1.1.2.1.2.1.1.1.1 47-1.1.1.2.1.2 47-1.1.1.2.1.2.1 47-1.1.1.2.1.2.1.r 48-1.1.1.2 50-1.1.1.2.2 51-1.1.1.2.2.3 52-1.1.1.2.2.3.1.1 53-1.1.1.2.2.3.1 (m2 / multi-sentence :snt2 (a / and~e.31 :op2 (r / reveal-01~e.37 :ARG0 (a2 / analyze-01~e.36 :manner (i / immunoprecipitate-01~e.35 :ARG3 (m8 / macro-molecular-complex :name (n7 / name :op1 "chromatin"~e.34)))) :ARG1 (a3 / and~e.30,31,48 :op1 (b / bind-01~e.39 :ARG1 (g2 / gene :name (n6 / name :op1 "Bach1"~e.41)) :ARG2~e.42 (m7 / molecular-physical-entity~e.47 :ARG0-of~e.47 (p2 / promote-01~e.47 :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6"~e.44,46))))) :op2 (d / detach-01~e.50 :ARG1 g2 :ARG2 m7 :time (a4 / after~e.51 :op1 (s2 / stress-02~e.53 :ARG3 (o / oxidize-01~e.52))))))) :snt1 (c / contrast-01~e.2 :ARG2 (h / high-02~e.22 :ARG1 (l / level~e.5 :quant-of~e.6 (p / protein :name (n / name :op1 "IL-6"~e.7,9)) :location (f / fluid~e.16 :source~e.17 (m4 / mouse~e.19 :ARG3-of (e / express-03 :ARG1 (g / gene :name (n3 / name :op1 "Bach1"~e.41) :ARG2-of (m5 / mutate-01 :mod "-/-")))) :mod (l3 / lavage~e.12,14 :mod~e.14 (a5 / alveolus~e.14 :mod~e.14 (b2 / bronchus~e.14))))) :degree~e.22 (m / more~e.22) :ARG1-of (s / significant-02~e.21) :ARG1-of (e2 / expect-01 :polarity -~e.0) :compared-to~e.23 (l2 / level~e.5 :mod~e.25 (m6 / mouse~e.27 :mod (w / wild-type~e.26)) :quant-of p)))) # ::id bel_pmid_1958_0863.2728 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibition of COX2 markedly reduced both IL @-@ 1 beta and IL @-@ 6 release . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.3 3-1.3.r 4-1 6-1.2.1.1.1.1 6-1.2.1.2.1.1 8-1.2.1.1.1.1 9-1.2.1.1.1.2 10-1.2.1 11-1.2.1.2.1.1 13-1.2.1.2.1.1 14-1.2 (r / reduce-01~e.4 :ARG0 (i / inhibit-01~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "COX2"~e.2))) :ARG1 (r2 / release-01~e.14 :ARG1 (a / and~e.10 :op1 (p / protein :name (n2 / name :op1 "IL-1"~e.6,8 :op2 "beta"~e.9)) :op2 (p2 / protein :name (n3 / name :op1 "IL-6"~e.6,11,13)))) :manner~e.3 (m / marked~e.3)) # ::id bel_pmid_1958_0863.38416 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The addition of IL @-@ 1b ( 100 pg/ml ) alone significantly increased the levels of IL @-@ 6 , and approximately to the same level as 160 lg @/@ cm2 silica . # ::alignments 1-1.1 1-1.2.3.1.1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 7-1.1.1.2.1 10-1.1.1.3 11-1.3 12-1 12-1.2.3.1.1 14-1.2 14-1.2.3.1 16-1.2.1.1.1 18-1.2.1.1.1 21-1.2.3 24-1.2.2 25-1.2 26-1.2.3.1.1.1.1.r 27-1.2.3.1.1.1.1.1.1 31-1.2.3.1.1.1.1 (i / increase-01~e.12 :ARG0 (a / add-02~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "IL-1b"~e.3,5) :quant (c / concentration-quantity :quant 100~e.7 :unit (p2 / picogram-per-milliliter)) :mod (a2 / alone~e.10))) :ARG1 (l / level~e.14,25 :quant-of (p3 / protein :name (n2 / name :op1 "IL-6"~e.16,18)) :ARG1-of (s3 / same-01~e.24) :ARG0-of (a4 / approximate-01~e.21 :ARG1 (l2 / level~e.14 :ARG4-of (i2 / increase-01~e.12 :ARG0 (a3 / add-02~e.1 :ARG1~e.26 (s2 / silica~e.31 :quant (c2 / concentration-quantity :quant 160~e.27 :unit (m / microgram-per-square-centimeter)))))))) :ARG2 (s / significant-02~e.11)) # ::id bel_pmid_1969_3649.9324 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In TNBS colitis , no differences were found in interleukin ( IL ) - 18 and tumor necrosis factor ( TNF ) - alpha expression between IRF4 knockout and wild @-@ type mice . However , significant differences were detected in IL @-@ 6 and IL @-@ 17 production . # ::alignments 0-1.1.1.4.r 1-1.1.1.4.1.1 2-1.1.1.4.1.2 4-1.1.1.1 4-1.1.1.1.r 5-1.1.1 7-1.1 8-1.1.1.4.r 9-1.1.1.2.1.1.1.1 11-1.2.1.1.1.1.1.1 11-1.2.1.1.2.1.1.1 14-1.1.1.3.1 15-1.1.1.3.1 16-1.1.1.3.1 17-1.1.1.3.1 18-1.1.1.3.1 19-1.1.1.3.1 20-1.1.1.3.1 21-1.1.1.3.1 22-1.1.1.3.1 23-1.1.1.3.1 24-1.1.1.3.1 25-1.1.1.3.1 26-1.1.1.3.1 27-1.1.1.3.1 28-1.1.1.3.1 29-1.1.1.3.2.1 31-1.1.1.3.2.1 32-1.1.1.2.2 32-1.1.1.3.2 34-1.2 36-1.2.1.1.3 37-1.2.1.1 39-1.2.1 40-1.1.1.4.r 41-1.2.1.1.1.1.1.1 41-1.2.1.1.2.1.1.1 43-1.2.1.1.1.1.1.1 45-1.2.1.1.1.1.1.1 45-1.2.1.1.2.1.1.1 47-1.2.1.1.2.1.1.1 48-1.2.1.1.1 48-1.2.1.1.2 (m / multi-sentence :snt1 (f / find-01~e.7 :ARG1 (d5 / differ-02~e.5 :polarity~e.4 -~e.4 :ARG1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "interleukin"~e.9 :op2 18)) :op2 (p2 / protein :name (n2 / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha"))) :ARG3 (m2 / mouse~e.32 :ARG3-of (e2 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "IRF4") :ARG1-of (k / knock-out-03))))) :ARG2 (e3 / express-03 :ARG1 e~e.14,15,16,17,18,19,20,21,22,23,24,25,26,27,28 :ARG3 (m4 / mouse~e.32 :mod (w / wild-type~e.29,31))) :prep-in~e.0,8,40 (d / disease :name (n4 / name :op1 "TNBS"~e.1 :op2 "colitis"~e.2)))) :snt2 (h / have-concession-91~e.34 :ARG2 (d3 / detect-01~e.39 :ARG1 (d4 / differ-02~e.37 :ARG1 (p3 / produce-01~e.48 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-6"~e.11,41,43,45))) :ARG2 (p6 / produce-01~e.48 :ARG1 (p5 / protein :name (n6 / name :op1 "IL-17"~e.11,41,45,47))) :ARG1-of (s / significant-02~e.36))))) # ::id bel_pmid_1970_6765.28338 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More importantly , persistent activation of IL @-@ 6 downstream Stat3 in AT II epithelial cellsdirec tly induced lung inflammation and bronchioalveolar adenocarcinoma ( 22 ) . # ::alignments 0-1.4.1 1-1.4 3-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1.1.2.2 10-1.1.1.2.1.1.1 11-1.1.3.r 12-1.1.3.1.1 13-1.1.3.1.2 14-1.1.3.2 17-1 18-1.2.1.1 19-1.2.1 20-1.2 21-1.2.2.2 22-1.2.2.1.1 24-1.5.1.1.1 (i / induce-01~e.17 :ARG0 (a / activate-01~e.4 :ARG1~e.5 (p / protein :name (n / name :op1 "IL-6"~e.6,8) :location (r / relative-position :op1 (p2 / protein :name (n2 / name :op1 "Stat3"~e.10)) :direction (d4 / downstream~e.9))) :ARG1-of (p3 / persist-01~e.3) :location~e.11 (c / cell-line :name (n3 / name :op1 "AT"~e.12 :op2 "II"~e.13) :mod (e / epithelium~e.14))) :ARG2 (a2 / and~e.20 :op1 (i2 / inflame-01~e.19 :ARG1 (l / lung~e.18)) :op2 (m2 / medical-condition :name (n4 / name :op1 "adenocarcinoma"~e.22) :mod (b / bronchioalveolar~e.21))) :ARG1-of (d / direct-02) :mod (i3 / important~e.1 :degree (m / more~e.0)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 22~e.24)))) # ::id bel_pmid_1970_6765.29240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 3A , there was a steady increase of BrdUrd pulse @-@ labeled AT II epithelial cells in the doxycycline @-@ treated bitransgenic mice compared with untreated littermates . The increase of MMP12 @-@ induced cell proliferation wastime dependent . # ::alignments 1-1.1.3 2-1.1.3.1.r 3-1.1.3.1 4-1.1.3.1.1 9-1.1.2 10-1.1 12-1.1.1.3.1.1.1.1 13-1.1.1.3.1 15-1.1.1.3 16-1.1.1.1.1 17-1.1.1.1.2 18-1.1.1.2 19-1.1.1 22-1.1.4.2.1.1.1 24-1.1.4.2 25-1.1.4.1 26-1.1.4 27-1.1.5.r 29-1.1.5.1 29-1.1.5.1.1 29-1.1.5.1.1.r 30-1.1.5 33-1.1 33-1.2.1 34-1.2.1.1.r 35-1.2.1.1.2.1.1.1 37-1.2.1.1.2 38-1.2.1.1.1 39-1.2.1.1 41-1.2 (m / multi-sentence :snt1 (i / increase-01~e.10,33 :ARG1 (c / cell-line~e.19 :name (n2 / name :op1 "AT"~e.16 :op2 "II"~e.17) :mod (e / epithelium~e.18) :ARG1-of (l / label-01~e.15 :ARG0 (p / pulse-01~e.13 :ARG1 (s4 / small-molecule :name (n / name :op1 "BrdUrd"~e.12))))) :ARG1-of (s / steady-01~e.9) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "3A"~e.4)) :location (m3 / mouse~e.26 :mod (b / bitransgenic~e.25) :ARG1-of (t2 / treat-04~e.24 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "doxycycline"~e.22)))) :compared-to~e.27 (l2 / littermate~e.30 :ARG1-of (t3 / treat-04~e.29 :polarity~e.29 -~e.29))) :snt2 (d / depend-01~e.41 :ARG0 (i2 / increase-01~e.33 :ARG1~e.34 (p2 / proliferate-01~e.39 :ARG0 (c2 / cell~e.38) :ARG2-of (i3 / induce-01~e.37 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MMP12"~e.35))))) :ARG1 (t4 / time))) # ::id bel_pmid_1970_6765.29242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MMP12 overexpression in lung epithelial cells , bitransgenic mice were treated with doxycycline for various time lengths . Histopathologic analyses revealed lung abnormalities in bitransgenic mice beginning at 6 weeks of doxycycline treatment . At this stage , marked inflammatory cell infiltration and emphysema were readily detectable ( Fig . 2A , +Dox 6W ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.2 4-1.1.1.2.1 5-1.1.1.2 7-1.1.2.1.1 8-1.1.2.1 10-1.1.2 12-1.1.2.2.1.1 14-1.1.2.3.1 15-1.1.2.3 15-1.2.2.3.1.2 15-1.3.4.r 19-1.2.1 20-1.2 21-1.2.2.1 22-1.2.2 23-1.2.2.2.r 24-1.2.2.2.1 25-1.2.2.2 26-1.2.2.3 28-1.2.2.3.1.2.1 29-1.2.2.3.1.2.2 31-1.1.2.2.1.1 31-1.2.2.3.1.1.1.1.1 32-1.1.2 32-1.2.2.3.1.1 35-1.3.4.1 36-1.3.4 38-1.3.1.1.2 39-1.3.1.1.1.1 40-1.3.1.1.1 41-1.3.1.1 42-1.3.1 43-1.3.1.2 45-1.3.3 45-1.3.3.r 46-1.3 48-1.3.5.1.1 50-1.3.5.1.1.1 52-1.3.5.1.2.1.1 53-1.3.5.1.2.1.2 (m / multi-sentence :snt1 (a / and :op1 (o / overexpress-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "MMP12"~e.0)) :location~e.2 (c / cell~e.5 :mod (e2 / epithelium~e.4) :mod (l / lung~e.3))) :op2 (t2 / treat-04~e.10,32 :ARG1 (m2 / mouse~e.8 :mod (b / bitransgenic~e.7)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "doxycycline"~e.12,31)) :duration (t4 / temporal-quantity~e.15 :mod (v / various~e.14)))) :snt2 (r / reveal-01~e.20 :ARG0 (a2 / analyze-01~e.19 :mod (h / histopahtology)) :ARG1 (a3 / abnormality~e.22 :mod (l3 / lung~e.21) :location~e.23 (m3 / mouse~e.25 :mod (b2 / bitransgenic~e.24)) :ARG1-of (b3 / begin-01~e.26 :time (a4 / after :op1 (t5 / treat-04~e.32 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "doxycycline"~e.31))) :quant (t / temporal-quantity~e.15 :quant 6~e.28 :unit (w / week~e.29)))))) :snt3 (d / detect-01~e.46 :ARG1 (a5 / and~e.42 :op1 (i / infiltrate-01~e.41 :ARG0 (c2 / cell~e.40 :ARG0-of (i2 / inflame-01~e.39)) :ARG1-of (m4 / mark-01~e.38)) :op2 (e3 / emphysema~e.43)) :ARG1-of (p / possible-01) :manner~e.45 (r2 / ready~e.45) :time~e.15 (s / stage~e.36 :mod (t7 / this~e.35)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (f / figure~e.48 :mod "2A"~e.50) :op2 (t3 / thing :name (n4 / name :op1 "+Dox"~e.52 :op2 "6W"~e.53)))))) # ::id bel_pmid_1970_6765.29244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok FACS analysis showed a more than 5 @-@ fold decrease of Annexin V @–@ labeled AT II epithelial cellsin 9 @-@ month doxycyclinetreated bitransgenic mice compared with untreated littermates ( 21.41 % versus 4.91 %) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 4-1.2.2 5-1.2.2 6-1.2.2.1.1 8-1.2.2.1 9-1.2 9-1.2.4 10-1.2.1.r 10-1.2.2.1 11-1.2.1.3.1.1.1 12-1.2.1.3.1.1.2 14-1.2.1.3 15-1.2.1.1.1 16-1.2.1.1.2 17-1.2.1.2 19-1.2.3.3.1 21-1.2.3.3 21-1.2.3.3.2 21-1.2.3.3.2.r 23-1.2.3.1 24-1.2.3 25-1.2.4.r 27-1.2.3.2 27-1.2.4.3.1 27-1.2.4.3.1.1 27-1.2.4.3.1.1.r 28-1.2.4.3 30-1.2.2.2.1.1 31-1.2.2.2.1 31-1.2.4.2 33-1.2.4.2.1 (s2 / show-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (t4 / thing :name (n3 / name :op1 "FACS"~e.0))) :ARG1 (d / decrease-01~e.9 :ARG1~e.10 (c / cell-line :name (n2 / name :op1 "AT"~e.15 :op2 "II"~e.16) :mod (e / epithelium~e.17) :ARG1-of (l / label-01~e.14 :ARG0 (p3 / protein :name (n / name :op1 "Annexin"~e.11 :op2 "V"~e.12)))) :ARG2 (m2 / more-than~e.4,5 :op1 (p4 / product-of~e.8,10 :value 5~e.6) :ARG1-of (m4 / mean-01 :ARG2 (p / percentage-entity~e.31 :value 21.41~e.30))) :location (m3 / mouse~e.24 :mod (b / bitransgenic~e.23) :ARG1-of (t2 / treat-04~e.27 :ARG2 (s / small-molecule :name (n4 / name :op1 "doxycycline"))) :age (t / temporal-quantity~e.21 :quant 9~e.19 :unit~e.21 (m / month~e.21))) :compared-to~e.25 (d3 / decrease-01~e.9 :ARG1 p3 :ARG2 (p2 / percentage-entity~e.31 :value 4.91~e.33) :location (l2 / littermate~e.28 :ARG1-of (t3 / treat-04~e.27 :polarity~e.27 -~e.27))))) # ::id bel_pmid_1970_6765.29246 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bronchioalveolar adenocarcinomas were observed in the lungs of bitransgenic mice after doxycycline treatment asearly as16 weeks ( Fig . 2A , +Dox 16W ) . # ::alignments 0-1.1.2 1-1.1.1.1 3-1 4-1.2.r 6-1.2 7-1.2.1.r 8-1.2.1.1 9-1.2.1 10-1.3 11-1.3.1.1.1.1 12-1.3.1 15-1.3.1.2.2 17-1.4.1.1 19-1.4.1.1.1 21-1.4.1.2.1.1 22-1.4.1.2.1.2 (o / observe-01~e.3 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "adenocarcinoma"~e.1) :mod (b / bronchioalveolar~e.0)) :location~e.4 (l / lung~e.6 :part-of~e.7 (m / mouse~e.9 :mod (b2 / bitransgenic~e.8))) :time (a2 / after~e.10 :op1 (t / treat-04~e.12 :ARG2 (s / small-molecule :name (n / name :op1 "doxycycline"~e.11)) :quant (t2 / temporal-quantity :quant 16 :unit (w / week~e.15) :mod (e / early)))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.17 :mod "2A"~e.19) :op2 (t3 / thing :name (n2 / name :op1 "+Dox"~e.21 :op2 "16W"~e.22))))) # ::id bel_pmid_1970_6765.29248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 10 to 15 weeksof doxycycline treatment , the bitransgenic mice began to develop adenomatoid hyperplasia in both parenchyma and small conducting airways( F ig . 2A , +Dox 10W ) , which resembles to the histopathologic feature of dysplasia in clinical lesions . # ::alignments 0-1.4 1-1.4.1.3.1.1 3-1.4.1.3.2.1 5-1.4.1.2.1.1 6-1.4.1 9-1.1.1 10-1.1 11-1 13-1.2 14-1.2.2.1 15-1.2.2 18-1.2.1.1 19-1.2.1 20-1.2.1.2.1 21-1.2.1.2.2 26-1.3.1.1.1 28-1.3.1.2.1.1 29-1.3.1.2.1.2 33-1.2.2.2 34-1.2.2.2.1.r 36-1.2.2.2.1.2 37-1.2.2.2.1 38-1.2.2.2.1.1.r 39-1.2.2.2.1.1 40-1.2.2.2.1.3.r 41-1.2.2.2.1.3.1 42-1.2.2.2.1.3 (b2 / begin-01~e.11 :ARG0 (m / mouse~e.10 :mod (b3 / bitransgenic~e.9)) :ARG1 (d / develop-01~e.13 :ARG1 (a2 / and~e.19 :op1 (p / parenchyma~e.18) :op2 (a3 / airway :mod (s / small~e.20) :ARG1-of (c / conduct-03~e.21)) :part-of m) :ARG2 (h / hyperplasia~e.15 :mod (a / adenomatoid~e.14) :ARG1-of (r / resemble-01~e.33 :ARG2~e.34 (f2 / feature~e.37 :poss~e.38 (d5 / dysplasia~e.39) :mod (h2 / histopathologic~e.36) :location~e.40 (l / lesion~e.42 :mod (c2 / clinic~e.41)))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2A"~e.26) :op2 (t3 / thing :name (n2 / name :op1 "+Dox"~e.28 :op2 "10W"~e.29)))) :time (a5 / after~e.0 :op1 (t / treat-04~e.6 :ARG1 m :ARG2 (s2 / small-molecule :name (n / name :op1 "doxycycline"~e.5)) :duration (b4 / between :op1 (t2 / temporal-quantity :quant 10~e.1 :unit (w2 / week)) :op2 (t4 / temporal-quantity :quant 15~e.3 :unit (w3 / week)))))) # ::id bel_pmid_1970_6765.29250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , Stat3 @-@ induced downstream developmental gene HNF4a wasup @-@ regulated to 78.6 @-@ fold , Foxa3 to 9.3 @-@ fold , and SHH to 3.3 @-@ fold ( Fig . 4D ) . # ::alignments 0-1 0-1.1 0-1.1.r 1-1 1-1.1 1-1.1.r 3-1.1.1.1.4.1.1.1 5-1.1.1.1.4 6-1.1.1.1.3 7-1.1.1.1.2 8-1.1.1.1 8-1.1.2.1 8-1.1.3.1 9-1.1.1.1.1.1 14-1.1.1.2.1 16-1.1.1.2 18-1.1.2.1.1.1 20-1.1.2.2.1 22-1.1.2.2 24-1.1 25-1.1.3.1.1.1 27-1.1.3.2.1 29-1.1.3.2 31-1.1.4.1 33-1.1.4.1.1 (a / and~e.0,1 :op2~e.0,1 (a3 / and~e.0,1,24 :op1 (u / upregulate-01 :ARG1 (g / gene~e.8 :name (n2 / name :op1 "HNF4a"~e.9) :mod (g2 / growth~e.7) :location (d / downstream~e.6) :ARG2-of (i / induce-01~e.5 :ARG0 (p / protein :name (n / name :op1 "Stat3"~e.3)))) :degree (p2 / product-of~e.16 :value 78.6~e.14)) :op2 (u2 / upregulate-01 :ARG1 (g3 / gene~e.8 :name (n3 / name :op1 "Foxa3"~e.18)) :degree (p4 / product-of~e.22 :value 9.3~e.20)) :op3 (u3 / upregulate-01 :ARG1 (g4 / gene~e.8 :name (n4 / name :op1 "SHH"~e.25)) :degree (p6 / product-of~e.29 :value 3.3~e.27)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "4D"~e.33)))) # ::id bel_pmid_1970_6765.29252 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 4A , IL @-@ 6 concentration in BALF of doxycycline @-@ treated mice was steadily increased compared with those in untreated bitransgenic mice in a time @-@ dependent fashion , # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1.1 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1 9-1.4 10-1.1.2.r 11-1.1.2 11-1.1.2.2 11-1.1.2.2.1 11-1.1.2.2.1.1 11-1.1.2.2.1.1.r 11-1.1.2.2.1.r 11-1.1.2.2.r 12-1.1.2.1.r 13-1.1.2.1.1.1.1.1 15-1.1.2.1.1 16-1.1.2.1 18-1.2 18-1.2.r 19-1 20-1.4.r 23-1.4.2.r 24-1.4.2.1 24-1.4.2.1.1 24-1.4.2.1.1.r 25-1.4.2.2 26-1.4.2 27-1.5.r 29-1.5.2 31-1.5 (i / increase-01~e.19 :ARG1 (c / concentrate-02~e.9 :ARG1 (p / protein :name (n / name :op1 "IL-6"~e.6,8)) :location~e.10 (f2 / fluid~e.11 :mod~e.12 (m / mouse~e.16 :ARG1-of (t / treat-04~e.15 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "doxycycline"~e.13)))) :mod~e.11 (l / lavage~e.11 :mod~e.11 (a / alveolus~e.11 :mod~e.11 (b / bronchus~e.11))))) :manner~e.18 (s / steady~e.18) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "4A"~e.4)) :compared-to~e.20 (c2 / concentrate-01~e.9 :ARG1 p :location~e.23 (m3 / mouse~e.26 :ARG1-of (t3 / treat-04~e.24 :polarity~e.24 -~e.24) :mod (b3 / bitransgenic~e.25))) :manner~e.27 (d2 / depend-01~e.31 :ARG0 i :ARG1 (t4 / time~e.29))) # ::id bel_pmid_1970_6765.29260 ::amr-annotator SDL-AMR-09 ::preferred # ::tok increased expression of several other MMPs was also observed in doxycycline @-@ treated bitransgenic mice compared with untreated mice . ( Fig 4D ) # ::alignments 0-1.1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2 4-1.1.1.1.3 7-1.2 8-1 10-1.4.2.1.1.1 12-1.1.2.1 13-1.4.1 14-1.4 15-1.1.2.r 17-1.1.2.1.1 17-1.4.2 18-1.1.2 18-1.4 21-1.3.1 22-1.3.1.1 (o2 / observe-01~e.8 :ARG1 (i / increase-01~e.0 :ARG1 (e / express-03~e.1 :ARG2~e.2 (e2 / enzyme :name (n / name :op1 "MMP") :quant (s / several~e.3) :mod (o / other~e.4))) :compared-to~e.15 (m2 / mouse~e.18 :ARG1-of (t2 / treat-04~e.12 :polarity -~e.17))) :mod (a / also~e.7) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.21 :mod "4D"~e.22)) :location (m / mouse~e.14,18 :mod (b / bitransgenic~e.13) :ARG1-of (t / treat-04~e.17 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "doxycycline"~e.10))))) # ::id bel_pmid_1974_2316.9502 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this study , we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1 @-@ deficient ( LRP1-/-) SMCs . # ::alignments 1-1.3.1 2-1.3 4-1.1 5-1 6-1.2.1.1 7-1.2.1 8-1.2.1.1.1.r 10-1.2.1.1.1 11-1.2.1.1.1.1.r 12-1.2.1.1.1.1 13-1.2.1.1.1.1.1 14-1.2 15-1.2.2.3 16-1.2.2.1 17-1.2.2 18-1.2.2.2.r 19-1.2.2.2.2.1.1 21-1.2.2.2.2 21-1.2.2.2.2.2 21-1.2.2.2.2.2.1 21-1.2.2.2.2.2.1.r 21-1.2.2.2.2.2.r (f / find-01~e.5 :ARG0 (w / we~e.4) :ARG1 (a / and~e.14 :op1 (a2 / actin~e.7 :ARG1-of (d / disorganize-01~e.6 :manner~e.8 (f2 / form~e.10 :mod~e.11 (m / membrane~e.12 :ARG1-of (r / ruffle-02~e.13))))) :op2 (m2 / migrate-01~e.17 :ARG0 (c / cell~e.16) :ARG1~e.18 (c2 / cell :name (n / name :op1 "SMC") :mod (p / protein~e.21 :name (n2 / name :op1 "LRP1"~e.19) :ARG2-of~e.21 (m3 / mutate-01~e.21 :mod~e.21 "-/-"~e.21))) :ARG1-of (e / enhance-01~e.15))) :medium (s / study-01~e.2 :mod (t / this~e.1))) # ::id bel_pmid_1974_2316.22040 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because PDGFRb activation , through transphosphorylation of tyrosine residues in its cytoplasmic domain , triggers a cascade of phosphorylation events which eventually lead to the activation of extracellular regulated @-@ protein kinases ( Erks ) , phosphorylated @- Erk1 @/@ 2 was used as an indicator of PDGFRb activation [ 7 ] . # ::alignments 0-1 1-1.1.1.1.1.1 2-1.1.1 7-1.1.1.2.1.1.1.1 8-1.1.1.2.1 10-1.1.1.2.1.1.2.2 10-1.1.1.2.1.1.2.2.r 11-1.1.1.2.1.1.2.1 12-1.1.1.2.1.1.2 14-1.1 16-1.1.2 18-1.1.2.1 21-1.1.3.2 22-1.1.3 23-1.1.3.1.r 25-1.1.3.1 26-1.1.3.1.1.r 27-1.1.3.1.1.1.1 28-1.1.3.1.1.1.2 30-1.1.3.1.1.1.2 31-1.1.3.1.1.1.3 36-1.1.2.1 36-1.2.1.2 38-1.2.1.1.1 40-1.2.1.1.1 42-1.2 43-1.1.3.2.r 43-1.2.2.r 45-1.2.2 45-1.2.2.1 45-1.2.2.1.r 46-1.2.2.1.1.r 47-1.2.2.1.1 48-1.2.2.1.1 50-1.3.1.1.1 (c / cause-01~e.0 :ARG0 (t2 / trigger-01~e.14 :ARG0 (a / activate-01~e.2 :ARG1 (p2 / protein :name (n / name :op1 "PDGFRb"~e.1)) :manner (t3 / transphosphorylate-01 :ARG1 (r / residue~e.8 :mod (a2 / amino-acid :name (n2 / name :op1 "tyrosine"~e.7) :part-of (d / domain~e.12 :mod (c2 / cytoplasm~e.11) :part-of~e.10 p2~e.10))))) :ARG1 (c3 / cascade-01~e.16 :subevent (p / phosphorylate-01~e.18,36)) :ARG0-of (l / lead-03~e.22 :ARG2~e.23 (a3 / activate-01~e.25 :ARG1~e.26 (e2 / enzyme :name (n3 / name :op1 "extracellular"~e.27 :op2 "regulated-protein"~e.28,30 :op3 "kinase"~e.31))) :time~e.43 (e / eventual~e.21))) :ARG1 (u / use-01~e.42 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Erk1/2"~e.38,40) :ARG1-of (p3 / phosphorylate-01~e.36)) :ARG2~e.43 (t / thing~e.45 :ARG0-of~e.45 (i / indicate-01~e.45 :ARG1~e.46 a~e.47,48))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 7~e.50)))) # ::id bel_pmid_1974_2316.28806 ::amr-annotator SDL-AMR-09 ::preferred # ::tok An approximately 2.5 @-@ fold increase of Smad2 phosphorylation at Ser 465 @/@ 467 was also detected in LDLR expressing , LRP1 @-@ deficient SMCs ( Figure 6B , C ) . # ::alignments 1-1.1.2 2-1.1.2.1.1 4-1.1.2.1 5-1.1 6-1.1.1.r 6-1.1.2.1 7-1.1.1.1.1.3.1.1 8-1.1.1 10-1.1.1.1.1.2.1 10-1.1.1.1.2.2.1 11-1.1.1.1.1.1 13-1.1.1.1.2.1 15-1.2 16-1 17-1.4.r 18-1.4.3.1.1.1 19-1.4.3 21-1.4.2.1.1 23-1.4.2 23-1.4.2.2 23-1.4.2.2.1 23-1.4.2.2.1.r 23-1.4.2.2.r 26-1.3.1.1 26-1.3.1.2 27-1.3.1.1.1 (d / detect-01~e.16 :ARG1 (i / increase-01~e.5 :ARG1~e.6 (p / phosphorylate-01~e.8 :ARG1 (a5 / and :op1 (a2 / amino-acid :mod 465~e.11 :name (n / name :op1 "serine"~e.10) :part-of (p2 / protein :name (n2 / name :op1 "Smad2"~e.7))) :op2 (a6 / amino-acid :mod 467~e.13 :name (n6 / name :op1 "serine"~e.10) :part-of p2))) :ARG2 (a3 / approximately~e.1 :op1 (p3 / product-of~e.4,6 :value 2.5~e.2))) :mod (a / also~e.15) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.26 :mod "6B"~e.27) :op2 (f2 / figure~e.26 :mod "6C"))) :location~e.17 (c / cell :name (n4 / name :op1 "SMC") :mod (p5 / protein~e.23 :name (n5 / name :op1 "LRP1"~e.21) :ARG2-of~e.23 (m / mutate-01~e.23 :mod~e.23 "-/-"~e.23)) :ARG3-of (e / express-03~e.19 :ARG2 (p4 / protein :name (n3 / name :op1 "LDLR"~e.18))))) # ::id bel_pmid_1974_2316.28914 ::amr-annotator SDL-AMR-09 ::preferred # ::tok About a two @-@ fold increase of PDGFRb expression was detected in smLRP1-/- mice regardless of LDLR genotype ( Figure 2A , C ) . Increased Erk1 @/@ 2 phosphorylation was also observed in these aortas ( Figure 2A ) . These data suggest that the expression and activation of PDGFRb is only regulated by LRP1 , not LDLR . # ::alignments 0-1.1.1.2 2-1.1.1.2.1.1 4-1.1.1.2.1 5-1.1.1 6-1.1.1.1.r 6-1.1.1.2.1 7-1.1.1.1.1.1.1 8-1.1.1.1 10-1.1 13-1.1.2 14-1.1.3 16-1.1.3.1.1.1.1 17-1.1.3.1 19-1.1.4.1.1 19-1.2.3.1 20-1.1.4.1.1.1 20-1.2.3.1.1 25-1.2.1.2 26-1.2.1.1.1.1 28-1.2.1.1.1.1 29-1.2.1 31-1.2.2 32-1.2 33-1.2.1.3.r 34-1.2.1.3.1 35-1.2.1.3 37-1.1.4.1.1 37-1.1.4.1.2 37-1.2.3.1 38-1.1.4.1.1.1 38-1.2.3.1.1 41-1.3.1.1 42-1.3.1 43-1.3 46-1.3.2.1.2.1 47-1.3.2.1.2 48-1.3.2.1.2.2 49-1.3.2.1.2.1.1.r 50-1.3.2.1.2.1.1.1.1 52-1.3.2.1.3 53-1.3.2.1 53-1.3.2.2 54-1.3.2.1.1.r 55-1.3.2.1.1.1.1 57-1.3.2.2.1 57-1.3.2.2.1.r 58-1.1.3.1.1.1.1 58-1.3.2.2.2.1.1 (m / multi-sentence :snt1 (d / detect-01~e.10 :ARG1 (i / increase-01~e.5 :ARG1~e.6 (e / express-03~e.8 :ARG2 (p2 / protein :name (n / name :op1 "PDGFRb"~e.7))) :ARG2 (a / about~e.0 :op1 (p3 / product-of~e.4,6 :value 2~e.2))) :location (m2 / mouse~e.13 :mod (p4 / protein :name (n2 / name :op1 "smLRP1") :ARG2-of (m3 / mutate-01 :mod "-/-"))) :ARG1-of (r3 / regardless-91~e.14 :ARG2 (g / genotype~e.17 :mod (p5 / protein :name (n3 / name :op1 "LDLR"~e.16,58)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.19,37 :mod "2A"~e.20,38) :op2 (f2 / figure~e.37 :mod "2C")))) :snt2 (o / observe-01~e.32 :ARG1 (p / phosphorylate-01~e.29 :ARG1 (e2 / enzyme :name (n4 / name :op1 "Erk1/2"~e.26,28)) :ARG1-of (i2 / increase-01~e.25) :location~e.33 (a4 / aorta~e.35 :mod (t / this~e.34))) :mod (a3 / also~e.31) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.19,37 :mod "2A"~e.20,38))) :snt3 (s / suggest-01~e.43 :ARG0 (d4 / data~e.42 :mod (t2 / this~e.41)) :ARG1 (c / contrast-01 :ARG1 (r / regulate-01~e.53 :ARG0~e.54 (p6 / protein :name (n5 / name :op1 "LRP1"~e.55)) :ARG1 (a5 / and~e.47 :op1 (e3 / express-03~e.46 :ARG2~e.49 (p7 / protein :name (n6 / name :op1 "PDGFRb"~e.50))) :op2 (a6 / activate-01~e.48 :ARG1 p7)) :mod (o2 / only~e.52)) :ARG2 (r2 / regulate-01~e.53 :polarity~e.57 -~e.57 :ARG0 (p8 / protein :name (n7 / name :op1 "LDLR"~e.58)) :ARG1 a5)))) # ::id bel_pmid_1974_2316.28918 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Studies from our laboratory have shown that LRP1 suppresses PDGF receptor b ( PDGFRb ) activation and protects against atherosclerosis . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1 5-1 6-1.2.r 7-1.2.1.1.1.1 8-1.2.1 9-1.2.1.2.1.1.1 10-1.2.1.2.1.1.2 11-1.2.1.2.1.1.3 15-1.2.1.2 16-1.2 17-1.2.2 18-1.2.2.2.r 19-1.2.2.2 (s / show-01~e.5 :ARG0 (s2 / study-01~e.0 :source~e.1 (l / laboratory~e.3 :poss-of~e.2 (w / we~e.2))) :ARG1~e.6 (a / and~e.16 :op1 (s3 / suppress-01~e.8 :ARG0 (p / protein :name (n / name :op1 "LRP1"~e.7)) :ARG1 (a2 / activate-01~e.15 :ARG1 (p2 / protein :name (n2 / name :op1 "PDGF"~e.9 :op2 "receptor"~e.10 :op3 "b"~e.11)))) :op2 (p3 / protect-01~e.17 :ARG0 p :ARG2~e.18 (a3 / atherosclerosis~e.19)))) # ::id bel_pmid_1980_5133.8276 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2 @-@ specific genes # ::alignments 0-1.1.2.1.1.1 1-1.1.2 3-1 4-1.1 5-1.1.3.r 6-1.1.3 7-1.1.4 8-1.1.1.r 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.1.1.1.1 13-1.1.1.1.1 14-1.1.1.1 (c2 / cause-01~e.3 :ARG1 (r / require-01~e.4 :ARG0~e.8 (u / upregulate-01~e.9 :ARG1~e.10 (g2 / gene~e.14 :ARG1-of (s / specific-02~e.13 :ARG2 (c / cell :name (n2 / name :op1 "M2"~e.11))))) :ARG1 (e2 / express-03~e.1 :ARG2 (p / protein :name (n / name :op1 "Cebpb"~e.0))) :purpose~e.5 (i / infiltrate-01~e.6) :location (m / macrophage~e.7))) # ::id bel_pmid_1980_5133.25992 ::amr-annotator SDL-AMR-09 ::preferred # ::tok deletion of two CREB @-@ binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation . This blocks the downstream induction of M2 @-@ specific Msr1 , Il10 , II13 ra , and Arg @-@ 1 genes , whereas the inflammatory ( M1 ) genes Il1 , Il6 , Tnfa , and Il12 are not affected # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1 3-1.1.1.1.2.1.1.1 5-1.1.1.1.2 6-1.1.1.1 7-1.1.1.1.3.r 9-1.1.1.1.3.1.1.1.1 10-1.1.1.1.3 10-1.1.1.1.3.1 10-1.1.1.1.3.1.r 11-1.1 12-1.1.2.1 13-1.1.2 15-1.1.3.1 16-1.1.3 18-1.2.1 19-1.2 21-1.2.2.2 22-1.2.2 23-1.2.2.1.r 24-1.2.2.1.2.1.1.1 26-1.2.2.1.2 27-1.2.2.1.1.1.1.1.1 29-1.2.2.1.1.1.2.1.1 34-1.2.2.1.1.1 35-1.2.2.1.1.1.4.1.1 37-1.2.2.1.1.1.4.1.1 38-1.2.2.1 40-1.2.3 42-1.2.3.1.2.2 46-1.2.3.1.2 47-1.2.3.1.2.1.1.1.1.1 49-1.2.3.1.2.1.1.2.1.1 51-1.2.3.1.2.1.1.3.1.1 54-1.2.3.1.2.1.1.4.1.1 56-1.2.3.1.1 56-1.2.3.1.1.r 57-1.2.3.1 (m / multi-sentence :snt1 (a / abrogate-01~e.11 :ARG0 (d / delete-01~e.0 :ARG1~e.1 (p / protein-segment~e.6 :quant 2~e.2 :ARG1-of (b / bind-01~e.5 :ARG2 (p2 / protein :name (n / name :op1 "CREB"~e.3))) :part-of~e.7 (m3 / molecular-physical-entity~e.10 :ARG0-of~e.10 (p3 / promote-01~e.10 :ARG1 (p4 / protein :name (n2 / name :op1 "Cebpb"~e.9)))))) :ARG1 (i / induce-01~e.13 :ARG2 p4~e.12) :time (a2 / activate-01~e.16 :ARG1 (m2 / macrophage~e.15))) :snt2 (b2 / block-01~e.19 :ARG0 (t2 / this~e.18) :ARG1 (i2 / induce-01~e.22 :ARG2~e.23 (g / gene~e.38 :ARG2-of (i3 / include-91 :ARG1 (a3 / and~e.34 :op1 (g2 / gene :name (n5 / name :op1 "Msr1"~e.27)) :op2 (g3 / gene :name (n6 / name :op1 "Il10"~e.29)) :op3 (g4 / gene :name (n7 / name :op1 "II13ra")) :op4 (g5 / gene :name (n8 / name :op1 "Arg-1"~e.35,37)))) :ARG1-of (s / specific-02~e.26 :ARG2 (c2 / cell :name (n4 / name :op1 "M2"~e.24)))) :mod (d2 / downstream~e.21)) :ARG1-of (c / contrast-01~e.40 :ARG2 (a4 / affect-01~e.57 :polarity~e.56 -~e.56 :ARG1 (g11 / gene~e.46 :ARG2-of (i4 / include-91 :ARG1 (a5 / and :op1 (g7 / gene :name (n10 / name :op1 "Il1"~e.47)) :op2 (g8 / gene :name (n11 / name :op1 "Il6"~e.49)) :op3 (g9 / gene :name (n12 / name :op1 "Tnfa"~e.51)) :op4 (g10 / gene :name (n13 / name :op1 "Il12"~e.54)))) :ARG0-of (i5 / inflame-01~e.42)))))) # ::id bel_pmid_1984_2832.19720 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Studies using TLR @-@ 4 -/- mice have demonstrated that induction of MCP @-@ 1 in BAL fluid upon exposure of mice to subacute ( exposed for a period of 5 weeks ) levels of CS depends on the presence of wild @-@ type TLR @-@ 4 , whereas TLR @-@ 4 plays a minor role in MCP @-@ 1 induction in the presence of chronic smoke exposure ( 26 weeks ) [ 45 ] . # ::alignments 0-1.1 1-1.1.1 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1.1.2.1 6-1.1.1.1 8-1 9-1.2.r 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.1 14-1.2.1.1.1.1 15-1.2.1.2.r 16-1.2.1.2.1 16-1.2.1.2.1.1 16-1.2.1.2.1.1.1 16-1.2.1.2.1.1.1.r 16-1.2.1.2.1.1.r 17-1.2.1.2 19-1.2.1.3 21-1.2.1.3.1 23-1.2.1.3.2.2 25-1.2.1.3 29-1.2.1.3.3.r 30-1.2.1.3.3.1 31-1.2.1.3.3.2 33-1.2.1.3.2 34-1.2.1.3.2.1.r 35-1.2.1.3.2.1.1.1 36-1.2 37-1.2.2.r 39-1.2.2 40-1.2.2.1.r 41-1.2.2.1.2 43-1.2.2.1.2 44-1.2.2.1.1.1 46-1.2.2.1.1.1 48-1.2.3 49-1.2.3.1.1 50-1.2.3.1.1 51-1.2.3.1.1 52-1.2.3.1 54-1.2.3.1.2.1 55-1.2.3.1.2 56-1.2.3.1.2.2.r 57-1.2.3.1.2.2.1 58-1.2.3.1.2.2.1 59-1.2.3.1.2.2.1 60-1.2.3.1.2.2 61-1.2.3.1.2.2.2.r 63-1.2.3.1.2.2.2 64-1.2.3.1.2.2.2.1.r 65-1.2.3.1.2.2.2.1.1.1 66-1.2.3.1.2.2.2.1.1 67-1.2.3.1.2.2.2.1 69-1.2.3.1.2.2.2.1.2.1 70-1.2.3.1.2.2.2.1.2.2 73-1.3.1.1.1 (d / demonstrate-01~e.8 :ARG0 (s / study-01~e.0 :ARG0-of (u / use-01~e.1 :ARG1 (m / mouse~e.6 :mod (p / protein :name (n / name :op1 "TLR-4"~e.2,4) :ARG2-of (m2 / mutate-01 :mod "-/-"~e.5))))) :ARG1~e.9 (d2 / depend-01~e.36 :ARG0 (i / induce-01~e.10 :ARG2~e.11 (p2 / protein :name (n2 / name :op1 "MCP-1"~e.12,14)) :location~e.15 (f / fluid~e.17 :mod (l2 / lavage~e.16 :mod~e.16 (a / alveolus~e.16 :mod~e.16 (b / bronchus~e.16)))) :time (e / expose-01~e.19,25 :ARG1 (m3 / mouse~e.21) :ARG2 (l / level~e.33 :quant-of~e.34 (p4 / protein :name (n4 / name :op1 "CS"~e.35)) :mod (s2 / subacute~e.23)) :duration~e.29 (t4 / temporal-quantity :quant 5~e.30 :unit (w / week~e.31)))) :ARG1~e.37 (p5 / present-02~e.39 :ARG1~e.40 (p6 / protein :name (n5 / name :op1 "TLR-4"~e.44,46) :mod (w3 / wild-type~e.41,43))) :ARG1-of (c / contrast-01~e.48 :ARG2 (p7 / play-02~e.52 :ARG0 p6~e.49,50,51 :ARG1 (r / role~e.55 :ARG1-of (m4 / minor-01~e.54) :domain~e.56 (i2 / induce-01~e.60 :ARG2 p2~e.57,58,59 :condition~e.61 (p8 / present-02~e.63 :ARG1~e.64 (e2 / expose-01~e.67 :ARG2 (s3 / smoke~e.66 :mod (c2 / chronic~e.65)) :duration (t2 / temporal-quantity :quant 26~e.69 :unit (w2 / week~e.70))))))))) :ARG1-of (d3 / describe-01 :ARG0 (p10 / publication :ARG1-of (c3 / cite-01 :ARG2 45~e.73)))) # ::id bel_pmid_1984_2832.26184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LPS stimulated pulmonary neutrophil recruitment , NF @-@ kB promoter activity , and TNF @-@ a secretion are found to be severely impaired in GM @-@ CSF-/- mice . # ::alignments 0-1.1.1.1.2.1.1.1 1-1.1.1.1.2 2-1.1.1.1.1.2 3-1.1.1.1.1.1.1 4-1.1.1.1 6-1.1.1.2.1.1.1.1.1 8-1.1.1.2.1.1.1.1.1 9-1.1.1.2.1 9-1.1.1.2.1.1 9-1.1.1.2.1.1.r 10-1.1.1.2 12-1.1.1 13-1.1.1.3.1.1.1 15-1.1.1.3.1.1.1 16-1.1.1.3 18-1 21-1.1.2 21-1.1.2.r 22-1.1 23-1.1.3.r 24-1.1.3.1.1.1 27-1.1.3 (f / find-01~e.18 :ARG1 (i / impair-01~e.22 :ARG1 (a / and~e.12 :op1 (r / recruit-01~e.4 :ARG1 (c / cell :name (n2 / name :op1 "neutrophil"~e.3) :mod (p / pulmonary~e.2)) :ARG1-of (s / stimulate-01~e.1 :ARG0 (m / molecular-physical-entity :name (n / name :op1 "LPS"~e.0)))) :op2 (a2 / activity-06~e.10 :ARG0 (t / thing~e.9 :ARG0-of~e.9 (p2 / promote-01~e.9 :ARG1 (p3 / protein :name (n3 / name :op1 "NF-kB"~e.6,8))))) :op3 (s2 / secrete-01~e.16 :ARG1 (p4 / protein :name (n4 / name :op1 "TNF-a"~e.13,15)))) :manner~e.21 (s3 / severe~e.21) :location~e.23 (m2 / mouse~e.27 :mod (p5 / protein :name (n5 / name :op1 "GM-CSF"~e.24) :ARG2-of (m3 / mutate-01 :mod "-/-"))))) # ::id bel_pmid_1984_2832.28124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 1b increased the production of neutrophil chemoattractants such as Gro @-@ alpha ( CXCL1 ) and MIP @-@ 2 ( CXCL2 ) in lungs . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 5-1.2 6-1.2.1.r 7-1.2.1.1 8-1.2.1 9-1.2.1.2.r 10-1.2.1.2.r 11-1.2.1.2.1.1.1 13-1.2.1.2.1.1.1 15-1.2.1.2.1.2.1.1.1 17-1.2.1.2 18-1.2.1.2.2.1.1 20-1.2.1.2.2.1.1 22-1.2.1.2.2.2.1.1.1 24-1.2.1.3.r 25-1.2.1.3 (i / increase-01~e.3 :ARG0 (p / protein :name (n / name :op1 "IL-1b"~e.0,2)) :ARG1 (p2 / produce-01~e.5 :ARG1~e.6 (c / chemoattractants~e.8 :mod (n2 / neutrophil~e.7) :example~e.9,10 (a / and~e.17 :op1 (p3 / protein :name (n3 / name :op1 "Gro-alpha"~e.11,13) :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n5 / name :op1 "CXCL1"~e.15)))) :op2 (p4 / protein :name (n4 / name :op1 "MIP-2"~e.18,20) :ARG1-of (m2 / mean-01 :ARG2 (p6 / protein :name (n6 / name :op1 "CXCL2"~e.22))))) :location~e.24 (l / lung~e.25)))) # ::id bel_pmid_1984_2832.31640 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tollip has been shown to associate directly with TLR @-@ 4 and inhibit TLR @-@ 4 @-@ mediated activation of NF @- kB luciferase reporter vectors in a mouse macrophage cell line ( RAW @-@ 264.7 ) . # ::alignments 0-1.1.1.1.1.1 3-1 5-1.1.1 6-1.1.1.3 7-1.1.1.2.r 8-1.1.1.2.1.1 10-1.1.1.2.1.1 11-1.1 12-1.1.2 13-1.1.2.2.2.1 14-1.1.2.2.2.1 15-1.1.2.2.2.1 17-1.1.2.2.2 18-1.1.2.2 19-1.1.2.2.1.r 20-1.1.2.2.1.1.1.1 22-1.1.2.2.1.1.1.2 23-1.1.2.2.1.1.1.3 24-1.1.2.2.1.1.1.4 25-1.1.2.2.1 26-1.1.2.3.r 28-1.1.2.3.2 29-1.1.2.3.3 30-1.1.2.3 31-1.1.2.3 33-1.1.2.3.1.1 35-1.1.2.3.1.1 (s / show-01~e.3 :ARG1 (a3 / and~e.11 :op1 (a / associate-01~e.5 :ARG1 (p2 / protein :name (n / name :op1 "Tollip"~e.0)) :ARG2~e.7 (p3 / protein :name (n2 / name :op1 "TLR-4"~e.8,10)) :ARG1-of (d / direct-02~e.6)) :op2 (i / inhibit-01~e.12 :ARG0 p2 :ARG1 (a2 / activate-01~e.18 :ARG1~e.19 (v / vector~e.25 :mod (p / protein :name (n3 / name :op1 "NF-"~e.20 :op2 "kB"~e.22 :op3 "luciferase"~e.23 :op4 "reporter"~e.24))) :ARG1-of (m / mediate-01~e.17 :ARG0 p3~e.13,14,15)) :location~e.26 (c / cell-line~e.30,31 :name (n4 / name :op1 "RAW-264.7"~e.33,35) :mod (m2 / mouse~e.28) :mod (m3 / macrophage~e.29))))) # ::id bel_pmid_1984_2832.34344 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of sputum cells from COPD patients with acetylcholine produced increased amounts of LTB4 , which was sensitive both to treatment with a muscarinic receptor antagonist and to the inhibition of ERK @- 1 @/@ 2 phosphorylation . This increased LTB4 synthesis also directly correlated with increased neutrophil chemotaxis . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1 3-1.1.1.1 4-1.1.1.1.2.r 5-1.1.1.1.2.1.1.1 6-1.1.1.1.2 7-1.1.1.2.r 8-1.1.1.2.1.1 9-1.1 10-1.1.2.1 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2.1.1 17-1.1.2.2 17-1.1.2.2.2 17-1.1.2.2.2.r 19-1.1.2.2.2.1.r 20-1.1.2.2.2.1.1 21-1.1.2.2.2.1.1.1.r 23-1.1.2.2.2.1.1.1.1.1 24-1.1.2.2.2.1.1.1.1.2 25-1.1.2.2.2.1.1.1.1.3 26-1.1.2.2.2.1 29-1.1.2.2.2.1.2 30-1.1.2.2.2.1.2.1.r 31-1.1.2.2.2.1.2.1.1.1.1 33-1.1.2.2.2.1.2.1.1.1.1 35-1.1.2.2.2.1.2.1.1.1.1 36-1.1.2.2.2.1.2.1 38-1.2.1.3 39-1.2.1.2 40-1.2.1.1.1.1 41-1.2.1 42-1.2.3 43-1.2.4 44-1.2 45-1.2.2.r 46-1.2.2.2 47-1.2.2.1 48-1.2.2 (m / multi-sentence :snt1 (p2 / produce-01~e.9 :ARG0 (t / treat-04~e.0 :ARG1~e.1 (c / cell~e.3 :mod (s / sputum~e.2) :source~e.4 (p3 / patient~e.6 :mod (d / disease :name (n2 / name :op1 "COPD"~e.5)))) :ARG2~e.7 (s4 / small-molecule :name (n / name :op1 "acetylcholine"~e.8))) :ARG1 (a / amount~e.11 :ARG1-of (i / increase-01~e.10) :quant-of~e.12 (p4 / protein~e.17 :name (n3 / name :op1 "LTB4"~e.13) :ARG0-of~e.17 (s2 / sensitive-03~e.17 :ARG1~e.19 (a3 / and~e.26 :op1 (t2 / treat-04~e.20 :ARG2~e.21 (p5 / protein :name (n4 / name :op1 "muscarinic"~e.23 :op2 "receptor"~e.24 :op3 "antagonist"~e.25))) :op2 (i2 / inhibit-01~e.29 :ARG1~e.30 (p / phosphorylate-01~e.36 :ARG1 (e2 / enzyme :name (n5 / name :op1 "ERK-1/2"~e.31,33,35))))))))) :snt2 (c2 / correlate-01~e.44 :ARG1 (s3 / synthesize-01~e.41 :ARG1 (p6 / protein :name (n6 / name :op1 "LTB4"~e.40)) :ARG1-of (i3 / increase-01~e.39) :mod (t3 / this~e.38)) :ARG2~e.45 (c3 / chemotaxis~e.48 :mod (n7 / neutrophil~e.47) :ARG1-of (i4 / increase-01~e.46)) :mod (a4 / also~e.42) :ARG1-of (d2 / direct-02~e.43))) # ::id bel_pmid_1984_2832.36854 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IRAK @-@ 1 activation and recruitment is essential for activation of TRAF6 ( TNF @-@ associated factor 6 ) , which is an essential adaptor for MyD88 @-@ dependent NF @-@ kB activation . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 3-1.1.3 4-1.1 5-1.1.2 6-1.1.r 7-1 9-1.1.1 10-1.1.3.1.r 11-1.1.3.1.1.1 23-1.1.3.1.2.2 26-1.1.3.1.2.1.2.1.1.1 28-1.1.3.1.2.1.2 29-1.1.3.1.2.1.1.1.1 31-1.1.3.1.2.1.1.1.1 32-1.1.3.1.2.1 (e / essential~e.7 :domain~e.6 (a / and~e.4 :op1 (a2 / activate-01~e.3,9 :ARG1 (e2 / enzyme :name (n / name :op1 "IRAK-1"~e.0,2))) :op2 (r / recruit-01~e.5 :ARG1 e2) :purpose (a3 / activate-01~e.3 :ARG1~e.10 (p / protein :name (n2 / name :op1 "TRAF6"~e.11) :ARG0-of (a4 / adapt-01 :ARG1 (a5 / activate-01~e.32 :ARG1 (p2 / protein :name (n3 / name :op1 "NF-kB"~e.29,31)) :ARG0-of (d / depend-01~e.28 :ARG1 (p3 / protein :name (n4 / name :op1 "MyD88"~e.26)))) :mod (e3 / essential~e.23)))))) # ::id bel_pmid_1984_2832.38430 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has also been shown that IL @-@ 1b stimulates the release and activity of MMP @-@ 9 ( matrix metalloproteinase @-@ 9 ) from AM obtained from COPD smokers , which is significantly higher in comparison with those obtained from healthy smokers and non @-@ smokers [ 155 ] . # ::alignments 2-1.2 4-1 5-1.1.r 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1 11-1.1.2.1 11-1.1.2.4.3.1 12-1.1.2 13-1.1.2.2 13-1.1.2.4.3.2 14-1.1.2.1.1.r 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 22-1.1.2.1.1.1.1 24-1.1.2.3.r 25-1.1.2.3.1.1 26-1.1.2.3.2 27-1.1.2.3.r 28-1.1.2.3.2.1.2.1.1 29-1.1.2.3.2.1 29-1.1.2.3.2.1.1 29-1.1.2.3.2.1.1.r 33-1.1.2.4.2 34-1.1.2.4 34-1.1.2.4.1 34-1.1.2.4.1.r 36-1.1.2.4.3.r 39-1.1.2.3.2 39-1.1.2.4.3.3 40-1.1.2.3.r 40-1.1.2.4.3.3.1.r 41-1.1.2.4.3.3.1.1.2 42-1.1.2.4.3.3.1.1 42-1.1.2.4.3.3.1.1.1 42-1.1.2.4.3.3.1.1.1.r 42-1.1.2.4.3.3.1.2 42-1.1.2.4.3.3.1.2.1 42-1.1.2.4.3.3.1.2.1.r 43-1.1.2.4.3.3.1 44-1.1.2.4.3.3.1.2.1.1 44-1.1.2.4.3.3.1.2.1.1.r 46-1.1.2.3.2.1.1.r 48-1.3.1.1.1 (s2 / show-01~e.4 :ARG1~e.5 (s3 / stimulate-01~e.9 :ARG0 (p2 / protein :name (n / name :op1 "IL-1b"~e.6,8)) :ARG1 (a2 / and~e.12 :op1 (r / release-01~e.11 :ARG1~e.14 (e / enzyme :name (n2 / name :op1 "MMP-9"~e.15,17,22))) :op2 (a3 / activity-06~e.13 :ARG0 e) :source~e.24,27,40 (s7 / small-molecule :name (n3 / name :op1 "AM"~e.25) :ARG1-of (o / obtain-01~e.26,39 :ARG2 (p / person~e.29 :ARG0-of~e.29,46 (s / smoke-02~e.29) :mod (d / disease :name (n4 / name :op1 "COPD"~e.28))))) :ARG1-of (h / high-02~e.34 :degree~e.34 (m / more~e.34) :ARG1-of (s4 / significant-02~e.33) :compared-to~e.36 (a5 / and :op1 (r2 / release-01~e.11 :ARG1 e) :op2 (a6 / activity-06~e.13 :ARG0 e) :ARG1-of (o2 / obtain-01~e.39 :ARG2~e.40 (a4 / and~e.43 :op1 (p3 / person~e.42 :ARG0-of~e.42 (s5 / smoke-02~e.42) :mod (h2 / healthy~e.41)) :op2 (p4 / person~e.42 :ARG0-of~e.42 (s6 / smoke-02~e.42 :polarity~e.44 -~e.44) :mod h2))))))) :mod (a / also~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 155~e.48)))) # ::id bel_pmid_1984_2832.38592 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , preincubation with F( ab ')2 fragments of a monoclonal anti @-@ human IL @-@ 8 antibody inhibited neutrophil chemotaxis to CB sputum supernatants by 75 % [ 30 ] . # ::alignments 0-1.6 7-1.1.1 8-1.1.1.1.r 10-1.1.1.1.2.1.1 11-1.1.1.1.2.1.2 11-1.1.1.1.2.2 13-1.1.1.1.2.1.2 13-1.1.1.1.2.2.1.2 14-1.1.1.1.2.1.3 14-1.1.1.1.2.2.1.1.1 16-1.1.1.1.2.1.3 16-1.1.1.1.2.2.1.1.1 17-1.1.1.1.2 17-1.1.1.1.2.1.4 18-1 19-1.2.1 20-1.2 23-1.3.1 24-1.3 25-1.4.r 26-1.4.1 27-1.4 29-1.5.1.1.1 (i / inhibit-01~e.18 :ARG0 (p2 / preincubate-01 :ARG2 (f / fragment-01~e.7 :ARG1~e.8 (s3 / small-molecule :name (n3 / name :op1 "F(ab')2") :part-of (a / antibody~e.17 :name (n4 / name :op1 "monoclonal"~e.10 :op2 "anti-human"~e.11,13 :op3 "IL-8"~e.14,16 :op4 "antibody"~e.17) :ARG0-of (c2 / counter-01~e.11 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-8"~e.14,16) :mod (h / human~e.13))) :mod (m / monoclone))))) :ARG1 (c / chemotaxis~e.20 :mod (n2 / neutrophil~e.19)) :location (s / supernatant~e.24 :mod (s2 / sputum~e.23 :mod (d2 / disease :name (n / name :op1 "chronic" :op2 "bronchitis")))) :quant~e.25 (p / percentage-entity~e.27 :value 75~e.26) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 30~e.29))) :ARG1-of (r / resemble-01~e.0)) # ::id bel_pmid_1984_6878.15410 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Including adenosine with IFN @-@ gamma treatment delayed any measureable increase in STAT1 activation by > 60 min , and led to significantly reduced STAT1 activity at 60 , 120 , and 240 min post @-@ stimulation compared with cells treated with IFN @-@ gamma alone ( p < 0.05 ; Fig. 4 ) . # ::alignments 0-1.1.1 1-1.1.1.1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1.1 5-1.1.1.2.1.1.1 6-1.1.1.2 7-1.1 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1.1.1.1 13-1.1.2.1 14-1.1.3.r 15-1.1.3 16-1.1.3.1.1 17-1.1.3.1.2 19-1 20-1.2 21-1.2.2.r 22-1.2.2.2 23-1.2.2 24-1.2.2.1.1 25-1.2.2.1 26-1.2.2.3.r 27-1.2.2.3.1.1.1.1 29-1.2.2.3.1.1.2.1 31-1.2.2.3.1.1 32-1.2.2.3.1.1.3.1 33-1.2.2.3.1.1.3.2 34-1.2.2.3 36-1.2.2.3.1 37-1.2.2.4.r 39-1.2.2.4 40-1.2.2.4.1 41-1.2.2.4.1.1.r 42-1.2.2.4.1.1 43-1.2.2.4.1.1 44-1.2.2.4.1.1 45-1.2.2.4.1.2 47-1.4 48-1.4.1 49-1.4.1.1 51-1.3.1 52-1.3.1.1 (a / and~e.19 :op1 (d / delay-01~e.7 :ARG0 (i / include-01~e.0 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "adenosine"~e.1)) :ARG2~e.2 (t / treat-04~e.6 :ARG2 (p / protein :name (n / name :op1 "IFN-gamma"~e.3,5)))) :ARG1 (i2 / increase-01~e.10 :ARG1~e.11 (a3 / activate-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT1"~e.12))) :ARG1-of (m / measure-01 :ARG1-of (p5 / possible-01))) :ARG2~e.14 (m2 / more-than~e.15 :op1 (t2 / temporal-quantity :quant 60~e.16 :unit (m3 / minute~e.17)))) :op2 (l / lead-03~e.20 :ARG0 i :ARG2~e.21 (r / reduce-01~e.23 :ARG1 (a4 / activity-06~e.25 :ARG0 p2~e.24) :ARG2 (s / significant-02~e.22) :time~e.26 (a2 / after~e.34 :op1 (s2 / stimulate-01~e.36 :quant (a5 / and~e.31 :op1 (t3 / temporal-quantity :quant 60~e.27 :unit m3) :op2 (t4 / temporal-quantity :quant 120~e.29 :unit m3) :op3 (t5 / temporal-quantity :quant 240~e.32 :unit m3~e.33)))) :compared-to~e.37 (c / cell~e.39 :ARG1-of (t6 / treat-04~e.40 :ARG2~e.41 p~e.42,43,44 :manner (a6 / alone~e.45))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.51 :mod 4~e.52)) :ARG1-of (s3 / statistical-test-91~e.47 :ARG2 (l2 / less-than~e.48 :op1 0.05~e.49))) # ::id bel_pmid_1984_6878.18750 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pretreatment with CCPA ( A1 receptor agonist ) , NECA ( non @-@ specific A1 and A2 receptor agonist ) , and CGS21680 ( A2A receptor agonist ) all resulted in a 14 @- to 15 @-@ fold increase in STAT1 activity over control cells , levels comparable to what was observed in cells treated with IFN @-@ gamma alone ( Fig . 6 , A ? C ) # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1.1 4-1.1.1.1.1.2.1.1.1.1 5-1.1.1.1.1.2.1.1 6-1.1.1.1.1.2.1 9-1.1.1.1.2.1.1 11-1.1.1.1.2.2.1.3.1 11-1.1.1.1.2.2.1.3.1.r 13-1.1.1.1.2.2.1.3 14-1.1.1.1.1.2.1.1.1.1 15-1.1.1.1 15-1.1.1.1.2.2.1 17-1.1.1.1.1.2.1.1 18-1.1.1.1.1 18-1.1.1.1.1.2.1 18-1.1.1.1.2 18-1.1.1.1.2.2.1.1 18-1.1.1.1.2.2.1.2 18-1.1.1.1.3 21-1.1.1.1 22-1.1.1.1.3.1.1 24-1.1.1.1.3.2.1.1.1.1 25-1.1.1.1.1.2.1.1 25-1.1.1.1.3.2.1.1 26-1.1.1.1.1.2.1 26-1.1.1.1.3.2.1 29-1.1 30-1.1.2.r 32-1.1.2.2.1.1 35-1.1.2.2.2.1 37-1.1.2.2.1 37-1.1.2.2.2 38-1.1.2 39-1.1.2.1.r 40-1.1.2.1.1.1.1 41-1.1.2.1 43-1.1.2.3.1 44-1.1.2.3 46-1.1.2.2.3.1 47-1.1.2.2.3 51-1.1.2.2.3.1.1 52-1.1.2.2.3.1.1.1.r 53-1.1.2.2.3.1.1.1 54-1.1.2.2.3.1.1.1.1 55-1.1.2.2.3.1.1.1.1.1.r 56-1.1.2.2.3.1.1.1.1.1.1.1 58-1.1.2.2.3.1.1.1.1.1.1.1 59-1.1.2.2.3.1.1.1.1.1.2 61-1.2.1.1 61-1.2.1.2 (a / and :op1 (r / result-01~e.29 :ARG1 (p / pretreat-01~e.0 :ARG3~e.1 (a2 / and~e.15,21 :op1 (a3 / agonist~e.18 :name (n / name :op1 "CCPA"~e.2) :ARG1-of (m / mean-01 :ARG2 (a12 / agonist~e.6,18,26 :mod (r3 / receptor~e.5,17,25 :name (n8 / name :op1 "A1"~e.4,14))))) :op2 (a4 / agonist~e.18 :name (n2 / name :op1 "NECA"~e.9) :ARG1-of (m2 / mean-01 :ARG2 (a10 / and~e.15 :op1 (a13 / agonist~e.18 :mod r2) :op2 (a14 / agonist~e.18 :mod r2) :ARG1-of (s / specific-02~e.13 :polarity~e.11 -~e.11)))) :op3 (a5 / agonist~e.18 :name (n3 / name :op1 "CGS21680"~e.22) :ARG1-of (m3 / mean-01 :ARG2 (a9 / agonist~e.26 :mod (r2 / receptor~e.25 :name (n7 / name :op1 "A2A"~e.24))))))) :ARG2~e.30 (i / increase-01~e.38 :ARG1~e.39 (a6 / activity-06~e.41 :ARG0 (p2 / protein :name (n4 / name :op1 "STAT1"~e.40))) :ARG2 (b / between :op1 (p3 / product-of~e.37 :value 14~e.32) :op2 (p4 / product-of~e.37 :value 15~e.35) :ARG1-of (c3 / comparable-03~e.47 :ARG2 (l2 / level~e.46 :ARG1-of (o / observe-01~e.51 :location~e.52 (c4 / cell~e.53 :ARG1-of (t2 / treat-04~e.54 :ARG2~e.55 (p5 / protein :name (n5 / name :op1 "IFN-gamma"~e.56,58) :mod (a7 / alone~e.59)))))))) :location (c / cell~e.44 :mod (c2 / control-01~e.43)))) :ARG1-of (d / describe-01 :ARG0 (a8 / and :op1 (f / figure~e.61 :mod "6A") :op2 (f2 / figure~e.61 :mod "6C")))) # ::id bel_pmid_1984_6878.27666 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , we found that IFN @-@ gamma led to a rapid rise in both JAK1 and JAK2 phosphorylation band density above baseline levels , and this IFN @-@ gamma @-@ induced JAK activation was not altered by adenosine treatment at any time point ( data not shown ) . # ::alignments 0-1.2.4.r 1-1.4 3-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.1.1 8-1.1.2.1.1.1 9-1.1.2 12-1.1.2.2.3 13-1.1.2.2 16-1.1.2.2.1.1.1.1.1.1.1 17-1.1.2.2.1.1.1.1 18-1.1.2.2.1.1.1.1.2.1.1 19-1.1.2.2.1.1.1 20-1.1.2.2.1.1 21-1.1.2.2.1 22-1.1.2.2.2 23-1.1.2.2.2.1.1 24-1.1.2.2.2.1 28-1.1.2.1.1.1 30-1.1.2.1.1.1 32-1.2.3.2 33-1.2.3.1.1.1 34-1.2.3 36-1.2.1 36-1.2.1.r 37-1.2 38-1.2.2.r 39-1.2.2.1.1.1 40-1.2.2 42-1.2.4.1 43-1.2.4.r 44-1.2.4 46-1.3.1 47-1.3.1.1.1 47-1.3.1.1.1.r 48-1.3.1.1 (a / and :op1 (f / find-01~e.4 :ARG0 (w / we~e.3) :ARG1~e.5 (l / lead-03~e.9 :ARG1 (p2 / protein :name (n / name :op1 "IFN-gamma"~e.6,8,28,30)) :ARG2 (r / rise-01~e.13 :ARG1 (d / density~e.21 :poss (b / band~e.20 :mod (p / phosphorylate-01~e.19 :ARG1 (a2 / and~e.17 :op1 (e3 / enzyme :name (n2 / name :op1 "JAK1"~e.16)) :op2 (e2 / enzyme :name (n3 / name :op1 "JAK2"~e.18)))))) :ARG4 (a7 / above~e.22 :op1 (l2 / level~e.24 :mod (b2 / baseline~e.23))) :mod (r2 / rapid~e.12)))) :op2 (a3 / alter-01~e.37 :polarity~e.36 -~e.36 :ARG0~e.38 (t / treat-04~e.40 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "adenosine"~e.39))) :ARG1 (a4 / activate-01~e.34 :ARG1 (e4 / enzyme :name (n4 / name :op1 "JAK"~e.33)) :ARG2-of (i / induce-01~e.32 :ARG0 p2)) :time~e.0,43 (p6 / point~e.44 :mod (a6 / any~e.42))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.46 :ARG1-of (s / show-01~e.48 :polarity~e.47 -~e.47))) :ARG1-of (e / expect-01~e.1)) # ::id bel_pmid_1996_7723.42048 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mechanistically , endothelial a6 @-@ integrin deficiency elevated significantly VEGF @-@ mediated angiogenesis both in vivo and ex vivo . # ::alignments 0-1.4 2-1.1.1.2 3-1.1.1.1.1 5-1.1.1.1.1 7-1 8-1.3 9-1.2.1.1.1.1 11-1.2.1 12-1.2 13-1.5.3 14-1.5.1 15-1.5.1 15-1.5.2 16-1.5 17-1.5.2 18-1.5.1 (e / elevate-01~e.7 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "a6-integrin"~e.3,5) :mod (e2 / endothelium~e.2))) :ARG1 (a / angiogenesis~e.12 :ARG1-of (m2 / mediate-01~e.11 :ARG0 (p2 / protein :name (n2 / name :op1 "VEGF"~e.9)))) :ARG1-of (s / significant-02~e.8) :manner (m / mechanistic~e.0) :manner (a2 / and~e.16 :op2 (i / in-vivo~e.14,15,18) :op2 (e3 / ex-vivo~e.15,17) :mod (b / both~e.13))) # ::id bel_pmid_1996_7723.42050 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In particular , a6 @-@ integrin @-@ deficient endothelial cells displayed increased levels of VEGF @-@ receptor 2 ( VEGFR2 ) and VEGF @-@ mediated downstream ERK1 @/@ 2 activation . # ::alignments 1-1.3 3-1.1.2.1.1.1 5-1.1.2.1.1.1 8-1.1.1 9-1.1 10-1 11-1.2.1.2 12-1.2.1 13-1.2.1.1.r 14-1.2.1.1.1.1 16-1.2.1.1.1.1 17-1.2.1.1.1.2 21-1.2 22-1.2.2.3.1.1.1 24-1.2.2.3 25-1.2.2.2 26-1.2.2.1.1.1 28-1.2.2.1.1.1 29-1.2.2 (d / display-01~e.10 :ARG0 (c / cell~e.9 :mod (e / endothelium~e.8) :ARG0-of (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "a6-integrin"~e.3,5)))) :ARG1 (a / and~e.21 :op1 (l2 / level~e.12 :quant-of~e.13 (p2 / protein :name (n2 / name :op1 "VEGF-receptor"~e.14,16 :op2 2~e.17)) :ARG1-of (i / increase-01~e.11)) :op2 (a2 / activate-01~e.29 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"~e.26,28)) :location (d2 / downstream~e.25) :ARG1-of (m / mediate-01~e.24 :ARG0 (p3 / protein :name (n4 / name :op1 "VEGF"~e.22))))) :mod (p4 / particular~e.1)) # ::id bel_pmid_1996_7723.42052 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Blood vessels associated with IDC showed a significant reduction in mean a6 @-@ integrin pixel intensity when compared with blood vessels from normal breast tissue (**p < 0.0001 , Figure 1b ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1.1 5-1 7-1.2.2 8-1.2 10-1.2.1.2 11-1.2.1.1.1.1.1 13-1.2.1.1.1.1.1 14-1.2.1.1 17-1.2.3.r 19-1.2.3.1 20-1.2.3 21-1.2.3.2.r 22-1.2.3.2.2 23-1.2.3.2.1 24-1.2.3.2 26-1.2.4.1 27-1.2.4.1.1 29-1.3.1 30-1.3.1.1 (s / show-01~e.5 :ARG0 (v / vessel~e.1 :mod (b / blood~e.0) :ARG1-of (a / associate-01~e.2 :ARG2~e.3 (d / disease :name (n3 / name :op1 "IDC"~e.4)))) :ARG1 (r / reduce-01~e.8 :ARG1 (i2 / intensify-01 :ARG1 (p / pixel~e.14 :mod (p4 / protein :name (n / name :op1 "a6-integrin"~e.11,13))) :mod (m / mean~e.10)) :ARG2 (s2 / significant-02~e.7) :compared-to~e.17 (v2 / vessel~e.20 :mod (b2 / blood~e.19) :location~e.21 (t / tissue~e.24 :mod (b3 / breast~e.23) :ARG1-of (n2 / normal-02~e.22))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than~e.26 :op1 0.0001~e.27))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod "1b"~e.30))) # ::id bel_pmid_1996_7723.42058 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed that there was a significant increase in tumour blood vessel density in a6 fl @/@ fl @-@ Tie1Cre+ mice compared with a6 fl @/@ fl @-@ Tie1Cre @- controls (*p < 0.02 , Figure 3b ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 7-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1.1.2 11-1.2.1.1.1 12-1.2.1.1 13-1.2.1 16-1.2.3.1.1.1 18-1.2.3.1.1.1 21-1.2.3 22-1.2.4 25-1.2.4.1.1.1.1 27-1.2.4.1.1.1.1 29-1.2.4.1.1.1.1 31-1.2.4.1 33-1.2.5.1 34-1.2.5.1.1 36-1.3.1 37-1.3.1.1 (s / show-01~e.2 :ARG0 (t2 / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1 (i / increase-01~e.8 :ARG1~e.9 (d / density~e.13 :poss (v / vessel~e.12 :mod (b / blood~e.11) :mod (t / tumor~e.10))) :ARG2 (s2 / significant-02~e.7) :location (m / mouse~e.21 :mod (g / gene :name (n / name :op1 "a6fl/fl-Tie1Cre"~e.16,18) :mod (w / wild-type))) :ARG1-of (c / compare-01~e.22 :ARG2 (c2 / control~e.31 :mod (g2 / gene :name (n2 / name :op1 "a6fl/fl-Tie1Cre"~e.25,27,29) :ARG2-of (m2 / mutate-01 :mod "-/-")))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than~e.33 :op1 0.02~e.34))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.36 :mod "3b"~e.37))) # ::id bel_pmid_1996_7723.42064 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As predicted , the absence of a6 @-@ integrin reduced the ability of the a6-/— cells to adhere and migrate to Lm but did not affect the ability of these cells to adhere or migrate on Fn , Col or Vn (*p < 0.05 , Figures 5c and 5d ) . # ::alignments 1-1.5 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.1.1.1.1 8-1.2.1.1.1.1 9-1 11-1.2 15-1.2.2.1.1 17-1.2.2.1 18-1.2.2 19-1.2.2.2 22-1.3 24-1.3.1.1 24-1.3.1.1.r 25-1.3.1 27-1.3.1.3 30-1.3.1.3.2.1.1 32-1.3.1.3.2.1 33-1.3.1.3.2.1.2 34-1.3.1.3.2.2 39-1.3.1.3.2.2.2 42-1.6.1 43-1.6.1.1 45-1.4.1.1 45-1.4.1.2 46-1.4.1.1.1 47-1.4.1 48-1.4.1.2.1 (r / reduce-01~e.9 :ARG0 (a / absent-01~e.4 :ARG1~e.5 (p / protein :name (n / name :op1 "a6-integrin"~e.6,8))) :ARG1 (c / capable-01~e.11 :ARG1 (c2 / cell :mod (p2 / protein :name (n2 / name :op1 "a6-integrin"~e.8) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG2 (a2 / and~e.18 :op1 (a3 / adhere-01~e.17 :ARG1 c2~e.15 :ARG2 (p3 / protein :name (n3 / name :op1 "laminin"))) :op2 (m2 / migrate-01~e.19 :ARG0 c2 :ARG2 p3))) :ARG1-of (c3 / contrast-01~e.22 :ARG2 (a4 / affect-01~e.25 :polarity~e.24 -~e.24 :ARG0 a :ARG1 (c4 / capable-01~e.27 :ARG1 c2 :ARG2 (a5 / and :op1 (a6 / adhere-01~e.32 :ARG1 c2~e.30 :ARG2 (o / or~e.33 :op1 (p4 / protein :name (n4 / name :op1 "fibronectin")) :op2 (p5 / protein :name (n5 / name :op1 "collagen")) :op3 (p6 / protein :name (n6 / name :op1 "vitronectin")))) :op2 (m3 / migrate-01~e.34 :ARG0 c2 :ARG1 (o2 / or~e.39 :op1 p4 :op2 p5 :op2 p6)))))) :ARG1-of (d / describe-01 :ARG0 (a7 / and~e.47 :op1 (f / figure~e.45 :mod "5c"~e.46) :op2 (f2 / figure~e.45 :mod "5d"~e.48))) :ARG1-of (p9 / predict-01~e.1) :ARG1-of (s / statistical-test-91 :ARG2 (l / less-than~e.42 :op1 0.05~e.43))) # ::id bel_pmid_1996_7723.42068 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis revealed that VEGF stimulated the phosphorylation of ERK1 @/@ 2 in both a6 fl @/@ fl @-@ Tie1Cre @-@ and a6 fl @/@ fl @-@ Tie1Cre+ endothelial cells and that the levels of phosphorylated ERK1 @/@ 2 ( pERK1 @/@ 2 ) detected in a6 fl @/@ fl @-@ Cre+ endothelial cells after a VEGF stimulus were dramatically higher than those detected in a6 fl @/@ flTie1Cre @- endothelial cells ( Figure 6b ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1.1 6-1.2.1 8-1.2.1.2 9-1.2.1.2.1.r 10-1.2.1.2.1.1.1 12-1.2.1.2.1.1.1 16-1.2.1.3.1.1.1.1 16-1.2.1.3.2.1.1.1 18-1.2.1.3.1.1.1.1 18-1.2.1.3.2.1.1.1 20-1.2.1.3.1.1.1.1 20-1.2.1.3.2.1.1.1 22-1.2.1.3 24-1.2.1.3.1.1.1.1 24-1.2.1.3.2.1.1.1 26-1.2.1.3.1.1.1.1 26-1.2.1.3.2.1.1.1 29-1.2.1.3.1.2 30-1.2.1.3.1 30-1.2.1.3.2 31-1.2.1.3 32-1.2.r 34-1.2.2.1 34-1.2.2.5.1 35-1.2.2.1.1.r 36-1.2.2.1.1.2 37-1.2.2.1.1.1.1 39-1.2.2.1.1.1.1 43-1.2.2.1.1.1.1 45-1.2.2.5.1.1 48-1.2.1.3.1.1.1.1 48-1.2.1.3.2.1.1.1 50-1.2.1.3.1.1.1.1 50-1.2.1.3.2.1.1.1 53-1.2.1.3.1.2 54-1.2.1.3.1 55-1.2.2.3 57-1.2.2.3.1.1 58-1.2.2.3.1 60-1.2.2.2 61-1.2.2 61-1.2.2.4 61-1.2.2.4.r 64-1.2.2.1.1.3 67-1.2.1.3.1.1.1.1 67-1.2.1.3.2.1.1.1 71-1.2.1.3.1.2 72-1.2.1.3.1 74-1.3.1 75-1.3.1.1 (r / reveal-01~e.3 :ARG0 (a5 / analyze-01~e.2 :manner (i / immunoblot-01~e.0,1)) :ARG1~e.4,32 (a2 / and :op1 (s / stimulate-01~e.6 :ARG0 (p / protein :name (n / name :op1 "VEGF"~e.5)) :ARG1 (p2 / phosphorylate-01~e.8 :ARG1~e.9 (e / enzyme :name (n2 / name :op1 "ERK1/2"~e.10,12))) :location (a3 / and~e.22,31 :op1 (c / cell~e.30,54,72 :mod (g2 / gene :name (n3 / name :op1 "a6fl/fl-Tie1Cre"~e.16,18,20,24,26,48,50,67) :ARG2-of (m / mutate-01 :mod "-/-")) :mod (e2 / endothelium~e.29,53,71)) :op2 (c2 / cell~e.30 :mod (g / gene :name (n4 / name :op1 "a6fl/fl-Tie1Cre"~e.16,18,20,24,26,48,50,67) :mod (w2 / wild-type)) :mod e2))) :op2 (h / high-02~e.61 :ARG1 (l / level~e.34 :quant-of~e.35 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"~e.37,39,43) :ARG3-of (p5 / phosphorylate-01~e.36) :ARG1-of (d2 / detect-01~e.64 :location c))) :mod (d / dramatic~e.60) :time (a4 / after~e.55 :op1 (s2 / stimulus~e.58 :mod p~e.57)) :degree~e.61 (m2 / more~e.61) :ARG1-of (c3 / compare-01 :ARG2 (l2 / level~e.34 :ARG1-of (d3 / detect-01~e.45 :location c2))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.74 :mod "6b"~e.75))) # ::id bel_pmid_1996_7723.42070 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , blockade of VEGFR2 using the function blocking monoclonal antibody to VEGFR2 , DC101 [ 26 ] , ablated these enhanced VEGF @-@ mediated responses , demonstrating that the enhanced ERK1 @/@ 2 phosphorylation was via VEGFR2 ( Figure 6b ) . # ::alignments 0-1 4-1.1.2.1.1.1 5-1.1.2.3 7-1.1.2.3.1.3.1.2.1 8-1.1.2 8-1.1.2.3.1.3.1.2 9-1.1.2.3.1.3.1.1 10-1.1.2.3.1.3.1 12-1.1.2.1.1.1 14-1.1.2.3.1.1.1 16-1.1.2.2.1.1.1 19-1.1 20-1.1.1.2 21-1.1.1.3 22-1.1.1.4.1.1.1 24-1.1.1.4 25-1.1.1 25-1.1.1.1 25-1.1.1.1.r 27-1.1.3 28-1.1.3.1.r 30-1.1.3.1.3 31-1.1.3.1.1.1.1 33-1.1.3.1.1.1.1 34-1.1.3.1 37-1.1.3.1.2 39-1.1.4.1 40-1.1.4.1.1 (a / and~e.0 :op2 (a2 / ablate-01~e.19 :ARG1 (t / thing~e.25 :ARG2-of~e.25 (r / respond-01~e.25) :mod (t2 / this~e.20) :ARG1-of (e2 / enhance-01~e.21) :ARG1-of (m2 / mediate-01~e.24 :ARG0 (p / protein :name (n5 / name :op1 "VEGF"~e.22)))) :ARG3 (b / block-01~e.8 :ARG1 (p3 / protein :name (n / name :op1 "VEGFR2"~e.4,12)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 26~e.16))) :ARG0-of (u / use-01~e.5 :ARG1 (s / small-molecule :name (n7 / name :op1 "DC101"~e.14) :ARG0-of (c3 / counter-01 :ARG1 p3) :ARG1-of (m / mean-01 :ARG2 (a3 / antibody~e.10 :mod (m3 / monoclonal~e.9) :ARG0-of (b2 / block-01~e.8 :ARG1 (f2 / function-01~e.7))))))) :ARG0-of (d2 / demonstrate-01~e.27 :ARG1~e.28 (p4 / phosphorylate-01~e.34 :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK1/2"~e.31,33)) :ARG2 p3~e.37 :ARG1-of (e4 / enhance-01~e.30))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.39 :mod "6b"~e.40)))) # ::id bel_pmid_2001_8915.2588 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mouse tumors mimic molecular hallmarks of their human tumor counterparts , including elevated IL @-@ 6/Stat3/Bcl @-@ X( L ) signaling . The newly developed mouse strains may provide a good preclinical research tool for the design and testing of new approaches to target IL @-@ 6 in treatment and prevention of human PCNs . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 8-1.1.2.2.1.1 9-1.1.2.2.1 10-1.1.2.2 12-1.1.2.3 13-1.1.2.3.1.2 14-1.1.2.3.1.1.1.1 21-1.1.2.3.1 24-1.2.1.1.2.1 25-1.2.1.1.2 26-1.2.1.1.1 27-1.2.1.1 28-1.2 29-1.2.1 31-1.2.1.2.4 32-1.2.1.2.1 33-1.2.1.2.2 34-1.2.1.2 35-1.2.1.2.3.r 37-1.2.1.2.3.1 38-1.2.1.2.3 39-1.2.1.2.3.2 40-1.2.1.2.3.1.1.r 41-1.2.1.2.3.1.1.2 42-1.2.1.2.3.1.1 44-1.2.1.2.3.1.1.1 45-1.2.1.2.3.1.1.1.1.1.1 47-1.2.1.2.3.1.1.1.1.1.1 48-1.2.1.2.3.1.1.1.2.r 49-1.2.1.2.3.1.1.1.2.1 50-1.2.1.2.3.1.1.1.2 51-1.2.1.2.3.1.1.1.2.2 52-1.2.1.2.3.1.1.1.2.1.1.r 53-1.2.1.2.3.1.1.1.2.1.1.2 (m / multi-sentence :snt1 (m2 / mimic-01~e.3 :ARG0 (t / tumor~e.2 :mod (m3 / mouse~e.1)) :ARG1 (h / hallmark~e.5 :mod (m4 / molecule~e.4) :poss (c / counterpart~e.10 :mod (t2 / tumor~e.9 :mod (h2 / human~e.8)) :poss m3) :ARG2-of (i / include-01~e.12 :ARG1 (s / signal-07~e.21 :ARG1 (p / pathway :name (n / name :op1 "IL-6/Stat3/Bcl-X(L)"~e.14)) :ARG1-of (e / elevate-01~e.13))))) :snt2 (p2 / possible-01~e.28 :ARG1 (p3 / provide-01~e.29 :ARG0 (s2 / strain~e.27 :mod (m5 / mouse~e.26) :ARG1-of (d / develop-02~e.25 :ARG1-of (n2 / new-01~e.24))) :ARG1 (t4 / tool~e.34 :mod (p4 / preclinical~e.32) :mod (r / research-01~e.33) :purpose~e.35 (a / and~e.38 :op1 (d2 / design-01~e.37 :ARG1~e.40 (a2 / approach-02~e.42 :ARG1 (t6 / target-01~e.44 :ARG1 (p5 / protein :name (n4 / name :op1 "IL-6"~e.45,47)) :purpose~e.48 (a3 / and~e.50 :op1 (t7 / treat-03~e.49 :ARG1~e.52 (d3 / disease :name (n5 / name :op1 "PCN") :mod (h3 / human~e.53))) :op2 (p6 / prevent-01~e.51 :ARG1 d3))) :ARG1-of (n3 / new-01~e.41))) :op2 (t5 / test-01~e.39 :ARG1 a2)) :ARG1-of (g / good-02~e.31))))) # ::id bel_pmid_2013_1264.5500 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast to TGFbeta1 @/@ IL @-@ 6 , IL @-@ 23 was critical for the induction of IL @-@ 22 in CD4+ T cells from both naive and CII @-@ immunized DBA/1 mice . # ::alignments 1-1.1 1-1.1.2 1-1.1.2.r 2-1.1.2.1.r 3-1.1.2.1.1.1.1 5-1.1.2.1.2.1.1 7-1.1.2.1.2.1.1 9-1.1.1.1 9-1.1.2.1.2.1.1 11-1.1.1.1 13-1 14-1.2.r 16-1.2 17-1.2.1.r 18-1.2.1.1.1 20-1.2.1.1.1 23-1.2.2.1.1 24-1.2.2 25-1.2.2.3.r 26-1.2.2.3.3 27-1.2.2.3.1.2 28-1.2.2.3 31-1.2.2.3.2.2 32-1.2.2.3.1.1.1 32-1.2.2.3.2.1.1 33-1.2.2.3.1.1.2 33-1.2.2.3.2.1.2 (c / critical-02~e.13 :ARG1 (p / protein~e.1 :name (n / name :op1 "IL-23"~e.9,11) :ARG1-of~e.1 (c3 / contrast-01~e.1 :ARG2~e.2 (m4 / macro-molecular-complex :part (p5 / protein :name (n8 / name :op1 "TGFbeta1"~e.3)) :part (p6 / protein :name (n9 / name :op1 "IL-6"~e.5,7,9))))) :ARG3~e.14 (i / induce-01~e.16 :ARG2~e.17 (p2 / protein :name (n2 / name :op1 "IL-22"~e.18,20)) :location (c2 / cell~e.24 :name (n3 / name :op1 "T"~e.23) :mod (p3 / protein :name (n4 / name :op1 "CD4") :mod (w / wild-type)) :source~e.25 (a / and~e.28 :op1 (o / organism :name (n5 / name :op1 "DBA/1"~e.32 :op2 "mouse"~e.33) :mod (n7 / naive~e.27)) :op2 (o2 / organism :name (n6 / name :op1 "DBA/1"~e.32 :op2 "mouse"~e.33) :ARG1-of (i2 / immunize-01~e.31 :ARG0 (p4 / protein :name (n10 / name :op1 "collagen" :op2 "II")))) :mod (b / both~e.26))))) # ::id bel_pmid_2013_1264.5504 ::amr-annotator SDL-AMR-09 ::preferred # ::tok : In CD4+ T cells from naive DBA/1 mice , IL @-@ 23 alone hardly induced retinoic acid @-@ related orphan receptor gammat ( RORgammat ) , Th17 polarization , and Th17 cytokines , but it inhibited T @-@ bet expression . # ::alignments 3-1.3.1.1 4-1.1.2.2.1 4-1.3 5-1.3.3.r 7-1.3.3.1.1 8-1.3.3.1.2 10-1.1.1.1.1 12-1.1.1.1.1 13-1.1.1.2 14-1.1.3 15-1.1 16-1.1.2.1.1.1 17-1.1.2.1.1.2 19-1.1.2.1.1.2 20-1.1.2.1.1.3 21-1.1.2.1.1.4 22-1.1.2.1.1.5 27-1.1.2.2.1.1.1 28-1.1.2.2 31-1.1.2.2.1.1.1 32-1.1.2.3 34-1 35-1.2.1 36-1.2 37-1.2.2.1.1.1 39-1.2.2.1.1.1 40-1.2.2 (c / contrast-01~e.34 :ARG1 (i / induce-01~e.15 :ARG0 (p / protein :name (n / name :op1 "IL-23"~e.10,12) :mod (a / alone~e.13)) :ARG2 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "retinoic"~e.16 :op2 "acid-related"~e.17,19 :op3 "orphan"~e.20 :op4 "receptor"~e.21 :op5 "gammat"~e.22)) :op2 (p3 / polarize-01~e.28 :ARG1 (c2 / cell~e.4 :name (n3 / name :op1 "Th17"~e.27,31))) :op3 (c3 / cytokine~e.32 :mod c2)) :manner (h / hardly~e.14)) :ARG2 (i2 / inhibit-01~e.36 :ARG0 p~e.35 :ARG1 (e / express-03~e.40 :ARG1 (p4 / protein :name (n4 / name :op1 "T-bet"~e.37,39)))) :location (c4 / cell~e.4 :name (n5 / name :op1 "T"~e.3) :mod (p5 / protein :name (n6 / name :op1 "CD4") :mod (w / wild-type)) :source~e.5 (o / organism :name (n8 / name :op1 "DBA/1"~e.7 :op2 "mouse"~e.8)))) # ::id bel_pmid_2013_1264.20312 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in CD4+ T cells from naive mice , IL @-@ 23 significantly increased the TGFbeta1 @/@ IL @-@ 6 @-@ induced Th17 polarization , including elevated levels of IL @-@ 17A and IL @-@ 17F and decreased expression of T @-@ bet and FoxP3 . Of note , the IL @-@ 23 @-@ induced increase in IL @-@ 17A and IL @-@ 17F levels was prevented in T @-@ bet @-@ deficient mice . # ::alignments 0-1.1 4-1.1.2.1.1 5-1.1.1.2.1 5-1.1.2 6-1.1.2.3.r 7-1.1.2.3.1 8-1.1.2.3 10-1.1.1.1.1.1 12-1.1.1.1.1.1 13-1.1.1.3 14-1.1.1 16-1.1.1.2.2.1.1.1.1 18-1.1.1.2.2.1.2.1.1 20-1.1.1.2.2.1.2.1.1 22-1.1.1.2.2 23-1.1.1.2.1.1.1 24-1.1.1.2 26-1.1.1.4 27-1.1.1.4.1.1.2 28-1.1.1.4.1.1 28-1.1.1.4.1.2 30-1.1.1.4.1.1.1.1.1 30-1.1.1.4.1.2.1.1.1 32-1.1.1.4.1.1.1.1.1 33-1.1.1.4.1 34-1.1.1.4.1.1.1.1.1 34-1.1.1.4.1.2.1.1.1 36-1.1.1.4.1.2.1.1.1 37-1.1.1.4.1 38-1.1.1.4.1.3.2 39-1.1.1.4.1.3 40-1.1.1.4.1.3.1.r 41-1.1.1.4.1.3.1.1.1.1 43-1.1.1.4.1.3.1.1.1.1 45-1.1.1.4.1.3.1.2.1.1 48-1.2.3 51-1.2.1.2.1.1.1 53-1.2.1.2.1.1.1 55-1.2.1.2 56-1.2.1 58-1.2.1.1.1.1.1.1 58-1.2.1.1.2.1.1.1 58-1.2.1.2.1.1.1 60-1.2.1.1.1.1.1.1 61-1.2.1.1 62-1.2.1.1.1.1.1.1 62-1.2.1.1.2.1.1.1 64-1.2.1.1.2.1.1.1 65-1.2.1.1.1 65-1.2.1.1.2 67-1.2 68-1.2.2.r 69-1.2.2.1.1.1.1 71-1.2.2.1.1.1.1 74-1.2.2 (m / multi-sentence :snt1 (c / contrast-01~e.0 :ARG2 (i / increase-01~e.14 :ARG0 (p / protein :name (n / name :op1 "IL-23"~e.10,12)) :ARG1 (p2 / polarize-01~e.24 :ARG1 (c2 / cell~e.5 :name (n2 / name :op1 "Th17"~e.23)) :ARG2-of (i2 / induce-01~e.22 :ARG0 (m2 / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "TGFbeta1"~e.16)) :part (p4 / protein :name (n4 / name :op1 "IL-6"~e.18,20))))) :ARG2 (s / significant-02~e.13) :ARG2-of (i3 / include-01~e.26 :ARG1 (a / and~e.33,37 :op1 (l / level~e.28 :quant-of (p5 / protein :name (n5 / name :op1 "IL-17A"~e.30,32,34)) :ARG1-of (e / elevate-01~e.27)) :op2 (l2 / level~e.28 :quant-of (p6 / protein :name (n6 / name :op1 "IL-17F"~e.30,34,36)) :ARG1-of e) :op3 (e2 / express-03~e.39 :ARG2~e.40 (a2 / and :op1 (p7 / protein :name (n7 / name :op1 "T-bet"~e.41,43)) :op2 (p8 / protein :name (n8 / name :op1 "FoxP3"~e.45))) :ARG1-of (d / decrease-01~e.38))))) :location (c3 / cell~e.5 :name (n9 / name :op1 "T"~e.4) :mod (p9 / protein :name (n10 / name :op1 "CD4") :mod (w / wild-type)) :source~e.6 (m4 / mouse~e.8 :mod (n11 / naive~e.7)))) :snt2 (p10 / prevent-01~e.67 :ARG1 (i4 / increase-01~e.56 :ARG1 (a3 / and~e.61 :op1 (l3 / level~e.65 :quant-of (p12 / protein :name (n13 / name :op1 "IL-17A"~e.58,60,62))) :op2 (l4 / level~e.65 :quant-of (p13 / protein :name (n14 / name :op1 "IL-17F"~e.58,62,64)))) :ARG2-of (i5 / induce-01~e.55 :ARG0 (p11 / protein :name (n12 / name :op1 "IL-23"~e.51,53,58)))) :location~e.68 (m5 / mouse~e.74 :ARG0-of (l5 / lack-01 :ARG1 (p14 / protein :name (n15 / name :op1 "T-bet"~e.69,71)))) :ARG1-of (n16 / note-01~e.48))) # ::id bel_pmid_2017_6957.28510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , on stimulation with R848 or CpG DNA , B cells from both young and old Irf5 -/- mice produced lower levels of IL @-@ 6 than the B cells from C57BL/6 mice . # ::alignments 0-1 4-1.1.r 5-1.1.3.1.1.1.1 6-1.1.3.1 7-1.1.3.1.2.1.1 8-1.1.3.1.2.1.2 10-1.1.1.1.1 11-1.1.1 12-1.1.1.2.r 13-1.1.1.2.3 14-1.1.1.2.1.1 15-1.1.1.2 16-1.1.1.2.2.1 17-1.1.1.2.1.2.1.1 18-1.1.1.2.1.2.2.1 19-1.1.1.2.1 20-1.1 21-1.1.2.2 21-1.1.2.2.1 21-1.1.2.2.1.r 22-1.1.2 23-1.1.2.1.r 24-1.1.2.1.1.1 26-1.1.2.1.1.1 27-1.1.2.3.r 29-1.1.2.3.1.1 30-1.1.2.3 31-1.1.2.3.2.r 32-1.1.2.3.2.1.1 33-1.1.1.2.2 33-1.1.2.3.2.1.2 (c / contrast-01~e.0 :ARG2~e.4 (p / produce-01~e.20 :ARG0 (c2 / cell~e.11 :name (n6 / name :op1 "B"~e.10) :source~e.12 (a / and~e.15 :op1 (m / mouse~e.19 :mod (y / young~e.14) :mod (p3 / protein :name (n2 / name :op1 "Irf5"~e.17) :ARG2-of (m2 / mutate-01 :mod "-/-"~e.18))) :op2 (m3 / mouse~e.33 :mod (o / old~e.16) :mod p3) :mod (b / both~e.13))) :ARG1 (l / level~e.22 :quant-of~e.23 (p2 / protein :name (n / name :op1 "IL-6"~e.24,26)) :ARG1-of (l2 / low-04~e.21 :degree~e.21 (m4 / more~e.21)) :compared-to~e.27 (c3 / cell~e.30 :name (n5 / name :op1 "B"~e.29) :source~e.31 (o3 / organism :name (n7 / name :op1 "C57BL/6"~e.32 :op2 "mouse"~e.33)))) :time (s / simulate-01 :ARG2 (o2 / or~e.6 :op1 (s2 / small-molecule :name (n3 / name :op1 "R848"~e.5)) :op2 (n8 / nucleic-acid :name (n4 / name :op1 "CpG"~e.7 :op2 "DNA"~e.8)))))) # ::id bel_pmid_2017_6957.28512 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There was also a decrease in IRF @-@ 4 expression in Irf5 -/- B cells , seen both on RNA and protein levels ( Fig . 4 A and B ) . # ::alignments 2-1.2 4-1 5-1.1.r 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1 10-1.1.2.r 11-1.1.2.2.1.1 12-1.1.2.2.2.1 13-1.1.2.1.1 14-1.1.2 16-1.3 18-1.3.1.r 19-1.3.1.1.1.1.1 20-1.3.1 21-1.3.1.2.1 22-1.3.1.1 22-1.3.1.2 24-1.4.1.1 24-1.4.1.2 26-1.1.1.1.1 29-1.1.2.1.1 (d / decrease-01~e.4 :ARG1~e.5 (e / express-03~e.9 :ARG2 (p / protein :name (n / name :op1 "IRF-4"~e.6,8,26)) :ARG3~e.10 (c2 / cell-line~e.14 :name (n3 / name :op1 "B"~e.13,29) :mod (p2 / protein :name (n2 / name :op1 "Irf5"~e.11) :ARG2-of (m / mutate-01 :mod "-/-"~e.12)))) :mod (a / also~e.2) :ARG1-of (s / see-01~e.16 :location~e.18 (a2 / and~e.20 :op1 (l2 / level~e.22 :quant-of (n4 / nucleic-acid :name (n5 / name :op1 "RNA"~e.19))) :op2 (l / level~e.22 :quant-of (p3 / protein~e.21)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.24 :mod "4A") :op2 (f2 / figure~e.24 :mod "4B")))) # ::id bel_pmid_2017_6957.28516 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of the expression of these factors by semiquantitative RT @-@ PCR shows that purified B cells from both young and old Irf5 -/- mice exhibit significantly lower levels of Blimp @-@ 1 mRNA than B cells from the age @-@ matched C57BL/6 mice ( Fig . 4A ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1 6-1.1.1.1 9-1.1.2.1.1 11-1.1.2.1.1 12-1 13-1.2.r 14-1.2.1.2 15-1.2.1.1.1 16-1.2.1 17-1.2.1.3.r 18-1.2.1.3.3 19-1.2.1.3.1.1 20-1.2.1.3 21-1.2.1.3.2.1 22-1.2.1.3.1.2.1.1 23-1.2.1.3.1.2.2.1 24-1.2.1.3.1 25-1.2 26-1.2.2.2.3 27-1.2.2.2 27-1.2.2.2.1 27-1.2.2.2.1.r 28-1.2.2 29-1.2.2.1.r 30-1.2.2.1.2.1.1.1 32-1.2.2.1.2.1.1.1 33-1.2.2.1.1.1 34-1.2.2.2.2.r 35-1.2.2.2.2.1.1 36-1.2.2.2.2 37-1.2.2.2.2.2.r 39-1.2.2.2.2.2.2.1 41-1.2.2.2.2.2.2 42-1.2.2.2.2.2.1.1 43-1.2.1.3.2 43-1.2.2.2.2.2.1.2 45-1.3.1 (s / show-01~e.12 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (e / express-03~e.3 :ARG2~e.4 (f / factor~e.6 :mod (t / this~e.5))) :manner (t2 / thing :name (n4 / name :op1 "RT-PCR"~e.9,11) :mod (q / quantity :degree (s2 / semi)))) :ARG1~e.13 (e2 / exhibit-01~e.25 :ARG0 (c / cell~e.16 :name (n6 / name :op1 "B"~e.15) :ARG1-of (p / purify-01~e.14) :source~e.17 (a2 / and~e.20 :op1 (m / mouse~e.24 :mod (y / young~e.19) :mod (p2 / protein :name (n / name :op1 "Irf5"~e.22) :ARG2-of (m2 / mutate-01 :mod "-/-"~e.23))) :op2 (m3 / mouse~e.43 :mod (o / old~e.21) :mod p2) :mod (b / both~e.18))) :ARG1 (l / level~e.28 :quant-of~e.29 (n8 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.33) :ARG0-of (e3 / encode-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Blimp-1"~e.30,32)))) :ARG1-of (l2 / low-04~e.27 :degree~e.27 (m5 / more~e.27) :compared-to~e.34 (c2 / cell~e.36 :name (n5 / name :op1 "B"~e.35) :source~e.37 (o2 / organism :name (n7 / name :op1 "C57BL/6"~e.42 :op2 "mouse"~e.43) :ARG1-of (m6 / match-01~e.41 :ARG2 (a3 / age~e.39)))) :ARG1-of (s3 / significant-02~e.26)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.45 :mod "A4"))) # ::id bel_pmid_2020_0353.35654 ::amr-annotator SDL-AMR-09 ::preferred # ::tok we found that IL @-@ 33R signaling induced a time @-@ dependent activation of Erk1 @/@ 2 , protein kinase B ( PKB ) , JNK1 @/@ 2 , NF @-@ kB , and p38 , and degradation of IkB ( supplemental Figure 1B ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 5-1.2.1.1.1.1 6-1.2.1 7-1.2 9-1.2.2.1.2.1 11-1.2.2.1.2 12-1.2.2.1 13-1.2.2.1.1.r 14-1.2.2.1.1.1.1.1 16-1.2.2.1.1.1.1.1 16-1.2.2.1.1.3.1.1 18-1.2.2.1.1.2.1.1 19-1.2.2.1.1.2.1.2 20-1.2.2.1.1.2.1.3 25-1.2.2.1.1.3.1.1 27-1.2.2.1.1.1.1.1 27-1.2.2.1.1.3.1.1 29-1.2.2.1.1.4.1.1 31-1.2.2.1.1.4.1.1 33-1.2.2.1.1 34-1.2.2.1.1.5.1.1 36-1.2.2 37-1.2.2.2 38-1.2.2.2.1.r 39-1.2.2.2.1.1.1 41-1.3.1.2 42-1.3.1 43-1.3.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (i2 / induce-01~e.7 :ARG0 (s / signal-07~e.6 :ARG0 (p / protein :name (n / name :op1 "IL-33R"~e.3,5))) :ARG2 (a3 / and~e.36 :op1 (a / activate-01~e.12 :ARG1~e.13 (a2 / and~e.33 :op1 (e / enzyme :name (n2 / name :op1 "Erk1/2"~e.14,16,27)) :op2 (e2 / enzyme :name (n3 / name :op1 "protein"~e.18 :op2 "kinase"~e.19 :op3 "B"~e.20)) :op3 (e3 / enzyme :name (n4 / name :op1 "JNK1/2"~e.16,25,27)) :op4 (p2 / protein :name (n5 / name :op1 "NF-kB"~e.29,31)) :op5 (e4 / enzyme :name (n6 / name :op1 "p38"~e.34))) :ARG0-of (d / depend-01~e.11 :ARG1 (t / time~e.9))) :op2 (d2 / degrade-01~e.37 :ARG1~e.38 (p4 / protein :name (n7 / name :op1 "IkB"~e.39))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.42 :mod "1B"~e.43 :mod (s2 / supplement~e.41)))) # ::id bel_pmid_2020_0353.38622 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Y721 @-@ c @-@ Kit is autophosphorylated in response to stem cell factor ( SCF ) . # ::alignments 2-1.1.3.1.1 4-1.1.3.1.1 6-1 7-1.3.r 8-1.3 9-1.3.1.r 10-1.3.1.1.1 11-1.3.1.1.2 12-1.3.1.1.3 (p / phosphorylate-01~e.6 :ARG1 (a / amino-acid :mod 721 :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "c-Kit"~e.2,4))) :ARG2 a :ARG2-of~e.7 (r / respond-01~e.8 :ARG1~e.9 (p3 / protein :name (n3 / name :op1 "stem"~e.10 :op2 "cell"~e.11 :op3 "factor"~e.12)))) # ::id bel_pmid_2022_6760.28942 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The supernatants from cultured LN cells were also collected and the production of various cytokines ( TNF @-@ alpha , IFN @-@ gamma , IL @-@ 6 , and IL @-@ 17 ) was measured ( Fig . 3B ) . The cytokine levels in BLT1-/- cells were significantly lower than those in BLT1+/+ cells # ::alignments 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1.1 5-1.1.1.1.1 7-1.1.1.2 8-1.1.1 9-1.1 11-1.1.2.1 12-1.1.2.1.1.r 13-1.1.2.1.1.1 14-1.1.2.1.1 14-1.1.2.1.1.2.1.1 14-1.1.2.1.1.2.1.2 14-1.1.2.1.1.2.1.3 14-1.1.2.1.1.2.1.4 16-1.1.2.1.1.2.1.1.1.1 18-1.1.2.1.1.2.1.1.1.1 20-1.1.2.1.1.2.1.2.1.1 22-1.1.2.1.1.2.1.2.1.1 24-1.1.2.1.1.2.1.3.1.1 24-1.1.2.1.1.2.1.4.1.1 26-1.1.2.1.1.2.1.3.1.1 29-1.1.2.1.1.2.1.3.1.1 29-1.1.2.1.1.2.1.4.1.1 31-1.1.2.1.1.2.1.4.1.1 34-1.1.2 36-1.1.3.1 38-1.1.3.1.1 42-1.2.1.1 43-1.2.1 43-1.2.4 46-1.2.1.2 46-1.2.4.1 48-1.2.3 49-1.2 49-1.2.2 49-1.2.2.r 50-1.2.4.r 54-1.2.1.2 (m / multi-sentence :snt1 (a / and~e.9 :op1 (c / collect-01~e.8 :ARG1 (s / supernatant~e.1 :source~e.2 (c2 / cell~e.5 :ARG1-of (c3 / culture-01~e.3) :mod (p8 / protein :name (n7 / name :op1 "laminin")))) :mod (a3 / also~e.7)) :op2 (m2 / measure-01~e.34 :ARG1 (p / produce-01~e.11 :ARG1~e.12 (c4 / cytokine~e.14 :mod (v / various~e.13) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (c8 / cytokine~e.14 :name (n / name :op1 "TNF-alpha"~e.16,18)) :op2 (c9 / cytokine~e.14 :name (n2 / name :op1 "IFN-gamma"~e.20,22)) :op3 (c10 / cytokine~e.14 :name (n3 / name :op1 "IL-6"~e.24,26,29)) :op4 (c11 / cytokine~e.14 :name (n4 / name :op1 "IL-17"~e.24,29,31))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "3B"~e.38))) :snt2 (l / low-04~e.49 :ARG1 (l3 / level~e.43 :quant-of (c5 / cytokine~e.42) :location (c6 / cell~e.46,54 :mod (p6 / protein :name (n5 / name :op1 "BLT1") :ARG2-of (m5 / mutate-01 :mod "-/-")))) :degree~e.49 (m4 / more~e.49) :ARG1-of (s2 / significant-02~e.48) :compared-to~e.50 (l4 / level~e.43 :location (c7 / cell~e.46 :mod (p7 / protein :name (n6 / name :op1 "BLT1") :mod (w / wild-type)))))) # ::id bel_pmid_2033_8026.31778 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 2 Comparison of expression ratios between microarray and RT @-@ qPCR , lipid and mixed annotated genes ## WT vs Tyk2-/- peritoneal macrophages ## # ::alignments 0-1.3.1 1-1.3.1.1 2-1.1 3-1.1.1 3-1.1.2 4-1.1.1.1 5-1.1.1 7-1.1.1.2 8-1.1.1.1.1 9-1.1.2.2.1.1 11-1.1.2.2.1.1 13-1.1.2.1 14-1.1.2.1 15-1.1.2.1 16-1.1.2.1 17-1.1.2.1 19-1.2.1.1 22-1.2.1.2 23-1.2.1 (m / multi-sentence :snt1 (c / compare-01~e.2 :ARG1 (r / ratio-of~e.3,5 :op1 (e / express-03~e.4 :ARG1 (a / and~e.8 :op1 (g / gene :mod (l / lipid)) :op2 (g2 / gene :mod (m3 / mixed)) :ARG1-of (a2 / annotate-01))) :mod (m2 / microarray~e.7)) :ARG2 (r2 / ratio-of~e.3 :op1 e~e.13,14,15,16,17 :mod (t / thing :name (n / name :op1 "RT-qPCR"~e.9,11)))) :snt2 (c2 / contrast-01 :ARG1 (m4 / macrophage~e.23 :mod (w / wild-type~e.19) :mod (p / peritoneum~e.22)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Tyk2") :ARG2-of (m5 / mutate-01 :mod "-/-") :mod p)) :ARG1-of (d / describe-01 :ARG0 (t2 / table~e.0 :mod 2~e.1))) # ::id bel_pmid_2049_7020.1770 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Leptin @-@ induced MUC5B expression was blocked by the ERK1 @/@ 2 and p38 pathway inhibitors , but not by the JAK2 @/@ STAT3 pathway inhibitor . # ::alignments 0-1.2.2.1.1.1 2-1.2.2 3-1.2.1.1.1 4-1.2 6-1 6-1.3.1 7-1.1.r 9-1.1.1.1.1.1.1 11-1.1.1.1.1.1.1 12-1.1.1.1 13-1.1.1.1.2.1.1 14-1.1.1.1.1 14-1.1.1.1.2 15-1.1 15-1.1.1 15-1.1.1.r 17-1.3 18-1.3.1.1 18-1.3.1.1.r 19-1.3.1.2.r 21-1.3.1.2.1.1.1.1 23-1.3.1.2.1.1.1.1 24-1.3.1.2.1.1 25-1.3.1.2 25-1.3.1.2.1 25-1.3.1.2.1.r (b / block-01~e.6 :ARG0~e.7 (m / molecular-physical-entity~e.15 :ARG0-of~e.15 (i2 / inhibit-01~e.15 :ARG1 (a2 / and~e.12 :op1 (p5 / pathway~e.14 :name (n3 / name :op1 "ERK1/2"~e.9,11)) :op2 (p3 / pathway~e.14 :name (n4 / name :op1 "p38"~e.13))))) :ARG1 (e / express-03~e.4 :ARG1 (p / protein :name (n / name :op1 "MUC5B"~e.3)) :ARG2-of (i / induce-01~e.2 :ARG0 (p2 / protein :name (n2 / name :op1 "leptin"~e.0)))) :ARG1-of (c / contrast-01~e.17 :ARG2 (b2 / block-01~e.6 :polarity~e.18 -~e.18 :ARG0~e.19 (m3 / molecular-physical-entity~e.25 :ARG0-of~e.25 (i3 / inhibit-01~e.25 :ARG1 (p4 / pathway~e.24 :name (n5 / name :op1 "JAK2/STAT3"~e.21,23)))) :ARG1 e))) # ::id bel_pmid_2060_5485.40420 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both IL @-@ 6 and G @-@ CSF treatment did not markedly change surface IL @-@ 4Ra amounts on BM cells ; moreover , IL @-@ 6 had a detrimental effect on cell viability , thereby preventing any further functional characterization . # ::alignments 0-1.1.2.1.3 1-1.1.2.1.1.1.1 3-1.1.2.1.1.1.1 4-1.1.2.1 5-1.1.2.1.2.1.1 7-1.1.2.1.2.1.1 8-1.1.2 10-1.1.1 10-1.1.1.r 11-1.1.4 12-1.1 13-1.1.3.1.2 14-1.1.3.1.1.1 16-1.1.3.1.1.1 17-1.1.3 20-1.1.5 22-1.2 24-1.2.1.1.1.1 26-1.2.1.1.1.1 29-1.2.1.3 30-1.2.1 31-1.2.1.2.r 32-1.2.1.2.1 33-1.2.1.2 35-1.1.4.r 36-1.2.1.4 37-1.2.1.4.1.3 38-1.2.1.4.1.2 39-1.2.1.4.1.1 40-1.2.1.4.1 (m / multi-sentence :snt1 (c / change-01~e.12 :polarity~e.10 -~e.10 :ARG0 (t / treat-04~e.8 :ARG2 (a / and~e.4 :op1 (p / protein :name (n / name :op1 "IL-6"~e.1,3)) :op2 (p2 / protein :name (n2 / name :op1 "G-CSF"~e.5,7)) :mod (b2 / both~e.0))) :ARG1 (a2 / amount~e.17 :quant-of (p3 / protein :name (n3 / name :op1 "IL-4Ra"~e.14,16) :mod (s / surface~e.13))) :manner~e.35 (m2 / marked~e.11) :location (c2 / cell~e.20) :mod (m3 / marrow :mod (b / bone))) :snt2 (a3 / and~e.22 :op2 (a4 / affect-01~e.30 :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6"~e.24,26)) :ARG1~e.31 (v / viability~e.33 :mod (c3 / cell~e.32)) :mod (d / detrimental~e.29) :ARG0-of (p5 / prevent-01~e.36 :ARG1 (c4 / characterize-01~e.40 :ARG0-of (f / function-01~e.39) :mod (f2 / further~e.38) :mod (a5 / any~e.37)))))) # ::id bel_pmid_2060_5485.40422 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the increased IL @-@ 4Ra expression following G @-@ CSF treatment , this cytokine did not induce any appreciable imunosuppressive function in BM cells . # ::alignments 0-1.5.r 2-1.5 3-1.5.1.1.1.1 5-1.5.1.1.1.1 6-1.5.1 7-1.5.1.2 8-1.5.1.2.1.1.1.1 10-1.5.1.2.1.1.1.1 11-1.5.1.2.1 13-1.2.1 14-1.2 16-1.1 16-1.1.r 17-1 18-1.3.3 19-1.3.1.1 20-1.3.2 21-1.3 24-1.4 (i / induce-01~e.17 :polarity~e.16 -~e.16 :ARG0 (c / cytokine~e.14 :mod (t / this~e.13)) :ARG2 (f / function~e.21 :ARG1-of (a / appreciate-03 :ARG1-of (p / possible-01~e.19)) :mod (i2 / imunosuppressive~e.20) :mod (a2 / any~e.18)) :location (c2 / cell~e.24 :mod (m / marrow :mod (b / bone))) :concession~e.0 (i3 / increase-01~e.2 :ARG1 (e / express-03~e.6 :ARG2 (p2 / protein :name (n / name :op1 "IL-4Ra"~e.3,5)) :ARG1-of (f2 / follow-01~e.7 :ARG2 (t2 / treat-04~e.11 :ARG2 (p3 / protein :name (n2 / name :op1 "G-CSF"~e.8,10))))))) # ::id bel_pmid_2060_5485.40424 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GM @-@ CSF induced a significant increase ( p = 0.028 versus untreated BM ) of IL @-@ 4Ra expression , and BM cells cultured with this cytokine inhibited CTL activity in a dose @-@ dependent fashion ( Figures 1A and 1B ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 5-1.1.2.2 6-1.1.2 8-1.1.2.3 10-1.1.2.3.1 12-1.1.2.3.2.2 12-1.1.2.3.2.2.1 12-1.1.2.3.2.2.1.r 15-1.1.2.1.r 16-1.1.2.1.1.1.1 18-1.1.2.1.1.1.1 19-1.1.2.1 21-1 23-1.1.2.3.2 23-1.2.1 24-1.2.1.2 25-1.2.1.2.1.r 26-1.2.1.2.1.1 27-1.2.1.2.1 28-1.2 29-1.2.2.1.1.1 30-1.2.2 31-1.2.3.r 33-1.2.3.2 35-1.2.3 38-1.3.1.1 38-1.3.1.2 39-1.3.1.1.1 40-1.3.1 41-1.3.1.2.1 (a / and~e.21 :op1 (i / induce-01~e.3 :ARG0 (p / protein :name (n / name :op1 "GM-CSF"~e.0,2)) :ARG2 (i2 / increase-01~e.6 :ARG1~e.15 (e2 / express-03~e.19 :ARG2 (p4 / protein :name (n2 / name :op1 "IL-4Ra"~e.16,18))) :ARG2 (s / significant-02~e.5) :ARG1-of (s2 / statistical-test-91~e.8 :ARG2 0.028~e.10 :ARG5 (c6 / cell-line~e.23 :mod m2 :ARG1-of (t / treat-04~e.12 :polarity~e.12 -~e.12))))) :op2 (i3 / inhibit-01~e.28 :ARG0 (c3 / cell-line~e.23 :mod (m2 / marrow :mod (b / bone)) :ARG1-of (c4 / culture-01~e.24 :instrument~e.25 (c5 / cytokine~e.27 :mod (t2 / this~e.26)))) :ARG1 (a2 / activity-06~e.30 :ARG0 (c2 / cell :name (n3 / name :op1 "CTL"~e.29))) :manner~e.31 (d / depend-01~e.35 :ARG0 a2 :ARG1 (d2 / dose-01~e.33))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.40 :op1 (f / figure~e.38 :mod "1A"~e.39) :op2 (f2 / figure~e.38 :mod "1B"~e.41)))) # ::id bel_pmid_2060_5485.40432 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When we analyzed the percentage of the different subsets of CD11b+Gr @-@ 1+ cells , percentages of CD11 bhiGr @-@ 1 hi and CD11 bhiGr @-@ 1 @- cells were decreased in both C/EBPp @-@ deficient strains , but subsets characterized by low and intermediate expression of the Gr @-@ 1 marker were significantly decreased only in fully ablated mice ( Figure 3D ) . # ::alignments 0-1.3.r 1-1.3.1 2-1.3 4-1.3.2 5-1.3.2.1.r 7-1.3.2.1.2 8-1.3.2.1 10-1.3.2.1.1.1.1 12-1.3.2.1.1.1.1 13-1.1.2.1 13-1.3.2.1.1 15-1.1.1 15-1.1.2 20-1.1.2.1.1.1 22-1.1 26-1.1.2.1.1.1 28-1.1.1.1 30-1 31-1.2.r 32-1.2.2 33-1.2.1.1.1.1 36-1.2 38-1.4 39-1.4.1.1 40-1.4.1.1.1 41-1.4.1.1.1.1.r 42-1.4.1.1.1.1.1.2 43-1.4.1.1.1.1 44-1.4.1.1.1.1.2.2 45-1.4.1.1.1.1.1 45-1.4.1.1.1.1.2 46-1.4.1.1.1.1.1.1.r 48-1.4.1.1.1.1.1.1.1.1.1 50-1.4.1.1.1.1.1.1.1.1.1 51-1.4.1.1.1.1.1.1 53-1.4.1.2 54-1.4.1 55-1.4.1.4 56-1.4.1.3.r 57-1.4.1.3.1.1 58-1.4.1.3.1 59-1.4.1.3 61-1.5.1 62-1.1.1.1.r 62-1.1.2.1.r 62-1.5.1.1 (d / decrease-01~e.30 :ARG1 (a / and~e.22 :op1 (p / percentage~e.15 :quant-of~e.62 (c / cell~e.28 :name (n / name :op1 "CD11bhiGr-1hi"))) :op2 (p2 / percentage~e.15 :quant-of~e.62 (c2 / cell~e.13 :name (n2 / name :op1 "CD11bhiGr-1-"~e.20,26)))) :location~e.31 (s / strain~e.36 :ARG0-of (l / lack-01 :ARG1 (p3 / protein :name (n3 / name :op1 "C/EBPp"~e.33))) :mod (b / both~e.32)) :time~e.0 (a2 / analyze-01~e.2 :ARG0 (w / we~e.1) :ARG1 (p4 / percentage~e.4 :quant-of~e.5 (s2 / subset~e.8 :poss (c3 / cell~e.13 :name (n4 / name :op1 "CD11b+Gr-1+"~e.10,12)) :ARG1-of (d4 / differ-02~e.7)))) :ARG1-of (c4 / contrast-01~e.38 :ARG2 (d2 / decrease-01~e.54 :ARG1 (s3 / subset~e.39 :ARG1-of (c5 / characterize-01~e.40 :ARG2~e.41 (a3 / and~e.43 :op1 (e / express-03~e.45 :ARG2~e.46 (m / marker~e.51 :mod (p5 / protein :name (n5 / name :op1 "Gr-1"~e.48,50))) :ARG1-of (l2 / low-04~e.42)) :op2 (e2 / express-03~e.45 :ARG2 m :mod (i / intermediate~e.44))))) :ARG2 (s4 / significant-02~e.53) :location~e.56 (m2 / mouse~e.59 :ARG1-of (a4 / ablate-01~e.58 :degree (f / full~e.57))) :mod (o / only~e.55))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.61 :mod "3D"~e.62))) # ::id bel_pmid_2060_5485.40442 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following separation of CD11b+ cells from MCA203 tumor infiltrate , we found that loss of C/EBPp caused a significant reduction in both arginase 1 ( Arg1 ) and nitric oxide synthase 2 ( Nos2 ) proteins ( Figure 6A ) , two enzymes that were described as crucial components of MDSC inhibitory machinery ( Bronte and Zanovello , 2005 ; Gabrilovich and Nagaraj , 2009 ) . # ::alignments 0-1.3 1-1.3.1 2-1.3.1.1.r 3-1.3.1.1.1.1.1 4-1.3.1.1 5-1.3.1.2.r 6-1.3.1.2.1.1.1 7-1.3.1.2.2 8-1.3.1.2 10-1.1 11-1 12-1.2.r 13-1.2.1 15-1.2.1.1.1.1 16-1.2 18-1.2.2.2 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.3 22-1.2.2.1.1.1.1 23-1.2.2.1.1.1.2 27-1.2.2.1 28-1.2.2.1.2.1.1 29-1.2.2.1.2.1.2 30-1.2.2.1.2.1.3 31-1.2.2.1.2.1.4 35-1.2.1.1 35-1.3.1.1.1 35-1.3.1.2.1 37-1.2.2.3.1 38-1.2.2.3.1.1 42-1.2.2.1.1 42-1.2.2.1.2 45-1.2.2.1.4 45-1.2.2.1.4.2 45-1.2.2.1.4.2.r 45-1.2.2.3 46-1.2.2.1.4.1.r 46-1.2.2.1.4.2.1.1.2.r 47-1.2.2.1.4.1.1 48-1.2.2.1.4.1 49-1.2.2.1.4.1.2.r 50-1.2.2.1.4.1.2.2.1.1 51-1.2.2.1.4.1.2.1 52-1.2.2.1.4.1.2 54-1.2.2.1.4.2.1.1.1.1.1.1 55-1.2.2.1.4.2.1.1.1 56-1.2.2.1.4.2.1.1.1.2.1.1 60-1.2.2.1.4.2.1.2.1.1.1.1 61-1.2.2.1.4.2.1.2.1 62-1.2.2.1.4.2.1.2.1.2.1.1 64-1.2.2.1.4.2.1.2.2.1 (f / find-01~e.11 :ARG0 (w / we~e.10) :ARG1~e.12 (c / cause-01~e.16 :ARG0 (l / lose-02~e.13 :ARG1 (p / protein~e.35 :name (n / name :op1 "C/EBPp"~e.15))) :ARG1 (r / reduce-01~e.19 :ARG1~e.20 (a / and~e.27 :op1 (e / enzyme~e.42 :name (n2 / name :op1 "arginase"~e.22 :op2 1~e.23)) :op2 (e2 / enzyme~e.42 :name (n3 / name :op1 "nitric"~e.28 :op2 "oxide"~e.29 :op3 "synthase"~e.30 :op4 2~e.31)) :mod (b / both~e.21) :ARG1-of (d2 / describe-01~e.45 :ARG2~e.46 (c3 / component~e.48 :mod (c4 / crucial~e.47) :part-of~e.49 (m / machinery~e.52 :ARG0-of (i2 / inhibit-01~e.51) :mod (c5 / cell :name (n6 / name :op1 "MDSC"~e.50)))) :ARG1-of~e.45 (d3 / describe-01~e.45 :ARG0 (a2 / and :op1 (p3 / publication-91 :ARG0 (a3 / and~e.55 :op1 (p4 / person :name (n7 / name :op1 "Bronte"~e.54)) :op2 (p5 / person :name (n8 / name :op1 "Zanovello"~e.56))) :time~e.46 (d4 / date-entity :year 2015)) :op2 (p6 / publication-91 :ARG0 (a4 / and~e.61 :op1 (p7 / person :name (n9 / name :op1 "Gabrilovich"~e.60)) :op2 (p8 / person :name (n10 / name :op1 "Nagaraj"~e.62))) :time (d5 / date-entity :year 2009~e.64)))))) :ARG2 (s2 / significant-02~e.18) :ARG1-of (d / describe-01~e.45 :ARG0 (f2 / figure~e.37 :mod "6A"~e.38)))) :ARG1-of (f3 / follow-01~e.0 :ARG2 (s / separate-01~e.1 :ARG1~e.2 (c2 / cell~e.4 :mod (p9 / protein~e.35 :name (n4 / name :op1 "CD11b+"~e.3))) :ARG2~e.5 (i / infiltrate-01~e.8 :ARG0 (p2 / protein~e.35 :name (n5 / name :op1 "MCA203"~e.6)) :mod (t / tumor~e.7))))) # ::id bel_pmid_2060_5485.40446 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytokines were able to upregulate IL @-@ 4Ra expression , but a more pronounced effect was obtained by G @-@ CSF+GM @-@ CSF combination ( Figure 7B and Figure S6B ) . # ::alignments 0-1.1.1 2-1 4-1.1 5-1.1.2.1.1.1 7-1.1.2.1.1.1 8-1.1.2 10-1.2 12-1.2.1.1.1.1 13-1.2.1.1.1 14-1.2.1.1 16-1.2.1 17-1.2.1.2.r 18-1.2.1.2.1.1.1 22-1.2.1.2.1.1.1 22-1.2.1.2.2.1.1 23-1.2.1.2 25-1.3.1.1 26-1.3.1.1.1 27-1.3.1 28-1.3.1.1 28-1.3.1.2 29-1.3.1.2.1 (p / possible-01~e.2 :ARG1 (u / upregulate-01~e.4 :ARG0 (c / cytokine~e.0) :ARG1 (e / express-03~e.8 :ARG1 (p2 / protein :name (n / name :op1 "IL-4Ra"~e.5,7)))) :ARG1-of (c2 / contrast-01~e.10 :ARG2 (o / obtain-01~e.16 :ARG1 (a2 / affect-01~e.14 :ARG1-of (p5 / pronounced-02~e.13 :degree (m / more~e.12))) :ARG2~e.17 (c3 / combine-01~e.23 :ARG1 (p3 / protein :name (n2 / name :op1 "G-CSF"~e.18,22)) :ARG2 (p4 / protein :name (n3 / name :op1 "GM-CSF"~e.22))))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.27 :op1 (f / figure~e.25,28 :mod "7B"~e.26) :op2 (f2 / figure~e.28 :mod "S6B"~e.29)))) # ::id bel_pmid_2069_3421.19238 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that the endogenous IL @-@ 33 @/@ ST2 signaling pathway enhances the expression of CCR3 on eosinophils . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1.3 6-1.2.1.1.1 8-1.2.1.1.1 10-1.2.1.1.1 11-1.2.1.2 12-1.2.1 13-1.2 15-1.2.2 16-1.2.2.1.r 17-1.2.2.1.1.1 18-1.2.2.2.r 19-1.2.2.2.1.1 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (e / enhance-01~e.13 :ARG0 (p / pathway~e.12 :name (n / name :op1 "IL-33/ST2"~e.6,8,10) :ARG0-of (s / signal-07~e.11) :mod (e2 / endogenous~e.5)) :ARG1 (e3 / express-03~e.15 :ARG2~e.16 (p2 / protein :name (n2 / name :op1 "CCR3"~e.17)) :ARG3~e.18 (c / cell :name (n3 / name :op1 "eosinophil"~e.19))))) # ::id bel_pmid_2069_3421.19240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 33 triggered the production of IL @-@ 13 and IL @-@ 6 and strongly increased the production of CCL17 and TGF @-@ b from WT eosinophils , but not ST2-/- eosinophils , in a dosedependent manner ( Fig . 5A ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1.1 9-1.1.2.1.1.1.1 10-1.1.2.1 11-1.1.2.1.1.1.1 11-1.1.2.1.2.1.1 13-1.1.2.1.2.1.1 14-1.2.1.2.1 15-1.2.1.3 16-1.2.1 16-1.2.2 18-1.2.1.2 18-1.2.2.3 19-1.2.1.2.1.r 20-1.2.1.2.1.1.1.1 21-1.2.1.2.1 22-1.2.1.2.1.2.1.1 24-1.2.1.2.1.2.1.1 25-1.2.1.2.1.3.r 26-1.2.1.2.1.3.2 27-1.2.1.2.1.3.1.1 27-1.2.2.3.1.3.1.1 29-1.2 30-1.2.2.1 30-1.2.2.1.r 32-1.2.1.2.1.3.1.1 32-1.2.2.3.1.3.1.1 37-1.2.1.4.r 39-1.3.1 41-1.3.1.1 (a / and :op1 (t / trigger-01~e.3 :ARG0 (p3 / protein :name (n / name :op1 "IL-33"~e.0,2)) :ARG1 (p4 / produce-01~e.5 :ARG1~e.6 (a2 / and~e.10 :op1 (p5 / protein :name (n2 / name :op1 "IL-13"~e.7,9,11)) :op2 (p6 / protein :name (n3 / name :op1 "IL-6"~e.11,13))))) :op2 (c / contrast-01~e.29 :ARG1 (i / increase-01~e.16 :ARG0 p3 :ARG1 (p / produce-01~e.18 :ARG1~e.19 (a3 / and~e.14,21 :op1 (p7 / protein :name (n4 / name :op1 "CCL17"~e.20)) :op2 (p8 / protein :name (n5 / name :op1 "TGF-b"~e.22,24)) :source~e.25 (c2 / cell :name (n6 / name :op1 "eosinophil"~e.27,32) :mod (w / wild-type~e.26)))) :ARG1-of (s / strong-02~e.15) :manner~e.37 (d / depend-01 :ARG1 (d2 / dose-01))) :ARG2 (i2 / increase-01~e.16 :polarity~e.30 -~e.30 :ARG0 p3 :ARG1 (p2 / produce-01~e.18 :ARG1 (a4 / and :op1 p7 :op2 p8 :source (c3 / cell :name (n7 / name :op1 "eosinophil"~e.27,32) :mod (g / gene :name (n8 / name :op1 "ST2") :ARG2-of (m / mutate-01 :mod "-/-"))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.39 :mod "5A"~e.41))) # ::id bel_pmid_2092_1519.3016 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pharmacological intervention with a VEGFR @-@ 2 @-@ neutralizing Ab ( anti @-@ Flk1 mAb ) abolished the production of IL @-@ 6 ( but not IL @-@ 12p70 ) and the subsequent development of allergen @-@ specific Th17 cell response . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.2.r 4-1.1.1.2.1.1.1.1 6-1.1.1.2.1.1.1.1 8-1.1.1.2.1 16-1.1 16-1.2 18-1.1.2.2 18-1.2.2 19-1.1.2.2.1.r 19-1.1.2.r 20-1.1.2.2.1.1.1 22-1.1.2.2.1.1.1 24-1 25-1.2.1 25-1.2.1.r 26-1.2.2.1.1.1 28-1.2.2.1.1.1 30-1.1.2 32-1.1.2.1.2 33-1.1.2.1 34-1.1.2.1.1.r 35-1.1.2.1.1.2.1 37-1.1.2.1.1.2 38-1.1.2.1.1.1.1.1 39-1.1.2.1.1.1 40-1.1.2.1.1 (c3 / contrast-01~e.24 :ARG1 (a / abolish-01~e.16 :ARG0 (i / intervene-01~e.1 :mod (p2 / pharmacology~e.0) :instrument~e.2 (a3 / antibody :ARG0-of (n / neutralize-01~e.8 :ARG1 (p6 / protein :name (n2 / name :op1 "VEGFR-2"~e.4,6))))) :ARG1~e.19 (a2 / and~e.30 :op2 (d / develop-01~e.33 :ARG1~e.34 (r / respond-01~e.40 :ARG0 (c2 / cell~e.39 :name (n5 / name :op1 "Th17"~e.38)) :ARG1-of (s2 / specific-02~e.37 :ARG2 (a5 / allergen~e.35))) :mod (s / subsequent~e.32)) :op2 (p / produce-01~e.18 :ARG1~e.19 (p3 / protein :name (n3 / name :op1 "IL-6"~e.20,22))))) :ARG2 (a6 / abolish-01~e.16 :polarity~e.25 -~e.25 :ARG1 (p4 / produce-01~e.18 :ARG1 (p5 / protein :name (n4 / name :op1 "IL-12p70"~e.26,28))))) # ::id bel_pmid_2092_1519.3466 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vivo production of VEGF and Th1 @- and Th17 @-@ polarizing cytokines ( IL @-@ 12p70 and IL @-@ 6 , respectively ) were upregulated by airway exposure to LPS . # ::alignments 0-1.2.2 1-1.2.2 2-1.2 3-1.2.1.r 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1.2.2.1.1.1 8-1.2.1 9-1.2.1.3.2.1.1.1 11-1.2.1.2.2 11-1.2.1.3.2 12-1.2.1.2 12-1.2.1.3 14-1.2.1.2.1.1 14-1.2.1.3.1.1 16-1.2.1.2.1.1 17-1.2.1 18-1.2.1.2.1.1 18-1.2.1.3.1.1 20-1.2.1.3.1.1 25-1 26-1.1.r 27-1.1.2 28-1.1 29-1.1.1.r 30-1.1.1.1.1 (u / upregulate-01~e.25 :ARG0~e.26 (e / expose-01~e.28 :ARG2~e.29 (m2 / molecular-physical-entity :name (n6 / name :op1 "LPS"~e.30)) :mod (a3 / airway~e.27)) :ARG1 (p / produce-01~e.2 :ARG1~e.3 (a / and~e.5,8,17 :op1 (p3 / protein :name (n3 / name :op1 "VEGF"~e.4)) :op2 (c / cytokine~e.12 :name (n / name :op1 "IL-12p70"~e.14,16,18) :ARG0-of (p2 / polarize-01~e.11 :ARG1 (p5 / protein :name (n4 / name :op1 "Th1"~e.6)))) :op3 (c2 / cytokine~e.12 :name (n2 / name :op1 "IL-6"~e.14,18,20) :ARG0-of (p4 / polarize-01~e.11 :ARG1 (c4 / cell :name (n5 / name :op1 "Th17"~e.9))))) :manner (i / in-vivo~e.0,1))) # ::id bel_pmid_2094_4008.19124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both Fyn and Hck phosphorylate the adaptor protein Gab2 to activate PI3K signaling and promote microtubule formation that is important for granule translocation to the plasma membrane ( 9 , 11 ) . # ::alignments 0-1.2.3 1-1.2.1.1.1 2-1.2 3-1.2.2.1.1 4-1 6-1.1.2 7-1.1 8-1.1.1.1 9-1.3.r 10-1.3.1 11-1.3.1.2.1.1.1 12-1.3.1.2 13-1.3 14-1.3.2 15-1.3.2.2.1 16-1.3.2.2 19-1.3.2.2.2 20-1.3.2.2.2.1.r 21-1.3.2.2.2.1.2 22-1.3.2.2.2.1 23-1.3.2.2.2.1.1.r 25-1.3.2.2.2.1.1.1 26-1.3.2.2.2.1.1 28-1.4.1.1.1.1 30-1.4.1.1.1.2 (p4 / phosphorylate-01~e.4 :ARG1 (p3 / protein~e.7 :name (n3 / name :op1 "Gab2"~e.8) :mod (a3 / adaptor~e.6)) :ARG2 (a2 / and~e.2 :op1 (e2 / enzyme :name (n / name :op1 "Fyn"~e.1)) :op2 (e3 / enzyme :name (n2 / name :op1 "Hck"~e.3)) :mod (b / both~e.0)) :purpose~e.9 (a4 / and~e.13 :op1 (a5 / activate-01~e.10 :ARG0 a2 :ARG1 (s / signal-07~e.12 :ARG0 (p6 / pathway :name (n4 / name :op1 "PI3K"~e.11)))) :op2 (p2 / promote-01~e.14 :ARG0 a2 :ARG1 (f / form-01~e.16 :ARG1 (m / microtubule~e.15) :mod (i / important~e.19 :purpose~e.20 (t / translocate-01~e.22 :ARG2~e.23 (m2 / membrane~e.26 :poss (p / plasma~e.25)) :path (g3 / granule~e.21)))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 9~e.28 :op2 11~e.30))))) # ::id bel_pmid_2094_4008.19126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PTP ? is required for SCF @-@ induced c @-@ Kit and Fyn activation , and in this way regulates a Fyn @-@ based c @-@ Kit signaling axis ( Fyn/Gab2/Shp2/Vav/PAK/Rac/JNK ) that mediates mast cell migration . # ::alignments 3-1.1 4-1.1.2.r 5-1.1.2.2.1.1.1 7-1.1.2.2 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 11-1.1.2.1 12-1.1.2.1.2.1.1 13-1.1.2 15-1 15-1.1.2.1 17-1.2.3.1 18-1.2.3 18-1.2.3.r 19-1.2 21-1.2.2.2.1 23-1.2.2.2 24-1.2.2.1.1 25-1.2.2.1.1 26-1.2.2.1.1 27-1.2.2.1 28-1.2.2 33-1.2.2.3 34-1.2.2.3.1.1.1 35-1.2.2.3.1.1 36-1.2.2.3.1 (a3 / and~e.15 :op1 (r / require-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "PTPβ")) :purpose~e.4 (a / activate-01~e.13 :ARG1 (a2 / and~e.11,15 :op1 (e2 / enzyme :name (n2 / name :op1 "c-Kit"~e.8,10)) :op2 (e3 / enzyme :name (n3 / name :op1 "Fyn"~e.12))) :ARG2-of (i / induce-01~e.7 :ARG0 (p3 / protein :name (n4 / name :op1 "SCF"~e.5))))) :op2 (r2 / regulate-01~e.19 :ARG0 e :ARG1 (a4 / axis~e.28 :ARG0-of (s / signal-07~e.27 :ARG1 e2~e.24,25,26) :ARG1-of (b / base-02~e.23 :ARG2 e3~e.21) :ARG0-of (m / mediate-01~e.33 :ARG1 (m2 / migrate-01~e.36 :ARG0 (c / cell~e.35 :mod (m3 / mast~e.34)))) :consist-of (a5 / and :op1 e2 :op2 (p / protein :name (n6 / name :op1 "Gab2")) :op3 (e6 / enzyme :name (n7 / name :op1 "Shp2")) :op4 (p2 / protein :name (n8 / name :op1 "Vav")) :op5 (e7 / enzyme :name (n9 / name :op1 "PAK")) :op6 (e8 / enzyme :name (n10 / name :op1 "Rac")) :op7 (e9 / enzyme :name (n11 / name :op1 "JNK")))) :manner~e.18 (w / way~e.18 :mod (t / this~e.17)))) # ::id bel_pmid_2108_5614.26518 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , we find that basal arginase 1 expression and associated arginase activity is markedly increased in MKP @-@ 2 deletion mice , a response which would also mediate a reduction in NO formation , this is again different to the findings in MKP @-@ 1?/? macrophages . # ::alignments 0-1 2-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1.2 6-1.1.2.1.1.1.1.1 7-1.1.2.1.1.1.1.1 8-1.1.2.1.1 9-1.1.2.1 10-1.1.2.1.2.2 11-1.1.2.1.2.1.1.1 12-1.1.2.1.2 14-1.1.2.2 15-1.1.2 16-1.1.2.3.r 17-1.1.2.3.1.1.1.1 19-1.1.2.3.1.1.1.1 20-1.1.2.3.1 21-1.1.2.3 24-1.1.2.4 27-1.1.2.4.1.2 28-1.1.2.4.1 30-1.1.2.4.1.1 31-1.1.2.4.1.1.1.r 32-1.1.2.4.1.1.1.1.1.1 33-1.1.2.4.1.1.1 37-1.1.2.5.2 38-1.1.2.5 39-1.1.2.5.1.r 41-1.1.2.5.1 41-1.1.2.5.1.1 41-1.1.2.5.1.1.r 42-1.1.2.5.1.1.1.r 43-1.1.2.5.1.1.1.2.2.1 46-1.1.2.5.1.1.1.1.1 (a / and~e.0 :op2 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (i / increase-01~e.15 :ARG1 (a2 / and~e.9 :op1 (e / express-03~e.8 :ARG2 (e2 / enzyme :name (n / name :op1 "arginase-1"~e.6,7) :mod (b / basal~e.5))) :op2 (a3 / activity-06~e.12 :ARG0 (e3 / enzyme :name (n2 / name :op1 "arginase"~e.11)) :ARG1-of (a4 / associate-01~e.10))) :ARG1-of (m / mark-01~e.14) :location~e.16 (m2 / mouse~e.21 :ARG2-of (d / delete-01~e.20 :ARG1 (e4 / enzyme :name (n3 / name :op1 "MKP-2"~e.17,19)))) :ARG2-of (r / respond-01~e.24 :ARG0-of (m3 / mediate-01~e.28 :ARG1 (r2 / reduce-01~e.30 :ARG1~e.31 (f2 / form-01~e.33 :ARG1 (s / small-molecule :name (n4 / name :op1 "NO"~e.32)))) :mod (a5 / also~e.27))) :ARG0-of (d2 / differ-01~e.38 :ARG1~e.39 (t / thing~e.41 :ARG1-of~e.41 (f3 / find-01~e.41 :location~e.42 (c / cell :name (n5 / name :op1 "macrophage"~e.46) :part (g / gene :mode interrogative :name (n6 / name :op1 "MKP-1"~e.43) :ARG2-of (m4 / mutate-01 :mod "-/-"))))) :mod (a6 / again~e.37))))) # ::id bel_pmid_2108_5614.26520 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MKP @-@ 2 negatively regulated IL @-@ 12 , IL @-@ 6 and TNF @-@ a expression and positively regulates IL @-@ 10 confirming this hypothesis . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 9-1.1.2.1.1.1.1 9-1.1.2.1.2.1.1 11-1.1.2.1.2.1.1 12-1.1.2.1 13-1.1.2.1.3.1.1 16-1.1.2 17-1 20-1.2.2.1.1 22-1.2.2.1.1 23-1.3 24-1.3.1.2 25-1.3.1 25-1.3.1.1 25-1.3.1.1.r (a / and~e.17 :op1 (d / downregulate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "MKP-2"~e.0,2)) :ARG1 (e / express-03~e.16 :ARG2 (a2 / and~e.12 :op1 (p / protein :name (n2 / name :op1 "IL-12"~e.5,7,9)) :op2 (p2 / protein :name (n3 / name :op1 "IL-6"~e.9,11)) :op3 (p3 / protein :name (n4 / name :op1 "TNF"~e.13))))) :op2 (u / upregulate-01 :ARG0 e2 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-10"~e.20,22))) :ARG0-of (c / confirm-01~e.23 :ARG1 (t2 / thing~e.25 :ARG1-of~e.25 (h / hypothesize-01~e.25) :mod (t / this~e.24)))) # ::id bel_pmid_2111_5688.4192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7 @- and TLR9 @-@ dependent recognition of nucleic acids . # ::alignments 2-1.3 4-1.1.3 4-1.1.3.r 5-1.1 7-1.1.2.2.1.1 8-1.1.2 9-1.1.2.1.1.1 10-1.1.2.1.1 10-1.1.2.2.1 11-1.1.2.1 11-1.1.2.2 12-1.1.2 14-1.2.3 15-1.2 16-1.2.2.1.1 17-1.2.2.1.2 22-1.2.4.2.1 25-1.2.4.2 26-1.2.4 27-1.2.4.1.r 28-1.2.4.1 29-1.2.4.1 (a / and :op1 (i / infiltrate-01~e.5 :ARG0 (e / enzyme :name (n / name :op1 "pDC")) :ARG1 (a2 / and~e.8,12 :op1 (w / wound~e.11 :mod (s / skin~e.10 :mod (h / human~e.9))) :op2 (w2 / wound~e.11 :location (s2 / skin~e.10 :mod (m / murine~e.7)))) :manner~e.4 (r / rapid~e.4)) :op2 (p / produce-01~e.15 :ARG0 e :ARG1 (p5 / protein :name (n6 / name :op1 "type"~e.16 :op2 "I"~e.17 :op3 "IFN")) :ARG1-of (t / transient-02~e.14) :instrument (r2 / recognize-02~e.26 :ARG1~e.27 (n2 / nucleic-acid~e.28,29) :ARG0-of (d / depend-01~e.25 :ARG1 (a3 / and~e.22 :op1 (p3 / protein :name (n3 / name :op1 "TLR-7")) :op2 (p4 / protein :name (n4 / name :op1 "TLR-9")))))) :ARG1-of (f / find-01~e.2)) # ::id bel_pmid_2111_5688.27614 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like pDC @-@ depleted mice , IFN @-@ alpha @/@ beta receptor @-@ deficient mice showed a significant delay in wound reepithelization ( Fig . 5 E ) and displayed a profound deficiency in IL @-@ 6 , IL @-@ 17 , and IL @-@ 22 expression levels in injured skin , without affecting the expression of IFN @-@ gamma ( Fig . 5 F ) . # ::alignments 0-1.1.3 1-1.1.3.1.1.1.1.1 3-1.1.3.1.1 4-1.1.3.1 6-1.1.1.1.1.1.1 8-1.1.1.1.1.1.1 10-1.1.1.1.1.1.1 11-1.1.1.1.1 14-1.1.1 15-1.1 17-1.1.2.2 18-1.1.2 20-1.1.2.1.1 23-1.1.4.1 23-1.2.4.1 28-1 29-1.2 31-1.2.2.2 34-1.2.2.1.1.1.1.1.1 34-1.2.2.1.1.1.2.1.1 34-1.2.2.1.1.1.3.1.1 36-1.2.2.1.1.1.1.1.1 38-1.2.2.1.1.1.1.1.1 38-1.2.2.1.1.1.2.1.1 38-1.2.2.1.1.1.3.1.1 40-1.2.2.1.1.1.2.1.1 42-1.2.2.1.1.1 43-1.2.2.1.1.1.1.1.1 43-1.2.2.1.1.1.2.1.1 43-1.2.2.1.1.1.3.1.1 45-1.2.2.1.1.1.3.1.1 46-1.2.2.1.1 47-1.2.2.1 48-1.2.2.1.2.r 49-1.2.2.1.2.1 50-1.2.2.1.2 52-1.2.3.1 52-1.2.3.1.r 53-1.2.3 55-1.2.3.2 56-1.2.3.2.1.r 57-1.2.3.2.1.1.1 59-1.2.3.2.1.1.1 61-1.1.4.1 61-1.2.4.1 (a / and~e.28 :op1 (s / show-01~e.15 :ARG0 (m2 / mouse~e.14 :consist-of (d6 / deficit :consist-of (r2 / receptor~e.11 :name (n2 / name :op1 "IFN-alpha/beta"~e.6,8,10)))) :ARG1 (d3 / delay-01~e.18 :ARG1 (r3 / reepithelize-00 :ARG1 (w / wound~e.20)) :ARG1-of (s3 / significant-02~e.17)) :ARG1-of (r / resemble-01~e.0 :ARG2 (m / mouse~e.4 :ARG2-of (d2 / deplete-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "pDC"~e.1))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.23,61 :mod "5E"))) :op2 (d / display-01~e.29 :ARG0 m2 :ARG1 (l2 / lack-01 :ARG1 (l3 / level~e.47 :degree-of (e2 / express-03~e.46 :ARG2 (a2 / and~e.42 :op1 (p / protein :name (n3 / name :op1 "IL-6"~e.34,36,38,43)) :op2 (p2 / protein :name (n4 / name :op1 "IL-17"~e.34,38,40,43)) :op3 (p3 / protein :name (n5 / name :op1 "IL-22"~e.34,38,43,45)))) :location~e.48 (s2 / skin~e.50 :ARG1-of (i / injure-01~e.49))) :mod (p5 / profound~e.31)) :ARG0-of (a3 / affect-01~e.53 :polarity~e.52 -~e.52 :ARG1 (e3 / express-03~e.55 :ARG2~e.56 (p4 / protein :name (n6 / name :op1 "IFN-gamma"~e.57,59)))) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure~e.23,61 :mod "5F")))) # ::id bel_pmid_2111_5688.31368 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of both IFN @-@ a2 and IFN @-@ b mRNA was found to be profoundly abrogated in TLR7 @-@ deficient mice # ::alignments 0-1.1 3-1.1.1.1.2.1.1.1 3-1.1.1.2.2.1.1.1 5-1.1.1.1.2.1.1.1 6-1.1.1 7-1.1.1.1.2.1.1.1 7-1.1.1.2.2.1.1.1 9-1.1.1.2.2.1.1.1 10-1.1.1.1.1.1 10-1.1.1.2.1.1 12-1.4 15-1.2 15-1.2.r 16-1 17-1.3.r 18-1.3.1.1.1.1 21-1.3 (a / abrogate-01~e.16 :ARG1 (e / express-03~e.0 :ARG2 (a3 / and~e.6 :op1 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.10) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n / name :op1 "IFN-a2"~e.3,5,7)))) :op2 (n7 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.10) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IFN-b"~e.3,7,9)))))) :manner~e.15 (p3 / profound~e.15) :location~e.17 (m / mouse~e.21 :ARG0-of (d / delete-01 :ARG1 (p4 / protein :name (n4 / name :op1 "TLR7"~e.18)))) :ARG1-of (f / find-01~e.12)) # ::id bel_pmid_2123_9520.35054 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the present study , we found that when RSK4 is inhibited in vitro using short hairpin RNA technology , cells can bypass stress @-@ induced senescence and oncogene @-@ induced senescence : normal human fibroblasts grew following oxidative stress , induction of DNA damage and KRAS( V12 ) or BRAF( E600 ) overexpression . # ::alignments 0-1.2.3 2-1.3.2.1 3-1.3.2 5-1.3.1 6-1.3 8-1.2.r 9-1.2.1.1.1 11-1.2 12-1.2.3 13-1.2.3 15-1.2.2.1.1.1 16-1.2.2.1.1.2 17-1.2.2.1.1.3 18-1.2.2 20-1.1.1 21-1 22-1.1 23-1.1.2.1.1.1 25-1.1.2.1.1 25-1.1.2.2.1 26-1.1.2.1 26-1.1.2.2 27-1.1.2 28-1.1.2.2.1.1 30-1.1.2.1.1 31-1.1.2.1 33-1.1.3.1.2 34-1.1.3.1.1 35-1.1.3.1 36-1.1.3 37-1.1.3.2 38-1.1.3.2.1.1 39-1.1.3.2.1 41-1.1.3.2.2 42-1.1.3.2.2.1.r 43-1.1.3.2.2.1.1.2.1 44-1.1.3.2.2.1 45-1.1.3.2.3.1 47-1.1.3.2.3.1.1.2.1 51-1.1.3.2.3.1.2.2.1 53-1.1.3.2.3 (p / possible-01~e.21 :ARG1 (b / bypass-01~e.22 :ARG0 (c / cell~e.20) :ARG1 (a / and~e.27 :op1 (s / senescence~e.26,31 :ARG2-of (i / induce-01~e.25,30 :ARG0 (s2 / stress-02~e.23))) :op2 (s3 / senescence~e.26 :ARG2-of (i2 / induce-01~e.25 :ARG0 (o / oncogene~e.28)))) :manner (g / grow-01~e.36 :ARG1 (f2 / fibroblast~e.35 :mod (h / human~e.34) :ARG1-of (n2 / normal-02~e.33)) :time (a2 / after~e.37 :op1 (s4 / stress-02~e.39 :ARG3 (o2 / oxidize-01~e.38)) :op2 (i5 / induce-01~e.41 :ARG2~e.42 (d / damage-01~e.44 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA"~e.43)))) :op3 (o3 / overexpress-01~e.53 :ARG1 (a3 / and~e.45 :op1 (e2 / enzyme :name (n5 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01 :value "V12"~e.47)) :op2 (e3 / enzyme :name (n6 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "E600"~e.51))))))) :time~e.8 (i3 / inhibit-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "RSK4"~e.9)) :instrument (t / technology~e.18 :mod (n8 / nucleic-acid :name (n3 / name :op1 "short"~e.15 :op2 "hairpin"~e.16 :op3 "RNA"~e.17))) :manner (i4 / in-vitro~e.0,12,13)) :ARG1-of (f / find-01~e.6 :ARG0 (w / we~e.5) :medium (s5 / study-01~e.3 :time (p2 / present~e.2)))) # ::id bel_pmid_2123_9520.37214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two days after BRAFE600 selection , we seeded cells at low density and performed growth curves . RSK4 inhibition partially rescued BRAFE600 @-@ induced senescence in both TIG3 and TIG3 p16 @-@ null ( Figure 4A ) . # ::alignments 0-1.1.3.2.1 1-1.1.3.2.2 2-1.1.3 4-1.1.3.1 6-1.1.1.1 7-1.1.1 8-1.1.1.2 8-1.2.3.1 8-1.2.3.2 9-1.1.1.3.r 10-1.1.1.3.1 11-1.1.1.3 12-1.1 13-1.1.2 14-1.1.2.2.1 15-1.1.2.2 17-1.2.1.1.1.1 18-1.2.1 19-1.2.1.2 19-1.2.1.2.r 20-1.2 23-1.2.2.1 24-1.2.2 27-1.2.3.1.1.1.1 27-1.2.3.2.1.1.1 28-1.2.3 29-1.2.3.1.1.1.1 29-1.2.3.2.1.1.1 30-1.2.3.2.2.1.1 32-1.1.3.1.1 32-1.1.3.1.1.2 32-1.1.3.1.1.2.r 32-1.2.2.1.1 32-1.2.2.1.1.2 32-1.2.2.1.1.2.r 32-1.2.3.2.2.2 34-1.2.4.1 35-1.2.4.1.1 (m / multi-sentence :snt1 (a / and~e.12 :op1 (s / seed-02~e.7 :ARG0 (w / we~e.6) :ARG2 (c / cell~e.8) :mod~e.9 (d2 / dense~e.11 :ARG1-of (l / low-04~e.10))) :op2 (p / perform-02~e.13 :ARG0 w :ARG1 (c2 / curve~e.15 :topic (g / grow-01~e.14))) :time (a2 / after~e.2 :op1 (s2 / select-01~e.4 :ARG1 (e2 / enzyme~e.32 :name (n / name :op1 "BRAF") :ARG2-of~e.32 (m2 / mutate-01~e.32 :value "E600"))) :quant (t2 / temporal-quantity :quant 2~e.0 :unit (d3 / day~e.1)))) :snt2 (r / rescue-01~e.20 :ARG0 (i / inhibit-01~e.18 :ARG1 (e / enzyme :name (n2 / name :op1 "RSK4"~e.17)) :degree~e.19 (p2 / part~e.19)) :ARG1 (s3 / senescence~e.24 :ARG2-of (i2 / induce-01~e.23 :ARG0 (e3 / enzyme~e.32 :name (n3 / name :op1 "BRAF") :ARG2-of~e.32 (m3 / mutate-01~e.32 :value "E600")))) :location (a3 / and~e.28 :op1 (c3 / cell~e.8 :mod (p3 / protein :name (n4 / name :op1 "TIG3"~e.27,29))) :op2 (c4 / cell~e.8 :mod (p4 / protein :name (n5 / name :op1 "TIG3"~e.27,29)) :mod (p5 / protein :name (n6 / name :op1 "p16"~e.30) :mod (n7 / null~e.32)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.34 :mod "4A"~e.35)))) # ::id bel_pmid_2123_9533.1678 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This IFNg @-@ stimulated expression of T @-@ bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 ( STAT1 ) and activates T @-@ bet @-@ dependent DNA binding activity # ::alignments 0-1.1.1.3 1-1.1.1.2.1.1.1 3-1.1.1.2 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1.1.1.1.1.1 10-1.1 11-1.1.2.r 12-1.1.2.1 14-1.1.2.1.1.1.1 15-1.1.2 16-1.1.2.2.1.1 17-1.1.2.2.1.2 18-1.1.2.2.1.3 19-1.1.2.2.1.4 20-1.1.2.2.1.5 21-1.1.2.2.1.6 22-1.1.2.2.1.7 26-1 27-1.2 28-1.2.2.2.1 29-1.2.2.2.1 30-1.2.2.2.1 32-1.2.2.2 33-1.2.2.1.1.2.1 34-1.2.2.1 35-1.2.2 (a3 / and~e.26 :op1 (d / depend-01~e.10 :ARG0 (e / express-03~e.4 :ARG2~e.5 (p3 / protein :name (n2 / name :op1 "T-bet"~e.6,8)) :ARG1-of (s / stimulate-01~e.3 :ARG0 (p / protein :name (n / name :op1 "IFNg"~e.1))) :mod (t4 / this~e.0)) :ARG1~e.11 (a2 / and~e.15 :op1 (s2 / signal-07~e.12 :instrument (e2 / enzyme :name (n3 / name :op1 "JAK2"~e.14))) :op2 (p4 / protein :name (n5 / name :op1 "signal"~e.16 :op2 "transducers"~e.17 :op3 "and"~e.18 :op4 "activators"~e.19 :op5 "of"~e.20 :op6 "transcription"~e.21 :op7 1~e.22)))) :op2 (a4 / activate-01~e.27 :ARG0 e :ARG1 (a / activity-06~e.35 :ARG1 (b / bind-01~e.34 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.33))) :ARG0-of (d3 / depend-01~e.32 :ARG1 p3~e.28,29,30)))) # ::id bel_pmid_2137_8275.40580 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the lung , the concentration of IL @-@ 6 was increased , which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells . # ::alignments 2-1.2 5-1.1 6-1.1.1.r 7-1.1.1.1.1 9-1.1.1.1.1 11-1 15-1.3 16-1.3.1 16-1.3.1.2 16-1.3.1.2.1.2.1 16-1.3.1.2.r 17-1.3.1.1.1 19-1 19-1.4 19-1.4.r 20-1.4.1 21-1.4.1.1.r 22-1.4.1.1.1.1 23-1.4.1.1.2 24-1.4.1.1 25-1.4.2.r 26-1.4.2.1.1.1 27-1.4.2.1.1 29-1.4.2 (i / increase-01~e.11,19 :ARG1 (c / concentrate-02~e.5 :ARG1~e.6 (p / protein :name (n / name :op1 "IL-6"~e.7,9))) :location (l / lung~e.2) :ARG0-of (a / activate-01~e.15 :ARG1 (p2 / protein~e.16 :name (n2 / name :op1 "Stat3"~e.17) :ARG0-of~e.16 (c3 / cause-01~e.16 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.16)))) :manner (a2 / aberrant)) :ARG0-of~e.19 (i2 / increase-01~e.19 :ARG1 (e / express-03~e.20 :ARG1~e.21 (g / gene~e.24 :name (n3 / name :op1 "Stat3"~e.22) :location (d / downstream~e.23))) :location~e.25 (c2 / cell~e.29 :ARG0-of (b / bear-02 :ARG1 (t / tumor~e.27 :mod (e2 / epithelium~e.26)))))) # ::id bel_pmid_2137_8275.40582 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 2-1.1 3-1.1.2.2 4-1.1.2.1.1 6-1.2 6-1.2.r 7-1 8-1.3 9-1.3.1.1.1.1 10-1.3.1 (d / develop-01~e.7 :ARG2 (a / and~e.2 :op1 (d2 / disease :name (n / name :op1 "emphysema"~e.1) :mod (s2 / spontaneous~e.0)) :op2 (m / medical-condition :name (n2 / name :op1 "adenocarcinoma"~e.4) :mod (l / lung~e.3))) :manner~e.6 (s / sequential~e.6) :time (a2 / after~e.8 :op1 (o / overexpress-01~e.10 :ARG1 (e / enzyme :name (n3 / name :op1 "MMP12"~e.9))))) # ::id bel_pmid_2137_8275.40590 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MMP12 suppresses T @-@ cell proliferation and function in vivo The CD4+ T @-@ lymphocyte population was significantly decreased in the spleen of doxycycline @-@ treated bitransgenic mice ( 5.58 %) compared with that in untreated ones ( 21.14 %) , while the CD8+ T @-@ lymphocyte population was less affected ( Figure 2A ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1.1.1 4-1.1.2.1.1.1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.2 8-1.1.3 9-1.1.3 11-1.2.1.1.2.1.1.1 12-1.2.1.1.1.1 14-1.2.1.1.1.1 15-1.2.1 15-1.2.5.1 17-1.2.3 18-1.2 18-1.2.5 19-1.1.3 19-1.2.4.r 21-1.2.4 23-1.2.4.1.1.1 25-1.2.4.1.1 26-1.2.4.1.2 27-1.2.4.1 27-1.2.5.3 29-1.2.2.1 31-1.2.5.r 34-1.1.3 34-1.2.5.3.1.r 35-1.2.5.3.1 35-1.2.5.3.1.1 35-1.2.5.3.1.1.r 38-1.2.5.2.1 41-1.2.7 43-1.2.7.1.1.1.3.1.1 44-1.2.7.1.1.1.1.1 46-1.2.7.1.1.1.1.1 47-1.2.7.1.1 49-1.2.7.1.2 50-1.2.7.1 52-1.2.6.1 53-1.2.6.1.1 (m2 / multi-sentence :snt1 (s / suppress-01~e.1 :ARG0 (e / enzyme :name (n / name :op1 "MMP12"~e.0)) :ARG1 (a / and~e.6 :op1 (p3 / proliferate-01~e.5 :ARG0 (c / cell :name (n2 / name :op1 "T-cell"~e.2,4))) :op2 (f / function-01~e.7 :ARG0 c)) :manner (i / in-vivo~e.8,9,19,34)) :snt2 (d / decrease-01~e.18 :ARG1 (p4 / population~e.15 :quant-of (c2 / cell :name (n3 / name :op1 "T-lymphocyte"~e.12,14) :ARG3-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n4 / name :op1 "CD4+"~e.11))))) :ARG2 (p5 / percentage-entity :value 5.58~e.29) :ARG1-of (s2 / significant-02~e.17) :location~e.19 (s3 / spleen~e.21 :part-of (m3 / mouse~e.27 :ARG1-of (t / treat-03~e.25 :ARG3 (d2 / doxycycline~e.23)) :mod (b / bitransgenic~e.26))) :compared-to~e.31 (d3 / decrease-01~e.18 :ARG1 (p6 / population~e.15 :quant-of c2) :ARG2 (p7 / percentage-entity :value 21.14~e.38) :location (m4 / mouse~e.27 :ARG1-of~e.34 (t2 / treat-04~e.35 :polarity~e.35 -~e.35))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.52 :mod "2A"~e.53)) :ARG1-of (c5 / contrast-01~e.41 :ARG2 (a3 / affect-01~e.50 :ARG1 (p8 / population~e.47 :quant-of (c4 / cell :name (n7 / name :op1 "T-lymphocyte"~e.44,46) :ARG1-of (e6 / express-03 :ARG2 e3) :mod (p / protein :name (n6 / name :op1 "CD8+"~e.43)))) :degree (l / less~e.49))))) # ::id bel_pmid_2137_8275.40594 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The culture medium showed decreased secretion of IL @-@ 2 , IL @-@ 4 , and IFN7 in the activated MMP12 @-@ treated samples ( Figure 2F ) . # ::alignments 1-1.1.1 2-1.1 3-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1.1.1 7-1.2.1.2.1.1 9-1.2.1.1.1.1 11-1.2.1.1.1.1 11-1.2.1.2.1.1 13-1.2.1.2.1.1 15-1.2.1 16-1.2.1.3.1.1 17-1.3.r 19-1.3.1.1.2 20-1.3.1.1.1.1 22-1.3.1 23-1.3 23-1.3.2 23-1.3.2.r 25-1.4.1 26-1.4.1.1 (s / show-01~e.3 :ARG0 (m / medium~e.2 :mod (c / culture~e.1)) :ARG1 (s2 / secrete-01~e.5 :ARG1~e.6 (a / and~e.15 :op1 (p / protein :name (n / name :op1 "IL-2"~e.7,9,11)) :op2 (p2 / protein :name (n2 / name :op1 "IL-4"~e.7,11,13)) :op3 (p3 / protein :name (n3 / name :op1 "IFN7"~e.16))) :ARG1-of (d2 / decrease-01~e.4)) :location~e.17 (t2 / thing~e.23 :ARG1-of (t / treat-04~e.22 :ARG2 (e / enzyme :name (n4 / name :op1 "MMP12"~e.20) :ARG1-of (a2 / activate-01~e.19))) :ARG1-of~e.23 (s3 / sample-01~e.23)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "2F"~e.26))) # ::id bel_pmid_2137_8275.40598 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CD11b+/Gr @-@ 1+ cells from doxcycline @-@ treated bitransgenic mice showed the strongest inhibition on proliferation of wild @-@ type CD4+ T cells ( Figure 3C ) . # ::alignments 2-1.1.1.2.1.1 3-1.1 4-1.1.2.r 7-1.1.2.2 8-1.1.2.1 9-1.1.2 10-1 12-1.2.2 12-1.2.2.1 12-1.2.2.1.r 13-1.2 14-1.2.1.r 15-1.2.1 16-1.2.1.1.r 17-1.2.1.1.3 19-1.2.1.1.3 20-1.2.1.1.2.1.1.1 21-1.2.1.1.1.1 22-1.2.1.1.1.1 24-1.3.1 25-1.3.1.1 (s / show-01~e.10 :ARG0 (c / cell~e.3 :mod (s2 / slash :op1 (p2 / protein :name (n / name :op1 "CD11b+")) :op2 (p3 / protein :name (n2 / name :op1 "Gr-1+"~e.2))) :source~e.4 (m / mouse~e.9 :mod (b / bitransgenic~e.8) :ARG1-of (t / treat-04~e.7 :ARG2 (s4 / small-molecule :name (n5 / name :op1 "doxycycline"))))) :ARG1 (i / inhibit-01~e.13 :ARG1~e.14 (p / proliferate-01~e.15 :ARG0~e.16 (c2 / cell :name (n3 / name :op1 "T-cell"~e.21,22) :ARG3-of (e / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "CD4+"~e.20))) :mod (w / wild-type~e.17,19))) :ARG1-of (s3 / strong-02~e.12 :degree~e.12 (m2 / most~e.12))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "3C"~e.25))) # ::id bel_pmid_2137_8275.40600 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This inhibition was further confirmed by a significant reduction of IL @-@ 2 and IL @-@ 4 secretion , implicating a functional impairment of CD4+ T cells by CD11b+/Gr @-@ 1+ cells from doxcycline @-@ treated bitransgenic mice ( Figure 3D ) . # ::alignments 0-1.2.1 1-1.2 3-1.3 4-1 5-1.1.r 7-1.1.2 8-1.1 9-1.1.1.r 10-1.1.1.1.1.1.1 10-1.1.1.1.2.1.1 12-1.1.1.1.1.1.1 13-1.1.1.1 14-1.1.1.1.1.1.1 14-1.1.1.1.2.1.1 16-1.1.1.1.2.1.1 17-1.1.1 19-1.4 21-1.4.1.2 22-1.4.1 23-1.4.1.2.1.r 24-1.4.1.2.1.2.1.1.1 25-1.4.1.2.1.1.1 26-1.4.1.1 26-1.4.1.2.1.1.1 30-1.4.1.1.1.2.1.1 31-1.4.1.1 32-1.4.1.1.2.r 35-1.4.1.1.2.2 36-1.4.1.1.2.1 37-1.4.1.1.2 39-1.5.1 40-1.5.1.1 (c / confirm-01~e.4 :ARG0~e.5 (r / reduce-01~e.8 :ARG1~e.9 (s / secrete-01~e.17 :ARG1 (a / and~e.13 :op1 (p / protein :name (n / name :op1 "IL-2"~e.10,12,14)) :op2 (p2 / protein :name (n2 / name :op1 "IL-4"~e.10,14,16)))) :ARG2 (s3 / significant-02~e.7)) :ARG1 (i / inhibit-01~e.1 :mod (t / this~e.0)) :degree (f / further~e.3) :ARG0-of (i2 / implicate-01~e.19 :ARG1 (i3 / impair-01~e.22 :ARG0 (c3 / cell~e.26,31 :part (s2 / slash :op1 (p3 / protein :name (n5 / name :op1 "CD11b+")) :op2 (p4 / protein :name (n6 / name :op1 "Gr-1+"~e.30))) :source~e.32 (m / mouse~e.37 :mod (b / bitransgenic~e.36) :ARG1-of (t2 / treat-04~e.35 :ARG2 (s4 / small-molecule :name (n7 / name :op1 "doxycycline"))))) :ARG1 (f2 / function-01~e.21 :ARG0~e.23 (c2 / cell :name (n3 / name :op1 "T-cell"~e.25,26) :ARG3-of (e / express-03 :ARG2 (p5 / protein :name (n4 / name :op1 "CD4+"~e.24))))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.39 :mod "3D"~e.40))) # ::id bel_pmid_2137_8275.40608 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Compared with doxycycline @-@ untreated bitransgenic mice , the expression levels of IL @-@ 1p , IL @-@ 6 , MIP @-@ 2 , and TNF @-@ a were abnormally increased in the plasma of doxycycline @-@ treated bitransgenic mice ( Figure 4A ) . # ::alignments 0-1.4.r 2-1.4.2.2 4-1.4.2 4-1.4.2.1 4-1.4.2.1.r 5-1.4.1 6-1.4 9-1.1.1 10-1.1 11-1.1.1.1.r 12-1.1.1.1.1.1.1 12-1.1.1.1.2.1.1 14-1.1.1.1.1.1.1 16-1.1.1.1.1.1.1 16-1.1.1.1.2.1.1 18-1.1.1.1.2.1.1 20-1.1.1.1.3.1.1 22-1.1.1.1.3.1.1 24-1.1.1.1 25-1.1.1.1.4.1.1 27-1.1.1.1.4.1.1 29-1.2 29-1.2.1 29-1.2.1.r 30-1 31-1.3.r 33-1.3 35-1.3.1.2.1.1.1 37-1.3.1.2 38-1.3.1.1 39-1.3.1 39-1.4 41-1.5.1 42-1.5.1.1 (i / increase-01~e.30 :ARG1 (l / level~e.10 :degree-of (e / express-03~e.9 :ARG2~e.11 (a2 / and~e.24 :op1 (p / protein :name (n / name :op1 "IL-1p"~e.12,14,16)) :op2 (p2 / protein :name (n2 / name :op1 "IL-6"~e.12,16,18)) :op3 (p3 / protein :name (n3 / name :op1 "MIP-2"~e.20,22)) :op4 (p4 / protein :name (n4 / name :op1 "TNF-a"~e.25,27))))) :ARG1-of (n5 / normal-02~e.29 :polarity~e.29 -~e.29) :location~e.31 (p5 / plasma~e.33 :part-of (m / mouse~e.39 :mod (b / bitransgenic~e.38) :ARG1-of (t / treat-04~e.37 :ARG2 (s / small-molecule :name (n6 / name :op1 "doxycycline"~e.35))))) :compared-to~e.0 (m2 / mouse~e.6,39 :mod (b2 / bitransgenic~e.5) :ARG1-of (t2 / treat-04~e.4 :polarity~e.4 -~e.4 :ARG2 s~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.41 :mod "4A"~e.42))) # ::id bel_pmid_2145_4454.35882 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine if the ERK @-@ MAPK pathway was also activated by TLR2 in megakaryocytes , lysates of Meg @-@ 01 cells were treated with 1 ?g/mL Pam3CSK4 for up to 1 hour and were immunoblotted for phosphorylated ERK1 @/@ 2 . As shown in Figure 1A , there was an increase in the phosphorylation of ERK beginning at 5 minutes that peaks at 30 minutes ( 105.8 % ± 3.9 ) . # ::alignments 1-1.1.3 4-1.1.3.1.3.1.1 6-1.1.3.1.3.1.1 7-1.1.3.1.3 9-1.1.3.1.5 10-1.1.3.1 11-1.1.3.1.2.r 12-1.1.3.1.2.1.1 14-1.1.3.1.4.1.1 16-1.1.1.1 18-1.1.1.1.1.1.1 20-1.1.1.1.1.1.1 20-1.1.1.2.2.1 21-1.1.1.1.1 21-1.1.3.1.4 23-1.1.1 24-1.1.1.2.r 25-1.1.1.2.2.1 27-1.1.1.2.1.1 28-1.1.1.3.r 29-1.1.1.3 30-1.1.1.3 31-1.1.1.3.1.1 32-1.1.1.3.1.2 33-1.1 37-1.1.2.1.3 39-1.1.2.1 40-1.1.2.1.2.1.1 43-1.2.4 44-1.2.4.1.r 45-1.2.4.1 46-1.2.4.1.1 51-1.2 52-1.2.1.r 54-1.2.1 55-1.2.1.1.r 56-1.2.1.1.1.1 57-1.2.2 59-1.2.2.1.1.1 60-1.2.2.1.1.2 62-1.2.3 64-1.2.3.2.1.1 65-1.2.3.2.1.2 67-1.2.3.1.1 68-1.2.3.1 68-1.2.3.1.2.1 68-1.2.3.1.3.1 70-1.2.3.1.2.1.1 70-1.2.3.1.3.1.1 (m4 / multi-sentence :snt1 (a / and~e.33 :op1 (t4 / treat-04~e.23 :ARG1 (l / lysate~e.16 :source (c / cell-line~e.21 :name (n2 / name :op1 "Meg-01"~e.18,20))) :ARG2~e.24 (p3 / protein :name (n3 / name :op1 "Pam3CSK4"~e.27) :quant (c3 / concentration-quantity :quant 1~e.20,25 :unit (g / gram-per-milliliter))) :duration~e.28 (u / up-to~e.29,30 :op1 (t6 / temporal-quantity :quant 1~e.31 :unit (h2 / hour~e.32)))) :op2 (i / immunoblot-01 :ARG1 (s / slash~e.39 :op1 (e2 / enzyme :name (n4 / name :op1 "ERK-1")) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK-2"~e.40)) :ARG1-of (p4 / phosphorylate-01~e.37)) :ARG2 l) :purpose (d / determine-01~e.1 :ARG1 (a2 / activate-01~e.10 :mode interrogative :ARG0~e.11 (p6 / protein :name (n7 / name :op1 "TLR2"~e.12)) :ARG1 (p5 / pathway~e.7 :name (n6 / name :op1 "ERK-MAPK"~e.4,6)) :location (c2 / cell~e.21 :name (n8 / name :op1 "megakaryocyte"~e.14)) :mod (a5 / also~e.9)))) :snt2 (i2 / increase-01~e.51 :ARG1~e.52 (p7 / phosphorylate-01~e.54 :ARG1~e.55 (e4 / enzyme :name (n9 / name :op1 "ERK"~e.56))) :ARG0-of (b / begin-01~e.57 :time (a6 / after :op1 (t3 / temporal-quantity :quant 5~e.59 :unit (m3 / minute~e.60)))) :ARG1-of (p8 / peak-01~e.62 :ARG2 (p9 / percentage-entity~e.68 :value 105.8~e.67 :ARG2-of (a4 / add-02 :ARG1 (p / percentage-entity~e.68 :value 3.9~e.70)) :ARG2-of (s3 / subtract-01 :ARG1 (p2 / percentage-entity~e.68 :value 3.9~e.70))) :time (a3 / after :op1 (t / temporal-quantity :quant 30~e.64 :unit (m2 / minute~e.65)))) :ARG1-of (s2 / show-01~e.43 :location~e.44 (f2 / figure~e.45 :mod "1A"~e.46)))) # ::id bel_pmid_2145_4454.35884 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GP1b is part of the GPIb @-@ IX @-@ V complex that binds vWF and thrombin . Its expression level was significantly increased by 162 % and cell surface expression , as determined by flow cytometry , was also increased by 114 % with Pam3CSK4 treatment ( Figure 5A and Supplemental Figure 4C ) . # ::alignments 0-1.1.1.1.1.1.1.1 0-1.2.2.1.1 2-1.2 5-1.2.1.1.1 7-1.2.1.1.1 9-1.2.1.1.1 10-1.2.1 12-1.2.1.2 13-1.2.1.2.1.1.1.1 14-1.2.1.2.1 15-1.2.1.2.1.2.1.1 18-1.1.1.1.1 19-1.1.1.1 21-1.1.1.3 22-1.1.1 23-1.1.1.2.r 24-1.1.1.2.1 25-1.1.1.2 26-1.1 27-1.1.2.1.2.1 28-1.1.2.1.2 29-1.1.2.1 31-1.1.2.1.3.r 32-1.1.2.1.3 33-1.1.2.1.3.1.r 34-1.1.2.1.3.1.1 35-1.1.2.1.3.1 38-1.1.2.3 39-1.1.2 40-1.1.2.2.r 41-1.1.2.2.1 42-1.1.2.2 43-1.1.2.4.r 44-1.1.2.4.1.1.1 45-1.1.2.4 47-1.1.3.1.1 48-1.1.3.1.1.1 49-1.1.3.1 50-1.1.3.1.2.2 51-1.1.3.1.2 52-1.1.3.1.2.1 (m / multi-sentence :snt2 (a / and~e.26 :op1 (i / increase-01~e.22 :ARG1 (l / level~e.19 :degree-of (e2 / express-03~e.18 :ARG2 (p6 / protein :name (n6 / name :op1 "GP1b"~e.0)))) :ARG2~e.23 (p / percentage-entity~e.25 :value 162~e.24) :ARG1-of (s / significant-02~e.21)) :op2 (i2 / increase-01~e.39 :ARG1 (e3 / express-03~e.29 :ARG2 p6 :location (s2 / surface~e.28 :poss (c2 / cell~e.27)) :ARG1-of~e.31 (d / determine-01~e.32 :ARG0~e.33 (c3 / cytometry~e.35 :mod (f / flow~e.34)))) :ARG2~e.40 (p2 / percentage-entity~e.42 :value 114~e.41) :mod (a2 / also~e.38) :instrument~e.43 (t / treat-04~e.45 :ARG2 (p5 / protein :name (n5 / name :op1 "Pam3CSK4"~e.44)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.49 :op1 (f2 / figure~e.47 :mod "5A"~e.48) :op2 (f3 / figure~e.51 :mod "4C"~e.52 :ARG2-of (s3 / supplement-01~e.50))))) :snt1 (h / have-part-91~e.2 :ARG1 (c / complex~e.10 :name (n2 / name :op1 "GPIb-IX-V"~e.5,7,9) :ARG1-of (b / bind-01~e.12 :ARG2 (a4 / and~e.14 :op1 (p4 / protein :name (n3 / name :op1 "vWF"~e.13)) :op2 (e / enzyme :name (n4 / name :op1 "thrombin"~e.15))))) :ARG2 (p3 / protein :name (n / name :op1 "GP1b"~e.0)))) # ::id bel_pmid_2145_4454.35890 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CD41 , also known as integrin ?IIb , part of the ?IIb ? III receptor that binds fibrinogen , was also significantly increased in the presence of Pam3CSK4 by 123 % ( Figure 5B ) . Surface expression of CD41 was increased by 125 % as shown by flow cytometry ( Supplemental Figure 4D ) . # ::alignments 0-1.1.1.1.1 0-1.2.1.1.1.1 2-1.1.1.2.2 3-1.1.1 3-1.1.1.2 3-1.1.1.2.1.2.r 3-1.1.1.2.r 4-1.1.1.2.1.2.r 5-1.1.1.2.1.2.1 8-1.1.1.3.r 12-1.1.1.2.1.1 12-1.1.1.2.1.1.r 14-1.1.1.3 16-1.1.1.3.2 17-1.1.1.3.2.1.1.1 20-1.1.1.3.2.1.2.3 21-1.1.1.3.2.1.2.2 22-1.1 22-1.1.1.3.2.1.2 23-1.1.1.3.2.1.2.4.r 25-1.1.1.3.2.1.2.4 26-1.1.1.3.2.1.2.4.1.r 27-1.1.1.3.2.1.2.4.1.1.1 28-1.1.1.3.2.1.2.1.r 29-1.1.1.3.2.1.2.1.1 30-1.1.1.3.2.1.2.1 32-1.1.3.1 33-1.1.3.1.1 36-1.2.1.2 37-1.2.1 38-1.2.1.1.r 39-1.2.1.1.1.1 41-1.2 42-1.2.2.r 43-1.2.2.1 44-1.2.2 45-1.2.3.r 46-1.2.3 47-1.2.3.1.r 48-1.2.3.1.1 49-1.2.3.1 51-1.2.4.1.2 52-1.2.4.1 53-1.2.4.1.1 (m / multi-sentence :snt1 (i / increase-01~e.22 :ARG1 (p3 / protein~e.3 :name (n / name :op1 "CD41"~e.0) :ARG1-of~e.3 (k / know-02~e.3 :ARG2 (p4 / protein :mode~e.12 interrogative~e.12 :name~e.3,4 (n2 / name :op1 "integrin-IIb"~e.5)) :mod (a / also~e.2)) :part-of~e.8 (r / receptor~e.14 :name (n3 / name :op1 "IIb/IIIa") :ARG0-of (b / bind-01~e.16 :ARG1 (p5 / protein :name (n4 / name :op1 "fibrinogen"~e.17) :ARG1-of (i2 / increase-01~e.22 :ARG2~e.28 (p / percentage-entity~e.30 :value 123~e.29) :ARG1-of (s2 / significant-02~e.21) :mod (a2 / also~e.20) :condition~e.23 (p6 / present-02~e.25 :ARG1~e.26 (p7 / protein :name (n5 / name :op1 "Pam3CSK4"~e.27)))))))) :ARG2 s2 :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "5B"~e.33))) :snt2 (i3 / increase-01~e.41 :ARG1 (e / express-03~e.37 :ARG2~e.38 (p8 / protein :name (n6 / name :op1 "CD41"~e.0,39)) :location (s3 / surface~e.36)) :ARG2~e.42 (p2 / percentage-entity~e.44 :value 125~e.43) :ARG1-of~e.45 (s4 / show-01~e.46 :ARG0~e.47 (c / cytometry~e.49 :mod (f2 / flow~e.48))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.52 :mod "4D"~e.53 :ARG2-of (s5 / supplement-01~e.51))))) # ::id bel_pmid_2151_8970.1890 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Unexpectedly , TGF @-@ beta treatment also induced increased IL @-@ 6 production by pDC . # ::alignments 0-1.3.1 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1 6-1.4 7-1 8-1.2.3 9-1.2.2.1.1 11-1.2.2.1.1 12-1.2 13-1.2.1.r 14-1.2.1.1.1 (i / induce-01~e.7 :ARG0 (t / treat-04~e.5 :ARG2 (p / protein :name (n / name :op1 "TGF-beta"~e.2,4))) :ARG2 (p2 / produce-01~e.12 :ARG0~e.13 (e / enzyme :name (n3 / name :op1 "pDC"~e.14)) :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"~e.9,11)) :ARG1-of (i2 / increase-01~e.8)) :ARG1-of (e2 / expect-01 :polarity -~e.0) :mod (a / also~e.6)) # ::id bel_pmid_2169_7282.25874 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Api6 overexpression in lung epithelial cells only caused regional inflammation , not systemic inflammation . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 4-1.1.1.2.1 5-1.1.1.2 6-1.1.3 7-1.1 7-1.2 8-1.1.2.1 9-1.1.2 9-1.2.3 11-1.2.1 11-1.2.1.r 13-1.1.2 (c3 / contrast-01 :ARG1 (c / cause-01~e.7 :ARG0 (o / overexpress-01~e.1 :ARG1 (p / protein :name (n / name :op1 "Api6"~e.0)) :location~e.2 (c2 / cell~e.5 :part-of (e / epithelium~e.4 :mod (l / lung~e.3)))) :ARG1 (i / inflame-01~e.9,13 :mod (r / region~e.8)) :mod (o2 / only~e.6)) :ARG2 (c4 / cause-01~e.7 :polarity~e.11 -~e.11 :ARG0 o :ARG1 (i2 / inflame-01~e.9 :ARG1 (s / system)))) # ::id bel_pmid_2169_7282.25878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the gene transcriptional level , Api6 overexpression stimulated mRNA expression of Stat3 and its upstream stimuli IL @-@ 6 in whole lung cells , AT II epithelial cells , and alveolar macrophages ( Fig . 4A ) . # ::alignments 2-1.3.1.1 3-1.3.1 4-1.3 6-1.1.1.1.1 7-1.1 8-1 9-1.2.1.1.1.1 10-1.2.1 10-1.2.2 11-1.2.1.2.r 12-1.2.1.2.1.1 13-1.2 14-1.2.2.1 14-1.2.2.1.r 15-1.2.2.2.3 16-1.2.2.2 16-1.2.2.2.2 16-1.2.2.2.2.r 17-1.2.2.2.1.1 19-1.2.2.2.1.1 20-1.4.r 21-1.4.1.2 22-1.4.1.1 23-1.4.1 25-1.4.2.1.1.1.1 26-1.4.2.1.1.1.1 27-1.4.2.1 28-1.4.2 30-1.4 31-1.4.3.2 32-1.4.3.1.1 34-1.5.1 36-1.5.1.1 (s / stimulate-01~e.8 :ARG0 (o / overexpress-01~e.7 :ARG1 (p / protein :name (n / name :op1 "Api6"~e.6))) :ARG1 (a / and~e.13 :op1 (e / express-03~e.10 :ARG1 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.9)) :ARG2~e.11 (p2 / protein :name (n2 / name :op1 "Stat3"~e.12))) :op2 (e2 / express-03~e.10 :ARG1~e.14 n7~e.14 :ARG2 (p3 / protein~e.16 :name (n4 / name :op1 "IL-6"~e.17,19) :ARG0-of~e.16 (s2 / stimulate-01~e.16 :ARG1 p2) :location (u / upstream~e.15)))) :location (l / level~e.4 :mod (t / transcribe-01~e.3 :ARG1 (g / gene~e.2))) :location~e.20 (a2 / and~e.30 :op1 (c / cell~e.23 :mod (l2 / lung~e.22) :mod (w / whole~e.21)) :op2 (c2 / cell~e.28 :part-of (e3 / epithelium~e.27 :part (p4 / protein :name (n5 / name :op1 "AT-II"~e.25,26)))) :op3 (c3 / cell :name (n6 / name :op1 "macrophage"~e.32) :mod (a3 / alveolus~e.31))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "4A"~e.36))) # ::id bel_pmid_2193_6896.27282 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significant reductions in brain levels of early cytokines , including IL @-@ 1 beta and IL @-@ 6 mRNA expression , and late cytokine high mobility group box @-@ 1 protein ( HMGB1 ) , were found in the gelsolin @-@ treated group compared to the placebo group at all time points ( Figure 4 ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.3.r 3-1.1.3.1 4-1.1.3 5-1.1.1.r 6-1.1.1.1.2 7-1.1.1.1 9-1.1.1.1.1 10-1.1.1.1.1.1.1.1.2.1.1.1 10-1.1.1.1.1.1.1.2.2.1.1.1 12-1.1.1.2.1.1.4 14-1.1.1.1.1.1.1 15-1.1.1.1.1.1.1.1.2.1.1.1 15-1.1.1.1.1.1.1.2.2.1.1.1 17-1.1.1.1.1.1.1.2.2.1.1.1 18-1.1.1.1.1.1.1.1.1.1 18-1.1.1.1.1.1.1.2.1.1 19-1.1.1.1.1.1 21-1.1.1 22-1.1.1.2.2 23-1.1.1.2 24-1.1.1.2.1.1.1 25-1.1.1.2.1.1.2 26-1.1.1.2.1.1.3 27-1.1.1.2.1.1.4 29-1.1.1.2.1.1.4 30-1.1.1.1.1.1.1.1.2.1 30-1.1.1.1.1.1.1.2.2.1 30-1.1.1.2.1 30-1.2.1.1 35-1.1.1.2.1.r 36-1 37-1.2.r 39-1.2.1.1.1.1 41-1.2.1 42-1.2 43-1.1.4.r 46-1.1.4.1 47-1.1.4 48-1.3.r 49-1.3.1.1 50-1.3.1 51-1.3 53-1.4.1 54-1.4.1.1 (f / find-01~e.36 :ARG1 (r / reduce-01~e.1 :ARG1~e.5 (a / and~e.21 :op1 (c / cytokine~e.7 :ARG2-of (i / include-91~e.9 :ARG1 (e / express-03~e.19 :ARG2 (a2 / and~e.14 :op1 (n7 / nucleic-acid :name (n / name :op1 "mRNA"~e.18) :ARG0-of (e2 / encode-01 :ARG1 (p / protein~e.30 :name (n2 / name :op1 "IL-1β"~e.10,15)))) :op2 (n8 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.18) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein~e.30 :name (n4 / name :op1 "IL-6"~e.10,15,17))))))) :mod (e4 / early~e.6)) :op2 (c2 / cytokine~e.23 :domain~e.35 (p3 / protein~e.30 :name (n5 / name :op1 "high"~e.24 :op2 "mobility"~e.25 :op3 "group"~e.26 :op4 "box-1"~e.12,27,29)) :mod (l / late~e.22))) :ARG2 (s / significant-02~e.0) :location~e.2 (l2 / level~e.4 :mod (b / brain~e.3)) :compared-to~e.43 (g / group~e.47 :mod (p4 / placebo~e.46))) :location~e.37 (g2 / group~e.42 :ARG1-of (t / treat-04~e.41 :ARG2 (p5 / protein~e.30 :name (n6 / name :op1 "gelsolin"~e.39)))) :time~e.48 (p6 / point~e.51 :mod (t2 / time~e.50 :mod (a3 / all~e.49))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.53 :mod 4~e.54))) # ::id bel_pmid_2213_2131.40908 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Factors from murine pancreatic cancer cells cause the down @-@ regulation of SHIP @-@ 1 expression , which may potentially contribute to MDSC expansion , and the suppression of CD8+ T cell immune responses . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.2.2.1 4-1.1.1.2.2.2 5-1.1.1 6-1 8-1.2 9-1.2 10-1.2 11-1.2.2.r 12-1.2.2.1.1.1 14-1.2.2.1.1.1 15-1.2.2 18-1.2.3.3 19-1.2.3.2 20-1.2.3 21-1.2.3.1.r 22-1.2.3.1.1.2.1.1 23-1.2.3.1.1 25-1.2.3.1 27-1.2.3.1.2 30-1.2.3.1.2.2.1.1.1.1 31-1.2.3.1.1.2 31-1.2.3.1.2.2.1.1 32-1.2.3.1.2.2.2 33-1.2.3.1.2.2 33-1.2.3.1.2.2.1 33-1.2.3.1.2.2.1.r (c / cause-01~e.6 :ARG0 (f / factor~e.0 :source~e.1 (c2 / cell~e.5 :part-of (o / organism :name (n2 / name :op1 "Muridae"~e.2)) :mod (d3 / disease :wiki "Pancreatic_cancer" :name (n7 / name :op1 "pancreatic"~e.3 :op2 "cancer"~e.4)))) :ARG1 (d2 / downregulate-01~e.8,9,10 :ARG0 f :ARG1~e.11 (e / express-03~e.15 :ARG2 (p2 / protein :name (n3 / name :op1 "SHIP-1"~e.12,14))) :ARG0-of (c3 / contribute-01~e.20 :ARG2~e.21 (a / and~e.25 :op1 (e2 / expand-01~e.23 :ARG0 d2 :ARG1 (c4 / cell~e.31 :name (n4 / name :op1 "MDSC"~e.22))) :op2 (s / suppress-01~e.27 :ARG0 d2 :ARG1 (t / thing~e.33 :ARG2-of~e.33 (r / respond-01~e.33 :ARG0 (c5 / cell~e.31 :name (n5 / name :op1 "T"~e.30) :mod (p3 / protein :name (n6 / name :op1 "CD8")))) :ARG1-of (i / immune-02~e.32)))) :mod (p4 / potential~e.19) :ARG1-of (p5 / possible-01~e.18)))) # ::id bel_pmid_2213_2131.40910 ::amr-annotator SDL-AMR-09 ::preferred # ::tok qRT @-@ PCR and Western blot analyses revealed the in vivo down @-@ regulation of SHIP @-@ 1 expression in splenocytes from TB mice . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1 4-1.1.2.1 5-1.1.2.1 6-1.1.1 6-1.1.2 7-1 9-1.2.2 10-1.2.2 11-1.2 12-1.2 13-1.2 14-1.2.1.r 15-1.2.1.1.1.1 17-1.2.1.1.1.1 18-1.2.1 19-1.2.2 19-1.2.3.r 20-1.2.3 21-1.2.3.1.r 23-1.2.3.1 (r / reveal-01~e.7 :ARG0 (a / and~e.3 :op1 (a2 / analyze-01~e.6 :instrument (t2 / thing :name (n / name :op1 "qRT-PCR"~e.0,2))) :op2 (a3 / analyze-01~e.6 :manner (i2 / immunoblot-01~e.4,5))) :ARG1 (d / downregulate-01~e.11,12,13 :ARG1~e.14 (e / express-03~e.18 :ARG2 (p / protein :name (n3 / name :op1 "SHIP-1"~e.15,17))) :manner (i / in-vivo~e.9,10,19) :location~e.19 (s / splenocyte~e.20 :source~e.21 (m / mouse~e.23 :ARG0-of (b / bear-01 :ARG1 (t / tumor)))))) # ::id bel_pmid_2213_2131.40912 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analyses also detected reduced SHIP @-@ 1 activity , increased AKT @-@ 1 and BAD hyper @-@ phosphorylation and up @-@ regulation of BCL @-@ 2 expression in splenocytes from TB mice . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1.3 4-1 5-1.2.1.2 6-1.2.1.1.1.1 8-1.2.1.1.1.1 9-1.2.1 11-1.2.2.1.2 12-1.2.2.1.1.1.1.1 14-1.2.2.1.1.1.1.1 15-1.2.2.1.1 16-1.2.2.1.1.2.1.1 20-1.2 20-1.2.2 20-1.2.2.1.1 20-1.2.2.r 21-1.2.3 22-1.2.3 23-1.2.3 24-1.2.3.1.r 25-1.2.3.1.1.1.1 27-1.2.3.1.1.1.1 28-1.2.3.1 29-1.4.r 30-1.4 31-1.4.1.r 33-1.4.1 (d / detect-01~e.4 :ARG0 (a / analyze-01~e.2 :manner (i2 / immunoblot-01~e.0,1)) :ARG1 (a2 / and~e.20 :op1 (a3 / activity-06~e.9 :ARG0 (p3 / protein :name (n2 / name :op1 "SHIP-1"~e.6,8)) :ARG1-of (r / reduce-01~e.5)) :op2~e.20 (a4 / and~e.20 :op1 (h / hyperphosphorylate-01 :ARG1 (a5 / and~e.15,20 :op1 (e2 / enzyme :name (n3 / name :op1 "AKT-1"~e.12,14)) :op2 (p / protein :name (n4 / name :op1 "BAD"~e.16))) :ARG1-of (i / increase-01~e.11))) :op3 (u / upregulate-01~e.21,22,23 :ARG1~e.24 (e3 / express-03~e.28 :ARG2 (p2 / protein :name (n5 / name :op1 "BCL-2"~e.25,27))))) :mod (a6 / also~e.3) :location~e.29 (s / splenocyte~e.30 :source~e.31 (m / mouse~e.33 :ARG0-of (b / bear-01 :ARG1 (t / tumor))))) # ::id bel_pmid_2213_2131.40914 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro , qRT @-@ PCR and Western blot analyses detected reduced SHIP @-@ 1 mRNA and protein expression in control splenocytes co @-@ cultured with Panc 02.03 cells . # ::alignments 0-1.4 1-1.4 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1 7-1.1.2.1 8-1.1.2.1 9-1.1.1 9-1.1.2 10-1 11-1.2.3 12-1.2.1.1.2.1.1.1 14-1.2.1.1.2.1.1.1 15-1.2.1.1.1.1 17-1.2.1.1.2.1 18-1.2.1 18-1.2.2 19-1.3.r 19-1.4 20-1.3.1 21-1.3 24-1.3.2.2 25-1.1.1.1.r 25-1.3.2.r 26-1.3.2.1.1.1 27-1.3.2.1.1.2 28-1.3.2.1 (d / detect-01~e.10 :ARG0 (a / and~e.6 :op1 (a2 / analyze-01~e.9 :instrument~e.25 (t / thing :name (n / name :op1 "qRT-PCR"~e.3,5))) :op2 (a3 / analyze-01~e.9 :manner (i2 / immunoblot-01~e.7,8))) :ARG1 (a4 / and :op1 (e / express-03~e.18 :ARG1 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.15) :ARG0-of (e2 / encode-01 :ARG1 (p / protein~e.17 :name (n4 / name :op1 "SHIP-1"~e.12,14))))) :op2 (e3 / express-03~e.18 :ARG2 p) :ARG1-of (r2 / reduce-01~e.11)) :location~e.19 (s / splenocyte~e.21 :ARG2-of (c / control-01~e.20) :op1-of~e.25 (a5 / and :op2 (c3 / cell~e.28 :name (n5 / name :op1 "Panc"~e.26 :op2 02.03~e.27)) :ARG1-of (c2 / culture-01~e.24))) :manner (i / in-vitro~e.0,1,19)) # ::id bel_pmid_2213_2131.40918 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results from the Inflammatory Cytometric Bead Analysis ( CBA ) Kit detected pro @-@ inflammatory factors Interleukin @-@ 6 ( IL @-@ 6 ) , Interleukin @-@ 10 ( IL @-@ 10 ) and Monocyte Chemoattractant Protein @-@ 1 ( MCP @-@ 1 ) to a greater extent than Tumor Necrosis Factor ( TNF ) , Interferon gamma ( IFN @-@ y and Interleukin @-@ 12p 70 ( IL @-@ 12p70 ) in the supernatants of cultured murine Panc 02.03 cells ( Figure 1a ) . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.2.r 3-1.1.2.1.1 4-1.1.2.1.2 5-1.1.2.1.3 6-1.1.2.1.4 10-1.1.2 11-1 12-1.2.2.4 14-1.2.2.4.1 16-1.2.2.1.1.1 16-1.2.2.2.1.1 16-1.2.3.3.1.1 18-1.2.2.1.1.1 22-1.2.2.1.1.1 25-1.2.2.1.1.1 25-1.2.2.2.1.1 27-1.2.2.2.1.1 31-1.2.2.2.1.1 33-1.2.2 34-1.2.2.3.1.1 35-1.2.2.3.1.2 36-1.2.2.3.1.3 38-1.2.2.3.1.3 42-1.2.2.3.1.3 46-1.2.1 46-1.2.1.1 46-1.2.1.1.r 47-1.2 48-1.2.3.r 49-1.2.3.1.1.1 50-1.2.3.1.1.2 51-1.2.3.1.1.3 56-1.2.3.2.1.1 57-1.2.3.2.1.2 63-1.2.3.3.1.1 65-1.2.3.3.1.1 66-1.2.3.3.1.1 72-1.3.r 74-1.3 75-1.3.1.r 76-1.3.1.3 77-1.3.1.2.1.1 78-1.3.1.1.1 79-1.3.1.1.2 80-1.3.1 82-1.4.1 83-1.4.1.1 (d / detect-01~e.11 :ARG0 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0) :source~e.1 (k / kit~e.10 :name (n / name :op1 "Inflammatory"~e.3 :op2 "Cytometric"~e.4 :op3 "Bead"~e.5 :op4 "Analysis"~e.6))) :ARG1 (e / extent~e.47 :mod (g / great~e.46 :degree~e.46 (m / more~e.46)) :domain (a / and~e.33 :op1 (p / protein :name (n2 / name :op1 "Interleukin-6"~e.16,18,22,25)) :op2 (p2 / protein :name (n3 / name :op1 "Interleukin-10"~e.16,25,27,31)) :op3 (p3 / protein :name (n4 / name :op1 "Monocyte"~e.34 :op2 "Chemoattractant"~e.35 :op3 "Protein-1"~e.36,38,42)) :ARG0-of (f8 / favor-01~e.12 :ARG1 (i2 / inflame-01~e.14))) :compared-to~e.48 (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "Tumor"~e.49 :op2 "Necrosis"~e.50 :op3 "Factor"~e.51)) :op2 (p5 / protein :name (n6 / name :op1 "Interferon"~e.56 :op2 "gamma"~e.57)) :op3 (p6 / protein :name (n7 / name :op1 "Interleukin-12p-70"~e.16,63,65,66)))) :location~e.72 (s / supernatant~e.74 :part-of~e.75 (c / cell~e.80 :name (n8 / name :op1 "Panc"~e.78 :op2 02.03~e.79) :part-of (o / organism :name (n9 / name :op1 "Muridae"~e.77)) :ARG1-of (c2 / culture-01~e.76))) :ARG1-of (d2 / describe-01 :ARG0 (f7 / figure~e.82 :mod "1a"~e.83))) # ::id bel_pmid_2213_2131.40920 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TB splenocytes have a reduction in SHIP @-@ 1 expression . # ::alignments 1-1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1 8-1.2.1.1.1.1 9-1.2.1 (h / have-03~e.2 :ARG0 (s / splenocyte~e.1 :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (r / reduce-01~e.4 :ARG1~e.5 (e / express-03~e.9 :ARG2 (p / protein :name (n / name :op1 "SHIP-1"~e.6,8))))) # ::id bel_pmid_2213_2131.40922 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Quantitative Reverse Transcription Polymerase Chain Reaction ( qRT @-@ PCR ) results detected a decrease in SHIP @-@ 1 mRNA expression in TB compared to control splenocytes ( Figure 3b ) . # ::alignments 0-1.1.2.1.1 1-1.1.2.1.2 2-1.1.2.1.3 3-1.1.2.1.4 4-1.1.2.1.5 5-1.1.2.1.6 11-1.1 11-1.1.1 11-1.1.1.r 12-1 14-1.2 15-1.2.1.r 16-1.2.1.1.2.1.1.1 18-1.2.1.1.2.1.1.1 19-1.2.1.1.1.1 20-1.2.1 23-1.2.3.r 25-1.2.3.1 26-1.2.2 26-1.2.3 28-1.3.1 29-1.3.1.1 (d / detect-01~e.12 :ARG0 (t / thing~e.11 :ARG2-of~e.11 (r / result-01~e.11) :source (t2 / thing :name (n / name :op1 "Quantitative"~e.0 :op2 "Reverse"~e.1 :op3 "Transcription"~e.2 :op4 "Polymerase"~e.3 :op5 "Chain"~e.4 :op6 "Reaction"~e.5))) :ARG1 (d2 / decrease-01~e.14 :ARG1~e.15 (e / express-03~e.20 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.19) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "SHIP-1"~e.16,18))))) :location (s / splenocyte~e.26 :ARG0-of (b / bear-01 :ARG1 (t3 / tumor))) :compared-to~e.23 (s2 / splenocyte~e.26 :ARG2-of (c / control-01~e.25))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.28 :mod "3b"~e.29))) # ::id bel_pmid_2213_2131.40924 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TB splenocytes have reduced SHIP @-@ 1 activity . # ::alignments 1-1.1 2-1 3-1.2.2 4-1.2.1.1.1 6-1.2.1.1.1 7-1.2 (h / have-03~e.2 :ARG0 (s / splenocyte~e.1 :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (a / activity-06~e.7 :ARG1 (p / protein :name (n / name :op1 "SHIP-1"~e.4,6)) :ARG1-of (r / reduce-01~e.3))) # ::id bel_pmid_2213_2131.40926 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analyses did not detect phosphorylation of tyrosine 1020 on SHIP @-@ 1 , in splenocytes from TB compared to control mice ( Figure 4a ) . # ::alignments 0-1.2.1 1-1.2.1 2-1.2 4-1.1 4-1.1.r 5-1 6-1.3 7-1.3.1.r 8-1.3.1.2.1 9-1.3.1.1 11-1.3.1.3.1.1 13-1.3.1.3.1.1 15-1.3.2.r 16-1.3.2 16-1.3.2.2 17-1.3.2.1.r 19-1.3.2.2.r 21-1.3.2.2.1.1 22-1.3.2.1 22-1.3.2.2.1 24-1.4.1 25-1.4.1.1 (d / detect-01~e.5 :polarity~e.4 -~e.4 :ARG0 (a / analyze-01~e.2 :manner (i / immunoblot-01~e.0,1)) :ARG1 (p / phosphorylate-01~e.6 :ARG1~e.7 (a2 / amino-acid :mod 1020~e.9 :name (n2 / name :op1 "tyrosine"~e.8) :part-of (p2 / protein :name (n3 / name :op1 "SHIP-1"~e.11,13))) :location~e.15 (s / splenocyte~e.16 :source~e.17 (m / mouse~e.22 :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :compared-to~e.19 (s2 / splenocyte~e.16 :source (m2 / mouse~e.22 :ARG2-of (c / control-01~e.21))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "4a"~e.25))) # ::id bel_pmid_2213_2131.40928 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TB splenocytes have increased AKT activity . # ::alignments 1-1.1 2-1 3-1.2.2 4-1.2.1.1.1 5-1.2 (h / have-03~e.2 :ARG0 (s / splenocyte~e.1 :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (a / activity-06~e.5 :ARG1 (e / enzyme :name (n / name :op1 "AKT"~e.4)) :ARG1-of (i / increase-01~e.3))) # ::id bel_pmid_2213_2131.40930 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western Blot results revealed hyper @-@ phosphorylation of AKT @-@ 1 at Ser473 in whole splenocytes from TB compared to control mice ( Figure 4b ) . # ::alignments 0-1.1.1.1 1-1.1.1.1 2-1.1 2-1.1.1 2-1.1.1.r 3-1 8-1.2.1.1.1 10-1.2.1.1.1 14-1.2.2.1 15-1.2.2 15-1.2.3 16-1.2.2.2.r 18-1.2.3.r 20-1.2.3.1.1 21-1.2.2.2 21-1.2.3.1 23-1.3.1 24-1.3.1.1 (r / reveal-01~e.3 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r2 / result-01~e.2 :ARG1 (i / immunoblot-01~e.0,1))) :ARG1 (h / hyperphosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT-1"~e.8,10) :part (a / amino-acid :mod 473 :name (n2 / name :op1 "serine"))) :location (s / splenocyte~e.15 :mod (w / whole~e.14) :source~e.16 (m / mouse~e.21 :ARG0-of (b / bear-01 :ARG1 (t3 / tumor)))) :compared-to~e.18 (s2 / splenocyte~e.15 :source (m2 / mouse~e.21 :ARG2-of (c / control-01~e.20)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "4b"~e.24))) # ::id bel_pmid_2213_2131.40932 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TB splenocytes have increased BCL @-@ 2 expression . # ::alignments 1-1.1 2-1 3-1.2.2 4-1.2.1.1.1 6-1.2.1.1.1 7-1.2 (h / have-03~e.2 :ARG0 (s / splenocyte~e.1 :ARG0-of (b / bear-01 :ARG1 (t / tumor))) :ARG1 (e / express-03~e.7 :ARG2 (p / protein :name (n / name :op1 "BCL-2"~e.4,6)) :ARG1-of (i / increase-01~e.3))) # ::id bel_pmid_2213_2131.40934 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western Blot results showed hyperphosphorylation of BAD at Ser112 in splenocytes from TB mice compared to control mice ( Figure 4c ) . # ::alignments 0-1.1.1.1 1-1.1.1.1 2-1.1 2-1.1.1 2-1.1.1.r 3-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1 10-1.2.2 10-1.2.3 11-1.2.2.1.r 13-1.2.2.1 14-1.2.3.r 15-1.2.3.1.r 16-1.2.3.1.1 17-1.2.3.1 19-1.3.1 20-1.3.1.1 (s / show-01~e.3 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2 :ARG1 (i / immunoblot-01~e.0,1))) :ARG1 (h / hyperphosphorylate-01~e.4 :ARG1~e.5 (p / protein :name (n / name :op1 "BAD"~e.6) :part (a / amino-acid :mod 112 :name (n2 / name :op1 "serine"))) :location (s2 / splenocyte~e.10 :source~e.11 (m / mouse~e.13 :ARG0-of (b / bear-01 :ARG1 (t3 / tumor)))) :compared-to~e.14 (s3 / splenocyte~e.10 :source~e.15 (m2 / mouse~e.17 :ARG2-of (c / control-01~e.16)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "4c"~e.20))) # ::id bel_pmid_2213_2131.40936 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot results revealed an up @-@ regulation in BCL @-@ 2 expression in splenocytes from TB mice ( Figure 4d ) compared to control . # ::alignments 0-1.1.1.1 1-1.1.1.1 2-1.1 2-1.1.1 2-1.1.1.r 3-1 5-1.2 6-1.2 7-1.2 8-1.2.1.r 9-1.2.1.1.1.1 11-1.2.1.1.1.1 12-1.2.1 14-1.2.2 14-1.2.3 15-1.2.2.1.r 17-1.2.2.1 17-1.2.3.1 19-1.2.2.2.1 20-1.2.2.2.1.1 22-1.2.3.r 24-1.2.3.1.1 (r / reveal-01~e.3 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r2 / result-01~e.2 :ARG1 (i / immunoblot-01~e.0,1))) :ARG1 (u / upregulate-01~e.5,6,7 :ARG1~e.8 (e / express-03~e.12 :ARG2 (p / protein :name (n2 / name :op1 "BCL-2"~e.9,11))) :location (s / splenocyte~e.14 :source~e.15 (m / mouse~e.17 :ARG0-of (b / bear-01 :ARG1 (t3 / tumor))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "4d"~e.20))) :compared-to~e.22 (s2 / splenocyte~e.14 :source (m2 / mouse~e.17 :ARG2-of (c / control-01~e.24))))) # ::id bel_pmid_2213_2131.40938 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Murine Panc 02.03 cells down @-@ regulate SHIP @-@ 1 expression in vitro . # ::alignments 0-1.1.2.1.1 1-1.1.1.1 2-1.1.1.2 3-1.1 7-1.2.1.1.1 9-1.2.1.1.1 10-1.2 11-1.3 12-1.3 (d / downregulate-01 :ARG0 (c / cell~e.3 :name (n / name :op1 "Panc"~e.1 :op2 02.03~e.2) :part-of (o / organism :name (n2 / name :op1 "Muridae"~e.0))) :ARG1 (e / express-03~e.10 :ARG2 (p / protein :name (n3 / name :op1 "SHIP-1"~e.7,9))) :manner (i / in-vitro~e.11,12)) # ::id bel_pmid_2213_2131.40940 ::amr-annotator SDL-AMR-09 ::preferred # ::tok qRT @-@ PCR analysis revealed a significant decrease in SHIP @-@ 1 mRNA expression in control splenocytes co @-@ cultured with Panc 02.03 cells compared to control splenocytes cultured alone ( Figure 5a ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 4-1 6-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.1.2.1.1.1 11-1.2.1.1.2.1.1.1 12-1.2.1.1.1.1 13-1.2.1 14-1.2.3.r 15-1.2.3.1 16-1.2.3 16-1.2.4 19-1.2.3.2.2 20-1.1.1.r 20-1.2.3.2.r 21-1.2.3.2.1.1.1 22-1.2.3.2.1.1.2 23-1.2.3.2.1 24-1.2.4.r 26-1.2.4.1 27-1.2.4 28-1.2.4.2 29-1.2.4.2.1 31-1.3.1 32-1.3.1.1 (r / reveal-01~e.4 :ARG0 (a / analyze-01~e.3 :instrument~e.20 (t / thing :name (n6 / name :op1 "qRT-PCR"~e.0,2))) :ARG1 (d / decrease-01~e.7 :ARG1~e.8 (e / express-03~e.13 :ARG1 (n5 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.12) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "SHIP-1"~e.9,11))))) :ARG2 (s / significant-02~e.6) :location~e.14 (s2 / splenocyte~e.16 :ARG2-of (c / control-01~e.15) :op1-of~e.20 (a3 / and :op2 (c3 / cell~e.23 :name (n4 / name :op1 "Panc"~e.21 :op2 02.03~e.22)) :ARG1-of (c2 / culture-01~e.19))) :compared-to~e.24 (s3 / splenocyte~e.16,27 :ARG2-of c~e.26 :ARG1-of (c4 / culture-01~e.28 :manner (a2 / alone~e.29)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "5a"~e.32))) # ::id bel_pmid_2213_2131.40942 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , western blot results revealed greater than a a 2 @-@ fold reduction in SHIP @-@ 1 protein expression in control splenocytes cocultured with Panc 02.03 cells compared to control splenocytes cultured alone ( Figure 5b ) . # ::alignments 0-1 1-1 1-1.1.2.3.3 3-1.1.1.1.1 4-1.1.1.1.1 5-1.1.1 5-1.1.1.1 5-1.1.1.1.r 6-1.1 7-1.1.2.2 7-1.1.2.2.1 7-1.1.2.2.1.r 8-1.1.2.2.2.r 11-1.1.2.2.2.1 13-1.1.2.2.2 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1.1.1 18-1.1.2.1.1.1.1 19-1.1.2.1.1 20-1.1.2.1 21-1.1.2.3.r 22-1.1.2.3.1 23-1.1.2.3 26-1.1.2.3.3.1.1.1 27-1.1.2.3.3.1.1.2 28-1.1.2.3.3.1 29-1.1.2.3.2.r 31-1.1.2.3.1 32-1.1.2.3 32-1.1.2.3.2 33-1.1.2.3.2.1 33-1.1.2.3.3.2 34-1.1.2.3.2.1.1 36-1.2.1 37-1.2.1.1 (a / and~e.0,1 :op2 (r / reveal-01~e.6 :ARG0 (t / thing~e.5 :ARG2-of~e.5 (r2 / result-01~e.5 :ARG1 (i / immunoblot-01~e.3,4))) :ARG1 (r3 / reduce-01~e.14 :ARG1~e.15 (e / express-03~e.20 :ARG2 (p / protein~e.19 :name (n2 / name :op1 "SHIP-1"~e.16,18))) :ARG2 (g / great~e.7 :degree~e.7 (m / more~e.7) :compared-to~e.8 (p2 / product-of~e.13 :op1 2~e.11)) :location~e.21 (s / splenocyte~e.23,32 :ARG2-of (c / control-01~e.22,31) :compared-to~e.29 (s2 / splenocyte~e.32 :ARG1-of (c4 / culture-01~e.33 :manner (a2 / alone~e.34))) :op1-of (a3 / and~e.1 :op2 (c3 / cell~e.28 :name (n3 / name :op1 "Panc"~e.26 :op2 02.03~e.27)) :ARG1-of (c2 / culture-01~e.33))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "5b"~e.37))) # ::id bel_pmid_2213_2131.40944 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results correlate with our in vivo data and show that Panc 02.03 cells are able to suppress SHIP @-@ 1 mRNA and protein expression in vitro . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1 3-1.1.2.r 4-1.1.2.2 4-1.1.2.2.r 5-1.1.2.1 6-1.1.2.1 7-1.1.2 8-1 9-1.2 10-1.2.2.r 11-1.2.2.1.1.1.1 12-1.2.2.1.1.1.2 13-1.2.2.1.1 15-1.2.2 17-1.2.2.1 18-1.2.2.1.2.1.1.2.1.1.1 20-1.2.2.1.2.1.1.2.1.1.1 21-1.2.2.1.2.1.1.1.1 23-1.2.2.1.2.1.1.2.1 24-1.2.2.1.2.1 24-1.2.2.1.2.2 25-1.2.2.1.3 26-1.2.2.1.3 (a / and~e.8 :op1 (c / correlate-01~e.2 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG2~e.3 (d / data~e.7 :manner (i / in-vivo~e.5,6) :poss~e.4 (w / we~e.4))) :op2 (s / show-01~e.9 :ARG0 t :ARG1~e.10 (p / possible-01~e.15 :ARG1 (s2 / suppress-01~e.17 :ARG0 (c2 / cell~e.13 :name (n / name :op1 "Panc"~e.11 :op2 02.03~e.12)) :ARG1 (a2 / and :op1 (e / express-03~e.24 :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.21) :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein~e.23 :name (n3 / name :op1 "SHIP-1"~e.18,20))))) :op2 (e3 / express-03~e.24 :ARG2 p2)) :manner (i2 / in-vitro~e.25,26))))) # ::id bel_pmid_2219_4859.25580 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In WT mice CH induced an approximate 2 @-@ fold increase in IL @-@ 6 mRNA at three weeks that was abrogated in C3 -/- mice ... We observed increases in lung intracellular adhesion molecule 1 ( ICAM @-@ 1 ) ... the increase in ICAM @-@ 1 was abrogated in C3 -/- mice ( Fig . 7 ) . # ::alignments 1-1.1.3.1 2-1.1.3 4-1.1 7-1.1.2.1.1 9-1.1.2.1 10-1.1.2.2 11-1.1.2.2.1.r 12-1.1.2.2.1.2.1.1.1 14-1.1.2.2.1.2.1.1.1 15-1.1.2.2.1.1.1 17-1.1.2.2.3.1.1 18-1.1.2.2.3.1.2 21-1.3 23-1.3.2.1.1.1 24-1.3.2.1.2.1 25-1.3.2 27-1.2.1 28-1.2 29-1.2.2 30-1.2.2.1.r 31-1.2.2.1.2 32-1.2.2.1.1.1 33-1.2.2.1.1.2 34-1.2.2.1.1.3 35-1.2.2.1.1.3 35-1.3.1.1.1.1 37-1.3.1.1.1.1 39-1.3.1.1.1.1 43-1.3.1 45-1.3.1.1.1.1 47-1.2.2.1.1.3 47-1.3.1.1.1.1 49-1.1.2.2.2 49-1.3 50-1.1.2.2.2.1.r 51-1.1.2.2.2.1.1.1.1 52-1.1.2.2.2.1.1.2.1 53-1.1.2.2.2.1 55-1.4.1 57-1.4.1.1 (m / multi-sentence :snt1 (i / induce-01~e.4 :ARG0 (m7 / medical-condition :name (n / name :op1 "chronic" :op2 "hypoxia")) :ARG2 (a / approximately :op1 (p / product-of~e.9 :op1 2~e.7) :op2 (i2 / increase-01~e.10 :ARG1~e.11 (n8 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.15) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6"~e.12,14)))) :ARG1-of (a2 / abrogate-01~e.49 :location~e.50 (m2 / mouse~e.53 :mod (p3 / protein :name (n4 / name :op1 "C3"~e.51) :ARG2-of (m3 / mutate-01 :mod "-/-"~e.52)))) :time (a4 / after :op1 (t / temporal-quantity :quant 3~e.17 :unit (w / week~e.18))))) :location (m4 / mouse~e.2 :mod (w2 / wild-type~e.1))) :snt2 (o / observe-01~e.28 :ARG0 (w3 / we~e.27) :ARG1 (i3 / increase-01~e.29 :ARG1~e.30 (p4 / protein :name (n5 / name :op1 "intracellular"~e.32 :op2 "adhesion"~e.33 :op3 "molecule-1"~e.34,35,47) :part-of (l / lung~e.31)))) :snt3 (a3 / abrogate-01~e.21,49 :ARG1 (i4 / increase-01~e.43 :ARG1 (p5 / protein :name (n6 / name :op1 "ICAM-1"~e.35,37,39,45,47))) :location (m5 / mouse~e.25 :mod (p6 / protein :name (n7 / name :op1 "C3"~e.23) :ARG2-of (m6 / mutate-01 :mod "-/-"~e.24)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.55 :mod 7~e.57))) # ::id bel_pmid_2220_9329.1840 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This Raf @-@ 1 @-@ mediated fine tuning of Rok @-@ a signaling allows the activation of junctional myosin and the timely maturation of AJ essential for maintaining cell cohesion during sprouting angiogenesis # ::alignments 0-1.1.3 1-1.1.2.1.1.1 3-1.1.2.1.1.1 5-1.1.2 9-1.1.1.1.1.1 12-1.1.1 13-1 15-1.2.1 16-1.2.1.1.r 17-1.2.1.1.2 18-1.2.1.1.1.1 19-1.2 21-1.2.2.2 22-1.2.2 23-1.2.2.1.r 24-1.2.2.1.1.1 25-1.2.3 26-1.2.3.1.r 27-1.2.3.1 28-1.2.3.1.1.1 30-1.2.3.1.2.r 31-1.2.3.1.2.1 32-1.2.3.1.2 (a / allow-01~e.13 :ARG0 (f2 / finetune-01 :ARG1 (s / signal-07~e.12 :ARG0 (e / enzyme :name (n / name :op1 "Rok-α"~e.9))) :ARG1-of (m / mediate-01~e.5 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Raf-1"~e.1,3))) :mod (t2 / this~e.0)) :ARG1 (a2 / and~e.19 :op1 (a3 / activate-01~e.15 :ARG1~e.16 (p / protein :name (n3 / name :op1 "myosin"~e.18) :mod (j / junctional~e.17))) :op2 (m2 / maturate-03~e.22 :ARG1~e.23 (p2 / protein :name (n4 / name :op1 "AJ"~e.24)) :ARG1-of (t3 / timely-03~e.21)) :mod (e3 / essential~e.25 :purpose~e.26 (m3 / maintain-01~e.27 :ARG1 (c / cohere-01 :ARG1 (c2 / cell~e.28)) :time~e.30 (a4 / angiogenesis~e.32 :ARG1-of (s2 / sprout-01~e.31)))))) # ::id bel_pmid_2226_7479.1138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In TLR2 agonist , heat @-@ killed Listeria monocytogenes @-@ activated human monocytes , NA reduced secretion of TNF-? ( by 48.6± 7.1 %) , interleukin @-@ 6 ( by 60.9± 1.6 %) , and monocyte chemoattractant protein @-@ 1 ( by 59.3± 5.3 %) # ::alignments 1-1.4.1.1 2-1.4 4-1.4.2.3.1.2.1 6-1.4.2.3.1.2 7-1.4.2.3.1.1.1 10-1.4.2.3 11-1.4.2.2 12-1.3.2.1.1.1 14-1.1.1.1.1 15-1.1 15-1.2 15-1.3 16-1.1.2 16-1.2.2 16-1.3.2 22-1.1.3.1.2.1.1 25-1.2.2.1.1.1 27-1.2.2.1.1.1 31-1.2.3.1.2.1.1 34-1 35-1.4.2.1.1 36-1.3.2.1.1.2 37-1.3.2.1.1.3 39-1.3.2.1.1.3 43-1.3.3.1.2.1.1 (a / and~e.34 :op1 (r / reduce-01~e.15 :ARG0 (s7 / small-molecule :name (n / name :op1 "NA"~e.14)) :ARG1 (s / secrete-01~e.16 :ARG1 (p / protein :name (n2 / name :op1 "TNF-α"))) :ARG2 (o / or :op1 (p4 / percentage-entity :value 48.6 :ARG2-of (a3 / add-02 :ARG1 (p5 / percentage-entity :value 7.1~e.22))) :op2 (p6 / percentage-entity :value 48.6 :ARG2-of (s2 / subtract-01 :ARG1 p5)))) :op2 (r2 / reduce-01~e.15 :ARG0 s7 :ARG1 (s5 / secrete-01~e.16 :ARG1 (p2 / protein :name (n3 / name :op1 "interleukin-6"~e.25,27))) :ARG2 (o3 / or :op1 (p7 / percentage-entity :value 60.9 :ARG2-of (a4 / add-02 :ARG1 (p8 / percentage-entity :value 1.6~e.31))) :op2 (p9 / percentage-entity :value 60.9 :ARG2-of (s3 / subtract-01 :ARG1 p8)))) :op3 (r3 / reduce-01~e.15 :ARG0 s7 :ARG1 (s6 / secrete-01~e.16 :ARG1 (p3 / protein :name (n4 / name :op1 "monocyte"~e.12 :op2 "chemoattractant"~e.36 :op3 "protein-1"~e.37,39))) :ARG2 (o4 / or :op1 (p10 / percentage-entity :value 59.3 :ARG2-of (a5 / add-02 :ARG1 (p11 / percentage-entity :value 5.3~e.43))) :op2 (p12 / percentage-entity :value 59.3 :ARG2-of (s4 / subtract-01 :ARG1 p11)))) :location (a6 / agonist~e.2 :name (n5 / name :op1 "TLR2"~e.1) :mod (c / cell :name (n6 / name :op1 "monocyte"~e.35) :part-of (h / human~e.11) :ARG1-of (a7 / activate-01~e.10 :ARG0 (o2 / organism :name (n7 / name :op1 "Listeria"~e.7 :op2 "monocytogene") :ARG1-of (k / kill-01~e.6 :ARG0 (h2 / heat-01~e.4))))))) # ::id bel_pmid_2236_7719.24892 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytokine determination within BAL fluid revealed that LPS challenged Tie2 @-@ adam17 -/- mice showed reduced release of IL @-@ 6 ( Fig 7A , 3.9 @-@ fold ) and TNF @-@ a ( Fig 7B , 1.6 @-@ fold ) , whereas no effect was observed in PBS @-@ challenged mice . # ::alignments 0-1.1.1 1-1.1 3-1.1.2.1 3-1.1.2.1.1 3-1.1.2.1.1.1 3-1.1.2.1.1.1.r 3-1.1.2.1.1.r 4-1.1.2 5-1 6-1.2.r 7-1.2.1.1.2.1.1.1 8-1.2.1.1.2 9-1.2.1.1.1.1.1 11-1.2.1.1.1.1.1 12-1.2.1.1.1.2.1 13-1.2.1.1 14-1.2.1 15-1.2.1.2.1.1.2 15-1.2.1.2.1.2.2 16-1.2.1.2 17-1.2.1.2.1.r 18-1.2.1.2.1.1.1.1 20-1.2.1.2.1.1.1.1 22-1.2.1.2.1.1.3.1 23-1.2.1.2.1.1.3.1.1 25-1.2.1.2.1.1.2.1.1 27-1.2.1.2.1.1.2.1 29-1.2.1.2.1 30-1.2.1.2.1.2.1.1 34-1.2.1.2.1.2.3.1 35-1.2.1.2.1.2.3.1.1 37-1.2.1.2.1.2.2.1.1 39-1.2.1.2.1.2.2.1 42-1.2 43-1.2.2.1 43-1.2.2.1.r 44-1.2.2.2 46-1.2.2 47-1.2.2.3.r 48-1.2.2.3.1.1.1.1 50-1.2.2.3.1 51-1.2.2.3 (r / reveal-01~e.5 :ARG0 (d / determine-01~e.1 :ARG1 (c / cytokine~e.0) :location (f / fluid~e.4 :mod (l / lavage~e.3 :mod~e.3 (a3 / alveolus~e.3 :mod~e.3 (b / bronchus~e.3))))) :ARG1~e.6 (c2 / contrast-01~e.42 :ARG1 (s / show-01~e.14 :ARG0 (m / mouse~e.13 :mod (e / enzyme :name (n2 / name :op1 "Tie2-adam17"~e.9,11) :ARG2-of (m2 / mutate-01 :mod "-/-"~e.12)) :ARG1-of (c3 / challenge-01~e.8 :ARG0 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS"~e.7)))) :ARG1 (r2 / release-01~e.16 :ARG1~e.17 (a / and~e.29 :op1 (p / protein :name (n4 / name :op1 "IL-6"~e.18,20) :ARG1-of (r3 / reduce-01~e.15 :ARG2 (p2 / product-of~e.27 :op1 3.9~e.25)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.22 :mod "7A"~e.23))) :op2 (p3 / protein :name (n5 / name :op1 "TNF-α"~e.30) :ARG1-of (r4 / reduce-01~e.15 :ARG2 (p4 / product-of~e.39 :op1 1.6~e.37)) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.34 :mod "7B"~e.35)))))) :ARG2 (o / observe-01~e.46 :polarity~e.43 -~e.43 :ARG1 (a2 / affect-01~e.44) :location~e.47 (m4 / mouse~e.51 :ARG1-of (c4 / challenge-01~e.50 :ARG0 (s2 / small-molecule :name (n6 / name :op1 "PBS"~e.48))))))) # ::id bel_pmid_2243_8032.25776 ::amr-annotator SDL-AMR-09 ::preferred # ::tok . The concentration of IL @-@ 6 , IL @-@ 13 and IL @-@ 17 was significantly higher in KO mice relative to wild @-@ type mice , while that of IL @-@ 12 was significantly higher in wild @-@ type mice relative to KO mice . # ::alignments 2-1.1.1 2-1.2.1 4-1.1.1.1.1.1.1 4-1.2.1.1.1.1 6-1.1.1.1.1.1.1 8-1.1.1.1.1.1.1 8-1.1.1.1.2.1.1 8-1.1.1.1.3.1.1 10-1.1.1.1.2.1.1 11-1.1.1.1 12-1.1.1.1.1.1.1 12-1.1.1.1.2.1.1 12-1.1.1.1.3.1.1 14-1.1.1.1.3.1.1 16-1.1.5 17-1.1 17-1.1.2 17-1.1.2.r 17-1.2 20-1.1.3 20-1.1.4.1 21-1.1.4 21-1.2.4 23-1.1.4.1.1 25-1.1.4.1.1 26-1.1.4.1 28-1 31-1.1.1.1.3.1.1 31-1.2.1.1.1.1 33-1.2.1.1.1.1 35-1.1.5 36-1.1 36-1.1.2 36-1.1.2.r 38-1.1.4.1.1 40-1.1.4.1.1 41-1.1.4.1 42-1.1.4 45-1.1.4.1 (c / contrast-01~e.28 :ARG1 (h / high-02~e.17,36 :ARG1 (c2 / concentrate-02~e.2 :ARG1 (a / and~e.11 :op1 (p / protein :name (n / name :op1 "IL-6"~e.4,6,8,12)) :op2 (p2 / protein :name (n2 / name :op1 "IL-13"~e.8,10,12)) :op3 (p3 / protein :name (n3 / name :op1 "IL-17"~e.8,12,14,31)))) :degree~e.17,36 (m / more~e.17,36) :location (m2 / mouse~e.20 :location-of (k / knock-out-03)) :ARG2-of (r / relative-05~e.21,42 :ARG3 (m3 / mouse~e.20,26,41,45 :mod (w / wild-type~e.23,25,38,40))) :ARG1-of (s / significant-02~e.16,35)) :ARG2 (h2 / high-02~e.17 :ARG1 (c3 / concentrate-02~e.2 :ARG1 (p4 / protein :name (n4 / name :op1 "IL-12"~e.4,31,33))) :degree m :location m3 :ARG2-of (r2 / relative-05~e.21 :ARG3 m2))) # ::id bel_pmid_2243_8032.25784 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the expression of tissue damage @-@ related proteins , TGF-? and mesothelin was more markedly increased in the lungs of KO mice relative to wild @-@ type mice . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.3.1.1 4-1.1.1.3.1 6-1.1.1.3 7-1.1.1.1 7-1.1.1.2 10-1.1.1 11-1.1.1.2.1.1 13-1.2.1 14-1.2 15-1 16-1.3.r 18-1.3 21-1.3.1 22-1.4 23-1.4.1.r 24-1.4.1.1 26-1.4.1.1 27-1.4.1 (i / increase-01~e.15 :ARG1 (e / express-03~e.1 :ARG2~e.2 (a / and~e.10 :op1 (p / protein~e.7 :name (n / name :op1 "TGF-βl")) :op2 (p2 / protein~e.7 :name (n2 / name :op1 "mesothelin"~e.11)) :ARG1-of (r / relate-01~e.6 :ARG2 (d / damage-01~e.4 :ARG1 (t / tissue~e.3))))) :ARG2 (m / marked~e.14 :degree (m2 / more~e.13)) :location~e.16 (l / lung~e.18 :part-of (m3 / mouse~e.21 :ARG1-of (k / knock-out-03))) :ARG2-of (r2 / relative-05~e.22 :ARG3~e.23 (m4 / mouse~e.27 :mod (w / wild-type~e.24,26)))) # ::id bel_pmid_2254_4933.40994 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this study , we identified microRNA @-@ 494 ( miR @-@ 494 ) , whose expression was dramatically induced by tumor @-@ derived factors , as an essential player in regulating the accumulation and activity of MDSCs by targeting of phosphatase and tensin homolog ( PTEN ) and activation of the Akt pathway . # ::alignments 1-1.3.1 2-1.3 4-1.1 5-1 8-1.2.1.1 12-1.2.1.1 16-1.2 16-1.2.3 16-1.2.3.r 18-1.2.3.1.2 18-1.2.3.1.3 19-1.2.3.1 20-1.2.3.1.1.r 21-1.2.3.1.1.1.1 23-1.2.3.1.1.1 24-1.2.3.1.1 28-1.2.3.1.3.3 29-1.2.3.1.3 30-1.2.3.1.3.2.r 31-1.2.3.1.3.2 33-1.2.3.1.3.2.1.1 34-1.2.3.1.3.2.1 35-1.2.3.1.3.2.1.2 36-1.2.3.1.3.2.1.1.1.r 37-1.2.3.1.3.2.1.1.1.1.1 38-1.2.3.1.3.2.2.r 39-1.2.3.1.3.2.2.1 40-1.2.3.1.3.2.2.1.2.r 41-1.2.3.1.3.2.2.1.2.1.1 42-1.2.3.1.3.2.2.1.2.1.2 43-1.2.3.1.3.2.2.1.2.1.3 44-1.2.3.1.3.2.2.1.2.1.4 46-1.2.3.1.3.2.2.1.2.2.1.1.1 48-1.2.3.1.3.2.2 49-1.2.3.1.3.2.2.2 50-1.2.3.1.3.2.2.2.2.r 52-1.2.3.1.3.2.2.2.2.1.1 53-1.2.3.1.3.2.2.2.2 (i / identify-01~e.5 :ARG0 (w / we~e.4) :ARG1 (n4 / nucleic-acid~e.16 :name (n / name :op1 "RNA-494"~e.8,12) :mod (m / micro) :ARG2-of~e.16 (e / express-03~e.16 :ARG2-of (i2 / induce-01~e.19 :ARG0~e.20 (f / factor~e.24 :ARG1-of (d2 / derive-01~e.23 :ARG2 (t3 / tumor~e.21))) :manner (d / dramatic~e.18) :manner (p / play-08~e.18,29 :ARG0 e :ARG1~e.30 (r2 / regulate-01~e.31 :ARG1 (a / and~e.34 :op1 (a2 / accumulate-01~e.33 :ARG1~e.36 (c / cell :name (n3 / name :op1 "MDSC"~e.37))) :op2 (a3 / activity-06~e.35 :ARG0 c)) :manner~e.38 (a5 / and~e.48 :op1 (t2 / target-01~e.39 :ARG0 e :ARG1~e.40 (p3 / protein :name (n2 / name :op1 "phosphatase"~e.41 :op2 "and"~e.42 :op3 "tensin"~e.43 :op4 "homolog"~e.44) :ARG1-of (m2 / mean-01 :ARG2 (p5 / protein :name (n7 / name :op1 "PTEN"~e.46))))) :op2 (a6 / activate-01~e.49 :ARG0 e :ARG1~e.50 (p2 / pathway~e.53 :name (n6 / name :op1 "Akt"~e.52))))) :mod (e3 / essential~e.28))))) :medium (s / study-01~e.2 :mod (t / this~e.1))) # ::id bel_pmid_2254_4933.41002 ::amr-annotator SDL-AMR-09 ::preferred # ::tok miR @-@ 494 is highly expressed in tumor @-@ expanded MDSCs . # ::alignments 0-1.1.1.1 2-1.1.1.1 4-1.3 5-1 6-1.2.r 7-1.2.2.1 9-1.2.2 10-1.2.1.1 (e / express-03~e.5 :ARG2 (n3 / nucleic-acid :name (n / name :op1 "miR-494"~e.0,2)) :ARG3~e.6 (c / cell :name (n2 / name :op1 "MDSC"~e.10) :ARG1-of (e2 / expand-01~e.9 :ARG0 (t / tumor~e.7))) :ARG1-of (h / high-02~e.4)) # ::id bel_pmid_2254_4933.41006 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 1C , significantly increased expression of miR @-@ 494 was detected in both subpopulations compared with their counterpart from tumor @-@ free mice ( granulocytic MDSCs , p < 0.01 ; monocytic MDSCs , p < 0.001 ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1.1 6-1.1.1.2.1 7-1.1.1.2 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1.1.1 12-1.1.1.1.1.1 14-1.1 14-1.2 18-1.4.r 21-1.4 22-1.4.1.r 23-1.4.1.1.1 25-1.4.1.1 26-1.4.1 28-1.1.2.2 29-1.1.2.1.1 31-1.1.3 32-1.1.3.1 33-1.1.3.1.1 35-1.2.2.2 36-1.2.2.1.1 38-1.2.3 39-1.2.3.1 40-1.2.3.1.1 (a2 / and :op1 (d / detect-01~e.14 :ARG1 (e / express-03~e.8 :ARG2~e.9 (n4 / nucleic-acid :name (n / name :op1 "miR-494"~e.10,12)) :ARG1-of (i / increase-01~e.7 :ARG2 (s2 / significant-02~e.6))) :location (c2 / cell :name (n2 / name :op1 "MDSC"~e.29) :mod (g / granulocytic~e.28)) :ARG1-of (s4 / statistical-test-91~e.31 :ARG2 (l / less-than~e.32 :op1 0.01~e.33))) :op2 (d2 / detect-01~e.14 :ARG1 e :location (c3 / cell :name (n3 / name :op1 "MDSC"~e.36) :mod (m3 / monocytic~e.35)) :ARG1-of (s5 / statistical-test-91~e.38 :ARG2 (l2 / less-than~e.39 :op1 0.001~e.40))) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "1C"~e.4)) :compared-to~e.18 (c / counterpart~e.21 :location~e.22 (m / mouse~e.26 :ARG1-of (f2 / free-04~e.25 :ARG2 (t / tumor~e.23))) :poss (a / and :op1 c2 :op2 c3))) # ::id bel_pmid_2254_4933.41010 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumor @-@ derived factors , especially TG'F @-@ fH , markedly induce the upregulation of miR @-@ 494 in MDSCs . # ::alignments 0-1.1.2.1 2-1.1.2 3-1.1 5-1.1.1.2 6-1.1.1.1.1 8-1.1.1.1.1 10-1.3 10-1.3.r 11-1 13-1.2 14-1.2.1.r 15-1.2.1.1.1 17-1.2.1.1.1 18-1.2.2.r 19-1.2.2.1.1 (i / induce-01~e.11 :ARG0 (f / factor~e.3 :example (p2 / protein :name (n2 / name :op1 "TG'F-fH"~e.6,8) :manner (e / especially~e.5)) :ARG1-of (d / derive-01~e.2 :ARG2 (t / tumor~e.0))) :ARG2 (u / upregulate-01~e.13 :ARG1~e.14 (n / nucleic-acid :name (n3 / name :op1 "miR-494"~e.15,17)) :location~e.18 (c / cell :name (n4 / name :op1 "MDSC"~e.19))) :manner~e.10 (m / marked~e.10)) # ::id bel_pmid_2254_4933.41012 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , we found that miR @-@ 494 expression was significantly induced by TCCM in a dose @-@ dependent manner ( Fig . 2A ) . # ::alignments 1-1.3 3-1.1 4-1 5-1.2.r 6-1.2.1.2.1.1 8-1.2.1.2.1.1 9-1.2.1 11-1.2.3 12-1.2 13-1.2.1.1.r 14-1.2.1.1.1.1 15-1.2.2.r 17-1.2.2.1 19-1.2.2 20-1.2.3.r 22-1.4.1 24-1.4.1.1 (f / find-01~e.4 :ARG0 (w / we~e.3) :ARG1~e.5 (i / induce-01~e.12 :ARG2 (e2 / express-03~e.9 :ARG1~e.13 (t / thing :name (n2 / name :op1 "TCCM"~e.14)) :ARG2 (n3 / nucleic-acid :name (n / name :op1 "miR-494"~e.6,8))) :ARG0-of~e.15 (d / depend-01~e.19 :ARG1 (d2 / dose-01~e.17)) :manner~e.20 (s / significant-02~e.11)) :ARG1-of (e / expect-01~e.1) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.22 :mod "2A"~e.24))) # ::id bel_pmid_2254_4933.41014 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 2B , we found that the expression of miR @-@ 494 in Gr @-@ 1+ CD11b+ cells was not affected by GM @-@ CSF and IL @-@ 6 , but interestingly , miR @-@ 494 expression was significantly induced by TGF @-@ b1 treatment ( p < 0.001 ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1.1 6-1.1 7-1 8-1.2.r 10-1.2.1.3 11-1.2.1.3.1.r 12-1.2.1.3.1.1.1 14-1.2.1.3.1.1.1 15-1.2.1.3.2.r 16-1.2.1.3.2.1.1.1 18-1.2.1.3.2.1.1.1 19-1.2.1.3.2.2.1.1 20-1.2.1.3.2 22-1.2.1.1 22-1.2.1.1.r 23-1.2.1 24-1.2.1.2.r 25-1.2.1.2.1.1.1 27-1.2.1.2.1.1.1 28-1.2.1.2 29-1.2.1.2.2.1.1 31-1.2.1.2.2.1.1 33-1.2 34-1.2.2.3 36-1.2.2.2 37-1.2.2.2 38-1.2.2.2 39-1.2.2.2 41-1.2.2.4 42-1.2.2 43-1.2.2.1.r 44-1.2.2.1.1.1.1 46-1.2.2.1.1.1.1 47-1.2.2.1 49-1.2.1.4 50-1.2.1.4.1 51-1.2.1.4.1.1 (f / find-01~e.7 :ARG0 (w / we~e.6) :ARG1~e.8 (c / contrast-01~e.33 :ARG1 (a / affect-01~e.23 :polarity~e.22 -~e.22 :ARG0~e.24 (a2 / and~e.28 :op1 (p3 / protein :name (n4 / name :op1 "GM-CSF"~e.25,27)) :op2 (p4 / protein :name (n5 / name :op1 "IL-6"~e.29,31))) :ARG1 (e / express-03~e.10 :ARG2~e.11 (n7 / nucleic-acid :name (n / name :op1 "miR-494"~e.12,14)) :ARG3~e.15 (c2 / cell~e.20 :mod (p / protein :name (n2 / name :op1 "Gr-1+"~e.16,18)) :mod (p2 / protein :name (n3 / name :op1 "CD11b+"~e.19)))) :ARG1-of (s3 / statistical-test-91~e.49 :ARG2 (l / less-than~e.50 :op1 0.001~e.51))) :ARG2 (i / induce-01~e.42 :ARG0~e.43 (t / treat-04~e.47 :ARG2 (p5 / protein :name (n6 / name :op1 "TGF-b1"~e.44,46))) :ARG2 e~e.36,37,38,39 :ARG2-of (i2 / interest-01~e.34) :ARG1-of (s2 / significant-02~e.41))) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f2 / figure~e.3 :mod "2B"~e.4))) # ::id bel_pmid_2254_4933.41016 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the induction of miR @-@ 494 was partially blocked by anti @-@ TGF @-@ p1 mAb in cells stimulated with 4T1 TCCM ( Fig . 2C ) , and the upregulation of miR @-@ 494 was impaired in Smad 3 @-@ deficient Gr @-@ 1+ CD11b+ cells isolated from the spleen of Smad 3_/_ mice ( Fig . 2D ) . # ::alignments 0-1 0-1.1 4-1.1.r 5-1.1.1.2.1.1.1 7-1.1.1.2.1.1.1 9-1.1.1.3 9-1.1.1.3.r 10-1.1.1 11-1.1.1.1.r 12-1.1.1.1 12-1.1.1.1.2 12-1.1.1.1.2.r 14-1.1.1.1.1.1 16-1.1.1.1.1.1 19-1.1.1.4 19-1.1.2.4.1 19-1.1.2.4.2 20-1.1.1.4.1 21-1.1.1.4.1.1.r 22-1.1.1.4.1.1.1.1 23-1.1.1.4.1.1.2.1.1 25-1.1.1.5.1 27-1.1.1.5.1.1 30-1.1 32-1.1.2.1 33-1.1.2.1.1.r 34-1.1.2.1.1 35-1.1.2.1.1 36-1.1.2.1.1 38-1.1.2 39-1.1.2.2.r 40-1.1.2.2.1.1.1.1.1.1 41-1.1.2.2.1.1.1.1.1.2 43-1.1.2.2.1.1.1.1 43-1.1.2.2.1.1.1.1.2 43-1.1.2.2.1.1.1.1.2.1 43-1.1.2.2.1.1.1.1.2.1.r 43-1.1.2.2.1.1.1.1.2.r 44-1.1.2.4.1.1.1.1 46-1.1.2.4.1.1.1.1 47-1.1.2.4.2.1.1.1 48-1.1.2.2 49-1.1.2.2.1 52-1.1.2.2.1.1 56-1.1.2.2.1.1.1 58-1.1.2.3.1 60-1.1.2.3.1.1 (a / and~e.0 :op2~e.4 (a2 / and~e.0,30 :op1 (b / block-01~e.10 :ARG0~e.11 (p2 / protein~e.12 :name (n2 / name :op1 "TGF-p1"~e.14,16) :ARG1-of~e.12 (c / counter-01~e.12 :ARG0 (a4 / antidoby))) :ARG1 (i2 / induct-02 :ARG1 (n9 / nucleic-acid :name (n / name :op1 "miR-494"~e.5,7))) :degree~e.9 (p / part~e.9) :location (c2 / cell~e.19 :ARG1-of (s / stimulate-01~e.20 :ARG2~e.21 (c5 / cell-line :name (n8 / name :op1 "4T1"~e.22) :part-of (t / thing :name (n4 / name :op1 "TCCM"~e.23))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "2C"~e.27))) :op2 (i / impair-01~e.38 :ARG1 (u / upregulate-01~e.32 :ARG1~e.33 n9~e.34,35,36) :location~e.39 (c3 / cell~e.48 :ARG1-of (i3 / isolate-01~e.49 :ARG2 (s2 / spleen~e.52 :part-of (m2 / mouse~e.56 :mod (p6 / protein~e.43 :name (n5 / name :op1 "Smad"~e.40 :op2 3~e.41) :ARG2-of~e.43 (m3 / mutate-01~e.43 :mod~e.43 "-/-"~e.43)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.58 :mod "2D"~e.60)) :location (a3 / and :op1 (c6 / cell~e.19 :mod (p4 / protein :name (n6 / name :op1 "Gr-1+"~e.44,46))) :op2 (c7 / cell~e.19 :mod (p3 / protein :name (n3 / name :op1 "CD11b+"~e.47))) :ARG0-of (l / lack-01 :ARG1 p6))))) # ::id bel_pmid_2254_4933.41022 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , the expression levels of ARG1 , MMP2 , MMP13 , and MMP14 were significantly upregulated in lv @-@ 494 @-@ infected MDSCs compared with those in lv @-@ ctrl @-@ infected MDSCs ( Fig . 4B ) ; moreover , lv @-@ sponge overtly blocked the induction in the expression of these molecules . # ::alignments 1-1.1.2 4-1.1.1.1 5-1.1.1 5-1.1.5 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1.1 9-1.1.1.1.1.2.1.1 11-1.1.1.1.1.3.1.1 13-1.1.1.1.1 14-1.1.1.1.1.4.1.1 16-1.1.3 17-1.1 18-1.1.4.r 19-1.1.4.2.1.1.1 21-1.1.4.2.1.1.1 23-1.1.4.2 24-1.1.4.1.1 25-1.1.5.r 28-1.1.5.1.r 29-1.1.5.1.2.1.1.1 31-1.1.5.1.2.1.1.1 33-1.1.4.2 33-1.1.5.1.2 34-1.1.4.1.1 34-1.1.5.1.1.1 36-1.1.6.1 38-1.1.6.1.1 41-1.2 43-1.2.1.1.1.1 45-1.2.1.1.1.1 46-1.2.1.3 46-1.2.1.3.r 47-1.2.1 49-1.2.1.2 50-1.2.1.2.1.r 52-1.2.1.2.1 55-1.1.4.2.1 55-1.1.5.1.2.1 55-1.2.1.1 (a / and :op1 (u / upregulate-01~e.17 :ARG1 (l2 / level~e.5 :degree-of (e3 / express-03~e.4 :ARG2~e.6 (a3 / and~e.13 :op1 (e4 / enzyme :name (n / name :op1 "ARG1"~e.7)) :op2 (e5 / enzyme :name (n2 / name :op1 "MMP2"~e.9)) :op3 (e6 / enzyme :name (n3 / name :op1 "MMP13"~e.11)) :op4 (e7 / enzyme :name (n4 / name :op1 "MMP14"~e.14))))) :ARG1-of (e2 / expect-01~e.1) :ARG1-of (s / significant-02~e.16) :location~e.18 (c / cell :name (n5 / name :op1 "MDSC"~e.24,34) :ARG1-of (i2 / infect-01~e.23,33 :ARG0 (s2 / small-molecule~e.55 :name (n6 / name :op1 "lv-494"~e.19,21)))) :compared-to~e.25 (l4 / level~e.5 :location~e.28 (c2 / cell :name (n7 / name :op1 "MDSC"~e.34) :ARG1-of (i3 / infect-01~e.33 :ARG0 (s4 / small-molecule~e.55 :name (n8 / name :op1 "lv-ctrl"~e.29,31)))) :degree-of e3) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.36 :mod "4B"~e.38))) :op2 (a2 / and~e.41 :op2 (b / block-01~e.47 :ARG0 (s3 / small-molecule~e.55 :name (n9 / name :op1 "lv-sponge"~e.43,45)) :ARG1 (i / induce-01~e.49 :ARG2~e.50 (e / express-03~e.52 :ARG1 a3)) :manner~e.46 (o / overt~e.46)))) # ::id bel_pmid_2254_4933.41028 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 4G , OT @-@ 1 CD8+ T cell proliferation was significantly suppressed by lv @-@ 494 @-@ infected MDSCs in comparison with lv @-@ ctrl @-@ infected MDSCs , and this suppressive activity could be partially blocked by an ARG1 inhibitor nor @-@ NOHA . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1.1 6-1.1.2.1.2.1.1 8-1.1.2.1.2.1.1 10-1.1.2.1.1.1 11-1.1.2.1.1.2 12-1.1.2 14-1.1.3 15-1.1 16-1.1.1.r 17-1.1.1.2.1.1.1 19-1.1.1.2.1.1.1 21-1.1.1.2 21-1.1.4.2 22-1.1.1.1.1 22-1.1.4.1.1 24-1.1.4.r 25-1.1.4.2.1.r 26-1.1.4.2.1.1.1 28-1.1.4.2.1.1.1 30-1.1.1.2 31-1.1.1.1.1 31-1.1.4.1.1 33-1 37-1.2 39-1.2.1.3 39-1.2.1.3.r 40-1.2.1 41-1.2.1.1.r 43-1.2.1.1.2.1.1.1 44-1.2.1.1 44-1.2.1.1.2 44-1.2.1.1.2.r 47-1.2.1.1.1.1 (a / and~e.33 :op1 (s / suppress-01~e.15 :ARG0~e.16 (c4 / cell :name (n6 / name :op1 "MDSC"~e.22,31) :ARG1-of (i2 / infect-01~e.21,30 :ARG0 (s5 / small-molecule :name (n7 / name :op1 "lv-494"~e.17,19)))) :ARG1 (p2 / proliferate-01~e.12 :ARG0 (c / cell :name (n3 / name :op1 "T"~e.10 :op2 "cell"~e.11) :source (o / organism :name (n4 / name :op1 "OT-1"~e.6,8)) :mod (p4 / protein :name (n5 / name :op1 "CD8") :mod (p5 / positive)))) :ARG1-of (s2 / significant-02~e.14) :compared-to~e.24 (c5 / cell :name (n8 / name :op1 "MDSC"~e.22,31) :ARG1-of (i3 / infect-01~e.21 :ARG0~e.25 (s4 / small-molecule :name (n9 / name :op1 "lv-ctrl"~e.26,28))))) :op2 (p3 / possible-01~e.37 :ARG1 (b / block-01~e.40 :ARG0~e.41 (s6 / small-molecule~e.44 :name (n / name :op1 "Nor-NOHA"~e.47) :ARG0-of~e.44 (i / inhibit-01~e.44 :ARG1 (e / enzyme :name (n2 / name :op1 "ARG1"~e.43)))) :ARG1 s :degree~e.39 (p / part~e.39))) :ARG1-of (s3 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "4G"~e.4))) # ::id bel_pmid_2254_4933.41038 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , the PTEN protein level was significantly downregulated in tumor @-@ expanded MDSCs compared with that in Gr @-@ 1+ CD11b+ cells from tumor @-@ free mice , whereas PTEN mRNA expression showed no difference ( Fig . 6A ) . # ::alignments 0-1.4 3-1.1.1.1.1.1 4-1.1.1.1 4-1.1.4.1.2.1.1 4-1.1.4.1.2.1.2 5-1.1.1 5-1.1.4 7-1.1.2 8-1.1 9-1.1.3.r 10-1.1.3.2.1 12-1.1.3.2 13-1.1.3.1.1 14-1.1.4.r 17-1.1.4.1.r 18-1.1.4.1.2.1.1.1.1 20-1.1.4.1.2.1.1.1.1 21-1.1.4.1.2.1.2.1.1 22-1.1.4.1 23-1.1.4.1.1.r 24-1.1.4.1.1.1.1 26-1.1.4.1.1.1 27-1.1.4.1.1 29-1 30-1.2.2.1.2 31-1.2.2.1.1.1 32-1.2.2 33-1.2 34-1.2.1 34-1.2.1.r 35-1.2.1.r 35-1.2.3 37-1.3.1 39-1.3.1.1 (c / contrast-01~e.29 :ARG1 (d2 / downregulate-01~e.8 :ARG1 (l / level~e.5 :quant-of (p / protein~e.4 :name (n / name :op1 "PTEN"~e.3))) :ARG1-of (s / significant-02~e.7) :location~e.9 (c2 / cell :name (n2 / name :op1 "MDSC"~e.13) :ARG1-of (e / expand-01~e.12 :ARG0 (t / tumor~e.10))) :compared-to~e.14 (l2 / level~e.5 :location~e.17 (c3 / cell~e.22 :source~e.23 (m / mouse~e.27 :ARG1-of (f2 / free-04~e.26 :ARG2 t~e.24)) :ARG1-of (m2 / mutate-01 :ARG2 (a / and :op1 (p2 / protein~e.4 :name (n3 / name :op1 "Gr-1+"~e.18,20)) :op2 (p3 / protein~e.4 :name (n4 / name :op1 "CD11b+"~e.21))))) :degree-of p)) :ARG2 (s2 / show-01~e.33 :polarity~e.34,35 -~e.34 :ARG0 (e2 / express-03~e.32 :ARG2 (n7 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.31) :mod p~e.30)) :ARG1 (d3 / differ-02~e.35)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.37 :mod "6A"~e.39)) :ARG1-of (n6 / notable-04~e.0)) # ::id bel_pmid_2254_4933.41040 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When the reporter plasmids with miR @-@ 494 mimics or the scrambled oligonucleotide were cotransfected to HEK @-@ 293 cells , we observed that the miR @-@ 494 mimics markedly decreased the luciferase activity ( Fig . 6B ) . # ::alignments 0-1.4.r 2-1.4.2.1.2 4-1.4.2.1.1.r 5-1.4.2.1.1 6-1.4.2.1.1 7-1.4.2.1.1 8-1.4.2.1.1 9-1.4.2 11-1.4.2.2.1 12-1.4.2.2 14-1.4 15-1.4.1.r 16-1.4.1.1.1 18-1.4.1.1.1 19-1.4.1 21-1.1 22-1 23-1.2.r 25-1.2.1.1.1.1 27-1.2.1.1.1.1 28-1.2.1 29-1.2.3 29-1.2.3.r 30-1.2 32-1.2.2.1 33-1.2.2 35-1.3.1 37-1.3.1.1 (o / observe-01~e.22 :ARG0 (w / we~e.21) :ARG1~e.23 (d / decrease-01~e.30 :ARG0 (m2 / mimic-01~e.28 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "miR-494"~e.25,27))) :ARG1 (a / activity-06~e.33 :ARG0 (l / luciferase~e.32)) :manner~e.29 (m / marked~e.29)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.35 :mod "6B"~e.37)) :time~e.0 (c / cotransfect-01~e.14 :ARG1~e.15 (c2 / cell~e.19 :name (n2 / name :op1 "HEK-293"~e.16,18)) :ARG2 (o2 / or~e.9 :op1 (p / plasmid :instrument~e.4 m2~e.5,6,7,8 :ARG0-of (r2 / report-01~e.2)) :op2 (o3 / oligonucleotide~e.12 :ARG1-of (s / scramble-02~e.11))))) # ::id bel_pmid_2254_4933.41042 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , transfection of lv @-@ 494 significantly decreased PTEN expression in MDSCs , thus suggesting that endogenous PTEN is targeted and regulated by miR @-@ 494 ( Fig . 6C ) .. To confirm whether miR @-@ 494 @-@ induced activation of MDSCs was mediated by targeting of PTEN expression , we designed a lentiviral vector encoding 39 @-@ UTR @-@ depleted PTEN to enforce the expression of PTEN in MDSCs . # ::alignments 0-1.1 2-1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 6-1.1.1.4.1.1.1.1.1 7-1.1.1.3 8-1.1.1 9-1.2.2.2.1.1.1 10-1.1.1.2 11-1.1.1.2.2.r 12-1.1.1.2.2.1.1 15-1.1.1.4 16-1.1.1.4.1.r 17-1.1.1.4.1.1.2.2 18-1.1.1.4.1.1.2.1.1 20-1.1.1.4.1.1 21-1.1.1.4.1 22-1.1.1.4.1.2 24-1.2.4.2.1.2.1.1.1 26-1.2.4.2.1.2.1.1.1 28-1.1.2.1 30-1.1.2.1.1 34-1.2.4 36-1.2.4.2.1.2.1.1.1 38-1.2.4.2.1.2.1.1.1 40-1.2.4.2.1.2 41-1.2.4.2.1 42-1.2.4.2.1.1.r 43-1.2.4.2.1.1 45-1.2.4.2 46-1.2.4.2.2.r 47-1.2.4.2.2 49-1.2.2.2.1.1.1 50-1.2.4.2.2.1 52-1.2.1 53-1.2 55-1.2.2.1 56-1.2.2 57-1.2.2.2 58-1.2.2.2.1.2.1.1.1 60-1.2.2.2.1.2.1.1.1 62-1.2.2.2.1.2 63-1.2.2.2.1.1.1 65-1.2.3 67-1.2.3.2 69-1.2.2.2.1.1.1 70-1.2.3.2.2.r 71-1.2.3.2.2.1.1 (m / multi-sentence :snt1 (a / and~e.0 :op2 (d2 / decrease-01~e.8 :ARG0 (t / transfect-01~e.2 :ARG2~e.3 (s3 / small-molecule :name (n / name :op1 "lv-494"~e.4,6))) :ARG1 (e / express-03~e.10 :ARG2 p2 :ARG3~e.11 (c / cell :name (n3 / name :op1 "MDSC"~e.12))) :ARG1-of (s / significant-02~e.7) :ARG0-of (s2 / suggest-01~e.15 :ARG1~e.16 (a2 / and~e.21 :op1 (t2 / target-01~e.20 :ARG0 (n9 / nucleic-acid :name (n4 / name :op1 "miR-494"~e.6)) :ARG1 (p2 / protein :name (n5 / name :op1 "PTEN"~e.18) :mod (m2 / monocot~e.17))) :op2 (r / regulate-01~e.22 :ARG0 n9 :ARG1 p2)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.28 :mod "6C"~e.30))) :snt2 (d / design-01~e.53 :ARG0 (w / we~e.52) :ARG1 (v / vector~e.56 :mod (l2 / lentiviral~e.55) :ARG0-of (e2 / encode-01~e.57 :ARG1 (p / protein :name (n2 / name :op1 "PTEN"~e.9,49,63,69) :ARG1-of (d5 / deplete-01~e.62 :ARG2 (d3 / dna-sequence :name (n6 / name :op1 "39-UTR"~e.58,60)))))) :purpose (e4 / enforce-01~e.65 :ARG0 v :ARG1 (e5 / express-03~e.67 :ARG2 p :ARG3~e.70 (c2 / cell :name (n7 / name :op1 "MDSC"~e.71)))) :purpose (c3 / confirm-01~e.34 :ARG0 w :ARG1 (m4 / mediate-01~e.45 :ARG0 (a3 / activate-01~e.41 :ARG1~e.42 c2~e.43 :ARG2-of (i / induce-01~e.40 :ARG0 (n10 / nucleic-acid :name (n8 / name :op1 "miR-494"~e.24,26,36,38)))) :ARG1~e.46 (t3 / target-01~e.47 :ARG1 (e6 / express-03~e.50)))))) # ::id bel_pmid_2254_4933.41044 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of PTEN in Gr @-@ 1+ CD11b+ cells did not affect the TDF @-@ induced miR @-@ 494 up @-@ regulation , whereas the increased expression of MMPs induced by TCCM were significantly blocked ( Fig . 6D ) , and SDF @-@ 1/CXCL12 @-@ mediated MDSC migration was abrogated ( Fig . 6E ) . # ::alignments 0-1.1.2 1-1.1.2.1.r 2-1.1.2.1.1.1 3-1.1.2.2.r 4-1.1.2.2.1.1.1.1.1 6-1.1.2.2.1.1.1.1.1 7-1.1.2.2.1.1.2.1.1 8-1.1.2.2 10-1.1.1 10-1.1.1.r 11-1.1 13-1.1.3.2.1.1.1 15-1.1.3.2 16-1.1.3.1.1.1 18-1.1.3.1.1.1 19-1.1.3 20-1.1.3 21-1.1.3 23-1 25-1.2.1.1.2 26-1.2.1.1 29-1.2.1.1.3 30-1.2.1.1.3.1.r 31-1.2.1.1.3.1.1.1 33-1.2.1.2 34-1.2.1 36-1.2.1.3.1 38-1.2.1.3.1.1 41-1.2 41-1.2.2.1.2.1 42-1.2.2.1.2.1.1.1.1 46-1.2.2.1.2 47-1.2.2.1.1.1.1 48-1.2.2.1 50-1.2.2 52-1.3.1 54-1.3.1.1 (c / contrast-01~e.23 :ARG1 (a / affect-01~e.11 :polarity~e.10 -~e.10 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (p3 / protein :name (n3 / name :op1 "PTEN"~e.2)) :location~e.3 (c2 / cell~e.8 :ARG1-of (m / mutate-01 :ARG0 (a3 / and :op1 (p / protein :name (n / name :op1 "Gr-1+"~e.4,6)) :op2 (p2 / protein :name (n2 / name :op1 "CD11b+"~e.7)))))) :ARG1 (u / upregulate-01~e.19,20,21 :ARG1 (n11 / nucleic-acid :name (n5 / name :op1 "miR-494"~e.16,18)) :ARG2-of (i / induce-01~e.15 :ARG0 (e2 / enzyme :name (n4 / name :op1 "TDF"~e.13))))) :ARG2 (a4 / and~e.41 :op1 (b / block-01~e.34 :ARG1 (e / express-03~e.26 :ARG2 (p5 / protein :name (n6 / name :op1 "MMP")) :ARG1-of (i2 / increase-01~e.25) :ARG2-of (i3 / induce-01~e.29 :ARG0~e.30 (t / thing :name (n7 / name :op1 "TCCM"~e.31)))) :ARG1-of (s / significant-02~e.33) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.36 :mod "6D"~e.38))) :op2 (a5 / abrogate-01~e.50 :ARG1 (m2 / migrate-01~e.48 :ARG0 (c3 / cell :name (n8 / name :op1 "MDSC"~e.47)) :ARG1-of (m3 / mediate-01~e.46 :ARG0 (a6 / and~e.41 :op1 (p7 / protein :name (n9 / name :op1 "SDF-1"~e.42)) :op2 (p8 / protein :name (n10 / name :op1 "CXCL12"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.52 :mod "6E"~e.54))) # ::id bel_pmid_2254_4933.41046 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significantly reduced PTEN expression was also detected in Gr @-@ 1+ CD11b+ cells after TCCM stimulation ( Fig . 6G ) ; this was inversely correlated with the phosphorylation levels of mTOR and NF @-@ kB . # ::alignments 0-1.1.1.2.1 1-1.1.1.2 2-1.1.1.1.1.1 3-1.1.1 5-1.1.2 6-1.1 7-1.1.3.r 8-1.1.3.1.1.1.1.1 10-1.1.3.1.1.1.1.1 11-1.1.3.1.1.2.1.1 12-1.1.3 13-1.1.4 14-1.1.4.1.1.1.1 15-1.1.4.1 17-1.1.5.1 19-1.1.5.1.1 22-1.2.1 24-1.2.3 24-1.2.3.r 25-1.2 26-1.2.2.r 28-1.2.2.1 29-1.2.2 29-1.2.2.1.1 30-1.2.2.1.1.1.r 31-1.2.2.1.1.1.1.1.1 32-1.2.2.1.1.1 33-1.2.2.1.1.1.2.1.1 35-1.2.2.1.1.1.2.1.1 (m / multi-sentence :snt1 (d / detect-01~e.6 :ARG1 (e / express-03~e.3 :ARG2 (p / protein :name (n / name :op1 "PTEN"~e.2)) :ARG1-of (r / reduce-01~e.1 :ARG2 (s / significant-02~e.0))) :mod (a / also~e.5) :location~e.7 (c / cell~e.12 :ARG1-of (m2 / mutate-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Gr-1+"~e.8,10)) :op2 (p3 / protein :name (n3 / name :op1 "CD11b+"~e.11))))) :time (a3 / after~e.13 :op1 (s2 / stimulate-01~e.15 :ARG0 (t2 / thing :name (n4 / name :op1 "TCCM"~e.14)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod "6G"~e.19))) :snt2 (c2 / correlate-01~e.25 :ARG1 (t / this~e.22) :ARG2~e.26 (l2 / level~e.29 :degree-of (p5 / phosphorylate-01~e.28 :ARG1 (l / level~e.29 :quant-of~e.30 (a4 / and~e.32 :op1 (p6 / protein :name (n5 / name :op1 "mTOR"~e.31)) :op2 (p7 / protein :name (n6 / name :op1 "NF-kB"~e.33,35)))))) :manner~e.24 (i / inverse~e.24))) # ::id bel_pmid_2254_4933.41048 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 6H , the increased levels of MMPs induced by TCCM were completely abolished by LY294002 , suggesting that the Akt activity is indispensable for the activation of MDSCs . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1.1 7-1.2.1 8-1.2 11-1.2.3 12-1.2.3.1.r 13-1.2.3.1.1.1 15-1.4 16-1 17-1.1.r 18-1.1.1.1 20-1.5 23-1.5.1.1.1.1.1.1 24-1.5.1.1.1 26-1.5.1.1 27-1.5.1.1.2.r 29-1.5.1.1.2 30-1.5.1.1.2.1.r 31-1.5.1.1.2.1.1.1 (a / abolish-01~e.16 :ARG0~e.17 (s3 / small-molecule :name (n / name :op1 "LY294002"~e.18)) :ARG1 (l / level~e.8 :ARG1-of (i / increase-01~e.7) :quant-of (e / enzyme :name (n2 / name :op1 "MMP")) :ARG2-of (i2 / induce-01~e.11 :ARG0~e.12 (t / thing :name (n3 / name :op1 "TCCM"~e.13)))) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "6H"~e.4)) :ARG1-of (c / complete-02~e.15) :ARG0-of (s / suggest-01~e.20 :ARG1 (p2 / possible-01 :ARG1 (i3 / indispensable-01~e.26 :ARG1 (a2 / activity-06~e.24 :ARG0 (p3 / pathway :name (n5 / name :op1 "Akt"~e.23))) :ARG2~e.27 (a3 / activate-01~e.29 :ARG1~e.30 (c2 / cell :name (n6 / name :op1 "MDSC"~e.31))))))) # ::id bel_pmid_2254_4933.41050 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BAY @-@ 117802 significantly blocked MMP13 expression but had a limited effect on the upregulation of MMP2 and MMP14 , whereas rapamycin eliminated the expression of all MMPs . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1.3 4-1.1.1 5-1.1.1.2.1.1.1 6-1.1.1.2 7-1.1 10-1.1.2.3 11-1.1.2 12-1.1.2.2.r 14-1.1.2.2 15-1.1.2.2.1.r 16-1.1.2.2.1.1.1.1 17-1.1.2.2.1 18-1.1.2.2.1.2.1.1 20-1 20-1.1 20-1.1.r 21-1.2.1 22-1.2 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1.2 (c / contrast-01~e.20 :ARG1~e.20 (c2 / contrast-01~e.7,20 :ARG1 (b / block-01~e.4 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "BAY-117802"~e.0,2)) :ARG1 (e4 / express-03~e.6 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MMP13"~e.5))) :ARG1-of (s / significant-02~e.3)) :ARG2 (a3 / affect-01~e.11 :ARG0 s2 :ARG1~e.12 (u / upregulate-01~e.14 :ARG1~e.15 (a2 / and~e.17 :op1 (e5 / enzyme :name (n4 / name :op1 "MMP2"~e.16)) :op2 (e6 / enzyme :name (n5 / name :op1 "MMP14"~e.18)))) :ARG1-of (l / limit-01~e.10))) :ARG2 (e / eliminate-01~e.22 :ARG0 (r / rapamycin~e.21) :ARG1 (e2 / express-03~e.24 :ARG2~e.25 (p / protein-family :name (n / name :op1 "MMP") :mod (a / all~e.26))))) # ::id bel_pmid_2254_4933.41052 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGF @-@ p1 @-@ induced miR @-@ 494 was involved in the negative regulation of PTEN expression . # ::alignments 0-1.1.2.1.1.1 2-1.1.2.1.1.1 4-1.1.2 5-1.1.1.1 7-1.1.1.1 9-1 10-1.2.r 12-1.2 13-1.2 14-1.2.1.r 15-1.2.1.1.1.1 16-1.2.1 (i / involve-01~e.9 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "miR-494"~e.5,7) :ARG2-of (i2 / induce-01~e.4 :ARG0 (p / protein :name (n2 / name :op1 "TGF-p1"~e.0,2)))) :ARG2~e.10 (d / downregulate-01~e.12,13 :ARG1~e.14 (e / express-03~e.16 :ARG2 (p2 / protein :name (n3 / name :op1 "PTEN"~e.15))))) # ::id bel_pmid_2295_2847.42202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transcriptional reprogramming of tumors via DmiR @-@ 580 , 588 or 190 over @-@ expression resulted in downregulation of pro @-@ angiogenic factors such as TIMP @-@ 3 , bFGF and TGFalpha . # ::alignments 0-1.1.2 3-1.1.1 4-1.1.3.r 5-1.1.3.1.1.1.1 5-1.1.3.1.2.1.1 5-1.1.3.1.3.1.1 7-1.1.3.1.1.1.1 9-1.1.3.1.2.1.1 10-1.1.3.1 11-1.1.3.1.3.1.1 15-1 16-1.2.r 17-1.2 18-1.2.1.r 19-1.2.1.1 22-1.2.1 23-1.2.1.2.r 24-1.2.1.2.r 25-1.2.1.2.1.1.1 27-1.2.1.2.1.1.1 29-1.2.1.2.2.1.1 30-1.2.1.2 31-1.2.1.2.3.1.1 (r / result-01~e.15 :ARG1 (r2 / reprogram-00 :ARG1 (t2 / tumor~e.3) :mod (t / transcribe-01~e.0) :path~e.4 (o / overexpress-01 :ARG1 (o2 / or~e.10 :op1 (n7 / nucleic-acid :name (n4 / name :op1 "DmiR-580"~e.5,7)) :op2 (n8 / nucleic-acid :name (n5 / name :op1 "DmiR-588"~e.5,9)) :op3 (n9 / nucleic-acid :name (n6 / name :op1 "DmiR-190"~e.5,11))))) :ARG2~e.16 (d / downregulate-01~e.17 :ARG1~e.18 (f / factor~e.22 :ARG0-of (f2 / favor-01~e.19 :ARG1 (a3 / angiogenesis)) :example~e.23,24 (a / and~e.30 :op1 (p / protein :name (n / name :op1 "TIMP-3"~e.25,27)) :op2 (p3 / protein :name (n2 / name :op1 "bFGF"~e.29)) :op3 (p4 / protein :name (n3 / name :op1 "TGFalpha"~e.31)))))) # ::id bel_pmid_2295_2847.42206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 2D shows the high rate of proliferative Ki67+ cells in a representative dormant miR @-@ 588 expressing A @-@ GBM tumor at day 113 post injection . # ::alignments 0-1.1 1-1.1.1 2-1 4-1.2.1 5-1.2 8-1.2.2.1.1 9-1.2.2 9-1.3.2.1.1 10-1.3.r 12-1.3 12-1.3.4 12-1.3.4.r 13-1.3.3 14-1.3.1.1 16-1.3.1.1 17-1.3.2 18-1.3.2.1.1.1.1 20-1.3.2.1.1.1.1 21-1.3.2.1 22-1.3.2.2.r 23-1.3.2.2.2.2 24-1.3.2.2.2.1 25-1.3.2.2 26-1.3.2.2.1 (s / show-01~e.2 :ARG0 (f / figure~e.0 :mod "2D"~e.1) :ARG1 (r / rate~e.5 :ARG1-of (h / high-02~e.4) :degree-of (c / cell~e.9 :name (n / name :op1 "Ki67+"~e.8) :ARG0-of (p / proliferate-01))) :location~e.10 (n4 / nucleic-acid~e.12 :name (n3 / name :op1 "miR-588"~e.14,16) :ARG1-of (e / express-03~e.17 :ARG2 (t / tumor~e.21 :mod (c2 / cell~e.9 :name (n2 / name :op1 "A-GBM"~e.18,20))) :time~e.22 (a / after~e.25 :op1 (i / inject-01~e.26) :quant (t2 / temporal-quantity :quant 113~e.24 :unit (d2 / day~e.23)))) :mod (d / dormant~e.13) :ARG0-of~e.12 (r3 / represent-01~e.12))) # ::id bel_pmid_2295_2847.42214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that antiangiogenic and dormancy promoting genes , Angiomotin ( AMOT @-@ 1 ) and Eph receptor A5 ( EphA5 ) , were both upregulated in all DmiR expressing A @-@ GBM tumors as compared to the GFP @-@ vector @- control A @-@ GBM cells ( Figure 4 ) . # ::alignments 0-1.1 1-1 4-1.2.1 5-1.2.1.3.1 6-1.2.1.3 7-1.2.1.1 7-1.2.1.2 9-1.2.1.1.1.1 15-1.2.1 16-1.2.1.2.1.1 17-1.2.1.2.1.2 18-1.2.1.2.1.3 25-1.2 26-1.2.3.r 27-1.2.3.2 28-1.2.3.1.2.1.1.1 29-1.2.3.1.2 30-1.2.3.1.1.1 32-1.2.3.1.1.1 33-1.2.3 35-1.2.2.r 38-1.2.2.1.1 40-1.2.2.1.1 42-1.2.2.1.1 43-1.2.2.1.2 45-1.2.2.1.2 46-1.2.2 46-1.2.3.1 48-1.3.1 49-1.3.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (u / upregulate-01~e.25 :ARG1 (a / and~e.4,15 :op1 (g / gene~e.7 :name (n / name :op1 "Angiomotin"~e.9)) :op2 (g3 / gene~e.7 :name (n3 / name :op1 "Eph"~e.16 :op2 "receptor"~e.17 :op3 "A5"~e.18)) :ARG0-of (p2 / promote-02~e.6 :ARG1 (d3 / dormancy~e.5)) :ARG0-of (c3 / counter-01 :ARG1 (a2 / angiogenesis))) :compared-to~e.35 (c / cell~e.46 :name (n6 / name :op1 "GFP-vector-control"~e.38,40,42 :op2 "A-GBM"~e.43,45)) :location~e.26 (t / tumor~e.33 :mod (c2 / cell~e.46 :name (n4 / name :op1 "A-GBM"~e.30,32) :ARG3-of (e / express-03~e.29 :ARG1 (n2 / nucleic-acid :name (n5 / name :op1 "Dmir"~e.28)))) :mod (a3 / all~e.27))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.48 :mod 4~e.49))) # ::id bel_pmid_2295_2847.42216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , genes involved in pro @-@ angiogenic signaling , including tissue inhibitor of metalloprotei @-@ nases 3 ( TIMP @-@ 3 ) , hypoxia @-@ induced factor 1 alpha ( HIF @-@ 1 @-@ alpha ) , basic fibroblast growth factor ( bFGF , FGF2 ) , and the K @-@ ras tumor oncogene , were consistently downregulated in DmiR expressing A @-@ GBM . # ::alignments 1-1 3-1.1.1 4-1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.1 9-1.1.1.1.1 11-1.1.1.2 12-1.1.1.2.1.1.1.1 13-1.1.1.2.1.1.1.2 14-1.1.1.2.1.1.1.3 15-1.1.1.2.1.1.1.4 18-1.1.1.2.1.1.1.5 22-1.1.1.2.1.1.1.5 25-1.1.1.2.1.2.1.1 27-1.1.1.2.1.2.1.1 28-1.1.1.2.1.2.1.2 29-1.1.1.2.1.2.1.3 34-1.1.1.2.1.2.1.3 39-1.1.1.2.1.3.1.1 40-1.1.1.2.1.3.1.2 41-1.1.1.2.1.3.1.3 42-1.1.1.2.1.3.1.4 49-1.1.1.2.1 51-1.1.1.2.1.4.1.1.1 53-1.1.1.2.1.4.1.1.1 54-1.1.1.2.1.4.2 55-1.1.1.2.1.4 58-1.1.3 59-1.1 60-1.1.2.r 61-1.1.2.2.1.1.1 62-1.1.2.2 63-1.1.2.1.1 65-1.1.2.1.1 (c / contrast-01~e.1 :ARG2 (d / downregulate-01~e.59 :ARG1 (g2 / gene~e.3 :ARG1-of (i / involve-01~e.4 :ARG2~e.5 (s / signal-07~e.9 :ARG0-of (f / favor-01~e.6 :ARG1 (a2 / angiogenesis)))) :ARG2-of (i2 / include-91~e.11 :ARG1 (a / and~e.49 :op1 (p / protein :name (n / name :op1 "tissue"~e.12 :op2 "inhibitor"~e.13 :op3 "of"~e.14 :op4 "metalloprotei-nase"~e.15 :op5 3~e.18,22)) :op2 (p3 / protein :name (n2 / name :op1 "hypoxia-induced"~e.25,27 :op2 "factor"~e.28 :op3 1~e.29,34)) :op3 (p4 / protein :name (n5 / name :op1 "basic"~e.39 :op2 "fibroblast"~e.40 :op3 "growth"~e.41 :op4 "factor"~e.42)) :op4 (o / oncogene~e.55 :mod (e / enzyme :name (n6 / name :op1 "K-ras"~e.51,53)) :mod (t / tumor~e.54))))) :ARG2~e.60 (c3 / cell :name (n3 / name :op1 "A-GBM"~e.63,65) :ARG3-of (e2 / express-03~e.62 :ARG1 (n7 / nucleic-acid :name (n4 / name :op1 "DmiR"~e.61)))) :manner (c2 / consistent-02~e.58))) # ::id bel_pmid_2295_2847.42218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , we found Bv8 also known as prokineticin 2 ( Prok2 ) to be markedly downregulated in all three DmiR expressing A @-@ GBM ( Figure 5A ) . # ::alignments 0-1.4 0-1.4.r 2-1.1 3-1 4-1.2.1.1.1 5-1.2.1.2.2 6-1.2.1 6-1.2.1.2 6-1.2.1.2.1.1.r 6-1.2.1.2.r 7-1.2.1.2.1.1.r 8-1.2.1.2.1.1.1 9-1.2.1.2.1.1.2 11-1.2.1.2.1.2.1.1.1 15-1.2.2 15-1.2.2.r 16-1.2 17-1.2.3.r 18-1.2.3.3 19-1.2.3.1 20-1.2.3.2.1 21-1.2.3.4 22-1.2.3.4.1.1.1 24-1.2.3.4.1.1.1 26-1.3.1 27-1.3.1.1 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1 (d2 / downregulate-01~e.16 :ARG1 (p / protein~e.6 :name (n / name :op1 "Bv8"~e.4) :ARG1-of~e.6 (k / know-02~e.6 :ARG2 (p2 / protein :name~e.6,7 (n5 / name :op1 "prokineticin"~e.8 :op2 2~e.9) :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n2 / name :op1 "Prok2"~e.11)))) :mod (a2 / also~e.5))) :manner~e.15 (m2 / marked~e.15) :location~e.17 (n6 / nucleic-acid :quant 3~e.19 :name (n3 / name :op1 "DmiR"~e.20) :mod (a / all~e.18) :ARG1-of (e / express-03~e.21 :ARG2 (c / cell :name (n4 / name :op1 "A-GBM"~e.22,24))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.26 :mod "5A"~e.27)) :manner~e.0 (i / important~e.0)) # ::id bel_pmid_2295_2847.42226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Over @-@ expression of miR @-@ 580 , miR @-@ 588 and miR @-@ 190 in fast @-@ growing angiogenic glioblastoma . # ::alignments 4-1.1.1.1.1 4-1.1.2.1.1 4-1.1.3.1.1 6-1.1.1.1.1 8-1.1.1.1.1 8-1.1.2.1.1 8-1.1.3.1.1 10-1.1.2.1.1 11-1.1 12-1.1.1.1.1 12-1.1.2.1.1 12-1.1.3.1.1 14-1.1.3.1.1 16-1.2.2.1 18-1.2.2 19-1.2.1 20-1.2 (o / overexpress-01 :ARG1 (a / and~e.11 :op1 (n4 / nucleic-acid :name (n / name :op1 "miR-580"~e.4,6,8,12)) :op2 (n5 / nucleic-acid :name (n2 / name :op1 "miR-588"~e.4,8,10,12)) :op3 (n6 / nucleic-acid :name (n3 / name :op1 "miR-190"~e.4,8,12,14))) :location (g / glioblastoma~e.20 :mod (a2 / angiogenic~e.19) :ARG1-of (g2 / grow-01~e.18 :ARG1-of (f / fast-02~e.16)))) # ::id bel_pmid_2313_1846.42236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , VEGF plugs in Pld1~-~ mice exhibited almost no vascularization ( Fig . 2 , A and B ) . # ::alignments 1-1 3-1.1.1.1.1.1 4-1.1.1 7-1.1.1.2 8-1.1 9-1.1.2.2 10-1.1.2.2.1 10-1.1.2.2.1.r 13-1.2.1.1 13-1.2.1.2 18-1.2.1 (c / contrast-01~e.1 :ARG2 (e / exhibit-01~e.8 :ARG0 (p / plug~e.4 :poss (p2 / protein :name (n / name :op1 "VEGF"~e.3)) :location (m / mouse~e.7 :mod (g / gene :name (n2 / name :op1 "Pld1") :ARG2-of (m2 / mutate-01 :mod "-/-")))) :ARG1 (v / vascularize-01 :ARG1 p :mod (a2 / almost~e.9 :polarity~e.10 -~e.10))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.18 :op1 (f / figure~e.13 :mod "2A") :op2 (f2 / figure~e.13 :mod "2B")))) # ::id bel_pmid_2313_1846.42240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PLD1 deficiency reduced basal phosphorylation of Ser473 in Akt and prevented VEGF @-@ induced phosphorylation of Akt at Ser473 ( Fig . 3 , C and D ) . # ::alignments 0-1.1.1.1.1.1 2-1.1 3-1.1.2.2 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 8-1.1.2.1.2.1.1 9-1 10-1.2 11-1.2.2.2.1.1.1 13-1.2.2.2 14-1.2.2 15-1.2.2.1.r 16-1.2.2.1 18-1.1.2.1.1.1 20-1.3.1.1 20-1.3.1.2 25-1.3.1 (a / and~e.9 :op1 (r / reduce-01~e.2 :ARG0 (l / lack-01 :ARG1 (p / protein :name (n / name :op1 "PLD1"~e.0))) :ARG1 (p3 / phosphorylate-01~e.4 :ARG1~e.5 (a3 / amino-acid :name (n2 / name :op1 "Ser473"~e.6,18) :part-of (e / enzyme :name (n4 / name :op1 "Akt"~e.8))) :mod (b / basal~e.3))) :op2 (p2 / prevent-01~e.10 :ARG0 l :ARG1 (p5 / phosphorylate-01~e.14 :ARG1~e.15 e~e.16 :ARG2-of (i / induce-01~e.13 :ARG0 (p6 / protein :name (n3 / name :op1 "VEGF"~e.11))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.25 :op1 (f / figure~e.20 :mod "3C") :op2 (f2 / figure~e.20 :mod "3D")))) # ::id bel_pmid_2313_1846.42242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pldl-- endothelial cells similarly exhibited a 50 % reduction in basal phosphorylation of ERK1 @/@ 2 but otherwise exhibited similar kinetics to wild @-@ type cells for VEGF @-@ induced phosphorylation of ERK1 @/@ 2 . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1.3 4-1.1 6-1.1.2.2.1 7-1.1.2.2 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.2 11-1.1.2.1 12-1.1.2.1.1.r 13-1.1.2.1.1.1.1 15-1.1.2.1.1.1.1 16-1 18-1.1 18-1.2 19-1.1.3 19-1.2.1.1.1 20-1.2.1.1 21-1.2.1.r 22-1.2.1.2.1 24-1.2.1.2.1 25-1.2.1.2 27-1.2.1.3.2.1.1.1 29-1.2.1.3.2 30-1.2.1.3 31-1.2.1.3.1.r 32-1.2.1.3.1 33-1.2.1.3.1 34-1.2.1.3.1 (c / contrast-01~e.16 :ARG1 (e / exhibit-01~e.4,18 :ARG0 (c2 / cell~e.2 :mod (e2 / endothelium~e.1) :mod (p3 / protein :name (n / name :op1 "Pldl") :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (r2 / reduce-01~e.8 :ARG1~e.9 (p2 / phosphorylate-01~e.11 :ARG1~e.12 (e4 / enzyme :name (n2 / name :op1 "ERK1/2"~e.13,15)) :mod (b / basal~e.10)) :ARG2 (p / percentage-entity~e.7 :value 50~e.6)) :manner (r / resemble-01~e.3,19)) :ARG2 (e3 / exhibit-01~e.18 :ARG1~e.21 (a / and :op1 (k / kinetics~e.20 :mod (r3 / resemble-01~e.19)) :op2 (c3 / cell~e.25 :mod (w / wild-type~e.22,24)) :purpose (p5 / phosphorylate-01~e.30 :ARG1~e.31 e4~e.32,33,34 :ARG2-of (i / induce-01~e.29 :ARG0 (p6 / protein :name (n3 / name :op1 "VEGF"~e.27))))))) # ::id bel_pmid_2313_1846.42248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histological and quantitative analyses of the tumors revealed a 79 % decrease in microvessels in the tumors that formed in FIPI @-@ treated mice ( Fig . 4C ) . # ::alignments 0-1.1.1.2 1-1.1 2-1.1.2.2 3-1.1.1 3-1.1.2 4-1.1.1.1.r 6-1.1.1.1 7-1 9-1.2.2.1 10-1.2.2 11-1.2 16-1.2.1.1 18-1.2.1.1.1 19-1.2.1.1.1.1.r 20-1.2.1.1.1.1.1.1.1.1 22-1.2.1.1.1.1.1 23-1.2.1.1.1.1 25-1.3.1 27-1.3.1.1 (r / reveal-01~e.7 :ARG0 (a / and~e.1 :op1 (a2 / analyze-01~e.3 :ARG1~e.4 (t / tumor~e.6) :mod (h / histology~e.0)) :op2 (a3 / analyze-01~e.3 :ARG1 t :mod (q / quantitative~e.2))) :ARG1 (d2 / decrease-01~e.11 :ARG1 (m / microvessel :part-of (t2 / tumor~e.16 :ARG0-of (f2 / form-01~e.18 :location~e.19 (m2 / mouse~e.23 :ARG1-of (t3 / treat-04~e.22 :ARG2 (s / small-molecule :name (n / name :op1 "FIPI"~e.20))))))) :ARG2 (p / percentage-entity~e.10 :value 79~e.9)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "4C"~e.27))) # ::id bel_pmid_2334_3326.26540 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Engagement of Gi @- and Gq @-@ protein @-@ coupled ETB receptors by ET @-@ 1 led to phosphorylation of ERK1 @/@ 2 , p38 MAPK , and JNK1 @/@ 2 and then activated transcription factor NF-?B . # ::alignments 0-1.1.1 1-1.1.1.2.r 2-1.1.1.2.2.1.1.1.1 4-1.1.1.2.2.1 5-1.1.1.2.2.1.2.1.1 7-1.1.1.1 7-1.1.1.2.2.1.1 7-1.1.1.2.2.1.2 9-1.1.1.2.2 10-1.1.1.2.1.1 11-1.1.1.2 13-1.1.1.1.1.1 13-1.1.2.1 15-1.1.1.1.1.1 16-1.1 17-1.1.2.r 18-1.1.2 19-1.1.2.1.r 20-1.1.2.1.1.1.1 24-1.1.2.1.3.1.1 25-1.1.2.1.3.1.2 28-1.1.2.1.4.1.1 31-1 32-1.2.3 33-1.2 34-1.2.2.2.1 35-1.2.2.2 (a4 / and~e.31 :op1 (l / lead-03~e.16 :ARG0 (e / engage-01~e.0 :ARG0 (p / protein~e.7 :name (n / name :op1 "ET-1"~e.13,15)) :ARG1~e.1 (r / receptor~e.11 :name (n2 / name :op1 "ETB"~e.10) :ARG1-of (c / couple-01~e.9 :ARG2 (a / and~e.4 :op1 (p2 / protein~e.7 :name (n3 / name :op1 "Gi"~e.2)) :op2 (p3 / protein~e.7 :name (n4 / name :op1 "Gq"~e.5)))))) :ARG2~e.17 (p4 / phosphorylate-01~e.18 :ARG1~e.19 (a2 / and~e.13 :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1"~e.20)) :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2")) :op3 (e4 / enzyme :name (n8 / name :op1 "p38"~e.24 :op2 "MAPK"~e.25)) :op4 (e6 / enzyme :name (n9 / name :op1 "JNK1"~e.28)) :op5 (e7 / enzyme :name (n10 / name :op1 "JNK2"))))) :op2 (a3 / activate-01~e.33 :ARG0 e :ARG1 (m / macro-molecular-complex :name (n11 / name :op1 "NF-kappaB") :mod (f / factor~e.35 :ARG0-of (t2 / transcribe-01~e.34))) :time (t / then~e.32))) # ::id bel_pmid_2334_3326.38068 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Engagement of Gi @- and Gq @-@ protein @-@ coupled ETB receptors by ET @-@ 1 led to phosphorylation of ERK1 @/@ 2 , p38 MAPK , and JNK1 @/@ 2 and then activated transcription factor NF-?B . # ::alignments 0-1.1.1 1-1.1.1.3.r 2-1.1.1.3.1.1.1.1 4-1.1.1.3.1 5-1.1.1.3.1.2.1.1 7-1.1.1.1 7-1.1.1.3.1.1 7-1.1.1.3.1.2 9-1.1.1.3 10-1.1.1.2.1.1 11-1.1.1.2 13-1.1.1.1.1.1 13-1.1.2.1 15-1.1.1.1.1.1 16-1.1 17-1.1.2.r 18-1.1.2 19-1.1.2.1.r 20-1.1.2.1.1.1.1 24-1.1.2.1.3.1.1 25-1.1.2.1.3.1.2 28-1.1.2.1.4.1.1 31-1 32-1.2.3 33-1.2 34-1.2.2.2.1 35-1.2.2.2 (a4 / and~e.31 :op1 (l / lead-03~e.16 :ARG0 (e / engage-01~e.0 :ARG0 (p / protein~e.7 :name (n / name :op1 "ET-1"~e.13,15)) :ARG1 (r / receptor~e.11 :name (n2 / name :op1 "ETB"~e.10)) :ARG1-of~e.1 (c / couple-01~e.9 :ARG2 (a / and~e.4 :op1 (p2 / protein~e.7 :name (n3 / name :op1 "Gi"~e.2)) :op2 (p3 / protein~e.7 :name (n4 / name :op1 "Gq"~e.5))))) :ARG2~e.17 (p4 / phosphorylate-01~e.18 :ARG1~e.19 (a2 / and~e.13 :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1"~e.20)) :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2")) :op3 (e4 / enzyme :name (n7 / name :op1 "p38"~e.24 :op2 "MAPK"~e.25)) :op4 (e5 / enzyme :name (n8 / name :op1 "JNK1"~e.28)) :op5 (e6 / enzyme :name (n9 / name :op1 "JNK2"))))) :op2 (a3 / activate-01~e.33 :ARG0 e :ARG1 (m / macro-molecular-complex :name (n10 / name :op1 "NF-kappaB") :mod (f / factor~e.35 :ARG0-of (t2 / transcribe-01~e.34))) :time (t / then~e.32))) # ::id bel_pmid_2364_0055.42272 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Against this background , we conducted in vitro phosphorylation studies of the phosphorylation of in @-@ tegrin avp3 dimer with activated ERK1 and found phosphorylation of the dimer ( Fig . 3A ) that was inhibited by the ERK inhibitor , FR180204 . # ::alignments 1-1.1.1 2-1.1 4-1.2.1.1 5-1.2.1 6-1.2.1.3 7-1.2.1.3 8-1.2.1.2.1 9-1.2.1.2 12-1.2.1.2.1 14-1.2.1.3 18-1.2.1.2.1.1 19-1.2.1.2.1.2.r 20-1.2.1.2.1.2.2 21-1.2.1.2.1.2.1.1 22-1.2 23-1.2.2 24-1.2.1.2.1 27-1.2.1.2.1.1 29-1.2.2.3.1 31-1.2.2.3.1.1 35-1.2.2.2 35-1.2.2.2.1.2 36-1.2.2.2.1.r 38-1.2.2.2.1.2.1.1.1 39-1.2.2.2.1.2 41-1.2.2.2.1.1.1 (c2 / contrast-01 :ARG1 (b / background~e.2 :mod (t / this~e.1)) :ARG2 (a / and~e.22 :op1 (c / conduct-01~e.5 :ARG0 (w / we~e.4) :ARG1 (s / study-01~e.9 :ARG1 (p / phosphorylate-01~e.8,12,24 :ARG1 (d / dimer~e.18,27 :name (n / name :op1 "integrin" :op2 "αVβ3")) :ARG2~e.19 (e / enzyme :name (n3 / name :op1 "ERK1"~e.21) :ARG1-of (a2 / activate-01~e.20)))) :manner (i / in-vitro~e.6,7,14)) :op2 (f / find-01~e.23 :ARG0 w :ARG1 (i2 / inhibit-01~e.35 :ARG0~e.36 (s2 / small-molecule :name (n4 / name :op1 "FR180204"~e.41) :ARG0-of (i3 / inhibit-01~e.35,39 :ARG1 (p2 / protein-family :name (n2 / name :op1 "ERK"~e.38)))) :ARG1 p) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.29 :mod "3A"~e.31))))) # ::id bel_pmid_2364_0055.42278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Integrin av bound to the COX @-@ 2 promoter in both OVCAR @-@ 3 and H522 cells in response to T4 ( Fig . 4A ) # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1 3-1.2.r 5-1.2.1.1.1.1 7-1.2.1.1.1.1 11-1.3.1.1.1 13-1.3.1.1.1 14-1.3 15-1.3.2.1.1 16-1.3.1 16-1.3.2 17-1.4.r 18-1.4 19-1.4.1.r 20-1.4.1.1.1 22-1.5.1 24-1.5.1.1 (b / bind-01~e.2 :ARG1 (p / protein :name (n / name :op1 "integrin"~e.0 :op2 "av"~e.1)) :ARG2~e.3 (m / molecular-physical-entity :ARG0-of (p2 / promote-02 :ARG1 (e / enzyme :name (n2 / name :op1 "COX-2"~e.5,7)))) :location (a / and~e.14 :op1 (c / cell-line~e.16 :name (n3 / name :op1 "OVCAR-3"~e.11,13)) :op2 (c2 / cell-line~e.16 :name (n4 / name :op1 "H522"~e.15))) :ARG2-of~e.17 (r / respond-01~e.18 :ARG1~e.19 (s / small-molecule :name (n5 / name :op1 "T4"~e.20))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.22 :mod "4A"~e.24))) # ::id bel_pmid_2364_0055.42282 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that although T4 increased complex formation between integrin av and NCoR/SMRT , the association between NCoR @/@ SMRT and DNA was unchanged . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 4-1.2 5-1.2.2.1.1.1 6-1.2.2 7-1.2.2.2.1 8-1.2.2.2 10-1.2.2.2.1.1.1.1 11-1.2.2.2.1.1.1.2 13-1.2.2.2.1.2.1.1 16-1.2.1.2 18-1.2.1.2.1 19-1.2.1.2.1 20-1.2.1.2.1 22-1.2.1.2.2.2.1 24-1.2.1 24-1.2.1.1 24-1.2.1.1.r (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1 (h / have-concession-91~e.4 :ARG1 (c / change-01~e.24 :polarity~e.24 -~e.24 :ARG1 (a / associate-01~e.16 :ARG1 m~e.18,19,20 :ARG2 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.22)))) :ARG2 (i / increase-01~e.6 :ARG0 (s2 / small-molecule :name (n / name :op1 "T4"~e.5)) :ARG1 (f / form-01~e.8 :ARG1 (m2 / macro-molecular-complex~e.7 :part (p / protein :name (n2 / name :op1 "integrin"~e.10 :op2 "av"~e.11)) :part (m / macro-molecular-complex :name (n3 / name :op1 "NCoR/SMRT"~e.13))))))) # ::id bel_pmid_2364_0055.42284 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The transcription of COX @-@ 2 , ERa , HIF @-@ la , and TR $ 1 was increased in thyroid hormone @-@ treated cells ( Fig . 4B ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 5-1.1.1.1.1.1 9-1.1.1.3.1.1 13-1.1.1 18-1 19-1.2.r 20-1.2.1.1.1 21-1.2.1.1 23-1.2.1 24-1.2 26-1.3.1 28-1.3.1.1 (i / increase-01~e.18 :ARG1 (t / transcribe-01~e.1 :ARG1~e.2 (a / and~e.13 :op1 (e / enzyme :name (n / name :op1 "COX-2"~e.3,5)) :op2 (p / protein :name (n2 / name :op1 "ERalpha")) :op3 (p2 / protein :name (n3 / name :op1 "HIF-1alpha"~e.9)) :op4 (p3 / protein :name (n4 / name :op1 "TRbeta1")))) :location~e.19 (c / cell~e.24 :ARG1-of (t2 / treat-04~e.23 :ARG2 (h / hormone~e.21 :source (t3 / thyroid~e.20)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "4B"~e.28))) # ::id bel_pmid_2382_4538.18804 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Abundant autophagosomes in K @-@ rasG12D/+;atg7+/+ but not in K @-@ rasG12D/+;atg7 -/- tumors were confirmed by electron microscopy ( Fig . 2B ) . # ::alignments 0-1.1.2.2 3-1.1.3.1.1.1.1 6-1 7-1.2.1 7-1.2.1.r 9-1.2.4.1.1 12-1.2.4.1.2.2.1 13-1.1.3 13-1.2.4 15-1.1 15-1.2 16-1.1.1.r 17-1.1.1.1 18-1.1.1 20-1.3.1 22-1.3.1.1 (c3 / contrast-01~e.6 :ARG1 (c / confirm-01~e.15 :ARG0~e.16 (m4 / microscopy~e.18 :mod (e2 / electron~e.17)) :ARG1 (s / small-molecule :name (n / name :op1 "autophagosome") :mod (a / abundant~e.0)) :location (t / tumor~e.13 :mod (s2 / slash :op1 (e / enzyme :name (n2 / name :op1 "K-ras"~e.3) :ARG2-of (m / mutate-01 :value "G12D")) :op2 (p2 / protein :name (n3 / name :op1 "atg7") :mod (w / wild-type))))) :ARG2 (c4 / confirm-01~e.15 :polarity~e.7 -~e.7 :ARG0 m4 :ARG1 s :location (t2 / tumor~e.13 :mod (s3 / slash :op1 e~e.9 :op2 (p3 / protein :name (n4 / name :op1 "atg7") :ARG2-of (m3 / mutate-01 :mod "-/-"~e.12))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "2B"~e.22))) # ::id bel_pmid_2382_4538.18808 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reduction of atg7 @-@ deficient tumor burden was coincident with reduced proliferation ( Ki67 ) and decreased levels of phospho @-@ MEK1 @/@ 2 ( P @-@ MEK1 @/@ 2 ) and P @-@ ERK1 @/@ 2 and p53 and p21 induction , compared with wild @-@ type tumors ( Fig . 1I ; Supplemental Figs . S4A @–@ C , S5A @–@ C ) , suggesting that inhibition of tumor cell proliferation upon atg7 deletion is the main cause of reduced tumor burden . # ::alignments 0-1.1 2-1.1.1.1.1.1.1 5-1.4.1.2.1 6-1.4.1.2 10-1.2.1.1 11-1.2.1 13-1.2.1.2.1.1.1 15-1.2 16-1.2.2.1 17-1.2.2 18-1.2.2.2.r 19-1.2.2.2.5 21-1.2.2.2.1.1.1 25-1.2.2.2.5 27-1.2.2.2.1.1.1 31-1.2.2.2 32-1.2.2.2.5 34-1.2.2.2.3.1.1 38-1.2.3.1.1.1.1 39-1.2.3.1 40-1.2.3.1.2.1.1 41-1.2.3 43-1.2.4.r 45-1.2.4.1 47-1.2.4.1 48-1.2.4 50-1.3.1.1 50-1.3.1.2.1 50-1.3.1.2.2 50-1.3.1.2.3 50-1.3.1.3.1 50-1.3.1.3.2 50-1.3.1.3.3 52-1.3.1.1.1 54-1.3.1.2.4 57-1.3.1.2.1.1 61-1.3.1.3.1.1 66-1.4 68-1.4.1.1 70-1.1.1.1 71-1.4.1.1.2.1 72-1.4.1.1.2 74-1.1.1.1.1.1.1 75-1.1.1.1.1 75-1.1.1.1.1.2 75-1.1.1.1.1.2.r 75-1.4.1.1.1 78-1.4.1.3 79-1.4.1 81-1.1 81-1.4.1.2.2 82-1.1.1.1 83-1.1.1 (c / coincide-01 :ARG1 (r / reduce-01~e.0,81 :ARG1 (b / burden-01~e.83 :ARG2 (t / tumor~e.70,82 :mod (p / protein~e.75 :name (n / name :op1 "atg7"~e.2,74) :ARG1-of~e.75 (d4 / delete-01~e.75))))) :ARG2 (a / and~e.15 :op1 (p2 / proliferate-01~e.11 :ARG1-of (r2 / reduce-01~e.10) :ARG1-of (m2 / measure-01 :ARG2 (p3 / protein :name (n2 / name :op1 "Ki67"~e.13)))) :op2 (l2 / level~e.17 :ARG1-of (d / decrease-01~e.16) :quant-of~e.18 (a2 / and~e.31 :op1 (e / enzyme :name (n3 / name :op1 "MEK1"~e.21,27)) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2")) :op3 (e3 / enzyme :name (n5 / name :op1 "ERK1"~e.34)) :op4 (e4 / enzyme :name (n6 / name :op1 "ERK2")) :ARG1-of (p4 / phosphorylate-01~e.19,25,32))) :op3 (i / induce-01~e.41 :ARG2 (a3 / and~e.39 :op1 (p5 / protein :name (n7 / name :op1 "p53"~e.38)) :op2 (p6 / protein :name (n8 / name :op1 "p21"~e.40)))) :compared-to~e.43 (t2 / tumor~e.48 :mod (w / wild-type~e.45,47))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.50 :mod "1I"~e.52) :op2 (a5 / and :op1 (f4 / figure~e.50 :mod "S4A"~e.57) :op2 (f5 / figure~e.50 :mod "S4B") :op3 (f6 / figure~e.50 :mod "S4C") :ARG2-of (s / supplement-01~e.54)) :op3 (a6 / and :op1 (f2 / figure~e.50 :mod "S5A"~e.61) :op2 (f7 / figure~e.50 :mod "S5B") :op3 (f8 / figure~e.50 :mod "S5C") :ARG2-of s))) :ARG0-of (s2 / suggest-01~e.66 :ARG1 (c2 / cause-01~e.79 :ARG0 (i2 / inhibit-01~e.68 :ARG0 (d3 / delete-01~e.75 :ARG1 p) :ARG1 (p7 / proliferate-01~e.72 :ARG0 (c3 / cell~e.71 :mod t3))) :ARG1 (b2 / burden-01~e.6 :ARG2 (t3 / tumor~e.5) :ARG1-of (r3 / reduce-01~e.81)) :mod (m / main~e.78)))) # ::id bel_pmid_2382_4538.18812 ::amr-annotator SDL-AMR-09 ::preferred # ::tok atg7 deficiency in tumors prevented LC3 @-@ I processing to LC3 @-@ II and caused accumulation of LC3 @-@ I and autophagy substrate p62 in large aggregates apparent at 6 wk that increased throughout tumorigenesis # ::alignments 0-1.1.1.1.1.1 3-1.1.1.2 4-1.1 5-1.1.2.1.1.1 5-1.1.2.2.1.1 7-1.1.2.1.1.1 8-1.1.2 10-1.1.2.1.1.1 10-1.1.2.2.1.1 12-1.1.2.2.1.1 13-1 14-1.2 15-1.2.2 17-1.1.2.1.1.1 17-1.1.2.2.1.1 19-1.1.2.1.1.1 20-1.2.2.1 21-1.2.2.1.2.2 22-1.2.2.1.2 23-1.2.2.1.2.1.1.1 24-1.2.2.2.r 25-1.2.2.2.1 26-1.2.2.2 29-1.2.2.2.2.1.2.1 32-1.2.2.2.3 33-1.2.2.2.3.1 34-1.2.2.2.3.1.1 (a / and~e.13 :op1 (p2 / prevent-01~e.4 :ARG0 (d / delete-01 :ARG1 (p / protein :name (n / name :op1 "atg7"~e.0)) :ARG2 (t / tumor~e.3)) :ARG1 (p3 / process-01~e.8 :ARG1 (p4 / protein :name (n2 / name :op1 "LC3-I"~e.5,7,10,17,19)) :ARG2 (p5 / protein :name (n3 / name :op1 "LC3-II"~e.5,10,12,17)))) :op2 (c / cause-01~e.14 :ARG0 d :ARG1 (a3 / accumulate-01~e.15 :ARG1 (a2 / and~e.20 :op1 p4 :op2 (s / substrate~e.22 :consist-of (p6 / protein :name (n4 / name :op1 "p62"~e.23)) :mod (a4 / autophagy~e.21))) :ARG1-of~e.24 (a5 / aggregate-01~e.26 :mod (l2 / large~e.25) :ARG1-of (a6 / appear-01 :time (a7 / after :op1 a3 :quant (t2 / temporal-quantity :quant 6~e.29 :unit (w / week)))) :ARG1-of (i / increase-01~e.32 :time (t3 / throughout~e.33 :op1 (c2 / create-01~e.34 :ARG1 t))))))) # ::id bel_pmid_2465_2403.41226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok e ALDH1 activity in human PC ( N = 11 ) ; representative flow cytometry plot of human PC tumor gated on live EpCAM+ cells using Aldefluor assay . # ::alignments 1-1.1.1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.3 9-1.1.2.4.1.1 12-1.2.1.2 13-1.2.1.1 14-1.2.1 15-1.2 16-1.2.2.r 17-1.2.2.1.3 19-1.2.2 20-1.2.2.1.4 21-1.2.2.1.4.2.r 22-1.2.2.1.4.2.2 23-1.2.2.1.4.2.1.1.1 24-1.2.2.1.4.2 25-1.2.2.1.4.1 26-1.2.2.1.4.1.1.1.1.1 27-1.2.2.1.4.1.1 (m / multi-sentence :snt1 (a / activity-06~e.2 :ARG0 (e / enzyme :name (n / name :op1 "ALDH1"~e.1)) :ARG1~e.3 (d2 / disease :wiki "Pancreatic_cancer" :name (n3 / name :op1 "pancreatic" :op2 "cancer") :mod h2~e.4 :ARG1-of (s / sample-01 :ARG2 (t2 / thing :quant 11~e.9)))) :snt2 (p2 / plot~e.15 :mod (c2 / cytometry~e.14 :mod (f / flow~e.13) :ARG0-of (r / represent-01~e.12)) :mod~e.16 (t3 / tumor~e.19 :mod (d4 / disease :wiki "Pancreatic_cancer" :name (n6 / name :op1 "pancreatic" :op2 "cancer") :mod (h2 / human~e.17) :ARG1-of (g / gate-01~e.20 :ARG0 (u / use-01~e.25 :ARG1 (a2 / assay-01~e.27 :instrument (t / thing :name (n5 / name :op1 "Aldefluor"~e.26)))) :location~e.21 (c / cell~e.24 :mod (p3 / protein :name (n4 / name :op1 "EpCAM+"~e.23)) :ARG0-of (l / live-01~e.22)))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "E"))) # ::id bel_pmid_2465_2403.41228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , GCSFR-/- mice exhibit a shift in the immune profile of PC tumors from a TH @-@ 2 to TH @-@ 1 immune response , characterized by increased expression of IFN @-@ y , TNF @-@ a and IL @-@ 12 with decreased expression of arginase @-@ 1 , IL @-@ 6 , TGF @-@ P , IL @-@ 10 compared to WT mice ( Fig . 2d ) . # ::alignments 0-1 3-1.1.1 4-1.1 5-1.1.2.1.2.1.1.1.2.1.1 6-1.1.2 9-1.1.2.1.1 10-1.1.2.1 13-1.1.2.1.3 15-1.1.2.1.2.1.1.1.2.1.1 16-1.1.2.2.1.1.1.1 16-1.1.2.3.1.1.1.1 18-1.1.2.3.1.1.1.1 20-1.1.2.2.1.1.1.1 20-1.1.2.3.1.1.1.1 22-1.1.2.2.1.1.1.1 23-1.1.2.2.1 23-1.1.2.3.1 24-1.1.2.2 24-1.1.2.3 26-1.1.2.1.2 28-1.1.2.1.2.1.1.2 29-1.1.2.1.2.1.1 30-1.1.2.1.2.1.1.1.r 31-1.1.2.1.2.1.1.1.1.1.1 33-1.1.2.1.2.1.1.1.1.1.1 35-1.1.2.1.2.1.1.1.2.1.1 37-1.1.2.1.2.1.1.1.2.1.1 38-1.1.2.1.2.1.1.1 39-1.1.2.1.2.1.1.1.3.1.1 41-1.1.2.1.2.1.1.1.3.1.1 42-1.1.2.1.2.1.r 43-1.1.2.1.2.1.2.2 44-1.1.2.1.2.1.2 44-1.1.2.1.2.1.2.2.1 45-1.1.2.1.2.1.2.1.r 46-1.1.2.1.2.1.2.1.1.1.1 48-1.1.2.1.2.1.2.1.1.1.1 50-1.1.2.1.2.1.2.1.2.1.1 50-1.1.2.1.2.1.2.1.4.1.1 52-1.1.2.1.2.1.2.1.2.1.1 54-1.1.2.1.2.1.2.1.3.1.1 56-1.1.2.1.2.1.2.1.3.1.1 58-1.1.2.1.2.1.2.1.2.1.1 58-1.1.2.1.2.1.2.1.4.1.1 60-1.1.2.1.2.1.2.1.4.1.1 61-1.1.2.1.2.1.2.2.1.r 62-1.1.2.1.2.1.2.2.1.2.r 63-1.1.2.1.2.1.2.2.1.2.1 64-1.1.2.1.2.1.2.2.1.2 66-1.2.1 68-1.2.1.1 (a / and~e.0 :op2 (e / exhibit-01~e.4 :ARG0 (m / mouse~e.3 :mod (p / protein :name (n / name :op1 "GCSFR") :ARG2-of (m2 / mutate-01 :mod "-/-"))) :ARG1 (s / shift-01~e.6 :ARG1 (p2 / profile~e.10 :ARG1-of (i / immune-02~e.9) :ARG1-of (c3 / characterize-01~e.26 :ARG2~e.42 (a2 / and :op1 (e2 / express-03~e.29 :ARG2~e.30 (a3 / and~e.38 :op1 (p3 / protein :name (n4 / name :op1 "IFN-y"~e.31,33)) :op2 (p4 / protein :name (n5 / name :op1 "TNF-a"~e.5,15,35,37)) :op3 (p5 / protein :name (n6 / name :op1 "IL-12"~e.39,41))) :ARG1-of (i2 / increase-01~e.28)) :op2 (e3 / express-03~e.44 :ARG2~e.45 (a4 / and :op1 (e4 / enzyme :name (n7 / name :op1 "arginase-1"~e.46,48)) :op2 (p6 / protein :name (n8 / name :op1 "IL-6"~e.50,52,58)) :op3 (p7 / protein :name (n9 / name :op1 "TGF-P"~e.54,56)) :op4 (p8 / protein :name (n10 / name :op1 "IL-10"~e.50,58,60))) :ARG1-of (d / decrease-01~e.43 :compared-to~e.61 (e5 / express-03~e.44 :ARG2 a4 :ARG3~e.62 (m3 / mouse~e.64 :mod (w / wild-type~e.63))))))) :mod (t / tumor~e.13 :mod (d4 / disease :wiki "Pancreatic_cancer" :name (n12 / name :op1 "pancreatic" :op2 "cancer")))) :ARG2 (r2 / respond-01~e.24 :ARG2 (i4 / immune-02~e.23 :ARG1 (c2 / cell :name (n3 / name :op1 "TH-1"~e.16,20,22)))) :ARG3 (r / respond-01~e.24 :ARG2 (i3 / immune-02~e.23 :ARG1 (c / cell :name (n2 / name :op1 "TH-2"~e.16,18,20)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.66 :mod "2d"~e.68))) # ::id bel_pmid_2465_2403.41236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These monocytes acquired a Mo @-@ MDSC phenotype characterized by a significantly decreased expression of HLA @-@ DR and increased expression of arginase @-@ 1 as well as the ability to suppress CD8+ T cell proliferation in vitro [ 29 @-@ 32 ] ( Fig . 4a @-@ c ) . # ::alignments 0-1.1.2 1-1.1.1.1 2-1 4-1.2.1.1.1 6-1.2.1.1.1 7-1.2 8-1.2.2 9-1.2.2.1.r 11-1.2.2.1.1.2.1 12-1.2.2.1.1.2 13-1.2.2.1.1 14-1.2.2.1.1.1.r 15-1.2.2.1.1.1.1.1 17-1.2.2.1.1.1.1.1 18-1.2.2.1 19-1.2.2.1.2.2 20-1.2.2.1.2 21-1.2.2.1.2.1.r 22-1.2.2.1.2.1.1.1 24-1.2.2.1.2.1.1.1 25-1.3.1 25-1.3.1.2 25-1.3.1.2.r 26-1.3.1 26-1.3.1.2 26-1.3.1.2.r 27-1.3.1 27-1.3.1.2 27-1.3.1.2.r 29-1.2.2.1.3 31-1.2.2.1.3.2 32-1.2.2.1.3.2.2.1.1.1 33-1.2.2.1.3.2.2.1.1.2 34-1.1 34-1.2.1 34-1.2.2.1.3.2.2.1 35-1.2.2.1.3.2.2 36-1.2.2.1.3.2.3 37-1.2.2.1.3.2.3 39-1.3.1.1.1.1.1 41-1.3.1.1.1.1.2 44-1.3.1.2.1 44-1.3.1.2.2 44-1.3.1.2.3 (a / acquire-01~e.2 :ARG0 (c / cell~e.34 :name (n / name :op1 "monocyte"~e.1) :mod (t / this~e.0)) :ARG1 (p / phenotype~e.7 :mod (c2 / cell~e.34 :name (n2 / name :op1 "Mo-MDSC"~e.4,6)) :ARG1-of (c3 / characterize-01~e.8 :ARG0~e.9 (a2 / and~e.18 :op1 (e / express-03~e.13 :ARG2~e.14 (p2 / protein :name (n3 / name :op1 "HLA-DR"~e.15,17)) :ARG1-of (d / decrease-01~e.12 :ARG2 (s / significant-02~e.11))) :op2 (e2 / express-03~e.20 :ARG2~e.21 (e3 / enzyme :name (n4 / name :op1 "arginase-1"~e.22,24)) :ARG1-of (i / increase-01~e.19)) :op3 (c4 / capable-01~e.29 :ARG1 c :ARG2 (s2 / suppress-01~e.31 :ARG0 c :ARG1 (p3 / proliferate-01~e.35 :ARG0 (c5 / cell~e.34 :name (n5 / name :op1 "CD8+"~e.32 :op2 "T"~e.33))) :manner (i2 / in-vitro~e.36,37)))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.25,26,27 :op1 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 (v2 / value-interval :op1 29~e.39 :op2 32~e.41))) :op2~e.25,26,27 (a4 / and~e.25,26,27 :op1 (f / figure~e.44 :mod "1a") :op2 (f2 / figure~e.44 :mod "1b") :op3 (f3 / figure~e.44 :mod "1c"))))) # ::id bel_pmid_2465_2403.41248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While we found that IL @-@ 6 mRNA gene expression was significantly downregulated by STAT3 inhibition ( Supplementary figure 11 ) , IL @-@ 6 blockade using anti @-@ IL @-@ 6 antibodies decreased but did not fully reverse the effect of Mo @-@ MDSC on increasing the prevalence of ALDH1Bright CSCs . # ::alignments 0-1 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.2.2.1.1.1 6-1.1.2.1.2.2.1.1.1 7-1.1.2.1.2.1.1 8-1.1.2.1.1 9-1.1.2.1 11-1.1.2.3 12-1.1.2 15-1.1.2.2 17-1.1.3.1.2 18-1.1.3.1 19-1.1.3.1.1 22-1.2.1.1.2.1.1 23-1.2.1.1.2.1.1 24-1.2.1.1.2.1.1 27-1.2.1.1.2.1 29-1.2.1.1.2.1.1 30-1.2.1.1.2.1.1 31-1.2.1.1.2.1.1 32-1.2.1.1.2 33-1.2.1 34-1.2 36-1.2.2.1 36-1.2.2.1.r 37-1.2.2.4 38-1.2.2 40-1.2.1.2 41-1.2.1.2.1.r 42-1.2.1.2.1.1.1 44-1.2.1.2.1.1.1 45-1.2.1.2.2.r 46-1.2.1.2.2 (c / contrast-01~e.0 :ARG1 (f / find-01~e.2 :ARG0 (w / we~e.1) :ARG1~e.3 (d / downregulate-01~e.12 :ARG1 (e / express-03~e.9 :ARG1 (g / gene~e.8) :ARG2 (n6 / nucleic-acid :name (n / name :op1 "mRNA"~e.7) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "IL-6"~e.4,6))))) :ARG2 (i / inhibit-01~e.15 :ARG1 (p2 / protein :name (n3 / name :op1 "STAT-3"))) :ARG1-of (s / significant-02~e.11)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.18 :mod 11~e.19 :ARG2-of (s2 / supplement-01~e.17)))) :ARG2 (c2 / contrast-01~e.34 :ARG1 (d3 / decrease-01~e.33 :ARG0 (b / block-01 :ARG1 p :ARG3 (a / antibody~e.32 :ARG0-of (c3 / counter-01~e.27 :ARG1 p~e.22,23,24,29,30,31))) :ARG1 (a2 / affect-01~e.40 :ARG0~e.41 (c4 / cell :name (n4 / name :op1 "Mo-MDSC"~e.42,44)) :ARG1~e.45 (i2 / increase-01~e.46 :ARG1 (p4 / prevail-01 :ARG0 (c5 / cell :name (n5 / name :op1 "ALDH1" :op2 "Bright" :op3 "CSC")))))) :ARG2 (r2 / reverse-01~e.38 :polarity~e.36 -~e.36 :ARG0 b :ARG1 a2 :degree (f3 / full~e.37)))) # ::id bel_pmid_247_2096.38400 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the 2 cytokines most intensively involved in eliciting the acute phase response are IL6 and IL1 # ::alignments 1-1.1 2-1 2-1.2.1 2-1.2.2 3-1.3.2.1 4-1.3.2 4-1.3.2.r 5-1.3 6-1.3.1.r 7-1.3.1 9-1.3.1.1.1.1.1 10-1.3.1.1.1.1 11-1.3.1.1 11-1.3.1.1.1 11-1.3.1.1.1.r 12-1.2.r 14-1.2 (c4 / cytokine~e.2 :quant 2~e.1 :domain~e.12 (a3 / and~e.14 :op1 (c / cytokine~e.2 :name (n / name :op1 "IL-6")) :op2 (c2 / cytokine~e.2 :name (n2 / name :op1 "IL-1"))) :ARG1-of (i2 / involve-01~e.5 :ARG2~e.6 (e / elicit-01~e.7 :ARG1 (t / thing~e.11 :ARG2-of~e.11 (r / respond-01~e.11 :ARG1 (p / phase~e.10 :mod (a2 / acute~e.9))))) :manner~e.4 (i / intensive~e.4 :degree (m / most~e.3)))) # ::id bel_pmid_248_3767.28356 ::amr-annotator SDL-AMR-09 ::preferred # ::tok alpha 2 @-@ macroglobulin , alpha 1 @-@ antichymotrypsin ( = contrapsin ) , cysteine protease inhibitor ( = thiostatin ) , alpha 1 @-@ antitrypsin , ceruloplasmin and fibrinogens are predominantly regulated by the keratinocyte @-@ derived HSF @-@ III/-II or IL @-@ 6 # ::alignments 0-1.2.1.1.1 0-1.2.2.1.1 0-1.2.4.1.1 1-1.2.1.1.1 3-1.2.1.1.1 5-1.2.1.1.1 5-1.2.2.1.1 5-1.2.4.1.1 6-1.2.2.1.2 6-1.2.4.1.2 8-1.2.2.1.2 11-1.2.2.2.1.1.1 14-1.2.3.2.1.1.1 15-1.2.3.2.1.1.2 16-1.2.3 16-1.2.3.2 16-1.2.3.2.r 19-1.2.3.1.1 22-1.2.1.1.1 22-1.2.4.1.1 23-1.2.4.1.2 25-1.2.4.1.2 27-1.2.5.1.1 28-1.2 29-1.2.6.1.1 31-1.3 31-1.3.r 32-1 33-1.1.r 35-1.1.3.1.1.1 37-1.1.3 38-1.1.1.1.1.1 38-1.1.1.2.1.1 41-1.1 42-1.1.2.1.1 44-1.1.2.1.1 (r / regulate-01~e.32 :ARG0~e.33 (o / or~e.41 :op1 (s / slash :op1 (p3 / protein :name (n2 / name :op1 "HSF-III"~e.38)) :op2 (p4 / protein :name (n3 / name :op1 "HSF-II"~e.38))) :op2 (p2 / protein :name (n / name :op1 "IL-6"~e.42,44)) :ARG1-of (d / derive-01~e.37 :ARG2 (c / cell :name (n4 / name :op1 "keratinocyte"~e.35)))) :ARG1 (a / and~e.28 :op1 (p5 / protein :name (n5 / name :op1 "alpha-2-macroglobulin"~e.0,1,3,5,22)) :op2 (p6 / protein :name (n6 / name :op1 "alpha"~e.0,5 :op2 "1-antichymotrypsin"~e.6,8) :ARG1-of (m2 / mean-01 :ARG2 (p9 / protein :name (n11 / name :op1 "contrapsin"~e.11)))) :op3 (p10 / protein~e.16 :name (n12 / name :op1 "thiostatin"~e.19) :ARG0-of~e.16 (i / inhibit-01~e.16 :ARG1 (e / enzyme :name (n7 / name :op1 "cysteine"~e.14 :op2 "protease"~e.15)))) :op4 (p7 / protein :name (n8 / name :op1 "alpha"~e.0,5,22 :op2 "1-antitrypsin"~e.6,23,25)) :op5 (e2 / enzyme :name (n9 / name :op1 "ceruloplasmin"~e.27)) :op6 (p8 / protein :name (n10 / name :op1 "fibrinogen"~e.29))) :manner~e.31 (p / predominant~e.31)) # ::id bel_pmid_2494_9077.41642 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mRNA expression of Foxp3 and RORyt in the spleen was very low in the normal control group but significantly higher in the model control group ( P < 0.05 ) . # ::alignments 1-1.1.1.1.1.1 2-1.1.1 4-1.1.1.1.2.1.1.1.1 5-1.1.1.1.2.1 6-1.1.1.1.2.1.2.1.1 7-1.1.1.2.r 9-1.1.1.2 11-1.1.2 12-1.1 13-1.1.3.r 15-1.1.3.1.1 16-1.1.3.1 17-1.1.3 18-1 19-1.2.3 20-1.2 20-1.2.2 20-1.2.2.r 21-1.2.4.r 23-1.2.4.1.1 24-1.2.4.1 25-1.2.4 27-1.3 28-1.3.1 29-1.3.1.1 (c / contrast-01~e.18 :ARG1 (l / low-04~e.12 :ARG1 (e / express-03~e.2 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.1) :ARG0-of (e2 / encode-01 :ARG1 (a / and~e.5 :op1 (p / protein :name (n2 / name :op1 "Foxp3"~e.4)) :op2 (p2 / protein :name (n3 / name :op1 "RORyt"~e.6))))) :ARG3~e.7 (s / spleen~e.9)) :degree (v / very~e.11) :location~e.13 (g / group~e.17 :mod (c2 / control-01~e.16 :ARG1-of (n4 / normal-02~e.15)))) :ARG2 (h / high-02~e.20 :ARG1 e :degree~e.20 (m / more~e.20) :ARG1-of (s2 / significant-02~e.19) :location~e.21 (g2 / group~e.25 :mod (c3 / control-01~e.24 :mod (m2 / model~e.23)))) :ARG1-of (s3 / statistical-test-91~e.27 :ARG2 (l2 / less-than~e.28 :op1 0.05~e.29))) # ::id bel_pmid_2494_9077.41646 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SOCS3 protein expression was significantly downregulated in all groups except for the normal control group ( P < 0.05 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1 2-1.1 4-1.2 5-1 6-1.3.r 7-1.3.1 8-1.3 9-1.3.2 10-1.3.2.1.r 12-1.3.2.1.1.1 13-1.3.2.1.1 14-1.3.2.1 16-1.4 17-1.4.1 18-1.4.1.1 (d / downregulate-01~e.5 :ARG1 (e / express-03~e.2 :ARG2 (p / protein~e.1 :name (n / name :op1 "SOCS3"~e.0))) :ARG1-of (s / significant-02~e.4) :location~e.6 (g / group~e.8 :mod (a / all~e.7) :ARG2-of (e2 / except-01~e.9 :ARG1~e.10 (g2 / group~e.14 :mod (c / control-01~e.13 :ARG1-of (n2 / normal-02~e.12))))) :ARG1-of (s2 / statistical-test-91~e.16 :ARG2 (l / less-than~e.17 :op1 0.05~e.18))) # ::id bel_pmid_2494_9077.41648 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Jak2 and STAT3 protein expression was significantly higher in the model control group than in all other groups ( P < 0.05 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1.1.2 4-1.1 6-1.3 7-1 7-1.2 7-1.2.r 8-1.4.r 10-1.4.1.1 11-1.4.1 12-1.4 13-1.5.r 15-1.5.1 16-1.5.2 17-1.5 19-1.6 20-1.6.1 21-1.6.1.1 (h2 / high-02~e.7 :ARG1 (e / express-03~e.4 :ARG2 (a / and~e.1 :op1 (e2 / enzyme :name (n / name :op1 "Jak2"~e.0)) :op2 (p2 / protein~e.3 :name (n2 / name :op1 "STAT3"~e.2)))) :degree~e.7 (m / more~e.7) :ARG1-of (s / significant-02~e.6) :location~e.8 (g / group~e.12 :mod (c / control-01~e.11 :mod (m3 / model~e.10))) :compared-to~e.13 (g2 / group~e.17 :mod (a2 / all~e.15) :mod (o / other~e.16)) :ARG1-of (s2 / statistical-test-91~e.19 :ARG2 (l / less-than~e.20 :op1 0.05~e.21))) # ::id bel_pmid_2506_3873.41328 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Blocking STAT3 activation with the small molecule inhibitor JSI @-@ 124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs . # ::alignments 0-1.1 1-1.1.1.1.1.1 2-1.1.1 3-1.1.2.r 5-1.1.2 6-1.1.2 7-1.1.2.2 8-1.1.2.1.1 10-1.1.2.1.1 11-1.3 12-1 14-1.2.1 15-1.2.1.2.r 16-1.2.1.2.1.1 17-1.2 18-1.2.2.1.1.1 19-1.2.2 20-1.2.2.2.r 21-1.2.2.2.1.1 (i2 / inhibit-01~e.12 :ARG0 (b / block-01~e.0 :ARG1 (a / activate-01~e.2 :ARG1 (p / protein :name (n / name :op1 "STAT3"~e.1))) :ARG3~e.3 (s / small-molecule~e.5,6 :name (n2 / name :op1 "JSI-124"~e.8,10) :ARG0-of (i / inhibit-01~e.7))) :ARG1 (a2 / and~e.17 :op1 (a3 / accumulate-01~e.14 :ARG0 c :ARG1~e.15 (e / enzyme :name (n3 / name :op1 "NIK"~e.16))) :op2 (e2 / express-03~e.19 :ARG2 (e3 / enzyme :name (n4 / name :op1 "IDO"~e.18)) :ARG3~e.20 (c / cell :name (n5 / name :op1 "MDSC"~e.21)))) :ARG1-of (s2 / significant-02~e.11)) # ::id bel_pmid_2506_3873.41330 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Knockdown of NIK in MDSCs suppressed IDO expression but not STAT3 activation . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.2.r 4-1.1.1.2.1.1 5-1.1 5-1.2 6-1.1.2.1.1.1 7-1.1.2 8-1 9-1.2.1 9-1.2.1.r 10-1.2.3.1.1.1 11-1.2.3 (c / contrast-01~e.8 :ARG1 (s / suppress-01~e.5 :ARG0 (k / knock-down-02~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "NIK"~e.2)) :location~e.3 (c2 / cell :name (n2 / name :op1 "MDSC"~e.4))) :ARG1 (e2 / express-03~e.7 :ARG2 (e3 / enzyme :name (n3 / name :op1 "IDO"~e.6)))) :ARG2 (s2 / suppress-01~e.5 :polarity~e.9 -~e.9 :ARG0 k :ARG1 (a / activate-01~e.11 :ARG1 (p / protein :name (n4 / name :op1 "STAT3"~e.10))))) # ::id bel_pmid_2506_3873.41332 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RelB @-@ p52 dimers were found to directly bind to the IDO promoter , leading to IDO expression in MDSCs . # ::alignments 0-1.1.1.2.1.1 2-1.1.1.1.1.1 3-1.1.1 5-1 7-1.1.3 8-1.1 9-1.1.2.r 11-1.1.2.1.1.1.1 12-1.1.2 12-1.1.2.1 12-1.1.2.1.r 14-1.1.4 15-1.1.4.1.r 16-1.1.4.1.1 17-1.1.4.1 18-1.1.4.1.2.r 19-1.1.4.1.2.1.1 (f / find-01~e.5 :ARG1 (b / bind-01~e.8 :ARG1 (d2 / dimer~e.3 :part (p3 / protein :name (n / name :op1 "p52"~e.2)) :part (p / protein :name (n2 / name :op1 "RelB"~e.0))) :ARG2~e.9 (m / molecular-physical-entity~e.12 :ARG0-of~e.12 (p2 / promote-01~e.12 :ARG1 (e / enzyme :name (n3 / name :op1 "IDO"~e.11)))) :ARG1-of (d / direct-02~e.7) :ARG0-of (l / lead-03~e.14 :ARG2~e.15 (e2 / express-03~e.17 :ARG2 e~e.16 :ARG3~e.18 (c / cell :name (n4 / name :op1 "MDSC"~e.19)))))) # ::id bel_pmid_2506_3873.41334 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAT3 activation @-@ induced IDO expression is independent of direct binding of STAT3 to the promoter region of IDO gene . # ::alignments 0-1.2.2.1.1.1.1 1-1.2.2.1 3-1.2.2 4-1.2.1.1.1 5-1.2 7-1 7-1.1 7-1.1.r 8-1.3.r 9-1.3.3 10-1.3 11-1.3.1.r 12-1.3.1 13-1.3.2.r 15-1.3.2.1 16-1.3.2 17-1.3.2.2.r 18-1.3.2.2.1.1 19-1.3.2.2 (d / depend-01~e.7 :polarity~e.7 -~e.7 :ARG0 (e / express-03~e.5 :ARG2 (e2 / enzyme :name (n / name :op1 "IDO"~e.4)) :ARG2-of (i / induce-01~e.3 :ARG0 (a / activate-01~e.1 :ARG1 (p / protein :name (n2 / name :op1 "STAT3"~e.0))))) :ARG1~e.8 (b / bind-01~e.10 :ARG1~e.11 p~e.12 :ARG2~e.13 (r / region~e.16 :ARG0-of (p2 / promote-01~e.15) :part-of~e.17 (g / gene~e.19 :ARG0-of (e3 / encode-01 :ARG1 e2~e.18))) :ARG1-of (d2 / direct-02~e.9))) # ::id bel_pmid_2506_3873.41344 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Blocking STAT3 activation by JSI @-@ 124 dramatically decreased the levels of p52 and RelB in nuclei ( Fig . 2C , p < 0.05 ) . # ::alignments 0-1.1 1-1.1.1.1.1.1 2-1.1.1 3-1.1.2.r 4-1.1.2.1.1 6-1.1.2.1.1 7-1.3 8-1 10-1.2 11-1.2.1.r 12-1.2.1.1.1.1 13-1.2.1 14-1.2.1.2.1.1 15-1.4.r 16-1.4 18-1.5.1 20-1.5.1.1 22-1.6 23-1.6.1 24-1.6.1.1 (d / decrease-01~e.8 :ARG0 (b / block-01~e.0 :ARG1 (a / activate-01~e.2 :ARG1 (p / protein :name (n / name :op1 "STAT3"~e.1))) :ARG3~e.3 (s / small-molecule :name (n2 / name :op1 "JSI-124"~e.4,6))) :ARG1 (l / level~e.10 :quant-of~e.11 (a2 / and~e.13 :op1 (p2 / protein :name (n3 / name :op1 "p52"~e.12)) :op2 (p3 / protein :name (n4 / name :op1 "RelB"~e.14)))) :degree (d2 / dramatic~e.7) :location~e.15 (n5 / nucleus~e.16) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.18 :mod "2C"~e.20)) :ARG1-of (s2 / statistical-test-91~e.22 :ARG2 (l2 / less-than~e.23 :op1 0.05~e.24))) # ::id bel_pmid_2506_3873.41346 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The level of STAT3 phosphorylation in MDSCs was reduced at 30 min and completely suppressed at 4 h after treatment with JSI @-@ 124 . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1 8-1.1 9-1.1.2.r 10-1.1.2.2.1 11-1.1.2.2.2 12-1 13-1.2.2 14-1.2 16-1.2.3.2.1 17-1.2.3.2.2 18-1.1.2 18-1.2.3 19-1.1.2.1 20-1.1.2.1.1.r 21-1.1.2.1.1.1.1 23-1.1.2.1.1.1.1 (a / and~e.12 :op1 (r / reduce-01~e.8 :ARG1 (l / level~e.1 :degree-of~e.2 (p / phosphorylate-01~e.4 :ARG1 (p2 / protein :name (n / name :op1 "STAT3"~e.3))) :location~e.5 (c / cell :name (n2 / name :op1 "MDSC"~e.6))) :time~e.9 (a2 / after~e.18 :op1 (t / treat-04~e.19 :ARG2~e.20 (s / small-molecule :name (n3 / name :op1 "JSI-124"~e.21,23))) :quant (t2 / temporal-quantity :quant 30~e.10 :unit (m / minute~e.11)))) :op2 (s2 / suppress-01~e.14 :ARG1 l :ARG1-of (c2 / complete-02~e.13) :time (a3 / after~e.18 :op1 t :quant (t3 / temporal-quantity :quant 4~e.16 :unit (h / hour~e.17))))) # ::id bel_pmid_2506_3873.41348 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistently , the level of NIK in MDSCs started to decline at 1 h and was completely blocked at 8 h after JSI @-@ 124 treatment . # ::alignments 0-1.3 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.2.r 7-1.1.1.2.1.1 8-1.1 10-1.1.2 11-1.1.3.r 12-1.1.3.2.1 13-1.1.3.2.2 14-1 16-1.2.2 17-1.2 19-1.2.3.2.1 20-1.2.3.2.2 21-1.1.3 21-1.2.3 22-1.1.3.1.1.1.1 24-1.1.3.1.1.1.1 25-1.1.3.1 (a / and~e.14 :op1 (s / start-01~e.8 :ARG0 (l / level~e.3 :quant-of~e.4 (e / enzyme :name (n / name :op1 "NIK"~e.5)) :location~e.6 (c / cell :name (n2 / name :op1 "MDSC"~e.7))) :ARG1 (d / decline-01~e.10 :ARG1 l) :time~e.11 (a2 / after~e.21 :op1 (t / treat-04~e.25 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "JSI-124"~e.22,24))) :quant (t2 / temporal-quantity :quant 1~e.12 :unit (h / hour~e.13)))) :op2 (b / block-01~e.17 :ARG1 l :ARG1-of (c2 / complete-02~e.16) :time (a3 / after~e.21 :op1 t :quant (t3 / temporal-quantity :quant 8~e.19 :unit h~e.20))) :manner (c3 / consistent-02~e.0)) # ::id bel_pmid_2506_3873.41350 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The level of IDO significantly decreased at 4 h after JSI @-@ 124 treatment ( Fig . 3A ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.2 5-1 6-1.3.r 7-1.3.2.1 8-1.3.2.2 9-1.3 10-1.3.1.1.1.1 12-1.3.1.1.1.1 13-1.3.1 15-1.4.1 17-1.4.1.1 (d / decrease-01~e.5 :ARG1 (l / level~e.1 :quant-of~e.2 (e / enzyme :name (n / name :op1 "IDO"~e.3))) :ARG2 (s / significant-02~e.4) :time~e.6 (a / after~e.9 :op1 (t / treat-04~e.13 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "JSI-124"~e.10,12))) :quant (t2 / temporal-quantity :quant 4~e.7 :unit (h / hour~e.8))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.15 :mod "3A"~e.17))) # ::id bel_pmid_2506_3873.41352 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In NIK knockdown MDSCs , the level of IDO protein was reduced significantly , but the level of pSTAT3 protein was not affected ( Fig . 3B , 3C ) . # ::alignments 1-1.3.2.1.1.1 2-1.3.2 3-1.3.1.1 6-1.1.1 6-1.2.2 7-1.1.1.1.r 8-1.1.1.1.1.1 9-1.2.2.1 11-1.1 12-1.1.2 14-1 16-1.2.2 19-1.2.2.1 21-1.2.1 21-1.2.1.r 22-1.2 24-1.4.1.1 24-1.4.1.2 26-1.4.1.1.1 28-1.4.1.2.1 (c / contrast-01~e.14 :ARG1 (r / reduce-01~e.11 :ARG1 (l / level~e.6 :quant-of~e.7 (e2 / enzyme :name (n3 / name :op1 "IDO"~e.8))) :ARG2 (s / significant-02~e.12)) :ARG2 (a / affect-01~e.22 :polarity~e.21 -~e.21 :ARG1 (l2 / level~e.6,16 :quant-of (p2 / protein~e.9,19 :name (n4 / name :op1 "STAT3")))) :location (c2 / cell :name (n / name :op1 "MDSC"~e.3) :mod (k / knock-down-02~e.2 :ARG1 (e / enzyme :name (n2 / name :op1 "NIK"~e.1)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.24 :mod "3B"~e.26) :op2 (f2 / figure~e.24 :mod "3C"~e.28)))) # ::id bel_pmid_2506_3873.41354 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , both IDO and NIK expression were reduced by JSI @-@ 124 treatment in MDSCs ( Fig . 3A ) . # ::alignments 1-1 4-1.1.2.1.1.1.1 5-1.1.2 6-1.1.2.2.1.1.1 7-1.1.2.1 7-1.1.2.2 9-1.1 10-1.1.1.r 11-1.1.1.1.1.1 13-1.1.1.1.1.1 14-1.1.1 15-1.1.2.1.2.r 16-1.1.2.1.2.1.1 18-1.2.1 20-1.2.1.1 (c / contrast-01~e.1 :ARG2 (r / reduce-01~e.9 :ARG0~e.10 (t / treat-04~e.14 :ARG2 (s / small-molecule :name (n3 / name :op1 "JSI-124"~e.11,13))) :ARG1 (a / and~e.5 :op1 (e / express-03~e.7 :ARG2 (e4 / enzyme :name (n / name :op1 "IDO"~e.4)) :ARG3~e.15 (c2 / cell :name (n4 / name :op1 "MDSC"~e.16))) :op2 (e2 / express-03~e.7 :ARG2 (e3 / enzyme :name (n2 / name :op1 "NIK"~e.6)) :ARG3 c2))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "3A"~e.20))) # ::id bel_pmid_2506_3873.41356 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RelB @/@ p52 dimers directly bind to the IDO promoter to regulate IDO expression in MDSCs . # ::alignments 0-1.1.2.1.1 2-1.1.1.1.1 3-1.1 4-1.3 5-1 6-1.2.r 8-1.2.1.1.1.1 9-1.2 9-1.2.1 9-1.2.1.r 11-1.4 12-1.4.2.1 13-1.4.2 14-1.4.2.2.r 15-1.4.2.2.1.1 (b / bind-01~e.5 :ARG1 (d3 / dimer~e.3 :part (p4 / protein :name (n / name :op1 "p52"~e.2)) :part (p / protein :name (n2 / name :op1 "RelB"~e.0))) :ARG2~e.6 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (p2 / promote-01~e.9 :ARG1 (e2 / enzyme :name (n3 / name :op1 "IDO"~e.8)))) :ARG1-of (d / direct-02~e.4) :purpose (r / regulate-01~e.11 :ARG0 d3 :ARG1 (e / express-03~e.13 :ARG2 e2~e.12 :ARG3~e.14 (c / cell :name (n4 / name :op1 "MDSC"~e.15))))) # ::id bel_pmid_2506_3873.41366 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We isolated CD11b+ MDSCs from the spleen of JSI @-@ 124 @-@ treated mice and found decreased expression of p @-@ STAT3 , NIK , and IDO protein in CD11b+ MDSCs compared with those isolated from the controls ( Fig . 6D ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.2.1.1 3-1.1.2.1.1 3-1.2.2.4.2.1.1 4-1.1.3.r 6-1.1.3 7-1.1.3.1.r 8-1.1.3.1.1.1.1.1 10-1.1.3.1.1.1.1.1 12-1.1.3.1.1 13-1.1.3.1 14-1 15-1.2 16-1.2.2.3 17-1.2.2 17-1.2.2.4 18-1.2.2.1.r 19-1.2.2.1.1.2 21-1.2.2.1.1.1.1 23-1.2.2.1.2.1.1 25-1.2.2.1 26-1.2.2.1.3.1.1 27-1.1.2.2 27-1.2.2.1.1 28-1.2.2.2.r 29-1.2.2.2 30-1.2.2.2 31-1.2.2.4.r 34-1.2.2.4.2.3 35-1.2.2.4.2.3.1.r 37-1.2.2.4.2.3.1 39-1.3.1 41-1.3.1.1 (a / and~e.14 :op1 (i / isolate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / cell :name (n / name :op1 "MDSC"~e.3) :mod (p / protein~e.27 :name (n2 / name :op1 "CD11b+"~e.2))) :ARG2~e.4 (s / spleen~e.6 :poss~e.7 (m / mouse~e.13 :ARG1-of (t / treat-04~e.12 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "JSI-124"~e.8,10)))))) :op2 (f / find-01~e.15 :ARG0 w :ARG1 (e / express-03~e.17 :ARG2~e.18 (a2 / and~e.25 :op1 (p2 / protein~e.27 :name (n4 / name :op1 "STAT3"~e.21) :ARG3-of (p3 / phosphorylate-01~e.19)) :op2 (e3 / enzyme :name (n5 / name :op1 "NIK"~e.23)) :op3 (e4 / enzyme :name (n6 / name :op1 "IDO"~e.26))) :ARG3~e.28 c~e.29,30 :ARG1-of (d / decrease-01~e.16) :compared-to~e.31 (e2 / express-03~e.17 :ARG2 a2 :ARG3 (c2 / cell :name (n7 / name :op1 "MDSC"~e.3) :mod p :ARG1-of (i2 / isolate-01~e.34 :ARG2~e.35 (c3 / control~e.37)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.39 :mod "6D"~e.41))) # ::id bel_pmid_2506_3873.41374 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , a specific IL @-@ 6 @-@ neutralizing Ab significantly decreased the levels of p @-@ STAT3 , NIK , and IDO in MDSCs ( Fig . 7E , p < 0.05 ) . # ::alignments 0-1 3-1.1.1.2 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 8-1.1.1.1 10-1.1.3 11-1.1 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.2 19-1.1.2.1.2.1.1 21-1.1.2.1 22-1.1.2.1.3.1.1 23-1.1.4.r 24-1.1.4.1.1 26-1.2.1 28-1.2.1.1 30-1.1.2.1.1.2 30-1.1.5 31-1.1.5.1 32-1.1.5.1.1 (a / and~e.0 :op2 (d / decrease-01~e.11 :ARG0 (a2 / antibody :ARG0-of (n / neutralize-01~e.8 :ARG1 (p / protein :name (n2 / name :op1 "IL-6"~e.4,6))) :ARG1-of (s2 / specific-02~e.3)) :ARG1 (l / level~e.13 :quant-of~e.14 (a3 / and~e.21 :op1 (p2 / protein :name (n3 / name :op1 "STAT-3") :ARG3-of (p3 / phosphorylate-01~e.15,30)) :op2 (e / enzyme :name (n4 / name :op1 "NIK"~e.19)) :op3 (e2 / enzyme :name (n5 / name :op1 "IDO"~e.22)))) :ARG2 (s / significant-02~e.10) :location~e.23 (c / cell :name (n6 / name :op1 "MDSC"~e.24)) :ARG1-of (s3 / statistical-test-91~e.30 :ARG2 (l2 / less-than~e.31 :op1 0.05~e.32))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26 :mod "7E"~e.28))) # ::id bel_pmid_778_0739.6222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mitogen @-@ activated protein ( MAP ) kinase is central to a signal transduction pathway that triggers cell proliferation or differentiation . Activation of the p42 mapk isoform requires its phosphorylation at two residues , Thr 183 and Tyr 185 , and this phosphorylation is catalysed by MAP kinase kinase ( MAPKK ) . # ::alignments 0-1.1.2.1.1 2-1.1.2.1.1 3-1.1.2.1.2 7-1.1.2.1.3 8-1.1.2.r 9-1.1 10-1.1.1.r 12-1.1.1.2.1 13-1.1.1.2 14-1.1.1 16-1.1.1.1 17-1.1.1.1.1.1.1 18-1.1.1.1.1.1 19-1.1.1.1.1 20-1.1.1.1.1.2 22-1.2.1 23-1.2.1.1.r 25-1.2.1.1.1.1 26-1.2.1.1.1.2 27-1.2.1.1.2 27-1.2.2.1.2 28-1.2 30-1.2.2 32-1.2.2.1.1 33-1.2.2.1 36-1.2.2.1.3.1 38-1.2.2.1.4.2.1 39-1.2.2.1.4.1 43-1.2.2 47-1.2.2.2.1.1.1 48-1.2.2.2.1.1.2 49-1.2.2.2.1.1.3 (m / multi-sentence :snt1 (c / central~e.9 :purpose~e.10 (p2 / pathway~e.14 :ARG0-of (t2 / trigger-01~e.16 :ARG1 (o / or~e.19 :op1 (p / proliferate-01~e.18 :ARG0 (c2 / cell~e.17)) :op2 (d / differentiate-01~e.20 :ARG1 c2))) :ARG2-of (t / transduce-01~e.13 :ARG1 (s / signal-07~e.12))) :domain~e.8 (e4 / enzyme :name (n / name :op1 "Mitogen-activated"~e.0,2 :op2 "protein"~e.3 :op3 "kinase"~e.7))) :snt2 (r / require-01~e.28 :ARG0 (a2 / activate-01~e.22 :ARG0~e.23 (e3 / enzyme :name (n7 / name :op1 "p42"~e.25 :op2 "MAPK"~e.26) :mod (i2 / isoform~e.27))) :ARG1 (p4 / phosphorylate-01~e.30,43 :ARG1 (r2 / residue~e.33 :quant 2~e.32 :part-of (i / isoform~e.27) :mod (a4 / amino-acid :mod 183~e.36 :name (n4 / name :op1 "threonine")) :mod (a5 / amino-acid :mod 185~e.39 :name (n5 / name :op1 "tyrosine"~e.38))) :ARG1-of (c3 / catalyze-01 :ARG0 (e / enzyme :name (n2 / name :op1 "MAP"~e.47 :op2 "kinase"~e.48 :op3 "kinase"~e.49)))))) # ::id bel_pmid_812_5955.5778 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stable transfection of activated Ha @-@ ras into a number of murine cells correlated with a down @-@ regulation of the expression of the NF1 genes NF1 @/@ CTF and NF1/X . # ::alignments 0-1.1.3 1-1.1 2-1.1.2.r 3-1.1.2.2 4-1.1.2.1.1 6-1.1.2.1.1 7-1.1.1.r 9-1.1.1.1 10-1.1.1.1.r 11-1.1.1.2 12-1.1.1 13-1 14-1.2.r 16-1.2 17-1.2 18-1.2 19-1.2.1.r 21-1.2.1 22-1.2.1.1.r 24-1.2.1.1.1.1.1 25-1.2.1.1.1 25-1.2.1.1.2 26-1.2.1.1.1.1.1 28-1.2.1.1.1.1.1 29-1.2.1.1 30-1.2.1.1.2.1.1 (c / correlate-01~e.13 :ARG1 (t / transfect-01~e.1 :ARG1~e.7 (c2 / cell~e.12 :quant~e.10 (n4 / number~e.9) :mod (m / murine~e.11)) :ARG2~e.2 (e2 / enzyme :name (n3 / name :op1 "Ha-ras"~e.4,6) :ARG1-of (a2 / activate-01~e.3)) :ARG1-of (s / stable-03~e.0)) :ARG2~e.14 (d / downregulate-01~e.16,17,18 :ARG1~e.19 (e / express-03~e.21 :ARG1~e.22 (a / and~e.29 :op1 (g / gene~e.25 :name (n / name :op1 "NF1/CTF"~e.24,26,28)) :op2 (g2 / gene~e.25 :name (n2 / name :op1 "NF1/X"~e.30)))))) # ::id bel_pmid_812_5955.9008 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The level of the DNA binding activity of the NF1 proteins was also reduced in Ha @-@ v @-@ ras @-@ transformed cells , and the expression of a gene that depends on this family of transcription factors was specifically repressed . # ::alignments 1-1.1.1 2-1.1.1.1.r 4-1.1.1.1.2.2.2.1 5-1.1.1.1.2 6-1.1.1.1 7-1.1.1.1.1.r 9-1.1.1.1.1.1.1 10-1.1.1.1.1 12-1.1.3 13-1.1 14-1.1.2.r 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 19-1.1.2.1.1.1.1 21-1.1.2.1 22-1.1.2 24-1 26-1.2.1 27-1.2.1.1.r 29-1.2.1.1 31-1.2.1.1.1 34-1.2.1.1.1.1 35-1.2.1.1.1.1.1.r 36-1.2.1.1.1.1.1.1 37-1.2.1.1.1.1.1 39-1.2.2 40-1.2 (a / and~e.24 :op1 (r / reduce-01~e.13 :ARG1 (l / level~e.1 :degree-of~e.2 (a3 / activity-06~e.6 :ARG0~e.7 (p / protein~e.10 :name (n / name :op1 "NF1"~e.9)) :ARG1 (b / bind-01~e.5 :ARG0 p :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.4))))) :location~e.14 (c / cell~e.22 :ARG2-of (t / transform-01~e.21 :ARG0 (g / gene :name (n2 / name :op1 "Ha-v-ras"~e.15,17,19)))) :mod (a2 / also~e.12)) :op2 (r2 / repress-01~e.40 :ARG1 (e / express-03~e.26 :ARG1~e.27 (g2 / gene~e.29 :ARG0-of (d2 / depend-01~e.31 :ARG1 (f / family~e.34 :consist-of~e.35 (f2 / factor~e.37 :ARG0-of (t3 / transcribe-01~e.36)) :mod p)))) :ARG1-of (s / specific-02~e.39))) # ::id bel_pmid_822_6933.9532 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK1 and MEK2 can also be activated by autophosphorylation . Autophosphorylation of MEKs correlates with their ability to phosphorylate and activate ERKs . # ::alignments 0-1.1.1.2.1.1.1 2-1.1.1.2.2.1.1 3-1.1 4-1.1.1.3 6-1.1.1 8-1.1.1.1 10-1.2.1 13-1.2 14-1.2.2.r 15-1.2.2.1 15-1.2.2.1.r 16-1.2.2 18-1.1.1.1 18-1.2.2.2.1 20-1.1.1 20-1.2.2.2.2 (m / multi-sentence :snt1 (p / possible-01~e.3 :ARG1 (a / activate-01~e.6,20 :ARG0 (p2 / phosphorylate-01~e.8,18 :ARG1 a2 :ARG2 a2) :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.0)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.2))) :mod (a5 / also~e.4))) :snt2 (c / correlate-01~e.13 :ARG1 (p3 / phosphorylate-01~e.10 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK")) :ARG2 e3) :ARG2~e.14 (c2 / capable-01~e.16 :ARG1~e.15 e3~e.15 :ARG2 (a3 / and :op1 (p4 / phosphorylate-01~e.18 :ARG2 (p5 / protein-family :name (n4 / name :op1 "ERK"))) :op2 (a4 / activate-01~e.20 :ARG1 p5))))) # ::id bel_pmid_854_8291.16558 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The two SAPK isoforms are 46 and 54 kDa . A 46 kDa kinase activity was induced in response to anisomycin but not in response to TPA . # ::alignments 1-1.1.3.1 2-1.1.1.1.1.1 3-1.1.1 3-1.1.2 3-1.1.3 4-1.1.3.r 5-1.1.1.2.1 6-1.1 7-1.1.2.2.1 8-1.1.1.2.2 8-1.1.2.2.2 8-1.2.1.1.1.2 11-1.2.1.1.1.1 12-1.1.2.2.2 12-1.2.1.1.1.2 13-1.2.1.1 14-1.2.1 16-1.2 16-1.2.3.1 18-1.2.2 18-1.2.3.1.3 20-1.2.2.1.1.1 21-1.2.3 22-1.2.3.1.1 22-1.2.3.1.1.r 24-1.2.2 25-1.2.3.1.3.1.r 26-1.2.3.1.3.1.1.1 (m / multi-sentence :snt1 (a / and~e.6 :op1 (i4 / isoform~e.3 :mod (e3 / enzyme :name (n5 / name :op1 "SAPK"~e.2)) :quant (m2 / mass-quantity :quant 46~e.5 :unit (k / kilodalton~e.8))) :op2 (i5 / isoform~e.3 :mod e3 :quant (m3 / mass-quantity :quant 54~e.7 :unit (k3 / kilodalton~e.8,12))) :domain~e.4 (i3 / isoform~e.3 :quant 2~e.1 :mod e3)) :snt2 (i / induce-01~e.16 :ARG2 (a2 / activity-06~e.14 :ARG0 (k2 / kinase~e.13 :quant (m4 / mass-quantity :quant 46~e.11 :unit (k4 / kilodalton~e.8,12)))) :ARG2-of (r / respond-01~e.18,24 :ARG1 (s / small-molecule :name (n6 / name :op1 "anisomycin"~e.20))) :ARG1-of (c / contrast-01~e.21 :ARG2 (i2 / induce-01~e.16 :polarity~e.22 -~e.22 :ARG2 a2 :ARG2-of (r2 / respond-01~e.18 :ARG1~e.25 (s2 / small-molecule :name (n4 / name :op1 "TPA"~e.26))))))) # ::id bel_pmid_854_8291.16560 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In NIH3T3 cells , co @-@ transfection of an expression vector for Gal @-@ Elk mediates expression from a transfected GAL @-@ CAT reporter gene , which , as shown in Figure 6a , b, is potentiated upon treatment of serum @-@ starved cells with anisomycin . Replacement of the major SAPK phosphorylation site in Gal @-@ Elk , Ser383 , with alanine ( Gal @-@ Elks 383 A ) abrogates induction of reporter gene expression . # ::alignments 1-1.1.3.1.1 2-1.1.3 6-1.1.2.1.3 9-1.1.1.1.1 10-1.1.1.1 12-1.2.1.1.1.3.1.1 14-1.2.1.1.1.3.1.1 15-1.1 16-1.1.2 19-1.1.2.1.3 20-1.1.2.1.1.1 22-1.1.2.1.1.1 23-1.1.2.1.2 24-1.1.2.1 29-1.1.2.2.2 31-1.1.2.2.2.1.1 31-1.1.2.2.2.1.2 32-1.1.2.2.2.1.1.1 38-1.1.2.2.1 39-1.1.2.2.1.1.r 40-1.1.2.2.1.1.1.1 42-1.1.2.2.1.1.1 43-1.1.2.2.1.1 44-1.1.2.2.1.2.r 45-1.1.2.2.1.2.1.1 47-1.2.1 50-1.2.1.1.2 51-1.2.1.1.1.4.1.1.1 52-1.2.1.1.1 52-1.2.1.1.1.4 52-1.2.1.1.1.4.r 53-1.2.1.1 54-1.2.1.2.r 55-1.2.1.2.3 56-1.2.1.2.3 57-1.2.1.2.3 62-1.2.1.2.2.1 64-1.1.1.1.1.1.1.1 67-1.2.1.1.1.1 67-1.2.1.2.1 70-1.2 71-1.2.2 72-1.2.2.2.r 73-1.2.2.2.1.1 74-1.2.2.2.1 75-1.2.2.2 (m2 / multi-sentence :snt1 (m / mediate-01~e.15 :ARG0 (c2 / cotransfect-01 :ARG2 (v / vector~e.10 :ARG1-of (e / express-03~e.9 :ARG2 (p / protein :name (n2 / name :op1 "Gal-Elk"~e.64))))) :ARG1 (e2 / express-03~e.16 :ARG1 (g / gene~e.24 :name (n3 / name :op1 "GAL-CAT"~e.20,22) :ARG0-of (r / report-01~e.23) :ARG2-of (t / transfect-01~e.6,19)) :ARG1-of (p2 / potentiate-01 :ARG2 (t2 / treat-04~e.38 :ARG1~e.39 (c3 / cell~e.43 :ARG1-of (s / starve-01~e.42 :ARG2 (s2 / serum~e.40))) :ARG2~e.44 (s4 / small-molecule :name (n7 / name :op1 "anisomycin"~e.45))) :ARG1-of (s3 / show-01~e.29 :ARG0 (a2 / and :op1 (f / figure~e.31 :mod "6a"~e.32) :op2 (f2 / figure~e.31 :mod "6b"))))) :location (c / cell-line~e.2 :name (n / name :op1 "NIH3T3"~e.1))) :snt2 (a3 / abrogate-01~e.70 :ARG0 (r2 / replace-01~e.47 :ARG1 (p5 / protein-segment~e.53 :mod (a / amino-acid~e.52 :mod 383~e.67 :name (n5 / name :op1 "serine") :part-of (p4 / protein :name (n6 / name :op1 "Gal-Elk"~e.12,14)) :ARG1-of~e.52 (p3 / phosphorylate-01~e.52 :ARG2 (e4 / enzyme :name (n8 / name :op1 "SAPK"~e.51)))) :ARG1-of (m3 / major-02~e.50)) :ARG2~e.54 (a5 / amino-acid :mod 383~e.67 :name (n4 / name :op1 "alanine"~e.62) :part-of p4~e.55,56,57)) :ARG1 (i / induce-01~e.71 :ARG0 r2 :ARG2~e.72 (e3 / express-03~e.75 :ARG1 (g2 / gene~e.74 :ARG0-of (r3 / report-01~e.73)))))) # ::id bel_pmid_854_8291.18250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Elk @-@ 1 is phosphorylated by both kinases ( MAPK8 and MAPK9 ) , each of which is strongly stimulated by pre @-@ treatment of cells with ultraviolet light . # ::alignments 0-1.1.1.1 2-1.1.1.1 4-1 5-1.2.r 6-1.2.4 7-1.2.1 7-1.2.2 9-1.2.1.1.1 10-1.2 11-1.2.2.1.1 18-1.2.3.2 19-1.2.3 23-1.2.3.1 24-1.2.3.1.1.r 25-1.2.3.1.1 26-1.2.3.1.2.r 27-1.2.3.1.2.1 28-1.2.3.1.2 (p / phosphorylate-01~e.4 :ARG1 (p2 / protein :name (n / name :op1 "Elk-1"~e.0,2)) :ARG2~e.5 (a / and~e.10 :op1 (k / kinase~e.7 :name (n2 / name :op1 "MAPK8"~e.9)) :op2 (k2 / kinase~e.7 :name (n3 / name :op1 "MAPK9"~e.11)) :ARG1-of (s / stimulate-01~e.19 :ARG0 (t / treat-04~e.23 :ARG1~e.24 (c / cell~e.25) :ARG2~e.26 (l / light~e.28 :mod (u / ultraviolet~e.27)) :time (b / before)) :ARG1-of (s2 / strong-02~e.18)) :mod (b2 / both~e.6))) # ::id bel_pmid_854_8291.21982 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 3b shows that activated SAPKs isolated from cells stimulate the formation of a ternary complex by Elk @-@ 1 ( Fig . 3b , lanes 8 and 10 ) . # ::alignments 0-1.1 1-1.1.1 2-1 3-1.2.r 4-1.2.2 6-1.2.3 7-1.2.3.1.r 8-1.2.3.1 9-1.2 9-1.2.4 9-1.2.4.r 11-1.2.4.1 12-1.2.4.1.2.r 14-1.2.4.1.2.1 15-1.2.4.1.2 16-1.2.4.1.1.r 17-1.2.4.1.1.1.1 19-1.2.4.1.1.1.1 21-1.3.1.2 22-1.3.1.2 23-1.3.1.2 25-1.3.1 26-1.3.1.1.1.1 27-1.3.1.1.1 28-1.3.1.1.1.2 (s / show-01~e.2 :ARG0 (f / figure~e.0 :mod "3b"~e.1) :ARG1~e.3 (e / enzyme~e.9 :name (n / name :op1 "SAPK") :ARG1-of (a / activate-01~e.4) :ARG1-of (i / isolate-01~e.6 :ARG2~e.7 (c / cell~e.8)) :ARG0-of~e.9 (s2 / stimulate-01~e.9 :ARG1 (f2 / form-01~e.11 :ARG0~e.16 (p / protein :name (n2 / name :op1 "Elk-1"~e.17,19)) :ARG1~e.12 (c2 / complex~e.15 :mod (t / ternary~e.14))))) :ARG1-of (d / describe-01 :ARG0 (l / lane~e.25 :ARG1-of (l2 / label-01 :ARG2 (a2 / and~e.27 :op1 8~e.26 :op2 10~e.28)) :part-of f~e.21,22,23))) # ::id bel_pmid_854_8291.22000 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 6e , expression of MEKK1 fails to activate either ERK1 or ERK2 , whereas both p46 SAPK and p54SAPK are activated at expression levels that result in reporter gene expression . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 4-1.4.1.1 6-1.1 7-1.1.1.r 8-1.1.1.1.1 9-1 11-1.2 13-1.2.2.1.1.1 14-1.2.2 15-1.2.2.2.1.1 17-1.3 18-1.3.1.2.3 19-1.3.1.2.1.1.1 20-1.3.1.2.1.1.2 21-1.3.1.2 24-1.2 24-1.3.1 25-1.3.1.1.r 26-1.3.1.1.2 27-1.3.1.1 29-1.3.1.1.1 30-1.3.1.1.1.1.r 31-1.3.1.1.1.1.1.1 32-1.3.1.1.1.1.1 33-1.3.1.1.1.1 (f2 / fail-01~e.9 :ARG1 (e / express-03~e.6 :ARG2~e.7 (e2 / enzyme :name (n / name :op1 "MEKK1"~e.8))) :ARG2 (a / activate-01~e.11,24 :ARG0 e :ARG1 (o / or~e.14 :op1 (e3 / enzyme :name (n2 / name :op1 "ERK1"~e.13)) :op2 (e4 / enzyme :name (n3 / name :op1 "ERK2"~e.15)))) :ARG1-of (c / contrast-01~e.17 :ARG2 (a2 / activate-01~e.24 :ARG0~e.25 (l / level~e.27 :ARG1-of (r / result-01~e.29 :ARG2~e.30 (e8 / express-03~e.33 :ARG1 (g / gene~e.32 :ARG0-of (r2 / report-01~e.31)))) :degree-of e~e.26) :ARG1 (a3 / and~e.21 :op1 (e5 / enzyme :name (n4 / name :op1 "p46"~e.19 :op2 "SAPK"~e.20)) :op2 (e6 / enzyme :name (n5 / name :op1 "p54" :op2 "SAPK")) :mod (b / both~e.18)))) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "6e"~e.4))) # ::id bel_pmid_854_8291.29024 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Co @-@ transfection of 1.25 ug MEKK1 expression vector elicited a 24 @-@ fold activation of Gal @-@ Elk @-@ dependent reporter expression in serum @-@ starved NIH3T3 cells ( Fig . 6c , d ) . # ::alignments 3-1.2.3 4-1.1.1.1.1.2.1 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1 9-1 11-1.2.3.1 13-1.2.3 14-1.2 15-1.2.2.r 15-1.2.3 16-1.2.2.1.2.1.1.1 18-1.2.2.1.2.1.1.1 20-1.2.2.1.2 21-1.2.2.1 21-1.2.2.1.1 21-1.2.2.1.1.r 22-1.2.2 23-1.2.2.2.r 24-1.2.2.2.2.1 26-1.2.2.2.2 27-1.2.2.2.1.1 28-1.2.2.2 30-1.3.1.1 30-1.3.1.2 32-1.3.1.1.1 (e / elicit-01~e.9 :ARG0 (c / cotransfect-01 :ARG2 (v / vector~e.8 :ARG1-of (e2 / express-03~e.7 :ARG2 (e3 / enzyme :name (n / name :op1 "MEKK1"~e.6) :quant (m / mass-quantity :quant 1.25~e.4 :unit (m2 / microgram)))))) :ARG1 (a / activate-01~e.14 :ARG0 c :ARG1~e.15 (e4 / express-03~e.22 :ARG1 (g / gene~e.21 :ARG0-of~e.21 (r / report-01~e.21) :ARG0-of (d / depend-01~e.20 :ARG1 (p2 / protein :name (n2 / name :op1 "Gal-Elk"~e.16,18)))) :ARG3~e.23 (c2 / cell-line~e.28 :name (n3 / name :op1 "NIH3T3"~e.27) :ARG1-of (s / starve-01~e.26 :ARG2 (s2 / serum~e.24)))) :quant (p / product-of~e.3,13,15 :op1 24~e.11)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.30 :mod "6c"~e.32) :op2 (f2 / figure~e.30 :mod "6d")))) # ::id bel_pmid_854_8291.32900 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The observation that Elk @-@ 1 is phosphorylated directly and activated by p46SAPK and p54SAPK further implicates it in the stress @-@ response induction of the c @-@ fos gene . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1.1 5-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.3 9-1.1.1 9-1.1.1.1.2 10-1.1.1.2 11-1.1.1.1.2.r 12-1.1.1.1.2.1.1.1 14-1.1.1.1.2.2.1.1 15-1.4 16-1 17-1.2 18-1.3.r 20-1.3.2.1 22-1.3.2 23-1.3 24-1.3.1.r 26-1.3.1.1.1 28-1.3.1.1.1 29-1.3.1 (i / implicate-01~e.16 :ARG0 (o / observe-01~e.1 :ARG1~e.2 (a / and~e.9 :op1 (p / phosphorylate-01~e.7 :ARG1 (p2 / protein :name (n / name :op1 "Elk-1"~e.3,5)) :ARG2~e.11 (a3 / and~e.9 :op1 (e / enzyme :name (n2 / name :op1 "p46SAPK"~e.12)) :op2 (e2 / enzyme :name (n3 / name :op1 "p54SAPK"~e.14))) :ARG1-of (d / direct-02~e.8)) :op2 (a2 / activate-01~e.10 :ARG0 a3 :ARG1 p2))) :ARG1 p2~e.17 :ARG2~e.18 (i2 / induce-01~e.23 :ARG2~e.24 (g / gene~e.29 :name (n4 / name :op1 "c-fos"~e.26,28)) :ARG2-of (r / respond-01~e.22 :ARG1 (s / stress-02~e.20))) :degree (f / further~e.15)) # ::id bel_pmid_854_8291.36930 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For comparison , ElkC was also phosphorylated using recombinant ERK1 that had been activated by phosphorylation with a constitutively active mutant of the MAPK @/@ ERK kinase MKK1 [ 23 ] . # ::alignments 1-1.3 3-1.1.1.1 5-1.4 6-1 7-1.2 7-1.3.r 8-1.2.1 8-1.2.1.2 8-1.2.1.2.r 9-1.2.1.1.1 13-1.2.1.3 14-1.2.1.3.1.r 15-1.2.1.3.1 16-1.2.1.3.1.2.r 18-1.2.1.3.1.2.2.1 19-1.2.1.3.1.2 19-1.2.1.3.1.2.2 19-1.2.1.3.1.2.2.r 23-1.2.1.3.1.2.3.1.1.1 25-1.2.1.3.1.2.3.1.1.1 27-1.2.1.3.1.2.1.1 29-1.5.1.1.1 (p / phosphorylate-01~e.6 :ARG1 (p2 / protein :name (n / name :op1 "ElkC"~e.3)) :ARG2 (u / use-01~e.7 :ARG1 (e / enzyme~e.8 :name (n2 / name :op1 "ERK1"~e.9) :ARG0-of~e.8 (r / recombine-01~e.8) :ARG1-of (a2 / activate-01~e.13 :ARG0~e.14 (p3 / phosphorylate-01~e.15 :ARG1 e :ARG2~e.16 (e2 / enzyme~e.19 :name (n3 / name :op1 "MKK1"~e.27) :ARG0-of~e.19 (a3 / activity-06~e.19 :mod (c2 / constitutive~e.18)) :ARG1-of (i / include-91 :ARG2 (p5 / protein-family :name (n5 / name :op1 "MAPK/ERK"~e.23,25)))))))) :purpose~e.7 (c / compare-01~e.1) :mod (a / also~e.5) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 23~e.29)))) # ::id bel_pmid_859_8496.27892 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the case of Th2 @-@ type cytokines , enhanced production of IL @-@ 4 and IL @-@ 6 was reduced by treatment with anti @-@ TGF-/3 or anti @-@ IL @- IO ( Fig . 5B ) . # ::alignments 4-1.1.1.1.1 6-1.1.1.2 7-1.1.1 9-1.2.2 10-1.2 11-1.2.1.r 12-1.2.1.1.1.1 14-1.2.1.1.1.1 15-1.2.1 16-1.2.1.1.1.1 16-1.2.1.2.1.1 18-1.2.1.2.1.1 20-1 22-1.1 23-1.1.2.r 24-1.1.2.1.1 24-1.1.2.2.1 26-1.1.2.1.1.1.1.1 27-1.1.2 28-1.1.2.1.1 28-1.1.2.2.1 30-1.1.2.2.1.1.1.1 32-1.1.2.2.1.1.1.1 34-1.3.1 36-1.3.1.1 (r / reduce-01~e.20 :ARG0 (t / treat-04~e.22 :ARG1 (c4 / cytokine~e.7 :name (n4 / name :op1 "Th2"~e.4) :ARG1-of (t2 / type-03~e.6)) :ARG2~e.23 (o / or~e.27 :op1 (a2 / antibody :ARG0-of (c3 / counter-01~e.24,28 :ARG1 (p4 / protein :name (n3 / name :op1 "TGF-/3"~e.26)))) :op2 (a3 / antibody :ARG0-of (c / counter-01~e.24,28 :ARG1 (p7 / protein :name (n5 / name :op1 "IL-IO"~e.30,32)))))) :ARG1 (p / produce-01~e.10 :ARG1~e.11 (a / and~e.15 :op1 (p2 / protein :name (n / name :op1 "IL-4"~e.12,14,16)) :op2 (p3 / protein :name (n2 / name :op1 "IL-6"~e.16,18))) :ARG1-of (e / enhance-01~e.9)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "5B"~e.36))) # ::id bel_pmid_859_8496.31126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 5A , reduced production of Th I -@ type cytokines ( IFN @-@ y , not detected ; IL @-@ 2 , 38.0 -@ t 10.0 %) by EL4 @-@ T was significantly rcstored by treatmcnt with anti @-@ TGF @-@ P ( IFN @-@ y , 191.0 i 21.9 % ; IL @-@ 2 , 8 I . 1 i 17.5 %) , while anti @-@ IL @- IO treatment had little etfect # ::alignments 1-1.5 2-1.5.1.r 3-1.5.1 4-1.5.1.1 6-1.1.2 7-1.1 10-1.3.2.1.1.2.1.1.3 10-1.3.2.1.1.2.2.1.3 10-1.3.2.1.1.2.2.1.6 12-1.1.1.2 13-1.1.1 15-1.1.1.3.1.1.1 17-1.1.1.3.1.1.1 19-1.1.1.3.1.2.1 19-1.1.1.3.1.2.1.r 20-1.1.1.3.1.2 22-1.1.1.3.2.1.1 26-1.1.1.3.2.1.2 28-1.1.1.3.2.1.3 29-1.1.1.3.2.2.1 31-1.1.2.1.r 32-1.1.2.1.1.1 34-1.1.2.1.1.1 36-1.2 41-1.3.2.1 43-1.3.2.1.1.1.1 45-1.3.2.1.1.1.1 47-1.1.1.3.1.1.1 47-1.3.2.1.1.2.1.1.1 49-1.1.1.3.1.1.1 51-1.3.2.1.1.2.1.1.2 52-1.3.2.1.1.2.1.1.3 53-1.3.2.1.1.2.1.2.1 54-1.1.1.3.2.2 54-1.3.2.1.1.2.1.2 54-1.3.2.1.1.2.2.2 56-1.3.2.1.1.2.2.1.1 60-1.3.2.1.1.2.2.1.2 61-1.3.2.1.1.2.2.1.3 61-1.3.2.1.1.2.2.1.5 61-1.3.2.1.1.2.2.1.6 62-1.3.2.1.1.2.2.1.4 63-1.3.2.1.1.2.2.1.5 64-1.3.2.1.1.2.2.1.3 64-1.3.2.1.1.2.2.1.5 64-1.3.2.1.1.2.2.1.6 65-1.3.2.1.1.2.2.2.1 68-1.4 69-1.4.1.1.2.1 71-1.4.1.1.2.1.1.1.1 73-1.4.1.1.2.1.1.1.1 74-1.3 74-1.4.1.1 76-1.4.1.3 (r / restore-01 :ARG1 (p / produce-01~e.7 :ARG1 (c3 / cytokine~e.13 :name (n8 / name :op1 "Th1") :ARG1-of (t3 / type-03~e.12) :example (a / and :op1 (p2 / protein :name (n2 / name :op1 "IFN-y"~e.15,17,47,49) :ARG1-of (d / detect-01~e.20 :polarity~e.19 -~e.19)) :op2 (p6 / protein :name (n5 / name :op1 "IL-2,"~e.22 :op2 38.0~e.26 :op3 "-t"~e.28) :quant (p7 / percentage-entity~e.54 :value 10.0~e.29)))) :ARG1-of (r2 / reduce-01~e.6 :ARG0~e.31 (c2 / cell :name (n / name :op1 "EL4-T"~e.32,34)))) :ARG1-of (s2 / significant-02~e.36) :manner (t / treat-04~e.74 :ARG1 c2 :ARG2 (a4 / antibody :ARG0-of (c6 / counter-01~e.41 :ARG1 (p5 / protein :name (n4 / name :op1 "TGF-P"~e.43,45) :example (a3 / and :op1 (p8 / protein :name (n6 / name :op1 "IFN-y,"~e.47 :op2 191.0~e.51 :op3 "i"~e.10,52) :quant (p9 / percentage-entity~e.54 :value 21.9~e.53)) :op2 (p10 / protein :name (n7 / name :op1 "IL-2,"~e.56 :op2 8~e.60 :op3 "I"~e.10,61,64 :op4 "."~e.62 :op5 1~e.61,63,64 :op6 "i"~e.10,61,64) :quant (p11 / percentage-entity~e.54 :value 17.5~e.65))))))) :ARG1-of (c4 / contrast-01~e.68 :ARG2 (a2 / affect-01 :ARG0 (t2 / treat-04~e.74 :ARG1 c2 :ARG2 (a5 / antibody :ARG0-of (c5 / counter-01~e.69 :ARG1 (p4 / protein :name (n3 / name :op1 "IL-IO"~e.71,73))))) :ARG1 c2 :degree (l / little~e.76))) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "5A"~e.4))) # ::id bel_pmid_862_1729.21570 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar observation that immunoprecipitated B @-@ Raf from EGF @-@ stimulated Swiss3T3 cells could activate both MEK1 and MEK2 was also obtained ( data not shown ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.2 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 7-1.1.1.1.1.2.1.r 8-1.1.1.1.1.2.1.2.1.1.1 10-1.1.1.1.1.2.1.2 11-1.1.1.1.1.2.1.1.1 12-1.1.1.1.1.2.1 13-1.1.1 14-1.1.1.1 15-1.1.1.1.2.3 16-1.1.1.1.2.1.1.1 17-1.1.1.1.2 18-1.1.1.1.2.2.1.1 20-1.2 21-1 23-1.3.1 24-1.3.1.1.1 24-1.3.1.1.1.r 25-1.3.1.1 (o / obtain-01~e.21 :ARG1 (o2 / observe-01~e.1 :ARG1~e.2 (p / possible-01~e.13 :ARG1 (a / activate-01~e.14 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf"~e.4,6) :ARG1-of (i / immunoprecipitate-01~e.3 :ARG2~e.7 (c / cell-line~e.12 :name (n2 / name :op1 "Swiss3T3"~e.11) :ARG1-of (s / stimulate-01~e.10 :ARG0 (p2 / protein :name (n3 / name :op1 "EGF"~e.8)))))) :ARG1 (a2 / and~e.17 :op1 (e2 / enzyme :name (n4 / name :op1 "MEK1"~e.16)) :op2 (e3 / enzyme :name (n5 / name :op1 "MEK2"~e.18)) :mod (b / both~e.15)))) :ARG1-of (r / resemble-01~e.0)) :mod (a3 / also~e.20) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.23 :ARG1-of (s2 / show-01~e.25 :polarity~e.24 -~e.24)))) # ::id bel_pmid_862_1729.36932 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activated GST @-@ MEK1 was then used to activate the purified recombinant extracellular signal @-@ regulated kinase 1 , whose activity was measured by the [ 32P @-@ g]ATP incorporation into MBP , an extracellular signal @-@ regulated kinase 1 substrate . # ::alignments 1-1.1.2 1-1.2 2-1.1.1.1 4-1.1.1.1 6-1.3 7-1 9-1.1.2 9-1.2 11-1.2.2.3 12-1.2.2 12-1.2.2.2 12-1.2.2.2.r 13-1.2.2.1.1 14-1.2.2.1.2 16-1.2.2.1.2 17-1.2.2.1.3 18-1.2.2.1.4 21-1.2.2.4 23-1.2.2.4.1 27-1.2.2.4.1.1.1.2.1.1 30-1.2.2.4.1.1 31-1.2.2.4.1.1.2.r 32-1.2.2.4.1.1.2.1.1 35-1.2.2.1.1 36-1.2.2.1.2 38-1.2.2.1.2 39-1.2.2.1.3 40-1.2.2.1.4 41-1.2.2.4.1.1.2.2.1 (u / use-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "GST-MEK1"~e.2,4) :ARG1-of (a / activate-01~e.1,9)) :ARG2 (a2 / activate-01~e.1,9 :ARG0 e :ARG1 (e2 / enzyme~e.12 :name (n2 / name :op1 "extracellular"~e.13,35 :op2 "signal-regulated"~e.14,16,36,38 :op3 "kinase"~e.17,39 :op4 1~e.18,40) :ARG0-of~e.12 (r / recombine-01~e.12) :ARG1-of (p / purify-01~e.11) :ARG0-of (a3 / activity-06~e.21 :ARG1-of (m / measure-01~e.23 :manner (i / incorporate-02~e.30 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP") :part (p3 / phosphate :quant (m2 / molecular-mass :value 32~e.27) :mod (g / gamma))) :ARG2~e.31 (p2 / protein :name (n4 / name :op1 "MBP"~e.32) :ARG1-of (m4 / mean-01 :ARG2 (s2 / substrate~e.41 :poss e2)))))))) :time (t / then~e.6)) # ::id bel_pmid_862_1729.37176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok c @-@ Raf activates MEK1 by phosphorylating at serine residues 218 and 222 ( 30 @–@ 32 ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.3.1.3.2.1.1 6-1.3 8-1.3.1.3.1.1 9-1.3.1 10-1.3.1.1 11-1.3.1.3.3 12-1.3.1.2 14-1.3.1.3.3.1.1 16-1.3.1.3.3.2.1 (a / activate-01~e.3 :ARG0 (e / enzyme :name (n / name :op1 "c-Raf"~e.0,2)) :ARG1 e3 :manner (p / phosphorylate-01~e.6 :ARG1 (r / residue~e.9 :mod 218~e.10 :mod 222~e.12 :mod (a2 / amino-acid :name (n3 / name :op1 "serine"~e.8) :part-of (e3 / enzyme :name (n4 / name :op1 "MEK1"~e.4)) :mod (b / between~e.11 :op1 (a3 / amino-acid :mod 30~e.14) :op2 (a4 / amino-acid :mod 32~e.16)))))) # ::id bel_pmid_862_2669.21840 ::amr-annotator SDL-AMR-09 ::preferred # ::tok activated MEK1 increased Elk @-@ 1 @- and c @-@ Jun @-@ dependent gene expression but not ATF2 @-@ dependent gene expression ( Fig . 4 ) . # ::alignments 0-1.1.2 1-1.1.1.1 2-1 2-1.3.1 3-1.2.1.1.1.1.1.1 5-1.2.1.1.1.1.1.1 7-1.2.1.1.1 8-1.2.1.1.1.2.1.1 10-1.2.1.1.1.2.1.1 12-1.2.1.1 12-1.3.1.3.1.1 13-1.2.1 13-1.3.1.3.1 14-1.2 14-1.3.1.3 15-1.3 16-1.3.1.1 16-1.3.1.1.r 17-1.3.1.3.1.1.1.1.1 19-1.2.1.1 20-1.2.1 21-1.2 23-1.4.1 25-1.4.1.1 (i / increase-01~e.2 :ARG0 (e / enzyme :name (n / name :op1 "MEK1"~e.1) :ARG1-of (a / activate-01~e.0)) :ARG1 (e2 / express-03~e.14,21 :ARG1 (g / gene~e.13,20 :ARG0-of (d / depend-01~e.12,19 :ARG1 (a2 / and~e.7 :op1 (p / protein :name (n2 / name :op1 "Elk-1"~e.3,5)) :op2 (p2 / protein :name (n3 / name :op1 "c-Jun"~e.8,10)))))) :ARG1-of (c / contrast-01~e.15 :ARG2 (i2 / increase-01~e.2 :polarity~e.16 -~e.16 :ARG0 e :ARG1 (e3 / express-03~e.14 :ARG1 (g2 / gene~e.13 :ARG0-of (d2 / depend-01~e.12 :ARG1 (p3 / protein :name (n4 / name :op1 "ATF2"~e.17))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.23 :mod 4~e.25))) # ::id bel_pmid_862_2669.21852 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MKK3( Glu ) increased ATF2 @- and Elk @-@ 1 @-@ dependent reporter gene expression but caused only a small increase in Jun @-@ dependent gene expression ( Fig . 4 ) . # ::alignments 3-1.1 4-1.1.2.1.2.1.1.1.1 6-1.1.2.1.2.1 7-1.1.2.1.2.1.2.1.1 9-1.1.2.1.2.1.2.1.1 11-1.1.2.1.2 12-1.1.2.1.1 13-1.1.2.1 14-1.1.2 15-1 16-1.2 17-1.2.2.2.1 19-1.2.2.2 20-1.2.2 22-1.2.2.1.1.1.1.1.1 24-1.2.2.1.1.1 25-1.2.2.1.1 26-1.1.2 26-1.2.2.1 28-1.3.1 30-1.3.1.1 (c / contrast-01~e.15 :ARG1 (i / increase-01~e.3 :ARG0 (e / enzyme :name (n / name :op1 "MKK3(Glu)")) :ARG1 (e2 / express-03~e.14,26 :ARG1 (g / gene~e.13 :ARG0-of (r / report-01~e.12) :ARG0-of (d / depend-01~e.11 :ARG1 (a / and~e.6 :op1 (p2 / protein :name (n2 / name :op1 "ATF2"~e.4)) :op2 (p / protein :name (n3 / name :op1 "Elk-1"~e.7,9))))))) :ARG2 (c2 / cause-01~e.16 :ARG0 e :ARG1 (i2 / increase-01~e.20 :ARG1 (e4 / express-03~e.26 :ARG1 (g2 / gene~e.25 :ARG0-of (d2 / depend-01~e.24 :ARG1 (p3 / protein :name (n4 / name :op1 "Jun"~e.22))))) :degree (s / small~e.19 :mod (o / only~e.17)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.28 :mod 4~e.30))) # ::id bel_pmid_862_2669.21858 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the effect of MKK6( Glu ) was markedly reduced in experiments using phosphorylation @-@ defective ( Ala @-@ 69 , Ala @-@ 71 ) ATF2 . # ::alignments 1-1 4-1.1.1 10-1.1.2 10-1.1.2.r 11-1.1 12-1.1.3.r 13-1.1.3 14-1.1.3.1 15-1.1.3.1.1 15-1.1.3.1.1.2 15-1.1.3.1.1.2.r 17-1.1.3.1.1.2.1 21-1.1.3.1.1.3.1 25-1.1.3.1.1.3.2 27-1.1.3.1.1.1.1 (c / contrast-01~e.1 :ARG2 (r / reduce-01~e.11 :ARG1 (a / affect-01~e.4 :ARG0 (e2 / enzyme :name (n / name :op1 "MKK6(Glu)"))) :manner~e.10 (m / marked~e.10) :topic~e.12 (e3 / experiment-01~e.13 :ARG2 (u / use-01~e.14 :ARG1 (p2 / protein~e.15 :name (n2 / name :op1 "ATF2"~e.27) :ARG2-of~e.15 (p / phosphorylate-01~e.15 :mod (d / defective~e.17)) :part (a4 / amino-acid :mod 69~e.21 :mod 71~e.25 :name (n5 / name :op1 "alanine"))))))) # ::id bel_pmid_862_2669.21860 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Increased ATF2 @-@ dependent gene expression was observed in cells transfected with MKK6( Glu ) . In contrast , MKK3( Glu ) did not increase ATF2 @-@ dependent gene expression in the absence of overexpression of p38 MAP kinase ( Fig . 8A ) . # ::alignments 0-1.2 1-1.2.3.1.1.1.1.1 3-1.1.1.1.1 3-1.2.3.1.1 4-1.1.1.1 4-1.2.3.1 5-1.1.1 5-1.2.3 7-1.1 8-1.1.1.2.r 9-1.1.1.2 10-1.1.1.2.1 17-1.2.4 23-1.2.1 23-1.2.1.r 24-1.1.1.3 24-1.2 25-1.1.1.1.1.1.1.1 25-1.2.3.1.1.1.1.1 27-1.2.3.1.1 28-1.2.3.1 29-1.2.3 30-1.2.5.r 32-1.2.5 33-1.2.5.1.r 34-1.2.5.1 36-1.2.5.1.1.1.1 37-1.2.5.1.1.1.2 38-1.2.5.1.1.1.3 40-1.2.6.1 42-1.2.6.1.1 (m / multi-sentence :snt1 (o / observe-01~e.7 :ARG1 (e / express-03~e.5 :ARG1 (g / gene~e.4 :ARG0-of (d / depend-01~e.3 :ARG1 (p / protein :name (n / name :op1 "ATF2"~e.25)))) :ARG3~e.8 (c / cell~e.9 :ARG1-of (t / transfect-01~e.10 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MKK6(Glu)")))) :ARG1-of (i / increase-01~e.24))) :snt2 (i2 / increase-01~e.0,24 :polarity~e.23 -~e.23 :ARG0 (e4 / enzyme :name (n3 / name :op1 "MKK3(Glu)")) :ARG1 (e5 / express-03~e.5,29 :ARG1 (g2 / gene~e.4,28 :ARG0-of (d2 / depend-01~e.3,27 :ARG1 (p2 / protein :name (n4 / name :op1 "ATF2"~e.1,25))))) :ARG2-of (c2 / contrast-01~e.17) :condition~e.30 (a / absent-01~e.32 :ARG1~e.33 (o2 / overexpress-01~e.34 :ARG1 (k / kinase :name (n5 / name :op1 "p38"~e.36 :op2 "MAP"~e.37 :op3 "kinase"~e.38)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.40 :mod "8A"~e.42)))) # ::id bel_pmid_872_5172.30236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Specifically , PTH and PTHrP rapidly and transiently induce expression of the mRNAs encoding IL @-@ 6 and LIF . # ::alignments 0-1.3 2-1.1.1.1.1 3-1.1 4-1.1.2.1.1 5-1.4 5-1.4.r 6-1.1 7-1.5 8-1 9-1.2 10-1.2.1.r 12-1.2.1.1.1 13-1.2.1.2 14-1.2.1.2.1.1.1.1 16-1.2.1.2.1.1.1.1 17-1.2.1.2.1 18-1.2.1.2.1.2.1.1 (i / induce-01~e.8 :ARG0 (a / and~e.3,6 :op1 (e / enzyme :name (n / name :op1 "PTH"~e.2)) :op2 (e2 / enzyme :name (n2 / name :op1 "PTHrP"~e.4))) :ARG2 (e3 / express-03~e.9 :ARG1~e.10 (n5 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.12) :ARG0-of (e4 / encode-01~e.13 :ARG1 (a2 / and~e.17 :op1 (p / protein :name (n3 / name :op1 "IL-6"~e.14,16)) :op2 (p2 / protein :name (n4 / name :op1 "LIF"~e.18)))))) :ARG1-of (s / specific-02~e.0) :manner~e.5 (r / rapid~e.5) :ARG1-of (t / transient-02~e.7)) # ::id bel_pmid_879_8479.3974 ::amr-annotator SDL-AMR-09 ::preferred # ::tok endogenous GMF is rapidly phosphorylated upon stimulation of astrocytes by phorbol 12 @-@ myristate 13 @-@ acetate We further observed that protein kinase A ( PKA ) - phosphorylated GMF is a potent inhibitor ( IC50 = 3 nM ) of the ERK1 @/@ ERK2 ( p44/p42 ) subfamily of mitogen @-@ activated protein ( MAP ) kinase . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 3-1.1.3 3-1.1.3.r 4-1.1 6-1.1.4 7-1.1.4.2.r 8-1.1.4.2 9-1.1.4.1.r 10-1.1.4.1.1.1 11-1.1.4.1.1.2 13-1.1.4.1.1.2 14-1.1.4.1.1.3 16-1.1.4.1.1.3 17-1.2.1 18-1.2.3 19-1.2 21-1.1.1 22-1.2.2.1.2.1.1.2 23-1.2.2.1.2.1.1.3 25-1.1.2.1.1 28-1.1 28-1.2.2.1.2 29-1.2.2.1.1.1 31-1.2.2.1.2.1.1.3 32-1.2.2.3 33-1.2.2 37-1.2.2.4.2.1 38-1.2.2.4.2.2 40-1.2.2.2.r 42-1.2.2.2.1.1.2 43-1.2.2.2 44-1.2.2.2.2.1.2 50-1.2.2.2.3.1.1.1 52-1.2.2.2.3.1.1.1 53-1.2.2.1.2.1.1.1 53-1.2.2.2.3.1.1.2 57-1.2.2.1.2.1.1.2 57-1.2.2.2.3.1.1.3 (m / multi-sentence :snt1 (p / phosphorylate-01~e.4,28 :ARG1 (p2 / protein~e.21 :name (n / name :op1 "GMF"~e.1) :mod (e / endogenous~e.0)) :ARG2 (e3 / enzyme :name (n6 / name :op1 "PKA"~e.25)) :manner~e.3 (r / rapid~e.3) :condition (s / stimulate-01~e.6 :ARG0~e.9 (s3 / small-molecule :name (n2 / name :op1 "phorbol"~e.10 :op2 "12-myristate"~e.11,13 :op3 "13-acetate"~e.14,16)) :ARG1~e.7 (a / astrocyte~e.8))) :snt2 (o / observe-01~e.19 :ARG0 (w / we~e.17) :ARG1 (i / inhibit-01~e.33 :ARG0 (p3 / protein :name (n3 / name :op1 "GMF"~e.29) :ARG1-of (p4 / phosphorylate-01~e.28 :ARG2 (e2 / enzyme :name (n10 / name :op1 "protein"~e.53 :op2 "kinase"~e.22,57 :op3 "A"~e.23,31)))) :ARG1~e.40 (s2 / slash~e.43 :op1 (e6 / enzyme :name (n4 / name :op1 "p44" :op2 "ERK1"~e.42)) :op2 (e7 / enzyme :name (n11 / name :op1 "p42" :op2 "ERK2"~e.44)) :ARG1-of (i2 / include-91 :ARG2 (p5 / protein-family :name (n9 / name :op1 "mitogen-activated"~e.50,52 :op2 "protein"~e.53 :op3 "kinase"~e.57)))) :mod (p6 / potent~e.32) :ARG3-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (c / concentration-quantity :quant 3~e.37 :unit (n5 / nanomolar~e.38)))) :degree (f / further~e.18))) # ::id bel_pmid_879_8479.8862 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PKA @-@ phosphorylated GMF strongly enhances the activity of a related but distinct subfamily of MAP kinase , the p38 MAP kinase , showing an increase of 60 @-@ fold over baseline and an EC50 of 7 nM . # ::alignments 0-1.1.1.2.1.1.1 2-1.1.1.2 3-1.1.1.1.1 4-1.1.3 5-1.1 7-1.1.2 10-1.1.2.1.2 11-1.1.2.1.2.2.r 12-1.1.2.1.2.2 15-1.1.2.1.3.1.1.1 16-1.1.2.1.3.1.1.2 19-1.1.2.1.1.1 20-1.1.2.1.1.2 20-1.1.2.1.3.1.1.1 21-1.1.2.1.3.1.1.2 23-1.2 25-1.2.2.1 26-1.2.2.1.2 27-1.2.2.1.2.1 29-1.2.2.1.2 30-1.2.2.1.3 31-1.2.2.1.3.1 35-1.2.2.1.2 36-1.2.2.2.3.1 37-1.2.2.2.3.2 (a / and :op1 (e / enhance-01~e.5 :ARG0 (p / protein :name (n / name :op1 "GMF"~e.3) :ARG1-of (p2 / phosphorylate-01~e.2 :ARG2 (e2 / enzyme :name (n2 / name :op1 "PKA"~e.0)))) :ARG1 (a2 / activity-06~e.7 :ARG0 (k / kinase :name (n4 / name :op1 "p38"~e.19 :op2 "MAP"~e.20) :ARG1-of (r / relate-01~e.10 :ARG2 p5 :concession-of~e.11 (d / distinct~e.12 :compared-to p5)) :ARG1-of (i2 / include-91 :ARG2 (p5 / protein-family :name (n6 / name :op1 "MAP"~e.15,20 :op2 "kinase"~e.16,21))))) :ARG1-of (s2 / strong-02~e.4)) :op2 (s / show-01~e.23 :ARG0 p :ARG1 (a3 / and :op1 (i / increase-01~e.25 :ARG1 k :ARG2 (p3 / product-of~e.26,29,35 :op1 60~e.27) :manner (o / over~e.30 :op1 (b / baseline~e.31))) :op2 (h / have-percentage-maximal-effective-concentration-01 :ARG2 50 :ARG1 p :ARG4 (c3 / concentration-quantity :quant 7~e.36 :unit (n5 / nanomolar~e.37)))))) # ::id bel_pmid_879_8479.16716 ::amr-annotator SDL-AMR-09 ::preferred # ::tok intracellular interaction of PKA , GMF , and p38 is supported by the phosphorylation of GMF upon cellular stimulation by forskolin ( blocked by PKA inhibitor ) and by the co @-@ immunoprecipitation of p38 with GMF from cell lysates . Withdrawal of nerve growth factor from PC12 leads to increased GMF phosphorylation with a time course similar to that reported for p38 activation . # ::alignments 0-1.1.1.1.2.2 1-1.1.2 3-1.1.1.1.2.1.2.1.1.1.1.1 5-1.1.1.2.2.1.1 7-1.1.1 7-1.1.2.1 8-1.1.1.2.1.1.1 10-1.1 13-1.1.1.1 15-1.1.1.2.2.1.1 17-1.1.1.1.2.2 18-1.1.1.1.2 20-1.1.1.1.2.1.1.1 22-1.1.1.1.2.1.2 24-1.1.1.1.2.1.2.1.1.1.1.1 25-1.1.1.1.2.1.2.1 25-1.1.1.1.2.1.2.1.1 25-1.1.1.1.2.1.2.1.1.r 27-1.1.1 34-1.1.1.2.1.1.1 36-1.1.1.2.2.1.1 37-1.1.1.2.2.2.r 38-1.1.1.2.2.2.1 39-1.1.1.2.2.2 41-1.2.1 42-1.2.1.1.r 43-1.2.1.1.1 44-1.2.1.1 45-1.2.1.1 46-1.1.1.2.2.2.r 46-1.2.1.2.r 47-1.2.1.2.1.1 48-1.2 49-1.2.2.r 50-1.2.2.1.2 51-1.2.2.1.1.1 52-1.2.2 55-1.2.2.2.1.1 55-1.2.2.2.1.2.1.1 56-1.2.2.2.1 56-1.2.2.2.1.2.1 57-1.2.2.2.1.2 60-1.2.2.2.1.2.1.2 61-1.2.2.2.1.2.1.2.1.r 62-1.2.2.2.1.2.1.2.1.1.1.1 63-1.2.2.2.1.2.1.2.1 (m / multi-sentence :snt1 (s / support-01~e.10 :ARG0 (a2 / and~e.7,27 :op1 (p / phosphorylate-01~e.13 :ARG1 p5 :ARG2 (s2 / stimulate-01~e.18 :ARG0 (s3 / small-molecule :name (n8 / name :op1 "forskolin"~e.20) :ARG1-of (b / block-01~e.22 :ARG0 (m2 / molecular-physical-entity~e.25 :ARG0-of~e.25 (i4 / inhibit-01~e.25 :ARG1 (e4 / enzyme :name (n9 / name :op1 "PKA"~e.3,24)))))) :ARG1 (c / cell~e.0,17))) :op2 (c2 / coimmunoprecipitate-01 :ARG1 (e / enzyme :name (n / name :op1 "p38"~e.8,34)) :ARG2 (p5 / protein :name (n3 / name :op1 "GMF"~e.5,15,36) :source~e.37,46 (l / lysate~e.39 :part-of (c3 / cell~e.38 :ARG0-of (c4 / contain-01 :ARG1 (p3 / protein))))))) :ARG1 (i / interact-01~e.1 :ARG0 (a / and~e.7 :op1 (e3 / enzyme) :op2 p3) :ARG1 e)) :snt2 (l2 / lead-03~e.48 :ARG1 (w / withdraw-01~e.41 :ARG1~e.42 (g / growth-factor~e.44,45 :mod (n2 / nerve~e.43)) :ARG2~e.46 (c5 / cell-line :name (n4 / name :op1 "PC12"~e.47))) :ARG2~e.49 (p2 / phosphorylate-01~e.52 :ARG1 (p4 / protein :name (n6 / name :op1 "GMF"~e.51) :ARG1-of (i3 / increase-01~e.50)) :ARG0-of (h / have-03 :ARG1 (c6 / course~e.56 :mod (t / time~e.55) :ARG1-of (r / resemble-01~e.57 :ARG2 (c7 / course~e.56 :mod (t2 / time~e.55) :ARG1-of (r2 / report-01~e.60 :topic~e.61 (a3 / activate-01~e.63 :ARG1 (e2 / enzyme :name (n7 / name :op1 "p38"~e.62))))))))))) # ::id bel_pmid_894_3354.24786 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , SHP @-@ 1 and its mutants showed similar association and dephosphorylation of the other Jak family members ( JAK1 , Tyk2 , and JAK3 ) but not c @-@ fes when coexpressed in Cos @-@ 7 cells ( data not shown ) . # ::alignments 0-1.1.2 1-1.1.2 3-1.1.1.1.1.1 3-1.1.1.2.1.1 5-1.1.1.1.1.1 5-1.1.1.2.1.1 8-1.1.1.2 8-1.1.1.2.2 8-1.1.1.2.2.r 9-1.1 10-1.1.2.3 11-1.1.2.1 12-1.1.2 13-1.1.2.2 14-1.1.2.2.1.r 16-1.1.2.2.1 17-1.1.2.2.1 18-1.1.2.2.1 19-1.1.2.2.1 20-1.1.2.2.1 21-1.1.2.2.1 22-1.1.2.2.1 23-1.1.2.2.1 24-1.1.2.2.1 25-1.1.2.2.1 26-1.1.2.2.1 27-1.1.2.2.1 28-1.1.2.2.1 29-1.2.1.1.1.r 30-1.1.2.1.2.3.1.1.1 32-1.1.2.1.2.3.1.1.1 33-1.1.3.r 36-1.1.3.2.1.1 38-1.1.3.2.1.1 39-1.1.3.2 41-1.2.1 42-1.2.1.1.1 42-1.2.1.1.1.r 43-1.2.1.1 (a / and :op2 (s / show-01~e.9 :ARG0 (a2 / and :op1 (e / enzyme :name (n / name :op1 "SHP-1"~e.3,5)) :op2 (e2 / enzyme~e.8 :name (n8 / name :op1 "SHP-1"~e.3,5) :ARG2-of~e.8 (m / mutate-01~e.8))) :ARG1 (a3 / and~e.0,1,12 :op1 (a4 / associate-01~e.11 :ARG1 a2 :ARG2 (m2 / member :mod (o / other) :ARG1-of (m3 / mean-01 :ARG2 (a5 / and :op1 (e3 / enzyme :name (n3 / name :op1 "JAK1")) :op2 (e4 / enzyme :name (n4 / name :op1 "Tyk2")) :op3 (e5 / enzyme :name (n5 / name :op1 "JAK3")))) :ARG1-of (c / contrast-01 :ARG2 (e8 / enzyme :name (n2 / name :op1 "c-fes"~e.30,32))) :ARG1-of (i2 / include-91 :ARG2 (p / protein-family :name (n6 / name :op1 "Jak"))))) :op2 (d / dephosphorylate-01~e.13 :ARG1~e.14 m2~e.16,17,18,19,20,21,22,23,24,25,26,27,28 :ARG2 a2) :ARG1-of (r / resemble-01~e.10)) :time~e.33 (c2 / coexpress-01 :ARG2 a2 :ARG3 (c3 / cell-line~e.39 :name (n7 / name :op1 "Cos-7"~e.36,38)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.41 :ARG1-of (s2 / show-01~e.43 :polarity~e.29,42 -~e.42)))) # ::id bel_pmid_902_3347.41730 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hypoxia was capable of inducing VEGF mRNA in both immortalized and transformed endothelial cells ( 4.5 @-@ fold in cells expressing SV40 large T antigen alone or in combination with H @-@ ras ) , but both baseline and induced VEGF mRNA expression was increased in cells containing activated ras ( Fig . 4 ) . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.3.1 4-1.1.2 5-1.1.2.1.2.1.1.1 6-1.1.2.1.1.1 8-1.1.2.2.4 9-1.1.2.2.1.1 10-1.1.2.2 11-1.1.2.2.2.1 12-1.1.2.2.3 13-1.1.2.2.1 13-1.1.2.2.2 15-1.1.2.3.1.1 17-1.1.2.3.1 19-1.1.2.3.2 20-1.1.2.3.2.1 21-1.1.2.3.2.1.1.1.1.1 22-1.1.2.3.2.1.1.1.1.2 23-1.1.2.3.2.1.1.1.1.3 24-1.1.2.3.2.1.1.1.1.4 25-1.1.2.3.2.1.1.1.2 26-1.1.2.3.2.1.1 27-1.1.2.3.2.1.1.r 28-1.1.2.3.2.1.1.2 29-1.1.2.3.2.1.1.2.2.r 30-1.1.2.3.2.1.1.2.2.1.1 32-1.2.2.1.1.1.1 35-1 36-1.2.1.3 37-1.2.1.1.2 38-1.1.2.2 38-1.2.1 39-1.1.2 40-1.1.2.1.2.1.1.1 41-1.1.2.1.1.1 42-1.2.1.1 42-1.2.1.2 44-1.2 46-1.2.2 47-1.2.2.1 48-1.2.2.1.1.2 49-1.2.2.1.1.1.1 51-1.3.1 53-1.3.1.1 (c8 / contrast-01~e.35 :ARG1 (c / capable-01~e.2 :ARG1 (h / hypoxia~e.0) :ARG2 (i2 / induce-01~e.4,39 :ARG2 (n3 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.6,41) :ARG0-of (e3 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "VEGF"~e.5,40)))) :location (a / and~e.10,38 :op1 (c2 / cell~e.13 :ARG1-of (i / immortalize-03~e.9)) :op2 (c3 / cell~e.13 :ARG1-of (t / transform-01~e.11)) :part-of (e4 / endothelium~e.12) :mod (b3 / both~e.8)) :ARG1-of (m2 / mean-01 :ARG2 (p2 / product-of~e.3,17 :op1 4.5~e.15) :location (c6 / cell~e.19 :ARG3-of (e7 / express-03~e.20 :ARG1~e.27 (o / or~e.26 :op1 (p3 / protein :name (n5 / name :op1 "SV40"~e.21 :op2 "large"~e.22 :op3 "T"~e.23 :op4 "antigen"~e.24) :mod (a4 / alone~e.25)) :op2 (c7 / combine-01~e.28 :ARG1 p3 :ARG2~e.29 (e / enzyme :name (n / name :op1 "H-Ras"~e.30))))))))) :ARG2 (i4 / increase-01~e.44 :ARG1 (a3 / and~e.38 :op1 (e5 / express-03~e.42 :ARG2 n3 :mod (b / baseline~e.37)) :op2 (e6 / express-03~e.42 :ARG2 n3 :ARG1-of i2) :mod (b2 / both~e.36)) :location (c4 / cell~e.46 :ARG0-of (c5 / contain-01~e.47 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.32,49) :ARG1-of (a2 / activate-01~e.48))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.51 :mod 4~e.53))) # ::id bel_pmid_902_3347.41732 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of cells with wortmannin , a steroidal inhibitor of phosphatidylinositol @-@ 3 @-@ kinase ( 15 ) , resulted in a decreased level of VEGF under hypoxic conditions but the fold stimulation of VEGF mRNA was not changed ( Fig . 5 ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 3-1.1.1.2.r 4-1.1.1.2.1.1 8-1.1.1.2 8-1.1.1.2.2 8-1.1.1.2.2.r 9-1.1.1.2.2.1.r 10-1.1.1.2.2.1.1.1 12-1.1.1.2.2.1.1.1 14-1.1.1.2.2.1.1.1 16-1.1.1.2.4.1.1.1 19-1.1 20-1.1.2.r 22-1.1.2.2 23-1.1.2 24-1.1.2.1.r 25-1.1.2.1.1.1 28-1.1.3.r 29-1 31-1.2.2.2 32-1.2.2 34-1.1.2.1.1.1 35-1.2.2.1.1.1 37-1.2.1 37-1.2.1.r 38-1.2 40-1.3.1 42-1.3.1.1 (c3 / contrast-01~e.29 :ARG1 (r / result-01~e.19 :ARG1 (t / treat-04~e.0 :ARG1~e.1 (c / cell~e.2) :ARG2~e.3 (s3 / small-molecule~e.8 :name (n / name :op1 "wortmannin"~e.4) :ARG0-of~e.8 (i3 / inhibit-01~e.8 :ARG1~e.9 (e / enzyme :name (n2 / name :op1 "phosphatidylinositol-3-kinase"~e.10,12,14))) :mod (s / steroid) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 15~e.16))))) :ARG2~e.20 (l / level~e.23 :quant-of~e.24 (p2 / protein :name (n3 / name :op1 "VEGF"~e.25,34)) :ARG1-of (d2 / decrease-01~e.22)) :condition~e.28 (h / hypoxia)) :ARG2 (c4 / change-01~e.38 :polarity~e.37 -~e.37 :ARG1 (s2 / stimulate-01~e.32 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.35) :ARG0-of (e2 / encode-01 :ARG1 p2)) :extent (f / fold~e.31))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.40 :mod 5~e.42))) # ::id bel_pmid_902_3347.41734 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells with activated ras demonstrated high level of expression of 72 @-@ kDa metalloproteinase ( MMP @-@ 2 , gelatinase A ) , and 92 @-@ kDa metalloproteinase ( MMP @-@ 9 , gelatinase B ) compared with cells containing SV40 large T antigen alone . # ::alignments 0-1.1 2-1.1.1.1.2 3-1.1.1.1.1.1 4-1 5-1.2.1 6-1.2 7-1.2.2.r 8-1.2.2 9-1.2.2.1.r 10-1.2.2.1.1.3.1 12-1.2.2.1.1.3.2 13-1.2.2.1.1.1.1 15-1.2.2.1.1.2.1.1.1.1 17-1.2.2.1.1.2.1.1.1.1 19-1.2.2.1.1.2.1.2.1.1 20-1.2.2.1.1.2.1.2.1.2 23-1.2.2.1 23-1.2.2.1.1.2.1 24-1.2.2.1.2.3.1 26-1.2.2.1.2.3.2 27-1.2.2.1.2.1.1 29-1.2.2.1.2.2.1.1.1.1 31-1.2.2.1.2.2.1.1.1.1 33-1.2.2.1.2.2.1.2.1.1 34-1.2.2.1.2.2.1.2.1.2 36-1.2.1.1.r 38-1.2.1.1 39-1.1.1 39-1.2.1.1.1 40-1.2.1.1.1.1.1.1 41-1.2.1.1.1.1.1.2 42-1.2.1.1.1.1.1.3 43-1.2.1.1.1.1.1.4 44-1.2.1.1.1.1.2 (d / demonstrate-01~e.4 :ARG0 (c / cell~e.0 :ARG0-of (c2 / contain-01~e.39 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.3) :ARG1-of (a / activate-01~e.2)))) :ARG1 (l / level~e.6 :ARG1-of (h / high-02~e.5 :compared-to~e.36 (c3 / cell~e.38 :ARG0-of (c4 / contain-01~e.39 :ARG1 (p / protein :name (n8 / name :op1 "SV40"~e.40 :op2 "large"~e.41 :op3 "T"~e.42 :op4 "antigen"~e.43) :mod (a5 / alone~e.44))))) :degree-of~e.7 (e2 / express-03~e.8 :ARG2~e.9 (a2 / and~e.23 :op1 (e3 / enzyme :name (n2 / name :op1 "metalloproteinase"~e.13) :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.23 :op1 (e5 / enzyme :name (n4 / name :op1 "MMP-2"~e.15,17)) :op2 (e6 / enzyme :name (n5 / name :op1 "gelatinase"~e.19 :op2 "A"~e.20)))) :quant (m3 / mass-quantity :quant 72~e.10 :unit (k / kilodalton~e.12))) :op2 (e4 / enzyme :name (n3 / name :op1 "metalloproteinase"~e.27) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (e7 / enzyme :name (n6 / name :op1 "MMP-9"~e.29,31)) :op2 (e8 / enzyme :name (n7 / name :op1 "gelatinase"~e.33 :op2 "B"~e.34)))) :quant (m4 / mass-quantity :quant 92~e.24 :unit (k2 / kilodalton~e.26))))))) # ::id bel_pmid_902_3347.41736 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of ras @-@ containing cells with wortmannin resulted in a decrease in MMP expression ( Fig . 6 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1 6-1.1.2.r 7-1.1.2.1.1 8-1 9-1.2.r 11-1.2 12-1.2.1.r 13-1.2.1.1.1.1 14-1.2.1 16-1.3.1 18-1.3.1.1 (r / result-01~e.8 :ARG1 (t / treat-04~e.0 :ARG1~e.1 (c / cell~e.5 :ARG0-of (c2 / contain-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.2)))) :ARG2~e.6 (s / small-molecule :name (n2 / name :op1 "wortmannin"~e.7))) :ARG2~e.9 (d / decrease-01~e.11 :ARG1~e.12 (e2 / express-03~e.14 :ARG2 (e3 / enzyme :name (n3 / name :op1 "MMP"~e.13)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.16 :mod 6~e.18))) # ::id bel_pmid_902_3347.41744 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since wortmannin inhibits VEGF and MMP activity , but does not restore TIMP activity , tumor @-@ igenesis is not expected to be fully suppressed . # ::alignments 0-1.3 1-1.3.1.1.1.1.1 2-1.3.1.1 3-1.3.1.1.2.1.1.1.1 4-1.3.1.1.2.1 5-1.3.1.1.2.1.2.1.1 6-1.3.1.1.2 8-1.3.1 10-1.3.1.2.1 10-1.3.1.2.1.r 11-1.3.1.2 12-1.3.1.2.3.1.1.1 13-1.3.1.2.3 15-1.2.1.1 19-1.1 19-1.1.r 20-1 21-1.3 23-1.2.2 24-1.2 (e / expect-01~e.20 :polarity~e.19 -~e.19 :ARG1 (s / suppress-01~e.24 :ARG1 (c3 / create-01 :ARG1 (t / tumor~e.15)) :degree (f / full~e.23)) :ARG1-of (c / cause-01~e.0,21 :ARG0 (c2 / contrast-01~e.8 :ARG1 (i / inhibit-01~e.2 :ARG0 (s2 / small-molecule :name (n / name :op1 "wortmannin"~e.1)) :ARG1 (a / activity-06~e.6 :ARG0 (a2 / and~e.4 :op1 (p / protein :name (n2 / name :op1 "VEGF"~e.3)) :op2 (e2 / enzyme :name (n3 / name :op1 "MMP"~e.5))))) :ARG2 (r / restore-01~e.11 :polarity~e.10 -~e.10 :ARG0 s2 :ARG1 (a3 / activity-06~e.13 :ARG0 (p2 / protein :name (n4 / name :op1 "TIMP"~e.12))))))) # ::id bel_pmid_902_3347.41748 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Wortmannin could inhibit ras @-@ mediated induction of VEGF , but it did not inhibit the hypoxic regulation of VEGF . # ::alignments 0-1.1.1.1.1.1 1-1.1 2-1.1.1 3-1.1.1.2.2.1.1.1 5-1.1.1.2.2 6-1.1.1.2 7-1.1.1.2.1.r 8-1.1.1.2.1.1.1 10-1 11-1.2.2 13-1.2.1 13-1.2.1.r 14-1.2 17-1.2.3 18-1.2.3.1.r 19-1.2.3.1 (c / contrast-01~e.10 :ARG1 (p / possible-01~e.1 :ARG1 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "wortmannin"~e.0)) :ARG1 (i2 / induce-01~e.6 :ARG2~e.7 (p2 / protein :name (n2 / name :op1 "VEGF"~e.8)) :ARG1-of (m2 / mediate-01~e.5 :ARG0 (e / enzyme :name (n3 / name :op1 "Ras"~e.3)))))) :ARG2 (i3 / inhibit-01~e.14 :polarity~e.13 -~e.13 :ARG0 s~e.11 :ARG1 (r / regulate-01~e.17 :ARG1~e.18 p2~e.19 :mod (h / hypoxia)))) # ::id bel_pmid_902_3347.41750 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This suggests that the hypoxic regulation of VEGF is independent of phosphatidylinositol @-@ 3 @-@ kinase . # ::alignments 0-1.1 1-1 5-1.2.2 6-1.2.2.1.r 7-1.2.2.1.1.1 9-1.2 9-1.2.1 9-1.2.1.r 10-1.2.3.r 11-1.2.3.1.1 13-1.2.3.1.1 15-1.2.3.1.1 (s / suggest-01~e.1 :ARG0 (t / this~e.0) :ARG1 (d / depend-01~e.9 :polarity~e.9 -~e.9 :ARG0 (r / regulate-01~e.5 :ARG1~e.6 (p / protein :name (n / name :op1 "VEGF"~e.7)) :mod (h / hypoxia)) :ARG1~e.10 (e / enzyme :name (n2 / name :op1 "phosphatidylinositol-3-kinase"~e.11,13,15)))) # ::id bel_pmid_911_5219.31418 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PITSLRE kinases are a superfamily of Cdc2 @-@ like kinases that have been implicated in apoptotic signaling and tumorigenesis . In this paper we report that tumor necrosis factor ( TNF ) - mediated apoptosis is associated with a CrmA @- and Bcl @-@ 2 @-@ inhibitable cleavage of PITSLRE kinases , indicating a role for CASPs . # ::alignments 0-1.1.1.1.1 1-1.1.1 2-1.1.1.r 4-1.1 6-1.1.3.1.1.1.1.1 8-1.1.3.1.1 9-1.1.3.1 12-1.1.1.r 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 16-1.1.2.1.1 17-1.1.2.1 18-1.1.2.1.2 18-1.1.2.1.2.1 18-1.1.2.1.2.1.r 21-1.2.3.1 22-1.2.3 23-1.2.1 24-1.2 26-1.1.2.1.2.1 30-1.2.2.1.1.1.1.1 33-1.2.2.1.1 34-1.2.2.1 36-1.2.2 37-1.2.2.2.r 39-1.2.2.2.2.1.1.1.1 41-1.2.2.2.2.1 42-1.2.2.2.2.1.2.1.1 44-1.2.2.2.2.1.2.1.1 47-1.2.2.2 48-1.2.2.2.1.r 49-1.2.2.2.1.1.1 50-1.2.2.2.1 52-1.2.4 54-1.2.4.1 (m / multi-sentence :snt1 (s / superfamily~e.4 :domain~e.2,12 (k2 / kinase~e.1 :name (n / name :op1 "PITSLRE"~e.0)) :ARG1-of (i / implicate-01~e.13 :ARG2~e.14 (a / and~e.17 :op1 (s2 / signal-07~e.16 :ARG1 (a2 / apoptosis~e.15)) :op2 (c2 / create-01~e.18 :ARG1~e.18 (t / tumor~e.18,26)))) :ARG2-of (i4 / include-91 :ARG1 (k / kinase~e.9 :ARG1-of (r / resemble-01~e.8 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Cdc2"~e.6)))))) :snt2 (r2 / report-01~e.24 :ARG0 (w / we~e.23) :ARG1 (a3 / associate-01~e.36 :ARG1 (a4 / apoptosis~e.34 :ARG1-of (m2 / mediate-01~e.33 :ARG0 (p4 / protein :name (n3 / name :op1 "TNF"~e.30)))) :ARG2~e.37 (c / cleave-01~e.47 :ARG1~e.48 (k3 / kinase~e.50 :name (n6 / name :op1 "PITSLRE"~e.49)) :ARG1-of (i2 / inhibit-01 :ARG0 (a5 / and~e.41 :op1 (p6 / protein :name (n4 / name :op1 "CrmA"~e.39)) :op1 (p7 / protein :name (n5 / name :op1 "Bcl-2"~e.42,44))) :ARG1-of (p5 / possible-01)))) :medium (p3 / paper~e.22 :mod (t2 / this~e.21)) :ARG0-of (i3 / indicate-01~e.52 :ARG1 (r3 / role~e.54 :poss (e / enzyme :name (n7 / name :op1 "CASP")))))) # ::id bel_pmid_930_0710.10502 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Elevated levels of human TNF @-@ alpha were accompanied by increases in synovial cell expression of murine IL @-@ 1 beta and IL @-@ 6 # ::alignments 0-1.2.1 1-1.2 2-1.2.2.r 3-1.2.2.2 4-1.2.2.1.1 6-1.2.2.1.1 8-1 9-1.1.r 10-1.1 11-1.1.1.r 12-1.1.1.2.1 13-1.1.1.2 14-1.1.1 15-1.1.1.1.r 16-1.1.1.1.3 17-1.1.1.1.1.1.1 17-1.1.1.1.2.1.1 21-1.1.1.1 22-1.1.1.1.1.1.1 22-1.1.1.1.2.1.1 24-1.1.1.1.2.1.1 (a / accompany-01~e.8 :ARG0~e.9 (i / increase-01~e.10 :ARG1~e.11 (e2 / express-03~e.14 :ARG2~e.15 (a2 / and~e.21 :op1 (p / protein :name (n / name :op1 "IL-1beta"~e.17,22)) :op2 (p3 / protein :name (n3 / name :op1 "IL-6"~e.17,22,24)) :mod (m / murine~e.16)) :ARG3 (c / cell~e.13 :mod (s / synovial~e.12)))) :ARG1 (l / level~e.1 :mod (e / elevated~e.0) :quant-of~e.2 (p2 / protein :name (n2 / name :op1 "TNF-alpha"~e.4,6) :mod (h / human~e.3)))) # ::id bel_pmid_930_5854.5780 ::amr-annotator SDL-AMR-09 ::preferred # ::tok e show here that oncogenic forms of Ha @-@ Ras activate NF @-@ kappaB , not through induced nuclear translocation , but rather through the activation of the transcriptional function of the NF @-@ kappaB RelA @/@ p65 subunit . # ::alignments 1-1 2-1.3 3-1.2.r 4-1.2.1 4-1.2.1.2 4-1.2.1.2.1.2.1 4-1.2.1.2.r 7-1.2.1.1.1 9-1.2.1.1.1 10-1.2 11-1.2.2.1.1 17-1.2.3.2.2 18-1.2.3.2.1 19-1.2.3.2 22-1.2.3 22-1.2.3.1.2 25-1.2.3.1 26-1.2.3 26-1.2.3.1.1.r 28-1.2.3.1.1.2 29-1.2.3.1.1 30-1.2.3 30-1.2.3.1.1.1.r 32-1.2.3.1.1.1.2 35-1.2.3.1.1.1.1.1 37-1.2.3.1.1.1.1.1 38-1.2.3.1.1.1.1.2 (s / show-01~e.1 :ARG0 (w / we) :ARG1~e.3 (a / activate-01~e.10 :ARG0 (e / enzyme~e.4 :name (n / name :op1 "Ha-Ras"~e.7,9) :ARG0-of~e.4 (c / cause-01~e.4 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.4)))) :ARG1 (p / protein :name (n2 / name :op1 "NF-kB"~e.11)) :manner (i / instead-of-91~e.22,26,30 :ARG1 (a2 / activate-01~e.25 :ARG1~e.26 (f2 / function-01~e.29 :ARG0~e.30 (p2 / protein :name (n5 / name :op1 "RelA/p65"~e.35,37 :op2 "subunit"~e.38) :part-of p~e.32) :ARG1 (t2 / transcribe-01~e.28)) :mod (r / rather~e.22)) :ARG2 (t / translocate-01~e.19 :ARG2 (n3 / nucleus~e.18) :ARG2-of (i2 / induce-01~e.17)))) :medium (h / here~e.2)) # ::id bel_pmid_930_5939.36880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 1 ) STAT proteins play an essential role in angiotensin II @-@ induced vascular smooth muscle cell proliferation , 2 ) JAK2 plays an essential role in the tyrosine phosphorylation of Raf @-@ 1 , and 3 ) convergent mitogenic signaling cascades involving the cytosolic kinases JAK2 , MEK1 , and ERK1 mediate vascular smooth muscle cell proliferation # ::alignments 0-1.1.1 2-1.1.2.1.1 3-1.1.2 4-1.1 6-1.1.4 8-1.1.3.r 9-1.1.3.2.1.1.1 10-1.1.3.2.1.1.2 12-1.1.3.2 13-1.1.3.1.1.2 14-1.1.3.1.1.1 15-1.1.3.1.1 16-1.1.3.1 17-1.1.3 19-1.2.1 21-1.2.2.1.1 22-1.2 24-1.1.4 26-1.2.3.r 28-1.2.3.1.1.1 29-1.2.3 31-1.2.3.1.2.1.1 33-1.1.1 33-1.2.3.1.2.1.1 35-1 36-1.3.1 38-1.3.2.2 39-1.3.2.1 40-1.3.2.3 41-1.3.2 42-1.3.2.4 44-1.3.2.4.1.1 45-1.3.2.4.1 46-1.3.2.4.1.2.1.1 48-1.3.2.4.1.2.1.2.1.1 50-1.3.2.4.1.2.1 51-1.3.2.4.1.2.1.3.1.1 52-1.3 53-1.3.3 54-1.3.3 55-1.3.3 56-1.3.3 57-1.3.3 (a / and~e.35 :op1 (p2 / play-08~e.4 :li 1~e.0,33 :ARG0 (p3 / protein~e.3 :name (n / name :op1 "STAT"~e.2)) :ARG1~e.8 (p4 / proliferate-01~e.17 :ARG0 (c / cell~e.16 :part-of (m / muscle~e.15 :ARG1-of (s / smooth-06~e.14) :mod (v / vascular~e.13))) :ARG2-of (i / induce-01~e.12 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "angiotensin"~e.9 :op2 "II"~e.10)))) :mod (e / essential~e.6,24)) :op2 (p5 / play-08~e.22 :li 2~e.19 :ARG0 (e2 / enzyme :name (n3 / name :op1 "JAK2"~e.21)) :ARG1~e.26 (p / phosphorylate-01~e.29 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine"~e.28) :part-of (e4 / enzyme :name (n5 / name :op1 "Raf-1"~e.31,33)))) :mod e) :op3 (m2 / mediate-01~e.52 :li 3~e.36 :ARG0 (c2 / cascade~e.41 :mod (m3 / mitogenic~e.39) :ARG0-of (c3 / converge-01~e.38) :ARG0-of (s3 / signal-07~e.40) :ARG2-of (i2 / involve-01~e.42 :ARG1 (k / kinase~e.45 :part-of (c4 / cytosol~e.44) :ARG1-of (m4 / mean-01 :ARG2 (a3 / and~e.50 :op1 e2~e.46 :op2 (e3 / enzyme :name (n6 / name :op1 "MEK1"~e.48)) :op3 (e5 / enzyme :name (n7 / name :op1 "ERK1"~e.51))))))) :ARG1 p4~e.53,54,55,56,57)) # ::id bel_pmid_934_4843.8622 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The present study demonstrates that erythropoietin ( Epo ) and IL @-@ 3 induce tyrosine phosphorylation of the SH2 @/@ SH3 @-@ containing adapter protein CrkL and its transient association with tyrosine @-@ phosphorylated SHP @-@ 2 , Shc , and Cbl in a murine IL @-@ 3 @-@ dependent cell line , 32D , expressing the Epo receptor ( EpoR ) . # ::alignments 1-1.1.1 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1.1 7-1.2.1.1.2.1.1.1 10-1.2.1.2.1.1 12-1.2.1.2.1.1 13-1.2 14-1.2.2.1.1.1.1 15-1.2.2.1 18-1.2.2.1.1.2.3.1.1.1.1 20-1.2.2.1.1.2.3.1.2.1.1 22-1.2.2.1.1.2.3 24-1.2.1.2 24-1.2.2.1.1.2 24-1.2.2.1.1.2.3.1.1 24-1.2.2.1.1.2.3.1.2 24-1.2.2.2.2.1.2 24-1.2.2.2.2.2.2 24-1.2.2.2.2.3.2 24-1.2.3.4.1 24-1.2.3.4.1.2.1 25-1.2.2.1.1.2.1.1 26-1.2.2 27-1.2.2.2.1 27-1.2.2.2.1.r 28-1.2.2.2.3 29-1.2.2.2 31-1.2.2.2.2.1.1.1 31-1.2.2.2.2.2.1.1 31-1.2.2.2.2.3.1.1 33-1.2.2.2.2.1.3 34-1.2.2.2.2.1.2.1.1 36-1.2.2.2.2.1.2.1.1 38-1.2.2.2.2.2.2.1.1 41-1.2.2.2.2.3.2.1.1 42-1.2.3.r 44-1.2.3.2 45-1.2.3.3.1 46-1.2.3.3.1 47-1.2.3.3.1 49-1.2.3.3 50-1.2.3 51-1.2.3 53-1.2.3.1.1 55-1.2.3.4 57-1.2.3.4.1.1.1 58-1.2.3.4.1.1.2 60-1.2.3.4.1.2.1.1.1 (d / demonstrate-01~e.3 :ARG0 (s / study-01~e.2 :time (p3 / present~e.1)) :ARG1~e.4 (i / induce-01~e.13 :ARG0 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "erythropoietin"~e.5) :ARG1-of (d2 / describe-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "Epo"~e.7)))) :op2 (p4 / protein~e.24 :name (n4 / name :op1 "IL-3"~e.10,12))) :ARG2 (a5 / and~e.26 :op1 (p2 / phosphorylate-01~e.15 :ARG1 (a2 / amino-acid :name (n / name :op1 "tyrosine"~e.14) :part-of (p / protein~e.24 :name (n5 / name :op1 "CrkL"~e.25) :ARG0-of (a3 / adapt-01) :ARG0-of (c / contain-01~e.22 :ARG1 (a4 / and :op1 (p5 / protein-segment~e.24 :name (n6 / name :op1 "SH2"~e.18)) :op2 (p6 / protein-segment~e.24 :name (n7 / name :op1 "SH3"~e.20))))))) :op2 (a6 / associate-01~e.29 :ARG1~e.27 p~e.27 :ARG2 (a7 / and :op1 (a8 / amino-acid :name (n14 / name :op1 "tyrosine"~e.31) :part-of (p11 / protein~e.24 :name (n8 / name :op1 "SHP-2"~e.34,36)) :ARG1-of (p8 / phosphorylate-01~e.33)) :op2 (a9 / amino-acid :name (n15 / name :op1 "tyrosine"~e.31) :part-of (p10 / protein~e.24 :name (n9 / name :op1 "Shc"~e.38)) :ARG1-of p8) :op3 (a10 / amino-acid :name (n16 / name :op1 "tyrosine"~e.31) :part-of (p12 / protein~e.24 :name (n10 / name :op1 "Cbl"~e.41)) :ARG1-of p8)) :ARG1-of (t / transient-02~e.28))) :location~e.42 (c3 / cell-line~e.50,51 :name (n12 / name :op1 "32D"~e.53) :mod (m / murine~e.44) :ARG0-of (d3 / depend-01~e.49 :ARG1 p4~e.45,46,47) :ARG3-of (e2 / express-03~e.55 :ARG2 (p7 / protein~e.24 :name (n11 / name :op1 "Epo"~e.57 :op2 "receptor"~e.58) :ARG1-of (d4 / describe-01 :ARG2 (p9 / protein~e.24 :name (n13 / name :op1 "EpoR"~e.60)))))))) # ::id bel_pmid_946_1509.18046 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The hsp90 beta gene promoter contains binding sites for the transcription factors nuclear factor IL @-@ 6 (\" NF @-@ IL6\") and signal transducer and activator of transcription 3 ( STAT @-@ 3 ) , which are activated respectively by the mitogen @-@ activated @-@ protein @-@ kinase and Jak @-@ kinase pathways following IL @-@ 6 treatment . # ::alignments 3-1.1.2.1 4-1.1 4-1.1.2 4-1.1.2.r 5-1 6-1.2.1 7-1.2 8-1.2.1.1.r 10-1.2.1.1.1 11-1.2.1.1 11-1.2.1.1.2.1.1.1.2 12-1.2.1.1.2.1.1.1.1 13-1.2.1.1.2.1.1.1.2 14-1.2.1.1.2.1.1.1.3 16-1.2.1.1.2.1.1.1.3 18-1.2.1.1.2.1.1.2.1.1.1 22-1.2.1.1.2.1.2.1.1 23-1.2.1.1.2.1.2.1.2 24-1.2.1.1.2.1.2.1.3 25-1.2.1.1.2.1.2.1.4 26-1.2.1.1.2.1.2.1.5 27-1.2.1.1.2.1.2.1.6 28-1.2.1.1.2.1.2.1.7 30-1.2.1.1.2.1.2.2.1.1.1 32-1.2.1.1.2.1.2.2.1.1.1 37-1.2.1.1.3 37-1.2.1.1.3.1.1.1.1 38-1.2.1.1.3.2 38-1.2.1.1.3.2.r 41-1.2.1.1.3.1.1.1.1 43-1.2.1.1.3.1.1.1.1 45-1.2.1.1.3.1.1.1.1 47-1.2.1.1.3.1.1.1.1 47-1.2.1.1.3.1.2.1.1 49-1.2.1.1.3.1.2.1.1 51-1.2.1.1.3.1.1.1.1 51-1.2.1.1.3.1.2.1.1 52-1.2.1.1.3.1.1 52-1.2.1.1.3.1.2 53-1.2.1.1.3.3 54-1.2.1.1.3.3.1.1.1.1 56-1.2.1.1.3.3.1.1.1.1 57-1.2.1.1.3.3.1 (c / contain-01~e.5 :ARG0 (p8 / protein~e.4 :name (n / name :op1 "hsp90beta") :ARG0-of~e.4 (p / promote-01~e.4 :ARG1 (g / gene~e.3))) :ARG1 (p2 / protein-segment~e.7 :ARG2-of (b / bind-01~e.6 :ARG1~e.8 (f4 / factor~e.11 :ARG0-of (t2 / transcribe-01~e.10) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (p5 / protein :name (n2 / name :op1 "nuclear"~e.12 :op2 "factor"~e.11,13 :op3 "IL-6"~e.14,16) :ARG1-of (d / describe-01 :ARG2 (p9 / protein :name (n7 / name :op1 "NF-IL6"~e.18)))) :op2 (p6 / protein :name (n3 / name :op1 "signal"~e.22 :op2 "transducer"~e.23 :op3 "and"~e.24 :op4 "activator"~e.25 :op5 "of"~e.26 :op6 "transcription"~e.27 :op7 3~e.28) :ARG1-of (d2 / describe-01 :ARG2 (p10 / protein :name (n8 / name :op1 "STAT-3"~e.30,32)))))) :ARG1-of (a3 / activate-01~e.37 :ARG0 (a4 / and :op1 (p3 / pathway~e.52 :name (n4 / name :op1 "mitogen-activated-protein-kinase"~e.37,41,43,45,47,51)) :op2 (p4 / pathway~e.52 :name (n5 / name :op1 "Jak-kinase"~e.47,49,51))) :manner~e.38 (r / respective~e.38) :ARG1-of (f / follow-01~e.53 :ARG2 (t / treat-04~e.57 :ARG2 (p7 / protein :name (n6 / name :op1 "IL-6"~e.54,56))))))))) # ::id bel_pmid_946_1509.22508 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , IL @-@ 1 , which activates only the \" NF @-@ IL6\" pathway , synergizes with heat shock to produce strong activation of hsp90 . # ::alignments 1-1 3-1.1.1.1.1 5-1.1.1.1.1 8-1.1.1 8-1.1.1.2 8-1.1.1.2.r 9-1.1.1.2.2 12-1.1.1.2.1.1.1 15-1.1.1.2.1 19-1.1.2.1 20-1.1.2 22-1.1.3 23-1.1.3.2.2 24-1.1.3.2 25-1.1.3.2.1.r 26-1.1.3.2.1.1.1 (c / contrast-01~e.1 :ARG2 (s / synergize-01 :ARG0 (p / protein~e.8 :name (n / name :op1 "IL-1"~e.3,5) :ARG0-of~e.8 (a / activate-01~e.8 :ARG1 (p2 / pathway~e.15 :name (n2 / name :op1 "NF-IL6"~e.12)) :mod (o / only~e.9))) :ARG1 (s2 / shock~e.20 :mod (h / heat~e.19)) :ARG2 (p3 / produce-01~e.22 :ARG0 p :ARG1 (a2 / activate-01~e.24 :ARG1~e.25 (p4 / protein :name (n3 / name :op1 "hsp90"~e.26)) :mod (s3 / strong~e.23))))) # ::id bel_pmid_982_0826.5420 ::amr-annotator SDL-AMR-09 ::preferred # ::tok formation of the hCAF @-@ 1/BTG1 complex is driven by phosphorylation at BTG1 ( Ser @-@ 159 ) and implicates this complex in the signalling events of cell division that lead to changes in cellular proliferation associated with cell @-@ cell contact . # ::alignments 0-1.1.2 1-1.1.2.1.r 3-1.1.2.1.1.1.1 6-1.1.2.1 8-1.1 9-1.1.1.r 10-1.1.1 11-1.1.2.1.2.r 12-1.1.2.1.2.1.1 14-1.1.1.1.2.1 16-1.1.1.1.1 18-1 19-1.2 21-1.2.2 22-1.2.3.r 24-1.2.3.1 25-1.2.3 26-1.2.3.2.r 27-1.2.3.2.1 28-1.2.3.2 30-1.2.3.3 31-1.2.3.3.1.r 32-1.2.3.3.1 33-1.2.3.3.1.1.r 34-1.2.3.3.1.1.1 35-1.2.3.3.1.1 36-1.2.3.3.1.1.2 38-1.2.3.2.1 40-1.2.3.2.1 40-1.2.3.3.1.1.2.1.1 41-1.2.3.3.1.1.2.1 (a2 / and~e.18 :op1 (d / drive-02~e.8 :ARG0~e.9 (p / phosphorylate-01~e.10 :ARG1 (a / amino-acid :mod 159~e.16 :name (n3 / name :op1 "serine"~e.14) :part-of p3)) :ARG1 (f / form-01~e.0 :ARG1~e.1 (m / macro-molecular-complex~e.6 :part (p2 / protein :name (n / name :op1 "hCAF-1"~e.3)) :part~e.11 (p3 / protein :name (n2 / name :op1 "BTG1"~e.12))))) :op2 (i / implicate-01~e.19 :ARG0 f :ARG1 m~e.21 :ARG2~e.22 (e / event~e.25 :ARG0-of (s / signal-07~e.24) :subevent-of~e.26 (d2 / divide-02~e.28 :ARG1 (c / cell~e.27,38,40)) :ARG0-of (l / lead-03~e.30 :ARG2~e.31 (c2 / change-01~e.32 :ARG1~e.33 (p4 / proliferate-01~e.35 :ARG0 c~e.34 :ARG1-of (a3 / associate-01~e.36 :ARG2 (c3 / contact-01~e.41 :ARG0 (c4 / cell~e.40) :ARG1 c)))))))) # ::id bel_pmid_982_0826.5840 ::amr-annotator SDL-AMR-09 ::preferred # ::tok in vitro the hCAF @-@ 1/BTG1 complex formation was dependent on the phosphorylation of a putative p34 cdc2 kinase site on BTG1 ( Ser @-@ 159 ) . # ::alignments 0-1.3 1-1.3 3-1.1.1.1.1.1 6-1.1.1 7-1.1 9-1 10-1.2.r 12-1.2 13-1.2.1.r 15-1.2.1.1 18-1.2.1.3 19-1.2.1 20-1.1.1.2.r 21-1.1.1.2.1.1 23-1.2.1.4.1.2.1 25-1.2.1.4.1.1 (d / depend-01~e.9 :ARG0 (f / form-01~e.7 :ARG1 (m / macro-molecular-complex~e.6 :part (p2 / protein :name (n / name :op1 "hCAF-1"~e.3)) :part~e.20 (p3 / protein :name (n2 / name :op1 "BTG1"~e.21)))) :ARG1~e.10 (p / phosphorylate-01~e.12 :ARG1~e.13 (p4 / protein-segment~e.19 :ARG1-of (t / think-01~e.15) :part-of p3 :mod (k / kinase~e.18 :name (n5 / name :op1 "p34cdc2")) :ARG1-of (m2 / mean-01 :ARG2 (a / amino-acid :mod 159~e.25 :name (n4 / name :op1 "serine"~e.23))))) :manner (i / in-vitro~e.0,1)) # ::id bel_pmid_982_0826.8154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The human BTG1 protein is thought to be a potential tumour suppressor because its overexpression inhibits NIH 3T3 cell proliferation . # ::alignments 1-1.1.1.2 2-1.1.1.1.1 3-1.1.1 5-1 6-1.2 9-1.1.3 10-1.1.2 11-1.1 12-1.2 13-1.2.1.1.1 13-1.2.1.1.1.r 14-1.2.1.1 15-1.2.1 16-1.2.1.2.1.1.1 17-1.2.1.2.1.1.2 18-1.2.1.2.1 19-1.2.1.2 (t / think-01~e.5 :ARG1 (s / suppress-01~e.11 :ARG0 (p / protein~e.3 :name (n / name :op1 "BTG1"~e.2) :mod (h / human~e.1)) :ARG1 (t2 / tumor~e.10) :mod (p2 / potential~e.9)) :ARG1-of (c / cause-01~e.6,12 :ARG0 (i / inhibit-01~e.15 :ARG0 (o / overexpress-01~e.14 :ARG1~e.13 p~e.13) :ARG1 (p3 / proliferate-01~e.19 :ARG0 (c2 / cell-line~e.18 :name (n2 / name :op1 "NIH"~e.16 :op2 "3T3"~e.17)))))) # ::id bel_pmid_982_3899.2738 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pak3 phosphorylates Raf @-@ 1 on serine 338 in vitro and in vivo . The p21 @-@ activated protein kinases are regulated by the Rho @-@ family GTPases Rac and Cdc42 . # ::alignments 0-1.1.2.1.1 1-1.1 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1.3.r 6-1.1.3.2.1 7-1.1.3.1 8-1.1.4.1 9-1.1.4.1 10-1.1.4 11-1.1.4.1 11-1.1.4.2 12-1.1.4.2 15-1.2.2.1.1.1.1 17-1.2.2.1 18-1.2.2.2 19-1.2.2 21-1.2 22-1.2.1.r 24-1.2.1.3.1.1.1 26-1.2.1.3.1 28-1.2.1.1.1.1 29-1.2.1 30-1.2.1.2.1.1 (m / multi-sentence :snt1 (p / phosphorylate-01~e.1 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Raf-1"~e.2,4)) :ARG2 (e / enzyme :name (n2 / name :op1 "Pak3"~e.0)) :location~e.5 (a / amino-acid :mod 338~e.7 :name (n / name :op1 "serine"~e.6) :part-of e2) :manner (a2 / and~e.10 :op1 (i / in-vitro~e.8,9,11) :op2 (i2 / in-vivo~e.11,12))) :snt2 (r / regulate-01~e.21 :ARG0~e.22 (a4 / and~e.29 :op1 (e5 / enzyme :name (n7 / name :op1 "Rac"~e.28)) :op2 (p5 / protein :name (n8 / name :op1 "Cdc42"~e.30)) :ARG1-of (i3 / include-91 :ARG2 (p4 / protein-family~e.26 :name (n4 / name :op1 "Rho"~e.24 :op2 "GTPase")))) :ARG1 (k / kinase~e.19 :ARG1-of (a3 / activate-01~e.17 :ARG0 (p2 / protein :name (n5 / name :op1 "p21"~e.15))) :mod (p3 / protein~e.18)))) # ::id bio.chicago_2015.9828 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The amino acids altered in mutation DECM2 ( YEG G ) , which have a strong effect on DEC binding to beta @-@ cateninArm in our assays , are bold and underlined . # ::alignments 1-1.1.1 2-1.1.1 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1 6-1.1.1.1.1.1.1.1 8-1.1.1.3.1.1 9-1.1.1.3.1.1 15-1.1.1.2.2 16-1.1.1.2 17-1.1.1.2.1.r 18-1.1.1.2.1.1.1.1 19-1.1.1.2.1 20-1.1.1.2.1.2.r 21-1.1.1.2.1.2.1.1 23-1.1.1.2.1.2.1.1 24-1.1.1.2.1.3.r 25-1.1.1.2.1.3.1 25-1.1.1.2.1.3.1.r 26-1.1.1.2.1.3 29-1.1 30-1 31-1.2 (a / and~e.30 :op1 (b / bold-03~e.29 :ARG1 (a6 / amino-acid~e.1,2 :ARG1-of (a3 / alter-01~e.3 :time~e.4 (m / mutate-01~e.5 :ARG2 (p3 / protein :name (n2 / name :op1 "DECM2"~e.6)))) :ARG0-of (a4 / affect-01~e.16 :ARG1~e.17 (b2 / bind-01~e.19 :ARG1 (p / protein :name (n3 / name :op1 "DEC"~e.18)) :ARG2~e.20 (p2 / protein :name (n4 / name :op1 "beta-cateninArm"~e.21,23)) :location~e.24 (a5 / assay-01~e.26 :ARG0~e.25 (w / we~e.25))) :ARG1-of (s / strong-02~e.15)) :ARG1-of (l / label-01 :ARG2 (s2 / string-entity :value "YEG-G"~e.8,9)))) :op2 (u / underline-01~e.31 :ARG1 a6)) # ::id bio.chicago_2015.19528 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The less efficient phosphorylation of MLC by Rho @-@ kinase may become sufficient when the myosin phosphatase activity is inhibited by Rho @-@ kinase . # ::alignments 1-1.1.1.3.1 2-1.1.1.3 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.2.r 7-1.1.1.2.1.1 9-1.1.1.2.1.1 10-1 12-1.1 15-1.2.2.1.1.1 16-1.2.2.1 17-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1 22-1.2.1 23-1.2.1 (p / possible-01~e.10 :ARG1 (s / suffice-01~e.12 :ARG0 (p2 / phosphorylate-01~e.3 :ARG1~e.4 (p3 / protein :name (n / name :op1 "MLC"~e.5)) :ARG2~e.6 (e2 / enzyme :name (n2 / name :op1 "Rho-kinase"~e.7,9)) :ARG1-of (e / efficient-01~e.2 :degree (l / less~e.1)))) :condition (i / inhibit-01~e.19 :ARG0~e.20 e2~e.21,22,23 :ARG1 (a / activity-06~e.17 :ARG0 (p4 / phosphatase~e.16 :name (n3 / name :op1 "myosin"~e.15))))) # ::id bio.chicago_2015.19534 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In support of these findings , it has also been found that displacement of Rb @-@ E2F complexes from promoters with a dominant @-@ negative E2F ( DN @-@ E2F ) containing a DNA binding domain but lacking an Rb binding site , or titration of Rb @-@ E2F complexes away from promoters by transfection of a plasmid containing multiple E2F binding site repeats , prevents Rb @-@ mediated repression of cyclin E and A expression and growth arrest by p16 ( Zhang et al. , 1999 ; # ::alignments 1-1.3 3-1.3.1.2 4-1 4-1.3.1 4-1.3.1.1 4-1.3.1.1.r 8-1.2 10-1 10-1.3.1 10-1.3.1.1 10-1.3.1.1.r 11-1.1.r 12-1.1.1.1 13-1.1.1.1.2.r 14-1.1.1.1.2.2.1.2.2.1.2.1.1.1.1 16-1.1.1.1.2.2.1.1.1 17-1.1.1.1.1 21-1.1.2.1.1.1.2.1.2 22-1.1.1.1.2.2.1 22-1.1.1.1.2.2.1.4 22-1.1.1.1.2.2.1.4.r 25-1.1.1.1.2.2.1.1.1 29-1.1.1.1.2.2.1.1.1 31-1.1.1.1.2.2.1.2 32-1.1.2.1.1.1.2.1.2 33-1.1.1.1.2.2.1.2.1.1.1.1.1 34-1.1.1.1.2.2.1.2.1.1 35-1.1.1.1.2.2.1.2.1 36-1.1.1.1.2.2.1.2.2 37-1.1.1.1.2.2.1.2.2.1 39-1.1.1.1.2.2.1.2.2.1.2.1.1.1.1 40-1.1.1.1.2.2.1.2.2.1.2.1 41-1.1.1.1.2.2.1.2.2.1.2 43-1.1.1 44-1.1.1.2 46-1.1.1.1.2.2.1.2.2.1.2.1.1.1.1 48-1.1.1.1.2.2.1.1.1 49-1.1.1.2.1 50-1.1.1.2.2 53-1.1.1.2.3.r 54-1.1.1.2.3 55-1.1.1.2.3.1.r 56-1.1.2.1.1.1.2.1.2 57-1.1.1.2.3.1 58-1.1.1.2.3.1.1 60-1.1.1.2.3.1.1.1.1.1.1.1.1 61-1.1.1.2.3.1.1.1.1.1 62-1.1.1.2.3.1.1.1.1 63-1.1.1.2.3.1.1.1 65-1.1 66-1.1.2.1.2.1 68-1.1.2.1.2 69-1.1.2.1 71-1.1.2.1.1.1.1.1.1 72-1.1.2.1.1.1.1.1.2 73-1.1.2.1.1.1 74-1.1.2.1.1.1.2.1.2 75-1.1.2.1.1 76-1.1.2 77-1.1.2.2.2 78-1.1.2.2 79-1.1.2.2.1.r 80-1.1.2.2.1.1.1 82-1.4.1.1.1.1.1 83-1.4.1.1 84-1.4.1.1.2.1 86-1.4.1.2.1 (f / find-01~e.4,10 :ARG1~e.11 (p7 / prevent-01~e.65 :ARG0 (o / or~e.43 :op1 (d / displace-01~e.12 :ARG1 (m5 / macro-molecular-complex~e.17 :part p3 :part p6) :ARG2~e.13 (m / molecular-physical-entity :ARG0-of (p / promote-02) :ARG0-of (h / have-03 :ARG1 (p14 / protein~e.22 :name (n2 / name :op1 "E2F"~e.16,25,29,48) :ARG0-of (c2 / contain-01~e.31 :ARG1 (d3 / domain~e.35 :ARG1-of (b / bind-01~e.34 :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "DNA"~e.33)))) :ARG1-of (c3 / contrast-01~e.36 :ARG2 (l / lack-01~e.37 :ARG0 p14 :ARG1 (s / site~e.41 :ARG2-of (b2 / bind-01~e.40 :ARG1 (p3 / protein :name (n5 / name :op1 "Rb"~e.14,39,46))))))) :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of~e.22 (d2 / dominate-01~e.22))))) :op2 (t / titrate-01~e.44 :ARG1 m5~e.49 :location (a2 / away~e.50 :op1 (m3 / molecular-physical-entity :ARG0-of (p2 / promote-02))) :manner~e.53 (t2 / transfect-01~e.54 :ARG1~e.55 (p5 / plasmid~e.57 :ARG0-of (c4 / contain-01~e.58 :ARG1 (r / repeat-01~e.63 :ARG1 (s2 / site~e.62 :ARG2-of (b3 / bind-01~e.61 :ARG1 (p6 / protein :name (n6 / name :op1 "E2F"~e.60)))))))))) :ARG1 (a4 / and~e.76 :op1 (r2 / repress-01~e.69 :ARG1 (e / express-03~e.75 :ARG2 (a3 / and~e.73 :op1 (p8 / protein :name (n7 / name :op1 "cyclin"~e.71 :op2 "E"~e.72)) :op2 (p9 / protein :name (n8 / name :op1 "cyclin" :op2 "A"~e.21,32,56,74)))) :ARG1-of (m4 / mediate-01~e.68 :ARG0 p3~e.66)) :op2 (a5 / arrest-02~e.78 :ARG0~e.79 (p10 / protein :name (n9 / name :op1 "p16"~e.80)) :ARG1 (g3 / grow-01~e.77)))) :mod (a / also~e.8) :ARG0-of (s3 / support-01~e.1 :ARG1 (t3 / thing~e.4,10 :ARG1-of~e.4,10 (f2 / find-01~e.4,10) :mod (t4 / this~e.3))) :ARG1-of (d5 / describe-01 :ARG0 (p11 / publication-91 :ARG0 (a6 / and~e.83 :op1 (p12 / person :name (n10 / name :op1 "Zhang"~e.82)) :op2 (p13 / person :mod (o2 / other~e.84))) :time (d6 / date-entity :year 1999~e.86)))) # ::id bio.chicago_2015.19551 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More recently , PSQ was found to colocalize and coimmunoprecipitate with TRL/ GAF , an interaction that was shown to depend on the BTB/ POZ domains of the two proteins ( 64 ) . # ::alignments 0-1.2.1 1-1.2 3-1.1.1.1.1.1.1 5-1 7-1.1.1 8-1.1 8-1.1.1.1 9-1.1.2 12-1.1.1.1.2.2.1.1 15-1.1.3.1 18-1.1.3.1.1.2 20-1.1.3.1.1 24-1.1.3.1.1.1.2.1.1 29-1.1.1.1.1 29-1.1.1.1.2.1 29-1.1.1.1.2.2 29-1.1.3.1.1.1.1 29-1.1.3.1.1.1.2 31-1.3.1.1.1 (f / find-01~e.5 :ARG1 (a / and~e.8 :op1 (c / colocalize-01~e.7 :ARG1 (a2 / and~e.8 :op1 (p / protein~e.29 :name (n / name :op1 "PSQ"~e.3)) :op2 (s / slash :op1 (p2 / protein~e.29 :name (n2 / name :op1 "TRL")) :op2 (p3 / protein~e.29 :name (n3 / name :op1 "GAF"~e.12))))) :op2 (c2 / coimmunoprecipitate-01~e.9 :ARG1 p :ARG2 s) :ARG1-of (m2 / mean-01 :ARG2 (i / interact-01~e.15 :ARG0-of (d / depend-01~e.20 :ARG1 (s2 / slash :op1 (p5 / protein-segment~e.29 :name (n4 / name :op1 "BTB")) :op2 (p6 / protein-segment~e.29 :name (n5 / name :op1 "POZ"~e.24)) :part-of s) :ARG1-of (s3 / show-01~e.18))))) :time (r / recent~e.1 :degree (m / more~e.0)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 64~e.31)))) # ::id bio.chicago_2015.19555 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PI3K inhibitory domain inhibits p110 , but not p110 # ::alignments 1-1.1.1.1.1.1.1 2-1.1.1.1 3-1.1.1 4-1.1 4-1.2 5-1.1.2.1.1 7-1 8-1.2.1 8-1.2.1.r 9-1.2.3 (c / contrast-01~e.7 :ARG1 (i / inhibit-01~e.4 :ARG0 (d / domain~e.3 :ARG0-of (i2 / inhibit-01~e.2 :ARG1 (e / enzyme :name (n2 / name :op1 "PI3K"~e.1)))) :ARG1 (p / protein :name (n / name :op1 "p110"~e.5))) :ARG2 (i3 / inhibit-01~e.4 :polarity~e.8 -~e.8 :ARG0 d :ARG1 p~e.9)) # ::id bio.chicago_2015.19589 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The spatial expression and sequence of ppa suggest that Ppa might negatively regulate Prd , either by transcriptional co @-@ repression or degradation of the Prd protein . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1 7-1 9-1.1.1.1.1.1 10-1.2 11-1.2.1 12-1.2.1 13-1.2.1.2.1.1 16-1.2.1.3.r 17-1.2.1.3.1.1 21-1.2.1.3 22-1.2.1.3.2 23-1.2.1.3.2.1.r 25-1.2.1.3.2.1 26-1.1.1.1 26-1.2.1.2 (s / suggest-01~e.7 :ARG0 (a / and~e.3 :op1 (e / express-03~e.2 :ARG2 (p / protein~e.26 :name (n / name :op1 "ppa"~e.9)) :mod (s2 / space~e.1)) :op2 (s3 / sequence~e.4 :poss~e.5 p~e.6 :mod s2)) :ARG1 (p2 / possible-01~e.10 :ARG1 (d2 / downregulate-01~e.11,12 :ARG0 p :ARG1 (p3 / protein~e.26 :name (n3 / name :op1 "Prd"~e.13)) :manner~e.16 (o / or~e.21 :op1 (c / corepress-00 :ARG1 (t / transcribe-01~e.17)) :op2 (d / degrade-01~e.22 :ARG1~e.23 p3~e.25))))) # ::id bio.chicago_2015.19651 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Within this complex , NDPK interacts with dynamin I through a proline @-@ rich domain , whereas its interaction with phocein is ill defined . # ::alignments 1-1.3.1 2-1.3 4-1.1.1.1.1 5-1.1 7-1.1.2.1.1 8-1.1.2.1.2 11-1.1.3.1.1.1.1 13-1.1.3.1 14-1.1.3 16-1 18-1.1 18-1.2 19-1.2.2.r 20-1.2.2.1.1 22-1.2.3.1 23-1.2.3 (c / contrast-01~e.16 :ARG1 (i / interact-01~e.5,18 :ARG0 (e / enzyme :name (n / name :op1 "NDPK"~e.4)) :ARG1 (p / protein :name (n2 / name :op1 "dynamin"~e.7 :op2 "I"~e.8)) :ARG2 (d / domain~e.14 :mod (r / rich~e.13 :mod (a / amino-acid :name (n3 / name :op1 "proline"~e.11))))) :ARG2 (i2 / interact-01~e.18 :ARG0 e :ARG1~e.19 (p2 / protein :name (n4 / name :op1 "phocein"~e.20)) :ARG1-of (d2 / define-01~e.23 :ARG1-of (i3 / ill-02~e.22))) :location (c2 / complex~e.2 :mod (t / this~e.1))) # ::id bio.chicago_2015.19673 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , although Rb has been shown to bind at least 10 distinct proteins including the transcription factors ATF @-@ 2 ( 44 ) and E2F ( 45 ) , direct interaction of Rb with Sp proteins has not been reported . # ::alignments 0-1 0-1.1 0-1.1.r 2-1.1 3-1.1.1.2.1.1.1 4-1.1 6-1.1.2 8-1.1.2.1 9-1.1.2.1.2.3 10-1.1.2.1.2.3 11-1.1.2.1.2.3.1 12-1.1.2.1.2.1 13-1.1.2.1.2 14-1.1.2.1.2.2 16-1.1.2.1.2.2.1.3.1 17-1.1.2.1.2.2.1.3 18-1.1.2.1.2.2.1.1.1.1 20-1.1.2.1.2.2.1.1.1.1 22-1.1.2.1.2.2.1.1.2.1.1.1 24-1.1.2.1.2.2.1 25-1.1.2.1.2.2.1.2.1.1 27-1.1.2.1.2.2.1.2.2.1.1.1 30-1.1.1.2.3 31-1.1.1.2 33-1.1.1.2.1.1.1 35-1.1.1.2.2.1.1 36-1.1.1.2.1 36-1.1.1.2.2 38-1.1.1.1 38-1.1.1.1.r 40-1.1.1 (c3 / contrast-01~e.0 :ARG2~e.0 (h / have-concession-91~e.0,2,4 :ARG1 (r / report-01~e.40 :polarity~e.38 -~e.38 :ARG1 (i / interact-01~e.31 :ARG0 (p / protein~e.36 :name (n / name :op1 "Rb"~e.3,33)) :ARG1 (p2 / protein~e.36 :name (n2 / name :op1 "Sp"~e.35)) :ARG1-of (d / direct-02~e.30))) :ARG2 (s / show-01~e.6 :ARG1 (b / bind-01~e.8 :ARG1 p :ARG2 (p3 / protein~e.13 :mod (d2 / distinct~e.12) :ARG2-of (i2 / include-01~e.14 :ARG1 (a2 / and~e.24 :op1 (p4 / protein :name (n3 / name :op1 "ATF-2"~e.18,20) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 44~e.22)))) :op2 (p5 / protein :name (n4 / name :op1 "E2F"~e.25) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 45~e.27)))) :mod (f / factor~e.17 :ARG0-of (t / transcribe-01~e.16)))) :quant (a / at-least~e.9,10 :op1 10~e.11)))))) # ::id bio.chicago_2015.19721 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , the amino @-@ terminal PTB domain can directly interact with EGFR and Syk @/@ Zap @-@ 70 ( Lupher and Thien ) . # ::alignments 0-1 1-1 4-1.1.1.1.2.1 6-1.1.1.1.2.1 7-1.1.1.1.3.2.1 9-1.1 10-1.1.1.3 11-1.1.1 12-1.1.1.2.r 13-1.1.1.2.1.2.1 14-1.1.1.2 15-1.1.1.2.2.1.2.1 16-1.1.1.2.2 17-1.1.1.2.2.2.2.1 19-1.1.1.2.2.2.2.1 21-1.1.2.1.1.1.2.1 22-1.1.2.1.1 23-1.1.2.1.1.2.2.1 (a / and~e.0,1 :op2 (p / possible-01~e.9 :ARG1 (i / interact-01~e.11 :ARG0 (p2 / protein-segment :wiki "N-terminus" :name (n7 / name :op1 "amino-terminus"~e.4,6) :part-of (p8 / protein :wiki "Polypyrimidine_tract-binding_protein" :name (n8 / name :op1 "PTB"~e.7))) :ARG1~e.12 (a3 / and~e.14 :op1 (e / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n2 / name :op1 "EGFR"~e.13)) :op2 (s / slash~e.16 :op1 (e2 / enzyme :wiki "Syk" :name (n3 / name :op1 "Syk"~e.15)) :op2 (e3 / enzyme :wiki "ZAP70" :name (n4 / name :op1 "Zap-70"~e.17,19)))) :ARG1-of (d / direct-02~e.10)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and~e.22 :op1 (p6 / person :wiki - :name (n5 / name :op1 "Lupher"~e.21)) :op2 (p7 / person :wiki - :name (n6 / name :op1 "Thien"~e.23))))))) # ::id bio.chicago_2015.19785 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here , we demonstrate that V @-@ ATPase binds directly to actin filaments . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2 9-1.2.3 10-1.2.2.r 11-1.2.2.1.1.1 12-1.2.2 (d / demonstrate-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (b / bind-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "V-ATPase"~e.5,7)) :ARG2~e.10 (f / filament~e.12 :part-of (p / protein :name (n2 / name :op1 "actin"~e.11))) :ARG1-of (d2 / direct-02~e.9)) :medium (h / here~e.0)) # ::id bio.chicago_2015.19847 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rho @-@ kinase phosphorylates MBS and consequently inactivates myosin phosphatase ( 12 ) . # ::alignments 0-1.1.2.1.1 2-1.1.2.1.1 3-1.1 4-1.1.1.1.1 6-1 7-1.2.1 8-1.2.3.1.1 9-1.2.3 11-1.3.1.1.1 (c / cause-01~e.6 :ARG0 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein-segment :name (n2 / name :op1 "MBS"~e.4)) :ARG2 (e2 / enzyme :name (n / name :op1 "Rho-kinase"~e.0,2))) :ARG1 (a / activate-01 :polarity -~e.7 :ARG0 e2 :ARG1 (p3 / phosphatase~e.9 :name (n3 / name :op1 "myosin"~e.8))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 12~e.11)))) # ::id bio.chicago_2015.19850 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Some E2F may remain bound to a partially phosphorylated Rb throughout the normal cell cycle . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 2-1 3-1.1 4-1.1.2 5-1.1.2.2.r 7-1.1.2.2.2.1 7-1.1.2.2.2.1.r 8-1.1.2.2.2 9-1.1.2.2.1.1 12-1.1.3.2 13-1.1.3.1 14-1.1.3 (p / possible-01~e.2 :ARG1 (r / remain-01~e.3 :ARG1 (p2 / protein :name (n / name :op1 "E2F"~e.1) :quant (s / some~e.0)) :ARG3 (b / bind-01~e.4 :ARG1 p2 :ARG2~e.5 (p3 / protein :name (n2 / name :op1 "Rb"~e.9) :ARG2-of (p4 / phosphorylate-01~e.8 :degree~e.7 (p5 / part~e.7)))) :duration (c / cycle-02~e.14 :ARG1 (c2 / cell~e.13) :ARG1-of (n3 / normal-02~e.12)))) # ::id bio.chicago_2015.19878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) A model on how the proneural complex encompassing Pnr , Chip , and the ( Ac/Sc )- Da heterodimer is regulated by Osa . # ::alignments 1-1.1 4-1 5-1.2.r 6-1.2.1.r 9-1.2.1.2 10-1.2.1.2.2 11-1.2.1.2.2.1.1.1.1 13-1.2.1.2.2.1.2.1.1 15-1.2.1.2.2.1 18-1.2.1.2.2.1.3.1.1.1 20-1.2.1.2.2.1.3.2.1.1 21-1.2.1.2.2.1.3 23-1.2.1 24-1.2.1.1.r 25-1.2.1.1.1.1 (m5 / model-01~e.4 :li "b"~e.1 :ARG1~e.5 (t / thing :manner-of~e.6 (r / regulate-01~e.23 :ARG0~e.24 (p2 / protein :name (n5 / name :op1 "Osa"~e.25)) :ARG1 (c / complex~e.9 :mod (p / proneuron) :ARG0-of (e / encompass-01~e.10 :ARG1 (a / and~e.15 :op1 (p3 / protein :name (n2 / name :op1 "pnr"~e.11)) :op2 (p4 / protein :name (n3 / name :op1 "chip"~e.13)) :op3 (h / heterodimer~e.21 :part (p5 / protein :name (n / name :op1 "Ac/Sc"~e.18)) :part (p6 / protein :name (n6 / name :op1 "Da"~e.20))))))))) # ::id bio.chicago_2015.19893 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This possibility is supported by the demonstration that phosphorylation of Thr @-@ 654 in the proximal membrane domain of the EGF receptor by protein kinase C decreases EGF @-@ dependent activation of the EGF receptor [ 6 . # ::alignments 0-1.3.1 1-1.3 3-1 4-1.2.r 6-1.2 7-1.2.1.r 8-1.2.1.1 12-1.2.1.1.1.1 13-1.2.1.1.3.r 15-1.2.1.1.3.1 16-1.2.1.1.3.1.1 17-1.2.1.1.3 18-1.2.1.1.3.2.r 20-1.2.1.1.3.2.1.1 21-1.2.1.1.3.2.1.2 22-1.2.1.1.2.r 23-1.2.1.1.2.1.1 24-1.2.1.1.2.1.2 25-1.2.1.1.2.1.3 26-1.2.1 27-1.2.1.2.2.1 29-1.2.1.2.2 30-1.2.1.2 31-1.2.1.2.1.r 33-1.2.1.2.1 34-1.2.1.2.1 36-1.1 (s / support-01~e.3 :li 6~e.36 :ARG0~e.4 (d / demonstrate-01~e.6 :ARG1~e.7 (d2 / decrease-01~e.26 :ARG0 (p / phosphorylate-01~e.8 :ARG1 (a2 / amino-acid :mod 654~e.12 :name (n4 / name :op1 "threonine")) :ARG2~e.22 (e2 / enzyme :name (n2 / name :op1 "protein"~e.23 :op2 "kinase"~e.24 :op3 "C"~e.25)) :location~e.13 (d3 / domain~e.17 :mod (p4 / proximal~e.15 :mod (m / membrane~e.16)) :part-of~e.18 (e / enzyme :name (n / name :op1 "EGF"~e.20 :op2 "receptor"~e.21)))) :ARG1 (a / activate-01~e.30 :ARG1~e.31 e~e.33,34 :ARG0-of (d4 / depend-01~e.29 :ARG1 e~e.27)))) :ARG1 (p2 / possible-01~e.1 :ARG1 (t / this~e.0))) # ::id bio.chicago_2015.19949 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , EGF failed to promote the spreading of MDCK cells and Paxillin displayed a diffuse distribution within the cytoplasm ( Figure 1A ) , similar to unstimulated MDCK cells ( Figure 1A ) . # ::alignments 1-1 3-1.1.1.1.1.1 4-1.1.1 6-1.1.1.2 8-1.1.1.2.2 9-1.1.1.2.2.1.r 10-1.1.1.2.2.1.1.1 11-1.1.1.2.2.1 12-1.1 13-1.1.2.1.1.1 14-1.1.2 16-1.1.2.2.1 17-1.1.2.2 20-1.1.2.2.2 22-1.1.2.2.3.2 23-1.1.2.2.3.2 26-1.1.2.2.3 29-1.1.2.2.3.1.1.1 30-1.1.2.2.3.1 32-1.1.2.2.3.2 33-1.1.2.2.3.2 (c / contrast-01~e.1 :ARG2 (a2 / and~e.12 :op1 (f / fail-01~e.4 :ARG1 (p3 / protein :name (n / name :op1 "EGF"~e.3)) :ARG2 (p / promote-01~e.6 :ARG0 p3 :ARG1 (s2 / spread-03~e.8 :ARG1~e.9 (c2 / cell~e.11 :name (n2 / name :op1 "MDCK"~e.10))))) :op2 (d / display-01~e.14 :ARG0 (p2 / protein :name (n3 / name :op1 "Paxillin"~e.13)) :ARG1 (d2 / distribute-01~e.17 :ARG1-of (d3 / diffuse-01~e.16) :location (c3 / cytoplasm~e.20) :ARG1-of (r / resemble-01~e.26 :ARG2 (c5 / cell~e.30 :name (n4 / name :op1 "MDCK"~e.29) :ARG1-of (s3 / stimulate-01 :polarity -)) :ARG1-of d4~e.22,23,32,33)) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "1A"))))) # ::id bio.chicago_2015.19979 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lack of PKA activity in the purified I B/PKAc fractions ( Figure 1A and data not shown ) and in purified NF @- B - I B - PKAc complexes ( Figure 1D ) suggested that the binding of I B to PKAc inhibits the enzymatic activity of PKA . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 7-1.1.1.2.1.2 10-1.1.1.2.1 12-1.1.1.2.1.3.1.1 13-1.1.1.2.1.3.1.1.1 14-1.1.1.2.1.3.1 15-1.1.1.2.1.3.1.2 16-1.1.1.2.1.3.1.2.1.1 16-1.1.1.2.1.3.1.2.1.1.r 17-1.1.1.2.1.3.1.2.1 19-1.1.1.2.1.3.1 21-1.1.1.2.1.2 22-1.1.1.2.2.1.1.1 24-1.1.1.2.2.1.1.1 27-1.1.1.2.2.1.1.1 30-1.1.1.2.2 32-1.1.1.2.2.4.1 33-1.1.1.2.2.4.1.1 35-1 36-1.2.r 38-1.2.1 41-1.1.1.2.2.1.1.1 44-1.2 46-1.2.2.2 47-1.1.1 47-1.2.2 49-1.1.1.1.1.1 (s / suggest-01~e.35 :ARG0 (l / lack-01~e.1 :ARG1~e.2 (a / activity-06~e.4,47 :ARG0 (e / enzyme :name (n / name :op1 "PKA"~e.3,49)) :ARG1 (a2 / and :op1 (f / fraction-01~e.10 :ARG1 (s3 / slash :op1 (e2 / enzyme :name (n2 / name :op1 "IB")) :op2 e) :ARG1-of (p / purify-01~e.7,21) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.14,19 :op1 (f2 / figure~e.12 :mod "1A"~e.13) :op2 (d2 / data~e.15 :ARG1-of (s2 / show-01~e.17 :polarity~e.16 -~e.16))))) :op2 (m3 / macro-molecular-complex~e.30 :part (p3 / protein :name (n3 / name :op1 "NF-B"~e.22,24,27,41)) :part e2 :part e :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.32 :mod "1D"~e.33)) :ARG1-of p)))) :ARG1~e.36 (i / inhibit-01~e.44 :ARG0 (b / bind-01~e.38 :ARG1 e2 :ARG2 e) :ARG1 (a4 / activity-06~e.47 :ARG0 e :mod (e4 / enzyme~e.46)))) # ::id bio.chicago_2015.20002 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E , concentration @-@ dependent inhibitory effect of AG1478 on EGF @-@ induced phosphorylation of the EGF @-@ R at Tyr1173 . # ::alignments 0-1.1 2-1.5.1 4-1.5 5-1.4 6-1 7-1.2.r 8-1.2.1.1 9-1.3.r 10-1.3.2.1.1.1 12-1.3.2 13-1.3 16-1.3.2.1.1.1 18-1.3.1.3.1.1 (a / affect-01~e.6 :li "e"~e.0 :ARG0~e.7 (s / small-molecule :name (n5 / name :op1 "AG1478"~e.8)) :ARG1~e.9 (p / phosphorylate-01~e.13 :ARG1 (a2 / amino-acid :mod 1173 :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n2 / name :op1 "EGF-R"~e.18))) :ARG2-of (i2 / induce-01~e.12 :ARG0 (p3 / protein :name (n4 / name :op1 "EGF"~e.10,16)))) :ARG2 (i / inhibit-01~e.5) :ARG0-of (d / depend-01~e.4 :ARG1 (c / concentrate-02~e.2))) # ::id bio.chicago_2015.20021 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , this peptide also blocked EGF activation of endogenous Ral . # ::alignments 0-1.4 2-1.1.1 3-1.1 4-1.3 5-1 6-1.2.1.1.1 7-1.2 8-1.2.2.r 9-1.2.2.2 10-1.2.2.1.1 (b / block-01~e.5 :ARG0 (p / peptide~e.3 :mod (t / this~e.2)) :ARG1 (a2 / activate-01~e.7 :ARG0 (p2 / protein :name (n / name :op1 "EGF"~e.6)) :ARG1~e.8 (p3 / protein :name (n2 / name :op1 "Ral"~e.10) :mod (e / endogenous~e.9))) :mod (a / also~e.4) :mod (i / important~e.0)) # ::id bio.chicago_2015.20023 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Kek1 inhibits ligand binding To examine the mechanistic details underlying Kek1 suppression of EGFR activity , we used the baculovirus/ Sf9 insect cell expression system . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1 3-1.1.2 5-1.2.3 7-1.2.3.2.1 8-1.2.3.2 9-1.2.3.2.2 10-1.2.3.2.2.1.1.1.1 11-1.2.3.2.2.1 12-1.2.3.2.2.1.2.r 13-1.2.3.2.2.1.2.1.1.1 14-1.2.3.2.2.1.2 16-1.2.1 17-1.2 20-1.2.2.1.2.1.1 21-1.2.2.1.2.2 22-1.2.2.1.2 23-1.2.2.1 24-1.2.2 (m / multi-sentence :snt1 (i / inhibit-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "Kek1"~e.0)) :ARG1 (b / bind-01~e.3 :ARG1 (l / ligand~e.2))) :snt2 (u2 / use-01~e.17 :ARG0 (w / we~e.16) :ARG1 (s2 / system~e.24 :mod (e3 / express-03~e.23 :ARG2 (o / organism :name (n4 / name :op1 "baculovirus")) :ARG3 (c2 / cell-line~e.22 :name (n5 / name :op1 "Sf9"~e.20) :mod (i2 / insect~e.21)))) :ARG2 (e2 / examine-01~e.5 :ARG0 w :ARG1 (d / detail~e.8 :mod (m2 / mechanistic~e.7) :ARG0-of (u / underlie-01~e.9 :ARG1 (s / suppress-01~e.11 :ARG0 (p / protein :name (n2 / name :op1 "Kek1"~e.10)) :ARG1~e.12 (a / activity-06~e.14 :ARG0 (e4 / enzyme :name (n3 / name :op1 "EGFR"~e.13))))))))) # ::id bio.chicago_2015.20029 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test whether the extracellular domain of Kek1 , which contains five LRR and one Ig motif ( Musacchio and Perrimon , 1996 ) , is required for the inhibition of the EGFR activity by Kek1 , we generated transgenic lines that contain either UAS @-@ kek1 extra or UAS @-@ kek1 intra . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 4-1.3.2.3.1 5-1.3.2.3 6-1.3.2.3.2.r 7-1.3.2.3.2.1.1 10-1.3.2.3.3 11-1.3.2.3.3.1.1.1 12-1.3.2.3.3.1.1.2.1 13-1.3.2.3.3.1 14-1.3.2.3.3.1.2.1 16-1.3.2.3.3.1.2 18-1.3.2.3.3.2.1.1.1.1.1 19-1.3.2.3.3.2.1.1 20-1.3.2.3.3.2.1.1.2.1.1 22-1.3.2.3.3.2.1.2.1 26-1.3.2 27-1.3.2.2.r 29-1.3.2.2 30-1.3.2.2.2.r 32-1.3.2.2.2.1.1.1 33-1.3.2.2.2 34-1.3.2.2.1.r 35-1.3.2.2.1 37-1.1 38-1 39-1.2.1 40-1.2 42-1.2.2 44-1.2.2.1.1.1.1 44-1.2.2.1.2.1.1 46-1.2.2.1.1.1.1 46-1.2.2.1.2.1.1 47-1.2.2.1.1.2 48-1.2.2.1 49-1.2.2.1.1.1.1 49-1.2.2.1.2.1.1 51-1.2.2.1.1.1.1 51-1.2.2.1.2.1.1 52-1.2.2.1.2.2 (g / generate-01~e.38 :ARG0 (w / we~e.37) :ARG1 (l / line~e.40 :mod (t / transgenic~e.39) :ARG0-of (c / contain-01~e.42 :ARG1 (o / or~e.48 :op1 (s / small-molecule :name (n2 / name :op1 "UAS-kek1"~e.44,46,49,51) :mod (e2 / extra~e.47)) :op2 (s2 / small-molecule :name (n3 / name :op1 "UAS-kek1"~e.44,46,49,51) :mod (i / intra~e.52))))) :purpose (t2 / test-01~e.1 :ARG0 w :ARG1 (r / require-01~e.26 :mode~e.2 interrogative~e.2 :ARG0~e.27 (i2 / inhibit-01~e.29 :ARG0~e.34 p5~e.35 :ARG1~e.30 (a / activity-06~e.33 :ARG0 (e / enzyme :name (n / name :op1 "EGFR"~e.32)))) :ARG1 (d2 / domain~e.5 :mod (e4 / extracellular~e.4) :mod~e.6 (p5 / protein :name (n4 / name :op1 "Kek1"~e.7)) :ARG0-of (c2 / contain-01~e.10 :ARG1 (a2 / and~e.13 :op1 (s3 / small-molecule :quant 5~e.11 :name (n5 / name :op1 "LRR"~e.12)) :op2 (m4 / motif~e.16 :quant 1~e.14 :mod (p3 / protein :name (n8 / name :op1 "immunoglobulin")))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.19 :op1 (p / person :name (n6 / name :op1 "Musacchio"~e.18)) :op2 (p2 / person :name (n7 / name :op1 "Perrimon"~e.20))) :time (d / date-entity :year 1996~e.22)))))))) # ::id bio.chicago_2015.20072 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pharmacological disruption of actin affects MT organization , and vice versa ( Lin and Forscher , 1993 ; Rochlin et al. , 1999 ) . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1 4-1.2 5-1.1.2.1.1.1 6-1.1.2 8-1 8-1.3.1 8-1.3.1.1.1 12-1.3.1.1.1.1.1.1 13-1.3.1.1.1 14-1.3.1.1.1.2.1.1 16-1.3.1.1.2.1 18-1.3.1.2.1.1.1.1 19-1.3.1.2.1 20-1.3.1.2.1.2.1 22-1.3.1.2.2.1 (a / and~e.8 :op1 (a2 / affect-01~e.4 :ARG0 (d3 / disrupt-01~e.1 :ARG1~e.2 (p5 / protein :name (n4 / name :op1 "actin"~e.3)) :mod (p / pharmacology~e.0)) :ARG1 (o / organize-01~e.6 :ARG1 (p6 / protein :name (n5 / name :op1 "MT"~e.5)))) :op2 (a3 / affect-01~e.4 :ARG0 o :ARG1 d3) :ARG1-of (d4 / describe-01 :ARG0 (a8 / and~e.8 :op1 (p7 / publication-91 :ARG0 (a5 / and~e.8,13 :op1 (p2 / person :name (n / name :op1 "Lin"~e.12)) :op2 (p3 / person :name (n2 / name :op1 "Forscher"~e.14))) :time (d / date-entity :year 1993~e.16)) :op2 (p8 / publication-91 :ARG0 (a6 / and~e.19 :op1 (p4 / person :name (n3 / name :op1 "Rochlin"~e.18)) :op2 (p9 / person :mod (o2 / other~e.20))) :time (d2 / date-entity :year 1999~e.22))))) # ::id bio.chicago_2015.20206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok An N @-@ terminal peptide of Ral @-@ GDS prevents EGF @-@ induced complex formation between PDK1 and Ral @-@ GDS and suppresses EGF @-@ induced activation of Ral If this hypothesis is correct , then expression of just the N @-@ terminus of Ral @-@ GDS ( N @-@ Ral @-@ GDS ) should bind to PDK1 in cells , block binding of PDK1 to Ral @-@ GDS and interfere with Ral activation by EGF . # ::alignments 1-1.1.1.1.1.1.1 3-1.1.1.1.1.1.1 4-1.1.1.1 4-1.2.1.1.2.2.2 6-1.1.1.1.1.2.1.1 8-1.1.1.1.1.2.1.1 9-1.1.1 10-1.1.2.2.2.1.1.1 12-1.1.2.2.2 13-1.1.1.2.1 14-1.1.1.2 16-1.2.1.1.1.2.1.1 18-1.1.1.1.1.2.1.1 20-1.1.1.1.1.2.1.1 21-1.1 22-1.1.2 23-1.1.2.2.2.1.1.1 25-1.1.2.2.2 26-1.1.2.2 27-1.1.2.2.1.r 28-1.1.2.2.1.1.1 29-1.2 30-1.2.2.1.2 31-1.2.2.1 31-1.2.2.1.1 31-1.2.2.1.1.r 33-1.2.2 35-1.2 36-1.2.1.1.1.1 37-1.2.1.1.1.1.1.r 38-1.2.1.1.1.1.1.2 40-1.1.1.1.1.1.1 40-1.2.1.1.1.1.1.1.1 42-1.1.1.1.1.1.1 42-1.2.1.1.1.1.1.1.1 44-1.1.2.2.1.1.1 46-1.1.1.1.1.2.1.1 48-1.1.1.1.1.1.1 50-1.1.1.1.1.2.1.1 52-1.1.1.1.1.2.1.1 54-1.2.1 55-1.2.1.1.2.2 56-1.2.1.1.2.2.1.r 57-1.2.1.1.2.2.1 58-1.2.1.1.1.1.2.r 59-1.2.1.1.1.1.2 61-1.2.1.1.2 62-1.2.1.1.1 64-1.1.1.2.1.1.1.1 64-1.2.1.1.1.2.1.1 66-1.1.2.2.1.1.1 68-1.1.1.1.1.2.1.1 69-1.2.1.1 70-1.2.1.1.3 71-1.2.1.1.3.2.r 72-1.2.1.1.3.2.2.1.1 73-1.2.1.1.3.2 74-1.2.1.1.3.2.1.r 75-1.2.1.1.3.2.1.1.1 (m / multi-sentence :snt1 (a / and~e.21 :op1 (p2 / prevent-01~e.9 :ARG0 (p13 / peptide~e.4 :part-of (p9 / protein-segment :name (n9 / name :op1 "N-terminus"~e.1,3,40,42,48) :part-of (p10 / protein :name (n10 / name :op1 "Ral-GDS"~e.6,8,18,20,46,50,52,68)))) :ARG1 (f / form-02~e.14 :ARG1 (m4 / macro-molecular-complex~e.13 :part (e3 / enzyme :name (n11 / name :op1 "PDK1"~e.64)) :part p10))) :op2 (s / suppress-01~e.22 :ARG0 p9 :ARG1 (a3 / activate-01~e.26 :ARG1~e.27 (p5 / protein :name (n4 / name :op1 "Ral"~e.28,44,66)) :ARG2-of (i2 / induce-01~e.12,25 :ARG0 (p3 / protein :name (n3 / name :op1 "EGF"~e.10,23)))))) :snt2 (h2 / have-condition-91~e.29,35 :ARG1 (r / recommend-01~e.54 :ARG1 (a4 / and~e.69 :op1 (b / bind-01~e.62 :ARG1 (e / express-03~e.36 :ARG2~e.37 (p / protein-segment :name (n / name :op1 "N-terminus"~e.40,42) :mod (j / just~e.38) :part-of p10) :ARG3~e.58 (c3 / cell~e.59)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "PDK1"~e.16,64))) :op2 (b2 / block-01~e.61 :ARG0 e :ARG1 (b3 / bind-01~e.55 :ARG1~e.56 e2~e.57 :ARG2 (p6 / peptide~e.4))) :op3 (i3 / interfere-01~e.70 :ARG0 e :ARG1~e.71 (a5 / activate-01~e.73 :ARG0~e.74 (p8 / protein :name (n8 / name :op1 "EGF"~e.75)) :ARG1 (p7 / protein :name (n7 / name :op1 "Ral"~e.72)))))) :ARG2 (c2 / correct-02~e.33 :ARG1 (t / thing~e.31 :ARG1-of~e.31 (h / hypothesize-01~e.31) :mod (t3 / this~e.30))))) # ::id bio.chicago_2015.20220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Surprisingly , we observed that KSR specifically blocks EGF and Ras @-@ induced phosphorylation and activation of ternary complex factors ( TCF ) , physiological substrates of MAP kinases , without affecting the activation of MAP kinase itself . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2.3 7-1.2 8-1.2.2.1.1.1 9-1.2.2 10-1.2.2.2.3.1.1.1 12-1.2.2.2.3 13-1.2.2.2.1 14-1.2.2.2 15-1.2.2.2.2 16-1.2.2.2.2.1.r 17-1.2.2.2.2.1.1.1 18-1.2.2.2.2.1.1.2 19-1.2.2.2.2.1.1.3 25-1.2.2.3 30-1.2.4.1 30-1.2.4.1.r 31-1.2.4 33-1.2.4.2 34-1.2.2.3.2.r 35-1.2.2.3.2.1.1 36-1.2.2.3.2.1.2 (o / observe-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (b / block-01~e.7 :ARG0 (e2 / enzyme :name (n / name :op1 "KSR"~e.5)) :ARG1 (a / and~e.9 :op1 (p2 / protein :name (n2 / name :op1 "EGF"~e.8)) :op2 (a5 / and~e.14 :op1 (p / phosphorylate-01~e.13 :ARG1 p5) :op2 (a2 / activate-01~e.15 :ARG1~e.16 (p5 / protein :name (n5 / name :op1 "ternary"~e.17 :op2 "complex"~e.18 :op3 "factor"~e.19))) :ARG2-of (i / induce-01~e.12 :ARG1 (e / enzyme :name (n3 / name :op1 "Ras"~e.10)))) :op4 (s2 / substrate~e.25 :mod (p3 / physiologic) :poss~e.34 (p6 / protein-family :name (n6 / name :op1 "MAP"~e.35 :op2 "kinase"~e.36)))) :ARG1-of (s / specific-02~e.6) :manner (a3 / affect-01~e.31 :polarity~e.30 -~e.30 :ARG1 (a4 / activate-01~e.33 :ARG1 (k / kinase)))) :ARG0-of (s3 / surprise-01~e.0)) # ::id bio.chicago_2015.20225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activation of DER by EGF leads to the stimulation of the Ras @/@ mitogen @-@ activated protein ( MAP ) kinase pathway ( 7 ) . # ::alignments 1-1.1 3-1.1.2.1.1 5-1.1.1.1.1 6-1 7-1.2.r 9-1.2 10-1.2.1.r 12-1.2.1.1.1 16-1.1 17-1.1.1 22-1.2.1 24-1.3.1.1.1 (l / lead-03~e.6 :ARG0 (a / activate-01~e.1,16 :ARG0 (p / protein~e.17 :name (n / name :op1 "EGF"~e.5)) :ARG1 (e / enzyme :name (n2 / name :op1 "DER"~e.3))) :ARG2~e.7 (s / stimulate-01~e.9 :ARG1~e.10 (p3 / pathway~e.22 :name (n5 / name :op1 "Ras/MAPK"~e.12))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 7~e.24)))) # ::id bio.chicago_2015.20250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ser1 expression is regulated positively by Notch activity ; Dl1 and Ser2 are regulated negatively ( 7 ) . # ::alignments 1-1.1.2 3-1.1 4-1.1.3 4-1.1.3.r 6-1.1.1.1.1.1 7-1.1.1 13-1.1 16-1.3.1.1.1 (a5 / and :op1 (r / regulate-01~e.3,13 :ARG0 (a / activity-06~e.7 :ARG0 (p / protein :name (n / name :op1 "Notch"~e.6))) :ARG1 (e / express-03~e.1 :ARG2 (a2 / amino-acid :mod 1 :name (n2 / name :op1 "serine"))) :manner~e.4 (p2 / positive~e.4)) :op2 (d2 / downregulate-01 :ARG1 (a3 / and :op1 (a4 / amino-acid :mod 11 :name (n3 / name :op1 "aspartate")) :op2 (a6 / amino-acid :mod 2 :name (n5 / name :op1 "serine")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 7~e.16)))) # ::id bio.chicago_2015.20268 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in cell lines expressing the dominant negative mutants S222A and K97A , which showed inhibition of RSK activation by EGF , the decrease in GSK @-@ 3 beta activity was partially blocked . # ::alignments 0-1 2-1.1.r 3-1.1.3 4-1.1.3 5-1.1.3.1 7-1.1.3.1.1.3 8-1.1.3.1.1.3.1 9-1.1.3.1.1.1 9-1.1.3.1.1.2 10-1.1.3.1.1.1.1 11-1.1.3.1.1 12-1.1.3.1.1.2.1 15-1.1.3.1.1.4 16-1.1.3.1.1.4.1 17-1.1.3.1.1.4.1.2.r 18-1.1.3.1.1.4.1.2.1.1.1 19-1.1.3.1.1.4.1.2 20-1.1.3.1.1.4.1.1.r 21-1.1.3.1.1.4.1.1.1.1 24-1.1.1 25-1.1.1.1.r 26-1.1.1.1.1.1.1 30-1.1.1.1 32-1.1.2 32-1.1.2.r 33-1.1 (c2 / contrast-01~e.0 :ARG2~e.2 (b / block-01~e.33 :ARG1 (d / decrease-01~e.24 :ARG1~e.25 (a / activity-06~e.30 :ARG0 (e4 / enzyme :name (n2 / name :op1 "GSK-3beta"~e.26)))) :degree~e.32 (p / part~e.32) :location (c / cell-line~e.3,4 :ARG3-of (e2 / express-03~e.5 :ARG2 (a2 / and~e.11 :op1 (m2 / mutate-01~e.9 :value "S222A"~e.10) :op2 (m3 / mutate-01~e.9 :value "K97A"~e.12) :ARG0-of (d2 / dominate-01~e.7 :mod (n / negative~e.8)) :ARG0-of (s / show-01~e.15 :ARG1 (i / inhibit-01~e.16 :ARG0~e.20 (p2 / protein :name (n6 / name :op1 "EGF"~e.21)) :ARG1~e.17 (a3 / activate-01~e.19 :ARG0 (e3 / enzyme :name (n5 / name :op1 "RSK"~e.18)))))))))) # ::id bio.chicago_2015.20273 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The antibody binds equally well to both the wt EGFR and deltaEGFR and does not affect the binding of EGF to the wt EGFR . # ::alignments 1-1.1.1 2-1.1 3-1.1.3.1 4-1.1.3 8-1.1.2.1.2 9-1.1.2.1.1.1 10-1 10-1.1.2 12-1 14-1.2.1 14-1.2.1.r 15-1.2 17-1.2.3 18-1.2.3.1.r 19-1.2.3.1.1.1 22-1.1.2.1.2 23-1.1.2.1.1.1 (a / and~e.10,12 :op1 (b / bind-01~e.2 :ARG1 (a2 / antibody~e.1) :ARG2 (a3 / and~e.10 :op1 (e / enzyme :name (n / name :op1 "EGFR"~e.9,23) :mod (w2 / wild-type~e.8,22)) :op2 (e5 / enzyme :name (n4 / name :op1 "delta-EGFR"))) :ARG1-of (w / well-09~e.4 :ARG1-of (e2 / equal-01~e.3))) :op2 (a4 / affect-01~e.15 :polarity~e.14 -~e.14 :ARG0 a2 :ARG1 (b3 / bind-01~e.17 :ARG1~e.18 (p / protein :name (n3 / name :op1 "EGF"~e.19)) :ARG2 e))) # ::id bio.chicago_2015.20290 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Instead , PtdIns( 4,5 )- P2 binding was found to inhibit alpha @-@ actinin binding to actin filaments and did not appear to be required for localization to focal adhesions . # ::alignments 0-1.3 5-1.1.1.1.1.2 6-1.1.1 8-1.1 10-1.1.1.2 11-1.1.1.2.1.1.1.1 13-1.1.1.2.1.1.1.1 14-1.1.1.2.1 15-1.1.1.2.1.2.r 16-1.1.1.2.1.2.1.1.1 17-1.1.1.2.1.2 18-1 20-1.2.1 20-1.2.1.r 21-1.2 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1 27-1.2.2.1.1.r 28-1.2.2.1.1.1 29-1.2.2.1.1 (a / and~e.18 :op1 (f / find-01~e.8 :ARG1 (b / bind-01~e.6 :ARG1 (s / small-molecule :name (n2 / name :op1 "PtdIns(4,5)-" :op2 "P2"~e.5)) :ARG0-of (i / inhibit-01~e.10 :ARG1 (b2 / bind-01~e.14 :ARG1 (p / protein :name (n / name :op1 "alpha-actinin"~e.11,13)) :ARG2~e.15 (f2 / filament~e.17 :mod (p2 / protein :name (n3 / name :op1 "actin"~e.16))))))) :op2 (a2 / appear-02~e.21 :polarity~e.20 -~e.20 :ARG1 (r / require-01~e.24 :ARG0~e.25 (l / localize-01~e.26 :location~e.27 (a3 / adhere-01~e.29 :mod (f3 / focal~e.28))) :ARG1 b)) :ARG1-of (i2 / instead-of-91~e.0)) # ::id bio.chicago_2015.20303 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our study establishes Rac/ Cdc42 @/@ Pak as an upstream module for Raf @-@ 1 activation in association with the integrity of microtubules , but not for EGF activation of Raf . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1 4-1.2.1.1 6-1.2.1.1 7-1.3.r 9-1.3.1 10-1.3 11-1.3.2.r 12-1.3.2.1.1.1 14-1.3.2.1.1.1 15-1.3.2 16-1.3.2.2.r 17-1.3.2.2 18-1.3.2.2.1.r 20-1.3.2.2.1 24-1.3.2.2.2 25-1.3.2.2.2.1.1 25-1.3.2.2.2.1.1.r 27-1.3.2.2.2.1.2.1.1 28-1.3.2.2.2.1 29-1.3.2.2.2.1.3.r 30-1.3.2.2.2.1.3.1.1 (e / establish-01~e.2 :ARG0 (s / study-01~e.1 :ARG0~e.0 (w / we~e.0)) :ARG1 (p3 / pathway :name (n3 / name :op1 "Rac/Cdc42/Pak"~e.4,6)) :ARG2~e.7 (m / module~e.10 :direction (u / upstream~e.9) :beneficiary~e.11 (a / activate-01~e.15 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Raf-1"~e.12,14)) :ARG1-of~e.16 (a3 / associate-01~e.17 :ARG2~e.18 (i / integrity~e.20 :poss (m2 / microtubule)) :ARG1-of (c / contrast-01~e.24 :ARG2 (a4 / activate-01~e.28 :polarity~e.25 -~e.25 :ARG0 (p / protein :name (n / name :op1 "EGF"~e.27)) :ARG1~e.29 (e2 / enzyme :name (n4 / name :op1 "Raf"~e.30)))))))) # ::id bio.chicago_2015.20312 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Enhancement of EGF @-@ induced EGF receptor autophosphorylation and MAPK phosphorylation by GD1a . # ::alignments 0-1.1 4-1.1.1.3 5-1.1.1.1.1.1 6-1.1.1.1.1.2 7-1.1.1 7-1.2 8-1 9-1.2.1.1.1 10-1.2 11-1.2.2.r 12-1.2.2.1.1 (a / and~e.8 :op1 (e / enhance-01~e.0 :ARG1 (p2 / phosphorylate-01~e.7 :ARG1 (e3 / enzyme :name (n2 / name :op1 "EGF"~e.5 :op2 "receptor"~e.6)) :ARG2 e3 :ARG2-of (i / induce-01~e.4 :ARG0 e3))) :op2 (p4 / phosphorylate-01~e.7,10 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK"~e.9)) :ARG2~e.11 (s / small-molecule :name (n3 / name :op1 "GD1a"~e.12)))) # ::id bio.chicago_2015.20319 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF receptor levels were significantly decreased following EGF stimulation of cells co @-@ expressing ACK2 and SH3PX1 , thus highlighting a novel role for ACK2 , working together with SH3PX1 to promote the degradation of the EGF receptor . # ::alignments 0-1.1.1.1.1.1 1-1.1.1.1.1.2 2-1.1.1 4-1.1.2 5-1.1 6-1.1.3 7-1.1.3.1.1 8-1.1.3.1 9-1.1.3.1.2.r 10-1.1.3.1.2 13-1.1.3.1.2.1 14-1.1.3.1.2.1.1.1.1.1 15-1.1.3.1.2.1.1 16-1.1.3.1.2.1.1.2.1.1 18-1 19-1.2.1 21-1.2.1.2.1 22-1.2.1.2 23-1.2.1.2.2.r 24-1.2.1.2.2 26-1.2.2 27-1.1.3.1.2.1.2 28-1.2.2.3.r 29-1.2.2.3 30-1 31-1.2.2.2 33-1.2.2.2.2 34-1.2.2.2.2.1.r 36-1.2.2.2.2.1 37-1.2.2.2.2.1 (c2 / cause-01~e.18,30 :ARG0 (d / decrease-01~e.5 :ARG1 (l / level~e.2 :quant-of (e2 / enzyme :name (n3 / name :op1 "EGF"~e.0 :op2 "receptor"~e.1))) :ARG1-of (s / significant-02~e.4) :ARG1-of (f / follow-01~e.6 :ARG2 (s2 / stimulate-01~e.8 :ARG0 e2~e.7 :ARG1~e.9 (c / cell~e.10 :ARG3-of (e / express-03~e.13 :ARG2 (a / and~e.15 :op1 (p / protein :name (n / name :op1 "ACK2"~e.14)) :op2 (p3 / protein :name (n5 / name :op1 "SH3PX1"~e.16))) :mod (t2 / together~e.27)))))) :ARG1 (a4 / and :op1 (h / highlight-01~e.19 :ARG0 l :ARG1 (r2 / role~e.22 :mod (n4 / novel~e.21) :beneficiary~e.23 p~e.24)) :op2 (w / work-01~e.26 :ARG0 l :ARG1 (p2 / promote-01~e.31 :ARG0 (a2 / and :op1 l :op2 p3) :ARG1 (d2 / degrade-01~e.33 :ARG1~e.34 e2~e.36,37)) :ARG3~e.28 p3~e.29))) # ::id bio.chicago_2015.20334 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the Z line , titin may determine the minimum extent and tropomyosin the maximum extent of thin filament overlap by regulating alpha @-@ actinin binding to actin , while a unique Z filament may bind to capZ and regulate barbed end capping . # ::alignments 2-1.3.1 3-1.3 5-1.1.1.1.1.1 6-1 6-1.2 7-1.1.1 7-1.1.2 9-1.1.1.2.1 10-1.1.1.2 11-1.1 12-1.1.2.1.1.1 14-1.1.2.2.1 15-1.1.2.2 16-1.1.1.2.2.r 17-1.1.1.2.2.1 18-1.1.1.2.2 19-1.1.1.2.2.2 20-1.1.1.2.2.2.1.r 21-1.1.1.2.2.2.1.1.2 22-1.1.1.2.2.2.1.1.1.1 24-1.1.1.2.2.2.1.1.1.1 25-1.1.1.2.2.2.1 26-1.1.1.2.2.2.1.2.r 27-1.1.1.2.2.2.1.2.1.1 29-1.2.r 31-1.2.1.1.1.2 32-1.2.1.1.1.1.1 33-1.2.1.1.1 34-1.2 35-1.2.1.1 36-1.2.1.1.2.r 37-1.2.1.1.2.1.1 38-1.2.1 39-1.2.1.2 40-1.2.1.2.2.1 41-1.2.1.2.2 42-1.2.1.2.2.2 (p / possible-01~e.6 :ARG1 (a / and~e.11 :op1 (d2 / determine-01~e.7 :ARG0 (p3 / protein :name (n2 / name :op1 "titin"~e.5)) :ARG1 (e / extent~e.10 :degree (m / minimum~e.9) :poss~e.16 (f / filament~e.18 :mod (t / thin~e.17) :ARG1-of (o / overlap-01~e.19 :ARG0~e.20 (b / bind-01~e.25 :ARG1 (p4 / protein :name (n3 / name :op1 "alpha-actinin"~e.22,24) :ARG0-of (r / regulate-01~e.21)) :ARG2~e.26 (p5 / protein :name (n4 / name :op1 "actin"~e.27))))))) :op2 (d3 / determine-01~e.7 :ARG0 (p2 / protein :name (n / name :op1 "tropomyosin"~e.12)) :ARG1 (e2 / extent~e.15 :degree (m2 / maximum~e.14) :poss f))) :time~e.29 (p6 / possible-01~e.6,34 :ARG1 (a2 / and~e.38 :op1 (b2 / bind-01~e.35 :ARG1 (f2 / filament~e.33 :name (n7 / name :op1 "Z"~e.32) :mod (u / unique~e.31)) :ARG2~e.36 (p7 / protein :name (n5 / name :op1 "capZ"~e.37))) :op2 (r2 / regulate-01~e.39 :ARG0 f2 :ARG1 (e3 / end~e.41 :ARG1-of (b3 / barb-01~e.40) :ARG0-of (c / cap-02~e.42))))) :location (l / line~e.3 :mod "Z"~e.2)) # ::id bio.chicago_2015.20374 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of Tubulin to Synaptotagmin I-- To identify soluble proteins that specifically interact with synaptotagmin I , the soluble fraction from the rat brain was incubated with GST fusion protein of the cytoplasmic portion of synaptotagmin I immobilized on glutathione @-@ Sepharose . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 4-1.1.2.1.1 7-1.2.3 8-1.2.3.1.1 9-1.2.3.1 11-1.2.3.1.2.2 12-1.2.3.1.2 13-1.2.3.1.2.1.r 14-1.2.3.1.2.1.1.1 15-1.2.3.1.2.1.1.2 18-1.2.1.1 19-1.2.1 20-1.2.1.2.r 20-1.2.2.3.r 22-1.2.1.2.1 23-1.2.1.2 25-1.2 27-1.2.2.1.1 28-1.2.2 28-1.2.2.2 28-1.2.2.2.r 29-1.2.2.3.1 32-1.2.2.3.2 33-1.2.2.3 35-1.2.2.3.1.1.1 36-1.2.2.3.1.1.2 37-1.2.2.3.1.2 38-1.2.2.3.1.2.1.r 39-1.2.2.3.1.2.1.1.1 41-1.2.2.3.1.2.1.1.1 (m / multi-sentence :snt1 (b / bind-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "tubulin"~e.2)) :ARG2~e.3 (p5 / protein :name (n2 / name :op1 "Synaptotagmin"~e.4 :op2 "I-"))) :snt2 (i / incubate-01~e.25 :ARG1 (f / fraction~e.19 :mod (s / soluble~e.18) :part-of~e.20 (b2 / brain~e.23 :part-of (r / rat~e.22))) :ARG2 (e / enzyme~e.28 :name (n3 / name :op1 "GST"~e.27) :ARG1-of~e.28 (f2 / fuse-01~e.28) :source~e.20 (p3 / portion-01~e.33 :ARG1 (p6 / protein~e.29 :name (n4 / name :op1 "synaptotagmin"~e.35 :op2 "I"~e.36) :ARG1-of (i2 / immobilize-01~e.37 :location~e.38 (s4 / small-molecule :name (n5 / name :op1 "glutathione-Sepharose"~e.39,41)))) :mod (c / cytoplasm~e.32))) :purpose (i3 / identify-01~e.7 :ARG1 (p4 / protein~e.9 :mod (s2 / soluble~e.8) :ARG0-of (i4 / interact-01~e.12 :ARG1~e.13 (p7 / protein :name (n6 / name :op1 "Synaptotagmin"~e.14 :op2 "I"~e.15)) :ARG1-of (s3 / specific-02~e.11)))))) # ::id bio.chicago_2015.20674 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As previously reported , CSP also binds to Hsc70 ( right diagram , col. # ::alignments 0-1.3.1.r 1-1.3.1 2-1.3 4-1.1.1.1 5-1.5 6-1 7-1.2.r 8-1.2.1.1 10-1.4.1.1.1 11-1.4.1.1 (b / bind-01~e.6 :ARG1 (p / protein :name (n / name :op1 "CSP"~e.4)) :ARG2~e.7 (p2 / protein :name (n2 / name :op1 "Hsc70"~e.8)) :ARG1-of (r / report-01~e.2 :time~e.0 (p3 / previous~e.1)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (d2 / diagram~e.11 :ARG1-of (r2 / right-04~e.10)) :op2 (c / col))) :mod (a2 / also~e.5)) # ::id bio.chicago_2015.20679 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , we provide the first evidence of interaction of NK @-@ 4 with the p300 coactivator and the Groucho corepressor . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2.2 5-1.1.2.2.1 5-1.1.2.2.1.r 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1 9-1.1.2.1.1.r 10-1.1.2.1.1.1.1 12-1.1.2.1.1.1.1 13-1.1.2.1.2.r 15-1.1.2.1.2.1.1.1 17-1.1.2.1.2 19-1.1.2.1.2.2.1.1 (a / and~e.0 :op2 (p / provide-01~e.3 :ARG0 (w / we~e.2) :ARG1 (e / evidence-01~e.6 :ARG1~e.7 (i / interact-01~e.8 :ARG0~e.9 (p3 / protein :name (n4 / name :op1 "NK-4"~e.10,12)) :ARG1~e.13 (a3 / and~e.17 :op1 (p2 / protein :name (n2 / name :op1 "p300"~e.15) :ARG0-of (a2 / activate-01 :mod t)) :op2 (p4 / protein :name (n / name :op1 "Groucho"~e.19)) :ARG0-of (r / repress-01 :mod (t / together)))) :mod (o / ordinal-entity~e.5 :value~e.5 1~e.5)))) # ::id bio.chicago_2015.20700 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note that despite the extensive cell @-@ cell rearrangements occurring after Raf activation , E @-@ cadherin still colocalizes with cortical actin at areas of cell @-@ cell contact ( in yellow @-@ orange ) . # ::alignments 0-1 2-1.2 4-1.2.2.3 5-1.2.2.2 7-1.2.2.2 8-1.2.2 10-1.2.2.4 11-1.2.2.4.1.1.1.1 12-1.2.2.4.1 14-1.2.1.1.1.1.1 16-1.2.1.1.1.1.1 17-1.2.1.3 18-1.2.1 19-1.2.1.1.r 20-1.2.1.1.2.2 21-1.2.1.1.2.1.1 22-1.2.1.2.r 23-1.2.1.2 25-1.2.2.2 27-1.2.2.2 28-1.2.1.2.1 31-1.3.1.1 33-1.3.1.2 (n2 / note-01~e.0 :ARG0 (y / you) :ARG1 (h / have-concession-91~e.2 :ARG1 (c / colocalize-01~e.18 :ARG1~e.19 (a5 / and :op1 (p2 / protein :name (n3 / name :op1 "E-cadherin"~e.14,16)) :op2 (p / protein :name (n / name :op1 "actin"~e.21) :mod (c4 / cortical~e.20))) :ARG2~e.22 (a2 / area~e.23 :mod (c5 / contact-01~e.28 :ARG0 c3 :ARG1 c3)) :mod (s / still~e.17)) :ARG2 (r / rearrange-01~e.8 :ARG0 c3 :ARG1 (c3 / cell~e.5,7,25,27) :ARG1-of (e / extensive-03~e.4) :time (a4 / after~e.10 :op1 (a / activate-01~e.12 :ARG1 (e2 / enzyme :name (n6 / name :op1 "Raf"~e.11)))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (y2 / yellow~e.31) :op2 (o / orange~e.33)))) # ::id bio.chicago_2015.20701 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In fact , an earlier report ( 31 ) suggests that Src , which can up @-@ regulate NMDA receptor activity , binds to the NMDA receptor complex . # ::alignments 0-1.3 1-1.3 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1.1 7-1.1.2.1.1.1 9-1 10-1.2.r 11-1.2.1.1.1 14-1.2.1.2.2 18-1.2.1.2.1.1 19-1.2.1.2.1.1 20-1.2.1.2.1 22-1.2 23-1.2.2.r 25-1.2.2.1.1.1 26-1.2.2.1 27-1.2.2 (s / suggest-01~e.9 :ARG0 (r / report-01~e.5 :mod (e2 / early~e.4 :degree~e.4 (m2 / more~e.4)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 31~e.7)))) :ARG1~e.10 (b / bind-01~e.22 :ARG1 (p2 / protein :name (n / name :op1 "Src"~e.11) :ARG0-of (u2 / upregulate-01 :ARG1 (a / activity-06~e.20 :ARG0 r3~e.18,19) :ARG1-of (p3 / possible-01~e.14))) :ARG2~e.23 (c2 / complex~e.27 :mod (r3 / receptor~e.26 :name (n2 / name :op1 "NMDA"~e.25)))) :mod (i / in-fact~e.0,1)) # ::id bio.chicago_2015.20736 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In SW 48 the beta @-@ catenin protein coprecipitated with E @-@ cadherin and APC but not with alpha @-@ catenin . # ::alignments 4-1.1.1.1.1.1 6-1.1.1.1.1.1 7-1.1.1.1 7-1.1.1.2.1 7-1.1.1.2.2 7-1.2.2.2 10-1.1.1.2.1.1.1 12-1.1.1.2.1.1.1 13-1.1.1.2 14-1.1.1.2.2.1.1 15-1 16-1.2.1 16-1.2.1.r 18-1.2.2.2.1.1 20-1.2.2.2.1.1 (c3 / contrast-01~e.15 :ARG1 (c / coprecipitate-01 :ARG1 (a2 / and :op1 (p / protein~e.7 :name (n2 / name :op1 "beta-catenin"~e.4,6)) :op2 (a / and~e.13 :op1 (p2 / protein~e.7 :name (n3 / name :op1 "E-cadherin"~e.10,12)) :op2 (p4 / protein~e.7 :name (n5 / name :op1 "APC"~e.14)))) :location (c2 / cell-line :name (n / name :op1 "SW48"))) :ARG2 (c4 / coprecipitate-01 :polarity~e.16 -~e.16 :ARG1 (a3 / and :op1 p :op2 (p3 / protein~e.7 :name (n4 / name :op1 "alpha-catenin"~e.18,20))) :location c2)) # ::id bio.chicago_2015.20797 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To study the significance of TFIID interactions with the Inr and downstream regions in greater detail , we performed DNase I footprinting , EMSA , and in vitro transcription experiments with the natural AdML promoter . # ::alignments 1-1.3 5-1.3.2.1.1.1.1 6-1.3.2.1 10-1.3.2.1.2 11-1.3.2.1.2.2.1 12-1.3.2.1.2.2 13-1.2.3.3 14-1.3.2.2.1 14-1.3.2.2.1.1 14-1.3.2.2.1.1.r 15-1.3.2.2 17-1.1 17-1.3.1 18-1 19-1.2.1.1.1.1 20-1.2.1.1.1.2 23-1.2.2.1.1 25-1.2 26-1.2.3.3 27-1.2.3.3 28-1.2.3.1 29-1.2.3 30-1.2.3.2.r 32-1.2.3.2.1 34-1.2.3.2 34-1.2.3.2.2 34-1.2.3.2.2.r (p / perform-01~e.18 :ARG0 (w / we~e.17) :ARG1 (a / and~e.25 :op1 (f / footprint :mod (e3 / enzyme :name (n6 / name :op1 "DNase"~e.19 :op2 "I"~e.20))) :op2 (t / thing :name (n / name :op1 "EMSA"~e.23)) :op3 (e / experiment-01~e.29 :ARG1 (t3 / transcribe-01~e.28) :ARG2~e.30 (m3 / molecular-physical-entity~e.34 :ARG1-of (n3 / natural-03~e.32) :ARG0-of~e.34 (p2 / promote-01~e.34) :mod (l / late :mod (m4 / major)) :mod (a3 / adenovirus)) :manner (i / in-vitro~e.13,26,27))) :purpose (s / study-01~e.1 :ARG0 (w2 / we~e.17) :ARG1 (s2 / signify-01 :ARG0 (i2 / interact-01~e.6 :ARG0 (p3 / protein :name (n4 / name :op1 "TFIID"~e.5)) :ARG1 (a2 / and~e.10 :op1 (m / molecular-physical-entity :ARG0-of (i3 / initiate-01)) :op2 (r / region~e.12 :direction (d / downstream~e.11)))) :manner (d2 / detail-01~e.15 :mod (g / great~e.14 :degree~e.14 (m2 / most~e.14)))))) # ::id bio.chicago_2015.20835 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , overexpression of a FAK mutant that is incapable of binding to Src fails to induce paxillin phosphorylation , and expression of the COOH @-@ terminal domain of FAK inhibits both FAK activation and paxillin tyrosine phosphorylation ( Schaller and Parsons , 1995 ; Richardson and Parsons , 1996 ) . # ::alignments 0-1 0-1.1 0-1.1.r 0-1.2.1 0-1.2.1.1.1 1-1 1-1.1 1-1.1.r 1-1.2.1 1-1.2.1.1.1 3-1.1.1.1 4-1.1.1.1.1.r 6-1.1.1.1.1.1.1 7-1.1.1.1.1 7-1.1.1.1.1.2 7-1.1.1.1.1.2.r 10-1.1.1.1.1.3 10-1.1.1.1.1.3.1 10-1.1.1.1.1.3.1.r 11-1.1.1.1.1.3.2.r 12-1.1.1.1.1.3.2 13-1.1.1.1.1.3.2.2.r 14-1.1.1.1.1.3.2.2.1.1 15-1.1.1 17-1.1.1.2 18-1.1.1.2.2.1.1.1 19-1.1.1.2.2 21-1.1 22-1.1.2.1 23-1.1.2.1.1.r 25-1.1.2.1.1.1.1 27-1.1.2.1.1.1.1 30-1.1.2.1.1.2.1.1 31-1.1.2 33-1.1.2.2.1.1 34-1.1.2.2.1 35-1.1 35-1.1.2.2 36-1.1.2.2.2.1.2 37-1.1.2.2.2.1.1.1 38-1.1.2.2.2 40-1.2.1.1.1.1.1.1 41-1.2.1.1.1 42-1.2.1.1.1.2.1.1 44-1.2.1.1.2.1 46-1.2.1.2.1.1.1.1 47-1.2.1 47-1.2.1.1.1 47-1.2.1.2.1 48-1.2.1.2.1.2 50-1.2.1.2.2.1 (a / and~e.0,1 :op2~e.0,1 (a2 / and~e.0,1,21,35 :op1 (f / fail-01~e.15 :ARG1 (o / overexpress-01~e.3 :ARG1~e.4 (e2 / enzyme~e.7 :name (n5 / name :op1 "FAK"~e.6) :ARG2-of~e.7 (m2 / mutate-01~e.7) :ARG1-of (c / capable-01~e.10 :polarity~e.10 -~e.10 :ARG2~e.11 (b / bind-01~e.12 :ARG1 e2 :ARG2~e.13 (p2 / protein :name (n2 / name :op1 "Src"~e.14)))))) :ARG2 (i / induce-01~e.17 :ARG0 e2 :ARG2 (p3 / phosphorylate-01~e.19 :ARG1 (p4 / protein :name (n3 / name :op1 "paxillin"~e.18))))) :op2 (i2 / inhibit-01~e.31 :ARG0 (e / express-03~e.22 :ARG3~e.23 (p5 / protein-segment :name (n / name :op1 "COOH-terminus"~e.25,27) :part-of (p12 / protein :name (n6 / name :op1 "FAK"~e.30)))) :ARG1 (a3 / and~e.35 :op1 (a4 / activate-01~e.34 :ARG1 p12~e.33) :op2 (p / phosphorylate-01~e.38 :ARG1 (a8 / amino-acid :name (n4 / name :op1 "tyrosine"~e.37) :part-of p4~e.36))))) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and~e.0,1,47 :op1 (p6 / publication-91 :ARG0 (a6 / and~e.0,1,41,47 :op1 (p8 / person :name (n7 / name :op1 "Schaller"~e.40)) :op2 (p9 / person :name (n8 / name :op1 "Parsons"~e.42))) :time (d / date-entity :year 1995~e.44)) :op2 (p7 / publication-91 :ARG0 (a7 / and~e.47 :op1 (p10 / person :name (n9 / name :op1 "Richardson"~e.46)) :op2 p9~e.48) :time (d2 / date-entity :year 1996~e.50))))) # ::id bio.chicago_2015.20957 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SRC can be activated by EGFR engagement in various cell types ( 51 @-@ 53 ) and potentiates the ability of the EGFR to transform murine fibroblasts ( 54 ) . # ::alignments 0-1.1.1.2.1.1 1-1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.r 8-1.1.1.1.2.1 9-1.1.1.1.2.2 10-1.1.1.1.2 12-1.1.2.1.1.1.1 14-1.1.2.1.1.1.2 16-1 17-1.2 19-1.2.2 20-1.2.2.2.r 22-1.2.2.2.1 24-1.2.2.2 25-1.2.2.2.2.1 26-1.2.2.2.2 28-1.3.1.1.1 (a / and~e.16 :op1 (p / possible-01~e.1 :ARG1 (a2 / activate-01~e.3 :ARG0~e.4 (e2 / engage-01~e.6 :ARG1 (e3 / enzyme :name (n3 / name :op1 "EGFR"~e.5)) :ARG2~e.7 (t / type~e.10 :mod (v / various~e.8) :mod (c / cell~e.9))) :ARG1 (p2 / protein :name (n2 / name :op1 "SRC"~e.0))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 (v2 / value-interval :op1 51~e.12 :op2 53~e.14))))) :op2 (p4 / potentiate-01~e.17 :ARG0 p2 :ARG1 (c2 / capable-01~e.19 :ARG1 e3 :ARG2~e.20 (t2 / transform-01~e.24 :ARG0 e3~e.22 :ARG1 (f / fibroblast~e.26 :mod (m / murine~e.25))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 54~e.28)))) # ::id bio.chicago_2015.20967 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anterior cells that receive high doses of Hh ( the AP wing organiser ) activate Col , which , in turn , upregulates expression of BS , vn , emc and mtv , and represses expression of EGFR ( aMohler et al. , 2000 ) . # ::alignments 0-1.1.1 0-1.1.2.1.1.2.1.1 1-1.1 3-1.1.2 4-1.1.2.1.2 5-1.1.2.1 6-1.1.2.1.1.r 7-1.1.2.1.1.1.1 11-1.1.2.1.1.2.1 12-1.1.2.1.1 12-1.1.2.1.1.2 12-1.1.2.1.1.2.r 14-1 15-1.2.1.1 19-1.2.2.2 20-1.2.2.2 22-1.2 22-1.2.2 22-1.2.2.r 23-1.2.2.1 24-1.2.2.1.1.r 25-1.2.2.1.1.1.1.1 27-1.2.2.1.1.2.1.1 29-1.2.2.1.1.3.1.1 30-1.2.2.1.1 31-1.2.2.1.1.4.1.1 33-1.2.2.1.1 34-1.2.3 35-1.2.3.1 36-1.2.3.1.1.r 37-1.2.3.1.1.1.1 40-1.3.1.1 41-1.3.1.1.2.1 43-1.3.1.2.1 (a / activate-01~e.14 :ARG0 (c / cell~e.1 :mod (a2 / anterior~e.0) :ARG0-of (r / receive-01~e.3 :ARG1 (d2 / dose-01~e.5 :ARG1~e.6 (p2 / protein~e.12 :name (n3 / name :op1 "Hh"~e.7) :ARG0-of~e.12 (o2 / organize-01~e.12 :ARG1 (w / wing~e.11 :mod (a5 / anterior~e.0) :mod (p9 / posterior)))) :ARG1-of (h / high-02~e.4)))) :ARG1 (e2 / enzyme~e.22 :name (n / name :op1 "Col"~e.15) :ARG0-of~e.22 (u / upregulate-01~e.22 :ARG1 (e3 / express-03~e.23 :ARG2~e.24 (a3 / and~e.30,33 :op1 (p4 / protein :name (n4 / name :op1 "BS"~e.25)) :op2 (p5 / protein :name (n5 / name :op1 "vn"~e.27)) :op3 (p6 / protein :name (n6 / name :op1 "emc"~e.29)) :op4 (p7 / protein :name (n7 / name :op1 "mtv"~e.31)))) :mod (i / in-turn~e.19,20)) :ARG0-of (r3 / repress-01~e.34 :ARG1 (e4 / express-03~e.35 :ARG2~e.36 (e / enzyme :name (n2 / name :op1 "EGFR"~e.37))))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and~e.40 :op1 (p / person :name (n8 / name :op1 "Mohler")) :op2 (p8 / person :mod (o / other~e.41))) :time (d / date-entity :year 2000~e.43)))) # ::id bio.chicago_2015.21011 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If this was the case , we would predict that increased levels of Dl expression would enhance the spl mutant phenotype . # ::alignments 0-1 1-1.2.1 4-1.2 6-1.1.1 8-1.1 9-1.1.2.r 10-1.1.2.1.1 11-1.1.2.1 14-1.1.2.1.2 16-1.1.2 19-1.1.2.2.1 19-1.1.2.2.1.2 19-1.1.2.2.1.2.r 20-1.1.2.2 (h / have-condition-91~e.0 :ARG1 (p / predict-01~e.8 :ARG0 (w / we~e.6) :ARG1~e.9 (e2 / enhance-01~e.16 :ARG0 (l / level~e.11 :ARG1-of (i / increase-01~e.10) :degree-of (e / express-03~e.14 :ARG1 (g / gene :name (n / name :op1 "D1")))) :ARG1 (p2 / phenotype~e.20 :mod (g2 / gene~e.19 :name (n2 / name :op1 "sp1") :ARG2-of~e.19 (m / mutate-01~e.19))))) :ARG2 (c / case-04~e.4 :ARG1 (t / this~e.1))) # ::id bio.chicago_2015.21196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Myosin phosphatase interacts with both ERM family proteins and adducin through MBS , and dephosphorylates the phosphorylated ERM family proteins and adducin ( Fukata et al. 1998 ; Kimura et al. 1998 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1 5-1.1.2.1.1.1 6-1.1.2.1 7-1.1.2.1 7-1.1.3 8-1.1.2 9-1.1.2.2.1.1 11-1.1.3.1.1 13-1.2.1 13-1.3.1 13-1.3.1.1.1 16-1.2.1.3 17-1.2.1.1 18-1.2.1.1 19-1.1.2.1 19-1.1.2.2 20-1.1.2 21-1.1.2.2.1.1 23-1.3.1.1.1.1.1.1 24-1.3.1.1.1 25-1.3.1.1.1.2.1 26-1.3.1.2.2 28-1.3.1.2.1.1.1.1 29-1.3.1 29-1.3.1.1.1 29-1.3.1.2.1 30-1.3.1.1.1.2.1 31-1.3.1.1.2.1 (a / and :op1 (i / interact-01~e.2 :ARG0 (e2 / enzyme :name (n7 / name :op1 "Myosin"~e.0 :op2 "phosphatase"~e.1)) :ARG1 (a2 / and~e.8,20 :op1 (p3 / protein-family~e.6,7,19 :name (n2 / name :op1 "ERM"~e.5)) :op2 (p4 / protein-family~e.19 :name (n3 / name :op1 "adducin"~e.9,21))) :manner (p / protein-segment~e.7 :name (n4 / name :op1 "MBS"~e.11))) :op2 (d2 / dephosphorylate-01 :ARG1 (a3 / and~e.13 :op1 p3~e.17,18 :op2 p4 :ARG3-of (p2 / phosphorylate-01~e.16)) :ARG2 e2) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.13,29 :op1 (p7 / publication-91 :ARG0 (a5 / and~e.13,24,29 :op1 (p5 / person :name (n5 / name :op1 "Fukata"~e.23)) :op2 (p9 / person :mod (o / other~e.25,30))) :time (d / date-entity :year 1998~e.31)) :op2 (p8 / publication-91 :ARG0 (a7 / and~e.29 :op1 (p6 / person :name (n6 / name :op1 "Kimura"~e.28)) :op2 p9) :time d~e.26)))) # ::id bio.chicago_2015.22716 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In Drosophila , it was reported that ceramide functions downstream of caspases during Rpr @-@ induced apoptosis on the basis of the effects of the tripeptide caspase inhibitor N @-@ benzyloxycarbonyl @-@ VAD @-@ fluoromethylketone ( zVAD . # ::alignments 1-1.2.1.1 5-1 6-1.1.r 7-1.1.1.1.1 8-1.1 9-1.1.2.2 12-1.1.3.r 13-1.1.3.1.1.1.1 15-1.1.3.1 17-1.1.4.r 19-1.1.4 20-1.1.4.1.r 22-1.1.4.1 23-1.1.4.1.1.r 25-1.1.4.1.1.2 26-1.1.2.1.1.1 27-1.1.4.1.1 27-1.1.4.1.1.3 27-1.1.4.1.1.3.r 28-1.1.4.1.1.1.1 30-1.1.4.1.1.1.1 32-1.1.4.1.1.1.1 34-1.1.4.1.1.1.1 (r / report-01~e.5 :ARG1~e.6 (f / function-01~e.8 :ARG0 (s / small-molecule :name (n / name :op1 "ceramide"~e.7)) :location (r2 / relative-position :op1 (p / protein :name (n6 / name :op1 "caspase"~e.26)) :direction (d / downstream~e.9)) :time~e.12 (a / apostosis :ARG2-of (i3 / induce-01~e.15 :ARG0 (e / enzyme :name (n2 / name :op1 "Rpr"~e.13)))) :ARG1-of~e.17 (b / base-02~e.19 :ARG2~e.20 (a2 / affect-01~e.22 :ARG0~e.23 (s2 / small-molecule~e.27 :name (n4 / name :op1 "N-benzyloxycarbonyl-VAD-fluoromethylketone"~e.28,30,32,34) :mod (t / tripeptide~e.25) :ARG0-of~e.27 (i / inhibit-01~e.27 :ARG1 p))))) :location (o / organism :name (n5 / name :op1 "Drosophila"~e.1))) # ::id bio.chicago_2015.22780 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 5 min of incubation , the reaction was stopped by the addition of 5 mul of 5 xLaemmli 's SDS @-@ sample buffer . # ::alignments 0-1.3 1-1.3.1.1.1 2-1.3.1.1.2 4-1.3.1 7-1.2 9-1 10-1.1.r 12-1.1 13-1.1.1.r 14-1.1.1.2.1 17-1.1.1.2.1 20-1.1.1.1.3 22-1.1.1.1.4 23-1.1.1.1.5 (s / stop-01~e.9 :ARG0~e.10 (a / add-02~e.12 :ARG1~e.13 (p / product :name (n / name :op1 "5x" :op2 "Laemmli" :op3 "SDS"~e.20 :op4 "sample"~e.22 :op5 "buffer"~e.23) :quant (v / volume-quantity :quant 5~e.14,17 :unit (m2 / milliliter)))) :ARG1 (r / react-01~e.7) :time (a2 / after~e.0 :op1 (i / incubate-01~e.4 :duration (t / temporal-quantity :quant 5~e.1 :unit (m4 / minute~e.2))))) # ::id bio.chicago_2015.22788 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We show that E2F1 has a clear role in the induction of p53 @-@ dependent apoptosis and , surprisingly , is also required for the tumor cell division cycle . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 4-1.2.1 6-1.2.1.2.1 7-1.2.1.2 8-1.2.1.2.2.r 10-1.2.1.2.2 11-1.2.1.2.2.1.r 12-1.2.1.2.2.1.1.1.1.1 14-1.2.1.2.2.1.1 15-1.2.1.2.2.1 16-1.2 18-1.2.2.3 21-1.2.2.4 22-1.2.2 23-1.2.2.1.r 25-1.2.2.1.1.1.1 26-1.2.2.1.1.1 27-1.2.2.1.1 28-1.2.2.1 (s / show-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (a / and~e.16 :op1 (h / have-03~e.4 :ARG0 (p / protein :name (n / name :op1 "E2F1"~e.3)) :ARG1 (r / role~e.7 :ARG1-of (c / clear-06~e.6) :prep-in~e.8 (i / induce-01~e.10 :ARG1~e.11 (a2 / apoptosis~e.15 :ARG0-of (d / depend-01~e.14 :ARG1 (p2 / protein :name (n2 / name :op1 "p53"~e.12))))))) :op1 (r2 / require-01~e.22 :ARG0~e.23 (c2 / cycle-02~e.28 :ARG1 (d2 / divide-02~e.27 :ARG1 (c3 / cell~e.26 :mod (t / tumor~e.25)))) :ARG1 p :ARG0-of (s2 / surprise-01~e.18) :mod (a3 / also~e.21)))) # ::id bio.chicago_2015.22808 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SV @-@ SOD1 wt , but not SV @-@ SOD1 M or SV @-@ SOD1 R , potentiates SV @-@ induced apoptosis . # ::alignments 3-1.1.1.2.1.2 5-1 6-1.2.1 6-1.2.1.r 11-1.2.2 17-1.1 17-1.2 20-1.1.2.1 21-1.1.2 (c / contrast-01~e.5 :ARG1 (p / potentiate-01~e.17 :ARG0 (v / virus :name (n / name :op1 "sindbis") :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "superoxide" :op2 "dismutase") :mod (w / wild-type~e.3)))) :ARG1 (a / apoptosis~e.21 :ARG1-of (i / induce-01~e.20 :ARG0 v))) :ARG2 (p2 / potentiate-01~e.17 :polarity~e.6 -~e.6 :ARG0 (o / or~e.11 :op1 (v3 / virus :name (n3 / name :op1 "sindbis") :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n4 / name :op1 "superoxide" :op2 "dismutase") :ARG2-of (m / mutate-01)))) :op2 (v2 / virus :name (n5 / name :op1 "sindbis") :ARG3-of (e5 / express-03 :ARG2 (e6 / enzyme :name (n6 / name :op1 "superoxide" :op2 "dismutase") :ARG1-of (r / reverse-01))))) :ARG1 a)) # ::id bio.chicago_2015.22836 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these studies provide substantial evidence that E2F1 has a key role in p53 @-@ dependent apoptosis associated with aberrant cell cycle activity in vivo . # ::alignments 0-1.3 2-1.1.1 3-1.1 4-1 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.1.1.1 9-1.2.1 11-1.2.1.2.1 12-1.2.1.2 13-1.2.1.2.1.1.2.2 14-1.2.1.2.1.1.1.1.1.1 16-1.2.1.2.1.1.1 17-1.2.1.2.1.1 18-1.2.1.2.1.1.2 19-1.2.1.2.1.1.2.1.r 20-1.2.1.2.1.1.2.1.3 21-1.2.1.2.1.1.2.1.1 22-1.2.1.2.1.1.2.1.2 23-1.2.1.2.1.1.2.1 24-1.2.1.2.1.1.2.2 25-1.2.1.2.1.1.2.2 (p / provide-01~e.4 :ARG0 (s / study-01~e.3 :mod (t2 / this~e.2)) :ARG1 (e / evidence-01~e.6 :ARG1~e.7 (h / have-03~e.9 :ARG0 (p2 / protein :name (n / name :op1 "E2F1"~e.8)) :ARG1 (r / role~e.12 :ARG1-of (k / key-02~e.11 :ARG2 (a / apoptosis~e.17 :ARG0-of (d / depend-01~e.16 :ARG1 (p3 / protein :name (n2 / name :op1 "p53"~e.14))) :ARG1-of (a2 / associate-01~e.18 :ARG2~e.19 (a3 / activity-06~e.23 :ARG0 (c / cell~e.21) :ARG1 (c2 / cycle-02~e.22 :ARG1 c) :mod (a4 / aberrant~e.20)) :manner (i / in-vivo~e.13,24,25)))))) :mod (s2 / substantial~e.5)) :manner (t / together~e.0)) # ::id bio.chicago_2015.22874 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PAK is involved in Agrin @-@ induced AChR clustering . # ::alignments 0-1.1.1.1 2-1 3-1.2.r 4-1.2.2.1.1.1 6-1.2.2 7-1.2.1.1.1 8-1.2 (i / involve-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "PAK"~e.0)) :ARG2~e.3 (c / cluster-01~e.8 :ARG1 (p2 / protein :name (n2 / name :op1 "AChR"~e.7)) :ARG2-of (i2 / induce-01~e.6 :ARG0 (p / protein :name (n3 / name :op1 "Agrin"~e.4))))) # ::id bio.chicago_2015.22906 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , Sina has also been implicated in ubiquitin @-@ dependent proteolysis ( 21 , 29 , 46 ) . # ::alignments 0-1 2-1.1.1.1.1 4-1.1.3 6-1.1 7-1.1.2.r 8-1.1.2.1.1.1.1 10-1.1.2.1 11-1.1.2 13-1.2.1.1.1.1 15-1.2.1.1.1.2 17-1.2.1.1.1.3 (c / contrast-01~e.0 :ARG2 (i / implicate-01~e.6 :ARG1 (p / protein :name (n / name :op1 "Sina"~e.2)) :ARG2~e.7 (p2 / proteolysis~e.11 :ARG0-of (d / depend-01~e.10 :ARG1 (p3 / protein :name (n2 / name :op1 "ubiquitin"~e.8)))) :mod (a / also~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 21~e.13 :op2 29~e.15 :op3 46~e.17))))) # ::id bio.chicago_2015.22931 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Induction of apoptosis by p53 is critical for the tumor suppressor function of p53 . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2 3-1.1.1.r 4-1.1.1.1.1 6-1 7-1.2.r 9-1.2.2.2 10-1.2.2 11-1.2 12-1.2.1.r 13-1.2.1 (c / critical-02~e.6 :ARG1 (i / induce-01~e.0 :ARG0~e.3 (p / protein :name (n / name :op1 "p53"~e.4)) :ARG2~e.1 (a / apoptosis~e.2)) :ARG2~e.7 (f / function-01~e.11 :ARG0~e.12 p~e.13 :ARG1 (s / suppress-01~e.10 :ARG0 p :ARG1 (t / tumor~e.9)))) # ::id bio.chicago_2015.23115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We conclude that TFIIE contamination is not responsible for the enhanced CTD phosphorylation by TFIIH relative to free CAK . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.2.1.1.1 4-1.2.2 6-1.2.1 6-1.2.1.r 7-1.2 8-1.2.3.r 10-1.2.3.3 12-1.2.3 13-1.2.3.2.r 14-1.2.3.2.1.1 15-1.2.3.4 16-1.2.3.4.1.r 17-1.2.3.4.1 17-1.2.3.4.1.2 17-1.2.3.4.1.2.r 18-1.2.3.4.1.1.1 (c / conclude-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (r / responsible-01~e.7 :polarity~e.6 -~e.6 :ARG0 (c2 / contaminate-01~e.4 :ARG2 (p2 / protein :name (n / name :op1 "TFIIE"~e.3))) :ARG1~e.8 (p / phosphorylate-01~e.12 :ARG1 (p4 / protein-segment :name (n3 / name :op1 "C-terminus")) :ARG2~e.13 (p5 / protein :name (n4 / name :op1 "TFIIH"~e.14)) :ARG1-of (e / enhance-01~e.10) :ARG1-of (r2 / relative-05~e.15 :ARG2~e.16 (e2 / enzyme~e.17 :name (n2 / name :op1 "CAK"~e.18) :ARG1-of~e.17 (f / free-04~e.17)))))) # ::id bio.chicago_2015.23123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok U1 snRNP bound to the 5 ' splice site , U2AF65 bound to the Py tract , and bridging activities , for which members of the SR family of factors are strong candidates . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1 3-1.1.2.r 5-1.1.2.1.1 6-1.1.2.1.1 7-1.1.2 7-1.1.2.2 7-1.1.2.2.r 8-1.1.2.1.2 10-1.2.1.1.1 11-1.2 12-1.2.2.r 14-1.2.2.1.1 15-1.2.2.1.2 17-1 18-1.3.1.1 19-1.3.1 23-1.3.2 26-1.3.2.1.1.1.1 27-1.3.2.1.1 28-1.3.2.1.1.2.r 29-1.3.2.1.1.2 30-1.3.2.r 31-1.3.3 32-1.3 (a / and~e.17 :op1 (b / bind-01~e.2 :ARG1 (p3 / protein :name (n / name :op1 "U1"~e.0 :op2 "snRNP"~e.1)) :ARG2~e.3 (d2 / dna-sequence~e.7 :name (n5 / name :op1 "5'"~e.5,6 :op2 "site"~e.8) :ARG1-of~e.7 (s2 / splice-01~e.7))) :op2 (b2 / bind-01~e.11 :ARG1 (p / protein :name (n2 / name :op1 "U2AF65"~e.10)) :ARG2~e.12 (d / dna-sequence :name (n3 / name :op1 "Py"~e.14 :op2 "tract"~e.15))) :op3 (c / candidate~e.32 :purpose (a2 / activity-06~e.19 :ARG1 (b3 / bridge-01~e.18)) :domain~e.30 (m / member~e.23 :ARG1-of (i / include-91 :ARG2 (p2 / protein-family~e.27 :name (n4 / name :op1 "SR"~e.26) :mod~e.28 (f2 / factor~e.29)))) :ARG1-of (s3 / strong-02~e.31))) # ::id bio.chicago_2015.23189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The observation that BDNF does not elicit calcium transients , but induces CREB phosphorylation also in acute slices of visual cortex strengthens the transferability in vivo of these results . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.2.1.1 5-1.1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1 7-1.1.1.1.3.1.1 8-1.1.1.1.3.1.2 10-1.1.1 11-1.1.1.2 12-1.1.1.2.2.1.1.1 13-1.1.1.2.2 14-1.1.1.2.2.2.3 15-1.2.1.2 16-1.1.1.2.2.2.1 17-1.1.1.2.2.2 18-1.1.1.2.2.2.2.r 19-1.1.1.2.2.2.2.1 20-1.1.1.2.2.2.2 21-1 24-1.2.1.2 25-1.2.1.2 27-1.2.1.1.2 28-1.2.1.1 28-1.2.1.1.1 28-1.2.1.1.1.r (s / strengthen-01~e.21 :ARG0 (o / observe-01~e.1 :ARG1~e.2 (c / contrast-01~e.10 :ARG1 (e / elicit-01~e.6 :polarity~e.5 -~e.5 :ARG0 (p2 / protein :name (n / name :op1 "BDNF"~e.3)) :ARG1 (e2 / event :name (n2 / name :op1 "calcium"~e.7 :op2 "transient"~e.8))) :ARG2 (i / induce-01~e.11 :ARG0 p2 :ARG2 (p / phosphorylate-01~e.13 :ARG2 (p3 / protein :name (n3 / name :op1 "CREB"~e.12)) :location (s2 / slice~e.17 :mod (a / acute~e.16) :part-of~e.18 (c2 / cortex~e.20 :mod (v / visual~e.19)) :mod (a2 / also~e.14)))))) :ARG1 (p4 / possible-01 :ARG1 (t / transfer-01 :ARG1 (t3 / thing~e.28 :ARG2-of~e.28 (r / result-01~e.28) :mod (t2 / this~e.27)) :ARG2 (i2 / in-vivo~e.15,24,25)))) # ::id bio.chicago_2015.23275 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been proposed that enhancers function by promoting binding of U2AF65 to weak Py tracts ( Wang et al. 1995 ; Zuo and Maniatis 1996 ; Bouck et al. 1998 ) . # ::alignments 3-1 6-1.1 7-1.1.2.r 8-1.1.2 9-1.1.2.2 10-1.1.2.2.1.r 11-1.1.2.2.1.1.1 12-1.1.2.2.2.r 13-1.1.2.2.2 13-1.1.2.2.2.2 13-1.1.2.2.2.2.r 14-1.1.2.2.2.1.1 15-1.1.2.2.2.1.2 17-1.2.1.1.1.1.1.1 18-1.2.1.1.1 19-1.2.1.1.1.2.1 20-1.2.1.1.2.1 22-1.2.1.2.1.1.1.1 23-1.2.1.2.1 24-1.2.1.2.1.2.1.1 25-1.2.1.2.2.1 27-1.2.1.3.1.1.1.1 28-1.2.1 28-1.2.1.1.1 28-1.2.1.3.1 29-1.2.1.1.1.2.1 30-1.2.1.3.2.1 (p / propose-01~e.3 :ARG1 (f / function-01~e.6 :ARG0 (m / molecular-physical-entity :ARG0-of (e / enhance-01)) :manner~e.7 (p2 / promote-01~e.8 :ARG0 m :ARG1 (b / bind-01~e.9 :ARG1~e.10 (p3 / protein :name (n / name :op1 "U2AF65"~e.11)) :ARG2~e.12 (d4 / dna-sequence~e.13 :name (n2 / name :op1 "Py"~e.14 :op2 "tract"~e.15) :ARG1-of~e.13 (w / weak-02~e.13))))) :ARG1-of (d5 / describe-01 :ARG0 (a / and~e.28 :op1 (p4 / publication-91 :ARG0 (a2 / and~e.18,28 :op1 (p5 / person :name (n3 / name :op1 "Wang"~e.17)) :op2 (p6 / person :mod (o / other~e.19,29))) :time (d / date-entity :year 1995~e.20)) :op2 (p7 / publication-91 :ARG0 (a3 / and~e.23 :op1 (p8 / person :name (n4 / name :op1 "Zuo"~e.22)) :op2 (p9 / person :name (n5 / name :op1 "Maniatis"~e.24))) :time (d2 / date-entity :year 1996~e.25)) :op3 (p10 / publication-91 :ARG0 (a4 / and~e.28 :op1 (p11 / person :name (n6 / name :op1 "Bouck"~e.27)) :op2 p6) :time (d3 / date-entity :year 1998~e.30))))) # ::id bio.chicago_2015.23324 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because the GTP @-@ bound form of Ras is a key transducer in the mitogen signaling pathway ( 18 ) , we decided to examine Ras GTP loading in anchored or suspended 3T3 cells treated with either PDGF or EGF . # ::alignments 0-1.3 2-1.3.1.4.2.1 4-1.3.1.4 4-1.3.1.4.2 4-1.3.1.4.2.r 7-1.3.1.4.1.1 8-1.3.1.4.r 10-1.3.1 10-1.3.1.2 10-1.3.1.2.r 12-1.3.1.3.r 14-1.3.1.3.1.1 15-1.3.1.3.1.2 16-1.3.1.3.1.3 18-1.3.2.1.1.1 21-1.1 22-1 23-1.3 24-1.2 25-1.2.2.3.1.1 26-1.2.2.2.1.1 27-1.2.2 28-1.2.2.1.r 28-1.3.1.3.r 29-1.2.2.1.1.2 30-1.2.2.1 31-1.2.2.1.2.2 32-1.2.2.1.1.1.1 32-1.2.2.1.2.1.1 33-1.2.2.1.1 33-1.2.2.1.2 34-1.2.2.1.3 37-1.2.2.1.3.1.1.1.1 38-1.2.2.1.3.1 39-1.2.2.1.3.1.2.1.1 (d / decide-01~e.22 :ARG0 (w / we~e.21) :ARG1 (e / examine-01~e.24 :ARG0 w :ARG1 (l / load-01~e.27 :ARG1~e.28 (o / or~e.30 :op1 (c / cell-line~e.33 :name (n3 / name :op1 "3T3"~e.32) :ARG1-of (a / anchor-01~e.29)) :op2 (c2 / cell-line~e.33 :name (n4 / name :op1 "3T3"~e.32) :ARG1-of (s2 / suspend-01~e.31)) :ARG1-of (t / treat-04~e.34 :ARG2 (o2 / or~e.38 :op1 (p2 / protein :name (n5 / name :op1 "PDGF"~e.37)) :op2 (p3 / protein :name (n6 / name :op1 "EGF"~e.39))))) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"~e.26)) :ARG3 (e2 / enzyme :name (n / name :op1 "Ras"~e.25)))) :ARG1-of (c3 / cause-01~e.0,23 :ARG0 (m / molecular-physical-entity~e.10 :ARG2-of (t2 / transduce-01) :ARG1-of~e.10 (k / key-02~e.10) :prep-in~e.12,28 (p5 / pathway :name (n8 / name :op1 "mitogen"~e.14 :op2 "signaling"~e.15 :op3 "pathway"~e.16)) :domain~e.8 (e3 / enzyme~e.4 :name (n7 / name :op1 "Ras"~e.7) :ARG1-of~e.4 (b / bind-01~e.4 :ARG2 s~e.2))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 18~e.18))))) # ::id bio.chicago_2015.23329 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also found that the CaMK antagonist KN93 , but not the inactive congener KN92 , blocked BDNF @-@ induced CREB phosphorylation , further suggesting that KN62 is acting specifically ( data not shown ) . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.r 5-1.2.1.1.2.1.1.1 7-1.2.1.1.1.1 9-1.2 10-1.2.2.1.r 12-1.2.2.1 13-1.2.2.2.2 14-1.2.2.2.1.1 16-1.2.1 16-1.2.2 17-1.2.1.2.2.1.1.1 19-1.2.1.2.2 20-1.2.1.2.1.1.1 21-1.2.1.2 23-1.2.3.2 24-1.2.3 25-1.2.3.1.r 26-1.2.3.1.1.1.1 28-1.2.2.2.2.1 28-1.2.3.1 29-1.2.3.1.2 31-1.4.1 32-1.2.2.2.2.1.1 32-1.4.1.1.1 32-1.4.1.1.1.r 33-1.4.1.1 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (c / contrast-01~e.9 :ARG1 (b / block-01~e.16 :ARG0 (s / small-molecule :name (n / name :op1 "KN93"~e.7) :ARG0-of (a2 / antagonize-01 :ARG1 (e / enzyme :name (n2 / name :op1 "CaMK"~e.5)))) :ARG1 (p / phosphorylate-01~e.21 :ARG1 (p2 / protein :name (n3 / name :op1 "CREB"~e.20)) :ARG2-of (i / induce-01~e.19 :ARG0 (p3 / protein :name (n4 / name :op1 "BDNF"~e.17))))) :ARG2 (b2 / block-01~e.16 :polarity~e.10 -~e.12 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "KN92"~e.14) :mod (c2 / congener~e.13 :ARG0-of (a3 / act-02~e.28 :polarity -~e.32))) :ARG1 p) :ARG0-of (s3 / suggest-01~e.24 :ARG1~e.25 (a4 / act-02~e.28 :ARG0 (s4 / small-molecule :name (n6 / name :op1 "KN62"~e.26)) :ARG1-of (s5 / specific-02~e.29)) :degree (f2 / further~e.23))) :mod (a / also~e.1) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.31 :ARG1-of (s6 / show-01~e.33 :polarity~e.32 -~e.32)))) # ::id bio.chicago_2015.23353 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the mechanism by which c @- myc induces apoptosis is unknown . # ::alignments 0-1 3-1.1.2 6-1.1.2.1.1.1.1 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2.1.2 12-1.1 12-1.1.1 12-1.1.1.r (c / contrast-01~e.0 :ARG2 (k / know-01~e.12 :polarity~e.12 -~e.12 :ARG1 (m / mechanism~e.3 :manner-of (i / induce-01~e.9 :ARG0 (p / protein :name (n / name :op1 "c-myc"~e.6,8)) :ARG2 (a / apoptosis~e.10))))) # ::id bio.chicago_2015.23361 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data show that activation of PKA by addition of cAMP or by depletion of the Bcy1p subunit stimulates phosphorylation of pyruvate kinase . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1 5-1.2.1.2.r 6-1.2.1.2.1.1 7-1.2.1.1.r 8-1.2.1.1.1 9-1.2.1.1.1.1.r 10-1.2.1.1.1.1.1.1 11-1.2.1.1 13-1.2.1.1.2 14-1.2.1.1.2.1.r 16-1.2.1.1.2.1.1.1.1 17-1.2.1.1.2.1 18-1.2 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.1.1 22-1.2.2.1.1.2 (s / show-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (s2 / stimulate-01~e.18 :ARG0 (a / activate-01~e.4 :ARG0~e.7 (o / or~e.11 :op1 (a2 / add-02~e.8 :ARG1~e.9 (s3 / small-molecule :name (n / name :op1 "cAMP"~e.10))) :op2 (d2 / deplete-01~e.13 :ARG1~e.14 (s4 / subunit~e.17 :mod (g / gene :name (n2 / name :op1 "Bcy1p"~e.16))))) :ARG1~e.5 (e / enzyme :name (n3 / name :op1 "PKA"~e.6))) :ARG1 (p / phosphorylate-01~e.19 :ARG1~e.20 (e2 / enzyme :name (n4 / name :op1 "pyruvate"~e.21 :op2 "kinase"~e.22))))) # ::id bio.chicago_2015.23365 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ub exists in a dynamic equilibrium between free and conjugated forms that is determined by the relative rates of conjugation , deubiquitinylation by Ub @-@ specific isopeptidases and Ub @-@ dependent proteolysis , which releases free Ub . # ::alignments 1-1 4-1.2.2 7-1.2.1.1.1 8-1.2.1 9-1.2.1.2.1 10-1.2.1.1 10-1.2.1.2 13-1.2.3 14-1.2.3.1.r 16-1.2.3.1.1.1 17-1.2.3.1.1 18-1.2.3.1.1.2.r 19-1.2.3.1.1.2 25-1.2.3.1.2.1 25-1.2.3.1.2.1.2 25-1.2.3.1.2.1.2.r 27-1.2.3.1 30-1.2.3.1.3.1 31-1.2.3.1.3 34-1.2.3.1.3.2 35-1.2.3.1.3.2.1.2 (e / exist-01~e.1 :ARG1 (p / protein :name (n / name :op1 "ubiquitin")) :ARG2 (e2 / equilibrate-01 :ARG1 (a / and~e.8 :op1 (f / form~e.10 :ARG1-of (f2 / free-04~e.7)) :op2 (f3 / form~e.10 :ARG1-of (c / conjugate-02~e.9))) :mod (d / dynamic~e.4) :ARG1-of (d2 / determine-01~e.13 :ARG0~e.14 (a2 / and~e.27 :op1 (r / rate~e.17 :ARG1-of (r2 / relative-05~e.16) :mod~e.18 c~e.19) :op2 (d3 / deubiquitinylate-00 :ARG0 (e3 / enzyme~e.25 :name (n2 / name :op1 "isopeptidase") :ARG1-of~e.25 (s / specific-02~e.25 :ARG2 p))) :op3 (p2 / proteolysis~e.31 :ARG0-of (d4 / depend-01~e.30 :ARG1 p) :ARG0-of (r3 / release-01~e.34 :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin") :ARG1-of f2~e.35))))))) # ::id bio.chicago_2015.23430 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to determine which sugars on Notch are required for Notch signaling and @/@ or for fringe to function , Jagged1 @-@ induced Notch signaling was measured in a series of CHO glycosylation mutants [ 2 and 50 ] . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 4-1.3.1 5-1.3.1.1 6-1.3.1.3.r 7-1.3.1.3 9-1.3.1.2 10-1.3.1.2.1.r 11-1.3.1.2.1.1.1 12-1.3.1.2.1.1 13-1.3.1.2.1 15-1.3.1.2.1 16-1.3.1.2.1.2.r 17-1.3.1.2.1.2.1 19-1.3.1.2.1.2 21-1.1.2.1.1.1 23-1.1.2 24-1.1.1.1.1 25-1.1 27-1 28-1.2.r 30-1.2.2 31-1.2.2.r 32-1.2.1.1 34-1.2 34-1.2.3 34-1.2.3.r 36-1.4.1.1.1.1 37-1.4.1.1.1 38-1.4.1.1.1.2 (m / measure-01~e.27 :ARG1 (s / signal-07~e.25 :ARG0 (p / pathway :name (n / name :op1 "Notch"~e.24)) :ARG1-of (i / induce-01~e.23 :ARG0 (p2 / protein :name (n2 / name :op1 "Jagged1"~e.21)))) :location~e.28 (c / cell-line~e.34 :name (n3 / name :op1 "CHO"~e.32) :quant~e.31 (s4 / series~e.30) :ARG2-of~e.34 (m2 / mutate-01~e.34 :ARG0 (g / glycosylate-01))) :purpose~e.0,1,2 (d / determine-01~e.3 :ARG1 (a / amr-unknown~e.4 :mod (s2 / sugar~e.5) :ARG1-of (r / require-01~e.9 :ARG0~e.10 (a4 / and-or~e.13,15 :op1 (s3 / signal-07~e.12 :ARG0 p~e.11) :op2~e.16 (f / function-01~e.19 :ARG0 (f2 / fringe~e.17)))) :part-of~e.6 p~e.7)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and~e.37 :op1 2~e.36 :op2 50~e.38))))) # ::id bio.chicago_2015.23434 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Unlike Mad2 or Mad2B , Emi1 can inhibit APC already activated by Cdc20 or Cdh1 . # ::alignments 0-1 0-1.1 0-1.1.r 1-1.3.1.1.1 2-1.3 3-1.3.2.1.1 5-1.2.1.1.1.1 6-1.2 7-1.2.1 8-1.2.1.2.1.1 9-1.2.1.2.2.2 10-1.2.1.2.2 11-1.2.1.2.2.1.r 12-1.2.1.2.2.1.1.1.1 13-1.2.1.2.2.1 14-1.2.1.2.2.1.2.1.1 (r / resemble-01~e.0 :polarity~e.0 -~e.0 :ARG1 (p / possible-01~e.6 :ARG1 (i / inhibit-01~e.7 :ARG0 (s / small-molecule :name (n / name :op1 "Emi1"~e.5)) :ARG1 (p2 / protein :name (n2 / name :op1 "APC"~e.8) :ARG1-of (a / activate-01~e.10 :ARG0~e.11 (o / or~e.13 :op1 (p3 / protein :name (n3 / name :op1 "Cdc20"~e.12)) :op2 (p4 / protein :name (n4 / name :op1 "Cdh1"~e.14))) :time (a2 / already~e.9))))) :ARG2 (o2 / or~e.2 :op1 (p5 / protein :name (n5 / name :op1 "Mad2"~e.1)) :op2 (p6 / protein :name (n6 / name :op1 "Mad2B"~e.3)))) # ::id bio.chicago_2015.23439 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upregulation of the p53 protein , mediated either by irradiation [ 81 ] or by a temperature @-@ sensitive p53 transgene [ 80 ] , together with E2F1 overexpression induced apoptosis even in the presence of serum growth factors . # ::alignments 0-1.1.1 3-1.1.1.1.1.1 4-1.1.1.1 4-1.1.2.1 6-1.1.1.2 8-1.1.1.2.1.r 9-1.1.1.2.1.1 11-1.1.1.2.1.1.1.1.1.1 13-1.1.1.2.1 16-1.1.1.2.1.2.2.1 18-1.1.1.2.1.2.2 19-1.1.1.2.1.2.1 20-1.1.1.2.1.2 22-1.1.1.2.1.2.3.1.1.1 27-1.1.2.1.1.1 28-1.1.2 29-1 30-1.2 32-1.3.r 34-1.3 35-1.3.1.r 36-1.3.1.1.1 37-1.3.1.1.2 38-1.3.1.1.3 (i / induce-01~e.29 :ARG0 (a2 / and :op1 (u / upregulate-01~e.0 :ARG1 (p2 / protein~e.4 :name (n2 / name :op1 "p53"~e.3)) :ARG1-of (m / mediate-01~e.6 :ARG0~e.8 (o / or~e.13 :op1 (i2 / irradiate-01~e.9 :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 81~e.11)))) :op2 (t / transgene~e.20 :mod p2~e.19 :ARG0-of (s2 / sensitive-03~e.18 :ARG1 (t2 / temperature~e.16)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 80~e.22))))))) :op2 (o2 / overexpress-01~e.28 :ARG1 (p3 / protein~e.4 :name (n3 / name :op1 "E2F1"~e.27)))) :ARG2 (a / apoptosis~e.30) :concession~e.32 (p / present-02~e.34 :ARG1~e.35 (s / small-molecule :name (n / name :op1 "serum"~e.36 :op2 "growth"~e.37 :op3 "factor"~e.38)))) # ::id bio.chicago_2015.23524 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) TRAF6 failed to activate IKK in Uev1A @-@ depleted extracts . # ::alignments 1-1.3.1.1 3-1.1.1.1 4-1 6-1.2 7-1.2.2.1.1 8-1.2.3.r 9-1.2.3.1.1.1.1 11-1.2.3.1 12-1.2.3 (f / fail-01~e.4 :ARG1 (p / protein :name (n / name :op1 "TRAF6"~e.3)) :ARG2 (a / activate-01~e.6 :ARG0 p :ARG1 (e / enzyme :name (n2 / name :op1 "IKK"~e.7)) :location~e.8 (e2 / extract~e.12 :ARG1-of (d / deplete-01~e.11 :ARG2 (p2 / protein :name (n3 / name :op1 "Uev1A"~e.9))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "B"~e.1))) # ::id bio.chicago_2015.23580 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , Ptc inhibits the activity of Smo and HH binding to Ptc releases Smo from this inhibitory process . # ::alignments 2-1.1.1.1.1.1 3-1.1.1 5-1.1.1.2 6-1.1.1.2.1.r 7-1.1.1.2.1.1.1 8-1.1 9-1.1.2.1.1.1.1 10-1.1.2.1 11-1.1.2.1.2.r 12-1.1.2.1.2 13-1.1.2 14-1.1.2.3.1.1 17-1.1.2.3.1 18-1.1.2.3 (i / infer-01 :ARG1 (a / and~e.8 :op1 (i2 / inhibit-01~e.3 :ARG0 (p / protein :name (n / name :op1 "Ptc"~e.2)) :ARG1 (a2 / activity-06~e.5 :ARG0~e.6 (p2 / protein :name (n2 / name :op1 "Smo"~e.7)))) :op2 (r / release-01~e.13 :ARG0 (b / bind-01~e.10 :ARG1 (p3 / pathway :name (n3 / name :op1 "HH"~e.9)) :ARG2~e.11 p~e.12) :ARG1 p2 :ARG2 (p4 / process-02~e.18 :ARG1 (i3 / inhibit-01~e.17 :ARG0 p2~e.14))))) # ::id bio.chicago_2015.23632 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data demonstrated that Tyr phosphorylation was not required for JNK activation by MKK7 . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.3.1.1.1 5-1.2.3 7-1.2.1 7-1.2.1.r 8-1.2 9-1.2.2.r 10-1.2.2.2.1.1 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1 (d / demonstrate-01~e.2 :ARG0 (d2 / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (r / require-01~e.8 :polarity~e.7 -~e.7 :ARG0~e.9 (a / activate-01~e.11 :ARG0~e.12 (e2 / enzyme :name (n2 / name :op1 "MKK7"~e.13)) :ARG1 (e / enzyme :name (n / name :op1 "JNK"~e.10))) :ARG1 (p / phosphorylate-01~e.5 :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine"~e.4))))) # ::id bio.chicago_2015.23691 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whereas the highly conserved cysteine @-@ rich domain is able to inhibit EGF @-@ induced MAP kinase activation , the amino @-@ terminal domain potentiates EGF @-@ induced MAP kinase activation by interfering with EGFR ubiquitination and down @-@ regulation . # ::alignments 0-1 2-1.2.2.1.2.1 3-1.2.2.1.2 4-1.2.2.1.1.1 6-1.2.2.1.1.1 7-1.2.2.1.1.2 9-1.2 11-1.2.2 12-1.1.2.2.1.1.1 14-1.1.2.2 15-1.1.2.1.1.1 16-1.1.2.1 17-1.1.2 20-1.1.1.1.1 22-1.1.1.1.1 23-1.1.1.1.2 24-1.1 25-1.1.2.2.1.1.1 27-1.1.2.2 28-1.1.2.1.1.1 29-1.1.2.1 30-1.1.2 31-1.1.3.r 32-1.1.3 33-1.1.3.2.r 34-1.1.3.2.1.1.1.1 35-1.1.3.2.1 36-1.1.3.2 37-1.1.3.2.2 38-1.1.3.2.2 39-1.1.3.2.2 (c / contrast-01~e.0 :ARG1 (p2 / potentiate-01~e.24 :ARG0 (p3 / protein-segment :name (n2 / name :op1 "amino-terminal"~e.20,22 :op2 "domain"~e.23)) :ARG1 (a / activate-01~e.17,30 :ARG1 (k / kinase~e.16,29 :name (n3 / name :op1 "MAP"~e.15,28)) :ARG2-of (i / induce-01~e.14,27 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF"~e.12,25)))) :manner~e.31 (i2 / interfere-01~e.32 :ARG0 p3 :ARG1~e.33 (a2 / and~e.36 :op1 (u / ubiquitinate-01~e.35 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.34))) :op2 (d / downregulate-01~e.37,38,39 :ARG1 e)))) :ARG2 (c3 / capable-01~e.9 :ARG1 p5 :ARG2 (i3 / inhibit-01~e.11 :ARG0 (p5 / protein-segment :name (n5 / name :op1 "cysteine-rich"~e.4,6 :op2 "domain"~e.7) :ARG1-of (c2 / conserve-01~e.3 :degree (h / high-02~e.2))) :ARG1 a))) # ::id bio.chicago_2015.23692 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reduction of profilin suppresses the disorganized actin phenotype caused by reduction of capping protein function , suggesting that profilin promotes actin assembly in the elongating bristle . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1.1 5-1.1.2.2 6-1.1.2.1.1.1 7-1.1.2 8-1.1.2.3 9-1.1.2.3.1.r 10-1.1.2.3.1 11-1.1.2.3.1.1.r 12-1.1.2.3.1.1.1.1.1 13-1.1.2.3.1.1.1.1.2 14-1.1.2.3.1.1 16-1 17-1.2.r 18-1.2.1 19-1.2 20-1.2.2.1 21-1.2.2 22-1.2.2.2.r 24-1.2.2.2.1 25-1.2.2.2 (s / suggest-01~e.16 :ARG0 (s2 / suppress-01~e.3 :ARG0 (r / reduce-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "profilin"~e.2))) :ARG1 (p2 / phenotype~e.7 :mod (p3 / protein :name (n2 / name :op1 "actin"~e.6)) :ARG1-of (d / disorganize-01~e.5) :ARG1-of (c / cause-01~e.8 :ARG0~e.9 (r2 / reduce-01~e.10 :ARG1~e.11 (f / function-01~e.14 :ARG0 (p4 / protein :name (n3 / name :op1 "capping"~e.12 :op2 "protein"~e.13))))))) :ARG1~e.17 (p5 / promote-01~e.19 :ARG0 p~e.18 :ARG1 (a / assemble-01~e.21 :ARG1 p3~e.20 :location~e.22 (b / bristle~e.25 :ARG0-of (e / elongate-01~e.24))))) # ::id bio.chicago_2015.23746 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significantly , it is shown that Zap @-@ 70 plays an adaptor role in Cbl @-@ induced Ub conjugation to TCRzeta chain . # ::alignments 0-1.2 4-1 5-1.1.r 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1 13-1.1.2.r 14-1.1.2.4.1.1.1 16-1.1.2.4 18-1.1.2 19-1.1.2.2.r 20-1.1.2.2.1.1 21-1.1.2.2.1.2 (s / show-01~e.4 :ARG1~e.5 (p / play-02~e.9 :ARG0 (e / enzyme :name (n / name :op1 "Zap-70"~e.6,8)) :ARG1~e.13 (c / conjugate-02~e.18 :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin")) :ARG2~e.19 (p4 / protein :name (n4 / name :op1 "TCRzeta"~e.20 :op2 "chain"~e.21)) :mod (m / molecular-physical-entity :ARG0-of (a / adapt-01)) :ARG2-of (i / induce-01~e.16 :ARG0 (p2 / protein :name (n2 / name :op1 "Cbl"~e.14))))) :ARG1-of (s2 / significant-02~e.0)) # ::id bio.chicago_2015.23757 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , Eya @-@ induced apoptosis involves both caspase @-@ dependent and caspase @-@ independent pathways . # ::alignments 0-1 2-1.1.2.1.1.1.1 4-1.1.2.1 5-1.1.2 6-1.1 8-1.1.1.2.1.2 10-1.1.1.2.1 11-1.1.1 12-1.1.1.2.1.2 14-1.1.1.1.1 14-1.1.1.2.1 14-1.1.1.2.1.1 14-1.1.1.2.1.1.r 15-1.1.1.1 15-1.1.1.2 (c / cause-01~e.0 :ARG1 (i2 / involve-01~e.6 :ARG1 (a2 / and~e.11 :op1 (p2 / pathway~e.15 :ARG0-of (d / depend-01~e.14 :ARG1 (p4 / protein :name (n2 / name :op1 "caspase")))) :op2 (p3 / pathway~e.15 :ARG0-of (d2 / depend-01~e.10,14 :polarity~e.14 -~e.14 :ARG1 p4~e.8,12))) :ARG2 (a / apoptosis~e.5 :ARG2-of (i3 / induce-01~e.4 :ARG0 (p / protein :name (n / name :op1 "Eya"~e.2)))))) # ::id bio.chicago_2015.23765 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A number of proteins have recently been identified that specifically interact with the GTP @-@ bound form of Rho ( reviewed in [ 30 ] ) . # ::alignments 1-1.1.1 2-1.1.1.r 3-1.1 5-1.2 7-1 9-1.1.2.2 10-1.1.2 11-1.1.2.1.r 13-1.1.2.1.2.1.1.1 15-1.1.2.1 15-1.1.2.1.2 15-1.1.2.1.2.r 18-1.1.2.1.1.1 20-1.1.3 23-1.1.3.1.1.1 (i / identify-01~e.7 :ARG1 (p / protein~e.3 :quant~e.2 (n / number~e.1) :ARG0-of (i2 / interact-01~e.10 :ARG1~e.11 (p3 / protein~e.15 :name (n3 / name :op1 "Rho"~e.18) :ARG1-of~e.15 (b / bind-01~e.15 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP"~e.13)))) :ARG1-of (s / specific-02~e.9)) :ARG1-of (r2 / review-01~e.20 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 30~e.23)))) :time (r / recent~e.5)) # ::id bio.chicago_2015.23795 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , this reduction in tension could contribute to checkpoint activation by other mechanisms , such as those that regulate BubR1 inhibition of Cdc20 activation of the APC/C ( Skoufias et al. , 2001 ; Sudakin et al. , 2001 ; Tang et al. , 2001 ) . # ::alignments 0-1 2-1.1.1.1.2 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1 6-1.1 7-1.1.1 8-1.1.1.2.r 9-1.1.1.2.2 10-1.1.1.2 11-1.1.1.2.1.r 12-1.1.1.2.1.1 13-1.1.1.2.1 13-1.1.1.2.1.2 15-1.1.1.2.1.2.r 16-1.1.1.2.1.2.r 19-1.1.1.2.1.2.1 20-1.1.1.2.1.2.1.1.1.1.1 21-1.1.1.2.1.2.1.1 22-1.1.1.2.1.2.1.1.2.r 23-1.1.1.2.1.2.1.1.2.1.1.1 24-1.1.1.2.1.2.1.1.2 25-1.1.1.2.1.2.1.1.2.2.r 27-1.1.1.2.1.2.1.1.2.2.1.1 29-1.2.1.1.1.1.1.1 30-1.2.1.1.1 31-1.2.1.1.1.2.1 33-1.2.1.2.2 35-1.2.1.2.1.1.1.1 36-1.2.1 36-1.2.1.1.1 36-1.2.1.2.1 36-1.2.1.3.1 37-1.2.1.1.1.2.1 39-1.2.1.3.2 41-1.2.1.3.1.1.1.1 42-1.2.1 42-1.2.1.1.1 42-1.2.1.2.1 42-1.2.1.3.1 43-1.2.1.1.1.2.1 45-1.2.1.1.2.1 (c / contrast-01~e.0 :ARG2 (p2 / possible-01~e.6 :ARG1 (c2 / contribute-01~e.7 :ARG0 (r / reduce-01~e.3 :ARG1~e.4 (t / tension~e.5) :mod (t2 / this~e.2)) :ARG2~e.8 (a / activate-01~e.10 :ARG0~e.11 (m / mechanism~e.13 :mod (o / other~e.12) :example~e.15,16 (m2 / mechanism~e.13 :ARG0-of (r2 / regulate-01~e.19 :ARG1 (i / inhibit-01~e.21 :ARG0 (e / enzyme :name (n / name :op1 "BubR1"~e.20)) :ARG1~e.22 (a2 / activate-01~e.24 :ARG0 (p3 / protein :name (n2 / name :op1 "Cdc20"~e.23)) :ARG1~e.25 (p4 / protein :name (n3 / name :op1 "APC/C"~e.27))))))) :ARG1 (c3 / checkpoint~e.9)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.36,42 :op1 (p5 / publication-91 :ARG0 (a4 / and~e.30,36,42 :op1 (p8 / person :name (n4 / name :op1 "Skoufias"~e.29)) :op2 (p9 / person :mod (o2 / other~e.31,37,43))) :time (d / date-entity :year 2001~e.45)) :op2 (p6 / publication-91 :ARG0 (a5 / and~e.36,42 :op1 (p10 / person :name (n5 / name :op1 "Sudakin"~e.35)) :op2 p9) :time d~e.33) :op3 (p7 / publication-91 :ARG0 (a6 / and~e.36,42 :op1 (p12 / person :name (n6 / name :op1 "Tang"~e.41)) :op2 p9) :time d~e.39)))) # ::id bio.chicago_2015.23851 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Axin binds directly to GSK @-@ 3 beta , beta @-@ catenin , and APC , whereas APC also directly binds to GSK @-@ 3 beta and beta @-@ catenin . # ::alignments 0-1.1.1.1.1 1-1.2 2-1.1.3 4-1.1.2.1.1.1 7-1.1.2.2.1.1 9-1.1.2.2.1.1 11-1.1.2.2.1.1 13-1.1.2 14-1.1.2.3.1.1 16-1 17-1.2.1 18-1.2.4 19-1.2.3 20-1.1 22-1.1.2.1.1.1 25-1.1.2.2.1.1 27-1.1.2.2.1.1 29-1.1.2.2.1.1 (c / contrast-01~e.16 :ARG1 (b / bind-01~e.20 :ARG1 (p / protein :name (n / name :op1 "axin"~e.0)) :ARG2 (a / and~e.13 :op1 (e / enzyme :name (n2 / name :op1 "GSK-3beta"~e.4,22)) :op2 (p2 / protein :name (n3 / name :op1 "beta-catenin"~e.7,9,11,25,27,29)) :op3 (p3 / protein :name (n4 / name :op1 "APC"~e.14))) :ARG1-of (d / direct-02~e.2)) :ARG2 (b2 / bind-01~e.1 :ARG1 p3~e.17 :ARG2 (a3 / and :op1 e :op2 p2) :ARG1-of d~e.19 :mod (a2 / also~e.18))) # ::id bio.chicago_2015.23862 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , prolonged or transient activation of ERK induced by nerve growth factor or EGF stimulation of PC12 cells , respectively ( 28 ) , may involve different VH @-@ 1 @-@ like PTPases . # ::alignments 0-1 2-1.1.1.2.1.2 3-1.1.1.2 4-1.1.1.2.2.2 5-1.1.1.2.1 5-1.1.1.2.2 6-1.1.1.2.1.1.r 7-1.1.1.2.1.1.1.1 8-1.1.1.2.1.3 8-1.1.1.2.2.3 9-1.1.1.2.1.3.1.r 10-1.1.1.2.1.3.1.1.1.1 11-1.1.1.2.1.3.1.1.1.2 12-1.1.1.2.1.3.1.1.1.3 13-1.1.1.2 14-1.1.1.2.2.3.1.1.1.1 15-1.1.1.2.1.3.1 15-1.1.1.2.2.3.1 16-1.1.1.2.1.3.1.2.r 17-1.1.1.2.1.3.1.2.1.1 18-1.1.1.2.1.3.1.2 22-1.1.1.2.1.3.2.1.1.1 25-1.1 26-1.1.1 27-1.1.1.1 27-1.1.1.1.2 27-1.1.1.1.2.r 27-1.1.1.1.3 27-1.1.1.1.3.r 28-1.1.1.1.3.1.1.1 30-1.1.1.1.3.1.1.1 32-1.1.1.1.3 (c3 / cause-01~e.0 :ARG1 (p2 / possible-01~e.25 :ARG1 (i2 / involve-01~e.26 :ARG1 (e / enzyme~e.27 :name (n5 / name :op1 "PTPase") :ARG1-of~e.27 (d2 / differ-02~e.27) :ARG1-of~e.27 (r / resemble-01~e.27,32 :ARG2 (e2 / enzyme :name (n6 / name :op1 "VH-1"~e.28,30)))) :ARG2 (o / or~e.3,13 :op1 (a / activate-01~e.5 :ARG1~e.6 (e3 / enzyme :name (n / name :op1 "ERK"~e.7)) :ARG1-of (p3 / prolong-01~e.2) :ARG2-of (i3 / induce-01~e.8 :ARG0~e.9 (s2 / stimulate-01~e.15 :ARG0 (p / protein :name (n2 / name :op1 "nerve"~e.10 :op2 "growth"~e.11 :op3 "factor"~e.12)) :ARG1~e.16 (c / cell-line~e.18 :name (n3 / name :op1 "PC12"~e.17))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 28~e.22))))) :op2 (a2 / activate-01~e.5 :ARG1 e3 :ARG1-of (t / transient-02~e.4) :ARG2-of (i4 / induce-01~e.8 :ARG0 (s3 / stimulate-01~e.15 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF"~e.14)) :ARG1 c) :ARG1-of d3)))))) # ::id bio.chicago_2015.23867 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , Ubc4 @/@ 5 cannot substitute for Ubc13 @/@ Uev1A in the activation of IKK by TRAF6 ( Figure 4D ) . # ::alignments 2-1.1.2.1.1.1 4-1.1.2.1.1.1 5-1.1 5-1.1.1 5-1.1.1.r 6-1.1.2 7-1.1.2.2.r 8-1.1.2.2.1.1 10-1.1.2.2.1.1 11-1.1.2.3.r 13-1.1.2.3 14-1.1.2.3.2.r 15-1.1.2.3.2.1.1 16-1.1.2.3.1.r 17-1.1.2.3.1.1.1 19-1.2.1 20-1.2.1.1 (c / contrast-01 :ARG1 (p / possible-01~e.5 :polarity~e.5 -~e.5 :ARG1 (s / substitute-01~e.6 :ARG1 (e / enzyme :name (n / name :op1 "Ubc4/5"~e.2,4)) :ARG2~e.7 (p2 / protein :name (n2 / name :op1 "Ubc13/Uev1A"~e.8,10)) :ARG3~e.11 (a / activate-01~e.13 :ARG0~e.16 (p3 / protein :name (n3 / name :op1 "TRAF6"~e.17)) :ARG1~e.14 (e3 / enzyme :name (n4 / name :op1 "IKK"~e.15))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "4D"~e.20))) # ::id bio.chicago_2015.23926 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A , lysates of biosynthetically labeled MOLT16 cells were first cleared with protein A @-@ Sepharose ( lane 1 ) or with GST coupled to glutathione @-@ Sepharose 4B beads ( lane 6 ) and then precipitated ( PP ) with mAb 6G4 coupled to protein A @-@ Sepharose ( lane 2 ) or GST @-@ DI ( lane 3 ) , GST @-@ DII ( lane 4 ) , or GST @-@ DIII ( lane 5 ) coupled to glutathione @-@ Sepharose 4B beads , as described under # ::alignments 0-1.3.1.1 2-1.1.2.2 5-1.1.2.3 6-1.1.2.1.1 7-1.1.2 9-1.1.3 10-1.1 11-1.2.2.r 12-1.2.2.1.3.1 13-1.3.1.1 15-1.1.1.1.1.1 15-1.1.1.2.2.1.1.1.1 17-1.1.1.1.2.1 18-1.1.1.1.2.1.1 20-1.1.1 20-1.2.2 21-1.1.1.r 21-1.2.2.r 22-1.1.1.2.1.1 23-1.1.1.2.2 23-1.2.2.2.1 23-1.2.2.4.2 27-1.1.1.1.1.1 27-1.1.1.2.2.1.1.1.1 28-1.1.1.2.2.1.1.1.2 29-1.1.1.2.2.1 31-1.1.1.2.3.1 32-1.1.1.2.3.1.1 34-1 35-1.2.3 36-1.2 40-1.2.2.r 43-1.2.2.1.1 43-1.2.2.2.1 43-1.2.2.4.2 45-1.1.1.1 45-1.2.2.1.3.1 46-1.1.1.1.1.1 46-1.3.1.1 48-1.1.1.1.1.1 48-1.1.1.2.2.1.1.1.1 50-1.2.2.1.2.1 51-1.2.2.1.2.1.1 53-1.1.1 54-1.1.1.2.1.1 56-1.2.2.1.2.1.1 56-1.2.2.2.1.1.1.1 58-1.2.2.2.2.1 59-1.2.2.2.2.1.1 62-1.2.2.2.1.1.1.1 62-1.2.2.3.1.1 62-1.2.2.4.1.1 64-1.2.2.3.1.1 66-1.2.2.3.2.1 67-1.2.2.3.2.1.1 70-1.1.1 71-1.1.1.2.1.1 73-1.2.2.4.1.1 75-1.2.2.4.3.1 76-1.2.2.4.3.1.1 78-1.1.1.2.2 78-1.2.2.4.2 82-1.1.1.1.1.1 82-1.1.1.2.2.1.1.1.1 83-1.1.1.2.2.1.1.1.2 84-1.1.1.2.2.1 87-1.1.1.1.2 87-1.1.1.2.3 87-1.2.2.1.2 87-1.2.2.2.2 87-1.2.2.3.2 87-1.2.2.4.3 87-1.3 (a / and~e.34 :op1 (c / clear-01~e.10 :ARG0~e.21 (o2 / or~e.20,53,70 :op1 (p3 / protein~e.45 :name (n2 / name :op1 "A-sepharose"~e.15,27,46,48,82) :ARG1-of (d / describe-01~e.87 :ARG0 (l3 / lane~e.17 :mod 1~e.18))) :op2 (e / enzyme :name (n3 / name :op1 "GST"~e.22,54,71) :ARG1-of (c3 / couple-01~e.23,78 :ARG2 (b2 / bead~e.29,84 :consist-of (s / small-molecule :name (n4 / name :op1 "gluthatione-Sepharose"~e.15,27,48,82 :op2 "4b"~e.28,83)))) :ARG1-of (d2 / describe-01~e.87 :ARG0 (l4 / lane~e.31 :mod 6~e.32)))) :ARG1 (c2 / cell-line~e.7 :name (n / name :op1 "MOLT16"~e.6) :ARG1-of (l / lysate-00~e.2) :ARG1-of (l2 / label-01~e.5 :ARG2 (b / biosynthetic))) :time (f / first~e.9)) :op2 (p / precipitate-00~e.36 :ARG1 c2 :instrument~e.11,21,40 (o3 / or~e.20 :op1 (a2 / antibody :ARG1-of (c4 / couple-01~e.43 :ARG2 p3) :ARG1-of (d5 / describe-01~e.87 :ARG0 (l5 / lane~e.50 :mod 2~e.51,56)) :ARG0-of (c7 / counter-01 :ARG1 (p2 / protein~e.12,45 :name (n5 / name :op1 "6G5"))) :mod (m3 / monoclone)) :op2 (a3 / antibody :ARG1-of (c5 / couple-01~e.23,43 :ARG2 (e2 / enzyme :name (n7 / name :op1 "GST-DI"~e.56,62))) :ARG1-of (d6 / describe-01~e.87 :ARG0 (l6 / lane~e.58 :mod 3~e.59)) :ARG0-of c7 :mod m3) :op3 (e3 / enzyme :name (n9 / name :op1 "GST-DII"~e.62,64) :ARG1-of (d7 / describe-01~e.87 :ARG0 (l7 / lane~e.66 :mod 4~e.67))) :op4 (e4 / enzyme :name (n8 / name :op1 "GST-DIII"~e.62,73) :ARG1-of (c6 / couple-01~e.23,43,78 :ARG2 s) :ARG1-of (d8 / describe-01~e.87 :ARG0 (l8 / lane~e.75 :mod 5~e.76)))) :time (t / then~e.35)) :ARG1-of (d3 / describe-01~e.87 :ARG0 (f2 / figure :mod "A"~e.0,13,46))) # ::id bio.chicago_2015.23937 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several proteins have been isolated as putative Rho effectors on the basis of their selective interaction with the GTP @-@ bound form of Rho . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.2 4-1 5-1.1.1.r 6-1.1.1.2 7-1.1.1.1.1.1 8-1.1.1 9-1.2.r 11-1.2 12-1.2.1.r 13-1.2.1.1 13-1.2.1.1.r 14-1.2.1.3 15-1.2.1 16-1.2.1.2.r 18-1.2.1.2.2.1.1.1 20-1.2.1.2 20-1.2.1.2.2 20-1.2.1.2.2.r 23-1.1.1.1.1.1 23-1.2.1.2.1.1 (i / isolate-01~e.4 :ARG1 (p / protein~e.1 :mod~e.5 (e / effector~e.8 :mod (p2 / protein :name (n / name :op1 "Rho"~e.7,23)) :ARG1-of (t / think-01~e.2,6)) :quant (s / several~e.0)) :ARG1-of~e.9 (b2 / base-02~e.11 :ARG2~e.12 (i2 / interact-01~e.15 :ARG0~e.13 p~e.13 :ARG1~e.16 (p3 / protein~e.20 :name (n3 / name :op1 "Rho"~e.23) :ARG1-of~e.20 (b / bind-01~e.20 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "GTP"~e.18)))) :manner (s2 / selective~e.14)))) # ::id bio.chicago_2015.23977 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results demonstrate that Sp1 and Sp3 can both bind to the Sp1 consensus sequence in the IGF @-@ II promoter . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1 3-1.2.r 4-1.2.1.1.1.1.1 5-1.2.1.1 6-1.2.1.1.2.1.1 7-1.2 9-1.2.1 10-1.2.1.2.r 12-1.2.1.2.3 13-1.2.1.2.1 14-1.2.1.2 15-1.2.1.2.2.r 17-1.2.1.2.2.1.1.1.1 19-1.2.1.2.2.1.1.1.1 20-1.2.1.2.2 20-1.2.1.2.2.1 20-1.2.1.2.2.1.r (d / demonstrate-01~e.2 :ARG0 (t2 / thing~e.1 :mod (t / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (p / possible-01~e.7 :ARG1 (b / bind-01~e.9 :ARG1 (a / and~e.5 :op1 (p2 / protein :name (n / name :op1 "Sp1"~e.4)) :op2 (p3 / protein :name (n2 / name :op1 "Sp3"~e.6))) :ARG2~e.10 (s / sequence~e.14 :mod (c / consensus~e.13) :part-of~e.15 (m / molecular-physical-entity~e.20 :ARG0-of~e.20 (p4 / promote-01~e.20 :ARG1 (p5 / protein :name (n3 / name :op1 "IGF-II"~e.17,19)))) :mod p2~e.12)))) # ::id bio.chicago_2015.24061 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternatively , the absence of an Xbra band in the ActRIIBdn cells would suggest that activin induces Xbra directly . # ::alignments 0-1.3 0-1.3.r 3-1.1 4-1.1.1.r 6-1.1.1.1.1.1 7-1.1.1 8-1.1.2.r 10-1.1.2.1.1 11-1.1.2 13-1 14-1.2.r 15-1.2.1.1.1 16-1.2 17-1.2.2 18-1.2.3 (s / suggest-01~e.13 :ARG0 (a2 / absent-01~e.3 :ARG1~e.4 (b / band~e.7 :mod (g / gene :name (n / name :op1 "Xbra"~e.6))) :ARG2~e.8 (c / cell-line~e.11 :name (n2 / name :op1 "ActRIIBdn"~e.10))) :ARG1~e.14 (i / induce-01~e.16 :ARG0 (p / protein :name (n3 / name :op1 "activin"~e.15)) :ARG1 g~e.17 :ARG1-of (d / direct-02~e.18)) :manner~e.0 (a / alternative~e.0)) # ::id bio.chicago_2015.24105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , as previously described ( 13 ) , co @-@ expression of kinase @-@ inactive MEKK1 markedly reduced NIK activation of JNK ( Fig . 7 B ) . # ::alignments 1-1 3-1.2.2.r 4-1.2.2 5-1.1.4 5-1.2 7-1.2.1.1.1 13-1.1.r 14-1.1.1.1.2.2 16-1.1.1.1 16-1.1.1.1.2 16-1.1.1.1.2.1 16-1.1.1.1.2.1.r 16-1.1.1.1.2.r 17-1.1.1.1.1.1 18-1.1.3 18-1.1.3.r 19-1.1 20-1.1.2.1.1.1 21-1.1.2 22-1.1.2.2.r 23-1.1.2.2.1.1 25-1.1.4.1 (c / contrast-01~e.1 :ARG2~e.13 (r / reduce-01~e.19 :ARG0 (c2 / coexpress-01 :ARG2 (e / enzyme~e.16 :name (n / name :op1 "MEKK1"~e.17) :ARG0-of~e.16 (a / activity-06~e.16 :polarity~e.16 -~e.16 :mod (k / kinase~e.14)))) :ARG1 (a2 / activate-01~e.21 :ARG0 (e2 / enzyme :name (n2 / name :op1 "NIK"~e.20)) :ARG1~e.22 (e3 / enzyme :name (n3 / name :op1 "JNK"~e.23))) :manner~e.18 (m / marked~e.18) :ARG1-of (d2 / describe-01~e.5 :ARG0 (f / figure~e.25 :mod "7B"))) :ARG1-of (d / describe-01~e.5 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 13~e.7)) :time~e.3 (p2 / previous~e.4))) # ::id bio.chicago_2015.24115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , we recently showed that kinase subdomain VIII of PAK1 could be phosphorylated in vitro by PDK1 , suggesting phosphorylation events within the catalytic domain may regulate PAK1 activity ( 26 ) . # ::alignments 0-1 2-1.1.1 3-1.1.3 4-1.1 8-1.1.2.1.1.1 10-1.1.2.1.1.2.1.1 11-1.1.2 13-1.1.2.1 14-1.1.2.1.3 15-1.1.2.1.3 16-1.1.2.1.2.r 17-1.1.2.1.2.1.1 19-1.1.2.2 20-1.1.2.2.1.1.1 24-1.1.2.2.1.1.1.1.1 25-1.1.2.2.1.1.1.1 26-1.1.2.2.1 27-1.1.2.2.1.1 28-1.1.2.2.1.1.2.1 29-1.1.2.2.1.1.2 31-1.1.4.1.1.1 (a / and~e.0 :op2 (s / show-01~e.4 :ARG0 (w / we~e.2) :ARG1 (p / possible-01~e.11 :ARG1 (p2 / phosphorylate-01~e.13 :ARG1 (p3 / protein-segment :mod 8~e.8 :part-of (e / enzyme :name (n2 / name :op1 "PAK1"~e.10))) :ARG2~e.16 (e2 / enzyme :name (n3 / name :op1 "PDK1"~e.17)) :manner (i / in-vitro~e.14,15)) :ARG0-of (s2 / suggest-01~e.19 :ARG1 (p4 / possible-01~e.26 :ARG1 (r2 / regulate-01~e.27 :ARG0 (p5 / phosphorylate-01~e.20 :location (d2 / domain~e.25 :mod (c / catalytic~e.24))) :ARG1 (a2 / activity-06~e.29 :ARG0 e~e.28))))) :time (r / recent~e.3) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 26~e.31))))) # ::id bio.chicago_2015.24118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Direct Phosphorylation and Inhibition of Cdc25 by Cds1 and Chk1 In Vitro # ::alignments 0-1.3 1-1.1 2-1 2-1.1.2 3-1.2 4-1.1.1.r 5-1.1.1.1.1 6-1.1.2.r 7-1.1.2.1.1.1 9-1.1.2.2.1.1 10-1.4 11-1.4 (a / and~e.2 :op1 (p / phosphorylate-01~e.1 :ARG1~e.4 (e / enzyme :name (n / name :op1 "Cdc25"~e.5)) :ARG2~e.6 (a2 / and~e.2 :op1 (e3 / enzyme :name (n2 / name :op1 "Cds1"~e.7)) :op2 (e2 / enzyme :name (n3 / name :op1 "Chk1"~e.9)))) :op2 (i / inhibit-01~e.3 :ARG0 a2 :ARG1 e) :ARG1-of (d / direct-02~e.0) :manner (i2 / in-vitro~e.10,11)) # ::id bio.chicago_2015.24126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is unclear why activation of endogenous PKC by TPA , which strongly inhibits the DNA @-@ binding activity of endogenous HES @-@ 1 protein , does not also induce neurite outgrowth although it greatly potentiates the response to NGF . # ::alignments 2-1 2-1.1 2-1.1.r 3-1.2 3-1.2.1 3-1.2.1.r 4-1.2.2.2 5-1.2.2.2.2.r 6-1.2.2.2.2.2 7-1.2.2.2.2.1.1 8-1.2.2.2.1.r 9-1.2.2.2.1.1.1 11-1.2.1 12-1.2.2.2.1.2.2 13-1.2.2.2.1 13-1.2.2.2.1.2 13-1.2.2.2.1.2.r 15-1.2.2.2.1.2.1.2.1.1.1 17-1.2.2.2.1.2.1.2 18-1.2.2.2.1.2.1 20-1.2.2.2.2.2 21-1.2.2.2.1.2.1.1.1.1 23-1.2.2.2.1.2.1.1.1.1 24-1.2.2.2.1.2.1.1 24-1.2.2.2.3.1.1.1 27-1.2.2.1 27-1.2.2.1.r 28-1.2.2.4 29-1.2.2 30-1.2.2.3.1 34-1.2.2.2.3.1.2 34-1.2.2.2.3.1.2.r 35-1.2.2.2.3.1 37-1.2.2.2.3.1.1 39-1.2.2.2.3.1.1.1.1.1 (c / clear-06~e.2 :polarity~e.2 -~e.2 :ARG1 (c2 / cause-01~e.3 :ARG0~e.3 (a / amr-unknown~e.3,11) :ARG1 (i / induce-01~e.29 :polarity~e.27 -~e.27 :ARG0 (a3 / activate-01~e.4 :ARG0~e.8 (s / small-molecule~e.13 :name (n / name :op1 "TPA"~e.9) :ARG0-of~e.13 (i2 / inhibit-01~e.13 :ARG1 (a4 / activity-06~e.18 :ARG0 (p / protein~e.24 :name (n3 / name :op1 "HES-1"~e.21,23)) :ARG1 (b / bind-01~e.17 :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"~e.15)))) :ARG1-of (s2 / strong-02~e.12))) :ARG1~e.5 (e / enzyme :name (n2 / name :op1 "PKC"~e.7) :mod (e2 / endogenous~e.6,20)) :ARG1-of (c3 / contrast-01 :ARG2 (p2 / potentiate-01~e.35 :ARG1 (r / respond-01~e.37 :ARG1 (p3 / protein~e.24 :name (n5 / name :op1 "NGF"~e.39))) :manner~e.34 (g2 / great~e.34)))) :ARG2 (o / outgrow-01 :ARG0 (n4 / neurite~e.30)) :mod (a2 / also~e.28)))) # ::id bio.chicago_2015.24129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C @-@ Daam1 activation of RhoA is not affected by deltaPDZ @-@ Dvl ( Figure 3A ) , which inhibits RhoA activation by Fz or Dvl ( Figure 1F ) , further demonstrating that Daam1 functions downstream of Dvl in Rho activation . # ::alignments 0-1.3.1.1.1 2-1.3.1.1.1 3-1.3 4-1.3.2.r 5-1.3.2.1.1 7-1.1 7-1.1.r 8-1 9-1.2.r 10-1.2.1.1 12-1.2.1.1 14-1.4.1 15-1.4.1.1 19-1.2 19-1.2.2 19-1.2.2.r 20-1.2.2.1.2 21-1.2.2.1 22-1.2.2.1.1.r 23-1.2.2.1.1.1.1.1 24-1.2.2.1.1 25-1.2.2.1.1.2.1.1 27-1.2.2.3.1 28-1.2.2.3.1.1 31-1.2.2.2.2 32-1.2.2.2 33-1.2.2.2.1.r 34-1.2.2.2.1.1.1.1 35-1.2.2.2.1 36-1.2.2.2.1.3.2 38-1.2.2.2.1.3.1 39-1.2.2.2.1.2.r 40-1.2.2.2.1.2.1.1.1 41-1.2.2.2.1.2 (a / affect-01~e.8 :polarity~e.7 -~e.7 :ARG0~e.9 (p / protein-segment~e.19 :name (n / name :op1 "deltaPDZ-Dvl"~e.10,12) :ARG0-of~e.19 (i / inhibit-01~e.19 :ARG1 (a3 / activate-01~e.21 :ARG0~e.22 (o / or~e.24 :op1 (p4 / protein :name (n4 / name :op1 "Fz"~e.23)) :op2 (p5 / protein :name (n5 / name :op1 "Dvl"~e.25))) :ARG1 p3~e.20) :ARG0-of (d2 / demonstrate-01~e.32 :ARG1~e.33 (f3 / function-01~e.35 :ARG0 (p6 / protein :name (n6 / name :op1 "Daam1"~e.34)) :ARG1~e.39 (a4 / activate-01~e.41 :ARG1 (p7 / protein :name (n7 / name :op1 "Rho"~e.40))) :location (r / relative-position :op1 p5~e.38 :direction (d3 / downstream~e.36))) :manner (f2 / further~e.31)) :ARG1-of (d4 / describe-01 :ARG0 (f4 / figure~e.27 :mod "1F"~e.28)))) :ARG1 (a2 / activate-01~e.3 :ARG0 (p2 / protein :name (n2 / name :op1 "C-Daam1"~e.0,2)) :ARG1~e.4 (p3 / protein :name (n3 / name :op1 "RhoA"~e.5))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "3A"~e.15))) # ::id bio.chicago_2015.24156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK @-@ 3 differs from canonical Wnt effects on - catenin stability and TCF activity . # ::alignments 0-1.1.2.2.2.2 2-1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.2 5-1.1.1.1.1.1.1.1.1 6-1.1.1.1.1.1 7-1.1.1.1.1 8-1.1.1.1.1.3.2 10-1.1.1.1.1.3.1.1.1 11-1.1.1 12-1.1.1.2.r 13-1.1.1.2.1 16-1.1.1.2.1.1.1.1.1 17-1.1.1.2.1.1.1.2 18-1.1.1.2.1.1.1 18-1.1.2.2.2.1 19-1.1.1.2 20-1.1.1.2.2 21-1.1.1.2.2.1 22-1.1.1.2.2.1.1.r 23-1.1.1.2.2.1.1.1.1.1 24-1.1.1.2.2.1.1 25-1.1.1.2.2.2 26-1.1.1.2.2.2 27-1.1 28-1.1.2 30-1.1.2.2.1.1 31-1.1.2.2.1 32-1.1.2.2.1.2.r 33-1.1.2.2.1.2.1.1 35-1.1.2.2.1.2.1.1 36-1.1.2.2 39-1.1.2.2.2.1.1.1 40-1.1.2.2.2 43-1.1.2.2.2.2.1.1.1.1 44-1.1.2.2.2.2.1 45-1.1.2.2.2.2 46-1.1.2.2.2.2.2.1.1.1 47-1.1.2.2.2.2.2 (a / and :op2 (c / contrast-01~e.27 :ARG1 (d / demonstrate-01~e.11 :ARG0 (m2 / manipulate-01~e.2 :ARG1~e.3 (m3 / molecule~e.7 :ARG0-of (s3 / signal-07~e.6 :ARG1 (g / gene :name (n4 / name :op1 "wingless"~e.5))) :mod (o / other~e.4) :location (r / relative-position :op1 (e / enzyme :name (n5 / name :op1 "shaggy"~e.10)) :direction (d3 / downstream~e.8)))) :ARG1~e.12 (m / modulate-01~e.19 :ARG0 (c2 / component~e.13 :ARG1-of (i / include-91 :ARG2 (p2 / pathway~e.18 :name (n / name :op1 "Wnt"~e.16) :ARG0-of (s2 / signal-07~e.17)))) :ARG1 (n2 / neurodegeneration~e.20 :ARG2-of (i2 / induce-01~e.21 :ARG0~e.22 (p3 / pathology~e.24 :mod (p4 / protein :name (n3 / name :op1 "tau"~e.23)))) :manner (i3 / in-vivo~e.25,26)))) :ARG2 (s / suggest-01~e.28 :ARG0 m2 :ARG1 (d2 / differ-02~e.36 :ARG1 (p / phosphorylate-01~e.31 :ARG1 p4~e.30 :ARG2~e.32 (e2 / enzyme :name (n7 / name :op1 "GSK-3"~e.33,35))) :ARG2 (a2 / affect-01~e.40 :ARG0 (p6 / pathway~e.18 :name (n8 / name :op1 "Wnt"~e.39)) :ARG1 (a3 / and~e.0,45 :op1 (s4 / stability~e.44 :mod (p7 / protein :name (n10 / name :op1 "β-catenin"~e.43))) :op2 (a4 / activity-06~e.47 :ARG0 (p5 / protein :name (n9 / name :op1 "TCF"~e.46)))) :mod (c3 / canon)))))) # ::id bio.chicago_2015.24160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cell surface expression of glypican @-@ 1 in these cells was analyzed by quantitative immunofluorescence flow cytometry ( data not shown ) , and the effects of cells expressing one @-@ chain ( SAA ) , two @-@ chain ( SSA ) , or wild @-@ type ( SSS ) forms of glypican @-@ 1 on FGF2 @-@ induced FGFR1 autophosphorylation were compared . # ::alignments 1-1.1.1.2 2-1.1.1.2.1 3-1.1.1 5-1.2.1.1.1.1.1.1.1 5-1.2.1.1.1.1.2.1.1 5-1.2.1.1.1.1.3.1.1 7-1.2.1.1.1.1.1.1.1 7-1.2.1.1.1.1.1.3.1 7-1.2.1.1.1.1.2.1.1 7-1.2.1.1.1.1.3.1.1 8-1.1.1.3.r 9-1.1.1.3.1 10-1.1.1.3 12-1.1 13-1.1.2.r 14-1.1.2.1.1 15-1.1.2.1 16-1.1.2.2 17-1.1.2 19-1.1.3.1 20-1.1.3.1.1.1 20-1.1.3.1.1.1.r 21-1.1.3.1.1 24-1 26-1.2.1 28-1.2.1.1 29-1.2.1.1.1 30-1.2.1.1.1.1.1.1.1 30-1.2.1.1.1.1.1.3.1 30-1.2.1.1.1.1.2.1.1 30-1.2.1.1.1.1.3.1.1 32-1.2.1.1.1.1.1.3 34-1.2.1.1.1.1.1.4.1.1 37-1.2.1.1.1.1.2.3.1 39-1.2.1.1.1.1.2.3 41-1.2.1.1.1.1.2.4.1.1 44-1.2.1.1.1.1 45-1.2.1.1.1.1.3.2 47-1.2.1.1.1.1.3.2 49-1.2.1.1.1.1.3.3.1.1 51-1.2.1.1.1.1.1.2 51-1.2.1.1.1.1.2.2 53-1.2.1.1.1.1.1.1.1 53-1.2.1.1.1.1.2.1.1 53-1.2.1.1.1.1.3.1.1 55-1.2.1.1.1.1.1.1.1 55-1.2.1.1.1.1.2.1.1 55-1.2.1.1.1.1.3.1.1 56-1.2.1.2.r 57-1.2.1.2.3.1.1.1 59-1.2.1.2.3 60-1.2.1.2.1.1.1 61-1.2.1.2 63-1.2 (a / and~e.24 :op1 (a2 / analyze-01~e.12 :ARG1 (e / express-03~e.3 :ARG2 (p2 / protein) :ARG3 (c / cell~e.1 :ARG1-of (s / surface-02~e.2)) :location~e.8 (c2 / cell~e.10 :mod (t / this~e.9))) :manner~e.13 (c3 / cytometry~e.17 :mod (i / immunofluoresce-01~e.15 :mod (q / quantitative~e.14)) :mod (f / flow~e.16)) :ARG1-of (d2 / describe-01 :ARG0 (d / data~e.19 :ARG1-of (s2 / show-01~e.21 :polarity~e.20 -~e.20)))) :op2 (c4 / compare-01~e.63 :ARG1 (a3 / affect-01~e.26 :ARG0 (c5 / cell~e.28 :ARG2-of (e2 / express-03~e.29 :ARG1 (o / or~e.44 :op1 (p / protein :name (n7 / name :op1 "glypican-1"~e.5,7,30,53,55) :mod (f3 / form~e.51) :mod (c11 / chain~e.32 :quant 1~e.7,30) :ARG1-of (m / mean-01 :ARG2 (n / name :op1 "SAA"~e.34))) :op2 (p6 / protein :name (n8 / name :op1 "glypican-1"~e.5,7,30,53,55) :mod (f4 / form~e.51) :mod (c12 / chain~e.39 :quant 2~e.37) :ARG1-of (m2 / mean-01 :ARG2 (n5 / name :op1 "SSA"~e.41))) :op3 (p7 / protein :name (n9 / name :op1 "glypican-1"~e.5,7,30,53,55) :mod (w2 / wild-type~e.45,47) :ARG1-of (m3 / mean-01 :ARG2 (n6 / name :op1 "SSS"~e.49)))))) :ARG1~e.56 (p3 / phosphorylate-01~e.61 :ARG1 (e4 / enzyme :name (n3 / name :op1 "FGFR1"~e.60)) :ARG2 e4 :ARG2-of (i2 / induce-01~e.59 :ARG0 (p4 / protein :name (n4 / name :op1 "FGF2"~e.57))))))) # ::id bio.chicago_2015.24247 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the Raf @-@ 1 bound to Ras membranes undergoes activation , whereas Raf @-@ 1 bound to control membranes does not ( Fig . 5A and C ) . # ::alignments 0-1 3-1.1.1.2.1.1 3-1.1.2.3.1.1 5-1.1.1.2.1.1 5-1.1.2.3.1.1 6-1.1.1.2 6-1.1.1.2.2 6-1.1.1.2.2.r 6-1.1.2.3 6-1.1.2.3.2 6-1.1.2.3.2.r 8-1.1.1.2.2.1.1.1.1 9-1.1.1.2.2.1 9-1.1.2.3.2.1 10-1.1.1 10-1.1.2 11-1.1.1.1 11-1.1.2.2 13-1.1 14-1.1.1.2.1.1 14-1.1.2.3.1.1 16-1.1.1.2.1.1 16-1.1.2.3.1.1 17-1.1.1.2 17-1.1.1.2.2 17-1.1.1.2.2.r 17-1.1.2.3 17-1.1.2.3.2 17-1.1.2.3.2.r 19-1.1.2.3.2.1.1 20-1.1.2.3.2.1 22-1.1.2.1 22-1.1.2.1.r 24-1.2.1.1 24-1.2.1.2 26-1.2.1.1.1 27-1.2.1 (a / and~e.0 :op2 (c / contrast-01~e.13 :ARG1 (u / undergo-28~e.10 :ARG1 (a2 / activate-01~e.11 :ARG1 e) :ARG2 (e / enzyme~e.6,17 :name (n2 / name :op1 "Raf-1"~e.3,5,14,16) :ARG1-of~e.6,17 (b / bind-01~e.6,17 :ARG2 (m / membrane~e.9 :mod (e2 / enzyme :name (n3 / name :op1 "Ras"~e.8)))))) :ARG2 (u2 / undergo-28~e.10 :polarity~e.22 -~e.22 :ARG1 (a3 / activate-01~e.11 :ARG1 e3) :ARG2 (e3 / enzyme~e.6,17 :name (n / name :op1 "Raf-1"~e.3,5,14,16) :ARG1-of~e.6,17 (b2 / bind-01~e.6,17 :ARG2 (m2 / membrane~e.9,20 :ARG0-of (c2 / control-01~e.19)))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.27 :op1 (f / figure~e.24 :mod "5A"~e.26) :op2 (f2 / figure~e.24 :mod "5C")))) # ::id bio.chicago_2015.24257 ::amr-annotator SDL-AMR-09 ::preferred # ::tok DAG activates PKC directly . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1 3-1.3 (a / activate-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "DAG"~e.0)) :ARG1 (e / enzyme :name (n2 / name :op1 "PKC"~e.2)) :ARG1-of (d / direct-02~e.3)) # ::id bio.chicago_2015.24353 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , PD98059 ( 50 muM ) reduced Cr( VI ) - activated ERK to endogenous levels and decreased Cr( VI ) - activated p38 by ~ 60 % , but did not significantly alter Cr( VI ) - activated JNK ( Figure 9 ) . # ::alignments 5-1.1.1.1.1.1.1 7-1.1.1.1.1.2.1 10-1.1.1.1 15-1.1.1.1.2.2 16-1.1.1.1.2.1.1 19-1.1.1.1.3 20-1.1.1 21-1.1.1.2 26-1.1.2.3.2 27-1.1.1.2.2.1.1 30-1.1.1.2.3.1.1 31-1.1.1.2.3.1 33-1 33-1.1 33-1.1.r 35-1.1.2.1 35-1.1.2.1.r 36-1.1.2.4 37-1.1.2 42-1.1.2.3.2 43-1.1.2.3.1.1 45-1.2.1 46-1.2.1.1 (c / contrast-01~e.33 :ARG2~e.33 (c2 / contrast-01~e.33 :ARG1 (a / and~e.20 :op1 (r / reduce-01~e.10 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "PD98059"~e.5) :mod (c3 / concentration-quantity :quant 50~e.7 :unit (m / micromolar))) :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"~e.16) :ARG1-of (a3 / activate-01~e.15 :ARG0 (s / small-molecule :name (n4 / name :op1 "Cr(VI)")))) :ARG4 (l / level~e.19 :mod (e2 / endogene))) :op2 (d / decrease-01~e.21 :ARG0 s3 :ARG1 (e4 / enzyme :name (n5 / name :op1 "p38"~e.27) :ARG1-of a3) :ARG2 (a6 / about :op1 (p / percentage-entity~e.31 :value 60~e.30)))) :ARG2 (a2 / alter-01~e.37 :polarity~e.35 -~e.35 :ARG0 s3 :ARG1 (e3 / enzyme :name (n / name :op1 "JNK"~e.43) :ARG1-of (a5 / activate-01~e.26,42 :ARG0 s)) :ARG1-of (s2 / significant-02~e.36))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.45 :mod 9~e.46))) # ::id bio.chicago_2015.24368 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , we do not believe that our findings exclude the possibility that MDM2 may also inhibit p53 @-@ dependent transcription by masking its activation domain from important basal factor contacts . # ::alignments 0-1 2-1.1.2 4-1.1.1 4-1.1.1.r 5-1.1 6-1.1.3.r 7-1.1.3.1.1.1 7-1.1.3.1.1.1.r 8-1.1.3.1 8-1.1.3.1.1 8-1.1.3.1.1.r 9-1.1.3 11-1.1.3.2 12-1.1.3.2.1.r 13-1.1.3.2.1.1.1.1 14-1.1.3.2.1.4 15-1.1.3.2.1.3 16-1.1.3.2.1 17-1.1.3.2.1.2.1.1.1.1 19-1.1.3.2.1.2.1 20-1.1.3.2.1.2 21-1.1.3.2.1.5.r 22-1.1.3.2.1.5 23-1.1.3.2.1.5.2.2 23-1.1.3.2.1.5.2.2.r 24-1.1.3.2.1.5.2.1 25-1.1.3.2.1.5.2 26-1.1.3.2.1.5.2.3.r 27-1.1.3.2.1.5.2.3.3 28-1.1.3.2.1.5.2.3.2 29-1.1.3.2.1.5.2.3.1 30-1.1.3.2.1.5.2.3 (c / contrast-01~e.0 :ARG2 (b / believe-01~e.5 :polarity~e.4 -~e.4 :ARG0 (w / we~e.2) :ARG1~e.6 (e / exclude-01~e.9 :ARG0 (t2 / thing~e.8 :ARG1-of~e.8 (f / find-01~e.8 :ARG0~e.7 w~e.7)) :ARG1 (p / possible-01~e.11 :ARG1~e.12 (i / inhibit-01~e.16 :ARG0 (p3 / protein :name (n / name :op1 "MDM2"~e.13)) :ARG1 (t / transcribe-01~e.20 :ARG0-of (d2 / depend-01~e.19 :ARG1 (p4 / protein :name (n2 / name :op1 "p53"~e.17)))) :mod (a / also~e.15) :ARG1-of (p2 / possible-01~e.14) :manner~e.21 (m / mask-01~e.22 :ARG0 p3 :ARG1 (d3 / domain~e.25 :location-of (a2 / activate-01~e.24) :poss~e.23 p3~e.23 :source~e.26 (c3 / contact~e.30 :mod (f3 / factor~e.29) :mod (b3 / basal~e.28) :mod (i2 / important~e.27))))))))) # ::id bio.chicago_2015.24456 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stoichiometry of Binding of eIF4A with eIF4G( 613 @-@ 1560 )-- The forgoing result indicated that one molecule of eIF4A could bind to either the central or COOH @-@ terminal sites of eIF4G . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1 7-1.1.1.2.2.1 9-1.1.1.2.2.2 12-1.2.1.2 13-1.2.1 13-1.2.1.1 13-1.2.1.1.r 14-1.2 15-1.2.2.r 16-1.2.2.1.1.1 17-1.2.2.1.1 18-1.2.2.1.1.2.r 19-1.2.2.1.1.2.1.1 20-1.2.2 21-1.2.2.1 25-1.2.2.1.2.1.1 26-1.2.2.1.2 27-1.2.2.1.2.2.1.1 29-1.2.2.1.2.2.1.1 30-1.2.2.1.2.1 32-1.1.1.2.1.1 32-1.2.2.1.2.3.1.1 (m / multi-sentence :snt1 (s / stoichiometry~e.0 :mod~e.1 (b2 / bind-01~e.2 :ARG1~e.3 (p / protein :name (n / name :op1 "eIF4A"~e.4)) :ARG3 (p3 / protein :name (n2 / name :op1 "eIF4G"~e.32) :mod (v / value-interval :op1 613~e.7 :op2 1560~e.9)))) :snt2 (i / indicate-01~e.14 :ARG0 (t / thing~e.13 :ARG1-of~e.13 (r / result-01~e.13) :ARG1-of (f / forgo-02~e.12)) :ARG1~e.15 (p2 / possible-01~e.20 :ARG1 (b4 / bind-01~e.21 :ARG1 (m4 / molecule~e.17 :quant 1~e.16 :mod~e.18 (p5 / protein :name (n3 / name :op1 "eIF4A"~e.19))) :ARG2 (o2 / or~e.26 :op1 (s4 / site~e.30 :mod (c2 / central~e.25)) :op2 (p4 / protein-segment :name (n4 / name :op1 "COOH-terminus"~e.27,29)) :part-of (p6 / protein :name (n5 / name :op1 "eIF4G"~e.32))))))) # ::id bio.chicago_2015.24491 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Rho @-@ N19 , but neither Rac @-@ N17 nor Cdc42 @-@ N17 , blocks RhoA activation by Wnt , Fz , Dvl , or C @-@ Daam1 . # ::alignments 1-1.1 3-1.2.1.1.1 5-1.2.1.1.1 7-1 8-1.3.1.r 9-1.3.2.1.1.1 11-1.3.2.1.1.1 11-1.3.2.2.1.1 12-1.3.1 12-1.3.1.r 13-1.3.2.2.1.1 15-1.3.2.1.1.1 15-1.3.2.2.1.1 17-1.2 17-1.3 18-1.2.2.2.1.1 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.1.1.1 23-1.2.2.1.2.1.1 25-1.2.2.1.3.1.1 27-1.2.2.1 28-1.2.2.1.4.1.1 30-1.2.2.1.4.1.1 (c / contrast-01~e.7 :li "B"~e.1 :ARG1 (b / block-01~e.17 :ARG0 (p5 / protein :name (n / name :op1 "Rho-N19"~e.3,5)) :ARG1 (a / activate-01~e.19 :ARG0~e.20 (o / or~e.27 :op1 (p / protein :name (n3 / name :op1 "Wnt"~e.21)) :op2 (p2 / protein :name (n4 / name :op1 "Fz"~e.23)) :op3 (p3 / protein :name (n5 / name :op1 "Dvl"~e.25)) :op4 (p4 / protein :name (n6 / name :op1 "C-Daam1"~e.28,30))) :ARG1 (p6 / protein :name (n2 / name :op1 "RhoA"~e.18)))) :ARG2 (b2 / block-01~e.17 :polarity~e.8,12 -~e.12 :ARG0 (a2 / and :op1 (e3 / enzyme :name (n7 / name :op1 "Rac-N17"~e.9,11,15)) :op2 (e4 / enzyme :name (n8 / name :op1 "Cdc42-N17"~e.11,13,15))) :ARG1 o)) # ::id bio.chicago_2015.24497 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although we could not evaluate the effect of PI3K inhibition on mutant huntingtin @-@ induced cell death due to the high toxicity of the PI3K inhibitor LY in striatal neurons , we found an increase in the percentage of striatal neurons containing intranuclear inclusions when treated with subtoxic doses of LY ( 100 nM ; data not shown ) . # ::alignments 0-1.3.r 1-1.1 2-1.3 3-1.3.1 3-1.3.1.r 4-1.3.2 6-1.3.2.2 8-1.3.2.2.1.1.1.1 9-1.3.2.2.1 10-1.3.2.2.2.r 11-1.3.2.2.2.3.1 11-1.3.2.2.2.3.1.2 11-1.3.2.2.2.3.1.2.r 12-1.3.2.2.2.3.1.1.1 14-1.3.2.2.2.3 15-1.3.2.2.2.1 16-1.3.2.2.2 17-1.3.2.2.2.2 18-1.3.2.2.2.2 20-1.3.2.2.2.2.1.1 21-1.3.2.2.2.2.1 24-1.3.2.2.1.1.1.1 25-1.3.2.2.1 25-1.3.2.2.2.2.1.3 25-1.3.2.2.2.2.1.3.2 25-1.3.2.2.2.2.1.3.2.r 26-1.3.2.2.2.2.1.3.1.1 29-1.3.2.2.2.2.1.2 31-1.1 32-1 34-1.2 35-1.2.1.r 37-1.2.1 40-1.2.1.1 41-1.2.1.1.2 42-1.2.1.1.2.1.1.1 43-1.2.1.1.2.1 43-1.2.1.1.2.1.1 43-1.2.1.1.2.1.1.r 44-1.2.2.r 45-1.2.2 46-1.2.2.2.r 47-1.2.2.2.2 48-1.2.2.2 49-1.2.2.2.1.r 50-1.2.2.2.1.1.1 52-1.2.2.2.1.2.1 53-1.2.2.2.1.2.2 55-1.4.1 56-1.4.1.1.1 56-1.4.1.1.1.r 57-1.4.1.1 (f / find-01~e.32 :ARG0 (w / we~e.1,31) :ARG1 (i2 / increase-01~e.34 :ARG1~e.35 (p2 / percentage~e.37 :quant-of (n / neuron~e.40 :mod (s / striatum) :ARG0-of (c / contain-01~e.41 :ARG1 (t / thing~e.43 :ARG1-of~e.43 (i3 / include-01~e.43 :location (i4 / intranuclear~e.42)))))) :time~e.44 (t2 / treat-04~e.45 :ARG1 n :ARG2~e.46 (d / dose-01~e.48 :ARG2~e.49 (s3 / small-molecule :name (n2 / name :op1 "LY"~e.50) :quant (c2 / concentration-quantity :quant 100~e.52 :unit (n3 / nanomolar~e.53))) :mod (s2 / subtoxic~e.47)))) :concession~e.0 (p3 / possible-01~e.2 :polarity~e.3 -~e.3 :ARG1 (e / evaluate-01~e.4 :ARG0 w :ARG1 (a / affect-01~e.6 :ARG0 (i / inhibit-01~e.9,25 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K"~e.8,24))) :ARG1~e.10 (d3 / die-01~e.16 :ARG1 (c3 / cell~e.15) :ARG1-of (c4 / cause-01~e.17,18 :ARG0 (t3 / toxicity~e.21 :ARG1-of (h / high-02~e.20) :location n~e.29 :poss (s5 / small-molecule~e.25 :name (n7 / name :op1 "LY"~e.26) :ARG0-of~e.25 (i5 / inhibit-01~e.25 :ARG1 e2)))) :ARG2-of (i6 / induce-01~e.14 :ARG0 (p5 / protein~e.11 :name (n5 / name :op1 "huntingtin"~e.12) :ARG2-of~e.11 (m / mutate-01~e.11))))))) :ARG2-of (d4 / describe-01 :ARG0 (d5 / data~e.55 :ARG1-of (s7 / show-01~e.57 :polarity~e.56 -~e.56)))) # ::id bio.chicago_2015.24503 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The morphologic features of apoptosis induced by Diva , including rounding and membrane blebbing ( Fig . 5 B ) as well as nuclear fragmentation ( Fig . 5 C ) were inhibited by vBcl @-@ 2 . # ::alignments 1-1.2.2 2-1.2 3-1.2.1.r 4-1.2.1 5-1.2.1.1 6-1.2.1.1.1.r 7-1.2.1.1.1.1.1 9-1.2.3 10-1.2.3.1.1 11-1.2.3.1 12-1.2.3.1.2.1 15-1.2.3.1.2.2.1 15-1.2.3.1.3.2.1 20-1.2.3.1 21-1.2.3.1 22-1.2.3.1 23-1.2.3.1.3.1 24-1.2.3.1.3 26-1.2.3.1.2.2.1 26-1.2.3.1.3.2.1 32-1 33-1.1.r 34-1.1.1.1 36-1.1.1.1 (i / inhibit-01~e.32 :ARG0~e.33 (p / protein :name (n / name :op1 "vBcl-2"~e.34,36)) :ARG1 (f / feature-01~e.2 :ARG1~e.3 (a / apoptosis~e.4 :ARG2-of (i2 / induce-01~e.5 :ARG0~e.6 (p2 / protein :name (n2 / name :op1 "Diva"~e.7)))) :mod (m / morphology~e.1) :ARG2-of (i3 / include-91~e.9 :ARG1 (a2 / and~e.11,20,21,22 :op1 (r / round-04~e.10) :op2 (b / bleb-00 :ARG1 (m3 / membrane~e.12) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.15,26 :mod "5B"))) :op3 (f5 / fragment-01~e.24 :ARG1 (n3 / nucleus~e.23) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.15,26 :mod "5C"))))))) # ::id bio.chicago_2015.24508 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mist1 efficiently inhibits MyoD from activating the TnI @-@ Luc gene whereas Mist1 mutbasic has no effect . # ::alignments 0-1.1.1.1.1 1-1.1.3 2-1.1 3-1.1.2.1.1 5-1.1.2.2 7-1.1.2.2.1.1.1 9-1.1.2.2.1.1.1 10-1.1.2.2.1 11-1 12-1.1.1.1.1 15-1.2.1 15-1.2.1.r 16-1.2 (c / contrast-01~e.11 :ARG1 (i / inhibit-01~e.2 :ARG0 (p / protein :name (n / name :op1 "Mist1"~e.0,12)) :ARG1 (p2 / protein :name (n2 / name :op1 "MyoD"~e.3) :ARG0-of (a / activate-01~e.5 :ARG1 (g / gene~e.10 :name (n3 / name :op1 "TnI-Luc"~e.7,9)))) :ARG2-of (e / efficient-01~e.1)) :ARG2 (a2 / affect-01~e.16 :polarity~e.15 -~e.15 :ARG0 (p3 / protein :name (n4 / name :op1 "Mist1mutbasic")))) # ::id bio.chicago_2015.24550 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is also well established that JNK and IKK are activated by LPS or the proinflammatory cytokines . # ::alignments 2-1.2 3-1.3 4-1 5-1.1.r 6-1.1.2.1.1.1 7-1.1.2 8-1.1.2.2.1.1 10-1.1 11-1.1.1.r 12-1.1.1.1.1.1 13-1.1.1 15-1.1.1.2.1 15-1.1.1.2.1.1 15-1.1.1.2.1.1.r 16-1.1.1.2 (e / establish-01~e.4 :ARG1~e.5 (a / activate-01~e.10 :ARG0~e.11 (o / or~e.13 :op1 (m / molecular-physical-entity :name (n3 / name :op1 "LPS"~e.12)) :op2 (c / cytokine~e.16 :ARG0-of (f / favor-01~e.15 :ARG1~e.15 (i / inflame-01~e.15)))) :ARG1 (a2 / and~e.7 :op1 (e2 / enzyme :name (n / name :op1 "JNK"~e.6)) :op2 (e3 / enzyme :name (n2 / name :op1 "IKK"~e.8)))) :mod (a3 / also~e.2) :mod (w / well~e.3)) # ::id bio.chicago_2015.24562 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The formation of a functional signaling complex of active ligand dimer and type I and II receptor dimer heterotetramer , results in the phosphorylation of type I receptor by the constitutively active type II receptor ( for review , see Massague 1998 ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.r 8-1.1.1.1.2.1.1 9-1.1.1.1.2.1 10-1.1.1.1.2 12-1.1.1.1.3.2.1.1 13-1.1.1.1.3.2.1.2 16-1.1.1.1.3.2.1.3 17-1.1.1.1.3.1 17-1.1.1.1.3.2 17-1.1.2.2 18-1.1.1.1.3 20-1.1 21-1.1.2.r 23-1.1.2 25-1.1.2.2.1.1 26-1.1.2.2.1.2 27-1.1.2.2.1.3 30-1.1.2.2.2.1 31-1.1.1.1.2.1.1 32-1.1.1.1.3.1.1.1 33-1.1.1.1.3.1.1.2 34-1.1.1.1.3.1.1.3 37-1.2.4 39-1.2 40-1.2.3.1.2.1 41-1.2.3.2.1 (a3 / and :op1 (r / result-01~e.20 :ARG1 (f / form-01~e.1 :ARG1~e.2 (m / macro-molecular-complex~e.6 :ARG0-of (s / signal-07~e.5 :ARG1-of (f2 / function-01~e.4)) :part~e.7 (d / dimer~e.10 :mod (l / ligand~e.9 :ARG0-of (a2 / activity-06~e.8,31))) :part (h / heterotetramer~e.18 :part (d3 / dimer~e.17 :name (n4 / name :op1 "type"~e.32 :op2 "II"~e.33 :op3 "receptor"~e.34)) :part (d2 / dimer~e.17 :name (n3 / name :op1 "type"~e.12 :op2 "I"~e.13 :op3 "receptor"~e.16))))) :ARG2~e.21 (p2 / phosphorylate-01~e.23 :ARG1 d2 :ARG3 (d5 / dimer~e.17 :name (n / name :op1 "type"~e.25 :op2 "I"~e.26 :op3 "receptor"~e.27) :ARG1-of (a / activate-01 :mod (c / constitutive~e.30))))) :op2 (s2 / see-01~e.39 :mode imperative :ARG0 (y / you) :ARG1 (p / publication-91 :ARG0 (p5 / person :wiki - :name (n5 / name :op1 "Massague"~e.40)) :time (d4 / date-entity :year 1998~e.41)) :purpose (r2 / review-01~e.37))) # ::id bio.chicago_2015.24596 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , association is accompanied by reciprocal phosphorylation of Dlar and Ena by Abl and dephosphorylation of phosphorylated Abl and Ena by Dlar . # ::alignments 0-1 2-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.3 7-1.1.2.1 9-1.1.2.1.1.1.1.1 11-1.1.2.1.1.2.1.1 13-1.1.2.1.2.1.1 14-1.1.2 14-1.1.2.2.1 15-1.1.2.2 17-1.1.2.1 17-1.1.2.2.1.3 18-1.1.2.1.2.1.1 19-1.1.2.1.1 20-1.1.2.1.1.2.1.1 22-1.1.2.1.1.1.1.1 (a / and~e.0 :op2 (a2 / accompany-01~e.4 :ARG0 (a3 / associate-01~e.2) :ARG1~e.5 (a4 / and~e.14 :op1 (p2 / phosphorylate-01~e.7,17 :ARG1 (a5 / and~e.19 :op1 (p3 / protein :name (n / name :op1 "Dlar"~e.9,22)) :op2 (p4 / protein :name (n2 / name :op1 "Ena"~e.11,20))) :ARG2 (p5 / protein :name (n3 / name :op1 "Abl"~e.13,18)) :manner (r / reciprocal~e.6)) :op2 (d / dephosphorylate-01~e.15 :ARG1 (a6 / and~e.14 :op1 p5 :op2 p4 :ARG3-of (p / phosphorylate-01~e.17)) :ARG2 p3)))) # ::id bio.chicago_2015.24600 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mad2 binds Cdc20 to inhibit APC activity ( Alexandru et al. , 1999 ; Fang et al. , 1998b ; Hwang et al. , 1998 ; Kallio et al. , 1998 ; Kim et al. , 1998 ; Li et al. , 1997 ; Wassmann and Benezra , 1998 ) , although how Mad2 inhibits APCCdc20 is not clear . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1 4-1.3 5-1.3.2.1.1.1 6-1.3.2 8-1.4.1.1.1.1.2.1 9-1.4.1.1.1 10-1.4.1.1.1.2.1 12-1.4.1.1.2.1 14-1.4.1.2.1.1.2.1 15-1.4.1 15-1.4.1.2.1 15-1.4.1.3.1 15-1.4.1.4.1 15-1.4.1.5.1 15-1.4.1.6.1 15-1.4.1.7.1 16-1.4.1.2.1.2.1 16-1.4.1.3.1.2.1 16-1.4.1.4.1.2.1 16-1.4.1.5.1.2.1 16-1.4.1.6.1.2.1 20-1.4.1.3.1.1.2.1 21-1.4.1 21-1.4.1.2.1 21-1.4.1.3.1 21-1.4.1.4.1 21-1.4.1.5.1 21-1.4.1.6.1 21-1.4.1.7.1 22-1.4.1.2.1.2.1 22-1.4.1.3.1.2.1 22-1.4.1.4.1.2.1 22-1.4.1.5.1.2.1 22-1.4.1.6.1.2.1 24-1.4.1.2.2.1 24-1.4.1.3.2.1 24-1.4.1.4.2.1 24-1.4.1.5.2.1 24-1.4.1.7.2.1 26-1.4.1.4.1.1.2.1 27-1.4.1 27-1.4.1.2.1 27-1.4.1.3.1 27-1.4.1.4.1 27-1.4.1.5.1 27-1.4.1.6.1 27-1.4.1.7.1 28-1.4.1.2.1.2.1 28-1.4.1.3.1.2.1 28-1.4.1.4.1.2.1 28-1.4.1.5.1.2.1 28-1.4.1.6.1.2.1 30-1.4.1.2.2.1 30-1.4.1.3.2.1 30-1.4.1.4.2.1 30-1.4.1.5.2.1 30-1.4.1.7.2.1 32-1.4.1.5.1.1.2.1 33-1.4.1 33-1.4.1.2.1 33-1.4.1.3.1 33-1.4.1.4.1 33-1.4.1.5.1 33-1.4.1.6.1 33-1.4.1.7.1 34-1.4.1.2.1.2.1 34-1.4.1.3.1.2.1 34-1.4.1.4.1.2.1 34-1.4.1.5.1.2.1 34-1.4.1.6.1.2.1 36-1.4.1.2.2.1 36-1.4.1.3.2.1 36-1.4.1.4.2.1 36-1.4.1.5.2.1 36-1.4.1.7.2.1 38-1.4.1.6.1.1.2.1 39-1.4.1.6.1 40-1.4.1.6.1.2.1 42-1.4.1.6.2.1 44-1.4.1.7.1.1.2.1 45-1.4.1.7.1 46-1.4.1.7.1.2.2.1 48-1.4.1.2.2.1 48-1.4.1.3.2.1 48-1.4.1.4.2.1 48-1.4.1.5.2.1 48-1.4.1.7.2.1 51-1.5.r 52-1.5.2.1.r 53-1.5.2.1.1 54-1.3 54-1.5.2.1 55-1.5.2.1.2.1.1 57-1.5.1 57-1.5.1.r 58-1.5 (b / bind-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "Mad2"~e.0)) :ARG1 (p3 / protein :name (n2 / name :op1 "Cdc20"~e.2)) :purpose (i / inhibit-01~e.4,54 :ARG0 p2 :ARG1 (a2 / activity-06~e.6 :ARG0 (p25 / protein :name (n3 / name :op1 "APC"~e.5)))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.15,21,27,33 :op1 (p / publication-91 :ARG0 (a4 / and~e.9 :op1 (p5 / person :wiki - :name (n5 / name :op1 "Alexandru"~e.8)) :op2 (p6 / person :mod (o / other~e.10))) :time (d2 / date-entity :year 1999~e.12)) :op2 (p7 / publication-91 :ARG0 (a5 / and~e.15,21,27,33 :op1 (p8 / person :wiki - :name (n6 / name :op1 "Fang"~e.14)) :op2 (p9 / person :mod (o2 / other~e.16,22,28,34))) :time (d3 / date-entity :year 1998~e.24,30,36,48 :li "b")) :op3 (p10 / publication-91 :ARG0 (a6 / and~e.15,21,27,33 :op1 (p11 / person :wiki - :name (n7 / name :op1 "Hwang"~e.20)) :op2 (p12 / person :mod (o3 / other~e.16,22,28,34))) :time (d4 / date-entity :year 1998~e.24,30,36,48)) :op4 (p13 / publication-91 :ARG0 (a7 / and~e.15,21,27,33 :op1 (p14 / person :wiki - :name (n8 / name :op1 "Kallio"~e.26)) :op2 (p15 / person :mod (o4 / other~e.16,22,28,34))) :time (d5 / date-entity :year 1998~e.24,30,36,48)) :op5 (p16 / publication-91 :ARG0 (a8 / and~e.15,21,27,33 :op1 (p17 / person :wiki - :name (n9 / name :op1 "Kim"~e.32)) :op2 (p18 / person :mod (o5 / other~e.16,22,28,34))) :time (d6 / date-entity :year 1998~e.24,30,36,48)) :op6 (p19 / publication-91 :ARG0 (a9 / and~e.15,21,27,33,39 :op1 (p20 / person :wiki - :name (n10 / name :op1 "Li"~e.38)) :op2 (p21 / person :mod (o6 / other~e.16,22,28,34,40))) :time (d7 / date-entity :year 1997~e.42)) :op7 (p22 / publication-91 :ARG0 (a10 / and~e.15,21,27,33,45 :op1 (p23 / person :wiki - :name (n11 / name :op1 "Wassmann"~e.44)) :op2 (p24 / person :wiki - :name (n12 / name :op1 "Benezra"~e.46))) :time (d8 / date-entity :year 1998~e.24,30,36,48)))) :concession~e.51 (c / clear-06~e.58 :polarity~e.57 -~e.57 :ARG1 (t / thing :manner-of~e.52 (i3 / inhibit-01~e.54 :ARG0 p2~e.53 :ARG1 (p4 / protein :name (n4 / name :op1 "APCCdc20"~e.55)))))) # ::id bio.chicago_2015.24623 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Aliquots of filtrate ( 10 mul ) were separated by SDS @-@ PAGE and processed for Western blotting using an anti @-@ cytochrome c monoclonal antibody . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 4-1.1.1.1.1.1 8-1.1 10-1.1.2.1.1.1 12-1.1.2.1.1.1 13-1 14-1.2 16-1.2.2 17-1.2.2 18-1.2.2.r 20-1.2.2.1.2 22-1.2.2.1.2.1.1.1 23-1.2.2.1.2.1.1.2 25-1.2.2.1 (a / and~e.13 :op1 (s / separate-01~e.8 :ARG1 (a2 / aliquot~e.0 :mod~e.1 (f / filtrate~e.2 :quant (c / concentration-quantity :quant 10~e.4 :unit (m / micromolar)))) :manner (a3 / analyze-01 :mod (t / thing :name (n2 / name :op1 "SDS-PAGE"~e.10,12)))) :op2 (p / process-01~e.14 :ARG1 a2 :purpose~e.18 (i / immunoblot-01~e.16,17 :ARG3 (a5 / antibody~e.25 :mod (m2 / monoclone) :ARG0-of (c2 / counter-01~e.20 :ARG1 (p3 / protein :name (n4 / name :op1 "cytochrome"~e.22 :op2 "c"~e.23))))))) # ::id bio.chicago_2015.24629 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The early , broad snail pattern might create a broad domain of potential Notch signaling by repressing components of the Notch pathway , such as Delta and T3 . # ::alignments 1-1.1.1.3 3-1.1.1.2 4-1.1.1.1.1.1 5-1.1.1 6-1 7-1.1 9-1.1.2.1 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2 13-1.1.2.3.1.1.1 14-1.1.2.3 15-1.1.3.r 16-1.1.3 17-1.1.3.1 20-1.1.2.3.1.1.1 21-1.1.2.3.1 23-1.1.3.1.2.r 24-1.1.3.1.2.r 25-1.1.3.1.2.1.1.1 26-1.1.3.1.2 27-1.1.3.1.2.2.1.1 (p2 / possible-01~e.6 :ARG1 (c2 / create-01~e.7 :ARG0 (p3 / pattern-01~e.5 :ARG1 (p7 / protein :name (n4 / name :op1 "snail"~e.4)) :ARG1-of (b / broad-02~e.3) :time (e / early~e.1)) :ARG1 (d / domain~e.10 :ARG1-of (b2 / broad-02~e.9) :mod~e.11 (p / potential~e.12) :poss (s2 / signal-07~e.14 :ARG0 (p4 / pathway~e.21 :name (n / name :op1 "Notch"~e.13,20)))) :manner~e.15 (r / repress-01~e.16 :ARG1 (c3 / component~e.17 :ARG1-of (i / include-91 :ARG2 p4) :example~e.23,24 (a / and~e.26 :op1 (p5 / protein :name (n2 / name :op1 "Delta"~e.25)) :op2 (p6 / protein :name (n3 / name :op1 "T3"~e.27))))))) # ::id bio.chicago_2015.24662 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The simplest mechanism by which Mck1p might inhibit PKA activity is by phosphorylating PKA . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 5-1.2.1.1.1 6-1.2.3 7-1.2 8-1.2.2.1.1.1 9-1.2.2 10-1.3.r 12-1.3 13-1.3.1 (m2 / mechanism~e.2 :ARG1-of (s / simple-02~e.1 :degree~e.1 (m / most~e.1)) :instrument-of (i / inhibit-01~e.7 :ARG0 (p3 / protein :name (n / name :op1 "Mck1p"~e.5)) :ARG1 (a / activity-06~e.9 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA"~e.8))) :ARG1-of (p2 / possible-01~e.6)) :domain~e.10 (p / phosphorylate-01~e.12 :ARG1 e2~e.13)) # ::id bio.chicago_2015.24678 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PTEN controls p53 transcriptional activity # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1.1.1 3-1.2.1 4-1.2 (c / control-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "PTEN"~e.0)) :ARG1 (a / activity-06~e.4 :ARG0 (t / transcribe-01~e.3 :ARG0 (p / protein :name (n2 / name :op1 "p53"~e.2))))) # ::id bio.chicago_2015.24683 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Histone H1 inhibits ERalpha @-@ mediated transcription in the presence of added p300 . # ::alignments 1-1.1 3-1.2.1.1 4-1.2.1.2 5-1 6-1.3.1.1.1.1 8-1.3.1 9-1.3 10-1.4.r 12-1.4 13-1.4.1.r 14-1.4.1.2 15-1.4.1.1.1 (i / inhibit-01~e.5 :li "A"~e.1 :ARG0 (p / protein :name (n / name :op1 "Histone"~e.3 :op2 "H1"~e.4)) :ARG1 (t / transcribe-01~e.9 :ARG1-of (m / mediate-01~e.8 :ARG0 (p4 / protein :name (n2 / name :op1 "ERalpha"~e.6)))) :condition~e.10 (p2 / present-02~e.12 :ARG1~e.13 (p3 / protein :name (n3 / name :op1 "p300"~e.15) :ARG1-of (a / add-02~e.14)))) # ::id bio.chicago_2015.24739 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At higher concentrations , inhibition of certain JNK isoforms may occur ; however , these kinases are not activated by LPS in the neutrophil under our experimental conditions ( 13 ) . # ::alignments 1-1.1.2.1 1-1.1.2.1.1 1-1.1.2.1.1.r 2-1.1.2 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.2 7-1.1.1.1.1.1.1 8-1.1.1.1 9-1.1 12-1 17-1.2.1 17-1.2.1.r 18-1.2 19-1.2.2.r 20-1.2.2.1.1 21-1.2.5.r 23-1.2.5.1.1 25-1.2.4.1 25-1.2.4.1.r 26-1.2.4 27-1.2.4.r 29-1.3.1.1.1 (c / contrast-01~e.12 :ARG1 (p / possible-01~e.9 :ARG1 (i / inhibit-01~e.4 :ARG1~e.5 (i2 / isoform~e.8 :mod (e2 / enzyme :name (n / name :op1 "JNK"~e.7)) :mod (c2 / certain~e.6))) :condition (c3 / concentrate-02~e.2 :ARG1-of (h2 / high-02~e.1 :degree~e.1 (m3 / more~e.1)))) :ARG2 (a / activate-01~e.18 :polarity~e.17 -~e.17 :ARG0~e.19 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.20)) :ARG1 i2 :condition~e.27 (e / experiment-01~e.26 :ARG0~e.25 (w / we~e.25)) :location~e.21 (c4 / cell :name (n4 / name :op1 "neutrophil"~e.23))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 13~e.29)))) # ::id bio.chicago_2015.24746 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , the back @-@ phosphorylation experiments demonstrated an increase in a PKC @-@ specific phosphorylation of AC7 within HEK 293 cells after exposure of the intact cells to ethanol . # ::alignments 0-1 1-1 4-1.1.1.1.1 6-1.1.1.1 7-1.1.1 8-1.1 10-1.1.2 11-1.1.2.1.r 13-1.1.2.1.2.1.1 15-1.1.2.1.3 16-1.1.2.1 17-1.1.2.1.1.r 18-1.1.2.1.1.1.1 19-1.1.2.2 20-1.1.2.1.4.1.1 21-1.1.2.1.4.1.2 22-1.1.2.1.4 23-1.1.2.2 24-1.1.2.2.1 25-1.1.2.2.1.1.r 27-1.1.2.2.1.1.1 28-1.1.2.2.1.1 29-1.1.2.2.1.2.r 30-1.1.2.2.1.2 (a / and~e.0,1 :op2 (d / demonstrate-01~e.8 :ARG0 (e / experiment-01~e.7 :ARG2 (p2 / phosphorylate-01~e.6 :ARG1-of (b / back-02~e.4))) :ARG1 (i / increase-01~e.10 :ARG1~e.11 (p3 / phosphorylate-01~e.16 :ARG1~e.17 (p / protein :name (n2 / name :op1 "AC7"~e.18)) :ARG2 (e2 / enzyme :name (n3 / name :op1 "PKC"~e.13)) :ARG1-of (s / specific-02~e.15) :location (c / cell~e.22 :name (n / name :op1 "HEK"~e.20 :op2 293~e.21))) :time (a2 / after~e.19,23 :op1 (e3 / expose-01~e.24 :ARG1~e.25 (c2 / cell~e.28 :mod (i2 / intact~e.27)) :ARG2~e.29 (e4 / ethanol~e.30)))))) # ::id bio.chicago_2015.24858 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More recent study demonstrated Akt also phosphorylates FKHRL1 , one of the Forkhead transcription factor family members , and transcriptionally regulates Fas @-@ dependent apoptosis in cerebellar granule neurons . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.1.2.1.1 5-1.2.1.3 6-1.2.1 7-1.2.1.1.1.1 12-1.2.1.1.2.1.1.1 13-1.2.1.1.2.1.2 15-1.2.1.1.2.1 19-1.2.1.1.2.1.2 20-1.2.2 21-1.2.2.2.1.1.1.1 23-1.2.2.2.1 24-1.2.2.2 25-1.2.r 26-1.2.3.2 27-1.2.3.1 28-1.2.3 (d / demonstrate-01~e.3 :ARG0 (s / study-01~e.2 :time (r2 / recent~e.1 :degree (m / more~e.0))) :ARG1~e.25 (a2 / and :op1 (p / phosphorylate-01~e.6 :ARG1 (p4 / protein :name (n2 / name :op1 "FKHRL1"~e.7) :ARG1-of (i / include-91 :ARG2 (p5 / protein-family~e.15 :name (n6 / name :op1 "Forkhead"~e.12) :ARG0-of (t / transcribe-01~e.13,19)))) :ARG2 (e / enzyme :name (n / name :op1 "Akt"~e.4)) :mod (a / also~e.5)) :op2 (r / regulate-01~e.20 :ARG0 e :ARG1 (a3 / apoptosis~e.24 :ARG0-of (d2 / depend-01~e.23 :ARG1 (p3 / protein :name (n4 / name :op1 "Fas"~e.21)))) :manner t) :location (n5 / neuron~e.28 :mod (g / granule~e.27) :mod (c / cerebellar~e.26)))) # ::id bio.chicago_2015.24920 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that p38 and JNK activation by Cr( VI ) is mediated differently through oxidative stress in CL3 cells , while ERK is less sensitive . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.2.1.1.1 5-1.2.1.1.2 6-1.2.1.1.2.2.1.1 7-1.2.1.1 13-1.2.1 14-1.2.1.2 16-1.2.1.2.1.1 17-1.2.1.2.1 18-1.2.1.2.1.2.r 19-1.2.1.2.1.2.1.1 20-1.2.1.2.1.2 22-1.2 23-1.2.2.1.1.1 25-1.2.2.2 26-1.2.2 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (c / contrast-01~e.22 :ARG1 (m / mediate-01~e.13 :ARG1 (a / activate-01~e.7 :ARG0 (s4 / small-molecule :name (n3 / name :op1 "Cr(VI)")) :ARG1 (a2 / and~e.5 :op1 (e3 / enzyme :name (n4 / name :op1 "p38"~e.4)) :op2 (e / enzyme :name (n5 / name :op1 "JNK"~e.6)))) :ARG1-of (d / differ-02~e.14 :manner (s2 / stress-02~e.17 :mod (o / oxidize-01~e.16) :location~e.18 (c2 / cell-line~e.20 :name (n2 / name :op1 "CL3"~e.19))))) :ARG2 (s3 / sensitive-03~e.26 :ARG0 (e2 / enzyme :name (n6 / name :op1 "ERK"~e.23)) :degree (l / less~e.25)))) # ::id bio.chicago_2015.24932 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have identified a new SH3 @-@ containing Rac target , POSH , which activates JNK when transfected into Cos @-@ 1 cells and induces nuclear translocation of NF @-@ kappaB . # ::alignments 0-1.1 2-1 4-1.2.4 5-1.2.3.1.1.1 7-1.2.3 8-1.2.2.1.1.1 9-1.2 9-1.2.2 9-1.2.2.r 11-1.2.1.1 14-1.2.2.2 15-1.2.2.2.1.1.1 17-1.2.2.2.2 18-1.2.2.2.2.1.r 19-1.2.2.2.2.1.1.1 21-1.2.2.2.2.1.1.1 22-1.2.2.2.2.1 24-1.2.2.3 25-1.2.2.3.1.2 26-1.2.2.3.1 27-1.2.2.3.1.1.r 28-1.2.2.3.1.1.1.1 30-1.2.2.3.1.1.1.1 (i / identify-01~e.2 :ARG0 (w2 / we~e.0) :ARG1 (p / protein~e.9 :name (n7 / name :op1 "POSH"~e.11) :ARG0-of~e.9 (t4 / target-01~e.9 :ARG1 (e / enzyme :name (n / name :op1 "Rac"~e.8)) :ARG0-of (a / activate-01~e.14 :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK"~e.15)) :condition (t2 / transfect-01~e.17 :ARG1~e.18 (c2 / cell-line~e.22 :name (n4 / name :op1 "Cos-1"~e.19,21)))) :ARG0-of (i2 / induce-01~e.24 :ARG2-of (t3 / translocate-01~e.26 :ARG1~e.27 (p2 / protein :name (n6 / name :op1 "NF-kappaB"~e.28,30)) :ARG3 (n5 / nucleus~e.25)))) :ARG0-of (c / contain-01~e.7 :ARG1 (p4 / protein-segment :name (n2 / name :op1 "SH3"~e.5))) :ARG1-of (n8 / new-02~e.4))) # ::id bio.chicago_2015.24982 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recent reports on Cdc42 and Rac1 activation of JNK also failed to establish a clear hierarchal action of these Rho @-@ related GTPases ( 38 , 39 ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.1.1 6-1.1.1 7-1.1.1.2.r 8-1.1.1.2.1.1 9-1.3 10-1 12-1.2 14-1.2.2.2.1 16-1.2.2 19-1.2.2.1.2.1.1.1 21-1.2.2.1.2 24-1.4.1.1.1.1 26-1.4.1.1.1.2 (f / fail-01~e.10 :ARG1 (r / report-01~e.1 :ARG1~e.2 (a2 / activate-01~e.6 :ARG0 (a3 / and~e.4 :op1 (p / protein :name (n / name :op1 "Cdc42"~e.3)) :op2 (p2 / protein :name (n2 / name :op1 "Rac1"~e.5))) :ARG1~e.7 (e3 / enzyme :name (n3 / name :op1 "JNK"~e.8))) :time (r3 / recent~e.0)) :ARG2 (e / establish-01~e.12 :ARG0 r :ARG1 (a4 / act-02~e.16 :ARG0 (e2 / enzyme :name (n4 / name :op1 "GTPase") :ARG1-of (r2 / relate-01~e.21 :ARG2 (p4 / protein-family :name (n5 / name :op1 "Rho"~e.19)))) :mod (h / hierarchy :ARG1-of (c / clear-06~e.14)))) :mod (a / also~e.9) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and :op1 38~e.24 :op2 39~e.26))))) # ::id bio.chicago_2015.25001 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A dominant negative form of RHAMMv4 inhibits mutant active Ras activation of ERK and coimmunoprecipitates with both mitogen @-@ activated protein kinase kinase and ERK , suggesting that the intracellular RHAMMv4 acts downstream of Ras , possibly at the level of mitogen @-@ activated protein kinase kinase @-@ ERK interactions . # ::alignments 1-1.1.1.2.1 3-1.1.1.2 4-1.1.1.2.r 5-1.1.1.1.1 6-1.1 7-1.1.1.2.2 7-1.1.2.1 7-1.1.2.1.2 7-1.1.2.1.2.r 9-1.1.2.1.1.1 10-1.1.2 10-1.1.2.1.3 11-1.1.2.2.r 12-1.1.2.2.1.1 13-1 13-1.2.2 17-1.2.2.1.1.1 19-1.2.2.1.1.1 20-1.2.2.1.1.2 21-1.2.2.1.1.3 22-1.2.2.1.1.3 23-1 23-1.2.2 24-1.1.2.2.1.1 26-1.3 27-1.3.1.r 29-1.3.1.1.2 30-1.3.1.1.1.1 31-1.3.1 32-1.3.1.2.2 34-1.3.1.2.1.1.1 36-1.3.1.3.2 39-1.3.1.3 41-1.2.2.1.1.1 43-1.2.2.1.1.1 44-1.2.2.1.1.2 45-1.2.2.1.1.3 46-1.2.2.1.1.3 48-1.1.2.2.1.1 49-1.3.1.3.1 (a5 / and~e.13,23 :op1 (i / inhibit-01~e.6 :ARG0 (p2 / protein :name (n3 / name :op1 "RHAMMv4"~e.5) :mod~e.4 (f / form~e.3 :ARG0-of (d / dominate-01~e.1) :ARG2-of (m / mutate-01~e.7 :mod "-/-"))) :ARG1 (a2 / activate-01~e.10 :ARG0 (e / enzyme~e.7 :name (n5 / name :op1 "Ras"~e.9) :ARG2-of~e.7 (m2 / mutate-01~e.7) :ARG1-of (a / activate-01~e.10)) :ARG1~e.11 (e3 / enzyme :name (n6 / name :op1 "ERK"~e.12,24,48)))) :op2 (c / coimmunoprecipitate-01 :ARG1 p2 :ARG2 (a3 / and~e.13,23 :op1 (e4 / enzyme :name (n7 / name :op1 "mitogen-activated"~e.17,19,41,43 :op2 "protein"~e.20,44 :op3 "kinase"~e.21,22,45,46)) :op2 e3)) :ARG0-of (s2 / suggest-01~e.26 :ARG1~e.27 (a4 / act-02~e.31 :ARG0 (p / protein :name (n / name :op1 "RHAMMv4"~e.30) :mod (i4 / intracellular~e.29)) :location (r / relative-position :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.34)) :direction (d2 / downstream~e.32)) :condition (l2 / level~e.39 :location-of (i3 / interact-01~e.49 :ARG0 e4 :ARG1 e3) :ARG1-of (p3 / possible-01~e.36))))) # ::id bio.chicago_2015.25013 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dishevelled decreases GSK @-@ 3 beta phosphorylation of tau . # ::alignments 0-1.1.1.1 1-1 2-1.2.2.1.1 6-1.2 7-1.2.1.r 8-1.2.1.1.1 (d / decrease-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "Dishevelled"~e.0)) :ARG1 (p3 / phosphorylate-01~e.6 :ARG1~e.7 (p / protein :name (n2 / name :op1 "tau"~e.8)) :ARG2 (e2 / enzyme :name (n3 / name :op1 "GSK-3beta"~e.2)))) # ::id bio.chicago_2015.25044 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Isolated S.cerevisiae mitochondria released cytochrome c , but did not induce apoptosis when incubated in Xenopus extracts ( R.M.Kluck , D.R.Green , M.Yaffe , E.Margoliash and D.D.Newmeyer , in preparation ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.1.1 5-1.1.2.1.2 7-1 9-1.2.1 9-1.2.1.r 10-1.2 11-1.2.3 13-1.4 14-1.4.2.r 15-1.4.2.1.1.1 16-1.4.2 18-1.3.1.1.1.1.1 20-1.3.1.1.2.1.1 22-1.3.1.1.3.1.1 24-1.3.1.1.4.1.1 25-1.3.1.1 26-1.3.1.1.5.1.1 29-1.3.1.2 (c / contrast-01~e.7 :ARG1 (r / release-01~e.3 :ARG0 (m / mitochondria~e.2 :part-of (o2 / organism :name (n8 / name :op1 "S.cerevisiae"~e.1) :ARG1-of (i3 / isolate-01~e.0))) :ARG1 (p8 / protein :name (n7 / name :op1 "cytochrome"~e.4 :op2 "c"~e.5))) :ARG2 (i / induce-01~e.10 :polarity~e.9 -~e.9 :ARG0 m :ARG2 (a2 / apoptosis~e.11)) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and~e.25 :op1 (p3 / person :name (n2 / name :op1 "R.M.Kluck"~e.18)) :op2 (p2 / person :name (n / name :op1 "D.R.Green"~e.20)) :op3 (p4 / person :name (n3 / name :op1 "M.Yaffe"~e.22)) :op4 (p5 / person :name (n4 / name :op1 "E.Margoliash"~e.24)) :op5 (p6 / person :name (n5 / name :op1 "D.D.Newmeyer"~e.26))) :ARG1-of (p7 / prepare-01~e.29))) :condition (i2 / incubate-01~e.13 :ARG1 m :location~e.14 (e / extract-01~e.16 :mod (o / organism :name (n6 / name :op1 "Xenopus"~e.15))))) # ::id bio.chicago_2015.25064 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Functional Rho is required for efficient VASP @-@ induced SRF activation . # ::alignments 1-1.1 3-1.3 3-1.3.2 3-1.3.2.r 4-1.3.1.1 6-1 7-1.2.r 8-1.2.2 9-1.2.3.1.1.1 11-1.2.3 12-1.2.1.1.1 13-1.2 (r / require-01~e.6 :li "A"~e.1 :ARG0~e.7 (a / activate-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "SRF"~e.12)) :ARG1-of (e2 / efficient-01~e.8) :ARG2-of (i / induce-01~e.11 :ARG0 (p / protein :name (n3 / name :op1 "VASP"~e.9)))) :ARG1 (e / enzyme~e.3 :name (n / name :op1 "Rho"~e.4) :ARG0-of~e.3 (f / function-01~e.3))) # ::id bio.chicago_2015.25079 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of AC7 by PKC . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 4-1.2.1.1 (p2 / phosphorylate-01~e.0 :ARG1~e.1 (p3 / protein :name (n2 / name :op1 "AC7"~e.2)) :ARG2~e.3 (e / enzyme :name (n / name :op1 "PKC"~e.4))) # ::id bio.chicago_2015.25123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PDK1 phosphorylation of PAK1 was not blocked by pretreatment with wortmannin or when PDK1 was mutated to prevent phosphatidylinositol binding , indicating this process is independent of phosphatidylinositol 3 @-@ kinase activity . # ::alignments 0-1.2.2.1.1 1-1.2 2-1.2.1.r 3-1.2.1.1.1 5-1.1 5-1.1.r 6-1 7-1.3.r 8-1.3.1 9-1.3.1.1.r 10-1.3.1.1.1.1 11-1.3 13-1.3.2.1 15-1.3.2 17-1.3.2.2 18-1.3.2.2.1.1.1.1 19-1.3.2.2.1 21-1.4 22-1.4.1.2.1 23-1.4.1.2 25-1.4.1 25-1.4.1.1 25-1.4.1.1.r 26-1.4.1.3.r 27-1.4.1.3.1.1.1 28-1.4.1.3.1.1.2 30-1.4.1.3.1.1.2 31-1.4.1.3 (b / block-01~e.6 :polarity~e.5 -~e.5 :ARG1 (p2 / phosphorylate-01~e.1 :ARG1~e.2 (e3 / enzyme :name (n2 / name :op1 "PAK1"~e.3)) :ARG2 (e / enzyme :name (n / name :op1 "PDK1"~e.0))) :ARG3~e.7 (o / or~e.11 :op1 (p3 / pretreat-01~e.8 :ARG3~e.9 (s / small-molecule :name (n3 / name :op1 "wortmannin"~e.10))) :op1 (m / mutate-01~e.15 :ARG1 e~e.13 :purpose (p / prevent-01~e.17 :ARG1 (b2 / bind-01~e.19 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "phosphatidylinositol"~e.18)))))) :ARG0-of (i / indicate-01~e.21 :ARG1 (d / depend-01~e.25 :polarity~e.25 -~e.25 :ARG0 (p5 / process-02~e.23 :mod (t / this~e.22)) :ARG1~e.26 (a / activity-06~e.31 :ARG0 (e2 / enzyme :name (n5 / name :op1 "phosphatidylinositol"~e.27 :op2 "3-kinase"~e.28,30)))))) # ::id bio.chicago_2015.25144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Requirements for Presenilin @-@ Dependent Cleavage of Notch and Other Transmembrane Proteins . # ::alignments 0-1 1-1.1.r 2-1.1.2.1.1.1 4-1.1.2 5-1.1 6-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.2 10-1.1.1.2.1 11-1.1.1.2 (r / require-01~e.0 :ARG0~e.1 (c / cleave-01~e.5 :ARG1~e.6 (a / and~e.8 :op1 (p / protein :name (n2 / name :op1 "Notch"~e.7)) :op2 (p2 / protein~e.11 :mod (t / transmembrane~e.10) :mod (o / other~e.9))) :ARG0-of (d / depend-01~e.4 :ARG1 (p3 / protein :name (n / name :op1 "Presenilin"~e.2))))) # ::id bio.chicago_2015.25172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , intersectin activated Elk @-@ 1 to levels 2 @- to 3 @-@ fold higher than the level obtained with maximal EGF stimulation ( see Fig. 2 ) . # ::alignments 1-1 3-1.1.1.1.1 4-1.1 5-1.1.2.1.1 7-1.1.2.1.1 8-1.1.3.r 9-1.1.3 10-1.1.3.2.1.1 13-1.1.3.2.1.2 15-1.1.3.2 16-1.1.3.3 16-1.1.3.3.2 16-1.1.3.3.2.r 17-1.1.3.3.1.r 19-1.1.3.3.1 20-1.1.3.3.1.1 21-1.1.3.3.1.1.1.r 22-1.1.3.3.1.1.1.2 23-1.1.3.3.1.1.1.1.1.1 24-1.1.3.3.1.1.1 26-1.2 27-1.2.3 28-1.2.3.1 (c / contrast-01~e.1 :ARG2 (a / activate-01~e.4 :ARG0 (p4 / protein :name (n / name :op1 "intersectin"~e.3)) :ARG1 (p / protein :name (n2 / name :op1 "Elk-1"~e.5,7)) :degree~e.8 (l / level~e.9 :quant-of p :degree (p2 / product-of~e.15 :op1 (b / between :op1 2~e.10 :op2 3~e.13)) :ARG1-of (h2 / high-02~e.16 :compared-to~e.17 (l2 / level~e.19 :ARG1-of (o / obtain-01~e.20 :condition~e.21 (s2 / stimulate-01~e.24 :ARG1 (p3 / protein :name (n3 / name :op1 "EGF"~e.23)) :degree (m2 / maximum~e.22)))) :degree~e.16 (m3 / more~e.16)))) :ARG1-of (s3 / see-01~e.26 :mode imperative :ARG0 (y / you) :medium (f / figure~e.27 :mod 2~e.28))) # ::id bio.chicago_2015.25207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , MEFs deficient in downstream Apaf @-@ 1 once again displayed only early protection from BIM @- or BAD @-@ induced death ( Figures 3B and 3C ) . # ::alignments 1-1 3-1.1.1.1.1 6-1.1.1.2.1.2 7-1.1.1.2.1.1.1 9-1.1.1.2.1.1.1 10-1.1.1.2.1.1.1 10-1.1.4.1 11-1.1.4 12-1.1 13-1.1.3 14-1.1.2.2 15-1.1.2 16-1.1.2.1.r 17-1.1.2.1.1.1.1.1.1 19-1.1.2.1.1.1 20-1.1.2.1.1.1.2.1.1 22-1.1.2.1.1 23-1.1.2.1 25-1.2.1.1 25-1.2.1.2 26-1.2.1.1.1 27-1.2.1 28-1.2.1.2.1 (c / contrast-01~e.1 :ARG2 (d / display-01~e.12 :ARG0 (c2 / cell :name (n / name :op1 "MEF"~e.3) :ARG0-of (l / lack-01 :ARG1 (p / protein :name (n2 / name :op1 "Apaf-1"~e.7,9,10) :location (d3 / downstream~e.6)))) :ARG1 (p2 / protect-01~e.15 :ARG2~e.16 (d4 / die-01~e.23 :ARG2-of (i / induce-01~e.22 :ARG0 (o3 / or~e.19 :op1 (p3 / protein :name (n3 / name :op1 "BIM"~e.17)) :op2 (p4 / protein :name (n4 / name :op1 "BAD"~e.20))))) :time (e / early~e.14)) :mod (o4 / only~e.13) :mod (a3 / again~e.11 :mod (o2 / once~e.10))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.27 :op1 (f / figure~e.25 :mod "3B"~e.26) :op2 (f2 / figure~e.25 :mod "3C"~e.28)))) # ::id bio.chicago_2015.25236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , the data indicate that PTEN can control p53 stability by both phosphatase and MDM2 @-@ dependent and -@ independent mechanisms . # ::alignments 0-1.3 1-1.3.2 4-1.1 5-1 6-1.2.r 7-1.2.1.1.1.1 8-1.2 9-1.2.1 10-1.2.1.2.1.1.1 11-1.2.1.2 14-1.2.1.3.1.1 15-1.2.1.3 16-1.2.1.3.2.1.1.1.1 18-1.2.1.3.2.2 21-1.2.1.3.2.1 21-1.2.1.3.2.2 21-1.2.1.3.2.2.1 21-1.2.1.3.2.2.1.r 22-1.2.1.3.1 22-1.2.1.3.2 (i / indicate-01~e.5 :ARG0 (d / data~e.4) :ARG1~e.6 (p / possible-01~e.8 :ARG1 (c / control-01~e.9 :ARG0 (p2 / protein :name (n / name :op1 "PTEN"~e.7)) :ARG1 (s / stability~e.11 :poss (p3 / protein :name (n2 / name :op1 "p53"~e.10))) :instrument (a / and~e.15 :op1 (m / mechanism~e.22 :mod (p4 / phosphatase~e.14)) :op2 (m2 / mechanism~e.22 :ARG0-of (d2 / depend-01~e.21 :ARG1 (p5 / protein :name (n3 / name :op1 "MDM2"~e.16))) :ARG0-of (d3 / depend-01~e.18,21 :polarity~e.21 -~e.21 :ARG1 p5))))) :condition (t / take-01~e.0 :ARG1 d :mod (t2 / together~e.1))) # ::id bio.chicago_2015.25358 ::amr-annotator SDL-AMR-09 ::preferred # ::tok p300 acetylates histones H3 and H4 within nucleosomes located in the promoter and 5 ' proximal regions of the template . # ::alignments 0-1.2.1.1 1-1 2-1.1.1.1.1 2-1.1.2.1.1 3-1.1.1.1.2 4-1.1 5-1.1.2.1.2 7-1.1.3 8-1.1.3.r 11-1.1.3.1.1.1 11-1.1.3.1.1.1.1 11-1.1.3.1.1.1.1.r 12-1.1.3.1 13-1.1.3.1.2.1.1 15-1.1.3.1.2.1 16-1.1.3.1.1 16-1.1.3.1.2 17-1.1.3.1.r 19-1.1.3.1.3 (a / acetylate-01~e.1 :ARG1 (a2 / and~e.4 :op1 (p2 / protein :name (n2 / name :op1 "histone"~e.2 :op2 "H3"~e.3)) :op2 (p3 / protein :name (n3 / name :op1 "histone"~e.2 :op2 "H4"~e.5)) :location~e.8 (n4 / nucleosome~e.7 :location~e.17 (a3 / and~e.12 :op1 (r2 / region~e.16 :mod (m / molecular-physical-entity~e.11 :ARG0-of~e.11 (p4 / promote-01~e.11))) :op2 (r3 / region~e.16 :mod (p5 / proximal~e.15 :mod 5~e.13)) :part-of (t / template~e.19)))) :ARG2 (p / protein :name (n / name :op1 "p300"~e.0))) # ::id bio.chicago_2015.25362 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The proposed cooperativity between sites may also explain why eIF4F complexes purified from plant ( 31 , 47 , 48 ) , yeast ( 33 ) , and Drosophila ( 35 ) do not contain eIF4A , despite the fact that direct binding of eIF4A to eIF4G can be demonstrated in wheat germ ( 49 , 50 ) and yeast ( 51 , 52 ) and that the affinity of yeast eIF4G for eIF4A ( K d 30 nM ; Ref . 52 ) is comparable with that of the central site of human eIF4G ( K d = 17 nM ; Fig. 6 ) . # ::alignments 1-1.1.1.2 4-1.1.1.1 5-1 5-1.1.3 6-1.1.4 7-1.1 8-1.1.2 8-1.1.2.1 8-1.1.2.1.r 9-1.1.2.1.1.2.2.1.1 10-1.1.2.1.1.2 11-1.1.2.1.1.2.1 12-1.1.2.1.1.2.1.1.r 13-1.1.2.1.1.2.1.1.1 15-1.1.2.1.1.2.1.1.1.1.1.1.1.1 17-1.1.2.1.1.2.1.1.1.1.1.1.1.2 19-1.1.2.1.1.2.1.1.1.1.1.1.1.3 22-1.1.2.1.1.2.1.1.2 24-1.1.2.1.1.2.1.1.2.1.1.1.1 27-1.1.2.1.1.2.1.1 27-1.1.2.1.1.2.1.1.1.1.1.1.1 28-1.1.2.1.1.2.1.1.3.1.1 30-1.1.2.1.1.2.1.1.3.2.1.1.1 33-1.1.2.1.1.1 33-1.1.2.1.1.1.r 34-1.1.2.1.1 35-1.1.2.1.1.3.1.1 37-1.1.3.r 41-1.1.3.1.1.1.3 42-1.1.3.1.1.1 44-1.1.2.1.1.3.1.1 45-1.1.2 45-1.1.2.1 45-1.1.2.1.r 46-1.1.3.1.1.2.1.1.1.1.1 47-1.1.3 49-1.1.3.1 50-1.1.3.1.1.1.4.r 51-1.1.3.1.1.1.4.1.1 52-1.1.3.1.1.1.4.1 54-1.1.3.1.1.1.4.1.2.1.1.1.1 56-1.1.3.1.1.1.4.1.2.1.1.1.2 58-1.1.3.1.1.1.4 58-1.1.3.1.1.1.4.1.2.1.1.1 59-1.1.3.1.1.1.4.2 61-1.1.3.1.1.1.4.2.1.1.1.1.1 63-1.1.3.1.1.1.4.2.1.1.1.1.2 65-1.1.3.1.1.1.4.2.1.1.1.1 68-1.1.3.1.1.2.1 68-1.1.3.1.1.2.2 70-1.1.3.1.1.2.1.1 71-1.1.3.1.1.2.1.1.1.1.1 73-1.1.2.1.1.3.1.1 77-1.1.3.1.1.2.1.1.1.2.1 78-1.1.3.1.1.2.1.1.1.2.2 82-1.1.3.1.1.2.1.2.1.1 85-1.1.3.1.1.2 88-1.1.3.1.1.2.2.1.r 90-1.1.3.1.1.2.2.1.1 91-1.1.3.1.1.2.2.1 92-1.1.3.1.1.2.2.1.2.r 93-1.1.3.1.1.2.2.1.2 94-1.1.3.1.1.2.2.1.3 99-1.1.3.1.1.2.2.2.1 100-1.1.3.1.1.2.2.2.2 102-1.1.3.1.1.2.2.3.1 103-1.1.3.1.1.2.2.3.1.1 (p / possible-01~e.5 :ARG1 (e / explain-01~e.7 :ARG0 (c / cooperate-01 :ARG0 (s / site~e.4) :ARG1-of (p2 / propose-01~e.1)) :ARG1 (t / thing~e.8,45 :ARG0-of~e.8,45 (c2 / cause-01~e.8,45 :ARG1 (c3 / contain-01~e.34 :polarity~e.33 -~e.33 :ARG0 (m / macro-molecular-complex~e.10 :ARG1-of (p3 / purify-01~e.11 :ARG2~e.12 (a2 / and~e.27 :op1 (p4 / plant~e.13 :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c8 / cite-01 :ARG2 (a10 / and~e.27 :op1 31~e.15 :op2 47~e.17 :op3 48~e.19))))) :op2 (y / yeast~e.22 :ARG1-of (d6 / describe-01 :ARG0 (p8 / publication :ARG1-of (c9 / cite-01 :ARG2 33~e.24)))) :op3 (o / organism :name (n2 / name :op1 "Drosophila"~e.28) :ARG1-of (d8 / describe-01 :ARG0 (p9 / publication :ARG1-of (c10 / cite-01 :ARG2 35~e.30)))))) :mod (p12 / protein :name (n / name :op1 "eIF4F"~e.9))) :ARG1 (p6 / protein :name (n3 / name :op1 "eIF4A"~e.35,44,73))))) :concession~e.37 (p5 / possible-01~e.5,47 :ARG1 (d10 / demonstrate-01~e.49 :ARG1 (a7 / and :op1 (b / bind-01~e.42 :ARG1 p6 :ARG2 p12 :ARG1-of (d / direct-02~e.41) :location~e.50 (a4 / and~e.58 :op1 (g / germ~e.52 :mod (w / wheat~e.51) :ARG1-of (d12 / describe-01 :ARG0 (p10 / publication :ARG1-of (c11 / cite-01 :ARG2 (a3 / and~e.58 :op1 49~e.54 :op2 50~e.56))))) :op2 (y2 / yeast~e.59 :ARG1-of (d15 / describe-01 :ARG0 (p11 / publication :ARG1-of (c12 / cite-01 :ARG2 (a5 / and~e.65 :op1 51~e.61 :op2 52~e.63))))))) :op2 (c4 / comparable-03~e.85 :ARG1 (a8 / affinity~e.68 :poss (y3 / yeast~e.70 :mod (p13 / protein :name (n4 / name :op1 "eIF4G"~e.46,71) :quant (c5 / concentration-quantity :quant 30~e.77 :unit (n6 / nanomolar~e.78)))) :ARG1-of (d18 / describe-01 :ARG0 (r / reference :mod 52~e.82)) :topic p6) :ARG2 (a9 / affinity~e.68 :poss~e.88 (s2 / site~e.91 :mod (c6 / central~e.90) :mod~e.92 (h / human~e.93) :part-of p13~e.94) :quant (c7 / concentration-quantity :quant 17~e.99 :unit (n5 / nanomolar~e.100)) :ARG1-of (d19 / describe-01 :ARG0 (f / figure~e.102 :mod 6~e.103))))))) :mod (a6 / also~e.6))) # ::id bio.chicago_2015.25364 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In somatic cells , Cdc20 and Cdh1 binding to the APC is differentially regulated , resulting in a peak of APCCdc20 activity in mitosis and APCCdh1 activity in G1 ( Kramer et al. , 2000 ; Shirayama et al. , 1998 ; Zachariae et al. , 1998 ) . # ::alignments 1-1.2.3.1 2-1.2.3 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 7-1.1 8-1.1.2.r 10-1.1.2.1.1 13-1 15-1.2 16-1.2.1.r 18-1.2.1 19-1.2.1.1.r 20-1.2.1.1.1.1.1.1 21-1.2.1.1.1 22-1.2.1.1.1.2.r 23-1.2.1.1.1.2 24-1.2.1.1 25-1.2.1.1.2.1.1.1 26-1.2.1.1.2 27-1.2.1.1.2.2.r 28-1.2.1.1.2.2.1.1 30-1.2.2.1.1.1.1.2.1 31-1.2.2.1.1.1 32-1.2.2.1.1.1.2.1 34-1.2.2.1.1.2.1 36-1.2.2.1.2.1.1.2.1 37-1.2.2.1.2.1 38-1.2.2.1.2.1.2.1 40-1.2.2.1.2.2.1 42-1.2.2.1.3.1.1.2.1 43-1.2.2.1 43-1.2.2.1.2.1 43-1.2.2.1.3.1 44-1.2.2.1.2.1.2.1 44-1.2.2.1.3.1.2.1 46-1.2.2.1.2.2.1 (r3 / regulate-01~e.13 :ARG1 (b / bind-01~e.7 :ARG1 (a2 / and~e.5 :op1 (p2 / protein :name (n / name :op1 "Cdc20"~e.4)) :op2 (p3 / protein :name (n2 / name :op1 "Cdh1"~e.6))) :ARG2~e.8 (p4 / protein :name (n3 / name :op1 "APC"~e.10))) :ARG1-of (r4 / result-01~e.15 :ARG2~e.16 (p5 / peak-01~e.18 :ARG1~e.19 (a3 / and~e.24 :op1 (a4 / activity-06~e.21 :ARG0 (p14 / protein :name (n4 / name :op1 "APCCdc20"~e.20)) :ARG1~e.22 (m / mitosis~e.23)) :op2 (a5 / activity-06~e.26 :ARG0 (p15 / protein :name (n5 / name :op1 "APCCdh1"~e.25)) :ARG1~e.27 (e / event :name (n6 / name :op1 "G1"~e.28))))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.43 :op1 (p6 / publication-91 :ARG0 (a6 / and~e.31 :op1 (p7 / person :wiki - :name (n7 / name :op1 "Kramer"~e.30)) :op2 (p / person :mod (o / other~e.32))) :time (d2 / date-entity :year 2000~e.34)) :op2 (p8 / publication-91 :ARG0 (a7 / and~e.37,43 :op1 (p9 / person :wiki - :name (n8 / name :op1 "Shirayama"~e.36)) :op2 (p10 / person :mod (o2 / other~e.38,44))) :time (d4 / date-entity :year 1998~e.40,46)) :op3 (p11 / publication-91 :ARG0 (a8 / and~e.43 :op1 (p12 / person :wiki - :name (n9 / name :op1 "Zachariae"~e.42)) :op2 (p13 / person :mod (o3 / other~e.44))) :time d4))) :location (c / cell~e.2 :mod (s / somatic~e.1))) :ARG1-of (d3 / differ-02)) # ::id bio.chicago_2015.25419 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibition of NESK @-@ induced JNK Activation by the Dominant Negative Mutants of MKK4 and MEKK1-- MKK4 is an upstream activator of JNK , which phosphorylates and activates JNK . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.2.1.1.1 4-1.1.2.2 5-1.1.2.1.1.1 6-1.1.2 9-1.1.1.4 11-1.1.1.3 12-1.1.1.r 13-1.1.1.1.1.1 14-1.1.1 16-1.1.1.1.1.1 16-1.2.1.1.1.1 19-1.2.1.3 20-1.2.1 22-1.2.1.2.1.1 25-1.2.2 26-1.2 27-1.2.1 27-1.2.3 28-1.2.1.2.1.1 (m / multi-sentence :snt1 (i / inhibit-01~e.0 :ARG0~e.12 (a3 / and~e.14 :op1 (e / enzyme :name (n4 / name :op1 "MKK4"~e.13,16)) :op2 (e2 / enzyme :name (n5 / name :op1 "MEKK1")) :ARG2-of (m2 / mutate-01~e.11 :mod "-/-") :ARG0-of (d / dominate-01~e.9)) :ARG1~e.1 (a2 / activate-01~e.6 :ARG1 (e3 / enzyme :name (n2 / name :op1 "JNK"~e.5)) :ARG2-of (i2 / induce-01~e.4 :ARG0 (e4 / enzyme :name (n / name :op1 "NESK"~e.2))))) :snt2 (a4 / and~e.26 :op1 (a6 / activate-01~e.20,27 :ARG0 (e7 / enzyme :name (n8 / name :op1 "MKK4"~e.16)) :ARG1 (e8 / enzyme :name (n9 / name :op1 "JNK"~e.22,28)) :location (u2 / upstream~e.19)) :op2 (p / phosphorylate-01~e.25 :ARG1 e8 :ARG2 e7) :op3 (a5 / activate-01~e.27 :ARG0 e7 :ARG1 e8))) # ::id bio.chicago_2015.25430 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The convex shape of the Scatchard plot indicated that Arg binds to F @-@ actin with positive cooperativity ( Fig . 1 G ; ref . 19 ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 5-1.1.1.1.1 6-1.1.1.1.2 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2 11-1.2.2.r 12-1.2.2.1.1 14-1.2.2.1.1 16-1.2.3.3 19-1.3.1.1 26-1.3.1.2.1.1 (i / indicate-01~e.7 :ARG0 (s / shape-01~e.2 :ARG1~e.3 (t / thing :name (n / name :op1 "Scatchard"~e.5 :op2 "plot"~e.6)) :ARG2 (c / convex~e.1)) :ARG1~e.8 (b / bind-01~e.10 :ARG1 (p / protein :name (n2 / name :op1 "Arg"~e.9)) :ARG2~e.11 (p2 / protein :name (n3 / name :op1 "F-actin"~e.12,14)) :manner (c2 / cooperate-01 :ARG0 p :ARG1 p2 :mod (p3 / positive~e.16))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.19 :mod "1G") :op2 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 19~e.26))))) # ::id bio.chicago_2015.25436 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Related chromosome binding sites for zeste , suppressors of zeste and Polycomb group proteins in Drosophila and their dependence on Enhancer of zeste function . # ::alignments 0-1.1.1.1.1.1 1-1.1.1.1.1 2-1.1.1.1 3-1.1.1 5-1.1.1.1.2.1.1 7-1.1.2 7-1.1.2.1 7-1.1.2.1.r 8-1.1.2.1.1.r 9-1.1.2.1.1.1 10-1.1.2.1.1 11-1.1.2.1.1.2.1.1 13-1.1.1.1.2 13-1.1.2.1.1.2 14-1.1.2.2.r 15-1.1.2.2.1.1 16-1 16-1.1 16-1.1.r 17-1.2.1 17-1.2.1.r 18-1.2 21-1.2.2.r 22-1.2.2.1.1.1 23-1.2.2.1.1 (a / and~e.16 :op1~e.16 (a2 / and~e.16 :op1 (s3 / site~e.3 :ARG2-of (b2 / bind-01~e.2 :ARG0 (c / chromosome~e.1 :ARG1-of (r / relate-01~e.0)) :ARG1 (p2 / protein~e.13 :name (n3 / name :op1 "zeste"~e.5)))) :op2 (m / molecular-physical-entity~e.7 :ARG0-of~e.7 (s4 / suppress-01~e.7 :ARG1~e.8 (a3 / and~e.10 :op1 p2~e.9 :op2 (p3 / protein-family~e.13 :name (n4 / name :op1 "Polycomb"~e.11)))) :location~e.14 (o / organism :name (n5 / name :op1 "Drosophila"~e.15)))) :op2 (d / depend-01~e.18 :ARG0~e.17 a2~e.17 :ARG1~e.21 (m2 / molecular-physical-entity :ARG0-of (e2 / enhance-01 :ARG1 (f2 / function-01~e.23 :ARG1 p2~e.22))))) # ::id bio.chicago_2015.25466 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The reason for the difference between this result in COS @-@ 7 cells and that in the yeast assay ( Fig . 1 B ) is not known , but the difference in mammalian cells and in yeast was also observed in the interaction of FKBP12 with TbetaR @-@ I ( 11 ) . # ::alignments 1-1.1.2 1-1.1.2.1 1-1.1.2.1.r 2-1.1.2.1.1.r 4-1.1.2.1.1 6-1.1.2.1.1.1.1.1 7-1.1.2.1.1.1 7-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1.r 7-1.1.2.1.1.2 7-1.1.2.1.1.2.1 7-1.1.2.1.1.2.1.r 8-1.1.2.1.1.1.2.r 9-1.1.2.1.1.1.2.1.1 11-1.1.2.1.1.1.2.1.1 12-1.1.2.1.1.1.2 15-1.1.2.1.1.2.2.r 17-1.1.2.1.1.2.2.1 18-1.1.2.1.1.2.2 20-1.1.3.1 26-1.1.1 26-1.1.1.r 27-1.1 29-1 31-1.1.1.r 31-1.2.1 32-1.2.1.1.r 32-1.2.r 33-1.2.1.1.1.1 34-1.2.1.1.1 35-1.2.1.1 37-1.2.1.1.2 39-1.2.4 40-1.2 41-1.2.2.r 43-1.2.2 44-1.2.2.1.r 45-1.2.2.1.1.1 46-1.1.2.1.1.2.2.1.r 46-1.2.2.2.r 47-1.2.2.2.1.1 49-1.2.2.2.1.1 51-1.2.3.1.1.1 (c / contrast-01~e.29 :ARG1 (k2 / know-01~e.27 :polarity~e.26,31 -~e.26 :ARG1 (t3 / thing~e.1 :ARG0-of~e.1 (c5 / cause-01~e.1 :ARG1~e.2 (d / differ-02~e.4 :ARG1 (t / thing~e.7 :ARG1-of~e.7 (r / result-01~e.7 :mod (t4 / this~e.6)) :location~e.8 (c3 / cell-line~e.12 :name (n / name :op1 "COS-7"~e.9,11))) :ARG2 (t2 / thing~e.7 :ARG1-of~e.7 (r2 / result-01~e.7) :time~e.15 (a / assay-01~e.18 :instrument~e.46 (y / yeast~e.17)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.20 :mod "1B"))) :ARG2~e.32 (o / observe-01~e.40 :ARG1 (d3 / differ-02~e.31 :location~e.32 (a2 / and~e.35 :op1 (c4 / cell~e.34 :mod (m / mammalian~e.33)) :op2 (y2 / yeast~e.37))) :time~e.41 (i / interact-01~e.43 :ARG0~e.44 (p2 / protein :name (n3 / name :op1 "FKBP12"~e.45)) :ARG1~e.46 (p / protein :name (n2 / name :op1 "TbetaR-I"~e.47,49))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 11~e.51))) :mod (a3 / also~e.39))) # ::id bio.chicago_2015.25467 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) A TSC syndrome @-@ related GAP mutant of TSC2 fails to inhibit Rheb @-@ induced S6K1 phosphorylation . # ::alignments 1-1.1 4-1.2.3.1.1.1 5-1.2.3.1 7-1.2.3 8-1.2.1.1.1 9-1.2 10-1.2.2.r 11-1.2.2.1.1 12-1 14-1.3 15-1.3.2.2.1.1.1 17-1.3.2.2 18-1.3.2.1.1.1 19-1.3.2 (f / fail-01~e.12 :li "C"~e.1 :ARG1 (m / mutate-01~e.9 :ARG1 (p / protein :name (n3 / name :op1 "GAP"~e.8)) :ARG3~e.10 (p5 / protein :name (n4 / name :op1 "TSC2"~e.11)) :ARG1-of (r / relate-01~e.7 :ARG2 (s / syndrome~e.5 :name (n5 / name :op1 "TSC"~e.4)))) :ARG2 (i / inhibit-01~e.14 :ARG0 m :ARG1 (p2 / phosphorylate-01~e.19 :ARG3 (e / enzyme :name (n / name :op1 "S6K1"~e.18)) :ARG2-of (i2 / induce-01~e.17 :ARG0 (p4 / protein :name (n2 / name :op1 "Rheb"~e.15)))))) # ::id bio.chicago_2015.25525 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tyr phosphorylation of PLSCR1 was detected by Western blotting with anti @-@ Tyr( P ) mAb PY99 ( upper panel , A ) and abundance of immunoprecipitated PLSCR1 protein was detected with anti @-@ PLSCR1 mAb 4D2 ( lower panel , A ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1.1.1.2.1.1 5-1.1 6-1.1.2.r 7-1.1.2 8-1.1.2 10-1.1.2.1.1 13-1.1.1 16-1.1.2.1.1.1.1.1 18-1.1.3.1.1 19-1.1.3.1 21-1.1.3.1.2.1 23-1 24-1.2.1 26-1.2.1.1.2 27-1.2.1.1.1.1 27-1.2.2.1.1.1.1 28-1.1.1.1.2 28-1.1.2.1.1.1 28-1.2.1.1 28-1.2.2.1.1 30-1.2 32-1.2.2.1 34-1.2.1.1.1.1 34-1.2.2.1.1.1.1 36-1.2.2.2.1.1 38-1.2.3.1.1 38-1.2.3.1.1.1 38-1.2.3.1.1.1.r 39-1.2.3.1 41-1.2.3.1.2 (a / and~e.23 :op1 (d / detect-01~e.5 :ARG1 (p2 / phosphorylate-01~e.1,13 :ARG1 (a3 / amino-acid :name (n2 / name :op1 "Tyrosine"~e.0) :part-of (p4 / protein~e.28 :name (n3 / name :op1 "PLSCR1"~e.3)))) :ARG2~e.6 (i2 / immunoblot-01~e.7,8 :ARG3 (a4 / antibody :ARG0-of (c3 / counter-01~e.10 :ARG1 (p3 / protein~e.28 :name (n8 / name :op1 "PY99"~e.16))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / panel~e.19 :mod (u / upper~e.18) :mod (s2 / string-entity :value "A"~e.21)))) :op2 (d2 / detect-01~e.30 :ARG1 (a2 / abound-01~e.24 :ARG2 (p7 / protein~e.28 :name (n6 / name :op1 "PLSCR1"~e.27,34) :ARG1-of (i / immunoprecipitate-01~e.26))) :ARG2 (a5 / antibody :ARG0-of (c / counter-01~e.32 :ARG1 (p8 / protein~e.28 :name (n7 / name :op1 "PLSCR1"~e.27,34))) :ARG1-of (l2 / label-01 :ARG2 (s / string-entity :value "4D2"~e.36)) :mod (m / monoclone)) :ARG1-of (d4 / describe-01 :ARG0 (p9 / panel~e.39 :ARG1-of (l / low-04~e.38 :degree~e.38 (m3 / more~e.38)) :mod s2~e.41)))) # ::id bio.chicago_2015.25541 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In transient transfection assays , we demonstrate that TLD cleaves SOG and that cleavage is stimulated by DPP . # ::alignments 1-1.3.1.1 2-1.3.1 3-1.3 5-1.1 6-1 7-1.2.r 8-1.2.1.1.1.1 9-1.2.1 10-1.2.1.2.1.1 13-1.2.1 15-1.2.2 16-1.2.2.1.r 17-1.2.2.1.1.1 (d / demonstrate-01~e.6 :ARG0 (w / we~e.5) :ARG1~e.7 (a / and :op1 (c / cleave-01~e.9,13 :ARG0 (p / protein :name (n / name :op1 "TLD"~e.8)) :ARG1 (p2 / protein :name (n2 / name :op1 "SOG"~e.10))) :op2 (s / stimulate-01~e.15 :ARG0~e.16 (p3 / protein :name (n3 / name :op1 "DPP"~e.17)) :ARG1 c)) :time (a2 / assay-01~e.3 :ARG1 (t4 / transfect-01~e.2 :ARG1-of (t5 / transient-02~e.1)))) # ::id bio.chicago_2015.25564 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro transcription and translation of full @-@ length wild @-@ type Sgk ( Wt Sgk ) , kinase dead Sgk ( K127 M Sgk ) , N @- and C -@ terminal deleted Sgk ( deltaN Sgk , deltaC Sgk ) , catalytic domain of Sgk ( Cat 60 @-@ 355 Sgk ) , and truncated fragments of the Sgk central catalytic domain ( 60 @-@ 157 Sgk ) and ( 66 @-@ 122 Sgk ) subcloned into pCDNA3 vectors or pCite vectors were performed using the TNT coupled rabbit reticulocyte kit ( Promega Corporation ) according to manufacturer 's instructions . # ::alignments 0-1.1.3 1-1.1.3 2-1.1.1 3-1.1 3-1.1.1.1 4-1.1.2 5-1.1.1.1.r 6-1.1.1.1.1.3.1 8-1.1.1.1.1 8-1.1.1.1.1.3 8-1.1.1.1.1.3.r 9-1.1.1.1.1.2 11-1.1.1.1.1.2 12-1.1.1.1.1.1.1 12-1.1.1.1.2.1.1 12-1.1.1.1.3.1.1 12-1.1.1.1.4.2.1.1 15-1.1.1.1.1.1.1 15-1.1.1.1.2.1.1 15-1.1.1.1.3.1.1 15-1.1.1.1.4.2.1.1 19-1.1.1.1.3 19-1.1.1.1.3.4 19-1.1.1.1.3.4.r 20-1.1.1.1.3.1.1 24-1.1.1.1.3.1.1 27-1.1.1.1.3.3.1.1.1.1 29-1.1.1.1.3.3.1 30-1.1.1.1.3.3.1.2.1.1 32-1.1.1.1.3.3.1.1.1.1 32-1.1.1.1.3.3.1.2.1.1 33-1.1.1.1.3.3.1.3 34-1.1.1.1.3.1.1 36-1.1.1.1.3.2.1.1.1.1 37-1.1.1.1.3.2.1.1.1.2 39-1.1.1.1.3.2.1.2.1.1 40-1.1.1.1.1.1.1 40-1.1.1.1.2.1.1 40-1.1.1.1.3.1.1 40-1.1.1.1.3.2.1.2.1.2 40-1.1.1.1.4.2.1.1 43-1.1.1.1.4.1 44-1.1.1.1.4 46-1.1.1.1.4.2.1.1 48-1.1.1.1.4.3.1.1.1 49-1.1.1.1.4.3.1.2.1.1 51-1.1.1.1.4.3.1.2.1.2 52-1.1.1.1.1.1.1 52-1.1.1.1.2.1.1 52-1.1.1.1.3.1.1 52-1.1.1.1.4.2.1.1 55-1.1.1.1.3.2.1 55-1.1.1.1.4.3.1.2.1 56-1.1.1.1.5.2 57-1.1.1.1.5 60-1.1.1.1.1.1.1 60-1.1.1.1.2.1.1 60-1.1.1.1.3.1.1 60-1.1.1.1.4.2.1.1 60-1.1.1.1.5.2.1.1.1.1 62-1.1.1.1.4.1 63-1.1.1.1.4 65-1.1.1.1.5.2.1.1.2.1 67-1.1.1.1.5.2.1.1.2.2 68-1.1.1.1.5.2.1.1.1.1 68-1.1.1.1.5.2.1.2.1.1 70-1.1.1.1.5.2.1.1.2 70-1.1.1.1.5.2.1.2.2 72-1.1.1.1.5.2.1.2.2.1 74-1.1.1.1.5.2.1.2.2.2 75-1.1.1.1.5.2.1.2.1.1 79-1.1.1.1.5.3.1.1.1.1 80-1.1.1.1.5.3.1.1 80-1.1.1.1.5.3.1.2 81-1.1.1.1.5.3.1 82-1.1.1.1.5.3.1.2.1.1 83-1.1.1.1.5.3.1.1 85-1 86-1.2 88-1.2.1.1.2.1.1 89-1.2.1.1.2.2 90-1.2.1.1.1 91-1.2.1.1 92-1.2.1 94-1.2.1.2.2.1 95-1.2.1.2.2.2 101-1.2.2 (p / perform-01~e.85 :ARG1 (a2 / and~e.3 :op1 (t2 / transcribe-01~e.2 :ARG1~e.5 (a3 / and~e.3 :op1 (e / enzyme~e.8 :name (n3 / name :op1 "Sgk"~e.12,15,40,52,60) :mod (w / wild-type~e.9,11) :ARG1-of~e.8 (l / long-03~e.8 :ARG2 (f / full~e.6))) :op2 (e2 / enzyme :name (n4 / name :op1 "Sgk"~e.12,15,40,52,60)) :op3 (e3 / enzyme~e.19 :name (n9 / name :op1 "Sgk"~e.12,15,20,24,34,40,52,60) :ARG1-of (m6 / mean-01 :ARG2 (a5 / and~e.55 :op1 (e4 / enzyme :name (n10 / name :op1 "deltaN"~e.36 :op2 "Sgk"~e.37)) :op2 (e5 / enzyme :name (n11 / name :op1 "deltaC"~e.39 :op2 "Sgk"~e.40)))) :ARG0-of (h / have-03 :ARG1 (a4 / and~e.29 :op1 (p5 / protein-segment :name (n12 / name :op1 "N-terminus"~e.27,32)) :op2 (p6 / protein-segment :name (n13 / name :op1 "C-terminus"~e.30,32)) :ARG1-of (d2 / delete-01~e.33))) :ARG1-of~e.19 (d / die-01~e.19)) :op4 (d3 / domain~e.44,63 :mod (c4 / catalytic~e.43,62) :mod (e6 / enzyme :name (n14 / name :op1 "Sgk"~e.12,15,40,46,52,60)) :ARG1-of (m11 / mean-01 :ARG2 (e7 / enzyme :name (n15 / name :op1 "Cat"~e.48 :op2 "Sgk") :extent (v / value :quant (b4 / between~e.55 :op1 60~e.49 :op2 355~e.51))))) :op5 (f2 / fragment-01~e.57 :ARG1 d3 :ARG1-of (t5 / truncate-01~e.56 :ARG4 (a6 / and :op1 (e8 / enzyme :name (n18 / name :op1 "Sgk"~e.60,68) :value (b5 / between~e.70 :op1 60~e.65 :op2 157~e.67)) :op2 (e9 / enzyme :name (n19 / name :op1 "Sgk"~e.68,75) :value (b6 / between~e.70 :op1 66~e.72 :op2 122~e.74)))) :ARG1-of (s / subclone-01 :ARG3 (o2 / or~e.81 :op1 (v3 / vector~e.80,83 :name (n17 / name :op1 "pCDNA3"~e.79)) :op2 (v2 / vector~e.80 :name (n16 / name :op1 "pCite"~e.82))))))) :op2 (t / translate-02~e.4 :ARG1 a3) :manner (i2 / in-vitro~e.0,1)) :ARG2 (u / use-01~e.86 :ARG1 (k / kit~e.92 :consist-of (r / reticulocyte~e.91 :part-of (r2 / rabbit~e.90) :mod (s2 / small-molecule :name (n / name :op1 "TNT"~e.88) :ARG1-of (c2 / couple-01~e.89))) :mod (o / organization :wiki - :name (n2 / name :op1 "Promega"~e.94 :op2 "Corporation"~e.95))) :ARG3-of (i / instruct-01~e.101 :ARG0 o))) # ::id bio.chicago_2015.25584 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that multiple positive @-@ feedback loops exist among these genes during normal eye development and raised the possibility that ey may be required for ectopic retinal induction by eya and dac . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1 3-1.1.2.r 4-1.1.2.1.3 5-1.1.2.1.2 7-1.1.2.1.1 8-1.1.2.1 9-1.1.2 10-1.1.2.2.1 11-1.1.2.2.1.1.1 12-1.1.2.2 12-1.1.2.2.1.1 13-1.1.2.3.r 14-1.1.2.3.2 15-1.1.2.3.1 16-1.1.2.3 17-1 18-1.2 20-1.2.2 20-1.2.2.1 20-1.2.2.1.r 22-1.2.2.1.1.2.1.1 23-1.2.2.1 25-1.2.2.1.1 26-1.2.2.1.1.1.r 27-1.2.2.1.1.1.2.1 28-1.2.2.1.1.1.2 29-1.2.2.1.1.1 30-1.2.2.1.1.1.1.r 31-1.2.2.1.1.1.1.1.1.1 32-1.2.2.1.1.1.1 33-1.2.2.1.1.1.1.2.1.1 (a / and~e.17 :op1 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (e / exist-01~e.9 :ARG1 (l / loop~e.8 :mod (f / feedback~e.7) :mod (p / positive~e.5) :quant (m / multiple~e.4)) :location (g / gene~e.12 :ARG1-of (i / include-91~e.10 :ARG2 (g2 / gene~e.12 :mod (t3 / this~e.11)))) :time~e.13 (d2 / develop-02~e.16 :ARG1 (e2 / eye~e.15) :ARG1-of (n / normal-02~e.14)))) :op1 (r2 / raise-01~e.18 :ARG0 t :ARG1 (p2 / possible-01~e.20 :ARG1~e.20 (p3 / possible-01~e.20,23 :ARG1 (r3 / require-01~e.25 :ARG0~e.26 (i2 / induce-01~e.29 :ARG0~e.30 (a2 / and~e.32 :op1 (g5 / gene :name (n3 / name :op1 "eya"~e.31)) :op2 (g4 / gene :name (n4 / name :op1 "dac"~e.33))) :ARG2 (r4 / retinal~e.28 :mod (e3 / ectopic~e.27))) :ARG1 (p4 / protein :name (n2 / name :op1 "ey"~e.22))))))) # ::id bio.chicago_2015.25656 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PKG phosphorylation of SF1 blocked its ability to bind to U2AF65 and inhibited pre @-@ spliceosome assembly . # ::alignments 0-1.1.1.2.1.1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1 5-1.1.2.1 5-1.1.2.1.r 6-1.1.2 8-1.1.2.2 9-1.1.2.2.2.r 10-1.1.2.2.2.1.1 11-1 12-1.2 15-1.2.2.1.1.1.1 16-1.2.2 (a / and~e.11 :op1 (b / block-01~e.4 :ARG0 (p / phosphorylate-01~e.1 :ARG1~e.2 (p2 / protein :name (n / name :op1 "SF1"~e.3)) :ARG2 (e / enzyme :name (n2 / name :op1 "PKG"~e.0))) :ARG1 (c / capable-01~e.6 :ARG1~e.5 e~e.5 :ARG2 (b2 / bind-01~e.8 :ARG1 e :ARG2~e.9 (p3 / protein :name (n3 / name :op1 "U2AF65"~e.10))))) :op2 (i / inhibit-01~e.12 :ARG0 p :ARG1 (a2 / assemble-01~e.16 :time (b3 / before :op1 (s / small-molecule :name (n4 / name :op1 "spliceosome"~e.15)))))) # ::id bio.chicago_2015.25659 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The possibility that caffeine inhibits ATM directly was therefore tested . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1.1.1.3 8-1.1.2 9-1 (t / test-01~e.9 :ARG1 (p2 / possible-01~e.1 :ARG1~e.2 (i / inhibit-01~e.4 :ARG0 (c / caffeine~e.3) :ARG1 (e / enzyme :name (n / name :op1 "ATM"~e.5)) :ARG1-of (d / direct-02~e.6)) :ARG0-of (c2 / cause-01~e.8))) # ::id bio.chicago_2015.25663 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In quiescent Swiss 3T3 fibroblasts , the activation of Rho induces the assembly of actin into bundles and stress fibers , while the activation of Rac and Cdc42 induces actin polymerization leading to ruffles and filopodia , respectively ( reviewed by Hall and Nobes , 2000 ) . # ::alignments 1-1.3.1 2-1.3.2.1.1 3-1.3.2.1.2 4-1.3 7-1.1.1 8-1.1.1.1.r 9-1.1.1.1.1.1 10-1.1 12-1.1.2 13-1.1.2.2.r 14-1.1.2.2.1.1 15-1.1.2.1.r 16-1.1.2.1.2 18-1.1.2.1.1 19-1.1.2.1 21-1 23-1.2.1 24-1.2.1.1.r 25-1.2.1.1.1.1.1 26-1.2.1.1 28-1.2 29-1.2.2.1 30-1.2.2 31-1.2.3 32-1.2.3.1.r 33-1.2.3.1.1 33-1.2.3.1.1.1 33-1.2.3.1.1.1.r 34-1.2.3.1 35-1.2.3.1.2 37-1.2.3.1.3 39-1.4 40-1.4.1.r 41-1.4.1.1.1.1 42-1.4.1 43-1.4.1.2.1.1 45-1.4.2.1 (c2 / contrast-01~e.21 :ARG1 (i / induce-01~e.10 :ARG0 (a / activate-01~e.7 :ARG1~e.8 (p / protein :name (n2 / name :op1 "Rho"~e.9))) :ARG2 (a2 / assemble-01~e.12 :ARG1~e.15 (f / fiber~e.19 :ARG1-of (s / stress-02~e.18) :ARG1-of (b / bundle-01~e.16)) :ARG2~e.13 (p2 / protein :name (n3 / name :op1 "actin"~e.14)))) :ARG2 (i2 / induce-01~e.28 :ARG0 (a3 / activate-01~e.23 :ARG1~e.24 (a4 / and~e.26 :op1 (e / enzyme :name (n4 / name :op1 "Rac"~e.25)) :op2 (p3 / protein :name (n5 / name :op1 "Cdc-42")))) :ARG2 (p4 / polymerize-01~e.30 :ARG1 p2~e.29) :ARG0-of (l / lead-03~e.31 :ARG2~e.32 (a5 / and~e.34 :op1 (t / thing~e.33 :ARG1-of~e.33 (r / ruffle-02~e.33)) :op2 (f2 / filopodia~e.35) :mod (r2 / respective~e.37)))) :location (f3 / fibroblast~e.4 :mod (q / quiescent~e.1) :mod (c4 / cell-line :name (n9 / name :op1 "Swiss"~e.2 :op2 "3T3"~e.3))) :ARG1-of (r3 / review-01~e.39 :ARG0~e.40 (a6 / and~e.42 :op1 (p5 / person :name (n7 / name :op1 "Hall"~e.41)) :op2 (p6 / person :name (n8 / name :op1 "Nobes"~e.43))) :time (d / date-entity :year 2000~e.45))) # ::id bio.chicago_2015.25683 ::amr-annotator SDL-AMR-09 ::preferred # ::tok firstly , the isolated SH3 domain binds tightly to dynamin in vitro ; and secondly , coexpression of both dynamin and the amphiphysin SH3 domain rescues the transferrin uptake . # ::alignments 0-1.1.5.1 3-1.1.1.2 4-1.1.1.1.1 5-1.1.1.1.2 6-1.1 7-1.1.3 8-1.1.2.r 9-1.1.2.1.1 10-1.1.4 11-1.1.4 14-1.1.5 14-1.2.3 14-1.2.3.1 14-1.2.3.1.r 19-1.2.1.1.1 20-1 20-1.2.1.1 22-1.2.1.1.2.2.1.1 23-1.2.1.1.2.1 24-1.2.1.1.2.1 25-1.2 27-1.2.2.1.1.1 (a / and~e.20 :op1 (b / bind-01~e.6 :ARG1 (p / protein-segment :name (n / name :op1 "SH3"~e.4 :op2 "domain"~e.5) :ARG1-of (i / isolate-01~e.3)) :ARG2~e.8 (p5 / protein :name (n2 / name :op1 "dynamin"~e.9)) :ARG1-of (t / tight-05~e.7) :manner (i2 / in-vitro~e.10,11) :ord (o / ordinal-entity~e.14 :value 1~e.0)) :op2 (r / rescue-01~e.25 :ARG0 (c / coexpress-01 :ARG2 (a2 / and~e.20 :op1 p5~e.19 :op2 (p2 / protein-segment :name n~e.23,24 :part-of (p3 / protein :name (n4 / name :op1 "amphiphysin"~e.22))))) :ARG1 (t2 / take-up-13 :ARG2 (p4 / protein :name (n5 / name :op1 "transferrin"~e.27))) :ord (o2 / ordinal-entity~e.14 :value~e.14 2~e.14))) # ::id bio.chicago_2015.25696 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RACK1 also interacted with the IGF @-@ 1R in fibroblasts and MCF @-@ 7 cells and with endogenous insulin receptor in COS cells . # ::alignments 0-1.1.1.1.1 1-1.1.3 2-1.1 2-1.2 3-1.1.2.r 5-1.1.2.1.1 7-1.1.2.1.1 8-1.1.4.r 9-1.1.4.1 10-1.1.4 11-1.1.4.2.1.1 13-1.1.4.2.1.1 14-1.1.4.2 14-1.2.3 15-1.1.4 16-1.2.2.r 17-1.2.2.2 18-1.2.2.1 19-1.2.2 21-1.2.3.1.1 22-1.1.4.2 (a / and :op1 (i / interact-01~e.2 :ARG0 (p / protein :name (n / name :op1 "RACK1"~e.0)) :ARG1~e.3 (p2 / protein :name (n2 / name :op1 "IGF-1R"~e.5,7)) :mod (a2 / also~e.1) :location~e.8 (a3 / and~e.10,15 :op1 (f / fibroblast~e.9) :op2 (c / cell-line~e.14,22 :name (n3 / name :op1 "MCF-7"~e.11,13)))) :op2 (i2 / interact-01~e.2 :ARG0 p :ARG1~e.16 (r2 / receptor~e.19 :mod (i3 / insulin~e.18) :mod (e / endogenous~e.17)) :location (c2 / cell-line~e.14 :name (n5 / name :op1 "COS"~e.21)))) # ::id bio.chicago_2015.25712 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given that DLAK has the most extensive sequence similarity with IKK and that DLAK exists in the form of a complex with Cactus and LPS @-@ induced Cactus degradation is specifically blocked by dominant @-@ negative DLAK , we could speculate that the dominant @-@ negative form of DLAK fails to transmit the Cactus degradation signal , essential for Rel/ NF @-@ kappaB activation and subsequently prevents LPS inducibility of at least certain kappaB @-@ dependent antimicrobial peptide genes . # ::alignments 2-1.1.1.2.1 3-1.1.1 5-1.1.1.2.4.1 6-1.1.1.2.4 7-1.1.1.2.3 8-1.1.1.2 9-1.1.1.2.2.r 10-1.1.1.2.2.1.1 11-1.1 13-1.1.1.1.1.1 14-1.1.2 15-1.1.2.2.r 17-1.1.2.2 18-1.1.2.2.2.r 20-1.1.2.2.2 22-1.1.3.2.1 23-1.1 23-1.1.2.2.1 24-1.1.3.2.2.1.1.1 26-1.1.3.2.2 26-1.2.1.2.2.2 27-1.1.2.2.1.2.1.1 28-1.1.3.2 30-1.1.3.3 31-1.1.3 32-1.1.3.1.r 33-1.1.3.1 33-1.1.3.1.3 33-1.1.3.1.3.r 36-1.1.1.1.1.1 36-1.1.3.1.1.1 38-1.2.1.1 39-1.2 39-1.2.1.2.2.2.3 40-1.2.1 41-1.2.1.2.r 43-1.2.1.2.1.1 46-1.2.1.2.1.2.1 48-1.1.1.1.1.1 48-1.1.3.1.1.1 49-1.2.1.2.1 51-1.2.1.2.1.2 53-1.1.2.2.1.2.1.1 54-1.2.1.2.1.2.2.1 55-1.2.1.2.1.2.2 57-1.2.1.2.1.2.2.2 60-1.2.1.2.1.2.2.3.1.2.1.1 62-1.2.1.2.1.2.2.3.1.2.1.1 63-1.2.1.2.1.2.2.3 64-1.2.1.2 65-1.2.1.2.2.3 65-1.2.1.2.2.3.r 66-1.2.1.2.2 67-1.2.1.2.2.2.1 69-1.2.1.2.2.2.2.r 70-1.2.1.2.2.2.2.4 71-1.2.1.2.2.2.2.4 72-1.2.1.2.2.2.2.5 73-1.2.1.2.2.2.2.3.1.1.1 75-1.2.1.2.2.2.2.3 77-1.2.1.2.2.2.2.1 78-1.2.1.2.2.2.2 (c / cause-01 :ARG0 (a2 / and~e.11,23 :op1 (h / have-03~e.3 :ARG0 (e / enzyme :name (n / name :op1 "DLAK"~e.13,36,48)) :ARG1 (r / resemble-01~e.8 :ARG1 e~e.2 :ARG2~e.9 (e2 / enzyme :name (n2 / name :op1 "IKK"~e.10)) :mod (s / sequence~e.7) :ARG1-of (e3 / extensive-03~e.6 :ARG2 (m / most~e.5)))) :op2 (e4 / exist-01~e.14 :ARG1 e :ARG2~e.15 (f / form-02~e.17 :ARG0 (a5 / and~e.23 :op1 e :op2 (p2 / protein :name (n3 / name :op1 "Cactus"~e.27,53))) :ARG1~e.18 (c2 / complex~e.20))) :op3 (b / block-01~e.31 :ARG0~e.32 (e5 / enzyme~e.33 :name (n6 / name :op1 "DLAK"~e.36,48) :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of~e.33 (d2 / dominate-01~e.33)) :ARG1 (d / degrade-01~e.28 :ARG1 p2~e.22 :ARG2-of (i / induce-01~e.26 :ARG0 (m3 / molecular-physical-entity :name (n5 / name :op1 "LPS"~e.24)))) :ARG1-of (s3 / specific-02~e.30))) :ARG1 (p / possible-01~e.39 :ARG1 (s4 / speculate-01~e.40 :ARG0 (w / we~e.38) :ARG1~e.41 (a4 / and~e.64 :op1 (f2 / fail-01~e.49 :ARG0 e5~e.43 :ARG1 (t / transmit-01~e.51 :ARG0 (f3 / form-02~e.46) :ARG1 (s5 / signal-07~e.55 :ARG1 d~e.54 :mod (e6 / essential~e.57) :condition-of (a3 / activate-01~e.63 :ARG1 (s7 / slash :op1 (p4 / protein :name (n7 / name :op1 "Rel")) :op2 (p3 / protein :name (n10 / name :op1 "NF-kappaB"~e.60,62))))))) :op2 (p6 / prevent-01~e.66 :ARG0 f3 :ARG1 (i2 / induce-01~e.26 :ARG0 m3~e.67 :ARG1~e.69 (g / gene~e.78 :mod (p8 / peptide~e.77) :ARG0-of (o / oppose-01 :ARG1 (m4 / microbe)) :ARG0-of (d3 / depend-01~e.75 :ARG1 (p5 / protein :name (n8 / name :op1 "kappaB"~e.73))) :mod (a / at-least~e.70,71) :mod (c3 / certain~e.72)) :ARG1-of (p7 / possible-01~e.39)) :time~e.65 (s6 / subsequent~e.65)))))) # ::id bio.chicago_2015.25761 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , only the JNK cascade can activate c @-@ Jun ( 16 , 65 , 66 , 67 ) . # ::alignments 0-1 2-1.1.1.3 4-1.1.1.1.1.1 6-1.1 7-1.1.1 8-1.1.1.2.1.1 10-1.1.1.2.1.1 12-1.2.1.1.1.1 14-1.2.1.1.1.2 16-1.2.1.1.1.3 18-1.2.1.1.1.4 (h / have-concession-91~e.0 :ARG1 (p4 / possible-01~e.6 :ARG1 (a / activate-01~e.7 :ARG0 (p / pathway :name (n3 / name :op1 "JNK"~e.4)) :ARG1 (p2 / protein :name (n2 / name :op1 "c-Jun"~e.8,10)) :mod (o / only~e.2))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 16~e.12 :op2 65~e.14 :op3 66~e.16 :op4 67~e.18))))) # ::id bio.chicago_2015.25828 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Under conditions where Rac induced strong actin polymerization and lamellipodia , POSH induced no detectable assembly of actin filaments ( data not shown ) . # ::alignments 1-1 3-1.2.1.1.1 4-1.2 5-1.2.2.1.2 6-1.2.2.1.1.1.1 7-1.2.2.1 8-1.2.2 9-1.2.2.2.1.1 11-1.1.1.1.1 12-1.1 13-1.1.2.2.1.1 13-1.1.2.2.1.1.r 14-1.1.2.2 15-1.1.2 16-1.1.2.1.r 17-1.1.2.1.1 18-1.1.2.1 20-1.3.1 21-1.3.1.1.1 21-1.3.1.1.1.r 22-1.3.1.1 (c / condition-01~e.1 :ARG1 (i2 / induce-01~e.12 :ARG0 (p5 / protein :name (n4 / name :op1 "POSH"~e.11)) :ARG2 (a2 / assemble-02~e.15 :ARG2~e.16 (f / filament~e.18 :mod p2~e.17) :ARG1-of (d / detect-01~e.14 :ARG1-of (p4 / possible-01 :polarity~e.13 -~e.13)))) :ARG2 (i / induce-01~e.4 :ARG0 (e / enzyme :name (n / name :op1 "Rac"~e.3)) :ARG2 (a / and~e.8 :op1 (p / polymerize-01~e.7 :ARG1 (p2 / protein :name (n2 / name :op1 "actin"~e.6)) :ARG1-of (s / strong-02~e.5)) :op2 (p3 / protein :name (n3 / name :op1 "lamellipodia"~e.9)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.20 :ARG1-of (s2 / show-01~e.22 :polarity~e.21 -~e.21)))) # ::id bio.chicago_2015.25847 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dvl2 Activation of JNK Does Not Require MEKK1 and Binding of Dvl2 to Axin Is Independent of the Axin @-@ MEKK1 Interaction-- We have previously demonstrated that MEKK1 binds Axin and is critical for Axin activation of JNK ( 22 ) . # ::alignments 0-1.1.1.2.1.1.1 1-1.1.1.2 2-1.1.1.2.2.r 3-1.1.1.2.2.1.1 5-1.1.1.1 5-1.1.1.1.r 6-1.1.1 7-1.1.1.3.1.1 8-1.1 9-1.1.2.2 10-1.1.2.2.1.r 11-1.1.2.2.1 12-1.1.2.2.2.r 13-1.1.2.2.2.1.1 15-1.1.2 15-1.1.2.1 15-1.1.2.1.r 18-1.2.2.2.1.1 20-1.2.2.1.1.1 22-1.2.1 24-1.2.3 25-1.2 27-1.2.2.1.1.1 28-1.2.2 29-1.2.2.2.1.1 32-1.2.2.3 33-1.2.2.3.1.r 34-1.2.2.3.1.1 35-1.2.2.3.1 36-1.2.2.3.1.2.r 37-1.2.2.3.1.2.1.1 39-1.2.4.1.1.1 (m / multi-sentence :snt1 (a / and~e.8 :op1 (r / require-01~e.6 :polarity~e.5 -~e.5 :ARG0 (a2 / activate-01~e.1 :ARG0 (p / protein :name (n / name :op1 "Dvl2"~e.0)) :ARG1~e.2 (e / enzyme :name (n2 / name :op1 "JNK"~e.3))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEKK1"~e.7))) :op2 (d / depend-01~e.15 :polarity~e.15 -~e.15 :ARG0 (b / bind-01~e.9 :ARG1~e.10 p~e.11 :ARG2~e.12 (p2 / protein :name (n4 / name :op1 "Axin"~e.13))) :ARG1 (i / interact-01 :ARG0 p2 :ARG1 e2))) :snt2 (d2 / demonstrate-01~e.25 :ARG0 (w2 / we~e.22) :ARG1 (b2 / bind-01~e.28 :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEKK1"~e.20,27)) :ARG2 (p3 / protein :name (n6 / name :op1 "Axin"~e.18,29)) :ARG1-of (c / critical-02~e.32 :ARG2~e.33 (a3 / activate-01~e.35 :ARG0 p3~e.34 :ARG1~e.36 (e4 / enzyme :name (n7 / name :op1 "JNK"~e.37))))) :time (p4 / previous~e.24) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 22~e.39))))) # ::id bio.chicago_2015.25875 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We show that the Tuberin @-@ Hamartin heterodimer inhibits Rheb @-@ induced S6K1 activation during conditions of amino acid withdrawal ( Figure 5A ) . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.1.1.1.1 6-1.2.1.2.1.1 7-1.2.1 8-1.2 9-1.2.2.2.1.1.1 11-1.2.2.2 12-1.2.2.1.1.1 13-1.2.2 15-1.2.3 16-1.2.3.1.r 17-1.2.3.1.1 18-1.2.3.1.1 19-1.2.3.1 21-1.3.1 22-1.3.1.1 (s / show-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (i / inhibit-01~e.8 :ARG0 (h / heterodimer~e.7 :part (p / protein :name (n / name :op1 "Tuberin"~e.4)) :part (p2 / protein :name (n2 / name :op1 "Hamartin"~e.6))) :ARG1 (a / activate-01~e.13 :ARG1 (e / enzyme :name (n3 / name :op1 "S6K1"~e.12)) :ARG2-of (i2 / induce-01~e.11 :ARG0 (p3 / protein :name (n4 / name :op1 "Rheb"~e.9)))) :ARG1-of (c / condition-01~e.15 :ARG2~e.16 (w2 / withdraw-01~e.19 :ARG1 (a2 / amino-acid~e.17,18)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "5A"~e.22))) # ::id bio.chicago_2015.25880 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , downregulation of Rho activity by Cdc42 may either involve activation of Rac or occur independently of Rac , possibly by a downstream signaling pathway shared by Cdc42 and Rac . # ::alignments 0-1 0-1.1.1.2.4 2-1.1.1.2.2 3-1.1.1.2.2 4-1.1.1.2.2 5-1.1.1.2.2 6-1.1.1.2.2 7-1.1.1.2.2 8-1.1.1.2.4.2 10-1.1.1.1 11-1.1.1.1.1 12-1.1.1.1.1.1.r 13-1.1.1.1.1.1.1.1 14-1.1.1 16-1.1.1.2.1 18-1.1.1.1.1.1.1.1 20-1.1 21-1.1.1.2.4.1.r 23-1.1.1.2.4.1.2.1.1 24-1.1.1.2.4.1.2.1 25-1.1.1.2.4.1.2 26-1.1.1.2.4.1 28-1.1.1.2.2 30-1.1.1.1.1.1.1.1 (c / cause-01~e.0 :ARG1 (p3 / possible-01~e.20 :ARG1 (o / or~e.14 :op1 (i / involve-01~e.10 :ARG1 (a2 / activate-01~e.11 :ARG1~e.12 (e / enzyme :name (n3 / name :op1 "Rac"~e.13,18,30))) :ARG2 (d / downregulate-01 :ARG1 (a / activity-06 :ARG0 (p / protein :name (n / name :op1 "Rho"))) :ARG2 (p2 / protein :name (n2 / name :op1 "Cdc42")))) :op2 (d3 / depend-01 :polarity -~e.16 :ARG0 d~e.2,3,4,5,6,7,28 :ARG1 e :ARG1-of (c2 / cause-01~e.0 :ARG0~e.21 (s / share-01~e.26 :ARG0 (a3 / and :op1 p2 :op2 e) :ARG1 (p5 / pathway~e.25 :ARG0-of (s2 / signal-07~e.24 :direction (d4 / downstream~e.23)))) :ARG1-of (p4 / possible-01~e.8)))))) # ::id bio.chicago_2015.25882 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ethanol @-@ induced Cbl tyrosine phosphorylation in rat cerebellum # ::alignments 0-1.2.1 2-1.2 3-1.1.2.1.1 4-1.1.1.1 5-1 6-1.3.r 7-1.3.1 8-1.3 (p2 / phosphorylate-01~e.5 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.4) :part-of (p3 / protein :name (n2 / name :op1 "Cbl"~e.3))) :ARG2-of (i / induce-01~e.2 :ARG0 (e / ethanol~e.0)) :location~e.6 (c / cerebellum~e.8 :mod (r / rat~e.7))) # ::id bio.chicago_2015.25952 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , the RNAi oligo inhibits RhoA activation by Wnt @-@ 1 , Fz , or Dvl , but not by Ephexin ( Figure 3C ) . # ::alignments 0-1.4 3-1.1.1.1.1 4-1.1.1.1.2 5-1.1 5-1.2 6-1.1.2.2.1.1 7-1.1.2 7-1.2.3 8-1.1.2.1.r 9-1.1.2.1.1.1.1 11-1.1.2.1.1.1.1 13-1.1.2.1.2.1.1 15-1.1.2.1 16-1.1.2.1.3.1.1 18-1 19-1.2.1 19-1.2.1.r 20-1.2.3.1.r 21-1.2.3.1.1.1 23-1.3.1 24-1.3.1.1 (c / contrast-01~e.18 :ARG1 (i / inhibit-01~e.5 :ARG0 (n / nucleic-acid :name (n8 / name :op1 "RNAi"~e.3 :op2 "oligo"~e.4)) :ARG1 (a / activate-01~e.7 :ARG0~e.8 (o / or~e.15 :op1 (p2 / protein :name (n3 / name :op1 "Wnt-1"~e.9,11)) :op2 (p3 / protein :name (n4 / name :op1 "Fz"~e.13)) :op3 (p4 / protein :name (n5 / name :op1 "Dvl"~e.16))) :ARG1 (p / protein :name (n6 / name :op1 "RhoA"~e.6)))) :ARG2 (i3 / inhibit-01~e.5 :polarity~e.19 -~e.19 :ARG0 (n2 / nucleic-acid :name (n9 / name :op1 "RNA")) :ARG1 (a2 / activate-01~e.7 :ARG0~e.20 (p5 / protein :name (n7 / name :op1 "Ephexin"~e.21)) :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "3C"~e.24)) :mod (i2 / important~e.0)) # ::id bio.chicago_2015.26022 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regulation of GSK @-@ 3 beta by PKA and PP1 in the AKAP220 Complex-- Finally we examined the physiological significance of the binding of GSK @-@ 3 beta to AKAP220 . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1 6-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.1.1 12-1.1.3.1.1.1 14-1.2.2.3 15-1.2.1 16-1.2 18-1.2.2.2 22-1.2.2.1 24-1.1.2.1.1 24-1.2.2.1.1.1.1 29-1.1.3.1.1.1 29-1.2.2.1.2.1.1 (m / multi-sentence :snt1 (r / regulate-01~e.0 :ARG0~e.6 (a / and~e.8 :op1 (e2 / enzyme :name (n2 / name :op1 "PKA"~e.7)) :op2 (p / protein :name (n3 / name :op1 "PP1"~e.9))) :ARG1~e.1 (e / enzyme :name (n / name :op1 "GSK-3beta"~e.2,24)) :location (c / complex :mod (p2 / protein :name (n4 / name :op1 "AKAP220"~e.12,29)))) :snt2 (e3 / examine-01~e.16 :ARG0 (w / we~e.15) :ARG1 (s / signify-01 :ARG0 (b / bind-01~e.22 :ARG1 (e4 / enzyme :name (n5 / name :op1 "GSK-3beta"~e.24)) :ARG2 (p4 / protein :name (n6 / name :op1 "AKAP220"~e.29))) :mod (p3 / physiology~e.18) :time (f / final~e.14)))) # ::id bio.chicago_2015.26080 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In accordance with our previous results in 32D @/@ EpoR @-@ Wt cells ( 4 ) , Epo stimulation induced activation of ERK1 and ERK2 , which was detected by their phosphorylation on tyrosines , in 32DE @/@ Tet @- CrkL cells ( Fig . 3 ) . # ::alignments 1-1.4 4-1.4.1.1.2 5-1.4.1 5-1.4.1.1 5-1.4.1.1.r 6-1.4.1.1.1.r 7-1.4.1.1.1.1.1 9-1.4.1.1.1.2.1.1 12-1.4.1.1.1 14-1.4.1.2.1.1.1 17-1.1.1.1.1 18-1.1 19-1 20-1.2 21-1.2.1.r 22-1.2.1.1.1.1 23-1.2.1 24-1.2.1.2.1.1 28-1.2.2 31-1.2.2.1 32-1.2.2.1.1.r 33-1.2.2.1.1.1.1 35-1.2.2.1.2.r 36-1.2.2.1.2.1.1 38-1.2.2.1.2.2.1.1 40-1.2.2.1.2.2.1.1 41-1.2.2.1.2 43-1.3.1 45-1.3.1.1 (i / induce-01~e.19 :ARG0 (s / stimulate-01~e.18 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "Epo"~e.17))) :ARG2 (a2 / activate-01~e.20 :ARG1~e.21 (a3 / and~e.23 :op1 (e / enzyme :name (n3 / name :op1 "ERK1"~e.22)) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2"~e.24))) :ARG1-of (d / detect-01~e.28 :ARG0 (p2 / phosphorylate-01~e.31 :ARG1~e.32 (a4 / amino-acid :name (n5 / name :op1 "tyrosine"~e.33) :part-of a3) :location~e.35 (c / cell-line~e.41 :name (n6 / name :op1 "32DE"~e.36) :mod (p / protein :name (n / name :op1 "Tet-CrkL"~e.38,40)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.43 :mod 3~e.45)) :ARG1-of (a / accord-02~e.1 :ARG2 (t / thing~e.5 :ARG2-of~e.5 (r / result-01~e.5 :ARG1~e.6 (c2 / cell-line~e.12 :name (n7 / name :op1 "32D"~e.7) :mod (p6 / protein :name (n8 / name :op1 "EpoR"~e.9) :mod (w / wild-type))) :time (p4 / previous~e.4)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 4~e.14)))))) # ::id bio.chicago_2015.26085 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB @-@ Dependent Transcription and ERK Nuclear Translocation # ::alignments 0-1.2.3 1-1.2 3-1.2.1.1.1 5-1.2.2.1.1 7-1 10-1.1.1 11-1.1.1.2.r 12-1.1.1.2.1.1.1.1 14-1.1.1.2.1 15-1.1.1.2 16-1.1 17-1.1.2.1 18-1.1.2.2 19-1.1.2 (r / require-01~e.7 :ARG0 (a / and~e.16 :op1 (s / stimulate-01~e.10 :ARG0 (c2 / calcium :ARG1-of (i / ionize-01 :value "2+")) :ARG1~e.11 (t2 / transcribe-01~e.15 :ARG0-of (d / depend-01~e.14 :ARG1 (p2 / protein :name (n3 / name :op1 "CREB"~e.12))))) :op2 (t3 / translocate-01~e.19 :ARG1 e2~e.17 :mod (n5 / nucleus~e.18))) :ARG1 (t / talk-01~e.1 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK"~e.3)) :ARG2 (e / enzyme :name (n2 / name :op1 "PKA"~e.5)) :ARG1-of (c / cross-01~e.0))) # ::id bio.chicago_2015.26119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Acetylation of MyoD Directed by PCAF Is Necessary for the Execution of the Muscle Program . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1.1 3-1.2.2 4-1.2.2.1.r 5-1.2.2.1.1.1 7-1 8-1.1.r 10-1.1 11-1.1.1.r 13-1.1.1.1 14-1.1.1 (n2 / need-01~e.7 :ARG0~e.8 (e / execute-02~e.10 :ARG1~e.11 (p2 / program~e.14 :mod (m / muscle~e.13))) :ARG1 (a / acetylate-01~e.0 :ARG1~e.1 (p / protein :name (n3 / name :op1 "MyoD"~e.2)) :ARG1-of (d / direct-01~e.3 :ARG0~e.4 (p3 / protein :name (n4 / name :op1 "PCAF"~e.5))))) # ::id bio.chicago_2015.26145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of Cdc20 and Cdh1 to the APC is differentially regulated . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 5-1.1.2.r 7-1.1.2.1.1 9-1.2 9-1.2.r 10-1 (r / regulate-01~e.10 :ARG1 (b / bind-01~e.0 :ARG1~e.1 (a / and~e.3 :op1 (p / protein :name (n / name :op1 "Cdc20"~e.2)) :op2 (p2 / protein :name (n2 / name :op1 "Cdh1"~e.4))) :ARG2~e.5 (p3 / protein :name (n3 / name :op1 "APC"~e.7))) :manner~e.9 (d / differential~e.9)) # ::id bio.chicago_2015.26161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 3 , neither of these fractions alone supported dATP @-@ dependent activation of CPP32 ( lanes 3 - 6 ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 4-1.4.1.1 6-1.1 6-1.1.r 8-1.2.1 9-1.2 10-1.2.2 11-1 12-1.3.2.1.2.1 14-1.3.2 15-1.3 16-1.3.1.r 17-1.3.1.2.1 19-1.5.1.1 19-1.5.1.2 20-1.5.1.1.1 22-1.5.1.2.1 (s / support-01~e.11 :polarity~e.6 -~e.6 :ARG0 (f / fraction-01~e.9 :mod (t / this~e.8) :mod (a / alone~e.10)) :ARG1 (a2 / activate-01~e.15 :ARG1~e.16 (p / protein :wiki "Caspase_3" :name (n / name :op1 "CPP32"~e.17)) :ARG0-of (d / depend-01~e.14 :ARG1 (s3 / small-molecule :wiki "Deoxyadenosine_triphosphate" :name (n2 / name :op1 "dATP"~e.12)))) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (f2 / figure~e.3 :mod 3~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (l / lane~e.19 :mod 3~e.20) :op2 (l2 / lane~e.19 :mod 6~e.22)))) # ::id bio.chicago_2015.26163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We do not know at present how Bni1p and Bnr1p are involved in this profilin @-@ actin interaction , but the genetic results that the phenotypes of the bni1 bnr1 mutant are similar to those of the pfy1 mutant indicate that the interactions of Bni1p and Bnr1p with profilin are important for the proper functions of profilin . # ::alignments 0-1.1.2 2-1.1.1 2-1.1.1.r 3-1.1 4-1.1.4.r 5-1.1.4 6-1.1.3.1.r 7-1.1.3.1.1.1.1.1 8-1.1.3.1.1 9-1.1.3.1.1.2.1.1 11-1.1.3.1 12-1.1.3.1.2.r 13-1.1.3.1.2.3 14-1.1.3.1.2.1.1.1 16-1.1.3.1.2.2.1.1 17-1.1.3.1.2 19-1 21-1.2.1.2 22-1.2.1 25-1.2.1.1.1.1 25-1.2.1.1.1.2 25-1.2.1.1.2 26-1.2.1.1.1.1.1.r 28-1.2.1.1.1.1.1.1.1 29-1.2.1.1.1.2.1.1.1 30-1.2.1.1.1.2.1.2 32-1.2.1.1 35-1.2.1.1.2.1.r 37-1.2.1.1.2.1.1.1 38-1.2.1.1.2.1.2 39-1.2 40-1.2.2.r 42-1.2.2.1 44-1.1.3.1.1.1.1.1 46-1.1.3.1.1.2.1.1 48-1.1.3.1.2.1.1.1 49-1.2.2.1.r 50-1.2.2 51-1.2.2.2.r 53-1.2.2.2.2 54-1.2.2.2 55-1.2.2.2.1.r 56-1.2.2.2.1 (c / contrast-01~e.19 :ARG1 (k / know-01~e.3 :polarity~e.2 -~e.2 :ARG0 (w / we~e.0) :ARG1 (t2 / thing :manner-of~e.6 (i / involve-01~e.11 :ARG1 (a / and~e.8 :op1 (p2 / protein :name (n / name :op1 "Bni1p"~e.7,44)) :op2 (p3 / protein :name (n2 / name :op1 "Bnr1p"~e.9,46))) :ARG2~e.12 (i2 / interact-01~e.17 :ARG0 (p4 / protein :name (n3 / name :op1 "profilin"~e.14,48)) :ARG1 (p5 / protein :name (n4 / name :op1 "actin"~e.16)) :mod (t / this~e.13)))) :time~e.4 (p / present~e.5)) :ARG2 (i3 / indicate-01~e.39 :ARG0 (r2 / result-01~e.22 :ARG2 (r / resemble-01~e.32 :ARG1 (a2 / and :op1 (p6 / phenotype~e.25 :mod~e.26 (p8 / protein :name (n5 / name :op1 "bni1"~e.28) :ARG2-of (m / mutate-01))) :op2 (p7 / phenotype~e.25 :mod (p9 / protein :name (n6 / name :op1 "bnr1"~e.29) :ARG2-of m~e.30))) :ARG2 (p10 / phenotype~e.25 :mod~e.35 (p11 / protein :name (n7 / name :op1 "pfy1"~e.37) :ARG2-of m~e.38))) :mod (g / genetic~e.21)) :ARG1~e.40 (i4 / important~e.50 :domain~e.49 (i5 / interact-01~e.42 :ARG0 (a3 / and :op1 p2 :op2 p3) :ARG1 p4) :purpose~e.51 (f / function-01~e.54 :ARG0~e.55 p4~e.56 :mod (p12 / proper~e.53))))) # ::id bio.chicago_2015.26193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , CBP/ p300 directly acetylates transcription factors such as GATA @-@ 1 ( 6 ) and p53 ( 21 ) . # ::alignments 0-1 3-1.1.1.2.1.1 4-1.1.3 5-1.1 6-1.1.2.1 7-1.1.2 8-1.1.2.2.r 9-1.1.2.2.r 10-1.1.2.2.1.1.1 12-1.1.2.2.1.1.1 14-1.1.2.2.1.2.1.1.1 16-1.1.2.2 17-1.1.2.2.2.1.1 19-1.1.2.2.2.2.1.1.1 (a / and~e.0 :op2 (a2 / acetylate-01~e.5 :ARG0 (s / slash :op1 (p / protein :name (n / name :op1 "CBP")) :op2 (p2 / protein :name (n2 / name :op1 "p300"~e.3))) :ARG1 (f / factor~e.7 :ARG0-of (t / transcribe-01~e.6) :example~e.8,9 (a3 / and~e.16 :op1 (p3 / protein :name (n3 / name :op1 "GATA-1"~e.10,12) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 6~e.14)))) :op2 (p4 / protein :name (n4 / name :op1 "p53"~e.17) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 21~e.19)))))) :ARG1-of (d / direct-02~e.4))) # ::id bio.chicago_2015.26198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To identify a direct target molecule of Ras , we have established a cell @-@ free assay system using Xenopus oocyte extract in which Ras activates ERK through MEK ( 39 ) . # ::alignments 1-1.4 3-1.4.2.2 4-1.4.2.1 5-1.4.2 7-1.3.1.2.1.1.1 9-1.1 11-1 13-1.2.1.1.1 15-1.2.1.1 16-1.2.1 17-1.2 18-1.4.r 19-1.3.1.1.1 20-1.3.1.1.2 21-1.3 24-1.3.1.2.1.1.1 25-1.3.1.2 26-1.3.1.2.2.1.1 27-1.3.1.2.3.r 28-1.3.1.2.3.1.1 30-1.5.1.1.1 (e / establish-01~e.11 :ARG0 (w2 / we~e.9) :ARG1 (s / system~e.17 :mod (a / assay-01~e.16 :ARG1-of (f / free-04~e.15 :ARG2 (c / cell~e.13)))) :instrument (e2 / extract-01~e.21 :ARG1 (c2 / cell :name (n3 / name :op1 "Xenopus"~e.19 :op2 "oocyte"~e.20) :location-of (a2 / activate-01~e.25 :ARG0 (e3 / enzyme :name (n / name :op1 "Ras"~e.7,24)) :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK"~e.26)) :path~e.27 (e5 / enzyme :name (n4 / name :op1 "MEK"~e.28))))) :purpose~e.18 (i / identify-01~e.1 :ARG0 w2 :ARG1 (m / molecule~e.5 :ARG1-of (t / target-01~e.4 :ARG0 e3) :ARG1-of (d / direct-02~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 39~e.30)))) # ::id bio.chicago_2015.26222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Chain Valence Mutants of Glypican @-@ 1 in FGF2 @-@ induced FGFR1 Phosphorylation-- All syndecans and glypicans carry multiple HS chains , which are clustered in one small domain of the protein . # ::alignments 0-1.1.3 1-1.1.2 2-1.1 4-1.2.1.2.1.1 6-1.1.1.1.1 8-1.1.4.2.1.1.1 10-1.1.4.2 11-1.1.4.1.1.1 13-1.2.1.3 15-1.2.1 17-1.2 18-1.2.2.3 19-1.2.2.1.1.1 20-1.2.2 24-1.2.2.2 25-1.2.2.2.1.r 26-1.2.2.2.1.1 27-1.2.2.2.1.2 31-1.2.2.2.1 31-1.2.2.2.1.3 31-1.2.2.2.1.3.r (m / multi-sentence :snt1 (m2 / mutate-01~e.2 :ARG2 (p / protein :name (n / name :op1 "Glypican-1"~e.6)) :mod (v / valence~e.1) :mod (c / chain~e.0) :location (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "FGFR1"~e.11)) :ARG2-of (i / induce-01~e.10 :ARG0 (e2 / enzyme :name (n3 / name :op1 "FGF2"~e.8))))) :snt2 (c2 / carry-01~e.17 :ARG0 (a / and~e.15 :op1 (p3 / protein :name (n4 / name :op1 "syndecan")) :op2 (p4 / protein :name (n5 / name :op1 "glypican"~e.4)) :mod (a2 / all~e.13)) :ARG1 (c3 / chain~e.20 :mod (s2 / small-molecule :name (n6 / name :op1 "HS"~e.19)) :ARG1-of (c4 / cluster-01~e.24 :ARG2~e.25 (p5 / protein-segment~e.31 :quant 1~e.26 :mod (s / small~e.27) :part-of~e.31 (p6 / protein~e.31))) :quant (m4 / multiple~e.18)))) # ::id bio.chicago_2015.26233 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For the case of PKC activation by PMA , we also tested the possibility of an increased Ca2+ sensitivity of the vesicle supply process without a change of the maximal activity . # ::alignments 2-1.4 3-1.4.1.r 4-1.4.1.2.1.1 5-1.4.1 6-1.4.1.1.r 7-1.4.1.1.1.1 9-1.1 10-1.3 11-1 13-1.2 14-1.2.1.r 16-1.2.1 18-1.2.1.1 19-1.2.1.1.1.r 21-1.2.1.1.1.1.1 22-1.2.1.1.1.1 23-1.2.1.1.1 24-1.2.1.2.1 24-1.2.1.2.1.r 26-1.2.1.2 27-1.2.1.2.2.r 29-1.2.1.2.2.1 30-1.2.1.2.2 (t / test-01~e.11 :ARG0 (w / we~e.9) :ARG1 (p / possible-01~e.13 :ARG1~e.14 (i / increase-01~e.16 :ARG1 (s / sensitive-03~e.18 :ARG0~e.19 (p2 / process-02~e.23 :ARG1 (s2 / supply-01~e.22 :ARG1 (v / vesicle~e.21))) :ARG1 (c3 / calcium :ARG1-of (i2 / ionize-01 :value "2+"))) :manner (c / change-01~e.26 :polarity~e.24 -~e.24 :ARG1~e.27 (a2 / activity-06~e.30 :mod (m2 / maximal~e.29))))) :mod (a / also~e.10) :purpose (c2 / case-04~e.2 :ARG1~e.3 (a3 / activate-01~e.5 :ARG0~e.6 (s3 / small-molecule :name (n3 / name :op1 "PMA"~e.7)) :ARG1 (e / enzyme :name (n2 / name :op1 "PKC"~e.4))))) # ::id bio.chicago_2015.26279 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using co @-@ immunoprecipitation approaches , we showed that dSlo binds only to free PKAc but not to the PKA holoenzyme , and that both PKA regulatory subunit and PKI inhibit the association between dSlo and PKAc . # ::alignments 0-1.3 4-1.3.2 6-1.1 7-1 8-1.2.r 9-1.2.1.1.1.1.1 10-1.2.1.1 10-1.2.1.2 11-1.2.1.1.3 12-1.2.1.1.2.r 13-1.2.1.1.2 13-1.2.1.1.2.2 13-1.2.1.1.2.2.r 14-1.2.1.1.2.1.1 15-1.2.1 16-1.2.1.2.1 16-1.2.1.2.1.r 17-1.2.1.2.3.r 19-1.2.1.2.3.1.1 20-1.2.1.2.3.2 25-1.2.1.2.3.1.1 26-1.2.2.1.1.1 27-1.2.2.1.1 28-1.2.2.1 29-1.2.2.1.2.1.1 30-1.2.2 32-1.2.2.2 34-1.2.2.2.1 36-1.2.1.1.2.1.1 (s / show-01~e.7 :ARG0 (w / we~e.6) :ARG1~e.8 (a / and :op1 (c / contrast-01~e.15 :ARG1 (b / bind-01~e.10 :ARG1 (p / protein :name (n / name :op1 "dSlo"~e.9)) :ARG2~e.12 (e / enzyme~e.13 :name (n2 / name :op1 "PKAc"~e.14,36) :ARG1-of~e.13 (f / free-04~e.13)) :mod (o / only~e.11)) :ARG2 (b2 / bind-01~e.10 :polarity~e.16 -~e.16 :ARG1 p :ARG2~e.17 (e2 / enzyme :name (n3 / name :op1 "PKA"~e.19,25) :mod (h / holoenzyme~e.20)))) :op2 (i / inhibit-01~e.30 :ARG0 (a2 / and~e.28 :op1 (s2 / subunit~e.27 :ARG0-of (r / regulate-01~e.26) :mod e2) :op2 (e3 / enzyme :name (n4 / name :op1 "PKI"~e.29))) :ARG1 (a3 / associate-01~e.32 :ARG1 p~e.34 :ARG2 (e4 / enzyme :name n2)))) :manner (u / use-01~e.0 :ARG0 w :ARG1 (a4 / approach-02~e.4 :mod (c2 / coimmunoprecipitate-01)))) # ::id bio.chicago_2015.26283 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , RBP interaction with TFIID and TFIIA alters optimal interaction between these two coactivators , not to dislodge them from the promoter , but instead to subvert activated transcription . # ::alignments 0-1 2-1.1.1.1.1.1 3-1.1.1 5-1.1.1.2.1.1.1 6-1.1.1.2 7-1.1.1.2.2.1.1 8-1.1 9-1.1.2.3 10-1.1.1 10-1.1.2 16-1.1.3.2.1 16-1.1.3.2.1.r 18-1.1.3.2 25-1.1.3 27-1.1.3.1 28-1.1.3.1.2.1 29-1.1.3.1.2 (c / cause-01~e.0 :ARG1 (a / alter-01~e.8 :ARG0 (i / interact-01~e.3,10 :ARG0 (p / protein-family :name (n / name :op1 "RBP"~e.2)) :ARG1 (a4 / and~e.6 :op1 (p2 / protein :name (n2 / name :op1 "TFIID"~e.5)) :op2 (p3 / protein :name (n3 / name :op1 "TFIIA"~e.7)) :ARG0-of (c2 / coactivate-01))) :ARG1 (i2 / interact-01~e.10 :ARG0 p2 :ARG1 p3 :mod (o / optimal~e.9)) :purpose (i3 / instead-of-91~e.25 :ARG1 (s / subvert-01~e.27 :ARG0 i :ARG1 (t2 / transcribe-01~e.29 :ARG1-of (a3 / activate-01~e.28))) :ARG2 (d / dislodge-01~e.18 :polarity~e.16 -~e.16 :ARG0 i :ARG1 a4 :ARG2 (t / thing :ARG1-of (p4 / promote-02)))))) # ::id bio.chicago_2015.26335 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Currently it is unclear whether within the centromere chromatin CENP @-@ A replaces all histone H3 subunits ( Choo , 2000 ; Lo et al. , 2001a ) . # ::alignments 0-1.3 3-1 3-1.1 3-1.1.r 4-1.2.1 4-1.2.1.r 7-1.2.4.1 8-1.2.4 9-1.2.2.1.1 11-1.2.2.1.1 12-1.2 13-1.2.3.2 14-1.2.3.1.1.1 15-1.2.3.1.1.2 16-1.2.3 18-1.4.1.1.1.1.1 20-1.4.1.1.2.1 22-1.4.1.2.1.1.1.1 23-1.4.1 23-1.4.1.2.1 24-1.4.1.2.1.2.1 (c / clear-06~e.3 :polarity~e.3 -~e.3 :ARG1 (r / replace-01~e.12 :mode~e.4 interrogative~e.4 :ARG0 (p / protein :name (n / name :op1 "CENP-A"~e.9,11)) :ARG1 (s / subunit~e.16 :part-of (p2 / protein :name (n2 / name :op1 "histone"~e.14 :op2 "H3"~e.15)) :mod (a / all~e.13)) :location (c2 / chromatin~e.8 :mod (c3 / centromere~e.7))) :time (c4 / current~e.0) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.23 :op1 (p3 / publication-91 :ARG0 (p4 / person :name (n3 / name :op1 "Choo"~e.18)) :time (d / date-entity :year 2000~e.20)) :op2 (p5 / publication-91 :ARG0 (a3 / and~e.23 :op1 (p6 / person :name (n4 / name :op1 "Lo"~e.22)) :op2 (p7 / person :mod (o / other~e.24))) :time (d2 / date-entity :year 2001))))) # ::id bio.chicago_2015.26340 ::amr-annotator SDL-AMR-09 ::preferred # ::tok d , in vitro reconstitution of SUMO @-@ 1 modification of the indicated HDAC1 mutants with (+) or without ( ) addition of the assay mix ( as in Fig. 1 b ) . # ::alignments 0-1.1 2-1.3 3-1.3 6-1.2.1.1.1 8-1.2.1.1.1 9-1.2 10-1.2.2.r 12-1.2.2.2 13-1.2.2.1.1.1 14-1.2.2 17-1.2.3 18-1.2.3.2.1 18-1.2.3.2.1.r 21-1.2.3.1 21-1.2.3.2 22-1.2.3.1.1.r 24-1.2.3.1.1.1 25-1.2.3.1.1 28-1.3 29-1.4.1 30-1.2.1.1.1 (r / reconstitute-01 :li "d"~e.0 :ARG2 (m / modify-01~e.9 :ARG0 (p / protein :name (n / name :op1 "SUMO-1"~e.6,8,30)) :ARG1~e.10 (m2 / mutate-01~e.14 :ARG2 (e / enzyme :name (n2 / name :op1 "HDAC1"~e.13)) :ARG1-of (i2 / indicate-01~e.12)) :manner (o2 / or~e.17 :op1 (a / add-02~e.21 :ARG1~e.22 (m3 / mix-01~e.25 :ARG1 (a2 / assay-01~e.24)) :mod (p2 / positive)) :op2 (a3 / add-02~e.21 :polarity~e.18 -~e.18 :ARG1 m3 :ARG2-of (n3 / negative-01)))) :manner (i / in-vitro~e.2,3,28) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "1b"))) # ::id bio.chicago_2015.26346 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore examined whether GSK @-@ 3 beta , PKA , and PP1 bind simultaneously to AKAP220 . # ::alignments 0-1.1.1 1-1 2-1.1 3-1.1.2.1 3-1.1.2.1.r 4-1.1.2.2.1.1.1 9-1.1.2.2.2.1.1 11-1.1.2.2 12-1.1.2.2.3.1.1 13-1.1.2 14-1.1.2.4 14-1.1.2.4.r 15-1.1.2.3.r 16-1.1.2.3.1.1 (c / cause-01~e.1 :ARG1 (e / examine-01~e.2 :ARG0 (w / we~e.0) :ARG1 (b / bind-01~e.13 :mode~e.3 interrogative~e.3 :ARG1 (a / and~e.11 :op1 (e2 / enzyme :name (n / name :op1 "GSK-3beta"~e.4)) :op2 (e3 / enzyme :name (n2 / name :op1 "PKA"~e.9)) :op3 (p / protein :name (n3 / name :op1 "PP1"~e.12))) :ARG2~e.15 (p2 / protein :name (n4 / name :op1 "AKAP220"~e.16)) :manner~e.14 (s / simultaneous~e.14)))) # ::id bio.chicago_2015.26365 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activin and TGFbeta also lead to the specific association of Smad2 and Smad4 as assessed by co @-@ immunoprecipitation from cultured cells following ligand binding ( 9 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1.3 4-1 5-1.2.r 7-1.2.3 8-1.2 9-1.2.1.r 10-1.2.1.1.1 12-1.2.2.1.1 13-1.4.r 14-1.4 20-1.4.1.1.1 21-1.4.1.1 22-1.4.2 23-1.4.2.1.1 24-1.4.2.1 26-1.5.1.1.1 (l / lead-03~e.4 :ARG0 (a / and~e.1 :op1 (p / protein :name (n / name :op1 "activin"~e.0)) :op2 (p2 / protein :name (n2 / name :op1 "TGFbeta"~e.2))) :ARG1~e.5 (a3 / associate-01~e.8 :ARG1~e.9 (p3 / protein :name (n3 / name :op1 "Smad2"~e.10)) :ARG2 (p4 / protein :name (n4 / name :op1 "Smad4"~e.12)) :ARG1-of (s / specific-02~e.7)) :mod (a2 / also~e.3) :ARG1-of~e.13 (a4 / assess-01~e.14 :ARG0 (c / coimmunoprecipitate-01 :ARG4 (c2 / cell~e.21 :ARG1-of (c3 / culture-01~e.20))) :ARG1-of (f / follow-01~e.22 :ARG2 (b / bind-01~e.24 :ARG1 (l2 / ligand~e.23)))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 9~e.26)))) # ::id bio.chicago_2015.26400 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PTB is known to bind to the CU elements within the 3 splice site upstream of N1 ( Chan and Black 1995 ) . # ::alignments 0-1.1.1.1.1 2-1 4-1.1 5-1.1.2.r 7-1.1.2.1.1.1 8-1.1.2 9-1.1.3.1.1.r 11-1.1.3.1.1 12-1.1.3.1.2 13-1.1.3 14-1.1.3.2.2 16-1.1.3.2.1.1.1 18-1.2.1.1.1.1.1 19-1.2.1.1 20-1.2.1.1.2.1.1 21-1.2.1.2.1 (k / know-01~e.2 :ARG1 (b / bind-01~e.4 :ARG1 (p / protein :name (n / name :op1 "PTB"~e.0)) :ARG2~e.5 (e / element~e.8 :mod (p2 / protein-family :name (n2 / name :op1 "CU"~e.7))) :location (s / site~e.13 :mod (d2 / distance-quantity :quant~e.9 3~e.11 :unit (s2 / splice~e.12)) :location (r / relative-position :op1 (e2 / enzyme :name (n3 / name :op1 "N1"~e.16)) :direction (u / upstream~e.14)))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and~e.19 :op1 (p4 / person :name (n4 / name :op1 "Chan"~e.18)) :op2 (p5 / person :name (n5 / name :op1 "Black"~e.20))) :time (d / date-entity :year 1995~e.21)))) # ::id bio.chicago_2015.26414 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , PKA @-@ induced PKB translocation is abolished after pretreatment of the cells with high concentrations ( 300 nM ) of wortmannin , implying that translocation to the cell surface may require the generation of phospholipids . # ::alignments 0-1 2-1.1.1.2.1.1.1 4-1.1.1.2 5-1.1.1.1.1.1 6-1.1.1 8-1.1 9-1.1.2 10-1.1.2.1 11-1.1.2.1.1.r 13-1.1.2.1.1 14-1.1.2.1.2.r 15-1.1.2.1.2.3 16-1.1.2.1.2 16-1.1.2.1.2.2 16-1.1.2.1.2.2.r 18-1.1.2.1.2.2.1 19-1.1.2.1.2.2.2 21-1.1.2.1.2.1.r 22-1.1.2.1.2.1.1.1 24-1.1.3 25-1.1.3.1.r 26-1.1.3.1.1.1 27-1.1.3.1.1.1.1.r 29-1.1.3.1.1.1.1.1 30-1.1.3.1.1.1.1 31-1.1.3.1 32-1.1.3.1.1 34-1.1.3.1.1.2 (h / have-concession-91~e.0 :ARG1 (a / abolish-01~e.8 :ARG1 (t / translocate-01~e.6 :ARG1 (e / enzyme :name (n / name :op1 "PKB"~e.5)) :ARG2-of (i / induce-01~e.4 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA"~e.2)))) :time (a2 / after~e.9 :op1 (p / pretreat-01~e.10 :ARG1~e.11 (c / cell~e.13) :ARG3~e.14 (c2 / concentrate-02~e.16 :ARG1~e.21 (s / small-molecule :name (n3 / name :op1 "wortmannin"~e.22)) :quant~e.16 (c3 / concentration-quantity~e.16 :quant 300~e.18 :unit (n4 / nanomolar~e.19)) :ARG1-of (h2 / high-02~e.15)))) :ARG0-of (i2 / imply-01~e.24 :ARG1~e.25 (p2 / possible-01~e.31 :ARG1 (r / require-01~e.32 :ARG0 (t2 / translocate-01~e.26 :ARG2~e.27 (s2 / surface~e.30 :mod (c4 / cell~e.29))) :ARG1 (g / generate-01~e.34 :ARG1 (p3 / phospholipid))))))) # ::id bio.chicago_2015.26430 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have thus examined whether actin binding of fascin can be regulated in a calcium @-@ dependent way by controlling actin binding of caldesmon with Ca2+/calmodulin . # ::alignments 0-1.1.1 2-1 3-1.1 4-1.1.2.1.1 4-1.1.2.1.1.r 5-1.1.2.1.3.1.1.1 6-1.1.2.1.3 7-1.1.2.1.3.2.r 8-1.1.2.1.3.2.1.1 9-1.1.2 11-1.1.2.1 14-1.1.2.1.2.1.3.1 14-1.1.2.1.4.1.1 16-1.1.2.1.4.1 17-1.1.2.1.4 17-1.1.2.1.4.r 18-1.1.2.1.2.r 19-1.1.2.1.2 20-1.1.2.1.2.1.1 21-1.1.2.1.2.1 22-1.1.2.1.2.1.2.r 23-1.1.2.1.2.1.2.1.1 (c / cause-01~e.2 :ARG1 (e / examine-01~e.3 :ARG0 (w2 / we~e.0) :ARG1 (p / possible-01~e.9 :ARG1 (r / regulate-01~e.11 :mode~e.4 interrogative~e.4 :ARG0~e.18 (c3 / control-01~e.19 :ARG1 (b2 / bind-01~e.21 :ARG1 p2~e.20 :ARG2~e.22 (p4 / protein :name (n3 / name :op1 "caldesmon"~e.23)) :ARG3 (s / slash :op1 (c4 / calcium~e.14 :ARG1-of (i / ionize-01 :value "2+")) :op2 (p5 / protein :name (n4 / name :op1 "calmodulin"))))) :ARG1 (b / bind-01~e.6 :ARG1 (p2 / protein :name (n / name :op1 "actin"~e.5)) :ARG2~e.7 (p3 / protein :name (n2 / name :op1 "fascin"~e.8))) :manner~e.17 (w3 / way~e.17 :ARG0-of (d / depend-01~e.16 :ARG1 (c2 / calcium~e.14))))))) # ::id bio.chicago_2015.26440 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Affinity chromatography demonstrates a direct binding between cytoplasmic dynein and the dynactin complex . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.3 5-1.2 7-1.2.1.2 8-1.2.1.1.1 11-1.2.2.1.1.1 12-1.2.2 (d / demonstrate-01~e.2 :ARG0 (c / chromatography~e.1 :mod (a / affinity~e.0)) :ARG1 (b / bind-01~e.5 :ARG1 (p / protein :name (n / name :op1 "dynein"~e.8) :mod (c2 / cytoplasmic~e.7)) :ARG2 (c3 / complex~e.12 :mod (p2 / protein :name (n2 / name :op1 "dynactin"~e.11))) :ARG1-of (d2 / direct-02~e.4))) # ::id bio.chicago_2015.26449 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In mink lung epithelial ( Mv1Lu ) cells , TNF @-@ alpha @-@ induced JNK activation and apoptosis were dependent on another upstream kinase , ASK1 , which displayed sequence similarities to upstream kinases in the S. cerevisiae HOG pathway ( 230 ) . # ::alignments 1-1.5.3 2-1.5.2 3-1.5.1 7-1.5 9-1.1.1.2.1.1.1 11-1.1.1.2.1.1.1 13-1.1.1.2 14-1.1.1.1.1.1 15-1.1.1 16-1.1 17-1.1.2 19-1 20-1.2.r 21-1.2.2.1 22-1.2.2.2 23-1.2.2 25-1.2.1.1 28-1.3 29-1.3.1.1 30-1.3.1 31-1.3.1.2.r 32-1.3.1.2.1 33-1.3.1.2 34-1.3.2.r 36-1.3.2.1.1 37-1.3.2.1.2 38-1.3.2.1.3 39-1.3.2 41-1.4.1.1.1 (d / depend-01~e.19 :ARG0 (a / and~e.16 :op1 (a2 / activate-01~e.15 :ARG1 (e / enzyme :name (n / name :op1 "JNK"~e.14)) :ARG2-of (i / induce-01~e.13 :ARG0 (p / protein :name (n2 / name :op1 "TNF-alpha-"~e.9,11)))) :op2 (a3 / apoptosis~e.17)) :ARG1~e.20 (e2 / enzyme :name (n3 / name :op1 "ASK1"~e.25) :mod (k / kinase~e.23 :mod (a4 / another~e.21) :direction (u / upstream~e.22))) :ARG0-of (d2 / display-01~e.28 :ARG1 (r / resemble-01~e.30 :ARG1 (s / sequence~e.29) :ARG2~e.31 (k2 / kinase~e.33 :direction u~e.32)) :ARG2~e.34 (p2 / pathway~e.39 :name (n4 / name :op1 "S."~e.36 :op2 "cerevisiae"~e.37 :op3 "HOG"~e.38))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 230~e.41))) :location (c2 / cell~e.7 :mod (e3 / epithelium~e.3) :mod (l / lung~e.2) :mod (m / mink~e.1))) # ::id bio.chicago_2015.26503 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the kinetics of their activation were different , i.e. Cr( VI ) activated p38 faster than JNK ( Figure 3 ) . # ::alignments 0-1 5-1.1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1 6-1.1.2 8-1.1 14-1.1.2 14-1.1.2.4 15-1.1.2.2.1.1 16-1.1.2.3 16-1.1.2.3.1 16-1.1.2.3.1.r 17-1.1.2.4.r 18-1.1.2.4.2.1.1 20-1.2.1 21-1.2.1.1 (h / have-concession-91~e.0 :ARG1 (d / differ-02~e.8 :ARG1 (k / kinetic :topic (a / activate-01~e.6 :ARG1~e.5 (t / they~e.5))) :ARG3 (a2 / activate-01~e.6,14 :ARG0 (s / small-molecule :name (n / name :op1 "Cr(VI)")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "p38"~e.15)) :ARG1-of (f / fast-02~e.16 :degree~e.16 (m / more~e.16)) :compared-to~e.17 (a3 / activate-01~e.14 :ARG0 s :ARG1 (e / enzyme :name (n3 / name :op1 "JNK"~e.18))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.20 :mod 3~e.21))) # ::id bio.chicago_2015.26513 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together with the finding that mutation of CREB Ser133 to alanine blocks PKA stimulation of CREB @-@ dependent transcription , it demonstrates that PKA phosphorylation is required for CREB activity . # ::alignments 0-1.1.2 1-1.1.2.1 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.2.2.1.1.1 10-1.1.1.1.1.2.r 11-1.1.1.1.1.2.1.1 12-1.1.1 13-1.2.1.1.1.1 14-1.1.1.2 15-1.1.1.2.2.r 16-1.1.1.2.2.1.1 18-1.1.1.2.2.1 19-1.1.1.2.2 21-1.1.1.2.1 22-1 24-1.2.1.1.1.1 25-1.2.1 27-1.2 29-1.2.2.1.1.1 30-1.2.2 (d / demonstrate-01~e.22 :ARG0 (f / find-01~e.4 :ARG1~e.5 (b / block-01~e.12 :ARG0 (a4 / and :op1 (m / mutate-01~e.6 :ARG1 (a / amino-acid :mod 133 :name (n4 / name :op1 "serine") :part-of p2) :ARG2~e.10 (a5 / amino-acid :name (n5 / name :op1 "alanine"~e.11)))) :ARG1 (s / stimulate-01~e.14 :ARG0 e~e.21 :ARG1~e.15 (t2 / transcribe-01~e.19 :ARG0-of (d2 / depend-01~e.18 :ARG1 p2~e.16)))) :ARG1-of (t / take-01~e.0 :manner (t3 / together~e.1))) :ARG1 (r / require-01~e.27 :ARG1 (p / phosphorylate-01~e.25 :ARG1 (e / enzyme :name (n2 / name :op1 "PKA"~e.13,24))) :purpose (a2 / activity-06~e.30 :ARG0 (p2 / protein :name (n3 / name :op1 "CREB"~e.8,29))))) # ::id bio.chicago_2015.26539 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of JNK , p38 and ERK by Cr( VI ) CL3 cells were treated with 10 - 80 muM Cr( VI ) in serum @-@ free medium for 3 h and a whole cell extract prepared to examine activation of JNK , p38 and ERK . # ::alignments 0-1.1.1 2-1.1.1.2.1.1.1 4-1.1.1.2.2.1.1 5-1.1.1.2 6-1.1.1.2.3.1.1 11-1.1.1.1.1.1 12-1.1.1.1 14-1.1 15-1.1.2.r 16-1.1.2.2.1.1 18-1.1.2.2.1.2 23-1.1.3.r 24-1.1.3.1.1 26-1.1.3.1 27-1.1.3 28-1.1.4.r 29-1.1.4.1 30-1.1.4.2 31-1 33-1.2.1.2 34-1.2.1.1 35-1.2.1 36-1.2 38-1.2.2 39-1.1.1 39-1.2.2.1 41-1.1.1.2.1.1.1 43-1.1.1.2.2.1.1 44-1.1.1.2 45-1.1.1.2.3.1.1 (a / and~e.31 :op1 (t / treat-04~e.14 :ARG1 (a2 / activate-01~e.0,39 :ARG0 (c / cell-line~e.12 :name (n5 / name :op1 "CL3"~e.11) :mod (s / small-molecule :name (n6 / name :op1 "Cr(VI)"))) :ARG1 (a3 / and~e.5,44 :op1 (e / enzyme :name (n2 / name :op1 "JNK"~e.2,41)) :op2 (e5 / enzyme :name (n3 / name :op1 "p38"~e.4,43)) :op3 (e2 / enzyme :name (n4 / name :op1 "ERK"~e.6,45)))) :ARG2~e.15 (s2 / small-molecule :name n6 :quant (c2 / concentration-quantity :quant (v / value-interval :op1 10~e.16 :op2 80~e.18) :unit (m / millimolar))) :location~e.23 (m2 / medium~e.27 :ARG1-of (f / free-04~e.26 :ARG2 (s3 / serum~e.24))) :duration~e.28 (t2 / temporal-quantity :quant 3~e.29 :unit (h / hour~e.30))) :op2 (p3 / prepare-02~e.36 :ARG1 (e3 / extract-01~e.35 :ARG1 (c3 / cell~e.34) :mod (w / whole~e.33)) :ARG2 (e4 / examine-01~e.38 :ARG1 (a4 / activate-01~e.39 :ARG1 a3)))) # ::id bio.chicago_2015.26566 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nor is it known whether the amyloid @-@ induced tau hyperphosphorylation and NFT formation observed recently in mutant tau transgenic mice ( Gotz et al. , 2001 ; Lewis et al. , 2001 ) occurs via tau phosphorylation by GSK @-@ 3 or an alternate pathway . # ::alignments 0-1.1 0-1.1.r 3-1 6-1.2.1.2.1.1.1 8-1.2.1.2 9-1.2.1.1.1.1 10-1.2.1 11-1.2 11-1.2.5.1 11-1.2.5.1.1.1 12-1.2.2.1.1.1 13-1.2.2 14-1.2.3 15-1.2.3.1 16-1.2.3.2.r 17-1.2.3.2.2 17-1.2.3.2.2.2 17-1.2.3.2.2.2.r 18-1.2.3.2.2.1 19-1.2.3.2.1 20-1.2.3.2 22-1.2.5.1.1.1.1.1.1 23-1.2.5.1.1.1 24-1.2.5.1.1.1.2.1 26-1.2.5.1.2.2 28-1.2.5.1.2.1.1.1.1 29-1.2.5.1 29-1.2.5.1.1.1 29-1.2.5.1.2.1 30-1.2.5.1.1.1.2.1 32-1.2.5.1.1.2.1 36-1.2.4.1.1 37-1.2.4.1 38-1.2.4.1.2.r 39-1.2.4.1.2.1.1 41-1.2.4.1.2.1.1 42-1.2.4 44-1.2.4.2.1 45-1.2.4.2 (k / know-01~e.3 :polarity~e.0 -~e.0 :ARG1 (a / and~e.11 :op1 (h / hyperphosphorylate-01~e.10 :ARG1 (p2 / protein :name (n / name :op1 "tau"~e.9)) :ARG2-of (i / induce-01~e.8 :ARG0 (s / small-molecule :name (n2 / name :op1 "amyloid"~e.6)))) :op2 (f / form-01~e.13 :ARG1 (p10 / protein :name (n3 / name :op1 "NFT"~e.12))) :ARG1-of (o / observe-01~e.14 :time (r / recent~e.15) :location~e.16 (m3 / mouse~e.20 :mod (t / transgenic~e.19) :mod (p3 / protein~e.17 :name n~e.18 :ARG2-of~e.17 (m4 / mutate-01~e.17)))) :manner (o2 / or~e.42 :op1 (p / phosphorylate-01~e.37 :ARG1 p2~e.36 :ARG2~e.38 (e / enzyme :name (n5 / name :op1 "GSK-3"~e.39,41))) :op2 (p4 / pathway~e.45 :ARG1-of (a2 / alternate-01~e.44))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.11,29 :op1 (p5 / publication-91 :ARG0 (a4 / and~e.11,23,29 :op1 (p6 / person :name (n6 / name :op1 "Gotz"~e.22)) :op2 (p7 / person :mod (o3 / other~e.24,30))) :time (d / date-entity :year 2001~e.32)) :op2 (p8 / publication-91 :ARG0 (a5 / and~e.29 :op1 (p9 / person :name (n7 / name :op1 "Lewis"~e.28)) :op2 p7) :time d~e.26))))) # ::id bio.chicago_2015.34132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Without Ca2+, Rho @-@ kinase but not MLCK can phosphorylate MLC , and this phosphorylation was completely inhibited by 10 mug @/@ ml HA1077 ( lane 3 ) . # ::alignments 0-1.1.1.3.1 0-1.1.1.3.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1 6-1.1.1.3.1 6-1.1.1.3.1.r 6-1.1.2.1 6-1.1.2.1.r 7-1.1.2.2.1.1 8-1 9-1.1.2 10-1.1.1.2.1.1 14-1.1.1 16-1.1.1.4.2 17-1.1.1.4 18-1.1.1.4.1.r 19-1.1.1.4.1.2.1 22-1.1.1.4.1.2.2 23-1.1.1.4.1.1.1 25-1.2.1 26-1.2.1.1 (p2 / possible-01~e.8 :ARG1 (c / contrast-01~e.5 :ARG1 (p / phosphorylate-01~e.14 :ARG0 (e / enzyme :name (n / name :op1 "Rho-kinase"~e.2,4)) :ARG1 (p3 / protein :name (n2 / name :op1 "MLC"~e.10)) :manner (c4 / calcium :polarity~e.0,6 -~e.0,6 :ARG1-of (i2 / ionize-01 :value "2+")) :ARG1-of (i / inhibit-01~e.17 :ARG0~e.18 (s / small-molecule :name (n5 / name :op1 "HA1077"~e.23) :quant (c3 / concentration-quantity :quant 10~e.19 :unit (m / microgram-per-milliliter~e.22))) :ARG1-of (c2 / complete-02~e.16))) :ARG2 (p4 / phosphorylate-01~e.9 :polarity~e.6 -~e.6 :ARG0 (e2 / enzyme :name (n3 / name :op1 "MLCK"~e.7)) :ARG1 p3)) :ARG1-of (d / describe-01 :ARG0 (l / lane~e.25 :mod 3~e.26))) # ::id bio.chicago_2015.34134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The fact that Rb preferentially associates with specific E2F target promoters during senescence suggests that it may play a particularly important role in SAHF formation and the silencing of E2F target promoters . # ::alignments 1-1.1 3-1.1.1.1.1.1 4-1.1.1.3 5-1.1.1 5-1.2.1.2.2.1.1.2 6-1.1.1.2.r 7-1.1.1.2.2 8-1.1.1.2.1.1.1.1.1 9-1.1.1.2.1.1 10-1.1.1.2 10-1.1.1.2.1 10-1.1.1.2.1.r 11-1.1.1.4.r 12-1.1.1.4 12-1.2.1.2.2.1.1.2.1 13-1 16-1.2 17-1.2.1 19-1.2.1.2.1.1 20-1.2.1.2.1 21-1.2.1.2 24-1.2.1.2.2.1 25-1.2.1.2.2 27-1.2.1.2.2.2 28-1.2.1.2.2.2.1.r 29-1.2.1.2.2.2.1 30-1.2.1.2.2.2.1 31-1.2.1.2.2.2.1 (s / suggest-01~e.13 :ARG0 (f / fact~e.1 :domain (a / associate-01~e.5 :ARG1 (p / protein :name (n / name :op1 "Rb"~e.3)) :ARG2~e.6 (m2 / molecular-physical-entity~e.10 :ARG0-of~e.10 (p3 / promote-01~e.10 :ARG1 (t2 / target-01~e.9 :ARG1 (p7 / protein :name (n2 / name :op1 "E2F"~e.8)))) :ARG1-of (s4 / specific-02~e.7)) :ARG1-of (p2 / prefer-01~e.4) :time~e.11 (s2 / senescence~e.12))) :ARG1 (p4 / possible-01~e.16 :ARG1 (p5 / play-01~e.17 :ARG0 f :ARG1 (r / role~e.21 :mod (i / important~e.20 :mod (p6 / particular~e.19)) :topic (a2 / and~e.25 :op1 (f2 / form-01~e.24 :ARG1 (f3 / focus :mod (h / heterochromatin) :ARG1-of (a3 / associate-01~e.5 :ARG2 (s5 / senescence~e.12)))) :op2 (s3 / silence-01~e.27 :ARG1~e.28 m2~e.29,30,31)))))) # ::id bio.chicago_2015.34138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We report that arsenite induces rapid phosphorylation and acetylation of histone H3 , events that precede the induction of both c @- fos and c @- jun in normal human diploid fibroblasts . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1 4-1.2 5-1.2.2.1.2 6-1.2.2.1 7-1.2.2 8-1.2.2.2 9-1.2.2.1.1.r 10-1.2.2.1.1.1.1 11-1.2.2.1.1.1.2 15-1.2.2.3 17-1.2.2.3.1 20-1.2.2.3.1.1.1.1.1 20-1.2.2.3.1.1.2.1.1 22-1.2.2.3.1.1.1.1.1 23-1.2.2.3.1.1 24-1.2.2.3.1.1.1.1.1 24-1.2.2.3.1.1.2.1.1 26-1.2.2.3.1.1.2.1.1 27-1.2.2.3.1.2.r 28-1.2.2.3.1.2.2 30-1.2.2.3.1.2.1 31-1.2.2.3.1.2 (r / report-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (i / induce-01~e.4 :ARG0 (s / small-molecule :name (n / name :op1 "arsenite"~e.3)) :ARG2 (a / and~e.7 :op1 (p / phosphorylate-01~e.6 :ARG1~e.9 (p2 / protein :name (n2 / name :op1 "histone"~e.10 :op2 "H3"~e.11)) :mod (r2 / rapid~e.5)) :op2 (a2 / acetylate-01~e.8 :ARG1 p2) :ARG1-of (p3 / precede-01~e.15 :ARG2 (i2 / induce-01~e.17 :ARG1 (a3 / and~e.23 :op1 (p5 / protein :name (n3 / name :op1 "c-fos"~e.20,22,24)) :op2 (p4 / protein :name (n4 / name :op1 "c-jun"~e.20,24,26))) :location~e.27 (f / fibroblast~e.31 :mod (d2 / diploid~e.30) :ARG1-of (n5 / normal-02~e.28))))))) # ::id bio.chicago_2015.34199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF stimulated the phosphorylation of Ser369 and Ser386 in the linker of RSK2 , apparently via activation of ERK and the CTK , respectively , and both sites contributed to the activation of RSK2 by EGF , as evidenced by mutational analysis . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 1-1.1.2 3-1.1.1.2 3-1.1.2.2 11-1.1.1.2.1.r 12-1.1.1.2.1.3.1.1.1 14-1.1.3 16-1.1.1.3 16-1.1.2.3 17-1.1.1.3.2.r 18-1.1.1.3.2.1.1 19-1.1 21-1.1.2.3.2.1.1 23-1.1.4 23-1.1.4.r 25-1.1 27-1.1.1.2.1.3 28-1.2 29-1.2.2.r 31-1.2.2 32-1.2.2.2.r 33-1.2.2.2 35-1.1.1.1.1.1 37-1.2.3.r 38-1.2.3 39-1.2.3.1.r 40-1.2.3.1.1 41-1.2.3.1 (a / and :op1 (a5 / and~e.19,25 :op1 (s / stimulate-01~e.1 :ARG0 (p2 / protein :name (n2 / name :op1 "EGF"~e.0,35)) :ARG1 (p3 / phosphorylate-01~e.3 :ARG1~e.11 (a3 / amino-acid :mod 369 :name (n3 / name :op1 "serine") :part-of (p / protein-segment~e.27 :part-of (e / enzyme :name (n5 / name :op1 "RSK2"~e.12)) :ARG0-of (l / link-01)))) :manner (a2 / activate-01~e.16 :ARG0 p2 :ARG1~e.17 (e2 / enzyme :name (n / name :op1 "ERK"~e.18)))) :op2 (s3 / stimulate-01~e.1 :ARG0 p2 :ARG1 (p4 / phosphorylate-01~e.3 :ARG1 (a4 / amino-acid :mod 386 :name (n4 / name :op1 "serine") :part-of p)) :manner (a6 / activate-01~e.16 :ARG0 p2 :ARG1 (e3 / enzyme :name (n6 / name :op1 "CTK"~e.21)))) :ARG1-of (a7 / appear-02~e.14) :manner~e.23 (r / respective~e.23)) :op2 (c / contribute-01~e.28 :ARG0 (a8 / and :op1 a3 :op2 a4) :ARG2~e.29 (a9 / activate-01~e.31 :ARG0 p2 :ARG1~e.32 e~e.33) :ARG1-of~e.37 (e4 / evidence-01~e.38 :ARG0~e.39 (a10 / analyze-01~e.41 :mod (m / mutate-01~e.40))))) # ::id bio.chicago_2015.34201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There appear to be multiple mechanisms through which p53 promotes apoptosis . # ::alignments 1-1 4-1.1.1 5-1.1 8-1.1.2.1.1.1 9-1.1.2 10-1.1.2.2 (a / appear-02~e.1 :ARG1 (m / mechanism~e.5 :quant (m2 / multiple~e.4) :manner-of (p / promote-02~e.9 :ARG0 (p2 / protein :name (n / name :op1 "p53"~e.8)) :ARG1 (a2 / apoptosis~e.10)))) # ::id bio.chicago_2015.34258 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , we found that paxillin alpha associates with both the kinase @-@ inactive and the Cdc42 @-@ activated forms of PAK3 in vivo ; and that the paxillin alpha binding to PAK3 could be competitive with the betaPIX binding to PAK3 in vivo and in vitro . # ::alignments 0-1 2-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1.1 6-1.1.2.1.1.1.2 7-1.1.2.1 11-1.1.2.1.2.1.2.2 13-1.1.2.1.2.1.2.1 14-1.1.2.1.2 16-1.1.2.1.2.2.2.1.1.1 18-1.1.2.1.2.1.2 18-1.1.2.1.2.2.2 21-1.1.2.2.1.1.2.1.1 22-1.1.2.1.3 23-1.1.2.1.3 28-1.1.2.1.1.1.1 29-1.1.2.1.1.1.2 30-1.1.2.2.1.1 32-1.1.2.2.1.1.2.1.1 33-1.1.2.2 35-1.1.2.2.1 38-1.1.2.2.1.2.1.1.1 39-1.1.2.2.1.1 39-1.1.2.2.1.2 41-1.1.2.1.2.1.1.1 41-1.1.2.1.2.2.1.1 42-1.1.2.1.3 43-1.1.2.1.3 44-1.1.2.2.2 45-1.1.2.2.2.2 46-1.1.2.2.2.2 (a / and~e.0 :op2 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (a2 / and :op1 (a3 / associate-01~e.7 :ARG1 (p2 / protein :name (n / name :op1 "paxillin"~e.5,28 :op2 "alpha"~e.6,29)) :ARG2 (a4 / and~e.14 :op1 (e / enzyme :name (n2 / name :op1 "PAK3"~e.41) :ARG1-of (a5 / activate-01~e.18 :polarity -~e.13 :mod (k / kinase~e.11))) :op2 (e2 / enzyme :name (n3 / name :op1 "PAK3"~e.41) :ARG1-of (a6 / activate-01~e.18 :ARG0 (p4 / protein :name (n4 / name :op1 "Cdc42"~e.16))))) :manner (i / in-vivo~e.22,23,42,43)) :op2 (p / possible-01~e.33 :ARG1 (c / compete-01~e.35 :ARG0 (b / bind-01~e.30,39 :ARG1 p2 :ARG2 (e4 / enzyme :name (n6 / name :op1 "PAK3"~e.21,32))) :ARG1 (b2 / bind-01~e.39 :ARG1 (p3 / protein :name (n5 / name :op1 "betaPIX"~e.38)) :ARG2 e4)) :manner (a7 / and~e.44 :op1 i :op2 (i2 / in-vitro~e.45,46)))))) # ::id bio.chicago_2015.34262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , our preliminary results indicate that when paxillin alpha was highly phosphorylated by PAK3 in vitro , these two phosphorylated proteins could no longer stay bound to each other . # ::alignments 0-1 2-1.1.1.2 2-1.1.1.2.r 3-1.1.1.3 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1.1 6-1.1.2.r 7-1.1.2.2.r 8-1.1.2.2.1.1.1 9-1.1.2.2.1.1.2 11-1.1.2.2.3 12-1.1.2.2 14-1.1.2.2.2.1.1 15-1.1.2.2.4 16-1.1.2.2.4 18-1.1.2.1.1.1.3 19-1.1.2.1.1.1.1 20-1.1.2.1.1.1.2 20-1.1.2.2 21-1.1.2.1.1.1 22-1.1.2 23-1.1.2.1.2 24-1.1.2.1.2 25-1.1.2.1 26-1.1.2.1.1 (c / contrast-01~e.0 :ARG2 (i / indicate-01~e.5 :ARG0 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :poss~e.2 (w / we~e.2) :mod (p2 / preliminary~e.3)) :ARG1~e.6 (p / possible-01~e.22 :ARG1 (s / stay-01~e.25 :ARG1 (b / bind-01~e.26 :ARG1 (p5 / protein~e.21 :quant 2~e.19 :ARG1-of (p6 / phosphorylate-01~e.20) :mod (t2 / this~e.18)) :ARG2 p5) :time (n / no-longer~e.23,24)) :time~e.7 (p3 / phosphorylate-01~e.12,20 :ARG1 (p4 / protein :name (n2 / name :op1 "paxillin"~e.8 :op2 "alpha"~e.9)) :ARG2 (e / enzyme :name (n3 / name :op1 "PAK3"~e.14)) :ARG1-of (h / high-02~e.11) :manner (i2 / in-vitro~e.15,16))))) # ::id bio.chicago_2015.34268 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While it is still unclear how Rac downregulates Rho and to what extent the influence of oncogenic Ras on the relative activities of Rac and Rho is common to epithelial cells other than MDCK cells , it is reasonable to assume that cross @-@ talk between Ras , Rac , and Rho contributes to the morphologic phenotype of Ras @-@ transformed cells . # ::alignments 0-1 3-1.1.3 4-1.1 4-1.1.1 4-1.1.1.r 5-1.1.2.1.1.r 6-1.1.2.1.1.2 7-1.1.2.1.1 8-1.1.2.1.1.1 9-1.1.2 9-1.2.1.1.1.1 11-1.1.2.1 11-1.1.2.2 12-1.1.2.2.1.r 14-1.1.2.2.1.1 15-1.1.2.2.1.1.1.r 16-1.1.2.2.1.1.1 16-1.1.2.2.1.1.1.2 16-1.1.2.2.1.1.1.2.1.2.1 16-1.1.2.2.1.1.1.2.r 17-1.1.2.2.1.1.1.1.1 18-1.1.2.2.1.1.2.r 20-1.1.2.2.1.1.2.3 21-1.1.2.2.1.1.2.1 21-1.1.2.2.1.1.2.2 22-1.2.r 23-1.2.1.1.1.1.2.1.1 24-1.2.1.1.1.1 25-1.2.1.1.1.1.3.1.1 26-1.1.2.2.1.1.r 27-1.1.2.2.1 28-1.1.2.2.1.2.r 29-1.1.2.2.1.2.1 30-1.1.2.2.1.2 33-1.1.2.2.1.2.2.1.1.1 34-1.1.2.2.1.2 37-1.1.2.2.1.1.r 38-1.2 39-1.1.2.2.1.2.r 40-1.2.1 46-1.2.1.1.1.1.1.1.1 48-1.2.1.1.1.1.2.1.1 50-1.2.1.1.1.1 51-1.2.1.1.1.1.3.1.1 52-1.2.1.1 53-1.2.1.1.2.r 55-1.2.1.1.2.1 56-1.2.1.1.2 57-1.2.1.1.2.2.r 58-1.2.1.1.2.2.1.1 60-1.2.1.1.2.2.1 61-1.2.1.1.2.2 (c4 / contrast-01~e.0 :ARG1 (c5 / clear-06~e.4 :polarity~e.4 -~e.4 :ARG1 (a3 / and~e.9 :op1 (t2 / thing~e.11 :manner-of~e.5 (d / downregulate-01~e.7 :ARG1 p2~e.8 :ARG2 e2~e.6)) :op2 (t3 / thing~e.11 :extent-of~e.12 (c6 / common~e.27 :domain~e.26,37 (i / influence-01~e.14 :ARG0~e.15 (e / enzyme~e.16 :name (n2 / name :op1 "Ras"~e.17) :ARG0-of~e.16 (c7 / cause-01~e.16 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.16)))) :ARG1~e.18 (a5 / and :op1 (a6 / act-02~e.21 :ARG0 e) :op2 (a7 / act-02~e.21 :ARG0 p2) :ARG1-of (r2 / relative-05~e.20))) :prep-to~e.28,39 (c9 / cell~e.30,34 :part-of (e3 / epithelium~e.29) :ARG2-of (e4 / except-01 :ARG1 (c10 / cell :name (n / name :op1 "MDCK"~e.33))))))) :mod (s / still~e.3)) :ARG2~e.22 (r / reasonable-02~e.38 :ARG1 (a / assume-02~e.40 :ARG1 (c / contribute-01~e.52 :ARG0 (c2 / crosstalk-00 :ARG0 (a2 / and~e.9,24,50 :op1 (e5 / enzyme :name (n5 / name :op1 "Ras"~e.46)) :op2 (e2 / enzyme :name (n3 / name :op1 "Rac"~e.23,48)) :op3 (p2 / protein :name (n4 / name :op1 "Rho"~e.25,51)))) :ARG2~e.53 (p3 / phenotype~e.56 :mod (m / morphology~e.55) :poss~e.57 (c3 / cell~e.61 :ARG1-of (t / transform-01~e.60 :ARG0 e5~e.58))))))) # ::id bio.chicago_2015.34272 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recently , using GST @-@ binding assays , we demonstrated that Sox10 can directly interact with Sp1 and Sp3 in vitro ( Melnikova et al. , 2000 ) . # ::alignments 0-1.3 2-1.4 3-1.4.2.1.1.1.1 5-1.4.2.1 6-1.4.2 8-1.1 9-1 10-1.2.r 11-1.2.1.1.1.1 12-1.2 13-1.2.1.3 14-1.2.1 15-1.2.1.2.r 16-1.2.1.2.1.1.1 17-1.2.1.2 18-1.2.1.2.2.1.1 19-1.2.1.4 20-1.2.1.4 22-1.5.1.1.1.1.1 23-1.5.1.1 24-1.5.1.1.2.1 26-1.5.1.2.1 (d2 / demonstrate-01~e.9 :ARG0 (w / we~e.8) :ARG1~e.10 (p / possible-01~e.12 :ARG1 (i / interact-01~e.14 :ARG0 (p2 / protein :name (n / name :op1 "Sox10"~e.11)) :ARG1~e.15 (a / and~e.17 :op1 (p3 / protein :name (n2 / name :op1 "Sp1"~e.16)) :op2 (p4 / protein :name (n3 / name :op1 "Sp3"~e.18))) :ARG1-of (d3 / direct-02~e.13) :manner (i2 / in-vitro~e.19,20))) :time (r / recent~e.0) :manner (u / use-01~e.2 :ARG0 w :ARG1 (a2 / assay-01~e.6 :ARG1 (b / bind-01~e.5 :ARG1 (e / enzyme :name (n4 / name :op1 "GST"~e.3))))) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and~e.23 :op1 (p7 / person :name (n5 / name :op1 "Melnikova"~e.22)) :op2 (p8 / person :mod (o / other~e.24))) :time (d / date-entity :year 2000~e.26)))) # ::id bio.chicago_2015.34275 ::amr-annotator SDL-AMR-09 ::preferred # ::tok duplicate Shc IPs were resolved by 15 % SDS @-@ PAGE and Grb2 associated with Shc was visualized by anti @-@ Grb2 blotting ( lanes 5 @-@ 8 ) . # ::alignments 0-1.1.2.2 1-1.1.2.1.1.1 4-1.1 5-1.1.1.r 6-1.1.1.2.1 7-1.1.1.2 8-1.1.1.1.1 10-1.1.1.1.1 11-1 12-1.2.1.1.1.1 13-1.2.1 15-1.1.2.1.1.1 17-1.2 19-1.2.2.1 21-1.2.2.1.1 24-1.3.1 25-1.3.1.1.1 27-1.3.1.1.2 (a / and~e.11 :op1 (r / resolve-01~e.4 :ARG0~e.5 (t / thing :name (n2 / name :op1 "SDS-PAGE"~e.8,10) :mod (p / percentage-entity~e.7 :value 15~e.6)) :ARG1 (i / immunoprecipitate-01 :ARG1 (p2 / protein :name (n / name :op1 "Shc"~e.1,15)) :ARG1-of (d / duplicate-01~e.0))) :op2 (v / visualize-01~e.17 :ARG1 (a2 / associate-01~e.13 :ARG1 (p3 / protein :name (n3 / name :op1 "Grb2"~e.12)) :ARG2 p2) :manner (i2 / immunoblot-01 :ARG0-of (c / counter-01~e.19 :ARG1 p3~e.21))) :ARG1-of (d2 / describe-01 :ARG0 (l / lane~e.24 :mod (v2 / value-interval :op1 5~e.25 :op2 8~e.27)))) # ::id bio.chicago_2015.34279 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , c @-@ Src inhibition of hSlo is enhanced by its beta1 subunit and switched on by micromolar Ca2+ (> 1.5 muM ) . # ::alignments 0-1 0-1.1 0-1.1.r 2-1.1.1.2.1.1.1 4-1.1.1.2.1.1.1 5-1.1.1.2 6-1.1.1.2.2.r 7-1.1.1.2.2.1.1 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.2 11-1.1.1.1.2.r 12-1.1.1.1.1.1 14-1.1 15-1.1.2 16-1.1.2.3 18-1.1.2.1.1.1.2 21-1.1.2.1.1.1.1 (a / and~e.0 :op2~e.0 (a2 / and~e.0,14 :op1 (e / enhance-01~e.9 :ARG0~e.10 (p3 / protein-segment :name (n3 / name :op1 "beta1"~e.12) :part-of~e.11 e2~e.11) :ARG1 (i / inhibit-01~e.5 :ARG0 (e2 / enzyme :name (n / name :op1 "c-Src"~e.2,4)) :ARG1~e.6 (p2 / protein :name (n2 / name :op1 "hSlo"~e.7)))) :op2 (s / switch-01~e.15 :ARG0 (c2 / calcium :quant (m2 / more-than :op1 (c / concentration-quantity :quant 1.5~e.21 :unit (m / micromolar~e.18))) :mod m :ARG1-of (i2 / ionize-01 :value "2+")) :ARG1 i :ARG2 (o / on~e.16)))) # ::id bio.chicago_2015.34309 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of cells with IL @-@ 1 activates endogenous TAK1 activity and consequently stimulates the MAPK cascade and IKK , leading to the activation of JNK/ p38 MAPKs and NF @-@ kappaB , respectively . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 3-1.1.1.2.r 4-1.1.1.2.1.1 6-1.1.1.2.1.1 7-1.1 8-1.1.2.1.2 9-1.1.2.1.1.1 10-1.1.2 11-1 12-1.2.3 13-1.2 15-1.2.2.1.1.1.1 16-1.2.2.1 17-1.2.2 18-1.2.2.2.1.1 20-1.3 21-1.3.1.r 23-1.3.1 24-1.3.1.1.r 25-1.3.1.1.1.1.1 26-1.3.1.1.1.1.2 28-1.3.1.1 29-1.3.1.1.2.1.1 31-1.3.1.1.2.1.1 33-1.3.1.1.3 33-1.3.1.1.3.r (a / and~e.11 :op1 (a2 / activate-01~e.7 :ARG0 (t / treat-04~e.0 :ARG1~e.1 (c / cell~e.2) :ARG2~e.3 (p2 / protein :name (n2 / name :op1 "IL-1"~e.4,6))) :ARG1 (a3 / act-02~e.10 :ARG0 (e / enzyme :name (n3 / name :op1 "TAK1"~e.9) :mod (e2 / endogenous~e.8)))) :op2 (s / stimulate-01~e.13 :ARG0 t :ARG1 (a4 / and~e.17 :op1 (c2 / cascade~e.16 :mod (p / pathway :name (n / name :op1 "MAPK"~e.15))) :op2 (e5 / enzyme :name (n4 / name :op1 "IKK"~e.18))) :ARG1-of (c3 / cause-01~e.12 :ARG0 a2)) :ARG0-of (l / lead-03~e.20 :ARG2~e.21 (a5 / activate-01~e.23 :ARG1~e.24 (a6 / and~e.28 :op1 (p3 / pathway :name (n5 / name :op1 "JNK/"~e.25 :op2 "p38"~e.26 :op3 "MAPK")) :op2 (m / macro-molecular-complex :name (n7 / name :op1 "NF-kappaB"~e.29,31)) :manner~e.33 (r / respective~e.33))))) # ::id bio.chicago_2015.34324 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using P19 cells , we show that BMP7 and activin bind to the common type II receptors , ActRII and IIB , but recruit different type I receptors into the ligand @-@ receptor complex and activate distinct Smad signaling pathways . # ::alignments 0-1.3 1-1.3.2.1.1 2-1.3.2 4-1.1 5-1 6-1.2.r 7-1.2.1.1.1.1.1 8-1.2.1.1 9-1.2.1.1.2.1.1 10-1.2.1 11-1.2.1.2.r 13-1.2.1.2.2 14-1.2.1.2.1 15-1.2.1.2.1.1.1 16-1.2.1.2 18-1.2.1.2.3.1.1.1.1 19-1.2.1.2.3.1 20-1.2.1.2.3.1.2.1.1 22-1.2 23-1.2.2.1 24-1.2.2.1.2.2 25-1.2.2.1.2.1 26-1.2.2.1.2.1.1.1 27-1.2.2.1.2 28-1.2.2.1.3.r 30-1.2.2.1.3.1 32-1.2.1.2.3.1.1 32-1.2.1.2.3.1.2 32-1.2.2.1.3.2 33-1.2.2.1.3 34-1.2.2 35-1.2.2.2 36-1.2.2.2.2.3 37-1.2.2.2.2.1.1 38-1.2.2.2.2.2 39-1.2.2.2.2 (s / show-01~e.5 :ARG0 (w / we~e.4) :ARG1~e.6 (c2 / contrast-01~e.22 :ARG1 (b / bind-01~e.10 :ARG1 (a / and~e.8 :op1 (p / protein :name (n2 / name :op1 "BMP7"~e.7)) :op2 (p2 / protein :name (n3 / name :op1 "activin"~e.9))) :ARG2~e.11 (r / receptor~e.16 :mod (t / type~e.14 :ord (o / ordinal-entity :value 2~e.15)) :mod (c3 / common~e.13) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.19 :op1 (r2 / receptor~e.32 :name (n4 / name :op1 "ActRII"~e.18)) :op2 (r3 / receptor~e.32 :name (n5 / name :op1 "IIB"~e.20)))))) :ARG2 (a3 / and~e.34 :op1 (r4 / recruit-01~e.23 :ARG0 a :ARG1 (r5 / receptor~e.27 :mod (t2 / type~e.25 :ord (o2 / ordinal-entity :value 1~e.26)) :ARG1-of (d / differ-02~e.24)) :ARG2~e.28 (c4 / complex~e.33 :part (l2 / ligand~e.30) :part (r6 / receptor~e.32))) :op2 (a4 / activate-01~e.35 :ARG0 a :ARG1 (p3 / pathway~e.39 :name (n6 / name :op1 "Smad"~e.37) :ARG0-of (s2 / signal-07~e.38) :mod (d2 / distinct~e.36))))) :manner (u / use-01~e.0 :ARG0 w :ARG1 (c / cell~e.2 :name (n / name :op1 "P19"~e.1)))) # ::id bio.chicago_2015.34338 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using COS cells we demonstrate that , in the absence of ectopically overexpressed proteins , endogenous PKB can be activated by cAMP @-@ elevating drugs . # ::alignments 0-1.3 1-1.3.2.1.1 2-1.3.2 3-1.1 4-1 7-1.2.r 9-1.2.2 12-1.2.2.1.1 13-1.2.2.1 15-1.2.1.2.2 16-1.2.1.2.1.1 17-1.2 19-1.2.1 20-1.2.1.1.r 21-1.2.1.1.1.1.1.1 23-1.2.1.1.1 24-1.2.1.1 (d / demonstrate-01~e.4 :ARG0 (w / we~e.3) :ARG1~e.7 (p / possible-01~e.17 :ARG1 (a / activate-01~e.19 :ARG0~e.20 (d2 / drug~e.24 :ARG0-of (e3 / elevate-01~e.23 :ARG1 (s / small-molecule :name (n3 / name :op1 "cAMP"~e.21)))) :ARG1 (e / enzyme :name (n2 / name :op1 "PKB"~e.16) :mod (e2 / endogenous~e.15))) :condition (a2 / absent-01~e.9 :ARG1 (p2 / protein~e.13 :ARG1-of (o / overexpress-01~e.12 :manner (e4 / ectopic))))) :manner (u / use-01~e.0 :ARG0 w :ARG1 (c / cell-line~e.2 :name (n / name :op1 "COS"~e.1)))) # ::id bio.chicago_2015.34339 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast to a preferential binding to GTP S @-@ bound Rac , PlexB binds to the GTP S and GDP @-@ bound forms of RhoA equally well ( Figure 3B , lanes 3 and 4 ) . # ::alignments 1-1 2-1.1.r 4-1.1.2 5-1.1 5-1.1.1.2 6-1.1.1.r 7-1.1.1.2.1.1.1 8-1.1.1.2.1.1.2 10-1.1.1.2 11-1.1.1.1.1 13-1.2.1.1.1 14-1.1.1.2 14-1.2 17-1.1.1.2.1.1.1 18-1.1.1.2.1.1.2 19-1.2.2 20-1.2.2.2.2.1.1.1 22-1.2.2.2 22-1.2.2.2.2 22-1.2.2.2.2.r 25-1.2.2.1.1.1 25-1.2.2.2.1.1 26-1.2.3.1 27-1.2.3 29-1.3.1.3 30-1.3.1.3.1 32-1.3.1.1 32-1.3.1.2 33-1.3.1.1.1 34-1.3.1 35-1.3.1.2.1 (c / contrast-01~e.1 :ARG1~e.2 (b2 / bind-01~e.5 :ARG2~e.6 (e / enzyme :name (n2 / name :op1 "Rac"~e.11) :ARG1-of (b3 / bind-01~e.5,10,14 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP"~e.7,17 :op2 "S"~e.8,18)))) :ARG1-of (p / prefer-01~e.4)) :ARG2 (b / bind-01~e.14 :ARG1 (p2 / protein :name (n4 / name :op1 "PlexB"~e.13)) :ARG2 (a / and~e.19 :op1 (p3 / protein :name (n5 / name :op1 "RhoA"~e.25) :ARG1-of b3) :op2 (p4 / protein~e.22 :name (n6 / name :op1 "RhoA"~e.25) :ARG1-of~e.22 (b4 / bind-01~e.22 :ARG2 (s3 / small-molecule :name (n7 / name :op1 "GDP"~e.20))))) :ARG1-of (w / well-09~e.27 :ARG1-of (e2 / equal-01~e.26))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.34 :op1 (l / lane~e.32 :mod 3~e.33) :op2 (l2 / lane~e.32 :mod 4~e.35) :part-of (f / figure~e.29 :mod "3B"~e.30)))) # ::id bio.chicago_2015.34385 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Heat shock induction of one GAL4 - HP1 transgene results in variegation . # ::alignments 1-1.1 3-1.2.1.1 4-1.2.1 5-1.2 6-1.2.2.r 7-1.2.2.1 8-1.2.2.2.1 10-1.2.2.2.1 11-1.2.2 12-1 13-1.3.r 14-1.3 (r / result-01~e.12 :li "B"~e.1 :ARG1 (i / induce-01~e.5 :ARG0 (s / shock-01~e.4 :ARG0 (h / heat~e.3)) :ARG2~e.6 (t / transgene~e.11 :quant 1~e.7 :name (n / name :op1 "GAL4-HP1"~e.8,10))) :ARG2~e.13 (v / variegation~e.14)) # ::id bio.chicago_2015.34424 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The binding sites on EVL for profilin , WW domains , and SH3 domains overlap , and several of these interactions are selectively modulated by PKA phosphorylation of EVL . # ::alignments 1-1.1.1.1.1 1-1.1.1.2.1 1-1.1.1.3.1 2-1.1.1.1 2-1.1.1.2 2-1.1.1.3 4-1.1.1.4.1.1 5-1.1.1.1.1.1.r 6-1.1.1.1.1.1.1.1 8-1.1.1.2.1.1.1.1 11-1.1.1 12-1.1.1.3.1.1.1.1 14-1.1 16-1 16-1.1.1 17-1.2.2.1 18-1.2.2.1.r 19-1.2.2.2 20-1.2.2 22-1.2.3 22-1.2.3.r 23-1.2 24-1.2.1.r 25-1.2.1.2.1.1 26-1.2.1 27-1.2.1.1.r 28-1.2.1.1 (a / and~e.16 :op1 (o / overlap-01~e.14 :ARG0 (a2 / and~e.11,16 :op1 (s / site~e.2 :location-of (b / bind-01~e.1 :ARG2~e.5 (p2 / protein :name (n / name :op1 "profilin"~e.6)))) :op2 (s2 / site~e.2 :location-of (b2 / bind-01~e.1 :ARG2 (p4 / protein-segment :name (n3 / name :op1 "WW"~e.8)))) :op3 (s3 / site~e.2 :location-of (b3 / bind-01~e.1 :ARG2 (p5 / protein-segment :name (n4 / name :op1 "SH3"~e.12)))) :part-of (p3 / protein :name (n2 / name :op1 "EVL"~e.4)))) :op2 (m / modulate-01~e.23 :ARG0~e.24 (p / phosphorylate-01~e.26 :ARG1~e.27 p3~e.28 :ARG2 (e / enzyme :name (n5 / name :op1 "PKA"~e.25))) :ARG1 (i / interact-01~e.20 :quant~e.18 (s5 / several~e.17) :mod (t / this~e.19)) :manner~e.22 (s4 / selective~e.22))) # ::id bio.chicago_2015.34435 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Those studies also suggested that we could create competition between the binding of HSF and a histone H2A @-@ H2B dimer by rotating the HSF binding determinants so that they face into the histone octamer . # ::alignments 0-1.1.1 1-1.1 2-1.3 3-1 4-1.1.1 4-1.2.r 5-1.2.1.1 6-1.2 7-1.2.1 8-1.2.1.2 9-1.2.1.2.1.r 11-1.2.1.2.1 13-1.2.1.2.1.1.1.1 14-1.2.1.2.2.r 16-1.2.1.2.2.1.1.1 17-1.2.1.2.2.1.1.2 19-1.2.1.2.2.2.1.2 20-1.2.1.2.2 21-1.2.1.3.r 22-1.2.1.3 24-1.2.1.2.1.1.1.1 25-1.2.1.2.1 25-1.2.1.3.2.1.1 27-1.2.1.3.3.r 28-1.2.1.3.3.r 29-1.2.1.3.3.1 30-1.2.1.3.3 31-1.2.1.3.3.2.r 33-1.2.1.3.3.2.1.1 34-1.2.1.3.3.2.1.2 (s / suggest-01~e.3 :ARG0 (s2 / study-01~e.1 :mod (t / that~e.0,4)) :ARG1~e.4 (p2 / possible-01~e.6 :ARG1 (c / create-01~e.7 :ARG0 (w / we~e.5) :ARG1 (c2 / compete-01~e.8 :ARG0~e.9 (b / bind-01~e.11,25 :ARG1 (p / protein :name (n / name :op1 "HSF"~e.13,24))) :ARG1~e.14 (d2 / dimer~e.20 :part (p3 / protein :name (n2 / name :op1 "histone"~e.16 :op2 "H2A"~e.17)) :part (p4 / protein :name (n3 / name :op1 "histone" :op2 "H2B"~e.19)))) :manner~e.21 (r / rotate-01~e.22 :ARG0 w :ARG1 (m3 / molecular-physical-entity :ARG0-of (d / determine-01 :ARG1 (b2 / bind-01~e.25 :ARG1 p))) :purpose~e.27,28 (f / face-01~e.30 :ARG0 m3~e.29 :ARG1~e.31 (m2 / macro-molecular-complex :name (n4 / name :op1 "histone"~e.33 :op2 "octamer"~e.34)))))) :mod (a / also~e.2)) # ::id bio.chicago_2015.34462 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibition of calcineurin activity by CsA suppresses biochemical markers of differentiation , as well as p21 WAF1 @/@ CIP1 and p27KIP1 expression . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1.1 3-1.1.2 4-1.1.1.r 5-1.1.1.1.1 6-1 7-1.2.1.1 8-1.2.1 9-1.2.1.2.r 10-1.2.1.2 12-1.2 13-1.2 14-1.2 14-1.2.r 15-1.2.2.1.1.1.1 16-1.2.2.1.1.1.2 18-1.2.2.1.1.1.2 19-1.2.2.1 20-1.2.2.1.2.1.1 21-1.2.2 (s / suppress-01~e.6 :ARG0 (i / inhibit-01~e.0 :ARG0~e.4 (s2 / small-molecule :name (n2 / name :op1 "CsA"~e.5)) :ARG1~e.1 (a / activity-06~e.3 :ARG0 (e2 / enzyme :name (n / name :op1 "calcineurin"~e.2)))) :ARG1~e.14 (a2 / and~e.12,13,14 :op1 (m / marker~e.8 :mod (b / biochemistry~e.7) :mod~e.9 (d / differentiate-01~e.10)) :op2 (e / express-03~e.21 :ARG2 (a3 / and~e.19 :op1 (p2 / protein :name (n3 / name :op1 "p21"~e.15 :op2 "WAF1/CIP1"~e.16,18)) :op2 (p3 / protein :name (n4 / name :op1 "p27KIP1"~e.20)))))) # ::id bio.chicago_2015.34464 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our finding that arsenite induces histone H3 phosphorylation @-@ acetylation may provide additional insight into the mechanisms for both the carcinogenic properties and the therapeutic effects of arsenite . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1.2 3-1.1.1.3.1.1.1 4-1.1.1.3 5-1.1.1.3.2.1.1.1.1 6-1.1.1.3.2.1.1.1.2 7-1.1.1.3.2.1 9-1.1.1.3.2.2 10-1 11-1.1 12-1.1.2.1 13-1.1.2 14-1.1.2.2.r 16-1.1.2.2.1 16-1.1.2.2.2 20-1.1.2.2.1.1.1.1 21-1.1.2.2.1.1 22-1.1.2.2 24-1.1.2.2.2.1.2 25-1.1.2.2.2.1 26-1.1.2.2.2.1.1.r 27-1.1.2.2.2.1.1 (p / possible-01~e.10 :ARG1 (p2 / provide-01~e.11 :ARG0 (t / thing :poss~e.0 (w / we~e.0) :ARG1-of (f / find-01~e.1) :topic (i / induce-01~e.4 :ARG0 (s / small-molecule :name (n / name :op1 "arsenite"~e.3)) :ARG2 (a / and :op1 (p3 / phosphorylate-01~e.7 :ARG1 (p4 / protein :name (n2 / name :op1 "histone"~e.5 :op2 "H3"~e.6))) :op2 (a2 / acetylate-01~e.9 :ARG1 p4)))) :ARG1 (i2 / insight~e.13 :mod (a3 / additional~e.12) :topic~e.14 (a4 / and~e.22 :op1 (m2 / mechanism~e.16 :mod (p5 / property~e.21 :ARG0-of (c / cause-01 :ARG1 (c2 / carcinoma~e.20)) :poss s)) :op2 (m3 / mechanism~e.16 :mod (a5 / affect-01~e.25 :ARG0~e.26 s~e.27 :mod (t2 / therapy~e.24))))))) # ::id bio.chicago_2015.34540 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , it should be noted that the amounts of vinculin as well as talin that bound to paxillin were quite low , compared with Fak binding to paxillin ( see Fig. 3 ) . # ::alignments 0-1 3-1.1 5-1.1.1 6-1.1.1.1.r 8-1.1.1.1.1.1 8-1.1.1.1.1.2 9-1.1.1.1.1.1.1.r 10-1.1.1.1.1.1.1.1.1 11-1.1.1.1.1 12-1.1.1.1.1 13-1.1.1.1.1 13-1.1.1.1.1.2.1.r 14-1.1.1.1.1.2.1.1.1 16-1.1.1.1.1.3 17-1.1.1.1.1.3.1.r 18-1.1.1.1.1.3.1.1.1 20-1.1.1.1.2 21-1.1.1.1 23-1.1.1.1.3.r 25-1.1.1.1.3.1.1.1 26-1.1.1.1.3 27-1.1.1.1.3.2.r 28-1.1.1.1.3.2 30-1.2.1.2 31-1.2.1 32-1.2.1.1 (h / have-concession-91~e.0 :ARG1 (r / recommend-01~e.3 :ARG1 (n / note-01~e.5 :ARG1~e.6 (l / low-04~e.21 :ARG1 (a / and~e.11,12,13 :op1 (a2 / amount~e.8 :quant-of~e.9 (p / protein :name (n2 / name :op1 "vinculin"~e.10))) :op2 (a3 / amount~e.8 :quant-of~e.13 (p2 / protein :name (n3 / name :op1 "talin"~e.14))) :ARG1-of (b / bind-01~e.16 :ARG2~e.17 (p3 / protein :name (n4 / name :op1 "paxillin"~e.18)))) :mod (q / quite~e.20) :compared-to~e.23 (b2 / bind-01~e.26 :ARG1 (e / enzyme :name (n5 / name :op1 "Fak"~e.25)) :ARG2~e.27 p3~e.28)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod 3~e.32 :ARG1-of (s / see-01~e.30 :mode imperative :ARG0 (y / you))))) # ::id bio.chicago_2015.34551 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mitochondrially targeted expression of ActA largely simulates the initial phase of actin recruitment , namely the formation of actin clouds , which normally occurs around intracytoplasmic Listeria . # ::alignments 1-1.1.3 2-1.1 3-1.1.1.r 4-1.1.1.1.1 5-1.3 6-1 8-1.2.1 9-1.2 10-1.2.2.r 11-1.2.2.1.1.1 12-1.2.2 14-1.2.3 16-1.2.3.1 17-1.2.3.1.1.r 18-1.2.3.1.1.1 19-1.2.3.1.1 22-1.2.3.1.2.2 24-1.2.3.1.2 25-1.2.3.1.2.1.2 26-1.2.3.1.2.1.1.1 (s / simulate-01~e.6 :ARG0 (e / express-03~e.2 :ARG2~e.3 (p / protein :name (n / name :op1 "ActA"~e.4)) :ARG3 (m / mitochondrion) :ARG1-of (t / target-01~e.1)) :ARG1 (p2 / phase~e.9 :mod (i / initial~e.8) :subevent-of~e.10 (r / recruit-01~e.12 :ARG1 (p3 / protein :name (n2 / name :op1 "actin"~e.11))) :ARG1-of (m2 / mean-01~e.14 :ARG2 (f / form-01~e.16 :ARG1~e.17 (c / cloud~e.19 :consist-of p3~e.18) :location (a / around~e.24 :op1 (o2 / organism :name (n4 / name :op1 "Listeria"~e.26) :mod (i2 / intracytoplasmic~e.25)) :ARG1-of (n3 / normal-02~e.22))))) :degree (l / large~e.5)) # ::id bio.chicago_2015.34559 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also analyzed functions of the specific phosphorylation of GFAP by Rho @-@ kinase during cytokinesis . # ::alignments 0-1.1 1-1.3 2-1 3-1.2 4-1.2.1.r 6-1.2.1.3 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1.1 10-1.2.1.2.r 11-1.2.1.2.1.1 13-1.2.1.2.1.1 14-1.2.2.r 15-1.2.2 (a / analyze-01~e.2 :ARG0 (w / we~e.0) :ARG1 (f / function-01~e.3 :ARG0~e.4 (p / phosphorylate-01~e.7 :ARG1~e.8 (p2 / protein :name (n / name :op1 "GFAP"~e.9)) :ARG2~e.10 (e / enzyme :name (n2 / name :op1 "Rho-kinase"~e.11,13)) :ARG1-of (s / specific-02~e.6)) :time~e.14 (c / cytokinesis~e.15)) :mod (a2 / also~e.1)) # ::id bio.chicago_2015.34560 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the association of TFIIA with TBP is an excellent candidate for regulation by posttranslational modification . # ::alignments 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1 6-1.1.2.2.r 7-1.1.2.2.1.1 8-1.1.2.r 11-1.1 13-1.1.1.1 14-1.1.1.1.1.r 15-1.1.1.1.1.1 15-1.1.1.1.1.1.1 15-1.1.1.1.1.1.1.r 16-1.1.1.1.1 (i / infer-01 :ARG1 (c / candidate~e.11 :ARG0-of (e / excel-01 :ARG1 (r / regulate-01~e.13 :ARG0~e.14 (m / modify-01~e.16 :time (a2 / after~e.15 :op1~e.15 (t / translate-02~e.15))))) :domain~e.8 (a / associate-01~e.3 :ARG1~e.4 (p / protein :name (n / name :op1 "TFIIA"~e.5)) :ARG2~e.6 (p2 / protein :name (n2 / name :op1 "TBP"~e.7))))) # ::id bio.chicago_2015.34581 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Snail represses sim in the mesoderm , and thereby restricts expression to lateral regions that form the mesectoderm ( Kasai et al. , 1992 ; Kasai et al. , 1998 ; Nibu et al. , 1998 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1.1.3.r 5-1.1.3 7-1 7-1.3.1 7-1.3.1.1.1 8-1.2.4 8-1.2.4.r 9-1.2 10-1.2.2 11-1.2.3.r 12-1.2.3.1 13-1.2.3 15-1.2.3.2 17-1.2.3.2.1 19-1.3.1.1.1.1.1.1 20-1.3.1.1.1 21-1.3.1.1.1.2.1 23-1.3.1.1.2.1 25-1.3.1.1.1.1.1.1 26-1.3.1.1.1 27-1.3.1.1.1.2.1 29-1.3.1.3.2 31-1.3.1.3.1.1.1.1 32-1.3.1 32-1.3.1.1.1 32-1.3.1.3.1 33-1.3.1.1.1.2.1 35-1.3.1.2.2.1 (a / and~e.7 :op1 (r / repress-01~e.1 :ARG0 (p7 / protein :name (n / name :op1 "Snail"~e.0)) :ARG1 (g / gene :name (n2 / name :op1 "sim"~e.2)) :location~e.3 (m / mesoderm~e.5)) :op2 (r2 / restrict-01~e.9 :ARG0 p7 :ARG1 (e2 / express-03~e.10 :ARG1 g) :ARG2~e.11 (r3 / region~e.13 :mod (l / lateral~e.12) :ARG0-of (f / form-01~e.15 :ARG1 (m2 / mesectoderm~e.17))) :manner~e.8 (t / thereby~e.8)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.7,32 :op1 (p / publication-91 :ARG0 (a3 / and~e.7,20,26,32 :op1 (p2 / person :name (n3 / name :op1 "Kasai"~e.19,25)) :op2 (p3 / person :mod (o / other~e.21,27,33))) :time (d / date-entity :year 1992~e.23)) :op2 (p4 / publication-91 :ARG0 a3 :time (d2 / date-entity :year 1998~e.35)) :op3 (p5 / publication-91 :ARG0 (a4 / and~e.32 :op1 (p6 / person :name (n4 / name :op1 "Nibu"~e.31)) :op2 p3) :time d2~e.29)))) # ::id bio.chicago_2015.34679 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GRB2 Becomes Associated with RasGAP and Shc , in Lateral Amygdala , following Fear Conditioning # ::alignments 0-1.1.1.1 1-1 2-1.2 3-1.2.2.r 4-1.2.2.1.1.1 5-1.2.2 6-1.2.2.2.1.1 8-1.3.r 9-1.3.1 10-1.3 12-1.4 13-1.4.1.1 14-1.4.1 (b / become-01~e.1 :ARG1 (p / protein :name (n / name :op1 "GRB2"~e.0)) :ARG2 (a / associate-01~e.2 :ARG1 p :ARG2~e.3 (a2 / and~e.5 :op1 (p2 / protein :name (n2 / name :op1 "RasGAP"~e.4)) :op2 (p3 / protein :name (n3 / name :op1 "Shc"~e.6)))) :location~e.8 (a3 / amygdala~e.10 :mod (l / lateral~e.9)) :ARG1-of (f / follow-01~e.12 :ARG2 (c / condition-01~e.14 :ARG0 (f2 / fear~e.13)))) # ::id bio.chicago_2015.34680 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We use signal transduction inhibitors and ES cells lacking p90RSK activity and ES cells deficient in MSK1 to demonstrate that phosphorylation of LKB1 induced by EGF and TPA is likely to be mediated by p90RSK rather than by MSK1 or S6K1 and that phosphorylation of LKB1 induced by forskolin is mediated by PKA . # ::alignments 0-1.1 1-1 2-1.2.1.1.1 3-1.2.1.1.2 4-1.2.1.1.3 5-1.2 6-1.2.2.1.1 6-1.2.3.1.1 7-1.2.2 7-1.2.3 8-1.2.2.2 8-1.2.3.2 9-1.2.2.2.1.1.1.1 10-1.2.2.2.1 12-1.2.2.1.1 13-1.2.2 15-1.2.3.2.1.r 16-1.2.3.2.1.1.1 18-1.3 19-1.3.2.r 20-1.3.2.1.1.2 21-1.3.2.1.1.2.1.r 22-1.3.2.1.1.2.1.1.1 23-1.3.2.1.1.2.2 24-1.3.2.1.1.2.2.1.r 25-1.3.2.1.1.2.2.1.1.1.1 26-1.3.2.1.1.2.2.1 27-1.3.2.1.1.2.2.1.2.1.1 29-1.3.2.1 32-1.3.2.1.1 32-1.3.2.2 34-1.2.2.2.1.1.1.1 35-1.3.2.1.1.3 38-1.3.2.1.1.3.1.1.1 39-1.3.2.1.1.3.1.1 40-1.3.2.1.1.3.1.1.2.1.1 41-1.3.2.1.1.3.1.2 42-1.3.2.1.1.3.1.2 43-1.3.2.1.1.3.1.2 44-1.3.2.1.1.3.1.2 45-1.3.2.1.1.3.1.2 46-1.3.2.2.2.2 47-1.3.2.2.2.2.1.r 48-1.3.2.2.2.2.1.1.1 50-1.3.2.1.1.3.1 51-1.3.2.2.1.r 52-1.3.2.2.1.1.1 (u / use-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / and~e.5 :op1 (s / small-molecule :name (n / name :op1 "signal"~e.2 :op2 "transduction"~e.3 :op3 "inhibitor"~e.4)) :op2 (c / cell~e.7,13 :name (n2 / name :op1 "ES"~e.6,12) :ARG0-of (l / lack-01~e.8 :ARG1 (a2 / act-02~e.10 :ARG0 (e / enzyme :name (n3 / name :op1 "p90RSK"~e.9,34))))) :op3 (c2 / cell~e.7 :name (n4 / name :op1 "ES"~e.6) :ARG0-of (l2 / lack-01~e.8 :ARG1~e.15 (e2 / enzyme :name (n5 / name :op1 "MSK1"~e.16))))) :ARG2 (d2 / demonstrate-01~e.18 :ARG0 w :ARG1~e.19 (a4 / and :op1 (l3 / likely-01~e.29 :ARG1 (m / mediate-01~e.32 :ARG0 e :ARG1 (p / phosphorylate-01~e.20 :ARG1~e.21 (e3 / enzyme :name (n6 / name :op1 "LKB1"~e.22)) :ARG2-of (i2 / induce-01~e.23 :ARG0~e.24 (a3 / and~e.26 :op1 (p3 / protein :name (n7 / name :op1 "EGF"~e.25)) :op2 (s3 / small-molecule :name (n8 / name :op1 "TPA"~e.27))))) :ARG1-of (i3 / instead-of-91~e.35 :ARG2 (m2 / mediate-01~e.50 :ARG0 (o / or~e.39 :op1 e2~e.38 :op2 (e4 / enzyme :name (n9 / name :op1 "S6K1"~e.40))) :ARG1 p~e.41,42,43,44,45)))) :op2 (m3 / mediate-01~e.32 :ARG0~e.51 (e5 / enzyme :name (n11 / name :op1 "PKA"~e.52)) :ARG1 (p2 / phosphorylate-01 :ARG1 e3 :ARG2-of (i4 / induce-01~e.46 :ARG0~e.47 (s4 / small-molecule :name (n10 / name :op1 "forskolin"~e.48)))))))) # ::id bio.chicago_2015.34743 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) EMSAs of the SMA promoter show that CRP2 and GATA4 recruited by SRF vastly increased cooperative SRF DNA binding affinity . # ::alignments 1-1.1 6-1.2.2.1.1 7-1.2.2 7-1.2.2.2 7-1.2.2.2.r 8-1 9-1.3.r 10-1.3.1.1.1.1 11-1.3.1 12-1.3.1.2.1.1 13-1.3.1.3 14-1.3.1.3.1.r 15-1.3.1.3.1.1.1 16-1.3.3 17-1.3 18-1.3.2.1.3 19-1.3.2.1.1 20-1.3.2.1.2.1.1 21-1.3.2.1 22-1.3.2 (s / show-01~e.8 :li "C"~e.1 :ARG0 (t / thing :name (n / name :op1 "EMSA") :mod (p / protein~e.7 :name (n2 / name :op1 "SMA"~e.6) :ARG0-of~e.7 (p2 / promote-01~e.7))) :ARG1~e.9 (i / increase-01~e.17 :ARG0 (a / and~e.11 :op1 (p3 / protein :name (n3 / name :op1 "CRP2"~e.10)) :op2 (p4 / protein :name (n4 / name :op1 "GATA4"~e.12)) :ARG1-of (r / recruit-01~e.13 :ARG0~e.14 (p5 / protein :name (n5 / name :op1 "SRF"~e.15)))) :ARG1 (a2 / affinity~e.22 :mod (b / bind-01~e.21 :ARG1 p5~e.19 :ARG2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"~e.20)) :mod (c / cooperate-01~e.18))) :ARG2 (v / vast~e.16))) # ::id bio.chicago_2015.34745 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because CsA inhibits calcineurin , this finding implicated the calcium @-@ calmodulin dependent phosphatase as an essential regulator of chondrogenesis , even in the absence of the calcium ionophore . # ::alignments 0-1.5 1-1.5.1.1.1.1 2-1.5.1 3-1.5.1.2.1.1 5-1.1.2 6-1.1 6-1.1.1 6-1.1.1.r 7-1 9-1.2.1.1 11-1.2.1.1 12-1.2.1.2 13-1.2.1.3 14-1.3.r 16-1.3.3 17-1.3 18-1.3.2.r 19-1.3.2 22-1.4.r 24-1.4 25-1.4.1.r 27-1.4.1.1.1 28-1.4.1.1.2 (i / implicate-01~e.7 :ARG0 (t / thing~e.6 :ARG1-of~e.6 (f / find-01~e.6) :mod (t2 / this~e.5)) :ARG1 (e / enzyme :name (n / name :op1 "calcium-calmodulin"~e.9,11 :op2 "dependent"~e.12 :op3 "phosphatase"~e.13)) :ARG2~e.14 (r2 / regulate-01~e.17 :ARG0 e :ARG1~e.18 (c / chondrogenesis~e.19) :mod (e2 / essential~e.16)) :concession~e.22 (a / absent-01~e.24 :ARG1~e.25 (s / small-molecule :name (n2 / name :op1 "calcium"~e.27 :op2 "ionophore"~e.28))) :ARG1-of (c2 / cause-01~e.0 :ARG0 (i2 / inhibit-01~e.2 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "CsA"~e.1)) :ARG1 (e3 / enzyme :name (n4 / name :op1 "calcineurin"~e.3))))) # ::id bio.chicago_2015.34748 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the absence of stimulation , basal Tyr phosphorylation of Fus3 is governed by the balance between autophosphorylation by the kinase and dephosphorylation by Ptp3 phosphatase . # ::alignments 2-1.3 3-1.3.1.r 4-1.3.1 6-1.2.2 7-1.2.1.1.1 8-1.2 10-1.2.1.2.1.1 12-1 13-1.1.r 15-1.1 17-1.1.1 18-1.1.1.2.r 20-1.1.1.2 22-1.1.2 23-1.1.2.1.r 24-1.1.2.1.1.1 25-1.1.2.1.1.2 (g / govern-01~e.12 :ARG0~e.13 (b2 / balance-01~e.15 :ARG1 (p3 / phosphorylate-01~e.17 :ARG1 k :ARG2~e.18 (k / kinase~e.20)) :ARG2 (d / dephosphorylate-01~e.22 :ARG2~e.23 (e / enzyme :name (n3 / name :op1 "Ptp3"~e.24 :op2 "phosphatase"~e.25)))) :ARG1 (p / phosphorylate-01~e.8 :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.7) :part-of (p2 / protein :name (n2 / name :op1 "Fus3"~e.10))) :mod (b / basal~e.6)) :condition (a3 / absent-01~e.2 :ARG1~e.3 (s / stimulate-01~e.4))) # ::id bio.chicago_2015.34764 ::amr-annotator SDL-AMR-09 ::preferred # ::tok R62C Defines a Novel Rab Mutation utations that have previously been studied for rab6 are those engineered based on the GTP @- and GDP @-@ bound forms of ras @-@ like molecules . # ::alignments 1-1.1 3-1.1.2.2 4-1.1.2.1.1.1 5-1.1.1 5-1.1.2 5-1.2 5-1.2.3 9-1.2.2.1 11-1.2.2 12-1.2.1.r 13-1.2.1.1.1 14-1.2.3.r 16-1.2.3.1 17-1.2.3.1.1 18-1.2.3.1.1.1.r 20-1.2.3.1.1.1.1.2.1.1.1 22-1.2.3.1.1.1 23-1.2.3.1.1.1.2.2.1.1.1 25-1.2.3.1.1.1.1.2 25-1.2.3.1.1.1.2.2 28-1.2.3.1.1.1.1.1.1.1.1 30-1.2.3.1.1.1.1.1 31-1.2.3.1.1.1.1 31-1.2.3.1.1.1.2 (m / multi-sentence :snt1 (d / define-01~e.1 :ARG0 (m6 / mutate-01~e.5 :ARG1 (a2 / amino-acid :mod 62 :name (n7 / name :op1 "arginine")) :ARG2 (a3 / amino-acid :name (n8 / name :op1 "cysteine"))) :ARG1 (m2 / mutate-01~e.5 :ARG1 (p / protein :name (n2 / name :op1 "Rab"~e.4)) :mod (n3 / novel~e.3))) :snt2 (m3 / mutate-01~e.5 :ARG1~e.12 (p4 / protein :name (n6 / name :op1 "Rab6"~e.13)) :ARG1-of (s2 / study-01~e.11 :time (p2 / previous~e.9)) :domain~e.14 (m7 / mutate-01~e.5 :ARG1-of (e / engineer-01~e.16 :ARG1-of (b / base-02~e.17 :ARG2~e.18 (a / and~e.22 :op1 (m4 / molecule~e.31 :ARG1-of (r2 / resemble-01~e.30 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.28))) :ARG1-of (b2 / bind-01~e.25 :ARG2 (s / small-molecule :name (n / name :op1 "GTP"~e.20)))) :op2 (m5 / molecule~e.31 :ARG1-of r2 :ARG1-of (b3 / bind-01~e.25 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "GDP"~e.23)))))))))) # ::id bio.chicago_2015.34874 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , our results demonstrate that YY1 was acetylated by both p300 and PCAF and was deacetylated by HDAC1 and HDAC2 . # ::alignments 0-1.3 2-1.1.1 2-1.1.1.r 3-1.1 3-1.1.2 3-1.1.2.r 4-1 5-1.2.r 6-1.2.1.1.1.1 8-1.2.1 11-1.2.1.2.1.1.1 12-1.2.1.2 13-1.2.1.2.2.1.1 14-1.2 14-1.2.2.2 18-1.2.2.2.1.1.1 19-1.2.2.2 20-1.2.2.2.2.1.1 (d / demonstrate-01~e.4 :ARG0 (t / thing~e.3 :poss~e.2 (w / we~e.2) :ARG2-of~e.3 (r / result-01~e.3)) :ARG1~e.5 (a / and~e.14 :op1 (a2 / acetylate-01~e.8 :ARG1 (p / protein :name (n / name :op1 "YY1"~e.6)) :ARG2 (a3 / and~e.12 :op1 (p2 / protein :name (n2 / name :op1 "p300"~e.11)) :op2 (p3 / protein :name (n3 / name :op1 "PCAF"~e.13)))) :op2 (d2 / deacetylate-01 :ARG1 p :ARG2 (a4 / and~e.14,19 :op1 (e / enzyme :name (n4 / name :op1 "HDAC1"~e.18)) :op2 (e2 / enzyme :name (n5 / name :op1 "HDAC2"~e.20))))) :mod (i / indeed~e.0)) # ::id bio.chicago_2015.34888 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oxidative stress differentially modulates phosphorylation of ERK , p38 and CREB induced by NGF or EGF in PC12 cells . # ::alignments 0-1.1.1 1-1.1 2-1.3 2-1.3.r 3-1 4-1.2.1 4-1.2.2 4-1.2.3 5-1.2.1.1.r 6-1.2.1.1.1.1 8-1.2.2.1.1.1 9-1.2 10-1.2.3.1.1.1 11-1.2.4 12-1.2.4.1.r 13-1.2.4.1.1.1.1 14-1.2.4.1 15-1.2.4.1.2.1.1 16-1.4.r 17-1.4.1.1 18-1.4 (m / modulate-01~e.3 :ARG0 (s / stress-02~e.1 :ARG0 (o / oxidize-01~e.0)) :ARG1 (a / and~e.9 :op1 (p / phosphorylate-01~e.4 :ARG1~e.5 (e / enzyme :name (n / name :op1 "ERK"~e.6))) :op2 (p2 / phosphorylate-01~e.4 :ARG1 (e2 / enzyme :name (n2 / name :op1 "p38"~e.8))) :op3 (p3 / phosphorylate-01~e.4 :ARG1 (p5 / protein :name (n3 / name :op1 "CREB"~e.10))) :ARG2-of (i / induce-01~e.11 :ARG0~e.12 (o2 / or~e.14 :op1 (p6 / protein :name (n4 / name :op1 "NGF"~e.13)) :op2 (p4 / protein :name (n5 / name :op1 "EGF"~e.15))))) :manner~e.2 (d / differential~e.2) :location~e.16 (c / cell-line~e.18 :name (n6 / name :op1 "PC12"~e.17))) # ::id bio.chicago_2015.34920 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB @-@ Dependent Transcription and ERK Nuclear Translocation . # ::alignments 3-1.2.1.1.1.1 4-1.2.1 5-1.2.1.2.1.1 7-1 10-1.1 11-1.1.2.r 12-1.1.2.1.1.1.1.1 14-1.1.2.1.1 15-1.1.2.1 16-1.1.2 16-1.2.1 17-1.1.2.2.1 18-1.1.2.2.2 19-1.1.2.2 (r / require-01~e.7 :ARG0 (s / stimulate-01~e.10 :ARG0 (c2 / calcium :ARG1-of (i / ionize-01 :value "2+")) :ARG1~e.11 (a3 / and~e.16 :op1 (t / transcribe-01~e.15 :ARG0-of (d / depend-01~e.14 :ARG1 (p / protein :name (n5 / name :op1 "CREB"~e.12)))) :op2 (t2 / translocate-01~e.19 :ARG1 e~e.17 :ARG2 (n6 / nucleus~e.18)))) :ARG1 (c / crosstalk-00 :ARG1 (a / and~e.4,16 :op1 (e / enzyme :name (n2 / name :op1 "ERK"~e.3)) :op2 (e2 / enzyme :name (n3 / name :op1 "PKA"~e.5))))) # ::id bio.chicago_2015.34944 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is conceivable that alpha @-@ adducin phosphorylated by PKC dissociates from a spectrin @-@ F @-@ actin meshwork during membrane ruffling . # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 6-1.1.1.1.1.1 7-1.1.1.1.2 8-1.1.1.1.2.1.r 9-1.1.1.1.2.1.1.1 10-1.1.1 11-1.1.1.2.r 13-1.1.1.2.1.1.1.1 15-1.1.1.2.1.2.1.1 17-1.1.1.2.1.2.1.1 18-1.1.1.2 19-1.1.1.3.r 20-1.1.1.3.1 21-1.1.1.3 (p / possible-01 :ARG1 (c / conceive-01~e.2 :ARG1~e.3 (d / dissociate-01~e.10 :ARG1 (p2 / protein :name (n / name :op1 "alpha-adducin"~e.4,6) :ARG1-of (p3 / phosphorylate-01~e.7 :ARG2~e.8 (e / enzyme :name (n2 / name :op1 "PKC"~e.9)))) :ARG2~e.11 (m / meshwork~e.18 :consist-of (a / and :op1 (p4 / protein :name (n3 / name :op1 "spectrin"~e.13)) :op2 (p5 / protein :name (n4 / name :op1 "F-actin"~e.15,17)))) :time~e.19 (r / ruffle-02~e.21 :ARG1 (m2 / membrane~e.20))))) # ::id bio.chicago_2015.34963 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since many of the inflammatory cytokines are produced by macrophages upon activation by LPS , a potent activator of the p38 MAPK pathway , LPS @-@ activated p38 MAPK activity in MKK3 @-@ deficient macrophages was studied . # ::alignments 0-1.2 1-1.2.1.2.2 2-1.2.1.2.2.r 4-1.2.1.2 4-1.2.1.2.3 4-1.2.1.2.3.r 5-1.2.1.2.1.1 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1 11-1.2.1.3 12-1.2.1.3.1.r 13-1.2.1.3.1.1.1 16-1.2.1.3.1.2 17-1.2.1.3.1 17-1.2.1.3.1.3 17-1.2.1.3.1.3.r 18-1.2.1.3.1.3.1.r 20-1.2.1.3.1.3.1 21-1.2.1.3.1.3.1 22-1.2.1.3.1.3.1 24-1.1.2.1 26-1.1.2 27-1.1.1.1.1 28-1.1.1.1.2 29-1.1 30-1.1.3.r 31-1.1.3.1.1.1.1 34-1.1.3 36-1 (s / study-01~e.36 :ARG1 (a2 / act-02~e.29 :ARG0 (p2 / pathway :name (n2 / name :op1 "p38"~e.27 :op2 "MAPK"~e.28)) :ARG1-of (a3 / activate-01~e.26 :ARG0 m4~e.24) :location~e.30 (m / macrophage~e.34 :ARG0-of (l / lack-01 :ARG1 (e / enzyme :name (n4 / name :op1 "MKK3"~e.31))))) :ARG1-of (c / cause-01~e.0 :ARG0 (p3 / produce-01~e.7 :ARG0~e.8 (m3 / macrophage~e.9) :ARG1 (p4 / protein~e.4 :name (n5 / name :op1 "cytokines"~e.5) :quant~e.2 (m2 / many~e.1) :ARG0-of~e.4 (i / inflame-01~e.4)) :time (a4 / activate-01~e.11 :ARG0~e.12 (m4 / molecular-physical-entity~e.17 :name (n3 / name :op1 "LPS"~e.13) :mod (p5 / potent~e.16) :ARG0-of~e.17 (a5 / activate-01~e.17 :ARG1~e.18 p2~e.20,21,22)) :ARG1 m3)))) # ::id bio.chicago_2015.34991 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stimulation of PKC by phorbol esters or Gq @-@ coupled receptors results in activation of Pyk2 ( 35 , 38 , 39 , 46 ) . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1 3-1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1 9-1.1.1.2.1.1 10-1.1.1.2.1.2 11-1 12-1.2.r 13-1.2 14-1.2.1.r 15-1.2.1.1.1 17-1.3.1.1.1.1 19-1.3.1.2.1.1 21-1.3.1.3.1.1 23-1.3.1.4.1.1 (r / result-01~e.11 :ARG1 (s / stimulate-01~e.0 :ARG0~e.3 (o / or~e.6 :op1 (e3 / ester :mod (s3 / small-molecule :name (n5 / name :op1 "phorbol"~e.4))) :op2 (p2 / protein :name (n3 / name :op1 "Gq-coupled"~e.7,9 :op2 "receptor"~e.10))) :ARG1~e.1 (e / enzyme :name (n / name :op1 "PKC"~e.2))) :ARG2~e.12 (a / activate-01~e.13 :ARG1~e.14 (e2 / enzyme :name (n4 / name :op1 "Pyk2"~e.15))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p3 / publication :ARG1-of (c / cite-01 :ARG2 35~e.17)) :op2 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 38~e.19)) :op3 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 39~e.21)) :op4 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 46~e.23))))) # ::id bio.chicago_2015.34994 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data indicate that the interactions of Gab1 with SHP @-@ 2 and PI @-@ 3 kinase are not simply mediated by interactions between phosphotyrosines and SH2 domains . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.3 7-1.2.3.1.1.1 9-1.2.3.2.1.1.1 11-1.2.3.2.1.1.1 12-1.2.3.2 13-1.2.3.2.2.1.1 15-1.2.3.2.2.1.1 16-1.2.3.2.1 16-1.2.3.2.2 18-1.2.1 18-1.2.1.r 19-1.2.4 20-1.2 22-1.2.2 22-1.2.3 25-1.2.3.2 26-1.2.2.2.1.1 27-1.2.2.2.1.2 (i / indicate-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (m / mediate-01~e.20 :polarity~e.18 -~e.18 :ARG0 (i3 / interact-01~e.22 :ARG0 (a2 / amino-acid :name (n4 / name :op1 "tyrosine") :ARG1-of (p2 / phosphorylate-01)) :ARG1 (p5 / protein-segment :name (n7 / name :op1 "SH2"~e.26 :op2 "domain"~e.27))) :ARG1 (i2 / interact-01~e.5,22 :ARG0 (p / protein :name (n / name :op1 "Gab1"~e.7)) :ARG1 (a / and~e.12,25 :op1 (k / kinase~e.16 :name (n2 / name :op1 "SHP-2"~e.9,11)) :op2 (k2 / kinase~e.16 :name (n3 / name :op1 "PI-3"~e.13,15)))) :ARG1-of (s / simple-02~e.19))) # ::id bio.chicago_2015.34997 ::amr-annotator SDL-AMR-09 ::preferred # ::tok First , Rabaptin @-@ 5 binds directly to the GTP @-@ bound form of Rab5 and is recruited to early endosomes by Rab5 in a GTP @-@ dependent manner ( Stenmark et al. , 1995b ) . # ::alignments 0-1.3 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1 5-1.1.2 5-1.1.2.2 5-1.1.2.2.r 6-1.1.3 7-1.1.2.r 9-1.1.2.2.1.1.1 11-1.1.2 11-1.1.2.2 11-1.1.2.2.r 14-1.1.2.1.1 15-1 15-1.4.1.1 17-1.2 19-1.2.3.1 21-1.2.1.r 22-1.2.1 23-1.2.1 24-1.2.1 25-1.2.4.2 27-1.2.4 28-1.2.4.r 30-1.4.1.1.1.1.1 31-1.4.1.1 32-1.4.1.1.2.1 (a / and~e.15 :op1 (b / bind-01~e.5 :ARG1 (p4 / protein :name (n / name :op1 "Rabaptin-5"~e.2,4)) :ARG2~e.7 (p5 / protein~e.5,11 :name (n2 / name :op1 "Rab5"~e.14) :ARG1-of~e.5,11 (b2 / bind-01~e.5,11 :ARG2 (s / small-molecule :name (n3 / name :op1 "GTP"~e.9)))) :ARG1-of (d2 / direct-02~e.6)) :op2 (r / recruit-01~e.17 :ARG0~e.21 p5~e.22,23,24 :ARG1 p4 :ARG2 (e3 / endosome :mod (e4 / early~e.19)) :manner~e.28 (d3 / depend-01~e.27 :ARG0 r :ARG1 s~e.25)) :time (f / first~e.0) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and~e.15,31 :op1 (p2 / person :name (n4 / name :op1 "Stenmark"~e.30)) :op2 (p3 / person :mod (o2 / other~e.32))) :time (d / date-entity :year 1995)))) # ::id bio.chicago_2015.35041 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since alpha @-@ catenin binds to actin , ARM ( or beta @-@ catenin ) establishes a bridge between cadherins and the actin cytoskeleton , a bridge that is needed for proper cell adhesion ( K EMLER 1993 ; C OX et al. 1996 ) . # ::alignments 0-1.3 1-1.3.1.1.1.1 3-1.3.1.1.1.1 4-1.3.1 5-1.3 5-1.3.1.2.r 6-1.3.1.2 8-1.1.1.1.1 10-1.1 11-1.1.2.1.1 13-1.1.2.1.1 15-1 17-1.2 18-1.2.1 20-1.2.1 22-1.2.1.2.1.1.1 23-1.2.1.2 26-1.2 29-1.2.2 30-1.2.2.1.r 31-1.2.2.1.2 32-1.2.2.1.1 33-1.2.2.1 37-1.4.1.1.2.1 41-1.4.1 41-1.4.1.2.1 42-1.4.1.2.1.2.1 43-1.4.1.2.2.1 (e / establish-01~e.15 :ARG0 (o / or~e.10 :op1 (p / protein-segment :name (n / name :op1 "ARM"~e.8)) :op2 (p2 / protein :name (n2 / name :op1 "beta-catenin"~e.11,13))) :ARG1 (b / bridge~e.17,26 :location (b2 / between~e.18,20 :op1 (p3 / protein-family :name (n3 / name :op1 "cadherin")) :op2 (c / cytoskeleton~e.23 :mod (p4 / protein :name (n4 / name :op1 "actin"~e.22)))) :ARG1-of (n5 / need-01~e.29 :ARG0~e.30 (a / adhere-01~e.33 :ARG1 (c2 / cell~e.32) :mod (p5 / proper~e.31)))) :ARG1-of (c3 / cause-01~e.0,5 :ARG0 (b3 / bind-01~e.4 :ARG1 (p6 / protein :name (n6 / name :op1 "alpha-catenin"~e.1,3)) :ARG2~e.5 p4~e.6)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.41 :op1 (p7 / publication-91 :ARG0 (p8 / person :name (n7 / name :op1 "Kemler")) :time (d / date-entity :year 1993~e.37)) :op2 (p9 / publication-91 :ARG0 (a3 / and~e.41 :op1 (p10 / person :name (n8 / name :op1 "Cox")) :op2 (p11 / person :mod (o2 / other~e.42))) :time (d2 / date-entity :year 1996~e.43))))) # ::id bio.chicago_2015.35048 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It previously has been shown that GSK3 beta can phosphorylate APC in vitro ( Rubinfeld et al. , 1996 ) , that Axin promotes this event ( Hart et al. , 1998 ) , and that this phosphorylation enhances the ability of APC to bind to beta @-@ catenin ( Rubinfeld et al. , 1996 ) . # ::alignments 1-1.2 4-1 5-1.1.r 6-1.1.1.1.2.1.1 7-1.1.1.1.2.1.2 8-1.1.1 9-1.1.1.1 10-1.1.1.1.1.1.1 11-1.1.1.1.3 12-1.1.1.1.3 14-1.1.1.2.1.1.1.1.1 15-1.1.1.2.1.1 16-1.1.1.2.1.1.2.1 18-1.1.1.2.1.2.1 21-1.1.r 22-1.1.2.1.1.1 23-1.1.2 27-1.1.2.3.1.1.1.1.1 28-1.1 28-1.1.1.2.1.1 28-1.1.2.3.1.1 29-1.1.1.2.1.1.2.1 31-1.1.2.3.1.2.1 34-1.1 34-1.1.1.2.1.1 37-1.1.1.1 38-1.1.3 40-1.1.3.2 41-1.1.3.2.2.r 42-1.1.3.2.2.1 44-1.1.3.2.2 45-1.1.3.2.2.2.r 46-1.1.3.2.2.2.1.1 48-1.1.3.2.2.2.1.1 50-1.1.3.3 51-1.1.3.3 52-1.1.3.3 53-1.1.3.3 54-1.1.3.3 (s / show-01~e.4 :ARG1~e.5,21 (a / and~e.28,34 :op1 (p3 / possible-01~e.8 :ARG1 (p / phosphorylate-01~e.9,37 :ARG1 (p4 / protein :name (n2 / name :op1 "APC"~e.10)) :ARG2 (e / enzyme :name (n / name :op1 "GSK3"~e.6 :op2 "beta"~e.7)) :manner (i / in-vitro~e.11,12)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and~e.15,28,34 :op1 (p6 / person :name (n3 / name :op1 "Rubinfeld"~e.14)) :op2 (p7 / person :mod (o / other~e.16,29))) :time (d / date-entity :year 1996~e.18)))) :op2 (p8 / promote-02~e.23 :ARG0 (p9 / protein :name (n4 / name :op1 "Axin"~e.22)) :ARG1 p :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a3 / and~e.28 :op1 (p11 / person :name (n5 / name :op1 "Hart"~e.27)) :op2 p7) :time (d2 / date-entity :year 1998~e.31)))) :op3 (e3 / enhance-01~e.38 :ARG0 p :ARG1 (c / capable-01~e.40 :ARG1 p4 :ARG2~e.41 (b / bind-01~e.44 :ARG1 p4~e.42 :ARG2~e.45 (p13 / protein :name (n6 / name :op1 "beta-catenin"~e.46,48)))) :ARG1-of d3~e.50,51,52,53,54)) :time (p2 / previous~e.1)) # ::id bio.chicago_2015.35049 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of N @-@ WASP by Cdc42 is required for initiating actin @-@ based motility of intracellular Shigella In vitro studies have indicated that activation of N @-@ WASP in cells requires Cdc42 bound to the GBD of N @-@ WASP ( 47 , 62 , 66 , 67 ) . # ::alignments 0-1.1.2 1-1.1.2.2.r 2-1.1.2.2.1.1 4-1.1.2.2.1.1 5-1.1.2.1.r 6-1.1.2.1.1.1 8-1.1 9-1.1.1.r 10-1.1.1 11-1.1.1.1.1.1.1.1 13-1.1.1.1.1 14-1.1.1.1 15-1.1.1.1.2.r 16-1.1.1.1.2.2 17-1.1.1.1.2.1.1 18-1.2.1.1 19-1.2.1.1 20-1.2.1 22-1.2 23-1.2.2.r 24-1.2.2.1 25-1.2.2.1.1.r 26-1.2.2.1.1.1.1 28-1.2.2.1.1.1.1 29-1.2.1.1 29-1.2.2.1.2.r 30-1.2.2.1.2 31-1.2.2 32-1.2.2.2.1.1.1 33-1.2.2.2 34-1.2.2.2.2.r 36-1.2.2.2.2.1.1 38-1.2.2.2.2.2 39-1.2.2.2.2.2 40-1.2.2.2.2.2 42-1.2.3.1.1.1.1 44-1.2.3.1.1.1.2 46-1.2.3.1.1.1.3 48-1.2.3.1.1.1.4 (m2 / multi-sentence :snt1 (r / require-01~e.8 :ARG0~e.9 (i / initiate-01~e.10 :ARG1 (m / motility~e.14 :ARG1-of (b / base-02~e.13 :ARG2 (p2 / protein :name (n3 / name :op1 "actin"~e.11))) :poss~e.15 (o / organism :name (n4 / name :op1 "Shigella"~e.17) :mod (i2 / intracellular~e.16)))) :ARG1 (a / activate-01~e.0 :ARG0~e.5 (p / protein :name (n2 / name :op1 "Cdc42"~e.6)) :ARG1~e.1 (p4 / protein :name (n / name :op1 "N-WASP"~e.2,4)))) :snt2 (i3 / indicate-01~e.22 :ARG0 (s / study-01~e.20 :manner (i4 / in-vitro~e.18,19,29)) :ARG1~e.23 (r2 / require-01~e.31 :ARG0 (a2 / activate-01~e.24 :ARG1~e.25 (p5 / protein :name (n6 / name :op1 "N-WASP"~e.26,28)) :location~e.29 (c / cell~e.30)) :ARG1 (b2 / bind-01~e.33 :ARG1 (p6 / protein :name (n7 / name :op1 "Cdc42"~e.32)) :ARG2~e.34 (p7 / protein-segment :name (n5 / name :op1 "GBD"~e.36) :part-of p5~e.38,39,40))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 47~e.42 :op2 62~e.44 :op3 66~e.46 :op4 67~e.48)))))) # ::id bio.chicago_2015.35062 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In oocytes from one @-@ third of Xenopus donors , the activation of CFTR by cGMP averaged 87 % of the level achieved by cAMP . # ::alignments 1-1.3.1.1 2-1.3.2.r 3-1.3.2.1 5-1.3.2.1 7-1.3.2.2.1 8-1.3.2 8-1.3.2.3 8-1.3.2.3.r 11-1.1 12-1.1.2.r 13-1.1.2.1.1 14-1.1.1.r 15-1.1.1.1.1 16-1 17-1.2.1 18-1.2 21-1.2.2.1 22-1.2.2.1.1 23-1.2.2.1.1.1.r 24-1.2.2.1.1.1.1.1 (a / average-01~e.16 :ARG1 (a2 / activate-01~e.11 :ARG0~e.14 (s2 / small-molecule :name (n2 / name :op1 "cGMP"~e.15)) :ARG1~e.12 (p3 / protein :name (n / name :op1 "CFTR"~e.13))) :ARG2 (p4 / percentage-entity~e.18 :value 87~e.17 :ARG3-of (i / include-91 :ARG2 (l / level~e.21 :ARG1-of (a3 / achieve-01~e.22 :ARG0~e.23 (s / small-molecule :name (n3 / name :op1 "cAMP"~e.24)))))) :location (c / cell :name (n4 / name :op1 "oocyte"~e.1) :source~e.2 (o / organism~e.8 :quant "1/3"~e.3,5 :name (n5 / name :op1 "Xenopus"~e.7) :ARG0-of~e.8 (d2 / donate-01~e.8)))) # ::id bio.chicago_2015.35082 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After washing with GST binding buffer , proteins associated with GST @-@ agarose beads were analyzed with 4 % - 20 % SDS @-@ PAGE and visualized by autoradiography . # ::alignments 0-1.3 1-1.3.1 2-1.1.2.r 2-1.3.1.2.r 3-1.3.1.2.1.1.1.1 4-1.3.1.2.1 5-1.3.1.2 7-1.1.1 8-1.1.1.1 9-1.1.2.r 10-1.1.1.1.1.1.1 12-1.3.1.1 13-1.3.1.1 15-1.1 16-1.1.2.r 17-1.1.2.2.1.1 18-1.1.2.2.1 20-1.1.2.2.2.1 21-1.1.2.2.2 22-1.1.2.1.1 24-1.1.2.1.1 25-1 26-1.2 27-1.2.2.r 28-1.2.2 (a3 / and~e.25 :op1 (a / analyze-01~e.15 :ARG1 (p3 / protein~e.7 :ARG1-of (a2 / associate-01~e.8 :ARG2 (b2 / bead :consist-of (a6 / and :op1 e~e.10 :op2 (a7 / agarose))))) :instrument~e.2,9,16 (t / thing :name (n2 / name :op1 "SDS-PAGE"~e.22,24) :quant (v / value-interval :op1 (p / percentage-entity~e.18 :value 4~e.17) :op2 (p2 / percentage-entity~e.21 :value 20~e.20)))) :op2 (v2 / visualize-01~e.26 :ARG1 p3 :instrument~e.27 (a4 / autoradiography~e.28)) :time (a5 / after~e.0 :op1 (w / wash-01~e.1 :ARG1 p3~e.12,13 :ARG2~e.2 (b3 / buffer~e.5 :ARG1-of (b4 / bind-01~e.4 :ARG2 (e / enzyme :name (n3 / name :op1 "GST"~e.3))))))) # ::id bio.chicago_2015.35109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 5 E , both the GTP @- and the GDP @-@ bound forms of RhoA are able to bind p116Rip . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 9-1.1.1.2.1.1.1 11-1.1 13-1.1.2.2.1.1.1 15-1.1.1.2 15-1.1.2.2 16-1.1.1 16-1.1.2 17-1.1.1.1.r 18-1.1.1.1.1.1 20-1 22-1.2 23-1.2.2.1.1 (c / capable-01~e.20 :ARG1 (a / and~e.11 :op1 (f / form~e.16 :mod~e.17 (p2 / protein :name (n2 / name :op1 "RhoA"~e.18)) :ARG1-of (b2 / bind-01~e.15 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GTP"~e.9)))) :op2 (f2 / form~e.16 :mod p2 :ARG1-of (b / bind-01~e.15 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "GDP"~e.13))))) :ARG2 (b3 / bind-01~e.22 :ARG1 a :ARG2 (p3 / protein :name (n5 / name :op1 "p116Rip"~e.23))) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f3 / figure~e.3 :mod "5E"))) # ::id bio.chicago_2015.35124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok beta @-@ Adrenergic receptor @-@ induced apoptosis requires tyrosine kinase Lck . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1.1 5-1.1.1 6-1.1 7-1 8-1.2 9-1.2 10-1.2.1.1 (r / require-01~e.7 :ARG0 (a / apoptosis~e.6 :ARG2-of (i / induce-01~e.5 :ARG0 (r2 / receptor~e.3 :name (n3 / name :op1 "beta-Adrenergic"~e.0,2)))) :ARG1 (t / tyrosine-kinase~e.8,9 :name (n2 / name :op1 "Lck"~e.10))) # ::id bio.chicago_2015.35127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like PKB , PKBR @-@ 1 kinase activity is stimulated in response to cAMP ; however , unlike the activation of PKB the activation of PKBR @-@ 1 is not inhibited by the PI3K inhibitor LY294002 ( Meili et al. 2000 ) . # ::alignments 0-1.4 1-1.4.1.1.1 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.1 7-1.1 9-1 10-1.2.r 11-1.2 12-1.2.1.r 13-1.2.1.1.1 15-1.3.r 17-1.3.4 17-1.3.4.1 19-1.3.4.2 21-1.3.4.2.1 23-1.3.3 23-1.3.4.2 25-1.1.1.1.1 27-1.1.1.1.1 29-1.3.1 29-1.3.1.r 29-1.3.4.1.r 30-1.3 30-1.3.2.2 31-1.3.2.r 33-1.3.2.2.1.1.1 34-1.3.2.2 35-1.3.2.1.1 37-1.5.1.1.1.1.1 38-1.5.1.1 39-1.5.1.1.2.1 40-1.5.1.2.1 (s / stimulate-01~e.9 :ARG1 (a / activity-06~e.7 :ARG0 (k / kinase~e.6 :name (n / name :op1 "PKBR-1"~e.3,5,25,27))) :ARG2-of~e.10 (r2 / respond-01~e.11 :ARG1~e.12 (s3 / small-molecule :name (n2 / name :op1 "cAMP"~e.13))) :concession-of~e.15 (i2 / inhibit-01~e.30 :polarity~e.29 -~e.29 :ARG0~e.31 (s2 / small-molecule :name (n4 / name :op1 "LY294002"~e.35) :ARG0-of (i3 / inhibit-01~e.30,34 :ARG1 (e2 / enzyme :name (n5 / name :op1 "PI3K"~e.33)))) :ARG1 (a2 / activate-01~e.23 :ARG1 k) :ARG1-of (r4 / resemble-01~e.17 :polarity~e.29 -~e.17 :ARG2 (a3 / activate-01~e.19,23 :ARG1 e~e.21))) :ARG1-of (r3 / resemble-01~e.0 :ARG2 (e / enzyme :name (n3 / name :op1 "PKB"~e.1))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and~e.38 :op1 (p2 / person :name (n6 / name :op1 "Meili"~e.37)) :op2 (p3 / person :mod (o / other~e.39))) :time (d3 / date-entity :year 2000~e.40)))) # ::id bio.chicago_2015.35185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rb association with E2F not only blocks transcriptional activation by E2F but also forms an active transcriptional repressor complex at promoters that can block transcription by recruiting histone deacetylase ( HDAC ) and remodeling chromatin [ 98 , 99 , 100 and 101 ] . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 6-1.1 7-1.1.2.2 8-1.1.2 10-1.2.1 12-1.2.3 13-1.2 15-1.2.2.2 16-1.2.2.1.1 17-1.2.2.1 18-1.2.2 22-1.2.2.3.3 23-1.2.2.3 24-1.2.2.3.1 25-1.2.2.3.2.r 26-1.2.2.3.2.1 27-1.2.2.3.2.1.1.1.1 28-1.2.2.3.2.1.1.1.2 32-1.2.2.3.2 33-1.2.2.3.2.2 34-1.2.2.3.2.2.1.1.1 36-1.3.1.1.1.1 38-1.3.1.1.1.2 40-1.3.1.1.1.3 41-1.3.1.1.1 42-1.3.1.1.1.4 (a3 / and :op1 (b / block-01~e.6 :ARG0 (a / associate-01~e.1 :ARG1 (p2 / protein :name (n / name :op1 "Rb"~e.0)) :ARG2~e.2 (p / protein :name (n2 / name :op1 "E2F"~e.3))) :ARG1 (a2 / activate-01~e.8 :ARG0 p :ARG1 (t / transcribe-01~e.7))) :op2 (f / form-01~e.13 :ARG0 a~e.10 :ARG1 (m / macro-molecular-complex~e.18 :ARG0-of (r2 / repress-01~e.17 :ARG1 t~e.16) :ARG0-of (a5 / activity-06~e.15) :ARG0-of (b2 / block-01~e.23 :ARG1 t~e.24 :ARG3~e.25 (a7 / and~e.32 :op1 (r3 / recruit-01~e.26 :ARG1 (e / enzyme :name (n4 / name :op1 "histone"~e.27 :op2 "deacetylase"~e.28))) :op2 (r4 / remodel-01~e.33 :ARG1 (m3 / macro-molecular-complex :name (n5 / name :op1 "chromatin"~e.34)))) :ARG1-of (p4 / possible-01~e.22))) :mod (a4 / also~e.12) :location (m2 / molecular-physical-entity :ARG0-of (p3 / promote-02))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and~e.41 :op1 98~e.36 :op2 99~e.38 :op3 100~e.40 :op4 101~e.42))))) # ::id bio.chicago_2015.35239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reactions were allowed to elongate for the indicated amounts of time at room temperature and were stopped by the addition of 200 mul of Sarkosyl Stop Solution ( 100 mM Tris , 100 mM NaCl , 10 mM EDTA , 1 % Sarkosyl , 200 mug @/@ ml tRNA ) . # ::alignments 0-1.1.1.1 0-1.1.1.1.1 0-1.1.1.1.1.r 2-1.1 4-1.1.1 5-1.1.1.2.r 7-1.1.1.2.2 8-1.1.1.2 9-1.1.1.2.1.r 10-1.1.1.2.1 11-1.1.1.3.r 12-1.1.1.3.1 13-1.1.1.3 14-1 16-1.2 17-1.2.2.r 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.2.1 24-1.2.2.1.1.1 25-1.2.2.1.1.2 26-1.2.2.1.1.3 28-1.2.2.1.3.1.1.2.1 28-1.2.2.1.3.1.2.2.1 29-1.2.2.1.3.1.1.2.2 29-1.2.2.1.3.1.2.2.2 29-1.2.2.1.3.1.3.2.2 30-1.2.2.1.3.1.1.1.1 32-1.2.2.1.3.1.1.2.1 32-1.2.2.1.3.1.2.2.1 33-1.2.2.1.3.1.1.2.2 33-1.2.2.1.3.1.2.2.2 33-1.2.2.1.3.1.3.2.2 34-1.2.2.1.3.1.2.1.1 36-1.2.2.1.3.1.3.2.1 37-1.2.2.1.3.1.3.2.2 38-1.2.2.1.3.1.3.1.1 40-1.2.2.1.3.1.4.2.1 41-1.2.2.1.3.1.4.2 42-1.2.2.1.3.1.4.1.1 44-1.2.2.1.3.1.5.2.1 47-1.2.2.1.3.1.5.2.2 48-1.2.2.1.3.1.5.1.1 (a3 / and~e.14 :op1 (a / allow-01~e.2 :ARG1 (e / elongate-01~e.4 :ARG0 (t / thing~e.0 :ARG2-of~e.0 (r / react-01~e.0)) :duration~e.5 (a2 / amount~e.8 :quant-of~e.9 (t2 / time~e.10) :ARG1-of (i / indicate-01~e.7)) :condition~e.11 (t3 / temperature~e.13 :mod (r2 / room~e.12)))) :op2 (s / stop-01~e.16 :ARG1 t :ARG2~e.17 (a4 / add-02~e.19 :ARG1~e.20 (p2 / product :name (n / name :op1 "Sarkosyl"~e.24 :op2 "Stop"~e.25 :op3 "Solution"~e.26) :quant (v / volume-quantity :quant 200~e.21 :unit (m / microlitre)) :ARG1-of (e2 / equal-01 :ARG2 (a5 / and :op1 (s2 / small-molecule :name (n2 / name :op1 "Tris"~e.30) :quant (c2 / concentration-quantity :quant 100~e.28,32 :unit (m3 / millimolar~e.29,33))) :op2 (s3 / small-molecule :name (n3 / name :op1 "NaCl"~e.34) :quant (c3 / concentration-quantity :quant 100~e.28,32 :unit (m4 / millimolar~e.29,33))) :op3 (s4 / small-molecule :name (n4 / name :op1 "EDTA"~e.38) :quant (c4 / concentration-quantity :quant 10~e.36 :unit (m5 / millimolar~e.29,33,37))) :op4 (s5 / small-molecule :name (n5 / name :op1 "Sarkosyl"~e.42) :quant (p / percentage-entity~e.41 :value 1~e.40)) :op5 (n7 / nucleic-acid :name (n6 / name :op1 "tRNA"~e.48) :quant (c5 / concentration-quantity :quant 200~e.44 :unit (m7 / microgram-per-milliliter~e.47))))))))) # ::id bio.chicago_2015.35250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding to the membrane is mediated by its PH domain , which binds PI( 4,5 ) P2 ( 14 , 15 ) , and by a region upstream of this domain that can directly penetrate into the lipid bilayer ( 16 ) . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1 5-1 6-1.1.r 7-1.1.1.2 7-1.1.1.2.r 8-1.1.1.1.1 12-1.1.1 12-1.1.1.3 12-1.1.1.3.r 18-1.1.1.3.1.1.2.1.1.1.1 20-1.1.1.3.1.1.2.1.1.1.2 23-1.1 23-1.1.1.3.1 23-1.1.1.3.1.1.2.1.1.1 26-1.1.2 27-1.1.2.3.2 33-1.1.2.4.1.3 34-1.1.2.4.1 35-1.1.2.4.1.2.r 37-1.1.2.4.1.2.1 38-1.1.2.4.1.2 40-1.1.2.2.1.1.1 (m2 / mediate-01~e.5 :ARG0~e.6 (a4 / and~e.23 :op1 (p7 / protein-segment~e.12 :name (n / name :op1 "PH"~e.8) :poss~e.7 m~e.7 :ARG2-of~e.12 (b2 / bind-01~e.12 :ARG1 (a / and~e.23 :op1 (s / small-molecule :name (n2 / name :op1 "PI(4,5)P2") :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and~e.23 :op1 14~e.18 :op2 15~e.20)))))))) :op2 (r / region~e.26 :part-of p7 :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 16~e.40))) :location (r3 / relative-position :op1 p7 :direction (u / upstream~e.27)) :ARG1-of (c3 / capable-01 :ARG2 (p5 / penetrate-01~e.34 :ARG0 p7 :ARG1~e.35 (b3 / bilayer~e.38 :mod (l / lipid~e.37)) :ARG1-of (d / direct-02~e.33))))) :ARG1 (b / bind-01~e.0 :ARG2~e.1 (m / membrane~e.3))) # ::id bio.chicago_2015.35259 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PKA phosphorylation of adducin reduced activity of adducin in association with spectrin @-@ actin complexes and in promoting binding of spectrin to F @-@ actin . # ::alignments 0-1.1.2.1.1 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1 5-1.2 7-1.1.1.1.1 8-1.1.3.r 9-1.1.3 10-1.1.3.1.r 11-1.1.3.1.1.1.1 13-1.1.3.1.2.1.1 14-1.1.3.1 16-1.1.4.r 17-1.1.4 18-1.1.4.1 19-1.1.4.1.1.r 20-1.1.4.1.1 21-1.1.4.1.2.r 22-1.1.4.1.2.1.1 24-1.1.3.1.2.1.1 (r / reduce-01~e.4 :ARG0 (p / phosphorylate-01~e.1 :ARG1~e.2 (p2 / protein :name (n / name :op1 "adducin"~e.3,7)) :ARG2 (e / enzyme :name (n2 / name :op1 "PKA"~e.0)) :ARG1-of~e.8 (a2 / associate-01~e.9 :ARG2~e.10 (m / macro-molecular-complex~e.14 :part (p4 / protein :name (n4 / name :op1 "spectrin"~e.11)) :part (p5 / protein :name (n5 / name :op1 "actin"~e.13,24)))) :purpose~e.16 (p3 / promote-02~e.17 :ARG1 (b / bind-01~e.18 :ARG1~e.19 p4~e.20 :ARG2~e.21 (p6 / protein :name (n3 / name :op1 "F-actin"~e.22))))) :ARG1 (a / activity-06~e.5 :ARG0 p2)) # ::id bio.chicago_2015.35282 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This domain mediates the association of NIK with MEKK1 and is critical for NIK activation of the SAPK pathway , suggesting that the C @-@ terminal domain of these proteins encodes a new protein domain family that couples these kinases to the SAPK pathway , possibly by interacting with MEKK1 . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 7-1.1.2.2.r 8-1.1.2.2.1.1 9-1 11-1.2 12-1.2.2.r 13-1.2.2.1 14-1.2.2 15-1.2.2.2.r 17-1.2.2.2.1.1 18-1.2.2.2 20-1.3 21-1.3.1.r 23-1.3.1.1.1.1 25-1.3.1.1.1.1 26-1.1.1 28-1.1.1.1 29-1.3.1.2 30-1.3.1 32-1.3.1.2.3 33-1.3.1.2 34-1.3.1.2.1 35-1.3.1.2 37-1.3.1.2.2 38-1.1.1.1 40-1.3.1.2.2.2.r 42-1.3.1.2.2.2 43-1.3.1.2.2.2 45-1.3.1.2.2.3.2 47-1.3.1.2.2.3 48-1.3.1.2.2.3.1.r 49-1.3.1.2.2.3.1 (a2 / and~e.9 :op1 (m / mediate-01~e.2 :ARG0 (d / domain~e.1,26 :mod (t / this~e.0,28,38)) :ARG1 (a / associate-01~e.4 :ARG1~e.5 (e / enzyme :name (n / name :op1 "NIK"~e.6)) :ARG2~e.7 (e2 / enzyme :name (n2 / name :op1 "MEKK1"~e.8)))) :op2 (c / critical-02~e.11 :ARG1 d :ARG3~e.12 (a3 / activate-01~e.14 :ARG0 e~e.13 :ARG1~e.15 (p / pathway~e.18 :name (n3 / name :op1 "SAPK"~e.17)))) :ARG0-of (s / suggest-01~e.20 :ARG1~e.21 (e3 / encode-01~e.30 :ARG0 (p4 / protein-segment :name (n4 / name :op1 "C-terminus"~e.23,25) :part-of (a4 / and :op1 e :op2 e2)) :ARG1 (p2 / protein-family~e.29,33,35 :mod (d3 / domain~e.34) :ARG0-of (c2 / couple-01~e.37 :ARG1 (a5 / and :op1 e :op2 e2) :ARG2~e.40 p~e.42,43 :manner (i / interact-01~e.47 :ARG1~e.48 e2~e.49 :ARG1-of (p3 / possible-01~e.45))) :ARG1-of (n5 / new-02~e.32))))) # ::id bio.chicago_2015.35301 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We conclude that ind represses msh and achaete gene expression directly or indirectly , and that ind is necessary for establishing proper intermediate @-@ column identity within the neuroectoderm . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 4-1.2.1 5-1.2.1.2.1.1.1.1 6-1.2.1.2.1 7-1.2.1.2.1.2.1.1 8-1.2.1.2.1.1 8-1.2.1.2.1.2 9-1.2.1.2 10-1.2.1.3.1 10-1.2.1.3.2 11-1.2.1.3 12-1.2.1.3.1 12-1.2.1.3.2 12-1.2.1.3.2.1 12-1.2.1.3.2.1.r 16-1.2.1.1.1.1 18-1.2.2 19-1.2.2.1.r 20-1.2.2.1 21-1.2.2.1.1.2 22-1.2.2.1.1.1.1 24-1.2.2.1.1.1 25-1.2.2.1.1 28-1.2.2.1.2 (c / conclude-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (a / and :op1 (r / repress-01~e.4 :ARG0 (p2 / protein :name (n2 / name :op1 "ind"~e.3,16)) :ARG1 (e2 / express-03~e.9 :ARG1 (a2 / and~e.6 :op1 (g / gene~e.8 :name (n3 / name :op1 "msh"~e.5)) :op2 (g2 / gene~e.8 :name (n4 / name :op1 "achaete"~e.7)))) :manner (o / or~e.11 :op1 (d / direct-02~e.10,12) :op2 (d2 / direct-02~e.10,12 :polarity~e.12 -~e.12))) :op2 (n / need-01~e.18 :ARG0~e.19 (e3 / establish-01~e.20 :ARG1 (i / identity~e.25 :mod (c2 / column~e.24 :mod (i2 / intermediate~e.22)) :mod (p / proper~e.21)) :location (n5 / neuroectoderm~e.28)) :ARG1 p2))) # ::id bio.chicago_2015.35359 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vivo analysis of the association of PML and Sp1 . # ::alignments 0-1.2 1-1.2 2-1 3-1.1.r 5-1.1 6-1.1.1.r 7-1.1.1.1.1 9-1.1.2.1.1 (a / analyze-01~e.2 :ARG1~e.3 (a2 / associate-01~e.5 :ARG1~e.6 (p2 / protein :name (n / name :op1 "PML"~e.7)) :ARG2 (p / protein :name (n2 / name :op1 "Sp1"~e.9))) :manner (i / in-vivo~e.0,1)) # ::id bio.chicago_2015.35392 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A gain @-@ of @-@ function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways . # ::alignments 1-1.1.2 5-1.1.2.1 6-1.1 7-1.1.1.r 8-1.1.1.2.1.1 9-1.1.1.1.1 10-1.1.1 11-1 12-1.2.1.1.2 13-1.2.1.1.1.1 14-1.2.1.1.1.2 15-1.2.1.1.1.3 16-1.2.1 17-1.2 (a / activate-01~e.11 :ARG0 (m / mutate-01~e.6 :ARG1~e.7 (k / kinase~e.10 :name (n / name :op1 "MAP"~e.9) :part-of (o / organism :name (n2 / name :op1 "Drosophila"~e.8))) :mod (g2 / gain-02~e.1 :mod (f / function-01~e.5))) :ARG1 (p / pathway~e.17 :ARG0-of (s / signal-07~e.16 :ARG1 (e / enzyme :name (n3 / name :op1 "receptor"~e.13 :op2 "tyrosine"~e.14 :op3 "kinase"~e.15) :mod (m2 / multiple~e.12))))) # ::id bio.chicago_2015.35414 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since DEDD was found to associate with FADD and caspase @-@ 8 in vitro , we tested whether under conditions with significant amounts of DEDD in the cytoplasm an association with endogenous FADD and @/@ or caspase @-@ 8 could be found in vivo . # ::alignments 0-1.3 1-1.2.2.1.1.1.1 3-1.3.1 4-1.3 5-1.2.2.1 5-1.3.1.2 7-1.2.2.1.2.1.1.1 8-1.2.2.1.2 9-1.2.2.1.2.2.1.1 11-1.2.2.1.2.2.1.1 12-1.3.1.2.3 13-1.3.1.2.3 15-1.1 16-1 17-1.2.1 17-1.2.1.r 19-1.2.2.3.r 21-1.2.2.3.1 22-1.2.2.3 23-1.2.2.3.2.r 24-1.2.2.3.2 25-1.2.2.3.3.r 25-1.3.1.2.3 27-1.2.2.3.3 29-1.2.2.1 31-1.2.2.1.2.1.2 32-1.2.2.1.2.1.1.1 33-1.2.2.1.2 35-1.2.2.1.2 36-1.2.2.1.2.2.1.1 38-1.2.2.1.2.2.1.1 39-1.2 41-1.2.2 42-1.2.2.2 43-1.2.2.2 (t / test-01~e.16 :ARG0 (w / we~e.15) :ARG1 (p / possible-01~e.39 :mode~e.17 interrogative~e.17 :ARG1 (f / find-01~e.41 :ARG1 (a / associate-01~e.5,29 :ARG1 (p4 / protein :name (n / name :op1 "DEDD"~e.1)) :ARG2 (a2 / and-or~e.8,33,35 :op1 (p2 / protein :name (n2 / name :op1 "FADD"~e.7,32) :mod (e / endogenous~e.31)) :op2 (p3 / protein :name (n3 / name :op1 "caspase-8"~e.9,11,36,38)))) :manner (i / in-vivo~e.42,43) :condition~e.19 (a4 / amount~e.22 :ARG1-of (s / significant-02~e.21) :quant-of~e.23 p4~e.24 :location~e.25 (c2 / cytoplasm~e.27)))) :ARG1-of (c / cause-01~e.0,4 :ARG0 (f2 / find-01~e.3 :ARG0 w :ARG1 (a5 / associate-01~e.5 :ARG1 p4 :ARG2 (a6 / and :op1 p2 :op2 p3) :manner (i2 / in-vitro~e.12,13,25))))) # ::id bio.chicago_2015.35423 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further , we also demonstrated that Dermo @-@ 1 represses the transactivation of MyoD and MEF2 through different mechanisms . # ::alignments 0-1.4 2-1.1 3-1.3 4-1 5-1.2.r 6-1.2.1.1.1 8-1.2.1.1.1 9-1.2 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1.1 14-1.2.2.1 15-1.2.2.1.2.1.1 17-1.2.3.1 18-1.2.3 (d / demonstrate-01~e.4 :ARG0 (w / we~e.2) :ARG1~e.5 (r / repress-01~e.9 :ARG0 (p / protein :name (n / name :op1 "Dermo-1"~e.6,8)) :ARG1 (t / transactivate-01~e.11 :ARG1~e.12 (a3 / and~e.14 :op1 (p2 / protein :name (n2 / name :op1 "MyoD"~e.13)) :op2 (p3 / protein :name (n3 / name :op1 "MEF2"~e.15)))) :instrument (m / mechanism~e.18 :ARG1-of (d2 / differ-02~e.17))) :mod (a / also~e.3) :mod (f / further~e.0)) # ::id bio.chicago_2015.35431 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary . # ::alignments 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.1.1 5-1.1.2 6-1 8-1.2.2 8-1.2.2.1 8-1.2.2.1.r 9-1.2 10-1.2.1.r 11-1.2.1.2 12-1.2.1.1 13-1.2.1 14-1.2.3.r 16-1.2.3.1.1.1 17-1.2.3 (a / affect-01~e.6 :ARG0 (g2 / group~e.2 :mod (n3 / novel~e.1) :consist-of~e.3 (m / mutate-01~e.5 :ARG1 (g / gene :name (n / name :op1 "pumilio"~e.4)))) :ARG1 (d / divide-02~e.9 :ARG1~e.10 (c / cell~e.13 :mod (s / stem~e.12) :mod (g3 / germline~e.11)) :mod (s2 / symmetric~e.8 :polarity~e.8 -~e.8) :location~e.14 (o / ovary~e.17 :part-of (o2 / organism :name (n2 / name :op1 "Drosophila"~e.16))))) # ::id bio.chicago_2015.35452 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , PAK activation by Agrin is dependent on Cdc42 and Rac , suggesting that PAK may be downstream of the small GTPases . # ::alignments 0-1 2-1.1.1.2.1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.1.1.1 10-1.1.2 11-1.1.2.2.1.1 13-1.1.3 15-1.1.1.2.1.1 16-1.1.3.1 17-1.1.3.1.1 18-1.1.3.1.1.2.2 21-1.1.3.1.1.2.1.2 (a3 / and~e.0 :op2 (d2 / depend-01~e.7 :ARG0 (a / activate-01~e.3 :ARG0~e.4 (p / protein :name (n2 / name :op1 "Agrin"~e.5)) :ARG1 (e / enzyme :name (n / name :op1 "PAK"~e.2,15))) :ARG1~e.8 (a2 / and~e.10 :op1 (p3 / protein :name (n3 / name :op1 "Cdc42"~e.9)) :op2 (e3 / enzyme :name (n4 / name :op1 "Rac"~e.11))) :ARG0-of (s / suggest-01~e.13 :ARG1 (p2 / possible-01~e.16 :ARG1 (b / be-located-at-91~e.17 :ARG1 e :ARG2 (r / relative-position :op1 (e4 / enzyme :name (n5 / name :op1 "GTPase") :mod (s2 / small~e.21)) :direction (d / downstream~e.18))))))) # ::id bio.chicago_2015.35459 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B , IKAP significantly potentiates MEKK1 @-@ induced JNK activation . # ::alignments 0-1.1 2-1.2.1.1 3-1.4 4-1 5-1.3.2.1.1.1 7-1.3.2 8-1.3.1.1.1 9-1.3 (p / potentiate-01~e.4 :li "b"~e.0 :ARG0 (p3 / protein :name (n2 / name :op1 "IKAP"~e.2)) :ARG1 (a2 / activate-01~e.9 :ARG1 (e / enzyme :name (n3 / name :op1 "JNK"~e.8)) :ARG2-of (i / induce-01~e.7 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEKK1"~e.5)))) :ARG1-of (s / significant-02~e.3)) # ::id bio.chicago_2015.35483 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been found that KSR is bound directly to MEK in the cytoplasm of quiescent cells ; upon activation of the MAPK pathway by growth factors or activated RAS , KSR is relocalized to the plasma membrane in a complex containing RAF , MEK , and MAPK ( M ICHAUD et al. 1997 ; D ENOUEL @-@ GALY et al. 1998 ; # ::alignments 3-1.1 4-1.1.1.r 5-1.1.1.1.1.1 7-1.1.1 8-1.1.1.3 9-1.1.1.2.r 10-1.1.1.2.1.1 11-1.1.1.4.r 13-1.1.1.4 14-1.1.1.4.1.r 15-1.1.1.4.1.1 16-1.1.1.4.1 19-1.2.3 20-1.2.3.2.r 22-1.2.3.2.1.1 23-1.2.3.2 24-1.2.3.1.r 25-1.2.3.1.1 26-1.2.3.1.1 27-1.2.3.1 28-1.2.3.1.2.2 29-1.2.3.1.2.1.1 31-1.2.1 33-1.2 34-1.2.2.r 36-1.2.2.1 37-1.2.2 38-1.2.2.2.r 40-1.2.2.2 41-1.2.2.2.1 42-1.2.2.2.1.1.1.1.1 44-1.2.2.2.1.1.2 46-1 46-1.2.2.2.1.1 46-1.3.1 47-1.2.2.2.1.1.3.1.1 51-1.3.1 52-1.3.1.1.1.2.1 52-1.3.1.2.1.2.1 53-1.3.1.1.2.1 59-1.3.1 59-1.3.1.1.1 59-1.3.1.2.1 60-1.3.1.1.1.2.1 60-1.3.1.2.1.2.1 61-1.3.1.2.2.1 (a / and~e.46 :op1 (f / find-01~e.3 :ARG1~e.4 (b / bind-01~e.7 :ARG1 (e5 / enzyme :name (n5 / name :op1 "KSR"~e.5)) :ARG2~e.9 (e / enzyme :name (n / name :op1 "MEK"~e.10)) :ARG1-of (d3 / direct-02~e.8) :location~e.11 (c / cytoplasm~e.13 :part-of~e.14 (c2 / cell~e.16 :mod (q / quiescent~e.15))))) :op2 (r / relocalize-00~e.33 :ARG1 e5~e.31 :destination~e.34 (m / membrane~e.37 :mod (p6 / plasma~e.36) :location~e.38 (m2 / macro-molecular-complex~e.40 :ARG0-of (c4 / contain-01~e.41 :ARG1 (a3 / and~e.46 :op1 (e3 / enzyme :name (n4 / name :op1 "Raf"~e.42)) :op2 e~e.44 :op3 (e4 / enzyme :name (n2 / name :op1 "MAPK"~e.47)))))) :condition (a4 / activate-01~e.19 :ARG0~e.24 (o / or~e.27 :op1 (g / growth-factor~e.25,26) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.29) :ARG1-of (a2 / activate-01~e.28))) :ARG1~e.20 (p / pathway~e.23 :name (n9 / name :op1 "MAPK"~e.22)))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and~e.46,51,59 :op1 (p7 / publication-91 :ARG0 (a6 / and~e.59 :op1 (p8 / person :name (n6 / name :op1 "Michaud")) :op2 (p9 / person :mod (o2 / other~e.52,60))) :time (d / date-entity :year 1997~e.53)) :op2 (p10 / publication-91 :ARG0 (a7 / and~e.59 :op1 (p11 / person :name (n7 / name :op1 "Denouel-Galy")) :op2 (p12 / person :mod (o3 / other~e.52,60))) :time (d2 / date-entity :year 1998~e.61))))) # ::id bio.chicago_2015.35489 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SXL associates with the U1 snRNP particle in embryonic extracts . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 4-1.2.1.1 5-1.2.2.1.1 6-1.2 7-1.3.r 8-1.3.1.1 9-1.3 9-1.3.1 9-1.3.1.r (a / associate-01~e.1 :ARG1 (p3 / protein :name (n / name :op1 "SXL"~e.0)) :ARG2~e.2 (p / particle~e.6 :name (n2 / name :op1 "U1"~e.4) :part-of (p2 / protein :name (n3 / name :op1 "snRNP"~e.5))) :location~e.7 (m / molecular-physical-entity~e.9 :ARG1-of~e.9 (e / extract-01~e.9 :ARG2 (e2 / embryo~e.8)))) # ::id bio.chicago_2015.35547 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ubc9 Binding to Mdm2 Is Decreased after UV Irradiation-- Since UV irradiation has been shown to reduce the degree of Mdm2 sumoylation , we have monitored possible changes in the association of Ubc9 with Mdm2 in UV @-@ treated cells . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 5-1.1 6-1.1.2 9-1.2.3 11-1.1.2.1 11-1.2.3.1.1.1 14-1.2.3.1 16-1.2.3.1.1 18-1.2.3.1.1.2 18-1.2.3.1.1.2.1.r 20-1.2.2.1.2.1.1 23-1.2.1 25-1.2 26-1.2.2.2 27-1.2.2 30-1.2.2.1 31-1.2.2.1.1.r 32-1.2.2.1.1.1.1 34-1.2.2.1.2.1.1 38-1.2.2.1.3.1 39-1.2.2.1.3 (m / multi-sentence :snt1 (d / decrease-01~e.5 :ARG1 (b / bind-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "Ubc9"~e.0)) :ARG2~e.2 (p2 / protein :name (n2 / name :op1 "Mdm2"~e.3))) :time (a / after~e.6 :op1 (i / irradiate-01~e.11 :ARG2 (u / ultraviolet)))) :snt2 (m2 / monitor-01~e.25 :ARG0 (w2 / we~e.23) :ARG1 (c / change-01~e.27 :ARG1 (a2 / associate-01~e.30 :ARG1~e.31 (e2 / enzyme :name (n3 / name :op1 "Ubc9"~e.32)) :ARG2 (p3 / protein :name (n4 / name :op1 "Mdm2"~e.20,34)) :location (c2 / cell~e.39 :ARG1-of (t / treat-04~e.38 :ARG2 u2))) :ARG1-of (p / possible-01~e.26)) :ARG1-of (c3 / cause-01~e.9 :ARG0 (s / show-01~e.14 :ARG1 (r / reduce-01~e.16 :ARG0 (i2 / irradiate-01~e.11 :ARG2 (u2 / ultraviolet)) :ARG1 (d2 / degree~e.18 :degree-of~e.18 (s2 / sumoylate-00 :ARG0 p2))))))) # ::id bio.chicago_2015.35599 ::amr-annotator SDL-AMR-09 ::preferred # ::tok From previous experiments it is known that a single application of 5HT induces STF , which declines to baseline levels within ~ 15 min , whereas five applications of 5HT induce LTF that lasts at least up to 24 hr after its induction ( Walters et al. , 1983 ; Emptage and Carew , 1993 ; # ::alignments 0-1.2.r 1-1.2.1 2-1.2 5-1 6-1.1.r 8-1.1.1.1.2 9-1.1.1.1 10-1.1.1.1.1.r 11-1.1.1.1.1.1.1 12-1.1.1 16-1.1.1.2.1 17-1.1.1.2.1.1.r 17-1.1.1.2.1.2 18-1.1.1.2.1.1.1 19-1.1.1.2.1.1 20-1.1.1.2.1.2.1.1.r 22-1.1.1.2.1.2.1.1 23-1.1.1.2.1.2.1.2 25-1.1 26-1.1.2.1.2.1 27-1.1.2.1 28-1.1.2.1.1.r 28-1.1.2.1.2 29-1.1.2.1.1 30-1.1.2 33-1.1.2.2.1 34-1.1.2.2.1.2 35-1.1.2.2.1.2 36-1.1.2.2.1.2.1 37-1.1.2.2.1.2.1 38-1.1.2.2.1.2.1.1.1 40-1.1.2.2.1.1 41-1.1.2.2.1.1.1 41-1.1.2.2.1.1.1.r 42-1.1.2 44-1.3.1.1.1.1.1.1 45-1.3.1.1.1 46-1.3.1.1.1.2.1 48-1.3.1.1.2.1 50-1.3.1.2.1.1.1.1 51-1.3.1.2.1 52-1.3.1.2.1.2.1.1 54-1.3.1.2.2.1 (k / know-01~e.5 :ARG1~e.6 (c / contrast-01~e.25 :ARG1 (i / induce-01~e.12 :ARG0 (a2 / apply-03~e.9 :ARG1~e.10 (e / enzyme :name (n / name :op1 "5HT"~e.11)) :ARG1-of (s / single-02~e.8)) :ARG2 (f / facilitate-01 :ARG1-of (d3 / decline-01~e.16 :ARG4~e.17 (l3 / level~e.19 :mod (b / baseline~e.18)) :time (u / up-to~e.17 :op1 (t2 / temporal-quantity :quant~e.20 15~e.22 :unit (m / minute~e.23)))) :ARG1-of (s2 / short-07))) :ARG2 (i2 / induce-01~e.30,42 :ARG0 (a3 / apply-03~e.27 :ARG1~e.28 e~e.29 :mod (p / product-of~e.28 :op1 5~e.26)) :ARG2 (f2 / facilitate-01 :ARG1-of (l / last-01~e.33 :ARG2 (a4 / after~e.40 :op1~e.41 i2~e.41) :quant (a8 / at-least~e.34,35 :op1 (u2 / up-to~e.36,37 :op1 (t4 / temporal-quantity :quant 24~e.38 :unit (h / hour))))) :ARG1-of (l2 / long-03)))) :source~e.0 (e2 / experiment-01~e.2 :time (p2 / previous~e.1)) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (p3 / publication-91 :ARG0 (a6 / and~e.45 :op1 (p4 / person :name (n4 / name :op1 "Walters"~e.44)) :op1 (p5 / person :mod (o / other~e.46))) :time (d / date-entity :year 1983~e.48)) :op2 (p6 / publication-91 :ARG0 (a7 / and~e.51 :op1 (p7 / person :name (n5 / name :op1 "Emptage"~e.50)) :op2 (p8 / person :name (n6 / name :op1 "Carew"~e.52))) :time (d2 / date-entity :year 1993~e.54))))) # ::id bio.chicago_2015.35619 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine whether AES interacts with p65 in cultured cells , we performed the co @-@ immunoprecipitation experiment . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.2.1.1 4-1.3.2 5-1.3.2.3.r 6-1.3.2.3.1.1 7-1.3.2.4.r 8-1.3.2.4.1 9-1.3.2.4 11-1.1 12-1 17-1.2 (p / perform-02~e.12 :ARG0 (w / we~e.11) :ARG1 (e / experiment-01~e.17 :ARG2 (c / coimmunoprecipitate-01)) :purpose (e2 / examine-01~e.1 :ARG0 w :ARG1 (i / interact-01~e.4 :mode~e.2 interrogative~e.2 :ARG0 (p3 / protein :name (n / name :op1 "AES"~e.3)) :ARG1~e.5 (p2 / protein :name (n2 / name :op1 "p65"~e.6)) :location~e.7 (c2 / cell~e.9 :ARG1-of (c3 / culture-01~e.8))))) # ::id bio.chicago_2015.35635 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our results show that the C @-@ terminal domains of the xCRYs are necessary for nuclear localization , but it is still unclear if this is achieved via importin binding to an authentic NLS within the C @-@ terminal domain or via a more indirect mechanism . # ::alignments 0-1.1.1.2 0-1.1.1.2.r 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1 3-1.1.2.r 5-1.1.2.2.1.1 7-1.1.2.2.1.1 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1 16-1.1.2.1 18-1 21-1.2.3 22-1.2 22-1.2.1 22-1.2.1.r 26-1.2.2 28-1.2.2.3.1.1.1.1 29-1.2.2.3.1 30-1.2.2.3.1.2.r 32-1.2.2.3.1.2 32-1.2.2.3.1.2.2 32-1.2.2.3.1.2.2.r 33-1.2.2.3.1.2.1.1 36-1.2.2.3.1.3 37-1.2.2.3.1.3 38-1.2.2.3.1.3 40-1.2.2.3 43-1.2.2.3.2.1.2 44-1.2.2.3.2.1 44-1.2.2.3.2.1.1 44-1.2.2.3.2.1.1.r 45-1.2.2.3.2 (c / contrast-01~e.18 :ARG1 (s / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :poss~e.0 (w / we~e.0)) :ARG1~e.3 (n / need-01~e.13 :ARG0~e.14 (l / localize-01~e.16 :ARG1 (n4 / nucleus~e.15)) :ARG1 (p2 / protein-segment :name (n2 / name :op1 "C-terminus"~e.5,7) :part-of (p3 / protein :name (n3 / name :op1 "xCRY"))))) :ARG2 (c2 / clear-06~e.22 :polarity~e.22 -~e.22 :ARG1 (a / achieve-01~e.26 :mode interrogative :ARG1 n :instrument (o / or~e.40 :op1 (b / bind-01~e.29 :ARG1 (p / protein :name (n5 / name :op1 "importin"~e.28)) :ARG2~e.30 (p4 / protein-segment~e.32 :name (n6 / name :op1 "NLS"~e.33) :ARG1-of~e.32 (a3 / authentic-02~e.32)) :location p2~e.36,37,38) :op2 (m / mechanism~e.45 :ARG1-of (d2 / direct-02~e.44 :polarity~e.44 -~e.44 :degree (m2 / more~e.43))))) :time (s2 / still~e.21))) # ::id bio.chicago_2015.35638 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Drosophila melanogaster suppressor of Hairy @-@ wing protein binds to specific sequences of the gypsy retrotransposon . # ::alignments 1-1.1.2.1.1 2-1.1.2.1.2 3-1.1 3-1.1.1 3-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1.1 9-1 10-1.2.r 11-1.2.1 12-1.2 13-1.2.2.r 15-1.2.2.2 16-1.2.2.1.1 (b / bind-01~e.9 :ARG1 (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (s / suppress-01~e.3 :ARG1 (p2 / protein~e.8 :name (n5 / name :op1 "Harry-wing"~e.7))) :mod (o / organism :name (n / name :op1 "Drosophila"~e.1 :op2 "melanogaster"~e.2))) :ARG2~e.10 (s2 / sequence~e.12 :ARG1-of (s3 / specific-02~e.11) :part-of~e.13 (d / dna-sequence :name (n4 / name :op1 "retrotransposon"~e.16) :mod (g / gypsy~e.15)))) # ::id bio.chicago_2015.35639 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The fat facets gene is required for Drosophila eye and embryo development . # ::alignments 1-1.2.1.1 2-1.2.1.2 3-1.2 5-1 6-1.1.r 7-1.1.1.3.1.1 8-1.1.1.1 9-1.1.1 10-1.1.1.2 11-1.1 (r / require-01~e.5 :ARG0~e.6 (d / develop-01~e.11 :ARG2 (a / and~e.9 :op1 (e / eye~e.8) :op2 (e2 / embryo~e.10) :part-of (o / organism :name (n / name :op1 "Drosophila"~e.7)))) :ARG1 (g / gene~e.3 :name (n2 / name :op1 "fat"~e.1 :op2 "facet"~e.2))) # ::id bio.chicago_2015.35656 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our data showing that full @-@ length TAF130p tightly binds TBP and prevents subsequent TBP @-@ TATA DNA interactions , as well as the published work of others ( see above ) , illustrates an intriguing conundrum . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1 2-1.1.1.2 3-1.1.1.2.1.r 4-1.1.1.2.1.1.1.2.1 6-1.1.1.2.1.1.1 6-1.1.1.2.1.1.1.2 6-1.1.1.2.1.1.1.2.r 7-1.1.1.2.1.1.1.1.1 8-1.1.1.2.1.1.3 9-1.1.1.2.1.1 10-1.1.1.2.1.1.2.1.1 11-1.1.1.2.1 12-1.1.1.2.1.2 13-1.1.1.2.1.2.2.3 13-1.1.1.2.1.2.2.3.r 14-1.1.1.2.1.1.2.1.1 16-1.1.1.2.1.2.2.2.2.1.1 17-1.1.1.2.1.2.2.2.1.1 18-1.1.1.2.1.2.2 20-1.1.1.2.1.2.2.3.r 21-1.1 22-1.1 24-1.1.2.2 25-1.1.2 26-1.1.2.1.r 27-1.1.2.1.1 29-1.1.2.3 30-1.1.2.3.3 33-1 35-1.2.1 36-1.2 (i / illustrate-01~e.33 :ARG0 (a2 / and~e.21,22 :op1 (d / data~e.1 :poss~e.0 (w / we~e.0) :ARG0-of (s / show-01~e.2 :ARG1~e.3 (a / and~e.11 :op1 (b / bind-01~e.9 :ARG1 (p6 / protein-segment~e.6 :name (n / name :op1 "TAF130p"~e.7) :ARG1-of~e.6 (l / long-03~e.6 :mod (f / full~e.4))) :ARG2 (p2 / protein :name (n2 / name :op1 "TBP"~e.10,14)) :ARG1-of (t2 / tight-05~e.8)) :op2 (p / prevent-01~e.12 :ARG0 p2 :ARG1 (i2 / interact-01~e.18 :ARG0 p2 :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "DNA"~e.17) :part-of (d2 / dna-sequence :name (n5 / name :op1 "TATA"~e.16))) :time~e.13,20 (s3 / subsequent~e.13)))))) :op2 (w2 / work-01~e.25 :ARG0~e.26 (p5 / person :mod (o / other~e.27)) :ARG1-of (p4 / publish-01~e.24) :ARG1-of (s2 / see-01~e.29 :mode imperative :ARG0 (y / you) :location (a3 / above~e.30)))) :ARG1 (c / conundrum~e.36 :ARG0-of (i3 / intrigue-01~e.35))) # ::id bio.chicago_2015.35670 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , we show that high Dpp signalling antagonizes Wg @-@ mediated repression . # ::alignments 0-1 2-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.2 6-1.1.2.1.1.1.1 7-1.1.2.1 8-1.1.2 9-1.1.2.2.1.1.1.1 11-1.1.2.2.1 12-1.1.2.2 (a / and~e.0 :op2 (s / show-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (a2 / antagonize-02~e.8 :ARG1 (s2 / signal-07~e.7 :ARG0 (p / pathway :name (n / name :op1 "Dpp"~e.6)) :ARG1-of (h / high-02~e.5)) :ARG2 (r / repress-01~e.12 :ARG1-of (m / mediate-01~e.11 :ARG0 (p2 / protein :name (n2 / name :op1 "Wg"~e.9))))))) # ::id bio.chicago_2015.35685 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The interaction of rAxin with beta @-@ catenin was confirmed by the yeast two @-@ hybrid method # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1.1 4-1.2.2.r 5-1.2.2.1.1 7-1.2.2.1.1 9-1 10-1.1.r 12-1.1.1.1 13-1.1.1.2 15-1.1.1.2 16-1.1 (c / confirm-01~e.9 :ARG0~e.10 (m / method~e.16 :name (n3 / name :op1 "yeast"~e.12 :op2 "two-hybrid"~e.13,15)) :ARG1 (i / interact-01~e.1 :ARG0~e.2 (p2 / protein :name (n / name :op1 "rAxin"~e.3)) :ARG1~e.4 (p / protein :name (n2 / name :op1 "beta-catenin"~e.5,7)))) # ::id bio.chicago_2015.35692 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with data shown in Fig. 1 , tyrosine phosphorylation of either cortactin or EC MLCK 1 by p60 src resulted in enhanced affinity with measured Kd 's of 0.2 M ( Fig. 2B ) and 0.1 M ( Fig. 2C ) , respectively . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1 3-1.3.1.1 4-1.3.1.1.1.r 5-1.3.1.1.1 6-1.3.1.1.1.1 8-1.1.1.1.1.1 8-1.1.1.2.1.1 9-1.1 12-1.1.1.1.2.1.1 13-1.1.1 14-1.1.1.2.2.1.1 15-1.1.1.2.2.1.2 16-1.1.1.2.2.1.3 17-1.1.2.r 18-1.1.2.1.1 19-1.1.2.1.2 20-1 21-1.2.r 22-1.2.1 23-1.2 25-1.2.2.1.1.2 29-1.2.2.1.1.1.1.1 30-1.2.2.1.1.1.1.2 32-1.2.2.1.1.3.1 33-1.2.2.1.1.3.1.1 35-1.2.2.1 36-1.2.2.1.2.1.1.1 37-1.2.2.1.2.1.1.2 39-1.2.2.1.2.3.1 40-1.2.2.1.2.3.1.1 (r / result-01~e.20 :ARG1 (p / phosphorylate-01~e.9 :ARG1 (o / or~e.13 :op1 (a / amino-acid :name (n / name :op1 "tyrosine"~e.8) :part-of (p2 / protein :name (n2 / name :op1 "cortactin"~e.12))) :op2 (a4 / amino-acid :name (n4 / name :op1 "tyrosine"~e.8) :part-of (p3 / protein :name (n3 / name :op1 "EC"~e.14 :op2 "MLCK"~e.15 :op3 1~e.16)))) :ARG2~e.17 (e5 / enzyme :name (n5 / name :op1 "p60"~e.18 :op2 "src"~e.19))) :ARG2~e.21 (a2 / affinity~e.23 :ARG1-of (e / enhance-01~e.22) :ARG0-of (h / have-03 :ARG1 (a3 / and~e.35 :op1 (d6 / dissociate-01 :ARG1 (e3 / equilibrium :quant (d / distance-quantity :quant 0.2~e.29 :unit (m / molar~e.30))) :ARG1-of (m3 / measure-01~e.25) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.32 :mod "2B"~e.33))) :op2 (d2 / dissociate-01 :ARG1 (e4 / equilibrium :quant (c2 / concentration-quantity :quant 0.1~e.36 :unit m~e.37)) :ARG1-of m3 :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.39 :mod "2C"~e.40)))))) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (d5 / data~e.2 :ARG1-of (s2 / show-01~e.3 :medium~e.4 (f3 / figure~e.5 :mod 1~e.6))))) # ::id bio.chicago_2015.35756 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Comparable to the interactions of GATA4 and FOG @-@ 2 , Pnr and Ush heterodimerize through the amino @-@ terminal zinc finger of Pnr ( 24 ) , and genetic studies have shown that Ush antagonizes the function of Pnr in the establishment of the thoracic bristle pattern in the adult ( 24 , 25 ) . # ::alignments 0-1.1.5 1-1.1.5.1.r 3-1.1.5.1 4-1.1.5.1.1.r 5-1.1.5.1.1.1.1 7-1.1.5.1.2.1.1 9-1.1.5.1.2.1.1 11-1.1.2.1.1 13-1.1.3.1.1 14-1.1 17-1.1.1.1.1 19-1.1.1.1.1 20-1.1.1.1.2 21-1.1.1.1.3 23-1.1.2.1.1 25-1.1.4.1.1.1 28-1.2.3.1.1.1 29-1.2.1.1 30-1.2.1 32-1.2 33-1.2.2.r 34-1.2.2.1 35-1.2.2 37-1.2.2.2 38-1.2.2.2.2.r 39-1.2.2.2.2.1 42-1.2.2.2.2 43-1.2.2.2.2.2.r 45-1.2.2.2.2.2.2 46-1.2.2.2.2.2.1 47-1.2.2.2.2.2 48-1.2.2.2.2.3.r 50-1.2.2.2.2.3 52-1.2.3.1.1.1.1 54-1.2.3.1.1.1.2 (a2 / and :op1 (h / heterodimerize-01~e.14 :ARG0 (p9 / protein-segment :name (n5 / name :op1 "amino-terminal"~e.17,19 :op2 "zinc"~e.20 :op3 "finger"~e.21)) :ARG1 (p7 / protein :name (n / name :op1 "Pnr"~e.11,23)) :ARG2 (p8 / protein :name (n2 / name :op1 "Ush"~e.13)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 24~e.25))) :ARG1-of (c2 / comparable-03~e.0 :ARG2~e.1 (i / interact-01~e.3 :ARG0~e.4 (p5 / protein :name (n3 / name :op1 "GATA4"~e.5)) :ARG1 (p6 / protein :name (n4 / name :op1 "FOG-2"~e.7,9))))) :op2 (s / show-01~e.32 :ARG0 (s2 / study-01~e.30 :mod (g / genetics~e.29)) :ARG1~e.33 (a3 / antagonize-02~e.35 :ARG1 p8~e.34 :ARG2 (f2 / function-01~e.37 :ARG0 p7 :ARG1~e.38 (e3 / establish-01~e.42 :ARG0 p7~e.39 :ARG1~e.43 (p2 / pattern~e.47 :mod (b / bristle~e.46) :mod (t3 / thoracic~e.45)) :location~e.48 (a / adult~e.50)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a5 / and~e.28 :op1 24~e.52 :op2 25~e.54)))))) # ::id bio.chicago_2015.35779 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test for functional association of DEDD with FADD or caspase @-@ 8 , suboptimal non @-@ cytotoxic concentrations of FADD or caspase @-@ 8 were co @-@ transfected with suboptimal concentrations of the DEDD deletion mutants ( Figure 4C ) . # ::alignments 0-1.2.1.1 1-1.3 2-1.3.1.r 3-1.3.1.3 4-1.3.1 5-1.3.1.1.r 6-1.3.1.1 7-1.2.r 8-1.1.1.1.2.1 9-1.1 9-1.3.1.2 10-1.1.2.1.2.1 12-1.1.2.1.2.1 14-1.1.3 15-1.1.4.1 15-1.1.4.1.r 17-1.1.4 18-1.1.1 18-1.1.2 20-1.1.1.1.2.1 21-1.1 22-1.1.2.1.2.1 24-1.1.2.1.2.1 29-1.2.r 30-1.1.3 31-1.2 32-1.2.1.1.1.r 32-1.2.1.r 34-1.2.1.1.1.1.2.1 35-1.2.1.1.1 36-1.2.1 38-1.4.1 39-1.4.1.1 (c / cotransfect-01 :ARG1 (o / or~e.9,21 :op1 (c2 / concentrate-02~e.18 :ARG1 (p2 / protein :wiki "FADD" :name (n / name :op1 "FADD"~e.8,20))) :op2 (c3 / concentrate-02~e.18 :ARG1 (p / protein :wiki "Caspase_8" :name (n2 / name :op1 "caspase-8"~e.10,12,22,24))) :mod (s / suboptimal~e.14,30) :mod (c4 / cytotoxic~e.17 :polarity~e.15 -~e.15)) :instrument~e.7,29 (c5 / concentrate-02~e.31 :ARG1~e.32 (m / mutate-01~e.36 :ARG1-of (c6 / cause-01~e.0 :ARG0~e.32 (d / delete-01~e.35 :ARG1 (p3 / protein :wiki "DEDD" :name (n3 / name :op1 "DEDD"~e.34))))) :mod s) :purpose (t3 / test-01~e.1 :ARG2~e.2 (a / associate-01~e.4 :ARG0~e.5 p3~e.6 :ARG1 (o2 / or~e.9 :op1 p2 :op2 p) :ARG0-of (f / function-01~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.38 :mod "4C"~e.39))) # ::id bio.chicago_2015.35797 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , Dox @-@ induced expression of Axin during the first 4 days ( aggregation ) , followed by withdrawal of Dox for the next 6 days ( differentiation ) , had no effect on betaIII @-@ tubulin expression ( Fig . 6 , compare lanes 2 and 6 ) . # ::alignments 0-1 2-1.1.2.2.1.1.1 4-1.1.2.2 5-1.1.2 7-1.1.2.1.1.1 10-1.1.2.3.3 10-1.1.2.3.3.1 10-1.1.2.3.3.1.r 11-1.1.2.3.1 12-1.1.2.3.2 14-1.1.2.4.1 17-1.1.2.5 18-1.1.2.5.1.r 19-1.1.2.5.1 20-1.1.2.5.1.1.r 21-1.1.2.5.1.1 22-1.1.2.5.1.2.r 24-1.1.2.5.1.2.3 25-1.1.2.5.1.2.1 26-1.1.2.5.1.2.2 28-1.1.2.5.1.3.1 32-1.1.1 32-1.1.1.r 33-1.1 35-1.1.3.1.1.1 37-1.1.3.1.1.1 38-1.1.2 38-1.1.3 40-1.2.1 42-1.2.1.1 42-1.2.1.2.4.1 44-1.2.1.2 45-1.2.1.2.3 45-1.2.1.2.4 46-1.2.1.2.3.1 48-1.2.1.2.4.1 (h / have-concession-91~e.0 :ARG1 (a / affect-01~e.33 :polarity~e.32 -~e.32 :ARG0 (e2 / express-03~e.5,38 :ARG2 (p2 / protein :name (n2 / name :op1 "Axin"~e.7)) :ARG2-of (i / induce-01~e.4 :ARG0 (s / small-molecule :name (n3 / name :op1 "Dox"~e.2))) :duration (t / temporal-quantity :quant 4~e.11 :unit (d / day~e.12) :ord (o2 / ordinal-entity~e.10 :value~e.10 1~e.10)) :ARG1-of (m / mean-01 :ARG2 (a2 / aggregate-01~e.14)) :ARG2-of (f / follow-01~e.17 :ARG1~e.18 (w / withdraw-01~e.19 :ARG1~e.20 s~e.21 :duration~e.22 (t2 / temporal-quantity :quant 6~e.25 :unit (d2 / day~e.26) :mod (n4 / next~e.24)) :ARG1-of (m2 / mean-01 :ARG2 (d3 / differentiate-01~e.28))))) :ARG1 (e / express-03~e.38 :ARG2 (p / protein :name (n / name :op1 "betaIII-tubulin"~e.35,37)))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.40 :mod 6~e.42 :location-of (c / compare-01~e.44 :mode imperative :ARG0 (y / you) :ARG1 (l / lane~e.45 :mod 2~e.46) :ARG2 (l2 / lane~e.45 :mod 6~e.42,48))))) # ::id bio.chicago_2015.35826 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , Robo2 does not control midline crossing of retinal axons , but rather shapes their pathway , by both preventing and correcting pathfinding errors . # ::alignments 0-1 2-1.1.1.2.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1.1.1 6-1.1.1.3.2 7-1.1.1.3 8-1.1.1.3.1.r 9-1.1.1.3.1.1 10-1.1.1.3.1 12-1.1 13-1.1 13-1.1.2.3 14-1.1.2 15-1.1.2.2.1 15-1.1.2.2.1.r 16-1.1.2.2 20-1.1.2.4.1 21-1.1.2.4 22-1.1.2.4.2 24-1.1.2.4.1.2 24-1.1.2.4.1.2.1 24-1.1.2.4.1.2.1.r (c6 / cause-01~e.0 :ARG1 (c4 / contrast-01~e.12,13 :ARG1 (c2 / control-01~e.5 :polarity~e.4 -~e.4 :ARG0 (p4 / protein :name (n / name :op1 "Robo2"~e.2)) :ARG1 (c3 / cross-01~e.7 :ARG1~e.8 (a2 / axon~e.10 :mod (r / retina~e.9)) :mod (m / midline~e.6))) :ARG2 (s / shape-01~e.14 :ARG0 p4 :ARG1 (p / pathway~e.16 :poss~e.15 a2~e.15) :mod (r2 / rather~e.13) :manner (a3 / and~e.21 :op1 (p2 / prevent-01~e.20 :ARG0 p4 :ARG1 (t / thing~e.24 :ARG1-of~e.24 (e / err-01~e.24) :ARG0-of (f / find-01 :ARG1 (p3 / path)))) :op2 (c5 / correct-01~e.22 :ARG0 p4 :ARG1 t))))) # ::id bio.chicago_2015.35827 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) PIASy represses LEF1 activity from a multimerized LEF1 reporter . # ::alignments 1-1.1 3-1.2.1.1 4-1 5-1.3.1.1.1 6-1.3 10-1.3.1.1.1 11-1.4 11-1.4.1 11-1.4.1.r (r2 / repress-01~e.4 :li "A"~e.1 :ARG0 (e / enzyme :name (n / name :op1 "PIASy"~e.3)) :ARG1 (a / activity-06~e.6 :ARG0 (p2 / protein :name (n2 / name :op1 "LEF1"~e.5,10))) :ARG2 (m / molecular-physical-entity~e.11 :ARG0-of~e.11 (r / report-01~e.11 :ARG1 p2) :ARG1-of (m2 / multimerize-00))) # ::id bio.chicago_2015.35949 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , gamma @-@ tubulin can interact with beta @-@ tubulin ( Leguy et al. , 2000 ) , the subunit exposed at the plus ends of microtubules ( Nogales et al. , 1999 ) . # ::alignments 0-1 2-1.1.1.1.1.1 4-1.1.1.1.1.1 4-1.1.1.2.1.1 5-1.1 6-1.1.1 7-1.1.1.2.r 8-1.1.1.2.1.1 10-1.1.1.2.1.1 12-1.1.1.2.2.1.1.1.1.1 13-1.1.1.2.2.1.1 14-1.1.1.2.2.1.1.2.1 16-1.1.1.2.2.1.2.1 20-1.1.1.3.1 21-1.1.1.3 24-1.1.1.3.2.2 24-1.1.1.3.3.1.1 25-1.1.1.3.2 29-1.1.1.3.3.1.1.1.1.1 30-1.1.1.3.3.1.1 31-1.1.1.3.3.1.1.2.1 33-1.1.1.3.3.1.1.3.1 (a / and~e.0 :op2 (p / possible-01~e.5 :ARG1 (i / interact-01~e.6 :ARG0 (p7 / protein-family :name (n / name :op1 "gamma-tubulin"~e.2,4)) :ARG1~e.7 (p8 / protein-family :name (n2 / name :op1 "beta-tubulin"~e.4,8,10) :ARG1-of (d3 / describe-01 :ARG0 (p9 / publication-91 :ARG0 (a3 / and~e.13 :op1 (p6 / person :name (n3 / name :op1 "Leguy"~e.12)) :op2 (p5 / person :mod (o / other~e.14))) :time (d / date-entity :year 2000~e.16)))) :manner (e / expose-01~e.21 :ARG1 (s / subunit~e.20) :location (e2 / end-02~e.25 :ARG1 (m4 / microtubule) :mod (p2 / plus~e.24)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a2 / and~e.24,30 :op1 (p3 / person :name (n4 / name :op1 "Nogales"~e.29)) :op2 (p4 / person :mod (o2 / other~e.31)) :time (d2 / date-entity :year 1999~e.33)))))))) # ::id bio.chicago_2015.35955 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , PDK1 phosphorylates and activates another pleckstrin homology domain containing protein kinase , Akt , as well ( 16 , 17 ) . # ::alignments 0-1.3 2-1.1.2.1.1 3-1.1 4-1 4-1.4.1.1.1 5-1.2 6-1.1.1.3 7-1.1.1.1.1 8-1.1.1.1.2 10-1.1.1.2 11-1.1.1.2.1.1.1 12-1.1.1.2.1.1.2 14-1.1.1.2.1.1.3 16-1.1.1.2.2 17-1.1.1.2.2 19-1.4.1.1.1.1 21-1.4.1.1.1.2 (a / and~e.4 :op1 (p / phosphorylate-01~e.3 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "pleckstrin"~e.7 :op2 "homology"~e.8) :ARG0-of (c2 / contain-01~e.10 :ARG1 (e / enzyme :name (n3 / name :op1 "protein"~e.11 :op2 "kinase"~e.12 :op3 "Akt"~e.14)) :mod (a4 / as-well~e.16,17)) :mod (a5 / another~e.6)) :ARG2 (e2 / enzyme :name (n / name :op1 "PDK1"~e.2))) :op2 (a2 / activate-01~e.5 :ARG0 e2 :ARG1 p3) :ARG2-of (i / interest-01~e.0) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and~e.4 :op1 16~e.19 :op2 17~e.21))))) # ::id bio.chicago_2015.36045 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Torso receptor tyrosine kinase can activate Raf in a Ras @-@ independent pathway . # ::alignments 1-1.1.1.1.1 2-1.1.1.1.2 3-1.1.1.1.3 4-1.1.1.1.4 5-1 6-1.1 7-1.1.2.1.1 8-1.1.3.r 10-1.1.3.1.2.1.1 12-1.1.3.1 12-1.1.3.1.1 12-1.1.3.1.1.r 13-1.1.3 (p / possible-01~e.5 :ARG1 (a / activate-01~e.6 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Torso"~e.1 :op2 "receptor"~e.2 :op3 "tyrosine"~e.3 :op4 "kinase"~e.4)) :ARG1 (e / enzyme :name (n / name :op1 "Raf"~e.7)) :location~e.8 (p2 / pathway~e.13 :ARG0-of (d / depend-01~e.12 :polarity~e.12 -~e.12 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.10)))))) # ::id bio.chicago_2015.36075 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Arabidopsis SGS2 and SGS3 Genes Are Required for Posttranscriptional Gene Silencing and Natural Virus Resistance . # ::alignments 0-1.2.3.1.1 1-1.2.1.1.1 2-1.2 3-1.2.2.1.1 4-1.2.1 4-1.2.2 6-1 9-1.1.1.1 10-1.1.1 11-1.1 12-1.1.2.2 13-1.1.2.1 14-1.1.2 (r / require-01~e.6 :ARG0 (a2 / and~e.11 :op1 (s / silence-01~e.10 :ARG1 (g3 / gene~e.9) :time (a3 / after :op1 (t / transcribe-01))) :op1 (r2 / resist-01~e.14 :ARG1 (v / virus~e.13) :ARG1-of (n4 / natural-03~e.12))) :ARG1 (a / and~e.2 :op1 (g / gene~e.4 :name (n2 / name :op1 "SGS2"~e.1)) :op2 (g2 / gene~e.4 :name (n3 / name :op1 "SGS3"~e.3)) :source (o / organism :name (n / name :op1 "Arabidopsis"~e.0)))) # ::id bio.chicago_2015.36082 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Spatially Restricted Activation of the SAX Receptor by SCW Modulates DPP/ TKV Signaling in Drosophila Dorsal - Ventral Patterning . # ::alignments 0-1.1.3.1 1-1.1.3 2-1.1 3-1.1.2.r 5-1.1.2.1.1 6-1.1.2.1.2 7-1.1.1.r 8-1.1.1.1.1 9-1 11-1.2.1.1.1 12-1.2 13-1.2.2.r 14-1.2.2.1.1.1 15-1.2.2.2 17-1.2.2.3 18-1.2.2 (m / modulate-01~e.9 :ARG0 (a / activate-01~e.2 :ARG0~e.7 (p2 / protein :name (n2 / name :op1 "SCW"~e.8)) :ARG1~e.3 (p / protein :name (n / name :op1 "SAX"~e.5 :op2 "Receptor"~e.6)) :ARG1-of (r / restrict-01~e.1 :manner (s / space~e.0))) :ARG1 (s4 / signal-07~e.12 :ARG0 (p3 / pathway :name (n3 / name :op1 "DPP/TKV"~e.11)) :time~e.13 (p4 / pattern-01~e.18 :ARG1 (o / organism :name (n5 / name :op1 "Drosophila"~e.14)) :mod (d / dorsal~e.15) :mod (v / ventral~e.17)))) # ::id bio.chicago_2015.36092 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Supernatants were diluted in 40 mM Tris @-@ HCl ( pH 8 ) , 0.1 M NaCl , 0.4 mg @/@ ml bovine serum albumin , 1 mM dithiothreitol , 0.45 mM okadaic acid ( Buffer 1 ) and incubated at 30 degrees C for 1 min in buffer 1 containing 1 mM of the peptide [ 32]- RII subunit of cyclic AMP @-@ dependent protein kinase ( PKA ) and either 0.1 mM calmodulin ( Sigma ) and 0.66 mM Ca2+ or 0.33 mM EGTA ( pH 7.5 ) . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.2.1 6-1.1.2.1.1.1 8-1.1.2.1.1.1 14-1.1.2.2.2.1 15-1.1.2.2.2.2 16-1.1.2.2.1.1 18-1.1.2.3.3.1 19-1.1.2.3.3.2 21-1.1.2.3.3.2 22-1.1.2.3.2.1 23-1.1.2.3.2 24-1.1.2.3.1.1 26-1.1.2.4.2.1 28-1.1.2.4.1.1 30-1.1.2.5.2.1 32-1.1.2.5.1.1 33-1.1.2.5.1.2 35-1.2.2 36-1.2.2.1 36-1.2.4.1 39-1.2 40-1.2.3.r 41-1.2.3.1 45-1.2.2.1 45-1.2.4.1 46-1.2.4.2 48-1.2.2 49-1.2.2.1 50-1.2.2.2 51-1.2.2.2.1.1.2.1 55-1.2.2.2.1.1 58-1.2.2.2.1.1.1.1 59-1.2.2.2.1.1.1.2 60-1.2.2.2.1.1.3.r 61-1.2.2.2.1.1.3.2 62-1.2.2.2.1.1.3.1.1 64-1.2.2.2.1.1.3.1.1 65-1.2.2.2.1.1.3.1.2 66-1.2.2.2.1.1.3.1.3 72-1.2.2.2.1.2.1.2.1 74-1.2.2.2.1.2.1.1.1 79-1.2.2.2.1.2.2.2.1 82-1.2.2.2.1.2 83-1.2.2.2.1.3.2.1 85-1.2.2.2.1.3.1.1 (a / and :op1 (d / dilute-01~e.2 :ARG1 (s / supernatant~e.0) :ARG3~e.3 (a2 / and :op1 (m12 / macro-molecular-complex :name (n / name :op1 "Tris-HCl"~e.6,8) :quant (c / concentration-quantity :quant 40~e.4 :unit (m / micromolar))) :op2 (s6 / small-molecule :name (n2 / name :op1 "NaCl"~e.16) :quant (c2 / concentration-quantity :quant 0.1~e.14 :unit (m2 / molar~e.15))) :op3 (p4 / protein :name (n9 / name :op1 "albumin"~e.24) :mod (s2 / serum~e.23 :source (b / bovine~e.22)) :quant (c3 / concentration-quantity :quant 0.4~e.18 :unit (m3 / milligram-per-milliliter~e.19,21))) :op4 (s7 / small-molecule :name (n3 / name :op1 "dithiothreitol"~e.28) :quant (c5 / concentration-quantity :quant 1~e.26 :unit (m4 / micromolar))) :op5 (s3 / small-molecule :name (n4 / name :op1 "okadaic"~e.32 :op2 "acid"~e.33) :quant (c4 / concentration-quantity :quant 0.45~e.30 :unit (m5 / micromolar))))) :op2 (i / incubate-01~e.39 :ARG1 s :ARG2 (b2 / buffer~e.35,48 :mod 1~e.36,45,49 :ARG0-of (c6 / contain-01~e.50 :ARG1 (a5 / and :op1 (p5 / peptide~e.55 :name (n10 / name :op1 "[32]-RII"~e.58 :op2 "subunit"~e.59) :quant (c7 / concentration-quantity :quant 1~e.51 :unit (m7 / micromolar)) :poss~e.60 (e / enzyme :name (n5 / name :op1 "AMP-dependent"~e.62,64 :op2 "protein"~e.65 :op3 "kinase"~e.66) :mod (c8 / cyclic~e.61))) :op2 (o2 / or~e.82 :op1 (p3 / protein :name (n6 / name :op1 "calmodulin"~e.74) :quant (c9 / concentration-quantity :quant 0.1~e.72 :unit (m8 / micromolar))) :op2 (s4 / small-molecule :name (n8 / name :op1 "calcium") :quant (c11 / concentration-quantity :quant 0.66~e.79 :unit (m11 / micromolar)) :ARG1-of (i2 / ionize-01 :value "2+"))) :op3 (s5 / small-molecule :name (n7 / name :op1 "EGTA"~e.85) :quant (c10 / concentration-quantity :quant 0.33~e.83 :unit (m9 / micromolar)))))) :mod~e.40 (t4 / temperature-quantity :quant 30~e.41 :scale (c12 / celsius)) :duration (t5 / temporal-quantity :quant 1~e.36,45 :unit (m6 / minute~e.46)))) # ::id bio.chicago_2015.36117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that the inhibition of EGF @-@ induced Erk2 activation by Abi @-@ 1 is specific to the Erk pathway . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.3.1.1.1 9-1.2.1.1.3 10-1.2.1.1.2.1.1 11-1.2.1.1 12-1.2.1.1.1.r 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1 17-1.2 18-1.2.2.r 20-1.2.2.1.1 21-1.2.2 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (s / specific-02~e.17 :ARG1 (i2 / inhibit-01~e.5 :ARG1~e.6 (a / activate-01~e.11 :ARG0~e.12 (p2 / protein :name (n2 / name :op1 "Abi-1"~e.13,15)) :ARG1 (e / enzyme :name (n3 / name :op1 "Erk2"~e.10)) :ARG2-of (i3 / induce-01~e.9 :ARG0 (p3 / protein :name (n4 / name :op1 "EGF"~e.7))))) :ARG2~e.18 (p / pathway~e.21 :name (n / name :op1 "Erk"~e.20)))) # ::id bio.chicago_2015.36125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The 60 kDa subunit of importin , importin , recognizes and directly binds the NLS ( reviewed in Gorlich and Mattaj , 1996 ) . # ::alignments 1-1.1.1.2.1 2-1.1.1.2.2 3-1.1.1.1.1 4-1.1.1.1.2 5-1.1.1.1.3 9-1.1 10-1 11-1.2.3 12-1.2 14-1.2.2.1.1 16-1.3 18-1.3.1.1.1.1.1 19-1.3.1.1 20-1.3.1.1.2.1.1 22-1.3.1.2.1 (a / and~e.10 :op1 (r / recognize-02~e.9 :ARG0 (p / protein-family :name (n / name :op1 "subunit"~e.3 :op2 "of"~e.4 :op3 "importin"~e.5) :quant (m / mass-quantity :quant 60~e.1 :unit (k / kilodalton~e.2))) :ARG1 p5) :op2 (b / bind-01~e.12 :ARG0 p :ARG1 (p5 / protein-segment :name (n2 / name :op1 "NLS"~e.14)) :ARG1-of (d2 / direct-02~e.11)) :ARG1-of (r2 / review-01~e.16 :ARG0 (p4 / publication-91 :ARG0 (a2 / and~e.19 :op1 (p2 / person :name (n3 / name :op1 "Gorlich"~e.18)) :op2 (p3 / person :name (n4 / name :op1 "Mattaj"~e.20))) :time (d / date-entity :year 1996~e.22)))) # ::id bio.chicago_2015.36130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previous studies showed that both Smad6 and Smurf1 inhibit BMP signals in vivo ( Tsuneizumi et al. , 1997 ; Hata et al. , 1998 ; Nakayama et al. , 1998 ; Zhang et al. , 2001 ) . # ::alignments 0-1.1.1 1-1.1 2-1 5-1.2.1.1.1.1 6-1.2.1 7-1.2.1.2.1.1 8-1.2 9-1.2.2.1.1.1 10-1.2.2 11-1.2.3 12-1.2.3 14-1.3.1.1.1.1.1.1 15-1.3.1.1.1 16-1.3.1.1.1.2.1 18-1.3.1.1.2.1 20-1.3.1.2.1.1.1.1 21-1.3.1 21-1.3.1.1.1 21-1.3.1.2.1 21-1.3.1.3.1 21-1.3.1.4.1 22-1.3.1.1.1.2.1 24-1.3.1.3.2 26-1.3.1.3.1.1.1.1 27-1.3.1 27-1.3.1.1.1 27-1.3.1.2.1 27-1.3.1.3.1 27-1.3.1.4.1 28-1.3.1.1.1.2.1 30-1.3.1.2.2.1 32-1.3.1.4.1.1.1.1 33-1.3.1 33-1.3.1.1.1 33-1.3.1.3.1 33-1.3.1.4.1 34-1.3.1.1.1.2.1 36-1.3.1.4.2.1 (s / show-01~e.2 :ARG0 (s2 / study-01~e.1 :time (p / previous~e.0)) :ARG1 (i / inhibit-01~e.8 :ARG0 (a / and~e.6 :op1 (p11 / protein :name (n / name :op1 "Smad6"~e.5)) :op2 (p12 / protein :name (n2 / name :op1 "Smurf1"~e.7))) :ARG1 (s3 / signal-07~e.10 :ARG0 (p2 / protein :name (n3 / name :op1 "BMP"~e.9))) :manner (i2 / in-vivo~e.11,12)) :ARG1-of (d6 / describe-01 :ARG0 (a6 / and~e.21,27,33 :op1 (p16 / publication-91 :ARG0 (a2 / and~e.15,21,27,33 :op1 (p3 / person :name (n4 / name :op1 "Tsuneizumi"~e.14)) :op2 (p4 / person :mod (o / other~e.16,22,28,34))) :time (d / date-entity :year 1997~e.18)) :op2 (p13 / publication-91 :ARG0 (a3 / and~e.21,27 :op1 (p5 / person :name (n5 / name :op1 "Hata"~e.20)) :op2 (p6 / person :mod o)) :time (d2 / date-entity :year 1998~e.30)) :op3 (p14 / publication-91 :ARG0 (a4 / and~e.21,27,33 :op1 (p8 / person :name (n6 / name :op1 "Nakayama"~e.26)) :op2 (p7 / person :mod o)) :time d2~e.24) :op4 (p15 / publication-91 :ARG0 (a5 / and~e.21,27,33 :op1 (p9 / person :name (n7 / name :op1 "Zhang"~e.32)) :op2 (p10 / person :mod o)) :time (d4 / date-entity :year 2001~e.36))))) # ::id bio.chicago_2015.36162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One prediction of these studies is that an overlap in MLL @-@ and CREB @-@ dependent target genes exists such that the cooperative interaction of MLL and CREB with CBP would play a role in regulating these genes ( Fig . 7 ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 4-1.2 6-1.3.r 8-1.3.1 10-1.3.2.1.1.1.1.1 13-1.3.2.1.1.2.1.1 16-1.3.1.1.1.1 16-1.3.1.1.2.1 17-1.3.1.1.1 17-1.3.1.1.2 18-1.3 19-1.3.2.r 20-1.3.2.r 22-1.3.2.1.3 23-1.3.2.1 25-1.3.2.1.1.1.1.1 26-1.3.2.1.1 27-1.3.2.1.1.2.1.1 28-1.3.2.1.2.r 29-1.3.2.1.2.1.1 31-1.3.2 34-1.3.2.2.r 35-1.3.2.2 36-1.2.1 37-1.3.1.1.1 39-1.4.1 41-1.4.1.1 (p / predict-01~e.1 :quant 1~e.0 :ARG0~e.2 (s / study-01~e.4 :mod (t / this~e.3,36)) :ARG1~e.6 (e / exist-01~e.18 :ARG1 (o / overlap-01~e.8 :ARG0 (a2 / and :op1 (g / gene~e.17,37 :ARG1-of (t2 / target-01~e.16 :ARG0 p3)) :op2 (g2 / gene~e.17 :ARG1-of (t3 / target-01~e.16 :ARG0 p5)))) :purpose~e.19,20 (p2 / play-02~e.31 :ARG0 (i / interact-01~e.23 :ARG0 (a / and~e.26 :op1 (p3 / protein :name (n / name :op1 "MLL"~e.10,25)) :op2 (p4 / protein :name (n2 / name :op1 "CREB"~e.13,27))) :ARG1~e.28 (p5 / protein :name (n3 / name :op1 "CBP"~e.29)) :ARG2-of (c / cooperate-01~e.22)) :ARG1~e.34 (r / regulate-01~e.35 :ARG0 i :ARG1 a2))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod 7~e.41))) # ::id bio.chicago_2015.36163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these results showed that the coiled @-@ coil domain of PML was required for the association of PML with Sp1 in vitro . # ::alignments 0-1.3 2-1.1.1 3-1.1 3-1.1.2 3-1.1.2.r 4-1 5-1.2.r 7-1.2.2.1.1 9-1.2.2.1.1 12-1.2.2.2.1.1 14-1.2 15-1.2.1.r 17-1.2.1 18-1.2.1.1.r 19-1.2.1.1 20-1.2.1.2.r 21-1.2.1.2.1.1 22-1.2.1.3 23-1.2.1.3 (s / show-01~e.4 :ARG0 (t2 / thing~e.3 :mod (t3 / this~e.2) :ARG2-of~e.3 (r / result-01~e.3)) :ARG1~e.5 (r2 / require-01~e.14 :ARG0~e.15 (a / associate-01~e.17 :ARG1~e.18 p~e.19 :ARG2~e.20 (p2 / protein :name (n2 / name :op1 "Sp1"~e.21)) :manner (i / in-vitro~e.22,23)) :ARG1 (p3 / protein-segment :name (n3 / name :op1 "coiled-coil"~e.7,9) :part-of (p / protein :name (n / name :op1 "PML"~e.12)))) :mod (t / together~e.0)) # ::id bio.chicago_2015.36212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Receptor serine/ threonine kinase implicated in the control of Drosophila body pattern by decapentaplegic.. # ::alignments 0-1.1.1 2-1.1.2 3-1.1.3 4-1.2 5-1.2.1.r 7-1.2.1 8-1.2.1.2.r 9-1.2.1.2.1.1.1.1 10-1.2.1.2.1 11-1.2.1.2 (e / enzyme :name (n / name :op1 "receptor"~e.0 :op2 "serine/threonine"~e.2 :op3 "kinase"~e.3) :ARG1-of (i / implicate-01~e.4 :ARG2~e.5 (c / control-01~e.7 :ARG0 (p2 / protein :name (n4 / name :op1 "decapentaplegic")) :ARG1~e.8 (p / pattern-01~e.11 :ARG2 (b / body~e.10 :mod (o / organism :name (n3 / name :op1 "Drosophila"~e.9))))))) # ::id bio.chicago_2015.36218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast to many soluble cytokines , UPD is associated with ECM ( extracellular matrix ) , which may help it bind to the receptor and limit the range of activity of the ligand . # ::alignments 1-1 2-1.2.r 3-1.2.2 4-1.2.1 5-1.2 7-1.1.1.1.1 9-1.1 13-1.1.2.2 14-1.1.2 18-1.1.2.1.3 19-1.1.2.1 21-1.1.2.1.2.1 22-1.1.2.1.2.1.2.r 24-1.1.2.1.2.1.2 25-1.1.2.1.2 26-1.1.2.1.2.2 28-1.1.2.1.2.2.1 29-1.1.2.1.2.2.1.1.r 30-1.1.2.1.2.2.1.1 31-1.1.2.1.2.2.1.1.1.r 33-1.1.2.1.2.2.1.1.1 (c / contrast-01~e.1 :ARG1 (a / associate-01~e.9 :ARG1 (p / protein :name (n / name :op1 "UPD"~e.7)) :ARG2 (m2 / matrix~e.14 :ARG0-of (h / help-01~e.19 :ARG1 p :ARG2 (a2 / and~e.25 :op1 (b / bind-01~e.21 :ARG1 p :ARG2~e.22 (r / receptor~e.24)) :op2 (l / limit-01~e.26 :ARG1 (r2 / range-01~e.28 :ARG1~e.29 (a3 / activity-06~e.30 :ARG0~e.31 (l2 / ligand~e.33))))) :ARG1-of (p2 / possible-01~e.18)) :mod (e / extracellular~e.13))) :ARG2~e.2 (c2 / cytokine~e.5 :mod (s / soluble~e.4) :quant (m / many~e.3))) # ::id bio.chicago_2015.36244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of ARC Inhibits Apoptosis Induced by Caspases in 293T Cells . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1 4-1.2 5-1.2.1 8-1.2.1.2.r 9-1.2.1.2.1.1 10-1.2.1.2 (i / inhibit-01~e.3 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (p / protein :name (n2 / name :op1 "ARC"~e.2))) :ARG1 (a / apoptosis~e.4 :ARG2-of (i2 / induce-01~e.5 :ARG0 (p2 / protein-family :name (n3 / name :op1 "caspase")) :location~e.8 (c / cell-line~e.10 :name (n / name :op1 "293T"~e.9))))) # ::id bio.chicago_2015.36265 ::amr-annotator SDL-AMR-09 ::preferred # ::tok activator interaction ( through Ada2 , Gcn5 , and Ada3 ) , histone acetylation ( by Gcn5 ) , and TBP interaction ( through Spt8 and Spt3 ) . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 1-1.1 4-1.1.2.1.1.1 6-1.1.2.2 8-1 9-1.1.2.3.1.1 12-1.2.1.1.1 13-1.2 15-1.2.2.r 16-1.2.2.1.1 19-1 19-1.1.2 20-1.3.1.1.1 21-1.3 24-1.3.2.1.1.1 26-1.3.2.2.1.1 (a2 / and~e.8,19 :op1 (i / interact-01~e.1 :ARG1 (m / molecular-physical-entity~e.0 :ARG0-of~e.0 (a3 / activate-01~e.0)) :instrument (a5 / and~e.19 :op1 (p3 / protein :name (n6 / name :op1 "Ada2"~e.4)) :op2 p5~e.6 :op3 (p4 / protein :name (n7 / name :op1 "Ada3"~e.9)))) :op2 (a / acetylate-01~e.13 :ARG1 (p / protein :name (n / name :op1 "histone"~e.12)) :ARG2~e.15 (p5 / protein :name (n5 / name :op1 "Gcn5"~e.16))) :op3 (i2 / interact-01~e.21 :ARG1 (p2 / protein :name (n2 / name :op1 "TBP"~e.20)) :instrument (a4 / and :op1 (p7 / protein :name (n3 / name :op1 "Spt8"~e.24)) :op2 (p6 / protein :name (n4 / name :op1 "Spt3"~e.26))))) # ::id bio.chicago_2015.36278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The molecular mechanisms of tinman induction by Dpp have largely been clarified . # ::alignments 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.2.1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1 9-1.2 11-1 (c / clarify-10~e.11 :ARG1 (m / mechanism~e.2 :mod (m2 / molecule~e.1) :instrument-of~e.3 (i / induce-01~e.5 :ARG0~e.6 (p / protein :name (n2 / name :op1 "Dpp"~e.7)) :ARG2 (p2 / protein :name (n / name :op1 "tinman"~e.4)))) :degree (l / large~e.9)) # ::id bio.chicago_2015.36299 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The interaction of p110C with PAK1 occurred within the residues 210 - 332 of PAK1 . # ::alignments 1-1 2-1.1.r 3-1.1.1.1 5-1.3.3 9-1.3.1 9-1.3.2 10-1.3.1.1 12-1.3.2.1 14-1.3.3 (i / interact-01~e.1 :ARG0~e.2 (e / enzyme :name (n / name :op1 "p110C"~e.3)) :ARG1 (e2 / enzyme :name (n2 / name :op1 "PAK1")) :location (b / between :op1 (r / residue~e.9 :mod 210~e.10) :op2 (r2 / residue~e.9 :mod 332~e.12) :part-of e2~e.5,14)) # ::id bio.chicago_2015.36305 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The protein phosphatase activity is involved in PTEN downregulation of IGF @-@ II signaling # ::alignments 1-1.1.1.1.1 2-1.1.1.1.2 3-1.1 5-1 6-1.2.r 7-1.2.2.1.1 8-1.2 9-1.2.1.r 10-1.2.1.1.1.1 12-1.2.1.1.1.1 13-1.2.1 (i / involve-01~e.5 :ARG1 (a / activity-06~e.3 :ARG1 (e / enzyme :name (n / name :op1 "protein"~e.1 :op2 "phosphatase"~e.2))) :ARG2~e.6 (d / downregulate-01~e.8 :ARG1~e.9 (s / signal-07~e.13 :ARG0 (p2 / protein :name (n3 / name :op1 "IGF-II"~e.10,12))) :ARG2 (p / protein :name (n2 / name :op1 "PTEN"~e.7)))) # ::id bio.chicago_2015.36312 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D ) Direct interaction of rAxin with beta @-@ catenin . # ::alignments 1-1.1 3-1.4 4-1 5-1.2.r 6-1.2.1.1 7-1.3.r 8-1.3.1.1 10-1.3.1.1 (i / interact-01~e.4 :li "D"~e.1 :ARG0~e.5 (p / protein :name (n2 / name :op1 "rAxin"~e.6)) :ARG1~e.7 (p2 / protein :name (n / name :op1 "beta-catenin"~e.8,10)) :ARG1-of (d / direct-02~e.3)) # ::id bio.chicago_2015.36320 ::amr-annotator SDL-AMR-09 ::preferred # ::tok JIP1 and JIP2 selectively bind components of the JNK signaling cascade such as JNK ( MAP kinase ) , MKK7 ( MAP kinase kinase ) , and mixed lineage kinase family proteins ( MAP kinase kinase kinase ) ( 23 , 24 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1.3 3-1.3.r 4-1 5-1.2 8-1.2.1.1.1 8-1.2.2.1.1.1 9-1.2.1.2 11-1.2.2.r 12-1.2.2.r 13-1.2.2.1.1.1 19-1.2.2.2.1.1 31-1.1.1 31-1.1.2 33-1.2.2.3.1.1 34-1.2.2.3.1.2 35-1.2.2.3.1.3 36-1.2.2.3.1.4 39-1.4.1.1.1.1 41-1.4.1.1.1.2 (b / bind-01~e.4 :ARG1 (a2 / and~e.1 :op1 (p2 / protein~e.31 :name (n / name :op1 "JIP1"~e.0)) :op2 (p3 / protein~e.31 :name (n2 / name :op1 "JIP2"~e.2))) :ARG2 (c2 / component~e.5 :part-of (p4 / pathway :name (n3 / name :op1 "JNK"~e.8) :ARG0-of (s2 / signal-07~e.9)) :example~e.11,12 (a3 / and :op1 (e / enzyme :name (n4 / name :op1 "JNK"~e.8,13)) :op2 (e3 / enzyme :name (n6 / name :op1 "MKK7"~e.19)) :op3 (e4 / enzyme :name (n5 / name :op1 "MAP"~e.33 :op2 "kinase"~e.34 :op3 "kinase"~e.35 :op4 "kinase"~e.36)))) :manner~e.3 (s / selective~e.3) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 23~e.39 :op2 24~e.41))))) # ::id bio.chicago_2015.36321 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , treatment of cells with okadaic acid inhibited DLK association with JIP and resulted in DLK dimerization in the presence of JIP . # ::alignments 0-1.3 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1 7-1.1.1.2.1.2 8-1.1 9-1.1.2.1.1.1 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2.1.1 13-1 14-1.2 15-1.2.2.r 16-1.2.2.1 17-1.2.2 18-1.2.2.2.r 20-1.2.2.2 21-1.2.2.2.1.r 22-1.2.2.2.1 (a / and~e.13 :op1 (i / inhibit-01~e.8 :ARG0 (t / treat-04~e.2 :ARG1~e.3 (c / cell~e.4) :ARG2~e.5 (s / small-molecule :name (n3 / name :op1 "okadaic"~e.6 :op2 "acid"~e.7))) :ARG1 (a3 / associate-01~e.10 :ARG1 (p / protein :name (n / name :op1 "DLK"~e.9)) :ARG2~e.11 (p2 / protein :name (n2 / name :op1 "JIP"~e.12)))) :op2 (r / result-01~e.14 :ARG1 t :ARG2~e.15 (d / dimerize-01~e.17 :ARG1 p~e.16 :condition~e.18 (p3 / present-02~e.20 :ARG1~e.21 p2~e.22))) :ARG1-of (r2 / resemble-01~e.0)) # ::id bio.chicago_2015.36328 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concomitant with the insulin @-@ stimulated decrease in association between Rap1 and Raf1 , there was a reciprocal increase in the amount of Raf1 that was associated with Ras ( Figure 1B ) . # ::alignments 3-1.2.2.1.1.1 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1 10-1.2.1.1.1.1 12-1.2.1.2 17-1.3 18-1 19-1.1.r 21-1.1 22-1.1.1.r 23-1.1.1.1.1 26-1.1.2 27-1.1.2.1.r 28-1.1.2.1.1.1 30-1.4.1 31-1.4.1.1 (i / increase-01~e.18 :ARG1~e.19 (a / amount~e.21 :quant-of~e.22 (e / enzyme :name (n / name :op1 "Raf1"~e.23)) :ARG1-of (a2 / associate-01~e.26 :ARG2~e.27 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.28)))) :time (d / decrease-01~e.6 :ARG1~e.7 (a3 / associate-01~e.8 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Rap1"~e.10)) :ARG2 e~e.12) :ARG1-of (s / stimulate-01~e.5 :ARG0 (p / protein :name (n4 / name :op1 "insulin"~e.3)))) :mod (r / reciprocal~e.17) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.30 :mod "1B"~e.31))) # ::id bio.chicago_2015.36331 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Colocalization of ASIP with aPKC and ZO @-@ 1 at cell junctions in rat intestinal epithelium and hepatic bile capillaries . # ::alignments 2-1.1.1.1.1 4-1.1.2.1.1.1 5-1.1.2 6-1.1.2.2.1.1 8-1.1.2.2.1.1 10-1.2.1 11-1.2 12-1.2.2.r 13-1.2.2.1.1.1 14-1.2.2.1.1 15-1.2.2.1 16-1.2.2 17-1.2.2.2.1.1 18-1.2.2.2.1 19-1.2.2.2 (c / colocalize-01 :ARG1 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "ASIP"~e.2)) :op2 (a2 / and~e.5 :op1 (e2 / enzyme :name (n / name :op1 "aPKC"~e.4)) :op2 (p2 / protein :name (n2 / name :op1 "ZO-1"~e.6,8)))) :ARG2 (j / junction~e.11 :mod (c2 / cell~e.10) :location~e.12 (a / and~e.16 :op1 (e / epithelium~e.15 :source (i / intestine~e.14 :mod (r / rat~e.13))) :op2 (c3 / capillary~e.19 :source (b / bile~e.18 :mod (h / hepatic~e.17)))))) # ::id bio.chicago_2015.36349 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.2.r 6-1.2.2.1.1.1.1 7-1.2.2.1 8-1.2.2 9-1.2.1.r 10-1.2.1.1.1 11-1.2.1.1.2 (a / and~e.2 :op1 (b / boundary~e.1 :mod (c2 / compartment~e.0)) :op2 (c / control-01~e.4 :ARG0~e.9 (p / protein-family :name (n / name :op1 "hedgehog"~e.10 :op2 "protein"~e.11)) :ARG1~e.5 (p2 / pattern-01~e.8 :ARG2 (l / limb~e.7 :mod (o / organism :name (n2 / name :op1 "Drosophila"~e.6)))))) # ::id bio.chicago_2015.36384 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To address the issue , we determined the molecular interaction of QRS with ASK1 in 293 cells . # ::alignments 1-1.3 3-1.3.2 5-1.3.1 6-1 8-1.2.3 9-1.2 10-1.2.1.r 11-1.2.1.1.1 12-1.2.2.r 13-1.2.2.1.1 14-1.2.4.r 15-1.2.4.1 16-1.2.4 (d / determine-01~e.6 :ARG0 w :ARG1 (i2 / interact-01~e.9 :ARG0~e.10 (m2 / macro-molecular-complex :name (n / name :op1 "QRS"~e.11)) :ARG1~e.12 (e / enzyme :name (n2 / name :op1 "ASK1"~e.13)) :ARG2 (m / molecule~e.8) :location~e.14 (c / cell~e.16 :quant 293~e.15)) :purpose (a / address-02~e.1 :ARG0 (w / we~e.5) :ARG1 (i / issue-02~e.3))) # ::id bio.chicago_2015.36390 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 7C shows that in contrast to Irak , Irak D358N did not activate p38 in COS @-@ 1 cells , although both proteins were expressed at a comparable level . # ::alignments 0-1.3.1 1-1.3.1.1 2-1.3 5-1.1 7-1.1.1.1.1 9-1.1.1.1.1 9-1.1.2.2.1.1 10-1.1.2.2.1.2 12-1.1.2.1 12-1.1.2.1.r 13-1.1.2 14-1.1.2.3.1.1 15-1.1.2.4.r 16-1.1.2.4.1.1 18-1.1.2.4.1.1 19-1.1.2.4 21-1 23-1.1.1 23-1.1.2.2 25-1.2 26-1.2.2.r 28-1.2.2.1 29-1.2.2 (h / have-concession-91~e.21 :ARG1 (c / contrast-01~e.5 :ARG1 (p / protein~e.23 :name (n / name :op1 "Irak"~e.7,9)) :ARG2 (a / activate-01~e.13 :polarity~e.12 -~e.12 :ARG0 (p2 / protein~e.23 :name (n2 / name :op1 "Irak"~e.9 :op2 "D358N"~e.10)) :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38"~e.14)) :location~e.15 (c2 / cell-line~e.19 :name (n3 / name :op1 "COS-1"~e.16,18)))) :ARG2 (e / express-03~e.25 :ARG2 (a2 / and :op1 p :op2 p2) :mod~e.26 (l / level~e.29 :ARG1-of (c3 / comparable-03~e.28))) :ARG1-of (s / show-01~e.2 :ARG0 (f / figure~e.0 :mod "7C"~e.1))) # ::id bio.chicago_2015.36404 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The fat facets gene is required for Drosophila eye and embryo development . # ::alignments 1-1.2.1.1 2-1.2.1.2 3-1.2 5-1 6-1.1.r 7-1.1.1.1.1 8-1.1.2.1 9-1.1.2 10-1.1.2.2 11-1.1 (r / require-01~e.5 :ARG0~e.6 (d / develop-01~e.11 :ARG1 (o / organism :name (n / name :op1 "Drosophila"~e.7)) :ARG2 (a / and~e.9 :op1 (e / eye~e.8) :op2 (e2 / embryo~e.10))) :ARG1 (g / gene~e.3 :name (n2 / name :op1 "fat"~e.1 :op2 "facets"~e.2))) # ::id bio.chicago_2015.36407 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B , HEL cells were exposed to increasing concentrations of chelerythrine for 30 min prior to the potentiation of PGE1 @-@ stimulated AC activity by the addition of ethanol ( 200 mM EtOH ) or PDBu ( 100 nM ) . # ::alignments 0-1.1 2-1.2.1.1 3-1.2 5-1 6-1.3.r 7-1.3.2 8-1.3 8-1.5.1.1.2.2.1.1.1 8-1.5.1.1.2.2.1.2.2 9-1.3.1.r 10-1.3.1.1.1 11-1.4.r 12-1.4.1 13-1.4.2 14-1.5 19-1.5.1.1.2.1.1.1 21-1.5.1.1.2 22-1.5.1.1.1.1.1 23-1.5.1.1 24-1.5.1.1.2.2.r 26-1.5.1.1.2.2 27-1.5.1.1.2.2.1.r 28-1.5.1.1.2.2.1.1 30-1.5.1.1.2.2.1.1.1.1 34-1.5.1.1.2.2.1 35-1.5.1.1.2.2.1.2.1.1 37-1.5.1.1.2.2.1.2.2.1 38-1.5.1.1.2.2.1.2.2.2 (e / expose-01~e.5 :li "B"~e.0 :ARG1 (c2 / cell~e.3 :name (n2 / name :op1 "HEL"~e.2)) :ARG2~e.6 (c3 / concentrate-02~e.8 :ARG1~e.9 (s3 / small-molecule :name (n / name :op1 "chelerythrine"~e.10)) :ARG1-of (i / increase-01~e.7)) :duration~e.11 (t / temporal-quantity :quant 30~e.12 :unit (m2 / minute~e.13)) :time (p / prior~e.14 :op1 (p2 / potentiate-01 :ARG1 (a2 / activity-06~e.23 :ARG0 (e2 / enzyme :name (n3 / name :op1 "AC"~e.22)) :ARG1-of (s / stimulate-01~e.21 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "PGE1"~e.19)) :ARG2~e.24 (a3 / add-02~e.26 :ARG1~e.27 (o / or~e.34 :op1 (e4 / ethanol~e.28 :quant (c6 / concentration-quantity~e.8 :quant 200~e.30 :unit (m / micromolar))) :op2 (s4 / small-molecule :name (n5 / name :op1 "PDBu"~e.35) :quant (c5 / concentration-quantity~e.8 :quant 100~e.37 :unit (n6 / nanomolar~e.38)))))))))) # ::id bio.chicago_2015.36416 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed that the 306 @-@ amino acid region between amino acids 827 and 1132 in the C @-@ terminal half of GLI3 bound to CBP with almost the same efficiency as full @-@ length GLI3 . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1.1 7-1.2.1.2 8-1.2.1.2 9-1.2.1 10-1.2.1.3 11-1.2.1.3.1 11-1.2.1.3.2 12-1.2.1.3.1 13-1.2.1.3.1.1 14-1.2.1.3 15-1.2.1.3.2.1 16-1.2.1.3.3.r 18-1.2.1.3.3.1.1.1 20-1.2.1.3.3.1.1.1 21-1.2.1.3.3 23-1.2.3.2.1.1.1 24-1.2 25-1.2.2.r 26-1.2.2.1.1 28-1.2.3.3 30-1.2.3.2 31-1.2.3 33-1.2.3.2.1.2.1 35-1.2.3.2.1 35-1.2.3.2.1.2 35-1.2.3.2.1.2.r 36-1.2.3.2.1.1.1 (s / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (b / bind-01~e.24 :ARG1 (r2 / region~e.9 :quant 306~e.5 :mod (a2 / amino-acid~e.7,8) :location (b2 / between~e.10,14 :op1 (a3 / amino-acid~e.11,12 :mod 827~e.13) :op2 (a4 / amino-acid~e.11 :mod 1132~e.15) :location~e.16 (h / half~e.21 :part-of (p2 / protein-segment :name (n3 / name :op1 "C-terminus"~e.18,20) :part-of p3)))) :ARG2~e.25 (p / protein :name (n / name :op1 "CBP"~e.26)) :manner (e / efficient-01~e.31 :ARG1 p :ARG1-of (s2 / same-01~e.30 :ARG2 (p3 / protein~e.35 :name (n2 / name :op1 "GLI3"~e.23,36) :ARG1-of~e.35 (l / long-03~e.35 :mod (f / full~e.33)))) :degree (a / almost~e.28)))) # ::id bio.chicago_2015.36428 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It appears that Su( fu ) binds directly to Fu and Ci , but not to Cos2 , and that the bulk of these interactions are stable in both the presence and absence of Hh . # ::alignments 1-1 4-1.1.1.1.2.1.1.1 6-1.1.1.1 6-1.1.1.2 7-1.1.1.1.3 9-1.1.1.1.2.1.1.1 10-1.1.1.1.2 11-1.1.1.1.2.2.1.1 13-1.1.1 14-1.1.1.2.1 14-1.1.1.2.1.r 15-1.1.1.2.3.r 16-1.1.1.2.3.1.1 18-1.1 19-1.1.r 21-1.1.2.1 22-1.1.2.1.1.r 23-1.1.2.1.1.1 24-1.1.2.1.1 26-1.1.2 30-1.1.2.2.1 31-1.1.2.2 32-1.1.2.2.2 33-1.1.2.2.1.1.r 34-1.1.2.2.1.1.1.1 (a / appear-01~e.1 :ARG1~e.19 (a2 / and~e.18 :op1 (c / contrast-01~e.13 :ARG1 (b2 / bind-01~e.6 :ARG1 (p3 / protein :name (n2 / name :op1 "Su(fu)")) :ARG2 (a4 / and~e.10 :op1 (p4 / protein :name (n3 / name :op1 "Fu"~e.4,9)) :op2 (p5 / protein :name (n4 / name :op1 "Ci"~e.11))) :ARG1-of (d / direct-02~e.7)) :ARG2 (b3 / bind-01~e.6 :polarity~e.14 -~e.14 :ARG1 p3 :ARG2~e.15 (p6 / protein :name (n5 / name :op1 "Cos2"~e.16)))) :op2 (s / stable-03~e.26 :ARG1 (b / bulk-01~e.21 :ARG1~e.22 (i / interact-01~e.24 :mod (t / this~e.23))) :condition (a5 / and~e.31 :op1 (p / present-02~e.30 :ARG2~e.33 (p2 / protein :name (n / name :op1 "Hh"~e.34))) :op3 (a3 / absent-01~e.32 :ARG1 p2))))) # ::id bio.chicago_2015.36448 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of the alpha @-@ subunit of eIF2 , catalysed by any of several eIF2 kinases , leads to inhibition of eIF2B since eIF2( alphaP ) is a potent competitive inhibitor of eIF2B ( reviewed in Clemens , 1996 ; Hinnebusch , 2000 ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 7-1.1.1.2.1.1.1.1.1 11-1.1.1.2.1.2 13-1.1.1.2.1.1.1.2 14-1.1.1.2.1.1.1.1.1 15-1.1.1.2.1 15-1.1.1.2.1.1.1 17-1 18-1.2.r 18-1.3 19-1.2 20-1.2.1.r 21-1.2.1 22-1.3 28-1.3.1.3 29-1.3.1.2.2 30-1.3.1 30-1.3.1.2 30-1.3.1.2.r 31-1.3.1.2.1.r 32-1.3.1.2.1.1.1 34-1.4 36-1.4.1.1.1.1.1 38-1.4.1.1.2.1 40-1.4.1.2.1.1.1 42-1.4.1.2.2.1 (l / lead-03~e.17 :ARG0 (p2 / phosphorylate-01~e.0 :ARG1~e.1 (p / protein-segment :name (n3 / name :op1 "alpha-subunit"~e.3,5) :ARG1-of (c3 / catalyze-01 :ARG0 (k / kinase~e.15 :ARG1-of (i4 / include-91 :ARG2 (k2 / kinase~e.15 :name (n6 / name :op1 "eIF2"~e.7,14) :quant (s / several~e.13))) :mod (a / any~e.11))) :part-of p3)) :ARG2~e.18 (i2 / inhibit-01~e.19 :ARG1~e.20 p4~e.21) :ARG1-of (c / cause-01~e.18,22 :ARG0 (p3 / protein~e.30 :name (n / name :op1 "eIF2(alphaP)") :ARG0-of~e.30 (i3 / inhibit-01~e.30 :ARG1~e.31 (p4 / protein :name (n2 / name :op1 "eIF2B"~e.32)) :ARG0-of (c2 / compete-01~e.29)) :mod (p5 / potent~e.28))) :ARG1-of (r / review-01~e.34 :ARG0 (a3 / and :op1 (p8 / publication-91 :ARG0 (p6 / person :name (n4 / name :op1 "Clemens"~e.36)) :time (d / date-entity :year 1996~e.38)) :op2 (p9 / publication-91 :ARG0 (p7 / person :name (n5 / name :op1 "Hinnebusch"~e.40)) :time (d2 / date-entity :year 2000~e.42))))) # ::id bio.chicago_2015.36507 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of CrkL did not significantly change the time course of Epo @-@ induced JNK activation , although the activation level at the peak was moderately enhanced ( Fig . 5 B ) . # ::alignments 0-1.1.2 1-1.1.2.1.r 2-1.1.2.1.1.1 4-1.1.1 4-1.1.1.r 5-1.1.4 6-1.1 8-1.1.3.2 9-1.1.3 10-1.1.3.1.r 11-1.1.3.1.2.1.1.1 13-1.1.3.1.2 14-1.1.3.1.1.1.1 15-1.1.3.1 17-1 19-1.2.1.1 20-1.2.1 21-1.2.1.2.r 23-1.2.1.2 25-1.2.2 26-1.2 28-1.3.1 (h / have-concession-91~e.17 :ARG1 (c / change-01~e.6 :polarity~e.4 -~e.4 :ARG0 (o / overexpress-01~e.0 :ARG2~e.1 (p2 / protein :name (n / name :op1 "CrkL"~e.2))) :ARG1 (c2 / course-01~e.9 :ARG0~e.10 (a2 / activate-01~e.15 :ARG1 (e2 / enzyme :name (n2 / name :op1 "JNK"~e.14)) :ARG2-of (i / induce-01~e.13 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "Epo"~e.11)))) :mod (t / time~e.8)) :ARG1-of (s / significant-02~e.5)) :ARG2 (e / enhance-01~e.26 :ARG1 (l / level~e.20 :degree-of (a / activate-01~e.19) :location~e.21 (p / peak~e.23)) :ARG1-of (m / moderate-01~e.25)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod "5B"))) # ::id bio.chicago_2015.36510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok APP and FE65 colocalize with actin and Mena , an Abl @-@ associated signaling protein thought to regulate actin dynamics , in lamellipodia . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.2.1.1 3-1 4-1.1.r 5-1.1.2.1.1.1 6-1.1.2 7-1.1.2.2.1.1 10-1.1.2.2.2.1.2.1.1.1 12-1.1.2.2.2.1.2 13-1.1.2.2.2.1.1 14-1.1.2.2.2.1 15-1.1.2.2.2.1.3 17-1.1.2.2.2.1.3.1 18-1.1.2.2.2.1.3.1.2.1 19-1.1.2.2.2.1.3.1.2 21-1.1.2.2.2.1.3.1.3.r 22-1.1.2.2.2.1.3.1.3.1.1 (c / colocalize-01~e.3 :ARG1~e.4 (a4 / and :op1 (a / and :op1 (p / protein :name (n / name :op1 "APP"~e.0)) :op2 (p2 / protein :name (n2 / name :op1 "FE65"~e.2))) :op2 (a2 / and~e.6 :op1 (p3 / protein :name (n3 / name :op1 "actin"~e.5)) :op2 (p4 / protein :name (n4 / name :op1 "Mena"~e.7) :ARG1-of (m / mean-01 :ARG2 (p5 / protein~e.14 :ARG0-of (s / signal-07~e.13) :ARG1-of (a3 / associate-01~e.12 :ARG2 (p7 / protein :name (n5 / name :op1 "Abl"~e.10))) :ARG1-of (t / think-01~e.15 :ARG2 (r / regulate-01~e.17 :ARG0 p4 :ARG1 (d / dynamic~e.19 :mod p3~e.18) :location~e.21 (p6 / protein :name (n6 / name :op1 "lamellipodia"~e.22)))))))))) # ::id bio.chicago_2015.36540 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CRIPT , a Novel Postsynaptic Protein that Binds to the Third PDZ Domain of PSD @-@ 95/SAP90 . # ::alignments 0-1.1.1 3-1.2.1.2 4-1.2.1.1 5-1.2.1 7-1.2.1.3 8-1.2.1.3.1.r 10-1.2.1.3.1.3 10-1.2.1.3.1.3.1 10-1.2.1.3.1.3.1.r 11-1.2.1.3.1.1.1 14-1.2.1.3.1.2.1.1 (p / protein :name (n / name :op1 "CRIPT"~e.0) :ARG1-of (m / mean-01 :ARG2 (p2 / protein~e.5 :mod (p3 / postsynaptic~e.4) :mod (n2 / novel~e.3) :ARG1-of (b / bind-01~e.7 :ARG2~e.8 (p4 / protein-segment :name (n3 / name :op1 "PDZ"~e.11) :part-of (p5 / protein-family :name (n4 / name :op1 "PSD-95/SAP90"~e.14)) :ord (o / ordinal-entity~e.10 :value~e.10 3~e.10)))))) # ::id bio.chicago_2015.36582 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We previously demonstrated that Wnt @-@ 11 and Wnt @-@ 1 activate RhoA via Fz @/@ Dvl signaling , and we identified Daam1 , a Formin @-@ homology protein , as being required for Wnt/ Fz @/@ Dvl activation of RhoA , Wnt @-@ induced Dvl @-@ RhoA complex formation , and CE movements during Xenopus gastrulation ( Habas et al. 2001 ) . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 3-1.1.2.r 4-1.1.2.1.1.1.1 6-1.1.2.1.1.1.1 7-1.1.2.1 8-1.2.2.1.1.1.1.1.1 10-1.1.2.1.2.1.1 11-1.1.2 12-1.1.2.2.1.1 14-1.1.2.3.1.1.1.1 15-1.1.2.3.1 16-1.1.2.3.1.2.1.1 17-1.1.2.3 20-1.2.1 21-1.2 22-1.2.2.2.1.1 25-1.2.2.2.2.1.1.1 27-1.2.2.2.2.1.1.1 28-1.1.2.1.1 28-1.1.2.1.2 28-1.1.2.2 28-1.1.2.3.1.1 28-1.1.2.3.1.2 28-1.2.2.1.1.1.1 28-1.2.2.2 28-1.2.2.2.2.1 30-1.1.3.r 32-1.2.2 35-1.2.2.1.1.1.2 36-1.2.2.1.1.1 37-1.2.2.1.1.1.3 38-1.2.2.1.1 39-1.2.2.1.1.2.r 40-1.2.2.1.1.2 42-1.1.2.1.2.1.1 44-1.2.2.1.2.2 45-1.1.2.3.1.2.1.1 47-1.1.2.2.1.1 48-1.2.2.1.2.1 49-1.2.2.1.2 51-1.2.2.1 53-1.2.2.1.3 54-1.2.2.1.3.1.r 55-1.2.2.1.3.1.1.1.1 58-1.3.1.1.1.1.1 59-1.3.1.1 60-1.3.1.1.2.1 61-1.3.1.2.1 (a / and :op1 (d3 / demonstrate-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (a3 / activate-01~e.11 :ARG0 (a4 / and~e.7 :op1 (p11 / protein~e.28 :name (n2 / name :op1 "Wnt-11"~e.4,6)) :op2 (p12 / protein~e.28 :name (n3 / name :op1 "Wnt-1"~e.10,42))) :ARG1 (p4 / protein~e.28 :name (n4 / name :op1 "RhoA"~e.12,47)) :manner (s / signal-07~e.17 :ARG0 (s2 / slash~e.15 :op1 (p5 / protein~e.28 :name (n5 / name :op1 "Fz"~e.14)) :op2 (p6 / protein~e.28 :name (n6 / name :op1 "Dvl"~e.16,45))))) :time~e.30 (p3 / previous~e.1)) :op2 (i / identify-01~e.21 :ARG0 w~e.20 :ARG1 (r / require-01~e.32 :ARG0 (a6 / and~e.51 :op1 (a5 / activate-01~e.38 :ARG0 (s3 / slash~e.36 :op1 (p9 / protein~e.28 :name (n9 / name :op1 "Wnt"~e.8)) :op2 p5~e.35 :op3 p6~e.37) :ARG1~e.39 p4~e.40) :op2 (f / form-01~e.49 :ARG1 (m2 / macro-molecular-complex~e.48 :part p6 :part p4) :ARG2-of (i2 / induce-01~e.44 :ARG0 p9)) :op3 (m3 / move-01~e.53 :time~e.54 (g3 / gastrulate-00 :ARG0 (o2 / organism :name (n11 / name :op1 "Xenopus"~e.55))) :mod (e / extension :mod (c / convergent)))) :ARG1 (p7 / protein~e.28 :name (n7 / name :op1 "Daam1"~e.22) :ARG1-of (m / mean-01 :ARG2 (p8 / protein~e.28 :name (n8 / name :op1 "Formin-homology"~e.25,27)))))) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a2 / and~e.59 :op1 (p / person :name (n / name :op1 "Habas"~e.58)) :op2 (p2 / person :mod (o / other~e.60))) :time (d / date-entity :year 2001~e.61)))) # ::id bio.chicago_2015.36590 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To verify that both the AHR and ARNT interact with TFIIB , similar coaffinity precipitation experiments were performed , except that we used either immobilized AHR or ARNT and 35S @-@ TFIIB ( Fig . 1B ) . # ::alignments 1-1.3 5-1.3.2.1.1.1.1 6-1.3.2.1 7-1.3.2.1.2.1.1 8-1.3.2 9-1.3.2.2.r 10-1.3.2.2.1.1 12-1.2.2 13-1.2.1.1 14-1.2.1 15-1.2 17-1 19-1.5 20-1.5.1.r 21-1.5.1.1 22-1.5.1 24-1.5.1.2.1.3 25-1.5.1.2.1.1 26-1.5.1.2.1 27-1.5.1.2.1.2 28-1.5.1.2 29-1.5.1.2.2.1.1 31-1.3.2.2.1.1 33-1.4.1 35-1.4.1.1 (p / perform-02~e.17 :ARG0 w :ARG1 (e / experiment-01~e.15 :ARG1 (p2 / precipitate-01~e.14 :ARG1 (c / coaffinity~e.13)) :ARG1-of (r / resemble-01~e.12)) :purpose (v / verify-01~e.1 :ARG0 w :ARG1 (i / interact-01~e.8 :ARG0 (a / and~e.6 :op1 (p3 / protein :name (n / name :op1 "AHR"~e.5)) :op2 (p4 / protein :name (n2 / name :op1 "ARNT"~e.7))) :ARG1~e.9 (p5 / protein :name (n3 / name :op1 "TFIIB"~e.10,31)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.33 :mod "1B"~e.35)) :ARG2-of (e2 / except-01~e.19 :ARG1~e.20 (u / use-01~e.22 :ARG0 (w / we~e.21) :ARG1 (a2 / and~e.28 :op1 (o / or~e.26 :op1 p3~e.25 :op2 p4~e.27 :ARG1-of (i2 / immobilize-01~e.24)) :op2 (p6 / protein :name (n4 / name :op1 "35S-TFIIB"~e.29)))))) # ::id bio.chicago_2015.36667 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E1A , an adenoviral oncoprotein , interacts with p300 or CBP and directly inhibits the histone acetyltransferase activity ( 29 ) . # ::alignments 0-1.1.1.1.1 3-1.1.1.3 6-1.1 7-1.1.2.r 8-1.1.2.1.1.1 9-1.1.2 10-1.1.2.2.1.1 11-1 12-1.2.2 13-1.2 15-1.2.1.1.1.1 16-1.2.1.1.1.2 17-1.2.1 19-1.3.1.1.1 (a / and~e.11 :op1 (i / interact-01~e.6 :ARG0 (p2 / protein :name (n / name :op1 "E1A"~e.0) :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :mod (a3 / adenoviral~e.3)) :ARG1~e.7 (o / or~e.9 :op1 (p3 / protein :name (n2 / name :op1 "p300"~e.8)) :op2 (p4 / protein :name (n3 / name :op1 "CBP"~e.10)))) :op2 (i2 / inhibit-01~e.13 :ARG1 (a2 / activity-06~e.17 :ARG0 (e / enzyme :name (n4 / name :op1 "histone"~e.15 :op2 "acetyltransferase"~e.16))) :ARG1-of (d2 / direct-02~e.12)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 29~e.19)))) # ::id bio.chicago_2015.36670 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of the 4E @-@ BPs to eIF4E is regulated by phosphorylation ( Lin et al. 1994 ; Pause et al. 1994 ) . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1.1.1 6-1.2.2.r 7-1.2.2.1.1 9-1 10-1.1.r 11-1.1 13-1.3.1.1.1.1.1.1 14-1.3.1.1.1 15-1.3.1.1.1.2.1 16-1.3.1.1.2.1 18-1.3.1.2.1.1.1.1 19-1.3.1 19-1.3.1.1.1 19-1.3.1.2.1 20-1.3.1.1.1.2.1 20-1.3.1.2.1.2.1 21-1.3.1.1.2.1 (r / regulate-01~e.9 :ARG0~e.10 (p / phosphorylate-01~e.11) :ARG1 (b / bind-01~e.0 :ARG1~e.1 (p2 / protein :name (n / name :op1 "4E-BP"~e.3)) :ARG2~e.6 (p3 / protein :name (n2 / name :op1 "eIF4E"~e.7))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.19 :op1 (p8 / publication-91 :ARG0 (a2 / and~e.14,19 :op1 (p4 / person :name (n3 / name :op1 "Lin"~e.13)) :op2 (p5 / person :mod (o / other~e.15,20))) :time (d2 / date-entity :year 1994~e.16,21)) :op2 (p9 / publication-91 :ARG0 (a3 / and~e.19 :op1 (p7 / person :name (n4 / name :op1 "Pause"~e.18)) :op2 (p6 / person :mod (o2 / other~e.20))) :time d2)))) # ::id bio.chicago_2015.36675 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test if oxidative stress modulates the activation of ERK1 @/@ 2 , p38 or CREB induced by NGF and EGF , PC12 cells were briefly ( 10 min ) exposed to 200 M H2O2 before treatment with NGF or EGF . # ::alignments 1-1.6 3-1.6.1.2.1 4-1.6.1.2 5-1.6.1 7-1.6.1.3 8-1.6.1.3.1.r 9-1.6.1.3.1.1.1.1 11-1.6.1.3.1.1.1.1 13-1.6.1.3.1.2.1.1 14-1.6.1.3.1 15-1.6.1.3.1.3.1.1 16-1.6.1.3.2 18-1.5.1.2.1.1.1 20-1.5.1.2.2.1.1 22-1.1.1.1 23-1.1 25-1.4 25-1.4.r 27-1.3.1 28-1.3.2 30-1 31-1.2.r 32-1.2.2.1 33-1.2.2.2 34-1.2.1.1 35-1.5 36-1.5.1 38-1.5.1.2.1.1.1 39-1.5.1.2 40-1.5.1.2.2.1.1 (e / expose-01~e.30 :ARG1 (c / cell-line~e.23 :name (n / name :op1 "PC12"~e.22)) :ARG2~e.31 (s2 / small-molecule :name (n2 / name :op1 "H2O2"~e.34) :mod (c2 / concentration-quantity :quant 200~e.32 :unit (m4 / molar~e.33))) :duration (t / temporal-quantity :quant 10~e.27 :unit (m2 / minute~e.28)) :manner~e.25 (b / brief~e.25) :time (b2 / before~e.35 :op1 (t2 / treat-04~e.36 :ARG1 c :ARG2 (o / or~e.39 :op1 (p3 / protein :name (n3 / name :op1 "NGF"~e.18,38)) :op2 (p2 / protein :name (n4 / name :op1 "EGF"~e.20,40))))) :purpose (t3 / test-01~e.1 :ARG2 (m / modulate-01~e.5 :mode interrogative :ARG0 (s3 / stress-02~e.4 :ARG0 (o4 / oxidize-01~e.3)) :ARG1 (a / activate-01~e.7 :ARG1~e.8 (o3 / or~e.14 :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1/2"~e.9,11)) :op2 (e3 / enzyme :name (n6 / name :op1 "p38"~e.13)) :op3 (p / protein :name (n7 / name :op1 "CREB"~e.15))) :ARG2-of (i / induce-01~e.16 :ARG0 (a2 / and :op1 p3 :op2 p2)))))) # ::id bio.chicago_2015.36678 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together with cell culture experiments showing binding and phosphorylation of mPER1 and mPER2 by CKI and research in Drosophila showing the importance of the CKI homolog DOUBLE @-@ TIME for destabilizing dPER , the genetic data in both rodents and humans strongly suggest that CKI -@ dependent phosphorylation of PER proteins is an essential and ancient part of the circadian clock mechanism ( references in Toh et al. , 2001 ) . # ::alignments 1-1.4.r 2-1.4.1.1.1 3-1.4.1.1 4-1.4.1 5-1.4.1.2 6-1.4.1.2.1.1 7-1.4.1.2.1 7-1.4.1.2.1.1.2 8-1.4.1.2.1.2 10-1.4.1.2.1.1.2.1.1.1 12-1.4.1.2.1.1.2.2.1.1 14-1.4.2.2.1.2.1.1 15-1.4 16-1.4.2 17-1.4.2.1.r 18-1.4.2.1.1.1 19-1.4.2.2 21-1.4.2.2.1 24-1.4.2.2.1.2.1.1 25-1.4.2.2.1.2.1.2 26-1.4.2.2.1.2.1.3 28-1.4.2.2.1.2.1.3 29-1.4.2.2.1.1.r 30-1.4.2.2.1.1 31-1.4.2.2.1.1.1.1.1 35-1.1 38-1.1.2.1 39-1.1.2 40-1.1.2.2 41-1.3 42-1 43-1.2.r 44-1.2.3.2.1.1.1 46-1.2.3.2 47-1.2.3 49-1.2.3.1.1.1 50-1.2.3.1 50-1.4.1.2.1.1.2.1 50-1.4.1.2.1.1.2.2 50-1.4.2.2.1.1.1 50-1.4.2.2.1.2 51-1.2.3.r 53-1.2.1 55-1.2.2 56-1.2 57-1.2.4.r 59-1.2.4.1.1 60-1.2.4.1 61-1.2.4 63-1.5 65-1.5.1.1.1.1.1 66-1.5.1.1 67-1.5.1.1.2.1 69-1.5.1.2.1 (s / suggest-01~e.42 :ARG0 (d2 / data~e.35 :topic (g / gene) :source (a / and~e.39 :op1 (r / rodent~e.38) :op2 (h / human~e.40))) :ARG1~e.43 (p2 / part~e.56 :mod (e / essential~e.53) :mod (a2 / ancient~e.55) :domain~e.51 (p3 / phosphorylate-01~e.47 :ARG1 (p4 / protein~e.50 :name (n2 / name :op1 "PER"~e.49)) :ARG0-of (d3 / depend-01~e.46 :ARG1 (e2 / enzyme :name (n / name :op1 "CKI"~e.44)))) :part-of~e.57 (m / mechanism~e.61 :mod (c / clock~e.60 :mod (c2 / circadian~e.59)))) :ARG1-of (s2 / strong-02~e.41) :accompanier~e.1 (a3 / and~e.15 :op1 (e3 / experiment-01~e.4 :ARG1 (c3 / culture~e.3 :mod (c4 / cell~e.2)) :ARG0-of (s3 / show-01~e.5 :ARG1 (a4 / and~e.7 :op1 (b / bind-01~e.6 :ARG0 e2 :ARG1 (a5 / and~e.7 :op1 (p8 / protein~e.50 :name (n3 / name :op1 "mPER1"~e.10)) :op2 (p9 / protein~e.50 :name (n4 / name :op1 "mPER2"~e.12)))) :op2 (p / phosphorylate-01~e.8 :ARG1 a5 :ARG2 e2)))) :op2 (r2 / research-01~e.16 :ARG1~e.17 (o / organism :name (n5 / name :op1 "Drosophila"~e.18)) :ARG0-of (s4 / show-01~e.19 :ARG1 (i / importance~e.21 :purpose~e.29 (d4 / destabilize-01~e.30 :ARG1 (p11 / protein~e.50 :name (n7 / name :op1 "dPER"~e.31))) :mod (p10 / protein~e.50 :name (n9 / name :op1 "CKI"~e.14,24 :op2 "homolog"~e.25 :op3 "DOUBLE-TIME"~e.26,28)))))) :ARG1-of (r3 / reference-04~e.63 :location (p5 / publication-91 :ARG0 (a6 / and~e.66 :op1 (p6 / person :name (n8 / name :op1 "Toh"~e.65)) :op2 (p7 / person :mod (o2 / other~e.67))) :time (d / date-entity :year 2001~e.69)))) # ::id bio.chicago_2015.36682 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In response to cAMP , CREB bound to the CRE enhancer is phosphorylated , which results in recruitment of CBP/ p300 and eventually transcriptional activation of cAMP @-@ responsive genes . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.2.1 5-1.1.2.1 6-1.1 6-1.1.3 6-1.1.3.r 7-1.1.3.1.r 9-1.1.3.1.2.1 10-1.1.3.1.3 12-1 15-1.3 16-1.3.1.r 17-1.3.1.1 20-1.3.1.1.1.2.2.1 21-1.3.1 22-1.3.1.2.3 23-1.3.1.2.2 24-1.3.1.2 25-1.3.1.2.1.r 26-1.3.1.2.1.1.1 28-1.3.1.2.1.1 29-1.3.1.2.1 (p / phosphorylate-01~e.12 :ARG1 (p2 / protein~e.6 :wiki "CREB" :name (n / name :op1 "CREB"~e.5) :ARG1-of~e.6 (b / bind-01~e.6 :ARG2~e.7 (e3 / enzyme :wiki "Cre_recombinase" :name (n2 / name :op1 "CRE"~e.9) :mod (e / enhancer~e.10)))) :ARG2-of (r / respond-01~e.1 :ARG1~e.2 (s / small-molecule :wiki "Cyclic_adenosine_monophosphate" :name (n3 / name :op1 "cAMP"~e.3))) :ARG1-of (r2 / result-01~e.15 :ARG2~e.16 (a / and~e.21 :op1 (r3 / recruit-01~e.17 :ARG1 (o / or :op1 (p3 / protein :wiki "CREB-binding_protein" :name (n4 / name :op1 "CBP")) :op2 (p4 / protein :wiki "EP300" :name (n5 / name :op1 "p300"~e.20)))) :op2 (a2 / activate-01~e.24 :ARG1~e.25 (g / gene~e.29 :ARG0-of (r4 / respond-01~e.28 :ARG1 s~e.26)) :mod (t / transcribe-01~e.23) :time (e2 / eventual~e.22))))) # ::id bio.chicago_2015.36695 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Association of DLC with nNOS in differentiated PC12 cells reduced nNOS activity . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 4-1.1.2.1.1 5-1.1.3.r 6-1.1.3.2 7-1.1.3.1.1 8-1.1.3 9-1 10-1.2.1 11-1.2 (r / reduce-01~e.9 :ARG0 (a / associate-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "DLC"~e.2)) :ARG2~e.3 (e / enzyme :name (n2 / name :op1 "nNOS"~e.4)) :location~e.5 (c / cell-line~e.8 :name (n3 / name :op1 "PC12"~e.7) :ARG1-of (d / differentiate-01~e.6))) :ARG1 (a2 / activity-06~e.11 :ARG0 e~e.10)) # ::id bio.chicago_2015.36696 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The time courses of p38 , ERK1 @/@ 2 and CREB phosphorylation induced by NGF and EGF . # ::alignments 1-1.2.2.1 2-1.2.2 4-1.2.1.1.1.1 6-1.2.1.2.1.1 8-1.2.1.2.1.1 9-1.2.1 10-1.2.1.3.1.1 11-1.2 12-1 13-1.1.r 14-1.1.1.1.1 15-1.1 16-1.1.2.1.1 (i / induce-01~e.12 :ARG0~e.13 (a2 / and~e.15 :op1 (p4 / protein :name (n4 / name :op1 "NGF"~e.14)) :op2 (p / protein :name (n5 / name :op1 "EGF"~e.16))) :ARG2 (p2 / phosphorylate-01~e.11 :ARG1 (a / and~e.9 :op1 (e2 / enzyme :name (n / name :op1 "p38"~e.4)) :op2 (e / enzyme :name (n2 / name :op1 "ERK1/2"~e.6,8)) :op3 (p3 / protein :name (n3 / name :op1 "CREB"~e.10))) :duration (c / course~e.2 :mod (t / time~e.1)))) # ::id bio.chicago_2015.36704 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regulation of Armadillo by a Drosophila APC Inhibits Neuronal Apoptosis during Retinal Development . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1 3-1.1.1.r 5-1.1.1.2.1.1 6-1.1.1.1.1 7-1 8-1.2.1 9-1.2 10-1.3.r 11-1.3.1 12-1.3 (i / inhibit-01~e.7 :ARG0 (r / regulate-01~e.0 :ARG0~e.3 (p / protein :name (n / name :op1 "APC"~e.6) :source (o / organism :name (n2 / name :op1 "Drosophila"~e.5))) :ARG1~e.1 (p2 / protein :name (n3 / name :op1 "Armadillo"~e.2))) :ARG1 (a / apoptosis~e.9 :mod (n4 / neuronal~e.8)) :time~e.10 (d2 / develop-01~e.12 :ARG2 (r2 / retina~e.11))) # ::id bio.chicago_2015.36735 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NGF induced co @-@ association of IRAK with TRAF6 and atypical PKC binding protein/ p62 . # ::alignments 0-1.1.1.1 1-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1 7-1.2.2.r 8-1.2.2.1.1.1 9-1.2.2 10-1.2.2.2.2 11-1.2.2.2.3.1.1.1 12-1.2.2.2.3 14-1.2.2.2.1.1 (i / induce-01~e.1 :ARG0 (p3 / protein :name (n / name :op1 "NGF"~e.0)) :ARG2 (a3 / associate-01~e.4 :ARG1~e.5 (e2 / enzyme :name (n2 / name :op1 "IRAK"~e.6)) :ARG2~e.7 (a / and~e.9 :op1 (p / protein :name (n3 / name :op1 "TRAF6"~e.8)) :op2 (p2 / protein :name (n4 / name :op1 "p62"~e.14) :mod (a2 / atypical~e.10) :ARG0-of (b / bind-01~e.12 :ARG1 (e / enzyme :name (n5 / name :op1 "PKC"~e.11))))))) # ::id bio.chicago_2015.36749 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PI3K induction of cyclin D1 was inhibited by a dominant negative Tcf , and a single Tcf site in the cyclin D1 promoter was required for its induction by IKKalpha and PI3K . # ::alignments 0-1.1.2.1.1.1 1-1.1.2 2-1.1.2.2.r 3-1.1.2.2.1.1 4-1.1.2.2.1.2 6-1.1 9-1.2.2.1 10-1.2.2.1 11-1.2.2.1 13-1 15-1.2.2.2 16-1.2.2.1 17-1.2.2 18-1.2.2.3.r 20-1.2.2.3.1.1 21-1.2.2.3.1.1 22-1.2.2.3 22-1.2.2.3.1 22-1.2.2.3.1.r 24-1.2 25-1.2.1.r 26-1.2.1.2 26-1.2.1.2.r 27-1.2.1 28-1.2.1.1.r 29-1.2.1.1.1.1.1 30-1 30-1.2.1.1 31-1.2.1.1.2 (a / and~e.13,30 :op1 (i / inhibit-01~e.6 :ARG0 (p2 / protein :name (n3 / name :op1 "Tcf") :ARG2-of (m2 / mutate-01 :mod "-/-") :ARG0-of (d / dominate-01)) :ARG1 (i2 / induce-01~e.1 :ARG0 (e / enzyme :name (n / name :op1 "PI3K"~e.0)) :ARG1~e.2 (p / protein :name (n2 / name :op1 "cyclin"~e.3 :op2 "D1"~e.4)))) :op2 (r / require-01~e.24 :ARG0~e.25 (i3 / induce-01~e.27 :ARG0~e.28 (a2 / and~e.30 :op1 (e2 / enzyme :name (n5 / name :op1 "IKKalpha"~e.29)) :op2 e~e.31) :ARG1~e.26 p~e.26) :ARG1 (s / site~e.17 :mod p2~e.9,10,11,16 :ARG1-of (s2 / single-02~e.15) :location~e.18 (m / molecular-physical-entity~e.22 :ARG0-of~e.22 (p3 / promote-01~e.22 :ARG1 p~e.20,21))))) # ::id bio.chicago_2015.36758 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , Zw5 does not bind to scs``; instead , scs`` has multiple target sites for the BEAF ( boundary element associated factor ) proteins , BEAF 32A and BEAF 32B . # ::alignments 0-1 2-1.1.2.1.1 4-1.1.1 4-1.1.1.r 5-1.1 8-1.2 10-1.1.3.1.1 11-1.2.1 12-1.2.1.2.2 13-1.2.1.2.1 14-1.2.1.2 19-1.2.1.2.3.3.1.1.1 20-1.2.1.2.3.3.1.1.2 21-1.2.1.2.3.3.1.1.3 22-1.2.1.2.3.3.1.1.4 24-1.1.2 24-1.1.3 24-1.2.1.2.3.1 24-1.2.1.2.3.2 24-1.2.1.2.3.3.1 26-1.2.1.2.3.1.1.1 27-1.2.1.2.3.1.1.2 28-1.2.1.2.3 29-1.2.1.2.3.2.1.1 30-1.2.1.2.3.2.1.2 (c / contrast-01~e.0 :ARG1 (b / bind-01~e.5 :polarity~e.4 -~e.4 :ARG1 (p / protein~e.24 :name (n / name :op1 "Zw5"~e.2)) :ARG2 (p5 / protein~e.24 :name (n2 / name :op1 "scs``"~e.10))) :ARG2-of (i / instead-of-91~e.8 :ARG1 (h / have-03~e.11 :ARG0 p5 :ARG1 (s / site~e.14 :mod (t2 / target~e.13) :quant (m / multiple~e.12) :beneficiary (a / and~e.28 :op1 (p2 / protein~e.24 :name (n3 / name :op1 "BEAF"~e.26 :op2 "32A"~e.27)) :op2 (p3 / protein~e.24 :name (n4 / name :op1 "BEAF"~e.29 :op2 "32B"~e.30)) :ARG1-of (i2 / include-01 :ARG2 (p4 / protein-family~e.24 :name (n6 / name :op1 "boundary"~e.19 :op2 "element"~e.20 :op3 "associated"~e.21 :op4 "factor"~e.22)))))))) # ::id bio.chicago_2015.36797 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More specifically , cortactin binds and activates the Arp2 @/@ 3 complex of actin polymerizing proteins at sites of peripheral cytoskeletal rearrangement while cross @-@ linking and stabilizing actin filaments against depolymerization [ 23 , 24 and 25 ] . # ::alignments 0-1.3.1 1-1.3 3-1.1.1.1.1 4-1.1 5-1 6-1.2 8-1.1.2.1.1 10-1.1.2.1.1 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2.1.1.1.1 14-1.1.2.2.1 15-1.1.2.2 16-1.1.3.r 17-1.1.3 18-1.1.3.1.r 19-1.1.3.1.2 20-1.1.3.1.1 21-1.1.3.1 22-1.5.r 23-1.5.1.3 25-1.5.1 26-1.5 27-1.5.2 28-1.5.2.2.1 29-1.5.2.2 30-1.5.2.3.r 33-1.4.1.1.1.1 35-1.4.1.1.1.2 36-1.4.1.1.1 37-1.4.1.1.1.3 (a / and~e.5 :op1 (b / bind-01~e.4 :ARG0 (p / protein :name (n / name :op1 "cortactin"~e.3)) :ARG1 (m / macro-molecular-complex~e.11 :name (n2 / name :op1 "Arp2/3"~e.8,10) :part~e.12 (p2 / protein~e.15 :ARG0-of (p3 / polymerize-01~e.14 :ARG1 (p4 / protein :name (n3 / name :op1 "actin"~e.13))))) :location~e.16 (s2 / site~e.17 :mod~e.18 (r / rearrange-01~e.21 :mod (c2 / cytoskeletal~e.20) :mod (p5 / peripheral~e.19)))) :op2 (a2 / activate-01~e.6 :ARG0 p :ARG1 m) :ARG1-of (s3 / specific-02~e.1 :degree (m2 / more~e.0)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and~e.36 :op1 23~e.33 :op2 24~e.35 :op3 25~e.37)))) :time~e.22 (a4 / and~e.26 :op1 (l / link-01~e.25 :ARG0 p :ARG1 f :manner (c / cross~e.23)) :op2 (s / stabilize-01~e.27 :ARG0 p :ARG1 (f / filament~e.29 :mod p4~e.28) :prep-against~e.30 (d / depolymerize-00)))) # ::id bio.chicago_2015.36801 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGIF Recruits CtBP To Activated Smad Complexes-- To investigate the possibility that TGIF can recruit CtBP to a TGF @-@ beta @-@ activated Smad complex , COS @-@ 1 cells were transfected with FLAG @-@ tagged CtBP , HA @-@ tagged TGIF , and Smad2 . # ::alignments 0-1.1.1.1.1 1-1.2.3.1.1 2-1.1.2.1.1 2-1.2.2.1.1.1 4-1.1.3.2 5-1.1.3.1.1.1 8-1.2.3 10-1.2.3.1 12-1.2.2.2.1.1 13-1.2.3.1 14-1.1 14-1.2.3.1.1 15-1.2.3.1.1.2 18-1.2.3.1.1.3.2.1.1.1 20-1.2.3.1.1.3.2.1.1.2 22-1.1.3.2 22-1.2.3.1.1.3.2 23-1.1.3.1.1.1 24-1.1.3 24-1.2.3.1.1.3 26-1.2.1.1.1 28-1.2.1.1.1 29-1.2.1 31-1.2 32-1.2.2.r 33-1.2.2.1.2.1.1.1 35-1.2.2.1.2 35-1.2.2.2.2 36-1.2.2.1.1.1 38-1.2.2.2.2.1.1.1 40-1.2.2.1.2 40-1.2.2.2.2 41-1.2.2.2.1.1 43-1.2.2 44-1.2.2.3.1.1 (m / multi-sentence :snt1 (r / recruit-01~e.14 :ARG0 (p8 / protein :name (n / name :op1 "TGIF"~e.0)) :ARG1 (p / protein :name (n2 / name :op1 "CtBP"~e.2)) :ARG2 (c / complex~e.24 :mod (p2 / protein :name (n3 / name :op1 "Smad"~e.5,23)) :ARG1-of (a / activate-01~e.4,22))) :snt2 (t / transfect-01~e.31 :ARG1 (c2 / cell-line~e.29 :name (n4 / name :op1 "COS-1"~e.26,28)) :ARG2~e.32 (a2 / and~e.43 :op1 (p3 / protein :name (n5 / name :op1 "CtBP"~e.2,36) :ARG1-of (t2 / tag-01~e.35,40 :ARG2 (p4 / protein :name (n6 / name :op1 "FLAG"~e.33)))) :op2 (p10 / protein :name (n7 / name :op1 "TGIF"~e.12,41) :ARG1-of (t3 / tag-01~e.35,40 :ARG2 (p5 / protein :name (n8 / name :op1 "HA"~e.38)))) :op3 (p6 / protein :name (n9 / name :op1 "Smad2"~e.44))) :purpose (i / investigate-01~e.8 :ARG1 (p7 / possible-01~e.10,13 :ARG1 (r2 / recruit-01~e.1,14 :ARG0 p10 :ARG1 p3~e.15 :ARG2 (c3 / complex~e.24 :mod p6 :ARG1-of (a3 / activate-01~e.22 :ARG0 (p9 / protein :name (n10 / name :op1 "TGF"~e.18 :op2 "beta"~e.20))))))))) # ::id bio.chicago_2015.36813 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of the RasN17 dominant @-@ negative mutant ( deVries @-@ Smits et al. , 1992 ; Wood et al. , 1992 ) blocked EGF @-@ induced Elk @-@ 1 phosphorylation ( Figure 5D ) . # ::alignments 0-1.1 4-1.1.1.3 7-1.1.1 7-1.1.1.2 7-1.1.1.2.r 9-1.1.2.1.1.1.1.1.1 11-1.1.2.1.1.1.1.1.1 12-1.1.2.1.1.1 13-1.1.2.1.1.1.2.1 15-1.1.2.1.2.2 17-1.1.2.1.2.1.1.1.1 18-1.1.2.1 18-1.1.2.1.1.1 18-1.1.2.1.2.1 19-1.1.2.1.1.1.2.1 21-1.1.2.1.1.2.1 23-1 24-1.2.2.1.1.1 26-1.2.2 27-1.2.1.1.1 29-1.2.1.1.1 30-1.2 32-1.3.1 33-1.3.1.1 (b / block-01~e.23 :ARG0 (e / express-03~e.0 :ARG2 (e2 / enzyme~e.7 :name (n / name :op1 "Ras") :ARG2-of~e.7 (m / mutate-01~e.7 :value "N17" :mod "-/-") :ARG0-of (d2 / dominate-01~e.4)) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.18 :op1 (p / publication-91 :ARG0 (a2 / and~e.12,18 :op1 (p5 / person :name (n5 / name :op1 "deVries-Smits"~e.9,11)) :op2 (p6 / person :mod (o / other~e.13,19))) :time (d / date-entity :year 1992~e.21)) :op2 (p7 / publication-91 :ARG0 (a / and~e.18 :op1 (p8 / person :name (n6 / name :op1 "Wood"~e.17)) :op2 p6) :time d~e.15)))) :ARG1 (p3 / phosphorylate-01~e.30 :ARG1 (p4 / protein :name (n3 / name :op1 "Elk-1"~e.27,29)) :ARG2-of (i / induce-01~e.26 :ARG0 (p2 / protein :name (n4 / name :op1 "EGF"~e.24)))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure~e.32 :mod "5D"~e.33))) # ::id bio.chicago_2015.36817 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rb Interacts with Histone Deacetylase to Repress Transcription . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1.1 4-1.2.1.2 6-1.3 7-1.3.2 (i / interact-01~e.1 :ARG0 (p / protein :name (n / name :op1 "Rb"~e.0)) :ARG1~e.2 (e / enzyme :name (n2 / name :op1 "Histone"~e.3 :op2 "Deacetylase"~e.4)) :ARG2 (r / repress-01~e.6 :ARG0 (a / and :op1 p :op2 e) :ARG1 (t / transcribe-01~e.7))) # ::id bio.chicago_2015.36902 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , inhibition of PKA by H89 did not inhibit process formation ( Figure 7e ) , contrary to inhibition of MARK by HD and did not inhibit the phosphorylation of KXGS motifs ( Figure 8b , lane 2 , staining with 12E8 ) . # ::alignments 0-1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 4-1.1.1.2.2.1.1 6-1.1.1.2.1.1.1 8-1.1.1.1 8-1.1.1.1.r 9-1.1.1 9-1.1.1.2 9-1.1.1.2.r 10-1.1.1.3.1 11-1.1.1.3 13-1.1.1.4.1 14-1.1.1.4.1.1 17-1.1.1.5 19-1.1.1 19-1.1.1.2 19-1.1.1.2.r 19-1.1.1.5.1 20-1.1.1.5.1.2.r 21-1.1.1.5.1.2.1.1 22-1.1.1.5.1.1.r 23-1.1.1.5.1.1.1.1 24-1.1 26-1.1.2.1 26-1.1.2.1.r 27-1.1.1 27-1.1.2 29-1.1.2.2 30-1.1.2.2.1.r 31-1.1.2.2.1.1.1 32-1.1.2.2.1.1.2 34-1.1.2.3.1.2.2 35-1.1.2.3.1.2.2.1 37-1.1.2.3.1.2 38-1.1.2.3.1.2.1 40-1.1.2.3.1 41-1.1.2.3.1.1.r 42-1.1.2.3.1.1.1.1 (c / contrast-01~e.0 :ARG2 (a / and~e.24 :op1 (i / inhibit-01~e.2,9,19,27 :polarity~e.8 -~e.8 :ARG0~e.2,9,19 (i2 / inhibit-01~e.2,9,19 :ARG0 (s / small-molecule :name (n / name :op1 "H89"~e.6)) :ARG1 (e / enzyme :name (n2 / name :op1 "PKA"~e.4))) :ARG1 (f / form-01~e.11 :ARG1 (p2 / process-02~e.10)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.13 :mod "7e"~e.14)) :ARG1-of (c2 / contrary-01~e.17 :ARG2 (i3 / inhibit-01~e.19 :ARG0~e.22 (s2 / small-molecule :name (n4 / name :op1 "HD"~e.23)) :ARG1~e.20 (e2 / enzyme :name (n3 / name :op1 "MARK"~e.21))))) :op2 (i4 / inhibit-01~e.27 :polarity~e.26 -~e.26 :ARG1 (p / phosphorylate-01~e.29 :ARG1~e.30 (p4 / protein-segment :name (n5 / name :op1 "KXGS"~e.31 :op2 "motif"~e.32))) :ARG1-of (d2 / describe-01 :ARG0 (s3 / stain-01~e.40 :ARG2~e.41 (p3 / protein :name (n6 / name :op1 "12E8"~e.42)) :location (l / lane~e.37 :mod 2~e.38 :part-of (f3 / figure~e.34 :mod "8b"~e.35))))))) # ::id bio.chicago_2015.36940 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Induction of LTP by tetanic stimulation ( at Time = 0 ; see Experimental Procedures ) is observed in hippocampal slices from wt ( n = 5 ) and - Syn / ( n = 5 ) mice . # ::alignments 0-1.1 4-1.1.1.1 8-1.1.1.2 8-1.1.1.2.r 10-1.1.1.2.1.1 12-1.1.1.3 13-1.1.1.3.1.1 14-1.1.1.3.1 17-1 20-1.2 21-1.2.2.r 22-1.2.2.1.2 26-1.2.2.1.1 28-1.2.2 30-1.2.2.2.2.1.1 35-1.2.2.1.1 35-1.2.2.2.1 37-1.2.2.1 37-1.2.2.2 (o / observe-01~e.17 :ARG1 (i / induce-01~e.0 :ARG0 (s / simulate-01 :mod (t2 / tetanic~e.4) :time~e.8 (t3 / time~e.8 :ARG1-of (e2 / equal-01 :ARG2 0~e.10)) :mod (s2 / see-01~e.12 :ARG1 (p / procedure~e.14 :mod (e / experiment-01~e.13)))) :ARG2 (p2 / potentiate-01 :ARG1-of (l / long-03))) :location (s3 / slice~e.20 :mod (h / hippocampus) :source~e.21 (a2 / and~e.28 :op1 (m / mouse~e.37 :quant 5~e.26,35 :mod (w / wild-type~e.22)) :op2 (m2 / mouse~e.37 :quant 5~e.35 :mod (e3 / enzyme :name (n2 / name :op1 "Syn"~e.30) :ARG2-of (m3 / mutate-01 :mod "-/+")))))) # ::id bio.chicago_2015.36945 ::amr-annotator SDL-AMR-09 ::preferred # ::tok About 10 min after synthesis , a maximal amount of gp160 was bound to calnexin and calreticulin and about half remained bound after 25 @-@ 35 min . # ::alignments 0-1.1.3.2 1-1.1.3.2.1.1 2-1.1.3.2.1.2 3-1.2.3 4-1.2.3.1 7-1.1.1.2 8-1.1.1 8-1.2.1 9-1.1.1.1.r 10-1.1.1.1.1.1 12-1.1 14-1.1.2.1.1.1 15-1.1.2 16-1.1.2.2.1.1 18-1.1.3.2 18-1.2.1.1.r 19-1.2.1.1 20-1.2 21-1.1 21-1.2.2 22-1.1.3 23-1.2.3.2.1.1 25-1.2.3.2.1.2 26-1.2.3.2.2 (a2 / and :op1 (b2 / bind-01~e.12,21 :ARG1 (a3 / amount~e.8 :quant-of~e.9 (p / protein :name (n / name :op1 "gp160"~e.10)) :quant (m / maximum~e.7)) :ARG2 (a4 / and~e.15 :op1 (p2 / protein :name (n2 / name :op1 "calnexin"~e.14)) :op2 (p3 / protein :name (n3 / name :op1 "calreticulin"~e.16))) :time (a7 / after~e.22 :op1 s :duration (a / about~e.0,18 :op1 (t2 / temporal-quantity :quant 10~e.1 :unit (m3 / minute~e.2))))) :op2 (r / remain-01~e.20 :ARG1 (a5 / amount~e.8 :quant~e.18 (h / half~e.19) :quant-of p) :ARG3 (b3 / bind-01~e.21 :ARG1 a5 :ARG2 a4) :time (a6 / after~e.3 :op1 (s / synthesize-01~e.4) :duration (t / temporal-quantity :quant (v / value-interval :op1 25~e.23 :op2 35~e.25) :unit (m2 / minute~e.26))))) # ::id bio.chicago_2015.36967 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of GST @-@ FKBP46 and FKBP46 by endogenous Sf9 CKII and human recombinant casein kinase II . # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1 4-1.1.2.1.1 5-1.1 6-1.1.2.1.1 7-1.2.r 8-1.2.3 9-1.2.4.1.1 10-1.2.1.1.1 11-1.2 12-1.2.2.1.1 13-1.2.2.1.2 14-1.2.2.1.3 15-1.2.2.1.4 16-1.2.2.1.5 (p2 / phosphorylate-01~e.0 :ARG1~e.1 (a / and~e.5 :op1 (p / protein :name (n / name :op1 "GST-FKBP46"~e.2)) :op2 (p3 / protein :name (n2 / name :op1 "FKBP46"~e.4,6))) :ARG2~e.7 (a2 / and~e.11 :op1 (e / enzyme :name (n3 / name :op1 "CKII"~e.10)) :op2 (e2 / enzyme :name (n5 / name :op1 "human"~e.12 :op2 "recombinant"~e.13 :op3 "casein"~e.14 :op4 "kinase"~e.15 :op5 "II"~e.16)) :mod (e3 / endogenous~e.8) :source (c / cell-line :name (n4 / name :op1 "Sf9"~e.9)))) # ::id bio.chicago_2015.37004 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , LTP induced by either theta burst or tetanic stimulation is blocked by pretreating slices with the TrkB @-@ IgG fusion protein , a protein that removes BDNF from extracellular fluids ( Figurov et al. 1996 ; Kang et al. 1997 ) , suggesting that endogenous BDNF is involved in the induction of LTP . # ::alignments 0-1 3-1.1.2.2 6-1.1.2.2.1.1 7-1.1.2.2.1.1 8-1.1.2.2.1 9-1.1.2.2.1.2.1 10-1.1.2.2.1.2 12-1.1 15-1.1.1.1 18-1.1.1.2.1.1 20-1.1.1.2.1.1 21-1.1.1.2.2 22-1.1.1.2 25-1.1.3.1.2.1 27-1.1.1.2.3 28-1.1.1.2.3.1.1.1 29-1.1.1.2.3.2.r 30-1.1.1.2.3.2.1 31-1.1.1.2.3.2 33-1.1.1.2.3.3.1.1.1.1.1.1 34-1.1.1.2.3.3.1.1.1 35-1.1.1.2.3.3.1.1.1.2.1 36-1.1.1.2.3.3.1.1.2.1 38-1.1.1.2.3.3.1.2.1.1.1.1 39-1.1.1.2.3.3.1 39-1.1.1.2.3.3.1.1.1 39-1.1.1.2.3.3.1.2.1 40-1.1.1.2.3.3.1.1.1.2.1 41-1.1.1.2.3.3.1.2.2.1 44-1.1.3 46-1.1.3.1.1.2 47-1.1.3.1.1.1.1 49-1.1.3.1 52-1.1.3.1.2 (a / and~e.0 :op2 (b / block-01~e.12 :ARG0 (p10 / pretreat-01 :ARG1 (s2 / slice~e.15) :ARG3 (p / protein~e.22 :name (n2 / name :op1 "TrkB-IgG"~e.18,20) :mod (f / fuse-01~e.21) :ARG0-of (r / remove-01~e.27 :ARG1 (p2 / protein :name (n3 / name :op1 "BDNF"~e.28)) :ARG2~e.29 (f2 / fluid~e.31 :mod (e / extracellular~e.30)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.39 :op1 (p4 / publication-91 :ARG0 (a3 / and~e.34,39 :op1 (p5 / person :name (n5 / name :op1 "Figurov"~e.33)) :op2 (p6 / person :mod (o2 / other~e.35,40))) :time (d / date-entity :year 1996~e.36)) :op2 (p7 / publication-91 :ARG0 (a4 / and~e.39 :op1 (p8 / person :name (n6 / name :op1 "Kang"~e.38)) :op2 p6) :time (d2 / date-entity :year 1997~e.41))))))) :ARG1 (p11 / potentiate-01 :ARG1-of (l / long-03) :ARG2-of (i / induce-01~e.3 :ARG0 (o / or~e.8 :op1 (t / theta-burst~e.6,7) :op2 (s / stimulate-01~e.10 :mod (t3 / tetanic~e.9))))) :ARG0-of (s3 / suggest-01~e.44 :ARG1 (i2 / involve-01~e.49 :ARG1 (p3 / protein :name (n4 / name :op1 "BDNF"~e.47) :mod (e2 / endogenous~e.46)) :ARG2 (i3 / induce-01~e.52 :ARG2 (p9 / protein~e.25)))))) # ::id bio.chicago_2015.37047 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TFIIA interaction with TBP . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1.1 (i / interact-01~e.1 :ARG0 (p / protein :name (n / name :op1 "TFIIA"~e.0)) :ARG1~e.2 (p2 / protein :name (n2 / name :op1 "TBP"~e.3))) # ::id bio.chicago_2015.37055 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Second , misexpression of ey can strongly induce dac . # ::alignments 0-1.2 0-1.2.1 0-1.2.1.r 4-1.1.1.1.1.1 5-1 6-1.1.3 7-1.1 8-1.1.2.1.1 (p4 / possible-01~e.5 :ARG1 (i / induce-01~e.7 :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "ey"~e.4)) :ARG1-of (w / wrong-04)) :ARG1 (p2 / protein :name (n2 / name :op1 "dac"~e.8)) :ARG1-of (s / strong-02~e.6)) :mod (o / ordinal-entity~e.0 :value~e.0 2~e.0)) # ::id bio.chicago_2015.37068 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PTB domains of scaffolding proteins such as Shc , FRS2 or IRS @-@ 1 bind autophosphorylated receptors , positioning these proteins for multisite phosphorylation and subsequent binding of SH2 domain targets such as Grb2 ( for Shc and FRS2 ) or PI 3 '' @-@ kinase ( for IRS @-@ 1 ) [ 98 , 99 and 100 ] . # ::alignments 1-1.2.1 2-1.2.1 5-1.2.3.2.1.2.1 6-1.2.3.2.1.2.r 7-1.2.3.2.1.2.r 8-1.1.1.2.2.1.1.1 10-1.1.1.2.2.2.1.1 11-1.2.3.2.1.2 12-1.1.1.2.2.3.1.1 14-1.1.1.2.2.3.1.1 15-1.1 16-1.1.2.1 17-1.1.2 19-1.2 20-1.2.2.1 21-1.1.1.2 21-1.2.2 22-1.2.3.2.1.2.1.2.r 22-1.2.3.2.1.2.2.2.r 22-1.2.3.r 23-1.2.3.1.1 24-1.2.3.1 25-1.2.3 25-1.2.3.2.1.2.1.2 26-1.2.3.2.2 26-1.2.3.2.2.r 27-1.2.3.2 29-1.2.3.2.1.1.1.1.1 30-1.2.3.2.1.1.1.1.2 31-1.2.3.2.1 31-1.2.3.2.1.1 31-1.2.3.2.1.1.r 32-1.1.1.2.2.r 33-1.2.3.2.2.r 34-1.2.3.2.1.2.1.1.1 36-1.2.3.2.1.2.1.2.r 36-1.2.3.2.1.2.2.2.r 37-1.1.1.2.2.1.1.1 39-1.1.1.2.2.2.1.1 41-1.2.3.2.1.2 42-1.2.3.2.1.2.2.1.1 46-1.2.3.2.1.2.2.1.2 48-1.2.3.2.1.2.1.2.r 48-1.2.3.2.1.2.2.2.r 49-1.2.3.2.1.2.2.2 50-1.2.3.2.1.2.2.2 51-1.2.3.2.1.2.2.2 54-1.3.1.1.1.1 56-1.3.1.1.1.2 57-1.3.1.1.1 58-1.3.1.1.1.3 (a / and :op1 (b / bind-01~e.15 :ARG0 (p12 / protein-segment :name (n8 / name :op1 "PTB" :op2 "domain") :part-of (p3 / protein~e.21 :mod (s / scaffold) :example~e.32 (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "Shc"~e.8,37)) :op2 (p5 / protein :name (n3 / name :op1 "FRS2"~e.10,39)) :op3 (p6 / protein :name (n4 / name :op1 "IRS-1"~e.12,14))))) :ARG1 (r / receptor~e.17 :ARG1-of (p2 / phosphorylate-01~e.16 :ARG2 r))) :op2 (p7 / position-01~e.19 :ARG0 p12~e.1,2 :ARG1 (p8 / protein~e.21 :mod (t / this~e.20)) :ARG2~e.22 (a4 / and~e.25 :op1 (p9 / phosphorylate-01~e.24 :mod (m / multisite~e.23)) :op2 (b2 / bind-01~e.27 :ARG1 (m2 / molecular-physical-entity~e.31 :ARG1-of~e.31 (t2 / target-01~e.31 :ARG0 (p10 / protein-segment :name (n5 / name :op1 "SH2"~e.29 :op2 "domain"~e.30))) :example~e.6,7 (o / or~e.11,41 :op1 (p11 / protein~e.5 :name (n6 / name :op1 "Grb2"~e.34) :prep-for~e.22,36,48 (a5 / and~e.25 :op1 p4 :op2 p5)) :op2 (e / enzyme :name (n7 / name :op1 "PI"~e.42 :op2 "3``-kinase"~e.46) :prep-for~e.22,36,48 p6~e.49,50,51))) :time~e.26,33 (s2 / subsequent~e.26)))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a6 / and~e.57 :op1 98~e.54 :op2 99~e.56 :op3 100~e.58))))) # ::id bio.chicago_2015.37115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like TAK1 , two other MAP kinase kinase kinases , MEKK1 and MLK3 , act downstream of HPK1 and upstream of MAPK kinase 4/SEK . However , we found that the dominant @-@ negative mutants of MEKK1 and MLK3 did not inhibit TAK1 @-@ induced JNK activity , indicating that the activation of JNK1 by TAK1 is independent of MEKK1 and MLK3 . # ::alignments 1-1.2.3.1.2.1 3-1.2.1.1 4-1.2.1.4 5-1.2.1.3.1 6-1.2.1.3.2 7-1.2.1.3.3 8-1.2.1 10-1.2.1.5.1.1.2.1 11-1.2.1.5.1 12-1.2.1.5.1.2.2.1 14-1.2 15-1.2.2.1.2 17-1.2.2.1.1.2.1 18-1.2.2 19-1.2.2.2.2 21-1.2.2.2.1.2.1 22-1.2.2.2.1.2.2 23-1.2.2.2.1.2.3 25-1 27-1.1.1 28-1.1 29-1.1.2.r 31-1.1.2.2.3 34-1.1.2.2.4 36-1.1.2.2.1 37-1.2.1.5.1 38-1.2.1.5.1.2.2.1 40-1.1.2.1 40-1.1.2.1.r 41-1.1.2 42-1.1.2.3.2.1 44-1.1.2.3.2 45-1.1.2.3.1.2.1 46-1.1.2.3 48-1.1.2.4 49-1.1.2.4.1.r 51-1.1.2.4.1.2 52-1.1.2.4.1.2.2.r 53-1.1.2.4.1.2.2.2.1 54-1.1.2.4.1.2.1.r 55-1.1.2.4.1.2.1 57-1.1.2.4.1 57-1.1.2.4.1.1 57-1.1.2.4.1.1.r 59-1.2.1.5.1.1.2.1 60-1.2.1.5.1 61-1.2.1.5.1.2.2.1 (h / have-concession-91~e.25 :ARG1 (f / find-01~e.28 :ARG0 (w / we~e.27) :ARG1~e.29 (i / inhibit-01~e.41 :polarity~e.40 -~e.40 :ARG0 (a4 / and :op1 e9~e.36 :op2 e8 :ARG0-of (d2 / dominate-01~e.31) :ARG2-of (m2 / mutate-01~e.34 :mod "-/-")) :ARG1 (a5 / activity-06~e.46 :ARG0 (e4 / enzyme :wiki "C-Jun_N-terminal_kinases" :name (n9 / name :op1 "JNK"~e.45)) :ARG2-of (i2 / induce-01~e.44 :ARG0 e5~e.42)) :ARG0-of (i3 / indicate-01~e.48 :ARG1~e.49 (d3 / depend-01~e.57 :polarity~e.57 -~e.57 :ARG0 (a6 / activate-01~e.51 :ARG0~e.54 e5~e.55 :ARG1~e.52 (e3 / enzyme :wiki "C-Jun_N-terminal_kinases" :name (n10 / name :op1 "JNK1"~e.53))) :ARG1 (a7 / and :op1 e9 :op2 e8))))) :ARG2 (a / act-02~e.14 :ARG0 (k / kinase~e.8 :quant 2~e.3 :wiki "MAP_kinase_kinase_kinase" :name (n2 / name :op1 "MAP"~e.5 :op2 "kinase"~e.6 :op3 "kinase"~e.7) :mod (o / other~e.4) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.11,37,60 :op1 (e9 / enzyme :wiki "MAP3K1" :name (n3 / name :op1 "MEKK1"~e.10,59)) :op2 (e8 / enzyme :wiki "MAP3K11" :name (n4 / name :op1 "MLK3"~e.12,38,61))))) :location (a3 / and~e.18 :op1 (r / relative-position :op1 (e7 / enzyme :wiki "MAP4K1" :name (n5 / name :op1 "HPK1"~e.17)) :direction (d / downstream~e.15)) :op2 (r2 / relative-position :op1 (p / pathway :wiki - :name (n / name :op1 "MAPK"~e.21 :op2 "kinase"~e.22 :op3 "4/SEK"~e.23)) :direction (u / upstream~e.19))) :ARG1-of (s / same-01 :ARG2 (e5 / enzyme :wiki "MAP3K7" :name (n7 / name :op1 "TAK1"~e.1))))) # ::id bio.chicago_2015.37124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , the modest activation of JNK exerted by Rac1 and Cdc42 , and the observation that the Rac1L61C40 mutant still inhibits differentiation , raise questions about the involvement of the JNK pathway with respect to the block of differentiation by expression of these proteins . # ::alignments 0-1.1.3 3-1.1.1.3 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 7-1.1.1.2 8-1.1.1.2.1.r 9-1.1.1.2.1.1.1.1 10-1.1.1.2.1 11-1.1.1.2.1.2.1.1 13-1.1 15-1.1.2 16-1.1.2.1.r 18-1.1.2.1.1.1.1 19-1.1.2.1.1 19-1.1.2.1.1.2 19-1.1.2.1.1.2.r 20-1.1.2.1.3 21-1.1.2.1 22-1.1.2.1.2 24-1 25-1.2 26-1.2.1.2.r 28-1.2.1 29-1.2.1.1.r 31-1.2.1.1.1.1 32-1.2.1.1 37-1.2.1.2 38-1.2.1.2.2.r 39-1.2.1.2.2 40-1.2.1.2.1.r 41-1.2.1.2.1 42-1.2.1.2.1.1.r 43-1.2.1.2.1.1.1 44-1.2.1.2.1.1 (r / raise-01~e.24 :ARG0 (a / and~e.13 :op1 (a2 / activate-01~e.4 :ARG1~e.5 (e3 / enzyme :name (n / name :op1 "JNK"~e.6)) :ARG1-of (e / exert-01~e.7 :ARG0~e.8 (a3 / and~e.10 :op1 (p / protein :name (n2 / name :op1 "Rac1"~e.9)) :op2 (p2 / protein :name (n3 / name :op1 "Cdc42"~e.11)))) :mod (m2 / modest~e.3)) :op2 (o / observe-01~e.15 :ARG1~e.16 (i / inhibit-01~e.21 :ARG0 (p3 / protein~e.19 :name (n4 / name :op1 "Rac1L61C40"~e.18) :ARG2-of~e.19 (m / mutate-01~e.19)) :ARG1 (d / differentiate-01~e.22) :mod (s / still~e.20))) :mod (t / together~e.0)) :ARG1 (q / question-01~e.25 :ARG1 (i2 / involve-01~e.28 :ARG1~e.29 (p4 / pathway~e.32 :name (n5 / name :op1 "JNK"~e.31)) :topic~e.26 (b / block-01~e.37 :ARG0~e.40 (e2 / express-03~e.41 :ARG2~e.42 (p5 / protein~e.44 :mod (t2 / this~e.43))) :ARG1~e.38 d~e.39)))) # ::id bio.chicago_2015.37139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recently , controversial results have been reported by our group indicating that cellular Cdc42 is certainly required for the actin @-@ based motility of Shigella in infected cells ( 83 ) . # ::alignments 0-1.3 2-1.2.2 3-1.2 3-1.2.1 3-1.2.1.r 6-1 7-1.1.r 8-1.1.1 8-1.1.1.r 9-1.1 10-1.2.3 11-1.2.3.1.r 12-1.2.3.1.2.2 13-1.2.3.1.2.1.1 15-1.2.3.1.3 15-1.2.3.1.3.r 16-1.2.3.1 17-1.2.3.1.1.r 19-1.2.3.1.1.1.1.1.1 21-1.2.3.1.1.1 22-1.2.3.1.1 23-1.2.3.1.1.2.r 24-1.2.3.1.1.2.1.1 26-1.2.3.1.1.3.1 27-1.2.3.1.1.3 27-1.2.3.1.2.2 29-1.4.1.1.1 (r / report-01~e.6 :ARG0~e.7 (g / group~e.9 :poss~e.8 (w / we~e.8)) :ARG1 (t / thing~e.3 :ARG2-of~e.3 (r2 / result-01~e.3) :mod (c / controversy~e.2) :ARG0-of (i / indicate-01~e.10 :ARG1~e.11 (r4 / require-01~e.16 :ARG0~e.17 (m / motility~e.22 :ARG1-of (b / base-02~e.21 :ARG2 (p2 / protein :name (n2 / name :op1 "actin"~e.19))) :mod~e.23 (o / organism :name (n3 / name :op1 "Shigella"~e.24)) :location (c4 / cell~e.27 :ARG1-of (i2 / infect-01~e.26))) :ARG1 (p / protein :name (n / name :op1 "Cdc42"~e.13) :mod (c2 / cellular~e.12,27)) :manner~e.15 (c3 / certain~e.15)))) :time (r3 / recent~e.0) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 83~e.29)))) # ::id bio.chicago_2015.37195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , ADP significantly inhibited the actin @-@ activated ATPase activity of myosin VIIA . # ::alignments 5-1.1.1.1.1 6-1.1.3 7-1.1 9-1.1.2.2.2.1.1.1 11-1.1.2.2.2 12-1.1.2.2.1.1 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 16-1.1.2.1.1.2 (c / contrast-01 :ARG2 (i / inhibit-01~e.7 :ARG0 (s / small-molecule :name (n / name :op1 "ADP"~e.5)) :ARG1 (a / activity-06~e.13 :ARG0~e.14 (p / protein :name (n2 / name :op1 "myosin"~e.15 :op2 "VIIA"~e.16)) :ARG1 (e / enzyme :name (n3 / name :op1 "ATPase"~e.12) :ARG1-of (a2 / activate-01~e.11 :ARG0 (p2 / protein :name (n4 / name :op1 "actin"~e.9))))) :ARG1-of (s2 / significant-02~e.6))) # ::id bio.chicago_2015.37242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ethanol inhibited D2L receptor coupling to adenylyl cyclase as a function of increasing ethanol concentration ( Fig . 2A ) . # ::alignments 0-1.1 1-1 2-1.2.1.1.1 3-1.2.1 4-1.2 5-1.2.2.r 6-1.2.2.1.1 7-1.2.2.1.2 8-1.3.r 10-1.3 11-1.3.1.r 12-1.3.1 13-1.3.1.1.1 14-1.3.1.1 16-1.4.1 18-1.4.1.1 (i / inhibit-01~e.1 :ARG0 (e / ethanol~e.0) :ARG1 (c / couple-01~e.4 :ARG1 (r / receptor~e.3 :name (n / name :op1 "D2L"~e.2)) :ARG2~e.5 (e2 / enzyme :name (n2 / name :op1 "adenylyl"~e.6 :op2 "cyclase"~e.7))) :ARG1-of~e.8 (f / function-01~e.10 :ARG0~e.11 (i2 / increase-01~e.12 :ARG1 (c2 / concentrate-02~e.14 :ARG1 e~e.13))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.16 :mod "2A"~e.18))) # ::id bio.chicago_2015.37257 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the Clk loop , CLK @-@ CYC heterodimers activate vri transcription via E boxes in the vri promoter . # ::alignments 2-1.3.1 3-1.3 5-1.1.1.1.1 7-1.1.2.1.1 8-1.1 9-1 10-1.2.1.1.1 11-1.2 13-1.2.2.1.1 14-1.2.2.1.2 17-1.2.2.2.1.1 18-1.2.2.2 18-1.2.2.2.1 18-1.2.2.2.1.r (a / activate-01~e.9 :ARG0 (h / heterodimer~e.8 :part (p / protein :name (n / name :op1 "CLK"~e.5)) :part (p2 / protein :name (n2 / name :op1 "CYC"~e.7))) :ARG1 (t / transcribe-01~e.11 :ARG1 (g / gene :name (n3 / name :op1 "vri"~e.10)) :instrument (d / dna-sequence :name (n4 / name :op1 "E"~e.13 :op2 "box"~e.14) :location (m / molecular-physical-entity~e.18 :ARG0-of~e.18 (p3 / promote-01~e.18 :ARG1 g~e.17)))) :location (l / loop~e.3 :mod p~e.2)) # ::id bio.chicago_2015.37286 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Caenorhabditis elegans unc @-@ 64 locus encodes a syntaxin that interacts genetically with synaptobrevin . # ::alignments 1-1.1.2.1.1 2-1.1.2.1.2 3-1.1.1.1 5-1.1.1.1 6-1.1.1.2 7-1 9-1.2.1.1 11-1.2 11-1.2.2 11-1.2.2.r 12-1.2.2.2 13-1.2.2.1.r 14-1.2.2.1.1.1 (e / encode-01~e.7 :ARG0 (g / gene :name (n / name :op1 "unc-64"~e.3,5 :op2 "locus"~e.6) :source (o / organism :name (n2 / name :op1 "Caenorhabditis"~e.1 :op2 "elegans"~e.2))) :ARG1 (p / protein~e.11 :name (n3 / name :op1 "syntaxin"~e.9) :ARG0-of~e.11 (i / interact-01~e.11 :ARG1~e.13 (p2 / protein :name (n4 / name :op1 "synaptobrevin"~e.14)) :manner (g2 / genetic~e.12)))) # ::id bio.chicago_2015.37333 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One of the modes by which interaction of E1A with p300 modulates transcription appears to involve disruption of a complex of p300 with a cellular acetyl transferase , P/CAF , which regulates transcription by chromatin remodeling ( 4 ) . # ::alignments 3-1.1 3-1.1.1.1 6-1.1.1.1.1.1 7-1.1.1.1.1.1.1.r 8-1.1.1.1.1.1.1.1.1 9-1.1.1.1.1.1.2.r 9-1.1.1.1.1.r 10-1.1.1.1.1.1.2.1.1 11-1.1.1.1.1 12-1.1.1.1.1.2 13-1 15-1.1.2 16-1.1.2.1 17-1.1.2.1.1.r 19-1.1.2.1.1 20-1.1.2.1.1.1.r 21-1.1.2.1.1.1 22-1.1.2.1.2.r 24-1.1.2.1.2.2.1.2 28-1.1.2.1.2.1.1 31-1.1.2.1.2 31-1.1.2.1.2.3 31-1.1.2.1.2.3.r 32-1.1.2.1.2.3.1 33-1.1.2.1.2.3.2.r 34-1.1.2.1.2.3.2.1 35-1.1.2.1.2.3.2 37-1.2.1.1.1 (a / appear-02~e.13 :ARG1 (m / mode~e.3 :ARG1-of (i / include-91 :ARG2 (m2 / mode~e.3 :instrument-of~e.9 (m3 / modulate-01~e.11 :ARG0 (i2 / interact-01~e.6 :ARG0~e.7 (p / protein :name (n / name :op1 "E1A"~e.8)) :ARG1~e.9 (p2 / protein :name (n2 / name :op1 "p300"~e.10))) :ARG1 (t / transcribe-01~e.12)))) :ARG2-of (i3 / involve-01~e.15 :ARG1 (d / disrupt-01~e.16 :ARG1~e.17 (c / complex~e.19 :mod~e.20 p2~e.21) :instrument~e.22 (e / enzyme~e.31 :name (n3 / name :op1 "P/CAF"~e.28) :ARG1-of (m4 / mean-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "acetyltransferase") :mod (c2 / cell~e.24))) :ARG0-of~e.31 (r / regulate-01~e.31 :ARG1 (t3 / transcribe-01~e.32) :instrument~e.33 (r2 / remodel-01~e.35 :ARG1 (c3 / chromatin~e.34))))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 4~e.37)))) # ::id bio.chicago_2015.37349 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternative splicing removes repeat six ( cortactin B ) or repeats 5 and 6 ( cortactin C ) ; all of these isoforms bind F @-@ actin . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.1.1.1 3-1.1.2.2.1.1.1 3-1.1.2.2.2.1.1 4-1.1.2.1.1.2 4-1.1.2.2.2.1.2 6-1.1.2.1.2.1.1 7-1.1.2.1.2.1.2 9-1.1.2 10-1.1.2.1.1.1 10-1.1.2.2.1.1.1 10-1.1.2.2.2.1.1 11-1.1.2.2.1.1.2 12-1.1.2.2 13-1.1.2.2.2.1.2 15-1.1.2.2.1.2.1.1 16-1.1.2.2.1.2.1.2 19-1.1.2.4 23-1.1.2.3 24-1.1.2.3.1.1.1 26-1.1.2.3.1.1.1 (m / multi-sentence :snt1 (r / remove-01~e.2 :ARG0 (s / splice-01~e.1 :mod (a / alternative~e.0)) :ARG1 (o / or~e.9 :op1 (d4 / dna-sequence :name (n7 / name :op1 "repeat"~e.3,10 :op2 6~e.4) :part-of (p / protein :name (n / name :op1 "cortactin"~e.6 :op2 "B"~e.7))) :op2 (a2 / and~e.12 :op1 (d / dna-sequence :name (n4 / name :op1 "repeat"~e.3,10 :op2 5~e.11) :part-of (p2 / protein :name (n2 / name :op1 "cortactin"~e.15 :op2 "C"~e.16))) :op2 (d5 / dna-sequence :name (n8 / name :op1 "repeat"~e.3,10 :op2 6~e.4,13) :part-of p2)) :ARG0-of (b / bind-01~e.23 :ARG1 (p3 / protein :name (n3 / name :op1 "F-actin"~e.24,26))) :mod (a3 / all~e.19)))) # ::id bio.chicago_2015.37392 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( iv ) Upon amino acid starvation , uncharged tRNA binds to the HisRS domain of Gcn2 and induces a conformational change that results in the release of Hsp90 . # ::alignments 1-1.1 4-1.4.2 5-1.4.2 6-1.4 9-1.2.1.1.1 10-1.2 11-1.2.2.r 13-1.2.2.1.1 14-1.2.2.1.2 16-1.2.2.2.1.1 17-1 18-1.3 20-1.3.2.1 21-1.3.2 23-1.3.2.2 24-1.3.2.2.1.r 26-1.3.2.2.1 27-1.3.2.2.1.1.r 28-1.3.2.2.1.1.1.1 (a / and~e.17 :li "iv"~e.1 :op1 (b / bind-01~e.10 :ARG0 (n5 / nucleic-acid :name (n / name :op1 "tRNA"~e.9) :ARG1-of (c / charge-03 :polarity -)) :ARG2~e.11 (p / protein-segment :name (n2 / name :op1 "HisRS"~e.13 :op2 "domain"~e.14) :part-of (e / enzyme :name (n3 / name :op1 "Gcn2"~e.16)))) :op2 (i / induce-01~e.18 :ARG0 n5 :ARG2 (c2 / change-01~e.21 :mod (c3 / conformational~e.20) :ARG1-of (r2 / result-01~e.23 :ARG2~e.24 (r3 / release-01~e.26 :ARG1~e.27 (p2 / protein :name (n4 / name :op1 "Hsp90"~e.28)))))) :condition (s / starve-01~e.6 :ARG1 n5 :ARG2 (a2 / amino-acid~e.4,5))) # ::id bio.chicago_2015.37393 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All four TnI @-@ derived sequences bound TnC , with hcTnI , dTnIA , and dTnIV exhibiting the most robust binding signals . # ::alignments 0-1.1.1.2 1-1.1.1.1 2-1.1.1.3.1.1.1 4-1.1.1.3 5-1.1.1 6-1.1 7-1.1.2.1.1 10-1.2.1.1.1.1 12-1.2.1.2.1.1 14-1.2.1 15-1.2.1.3.1.1 16-1.2 18-1.2.2.2.1 19-1.2.2.2 20-1.2.2.1 21-1.2.2 (a / and :op1 (b / bind-01~e.6 :ARG0 (s / sequence~e.5 :quant 4~e.1 :mod (a2 / all~e.0) :ARG1-of (d / derive-01~e.4 :ARG2 (p / protein :name (n / name :op1 "TnI"~e.2)))) :ARG1 (p2 / protein :name (n2 / name :op1 "TnC"~e.7))) :op2 (e / exhibit-01~e.16 :ARG0 (a3 / and~e.14 :op1 (p3 / protein-segment :name (n3 / name :op1 "hcTnI"~e.10)) :op2 (p4 / protein-segment :name (n4 / name :op1 "dTnIA"~e.12)) :op3 (p5 / protein-segment :name (n5 / name :op1 "dTnIV"~e.15))) :ARG1 (s2 / signal-07~e.21 :ARG3 (b2 / bind-01~e.20) :mod (r / robust~e.19 :degree (m / most~e.18))))) # ::id bio.chicago_2015.37409 ::amr-annotator SDL-AMR-09 ::preferred # ::tok N @-@ Wasp and cortactin can bind simultaneously to the Arp2 @/@ 3 complex and activate actin assembly ( Weaver et al. , 2002 ) . # ::alignments 0-1.1.1.1.1.1.1 2-1.1.1.1.1.1.1 4-1.1.1.1.2.1.1 5-1.1 6-1.1.1 7-1.1.1.3 7-1.1.1.3.r 8-1.1.1.2.r 10-1.1.1.2.1.1 12-1.1.1.2.1.1 13-1.1.1.2 14-1 14-1.3.1.1 15-1.2 16-1.2.2.1.1.1 17-1.2.2 19-1.3.1.1.1.1.1 20-1.1.1.1 20-1.3.1.1 21-1.3.1.1.2.1 23-1.3.1.2.1 (a / and~e.14 :op1 (p7 / possible-01~e.5 :ARG1 (b / bind-01~e.6 :ARG0 (a2 / and~e.20 :op1 (p / protein :name (n / name :op1 "N-Wasp"~e.0,2)) :op2 (p2 / protein :name (n2 / name :op1 "cortactin"~e.4))) :ARG2~e.8 (m / macro-molecular-complex~e.13 :name (n3 / name :op1 "Arp2/3"~e.10,12)) :manner~e.7 (s / simultaneous~e.7))) :op2 (a3 / activate-01~e.15 :ARG0 a2 :ARG1 (a4 / assemble-01~e.17 :ARG2 (p3 / protein :name (n4 / name :op1 "actin"~e.16)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a5 / and~e.14,20 :op1 (p5 / person :name (n5 / name :op1 "Weaver"~e.19)) :op2 (p6 / person :mod (o / other~e.21))) :time (d / date-entity :year 2002~e.23)))) # ::id bio.chicago_2015.37426 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rb interacts with histone deacetylase to repress transcription . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1.1 4-1.2.1.2 6-1.3 7-1.3.2 (i / interact-01~e.1 :ARG0 (p / protein :name (n / name :op1 "Rb"~e.0)) :ARG1~e.2 (e / enzyme :name (n2 / name :op1 "histone"~e.3 :op2 "deacetylase"~e.4)) :ARG2 (r / repress-01~e.6 :ARG0 (a / and :op1 p :op2 e) :ARG1 (t / transcribe-01~e.7))) # ::id bio.chicago_2015.37451 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although TIM can interact with dCLOCK in the absence of PER ( Figure 4 ) , dCLOCK appears to have a higher affinity for the PER @-@ TIM complex compared to a version of TIM that does not associate with PER ( Figure 5 ) . # ::alignments 0-1 1-1.2.1.1.1.1 2-1.2 3-1.2.1 4-1.2.1.2.r 5-1.2.1.2.1.1 6-1.2.1.3.r 8-1.2.1.3 9-1.2.1.3.1.r 10-1.2.1.3.1.1.1 12-1.2.1.4.1 13-1.2.1.4.1.1 16-1.2.1.2.1.1 17-1.1 19-1.1.1 21-1.1.1.2.1 21-1.1.1.2.1.1 21-1.1.1.2.1.1.r 22-1.1.1.2 25-1.2.1.3.1.1.1 27-1.1.1.2.2.2 28-1.1.1.2.2 29-1.1.1.2.3.r 32-1.1.1.2.3 33-1.1.1.2.3.1.r 34-1.1.1.2.3.1 37-1.1.1.2.3.2.1 37-1.1.1.2.3.2.1.r 38-1.1.1.2.3.2 39-1.1.1.2.3.2.2.r 40-1.1.1.2.3.2.2 42-1.1.2.1 43-1.1.2.1.1 (h3 / have-concession-91~e.0 :ARG1 (a2 / appear-02~e.17 :ARG1 (h / have-03~e.19 :ARG0 p3 :ARG1 (a3 / affinity~e.22 :ARG1-of (h2 / high-02~e.21 :degree~e.21 (m / more~e.21)) :topic (m2 / macro-molecular-complex~e.28 :part p4 :part p2~e.27) :compared-to~e.29 (v / version~e.32 :poss~e.33 p2~e.34 :ARG1-of (a4 / associate-01~e.38 :polarity~e.37 -~e.37 :ARG2~e.39 p4~e.40)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.42 :mod 5~e.43))) :ARG2 (p / possible-01~e.2 :ARG1 (i / interact-01~e.3 :ARG0 (p2 / protein :name (n / name :op1 "TIM"~e.1)) :ARG2~e.4 (p3 / protein :name (n2 / name :op1 "dCLOCK"~e.5,16)) :condition~e.6 (a / absent-01~e.8 :ARG1~e.9 (p4 / protein :name (n3 / name :op1 "PER"~e.10,25))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.12 :mod 4~e.13))))) # ::id bio.chicago_2015.37483 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In an ATP @-@ consuming reaction , the C terminus of ubiquitin is first activated by an enzyme called E1 , to which it becomes attached by a thiolester bond . # ::alignments 2-1.4.1.1.1.1 4-1.4.1 5-1.4 8-1.2.1.1 9-1.2.1.2 11-1.2.2.1.1 13-1.3 14-1 17-1.1 17-1.2 17-1.2.2 17-1.2.2.r 18-1.1.1.r 18-1.2.1.r 18-1.2.2.1.r 19-1.1.1.1 23-1.2.3.1 24-1.2.3.3 25-1.2.3 26-1.2.3.2.r 28-1.2.3.2.1.1 29-1.2.3.2.2 (a / activate-01~e.14 :ARG0 (e / enzyme~e.17 :name~e.18 (n / name :op1 "E1"~e.19)) :ARG1 (p / protein-segment~e.17 :name~e.18 (n2 / name :op1 "C"~e.8 :op2 "terminus"~e.9) :part-of~e.17 (p2 / protein~e.17 :name~e.18 (n3 / name :op1 "ubiquitin"~e.11)) :ARG1-of (a2 / attach-01~e.25 :ARG2 e~e.23 :ARG3~e.26 (s2 / small-molecule :name (n6 / name :op1 "thiolester"~e.28) :ARG3-of (b2 / bond-01~e.29)) :ARG1-of (b / become-01~e.24))) :time (f / first~e.13) :condition (r / react-01~e.5 :ARG0-of (c / consume-01~e.4 :ARG1 (s / small-molecule :name (n4 / name :op1 "ATP"~e.2))))) # ::id bio.chicago_2015.37518 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , HGF also increases the amount of newly synthesized E @-@ cadherin molecules found in beta @-@ catenin complexes . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.3 4-1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.2.1 9-1.1.2.1.2 10-1.1.2.1.1.1.1 12-1.1.2.1.1.1.1 13-1.1.2.1 14-1.1.2.1.3 15-1.1.2.1.3.1.r 16-1.1.2.1.3.1.1.1.1 18-1.1.2.1.3.1.1.1.1 19-1.1.2.1.3.1 (a3 / and~e.0 :op2 (i / increase-01~e.4 :ARG0 (p / protein :name (n / name :op1 "HGF"~e.2)) :ARG1 (a2 / amount~e.6 :quant-of~e.7 (m / molecule~e.13 :mod (p2 / protein :name (n2 / name :op1 "E-cadherin"~e.10,12)) :ARG1-of (s / synthesize-01~e.9 :ARG1-of (n3 / new-01~e.8)) :ARG1-of (f / find-01~e.14 :location~e.15 (m2 / macro-molecular-complex~e.19 :part (p3 / protein :name (n4 / name :op1 "beta-catenin"~e.16,18)))))) :mod (a / also~e.3))) # ::id bio.chicago_2015.37572 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Evidence suggests that DREF is required for DNA replication in both the endo and mitotic cell cycles . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.2.1.1 5-1.2 6-1.2.1.r 7-1.2.1.1.2.1 8-1.2.1 12-1.2.1.2.1.1.1 13-1.2.1.2 14-1.2.1.2.2.1.1 15-1.2.1.2.1.1 15-1.2.1.2.2.1 16-1.2.1.2.1 16-1.2.1.2.2 (s / suggest-01~e.1 :ARG0 (e / evidence-01~e.0) :ARG1~e.2 (r / require-01~e.5 :ARG0~e.6 (r2 / replicate-01~e.8 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.7)) :time (a / and~e.13 :op1 (c / cycle~e.16 :mod (c2 / cell~e.15 :mod (e2 / endo~e.12))) :op2 (c3 / cycle~e.16 :mod (c4 / cell~e.15 :mod (m / mitosis~e.14))))) :ARG1 (p / protein :name (n / name :op1 "DREF"~e.3)))) # ::id bio.chicago_2015.37588 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Induction of p21 by p16 . # ::alignments 0-1 1-1.2.r 2-1.2.1.1 3-1.1.r 4-1.1.1.1 (i / induce-01~e.0 :ARG0~e.3 (p / protein :name (n / name :op1 "p16"~e.4)) :ARG1~e.1 (p2 / protein :name (n2 / name :op1 "p21"~e.2))) # ::id bio.chicago_2015.37589 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro , OTK associates with Plexins . # ::alignments 0-1.3 1-1.3 3-1.1.1.1 4-1 (a / associate-01~e.4 :ARG1 (p / protein :name (n / name :op1 "OTK"~e.3)) :ARG2 (p2 / protein :name (n2 / name :op1 "Plexin")) :manner (i / in-vitro~e.0,1)) # ::id bio.chicago_2015.37606 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It remains to be determined how the interaction of either the AHR or ARNT with TFIIB may influence the ability of either of these proteins to activate genes . # ::alignments 1-1 4-1.1 5-1.1.1.1.r 7-1.1.1.1.1 11-1.1.1.1.1.1.1.1.1 12-1.1.1.1.1.1 13-1.1.1.1.1.1.2.1.1 15-1.1.1.1.1.2.1.1 16-1.1.1.1.3 17-1.1.1.1 19-1.1.1.1.2 24-1.1.1.1.1.1.1 24-1.1.1.1.1.1.2 24-1.1.1.1.1.2 26-1.1.1.1.2.2 27-1.1.1.1.2.2.2 (r / remain-01~e.1 :ARG1 (d / determine-01~e.4 :ARG1 (t / thing :manner-of~e.5 (i / influence-01~e.17 :ARG0 (i2 / interact-01~e.7 :ARG0 (o / or~e.12 :op1 (p / protein~e.24 :name (n / name :op1 "AHR"~e.11)) :op2 (p2 / protein~e.24 :name (n2 / name :op1 "ARNT"~e.13))) :ARG1 (p3 / protein~e.24 :name (n3 / name :op1 "TFIIB"~e.15))) :ARG1 (c / capable-01~e.19 :ARG1 o :ARG2 (a / activate-01~e.26 :ARG0 o :ARG1 (g / gene~e.27))) :ARG1-of (p4 / possible-01~e.16))))) # ::id bio.chicago_2015.37655 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hypoxia also induces VEGF ( 76 @-@ 84 ) , and there are also several cellular conditions or factors that down @-@ regulate expression of this gene product , including the tumor suppressor gene p53 and the von Hippel @-@ Lindau tumor suppressor gene product ( 85 @-@ 89 ) . # ::alignments 0-1.1.1 1-1.1.4 2-1.1 3-1.1.2.1.1 5-1.1.3.1.1.1.1 7-1.1.3.1.1.1.2 10-1 10-1.1.3.1.1.1 13-1.2.3 14-1.2.1.1.2 15-1.2.1.1.1 16-1.2.1.1 17-1.2.1 18-1.2.1.2 23-1.2.2 26-1.2.1.3.1.1.2.1 27-1.2.1.3.1.1 27-1.2.1.3.1.1.2 27-1.2.1.3.1.1.2.r 29-1.2.1.3 31-1.2.1.3.1.1.2.1.1.1 32-1.2.1.3.1.1.2.1.1 33-1.2.1.3.1.1.2.1 34-1.2.1.3.1.1.1.1 35-1.2.1.3.1 38-1.2.1.3.1.2.1.1.1.1.1 40-1.2.1.3.1.2.1.1.1.1.1 41-1.2.1.3.1.1.2.1.1.1 42-1.2.1.3.1.1.2.1.1 42-1.2.1.3.1.2.1.1 43-1.1.2.2.1 43-1.2.1.3.1.2.1 44-1.1.2 44-1.1.2.2 44-1.1.2.2.r 44-1.2.1.3.1.2 46-1.2.4.1.1.1.1 48-1.2.4.1.1.1.2 (a / and~e.10 :op1 (i / induce-01~e.2 :ARG0 (h / hypoxia~e.0) :ARG1 (p / protein~e.44 :name (n / name :op1 "VEGF"~e.3) :ARG1-of~e.44 (p2 / produce-01~e.44 :ARG0 (g / gene~e.43))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 (b / between~e.10 :op1 76~e.5 :op2 84~e.7)))) :mod a3~e.1) :op2 (d / downregulate-01 :ARG0 (o / or~e.17 :op1 (c / condition~e.16 :mod (c2 / cell~e.15) :quant (s / several~e.14)) :op2 (f / factor~e.18 :mod c2 :quant s) :ARG2-of (i2 / include-01~e.29 :ARG1 (a2 / and~e.35 :op1 (p3 / protein~e.27 :name (n2 / name :op1 "p53"~e.34) :ARG1-of~e.27 (p4 / produce-01~e.27 :ARG0 (g2 / gene~e.26,33 :ARG0-of (s3 / suppress-01~e.32,42 :ARG1 (t / tumor~e.31,41))))) :op2 (p5 / product~e.44 :poss (g3 / gene~e.43 :ARG0-of (s4 / suppress-01~e.42 :ARG1 (d2 / disease :name (n3 / name :op1 "Hippel-Lindau"~e.38,40)))))))) :ARG1 (e / express-03~e.23 :ARG2 p) :mod (a3 / also~e.13) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c5 / cite-01 :ARG2 (b2 / between :op1 85~e.46 :op2 89~e.48)))))) # ::id bio.chicago_2015.37678 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Extracellular death pathway Experiments using the egfrts1a allele confirmed that EGFR was required for survival of pupal retinal cells , as suggested by prior misexpression experiments ( Miller and Cagan , 1998 ; Sawamoto et al. , 1998 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1.1.1.3 3-1.1 6-1.1.2.1.1 7-1.1.2 8-1 9-1.2.r 10-1.2.2.1.1 12-1.2 13-1.2.1.r 14-1.2.1 17-1.2.1.1.1 18-1.2.1.1 20-1.2.3.r 21-1.2.3 22-1.2.3.1.r 23-1.2.3.1.2 25-1.2.3.1 27-1.3.1.1.1.1.1.1 28-1.3.1.1.1 29-1.3.1.1.1.2.1.1 31-1.3.1.1.2.1 33-1.3.1.2.1.1.1.1 34-1.3.1 34-1.3.1.2.1 35-1.3.1.2.1.2.1 37-1.3.1.2.2 (c / confirm-01~e.8 :ARG0 (e / experiment-01~e.3 :ARG1 (p / pathway :name (n / name :op1 "Extracellular"~e.0 :op2 "death"~e.1 :op3 "pathway"~e.2)) :ARG2 (a / allele~e.7 :name (n2 / name :op1 "egfrts1a"~e.6))) :ARG1~e.9 (r / require-01~e.12 :ARG0~e.13 (s / survive-01~e.14 :ARG0 (c2 / cell~e.18 :source (r2 / retina~e.17) :mod (p2 / pupa))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "EGFR"~e.10)) :ARG1-of~e.20 (s2 / suggest-01~e.21 :ARG0~e.22 (e3 / experiment-01~e.25 :ARG1 (e4 / express-03 :ARG1-of (w / wrong-04)) :time (p3 / prior~e.23)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.34 :op1 (p4 / publication-91 :ARG0 (a2 / and~e.28 :op1 (p5 / person :name (n4 / name :op1 "Miller"~e.27)) :op2 (p6 / person :name (n5 / name :op1 "Cagan"~e.29))) :time (d2 / date-entity :year 1998~e.31)) :op2 (p7 / publication-91 :ARG0 (a4 / and~e.34 :op1 (p8 / person :name (n6 / name :op1 "Sawamoto"~e.33)) :op2 (p9 / person :mod (o / other~e.35))) :time d2~e.37)))) # ::id bio.chicago_2015.37682 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using Biacore and yeast two @-@ hybrid analyses , they found that Hrs interacts with Tsg101 , although the PSAP @-@ containing peptide from Hrs bound with lower affinity than that from HIV p6 to the UEV domain of Tsg101 ( Pornillos et al. , 2003 ) . # ::alignments 1-1.3.1.1.1.1 2-1.3 3-1.3.2.1.1 4-1.3.2.1.2 6-1.3.2.1.2 7-1.3.1 7-1.3.2 9-1.1 10-1 12-1.2.1.1.1.1 13-1.2.1 14-1.2.1.2.r 14-1.3.r 15-1.2.1.2.1.1 17-1.2 19-1.2.2.1.1.1.1.1 21-1.2.2.1.1 22-1.2.2.1 22-1.2.2.2.1.2 23-1.2.2.1.2.r 24-1.2.2.1.2 25-1.2.2 25-1.2.2.2.1.2.1 25-1.2.2.2.1.2.1.2 25-1.2.2.2.1.2.1.2.r 26-1.2.2.2.r 26-1.3.r 27-1.2.2.2.1 27-1.2.2.2.1.1 27-1.2.2.2.1.1.r 28-1.2.2.2 29-1.2.2.2.1.2.r 31-1.2.2.1.2.r 32-1.2.2.2.1.2.1.1.1 33-1.2.2.2.1.2.1.1.2 34-1.2.2.2.1.2.1.2.1.r 36-1.2.2.2.1.2.1.2.1.1.1 39-1.2.2.2.1.2.1.2.1.2 41-1.4.1.1.1.1.1 42-1.4.1.1 43-1.4.1.1.2.1 45-1.4.1.2.1 (f / find-01~e.10 :ARG0 (t / they~e.9) :ARG1 (h2 / have-concession-91~e.17 :ARG1 (i / interact-01~e.13 :ARG0 (p9 / protein :name (n2 / name :op1 "Hrs"~e.12)) :ARG1~e.14 (p10 / protein :name (n4 / name :op1 "Tsg101"~e.15))) :ARG2 (b / bind-01~e.25 :ARG1 (p / peptide~e.22 :ARG0-of (c3 / contain-01~e.21 :ARG1 (p2 / protein :name (n3 / name :op1 "PSAP"~e.19))) :source~e.23,31 p9~e.24) :manner~e.26 (a4 / affinity~e.28 :ARG1-of (l / low-04~e.27 :degree~e.27 (m / more~e.27) :compared-to~e.29 (p3 / peptide~e.22 :source (p11 / protein~e.25 :name (n9 / name :op1 "HIV"~e.32 :op2 "p6"~e.33) :ARG1-of~e.25 (b2 / bind-01~e.25 :ARG2~e.34 (p5 / protein-segment :name (n6 / name :op1 "UEV"~e.36) :part-of p10~e.39)))))))) :instrument~e.14,26 (a / and~e.2 :op1 (a2 / analyze-01~e.7 :mod (c / company :name (n / name :op1 "Biacore"~e.1))) :op2 (a3 / analyze-01~e.7 :name (n5 / name :op1 "yeast"~e.3 :op2 "two-hybrid"~e.4,6))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a5 / and~e.42 :op1 (p7 / person :name (n7 / name :op1 "Pornillos"~e.41)) :op2 (p8 / person :mod (o / other~e.43))) :time (d3 / date-entity :year 2003~e.45)))) # ::id bio.chicago_2015.37689 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Parallel experiments in which the effects of PD098059 on IL @-@ 2 activation of E2F were monitored ( Figure 4C ) showed that IL @-@ 2 can potently induce E2F activity in the presence of levels of PD098059 that completely block IL @-@ 2 activation of Elk @-@ 1 . # ::alignments 0-1.1.2 1-1.1 5-1.1.1.1 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1 8-1.1.1.1.2.r 9-1.1.1.1.2.1.1.1 11-1.1.1.1.2.1.1.1 12-1.1.1.1.2 13-1.1.1.1.2.2.r 14-1.1.1.1.2.2.1.1 16-1.1.1 18-1.1.1.2.1 19-1.1.1.2.1.1 21-1 23-1.1.1.1.2.1.1.1 25-1.1.1.1.2.1.1.1 26-1.2 27-1.2.1.3 27-1.2.1.3.r 28-1.2.1 29-1.2.1.2.1 30-1.2.1.2 31-1.2.1.4.r 33-1.2.1.4 34-1.2.1.4.1.r 35-1.2.1.4.1 36-1.2.1.4.1.1.r 37-1.2.1.4.1.1 39-1.2.1.4.1.2.2 40-1.2.1.4.1.2 41-1.2.1.4.1.2.1.1 42-1.2.1.4.1.2.1.1 43-1.2.1.4.1.2.1.1 44-1.2.1.4.1.2.1 45-1.2.1.4.1.2.1.2.r 46-1.2.1.4.1.2.1.2.1.1 48-1.2.1.4.1.2.1.2.1.1 (s / show-01~e.21 :ARG0 (e / experiment-01~e.1 :ARG1 (m / monitor-01~e.16 :ARG1 (a / affect-01~e.5 :ARG0~e.6 (s2 / small-molecule :name (n / name :op1 "PD098059"~e.7)) :ARG1~e.8 (a2 / activate-01~e.12 :ARG0 (p3 / protein :name (n3 / name :op1 "IL-2"~e.9,11,23,25)) :ARG1~e.13 (p2 / protein :name (n2 / name :op1 "E2F"~e.14)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "4C"~e.19))) :ARG0-of (p / parallel-01~e.0)) :ARG1 (p4 / possible-01~e.26 :ARG1 (i / induce-01~e.28 :ARG0 p3 :ARG2 (a3 / activity-06~e.30 :ARG0 p2~e.29) :manner~e.27 (p5 / potent~e.27) :condition~e.31 (p6 / present-02~e.33 :ARG1~e.34 (l / level~e.35 :quant-of~e.36 s2~e.37 :ARG0-of (b / block-01~e.40 :ARG1 (a4 / activate-01~e.44 :ARG0 p3~e.41,42,43 :ARG1~e.45 (p7 / protein :name (n4 / name :op1 "Elk-1"~e.46,48))) :ARG1-of (c / complete-02~e.39))))))) # ::id bio.chicago_2015.37690 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of rAxin by GSK @-@ 3 beta . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 4-1.2.1.1 (p / phosphorylate-01~e.0 :ARG1~e.1 (p2 / protein :name (n2 / name :op1 "rAxin"~e.2)) :ARG2~e.3 (e / enzyme :name (n / name :op1 "GSK-3beta"~e.4))) # ::id bio.chicago_2015.37704 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of Munc @-@ 18 by PKC . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 4-1.1.1.1 5-1.2.r 6-1.2.1.1 (p / phosphorylate-01~e.0 :ARG1~e.1 (p2 / protein :name (n2 / name :op1 "Munc-18"~e.2,4)) :ARG2~e.5 (e / enzyme :name (n / name :op1 "PKC"~e.6))) # ::id bio.chicago_2015.37713 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The GCKH domain of NIK interacted with MEKK1 , and the dominant negative mutant of MEKK1 inhibited NIK @-@ induced JNK activation ( 12 ) . # ::alignments 1-1.1.1.1.1 4-1.1.1.2.1.1 5-1.1 7-1.1.2.1.1 7-1.2.1.1.1 9-1 11-1.2.1.3 13-1.2.1 13-1.2.1.2 13-1.2.1.2.r 15-1.2.1.1.1 16-1.2 17-1.2.2.2.1 19-1.2.2.2 20-1.2.2.1.1.1 21-1.2.2 23-1.3.1.1.1 (a / and~e.9 :op1 (i / interact-01~e.5 :ARG0 (p / protein-segment :name (n / name :op1 "GCKH"~e.1) :part-of (e4 / enzyme :name (n2 / name :op1 "NIK"~e.4))) :ARG1 (e / enzyme :name (n3 / name :op1 "MEKK1"~e.7))) :op2 (i2 / inhibit-01~e.16 :ARG0 (e2 / enzyme~e.13 :name (n4 / name :op1 "MEKK1"~e.7,15) :ARG2-of~e.13 (m / mutate-01~e.13 :mod "-/-") :ARG0-of (d / dominate-01~e.11)) :ARG1 (a2 / activate-01~e.21 :ARG1 (e3 / enzyme :name (n5 / name :op1 "JNK"~e.20)) :ARG2-of (i3 / induce-01~e.19 :ARG0 e4~e.17))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 12~e.23)))) # ::id bio.chicago_2015.37728 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , CKI binds to mPER1 in a region that has no obvious sequence similarity to the suggested DBT @-@ binding region of dPER ( 27 ) . # ::alignments 0-1.4 2-1.1.1.1 3-1 4-1.2.r 5-1.2.1.1 6-1.3.r 8-1.3 10-1.3.1 11-1.3.1.1.3.1 11-1.3.1.1.3.1.r 12-1.3.1.1.3 13-1.3.1.1.1 14-1.3.1.1 15-1.3.1.1.2.r 17-1.3.1.1.2.1 18-1.3.1.1.2.2.1.1.1 20-1.3.1.1.2.2 21-1.3.1.1.2 22-1.3.1.1.2.3.r 23-1.3.1.1.2.3.1.1 25-1.5.1.1.1 (b / bind-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "CKI"~e.2)) :ARG2~e.4 (p3 / protein :name (n2 / name :op1 "mPER1"~e.5)) :location~e.6 (r / region~e.8 :ARG0-of (h / have-03~e.10 :ARG1 (r2 / resemble-01~e.14 :ARG1 (s / sequence~e.13) :ARG2~e.15 (r3 / region~e.21 :ARG1-of (s2 / suggest-01~e.17) :ARG1-of (b2 / bind-01~e.20 :ARG2 (p / protein :name (n3 / name :op1 "DBT"~e.18))) :part-of~e.22 (p2 / protein :name (n4 / name :op1 "dPER"~e.23))) :ARG1-of (o / obvious-01~e.12 :polarity~e.11 -~e.11)))) :ARG2-of (i / interest-01~e.0) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 27~e.25)))) # ::id bio.chicago_2015.37742 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The binding of Sp1 to the EBS and to the downstream canonical Sp1 site occurred with comparable affinities . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1.1 4-1.2.2.r 6-1.2.2.1.1.1 7-1.2.2 10-1.2.2.2.1.3 11-1.2.2.2.1.2 12-1.2.2.2.1.1.1 13-1.2.2.2 16-1.1 17-1 (a / affinity~e.17 :ARG1-of (c / comparable-03~e.16) :topic (b / bind-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "Sp1"~e.3)) :ARG2~e.4 (a2 / and~e.7 :op1 (p2 / protein :name (n2 / name :op1 "EBS"~e.6)) :op2 (s / site~e.13 :mod (p3 / protein :name (n3 / name :op1 "Sp1"~e.12) :mod (c2 / canonical~e.11) :mod (d / downstream~e.10)))))) # ::id bio.chicago_2015.37761 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Perhaps intersectin plays a role in EGF @-@ stimulated Ras activation specifically at clathrin @-@ coated pits . # ::alignments 0-1 1-1.1.1.1.1 2-1.1 4-1.1.2 5-1.1.3.r 6-1.1.3.2.1.1.1 8-1.1.3.2 9-1.1.3.1.1.1 10-1.1.3 11-1.1.4.2 13-1.1.4.1.1.1.1 15-1.1.4.1 16-1.1.4 (p / possible-01~e.0 :ARG1 (p2 / play-02~e.2 :ARG0 (p3 / protein :name (n / name :op1 "intersectin"~e.1)) :ARG1 (r / role~e.4) :topic~e.5 (a / activate-01~e.10 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.9)) :ARG1-of (s / stimulate-01~e.8 :ARG0 (p4 / protein :name (n3 / name :op1 "EGF"~e.6)))) :location (p5 / pit~e.16 :ARG1-of (c / coat-01~e.15 :ARG2 (p6 / protein :name (n4 / name :op1 "clathrin"~e.13))) :ARG1-of (s2 / specific-02~e.11)))) # ::id bio.chicago_2015.37797 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The substance has been shown previously not only to prevent phosphorylation @-@ dependent activation of MEK by Raf @-@ 1 but also to interfere with signaling from activated MEK1 ( 1 , 22 ) . # ::alignments 1-1.1.1.1 4-1 5-1.2 9-1.1.1 10-1.1.1.2.3.1 12-1.1.1.2.3 13-1.1.1.2 14-1.1.1.2.2.r 15-1.1.1.2.2.1.1 16-1.1.1.2.1.r 17-1.1.1.2.1.1.1 19-1.1.1.2.1.1.1 21-1.1.2.3 23-1.1.2 24-1.1.2.2.r 25-1.1.2.2 26-1.1.2.2.1.r 27-1.1.2.2.1.2 28-1.1.2.2.1.1.1 30-1.3.1.1.1.1 32-1.3.1.1.1.2 (s / show-01~e.4 :ARG1 (a / and :op1 (p / prevent-01~e.9 :ARG0 (s2 / substance~e.1) :ARG1 (a2 / activate-01~e.13 :ARG0~e.16 (e2 / enzyme :name (n2 / name :op1 "Raf-1"~e.17,19)) :ARG1~e.14 (e / enzyme :name (n / name :op1 "MEK"~e.15)) :ARG0-of (d / depend-01~e.12 :ARG1 (p3 / phosphorylate-01~e.10)))) :op2 (i / interfere-01~e.23 :ARG0 s2 :ARG1~e.24 (s3 / signal-07~e.25 :ARG0~e.26 (e3 / enzyme :name (n3 / name :op1 "MEK1"~e.28) :ARG1-of (a3 / activate-01~e.27))) :mod (a5 / also~e.21))) :time (p2 / previous~e.5) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 1~e.30 :op2 22~e.32))))) # ::id bio.chicago_2015.37803 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Repression of hsp70 heat shock gene transcription by the suppressor of Hairy @-@ wing protein of Drosophila melanogaster.. # ::alignments 0-1 1-1.2.r 2-1.2.1.1.1.1.1 3-1.2.1.1.1.1.2 4-1.2.1.1.1.1.3 5-1.2.1 6-1.2 7-1.1.r 9-1.1 9-1.1.1 9-1.1.1.r 10-1.1.1.1.r 11-1.1.1.1.1.1 13-1.1.1.1.1.1 14-1.1.1.1 14-1.2.1.1.1 15-1.1.1.1.2.r 16-1.1.1.1.2.1.1 (r / repress-01~e.0 :ARG0~e.7 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (s / suppress-01~e.9 :ARG1~e.10 (p2 / protein~e.14 :name (n2 / name :op1 "Hairy-wing"~e.11,13) :source~e.15 (o / organism :name (n3 / name :op1 "Drosophila"~e.16 :op2 "melanogaster"))))) :ARG1~e.1 (t / transcribe-01~e.6 :ARG1 (g / gene~e.5 :ARG0-of (e / encode-01 :ARG1 (p / protein~e.14 :name (n / name :op1 "hsp70"~e.2 :op2 "heat"~e.3 :op3 "shock"~e.4)))))) # ::id bio.chicago_2015.37835 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate whether the binding of E1A to p300 correlates with a loss of p300 transcriptional activity , we examined the binding of full @-@ length E1A to the series of mutant p300 proteins . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 4-1.3.2.2 5-1.3.2.2.1.r 6-1.3.2.2.1 8-1.3.2.2.2.1.1 9-1.3.2 10-1.3.2.3.r 12-1.3.2.3 13-1.3.2.3.1.r 14-1.3.2.3.1.2.1 15-1.3.2.3.1.2 16-1.3.2.3.1 18-1.1 19-1 21-1.2 23-1.2.1.2.1 25-1.2.1.2 26-1.2.1.1.1 27-1.2.2.r 29-1.2.2 31-1.2.2.1.2 32-1.2.2.1.1.1 33-1.2.1 33-1.2.2.1 33-1.3.2.2.2 (e / examine-01~e.19 :ARG0 (w / we~e.18) :ARG1 (b / bind-01~e.21 :ARG1 (p / protein~e.33 :name (n / name :op1 "E1A"~e.26) :ARG1-of (l2 / long-03~e.25 :ARG1-of (f / full-09~e.23))) :ARG2~e.27 (s / series~e.29 :consist-of (p3 / protein~e.33 :name (n2 / name :op1 "p300"~e.32) :ARG2-of (m / mutate-01~e.31)))) :purpose (i / investigate-01~e.1 :ARG0 w :ARG1 (c / correlate-01~e.9 :mode~e.2 interrogative~e.2 :ARG1 (b2 / bind-01~e.4 :ARG1~e.5 p~e.6 :ARG2 (p2 / protein~e.33 :name (n3 / name :op1 "p300"~e.8))) :ARG2~e.10 (l / lose-02~e.12 :ARG1~e.13 (a / activity-06~e.16 :ARG0 p2 :ARG1 (t / transcribe-01~e.15 :ARG0 p2~e.14)))))) # ::id bio.chicago_2015.37883 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We recently presented evidence that the rate of dephosphorylation of Cdc2 on tyrosine @-@ 15 is decreased in cells arrested in early S with HU , which indicates that Cdc25 might be inhibited by the S @-@ M replication checkpoint ( Rhind and Russell , 1998a ) . # ::alignments 0-1.1 1-1.3 2-1 3-1.2 4-1.2.1.r 6-1.2.1.1 7-1.2.1.1.1.r 8-1.2.1.1.1 9-1.2.1.1.1.1.r 10-1.2.1.1.1.1.3.1.1 12-1.2.1.1.1.1.2.1 14-1.2.1.1.1.1.1 16-1.2.1 17-1.2.1.2.r 18-1.2.1.2 19-1.2.1.2.1 20-1.2.1.2.1.2.r 21-1.2.1.2.1.2 22-1.2.1.2.1.2.1.1.1 23-1.2.1.2.1.1.r 24-1.2.1.2.1.1.1.1 27-1.2.1.3 28-1.2.1.3.1.r 29-1.2.1.3.1.1.2.1.1 30-1.2.1.3.1 32-1.2.1.3.1.1 33-1.2.1.3.1.1.1.r 35-1.2.1.3.1.1.1.1.1.1.1 37-1.2.1.3.1.1.1.1.1.1.1 38-1.2.1.3.1.1.1.1 39-1.2.1.3.1.1.1 41-1.2.1.3.2.1.1.1.1.1 42-1.2.1.3.2.1.1 43-1.2.1.3.2.1.1.2.1.1 (p / present-01~e.2 :ARG0 (w / we~e.0) :ARG1 (e / evidence-01~e.3 :ARG1~e.4 (d / decrease-01~e.16 :ARG1 (r / rate~e.6 :degree-of~e.7 (d2 / dephosphorylate-01~e.8 :ARG1~e.9 (a / amino-acid :mod 15~e.14 :name (n2 / name :op1 "tyrosine"~e.12) :part-of (e2 / enzyme :name (n / name :op1 "Cdc2"~e.10))))) :location~e.17 (c / cell~e.18 :ARG1-of (a2 / arrest-02~e.19 :instrument~e.23 (s / small-molecule :name (n8 / name :op1 "HU"~e.24)) :time~e.20 (e3 / early~e.21 :op1 (p2 / phase :name (n3 / name :op1 "S"~e.22))))) :ARG0-of (i / indicate-01~e.27 :ARG1~e.28 (p3 / possible-01~e.30 :ARG1 (i2 / inhibit-01~e.32 :ARG0~e.33 (c2 / checkpoint~e.39 :mod (r2 / replicate-01~e.38 :ARG1 (p4 / phase :name (n5 / name :op1 "S-M"~e.35,37)))) :ARG1 (e4 / enzyme :name (n4 / name :op1 "Cdc25"~e.29)))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and~e.42 :op1 (p6 / person :name (n6 / name :op1 "Rhind"~e.41)) :op2 (p7 / person :name (n7 / name :op1 "Russell"~e.43))) :time (d4 / date-entity :year 1998)))))) :time (r3 / recent~e.1)) # ::id bio.chicago_2015.37893 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MSL2 and MSL3 interact with MSL1 in a yeast two @-@ hybrid system ( Copps et al. , 1998 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1 4-1.2.r 5-1.2.1.1 6-1.3.r 8-1.3.1.1 9-1.3.1.2 11-1.3.1.2 12-1.3 14-1.4.1.1.1.1.1 15-1.4.1.1 16-1.4.1.1.2.1 18-1.4.1.2.1 (i / interact-01~e.3 :ARG0 (a / and~e.1 :op1 (p4 / protein :name (n / name :op1 "MSL2"~e.0)) :op2 (p5 / protein :name (n2 / name :op1 "MSL3"~e.2))) :ARG1~e.4 (p6 / protein :name (n3 / name :op1 "MSL1"~e.5)) :condition~e.6 (s / system~e.12 :name (n4 / name :op1 "yeast"~e.8 :op2 "two-hybrid"~e.9,11)) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and~e.15 :op1 (p2 / person :name (n5 / name :op1 "Copps"~e.14)) :op2 (p3 / person :mod (o / other~e.16))) :time (d2 / date-entity :year 1998~e.18)))) # ::id bio.chicago_2015.37903 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of eIF2 alpha by Hri1p and Hri2p is induced by heat shock or arsenic . # ::alignments 0-1.2 4-1.2.2.r 5-1.2.2.1.1.1 6-1.2.2 7-1.2.2.2.1.1 9-1 10-1.1.r 11-1.1.1.1.1 12-1.1.1.1.2 14-1.1.2 (i / induce-01~e.9 :ARG0~e.10 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "heat"~e.11 :op2 "shock"~e.12)) :op2 (a3 / arsenic~e.14)) :ARG2 (p / phosphorylate-01~e.0 :ARG1 (p2 / protein :name (n / name :op1 "eIF2alpha")) :ARG2~e.4 (a / and~e.6 :op1 (e / enzyme :name (n2 / name :op1 "Hri1p"~e.5)) :op2 (e2 / enzyme :name (n3 / name :op1 "Hri2p"~e.7))))) # ::id bio.chicago_2015.37947 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Polyglutamine @-@ Expanded Human Huntingtin Transgenes Induce Degeneration of Drosophila Photoreceptor Neurons . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1.1.1.2 4-1.1.1.3 6-1 7-1.2 8-1.2.1.r 9-1.2.1.2.1.1 10-1.2.1.1 11-1.2.1 (i / induce-01~e.6 :ARG0 (t / transgene :name (n / name :op1 "Polyglutamine-Expanded"~e.0,2 :op2 "Human"~e.3 :op3 "Huntingtin"~e.4)) :ARG2 (d / degenerate-01~e.7 :ARG1~e.8 (n2 / neuron~e.11 :mod (p2 / photoreceptor~e.10) :source (o / organism :name (n3 / name :op1 "Drosophila"~e.9))))) # ::id bio.chicago_2015.37956 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Scattering measurements have suggested that the rate of activation of transducin by photoexcited rhodopsin could proceed as rapidly as 700 - 1000 s @-@ 1 ( Vuong et al 1984 , Kahlert & Hofmann 1991 , Bruckert et al 1992 ) under conditions of saturating guanosine triphosphate ( GTP ) . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 6-1.2.1.1 8-1.2.1.1.3 9-1.2.1.1.3.2.r 10-1.2.1.1.3.2.1.1 13-1.2.1.1.3.1.1.1 14-1.2 15-1.2.1 17-1.2.1.1.1.3 19-1.2.1.1.1.1 21-1.2.1.1.1.1.r 21-1.2.1.1.1.2 21-1.2.1.1.3.1.1.1.r 22-1.2.1.1.1.1.r 22-1.2.1.1.1.2 24-1.2.1.1.2.1 26-1.2.1.3.1.1.1.1.1.1 27-1.2.1.3.1.1.1 28-1.2.1.3.1.1.1.2.1 29-1.2.1.3.1.1.2.1 31-1.2.1.3.1.2.1.1.1.1 32-1.2.1.3.1.2.1 33-1.2.1.3.1.2.1.2.1.1 34-1.2.1.3.1.2.2.1 36-1.2.1.3.1.3.1.1.1.1 37-1.2.1.3.1 37-1.2.1.3.1.1.1 37-1.2.1.3.1.3.1 38-1.2.1.3.1.1.1.2.1 39-1.2.1.3.1.3.2.1 42-1.2.1.2.r 44-1.2.1.2.2 45-1.2.1.2.1.1 46-1.2.1.2.1.2 (s / suggest-01~e.3 :ARG0 (m / measure-01~e.1 :ARG0-of (s2 / scatter-01~e.0)) :ARG1~e.4 (p / possible-01~e.14 :ARG1 (p2 / proceed-01~e.15 :ARG1 (r / rate-entity-91~e.6 :ARG1 (b / between :op1~e.21,22 700~e.19 :op2 1000~e.21,22 :mod (r2 / rapid~e.17)) :ARG2 (t / temporal-quantity :quant -1~e.24 :unit (s3 / second)) :degree-of (a / activate-01~e.8 :ARG0 (p4 / protein :name (n2 / name :op1~e.21 "rhodopsin"~e.13) :ARG1-of (p5 / photoexcite-00)) :ARG1~e.9 (p3 / protein :name (n / name :op1 "transducin"~e.10)))) :condition~e.42 (s5 / small-molecule :name (n3 / name :op1 "guanosine"~e.45 :op2 "triphosphate"~e.46) :ARG2-of (s4 / saturate-01~e.44)) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.37 :op1 (p6 / publication-91 :ARG0 (a3 / and~e.27,37 :op1 (p7 / person :name (n4 / name :op1 "Vuong"~e.26)) :op2 (p8 / person :mod (o / other~e.28,38))) :time (d2 / date-entity :year 1984~e.29)) :op2 (p9 / publication-91 :ARG0 (a4 / and~e.32 :op1 (p10 / person :name (n5 / name :op1 "Kahlert"~e.31)) :op2 (p11 / person :name (n6 / name :op1 "Hofmann"~e.33))) :time (d3 / date-entity :year 1991~e.34)) :op3 (p12 / publication-91 :ARG0 (a5 / and~e.37 :op1 (p13 / person :name (n7 / name :op1 "Bruckert"~e.36)) :op2 p8) :time (d4 / date-entity :year 1992~e.39))))))) # ::id bio.chicago_2015.38037 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It was also shown that the GST @-@ A box of HMG @-@ 1 was able to pull down TFIID in crude HeLa extract , suggesting that HMG @-@ 1 binds to TBP and @/@ or other TFIID components ( 41 ) . # ::alignments 2-1.2 3-1 4-1.1.r 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1.1.1.2 11-1.1.1.2.1.1 13-1.1.1.2.1.1 15-1.1 16-1.1.2.r 17-1.1.2 18-1.1.2 19-1.1.2.1.1.1 20-1.1.2.2.r 21-1.1.2.2.2 22-1.1.2.2.1.1.1 23-1.1.2.2 25-1.1.3 26-1.1.3.1.r 27-1.1.3.1.1 28-1.1.3.1.1 29-1.1.3.1.1 30-1.1.3.1 31-1.1.3.1.2.r 32-1.1.3.1.2.1.1.1.1 33-1.1.3.1.2 33-1.1.3.1.2.1 33-1.1.3.1.2.1.r 35-1.1.3.1.2 35-1.1.3.1.2.2 35-1.1.3.1.2.2.r 36-1.1.3.1.2.1.2.2 37-1.1.3.1.2.1.2.1 38-1.1.3.1.2.1.2 40-1.3.1.1.1 (s / show-01~e.3 :ARG1~e.4 (c / capable-01~e.15 :ARG1 (d / dna-sequence :name (n / name :op1 "GST-A"~e.6,8 :op2 "box"~e.9) :part-of (g / gene :name (n2 / name :op1 "HMG-1"~e.11,13))) :ARG2~e.16 (p / pull-down-08~e.17,18 :ARG1 (p2 / protein :name (n3 / name :op1 "TFIID"~e.19)) :ARG2~e.20 (e / extract-01~e.23 :ARG2 (c2 / cell-line :name (n4 / name :op1 "HeLa"~e.22)) :mod (c3 / crude~e.21)) :ARG3 d) :ARG0-of (s2 / suggest-01~e.25 :ARG1~e.26 (b / bind-01~e.30 :ARG1 g~e.27,28,29 :ARG2~e.31 (a3 / and-or~e.33,35 :op1~e.33 (a2 / and~e.33 :op1 (p3 / protein :name (n5 / name :op1 "TBP"~e.32)) :op2 (c4 / component~e.38 :part-of p2~e.37 :mod (o / other~e.36))) :op2~e.35 (o2 / or~e.35 :op1 p3 :op2 c4))))) :mod (a / also~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 41~e.40)))) # ::id bio.chicago_2015.38040 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If a similar structure mediates the formation of the MSL1 @-@ MSL2 heterodimer , then part of the region of MSL2 that interacts with MSL1 should form a coiled @-@ coil structure . # ::alignments 0-1 2-1.2.1.1 3-1.2.1 4-1.2 6-1.2.2 7-1.2.2.1.r 9-1.2.2.1.1.1.1 11-1.2.2.1.2.1.1 12-1.2.2.1 14-1 15-1.1.1.1 15-1.2.2.1.1.r 15-1.2.2.1.2.r 16-1.1.1.1.1.r 18-1.1.1.1.1 19-1.1.1.1.1.1.r 20-1.1.1.1.1.1.1.1 22-1.1.1.1.1.1 22-1.1.1.1.1.1.2 22-1.1.1.1.1.1.2.r 23-1.1.1.1.1.1.2.1.r 24-1.1.1.1.1.1.2.1 25-1.1 26-1.1.1 28-1.1.1.2.1 28-1.1.1.2.1.1 28-1.1.1.2.1.1.r 30-1.1.1.2.1 30-1.1.1.2.1.1 30-1.1.1.2.1.1.r 31-1.1.1.2 (h / have-condition-91~e.0,14 :ARG1 (r2 / recommend-01~e.25 :ARG1 (f2 / form-01~e.26 :ARG0 (p3 / part~e.15 :part-of~e.16 (r3 / region~e.18 :part-of~e.19 (p4 / protein~e.22 :name (n3 / name :op1 "MSL2"~e.20) :ARG0-of~e.22 (i / interact-01~e.22 :ARG1~e.23 p~e.24)))) :ARG1 (s3 / structure~e.31 :mod (c / coil~e.28,30 :ARG1-of~e.28,30 (c2 / coil-01~e.28,30))))) :ARG2 (m / mediate-01~e.4 :ARG0 (s / structure~e.3 :ARG1-of (r / resemble-01~e.2)) :ARG1 (f / form-01~e.6 :ARG1~e.7 (h2 / heterodimer~e.12 :part~e.15 (p / protein :name (n / name :op1 "MSL1"~e.9)) :part~e.15 (p2 / protein :name (n2 / name :op1 "MSL2"~e.11)))))) # ::id bio.chicago_2015.38085 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC @-@ dependent degradation of the anaphase inhibitor Pds1p . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1 4-1.1.2.1.2 6-1 7-1.2.r 9-1.2.2.1.1.1 11-1.2.2 12-1.2 13-1.2.1.r 15-1.2.1.2.1 16-1.2.1 16-1.2.1.2 16-1.2.1.2.r 17-1.2.1.1.1 (c / control-01~e.6 :ARG1 (i / initiate-01~e.1 :ARG1 (a / anaphase~e.0) :location~e.2 (o / organism :name (n / name :op1 "Saccharomyces"~e.3 :op2 "cerevisiae"~e.4))) :ARG2~e.7 (d / degrade-01~e.12 :ARG1~e.13 (p / protein~e.16 :name (n2 / name :op1 "Pds1p"~e.17) :ARG0-of~e.16 (i2 / inhibit-01~e.16 :ARG1 a~e.15)) :ARG0-of (d2 / depend-01~e.11 :ARG1 (p2 / protein :name (n3 / name :op1 "APC"~e.9))))) # ::id bio.chicago_2015.38107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The role of these virus @-@ like particles , if any , in neuronal cell death induced by huntingtin transgenes requires further analysis . # ::alignments 1-1 2-1.1.r 3-1.1.2 4-1.1.1.1 6-1.1.1 7-1.1 9-1.2.r 10-1.2 14-1.4.1 15-1.4 16-1.4.2 18-1.4.2.1.1.1 20-1.3 21-1.3.1.1 22-1.3.1 (r / role~e.1 :poss~e.2 (p / particle~e.7 :ARG1-of (r2 / resemble-01~e.6 :ARG2 (v / virus~e.4)) :mod (t2 / this~e.3)) :condition~e.9 (a / any~e.10) :ARG0-of (r3 / require-01~e.20 :ARG1 (a2 / analyze-01~e.22 :mod (f / further~e.21))) :topic (d / die-01~e.15 :ARG1 (c / cell~e.14 :mod (n / neuron)) :ARG2-of (i / induce-01~e.16 :ARG0 (t / transgene :name (n2 / name :op1 "huntingtin"~e.18))))) # ::id bio.chicago_2015.38113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These date indicate that MEK plays a crucial role in Epo @-@ induced activation of Elk @-@ 1 and is also involved in CrkL @-@ enhanced activation of Elk @-@ 1 . # ::alignments 0-1.1.1 2-1 3-1.2.r 4-1.2.1.1.1.1 5-1.2.1 7-1.2.1.2.1 8-1.2.1.2 9-1.2.1.2.2.r 10-1.2.1.2.2.2.1.1.1 12-1.2.1.2.2.2 13-1.2.1.2.2 14-1.2.1.2.2.1.r 15-1.2.1.2.2.1.1.1 17-1.2.1.2.2.1.1.1 18-1.2 20-1.2.2.3 21-1.2.2 22-1.2.2.2.r 23-1.2.2.2.2.1.1.1 25-1.2.2.2.2 26-1.2.2.2 27-1.2.2.2.1.r 28-1.2.2.2.1 29-1.2.2.2.1 30-1.2.2.2.1 (i / indicate-01~e.2 :ARG0 (d / data :mod (t / this~e.0)) :ARG1~e.3 (a / and~e.18 :op1 (p / play-02~e.5 :ARG0 (e / enzyme :name (n / name :op1 "MEK"~e.4)) :ARG1 (r / role~e.8 :mod (c / crucial~e.7) :topic~e.9 (a2 / activate-01~e.13 :ARG1~e.14 (p2 / protein :name (n2 / name :op1 "Elk-1"~e.15,17)) :ARG2-of (i2 / induce-01~e.12 :ARG0 (s / small-molecule :name (n3 / name :op1 "Epo"~e.10)))))) :op2 (i3 / involve-01~e.21 :ARG1 e :ARG2~e.22 (a3 / activate-01~e.26 :ARG1~e.27 p2~e.28,29,30 :ARG1-of (e2 / enhance-01~e.25 :ARG0 (p3 / protein :name (n4 / name :op1 "CrkL"~e.23)))) :mod (a4 / also~e.20)))) # ::id bio.chicago_2015.38119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because APC inhibition by Mad2 or proteasome inhibition by addition of MG132 ( J.D.R.R . and P.J . , unpublished data ) , rescued mitosis in Emi1 @-@ depleted extracts , Emi1 most likely affects cyclin B ubiquitylation and destruction , rather than , for example , its translation . # ::alignments 0-1 1-1.1.1.1.2.1.1 2-1.1.1.2 4-1.1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.2.1.1 7-1.1.1.1 7-1.1.1.2 8-1.1.1.2.1.r 9-1.1.1.2.1 10-1.1.1.2.1.1.r 11-1.1.1.2.1.1.1.1 15-1.1.1.3.1 15-1.1.1.3.1.1.1 19-1.1.1.3.1.1 19-1.1.1.3.1.2.1 19-1.1.1.3.1.2.1.1 19-1.1.1.3.1.2.1.1.r 20-1.1.1.3.1.2 23-1.1 24-1.1.2 25-1.1.3.r 26-1.1.3.1.1.1.1 28-1.1.3.1 29-1.1.3 31-1.2.1 32-1.2.3.1 33-1.2.3 34-1.2 35-1.2.2.1.1.1.1 36-1.2.2.1.1.1.2 38-1.2.2 39-1.2.2.2 41-1.2.2.3 44-1.2.2.3.1.2 45-1.2.2.3.1.2 47-1.2.2.3.1.1 47-1.2.2.3.1.1.r 48-1.2.2.3.1 (c / cause-01~e.0 :ARG0 (r / rescue-01~e.23 :ARG0 (o / or~e.5 :op1 (i / inhibit-01~e.7 :ARG0 (p / protein :name (n / name :op1 "Mad2"~e.4)) :ARG1 (p9 / protein :name (n2 / name :op1 "APC"~e.1))) :op2 (i2 / inhibit-01~e.2,7 :ARG0~e.8 (a / add-02~e.9 :ARG1~e.10 (s / small-molecule :name (n4 / name :op1 "MG132"~e.11))) :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "proteasome"~e.6))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.15 :op1 (p4 / publication-91~e.19 :ARG0 (a3 / and~e.15 :op1 (p5 / person :name (n6 / name :op1 "J.D.R.R.")) :op2 (p6 / person :name (n7 / name :op1 "P.J.")))) :op2 (d3 / data~e.20 :ARG1-of (p7 / publish-01~e.19 :polarity~e.19 -~e.19))))) :ARG1 (m3 / mitosis~e.24) :condition~e.25 (e / extract-01~e.29 :ARG1-of (d / deplete-01~e.28 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "Emi1"~e.26))))) :ARG1 (a4 / affect-01~e.34 :ARG0 s2~e.31 :ARG1 (a5 / and~e.38 :op1 (u / ubiquitylate-00 :ARG1 (p8 / protein :name (n8 / name :op1 "cyclin"~e.35 :op2 "B"~e.36))) :op2 (d4 / destroy-01~e.39 :ARG1 p8) :ARG1-of (i3 / instead-of-91~e.41 :ARG2 (t / translate-02~e.48 :ARG1~e.47 p8~e.47 :ARG0-of (e2 / exemplify-01~e.44,45)))) :ARG1-of (l / likely-01~e.33 :degree (m4 / most~e.32)))) # ::id bio.chicago_2015.38154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vivo , we observed that overexpression of the cytoplasmic domain of plexin @-@ B1 inhibited the activation of PAK by Rac . # ::alignments 0-1.3 1-1.3 3-1.1 4-1 5-1.2.r 6-1.2.1 7-1.2.1.1.r 9-1.2.1.1.1 10-1.2.1.1 11-1.2.1.1.2.r 12-1.2.1.1.2.1.1 14-1.2.1.1.2.1.1 15-1.2 17-1.2.2 18-1.2.2.2.r 19-1.2.2.2.1.1 20-1.2.2.1.r 21-1.2.2.1.1.1 (o / observe-01~e.4 :ARG0 (w / we~e.3) :ARG1~e.5 (i2 / inhibit-01~e.15 :ARG0 (o2 / overexpress-01~e.6 :ARG1~e.7 (d / domain~e.10 :mod (c / cytoplasm~e.9) :part-of~e.11 (p / protein :name (n / name :op1 "plexin-B1"~e.12,14)))) :ARG1 (a / activate-01~e.17 :ARG0~e.20 (e2 / enzyme :name (n3 / name :op1 "Rac"~e.21)) :ARG1~e.18 (e / enzyme :name (n2 / name :op1 "PAK"~e.19)))) :manner (i / in-vivo~e.0,1)) # ::id bio.chicago_2015.38179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The transcriptional and genetic relationships we have identified between sens and ro imply that the process of R8 differentiation involves a hierarchical interaction where sens normally represses ro to prevent both ro repression of R8 and ro induction of R2/R5 . # ::alignments 1-1.1.1.2 2-1.1 3-1.1.2.2 4-1.1.1 4-1.1.2 5-1.1.3.1 7-1.1.3 9-1.1.1.1.1.1 11-1.1.1.3.1.1 12-1 13-1.2.r 15-1.2.1 16-1.2.1.1.r 17-1.2.1.1.1.1.1 18-1.2.1.1 19-1.2 22-1.2.2 24-1.2.2.2.1 25-1.2.2.2.3 26-1.2.2.2 27-1.2.2.2.2 29-1.2.2.2.4 31-1.1.1.3.1.1 32-1.2.2.2 32-1.2.2.2.4.2.1 34-1.2.1.1.1.1.1 35-1.2.2.2.4.2 36-1.2.2.2.4.2.2.1 37-1.2.2.2.4.2.2 (i / imply-01~e.12 :ARG0 (a / and~e.2 :op1 (r / relation-03~e.4 :ARG0 (p / protein :name (n / name :op1 "sens"~e.9)) :ARG1 (t / transcribe-01~e.1) :ARG2 (p2 / protein :name (n2 / name :op1 "ro"~e.11,31))) :op2 (r2 / relation-03~e.4 :ARG0 p :ARG1 (g / genetic~e.3) :ARG2 p2) :ARG1-of (i2 / identify-01~e.7 :ARG0 (w / we~e.5))) :ARG1~e.13 (i3 / involve-01~e.19 :ARG0 (p3 / process-02~e.15 :ARG1~e.16 (d / differentiate-01~e.18 :ARG1 (p4 / protein :name (n3 / name :op1 "R8"~e.17,34)))) :ARG1 (i4 / interact-01~e.22 :ARG2 (h / hierarchy) :time (r3 / repress-01~e.26,32 :ARG0 p~e.24 :ARG1 p2~e.27 :ARG1-of (n4 / normal-02~e.25) :purpose (p5 / prevent-01~e.29 :ARG0 p :ARG1 (a2 / and~e.35 :op1 (r4 / repress-01~e.32 :ARG0 p2 :ARG1 p4) :op2 (i5 / induce-01~e.37 :ARG0 p2~e.36 :ARG1 (s / slash :op1 (p6 / protein :name (n5 / name :op1 "R2")) :op2 (p7 / protein :name (n6 / name :op1 "R5")))))))))) # ::id bio.chicago_2015.38213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detection of bound probe employed anti @-@ digoxigenin Fab conjugated to alkaline phosphatase , which catalyzed the degradation of the chemiluminescent substrate CDP @-@ Star ( Tropix , Bedford , MA ) , following the protocol of Engler @-@ Blum et al. ( 26 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1 4-1 5-1.2.1.1 7-1.2.1.1 8-1.2.1.2 9-1.2.2 10-1.2.2.1.r 11-1.2.2.1.1.1 12-1.2.2.1.1.2 15-1.3 17-1.3.1 18-1.3.1.1.r 20-1.3.1.1.2 21-1.3.1.1 22-1.3.1.1.1.1 24-1.3.1.1.1.1 26-1.3.1.1.3.1.1 28-1.3.1.1.3.2.2.1.1 30-1.3.1.1.3.2.1.1.1 33-1.4 35-1.4.1 37-1.4.1.1.1.1.1.1.1.1 39-1.4.1.1.1.1.1.2.1.1 40-1.4.1.1.1 40-1.4.1.1.1.1.1 41-1.4.1.1.1.1.1.3.1 43-1.4.1.1.1.2.1.1 (e / employ-02~e.4 :ARG0 (d / detect-01~e.0 :ARG1~e.1 (p / probe~e.3 :ARG1-of (b / bind-01~e.2))) :ARG1 (p2 / protein :name (n / name :op1 "anti-digoxigenin"~e.5,7 :op2 "Fab"~e.8) :ARG1-of (c / conjugate-02~e.9 :ARG2~e.10 (e2 / enzyme :name (n2 / name :op1 "alkaline"~e.11 :op2 "phosphatase"~e.12)))) :ARG0-of (c2 / catalyze-01~e.15 :ARG1 (d2 / degrade-01~e.17 :ARG1~e.18 (s / substrate~e.21 :name (n3 / name :op1 "CDP-Star"~e.22,24) :mod (c3 / chemiluminescent~e.20) :source (c4 / company :name (n4 / name :op1 "Tropix"~e.26) :location (s2 / street-address-91 :ARG2 (s3 / state :name (n6 / name :op1 "MA"~e.30)) :ARG4 (c5 / city :name (n5 / name :op1 "Bedford"~e.28))))))) :ARG0-of (f / follow-02~e.33 :ARG1 (p8 / protocol~e.35 :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.40 :op1 (p3 / publication-91 :ARG0 (a / and~e.40 :op1 (p4 / person :name (n7 / name :op1 "Engler"~e.37)) :op2 (p5 / person :name (n8 / name :op1 "Blum"~e.39)) :op3 (p6 / person :mod (o / other~e.41)))) :op2 (p7 / publication :ARG1-of (c6 / cite-01 :ARG2 26~e.43))))))) # ::id bio.chicago_2015.38247 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ou group showed that Nedd8 acts genetically downstream of Hh signaling components Smoothened ( Smo ) and PKA to regulate Ci processing in cells anterior to the MF . # ::alignments 1-1.1.1.1 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2 7-1.2.3 8-1.2.2.2 10-1.2.2.1.3.1.1.1 11-1.2.2.1.3 13-1.2.2.1.1.1.1 17-1.2.2.1 18-1.2.2.1.2.1.1 20-1.2.4 21-1.2.4.2.1.1.1 22-1.2.4.2 23-1.2.4.2.2.r 24-1.2.4.2.2 25-1.2.4.2.3 26-1.2.4.2.3.1.r 28-1.2.4.2.3.1.1.1 (s / show-01~e.3 :ARG0 (g / group~e.2 :name (n / name :op1 "Ou"~e.1)) :ARG1~e.4 (a / act-02~e.6 :ARG0 (p / protein :name (n2 / name :op1 "Nedd8"~e.5)) :location (r / relative-position :op1 (a2 / and~e.17 :op1 (p3 / protein :name (n4 / name :op1 "Smoothened"~e.13)) :op2 (p4 / protein :name (n5 / name :op1 "PKA"~e.18)) :ARG0-of (s2 / signal-07~e.11 :ARG1 (p2 / protein :name (n3 / name :op1 "Hh"~e.10)))) :direction (d / downstream~e.8)) :mod (g2 / genetic~e.7) :purpose (r2 / regulate-01~e.20 :ARG0 p :ARG1 (p5 / process-01~e.22 :ARG1 (p6 / protein :name (n6 / name :op1 "Ci"~e.21)) :location~e.23 (c / cell~e.24) :time (a3 / anterior~e.25 :op1~e.26 (p7 / protein :name (n7 / name :op1 "MF"~e.28))))))) # ::id bio.chicago_2015.38248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Association of CIZ with Cas . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 4-1.2.1.1 (a / associate-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "CIZ"~e.2)) :ARG2~e.3 (p2 / protein :name (n2 / name :op1 "Cas"~e.4))) # ::id bio.chicago_2015.38266 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Repression activity of MM @-@ 1 toward c @-@ Myc was sensitive to TSA , a specific inhibitor of HDAC , indicating that HDAC is involved in the N @-@ terminal transrepression pathway of c @-@ Myc . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.3.r 7-1.1.3.1.1 9-1.1.3.1.1 11-1 12-1.2.r 13-1.2.1.1 16-1.2.3 17-1.2 17-1.2.2 17-1.2.2.r 18-1.2.2.1.r 19-1.2.2.1.1.1 21-1.3 22-1.3.1.r 23-1.3.1.1 25-1.3.1 26-1.3.1.2.r 28-1.3.1.2.1.1.1.1 30-1.3.1.2.1.1.1.1 32-1.3.1.2 33-1.3.1.2.2.r 34-1.3.1.2.2 35-1.3.1.2.2 36-1.3.1.2.2 (s / sensitive-03~e.11 :ARG0 (a / activity-06~e.1 :ARG0~e.2 (p / protein :name (n / name :op1 "MM-1"~e.3,5)) :ARG1 (r / repress-01~e.0) :direction~e.6 (p2 / protein :name (n2 / name :op1 "c-Myc"~e.7,9))) :ARG1~e.12 (s2 / small-molecule~e.17 :name (n3 / name :op1 "TSA"~e.13) :ARG0-of~e.17 (i / inhibit-01~e.17 :ARG1~e.18 (e / enzyme :name (n4 / name :op1 "HDAC"~e.19))) :ARG1-of (s3 / specific-02~e.16)) :ARG0-of (i2 / indicate-01~e.21 :ARG1~e.22 (i3 / involve-01~e.25 :ARG1 e~e.23 :ARG2~e.26 (p3 / pathway~e.32 :ARG0-of (t / transrepress-00 :ARG1 (p4 / protein-segment :name (n5 / name :op1 "N-terminus"~e.28,30))) :poss~e.33 p2~e.34,35,36)))) # ::id bio.chicago_2015.38278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were washed with phosphate @-@ buffered saline and fed with 3 ml of either phosphate @-@ free or methionine @-@ free Dulbecco 's modified Eagle 's medium containing 10 % dialyzed fetal bovine serum . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.2.1 6-1.1.2.2.1 7-1.1.2.2.2 8-1 9-1.2 10-1.2.1.r 11-1.2.1.1.3.1 12-1.2.1.1.3.2 13-1.2.1.1.3.r 15-1.2.1.1.4.1 17-1.2.1.1 17-1.2.1.1.4 17-1.2.1.1.4.r 17-1.2.1.2 17-1.2.1.2.4 17-1.2.1.2.4.r 18-1.2.1 19-1.2.1.2.4.1.2.1 21-1.2.1.1 21-1.2.1.1.4 21-1.2.1.1.4.r 21-1.2.1.2 21-1.2.1.2.4 21-1.2.1.2.4.r 22-1.2.1.1.2.1 22-1.2.1.2.2.1 23-1.2.1.1.2.1 23-1.2.1.1.2.3 23-1.2.1.2.2.1 23-1.2.1.2.2.3 24-1.2.1.1.2.2 24-1.2.1.2.2.2 25-1.2.1.1.2.3 25-1.2.1.2.2.3 26-1.2.1.1.2.1 26-1.2.1.1.2.3 26-1.2.1.2.2.1 26-1.2.1.2.2.3 27-1.2.1.1.2.4 27-1.2.1.2.2.4 28-1.2.1.1.5 29-1.2.1.1.5.1.3.1 30-1.2.1.1.5.1.3 31-1.2.1.1.5.1.2 32-1.2.1.1.5.1.1 33-1.2.1.1.5.1.1.1 34-1.2.1.1.5.1 (a / and~e.8 :op1 (w / wash-01~e.2 :ARG1 (c / cell~e.0) :ARG2~e.3 (s2 / small-molecule :wiki "Phosphate-buffered_saline" :name (n3 / name :op1 "phosphate-buffered"~e.4,6 :op2 "saline"~e.7))) :op2 (f / feed-01~e.9 :ARG1~e.10 (o / or~e.18 :op1 (t / thing~e.17,21 :wiki "Eagle's_minimal_essential_medium" :name (n / name :op1 "Dulbecco's"~e.22,23,26 :op2 "Modified"~e.24 :op3 "Eagle's"~e.23,25,26 :op4 "Medium"~e.27) :quant~e.13 (c2 / concentration-quantity :quant 3~e.11 :unit (m / milliliter~e.12)) :ARG1-of~e.17,21 (f2 / free-04~e.17,21 :ARG2 (p2 / phosphate~e.15)) :ARG0-of (c3 / contain-01~e.28 :ARG1 (s / serum~e.34 :source (f4 / fetus~e.32 :mod (b / bovine~e.33)) :ARG1-of (d2 / dialyze-00~e.31) :quant (p3 / percentage-entity~e.30 :value 10~e.29)))) :op2 (t2 / thing~e.17,21 :wiki "Eagle's_minimal_essential_medium" :name (n2 / name :op1 "Dulbecco's"~e.22,23,26 :op2 "Modified"~e.24 :op3 "Eagle's"~e.23,25,26 :op4 "Medium"~e.27) :quant c2 :ARG1-of~e.17,21 (f3 / free-04~e.17,21 :ARG2 (a2 / amino-acid :wiki "Methionine" :name (n4 / name :op1 "methionine"~e.19))) :ARG0-of c3)) :ARG2 c)) # ::id bio.chicago_2015.38344 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( a ) Plexin @-@ B1 interacts with Rac in a GTP @-@ dependent manner . # ::alignments 3-1.1.1.1 5-1.1.1.1 6-1 7-1.2.r 8-1.2.1.1 11-1.3.1.1.1 13-1.3 14-1.3.r (i / interact-01~e.6 :ARG0 (p / protein :name (n / name :op1 "Plexin-B1"~e.3,5)) :ARG1~e.7 (e / enzyme :name (n2 / name :op1 "Rac"~e.8)) :manner~e.14 (d / depend-01~e.13 :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP"~e.11))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "A"))) # ::id bio.chicago_2015.38348 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recovery of IKK was determined by immunoblotting ( IB ) . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1.1 4-1 5-1.1.r 6-1.1 (d / determine-01~e.4 :ARG0~e.5 (i / immunoblot-01~e.6) :ARG1 (r / recover-02~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "IKK"~e.2)))) # ::id bio.chicago_2015.38364 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sprouty , an intracellular inhibitor of Ras signaling . # ::alignments 0-1.1.1.1 3-1.1.2 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2 (i / inhibit-01~e.4 :ARG0 (p / protein :name (n / name :op1 "Sprouty"~e.0) :mod (i2 / intracellular~e.3)) :ARG1~e.5 (s / signal-07~e.7 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"~e.6)))) # ::id bio.chicago_2015.38368 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interaction of RGL with Ras Effector Loop Mutants # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.2.r 4-1.2.3.1.1 5-1.2.2 6-1.2 7-1.2.1 (i / interact-01~e.0 :ARG0~e.1 (p / protein :name (n / name :op1 "RGL"~e.2)) :ARG1~e.3 (l / loop~e.6 :ARG2-of (m / mutate-01~e.7) :mod (e / effector~e.5) :mod (p2 / protein-family :name (n2 / name :op1 "Ras"~e.4)))) # ::id bio.chicago_2015.38377 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Actin Binding Assay-- Actin binding of cultured cell TMs , caldesmon , and human fascin was assayed in the following four conditions . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.2 7-1.1.2.1 8-1.1.2.1.1.1 10-1.1.2.2.1.1 12-1.1.2 13-1.1.2.3.2 14-1.1.2.3.1.1 16-1 17-1.2.r 19-1.2.2 20-1.2.1 21-1.2 (a2 / assay-01~e.16 :ARG1 (b / bind-01~e.1,4 :ARG1 (p / protein :name (n / name :op1 "Actin"~e.0,3)) :ARG2~e.5 (a / and~e.12 :op1 (c2 / cell~e.7 :name (n2 / name :op1 "TMs"~e.8) :ARG1-of (c3 / culture-01~e.6)) :op2 (p2 / protein :name (n3 / name :op1 "caldesmon"~e.10)) :op3 (p3 / protein :name (n4 / name :op1 "fascin"~e.14) :mod (h / human~e.13)))) :manner~e.17 (c / condition~e.21 :quant 4~e.20 :ARG1-of (f / follow-04~e.19))) # ::id bio.chicago_2015.38397 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that CIZ binds Cas at focal adhesions , at least when they are formed . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2 6-1.2.2.1.1 7-1.2.3.r 7-1.2.4.2 8-1.2.3.1 9-1.2.3 11-1.2.4.2 12-1.2.4.2 13-1.2.4.r 14-1.2.4.1 16-1.2.4 (s / suggest-01~e.2 :ARG0 (t2 / thing~e.1 :mod (t / this~e.0) :ARG2-of~e.1 (r2 / result-01~e.1)) :ARG1~e.3 (b / bind-01~e.5 :ARG1 (p / protein :name (n / name :op1 "CIZ"~e.4)) :ARG2 (p2 / protein :name (n2 / name :op1 "Cas"~e.6)) :location~e.7 (a2 / adhere-01~e.9 :mod (f2 / focal~e.8)) :time~e.13 (f / form-01~e.16 :ARG1 a2~e.14 :mod (a / at-least~e.7,11,12)))) # ::id bio.chicago_2015.38411 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , when the full @-@ length Dlx3 protein was phosphorylated by PKC , a decreased DNA binding activity was observed . # ::alignments 0-1 2-1.1.2.r 4-1.1.2.1.2.1 6-1.1.2.1.2 7-1.1.2.1.1.1 8-1.1.2.1 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2.1.1 15-1.1.1.2 16-1.1.1.1.1.2.1 17-1.1.1.1 18-1.1.1 20-1.1 (h / have-concession-91~e.0 :ARG2 (o / observe-01~e.20 :ARG1 (a / activity-06~e.18 :ARG1 (b / bind-01~e.17 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"~e.16))) :ARG1-of (d / decrease-01~e.15)) :time~e.2 (p / phosphorylate-01~e.10 :ARG1 (p2 / protein~e.8 :name (n3 / name :op1 "Dlx3"~e.7) :ARG1-of (l / long-03~e.6 :ARG1-of (f / full-09~e.4))) :ARG2~e.11 (e / enzyme :name (n4 / name :op1 "PKC"~e.12))))) # ::id bio.chicago_2015.38447 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regardless of the extent of TRP binding to INAD in the InaD P215 mutant , however , the results of this study suggest that the presence of TRPL stabilizes the TRP channel and allows the latter to contribute to the photoreceptor response in InaD P215 , implying physical interactions between these two proteins . # ::alignments 0-1.1.3 3-1.1.3.1 6-1.1.3.1.1 8-1.1.2.2.2.2.2.1.1 8-1.1.3.1.1.2.1.1 11-1.1.2.2.2.2.2.1.1 11-1.1.3.1.1.2.1.1 12-1.1.2.2.2.2.2.2.1 13-1.1.2.2.2.2.2 13-1.1.2.2.2.2.2.2 13-1.1.2.2.2.2.2.2.r 15-1 18-1.1.1 18-1.1.1.1 18-1.1.1.1.r 19-1.1.1.1.1.r 20-1.1.1.1.1.1 21-1.1.1.1.1 22-1.1 23-1.1.2.r 25-1.1.2.1.1 26-1.1.2.1.1.1.r 27-1.1.2.1.1.1.1.1 28-1.1.2.1 30-1.1.2.1.2.1.1 31-1.1.2.1.2.1.2 32-1.1.2 33-1.1.2.2 37-1.1.2.2.2 40-1.1.2.2.2.2.1 41-1.1.2.2.2.2 43-1.1.2.2.2.2.2.1.1 44-1.1.2.2.2.2.2.2.1 46-1.1.2.3 47-1.1.2.3.1.3 48-1.1.2.3.1 50-1.1.1.1.1.1 52-1.1.2.2.2.1 (c / contrast-01~e.15 :ARG2 (s / suggest-01~e.22 :ARG0 (t / thing~e.18 :ARG2-of~e.18 (r3 / result-01~e.18 :ARG1~e.19 (s2 / study~e.21 :mod (t2 / this~e.20,50)))) :ARG1~e.23 (a / and~e.32 :op1 (s3 / stabilize-01~e.28 :ARG0 (p / present-02~e.25 :ARG1~e.26 (p2 / protein :name (n / name :op1 "TRPL"~e.27))) :ARG1 (p8 / protein :name (n5 / name :op1 "TRP"~e.30 :op2 "channel"~e.31))) :op2 (a2 / allow-01~e.33 :ARG0 p2 :ARG1 (c2 / contribute-01~e.37 :ARG0 (p5 / protein~e.52) :ARG2 (r2 / respond-01~e.41 :ARG0 (p3 / photoreceptor~e.40) :location (p4 / protein~e.13 :name (n3 / name :op1 "INAD"~e.8,11,43) :ARG2-of~e.13 (m / mutate-01~e.13 :value "P215"~e.12,44))))) :ARG0-of (i / imply-01~e.46 :ARG1 (i2 / interact-01~e.48 :ARG1 p2 :ARG2 p5 :manner (p6 / physical~e.47)))) :ARG1-of (r / regardless-91~e.0 :ARG2 (e / extent~e.3 :degree-of (b / bind-01~e.6 :ARG1 p5 :ARG2 (p7 / protein :name (n4 / name :op1 "INAD"~e.8,11)) :location p4))))) # ::id bio.chicago_2015.38490 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We investigated the association of CIZ with Cas by overexpressing CIZ @-@ FLAG and Cas in COS @-@ 7 cells . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1.1 6-1.2.2.r 7-1.2.2.1.1 8-1.3.r 9-1.3 10-1.3.1.1.1.1 12-1.3.1.1.1.1 13-1.3.1 14-1.3.1.2 15-1.3.2.r 16-1.3.2.1.1 18-1.3.2.1.1 19-1.3.2 (i / investigate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / associate-01~e.3 :ARG1~e.4 (p / protein :name (n / name :op1 "CIZ"~e.5)) :ARG2~e.6 (p2 / protein :name (n2 / name :op1 "Cas"~e.7))) :manner~e.8 (o / overexpress-01~e.9 :ARG1 (a2 / and~e.13 :op1 (p3 / protein :name (n3 / name :op1 "CIZ-FLAG"~e.10,12)) :op2 p2~e.14) :location~e.15 (c / cell-line~e.19 :name (n4 / name :op1 "COS-7"~e.16,18)))) # ::id bio.chicago_2015.38505 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sexual orientation in Drosophila is altered by the satori mutation in the sex @-@ determination gene fruitless that encodes a zinc finger protein with a BTB domain . # ::alignments 0-1.2.2 1-1.2 2-1.2.1.r 3-1.2.1.1.1 5-1 6-1.1.r 8-1.1.2 9-1.1 10-1.1.1.r 12-1.1.1.2.1 14-1.1.1.2 15-1.1.1 16-1.1.1.1.1 18-1.1.1.3 20-1.1.1.3.1.1.1 21-1.1.1.3.1.1.2 22-1.1.1.3.1 22-1.1.1.3.1.2 22-1.1.1.3.1.2.r 25-1.1.1.3.1.2.1.1 26-1.1.1.3.1.2.1.2 (a / alter-01~e.5 :ARG0~e.6 (m / mutate-01~e.9 :ARG1~e.10 (g2 / gene~e.15 :name (n3 / name :op1 "fruitless"~e.16) :ARG0-of (d / determine-01~e.14 :ARG1 (s4 / sex~e.12)) :ARG0-of (e / encode-01~e.18 :ARG1 (p3 / protein~e.22 :name (n4 / name :op1 "zinc"~e.20 :op2 "finger"~e.21) :part~e.22 (p4 / protein-segment~e.22 :name (n5 / name :op1 "BTB"~e.25 :op2 "domain"~e.26))))) :ARG2 (s3 / satori~e.8)) :ARG1 (o / orient-01~e.1 :ARG1~e.2 (o2 / organism :name (n / name :op1 "Drosophila"~e.3)) :ARG3 (s / sex~e.0))) # ::id bio.chicago_2015.38519 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of HeLa cells with leptomycin B ( LMB ) , a specific inhibitor of the NES @-@ dependent transport , resulted in nuclear accumulation of cyclin B1 in G2 phase . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1 6-1.1.2.1.2 12-1.1.2.2.2 13-1.1.2 13-1.1.2.2 13-1.1.2.2.r 14-1.1.2.2.1.r 16-1.1.2.2.1.1.1.1.1 18-1.1.2.2.1.1 19-1.1.2.2.1 21-1 22-1.2.r 23-1.2.2 24-1.2 25-1.2.1.r 26-1.2.1.1.1 27-1.2.1.1.2 29-1.2.1.2.1.2 30-1.2.1.2.1.1 (r / result-01~e.21 :ARG1 (t2 / treat-04~e.0 :ARG1~e.1 (c / cell-line~e.3 :name (n / name :op1 "hela"~e.2)) :ARG2 (s2 / small-molecule~e.13 :name (n6 / name :op1 "leptomicin" :op2 "B"~e.6) :ARG0-of~e.13 (i / inhibit-01~e.13 :ARG1~e.14 (t3 / transport-01~e.19 :ARG0-of (d / depend-01~e.18 :ARG1 (p4 / protein-segment :name (n2 / name :op1 "NES"~e.16)))) :ARG1-of (s / specific-02~e.12)))) :ARG2~e.22 (a / accumulate-01~e.24 :ARG1~e.25 (p / protein :name (n4 / name :op1 "cyclin"~e.26 :op2 "B1"~e.27) :mod (e / event :name (n7 / name :op1 "phase"~e.30 :op2 "G2"~e.29))) :mod (n3 / nucleus~e.23))) # ::id bio.chicago_2015.38552 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Raf/ MEK/ ERK Signaling Pathway Is Involved in the CrkL @-@ enhanced Activation of Elk @-@ 1-- To define the downstream signal transduction pathway leading to the Elk @-@ 1 activation , we next examined the possible involvement of the Raf/ MEK/ ERK cascade . # ::alignments 3-1.1.1.1.1 4-1.1.1.2 5-1.1.1 7-1.1 8-1.1.2.r 10-1.1.2.2.1.1.1 12-1.1.2.2 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 19-1.2.4 21-1.2.4.2.2.1.1 22-1.2.4.2.2.1 23-1.2.4.2.2 24-1.2.4.2 25-1.2.4.2.1 26-1.2.4.2.1.1.r 28-1.2.4.2.1.1.1.1.1 30-1.2.4.2.1.1.1.1.1 31-1.2.4.2.1.1 33-1.2.1 34-1.2.3 35-1.2 37-1.2.2.2 38-1.2.2 43-1.2.2.1.1.1.1 44-1.2.2.1 (m / multi-sentence :snt1 (i / involve-01~e.7 :ARG1 (p2 / pathway~e.5 :name (n2 / name :op1 "Raf/MEK/ERK"~e.3) :ARG0-of (s / signal-07~e.4)) :ARG2~e.8 (a / activate-01~e.13 :ARG1~e.14 (p / protein :name (n / name :op1 "Elk-1"~e.15)) :ARG1-of (e / enhance-01~e.12 :ARG0 (p3 / protein :name (n3 / name :op1 "CrkL"~e.10))))) :snt2 (e2 / examine-01~e.35 :ARG0 (w / we~e.33) :ARG1 (i2 / involve-01~e.38 :ARG1 (c / cascade-01~e.44 :ARG1 (p4 / pathway :name (n4 / name :op1 "Raf/MEK/ERK"~e.43))) :ARG1-of (p5 / possible-01~e.37)) :time (n5 / next~e.34) :purpose (d / define-01~e.19 :ARG0 w :ARG1 (p9 / pathway~e.24 :ARG0-of (l / lead-01~e.25 :ARG4~e.26 (a2 / activate-01~e.31 :ARG1 (p10 / protein :name (n9 / name :op1 "Elk-1"~e.28,30)))) :ARG2-of (t / transduce-01~e.23 :ARG1 (s3 / signal-07~e.22 :direction (d2 / downstream~e.21))))))) # ::id bio.chicago_2015.38555 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We show that precocious induction of Hoxb1 and Hoxb2 by RA is operational at E6.0 already , before primitive streak formation and long before the gene is transcriptionally initiated . # ::alignments 0-1.1 1-1 3-1.2.1.1.3 4-1.2.1.1 5-1.2.1.1.2.r 6-1.2.1.1.2.1.1.1 7-1.2.1.1.2 8-1.2.1.1.2.2.1.1 9-1.2.1.1.1.r 10-1.2.1.1.1.1.1 12-1.2.1 15-1.2.1.3 17-1.2.1.2.1 18-1.2.1.2.1.1.1.1 19-1.2.1.2.1.1.1 20-1.2.1.2.1.1 21-1.2.1.2 22-1.2.1.2.2.2 23-1.2.1.2.2 25-1.2.1.2.2.1.1 27-1.2.1.2.2.1.2 28-1.2.1.2.2.1 (s / show-01~e.1 :ARG0 (w / we~e.0) :ARG1 (p4 / possible-01 :ARG1 (o2 / operate-01~e.12 :ARG0 (i / induce-01~e.4 :ARG0~e.9 (s3 / small-molecule :name (n3 / name :op1 "RA"~e.10)) :ARG1~e.5 (a / and~e.7 :op1 (p2 / protein :name (n / name :op1 "Hoxb1"~e.6)) :op2 (p3 / protein :name (n2 / name :op1 "Hoxb2"~e.8))) :mod (p / precocious~e.3)) :time (a3 / and~e.21 :op1 (b / before~e.17 :op1 (f / form-01~e.20 :ARG1 (s2 / streak~e.19 :mod (p5 / primitive~e.18)))) :op2 (b2 / before~e.23 :op1 (i2 / initiate-01~e.28 :ARG1 (g / gene~e.25) :manner (t / transcribe-01~e.27)) :ARG1-of (l / long-03~e.22))) :time (a2 / already~e.15) :time (a4 / age-01 :ARG1 (e / embryo) :ARG2 (t2 / temporal-quantity :quant 6 :unit (d / day)))))) # ::id bio.chicago_2015.38557 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because half @-@ maximal binding of syntaxin 1A to the C2A domain of synaptotagmin 1 occurs at calcium levels required for vesicle fusion ( 200 muM calcium ) ( Heidelberger et al. , 1994 ) , this interaction may be particularly important for regulating neurotransmitter release by providing a direct means for calcium to regulate vesicle @-@ plasma membrane fusion . # ::alignments 0-1 1-1.1.3.1 3-1.1.3 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.1.2.r 10-1.1.2.1.1 13-1.1.2.2.1.1 14-1.1.2.2.1.2 16-1.1.4.r 17-1.1.4.3.1 18-1.1.4 19-1.1.4.1 21-1.1.4.1.1.1 22-1.1.4.1.1 22-1.2.1.3.3.4.2 24-1.1.4.3.1.1 26-1.1.4.3.1 29-1.1.5.1.1.1.1 30-1.1.5.1 31-1.1.5.1.2.1 33-1.1.5.2.1 36-1.2.1.1.1 37-1.2.1.1 38-1.2 39-1.2.1.1.r 40-1.2.1.2 40-1.2.1.2.r 41-1.2.1 42-1.2.1.3.r 43-1.2.1.3 44-1.2.1.3.2.1 45-1.2.1.3.2 46-1.2.1.3.3.r 47-1.2.1.3.3 49-1.2.1.3.3.2.1 50-1.1.4.3 50-1.2.1.3.3.2 51-1.2.1.3.3.3.r 52-1.2.1.3.3.3 54-1.2.1.3.3.4 55-1.2.1.3.3.4.2.1 57-1.2.1.3.3.4.2.2.1 58-1.2.1.3.3.4.2.2 59-1.2.1.3.3.4.2 (c4 / cause-01~e.0 :ARG0 (b / bind-01~e.4 :ARG1~e.5 (p9 / protein :name (n6 / name :op1 "syntaxin"~e.6 :op2 "A1")) :ARG2~e.8 (p5 / protein-segment :name (n4 / name :op1 "C2A"~e.10) :part-of (p7 / protein :name (n2 / name :op1 "synaptotagmin"~e.13 :op2 1~e.14))) :mod (m2 / maximal~e.3 :degree (h2 / half~e.1)) :condition~e.16 (l / level~e.18 :ARG1-of (r4 / require-01~e.19 :ARG0 (f2 / fuse-01~e.22 :ARG1 v~e.21)) :quant-of c :ARG1-of (m3 / mean-01~e.50 :ARG2 (c3 / calcium~e.17,26 :quant 200~e.24 :unit (m6 / millimolar)))) :ARG1-of (d4 / describe-01 :ARG0 (a / and~e.30 :op1 (p6 / person :name (n3 / name :op1 "Heidelberger"~e.29)) :op2 (p8 / person :mod (o / other~e.31))) :time (d / date-entity :year 1994~e.33))) :ARG1 (p / possible-01~e.38 :ARG1 (i / important~e.41 :domain~e.39 (i2 / interact-01~e.37 :mod (t / this~e.36)) :manner~e.40 (p2 / particular~e.40) :topic~e.42 (r / regulate-01~e.43 :ARG0 i2 :ARG1 (r2 / release-01~e.45 :ARG1 (n / neurotransmitter~e.44)) :manner~e.46 (p3 / provide-01~e.47 :ARG0 i2 :ARG1 (m / mean~e.50 :ARG1-of (d3 / direct-01~e.49)) :ARG2~e.51 (c / calcium~e.52) :purpose (r3 / regulate-01~e.54 :ARG0 c :ARG1 (f / fuse-01~e.22,59 :ARG1 (v / vesicle~e.55) :ARG2 (m5 / membrane~e.58 :mod (p4 / plasma~e.57))))))))) # ::id bio.chicago_2015.38559 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Second , DRB potently inhibits phosphorylation of the CTD by P @-@ TEFb , and DRB inhibition of P @-@ TEFb kinase correlates well with DRB @-@ induced inhibition of elongation by RNA polymerase II . # ::alignments 0-1.3 0-1.3.1 0-1.3.1.r 2-1.1.1.1.1 3-1.1.3 3-1.1.3.r 4-1.1 5-1.1.2 10-1.1.2 10-1.1.2.2.1.1 12-1.1.2.2.1.1 15-1.1.1.1.1 16-1.1 16-1.2.1 18-1.1.2 18-1.1.2.2.1.1 20-1.1.2.2.1.1 21-1.1.2.2 22-1.2 23-1.2.3 24-1.2.2.r 25-1.2.2.2.1 27-1.2.2.2 28-1.2.2 29-1.2.2.1.r 30-1.2.2.1 31-1.2.2.1.1.r 32-1.2.2.1.1.1.1 33-1.2.2.1.1.2.1.1.1 34-1.2.2.1.1.2.1.1.2 (a / and :op1 (i / inhibit-01~e.4,16 :ARG0 (s / small-molecule :name (n / name :op1 "DRB"~e.2,15)) :ARG1 (p3 / phosphorylate-01~e.5,10,18 :ARG1 (p / protein-segment :name (n2 / name :op1 "C-terminus")) :ARG2 (k / kinase~e.21 :name (n3 / name :op1 "P-TEFb"~e.10,12,18,20))) :manner~e.3 (p2 / potent~e.3)) :op2 (c / correlate-01~e.22 :ARG1 (i2 / inhibit-01~e.16 :ARG0 s :ARG1 k) :ARG2~e.24 (i3 / inhibit-01~e.28 :ARG1~e.29 (e2 / elongate-01~e.30 :ARG0~e.31 (n4 / nucleic-acid :name (n6 / name :op1 "RNA"~e.32) :ARG0-of (e3 / encode-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "polymerase"~e.33 :op2 "II"~e.34))))) :ARG2-of (i4 / induce-01~e.27 :ARG0 s~e.25)) :ARG1-of (w / well-09~e.23)) :mod (o / ordinal-entity~e.0 :value~e.0 2~e.0)) # ::id bio.chicago_2015.38566 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NIK can interact in vivo with MEKK1 . # ::alignments 0-1.1.1.1.1 1-1 2-1.1 3-1.1.3 4-1.1.3 5-1.1.2.r 6-1.1.2.1.1 (p / possible-01~e.1 :ARG1 (i / interact-01~e.2 :ARG0 (e2 / enzyme :name (n / name :op1 "NIK"~e.0)) :ARG1~e.5 (e / enzyme :name (n2 / name :op1 "MEKK1"~e.6)) :manner (i2 / in-vivo~e.3,4))) # ::id bio.chicago_2015.38569 ::amr-annotator SDL-AMR-09 ::preferred # ::tok P120 ctn is colocalized with Vav2 within growth cones and a subset of dendritic spines # ::alignments 3-1 4-1.1.r 5-1.1.2.1.1 7-1.2.1.1 8-1.2.1 9-1.2 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1 14-1.2.2.1 (c / colocalize-01~e.3 :ARG1~e.4 (a2 / and :op1 (p / protein :name (n / name :op1 "P120ctn")) :op2 (p2 / protein :name (n2 / name :op1 "Vav2"~e.5))) :ARG2 (a / and~e.9 :op1 (c2 / cone~e.8 :mod (g / grow-01~e.7)) :op2 (s / subset~e.11 :mod~e.12 (s2 / spine~e.14 :mod (d / dendrite~e.13))))) # ::id bio.chicago_2015.38579 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the present study , we have shown that TFIIB interacts with the AHR at a site ( the region bordered by amino acids 81 and 183 ) that lies slightly adjacent to its ARNT dimerization motif as well as interacting with its carboxyl terminus . # ::alignments 2-1.3.1 3-1.3 5-1.1 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2 13-1.2.2.1.1.1 16-1.2.3 19-1.2.3.1.1 20-1.2.3.1.1.1 21-1.2.3.1.1.1.1.r 22-1.2.3.1.1.1.1.1 23-1.2.3.1.1.1.1.1 23-1.2.3.1.1.1.1.2 24-1.2.3.1.1.1.1.1.1 25-1.2.3.1.1.1.1 26-1.2.3.1.1.1.1.2.1 30-1.2.3.2.1.2.1 31-1.2.3.2.1.2 33-1.2.3.2.1.1.2 33-1.2.3.2.1.1.2.r 34-1.2.3.2.1.1.1.1.1.1 35-1.2.3.2.1.1.1 36-1.2.3.2.1.1 37-1.2.2 38-1.2.2 39-1.2.2 40-1.2 41-1.2.2.r 42-1.2.2.2.2 42-1.2.2.2.2.r 43-1.2.2.2.1.1 44-1.2.2.2.1.2 (s / show-01~e.7 :ARG0 (w / we~e.5) :ARG1~e.8 (i / interact-01~e.10,40 :ARG0 (p3 / protein :name (n / name :op1 "TFIIB"~e.9)) :ARG1~e.41 (a5 / and~e.37,38,39 :op1 (p / protein :name (n2 / name :op1 "AHR"~e.13)) :op2 (p4 / protein-segment :name (n4 / name :op1 "carboxyl"~e.43 :op2 "terminus"~e.44) :part-of~e.42 p3~e.42)) :location (s2 / site~e.16 :ARG1-of (m2 / mean-01 :ARG2 (r / region~e.19 :ARG2-of (b / border-01~e.20 :ARG1~e.21 (a / and~e.25 :op1 (a2 / amino-acid~e.22,23 :mod 81~e.24) :op2 (a3 / amino-acid~e.23 :mod 183~e.26))))) :ARG1-of (l / lay-01 :ARG2 (r2 / relative-position :op1 (m3 / motif~e.36 :ARG0-of (d / dimerize-01~e.35 :ARG1 (p5 / protein :name (n3 / name :op1 "ARNT"~e.34))) :part-of~e.33 p3~e.33) :mod (a4 / adjacent~e.31 :degree (s3 / slight~e.30)))))) :medium (s4 / study-01~e.3 :mod (p2 / present~e.2))) # ::id bio.chicago_2015.38598 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whereas removal of Ci activity from clones of cells was shown to result in the loss of expression of some Hh target genes , notably ptc ( Dominguez et al. 1996 ) , consistent with Hh activation of ptc transcription being mediated by Ci ( Alexandre et al. 1996 ) , other Hh targets , such as dpp , were found to be activated in the absence of Ci , albeit at a lower level than in their normal domain close to the compartment border . # ::alignments 0-1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.2.r 6-1.1.1.2 7-1.1.1.2.1.r 8-1.1.1.2.1 10-1.1 12-1.1.2 13-1.1.2.1.r 15-1.1.2.1 16-1.1.2.1.1.r 17-1.1.2.1.1 18-1.1.2.1.1.1.r 19-1.1.2.1.1.1.1 20-1.1.2.1.1.1.2.1.1.1 21-1.1.2.1.1.1.2 21-1.2.1.4 22-1.1.2.1.1.1 22-1.2.1 24-1.1.2.1.1.1.3 25-1.1.2.1.1.1.3.1.1.1 27-1.1.3.1.1.1.1 28-1.1.3.1 29-1.2.1.1 30-1.1.3.1.3.1 33-1.1.2.1.1.1.3.1 33-1.1.2.1.1.1.3.1.2 33-1.1.2.1.1.1.3.1.2.r 34-1.1.2.1.1.1.3.1.2.1.r 35-1.1.2.1.1.1.3.1.2.1.1 36-1.1.2.1.1.1.3.1.2.1 38-1.1.2.1.1.1.3.1.1.1 39-1.1.2.1.1.1.3.1.2.1.2 41-1.1.2.1.1.1.3.1.2.1.2.2 42-1.1.2.1.1.1.3.1.2.1.2.2.1.r 43-1.1.2.1.1.1.3.1.2.1.2.2.1 45-1.1.2.1.1.1.3.1.2.2.1.1.1.1 46-1.1.2.1.1.1.3.1.2.2.1 46-1.1.3.1 47-1.1.2.1.1.1.3.1.2.2.1.2.1 48-1.1.3.1.3.1 51-1.1.2.1.1.1.3.1.2.2.1.2.1 52-1.1.2.1.1.1.2.1.1.1 53-1.1.2.1.1.1.2 55-1.2.1.2.r 56-1.1.3.1.3.r 57-1.2.1.2.1.1 60-1.2 63-1.2.1.3 63-1.2.1.3.2 63-1.2.1.3.2.r 64-1.2.1.3.1.r 66-1.2.1.3.1 67-1.2.1.3.1.1.r 68-1.2.1.3.1.1 71-1.2.1.3.2.2.r 73-1.2.1.3.2.2.1 73-1.2.1.3.2.2.1.1 73-1.2.1.3.2.2.1.1.r 74-1.2.1.3.2.2 75-1.2.1.3.2.2.2.r 77-1.2.1.3.2.2.2.2 77-1.2.1.3.2.2.2.2.r 78-1.2.1.3.2.2.2.1 79-1.2.1.3.2.2.2 80-1.2.1.3.2.2.3 83-1.2.1.3.2.2.3.1.1 84-1.2.1.3.2.2.3.1 (c / contrast-01~e.0 :ARG1 (s / show-01~e.10 :ARG1 (r / remove-01~e.1 :ARG1~e.2 (a / activity-06~e.4 :ARG0 (p3 / protein :name (n / name :op1 "Ci"~e.3))) :ARG2~e.5 (c2 / clone-01~e.6 :ARG1~e.7 (c3 / cell~e.8))) :ARG1-of (r2 / result-01~e.12 :ARG2~e.13 (l / lose-02~e.15 :ARG1~e.16 (e / express-03~e.17 :ARG1~e.18 (g / gene~e.22 :mod (s2 / some~e.19) :ARG1-of (t / target-01~e.21,53 :ARG0 (p5 / protein :name (n3 / name :op1 "Hh"~e.20,52))) :ARG2-of (n8 / notable-04~e.24 :ARG1 (g4 / gene~e.33 :name (n9 / name :op1 "ptc"~e.25,38) :ARG1-of~e.33 (c4 / consistent-01~e.33 :ARG2~e.34 (a4 / activate-01~e.36 :ARG0 p5~e.35 :ARG1 (t2 / transcribe-01~e.39 :ARG1 g4 :ARG1-of (m3 / mediate-01~e.41 :ARG0~e.42 p3~e.43))) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and~e.46 :op1 (p / person :name (n4 / name :op1 "Alexandre"~e.45)) :op2 (p4 / person :mod (o2 / other~e.47,51)) :time d))))))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.28,46 :op1 (p2 / person :name (n7 / name :op1 "Dominguez"~e.27)) :op2 p4 :time~e.56 (d / date-entity :year 1996~e.30,48)))) :ARG2 (f / find-01~e.60 :ARG1 (g2 / gene~e.22 :mod (o / other~e.29) :example~e.55 (g3 / gene :name (n5 / name :op1 "dpp"~e.57)) :ARG1-of (a7 / activate-01~e.63 :condition~e.64 (a8 / absent-01~e.66 :ARG1~e.67 p3~e.68) :concession~e.63 (a3 / activate-01~e.63 :ARG1 g2 :degree~e.71 (l3 / level~e.74 :ARG1-of (l4 / low-04~e.73 :degree~e.73 (m4 / more~e.73)) :compared-to~e.75 (d5 / domain~e.79 :ARG1-of (n6 / normal-02~e.78) :part-of~e.77 p3~e.77) :location (c5 / close-06~e.80 :ARG2 (b / border-01~e.84 :ARG2 (c6 / compartment~e.83)))))) :ARG1-of (t3 / target-01~e.21 :ARG0 p5)))) # ::id bio.chicago_2015.38602 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mutation in the APPKPPR sequence ( mPR ) abolished the binding of CIZ to Cas SH3 ( Fig . 3B , lanes 1 , 2 ) , strongly suggesting that this sequence was the binding site for Cas SH3 . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.1.1 5-1.1.1 9-1 11-1.2 13-1.2.1.1.1 15-1.2.2.2.1.1 16-1.2.2.1.1 18-1.2.2.3.1.1 20-1.2.2.3.1.1.1 22-1.2.2.3.1.2 22-1.2.2.3.1.3 23-1.2.2.3.1.2.1 25-1.2.2.3.1.3.1 28-1.3.2 29-1.3 31-1.1.1.2 32-1.1.1 33-1.3.1.2.r 35-1.2 35-1.3.1.1 36-1.3.1 38-1.2.2.2.1.1 39-1.2.2.1.1 (a / abolish-01~e.9 :ARG0 (m / mutate-01~e.1 :ARG1~e.2 (d / dna-sequence~e.5,32 :name (n / name :op1 "APPKPPR"~e.4) :mod (t / this~e.31))) :ARG1 (b / bind-01~e.11,35 :ARG1 (p / protein :name (n2 / name :op1 "CIZ"~e.13)) :ARG2 (p4 / protein-segment :name (n4 / name :op1 "SH3"~e.16,39) :part-of (p3 / protein :name (n3 / name :op1 "Cas"~e.15,38)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.18 :mod "3B"~e.20) :op2 (l / lane~e.22 :mod 1~e.23) :op3 (l2 / lane~e.22 :mod 2~e.25))))) :ARG0-of (s / suggest-01~e.29 :ARG1 (s3 / site~e.36 :ARG1-of (b2 / bind-01~e.35 :ARG2 p4) :domain~e.33 d) :ARG1-of (s2 / strong-02~e.28))) # ::id bio.chicago_2015.38616 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The conclusion that spen is partially required for Wg @-@ dependent bristle inhibition is complicated by the fact that loss of spen causes an increase in Ac expression in wild @-@ type eyes as well ( Fig. 3E , F ) . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.2.1.1 5-1.2.1.3 5-1.2.1.3.r 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.2.1.1.1 10-1.2.1.1.2 11-1.2.1.1.1 12-1.2.1.1 14-1 15-1.1.r 17-1.1 19-1.1.1.1 20-1.1.1.1.1.r 21-1.1.1.1.1 22-1.1.1 24-1.1.1.2 25-1.1.1.2.1.r 26-1.1.1.2.1.1.1.1 27-1.1.1.2.1 28-1.1.1.2.1.2.r 29-1.1.1.2.1.2.1 31-1.1.1.2.1.2.1 32-1.1.1.2.1.2 33-1.1.1.3 34-1.1.1.3 36-1.3.1.1 36-1.3.1.2 37-1.3.1.1.1 (c / complicate-01~e.14 :ARG0~e.15 (f / fact~e.17 :mod (c3 / cause-01~e.22 :ARG0 (l / lose-02~e.19 :ARG1~e.20 p2~e.21) :ARG1 (i2 / increase-01~e.24 :ARG1~e.25 (e / express-03~e.27 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ac"~e.26)) :ARG3~e.28 (e2 / eye~e.32 :mod (w / wild-type~e.29,31)))) :mod (a / as-well~e.33,34))) :ARG1 (c2 / conclude-01~e.1 :ARG1~e.2 (r / require-01~e.6 :ARG0~e.7 (i / inhibit-01~e.12 :ARG1 (b / bristle-01~e.11) :ARG0-of (d / depend-01~e.10 :ARG1 (p3 / protein :name (n / name :op1 "Wg"~e.8)))) :ARG1 (p2 / protein :name (n3 / name :op1 "spen"~e.3)) :degree~e.5 (p / part~e.5))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure~e.36 :mod "3E"~e.37) :op2 (f3 / figure~e.36 :mod "3F")))) # ::id bio.chicago_2015.38618 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings indicate that DTRAF1 activates JNK , but -- in contrast to the activation of JNK by mammalian TRAFs 2 , 5 and 6 -- this activation does not require either the Ring @-@ finger or zinc @-@ finger domains [ 10,11 ] . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.2.2 5-1.2.2.4.1 6-1.2.2.4.1.2 8-1.2.2.4 11-1.2 11-1.2.2.4 14-1.2.1 14-1.2.2.4.1 16-1.2.2.4.1.2 17-1.2.2.4.1.1.r 18-1.2.2.4.1.1.4 23-1.2.2.4.1.1 23-1.3.1.1.1 26-1.1.2 27-1.2.2.2 29-1.2.2.1 29-1.2.2.1.r 30-1.2.2 31-1.2.2.5 33-1.2.2.3.1.1.1 35-1.2.2.3.1.1.1 35-1.2.2.3.2.1.1 36-1.2.2.3 37-1.2.2.3.2.1.1 39-1.2.2.3.1.1.1 39-1.2.2.3.2.1.1 40-1.2.2.3.1.1.2 40-1.2.2.3.2.1.2 (i / indicate-01~e.2 :ARG0 (t2 / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :mod (t / this~e.0,26)) :ARG1~e.3 (c / contrast-01~e.11 :ARG1 (a / activate-01~e.14 :ARG0 (p3 / protein :name (n / name :op1 "DTRAF1")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "JNK"))) :ARG2 (r / require-01~e.30 :polarity~e.29 -~e.29 :ARG0 a~e.4,27 :ARG1 (o / or~e.36 :op1 (p4 / protein-segment :name (n4 / name :op1 "ring-finger"~e.33,35,39 :op2 "domain"~e.40)) :op2 (p5 / protein-segment :name (n5 / name :op1 "zinc-finger"~e.35,37,39 :op2 "domain"~e.40))) :ARG1-of (c2 / contrast-01~e.8,11 :ARG2 (a2 / activate-01~e.5,14 :ARG0~e.17 (a4 / and~e.23 :op1 (p / protein :name (n3 / name :op1 "TRAF2")) :op2 (p6 / protein :name (n6 / name :op1 "TRAF5")) :op3 (p7 / protein :name (n7 / name :op1 "TRAF6")) :mod (m / mammal~e.18)) :ARG1 e2~e.6,16)) :mod (e / either~e.31))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and~e.23 :op1 10 :op2 11))))) # ::id bio.chicago_2015.38621 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If the binding of c @-@ Myb to S2 is important for silencer function , we could predict that the site @-@ specific mutation of the c @-@ Myb recognition site in S2 in the appropriate context would lead to abrogation of silencer function . # ::alignments 0-1 2-1.2.1 3-1.2.1.1.r 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1.2.r 8-1.2.1.2.1.1 9-1.2.1.r 10-1.2 11-1.2.2.r 12-1.2.2.1 13-1.2.2 15-1.1.1.1 16-1.1 17-1.1.1 18-1.1.1.2.r 20-1.1.1.2.1.2.1 22-1.1.1.2.1.2 23-1.1.1.2.1 24-1.1.1.2.1.1.r 26-1.1.1.2.1.1.1.1 27-1.1.1.2.1.1.1.1 28-1.1.1.2.1.1.1.1 29-1.1.1.2.1.1.1 30-1.1.1.2.1.1 31-1.1.1.2.1.1.1.2.r 32-1.1.1.2.1.1.1.2 33-1.1.1.2.1.1.1.3.r 35-1.1.1.2.1.1.1.3.1 36-1.1.1.2.1.1.1.3 38-1.1.1.2 39-1.1.1.2.2.r 40-1.1.1.2.2 41-1.1.1.2.2.1.r 42-1.1.1.2.2.1 43-1.1.1.2.2.1 (h / have-condition-91~e.0 :ARG1 (p4 / possible-01~e.16 :ARG1 (p3 / predict-01~e.17 :ARG0 (w / we~e.15) :ARG1~e.18 (l / lead-03~e.38 :ARG0 (m / mutate-01~e.23 :ARG1~e.24 (s4 / site~e.30 :ARG0-of (r / recognize-02~e.29 :ARG1 p~e.26,27,28 :location~e.31 p2~e.32 :location~e.33 (c / context~e.36 :ARG1-of (a / appropriate-02~e.35)))) :ARG1-of (s2 / specific-02~e.22 :ARG2 (s3 / site~e.20))) :ARG2~e.39 (a2 / abrogate-01~e.40 :ARG1~e.41 f~e.42,43)))) :ARG2 (i / important~e.10 :domain~e.9 (b / bind-01~e.2 :ARG1~e.3 (p / protein :name (n / name :op1 "c-Myb"~e.4,6)) :ARG2~e.7 (p2 / protein :name (n2 / name :op1 "S2"~e.8))) :purpose~e.11 (f / function-01~e.13 :ARG0 (s / silencer~e.12)))) # ::id bio.chicago_2015.38629 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mammalian isopeptidase T , similar in its functional properties to yeast Ubp14 ( 351 ) , stimulates the degradation of ubiquitinated proteins specifically by deconjugating free Lys @-@ 48 - linked Ub chains after the degradation of the target protein ( 281 , 350 , 375 ) . # ::alignments 0-1.1.2 1-1.1.1.1 2-1.1.1.2 4-1.1 4-1.1.3 4-1.1.3.r 7-1.1.3.2.1 8-1.1.3.2 9-1.1.3.1.r 10-1.1.3.1.2 11-1.1.3.1.1.1 13-1.1.3.3.1.1.1 16-1 18-1.2 19-1.2.1.r 20-1.2.1.1 21-1.2.1 22-1.4 25-1.2.2.2.1 25-1.2.2.2.1.3 25-1.2.2.2.1.3.r 26-1.2.2.2.1.2.1.2.1 28-1.2.2.2.1.2.1.1 30-1.2.2.2.1.2 31-1.2.2.2.1.1.1 32-1.2.2.2 33-1.3 35-1.3.1 36-1.3.1.1.r 38-1.3.1.1.1 39-1.3.1.1 41-1.5.1.1.1.1 43-1.5.1.1.1.2 45-1.5.1.1.1.3 (s / stimulate-01~e.16 :ARG0 (e / enzyme~e.4 :name (n4 / name :op1 "isopeptidase"~e.1 :op2 "t"~e.2) :mod (m / mammal~e.0) :ARG1-of~e.4 (r2 / resemble-01~e.4 :ARG2~e.9 (e2 / enzyme :name (n / name :op1 "Ubp14"~e.11) :mod (y2 / yeast~e.10)) :topic (p / property~e.8 :mod (f / function-01~e.7)) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 351~e.13))))) :ARG1 (d / degrade-01~e.18 :ARG1~e.19 (p2 / protein~e.21 :ARG1-of (u / ubiquitinate-01~e.20)) :manner (c2 / conjugate-02 :polarity - :ARG1 (c / chain~e.32 :mod (p5 / protein~e.25 :name (n2 / name :op1 "Ub"~e.31) :ARG1-of (l / link-01~e.30 :ARG2 (a3 / amino-acid :mod 48~e.28 :name (n3 / name :op1 "lysine"~e.26))) :ARG1-of~e.25 (f2 / free-04~e.25))))) :time (a / after~e.33 :op1 (d3 / degrade-01~e.35 :ARG1~e.36 (p4 / protein~e.39 :ARG1-of (t / target-01~e.38)))) :ARG1-of (s3 / specific-02~e.22) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 281~e.41 :op2 350~e.43 :op3 375~e.45))))) # ::id bio.chicago_2015.38647 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One such mutation , R89L , is located in the RBD and prevents the binding and activation of Raf @-@ 1 by Ras ( 17 , 28 , 29 ) . # ::alignments 0-1.1.1.2 1-1.1.1.3 2-1.1.1 4-1.1.1.1 6-1.1 7-1.1 10-1.1.2.1.1 11-1 12-1.2 14-1.2.2.1 15-1.2.2 16-1.2.2.2 17-1.2.2.1.2.r 18-1.2.2.1.2.1.1 20-1.2.2.1.2.1.1 21-1.2.2.1.1.r 22-1.2.2.1.1.1.1 24-1.3.1.1.1.1 26-1.3.1.1.1.2 28-1.3.1.1.1.3 (a / and~e.11 :op1 (b2 / be-located-at-91~e.6,7 :ARG1 (m / mutate-01~e.2 :value "R89L"~e.4 :mod (o / one~e.0) :mod (s / such~e.1)) :ARG2 (p / protein-segment :name (n2 / name :op1 "RBD"~e.10))) :op2 (p2 / prevent-01~e.12 :ARG0 m :ARG1 (a2 / and~e.15 :op1 (b / bind-01~e.14 :ARG0~e.21 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.22)) :ARG1~e.17 (e / enzyme :name (n3 / name :op1 "Raf-1"~e.18,20))) :op2 (a3 / activate-01~e.16 :ARG0 e2 :ARG1 e))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 17~e.24 :op2 28~e.26 :op3 29~e.28))))) # ::id bio.chicago_2015.38657 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In three experiments , the binding of Ras to Raf @-@ 1 peptide increased upon antigen stimulation and showed similar maximal increases at 1 @-@ 2 min in both control ( 2.0 plus @-@ or @-@ minus 0.5 @-@ fold , mean plus @-@ or @-@ minus S.E.) and dexamethasone @-@ treated ( 1.9 plus @-@ or @-@ minus 0.3 @-@ fold ) cells . # ::alignments 1-1.3.1 2-1.3 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 8-1.1.1.2.r 9-1.1.1.2.1.1 11-1.1.1.2.1.1 12-1.1.1.2 13-1.1 15-1.1.2.1 16-1.1.2 17-1 18-1.2 19-1.2.2.1 20-1.2.2.2 21-1.2.2 23-1.2.2.3.1.1.1 25-1.2.2.3.1.1.2 25-1.2.3.1.2.1.1.1.1 25-1.2.3.1.2.1.1.2.1 26-1.2.2.3.1.2 29-1.2.3.1.1 32-1 37-1.2.3.1.2.1.1.1.2.1 39-1.2.3.1.2.1.1.1.2 41-1.2.3.1.2 41-1.2.3.1.2.1.2.1.2 41-1.2.3.2.2 42-1.2.3.1.2.1 48-1.2.3.1.2.1 49-1.2.3.2.1.1.1.1 51-1.2.3.2.1 53-1.2.3.2.2.1.1.1 53-1.2.3.2.2.1.2.1 54-1.2.3 59-1.2.3.2.2.1.1.2.1 61-1.2.3.2.2.1.1.2 63-1.2.3.1 63-1.2.3.2 (a / and~e.17,32 :op1 (i / increase-01~e.13 :ARG1 (b2 / bind-01~e.5 :ARG1~e.6 (e3 / enzyme :name (n / name :op1 "Ras"~e.7)) :ARG2~e.8 (p / peptide~e.12 :name (n2 / name :op1 "Raf-1"~e.9,11))) :time (s2 / stimulate-01~e.16 :ARG0 (a2 / antigen~e.15))) :op2 (s / show-01~e.18 :ARG0 b2 :ARG1 (i2 / increase-01~e.21 :ARG1-of (r / resemble-01~e.19 :ARG2 i) :mod (m / maximal~e.20) :time (a4 / after :op1 (t2 / temporal-quantity :quant (v4 / value-interval :op1 1~e.23 :op2 2~e.25) :unit (m2 / minute~e.26)))) :location (a3 / and~e.54 :op1 (c / cell~e.63 :ARG0-of (c2 / control-01~e.29) :ARG1-of (m3 / mean-01~e.41 :ARG2 (a5 / and~e.42,48 :op1 (v2 / value-interval :op1 (a6 / add-02 :ARG2 2~e.25 :ARG1 (p4 / product-of~e.39 :op1 0.5~e.37)) :op2 (s3 / subtract-01 :ARG2 2~e.25 :ARG1 p4)) :op2 (v3 / value-interval :op1 (a7 / add-02 :ARG1 (e / err-01 :ARG1-of (s5 / standard-02)) :ARG2 (m4 / mean~e.41)) :op2 (s6 / subtract-01 :ARG1 e :ARG2 m4))))) :op2 (c3 / cell~e.63 :ARG1-of (t / treat-04~e.51 :ARG2 (s4 / small-molecule :name (n7 / name :op1 "dexamethasone"~e.49))) :ARG1-of (m5 / mean-01~e.41 :ARG2 (v / value-interval :op1 (a8 / add-02 :ARG1 1.9~e.53 :ARG2 (p2 / product-of~e.61 :op1 0.3~e.59)) :op2 (s7 / subtract-01 :ARG2 1.9~e.53 :ARG1 p2)))))) :location (e2 / experiment-01~e.2 :quant 3~e.1)) # ::id bio.chicago_2015.38673 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Data in Figure 5A show that Elk @-@ 1 phosphorylation was acutely stimulated by EGF with maximum phosphorylation occurring at 5 min . Co @-@ transfection of KSR completely blocked EGF @-@ stimulated Elk @-@ 1 phosphorylation ( Figure 5B , panel pElk @-@ 1 ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 3-1.1.1.1.1 4-1.1 6-1.2.2.1.1.1 8-1.3.1.2.1.1 9-1.2.2 11-1.1.2.3 11-1.1.2.3.r 12-1.1.2 13-1.1.2.1.r 14-1.1.2.1.1.1 15-1.1.2.2.r 16-1.1.2.2.2 17-1.1.2.2 20-1.1.2.2.3.1.1 21-1.1.2.2.3.1.2 27-1.2.1.1.1.1 28-1.2.3 29-1.2 30-1.2.2.2.1.1.1 32-1.2.2.2 33-1.2.2.1.1.1 35-1.2.2.1.1.1 36-1.2.2 38-1.3.1.1 39-1.3.1.1.1 41-1.3.1.2 44-1.1.2.2.1.1.1 44-1.2.2.1.1.1 44-1.3.1.2.1.1 (m3 / multi-sentence :snt1 (s / show-01~e.4 :ARG0 (d / data~e.0 :location~e.1 (f / figure~e.2 :mod "5A"~e.3)) :ARG1 (s2 / stimulate-01~e.12 :ARG0~e.13 (p4 / protein :name (n2 / name :op1 "EGF"~e.14)) :ARG1~e.15 (p2 / phosphorylate-01~e.17 :ARG1 (p3 / protein :name (n / name :op1 "Elk-1"~e.44)) :mod (m / maximum~e.16) :time (a3 / after :op1 (t2 / temporal-quantity :quant 5~e.20 :unit (m4 / minute~e.21)))) :manner~e.11 (a2 / acute~e.11))) :snt2 (b / block-01~e.29 :ARG0 (c2 / cotransfect-01 :ARG2 (e / enzyme :name (n3 / name :op1 "KSR"~e.27))) :ARG1 (p / phosphorylate-01~e.9,36 :ARG1 (p5 / protein :name (n4 / name :op1 "Elk-1"~e.6,33,35,44)) :ARG1-of (s3 / stimulate-01~e.32 :ARG0 (p6 / protein :name (n5 / name :op1 "EGF"~e.30)))) :ARG1-of (c / complete-02~e.28)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure~e.38 :mod "5b"~e.39) :op2 (p7 / panel~e.41 :name (n6 / name :op1 "pElka-1"~e.8,44))))) # ::id bio.chicago_2015.38676 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding features of DSL proteins to Notch2 . # ::alignments 0-1.1 1-1 3-1.1.1.1.1 4-1.1.1 4-1.1.2 6-1.1.2.1.1 (f / feature~e.1 :mod (b / bind-01~e.0 :ARG1 (p / protein~e.4 :name (n / name :op1 "DSL"~e.3)) :ARG2 (p2 / protein~e.4 :name (n2 / name :op1 "Notch2"~e.6)))) # ::id bio.chicago_2015.38704 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm the specific binding of magoh to Y14 , we carried out in vitro binding assays using recombinant GST - magoh . # ::alignments 1-1.2 3-1.2.2.3 4-1.2.2 5-1.2.2.1.r 6-1.2.2.1.1.1 10-1.1.1 11-1.1 12-1.1 13-1.1.3 14-1.1.3 15-1.1.2.1 16-1.1.2 17-1 17-1.1.4 18-1.1.4.2.2 19-1.1.4.2.1.1 21-1.2.2.1.1.1 (h / have-purpose-91~e.17 :ARG1 (c2 / carry-out-03~e.11,12 :ARG0 (w / we~e.10) :ARG1 (a / assay-01~e.16 :ARG1 (b2 / bind-01~e.15)) :mod (i / in-vitro~e.13,14) :manner (u / use-01~e.17 :ARG0 w :ARG1 (p / protein :name (n3 / name :op1 "GST"~e.19 :op2 "magoh") :ARG3-of (r2 / recombine-01~e.18)))) :ARG2 (c / confirm-01~e.1 :ARG0 w :ARG1 (b / bind-01~e.4 :ARG1~e.5 (p2 / protein :name (n2 / name :op1 "magoh"~e.6,21)) :ARG2 (a2 / amino-acid :mod 14 :name (n / name :op1 "tyrosine")) :ARG1-of (s / specific-02~e.3)))) # ::id bio.chicago_2015.38710 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although PKB can phosphorylate GSK @-@ 3 at this site and inhibit its activity , our results also implicate a direct role for ILK in the regulation of GSK @-@ 3 activity . # ::alignments 0-1 1-1.2.1.1.2.1.1 2-1.2 3-1.2.1.1 4-1.2.1.1.1.1.1 6-1.2.1.1.1.1.1 7-1.2.1.1.3.r 8-1.2.1.1.3.1 9-1.2.1.1.3 10-1.2.1 11-1.2.1.2 13-1.2.1.2.2 15-1.1.1.1.1 15-1.1.1.1.1.r 16-1.1.1 16-1.1.1.1 16-1.1.1.1.r 17-1.1.3 18-1.1 20-1.1.2.2 21-1.1.2 22-1.1.2.3.r 23-1.1.2.3.1.1 24-1.1.2.1.r 26-1.1.2.1 27-1.1.2.1.2.r 28-1.1.2.1.2.1 29-1.1.2.1.2.1 30-1.1.2.1.2.1 31-1.1.2.1.2 (h / have-concession-91~e.0 :ARG1 (i2 / implicate-01~e.18 :ARG0 (t2 / thing~e.16 :ARG2-of~e.16 (r / result-01~e.16 :ARG1~e.15 (w / we~e.15))) :ARG1 (r2 / role~e.21 :topic~e.24 (r3 / regulate-01~e.26 :ARG0 e2 :ARG1~e.27 (a4 / activity-06~e.31 :ARG0 e3~e.28,29,30)) :ARG1-of (d / direct-02~e.20) :poss~e.22 (e2 / enzyme :name (n3 / name :op1 "ILK"~e.23))) :mod (a3 / also~e.17)) :ARG2 (p / possible-01~e.2 :ARG1 (a / and~e.10 :op1 (p2 / phosphorylate-01~e.3 :ARG1 (e3 / enzyme :name (n2 / name :op1 "GSK-3"~e.4,6)) :ARG2 (e / enzyme :name (n / name :op1 "PKB"~e.1)) :location~e.7 (s / site~e.9 :mod (t / this~e.8))) :op2 (i / inhibit-01~e.11 :ARG0 e :ARG1 (a2 / activity-06~e.13 :ARG0 e3))))) # ::id bio.chicago_2015.38763 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of K Protein by JNK and ERK in Vivo-- To confirm phosphorylation of the K protein by JNK or ERK in vivo , we performed orthophosphate labeling of cells that had been transfected with the K protein and the respective upstream kinases for ERK , p38 , or JNK . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1 4-1.1.2.r 5-1.1.2.1.1.1 6-1.1.2 7-1.1.2.2.1.1 8-1.1.3 8-1.2.3.2.2.3 11-1.2.3 12-1.2.3.2 13-1.2.3.2.1.r 15-1.2.3.2.1.1.1 16-1.2.3.2.1 18-1.1.2.1.1.1 18-1.2.3.2.2.1.1.1 20-1.1.2.2.1.1 20-1.2.3.2.2.2.1.1 21-1.1.3 22-1.1.3 24-1.2.1 25-1.2 26-1.2.2.2.1.1 27-1.2.2 28-1.2.2.1.r 29-1.2.2.1 33-1.2.2.1.1 36-1.1.1.1.1 36-1.2.3.2.1.1.1 37-1.1.1 38-1.2.2.1.1.1 40-1.2.2.1.1.1.2.3 41-1.2.2.1.1.1.2.2 42-1.2.2.1.1.1.2 43-1.2.3.2.2.r 44-1.2.3.2.2.2.1.1 46-1.2.2.1.1.1.2.1.2.1.1 49-1.1.2.1.1.1 (m / multi-sentence :snt1 (p / phosphorylate-01~e.0 :ARG1~e.1 (p3 / protein~e.3,37 :name (n2 / name :op1 "K"~e.2,36)) :ARG2~e.4 (a / and~e.6 :op1 (e / enzyme :name (n3 / name :op1 "JNK"~e.5,18,49)) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK"~e.7,20))) :manner (i / in-vivo~e.8,21,22)) :snt2 (p4 / perform-02~e.25 :ARG0 (w / we~e.24) :ARG1 (l / label-01~e.27 :ARG1~e.28 (c / cell~e.29 :ARG1-of (t / transfect-01~e.33 :ARG2 (a2 / and~e.38 :op1 p5 :op2 (k / kinase~e.42 :beneficiary (a3 / and :op1 e5 :op2 (e3 / enzyme :name (n / name :op1 "p38"~e.46)) :op3 e4) :direction (u / upstream~e.41) :mod (r / respective~e.40))))) :ARG2 (s / small-molecule :name (n8 / name :op1 "orthophosphate"~e.26))) :purpose (c2 / confirm-01~e.11 :ARG0 w :ARG1 (p2 / phosphorylate-01~e.12 :ARG1~e.13 (p5 / protein~e.16 :name (n5 / name :op1 "K"~e.15,36)) :ARG2~e.43 (a4 / and :op1 (e4 / enzyme :name (n6 / name :op1 "JNK"~e.18)) :op2 (e5 / enzyme :name (n7 / name :op1 "ERK"~e.20,44)) :manner (i2 / in-vivo~e.8)))))) # ::id bio.chicago_2015.38801 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Insulin and PMA Induce Dissociation of the Grb2 @-@ SOS Complex-- Previous studies have observed that agents that activate the Ras/ Raf/ MEK/ ERK pathway can also induce the serine/ threonine phosphorylation of SOS and dissociation of the Grb2 @-@ SOS complex ( 29 , 35 , 36 ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1 4-1.1.2 7-1.1.2.1.1.1.1 9-1.1.2.1.2.1.1 11-1.2.1.1 12-1.2.1 14-1.2 15-1.2.2.r 16-1.2.2.1.1 18-1.2.2.1.1.1 23-1.2.2.1.1.1.1.1.1 24-1.2.2.1.1.1.1 25-1.2.2 26-1.2.2.1.3 27-1.2.2.1 30-1.2.2.1.2.1.1.2.1.1 31-1.2.2.1.2.1 33-1.2.2.1.2.1.1.3.1.1 34-1.2.2.1.2 35-1.2.2.1.2.2 38-1.2.2.1.2.2.1.1.1.1 40-1.2.2.1.2.2.1.2 41-1.1.2.1 41-1.2.2.1.2.2.1 43-1.2.3.1.1.1.1 45-1.2.3.1.1.1.2 47-1.2.3.1.1.1.3 (m / multi-sentence :snt1 (i / induce-01~e.3 :ARG0 (a2 / and~e.1 :op1 (i2 / insulin~e.0) :op2 (s / small-molecule :name (n3 / name :op1 "PMA"~e.2))) :ARG2 (d / dissociate-01~e.4 :ARG1 (m2 / macro-molecular-complex~e.41 :part (p7 / protein :name (n / name :op1 "Grb2"~e.7)) :part (p8 / protein :name (n8 / name :op1 "SOS"~e.9))))) :snt2 (o / observe-01~e.14 :ARG0 (s2 / study-01~e.12 :mod (p3 / previous~e.11)) :ARG1~e.15 (p4 / possible-01~e.25 :ARG1 (i3 / induce-01~e.27 :ARG0 (a3 / agent~e.16 :ARG0-of (a4 / activate-01~e.18 :ARG1 (p6 / pathway~e.24 :name (n4 / name :op1 "Ras/Raf/MEK/ERK"~e.23)))) :ARG2 (a6 / and~e.34 :op1 (p2 / phosphorylate-01~e.31 :ARG1 (s3 / slash :op1 (a5 / amino-acid :name (n5 / name :op1 "serine")) :op2 (a / amino-acid :name (n2 / name :op1 "threonine"~e.30)) :part-of (p5 / protein :name (n6 / name :op1 "SOS"~e.33)))) :op2 (d2 / dissociate-01~e.35 :ARG1 (m3 / macro-molecular-complex~e.41 :part (p9 / protein :name (n9 / name :op1 "Grb2"~e.38)) :part p5~e.40))) :mod (a8 / also~e.26))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 (a7 / and :op1 29~e.43 :op2 35~e.45 :op3 36~e.47)))))) # ::id bio.chicago_2015.38881 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest that sens normally represses Ro in the differentiating R8 photoreceptor . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2.4 6-1.2 7-1.2.2.1.1 8-1.2.3.r 10-1.2.3 11-1.2.3.1.1.1.1 12-1.2.3.1 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (r / repress-01~e.6 :ARG0 (p4 / protein :name (n4 / name :op1 "sens"~e.4)) :ARG1 (p2 / protein :name (n2 / name :op1 "Ro"~e.7)) :ARG2~e.8 (d2 / differentiate-01~e.10 :ARG1 (p3 / photoreceptor~e.12 :part-of (p / protein :name (n3 / name :op1 "R8"~e.11)))) :ARG1-of (n / normal-02~e.5))) # ::id bio.chicago_2015.38884 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rather surprisingly , however , experiments with the deltaGP5 mutant indicate this did not require profilin binding to VASP . # ::alignments 0-1 0-1.2.1 1-1.2 3-1 5-1.1.1 6-1.1.1.1.r 8-1.1.1.1.1.1 9-1.1.1.1 9-1.1.1.1.2 9-1.1.1.1.2.r 10-1.1 11-1.1.2.2 13-1.1.2.1 13-1.1.2.1.r 14-1.1.2 15-1.1.2.3.1.1.1 16-1.1.2.3 17-1.1.2.3.2.r 18-1.1.2.3.2.1.1 (c / contrast-01~e.0,3 :ARG2 (i / indicate-01~e.10 :ARG0 (e / experiment-01~e.5 :ARG1~e.6 (e2 / enzyme~e.9 :name (n / name :op1 "deltaGP5"~e.8) :ARG2-of~e.9 (m2 / mutate-01~e.9))) :ARG1 (r / require-01~e.14 :polarity~e.13 -~e.13 :ARG0 (t / this~e.11) :ARG1 (b / bind-01~e.16 :ARG1 (p / protein :name (n2 / name :op1 "profilin"~e.15)) :ARG2~e.17 (p2 / protein :name (n3 / name :op1 "VASP"~e.18))))) :ARG0-of (s / surprise-01~e.1 :degree (r2 / rather~e.0))) # ::id bio.chicago_2015.38908 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One report shows that , in addition to activating Rho , Wnt signaling can also activate Rac but not Cdc42 ( Habas et al. , 2003 ) . # ::alignments 0-1.1.1 1-1.1 2-1 5-1.2 5-1.3.1 6-1.2 6-1.3.1 7-1.2.r 8-1.2.1 9-1.2.1.2.1.1 11-1.2.2.1.1.1.1.1 12-1.2.2.1.1.1.2 13-1.2.2 14-1.2.2.2 15-1.2.2.1.1 15-1.2.2.1.2 16-1.2.2.1.1.2.1.1 17-1.2.2.1 18-1.2.2.1.2.1 18-1.2.2.1.2.1.r 19-1.2.2.1.2.3.1.1 21-1.3.1.1.1.1 22-1.3.1 23-1.3.1.2.1 25-1.3.1.3.1 (s / show-01~e.2 :ARG0 (r / report~e.1 :mod (o / one~e.0)) :ARG1~e.7 (a4 / and~e.5,6 :op1 (a5 / activate-01~e.8 :ARG0 p2 :ARG1 (p3 / protein :name (n4 / name :op1 "Rho"~e.9))) :op2 (p / possible-01~e.13 :ARG1 (c / contrast-01~e.17 :ARG1 (a / activate-01~e.15 :ARG0 (p2 / protein :name (n / name :op1 "Wnt"~e.11) :ARG0-of (s2 / signal-07~e.12)) :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"~e.16))) :ARG2 (a3 / activate-01~e.15 :polarity~e.18 -~e.18 :ARG0 p2 :ARG1 (p6 / protein :name (n3 / name :op1 "Cdc42"~e.19)))) :mod (a2 / also~e.14))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and~e.5,6,22 :op1 (p4 / person :name (n5 / name :op1 "Habas"~e.21)) :op2 (p5 / person :mod (o2 / other~e.23)) :time (d / date-entity :year 2003~e.25)))) # ::id bio.chicago_2015.38917 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Shank , a Novel Family of Postsynaptic Density Proteins that Binds to the NMDA Receptor/ PSD @-@ 95 @/@ GKAP Complex and Cortactin # ::alignments 0-1.1.1 3-1.2 4-1 5-1.3.r 6-1.3.1.1 7-1.3.1 8-1.3 10-1.3.2 11-1.3.2.1.r 13-1.3.2.1.1.1.1.1 15-1.3.2.1.1.2.1.1 17-1.3.2.1.1.2.1.1 19-1.3.2.1.1.3.1.1 20-1.3.2.1.1 21-1.3.2.1 22-1.3.2.1.2.1.1 (p8 / protein-family~e.4 :name (n2 / name :op1 "Shank"~e.0) :mod (n / novel~e.3) :consist-of~e.5 (p / protein~e.8 :mod (d / density~e.7 :mod (p2 / postsynaptic~e.6)) :ARG1-of (b / bind-01~e.10 :ARG2~e.11 (a / and~e.21 :op1 (m / macro-molecular-complex~e.20 :part (p4 / protein :name (n4 / name :op1 "NMDA"~e.13 :op2 "Receptor")) :part (p5 / protein :name (n5 / name :op1 "PSD-95"~e.15,17)) :part (p6 / protein :name (n6 / name :op1 "GKAP"~e.19))) :op2 (p3 / protein :name (n3 / name :op1 "cortactin"~e.22)))))) # ::id bio.chicago_2015.38985 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D ) Association between CIZ and Cas expressed in COS @-@ 7 cells . # ::alignments 1-1.1 3-1.2 5-1.2.1.1.1 7-1.2.2.1.1 8-1 9-1.3.r 10-1.3.1.1 12-1.3.1.1 13-1.3 (e / express-03~e.8 :li "D"~e.1 :ARG2 (a2 / associate-01~e.3 :ARG1 (p / protein :name (n2 / name :op1 "CIZ"~e.5)) :ARG2 (p2 / protein :name (n3 / name :op1 "Cas"~e.7))) :ARG3~e.9 (c / cell-line~e.13 :name (n / name :op1 "COS-7"~e.10,12))) # ::id bio.chicago_2015.39001 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ORC and regulation of the metazoan cell cycle In yeast , where ORC remains stably bound to chromatin throughout the cell cycle ( see Introduction ) , conversion of ORCs into pre @-@ RCs is delayed until mitosis is completed , because Cdk1 @/@ cyclin B simultaneously promotes mitosis and inhibits binding of Cdc6 to ORC ( Dahmann et al. , 1995 ; Piatti et al. , 1996 ) , apparently by phosphorylation of Cdc6 protein ( Jallepalli et al. , 1997 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2 3-1.1.2.1.r 5-1.1.2.1.1.1 6-1.1.2.1.1 7-1.1.2.1 9-1.2.3 11-1.2.3.1.r 11-1.2.3.r 12-1.2.3.1.1 13-1.2.3.1 14-1.2.3.1.2.3 15-1.2.3.1.2 16-1.2.3.1.2.2.r 17-1.2.3.1.2.2.1.1 20-1.2.3.1.3.1 21-1.2.3.1.3 23-1.2.3.1.4.1.1 24-1.2.3.1.4.1 27-1.2.1 30-1.2.1.2.r 31-1.2.1.2.1.1 33-1.2.1.2.1.1 35-1.2 36-1.2.2 37-1.2.2.1.1 39-1.2.2.1 41-1.2.4 42-1.2.4.1.1.1.1.1.1 44-1.2.4.1.1.1.2.1.1 45-1.2.4.1.1.1.2.1.2 46-1.2.4.1.5 46-1.2.4.1.5.r 47-1.2.4.1.1 48-1.2.4.1.1.2 49-1.2.4.1 49-1.2.4.1.4.1 49-1.2.4.1.4.1.1.1 50-1.2.4.1.2 51-1.2.4.1.2.2 53-1.2.4.1.2.2.1.1.1 54-1.2.1.1.r 54-1.2.4 55-1.2.1.1.1.1 57-1.2.4.1.4.1.1.1.1.1.1 58-1.2.4.1.4.1.1.1 59-1.2.4.1.4.1.1.1.2.1 61-1.2.4.1.4.1.1.2.1 63-1.2.4.1.4.1.2.1.1.1.1 64-1.2.4.1.4.1 64-1.2.4.1.4.1.1.1 64-1.2.4.1.4.1.2.1 65-1.2.4.1.4.1.1.1.2.1 67-1.2.4.1.4.1.2.2.1 70-1.2.4.1.3.2 72-1.2.4.1.3 73-1.2.4.1.3.1.r 74-1.2.4.1.3.1 75-1.2.4.1.1.1.2 75-1.2.4.1.2.2.1 77-1.2.4.1.3.3.1.1.1.1.1 78-1.2.4.1 78-1.2.4.1.3.3.1.1 78-1.2.4.1.4.1 78-1.2.4.1.4.1.1.1 79-1.2.4.1.4.1.1.1.2.1 81-1.2.4.1.3.3.1.2.1 (m / multi-sentence :snt1 (a / and~e.1 :op1 (m6 / macro-molecular-complex :name (n / name :op1 "ORC"~e.0)) :op2 (r / regulate-01~e.2 :ARG1~e.3 (c / cycle~e.7 :mod (c2 / cell~e.6 :mod (m2 / metazoan~e.5))))) :snt2 (d4 / delay-01~e.35 :ARG1 (c3 / convert-01~e.27 :ARG1~e.54 (m4 / macro-molecular-complex :name (n2 / name :op1 "ORC"~e.55)) :ARG2~e.30 (m5 / macro-molecular-complex :name (n3 / name :op1 "pre-RCs"~e.31,33))) :ARG2 (u / until~e.36 :op1 (c4 / complete-01~e.39 :ARG1 (m3 / mitosis~e.37))) :location~e.11 (y / yeast~e.9 :location-of~e.11 (r2 / remain-01~e.13 :ARG1 m4~e.12 :ARG3 (b / bind-01~e.15 :ARG1 m4 :ARG2~e.16 (m7 / macro-molecular-complex :name (n4 / name :op1 "chromatin"~e.17)) :ARG1-of (s / stable-03~e.14)) :duration (c5 / cycle~e.21 :mod (c6 / cell~e.20)) :ARG1-of (d7 / describe-01 :ARG0 (i2 / introduce-01~e.24 :ARG1-of (s2 / see-01~e.23 :ARG0 (y2 / you)))))) :ARG1-of (c7 / cause-01~e.41,54 :ARG0 (a2 / and~e.49,78 :op1 (p2 / promote-01~e.47 :ARG0 (m8 / macro-molecular-complex :part (e / enzyme :name (n5 / name :op1 "Cdk1"~e.42)) :part (p12 / protein~e.75 :name (n6 / name :op1 "cyclin"~e.44 :op2 "B"~e.45))) :ARG1 m3~e.48) :op2 (i / inhibit-01~e.50 :ARG0 m8 :ARG1 (b2 / bind-01~e.51 :ARG1 (p4 / protein~e.75 :name (n7 / name :op1 "Cdc6"~e.53)) :ARG2 m4)) :manner (p / phosphorylate-01~e.72 :ARG1~e.73 p4~e.74 :ARG1-of (a3 / appear-02~e.70) :ARG1-of (d6 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a7 / and~e.78 :op1 (p11 / person :name (n10 / name :op1 "Jallepalli"~e.77)) :op2 p7) :time (d3 / date-entity :year 1997~e.81)))) :ARG1-of (d5 / describe-01 :ARG0 (a5 / and~e.49,64,78 :op1 (p5 / publication-91 :ARG0 (a4 / and~e.49,58,64,78 :op1 (p6 / person :name (n8 / name :op1 "Dahmann"~e.57)) :op2 (p7 / person :mod (o / other~e.59,65,79))) :time (d / date-entity :year 1995~e.61)) :op2 (p8 / publication-91 :ARG0 (a6 / and~e.64 :op1 (p9 / person :name (n9 / name :op1 "Piatti"~e.63)) :op2 p7) :time (d2 / date-entity :year 1996~e.67)))) :manner~e.46 (s3 / simultaneous~e.46))))) # ::id bio.chicago_2015.39049 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The association of alpha @-@ catenin with beta @-@ catenin was also markedly increased in ApcMin/ adenoma cells ( Fig . 8 B ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 5-1.1.2.1.1 6-1.1.2.r 7-1.1.2.1.1 9-1.1.1.1.1 9-1.1.2.1.1 11-1.3 12-1.2 13-1 16-1.4.2.1.1 17-1.4 19-1.5.1 (i / increase-01~e.13 :ARG1 (a / associate-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "alpha-catenin"~e.3,5,9)) :ARG2~e.6 (p2 / protein :name (n2 / name :op1 "beta-catenin"~e.5,7,9))) :ARG2 (m / mark-01~e.12) :mod (a2 / also~e.11) :location (c / cell~e.17 :mod (g / gene :name (n3 / name :op1 "ApcMin")) :mod (m2 / medical-condition :name (n4 / name :op1 "adenoma"~e.16))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "8B"))) # ::id bio.chicago_2015.39066 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The disassembly of a Lys @-@ 48 - linked Ub chain by PA700 isopeptidase proceeds by sequentially removing the distal Ub moiety [ 346 ; Figure 6 b ( right )] . # ::alignments 4-1.2.3.2.1.2.1 6-1.2.3.2.1.1 8-1.2.3.2 10-1.2.3 12-1.2.2.1.1 13-1.2.2 14-1 15-1.1.r 16-1.1.2 17-1.1 19-1.1.1.1.2 21-1.1.1 23-1.4.1.1.1 25-1.3.1 29-1.3.1.2 (p / proceed-01~e.14 :ARG0~e.15 (r / remove-01~e.17 :ARG1 (m / moiety~e.21 :mod (p3 / protein :name (n4 / name :op1 "ubiquitin") :mod (d / distal~e.19))) :manner (s / sequence~e.16)) :ARG1 (a / assemble-01 :polarity - :ARG0 (i / isopeptidase~e.13 :name (n / name :op1 "PA700"~e.12)) :ARG1 (c / chain~e.10 :mod (p2 / protein :name (n2 / name :op1 "ubiquitin")) :ARG1-of (l / link-01~e.8 :ARG2 (a2 / amino-acid :mod 48~e.6 :name (n3 / name :op1 "lysine"~e.4))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.25 :mod "6b" :ARG1-of (r2 / right-04~e.29))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 346~e.23)))) # ::id bio.chicago_2015.39083 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Amphiphysin 1 can bind simultaneously to dynamin and either clathrin or AP @-@ 2 . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1 3-1.1 4-1.1.3 4-1.1.3.r 5-1.1.2.r 6-1.1.2.1.1.1 7-1.1.2 9-1.1.2.2.1.1.1 10-1.1.2.2 11-1.1.2.2.2.1.1 13-1.1.2.2.2.1.1 (p4 / possible-01~e.2 :ARG1 (b / bind-01~e.3 :ARG1 (p / protein :name (n / name :op1 "Amphiphysin"~e.0 :op2 1~e.1)) :ARG2~e.5 (a / and~e.7 :op1 (p5 / protein :name (n2 / name :op1 "dynamin"~e.6)) :op2 (o / or~e.10 :op1 (p2 / protein :name (n3 / name :op1 "clathrin"~e.9)) :op2 (p3 / protein :name (n4 / name :op1 "AP-2"~e.11,13)))) :manner~e.4 (s / simultaneous~e.4))) # ::id bio.chicago_2015.39129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEKK1 Can Phosphorylate the N Terminus of p300 in Vitro-- Given the fact that JNK1 is not involved in the response of p300 to MEKK1 , nor are the other potential downstream kinases such as p38 and IkappaBalpha , we considered the possibility that MEKK1 delta may be able to directly phosphorylate p300 . # ::alignments 0-1.1.1.2.1.1 1-1.1 2-1.1.1 4-1.1.1.1.1.1 5-1.1.1.1.1.1 7-1.1.1.1.2.1.1 8-1.1.1.3 14-1.2.3.1.2.1.1.1 16-1.2.3.1.1 16-1.2.3.1.1.r 17-1.2.3.1 18-1.1.1.3 18-1.2.3.1.3.r 20-1.2.3.1.3 21-1.2.3.1.3.1.r 22-1.2.3.1.3.1 24-1.1.1.2.1.1 26-1.2.3.1.2 29-1.2.3.1.2.2.1 30-1.2.3.1.2.2.3 31-1.2.3.1.2.2.2 32-1.2.3.1.2.2 32-1.2.3.1.2.2.4.1.1 32-1.2.3.1.2.2.4.1.2 35-1.2.3.1.2.2.4.1.1.1.1 36-1.2.3.1.2.2.4.1 37-1.2.3.1.2.2.4.1.2.1.1 39-1.2.1 40-1.2 42-1.2.2 44-1.1.1.2.1.1 46-1.2.2 48-1.2.2 48-1.2.2.1 48-1.2.2.1.r 50-1.2.2.1.1.3 51-1.2.2.1.1 52-1.2.2.1.1.1 (m / multi-sentence :snt1 (p / possible-01~e.1 :ARG1 (p2 / phosphorylate-01~e.2 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "N-Terminus"~e.4,5) :part-of (p4 / protein :name (n3 / name :op1 "p300"~e.7))) :ARG2 (e / enzyme :name (n / name :op1 "MEKK1"~e.0,24,44)) :manner (i / in-vitro~e.8,18))) :snt2 (c / consider-01~e.40 :ARG0 (w / we~e.39) :ARG1 (p5 / possible-01~e.42,46,48 :ARG1~e.48 (c2 / capable-01~e.48 :ARG1 (p6 / phosphorylate-01~e.51 :ARG1 p4~e.52 :ARG2 (e2 / enzyme :name (n4 / name :op1 "MEKK1delta")) :ARG1-of (d2 / direct-02~e.50)))) :ARG1-of (c3 / cause-01 :ARG0 (i2 / involve-01~e.17 :polarity~e.16 -~e.16 :ARG1 (o / or~e.26 :op1 (e3 / enzyme :name (n5 / name :op1 "JNK1"~e.14)) :op2 (k / kinase~e.32 :mod (o2 / other~e.29) :direction (d3 / downstream~e.31) :mod (p7 / potential~e.30) :ARG2-of (i3 / include-91 :ARG1 (a / and~e.36 :op1 (k2 / kinase~e.32 :name (n6 / name :op1 "p38"~e.35)) :op2 (k3 / kinase~e.32 :name (n7 / name :op1 "IkappaBalpha"~e.37)))))) :ARG2~e.18 (r / respond-01~e.20 :ARG0~e.21 p4~e.22 :ARG1 e))))) # ::id bio.chicago_2015.39166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cdk1 @/@ cyclin B simultaneously promotes mitosis and inhibits binding of Cdc6 to ORC by phosphorylating Cdc6 . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.2.1.1 3-1.1.1.2.1.2 4-1.3 4-1.3.r 5-1.1 6-1.1.2 7-1 8-1.2 9-1.2.2 10-1.2.2.1.r 11-1.2.2.1.1.1 12-1.2.2.2.r 13-1.2.2.2.1.1 15-1.4 16-1.4.1 (a / and~e.7 :op1 (p / promote-01~e.5 :ARG0 (m2 / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "Cdk1"~e.0)) :part (p6 / protein :name (n2 / name :op1 "cyclin"~e.2 :op2 "B"~e.3))) :ARG1 (m / mitosis~e.6)) :op2 (i / inhibit-01~e.8 :ARG0 m2 :ARG1 (b / bind-01~e.9 :ARG1~e.10 (p3 / protein :name (n3 / name :op1 "Cdc6"~e.11)) :ARG2~e.12 (m3 / macro-molecular-complex :name (n4 / name :op1 "ORC"~e.13)))) :manner~e.4 (s2 / simultaneous~e.4) :manner (p5 / phosphorylate-01~e.15 :ARG1 p3~e.16 :ARG2 m2)) # ::id bio.chicago_2015.39206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our genetic analyses suggest that the vein phenotype and wing shape alterations are due to an effect on the balance between TGF and Wnt signaling and the subsequent activation of JNK signaling that ensues . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1 3-1 4-1.2.r 6-1.2.2.1.1.1 7-1.2.2.1.1 8-1.2.2.1 9-1.2.2.1.2.1 10-1.2.2.1.2 11-1.2.2 13-1.2 14-1.2 16-1.2.1 17-1.2.1.1.r 19-1.2.1.1 21-1.2.1.1.1.1.1.1.1 22-1.2.1.1.1.1 23-1.2.1.1.1.1.2.1.1 24-1.2.1.1.1 25-1.2.1.1.1.1 27-1.2.1.1.2.2 28-1.2.1.1.2 29-1.2.1.1.2.1.r 30-1.2.1.1.2.1.1.1.1 31-1.2.1.1.2.1 33-1.2.1.1.2.3 (s / suggest-01~e.3 :ARG0 (a / analyze-01~e.2 :ARG0~e.0 (w / we~e.0) :ARG1 (g / genetics~e.1)) :ARG1~e.4 (c / cause-01~e.13,14 :ARG0 (a2 / affect-01~e.16 :ARG1~e.17 (b / balance-01~e.19 :ARG1 (s2 / signal-07~e.24 :ARG0 (a3 / and~e.22,25 :op1 (p / protein :name (n / name :op1 "TGF"~e.21)) :op2 (p2 / protein :name (n2 / name :op1 "Wnt"~e.23)))) :ARG2 (a4 / activate-01~e.28 :ARG1~e.29 (s4 / signal-07~e.31 :ARG0 (e / enzyme :name (n3 / name :op1 "JNK"~e.30))) :mod (s3 / subsequent~e.27) :ARG1-of (e2 / ensue-01~e.33)))) :ARG1 (a5 / alter-01~e.11 :ARG1 (a6 / and~e.8 :op1 (p3 / phenotype~e.7 :mod (v / vein~e.6)) :op2 (s5 / shape~e.10 :mod (w2 / wing~e.9)))))) # ::id bio.chicago_2015.39226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IKK recovery was determined by immunoblotting ( IB ) with antibody to IKKgamma . # ::alignments 0-1.1.1.1.1 1-1.1 3-1 4-1.2.r 5-1.2 9-1.2.2.r 10-1.2.2 12-1.2.2.1.1.1.1 (d / determine-01~e.3 :ARG1 (r / recover-02~e.1 :ARG1 (e / enzyme :name (n / name :op1 "IKK"~e.0))) :ARG2~e.4 (i / immunoblot-01~e.5 :ARG1 e :ARG3~e.9 (a / antibody~e.10 :ARG0-of (o / oppose-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "IKKgamma"~e.12)))))) # ::id bio.chicago_2015.39236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other studies showed that PI3K is also activated by small GTPase molecules such as Ras and Rac1 ( Nishida et al. , 1999 ; Rodriguez @-@ Viciana et al. , 1994 ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.2.1.1 6-1.2.3 7-1.2 8-1.2.1.r 9-1.2.1.2 10-1.2.1.1.1.1 11-1.2.1 14-1.2.1.3.1.1.1.1 15-1.2.1.3.1 16-1.2.1.3.1.2.1.1 18-1.3.1.1.1.1.1.1 19-1.3.1.1.1 20-1.3.1.1.1.2.1 22-1.3.1.1.2.1 24-1.3.1.2.1.1.1.1 26-1.3.1.2.1.1.1.1 27-1.3.1 27-1.3.1.2.1 28-1.3.1.1.1.2.1 30-1.3.1.2.2.1 (s / show-01~e.2 :ARG0 (s2 / study-01~e.1 :mod (o / other~e.0)) :ARG1~e.3 (a / activate-01~e.7 :ARG0~e.8 (m / molecule~e.11 :mod (p / protein-family :name (n / name :op1 "GTPase"~e.10)) :mod (s3 / small~e.9) :ARG2-of (i / include-91 :ARG1 (a2 / and~e.15 :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.14)) :op2 (p2 / protein :name (n5 / name :op1 "Rac1"~e.16))))) :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K"~e.4)) :mod (a3 / also~e.6)) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.27 :op1 (p3 / publication-91 :ARG0 (a5 / and~e.19 :op1 (p4 / person :name (n6 / name :op1 "Nishida"~e.18)) :op2 (p6 / person :mod (o2 / other~e.20,28))) :time (d / date-entity :year 1999~e.22)) :op2 (p7 / publication-91 :ARG0 (a6 / and~e.27 :op1 (p8 / person :name (n4 / name :op1 "Rodriguez-Viciana"~e.24,26)) :op2 p6) :time (d2 / date-entity :year 1994~e.30))))) # ::id bio.chicago_2015.39239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PI bound to PI @-@ TPalpha is delivered as a substrate for phospholipase A2 ( PLA2 ) . # ::alignments 1-1.1.1.1.1 2-1.1 4-1.1.1.1.1 6-1.1.2.1.1 8-1 9-1.1.3.r 11-1.1.3 12-1.1.3.1.r 13-1.1.3.1.1.1 14-1.1.3.1.1.2 (d / deliver-01~e.8 :ARG1 (b / bind-01~e.2 :ARG1 (s2 / small-molecule :name (n / name :op1 "PI"~e.1,4)) :ARG2 (p2 / protein :name (n2 / name :op1 "PI-TPalpha"~e.6)) :purpose~e.9 (s / substrate~e.11 :beneficiary~e.12 (e / enzyme :name (n3 / name :op1 "phospholipase"~e.13 :op2 "A2"~e.14))))) # ::id bio.chicago_2015.39287 ::amr-annotator SDL-AMR-09 ::preferred # ::tok sepA Is Required for Actin Ring Formation # ::alignments 0-1.2.1.1 2-1 3-1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1 (r / require-01~e.2 :ARG0~e.3 (f / form-01~e.6 :ARG1 (r2 / ring~e.5 :mod (p2 / protein :name (n2 / name :op1 "actin"~e.4)))) :ARG1 (p / protein :name (n / name :op1 "sepA"~e.0))) # ::id bio.chicago_2015.39301 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this study , we show that Cos2 inhibits Ci activity by tethering it in the cytoplasm via a 125 amino acid domain in the C @-@ terminal region of Ci , whereas Su( fu ) inhibits Ci nuclear import through the N @-@ terminal region of Ci . # ::alignments 1-1.3.1 2-1.3 4-1.1 5-1 6-1.2.r 7-1.2.1.1.1.1 8-1.2.1 9-1.2.1.2.1.1.1 10-1.2.1.2 11-1.2.1.3.r 12-1.2.1.3 14-1.2.1.3.3.r 16-1.2.1.3.3 19-1.2.1.3.4.1.1 20-1.2.1.3.4.1 21-1.2.1.3.4.1 22-1.2.1.3.4 23-1.2.1.3.4.1.2.r 25-1.2.1.3.4.1.2.1.1.1 27-1.2.1.3.4.1.2.1.1.1 28-1.2.1.3.4.1.2 29-1.2.1.3.2.r 30-1.2.1.3.2 32-1.2 36-1.2.2 37-1.2.2.2.1.1 38-1.2.2.2.1 39-1.2.2.2 42-1.2.2.2.2.1.1.1 44-1.2.2.2.2.1.1.1 45-1.2.2.2.2 47-1.2.1.2.1.1.1 (s / show-01~e.5 :ARG0 (w / we~e.4) :ARG1~e.6 (c3 / contrast-01~e.32 :ARG1 (i3 / inhibit-01~e.8 :ARG0 (p / protein :name (n / name :op1 "Cos2"~e.7)) :ARG1 (a / activity-06~e.10 :ARG0 (p2 / protein :name (n2 / name :op1 "Ci"~e.9,47))) :manner~e.11 (t / tether-01~e.12 :ARG0 p :ARG1~e.29 p2~e.30 :location~e.14 (c4 / cytoplasm~e.16) :manner (d / domain~e.22 :mod (a2 / amino-acid~e.20,21 :mod 125~e.19 :location~e.23 (r / region~e.28 :mod (p3 / protein-segment :name (n3 / name :op1 "C-terminus"~e.25,27) :part-of p2)))))) :ARG2 (i4 / inhibit-01~e.36 :ARG0 (p4 / protein :name (n4 / name :op1 "Su(fu)")) :ARG1 (i5 / import-01~e.39 :ARG1 (n5 / nucleus~e.38 :part-of p2~e.37) :location (r2 / region~e.45 :mod (p5 / protein-segment :name (n6 / name :op1 "N-terminus"~e.42,44) :part-of p2))))) :location (s2 / study-01~e.2 :mod (t2 / this~e.1))) # ::id bio.chicago_2015.39321 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore we analyzed the role of p38MAPK in TNF @-@ induced inhibition of conventional kinesin and KLC hyperphosphorylation . # ::alignments 0-1 1-1.1.1 2-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 7-1.1.2.2.r 8-1.1.2.2.2.1.1.1 10-1.1.2.2.2 11-1.1.2.2 12-1.1.2.2.1.r 13-1.1.2.2.1.1.2 14-1.1.2.2.1.1.1.1 15-1.1.2.2.1 16-1.1.2.2.1.2.1.1.1 17-1.1.2.2.1.2 (c / cause-01~e.0 :ARG1 (a / analyze-01~e.2 :ARG0 (w / we~e.1) :ARG1 (r / role~e.4 :poss~e.5 (e / enzyme :name (n / name :op1 "p38MAPK"~e.6)) :topic~e.7 (i / inhibit-01~e.11 :ARG1~e.12 (a2 / and~e.15 :op1 (p3 / protein :name (n3 / name :op1 "kinesin"~e.14) :mod (c2 / conventional~e.13)) :op2 (h / hyperphosphorylate-01~e.17 :ARG1 (p4 / protein :name (n4 / name :op1 "KLC"~e.16)))) :ARG2-of (i2 / induce-01~e.10 :ARG0 (p2 / protein :name (n2 / name :op1 "TNF"~e.8))))))) # ::id bio.chicago_2015.39324 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The semiquantification in Fig. 2C and F shows that the ME significantly decreased the CRE @-@ DNA binding activity of CREB to 77 and 63 % of the control in the ipsilateral cerebral cortex on the third and seventh days , respectively , after the operation ( Fig. 2C ) , and to 74 and 59 % , respectively , in the ipsilateral hippocampus ( Fig. 2F ) . # ::alignments 3-1.1.2.1 3-1.1.2.2 3-1.2.1.7.1 4-1.1.2.1.1 4-1.2.1.7.1.1 5-1.1.2 5-1.2 6-1.1.2.2.1 7-1 11-1.2.1.3 12-1.2.1 12-1.2.2 14-1.2.1.2.2.2.1.1 16-1.2.1.2.2.2.1.1 17-1.2.1.2.2 18-1.2.1.2 19-1.2.1.2.1.r 20-1.2.1.2.1.1.1 22-1.2.1.4.1.1 23-1.2.1.4 24-1.2.1.4.2.1 25-1.2.1.4.1 25-1.2.1.4.2 26-1.2.1.4.r 28-1.2.1.4.3 29-1.2.1.4.3.1.r 31-1.2.1.4.3.1.2 32-1.2.1.4.3.1.1 33-1.2.1.4.3.1 34-1.2.1.5.r 36-1.2.1.5.1.1 36-1.2.1.5.1.1.1 36-1.2.1.5.1.1.1.r 37-1.2.1.5 38-1.2.1.5.1.1 38-1.2.1.5.2.1 38-1.2.1.5.2.1.1 38-1.2.1.5.2.1.1.r 39-1.2.1.5.1 39-1.2.1.5.2 41-1.2.1.5.3 41-1.2.1.5.3.r 43-1.2.1.6 45-1.2.1.6.1 47-1.2.1.7.1 48-1.2.1.7.1.1 52-1.2.2.4.r 53-1.2.2.4.1.1 54-1.2.2.4 55-1.2.2.4.2.1 56-1.2.2.4.1 56-1.2.2.4.2 58-1.2.2.4.3 60-1.2.2.5.r 62-1.2.2.5.1 63-1.2.2.5 65-1.2.2.6.1 66-1.2.2.6.1.1 (s / show-01~e.7 :ARG0 (q / quantify-01 :degree (s2 / semi) :location (a / and~e.5 :op1 (f / figure~e.3 :mod "2C"~e.4) :op2 (f2 / figure~e.3 :mod "F"~e.6))) :ARG1 (a3 / and~e.5 :op1 (d / decrease-01~e.12 :ARG0 (m / medical-condition :name (n / name :op1 "microsphere" :op2 "embolism")) :ARG1 (a2 / activity-06~e.18 :ARG0~e.19 (p3 / protein :name (n2 / name :op1 "CREB"~e.20)) :ARG1 (b / bind-01~e.17 :ARG1 p3 :ARG2 (e / enzyme :name (n3 / name :op1 "CRE-DNA"~e.14,16)))) :ARG2 (s3 / significant-02~e.11) :ARG4~e.26 (a4 / and~e.23 :op1 (p4 / percentage-entity~e.25 :value 77~e.22) :op2 (p / percentage-entity~e.25 :value 63~e.24) :quant-of (c / control-01~e.28 :ARG1~e.29 (c2 / cortex~e.33 :mod (c3 / cerebral~e.32) :mod (i / ipsilateral~e.31)))) :time~e.34 (a5 / and~e.37 :op1 (d2 / day~e.39 :ord (o2 / ordinal-entity~e.36,38 :value~e.36 3~e.36)) :op2 (d3 / day~e.39 :ord (o3 / ordinal-entity~e.38 :value~e.38 7~e.38)) :manner~e.41 (r / respective~e.41)) :time (a6 / after~e.43 :op1 (o4 / operate-02~e.45)) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure~e.3,47 :mod "2C"~e.4,48))) :op2 (d5 / decrease-01~e.12 :ARG0 m :ARG1 a2 :ARG2 s3 :ARG4~e.52 (a7 / and~e.54 :op1 (p5 / percentage-entity~e.56 :value 74~e.53) :op2 (p2 / percentage-entity~e.56 :value 59~e.55) :manner r~e.58) :location~e.60 (h / hippocampus~e.63 :mod (i2 / ipsilateral~e.62)) :ARG1-of (d6 / describe-01 :ARG0 (f4 / figure~e.65 :mod "2F"~e.66))))) # ::id bio.chicago_2015.39367 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( d ) NAK is activated by recombinant Nef and CDC42 in vitro . # ::alignments 1-1.1 3-1.3.1.1 5-1 6-1.2.r 7-1.2.3 8-1.2.1.1.1 9-1.2 10-1.2.2.1.1 11-1.4 12-1.4 (a / activate-01~e.5 :li "d"~e.1 :ARG0~e.6 (a2 / and~e.9 :op1 (p2 / protein :name (n2 / name :op1 "Nef"~e.8)) :op2 (p3 / protein :name (n3 / name :op1 "CDC42"~e.10)) :ARG3-of (r / recombine-01~e.7)) :ARG1 (p / protein :name (n / name :op1 "NAK"~e.3)) :manner (i / in-vitro~e.11,12)) # ::id bio.chicago_2015.39416 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , it has been shown that GSK @-@ 3 beta phosphorylates APC and that the phosphorylation enhances the binding of APC to beta @-@ catenin ( Rubinfeld et al. , 1996 ) . # ::alignments 0-1 5-1.1 6-1.1.1.r 7-1.1.1.2.1 10-1.1.1.2.2.2.1.1 11-1.1.1.1 12-1.1.1.1.1.1.1 16-1.1.1.1 17-1.1.1.2 19-1.1.1.2.2 21-1.1.1.1.1.1.1 23-1.1.1.2.2.2.1.1 25-1.1.1.2.2.2.1.1 27-1.1.2.1.1.1.1.1 28-1.1.1 28-1.1.2.1.1 29-1.1.2.1.1.2.1 31-1.1.2.1.2.1 (a / and~e.0 :op2 (s / show-01~e.5 :ARG1~e.6 (a2 / and~e.28 :op1 (p3 / phosphorylate-01~e.11,16 :ARG1 (p4 / protein :name (n / name :op1 "APC"~e.12,21)) :ARG2 (e / enzyme :name (n2 / name :op1 "GSK-3beta"))) :op2 (e2 / enhance-01~e.17 :ARG0 p3~e.7 :ARG1 (b / bind-01~e.19 :ARG1 p4 :ARG2 (p5 / protein :name (n3 / name :op1 "beta-catenin"~e.10,23,25))))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and~e.28 :op1 (p7 / person :name (n4 / name :op1 "Rubinfeld"~e.27)) :op2 (p8 / person :mod (o / other~e.29))) :time (d / date-entity :year 1996~e.31))))) # ::id bio.chicago_2015.39423 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All the results indicate that the activation of MAPK through Ras inhibits Fas @-@ mediated apoptosis in Balb3T3 cells , which may play a role in oncogenesis . # ::alignments 0-1.1.2 2-1.1 2-1.1.1 2-1.1.1.r 3-1 4-1.2.r 6-1.2.1 7-1.2.1.2.r 8-1.2.1.2.1.1 10-1.2.1.1.1.1 11-1.2 12-1.2.2.2.1.1.1 14-1.2.2.2 15-1.2.2 16-1.2.2.1.r 17-1.2.2.1.1.1 18-1.2.2.1 21-1.2.3.2 22-1.2.3 (i / indicate-01~e.3 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2) :mod (a / all~e.0)) :ARG1~e.4 (i2 / inhibit-01~e.11 :ARG0 (a2 / activate-01~e.6 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"~e.10)) :ARG1~e.7 (p / pathway :name (n / name :op1 "MAPK"~e.8))) :ARG1 (a3 / apoptosis~e.15 :location~e.16 (c / cell~e.18 :name (n3 / name :op1 "Balb3T3"~e.17)) :ARG1-of (m / mediate-01~e.14 :ARG0 (p3 / protein :name (n4 / name :op1 "Fas"~e.12)))) :ARG0-of (p4 / play-08~e.22 :ARG1 (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :ARG1-of (p5 / possible-01~e.21)))) # ::id bio.chicago_2015.39438 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mapping the region of HBO1 that interacts with MCM2 and ORC1 . # ::alignments 0-1 2-1.1 3-1.1.1.r 4-1.1.1.1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2.1.2.1.1 (m / map-01~e.0 :ARG1 (r / region~e.2 :poss~e.3 (e / enzyme :name (n / name :op1 "HBO1"~e.4)) :ARG0-of (i / interact-01~e.6 :ARG1~e.7 (a / and~e.9 :op1 (p / protein :name (n2 / name :op1 "MCM2"~e.8)) :op2 (p2 / protein :name (n3 / name :op1 "ORC1"~e.10)))))) # ::id bio.chicago_2015.39496 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To illustrate , elevated levels of cAMP that induce the activation of PKA can determine which Raf isoform will be engaged in a cell to stimulate MEKs . # ::alignments 1-1.1.3 3-1.1.1.1 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1 8-1.1.1.2 8-1.1.1.2.2 8-1.1.1.2.2.r 10-1.1.1.2.2.1 11-1.1.1.2.2.1.1.r 12-1.1.1.2.2.1.1.1.1 13-1 14-1.1 15-1.1.2.1 16-1.1.2.1.1.1.1.1.1 17-1.1.2.1.1.1 20-1.1.2 21-1.1.2.2.r 23-1.1.2.2 25-1.1.2.3 (p2 / possible-01~e.13 :ARG1 (d / determine-01~e.14 :ARG0 (l / level~e.4 :ARG1-of (e / elevate-01~e.3) :quant-of~e.5 (s2 / small-molecule~e.8 :name (n2 / name :op1 "cAMP"~e.6) :ARG0-of~e.8 (i / induce-01~e.8 :ARG2 (a / activate-01~e.10 :ARG1~e.11 (e2 / enzyme :name (n3 / name :op1 "PKA"~e.12)))))) :ARG1 (e3 / engage-01~e.20 :ARG1 (a2 / amr-unknown~e.15 :ARG1-of (i2 / include-91 :ARG2 (i3 / isoform~e.17 :mod (e4 / enzyme :name (n / name :op1 "Raf"~e.16))))) :ARG2~e.21 (c / cell~e.23) :purpose (s / stimulate-01~e.25 :ARG0 a2 :ARG1 (p4 / protein-family :name (n4 / name :op1 "MEK")))) :purpose (i4 / illustrate-01~e.1))) # ::id bio.chicago_2015.39508 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of SR Proteins by SRPK1 and Clk @/@ ty # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.1 4-1.2.r 5-1.2.1.1.1 6-1.2 7-1.2.2.1.1 9-1.2.2.1.1 (p / phosphorylate-01~e.0 :ARG1~e.1 (p2 / protein-family~e.3 :name (n / name :op1 "SR"~e.2)) :ARG2~e.4 (a / and~e.6 :op1 (e / enzyme :name (n2 / name :op1 "SRPK1"~e.5)) :op2 (e2 / enzyme :name (n3 / name :op1 "Clk/ty"~e.7,9)))) # ::id bio.chicago_2015.39510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fzr can not activate the APC/C in these cells because cdk1 - cyclin B1 phosphorylates fzr and prevents its binding to the APC/C ( Zachariae et al. , 1998 ; Lukas et al. , 1999 ; Listovsky et al. , 2000 ) . # ::alignments 0-1.2.2.1.1.1 1-1.2 2-1.2.1 2-1.2.1.r 3-1.2.2 5-1.2.2.2.1.1 6-1.2.2.3.r 7-1.2.2.3.1 8-1.2.2.3 9-1 10-1.1.1.2.1.1.1 12-1.1.1.2.2.1.1 13-1.1.1.2.2.1.2 14-1.1.1 15-1.1.1.1 16-1.1 16-1.3.1 16-1.3.1.1.1 17-1.1.2 19-1.1.2.2 20-1 20-1.1.2.2.2.r 22-1.1.2.2.2 24-1.3.1.1.1.1.1.1 25-1.3.1.1.1 26-1.3.1.1.1.2.1 28-1.3.1.1.2.1 30-1.3.1.2.1.1.1.1 31-1.3.1 31-1.3.1.1.1 31-1.3.1.2.1 31-1.3.1.3.1 32-1.3.1.1.1.2.1 34-1.3.1.2.2.1 36-1.3.1.3.1.1.1.1 37-1.3.1 37-1.3.1.1.1 37-1.3.1.3.1 38-1.3.1.1.1.2.1 40-1.3.1.3.2.1 (c / cause-01~e.9,20 :ARG0 (a2 / and~e.16 :op1 (p4 / phosphorylate-01~e.14 :ARG1 p2~e.15 :ARG2 (m / macro-molecular-complex :part (e / enzyme :name (n3 / name :op1 "cdk1"~e.10)) :part (p14 / protein :name (n7 / name :op1 "cyclin"~e.12 :op2 "B1"~e.13)))) :op2 (p5 / prevent-01~e.17 :ARG0 m :ARG1 (b / bind-01~e.19 :ARG1 p2 :ARG2~e.20 p3~e.22))) :ARG1 (p / possible-01~e.1 :polarity~e.2 -~e.2 :ARG1 (a / activate-01~e.3 :ARG0 (p2 / protein :name (n / name :op1 "Fzr"~e.0)) :ARG1 (p3 / protein :name (n2 / name :op1 "APC/C"~e.5)) :location~e.6 (c2 / cell~e.8 :mod (t / this~e.7)))) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and~e.16,31,37 :op1 (p7 / publication-91 :ARG0 (a4 / and~e.16,25,31,37 :op1 (p8 / person :name (n4 / name :op1 "Zachariae"~e.24)) :op2 (p9 / person :mod (o / other~e.26,32,38))) :time (d / date-entity :year 1998~e.28)) :op2 (p10 / publication-91 :ARG0 (a5 / and~e.31 :op1 (p11 / person :name (n5 / name :op1 "Lukas"~e.30)) :op2 p9) :time (d2 / date-entity :year 1999~e.34)) :op3 (p12 / publication-91 :ARG0 (a6 / and~e.31,37 :op1 (p13 / person :name (n6 / name :op1 "Listovsky"~e.36)) :op2 p9) :time (d3 / date-entity :year 2000~e.40))))) # ::id bio.chicago_2015.39521 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SRF Activation by LIMK @-@ 1 Is Largely Dependent on RhoA # ::alignments 0-1.1.2.1.1 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 7-1.3 8-1 9-1.2.r 10-1.2.1.1 (d / depend-01~e.8 :ARG0 (a / activate-01~e.1 :ARG0~e.2 (e / enzyme :name (n / name :op1 "LIMK-1"~e.3,5)) :ARG1 (p / protein :name (n2 / name :op1 "SRF"~e.0))) :ARG1~e.9 (p2 / protein :name (n3 / name :op1 "RhoA"~e.10)) :degree (l / large~e.7)) # ::id bio.chicago_2015.39527 ::amr-annotator SDL-AMR-09 ::preferred # ::tok APC appears to be critical for the rapid turnover of beta @-@ catenin ( Munemitsu et al. , 1995 ) , and phosphorylation of APC by GSK @-@ 3 appears to enhance the interaction of APC and beta @-@ catenin ( Rubinfeld et al. , 1996 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1 4-1.1.1 7-1.1.1.2.2 10-1.1.1.2.1.1.1 12-1.1.1.2.1.1.1 14-1.1.2.1.1.1.1.1 15-1.1.2.1.1 16-1.1.2.1.1.2.1 18-1.1.2.1.2.1 21-1 21-1.1.2.1.1 22-1.2.1.1 23-1.2.1.1.1.r 24-1.2.1.1.1 25-1.2.1.1.2.r 26-1.2.1.1.2.1.1 28-1.2.1.1.2.1.1 29-1.2 31-1.2.1 33-1.2.1.2 34-1.2.1.2.1.r 35-1.2.1.2.1 37-1.1.1.2.1.1.1 39-1.1.1.2.1.1.1 41-1.2.2.1.1.1.1.1 42-1 42-1.1.2.1.1 42-1.2.2.1.1 43-1.1.2.1.1.2.1 45-1.2.2.1.2.1 (a2 / and~e.21,42 :op1 (a3 / appear-02~e.1 :ARG1 (c2 / critical-02~e.4 :ARG1 (p3 / protein :name (n / name :op1 "APC"~e.0)) :ARG2 (t / turn-over-12 :ARG1 (p4 / protein :name (n2 / name :op1 "beta-catenin"~e.10,12,37,39)) :mod (r / rapid~e.7))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and~e.15,21,42 :op1 (p5 / person :name (n3 / name :op1 "Munemitsu"~e.14)) :op2 (p6 / person :mod (o / other~e.16,43))) :time (d / date-entity :year 1995~e.18)))) :op2 (a5 / appear-02~e.29 :ARG1 (e / enhance-01~e.31 :ARG0 (p8 / phosphorylate-01~e.22 :ARG1~e.23 p3~e.24 :ARG2~e.25 (e2 / enzyme :name (n4 / name :op1 "GSK-3"~e.26,28))) :ARG1 (i / interact-01~e.33 :ARG0~e.34 p3~e.35 :ARG1 p4)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication-91 :ARG0 (a6 / and~e.42 :op1 (p11 / person :name (n6 / name :op1 "Rubinfeld"~e.41)) :op2 p6) :time (d2 / date-entity :year 1996~e.45))))) # ::id bio.chicago_2015.39535 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is interesting to note that the results we obtained by assaying BDNF @-@ induced c @- fos expression in transient gene reporter assays were qualitatively similar to those we obtained by assaying BDNF @-@ induced expression of endogenous Fos ( compare Figure 1 and Figure 2 ) . # ::alignments 2-1 4-1.1 5-1.1.1.r 7-1.1.1.1 7-1.1.1.1.1 7-1.1.1.1.1.r 7-1.1.1.2 7-1.1.1.2.1 7-1.1.1.2.1.r 8-1.1.1.1.2.1 9-1.1.1.1.2 11-1.1.1.1.2.2 12-1.1.1.1.2.2.2.2.1.1.1 14-1.1.1.1.2.2.2.2 15-1.1.1.1.2.2.2.1.1.1 17-1.1.1.1.2.2.2.1.1.1 18-1.1.1.1.2.2.2 20-1.1.1.1.2.2.2.3.1.1 21-1.1.1.1.2.2.2.3.1 22-1.1.1.1.2.2.2.3.1.2 23-1.1.1.1.2.2.2.3 25-1.1.1.3 26-1.1.1 29-1.1.1.1.2.1 30-1.1.1.1.2 30-1.1.1.2.1.1 32-1.1.1.1.2.2 32-1.1.1.2.1.1.2 33-1.1.1.1.2.2.2.2.1.1.1 35-1.1.1.1.2.2.2.2 36-1.1.1.1.2.2.2 36-1.1.1.2.1.1.2.2 37-1.1.1.2.1.1.2.2.1.r 38-1.1.1.2.1.1.2.2.1.2 39-1.1.1.2.1.1.2.2.1.1.1 41-1.2.1 42-1.2.1.1 42-1.2.1.2 43-1.2.1.1.1 45-1.2.1.2 46-1.2.1.2.1 (i / interest-01~e.2 :ARG0 (n / note-01~e.4 :ARG1~e.5 (r2 / resemble-01~e.26 :ARG1 (t / thing~e.7 :ARG2-of~e.7 (r3 / result-01~e.7) :ARG1-of (o / obtain-01~e.9,30 :ARG0 (w / we~e.8,29) :ARG2 (a / assay-01~e.11,32 :ARG0 w :ARG1 (e / express-03~e.18,36 :ARG2 (p2 / protein :name (n2 / name :op1 "c-fos"~e.15,17)) :ARG2-of (i2 / induce-01~e.14,35 :ARG0 (p3 / protein :name (n3 / name :op1 "BDNF"~e.12,33))) :location (a2 / assay-01~e.23 :ARG1 (g2 / gene~e.21 :ARG1-of (t2 / transient-02~e.20) :ARG0-of (r / report-01~e.22))))))) :ARG2 (t3 / thing~e.7 :ARG2-of~e.7 (r5 / result-01~e.7 :ARG1-of (o2 / obtain-01~e.30 :ARG0 w :ARG2 (a3 / assay-01~e.32 :ARG0 w :ARG1 (e2 / express-03~e.36 :ARG2~e.37 (p4 / protein :name (n4 / name :op1 "Fos"~e.39) :mod (e3 / endogenous~e.38)) :ARG2-of i2))))) :mod (q / qualitative~e.25))) :ARG1-of (d / describe-01 :ARG0 (c / compare-01~e.41 :ARG1 (f / figure~e.42 :mod 1~e.43) :ARG2 (f2 / figure~e.42,45 :mod 2~e.46)))) # ::id bio.chicago_2015.39542 ::amr-annotator SDL-AMR-09 ::preferred # ::tok amphiphysin binds to clathrin , AP2 , synaptojanin , and dynamin , while epsin binds to AP2 and clathrin ( reviewed by [ 34 , 38 ] ) . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2.1.1.1 5-1.1.2.2.1.1 7-1.1.2.3.1.1 9-1.1.2 10-1.1.2.4.1.1 12-1 13-1.2.1.1.1 14-1.1 14-1.2 16-1.1.2.2.1.1 17-1.1.2 18-1.1.2.1.1.1 20-1.3.1.2 23-1.3.1.1.1.1 25-1.3.1.1.1.2 (c / contrast-01~e.12 :ARG1 (b / bind-01~e.1,14 :ARG1 (p / protein :name (n / name :op1 "amphiphysin"~e.0)) :ARG2 (a / and~e.9,17 :op1 (p2 / protein :name (n2 / name :op1 "clathrin"~e.3,18)) :op2 (p3 / protein :name (n3 / name :op1 "AP2"~e.5,16)) :op3 (p4 / protein :name (n4 / name :op1 "synaptojanin"~e.7)) :op4 (p8 / protein :name (n5 / name :op1 "dynamin"~e.10)))) :ARG2 (b2 / bind-01~e.14 :ARG1 (p5 / protein :name (n6 / name :op1 "epsin"~e.13)) :ARG2 (a2 / and :op1 p3 :op2 p2)) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 34~e.23 :op2 38~e.25)) :ARG0-of (r / review-01~e.20)))) # ::id bio.chicago_2015.39546 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , FynKD is able to inhibit Cbl phosphorylation by Abl ( unpublished result ) . # ::alignments 0-1.3 2-1.2.1.1.1 4-1 6-1.2 7-1.2.2.1.1.1 8-1.2.2 9-1.2.2.2.r 10-1.2.2.2.1.1 12-1.4.1.2 12-1.4.1.2.1 12-1.4.1.2.1.r 13-1.4.1 13-1.4.1.1 13-1.4.1.1.r (c / capable-01~e.4 :ARG1 p :ARG2 (i / inhibit-01~e.6 :ARG0 (p / protein :name (n / name :op1 "FynKD"~e.2)) :ARG1 (p2 / phosphorylate-01~e.8 :ARG1 (p3 / protein :name (n2 / name :op1 "Cbl"~e.7)) :ARG2~e.9 (p4 / protein :name (n3 / name :op1 "Abl"~e.10)))) :mod (i2 / indeed~e.0) :ARG1-of (d / describe-01 :ARG0 (t / thing~e.13 :ARG2-of~e.13 (r / result-01~e.13) :ARG1-of (p5 / publish-01~e.12 :polarity~e.12 -~e.12)))) # ::id bio.chicago_2015.39559 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because binding of p53 by mdm2 is required for mdm2 @-@ mediated p53 degradation ( 15 , 16 ) , these results suggest that TAFII31 either out @-@ competes mdm2 for binding to p53 or excludes mdm2 from the p53 complex , thus preventing mdm2 @-@ mediated p53 degradation . # ::alignments 0-1.3 1-1.2.1.3 3-1.2.1.3.2.1.1 5-1.2.1.2.1.1 7-1.3.1 9-1.2.2.4.1.2.1 11-1.2.2.4.1.2 12-1.2.1.3.2.1.1 13-1.2.2.4.1 15-1.3.2.1.1.1.1 17-1.3.2.1.1.1.2 20-1.1.2 21-1.1 21-1.1.1 21-1.1.1.r 22-1 24-1.2.1.1.1.1 29-1.2.1.2.1.1 31-1.2.1.3 33-1.2.1.3.2.1.1 34-1.2 35-1.2.2 36-1.2.1.2.1.1 37-1.2.2.3.r 39-1.2.2.3.1 40-1.2.2.3 42-1.3 43-1.2.2.4 44-1.2.2.4.1.2.1 46-1.2.2.4.1.2 47-1.2.2.4.1.1 48-1.2.2.4.1 (s / suggest-01~e.22 :ARG0 (t / thing~e.21 :ARG2-of~e.21 (r / result-01~e.21) :mod (t2 / this~e.20)) :ARG1 (o / or~e.34 :op1 (o2 / outcompete-00 :ARG0 (p / protein :name (n / name :op1 "TAFII31"~e.24)) :ARG1 (p2 / protein :name (n2 / name :op1 "mdm2"~e.5,29,36)) :ARG3 (b / bind-01~e.1,31 :ARG1 p :ARG2 (p3 / protein :name (n3 / name :op1 "p53"~e.3,12,33)))) :op1 (e / exclude-01~e.35 :ARG0 p :ARG1 p2 :ARG2~e.37 (c / complex~e.40 :mod p3~e.39) :ARG0-of (p4 / prevent-01~e.43 :ARG1 (d / degrade-01~e.13,48 :ARG1 p3~e.47 :ARG1-of (m / mediate-01~e.11,46 :ARG0 p2~e.9,44))))) :ARG1-of (c2 / cause-01~e.0,42 :ARG0 (r2 / require-01~e.7 :ARG0 d :ARG1 b) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 15~e.15 :op2 16~e.17)))))) # ::id bio.chicago_2015.39560 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytochrome c and dATP @-@ dependent formation of Apaf @-@ 1/caspase @-@ 9 complex initiates an apoptotic protease cascade . # ::alignments 0-1.1.2.1.1.1.1 1-1.1.2.1.1.1.2 2-1.1.2.1 3-1.1.2.1.2.1.1 5-1.1.2 6-1.1 7-1.1.1.r 8-1.1.1.1.1.1 12-1.1.1.2.1.1 13-1.1.1 14-1 16-1.2.2 17-1.2.1 18-1.2 (i / initiate-01~e.14 :ARG0 (f / form-01~e.6 :ARG1~e.7 (m / macro-molecular-complex~e.13 :part (p / protein :name (n / name :op1 "Apaf-1"~e.8)) :part (e / enzyme :name (n2 / name :op1 "caspase-9"~e.12))) :ARG0-of (d / depend-01~e.5 :ARG1 (a2 / and~e.2 :op1 (p3 / protein :name (n3 / name :op1 "Cytochrome"~e.0 :op2 "c"~e.1)) :op2 (s / small-molecule :name (n4 / name :op1 "dATP"~e.3))))) :ARG1 (c / cascade~e.18 :mod (p2 / protease~e.17) :mod (a / apoptotic~e.16))) # ::id bio.chicago_2015.39589 ::amr-annotator SDL-AMR-09 ::preferred # ::tok kuz Is Required for the Proteolytic Processing of Notch # ::alignments 0-1.2.1.1 2-1 3-1.1.r 5-1.1.2 6-1.1 7-1.1.1.r 8-1.1.1.1.1 (r / require-01~e.2 :ARG0~e.3 (p2 / process-01~e.6 :ARG1~e.7 (p3 / protein :name (n2 / name :op1 "Notch"~e.8)) :mod (p4 / proteolysis~e.5)) :ARG1 (p / protein :name (n / name :op1 "kuz"~e.0))) # ::id bio.chicago_2015.39645 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because CI is caused by the presence of Wolbachia in male reproductive cells , this 10 @-@ fold difference alone would seem sufficient to explain the very low CI phenotype exhibited by Wien 5 males in contrast with the high CI exhibited by transinfected ME males . # ::alignments 0-1.1 3-1.1 3-1.1.1.2.1 4-1.1.1.r 6-1.1.1 7-1.1.1.1.r 8-1.1.1.1.1.1 9-1.1.1.2.r 10-1.1.1.2.2 12-1.1.1.2 15-1.2.1.1.2.1 17-1.2.1.1.2 18-1.2.1.1 18-1.2.1.2.2.1.2.1 18-1.2.1.2.2.3.1.1.1 19-1.2.1.1.1 21-1.2 22-1.2.1 24-1.2.1.2 26-1.2.1.2.2.2 27-1.2.1.2.2 29-1.2.1.2.2.1 30-1.2.1.2.2.1.1 32-1.2.1.2.2.1.1.1.1.1.1 33-1.2.1.2.2.1.1.1.1.1.2 34-1.2.1.2.2.1.1.1 35-1.2.1.2.2.3.r 36-1.2.1.2.2.3 37-1.2.1.2.2.3.1.r 39-1.2.1.2.2.3.1 41-1.2.1.2.2.3.1.1.2 44-1.2.1.2.2.3.1.1.2.1.1.1.1 45-1.2.1.2.2.1.1.1 45-1.2.1.2.2.3.1.1.2.1 (c3 / cause-01 :ARG0 (c4 / cause-01~e.0,3 :ARG0~e.4 (p / present-02~e.6 :ARG1~e.7 (o / organism :name (n2 / name :op1 "Wolbachia"~e.8)) :ARG2~e.9 (c5 / cell~e.12 :ARG0-of (c6 / cause-01~e.3 :ARG1 (r / reproduce-01)) :mod (m2 / male~e.10))) :ARG1 c) :ARG1 (s / seem-01~e.21 :ARG1 (s2 / suffice-01~e.22 :ARG0 (d / differ-02~e.18 :mod (a / alone~e.19) :mod (p2 / product-of~e.17 :op1 10~e.15)) :ARG1 (e / explain-01~e.24 :ARG0 d :ARG1 (l / low-04~e.27 :ARG1 (p3 / phenotype~e.29 :ARG1-of (e2 / exhibit-01~e.30 :ARG0 (m3 / male~e.34,45 :mod (o3 / organism :name (n4 / name :op1 "Wien"~e.32 :op2 5~e.33)))) :mod (c / compatible :polarity -~e.18 :mod (c2 / cytoplasm))) :degree (v / very~e.26) :ARG1-of~e.35 (c7 / contrast-01~e.36 :ARG2~e.37 (h / high-02~e.39 :ARG1 (c8 / compatible :polarity -~e.18 :ARG1-of (e3 / exhibit-01~e.41 :ARG0 (m4 / male~e.45 :mod (o2 / organism :name (n6 / name :op1 "ME"~e.44))) :ARG1-of (t2 / transinfect-00)) :mod c2)))))))) # ::id bio.chicago_2015.39663 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that , although it strongly stimulates caspase activation , the cell death induced by the down @-@ regulation of DIAP1 can be executed through a caspase @-@ independent pathway . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 5-1.2.1.3.r 6-1.2.1.3.1 7-1.2.1.3.3 8-1.2.1.3 9-1.2.1.3.2.1 10-1.2.1.3.2 13-1.2.1.1.1 14-1.2.1.1 15-1.2.1.1.2 16-1.2.1.1.2.1.r 18-1.2.1.1.2.1 19-1.2.1.1.2.1 20-1.2.1.1.2.1 21-1.2.1.1.2.1.1.r 22-1.2.1.1.2.1.1.1.1 23-1.2 25-1.2.1 28-1.2.1.2.1.2.1.1 30-1.2.1.2.1 30-1.2.1.2.1.1 30-1.2.1.2.1.1.r 31-1.2.1.2 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1 (p / possible-01~e.23 :ARG1 (e / execute-02~e.25 :ARG1 (d / die-01~e.14 :ARG1 (c / cell~e.13) :ARG2-of (i / induce-01~e.15 :ARG0~e.16 (d2 / downregulate-01~e.18,19,20 :ARG1~e.21 (p2 / protein :name (n / name :op1 "DIAP1"~e.22))))) :ARG3 (p3 / pathway~e.31 :ARG0-of (d3 / depend-01~e.30 :polarity~e.30 -~e.30 :ARG1 (p4 / protein :name (n2 / name :op1 "caspase"~e.28)))) :concession~e.5 (s2 / stimulate-01~e.8 :ARG0 d~e.6 :ARG1 (a / activate-01~e.10 :ARG1 p4~e.9) :ARG1-of (s3 / strong-02~e.7))))) # ::id bio.chicago_2015.39706 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TSH rapidly activated Rap1 , an effect that was reproduced by cAMP elevating agents , but PKA independent . # ::alignments 0-1.1.1.1 1-1.3 1-1.3.r 2-1 3-1.2.1.1 6-1.4 9-1.4.1 10-1.4.1.1.r 11-1.4.1.1.2.1.1 12-1.4.1.1.1 13-1.4.1.1 15-1.4.1.2 16-1.4.1.2.1.3.1.1 17-1.4.1.2.1 17-1.4.1.2.1.1 17-1.4.1.2.1.1.r (a / activate-01~e.2 :ARG0 (s2 / small-molecule :name (n / name :op1 "TSH"~e.0)) :ARG1 (e3 / enzyme :name (n2 / name :op1 "Rap1"~e.3)) :manner~e.1 (r / rapid~e.1) :ARG2-of (a2 / affect-01~e.6 :ARG1-of (r2 / reproduce-01~e.9 :ARG0~e.10 (a3 / agent~e.13 :ARG0-of (e / elevate-01~e.12) :mod (s / small-molecule :name (n3 / name :op1 "cAMP"~e.11))) :ARG1-of (c / contrast-01~e.15 :ARG2 (d / depend-01~e.17 :polarity~e.17 -~e.17 :ARG0 a2 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PKA"~e.16))))))) # ::id bio.chicago_2015.39736 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of Cdc25 by Cds1 and @/@ or Chk1 inhibits its activity and thereby prevents dephosphorylation and activation of Cdc2 @-@ Cyclin B. # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 4-1.1.2.1.1.1 5-1.1.2 7-1.1.2 8-1.1.2.2.1.1 9-1 10-1.2.1 10-1.2.1.r 11-1.2 12-1.3.1.2 14-1.3.1 15-1.3.1.2.1 16-1.3.1.2 17-1.3.1.2.2 18-1.3.1.2.1.1.r 19-1.3.1.2.1.1.1.1.1 21-1.3.1.2.1.1.2.1.1 (i / inhibit-01~e.9 :ARG0 (p / phosphorylate-01~e.0 :ARG1~e.1 (e4 / enzyme :name (n / name :op1 "Cdc25"~e.2)) :ARG2~e.3 (a / and-or~e.5,7 :op1 (e / enzyme :name (n2 / name :op1 "Cds1"~e.4)) :op2 (e2 / enzyme :name (n3 / name :op1 "Chk1"~e.8)))) :ARG1 (a2 / activity-06~e.11 :ARG0~e.10 e4~e.10) :ARG0-of (c / cause-01 :ARG1 (p3 / prevent-01~e.14 :ARG0 p :ARG1 (a3 / and~e.12,16 :op1 (d / dephosphorylate-01~e.15 :ARG1~e.18 (m / macro-molecular-complex :part (e3 / enzyme :name (n4 / name :op1 "Cdc2"~e.19)) :part (p5 / protein :name (n5 / name :op1 "Cyclin"~e.21 :op2 "B")))) :op2 (a4 / activate-01~e.17 :ARG1 m))))) # ::id bio.chicago_2015.39738 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GBP might sterically block access of protein substrates to the active site of GSK @-@ 3 , and we are currently attempting to map the residues of Xgsk @-@ 3 that are important for GBP binding to Xgsk @-@ 3 to determine if GBP might bind in the region of Xgsk @-@ 3 's active site . # ::alignments 0-1.1.1.1.1.1 1-1.1 3-1.1.1 4-1.1.1.2 5-1.1.1.2.1.r 6-1.1.1.2.1.1 7-1.1.1.2.1 8-1.1.1.2.2.r 10-1.1.1.2.2.2 11-1.1.1.2.2 12-1.1.1.2.2.1.r 13-1.1.1.2.2.1.1.1 15-1.1.1.2.2.1.1.1 17-1 18-1.2.1 20-1.2.3 21-1.2 23-1.2.2 25-1.2.2.2 26-1.2.2.2.1.r 27-1.2.2.2.1.1.1 29-1.2.2.2.1.1.1 32-1.2.2.2.2 34-1.2.2.2.2.1.1 35-1.2.2.2.2.1 36-1.2.2.2.2.1.2.r 37-1.2.2.2.2.1.2 38-1.2.2.2.2.1.2 39-1.2.2.2.2.1.2 41-1.2.2.2.2.2 43-1.1.1.1.1.1 44-1.2.2.2.2.2.2 45-1.2.2.2.2.2.2.2 46-1.2.2.2.2.2.2.2.2.r 48-1.2.2.2.2.2.2.2.2 50-1.2.2.2.1.1.1 52-1.2.2.2.1.1.1 53-1.2.2.2.2 54-1.2.2.2.2.2.2.2.2.1.1 55-1.2.2.2.2.2.2.2.2.1 (a3 / and~e.17 :op1 (p / possible-01~e.1 :ARG1 (b / block-01~e.3 :ARG0 (p4 / protein :name (n2 / name :op1 "GBP"~e.0,43)) :ARG1 (a / access-01~e.4 :ARG0~e.5 (s / substrate~e.7 :mod (p2 / protein~e.6)) :ARG1~e.8 (s2 / site~e.11 :part-of~e.12 (e / enzyme :name (n / name :op1 "GSK-3"~e.13,15)) :ARG1-of (a2 / activity-06~e.10))) :manner (s3 / steric))) :op2 (a4 / attempt-01~e.21 :ARG0 (w / we~e.18) :ARG1 (m / map-02~e.23 :ARG0 w :ARG1 (r / residue~e.25 :poss~e.26 (p5 / protein :name (n3 / name :op1 "Xgsk-3"~e.27,29,50,52)) :mod (i / important~e.32,53 :topic (b2 / bind-01~e.35 :ARG1 p4~e.34 :ARG2~e.36 p5~e.37,38,39) :purpose (d / determine-01~e.41 :ARG0 w :ARG1 (p6 / possible-01~e.44 :mode interrogative :ARG1 (b3 / bind-01~e.45 :ARG1 p4 :ARG2~e.46 (r2 / region~e.48 :poss (s4 / site~e.55 :ARG1-of a2~e.54 :mod p5)))))))) :time (c / current~e.20))) # ::id bio.chicago_2015.39759 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The defect appears to be caused by the lack of filamin , as reintroduction of filamin restores NF @-@ kappaB activation by TNF and constitutively active TLR4 or TRAF6 . # ::alignments 1-1.1.2 2-1 3-1.1 3-1.2 5-1.1 6-1.1.1.r 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1.1.1 15-1.1.1.1.1.1 16-1.2.1 17-1.2.1.2.2.1.1 19-1.2.1.2.2.1.1 20-1.2.1.2 21-1.2.1.2.1.r 22-1.2.1.2.1.1.1.1 23-1.2.1.2.1 24-1.2.1.2.1.2.3.1 25-1.2.1.2.1.2.3 26-1.2.1.2.1.2.1.1.1 27-1.2.1.2.1.2 28-1.2.1.2.1.2.2.1.1 (a / appear-02~e.2 :ARG1 (c / cause-01~e.3,5 :ARG0~e.6 (l / lack-01~e.8 :ARG1~e.9 (p / protein :name (n / name :op1 "filamin"~e.10,15))) :ARG1 (d / defect~e.1)) :ARG1-of (c2 / cause-01~e.3 :ARG0 (r / restore-01~e.16 :ARG0 (r2 / reintroduce-02 :ARG1 p) :ARG1 (a2 / activate-01~e.20 :ARG0~e.21 (a3 / and~e.23 :op1 (p3 / protein :name (n3 / name :op1 "TNF"~e.22)) :op2 (o / or~e.27 :op1 (p4 / protein :name (n4 / name :op1 "TLR4"~e.26)) :op2 (p5 / protein :name (n5 / name :op1 "TRAF6"~e.28)) :ARG0-of (a4 / activity-06~e.25 :mod (c3 / constitutive~e.24)))) :ARG1 (p2 / protein :name (n2 / name :op1 "NF-kappaB"~e.17,19)))))) # ::id bio.chicago_2015.39792 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Residues 170 to 200 of YY1 are acetylated by p300 and PCAF , while the C @-@ terminal zinc finger domain is acetylated only by PCAF ( Fig . 9A ) . # ::alignments 0-1.1.2 1-1.1.2.2.1 3-1.1.2.2.2 4-1.1.2.1.r 5-1.1.2.1.1.1 7-1.1 8-1.1.1.r 9-1.1.1.1.1.1 10-1.1.1 11-1.1.1.2.1.1 13-1 15-1.2.2.1.1 17-1.2.2.1.1 18-1.2.2.1.2 19-1.2.2.1.3 20-1.2.2.1.4 22-1.2 23-1.2.3 24-1.2.1.r 25-1.2.1 27-1.3.1 29-1.3.1.1 (c / contrast-01~e.13 :ARG1 (a / acetylate-01~e.7 :ARG0~e.8 (a2 / and~e.10 :op1 (p2 / protein :name (n2 / name :op1 "p300"~e.9)) :op2 (p3 / protein :name (n3 / name :op1 "PCAF"~e.11))) :ARG1 (r / residue~e.0 :part-of~e.4 (p / protein :name (n / name :op1 "YY1"~e.5)) :mod (v / value-interval :op1 170~e.1 :op2 200~e.3))) :ARG2 (a3 / acetylate-01~e.22 :ARG0~e.24 p3~e.25 :ARG1 (p4 / protein-segment :name (n4 / name :op1 "C-terminal"~e.15,17 :op2 "zinc"~e.18 :op3 "finger"~e.19 :op4 "domain"~e.20)) :mod (o / only~e.23)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "9A"~e.29))) # ::id bio.chicago_2015.39808 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , mutant analysis indicates that msh is repressed ventrally by DER ( D'Alessio and Frasch 1996 ; Skeath 1998 ) , by ind ( Weiss et al. 1998 ) , and by vnd ( this work ) ; ind is repressed by vnd ( McDonald et al. 1998 ) , and vnd and rho are repressed by snail ( Ip et al. 1992 ; Mellerick and Nirenberg 1995 ) , a mesoderm master gene that is expressed in the ventral @-@ most region of the blastoderm . # ::alignments 0-1.1.3 2-1.1.1.1 3-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.2.1.1 8-1.2.2 11-1.1.2.1.1.1.1 13-1.1.2.1.3.1.1.1.1.1.1 14-1.1.2.1.3.1.1.1 15-1.1.2.1.3.1.1.1.2.1.1 16-1.1.2.1.3.1.1.2.1 18-1.1.2.1.3.1.2.1.1.1 19-1.1.2.1.3.1.2.2.1 22-1.1.2.r 23-1.1.2.2.1.1.1 25-1.1.2.2.3.1.1.1.1.1 26-1.1.2.2.3.1.1 27-1.1.2.2.3.1.1.2.1 28-1.1.2.1.3.1.2.2.1 31-1.1.2.1.3.1 31-1.1.2.2.3.1.1 35-1.1.2.3.3.1.1 36-1.1.2.3.3.1 39-1.1.2.2.1.1.1 41-1.2.2 45-1.2.1.3.1.1.1.1.1 46-1.1.2.1.3.1 46-1.1.2.2.3.1.1 46-1.2 46-1.2.1.3.1.1 46-1.2.2.3.1 46-1.2.2.3.1.1.1 47-1.1.2.2.3.1.1.2.1 48-1.1.2.1.3.1.2.2.1 51-1.1.2.1.3.1 51-1.1.2.2.3.1.1 51-1.2 51-1.2.1.3.1.1 51-1.2.2.3.1 51-1.2.2.3.1.1.1 53-1.1.2 53-1.1.2.1.3.1 53-1.1.2.2.3.1.1 53-1.2.1.3.1.1 53-1.2.2.2 53-1.2.2.3.1 53-1.2.2.3.1.1.1 54-1.2.2.2.2.1.1 56-1.1.2.1 56-1.1.2.2 56-1.1.2.3 56-1.2.1 56-1.2.2 57-1.2.2.1.r 58-1.2.2.1.1.1 60-1.2.2.3.1.1.1.1.1.1 61-1.1.2.1.3.1 61-1.1.2.2.3.1.1 61-1.2 61-1.2.1.3.1.1 61-1.2.2.3.1 61-1.2.2.3.1.1.1 61-1.2.2.3.1.2.1 62-1.1.2.2.3.1.1.2.1 63-1.2.2.3.1.1.2.1 65-1.2.2.3.1.2.1.1.1.1 66-1.2.2.3.1.2.1 67-1.2.2.3.1.2.1.2.1.1 68-1.2.2.3.1.2.2.1 72-1.2.2.1.3 73-1.2.2.1.4 74-1.1.2.1.2 74-1.2.2.1 77-1.2.2.1.2 80-1.1.2.1.4 80-1.2.2.1.2.1.1 82-1.2.2.1.2.1.1.1 83-1.2.2.1.2.1 84-1.2.2.1.2.1.2.r 86-1.2.2.1.2.1.2 (a12 / and :op1 (i4 / indicate-01~e.4 :ARG0 (a / analyze-01~e.3 :ARG1 (m / mutate-01~e.2)) :ARG1~e.5,22 (a2 / and~e.53 :op1 (r / repress-01~e.56 :ARG0 (e2 / enzyme :name (n2 / name :op1 "DER"~e.11)) :ARG1 (g2 / gene~e.74 :name (n / name :op1 "msh"~e.6)) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.31,46,51,53,61 :op1 (p5 / publication-91 :ARG0 (a3 / and~e.14 :op1 (p6 / person :name (n3 / name :op1 "D'Alessio"~e.13)) :op2 (p7 / person :name (n4 / name :op1 "Frasch"~e.15))) :time (d / date-entity :year 1996~e.16)) :op2 (p8 / publication-91 :ARG0 (p9 / person :name (n5 / name :op1 "Skeath"~e.18)) :time (d2 / date-entity :year 1998~e.19,28,48)))) :manner (v2 / ventral~e.80)) :op2 (r2 / repress-01~e.56 :ARG0 (p10 / protein :name (n6 / name :op1 "ind"~e.23,39)) :ARG1 g2 :ARG1-of (d4 / describe-01 :ARG0 (p11 / publication-91 :ARG0 (a5 / and~e.26,31,46,51,53,61 :op1 (p12 / person :name (n7 / name :op1 "Weiss"~e.25)) :op2 (p13 / person :mod (o2 / other~e.27,47,62))) :time d2))) :op3 (r3 / repress-01~e.56 :ARG0 (p14 / protein :name (n8 / name :op1 "vdn")) :ARG1 g2 :ARG1-of (d7 / describe-01 :ARG0 (w / work~e.36 :mod (t / this~e.35))))) :mod (i / indeed~e.0)) :op2 (a6 / and~e.46,51,61 :op1 (r4 / repress-01~e.56 :ARG0 p14 :ARG1 p10 :ARG1-of (d8 / describe-01 :ARG0 (p15 / publication-91 :ARG0 (a7 / and~e.46,51,53,61 :op1 (p16 / person :name (n9 / name :op1 "McDonald"~e.45)) :op2 p13) :time d2))) :op2 (r5 / repress-01~e.8,41,56 :ARG0~e.57 (g / gene~e.74 :name (n10 / name :op1 "snail"~e.58) :ARG1-of (e / express-03~e.77 :ARG3 (r6 / region~e.83 :mod (v / ventral~e.80 :degree (m5 / most~e.82)) :poss~e.84 (b / blastoderm~e.86))) :mod (m3 / mesoderm~e.72) :mod (m4 / master~e.73)) :ARG1 (a8 / and~e.53 :op1 p14 :op2 (p18 / protein :name (n11 / name :op1 "rho"~e.54))) :ARG1-of (d9 / describe-01 :ARG0 (a9 / and~e.46,51,53,61 :op1 (p19 / publication-91 :ARG0 (a10 / and~e.46,51,53,61 :op1 (p20 / person :name (n12 / name :op1 "Ip"~e.60)) :op2 p13) :time (d5 / date-entity :year 1992~e.63)) :op2 (p21 / publication-91 :ARG0 (a11 / and~e.61,66 :op1 (p22 / person :name (n13 / name :op1 "Mellerick"~e.65)) :op2 (p23 / person :name (n14 / name :op1 "Nirenberg"~e.67))) :time (d6 / date-entity :year 1995~e.68))))))) # ::id bio.chicago_2015.39809 ::amr-annotator SDL-AMR-09 ::preferred # ::tok the Ras @-@ binding domain ( RBD ) of Raf @-@ 1 , which specifically binds the active , GTP @-@ bound form of Ras , and the Rap1 @-@ binding domain of Ral @-@ GDS , which binds the GTP @-@ bound form of Rap1 . # ::alignments 1-1.1.3.1.1.1 3-1.1.3.1.3 4-1.2 6-1.1.1.1 9-1.1.2.1.1 11-1.1.2.1.1 14-1.1.3.2 15-1.1 15-1.1.3 15-1.1.3.1.3 15-1.1.3.r 17-1.1.3.1 17-1.1.3.1.2 17-1.1.3.1.2.r 19-1.1.3.1.3.1.1.1 21-1.1.3.1.3 24-1.1.3.1.1.1 26-1 28-1.2.2.1.1.1 30-1.2.2 31-1.2 32-1.2.1.r 33-1.2.1.1.1 35-1.2.1.1.1 38-1.1.3.1.3 38-1.2.2 40-1.1.3.1.3.1.1.1 42-1.1.3.1.3 42-1.2.2 45-1.2.2.1.1.1 (a / and~e.26 :op1 (p5 / protein-segment~e.15 :name (n6 / name :op1 "RBD"~e.6) :part-of (e / enzyme :name (n2 / name :op1 "Raf-1"~e.9,11)) :ARG0-of~e.15 (b2 / bind-01~e.15 :ARG1 (e2 / enzyme~e.17 :name (n7 / name :op1 "Ras"~e.1,24) :ARG0-of~e.17 (a2 / activity-06~e.17) :ARG2-of (b3 / bind-01~e.3,15,21,38,42 :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP"~e.19,40)))) :ARG1-of (s2 / specific-02~e.14))) :op2 (d2 / domain~e.4,31 :part-of~e.32 (p3 / protein :name (n4 / name :op1 "Ral-GDS"~e.33,35)) :ARG0-of (b5 / bind-01~e.30,38,42 :ARG1 (p4 / protein :name (n5 / name :op1 "Rap1"~e.28,45) :ARG1-of b3)))) # ::id bio.chicago_2015.39838 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Amphiphysin , a cytosolic protein that can simultaneously bind the AP2 alpha ear and dynamin through different domains ( 39 ) , has been implicated in dynamin recruitment . # ::alignments 0-1.1.1.1 3-1.1.2 4-1.1 4-1.1.3.1.1 4-1.1.3.1.1.2 4-1.1.3.1.1.2.r 4-1.1.3.1.2 6-1.1.3.2 7-1.1.3.3 7-1.1.3.3.r 8-1.1.3 10-1.1.3.1.1.2.1.1 11-1.1.3.1.1.2.1.2 12-1.1.3.1.1.1.1 13-1.1.3.1 14-1.1.3.1.2.1.1 16-1.1.3.4.1 17-1.1.3.4 19-1.1.3.5.1.1.1 24-1 25-1.2.r 26-1.2.1 27-1.2 (i / implicate-01~e.24 :ARG1 (p / protein~e.4 :name (n / name :op1 "amphiphysin"~e.0) :mod (c / cytosolic~e.3) :ARG0-of (b / bind-01~e.8 :ARG1 (a / and~e.13 :op1 (p6 / protein-segment~e.4 :name (n2 / name :op1 "ear"~e.12) :part-of~e.4 (p3 / protein~e.4 :name (n3 / name :op1 "AP2"~e.10 :op2 "alpha"~e.11))) :op2 (p4 / protein~e.4 :name (n4 / name :op1 "dynamin"~e.14))) :ARG1-of (p2 / possible-01~e.6) :manner~e.7 (s / simultaneous~e.7) :manner (d / domain~e.17 :ARG1-of (d2 / differ-02~e.16)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 39~e.19))))) :ARG2~e.25 (r / recruit-01~e.27 :ARG1 p4~e.26)) # ::id bio.chicago_2015.39840 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cos2 inhibits Ci activity independent of Ci processing # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1.1 3-1.2 4-1.3 4-1.3.1 4-1.3.1.r 5-1.3.2.r 6-1.3.2.1 7-1.3.2 (i / inhibit-01~e.1 :ARG0 (p / protein :name (n / name :op1 "Cos2"~e.0)) :ARG1 (a / activity-06~e.3 :ARG1 (p2 / protein :name (n2 / name :op1 "Ci"~e.2))) :ARG0-of (d / depend-01~e.4 :polarity~e.4 -~e.4 :ARG1~e.5 (p3 / process-01~e.7 :ARG1 p2~e.6))) # ::id bio.chicago_2015.39843 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC @-@ dependent degradation of the anaphase inhibitor Pds1p . # ::alignments 0-1.2.1 1-1.2 2-1.2.2.r 3-1.2.2.1.1 4-1.2.2.1.2 6-1 7-1.1.r 9-1.1.2.1.1.1 11-1.1.2 12-1.1 13-1.1.1.r 15-1.1.1.2.1 16-1.1.1 16-1.1.1.2 16-1.1.1.2.r 17-1.1.1.1.1 (c / control-01~e.6 :ARG0~e.7 (d / degrade-01~e.12 :ARG1~e.13 (p2 / protein~e.16 :name (n2 / name :op1 "Pds1p"~e.17) :ARG0-of~e.16 (i / inhibit-01~e.16 :ARG1 (a / anaphase~e.15))) :ARG0-of (d2 / depend-01~e.11 :ARG1 (p / protein :name (n / name :op1 "APC"~e.9)))) :ARG1 (i2 / initiate-01~e.1 :ARG1 a~e.0 :location~e.2 (o / organism :name (n3 / name :op1 "Saccharomyces"~e.3 :op2 "cerevisiae"~e.4)))) # ::id bio.chicago_2015.39899 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A reverse @-@ function mutant of Nkx3.2 can block the induction of Sox9 and cartilage gene expression by Shh/ BMP signals # ::alignments 1-1.1.1.2 3-1.1.1.2.1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 7-1 8-1.1 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2.1.1.1.1 13-1.1.2.2.1 14-1.1.2.2.1.2.1 15-1.1.2.2.1.2 16-1.1.2.2 19-1.1.2.1.1.2.1.1 20-1.1.2.1 (p / possible-01~e.7 :ARG1 (b / block-01~e.8 :ARG0 (m2 / mutate-01~e.4 :ARG1~e.5 (p4 / protein :name (n4 / name :op1 "Nkx3.2"~e.6)) :ARG0-of (r / reverse-01~e.1 :ARG1 (f / function-01~e.3))) :ARG1 (i / induce-01~e.10 :ARG0 (s / signal-07~e.20 :ARG0 (m / macro-molecular-complex :part (p2 / protein :name (n2 / name :op1 "Shh")) :part (p3 / protein :name (n3 / name :op1 "BMP"~e.19)))) :ARG2~e.11 (e / express-03~e.16 :ARG1 (a / and~e.13 :op1 (g / gene :name (n / name :op1 "Sox9"~e.12)) :op2 (g2 / gene~e.15 :mod (c / cartilage~e.14))))))) # ::id bio.chicago_2015.39944 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , activation of TAK1 induces phosphorylation of TCF @-@ 4 through NLK . # ::alignments 0-1 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1 10-1.1.2.1.1.1 12-1.1.2.2.1.1 (c / cause-01~e.0 :ARG1 (i / induce-01~e.5 :ARG0 (a / activate-01~e.2 :ARG1~e.3 (e / enzyme :name (n3 / name :op1 "TAK1"~e.4))) :ARG2 (p2 / phosphorylate-01~e.6 :ARG1~e.7 (p3 / protein :name (n / name :op1 "TCF-4"~e.8,10)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "NLK"~e.12))))) # ::id bio.chicago_2015.39948 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , phosphorylation of APC by GSK @-@ 3 beta stimulates its ability to bind beta @-@ catenin and overexpression of APC following transfection substantially reduces beta @-@ catenin levels ( Munemitsu et al. 1995 ) . # ::alignments 0-1.3 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1 9-1.1.2.2.2.1.1 10-1.1 12-1.1.2 14-1.1.2.2 15-1.1.2.2.2.1.1 17-1.1.2.2.2.1.1 18-1 18-1.4.1.1 19-1.2.1 20-1.2.1.1.r 21-1.2.1.1 22-1.2.1.2 23-1.2.1.2.1 24-1.2.3 25-1.2 26-1.2.2.1 27-1.2.2.1 28-1.2.2.1 29-1.2.2 31-1.4.1.1.1.1.1 32-1.4.1.1 33-1.4.1.1.2.1 34-1.4.1.2.1 (a2 / and~e.18 :op1 (s / stimulate-01~e.10 :ARG0 (p3 / phosphorylate-01~e.2 :ARG1~e.3 (p4 / protein :name (n / name :op1 "APC"~e.4)) :ARG2~e.5 (e / enzyme :name (n2 / name :op1 "GSK-3beta"~e.6))) :ARG1 (c2 / capable-01~e.12 :ARG1 p4 :ARG2 (b / bind-01~e.14 :ARG0 p4 :ARG1 (p5 / protein :name (n3 / name :op1 "beta-catenin"~e.9,15,17))))) :op2 (r / reduce-01~e.25 :ARG0 (o / overexpress-01~e.19 :ARG1~e.20 p4~e.21 :ARG1-of (f / follow-01~e.22 :ARG2 (t / transfect-01~e.23))) :ARG1 (l / level~e.29 :quant-of p5~e.26,27,28) :ARG2 (s2 / substantial~e.24)) :mod (i / indeed~e.0) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and~e.18,32 :op1 (p7 / person :name (n4 / name :op1 "Munemitsu"~e.31)) :op2 (p8 / person :mod (o2 / other~e.33))) :time (d / date-entity :year 1995~e.34)))) # ::id bio.chicago_2015.39970 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At low levels of expression , dynamin @-@ 2 specifically induces cell death . # ::alignments 1-1.4 2-1.4.1 3-1.4.1.1.r 4-1.4.1.1 6-1.1.1.1 8-1.1.1.1 9-1.3 10-1 11-1.2.1 12-1.2 (i / induce-01~e.10 :ARG0 (p / protein :name (n / name :op1 "dynamin-2"~e.6,8)) :ARG2 (d / die-01~e.12 :ARG1 (c / cell~e.11)) :ARG1-of (s / specific-02~e.9) :condition (l / low-04~e.1 :ARG1 (l2 / level~e.2 :quant-of~e.3 (e / express-03~e.4 :ARG2 p)))) # ::id bio.chicago_2015.40024 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like TAK1 , both MEKK1 and MLK3 also activate JNK through SEK1 . # ::alignments 0-1.5 1-1.5.1.1.1 4-1.1.1.1.1 5-1.1 6-1.1.2.1.1 7-1.3 8-1 9-1.2.1.1 11-1.4.1.1 (a / activate-01~e.8 :ARG0 (a2 / and~e.5 :op1 (e / enzyme :name (n / name :op1 "MEKK1"~e.4)) :op2 (e3 / enzyme :name (n2 / name :op1 "MLK3"~e.6))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK"~e.9)) :mod (a3 / also~e.7) :instrument (e5 / enzyme :name (n4 / name :op1 "SEK1"~e.11)) :ARG1-of (r / resemble-01~e.0 :ARG2 (e4 / enzyme :name (n5 / name :op1 "TAK1"~e.1)))) # ::id bio.chicago_2015.40045 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A , LEF1 represses Runx2 @-@ mediated activation of a mOG2 @-@ luc reporter lacking the LEF1 DNA binding site . # ::alignments 0-1.1 2-1.2.1.1 3-1 4-1.3.2.1.1.1 6-1.3.2 7-1.3 8-1.3.1.r 9-1.1 10-1.3.1.1.1.1.1 12-1.3.1.1.1.1.1 13-1.3.1 13-1.3.1.1 13-1.3.1.1.r 14-1.3.1.2 16-1.2.1.1 17-1.3.1.2.1.1.1.1.1 18-1.3.1.2.1.1 19-1.3.1.2.1 (r2 / repress-01~e.3 :li "a"~e.0,9 :ARG0 (p2 / protein :name (n3 / name :op1 "LEF1"~e.2,16)) :ARG1 (a / activate-01~e.7 :ARG1~e.8 (m2 / molecular-physical-entity~e.13 :ARG0-of~e.13 (r / report-01~e.13 :ARG1 (e / enzyme :name (n4 / name :op1 "mOG2-luc"~e.10,12))) :ARG0-of (l / lack-01~e.14 :ARG1 (s / site~e.19 :ARG1-of (b / bind-01~e.18 :ARG2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"~e.17) :ARG0-of (e2 / encode-01 :ARG1 p2)))))) :ARG1-of (m / mediate-01~e.6 :ARG0 (p3 / protein :name (n5 / name :op1 "Runx2"~e.4))))) # ::id bio.chicago_2015.40110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , we showed that CED @-@ 12 physically interacts with CED @-@ 5 and forms a ternary complex with CED @-@ 2 in vitro , with CED @-@ 5 bridging CED @-@ 2 and CED @-@ 12 . # ::alignments 0-1 2-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 8-1.1.2.1.3 8-1.1.2.1.3.r 9-1.1.2.1 10-1.1.2.2.3.r 11-1.1.2.1.1.1.1 11-1.1.2.1.2.1.1 11-1.1.2.2.3.1.1 13-1.1.2.1.2.1.1 14-1.1.2 15-1.1.2.2 17-1.1.2.2.2.1 18-1.1.2.2.2 19-1.1.2.2.3.r 20-1.1.2.2.3.1.1 22-1.1.2.2.3.1.1 23-1.1.2.2.4 24-1.1.2.2.4 26-1.1.2.2.3.r 27-1.1.2.1.1.1.1 27-1.1.2.1.2.1.1 27-1.1.2.2.3.1.1 29-1.1.2.2.5.1 30-1.1.2.2.5 31-1.1.2.2.5.2 32-1.1.2.2.5.2 33-1.1.2.2.5.2 34-1.1.2 35-1.1.2.1.1.1.1 35-1.1.2.1.2.1.1 35-1.1.2.2.3.1.1 37-1.1.2.1.1.1.1 (a / and~e.0 :op2 (s / show-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (a2 / and~e.14,34 :op1 (i / interact-01~e.9 :ARG0 (p / protein :name (n / name :op1 "CED-12"~e.5,7,11,27,35,37)) :ARG1 (p3 / protein :name (n2 / name :op1 "CED-5"~e.11,13,27,35)) :manner~e.8 (p2 / physical~e.8)) :op2 (f / form-01~e.15 :ARG0 p :ARG1 (c / complex~e.18 :mod (t / ternary~e.17)) :accompanier~e.10,19,26 (p4 / protein :name (n3 / name :op1 "CED-2"~e.11,20,22,27,35)) :manner (i2 / in-vitro~e.23,24) :manner (b / bridge-01~e.30 :ARG0 p3~e.29 :ARG1 p4~e.31,32,33 :ARG2 p))))) # ::id bio.chicago_2015.40137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Drosophila endocycle is controlled by cyclin E and lacks a checkpoint ensuring S @-@ phase completion . # ::alignments 1-1.1.2.1.1.1 2-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1.1.1 7-1.1.1.1.2 8-1 9-1.2 11-1.2.2 12-1.2.2.1 13-1.2.2.1.1.1.1.1 15-1.2.2.1.1.1.1.1 16-1.2.2.1.1 (a / and~e.8 :op1 (c / control-01~e.4 :ARG0~e.5 (p / protein :name (n2 / name :op1 "cyclin"~e.6 :op2 "E"~e.7)) :ARG1 (e / endocycle~e.2 :mod (o / organism :name (n / name :op1 "Drosophila"~e.1)))) :op2 (l / lack-01~e.9 :ARG0 e :ARG1 (c2 / checkpoint~e.11 :ARG0-of (e2 / ensure-01~e.12 :ARG1 (c3 / complete-01~e.16 :ARG1 (e3 / event :name (n3 / name :op1 "S-phase"~e.13,15))))))) # ::id bio.chicago_2015.40191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because HC @-@ Pro suppression of PTGS is accompanied by the loss of smRNAs [ 5 , 6 ] , this viral protein can potentially provide a tool to study RNA requirements for RdDM . # ::alignments 0-1 1-1.1.2.1.1.1 3-1.1.2.1.1.1 4-1.1.2 5-1.1.2.2.r 6-1.1.2.2.1.1 8-1.1 9-1.1.1.r 11-1.1.1 15-1.1.3.1.1.1.1 17-1.1.3.1.1.1.2 20-1.2.1.1.2 21-1.2.1.1.1 22-1.2.1.1 23-1.2 24-1.2.1.3 25-1.2.1 27-1.2.1.2.1 29-1.2.1.2.2 30-1.2.1.2.2.1.2.2.1 31-1.2.1.2.2.1 32-1.2.1.2.2.1.1.r 33-1.2.1.2.2.1.1.1.1 (c / cause-01~e.0 :ARG0 (a / accompany-01~e.8 :ARG0~e.9 (l / lose-02~e.11 :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "smRNA"))) :ARG1 (s / suppress-01~e.4 :ARG0 (p / protein :name (n3 / name :op1 "HC-Pro"~e.1,3)) :ARG1~e.5 (p2 / protein-family :name (n4 / name :op1 "PTGS"~e.6))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 5~e.15 :op2 6~e.17))))) :ARG1 (p4 / possible-01~e.23 :ARG1 (p5 / provide-01~e.25 :ARG0 (p6 / protein~e.22 :mod (v / viral~e.21) :mod (t / this~e.20)) :ARG1 (t3 / thing :ARG3-of (t2 / tool-03~e.27) :instrument-of (s2 / study-01~e.29 :ARG1 (r / require-01~e.31 :ARG0~e.32 (t4 / thing :name (n7 / name :op1 "RdDM"~e.33)) :ARG1 (n / nucleic-acid :wiki "RNA" :name (n2 / name :op1 "RNA"~e.30))))) :mod (p7 / potential~e.24)))) # ::id bio.chicago_2015.40291 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with this localization , we have previously shown that in HeLa cells overexpression of GTP @-@ bound forms of rab6 ( wt rab6 and rab6 Q72L ) affects transport of both membrane and secretory proteins between an alpha @-@ mannosidase II @-@ positive and a sialyl @-@ transferase @-@ positive Golgi compartment ( 15 ) . # ::alignments 0-1.4 2-1.4.1.1 3-1.4.1 5-1.1 7-1.3 8-1 10-1.2.r 11-1.2.1.2.1.1 12-1.2.1.2 13-1.2.1 14-1.2.1.1.r 15-1.2.1.1.3.1.1.1 17-1.2.1.1 17-1.2.1.1.3 17-1.2.1.1.3.r 20-1.2.1.1.1.1 20-1.2.1.1.2.1.1.1.1 22-1.2.1.1.2.1.1.2 23-1.2.1.1.2.1.1.1.1 23-1.2.1.1.2.1.2.1.1 25-1.2.1.1.2.1.1.1.1 25-1.2.1.1.2.1.2.1.1 26-1.2.1.1.2.1.2.2.1 28-1.2 29-1.2.2 32-1.2.2.1.1.1 33-1.2.2.1 34-1.2.2.1.2.1 35-1.2.2.1.1 35-1.2.2.1.2 38-1.2.2.2.3.1.1 40-1.2.2.2.3.1.1 41-1.2.2.2.3.1.2 43-1.2.2.2.2 44-1.2.2.1 46-1.2.2.3.3.1.1 48-1.2.2.3.3.1.1 50-1.2.2.2.2 50-1.2.2.3.2 51-1.2.2.2.1.1.1 52-1.2.2.2 52-1.2.2.3 54-1.5.1.1.1 (s / show-01~e.8 :ARG0 (w2 / we~e.5) :ARG1~e.10 (a / affect-01~e.28 :ARG0 (o / overexpress-01~e.13 :ARG1~e.14 (p2 / protein-family~e.17 :name (n2 / name :op1 "Rab6"~e.20) :ARG2-of (i / include-91 :ARG1 (a2 / and :op1 (p9 / protein :name (n4 / name :op1 "Rab6"~e.20,23,25) :mod (w3 / wild-type~e.22)) :op2 (p3 / protein :name (n5 / name :op1 "Rab6"~e.23,25) :ARG2-of (m / mutate-01 :value "Q72L"~e.26)))) :ARG1-of~e.17 (b / bind-01~e.17 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP"~e.15)))) :location (c / cell-line~e.12 :name (n / name :op1 "HeLa"~e.11))) :ARG1 (t / transport-01~e.29 :ARG1 (a3 / and~e.33,44 :op1 (p4 / protein~e.35 :mod (m2 / membrane~e.32)) :op2 (p5 / protein~e.35 :ARG0-of (s4 / secrete-01~e.34))) :ARG2 (c2 / compartment~e.52 :mod (t3 / thing :name (n6 / name :op1 "Golgi"~e.51)) :mod (p6 / positive~e.43,50) :mod (e2 / enzyme :name (n8 / name :op1 "alpha-mannosidase"~e.38,40 :op2 "II"~e.41))) :ARG3 (c3 / compartment~e.52 :mod t3 :mod (p7 / positive~e.50) :mod (e / enzyme :name (n7 / name :op1 "sialyl-transferase"~e.46,48))))) :time (p / previous~e.7) :ARG1-of (c4 / consistent-01~e.0 :ARG2 (b2 / be-located-at-91~e.3 :mod (t2 / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c5 / cite-01 :ARG2 15~e.54)))) # ::id bio.chicago_2015.40308 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , simultaneous overexpression of both Hsp90 and Flag @-@ p50Cdc37 did not increase the association of Hsp90 with tsHck499F above that seen upon overexpression of Flag @-@ p50Cdc37 alone ( Fig . 7A ) . # ::alignments 0-1.1.2.1 2-1.1.2.2 3-1.1.2 6-1.1.2.1.1.1.1 7-1.1.2.1 8-1.1.4.1.1.1.1.3.1.1.1 10-1.1.2.1.2.1.1 10-1.1.4.1.1.1.1.1.1 12-1.1.1 12-1.1.1.r 13-1.1 13-1.1.4.1 15-1.1.3 16-1.1.3.1.r 17-1.1.3.1 18-1.1.3.2.r 19-1.1.3.2.1.1 20-1.1.4 21-1.1.4.1.2 22-1.1.4.1.1 24-1.1.4.1.1.1 26-1.1.4.1.1.1.1.3.1.1.1 28-1.1.4.1.1.1.1.1.1 29-1.1.4.1.1.1.1.2 31-1.2.1 33-1.2.1.1 (a / and :op2 (i / increase-01~e.13 :polarity~e.12 -~e.12 :ARG0 (o / overexpress-01~e.3 :ARG1 (a2 / and~e.0,7 :op1 (p / protein :name (n / name :op1 "Hsp90"~e.6)) :op2 (p2 / protein :name (n2 / name :op1 "p50Cdc37"~e.10) :ARG1-of t2)) :mod (s / simultaneous~e.2)) :ARG1 (a3 / associate-01~e.15 :ARG1~e.16 p~e.17 :ARG2~e.18 (e / enzyme :name (n3 / name :op1 "tsHck499F"~e.19) :ARG2-of (m / mutate-01))) :ARG2 (a4 / above~e.20 :op1 (i2 / increase-01~e.13 :ARG1-of (s2 / see-01~e.22 :location (o2 / overexpress-01~e.24 :ARG1 (p3 / protein :name (n4 / name :op1 "p50Cdc37"~e.10,28) :mod (a5 / alone~e.29) :ARG1-of (t2 / tag-01 :ARG2 (p4 / protein-segment :name (n5 / name :op1 "Flag"~e.8,26)))))) :mod (t / that~e.21)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "7A"~e.33))) # ::id bio.chicago_2015.40323 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these data suggest that intersectin regulates MAPK activation through regulation of EGFR endocytosis as well as Ras activation . # ::alignments 0-1.1.2 2-1.1.1 3-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2 8-1.2.2.1.1.1 9-1.2.2 11-1.2 11-1.2.3 11-1.2.3.r 12-1.2.3.1.r 13-1.2.3.1.1.1.1.1 14-1.2.3.1.1 15-1.2.3.1 16-1.2.3.1 17-1.2.3.1 18-1.2.3.1.2.1.1.1 19-1.2.3.1.2 (s / suggest-01~e.4 :ARG0 (d / data~e.3 :mod (t / this~e.2) :mod (t2 / together~e.0)) :ARG1~e.5 (r / regulate-01~e.7,11 :ARG0 (p3 / protein :name (n4 / name :op1 "intersectin"~e.6)) :ARG1 (a / activate-01~e.9 :ARG1 (p / pathway :name (n5 / name :op1 "MAPK"~e.8))) :manner~e.11 (r2 / regulate-01~e.11 :ARG1~e.12 (a2 / and~e.15,16,17 :op1 (e3 / endocytosis~e.14 :mod (e / enzyme :name (n2 / name :op1 "EGFR"~e.13))) :op2 (a3 / activate-01~e.19 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.18))))))) # ::id bio.chicago_2015.40343 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , a wide variety of studies using both dominant negative mutants and SHP @-@ 2 mutant fibroblasts have shown that SHP @-@ 2 function is required for full activation of MAPK in response to growth factors , cytokines , antigen receptors , and integrin engagement . # ::alignments 0-1.1.1.3.1 3-1.1.1.2 4-1.1.1.1 6-1.1.1 7-1.1.1.3 9-1.1.1.3.1.1.2 11-1.1.1.3.1.1 11-1.1.1.3.1.2.1 11-1.1.1.3.1.2.1.2 11-1.1.1.3.1.2.1.2.r 12-1.1.1.3.1 13-1.1.1.3.1.2.1.1.1 15-1.1.1.3.1.2.1.1.1 16-1.1.1.3.1.1 16-1.1.1.3.1.2.1 16-1.1.1.3.1.2.1.2 16-1.1.1.3.1.2.1.2.r 17-1.1.1.3.1.2 19-1.1 21-1.1.1.3.1.2.1.1.1 21-1.1.2.2.1.1.1 23-1.1.1.3.1.2.1.1.1 23-1.1.2.2.1.1.1 24-1.1.2.2 26-1.1.2 27-1.1.2.1.r 28-1.1.2.1.2 29-1.1.2.1 30-1.1.2.1.1.r 31-1.1.2.1.1.1.1 32-1.1.2.3.r 33-1.1.2.3 34-1.1.2.3.1.r 35-1.1.2.3.1.1 36-1.1.2.3.1.1 38-1.1.2.3.1.2 40-1.1.2.3.1.3.1 41-1.1.2.3.1.3 43-1.1.2.3.1 44-1.1.2.3.1.4.1.1.1 45-1.1.2.3.1.4 (a / and :op2 (s / show-01~e.19 :ARG0 (s2 / study-01~e.6 :mod (v / variety~e.4) :ARG1-of (w / wide-02~e.3) :ARG0-of (u / use-01~e.7 :ARG1 (a2 / and~e.0,12 :op1 (m / mutate-01~e.11,16 :mod "-/-" :ARG0-of (d / dominate-01~e.9)) :op2 (f / fibroblasts~e.17 :mod (p2 / protein~e.11,16 :name (n3 / name :op1 "SHP-2"~e.13,15,21,23) :ARG2-of~e.11,16 (m2 / mutate-01~e.11,16)))))) :ARG1 (r / require-01~e.26 :ARG0~e.27 (a3 / activate-01~e.29 :ARG1~e.30 (p / pathway :name (n5 / name :op1 "MAPK"~e.31)) :ARG1-of (f3 / full-09~e.28)) :ARG1 (f2 / function-01~e.24 :ARG0 (p3 / protein :name (n4 / name :op1 "SHP-2"~e.21,23))) :ARG2-of~e.32 (r2 / respond-01~e.33 :ARG1~e.34 (a4 / and~e.43 :op1 (g / growth-factor~e.35,36) :op2 (c / cytokine~e.38) :op3 (r3 / receptor~e.41 :mod (a5 / antigen~e.40)) :op4 (e2 / engage-01~e.45 :ARG1 (p4 / protein :name (n7 / name :op1 "integrin"~e.44)))))))) # ::id bio.chicago_2015.40381 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation site mapping studies performed in vitro also support the hypothesis that Cds1 and Chk1 inhibit Cdc25 . # ::alignments 0-1.1.1 1-1.1 2-1.1.2 3-1.1.2.1 4-1.1.2.1.1 5-1.1.2.1.1.1 6-1.1.2.1.1.1 7-1.3 8-1 10-1.2 11-1.2.1.r 12-1.2.1.1.1.1.1 13-1.2.1.1 14-1.2.1.1.2.1.1 15-1.2.1 16-1.2.1.2.1.1 (s / support-01~e.8 :ARG0 (s2 / site~e.1 :mod (p / phosphorylate-01~e.0) :ARG0-of (m / map-01~e.2 :ARG1 (s3 / study-01~e.3 :ARG1-of (p2 / perform-01~e.4 :manner (i / in-vitro~e.5,6))))) :ARG1 (h / hypothesize-01~e.10 :ARG1~e.11 (i2 / inhibit-01~e.15 :ARG0 (a2 / and~e.13 :op1 (e / enzyme :name (n / name :op1 "Cds1"~e.12)) :op2 (e2 / enzyme :name (n2 / name :op1 "Chk1"~e.14))) :ARG1 (e3 / enzyme :name (n3 / name :op1 "Cdc25"~e.16)))) :mod (a / also~e.7)) # ::id bio.chicago_2015.40436 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the interaction of Duplin with beta @-@ catenin using the purified proteins in vitro , GST @-@ beta @-@ catenin and its deletion mutants ( 0.5 muM ) were incubated with MBP @-@ Duplin-( 482 @-@ 749 ) ( 30 pmol ) immobilized on amylose resin in 100 mul of reaction mixture ( 20 mM Tris/ Cl , pH 7.5 , 1 mM DTT ) for 1 h at 4 degrees C. MBP @-@ Duplin was precipitated by centrifugation , and then the precipitates were probed with the anti @-@ GST antibody . # ::alignments 1-1.1.3 3-1.1.3.1 4-1.1.3.1.1.r 5-1.1.3.1.1 6-1.2.2.2.r 7-1.1.1.1.2.2.1 9-1.1.1.1.2.2.1 10-1.1.3.2 10-1.1.3.r 12-1.1.3.2.1.1 13-1.1.3.2.1 14-1.1.3.2.1.1.1 15-1.1.3.2.1.1.1 17-1.1.1.1.1.2.1 19-1.1.1.1.2.2.1 21-1.1.1.1.2.2.1 22-1.1.1 24-1.1.1.2.1 25-1.1.1.2 27-1.1.1.2.2.1 31-1.1 32-1.2.2.2.r 33-1.1.2.1.2.1 33-1.2.1.2.1.2.1 36-1.1.2.5.1 38-1.1.2.5.2 41-1.1.2.3.1 44-1.1.2.4 45-1.1.2.4.1.r 46-1.1.2.4.1.2.1 47-1.1.2.4.1.2.2 48-1.1.2.4.4.r 48-1.1.3.2.1.1.1 49-1.1.2.4.4.1 50-1.1.2.4.4 51-1.1.2.4.4.2.r 52-1.1.2.4.4.2.1 53-1.1.2.4.4.2 55-1.1.2.4.4.2.2.1.3.1 56-1.1.2.4.4.2.2.1.3.2 58-1.1.2.4.4.2.2.1.2.1 60-1.1.2.4.4.2.3.2 61-1.1.2.4.4.2.3.1 63-1.1.2.4.4.2.2.2.3.1 64-1.1.2.4.4.2.2.2.3.2 65-1.1.2.4.4.2.2.2.2.1 68-1.1.2.4.2.1 68-1.1.2.4.4.2.2.2.3.1 69-1.1.2.4.2.2 70-1.1.2.4.3.r 71-1.1.2.4.3.1 74-1.1.2.1.2.1 74-1.2.1.2.1.2.1 76-1.1.2.2.2.1 76-1.2.1.2.2.2.1 78-1.2.1 80-1.2.1.1 82-1.2 83-1.2.2.3 85-1.2.1 87-1.2.2 88-1.2.2.2.r 90-1.2.2.2.1 92-1.2.2.2.1.1.2.1 93-1.2.2.2 (m2 / multi-sentence :snt1 (i / incubate-01~e.31 :ARG1 (a / and~e.22 :op1 (m3 / macro-molecular-complex :part (e / enzyme :wiki "Glutathione_S-transferase" :name (n / name :op1 "GST"~e.17)) :part (p / protein :wiki "Beta-catenin" :name (n2 / name :op1 "beta-catenin"~e.7,9,19,21))) :op2 (m4 / mutate-01~e.25 :ARG0-of (d2 / delete-01~e.24) :quant (c / concentration-quantity :quant 0.5~e.27 :unit m7))) :ARG2 (m / macro-molecular-complex :part (p6 / protein :wiki "Maltose-binding_protein" :name (n9 / name :op1 "MBP"~e.33,74)) :part (p9 / protein :wiki - :name (n10 / name :op1 "Duplin"~e.76)) :quant (c2 / concentration-quantity :quant 30~e.41 :unit (p2 / picomol)) :ARG1-of (i2 / immobilize-01~e.44 :ARG0~e.45 (s2 / small-molecule :wiki - :name (n4 / name :op1 "amylose"~e.46 :op2 "resin"~e.47)) :duration (t / temporal-quantity :quant 1~e.68 :unit (h / hour~e.69)) :condition~e.70 (t2 / temperature-quantity :quant 4~e.71 :scale (c5 / celsius)) :location~e.48 (m5 / mul~e.50 :value 100~e.49 :consist-of~e.51 (m6 / mixture~e.53 :ARG0-of (r / react-01~e.52) :consist-of (a2 / and :op1 (s3 / small-molecule :wiki "Tris" :name (n5 / name :op1 "Tris/Cl"~e.58) :quant (c3 / concentration-quantity :quant 20~e.55 :unit (m7 / millimolar~e.56))) :op2 (s4 / small-molecule :wiki "Dithiothreitol" :name (n6 / name :op1 "DTT"~e.65) :quant (c4 / concentration-quantity :quant 1~e.63,68 :unit m7~e.64))) :mod (a3 / acidity-quantity :quant 7.5~e.61 :scale (p3 / ph~e.60))))) :mod (v / value-interval :op1 482~e.36 :op2 749~e.38)) :purpose~e.10 (e3 / examine-01~e.1 :ARG1 (i3 / interact-01~e.3 :ARG1~e.4 m~e.5 :ARG2 p) :manner (u / use-01~e.10 :ARG1 (p7 / protein~e.13 :ARG1-of (p8 / purify-01~e.12 :manner (i4 / in-vitro~e.14,15,48)))))) :snt2 (a4 / and~e.82 :op1 (p4 / precipitate-01~e.78,85 :ARG0 (c6 / centrifugation~e.80) :ARG1 (m8 / macro-molecular-complex :part (p10 / protein :wiki "Maltose-binding_protein" :name (n3 / name :op1 "MBP"~e.33,74)) :part (p11 / protein :wiki - :name (n11 / name :op1 "Duplin"~e.76)))) :op2 (p5 / probe-01~e.87 :ARG1 p4 :instrument~e.6,32,88 (a5 / antibody~e.93 :ARG0-of (o / oppose-01~e.90 :ARG1 (e2 / enzyme :wiki "Glutathione_S-transferase" :name (n8 / name :op1 "GST"~e.92)))) :time (t3 / then~e.83)))) # ::id bio.chicago_2015.40510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , both Sox9 and Nkx3.2 are induced by Shh , prior to the expression of cartilage differentiation markers . # ::alignments 0-1 3-1.1.2.1.1.1 4-1.1.2 5-1.1.2.2.1.1 7-1.1 8-1.1.1.r 9-1.1.1.1.1 11-1.1.3 12-1.1.3.1.r 14-1.1.3.1 15-1.1.3.1.1.r 16-1.1.3.1.1.1.1 17-1.1.3.1.1.1 18-1.1.3.1.1 (c / cause-01~e.0 :ARG1 (i / induce-01~e.7 :ARG0~e.8 (p3 / protein :name (n3 / name :op1 "Shh"~e.9)) :ARG1 (a / and~e.4 :op1 (p / protein :name (n / name :op1 "Sox9"~e.3)) :op2 (p2 / protein :name (n2 / name :op1 "Nkx3.2"~e.5))) :time (p4 / prior~e.11 :op1~e.12 (e / express-03~e.14 :ARG1~e.15 (m / marker~e.18 :mod (d / differentiate-01~e.17 :ARG1 (c2 / cartilage~e.16))))))) # ::id bio.chicago_2015.40538 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Resistance of RNA @-@ mediated TGS to HC @-@ Pro , a viral suppressor of PTGS , suggests alternative pathways for dsRNA processing . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2.1.1.1 4-1.1.1.2 5-1.1.1.1.1 6-1.1.2.r 7-1.1.2.1.1 9-1.1.2.1.1 12-1.1.2.3 13-1.1.2 13-1.1.2.2 13-1.1.2.2.r 14-1.1.2.2.1.r 15-1.1.2.2.1.1.1 17-1 18-1.2.1 19-1.2 20-1.2.2.r 21-1.2.2.1.1.1 22-1.2.2 (s / suggest-01~e.17 :ARG0 (r / resist-01~e.0 :ARG0~e.1 (p / protein :name (n / name :op1 "TGS"~e.5) :ARG1-of (m / mediate-01~e.4 :ARG0 (n2 / nucleic-acid :name (n3 / name :op1 "RNA"~e.2)))) :ARG1~e.6 (p2 / protein~e.13 :name (n4 / name :op1 "HC-Pro"~e.7,9) :ARG0-of~e.13 (s2 / suppress-01~e.13 :ARG1~e.14 (p3 / protein-family :name (n5 / name :op1 "PTGS"~e.15))) :mod (v / viral~e.12))) :ARG1 (p4 / pathway~e.19 :mod (a / alternative~e.18) :beneficiary~e.20 (p5 / process-01~e.22 :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "dsRNA"~e.21))))) # ::id bio.chicago_2015.40555 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytochrome c and dATP @-@ Dependent Formation of Apaf @-@ 1/Caspase @-@ 9 Complex Initiates an Apoptotic Protease Cascade . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1 3-1.1.2.2.1.1.1 5-1.1.2.2 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1.1 12-1.1.2.1.2.1.1 13-1.1.2.1 14-1 16-1.2.1.1 17-1.2.1 18-1.2 (i / initiate-01~e.14 :ARG0 (a / and~e.2 :op1 (p / protein :name (n / name :op1 "Cytochrome"~e.0 :op2 "c"~e.1)) :op2 (f / form-01~e.6 :ARG1~e.7 (m2 / macro-molecular-complex~e.13 :part (p2 / protein :name (n2 / name :op1 "Apaf-1"~e.8)) :part (e / enzyme :name (n3 / name :op1 "Caspase-9"~e.12))) :ARG0-of (d / depend-01~e.5 :ARG1 (s / small-molecule :name (n4 / name :op1 "dATP"~e.3))))) :ARG1 (c2 / cascade~e.18 :mod (p3 / protease~e.17 :mod (a3 / apoptotic~e.16)))) # ::id bio.chicago_2015.40576 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It remains possible , however , that the phosphorylation of Dsh by CK2 and by perhaps other unidentified kinases is required but not sufficient for the transduction of the Wg signal . # ::alignments 1-1.1 2-1.1.1 2-1.1.1.1.1.2.2.3 4-1 4-1.1.1.1 8-1.1.1.1.1.2.1 8-1.1.1.1.1.2.2 9-1.1.1.1.1.2.1.2.r 10-1.1.1.1.1.2.1.2.1.1 11-1.1.1.1.1.2.1.1.r 12-1.1.1.1.1.2.1.1.1.1 13-1.1.1.1.1.2 15-1.1.1 16-1.1.1.1.1.2.2.1.2 17-1.1.1.1.1.2.2.1.1 17-1.1.1.1.1.2.2.1.1.1 17-1.1.1.1.1.2.2.1.1.1.r 18-1.1.1.1.1.2.2.1 20-1.1.1.1.1 21-1.1.1.1 22-1.1.1.1.2.1 22-1.1.1.1.2.1.r 23-1.1.1.1.2 24-1.1.1.1.2.3.r 26-1.1.1.1.2.3 27-1.1.1.1.2.3.1.r 29-1.1.1.1.2.3.1.1.1.1 30-1.1.1.1.2.3.1 (h / have-concession-91~e.4 :ARG1 (r / remain-01~e.1 :ARG1 (p3 / possible-01~e.2,15 :ARG1 (c / contrast-01~e.4,21 :ARG1 (r2 / require-01~e.20 :ARG0 t :ARG1 (a2 / and~e.13 :op1 (p / phosphorylate-01~e.8 :ARG0~e.11 (e / enzyme :name (n2 / name :op1 "CK2"~e.12)) :ARG1~e.9 (p4 / protein-family :name (n / name :op1 "Dsh"~e.10))) :op2 (p5 / phosphorylate-01~e.8 :ARG0 (k / kinase~e.18 :ARG1-of (i / identify-01~e.17 :polarity~e.17 -~e.17) :mod (o / other~e.16)) :ARG1 p4 :ARG1-of (p6 / possible-01~e.2)))) :ARG2 (s / suffice-01~e.23 :polarity~e.22 -~e.22 :ARG0 a2 :ARG1~e.24 (t / transduce-01~e.26 :ARG1~e.27 (s2 / signal-07~e.30 :ARG1 (p7 / protein :name (n3 / name :op1 "Wg"~e.29))) :ARG2 a2)))))) # ::id bio.chicago_2015.53561 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In control experiments , ERK2 was strongly activated by an activated Raf mutant , RafBxB , to phosphorylate MBP ( Fig. 4B ) , and p38 was activated by ultraviolet irradiation and cotransfection of a MKK6 expression vector ( Fig. 4C ) . # ::alignments 1-1.3.2 2-1.3 2-1.3.1 2-1.3.1.r 4-1.1.2.1.1 6-1.1.5 7-1.1 10-1.1 10-1.1.1.2 11-1.1.1.3.1.1 12-1.1.1 14-1.1.1.1.1.1 17-1.1.3 18-1.1.3.1.1.1 20-1.1.4.1 21-1.1.4.1.1 24-1 25-1.2.2.1.1 27-1.2 28-1.2.1.r 29-1.2.1.1.1 30-1.2.1.1 31-1.2.1 32-1.2.1.2 33-1.2.1.2.1.r 35-1.2.1.2.1.2.1.1 36-1.2.1.2.1 37-1.2.1.2.1.1 39-1.2.3.1 40-1.2.3.1.1 (a / and~e.24 :op1 (a2 / activate-01~e.7,10 :ARG0 (m / mutate-01~e.12 :ARG2 (e2 / enzyme :name (n3 / name :op1 "RafBxB"~e.14)) :ARG1-of (a3 / activate-01~e.10) :mod (e6 / enzyme :name (n / name :op1 "Raf"~e.11))) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK2"~e.4)) :purpose (p2 / phosphorylate-01~e.17 :ARG1 (p3 / protein :name (n4 / name :op1 "MBP"~e.18)) :ARG2 e) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "4B"~e.21)) :ARG1-of (s / strong-02~e.6)) :op2 (a4 / activate-01~e.27 :ARG0~e.28 (a5 / and~e.31 :op1 (i / irradiate-01~e.30 :ARG2 (u / ultraviolet~e.29)) :op2 (c / cotransfect-01~e.32 :ARG1~e.33 (e3 / express-03~e.36 :ARG1 (v / vector~e.37) :ARG2 (e4 / enzyme :name (n6 / name :op1 "MKK6"~e.35))))) :ARG1 (e7 / enzyme :name (n5 / name :op1 "p38"~e.25)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.39 :mod "4C"~e.40))) :location (t / thing~e.2 :ARG1-of~e.2 (e5 / experiment-01~e.2) :mod (c2 / control~e.1))) # ::id bio.chicago_2015.53577 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether NIK mediates JNK activation by EphB1 , we used the RevTet @-@ On system to inducibly express NIK( KD ) in P19 cells . # ::alignments 1-1.4 2-1.4.2.1 2-1.4.2.1.r 4-1.4.2 5-1.4.2.3.2.1.1 6-1.4.2.3 7-1.4.2.3.1.r 8-1.4.2.3.1.1.1 10-1.1 11-1 11-1.4.r 13-1.2.1.1 15-1.2.1.1 16-1.2 19-1.3 23-1.3.2.r 24-1.3.2.1.1 25-1.3.2 (u / use-01~e.11 :ARG0 (w / we~e.10) :ARG1 (s / system~e.16 :name (n / name :op1 "RevTet-On"~e.13,15)) :ARG2 (e / express-03~e.19 :ARG2 (e2 / enzyme :name (n2 / name :op1 "NIK(KD)")) :ARG3~e.23 (c / cell~e.25 :name (n3 / name :op1 "P19"~e.24)) :manner (i / induce-01 :ARG1-of (p / possible-01))) :purpose~e.11 (d / determine-01~e.1 :ARG0 w :ARG1 (m / mediate-01~e.4 :mode~e.2 interrogative~e.2 :ARG0 e2 :ARG1 (a / activate-01~e.6 :ARG0~e.7 (p2 / protein :name (n4 / name :op1 "EphB1"~e.8)) :ARG1 (e3 / enzyme :name (n5 / name :op1 "JNK"~e.5)))))) # ::id bio.chicago_2015.53583 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regardless of the receptor @-@ coupling mechanism involved , TGF @-@ beta activation of JNK or p38 in some cell lines and conditions can be rapid and mediate transcriptional responses by activating AP @-@ 1 complexes via phosphorylation of c @-@ Jun transcription factor ( Hocevar et al. 1999 ) or CRE @-@ regulatory complexes via phosphorylation of ATF2 transcription factor ( Sano et al. 1999 ) . # ::alignments 0-1 3-1.2.1.1.1 5-1.2.1.1 6-1.2.1 7-1.2 9-1.1.1.1.1.1.1.1.1 11-1.1.1.1.1.1.1.1.1 12-1.1.1.1.1.1 12-1.1.2.3.2 13-1.1.1.1.1.1.2.r 14-1.1.1.1.1.1.2.1.1.1 15-1.1.1.1.1.1.2 16-1.1.1.1.1.1.2.2.1.1 17-1.1.1.1.1.1.3.r 18-1.1.1.1.1.1.3.1 19-1.1.1.1.1.1.3 20-1.1.1.1.1.1.3 22-1.1.1.1.1.2 22-1.1.1.1.1.2.1 22-1.1.1.1.1.2.1.r 23-1.1.1 24-1.1.1.1.1.r 25-1.1.1.1 26-1.1 27-1.1.2 28-1.1.2.2.1 29-1.1.2.2 30-1.1.2.3.r 31-1.1.2.3.1 32-1.1.2.3.1.2.1.1.1 34-1.1.2.3.1.2.1.1.1 35-1.1.2.3.1.2 37-1.1.2.3.1.1 37-1.1.2.3.2.1 39-1.1.2.3.1.1.1.1.1.1.1 41-1.1.2.3.1.1.1.1.1.1.1 42-1.1.2.3.1.1.1.1 43-1.1.2.3.1.1.1 45-1.1.2.3.1.3.1.1.1.1.1 46-1.1.2.3.1.3.1.1 47-1.1.2.3.1.3.1.1.2.1 48-1.1.2.3.1.3.1.2.1 50-1.1.2.3 51-1.1.2.3.2.2.1.1.1.1 53-1.1.2.3.2.2.1 54-1.1.2.3.2.2 56-1.1.2.3.1.1 57-1.1.2.3.2.1.1.r 58-1.1.2.3.2.1.1.1.1 59-1.1.2.3.1.1.1.1 60-1.1.2.3.1.1.1 62-1.1.2.3.2.3.1.1.1.1.1 63-1.1.1.1.1 63-1.1.2.3.1.3.1.1 63-1.1.2.3.2.3.1.1 64-1.1.2.3.1.3.1.1.2.1 64-1.1.2.3.2.3.1.1.2.1 65-1.1.2.3.1.3.1.2.1 (r5 / regardless-91~e.0 :ARG1 (a / and~e.26 :op1 (p2 / possible-01~e.23 :ARG1 (r2 / rapid~e.25 :domain~e.24 (a2 / and~e.63 :op1 (a3 / activate-01~e.12 :ARG0 (p14 / protein :name (n / name :op1 "TGF-beta"~e.9,11)) :ARG1~e.13 (o / or~e.15 :op1 (e2 / enzyme :name (n2 / name :op1 "JNK"~e.14)) :op2 (e / enzyme :name (n3 / name :op1 "p38"~e.16))) :location~e.17 (c2 / cell-line~e.19,20 :quant (s / some~e.18))) :op2 (t / thing~e.22 :ARG2-of~e.22 (c3 / condition-01~e.22))))) :op2 (m2 / mediate-01~e.27 :ARG0 a2 :ARG1 (r3 / respond-01~e.29 :ARG2 (t2 / transcribe-01~e.28)) :manner~e.30 (o3 / or~e.50 :op1 (a4 / activate-01~e.31 :ARG0 (p / phosphorylate-01~e.37,56 :ARG1 (f / factor~e.43,60 :ARG0-of (t3 / transcribe-01~e.42,59 :ARG1 (p5 / protein :name (n5 / name :op1 "c-Jun"~e.39,41))))) :ARG1 (c4 / complex~e.35 :mod (p4 / protein :name (n4 / name :op1 "AP-1"~e.32,34))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a5 / and~e.46,63 :op1 (p7 / person :name (n6 / name :op1 "Hocevar"~e.45)) :op2 (p8 / person :mod (o2 / other~e.47,64))) :time (d / date-entity :year 1999~e.48,65)))) :op2 (a6 / activate-01~e.12 :ARG0 (p9 / phosphorylate-01~e.37 :ARG1~e.57 (p10 / protein :name (n8 / name :op1 "ATF2"~e.58))) :ARG1 (c5 / complex~e.54 :ARG0-of (r4 / regulate-01~e.53 :ARG1 (e3 / enzyme :name (n7 / name :op1 "CRE"~e.51)))) :ARG1-of (d3 / describe-01 :ARG0 (p11 / publication-91 :ARG0 (a7 / and~e.63 :op1 (p12 / person :name (n9 / name :op1 "Sano"~e.62)) :op2 (p13 / person :mod (o4 / other~e.64))) :time d)))))) :ARG2 (i / involve-01~e.7 :ARG1 (m / mechanism~e.6 :ARG0-of (c / couple-01~e.5 :ARG1 (r / receptor~e.3))))) # ::id bio.chicago_2015.53648 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of PKC with TPA leads to inactivation of GSK3 in the absence of a wnt signal and downregulation of PKC by prolonged treatment with TPA prevents wnt @-@ mediated inactivation of GSK3 [ 113 ] . # ::alignments 0-1.1.2 2-1.1.1.2.1.1 4-1.1.1.1.1.1 5-1.1 7-1.1.1 7-1.1.2 7-1.1.2.1 7-1.1.2.1.r 8-1.1.2.2.r 9-1.1.2.2.1.1 10-1.1.3.r 12-1.1.3 13-1.1.3.1.r 15-1.1.3.1.1.1.1 16-1.1.3.1 17-1 18-1.2.1 19-1.2.1.1.r 20-1.2.1.1 21-1.2.1.2.r 22-1.2.1.2.2 23-1.2.1.2 24-1.2.1.2.1.r 25-1.2.1.2.1 26-1.2 27-1.2.2.3.1 29-1.2.2.3 30-1.2.2 30-1.2.2.1 30-1.2.2.1.r 31-1.2.2.2.r 32-1.2.2.2 34-1.3.1.1.1 (a / and~e.17 :op1 (l / lead-03~e.5 :ARG0 (a2 / activate-01~e.7 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.4)) :ARG1 (e / enzyme :name (n / name :op1 "PKC"~e.2))) :ARG2 (a3 / activate-01~e.0,7 :polarity~e.7 -~e.7 :ARG1~e.8 (e2 / enzyme :name (n3 / name :op1 "GSK3"~e.9))) :condition~e.10 (a4 / absent-01~e.12 :ARG1~e.13 (s / signal-07~e.16 :ARG0 (p2 / pathway :name (n4 / name :op1 "wnt"~e.15))))) :op2 (p3 / prevent-01~e.26 :ARG0 (d / downregulate-01~e.18 :ARG1~e.19 e~e.20 :ARG2~e.21 (t / treat-04~e.23 :ARG2~e.24 s2~e.25 :ARG1-of (p4 / prolong-01~e.22))) :ARG1 (a5 / activate-01~e.30 :polarity~e.30 -~e.30 :ARG1~e.31 e2~e.32 :ARG1-of (m / mediate-01~e.29 :ARG0 p2~e.27))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 113~e.34)))) # ::id bio.chicago_2015.53659 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm that p65 activates PI3K in vivo , 3 @-@ phosphorylated inositol lipid levels were measured in different cells expressing p65 or p85 alpha . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.1 4-1.3.1 5-1.3.1.2.1.1 6-1.3.1.3 7-1.3.1.3 9-1.1.1 9-1.1.3.1.1 11-1.1.2 11-1.1.3.1.1 12-1.1.3.1.2 13-1.1.3 14-1.1 16-1 17-1.2.r 17-1.3.1.3 18-1.2.1 19-1.2 20-1.2.2 21-1.2.2.1.1.1.1 22-1.2.2.1 (m / measure-01~e.16 :ARG1 (l / level~e.14 :quant 3~e.9 :ARG1-of (p / phosphorylate-01~e.11) :quant-of (l3 / lipid~e.13 :name (n5 / name :op1 "3-phosphorylated"~e.9,11 :op2 "inositol"~e.12))) :location~e.17 (c / cell~e.19 :ARG1-of (d / differ-02~e.18) :ARG3-of (e / express-03~e.20 :ARG2 (o / or~e.22 :op1 (p2 / protein :name (n2 / name :op1 "p65"~e.21)) :op2 (p3 / protein-segment :name (n3 / name :op1 "p85alpha"))))) :purpose (c2 / confirm-01~e.1 :ARG1~e.2 (a / activate-01~e.4 :ARG0 p2~e.3 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K"~e.5)) :manner (i / in-vivo~e.6,7,17)))) # ::id bio.chicago_2015.53662 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in slp mutants , in contrast to the slp+ situation , VP16En activates hh expression ( compare Fig. 6D with Fig. 4B ) and also that of en ( not shown ) . # ::alignments 0-1 3-1.1.3.1.1 3-1.1.3.3.1.1.1.1 4-1.1.3 4-1.1.3.2 4-1.1.3.2.r 6-1.1.3.3.r 7-1.1.3.3 11-1.1.3.3.1 13-1.1.1.1.1.1 14-1.1.1 14-1.1.2 15-1.1.1.2.1.1.1 16-1.1.1.2 16-1.1.2.2 18-1.1.1.3.1 19-1.1.1.3.1.1 19-1.1.1.3.1.2 20-1.1.1.3.1.1.1 22-1.1.1.3.1.2 23-1.1.1.3.1.2.1 25-1.1 26-1.1.2.4 28-1.1.2.2.1.r 29-1.1.2.2.1.1.1 31-1.1.2.3.1 31-1.1.2.3.1.r 32-1.1.2.3 (h / have-concession-91~e.0 :ARG1 (a2 / and~e.25 :op1 (a / activate-01~e.14 :ARG0 (p / protein :name (n / name :op1 "VP16En"~e.13)) :ARG1 (e / express-03~e.16 :ARG2 (p2 / protein :name (n2 / name :op1 "Hh"~e.15))) :ARG1-of (d / describe-01 :ARG0 (c / compare-01~e.18 :ARG1 (f / figure~e.19 :mod "6D"~e.20) :ARG2 (f2 / figure~e.19,22 :mod "4B"~e.23)))) :op2 (a3 / activate-01~e.14 :ARG0 p :ARG1 (e2 / express-03~e.16 :ARG2~e.28 (p3 / protein :name (n3 / name :op1 "En"~e.29))) :ARG1-of (s / show-01~e.32 :polarity~e.31 -~e.31) :mod (a4 / also~e.26)) :location (g / gene~e.4 :name (n4 / name :op1 "SLP"~e.3) :ARG2-of~e.4 (m / mutate-01~e.4) :ARG1-of~e.6 (c2 / contrast-01~e.7 :ARG2 (s2 / situation~e.11 :mod (g2 / gene :name (n5 / name :op1 "SLP"~e.3) :mod (w / wild-type))))))) # ::id bio.chicago_2015.53694 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A , Responses to 10 msec flashes recorded in WT photoreceptors in controls and in the presence of 8 @-@ Br @- cGMP ( 5 mM ) , 8 @-@ Br @-@ cAMP ( 5 mM ) , IBMX ( 100 muM ) , and photoreceptors from flies expressing activated Gsalpha ( Gsalpha*) . # ::alignments 0-1.1 2-1.2 2-1.2.1 2-1.2.1.r 3-1.2.1.1.r 4-1.2.1.1.1.1 5-1.2.1.1.1.2 6-1.2.1.1 7-1.2.1.1.2 9-1.2.1.1.2.1.1 12-1.2.1.1.2.1.2 16-1.2.1.1.2.1.3 17-1.2.1.1.2.1.3.1.r 18-1.2.1.1.2.1.3.1.1.1.1 18-1.2.1.1.2.1.3.1.2.1.1 20-1.2.1.1.2.1.3.1.1.1.1 20-1.2.1.1.2.1.3.1.2.1.1 22-1.2.1.1.2.1.3.1.1.1.1 24-1.2.1.1.2.1.3.1.1.2.1 25-1.2.1.1.2.1.3.1.3.2.2 28-1.2.1.1.2.1.3.1.1.1.1 28-1.2.1.1.2.1.3.1.2.1.1 30-1.2.1.1.2.1.3.1.1.1.1 30-1.2.1.1.2.1.3.1.2.1.1 32-1.2.1.1.2.1.3.1.2.1.1 34-1.2.1.1.2.1.3.1.2.2 35-1.2.1.1.2.1.3.1.3.2.2 38-1.2.1.1.2.1.3.1.3.1.1 40-1.2.1.1.2.1.3.1.3.2.1 44-1.2.1.1.2.1.3.1 46-1.3.1.r 47-1.3.1 48-1.3.1.1 49-1.3.1.1.1.2 50-1.3.1.1.1.1.1 (a2 / and :li "a"~e.0 :op1 (t / thing~e.2 :ARG2-of~e.2 (r / respond-01~e.2 :ARG1~e.3 (f / flash-01~e.6 :duration (t2 / temporal-quantity :quant 10~e.4 :unit (m2 / millisecond~e.5)) :ARG1-of (r2 / record-01~e.7 :location (p / photoreceptor :mod (w / wild-type~e.9) :location (c / control~e.12) :ARG2-of (p2 / present-02~e.16 :ARG1~e.17 (a / and~e.44 :op1 (s / small-molecule :name (n / name :op1 "8-Br-cGMP"~e.18,20,22,28,30) :quant (c2 / concentration-quantity :quant 5~e.24 :unit (m3 / millmolar))) :op2 (s2 / small-molecule :name (n2 / name :op1 "8-Br-cAMP"~e.18,20,28,30,32) :quant c2~e.34) :op3 (s3 / small-molecule :name (n3 / name :op1 "IBMX"~e.38) :quant (c3 / concentration-quantity :quant 100~e.40 :unit (m4 / millimolar~e.25,35)))))))))) :op2 (p3 / photoreceptor :source~e.46 (f2 / fly~e.47 :ARG3-of (e / express-03~e.48 :ARG2 (p4 / protein :name (n4 / name :op1 "Gsalpha"~e.50) :ARG1-of (a3 / activate-01~e.49)))))) # ::id bio.chicago_2015.53701 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the findings in Drosophila , Habas et al. ( 2001 ) recently demonstrated biochemically in mammalian cells that Fz @/@ Dvl ( mouse Disheveled ) signaling activates Rho and weakly Rac , but not Cdc42 . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1 3-1.3.1.1 3-1.3.1.1.r 4-1.3.1.2.r 5-1.3.1.2.1.1 7-1.4.1.1.1.1.1 8-1.4.1.1 9-1.4.1.1.2.1 11-1.4.1.2.1 13-1.2 14-1 15-1.1.1.1.3 15-1.1.1.1.3.r 17-1.1.1.3.1 18-1.1.1.3 20-1.1.1.1.1.1.1.1 22-1.1.1.1.1.1.1.1 24-1.1.1.1.1.2 25-1.1.1.1.1.2.1.1 27-1.1.1.1.1 28-1.1.1.1 28-1.1.1.2 28-1.1.2 29-1.1.1.1.2.1.1 30-1.1.1 31-1.1.1.2.3 32-1.1.1.2.2.1.1 34-1.1 35-1.1.2.1 35-1.1.2.1.r 36-1.1.2.3.1.1 (d2 / demonstrate-01~e.14 :ARG1 (c / contrast-01~e.34 :ARG1 (a3 / and~e.30 :op1 (a2 / activate-01~e.28 :ARG0 (s / signal-07~e.27 :ARG0 (p3 / pathway :name (n2 / name :op1 "Fz/Dvl"~e.20,22)) :location (m / mouse~e.24 :name (n3 / name :op1 "Disheveled"~e.25))) :ARG1 (p4 / protein :name (n4 / name :op1 "Rho"~e.29)) :manner~e.15 (b / biochemical~e.15)) :op2 (a4 / activate-01~e.28 :ARG0 s :ARG1 (e / enzyme :name (n5 / name :op1 "Rac"~e.32)) :ARG1-of (w / weak-02~e.31)) :location (c2 / cell~e.18 :mod (m2 / mammal~e.17))) :ARG2 (a5 / activate-01~e.28 :polarity~e.35 -~e.35 :ARG0 s :ARG1 (p5 / protein :name (n6 / name :op1 "Cdc42"~e.36)) :location c2)) :time (r / recent~e.13) :ARG1-of (c3 / consistent-01~e.0 :ARG2~e.1 (t / thing~e.3 :ARG1-of~e.3 (f / find-01~e.3) :location~e.4 (o2 / organism :name (n7 / name :op1 "Drosophila"~e.5)))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a / and~e.8 :op1 (p / person :name (n / name :op1 "Habas"~e.7)) :op2 (p2 / person :mod (o / other~e.9))) :time (d / date-entity :year 2001~e.11)))) # ::id bio.chicago_2015.53712 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NPAT activates histone gene transcription # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1.1 3-1.2.1 4-1.2 (a / activate-01~e.1 :ARG0 (p / protein :name (n / name :op1 "NPAT"~e.0)) :ARG1 (t / transcribe-01~e.4 :ARG1 (g2 / gene~e.3 :name (n2 / name :op1 "histone"~e.2)))) # ::id bio.chicago_2015.53750 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KN @-@ CKI inhibited the activation of Lef @-@ 1 reporter by Wnt @-@ 1 ( Fig . 3 c ) , suggesting the involvement of endogenous CKI during the Wnt signal . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 5-1.2 6-1.2.2.r 7-1.2.2.1.1.1.1 9-1.2.2.1.1.1.1 10-1.2.2 10-1.2.2.1 10-1.2.2.1.r 11-1.2.1.r 12-1.2.1.1.1 14-1.2.1.1.1 16-1.3.1 22-1.4 24-1.4.1 25-1.4.1.1.r 26-1.4.1.1.2 27-1.4.1.1.1.1 28-1.4.1.2.r 30-1.4.1.2.1.1.1 31-1.4.1.2 (i / inhibit-01~e.3 :ARG0 (e / enzyme :name (n / name :op1 "KN-CKI"~e.0,2)) :ARG1 (a / activate-01~e.5 :ARG0~e.11 (p2 / protein :name (n2 / name :op1 "Wnt-1"~e.12,14)) :ARG1~e.6 (m / molecular-physical-entity~e.10 :ARG0-of~e.10 (r / report-01~e.10 :ARG1 (p3 / protein :name (n3 / name :op1 "Lef-1"~e.7,9))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "3C")) :ARG0-of (s / suggest-01~e.22 :ARG1 (i2 / involve-01~e.24 :ARG1~e.25 (e2 / enzyme :name (n4 / name :op1 "CKI"~e.27) :mod (e3 / endogenous~e.26)) :time~e.28 (s2 / signal-07~e.31 :ARG0 (p4 / pathway :name (n5 / name :op1 "Wnt"~e.30)))))) # ::id bio.chicago_2015.53769 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Initial integrin clustering results in rapid activation of Rac and Cdc42 , and this activation of Rac and Cdc42 induces formation of lamellipodia and filopodia , leading to cell spreading and subsequent activation of Rho . # ::alignments 0-1.1.1.3 1-1.1.1.1.1 2-1.1.1.2 3-1.1 4-1.1.2.r 5-1.1.2.2 6-1.1.2 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2.1.2.1.1 12-1.1.2.1 14-1.1.2 16-1.1.2.1.1.1.1 18-1.1.2.1.2.1.1 19-1 20-1.2 21-1.2.1.r 22-1.2.1.1 23-1.2.1 24-1.2.1.2 26-1.3 27-1.3.1.r 28-1.3.1.1.1 29-1.3.1.1 30-1.3.1 31-1.3.1.2.2 32-1.3.1.2 33-1.3.1.2.1.r 34-1.3.1.2.1.1.1 (i / induce-01~e.19 :ARG0 (r / result-01~e.3 :ARG1 (p / protein :name (n / name :op1 "integrin"~e.1) :ARG0-of (c / cluster-01~e.2) :mod (i2 / initial~e.0)) :ARG2~e.4 (a2 / activate-01~e.6,14 :ARG1 (a3 / and~e.9,12 :op1 (e / enzyme :name (n2 / name :op1 "Rac"~e.8,16)) :op2 (p2 / protein :name (n3 / name :op1 "Cdc42"~e.10,18))) :mod (r2 / rapid~e.5))) :ARG2 (f / form-01~e.20 :ARG1~e.21 (a4 / and~e.23 :op1 (l / lamellipodia~e.22) :op2 (f2 / filopodia~e.24))) :ARG0-of (l2 / lead-01~e.26 :ARG2~e.27 (a5 / and~e.30 :op1 (s / spread-03~e.29 :ARG1 (c2 / cell~e.28)) :op2 (a6 / activate-01~e.32 :ARG1~e.33 (p3 / protein :name (n4 / name :op1 "Rho"~e.34)) :mod (s2 / subsequent~e.31))))) # ::id bio.chicago_2015.53781 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is , therefore , possible that Ad2 activation of PKA involves both integrins and functional F @-@ actin . # ::alignments 3-1 5-1.1 6-1.1.1.r 7-1.1.1.2.1.1.1 8-1.1.1.2 9-1.1.1.2.2.r 10-1.1.1.2.2.1.1 11-1.1.1 13-1.1.1.1.1.1.1 14-1.1.1.1 15-1.1.1.1.2 15-1.1.1.1.2.2 15-1.1.1.1.2.2.r 16-1.1.1.1.2.1.1 18-1.1.1.1.2.1.1 (c / cause-01~e.3 :ARG1 (p / possible-01~e.5 :ARG1~e.6 (i / involve-01~e.11 :ARG1 (a2 / and~e.14 :op1 (p3 / protein :name (n3 / name :op1 "integrin"~e.13)) :op2 (p4 / protein~e.15 :name (n4 / name :op1 "F-actin"~e.16,18) :ARG0-of~e.15 (f / function-01~e.15))) :ARG2 (a / activate-01~e.8 :ARG0 (p2 / protein :name (n / name :op1 "Ad2"~e.7)) :ARG1~e.9 (e / enzyme :name (n2 / name :op1 "PKA"~e.10)))))) # ::id bio.chicago_2015.53810 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One answer to how PYK2 might activate Ras comes from analysis of a structurally homologous protein , the focal adhesion kinase ( p125FAK or FAK ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.r 4-1.1.2.1.1.1.1 5-1.1.2.1.3 6-1.1.2.1 7-1.1.2.1.2.1.1 8-1 9-1.2.r 10-1.2 11-1.2.1.r 13-1.2.1.2 14-1.2.1.1 15-1.2.1 18-1.2.1.3.1.1.1 19-1.2.1.3.1.1.2 20-1.2.1.3.1.1.3 22-1.2.1.3.1.2.1.1.1.1 24-1.2.1.3.1.2.1.2.1.1 (c / come-03~e.8 :ARG1 (a / answer-01~e.1 :quant 1~e.0 :ARG1~e.2 (t / thing :manner-of~e.3 (a2 / activate-01~e.6 :ARG0 (e / enzyme :name (n2 / name :op1 "PYK2"~e.4)) :ARG1 (e2 / enzyme :name (n / name :op1 "Ras"~e.7)) :ARG1-of (p / possible-01~e.5)))) :ARG2~e.9 (a3 / analyze-01~e.10 :ARG1~e.11 (p3 / protein~e.15 :mod (h / homologous~e.14) :mod (s / structural~e.13) :ARG1-of (m / mean-01 :ARG2 (e5 / enzyme :name (n3 / name :op1 "focal"~e.18 :op2 "adhesion"~e.19 :op3 "kinase"~e.20) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (e4 / enzyme :name (n4 / name :op1 "p125FAK"~e.22)) :op1 (e3 / enzyme :name (n5 / name :op1 "FAK"~e.24))))))))) # ::id bio.chicago_2015.53850 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test whether GSK @-@ 3 activity is required for this response , we tested the effect of LiCl in the `collapse assay` since it is an established inhibitor of both GSK @-@ 3 alpha and GSK @-@ 3 beta ( Stambolic et al. , 1996 ) and can prevent the Sema 3A activation of GSK @-@ 3 ( Fig. 4 ) . # ::alignments 0-1.3 1-1 2-1.4.2.1 2-1.4.2.1.r 3-1.4.2.3.1 4-1.4.2.3.1 5-1.4.2.3.1 6-1.4.2.3 8-1.4.2 9-1.4.2.2.r 10-1.4.2.2.2 11-1.4.2.2 11-1.4.2.2.1 11-1.4.2.2.1.r 13-1.1 14-1 14-1.4 16-1.2 17-1.2.1.r 18-1.2.1.1.1 23-1.4.r 27-1.3.1.1 28-1.3.1.1.2 31-1.3.1.1.2.2.1.1.1 31-1.3.1.1.2.2.2.1.1 31-1.3.1.2.1.2.2.1.1 33-1.3.1.2.1.2.2.1.1 36-1.3.1.2.1.2.2.1.1 38-1.3.1.2.1.2.2.1.1 41-1.3.1.1.3.1.1.1.1.1 42-1.3.1.1.3.1.1 43-1.3.1.1.3.1.1.2.1 45-1.3.1.1.3.1.2.1 47-1.3.1 48-1.3.1.2 49-1.3.1.2.1 51-1.3.1.2.1.2.1.1.1 52-1.3.1.2.1.2.1.1.2 53-1.3.1.2.1.2 55-1.3.1.2.1.2.2.1.1 57-1.3.1.2.1.2.2.1.1 59-1.3.1.2.2.1 60-1.3.1.2.2.1.1 (t2 / test-01~e.1,14 :ARG0 (w / we~e.13) :ARG1 (a / affect-01~e.16 :ARG0~e.17 (s / small-molecule :name (n / name :op1 "LiCl"~e.18)) :location (a2 / assay-01 :mod (c / collapse-01))) :ARG1-of (c2 / cause-01~e.0 :ARG0 (a3 / and~e.47 :op1 (e / establish-01~e.27 :ARG1 s :ARG2 (i2 / inhibit-01~e.28 :ARG0 s :ARG1 (a4 / and :op1 (e2 / enzyme :name (n2 / name :op1 "GSK-3alpha"~e.31)) :op2 (e3 / enzyme :name (n3 / name :op1 "GSK-3beta"~e.31)))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a5 / and~e.42 :op1 (p2 / person :name (n4 / name :op1 "Stambolic"~e.41)) :op2 (p3 / person :mod (o / other~e.43))) :time (d / date-entity :year 1996~e.45)))) :op2 (p4 / possible-01~e.48 :ARG1 (p5 / prevent-01~e.49 :ARG0 s :ARG1 (a6 / activate-01~e.53 :ARG0 (p6 / protein :name (n6 / name :op1 "Sema"~e.51 :op2 "3A"~e.52)) :ARG1 (e4 / enzyme :name (n5 / name :op1 "GSK-3"~e.31,33,36,38,55,57)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.59 :mod 4~e.60))))) :purpose~e.23 (t3 / test-01~e.14 :ARG0 w :ARG1 (r / require-01~e.8 :mode~e.2 interrogative~e.2 :ARG0~e.9 (t4 / thing~e.11 :ARG2-of~e.11 (r2 / respond-01~e.11) :mod (t5 / this~e.10)) :ARG1 (a7 / activity-06~e.6 :ARG0 e4~e.3,4,5)))) # ::id bio.chicago_2015.53852 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In support of this observation , when oligonucleotide C3 @-@ 3PmA was used as 32P @-@ labeled probe in the presence of a nuclear extract from PMA/ PHA activated fresh human T lymphocytes , no binding activity was observed ( lane 9 ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1.2 4-1 4-1.4.1.1 6-1.2.r 7-1.2.1 8-1.2.1.1.1 10-1.2.1.1.1 12-1.2 13-1.2.2.r 13-1.2.r 14-1.2.2.1.1 14-1.2.2.1.1.1.1 16-1.2.2.1 17-1.2.2 18-1.2.3.r 20-1.2.3 21-1.2.3.1.r 23-1.2.3.1.2 24-1.2.3.1 27-1.2.3.1.1.4.1.2.1.1 28-1.2.3.1.1.4 29-1.2.3.1.1 29-1.2.3.1.1.3 29-1.2.3.1.1.3.r 30-1.2.3.1.1.2 31-1.2.3.1.1.1.1 32-1.2.3.1.1.1.2 34-1.1.1 34-1.1.1.r 35-1.1.2 36-1.1 38-1 38-1.4.1.1 40-1.3.1 41-1.3.1.1 (o / observe-01~e.4,38 :ARG1 (a2 / activity-06~e.36 :polarity~e.34 -~e.34 :ARG1 (b / bind-01~e.35)) :time~e.6,13 (u / use-01~e.12 :ARG1 (o3 / oligonucleotide~e.7 :name (n / name :op1 "C3-3PmA"~e.8,10)) :ARG2~e.13 (p3 / probe-01~e.17 :ARG1-of (l / label-01~e.16 :ARG2 (p4 / phosphorus~e.14 :mod (m / molecular-mass :value 32~e.14)))) :manner~e.18 (p / present-02~e.20 :ARG1~e.21 (e / extract-01~e.24 :ARG2 (c / cell~e.29 :name (n4 / name :op1 "T"~e.31 :op2 "lymphocytes"~e.32) :mod (h / human~e.30) :ARG1-of~e.29 (f / fresh-04~e.29) :ARG1-of (a / activate-01~e.28 :ARG0 (s / slash :op1 (s2 / small-molecule :name (n5 / name :op1 "PMA")) :op2 (p2 / protein :name (n6 / name :op1 "PHA"~e.27))))) :mod (n3 / nucleus~e.23)))) :ARG1-of (d / describe-01 :ARG0 (l2 / lane~e.40 :mod 9~e.41)) :ARG0-of (s3 / support-01~e.1 :ARG1~e.2 (t / thing :ARG1-of (o2 / observe-01~e.4,38) :mod (t2 / this~e.3)))) # ::id bio.chicago_2015.53861 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins . # ::alignments 0-1.3 1-1 2-1.2.r 3-1.2.1.1 4-1.2.1 5-1.2 6-1.1.r 7-1.1.1.1.1 8-1.1 9-1.1.2.2 10-1.1.2.1.1 11-1.1.1 11-1.1.2 (a / activate-01~e.1 :ARG0~e.6 (a2 / and~e.8 :op1 (p / protein~e.11 :name (n / name :op1 "MEF2"~e.7)) :op2 (p2 / protein~e.11 :name (n2 / name :op1 "bHLH"~e.10) :mod (m2 / myogenic~e.9))) :ARG1~e.2 (e / express-03~e.5 :ARG1 (g / gene~e.4 :mod (m / muscle~e.3))) :ARG0-of (c / cooperate-01~e.0)) # ::id bio.chicago_2015.53933 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because the single channel conductances of GABAA receptors activated by GABA and pentobarbital are similar ( Jackson et al. , 1982 ; Akk and Steinbach , 2000 ) , it is likely that the open states of receptors activated by either of these compounds have similar conformations . # ::alignments 0-1 2-1.1.1.3 3-1.1.1.2 6-1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.2 9-1.1.1.1.2.1.r 10-1.1.1.1.2.1.1.1 11-1.1.3.1 11-1.1.3.1.1.1 12-1.1.2 14-1.1 16-1.1.3.1.1.1.1.1.1 17-1.1.3.1.1.1 18-1.1.3.1.1.1.2.1 20-1.1.3.1.1.2.1 22-1.1.3.1.2.1.1.1.1 23-1.1.3.1.2.1 24-1.1.3.1.2.1.2.1.1 26-1.1.3.1.2.2.1 31-1.2 32-1.2.1.r 34-1.2.1.1.1 35-1.2.1.1 36-1.2.1.1.2.r 37-1.2.1.1.2 38-1.2.1.1.2.1 39-1.2.1.1.2.1.1.r 40-1.2.1.1.2.1.1.1 42-1.2.1.1.2.1.1.2 43-1.2.1.1.2.1.1 44-1.2.1 45-1.2.1.2 46-1.2.1.2.1 (c / cause-01~e.0 :ARG0 (r / resemble-01~e.14 :ARG1 (c2 / conduct-03 :ARG2 (r3 / receptor~e.7 :name (n2 / name :op1 "GABAA"~e.6) :ARG1-of (a / activate-01~e.8 :ARG0~e.9 (s2 / small-molecule :name (n3 / name :op1 "GABA"~e.10)))) :mod (c3 / channel~e.3) :ARG1-of (s / single-02~e.2)) :ARG2 (p2 / pentobarbital~e.12) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.11 :op1 (p3 / publication-91 :ARG0 (a3 / and~e.11,17 :op1 (p4 / person :name (n4 / name :op1 "Jackson"~e.16)) :op2 (p5 / person :mod (o / other~e.18))) :time (d / date-entity :year 1982~e.20)) :op2 (p6 / publication-91 :ARG0 (a4 / and~e.23 :op1 (p7 / person :name (n5 / name :op1 "Akk"~e.22)) :op2 (p8 / person :name (n6 / name :op1 "Steinbach"~e.24))) :time (d2 / date-entity :year 2000~e.26))))) :ARG1 (l / likely-01~e.31 :ARG1~e.32 (h / have-03~e.44 :ARG0 (s3 / state~e.35 :ARG1-of (o2 / open-01~e.34) :mod~e.36 (r2 / receptor~e.37 :ARG1-of (a5 / activate-01~e.38 :ARG0~e.39 (c4 / compound~e.43 :mod (e / either~e.40) :mod (t / this~e.42))))) :ARG1 (r4 / resemble-01~e.45 :ARG1 (c5 / conformation~e.46))))) # ::id bio.chicago_2015.53950 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of GCN2 by various starvation or stress conditions requires the tRNA binding activity of its HisRS @-@ like domain ( for review , see Hinnebusch and Natarajan 2002 ) . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1 3-1.1.1.r 4-1.1.1.2 5-1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2 8-1.1.1 9-1 11-1.2.2.2.1.1 12-1.2.2 13-1.2 16-1.2.1.1.1 18-1.2.1.1.1 19-1.2.1.1.2 19-1.2.2.1 21-1.3.r 22-1.3 24-1.3.1 25-1.3.1.1.1.1.1.1 26-1.3.1.1.1 27-1.3.1.1.1.2.1.1 28-1.3.1.1.2.1 (r / require-01~e.9 :ARG0 (a / activate-01~e.0 :ARG0~e.3 (c / condition-02~e.8 :ARG1 (o / or~e.6 :op1 (s / starve-01~e.5) :op2 (s2 / stress-02~e.7)) :quant (v / various~e.4)) :ARG1~e.1 (e / enzyme :name (n / name :op1 "GCN2"~e.2))) :ARG1 (a2 / activity-06~e.13 :ARG0 (p4 / protein-segment :name (n7 / name :op1 "HisRS-like"~e.16,18 :op2 "domain"~e.19)) :ARG1 (b / bind-01~e.12 :ARG1 (d2 / domain~e.19) :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "tRNA"~e.11)))) :ARG1-of~e.21 (r2 / review-01~e.22 :purpose-of (s4 / see-01~e.24 :ARG1 (p / publication-91 :ARG0 (a3 / and~e.26 :op1 (p2 / person :name (n5 / name :op1 "Hinnebusch"~e.25)) :op2 (p3 / person :name (n6 / name :op1 "Natarajan"~e.27))) :time (d / date-entity :year 2002~e.28))))) # ::id bio.chicago_2015.53994 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ubiquitination is a multi @-@ step process that begins with the activation of a Ub molecule by an E1 or Ub @-@ activating enzyme . # ::alignments 0-1.1 6-1 8-1.3 9-1.3.1.r 11-1.3.1 12-1.3.1.2.r 14-1.3.1.2.1.1.1 15-1.3.1.2 16-1.3.1.1.r 18-1.3.1.1.1.1.1 19-1.3.1.1 20-1.3.1.1.2.1.1 22-1.3.1.1.2.1 23-1.3.1.1.2 (p / process-02~e.6 :ARG1 (u / ubiquitinate-01~e.0) :mod (m / multistep) :ARG1-of (b / begin-01~e.8 :ARG2~e.9 (a / activate-01~e.11 :ARG0~e.16 (o / or~e.19 :op1 (e / enzyme :name (n2 / name :op1 "E1"~e.18)) :op2 (e2 / enzyme~e.23 :ARG1-of (a2 / activate-01~e.22 :ARG0 m2~e.20))) :ARG1~e.12 (m2 / molecule~e.15 :mod (p2 / protein :name (n / name :op1 "Ub"~e.14)))))) # ::id bio.chicago_2015.54023 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At this concentration forskolin slightly enhanced Rap1 activation by PDGF ( e.g . 1.9 @- to 2.6 @-@ fold in Figure 4C ) . # ::alignments 1-1.2.1 2-1.2 3-1.1.1.1.1 4-1.1.4 5-1.1 6-1.1.2.2.1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.1 13-1.1.3.1.1 16-1.1.3.2.1 18-1.1.3.1 18-1.1.3.2 20-1.3.1 21-1.3.1.1 (h / have-condition-91 :ARG1 (e / enhance-01~e.5 :ARG0 (s / small-molecule :name (n / name :op1 "forskolin"~e.3)) :ARG1 (a / activate-01~e.7 :ARG0~e.8 (p3 / protein :name (n2 / name :op1 "PDGF"~e.9)) :ARG1 (e3 / enzyme :name (n3 / name :op1 "Rap1"~e.6))) :ARG3 (v / value-interval :op1 (p / product-of~e.18 :op1 1.9~e.13) :op2 (p2 / product-of~e.18 :op2 2.6~e.16)) :degree (s2 / slight~e.4)) :ARG2 (c / concentrate-01~e.2 :mod (t / this~e.1)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "4C"~e.21))) # ::id bio.chicago_2015.54073 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , compared to native channels , -@ only channels have decreased Ca2+ permeability , less voltage dependence , a lack of Ca2+/calmodulin modulation , less flickery single @-@ channel records , lower apparent affinity for cGMP , and minimal activation by cAMP . # ::alignments 0-1.2 1-1.2 3-1 4-1.1.r 5-1.1.1 6-1.1 9-1.1.2 10-1.1 11-1.1.3 12-1.1.3.1.1.1 14-1.1.3.1.1 16-1.1.3.1.2.3 17-1.1.3.1.2.2 18-1.1.3.1.2 21-1.1.3.1.3 24-1.1.3.1.3.2 26-1.1.3.1.4.2 27-1.1.3.1.4.1.2 28-1.1.3.1.4.1.1 30-1.1.3.1.4.1 31-1.1.3.1.4 33-1.1.3.1.5.3 33-1.1.3.1.5.3.1 33-1.1.3.1.5.3.1.r 34-1.1.3.1.5.2 35-1.1.3.1.5 36-1.1.3.1.5.1.r 37-1.1.3.1.5.1.1.1 39-1.1.3.1 40-1.1.3.1.6.3 41-1.1.3.1.6 42-1.1.3.1.6.1.r 43-1.1.3.1.6.1.1.1 (c2 / compare-01~e.3 :ARG1~e.4 (c3 / channel~e.6,10 :mod (n / native~e.5) :mod (o / only~e.9) :ARG0-of (h / have-03~e.11 :ARG1 (a / and~e.39 :op1 (p / permeability~e.14 :ARG1-of (d / decrease-01~e.12) :mod (c / calcium :ARG1-of (i / ionize-01 :value "2+"))) :op2 (d2 / depend-01~e.18 :ARG0 c3 :ARG1 (v / voltage~e.17) :mod (l2 / less~e.16)) :op3 (l3 / lack-01~e.21 :ARG0 c3 :ARG1 (m3 / modulate-01~e.24 :ARG1 (p2 / protein :name (n3 / name :op1 "calmodulin")) :mod c)) :op4 (r / record~e.31 :mod (c4 / channel~e.30 :ARG1-of (s / single-02~e.28) :mod (f / flickery~e.27)) :mod l2~e.26) :op5 (a2 / affinity~e.35 :beneficiary~e.36 (s2 / small-molecule :name (n4 / name :op1 "cGMP"~e.37)) :ARG1-of (a3 / appear-02~e.34) :ARG1-of (l4 / low-04~e.33 :degree~e.33 (m5 / more~e.33))) :op6 (a4 / activate-01~e.41 :ARG0~e.42 (s3 / small-molecule :name (n5 / name :op1 "cAMP"~e.43)) :ARG1 c3 :ARG1-of (m6 / minimal-02~e.40))))) :ARG0-of (e2 / exemplify-01~e.0,1)) # ::id bio.chicago_2015.54091 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upon stimulation of the bombesin receptors , KUZ increases the docking and activation of adaptors Src homology 2 domain - containing protein and Gab1 on the EGFR , and activation of Ras and Erk . # ::alignments 1-1.3 2-1.3.1.r 4-1.3.1.1.1.1 5-1.3.1 7-1.1.1.1 8-1 10-1.2.1 11-1.2 11-1.2.1.1 12-1.2.2 12-1.2.3 13-1.2.1.1.r 14-1.2.1.1.1 15-1.2.1.1.1.1.1.1.1.1 16-1.2.1.1.1.1.1.1.1.2 17-1.2.1.1.1.1.1.1.1.3 18-1.2.1.1.1.1.1.1.1.4 20-1.2.1.1.1.1.1 21-1.2.1.1.1.1 22-1.2.1.1 23-1.2.1.1.2.1.1 24-1.2.1.2.r 26-1.2.1.2.1.1 28-1.2 29-1.2.3 30-1.2.3.1.r 31-1.2.3.1.1.1.1 33-1.2.3.1.2.1.1 (i / increase-01~e.8 :ARG0 (p3 / protein :name (n4 / name :op1 "KUZ"~e.7)) :ARG1 (a / and~e.11,28 :op1 (d / dock-01~e.10 :ARG1~e.13 (a5 / and~e.11,22 :op1 (a3 / adaptor~e.14 :mod (p4 / protein~e.21 :ARG0-of (c / contain-01~e.20 :ARG1 (p5 / protein-segment :name (n5 / name :op1 "Src"~e.15 :op2 "homology"~e.16 :op3 2~e.17 :op4 "domain"~e.18))))) :op2 (p6 / protein :name (n6 / name :op1 "GAb1"~e.23))) :ARG2~e.24 (e / enzyme :name (n / name :op1 "EGFR"~e.26))) :op2 (a2 / activate-01~e.12 :ARG0 e :ARG1 a5) :op3 (a4 / activate-01~e.12,29 :ARG1~e.30 (a6 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.31)) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK"~e.33))))) :time (s / stimulate-01~e.1 :ARG1~e.2 (r / receptor~e.5 :mod (s2 / small-molecule :name (n7 / name :op1 "bombesin"~e.4))))) # ::id bio.chicago_2015.54241 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tinman is a direct activator of D @-@ mef2 in heart precursor cells and this regulation probably requires a Tinman co @-@ activator protein , since Tinman expression in the dorsal mesoderm is much broader than D @-@ mef2 , and ectopic Tinman expression can activate the D @-@ mef2 cardiac enhancer in some but not all regions of the embryo . # ::alignments 0-1.1.1.1.1 3-1.1.3 4-1.1 6-1.1.2.1.1 8-1.1.2.1.1 10-1.1.4.2 11-1.1.4.1 12-1.1.4 13-1 14-1.2.1.1 15-1.2.1 16-1.2.3 17-1.2 19-1.1.1.1.1 22-1.1 23-1.2.2 25-1.3 26-1.1.1.1.1 27-1.3.1.1.1 27-1.3.1.1.3.1 28-1.3.1.1.1.2.r 30-1.3.1.1.1.2.1 31-1.3.1.1.1.2 34-1.3.1.1 34-1.3.1.1.2 34-1.3.1.1.2.r 34-1.3.1.1.3 35-1.3.1.1.3.r 36-1.3.1.1.3.1.1 37-1.3.1.1.3.1.1 38-1.3.1.1.3.1.1 40-1.3.1 41-1.3.1.2.1.1.2 42-1.3.1.2.1.1.1 43-1.3.1.2.1.1 44-1.3.1.2 45-1.3.1.2.1 45-1.3.1.2.1.4.1 47-1.3.1.2.1.2.1.1 48-1.3.1.2.1.2.1.1 49-1.3.1.2.1.2.1.1 50-1.3.1.2.1.2.1.2 52-1.3.1.2.1.3.r 53-1.3.1.2.1.3.1 54-1.3.1.2.1.4 55-1.3.1.2.1.4.1.1 55-1.3.1.2.1.4.1.1.r 56-1.3.1.2.1.4.1.4.1 57-1.3.1.2.1.3 57-1.3.1.2.1.4.1.4 58-1.3.1.2.1.3.2.r 60-1.3.1.2.1.3.2 (a2 / and~e.13 :op1 (a3 / activate-01~e.4,22 :ARG0 (p / protein :name (n / name :op1 "Tinman"~e.0,19,26)) :ARG1 (p2 / protein :name (n2 / name :op1 "D-mef2"~e.6,8)) :ARG1-of (d / direct-02~e.3) :location (c / cell~e.12 :mod (p3 / precursor~e.11) :mod (h / heart~e.10))) :op2 (r / require-01~e.17 :ARG0 (r2 / regulate-01~e.15 :mod (t2 / this~e.14)) :ARG1 (p4 / protein~e.23 :ARG0-of (c2 / coactivate-01 :ARG1 p)) :mod (p5 / probable~e.16)) :ARG1-of (c5 / cause-01~e.25 :ARG0 (a4 / and~e.40 :op1 (b / broad-02~e.34 :ARG1 (e / express-03~e.27 :ARG2 p :ARG3~e.28 (m / mesoderm~e.31 :mod (d2 / dorsal~e.30))) :degree~e.34 (m2 / more~e.34) :compared-to~e.35 (b2 / broad-02~e.34 :ARG1 (e2 / express-03~e.27 :ARG2 p2~e.36,37,38))) :op2 (p6 / possible-01~e.44 :ARG1 (a5 / activate-01~e.45 :ARG0 (e4 / express-03~e.43 :ARG2 p~e.42 :mod (e3 / ectopic~e.41)) :ARG1 (m3 / molecular-physical-entity :ARG0-of (e5 / enhance-01 :ARG1 p2~e.47,48,49 :mod (c3 / cardiac~e.50))) :location~e.52 (r3 / region~e.57 :quant (s / some~e.53) :location~e.58 (e6 / embryo~e.60)) :ARG1-of (c4 / contrast-01~e.54 :ARG2 (a6 / activate-01~e.45 :polarity~e.55 -~e.55 :ARG0 e4 :ARG1 m3 :location (r4 / region~e.57 :mod (a7 / all~e.56) :location e6)))))))) # ::id bio.chicago_2015.54249 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TAK1 activates p38 @-@ MAPK activity through MAPK kinase 4/SEK1 by a coupled kinase assay ( 16 ) . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1.1 4-1.2.1.1.1 5-1.2 6-1.5.r 7-1.5.1.1 8-1.5.1.2 9-1.5.1.3 12-1.4.1.2 13-1.4.1.1 14-1.4.1 16-1.3.1.1.1 (a / activate-01~e.1 :ARG0 (e / enzyme :name (n2 / name :op1 "TAK1"~e.0)) :ARG1 (a2 / activity-06~e.5 :ARG0 (e2 / enzyme :name (n / name :op1 "p38-MAPK"~e.2,4))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 16~e.16))) :ARG1-of (s / say-01 :ARG0 (a3 / assay-01~e.14 :ARG1 (k / kinase~e.13) :ARG1-of (c / couple-01~e.12))) :path~e.6 (p2 / pathway :name (n3 / name :op1 "MAPK"~e.7 :op2 "kinase"~e.8 :op3 "4/SEK1"~e.9))) # ::id bio.chicago_2015.54262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While only 4 deficiencies were identified as specifically inducing ectopic activation of the ems HRE , 11 were found to severely reduce [ Df( 2L ) al , Df( 2L ) dp @-@ 79b , Df( 2L ) TW84 , Df( 3L ) lxd6 , and Df( 3R ) B81 ] or abolish [ Df( 2L ) H20 , Df( 2R ) H3E1 , Df( 2R ) Jp1 , Df( 2R ) AA21 , Df( 3L ) h @-@ i22 , and Df( 3R ) e @-@ R1 ] its activity [ Table 2 ; shown in Fig 5E and Fig F , and Fig 4C for Df( 2L ) dp @-@ 79b , Df( 3R ) e @-@ F1 , and Df( 3R ) B81 ] . # ::alignments 0-1 1-1.1.1.3 2-1.1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.3 8-1.1.2 9-1.1.2.2.2 10-1.1.2.2 11-1.1.2.2.1.r 13-1.1.2.2.1.2.1.1.1 14-1.1.2.2.1.1.1 16-1.2.1.1 18-1.2 19-1.2.2.r 20-1.2.2.1.3 20-1.2.2.1.3.r 21-1.2.2.1 33-1.2.2.1.1.2.1.2.1.1 45-1.2.2.1.1.2.1 51-1.2.2 52-1.2.2.2 79-1.2.2.2.1.2.1.5.1.1 81-1.2.2.2.1.2.1 87-1.2.2.2.1.2.1.6.1.1 90-1.2.2.1.2 92-1.3.1 95-1.2.2.1.1.2.1.2 95-1.2.2.1.1.2.1.2.2 95-1.2.2.1.1.2.1.2.2.r 95-1.2.2.1.1.2.1.5 95-1.2.2.1.1.2.1.5.2 95-1.2.2.1.1.2.1.5.2.r 95-1.2.2.2.1.2.1.6 95-1.2.2.2.1.2.1.6.2 95-1.2.2.2.1.2.1.6.2.r 97-1.2.2.1.1.2.1.2.2.1 97-1.2.2.2.1.2.1.6.2.1 98-1.2.2.1.1.2.1.2.2.1.1 100-1.2.2.1.1.2.1.2.2.1 103-1.2.2.1.1.2.1 104-1.2.2.1.1.2.1.5.2.1 105-1.2.2.1.1.2.1.5.2.1.1 112-1.2.2.1.1.2.1.2.1.1 121-1.2.2.1.1.2.1 121-1.2.2.2.1.2.1 (c / contrast-01~e.0 :ARG1 (i / identify-01~e.5 :ARG1 (m / molecular-physical-entity :quant 4~e.2 :ARG1-of (l / lack-01) :mod (o / only~e.1)) :ARG2~e.6 (i2 / induce-01~e.8 :ARG0 m :ARG2 (a / activate-01~e.10 :ARG1~e.11 (d2 / dna-sequence :name (n2 / name :op1 "HRE"~e.14) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "ems"~e.13)))) :mod (e / ectopic~e.9)) :ARG1-of (s5 / specific-02~e.7))) :ARG2 (f / find-01~e.18 :ARG1 (m2 / molecular-physical-entity :quant 11~e.16 :ARG1-of (l2 / lack-01)) :ARG2~e.19 (o2 / or~e.51 :op1 (r / reduce-01~e.21 :ARG0 (m3 / molecular-physical-entity :ARG1-of (i4 / include-91 :ARG2 m2) :ARG1-of (m4 / mean-01 :ARG2 (a4 / and~e.45,103,121 :op1 (m5 / molecular-physical-entity :name (n4 / name :op1 "Df(2L)al")) :op2 (m6 / molecular-physical-entity~e.95 :name (n5 / name :op1 "Df(2L)dp-79b"~e.33,112) :ARG1-of~e.95 (s2 / show-01~e.95 :ARG0 (f2 / figure~e.97,100 :mod "5E"~e.98))) :op3 (m7 / molecular-physical-entity :name (n6 / name :op1 "Df(2L)TW84")) :op4 (m8 / molecular-physical-entity :name (n7 / name :op1 "Df(3L)lxd6")) :op5 (m9 / molecular-physical-entity~e.95 :name (n8 / name :op1 "Df(3R)B81") :ARG1-of~e.95 (s4 / show-01~e.95 :ARG0 (f4 / figure~e.104 :mod "4C"~e.105)))))) :ARG1 (a3 / activity-06~e.90 :ARG0 d2) :manner~e.20 (s / severe~e.20)) :op2 (a2 / abolish-01~e.52 :ARG0 (m10 / molecular-physical-entity :ARG1-of (i3 / include-91 :ARG2 m2) :ARG1-of (m11 / mean-01 :ARG2 (a5 / and~e.81,121 :op1 (m12 / molecular-physical-entity :name (n9 / name :op1 "Df(2L)H20")) :op2 (m13 / molecular-physical-entity :name (n10 / name :op1 "Df(2R)H3E1")) :op3 (m14 / molecular-physical-entity :name (n11 / name :op1 "Df(2R)Jp1")) :op4 (m15 / molecular-physical-entity :name (n12 / name :op1 "Df(2R)AA21")) :op5 (m16 / molecular-physical-entity :name (n13 / name :op1 "Df(3L)h-i22"~e.79)) :op6 (m17 / molecular-physical-entity~e.95 :name (n14 / name :op1 "Df(3R)e-R1"~e.87) :ARG1-of~e.95 (s3 / show-01~e.95 :ARG0 (f3 / figure~e.97 :mod "5F")))))) :ARG1 a3))) :ARG1-of (d / describe-01 :ARG0 (t / table~e.92 :mod 1))) # ::id bio.chicago_2015.54288 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Initially , ubiquitin is activated by the ATP @-@ dependent formation of a high @-@ energy thioester intermediate between the ubiquitin @-@ activating enzyme ( E1 ) and the C terminus of ubiquitin . # ::alignments 0-1.3 2-1.2.1.1 4-1 5-1.1.r 7-1.1.3.1.1.1 9-1.1.3 10-1.1 11-1.1.2.r 13-1.1.2.1.2.1 15-1.1.2.1.2 16-1.1.2.1.1.1 17-1.1.2 20-1.1.1.1.1.1 22-1.1.1.1.1.1 23-1.1.1.1.1.2 27-1.1.1 29-1.1.1.2.1.1 30-1.1.1.2.1.2 32-1.2.1.1 (a / activate-01~e.4 :ARG0~e.5 (f / form-02~e.10 :ARG0 (a2 / and~e.27 :op1 (e2 / enzyme :name (n5 / name :op1 "ubiquitin-activating"~e.20,22 :op2 "enzyme"~e.23)) :op2 (p3 / protein-segment :name (n6 / name :op1 "C"~e.29 :op2 "terminus"~e.30) :part-of p2)) :ARG1~e.11 (i / intermediate~e.17 :mod (s2 / small-molecule :name (n4 / name :op1 "thioester"~e.16) :mod (e / energy~e.15 :ARG1-of (h / high-02~e.13)))) :ARG0-of (d / depend-01~e.9 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP"~e.7)))) :ARG1 (p2 / protein :name (n2 / name :op1 "ubiquitin"~e.2,32)) :time (i2 / initial~e.0)) # ::id bio.chicago_2015.54303 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine wether activation of JNK by SLK occurs through a known MEKK , transfections were performed in the presence of dominant negative versions of MEKK or SEK1 , both upstream activators of JNK ( 13 ) . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.3.r 5-1.3.1.3 6-1.3.1.2.r 7-1.3.1.2.1.1 11-1.3.1.4 11-1.3.1.4.2 11-1.3.1.4.2.r 12-1.2.1.1.2.1.1 12-1.3.1.4.1.1 16-1 17-1.2.r 19-1.2 20-1.2.1.r 21-1.2.1.1.1 23-1.2.1.1 23-1.2.1.2 24-1.2.1.1.2.r 25-1.2.1.1.2.1.1 26-1.2.1 27-1.2.1.2.2.1.1 30-1.2.1.3.2 31-1.2.1.3 32-1.2.1.3.1.r 33-1.2.1.3.1.1.1 (p / perform-01~e.16 :ARG1 (t2 / transfect-01) :condition~e.17 (p2 / present-02~e.19 :ARG1~e.20 (o / or~e.26 :op1 (v / version~e.23 :ARG0-of (d / dominate-01~e.21) :mod~e.24 (e / enzyme :name (n2 / name :op1 "MEKK"~e.12,25)) :ARG2-of (m / mutate-01 :mod "-/-")) :op2 (v2 / version~e.23 :ARG0-of d :mod (e2 / enzyme :name (n3 / name :op1 "SEK1"~e.27)) :ARG2-of m) :ARG0-of (a2 / activate-01~e.31 :ARG1~e.32 (e3 / enzyme :name (n4 / name :op1 "JNK"~e.33)) :direction (u / upstream~e.30)))) :purpose (d2 / determine-01~e.1 :ARG1 (a3 / activate-01~e.3 :mode interrogative :ARG0~e.6 (e4 / enzyme :name (n5 / name :op1 "SLK"~e.7)) :ARG1~e.4 e3~e.5 :manner (e5 / enzyme~e.11 :name (n6 / name :op1 "MEKK"~e.12) :ARG1-of~e.11 (k / know-01~e.11))))) # ::id bio.chicago_2015.54322 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In PC12 cells , NGF activates CREB phosphorylation through sequential activation of Ras , Raf , MEK , ERK , and RSK ( Xing et al. 1996 ) . # ::alignments 1-1.4.1.1 2-1.4 4-1.1.1.1 5-1 6-1.2.1.1.1 7-1.2 9-1.3.2 10-1.3 11-1.3.1.r 12-1.3.1.1.1.1 14-1.3.1.2.1.1 16-1.3.1.3.1.1 18-1.3.1.4.1.1 20-1.3.1 21-1.3.1.5.1.1 23-1.5.1.1.1.1.1 24-1.5.1.1 25-1.5.1.1.2.1 26-1.5.1.2.1 (a / activate-01~e.5 :ARG0 (p6 / protein :name (n5 / name :op1 "NGF"~e.4)) :ARG1 (p / phosphorylate-01~e.7 :ARG1 (p7 / protein :name (n6 / name :op1 "CREB"~e.6))) :manner (a2 / activate-01~e.10 :ARG1~e.11 (a3 / and~e.20 :op1 (e / enzyme :name (n / name :op1 "Ras"~e.12)) :op2 (e2 / enzyme :name (n2 / name :op1 "Raf"~e.14)) :op3 (e3 / enzyme :name (n3 / name :op1 "MEK"~e.16)) :op4 (e4 / enzyme :name (n4 / name :op1 "ERK"~e.18)) :op5 (e5 / enzyme :name (n9 / name :op1 "RSK"~e.21))) :mod (s / sequential~e.9)) :location (c / cell-line~e.2 :name (n7 / name :op1 "PC12"~e.1)) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a4 / and~e.24 :op1 (p9 / person :name (n8 / name :op1 "Xing"~e.23)) :op2 (p10 / person :mod (o / other~e.25))) :time (d / date-entity :year 1996~e.26)))) # ::id bio.chicago_2015.54328 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GTP @-@ dependent adenylyl cyclase activity in control ( cn , ry ) flies and flies expressing the activated Gsalpha subunit # ::alignments 0-1.1.1.2.1.1.1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 3-1.1.1.1.1 4-1.1.1.1.2 5-1.1 7-1.1.2.1.1 9-1.1.2.1.2.1.1 11-1.1.2.2.2.1.1 13-1.1.2.1 13-1.1.2.2 14-1 14-1.1.2 15-1.2.2 16-1.2 18-1.2.1.2 19-1.2.1.1.1.1 20-1.2.1 (a / and~e.14 :op1 (a2 / activity-06~e.5 :ARG0 (e / enzyme~e.2 :name (n / name :op1 "adenylyl"~e.3 :op2 "cyclase"~e.4) :ARG0-of~e.2 (d / depend-01~e.2 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"~e.0)))) :location (a4 / and~e.14 :op1 (f / fly~e.13 :mod (c / control~e.7) :mod (o / organism :name (n4 / name :op1 "cn"~e.9))) :op2 (f3 / fly~e.13 :mod c :mod (o2 / organism :name (n5 / name :op1 "ry"~e.11))))) :op2 (e2 / express-03~e.16 :ARG2 (s2 / subunit~e.20 :part-of (p / protein :name (n3 / name :op1 "Gsalpha"~e.19)) :ARG1-of (a3 / activate-01~e.18)) :ARG3 (f2 / fly~e.15))) # ::id bio.chicago_2015.54349 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( c ) That Ephexin can also activate Cdc42 raises the possibility that it may function to control cytoskeletal dynamics downstream from attractant receptors through Pak activation # ::alignments 1-1.1 4-1.2.1.1.1 5-1 6-1.2.3 7-1.2 8-1.2.2.1.1 9-1.3.1 11-1.3.1.1 14-1.3.1.1 14-1.3.1.1.1 14-1.3.1.1.1.r 15-1.3.1.1.1.1 17-1.3.1.1.1.1.2 18-1.3.1.1.1.1.2.2.1 19-1.3.1.1.1.1.2.2 20-1.3.1.1.1.1.2.3 23-1.3.1.1.1.1.2.3.1 25-1.3.1.1.1.1.2.3.1.1.1.1.1.1 26-1.2 26-1.3.1.1.1.1.2.3.1.1.1 (p2 / possible-01~e.5 :li "c"~e.1 :ARG1 (a / activate-01~e.7,26 :ARG0 (p / protein :name (n / name :op1 "Ephexin"~e.4)) :ARG1 (p3 / protein :name (n2 / name :op1 "Cdc42"~e.8)) :mod (a2 / also~e.6)) :ARG0-of (c / cause-01 :ARG1 (r / raise-01~e.9 :ARG1 (p4 / possible-01~e.11,14 :ARG1~e.14 (p5 / possible-01~e.14 :ARG1 (f / function-01~e.15 :ARG0 a :ARG1 (c2 / control-01~e.17 :ARG0 a :ARG1 (d2 / dynamic~e.19 :mod (c3 / cytoskeletal~e.18)) :direction (d3 / downstream~e.20 :op1 (r2 / receptor~e.23 :ARG0-of (a3 / attract-01 :manner (a4 / activate-01~e.26 :ARG1 (e / enzyme :name (n3 / name :op1 "Pak"~e.25))))))))))))) # ::id bio.chicago_2015.54352 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since the expression of either active Rit or RGL3 is sufficient to induce Ral GDP/ GTP exchange , the amount of individual expression vectors was adjusted to limit endogenous Ral activation by either RitQ79L or RGL3 expression alone . # ::alignments 0-1.3 2-1.2.1.1 6-1.3.1.1.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1.1 10-1.3.1 12-1.3.1.2 13-1.3.1.2.2.1 15-1.3.1.2.2.3.1.1 16-1.3.1.2.2 19-1.1 20-1.1.1.r 21-1.1.1.2 22-1.1.1.1 23-1.1.1 25-1 26-1.3 27-1.2 28-1.2.2.1.2 29-1.2.2.1.1.1 30-1.2.2 30-1.3.1.1.1.3 33-1.2.1.1.1.1.1 34-1.2.1 34-1.3.1.1.1 35-1.2.1.2.1.1.1 36-1.2.1.1 36-1.2.1.2 36-1.3.1.1 37-1.2.1.3 (a / adjust-01~e.25 :ARG1 (a2 / amount~e.19 :quant-of~e.20 (v / vector~e.23 :ARG3-of (e / express-03~e.22) :mod (i / individual~e.21))) :ARG4 (l / limit-01~e.27 :ARG0 (o / or~e.7,34 :op1 (e4 / express-03~e.2,36 :ARG2 (p3 / protein :name (n3 / name :op1 "RitQ79L"~e.33))) :op2 (e5 / express-03~e.36 :ARG2 (p2 / protein :name (n4 / name :op1 "RGL3"~e.8,35))) :mod (a4 / alone~e.37)) :ARG1 (a3 / activate-01~e.30 :ARG1 (p / protein :name (n2 / name :op1 "Ral"~e.29) :mod (e2 / endogenous~e.28)))) :ARG1-of (c / cause-01~e.0,26 :ARG0 (s2 / suffice-01~e.10 :ARG0 (e3 / express-03~e.36 :ARG2 (o2 / or~e.34 :op1 (p4 / protein :name (n5 / name :op1 "Rit"~e.6)) :op2 p2 :ARG1-of (a5 / activate-01~e.30))) :ARG1 (i2 / induce-01~e.12 :ARG0 e3 :ARG2 (e7 / exchange-01~e.16 :ARG0 p~e.13 :ARG1 (s4 / small-molecule :name (n6 / name :op1 "GDP")) :ARG3 (s / small-molecule :name (n / name :op1 "GTP"~e.15))))))) # ::id bio.chicago_2015.54392 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , activation of Rap1 by both thrombin and TCR stimulation in platelets and T cells , respectively , displayed similar calcium dependences . # ::alignments 0-1 2-1.1.1.1 2-1.1.1.2 3-1.1.1.1.2.r 4-1.1.1.1.2.1.1 7-1.1.1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.1.1.1.1 10-1.1.1.1.1 10-1.1.1.2.1 11-1.1.1.1.3.r 12-1.1.1.1.3.1 13-1.1.1 14-1.1.1.2.3.1.1 15-1.1.1.1.3 17-1.1.1.3 19-1.1 20-1.1.2.3 21-1.1.2.2.1.1 22-1.1.2 (h / have-concession-91~e.0 :ARG1 (d / display-01~e.19 :ARG0 (a / and~e.8,13 :op1 (a2 / activate-01~e.2 :ARG0 (s2 / stimulate-01~e.10 :ARG1 (e2 / enzyme :name (n3 / name :op1 "thrombin"~e.7))) :ARG1~e.3 (e / enzyme :name (n2 / name :op1 "Rap1"~e.4)) :location~e.11 (c / cell~e.15 :part-of (p / platelet~e.12))) :op2 (a3 / activate-01~e.2 :ARG0 (s3 / stimulate-01~e.10 :ARG1 (p2 / protein :name (n4 / name :op1 "TCR"~e.9))) :ARG1 e :location (c2 / cell :name (n5 / name :op1 "T"~e.14))) :mod (r / respective~e.17)) :ARG1 (d2 / depend-01~e.22 :ARG0 a :ARG1 (s / small-molecule :name (n / name :op1 "calcium"~e.21)) :ARG1-of (r2 / resemble-01~e.20)))) # ::id bio.chicago_2015.54403 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We demonstrate that inhibition of dMLK using gene silencing with RNAi specifically blocked JNK activation without inhibiting activation of p38 or ERK by ceramide ( Figure 1E ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 4-1.2.1.2.r 5-1.2.1.2.1.1 6-1.2.1.1 7-1.2.1.1.1.2 8-1.2.1.1.1 11-1.2.3 12-1.2 13-1.2.2.1.1.1 14-1.2.2 15-1.2.4.1 15-1.2.4.1.r 16-1.2.4 17-1.2.4.3.1 17-1.2.4.3.2 18-1.2.4.3.1.2.r 19-1.2.4.3.1.2.1.1 20-1.2.4.3 21-1.2.4.3.2.2.1.1 22-1.2.4.3.1.1.r 23-1.2.4.3.1.1.1.1 25-1.3.1 26-1.3.1.1 (d / demonstrate-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (b / block-01~e.12 :ARG0 (i / inhibit-01~e.3 :ARG0 (u / use-01~e.6 :ARG1 (s / silence-01~e.8 :ARG0 (i2 / interfere-01 :ARG0 (n / nucleic-acid :name (n7 / name :op1 "RNA"))) :ARG1 (g / gene~e.7))) :ARG1~e.4 (e / enzyme :name (n2 / name :op1 "dMLK"~e.5))) :ARG1 (a / activate-01~e.14 :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK"~e.13))) :ARG1-of (s2 / specific-02~e.11) :manner (i3 / inhibit-01~e.16 :polarity~e.15 -~e.15 :ARG0 i :ARG1 (o / or~e.20 :op1 (a2 / activate-01~e.17 :ARG0~e.22 (s3 / small-molecule :name (n6 / name :op1 "ceramide"~e.23)) :ARG1~e.18 (e3 / enzyme :name (n4 / name :op1 "p38"~e.19))) :op2 (a3 / activate-01~e.17 :ARG0 s3 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK"~e.21)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.25 :mod "1E"~e.26))) # ::id bio.chicago_2015.54425 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of intracellular CaM @-@ KII by GD3 , GD1b , GT1b and its oligosaccharide . # ::alignments 0-1 1-1.2.r 2-1.2.2 3-1.2.1.1 5-1.2.1.1 6-1.1.r 7-1.1.1.1.1 9-1.1.2.1.1 11-1.1.3.1.1 12-1.1 13-1.1.4.1 13-1.1.4.1.r 14-1.1.4 (a / activate-01~e.0 :ARG0~e.6 (a2 / and~e.12 :op1 (s / small-molecule :name (n2 / name :op1 "GD3"~e.7)) :op2 (s2 / small-molecule :name (n3 / name :op1 "GD1b"~e.9)) :op3 (s3 / small-molecule :name (n4 / name :op1 "GT1b"~e.11)) :op4 (o / oligosaccharide~e.14 :poss~e.13 s3~e.13)) :ARG1~e.1 (e / enzyme :name (n / name :op1 "CaM-KII"~e.3,5) :mod (i / intracellular~e.2))) # ::id bio.chicago_2015.54432 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All three RTKs are known to activate an overlapping set of intracellular signaling proteins , such as Ras , MAP kinase , PLC @-@ gamma , and Src family kinases . # ::alignments 0-1.1.1.3 1-1.1.1.1 4-1 6-1.1 8-1.1.2.1 9-1.1.2 10-1.1.2.2.r 11-1.1.2.2.1 12-1.1.2.2.2 13-1.1.2.2 15-1.1.2.2.3.r 16-1.1.2.2.3.r 17-1.1.2.2.3.1.1.1 19-1.1.2.2.3.2.1.1 20-1.1.2.2.3.2.1.2 22-1.1.2.2.3.3.1.1 24-1.1.2.2.3.3.1.1 26-1.1.2.2.3 27-1.1.2.2.3.4.1.1 28-1.1.2.2.3.1 28-1.1.2.2.3.2 28-1.1.2.2.3.3 28-1.1.2.2.3.4 (k / know-01~e.4 :ARG1 (a / activate-01~e.6 :ARG0 (e / enzyme :quant 3~e.1 :name (n2 / name :op1 "RTK") :mod (a2 / all~e.0)) :ARG1 (s / set~e.9 :ARG0-of (o / overlap-01~e.8) :consist-of~e.10 (p2 / protein~e.13 :mod (i / intracellular~e.11) :ARG0-of (s2 / signal-07~e.12) :example~e.15,16 (a3 / and~e.26 :op1 (p / protein-family~e.28 :name (n / name :op1 "Ras"~e.17)) :op2 (p3 / protein-family~e.28 :name (n3 / name :op1 "MAP"~e.19 :op2 "kinase"~e.20)) :op3 (p4 / protein-family~e.28 :name (n4 / name :op1 "PLC-gamma"~e.22,24)) :op4 (p5 / protein-family~e.28 :name (n5 / name :op1 "Src"~e.27))))))) # ::id bio.chicago_2015.54450 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because most extracellular stimuli that activate MKK7 also activate MKK4 in parallel , it is difficult to assess the function of MKK7 independently from MKK4 . # ::alignments 0-1.2 1-1.2.1.1.1 2-1.2.1.1.2 3-1.2.1.1 5-1.2.1 5-1.2.1.1.3 6-1.1.1.1.1.1 7-1.2.1.3 8-1.2.1 9-1.1.1.2.3.1.1 10-1.2.1.4.r 11-1.2.1.4 13-1.2.1.2 14-1.1.r 15-1 16-1.2 17-1.1 19-1.1.1 21-1.1.1.1.1.1 22-1.1.1.2.1 24-1.1.1.2.3.1.1 (d / difficult~e.15 :domain~e.14 (a / assess-01~e.17 :ARG1 (f / function-01~e.19 :ARG0 (e / enzyme :name (n / name :op1 "MKK7"~e.6,21)) :manner (d2 / depend-01 :polarity -~e.22 :ARG0 f :ARG1 (e2 / enzyme :name (n2 / name :op1 "MKK4"~e.9,24))))) :ARG1-of (c / cause-01~e.0,16 :ARG0 (a2 / activate-01~e.5,8 :ARG0 (s / stimulus~e.3 :quant (m / most~e.1) :mod (e3 / extracellular~e.2) :ARG0-of (a3 / activate-01~e.5 :ARG1 e)) :ARG1 e2~e.13 :mod (a4 / also~e.7) :manner~e.10 (p / parallel~e.11)))) # ::id bio.chicago_2015.54455 ::amr-annotator SDL-AMR-09 ::preferred # ::tok induction of cyclin D1 is required for S @-@ phase entry in Rb @-@ expressing cells . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1.1 3-1.2.1.1.2 5-1 6-1.1.r 7-1.1.2.1.1 9-1.1.2.1.1 10-1.1 11-1.1.1.r 12-1.1.1.1.1.1.1 14-1.1.1.1 15-1.1.1 (r / require-01~e.5 :ARG0~e.6 (e / enter-01~e.10 :ARG0~e.11 (c / cell~e.15 :ARG3-of (e2 / express-03~e.14 :ARG2 (p3 / protein :name (n2 / name :op1 "Rb"~e.12)))) :ARG1 (e3 / event :name (n3 / name :op1 "S-phase"~e.7,9))) :ARG1 (i / induce-01~e.0 :ARG2~e.1 (p / protein :name (n / name :op1 "cyclin"~e.2 :op2 "D1"~e.3)))) # ::id bio.chicago_2015.54458 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphoinositides , particularly PIP2 , formed secondarily to ARF activation of phospholipase D , have been implicated in the recruitment of COPI coat proteins onto the membranes of the Golgi stacks ( Donaldson et al. 1992 ; Palmer et al. 1993 ; Ktistakis et al. 1996 ) . # ::alignments 2-1.1.2.2 2-1.1.2.2.r 3-1.1.2.1.1 5-1.1.3 6-1.1.3.2 6-1.1.3.2.r 7-1.1.3.1.r 8-1.1.3.1.1.1.1 9-1.1.3.1 10-1.1.3.1.2.r 11-1.1.3.1.2.1.1 12-1.1.3.1.2.1.2 16-1 17-1.2.r 19-1.2 20-1.2.1.r 21-1.2.1.1.1 22-1.2.1.1.2 23-1.2.1.1.3 26-1.2.2 27-1.2.2.1.r 29-1.2.2.1.1.1.1 30-1.2.2.1 32-1.3.1.1.1.1.1.1 33-1.3.1.1.1 34-1.3.1.1.1.2.1 35-1.3.1.1.2.1 37-1.3.1.2.1.1.1.1 38-1.3.1 38-1.3.1.1.1 38-1.3.1.2.1 38-1.3.1.3.1 39-1.3.1.1.1.2.1 40-1.3.1.2.2.1 42-1.3.1.3.1.1.1.1 43-1.1 43-1.3.1 43-1.3.1.1.1 43-1.3.1.3.1 44-1.3.1.1.1.2.1 45-1.3.1.3.2.1 (i / implicate-01~e.16 :ARG1 (a / and~e.43 :op1 (s / small-molecule :name (n / name :op1 "phosphoinositide")) :op2 (s2 / small-molecule :name (n2 / name :op1 "PIP2"~e.3) :manner~e.2 (p / particular~e.2)) :ARG1-of (f / form-01~e.5 :ARG2~e.7 (a2 / activate-01~e.9 :ARG0 (p2 / protein :name (n3 / name :op1 "ARF"~e.8)) :ARG1~e.10 (e / enzyme :name (n4 / name :op1 "phospholipase"~e.11 :op2 "D"~e.12))) :manner~e.6 (s3 / secondary~e.6))) :ARG2~e.17 (r / recruit-01~e.19 :ARG1~e.20 (p10 / protein :name (n5 / name :op1 "COPI"~e.21 :op2 "coat"~e.22 :op3 "protein"~e.23)) :ARG2 (m2 / membrane~e.26 :part-of~e.27 (s4 / stack~e.30 :mod (t / thing :name (n9 / name :op1 "Golgi"~e.29))))) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and~e.38,43 :op1 (p3 / publication-91 :ARG0 (a4 / and~e.33,38,43 :op1 (p4 / person :name (n6 / name :op1 "Donaldson"~e.32)) :op2 (p5 / person :mod (o / other~e.34,39,44))) :time (d / date-entity :year 1992~e.35)) :op2 (p6 / publication-91 :ARG0 (a5 / and~e.38 :op1 (p7 / person :name (n7 / name :op1 "Palmer"~e.37)) :op2 p5) :time (d2 / date-entity :year 1993~e.40)) :op3 (p8 / publication-91 :ARG0 (a6 / and~e.38,43 :op1 (p9 / person :name (n8 / name :op1 "Ktistakis"~e.42)) :op2 p5) :time (d3 / date-entity :year 1996~e.45))))) # ::id bio.chicago_2015.54513 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , in most pheochromocytoma 12 ( PC12 ) cell lines , transient Erk activation [ evoked by epidermal growth factor ( EGF )] results in cell proliferation , whereas sustained Erk activation ( evoked by NGF ) causes these cells to leave the cell cycle and differentiate toward a neuronal phenotype ( Traverse et al. , 1992 ; Yaka et al. , 1998 ; York et al. , 1998 ) . # ::alignments 0-1.3 1-1.3 4-1.4.2 5-1.4.1.1 6-1.4.1.2 10-1.4 11-1.4 13-1.1.1.2 14-1.1.1.1.1.1 15-1.1.1 17-1.1.1.3 18-1.1.1.3.1.r 19-1.1.1.3.1.1.1 20-1.1.1.3.1.1.2 21-1.1.1.3.1.1.3 25-1.1 26-1.1.2.r 27-1.1.2.1 28-1.1.2 30-1 31-1.2.1.2 32-1.2.1.1 33-1.2.1 35-1.2.1.3 36-1.2.1.3.1.r 37-1.2.1.3.1.1.1 39-1.2 41-1.2.2.1.2.1 43-1.2.2.1 45-1.2.2.1.2.1 46-1.2.2.1.2 47-1.2.2 48-1.2.2.2 52-1.2.2.2.2 54-1.5.1.1.1.1.1.1 55-1.5.1.1.1 56-1.5.1.1.1.2.1 58-1.5.1.1.2.1 60-1.5.1.2.1.1.1.1 61-1.5.1 61-1.5.1.1.1 61-1.5.1.2.1 61-1.5.1.3.1 62-1.5.1.1.1.2.1 64-1.5.1.3.2 66-1.5.1.3.1.1.1.1 67-1.5.1 67-1.5.1.1.1 67-1.5.1.2.1 67-1.5.1.3.1 68-1.5.1.1.1.2.1 70-1.5.1.2.2.1 (c / contrast-01~e.30 :ARG1 (r / result-01~e.25 :ARG1 (a / activate-01~e.15 :ARG1 (e / enzyme :name (n / name :op1 "Erk"~e.14)) :ARG1-of (t / transient-02~e.13) :ARG1-of (e3 / evoke-01~e.17 :ARG0~e.18 (p10 / protein :name (n3 / name :op1 "epidermal"~e.19 :op2 "growth"~e.20 :op3 "factor"~e.21)))) :ARG2~e.26 (p2 / proliferate-01~e.28 :ARG0 c7~e.27)) :ARG2 (c3 / cause-01~e.39 :ARG0 (a2 / activate-01~e.33 :ARG1 e~e.32 :ARG1-of (s2 / sustain-01~e.31) :ARG1-of (e4 / evoke-01~e.35 :ARG0~e.36 (p11 / protein :name (n4 / name :op1 "NGF"~e.37)))) :ARG1 (a3 / and~e.47 :op1 (l / leave-11~e.43 :ARG0 c7 :ARG1 (c2 / cycle-02~e.46 :ARG1 (c6 / cell~e.41,45))) :op2 (d3 / differentiate-101~e.48 :ARG1 c7 :ARG3 (p / phenotype~e.52 :mod (n5 / neuron))))) :ARG0-of (e5 / exemplify-01~e.0,1) :location (c7 / cell-line~e.10,11 :name (n6 / name :op1 "pheochromocytoma"~e.5 :op2 12~e.6) :quant (m / most~e.4)) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and~e.61,67 :op1 (p3 / publication-91 :ARG0 (a5 / and~e.55,61,67 :op1 (p4 / person :name (n7 / name :op1 "Traverse"~e.54)) :op2 (p5 / person :mod (o / other~e.56,62,68))) :time (d / date-entity :year 1992~e.58)) :op2 (p6 / publication-91 :ARG0 (a6 / and~e.61,67 :op1 (p7 / person :name (n8 / name :op1 "Yaka"~e.60)) :op2 p5) :time (d2 / date-entity :year 1998~e.70)) :op3 (p8 / publication-91 :ARG0 (a7 / and~e.61,67 :op1 (p9 / person :name (n9 / name :op1 "York"~e.66)) :op2 p5) :time d2~e.64)))) # ::id bio.chicago_2015.54546 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exchange of T145 , Q156 , K157 , Q166 , T167 , K171 , or H175 for alanine enhanced transactivation by Raf basal activity 1.5 @- to 2.5 @-@ fold and increased Ras( G12V ) - induced Raf activation accordingly , to 1.5 @- to 2 @-@ fold over the activity achieved by activation of Raf( wt ) by Ras( G12V ) ( Fig . 2A ) . # ::alignments 0-1.1.1 14-1.1.1.1 16-1.1.1.2.r 17-1.1.1.2.1.1 18-1.1 19-1.1.2 20-1.1.2.1.r 21-1.1.2.1.1.1.1 22-1.1.2.1.2 23-1.1.2.1 24-1.2.3 25-1.2.3 26-1.2.3 27-1.2.3 28-1.2.3 29-1.2.3 30-1 31-1.2 33-1.2.2.2.1.2.1 36-1.2.2.2 37-1.1.2.1.1.1.1 38-1.2.2 39-1.2.5 41-1.1.3.r 42-1.1.3.1.1 47-1.1.3.1 50-1.2.4.1 51-1.2.4.1.1 52-1.2.4.1.1.1.r 53-1.2.4.1.1.1 54-1.1.3.1 56-1.2.4.1.1.1.2 60-1.2.2.2.1.2.1 63-1.3.1 65-1.3.1.1 (a / and~e.30 :op1 (e / enhance-01~e.18 :ARG0 (e2 / exchange-01~e.0 :ARG1 (o / or~e.14 :op1 (a2 / amino-acid :mod 145 :name (n / name :op1 "threonine")) :op2 (a3 / amino-acid :mod 156 :name (n2 / name :op1 "glutamine")) :op3 (a4 / amino-acid :mod 157 :name (n3 / name :op1 "lysine")) :op4 (a5 / amino-acid :mod 166 :name (n4 / name :op1 "threonine")) :op5 (a6 / amino-acid :mod 167 :name (n5 / name :op1 "glutamine")) :op7 (a7 / amino-acid :mod 171 :name (n6 / name :op1 "lysine")) :op8 (a8 / amino-acid :mod 175 :name (n7 / name :op1 "histidine"))) :ARG3~e.16 (a9 / amino-acid :name (n8 / name :op1 "alanine"~e.17))) :ARG1 (t / transactivate-01~e.19 :ARG2~e.20 (a10 / activity-06~e.23 :ARG0 (e3 / enzyme :name (n9 / name :op1 "Raf"~e.21,37) :mod (w / wild-type)) :mod (b / basal~e.22))) :ARG3~e.41 (v / value-interval :op1 (p / product-of~e.47,54 :op1 1.5~e.42) :op2 (p2 / product-of :op1 2.5))) :op2 (i / increase-01~e.31 :ARG0 e2 :ARG1 (a11 / activate-01~e.38 :ARG1 e3 :ARG2-of (i2 / induce-01~e.36 :ARG0 (e4 / enzyme :name (n10 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "G12V"~e.33,60)))) :ARG2 v~e.24,25,26,27,28,29 :ARG4 (m2 / more-than :op1 (a13 / activity-06~e.50 :ARG1-of (a14 / achieve-01~e.51 :ARG0~e.52 (a15 / activate-01~e.53 :ARG0 e4 :ARG1 e3~e.56)))) :manner (a12 / accordingly~e.39)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.63 :mod "2A"~e.65))) # ::id bio.chicago_2015.54584 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previous studies have shown that rRNA transcription is up @-@ regulated in both mammalian ( 1 , 51 ) and Drosophila ( 54 , 64 ) cells by the phorbol ester tetradecanoyl phorbol acetate ( TPA ) , a potent activator of protein kinase C ( PKC ) . # ::alignments 0-1.1.1 1-1.1 3-1 5-1.2.1.1.1.1 6-1.2.1 13-1.2.3.1.1 15-1.2.3.1.2.1.1.1.1 17-1.2.3.1.2.1.2.1.1 19-1.2.3 19-1.2.3.1.2.1 20-1.2.3.2.2.1.1 22-1.2.3.2.1.1.1.1.1 24-1.2.3.2.1.1.2.1.1 26-1.2.3.1 26-1.2.3.2 29-1.2.2.2.1.1 30-1.2.2 31-1.2.2.1.1 32-1.2.2.1.2 33-1.2.2.1.3 39-1.2.2.3.2 40-1.2.2.3 41-1.2.2.3.1.r 42-1.2.2.3.1.1.1 43-1.2.2.3.1.1.2 44-1.2.2.3.1.1.3 (s / show-01~e.3 :ARG0 (s2 / study-01~e.1 :time (p / previous~e.0)) :ARG1 (u / upregulate-01 :ARG1 (t2 / transcribe-01~e.6 :ARG1 (n5 / nucleic-acid :name (n / name :op1 "rRNA"~e.5))) :ARG2 (e / ester~e.30 :name (n2 / name :op1 "tetradecanoyl"~e.31 :op2 "phorbol"~e.32 :op3 "acetate"~e.33) :mod (s3 / small-molecule :name (n3 / name :op1 "phorbol"~e.29)) :ARG0-of (a5 / activate-01~e.40 :ARG1~e.41 (e2 / enzyme :name (n4 / name :op1 "protein"~e.42 :op2 "kinase"~e.43 :op3 "C"~e.44)) :mod (p6 / potent~e.39))) :location (a2 / and~e.19 :op1 (c / cell~e.26 :mod (m / mammal~e.13) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.19 :op1 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 1~e.15)) :op2 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 51~e.17))))) :op2 (c2 / cell~e.26 :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 54~e.22)) :op2 (p5 / publication :ARG1-of (c6 / cite-01 :ARG2 64~e.24)))) :mod (o / organism :name (n6 / name :op1 "Drosophila"~e.20)))))) # ::id bio.chicago_2015.54586 ::amr-annotator SDL-AMR-09 ::preferred # ::tok S6k1 is one of the major cellular targets for the immunosuppressant rapamycin and it was recognised several years ago that IL @-@ 2 activation of p70S6k was blocked by rapamycin [ 28 ] . # ::alignments 0-1.1.3.1.1 1-1.1.3.r 2-1.1.1 2-1.2.2.2.1.1 5-1.1.4 6-1.1.2.2 7-1.1 7-1.1.2 7-1.1.2.r 11-1.1.2.1.1.1 14-1.1.3.r 16-1.2.2.2 17-1.2.2.2.1.2 18-1.2.2 18-1.2.2.1 18-1.2.2.1.r 20-1.2.1.2.1.1.1 22-1.2.1.2.1.1.1 23-1.2.1.2 24-1.2.1.2.2.r 25-1.2.1.2.2.1.1 27-1.2.1 28-1.2.1.1.r 29-1.2.1.1 31-1.3.1.1.1 (a / and :op1 (t3 / thing~e.7 :quant 1~e.2 :ARG1-of~e.7 (t2 / target-01~e.7 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "rapamycin"~e.11) :ARG0-of (s3 / suppress-01 :ARG1 (i / immunity))) :mod (c / cell~e.6)) :domain~e.1,14 (e / enzyme :name (n3 / name :op1 "S6k1"~e.0)) :ARG1-of (m / major-02~e.5)) :op2 (r / recognize-02 :ARG1 (b3 / block-01~e.27 :ARG0~e.28 s2~e.29 :ARG1 (a2 / activate-01~e.23 :ARG0 (p / protein :name (n5 / name :op1 "IL-2"~e.20,22)) :ARG1~e.24 (p2 / protein :name (n6 / name :op1 "p70S6k"~e.25)))) :time (b / before~e.18 :op1~e.18 (n / now~e.18) :quant (s / several~e.16 :op1 (t / temporal-quantity :quant 1~e.2 :unit (y / year~e.17))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 28~e.31)))) # ::id bio.chicago_2015.54598 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We initially utilized the dsRNAi @-@ mediated gene silencing method ( Clemens et al. , 2000 ) to identify an agonist that induces JNK activation through dMLK . # ::alignments 0-1.1 1-1.3 2-1 6-1.2.2 7-1.2.1.1 8-1.2.1 9-1.2 11-1.2.3.1.1.1.1.1 12-1.2.3.1.1 13-1.2.3.1.1.2.1 15-1.2.3.1.1.3.1 18-1.4 20-1.4.2 22-1.4.2.1 23-1.4.2.1.1.2.1.1 24-1.4.2.1.1 26-1.4.2.1.1.1.1.1 (u / utilize-01~e.2 :ARG0 (w / we~e.0) :ARG1 (m / method~e.9 :ARG0-of (s / silence-01~e.8 :ARG1 (g / gene~e.7)) :ARG1-of (m2 / mediate-01~e.6 :ARG0 (i2 / interfere-01 :ARG0 (n5 / nucleic-acid :name (n / name :op1 "dsRNA")))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and~e.12 :op1 (p2 / person :name (n2 / name :op1 "Clemens"~e.11)) :op2 (p3 / person :mod (o / other~e.13)) :time (d / date-entity :year 2000~e.15))))) :time (i / initial~e.1) :purpose (i3 / identify-01~e.18 :ARG0 w :ARG1 (a2 / agonist~e.20 :ARG0-of (i4 / induce-01~e.22 :ARG2 (a3 / activate-01~e.24 :ARG0 (e2 / enzyme :name (n4 / name :op1 "dMLK"~e.26)) :ARG1 (e / enzyme :name (n3 / name :op1 "JNK"~e.23))))))) # ::id bio.chicago_2015.54639 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This finding was unexpected , since in vitro aMKII , when compared to CaMKIV , is a more potent activator of CREB Ser133 phosphorylation . # ::alignments 0-1.2.1 1-1.2 1-1.2.2 1-1.2.2.r 3-1 3-1.1 3-1.1.r 5-1.3 6-1.3.1.2.3 7-1.3.1.2.3 11-1.3.1.2.2.2.r 13-1.3.1.2.2.2.1.1 17-1.3.1.2.2.1 18-1.3.1.2.2 19-1.3.1 19-1.3.1.2 19-1.3.1.2.r 20-1.3.1.2.1.r 21-1.3.1.2.1.1.3.1.1 23-1.3.1.2.1 (e / expect-01~e.3 :polarity~e.3 -~e.3 :ARG1 (t2 / thing~e.1 :mod (t3 / this~e.0) :ARG1-of~e.1 (f / find-01~e.1)) :ARG1-of (c / cause-01~e.5 :ARG0 (e3 / enzyme~e.19 :name (n / name :op1 "CaMKII") :ARG0-of~e.19 (a2 / activate-01~e.19 :ARG1~e.20 (p3 / phosphorylate-01~e.23 :ARG1 (a3 / amino-acid :mod 133 :name (n2 / name :op1 "serine") :part-of (p / protein :name (n3 / name :op1 "CREB"~e.21)))) :mod (p2 / potent~e.18 :degree (m2 / more~e.17) :compared-to~e.11 (e4 / enzyme :name (n4 / name :op1 "CaMKIV"~e.13))) :manner (i / in-vitro~e.6,7))))) # ::id bio.chicago_2015.54645 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whereas MKK4 also activates p38 MAPK , experiments with ectopically expressed or recombinant MKK7 revealed that it activates JNK but not ERK or p38 MAPKs in vivo and in vitro ( 3 @-@ 6 ) . # ::alignments 0-1 1-1.2.1.1.1 2-1.2.3 3-1.2 4-1.2.2 5-1.2.2 7-1.1.1 10-1.1.1.1.1.2 11-1.1.1.1 12-1.1.1.1.2 12-1.1.1.1.2.2 12-1.1.1.1.2.2.r 13-1.1.1.1.1.1.1 13-1.1.1.1.2.1.1 14-1.1 17-1.1.2.1 17-1.1.2.2 18-1.1.2.1.2.1.1 19-1.1.2 20-1.1.2.2.1 20-1.1.2.2.1.r 21-1.1.2.2.3.1.1.1 22-1.1.2.2.3 23-1.1.2.2.3.2.1.1 25-1.1.2.3.1 26-1.1.2.3.1 27-1.1.2.3 28-1.1.2.3.1 28-1.1.2.3.2 29-1.1.2.3.2 31-1.3.1.1.1.1 33-1.3.1.1.1.2 (c2 / contrast-01~e.0 :ARG1 (r / reveal-01~e.14 :ARG0 (e / experiment-01~e.7 :ARG2 (o / or~e.11 :op1 (e2 / enzyme :name (n3 / name :op1 "MKK7"~e.13) :ARG2-of (e3 / express-03~e.10 :manner (e4 / ectopic))) :op2 (e5 / enzyme~e.12 :name (n4 / name :op1 "MKK7"~e.13) :ARG1-of~e.12 (r2 / recombine-01~e.12)))) :ARG1 (c / contrast-01~e.19 :ARG1 (a / activate-01~e.17 :ARG0 o :ARG1 (e6 / enzyme :name (n5 / name :op1 "JNK"~e.18))) :ARG2 (a2 / activate-01~e.17 :polarity~e.20 -~e.20 :ARG0 o :ARG1 (o2 / or~e.22 :op1 (p3 / protein-family :name (n6 / name :op1 "ERK"~e.21)) :op2 (p2 / protein-family :name (n7 / name :op1 "p38"~e.23 :op2 "MAPK")))) :manner (a3 / and~e.27 :op1 (i / in-vivo~e.25,26,28) :op2 (i2 / in-vitro~e.28,29)))) :ARG2 (a4 / activate-01~e.3 :ARG0 (e9 / enzyme :name (n8 / name :op1 "MKK4"~e.1)) :ARG1 p2~e.4,5 :mod (a5 / also~e.2)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 3~e.31 :op2 6~e.33))))) # ::id bio.chicago_2015.54654 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phototransduction in Drosophila is mediated by a phosphoinositide ( PI ) cascade , whereby absorption of light by rhodopsin activates sequentially a heterotrimeric Gq protein and phospholipase C ( PLC ) ( reviewed by Hardie and Minke 1995 ; Minke and Selinger 1996 ; Scott and Zuker 1998a ) . # ::alignments 2-1.1.3.1.1 4-1.1 5-1.1.1.r 7-1.1.1.1.1.1 11-1.1.1 14-1.2.1 15-1.2.1.2.r 16-1.2.1.2 18-1.2.1.1.1.1 19-1.2 20-1.2.3 22-1.2.2.1.2 23-1.2.2.1.1.1 24-1.2.1.1 24-1.2.2.1 25-1.2.2 26-1.2.2.2.1.1 27-1.2.2.2.1.2 32-1.3.1.1.1 33-1.3.1.1.1.1.r 34-1.3.1.1.1.1.1.1.1 35-1.3.1.1.1.1 36-1.3.1.1.1.1.2.1.1 37-1.3.1.1.2.1 39-1.3.1.2.1.1 40-1.3.1 40-1.3.1.1.1.1 40-1.3.1.2.1 40-1.3.1.3.1 41-1.3.1.2.1.2.1.1 42-1.3.1.2.2.1 44-1.3.1.3.1.1.1.1 45-1.3.1.3.1 46-1.3.1.3.1.2.1.1 (c / contrast-01 :ARG1 (m / mediate-01~e.4 :ARG0~e.5 (c2 / cascade~e.11 :mod (s / small-molecule :name (n / name :op1 "phosphoinositide"~e.7))) :ARG1 (t / transduce-01 :ARG1 l) :location (o / organism :name (n10 / name :op1 "Drosophila"~e.2))) :ARG2 (a / activate-01~e.19 :ARG0 (a2 / absorb-01~e.14 :ARG0 (p2 / protein~e.24 :name (n2 / name :op1 "rhodopsin"~e.18)) :ARG1~e.15 (l / light~e.16)) :ARG1 (a3 / and~e.25 :op1 (p / protein~e.24 :name (n3 / name :op1 "Gq"~e.23) :mod (h / heterotrimeric~e.22)) :op2 (e / enzyme :name (n4 / name :op1 "phospholipase"~e.26 :op2 "C"~e.27))) :manner (s2 / sequence~e.20)) :ARG1-of (d5 / describe-01 :ARG0 (a4 / and~e.40 :op1 (p3 / publication-91 :ARG1-of (r / review-01~e.32 :ARG0~e.33 (a5 / and~e.35,40 :op1 (p4 / person :name (n5 / name :op1 "Hardie"~e.34)) :op2 (p5 / person :name (n6 / name :op1 "Minke"~e.36)))) :time (d / date-entity :year 1995~e.37)) :op2 (p6 / publication-91 :ARG0 (a6 / and~e.40 :op1 p5~e.39 :op2 (p7 / person :name (n7 / name :op1 "Selinger"~e.41))) :time (d2 / date-entity :year 1996~e.42)) :op3 (p8 / publication-91 :ARG0 (a7 / and~e.40,45 :op1 (p9 / person :name (n8 / name :op1 "Scott"~e.44)) :op2 (p10 / person :name (n9 / name :op1 "Zuker"~e.46))) :time (d3 / date-entity :year 1998))))) # ::id bio.chicago_2015.54672 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KSR inhibits ERK MAP kinase activation by activated forms of Ras , Raf , and MEK . # ::alignments 0-1.1.1.1 1-1 2-1.2.2.1.1 3-1.2.2.1.2 4-1.2.2 5-1.2 7-1.2 7-1.2.1.4 9-1.2.1.r 10-1.2.1.1.1.1 12-1.2.1.2.1.1 14-1.2.1 15-1.2.1.3.1.1 (i / inhibit-01~e.1 :ARG0 (e / enzyme :name (n5 / name :op1 "KSR"~e.0)) :ARG1 (a / activate-01~e.5,7 :ARG0~e.9 (a2 / and~e.14 :op1 (e2 / enzyme :name (n7 / name :op1 "Ras"~e.10)) :op2 (e3 / enzyme :name (n8 / name :op1 "Raf"~e.12)) :op3 (e4 / enzyme :name (n9 / name :op1 "MEK"~e.15)) :ARG1-of (a3 / activate-01~e.7)) :ARG1 (k / kinase~e.4 :name (n6 / name :op1 "ERK"~e.2 :op2 "MAP"~e.3)))) # ::id bio.chicago_2015.54723 ::amr-annotator SDL-AMR-09 ::preferred # ::tok From in vitro experiments using cultured cells and biochemical assays , Dbl is known to activate mainly Rho and Cdc42 . # ::alignments 1-1.2.1.1 2-1.2.1.1 3-1.2.1 4-1.2.1.2 5-1.2.1.2.1.1.1 6-1.2.1.2.1.1 7-1.2.1.2.1 8-1.2.1.2.1.2.1 9-1.2.1.2.1.2 11-1.1.1.1.1 13-1 14-1.2 15-1.1 16-1.1.3 16-1.1.3.r 17-1.1.2.1.1.1 18-1.1.2 19-1.1.2.2.1.1 (k / know-01~e.13 :ARG1 (a / activate-01~e.15 :ARG0 (p / protein :name (n / name :op1 "Dbl"~e.11)) :ARG1 (a2 / and~e.18 :op1 (p2 / protein :name (n2 / name :op1 "Rho"~e.17)) :op2 (p3 / protein :name (n3 / name :op1 "Cdc42"~e.19))) :manner~e.16 (m / main~e.16)) :ARG1-of (c / cause-01~e.14 :ARG0 (e2 / experiment-01~e.3 :manner (i / in-vitro~e.1,2) :ARG0-of (u / use-01~e.4 :ARG1 (a3 / and~e.7 :op1 (c2 / cell~e.6 :ARG1-of (c3 / culture-01~e.5)) :op2 (a4 / assay-01~e.9 :mod (b / biochemistry~e.8))))))) # ::id bio.chicago_2015.54732 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At concentrations substantially greater than those required to modulate the GABA @-@ evoked response , 5 3 ( 300 nM @-@ 10 M ) directly ( i.e . in the absence of GABA ) activated all the recombinant GABAA receptors investigated . # ::alignments 1-1.4 1-1.4.2.3 1-1.4.3.1.1 1-1.4.3.1.2 2-1.4.2.2 2-1.4.2.2.r 3-1.4.2 3-1.4.2.1 3-1.4.2.1.r 4-1.4.2.3.r 6-1.4.2.3.1 8-1.4.2.3.1.1 10-1.4.2.3.1.1.1.1.1 12-1.4.2.3.1.1.1.1 13-1.4.2.3.1.1.1 18-1.4.3.1.1.1 19-1.4.3.1.1.2 21-1.4.3.1.2.1 22-1.4.3.1.2.2 24-1.3 30-1.3.1.1 31-1.3.1.1.1.r 32-1.3.1.1.1.1.1 34-1 35-1.2.3 37-1.2 37-1.2.2 37-1.2.2.r 38-1.2.1.1 39-1.2.1.2 40-1.2.4 (a / activate-01~e.34 :ARG0 (a4 / amr-unintelligible :value 53) :ARG1 (p / protein~e.37 :name (n / name :op1 "GABAA"~e.38 :op2 "receptor"~e.39) :ARG0-of~e.37 (r / recombine-01~e.37) :mod (a2 / all~e.35) :ARG1-of (i / investigate-01~e.40)) :ARG1-of (d / direct-02~e.24 :ARG1-of (m2 / mean-01 :ARG2 (a3 / absent-01~e.30 :ARG1~e.31 (s2 / small-molecule :name (n2 / name :op1 "GABA"~e.32))))) :condition (c / concentrate-02~e.1 :ARG1 a4 :mod (g / great~e.3 :degree~e.3 (m / more~e.3) :manner~e.2 (s / substantial~e.2) :compared-to~e.4 (c2 / concentrate-01~e.1 :ARG1-of (r2 / require-01~e.6 :ARG0 (m3 / modulate-01~e.8 :ARG1 (r3 / respond-01~e.13 :ARG1-of (e / evoke-01~e.12 :ARG0 s2~e.10)))))) :ARG1-of (m4 / mean-01 :ARG2 (v / value-interval :op1 (c4 / concentration-quantity~e.1 :quant 300~e.18 :unit (n3 / nanomolar~e.19)) :op2 (c5 / concentration-quantity~e.1 :quant 10~e.21 :unit (m5 / molar~e.22)))))) # ::id bio.chicago_2015.54762 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , TNF , IL @-@ 1 , and LPS are potent activators of the IKK and JNK pathways , which lead to stimulation of NF @- B and AP @-@ 1 activities . # ::alignments 0-1 2-1.1.1.2.1 4-1.1.2.2.1 6-1.1.2.2.1 8-1.1 9-1.1.3.2.1 11-1.1.4.2 12-1.1.4 13-1.1.4.1.r 15-1.1.4.1.1.2.1 16-1.1.4.1 17-1.1.4.1.2.2.1 18-1.1.4.1.1 18-1.1.4.1.2 21-1.1.4.1.3 22-1.1.4.1.3.1.r 23-1.1.4.1.3.1 24-1.1.4.1.3.1.1.r 25-1.1.4.1.3.1.1.1.1.2.1 27-1.1.4.1.3.1.1.1.1.2.1 28-1.1.4.1.3.1.1 29-1.1.4.1.3.1.1.2.1.2.1 31-1.1.4.1.3.1.1.2.1.2.1 32-1.1.4.1.3.1.1.1 32-1.1.4.1.3.1.1.2 (h / have-concession-91~e.0 :ARG1 (a2 / and~e.8 :op1 (p / protein :wiki "Tumor_necrosis_factors" :name (n / name :op1 "TNF"~e.2)) :op2 (p2 / protein :wiki "Interleukin_1_family" :name (n2 / name :op1 "IL-1"~e.4,6)) :op3 (m / molecular-physical-entity :wiki "Lipopolysaccharide" :name (n3 / name :op1 "LPS"~e.9)) :ARG0-of (a3 / activate-01~e.12 :ARG1~e.13 (a4 / and~e.16 :op1 (p4 / pathway~e.18 :wiki - :name (n4 / name :op1 "IKK"~e.15)) :op2 (p5 / pathway~e.18 :wiki - :name (n5 / name :op1 "JNK"~e.17)) :ARG0-of (l / lead-03~e.21 :ARG2~e.22 (s / stimulate-01~e.23 :ARG1~e.24 (a / and~e.28 :op1 (a5 / activity-06~e.32 :ARG0 (p7 / protein :wiki "NF-κB" :name (n6 / name :op1 "NF-B"~e.25,27))) :op2 (a6 / activity-06~e.32 :ARG0 (p6 / protein :wiki "AP-1_transcription_factor" :name (n7 / name :op1 "AP-1"~e.29,31))))))) :mod (p3 / potent~e.11)))) # ::id bio.chicago_2015.54870 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note that importin beta , the importin alpha/ beta heterodimer , transportin , RanBP5 and RanBP7 all bound specifically to rpL23a . # ::alignments 0-1 1-1.3.r 2-1.3.1.1.1.1 3-1.3.1.1.1.2 9-1.3.1.2 11-1.3.1.3.1.1 13-1.3.1.4.1.1 14-1.3.1 15-1.3.1.5.1.1 16-1.3.1.6 17-1.3 18-1.3.3 19-1.3.2.r 20-1.3.2.1.1 (n / note-01~e.0 :mode imperative :ARG0 (y / you) :ARG1~e.1 (b / bind-01~e.17 :ARG1 (a / and~e.14 :op1 (p / protein :name (n2 / name :op1 "importin"~e.2 :op2 "beta"~e.3)) :op2 (h / heterodimer~e.9 :part (p2 / protein :name (n3 / name :op1 "importin" :op2 "alpha")) :part p) :op3 (p3 / protein :name (n4 / name :op1 "transportin"~e.11)) :op4 (p4 / protein :name (n5 / name :op1 "RanBP5"~e.13)) :op5 (p5 / protein :name (n6 / name :op1 "RanBP7"~e.15)) :mod (a2 / all~e.16)) :ARG2~e.19 (p6 / protein :name (n7 / name :op1 "rpL23a"~e.20)) :ARG1-of (s / specific-02~e.18))) # ::id bio.chicago_2015.54875 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , transcriptional repression by Gal4 fusions to PHO polypeptides that could bind PC [ PHO( 1 @-@ 356 ) and PHO( 118 @-@ 172 )] was markedly enhanced by overexpression of PC ( Fig . 7B ) . # ::alignments 0-1.4 2-1.2.2 3-1.2 4-1.2.1.r 5-1.2.1.1.1.1 6-1.2.1 7-1.2.1.2.r 8-1.2.1.2.1.1 9-1.2.1.2 11-1.2.1.2.2.2 12-1.2.1.2.2 13-1.2.1.2.2.1.1.1 16-1.2.1.2.3.1.1.1.1 18-1.2.1.2.3.1.1.1.2 20-1.2.1.2.3.1 20-1.2.1.2.3.1.1.1 20-1.2.1.2.3.1.2.1 22-1.2.1.2.3.1.2.1.1 24-1.2.1.2.3.1.2.1.2 27-1.3 28-1 29-1.1.r 30-1.1 31-1.1.1.r 32-1.1.1 34-1.5.1 36-1.5.1.1 (e / enhance-01~e.28 :ARG0~e.29 (o2 / overexpress-01~e.30 :ARG1~e.31 p2~e.32) :ARG1 (r / repress-01~e.3 :ARG0~e.4 (f / fuse-01~e.6 :ARG1 (g / gene :name (n2 / name :op1 "Gal4"~e.5)) :ARG2~e.7 (p / polypeptide~e.9 :name (n4 / name :op1 "PHO"~e.8) :ARG1-of (b3 / bind-01~e.12 :ARG2 (p2 / protein :name (n5 / name :op1 "PC"~e.13)) :ARG1-of (p5 / possible-01~e.11)) :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.20 :op1 (p6 / protein-segment :quant (b / between~e.20 :op1 1~e.16 :op2 356~e.18)) :op2 (p7 / protein-segment :quant (b2 / between~e.20 :op1 118~e.22 :op2 172~e.24)) :part-of p)))) :ARG1 (t / transcribe-01~e.2)) :ARG1-of (m2 / mark-01~e.27) :mod (i / indeed~e.0) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.34 :mod "7B"~e.36))) # ::id bio.chicago_2015.54886 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of ERM Proteins to CD43 and ICAM @-@ 2 As Well As CD44 through Their Juxta @-@ Membrane Positively Charged Amino Acid Clusters # ::alignments 0-1.1 2-1.1.1.1.1 3-1.1.1 3-1.1.2.1 3-1.1.2.2 3-1.1.2.3 4-1.1.2.r 5-1.1.2.1.1.1 6-1.1.2 7-1.1.2.2.1.1 9-1.1.2.2.1.1 10-1.1.2 11-1.1.2 12-1.1.2 13-1.1.2.3.1.1 15-1.1.3.2 15-1.1.3.2.r 18-1.1.3 19-1.3 19-1.3.r 20-1 21-1.2.1 22-1.2.1 23-1.2 (c / charge-03~e.20 :ARG0 (b / bind-01~e.0 :ARG1 (p / protein-family~e.3 :name (n / name :op1 "ERM"~e.2)) :ARG2~e.4 (a / and~e.6,10,11,12 :op1 (p2 / protein~e.3 :name (n2 / name :op1 "CD43"~e.5)) :op2 (p3 / protein~e.3 :name (n3 / name :op1 "ICAM-2"~e.7,9)) :op3 (p4 / protein~e.3 :name (n4 / name :op1 "CD44"~e.13))) :ARG3 (m / membrane~e.18 :mod (j / juxtra) :poss~e.15 p~e.15)) :ARG1 (c2 / cluster-01~e.23 :ARG1 (a2 / amino-acid~e.21,22)) :manner~e.19 (p5 / positive~e.19)) # ::id bio.chicago_2015.54932 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significant binding of Arp1 to the DI and DIII constructs was observed . # ::alignments 0-1.1.3 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.2.r 6-1.1.2.1.1.1.1 7-1.1.2 8-1.1.2.2.1.1.1 9-1.1.2.1 9-1.1.2.2 11-1 (o / observe-01~e.11 :ARG1 (b / bind-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "Arp1"~e.3)) :ARG2~e.4 (a / and~e.7 :op1 (c / construct-01~e.9 :ARG2 (p2 / protein :name (n2 / name :op1 "DI"~e.6))) :op2 (c2 / construct-01~e.9 :ARG1 (p3 / protein :name (n3 / name :op1 "DIII"~e.8)))) :ARG1-of (s / significant-02~e.0))) # ::id bio.chicago_2015.54956 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The above data support the idea that eIF4G just binds a single eIF4A molecule , either eIF4AI or eIF4AII . # ::alignments 1-1.1.1 2-1.1 3-1 5-1.2 7-1.2.1.1.1.1 8-1.2.1.3 9-1.2.1 11-1.2.1.2.2 12-1.2.1.2.1.1.1 13-1.2.1.2 16-1.2.1.2.3.1.1.1.1 17-1.2.1.2.3.1 18-1.2.1.2.3.1.2.1.1 (s / support-01~e.3 :ARG0 (d / data~e.2 :location (a / above~e.1)) :ARG1 (i / idea~e.5 :topic (b / bind-01~e.9 :ARG1 (p / protein :name (n / name :op1 "eIF4G"~e.7)) :ARG2 (m / molecule~e.13 :part-of (p2 / protein-family :name (n2 / name :op1 "eIF4A"~e.12)) :ARG1-of (s2 / single-02~e.11) :ARG1-of (m2 / mean-01 :ARG2 (o / or~e.17 :op1 (p3 / protein :name (n3 / name :op1 "eIF4AI"~e.16)) :op2 (p4 / protein :name (n4 / name :op1 "eIF4AII"~e.18))))) :mod (j / just~e.8)))) # ::id bio.chicago_2015.54971 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have hypothesized that the binding of PP2A to the Axin complex might counteract the phosphorylation of beta @-@ catenin by GSK3 beta ( Hsu et al. , 1999 ) that could account for the increased ventralization activity in the absence of this domain . # ::alignments 0-1.1 2-1 3-1.2.r 5-1.2.1.1 6-1.2.1.1.1.r 7-1.2.1.1.1.1.1 8-1.2.1.1.2.r 10-1.2.1.1.2.1.1.1 11-1.2.1.1.2 12-1.2 13-1.2.1 15-1.2.1.2 16-1.2.1.2.1.r 17-1.2.1.2.1.1.1 19-1.2.1.2.1.1.1 20-1.2.1.2.2.r 21-1.2.1.2.2.1.1 22-1.2.1.2.2.1.2 24-1.2.2.1.1.1.1.1 25-1.2.2.1.1 26-1.2.2.1.1.2.1 28-1.2.2.1.2.1 31-1.2.1.2.3.2 32-1.2.1.2.3 33-1.2.1.2.3.1.r 35-1.2.1.2.3.1.2 36-1.2.1.2.3.1.1 37-1.2.1.2.3.1 38-1.2.1.2.3.3.r 40-1.2.1.2.3.3 41-1.2.1.2.3.3.1.r 42-1.2.1.2.3.3.1.1 43-1.2.1.2.3.3.1 (h2 / hypothesize-01~e.2 :ARG0 (w2 / we~e.0) :ARG1~e.3 (p / possible-01~e.12 :ARG1 (c / counteract-01~e.13 :ARG0 (b / bind-01~e.5 :ARG1~e.6 (e2 / enzyme :name (n2 / name :op1 "PP2A"~e.7)) :ARG2~e.8 (m / macro-molecular-complex~e.11 :part (p3 / protein :name (n3 / name :op1 "Axin"~e.10)))) :ARG1 (p2 / phosphorylate-01~e.15 :ARG1~e.16 (p4 / protein :name (n4 / name :op1 "beta-catenin"~e.17,19)) :ARG2~e.20 (e3 / enzyme :name (n5 / name :op1 "GSK3"~e.21 :op2 "beta"~e.22)) :ARG0-of (a / account-01~e.32 :ARG1~e.33 (a2 / activity-06~e.37 :ARG1 (v / ventralization~e.36) :ARG1-of (i / increase-01~e.35)) :ARG1-of (p5 / possible-01~e.31) :condition~e.38 (a3 / absent-01~e.40 :ARG1~e.41 (d2 / domain~e.43 :mod (t / this~e.42)))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a4 / and~e.25 :op1 (p7 / person :name (n6 / name :op1 "Hsu"~e.24)) :op2 (p8 / person :mod (o / other~e.26))) :time (d / date-entity :year 1999~e.28))))) # ::id bio.chicago_2015.54984 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CEP2 and CEP5 bind to Cdc42 . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1 4-1.2.r 5-1.2.1.1 (b / bind-01~e.3 :ARG1 (a / and~e.1 :op1 (p / protein :name (n / name :op1 "CEP2"~e.0)) :op2 (p2 / protein :name (n2 / name :op1 "CEP5"~e.2))) :ARG2~e.4 (p3 / protein :name (n3 / name :op1 "Cdc42"~e.5))) # ::id bio.chicago_2015.55013 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also introduced two amino acid substitutions into the JNK @-@ binding motif of JIP3 ( Kelkar et al. , 2000 ) . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 4-1.2.2 5-1.2.2 6-1.2 7-1.2.3.r 9-1.2.3.1.1.1.1 11-1.2.3.1 12-1.2.3 13-1.2.3.2.r 14-1.2.3.2.1.1 16-1.4.1.1.1.1.1 17-1.4.1.1 18-1.4.1.1.2.1 20-1.4.1.2.1 (i / introduce-02~e.2 :ARG0 (w / we~e.0) :ARG1 (s / substitute-01~e.6 :quant 2~e.3 :ARG1 (a2 / amino-acid~e.4,5) :location~e.7 (p / protein-segment~e.12 :ARG1-of (b / bind-01~e.11 :ARG2 (e / enzyme :name (n / name :op1 "JNK"~e.9))) :part-of~e.13 (p2 / protein :name (n2 / name :op1 "JIP3"~e.14)))) :mod (a / also~e.1) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.17 :op1 (p4 / person :name (n3 / name :op1 "Kelkar"~e.16)) :op2 (p5 / person :mod (o / other~e.18))) :time (d / date-entity :year 2000~e.20)))) # ::id bio.chicago_2015.55022 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NF @-@ 1 was detected as described for panel B. ( D ) GR and hSwi/ nf facilitation of binding of NF @-@ 1 to MMTV chromatin . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 4-1.1 5-1.1.2.r 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1 11-1.2.1 13-1.2.2.1.1.1 14-1.2.2 17-1.2 18-1.2.3.r 19-1.2.3 20-1.2.3.1.r 21-1.2.3.1.1.1 23-1.2.3.1.1.1 24-1.2.3.2.r 25-1.2.3.2.2.1.1 26-1.2.3.2.1.1 (m / multi-sentence :snt1 (d / detect-01~e.4 :ARG1 (p / protein :name (n / name :op1 "NF-1"~e.0,2)) :ARG2-of~e.5 (d2 / describe-01~e.6 :ARG1~e.7 (p2 / panel~e.8 :ARG1-of (l / label-01 :ARG2 (s / string-entity :value "B"))))) :snt2 (f / facilitate-01~e.17 :li "D"~e.11 :ARG0 (a / and~e.14 :op1 (p3 / protein :name (n2 / name :op1 "GR"~e.13)) :op2 (m2 / macro-molecular-complex :part (p4 / protein :name (n3 / name :op1 "hSwi")) :part (p5 / protein :name (n4 / name :op1 "hSnf")))) :ARG1~e.18 (b / bind-01~e.19 :ARG1~e.20 (p6 / protein :name (n5 / name :op1 "NF-1"~e.21,23)) :ARG2~e.24 (m3 / macro-molecular-complex :name (n7 / name :op1 "chromatin"~e.26) :part-of (o / organism :name (n6 / name :op1 "MMTV"~e.25)))))) # ::id bio.chicago_2015.55025 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effects of Tcf3 phosphorylation on its activity These experiments establish that both GSK3 and CK1 epsilon can bind and phosphorylate Tcf3 and suggest a possible role for both GSK3 and CK1 epsilon in modulating Tcf3 activity . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.2.1 3-1.1.1 4-1.1.2.r 5-1.1.2.1 5-1.1.2.1.r 6-1.1.2 7-1.2.1.1.1 8-1.2.1.1 9-1.2.1 12-1.2.1.2.1.1.1.1.2.1 13-1.2.1.2.1 16-1.2.1.2 17-1.2.1.2.1.1 18-1.2.1.2.1 18-1.2.1.2.1.1.1 19-1.2.1.2.1.2 20-1.2.1.2.1.2.1.2.1 21-1.2 22-1.2.2 24-1.2.2.2.1 25-1.2.2.2 28-1.2.2.2.3.1 29-1.2.2.2.3.1 33-1.2.2.2.3 34-1.2.2.2.3.2.1 35-1.2.2.2.3.2 (m / multi-sentence :snt1 (a / affect-01~e.0 :ARG0~e.1 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein :wiki "TCF3" :name (n / name :op1 "Tcf3"~e.2))) :ARG1~e.4 (a2 / activity-06~e.6 :ARG0~e.5 p2~e.5)) :snt2 (a3 / and~e.21 :op1 (e / establish-01~e.9 :ARG0 (e2 / experiment-01~e.8 :mod (t / this~e.7)) :ARG1 (p3 / possible-01~e.16 :ARG1 (a5 / and~e.13,18 :op1 (b / bind-01~e.17 :ARG1 (a4 / and~e.18 :op1 (e3 / enzyme :wiki "GSK-3" :name (n2 / name :op1 "GSK3"~e.12)) :op2 (p4 / protein :wiki "Casein_kinase_1_isoform_epsilon" :name (n3 / name :op1 "CK1epsilon"))) :ARG2 p6) :op2 (p5 / phosphorylate-01~e.19 :ARG1 (p6 / protein :wiki "TCF3" :name (n4 / name :op1 "Tcf3"~e.20)) :ARG2 a4)))) :op2 (s / suggest-01~e.22 :ARG0 e2 :ARG1 (r / role~e.25 :ARG1-of (p7 / possible-01~e.24) :poss a4 :topic (m2 / modulate-01~e.33 :ARG0 a4~e.28,29 :ARG1 (a6 / activity-06~e.35 :ARG0 p6~e.34)))))) # ::id bio.chicago_2015.55068 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Table I , RitS35N , which corresponds to the RasS17N dominant negative mutant and would be expected to be predominantly GDP @-@ bound , showed no detectable interaction with RGL3 @-@ RBD , suggesting that RGL3 showed preferential binding to the active GTP @-@ bound form of Rit . # ::alignments 1-1 1-1.4 1-1.4.r 2-1.4.1.r 3-1.4.1 4-1.4.1.1 6-1.1.1.1 9-1.1 9-1.1.2 9-1.1.2.r 10-1.1.2.1.r 12-1.1.2.1.1.1 13-1.1.2.1.3 15-1.1.2.1 15-1.1.2.1.2 15-1.1.2.1.2.r 19-1.1.3.2.1 22-1.1.3.2 23-1.1.3.1.1.1 25-1.1.3 27-1.3.1 28-1.2.1 28-1.2.1.r 29-1.2.4 30-1.2 31-1.2.3.r 32-1.2.3.1.1 34-1.2.3.1.1 36-1.3 38-1.3.1.1.1.1 39-1.3.1 40-1.3.1.2.3 41-1.3.1.2 41-1.3.1.2.2.3 45-1.3.1.2.2.3.1.1.1 47-1.3.1.2.2.3 50-1.3.1.2.2.1.1 (s / show-01~e.1 :ARG0 (p / protein~e.9 :name (n / name :op1 "RitS35N"~e.6) :ARG0-of~e.9 (c / correspond-01~e.9 :ARG1~e.10 (p2 / protein~e.15 :name (n2 / name :op1 "RasS17N"~e.12) :ARG2-of~e.15 (m / mutate-01~e.15 :mod "-/-") :ARG1-of (d / dominate-01~e.13))) :ARG1-of (b / bind-01~e.25 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "GDP"~e.23)) :ARG1-of (p3 / predominate-01~e.22 :ARG1-of (e / expect-01~e.19)))) :ARG1 (i / interact-01~e.30 :polarity~e.28 -~e.28 :ARG0 p :ARG1~e.31 (p5 / protein :name (n5 / name :op1 "RGL3-RBD"~e.32,34)) :ARG1-of (d2 / detect-01~e.29 :ARG1-of (p4 / possible-01))) :ARG0-of (s3 / suggest-01~e.36 :ARG1 (s4 / show-01~e.27,39 :ARG0 (p6 / protein :name (n6 / name :op1 "RGL3"~e.38)) :ARG1 (b2 / bind-01~e.41 :ARG1 p6 :ARG2 (p8 / protein :name (n7 / name :op1 "Rit"~e.50) :ARG1-of (a / activate-01) :ARG1-of (b3 / bind-01~e.41,47 :ARG2 (s5 / small-molecule :name (n8 / name :op1 "GTP"~e.45)))) :ARG1-of (p7 / prefer-01~e.40 :ARG0 p6)))) :ARG1-of~e.1 (s6 / show-01~e.1 :medium~e.2 (t / table~e.3 :mod "I"~e.4))) # ::id bio.chicago_2015.55070 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) p120 ctn isoforms bind to both GST @-@ Prox and GST @-@ FL . # ::alignments 1-1.1 5-1.2 6-1 9-1.3.1.1.1 9-1.3.2.1.1 11-1.3.1.1.1 12-1.3 13-1.3.1.1.1 13-1.3.2.1.1 15-1.3.2.1.1 (b / bind-01~e.6 :li "A"~e.1 :ARG1 (i / isoform~e.5 :mod (p / protein :name (n / name :op1 "p120ctn"))) :ARG2 (a / and~e.12 :op1 (p2 / protein :name (n2 / name :op1 "GST-Prox"~e.9,11,13)) :op2 (p3 / protein :name (n3 / name :op1 "GST-FL"~e.9,13,15)))) # ::id bio.chicago_2015.55128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In stark contrast to the Sly1p @/@ Sed5p @-@ complex , Munc18a binds syntaxin in the central cleft via interactions that involve both the Habc domain and the SNARE motif ( Misura et al. , 2000 ) . # ::alignments 1-1.4.2 2-1.4 3-1.4.1.r 5-1.4.1.1.1.1 7-1.4.1.2.1.1 9-1.4.1 11-1.1.1.1 12-1 13-1.2.2.1.1 16-1.2.1 17-1.2 19-1.3 21-1.3.1 24-1.3.1.1.1.1.1 26-1.3.1.1 28-1.3.1.1.2.1.1 29-1.3.1.1.1 29-1.3.1.1.2 31-1.5.1.1.1.1.1 32-1.5.1.1 33-1.5.1.1.2.1 35-1.5.1.2.1 (b / bind-01~e.12 :ARG1 (p3 / protein :name (n3 / name :op1 "Munc18a"~e.11)) :ARG2 (c2 / cleft~e.17 :mod (c3 / center~e.16) :part-of (p4 / protein :name (n4 / name :op1 "syntaxin"~e.13))) :ARG3 (i / interact-01~e.19 :ARG0-of (i2 / involve-01~e.21 :ARG1 (a / and~e.26 :op1 (p5 / protein-segment~e.29 :name (n5 / name :op1 "Habc"~e.24)) :op2 (p6 / protein-segment~e.29 :name (n6 / name :op1 "SNARE"~e.28)) :part-of p4))) :ARG1-of (c / contrast-01~e.2 :ARG2~e.3 (m / macro-molecular-complex~e.9 :part (p / protein :name (n / name :op1 "Sly1p"~e.5)) :part (p2 / protein :name (n2 / name :op1 "Sed5p"~e.7))) :mod (s / stark~e.1)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a2 / and~e.32 :op1 (p8 / person :name (n7 / name :op1 "Misura"~e.31)) :op2 (p9 / person :mod (o / other~e.33))) :time (d / date-entity :year 2000~e.35)))) # ::id bio.chicago_2015.55187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Gab1 mutants were expressed as LexA @-@ tpr @-@ met fusion proteins and tested for yeast two @-@ hybrid interactions with substrates as in Fig 3 A. CBR represents the CRKL @-@ binding region of Gab1 . # ::alignments 1-1.1.1 3-1.1.2.1.1.1 4-1.1.2.1.2 6-1.1.2 8-1.1.2.2.1.1 10-1.1.2.2.1.1 12-1.1.2.2.1.1 13-1.1.2.2.2 14-1.1.2.1 14-1.1.2.2 14-1.2.1 14-1.2.2.1.1 14-1.2.2.2 15-1.1 16-1.1.3 17-1.1.3.2.r 18-1.1.3.2.3 19-1.1.3.2.1.1 21-1.1.3.2.1 22-1.1.3.2 23-1.1.3.2.2.r 24-1.1.3.2.2 27-1.1.4.1 30-1.2.1.1.1 31-1.2 33-1.2.2.1.1.1.1 35-1.2.2.1 36-1.2.2 38-1.2.2.2.1.1 (m / multi-sentence :snt1 (a / and~e.15 :li "A"~e.1 :op1 (e / express-03~e.6 :ARG2 (p / protein~e.14 :name (n / name :op1 "Gab1"~e.3) :ARG2-of (m2 / mutate-01~e.4)) :manner (p2 / protein~e.14 :name (n2 / name :op1 "LexA-tpr-met"~e.8,10,12) :ARG1-of (f2 / fuse-01~e.13))) :op2 (t / test-01~e.16 :ARG1 p :ARG2~e.17 (i / interact-01~e.22 :ARG0 (h / hybrid~e.21 :quant 2~e.19) :ARG1~e.23 (s / substrate~e.24) :location (y / yeast~e.18))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "3A"))) :snt2 (r / represent-01~e.31 :ARG0 (p3 / protein-segment~e.14 :name (n4 / name :op1 "CBR"~e.30)) :ARG1 (r2 / region~e.36 :ARG1-of (b / bind-01~e.35 :ARG2 (p4 / protein~e.14 :name (n5 / name :op1 "CRKL"~e.33))) :part-of (p5 / protein~e.14 :name (n6 / name :op1 "Gab1"~e.38))))) # ::id bio.chicago_2015.55208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of Sp1 and Smad2 , Smad3 , Smad4 and Sp1 to the wild @-@ type oligonucleotide , as was also done in ( E ) , was compared with their binding to the corresponding mutant oligonucleotides , in which the SBEs and Sp1 binding sequences were mutated , as shown in Figure 3A . # ::alignments 0-1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 6-1.1.1.3.1.1 8-1.1.1.4.1.1 9-1.1.1 10-1.1.1.1.1.1 13-1.1.2.1 15-1.1.2.1 16-1.1.2 20-1.1.3.1 21-1.1.3 24-1.1.3.2.1 28-1 29-1.2.r 30-1.2.1 30-1.2.1.r 31-1.2 34-1.2.2.2 35-1.2.2.1 35-1.2.2.3 36-1.2.2 42-1.1.1 42-1.2.2.3.1 43-1.1.1.1.1.1 44-1.1 44-1.2 44-1.2.2.3.1.1.1 44-1.2.2.3.1.2.1 45-1.2.2.3.1.1 45-1.2.2.3.1.2 47-1.2.2.3 49-1.2.2.3.2.r 50-1.2.2.3.2 52-1.1.3.2 52-1.2.2.3.2.1 53-1.2.2.3.2.1.1 (c / compare-01~e.28 :ARG1 (b / bind-01~e.0,44 :ARG1 (a / and~e.3,9,42 :op1 (p / protein :name (n / name :op1 "Sp1"~e.2,10,43)) :op2 (p2 / protein :name (n2 / name :op1 "Smad2"~e.4)) :op3 (p3 / protein :name (n3 / name :op1 "Smad3"~e.6)) :op4 (p4 / protein :name (n4 / name :op1 "Smad4"~e.8)) :op5 p) :ARG2 (o / oligonucleotide~e.16 :mod (w / wild-type~e.13,15)) :ARG1-of (d / do-02~e.21 :mod (a2 / also~e.20) :medium (f2 / figure~e.52 :mod "E"~e.24))) :ARG2~e.29 (b2 / bind-01~e.31,44 :ARG1~e.30 a~e.30 :ARG2 (o2 / oligonucleotide~e.36 :ARG2-of (m / mutate-01~e.35) :ARG1-of (c2 / correspond-02~e.34) :location-of (m2 / mutate-01~e.35,47 :ARG1 (a3 / and~e.42 :op1 (s / sequence~e.45 :ARG1-of (b3 / bind-01~e.44 :ARG2 (p5 / protein-segment :name (n5 / name :op1 "SBE")))) :op2 (s2 / sequence~e.45 :ARG1-of (b4 / bind-01~e.44 :ARG2 p))) :ARG1-of~e.49 (s3 / show-01~e.50 :medium (f / figure~e.52 :mod "3A"~e.53)))))) # ::id bio.chicago_2015.55244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The finding that LARFN5C binds to LAR and the absence of the LARFN5C N @-@ terminal sequence in LAR make the possibility of N @-@ terminal to N @-@ terminal isologous homophilic binding unlikely . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 6-1.1.2.2 7-1.1 9-1.1.2 10-1.1.2.1.r 12-1.1.2.1.2 13-1.1.2.1.1.1 15-1.1.2.1.1.1 18-1.1.2.2 19-1 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1.1.1 25-1.2.2.1.1.1.1 27-1.2.2.1.1.1.1 29-1.2.2.1.1.1.1 31-1.2.2.1.3 32-1.2.2.1 33-1.2 33-1.2.1 33-1.2.1.r (m / make-02~e.19 :ARG0 (a / and~e.7 :op1 (f / find-01~e.1 :ARG1~e.2 (b / bind-01~e.4 :ARG1 (p / protein-segment :name (n / name :op1 "LARFN5C"~e.3)) :ARG2 (e / enzyme :name (n2 / name :op1 "LAR")))) :op2 (a2 / absent-01~e.9 :ARG1~e.10 (p3 / protein-segment :name (n3 / name :op1 "N-terminus"~e.13,15) :part-of p~e.12) :ARG2 e~e.6,18)) :ARG1 (l / likely-01~e.33 :polarity~e.33 -~e.33 :ARG1 (p4 / possible-01~e.21 :ARG1~e.22 (b2 / bind-01~e.32 :ARG1 (p5 / protein-segment :name (n4 / name :op1 "N-terminus"~e.23,25,27,29)) :ARG2 (i / isologus :mod p5) :mod (h / homophilic~e.31))))) # ::id bio.chicago_2015.55261 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dystroglycan , which binds to laminins , agrin , and perlecan through its subunit , has been another candidate for mediation of basement membrane assembly ( Henry and Campbell , 1998 ) . # ::alignments 0-1.2.1.1 3-1.2 3-1.2.2 3-1.2.2.r 7-1.2.2.1.2.1.1 9-1.2.2.1 10-1.2.2.1.3.1.1 16-1.2.r 17-1.1 18-1 19-1.3.r 20-1.3 21-1.3.1.r 22-1.3.1.1.1 23-1.3.1.1 24-1.3.1 26-1.4.1.1.1.1.1 27-1.4.1.1 28-1.4.1.1.2.1.1 30-1.4.1.2.1 (c / candidate~e.18 :mod (a / another~e.17) :domain~e.16 (p / protein~e.3 :name (n / name :op1 "dystroglycan"~e.0) :ARG1-of~e.3 (b / bind-01~e.3 :ARG2 (a2 / and~e.9 :op1 (p2 / protein :name (n2 / name :op1 "laminin")) :op2 (p3 / protein :name (n3 / name :op1 "agrin"~e.7)) :op3 (p4 / protein :name (n4 / name :op1 "perlecan"~e.10))) :ARG3 (p5 / protein-segment :part-of p))) :ARG0-of~e.19 (m / mediate-01~e.20 :ARG1~e.21 (a3 / assemble-01~e.24 :ARG1 (m2 / membrane~e.23 :mod (b2 / basement~e.22)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a4 / and~e.27 :op1 (p7 / person :name (n5 / name :op1 "Henry"~e.26)) :op2 (p8 / person :name (n6 / name :op1 "Campbell"~e.28))) :time (d / date-entity :year 1998~e.30)))) # ::id bio.chicago_2015.55278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of the VHL protein and Elongin A to the Elongin BC complex is mutually exclusive in vitro ( 101 ) . # ::alignments 0-1.1.1 0-1.1.2 3-1.1.1.1.1.1 4-1.1.1.1 4-1.1.2.1 4-1.1.2.2.1 4-1.1.2.2.2 5-1.1 6-1.1.2.1.1.1 7-1.1.2.1.1.2 8-1.1.2.2.r 10-1.1.2.2.1.1.1 10-1.1.2.2.2.1.1 12-1.1.2.2 14-1.2 14-1.2.r 16-1.3 17-1.3 19-1.4.1.1.1 (e / exclude-01 :ARG1 (a / and~e.5 :op1 (b / bind-01~e.0 :ARG1 (p / protein~e.4 :name (n / name :op1 "VHL"~e.3)) :ARG2 m) :op2 (b2 / bind-01~e.0 :ARG1 (p2 / protein~e.4 :name (n2 / name :op1 "Elongin"~e.6 :op2 "A"~e.7)) :ARG2~e.8 (m / macro-molecular-complex~e.12 :part (p3 / protein~e.4 :name (n3 / name :op1 "Elongin"~e.10 :op2 "B")) :part (p4 / protein~e.4 :name (n4 / name :op1 "Elongin"~e.10 :op2 "C"))))) :manner~e.14 (m2 / mutual~e.14) :manner (i / in-vitro~e.16,17) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 101~e.19)))) # ::id bio.chicago_2015.55289 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here , we have demonstrated that intact p140 mDia can bind to profilin in vitro , and its distribution in vivo largely overlaps with that of profilin in cells . # ::alignments 0-1.3 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1.2 9-1.2.1 10-1.2.1.1 11-1.2.1.1.2.r 12-1.2.1.1.2.1.1 13-1.2.1.1.3 14-1.2.1.1.3 16-1.2 18-1.2.2.1 18-1.2.2.2 19-1.2.2.1.2 20-1.2.2.1.2 21-1.2.2.3 22-1.2.2 26-1.2.1.1.2.1.1 27-1.2.2.1.2 27-1.2.2.2.2.r 28-1.2.2.2.2 (d / demonstrate-01~e.4 :ARG0 (w2 / we~e.2) :ARG1~e.5 (a / and~e.16 :op1 (p / possible-01~e.9 :ARG1 (b / bind-01~e.10 :ARG1 (p2 / protein :name (n / name :op1 "p140mDia") :mod (i / intact~e.6)) :ARG2~e.11 (p3 / protein :name (n2 / name :op1 "profilin"~e.12,26)) :manner (i2 / in-vitro~e.13,14))) :op2 (o / overlap-01~e.22 :ARG0 (d2 / distribute-01~e.18 :ARG1 p2 :manner (i3 / in-vivo~e.19,20,27)) :ARG1 (d3 / distribute-01~e.18 :ARG0 p3 :location~e.27 (c / cell~e.28)) :ARG2 (l / large~e.21))) :medium (h2 / here~e.0)) # ::id bio.chicago_2015.55319 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The finding that p115 binding to GM130 is inhibited by phosphorylation of GM130 on serine 25 suggests that this residue must be dephosphorylated for Golgi reassembly to occur . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2.1.1.1 4-1.1.1.2 5-1.1.1.2.2.r 6-1.1.1.2.2.1.1 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1 11-1.1.1.1.1.r 12-1.1.1.1.1.3 14-1.1.1.1.1.2.1 15-1.1.1.1.1.1 16-1 20-1.2 22-1.2.1 24-1.2.1.2.1.1.1 26-1.2 (s / suggest-01~e.16 :ARG0 (f / find-01~e.1 :ARG1~e.2 (i / inhibit-01~e.8 :ARG0~e.9 (p / phosphorylate-01~e.10 :ARG1~e.11 (a2 / amino-acid :mod 25~e.15 :name (n4 / name :op1 "serine"~e.14) :part-of p3~e.12)) :ARG1 (b / bind-01~e.4 :ARG1 (p2 / protein :name (n2 / name :op1 "p115"~e.3)) :ARG2~e.5 (p3 / protein :name (n3 / name :op1 "GM130"~e.6))))) :ARG1 (o / obligate-01~e.20,26 :ARG2 (d / dephosphorylate-01~e.22 :ARG1 a2 :purpose (a3 / assemble-01 :ARG1 (t / thing :name (n / name :op1 "Golgi"~e.24)) :mod (a4 / again))))) # ::id bio.chicago_2015.55330 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with C3 exoenzyme ( C3 ) may block m1 mAChR - mediated suppression of Kv1.2 or may disrupt the binding between RhoA and Kv1.2 . # ::alignments 0-1.1.1.1 1-1.1.1.1.1.r 2-1.1.1.1.1.1.1 3-1.1.1.1.1.1.2 7-1.1 8-1.1.1 9-1.1.1.2.2.1.1.1 10-1.1.1.2.2.1.1.2 12-1.1.1.2.2 13-1.1.1.2 14-1.1.1.2.1.r 15-1.1.1.2.1.1.1 16-1 17-1.1 17-1.2 18-1.2.1 20-1.2.1.2 22-1.2.1.2.1.1.1 24-1.2.1.2.2 (o / or~e.16 :op1 (p / possible-01~e.7,17 :ARG1 (b / block-01~e.8 :ARG0 (t / treat-04~e.0 :ARG2~e.1 (e / enzyme :name (n / name :op1 "C3"~e.2 :op2 "exoenzyme"~e.3))) :ARG1 (s / suppress-01~e.13 :ARG1~e.14 (p3 / protein :name (n3 / name :op1 "Kv1.2"~e.15)) :ARG1-of (m / mediate-01~e.12 :ARG0 (p2 / protein :name (n2 / name :op1 "m1"~e.9 :op2 "mAChR"~e.10)))))) :op2 (p4 / possible-01~e.17 :ARG1 (d2 / disrupt-01~e.18 :ARG0 t :ARG1 (b2 / bind-01~e.20 :ARG1 (p5 / protein :name (n4 / name :op1 "RhoA"~e.22)) :ARG2 p3~e.24)))) # ::id bio.chicago_2015.55334 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reconstitution of the binding of alpha @-@ actinin to VPMs in the presence of actin stress fibers . # ::alignments 3-1.1 4-1.1.1.r 5-1.1.1.2.1 7-1.1.1.2.1 12-1.2 13-1.2.1.r 14-1.2.1.2.2.1 15-1.2.1.1 16-1.2.1 (r / reconstitute-01 :ARG1 (b / bind-01~e.3 :ARG1~e.4 (p / protein :wiki "Actinin,_alpha_1" :name (n / name :op1 "alpha-actinin"~e.5,7)) :ARG2 (m / membrane :mod (p5 / plasma :mod (v / ventral)))) :condition (p3 / present-02~e.12 :ARG1~e.13 (f / fiber~e.16 :mod (s / stress~e.15) :consist-of (p4 / protein :wiki "Actin" :name (n3 / name :op1 "actin"~e.14))))) # ::id bio.chicago_2015.55368 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The binding of the native CaMKII to projectin ( maximally bound CaMKII ( native ) / projectin= 1.38 plus @-@ or @-@ minus 0.02 mol mol @-@ 1 ) had a higher stoichiometry than the in vitro autophosphorylated CaMKII ( maximally bound CaMKII ( autophosphorylated ) / projectin= 0.86 plus @-@ or @-@ minus 0.04 mol mol @-@ 1 ) . # ::alignments 1-1.1.3.1 4-1.1.3.1.1 5-1.1.3.1.1 7-1.1.2.1.1 9-1.1.3.1.3 10-1.1.3.1 11-1.1.1.1.1 13-1.1.1.2 17-1.1.3.1.4.1.2 17-1.1.3.1.4.2.2 23-1.1.3.1.4.1.1 23-1.1.3.1.4.2.1 29-1 31-1.2.1 31-1.2.1.1 31-1.2.1.1.r 32-1.2 33-1.2.1.2.r 35-1.2.1.2.2.2 36-1.2.1.2.2.2 37-1.2.1.2.2 38-1.1.1.1.1 38-1.2.1.2.1.1 40-1.1.3.1.3 41-1.1 41-1.1.3.1 41-1.2.1.3.1 42-1.2.1.3.1.1 43-1.2.1.3.1.1 44-1.2.1.3.1.1 48-1.2.1.3.1.4.1.2 48-1.2.1.3.1.4.2.2 54-1.2.1.3.1.4.1.1 54-1.2.1.3.1.4.2.1 (h / have-03~e.29 :ARG0 (b / bind-01~e.41 :ARG1 (e / enzyme :name (n / name :op1 "CaMKII"~e.11,38) :mod (n3 / native~e.13)) :ARG2 (p / protein :name (n2 / name :op1 "projectin"~e.7)) :ARG1-of (m2 / mean-01 :ARG2 (b2 / bind-01~e.1,10,41 :ARG1 e~e.4,5 :ARG2 p :degree (m3 / maximum~e.9,40) :quant (v / value-interval :op1 (a / add-02 :ARG1 0.02~e.23 :ARG2 1.38~e.17) :op2 (s2 / subtract-01 :ARG1 0.02~e.23 :ARG2 1.38~e.17) :unit (m5 / molar))))) :ARG1 (s / stoichiometry~e.32 :ARG1-of (h2 / high-02~e.31 :degree~e.31 (m / more~e.31) :compared-to~e.33 (e2 / enzyme :name (n4 / name :op1 "CaMKII"~e.38) :ARG1-of (p2 / phosphorylate-01~e.37 :ARG2 e2 :manner (i / in-vitro~e.35,36))) :ARG1-of (m4 / mean-01 :ARG2 (b3 / bind-01~e.41 :ARG1 e2~e.42,43,44 :ARG2 p :degree m3 :quant (v2 / value-interval :op1 (a2 / add-02 :ARG1 0.04~e.54 :ARG2 0.86~e.48) :op2 (s3 / subtract-01 :ARG1 0.04~e.54 :ARG2 0.86~e.48) :unit (m6 / molar))))))) # ::id bio.chicago_2015.55380 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oct @-@ 1 binds to the PRL3 element . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2.r 6-1.2.1.1.1 7-1.2 (b / bind-01~e.3 :ARG1 (p / protein :name (n / name :op1 "Oct-1"~e.0,2)) :ARG2~e.4 (e / element~e.7 :mod (e2 / enzyme :name (n2 / name :op1 "PRL3"~e.6)))) # ::id bio.chicago_2015.55448 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the interaction between the mutated CtIP and GST @-@ BRCT was unaffected ( Fig . 4 A , compare lanes 3 and 7 ) , suggesting that CtIP binds to CtBP and the BRCT repeats of BRCA1 using different motifs . # ::alignments 0-1 3-1.1.2 6-1.1.2.1.2 7-1.1.2.1.1.1 9-1.1.2.2.1.1 11-1.1.2.2.1.1 13-1.1 13-1.1.1 13-1.1.1.r 15-1.1.3.1 20-1.1.3.1.2 21-1.1.3.1.2.3 21-1.1.3.1.2.4 22-1.1.3.1.2.3.1 24-1.1.3.1.2.4.1 27-1.1.4 28-1.1.4.1.r 29-1.1.4.1.1 30-1.1.4.1 31-1.1.4.1.2.r 32-1.1.4.1.2.1.1.1 33-1.1.4.1.2 35-1.1.4.1.2.2.2.1.1 36-1.1.4.1.2.2 37-1.1.4.1.2.2.1.r 38-1.1.4.1.2.2.1.1.1 39-1.1.4.1.3 40-1.1.4.1.3.2.1 41-1.1.4.1.3.2 (h / have-concession-91~e.0 :ARG1 (a / affect-01~e.13 :polarity~e.13 -~e.13 :ARG1 (i / interact-01~e.3 :ARG0 (p / protein :name (n / name :op1 "CtIP"~e.7) :ARG2-of (m / mutate-01~e.6)) :ARG2 (p2 / protein :name (n2 / name :op1 "GST-BRCT"~e.9,11))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod "4A" :location-of (c2 / compare-01~e.20 :mode imperative :ARG0 (y / you) :ARG1 (l / lane~e.21 :mod 3~e.22) :ARG2 (l2 / lane~e.21 :mod 7~e.24)))) :ARG0-of (s / suggest-01~e.27 :ARG1~e.28 (b / bind-01~e.30 :ARG1 p~e.29 :ARG2~e.31 (a2 / and~e.33 :op1 (p3 / protein :name (n3 / name :op1 "CtBP"~e.32)) :op2 (r / repeat-01~e.36 :ARG1~e.37 (p5 / protein :name (n5 / name :op1 "BRCA1"~e.38)) :mod (p4 / protein :name (n4 / name :op1 "BRCT"~e.35)))) :ARG3 (u / use-01~e.39 :ARG0 p :ARG1 (p6 / protein-segment~e.41 :ARG1-of (d2 / differ-02~e.40))))))) # ::id bio.chicago_2015.55495 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , although the HDL binding activities of the COS [ mSR @-@ BI ] and COS[hCD36 ] cells differed by only ~ 50 % in this experiment ( see legend ) , there were essentially only control ( background ) levels of DiI uptake mediated by hCD36 in the COS[hCD36 ] cells . # ::alignments 1-1 3-1.1.4.r 5-1.1.4.1.2.1.1.1 6-1.1.4.1.2 7-1.1.4.1 7-1.1.4.2 19-1.1.4.1.1 20-1.1.4 22-1.1.1.2 23-1.1.4.4 24-1.1.4.4.1.1 25-1.1.4.4.1 26-1.1.4.3.r 27-1.1.4.3.1 28-1.1.4.3 30-1.1.4.3.2 31-1.1.4.3.2.3 36-1.1.2 36-1.1.2.r 37-1.1.1.2 38-1.1.1.1 40-1.1.1.1.1.1 42-1.1.1 43-1.1.1.3.r 44-1.1.1.3.1.1.1 45-1.1.1.3 46-1.1.1.3.2 47-1.1.1.3.2.1.r 48-1.1.1.3.2.1.1.1 53-1.1.3 (c5 / contrast-01~e.1 :ARG2 (p / present-02 :ARG1 (l / level~e.42 :mod (c / control~e.38 :ARG1-of (m / mean-01 :ARG2 (b / background~e.40))) :mod (o / only~e.22,37) :quant-of~e.43 (u / uptake~e.45 :mod (p2 / protein :name (n / name :op1 "DiI"~e.44)) :ARG1-of (m2 / mediate-01~e.46 :ARG0~e.47 (p3 / protein :name (n2 / name :op1 "hCD36"~e.48))))) :manner~e.36 (e / essential~e.36) :location (c2 / cell-line~e.53 :name (n3 / name :op1 "COS[hCD36]")) :concession~e.3 (d / differ-02~e.20 :ARG1 (a / activity-06~e.7 :ARG0 (c3 / cell-line~e.19 :name (n5 / name :op1 "COS[mSR-BI]")) :ARG1 (b2 / bind-01~e.6 :ARG1 (p4 / protein :name (n4 / name :op1 "HDL"~e.5)))) :ARG2 (a2 / activity-06~e.7 :ARG0 c2 :ARG1 b2) :condition~e.26 (e2 / experiment-01~e.28 :mod (t / this~e.27) :ARG1-of (s / see-01~e.30 :mode imperative :ARG0 (y / you) :medium (l2 / legend~e.31))) :extent (a3 / approximately~e.23 :op1 (p5 / percentage-entity~e.25 :value 50~e.24 :mod o))))) # ::id bio.chicago_2015.55503 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Second , noggin and follistatin bind BMPs with greater affinity than BMP receptors ( Holley et al. , 1996 ; Zimmerman et al. , 1996 ; Fainsod et al. , 1997 ; Iemura et al. , 1998 ) , so it is unlikely that the extracellular compartment contains significant levels of antagonist not complexed to BMPs . # ::alignments 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 5-1.1 7-1.1.3.r 8-1.1.3.1 8-1.1.3.1.1 8-1.1.3.1.1.r 9-1.1.3 10-1.1.3.1.2.r 11-1.1.2.1.1 12-1.1.3.1.2 14-1.1.5.1.1.1.1.1.1 15-1.1.5.1.1.1 16-1.1.5.1.1.1.2.1 18-1.1.5.1.2.2 20-1.1.5.1.2.1.1.1.1 21-1.1.5.1 21-1.1.5.1.1.1 21-1.1.5.1.2.1 21-1.1.5.1.3.1 21-1.1.5.1.4.1 22-1.1.5.1.1.1.2.1 24-1.1.5.1.1.2.1 26-1.1.5.1.3.1.1.1.1 27-1.1.5.1 27-1.1.5.1.1.1 27-1.1.5.1.2.1 27-1.1.5.1.3.1 27-1.1.5.1.4.1 28-1.1.5.1.1.1.2.1 30-1.1.5.1.3.2.1 32-1.1.5.1.4.1.1.1.1 33-1.1.5.1 33-1.1.5.1.1.1 33-1.1.5.1.2.1 33-1.1.5.1.4.1 34-1.1.5.1.1.1.2.1 36-1.1.5.1.4.2.1 39-1.1.4 42-1.1.4.1 42-1.1.4.1.1 43-1.1.4.1.2.r 45-1.1.4.1.2.1.1 46-1.1.4.1.2.1 47-1.1.4.1.2 48-1.1.4.1.2.2.1 49-1.1.4.1.2.2 50-1.1.4.1.2.2.2.r 51-1.1.4.1.2.2.2 52-1.1.4.1.1.r 52-1.1.4.1.2.2.2.1.1 52-1.1.4.1.2.2.2.1.1.r 54-1.1.4 (a4 / and :op2 (b / bind-01~e.5 :ARG1 (a / and~e.3 :op1 (p / protein :name (n / name :op1 "noggin"~e.2)) :op2 (p2 / protein :name (n2 / name :op1 "follistatin"~e.4))) :ARG2 (p3 / protein :name (n3 / name :op1 "BMP"~e.11)) :manner~e.7 (a2 / affinity~e.9 :mod (g / great~e.8 :degree~e.8 (m / more~e.8) :compared-to~e.10 (r / receptor~e.12 :mod p3))) :ARG0-of (c / cause-01~e.39,54 :ARG1 (l / likely-01~e.42 :polarity~e.52 -~e.42 :ARG1~e.43 (c2 / contain-01~e.47 :ARG0 (c3 / compartment~e.46 :mod (e / extracellular~e.45)) :ARG1 (l2 / level~e.49 :ARG1-of (s / significant-02~e.48) :quant-of~e.50 (a3 / antagonist~e.51 :ARG2-of (h / have-part-91 :polarity~e.52 -~e.52 :ARG1 (m2 / macro-molecular-complex :part p3))))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.21,27,33 :op1 (p4 / publication-91 :ARG0 (a6 / and~e.15,21,27,33 :op1 (p5 / person :name (n4 / name :op1 "Holley"~e.14)) :op2 (p6 / person :mod (o2 / other~e.16,22,28,34))) :time (d / date-entity :year 1996~e.24)) :op2 (p7 / publication-91 :ARG0 (a8 / and~e.21,27,33 :op1 (p8 / person :name (n5 / name :op1 "Zimmerman"~e.20)) :op2 p6) :time d~e.18) :op3 (p9 / publication-91 :ARG0 (a7 / and~e.21,27 :op1 (p10 / person :name (n6 / name :op1 "Fainsod"~e.26)) :op2 p6) :time (d3 / date-entity :year 1997~e.30)) :op4 (p11 / publication-91 :ARG0 (a9 / and~e.21,27,33 :op1 (p12 / person :name (n7 / name :op1 "Iemura"~e.32)) :op2 p6) :time (d4 / date-entity :year 1998~e.36)))))) # ::id bio.chicago_2015.55550 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lack of observed binding between Sog and alphaPS3 could result from a difficulty in detecting an alternatively processed form of Sog bound to alphaPS3 , or may reflect an indirect mode of action of scb ( e.g . by altering the abundance of interacting integrins such as alphaPS1 betaPS or by binding to a different Bmp inhibitor ) . # ::alignments 1-1.1.1.2 3-1.1.1.1.1.1.2.2 4-1.1.1.1.1.1.2 6-1.1.1.1.1.1.1.1 8-1.1.1.1.1.1.2.1.1.1 9-1.1 10-1.1.1 13-1.1.1.1 15-1.1.1.1.1 18-1.1.1.1.1.1.3 21-1.1.1.1.1.1.1.1 21-1.1.1.2.1.1.1.1 22-1.1.1.2.1 23-1.1.1.2.1.2.r 24-1.1.1.2.1.2 26-1 27-1.1 27-1.2 28-1.2.1 30-1.2.1.2.1.2 30-1.2.1.2.1.2.1 30-1.2.1.2.1.2.1.r 31-1.2.1.2 33-1.2.1.2.1 34-1.2.1.2.1.1.r 35-1.2.1.2.1.1.1.1 39-1.2.1.2.1.2.2.r 40-1.2.1.2.1.2.2.1 42-1.2.1.2.1.2.2.1.2 43-1.2.1.2.1.2.2.1.2.1.r 44-1.2.1.2.1.2.2.1.2.1.2 45-1.2.1.2.1.2.2.1.2.1.1.1 46-1.2.1.2.1.2.2.1.2.1.3.r 47-1.2.1.2.1.2.2.1.2.1.3.r 50-1.2.1.2.1.2.2 52-1.2.1.2.1.2.2.2 53-1.2.1.2.1.2.2.2.2.r 55-1.2.1.2.1.2.2.2.2.2 56-1.2.1.2.1.2.2.2.2.1.1.1.1 57-1.2.1.2.1.2.2.2.2 57-1.2.1.2.1.2.2.2.2.1 57-1.2.1.2.1.2.2.2.2.1.r (o / or~e.26 :op1 (p2 / possible-01~e.9,27 :ARG1 (r / result-01~e.10 :ARG1 (d / difficult~e.13 :domain (d3 / detect-01~e.15 :ARG1 (p6 / protein :name (n3 / name :op1 "Sog"~e.6,21) :ARG1-of (b2 / bind-01~e.4 :ARG2 (p7 / protein :name (n4 / name :op1 "alphaPS3"~e.8)) :ARG1-of (o3 / observe-01~e.3)) :ARG1-of (p5 / process-01~e.18 :ARG1-of (a / alternate-01))))) :ARG2 (l / lack-01~e.1 :ARG1 (b / bind-01~e.22 :ARG1 (p3 / protein :name (n / name :op1 "Sog"~e.21)) :ARG2~e.23 p7~e.24)))) :op2 (p / possible-01~e.27 :ARG1 (r2 / reflect-01~e.28 :ARG1 l :ARG2 (m / mode~e.31 :manner-of (a2 / act-01~e.33 :ARG0~e.34 (p8 / protein :name (n5 / name :op1 "scb"~e.35)) :ARG1-of (d4 / direct-02~e.30 :polarity~e.30 -~e.30 :example~e.39 (o2 / or~e.50 :op1 (a3 / alter-01~e.40 :ARG0 p8 :ARG1 (a4 / abound-01~e.42 :ARG1~e.43 (p4 / protein-family :name (n2 / name :op1 "integrin"~e.45) :ARG0-of (i3 / interact-01~e.44) :example~e.46,47 (p9 / protein :name (n6 / name :op1 "alphaPS1betaPS"))))) :op2 (b3 / bind-01~e.52 :ARG1 p8 :ARG2~e.53 (m4 / molecular-physical-entity~e.57 :ARG0-of~e.57 (i4 / inhibit-01~e.57 :ARG1 (p10 / protein :name (n7 / name :op1 "Bmp"~e.56))) :ARG1-of (d2 / differ-02~e.55)))))))))) # ::id bio.chicago_2015.55555 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Screening a brain library demonstrates that the PDZ @-@ containing domain of nNOS binds to PDZ repeats in postsynaptic density 95 ( PSD @-@ 95 ) ( Cho et al. , 1992 ) and a novel related protein , PSD @-@ 93 . # ::alignments 0-1.1 2-1.1.1.1 3-1.1.1 4-1 5-1.2.r 7-1.2.2.1.1 9-1.2.1.2 12-1.2.1.1.1.1 13-1.2 15-1.2.2.1.1 16-1.2.2.1.2 17-1.2.3.r 18-1.2.3.1.1.1 19-1.2.3.1.1.2 20-1.2.3.1.1.3 22-1.2.3.2.1.1 27-1.2.3.1.2.1.1.1.1.1 28-1.2.3.1.2.1.1 29-1.2.3.1.2.1.1.2.1 31-1.2.3.1.2.1.2.1 33-1.2.3 35-1.2.3.2.2 36-1.2.3.2.3 37-1.2.1 39-1.2.3.2.1.1 41-1.2.3.2.1.1 (d2 / demonstrate-01~e.4 :ARG0 (s / screen-01~e.0 :ARG1 (l / library~e.3 :mod (b / brain~e.2))) :ARG1~e.5 (b2 / bind-01~e.13 :ARG1 (p / protein-segment~e.37 :part-of (e / enzyme :name (n2 / name :op1 "nNOS"~e.12)) :ARG0-of (c / contain-01~e.9 :ARG1 (p2 / protein-segment :name (n / name :op1 "PZD")))) :ARG2 (p8 / protein-segment :name (n8 / name :op1 "PDZ"~e.7,15 :op2 "repeat"~e.16)) :location~e.17 (a / and~e.33 :op1 (p3 / protein :name (n4 / name :op1 "postsynaptic"~e.18 :op2 "density"~e.19 :op3 95~e.20) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and~e.28 :op1 (p6 / person :name (n7 / name :op1 "Cho"~e.27)) :op2 (p7 / person :mod (o / other~e.29))) :time (d / date-entity :year 1992~e.31)))) :op2 (p4 / protein :name (n5 / name :op1 "PSD-93"~e.22,39,41) :mod (n6 / novel~e.35) :ARG1-of (r2 / relate-01~e.36 :ARG2 p3))))) # ::id bio.chicago_2015.55576 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Panel A , mutations introduced in the AP @-@ 2 and clathrin binding regions of amphiphysin 1 . # ::alignments 0-1.3.1 1-1.3.1.1.1 3-1.1 4-1 5-1.2.r 7-1.2.1.1.1.1.1 9-1.2.1.1.1.1.1 10-1.2.1.1 11-1.2.1.1.2.1.1 12-1.2.1 13-1.2 14-1.2.2.r 15-1.2.2.1.1 16-1.2.2.1.2 (i / introduce-02~e.4 :ARG1 (m / mutate-01~e.3) :ARG2~e.5 (r / region~e.13 :ARG2-of (b / bind-01~e.12 :ARG1 (a / and~e.10 :op1 (p / protein :name (n / name :op1 "AP-2"~e.7,9)) :op2 (p2 / protein :name (n2 / name :op1 "clathrin"~e.11)))) :part-of~e.14 (p3 / protein :name (n3 / name :op1 "amphiphysin"~e.15 :op2 1~e.16))) :ARG1-of (d / describe-01 :ARG0 (p4 / panel~e.0 :mod (s / string-entity :value "A"~e.1)))) # ::id bio.chicago_2015.55580 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results argue that a factor that binds to poly @-@ U Sepharose and that is eluted from the resin at 2 M KCl is necessary for efficient recruitment of U1 snRNP to msl @-@ 2 5 ss , but not for U1 snRNP binding to a consensus 5 ss lacking downstream U @-@ rich sequences . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2 7-1.2.1 9-1.2.1.1.1.1 11-1.2.1.1.1.1 12-1.2.1.1.1.2 16-1.2.2 17-1.2.2.1.r 19-1.2.2.1 20-1.2.2.2.r 21-1.2.2.2.2.1 22-1.2.2.2.2.2 23-1.2.2.2.1.1 25-1.2.3 25-1.2.3.2.1 26-1.2.3.1.r 27-1.2.3.1.3 28-1.2.3.1 28-1.2.3.2.1.2 29-1.2.3.1.1.r 30-1.2.3.1.1.1.1 31-1.2.3.1.1.1.2 32-1.2.3.1.2.r 33-1.2.3.1.2.2.1.1 35-1.2.3.1.2.2.1.1 36-1.2.3.1.2.1.1 37-1.2.3.1.2.1.2 39-1.2.3.2 40-1.2.3.2.1.1 40-1.2.3.2.1.1.r 42-1.2.3.1.1.1.1 43-1.2.3.1.1.1.2 44-1.2.1 45-1.2.3.2.1.2.2.r 47-1.2.3.2.1.2.2.2 48-1.2.3.1.2.1.1 49-1.2.3.1.2.1.2 50-1.2.3.2.1.2.2.3 51-1.2.3.2.1.2.2.3.1.2 52-1.2.3.2.1.2.2.3.1.1.1 54-1.2.3.2.1.2.2.3.1.1.1 55-1.2.3.2.1.2.2 55-1.2.3.2.1.2.2.3.1 (a / argue-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (f / factor~e.5 :ARG1-of (b / bind-01~e.7,44 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "poly-U"~e.9,11 :op2 "Sepharose"~e.12))) :ARG1-of (e / elute-01~e.16 :ARG2~e.17 (r5 / resin~e.19) :condition~e.20 (s3 / small-molecule :name (n3 / name :op1 "KCl"~e.23) :quant (c / concentration-quantity :quant 2~e.21 :unit (m2 / molar~e.22)))) :ARG1-of (n4 / need-01~e.25 :ARG0~e.26 (r2 / recruit-01~e.28 :ARG1~e.29 (p / protein :name (n5 / name :op1 "U1"~e.30,42 :op2 "snRNP"~e.31,43)) :ARG2~e.32 (p4 / protein-segment :name (n6 / name :op1 "5'"~e.36,48 :op2 "ss"~e.37,49) :part-of (p2 / protein :name (n8 / name :op1 "msl-2"~e.33,35))) :ARG2-of (e2 / efficient-01~e.27)) :ARG1-of (c2 / contrast-01~e.39 :ARG2 (n7 / need-01~e.25 :polarity~e.40 -~e.40 :ARG0 (r3 / recruit-01~e.28 :ARG1 p :ARG2~e.45 (d / dna-sequence~e.55 :name (n / name :op1 "5'ss") :mod (c3 / consensus~e.47) :ARG0-of (l / lack-01~e.50 :ARG1 (s / sequence~e.55 :name (n10 / name :op1 "U-rich"~e.52,54) :direction (d2 / downstream~e.51))))) :ARG1 f))))) # ::id bio.chicago_2015.55595 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Degradation of any endogenous ATP present in retinal extracts resulted in no change of binding activity of P112 to CLD ( Fig . 2 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.4 3-1.1.1.2 4-1.1.1.1.1 5-1.1.1 5-1.1.1.3 5-1.1.1.3.r 6-1.1.1.3.1.r 7-1.1.1.3.1.1.1 8-1.1.1.3.1 8-1.1.1.3.1.1 8-1.1.1.3.1.1.r 9-1 10-1.2.r 11-1.2.1 11-1.2.1.r 12-1.2 13-1.2.2.r 14-1.2.2.1 15-1.2.2 16-1.2.2.1.1.r 17-1.2.2.1.1.1.1 18-1.2.2.1.2.r 19-1.2.2.1.2.1.1 21-1.3.1 23-1.3.1.1 (r / result-01~e.9 :ARG1 (d / degrade-01~e.0 :ARG1~e.1 (s / small-molecule~e.5 :name (n / name :op1 "ATP"~e.4) :mod (e2 / endogenous~e.3) :ARG1-of~e.5 (p / present-02~e.5 :ARG2~e.6 (m / molecular-physical-entity~e.8 :ARG1-of~e.8 (e3 / extract-01~e.8 :ARG2 (r2 / retina~e.7)))) :mod (a2 / any~e.2))) :ARG2~e.10 (c / change-01~e.12 :polarity~e.11 -~e.11 :ARG1~e.13 (a / activity-06~e.15 :ARG1 (b / bind-01~e.14 :ARG1~e.16 (p2 / protein :name (n2 / name :op1 "P112"~e.17)) :ARG2~e.18 (p3 / protein :name (n3 / name :op1 "CLD"~e.19))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.21 :mod 2~e.23))) # ::id bio.chicago_2015.55666 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next tested the contribution of the IAP binding activity of Omi to its killing activity . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 7-1.2.1.2.2.1.1 8-1.2.1.2 9-1.2.1 10-1.2.1.2.1.r 11-1.2.1.2.1.1.1 14-1.2.2.2 15-1.2.2 (t / test-01~e.2 :ARG0 (w / we~e.0) :ARG1 (c / contribute-01~e.4 :ARG0~e.5 (a / activity-06~e.9 :ARG0 p2 :ARG1 (b / bind-01~e.8 :ARG1~e.10 (p2 / protein :name (n3 / name :op1 "Omi"~e.11)) :ARG2 (p / protein :name (n2 / name :op1 "IAP"~e.7)))) :ARG2 (a2 / activity-06~e.15 :ARG0 p2 :ARG1 (k / kill-01~e.14 :ARG0 p2))) :time (n / next~e.1)) # ::id bio.chicago_2015.55671 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the binding experiments described above demonstrated that the C @-@ terminal 378 residues of E6TP1 , which lack the PDZ domain , were sufficient for E6 binding , it remained possible that the PDZ domain of E6TP1 could also bind to E6 , either independently or cooperatively with the C @-@ terminal region . # ::alignments 0-1 2-1.2.1.1 3-1.2.1 4-1.2.1.2 5-1.2.1.2.1 6-1.2 7-1.2.2.r 9-1.2.2.1.2.2.1.1 11-1.2.2.1.2.2.1.1 12-1.2.2.1.2.1 13-1.2.2.1 15-1.2.2.1.2.2.2.1.1 18-1.2.2.1.1 20-1.2.2.1.1.1 21-1.2.2.1.1.1 24-1.2.2 25-1.2.2.2.r 26-1.2.2.2.1.1.1 27-1.2.2.2 30-1.1 31-1.1.1 34-1.1.1.1.1.1.1 35-1.1.1.1.1.1.2 37-1.1.1.1.1.2 38-1.1.1 39-1.1.1.1.4 40-1.1.1.1 41-1.1.1.1.2.r 42-1.1.1.1.2 45-1.1.1.1.3.1.1 46-1.1.1.1.3 47-1.1.1.1.3.2 48-1.1.1.1.3.2.2.r 50-1.1.1.1.3.2.2.1.1 52-1.1.1.1.3.2.2.1.1 (h / have-concession-91~e.0 :ARG1 (r3 / remain-01~e.30 :ARG1 (p4 / possible-01~e.31,38 :ARG1 (b3 / bind-01~e.40 :ARG1 (p8 / protein-segment :name (n7 / name :op1 "PDZ"~e.34 :op2 "domain"~e.35) :part-of p2~e.37) :ARG2~e.41 p6~e.42 :manner (o / or~e.46 :op1 (d3 / depend-01 :polarity -~e.45 :ARG0 p8) :op2 (c / cooperate-01~e.47 :ARG0 p8 :ARG1~e.48 (p3 / protein-segment :name (n6 / name :op1 "C-terminus"~e.50,52)))) :mod (a3 / also~e.39)))) :ARG2 (d / demonstrate-01~e.6 :ARG0 (e / experiment-01~e.3 :ARG1 (b / bind-01~e.2) :ARG1-of (d2 / describe-01~e.4 :location (a / above~e.5))) :ARG1~e.7 (s / suffice-01~e.24 :ARG0 (r2 / residue~e.13 :ARG0-of (l / lack-01~e.18 :ARG1 p8~e.20,21) :mod (a2 / amino-acid :mod 378~e.12 :part-of (p / protein-segment :name (n / name :op1 "C-terminus"~e.9,11) :part-of (p2 / protein :name (n2 / name :op1 "E6TP1"~e.15))))) :ARG1~e.25 (b2 / bind-01~e.27 :ARG2 (p6 / protein :name (n5 / name :op1 "E6"~e.26)))))) # ::id bio.chicago_2015.55702 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C , summary of the Rab binding specificity of the mouse or human Slp family ( Slp1 @-@ 5 ) , the Slac2 family ( Slac2 @-@ a/b/c ) , Rim1 , Rim2 , Noc2 , and rabphilin ( see also Fig. 5 ) . # ::alignments 0-1.1 2-1 5-1.2.1.2.1.1 6-1.2.1 8-1.2.1.1.r 10-1.2.1.1.1.2 11-1.2.1.1.1.2.1 12-1.2.1.1.1.2.1.1 13-1.2.1.1.1.1.1 14-1.2.1.1.1 14-1.2.1.2 16-1.2.1.1.1.3.1.1.1.1 18-1.3.1.1 22-1.2.1.1.2.1.1 23-1.2.1.1.2 25-1.2.1.1.2.1.1 30-1.2.1.1.3.1.1 32-1.2.1.1.4.1.1 34-1.2.1.1.5.1.1 36-1.2.1.1 36-1.2.1.1.2.2.1 37-1.2.1.1.6 39-1.3.1.2 40-1.3.1.2.3 41-1.3.1 42-1.3.1.1 (s2 / summarize-01~e.2 :li "c"~e.0 :ARG1 (s3 / specific-02 :ARG1 (b / bind-01~e.6 :ARG1~e.8 (a / and~e.36 :op1 (p2 / protein-family~e.14 :name (n2 / name :op1 "Slp"~e.13) :mod (m / mouse~e.10 :op1-of (o / or~e.11 :op2 (h / human~e.12))) :ARG1-of (m3 / mean-01 :ARG2 (v / value-interval :op1 (p10 / protein :name (n10 / name :op1 "Slp1"~e.16)) :op2 (p11 / protein :name (n11 / name :op1 "Slp5"))))) :op2 (p3 / protein-family~e.23 :name (n3 / name :op1 "Slac2"~e.22,25) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.36 :op1 (p7 / protein :name (n7 / name :op1 "Slac2-a")) :op2 (p8 / protein :name (n8 / name :op1 "Slac2-b")) :op3 (p9 / protein :name (n9 / name :op1 "Slac2-c"))))) :op3 (p4 / protein :name (n4 / name :op1 "Rim1"~e.30)) :op4 (p5 / protein :name (n5 / name :op1 "Rim2"~e.32)) :op5 (p6 / protein :name (n6 / name :op1 "Noc2"~e.34)) :op6 (r / rabphilin~e.37)) :ARG2 (p / protein-family~e.14 :name (n / name :op1 "Rab"~e.5)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.41 :mod 5~e.18,42 :ARG1-of (s4 / see-01~e.39 :mode imperative :ARG0 (y / you) :mod (a3 / also~e.40))))) # ::id bio.chicago_2015.55713 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exchange of the GDP bound to eIF2 with GTP is catalyzed by eIF2B . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1.2.1 4-1.2.1 4-1.2.1.3 4-1.2.1.3.r 5-1.2.1.3.1.r 6-1.2.1.3.1.1.1 7-1.2.2.r 8-1.2.2.1.1 10-1 11-1.1.r 12-1.1.1.1 (c / catalyze-01~e.10 :ARG0~e.11 (p3 / protein :name (n4 / name :op1 "eIF2B"~e.12)) :ARG1 (e / exchange-01~e.0 :ARG1~e.1 (s / small-molecule~e.4 :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP"~e.3) :ARG1-of~e.4 (b / bind-01~e.4 :ARG2~e.5 (p2 / protein :name (n3 / name :op1 "eIF2"~e.6)))) :ARG3~e.7 (s2 / small-molecule :name (n2 / name :op1 "GTP"~e.8)))) # ::id bio.chicago_2015.55730 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of PTB or PTB to uniformly labeled MSE1 @-@ 4 RNA was assayed by UV crosslinking followed by immunoprecipitation using the AntiXpress antibody . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.1.1.1 5-1.1.2.r 6-1.1.2.2.1 7-1.1.2.2 8-1.1.2.3.1.1.1 10-1.1.2.3.1.1.1 11-1.1.2.1.1 13-1 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1 23-1.2.2.1.1 (a / assay-01~e.13 :ARG1 (b / bind-01~e.0 :ARG1~e.1 (o / or~e.3 :op1 (p / protein :name (n3 / name :op1 "PTB"~e.2,4)) :op2 p) :ARG2~e.5 (n4 / nucleic-acid :name (n5 / name :op1 "RNA"~e.11) :ARG1-of (l / label-01~e.7 :ARG1-of (u / uniform-02~e.6)) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n / name :op1 "MSE1-4"~e.8,10))))) :manner (c / crosslink-00 :ARG0 (l2 / light :mod (u2 / ultraviolet)) :ARG2-of (f / follow-01~e.17 :ARG1~e.18 (i / immunoprecipitate-01~e.19 :ARG3 (a2 / antibody~e.23 :name (n7 / name :op1 "AntiXpressdd")))))) # ::id bio.chicago_2015.55746 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The N @-@ terminal boundary for PABP binding resides between amino acids 132 and 139 , because eIF4GI( 132 @-@ 329 ) bound PABP , but eIF4GI( 139 @-@ 329 ) did not ( Figure 3B , compare lanes 3 and 4 ) . # ::alignments 1-1.2.1.1.1.1 3-1.2.1.1.1.1 4-1.2.1 5-1.2.1.2.r 6-1.2.1.2.1.1.1 7-1.2.1.2 8-1.2 9-1.2.2 10-1.1.1.2.2 10-1.2.2.1 10-1.2.2.2 11-1.1.1.2.2 11-1.1.2.3.2 11-1.2.2.1 12-1.1.1.2.2.1.1 13-1.2.2 14-1.1.2.3.2.1.1 14-1.2.2.1.1 16-1 18-1.1.1.2.2.1.1 20-1.1.1.2.2.1.2 20-1.1.2.3.2.1.2 22-1.1.1 22-1.1.2 23-1.2.1.2.1.1.1 25-1.1 27-1.1.2.3.2.1.1 29-1.1.1.2.2.1.2 29-1.1.2.3.2.1.2 29-1.2.2.2.1 32-1.1.2.1 32-1.1.2.1.r 34-1.3.1 35-1.3.1.1 37-1.3.1.2 38-1.3.1.2.3 38-1.3.1.2.4 39-1.3.1.2.3.1 41-1.3.1.2.4.1 (c / cause-01~e.16 :ARG0 (c2 / contrast-01~e.25 :ARG1 (b6 / bind-01~e.22 :ARG1 p2 :ARG2 (p3 / protein :name (n5 / name :op1 "eIF4GI") :part (a3 / amino-acid~e.10,11 :mod (v / value-interval :op1 132~e.12,18 :op2 329~e.20,29)))) :ARG2 (b7 / bind-01~e.22 :polarity~e.32 -~e.32 :ARG1 p2 :ARG2 (p4 / protein :name (n6 / name :op1 "eIF4GI") :part (a4 / amino-acid~e.11 :mod (v2 / value-interval :op1 139~e.14,27 :op2 329~e.20,29))))) :ARG1 (r / reside-01~e.8 :ARG0 (b3 / boundary~e.4 :mod (p / protein-segment :name (n / name :op1 "N-terminus"~e.1,3)) :purpose~e.5 (b4 / bind-01~e.7 :ARG2 (p2 / protein :name (n2 / name :op1 "PABP"~e.6,23)))) :ARG1 (b5 / between~e.9,13 :op1 (a / amino-acid~e.10,11 :mod 139~e.14) :op2 (a2 / amino-acid~e.10 :mod 329~e.29))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "3B"~e.35 :location-of (c3 / compare-01~e.37 :mode imperative :ARG0 (y / you) :ARG1 (l / lane~e.38 :mod 3~e.39) :ARG2 (l2 / lane~e.38 :mod 4~e.41))))) # ::id bio.chicago_2015.55796 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This sequence shows marked homology to the amino @-@ terminal sequence determined here for processed Smac/ DIABLO bound to XIAP , AVPIAQ ; Smac/ DIABLO has been processed here to remove the first 55 amino acids . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.2 4-1.1.2 5-1.1.2.1.r 7-1.1.2.1.2.1.1 9-1.1.2.1.2.1.1 10-1.1.2.1 11-1.1.2.1.1 12-1.1.2.1.1.2 13-1.1.2.1.1.1.r 14-1.1.2.1.1.1.2 16-1.1.2.1.1.1.1.1 17-1.1.2.1.1.1 17-1.1.2.1.1.1.3 17-1.1.2.1.1.1.3.r 18-1.1.2.1.1.1.3.1.r 19-1.1.2.1.1.1.3.1.1.1.1 21-1.1.2.1.1.1.3.1.2.1.1 24-1.1.2.1.1.1.1.1 24-1.2.1.1.1 27-1.1.2.1.1.1.2 27-1.2 28-1.1.2.1.1.2 30-1.2.2 32-1.2.2.2.2 32-1.2.2.2.2.1 32-1.2.2.2.2.1.r 33-1.2.2.2.1 34-1.2.2.2 35-1.2.2.2 (a3 / and :op1 (s / show-01~e.2 :ARG0 (s2 / sequence~e.1 :mod (t / this~e.0)) :ARG1 (h / homologous~e.4 :compared-to~e.5 (s3 / sequence~e.10 :ARG1-of (d / determine-01~e.11 :ARG2~e.13 (p / protein~e.17 :name (n / name :op1 "Smac/DIABLO"~e.16,24) :ARG1-of (p2 / process-01~e.14,27) :ARG1-of~e.17 (b / bind-01~e.17 :ARG2~e.18 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "XIAP"~e.19)) :op2 (p4 / protein :name (n3 / name :op1 "AVPIAQ"~e.21))))) :location (h3 / here~e.12,28)) :mod (p6 / protein-segment :name (n4 / name :op1 "amino-terminus"~e.7,9))) :ARG1-of (m / mark-01~e.3))) :op2 (p5 / process-01~e.27 :ARG1 (p7 / protein :name (n5 / name :op1 "Smac/DIABLO"~e.24)) :purpose (r / remove-01~e.30 :ARG0 p7 :ARG1 (a4 / amino-acid~e.34,35 :quant 55~e.33 :ord (o / ordinal-entity~e.32 :value~e.32 1~e.32))) :location h3)) # ::id bio.chicago_2015.55877 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rab binding properties of the Slp family , the Slac2 family , Rim1 , Rim2 , Noc2 , and rabphilin . # ::alignments 0-1.1.2.1.1 1-1.1 2-1 3-1.1.1.r 5-1.1.1.1.1.1 6-1.1.2 9-1.1.1.2.1.1 10-1.1.1.1 10-1.1.1.2 12-1.1.1.3.1.1 14-1.1.1.4.1.1 16-1.1.1.5.1.1 18-1.1.1 19-1.1.1.6.1.1 (p / property~e.2 :mod (b / bind-01~e.1 :ARG1~e.3 (a / and~e.18 :op1 (p3 / protein-family~e.10 :name (n2 / name :op1 "Slp"~e.5)) :op2 (p4 / protein-family~e.10 :name (n3 / name :op1 "Slac2"~e.9)) :op3 (p5 / protein :name (n4 / name :op1 "Rim1"~e.12)) :op4 (p6 / protein :name (n5 / name :op1 "Rim2"~e.14)) :op5 (p7 / protein :name (n6 / name :op1 "Noc2"~e.16)) :op6 (p8 / protein :name (n7 / name :op1 "rabphilin"~e.19))) :ARG2 (p2 / protein-family~e.6 :name (n / name :op1 "Rab"~e.0)))) # ::id bio.chicago_2015.55886 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Raf did not inhibit the binding of RGL to RasG12V @/@ E37G under the condition that Raf inhibited that of RGL to RasG12V . # ::alignments 0-1.2.1.1 2-1.1 2-1.1.r 3-1 3-1.4 5-1.3 5-1.4.2 6-1.3.1.r 7-1.3.1.1.1 11-1.3.2.3.1 14-1.4.r 16-1.4.1 17-1 20-1.3.1.1.1 (i / inhibit-01~e.3,17 :polarity~e.2 -~e.2 :ARG0 (e4 / enzyme :name (n2 / name :op1 "Raf"~e.0)) :ARG1 (b / bind-01~e.5 :ARG1~e.6 (p / protein :name (n3 / name :op1 "RGL"~e.7,20)) :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (m / mutate-01 :value "G12V") :ARG1-of (m2 / mutate-01 :value "E37G"~e.11))) :condition~e.14 (i2 / inhibit-01~e.3 :ARG0 e4~e.16 :ARG1 (b2 / bind-01~e.5 :ARG1 p :ARG2 (e / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (m3 / mutate-01 :value "G12V"))))) # ::id bio.chicago_2015.55914 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because Src does not bind to Abl ( not shown ) , its binding to Cbl in the presence of Abl could be explained by a modification of Cbl conformation induced by its binding to Abl . # ::alignments 0-1 1-1.1.2.1.1 3-1.1.1 3-1.1.1.r 4-1.1 6-1.1.3.1.1 8-1.1.4.1 8-1.1.4.1.r 9-1.1.4 13-1.1 13-1.2.1.1 14-1 14-1.2.1.1.2.r 15-1.2.1.1.2.1.1 16-1.2.1.1.3.r 18-1.2.1.1.3 19-1.2.1.1.3.1.r 20-1.2.1.1.3.1 21-1.2 23-1.2.1 24-1.2.1.2.r 26-1.2.1.2 27-1.2.1.2.1.r 28-1.2.1.2.1.1 29-1.2.1.2.1 30-1.2.1.2.2 33-1.1 33-1.2.1.2.2.1 34-1 35-1.1.3.1.1 (c / cause-01~e.0,14,34 :ARG0 (b / bind-01~e.4,13,33 :polarity~e.3 -~e.3 :ARG1 (p2 / protein :name (n / name :op1 "Src"~e.1)) :ARG2 (p4 / protein :name (n2 / name :op1 "Abl"~e.6,35)) :ARG1-of (s / show-01~e.9 :polarity~e.8 -~e.8)) :ARG1 (p / possible-01~e.21 :ARG1 (e / explain-01~e.23 :ARG1 (b2 / bind-01~e.13 :ARG1 p2 :ARG2~e.14 (p5 / protein :name (n3 / name :op1 "Cbl"~e.15)) :condition~e.16 (p3 / present-02~e.18 :ARG1~e.19 p4~e.20)) :manner~e.24 (m / modify-01~e.26 :ARG1~e.27 (c2 / conform-01~e.29 :ARG1 p5~e.28) :ARG2-of (i / induce-01~e.30 :ARG0 (b3 / bind-01~e.33 :ARG1 p2 :ARG2 p4)))))) # ::id bio.chicago_2015.55915 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In agreement with the published data [ 7,19 ] , we readily demonstrated that a PAK CRIB peptide can bind directly to both Cdc42 and Rac1 , whereas an N @-@ WASP CRIB peptide bound only to Cdc42 . # ::alignments 1-1.3 2-1.3.1.r 4-1.3.1.1 4-1.3.1.2.1 5-1.3.1 10-1.1.1 11-1.1.3 12-1.1 13-1.1.2.r 15-1.1.2.1.1.1.1 16-1.1.2.1.1.1.2 17-1.1.2.1.1 18-1.1.2 19-1.1.2.1 20-1.1.2.1.3 23-1.1.2.1.2.1.1.1 24-1.1.2.1.2 25-1.1.2.1.2.2.1.1 27-1 29-1.2.1.1.1 31-1.2.1.1.1 32-1.2.1.1.2 33-1.2.1 34-1.2 35-1.2.3 36-1.2.2.r 37-1.2.2 (c / contrast-01~e.27 :ARG1 (d / demonstrate-01~e.12 :ARG0 (w / we~e.10) :ARG1~e.13 (p / possible-01~e.18 :ARG1 (b / bind-01~e.19 :ARG1 (p2 / peptide~e.17 :name (n / name :op1 "PAK"~e.15 :op2 "CRIB"~e.16)) :ARG2 (a / and~e.24 :op1 (p3 / protein :name (n2 / name :op1 "Cdc42"~e.23)) :op2 (p7 / protein :name (n3 / name :op1 "Rac1"~e.25))) :ARG1-of (d2 / direct-02~e.20))) :ARG2-of (r / ready-02~e.11)) :ARG2 (b2 / bind-01~e.34 :ARG1 (p4 / peptide~e.33 :name (n4 / name :op1 "N-WASP"~e.29,31 :op2 "CRIB"~e.32)) :ARG2~e.36 p3~e.37 :mod (o / only~e.35)) :ARG1-of (a2 / agree-01~e.1 :ARG2~e.2 (d3 / data~e.5 :ARG1-of (p5 / publish-01~e.4) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication~e.4 :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 7 :op2 19))))))) # ::id bio.chicago_2015.55927 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TLP can bind TFIIA and TFIIB , like TBP , but does not bind to the TATA sequence ( 40 , 42 , 48 , 57 ) . # ::alignments 0-1.1.1.2.1.1 0-1.2.2.1.1 1-1.1 2-1.1.1 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.1.1 7-1.1.1.2 7-1.1.1.2.2 7-1.1.1.2.2.r 8-1.1.1.2.2.1.1.1 10-1 12-1.2.1 12-1.2.1.r 13-1.2 14-1.2.3.r 16-1.2.3.1.1 17-1.2.3 19-1.3.1.1.1.1 21-1.3.1.1.1.2 23-1.3.1.1.1.3 25-1.3.1.1.1.4 (c / contrast-01~e.10 :ARG1 (p / possible-01~e.1 :ARG1 (b / bind-01~e.2 :ARG1 (a / and~e.4 :op1 (p3 / protein :name (n2 / name :op1 "TFIIA"~e.3)) :op2 (p4 / protein :name (n3 / name :op1 "TFIIB"~e.5))) :ARG2 (p2 / protein~e.7 :name (n / name :op1 "TLP"~e.0) :ARG1-of~e.7 (r / resemble-01~e.7 :ARG2 (p5 / protein :name (n4 / name :op1 "TBP"~e.8)))))) :ARG2 (b2 / bind-01~e.13 :polarity~e.12 -~e.12 :ARG1 (p7 / protein :name (n6 / name :op1 "TLP"~e.0)) :ARG2~e.14 (d2 / dna-sequence~e.17 :name (n5 / name :op1 "TATA"~e.16))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 40~e.19 :op2 42~e.21 :op3 48~e.23 :op4 57~e.25))))) # ::id bio.chicago_2015.55934 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For this , nonspecific binding of the PTN radioligand to 32D @/@ control cells was subtracted from the total binding to 32D @/@ ALK cells to obtain the amount of PTN bound to ALK at different concentrations of PTN . # ::alignments 1-1.4 3-1.1.3 3-1.1.3.1 3-1.1.3.1.r 4-1.1 5-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1 9-1.1.2.r 10-1.1.2.1.1.1 11-1.1.2 12-1.1.2.2.1 13-1.1.2.2 15-1 16-1.2.r 18-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1.1 22-1.2.1 23-1.3.1.1.2.1.1.1 24-1.2.1.2 26-1.3 28-1.3.1 30-1.3.1.1.1.1 31-1.3.1.1 31-1.3.1.1.2 31-1.3.1.1.2.r 33-1.3.1.1.2.1.1.1 34-1.3.1.1.2.2.r 35-1.3.1.1.2.2.1 36-1.3.1.1.2.2 38-1.3.1.1.1.1 (s / subtract-01~e.15 :ARG1 (b / bind-01~e.4 :ARG1~e.5 (r / radioligand~e.8 :mod (p2 / protein :name (n3 / name :op1 "PTN"~e.7))) :ARG2~e.9 (s3 / slash~e.11 :op1 (c / cell-line :name (n2 / name :op1 "32D"~e.10)) :op2 (c6 / cell~e.13 :ARG0-of (c2 / control-01~e.12))) :ARG1-of (s2 / specific-02~e.3 :polarity~e.3 -~e.3)) :ARG2~e.16 (b2 / bind-01~e.19 :ARG2~e.20 (s4 / slash~e.22 :op1 c~e.21 :op2 (c4 / cell~e.24 :mod e)) :mod (t / total~e.18)) :purpose (o / obtain-01~e.26 :ARG1 (a / amount~e.28 :quant-of (p / protein~e.31 :name (n5 / name :op1 "PTN"~e.30,38) :ARG1-of~e.31 (b3 / bind-01~e.31 :ARG2 (e / enzyme :name (n6 / name :op1 "ALK"~e.23,33)) :condition~e.34 (c5 / concentrate-02~e.36 :ARG1-of (d / differ-02~e.35)))))) :purpose (t2 / this~e.1)) # ::id bio.chicago_2015.55945 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The crystal structures of both the GDP @- and GTP @-@ bound forms of ARF1 have been solved ( 1 , 20 , 21 ) . # ::alignments 1-1.1.2 2-1.1 6-1.1.1.1.2.1.1.1.1 8-1.1.1 8-1.1.1.1.2.1 9-1.1.1.2.2.1.1.1 11-1.1.1.1 11-1.1.1.1.2 11-1.1.1.1.2.r 11-1.1.1.2 11-1.1.1.2.2 11-1.1.1.2.2.r 14-1.1.1.1.1.1 14-1.1.1.2.1.1 17-1 19-1.2.1.1.1.1 21-1.2.1.1.1.2 23-1.2.1.1.1.3 (s2 / solve-01~e.17 :ARG1 (s3 / structure-01~e.2 :ARG1 (a3 / and~e.8 :op1 (p / protein~e.11 :name (n / name :op1 "ARF1"~e.14) :ARG1-of~e.11 (b2 / bind-01~e.11 :ARG2 (a / and~e.8 :op1 (s4 / small-molecule :name (n2 / name :op1 "GDP"~e.6))))) :op2 (p3 / protein~e.11 :name (n5 / name :op1 "ARF1"~e.14) :ARG1-of~e.11 (b3 / bind-01~e.11 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "GTP"~e.9))))) :ARG2 (c / crystal~e.1)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 1~e.19 :op2 20~e.21 :op3 21~e.23))))) # ::id bio.chicago_2015.55950 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pins nearly completely abolishes the binding between Galphai and Gbeta13F . # ::alignments 0-1.1.1.1 1-1.3.1 2-1.3 3-1 5-1.2 7-1.2.1.1.1 9-1.2.2.1.1 (a / abolish-01~e.3 :ARG0 (p3 / protein :name (n2 / name :op1 "Pins"~e.0)) :ARG1 (b / bind-01~e.5 :ARG1 (p / protein :name (n3 / name :op1 "Galphai"~e.7)) :ARG2 (p2 / protein :name (n4 / name :op1 "Gbeta13F"~e.9))) :ARG1-of (c / complete-02~e.2 :degree (n / near~e.1))) # ::id bio.chicago_2015.55988 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Crk Binding to CAS Is Required for the Induction of Cell Migration # ::alignments 0-1.2.1.1.1 1-1.2 2-1.2.2.r 3-1.2.2.1.1 5-1 6-1.1.r 8-1.1 9-1.1.1.r 10-1.1.1 11-1.1.2 (r / require-01~e.5 :ARG0~e.6 (i / induce-01~e.8 :ARG1~e.9 (c / cell~e.10) :ARG2 (m / migrate-01~e.11 :ARG0 c)) :ARG1 (b / bind-01~e.1 :ARG1 (p2 / protein :name (n / name :op1 "Crk"~e.0)) :ARG2~e.2 (p / protein :name (n2 / name :op1 "CAS"~e.3)))) # ::id bio.chicago_2015.56033 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that FAST2 constitutively binds the gsc promoter and that Smad2 and Smad4 expressed in mammalian cells cannot interact directly with the element . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 5-1.2.1.3 5-1.2.1.3.r 6-1.2.1 8-1.2.1.2.1.1.1.1 9-1.2.1.2 9-1.2.1.2.1 9-1.2.1.2.1.r 10-1.2 11-1.2.r 12-1.2.2.2.1.1.1.1 13-1.2.2.2.1 14-1.2.2.2.1.2.1.1 15-1.2.2.2.1.3 16-1.2.2.2.1.3.1.r 17-1.2.2.2.1.3.1.1 18-1.2.2.2.1.3.1 19-1.2.2 19-1.2.2.1 19-1.2.2.1.r 20-1.2.2.2 21-1.2.2.2.3 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3,11 (a / and~e.10 :op1 (b / bind-01~e.6 :ARG1 (p2 / protein :name (n / name :op1 "FAST2"~e.4)) :ARG2 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (p3 / promote-01~e.9 :ARG1 (p4 / protein :name (n2 / name :op1 "gsc"~e.8)))) :manner~e.5 (c / constitutive~e.5)) :op2 (p / possible-01~e.19 :polarity~e.19 -~e.19 :ARG1 (i2 / interact-01~e.20 :ARG0 (a2 / and~e.13 :op1 (p5 / protein :name (n3 / name :op1 "Smad2"~e.12)) :op2 (p6 / protein :name (n4 / name :op1 "Smad4"~e.14)) :ARG2-of (e / express-03~e.15 :ARG3~e.16 (c2 / cell~e.18 :mod (m2 / mammal~e.17)))) :ARG1 m :ARG1-of (d / direct-02~e.21))))) # ::id bio.chicago_2015.56052 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This observation suggests that APP may play an important role in neurotransmitter release at nerve terminals or that Mint @-@ 2 may regulate the binding ability of X11L to APP . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1.1.1 5-1.2.1 6-1.2.1.1 8-1.2.1.1.2.1 9-1.2.1.1.2 10-1.2.1.1.2.2.r 11-1.2.1.1.2.2.1 12-1.2.1.1.2.2 13-1.2.1.1.2.2.2.r 14-1.2.1.1.2.2.2.1 15-1.2.1.1.2.2.2 16-1.2 17-1.2.r 18-1.2.2.1.1.1.1 20-1.2.2.1.1.1.1 21-1.2.2 22-1.2.2.1 24-1.2.2.1.2.2 25-1.2.2.1.2 26-1.2.2.1.2.1.r 27-1.2.2.1.2.1.1.1 29-1.2.1.1.1.1.1 (s / suggest-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t2 / this~e.0)) :ARG1~e.3,17 (o2 / or~e.16 :op1 (p / possible-01~e.5 :ARG1 (p2 / play-02~e.6 :ARG0 (p3 / protein :name (n / name :op1 "APP"~e.4,29)) :ARG1 (r / role~e.9 :mod (i / important~e.8) :purpose~e.10 (r2 / release-01~e.12 :ARG1 (n2 / neurotransmitter~e.11) :location~e.13 (t / terminal~e.15 :part-of (n3 / nerve~e.14)))))) :op2 (p4 / possible-01~e.21 :ARG1 (r3 / regulate-01~e.22 :ARG0 (p6 / protein :name (n4 / name :op1 "Mint-2"~e.18,20)) :ARG1 (c / capable-01~e.25 :ARG1~e.26 (p5 / protein :name (n5 / name :op1 "X11L"~e.27)) :ARG2 (b / bind-01~e.24 :ARG1 p5 :ARG2 p3)))))) # ::id bio.chicago_2015.56121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SLBP associated with the pre @-@ mRNA stabilizes the binding of U7 snRNP , suggesting that SLBP bound to the pre @-@ mRNA might interact with one of the U7 snRNP specific proteins ( Dominski et al. 1999 ) . # ::alignments 0-1.1.1.1 1-1.1.2 2-1.1.2.1.r 4-1.1.2.1.1.1 6-1.1.2.1.1.1 7-1 9-1.2 11-1.2.1.1.1 12-1.2.1.1.2 14-1.3 16-1.1.1.1 16-1.3.1.1.1.1.1 17-1.2 17-1.3.1.1.1 17-1.3.1.1.1.2 17-1.3.1.1.1.2.r 20-1.1.2.1.1.1 22-1.1.2.1.1.1 23-1.3.1 24-1.3.1.1 27-1.3.1.1.2.r 29-1.3.1.1.2.1.1 30-1.3.1.1.2.1.1 31-1.3.1.1.2.1 32-1.3.1.1.2 34-1.4.1.1.1.1.1 35-1.4.1.1 36-1.4.1.1.2.1 37-1.4.1.2.1 (s / stabilize-01~e.7 :ARG0 (p7 / protein :name (n / name :op1 "SLBP"~e.0,16) :ARG1-of (a / associate-01~e.1 :ARG2~e.2 (n2 / nucleic-acid :name (n3 / name :op1 "pre-mRNA"~e.4,6,20,22)))) :ARG1 (b / bind-01~e.9,17 :ARG1 (p2 / protein :name (n4 / name :op1 "U7"~e.11 :op2 "snRNP"~e.12))) :ARG0-of (s2 / suggest-01~e.14 :ARG1 (p / possible-01~e.23 :ARG1 (i / interact-01~e.24 :ARG0 (p8 / protein~e.17 :name (n5 / name :op1 "SLBP"~e.16) :ARG1-of~e.17 (b2 / bind-01~e.17 :ARG2 n2)) :ARG1~e.27 (p3 / protein~e.32 :ARG1-of (s3 / specific-02~e.31 :ARG2 p2~e.29,30))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and~e.35 :op1 (p5 / person :name (n6 / name :op1 "Dominski"~e.34)) :op2 (p6 / person :mod (o / other~e.36))) :time (d / date-entity :year 1999~e.37)))) # ::id bio.chicago_2015.56140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have shown that the region downstream of the DNA -@ binding domain in D @-@ Myb binds to dCBP . # ::alignments 0-1.1 2-1 3-1.2.r 5-1.2.1 6-1.2.1.1.2 9-1.2.1.1.1.1.1.1.1 11-1.2 11-1.2.1.1.1.1 12-1.2.1.1.1 13-1.2.1.1.1.2.r 14-1.2.1.1.1.2.1.1 16-1.2.1.1.1.2.1.1 17-1.2.1.1.1.1 18-1.2.2.r 19-1.2.2.1.1 (s / show-01~e.2 :ARG0 (w2 / we~e.0) :ARG1~e.3 (b / bind-01~e.11 :ARG1 (r / region~e.5 :location (r2 / relative-position :op1 (d2 / domain~e.12 :ARG2-of (b2 / bind-01~e.11,17 :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "DNA"~e.9))) :location~e.13 (p2 / protein :name (n5 / name :op1 "D-Myb"~e.14,16))) :direction (d / downstream~e.6))) :ARG2~e.18 (p / protein :name (n6 / name :op1 "dCBP"~e.19)))) # ::id bio.chicago_2015.56172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The inhibition of Sp1 binding by EDTA was not abrogated by the addition of ZnCl2 . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.1.1.1 4-1.3.1 5-1.3.1.2.r 6-1.3.1.2.1.1 8-1.1 8-1.1.r 9-1 10-1.2.r 12-1.2 13-1.2.1.r 14-1.2.1.1.1 (a / abrogate-01~e.9 :polarity~e.8 -~e.8 :ARG0~e.10 (a3 / add-02~e.12 :ARG1~e.13 (s / small-molecule :name (n3 / name :op1 "ZnCl2"~e.14))) :ARG1 (i / inhibit-01~e.1 :ARG1~e.2 (b / bind-01~e.4 :ARG1 (p / protein :name (n / name :op1 "Sp1"~e.3)) :ARG2~e.5 (s2 / small-molecule :name (n2 / name :op1 "EDTA"~e.6))))) # ::id bio.chicago_2015.56218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Binding of Dfd and Dfd @-@ VP16 to the 2 xD site ( see Figure 4 for sequence ) in EMSAs . # ::alignments 1-1.4.1.1 3-1 4-1.1.r 5-1.1.1.1.1 6-1.1 7-1.1.1.1.1 9-1.1.2.1.1 14-1.2.1.2 16-1.2.2.1.2 17-1.2.2.1 17-1.4.1 18-1.2.2.1.1 19-1.2.2.1.2.3.r 20-1.2.2.1.2.3 (b / bind-01~e.3 :ARG1~e.4 (a / and~e.6 :op1 (p / protein :name (n / name :op1 "Dfd"~e.5,7)) :op2 (p2 / protein :name (n2 / name :op1 "Dfd-VP16"~e.9))) :ARG2 (p3 / protein-segment :name (n5 / name :op1 "2xD" :op2 "site"~e.14) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod 4~e.18 :ARG1-of (s2 / see-01~e.16 :mode imperative :ARG0 (y / you) :purpose~e.19 (s3 / sequence~e.20))))) :location (a2 / assay-01 :instrument (t / thing :name (n3 / name :op1 "EMSA"))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.17 :mod "B"~e.1))) # ::id bio.chicago_2015.56261 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Actin binds so tightly to Brg1 that only denaturing conditions will separate them , and it has not been established that Brg is active as an ATPase in the absence of actin . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.3.1 3-1.1.1.3 4-1.1.1.2.r 5-1.1.1.2.1.1 7-1.1.2.1.2 9-1.1.2.1 11-1.1.2 14-1 14-1.1.2.2 17-1.2.1 17-1.2.1.r 19-1.2 20-1.2.2.r 21-1.2.2.1.1.1 23-1.2.2 24-1.2.2.2.r 26-1.2.2.2.1.1 27-1.2.2.3.r 29-1.2.2.3 30-1.2.2.3.1.r 31-1.2.2.3.1 (a / and~e.14 :op1 (c / cause-01 :ARG0 (b / bind-01~e.1 :ARG1 (p / protein :name (n / name :op1 "Actin"~e.0)) :ARG2~e.4 (p2 / protein :name (n2 / name :op1 "Brg1"~e.5)) :ARG1-of (t / tight-05~e.3 :degree (s2 / so~e.2))) :ARG1 (s / separate-01~e.11 :ARG0 (c2 / condition~e.9 :ARG0-of (d / denaturate-00) :mod (o / only~e.7)) :ARG1 (a2 / and~e.14 :op1 p :op2 p2))) :op2 (e / establish-01~e.19 :polarity~e.17 -~e.17 :ARG1~e.20 (a3 / activity-06~e.23 :ARG0 (p3 / protein :name (n3 / name :op1 "Brg"~e.21)) :ARG1~e.24 (e2 / enzyme :name (n4 / name :op1 "ATPase"~e.26)) :condition~e.27 (a4 / absent-01~e.29 :ARG1~e.30 p~e.31)))) # ::id bio.chicago_2015.56319 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transcription factor IIE binds preferentially to RNA polymerase IIA and recruits TFIIH a model for promoter clearance . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.1 3-1.1 4-1.1.3 5-1.1.2.r 6-1.1.2.1.1 7-1.1.2.1.2 8-1.1.2.1.3 9-1 10-1.2 11-1.2.2.1.1 13-1.2.2.2.1 14-1.2.2.2.1.1.r 15-1.2.2.2.1.1.1 15-1.2.2.2.1.1.1.1 15-1.2.2.2.1.1.1.1.r 16-1.2.2.2.1.1 (a / and~e.9 :op1 (b / bind-01~e.3 :ARG1 (f / factor~e.1 :name (n3 / name :op1 "IIE"~e.2) :ARG0-of (t / transcribe-01~e.0)) :ARG2~e.5 (e2 / enzyme :name (n6 / name :op1 "RNA"~e.6 :op2 "polymerase"~e.7 :op3 "IIA"~e.8)) :ARG1-of (p / prefer-01~e.4)) :op2 (r / recruit-01~e.10 :ARG0 f :ARG1 (p2 / protein :name (n5 / name :op1 "TFIIH"~e.11) :ARG1-of (m / mean-01 :ARG2 (m2 / model-01~e.13 :ARG2~e.14 (c / clear-02~e.16 :ARG1 (m3 / molecular-physical-entity~e.15 :ARG0-of~e.15 (p3 / promote-01~e.15)))))))) # ::id bio.chicago_2015.56329 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of both SLBP and U7 snRNP to the pre @-@ mRNA results in formation of a stable complex due to interaction between these two factors and their mutual stabilization on the substrate . # ::alignments 0-1.2.1 3-1.2.1.1.1.1.1 4-1.2.1.1 5-1.2.1.1.2.1.1 6-1.2.1.1.2.1.2 7-1.2.1.2.r 9-1.2.1.2.1.1 11-1.2.1.2.1.1 12-1.2 13-1.2.2.r 14-1.2.2 15-1.2.2.1.r 17-1.2.2.1.1 18-1.2.2.1 19-1 20-1 21-1.1.1 26-1.1 26-1.1.2.1 28-1.1.2.3 29-1.1.2 30-1.1.2.2.r 32-1.1.2.2 (c / cause-01~e.19,20 :ARG0 (a2 / and~e.26 :op1 (i / interact-01~e.21 :ARG0 p2 :ARG1 p) :op2 (s2 / stabilize-01~e.29 :ARG1 (a4 / and~e.26 :op1 p :op2 p2) :location~e.30 (s3 / substrate~e.32) :mod (m2 / mutual~e.28))) :ARG1 (r / result-01~e.12 :ARG1 (b / bind-01~e.0 :ARG1 (a / and~e.4 :op1 (p2 / protein :name (n / name :op1 "SLBP"~e.3)) :op2 (p / protein :name (n2 / name :op1 "U7"~e.5 :op2 "snRNP"~e.6))) :ARG2~e.7 (n3 / nucleic-acid :name (n4 / name :op1 "pre-mRNA"~e.9,11))) :ARG2~e.13 (f / form-01~e.14 :ARG1~e.15 (m / macro-molecular-complex~e.18 :ARG1-of (s / stable-03~e.17))))) # ::id bio.chicago_2015.56330 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Yeast two @-@ hybrid liquid assays , affinity chromatography , and coimmunoprecipitation experiments confirm binding between PS2 and calmyrin . # ::alignments 0-1.1.1.3 1-1.1.1.2.1 3-1.1.1.2 4-1.1.1.1 5-1.1.1 7-1.1.2.1 8-1.1.2 10-1.1 11-1.1.3.1 12-1.1.3 13-1 14-1.2 16-1.2.1.1.1 18-1.2.2.1.1 (c / confirm-01~e.13 :ARG0 (a / and~e.10 :op1 (a2 / assay-01~e.5 :mod (l / liquid~e.4) :mod (h / hybrid~e.3 :quant 2~e.1) :mod (y / yeast~e.0)) :op2 (c2 / chromatography~e.8 :mod (a3 / affinity~e.7)) :op3 (e / experiment-01~e.12 :ARG2 (c3 / coimmunoprecipitate-01~e.11))) :ARG1 (b / bind-01~e.14 :ARG1 (p2 / protein :name (n / name :op1 "PS2"~e.16)) :ARG2 (p / protein :name (n2 / name :op1 "calmyrin"~e.18)))) # ::id bio.chicago_2015.56367 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is not clear whether PS1 binds directly to E @-@ cadherin ; their interaction might be mediated by other components of the cadherin/ catenin system . # ::alignments 2-1.1.1 2-1.1.1.r 3-1.1 4-1.1.2.1 4-1.1.2.1.r 5-1.1.2.2.1.1 6-1.1.2 7-1.1.2.4 8-1.1.2.3.r 9-1.1.2.3.1.1 11-1.2.1.1.1.1.1.1 14-1.2.1.2 15-1.2 17-1.2.1 19-1.2.1.1.2 20-1.2.1.1 24-1.2.1.1.1.2.1.1 25-1.2.1.1.1 (a / and :op1 (c / clear-06~e.3 :polarity~e.2 -~e.2 :ARG1 (b / bind-01~e.6 :mode~e.4 interrogative~e.4 :ARG1 (p3 / protein :name (n / name :op1 "PS1"~e.5)) :ARG2~e.8 (p2 / protein :name (n2 / name :op1 "E-cadherin"~e.9)) :ARG1-of (d / direct-02~e.7))) :op2 (p / possible-01~e.15 :ARG1 (m / mediate-01~e.17 :ARG0 (c2 / component~e.20 :part-of (s / system~e.25 :part (p4 / protein :name (n3 / name :op1 "cadherin"~e.11)) :part (p5 / protein :name (n4 / name :op1 "catenin"~e.24))) :mod (o / other~e.19)) :ARG1 (i / interact-01~e.14 :ARG0 p3 :ARG1 p2)))) # ::id bio.chicago_2015.56383 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While a highly purified preparation of TFII @-@ I bound to an intact Inr element ( Fig . 2B , lane 2 ) , the binding of TFII @-@ I to the mutant Inr probe is nearly abrogated ( about fivefold less as revealed by densitometric measurements ) ( Fig . 2B , lane 5 ) . # ::alignments 0-1 2-1.1.1.2.1 3-1.1.1.2 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1 8-1.1.1.1.1.1.1 9-1.1 10-1.1.2.r 12-1.1.2.1 14-1.1.2.2 16-1.1.3.1.1 18-1.1.3.1.1.1 20-1.1.3.1.2 21-1.1.3.1.2.1 25-1.2.1 26-1.2.1.1.r 26-1.2.3.1.1 27-1.2.1.1 28-1.2.1.1 29-1.2.1.1 30-1.2.1.2.r 32-1.2.1.2 32-1.2.1.2.1 32-1.2.1.2.1.r 34-1.2.1.2.2 36-1.2.2 37-1.2 41-1.2.3.1 42-1.2.3.1.2.r 43-1.2.3.1.2 44-1.2.3.1.2.1.r 45-1.2.3.1.2.1.1 46-1.2.3.1.2.1 49-1.2.4.1.1 51-1.2.4.1.1.1 53-1.2.4.1.2 54-1.2.3.1.1.1 54-1.2.4.1.2.1 (c / contrast-01~e.0 :ARG1 (b / bind-01~e.9 :ARG1 (t / thing~e.4 :ARG1-of~e.4 (p / prepare-01~e.4 :ARG2~e.5 (p2 / protein :name (n / name :op1 "TFII-I"~e.6,8))) :ARG1-of (p3 / purify-01~e.3 :ARG1-of (h / high-02~e.2))) :ARG2~e.10 (m5 / molecular-physical-entity :mod (i / intact~e.12) :mod (e / element~e.14) :ARG0-of (i2 / initiate-01)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.16 :mod "2B"~e.18) :op2 (l / lane~e.20 :mod 2~e.21)))) :ARG2 (a2 / abrogate-01~e.37 :ARG1 (b2 / bind-01~e.25 :ARG1~e.26 p2~e.27,28,29 :ARG2~e.30 (m4 / molecular-physical-entity~e.32 :ARG2-of~e.32 (m / mutate-01~e.32) :ARG1-of (p4 / probe-01~e.34) :ARG1-of i2)) :degree (n3 / near~e.36) :ARG1-of (m2 / mean-01 :ARG2 (l2 / less~e.41 :quant (p5 / product-of~e.26 :op1 5~e.54) :ARG1-of~e.42 (r / reveal-01~e.43 :ARG0~e.44 (m3 / measure-01~e.46 :mod (d2 / densitometric~e.45))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure~e.49 :mod "2B"~e.51) :op2 (l3 / lane~e.53 :mod 5~e.54))))) # ::id bio.chicago_2015.56386 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , a specific binding of GST @-@ HP1 to the linker histone H1 , isolated from either calf thymus ( Figure 4D , lane 5 ) or P19 nuclei ( Figure 4D , lane 6 ) , was observed , indicating that HP1 , but neither HP1 nor HP1 ( Figures 4E and 4F , lane 5 ) , can bind to both H3 and H1 . # ::alignments 1-1.1.2.1 4-1.1.1.3 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 9-1.1.1.1.1.1 13-1.1.1.2.1.1 14-1.1.1.2.1.2 16-1.1.1.4 19-1.1.1.4.1.1.1.1 20-1.1.1.4.1.1.1.2 22-1.1.1.4.1.1.2.1.1 23-1.1.1.4.1.1.2.1.1.1 25-1.1.1.4.1.1.2.1.2 26-1.1.1.4.1.1.2.1.2.1 28-1.1.1.4.1 29-1.1.1.4.1.2.2.1.1 30-1.1.1.4.1.2 32-1.1.1.4.1.2.1.1.1 33-1.1.1.4.1.2.1.1.1 35-1.1.1.4.1.2.1.1.2 36-1.1.1.4.1.2.1.1.2.1 40-1.1 42-1.1.2 44-1.1.2.1.1.1.1.1 46-1 46-1.1.2.1 47-1.1.2.1.2.1.r 48-1.1.2.1.1.1.1.1 49-1.1.2.1.2.1 49-1.1.2.1.2.1.r 49-1.1.2.1.2.2 50-1.1.2.1.1.1.1.1 52-1.1.2.1.2.4.1.1.1 52-1.1.2.1.2.4.1.1.2 53-1.1.2.1.2.4.1.1.1.1 54-1.1.2.1.2.4.1.1 55-1.1.2.1.2.4.1.1.2.1 57-1.1.2.1.2.4.1.2 58-1.1.2.1.2.4.1.2.1 62-1.1.2.1.1 62-1.1.2.1.2 65-1.1.2.1.1.2.1.1.1 66-1.1.2.1.1.2 67-1.1.2.1.1.2.2.1.1 (c / contrast-01~e.46 :ARG2 (o / observe-01~e.40 :ARG1 (b / bind-01~e.5 :ARG1~e.6 (p4 / protein :name (n / name :op1 "GST-HP1"~e.7,9)) :ARG2 (p5 / protein :name (n2 / name :op1 "histone"~e.13 :op2 "H1"~e.14) :ARG0-of (l / link-01)) :ARG1-of (s / specific-02~e.4) :ARG1-of (i / isolate-01~e.16 :ARG2 (o2 / or~e.28 :op1 (d / dna-sequence :name (n3 / name :op1 "calf"~e.19 :op2 "thymus"~e.20) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure~e.22 :mod "4D"~e.23) :op2 (l2 / lane~e.25 :mod 5~e.26)))) :op2 (n4 / nucleus~e.30 :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 f~e.32,33 :op2 (l3 / lane~e.35 :mod 6~e.36))) :part-of (c3 / cell :name (n5 / name :op1 "P19"~e.29)))))) :ARG0-of (i2 / indicate-01~e.42 :ARG1 (c2 / contrast-01~e.1,46 :ARG1 (b2 / bind-01~e.62 :ARG1 (p / protein :name (n6 / name :op1 "HP1"~e.44,48,50)) :ARG2 (a3 / and~e.66 :op1 (p2 / protein :name (n7 / name :op1 "H3"~e.65)) :op2 (p3 / protein :name (n8 / name :op1 "H1"~e.67)))) :ARG2 (b3 / bind-01~e.62 :polarity~e.47,49 -~e.49 :ARG1 (o3 / or~e.49 :op1 p :op2 p) :ARG2 a3 :ARG1-of (d4 / describe-01 :ARG0 (a4 / and :op1 (a5 / and~e.54 :op1 (f2 / figure~e.52 :mod "4E"~e.53) :op2 (f3 / figure~e.52 :mod "4F"~e.55)) :op2 (l4 / lane~e.57 :mod 5~e.58)))))))) # ::id bio.chicago_2015.56388 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our data further suggest that this element might be an NES because its activity is inhibited by the antibiotic LMB , which specifically binds to the NES receptor , CRM1 . # ::alignments 0-1.2.1.1 0-1.2.1.1.r 1-1.2.1 2-1.2.3 3-1.2 4-1.2.2.r 5-1.2.2.1.1 6-1.2.2.1 7-1.2.2 10-1.2.2.1.2.1.1 11-1 12-1.1.2.1 12-1.1.2.1.r 13-1.1.2 15-1.1 16-1.1.1.r 18-1.1.1 19-1.1.1.1.1 22-1.1.1.2.2 23-1.1.1.2 24-1 24-1.1.1.2.1.r 26-1.1.1.2.1.2 27-1.1.1.2.1 29-1.1.1.2.1.1.1 (c / cause-01~e.11,24 :ARG0 (i / inhibit-01~e.15 :ARG0~e.16 (a3 / antibiotic~e.18 :name (n2 / name :op1 "LMB"~e.19) :ARG1-of (b / bind-01~e.23 :ARG2~e.24 (r / receptor~e.27 :name (n3 / name :op1 "CRM1"~e.29) :mod p2~e.26) :ARG1-of (s2 / specific-02~e.22))) :ARG1 (a2 / activity-06~e.13 :ARG0~e.12 e~e.12)) :ARG1 (s / suggest-01~e.3 :ARG0 (d / data~e.1 :poss~e.0 (w / we~e.0)) :ARG1~e.4 (p / possible-01~e.7 :ARG1 (e / element~e.6 :mod (t / this~e.5) :mod (p2 / protein-segment :name (n / name :op1 "NES"~e.10)))) :mod (f / further~e.2))) # ::id bio.chicago_2015.56477 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the presence of the anti @-@ STII @-@ C2B antibody , the IP binding activity of both GST @-@ STII @-@ C2B and purified synaptotagmin II was completely inhibited dose dependently ( Fig. 1 , B and C ) . # ::alignments 2-1.4 3-1.4.1.r 5-1.4.1.1 7-1.4.1.1.1.1.1 9-1.4.1.1.1.1.1 10-1.4.1 14-1.1.2 15-1.1 18-1.1.1.1.1.1 20-1.1.1.1.1.1 22-1.1.1.1.1.1 23-1.1.1 24-1.1.1.2.2 25-1.1.1.2.1.1 26-1.1.1.2.1.2 28-1.2 29-1 30-1.3.1 31-1.3 33-1.5.1.1 33-1.5.1.2 33-1.5.1.3 34-1.5.1.1.1 36-1.5.1.2.1 37-1.5.1 38-1.5.1.3.1 (i4 / inhibit-01~e.29 :ARG1 (a / activity-06~e.15 :ARG0 (a3 / and~e.23 :op1 (p / protein :name (n / name :op1 "GST-STII-C2B"~e.18,20,22)) :op2 (p2 / protein :name (n2 / name :op1 "synaptotagmin"~e.25 :op2 "II"~e.26) :ARG1-of (p3 / purify-01~e.24))) :ARG1 (b / bind-01~e.14) :mod (i3 / immunoprecipitate-01)) :ARG1-of (c / complete-01~e.28) :ARG0-of (d / depend-01~e.31 :ARG1 (d2 / dose~e.30)) :condition (p4 / present-02~e.2 :ARG1~e.3 (a4 / antibody~e.10 :ARG0-of (o2 / oppose-01~e.5 :ARG1 (p5 / protein :name (n3 / name :op1 "STII-C2B"~e.7,9))))) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and~e.37 :op1 (f / figure~e.33 :mod 1~e.34) :op2 (f2 / figure~e.33 :mod "B"~e.36) :op3 (f3 / figure~e.33 :mod "C"~e.38)))) # ::id bio.chicago_2015.56492 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because the proline @-@ rich core of Mena binds to the profilin , WW , and SH3 domains , it will be important to determine which of these interactions are compatible and which are competitive . # ::alignments 0-1 2-1.1.1.2.1.1.1 4-1.1.1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 8-1.1 9-1.1.2.r 11-1.1.2.1.1.1.1 13-1.1.2.2.1.1 15-1.1.2 16-1.1.2.3.1.1 21-1.2.1.r 22-1.2 24-1.2.1 26-1.2.1.1.r 27-1.2.1.1.1.1.1 28-1.2.1.1.1.1 29-1.2.1.1.1.1.r 30-1.2.1.1.1 33-1.2.1.1.1.1.r 34-1.2.1.1.2 (c / cause-01~e.0 :ARG0 (b / bind-01~e.8 :ARG1 (c2 / core~e.5 :part-of~e.6 (p / protein :name (n / name :op1 "Mena"~e.7)) :mod (r / rich~e.4 :mod (a / amino-acid :name (n2 / name :op1 "proline"~e.2)))) :ARG2~e.9 (a2 / and~e.15 :op1 (p2 / protein-segment :part-of (p5 / protein :name (n3 / name :op1 "profilin"~e.11))) :op2 (p3 / protein-segment :name (n4 / name :op1 "WW"~e.13)) :op2 (p4 / protein-segment :name (n5 / name :op1 "SH3"~e.16)))) :ARG1 (i / important~e.22 :domain~e.21 (d / determine-01~e.24 :ARG1~e.26 (a3 / and :op1 (c3 / compatible~e.30 :domain~e.29,33 (i2 / interact-01~e.28 :mod (t / this~e.27))) :op2 (c4 / compete-01~e.34 :ARG0 i2))))) # ::id bio.chicago_2015.56510 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The checkpoint @-@ resistant Cdc20 mutants greatly diminished the binding of Mad2 and Mad3 to Cdc20 ( Fig . 3C ) but had no effect on the overall level of Mad1 , Mad2 , or Mad3 in the cell ( 21 ) . # ::alignments 1-1.1.1.3.1 3-1.1.1.3 4-1.1.1.1.1 5-1.1.1 5-1.1.1.2 5-1.1.1.2.r 6-1.1.3 7-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1 12-1.1.2.1 13-1.1.2.1.2.1.1 15-1.1.1.1.1 15-1.1.2.2.1.1 17-1.1.4.1 19-1.1.4.1.1 21-1 23-1.2.1 23-1.2.1.r 24-1.2 25-1.2.3.r 27-1.2.3.1.1 28-1.2.3.1 28-1.2.3.2 28-1.2.3.3 29-1.2.3.1.3.r 30-1.2.3.1.3.1.1 32-1.1.2.1.1.1.1 34-1.2.3 35-1.1.2.1.2.1.1 36-1.2.3.1.2.r 38-1.2.3.1.2 40-1.2.4.1.1.1 (c / contrast-01~e.21 :ARG1 (d / diminish-01~e.7 :ARG0 (p6 / protein~e.5 :name (n / name :op1 "Cdc20"~e.4,15) :ARG2-of~e.5 (m / mutate-01~e.5) :ARG0-of (r / resist-01~e.3 :ARG1 (c2 / checkpoint~e.1))) :ARG1 (b / bind-01~e.9 :ARG1~e.10 (a / and~e.12 :op1 (p / protein :name (n2 / name :op1 "Mad2"~e.11,32)) :op2 (p2 / protein :name (n3 / name :op1 "Mad3"~e.13,35))) :ARG2 (p5 / protein :name (n4 / name :op1 "Cdc20"~e.15))) :degree (g2 / great~e.6) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod "3C"~e.19))) :ARG2 (a2 / affect-01~e.24 :polarity~e.23 -~e.23 :ARG0 p6 :ARG1~e.25 (o2 / or~e.34 :op1 (l2 / level~e.28 :mod (o / overall~e.27) :location~e.36 (c3 / cell~e.38) :quant-of~e.29 (p3 / protein :name (n5 / name :op1 "Mad1"~e.30))) :op2 (l3 / level~e.28 :mod o :location c3 :quant-of p) :op3 (l4 / level~e.28 :mod o :location c3 :quant-of p2)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 21~e.40))))) # ::id bio.chicago_2015.56529 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Corto binds to ESC and E( Z ) , two members of the PcG initiation complex We first performed GST pull @-@ down assays to check the interactions between Corto and ESC and between Corto and E( Z ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1.1 4-1.1.2 13-1.1.2.3.1.1.1.1.1 14-1.1.2.3.1.1 15-1.1.2.3.1 16-1.2.1 17-1.2.4 18-1.2 19-1.2.2.1.1.1.1 20-1.2.2.1 22-1.2.2.1 23-1.2.2 25-1.2.3 27-1.2.3.2.1 27-1.2.3.2.2 29-1.1.1.1.1 31-1.1.2.1.1.1 34-1.1.1.1.1 35-1.2.3.2 (m / multi-sentence :snt1 (b / bind-01~e.1 :ARG1 (p / protein :name (n / name :op1 "Corto"~e.0,29,34)) :ARG2~e.2 (a / and~e.4 :op1 (p2 / protein :name (n2 / name :op1 "ESC"~e.3,31)) :op2 (p3 / protein :name (n3 / name :op1 "E(Z)")) :ARG1-of (i / include-91 :ARG2 (m2 / macro-molecular-complex~e.15 :ARG0-of (i2 / initiate-01~e.14 :ARG1 (p7 / protein :name (n4 / name :op1 "PcG"~e.13))))))) :snt2 (p4 / perform-02~e.18 :ARG0 (w / we~e.16) :ARG1 (a2 / assay-01~e.23 :ARG1 (p5 / pull-down-08~e.20,22 :ARG1 (e / enzyme :name (n5 / name :op1 "GST"~e.19)))) :purpose (c / check-01~e.25 :ARG0 w :ARG1 (a4 / and~e.35 :op1 (i3 / interact-01~e.27 :ARG0 p :ARG1 p2) :op2 (i4 / interact-01~e.27 :ARG0 p :ARG1 p3))) :time (f / first~e.17))) # ::id bio.chicago_2015.56563 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , it has been shown that mutations in the N @-@ terminal region of actin , which yielded a change of charge , affect myosin S1 binding to actin and thereby reduce in vitro motility ( Aspenstrom and Karlsson , 1991 ; Aspenstrom et al. , 1992 ; Sutoh et al. , 1991 ; Miller et al. , 1996 ) . # ::alignments 0-1 5-1.1 6-1.1.1.r 7-1.1.1.3.1.1 8-1.1.1.3.1.2.1 10-1.1.1.1.1.1.1 12-1.1.1.1.1.1.1 15-1.1.1.1.1.2.1.1 18-1.1.1.1.2 20-1.1.1.1.2.1 21-1.1.1.1.2.1.1.r 22-1.1.1.1.2.1.1 24-1.1.1 25-1.1.1.2.1.2.1.1 26-1.1.1.2.1.1.1 27-1.1.1.2 28-1.1.1.2.2.r 28-1.1.1.3 29-1.1.1.2.2 32-1.1.1.3.1 33-1.1.1.3.1.2.1 34-1.1.1.3.1.2.1 35-1.1.1.3.1.2 37-1.1.2.1.1.1.1.1.1 38-1.1.2.1.1.1 39-1.1.2.1.1.1.2.1.1 41-1.1.2.1.1.2.1 43-1.1.2.1.1.1.1.1.1 44-1.1.2.1 44-1.1.2.1.1.1 44-1.1.2.1.2.1 44-1.1.2.1.3.1 44-1.1.2.1.4.1 45-1.1.2.1.2.1.2.1 45-1.1.2.1.3.1.2.1 45-1.1.2.1.4.1.2.1 47-1.1.2.1.2.2.1 49-1.1.2.1.3.1.1.1.1 50-1.1.2.1 50-1.1.2.1.1.1 50-1.1.2.1.2.1 50-1.1.2.1.3.1 50-1.1.2.1.4.1 51-1.1.2.1.2.1.2.1 51-1.1.2.1.3.1.2.1 51-1.1.2.1.4.1.2.1 53-1.1.2.1.1.2.1 55-1.1.2.1.4.1.1.1.1 56-1.1.2.1.4.1 57-1.1.2.1.4.1.2.1 59-1.1.2.1.4.2.1 (a / and~e.0 :op2 (s / show-01~e.5 :ARG1~e.6 (a2 / affect-01~e.24 :ARG0 (m / mutate-01 :ARG1 (p / protein-segment :name (n / name :op1 "N-terminus"~e.10,12) :part-of (p2 / protein :name (n2 / name :op1 "actin"~e.15))) :ARG0-of (y / yield-01~e.18 :ARG1 (c / change-01~e.20 :ARG1~e.21 (c2 / charge-03~e.22)))) :ARG1 (b / bind-01~e.27 :ARG1 (p3 / protein-segment :name (n3 / name :op1 "S1"~e.26) :part-of (p4 / protein :name (n4 / name :op1 "myosin"~e.25))) :ARG2~e.28 p2~e.29) :ARG0-of (c3 / cause-01~e.28 :ARG1 (r / reduce-01~e.32 :ARG0 m~e.7 :ARG1 (m2 / motility~e.35 :mod (i / in-vitro~e.8,33,34))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.44,50 :op1 (p6 / publication-91 :ARG0 (a4 / and~e.38,44,50 :op1 (p7 / person :name (n6 / name :op1 "Aspenstrom"~e.37,43)) :op2 (p8 / person :name (n7 / name :op1 "Karlsson"~e.39))) :time (d2 / date-entity :year 1991~e.41,53)) :op2 (p9 / publication-91 :ARG0 (a5 / and~e.44,50 :op1 p7 :op2 (p11 / person :mod (o / other~e.45,51))) :time (d3 / date-entity :year 1992~e.47)) :op3 (p12 / publication-91 :ARG0 (a6 / and~e.44,50 :op1 (p13 / person :name (n9 / name :op1 "Sutoh"~e.49)) :op2 (p14 / person :mod (o2 / other~e.45,51))) :time d2) :op4 (p15 / publication-91 :ARG0 (a7 / and~e.44,50,56 :op1 (p16 / person :name (n10 / name :op1 "Miller"~e.55)) :op2 (p17 / person :mod (o3 / other~e.45,51,57))) :time (d5 / date-entity :year 1996~e.59)))))) # ::id bio.chicago_2015.56580 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dimerization of Rabaptin @-@ 5 could also form a divalent Rab5 @-@ binding site , since single Rabaptin @-@ 5 chains can bind Rab5 ( Horiuchi et al. , 1997 ) . # ::alignments 0-1.2.1.1 1-1.2.1.1.1.r 2-1.2.1.1.1 3-1.2.1.1.1 4-1.2.1.1.1 5-1.2 6-1.2.2 7-1.2.1 9-1.2.1.2.2 10-1.2.1.2.1.1 12-1.2.1.2.1 13-1.2.1.2 15-1 16-1.1.1.1.2 17-1.1.1.1.1.1.1 19-1.1.1.1.1.1.1 20-1.1.1.1 21-1.1 22-1.1.1 23-1.1.1.2.1.1 25-1.3.1.1.1.1.1 26-1.3.1.1 27-1.3.1.1.2.1 29-1.3.1.2.1 (c / cause-01~e.15 :ARG0 (p / possible-01~e.21 :ARG1 (b / bind-01~e.22 :ARG1 (c2 / chain-01~e.20 :ARG0 (p2 / protein :name (n / name :op1 "Rabaptin-5"~e.17,19)) :ARG1-of (s / single-02~e.16)) :ARG2 (p3 / protein :name (n2 / name :op1 "Rab5"~e.23)))) :ARG1 (p4 / possible-01~e.5 :ARG1 (f / form-01~e.7 :ARG0 (d / dimerize-01~e.0 :ARG1~e.1 p2~e.2,3,4) :ARG1 (s2 / site~e.13 :ARG1-of (b2 / bind-01~e.12 :ARG2 p3~e.10) :mod (d2 / divalent~e.9))) :mod (a / also~e.6)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and~e.26 :op1 (p6 / person :name (n3 / name :op1 "Horiuchi"~e.25)) :op2 (p7 / person :mod (o / other~e.27))) :time (d4 / date-entity :year 1997~e.29)))) # ::id bio.chicago_2015.56582 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Originally identified by virtue of its physical binding to Src , the mDab1 protein also binds other nonreceptor tyrosine kinases such as Fyn and Abl ( Howell et al. , 1997a ) . # ::alignments 0-1.4.2 1-1.4 5-1.4.1.1.1 5-1.4.1.1.1.r 6-1.4.1.1.3 7-1.4.1.1 9-1.4.1.1.2.1.1 12-1.1.1.1 13-1.1 13-1.4.1.1.2 14-1.3 15-1 16-1.5.1.1.2.1 17-1.2.1.1 18-1.2.1.2 19-1.2.1.3 19-1.2.2.1 19-1.2.2.2 20-1.2.2.r 21-1.2.2.r 22-1.2.2.1.1.1 23-1.2.2 24-1.2.2.2.1.1 26-1.5.1.1.1.1.1 27-1.5.1.1 28-1.5.1.1.2.1 (b / bind-01~e.15 :ARG1 (p / protein~e.13 :name (n / name :op1 "mDab1"~e.12)) :ARG2 (e / enzyme :name (n2 / name :op1 "nonreceptor"~e.17 :op2 "tyrosine"~e.18 :op3 "kinase"~e.19) :example~e.20,21 (a2 / and~e.23 :op1 (k2 / kinase~e.19 :name (n3 / name :op1 "Fyn"~e.22)) :op2 (k / kinase~e.19 :name (n4 / name :op1 "Abl"~e.24)))) :mod (a / also~e.14) :ARG1-of (i / identify-01~e.1 :ARG1-of (c / cause-01 :ARG0 (b2 / bind-01~e.7 :ARG1~e.5 p~e.5 :ARG2 (p2 / protein~e.13 :name (n5 / name :op1 "Src"~e.9)) :mod (p3 / physical~e.6))) :mod (o / original~e.0)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.27 :op1 (p5 / person :name (n6 / name :op1 "Howell"~e.26)) :op2 (p6 / person :mod (o2 / other~e.16,28))) :time (d2 / date-entity :year 1997 :li "a")))) # ::id bio.chicago_2015.56594 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Evidently , the peptide only slightly affected binding of c @-@ Cbl to EGFR , but it almost completely abolished the interaction with the shorter viral form of Cbl . # ::alignments 0-1.3 3-1.1.1 4-1.1.3.1 5-1.1.3 6-1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.1 11-1.1.2.1.1.1 12-1.1.2.2.r 13-1.1.2.2.1.1 15-1 16-1.2.1 17-1.2.3.1 18-1.2.3 19-1.2 21-1.2.2 22-1.2.2.1.r 24-1.2.2.1.2 24-1.2.2.1.2.1 24-1.2.2.1.2.1.r 25-1.2.2.1.1 26-1.2.2.1 27-1.2.2.1.3.r 28-1.2.2.1.3.1.1 (c / contrast-01~e.15 :ARG1 (a / affect-01~e.6 :ARG0 (p / peptide~e.3) :ARG1 (b / bind-01~e.7 :ARG1~e.8 (p2 / protein :name (n / name :op1 "c-Cbl"~e.9,11)) :ARG2~e.12 (e / enzyme :name (n2 / name :op1 "EGFR"~e.13))) :degree (s / slight~e.5 :mod (o / only~e.4))) :ARG2 (a2 / abolish-01~e.19 :ARG0 p~e.16 :ARG1 (i / interact-01~e.21 :ARG1~e.22 (f / form~e.26 :mod (v / viral~e.25) :ARG1-of (s2 / short-07~e.24 :degree~e.24 (m / more~e.24)) :mod~e.27 (p3 / protein :name (n3 / name :op1 "Cbl"~e.28)))) :ARG1-of (c2 / complete-02~e.18 :degree (a3 / almost~e.17))) :ARG1-of (e2 / evidence-01~e.0)) # ::id bio.chicago_2015.56667 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data prompted us to test for a disruption of TFIID binding to various DCE mutations ( Fig . 6 ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2 5-1.3 6-1.3.2.r 8-1.3.2 9-1.3.2.1.r 10-1.3.2.1.1.1.1 11-1.3.2.1 12-1.3.2.1.2.r 13-1.3.2.1.2.2 14-1.3.2.1.2.1.1.1 15-1.3.2.1.2 17-1.4.1 19-1.4.1.1 (p / prompt-02~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1 (w / we~e.3) :ARG2 (t2 / test-01~e.5 :ARG0 w :ARG2~e.6 (d2 / disrupt-01~e.8 :ARG1~e.9 (b / bind-01~e.11 :ARG1 (p2 / protein :name (n / name :op1 "TFIID"~e.10)) :ARG2~e.12 (m / mutate-01~e.15 :ARG2 (p3 / protein :name (n2 / name :op1 "DCE"~e.14)) :mod (v / various~e.13))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.17 :mod 6~e.19))) # ::id bio.chicago_2015.56680 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hence , it can be predicted that BAG4 binds Hsc70 in a manner analogous to BAG1 ( 3 , 15 ) . # ::alignments 0-1 3-1.1 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1.1 8-1.1.1.1 8-1.1.1.1.3.1 9-1.1.1.1.2.1.1 14-1.1.1.1.3.1.1.r 15-1.1.1.1.3.1.1.1.1 17-1.2.1.1.1.1 19-1.2.1.1.1.2 (c2 / cause-01~e.0 :ARG1 (p4 / possible-01~e.3 :ARG1 (p / predict-01~e.5 :ARG1~e.6 (b / bind-01~e.8 :ARG1 (p5 / protein :name (n / name :op1 "BAG4"~e.7)) :ARG2 (p2 / protein :name (n2 / name :op1 "Hsc70"~e.9)) :ARG1-of (r / resemble-01 :ARG2 (b2 / bind-01~e.8 :ARG1~e.14 (p7 / protein :name (n3 / name :op1 "BAG1"~e.15))))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 3~e.17 :op2 15~e.19))))) # ::id bio.chicago_2015.56736 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blotting confirmed that the Cdc11 septin binds to the Gin4 affinity column ( Fig . 2 B ) . # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1 3-1.2.r 5-1.2.1.1.1 6-1.2.1 7-1.2 8-1.2.2.r 10-1.2.2.2.1.1 11-1.2.2.1 12-1.2.2 14-1.3.1 (c / confirm-01~e.2 :ARG0 (t / thing :name (n / name :op1 "Western"~e.0 :op2 "blotting"~e.1)) :ARG1~e.3 (b / bind-01~e.7 :ARG1 (s / septin~e.6 :name (n2 / name :op1 "Cdc11"~e.5)) :ARG2~e.8 (c2 / column~e.12 :mod (a2 / affinity~e.11) :mod (p / protein :name (n3 / name :op1 "Gin4"~e.10)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "2B"))) # ::id bio.chicago_2015.56738 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HMG @-@ I( Y ) and NF @-@ kappaB subunit p50 bind to the iNOS promoter @/@ enhancer and form a ternary DNA @-@ protein complex . # ::alignments 0-1.1.1.1.2.1.1 5-1.1.1 6-1.1.1.2.2.1.1 8-1.1.1.2.2.1.1 10-1.1.1.1.1.1 10-1.1.1.2.1.1 11-1.1 12-1.1.2.r 14-1.1.2.1.1.1.1.1 16-1.1.2 18-1 19-1.2 21-1.2.2.3 22-1.2.2.2.2.1 24-1.2.2.1 25-1.2.2 (a / and~e.18 :op1 (b / bind-01~e.11 :ARG1 (a2 / and~e.5 :op1 (p6 / protein :name (n / name :op1 "p50"~e.10) :part-of (m2 / macro-molecular-complex :name (n2 / name :op1 "HMG-I(Y)"~e.0))) :op2 (p7 / protein :name (n3 / name :op1 "p50"~e.10) :part-of (m5 / macro-molecular-complex :name (n4 / name :op1 "NF-kappaB"~e.6,8)))) :ARG2~e.12 (s3 / slash~e.16 :op1 (m3 / molecular-physical-entity :ARG0-of (p4 / promote-02 :ARG1 (e2 / enzyme :name (n5 / name :op1 "iNOS"~e.14)))) :op2 (m4 / molecular-physical-entity :ARG0-of (e / enhance-01 :ARG1 e2)))) :op2 (f / form-01~e.19 :ARG0 a2 :ARG1 (m / macro-molecular-complex~e.25 :part (p5 / protein~e.24) :part (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA"~e.22)) :mod (t / ternary~e.21)))) # ::id bio.chicago_2015.56780 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the fact that myo @-@ D and P/CAF bind to distinct CBP/ p300 sites , both interactions are disrupted by E1A . # ::alignments 0-1 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1 9-1.2 11-1.2.2.1.2 13-1.2.2.2.1.1.1 14-1.2.2.1 14-1.2.2.2 19-1.1 20-1.1.1.r 21-1.1.1.1.1 (h / have-concession-91~e.0 :ARG1 (d2 / disrupt-01~e.19 :ARG0~e.20 (p5 / protein :name (n5 / name :op1 "E1A"~e.21)) :ARG1 b) :ARG2 (b / bind-01~e.9 :ARG1 (a / and~e.7 :op1 (p / protein :name (n / name :op1 "myo-D"~e.4,6)) :op2 (e / enzyme :name (n2 / name :op1 "P/CAF"~e.8))) :ARG2 (a2 / and :op1 (s / site~e.14 :mod (p3 / protein :name (n3 / name :op1 "CBP")) :mod (d / distinct~e.11)) :op2 (s2 / site~e.14 :mod (p4 / protein :name (n4 / name :op1 "p300"~e.13)) :mod d)))) # ::id bio.chicago_2015.56853 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In mammals , however , there has been no evidence that eIF4G binds PABP . # ::alignments 1-1.1.3 3-1 6-1 8-1.1.1 8-1.1.1.r 9-1.1 10-1.1.2.r 11-1.1.2.1.1.1 12-1.1.2 13-1.1.2.2.1.1 (h / have-concession-91~e.3,6 :ARG1 (e / evidence-01~e.9 :polarity~e.8 -~e.8 :ARG1~e.10 (b / bind-01~e.12 :ARG1 (p / protein :name (n / name :op1 "eIF4G"~e.11)) :ARG2 (p2 / protein :name (n2 / name :op1 "PABP"~e.13))) :location (m / mammal~e.1))) # ::id bio.chicago_2015.56858 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A mutation within the 6 @-@ aa motif that mediates the binding between CtBP and HPC2 results in a significant but only small decrease in the repressing abilities of HPC2 ( Fig . 9 ) . # ::alignments 1-1.1 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1.1.1.2 9-1.1.1 9-1.1.1.2 9-1.1.1.2.r 11-1.1.1.2.1 13-1.1.1.2.1.1.1.1 15-1.1.1.2.1.2.1.1 16-1 17-1.2.r 19-1.2.2 20-1.2.2.1 21-1.2.2.1.1.1 22-1.2.2.1.1 23-1.2 24-1.2.1.r 26-1.2.1.2 27-1.2.1 28-1.2.1.1.r 29-1.2.1.1 31-1.3.1 33-1.3.1.1 (r / result-01~e.16 :ARG1 (m / mutate-01~e.1 :ARG1 (d3 / dna-sequence~e.9 :name (n / name :op1 "6-aa"~e.4,6 :op2 "motif"~e.7) :ARG0-of~e.9 (m2 / mediate-01~e.9 :ARG1 (b / bind-01~e.11 :ARG1 (p / protein :name (n2 / name :op1 "CtBP"~e.13)) :ARG2 (p2 / protein :name (n3 / name :op1 "HPC2"~e.15)))))) :ARG2~e.17 (d / decrease-01~e.23 :ARG1~e.24 (c2 / capable-01~e.27 :ARG1~e.28 p2~e.29 :ARG2 (r2 / repress-01~e.26 :ARG0 p2)) :ARG1-of (s / significant-02~e.19 :ARG1-of (c / contrast-01~e.20 :ARG2 (s2 / small~e.22 :mod (o / only~e.21))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod 9~e.33))) # ::id bio.chicago_2015.56861 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Each binding site in eIF4G can bind either eIF4AI or eIF4AII . # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1.1.1 3-1.1.1.3.r 4-1.1.1.3.1.1 5-1 6-1.1 8-1.1.2.1.1.1 9-1.1.2 10-1.1.2.2.1.1 (p / possible-01~e.5 :ARG1 (b / bind-01~e.6 :ARG1 (s / site~e.2 :mod (e / each~e.0) :ARG2-of (b2 / bind-01~e.1) :location~e.3 (p2 / protein :name (n / name :op1 "eIF4G"~e.4))) :ARG2 (o / or~e.9 :op1 (p3 / protein :name (n2 / name :op1 "eIF4AI"~e.8)) :op2 (p4 / protein :name (n3 / name :op1 "eIF4AII"~e.10))))) # ::id bio.chicago_2015.56879 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ura4+ at 30 and 32 degrees C , where the effects of the mts3 @-@ 1 mutation will be greater than at 25 degrees C , is due to the lack of polyubiquitin binding by Pus1N5 to bind conjugates . # ::alignments 0-1.2.1.1 2-1.2.3.1 4-1.2.4.1 5-1.2.2.1.2.1.r 10-1.2.2.1 11-1.2.2.1.1.r 13-1.2.2.1.1.1.1.1 15-1.2.2.1.1.1.1.1 16-1.2.2.1.1 19-1.2.2.1.2 19-1.2.2.1.2.1 19-1.2.2.1.2.1.r 20-1.2.2.1.2.2.r 22-1.2.2.1.2.2.1 23-1.2.2.1.2.1.r 27-1 27-1.2 27-1.2.2 27-1.2.2.r 27-1.2.r 28-1 30-1.1 31-1.1.1.r 32-1.1.1.2.1.1 33-1.1.1 33-1.1.1.3 33-1.1.1.3.r 35-1.1.1.1.1.1 37-1.1.1 37-1.1.1.3 37-1.1.1.3.r 38-1.1.1.3.1.1 (c / cause-01~e.27,28 :ARG0 (l / lack-01~e.30 :ARG1~e.31 (b / bind-01~e.33,37 :ARG1 (p2 / protein :name (n3 / name :op1 "Pus1N5"~e.35)) :ARG2 (p / protein :name (n2 / name :op1 "polyubiquitin"~e.32)) :ARG1-of~e.33,37 (b2 / bind-01~e.33,37 :ARG2 (m / molecular-physical-entity :ARG3-of (c3 / conjugate-02~e.38))))) :ARG1~e.27 (g / gene~e.27 :name (n / name :op1 "ura4+"~e.0) :ARG0-of~e.27 (c4 / cause-01~e.27 :ARG1 (a2 / affect-01~e.10 :ARG0~e.11 (m2 / mutate-01~e.16 :ARG1 (p3 / protein :name (n4 / name :op1 "mts3-1"~e.13,15))) :mod (g3 / great~e.19 :degree~e.5,19,23 (m3 / more~e.19) :compared-to~e.20 (t3 / temperature-quantity :quant 25~e.22 :scale (c5 / celsius))))) :mod (t / temperature-quantity :quant 30~e.2 :scale (c2 / celsius)) :mod (t2 / temperature-quantity :quant 32~e.4 :scale c2))) # ::id bio.chicago_2015.56963 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also find that three lysine @-@ rich boxes in the N @-@ terminal segment of eIF2 beta mediate the binding of eIF2 to both eIF5 and eIF2B . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.r 4-1.2.1.1 5-1.2.1.2.1.1.1 7-1.2.1.2 8-1.2.1 9-1.2.1.3.r 11-1.2.1.3.1.1 13-1.2.1.3.1.1 14-1.2.1.3 16-1.2.2.1.1.1 18-1.2 20-1.2.2 22-1.2.2.1.1.1 25-1.2.2.2.1.1.1 26-1.2.2.2 27-1.2.2.2.2.1.1 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (m / mediate-01~e.18 :ARG0 (b / box~e.8 :quant 3~e.4 :mod (r / rich~e.7 :mod (a / amino-acid :name (n / name :op1 "lysine"~e.5))) :location~e.9 (p / protein-segment~e.14 :name (n2 / name :op1 "N-terminus"~e.11,13) :part-of (p2 / protein :name (n3 / name :op1 "eIF2beta")))) :ARG1 (b2 / bind-01~e.20 :ARG1 (p3 / protein :name (n4 / name :op1 "eIF2"~e.16,22)) :ARG2 (a3 / and~e.26 :op1 (p4 / protein :name (n5 / name :op1 "eIF5"~e.25)) :op2 (p5 / protein :name (n6 / name :op1 "eIF2B"~e.27))))) :mod (a2 / also~e.1)) # ::id bio.chicago_2015.56965 ::amr-annotator SDL-AMR-09 ::preferred # ::tok DAG binding to UNC @-@ 13 is required to stimulate acetylcholine release . # ::alignments 0-1.2.1.1.1 1-1.2 2-1.2.2.r 3-1.2.2.1.1 5-1.2.2.1.1 7-1 9-1.1 10-1.1.1.1.1.1 11-1.1.1 (r / require-01~e.7 :ARG0 (s / stimulate-01~e.9 :ARG1 (r2 / release-01~e.11 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "acetylcholine"~e.10)))) :ARG1 (b / bind-01~e.1 :ARG1 (s2 / small-molecule :name (n / name :op1 "DAG"~e.0)) :ARG2~e.2 (p2 / protein :name (n2 / name :op1 "UNC-13"~e.3,5)))) # ::id bio.chicago_2015.56989 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , minimal binding of Arp1 to the DII and GST columns was observed . # ::alignments 1-1 3-1.1.1.3 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 7-1.1.1.2.r 9-1.1.1.2.1.1.1.1 10-1.1.1.2 11-1.1.1.2.2.1.1.1 12-1.1.1.2.1 12-1.1.1.2.2 14-1.1 (c / contrast-01~e.1 :ARG2 (o / observe-01~e.14 :ARG1 (b / bind-01~e.4 :ARG1~e.5 (p / protein :name (n / name :op1 "Arp1"~e.6)) :ARG2~e.7 (a / and~e.10 :op1 (c2 / column~e.12 :mod (p2 / protein :name (n2 / name :op1 "DII"~e.9))) :op2 (c3 / column~e.12 :mod (e / enzyme :name (n3 / name :op1 "GST"~e.11)))) :ARG1-of (m / minimal-02~e.3)))) # ::id bio.chicago_2015.56998 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ena is phosphorylated on multiple tyrosine residues , most of which are found near proline @-@ rich sequences that mediate Ena 's binding to the Abl and Src SH3 domains . # ::alignments 0-1.1.1.2.1.1 2-1 4-1.1.2 5-1.1.1.1.1 6-1.1 6-1.1.3.1 8-1.1.3.2 12-1.1.3.1.1 13-1.1.3.1.1.1 14-1.1.3.1.1.1.1.1.1.1.1 16-1.1.3.1.1.1.1.1 17-1.1.3.1.1.1.1 19-1.1.3.1.1.1.1.2 20-1.1.3.1.1.1.1.2.1.1 21-1.1.3.1.1.1.1.2.1.1.r 22-1.1.3.1.1.1.1.2.1 23-1.1.3.1.1.1.1.2.1.2.r 25-1.1.3.1.1.1.1.2.1.2.1.2.1.1 26-1.1.3.1.1.1.1.2.1.2 27-1.1.3.1.1.1.1.2.1.2.2.2.1.1 28-1.1.3.1.1.1.1.2.1.2.1.1.1 28-1.1.3.1.1.1.1.2.1.2.2.1.1 (p / phosphorylate-01~e.2 :ARG1 (r / residue~e.6 :mod (a / amino-acid :name (n / name :op1 "tyrosine"~e.5) :part-of (p2 / protein :name (n2 / name :op1 "Ena"~e.0))) :quant (m / multiple~e.4) :ARG2-of (i / include-91 :ARG1 (r2 / residue~e.6 :ARG1-of (f / find-01~e.12 :ARG1-of (n3 / near-02~e.13 :ARG2 (s / sequence~e.17 :mod (r3 / rich~e.16 :mod (a3 / amino-acid :name (n4 / name :op1 "proline"~e.14))) :ARG0-of (m3 / mediate-01~e.19 :ARG1 (b / bind-01~e.22 :ARG1~e.21 p2~e.20 :ARG2~e.23 (a2 / and~e.26 :op1 (p4 / protein-segment :name (n5 / name :op1 "SH3"~e.28) :part-of (p6 / protein :name (n7 / name :op1 "Abl"~e.25))) :op1 (p7 / protein-segment :name (n8 / name :op1 "SH3"~e.28) :part-of (p5 / protein :name (n6 / name :op1 "Src"~e.27)))))))))) :mod (m2 / most~e.8)))) # ::id bio.chicago_2015.57043 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Complex Formation of GSK @-@ 3 beta , AKAP220 , PKA , and PP1-- It has been shown that AKAP220 binds to PP1 in addition to PKA ( 29 ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 8-1.1.1.2.1.1 10-1.1.1.3.1.1 17-1.2 18-1.2.1.r 19-1.2.1.1.1.1 20-1.2.1 22-1.1.1.4.1.1 22-1.2.1.2.1.1.1 23-1.2.1.2 24-1.2.1.2 25-1.2.1.2.r 26-1.2.1.2.2.1.1 28-1.2.2.1.1.1 (m / multi-sentence :snt1 (f / form-01~e.1 :ARG1 (m2 / macro-molecular-complex~e.0 :part~e.2 (e / enzyme :name (n / name :op1 "GSK-3beta"~e.3)) :part (p / protein :name (n2 / name :op1 "AKAP220"~e.8)) :part (e2 / enzyme :name (n3 / name :op1 "PKA"~e.10)) :part (p2 / protein :name (n4 / name :op1 "PP1"~e.22)))) :snt2 (s / show-01~e.17 :ARG1~e.18 (b / bind-01~e.20 :ARG1 (p4 / protein :name (n5 / name :op1 "AKAP220"~e.19)) :ARG2~e.25 (a / and~e.23,24 :op1 (p5 / protein :name (n6 / name :op1 "PP1"~e.22)) :op2 (e3 / enzyme :name (n7 / name :op1 "PKA"~e.26)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 29~e.28))))) # ::id bio.chicago_2015.57105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The GTP @-@ bound form of ARF1 recruits protein coats , including the clathrin @-@ associated adaptor proteins AP @-@ 1 and AP @-@ 3 and the nonclathrin coatomer , to membranes and initiates budding of the membrane vesicles ( Lenhard et al. , 1992 ; Donaldson and Klausner , 1994 ; Boman and Kahn , 1995 ; Dittie et al. , 1996 ; Ooi et al. , 1998 ; Springer et al. , 1999 ) . # ::alignments 1-1.1.1.2.1.1.1 3-1.1.1 3-1.1.1.2 3-1.1.1.2.r 6-1.1.1.1.1 7-1.1 8-1.1.2.1 9-1.1.2 11-1.1.2.2 13-1.1.2.2.1.1.3.1.1.1 15-1.1.2.2.1.1.3 16-1.1.2.2.1.1.2 17-1.1.2.2.1.1 17-1.1.2.2.1.1.3.1 17-1.1.2.2.1.2 17-1.1.2.2.1.3 18-1.1.2.2.1.1.1.1 20-1.1.2.2.1.1.1.1 21-1.1.2.2.1 22-1.1.2.2.1.1.1.1 22-1.1.2.2.1.2.1.1 24-1.1.2.2.1.2.1.1 25-1.1.2.2.1 27-1.1.2.2.1.3.1.1 28-1.1.2.2.1.3.1.2 30-1.1.3.r 31-1.1.3 32-1 32-1.3.1 32-1.3.1.1.1 33-1.2 34-1.2.2 35-1.2.2.1.r 37-1.2.2.1.1 38-1.2.2.1 40-1.3.1.1.1.1.1.1 41-1.3.1.1.1 42-1.3.1.1.1.2.1 44-1.3.1.1.2.1 46-1.3.1.2.1.1.1.1 47-1.3.1.2.1 48-1.3.1.2.1.2.1.1 50-1.3.1.2.2.1 52-1.3.1.3.1.1.1.1 53-1.3.1.3.1 54-1.3.1.3.1.2.1.1 56-1.3.1.3.2.1 58-1.3.1.4.1.1.1.1 59-1.3.1.4.1 60-1.3.1.4.1.2.1 62-1.3.1.4.2.1 64-1.3.1.5.1.1.1.1 65-1.3.1.5.1 66-1.3.1.5.1.2.1 68-1.3.1.5.2.1 70-1.3.1.6.1.1.1.1 71-1.3.1.6.1 72-1.3.1.6.1.2.1 74-1.3.1.6.2.1 (a4 / and~e.32 :op1 (r / recruit-01~e.7 :ARG0 (p / protein~e.3 :name (n2 / name :op1 "ARF1"~e.6) :ARG2-of~e.3 (b / bind-01~e.3 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.1)))) :ARG1 (c / coat-01~e.9 :ARG2 (p2 / protein~e.8) :ARG2-of (i / include-01~e.11 :ARG1 (a / and~e.21,25 :op1 (p3 / protein~e.17 :name (n3 / name :op1 "AP-1"~e.18,20,22) :mod (a2 / adaptor~e.16) :ARG1-of (a3 / associate-01~e.15 :ARG2 (p5 / protein~e.17 :name (n5 / name :op1 "clathrin"~e.13)))) :op2 (p4 / protein~e.17 :name (n4 / name :op1 "AP-3"~e.22,24) :mod a2 :ARG1-of a3) :op3 (p6 / protein~e.17 :name (n6 / name :op1 "nonclathrin"~e.27 :op2 "coatomer"~e.28))))) :purpose~e.30 (m / membrane~e.31)) :op2 (i2 / initiate-01~e.33 :ARG0 p :ARG1 (b2 / bud-01~e.34 :ARG1~e.35 (v / vesicle~e.38 :mod m~e.37))) :ARG1-of (d / describe-01 :ARG0 (a5 / and~e.32 :op1 (p7 / publication-91 :ARG0 (a6 / and~e.32,41 :op1 (p8 / person :name (n7 / name :op1 "Lenhard"~e.40)) :op2 (p9 / person :mod (o / other~e.42))) :time (d2 / date-entity :year 1992~e.44)) :op2 (p10 / publication-91 :ARG0 (a7 / and~e.47 :op1 (p11 / person :name (n8 / name :op1 "Donaldson"~e.46)) :op2 (p12 / person :name (n9 / name :op1 "Klausner"~e.48))) :time (d3 / date-entity :year 1994~e.50)) :op3 (p13 / publication-91 :ARG0 (a8 / and~e.53 :op1 (p14 / person :name (n10 / name :op1 "Boman"~e.52)) :op2 (p15 / person :name (n11 / name :op1 "Kahn"~e.54))) :time (d4 / date-entity :year 1995~e.56)) :op4 (p16 / publication-91 :ARG0 (a9 / and~e.59 :op1 (p17 / person :name (n12 / name :op1 "Dittie"~e.58)) :op2 (p18 / person :mod (o2 / other~e.60))) :time (d5 / date-entity :year 1996~e.62)) :op5 (p19 / publication-91 :ARG0 (a10 / and~e.65 :op1 (p20 / person :name (n13 / name :op1 "Ooi"~e.64)) :op2 (p21 / person :mod (o3 / other~e.66))) :time (d6 / date-entity :year 1998~e.68)) :op6 (p22 / publication-91 :ARG0 (a11 / and~e.71 :op1 (p23 / person :name (n14 / name :op1 "Springer"~e.70)) :op2 (p24 / person :mod (o4 / other~e.72))) :time (d7 / date-entity :year 1999~e.74))))) # ::id bio.chicago_2015.57113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This analysis revealed specific in vivo binding of NFAT5 to the TNF proximal promoter and the aldose reductase enhancer in response to hypertonic stimulation , either alone or in combination with PMA ( Figure 6D , right , top and middle panels , lanes 5 and 6 ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.3 4-1.2.4 5-1.2.4 6-1.2 7-1.2.1.r 8-1.2.1.1.1 9-1.2.2.r 11-1.2.2.1.1.1.1.1 12-1.2.2.1.2 13-1.2.2.1 13-1.2.2.1.1 13-1.2.2.1.1.r 14-1.2.2 16-1.2.2.2.1.1.1.1 17-1.2.2.2.1.1.1.2 19-1.2.4 19-1.2.5.r 20-1.2.5 21-1.2.5.1.r 22-1.2.5.1.1.1 23-1.2.5.1.1 26-1.2.5.1.1.2 27-1.2.5.1 28-1.2.4 29-1.2.5.1.2 30-1.2.5.1.2.2.r 31-1.2.5.1.2.2.1.1 33-1.3.1.3 34-1.3.1.3.1 36-1.3.1.2.1.1 38-1.3.1.2.2.1 39-1.3.1.2 40-1.3.1.2.3.1 41-1.3.1.2.1 41-1.3.1.2.2 41-1.3.1.2.3 43-1.3.1.1.1 43-1.3.1.1.2 44-1.3.1.1.1.1 45-1.3.1.1 46-1.3.1.1.2.1 (r / reveal-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (t / this~e.0)) :ARG1 (b / bind-01~e.6 :ARG1~e.7 (p / protein :name (n / name :op1 "NFAT5"~e.8)) :ARG2~e.9 (a2 / and~e.14 :op1 (m / molecular-physical-entity~e.13 :ARG0-of~e.13 (p2 / promote-01~e.13 :ARG1 (p3 / protein :name (n2 / name :op1 "TNF"~e.11))) :mod (p4 / proximal~e.12)) :op2 (m2 / molecular-physical-entity :ARG0-of (e / enhance-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "aldose"~e.16 :op2 "reductase"~e.17))))) :ARG1-of (s / specific-02~e.3) :manner (i / in-vivo~e.4,5,19,28) :ARG2-of~e.19 (r2 / respond-01~e.20 :ARG1~e.21 (o / or~e.27 :op1 (s2 / stimulate-01~e.23 :ARG0 (h / hypertonic~e.22) :mod (a3 / alone~e.26)) :op2 (c / combine-01~e.29 :ARG1 s2 :ARG2~e.30 (s3 / small-molecule :name (n4 / name :op1 "PMA"~e.31)))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (a5 / and~e.45 :op1 (l / lane~e.43 :mod 5~e.44) :op2 (l2 / lane~e.43 :mod 6~e.46)) :op2 (a6 / and~e.39 :op1 (p5 / panel~e.41 :ARG1-of (r3 / right-04~e.36)) :op2 (p6 / panel~e.41 :location (t2 / top~e.38)) :op3 (p7 / panel~e.41 :location (m3 / middle~e.40))) :part-of (f / figure~e.33 :mod "6D"~e.34)))) # ::id bio.chicago_2015.57142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C , DNA binding of Smad5 and Smad4 to the GC @-@ rich sequence is shown . # ::alignments 2-1.1.1.2.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1 6-1.1.2 7-1.1.2.2.1.1 12-1.1.3.1 13-1.1.3 15-1 (s / show-01~e.15 :ARG1 (b / bind-01~e.3 :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.2)) :ARG1~e.4 (a / and~e.6 :op1 (p2 / protein :name (n4 / name :op1 "Smad5"~e.5)) :op2 (p3 / protein :name (n5 / name :op1 "Smad4"~e.7))) :ARG2 (s2 / sequence~e.13 :mod (r / rich~e.12 :op1 (s3 / small-molecule :name (n / name :op1 "guanine")) :op2 (s4 / small-molecule :name (n6 / name :op1 "cytosine"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4C"))) # ::id bio.chicago_2015.57166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because Sec15p also binds to activated Sec4p , the exocyst might be an effector for this Rab @-@ like GTPase that is necessary for the targeting or tethering of secretory vesicles to sites of secretion . # ::alignments 0-1 1-1.1.1.1.1 2-1.1.3 3-1.1 4-1.1.2.r 5-1.1.2.2 6-1.1.2.1.1 9-1.2.1.1.1.1 10-1.2 11-1.2.1.1.r 13-1.2.1 14-1.2.1.2.r 15-1.2.1.2.4 16-1.2.1.2.2.1.1.1 18-1.2.1.2 18-1.2.1.2.2 18-1.2.1.2.2.r 19-1.2.1.2.1.1 22-1.2.1.2.3 23-1.2.1.2.3.1.r 25-1.2.1.2.3.1.1 26-1.2.1.2.3.1 27-1.2.1.2.3.1.2 28-1.2.1.2.3.1.1.1.r 29-1.2.1.2.3.1.1.1.1 30-1.2.1.2.3.1.1.1 31-1.2.1.2.3.1.1.2.r 32-1.2.1.2.3.1.1.2 33-1.2.1.2.3.1.1.2.1.r 34-1.2.1.2.3.1.1.2.1 (c / cause-01~e.0 :ARG0 (b / bind-01~e.3 :ARG1 (p / protein :name (n / name :op1 "Sec15p"~e.1)) :ARG2~e.4 (p2 / protein :name (n2 / name :op1 "Sec4p"~e.6) :ARG1-of (a / activate-01~e.5)) :mod (a3 / also~e.2)) :ARG1 (p3 / possible-01~e.10 :ARG1 (e / effector~e.13 :domain~e.11 (p4 / protein :name (n3 / name :op1 "exocyst"~e.9)) :beneficiary~e.14 (e2 / enzyme~e.18 :name (n4 / name :op1 "GTPase"~e.19) :ARG1-of~e.18 (r / resemble-01~e.18 :ARG2 (p5 / protein :name (n5 / name :op1 "Rab"~e.16))) :ARG1-of (n6 / need-01~e.22 :ARG0~e.23 (o / or~e.26 :op1 (t / target-01~e.25 :ARG0~e.28 (v / vesicle~e.30 :ARG0-of (s / secrete-01~e.29)) :ARG1~e.31 (s2 / site~e.32 :location-of~e.33 (s3 / secrete-01~e.34))) :op2 (t2 / tether-01~e.27 :ARG0 v :ARG1 s2))) :mod (t3 / this~e.15))))) # ::id bio.chicago_2015.57186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Calmodulin binding activities of the adducin recombinant polypeptides and the MARCKS @-@ related domain peptide were inhibited by PKA and PKC phosphorylation . # ::alignments 0-1.2.1.2.1.1.1 1-1.2.1.2 2-1.2.1 3-1.2.1.1.r 5-1.2.1.1.1.1 6-1.2.1.1.1.2 7-1.2.1.1 8-1.2 10-1.2.2.1.1.1.1.1 12-1.2.2.1.1 13-1.2.2.1 14-1.2.2 16-1 17-1.1.r 18-1.1.1.1.1.1 19-1.1.1 20-1.1.1.2.1.1 21-1.1 (i / inhibit-01~e.16 :ARG0~e.17 (p / phosphorylate-01~e.21 :ARG1 (a / and~e.19 :op1 (e / enzyme :name (n / name :op1 "PKA"~e.18)) :op2 (e2 / enzyme :name (n2 / name :op1 "PKC"~e.20)))) :ARG1 (a2 / and~e.8 :op1 (a3 / activity-06~e.2 :ARG0~e.3 (p5 / polypeptide~e.7 :name (n4 / name :op1 "adducin"~e.5 :op2 "recombinant"~e.6)) :ARG1-of (b / bind-01~e.1 :ARG2 (p4 / protein :name (n3 / name :op1 "calmodulin"~e.0)))) :op2 (p6 / peptide~e.14 :part-of (d / domain~e.13 :ARG1-of (r / relate-01~e.12 :ARG2 (p7 / protein :name (n5 / name :op1 "MARCKS"~e.10))))))) # ::id bio.chicago_2015.57199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All of these results indicate that the binding of Axin to Dvl is probably mediated by two interactions ; one between DvlN and AxinC and the other between DvlPDZ and an N @-@ terminal sequence of Axin . # ::alignments 0-1.1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 5-1.2.r 7-1.2.2 8-1.2.2.1.r 9-1.2.2.1.1.1 10-1.2.2.2.r 11-1.2.2.2.1.1 13-1.2.3 14-1.2 17-1.2.1.1 17-1.2.1.2 21-1.2.1.1.1.1.1 23-1.2.1.1.2.1.1 24-1.2.1 28-1.2.1.2.1.1.1 31-1.2.1.2.2.1.1 33-1.2.1.2.2.1.1 36-1.2.1.2.2.2 (i / indicate-01~e.4 :ARG0 (t / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :mod (t2 / this~e.2) :mod (a / all~e.0)) :ARG1~e.5 (m / mediate-01~e.14 :ARG0 (a2 / and~e.24 :op1 (i2 / interact-01~e.17 :ARG0 (p3 / protein :name (n3 / name :op1 "DvlN"~e.21)) :ARG1 (p5 / protein :name (n4 / name :op1 "AxinC"~e.23))) :op2 (i3 / interact-01~e.17 :ARG0 (p4 / protein :name (n5 / name :op1 "DvlPDZ"~e.28)) :ARG1 (p7 / protein-segment :name (n7 / name :op1 "N-terminus"~e.31,33) :part-of p6~e.36))) :ARG1 (b / bind-01~e.7 :ARG1~e.8 (p6 / protein :name (n / name :op1 "Axin"~e.9)) :ARG2~e.10 (p / protein :name (n2 / name :op1 "Dvl"~e.11))) :mod (p2 / probable~e.13))) # ::id bio.chicago_2015.57217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TIF1 alpha and TIF1 beta bind directly to HP1 alpha , - beta and -@ gamma in vitro # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1 3-1.1.2.1.1 4-1.1.2.1.2 5-1 6-1.3 7-1.2.r 8-1.2.1.1.1 9-1.2.1.1.2 12-1.2.2.1.2 15-1.2.3.1.2 16-1.4 17-1.4 (b / bind-01~e.5 :ARG1 (a / and~e.2 :op1 (p / protein :name (n / name :op1 "TIF1"~e.0 :op2 "alpha"~e.1)) :op2 (p2 / protein :name (n2 / name :op1 "TIF1"~e.3 :op2 "beta"~e.4))) :ARG2~e.7 (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "HP1"~e.8 :op2 "alpha"~e.9)) :op2 (p4 / protein :name (n4 / name :op1 "HP1" :op2 "beta"~e.12)) :op3 (p5 / protein :name (n5 / name :op1 "HP1" :op2 "gamma"~e.15))) :ARG1-of (d / direct-02~e.6) :manner (i / in-vitro~e.16,17)) # ::id bio.chicago_2015.57274 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mechanism of indirect binding of ERM proteins to integral membrane proteins has also been reported . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.3 3-1.1.1.3.1 3-1.1.1.3.1.r 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 7-1.1.1.2.1.3 9-1.1.1.2.1.1 10-1.1.1.2.1.2 11-1.1.1.2.1.3 13-1.2 15-1 (r / report-01~e.15 :ARG1 (m / mechanism~e.1 :instrument-of~e.2 (b / bind-01~e.4 :ARG1~e.5 (p / protein-family :name (n / name :op1 "ERM"~e.6)) :ARG2 (p2 / protein :name (n2 / name :op1 "integral"~e.9 :op2 "membrane"~e.10 :op3 "protein"~e.7,11)) :ARG1-of (d / direct-02~e.3 :polarity~e.3 -~e.3))) :mod (a / also~e.13)) # ::id bio.chicago_2015.57316 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Tyr43 @/@ Asp49 conformational switch is the most probable explanation for the GTP @-@ dependent binding of Sec5 to RalA . # ::alignments 2-1.1.1.1 5-1.1 8-1.3.1 9-1.3 10-1 11-1.2.r 13-1.2.3.1.1.1 15-1.2.3 16-1.2 17-1.2.1.r 18-1.2.1.1.1 19-1.2.2.r 20-1.2.2.1.1 (e / explain-01~e.10 :ARG0 (s / switch-01~e.5 :ARG1-of (c / conform-01 :ARG2 (s2 / slash~e.2 :op1 (a / amino-acid :mod 43 :name (n6 / name :op1 "tyrosine")) :op2 (a2 / amino-acid :mod 49 :name (n / name :op1 "aspartic" :op2 "acid"))))) :ARG1~e.11 (b / bind-01~e.16 :ARG1~e.17 (p3 / protein :name (n3 / name :op1 "Sec5"~e.18)) :ARG2~e.19 (p4 / protein :name (n4 / name :op1 "RalA"~e.20)) :ARG0-of (d / depend-01~e.15 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "GTP"~e.13)))) :mod (p5 / probable~e.9 :degree (m / most~e.8))) # ::id bio.chicago_2015.57334 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In our studies no increase in endogenous plakoglobin levels was detected in response to the expression of E @-@ cadherin in L cells , despite the fact that plakoglobin can effectively bind to E @-@ cadherin in other cell types ( 24 , 25 ) . # ::alignments 1-1.1.3.1 1-1.1.3.1.r 2-1.1.3 3-1.1.1 3-1.1.1.r 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.2 7-1.1.2.1.1.1.1 8-1.1.2.1 10-1.1 11-1.1.2.2.r 12-1.1.2.2 13-1.1.2.2.1.r 15-1.1.2.2.1 16-1.1.2.2.1.1.r 17-1.1.2.2.1.1.1.1 19-1.1.2.2.1.1.1.1 20-1.1.2.2.1.2.r 21-1.1.2.2.1.2.1.1 22-1.1.2.2.1.2 24-1 28-1.1.2.1.1.1.1 29-1.2 30-1.2.1.3 31-1.2.1 32-1.2.1.2.r 33-1.2.1.2 34-1.2.1.2 35-1.2.1.2 36-1.2.1.4.r 37-1.2.1.4.2 38-1.2.1.4 39-1.2.1.4.1 41-1.3.1.1.1.1 43-1.3.1.1.1.2 (h / have-concession-91~e.24 :ARG1 (d / detect-01~e.10 :polarity~e.3 -~e.3 :ARG1 (i / increase-01~e.4 :ARG1~e.5 (l / level~e.8 :quant-of (p / protein :name (n / name :op1 "plakoglobin"~e.7,28) :mod (e / endogenous~e.6))) :ARG2-of~e.11 (r / respond-01~e.12 :ARG1~e.13 (e2 / express-03~e.15 :ARG2~e.16 (p2 / protein :name (n2 / name :op1 "E-cadherin"~e.17,19)) :ARG3~e.20 (c / cell~e.22 :name (n3 / name :op1 "L"~e.21))))) :ARG2 (s / study-01~e.2 :ARG0~e.1 (w / we~e.1))) :ARG2 (p3 / possible-01~e.29 :ARG1 (b / bind-01~e.31 :ARG1 p :ARG2~e.32 p2~e.33,34,35 :ARG1-of (e3 / effective-04~e.30) :location~e.36 (c4 / cell~e.38 :mod (t / type~e.39) :mod (o / other~e.37)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 24~e.41 :op2 25~e.43))))) # ::id bio.chicago_2015.57387 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of Smad3 and Sp1 was demonstrated upon immunodetection with specific antibodies . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 6-1 10-1.2.1.1 11-1.2.1 (d / demonstrate-01~e.6 :ARG1 (b / bind-01~e.0 :ARG1~e.1 (a / and~e.3 :op1 (p / protein :name (n / name :op1 "Smad3"~e.2)) :op2 (p2 / protein :name (n2 / name :op1 "Sp1"~e.4)))) :time (i / immunodetect-01 :ARG3 (a2 / antibody~e.11 :ARG1-of (s / specific-02~e.10)))) # ::id bio.chicago_2015.57447 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While the homeodomain alone of Pbx1 or exd binds DNA cooperatively with Hox proteins , studies with Pbx1 have shown that a 16 @-@ residue C @-@ terminal tail , which is conserved in exd , is required for maximal cooperative interactions with Hox partners ( Chang et al. , 1995 ; Lu and Kamps , 1996 ; Green et al. , 1998 ) and for maximal binding of monomeric Pbx1 homeodomain to DNA ( Lu and Kamps , 1996 ; Green et al. , 1998 ) . # ::alignments 0-1 2-1.2.1.1 2-1.2.1.2 3-1.2.1.1.2 4-1.1.r 5-1.1.1.1.1.1 6-1.2.1 8-1.2 9-1.2.2 10-1.1.2.1.1.3 12-1.1.2.1.1.1.1.1.1 13-1.1.1.1 13-1.1.2.1.1.1.1 13-1.1.2.1.2.1.1 13-1.1.2.2.2.1 13-1.1.2.2.3 15-1.1.1 17-1.1.1.1.1.1 17-1.1.2.1.2.1.1.1.1 19-1.1 22-1.1.2.2.1.1 24-1.1.2.2.1 25-1.1.2.2.3.1.1 27-1.1.2.2.3.1.1 28-1.1.2.2 32-1.1.2.2.2 37-1.1.2 39-1.1.2.1.1.2 40-1.1.2.1.1.3 41-1.1.2.1.1 43-1.1.2.1.1.1.1.1.1 44-1.1.2.1.1.1 46-1.1.2.1.1.4.1.1.1.1.1.1 47-1.1.2.1.1.4.1.1.1 48-1.1.2.1.1.4.1.1.1.2.1 50-1.1.2.1.1.4.1.1.2.1 52-1.1.2.1.1.4.1.2.1.1.1.1 53-1.1.2.1.1.4.1.2.1 54-1.1.2.1.1.4.1.2.1.2.1.1 56-1.1.2.1.1.4.1.2.2.1 58-1.1.2.1.1.4.1.3.1.1.1.1 59-1.1.2.1.1.4.1.3.1 60-1.1.2.1.1.4.1.3.1.2.1 62-1.1.2.1.1.4.1.3.2.1 64-1.1.2.1.1.4.1 64-1.1.2.1.1.4.1.2.1 64-1.1.2.1.1.4.1.3.1 66-1.1.2.1.1.2 67-1.1.2.1.2 68-1.1.2.1.2.1.1.2.r 68-1.1.2.1.2.1.r 69-1.1.2.1.2.1.1.2 70-1.1.2.1.2.1.1.1.1 71-1.1.2.1.2.1 72-1.1.2.1.2.2.r 73-1.1.2.1.2.2.2.1 75-1.1.2.1.1.4.1.2.1.1.1.1 76-1.1.2.1.1.4.1.2.1 77-1.1.2.1.1.4.1.2.1.2.1.1 79-1.1.2.1.1.4.1.2.2.1 81-1.1.2.1.1.4.1.3.1.1.1.1 82-1.1.2.1 82-1.1.2.1.1.4.1.3.1 82-1.1.2.1.2.4.1 83-1.1.2.1.1.4.1.3.1.2.1 85-1.1.2.1.1.4.1.3.2.1 (c3 / contrast-01~e.0 :ARG1~e.4 (s / show-01~e.19 :ARG0 (s2 / study-01~e.15 :ARG1 (p / protein~e.13 :name (n / name :op1 "Pbx1"~e.5,17))) :ARG1 (r / require-01~e.37 :ARG0 (a / and~e.82 :op1 (i / interact-01~e.41 :ARG1 (p3 / partner-01~e.44 :ARG1 (p2 / protein-family~e.13 :name (n3 / name :op1 "Hox"~e.12,43))) :degree (m / maximal~e.39,66) :manner (c2 / cooperate-01~e.10,40) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.64 :op1 (p7 / publication-91 :ARG0 (a4 / and~e.47 :op1 (p10 / person :name (n8 / name :op1 "Chang"~e.46)) :op2 (p11 / person :mod (o2 / other~e.48))) :time (d2 / date-entity :year 1995~e.50)) :op2 (p8 / publication-91 :ARG0 (a5 / and~e.53,64,76 :op1 (p12 / person :name (n9 / name :op1 "Lu"~e.52,75)) :op2 (p13 / person :name (n10 / name :op1 "Kamps"~e.54,77))) :time (d3 / date-entity :year 1996~e.56,79)) :op3 (p9 / publication-91 :ARG0 (a6 / and~e.59,64,82 :op1 (p14 / person :name (n11 / name :op1 "Green"~e.58,81)) :op2 (p15 / person :mod (o3 / other~e.60,83))) :time (d4 / date-entity :year 1998~e.62,85))))) :op2 (b / bind-01~e.67 :ARG1~e.68 (h4 / homeodomain~e.71 :part-of (p5 / protein~e.13 :name (n4 / name :op1 "Pbx1"~e.17,70) :mod~e.68 (m3 / monomeric~e.69))) :ARG2~e.72 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.73)) :degree m :ARG1-of (d5 / describe-01 :ARG0 (a7 / and~e.82 :op1 p8 :op2 p9)))) :ARG1 (t / tail~e.28 :mod (r2 / residue~e.24 :mod 16~e.22) :ARG1-of (c / conserve-01~e.32 :location (p6 / protein~e.13 :name (n7 / name :op1 "edx"))) :part-of (p16 / protein-segment~e.13 :name (n12 / name :op1 "C-terminus"~e.25,27))))) :ARG2 (b2 / bind-01~e.8 :ARG1 (o / or~e.6 :op1 (h2 / homeodomain~e.2 :part-of p :mod (a3 / alone~e.3)) :op2 (h3 / homeodomain~e.2 :part-of p6 :mod a3)) :ARG2 n5~e.9 :ARG3 p2 :ARG2-of c2)) # ::id bio.chicago_2015.57503 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Incubation of wild @-@ type Tsg protein with Chordin and BMP4 generated a ternary complex corresponding to a Tsg dimer bound to a BMP4 dimer and Chordin ( Fig. 4D , lane 3 ) . # ::alignments 0-1.1 2-1.1.1.2 4-1.1.1.2 5-1.1.1.1.1 6-1.1.1 6-1.1.2.1 6-1.1.2.2 6-1.2.2.1 6-1.2.2.1.2.1.1 7-1.1.2.r 8-1.1.2.1.1.1 9-1.1.2 10-1.1.2.2.1.1 11-1 13-1.2.1 14-1.2 15-1.2.2 18-1.2.2.1.1.1 20-1.2.2.1.2 21-1.2.2.1.2.1.r 23-1.2.2.1.2.1.1.1.1 25-1.2.2.1.2.1 26-1.2.2.1.2.1.2 28-1.3.1 29-1.3.1.1 31-1.3.1.2 32-1.3.1.2.1 (g / generate-01~e.11 :ARG0 (i / incubate-01~e.0 :ARG1 (p / protein~e.6 :name (n / name :op1 "Tsg"~e.5) :mod (w / wild-type~e.2,4)) :ARG2~e.7 (a / and~e.9 :op1 (p2 / protein~e.6 :name (n2 / name :op1 "Chordin"~e.8)) :op2 (p3 / protein~e.6 :name (n3 / name :op1 "BMP4"~e.10)))) :ARG1 (m / macro-molecular-complex~e.14 :mod (t / ternary~e.13) :ARG1-of (c / correspond-02~e.15 :ARG2 (p5 / protein~e.6 :name (n4 / name :op1 "Tsg"~e.18) :ARG1-of (b / bind-01~e.20 :ARG2~e.21 (a2 / and~e.25 :op1 (p4 / protein~e.6 :name (n5 / name :op1 "BMP4"~e.23) :ARG3-of (d2 / dimerize-01)) :op2 p2~e.26)) :ARG3-of (d / dimerize-01)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.28 :mod "4D"~e.29 :location (l / lane~e.31 :mod 3~e.32)))) # ::id bio.chicago_2015.57541 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) Differential binding of recombinant s @-@ synaphin constructs to syntaxin . # ::alignments 1-1.4.1.1 3-1.3 4-1 5-1.1.r 6-1.1.1.2 7-1.1.1.1.1 9-1.1.1.1.1 10-1.1 11-1.2.r 12-1.2.1.1 (b / bind-01~e.4 :ARG1~e.5 (c / construct~e.10 :mod (p / protein :name (n / name :op1 "s-synaphin"~e.7,9) :ARG3-of (r / recombine-01~e.6))) :ARG2~e.11 (p2 / protein :name (n2 / name :op1 "syntaxin"~e.12)) :ARG1-of (d2 / differ-02~e.3) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"~e.1))) # ::id bio.chicago_2015.57550 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding of actin to tropomyosin is directly demonstrated by cosedimentation and SDS @-@ gel electrophoresis ( Fig. 1 ) . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1.1 3-1.2.2.r 4-1.2.2.1.1 6-1.3 7-1 8-1.1.r 9-1.1.1 10-1.1 11-1.1.2.1.1.1 13-1.1.2.1.1.2 14-1.1.2 16-1.4.1 17-1.4.1.1 (d / demonstrate-01~e.7 :ARG0~e.8 (a / and~e.10 :op1 (c / cosedimentation~e.9) :op2 (e / electrophoresis~e.14 :instrument (t / thing :name (n3 / name :op1 "SDS"~e.11 :op2 "gel"~e.13)))) :ARG1 (b / bind-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "actin"~e.2)) :ARG2~e.3 (p2 / protein :name (n2 / name :op1 "tropomyosin"~e.4))) :ARG1-of (d2 / direct-02~e.6) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.16 :mod 1~e.17))) # ::id bio.chicago_2015.57613 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As Fig. 4 b shows , the amount of MYPT bound to phosphorylated myosin was two to three times higherR using MYPT phosphorylated with mitotic extracts compared to the MYPT phosphorylated by interphase extracts . # ::alignments 0-1.4.1.2.1.1.1.r 1-1.5.1 4-1.5 7-1.1 8-1.1.1.r 9-1.1.1.1.1 10-1.1.1 10-1.1.1.2 10-1.1.1.2.r 11-1.1.1.2.1.r 12-1.1.1.2.1.2 13-1.1.1.2.1.1.1 15-1.3.1.1 17-1.3.2.1 18-1.3.2 18-1.4.1.2.1.1.1.r 20-1.4 21-1.4.1.1.1 21-1.4.2.1.1 22-1.4.1.2 24-1.4.1.2.1.1.1 25-1.4.1.2.1 25-1.4.1.2.1.1 25-1.4.1.2.1.1.r 26-1.4.2.r 29-1.4.2.1.1 30-1.4.2.2 31-1.4.2.2.1.r 32-1.4.2.2.1.1.1 33-1.4.2.2.1 33-1.4.2.2.1.1 33-1.4.2.2.1.1.r (h2 / high-02 :ARG1 (a / amount~e.7 :quant-of~e.8 (p / protein~e.10 :name (n / name :op1 "MYPT"~e.9) :ARG1-of~e.10 (b / bind-01~e.10 :ARG2~e.11 (p2 / protein :name (n2 / name :op1 "myosin"~e.13) :ARG3-of (p3 / phosphorylate-01~e.12))))) :degree (m / more) :degree (b2 / between :op1 (p4 / product-of :op1 2~e.15) :op2 (p5 / product-of~e.18 :op2 3~e.17)) :condition (u / use-01~e.20 :ARG1 (p6 / protein :name (n3 / name :op1 "MYPT"~e.21) :ARG3-of (p7 / phosphorylate-01~e.22 :ARG2 (m3 / molecular-physical-entity~e.25 :ARG1-of~e.25 (e / extract-01~e.25 :time~e.0,18 (m2 / mitosis~e.24))))) :compared-to~e.26 (p8 / protein :name (n4 / name :op1 "MYPT"~e.21,29) :ARG3-of (p9 / phosphorylate-01~e.30 :ARG2~e.31 (m4 / molecular-physical-entity~e.33 :ARG1-of~e.33 (e2 / extract-01~e.33 :time (i / interphase~e.32)))))) :ARG1-of (s / show-01~e.4 :ARG0 (f / figure~e.1 :mod "4b"))) # ::id bio.chicago_2015.57633 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , NIMA can phosphorylate histone H3 at Ser @-@ 10 in vitro . # ::alignments 0-1.1 0-1.1.r 2-1.2.2.1.1 3-1 4-1.2 5-1.2.1.3.1.1 6-1.2.1.3.1.2 8-1.2.1.2.1 10-1.2.1.1 11-1.2.3 12-1.2.3 (p / possible-01~e.3 :li~e.0 -1~e.0 :ARG1 (p2 / phosphorylate-01~e.4 :ARG1 (a / amino-acid :mod 10~e.10 :name (n / name :op1 "serine"~e.8) :part-of (p3 / protein :name (n2 / name :op1 "histone"~e.5 :op2 "H3"~e.6))) :ARG2 (e / enzyme :name (n3 / name :op1 "NIMA"~e.2)) :manner (i / in-vitro~e.11,12))) # ::id bio.chicago_2015.57664 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although Pax6 is phosphorylated by two members of the MAPK family ( ERK and p38 ) , it is not phosphorylated by JNK ( Mikkola et al. 1999 ) ; JNK @-@ dependent Pax6 regulation may therefore be indirect . # ::alignments 0-1.2 1-1.2.2.1.1.1 3-1.2.2 7-1.2.2.2.r 9-1.2.2.2.3.1.1.1 10-1.2.2.2.3.1 12-1.2.2.2.1.1.1 13-1.2.2.2 14-1.2.2.2.2.1.1 19-1.2.1.1 19-1.2.1.1.r 20-1.2.1 21-1.2.1.3.r 22-1.2.1.3.1.1 24-1.2.1.4.1.1.1.1.1 25-1.2.1.4.1.1 26-1.2.1.4.1.1.2.1 27-1.2.1.4.1.2.1 30-1.2.1.3.1.1 32-1.1.1.2.2 33-1.1.1.2.1 34-1.1.1.2 35-1.1 36-1 38-1.1.1 38-1.1.1.1 38-1.1.1.1.r (i / infer-01~e.36 :ARG1 (p7 / possible-01~e.35 :ARG1 (d3 / direct-02~e.38 :polarity~e.38 -~e.38 :ARG1 (r / regulate-01~e.34 :ARG1 p2~e.33 :ARG0-of (d4 / depend-01~e.32 :ARG1 e4)))) :ARG2 (h / have-concession-91~e.0 :ARG1 (p3 / phosphorylate-01~e.20 :polarity~e.19 -~e.19 :ARG1 p2 :ARG2~e.21 (e4 / enzyme :name (n5 / name :op1 "JNK"~e.22,30)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a2 / and~e.25 :op1 (p4 / person :name (n6 / name :op1 "Mikkola"~e.24)) :op2 (p5 / person :mod (o / other~e.26))) :time (d2 / date-entity :year 1999~e.27)))) :ARG2 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein :name (n / name :op1 "Pax6"~e.1)) :ARG2~e.7 (a / and~e.13 :op1 (e / enzyme :name (n2 / name :op1 "ERK"~e.12)) :op2 (e2 / enzyme :name (n3 / name :op1 "p38"~e.14)) :ARG1-of (i2 / include-91 :ARG2 (p8 / protein-family~e.10 :name (n4 / name :op1 "MAPK"~e.9))))))) # ::id bio.chicago_2015.57688 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , we found a weak but direct interaction between Pelle and dTRAF2 in vitro , and showed that dTRAF2 can be phosphorylated by Pelle . # ::alignments 0-1.3 2-1.1.1 3-1.1 5-1.1.2.4 6-1.1.2.4.1 7-1.1.2.4.1.1 8-1.1.2 10-1.1.2.1.1.1 12-1.1.2.2.1.1 13-1.1.2.3 14-1.1.2.3 16-1 17-1.2 19-1.1.2.2.1.1 20-1.2.2 22-1.2.2.1 23-1.2.2.1.2.r 24-1.2.2.1.2 (a / and~e.16 :op1 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1 (i / interact-01~e.8 :ARG0 (e / enzyme :name (n / name :op1 "Pelle"~e.10)) :ARG1 (p2 / protein :name (n2 / name :op1 "dTRAF2"~e.12,19)) :manner (i2 / in-vitro~e.13,14) :ARG1-of (w2 / weak-02~e.5 :ARG1-of (c / contrast-01~e.6 :ARG2 (d / direct-02~e.7 :ARG1 i))))) :op2 (s / show-01~e.17 :ARG0 w :ARG1 (p3 / possible-01~e.20 :ARG1 (p4 / phosphorylate-01~e.22 :ARG1 p2 :ARG2~e.23 e~e.24))) :mod (i3 / important~e.0)) # ::id bio.chicago_2015.57709 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This view is consistent with previous data that suggest ATM phosphorylates Nbs1 when it is bound to DNA damage ( 37 ) ( Fig . 8 ) . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.2 6-1.2 8-1.2.1 9-1.2.1.1.2.1.1 10-1.2.1.1 11-1.2.1.1.1.1.1 12-1.2.1.1.3.r 13-1.2.1.1.3.1 15-1.2.1.1.3 17-1.2.1.1.3.2.1.1.1 18-1.2.1.1.3.2 20-1.4.1.1.1 23-1.3.1 25-1.3.1.1 (c / consistent-01~e.3 :ARG1 (v / view-02~e.1 :mod (t / this~e.0)) :ARG2~e.4 (d3 / data~e.6 :ARG0-of (s / suggest-01~e.8 :ARG1 (p2 / phosphorylate-01~e.10 :ARG1 (p3 / protein :name (n4 / name :op1 "Nbs1"~e.11)) :ARG2 (e / enzyme :name (n / name :op1 "ATM"~e.9)) :time~e.12 (b2 / bind-01~e.15 :ARG1 p3~e.13 :ARG2 (d4 / damage-01~e.18 :ARG1 (n2 / nucleic-acid :name (n3 / name :op1 "DNA"~e.17)))))) :time (p4 / previous~e.5)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod 8~e.25)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 37~e.20)))) # ::id bio.chicago_2015.57767 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The data presented in Fig. 1 suggest that KSR is phosphorylated by MAPK in response to Ras activation . # ::alignments 1-1.1 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1 5-1.1.1.1.1 6-1 7-1.2.r 8-1.2.1.1.1 10-1.2 11-1.2.2.r 12-1.2.2.1.1 13-1.2.3.r 14-1.2.3 15-1.2.3.1.r 16-1.2.3.1.1.1.1 17-1.2.3.1 (s / suggest-01~e.6 :ARG0 (d / data~e.1 :ARG1-of (p / present-01~e.2 :location~e.3 (f / figure~e.4 :op1 1~e.5))) :ARG1~e.7 (p4 / phosphorylate-01~e.10 :ARG1 (e2 / enzyme :name (n3 / name :op1 "KSR"~e.8)) :ARG2~e.11 (e / enzyme :name (n4 / name :op1 "MAPK"~e.12)) :ARG2-of~e.13 (r / respond-01~e.14 :ARG1~e.15 (a / activate-01~e.17 :ARG1 (e3 / enzyme :name (n5 / name :op1 "Ras"~e.16)))))) # ::id bio.chicago_2015.57774 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PTP2C inhibits PLC tyrosine phosphorylation by c @-@ Src . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.2.1.1 3-1.2.1.1.1 4-1.2 5-1.2.2.r 6-1.2.2.1.1 8-1.2.2.1.1 (i / inhibit-01~e.1 :ARG0 (e / enzyme :name (n / name :op1 "PTP2C"~e.0)) :ARG1 (p2 / phosphorylate-01~e.4 :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine"~e.3) :part-of (e3 / enzyme :name (n2 / name :op1 "PLC"~e.2))) :ARG2~e.5 (e2 / enzyme :name (n3 / name :op1 "c-Src"~e.6,8)))) # ::id bio.chicago_2015.57802 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previous data from Wahba and colleagues ( Dholakia and Wahba , 1988 ) suggested that phosphorylation of eIF2Bepsilon by CK2 increased its activity in nucleotide exchange , and our findings thus provide an explanation of this effect . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1.1 4-1.1.1.2 5-1.1.1.2.2 7-1.1.1.3.1.1.1.1.1 8-1.1.1.2 8-1.1.1.3.1.1 9-1.1.1.3.1.1.2 11-1.1.1.3.1.2.1 13-1.1 14-1.1.2.r 15-1.1.2.1 16-1.1.2.1.1.r 17-1.1.2.1.1.1.1 18-1.1.2.1.2.r 19-1.1.2.1.2.1.1 20-1.1.2 21-1.1.2.2.1 21-1.1.2.2.1.r 22-1.1.2.2 23-1.1.2.2.2.r 24-1.1.2.2.2.1 25-1.1.2.2.2 27-1 28-1.2.1.1.1 28-1.2.1.1.1.r 29-1.2.1 29-1.2.1.1 29-1.2.1.1.r 30-1.2.3 31-1.2 33-1.2.2 34-1.2.2.1.r 35-1.2.2.1.1 36-1.2.2.1 (a / and~e.27 :op1 (s / suggest-01~e.13 :ARG0 (d2 / data~e.1 :time (p3 / previous~e.0) :source~e.2 (a3 / and~e.4,8 :op1 (p4 / person :name (n2 / name :op1 "Wahba"~e.3)) :op2 (c / colleagues~e.5)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and~e.8 :op1 (p6 / person :name (n / name :op1 "Dholakia"~e.7)) :op2 p4~e.9) :time (d / date-entity :year 1988~e.11)))) :ARG1~e.14 (i / increase-01~e.20 :ARG0 (p / phosphorylate-01~e.15 :ARG1~e.16 (p7 / protein :name (n3 / name :op1 "eIF2Bepsilon"~e.17)) :ARG2~e.18 (e3 / enzyme :name (n4 / name :op1 "CK2"~e.19))) :ARG1 (a5 / activity-06~e.22 :ARG0~e.21 p7~e.21 :ARG1~e.23 (e2 / exchange-01~e.25 :ARG1 (n5 / nucleotide~e.24))))) :op2 (p2 / provide-01~e.31 :ARG0 (t2 / thing~e.29 :ARG1-of~e.29 (f / find-01~e.29 :ARG0~e.28 (w / we~e.28))) :ARG1 (e / explain-01~e.33 :ARG1-of~e.34 (a2 / affect-01~e.36 :mod (t / this~e.35))) :ARG1-of (c2 / cause-01~e.30))) # ::id bio.chicago_2015.57826 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The regulation of Chk1 is perhaps best characterized in Xenopus , where it has been demonstrated that Chk1 is phosphorylated and activated by ATR and that the ATR @-@ Chk1 pathway responds to unreplicated DNA and UV @-@ damaged DNA ( 26 ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.2 6-1.3 6-1.3.1 6-1.3.1.r 7-1 8-1.4.r 9-1.4.1.1 11-1.4.2.r 15-1.4.2.1 17-1.4.2.2.1.1.1 19-1.4.2.1.1.1 20-1.4.2.1.1 21-1.4.2.1.1.2 22-1.4.2.1.1.1.2.r 23-1.4.2.1.1.1.2.1.1 24-1.4.2.1.1 27-1.4.2.2.1.1.1 29-1.4.2.2.1.1.1 30-1.4.2.2.1 31-1.4.2.2 34-1.4.2.2.2.1.1.1 34-1.4.2.2.2.2.1.1 35-1.4.2.2.2 38-1.4.2.2.2.2.2 39-1.4.2.2.2.1.1.1 39-1.4.2.2.2.2.1.1 41-1.5.1.1.1 (c / characterize-01~e.7 :ARG1 (r / regulate-01~e.1 :ARG1~e.2 (e / enzyme :name (n3 / name :op1 "Chk1"~e.3))) :ARG1-of (p3 / possible-01~e.5) :ARG1-of (g / good-02~e.6 :degree~e.6 (m / most~e.6)) :location~e.8 (o / organism :name (n4 / name :op1 "Xenopus"~e.9) :location-of~e.11 (a / and :op1 (d / demonstrate-01~e.15 :ARG1 (a3 / and~e.20,24 :op1 (p / phosphorylate-01~e.19 :ARG1 e :ARG2~e.22 (e2 / enzyme :name (n9 / name :op1 "ATR"~e.23))) :op1 (a4 / activate-01~e.21 :ARG0 e2 :ARG1 e))) :op2 (r2 / respond-01~e.31 :ARG0 (p4 / pathway~e.30 :name (n5 / name :op1 "ATR-Chk1"~e.17,27,29)) :ARG1 (a2 / and~e.35 :op1 (n / nucleic-acid :name (n2 / name :op1 "DNA"~e.34,39) :ARG1-of (r3 / replicate-01 :polarity -)) :op2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"~e.34,39) :ARG1-of (d2 / damage-01~e.38 :polarity - :ARG0 (l / light :mod (u / ultraviolet)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 26~e.41)))) # ::id bio.chicago_2015.57852 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to JNK , JNKK1 also phosphorylates p38 in in @-@ vitro kinase assay and activates p38 in cotransfection assay ( Derijard et al. , 1995 ; Lin et al. , 1995 ) . # ::alignments 0-1.3.1 0-1.3.1.1.1 1-1.1.4 1-1.3.1 1-1.3.1.1.1 3-1.1.4.1.1.1.1 5-1.1.2.1.1 6-1.1.3 7-1.1 7-1.1.4.1 8-1.1.1.1.1.1 9-1.1.1.2.2 10-1.1.1.2.2 12-1.1.1.2.2 13-1.1.1.2.1 14-1.1.1.2 15-1 15-1.1.1 15-1.3.1 15-1.3.1.1.1 16-1.2 17-1.2.2 18-1.1.1.2.2 18-1.2.3.r 19-1.2.3.1 20-1.2.3 22-1.3.1.1.1.1.1.1 23-1.3.1.1.1 24-1.3.1.1.1.2.1 26-1.3.1.3.1 28-1.3.1.2.1.1.1.1 29-1.3.1 29-1.3.1.1.1 29-1.3.1.2.1 30-1.3.1.1.1.2.1 32-1.3.1.3.1 (a5 / and~e.15 :op1 (p / phosphorylate-01~e.7 :ARG1 (a3 / and~e.15 :op1 (e / enzyme :name (n / name :op1 "p38"~e.8)) :location (a4 / assay-01~e.14 :ARG1 (k / kinase~e.13) :manner (i / in-vitro~e.9,10,12,18))) :ARG2 (e2 / enzyme :name (n2 / name :op1 "JNKK1"~e.5)) :mod (a / also~e.6) :ARG1-of (a2 / add-02~e.1 :ARG2 (p2 / phosphorylate-01~e.7 :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK"~e.3)) :ARG2 e2))) :op2 (a6 / activate-01~e.16 :ARG0 e2 :ARG1 e~e.17 :location~e.18 (a7 / assay-01~e.20 :ARG1 (c / cotransfect-01~e.19))) :ARG1-of (d2 / describe-01 :ARG0 (a8 / and~e.0,1,15,29 :op1 (p3 / publication-91 :ARG0 (a9 / and~e.0,1,15,23,29 :op1 (p5 / person :name (n4 / name :op1 "Derijard"~e.22)) :op2 (p8 / person :mod (o / other~e.24,30)))) :op2 (p4 / publication-91 :ARG0 (a10 / and~e.29 :op1 (p7 / person :name (n5 / name :op1 "Lin"~e.28)) :op2 p8)) :time (d / date-entity :year 1995~e.26,32)))) # ::id bio.chicago_2015.57855 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hsc70 Is Not Phosphorylated by p16 # ::alignments 0-1.2.1.1 2-1.1 2-1.1.r 3-1 4-1.3.r 5-1.3.1.1 (p / phosphorylate-01~e.3 :polarity~e.2 -~e.2 :ARG1 (p2 / protein :name (n / name :op1 "Hsc70"~e.0)) :ARG2~e.4 (p3 / protein :name (n2 / name :op1 "p16"~e.5))) # ::id bio.chicago_2015.57886 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Tryptic peptide map of MBP phosphorylated by GST - LKB1 and GST - LKB1 @/@ flag @-@ STRAD ( left panel ) , and the corresponding Edman degradation diagram ( right panel ) and PAA analysis ( insert ) . # ::alignments 1-1.1 3-1.2.2.1.1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1.1 8-1.2.1.2 9-1.2.1.2.1.r 10-1.2.1.2.1.1.1.1 12-1.2.1.2.1.1.1.1 14-1.2.1.2.1.1.1.1 16-1.2.1.2.1.1.1.1 17-1.2.1.2.1.2 20-1.2.1.2.1.2.2.1.1 22-1.2.1.2.1.2.2.2.1.1 23-1.2.1.2.1.2.2.2.1 26-1 26-1.3 26-1.3.r 28-1.3.1.3 29-1.3.1.1.1.1.1 30-1.3.1.1 31-1.3.1 33-1.3.1.2.1.1 34-1.3.1.2.1 36-1.3 37-1.3.2.1.1 38-1.3.2 40-1.3.2.2.1 (a / and~e.26 :li "B"~e.1 :op1 (m / map-01~e.5 :ARG1~e.6 (p2 / protein :name (n6 / name :op1 "MBP"~e.7) :ARG1-of (p3 / phosphorylate-01~e.8 :ARG2~e.9 (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "GST-LKB1"~e.10,12,14,16)) :op2 (s / slash~e.17 :op1 p4 :op2 (p6 / protein :name (n4 / name :op1 "Flag-STRAD"~e.20) :ARG1-of (d / describe-01 :ARG0 (p5 / panel~e.23 :ARG1-of (l / left-20~e.22)))))))) :mod (p / peptide~e.4 :name (n / name :op1 "trypsin"~e.3))) :op2~e.26 (a3 / and~e.26,36 :op1 (d2 / diagram-01~e.31 :ARG1 (d3 / degrade-01~e.30 :mod (p7 / person :name (n3 / name :op1 "Edman"~e.29))) :ARG1-of (d4 / describe-01 :ARG0 (p9 / panel~e.34 :ARG1-of (r / right-04~e.33))) :ARG1-of (c / correspond-01~e.28)) :op2 (a4 / analyze-01~e.38 :name (n5 / name :op1 "PAA"~e.37) :ARG1-of (d5 / describe-01 :ARG0 (i / insert~e.40))))) # ::id bio.chicago_2015.57908 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Src family kinases phosphorylate c @-@ Abl # ::alignments 0-1.2.1.1 1-1.2 2-1.2.1.2 3-1 4-1.1.1.1 6-1.1.1.1 (p / phosphorylate-01~e.3 :ARG1 (p3 / protein :name (n2 / name :op1 "c-Abl"~e.4,6)) :ARG2 (p2 / protein-family~e.1 :name (n / name :op1 "Src"~e.0 :op2 "kinase"~e.2))) # ::id bio.chicago_2015.57910 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of PTC1 did not inhibit Tyr phosphorylation of Hog1 , suggesting it does not act on Pbs2 ( Fig . 4A ) . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.2.1 4-1.1 4-1.1.r 5-1 6-1.3.1.2.1 7-1.3 9-1.3.1.3.2.1 11-1.5 12-1.5.1.2 14-1.5.1.1 14-1.5.1.1.r 15-1.5.1 16-1.5.1.3.r 17-1.5.1.3.2.1 19-1.4.1 21-1.4.1.1 (i / inhibit-01~e.5 :polarity~e.4 -~e.4 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (e / enzyme :wiki "Ptc1" :name (n / name :op1 "PTC1"~e.2))) :ARG1 (p / phosphorylate-01~e.7 :ARG1 (a / amino-acid :wiki "Tyrosine" :name (n2 / name :op1 "tyrosine"~e.6) :part-of (p2 / protein :wiki - :name (n3 / name :op1 "Hog1"~e.9)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "4A"~e.21)) :ARG0-of (s / suggest-01~e.11 :ARG1 (a2 / act-02~e.15 :polarity~e.14 -~e.14 :ARG0 o~e.12 :ARG1~e.16 (e2 / enzyme :wiki - :name (n4 / name :op1 "Pbs2"~e.17))))) # ::id bio.chicago_2015.57934 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The plus sign (+) indicates the serine residue potentially phosphorylated by casein kinase II . # ::alignments 2-1.1 4-1 6-1.2.1.1.1.1 7-1.2.1 8-1.2.3 9-1.2 10-1.2.2.r 11-1.2.2.1.1 12-1.2.2.1.2 13-1.2.2.1.3 (i / indicate-01~e.4 :ARG0 (s / sign~e.2 :mod (s2 / string-entity :value +)) :ARG1 (p2 / phosphorylate-01~e.9 :ARG1 (r / residue~e.7 :mod (a / amino-acid :name (n / name :op1 "serine"~e.6))) :ARG2~e.10 (e / enzyme :name (n2 / name :op1 "casein"~e.11 :op2 "kinase"~e.12 :op3 "II"~e.13)) :mod (p3 / potential~e.8))) # ::id bio.chicago_2015.57958 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TFIIH phosphorylates CDC2 , CDK2 , TFIIF , TFIIE , TATA @-@ binding protein ( TBP ) and the CTD ( Lu et al. , 1992 ; Serizawa et al. , 1992 ; Ohkuma and Roeder , 1994 ; Serizawa et al. , 1995 ; Shiekhattar et al. , 1995 ) . # ::alignments 0-1.2.1.1 1-1 2-1.1.1.1.1 4-1.1.2.1.1 6-1.1.3.1.1 8-1.1.4.1.1 10-1.1.5.1.1 12-1.1.5.1.1 13-1.1.5.1.2 17-1.1 17-1.3.1 17-1.3.1.1.1 17-1.3.1.4.1 21-1.3.1.1.1.1.1.1 22-1.3.1.1.1 23-1.3.1.1.1.2.1 25-1.3.1.2.2.1 27-1.3.1.2.1.1.1.1 28-1.3.1 28-1.3.1.1.1 28-1.3.1.2.1 28-1.3.1.3.1 28-1.3.1.3.1.1 28-1.3.1.3.1.1.r 28-1.3.1.4.1 29-1.3.1.1.1.2.1 31-1.3.1.2.2.1 33-1.3.1.3.1.1.1.1.1 34-1.3.1.3.1.1 35-1.3.1.3.1.1.2.1.1 37-1.3.1.3.1.1.3.1 39-1.3.1.2.1.1.1.1 40-1.3.1 40-1.3.1.1.1 40-1.3.1.2.1 40-1.3.1.3.1 40-1.3.1.3.1.1 40-1.3.1.3.1.1.r 40-1.3.1.4.1 41-1.3.1.1.1.2.1 43-1.3.1.5.2.1 45-1.3.1.5.1.1.1.1 46-1.3.1 46-1.3.1.1.1 46-1.3.1.2.1 46-1.3.1.3.1 46-1.3.1.3.1.1 46-1.3.1.3.1.1.r 46-1.3.1.4.1 46-1.3.1.5.1 47-1.3.1.1.1.2.1 49-1.3.1.5.2.1 (p / phosphorylate-01~e.1 :ARG1 (a / and~e.17 :op1 (e / enzyme :name (n2 / name :op1 "CDC2"~e.2)) :op2 (e2 / enzyme :name (n3 / name :op1 "CDK2"~e.4)) :op3 (p4 / protein :name (n4 / name :op1 "TFIIF"~e.6)) :op4 (p5 / protein :name (n5 / name :op1 "TFIIE"~e.8)) :op5 (p6 / protein :name (n6 / name :op1 "TATA-binding"~e.10,12 :op2 "protein"~e.13)) :op6 (p3 / protein-segment :name (n7 / name :op1 "C-terminus"))) :ARG2 (p2 / protein :name (n / name :op1 "TFIIH"~e.0)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.17,28,40,46 :op1 (p8 / publication-91 :ARG0 (a3 / and~e.17,22,28,40,46 :op1 (p13 / person :name (n8 / name :op1 "Lu"~e.21)) :op2 (p18 / person :mod (o / other~e.23,29,41,47))) :time d) :op2 (p9 / publication-91 :ARG0 (a4 / and~e.28,40,46 :op1 (p14 / person :name (n9 / name :op1 "Serizawa"~e.27,39)) :op2 p18) :time (d / date-entity :year 1992~e.25,31)) :op3 (p10 / publication-91 :ARG0 (a5 / and~e.28,40,46 :op1~e.28,40,46 (a8 / and~e.28,34,40,46 :op1 (p15 / person :name (n10 / name :op1 "Ohkuma"~e.33)) :op2 (p23 / person :name (n13 / name :op1 "Roeder"~e.35)) :time (d3 / date-entity :year 1994~e.37)) :op2 p18)) :op4 (p11 / publication-91 :ARG0 (a6 / and~e.17,28,40,46 :op1 p14 :op2 p18 :time d4)) :op5 (p12 / publication-91 :ARG0 (a7 / and~e.46 :op1 (p17 / person :name (n12 / name :op1 "Shiekhattar"~e.45)) :op2 p18) :time (d4 / date-entity :year 1995~e.43,49))))) # ::id bio.chicago_2015.57959 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tyrosine phosphorylation of the Kv1.3 potassium channel . # ::alignments 0-1.1.1.1 1-1 4-1.1.2.1.1 5-1.1.2.1.2 6-1.1.2.1.3 (p / phosphorylate-01~e.1 :ARG1 (a / amino-acid :name (n2 / name :op1 "Tyrosine"~e.0) :part-of (p2 / protein :name (n / name :op1 "Kv1.3"~e.4 :op2 "potassium"~e.5 :op3 "channel"~e.6)))) # ::id bio.chicago_2015.57964 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Experiments with transgenic mice also support a crucial role of CaM @-@ KII phosphorylation of GluR1 as an important component of CA1 LTP in mature animals . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1 4-1.3 5-1 7-1.2.1 8-1.2 9-1.2.2.r 10-1.2.2.2.1.1 12-1.2.2.2.1.1 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.1.1 16-1.2.3.r 18-1.2.3.1 19-1.2.3 21-1.2.3.2.1.1.1 24-1.2.3.2.2.1 25-1.2.3.2.2 (s / support-01~e.5 :ARG0 (e / experiment-01~e.0 :ARG1~e.1 (m / mouse~e.3 :mod (t / transgenic~e.2))) :ARG1 (r / role~e.8 :mod (c / crucial~e.7) :poss~e.9 (p / phosphorylate-01~e.13 :ARG1~e.14 (p2 / protein :name (n2 / name :op1 "GluR1"~e.15)) :ARG2 (e2 / enzyme :name (n / name :op1 "CaM-KII"~e.10,12))) :domain~e.16 (c2 / component~e.19 :mod (i / important~e.18) :purpose (p3 / potentiate-01 :ARG1 (g / gene :name (n3 / name :op1 "CA1"~e.21)) :location (a2 / animal~e.25 :ARG1-of (m2 / mature-01~e.24)) :ARG1-of (l / long-03)))) :mod (a / also~e.4)) # ::id bio.chicago_2015.58014 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of Myosin VI by PAK In Vitro # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.1.1.2 4-1.2.r 5-1.2.1.1 6-1.3 7-1.3 (p / phosphorylate-01~e.0 :ARG1~e.1 (p2 / protein :name (n / name :op1 "Myosin"~e.2 :op2 "VI"~e.3)) :ARG2~e.4 (e / enzyme :name (n2 / name :op1 "PAK"~e.5)) :manner (i / in-vitro~e.6,7)) # ::id bio.chicago_2015.58026 ::amr-annotator SDL-AMR-09 ::preferred # ::tok dTRAF2 Is Phosphorylated by Pelle . # ::alignments 0-1.1.1.1 2-1 3-1.2.r 4-1.2.1.1 (p / phosphorylate-01~e.2 :ARG1 (p2 / protein :name (n / name :op1 "dTRAF2"~e.0)) :ARG2~e.3 (e / enzyme :name (n2 / name :op1 "Pelle"~e.4))) # ::id bio.chicago_2015.58031 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the phosphorylation of MEF2 by p38 MAP kinase and ERK5 @/@ BMK1 may precede or stabilise the Smad - MEF2 interaction . # ::alignments 0-1 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1 6-1.1.1.1.2.r 7-1.1.1.1.2.1.1.1 8-1.1.1.1.2.1.1.2 9-1.1.1.1.2.1.1.3 10-1.1.1.1.2 11-1.1.1.1.2.2.1.1 13-1.1.1.1.2.2.1.1 14-1.1.3 15-1.1.1 16-1.1 19-1.1.1.2.1.1.1 21-1.1.1.2.2.1.1 22-1.1.1.2 (c / cause-01~e.0 :ARG1 (o / or~e.16 :op1 (p2 / precede-01~e.15 :ARG1 (p3 / phosphorylate-01~e.3 :ARG1~e.4 p~e.5 :ARG2~e.6 (a / and~e.10 :op1 (k / kinase :name (n / name :op1 "p38"~e.7 :op2 "MAP"~e.8 :op3 "kinase"~e.9)) :op2 (p5 / pathway :name (n2 / name :op1 "ERK5/BMK1"~e.11,13)))) :ARG2 (i / interact-01~e.22 :ARG0 (p6 / protein :name (n4 / name :op1 "Smad"~e.19)) :ARG1 (p / protein :name (n5 / name :op1 "MEF2"~e.21)))) :op2 (s / stabilize-01 :ARG0 p3 :ARG1 i) :ARG1-of (p4 / possible-01~e.14))) # ::id bio.chicago_2015.58034 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A number of transcription factors are phosphorylated in response to SAPK activation ; for example , the c @-@ Jun factor is regulated by JNK ( Hibi et al. , 1993 ; Derijard et al. , 1994 ; Kyriakis et al. , 1994 ) but not by p38 , whereas ATF2 is phosphorylated and regulated by both JNK ( Gupta et al. , 1995 ; Livingstone et al. , 1995 ; van Dam et al. , 1995 ) and p38 ( Raingeaud et al. , 1995 ) . # ::alignments 1-1.1.1.2 2-1.1.1.2.r 3-1.1.1.1 4-1.1.1 6-1.1 7-1.1.2.r 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.1.1.1 11-1.1.2.1 13-1.2.1 14-1.2.1 17-1.2.1.1.2.1.1 19-1.2.1.1.2.1.1 20-1.1.1 22-1.2.1.1 23-1.2.1.1.1.r 24-1.2.1.1.1.1.1 26-1.2.1.2.1.1.1.1.1.1 27-1.2.1.2.1.1.1 28-1.2.1.2.1.1.1.2.1 30-1.2.1.2.1.1.2.1 32-1.2.1.2.1.2.1.1.1.1 33-1.2.1.2.1 33-1.2.1.2.1.1.1 33-1.2.1.2.1.2.1 33-1.2.1.2.1.3.1 34-1.2.1.2.1.1.1.2.1 36-1.2.1.2.1.3.2 38-1.2.1.2.1.3.1.1.1.1 39-1.2.1.2.1 39-1.2.1.2.1.1.1 39-1.2.1.2.1.2.1 39-1.2.1.2.1.3.1 40-1.2.1.2.1.1.1.2.1 42-1.2.1.2.1.2.2.1 44-1.2.3 45-1.2.2.1 45-1.2.2.1.r 47-1.2.2.2.1.1 49-1.2 49-1.2.3 49-1.2.3.r 50-1.2.3.1.1.1.1.1 52-1.2.3.1.1 53-1.2.1.2.1 53-1.2.1.2.1.1.1 53-1.2.1.2.1.3.1 53-1.2.3.1 53-1.2.3.1.1.2 53-1.2.3.1.1.3.1 53-1.2.3.1.1.3.1.1.1 53-1.2.3.1.2.3.1.1 54-1.2.2 54-1.2.3.1.2 57-1.2.1.1.1.1.1 59-1.2.3.1.1.3.1.1.1.1.1.1 60-1.2.1.2.1 60-1.2.1.2.1.1.1 60-1.2.1.2.1.3.1 60-1.2.3.1 60-1.2.3.1.1.3.1 60-1.2.3.1.1.3.1.1.1 60-1.2.3.1.1.3.1.2.1 60-1.2.3.1.1.3.1.3.1 60-1.2.3.1.2.3.1.1 61-1.2.1.2.1.1.1.2.1 63-1.2.3.1.1.3.1.2.2 65-1.2.3.1.1.3.1.2.1.1.1.1 66-1.2.1.2.1 66-1.2.1.2.1.1.1 66-1.2.1.2.1.3.1 66-1.2.3.1 66-1.2.3.1.1.3.1 66-1.2.3.1.1.3.1.1.1 66-1.2.3.1.1.3.1.2.1 66-1.2.3.1.1.3.1.3.1 66-1.2.3.1.2.3.1.1 67-1.2.1.2.1.1.1.2.1 69-1.2.3.1.1.3.1.3.2 71-1.2.3.1.1.3.1.3.1.1.1.1 72-1.2.3.1.1.3.1.3.1.1.1.2 73-1.2.1.2.1 73-1.2.1.2.1.1.1 73-1.2.1.2.1.3.1 73-1.2.3.1 73-1.2.3.1.1.3.1 73-1.2.3.1.1.3.1.1.1 73-1.2.3.1.1.3.1.2.1 73-1.2.3.1.1.3.1.3.1 73-1.2.3.1.2.3.1.1 74-1.2.1.2.1.1.1.2.1 76-1.2.3.1.1.3.1.1.2.1 78-1.2.1.2.1 78-1.2.1.2.1.1.1 78-1.2.1.2.1.3.1 78-1.2.3.1 78-1.2.3.1.1.3.1 78-1.2.3.1.1.3.1.1.1 78-1.2.3.1.1.3.1.2.1 78-1.2.3.1.1.3.1.3.1 78-1.2.3.1.2.3.1.1 79-1.2.2.2.1.1 81-1.2.3.1.2.3.1.1.1.2.1 82-1.2.1.2.1 82-1.2.1.2.1.1.1 82-1.2.1.2.1.3.1 82-1.2.3.1 82-1.2.3.1.1.3.1 82-1.2.3.1.1.3.1.1.1 82-1.2.3.1.1.3.1.2.1 82-1.2.3.1.1.3.1.3.1 82-1.2.3.1.2.3.1.1 83-1.2.1.2.1.1.1.2.1 85-1.2.3.1.1.3.1.1.2.1 (m / multi-sentence :snt1 (p / phosphorylate-01~e.6 :ARG1 (f / factor~e.4,20 :ARG0-of (t / transcribe-01~e.3) :quant~e.2 (n13 / number~e.1)) :ARG2-of~e.7 (r / respond-01~e.8 :ARG1~e.9 (a / activate-01~e.11 :ARG1 (e2 / enzyme :name (n2 / name :op1 "SAPK"~e.10))))) :snt2 (c / contrast-01~e.49 :ARG1 (e3 / exemplify-01~e.13,14 :ARG0 (r2 / regulate-01~e.22 :ARG0~e.23 (e / enzyme :name (n4 / name :op1 "JNK"~e.24,57)) :ARG1 (p2 / protein :name (n3 / name :op1 "c-Jun"~e.17,19))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.33,39,53,60,66,73,78,82 :op1 (p5 / publication-91 :ARG0 (a5 / and~e.27,33,39,53,60,66,73,78,82 :op1 (p8 / person :name (n6 / name :op1 "Hibi"~e.26)) :op2 (p9 / person :mod (o / other~e.28,34,40,61,67,74,83))) :time (d / date-entity :year 1993~e.30)) :op2 (p6 / publication-91 :ARG0 (a6 / and~e.33,39 :op1 (p10 / person :name (n7 / name :op1 "Derijard"~e.32)) :op2 p9) :time (d2 / date-entity :year 1994~e.42)) :op3 (p7 / publication-91 :ARG0 (a7 / and~e.33,39,53,60,66,73,78,82 :op1 (p12 / person :name (n8 / name :op1 "Kyriakis"~e.38)) :op2 p9) :time d2~e.36)))) :ARG2 (r3 / regulate-01~e.54 :polarity~e.45 -~e.45 :ARG0 (e4 / enzyme :name (n5 / name :op1 "p38"~e.47,79)) :ARG1 p2) :ARG1-of~e.49 (c2 / contrast-01~e.44,49 :ARG2 (a2 / and~e.53,60,66,73,78,82 :op1 (p4 / phosphorylate-01~e.52 :ARG1 (p3 / protein :name (n14 / name :op1 "ATF2"~e.50)) :ARG2 (a3 / and~e.53 :op1 e :op2 e4) :ARG1-of (d5 / describe-01 :ARG0 (a8 / and~e.53,60,66,73,78,82 :op1 (p14 / publication-91 :ARG0 (a9 / and~e.53,60,66,73,78,82 :op1 (p17 / person :name (n9 / name :op1 "Gupta"~e.59)) :op2 p9) :time (d4 / date-entity :year 1995~e.76,85)) :op2 (p15 / publication-91 :ARG0 (a10 / and~e.60,66,73,78,82 :op1 (p19 / person :name (n10 / name :op1 "Livingstone"~e.65)) :op2 p9) :time d4~e.63) :op3 (p16 / publication-91 :ARG0 (a11 / and~e.60,66,73,78,82 :op1 (p21 / person :name (n11 / name :op1 "Van"~e.71 :op2 "Dam"~e.72)) :op2 p9) :time d4~e.69)))) :op2 (r4 / regulate-01~e.54 :ARG0 a3 :ARG1 p3 :ARG1-of (d6 / describe-01 :ARG0 (p23 / publication-91 :ARG0 (a12 / and~e.53,60,66,73,78,82 :op1 (p24 / person :op2 p9 :name (n12 / name :op1 "Raingeaud"~e.81))) :time d4))))))) # ::id bio.chicago_2015.58063 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether Src family kinases could directly phosphorylate c @-@ Abl , we produced Src and Fyn in baculovirus @-@ infected Sf9 insect cells , and incubated Src or Fyn immunoprecipitates with various GST @-@ Abl fragments . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.2.2.1 4-1.3.2.2.2.1 5-1.3.2.2.2 6-1.3.2 7-1.3.2.2.3 8-1.3.2.2 9-1.3.2.2.1.1.1 11-1.3.2.2.1.1.1 13-1.1.1 14-1.1 15-1.1.2.1.1.1 16-1.1.2 17-1.1.2.2.1.1 18-1.1.3.r 19-1.1.3.2.1.1.1.1 21-1.1.3.2.1 22-1.1.3.1.1 23-1.1.3.2 24-1.1.3 26-1 27-1.2 28-1.1.2.1.1.1 29-1.2.2 30-1.1.2.2.1.1 31-1.2.2.1 31-1.2.2.2 34-1.2.3.1.1.1 36-1.2.3.1.1.1 37-1.2.3 (a2 / and~e.26 :op1 (p2 / produce-01~e.14 :ARG0 (w / we~e.13) :ARG1 (a / and~e.16 :op1 (p / protein-family :name (n3 / name :op1 "Src"~e.15,28)) :op2 (e / enzyme :name (n4 / name :op1 "Fyn"~e.17,30))) :location~e.18 (c / cell-line~e.24 :name (n / name :op1 "Sf9"~e.22) :part-of (i / insect~e.23 :ARG1-of (i2 / infect-01~e.21 :ARG2 (o2 / organism :name (n6 / name :op1 "baculovirus"~e.19)))))) :op2 (i3 / incubate-01~e.27 :ARG0 w :ARG1 (o / or~e.29 :op1 (i4 / immunoprecipitate-01~e.31 :ARG1 p) :op2 (i5 / immunoprecipitate-01~e.31 :ARG1 e)) :ARG2 (f / fragment-01~e.37 :ARG1 (p8 / protein :name (n5 / name :op1 "GST-Abl"~e.34,36)) :ARG1-of (v / vary-01))) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (p5 / possible-01~e.6 :mode~e.2 interrogative~e.2 :ARG1 (p3 / phosphorylate-01~e.8 :ARG1 (p6 / protein :name (n2 / name :op1 "c-Abl"~e.9,11)) :ARG2 (k / kinase~e.5 :mod p~e.3,4) :ARG1-of (d2 / direct-02~e.7))))) # ::id bio.chicago_2015.58067 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our lab and others have recently identified S6K2 , a homolog of S6K1 that phosphorylates S6 in vitro ( 4 @-@ 7 ) . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1 1-1.1.2 2-1.1 3-1.1.2.1 5-1.3 6-1 7-1.2.1.1 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.1.1 14-1.2.2.1 14-1.2.2.1.2 14-1.2.2.1.2.r 15-1.2.2.1.2.1.1.1 16-1.2.2.1.2.2 17-1.2.2.1.2.2 19-1.4.2.1.1 21-1.4.2.1.2 (i / identify-01~e.6 :ARG0 (a / and~e.2 :op1 (l / lab~e.1 :poss~e.0 (w / we~e.0)) :op2 (l2 / lab~e.1 :mod (o / other~e.3))) :ARG1 (e / enzyme :name (n / name :op1 "S6K2"~e.7) :domain (h / homolog~e.10 :poss~e.11 (e2 / enzyme~e.14 :name (n2 / name :op1 "S6K1"~e.12) :ARG2-of~e.14 (p / phosphorylate-01~e.14 :ARG1 (e3 / enzyme :name (n3 / name :op1 "S6"~e.15)) :manner (i2 / in-vitro~e.16,17))))) :time (r / recent~e.5) :ARG1-of (d / describe-01 :ARG0 (p3 / publication) :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 4~e.19 :op2 7~e.21)))) # ::id bio.chicago_2015.58101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Myosin II was phosphorylated by MLCK in the presence of various concentrations of isolated RLC @-@ GFP . # ::alignments 0-1.1.1.1 1-1.1.1.2 3-1 4-1.2.r 5-1.2.1.1 6-1.3.r 8-1.3 11-1.3.1 12-1.3.1.1.r 13-1.3.1.1.2 14-1.3.1.1.1.1 16-1.3.1.1.1.1 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein :name (n / name :op1 "Myosin"~e.0 :op2 "II"~e.1)) :ARG2~e.4 (e / enzyme :name (n2 / name :op1 "MLCK"~e.5)) :ARG2-of~e.6 (p3 / present-02~e.8 :ARG1 (c / concentrate-02~e.11 :ARG1~e.12 (m / macro-molecular-complex :name (n3 / name :op1 "RLC-GFP"~e.14,16) :ARG1-of (i / isolate-01~e.13)) :ARG1-of (v / vary-01)))) # ::id bio.chicago_2015.58172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This initial phosphorylation of Rb by cyclin D/Cdk4 also disrupts its interaction with HDAC , thereby relieving the repression of the cyclin E gene and allowing further progression into S phase ( Zhang et al. , 2000 ) . # ::alignments 0-1.1.1.4 1-1.1.1.3 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1.1 8-1.1.3 9-1.1 10-1.1.2.1 10-1.1.2.1.r 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2.1.1 16-1.2.1 18-1.2.1.2 19-1.2.1.2.1.r 21-1.2.1.2.1.1.1 22-1.2.1.2.1.1.2 23-1.2.1.2.1 24-1.2 25-1.2.2 26-1.2.2.2.2 27-1.2.2.2 28-1.2.2.2.1.r 29-1.2.2.2.1.1.1 30-1.2.2.2.1 32-1.3.1.1.1.1.1 33-1.3.1.1 34-1.3.1.1.2.1 36-1.3.1.2.1 (c / cause-01 :ARG0 (d2 / disrupt-01~e.9 :ARG0 (p2 / phosphorylate-01~e.2 :ARG1~e.3 (p3 / protein :name (n / name :op1 "Rb"~e.4)) :ARG2~e.5 (m / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "Cyclin"~e.6 :op2 "D")) :part (e2 / enzyme :name (n7 / name :op1 "Cdk4"))) :mod (i / initial~e.1) :mod (t / this~e.0)) :ARG1 (i2 / interact-01~e.11 :ARG0~e.10 p2~e.10 :ARG1~e.12 (e / enzyme :name (n3 / name :op1 "HDAC"~e.13))) :mod (a / also~e.8)) :ARG1 (a2 / and~e.24 :op1 (r / relieve-01~e.16 :ARG0 p2 :ARG1 (r2 / repress-01~e.18 :ARG0~e.19 (g / gene~e.23 :name (n4 / name :op1 "cyclin"~e.21 :op2 "E"~e.22)))) :op2 (a3 / allow-01~e.25 :ARG0 p2 :ARG1 (p5 / progress-01~e.27 :ARG3~e.28 (p6 / phase~e.30 :name (n6 / name :op1 "S"~e.29)) :degree (f / further~e.26)))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and~e.33 :op1 (p / person :name (n5 / name :op1 "Zhang"~e.32)) :op2 (p8 / person :mod (o / other~e.34))) :time (d / date-entity :year 2000~e.36)))) # ::id bio.chicago_2015.58176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation and activation of myosin by Rho @-@ associated kinase ( Rho @-@ kinase ) . # ::alignments 0-1.1 1-1 2-1.2 3-1.1.1.r 4-1.1.1.1.1 5-1.1.2.r 6-1.1.2.1.1 8-1.1.2.1.1 9-1.1.2.1.2 11-1.1.2.1.1 13-1.1.2.1.2 (a / and~e.1 :op1 (p / phosphorylate-01~e.0 :ARG1~e.3 (p2 / protein :name (n / name :op1 "myosin"~e.4)) :ARG2~e.5 (e / enzyme :name (n2 / name :op1 "Rho-associated"~e.6,8,11 :op2 "kinase"~e.9,13))) :op2 (a2 / activate-01~e.2 :ARG0 e :ARG1 p2)) # ::id bio.chicago_2015.58200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok p34 cdc2 phosphorylated the threonine residue located in the tail domain that is conserved within the bimC family of kinesin @-@ related protein . # ::alignments 0-1.2.1.1 1-1.2.1.2 2-1 4-1.1.1.1.1 5-1.1 6-1.1.2.r 9-1.1.2.1 10-1.1.2 13-1.1.2.2 16-1.1.2.2.1.1.1 17-1.1.2.2.1 19-1.1.2.2.1.2.1.1.1 21-1.1.2.2.1.2 22-1.1.2.2.1 22-1.1.2.2.1.2.1 (p / phosphorylate-01~e.2 :ARG1 (r / residue~e.5 :mod (a2 / amino-acid :name (n3 / name :op1 "threonine"~e.4)) :location~e.6 (d / domain~e.10 :mod (t / tail~e.9) :ARG1-of (c / conserve-01~e.13 :location (p2 / protein-family~e.17,22 :name (n4 / name :op1 "BimC"~e.16) :ARG1-of (r2 / relate-01~e.21 :ARG2 (p3 / protein~e.22 :name (n / name :op1 "kinesin"~e.19))))))) :ARG2 (e / enzyme :name (n2 / name :op1 "p34"~e.0 :op2 "cdc2"~e.1))) # ::id bio.chicago_2015.58215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is possible , however , that Myt1 can phosphorylate Cdk2 that has been initially phosphorylated on Tyr15 , as has been previously suggested ( 11 ) . # ::alignments 2-1 4-1.2 6-1.1.r 7-1.1.1.2.1.1 8-1.1 9-1.1.1 10-1.1.1.1.1.1 14-1.1.1.1.3.1 15-1.1.1.1.3 19-1.1.1.1.3.1.r 19-1.1.1.1.3.2.1.r 22-1.1.1.1.3.2.1 23-1.1.1.1.3.2 25-1.3.1.1.1 (p / possible-01~e.2 :ARG1~e.6 (p2 / possible-01~e.8 :ARG1 (p3 / phosphorylate-01~e.9 :ARG1 (e / enzyme :name (n2 / name :op1 "Cdk2"~e.10) :part-of (a / amino-acid :mod 15 :name (n3 / name :op1 "Tyrosine")) :ARG3-of (p6 / phosphorylate-01~e.15 :time~e.19 (i / initial~e.14) :ARG1-of (s / suggest-01~e.23 :time~e.19 (p7 / previous~e.22)))) :ARG2 (p4 / protein :name (n / name :op1 "Myt1"~e.7)))) :ARG2-of (c2 / contrast-01~e.4) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c / cite-01 :ARG2 11~e.25)))) # ::id bio.chicago_2015.58274 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Similar amounts of Cdc2 can be precipitated from either wild @-@ type or mutant embryos using anti @-@ Cyclin B antibodies but the fast migrating ( Thr @-@ 161 phosphorylated ) isoform of Cdc2 ( Edgar et al. 1994 ) is reduced in the cdk7 ts embryos as compared to wild type . # ::alignments 1-1.1 3-1.2.1.1.2 4-1.2.1.1 5-1.2.1.1.1.r 6-1.2.1.1.1.1.1 7-1.2 9-1.2.1 10-1.2.1.2.r 12-1.2.1.2.1.1 14-1.2.1.2.1.1 15-1.2.1.2 16-1.2.1.2.2.1 17-1.2.1.2.1 17-1.2.1.2.2 19-1.2.1.3.1 21-1.2.1.3.1.1.1.1 22-1.2.1.3.1.1.1.2 23-1.2.1.3 24-1 26-1.3.1.1.1 27-1.3.1.1 31-1.3.1.4.1 32-1.3.1.4.3 34-1.3.1 35-1.3.1.2.r 36-1.3.1.2 38-1.3.1.3.1.1.1.1.1 39-1.3.1.3.1.1 40-1.3.1.3.1.1.2.1 41-1.3.1.3.1.2.1 44-1.3 49-1.3.2 50-1.3.1.3.1.2.r 50-1.3.3.r 51-1.3.3 52-1.3.3.1.r 53-1.3.3.1 54-1.3.3.1 (c / contrast-01~e.24 :li "B"~e.1 :ARG1 (p / possible-01~e.7 :ARG1 (p2 / precipitate-01~e.9 :ARG1 (a / amount-01~e.4 :ARG1~e.5 (e5 / enzyme :name (n / name :op1 "Cdc2"~e.6)) :ARG1-of (r / resemble-01~e.3)) :source~e.10 (o / or~e.15 :op1 (e / embryo~e.17 :mod (w / wild-type~e.12,14)) :op2 (e2 / embryo~e.17 :ARG2-of (m / mutate-01~e.16))) :instrument (a2 / antibody~e.23 :ARG0-of (c2 / counter-01~e.19 :ARG1 (p4 / protein :name (n2 / name :op1 "Cyclin"~e.21 :op2 "B"~e.22)))))) :ARG2 (r2 / reduce-01~e.44 :ARG1 (i / isoform~e.34 :ARG0-of (m2 / migrate-01~e.27 :ARG1-of (f / fast-02~e.26)) :mod~e.35 e5~e.36 :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and~e.39 :op1 (p6 / person :name (n3 / name :op1 "Edgar"~e.38)) :op2 (p7 / person :mod (o2 / other~e.40))) :time~e.50 (d / date-entity :year 1994~e.41))) :part (a4 / amino-acid :mod 161~e.31 :name (n5 / name :op1 "Threonine") :ARG3-of (p3 / phosphorylate-01~e.32))) :location (e3 / embryo~e.49 :mod (p8 / protein :name (n4 / name :op1 "cdk7ts"))) :ARG1-of~e.50 (c3 / compare-01~e.51 :ARG2~e.52 e~e.53,54))) # ::id bio.chicago_2015.58292 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm further the specific phosphorylation of MARCKS by PKC , we included the PKC inhibitor peptide ( 19 @-@ 31 ) in the phosphorylation assay . # ::alignments 1-1.4 2-1.4.3 4-1.4.2.3 5-1.4.2 6-1.4.2.1.r 7-1.4.2.1.1.1 8-1.4.2.2.r 9-1.4.2.2 11-1.1 12-1 14-1.2.1.1.1.1 15-1.2.1 16-1.2 18-1.2.2.1.1.1.1 20-1.2.2.1.1.1.2 22-1.3.r 24-1.3.1 25-1.3 (i2 / include-01~e.12 :ARG0 (w / we~e.11) :ARG1 (p2 / peptide~e.16 :ARG0-of (i3 / inhibit-01~e.15 :ARG1 (e / enzyme :name (n / name :op1 "PKC"~e.14))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 19~e.18 :op2 31~e.20))))) :ARG2~e.22 (a / assay-01~e.25 :ARG1 (p / phosphorylate-01~e.24)) :purpose (c / confirm-01~e.1 :ARG0 w :ARG1 (p3 / phosphorylate-01~e.5 :ARG1~e.6 (p5 / protein :name (n2 / name :op1 "MARCKS"~e.7)) :ARG2~e.8 e~e.9 :ARG1-of (s / specific-02~e.4)) :degree (f / further~e.2))) # ::id bio.chicago_2015.58296 ::amr-annotator SDL-AMR-09 ::preferred # ::tok N @-@ terminal KSR was phosphorylated by Nm23 @-@ H1 only under the specific conditions of transfection with Pyo @-@ tagged N @-@ terminal KSR , immunoprecipitation with anti @-@ Pyo , and incubation with wild type autophosphorylated Nm23 @-@ H1 ( upper panel ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1.1.1.2 5-1 7-1.2.1.1 9-1.2.1.1 10-1.5 13-1.3.4 14-1.3.r 16-1.3.1 17-1.3.1.2.r 18-1.3.1.2.2.1 20-1.3.1.2.2 21-1.3.1.2.1.1 23-1.3.1.2.1.1 24-1.3.1.2.1.2 26-1.3.2 27-1.3.2.2.r 28-1.3.2.2 28-1.3.2.2.1 28-1.3.2.2.1.r 30-1.3.2.2.1.1.1.1 32-1.3 33-1.3.3 34-1.3.3.2.r 35-1.3.3.2.2 36-1.3.3.2.2 37-1 37-1.3.3.2.3 38-1.2.1.1 38-1.3.3.2.1.1 40-1.2.1.1 40-1.3.3.2.1.1 42-1.4.1.1 43-1.4.1 (p / phosphorylate-01~e.5,37 :ARG1 (e / enzyme :name (n / name :op1 "N-terminal"~e.0,2 :op2 "KSR"~e.3)) :ARG2 (p4 / protein :name (n2 / name :op1 "Nm23-H1"~e.7,9,38,40)) :condition~e.14 (a / and~e.32 :op1 (t / transfect-01~e.16 :ARG1 e :ARG2~e.17 (e2 / enzyme :name (n3 / name :op1 "N-terminal"~e.21,23 :op2 "KSR"~e.24) :ARG1-of (t2 / tag-01~e.20 :ARG2 s~e.18))) :op2 (i / immunoprecipitate-01~e.26 :ARG1 e :ARG3~e.27 (m / molecular-physical-entity~e.28 :ARG0-of~e.28 (c / counter-01~e.28 :ARG1 (s / small-molecule :name (n4 / name :op1 "Pyo"~e.30))))) :op3 (i2 / incubate-01~e.33 :ARG1 e :ARG2~e.34 (p5 / protein :name (n5 / name :op1 "Nm23-H1"~e.38,40) :mod (w / wild-type~e.35,36) :ARG1-of (p3 / phosphorylate-01~e.37 :ARG2 p4))) :ARG1-of (s2 / specific-02~e.13)) :ARG1-of (d / describe-01 :ARG0 (p2 / panel~e.43 :mod (u / upper~e.42))) :mod (o / only~e.10)) # ::id bio.chicago_2015.58306 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PKC directly phosphorylates GluR2 but not GluR2S880A mutant fusion proteins . # ::alignments 0-1.1.2.1.1 1-1.1.3 2-1.1 2-1.2 3-1.1.1.1.1 4-1 5-1.2.1 5-1.2.1.r 6-1.2.2.1.1 7-1.2.2.3 8-1.2.2.2 9-1.1.1 9-1.2.2 (c / contrast-01~e.4 :ARG1 (p / phosphorylate-01~e.2 :ARG1 (p4 / protein~e.9 :name (n2 / name :op1 "GluR2"~e.3)) :ARG2 (e / enzyme :name (n / name :op1 "PKC"~e.0)) :ARG1-of (d / direct-02~e.1)) :ARG2 (p2 / phosphorylate-01~e.2 :polarity~e.5 -~e.5 :ARG1 (p3 / protein~e.9 :name (n3 / name :op1 "GluR2S880A"~e.6) :ARG1-of (f / fuse-01~e.8) :ARG2-of (m / mutate-01~e.7)) :ARG2 e)) # ::id bio.chicago_2015.58325 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It did , however , inhibit the phosphorylation and binding of endogenous Shc to MT and Grb2 . # ::alignments 3-1 5-1.1 7-1.1.1.1 8-1.1.1 9-1.1.1.2 10-1.1.1.1.1.r 11-1.1.1.1.1.2 13-1.1.1.2.2.r 14-1.1.1.2.2.1.1.1 16-1.1.1.2.2.2.1.1 (c / contrast-01~e.3 :ARG2 (i / inhibit-01~e.5 :ARG1 (a / and~e.8 :op1 (p2 / phosphorylate-01~e.7 :ARG1~e.10 (p / protein :name (n / name :op1 "Sch") :mod (e / endogenous~e.11))) :op2 (b / bind-01~e.9 :ARG1 p :ARG2~e.13 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "MT"~e.14)) :op2 (p4 / protein :name (n3 / name :op1 "Grb2"~e.16))))))) # ::id bio.chicago_2015.58328 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , Frat @-@ 1 prefers Dvl @-@ 1 phosphorylated by CKIepsilon , and the amino acid region 228 @-@ 250 of Dvl @-@ 1 is necessary for the direct binding of Dvl @-@ 1 to Frat @-@ 1 . # ::alignments 0-1.3 1-1.3.1 3-1.1.1.1.1 5-1.1.1.1.1 5-1.1.2.1.1.1 6-1.1 7-1.1.2.1.1.1 9-1.1.2.1.1.1 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2.1.1 14-1 16-1.2.2.1 17-1.2.2.1 18-1.2.2 19-1.2.2.3.1 21-1.2.2.3.2 22-1.2.2.2.r 23-1.2.2.2 25-1.1.1.1.1 25-1.1.2.1.1.1 27-1.2 28-1.2.1.r 30-1.2.1.3 31-1.2.1 32-1.2.1.1.r 33-1.2.1.1 35-1.1.1.1.1 35-1.1.2.1.1.1 37-1.1.1.1.1 39-1.1.1.1.1 39-1.1.2.1.1.1 (a / and~e.14 :op1 (p / prefer-01~e.6 :ARG0 (p2 / protein :name (n3 / name :op1 "Frat-1"~e.3,5,25,35,37,39)) :ARG1 (p4 / phosphorylate-01~e.10 :ARG1 (p5 / protein :name (n5 / name :op1 "Dvl-1"~e.5,7,9,25,35,39)) :ARG2~e.11 (e / enzyme :name (n4 / name :op1 "CKIepsilon"~e.12)))) :op2 (n2 / need-01~e.27 :ARG0~e.28 (b2 / bind-01~e.31 :ARG1~e.32 p5~e.33 :ARG2 p2 :ARG1-of (d / direct-02~e.30)) :ARG1 (r / region~e.18 :mod (a2 / amino-acid~e.16,17) :part-of~e.22 p5~e.23 :mod (v / value-interval :op1 228~e.19 :op2 250~e.21))) :ARG1-of (t2 / take-01~e.0 :manner (t / together~e.1))) # ::id bio.chicago_2015.58338 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , PKG phosphorylation of SF1 @-@ C4 completely inhibited spliceosome assembly ( Figure 7B , lanes 7 @-@ 9 ) . # ::alignments 1-1 3-1.1.1.2.1.1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1.1.1.1.1.1 9-1.1.3 10-1.1 11-1.1.2.1 12-1.1.2 14-1.2.1.1 15-1.2.1.1.1 17-1.2.1.2 18-1.2.1.2.1.1 20-1.2.1.2.1.2 (c / contrast-01~e.1 :ARG2 (i / inhibit-01~e.10 :ARG0 (p2 / phosphorylate-01~e.4 :ARG1~e.5 (p3 / protein :name (n / name :op1 "SF1-C4"~e.6,8)) :ARG2 (e / enzyme :name (n2 / name :op1 "PKG"~e.3))) :ARG1 (a / assembly~e.12 :mod (s / spliceosome~e.11)) :ARG1-of (c2 / complete-02~e.9)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.14 :mod "7B"~e.15) :op2 (l / lane~e.17 :mod (v / value-interval :op1 7~e.18 :op2 9~e.20))))) # ::id bio.chicago_2015.62138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Emi1 can bind Cdc20 and Cdh1 already associated with the APC . # ::alignments 1-1.1 3-1.2.1.1.1 4-1 5-1.2 6-1.2.2.1.1.1 7-1.2.2 8-1.2.2.2.1.1 9-1.2.2.3.2 10-1.2.2.3 11-1.2.2.3.1.r 13-1.2.2.3.1.1.1 (p2 / possible-01~e.4 :li "A"~e.1 :ARG1 (b / bind-01~e.5 :ARG1 (s / small-molecule :name (n4 / name :op1 "Emi1"~e.3)) :ARG2 (a2 / and~e.7 :op1 (p4 / protein :name (n2 / name :op1 "Cdc20"~e.6)) :op2 (p5 / protein :name (n3 / name :op1 "Cdh1"~e.8)) :ARG1-of (a / associate-01~e.10 :ARG2~e.11 (p / protein :name (n / name :op1 "APC"~e.13)) :time (a3 / already~e.9))))) # ::id bio.chicago_2015.68191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig. 2D , M. tuberculosis stimulation of J774 cells results in the inducible binding of ATF @-@ 2 , c @-@ jun , Ets @-@ 1 @/@ 2 , Egr @-@ 1 , and Sp1 to the TNF @-@ alpha promoter in vivo . # ::alignments 1-1 2-1.1.r 2-1.2.2.4 3-1.1 4-1.1.1 4-1.2.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1.1.1.2 8-1.2.1 9-1.2.1.2.r 10-1.2.1.2.1.1 11-1.2.1.2 12-1.2 13-1.2.2.4 15-1.2.2.3 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1.1.1.1 20-1.2.2.1.1.1.1 20-1.2.2.1.3.1.1 22-1.2.2.1.2.1.1 24-1.2.2.1.2.1.1 26-1.2.2.1.3.1.1 28-1.2.2.1.3.1.1 28-1.2.2.1.4.1.1 30-1.2.2.1.1.1.1 30-1.2.2.1.3.1.1 32-1.2.2.1.4.1.1 34-1.2.2.1.3.1.1 34-1.2.2.1.4.1.1 36-1.2.2.1 37-1.2.2.1.5.1.1 38-1.2.2.2.r 40-1.2.2.2.1.1.1.1 42-1.2.2.2.1.1.1.1 44-1.2.2.4 45-1.2.2.4 (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "2D"~e.4) :ARG1 (r / result-01~e.12 :ARG1 (s2 / stimulate-01~e.8 :ARG0 (o / organism :name (n / name :op1 "M."~e.6 :op2 "tuberculosis"~e.7)) :ARG1~e.9 (c / cell-line~e.11 :name (n2 / name :op1 "J774"~e.10))) :ARG2 (b / bind-01~e.16 :ARG1~e.17 (a / and~e.36 :op1 (p / protein :name (n3 / name :op1 "ATF-2"~e.4,18,20,30)) :op2 (p2 / protein :name (n4 / name :op1 "c-jun"~e.22,24)) :op3 (p3 / protein :name (n5 / name :op1 "Ets-1/2"~e.20,26,28,30,34)) :op4 (p4 / protein :name (n6 / name :op1 "Egr-1"~e.28,32,34)) :op5 (p5 / protein :name (n7 / name :op1 "Sp1"~e.37))) :ARG2~e.38 (m / molecular-physical-entity :ARG0-of (p6 / promote-02 :ARG1 (p7 / protein :name (n8 / name :op1 "TNF-alpha"~e.40,42)))) :ARG2-of (i2 / induce-01~e.15 :ARG1-of (p8 / possible-01)) :manner (i / in-vivo~e.2,13,44,45)))) # ::id bio.chicago_2015.68528 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This result again supports the notion that binding of the GATA family factors to the GATA motif is important for E4 bp4 expression in IL @-@ 3 @-@ dependent Ba @/@ F3 cells . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1.3 3-1 5-1.2 7-1.2.1.1 8-1.2.1.1.1.r 10-1.2.1.1.1.1.1.1 11-1.2.1.1.1.1 12-1.2.1.1.1 15-1.2.1.1.1.1.1.1 16-1.2.1.1.2 17-1.2.1.1.r 18-1.2.1 22-1.2.1.2 23-1.2.1.2.2.r 24-1.2.1.2.2.2.1.1.1 26-1.2.1.2.2.2.1.1.1 28-1.2.1.2.2.2 29-1.2.1.2.2.1.1 31-1.2.1.2.2.1.1 32-1.2.1.2.2 (s / support-01~e.3 :ARG0 (t / thing~e.1 :mod (t2 / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG1 (n / notion~e.5 :topic (i / important~e.18 :domain~e.17 (b / bind-01~e.7 :ARG1~e.8 (f / factor~e.12 :mod (p / protein-family~e.11 :name (n2 / name :op1 "GATA"~e.10,15))) :ARG2 (m / motif~e.16 :part-of p)) :purpose (e / express-03~e.22 :ARG2 (p3 / protein :name (n4 / name :op1 "E4bp4")) :ARG3~e.23 (c / cell-line~e.32 :name (n6 / name :op1 "Ba/F3"~e.29,31) :ARG0-of (d / depend-01~e.28 :ARG1 (p4 / protein :name (n5 / name :op1 "IL-3"~e.24,26))))))) :mod (a / again~e.2)) # ::id bio.chicago_2015.68624 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We tested cells growing in low and high serum for mDia1 and mDia2 associated Src activity ( shown in pairs ) . # ::alignments 0-1.1 1-1 2-1.2 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.1.1 6-1.2.1.1 7-1.2.1.1.2.1 8-1.2.1.1.1 8-1.2.1.1.2 9-1.3.r 10-1.3.1.1.1 11-1.3 12-1.3.2.1.1 13-1.3.3 14-1.3.3.1.1.1.1 15-1.3.3.1 17-1.4 18-1.4.1.r 19-1.4.1 (t / test-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / cell~e.2 :ARG1-of (g / grow-01~e.3 :location~e.4 (a / and~e.6 :op1 (s / serum~e.8 :ARG1-of (l / low-04~e.5)) :op2 (s2 / serum~e.8 :ARG1-of (h / high-02~e.7))))) :ARG2~e.9 (a2 / and~e.11 :op1 (p / protein :name (n / name :op1 "mDia1"~e.10)) :op2 (p2 / protein :name (n3 / name :op1 "mDia2"~e.12)) :ARG1-of (a3 / associate-01~e.13 :ARG2 (a4 / activity-06~e.15 :ARG0 (p3 / protein :name (n2 / name :op1 "Src"~e.14))))) :ARG1-of (s3 / show-01~e.17 :manner~e.18 (p4 / pair~e.19))) # ::id bio.chicago_2015.69904 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The oxysterol binding protein and beta @-@ spectrin PH domains bound PtdIns @-@ 3,4,5 @-@ P3 and PtdIns @-@ 4,5 @-@ P2 with similar affinities . # ::alignments 1-1.1.1.1.1 2-1.1.1.1 3-1.1.1 4-1.1 5-1.1.2.1.1 7-1.1.2.1.1 8-1.1.2.1.2 9-1.1.2 10-1 11-1.2.1.1.1 11-1.2.2.1.1 13-1.2.1.1.1 15-1.2.1.1.1 17-1.2.1.1.1 17-1.2.2.1.1 19-1.2.2.1.1 21-1.2.2.1.1 22-1.3.r 23-1.3.1 24-1.3 (b / bind-01~e.10 :ARG1 (a / and~e.4 :op1 (p / protein~e.3 :ARG1-of (b2 / bind-01~e.2 :ARG2 (o / oxysterol~e.1))) :op2 (d / domain~e.9 :name (n / name :op1 "beta-spectrin"~e.5,7 :op2 "PH"~e.8))) :ARG2 (a2 / and :op1 (e / enzyme :name (n2 / name :op1 "PtdIns-3,4,5-P3"~e.11,13,15,17)) :op2 (e2 / enzyme :name (n3 / name :op1 "PtdIns-4,5-P2"~e.11,17,19,21))) :ARG3~e.22 (a3 / affinity~e.24 :ARG1-of (r / resemble-01~e.23))) # ::id bio.chicago_2015.70184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effect of okadaic acid on apoB and apoA @-@ I secretion by CaCo @-@ 2 cells . # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.1.1.2 4-1.2.r 5-1.2.2.1.1.1 6-1.2.2 7-1.2.2.2.1.1 9-1.2.2.2.1.1 10-1.2 11-1.2.1.r 12-1.2.1.1.1 14-1.2.1.1.1 15-1.2.1 (a / affect-01~e.0 :ARG0~e.1 (s2 / small-molecule :name (n4 / name :op1 "okadaic"~e.2 :op2 "acid"~e.3)) :ARG1~e.4 (s / secrete-01~e.10 :ARG0~e.11 (c2 / cell-line~e.15 :name (n3 / name :op1 "CaCo-2"~e.12,14)) :ARG1 (a3 / and~e.6 :op1 (p2 / protein :name (n / name :op1 "apoB"~e.5)) :op2 (p / protein :name (n2 / name :op1 "apoA-I"~e.7,9))))) # ::id bio.chicago_2015.70354 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A simple alfalfa seedling infection model for Pseudomonas aeruginosa strains associated with cystic fibrosis shows AlgT ( sigma @-@ 22 ) and RhlR contribute to pathogenesis . # ::alignments 1-1.1.3 2-1.1.2.1.1.1.1 3-1.1.2.1 4-1.1.2 5-1.1 6-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1.1.1.2 9-1.1.1 10-1.1.1.2 11-1.1.1.2.1.r 12-1.1.1.2.1.1.1 13-1.1.1.2.1.1.2 14-1 15-1.2.1.1.1.1 17-1.2.1.1.1.2 19-1.2.1.1.1.2 21-1.2.1 22-1.2.1.2.1.1 23-1.2 24-1.2.2.r 25-1.2.2 (s / show-01~e.14 :ARG0 (m / model-01~e.5 :ARG1~e.6 (s2 / strain-01~e.9 :ARG0 (o / organism :name (n / name :op1 "Pseudomonas"~e.7 :op2 "aeruginosa"~e.8)) :ARG1-of (a2 / associate-01~e.10 :ARG2~e.11 (d / disease :name (n5 / name :op1 "cystic"~e.12 :op2 "fibrosis"~e.13)))) :topic (i / infect-01~e.4 :ARG1 (s3 / seedling~e.3 :mod (o2 / organism :name (n3 / name :op1 "Alfalfa"~e.2)))) :ARG1-of (s4 / simple-02~e.1)) :ARG1 (c / contribute-01~e.23 :ARG0 (a / and~e.21 :op1 (p4 / protein :name (n6 / name :op1 "AlgT"~e.15 :op2 "sigma-22"~e.17,19)) :op2 (p3 / protein :name (n4 / name :op1 "RhlR"~e.22))) :ARG2~e.24 (p / pathogenesis~e.25))) # ::id bio.chicago_2015.70864 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concurrently , gp41 dissociates from gp120 , associates with the target membrane and mediates fusion of the viral and the cellular membranes by a process that involves the N @-@ terminal hydrophobic region of gp41 , termed the fusion peptide ( Gallaher , 1987 ) . # ::alignments 0-1.5 2-1.1.1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1.1 7-1.2 10-1.2.2.1 11-1.2.2 11-1.3.2.1.1 12-1 13-1.3 14-1.3.2 15-1.3.2.1.1.1.r 15-1.3.2.1.r 17-1.3.2.1.1.1 18-1.3.2.1 20-1.3.2.1.2.1 21-1.3.2.1.2 22-1.3.3.r 24-1.3.3 26-1.3.3.1 28-1.3.3.1.1.3.1.1 30-1.3.3.1.1.3.1.1 31-1.3.3.1.1.1 32-1.3.3.1.1 33-1.3.3.1.1.2.r 34-1.3.3.1.1.2 36-1.3.3.2 38-1.3.3.2.1.1 39-1.3.3.2.1 41-1.4.1.1.1.1 43-1.4.1.2.1 (a / and~e.12 :op1 (d3 / dissociate-01~e.3 :ARG1 (p3 / protein :name (n2 / name :op1 "gp41"~e.2)) :ARG2~e.4 (p4 / protein :name (n3 / name :op1 "gp120"~e.5))) :op2 (a2 / associate-01~e.7 :ARG1 p3 :ARG2 (m2 / membrane~e.11 :ARG1-of (t / target-01~e.10))) :op3 (m / mediate-01~e.13 :ARG0 p3 :ARG1 (f / fuse-01~e.14 :ARG1~e.15 (a3 / and~e.18 :op1 (m3 / membrane~e.11 :mod~e.15 (v / viral~e.17)) :op2 (m4 / membrane~e.21 :mod (c2 / cell~e.20)))) :manner~e.22 (p5 / process-02~e.24 :ARG2-of (i / involve-01~e.26 :ARG1 (r / region~e.32 :mod (h / hydrophobic~e.31) :part-of~e.33 p3~e.34 :mod (p7 / protein-segment :name (n4 / name :op1 "N-terminus"~e.28,30)))) :ARG1-of (t2 / term-01~e.36 :ARG0 (p6 / peptide~e.39 :ARG0-of (f2 / fuse-01~e.38))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (p2 / person :name (n / name :op1 "Gallaher"~e.41)) :time (d / date-entity :year 1987~e.43))) :ARG1-of (c / concurrent-02~e.0)) # ::id bio.chicago_2015.70878 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AAK1 localizes to regions active in endocytosis AAK1 binds directly to AP2 . # ::alignments 0-1.1.1.1.1 0-1.2.1.1.1 1-1.1 2-1.1.2.r 3-1.1.2 4-1.1.2.1 5-1.1.2.1.1.r 6-1.1.2.1.1 7-1.1.1.1.1 7-1.2.1.1.1 8-1.2 9-1.2.3 10-1.2.2.r 11-1.2.2.1.1 (m / multi-sentence :snt1 (l / localize-01~e.1 :ARG1 (p2 / protein :name (n / name :op1 "AAK1"~e.0,7)) :location~e.2 (r / region~e.3 :ARG0-of (a / activity-06~e.4 :ARG1~e.5 (e / endocytosis~e.6)))) :snt2 (b / bind-01~e.8 :ARG1 (p3 / protein :name (n3 / name :op1 "AAK1"~e.0,7)) :ARG2~e.10 (p / protein :name (n2 / name :op1 "AP2"~e.11)) :ARG1-of (d / direct-02~e.9))) # ::id bio.chicago_2015.70927 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Characterization of a novel member of the DOK family that binds and modulates Abl signaling . # ::alignments 0-1 1-1.1.r 3-1.1.1 4-1.1 5-1.1.2.r 7-1.1.2.1.1 8-1.1.2 10-1.1.3 12-1.1.4 13-1.1.3.1.1.1.1 14-1.1.3.1 (c / characterize-01~e.0 :ARG1~e.1 (m / member~e.4 :mod (n / novel~e.3) :poss~e.5 (p / protein-family~e.8 :name (n2 / name :op1 "DOK"~e.7)) :ARG0-of (b / bind-01~e.10 :ARG1 (s / signal-07~e.14 :ARG0 (p2 / protein :name (n3 / name :op1 "Abl"~e.13)))) :ARG0-of (m2 / modulate-01~e.12 :ARG1 s))) # ::id bio.chicago_2015.71093 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The tyrosine phosphatase PTP1C associates with Vav , Grb2 , and mSos1 in hematopoietic cells . # ::alignments 1-1.1.1.1 2-1.1.1.2 3-1.1.1.3 4-1 5-1.2.r 6-1.2.1.1.1 8-1.2.2.1.1 10-1.2 12-1.3.r 13-1.3.1 14-1.3 (a / associate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "tyrosine"~e.1 :op2 "phosphatase"~e.2 :op3 "PTP1C"~e.3)) :ARG2~e.5 (a2 / and~e.10 :op1 (p2 / protein :name (n2 / name :op1 "Vav"~e.6)) :op2 (p3 / protein :name (n3 / name :op1 "Grb2"~e.8)) :op2 (p4 / protein :name (n4 / name :op1 "Sos1") :part-of (m / mouse))) :location~e.12 (c / cell~e.14 :mod (h / hematopoietic~e.13))) # ::id bio.chicago_2015.71185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok S phase induction and c @-@ MYC RNA and c @-@ JUN protein in quiescent MCF10A cells infected at 20 pfu @/@ cell with dl1500 ( wild @-@ type E1A ) and dl2 @-@ 36 ( mutant E1A that does not bind to p300 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.1.2.1.1.1 4-1.2.2.1.1 6-1.2.1.2.1.1.1 7-1.2.1.1.1 8-1.2 9-1.2.2.1.1 11-1.2.2.1.1 12-1.2.1.2.1 12-1.2.2 12-1.3.3.1.1.2.1 12-1.3.3.1.2.2.1 12-1.3.3.1.2.2.1.3.2 14-1.3.2 15-1.3.1.1 16-1.3 17-1.3.3 19-1.3.3.2.1.1 22-1.3.3.2.2 24-1.3.3.1.1.1.1 26-1.3.3.1.1.2.1.2 28-1.3.3.1.1.2.1.2 29-1.3.3.1.1.2.1.1.1 32-1.3.3.1.2.1.1 34-1.3.3.1.2.1.1 36-1.3.3.1.2.2.1.2 37-1.3.3.1.2.2.1.1.1 40-1.3.3.1.2.2.1.3.1 40-1.3.3.1.2.2.1.3.1.r 41-1.3.3.1.2.2.1.3 43-1.3.3.1.2.2.1.3.2.1.1 (a / and~e.3 :op1 (i / induce-01~e.2 :ARG2 (p / phase~e.1 :name (n / name :op1 "S"~e.0))) :op2 (a2 / and~e.8 :op1 (n3 / nucleic-acid :name (n4 / name :op1 "RNA"~e.7) :ARG0-of (e3 / encode-01 :ARG1 (p7 / protein~e.12 :name (n2 / name :op1 "c-MYC"~e.4,6)))) :op2 (p2 / protein~e.12 :name (n5 / name :op1 "c-JUN"~e.4,9,11))) :location (c / cell-line~e.16 :name (n6 / name :op1 "MCF10A"~e.15) :mod (q / quiescent~e.14) :ARG1-of (i2 / infect-01~e.17 :ARG2 (a3 / and :op1 (v / virus :name (n7 / name :op1 "dl1500"~e.24) :ARG1-of (e / express-03 :ARG2 (p3 / protein~e.12 :name (n8 / name :op1 "E1A"~e.29) :mod (w / wild-type~e.26,28)))) :op2 (v2 / virus :name (n9 / name :op1 "dl2-36"~e.32,34) :ARG1-of (e2 / express-03 :ARG2 (p4 / protein~e.12 :name (n10 / name :op1 "E1A"~e.37) :ARG2-of (m3 / mutate-01~e.36) :ARG1-of (b / bind-01~e.41 :polarity~e.40 -~e.40 :ARG2 (p5 / protein~e.12 :name (n11 / name :op1 "p300"~e.43))))))) :mod (r / rate-entity-91 :ARG1 (u / unit :quant 20~e.19 :ARG0-of (f / form-01 :ARG1 (p6 / plaque))) :ARG2 (c2 / cell~e.22 :quant 1))))) # ::id bio.chicago_2015.71284 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Characterization of a representative U2OS clone conditionally coexpressing Rbdeltacdk with cyclin E ( clone B3B4 ) . # ::alignments 0-1 1-1.1.r 3-1.1.2 4-1.1.1.1.1 5-1.1 5-1.1.3.1.2.2.1 10-1.1.3.1.2.1.1 11-1.1.3.1.2.1.2 13-1.1 13-1.1.3.1.2.2.1 (c / characterize-01~e.0 :ARG1~e.1 (c2 / clone-01~e.5,13 :ARG1 (c3 / cell :name (n / name :op1 "U2OS"~e.4)) :ARG0-of (r / represent-01~e.3) :ARG3-of (c4 / coexpress-01 :ARG2 (a / and :op1 (p / protein :name (n2 / name :op1 "RbΔcdk")) :op2 (p2 / protein :name (n3 / name :op1 "cyclin"~e.10 :op2 "E"~e.11) :ARG1-of (m / mean-01 :ARG2 (c5 / clone-01~e.5,13 :ARG1 (a2 / and :op1 (p3 / protein :name (n4 / name :op1 "cyclin" :op2 "B3")) :op2 (p4 / protein :name (n5 / name :op1 "cyclin" :op2 "B4"))))))) :ARG1-of (c6 / condition-01)))) # ::id bio.chicago_2015.71299 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In summary , the results of these experiments are consistent with previous studies in the Hepa @-@ 1 cell line ( Gassmann et al. , 1997 ) and support the hypothesis that the formation of AHR/ ARNT complexes capable of binding DNA is not affected by conditions in which up to 15 % of the ARNT protein pool has been recruited to the hypoxia signaling pathway . # ::alignments 1-1.3 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.r 6-1.1.1.1.1.1 7-1.1.1.1.1 9-1.1 10-1.1.2.r 11-1.1.2.2 12-1.1.2 13-1.1.2.1.r 15-1.1.2.1.1.1 17-1.1.2.1.1.1 18-1.1.2.1 19-1.1.2.1 21-1.1.3.1.1.1.1.1 22-1.1.3.1.1 23-1.1.3.1.1.2.1 25-1.1.3.1.2.1 27-1 28-1.2 30-1.2.2 31-1.2.2.1.r 33-1.2.2.1.3 36-1.2.2.1.3.1.2 37-1.2.2.1.3.1 38-1.2.2.1.3.1.3 39-1.2.2.1.3.1.3.1.r 40-1.2.2.1.3.1.3.1 41-1.2.2.1.3.1.3.1.2.1.1 43-1.2.2.1.1 43-1.2.2.1.1.r 44-1.2.2.1 45-1.2.2.1.2.r 46-1.2.2.1.2 49-1.2.2.1.2.1.1.2 50-1.2.2.1.2.1.1.2 51-1.2.2.1.2.1.1.2.1.1 52-1.2.2.1.2.1.1.2.1 53-1.2.2.1.2.1.1.2.r 55-1.2.2.1.2.1.1.1.1.1 56-1.2.2.1.2.1.1.1 56-1.2.2.1.3.1.1 57-1.2.2.1.2.1.1 60-1.2.2.1.2.1 61-1.2.2.1.2.1.2.r 63-1.2.2.1.2.1.2.1.1 64-1.2.2.1.2.1.2.2 65-1.2.2.1.2.1.2 (a / and~e.27 :op1 (c / consistent-01~e.9 :ARG1 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4 :ARG1~e.5 (e / experiment-01~e.7 :mod (t2 / this~e.6)))) :ARG2~e.10 (s / study-01~e.12 :ARG1~e.13 (c2 / cell-line~e.18,19 :name (n / name :op1 "Hepa-1"~e.15,17)) :time (p / previous~e.11)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.22 :op1 (p3 / person :name (n2 / name :op1 "Gassmann"~e.21)) :op2 (p4 / person :mod (o / other~e.23))) :time (d2 / date-entity :year 1997~e.25)))) :op2 (s2 / support-01~e.28 :ARG0 t :ARG1 (h / hypothesize-01~e.30 :ARG1~e.31 (a3 / affect-01~e.44 :polarity~e.43 -~e.43 :ARG0~e.45 (c3 / condition-01~e.46 :ARG2 (r2 / recruit-01~e.60 :ARG1 (p5 / pool-01~e.57 :ARG1 (p6 / protein~e.56 :name (n3 / name :op1 "ARNT"~e.55)) :quant~e.53 (u / up-to~e.49,50 :op1 (p7 / percentage-entity~e.52 :value 15~e.51))) :ARG2~e.61 (p8 / pathway~e.65 :name (n4 / name :op1 "hypoxia"~e.63) :ARG0-of (s3 / signal-07~e.64)))) :ARG1 (f / form-01~e.33 :ARG1 (m / macro-molecular-complex~e.37 :part (p9 / protein~e.56 :name (n5 / name :op1 "AHR")) :part p6~e.36 :ARG1-of (c4 / capable-01~e.38 :ARG2~e.39 (b / bind-01~e.40 :ARG0 m :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"~e.41))))))))) :ARG2-of (s4 / summarize-01~e.1)) # ::id bio.chicago_2015.71300 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To independently prove that IkappaBalpha is linked to ubiquitin , cells were treated with TNFalpha and Z @-@ LLL @-@ H , and extracts were immunoprecipitated with antibodies to IkappaBalpha , NF @-@ kappaB p50 , NF @-@ kappaB p65 , or nonimmune serum prior to detection of bound ubiquitin by Western blotting with a monoclonal antibody directed against ubiquitin ( 59 ) . # ::alignments 1-1.4.2.1 2-1.4 6-1.4.1 8-1.3.1.1.1.1 10-1.1.1 12-1.1 15-1.1.2 16-1.1.2.2.1.1 18-1.1.2.2.1.1 20-1.1.2.2.1.1 22-1 23-1.2.1 23-1.2.1.1 23-1.2.1.1.r 25-1.2 26-1.2.2.r 27-1.2.2.1.1 31-1.2.2.1.2.1.1.2.1.1 34-1.2.2.1.2.1.1.1.1 36-1.2.2.1.2.1.1.2.1.1 39-1.2.2.1.3.1.1.1.1 41-1.2.2 42-1.2.2.2.1 42-1.2.2.2.1.1 42-1.2.2.2.1.1.r 43-1.2.2.2 44-1.3 46-1.3.1 48-1.3.1.1 48-1.3.1.1.2 48-1.3.1.1.2.r 49-1.3.1.1.1.1 50-1.3.1.2.r 51-1.3.1.2 52-1.3.1.2 53-1.3.1.2.1.r 55-1.3.1.2.1.1 56-1.2.2.1.2 56-1.2.2.1.3 56-1.3.1.2.1 57-1.3.1.2.1.2 58-1.2.2.1.1.1 58-1.2.2.1.2.1 58-1.2.2.1.3.1 58-1.3.1.2.1.2.1 59-1.3.1.1.1.1 59-1.3.1.2.1.2.1.1.1.1 61-1.5.1.1.1 (a / and~e.22 :op1 (t / treat-04~e.12 :ARG1 (c / cell~e.10) :ARG2 (a2 / and~e.15 :op1 (p / protein :name (n / name :op1 "TNFα")) :op2 (s2 / small-molecule :name (n2 / name :op1 "Z-LLL-H"~e.16,18,20)))) :op2 (i / immunoprecipitate-01~e.25 :ARG2 (m2 / molecular-physical-entity~e.23 :ARG1-of~e.23 (e / extract-01~e.23)) :ARG3~e.26 (o / or~e.41 :op1 (a3 / and :op1 (a4 / antibody~e.27 :ARG0-of (c2 / counter-01~e.58 :ARG1 (p2 / protein :name (n3 / name :op1 "IκBα")))) :op2 (a5 / antibody~e.56 :ARG0-of (c3 / counter-01~e.58 :ARG1 (p3 / protein :name (n4 / name :op1 "p50"~e.34) :part-of (m3 / macro-molecular-complex :name (n5 / name :op1 "NF-κB"~e.31,36))))) :op3 (a6 / antibody~e.56 :ARG0-of (c4 / counter-01~e.58 :ARG1 (p4 / protein :name (n6 / name :op1 "p65"~e.39) :part-of m3)))) :op2 (s / serum~e.43 :ARG1-of (i2 / immune-02~e.42 :polarity~e.42 -~e.42)))) :time (p5 / prior~e.44 :op1 (d / detect-01~e.46 :ARG1 (p6 / protein~e.48 :name (n8 / name :op1 "ubiquitin"~e.8,49,59) :ARG1-of~e.48 (b / bind-01~e.48)) :ARG2~e.50 (i3 / immunoblot-01~e.51,52 :ARG3~e.53 (a7 / antibody~e.56 :mod (m4 / monoclonal~e.55) :ARG1-of (d2 / direct-01~e.57 :ARG2 (a8 / against~e.58 :op1 (p7 / protein :name (n9 / name :op1 "ubiquitin"~e.59)))))))) :purpose (p8 / prove-01~e.2 :ARG1 (l / link-01~e.6 :ARG1 p2 :ARG2 p7) :ARG0-of (d3 / depend-01 :polarity -~e.1)) :ARG1-of (d4 / describe-01 :ARG0 (p9 / publication :ARG1-of (c5 / cite-01 :ARG2 59~e.61)))) # ::id bio.chicago_2015.71532 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Skb1 and Shk1 Associate with Cdc2 in S. pombe . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1 4-1.2.r 5-1.2.1.1 8-1.3.1.2 (a / associate-01~e.3 :ARG1 (a2 / and~e.1 :op1 (p / protein :name (n / name :op1 "Skb1"~e.0)) :op2 (p2 / protein :name (n2 / name :op1 "Shk1"~e.2))) :ARG2~e.4 (e2 / enzyme :name (n3 / name :op1 "Cdc2"~e.5)) :location (o / organism :name (n4 / name :op1 "Schizosaccharomyces" :op2 "pombe"~e.8))) # ::id bio.chicago_2015.71733 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The labels RNAP IIO and IIA represent hyperphosphorylated and hypophosphorylated forms of the RNAP II larger subunit , respectively . # ::alignments 1-1.1.1 1-1.1.1.2 1-1.1.1.2.r 2-1.1.1.1.1 3-1.1.1.1.2 4-1 5-1.2.1.1.2 6-1.1 6-1.2 7-1.1.2.1 8-1 9-1.2.2.1 13-1.1.2.2.1.1 14-1.1.2.2.1.2 15-1.1.2.3 15-1.1.2.3.1 15-1.1.2.3.1.r 16-1.1.2 16-1.2.2 (a / and~e.4,8 :op1 (r / represent-01~e.6 :ARG0 (e / enzyme~e.1 :name (n / name :op1 "RNAP"~e.2 :op2 "IIO"~e.3) :ARG2-of~e.1 (l / label-01~e.1)) :ARG1 (s / subunit~e.16 :ARG1-of (h / hyperphosphorylate-01~e.7) :mod (e2 / enzyme :name (n2 / name :op1 "RNAP"~e.13 :op2 "II"~e.14)) :mod (l2 / large~e.15 :degree~e.15 (m / more~e.15)))) :op2 (r2 / represent-01~e.6 :ARG0 (e3 / enzyme :name (n3 / name :op1 "RNAP" :op2 "IIA"~e.5) :ARG2-of l) :ARG1 (s2 / subunit~e.16 :ARG1-of (h2 / hypophosphorylate-00~e.9) :mod e2 :mod l2))) # ::id bio.chicago_2015.71734 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The fluorescent microscopy method has allowed us to examine how quickly caldesmon coupled with TM can disassemble preformed fascin @-@ actin bundles . # ::alignments 2-1.1.1 3-1.1 5-1 6-1.2.1 8-1.2 9-1.2.2.2 10-1.2.2 11-1.2.2.1.1.1.2.1 12-1.2.2.1.1.1.3 15-1.2.2.1 16-1.2.2.1.1 17-1.2.2.1.1.2.2 18-1.2.2.1.1.2.1.1.2.1 20-1.2.2.1.1.2.1.2.2.1 21-1.2.2.1.1.2 (a / allow-01~e.5 :ARG0 (m / method~e.3 :mod (m2 / microscopy~e.2 :mod (f / fluoresce-01))) :ARG1 (e / examine-01~e.8 :ARG0 (w / we~e.6) :ARG1 (q / quick-02~e.10 :ARG1 (p / possible-01~e.15 :ARG1 (d / disassemble-01~e.16 :ARG0 (p2 / protein :wiki "Caldesmon" :name (n2 / name :op1 "caldesmon"~e.11) :ARG1-of (c / couple-01~e.12 :ARG2 (p3 / protein :wiki "Tropomyosin" :name (n3 / name :op1 "tropomyosin")))) :ARG1 (b / bundle-01~e.21 :ARG2 (a2 / and :op1 (p4 / protein :wiki "Fascin" :name (n4 / name :op1 "fascin"~e.18)) :op2 (p5 / protein :wiki "Actin" :name (n5 / name :op1 "actin"~e.20))) :ARG1-of (p6 / preform-01~e.17)))) :degree (a3 / amr-unknown~e.9)))) # ::id bio.chicago_2015.71778 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As determined by immunoprecipitation , these affinity @-@ purified antisera detected a single protein band of ~ 43 kDa in an SDS @-@ PAGE using in vitro translated Spy1 ( Figure 3A , lane 4 ) . # ::alignments 1-1.5 2-1.5.1.r 3-1.5.1 5-1.1.2 6-1.1.1.1 8-1.1.1 10-1 12-1.2.2 13-1.2.1 14-1.2 15-1.2.1.1.r 16-1.2.1.1 17-1.2.1.1.1.1 18-1.2.1.1.1.2 19-1.3.r 19-1.4.1.2.1 21-1.3.1.1 23-1.3.1.1 24-1.4 25-1.4.1.2.1 26-1.4.1.2.1 27-1.4.1.2 28-1.4.1.1.1 30-1.6.1.2 31-1.6.1.2.1 33-1.6.1 34-1.6.1.1 (d / detect-01~e.10 :ARG0 (a / antiserum :ARG1-of (p / purify-01~e.8 :ARG2 (a2 / affinity~e.6)) :mod (t / this~e.5)) :ARG1 (b / band~e.14 :mod (p2 / protein~e.13 :quant~e.15 (a3 / approximately~e.16 :op1 (m / mass-quantity :quant 43~e.17 :unit (k / kilodalton~e.18)))) :ARG1-of (s / single-02~e.12)) :ARG2~e.19 (t2 / thing :name (n / name :op1 "SDS-PAGE"~e.21,23)) :ARG2-of (u / use-01~e.24 :ARG1 (p3 / protein :name (n2 / name :op1 "Spy1"~e.28) :ARG2-of (t3 / translate-02~e.27 :manner (i / in-vitro~e.19,25,26)))) :ARG1-of (d2 / determine-01~e.1 :ARG0~e.2 (i2 / immunoprecipitate-01~e.3)) :ARG1-of (d3 / describe-01 :ARG0 (l / lane~e.33 :mod 4~e.34 :part-of (f / figure~e.30 :mod "3A"~e.31)))) # ::id bio.chicago_2015.71791 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Actin depolymerization with latrunculin delocalized myosin II and anillin , as expected , and had little effect on the organization of cytokinesis @-@ associated microtubules . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 5-1.1.2.1.1.1 6-1.1.2.1.1.2 7-1.1.2 8-1.1.2.2.1.1 11-1.1.3 13-1 15-1.2.3 16-1.2 17-1.2.2.r 19-1.2.2 21-1.2.2.1.1.1 23-1.2.2.1.1 (a / and~e.13 :op1 (d / delocalize-01 :ARG0 (d2 / depolymerize-00 :ARG1 (p / protein :name (n / name :op1 "actin"~e.0)) :instrument~e.2 (s / small-molecule :name (n4 / name :op1 "latrunculin"~e.3))) :ARG1 (a2 / and~e.7 :op1 (p2 / protein :name (n2 / name :op1 "myosin"~e.5 :op2 "II"~e.6)) :op2 (p3 / protein :name (n3 / name :op1 "anillin"~e.8))) :ARG1-of (e / expect-01~e.11)) :op2 (a3 / affect-01~e.16 :ARG0 d2 :ARG1~e.17 (o / organize-01~e.19 :ARG1 (m2 / microtubule :ARG1-of (a4 / associate-01~e.23 :ARG2 (c / cytokinesis~e.21)))) :degree (l2 / little~e.15))) # ::id bio.chicago_2015.71819 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The synergistic interaction between cofilin and Arp2 @/@ 3 , where Arp2 @/@ 3 caps and stabilizes short filaments produced by cofilin severing activity , may resolve the inconsistencies inherent in the above two mechanisms ( Bailly et al. 1999 ) . # ::alignments 1-1.1.1.3 2-1.1.1 4-1.1.1.1.1.1 5-1.1.1.4 6-1.1.1.2.1.1.1 10-1.1.1.4.r 11-1.1.1.4.1.1 14-1.1.1.4.1 15-1.1.1.4 16-1.1.1.4.2 17-1.1.1.4.2.2 18-1.1.1.4.2.2 19-1.1.1.4.2.2 21-1.1.1.4.1.2.2.1.2.1 22-1.1.1.4.1.2.2.1.2 23-1.1.1.4.1.2.2.1 25-1 26-1.1 28-1.1.2.1 29-1.1.2.4 36-1.2.1.1.1.1.1 37-1.2.1.1 38-1.2.1.1.2.1 39-1.2.1.2.1 (p / possible-01~e.25 :ARG1 (r / resolve-01~e.26 :ARG0 (i / interact-01~e.2 :ARG0 (p2 / protein :name (n / name :op1 "cofilin"~e.4)) :ARG1 (m / macro-molecular-complex :part (p3 / protein :name (n2 / name :op1 "Arp2"~e.6)) :part (p4 / protein :name (n3 / name :op1 "Arp3"))) :ARG0-of (s / synergize-01~e.1) :location-of~e.10 (a / and~e.5,15 :op1 (c / cap-02~e.14 :ARG0 m~e.11 :ARG1 (f / filament :ARG1-of (s2 / short-07) :ARG1-of (p5 / produce-01 :ARG0 (a2 / activity-06~e.23 :ARG0 p2 :ARG1 (s3 / sever-01~e.22 :ARG0 p2~e.21))))) :op2 (s4 / stabilize-01~e.16 :ARG0 m :ARG1 f~e.17,18,19))) :ARG1 (c2 / consistent-01 :polarity -~e.28 :ARG1 c :ARG2 s4 :mod (i2 / inherent~e.29))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a3 / and~e.37 :op1 (p7 / person :name (n4 / name :op1 "Bailly"~e.36)) :op2 (p8 / person :mod (o / other~e.38))) :time (d2 / date-entity :year 1999~e.39)))) # ::id bio.chicago_2015.72000 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the MSI ( ) tumors , 11 of 37 ( 30 %) displayed methylation of p16 , and , in contrast , in sporadic MSI(+) tumors hypermethylation of p16 was observed in 14 of 20 ( 70 %) ( P < 0.05 versus MSI @-@ negative ) . # ::alignments 5-1.1.1 5-1.1.1.3.1 7-1.1.1.1 9-1.1.1.3.1.1 11-1.1.1.3.2.1 13-1.1 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1.1 21-1 23-1.2.r 24-1.2.2.3 26-1.2.2 26-1.2.2.4.1 29-1.1.2.1.1.1 31-1.2 33-1.2.2.1 35-1.2.2.4.1.1 37-1.2.2.4.2.1 40-1.2.3 41-1.2.3.1 42-1.2.3.1.1 (c / contrast-01~e.21 :ARG1 (d / display-01~e.13 :ARG0 (t / tumor~e.5 :quant 11~e.7 :ARG1-of (s3 / stable-03 :mod (m2 / microsatellite)) :ARG1-of (i / include-91 :ARG2 (t3 / tumor~e.5 :quant 37~e.9 :ARG1-of s3) :ARG3 (p / percentage-entity :value 30~e.11))) :ARG1 (m / methylate-01~e.14 :ARG1~e.15 (p2 / protein :name (n2 / name :op1 "p16"~e.16,29)))) :ARG2~e.23 (o / observe-01~e.31 :ARG1 (h / hypermethylate-01 :ARG2 p2) :location (t4 / tumor~e.26 :quant 14~e.33 :ARG1-of (s2 / stable-03 :polarity - :mod m2) :mod (s / sporadic~e.24) :ARG1-of (i2 / include-91 :ARG2 (t6 / tumor~e.26 :quant 20~e.35 :ARG1-of s2 :mod s) :ARG3 (p3 / percentage-entity :value 70~e.37))) :ARG1-of (s4 / statistical-test-91~e.40 :ARG2 (l / less-than~e.41 :op1 0.05~e.42) :ARG5 t))) # ::id bio.chicago_2015.72003 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is true for intraphylum splits in many animal groups ( 19 , 33 ) , the origin and divergences of major insect clades ( 34 ) , early ( Paleozoic ) splits among basal vertebrates ( 35 ) and tetrapods ( 12 , 32 ) , and most intraordinal splits among birds ( 28 , 29 ) and mammals ( 32 , 36 , 37 ) . # ::alignments 0-1.1 2-1 3-1.2.r 4-1.2.1.1 5-1.2.1 6-1.2.1.2.r 7-1.2.1.2.2 8-1.2.1.2.1 9-1.2.1.2 11-1.2.1.3.1.1.1.1 13-1.2.1.3.1.1.1.2 17-1.2.2.1 18-1.2.2 19-1.2.2.2 21-1.2.2.1.1.2 22-1.2.2.1.1.1 25-1.2.2.3.1.1.1 28-1.2.3.2 30-1.2.3.2.1.1.1.1 32-1.2.3 34-1.2.3.1.1.1 35-1.2.3.1.1 37-1.2.3.1.1.2.1.1.1 39-1.2.3.1 40-1.2.3.1.2 42-1.2.3.1.2.1.1.1.1.1 44-1.2.3.1.2.1.1.1.1.2 47-1.2 47-1.2.3.1.2.1.1.1.1 48-1.2.4.3 49-1.2.4.2 50-1.2.4 52-1.2.4.1.1 54-1.2.4.1.1.1.1.1.1.1 56-1.2.4.1.1.1.1.1.1.2 58-1.2.4.1 58-1.2.4.1.1.1.1.1.1 59-1.2.4.1.2 61-1.2.4.1.2.1.1.1.1.1 63-1.2.4.1.2.1.1.1.1.2 65-1.2.4.1.2.1.1.1.1.3 (t / true-01~e.2 :ARG1 (t2 / this~e.0) :ARG2~e.3 (a / and~e.47 :op1 (s / split-01~e.5 :mod (i / intraphylum~e.4) :location~e.6 (g / group-01~e.9 :ARG2 (a2 / animal~e.8) :quant (m / many~e.7)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 19~e.11 :op2 33~e.13))))) :op2 (a4 / and~e.18 :op1 (o / originate-01~e.17 :ARG1 (c2 / clade :mod (i2 / insect~e.22) :ARG1-of (m2 / major-02~e.21))) :op2 (d2 / diverge-01~e.19 :ARG0 c2) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 34~e.25)))) :op3 (s2 / split-01~e.32 :ARG2 (a5 / and~e.39 :op1 (v / vertebrate~e.35 :mod (b / basal~e.34) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 35~e.37)))) :op2 (t3 / tetrapod~e.40 :ARG1-of (d5 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 (a6 / and~e.47 :op1 12~e.42 :op2 32~e.44)))))) :time (e / early~e.28 :ARG1-of (m3 / mean-01 :ARG2 (e2 / era :name (n / name :op1 "Paleozoic"~e.30))))) :op4 (s3 / split-01~e.50 :ARG2 (a7 / and~e.58 :op1 (b2 / bird~e.52 :ARG1-of (d6 / describe-01 :ARG0 (p5 / publication :ARG1-of (c6 / cite-01 :ARG2 (a8 / and~e.58 :op1 28~e.54 :op2 29~e.56))))) :op2 (m4 / mammal~e.59 :ARG1-of (d7 / describe-01 :ARG0 (p6 / publication :ARG1-of (c7 / cite-01 :ARG2 (a9 / and :op1 32~e.61 :op2 36~e.63 :op3 37~e.65)))))) :mod (i3 / intraordinal~e.49) :quant (m5 / most~e.48)))) # ::id bio.chicago_2015.72086 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A membrane location for this a @-@ factor NH2 @-@ terminal protease is consistent with our previous observation that all COOH @-@ terminally prenylated a @-@ factor intermediates , including P1 , are membrane associated ( Chen , 1993 ; Chen et al. , 1997 ) . # ::alignments 0-1.1.1.3.1.1 1-1.2.2.2 2-1.2.2.1.2.1.r 4-1.1.1.4 5-1.1.1.3.1.1 7-1.1.1.3.1.1 8-1.1.1.2.1.1 10-1.1.1.2.1.1 11-1.1.1.1.1 12-1.1 13-1 15-1.2.1 15-1.2.1.r 16-1.2.3 17-1.2 19-1.2.2.1.3 20-1.2.2.1.2.1.1.1 22-1.1.1.2.1.1 22-1.2.2.1.2.1.1.1 24-1.2.2.1.1 25-1.2.2.1.1 26-1.2.2.1.1 27-1.2.2.1 27-1.2.2.1.4.1 29-1.2.2.1.4 30-1.2.2.1.4.1.1.1 32-1.1 33-1.2.2.2 34-1.2.2 36-1.3.1.1.1.1.1 38-1.3.1.1.2.1 40-1.3.1.1.1.1.1 41-1.3.1 41-1.3.1.2.1 42-1.3.1.2.1.2.1 44-1.3.1.2.2.1 (c / consistent-01~e.13 :ARG1 (b / be-located-at-91~e.12,32 :ARG1 (e / enzyme :name (n / name :op1 "protease"~e.11) :part (p / protein-segment :name (n2 / name :op1 "NH2-terminus"~e.8,10,22)) :mod (g / gene :name (n3 / name :op1 "a-factor"~e.0,5,7)) :mod (t / this~e.4)) :ARG2 (m2 / membrane)) :ARG2 (o / observe-01~e.17 :ARG0~e.15 (w / we~e.15) :ARG1 (a / associate-01~e.34 :ARG1 (i / intermediate~e.27 :mod g~e.24,25,26 :ARG1-of (p2 / prenylate-00 :location~e.2 (p3 / protein-segment :name (n4 / name :op1 "COOH-terminus"~e.20,22))) :mod (a2 / all~e.19) :ARG2-of (i2 / include-91~e.29 :ARG1 (i3 / intermediate~e.27 :name (n5 / name :op1 "P1"~e.30)))) :ARG2 m2~e.1,33) :time (p4 / previous~e.16)) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.41 :op1 (p5 / publication-91 :ARG0 (p6 / person :name (n6 / name :op1 "Chen"~e.36,40)) :time (d2 / date-entity :year 1993~e.38)) :op2 (p7 / publication-91 :ARG0 (a4 / and~e.41 :op1 p6 :op2 (p8 / person :mod (o2 / other~e.42))) :time (d3 / date-entity :year 1997~e.44))))) # ::id bio.chicago_2015.72090 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If Ste5 constrains Ste11 and Ste7 to within , say , 10 nm of each other , then the effective concentration of the scaffold @-@ bound Ste7 in the eyes of the scaffold @-@ bound Ste11 will be 250,000 molecules per fl , an increase of more than 104 @-@ fold . # ::alignments 0-1.4.r 1-1.4.1.1.1 2-1.4 3-1.3.1.1.1 4-1.4.2 5-1.1.1.1 7-1.1.3.1.r 7-1.1.3.r 7-1.4.3 7-1.4.3.1.2.1.r 7-1.4.3.1.2.r 11-1.4.3.1.2.1 12-1.4.3.1.2.2 19-1.2 20-1 20-1.1.3 20-1.3 20-1.3.r 23-1.1.2.1 25-1.1 25-1.1.2 25-1.1.2.r 26-1.1.1.1 32-1.1.2.1 34-1.1 34-1.1.2 34-1.1.2.r 35-1.3.1.1.1 38-1.1.3.1 39-1.1.3.2 40-1.1.3.2 44-1.1.3.3 45-1.1.3.3.1.1 46-1.1.3.3.1 47-1.1.3.3.1 48-1.1.3.3.1.1.1 50-1.1.3.3.1.1 (c / concentrate-01~e.20 :ARG2 (e / enzyme~e.25,34 :name (n / name :op1 "Ste7"~e.5,26) :ARG1-of~e.25,34 (b / bind-01~e.25,34 :ARG2 (s / scaffold~e.23,32)) :quant~e.7 (c2 / concentration-quantity~e.20 :quant~e.7 250000~e.38 :unit (m / molecule-per-femtoliter~e.39,40) :ARG1-of (i / increase-01~e.44 :ARG2 (m2 / more-than~e.46,47 :op1 (p / product-of~e.45,50 :op1 104~e.48))))) :ARG0-of (e2 / effective-04~e.19) :compared-to~e.20 (c3 / concentrate-01~e.20 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ste11"~e.3,35) :ARG1-of b)) :condition~e.0 (c4 / constrain-01~e.2 :ARG0 (e4 / enzyme :name (n3 / name :op1 "Ste5"~e.1)) :ARG1 (a / and~e.4 :op1 e3 :op2 e) :degree (w / within~e.7 :example (r / relative-position :op1 a :quant~e.7 (d / distance-quantity :quant~e.7 10~e.11 :unit (n4 / nanometer~e.12)))))) # ::id bio.chicago_2015.72096 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 2 shows that all Gcn4 genes tested here , i.e. , TRP3 , ARG1 , HIS3 , CPA1 , and CPA2 , displayed H3 hyperacetylation similar to HIS3 . # ::alignments 0-1.1 1-1.1.1 2-1 3-1.2.r 4-1.2.1.2 5-1.2.1.1.1.1.1 6-1.2.1 7-1.2.1.3 8-1.2.1.3.1 12-1.2.1.4.1.1.1 14-1.2.1.4.2.1.1 16-1.2.1.4.3.1.1 18-1.2.1.4.4.1.1 20-1.2.1.4 21-1.2.1.4.5.1.1 23-1.2 24-1.2.2.1.1.1 26-1.2.2.2 28-1.2.2.2.1.1 (s / show-01~e.2 :ARG0 (f / figure~e.0 :mod 2~e.1) :ARG1~e.3 (d / display-01~e.23 :ARG0 (g / gene~e.6 :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "Gcn4"~e.5))) :mod (a / all~e.4) :ARG1-of (t / test-01~e.7 :location (h / here~e.8)) :example (a2 / and~e.20 :op1 (g2 / gene :name (n3 / name :op1 "TRP3"~e.12)) :op2 (g3 / gene :name (n4 / name :op1 "ARG1"~e.14)) :op3 (g4 / gene :name (n5 / name :op1 "HIS3"~e.16)) :op4 (g5 / gene :name (n6 / name :op1 "CPA1"~e.18)) :op5 (g6 / gene :name (n7 / name :op1 "CPA2"~e.21)))) :ARG1 (h2 / hyperacetylate-00 :ARG1 (p2 / protein :name (n8 / name :op1 "H3"~e.24)) :ARG1-of (r / resemble-01~e.26 :ARG2 (h3 / hyperacetylate-00 :ARG1 g4~e.28))))) # ::id bio.chicago_2015.72107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AD designated as the sole or principal cause and no contributing cerebrovascular disease ; AD with contributing cerebrovascular disease ( CVD ) ; VaD as the sole or principal cause without any apparent AD component ; and other dementias attributed to Parkinson s disease , progressive supranuclear palsy , subdural hematoma , trauma , and vitamin B12 deficiency . # ::alignments 1-1.1.1 2-1.1.1.2.r 4-1.1.1.2.1.1 5-1.1.1.2.1 6-1.1.1.2.1.2 7-1.1.1.2 8-1.1 9-1.1.2.2.1 9-1.1.2.2.1.r 10-1.1.2.2 10-1.2.3.2 11-1.1.2.1 12-1.1.2 12-1.2.3 15-1.2.3.r 15-1.3.3.r 16-1.2.3.2 17-1.2.3.1 18-1.2.3 26-1.1.1.2.1.1 26-1.3.2.1.1 27-1.1.1.2.1 27-1.3.2.1 28-1.1.1.2.1.2 28-1.3.2.1.2 29-1.1.1.2 29-1.3 29-1.3.2 29-1.3.2.r 30-1.3.3.1 30-1.3.3.1.r 31-1.3.3.4 34-1.3.3 36-1.4 37-1.4.1.1 38-1.3.1.2 38-1.4.1 39-1.4.1.2 40-1.4.1.2.1.r 41-1.4.1.2.1.1.2.1 43-1.2 43-1.3.3.2 45-1.4.1.2.1.2.1.1 46-1.4.1.2.1.2.1.2 47-1.4.1.2.1.2.1.3 49-1.4.1.2.1.3.1 50-1.4.1.2.1.3 52-1.4.1.2.1.4 54-1.4.1.2.1 55-1.4.1.2.1.5.1 56-1.4.1.2.1.5.1.1.1 57-1.4.1.2.1.5 (m / multi-sentence :snt1 (a / and~e.8 :op1 (d / designate-01~e.1 :ARG1 (d2 / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer's")) :ARG2~e.2 (c / cause-01~e.7,29 :mod (o / or~e.5,27 :op1 (s / sole~e.4,26) :op2 (p / principal~e.6,28)))) :op2 (d3 / disease~e.12 :mod (c2 / cerebrovascular~e.11) :ARG0-of (c3 / contribute-01~e.10 :polarity~e.9 -~e.9))) :snt2 (d4 / disease~e.43 :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's") :accompanier~e.15 (d5 / disease~e.12,18 :mod (c4 / cerebrovascular~e.17) :ARG0-of (c5 / contribute-01~e.10,16))) :snt3 (m2 / medical-condition~e.29 :name (n3 / name :op1 "vascular" :op2 "dementia"~e.38) :ARG0-of~e.29 (c6 / cause-01~e.29 :mod (o2 / or~e.27 :op1 (s2 / sole~e.26) :op2 (p2 / principal~e.28))) :accompanier~e.15 (c7 / component~e.34 :polarity~e.30 -~e.30 :mod (d7 / disease~e.43 :wiki "Alzheimer's_disease" :name (n4 / name :op1 "Alzheimer's")) :ARG1-of (a2 / appear-01) :mod (a3 / any~e.31))) :snt4 (a4 / and~e.36 :op2 (d8 / dementia~e.38 :mod (o3 / other~e.37) :ARG1-of (a5 / attribute-01~e.39 :ARG2~e.40 (a6 / and~e.54 :op1 (d9 / disease :wiki "Parkinson's_disease" :name (n5 / name :op1 "Parkinson's"~e.41)) :op2 (d10 / disease :name (n6 / name :op1 "progressive"~e.45 :op2 "supranuclear"~e.46 :op3 "palsy"~e.47)) :op3 (h / hematoma~e.50 :mod (s3 / subdural~e.49)) :op4 (t / trauma~e.52) :op5 (d11 / deficiency~e.57 :mod (v / vitamin~e.55 :name (n7 / name :op1 "B12"~e.56)))))))) # ::id bio.chicago_2015.72190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of 22 omp @-@ 1 paralogs examined by RT @-@ PCR , omp @-@ 1B was the only omp @-@ 1 transcript detected in all 16 groups of tick tissues ( Fig . 2 ) . # ::alignments 1-1.2.4.1.1 2-1.1.1.1 2-1.2.1.1 4-1.2.4.1.2 6-1.2.4.1.3 7-1.2.4.1.3.1.r 8-1.2.4.1.3.1.1.1 10-1.2.4.1.3.1.1.1 12-1.2.1.1 14-1.2.1.1 15-1.2.r 17-1.2.2 18-1.1.1.1 18-1.2.1.1 20-1.1.1.1 21-1 22-1.2.3 23-1.2.3.1.r 24-1.2.3.1.3 25-1.2.3.1.1 26-1.2.3.1 27-1.2.3.1.2.r 28-1.2.3.1.2.1 29-1.2.3.1.2 31-1.3.1 33-1.3.1.1 (t / transcript~e.21 :mod (p / protein :name (n / name :op1 "omp-1"~e.2,18,20)) :domain~e.15 (p2 / protein :name (n2 / name :op1 "omp-1B"~e.2,12,14,18) :mod (o / only~e.17) :ARG1-of (d / detect-01~e.22 :location~e.23 (g / group-01~e.26 :quant 16~e.25 :ARG2~e.27 (t2 / tissue~e.29 :mod (t3 / tick~e.28)) :mod (a / all~e.24))) :ARG1-of (i / include-91 :ARG2 (p3 / paralog :quant 22~e.1 :mod p~e.4 :ARG1-of (e / examine-01~e.6 :instrument~e.7 (t4 / thing :name (n3 / name :op1 "RT-PCR"~e.8,10)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod 2~e.33))) # ::id bio.chicago_2015.72229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , Southern analysis following 5 @-@ azaC treatment ruled out the demethylation of RI and RII genes as a contributor to RI and RII expression ( 14 , 16 ) . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1.1.2 4-1.1.1.2 5-1.1.1.2.1.1.1.1 7-1.1.1.2.1.1.1.1 8-1.1.1.2.1 9-1.1 10-1.1 12-1.1.2.1 13-1.1.2.1.1.r 14-1.1.2.1.1.1.1.1 15-1.1.2.1.1 16-1.1.2.1.1.2.1.1 17-1.1.2.1.1.1 17-1.1.2.1.1.2 20-1.1.2 21-1.1.2.2.r 22-1.1.2.2.1 23-1.1.2.2.1 24-1.1.2.2.1 25-1.1.2.2 27-1.2.1.1.1.1 29-1.2.1.1.1.2 (h / have-concession-91~e.0 :ARG2 (r / rule-out-02~e.9,10 :ARG0 (t / thing :name (n / name :op1 "Southern"~e.2 :op2 "analysis"~e.3) :ARG1-of (f / follow-01~e.4 :ARG2 (t2 / treat-04~e.8 :ARG2 (s / small-molecule :name (n2 / name :op1 "5-azaC"~e.5,7))))) :ARG1 (c / contribute-01~e.20 :ARG0 (d / demethylate-01~e.12 :ARG1~e.13 (a / and~e.15 :op1 (g / gene~e.17 :name (n3 / name :op1 "RI"~e.14)) :op2 (g2 / gene~e.17 :name (n4 / name :op1 "RII"~e.16)))) :ARG2~e.21 (e / express-03~e.25 :ARG1 a~e.22,23,24))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 14~e.27 :op2 16~e.29))))) # ::id bio.chicago_2015.72242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other less exquisitely specific proteases produced by some bacteria ( e.g . , Pseudomonas aeruginosa , Porphyromonas gingivalis , or Proteus mirabilis ) can completely break down IgA and other Igs ( 9 , 14 , 24 ) but do not achieve this effect . # ::alignments 0-1.1.1.1.4 0-1.1.1.2.2.2 1-1.1.1.1.2.1.1 2-1.1.1.1.2.1 3-1.1.1.1 3-1.1.1.1.2 3-1.1.1.1.2.r 4-1.1.1.1.1.1 5-1.1.1.1.3 6-1.1.1.1.3.1.r 7-1.1.1.1.3.1.1 8-1.1.1.1.3.1 13-1.1.1.1.3.1.2.1.1.1 14-1.1.1.1.3.1.2.1.1.2 16-1.1.1.1.3.1.2.2.1.1 17-1.1.1.1.3.1.2.2.1.2 19-1.1.1.1.3.1.2 20-1.1.1.1.3.1.2.3.1.1 21-1.1.1.1.3.1.2.3.1.2 23-1.1 24-1.1.1.3 25-1.1.1 26-1.1.1 27-1.1.1.2.1.1.1 28-1.1.1.2 29-1.1.1.1.4 29-1.1.1.2.2.2 32-1.1.2.1.1.1.1 34-1.1.2.1.1.1.2 36-1.1.2.1.1.1.3 38-1 40-1.2.1 40-1.2.1.r 41-1.2 43-1.2.3 (c / contrast-01~e.38 :ARG1 (p / possible-01~e.23 :ARG1 (b / break-down-12~e.25,26 :ARG0 (e / enzyme~e.3 :name (n / name :op1 "protease"~e.4) :ARG1-of~e.3 (s / specific-02~e.3 :degree (e2 / exquisite~e.2 :degree (l / less~e.1))) :ARG1-of (p2 / produce-01~e.5 :ARG0~e.6 (b2 / bacteria~e.8 :quant (s2 / some~e.7) :example (o / or~e.19 :op1 (o2 / organism :name (n2 / name :op1 "Pseudomonas"~e.13 :op2 "aeruginosa"~e.14)) :op2 (o3 / organism :name (n3 / name :op1 "Porphyromonas"~e.16 :op2 "gingivalis"~e.17)) :op3 (o4 / organism :name (n4 / name :op1 "Proteus"~e.20 :op2 "mirabilis"~e.21))))) :mod (o5 / other~e.0,29)) :ARG1 (a / and~e.28 :op1 (p3 / protein :name (n5 / name :op1 "IgA"~e.27)) :op2 (p4 / protein :name (n6 / name :op1 "Ig") :mod (o6 / other~e.0,29))) :ARG1-of (c2 / complete-02~e.24)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 9~e.32 :op2 14~e.34 :op3 24~e.36))))) :ARG2 (a3 / achieve-01~e.41 :polarity~e.40 -~e.40 :ARG0 e :ARG1 (a4 / affect-01~e.43 :ARG2 b))) # ::id bio.chicago_2015.72284 ::amr-annotator SDL-AMR-09 ::preferred # ::tok UBPs also have been found to stimulate protein degradation by editing the size of polyubiquitin chains , releasing ubiquitin after the protein has been targeted to the proteasome , or disassembling polyubiquitin chains to restore the cellular pool of free ubiquitin . # ::alignments 1-1.2 4-1 6-1.1 7-1.1.2.1 8-1.1.2 9-1.1.3.r 10-1.1.3.1 12-1.1.3.1.2 13-1.1.3.1.2.1.r 14-1.1.3.1.2.1.1.1.1 15-1.1.3.1.2.1 17-1.1.3.2 18-1.1.3.2.2.1.1 19-1.1.3.2.3 21-1.1.3.1.2.1.1 21-1.1.3.2.2 21-1.1.3.3.3.2.1 24-1.1.3.2.3.1 29-1.1.3 30-1.1.3.3 31-1.1.3.3.2 32-1.1.3.3.2 34-1.1.3.3.3 36-1.1.3.3.3.2.2 37-1.1.3.3.3.2 39-1.1.3.3 39-1.1.3.3.3.2.1.2 40-1.1.3.2.2.1.1 40-1.1.3.3.3.2.1.1.1 (f / find-01~e.4 :ARG1 (s / stimulate-01~e.6 :ARG0 (s3 / small-molecule :name (n / name :op1 "UBP")) :ARG1 (d / degrade-01~e.8 :ARG1 (p / protein~e.7)) :ARG2~e.9 (o / or~e.29 :op1 (e / edit-01~e.10 :ARG0 s3 :ARG1 (s2 / size-01~e.12 :ARG1~e.13 (c / chain-01~e.15 :ARG1 (p2 / protein~e.21 :name (n2 / name :op1 "polyubiquitin"~e.14))))) :op2 (r / release-01~e.17 :ARG0 s3 :ARG1 (p3 / protein~e.21 :name (n3 / name :op1 "ubiquitin"~e.18,40)) :time (a / after~e.19 :op1 (t / target-01~e.24 :ARG0 s3 :ARG1 p3))) :op3 (d2 / disassemble-01~e.30,39 :ARG0 s3 :ARG1 c~e.31,32 :purpose (r2 / restore-02~e.34 :ARG0 s3 :ARG1 (p4 / pool-01~e.37 :ARG1 (p5 / protein~e.21 :name (n4 / name :op1 "ubiquitin"~e.40) :ARG1-of (f2 / free-04~e.39)) :mod (c2 / cell~e.36)))))) :mod (a2 / also~e.1)) # ::id bio.chicago_2015.72524 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B , Rats were restrained for the indicated time ( x axis ) , then returned to their cages for the remainder of the time period ( up to 60 minutes ) , at which time they were euthanatized and analyzed for hsp70 expression . # ::alignments 0-1.3.1.1 2-1.1.1 4-1.1 5-1.1.2.r 7-1.1.2.1 8-1.1.2 10-1.1.2.1.1.1.1.1 11-1.1.2.1.1 14-1.2.4 15-1.2 18-1.2.2 24-1.2.3.1.1 25-1.2.3.1 27-1.2.3.1.1.1 28-1.2.3.1.1.1 29-1.2.3.1.1.1.1.1 30-1.2.3.1.1.1.1.2 35-1.2.3.1.1.1.1 35-1.2.3.2.r 36-1.2.3.2.2.1 39-1.2.3.2 40-1.2.3.2.2 41-1.2.3.2.2.2.r 42-1.2.3.2.2.2.1.1.1 43-1.2.3.2.2.2 (a / and :op1 (r / restrain-01~e.4 :ARG1 (r2 / rat~e.2) :duration~e.5 (t / time~e.8 :ARG1-of (i / indicate-01~e.7 :ARG0 (a2 / axis~e.11 :ARG1-of (l / label-01 :ARG2 (s / string-entity :value "x"~e.10)))))) :op2 (r3 / return-04~e.15 :ARG1 r2 :ARG2 (c / cage-01~e.18 :ARG1 r2) :duration (r4 / remain-01 :ARG1 (p / period~e.25 :mod (t2 / time-01~e.24 :ARG2 (u / up-to~e.27,28 :op1 (t3 / temporal-quantity~e.35 :quant 60~e.29 :unit (m / minute~e.30))))) :time-of~e.35 (a3 / and~e.39 :op1 (e / euthanize-00 :ARG1 r2) :op2 (a4 / analyze-01~e.40 :ARG1 r2~e.36 :purpose~e.41 (e2 / express-03~e.43 :ARG2 (p2 / protein :name (n2 / name :op1 "hsp70"~e.42)))))) :time (t4 / then~e.14)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"~e.0))) # ::id bio.chicago_2015.72571 ::amr-annotator SDL-AMR-09 ::preferred # ::tok So , although both the GAPDH and CA genes exhibit hyperacetylation of H3 and H4 only at the 5 '' @-@ end of the genes , in contrast to the betaA @-@ globin gene , it is not at present possible to conclude that this is a promoter @-@ specific effect , particularly as regards histone H4 . # ::alignments 2-1.1.4.r 5-1.1.4.1.1.1.1.1 6-1.1.4.1.1 7-1.1.4.1.1.2.1.1 8-1.1.4.1.1.1 8-1.1.4.1.1.2 8-1.1.4.2.2 9-1.1.4.1 9-1.1.4.2 12-1.1.4.1.2.1.1.1.1 13-1.1.4.1.1 13-1.1.4.1.2.1 14-1.1.4.1.2.1.2 15-1.1.4.1.3.2 21-1.1.4.1.3.1.1 24-1.1.4.1.3.3 27-1.1.4 30-1.1.4.2.2.1.1 32-1.1.4.2.2.1.1 33-1.1.4.1.1.1 37-1.1.1 37-1.1.1.r 37-1.1.4.2.1 39-1.1.3 40-1.1 42-1.1.2 43-1.1.2.1.r 44-1.1.2.1.1 47-1.1.2.1.2.1 47-1.1.2.1.2.1.1 47-1.1.2.1.2.1.1.r 49-1.1.2.1.2 50-1.1.2.1 52-1.1.2.1.3.2 53-1.1.3.r 54-1.1.2.1.3 55-1.1.2.1.3.1.1.1 56-1.1.2.1.3.1.1.2 (i / infer-01 :ARG1 (p / possible-01~e.40 :polarity~e.37 -~e.37 :ARG1 (c / conclude-01~e.42 :ARG1~e.43 (a / affect-01~e.50 :ARG2 (t / this~e.44) :ARG1-of (s / specific-02~e.49 :ARG2 (m / molecular-physical-entity~e.47 :ARG0-of~e.47 (p2 / promote-01~e.47))) :ARG0-of (r / regard-01~e.54 :ARG1 (p3 / protein :name (n / name :op1 "histone"~e.55 :op2 "H4"~e.56)) :mod (p4 / particular~e.52)))) :time~e.53 (p5 / present~e.39) :concession~e.2 (c2 / contrast-01~e.27 :ARG1 (e / exhibit-01~e.9 :ARG0 (a2 / and~e.6,13 :op1 (g / gene~e.8,33 :name (n2 / name :op1 "GAPDH"~e.5)) :op2 (g2 / gene~e.8 :name (n3 / name :op1 "CA"~e.7))) :ARG1 (h / hyperacetylate-00 :ARG1 (a3 / and~e.13 :op1 (p6 / protein :name (n4 / name :op1 "H3"~e.12)) :op2 p3~e.14)) :location (d / dna-sequence :name (n6 / name :op1 "5''-end"~e.21) :mod (o / only~e.15) :part-of a2~e.24)) :ARG2 (e3 / exhibit-01~e.9 :polarity -~e.37 :ARG0 (g3 / gene~e.8 :name (n5 / name :op1 "betaA-globin"~e.30,32)) :ARG1 h)))) # ::id bio.chicago_2015.72676 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In hepatocytes , inhibition of cAMP @-@ PDE activity in the absence of additional effectors has no effect on the activity of PKA ( attributable to a low basal level of adenylate cyclase activity ) . # ::alignments 1-1.5.1.1 3-1.2 4-1.2.1.r 5-1.2.1.2.1.1.1 7-1.2.1.1.1.1 8-1.2.1 9-1.2.2.r 11-1.2.2 14-1.2.2.1 16-1.1 16-1.1.r 17-1 18-1.3.r 20-1.3 21-1.3.1.r 22-1.3.1.1.1 27-1.4.1.3 28-1.4.1.2 29-1.4.1 30-1.4.1.1.r 31-1.4.1.1.1.1.1 32-1.4.1.1.1.1.2 33-1.4.1.1 (a / affect-01~e.17 :polarity~e.16 -~e.16 :ARG0 (i / inhibit-01~e.3 :ARG1~e.4 (a2 / activity-06~e.8 :ARG0 (e / enzyme :name (n / name :op1 "PDE"~e.7)) :ARG1-of (s / specific-02 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "cAMP"~e.5)))) :ARG2-of~e.9 (a3 / absent-01~e.11 :ARG1 (e2 / effector~e.14 :ARG1-of (a4 / add-02)))) :ARG1~e.18 (a5 / activity-06~e.20 :ARG0~e.21 (e3 / enzyme :name (n3 / name :op1 "PKA"~e.22))) :ARG1-of (a6 / attribute-01 :ARG2 (l / level~e.29 :quant-of~e.30 (a7 / activity-06~e.33 :ARG0 (e4 / enzyme :name (n4 / name :op1 "adenylate"~e.31 :op2 "cyclase"~e.32))) :mod (b / basal~e.28) :ARG1-of (l2 / low-04~e.27)) :ARG1-of (p / possible-01)) :location (c / cell :name (n5 / name :op1 "hepatocyte"~e.1))) # ::id bio.chicago_2015.72680 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , bypassing this reaction with pyruvate , dihydroxyacetone , or glycerol uncovers constraints imposed by mitochondrial metabolism , each of which attains a similar maximal limit of insulin secretion . # ::alignments 0-1 2-1.1.1 3-1.1.1.2.1 4-1.1.1.2 5-1.1.1.1.r 6-1.1.1.1.1.2.1 8-1.1.1.1.2.2.1 10-1.1.1.1 11-1.1.1.1.3.2.1 12-1.1 14-1.1.2.2 19-1.1.1.1.4.2 22-1.1.1.1.4 24-1.1.1.1.4.1.3 25-1.1.1.1.4.1.2 26-1.1.1.1.4.1 27-1.1.1.1.4.1.1.r 28-1.1.1.1.4.1.1.1.2.1 29-1.1.1.1.4.1.1 (h / have-concession-91~e.0 :ARG2 (u / uncover-01~e.12 :ARG0 (b / bypass-01~e.2 :ARG0~e.5 (o / or~e.10 :op1 (s2 / small-molecule :wiki "Pyruvic_acid" :name (n / name :op1 "pyruvate"~e.6)) :op2 (s3 / small-molecule :wiki "Dihydroxyacetone" :name (n2 / name :op1 "dihydroxyacetone"~e.8)) :op3 (s4 / small-molecule :wiki "Glycerol" :name (n3 / name :op1 "glycerol"~e.11)) :ARG0-of (a / attain-01~e.22 :ARG1 (l / limit-01~e.26 :ARG1~e.27 (s / secrete-01~e.29 :ARG1 (p / protein :wiki "Insulin" :name (n4 / name :op1 "insulin"~e.28))) :mod (m4 / maximal~e.25) :ARG1-of (r / resemble-01~e.24)) :mod (e / each~e.19))) :ARG1 (r2 / react-01~e.4 :mod (t / this~e.3))) :ARG1 (t2 / thing :ARG1-of (c / constrain-01) :ARG1-of (i2 / impose-01~e.14 :ARG0 (m5 / metabolize-01 :ARG1 (m6 / mitochondrium)))))) # ::id bio.chicago_2015.72720 ::amr-annotator SDL-AMR-09 ::preferred # ::tok p53 may act synergistically with E2A , to activate p21 expression in wild @-@ type cells . # ::alignments 0-1.1.1.1.1 1-1 3-1.1 4-1.1.2.r 5-1.1.2.1.1 8-1.1.3 9-1.1.3.2.1.1.1 10-1.1.3.2 11-1.1.3.3.r 12-1.1.3.3.1 14-1.1.3.3.1 15-1.1.3.3 (p / possible-01~e.1 :ARG1 (s / synergize-01~e.3 :ARG0 (p2 / protein :name (n / name :op1 "p53"~e.0)) :ARG1~e.4 (p3 / protein :name (n2 / name :op1 "E2A"~e.5)) :ARG2 (a3 / activate-01~e.8 :ARG0 (a2 / and :op1 p2 :op2 p3) :ARG1 (e / express-03~e.10 :ARG2 (p4 / protein :name (n3 / name :op1 "p21"~e.9))) :location~e.11 (c / cell~e.15 :mod (w / wild-type~e.12,14))))) # ::id bio.chicago_2015.72786 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Earlier studies also reported that ERK depolymerizes interphase microtubules and forms mitotic microtubules in Xenopus cell extracts ( 19 ) . # ::alignments 0-1.1.1.1 0-1.1.1.1.1 0-1.1.1.1.1.r 1-1.1 1-1.1.1 1-1.1.1.r 2-1.3 3-1 4-1.2.r 5-1.2.1.1.1.1 7-1.2.1.2.1 9-1.2 10-1.2.2 11-1.2.2.2.1 13-1.2.r 14-1.2.3.2.1.1 15-1.2.3 16-1.2.3.1 18-1.4.1.1.1 (r / report-01~e.3 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (s / study-01~e.1 :time (e / early~e.0 :degree~e.0 (m / more~e.0)))) :ARG1~e.4,13 (a / and~e.9 :op1 (d / depolymerize-00 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK"~e.5)) :ARG1 (m2 / microtubule :mod (i / interphase~e.7))) :op2 (f / form-01~e.10 :ARG0 e2 :ARG1 (m3 / microtubule :mod (m4 / mitosis~e.11))) :location (c / cell~e.15 :ARG1-of (e3 / extract-01~e.16) :part-of (o / organism :name (n2 / name :op1 "Xenopus"~e.14)))) :mod (a2 / also~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 19~e.18)))) # ::id bio.chicago_2015.72820 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytochalasin D disassembles bcl10 filament and bcl10 @-@ induced NF @-@ kappaB activation . # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1 3-1.2.1.1.1.1 4-1.2.1 6-1.2.1.1.1.1 8-1.2.2.2 9-1.2.2.1.1.1 11-1.2.2.1.1.1 12-1.2.2 (d / disassemble-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "Cytochalasin"~e.0 :op2 "D"~e.1)) :ARG1 (a / and :op1 (f / filament~e.4 :mod (p / protein :name (n2 / name :op1 "bcl10"~e.3,6))) :op2 (a2 / activate-01~e.12 :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "NF-kappaB"~e.9,11)) :ARG2-of (i / induce-01~e.8 :ARG0 p)))) # ::id bio.chicago_2015.72824 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The insert encodes the cleavage site of TEV protease that can proteolyze target proteins in vivo , in vitro , or on the extracellular side of whole cells when the recognition sequence is surface accessible . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 4-1.2.1 5-1.2 6-1.2.1.1.r 7-1.2.1.1.1.1 8-1.2.1.1.1.2 10-1.2.2.4 10-1.2.2.5 11-1.2.2 12-1.2.2.1.1 13-1.2.2.1 14-1.2.2.2.1 15-1.2.2.2.1 17-1.2.2.2.1 17-1.2.2.2.r 18-1.2.2.2.2 20-1.2.2.2 20-1.2.2.3 21-1.2.2.3.r 23-1.2.2.3.1.1 24-1.2.2.3.1 25-1.2.2.3.1.2.r 26-1.2.2.3.1.2.1 27-1.2.2.3.1.2 28-1.2.2.5.r 30-1.2.2.5.1.1.1 31-1.2.2.5.1.1 33-1.2.2.5.2 (e / encode-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (i / insert-01~e.1)) :ARG1 (s / site~e.5 :mod (c / cleave-01~e.4 :ARG1~e.6 (e2 / enzyme :name (n / name :op1 "TEV"~e.7 :op2 "protease"~e.8))) :ARG0-of (p / proteolyze-00~e.11 :ARG1 (p2 / protein~e.13 :ARG1-of (t2 / target-01~e.12)) :manner~e.17 (o / or~e.20 :op1 (i2 / in-vivo~e.14,15,17) :op2 (i3 / in-vitro~e.18)) :location~e.21 (o2 / or~e.20 :op2 (s2 / side~e.24 :mod (e3 / extracellular~e.23) :part-of~e.25 (c2 / cell~e.27 :mod (w / whole~e.26)))) :ARG1-of (p3 / possible-01~e.10) :time~e.28 (p4 / possible-01~e.10 :ARG1 (a / access-01 :ARG1 (s3 / sequence~e.31 :ARG1-of (r / recognize-02~e.30))) :mod (s4 / surface~e.33))))) # ::id bio.chicago_2015.72930 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LC spontaneous discharge and activation by intracerebroventricularly administered CRF , hypotensive challenge , sciatic nerve stimulation , and carbachol were compared in adrenalectomized and sham @-@ operated halothane @-@ anesthetized rats . # ::alignments 1-1.1.2 2-1.1 3-1.2.1 4-1.2 5-1.2.1.r 6-1.2.1.1.2.1 7-1.2.1.1.2 8-1.2.1.1.1.1 10-1.2.1.2.2 11-1.2.1.2 13-1.2.1.3.1.1 14-1.2.1.3.1 15-1.2.1.3 17-1.2.1 18-1.2.1.4.1.1 20-1 23-1.2.1 24-1.3.3.1 26-1.3.3 27-1.3.2.1.1.1 29-1.3.2 30-1.3 (c / compare-01~e.20 :ARG1 (d / discharge-101~e.2 :ARG0 (c3 / ceruleus :mod (l / locus)) :manner (s / spontaneous~e.1)) :ARG2 (a / activate-01~e.4 :ARG0~e.5 (a2 / and~e.3,17,23 :op1 (s5 / small-molecule :name (n2 / name :op1 "CRF"~e.8) :ARG1-of (a3 / administer-01~e.7 :manner (i / intracerebroventricularly~e.6))) :op2 (c2 / challenge-01~e.11 :ARG1 (m / molecular-physical-entity) :mod (h / hypotensive~e.10)) :op3 (s2 / stimulate-01~e.15 :ARG1 (n3 / nerve~e.14 :mod (s3 / sciatic~e.13))) :op4 (s7 / small-molecule :name (n4 / name :op1 "carbachol"~e.18))) :ARG1 m) :location (r / rat~e.30 :ARG1-of (a4 / adrenalectomize-00) :ARG1-of (a5 / anesthetize-01~e.29 :ARG2 (s6 / small-molecule :name (n5 / name :op1 "halothane"~e.27))) :ARG1-of (o / operate-02~e.26 :manner (s4 / sham~e.24)))) # ::id bio.chicago_2015.73032 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to investigate the importance of the chitin deacetylation process to cell wall assembly , we took advantage of the natural fluorescence that wild type spores emit when excited by ultraviolet light , as well as their resistance to hydrolytic enzymes , ether , and heat shock ( 8 , 10 ) . # ::alignments 0-1.4.r 1-1.4.r 2-1.4.r 3-1.4 5-1.4.2 6-1.4.2.1.r 8-1.4.2.1.1.1.1.1 9-1.4.2.1.1 10-1.4.2.1 11-1.4.2.2.r 12-1.4.2.2.1.1 13-1.4.2.2.1 14-1.4.2.2 16-1.1 17-1 18-1.2 19-1.3.r 21-1.3.1.1 22-1.3.1 24-1.3.1.2.1.1 25-1.3.1.2.1.1 26-1.3.1.2.1 27-1.3.1.2 28-1.3.1.2.2.r 29-1.3.1.2.2 30-1.3.1.2.2.1.r 31-1.3.1.2.2.1.1 32-1.3.1.2.2.1 34-1.3.2.2 35-1.3.2.2 36-1.3 36-1.3.2.2 38-1.3.2 39-1.3.2.2.r 40-1.3.2.2.1.1 41-1.3.2.2.1 43-1.3.2.2.2 45-1.3.2.2 46-1.3.2.2.3.1 47-1.3.2.2.3 49-1.5.1.1.1.1 51-1.5.1.1.1.2 (t / take-01~e.17 :ARG0 (w / we~e.16) :ARG1 (a / advantage~e.18) :ARG2~e.19 (a2 / and~e.36 :op1 (f / fluorescence~e.22 :ARG1-of (n / natural-03~e.21) :ARG1-of (e / emit-01~e.27 :ARG0 (s / spore~e.26 :mod (w2 / wild-type~e.24,25)) :time~e.28 (e2 / excite-01~e.29 :ARG0~e.30 (l / light~e.32 :mod (u / ultraviolet~e.31)) :ARG1 s))) :op2 (r / resist-01~e.38 :ARG0 s :ARG1~e.39 (a3 / and~e.34,35,36,45 :op1 (e3 / enzyme~e.41 :mod (h / hydrolytic~e.40)) :op2 (e4 / ether~e.43) :op3 (s2 / shock-01~e.47 :ARG0 (h2 / heat~e.46) :ARG1 s)))) :purpose~e.0,1,2 (i / investigate-01~e.3 :ARG0 w :ARG1 (i2 / importance~e.5 :poss~e.6 (p / process-01~e.10 :ARG1 (d / deacetylate-01~e.9 :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "chitin"~e.8)))) :beneficiary~e.11 (a4 / assemble-01~e.14 :ARG1 (w3 / wall~e.13 :mod (c / cell~e.12))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 8~e.49 :op2 10~e.51))))) # ::id bio.chicago_2015.73037 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Spontaneous or induced deamination of cytosine , adenine , guanine or 5 @-@ methylcytosine converts these bases to the miscoding uracil , hypoxanthine , xanthine and thymine , respectively 4 . # ::alignments 0-1.1.1.2 1-1.1 2-1.1.2.2 5-1.1.2.1.1.1.1 7-1.1.2.1.2.1.1 9-1.1.2.1.3.1.1 10-1.1.2.1 11-1.1.2.1.4.1.1 13-1.1.2.1.4.1.1 14-1 15-1.2.1 16-1.2 20-1.3.1.1.1 22-1.3.2.1.1 24-1.3.3.1.1 25-1.3 26-1.3.4.1.1 28-1.3.6 28-1.3.6.r 29-1.4.1.1.1 (c / convert-01~e.14 :ARG0 (o / or~e.1 :op1 (d / deaminate-01 :ARG1 o2 :mod (s / spontaneous~e.0)) :op2 (d2 / deaminate-01 :ARG1 (o2 / or~e.10 :op1 (s2 / small-molecule :name (n / name :op1 "cytosine"~e.5)) :op2 (s3 / small-molecule :name (n2 / name :op1 "adenine"~e.7)) :op3 (s4 / small-molecule :name (n3 / name :op1 "guanine"~e.9)) :op4 (s5 / small-molecule :name (n4 / name :op1 "5-methylcytosine"~e.11,13))) :ARG2-of (i / induce-01~e.2))) :ARG1 (b / base~e.16 :mod (t / this~e.15)) :ARG2 (a / and~e.25 :op1 (s6 / small-molecule :name (n5 / name :op1 "uracil"~e.20)) :op2 (s7 / small-molecule :name (n6 / name :op1 "hypoxanthine"~e.22)) :op3 (s8 / small-molecule :name (n7 / name :op1 "xanthine"~e.24)) :op4 (s9 / small-molecule :name (n8 / name :op1 "thymine"~e.26)) :ARG0-of (m9 / miscode-00) :manner~e.28 (r / respective~e.28)) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.29)))) # ::id bio.chicago_2015.73068 ::amr-annotator SDL-AMR-09 ::preferred # ::tok pRb indicates hypophosphorylated retinoblastoma protein ; ppRb , hyperphosphorylated pRb . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.2 2-1.1.2.2 3-1.1.2.1.1 4-1.1.2.1.2 6-1.2.1.1.1 8-1.2.2.2 9-1.1.1.1.1 9-1.2.2.1.1 (a / and :op1 (i / indicate-01~e.1 :ARG0 (p / protein :name (n / name :op1 "pRb"~e.0,9)) :ARG1 (p4 / protein :name (n4 / name :op1 "retinoblastoma"~e.3 :op2 "protein"~e.4) :ARG1-of (h / hypophosphorylate-00~e.2))) :op2 (i2 / indicate-01~e.1 :ARG0 (p2 / protein :name (n2 / name :op1 "ppRb"~e.6)) :ARG1 (p3 / protein :name (n3 / name :op1 "pRb"~e.9) :ARG1-of (h2 / hyperphosphorylate-01~e.8)))) # ::id bio.chicago_2015.73070 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Toll receptors , CD14 , and macrophage activation and deactivation by LPS . # ::alignments 0-1.1.1.1 1-1.1.1.2 3-1.3.1.1 5-1 5-1.2 5-1.2.r 6-1.2.1.2 7-1.2.1 8-1.2 9-1.2.2 10-1.2.1.1.r 11-1.2.1.1.1.1 (a / and~e.5 :op1 (p / protein-family :name (n / name :op1 "Toll"~e.0 :op2 "receptor"~e.1)) :op1~e.5 (a2 / and~e.5,8 :op1 (a3 / activate-01~e.7 :ARG0~e.10 (m / molecular-physical-entity :name (n3 / name :op1 "LPS"~e.11)) :ARG1 (m2 / macrophage~e.6)) :op2 (d / deactivate-01~e.9 :ARG0 m :ARG1 m2)) :op2 (p2 / protein :name (n2 / name :op1 "CD14"~e.3))) # ::id bio.chicago_2015.73119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CpG island methylation and deacetylation of histone are involved in the creation of transcription suppressive domains ( 54 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1.1.1.2 2-1.1.1 3-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 8-1 9-1.2.r 11-1.2 12-1.2.1.r 13-1.2.1.1.1 15-1.2.1 17-1.3.1.1.1 (i / involve-01~e.8 :ARG1 (a / and~e.3 :op1 (m / methylate-01~e.2 :ARG1 (d / dna-sequence :name (n / name :op1 "CpG"~e.0 :op2 "island"~e.1))) :op2 (d2 / deacetylate-01~e.4 :ARG1~e.5 (p / protein :name (n2 / name :op1 "histone"~e.6)))) :ARG2~e.9 (c / create-01~e.11 :ARG1~e.12 (d3 / domain~e.15 :ARG0-of (s / suppress-01 :ARG1 (t / transcribe-01~e.13)))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 54~e.17)))) # ::id bio.chicago_2015.73121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The signaling from Ras through Raf prompted us to ask whether Raf itself could elicit senescence . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.2.r 5-1.1.2.1.1 6-1 7-1.2.1 9-1.2 10-1.2.2.1 10-1.2.2.1.r 11-1.1.2.1.1 13-1.2.2 14-1.2.2.2 15-1.2.2.2.2 (p4 / prompt-01~e.6 :ARG0 (s / signal-07~e.1 :ARG0~e.2 (e2 / enzyme :name (n / name :op1 "Ras"~e.3)) :path~e.4 (e3 / enzyme :name (n2 / name :op1 "Raf"~e.5,11))) :ARG1 (a / ask-01~e.9 :ARG0 (w / we~e.7) :ARG1 (p3 / possible-01~e.13 :mode~e.10 interrogative~e.10 :ARG1 (e / elicit-01~e.14 :ARG0 e3 :ARG1 (s2 / senescence~e.15))))) # ::id bio.chicago_2015.73158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Assuming a 100 % increase in LC discharge rate as the maximum effect produced by CRF ( Curtis et al. , 1997 ) , the CRF ED50 value in naive rats was 0.9 mug , similar to the value previously reported by this laboratory ( Curtis et al. , 1997 ) . # ::alignments 0-1.5 2-1.5.2.2.1 3-1.5.2.2 4-1.5.2 7-1.5.2.1.1 8-1.5.2.1 11-1 11-1.5.1.1 12-1.5.1 13-1.5.1.2 14-1.5.1.2.1.r 15-1.5.1.2.1 17-1.5.3.1.1.1.1.1 18-1.5.3.1.1 19-1.5.3.1.1.2.1 21-1.5.3.1.2.1 25-1.2.1.1 27-1.3.3.1 28-1.4.r 29-1.4.1 30-1.4 32-1.3.1 35-1.3.3 38-1.3.3.1 39-1.3.3.1.1.2 40-1.3.3.1.1 41-1.3.3.1.1.1.r 42-1.3.3.1.1.1.1 43-1.3.3.1.1.1 45-1.5.3.1.1.1.1.1 46-1.5.3.1.1 47-1.5.3.1.1.2.1 49-1.5.3.1.2.1 (h / have-percentage-maximal-effective-dose-01~e.11 :ARG2 50 :ARG1 (s / small-molecule :name (n2 / name :op1 "CRF"~e.25)) :ARG4 (m4 / mass-quantity :quant 0.9~e.32 :unit (m5 / microgram) :ARG1-of (r3 / resemble-01~e.35 :ARG2 (v2 / value~e.27,38 :ARG1-of (r4 / report-01~e.40 :ARG0~e.41 (l / laboratory~e.43 :mod (t2 / this~e.42)) :time (p / previous~e.39)) :ARG1-of (d4 / describe-01 :ARG0 a3)))) :ARG5~e.28 (r2 / rat~e.30 :mod (n3 / naive~e.29)) :condition (a / assume-01~e.0 :ARG1 (a2 / affect-01~e.12 :mod (m3 / maximum~e.11) :ARG1-of (p3 / produce-01~e.13 :ARG0~e.14 s~e.15)) :ARG2 (i / increase-01~e.4 :ARG1 (r5 / rate~e.8 :degree-of (d2 / discharge-01~e.7 :ARG0 (c2 / ceruleus :mod (l2 / locus)))) :ARG2 (p2 / percentage-entity~e.3 :value 100~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.18,46 :op1 (p5 / person :name (n5 / name :op1 "Curtis"~e.17,45)) :op2 (p6 / person :mod (o / other~e.19,47))) :time (d / date-entity :year 1997~e.21,49))))) # ::id bio.chicago_2015.73159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HPLC was used to resolve the 3H @-@ labeled inositol phosphates ( polarity Ins P2 ) in DDT1 MF @-@ 2 cells ( Figure 2 ) ; there were three diphosphorylated compounds ( PP @-@ Ins P4 , peak v ; PP @-@ Ins P5 , peak vii ; [ PP]2 @-@ Ins P4 , peak viii ) , all of which have been observed previously in other mammalian cells ( Menniti et al. , 1993 ; # ::alignments 0-1.1.1.1.1 2-1.1 4-1.1.2 6-1.1.2.2.2.1.1.1 8-1.1.2.2.2 9-1.1.2.2.1.1 10-1.1.2.2.1.2 12-1.1.2.2.3 13-1.1.2.2.3.1.1.1 14-1.1.2.2.3.1.1.2 16-1.1.2.3.r 17-1.1.2.3.1.1 18-1.1.2.3.1.2 20-1.1.2.3.1.2 21-1.1.2.3 23-1.1.2.4.1 24-1.1.2.4.1.1 29-1.2.1.1 31-1.2.1 33-1.2.1.2.1.1.1.1 33-1.2.1.2.1.2.1.1 35-1.2.1.2.1.1.1.1 35-1.2.1.2.1.2.1.1 35-1.2.1.2.1.3.1.1 36-1.2.1.2.1.1.1.2 36-1.2.1.2.1.3.1.2 38-1.2.1.2.1.1.2.1 39-1.2.1.2.1.1.2.1.1 41-1.2.1.2.1.1.1.1 41-1.2.1.2.1.2.1.1 43-1.2.1.2.1.1.1.1 43-1.2.1.2.1.2.1.1 43-1.2.1.2.1.3.1.1 44-1.2.1.2.1.2.1.2 46-1.2.1.2.1.2.2.1 47-1.2.1.2.1.2.2.1.1 52-1.2.1.2.1.1.1.1 52-1.2.1.2.1.3.1.1 53-1.2.1.2.1.1.1.2 53-1.2.1.2.1.3.1.2 55-1.2.1.2.1.3.2.1 56-1.2.1.2.1.3.2.1.1 59-1.2.1.4 64-1.2 65-1.2.2 67-1.2.3.2 67-1.2.4.1.1.2.1 68-1.2.3.1 69-1.2.3 71-1.2.4.1.1.1.1.1 72-1.2.1.2.1 72-1.2.4.1.1 73-1.2.4.1.1.2.1 75-1.2.4.1.2.1 (m / multi-sentence :snt1 (u / use-01~e.2 :ARG1 (t / thing :name (n / name :op1 "HPLC"~e.0)) :ARG2 (r / resolve-03~e.4 :ARG0 t :ARG1 (s / small-molecule :name (n2 / name :op1 "inositol"~e.9 :op2 "phosphates"~e.10) :ARG1-of (l / label-01~e.8 :ARG0 (s5 / small-molecule :name (n3 / name :op1 "3H"~e.6))) :mod (p / polarity~e.12 :mod (t3 / thing :name (n4 / name :op1 "Ins"~e.13 :op2 "P2"~e.14)))) :location~e.16 (c / cell~e.21 :name (n5 / name :op1 "DDT1"~e.17 :op2 "MF-2"~e.18,20)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.23 :mod 2~e.24)))) :snt2 (o / observe-01~e.64 :ARG1 (c2 / compound~e.31 :quant 3~e.29 :ARG1-of (m3 / mean-01 :ARG2 (a3 / and~e.72 :op1 (s2 / small-molecule :name (n7 / name :op1 "PP-Ins"~e.33,35,41,43,52 :op2 "P4"~e.36,53) :ARG1-of (d5 / describe-01 :ARG0 (p6 / peak~e.38 :li "v"~e.39))) :op2 (s3 / small-molecule :name (n8 / name :op1 "PP-Ins"~e.33,35,41,43 :op2 "P5"~e.44) :ARG1-of (d6 / describe-01 :ARG0 (p7 / peak~e.46 :li "vii"~e.47))) :op3 (s4 / small-molecule :name (n9 / name :op1 "[PP]2-Ins"~e.35,43,52 :op2 "P4"~e.36,53) :ARG1-of (d7 / describe-01 :ARG0 (p8 / peak~e.55 :li "viii"~e.56))))) :ARG1-of (d3 / diphosphorylate-00) :mod (a / all~e.59)) :time (p2 / previous~e.65) :location (c3 / cell~e.69 :mod (m2 / mammal~e.68) :mod (o2 / other~e.67)) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and~e.72 :op1 (p4 / person :name (n6 / name :op1 "Menniti"~e.71)) :op2 (p5 / person :mod (o3 / other~e.67,73))) :time (d / date-entity :year 1993~e.75))))) # ::id bio.chicago_2015.73189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Gfi @-@ 1B was in vitro transcribed and translated by the TNTtm T7 coupled reticulocyte lysate system ( Promega ) . # ::alignments 0-1.1.2.1.1 2-1.1.2.1.1 4-1.3 5-1.3 6-1.1 7-1 8-1.2 9-1.1.1.r 11-1.1.1.1.1 12-1.1.1.1.2 13-1.1.1.1.3 14-1.1.1.1.4 15-1.1.1.1.5 16-1.1.1.1.6 18-1.1.1.2.1.1 (a / and~e.7 :op1 (t / transcribe-01~e.6 :ARG0~e.9 (t3 / thing :name (n2 / name :op1 "TNTtm"~e.11 :op2 "T7"~e.12 :op3 "coupled"~e.13 :op4 "reticulocyte"~e.14 :op5 "lysate"~e.15 :op6 "system"~e.16) :mod (c / company :name (n3 / name :op1 "Promega"~e.18))) :ARG1 (g / gene :name (n / name :op1 "Gfi-1B"~e.0,2))) :op2 (t2 / translate-02~e.8 :ARG1 g) :manner (i / in-vitro~e.4,5)) # ::id bio.chicago_2015.73212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This would suggest that the capacity for anaerobic glycolysis is adequate to stoichiometrically replace the ATP attributable to oxidative metabolism . # ::alignments 0-1.1 2-1 3-1.2.r 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.1 8-1.2.1.1 9-1.2.1.r 10-1.2 13-1.2.2 15-1.2.2.1.1.1 18-1.2.2.1.2.1.1 (s / suggest-01~e.2 :ARG0 (t / this~e.0) :ARG1~e.3 (a / adequate~e.10 :domain~e.9 (c / capacity~e.5 :prep-for~e.6 (g / glycolysis~e.8 :mod (a2 / anaerobic~e.7))) :purpose (r / replace-01~e.13 :ARG1 (s3 / small-molecule :name (n / name :op1 "ATP"~e.15) :ARG1-of (a3 / attribute-01 :ARG2 (m / metabolize-01 :ARG1-of (o / oxidize-01~e.18)) :ARG1-of (p / possible-01))) :manner (s2 / stoichiometric)))) # ::id bio.chicago_2015.73264 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NE10790 specifically inhibits Rab prenylation by Rab GGTase , demonstrating for the first time that Rab proteins are also required for osteoclastic bone resorption . # ::alignments 0-1.1.1.1 1-1.3 2-1 3-1.2.2.1.1 6-1.2.1.1.1 6-1.2.2.1.1 7-1.2.1.1.2 9-1.4 10-1.4.2.r 12-1.4.2 12-1.4.2.1 12-1.4.2.1.r 15-1.2.2.1.1 16-1.2.2 18-1.4.1.3 19-1.4.1 22-1.4.1.1.2 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "NE10790"~e.0)) :ARG1 (p / prenylate-00 :ARG0 (e / enzyme :name (n3 / name :op1 "Rab"~e.6 :op2 "GGTase"~e.7)) :ARG1 (p2 / protein-family~e.16 :name (n2 / name :op1 "Rab"~e.3,6,15))) :ARG1-of (s2 / specific-02~e.1) :ARG0-of (d / demonstrate-01~e.9 :ARG1 (r / require-01~e.19 :ARG0 (r2 / resorb-01 :ARG0 (o2 / osteoclast) :ARG1 (b / bone~e.22)) :ARG1 p2 :mod (a / also~e.18)) :ord~e.10 (o / ordinal-entity~e.12 :value~e.12 1~e.12))) # ::id bio.chicago_2015.73355 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been shown that both Tris @-@ HCl and sodium phosphate buffers hydrolyse FDA to fluorescein and neither are particularly suitable for use in the FDA assay . # ::alignments 3-1 6-1.1.1.2.1.1.1.1 9-1.1.1.2 10-1.1.1.2.2.1.1.1 11-1.1.1.2.2.1.1.2 12-1.1.1.2.1 12-1.1.1.2.2 14-1.1.1.1.1.1 16-1.1.1.3.1.1 17-1.1.1.2 18-1.1.2.1 18-1.1.2.1.r 20-1.1.2.4 20-1.1.2.4.r 23-1.1.2.3 24-1.1.2.3.2.r 26-1.1.2.3.2.1 27-1.1.2.3.2 (s / show-01~e.3 :ARG1 (a / and :op1 (h / hydrolyze-01 :ARG1 (s6 / small-molecule :name (n3 / name :op1 "FDA"~e.14)) :ARG2 (a2 / and~e.9,17 :op1 (b / buffer~e.12 :mod (m / macro-molecular-complex :name (n / name :op1 "Tris-HC1"~e.6))) :op2 (b2 / buffer~e.12 :mod (s3 / small-molecule :name (n2 / name :op1 "sodium"~e.10 :op2 "phosphate"~e.11)))) :ARG3 (s4 / small-molecule :name (n4 / name :op1 "fluorescein"~e.16))) :op2 (s5 / suit-01 :polarity~e.18 -~e.18 :ARG1 a2 :ARG2 (u / use-01~e.23 :ARG1 a2 :ARG2~e.24 (a3 / assay-01~e.27 :ARG1 s6~e.26)) :manner~e.20 (p / particular~e.20)))) # ::id bio.chicago_2015.73390 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Divergence times for hedgehog and primate apo( a ) s were calculated according to Li and Graur ( 15 ) , by using the divergence times for the rhesus/ human split ( 25 Myr ago ) , rodent/ primate split ( 75 Myr ) , and cow/ primate split ( 80 Myr ) of Li et al. ( 16 ) . # ::alignments 0-1.1.1 0-1.3.1.1.1 0-1.3.1.2.1 0-1.3.1.3.1 1-1.1 1-1.1.1.r 1-1.3.1.1 1-1.3.1.2 1-1.3.1.3 3-1.1.1.1.2 5-1.1.1.2.2 11-1 12-1.2.1 13-1.2.1 14-1.2.1.1.1.1.1 15-1.2.1.1 16-1.2.1.1.2.1.1 18-1.2.2.1.1.1 21-1.3.r 22-1.3 24-1.1.1 25-1.1.1.r 25-1.3.1.1.1.1.3.2 25-1.3.1.1.1.1.3.r 25-1.3.1.2.1.1.3.2 25-1.3.1.3.1.1.3.2 25-1.3.1.3.1.1.3.r 29-1.3.1.1.1.1.2 30-1.3.1.1.1.1 34-1.3.1.1.1.1.3 34-1.3.1.1.1.1.3.1 34-1.3.1.1.1.1.3.1.r 34-1.3.1.2.1.1.3 34-1.3.1.3.1.1.3 38-1.1.1.2.2 39-1.3.1.2.1.1 39-1.3.1.3.1.1 45-1.3.1 45-1.3.1.4 45-1.3.1.4.r 47-1.3.1.2.1.1.2 48-1.3.1.2.1.1 54-1.2.1.1.1.1.1 55-1.3.1 55-1.3.1.4 55-1.3.1.4.r 56-1.3.1.4.2.1 58-1.3.1.4.3.1.1.1 (c / calculate-01~e.11 :ARG1 (t / time~e.1 :time-of~e.1,25 (d / diverge-01~e.0,24 :ARG0 (p / protein :name (n2 / name :op1 "Apo(a)") :mod (h / hedgehog~e.3)) :ARG1 (p2 / protein :name (n3 / name :op1 "Apo(a)") :mod (p3 / primate~e.5,38)))) :manner (t2 / thing :ARG1-of (s / say-01~e.12,13 :ARG0 (a / and~e.15 :op1 (p4 / person :name (n4 / name :op1 "Li"~e.14,54)) :op2 (p5 / person :name (n5 / name :op1 "Graur"~e.16)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 15~e.18)))) :manner~e.21 (u / use-01~e.22 :ARG1 (a2 / and~e.45,55 :op1 (t3 / time~e.1 :time-of (d5 / diverge-01~e.0 :ARG1 (s2 / split-01~e.30 :ARG1 (r / rhesus) :ARG3 (h2 / human~e.29) :time~e.25 (b2 / before~e.34 :op1~e.34 (n6 / now~e.34) :duration (t4 / temporal-quantity~e.25 :quant 25000000 :unit (y / year)))))) :op2 (t7 / time~e.1 :time-of (d6 / diverge-01~e.0 :ARG1 (s3 / split-01~e.39,48 :ARG1 (r2 / rodent) :ARG3 p3~e.47 :time (b / before~e.34 :op1 n6 :duration (t5 / temporal-quantity~e.25 :quant 75000000 :unit y))))) :op3 (t8 / time~e.1 :time-of (d7 / diverge-01~e.0 :ARG1 (s4 / split-01~e.39 :ARG1 (c3 / cow) :ARG3 p3 :time~e.25 (b3 / before~e.34 :op1 n6 :duration (t6 / temporal-quantity~e.25 :quant 80000000 :unit y))))) :poss~e.45,55 (a3 / and~e.45,55 :op1 p4 :op2 (p9 / person :mod (o / other~e.56)) :ARG1-of (d4 / describe-01 :ARG0 (p10 / publication :ARG1-of (c4 / cite-01 :ARG2 16~e.58))))))) # ::id bio.chicago_2015.73401 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Within these tumors , one subgroup ( a ) had additional methylation in HOXA5 , WT1 , and uPA loci , whereas the other subgroup ( b ) acquired frequent hypermethylation of 3OST3B , BRCA1 , and DAPK1 genes ( see Figure 5B ) . # ::alignments 0-1.1.1.1.r 1-1.1.1.3.1.1 2-1.1.1.3.1 4-1.1.1.1 5-1.1.1 7-1.1.1.2 9-1.1 10-1.1.2.2 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1.1.1 15-1.1.2.1.2.1.1.1 17-1.1.2.1 18-1.1.2.1.3.1.1.1 21-1 23-1.2.1.2 24-1.2.1 26-1.2.1.1 28-1.2 29-1.2.2.2 32-1.2.2.1.1.1.1 34-1.2.2.1.2.1.1 36-1.2.2.1 37-1.2.2.1.3.1.1 38-1.1.2.1.1.1 38-1.1.2.1.2.1 38-1.1.2.1.3.1 38-1.2.2.1.1 38-1.2.2.1.2 38-1.2.2.1.3 40-1.3 41-1.3.1 42-1.3.1.1 (c / contrast-01~e.21 :ARG1 (h / have-03~e.9 :ARG0 (s / subgroup~e.5 :quant~e.0 1~e.4 :li "a"~e.7 :ARG1-of (i / include-91 :ARG2 (t / tumor~e.2 :mod (t2 / this~e.1)))) :ARG1 (m / methylate-01~e.11 :ARG1~e.12 (a3 / and~e.17 :op1 (l / locus :mod (g4 / gene~e.38 :name (n / name :op1 "HOXA5"~e.13))) :op2 (l2 / locus :mod (g5 / gene~e.38 :name (n2 / name :op1 "WT1"~e.15))) :op3 (l3 / locus :mod (g6 / gene~e.38 :name (n3 / name :op1 "uPA"~e.18)))) :mod (a2 / additional~e.10))) :ARG2 (a4 / acquire-01~e.28 :ARG0 (s2 / subgroup~e.24 :li "b"~e.26 :mod (o / other~e.23) :ARG1-of i) :ARG1 (h2 / hypermethylate-01 :ARG2 (a5 / and~e.36 :op1 (g / gene~e.38 :name (n4 / name :op1 "3OST3B"~e.32)) :op2 (g2 / gene~e.38 :name (n5 / name :op1 "BRCA1"~e.34)) :op3 (g3 / gene~e.38 :name (n6 / name :op1 "DAPK1"~e.37))) :ARG1-of (f2 / frequent-02~e.29))) :ARG1-of (s3 / see-01~e.40 :medium (f / figure~e.41 :mod "5B"~e.42))) # ::id bio.chicago_2015.73405 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recombinant ADAM 12 @-@ S partially purified from conditioned medium on a heparin @-@ Sepharose column also proteolyzed IGFBP @-@ 3 . # ::alignments 0-1.1.3 1-1.1.1.1 2-1.1.1.2 4-1.1.1.2 5-1.1.2.2 5-1.1.2.2.r 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1 9-1.1.2.1 10-1.1.2.1.2.r 12-1.1.2.1.2.1.1.1.1 14-1.1.2.1.2.1.2.1.1 15-1.1.2.1.2 16-1.3 18-1.2.1.1 20-1.2.1.1 (p / proteolyze-00 :ARG0 (e / enzyme :name (n / name :op1 "ADAM"~e.1 :op2 "12-S"~e.2,4) :ARG1-of (p3 / purify-01~e.6 :ARG2~e.7 (m / medium~e.9 :ARG1-of (c / condition-02~e.8) :location~e.10 (c2 / column~e.15 :consist-of (a2 / and :op1 (s / small-molecule :name (n4 / name :op1 "heparin"~e.12)) :op2 (s2 / small-molecule :name (n5 / name :op1 "Sepharose"~e.14))))) :degree~e.5 (p2 / part~e.5)) :ARG3-of (r / recombine-01~e.0)) :ARG1 (p5 / protein :name (n3 / name :op1 "IGFBP-3"~e.18,20)) :mod (a / also~e.16)) # ::id bio.chicago_2015.73467 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High and nonperiodic APC @-@ Cdh1 activity apparently supported progressive accumulation of Skp2 F @-@ box protein , a crucial SCF component , and thus created conditions permissive for a rapid turnover of p27 CDK inhibitor that would otherwise restrain S @-@ phase @-@ promoting CDK activities . # ::alignments 0-1.1.2 2-1.1.3 2-1.1.3.1 2-1.1.3.1.r 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1 7-1.3 8-1 10-1.2 11-1.2.1.r 12-1.2.1.1.1 13-1.2.1.1.2 15-1.2.1.1.2 16-1.1.1 16-1.2.1 16-1.2.1.2.1 16-1.4.1.2.1.1.1 19-1.2.1.2.2 20-1.2.1.2.1.1.1 21-1.2.1.2 24-1.4 25-1.4.1 26-1.4.1.2 30-1.4.1.2.1.1.2 33-1.4.1.2.1.1.1.1.1 34-1.4.1.2.1.1.1.3.1.1.1 35-1.4.1.2.1.1.1.3 38-1.4.1.2.1.1.1.2.2 39-1.4.1.2.1.1.1.2 40-1.4.1.2.1.1.1.2.1.2.1.1.1 42-1.4.1.2.1.1.1.2.1.2.1.1.1 44-1.4.1.2.1.1.1.2.1.2 45-1.4.1.2.1.1.1.2.1.1 46-1.4.1.2.1.1.1.2.1 (s / support-01~e.8 :ARG0 (a2 / activity-06~e.6 :ARG0 (p / protein~e.16 :name (n / name :op1 "APC-Cdh1"~e.3,5)) :ARG1-of (h / high-02~e.0) :frequency (p2 / periodic~e.2 :polarity~e.2 -~e.2)) :ARG1 (a4 / accumulate-01~e.10 :ARG1~e.11 (p4 / protein~e.16 :name (n2 / name :op1 "Skp2"~e.12 :op2 "F-box"~e.13,15) :mod (c / component~e.21 :mod (p8 / protein~e.16 :name (n3 / name :op1 "SCF"~e.20)) :mod (c2 / crucial~e.19))) :ARG1-of (p3 / progress-01)) :ARG1-of (a3 / appear-02~e.7) :ARG0-of (c3 / cause-01~e.24 :ARG1 (c4 / create-01~e.25 :ARG0 a2 :ARG1 (c5 / condition-01~e.26 :ARG0-of (p5 / permit-01 :ARG1 (t2 / turn-over-12 :ARG1 (p6 / protein~e.16 :name (n5 / name :op1 "p27"~e.33) :ARG0-of (r2 / restrain-01~e.39 :ARG1 (a / activity-06~e.46 :ARG0 e~e.45 :ARG1 (p7 / promote-01~e.44 :ARG1 (e2 / event :name (n6 / name :op1 "S-phase"~e.40,42)))) :mod (o / otherwise~e.38)) :ARG0-of (i2 / inhibit-01~e.35 :ARG1 (e / enzyme :name (n4 / name :op1 "CDK"~e.34)))) :mod (r / rapid~e.30))))))) # ::id bio.chicago_2015.73500 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activated insulin @-@ like growth factor I receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK , Cas , and paxillin . # ::alignments 1-1.1.2 2-1.1.3.1.1.1 4-1.1 4-1.1.3 4-1.1.3.r 5-1.1.1.1 6-1.1.1.2 7-1.1.1.3 8-1.1.1.4 9-1 12-1.2.1.2 13-1.2.1.1 14-1.2.1 15-1.2.2 16-1.2.2.1.r 17-1.2.2.1.1.1.1.1.1 18-1.2.2.1.1.1 19-1.2.2.1.1 20-1.2.2.1 21-1.2.2.1.2.2.1.1 22-1.2.2.1.2 23-1.2.2.1.2.1.r 24-1.2.2.1.2.1.1.1.1 26-1.2.2.1.2.1.2.1.1 29-1.2.2.1.2.1.3.1.1 (i / induce-01~e.9 :ARG0 (p5 / protein~e.4 :name (n / name :op1 "growth"~e.5 :op2 "factor"~e.6 :op3 "I"~e.7 :op4 "receptor"~e.8) :ARG1-of (a / activate-01~e.1) :ARG1-of~e.4 (r / resemble-01~e.4 :ARG2 (p6 / protein :name (n7 / name :op1 "insulin"~e.2)))) :ARG2 (d / depolarize-00 :ARG1 (c / cell~e.14 :mod (e / epithelium~e.13) :mod (b / breast~e.12)) :ARG1-of (c2 / characterize-01~e.15 :ARG2~e.16 (a2 / and~e.20 :op1 (d2 / disassemble-01~e.19 :ARG0 (f / filament~e.18 :mod (p / protein :name (n2 / name :op1 "actin"~e.17)))) :op2 (d3 / dephosphorylate-01~e.22 :ARG1~e.23 (a4 / and :op1 (e2 / enzyme :name (n4 / name :op1 "FAK"~e.24)) :op2 (p3 / protein :name (n5 / name :op1 "Cas"~e.26)) :op3 (p4 / protein :name (n6 / name :op1 "paxillin"~e.29))) :ARG2 (a3 / amino-acid :name (n3 / name :op1 "tyrosine"~e.21))))))) # ::id bio.chicago_2015.73683 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Myristoylated ARF1 and ARF6 ( referred in the text as ARF1 and ARF6 ) , myristoylated ARF1 mutant N52R @-@ ARF1 ( referred in the text as N52R @-@ ARF1 ) , and PITPalpha were expressed in Escherichia coli and purified exactly as described ( 7 , 37 ) . # ::alignments 1-1.1.1.1.1.1.1 2-1.1.1.1 2-1.1.1.1.4.1 3-1.1.1.1.2.1.1 5-1.1.1.1.4 8-1.1.1.1.4.2 10-1.1.1.1.1.1.1 11-1.1.1.1 12-1.1.1.1.2.1.1 16-1.1.1.2.2.1 17-1.1.1.2 17-1.1.1.2.2 17-1.1.1.2.2.r 18-1.1.1.2.1.1 20-1.1.1.1.1.1.1 22-1.1.1.1.4 22-1.1.1.2.4 25-1.1.1.1.4.2 27-1.1.1.2.1.1 29-1.1.1.1.1.1.1 32-1.1.1 32-1.1.1.1 32-1.1.1.1.r 33-1.1.1.3.1.1 35-1.1 36-1.1.2.r 37-1.1.2.1.1 38-1.1.2.1.2 39-1 40-1.2 41-1.2.2 41-1.2.2.r 42-1.2.3.r 43-1.2.3 45-1.2.3.1.1.1.1 47-1.2.3.1.1.1.2 (a / and~e.39 :op1 (e / express-03~e.35 :ARG2 (a2 / and~e.32 :op1~e.32 (a3 / and~e.2,11,32 :op1 (p2 / protein :name (n / name :op1 "ARF1"~e.1,10,20,29)) :op2 (p3 / protein :name (n2 / name :op1 "ARF6"~e.3,12)) :ARG1-of (m / myristoylate-00) :ARG1-of (r / refer-01~e.5,22 :ARG2 (a4 / and~e.2 :op1 p2 :op2 p3) :location (t / text~e.8,25))) :op2 (p4 / protein~e.17 :name (n3 / name :op1 "N52R-ARF1"~e.18,27) :ARG2-of~e.17 (m2 / mutate-01~e.17 :ARG1 p2~e.16) :ARG1-of m :ARG1-of (r2 / refer-01~e.22 :ARG2 p4 :location t)) :op3 (p5 / protein :name (n4 / name :op1 "PITPalpha"~e.33))) :ARG3~e.36 (o / organism :name (n5 / name :op1 "Escherichia"~e.37 :op2 "coli"~e.38))) :op2 (p / purify-01~e.40 :ARG1 p5 :manner~e.41 (e2 / exact~e.41) :ARG1-of~e.42 (d / describe-01~e.43 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a5 / and :op1 7~e.45 :op2 37~e.47)))))) # ::id bio.chicago_2015.73782 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Confirmation that Narf specifically recognizes preAct , and not just a prenylated cysteine residue , came from in vitro binding assays . # ::alignments 0-1.1 2-1.1.1.1.1.1.1 3-1.1.1.1.3 4-1.1.1.1 4-1.1.1.2 5-1.1.1.1.2.1.1 8-1.1.1.2.1 8-1.1.1.2.1.r 9-1.1.1.2.4 12-1.1.1.2.3.1.1.1 13-1.1.1.2.3 15-1 16-1.2.r 17-1.2.2 18-1.2.2 19-1.2.1 20-1.2 (c / come-03~e.15 :ARG1 (c2 / confirm-01~e.0 :ARG1 (c3 / contrast-01 :ARG1 (r / recognize-02~e.4 :ARG0 (p / protein :name (n2 / name :op1 "Narf"~e.2)) :ARG1 (s2 / small-molecule :name (n / name :op1 "preAct"~e.5)) :ARG1-of (s / specific-02~e.3)) :ARG2 (r3 / recognize-02~e.4 :polarity~e.8 -~e.8 :ARG0 p :ARG1 (r2 / residue~e.13 :mod (a2 / amino-acid :name (n3 / name :op1 "cysteine"~e.12) :ARG1-of (p2 / prenylate-00))) :mod (j / just~e.9)))) :ARG2~e.16 (a3 / assay-01~e.20 :ARG1 (b / bind-01~e.19) :manner (i / in-vitro~e.17,18))) # ::id bio.chicago_2015.73823 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Esterified lipids of LDL are hydrolysed by lipases like phospholipase A2 or lipoprotein lipase . # ::alignments 0-1.2.1 1-1.2 2-1.2.2.r 3-1.2.2.1.1 8-1.1.2.r 9-1.1.2.1.1.1 10-1.1.2.1.1.2 11-1.1.2 12-1.1.2.2.1.1 13-1.1.1.1 13-1.1.2.2.1.2 (h / hydrolyze-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "lipase"~e.13) :example~e.8 (o / or~e.11 :op1 (e3 / enzyme :name (n3 / name :op1 "phospholipase"~e.9 :op2 "A2"~e.10)) :op2 (e4 / enzyme :name (n4 / name :op1 "lipoprotein"~e.12 :op2 "lipase"~e.13)))) :ARG1 (l / lipid~e.1 :ARG1-of (e / esterify-00~e.0) :mod~e.2 (p / protein :name (n / name :op1 "LDL"~e.3)))) # ::id bio.chicago_2015.73906 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Enlargement of plant cells is constrained by a resistant cell wall composed of cellulose microfibrils , crosslinked by other polysaccharides such as xyloglucans ( 16 ) . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1 3-1.2.1 5-1 6-1.1.r 8-1.1.2 9-1.1.1 10-1.1 11-1.1.3 13-1.1.3.1.1 18-1.1.3.1.2.1.1 19-1.1.3.1.2.1 20-1.1.3.1.2.1.2.r 21-1.1.3.1.2.1.2.r 24-1.3.1.1.1 (c / constrain-01~e.5 :ARG0~e.6 (w / wall~e.10 :mod (c2 / cell~e.9) :ARG0-of (r / resist-01~e.8) :ARG1-of (c4 / compose-01~e.11 :ARG2 (m / microfibril :mod (c5 / cellulose~e.13) :ARG1-of (c6 / crosslink-00 :ARG0 (p3 / polysaccharide~e.19 :mod (o / other~e.18) :example~e.20,21 (s / small-molecule :name (n2 / name :op1 "xyloglucan"))))))) :ARG1 (e / enlarge-01~e.0 :ARG1~e.1 (c3 / cell~e.3 :mod (p / plant~e.2))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c7 / cite-01 :ARG2 16~e.24)))) # ::id bio.chicago_2015.73940 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only sagittal and oblique sections following BDA injections in the rostral prelimbic area are presented here because coronal sections severed most of the rostral prelimbic PFC to NAc projecting fibers . # ::alignments 0-1.1.3 1-1.1.1.1 2-1.1 3-1.1.2.1 4-1.1.1 4-1.1.2 5-1.1.4 6-1.1.4.1.1.1.1 7-1.1.4.1 8-1.1.4.1.2.r 10-1.1.4.1.2.1.1 12-1.1.4.1.2 14-1 15-1.2 16-1.3 17-1.3.1.1.1 18-1.3.1.1 19-1.3.1 20-1.3.1.2.3 21-1.3.1.2.3.r 23-1.3.1.2.2.2 25-1.3.1.2.2.1.1 27-1.3.1.2.1.1.1.1 28-1.3.1.2.1 29-1.3.1.2 (p / present-01~e.14 :ARG1 (a / and~e.2 :op1 (s / section-01~e.4 :mod (s2 / sagittal~e.1)) :op2 (s3 / section-01~e.4 :mod (o / oblique~e.3)) :mod (o2 / only~e.0) :ARG1-of (f2 / follow-01~e.5 :ARG2 (i / inject-01~e.7 :ARG1 (s4 / small-molecule :name (n / name :op1 "BDA"~e.6)) :ARG2~e.8 (a3 / area~e.12 :mod (p2 / prelimb :mod (r / rostral~e.10)))))) :medium (h / here~e.15) :ARG1-of (c / cause-01~e.16 :ARG0 (s5 / sever-01~e.19 :ARG0 (s6 / section-01~e.18 :mod (c2 / coronal~e.17)) :ARG1 (f / fiber~e.29 :ARG1-of (p3 / project-01~e.28 :mod (t2 / thing :name (n3 / name :op1 "NAc"~e.27))) :mod (t / thing :name (n2 / name :op1 "PFC"~e.25) :mod p2~e.23) :quant~e.21 (m / most~e.20))))) # ::id bio.chicago_2015.73959 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) Both N @-@ terminal bacterially expressed hCdc20 and hCdh1 bind the N @-@ terminal fragment of Xenopus cyclin B containing the D box , but fail to recover the D @-@ box deleted N @-@ terminal cyclin B. ( D ) In vitro @-@ translated cyc A binds MTCdc20 and MTCdh1 , but not to MT alone . # ::alignments 1-1.1.1 4-1.1.2.1.4.1.1 6-1.1.2.1.4.1.1 7-1.1.2.1.3.1 7-1.1.2.1.3.1.r 8-1.1.2.1.3 9-1.1.2.1.1.1.1 10-1.1.2.1 11-1.1.2.1.2.1.1 12-1.1.2 14-1.1.2.2.3 15-1.1.2.2.3 16-1.1.2.2.3 17-1.1.2.2 18-1.1.2.2.1.r 19-1.1.2.2.1.2.1.1 20-1.1.2.2.1.1.1 21-1.1.2.2.1.1.2 22-1.1.2.2.2 24-1.1.2.2.2.1.1.1 25-1.1.2.2.2.1.1.2 27-1.1 28-1.1.3 30-1.1.3.2 32-1.1.3.2.2.2.1 33-1.1.3.2.2.2.1 34-1.1.3.2.2.2.1 35-1.1.3.2.2.2 36-1.1.3.2.2.3 37-1.1.3.2.2.3 38-1.1.3.2.2.3 39-1.1.3.2.2.1.1 42-1.2.1 44-1.2.2.1.2.1 45-1.2.2.1.2.1 47-1.2.2.1.2 48-1.2.2.1.1.1 49-1.2.2.1.1.2 50-1.2.2 50-1.2.3 51-1.2.2.2.1.1.1 52-1.2.2.2 53-1.2.2.2.2.1.1 55-1.2 56-1.2.3.1 56-1.2.3.1.r 57-1.2.3.3.r 58-1.2.3.3.1.1 59-1.2.3.4 (m / multi-sentence :snt1 (c / contrast-01~e.27 :li "C"~e.1 :ARG1 (b / bind-01~e.12 :ARG1 (a / and~e.10 :op1 (p / protein :name (n / name :op1 "hCdc20"~e.9)) :op2 (p2 / protein :name (n2 / name :op1 "hCdh1"~e.11)) :ARG1-of (e / express-03~e.8 :manner~e.7 (b2 / bacterial~e.7)) :mod (p9 / protein-segment :name (n10 / name :op1 "N-terminal"~e.4,6))) :ARG2 (f / fragment~e.17 :part-of~e.18 (p3 / protein :name (n3 / name :op1 "cyclin"~e.20 :op2 "B"~e.21) :mod (o / organism :name (n11 / name :op1 "Xenopus"~e.19))) :ARG0-of (c2 / contain-01~e.22 :ARG1 (t / thing :name (n4 / name :op1 "D"~e.24 :op2 "box"~e.25))) :mod p9~e.14,15,16)) :ARG2 (f2 / fail-01~e.28 :ARG0 a :ARG1 (r / recover-02~e.30 :ARG0 a :ARG1 (p4 / protein :name (n5 / name :op1 "cyclin"~e.39 :op2 "B") :ARG1-of (d / delete-01~e.35 :ARG0 t~e.32,33,34) :mod p9~e.36,37,38)))) :snt2 (c3 / contrast-01~e.55 :li "D"~e.42 :ARG1 (b3 / bind-01~e.50 :ARG1 (p5 / protein :name (n6 / name :op1 "cyc"~e.48 :op2 "A"~e.49) :ARG2-of (t2 / translate-02~e.47 :manner (i / in-vitro~e.44,45))) :ARG2 (a2 / and~e.52 :op1 (p6 / protein :name (n7 / name :op1 "MTCdc20"~e.51)) :op2 (p7 / protein :name (n8 / name :op1 "MTCdh1"~e.53)))) :ARG2 (b4 / bind-01~e.50 :polarity~e.56 -~e.56 :ARG1 p5 :ARG2~e.57 (p8 / protein :name (n9 / name :op1 "MT"~e.58)) :mod (a3 / alone~e.59)))) # ::id bio.chicago_2015.73961 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the case of histone H3 , both RPD3 and HDA1 deacetylate the five lysines ( K9 , K14 , K18 , K23 and K27 ; Figure 1D ) that are acetylated by GCN5 ( Figure 1D ) . # ::alignments 4-1.3.1.1 5-1.3.1.2 8-1.1.1.1.1 9-1.1 10-1.1.2.1.1 11-1 13-1.2.1 14-1.2.2.1 14-1.2.3.1.1.2.1 14-1.2.3.1.2.2.1 14-1.2.3.1.3.2.1 14-1.2.3.1.4.2.1 14-1.2.3.1.5.2.1 23-1.2.3.1 26-1.2.4.1 27-1.2.4.1.1 31-1.2.5 32-1.2.5.1.r 33-1.2.5.1.1.1 35-1.2.4.1 36-1.2.4.1.1 (d / deacetylate-01~e.11 :ARG0 (a / and~e.9 :op1 (p / protein :name (n / name :op1 "RPD3"~e.8)) :op2 (p2 / protein :name (n2 / name :op1 "HDA1"~e.10))) :ARG1 (a2 / amino-acid :quant 5~e.13 :name (n3 / name :op1 "lysine"~e.14) :ARG2-of (m / mean-01 :ARG1 (a3 / and~e.23 :op1 (a4 / amino-acid :mod 9 :name (n4 / name :op1 "lysine"~e.14)) :op2 (a5 / amino-acid :mod 14 :name (n5 / name :op1 "lysine"~e.14)) :op3 (a6 / amino-acid :mod 18 :name (n6 / name :op1 "lysine"~e.14)) :op4 (a7 / amino-acid :mod 23 :name (n7 / name :op1 "lysine"~e.14)) :op5 (a8 / amino-acid :mod 27 :name (n8 / name :op1 "lysine"~e.14)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26,35 :mod "1D"~e.27,36)) :ARG1-of (a9 / acetylate-01~e.31 :ARG2~e.32 (p3 / protein :name (n9 / name :op1 "GCN5"~e.33)) :ARG1-of (d3 / describe-01 :ARG0 f))) :topic (p4 / protein :name (n10 / name :op1 "histone"~e.4 :op2 "H3"~e.5))) # ::id bio.chicago_2015.73964 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Loss of DNA methylation may also result from active mechanisms involving either an enzymatic activity , which removes methylcytosine and replaces it by cytosine , or a deamination of methylated CpGs , creating a mismatch that is then repaired ( Jost and Saluz 1993 ; Weiss et al. 1996 ) . # ::alignments 0-1.1.2 2-1.1.2.1.1.2.1 3-1.1.1.2.1.2.1 3-1.1.1.2.1.2.1.2 3-1.1.1.2.1.2.1.2.r 3-1.1.2.1 4-1 5-1.3 6-1.1 7-1.1.1.r 8-1.1.1.1 9-1.1.1 10-1.1.1.2 13-1.1.1.2.1.1.1 14-1.1.1.2.1.1 17-1.1.1.2.1.1.2 18-1.1.1.2.1.1.2.1.1.1 20-1.1.1.2.1.1.3 21-1.1.1.2.1.1.3.1 22-1.1.1.2.1.1.3.2.r 23-1.1.1.2.1.1.3.2.1.1 25-1.1.1.2.1 32-1.1.1.2.1.2.2 34-1.1.1.2.1.2.2.1 37-1.1.1.2.1.2.2.1.1.1 38-1.1.1.2.1.2.2.1.1 40-1.2.1.1.1.1.1.1 41-1.2.1.1.1 42-1.2.1.1.1.2.1.1 43-1.2.1.1.2.1 45-1.2.1.2.1.1.1.1 46-1.2.1 46-1.2.1.2.1 47-1.2.1.2.1.2.1 48-1.2.1.2.2.1 (p / possible-01~e.4 :ARG1 (r / result-01~e.6 :ARG1~e.7 (m2 / mechanism~e.9 :ARG0-of (a / activity-06~e.8) :ARG2-of (i / involve-01~e.10 :ARG1 (o / or~e.25 :op1 (a2 / activity-06~e.14 :ARG1 (e / enzymatic~e.13) :ARG0-of (r2 / remove-01~e.17 :ARG1 (s / small-molecule :name (n3 / name :op1 "methylcytosine"~e.18))) :ARG0-of (r3 / replace-01~e.20 :ARG1 s~e.21 :ARG2~e.22 (s2 / small-molecule :name (n4 / name :op1 "cytosine"~e.23)))) :op2 (d5 / deaminate-01 :ARG1 (d6 / dna-sequence~e.3 :name (n5 / name :op1 "CpG") :ARG1-of~e.3 (m3 / methylate-01~e.3)) :ARG0-of (c / create-01~e.32 :ARG1 (m4 / mismatch~e.34 :ARG1-of (r4 / repair-01~e.38 :time (t / then~e.37)))))))) :ARG2 (l / lose-02~e.0 :ARG1 (m / methylate-01~e.3 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"~e.2))))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and~e.46 :op1 (p2 / publication-91 :ARG0 (a5 / and~e.41 :op1 (p4 / person :name (n6 / name :op1 "Jost"~e.40)) :op2 (p5 / person :name (n8 / name :op1 "Saluz"~e.42))) :time (d2 / date-entity :year 1993~e.43)) :op2 (p3 / publication-91 :ARG0 (a6 / and~e.46 :op1 (p6 / person :name (n7 / name :op1 "Weiss"~e.45)) :op2 (p7 / person :mod (o2 / other~e.47))) :time (d3 / date-entity :year 1996~e.48)))) :mod (a7 / also~e.5)) # ::id bio.chicago_2015.74011 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This demonstrates the testis @-@ specific demethylation of the Pgk @-@ 2/CAT transgenes , the ubiquitous hypomethylation of the transferrin/ CAT transgene , and the ubiquitous hypermethylation of the CAT @-@ only transgene . # ::alignments 0-1.1 1-1 3-1.2.1.2.1 5-1.2.1.2 6-1.2.1 9-1.2.1.1.1.1 15-1.2.2.2 20-1.2.2.1.1.1 21-1.2.2.1 25-1.2.2.2 29-1.2.1.1.1.1 29-1.2.2.1.1.1 29-1.2.3.1.1.1 31-1.2.3.1.1.1 32-1.2.1.1 32-1.2.2.1 32-1.2.3.1 (d / demonstrate-01~e.1 :ARG0 (t / this~e.0) :ARG1 (a / and :op1 (d2 / demethylate-01~e.6 :ARG1 (t3 / transgene~e.32 :name (n / name :op1 "Pgk-2/CAT"~e.9,29)) :ARG1-of (s / specific-02~e.5 :ARG2 (t2 / testis~e.3))) :op2 (h / hypomethylate-00 :ARG1 (t4 / transgene~e.21,32 :name (n2 / name :op1 "transferrin/CAT"~e.20,29)) :mod (u / ubiquitous~e.15,25)) :op3 (h2 / hypermethylate-01 :ARG2 (t5 / transgene~e.32 :name (n3 / name :op1 "CAT-only"~e.29,31)) :mod u))) # ::id bio.chicago_2015.74036 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When a lesion is detected , the UvrB protein hydrolyses its bound ATP molecule , leading to formation of the pro @-@ pre @-@ incision complex ( Moolenaar et al. , 2000b ) . # ::alignments 0-1.4.r 0-1.5.1.2.r 2-1.4.1 4-1.4 7-1.2.1.1 8-1.2 10-1.1.3 10-1.1.3.r 11-1.1.2 12-1.1.1.1 13-1.1 15-1.3 16-1.3.1.r 17-1.3.1 18-1.3.1.1.r 20-1.3.1.1.1 25-1.3.1.1 27-1.5.1.1.1.1.1 28-1.5.1.1 29-1.5.1.1.2.1 (h / hydrolyze-01 :ARG1 (s2 / small-molecule~e.13 :name (n2 / name :op1 "ATP"~e.12) :ARG1-of (b / bind-01~e.11) :poss~e.10 p~e.10) :ARG2 (p / protein~e.8 :name (n / name :op1 "UvrB"~e.7)) :ARG0-of (l / lead-03~e.15 :ARG1~e.16 (f / form-01~e.17 :ARG1~e.18 (c / complex~e.25 :ARG0-of (f2 / favor-01~e.20 :ARG1 (p2 / preincise-00))))) :time~e.0 (d2 / detect-01~e.4 :ARG1 (l2 / lesion~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and~e.28 :op1 (p4 / person :name (n3 / name :op1 "Moolenaar"~e.27)) :op2 (p5 / person :mod (o / other~e.29))) :time~e.0 (d / date-entity :year 2000 :li "b")))) # ::id bio.chicago_2015.74144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As phosphatidylinositol ( PI ) 3 @-@ kinase and Akt play a critical role in survival pathways in response to both growth factors and extracellular stimuli , these observations prompted us to explore whether E @-@ cadherins could affect intracellular molecules regulating the activity of the PI 3 @-@ kinase @/@ Akt signaling cascade . # ::alignments 1-1.1.1.1.1.1 3-1.2.2.2.2.2.1.1.1.1.1 5-1.1.1.1.1.2 5-1.2.2.2.2.2.1.1.1.1.2 7-1.1.1.1.1.2 7-1.2.2.2.2.2.1.1.1.1.2 8-1.1.1 9-1.1.1.2.1.1 10-1.1 12-1.1.2.1 13-1.1.2 14-1.1.2.2.r 15-1.1.2.2.1 16-1.1.2.2 17-1.1.3.r 18-1.1.3 21-1.1.3.1.1 22-1.1.3.1.1 23-1.1.3.1 24-1.1.3.1.2.1 25-1.1.3.1.2 27-1.2.1.1 28-1.2.1 29-1.2 30-1.2.2.1 32-1.2.2 33-1.2.2.2.1 33-1.2.2.2.1.r 34-1.2.2.2.2.1.1.1 37-1.2.2.2 38-1.2.2.2.2 39-1.2.2.2.2.2.2 40-1.2.2.2.2.2 41-1.2.2.2.2.2.1 43-1.2.2.2.2.2.1.1 46-1.2.2.2.2.2.1.1.1.1.1 47-1.2.2.2.2.2.1.1.1.1.2 49-1.2.2.2.2.2.1.1.1.1.2 51-1.2.2.2.2.2.1.1.1.1.2 52-1.2.2.2.2.2.1.1.1.2 (c / cause-01 :ARG0 (p2 / play-02~e.10 :ARG0 (a5 / and~e.8 :op1 (e3 / enzyme :name (n2 / name :op1 "phosphatidylinositol"~e.1 :op2 "3-kinase"~e.5,7)) :op2 (e4 / enzyme :name (n3 / name :op1 "Akt"~e.9))) :ARG1 (r / role~e.13 :ARG1-of (c3 / critical-02~e.12) :topic~e.14 (p3 / pathway~e.16 :mod (s / survive-01~e.15))) :ARG2-of~e.17 (r2 / respond-01~e.18 :ARG1 (a / and~e.23 :op1 (g / growth-factor~e.21,22) :op2 (s3 / stimulus~e.25 :mod (e / extracellular~e.24))))) :ARG1 (p4 / prompt-01~e.29 :ARG0 (o / observe-01~e.28 :mod (t / this~e.27)) :ARG1 (e2 / explore-01~e.32 :ARG0 (w / we~e.30) :ARG1 (p5 / possible-01~e.37 :mode~e.33 interrogative~e.33 :ARG1 (a2 / affect-01~e.38 :ARG0 (p / protein :name (n4 / name :op1 "E-cadherin"~e.34)) :ARG1 (m / molecule~e.40 :ARG0-of (r3 / regulate-01~e.41 :ARG1 (a3 / activity-06~e.43 :ARG1 (p6 / pathway :name (n5 / name :op1 "PI"~e.3,46 :op2 "3-kinase/Akt"~e.5,7,47,49,51) :ARG0-of (s4 / signal-07~e.52)))) :mod (i / intracellular~e.39))))))) # ::id bio.chicago_2015.74146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , HDL inhibited thromboxane A2 liberation , and addition of HDL to clotting blood diminished platelet thromboxane A2 formation capacity . # ::alignments 0-1 0-1.1 0-1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1.1 5-1.1.1.2.1.1.2 6-1.1.1.2 8-1.1 9-1.1.2.1 10-1.1.2.1.1.r 11-1.1.2.1.1 12-1.1.2.1.2.r 13-1.1.2.1.2.1 14-1.1.2.1.2 15-1.1.2 16-1.1.2.2.1.1.2 17-1.1.2.2.1.1.1.1 18-1.1.2.2.1.1.1.2 19-1.1.2.2.1 20-1.1.2.2 (a / and~e.0 :op2~e.0 (a2 / and~e.0,8 :op1 (i / inhibit-01~e.3 :ARG0 (p2 / protein :name (n / name :op1 "HDL"~e.2)) :ARG1 (l / liberate-01~e.6 :ARG1 (s / small-molecule :name (n2 / name :op1 "thromboxane"~e.4 :op2 "A2"~e.5)))) :op2 (d / diminish-01~e.15 :ARG0 (a3 / add-02~e.9 :ARG1~e.10 p2~e.11 :ARG2~e.12 (b / blood~e.14 :ARG0-of (c / clot-00~e.13))) :ARG1 (c2 / capable-01~e.20 :ARG2 (f / form-01~e.19 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "thromboxane"~e.17 :op2 "A2"~e.18) :mod (p / platelet~e.16))))))) # ::id bio.chicago_2015.74199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data indicate that NHERF @-@ 1 specifically associates with Pin1 , but only when NHERF @-@ 1 is hyperphosphorylated by cyclin @-@ dependent kinases in mitosis phase . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1 6-1.2.1.1.1 7-1.2.3 8-1.2 9-1.2.2.r 10-1.2.2.1.1 13-1.2.4.4 14-1.2.4.3.r 15-1.2.1.1.1 17-1.2.1.1.1 19-1.2.4 20-1.2.4.2.r 21-1.2.4.2.1.1.1.1 23-1.2.4.2.1 24-1.2.4.2 26-1.2.4.3.1 27-1.2.4.3 (i / indicate-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (a / associate-01~e.8 :ARG1 (p / protein :name (n2 / name :op1 "NHERF-1"~e.4,6,15,17)) :ARG2~e.9 (e2 / enzyme :name (n3 / name :op1 "Pin1"~e.10)) :ARG1-of (s / specific-02~e.7) :condition (h / hyperphosphorylate-01~e.19 :ARG1 p :ARG2~e.20 (k / kinase~e.24 :ARG0-of (d2 / depend-01~e.23 :ARG1 (p2 / protein :name (n4 / name :op1 "cyclin"~e.21)))) :time~e.14 (p3 / phase~e.27 :mod (m / mitosis~e.26)) :mod (o / only~e.13)))) # ::id bio.chicago_2015.74221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Elafin also reduces the liberation of matrix @-@ bound growth factors which may be responsible for the proliferation of vascular smooth muscle cells . # ::alignments 0-1.1.1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1 8-1.2.1.1 9-1.2.1 10-1.2.1 12-1.4.2 14-1.4 15-1.4.1.r 17-1.4.1 18-1.4.1.1.r 19-1.4.1.1.2 20-1.4.1.1.1.1 21-1.4.1.1.1 22-1.4.1.1 (r / reduce-01~e.2 :ARG0 (p / protein :name (n2 / name :op1 "elafin"~e.0)) :ARG1 (l / liberate-01~e.4 :ARG1~e.5 (g / growth-factor~e.9,10 :ARG1-of (b / bind-01~e.8 :ARG2 (m / matrix~e.6)))) :mod (a / also~e.1) :ARG0-of (r2 / responsible-01~e.14 :ARG1~e.15 (p3 / proliferate-01~e.17 :ARG0~e.18 (c / cell~e.22 :mod (m2 / muscle~e.21 :mod (s2 / smooth~e.20)) :mod (v / vascular~e.19))) :ARG1-of (p2 / possible-01~e.12))) # ::id bio.chicago_2015.74264 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Such bacteria may be responsible for the high rates of H2 @-@ dependent 14CO2 reduction to formate observed in the P1 section of C. orthognathus ( Fig . 4B ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 4-1.1 5-1.1.2.r 7-1.1.2.1 8-1.1.2 9-1.1.2.2.r 10-1.1.2.2.3.1.1.1 12-1.1.2.2.3 13-1.1.2.2.1.1.1 14-1.1.2.2 15-1.1.2.2.2.r 16-1.1.2.2.2.1.1 17-1.1.2.3 18-1.1.2.3.1.r 20-1.1.2.3.1.1 21-1.1.2.3.1 22-1.1.2.3.1.2.r 23-1.1.2.3.1.2.1.1 24-1.1.2.3.1.2.1.2 26-1.2.1 28-1.2.1.1 (p / possible-01~e.2 :ARG1 (r / responsible-01~e.4 :ARG0 (b / bacteria~e.1 :mod (s / such~e.0)) :ARG1~e.5 (r2 / rate~e.8 :ARG1-of (h / high-02~e.7) :degree-of~e.9 (r3 / reduce-01~e.14 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "14CO2"~e.13)) :ARG4~e.15 (s4 / small-molecule :name (n3 / name :op1 "formate"~e.16)) :ARG0-of (d2 / depend-01~e.12 :ARG1 (s3 / small-molecule :name (n / name :op1 "H2"~e.10)))) :ARG1-of (o / observe-01~e.17 :location~e.18 (s5 / section~e.21 :mod "P1"~e.20 :part-of~e.22 (o2 / organism :name (n5 / name :op1 "C."~e.23 :op2 "orthognathus"~e.24)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "4B"~e.28))) # ::id bio.chicago_2015.74340 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PLC @- isozymes have a multidomain array ( a PH domain split by two SH2 domains and an SH3 domain ) inserted between two halves of the catalytic domain . # ::alignments 1-1.1.1.1 4-1 6-1.2.1 7-1.2 10-1.2.2.1.1.1 11-1.2.3.1.2 12-1.2.2.1 12-1.2.2.1.2 12-1.2.2.1.2.r 13-1.2.2.1.2.1.r 14-1.2.2.1.2.1.1.1 15-1.2.2.1.2.1.1.2.1 16-1.2.3.1.2 17-1.2.2.1.2.1 19-1.2.2.1.2.1.2.1.1 20-1.2.3.1.2 22-1.2.3 24-1.2.3.1.1 25-1.2.3.1 28-1.2.3.1.2.1 29-1.2.3.1.2 (h / have-03~e.4 :ARG0 (i2 / isozyme :name (n / name :op1 "PLC"~e.1)) :ARG1 (a / array-01~e.7 :ARG1 (m2 / multidomain~e.6) :ARG1-of (m3 / mean-01 :ARG2 (p / protein-segment~e.12 :name (n2 / name :op1 "PH"~e.10) :ARG1-of~e.12 (s / split-01~e.12 :ARG2~e.13 (a2 / and~e.17 :op1 (p3 / protein-segment :quant 2~e.14 :name (n3 / name :op1 "SH2"~e.15)) :op2 (p2 / protein-segment :name (n4 / name :op1 "SH3"~e.19)))))) :ARG1-of (i / insert-01~e.22 :ARG2 (h2 / half~e.25 :quant 2~e.24 :mod (d4 / domain~e.11,16,20,29 :mod (c / catalysis~e.28)))))) # ::id bio.chicago_2015.74386 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recent accumulating evidences suggest that induction of histone hyperacetylation by HDAC inhibitors is responsible for the antiproliferative activity and reversal of neoplastic characteristics through selective induction of genes , which play important roles in the cell cycle and cell morphology ( 14 ) . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 3-1 4-1.2.r 5-1.2.1 7-1.2.1.2.1.1.1 9-1.2.1.1.r 10-1.2.1.1.1.1 11-1.2.1.1 11-1.2.1.1.2 11-1.2.1.1.2.r 13-1.2 14-1.2.2.r 16-1.2.2.1.1 16-1.2.2.1.1.1 16-1.2.2.1.1.1.r 17-1.2.2.1 18-1.2.2 19-1.2.2.2 20-1.2.2.2.1.r 21-1.2.2.2.1.1.1 22-1.2.2.2.1 22-1.2.2.2.1.1 22-1.2.2.2.1.1.r 24-1.2.2.3.2 25-1.2.2.3 26-1.2.2.3.1.r 27-1.2.2.3.1 30-1.2.2.4 31-1.2.2.4.1.1 32-1.2.2.4.1 33-1.2.2.4.1.2.r 35-1.2.2.4.1.2.1.1 36-1.2.2.4.1.2.1 38-1.2.2.4.1.2.1.1 39-1.2.2.4.1.2.2 41-1.3.1.1.1 (s / suggest-01~e.3 :ARG0 (e / evidence-01~e.2 :ARG1-of (a / accumulate-01~e.1) :time (r / recent~e.0)) :ARG1~e.4 (r2 / responsible-01~e.13 :ARG0 (i2 / induce-01~e.5 :ARG0~e.9 (e2 / enzyme~e.11 :name (n2 / name :op1 "HDAC"~e.10) :ARG0-of~e.11 (i / inhibit-01~e.11)) :ARG2 (h / hyperacetylate-00 :ARG1 (p / protein :name (n / name :op1 "histone"~e.7)))) :ARG1~e.14 (a2 / and~e.18 :op1 (a3 / activity-06~e.17 :ARG1 (c / counter-01~e.16 :ARG1~e.16 (p2 / proliferate-01~e.16))) :op1 (r3 / reverse-01~e.19 :ARG1~e.20 (t / thing~e.22 :ARG2-of~e.22 (c2 / characteristic-02~e.22 :ARG1 (n3 / neoplasm~e.21)))) :manner (i3 / induce-01~e.25 :ARG1~e.26 (g / gene~e.27) :mod (s2 / selective~e.24)) :ARG0-of (p3 / play-02~e.30 :ARG1 (r4 / role~e.32 :mod (i4 / important~e.31) :time~e.33 (a4 / and :op1 (c3 / cycle-02~e.36 :mod (c4 / cell~e.35,38)) :op2 (m / morphology~e.39 :mod c4)))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 14~e.41)))) # ::id bio.chicago_2015.74432 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with DNase I failed to liberate GAPDH from the nuclear fraction ( Fig . 6 B ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1.1.2 4-1 6-1.2 7-1.2.2.1.1 8-1.2.3.r 10-1.2.3.1 11-1.2.3 13-1.3.1 (f / fail-01~e.4 :ARG1 (t / treat-04~e.0 :ARG2~e.1 (e / enzyme :name (n / name :op1 "DNase"~e.2 :op2 "I"~e.3))) :ARG2 (l / liberate-01~e.6 :ARG0 t :ARG1 (e2 / enzyme :name (n2 / name :op1 "GAPDH"~e.7)) :ARG2~e.8 (f2 / fraction-01~e.11 :ARG1 (n3 / nucleus~e.10))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure~e.13 :mod "6B"))) # ::id bio.chicago_2015.74470 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here , we report that a short incubation of control cells with the F @-@ actin depolymerizing agent cytochalasin D triggered cytochrome c release and procaspase 3 @-@ like activation . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 6-1.2.1.3 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1 10-1.2.1.1 11-1.2.1.2.r 13-1.2.1.2.3.1.1.1 15-1.2.1.2.3.1.1.1 17-1.2.1.2.2 18-1.2.1.2.1.1 19-1.2.1.2.1.2 20-1.2 21-1.2.2.1.1.1.1 22-1.2.2.1.1.1.2 23-1.2.2.1 24-1.2.2 25-1.2.2.2.1.1.1 26-1.2.2.2.1.1.2 28-1.2.2.2.1.1.2 29-1.2.2.2 (r / report-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (t / trigger-01~e.20 :ARG0 (i / incubate-01~e.7 :ARG1~e.8 (c / cell~e.10 :mod (c2 / control~e.9)) :ARG2~e.11 (s2 / small-molecule :name (n / name :op1 "cytochalasin"~e.18 :op2 "D"~e.19) :mod (a / agent~e.17) :ARG0-of (d / depolymerize-00 :ARG1 (p / protein :name (n2 / name :op1 "F-actin"~e.13,15)))) :ARG1-of (s / short-07~e.6)) :ARG1 (a2 / and~e.24 :op1 (r2 / release-01~e.23 :ARG1 (p2 / protein :name (n3 / name :op1 "cytochrome"~e.21 :op2 "c"~e.22))) :op2 (a3 / activate-01~e.29 :ARG1 (p3 / protein :name (n4 / name :op1 "procaspase"~e.25 :op2 "3-like"~e.26,28))))) :medium (h / here~e.0)) # ::id bio.chicago_2015.74541 ::amr-annotator SDL-AMR-09 ::preferred # ::tok p @-@ Nitroanilines liberated by trypsin activity were measured with a spectrophotometer at 410 nm . Dependency of the reactions on enterokinase activation was studied by performing the same reaction in the absence of enterokinase and comparing the results . # ::alignments 0-1.1.1.1.1 3-1.1.1.2 4-1.1.1.2.1.r 5-1.1.1.2.1.1.1.1 6-1.1.1.2.1 8-1.1 9-1.1.2.r 11-1.1.2 13-1.1.3.1 14-1.1.3.2 16-1.2.1 17-1.2.1.1.r 19-1.2.1.1 20-1.2.1.2.r 21-1.2.1.2.1.1.1 22-1.2.1.2 24-1.2 25-1.2.2.r 26-1.2.2.1 28-1.2.2.1.1.1 29-1.2.2.1.1 30-1.2.2.1.2.r 32-1.2.2.1.2 33-1.2.2.1.2.1.r 34-1.2.2.1.2.1 35-1.2.2 36-1.2.2.2 38-1.2.2.2.1 38-1.2.2.2.1.1 38-1.2.2.2.1.1.r (m3 / multi-sentence :snt1 (m / measure-01~e.8 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "p-Nitroaniline"~e.0) :ARG1-of (l / liberate-01~e.3 :ARG0~e.4 (a2 / activity-06~e.6 :ARG0 (e / enzyme :name (n / name :op1 "trypsin"~e.5))))) :ARG2~e.9 (s / spectrophotometer~e.11) :condition (f / frequence :value 410~e.13 :unit (n3 / nanometer~e.14))) :snt2 (s2 / study-01~e.24 :ARG1 (d / depend-01~e.16 :ARG0~e.17 (r / react-01~e.19) :ARG1~e.20 (a3 / activate-01~e.22 :ARG1 (e2 / enzyme :name (n4 / name :op1 "enterokinase"~e.21)))) :manner~e.25 (a6 / and~e.35 :op1 (p / perform-01~e.26 :ARG1 (r2 / react-01~e.29 :ARG1-of (s3 / same-01~e.28)) :condition~e.30 (a4 / absent-01~e.32 :ARG1~e.33 e2~e.34)) :op2 (c / compare-01~e.36 :ARG1 (t / thing~e.38 :ARG2-of~e.38 (r3 / result-01~e.38)))))) # ::id bio.chicago_2015.74615 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Proteins in the pathways that regulate contractility and actin depolymerization downstream of Rho and ROK , such as myosin light @-@ chain kinase and phosphatase and cofilin , are candidate targets for aPKCs , but the precise mechanism by which Cdc42 and aPKCs regulate stress fibers is not yet clear . # ::alignments 0-1.1.3 1-1.1.3.1.r 3-1.1.3.1 5-1.1.3.2 6-1.1.3.2.1.1 7-1.1.3.2.1 8-1.1.3.2.1.2.1.1.1 10-1.1.3.2.2.2 12-1.1.3.2.2.1.1.1.1 14-1.1.3.2.2.1.2.1.1 16-1.1.3.3.r 17-1.1.3.3.r 18-1.1.3.3.1.1.1 19-1.1.3.3.1.1.2 21-1.1.3.3.1.1.2 22-1.1.3.3.1.1.3 24-1.1.3.3.2.1.1 26-1.1.3.3.3.1.1 28-1.1.3.r 29-1.1.1 30-1.1 30-1.1.2 30-1.1.2.r 34-1 36-1.2.2.1 37-1.2.2 40-1.2.2.2.1.1.1.1 41-1.2.2.2.1 43-1.2.2.2 44-1.2.2.2.2.1 45-1.2.2.2.2 47-1.2.1 47-1.2.1.r 48-1.2.3 49-1.2 (c / contrast-01~e.34 :ARG1 (t / thing~e.30 :mod (c2 / candidate~e.29) :ARG1-of~e.30 (t2 / target-01~e.30 :ARG0 (e / enzyme :name (n7 / name :op1 "aPKC"))) :domain~e.28 (p / protein~e.0 :part-of~e.1 (p2 / pathway~e.3) :ARG0-of (r / regulate-01~e.5 :ARG1 (a / and~e.7 :op1 (c3 / contractility~e.6) :op2 (d / depolymerize-00 :ARG1 (p3 / protein :name (n / name :op1 "actin"~e.8)))) :location (r3 / relative-position :op1 (a2 / and :op1 (p4 / protein :name (n2 / name :op1 "Rho"~e.12)) :op2 (p5 / protein :name (n3 / name :op1 "ROK"~e.14))) :direction (d2 / downstream~e.10))) :example~e.16,17 (a3 / and :op1 (e2 / enzyme :name (n4 / name :op1 "myosin"~e.18 :op2 "light-chain"~e.19,21 :op3 "kinase"~e.22)) :op2 (e3 / enzyme :name (n5 / name :op1 "phosphatase"~e.24)) :op3 (p8 / protein :name (n6 / name :op1 "cofilin"~e.26))))) :ARG2 (c4 / clear-06~e.49 :polarity~e.47 -~e.47 :ARG1 (m / mechanism~e.37 :mod (p9 / precise~e.36) :instrument-of (r2 / regulate-01~e.43 :ARG0 (a4 / and~e.41 :op1 (p10 / protein :name (n8 / name :op1 "Cdc42"~e.40)) :op2 e) :ARG1 (f / fiber~e.45 :mod (s / stress~e.44)))) :time (y / yet~e.48))) # ::id bio.chicago_2015.74675 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Strikingly , while Bdf1 prefers hyperacetylated forms of histone H4 , Bdf2 binds equally well to all histone H4 species ( Figure 2B ) . # ::alignments 0-1.3 2-1 3-1.2.1.1.1 4-1.2 6-1.2.2 7-1.2.2.2.r 8-1.2.2.2.1.1 9-1.2.2.2.1.2 11-1.1.1.1.1 12-1.1 13-1.1.3.1 14-1.1.3 15-1.1.2.r 16-1.1.2.2 17-1.1.2.1 18-1.1.2.1 19-1.1.2 21-1.4.1 22-1.4.1.1 (c / contrast-01~e.2 :ARG1 (b / bind-01~e.12 :ARG1 (p4 / protein :name (n3 / name :op1 "Bdf2"~e.11)) :ARG2~e.15 (s / species~e.19 :mod p3~e.17,18 :mod (a / all~e.16)) :ARG1-of (g / good-02~e.14 :degree (e / equal~e.13))) :ARG2 (p / prefer-01~e.4 :ARG0 (p2 / protein :name (n / name :op1 "Bdf1"~e.3)) :ARG1 (f / form~e.6 :ARG1-of (h / hyperacetylate-00) :mod~e.7 (p3 / protein :name (n2 / name :op1 "histone"~e.8 :op2 "H4"~e.9)))) :ARG1-of (s2 / strike-04~e.0) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.21 :mod "2B"~e.22))) # ::id bio.chicago_2015.74682 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reasoning that dC dU deamination of the retroviral reverse transcripts ( cDNA ) could give rise to inactivating mutations of the GFP gene , we speculated that some of the GFP @-@ negative target cells could nevertheless have been infected but with the GFP gene having been rendered nonfunctional by CEM15 @/@ APOBEC3G @-@ induced mutations . # ::alignments 0-1 0-1.1 0-1.1.r 1-1.1.2.r 2-1.1.2.1.1.2.1.1 3-1.1.2.1.1.2.1.2 8-1.1.2.1.1.1.1 9-1.1.2.1.1.1 13-1.1.2 14-1.1.2.1 15-1.1.2.1 16-1.1.2.1 17-1.1.2.1.2.2.1 18-1.1.2.1.2 18-1.2.2.1.1.2.2.1.2.2 21-1.1.2.1.2.1.1.1 22-1.1.2.1.2.1 22-1.2.2.1.1.2.2.1.2 24-1.1.1 25-1.2 26-1.2.2.r 27-1.2.2.1.1.2.1 28-1.2.2.1.1.2.1.r 30-1.2.2.1.1.2.2.1.2.1.1 33-1.2.2.1.1.2.2.1.1 34-1.2.2.1.1.2 34-1.2.2.1.1.2.2.1 35-1.2.2 36-1.2.2.1 37-1.2.2.1 39-1.2.2.1.1 40-1.2.2.1 41-1.2.2.1.1.1.r 43-1.2.2.1.1.1.1.1 44-1.2.2.1.1.1 47-1.2.2.1.1.1.2 48-1.2.2.1.1.1.2.2 48-1.2.2.1.1.1.2.2.1 48-1.2.2.1.1.1.2.2.1.r 49-1.2.2.1.1.1.2.1.r 50-1.2.2.1.1.1.2.1.1.1.1.1 52-1.2.2.1.1.1.2.1.1.1.1.1 54-1.2.2.1.1.1.2.1.1 55-1.2.2.1.1.1.2.1 (c / cause-01~e.0 :ARG0~e.0 (r / reason-01~e.0 :ARG0 (w / we~e.24) :ARG1~e.1 (p2 / possible-01~e.13 :ARG1 (g / give-rise-to-10~e.14,15,16 :ARG0 (d / deaminate-01 :ARG1 (t / transcript~e.9 :mod (r2 / reverse-01~e.8) :mod (r3 / retrovirus)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "dC"~e.2 :op2 "dU"~e.3))) :ARG2 (m / mutate-01~e.18 :ARG1 (g2 / gene~e.22 :name (n / name :op1 "GFP"~e.21)) :ARG0-of (a / activate-01 :polarity -~e.17))))) :ARG1 (s / speculate-01~e.25 :ARG0 w :ARG1~e.26 (p / possible-01~e.35 :ARG1 (h / have-concession-91~e.36,37,40 :ARG1 (i / infect-01~e.39 :ARG0~e.41 (g4 / gene~e.44 :name (n5 / name :op1 "GFP"~e.43) :ARG1-of (r4 / render-01~e.47 :ARG0~e.49 (m3 / mutate-01~e.55 :ARG2-of (i2 / induce-01~e.54 :ARG0 (e / enzyme :name (n6 / name :op1 "CEM15/APOBEC3G"~e.50,52)))) :ARG2 (f / function-01~e.48 :polarity~e.48 -~e.48 :ARG0 g4))) :ARG1 (c3 / cell~e.34 :quant~e.28 (s2 / some~e.27) :ARG1-of (i3 / include-91 :ARG2 (c2 / cell~e.34 :ARG1-of (t2 / target-01~e.33) :mod (g3 / gene~e.22 :name (n3 / name :op1 "GFP"~e.30) :ARG2-of (m4 / mutate-01~e.18 :mod "-/-")))))))))) # ::id bio.chicago_2015.74687 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Compared with PMNs receiving inputs that lacked oscillations ( Fig. 2 F ) , discharge patterns of PMNs receiving inputs with consistent oscillations showed much less variability for consecutive spontaneous bursts ( Fig. 2 E ) . # ::alignments 0-1.1.3.r 3-1.1.3.2 4-1.1.3.2.1 6-1.1.3.2.1.1 7-1.1.3.2.1.1.1 9-1.1.3.3.1 14-1.1.1 15-1.1 18-1.1.2.2 19-1.1.2.2.1 20-1.1.2.2.1.1.r 21-1.1.2.2.1.1.1 22-1.1.2.2.1.1 23-1 24-1.2.1.1 25-1.2.1 26-1.2 27-1.2.2.r 28-1.2.2.2 29-1.2.2.1 30-1.2.2 32-1.2.3.1 (s / show-01~e.23 :ARG0 (p / pattern~e.15 :mod (d / discharge-01~e.14) :mod (c / cell :name (n / name :op1 "PMN") :ARG0-of (r / receive-01~e.18 :ARG1 (i / input~e.19 :ARG1-of~e.20 (o / oscillate-01~e.22 :ARG1-of (c2 / consistent-02~e.21))))) :compared-to~e.0 (c4 / cell :name (n2 / name :op1 "PMN") :ARG0-of (r2 / receive-01~e.3 :ARG1 (i2 / input~e.4 :ARG0-of (l2 / lack-01~e.6 :ARG1 (o2 / oscillate-01~e.7)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.9 :mod "2F")))) :ARG1 (v / variability~e.26 :degree (l / less~e.25 :quant (m / much~e.24)) :mod~e.27 (b / burst-01~e.30 :mod (s2 / spontaneous~e.29) :mod (c3 / consecutive~e.28)) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.32 :mod "2E")))) # ::id bio.chicago_2015.74732 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to GST @-@ CIIS , the S. pombe FTase also efficiently farnesylated another C AAX protein , S. cerevisiae Rho3 , while prenylating two different C AAL proteins , Cdc42 and RhoA , with very low efficiency ( Fig . 3 C ) . # ::alignments 0-1 0-1.1.1 1-1 1-1.1.1 3-1.1.1.1.1.1 5-1.1.1.1.1.1 8-1.1.2.2.1.1 9-1.1.2.2.1.2 10-1.1.2.1.1 11-1.1.3 12-1.1.4 14-1.1.1.2.1 15-1.1.1.2.2.1.1.1 16-1.1.1.2.2.1.1.2 17-1.1.1.2 19-1.1.1.2.3.1.2.1.1 20-1.1.1.2.3.1.2.1.2 21-1.1.1.2.3.1.1.1 25-1.2.1.1 26-1.2.1.2 27-1.2.1.3.1.1.1 28-1.2.1.3.1.1.2 29-1.2.1 31-1.2.1.4.1.1.1.1 32-1.2.1.4.1 33-1.2.1.4.1.2.1.1 36-1.2.3.1.1 37-1.2.3.1 38-1.1.4 38-1.2.3 40-1.3.1 (a4 / and~e.0,1 :op1 (f / farnesylate-01 :ARG1 (a2 / and~e.0,1 :op1 (p / protein :name (n2 / name :op1 "GST-CIIS"~e.3,5)) :op2 (p5 / protein~e.17 :mod (a3 / another~e.14) :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n3 / name :op1 "C"~e.15 :op2 "AAX"~e.16))) :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n4 / name :op1 "Rho3"~e.21) :mod (o2 / organism :name (n9 / name :op1 "S."~e.19 :op2 "cerevisiae"~e.20)))))) :ARG2 (e / enzyme :name (n / name :op1 "FTase"~e.10) :mod (o / organism :name (n8 / name :op1 "S."~e.8 :op2 "pombe"~e.9))) :mod (a / also~e.11) :ARG1-of (e2 / efficient-01~e.12,38)) :op2 (p4 / prenylate-00 :ARG1 (p6 / protein~e.29 :quant 2~e.25 :ARG1-of (d / differ-02~e.26) :ARG1-of (i2 / include-91 :ARG2 (p7 / protein-family :name (n5 / name :op1 "C"~e.27 :op2 "AAL"~e.28))) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and~e.32 :op1 (p8 / protein :name (n6 / name :op1 "Cdc42"~e.31)) :op2 (p9 / protein :name (n7 / name :op1 "RhoA"~e.33))))) :ARG2 e :ARG1-of (e3 / efficient-01~e.38 :ARG1-of (l / low-04~e.37 :degree (v / very~e.36)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.40 :mod "3C"))) # ::id bio.chicago_2015.74770 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the case of I B , which holds the transcription factor NF B in an inactive cytoplasmic complex , cytokines induce the phosphorylation of the two serine residues ( Ser32 and Ser36 ) in the I B destruction motif , leading to its ubiquitination by SCF -@ TrCP1 , destruction by the proteasome , and liberation of NF B ( Winston et al. , 1999a ; Yaron et al. , 1998 ; Li and Verma , 2002 ) . # ::alignments 4-1.4.1.1 5-1.4.1.2 8-1.4 8-1.4.2 8-1.4.2.r 10-1.4.2.1.2 11-1.4.2.1 12-1.4.2.1.1.1 13-1.4.2.1.1.2 14-1.4.2.2.r 16-1.4.2.2.2 16-1.4.2.2.2.1 16-1.4.2.2.2.1.r 17-1.4.2.2.1 18-1.4.2.2 20-1.1.1.1 21-1 23-1.2 24-1.2.1.r 26-1.2.1.1 27-1.2.1.2.1.1 27-1.2.1.3.1.1.2.1 27-1.2.1.3.1.2.2.1 28-1.2.1 31-1.2.1.3.1 31-1.3.1 31-1.3.1.1.1 34-1.2.3.r 36-1.2.3.2 37-1.2.3.2 38-1.2.3.1 39-1.2.3 41-1.2.2 42-1.2.2.1.r 43-1.2.2.1.1.1 43-1.2.2.1.1.1.r 44-1.2.2.1.1 45-1.2.2.1.1.2.r 46-1.2.2.1.1.2.1.1 48-1.2.2.1.1.2.1.1 50-1.2.2.1.2 51-1.2.2.1.2.1.r 53-1.2.2.1.2.1.1.1 55-1.2.2.1 56-1.2.2.1.3 57-1.2.2.1.3.2.r 58-1.2.2.1.3.2 61-1.3.1.1.1.1.1.1 62-1.3.1 62-1.3.1.1.1 62-1.3.1.2.1 62-1.3.1.3.1 63-1.3.1.1.1.2.1 63-1.3.1.2.1.2.1 67-1.3.1.2.1.1.1.1 68-1.3.1.2.1 69-1.3.1.2.1.2.1 71-1.3.1.2.2.1 73-1.3.1.3.1.1.1.1 74-1.3.1.3.1 75-1.3.1.3.1.2.1.1 77-1.3.1.3.2.1 (i / induce-01~e.21 :ARG0 (p2 / protein :name (n2 / name :op1 "cytokine"~e.20)) :ARG2 (p3 / phosphorylate-01~e.23 :ARG1~e.24 (r / residue~e.28 :quant 2~e.26 :mod (a / amino-acid :name (n / name :op1 "serine"~e.27)) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.31 :op1 (a3 / amino-acid :mod 32 :name (n3 / name :op1 "serine"~e.27)) :op2 (a4 / amino-acid :mod 36 :name (n5 / name :op1 "serine"~e.27))))) :ARG0-of (l / lead-03~e.41 :ARG2~e.42 (a5 / and~e.55 :op1 (u / ubiquitinate-01~e.44 :ARG1~e.43 m2~e.43 :ARG2~e.45 (p / protein :name (n6 / name :op1 "SCF-TrCP1"~e.46,48))) :op2 (d4 / destroy-01~e.50 :ARG0~e.51 (m4 / macro-molecular-complex :name (n7 / name :op1 "proteasome"~e.53)) :ARG1 m2) :op3 (l2 / liberate-01~e.56 :ARG0 m2 :ARG1~e.57 f2~e.58))) :location~e.34 (m2 / motif~e.39 :ARG0-of (d6 / destroy-01~e.38) :mod p6~e.36,37)) :ARG1-of (d5 / describe-01 :ARG0 (a7 / and~e.31,62 :op1 (p8 / publication-91 :ARG0 (a8 / and~e.31,62 :op1 (p11 / person :name (n11 / name :op1 "Winston"~e.61)) :op2 (p12 / person :mod (o / other~e.63))) :time (d / date-entity :year 1999 :li "a")) :op2 (p9 / publication-91 :ARG0 (a9 / and~e.62,68 :op1 (p13 / person :name (n12 / name :op1 "Yaron"~e.67)) :op2 (p14 / person :mod (o2 / other~e.63,69))) :time (d2 / date-entity :year 1998~e.71)) :op3 (p10 / publication-91 :ARG0 (a10 / and~e.62,74 :op1 (p15 / person :name (n13 / name :op1 "Li"~e.73)) :op2 (p16 / person :name (n14 / name :op1 "Verma"~e.75))) :time (d3 / date-entity :year 2002~e.77)))) :topic (p6 / protein~e.8 :name (n9 / name :op1 "I"~e.4 :op2 "B"~e.5) :ARG0-of~e.8 (h / hold-01~e.8 :ARG1 (f2 / factor~e.11 :name (n10 / name :op1 "NF"~e.12 :op2 "B"~e.13) :ARG0-of (t2 / transcribe-01~e.10)) :ARG3~e.14 (m3 / macro-molecular-complex~e.18 :mod (c3 / cytoplasm~e.17) :ARG0-of (a6 / activity-06~e.16 :polarity~e.16 -~e.16))))) # ::id bio.chicago_2015.74847 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is conceivable that Mxi2 could somehow interfere with MEK retrophosphorylation by ERKs , something that would hinder the negative feedback control of MEK exerted by ERKs ( 2 ) , resulting in prolonged MEK activity . # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1.1 5-1 5-1.1.1 6-1.1.1.1.4 7-1.1.1.1 9-1.1.1.1.2.1.1.1 17-1.1.1.1.3 19-1.1.1.1.3.1.2.1 20-1.1.1.1.3.1.2 21-1.1.1.1.3.1 22-1.1.1.1.3.1.1.r 23-1.1.1.1.3.1.1 24-1.1.1.1.3.1.3 28-1.1.1.1.3.2.1.1.1 31-1.1.1.1.3.3 32-1.1.1.1.3.3.1.r 33-1.1.1.1.3.3.1.2 34-1.1.1.1.3.3.1.1 35-1.1.1.1.3.3.1 (p3 / possible-01~e.5 :ARG1 (c / conceive-01~e.2 :ARG1~e.3 (p4 / possible-01~e.5 :ARG1 (i / interfere-01~e.7 :ARG0 (p5 / protein :name (n2 / name :op1 "Mxi2"~e.4)) :ARG1 (r / retrophosphorylate-00 :ARG1 (e3 / enzyme :name (n / name :op1 "MEK"~e.9)) :ARG2 (p / protein-family :name (n3 / name :op1 "ERK"))) :ARG0-of (h / hinder-01~e.17 :ARG1 (c2 / control-01~e.21 :ARG0~e.22 e3~e.23 :mod (f / feedback~e.20 :ARG0-of (n4 / negative-03~e.19)) :ARG1-of (e2 / exert-01~e.24 :ARG0 p)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 2~e.28))) :ARG1-of (r2 / result-01~e.31 :ARG2~e.32 (a / activity-06~e.35 :ARG1 e3~e.34 :ARG1-of (p7 / prolong-01~e.33)))) :manner (s / somehow~e.6))))) # ::id bio.chicago_2015.74892 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Injection of lefty into mouse blastocysts leads to neurogenesis , a function attributable to BMP inhibitors such as chordin , noggin , and follistatin ( 41 , 44 @-@ 47 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 4-1.1.2.1 6-1 7-1.2.r 8-1.2 11-1.2.1 14-1.2.1.1.1.1.1.1.1 15-1.2.1.1.1 15-1.2.1.1.1.1 15-1.2.1.1.1.1.r 16-1.2.1.1.1.2.r 17-1.2.1.1.1.2.r 18-1.2.1.1.1.2.1.1.1 20-1.2.1.1.1.2.2.1.1 22-1.2.1.1.1.2 23-1.2.1.1.1.2.3.1.1 25-1.3.1.1.1.1 27-1.3.1.1.1.2.1.1 29-1.3.1.1.1.2.1.2 (l / lead-03~e.6 :ARG0 (i2 / inject-01~e.0 :ARG1~e.1 (p / protein :name (n / name :op1 "lefty"~e.2)) :ARG2 (b2 / blastocyst :mod (m / mouse~e.4))) :ARG2~e.7 (n2 / neurogenesis~e.8 :mod (f / function-01~e.11 :ARG1-of (a / attribute-01 :ARG2 (m2 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1 (p3 / protein :name (n3 / name :op1 "BMP"~e.14))) :example~e.16,17 (a2 / and~e.22 :op1 (p4 / protein :name (n4 / name :op1 "chordin"~e.18)) :op2 (p5 / protein :name (n5 / name :op1 "noggin"~e.20)) :op3 (p6 / protein :name (n6 / name :op1 "follistatin"~e.23)))) :ARG1-of (p2 / possible-01)))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 41~e.25 :op2 (v / value-interval :quant (b / between :op1 44~e.27 :op2 47~e.29))))))) # ::id bio.chicago_2015.74899 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The ADAM 12 propeptide remains bound to the protease after cleavage by furin [ 9 ] , therefore the cysteine switch is potentially still functional in furin @-@ cleaved ADAM 12 @-@ S . Cu( II ) could conceivably disengage the cysteine switch by binding to or oxidizing Cys179 , similar to the way in which ADAM 12 or MMP proforms can be activated by alkylation of the free cysteine in the propeptide [ 11 and 13 ] . # ::alignments 1-1.1.1.1.1 2-1.1.1.1.2 3-1.1.1 4-1.1 5-1.1.2 6-1.1.2.2.r 8-1.1.2.2.1.1 9-1.1.3 10-1.1.3.1 12-1.1.3.1.1.1.1 14-1.1.4.1.1.1 17-1.1.5 19-1.1.5.1.1.1.1.1 20-1.1.5.1.1 22-1.1.5.1.2 22-1.1.5.1.2.r 23-1.1.5.1.3 24-1.1.5.1 26-1.1.3.1.1.1.1 28-1.1.3.1 28-1.1.5.1.4.2 29-1.1.1.1.1 30-1.1.1.1.2 32-1.1.5.1.4.1.2 37-1.2 39-1.2.1 41-1.2.1.2.1.1.1 41-1.2.1.3.1.2.2.1 42-1.2.1.2 43-1.2.1.3.r 44-1.2.1.3.1 46-1.2.1.3 47-1.2.1.3.2 50-1.2.1.4 51-1.2.1.4.1.r 53-1.2.1.4.1 53-1.2.1.4.1.1.r 56-1.2.1.4.1.1.1.1.1.1.1.1 57-1.2.1.4.1.1.1.1.1.1.1.2 58-1.2.1.4.1.1.1.1 59-1.2.1.4.1.1.1.1.2.1.1.1 61-1.2.1.4.1.1 63-1.2.1.4.1.1.1 68-1.2.1.4.1.1.1.2.1 68-1.2.1.4.1.1.1.2.1.2 68-1.2.1.4.1.1.1.2.1.2.r 69-1.2.1.4.1.1.1.2.1.1.1 72-1.2.1.4.1.1.1.2.2 74-1.2.3.1.1.1.1 75-1.2.3.1.1.1 76-1.2.3.1.1.1.2 (m / multi-sentence :snt1 (r2 / remain-01~e.4 :ARG1 (p2 / propeptide~e.3 :name (n / name :op1 "ADAM"~e.1,29 :op2 12~e.2,30)) :ARG3 (b / bind-01~e.5 :ARG1 p2 :ARG2~e.6 (e2 / enzyme :name (n2 / name :op1 "protease"~e.8))) :time (a / after~e.9 :op1 (c / cleave-01~e.10,28 :ARG0 (p3 / protein :name (n3 / name :op1 "furin"~e.12,26)) :ARG1 p2)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 9~e.14))) :ARG0-of (c3 / cause-01~e.17 :ARG1 (f / function-01~e.24 :ARG0 (s / switch-01~e.20 :ARG1 (a2 / amino-acid :name (n4 / name :op1 "cysteine"~e.19))) :manner~e.22 (p5 / potential~e.22) :mod (s2 / still~e.23) :location (e3 / enzyme :name (n5 / name :op1 "ADAM" :op2 "12-S"~e.32) :ARG1-of (c4 / cleave-01~e.28 :ARG0 p3))))) :snt2 (p6 / possible-01~e.37 :ARG1 (d2 / disengage-01~e.39 :ARG0 (s3 / small-molecule :name (n6 / name :op1 "Cu(II)")) :ARG1 (s4 / switch-01~e.42 :ARG1 (a3 / amino-acid :name (n7 / name :op1 "cysteine"~e.41))) :manner~e.43 (o / or~e.46 :op1 (b2 / bind-01~e.44 :ARG1 s3 :ARG2 (a8 / amino-acid :mod 179 :name (n8 / name :op1 "cysteine"~e.41))) :op2 (o2 / oxidize-01~e.47 :ARG0 s3 :ARG1 a8)) :ARG1-of (r3 / resemble-01~e.50 :ARG2~e.51 (w / way~e.53 :manner-of~e.53 (p7 / possible-01~e.61 :ARG1 (a4 / activate-01~e.63 :ARG1 (o4 / or~e.58 :op1 (p / proform :mod (e4 / enzyme :name (n9 / name :op1 "ADAM"~e.56 :op2 12~e.57))) :op2 (p11 / proform :mod (e5 / enzyme :name (n10 / name :op1 "MMP"~e.59)))) :manner (a5 / alkylate-01 :ARG1 (a6 / amino-acid~e.68 :name (n11 / name :op1 "cysteine"~e.69) :ARG1-of~e.68 (f2 / free-04~e.68)) :location (p9 / propeptide~e.72))))))) :ARG1-of (c5 / conceive-01) :ARG1-of (d3 / describe-01 :ARG0 (p10 / publication :ARG1-of (c6 / cite-01 :ARG2 (a7 / and~e.75 :op1 11~e.74 :op2 13~e.76)))))) # ::id bio.chicago_2015.74919 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The 432 @-@ bp 2 coding sequence is interrupted by two introns , the first ( I1 ) splitting codon 32 and the second ( I2 ) separating codons 101 and 102 . # ::alignments 1-1.2.1.1 3-1.2.1.1 4-1.2.1.2 5-1.2.2 6-1.1 6-1.2 8-1 10-1.1.1 11-1.1.2.1 11-1.1.3.1.1 11-1.1.3.1.2 14-1.1.3.1.1.2 14-1.1.3.1.1.2.1 14-1.1.3.1.1.2.1.r 16-1.1.3.1.1.3.1.1 18-1.1.3.1.1.1 19-1.1.3.1.1.1.1 20-1.1.3.1.1.1.1.1 21-1.1.3.1 23-1.1.3.1.2.2 23-1.1.3.1.2.2.1 23-1.1.3.1.2.2.1.r 25-1.1.3.1.2.3.1.1 27-1.1.3.1.2.1 28-1.1.3.1.2.1.1.1 28-1.1.3.1.2.1.1.2 29-1.1.3.1.2.1.1.1.1 30-1.1.3.1.2.1.1 31-1.1.3.1.2.1.1.2.1 (i / interrupt-01~e.8 :ARG0 (d / dna-sequence~e.6 :quant 2~e.10 :name (n / name :op1 "intron"~e.11) :ARG1-of (m / mean-01 :ARG2 (a / and~e.21 :op1 (i2 / intron~e.11 :ARG0-of (s / split-01~e.18 :ARG1 (c / codon~e.19 :mod 32~e.20)) :ord (o / ordinal-entity~e.14 :value~e.14 1~e.14) :ARG1-of (l / label-01 :ARG2 (n4 / name :op1 "I1"~e.16))) :op2 (i3 / intron~e.11 :ARG0-of (s2 / separate-01~e.27 :ARG1 (a2 / and~e.30 :op1 (c2 / codon~e.28 :mod 101~e.29) :op2 (c3 / codon~e.28 :mod 102~e.31))) :ord (o2 / ordinal-entity~e.23 :value~e.23 2~e.23) :ARG1-of (l2 / label-01 :ARG2 (n3 / name :op1 "I2"~e.25)))))) :ARG1 (d2 / dna-sequence~e.6 :name (n2 / name :op1 "432-bp"~e.1,3 :op2 2~e.4) :ARG0-of (c4 / code-01~e.5))) # ::id bio.chicago_2015.75018 ::amr-annotator SDL-AMR-09 ::preferred # ::tok COX @-@ 1 mediates epithelial regeneration in a model of irradiation @-@ induced intestinal injury in mice ( 9 ) , which supports the cytoprotective role attributed to COX @-@ 1 in gastrointestinal inflammation . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2.1 5-1.2 6-1.2.2.r 8-1.2.2 9-1.2.2.1.r 10-1.2.2.1.2.1 12-1.2.2.1.2 13-1.2.2.1.1 14-1.2.2.1 15-1.2.2.1.3.r 16-1.2.2.1.3 18-1.2.3.1.1.1 22-1.2.4 24-1.2.4.1.1 25-1.2.4.1 26-1.2.4.1.2 27-1.2.4.1.2.1.r 28-1.2.4.1.2.1 29-1.2.4.1.2.1 30-1.2.4.1.2.1 33-1.2.4.1.2.2 (m / mediate-01~e.3 :ARG0 (e / enzyme :name (n / name :op1 "COX-1"~e.0,2)) :ARG1 (r / regenerate-01~e.5 :ARG1 (e2 / epithelium~e.4) :location~e.6 (m2 / model-01~e.8 :ARG1~e.9 (i / injure-01~e.14 :ARG1 (i2 / intestine~e.13) :ARG2-of (i3 / induce-01~e.12 :ARG0 (i4 / irradiate-01~e.10)) :location~e.15 (m3 / mouse~e.16))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 9~e.18))) :ARG0-of (s / support-01~e.22 :ARG1 (r2 / role~e.25 :mod (c2 / cytoprotective~e.24) :ARG1-of (a / attribute-01~e.26 :ARG2~e.27 e~e.28,29,30 :time (i5 / inflame-01~e.33 :ARG1 (g / gastrointestine))))))) # ::id bio.chicago_2015.75030 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The initial observations that marijuana produced unique behavioral and pharmacological effects in humans and laboratory animals prompted chemists to prepare synthetic agonists and antagonists . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1 5-1.1.1 6-1.1.1.2.4 7-1.1.1.2.3.1 8-1.1.1.2.3 9-1.1.1.2.3.2 10-1.1.1.2 11-1.1.1.2.2.r 12-1.1.1.2.2.1 13-1.1.1.2.2 14-1.1.1.2.2.2.1 15-1.1.1.2.2.2 16-1 17-1.2.1 19-1.2 20-1.2.2.3 22-1.2.2 23-1.2.2.2 (p / prompt-01~e.16 :ARG0 (o / observe-01~e.2 :ARG1~e.3 (p2 / produce-01~e.5 :ARG0 (m / marijuana~e.4) :ARG1 (a / affect-01~e.10 :ARG0 m :ARG1~e.11 (a3 / and~e.13 :op1 (h / human~e.12) :op2 (a4 / animal~e.15 :mod (l / laboratory~e.14))) :ARG2 (a2 / and~e.8 :op1 (b / behave-01~e.7) :op2 (p3 / pharmacology~e.9)) :mod (u / unique~e.6))) :time (i / initial~e.1)) :ARG1 (p4 / prepare-01~e.19 :ARG0 (c / chemist~e.17) :ARG1 (a5 / and~e.22 :op1 (a6 / agonist) :op2 (a7 / antagonist~e.23) :mod (s / synthetic~e.20)))) # ::id bio.chicago_2015.75156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The uniqueness of the incomplete inhibition by BoNT A was indicated by the finding that Tetx or BoNT B and BoNT C , which extensively proteolyzed synaptobrevin and syntaxin , respectively ( not shown ) , completely inhibited Ca2+-activated secretion in ATP @-@ primed cells ( Fig . 4 B ) . # ::alignments 1-1.2 2-1.2.1.r 4-1.2.1.2 4-1.2.1.2.1 4-1.2.1.2.1.r 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.1.1 8-1.2.1.1.1.2 10-1 11-1.1.r 13-1.1 14-1.1.1.r 15-1.1.1.1.1.1.1 16-1.1.1.1 17-1.1.1.1.2.1.1.1 18-1.1.1.1.2.1.1.2 19-1.1.1.1.2 20-1.1.1.1.2.2.1.1 21-1.1.1.1.2.2.1.2 24-1.1.1.1.2.1.2.2 26-1.1.1.1.2.1.2.1.1.1 27-1.1.1.1.2 28-1.1.1.1.2.2.2.1.1.1 30-1.1.1.1.2.3 30-1.1.1.1.2.3.r 32-1.1.1.1.2.4.1 32-1.1.1.1.2.4.1.r 33-1.1.1.1.2.4 36-1.1.1.3 37-1.1.1 39-1.1.1.2 40-1.1.1.2.1.r 41-1.1.1.2.1.1.1.1.1 43-1.1.1.2.1.1 44-1.1.1.2.1 46-1.3.1 (i / indicate-01~e.10 :ARG0~e.11 (f / find-01~e.13 :ARG1~e.14 (i3 / inhibit-01~e.37 :ARG0 (o2 / or~e.16 :op1 (p2 / protein :name (n2 / name :op1 "Tetx"~e.15)) :op2 (a / and~e.19,27 :op1 (p3 / protein :name (n3 / name :op1 "BoNT"~e.17 :op2 "B"~e.18) :ARG0-of (p5 / proteolyze-00 :ARG1 (p6 / protein :name (n5 / name :op1 "synaptobrevin"~e.26)) :ARG1-of (e / extensive-03~e.24))) :op2 (p4 / protein :name (n4 / name :op1 "BoNT"~e.20 :op2 "C"~e.21) :ARG0-of (p7 / proteolyze-00 :ARG1 (p8 / protein :name (n6 / name :op1 "syntaxin"~e.28)) :ARG1-of e)) :manner~e.30 (r / respective~e.30) :ARG1-of (s / show-01~e.33 :polarity~e.32 -~e.32))) :ARG1 (s2 / secrete-01~e.39 :ARG0~e.40 (c3 / cell~e.44 :ARG1-of (p9 / prime-01~e.43 :ARG0 (s4 / small-molecule :name (n8 / name :op1 "ATP"~e.41)))) :ARG1-of (a2 / activate-01 :ARG0 (s3 / small-molecule :name (n7 / name :op1 "calcium") :ARG1-of (i4 / ionize-01 :value "2+")))) :ARG1-of (c2 / complete-02~e.36))) :ARG1 (u / uniqueness~e.1 :poss~e.2 (i2 / inhibit-01~e.5 :ARG0~e.6 (p / protein :name (n / name :op1 "BoNT"~e.7 :op2 "A"~e.8)) :ARG1-of (c / complete-02~e.4 :polarity~e.4 -~e.4))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.46 :mod "4B"))) # ::id bio.chicago_2015.75158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicated that LPA @-@ induced actin depolymerization through alpha @-@ actinin was involved in regulation of growth cone morphology of primary neurons . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1 3-1.2.r 4-1.2.1.4.1.1.1 6-1.2.1.4 7-1.2.1.2.1.1 10-1.2.1.3.1.1 12-1.2.1.3.1.1 14-1.2 15-1.2.2.r 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1.1.1 19-1.2.2.1.1 20-1.2.2.1 21-1.2.2.1.1.2.r 22-1.2.2.1.1.2.1 23-1.2.2.1.1.2 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :mod (t2 / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (i2 / involve-01~e.14 :ARG1 (p / polymerize-01 :polarity - :ARG1 (p2 / protein :name (n / name :op1 "actin"~e.7)) :ARG2 (p3 / protein :name (n3 / name :op1 "alpha-actinin"~e.10,12)) :ARG2-of (i3 / induce-01~e.6 :ARG0 (s / small-molecule :name (n2 / name :op1 "LPA"~e.4)))) :ARG2~e.15 (r2 / regulate-01~e.16 :ARG1~e.17 (m / morphology~e.20 :poss (c / cone~e.19 :mod (g / growth~e.18) :part-of~e.21 (n4 / neuron~e.23 :mod (p4 / primary~e.22))))))) # ::id bio.chicago_2015.75270 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IKACh activation by adenosine may be responsible for the profound transient bradycardia and atrioventricular block seen in humans after administration of adenosine ( DiMarco et al. 1983 ; Clemo and Belardinelli 1986 ; Kurachi et al. 1986 ) . # ::alignments 0-1.1.1.2.1.1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1 6-1.1 7-1.1.2.r 9-1.1.2.1.2 10-1.1.2.1.1 11-1.1.2.1 12-1.1.2 13-1.1.2.2.1 14-1.1.2.2 15-1.1.2.3 16-1.1.2.3.1.r 17-1.1.2.3.1 18-1.1.2.3.2 19-1.1.2.3.2.1 20-1.1.2.3.2.1.1.r 21-1.1.2.3.2.1.1 24-1.2.1 24-1.2.1.1.1 25-1.2.1.1.1.2.1 26-1.2.1.1.2.1 28-1.2.1.2.1.1.1.1 29-1.2.1.2.1 30-1.2.1.2.1.2.1.1 31-1.2.1.2.2.1 33-1.2.1.3.1.1.1.1 34-1.2.1 34-1.2.1.1.1 34-1.2.1.2.1 34-1.2.1.3.1 35-1.2.1.1.1.2.1 36-1.2.1.2.2.1 (p / possible-01~e.4 :ARG1 (r / responsible-03~e.6 :ARG0 (a2 / activate-01~e.1 :ARG0~e.2 (s / small-molecule :name (n2 / name :op1 "adenosine"~e.3)) :ARG1 (p2 / protein :name (n / name :op1 "IKACh"~e.0))) :ARG1~e.7 (a3 / and~e.12 :op1 (b / bradycardia~e.11 :ARG1-of (t / transient-02~e.10) :mod (p3 / profound~e.9)) :op2 (b2 / block-01~e.14 :mod (a / atrioventricular~e.13)) :ARG1-of (s2 / see-01~e.15 :location~e.16 (h / human~e.17) :time (a6 / after~e.18 :op1 (a7 / administer-01~e.19 :ARG1~e.20 s~e.21))))) :ARG1-of (d4 / describe-01 :ARG0 (a8 / and~e.24,34 :op1 (p4 / publication-91 :ARG0 (a9 / and~e.24,34 :op1 (p5 / person :name (n3 / name :op1 "Di" :op2 "Marco")) :op1 (p6 / person :mod (o / other~e.25,35))) :time (d2 / date-entity :year 1983~e.26)) :op2 (p7 / publication-91 :ARG0 (a10 / and~e.29,34 :op1 (p8 / person :name (n4 / name :op1 "Clemo"~e.28)) :op2 (p9 / person :name (n5 / name :op1 "Belardinelli"~e.30))) :time (d3 / date-entity :year 1986~e.31,36)) :op3 (p10 / publication-91 :ARG0 (a11 / and~e.34 :op1 (p11 / person :name (n6 / name :op1 "Kurachi"~e.33)) :op2 p6) :time d3)))) # ::id bio.chicago_2015.75329 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The global burden of disease and injury attributable to selected risk factors in 1990 ( 12 ) . # ::alignments 1-1.2 2-1 3-1.1.r 4-1.1.1 5-1.1 6-1.1.2 9-1.3.1.2 10-1.3.1.1 11-1.3.1 13-1.3.3.1 15-1.4.1.1.1 (b / burden-01~e.2 :ARG2~e.3 (a / and~e.5 :op1 (d2 / disease~e.4) :op2 (i / injure-01~e.6)) :mod (g / globe~e.1) :ARG1-of (a2 / attribute-01 :ARG2 (f / factor~e.11 :mod (r / risk~e.10) :ARG1-of (s / select-01~e.9)) :ARG1-of (p / possible-01) :time (d / date-entity :year 1990~e.13)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 12~e.15)))) # ::id bio.chicago_2015.75347 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Abeta peptides ( amyloid plaques ) , hyperphosphorylated tau proteins ( NFTs , NTs ) , and alpha @-@ synuclein ( LBs , GCIs ) . # ::alignments 0-1.1.1.1 1-1.1.1.2 3-1.1.2.1 4-1.1.2 7-1.2.2 8-1.2.1.1 9-1.2 9-1.2.3.1 9-1.2.3.2 9-1.3 9-1.3.2.1 9-1.3.2.2 16-1 16-1.2.3 17-1.3.1.1 19-1.3.1.1 21-1.3.2.1.1.1 (a / and~e.16 :op1 (p / protein-segment :name (n / name :op1 "abeta"~e.0 :op2 "peptide"~e.1) :part-of (p2 / plaque~e.4 :mod (a4 / amyloid~e.3))) :op2 (p4 / protein~e.9 :name (n3 / name :op1 "tau"~e.8) :ARG1-of (h / hyperphosphorylate-01~e.7) :part-of (a2 / and~e.16 :op1 (p3 / protein-family~e.9 :name (n4 / name :op1 "NFT")) :op2 (p5 / protein-family~e.9 :name (n5 / name :op1 "NT")))) :op3 (p7 / protein~e.9 :name (n6 / name :op1 "alpha-synuclein"~e.17,19) :part-of (a3 / and :op1 (p6 / protein-family~e.9 :name (n8 / name :op1 "LB"~e.21)) :op2 (p8 / protein-family~e.9 :name (n7 / name :op1 "GCI"))))) # ::id bio.chicago_2015.75367 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It contains all six motifs ( PM1 @-@ PM3 , G1 @-@ G3 ) involved in nucleotide binding ( Valencia et al. , 1991 ) , and a recombinant protein isolated from E. coli indeed binds and hydrolyses GTP . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.2 3-1.1.2.1 4-1.1.2 6-1.1.2.3.1.1.1.1.1.1 8-1.1.2.3.1.1.1.2.1.1 10-1.1.2.3.1.2.1.1.1.1 12-1.1.2.3.1.2.1.2.1.1 14-1.1.2.4 15-1.1.2.4.1.r 16-1.1.2.4.1.2 17-1.1.2.4.1 19-1.1.3.1.1.1.1.1 20-1 20-1.1.3.1.1 21-1.1.3.1.1.2.1 23-1.1.3.1.2.1 28-1.2.1.1.1 29-1.1.2.3.1.1 29-1.1.2.3.1.2 29-1.2.1.1 30-1.2.1.1.2 31-1.2.1.1.2.1.r 32-1.2.1.1.2.1.1.1 33-1.2.1.1.2.1.1.2 34-1.2.3 35-1.2.1 36-1.2 38-1.2.2.1.1.1 (a / and~e.20 :op1 (c / contain-01~e.1 :ARG0 (i / it~e.0) :ARG1 (p / protein-segment~e.4 :quant 6~e.3 :mod (a2 / all~e.2) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (p2 / protein-segment~e.29 :mod (v / value-interval :op1 (p8 / protein-segment :name (n5 / name :op1 "PM1"~e.6)) :op2 (p9 / protein-segment :name (n6 / name :op1 "PM3"~e.8)))) :op2 (p3 / protein-segment~e.29 :mod (v2 / value-interval :op1 (p10 / protein-segment :name (n7 / name :op1 "G1"~e.10)) :op2 (p11 / protein-segment :name (n8 / name :op1 "G3"~e.12)))))) :ARG1-of (i2 / involve-01~e.14 :ARG2~e.15 (b / bind-01~e.17 :ARG1 p :ARG2 (n2 / nucleotide~e.16)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and~e.20 :op1 (p5 / person :name (n3 / name :op1 "Valencia"~e.19)) :op2 (p6 / person :mod (o / other~e.21))) :time (d / date-entity :year 1991~e.23)))) :op2 (a5 / and~e.36 :op1 (b2 / bind-01~e.35 :ARG1 (p7 / protein~e.29 :ARG1-of (r / recombine-01~e.28) :ARG1-of (i3 / isolate-01~e.30 :ARG2~e.31 (o2 / organism :name (n4 / name :op1 "E."~e.32 :op2 "coli"~e.33)))) :ARG2 s) :op2 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.38)) :ARG2 p7) :mod (i4 / indeed~e.34))) # ::id bio.chicago_2015.75388 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In budding yeast , Mad1p becomes hyperphosphorylated and associates with Bub1p and Bub3p , and the formation of this complex occurs in a Mad2p @- and Mps1p @-@ dependent fashion and is crucial for checkpoint function ( 8 ) . # ::alignments 1-1.5.1 2-1.5 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2 7-1.1 8-1.1.2 9-1.1.2.2.r 10-1.1.2.2.1.1.1 12-1.1.2.2.2.1.1 14-1 16-1.2 17-1.2.1.r 18-1.2.1.4 19-1.2.1 21-1.2.2.r 23-1.2.2.1.1.1.1 25-1.2.2.1 26-1.2.2.1.2.1.1 28-1.2.2 30-1 31-1.3.1.r 32-1.3 33-1.3.2.r 34-1.3.2.1 35-1.3.2 37-1.4.1.1.1 (a / and~e.14,30 :op1 (a2 / and~e.7 :op1 (b / become-01~e.5 :ARG1 (p / protein :name (n / name :op1 "Mad1p"~e.4)) :ARG2 (h / hyperphosphorylate-01~e.6 :ARG1 p)) :op2 (a3 / associate-01~e.8 :ARG1 p :ARG2~e.9 (a4 / and :op1 (e / enzyme :name (n2 / name :op1 "Bub1p"~e.10)) :op2 (e2 / enzyme :name (n3 / name :op1 "Bub3p"~e.12))))) :op2 (f / form-01~e.16 :ARG1~e.17 (m / macro-molecular-complex~e.19 :part p :part e :part e2 :mod (t / this~e.18)) :ARG0-of~e.21 (d / depend-01~e.28 :ARG1 (a5 / and~e.25 :op1 (p2 / protein :name (n4 / name :op1 "Mad2p"~e.23)) :op2 (e3 / enzyme :name (n5 / name :op1 "Mps1p"~e.26))))) :op3 (c / crucial~e.32 :domain~e.31 f :purpose~e.33 (f3 / function-01~e.35 :ARG1 (c2 / checkpoint~e.34))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 8~e.37))) :location (y / yeast~e.2 :ARG1-of (b2 / bud-01~e.1))) # ::id bio.chicago_2015.75391 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The structural and functional conservation of basal transcription machineries between yeast and mammals prompted us to investigate whether TFIIH is involved in rDNA transcription in vivo . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1.1.2 4-1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.2 7-1.1.1.1.1.1 8-1.1.1.1.1 10-1.1.2.1 11-1.1.2 12-1.1.2.2 13-1 14-1.2.1 16-1.2 17-1.2.2.1 17-1.2.2.1.r 18-1.2.2.2.1.1 20-1.2.2 21-1.2.2.3.r 21-1.2.2.4 22-1.2.2.3.1.1.1 23-1.2.2.3 24-1.2.2.4 25-1.2.2.4 (p / prompt-01~e.13 :ARG0 (c / conserve-01~e.4 :ARG1 (a / and~e.2 :op1 (s / structure-01~e.1 :ARG1~e.5 (m / machinery~e.8 :ARG0-of (t / transcribe-01~e.7) :mod (b / basal~e.6))) :op2 (f / function-01~e.3 :ARG0 m)) :location (a2 / and~e.11 :op1 (y / yeast~e.10) :op2 (m2 / mammal~e.12))) :ARG1 (i / investigate-01~e.16 :ARG0 (w / we~e.14) :ARG1 (i2 / involve-01~e.20 :mode~e.17 interrogative~e.17 :ARG1 (p2 / protein :name (n / name :op1 "TFIIH"~e.18)) :ARG2~e.21 (t2 / transcribe-01~e.23 :ARG1 (n2 / nucleic-acid :name (n3 / name :op1 "rDNA"~e.22))) :manner (i3 / in-vivo~e.21,24,25)))) # ::id bio.chicago_2015.75414 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the 30 tests ( data not shown ) , all but 1 received P values > 0.05 , and the one exception , reductase constrained to the ammonia ligase consensus , received a P value of 0.0338 . # ::alignments 2-1.1.1.2.1.1 3-1.1.1 3-1.1.1.2.1 3-1.1.1.3.1 5-1.1.1.2.1.2.1 6-1.1.1.2.1.2.1.1.1 6-1.1.1.2.1.2.1.1.1.r 7-1.1.1.2.1.2.1.1 10-1.1.1.1 11-1.1.1.3 12-1.1.1.3.1.1 13-1.1 14-1.1.2 16-1.1.2.2 17-1.1.2.2.1 21-1.1.2.1 22-1.1.2.1 23-1.1.2.1 24-1.1.2.1 25-1.1.2.1 26-1.1.2.1 27-1.1.2.1 28-1.1.2.1 29-1.1.2.1 32-1.2 34-1.2.2 37-1.2.2.1 (a / and :op1 (r / receive-01~e.13 :ARG0 (t2 / test~e.3 :mod (a2 / all~e.10) :ARG1-of (i / include-01 :ARG2 (t / test~e.3 :quant 30~e.2 :ARG1-of (d2 / describe-01 :ARG0 (d / data~e.5 :ARG1-of (s / show-01~e.7 :polarity~e.6 -~e.6))))) :ARG2-of (e / except-01~e.11 :ARG1 (t3 / test~e.3 :quant 1~e.12 :ARG1-of (m2 / mean-01 :ARG2 (c / constrain-01 :ARG0 (c2 / consent-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "ammonia" :op2 "ligase"))) :ARG1 (e2 / enzyme :name (n / name :op1 "reductase"))))))) :ARG1 (s2 / statistical-test-91~e.14 :ARG1 t2~e.21,22,23,24,25,26,27,28,29 :ARG2 (m / more-than~e.16 :op1 0.05~e.17))) :op2 (r2 / receive-01~e.32 :ARG0 t3 :ARG1 (s3 / statistical-test-91~e.34 :ARG2 0.0338~e.37 :ARG1 t3))) # ::id bio.chicago_2015.75551 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GLP @-@ 1-( 1 @-@ 36 ) - amide and GLP @-@ 1( 1137 ) synthetic peptides were iodinated by the chloramine @-@ T method . # ::alignments 0-1.2.1.1.1 0-1.2.2.1.1 3-1.2.1.1.1 8-1.2.1.1.1 9-1.2 10-1.2.1.1.1 10-1.2.2.1.1 15-1.2.3 16-1.2.1 16-1.2.2 18-1 19-1.1.r 21-1.1.1.1.1 23-1.1.1.1.1 24-1.1 (i / iodinate-00~e.18 :ARG0~e.19 (m / method~e.24 :mod (s2 / small-molecule :name (n3 / name :op1 "chloramine-T"~e.21,23))) :ARG1 (a / and~e.9 :op1 (p / peptide~e.16 :name (n / name :op1 "GLP-1-(1-36)-amide"~e.0,3,8,10)) :op2 (p2 / peptide~e.16 :name (n2 / name :op1 "GLP-1(1137)"~e.0,10)) :mod (s / synthetic~e.15))) # ::id bio.chicago_2015.79572 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A strong FRET signal is detected from DABCYL @-@ tagged PLCbeta2 in the presence of coumarin @-@ tagged prenylated betagamma complex . # ::alignments 1-1.1.3 2-1.1.2.1.1 3-1.1 5-1 6-1.1.1.r 7-1.1.1.2.1.1.1 9-1.1.1.2 10-1.1.1.1.1 11-1.2.r 13-1.2 14-1.2.1.r 15-1.2.1.4.1.1.1 17-1.2.1.4 20-1.2.1 (d / detect-01~e.5 :ARG1 (s / signal-07~e.3 :ARG0~e.6 (e / enzyme :name (n2 / name :op1 "PLCbeta2"~e.10) :ARG1-of (t2 / tag-01~e.9 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "DABCYL"~e.7)))) :ARG1 (t / thing :name (n / name :op1 "FRET"~e.2)) :ARG1-of (s2 / strong-02~e.1)) :condition~e.11 (p / present-02~e.13 :ARG1~e.14 (m / macro-molecular-complex~e.20 :part (p2 / protein :name (n4 / name :op1 "beta")) :part (p3 / protein :name (n5 / name :op1 "gamma")) :ARG1-of (p4 / prenylate-00) :ARG1-of (t3 / tag-01~e.17 :ARG0 (s4 / small-molecule :name (n6 / name :op1 "coumarin"~e.15)))))) # ::id bio.chicago_2015.79887 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Elevated A{beta}42 in Skeletal Muscle of Alzheimer Disease Patients Suggests Peripheral Alterations of A{beta}PP Metabolism . # ::alignments 0-1.1.2 4-1.1.3 5-1.1.3.2.r 6-1.1.3.2.2.1.2.1 7-1.1.3.2.2.1.2.2 8-1.1.3.2.1.1 9-1 10-1.2.2 11-1.2 (s / suggest-01~e.9 :ARG0 (p / protein :name (n2 / name :op1 "A-beta" :op2 42) :ARG1-of (e / elevate-01~e.0) :location (m / muscle~e.4 :mod (s2 / skeleton) :poss~e.5 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.8)) :ARG0-of (h2 / have-03 :ARG1 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"~e.6 :op2 "disease"~e.7)))))) :ARG1 (a / alter-01~e.11 :ARG1 (m2 / metabolize-01 :ARG1 (p5 / protein :name (n3 / name :op1 "A-beta" :op2 "PP"))) :mod (p4 / peripheral~e.10))) # ::id bio.chicago_2015.79978 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cystic Fibrosis Phenotype Associated with Pancreatic Insufficiency Does Not Always Reflect the cAMP @-@ dependent Chloride Conductive Pathway Defect . # ::alignments 0-1.2.1.1.1 1-1.2.1.1.2 2-1.2 3-1.2.2 4-1.2.2.1.r 5-1.2.2.1.1.1 6-1.2.2.1.1.2 8-1.1 8-1.1.r 9-1.4 10-1 12-1.3.1.3.1.1.1 14-1.3.1.3 15-1.3.1.1.1.1 17-1.3.1 18-1.3 (r / reflect-01~e.10 :polarity~e.8 -~e.8 :ARG1 (p / phenotype~e.2 :mod (d / disease :name (n / name :op1 "cystic"~e.0 :op2 "fibrosis"~e.1)) :ARG1-of (a / associate-01~e.3 :ARG2~e.4 (m2 / medical-condition :name (n2 / name :op1 "pancreatic"~e.5 :op2 "insufficiency"~e.6)))) :ARG2 (d3 / defect-01~e.18 :ARG0 (p2 / pathway~e.17 :mod (s2 / small-molecule :name (n3 / name :op1 "chloride"~e.15)) :ARG1-of (c / conduct-03) :ARG0-of (d4 / depend-01~e.14 :ARG1 (s / small-molecule :name (n4 / name :op1 "cAMP"~e.12))))) :time (a2 / always~e.9)) # ::id bio.chicago_2015.80319 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Potential Mechanisms for Exacerbation of Diabetic Retinopathy by Hypertension . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2 4-1.2.2.r 5-1.2.2.1.1.1 6-1.2.2 7-1.2.1.r 8-1.2.1 (m / mechanism~e.1 :mod (p / potential~e.0) :instrument-of~e.2 (e / exacerbate-01~e.3 :ARG0~e.7 (h / hypertension~e.8) :ARG1~e.4 (r / retinopathy~e.6 :mod (d / disease :name (n / name :op1 "diabetes"~e.5))))) # ::id bio.chicago_2015.80327 ::amr-annotator SDL-AMR-09 ::preferred # ::tok D , HT @-@ induced phosphorylation of myrAkt delta4 @-@ 129 @-@ ER . # ::alignments 0-1.1 2-1.3.1.1.1 4-1.3 5-1 10-1.2.1.2 12-1.2.1.2 (p / phosphorylate-01~e.5 :li "D"~e.0 :ARG1 (g / gene :name (n / name :op1 "myrAKT" :op2 "Delta4-129-ER"~e.10,12)) :ARG2-of (i / induce-01~e.4 :ARG0 (s / small-molecule :name (n2 / name :op1 "HT"~e.2)))) # ::id bio.chicago_2015.80330 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vivo , iNOS concentrations increase in parallel with diabetes onset in a model of T @-@ cell transfer 69 and after cyclophosphamide treatment of insulitic animals 70 ; moreover , an inhibitor of iNOS activity can block diabetes transfer 69 . # ::alignments 0-1.1.2 1-1.1.2 3-1.1.1.1.1.1 4-1.1.1 5-1.1 6-1.1.2 6-1.1.3.r 7-1.1.3 8-1.1.3.1.r 9-1.1.3.1.1.1.1 10-1.1.3.1 11-1.1.2 11-1.1.4.r 13-1.1.4 14-1.1.4.1.r 15-1.1.4.1.1.1.1 17-1.1.4.1.1 18-1.1.4.1 19-1.1.4.2.1.1.1 21-1.1.5 22-1.1.5.1.2.1.1 23-1.1.5.1 24-1.1.5.1.1.r 25-1.1.5.1.1.1 26-1.1.5.1.1 27-1.1.5.2.1.1.1 29-1.2 32-1.2.1.1.1 32-1.2.1.1.1.1 32-1.2.1.1.1.1.r 33-1.2.1.1.1.1.1.r 34-1.2.1.1.1.1.1.1.1.1 35-1.2.1.1.1.1.1 36-1.2.1 37-1.2.1.1 38-1.2.1.1.2.1.1.1 39-1.2.1.1.2 40-1.2.2.1.1.1 (m / multi-sentence :snt1 (i2 / increase-01~e.5 :ARG1 (c / concentrate-02~e.4 :ARG1 (e / enzyme :name (n / name :op1 "iNOS"~e.3))) :manner (i3 / in-vivo~e.0,1,6,11) :ARG0-of~e.6 (p / parallel-01~e.7 :ARG1~e.8 (o / onset~e.10 :mod (d4 / disease :name (n2 / name :op1 "diabetes"~e.9)))) :location~e.11 (m2 / model~e.13 :mod~e.14 (t2 / transfer-01~e.18 :ARG1 (c2 / cell~e.17 :name (n4 / name :op1 "T"~e.15))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 69~e.19)))) :time (a / after~e.21 :op1 (t3 / treat-04~e.23 :ARG1~e.24 (a2 / animal~e.26 :mod (i4 / insulitic~e.25)) :ARG2 (s / small-molecule :name (n3 / name :op1 "cyclophosphamide"~e.22))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 70~e.27))))) :snt2 (a3 / and~e.29 :op2 (p4 / possible-01~e.36 :ARG1 (b / block-01~e.37 :ARG0 (m3 / molecular-physical-entity~e.32 :ARG0-of~e.32 (i5 / inhibit-01~e.32 :ARG1~e.33 (a4 / activity-06~e.35 :ARG0 (e2 / enzyme :name (n5 / name :op1 "iNOS"~e.34))))) :ARG1 (t4 / transfer-01~e.39 :ARG1 (d6 / disease :name (n6 / name :op1 "diabetes"~e.38))))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication :ARG1-of (c5 / cite-01 :ARG2 69~e.40))))) # ::id bio.chicago_2015.80669 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with this prediction , when families were divided into two groups according to the presence or absence in the probands of the risk allele of SNP V26 ( the most significant SNP in BLOCK I ) , significance of the schizophrenia associations with BLOCK I SNPs V23 @-@ 27 increased dramatically in families with the V26 risk allele present . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.2 3-1.4.1 3-1.4.1.1 3-1.4.1.1.r 5-1.5.r 6-1.5.1 8-1.5 9-1.5.2.r 10-1.5.2.1 11-1.5.2 12-1.5.3 13-1.5.3.1.r 15-1.5.3.1.1 16-1.5.3.1 17-1.5.3.1.2 21-1.5.3.1.2.1.r 23-1.5.3.1.2.1 24-1.5.3.1.2.1 25-1.5.3.1.2.1 26-1.5.3.1.2.1 27-1.5.3.1.2.1 28-1.5.3.1.2.1 29-1.5.3.1.2.1 30-1.5.3.1.2.1 31-1.5.3.1.2.1 32-1.5.3.1.2.1 33-1.5.3.1.2.1 34-1.5.3.1.2.1 35-1.5.3.1.2.1 36-1.5.3.1.2.1 37-1.5.3.1.2.1 38-1.5.3.1.2.1 41-1.1.1.1.1.1 42-1.1.1 44-1.1.1.2.3 45-1.1.1.2.3 47-1.1.1.2.2.1.1.1 50-1 51-1.2 52-1.3.r 53-1.3 56-1.3.1.1 57-1.3.1.1 58-1.3.1.1 59-1.3.1 59-1.5.3.1.1 (i / increase-01~e.50 :ARG1 (s / signify-01 :ARG0 (a / associate-01~e.42 :ARG1 (m2 / medical-condition :name (n / name :op1 "schizophrenia"~e.41)) :ARG2 (p5 / polymorphism :mod (n4 / nucleotide :ARG1-of (s3 / single-02)) :mod (v / value-interval :op1 (m3 / molecular-physical-entity :ARG1-of (s4 / substitute-01 :value "V23"~e.47)) :op2 (m4 / molecular-physical-entity :ARG1-of (s5 / substitute-01 :value "V27"))) :location b~e.44,45))) :ARG2 (d2 / dramatic~e.51) :location~e.52 (f / family~e.53 :ARG2-of (p / present-02~e.59 :ARG1 a2~e.56,57,58)) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (t2 / thing~e.3 :ARG1-of~e.3 (p2 / predict-01~e.3) :mod (t3 / this~e.2))) :time~e.5 (d3 / divide-02~e.8 :ARG1 (f2 / family~e.6) :ARG2~e.9 (g / group~e.11 :quant 2~e.10) :ARG1-of (a3 / accord-02~e.12 :ARG2~e.13 (o2 / or~e.16 :op1 (p3 / present-02~e.15,59 :ARG1 (a2 / allele :mod (r / risk) :mod (p6 / polymorphism :mod n4 :ARG1-of (s2 / significant-02 :degree (m / most) :location (b / block :ord (o / ordinal-entity :value 1))) :mod (m5 / molecular-physical-entity :ARG1-of (s6 / substitute-01 :value "V26")))) :ARG2 (p4 / proband)) :op2 (a4 / absent-01~e.17 :ARG1~e.21 a2~e.23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38 :ARG2 p4))))) # ::id bio.chicago_2015.80727 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mice and rats with spontaneously occurring Lepr mutations affecting the expression of all ( db3J , dbPas , faf , fa ) , or only one ( db ) , of the LEPR isoforms have provided useful models for determining the physiological function( s ) of LEPR isoforms in various tissues . # ::alignments 0-1.1.1 1-1.1 2-1.1.2 4-1.1.3.1.2 6-1.1.3.1.1.2.1 7-1.1.3.1 8-1.1.3.1.3 10-1.1.3.1.3.1.1 10-1.1.3.1.3.1.2 12-1.1.3.1.3.1.1.1.1 14-1.1.3.1.3.1.1.1.2.1.1.1.1 16-1.1.3.1.3.1.1.1.2.1.2.1.1 18-1.1.3.1.3.1.1.1.2.1.3.1.1 20-1.1.3.1.3.1.1.1.2.1.4.1.1 24-1.1.3.1.3.1.2.1.2 25-1.1.3.1.3.1.2.1.1 27-1.1.3.1.3.1.2.1.3.1.1.1 32-1.1.3.1.1.2.1 33-1.1.3.1.3.1.1.1 33-1.1.3.1.3.1.1.1.2.1.1 33-1.1.3.1.3.1.1.1.2.1.2 33-1.1.3.1.3.1.1.1.2.1.3 33-1.1.3.1.3.1.1.1.2.1.4 33-1.1.3.1.3.1.2.1 33-1.1.3.1.3.1.2.1.3.1 34-1.1.3 35-1 36-1.2.1 37-1.2 38-1.2.1.1.r 39-1.2.1.1 41-1.2.1.1.1.2 46-1.1.3.1.1.2.1 47-1.1.3.1.3.1.1.1.3.1 47-1.2.1.1.1.1 49-1.2.1.1.1.3.1 50-1.2.1.1.1.3 (p / provide-01~e.35 :ARG0 (a / and~e.1 :op1 (m / mouse~e.0) :op2 (r / rat~e.2) :ARG0-of (h / have-03~e.34 :ARG1 (m2 / mutate-01~e.7 :ARG1 (p7 / protein :wiki "Leptin_receptor" :name (n / name :op1 "Lepr"~e.6,32,46)) :mod (s / spontaneous~e.4) :ARG0-of (a2 / affect-01~e.8 :ARG1 (a3 / and :op1 (e / express-03~e.10 :ARG2 (i / isoform~e.33 :mod (a4 / all~e.12) :ARG1-of (m3 / mean-01 :ARG2 (a5 / and :op1 (i6 / isoform~e.33 :name (n2 / name :op1 "db3J"~e.14)) :op2 (i7 / isoform~e.33 :name (n3 / name :op1 "dbPas"~e.16)) :op3 (i8 / isoform~e.33 :name (n4 / name :op1 "faf"~e.18)) :op4 (i9 / isoform~e.33 :name (n5 / name :op1 "fa"~e.20)))) :ARG1-of (i4 / include-91 :ARG2 (i3 / isoform~e.47 :mod p7)))) :op2 (e2 / express-03~e.10 :ARG2 (i2 / isoform~e.33 :quant 1~e.25 :mod (o / only~e.24) :ARG1-of (m4 / mean-01 :ARG2 (i10 / isoform~e.33 :name (n6 / name :op1 "db"~e.27))) :ARG1-of i4))))))) :ARG1 (m5 / model~e.37 :ARG1-of (u / useful-05~e.36 :ARG2~e.38 (d / determine-01~e.39 :ARG1 (f / function-01 :ARG0 (i5 / isoform~e.47 :mod p7) :mod (p8 / physiology~e.41) :location (t / tissue~e.50 :mod (v / various~e.49))))))) # ::id bio.chicago_2015.80768 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Linkage and association of tumor necrosis factor receptor 2 locus with hypertension , hypercholesterolemia and plasma shed receptor . # ::alignments 0-1.1 1-1 1-1.1.2 2-1.2 3-1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1.1.1.2 6-1.1.1.1.1.1.3 7-1.1.1.1.1.1.4 8-1.1.1.1.1.1.5 9-1.1.1 10-1.1.2.r 11-1.1.2.1 13-1.1.2.2 14-1.1.2 15-1.1.2.3.2 16-1.1.2.3.1.1 17-1.1.2.3.1.2 (a / and~e.1 :op1 (l / link-01~e.0 :ARG1~e.3 (l2 / locus~e.9 :ARG0-of (c / contain-01 :ARG1 (p / protein :name (n / name :op1 "tumor"~e.4 :op2 "necrosis"~e.5 :op3 "factor"~e.6 :op4 "receptor"~e.7 :op5 2~e.8)))) :ARG2~e.10 (a3 / and~e.1,14 :op1 (h / hypertension~e.11) :op2 (h2 / hypercholesterolemia~e.13) :op3 (p2 / protein :name (n2 / name :op1 "shed"~e.16 :op2 "receptor"~e.17) :mod (p3 / plasma~e.15)))) :op2 (a2 / associate-01~e.2 :ARG1 l2 :ARG2 a3)) # ::id bio.chicago_2015.80775 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , little is known about how chronic hypoxia and @/@ or pulmonary hypertension affect PDE expression and activity . # ::alignments 0-1 2-1.1.1.2 4-1.1 6-1.1.1.1.r 7-1.1.1.1.1.1.1 8-1.1.1.1.1.1 9-1.1.1.1.1 11-1.1.1.1.1 13-1.1.1.1.1.2 14-1.1.1.1 15-1.1.1.1.2.1.1.1.1 16-1.1.1.1.2.1 17-1.1.1.1.2 18-1.1.1.1.2.2 (h / have-concession-91~e.0 :ARG1 (k / know-01~e.4 :ARG1 (t / thing :manner-of~e.6 (a / affect-01~e.14 :ARG0 (a2 / and-or~e.9,11 :op1 (h2 / hypoxia~e.8 :mod (c / chronic~e.7)) :op2 (h3 / hypertension~e.13 :mod (l2 / lung))) :ARG1 (a3 / and~e.17 :op1 (e / express-03~e.16 :ARG2 (e2 / enzyme :name (n / name :op1 "PDE"~e.15))) :op2 (a4 / activity-06~e.18 :ARG0 e2))) :degree (l / little~e.2)))) # ::id bio.chicago_2015.80886 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Association between schizophrenia and T102C polymorphism of the 5 @-@ hydroxytryptamine type 2a @-@ receptor gene . # ::alignments 0-1 2-1.1 4-1.2.1.2.1 5-1.2 8-1.2.1.1.1.1.1 10-1.2.1.1.1.1.1 11-1.2.1.1.1.1.2 12-1.2.1.1.1.1.3 14-1.2.1.1.1.1.3 15-1.2.1 (a / associate-01~e.0 :ARG1 (s / schizophrenia~e.2) :ARG2 (p / polymorphism~e.5 :mod (g / gene~e.15 :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n / name :op1 "5-hydroxytryptamine"~e.8,10 :op2 "type"~e.11 :op3 "2a-receptor"~e.12,14))) :ARG1-of (m / mutate-01 :value "T102C"~e.4)))) # ::id bio.chicago_2015.80961 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PPL in the NIDDM group resulted in the production of TG rich lipoproteins , with AUC for TG content of HDL , LDL and VLDL being significantly greater in the NIDDM group than controls ( Table 3 ) . # ::alignments 4-1.1.1.3 5-1.1 6-1.1.2.r 8-1.1.2 11-1.1.2.1.3 12-1.1.2.1.2.1 12-1.2.1.1.1.2.1 12-1.2.1.1.2.2.1 12-1.2.1.1.3.2.1 18-1.2.1 23-1.2.1.1 26-1.2.3.2 27-1.2.3 27-1.2.3.1 27-1.2.3.1.r 31-1.2.3.3 32-1.2.3.4.r 33-1.2.3.4 35-1.3.1 36-1.3.1.1 (a3 / and :op1 (r / result-01~e.5 :ARG1 (d4 / disease :wiki - :name (n8 / name :op1 "postprandial" :op2 "lipaemia") :location (g2 / group~e.4 :mod (d / disease :wiki "Diabetes_mellitus_type_2" :name (n / name :op1 "diabetes" :op2 "mellitus" :op3 "type" :op4 2)))) :ARG2~e.6 (p / produce-01~e.8 :ARG1 (p2 / protein :wiki "Lipoprotein" :name (n3 / name :op1 "lipoprotein"~e.12) :mod (r2 / rich~e.11 :topic (s / small-molecule :wiki "Triglyceride" :name (n4 / name :op1 "triglyceride")))))) :op2 (h / have-03 :ARG0 (c2 / contain-01~e.18 :ARG0 (a2 / and~e.23 :op1 (p3 / protein :wiki "Lipoprotein" :name (n5 / name :op1 "lipoprotein"~e.12) :mod (d2 / density :ARG1-of (h2 / high-02))) :op2 (p4 / protein :wiki "Lipoprotein" :name (n6 / name :op1 "lipoprotein"~e.12) :mod (d5 / density :ARG1-of (l / low-04))) :op3 (p5 / protein :wiki "Lipoprotein" :name (n7 / name :op1 "lipoprotein"~e.12) :mod (d6 / density :ARG1-of (l2 / low-04 :degree (v / very))))) :ARG1 s) :ARG1 (a / area :location (u / under :op1 (c / curve))) :mod (g3 / great~e.27 :degree~e.27 (m2 / more~e.27) :ARG1-of (s2 / significant-02~e.26) :location g2~e.31 :compared-to~e.32 (c3 / control~e.33))) :ARG1-of (d3 / describe-01 :ARG0 (t / table~e.35 :mod 3~e.36))) # ::id bio.chicago_2015.81024 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine this point , tetanic stimulation of the CF in current clamp mode was applied twice with a 5 min interval ( Figure 3 ) . # ::alignments 1-1.2 2-1.2.1.1 3-1.2.1 3-1.2.r 5-1.1.2 6-1.1 10-1.1.3.r 11-1.1.3.1.1 12-1.1.3.1 13-1.1.3 15-1 16-1.4.1 16-1.4.r 19-1.4.2.1.1 20-1.4.2.1.2 21-1.4.2 23-1.3.1 24-1.3.1.1 (a / apply-02~e.15 :ARG1 (s / stimulate-01~e.6 :ARG1 (f2 / fiber :ARG0-of (c4 / climb-01)) :mod (t / tetanic~e.5) :manner~e.10 (m / mode~e.13 :mod (c2 / clamp-01~e.12 :ARG1 (c3 / current~e.11)))) :purpose~e.3 (e / examine-01~e.1 :ARG1 (p / point~e.3 :mod (t3 / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod 3~e.24)) :frequency~e.16 (r / rate-entity-91 :ARG1 (t4 / twice~e.16) :ARG3 (i / interval~e.21 :duration (t2 / temporal-quantity :quant 5~e.19 :unit (m2 / minute~e.20))))) # ::id bio.chicago_2015.81034 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In fact , our results indicate that DNA derived from the sputum of patients with cystic fibrosis initiates an inflammatory response in the lower respiratory tract . # ::alignments 0-1.3 1-1.3 3-1.1.1 3-1.1.1.r 4-1.1 4-1.1.2 4-1.1.2.r 5-1 6-1.2.r 7-1.2.1.1.1 8-1.2.1.2 9-1.2.1.2.1.r 11-1.2.1.2.1 12-1.2.1.2.1.1.r 13-1.2.1.2.1.1.1.1 15-1.2.1.2.1.1.2.1.1.1 16-1.2.1.2.1.1.2.1.1.2 17-1.2 19-1.2.2.1 20-1.2.2 21-1.2.3.r 21-1.3 23-1.2.3.1 23-1.2.3.1.1 23-1.2.3.1.1.r 25-1.2.3 (i / indicate-01~e.5 :ARG0 (t / thing~e.4 :poss~e.3 (w / we~e.3) :ARG2-of~e.4 (r / result-01~e.4)) :ARG1~e.6 (i2 / initiate-01~e.17 :ARG0 (n3 / nucleic-acid :name (n4 / name :op1 "DNA"~e.7) :ARG1-of (d / derive-01~e.8 :ARG2~e.9 (s / sputum~e.11 :poss~e.12 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.13)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :name (n5 / name :op1 "cystic"~e.15 :op2 "fibrosis"~e.16))))))) :ARG1 (r2 / respond-01~e.20 :ARG2 (i3 / inflame-01~e.19)) :location~e.21 (t2 / tract~e.25 :ARG1-of (l / low-04~e.23 :degree~e.23 (m / more~e.23)) :ARG0-of (r3 / respire-01))) :mod (i4 / in-fact~e.0,1,21)) # ::id bio.chicago_2015.81265 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After exclusion of subjects who were being treated for hypertension , hypercholesterolemia , or diabetes , substitution of SBP , HDL and LDL cholesterol , and blood glucose levels for hypertension , hypercholesterolemia , and diabetes , respectively , yielded very close results . # ::alignments 0-1.3 1-1.3.1 2-1.3.1.1.r 3-1.3.1.1.1 3-1.3.1.1.2 3-1.3.1.1.3 7-1.3.1.1.1.1 7-1.3.1.1.2.1 7-1.3.1.1.3.1 9-1.1.1.2 11-1.1.2.2 13-1.3.1.1 14-1.1.3.2.1.1 16-1.1.1 16-1.1.2 16-1.1.3 20-1.1.2.1.1.1.1 21-1.1.2.1 22-1.1.2.1.2.1.1 23-1.1.2.1.2.1.2 25-1.1 26-1.1.3.1.1.2 27-1.1.3.1.1.1.1 28-1.1.3.1 30-1.1.1.2 32-1.1.2.2 34-1.1 35-1.1.3.2.1.1 37-1.1.4 37-1.1.4.r 39-1 40-1.2.2.1 41-1.2.2 42-1.2 42-1.2.1 42-1.2.1.r (y / yield-01~e.39 :ARG0 (a / and~e.25,34 :op1 (s / substitute-01~e.16 :ARG1 (p / pressure-01 :ARG0 b :mod (s11 / systole)) :ARG2 (h / hypertension~e.9,30)) :op2 (s3 / substitute-01~e.16 :ARG1 (a2 / and~e.21 :op1 (s4 / small-molecule :name (n2 / name :op1 "HDL"~e.20 :op2 "cholesterol")) :op2 (s5 / small-molecule :name (n3 / name :op1 "LDL"~e.22 :op2 "cholesterol"~e.23))) :ARG2 (h2 / hypercholesterolemia~e.11,32)) :op3 (s6 / substitute-01~e.16 :ARG1 (l3 / level~e.28 :quant-of (s7 / small-molecule :name (n5 / name :op1 "glucose"~e.27) :mod (b / blood~e.26))) :ARG2 (d / disease :name (n / name :op1 "diabetes"~e.14,35))) :manner~e.37 (r2 / respective~e.37)) :ARG1 (t / thing~e.42 :ARG2-of~e.42 (r / result-01~e.42) :ARG1-of (c / close-10~e.41 :degree (v / very~e.40))) :time (a3 / after~e.0 :op1 (e / exclude-01~e.1 :ARG1~e.2 (o / or~e.13 :op1 (s8 / subject~e.3 :ARG1-of (t2 / treat-03~e.7 :ARG2 h)) :op2 (s9 / subject~e.3 :ARG1-of (t3 / treat-03~e.7 :ARG2 h2)) :op3 (s10 / subject~e.3 :ARG1-of (t4 / treat-03~e.7 :ARG2 d)))))) # ::id bio.chicago_2015.81467 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin @-@ 8 gene expression in a human bronchial epithelial cell line . # ::alignments 0-1.1.1.1 1-1.1.1.2 4-1.1.2.1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.1.1.2.r 8-1.1.2.1.1.2 10-1.1.2.1.1.2.1.1.1.1 11-1.1.2.1.1.2.1.1.1.2 12-1 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1 16-1.2.1 17-1.2 18-1.2.2.r 20-1.2.2.1.1.1 21-1.2.2.1.1 22-1.2.2.1 23-1.2.2 24-1.2.2 (i / induce-01~e.12 :ARG0 (e / enzyme :name (n / name :op1 "neutrophil"~e.0 :op2 "elastase"~e.1) :location (f / fluid~e.6 :ARG0-of (l / line-01~e.5 :ARG1 (e2 / epithelium~e.4 :ARG0-of (r / respire-01) :part-of~e.7 (i2 / individual~e.8 :ARG0-of (h / have-03 :ARG1 (d / disease :name (n2 / name :op1 "cystic"~e.10 :op2 "fibrosis"~e.11)))))))) :ARG2 (e3 / express-03~e.17 :ARG1 (g / gene~e.16 :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "interleukin-8"~e.13,15)))) :ARG3~e.18 (c / cell-line~e.23,24 :part-of (e5 / epithelium~e.22 :part-of (b / bronchus~e.21 :mod (h2 / human~e.20)))))) # ::id bio.chicago_2015.81509 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hypertension Associated with Decreased Testosterone Levels in Natriuretic Peptide Receptor @-@ A Gene @-@ Knockout and Gene @-@ Duplicated Mutant Mouse Models . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 4-1.2.2.1.1 5-1.2 6-1.3.r 7-1.3.1.1.1.1.1.1.1 8-1.3.1.1.1.1.1.1.2 9-1.3.1.1.1.1.1.1.3 11-1.3.1.1.1.1.1.1.3 12-1.3.1.1.1 14-1.3.1.1.1.2 15-1.3 16-1.3.1.1.1 16-1.3.2.1.2 18-1.3.2.1.2.1 19-1.3.2.1.1 20-1.3.1.1 20-1.3.2.1 21-1.3.1 21-1.3.2 (a / associate-01~e.1 :ARG1 (h / hypertension~e.0) :ARG2~e.2 (l / level~e.5 :ARG1-of (d / decrease-01~e.3) :quant-of (s / small-molecule :name (n / name :op1 "testosterone"~e.4))) :location~e.6 (a2 / and~e.15 :op1 (m / model~e.21 :mod (m5 / mouse~e.20 :mod (g / gene~e.12,16 :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "natriuretic"~e.7 :op2 "peptide"~e.8 :op3 "receptor-A"~e.9,11))) :ARG1-of (k / knock-out-03~e.14)) :ARG1-of m4)) :op2 (m2 / model~e.21 :mod (m3 / mouse~e.20 :ARG2-of (m4 / mutate-01~e.19) :mod (g3 / gene~e.16 :ARG1-of (d2 / duplicate-01~e.18)))))) # ::id bio.chicago_2015.81555 ::amr-annotator SDL-AMR-09 ::preferred # ::tok APL modulation of spontaneous diabetes in NOD mice . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.2 4-1.2.1.1 7-1.3 (m / modulate-01~e.1 :ARG0 (p / protein :name (n / name :op1 "APL"~e.0)) :ARG1~e.2 (d2 / disease :name (n2 / name :op1 "diabetes"~e.4) :mod (s / spontaneous~e.3)) :location (m2 / mouse~e.7 :mod (o / obese :polarity -) :mod d2)) # ::id bio.chicago_2015.81850 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Refractory hypertension is associated with the haptoglobin 2 @-@ 2 phenotype . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 6-1.2.1.1.1 7-1.2.1.1.2 9-1.2.1.1.2 10-1.2 (a / associate-01~e.3 :ARG1 (h / hypertension~e.1 :mod (r / refractory~e.0)) :ARG2~e.4 (p / phenotype~e.10 :mod (p2 / protein :name (n / name :op1 "haptoglobin"~e.6 :op2 "2-2"~e.7,9)))) # ::id bio.chicago_2015.81979 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 14 Studies in men revealed a dose @-@ dependent vasodilation of forearm arterioles in healthy subjects as well as in patients with essential hypertension , which was inhibited by the NOS inhibitor L @-@ NMMA . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2 4-1 6-1.2.2.1 8-1.2.2 11-1.2.1.1 12-1.2.1 13-1.3.r 14-1.3.1.1 15-1.3.1 16-1.3 17-1.3 18-1.3 20-1.3.2.1.1 22-1.3.2.2.1.1 23-1.3.2.2.1 27-1.2.3 27-1.2.3.1.2 28-1.2.3.1.r 30-1.2.3.1.2.1.1.1 31-1.2.3.1.2 32-1.2.3.1.1.1 34-1.2.3.1.1.1 (r / reveal-01~e.4 :ARG0 (s / study-01~e.1 :quant 14~e.0 :ARG1~e.2 (m / man~e.3)) :ARG1 (d3 / dilate-01 :ARG1 (a / arteriole~e.12 :part-of (f / forearm~e.11)) :ARG0-of (d / depend-01~e.8 :ARG1 (d2 / dose-01~e.6)) :ARG1-of (i / inhibit-01~e.27 :ARG0~e.28 (s3 / small-molecule :name (n / name :op1 "L-NMMA"~e.32,34) :ARG0-of (i2 / inhibit-01~e.27,31 :ARG1 (e2 / enzyme :name (n2 / name :op1 "NOS"~e.30)))))) :location~e.13 (a2 / and~e.16,17,18 :op1 (s2 / subject~e.15 :mod (h / healthy~e.14)) :op2 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.20)) :ARG0-of (h3 / have-03 :ARG1 (h4 / hypertension~e.23 :mod (e / essential~e.22)))))) # ::id bio.chicago_2015.82087 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Subgroup analysis on men showed a significant association of tPA and diabetes , smoking , hypertension , BMI , cholesterol , and apoA @-@ I in multivariate conditional logistic regression , whereas no significant association could be shown when PAI @-@ 1 , vWF , TM , or DHEAS was included in the model ( data not shown ) . # ::alignments 0-1.1.1.1.1 1-1.1.1 3-1.1.1.1 4-1.1 6-1.1.2.3 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.1 10-1.1.2.2 11-1.1.2.2.1.1.1 13-1.1.2.2.2 15-1.1.2.2.3 19-1.1.2.2.5.1.1 21-1.1.2.2 22-1.1.2.2.6.1.1 24-1.1.2.2.6.1.1 26-1.1.3.3 28-1.1.3.1 31-1 32-1.2.1 32-1.2.1.r 33-1.2.2.1.1 34-1.2.2.1 35-1.2 37-1.2.2 38-1.2.3.r 39-1.2.3.1.1.1.1 41-1.2.3.1.1.1.1 43-1.2.3.1.2.1.1 45-1.2.3.1.3.1.1 47-1.2.3.1 48-1.2.3.1.4.1.1 50-1.2.3 51-1.2.3.2.r 53-1.2.3.2 55-1.3.1 56-1.3.1.1.1 56-1.3.1.1.1.r 57-1.3.1.1 (c / contrast-01~e.31 :ARG1 (s / show-01~e.4 :ARG0 (a / analyze-01~e.1 :ARG1 (m / man~e.3 :mod (s2 / subgroup~e.0))) :ARG1 (a2 / associate-01~e.7 :ARG1~e.8 (e / enzyme :name (n / name :op1 "tPA"~e.9)) :ARG2 (a3 / and~e.10,21 :op1 (d4 / disease :name (n8 / name :op1 "diabetes"~e.11)) :op2 (s4 / smoke-02~e.13) :op3 (h / hypertension~e.15) :op4 (i2 / index-01 :ARG1 (m4 / mass :mod (b2 / body))) :op5 (s5 / small-molecule :name (n2 / name :op1 "cholesterol"~e.19)) :op6 (p2 / protein :name (n3 / name :op1 "apoA-I"~e.22,24))) :ARG1-of (s3 / significant-02~e.6)) :condition (r / regress-01 :mod (l / logistic~e.28) :mod (c2 / condition) :mod (m2 / multivariate~e.26))) :ARG2 (p / possible-01~e.35 :polarity~e.32 -~e.32 :ARG1 (s6 / show-01~e.37 :ARG1 (a4 / associate-01~e.34 :ARG1-of (s7 / significant-02~e.33))) :time~e.38 (i / include-01~e.50 :ARG1 (o / or~e.47 :op1 (p3 / protein :name (n4 / name :op1 "PAI-1"~e.39,41)) :op2 (p4 / protein :name (n5 / name :op1 "vWF"~e.43)) :op3 (p5 / protein :name (n6 / name :op1 "TM"~e.45)) :op4 (s8 / small-molecule :name (n7 / name :op1 "DHEAS"~e.48))) :ARG2~e.51 (m3 / model~e.53))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.55 :ARG1-of (s9 / show-01~e.57 :polarity~e.56 -~e.56)))) # ::id bio.chicago_2015.82191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The observation that the hypophosphorylated CUG @-@ BP/ hNab50 form ( CUG @-@ BP2 ) was accumulated in the nuclei of patients with DM ( containing low levels of DMPK ) suggested that DMPK activity may be required for CUG @-@ BP/ hNab50 phosphorylation . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.2.3 5-1.1.1.2.1.1 5-1.1.1.2.2.1.1 8-1.1.1.2.1.1 11-1.1.1.2.1.1 11-1.1.1.2.2.1.1 13-1.1.1.2.2.1.1 16-1.1.1 17-1.1.1.1.r 19-1.1.1.1 20-1.1.1.1.1.r 21-1.1.1.1.1.1.1 25-1.1.1.1.2 26-1.1.1.1.2.1.1 27-1.1.1.1.2.1 28-1.1.1.1.2.1.2.r 29-1.1.1.1.2.1.2.1.1 31-1 32-1.2.r 33-1.2.1.2.1 34-1.2.1.2 35-1.2 37-1.2.1 38-1.2.1.1.r 39-1.2.1.1.1 40-1.2.1.1.1 41-1.2.1.1.1 42-1.2.1.1.1 43-1.2.1.1 (s / suggest-01~e.31 :ARG0 (o / observe-01~e.1 :ARG1~e.2 (a / accumulate-01~e.16 :ARG0~e.17 (n2 / nucleus~e.19 :poss~e.20 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.21)) :ARG0-of (h2 / have-03 :ARG1 (d / dystrophy :mod (m / myotonic)))) :ARG0-of (c2 / contain-01~e.25 :ARG1 (l2 / level~e.27 :ARG1-of (l3 / low-04~e.26) :quant-of~e.28 (e / enzyme :name (n3 / name :op1 "DMPK"~e.29))))) :ARG1 (p2 / protein :name (n / name :op1 "CUG-BP/hNab50"~e.5,8,11) :ARG1-of (l / label-01 :ARG2 (n5 / name :op1 "CUG-BP2"~e.5,11,13)) :ARG1-of (h3 / hypophosphorylate-00~e.4)))) :ARG1~e.32 (p5 / possible-01~e.35 :ARG1 (r / require-01~e.37 :ARG0~e.38 (p / phosphorylate-01~e.43 :ARG1 p2~e.39,40,41,42) :ARG1 (a2 / activity-06~e.34 :ARG0 e~e.33)))) # ::id bio.chicago_2015.82428 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of A peptides terminating at 42( 43 ) , species that foster A deposition . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.3 4-1.2 5-1.2.2.r 7-1.2.2 8-1.2.2.1.r 9-1.2.2.1.1 10-1.2.2.1 13-1.2.2.1.2.1.3 14-1.2.2.1.2.1 14-1.2.2.1.2.1.2 14-1.2.2.1.2.1.2.r 15-1.2.2.1.2.1.1.1 16-1.2.2.1.2 18-1.2.2.1.3.r 20-1.2.2.1.3 22-1.2.2.1.3.2.2 23-1.2.2.1.3.2 24-1.2.2.1.3.2.1.r 26-1.2.2.1.3.2.1.1.2 27-1.2.2.1.3.2.1.2 30-1.2.2.1.3.3.1.1.1 33-1.2.2.1.3.2.1.3 35-1.2.2.1.3.2.1.3.1 37-1.2.2.1.3.2.1.3.1.1 (p / provide-01~e.2 :ARG0 (s / study-01~e.1 :mod (t / this~e.0)) :ARG1 (s2 / support-01~e.4 :ARG0 s :ARG1~e.5 (v / view-02~e.7 :ARG1~e.8 (m / mechanism~e.10 :quant 1~e.9 :instrument-of (c2 / cause-01~e.16 :ARG0 (p2 / protein~e.14 :name (n / name :op1 "PS1"~e.15) :ARG1-of~e.14 (m2 / mutate-01~e.14) :mod t~e.13) :ARG1 (d2 / disease :wiki "Alzheimer's_disease" :name (n3 / name :op1 "Alzheimer's"))) :domain~e.18 (i / increase-01~e.20 :ARG0 p2 :ARG1 (c3 / concentrate-02~e.23 :ARG1~e.24 (p3 / protein-segment :name (n2 / name :op1 "Abeta" :op2 "peptide"~e.26) :ARG1-of (t2 / terminate-01~e.27 :location (a2 / amino-acid :mod 42)) :mod (s3 / species~e.33 :ARG0-of (f / foster-01~e.35 :ARG1 (d / depose-03~e.37 :ARG1 p3)))) :mod (e / extracellular~e.22)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 43~e.30)))))) :ARG0-of (c / compel-01~e.3))) # ::id bio.chicago_2015.83036 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation of the beta @-@ amyloid precursor protein in familial Alzheimer 's disease increases beta @-@ protein production . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1.2 7-1.1.1 8-1.1.2.r 9-1.1.2.3 10-1.1.2.2.1 12-1.1.2 13-1 14-1.2.1.1.1 16-1.2.1 17-1.2 (i / increase-01~e.13 :ARG0 (m / mutate-01~e.0 :ARG1~e.1 (p / protein~e.7 :name (n2 / name :op1 "beta-amyloid"~e.3,5 :op2 "precursor"~e.6)) :location~e.8 (d / disease~e.12 :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"~e.10) :mod (f / family~e.9))) :ARG1 (p2 / produce-01~e.17 :ARG1 (p3 / protein~e.16 :name (n4 / name :op1 "beta"~e.14)))) # ::id bio.chicago_2015.83072 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Wnt/{ beta}-Catenin/ cf Signaling Induces the Transcription of Axin2 , a Negative Regulator of the Signaling Pathway . # ::alignments 3-1.1 4-1 6-1.2 7-1.2.1.r 8-1.2.1.1.1 11-1.2.1 11-1.2.1.2 11-1.2.1.2.r 12-1.2.1 12-1.2.1.2 12-1.2.1.2.r 15-1.1 16-1.1.1 (i / induce-01~e.4 :ARG0 (s / signal-07~e.3,15 :ARG0 (p / pathway~e.16 :name (n / name :op1 "Wnt/beta-catenin/Tcf"))) :ARG2 (t / transcribe-01~e.6 :ARG1~e.7 (p2 / protein~e.11,12 :name (n2 / name :op1 "Axin2"~e.8) :ARG2-of~e.11,12 (d / downregulate-01~e.11,12 :ARG1 p)))) # ::id bio.chicago_2015.83176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Insulin @-@ dependent diabetes mellitus ( IDDM ) is associated with CTLA4 polymorphisms in multiple ethnic groups . # ::alignments 0-1.1.3.1.1.1 2-1.1 2-1.1.3 2-1.1.3.r 3-1.1.1.1 4-1.1.2 6-1.1.4.1.1 9-1 10-1.2.r 11-1.2.1.1.1 12-1.2 13-1.3.r 14-1.3.1 15-1.3 16-1.3 (a / associate-01~e.9 :ARG1 (d3 / disease~e.2 :name (n2 / name :op1 "diabetes"~e.3) :mod (m / mellitus~e.4) :ARG0-of~e.2 (d2 / depend-01~e.2 :ARG1 (p3 / protein :name (n3 / name :op1 "insulin"~e.0))) :ARG1-of (l / label-01 :ARG2 (n4 / name :op1 "IDDM"~e.6))) :ARG2~e.10 (p / polymorphism~e.12 :mod (p2 / protein :name (n / name :op1 "CTLA4"~e.11))) :location~e.13 (e2 / ethnic-group~e.15,16 :mod (m2 / multiple~e.14))) # ::id bio.chicago_2015.83187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the underlying mechanisms remain unknown , based on our results that A , an AD @-@ related molecule , upregulated SCD @-@ 1 in macrophages , it can be considered that there is a link between SCD @-@ 1 and AD . # ::alignments 0-1 2-1.2.1.1 3-1.2.1 4-1.2 5-1.2.2 5-1.2.2.1 5-1.2.2.1.r 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.2 9-1.1.2.1.2.r 10-1.1.2.1 10-1.1.2.1.1 10-1.1.2.1.1.r 17-1.1.2.1.3.2.2 20-1.1.2.1.3 21-1.1.1.1.1.1.1 23-1.1.1.1.1.1.1 24-1.1.2.1.3.3.r 25-1.1.2.1.3.3 27-1.1.2.1.3.1 28-1.1 30-1.1.1 35-1.1.1.1 37-1.1.1.1.1.1.1 39-1.1.1.1.1.1.1 (h / have-concession-91~e.0 :ARG1 (p / possible-01~e.28 :ARG1 (c / consider-01~e.30 :ARG1 (l / link-01~e.35 :ARG1 (p2 / protein :name (n / name :op1 "SCD-1"~e.21,23,37,39)) :ARG2 (d / disease :wiki "Alzheimer's_disease" :name (n3 / name :op1 "Alzheimer's")))) :ARG1-of (b / base-02~e.7 :ARG2~e.8 (t / thing~e.10 :ARG2-of~e.10 (r2 / result-01~e.10) :poss~e.9 (w / we~e.9) :topic (u2 / upregulate-01~e.20 :ARG1 p2~e.27 :ARG2 (p3 / protein :name (n2 / name :op1 "Abeta") :ARG1-of (r3 / relate-01~e.17 :ARG2 d)) :location~e.24 (m2 / macrophage~e.25))))) :ARG2 (r / remain-01~e.4 :ARG1 (m / mechanism~e.3 :ARG0-of (u / underlie-01~e.2)) :ARG3 (k / know-01~e.5 :polarity~e.5 -~e.5 :ARG1 m))) # ::id bio.chicago_2015.83472 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The column , absorbed with bc1 complexes , was then subjected to a sequence of washings with TN buffer ( 50 mM Tris @-@ Cl ( pH 8.0 at 4 degrees C ) and 200 mM NaCl ) containing 0.01 % DM , TN buffer containing 5 mM histidine and 0.01 % DM , and TN buffer containing 5 mM histidine and 0.5 % octyl glucoside . # ::alignments 1-1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.1 9-1.3 10-1 11-1.2.r 13-1.2 15-1.2.1.1 15-1.2.1.2 15-1.2.1.3 16-1.2.1.2.2.r 17-1.2.1.2.2.1 18-1.2.1.2.2 20-1.2.1.2.2.1 21-1.2.1.2.2.1 22-1.2.1.2.2.1 23-1.2.1.2.2.1 24-1.2.1.2.2.1 25-1.2.1.2.2.1 26-1.2.1.2.2.1 27-1.2.1.2.2.1 28-1.2.1.2.2.1 29-1.2.1.2.2.1 30-1.2.1.2.2.1 31-1.2.1.2.2.1 32-1.2.1.2.2.1 33-1.2.1.2.2.1 34-1.2.1.2.2.1 35-1.2.1.1.2.1.2.2.2.2 38-1.2.1.2.2.2 39-1.2.1.1.2.2.1.2.1 40-1.2.1.1.2.2.1.2 41-1.2.1.1.2.2.1.1.1 43-1.2.1.1.2.1.1.1 44-1.2.1.1.2 44-1.2.1.2.2 45-1.2.1.1.2.2 45-1.2.1.2.2.2 46-1.2.1.2.2.2.1.1.2.1 47-1.2.1.1.2.1.2.1.2.2 48-1.2.1.2.2.2.1.1.1.1 49-1.2.1.1.2.1.2 49-1.2.1.2.2.2.1 50-1.2.1.1.2.2.1.2.1 51-1.2.1.1.2.2.1.2 52-1.2.1.1.2.2.1.1.1 54-1.2.1.1.2.1.2 55-1.2.1.1.2.1.1.1 56-1.2.1.1.2 56-1.2.1.3.2 57-1.2.1.1.2.2 57-1.2.1.3.2.2 58-1.2.1.2.2.2.1.1.2.1 59-1.2.1.2.2.2.1.1.2.2 60-1.2.1.3.2.2.1.1 61-1.2.1.1.2.1.2 61-1.2.1.2.2.2.1 62-1.2.1.3.2.2.1.2.2.1 63-1.2.1.3.2.2.1.2.2 64-1.2.1.3.2.2.1.2.1.1 65-1.2.1.3.2.2.1.2.1.2 (s / subject-01~e.10 :ARG1 (c / column~e.1 :ARG0-of (a2 / absorb-01~e.3 :ARG1~e.4 (m4 / macro-molecular-complex~e.6 :name (n2 / name :op1 "bc1"~e.5)))) :ARG2~e.11 (s2 / sequence~e.13 :consist-of (a3 / and :op1 (w / wash-01~e.15 :ARG1 c :ARG2 (b / buffer~e.44,56 :mod (s3 / small-molecule :name (n3 / name :op1 "TN"~e.43,55) :consist-of (a4 / and~e.49,54,61 :op1 (s5 / small-molecule :name (n / name :op1 "tris(hydroxymethyl)aminomethane") :quant (c3 / concentration-quantity :quant 50 :unit (m5 / millimolar~e.47)) :mod (a5 / acidity-quantity :quant 8.0 :scale (p4 / ph)) :mod (t / temperature-quantity :quant 4 :scale (c5 / celsius))) :op2 (s6 / small-molecule :name (n5 / name :op1 "sodium" :op2 "chloride") :quant (c4 / concentration-quantity :quant 200 :unit m5~e.35)))) :ARG0-of (c2 / contain-01~e.45,57 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "DM"~e.41,52) :quant (p2 / percentage-entity~e.40,51 :value 0.01~e.39,50))))) :op2 (w2 / wash-01~e.15 :ARG1 c :ARG2~e.16 (b2 / buffer~e.18,44 :mod s3~e.17,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34 :ARG0-of (c6 / contain-01~e.38,45 :ARG1 (a6 / and~e.49,61 :op1 (a7 / amino-acid :name (n7 / name :op1 "histidine"~e.48) :quant (c8 / concentration-quantity :quant 5~e.46,58 :unit m5~e.59)) :op2 s4)))) :op3 (w3 / wash-01~e.15 :ARG1 c :ARG2 (b3 / buffer~e.56 :mod s3 :ARG0-of (c7 / contain-01~e.57 :ARG1 (a8 / and :op1 a7~e.60 :op2 (s7 / small-molecule :name (n8 / name :op1 "octyl"~e.64 :op2 "glucoside"~e.65) :quant (p5 / percentage-entity~e.63 :value 0.5~e.62)))))))) :time (t2 / then~e.9)) # ::id bio.chicago_2015.83519 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus . # ::alignments 0-1.3 1-1.4.1 1-1.4.1.1 1-1.4.1.1.r 2-1.4 3-1.2.1.1 4-1 7-1.1.r 9-1.1.1.1.1.1.1.1.1 10-1.1.1.1.1.1.1.1.2 11-1.1.1.1.1 12-1.1.1.1 13-1.5 14-1.5.1.r 15-1.5.1.3 16-1.5.1.3.1 17-1.5.1.1.1 18-1.5.1.2 (s / secrete-01~e.4 :ARG0~e.7 (p2 / person :ARG0-of (c / carry-01 :ARG1 (v / vary-01~e.12 :ARG1 (g / gene~e.11 :ARG0-of (e / encode-01 :ARG1 (p3 / protein :name (n / name :op1 "sulphonylurea"~e.9 :op2 "receptor"~e.10))))))) :ARG1 (p4 / protein :name (n2 / name :op1 "insulin"~e.3)) :ARG1-of (r / reduce-01~e.0) :time (p / phase~e.2 :ord (o2 / ordinal-entity~e.1 :value~e.1 2~e.1)) :ARG1-of (a / associate-01~e.13 :ARG2~e.14 (d2 / disease :name (n3 / name :op1 "diabetes"~e.17) :mod (m / mellitus~e.18) :mod (t / type~e.15 :ord o2~e.16)))) # ::id bio.chicago_2015.83813 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In humans , insulin @-@ receptor mutations cause diabetes rather than longevity ; however , these mutations lead ultimately to a severe loss of insulin production and so may not mimic the weak signalling mutations of C. elegans . # ::alignments 1-1.2.3 3-1.2.1.1.1.1 5-1.2.1.1.1.2 6-1.2.1 7-1.2 8-1.2.2 9-1.2.2.1 11-1.2.2.1.1 13-1 16-1.1.1.1 17-1.1.1 18-1.1.1.3 19-1.1.1.2.r 21-1.1.1.2.2 22-1.1.1.2 23-1.1.1.2.1.r 24-1.1.1.2.1.1.1.1 25-1.1.1.2.1 26-1.1 26-1.1.2.2 27-1.1.2.2 28-1.1.2 29-1.1.2.1.1 29-1.1.2.1.1.r 30-1.1.2.1 32-1.1.2.1.3.2 33-1.1.2.1.3.3 34-1.1.2.1.3 (h / have-concession-91~e.13 :ARG1 (a / and~e.26 :op1 (l2 / lead-03~e.17 :ARG0 m~e.16 :ARG2~e.19 (l3 / lose-01~e.22 :ARG1~e.23 (p2 / produce-01~e.25 :ARG1 (p4 / protein :name (n3 / name :op1 "insulin"~e.24))) :ARG2 (s / severe~e.21)) :time (u / ultimate~e.18)) :op2 (p3 / possible-01~e.28 :ARG1 (m2 / mimic-01~e.30 :polarity~e.29 -~e.29 :ARG0 m :ARG1 (m3 / mutate-01~e.34 :ARG1 (o / organism :name (n2 / name :op1 "C" :op2 "elegan")) :ARG1-of (w / weak-02~e.32) :ARG0-of (s2 / signal-07~e.33))) :ARG1-of (c2 / cause-01~e.26,27 :ARG0 l3))) :ARG2 (c / cause-01~e.7 :ARG0 (m / mutate-01~e.6 :ARG1 (p / protein :name (n / name :op1 "insulin"~e.3 :op2 "receptor"~e.5))) :ARG1 (d2 / diabetes~e.8 :ARG1-of (i / instead-of-91~e.9 :ARG2 (l / longevity~e.11))) :location (h2 / human~e.1))) # ::id bio.chicago_2015.83846 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We conclude that lack of HNF @-@ 6 results in diabetes . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.1.1 7-1.2.1.1.1.1 8-1.2 9-1.2.2.r 10-1.2.2.1.1 (c / conclude-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (r / result-01~e.8 :ARG1 (l / lack-01~e.3 :ARG1~e.4 (p / protein :name (n / name :op1 "HNF-6"~e.5,7))) :ARG2~e.9 (d2 / disease :name (n2 / name :op1 "diabetes"~e.10)))) # ::id bio.chicago_2015.83848 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Early @-@ onset type @-@ II diabetes mellitus ( MODY4 ) linked to IPF @-@ 1 . # ::alignments 0-1.1.3.1 2-1.1.3 3-1.1.4 5-1.1.4.1.1 6-1.1.1.1 7-1.1.2 9-1.1.5.1.1 11-1 12-1.2.r 13-1.2.1.1 15-1.2.1.1 (l / link-01~e.11 :ARG1 (d2 / disease :name (n2 / name :op1 "diabetes"~e.6) :mod (m / mellitus~e.7) :mod (o / onset~e.2 :time (e / early~e.0)) :mod (t / type~e.3 :ord (o2 / ordinal-entity :value 2~e.5)) :ARG1-of (l2 / label-01 :ARG2 (n3 / name :op1 "MODY4"~e.9))) :ARG2~e.12 (p / protein :name (n / name :op1 "IPF-1"~e.13,15))) # ::id bio.chicago_2015.84036 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two Novel Mutations of the Vasopressin Gene Associated with Familial Diabetes Insipidus and Identification of an Asymptomatic Carrier Infant . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 3-1.1.2.r 5-1.1.2.1.1.1.1 6-1.1.2 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2.1.1.2 12-1.2 13-1.2.2 14-1.2.2.1.r 16-1.2.2.1.1 16-1.2.2.1.1.1 16-1.2.2.1.1.1.r 17-1.2.2.1.2 18-1.2.2.1 (a / associate-01~e.7 :ARG1 (m / mutate-01~e.2 :quant 2~e.0 :ARG1~e.3 (g / gene~e.6 :ARG0-of (e / encode-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "vasopressin"~e.5)))) :mod (n / novel~e.1)) :ARG2~e.8 (a2 / and~e.12 :op1 (d / disease :name (n4 / name :op1 "familial"~e.9 :op2 "diabetes"~e.10)) :op2 (i2 / identify-01~e.13 :ARG1~e.14 (i3 / infant~e.18 :mod (s2 / symptom~e.16 :polarity~e.16 -~e.16) :mod (c / carrier~e.17 :mod m))))) # ::id bio.chicago_2015.84144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Confirmation of the genetic association of interleukin @-@ 1A with early onset sporadic Alzheimer 's disease . # ::alignments 0-1 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.1.1.1.1 9-1.1.2.r 10-1.1.2.3.1 11-1.1.2.3 12-1.1.2.4 13-1.1.2.2.1 15-1.1.2 (c / confirm-01~e.0 :ARG1 (a / associate-01~e.4 :ARG1~e.5 (p / protein :name (n2 / name :op1 "interleukin-1A"~e.6,8)) :ARG2~e.9 (d / disease~e.15 :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"~e.13) :mod (o / onset~e.11 :time (e / early~e.10)) :mod (s / sporadic~e.12)) :mod (g / gene))) # ::id bio.chicago_2015.84177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Specifically , LTD was induced by low @-@ frequency pairing of CF and PF activity , while PF @-@ mediated Ca2+ signals were measured following high @-@ frequency PF activity . # ::alignments 0-1.3 4-1.1 5-1.1.1.r 6-1.1.1.3.1 8-1.1.1.3 9-1.1.1 14-1.1.1.1 14-1.1.1.2 16-1 19-1.2.1.2 21-1.2.1 23-1.2 24-1.2.2 25-1.2.2.1.2.1 27-1.2.2.1.2 29-1.2.2.1 (c2 / contrast-01~e.16 :ARG1 (i2 / induce-01~e.4 :ARG0~e.5 (p / pair-01~e.9 :ARG1 (a / activity-06~e.14 :ARG0 (f4 / fiber :ARG0-of (c / climb-01))) :ARG2 (a2 / activity-06~e.14 :ARG0 (f5 / fiber :mod (p3 / parallel))) :mod (f / frequency~e.8 :ARG1-of (l2 / low-04~e.6))) :ARG2 (d / depress-01 :ARG1 (s4 / synapse) :duration (t / term :ARG1-of (l3 / long-03)))) :ARG2 (m / measure-01~e.23 :ARG1 (s / signal-07~e.21 :ARG0 (s2 / small-molecule :name (n / name :op1 "calcium") :ARG1-of (i / ionize-01 :value "2+")) :ARG1-of (m2 / mediate-01~e.19 :ARG0 f5)) :ARG1-of (f2 / follow-01~e.24 :ARG2 (a3 / activity-06~e.29 :ARG0 f5 :mod (f3 / frequency~e.27 :ARG1-of (h / high-02~e.25))))) :ARG1-of (s3 / specific-02~e.0)) # ::id bio.chicago_2015.84183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci . # ::alignments 1-1.1 3-1.1.1.1.1.1 5-1.1.2.r 6-1.1.2.1.1 7-1 9-1.2.3 10-1.2 11-1.2.1.r 12-1.2.1.2 13-1.2.1.2.1.1 14-1.2.1.1.1 15-1.2.2.r 16-1.2.2.1.1.1.1 17-1.2.2 18-1.2.2.2.1.1.1 (s / suggest-01~e.7 :ARG0 (d / distribute-01~e.1 :ARG1 (h / haplotype :mod (p / protein :name (n / name :op1 "DR4"~e.3))) :location~e.5 (c / country-region :name (n2 / name :op1 "Sardinia"~e.6))) :ARG1 (a / associate-01~e.10 :ARG1~e.11 (d3 / disease :name (n5 / name :op1 "diabetes"~e.14) :mod (t / type~e.12 :ord (o / ordinal-entity :value 1~e.13))) :ARG2~e.15 (a2 / and~e.17 :op1 (l / locus :mod (g / gene :name (n3 / name :op1 "DRB1"~e.16))) :op2 (l2 / locus :mod (g2 / gene :name (n4 / name :op1 "DQB1"~e.18)))) :mod (p2 / primary~e.9))) # ::id bio.chicago_2015.84212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The identification of APP , PS1 , and PS2 mutations associated with hereditary Alzheimer 's disease [ 34 ] has increased our understanding of its molecular basis [ 32 ] . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1.1 5-1.1.1.1.2.1.1 7-1.1.1.1 8-1.1.1.1.3.1.1 9-1.1.1 10-1.1.1.2 11-1.1.1.2.1.r 12-1.1.1.2.1.3 13-1.1.1.2.1.2.1 15-1.1.1.2.1 17-1.1.1.2.2.1.1.1 20-1 21-1.2.1 21-1.2.1.r 22-1.2 23-1.2.2.r 24-1.2.2.2 24-1.2.2.2.r 25-1.2.2.1 26-1.2.2 28-1.3.1.1.1 (i / increase-01~e.20 :ARG0 (i2 / identify-01~e.1 :ARG1~e.2 (m / mutate-01~e.9 :ARG1 (a / and~e.7 :op1 (p3 / protein :name (n2 / name :op1 "APP"~e.3)) :op2 (p4 / protein :name (n3 / name :op1 "PS1"~e.5)) :op3 (p5 / protein :name (n4 / name :op1 "PS2"~e.8))) :ARG1-of (a2 / associate-01~e.10 :ARG2~e.11 (d / disease~e.15 :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"~e.13) :mod (h / hereditary~e.12)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 34~e.17)))))) :ARG1 (u / understand-01~e.22 :ARG0~e.21 (w / we~e.21) :ARG1~e.23 (b / basis~e.26 :mod (m2 / molecule~e.25) :poss~e.24 d~e.24)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 32~e.28)))) # ::id bio.chicago_2015.84243 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No association between DLST gene and Alzheimer s disease or Wernicke - Korsakoff syndrome . # ::alignments 0-1.1 0-1.1.r 1-1 3-1.2.1.1 4-1.2 6-1.3.1.2.1 8-1.3.1 8-1.3.2 9-1.3 10-1.3.2.1.1 13-1.3.2.1.2 (a / associate-01~e.1 :polarity~e.0 -~e.0 :ARG1 (g / gene~e.4 :name (n2 / name :op1 "DLST"~e.3)) :ARG2 (o / or~e.9 :op1 (d / disease~e.8 :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"~e.6)) :op2 (d2 / disease~e.8 :name (n3 / name :op1 "Wernicke-Kirsakoff"~e.10 :op2 "syndrome"~e.13)))) # ::id bio.chicago_2015.84567 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta @-@ cell dysfunction in the Mody mouse . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.1.1 5-1.1.1.1.2 6-1.1.1 7-1 8-1.2.1.1 10-1.1.2.1.3 11-1.1.2.1.2.2 12-1.1.2.1.2.1.1 14-1.1.2.1.2.1.1 18-1.1.2.1.4.1.1 19-1.1.2.1.4.1.2 (i / induce-01~e.7 :ARG0 (m / mutate-01~e.1 :ARG1~e.2 (g / gene~e.6 :name (n / name :op1 "insulin"~e.4 :op2 2~e.5)) :ARG0-of (c / cause-01 :ARG1 (f / function-01 :polarity - :ARG1 (c2 / cell :name (n3 / name :op1 "beta-cell"~e.12,14) :mod (p / pancreas~e.11)) :degree (s / severe~e.10) :location (o / organism :name (n4 / name :op1 "Mody"~e.18 :op2 "mouse"~e.19))))) :ARG2 (d / disease :name (n2 / name :op1 "diabetes"~e.8))) # ::id bio.chicago_2015.84636 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The ob gene and leptin Recessive mutations in the mouse obese ( ob ) and diabetes ( db ) genes result in obesity and diabetes in a syndrome resembling morbid human obesity 3 , 7 . # ::alignments 1-1.1.1.1.1 2-1.2.1.1.1 3-1.1 4-1.1.2.1.1 6-1.2.1 7-1.2.1.1.r 9-1.2.1.1.2.1 12-1.1.1.1.1 14-1.2.1.1 15-1.2.1.1.2.2 19-1.2.1.1.2 20-1.2 21-1.2.2.r 22-1.2.2.1.1.1 23-1.2.2 24-1.2.2.2.1.1 27-1.2.2.3.1 28-1.2.2.3.1.1 29-1.2.2.3.1.1.1.3 30-1.2.2.3.1.1.1.2 31-1.2.2.1.1.1 31-1.2.2.3.1.1.1.1.1 32-1.2.3.1.1.1.1 34-1.2.3.1.1.1.2 (m3 / multi-sentence :snt1 (a3 / and~e.3 :op1 (g / gene :name (n / name :op1 "ob"~e.1,12)) :op2 (p2 / protein :name (n3 / name :op1 "leptin"~e.4))) :snt2 (r / result-01~e.20 :ARG1 (m / mutate-01~e.6 :ARG1~e.7 (a2 / and~e.14 :op1 (g3 / gene~e.2 :mod m2 :mod m6) :op2 (g2 / gene~e.19 :mod (m2 / mouse~e.9) :mod d2~e.15)) :ARG0-of (r2 / recede-01)) :ARG2~e.21 (a / and~e.23 :op1 (m6 / medical-condition :name (n5 / name :op1 "obesity"~e.22,31)) :op2 (d2 / disease :name (n6 / name :op1 "diabetes"~e.24)) :ARG1-of (m4 / mean-01 :ARG2 (s2 / syndrome~e.27 :ARG1-of (r3 / resemble-01~e.28 :ARG2 (m7 / medical-condition :name (n7 / name :op1 "obesity"~e.31) :mod (h / human~e.30) :mod (m5 / morbid~e.29)))))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 3~e.32 :op2 7~e.34)))))) # ::id bio.chicago_2015.84698 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lane 1 , GST @-@ Grb2 ; lane 2 , GST only ; lane 3 , GST @-@ neuron isoform ( containing exons AD ) ; and lane 4 , GST @-@ astrocyte isoform ( containing exons BD ) . # ::alignments 0-1.1.1 1-1.1.1.1 3-1.1.2.1.1 5-1.1.3.1.1 7-1.2.3 8-1.2.3.1 10-1.2.1.1 11-1.2.2 13-1.3.3 14-1.3.3.1 16-1.3.1.1 18-1.3.1.1 19-1.3 21-1.3.2 23-1.3.2.1.1.1 26-1 27-1.4.3 28-1.4.3.1 30-1.4.1.1 32-1.4.1.1 33-1.4 35-1.4.2 37-1.4.2.1.1.1 (a / and~e.26 :op1 (m / macro-molecular-complex :location (l / lane~e.0 :mod 1~e.1) :part (e2 / enzyme :name (n / name :op1 "GST"~e.3)) :part (p / protein :name (n3 / name :op1 "Grb2"~e.5))) :op2 (e / enzyme :name (n2 / name :op1 "GST"~e.10) :mod (o / only~e.11) :location (l2 / lane~e.7 :mod 2~e.8)) :op3 (i / isoform~e.19 :name (n4 / name :op1 "GST-neuron"~e.16,18) :ARG0-of (c / contain-01~e.21 :ARG1 (e3 / exon :name (n5 / name :op1 "AD"~e.23))) :location (l3 / lane~e.13 :mod 3~e.14)) :op4 (i2 / isoform~e.33 :name (n6 / name :op1 "GST-astrocyte"~e.30,32) :ARG0-of (c2 / contain-01~e.35 :ARG1 (e4 / exon :name (n7 / name :op1 "BD"~e.37))) :location (l4 / lane~e.27 :mod 4~e.28))) # ::id bio.chicago_2015.84741 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A P387L Variant in Protein Tyrosine Phosphatase @-@ 1B ( PTP @-@ 1B ) Is Associated With Type 2 Diabetes and Impaired Serine Phosphorylation of PTP @-@ 1B In Vitro . # ::alignments 1-1.1.1.1 3-1.2.2.3 4-1.1 4-1.1.2 4-1.1.2.r 5-1.1.2.1.1 6-1.1.2.1.2 8-1.1.2.1.2 12-1.1.2.1.2 15-1 16-1.2.r 17-1.2.1.2.1 18-1.2.1.2.2 19-1.2.1.2.3 20-1.2 21-1.2.2.2 22-1.2.2.1.1.1 23-1.2.2 27-1.1.2.1.2 28-1.2.2.3 29-1.2.2.3 (a2 / associate-01~e.15 :ARG1 (p3 / protein-segment~e.4 :name (n4 / name :op1 "P387L"~e.1) :part-of~e.4 (p2 / protein~e.4 :name (n3 / name :op1 "Tyrosine"~e.5 :op2 "Phosphatase-1B"~e.6,8,12,27))) :ARG2~e.16 (a3 / and~e.20 :op1 (d / disease :wiki "Diabetes_mellitus_type_2" :name (n / name :op1 "type"~e.17 :op2 2~e.18 :op3 "diabetes"~e.19)) :op2 (p / phosphorylate-01~e.23 :ARG1 (a / amino-acid :name (n2 / name :op1 "serine"~e.22) :part-of p2) :ARG1-of (i / impair-01~e.21) :manner (i2 / in-vitro~e.3,28,29)))) # ::id bio.chicago_2015.85035 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dominant negative mutations in human PPARgamma associated with severe insulin resistance , diabetes mellitus and hypertension . # ::alignments 0-1.1.3 2-1.1 3-1.1.2.r 4-1.1.2.2 5-1.1.2.1.1 6-1 7-1.2.r 8-1.2.1.2 9-1.2.1.1 10-1.2.1 12-1.2.2.1.1 13-1.2.2.1.2 14-1.2 15-1.2.3 (a / associate-01~e.6 :ARG1 (m / mutate-01~e.2 :mod "-/-" :ARG1~e.3 (p / protein :name (n / name :op1 "PPARgamma"~e.5) :mod (h / human~e.4)) :ARG0-of (d / dominate-01~e.0)) :ARG2~e.7 (a2 / and~e.14 :op1 (r / resist-01~e.10 :ARG1 (i / insulin~e.9) :degree (s / severe~e.8)) :op2 (d2 / disease :name (n3 / name :op1 "diabetes"~e.12 :op2 "mellitus"~e.13)) :op3 (h2 / hypertension~e.15))) # ::id bio.chicago_2015.85089 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the genes induced by TNF @-@ alpha , secreted VCAM @-@ 1 , fibronectin , tenascin C , ceruloplasmin , PAI @-@ 1 , and adrenomedullin have been associated with type 2 diabetes or an excessive rate of cardiovascular diseases ( 51 - 53 ) . # ::alignments 0-1.1.7 2-1.1.7.1 3-1.1.7.1.1 4-1.1.7.1.1.1.r 5-1.1.7.1.1.1.1.1 7-1.1.7.1.1.1.1.1 9-1.1.1.2 10-1.1.1.1.1 12-1.1.1.1.1 12-1.1.6.1.1 14-1.1.2.1.1 16-1.1.4.1.1 17-1.1.4.1.2 19-1.1.5.1.1 21-1.1.6.1.1 23-1.1.1.1.1 23-1.1.6.1.1 25-1.1 26-1.1.3.1.1 29-1 30-1.2.r 31-1.2.1.2.1 32-1.2.1.2.2 33-1.2.1.2.3 34-1.2 36-1.2.2.1 37-1.2.2 38-1.2.2.2.r 39-1.2.2.2.1 40-1.2.2.2 42-1.3.1.1.1.1 44-1.3.1.1.1.2 (a / associate-01~e.29 :ARG1 (a2 / and~e.25 :op1 (g / gene :name (n2 / name :op1 "VCAM-1"~e.10,12,23) :ARG1-of (s / secrete-01~e.9)) :op2 (g2 / gene :name (n3 / name :op1 "fibronectin"~e.14)) :op2 (g6 / gene :name (n7 / name :op1 "adrenomedullin"~e.26)) :op3 (g3 / gene :name (n4 / name :op1 "tenascin"~e.16 :op2 "C"~e.17)) :op4 (g4 / gene :name (n5 / name :op1 "ceruloplasmin"~e.19)) :op5 (g5 / gene :name (n6 / name :op1 "PAI-1"~e.12,21,23)) :ARG1-of (i / include-91~e.0 :ARG2 (g7 / gene~e.2 :ARG2-of (i2 / induce-01~e.3 :ARG0~e.4 (p / protein :name (n8 / name :op1 "TNF-alpha"~e.5,7)))))) :ARG2~e.30 (o / or~e.34 :op1 (d / disease :wiki "Diabetes_mellitus_type_2" :name (n / name :op1 "type"~e.31 :op2 2~e.32 :op3 "diabetes"~e.33)) :op2 (r / rate~e.37 :ARG1-of (e / excessive-02~e.36) :mod~e.38 (d2 / disease~e.40 :mod (c2 / cardiovascular~e.39)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 51~e.42 :op2 53~e.44))))) # ::id bio.chicago_2015.85434 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The findings that both SR @-@ A and SR @-@ BI are expressed by monocytes and macrophages from adult mice and humans , 1 , 7 @- 9 by microglia from newborn mice , 36 and Bell et al 13 , but not by adult mouse or human microglia , and that SR @-@ A , but not SR @-@ BI , is expressed on microglia associated with senile plaques in AD brains , 2 , 3 indicate that microglia can regulate SR @-@ A and SR @-@ BI expression by independent mechanisms . # ::alignments 1-1.1 4-1.1.1.1.1.1.1.1 4-1.1.1.1.1.2.1.1 6-1.1.1.1.1.1.1.1 8-1.1.1.1.1.1.1.1 8-1.1.1.1.1.2.1.1 10-1.1.1.1.1.2.1.1 12-1.1.1.1 12-1.1.1.3 12-1.2.1.2 13-1.1.1.1.2.r 14-1.1.1.1.2.1.1.1 16-1.1.1.1.2.2.1.1 17-1.1.1.1.2.3.r 18-1.1.1.1.2.3.1.1 19-1.1.1.1.2.3.1 20-1.1.1.1.2.3 21-1.1.1.1.2.3.2 23-1.1.1.1.3.1.1.1.1 25-1.1.1.1.3.1.1.1.2.1 27-1.1.1.1.3.1.1.1.2.2 28-1.1.1.3.2.r 29-1.1.1.3.2.1.1 30-1.1.1.2.2.2.r 30-1.1.1.2.4.1.1.2.r 31-1.1.1.2.2.2.1 32-1.1.1.2.2.2 34-1.1.1.2.3.1.1.1.1 35-1.1.1.2.3.1 35-1.1.1.2.3.1.2.1 36-1.1.1.2.3.1.2.1.1.1.1 37-1.1.1.2.3.1.2.1 38-1.1.1.2.3.1.2.1.2.1 39-1.1.1.2.3.1.2.2.1 41-1.1.1.2.4 41-1.1.1.3.4 42-1.1.1.3.4.1.1.r 44-1.1.1.1.2.3.1.1 45-1.1.1.1.2.3.1 47-1.1.1.1.2.3.2 48-1.1.1.2.2.1.1 48-1.1.1.2.4.1.1.1.1 48-1.1.1.3.2.1.1 50-1.1.1.1.2.3 50-1.1.1.2.3.1 52-1.1.1.2.1 53-1.1.1.2.1 54-1.1.1.2.1 56-1.1.1.2.4 57-1.1.1.3.4.1.1.r 58-1.1.1.2.1 59-1.1.1.2.1 60-1.1.1.2.1 63-1.1.1.2 63-1.1.1.2.4.1 65-1.1.1.3.2.1.1 66-1.1.1.3.2.2 67-1.1.1.3.2.2.1.r 67-1.2.1.3.r 68-1.1.1.3.2.2.1.1 69-1.1.1.3.2.2.1 72-1.1.1.3.2.2.1.2 74-1.1.1.3.3.1.1.1.1 76-1.1.1.3.3.1.1.1.2 77-1 79-1.1.1.3.2.1.1 80-1.2 81-1.2.1 82-1.1.1.1.1.1.1.1 82-1.1.1.1.1.2.1.1 84-1.1.1.1.1.1.1.1 86-1.1.1.1.1.1.1.1 86-1.1.1.1.1.2.1.1 88-1.1.1.1.1.2.1.1 89-1.1.1.3.4.1 91-1.1.1.3.4.1.1 91-1.2.1.3.1 91-1.2.1.3.1.1 91-1.2.1.3.1.1.r 92-1.2.1.3 (i / indicate-01~e.77 :ARG0 (f / find-01~e.1 :ARG1 (a / and :op1 (e / express-03~e.12 :ARG2 (a3 / and :op1 (p / protein :name (n3 / name :op1 "SR-A"~e.4,6,8,82,84,86)) :op2 (p2 / protein :name (n4 / name :op1 "SR-BI"~e.4,8,10,82,86,88))) :ARG3~e.13 (a2 / and :op1 (c / cell :name (n / name :op1 "monocytes"~e.14)) :op2 (c2 / cell :name (n2 / name :op1 "macrophages"~e.16)) :source~e.17 (a5 / and~e.20,50 :op1 (m / mouse~e.19,45 :mod (a4 / adult~e.18,44)) :op2 (h / human~e.21,47))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 1~e.23 :op2 (v / value-interval :op1 7~e.25 :op2 9~e.27)))))) :op2 (e2 / express-03~e.63 :ARG2 a3~e.52,53,54,58,59,60 :ARG3 (c4 / cell :name (n5 / name :op1 "microglia"~e.48) :source~e.30 (m2 / mouse~e.32 :mod (n6 / newborn~e.31))) :ARG1-of (d2 / describe-01 :ARG0 (a7 / and~e.35,50 :op1 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 36~e.34)) :op2 (p5 / publication-91 :ARG0 (a8 / and~e.35,37 :op1 (p6 / person :name (n7 / name :op1 "Bell"~e.36)) :op2 (p7 / person :mod (o / other~e.38))) :ARG1-of (c6 / cite-01 :ARG2 13~e.39)))) :ARG1-of (c7 / contrast-01~e.41,56 :ARG2 (e3 / express-03~e.63 :ARG1 (c8 / cell :name (n8 / name :op1 "microglia"~e.48) :source~e.30 a5)))) :op3 (e4 / express-03~e.12 :ARG2 p :ARG3~e.28 (c9 / cell :name (n9 / name :op1 "microglia"~e.29,48,65,79) :ARG1-of (a9 / associate-01~e.66 :ARG2~e.67 (p8 / plaque~e.69 :mod (s / senile~e.68) :location (b2 / brain~e.72 :mod (d3 / disease :wiki "Alzheimer's_disease" :name (n10 / name :op1 "Alzheimer's")))))) :ARG1-of (d4 / describe-01 :ARG0 (p9 / publication :ARG1-of (c10 / cite-01 :ARG2 (a10 / and :op1 2~e.74 :op2 3~e.76)))) :ARG1-of (c11 / contrast-01~e.41 :ARG2 (e6 / express-03~e.89 :polarity~e.42,57 -~e.91 :ARG2 p2))))) :ARG1 (p10 / possible-01~e.80 :ARG1 (r / regulate-01~e.81 :ARG0 c4 :ARG1 (e5 / express-03~e.12 :ARG2 a3) :instrument~e.67 (m3 / mechanism~e.92 :ARG0-of (d5 / depend-01~e.91 :polarity~e.91 -~e.91))))) # ::id bio.chicago_2015.85464 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Localization of P. aeruginosa and beads in transported and stationary ASL ( mucus ) produced by planar CF cultures . # ::alignments 0-1 3-1.1.1.1.2 4-1.1 5-1.1.2 7-1.1.3.3 9-1.1.3.2 12-1.1.3.1.1 14-1.1.3.4 15-1.1.3.4.1.r 16-1.1.3.4.1.1 18-1.1.3.4.1 (l / localize-01~e.0 :ARG1 (a / and~e.4 :op1 (o / organism :name (n / name :op1 "Pseudomonas" :op2 "aeruginosa"~e.3)) :op2 (b / bead~e.5) :location (l2 / liquid :ARG1-of (m / mean-01 :ARG2 (m2 / mucus~e.12)) :mod (s / stationary~e.9) :ARG1-of (t2 / transport-01~e.7) :ARG1-of (p / produce-01~e.14 :ARG0~e.15 (c / culture~e.18 :mod (p2 / planar~e.16) :mod (d / disease :name (n3 / name :op1 "cystic" :op2 "fibrosis")))) :mod (s2 / surface :part-of (a2 / airway))))) # ::id bio.chicago_2015.85539 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here we show that mab @-@ 23 encodes a DM ( Doublesex/ MAB @-@ 3 ) domain transcription factor necessary for specific aspects of differentiation in sex @-@ specific tissues of the male . # ::alignments 0-1.3 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1 4-1.2.2.1.1 6-1.2.1.1.1 7-1.2 12-1.2.1.1.1 12-1.2.2.1.1 14-1.2.2.1.1 17-1.2.2.1.2 18-1.2.2.1.3 19-1.2.2 19-1.2.2.2 19-1.2.2.2.r 20-1.2.2.2.1.r 21-1.2.2.2.1.1 22-1.2.2.2.1 23-1.2.2.2.1.1.1.r 24-1.2.2.2.1.1.1 25-1.2.2.2.1.1.1.1.r 26-1.2.2.2.1.1.1.1.1.1 28-1.2.2.2.1.1.1.1.1 29-1.2.2.2.1.1.1.1 30-1.2.2.2.1.1.1.1.2.r 32-1.2.2.2.1.1.1.1.2 (s / show-01~e.2 :ARG0 (w / we~e.1) :ARG1~e.3 (e / encode-01~e.7 :ARG0 (g / gene :name (n2 / name :op1 "mab-23"~e.4,6,12)) :ARG1 (p / protein-segment~e.19 :name (n4 / name :op1 "doublesex/mab-3"~e.4,12,14 :op2 "transcription"~e.17 :op3 "factor"~e.18) :ARG1-of~e.19 (n / need-01~e.19 :ARG0~e.20 (a / aspect~e.22 :ARG1-of (s2 / specific-02~e.21 :ARG2~e.23 (d / differentiate-101~e.24 :ARG1~e.25 (t / tissue~e.29 :ARG1-of (s3 / specific-02~e.28 :ARG2 (s4 / sex~e.26)) :poss~e.30 (m / male~e.32)))))))) :location (h / here~e.0)) # ::id bio.chicago_2015.85555 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We then used the radiometric technique to test the hypothesis that P. aeruginosa in CF sputum produces acyl @-@ HSL signals . # ::alignments 0-1.1 0-1.3.1 1-1.4 2-1 4-1.2.1 5-1.2 7-1.3 9-1.3.2 10-1.3.2.2.r 11-1.3.2.2.1.1.1 12-1.3.2.2.1.1.2 15-1.3.2.2.1.2 16-1.3.2.2 17-1.3.2.2.2.1.1.1 19-1.3.2.2.2.1.1.1 20-1.3.2.2.2 (u / use-01~e.2 :ARG0 (w / we~e.0) :ARG1 (t2 / technique~e.5 :mod (r / radiometric~e.4)) :ARG2 (t3 / test-01~e.7 :ARG0 (w2 / we~e.0) :ARG1 (h / hypothesize-01~e.9 :ARG0 w :ARG1~e.10 (p / produce-01~e.16 :ARG0 (o / organism :name (n / name :op1 "P."~e.11 :op2 "aeruginosa"~e.12) :location (s / sputum~e.15 :mod (d / disease :name (n2 / name :op1 "cystic" :op2 "fibrosis")))) :ARG1 (s2 / signal-07~e.20 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "acyl-HSL"~e.17,19)))))) :time (t / then~e.1)) # ::id bio.chicago_2015.85798 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , it is this stretch of amino acids in GRF2 that contains the PEST region and the DB . # ::alignments 0-1.3 4-1.1.2 5-1.1 6-1.1.1.r 7-1.1.1 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1.1.1 12-1 14-1.2.1.1.1 16-1.2 18-1.2.2.1.1 (c / contain-01~e.12 :ARG0 (s / stretch~e.5 :poss~e.6 (a / amino-acid~e.7,8 :part-of~e.9 (p / protein :name (n / name :op1 "GRF2"~e.10))) :mod (t / this~e.4)) :ARG1 (a2 / and~e.16 :op1 (p2 / protein-segment :name (n2 / name :op1 "PEST"~e.14)) :op2 (p3 / protein-segment :name (n3 / name :op1 "DB"~e.18))) :ARG2-of (i / interest-01~e.0)) # ::id bio.chicago_2015.85825 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Early @-@ onset type @-@ II diabetes mellitus ( MODY4 ) linked to IPF1 . # ::alignments 0-1.1.2 2-1.1 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1.2 7-1.1.1.1.3 11-1 12-1.2.r 13-1.2.1.1 (l / link-01~e.11 :ARG1 (o / onset~e.2 :poss (d / disease :name (n2 / name :op1 "type-II"~e.3,5 :op2 "diabetes"~e.6 :op3 "mellitus"~e.7)) :time (e / early~e.0)) :ARG2~e.12 (p / protein :name (n / name :op1 "IPF1"~e.13))) # ::id bio.chicago_2015.85926 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PGE2 @-@ induced sensitization of the HT MS channels was presumably mediated by the cAMP @-@ dependent protein kinase pathway , because the pretreatment of sensory neurons with H @-@ 89 ( 10 muM ) , a membrane @-@ permeable inhibitor of protein kinase A , completely blocked the sensitization of the channel by PGE2 ( Fig . 7 B , C ) . # ::alignments 1-1.2.2.1.1.1 3-1.2.2 4-1.2 9-1.2.1 11-1.3 12-1 13-1.1.r 15-1.1.1.1 17-1.1.1.1 18-1.1.1.2 19-1.1.1.3 20-1.1 22-1.4 24-1.4.1.1 25-1.4.1.1.1.r 26-1.4.1.1.1.1 27-1.4.1.1.1 28-1.4.1.1.2.r 29-1.4.1.1.2.1.1 31-1.4.1.1.2.1.1 33-1.4.1.1.2.2.1 38-1.4.1.1.2.4.1 40-1.4.1.1.2.4 41-1.4.1.1.2 41-1.4.1.1.2.3 41-1.4.1.1.2.3.r 42-1.4.1.1.2.3.1.r 43-1.4.1.1.2.3.1.1.1 44-1.4.1.1.2.3.1.1.2 45-1.4.1.1.2.3.1.1.3 47-1.4.1.3 48-1.4.1 50-1.4.1.2 51-1.4.1.2.2.r 53-1.4.1.2.2 55-1.2.2.1.1.1 57-1.5.1.1 57-1.5.1.2 (m / mediate-01~e.12 :ARG0~e.13 (p / pathway~e.20 :name (n / name :op1 "cAMP-dependent"~e.15,17 :op2 "protein"~e.18 :op3 "kinase"~e.19)) :ARG1 (s / sensitize-01~e.4 :ARG1 (c / channel~e.9 :mod (m2 / mechanosensitive) :mod (t2 / threshold :ARG1-of (h / high-02))) :ARG2-of (i2 / induce-01~e.3 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "PGE2"~e.1,55)))) :ARG1-of (p2 / presume-01~e.11) :ARG1-of (c2 / cause-01~e.22 :ARG0 (b / block-01~e.48 :ARG0 (p3 / pretreat-01~e.24 :ARG1~e.25 (n3 / neuron~e.27 :mod (s4 / sensory~e.26)) :ARG3~e.28 (s5 / small-molecule~e.41 :name (n4 / name :op1 "H-89"~e.29,31) :quant (c3 / concentration-quantity :quant 10~e.33 :unit (m3 / micromolar)) :ARG0-of~e.41 (i / inhibit-01~e.41 :ARG1~e.42 (e / enzyme :name (n5 / name :op1 "protein"~e.43 :op2 "kinase"~e.44 :op3 "A"~e.45))) :mod (p4 / permeable~e.40 :mod (m4 / membrane~e.38)))) :ARG1 (s3 / sensitize-01~e.50 :ARG0 s2 :ARG1~e.51 c~e.53) :ARG1-of (c4 / complete-02~e.47))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.57 :mod "7B") :op2 (f2 / figure~e.57 :mod "7C")))) # ::id bio.chicago_2015.86087 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Twenty @-@ three of the 33 sera contained antibodies against PcrV , a protein involved in translocation of type III cytotoxins into eukaryotic cells , and 11 of 33 had antibodies against ExoS , while most CF sera contained antibodies against PopB and PopD , components of the type III apparatus . # ::alignments 5-1.1.1.1.2.1.1 7-1.1.1 8-1.1.1.2 9-1.1.1.2.1 10-1.1.1.2.1.1.1.1 13-1.1.1.2.1.1 13-1.1.2.2.1.1 13-1.2.2.1.1.1 13-1.2.2.1.1.2 13-1.2.2.1.1.3.1 14-1.1.1.2.1.1.2 15-1.1.1.2.1.1.2.1.r 16-1.1.1.2.1.1.2.1 20-1.1.1.2.1.1.2.1.1 21-1.1.1.2.1.1.2.1.2.r 22-1.1.1.2.1.1.2.1.2.1 23-1.1.1.2.1.1.2.1.2 25-1.1 26-1.1.2.1.1 28-1.1.2.1.2 29-1.1.2 30-1.1.2.2 31-1.1.2.2.1 32-1.1.2.2.1.1.1.1 34-1 35-1.2.1.2 38-1.2 39-1.2.2 40-1.2.2.1 41-1.2.2.1.1.1.1.1 42-1.2.2.1.1 43-1.2.2.1.1.2.1.1 48-1.2.2.1.1.3.1.1.1 49-1.2.2.1.1.3.1.1.2 50-1.2.2.1.1.3.1.1.3 (c4 / contrast-01~e.34 :ARG1 (a2 / and~e.25 :op1 (c / contain-01~e.7 :ARG0 (s / serum :quant 23 :ARG1-of (i / include-91 :ARG2 (s2 / serum :quant 33~e.5))) :ARG1 (a / antibody~e.8 :ARG0-of (c2 / counter-01~e.9 :ARG1 (p / protein~e.13 :name (n / name :op1 "PcrV"~e.10) :ARG1-of (i2 / involve-01~e.14 :ARG2~e.15 (t / translocate-01~e.16 :ARG1 (c8 / cytotoxins~e.20) :ARG2~e.21 (c3 / cell~e.23 :mod (e / eukaryotic~e.22)))))))) :op2 (h / have-03~e.29 :ARG0 (s4 / serum :quant 11~e.26 :ARG1-of i~e.28) :ARG1 (a3 / antibody~e.30 :ARG0-of (c5 / counter-01~e.31 :ARG1 (p2 / protein~e.13 :name (n4 / name :op1 "ExoS"~e.32)))))) :ARG2 (c6 / contain-01~e.38 :ARG0 (s5 / serum :mod (d / disease :name (n5 / name :op1 "cystic" :op2 "fibrosis")) :quant (m / most~e.35)) :ARG1 (a4 / antibody~e.39 :ARG0-of (c7 / counter-01~e.40 :ARG1 (a5 / and~e.42 :op1 (p3 / protein~e.13 :name (n6 / name :op1 "PopB"~e.41)) :op2 (p4 / protein~e.13 :name (n7 / name :op1 "PopD"~e.43)) :ARG1-of (i3 / include-91 :ARG2 (p5 / protein-family~e.13 :name (n8 / name :op1 "type"~e.48 :op2 "III"~e.49 :op3 "apparatus"~e.50)))))))) # ::id bio.chicago_2015.86563 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interaction of Tau Isoforms with Alzheimer 's Disease Abnormally Hyperphosphorylated Tau and in Vitro Phosphorylation into the Disease -@ like Protein . # ::alignments 0-1.1.2 1-1.1.2.1.r 2-1.1.2.1.1 3-1.1.2.1 4-1.1.2.2.r 5-1.1.2.2.2.1 7-1.1.2.2 8-1.1.3 8-1.1.3.1 8-1.1.3.1.r 9-1.1 10-1.1.1.1.1 11-1 12-1.2.2 13-1.2.2 14-1.2 15-1.2.1.r 17-1.2.1.1.1 19-1.2.1.1 20-1.2.1 (a / and~e.11 :op1 (h / hyperphosphorylate-01~e.9 :ARG1 (p2 / protein :name (n4 / name :op1 "Tau"~e.10)) :ARG2 (i / interact-01~e.0 :ARG0~e.1 (i2 / isoform~e.3 :mod p2~e.2) :ARG1~e.4 (d / disease~e.7 :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"~e.5))) :ARG1-of (n3 / normal-02~e.8 :polarity~e.8 -~e.8)) :op2 (p / phosphorylate-01~e.14 :ARG1~e.15 (p3 / protein~e.20 :ARG1-of (r / resemble-01~e.19 :ARG2 d~e.17)) :manner (i3 / in-vitro~e.12,13))) # ::id bio.chicago_2015.87018 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Scopolamine has been used as a pharmacological tool for understanding pathological impairments such as AD , because it produces amnesiac effects similar to those identified in AD ( Sakhakian et al. , 1987 ) . # ::alignments 0-1.2.1.1.1 3-1.2 4-1.3.1.2.r 7-1.2.2 8-1.2.2.2.r 9-1.2.2.2 10-1.2.2.2.1.2 11-1.2.2.2.1 12-1.2.2.2.1.1.r 13-1.2.2.2.1.1.r 13-1.3.1.2.r 16-1 17-1.1.1 18-1.1 20-1.1.2 20-1.1.2.3.1 21-1.1.2.3 24-1.1.2.3.1.1 28-1.3.1.1.1.1.1 29-1.3.1.1 30-1.3.1.1.2.1 32-1.3.1.2.1 (c / cause-01~e.16 :ARG0 (p3 / produce-01~e.18 :ARG0 s~e.17 :ARG1 (a / affect-01~e.20 :ARG0 s :ARG2 (a2 / amnesia) :ARG1-of (r / resemble-01~e.21 :ARG2 (a3 / affect-01~e.20 :ARG1-of (i2 / identify-01~e.24 :location d2))))) :ARG1 (u / use-01~e.3 :ARG1 (s / small-molecule :name (n / name :op1 "scopolamine"~e.0)) :ARG2 (t / tool~e.7 :mod (p2 / pharmacologic) :purpose~e.8 (u2 / understand-01~e.9 :ARG1 (i / impair-01~e.11 :example~e.12,13 (d2 / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's")) :mod (p / pathology~e.10))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and~e.29 :op1 (p5 / person :name (n3 / name :op1 "Sakhakian"~e.28)) :op2 (p6 / person :mod (o / other~e.30))) :time~e.4,13 (d / date-entity :year 1987~e.32)))) # ::id bio.chicago_2015.87155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If the pancreas is allowed to develop with an intact pdx1 gene , and the pdx1 gene is disrupted only in mature beta cells , diabetes ensues due to impaired beta @-@ cell function ( 3 ) . # ::alignments 0-1 2-1.2.1.1.1 4-1.2.1 6-1.2.1.1 9-1.2.1.1.2.2.2 10-1.2.1.1.2.2.1.1 11-1.2.1.1.2.2 15-1.2.1.1.2.2.1.1 16-1.2.1.1.2.2 18-1.2.2 19-1.2.2.3 20-1.2.2.2.r 21-1.2.2.2.2 22-1.2.2.2.1.1 23-1.2.2.2 25-1.1.1.1.1 26-1.1 27-1.1.2 28-1.1.2 29-1.1.2.1.2 30-1.1.2.1.1.1.1 32-1.1.2.1.1 33-1.1.2.1 35-1.3.1.1.1 (h / have-condition-91~e.0 :ARG1 (e / ensue-01~e.26 :ARG1 (d3 / disease :name (n3 / name :op1 "diabetes"~e.25)) :ARG1-of (c2 / cause-01~e.27,28 :ARG0 (f / function-01~e.33 :ARG0 (c4 / cell~e.32 :name (n4 / name :op1 "beta"~e.30)) :ARG1-of (i2 / impair-01~e.29)))) :ARG2 (a2 / and :op1 (a / allow-01~e.4 :ARG1 (d / develop-02~e.6 :ARG1 (p / pancreas~e.2) :condition (h2 / have-03 :ARG0 p :ARG1 (g / gene~e.11,16 :name (n / name :op1 "pdx1"~e.10,15) :mod (i / intact~e.9))))) :op2 (d2 / disrupt-01~e.18 :ARG1 g :location~e.20 (c / cell~e.23 :name (n2 / name :op1 "beta"~e.22) :ARG1-of (m / mature-01~e.21)) :mod (o / only~e.19))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 3~e.35)))) # ::id bio.chicago_2015.87157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neurons in AD brains express fetal antigens , including the fetal type of tau antigen ( 112 ) , the A68 protein recognized by the monoclonal antibody ALZ @-@ 50 ( 113 ) , gangliosides recognized by the monoclonal antibody A2B5 ( 114 ) , and a fetal form of alpha @-@ tubulin . # ::alignments 0-1.2 3-1.2.1 4-1 5-1.1.1 6-1.1 8-1.1.2 10-1.1.2.1.1.2.1 11-1.1.2.1.1.2 12-1.1.2.1.1.2.r 13-1.1.2.1.1.1.1.1 14-1.1.2.1.1 16-1.1.2.1.1.3.1.1.1 20-1.1.2.1.2.1.1 21-1.1.2.1.1.1 21-1.1.2.1.2 21-1.1.2.1.4.2 22-1.1.2.1.2.2 25-1.1.2.1.2.2.1.2 26-1.1.2.1.2.2.1 27-1.1.2.1.2.2.1.1.1 29-1.1.2.1.2.2.1.1.1 31-1.1.2.1.2.3.1.1.1 35-1.1.2.1.2.2 35-1.1.2.1.3.2 38-1.1.2.1.2.2.1.2 39-1.1.2.1.2.2.1 39-1.1.2.1.3.2.1 40-1.1.2.1.3.2.1.1.1 42-1.1.2.1.3.3.1.1.1 45-1.1.2.1 47-1.1.2.1.4.1 48-1.1.2.1.4 50-1.1.2.1.4.2.1.1 52-1.1.2.1.4.2.1.1 (e / express-03~e.4 :ARG2 (a / antigen~e.6 :mod (f / fetus~e.5) :ARG2-of (i / include-01~e.8 :ARG1 (a2 / and~e.45 :op1 (a3 / antigen~e.14 :mod (p / protein~e.21 :name (n3 / name :op1 "tau"~e.13)) :mod~e.12 (t / type~e.11 :mod f~e.10) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 112~e.16)))) :op2 (p3 / protein~e.21 :name (n4 / name :op1 "A68"~e.20) :ARG1-of (r / recognize-01~e.22,35 :ARG0 (a4 / antibody~e.26,39 :name (n5 / name :op1 "ALZ-50"~e.27,29) :mod (m / monoclonal~e.25,38))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 113~e.31)))) :op3 (s / small-molecule :name (n6 / name :op1 "ganglioside") :ARG1-of (r2 / recognize-01~e.35 :ARG0 (a5 / antibody~e.39 :name (n7 / name :op1 "A2B5"~e.40) :mod m)) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 114~e.42)))) :op4 (f2 / form~e.48 :mod f~e.47 :poss (p6 / protein~e.21 :name (n8 / name :op1 "alpha-tubulin"~e.50,52)))))) :ARG3 (n / neuron~e.0 :part-of (b / brain~e.3 :mod (d / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's"))))) # ::id bio.chicago_2015.87198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To elucidate the role of C @-@ AD in a physiological situation , full @-@ length and C @-@ AD @-@ truncated NDRFs were analysed in the mouse IP3R1 promoter . # ::alignments 1-1.2 3-1.2.1 5-1.1.2.2.1.1.1 7-1.1.2.2.1.1.1 8-1.2.1.2.r 10-1.2.1.2.1 11-1.2.1.2 13-1.1.1.2.1 15-1.1.1.2 16-1.1 17-1.1.2.2.1.1.1 19-1.1.2.2.1.1.1 21-1.1.2.2 24-1 25-1.3.r 27-1.3.1.1.2 28-1.3.1.1.1.1 29-1.3 29-1.3.1 29-1.3.1.r (a / analyze-01~e.24 :ARG1 (a2 / and~e.16 :op1 (p / protein :name (n / name :op1 "NDRF") :mod (l / length~e.15 :ARG1-of (f / full-09~e.13))) :op2 (p2 / protein :name (n2 / name :op1 "NDRF") :ARG1-of (t / truncate-01~e.21 :ARG2 (p3 / protein-segment :name (n3 / name :op1 "C-AD"~e.5,7,17,19))))) :purpose (e / elucidate-01~e.1 :ARG1 (r / role~e.3 :ARG1-of (h / have-03 :ARG0 p3) :topic~e.8 (s / situation~e.11 :mod (p4 / physiology~e.10)))) :location~e.25 (m2 / molecular-physical-entity~e.29 :ARG0-of~e.29 (p5 / promote-01~e.29 :ARG1 (p6 / protein :name (n4 / name :op1 "IP3R1"~e.28) :mod (m / mouse~e.27))))) # ::id bio.chicago_2015.87332 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The major known genetic risk factor for late @-@ onset AD is the 4 allele of the apolipoprotein E ( ApoE ) gene ( ApoE4 ) ; however , at least half of the people who develop AD do not carry ApoE4 , and not all who carry ApoE4 develop AD . # ::alignments 1-1.1.3.1 2-1.1.3.3 3-1.1.3.2 4-1.1.3.4 5-1.1.3 6-1.1.3.4.1.r 7-1.1.3.4.1.1 9-1.1.3.4.1 11-1.1.3.r 13-1.1.1 14-1.1 17-1.1.2.1.1 18-1.1.2.1.2 22-1.1.2 22-1.2.1.1.3 24-1.2.1.1.3.1.1 27-1.2 29-1.2.1.1.2.1 30-1.2.1.1.2.1 31-1.2.1.1.2.1.1 32-1.2.1.1.2.1.r 34-1.2.1.1.2 34-1.2.1.1.2.2.1 34-1.2.1.2.2 36-1.2.1.1.2.2.1.1 39-1.2.1.1.1 39-1.2.1.1.1.r 39-1.2.1.2.1 40-1.2.1.1 40-1.2.1.2.2.2 41-1.2.1.1.3.1.1 43-1.2.1 44-1.2.1.2.1.r 45-1.2.1.2.2.1 47-1.2.1.1 48-1.2.1.1.3.1.1 49-1.2.1.2 (m / multi-sentence :snt1 (a2 / allele~e.14 :quant 4~e.13 :part-of (g / gene~e.22 :name (n / name :op1 "apolipoprotein"~e.17 :op2 "E"~e.18)) :domain~e.11 (f / factor~e.5 :ARG1-of (m2 / major-02~e.1) :mod (g2 / genetics~e.3) :ARG1-of (k / know-02~e.2) :mod (r / risk-01~e.4 :ARG2~e.6 (o / onset~e.9 :mod (l / late~e.7) :mod (d / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's")))))) :snt2 (h / have-concession-91~e.27 :ARG1 (a3 / and~e.43 :op1 (c / carry-01~e.40,47 :polarity~e.39 -~e.39 :ARG0 (p / person~e.34 :quant~e.32 (a / at-least~e.29,30 :op1 (h2 / half~e.31)) :ARG1-of (i / include-91 :ARG2 (p2 / person~e.34 :ARG0-of (d2 / develop-02~e.36 :ARG1 d4)))) :ARG1 (g3 / gene~e.22 :name (n3 / name :op1 "ApoE4"~e.24,41,48))) :op2 (d3 / develop-02~e.49 :polarity~e.44 -~e.39 :ARG0 (p4 / person~e.34 :mod (a4 / all~e.45) :ARG0-of (c2 / carry-01~e.40 :ARG1 g3)) :ARG1 (d4 / disease :wiki "Alzheimer's_disease" :name (n4 / name :op1 "Alzheimer's")))))) # ::id bio.chicago_2015.87380 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , AD patients have increased serum levels of TNF and IL @-@ 6 have been established in [ 20 and 47 ] . # ::alignments 0-1.2.3 1-1.3 4-1.1.1.1 5-1 5-1.1.1 6-1.2.2 7-1.2.1 8-1.2 9-1.2.3.r 10-1.2.3.1.1.1 11-1.2.3 12-1.2.3.2.1.1 14-1.2.3.2.1.1 17-1.2.4 20-1.4.1.1.1.1 21-1.4.1.1.1 22-1.4.1.1.1.2 (h / have-03~e.5 :ARG0 (p / person :ARG0-of (h2 / have-org-role-91~e.5 :ARG2 (p2 / patient~e.4)) :mod (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer's"))) :ARG1 (l / level~e.8 :mod (s / serum~e.7) :ARG1-of (i / increase-01~e.6) :quant-of~e.9 (a / and~e.0,11 :op1 (p3 / protein :name (n2 / name :op1 "TNF"~e.10)) :op2 (p4 / protein :name (n3 / name :op1 "IL-6"~e.12,14))) :ARG1-of (e / establish-01~e.17)) :ARG1-of (a2 / add-02~e.1) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and~e.21 :op1 20~e.20 :op2 47~e.22))))) # ::id bio.chicago_2015.87430 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , Lad @/@ Ad interacts with the receptor tyrosine kinases PDGFR and vascular endothelial cell growth factor receptor ( VEGFR ) KDR , as well as several components of receptor signaling networks , including Grb2 , phosphatidylinositol 3 @-@ kinase , and phospholipase Cgamma ( PLC @-@ gamma ) ( 11 , 41 , 58 ) . # ::alignments 0-1.3 2-1.1.1.1 4-1.1.1.1 5-1 6-1.2.r 8-1.2.1.1.1 9-1.2.1.1.2 10-1.2.1.1.3 11-1.2.1.1.4 12-1.2 13-1.2.2.1.1 14-1.2.2.1.2 15-1.2.2.1.3 16-1.2.2.1.4 17-1.2.2.1.5 18-1.2.2.1.6 24-1.2 25-1.2 26-1.2 27-1.2.3.1 28-1.2.3 31-1.2.3.2.1 32-1.2.3.2 34-1.2.3.2.2 35-1.2.3.2.2.1.1.1.1 37-1.2.3.2.2.1.2.1.1 38-1.2.3.2.2.1.2.1.2 40-1.2.3.2.2.1.2.1.2 42-1.2.3.2.2.1 43-1.2.3.2.2.1.3.1.1 44-1.2.3.2.2.1.3.1.2 51-1.4.1.1.1.1 53-1.4.1.1.1.2 55-1.4.1.1.1.3 (i / interact-01~e.5 :ARG0 (p / protein :name (n2 / name :op1 "Lad/Ad"~e.2,4)) :ARG1~e.6 (a / and~e.12,24,25,26 :op1 (p2 / protein :name (n3 / name :op1 "receptor"~e.8 :op2 "tyrosine"~e.9 :op3 "kinases"~e.10 :op4 "PDGFR"~e.11)) :op2 (p3 / protein :name (n4 / name :op1 "vascular"~e.13 :op2 "endothelial"~e.14 :op3 "cell"~e.15 :op4 "growth"~e.16 :op5 "factor"~e.17 :op6 "receptor"~e.18)) :op3 (c / component~e.28 :quant (s2 / several~e.27) :poss (n / network~e.32 :ARG0-of (s / signal-07~e.31) :ARG2-of (i2 / include-01~e.34 :ARG1 (a2 / and~e.42 :op1 (p4 / protein :name (n5 / name :op1 "Grb2"~e.35)) :op2 (e / enzyme :name (n6 / name :op1 "phosphatidylinositol"~e.37 :op2 "3-kinase"~e.38,40)) :op3 (e2 / enzyme :name (n7 / name :op1 "phospholipase"~e.43 :op2 "Cgamma"~e.44))))))) :mod (i3 / indeed~e.0) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 11~e.51 :op2 41~e.53 :op3 58~e.55))))) # ::id bio.chicago_2015.87520 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , at least 10 of those known genes have been previously characterized in AD , which include p21 ras , mitogen @-@ activated protein kinase ( MAPK ) kinase 1 , alpha @-@ enolase 1 , carbonyl reductase , apolipoprotein D , transferrin , phosphotriesterase protein , glutamate dehydrogenase , calpain , and Cu @/@ Zn superoxide dismutase ( SOD1 ) . # ::alignments 0-1.4 2-1.1.1 3-1.1.1 4-1.1.1.1 5-1.1.1.r 6-1.1.2.1.3 7-1.1.2.1.1 8-1.1 8-1.1.2.1 9-1.4 11-1.2 12-1 17-1.1.2 17-1.1.2.1.2 21-1.1.2.1.2.1.2.1.1 23-1.1.2.1.2.1.2.1.1 24-1.1.2.1.2.1.2.1.2 25-1.1.2.1.2.1.2.1.3 29-1.1.2.1.2.1.2.1.3 30-1.1.2.1.2.1.2.1.4 30-1.1.2.1.2.1.3.1.2 32-1.1.2.1.2.1.3.1.1 34-1.1.2.1.2.1.3.1.1 35-1.1.2.1.2.1.2.1.4 35-1.1.2.1.2.1.3.1.2 37-1.1.2.1.2.1.4.1.1 38-1.1.2.1.2.1.4.1.2 40-1.1.2.1.2.1.5.1.1 41-1.1.2.1.2.1.5.1.2 43-1.1.2.1.2.1.6.1.1 45-1.1.2.1.2.1.7.1.1 46-1.1.2.1.2.1.2.1.2 48-1.1.2.1.2.1.8.1.1 49-1.1.2.1.2.1.8.1.2 51-1.1.2.1.2.1.9.1.1 53-1.1.2.1.2.1 54-1.1.2.1.2.1.10.1.1 56-1.1.2.1.2.1.10.1.1 57-1.1.2.1.2.1.10.1.2 58-1.1.2.1.2.1.10.1.3 (c / characterize-01~e.12 :ARG1 (g / gene~e.8 :quant~e.5 (a / at-least~e.2,3 :op1 10~e.4) :ARG1-of (i / include-91~e.17 :ARG2 (g2 / gene~e.8 :ARG1-of (k / know-01~e.7) :ARG2-of (i2 / include-01~e.17 :ARG1 (a3 / and~e.53 :op1 (g3 / gene :name (n4 / name :op1 "p21ras")) :op2 (g4 / gene :name (n5 / name :op1 "mitogen-activated"~e.21,23 :op2 "protein"~e.24,46 :op3 "kinase"~e.25,29 :op4 1~e.30,35)) :op3 (g5 / gene :name (n6 / name :op1 "alpha-enolase"~e.32,34 :op2 1~e.30,35)) :op4 (g6 / gene :name (n7 / name :op1 "carbonyl"~e.37 :op2 "reductase"~e.38)) :op5 (g7 / gene :name (n8 / name :op1 "apolipoprotein"~e.40 :op2 "D"~e.41)) :op6 (g8 / gene :name (n9 / name :op1 "transferrin"~e.43)) :op7 (g9 / gene :name (n10 / name :op1 "phosphotriesterase"~e.45)) :op8 (g10 / gene :name (n11 / name :op1 "glutamate"~e.48 :op2 "dehydrogenase"~e.49)) :op9 (g11 / gene :name (n12 / name :op1 "calpain"~e.51)) :op10 (g12 / gene :name (n13 / name :op1 "Cu/Zn"~e.54,56 :op2 "superoxide"~e.57 :op3 "dismutase"~e.58)))) :mod (t / that~e.6)))) :time (p3 / previous~e.11) :location (d / disease :wiki "Alzheimer's_disease" :name (n3 / name :op1 "Alzheimer's")) :mod (i3 / important~e.0,9)) # ::id bio.chicago_2015.88023 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , cortical neurons of AD patients express p75NTR , but this receptor is only infrequently expressed in cortical neurons of nonaffected aged @-@ matched controls ( 15 ) . # ::alignments 0-1 2-1.1.2.2.1 3-1.1.2.2 6-1.1.1.2.2.1.1 7-1.1.2 10-1.1 14-1.1.2.3.2 15-1.1.2.2.2.1.1 15-1.1.2.3 15-1.1.2.3.1 15-1.1.2.3.1.r 16-1.1.1 16-1.1.2 18-1.1.1.2.1 19-1.1.1.2 19-1.1.2.2 22-1.1.2.2.2.2.1 24-1.1.2.2.2.2 25-1.1.2.2.2 (a / and~e.0 :op2 (c / contrast-01~e.10 :ARG1 (e / express-03~e.16 :ARG2 (p3 / protein :name (n3 / name :op1 "75NTR") :ARG3-of (p4 / phosphorylate-01)) :ARG3 (n / neuron~e.19 :mod (c2 / cortex~e.18) :part-of (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p2 / patient~e.6)) :mod (d / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's"))))) :ARG2 (e2 / express-03~e.7,16 :ARG2 p3 :ARG3 (n4 / neuron~e.3,19 :mod c2~e.2 :poss (c3 / control~e.25 :ARG1-of (a2 / affect-01 :polarity -~e.15) :ARG1-of (m / match-01~e.24 :ARG2 (a3 / age~e.22)))) :ARG1-of (f / frequent-02~e.15 :polarity~e.15 -~e.15 :mod (o / only~e.14)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 14)))) # ::id bio.chicago_2015.88844 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Considering the increasing evidence for neuronal apoptosis in Alzheimer 's disease ( 50 @-@ 54 ) , the transcriptional control of PS1 and its down @-@ regulation by p53 may relate directly to the pathology of the disease . # ::alignments 0-1.2 2-1.2.1.2 3-1.2.1 6-1.2.1.1 7-1.2.1.1.2.r 8-1.2.1.1.2.2.1 10-1.2.1.1.2 12-1.2.2.1.1.1.1 14-1.2.2.1.1.1.2 18-1.1.1.1.3 19-1.1.1.1 20-1.1.1.1.2.r 21-1.1.1.1.2.1.1 22-1.1.1 24-1.1.1.2 25-1.1.1.2 26-1.1.1.2 27-1.1.1.2.2.r 28-1.1.1.2.2.1.1 29-1 30-1.1 31-1.1.3 32-1.1.2.r 34-1.1.2 35-1.1.2.1.r 37-1.1.2.1 (p / possible-01~e.29 :ARG1 (r / relate-01~e.30 :ARG1 (a / and~e.22 :op1 (c / control-01~e.19 :ARG0 p4 :ARG1~e.20 (p3 / protein :name (n2 / name :op1 "PS1"~e.21)) :ARG0-of (t / transcribe-01~e.18)) :op2 (d4 / downregulate-01~e.24,25,26 :ARG1 p3 :ARG2~e.27 (p4 / protein :name (n3 / name :op1 "p53"~e.28)))) :ARG2~e.32 (p2 / pathology~e.34 :mod~e.35 d2~e.37) :ARG1-of (d3 / direct-02~e.31)) :condition (c2 / consider-02~e.0 :ARG1 (e / evidence-01~e.3 :ARG1 (a2 / apoptosis~e.6 :mod (n4 / neuron) :location~e.7 (d2 / disease~e.10 :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"~e.8))) :ARG1-of (i / increase-01~e.2)) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 50~e.12 :op2 54~e.14)))))) # ::id bio.chicago_2015.88939 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recombinant Adenoviral Vectors and Adenoviral Infection-- The recombinant adenovirus vector AdCox @-@ 2 , expressing COX @-@ 2 , was constructed from replication @-@ deficient adenovirus type 5( Ad5 ) with deletions in the E1 and E3 genes , Ad dl327 , and a plasmid containing Ad5 sequences from 22 to 5790 with a deletion of the E1 region from bp 342 to 3523 , a polycloning site under control of the cytomegalovirus promoter , the COX @-@ 2 cDNA , and the simian virus 40 polyadenylation signal . # ::alignments 0-1.1.1.1.1 2-1.1.1 3-1.1 7-1.2.1.2.1 8-1.1.1.1 8-1.1.2.1 8-1.2.1.2 9-1.2.1 10-1.2.1.1.1 12-1.2.1.1.1 14-1.2.1.3 15-1.2.1.3.1.1.1 17-1.2.1.1.1 17-1.2.1.3.1.1.1 20-1.2 21-1.2.2.r 22-1.2.2.1.2.1 25-1.2.2.1 28-1.2.2.3.1.1.2.1.1 30-1.2.2.1.3.r 31-1.2.2.1.3 32-1.2.2.1.3.1.r 34-1.2.2.1.3.1.1.1.1 35-1.2.2.1.3.1 36-1.2.2.1.3.1.2.1.1 37-1.2.2.1.3.1.1 37-1.2.2.1.3.1.2 39-1.2.2.2.1.1 40-1.2.2.2.1.1 42-1.2.2 44-1.2.2.3 45-1.2.2.3.1 46-1.2.2.3.1.1.2.1.1 47-1.2.2.3.1.1 48-1.2.2.3.1.1.1.r 49-1.2.2.3.1.1.1.1 51-1.2.2.3.1.1.1.2 54-1.2.2.3.1.1.2 54-1.2.2.3.1.1.2.2 54-1.2.2.3.1.1.2.2.r 55-1.2.2.3.1.1.2.2.1.r 57-1.2.2.3.1.1.2.2.1.3 61-1.2.2.3.1.1.2.2.1.1.1 63-1.2.2.3.1.1.2.2.1.1.2 67-1.2.2.3.1.1.2.2.1 67-1.2.2.3.1.1.2.2.1.2.1 69-1.2.2.3.1.1.2.2.1.2.1.2 70-1.2.2.3.1.1.2.2.1.2.1.2.1.r 72-1.2.2.3.1.1.2.2.1.2.1.2.1.1.2.1.1.1 73-1.2.2.3.1.1.2.2.1.2.1.2.1.1 73-1.2.2.3.1.1.2.2.1.2.1.2.1.1.2 73-1.2.2.3.1.1.2.2.1.2.1.2.1.1.2.r 76-1.2.2.3.1.1.2.2.1.2.1.2.1.1.3 78-1.2.1.1.1 78-1.2.1.3.1.1.1 79-1.2.2.3.1.1.2.2.1.2.1.2.1.1.1.1 81-1.2.2.3.1.1.2.2.1.2.1.2.1 83-1.2.2.3.1.1.2.2.1.2.1.2.1.2.1.1.1 84-1.2.2.3.1.1.2.2.1.2.1.2.1.2.1.1.2 85-1.2.2.3.1.1.2.2.1.2.1.2.1.2.1.1.3 86-1.2.2.3.1.1.2.2.1.2.1.2.1.2.2 87-1.2.2.3.1.1.2.2.1.2.1.2.1.2 (m / multi-sentence :snt1 (a / and~e.3 :op1 (v / vector~e.2 :mod (a6 / adenovirus~e.8 :ARG3-of (r / recombine-01~e.0))) :op2 (i / infect-01 :ARG2 (a7 / adenovirus~e.8))) :snt2 (c2 / construct-01~e.20 :ARG1 (v3 / vector~e.9 :name (n3 / name :op1 "AdCox-2"~e.10,12,17,78) :mod (a2 / adenovirus~e.8 :ARG3-of (r2 / recombine-01~e.7)) :ARG1-of (e / express-03~e.14 :ARG2 (e2 / enzyme :name (n4 / name :op1 "COX-2"~e.15,17,78)))) :ARG2~e.21 (a4 / and~e.42 :op1 (a8 / adenovirus~e.25 :mod 5 :ARG0-of (l / lack-01 :ARG1 (r3 / replicate-01~e.22 :ARG1 a8)) :ARG2-of~e.30 (d / delete-01~e.31 :ARG1~e.32 (a3 / and~e.35 :op1 (g / gene~e.37 :name (n6 / name :op1 "E1"~e.34)) :op2 (g2 / gene~e.37 :name (n7 / name :op1 "E3"~e.36))))) :op2 (s / small-molecule :name (n8 / name :op1 "Ad-dl327"~e.39,40)) :op3 (p / plasmid~e.44 :ARG0-of (c3 / contain-01~e.45 :ARG1 (s2 / sequence~e.47 :mod~e.48 (v6 / value-interval :op1 22~e.49 :op2 5790~e.51) :mod (d3 / dna-sequence~e.54 :name (n9 / name :op1 "Ad5"~e.28,46) :ARG2-of~e.54 (d2 / delete-01~e.54 :ARG1~e.55 (p3 / protein-segment~e.67 :mod (v7 / value-interval :op1 342~e.61 :op2 3523~e.63) :ARG1-of (m2 / mean-01 :ARG2 (s3 / site~e.67 :mod (p4 / polyclone) :ARG1-of (c4 / control-01~e.69 :ARG0~e.70 (a5 / and~e.81 :op1 (n5 / nucleic-acid~e.73 :name (n / name :op1 "cDNA"~e.79) :ARG0-of~e.73 (p7 / promote-01~e.73 :ARG1 (v8 / virus :name (n13 / name :op1 "cytomegalovirus"~e.72))) :mod e2~e.76) :op2 (s4 / signal-07~e.87 :ARG0 (s5 / small-molecule :name (n12 / name :op1 "simian"~e.83 :op2 "virus"~e.84 :op3 40~e.85)) :mod (p6 / polyadenylation~e.86)))))) :part-of g~e.57))))))))) # ::id biomed_0004.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The receptor tyrosine kinase EGFR binds the growth factor ligand EGF . # ::alignments 1-1.1 2-1.1 3-1.1 4-1.1.1.1 5-1 7-1.2 8-1.2 9-1.2 10-1.2.1.1 (b / bind-01~e.5 :ARG1 (r / receptor-tyrosine-kinase~e.1,2,3 :name (n3 / name :op1 "EGFR"~e.4)) :ARG2 (g / growth-factor-ligand~e.7,8,9 :name (n / name :op1 "EGF"~e.10))) # ::id biomed_0004.2 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The EGFR @-@ EGF complex binds another EGFR @-@ EGF complex . # ::alignments 1-1.1.1.2.1 3-1.1.2.2.1 4-1.1 4-1.2 5-1 6-1.2.3 7-1.2.1 9-1.1.2.2.1 10-1.2 (b / bind-01~e.5 :ARG1 (m / macro-molecular-complex~e.4 :part (e / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n / name :op1 "EGFR"~e.1)) :part (p / protein :wiki "Epidermal_growth_factor" :name (n2 / name :op1 "EGF"~e.3,9))) :ARG2 (m2 / macro-molecular-complex~e.4,10 :part e~e.7 :part p :mod (a / another~e.6))) # ::id biomed_0004.3 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGFR , bound to EGFR , transphosphorylates itself on a tyrosine residue . # ::alignments 0-1.1.1.1 0-1.1.2.1.1.1 2-1.1 2-1.1.2 2-1.1.2.r 4-1.1.1.1 4-1.1.2.1.1.1 10-1.2.1.1.1 11-1.2 (t / transphosphorylate-01 :ARG0 (e / enzyme~e.2 :name (n / name :op1 "EGFR"~e.0,4) :ARG1-of~e.2 (b / bind-01~e.2 :ARG2 (e2 / enzyme :name (n3 / name :op1 "EGFR"~e.0,4)))) :ARG1 (r / residue~e.11 :mod (a / amino-acid :name (n2 / name :op1 "tyrosine"~e.10)) :part-of e)) # ::id biomed_0004.4 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The adaptor protein GRB2 can bind EGFR that is phosphorylated on tyrosine . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1.1.1.1 4-1 5-1.1 6-1.1.2.1.1 9-1.1.2.2 10-1.1.2.2.1.r 11-1.1.2.2.1.1.1 (p / possible-01~e.4 :ARG1 (b / bind-01~e.5 :ARG1 (p2 / protein~e.2 :name (n2 / name :op1 "GRB2"~e.3) :mod (a2 / adaptor~e.1)) :ARG2 (e / enzyme :name (n3 / name :op1 "EGFR"~e.6) :ARG3-of (p3 / phosphorylate-01~e.9 :ARG1~e.10 (a / amino-acid :name (n4 / name :op1 "tyrosine"~e.11)))))) # ::id biomed_0004.5 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGFR @-@ bound GRB2 binds SOS1 and the SOS1 @-@ GRB2 complex binds HRAS . # ::alignments 0-1.1.1.2.1.1.1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 3-1.1.1.1.1 4-1.1 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 4-1.1.1.r 5-1.1.2.1.1 8-1.1.2.1.1 10-1.1.1.1.1 11-1.2.1 12-1.2 13-1.2.2.1.1 (a / and :op1 (b / bind-01~e.4 :ARG1~e.4 (p / protein~e.2,4 :name (n / name :op1 "GRB2"~e.3,10) :ARG1-of~e.2,4 (b2 / bind-01~e.2,4 :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR"~e.0)))) :ARG2 (p2 / protein :name (n3 / name :op1 "SOS1"~e.5,8))) :op2 (b3 / bind-01~e.12 :ARG1 (m / macro-molecular-complex~e.11 :part p2 :part p) :ARG2 (e2 / enzyme :name (n4 / name :op1 "HRAS"~e.13)))) # ::id biomed_0004.6 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HRAS , bound to SOS1 , binds GTP . # ::alignments 0-1.1.1.1 2-1.1 2-1.1.2 2-1.1.2.r 4-1.1.2.1.1.1 6-1 6-1.1 6-1.1.2 6-1.1.2.r 6-1.1.r 7-1.2.1.1 (b / bind-01~e.6 :ARG1~e.6 (e / enzyme~e.2,6 :name (n2 / name :op1 "HRAS"~e.0) :ARG1-of~e.2,6 (b2 / bind-01~e.2,6 :ARG2 (p / protein :name (n3 / name :op1 "SOS1"~e.4)))) :ARG2 (s / small-molecule :name (n4 / name :op1 "GTP"~e.7))) # ::id biomed_0004.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HRAS , bound to GTP , binds RAF1 . # ::alignments 0-1.1.1.1 2-1.1 2-1.1.2 2-1.1.2.r 4-1.1.2.1.1.1 6-1 6-1.1 6-1.1.2 6-1.1.2.r 6-1.1.r 7-1.2.1.1 (b / bind-01~e.6 :ARG1~e.6 (e / enzyme~e.2,6 :name (n2 / name :op1 "HRAS"~e.0) :ARG1-of~e.2,6 (b2 / bind-01~e.2,6 :ARG2 (s / small-molecule :name (n3 / name :op1 "GTP"~e.4)))) :ARG2 (e2 / enzyme :name (n4 / name :op1 "RAF1"~e.7))) # ::id biomed_0004.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RAF1 , bound to HRAS , phosphorylates itself at Thr491 and Ser494 . # ::alignments 0-1.2.1.1 2-1.2 2-1.2.2 2-1.2.2.r 3-1.2.2.1.r 4-1.2.2.1.1.1 6-1 10-1.1 (p / phosphorylate-01~e.6 :ARG1 (a / and~e.10 :op1 (a2 / amino-acid :mod 491 :name (n3 / name :op1 "threonine")) :op2 (a3 / amino-acid :mod 494 :name (n4 / name :op1 "serine")) :part-of e) :ARG2 (e / enzyme~e.2 :name (n / name :op1 "RAF1"~e.0) :ARG1-of~e.2 (b / bind-01~e.2 :ARG2~e.3 (e2 / enzyme :name (n2 / name :op1 "HRAS"~e.4))))) # ::id biomed_0004.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RAF1 phosphorylated at Thr491 and Ser494 is activated . # ::alignments 0-1.1.1.1 1-1.1.2 4-1.1.2.1 7-1 (a / activate-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "RAF1"~e.0) :ARG3-of (p / phosphorylate-01~e.1 :ARG1 (a2 / and~e.4 :op1 (a3 / amino-acid :mod 491 :name (n2 / name :op1 "threonine")) :op2 (a4 / amino-acid :mod 494 :name (n3 / name :op1 "serine")))))) # ::id biomed_0004.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active RAF1 phosphorylates MEK1 at Ser218 and Ser222 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 6-1.1 (p / phosphorylate-01~e.2 :ARG1 (a / and~e.6 :op1 (a2 / amino-acid :mod 218 :name (n / name :op1 "serine")) :op2 (a3 / amino-acid :mod 222 :name (n2 / name :op1 "serine")) :part-of (e / enzyme :name (n3 / name :op1 "MEK1"~e.3))) :ARG2 (e2 / enzyme~e.0 :name (n4 / name :op1 "RAF1"~e.1) :ARG0-of~e.0 (a4 / activity-06~e.0))) # ::id biomed_0004.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK1 phosphorylated at Ser218 and Ser222 is activated . # ::alignments 0-1.1.1.1 1-1.1.2 4-1.1.2.1 7-1 (a / activate-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "MEK1"~e.0) :ARG3-of (p / phosphorylate-01~e.1 :ARG1 (a2 / and~e.4 :op1 (a3 / amino-acid :mod 218 :name (n2 / name :op1 "serine")) :op2 (a4 / amino-acid :mod 222 :name (n3 / name :op1 "serine")))))) # ::id biomed_0004.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active MEK1 phosphorylates ERK2 at Tyr187 and Thr185 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 6-1.1 (p / phosphorylate-01~e.2 :ARG1 (a / and~e.6 :op1 (a3 / amino-acid :mod 187 :name (n2 / name :op1 "tyrosine")) :op2 (a4 / amino-acid :mod 185 :name (n3 / name :op1 "threonine")) :part-of (e2 / enzyme :name (n4 / name :op1 "ERK2"~e.3))) :ARG2 (e / enzyme~e.0 :name (n / name :op1 "MEK1"~e.1) :ARG0-of~e.0 (a2 / activity-06~e.0))) # ::id biomed_0004.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras bound to GTP binds to BRAF . # ::alignments 0-1.1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 3-1.1.2.1.1.1 4-1 4-1.1 4-1.1.2 4-1.1.2.r 4-1.1.r 5-1.2.r 6-1.2.1.1 (b / bind-01~e.4 :ARG1~e.4 (e / enzyme~e.1,4 :name (n / name :op1 "Ras"~e.0) :ARG1-of~e.1,4 (b2 / bind-01~e.1,4 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"~e.3)))) :ARG2~e.5 (e2 / enzyme :name (n3 / name :op1 "BRAF"~e.6))) # ::id biomed_0004.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF bound to Ras transphosphorylates itself at Thr598 and Ser601 . # ::alignments 0-1.1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1.1.2.1.r 3-1.1.2.1.1.1 8-1.2 (t / transphosphorylate-01 :ARG0 (e / enzyme~e.1 :name (n2 / name :op1 "BRAF"~e.0) :ARG1-of~e.1 (b / bind-01~e.1 :ARG2~e.2 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.3)))) :ARG1 (a / and~e.8 :op1 (a2 / amino-acid :mod 598 :name (n4 / name :op1 "threonine")) :op2 (a3 / amino-acid :mod 601 :name (n / name :op1 "serine")) :part-of e)) # ::id biomed_0004.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation at Thr598 and Ser601 activates BRAF . # ::alignments 0-1.1 3-1.1.1 5-1 6-1.2.1.1 (a / activate-01~e.5 :ARG0 (p / phosphorylate-01~e.0 :ARG1 (a2 / and~e.3 :op1 (a3 / amino-acid :mod 598 :name (n / name :op1 "threonine")) :op2 (a4 / amino-acid :mod 601 :name (n2 / name :op1 "serine")) :part-of e)) :ARG1 (e / enzyme :name (n3 / name :op1 "BRAF"~e.6))) # ::id biomed_0004.16 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF is activated by being phosphorylated at Thr598 and Ser601 . # ::alignments 0-1.2.1.1 2-1 5-1.1 8-1.1.1 (a / activate-01~e.2 :ARG0 (p / phosphorylate-01~e.5 :ARG1 (a2 / and~e.8 :op1 (a3 / amino-acid :mod 598 :name (n2 / name :op1 "threonine")) :op2 (a4 / amino-acid :mod 601 :name (n3 / name :op1 "serine")) :part-of e)) :ARG1 (e / enzyme :name (n / name :op1 "BRAF"~e.0))) # ::id biomed_0004.17 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active BRAF phosphorylates MEK1 at Ser218 and Ser222 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 6-1.1 (p / phosphorylate-01~e.2 :ARG1 (a2 / and~e.6 :op1 (a3 / amino-acid :mod 218 :name (n2 / name :op1 "serine")) :op2 (a4 / amino-acid :mod 222 :name (n3 / name :op1 "serine")) :part-of (e2 / enzyme :name (n4 / name :op1 "MEK1"~e.3))) :ARG2 (e / enzyme~e.0 :name (n / name :op1 "BRAF"~e.1) :ARG0-of~e.0 (a / activity-06~e.0))) # ::id biomed_0004.18 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation at Ser218 and Ser222 activates MEK1 . # ::alignments 0-1.1 3-1.1.1 5-1 6-1.2.1.1 (a / activate-01~e.5 :ARG0 (p2 / phosphorylate-01~e.0 :ARG1 (a2 / and~e.3 :op1 (a3 / amino-acid :mod 218 :name (n / name :op1 "serine")) :op2 (a4 / amino-acid :mod 222 :name (n2 / name :op1 "serine")) :part-of e)) :ARG1 (e / enzyme :name (n3 / name :op1 "MEK1"~e.6))) # ::id biomed_0004.19 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK1 is activated by being phosphorylated at Ser218 and Ser222 . # ::alignments 0-1.2.1.1 2-1 5-1.1 8-1.1.1 (a / activate-01~e.2 :ARG0 (p / phosphorylate-01~e.5 :ARG1 (a2 / and~e.8 :op1 (a3 / amino-acid :mod 218 :name (n2 / name :op1 "serine")) :op2 (a4 / amino-acid :mod 222 :name (n3 / name :op1 "serine")) :part-of e)) :ARG1 (e / enzyme :name (n / name :op1 "MEK1"~e.0))) # ::id biomed_0004.20 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active MEK1 phosphorylates ERK2 at Thr202 and Thr185 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 6-1.1 (p / phosphorylate-01~e.2 :ARG1 (a2 / and~e.6 :op1 (a3 / amino-acid :mod 202 :name (n2 / name :op1 "threonine")) :op2 (a4 / amino-acid :mod 185 :name (n3 / name :op1 "threonine")) :part-of (e2 / enzyme :name (n4 / name :op1 "ERK2"~e.3))) :ARG2 (e / enzyme~e.0 :name (n / name :op1 "MEK1"~e.1) :ARG0-of~e.0 (a / activity-06~e.0))) # ::id biomed_0004.21 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF bound to Ras transphosphorylates itself at Thr598 . # ::alignments 0-1.1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1.1.2.1.r 3-1.1.2.1.1.1 (t / transphosphorylate-01 :ARG0 (e2 / enzyme~e.1 :name (n2 / name :op1 "BRAF"~e.0) :ARG1-of~e.1 (b / bind-01~e.1 :ARG2~e.2 (e / enzyme :name (n / name :op1 "Ras"~e.3)))) :ARG1 (a / amino-acid :mod 598 :name (n3 / name :op1 "threonine") :part-of e2)) # ::id biomed_0004.22 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF bound to Ras transphosphorylates itself at Ser601 . # ::alignments 0-1.1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1.1.2.1.r 3-1.1.2.1.1.1 (t / transphosphorylate-01 :ARG0 (e2 / enzyme~e.1 :name (n2 / name :op1 "BRAF"~e.0) :ARG1-of~e.1 (b / bind-01~e.1 :ARG2~e.2 (e / enzyme :name (n3 / name :op1 "Ras"~e.3)))) :ARG1 (a / amino-acid :mod 601 :name (n4 / name :op1 "serine") :part-of e2)) # ::id biomed_0004.23 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active BRAF phosphorylates MEK1 at Ser222 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 (p / phosphorylate-01~e.2 :ARG1 (a2 / amino-acid :mod 222 :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "MEK1"~e.3))) :ARG2 (e / enzyme~e.0 :name (n / name :op1 "BRAF"~e.1) :ARG0-of~e.0 (a / activity-06~e.0))) # ::id biomed_0004.24 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active MEK1 phosphorylates ERK2 at Thr202 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 (p / phosphorylate-01~e.2 :ARG1 (a2 / amino-acid :mod 202 :name (n2 / name :op1 "threonine") :part-of (e2 / enzyme :name (n3 / name :op1 "ERK2"~e.3))) :ARG2 (e / enzyme~e.0 :name (n / name :op1 "MEK1"~e.1) :ARG0-of~e.0 (a / activity-06~e.0))) # ::id biomed_0004.25 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active MEK1 phosphorylates ERK2 at Thr185 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 (p / phosphorylate-01~e.2 :ARG1 (a2 / amino-acid :mod 185 :name (n2 / name :op1 "threonine") :part-of (e2 / enzyme :name (n3 / name :op1 "ERK2"~e.3))) :ARG2 (e / enzyme~e.0 :name (n / name :op1 "MEK1"~e.1) :ARG0-of~e.0 (a / activity-06~e.0))) # ::id biomed_0004.26 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of BRAF at Thr598 and Ser601 activates it . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.3.2.1 5-1.1.1 7-1 8-1.2 (a / activate-01~e.7 :ARG0 (p2 / phosphorylate-01~e.0 :ARG1~e.1 (a2 / and~e.5 :op1 (a3 / amino-acid :mod 598 :wiki "Threonine" :name (n / name :op1 "threonine")) :op2 (a4 / amino-acid :mod 601 :wiki "Serine" :name (n2 / name :op1 "serine")) :part-of (e / enzyme :wiki - :name (n3 / name :op1 "BRAF"~e.2)))) :ARG1 e~e.8) # ::id biomed_0004.27 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Active BRAF phosphorylates MEK1 at Ser218 . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.1.1 2-1 3-1.1.3.1.1 (p / phosphorylate-01~e.2 :ARG1 (a / amino-acid :mod 218 :name (n / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "MEK1"~e.3))) :ARG2 (e / enzyme~e.0 :name (n2 / name :op1 "BRAF"~e.1) :ARG0-of~e.0 (a2 / activity-06~e.0))) # ::id biomed_0004.28 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of MEK1 at Ser218 and Ser222 activates it . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1 5-1.1.1 7-1 8-1.2 (a / activate-01~e.7 :ARG0 (p2 / phosphorylate-01~e.0 :ARG1 (a2 / and~e.5 :op1 (a3 / amino-acid :mod 218 :name (n / name :op1 "serine")) :op2 (a4 / amino-acid :mod 222 :name (n2 / name :op1 "serine"))) :part-of~e.1 (e / enzyme :name (n3 / name :op1 "MEK1"~e.2))) :ARG1 e~e.8) # ::id pmid_1177_7939.30 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 0-1 0-1.1 0-1.1.r (t2 / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) # ::id pmid_1177_7939.31 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The S/E/E8 complex exists under physiological conditions # ::alignments 2-1.1 3-1 5-1.2 6-1.2.r (e / exist-01~e.3 :ARG1 (m / macro-molecular-complex~e.2 :part (s / slash :op1 (p / protein :name (n / name :op1 "S")) :op2 (p2 / protein :name (n2 / name :op1 "E")) :op2 (p3 / protein :name (n3 / name :op1 "E8")))) :condition~e.6 (p4 / physiology~e.5)) # ::id pmid_1177_7939.32 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In previous studies , we showed that Sos @-@ 1 , E3b1 , and Eps8 could form a trimeric complex in vivo upon concomitant overexpression of the three proteins . # ::alignments 0-1.2.4 1-1.3.1 2-1.3 4-1.1 5-1 7-1.2.1.1.1.1 9-1.2.1.1.1.1 11-1.2.1.2.1.1 13-1.2.1 14-1.2.1.3.1.1 15-1.2.3 16-1.2 18-1.2.2.1 19-1.2.2 20-1.2.4 21-1.2.4 23-1.2.5.2 24-1.2.5 28-1.2.5.1 (s / show-01~e.5 :ARG0 (w / we~e.4) :ARG1 (f / form-01~e.16 :ARG0 (a / and~e.13 :op1 (p2 / protein :name (n / name :op1 "Sos-1"~e.7,9)) :op2 (p3 / protein :name (n2 / name :op1 "E3b1"~e.11)) :op3 (e2 / enzyme :name (n3 / name :op1 "Eps8"~e.14))) :ARG1 (m / macro-molecular-complex~e.19 :mod (t / trimeric~e.18)) :ARG1-of (p / possible-01~e.15) :manner (i / in-vivo~e.0,20,21) :condition (o / overexpress-01~e.24 :ARG1 a~e.28 :ARG2 (c / concomitant~e.23))) :medium (s2 / study~e.2 :time (p5 / previous~e.1))) # ::id pmid_1177_7939.33 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , we failed to detect the existence of an endogenous S/E/E8 complex ( Scita et al. , 1999 ) . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2 7-1.1.2.2 8-1.1.2.2.1.r 10-1.1.2.2.1.1 12-1.1.2.2.1 15-1.2.1.1.1.1.1 16-1.2.1.1 17-1.2.1.1.2.1 19-1.2.1.2.1 (c / contrast-01~e.0 :ARG2 (f / fail-01~e.3 :ARG1 (w / we~e.2) :ARG2 (d / detect-01~e.5 :ARG0 w :ARG1 (e / exist-01~e.7 :ARG1~e.8 (m / macro-molecular-complex~e.12 :mod (e2 / endogenous~e.10) :part (s / slash :op1 (p / protein :name (n / name :op1 "S")) :op2 (p2 / protein :name (n2 / name :op1 "E")) :op3 (p3 / protein :name (n3 / name :op1 "E8"))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a / and~e.16 :op1 (p5 / person :name (n4 / name :op1 "Scita"~e.15)) :op2 (p6 / person :mod (o / other~e.17))) :time (d3 / date-entity :year 1999~e.19)))) # ::id pmid_1177_7939.34 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We reasoned that this could be due to the low efficiency of the immunoprecipitating antibodies used . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.2 4-1.2 6-1.2.1 7-1.2.1 9-1.2.1.1.2 10-1.2.1.1 14-1.2.1.1.1 15-1.2.1.1.1.1 (r / reason-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (p2 / possible-01~e.4 :ARG1 (c / cause-01~e.6,7 :ARG0 (e / efficient-01~e.10 :ARG1 (a / antibody~e.14 :ARG1-of (u / use-01~e.15 :ARG2 (i2 / immunoprecipitate-01))) :ARG1-of (l / low-04~e.9)) :ARG1 (t / this~e.3)))) # ::id pmid_1177_7939.35 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We thus sought to exploit the availability of eps8 @^−/− fibroblasts to circumvent this problem . # ::alignments 0-1.1 1-1.3 2-1 3-1.3 4-1.2 6-1.2.2 7-1.2.2.1.r 8-1.2.2.1.1.1.1.1 10-1.2.2.1.1.1.2.1 12-1.2.2.1 14-1.2.3 15-1.2.3.2.1 16-1.2.3.2 (s / seek-01~e.2 :ARG0 (w / we~e.0) :ARG1 (e / exploit-01~e.4 :ARG0 w :ARG1 (a / available-02~e.6 :ARG2~e.7 (f2 / fibroblast~e.12 :ARG0-of (c3 / contain-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "eps8"~e.8) :ARG2-of (m / mutate-01 :mod "−/−"~e.10))))) :purpose (c2 / circumvent-01~e.14 :ARG0 w :ARG1 (p / problem~e.16 :mod (t / this~e.15)))) :ARG0-of (c / cause-01~e.1,3)) # ::id pmid_1177_7939.36 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To this end , we performed immunoprecipitation experiments using eps8 @^−/− fibroblasts in which the expression of Eps8 was restored , to physiological levels , with an expression vector encoding a myc epitope @-@ tagged Eps8 (−/− [ Eps8 myc ] cells ) . # ::alignments 1-1.3 4-1.1 5-1 6-1.2.1 7-1.2 8-1.3.r 9-1.2.1.1.1.1.1.1.1 9-1.2.1.1.2.1.1.1 11-1.2.1.1.2.1.2.1 13-1.2.1.1 17-1.2.1.1.1.1 18-1.2.1.1.1.1.1.r 19-1.2.1.1.1.1.1.1.1 21-1.2.1.1.1 23-1.2.1.1.1.2.r 24-1.2.1.1.1.2.1 25-1.2.1.1.1.2 27-1.2.1.1.1.3.r 29-1.2.1.1.1.3.2 30-1.2.1.1.1.3 31-1.2.1.1.1.3.1 33-1.2.1.1.1.3.1.1.2.1.1.1.1 34-1.2.1.1.1.3.1.1.2.1 36-1.2.1.1.1.3.1.1.2 37-1.2.1.1.1.3.1.1.1.1 40-1.2.1.1.1.3.1.1.1.1 41-1.2.1.1.1.3.1.1.2.1.1.1.1 (p / perform-02~e.5 :ARG0 (w / we~e.4) :ARG1 (e / experiment-01~e.7 :ARG2 (i / immunoprecipitate-01~e.6 :ARG2 (f / fibroblast~e.13 :location-of (r / restore-01~e.21 :ARG1 (e2 / express-03~e.17 :ARG2~e.18 (e4 / enzyme :name (n2 / name :op1 "Eps8"~e.9,19))) :ARG2~e.23 (l / level~e.25 :mod (p3 / physiology~e.24)) :instrument~e.27 (v / vector~e.30 :ARG0-of (e3 / encode-01~e.31 :ARG1 (e6 / enzyme :name (n / name :op1 "Eps8"~e.37,40) :ARG1-of (t2 / tag-01~e.36 :ARG2 (e7 / epitope~e.34 :mod (p2 / protein :name (n3 / name :op1 "myc"~e.33,41)))))) :ARG2-of (e8 / express-03~e.29))) :ARG0-of (c2 / contain-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "eps8"~e.9) :ARG2-of (m / mutate-01 :mod "−/−"~e.11)))))) :purpose~e.8 (t / this~e.1)) # ::id pmid_1177_7939.37 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We selected transfected clones in which the levels of expression of Eps8 myc were very similar to those present in wild @-@ type fibroblasts ( Fig . 1 A ) . # ::alignments 0-1.1 1-1 2-1.2.1 3-1.2 7-1.2.2.2 7-1.2.2.2.1.1 9-1.2.2 14-1.2.2.2.1.2 15-1.2.2.2.1 18-1.2.2.2.1.1.1 19-1.2.2.2.1.1.1.1.r 20-1.2.2.2.1.1.1.1.1 22-1.2.2.2.1.1.1.1.1 23-1.2.2.2.1.1.1.1 26-1.2.2.3.1 (s / select-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / clone~e.3 :ARG1-of (t / transfect-01~e.2) :ARG3-of (e / express-03~e.9 :ARG2 (p2 / protein :name (n2 / name :op1 "Eps8myc")) :degree (l / level~e.7 :ARG1-of (r / resemble-01~e.15 :ARG2 (l2 / level~e.7 :ARG1-of (p / present-02~e.18 :ARG2~e.19 (f / fibroblast~e.23 :mod (w2 / wild-type~e.20,22)))) :degree (v / very~e.14))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.26 :mod "1A"))))) # ::id pmid_1177_7939.38 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Endogenous Sos @-@ 1 and E3b1 could be detected in anti @-@ myc immunoprecipitates from lysates of Eps8 myc @-@ reconstituted , but not from eps8 @^−/− fibroblasts ( Fig . 1 B ) . # ::alignments 0-1.1.1.3 1-1.1.1.1.1.1 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1 8-1.1 8-1.1.3.1 9-1.1.2.r 10-1.1.2.2 12-1.1.2.2.1.1.1 13-1.1.2 13-1.1.2.1 13-1.1.2.1.r 13-1.1.3.1.3 13-1.1.3.1.3.1 13-1.1.3.1.3.1.r 14-1.1.2.1.1.1.r 15-1.1.2.1.1 16-1.1.3.r 17-1.1.3.1.3.1.1.1.1.1.1 18-1.1.2.2.1.1.1 20-1.1.2.1.1.1.1.1.2 22-1.1.3 23-1.1.3.1.1 23-1.1.3.1.1.r 24-1.1.2.1.1.1.r 25-1.1.3.1.3.1.1.1.1.1.1 27-1.1.3.1.3.1.1.1.1.2.1 29-1.1.2.1.1.1 29-1.1.3.1.3.1.1 32-1.2.1 34-1.1.1.1.1.1 (p / possible-01~e.6 :ARG1 (d / detect-01~e.8 :ARG1 (a / and~e.4 :op1 (p3 / protein :name (n / name :op1 "Sos-1"~e.1,3,34)) :op2 (p4 / protein :name (n2 / name :op1 "E3b1"~e.5)) :mod (e / endogenous~e.0)) :location~e.9 (p5 / protein~e.13 :ARG1-of~e.13 (i3 / immunoprecipitate-01~e.13 :ARG2 (l / lysate~e.15 :source~e.14,24 (f3 / fibroblast~e.29 :ARG0-of (c5 / contain-01 :ARG1 (p7 / protein :name (n7 / name :op1 "Eps8myc") :ARG1-of (r / reconstitute-01~e.20)))))) :ARG0-of (c / counter-01~e.10 :ARG1 (p2 / protein :name (n3 / name :op1 "myc"~e.12,18)))) :ARG1-of~e.16 (c4 / contrast-01~e.22 :ARG2 (d2 / detect-01~e.8 :polarity~e.23 -~e.23 :ARG1 a :location (p6 / protein~e.13 :ARG1-of~e.13 (i / immunoprecipitate-01~e.13 :ARG2 (f / fibroblast~e.29 :ARG0-of (c2 / contain-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "eps8"~e.17,25) :ARG2-of (m / mutate-01 :mod "−/−"~e.27))))))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.32 :mod "1B"))) # ::id pmid_1177_7939.39 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether E3b1 mediates the interaction between Eps8 and Sos @-@ 1 , as it would be expected according to the tricomplex model , we performed coimmunoprecipitation experiments under conditions in which the association between Eps8 and E3b1 was disrupted . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.2 4-1.3.2 6-1.3.2.3 8-1.3.2.3.1.1 9-1.3.2.3.1 10-1.3.2.3.1.2.1.1 12-1.3.2.3.1.2.1.1 18-1.3.2.4 19-1.3.2.4.1 20-1.3.2.4.1 22-1.3.2.4.1.1.1 23-1.3.2.4.1.1 25-1.1 26-1 27-1.2.1 28-1.2 30-1.2.2.r 34-1.2.2.1 36-1.2.2.1.1.1.1 38-1.2.2.1.2.1.1 40-1.2.2 (p / perform-02~e.26 :ARG0 (w / we~e.25) :ARG1 (e / experiment-01~e.28 :ARG2 (c / coimmunoprecipitate-01~e.27) :condition~e.30 (d / disrupt-01~e.40 :ARG1 (a / associate-01~e.34 :ARG1 (e3 / enzyme :name (n / name :op1 "Eps8"~e.36)) :ARG2 (p3 / protein :name (n2 / name :op1 "E3b1"~e.38))))) :purpose (d2 / determine-01~e.1 :ARG0 w :ARG1 (m / mediate-01~e.4 :mode~e.2 interrogative~e.2 :ARG0 p3~e.3 :ARG1 (i / interact-01~e.6 :ARG0 (a2 / and~e.9 :op1 e3~e.8 :op2 (p4 / protein :name (n3 / name :op1 "Sos-1"~e.10,12)))) :ARG1-of (e2 / expect-01~e.18 :ARG1-of (s / say-01~e.19,20 :ARG0 (m2 / model~e.23 :mod (t / tricomplex~e.22))))))) # ::id pmid_1177_7939.40 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The binding site of E3b1 to the SH3 domain of Eps8 was previously mapped to the amino acid sequence , PPPPPVDYTEDEE , where the D and the Y residues are critical for efficient binding ( Mongiovi et al. , 1999 ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1 5-1.1.2.1.r 7-1.1.2.1.1.1 8-1.1.2.1.1.2 10-1.1.2.1.2.1.1 12-1.4 13-1 14-1.2.r 16-1.2.3 17-1.2.2.1.1.1.1.2 17-1.2.3 18-1.2 20-1.2.1.1 25-1.2.2.1 28-1.2.2.1.1 28-1.2.2.1.2 30-1.2.2.1.3 31-1.2.2.1.3.1.r 32-1.2.2.1.3.1 33-1.2.2.1.3.1.1 36-1.3.1.1.1.1.1 37-1.3.1.1 38-1.3.1.1.2.1 40-1.3.1.2.1 (m / map-02~e.13 :ARG1 (p / protein-segment~e.2 :part-of~e.3 (p3 / protein :name (n8 / name :op1 "E3b1"~e.4)) :ARG1-of (b / bind-01~e.1 :ARG2~e.5 (p2 / protein-segment :name (n2 / name :op1 "SH3"~e.7 :op2 "domain"~e.8) :part-of (e / enzyme :name (n3 / name :op1 "Eps8"~e.10))))) :ARG2~e.14 (d3 / dna-sequence~e.18 :name (n / name :op1 "PPPPPVDYTEDEE"~e.20) :ARG2-of (i / include-91 :ARG1 (a2 / and~e.25 :op1 (r3 / residue~e.28 :mod (a4 / amino-acid :name (n5 / name :op1 "aspartic" :op2 "acid"~e.17))) :op2 (r / residue~e.28 :mod (a5 / amino-acid :name (n6 / name :op1 "tyrosine"))) :ARG1-of (c / critical-02~e.30 :ARG3~e.31 (e2 / efficient-01~e.32 :ARG2 b~e.33)))) :mod (a / amino-acid~e.16,17)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.37 :op1 (p5 / person :name (n7 / name :op1 "Mongiovi"~e.36)) :op2 (p6 / person :mod (o / other~e.38))) :time (d2 / date-entity :year 1999~e.40))) :time (p7 / previous~e.12)) # ::id pmid_1177_7939.41 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , a peptide encompassing this region should specifically disrupt the Eps8 @–@ E3b1 association . # ::alignments 3-1.1.1.1 4-1.1.1.1.1 5-1.1.1.1.1.1.1 6-1.1.1.1.1.1 7-1.1 8-1.1.1.3 9-1.1.1 11-1.1.1.2.1.1.1 13-1.1.1.2.2.1.1 14-1.1.1.2 (i / infer-01 :ARG1 (r / recommend-01~e.7 :ARG1 (d / disrupt-01~e.9 :ARG0 (p / peptide~e.3 :ARG0-of (e / encompass-01~e.4 :ARG1 (r2 / region~e.6 :mod (t / this~e.5)))) :ARG1 (a / associate-01~e.14 :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8"~e.11)) :ARG2 (p3 / protein :name (n2 / name :op1 "E3b1"~e.13))) :ARG1-of (s / specific-02~e.8)))) # ::id pmid_1177_7939.42 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , no E3b1 could be recovered in anti @-@ myc immunoprecipitates from lysates of Eps8 myc @-@ reconstituted cells , when the immunoprecipitation was performed in the presence of an excess of the competing peptide . # ::alignments 0-1.3 2-1.1 2-1.1.r 3-1.2.1.1.1 4-1 6-1.2 7-1.2.2.r 8-1.2.2.1.2 10-1.2.2.1.2.1.1.1 11-1.2.2 11-1.2.2.1 11-1.2.2.1.r 12-1.2.2.1.1.1.r 13-1.2.2.1.1 16-1.2.2.1.2.1.1.1 18-1.2.2.1.1.1.1.1.2 19-1.2.2.1.1.1 23-1.4.1 25-1.4 26-1.4.2.r 28-1.4.2 29-1.4.2.1.r 31-1.4.2.1 32-1.4.2.1.1.r 34-1.4.2.1.1.1 35-1.4.2.1.1 (p / possible-01~e.4 :polarity~e.2 -~e.2 :ARG1 (r / recover-02~e.6 :ARG1 (p2 / protein :name (n / name :op1 "E3b1"~e.3)) :location~e.7 (p6 / protein~e.11 :ARG1-of~e.11 (i3 / immunoprecipitate-01~e.11 :ARG2 (l / lysate~e.13 :source~e.12 (c5 / cell~e.19 :ARG0-of (c6 / contain-01 :ARG1 (p8 / protein :name (n5 / name :op1 "Eps8myc") :ARG1-of (r2 / reconstitute-01~e.18))))) :ARG0-of (c3 / counter-01~e.8 :ARG1 (p4 / protein :name (n4 / name :op1 "myc"~e.10,16)))))) :mod (i2 / indeed~e.0) :condition (p3 / perform-02~e.25 :ARG1 (i / immunoprecipitate-01~e.23) :condition~e.26 (p7 / present-02~e.28 :ARG1~e.29 (e / exceed-01~e.31 :ARG0~e.32 (p5 / peptide~e.35 :ARG0-of (c4 / compete-01~e.34)))))) # ::id pmid_1177_7939.43 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The association was , however , preserved when a control peptide , bearing a Y→A substitution and unable to bind to Eps8 ( Mongiovi et al. , 1999 ) , was used ( Fig . 1 C ) . # ::alignments 1-1.1.1 4-1 6-1.1 7-1.1.3.1.2.r 9-1.1.2.1.1 10-1.1.2.1 12-1.1.2.1.2 15-1.1.2.1.2.1 17-1.1.2.1.3.2 17-1.1.2.1.3.2.1 17-1.1.2.1.3.2.1.r 19-1.1.2.1.3 20-1.1.2.1.3.1.r 21-1.1.2.1.3.1.1.1 24-1.1.3.1.1.1.1.1 25-1.1.3.1.1 26-1.1.3.1.1.2.1 28-1.1.3.1.2.1 33-1.1.2 36-1.1.2.2.1 (c / contrast-01~e.4 :ARG2 (p / preserve-01~e.6 :ARG1 (a / associate-01~e.1) :condition (u / use-01~e.33 :ARG1 (p2 / peptide~e.10 :purpose (c2 / control-01~e.9) :ARG0-of (b / bear-01~e.12 :ARG1 (s / substitute-01~e.15 :ARG1 (a3 / amino-acid :name (n2 / name :op1 "alanine")) :ARG2 (a2 / amino-acid :name (n / name :op1 "tyrosine")))) :ARG1-of (b2 / bind-01~e.19 :ARG2~e.20 (e / enzyme :name (n3 / name :op1 "Eps8"~e.21)) :ARG1-of (p4 / possible-01~e.17 :polarity~e.17 -~e.17))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.36 :mod "1C"))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and~e.25 :op1 (p6 / person :name (n4 / name :op1 "Mongiovi"~e.24)) :op2 (p7 / person :mod (o / other~e.26))) :time~e.7 (d2 / date-entity :year 1999~e.28))))) # ::id pmid_1177_7939.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , no Sos @-@ 1 could be recovered in anti @-@ myc immunoprecipitates in the presence of the competing , but not of the control , peptide ( Fig . 1 C ) . # ::alignments 0-1.3 2-1.1 2-1.1.r 3-1.2.1.1.1 5-1.2.1.1.1 6-1 6-1.5.1 8-1.2 9-1.2.2.r 10-1.2.2 10-1.2.2.1 10-1.2.2.1.r 12-1.2.2.1.1.1.1 13-1.2.2.2 14-1.6.r 16-1.6 19-1.6.1.1 21-1.5 22-1.1.r 25-1.5.1.2.1 27-1.5.1.2 27-1.6.1 30-1.4.1 32-1.2.1.1.1 (p / possible-01~e.6 :polarity~e.2,22 -~e.2 :ARG1 (r2 / recover-02~e.8 :ARG1 (p2 / protein :name (n / name :op1 "Sos-1"~e.3,5,32)) :location~e.9 (p5 / protein~e.10 :ARG0-of~e.10 (c / counter-01~e.10 :ARG1 (p3 / protein :name (n2 / name :op1 "myc"~e.12))) :ARG1-of (i / immunoprecipitate-01~e.13))) :ARG1-of (r / resemble-01~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "1C")) :ARG1-of (c4 / contrast-01~e.21 :ARG2 (p7 / possible-01~e.6 :ARG1 r2 :condition (p6 / peptide~e.27 :ARG0-of (c3 / control-01~e.25)))) :condition~e.14 (p8 / present-02~e.16 :ARG1 (p4 / peptide~e.27 :ARG0-of (c2 / compete-01~e.19)))) # ::id pmid_1177_7939.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , under physiological conditions , the coimmunoprecipitation of Eps8 and Sos @-@ 1 depends on the integrity of the Eps8 @–@ E3b1 interaction , pointing to the existence of a physiological S/E/E8 complex . # ::alignments 3-1.1.3 4-1.1.3.r 7-1.1.1 8-1.1.1.1.r 9-1.1.1.1.1.1 11-1.1.1.2.1.1 13-1.1.1.2.1.1 14-1.1 15-1.1.2.r 17-1.1.2 18-1.1.2.1.r 20-1.1.2.1.1 22-1.1.2.1.2.1.1 23-1.1.2.1 25-1.1.4 26-1.1.4.1.r 28-1.1.4.1 29-1.1.4.1.1.r 31-1.1.4.1.1.1 33-1.1.4.1.1 (i / infer-01 :ARG1 (d / depend-01~e.14 :ARG0 (c / coimmunoprecipitate-01~e.7 :ARG1~e.8 (e2 / enzyme :name (n / name :op1 "Eps8"~e.9)) :ARG2 (p3 / protein :name (n2 / name :op1 "Sos-1"~e.11,13))) :ARG1~e.15 (i2 / integrity~e.17 :mod~e.18 (i3 / interact-01~e.23 :ARG0 e2~e.20 :ARG1 (p4 / protein :name (n3 / name :op1 "E3b1"~e.22)))) :condition~e.4 (p / physiology~e.3) :ARG0-of (p2 / point-01~e.25 :ARG1~e.26 (e / exist-01~e.28 :ARG1~e.29 (m / macro-molecular-complex~e.33 :mod (p5 / physiology~e.31) :part (s / slash :op1 (p6 / protein :name (n4 / name :op1 "S")) :op2 (p7 / protein :name (n5 / name :op1 "E")) :op3 (p8 / protein :name (n6 / name :op1 "E8")))))))) # ::id pmid_1177_7939.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It cannot be formally excluded that Eps8 , E3b1 , and Sos @-@ 1 associate after cell lysis , thus allowing coimmunoprecipitation . # ::alignments 1-1 1-1.1 1-1.1.r 3-1.2.2 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1.1 8-1.2.1.1.2.1.1 10-1.2.1.1 11-1.2.1.2.1.1 13-1.2.1.2.1.1 14-1.2.1 15-1.2.1.3 16-1.2.1.3.1.1 20-1.2.1.4 21-1.2.1.4.1 (p / possible-01~e.1 :polarity~e.1 -~e.1 :ARG1 (e / exclude-01~e.4 :ARG1~e.5 (a / associate-01~e.14 :ARG1 (a2 / and~e.10 :op1 (e2 / enzyme :name (n / name :op1 "Eps8"~e.6)) :op2 (p3 / protein :name (n2 / name :op1 "E3b1"~e.8))) :ARG2 (p4 / protein :name (n3 / name :op1 "Sos-1"~e.11,13)) :time (a3 / after~e.15 :op1 (l / lyse-01 :ARG1 (c / cell~e.16))) :ARG0-of (a4 / allow-01~e.20 :ARG1 (c3 / coimmunoprecipitate-01~e.21 :ARG1 a2 :ARG2 p4))) :mod (f / formal~e.3))) # ::id pmid_1177_7939.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , we have previously demonstrated ( Scita et al. , 2001 ) that the three endogenous proteins also colocalize in vivo in dynamic actin structures . # ::alignments 0-1 2-1.1.1 4-1.1.3 5-1.1 8-1.1.4.1.1.1.1.1 9-1.1.4.1.1 10-1.1.4.1.1.2.1 12-1.1.4.1.2.1 15-1.1.2.r 17-1.1.2.1.1 18-1.1.2.1.2 19-1.1.2.1 20-1.1.2.3 21-1.1.2 22-1.1.2.4 23-1.1.2.4 24-1.1.2.2.r 24-1.1.2.4 25-1.1.2.2.1 26-1.1.2.2.2 27-1.1.2.2 (c / contrast-01~e.0 :ARG2 (d / demonstrate-01~e.5 :ARG0 (w / we~e.2) :ARG1~e.15 (c2 / colocalize-01~e.21 :ARG1 (p5 / protein~e.19 :quant 3~e.17 :mod (e / endogenous~e.18)) :ARG2~e.24 (s / structure~e.27 :mod (d4 / dynamic~e.25) :mod (a3 / actin~e.26)) :mod (a2 / also~e.20) :manner (i / in-vivo~e.22,23,24)) :time (p / previous~e.4) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and~e.9 :op1 (p3 / person :name (n / name :op1 "Scita"~e.8)) :op2 (p4 / person :mod (o / other~e.10))) :time (d3 / date-entity :year 2001~e.12))))) # ::id pmid_1177_7939.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the sum of our results strongly argues in favor of the existence of a physiological S/E/E8 complex . # ::alignments 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.2 5-1.1.1.1.2.r 6-1.1.1.1 6-1.1.1.1.1 6-1.1.1.1.1.r 7-1.1.3 8-1.1 11-1.1.2.r 13-1.1.2 14-1.1.2.1.r 16-1.1.2.1.1 18-1.1.2.1 (i / infer-01 :ARG1 (a / argue-01~e.8 :ARG0 (s3 / sum~e.3 :mod~e.4 (t / thing~e.6 :ARG2-of~e.6 (r / result-01~e.6) :poss~e.5 (w / we~e.5))) :ARG1~e.11 (e / exist-01~e.13 :ARG1~e.14 (m / macro-molecular-complex~e.18 :mod (p / physiology~e.16) :part (s2 / slash :op1 (p2 / protein :name (n / name :op1 "S")) :op2 (p3 / protein :name (n2 / name :op1 "E")) :op3 (p4 / protein :name (n3 / name :op1 "E8"))))) :ARG1-of (s / strong-02~e.7))) # ::id pmid_1177_7939.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , it cannot be formally excluded that other interactors of the SH3 domain of Eps8 , besides E3b1 , mediate the formation of the endogenous trimeric complex . # ::alignments 0-1.3 3-1 3-1.1 3-1.1.r 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.1.2 12-1.2.1.1.1.1.1 13-1.2.1.1.1.1.2 15-1.2.1.1.1.2.1.1 17-1.2.1.1.3 18-1.2.1.1.3.1.1.1 20-1.2.1 22-1.2.1.2 23-1.2.1.2.1.r 25-1.2.1.2.1.2 26-1.2.1.2.1.1 27-1.2.1.2.1 (p / possible-01~e.3 :polarity~e.3 -~e.3 :ARG1 (e / exclude-01~e.6 :ARG1~e.7 (m / mediate-01~e.20 :ARG0 (i / interact-01 :ARG0 (p4 / protein-segment :name (n3 / name :op1 "SH3"~e.12 :op2 "domain"~e.13) :part-of (e4 / enzyme :name (n2 / name :op1 "Eps8"~e.15))) :mod (o / other~e.8) :ARG2-of (e2 / except-01~e.17 :ARG1 (p2 / protein :name (n / name :op1 "E3b1"~e.18)))) :ARG1 (f2 / form-01~e.22 :ARG1~e.23 (m2 / macro-molecular-complex~e.27 :mod (t / trimeric~e.26) :mod (e3 / endogenous~e.25)))) :mod (f / formal~e.5)) :ARG1-of (r / resemble-01~e.0)) # ::id pmid_1177_7939.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is , however , unlikely since no coimmunoprecipitation between Eps8 and Sos @-@ 1 could be detected when the two proteins were overexpressed in cell lines with relative low levels of E3b1 ( Scita et al. , 1999 ; unpublished data ) . # ::alignments 0-1.1.2 3-1 5-1.1 5-1.1.1 5-1.1.1.r 6-1.1.3 7-1.1.3.1.1 7-1.1.3.1.1.r 8-1.1.3.1.2.1 10-1.1.3.1.2.1.1.2.1 12-1.1.3.1.2.1.2.2.1 14-1.1.3.1.2.1.2.2.1 15-1.1.3.1 17-1.1.3.1.2 18-1.2.1.1.2.r 21-1.1.3.1.2.1.2 21-1.1.3.1.2.2.2.1 23-1.1.3.1.2.2 24-1.1.3.1.2.2.2.r 25-1.1.3.1.2.2.2 26-1.1.3.1.2.2.2 27-1.1.3.1.2.2.2.1.3.r 28-1.1.3.1.2.2.2.1.3.1.1 29-1.1.3.1.2.2.2.1.3.1 30-1.1.3.1.2.2.2.1.3 32-1.1.3.1.2.2.2.1.2.1 35-1.2.1.1.1.1.2.1 36-1.2.1 36-1.2.1.1.1 37-1.2.1.1.1.2.1 39-1.2.1.1.2.1 42-1.2.1.2.1.1 43-1.2.1.2 (c / contrast-01~e.3 :ARG2 (l3 / likely-01~e.5 :polarity~e.5 -~e.5 :ARG1 (t / this~e.0) :ARG1-of (c2 / cause-01~e.6 :ARG0 (p / possible-01~e.15 :polarity~e.7 -~e.7 :ARG1 (d / detect-01~e.17 :ARG1 (c3 / coimmunoprecipitate-01~e.8 :ARG1 (e2 / enzyme :wiki "EPS8" :name (n / name :op1 "Eps8"~e.10)) :ARG2 (p3 / protein~e.21 :wiki "SOS1" :name (n2 / name :op1 "Sos-1"~e.12,14))) :condition (o3 / overexpress-01~e.23 :ARG1 (a4 / and :op1 e2 :op2 p3) :location~e.24 (c4 / cell-line~e.25,26 :part (p4 / protein~e.21 :wiki - :name (n3 / name :op1 "E3b1"~e.32) :quant~e.27 (l / level~e.30 :ARG1-of (l2 / low-04~e.29 :ARG2-of (r / relative-05~e.28)))))))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.36 :op1 (p5 / publication-91 :ARG0 (a2 / and~e.36 :op1 (p6 / person :wiki - :name (n4 / name :op1 "Scita"~e.35)) :op2 (p7 / person :mod (o2 / other~e.37))) :time~e.18 (d3 / date-entity :year 1999~e.39)) :op2 (d4 / data~e.43 :ARG1-of (p8 / publish-01 :polarity -~e.42))))) # ::id pmid_1177_7939.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , neither RN @-@ tre , nor JIK , two other known interactors of the SH3 domain of Eps8 ( Biesova et al. , 1997 ; Mongiovi et al. , 1999 ) , were able to bind to Sos @-@ 1 ( unpublished data ) . # ::alignments 0-1 2-1.2.1 2-1.2.1.r 3-1.1.2.1.1.1.1 5-1.1.2.1.1.1.1 7-1.1.1.r 8-1.1.2.1.2.1.1 11-1.1.2.1.3.2 11-1.1.2.1.4.1.1.1.2.1 12-1.1.2.1.3.3 16-1.1.2.1.3.1.1.1 17-1.1.2.1.3.1.1.2 19-1.1.2.1.3.1.2.1.1 22-1.1.2.1.4.1.1.1.1.1.1 23-1.1.2.1.4.1.1.1 24-1.1.2.1.4.1.1.1.2.1 26-1.1.2.1.4.1.1.2.1 30-1.1.2.1.4.1.2.1.1.1.1 31-1.1.2.1 31-1.1.2.1.4.1 31-1.1.2.1.4.1.2.1 32-1.1.2.1.4.1.2.1.2.1 34-1.1.2.1.4.1.2.2.1 39-1.1 41-1.1.2 42-1.1.2.2.r 43-1.1.2.2.1.1 45-1.1.2.2.1.1 47-1.1.1 47-1.2.1 (a / and~e.0 :op2 (p / possible-01~e.39 :polarity~e.7 -~e.47 :ARG1 (b / bind-01~e.41 :ARG1 (a2 / and~e.31 :op1 (p4 / protein :name (n3 / name :op1 "RN-tre"~e.3,5)) :op2 (p5 / protein :name (n4 / name :op1 "JIK"~e.8)) :ARG0-of (i2 / interact-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "SH3"~e.16 :op2 "domain"~e.17) :part-of (e / enzyme :name (n5 / name :op1 "Eps8"~e.19))) :mod (o / other~e.11) :ARG1-of (k / know-01~e.12)) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.31 :op1 (p7 / publication-91 :ARG0 (a4 / and~e.23 :op1 (p8 / person :name (n6 / name :op1 "Biesova"~e.22)) :op2 (p9 / person :mod (o2 / other~e.11,24))) :time (d2 / date-entity :year 1997~e.26)) :op2 (p10 / publication-91 :ARG0 (a5 / and~e.31 :op1 (p11 / person :name (n7 / name :op1 "Mongiovi"~e.30)) :op2 (p12 / person :mod (o3 / other~e.32))) :time (d3 / date-entity :year 1999~e.34))))) :ARG2~e.42 (p2 / protein :name (n / name :op1 "Sos-1"~e.43,45)))) :ARG1-of (p13 / publish-01 :polarity~e.2 -~e.2,47)) # ::id pmid_1177_7939.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The adaptor molecules , E3b1 and Grb2 , compete for binding to Sos @-@ 1 both in vitro and in vivo # ::alignments 1-1.1.1.3 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 8-1.1 8-1.2 9-1.1.2.r 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2.1.1 14-1.1.2.2.1.1 16-1.1.3 17-1.1.3 19-1.1.3 19-1.2.3.r 20-1.2.3 (a3 / and :op1 (c / compete-01~e.8 :ARG0 (a2 / and~e.5 :op1 (p3 / protein :name (n3 / name :op1 "E3b1"~e.4)) :op2 (p4 / protein :name (n4 / name :op1 "Grb2"~e.6)) :mod (a4 / adaptor~e.1)) :ARG2~e.9 (b2 / bind-01~e.10 :ARG1 a2 :ARG2~e.11 (p / protein :name (n / name :op1 "Sos-1"~e.12,14))) :manner (i / in-vitro~e.16,17,19)) :op2 (c2 / compete-01~e.8 :ARG0 a2 :ARG1 b2 :manner~e.19 (i2 / in-vivo~e.20))) # ::id pmid_1177_7939.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sos @-@ 1 has been shown to be part of a signaling complex with Grb2 , which mediates the activation of Ras upon RTK stimulation . # ::alignments 0-1.1.2.1.1 2-1.1.2.1.1 3-1.1 5-1 8-1.1 11-1.1.1.1 12-1.1.1 13-1.1.1.2.r 14-1.1.1.2.1.1 17-1.1.1.2 17-1.1.1.2.2 17-1.1.1.2.2.r 19-1.1.1.2.2.1 20-1.1.1.2.2.1.1.r 21-1.1.1.2.2.1.1.1.1 23-1.1.1.2.2.1.2.1.1.1 24-1.1.1.2.2.1.2 (s / show-01~e.5 :ARG1 (h / have-part-91~e.3,8 :ARG1 (m / macro-molecular-complex~e.12 :ARG0-of (s2 / signal-07~e.11) :part~e.13 (p2 / protein~e.17 :name (n2 / name :op1 "Grb2"~e.14) :ARG0-of~e.17 (m2 / mediate-01~e.17 :ARG1 (a / activate-01~e.19 :ARG1~e.20 (e / enzyme :name (n3 / name :op1 "Ras"~e.21)) :condition (s3 / stimulate-01~e.24 :ARG1 (e2 / enzyme :name (n4 / name :op1 "RTK"~e.23))))))) :ARG2 (p / protein :name (n / name :op1 "Sos-1"~e.0,2)))) # ::id pmid_1177_7939.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our finding that , under physiological conditions , Sos @-@ 1 also participates in a complex with Eps8 and E3b1 raises the question of the physical and functional relationships between these two Sos @-@ 1 @–@ containing complexes . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 5-1.1.2.2 6-1.1.2.2.r 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 11-1.1.2.1.1.2 15-1.1.2 16-1.1.2.1.r 17-1.1.2.1.2.1.1 18-1.1.2.1 19-1.1.2.1.3.1.1 20-1 22-1.2 23-1.2.1.r 25-1.2.1.2.1 26-1.2.1.2 27-1.2.1.2.2 28-1.2.1 32-1.2.1.3.1.1 33-1.2.1.3.1.1 34-1.2.1.3.1.1 37-1.2.1.3 (r / raise-01~e.20 :ARG0 (f / find-01~e.1 :ARG0~e.0 (w / we~e.0) :ARG1 (m / macro-molecular-complex~e.15 :part~e.16 (a / and~e.18 :op1 (p2 / protein :name (n / name :op1 "Sos-1"~e.8,10) :mod (a2 / also~e.11)) :op2 (e / enzyme :name (n2 / name :op1 "Eps8"~e.17)) :op3 (p4 / protein :name (n3 / name :op1 "E3b1"~e.19))) :condition~e.6 (p / physiology~e.5))) :ARG1 (q / question-01~e.22 :ARG1~e.23 (r2 / relation-03~e.28 :ARG0 a :ARG1 (a5 / and~e.26 :op1 (p5 / physical~e.25) :op2 (f2 / functional~e.27)) :ARG2 (m2 / macro-molecular-complex~e.37 :part (a3 / and :op1 p2~e.32,33,34 :op2 (p6 / protein :name (n4 / name :op1 "Grb2"))))))) # ::id pmid_1177_7939.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To gain insight into this issue , we initially mapped the region of E3b1 responsible for the interaction with Sos @-@ 1 by using a series of deletion mutants of E3b1 fused to glutathione S @ -@ transferase ( GST ) . # ::alignments 0-1.3 3-1.3.2.r 4-1.3.2.1 5-1.3.2 7-1.1 8-1.4 9-1 11-1.2 12-1.2.1.r 13-1.2.1.1.1 14-1.2.2 15-1.2.2.1.r 17-1.2.2.1 18-1.2.2.1.1.r 19-1.2.2.1.1.1.1 21-1.2.2.1.1.1.1 22-1.2.2.1.2.r 23-1.2.2.1.2 25-1.2.2.1.2.2.3 26-1.2.2.1.2.2.3.r 27-1.2.2.1.2.2.4.1 28-1.2.2.1.2.2 28-1.2.2.1.2.2.4 28-1.2.2.1.2.2.4.r 30-1.2.2.1.2.2.1.1 31-1.2.2.1.2.2.2 32-1.2.2.1.2.2.2.1.r 33-1.2.2.1.2.2.2.1.1.1 35-1.2.2.1.2.2.2.1.1.2 38-1.2.2.1.2.2.2.1.1.2 (m / map-01~e.9 :ARG0 (w / we~e.7) :ARG1 (r2 / region~e.11 :part-of~e.12 (p / protein :name (n / name :op1 "E3b1"~e.13)) :ARG0-of (r / responsible-01~e.14 :ARG1~e.15 (i2 / interact-01~e.17 :ARG1~e.18 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.19,21)) :manner~e.22 (u2 / use-01~e.23 :ARG0 w :ARG1 (p3 / protein~e.28 :name (n3 / name :op1 "E3b1"~e.30) :ARG1-of (f / fuse-01~e.31 :ARG3~e.32 (e2 / enzyme :name (n5 / name :op1 "glutathione"~e.33 :op2 "S-transferase"~e.35,38))) :quant~e.26 (s / series~e.25) :ARG2-of~e.28 (m2 / mutate-01~e.28 :manner (d3 / delete-01~e.27))))))) :purpose (u / understand-01~e.0 :ARG0 w :ARG1~e.3 (i3 / issue-02~e.5 :mod (t / this~e.4))) :time (i / initial~e.8)) # ::id pmid_1177_7939.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Native Sos @-@ 1 could be efficiently recovered onto GST @-@ E3b1 full length ( Fig . 2 A , amino acids [ aa ] 2 @–@ 480 ) . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 3-1.1.1.1.1 4-1 6-1.1.2 7-1.1 9-1.1.3.2.1.1 11-1.1.3.2.1.1 12-1.1.3.1 13-1.1.3 16-1.2.1 18-1.2.1.2.1.1 22-1.2.1.2.1 23-1.2.1.2.1 23-1.2.1.2.2 27-1.2.1.2.1.1 29-1.2.1.2.2.1 (p2 / possible-01~e.4 :ARG1 (r / recover-02~e.7 :ARG1 (p / protein :name (n / name :op1 "Sos-1"~e.1,3) :mod (n2 / native~e.0)) :ARG2-of (e / efficient-01~e.6) :manner (l / length~e.13 :degree (f / full~e.12) :poss (p3 / protein :name (n3 / name :op1 "GST-E3b1"~e.9,11)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.16 :mod "2A" :mod (b / between :op1 (a2 / amino-acid~e.22,23 :value 2~e.18,27) :op2 (a3 / amino-acid~e.23 :value 480~e.29))))) # ::id pmid_1177_7939.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further mapping revealed that the SH3 domain of E3b1 ( aa 416 @–@ 480 ) was necessary and sufficient for binding ( Fig . 2 A ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.1.2.1.1 8-1.2.1.2.2.1.1 11-1.2.1.2.3.1.1 13-1.2.1.2.3.2.1 16-1.2.1 17-1.2 17-1.2.1.2.3 18-1.2.2 19-1.2.1.1.r 20-1.2.1.1 23-1.3.1 (r / reveal-01~e.2 :ARG0 (m / map-01~e.1 :degree (f / further~e.0)) :ARG1~e.3 (a / and~e.17 :op1 (n / need-01~e.16 :ARG0~e.19 (b / bind-01~e.20 :ARG2 p) :ARG1 (p / protein-segment :name (n2 / name :op1 "SH3"~e.5) :part-of (p2 / protein :name (n3 / name :op1 "E3b1"~e.8)) :consist-of (b2 / between~e.17 :op1 (a3 / amino-acid :value 416~e.11) :op2 (a4 / amino-acid :value 480~e.13)))) :op2 (s / suffice-01~e.18 :ARG0 p :ARG1 b)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.23 :mod "2A"))) # ::id pmid_1177_7939.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have previously shown that E3b1 binds to the proline @-@ rich , COOH @-@ terminal tail of Sos @-@ 1 ( aa 1131 @–@ 1333 ) ( Scita et al. , 1999 ) , which also binds to the SH3 of Grb2 ( Li et al. , 1993 ; Cussac et al. , 1994 ) . # ::alignments 0-1.1 2-1.3 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2 7-1.2.2.r 9-1.2.2.1.2.1.1.1 11-1.2.2.1.2 13-1.2.2.1.1.1 15-1.2.2.1.1.1 16-1.2.2 18-1.2.2.1.3.1.1 20-1.2.2.1.3.1.1 23-1.2.2.1.5.1.1.1 25-1.2.2.1.5.1.2.1 29-1.2.3.1.1.1.1.1 30-1.2.3.1.1 31-1.2.3.1.1.2.1 33-1.2.3.1.2.1 38-1.2.2.1.4.2 39-1.2.2.1 39-1.2.2.1.4 39-1.2.2.1.4.r 40-1.2.2.1.4.1.r 42-1.2.2.1.4.1.1.1 44-1.2.2.1.4.1.2.1.1 47-1.2.2.1.4.3.1.1.1.1.1.1 48-1.2.2.1.4.3.1.1.1 49-1.2.2.1.4.3.1.1.1.2.1 51-1.2.2.1.4.3.1.1.2.1 55-1.2.2.1.4.3.1.2.1.1.1.1 56-1.2.2.1.4.3.1 56-1.2.2.1.4.3.1.2.1 57-1.2.2.1.4.3.1.2.1.2.1 59-1.2.2.1.4.3.1.2.2.1 (s / show-01~e.3 :ARG0 (w / we~e.0) :ARG1~e.4 (b / bind-01~e.6 :ARG1 (p / protein :name (n / name :op1 "E3b1"~e.5)) :ARG2~e.7 (t / tail~e.16 :part-of (p2 / protein-segment~e.39 :name (n2 / name :op1 "COOH-terminus"~e.13,15) :mod (r / rich~e.11 :topic (a / amino-acid :name (n3 / name :op1 "proline"~e.9))) :part-of (p3 / protein :name (n4 / name :op1 "Sos-1"~e.18,20)) :ARG1-of~e.39 (b2 / bind-01~e.39 :ARG2~e.40 (p7 / protein-segment :name (n6 / name :op1 "SH3"~e.42) :part-of (p8 / protein :name (n7 / name :op1 "Grb2"~e.44))) :mod (a3 / also~e.38) :ARG1-of (d5 / describe-01 :ARG0 (a4 / and~e.56 :op1 (p9 / publication-91 :ARG0 (a5 / and~e.48 :op1 (p10 / person :name (n8 / name :op1 "Li"~e.47)) :op2 (p11 / person :mod (o2 / other~e.49))) :time (d2 / date-entity :year 1993~e.51)) :op2 (p12 / publication-91 :ARG0 (a6 / and~e.56 :op1 (p13 / person :name (n9 / name :op1 "Cussac"~e.55)) :op2 (p14 / person :mod (o3 / other~e.57))) :time (d3 / date-entity :year 1994~e.59))))) :ARG1-of (m / mean-01 :ARG2 (b3 / between :op1 (a8 / amino-acid :value 1131~e.23) :op2 (a9 / amino-acid :value 1333~e.25))))) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and~e.30 :op1 (p5 / person :name (n5 / name :op1 "Scita"~e.29)) :op2 (p6 / person :mod (o / other~e.31))) :time (d / date-entity :year 1999~e.33)))) :time (p15 / previous~e.2)) # ::id pmid_1177_7939.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , Grb2 and E3b1 might compete for binding to Sos @-@ 1 . # ::alignments 2-1.1.1.1.1.1 3-1.1.1.3.1 4-1.1.1.2.1.1 5-1.1 6-1.1.1 7-1.1.1.3.r 8-1.1.1.3 9-1.1.1.3.2.r 10-1.1.1.3.2.1.1 12-1.1.1.3.2.1.1 (i / infer-01 :ARG1 (p / possible-01~e.5 :ARG1 (c / compete-01~e.6 :ARG0 (p2 / protein :name (n / name :op1 "Grb2"~e.2)) :ARG1 (p3 / protein :name (n2 / name :op1 "E3b1"~e.4)) :ARG2~e.7 (b / bind-01~e.8 :ARG1 (a / and~e.3 :op1 p2 :op2 p3) :ARG2~e.9 (p4 / protein :name (n3 / name :op1 "Sos-1"~e.10,12)))))) # ::id pmid_1177_7939.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This hypothesis was validated by a series of experiments performed both in vitro and in vivo . # ::alignments 0-1.2.2 1-1.2 1-1.2.1 1-1.2.1.r 3-1 4-1.1.r 6-1.1 7-1.1.1.r 8-1.1.1 9-1.1.1.1 11-1.1.1.1.1.1 12-1.1.1.1.1.1 13-1.1.1.1.1 14-1.1.1.1.1.1 14-1.1.1.1.1.2 15-1.1.1.1.1.2 (v / validate-01~e.3 :ARG0~e.4 (s / series~e.6 :consist-of~e.7 (e / experiment-01~e.8 :ARG1-of (p / perform-02~e.9 :manner (a / and~e.13 :op1 (i / in-vitro~e.11,12,14) :op2 (i2 / in-vivo~e.14,15))))) :ARG1 (t / thing~e.1 :ARG1-of~e.1 (h / hypothesize-01~e.1) :mod (t2 / this~e.0))) # ::id pmid_1177_7939.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We could demonstrate that ( @ a ) the SH3 of Grb2 , but not of Eps8 , efficiently competed with the SH3 of E3b1 for binding to the proline @-@ rich COOH @-@ terminal tail of Sos @-@ 1 in vitro ( Fig . 2 B ) ; ( b ) the Sos @-@ 1 peptide VPVPPPVPPRRR , known to constitute a Grb2 @-@ SH3 binding site ( Li et al. , 1993 ; Cussac et al. , 1994 ) , competed equally well the binding of the COOH @-@ terminal tail of Sos @-@ 1 to the SH3s of Grb2 or E3b1 ( Fig . 2 C ) ; ( c ) the binding constants of the interaction between the proline rich COOH @-@ terminal tail of Sos @-@ 1 and the SH3 domains of Grb2 and E3b1 were very similar ( Fig . 2 D ) ; ( d ) overexpression of Grb2 abolished the ability of GST @-@ E3b1 to bind to native Sos @-@ 1 ( Fig . 3 A ) ; and ( e ) overexpression of E3b1 significantly decreased the coimmunoprecipitation between Grb2 and Sos @-@ 1 ( Fig . 3 B ) . # ::alignments 0-1.1.1 1-1 2-1.1 7-1.1.2.1.1 10-1.1.2.1.2.1.1 10-1.1.2.1.3.1.1 11-1.1.2.1.5.1 12-1.1.2.1.5.1 13-1.1.2.1.5.1 14-1.1.2.1.5.1 15-1.1.2.1.5.1 16-1.1.2.1.5.1 17-1.1.2.1.5.1 19-1.1.2.1.5 20-1.1.2.1 23-1.1.2.1.2.1.1 23-1.1.2.1.2.3.1.1.1 23-1.1.2.1.3.1.1 24-1.1.2.1.2.3 24-1.1.2.1.3.r 25-1.1.2.1.3.2.1.1 26-1.1.2.1.4.r 27-1.1.2.1.4 28-1.1.2.1.4.1.r 30-1.1.2.1.4.1.1.3.1.1.1 32-1.1.2.1.4.1.1.3 33-1.1.2.1.4.1.1.1.1 35-1.1.2.1.4.1.1.1.1 36-1.1.2.1.4.1 38-1.1.2.1.4.1.1.2.1.1 40-1.1.2.1.4.1.1.2.1.1 41-1.1.2.1.4.2 42-1.1.2.1.4.2 45-1.1.2.1.6.1 45-1.1.2.2.5.1 45-1.1.2.3.5.1 45-1.1.2.4.4.1 45-1.1.2.5.5.1 49-1.1.2.2.1 53-1.1.2.2.1 56-1.1.2.1.4.1.1.2.1.1 58-1.1.2.1.4.1.1.2.1.1 59-1.1.2.1.2.3.1 59-1.1.2.1.4.1.1 59-1.1.2.2.2 60-1.1.2.2.2.1.1 62-1.1.2.2.2.3.3 64-1.1.2.2.2.3 65-1.1.2.1.1 66-1.1.2.1.2.2.1.1 68-1.1.2.1.2.1.1 68-1.1.2.1.2.3.1.1.1 68-1.1.2.1.3.1.1 69-1.1.2.2.2.3.1.1 70-1.1.2.2.2.3.1 73-1.1.2.2.2.3.2.1.1.1.1.1.1 74-1.1.2.2.2.3.2.1.1.1 75-1.1.2.2.2.3.2.1.1.1.2.1 77-1.1.2.2.2.3.2.1.1.2.1 81-1.1.2.2.2.3.2.1.2.1.1.1.1 82-1.1.2.2.2.3.2.1.2.1 83-1.1.2.2.2.3.2.1.2.1.2.1 85-1.1.2.2.2.3.2.1.2.2.1 89-1.1.2.2 90-1.1.2.2.4.1 91-1.1.2.2.4 93-1.1.2.2.3 94-1.1.2.1.2.3 94-1.1.2.2.3.1.r 96-1.1.2.2.3.1 97-1.1.2.2.3.1 98-1.1.2.2.3.1 99-1.1.2.2.3.1 100-1.1.2.2.3.1 101-1.1.2.2.3.1 102-1.1.2.2.3.1 103-1.1.2.2.3.1 107-1.1.2.2.3.2.1 108-1.1.2.2.3.2.1 109-1.1.2.2.3.2 110-1.1.2.2.3.2.2 113-1.1.2.1.6.1 113-1.1.2.2.5.1 113-1.1.2.3.5.1 113-1.1.2.4.4.1 113-1.1.2.5.5.1 117-1.1.2.3.1 121-1.1.2.3.1 124-1.1.2.3.2.1.3 124-1.1.2.3.3.1.3 125-1.1.2.3.2 125-1.1.2.3.3 128-1.1.2.3.2.1 128-1.1.2.3.3.1 131-1.1.2.1.4.1.1.3.1.1.1 132-1.1.2.1.4.1.1.3 133-1.1.2.1.4.1.1.1.1 135-1.1.2.1.4.1.1.1.1 136-1.1.2.1.4.1 137-1.1.2.1.2.3 137-1.1.2.r 138-1.1.2.4.3.2.2.1.1 140-1.1.2.4.3.2.2.1.1 143-1.1.2.1.2.1.1 143-1.1.2.1.2.3.1.1.1 143-1.1.2.1.3.1.1 145-1.1.2.1.2.3 146-1.1.2.1.2.2.1.1 147-1.1.2 147-1.1.2.2.2.3.2.1 148-1.1.2.1.3.2.1.1 150-1.1.2.3.4 151-1.1.2.3 154-1.1.2.1.6.1 154-1.1.2.2.5.1 154-1.1.2.3.5.1 154-1.1.2.4.4.1 154-1.1.2.5.5.1 158-1.1.2.4.1 162-1.1.2.4.1 164-1.1.2.4.2 165-1.1.2.1.2.3 165-1.1.2.4.2.1.r 166-1.1.2.4.2.1 167-1.1.2.4 169-1.1.2.4.3 170-1.1.2.4.3.1.r 171-1.1.2.4.3.1.1.1 173-1.1.2.4.3.1.1.1 175-1.1.2.4.3.2 177-1.1.2.4.3.2.2.2 178-1.1.2.4.3.2.2.1.1 180-1.1.2.4.3.2.2.1.1 183-1.1.2.1.6.1 183-1.1.2.2.5.1 183-1.1.2.3.5.1 183-1.1.2.4.4.1 183-1.1.2.5.5.1 187-1.1.2.1.1 190-1.1.2 190-1.1.2.2.2.3.2.1 192-1.1.2.5.1 194-1.1.2.5.2 195-1.1.2.1.2.3 195-1.1.2.5.2.1.r 196-1.1.2.5.2.1 197-1.1.2.5.4 198-1.1.2.5 202-1.1.2.1.2.2.1.1 203-1.1.2 203-1.1.2.2.2.3.2.1 204-1.1.2.4.3.2.2.1.1 206-1.1.2.4.3.2.2.1.1 209-1.1.2.1.6.1 209-1.1.2.2.5.1 209-1.1.2.3.5.1 209-1.1.2.4.4.1 209-1.1.2.5.5.1 213-1.1.2.2.1 (p / possible-01~e.1 :ARG1 (d3 / demonstrate-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.137 (a2 / and~e.147,190,203 :op1 (c / compete-01~e.20 :li "a"~e.7,65,187 :ARG0 (p2 / protein-segment :name (n2 / name :op1 "SH3"~e.10,23,68,143) :part-of (p3 / protein :name (n3 / name :op1 "Grb2"~e.66,146,202)) :ARG1-of (i / instead-of-91~e.24,94,137,145,165,195 :ARG2 (p4 / protein-segment~e.59 :name (n4 / name :op1 "SH3"~e.23,68,143) :part-of (e3 / enzyme :name (n5 / name :op1 "Eps8"))))) :ARG1~e.24 (p6 / protein-segment :name (n6 / name :op1 "SH3"~e.10,23,68,143) :part-of (p7 / protein :name (n7 / name :op1 "E3b1"~e.25,148))) :ARG2~e.26 (b / bind-01~e.27 :ARG2~e.28 (t2 / tail~e.36,136 :part-of (p8 / protein-segment~e.59 :name (n8 / name :op1 "COOH-terminus"~e.33,35,133,135) :part-of (p19 / protein :name (n9 / name :op1 "Sos-1"~e.38,40,56,58)) :mod (r2 / rich~e.32,132 :topic (a3 / amino-acid :name (n10 / name :op1 "proline"~e.30,131))))) :manner (i2 / in-vitro~e.41,42)) :ARG2-of (e / efficient-01~e.19 :ARG1 p2~e.11,12,13,14,15,16,17) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.45,113,154,183,209 :mod "2B"))) :op2 (c2 / compete-01~e.89 :li "b"~e.49,53,213 :ARG0 (p10 / peptide~e.59 :name (n15 / name :op1 "VPVPPPVPPRRR"~e.60) :part-of p19 :ARG0-of (c3 / constitute-01~e.64 :ARG1 (p9 / protein-segment~e.70 :ARG1-of (b2 / bind-01~e.69 :ARG2 p2)) :ARG1-of (d5 / describe-01 :ARG0 (a5 / and~e.147,190,203 :op1 (p11 / publication-91 :ARG0 (a4 / and~e.74 :op1 (p12 / person :name (n11 / name :op1 "Li"~e.73)) :op2 (p13 / person :mod (o / other~e.75))) :time (d / date-entity :year 1993~e.77)) :op2 (p14 / publication-91 :ARG0 (a6 / and~e.82 :op1 (p15 / person :name (n12 / name :op1 "Cussac"~e.81)) :op2 (p16 / person :mod (o2 / other~e.83))) :time (d2 / date-entity :year 1994~e.85)))) :ARG1-of (k / know-01~e.62))) :ARG1 (b3 / bind-01~e.93 :ARG1~e.94 t2~e.96,97,98,99,100,101,102,103 :ARG2 (o3 / or~e.109 :op1 p2~e.107,108 :op2 p6~e.110)) :mod (w2 / well~e.91 :degree (e2 / equal~e.90)) :ARG1-of (d6 / describe-01 :ARG0 (f2 / figure~e.45,113,154,183,209 :mod "2C"))) :op3 (r / resemble-01~e.151 :li "c"~e.117,121 :ARG1 (c4 / constant~e.125 :value-of (i3 / interact-01~e.128 :ARG0 t2 :ARG1 p2 :ARG0-of (b4 / bind-01~e.124))) :ARG2 (c5 / constant~e.125 :value-of (i4 / interact-01~e.128 :ARG0 t2 :ARG1 p6 :ARG0-of (b5 / bind-01~e.124))) :degree (v / very~e.150) :ARG1-of (d7 / describe-01 :ARG0 (f3 / figure~e.45,113,154,183,209 :mod "2D"))) :op4 (a / abolish-01~e.167 :li "d"~e.158,162 :ARG0 (o4 / overexpress-01~e.164 :ARG1~e.165 p3~e.166) :ARG1 (c7 / capable-01~e.169 :ARG1~e.170 (p18 / protein :name (n / name :op1 "GST-E3b1"~e.171,173)) :ARG2 (b6 / bind-01~e.175 :ARG1 p18 :ARG2 (p20 / protein :name (n13 / name :op1 "Sos-1"~e.138,140,178,180,204,206) :mod (n14 / native~e.177)))) :ARG1-of (d8 / describe-01 :ARG0 (f4 / figure~e.45,113,154,183,209 :mod "3A"))) :op5 (d9 / decrease-01~e.198 :li "e"~e.192 :ARG0 (o5 / overexpress-01~e.194 :ARG1~e.195 p7~e.196) :ARG1 (p17 / precipitate-01 :ARG0 (a7 / antibody) :ARG1 (m / macro-molecular-complex :part p3 :part p19)) :ARG2 (s / significant-02~e.197) :ARG1-of (d10 / describe-01 :ARG0 (f5 / figure~e.45,113,154,183,209 :mod "3B")))))) # ::id pmid_1177_7939.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , Sos @-@ 1 binds either E3b1 or Grb2 , in a mutually exclusive fashion , suggesting that two distinct pools of Sos @-@ 1 exist in the cells . # ::alignments 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1 7-1.1.2.1.1.1 8-1.1.2 9-1.1.2.2.1.1 11-1.1.3.r 13-1.1.3.1 14-1.1.3 17-1.1.4 18-1.1.4.1.r 19-1.1.4.1.1.1 20-1.1.4.1.1.3 21-1.1.4.1.1 22-1.1.4.1.1.2.r 23-1.1.4.1.1.2 24-1.1.4.1.1.2 25-1.1.4.1.1.2 26-1.1.4.1 27-1.1.4.1.2.r 29-1.1.4.1.2 (i / infer-01 :ARG1 (b / bind-01~e.5 :ARG1 (p / protein :name (n / name :op1 "Sos-1"~e.2,4)) :ARG2 (o / or~e.8 :op1 (p2 / protein :name (n2 / name :op1 "E3b1"~e.7)) :op2 (p3 / protein :name (n3 / name :op1 "Grb2"~e.9))) :ARG0-of~e.11 (e / exclusive-02~e.14 :mod (m / mutual~e.13)) :ARG0-of (s / suggest-01~e.17 :ARG1~e.18 (e2 / exist-01~e.26 :ARG1 (p4 / pool~e.21 :quant 2~e.19 :consist-of~e.22 p~e.23,24,25 :mod (d / distinct~e.20)) :location~e.27 (c / cell~e.29))))) # ::id pmid_1177_7939.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this possibility in vivo , we set out to perturb the equilibrium between the Sos @-@ 1 @–@ E3b1 ( S/E ) and Sos @-@ 1 @–@ Grb2 ( S/G ) complexes , by increasing the levels of E3b1 within the cell . # ::alignments 1-1.3 2-1.3.2.1 3-1.3.2 4-1.3.3 5-1.3.3 7-1.1 8-1 9-1 11-1.2 16-1.2.2.1.1.1.1.1 18-1.2.2.1.1.1.1.1 20-1.2.2.1.1.2.1.1 25-1.2.2.1.2.1 26-1.2.2.1.2.1 27-1.2.2.1.2.1 29-1.2.2.1.2.2.1.1 33-1.2.2.1.1 33-1.2.2.1.2 35-1.2.3.r 36-1.2.3 38-1.2.3.2 40-1.2.3.2.1 41-1.2.3.2.1.r 43-1.2.3.3 (s / set-out-06~e.8,9 :ARG0 (w / we~e.7) :ARG1 (p / perturb-01~e.11 :ARG0 w :ARG1 (e / equilibrate-01 :ARG1 (a / and :op1 (m / macro-molecular-complex~e.33 :part (p2 / protein :name (n / name :op1 "Sos-1"~e.16,18)) :part (p3 / protein :name (n2 / name :op1 "E3b1"~e.20))) :op2 (m2 / macro-molecular-complex~e.33 :part p2~e.25,26,27 :part (p4 / protein :name (n3 / name :op1 "Grb2"~e.29))))) :instrument~e.35 (i / increase-01~e.36 :ARG0 w :ARG1 (l / level~e.38 :quant-of~e.41 p3~e.40) :location (c / cell~e.43))) :purpose (t / test-01~e.1 :ARG0 w :ARG1 (p5 / possible-01~e.3 :ARG1 (t2 / this~e.2)) :manner (i2 / in-vivo~e.4,5))) # ::id pmid_1177_7939.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If the two complexes are functionally distinct , then the overexpression of E3b1 , by competing the S/G interaction , should result in ( a ) reduced Sos @-@ 1 recruitment in vivo to active EGFR , ( b ) consequent reduction in Ras activation , as measured by reduced Ras @-@ GTP levels , ( c ) reduced activation of Ras @-@ dependent pathways , as measured by activation of MAPK , and finally ( d ) reduced proliferative response . # ::alignments 0-1.2.r 2-1.2.1.1 3-1.1.2.2.4.1.1 3-1.2.1 5-1.2 6-1.2.2 10-1.1.1 11-1.1.1.1.r 12-1.1.1.1.1.1 15-1.1.3 18-1.1.3.2 20-1 21-1.1 22-1.1.2.1.5 24-1.1.2.1.1 26-1.1.2.1.4 27-1.1.3.2.1.1.1 29-1.1.2.4.2 29-1.1.3.2.1.1.1 30-1.1.2.1 31-1.1.2.1.5 32-1.1.2.1.5 33-1.1.2.1.3.r 34-1.1.2.1.3 34-1.1.2.1.3.2 34-1.1.2.1.3.2.r 35-1.1.2.1.3.1.1 38-1.1.2.2.1 40-1.1.2.2.3 41-1.1.2.2 42-1.1.2.1.5 43-1.1.2.2.2.1.1.1 44-1.1.2.3 47-1.1.2.2.4 49-1.1.2.2 49-1.1.2.2.4.1.2 50-1.1.2.2.4.1.1.1 52-1.1.2.2.4.1.1.2.1.1 53-1.1.2.2.4.1 56-1.1.2.3.1 58-1.1.2.2 58-1.1.2.3.3 59-1.1.2.2.2 59-1.1.2.3 60-1.1.2.3.2.r 61-1.1.2.3.2.1.1 63-1.1.2.3.2.1 64-1.1.2.3.2 66-1.1.2.3.4.r 67-1.1.2.3.4 68-1.1.2.3.4.1.r 69-1.1.2.3.4.1 70-1.1.2.3.4.1.1.r 71-1.1.2.3.4.1.1.1.1 73-1.1.2 74-1.1.2.4.1.r 74-1.1.2.4.2 74-1.1.2.4.2.r 76-1.1.2.4.1 78-1.1.2.4.3 80-1.1.2.4 (r / recommend-01~e.20 :ARG1 (r2 / result-01~e.21 :ARG1 (o / overexpress-01~e.10 :ARG1~e.11 (p2 / protein :name (n4 / name :op1 "E3b1"~e.12))) :ARG2 (a / and~e.73 :op1 (r3 / recruit-01~e.30 :li "a"~e.24 :ARG1 p3 :ARG2~e.33 (e / enzyme~e.34 :name (n / name :op1 "EGFR"~e.35) :ARG0-of~e.34 (a2 / activity-06~e.34)) :ARG1-of (r4 / reduce-01~e.26) :manner (i2 / in-vivo~e.22,31,32,42)) :op2 (r5 / reduce-01~e.41,49,58 :li "b"~e.38 :ARG1 (a3 / activate-01~e.59 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.43))) :ARG1-of (c2 / cause-01~e.40 :ARG0 r3) :ARG1-of (m / measure-01~e.47 :ARG2 (l / level~e.53 :quant-of (m2 / macro-molecular-complex~e.3 :part e2~e.50 :part (s / small-molecule :name (n7 / name :op1 "GTP"~e.52))) :ARG1-of (r6 / reduce-01~e.49)))) :op3 (a4 / activate-01~e.44,59 :li "c"~e.56 :ARG1~e.60 (p5 / pathway~e.64 :ARG0-of (d / depend-01~e.63 :ARG1 e2~e.61)) :ARG1-of (r7 / reduce-01~e.58) :ARG1-of~e.66 (m3 / measure-01~e.67 :ARG2~e.68 (a5 / activate-01~e.69 :ARG1~e.70 (p / pathway :name (n3 / name :op1 "MAPK"~e.71))))) :op4 (r8 / respond-01~e.80 :li~e.74 "d"~e.76 :li~e.74 -1~e.29,74 :ARG1-of (r9 / reduce-01~e.78) :mod (p6 / proliferate-01))) :manner (c / compete-01~e.15 :ARG0 o :ARG1 (i / interact-01~e.18 :ARG0 (p3 / protein :name (n5 / name :op1 "Sos-1"~e.27,29)) :ARG1 (p4 / protein :name (n6 / name :op1 "Grb2"))))) :condition~e.0 (f2 / function-01~e.5 :ARG0 (m4 / macro-molecular-complex~e.3 :quant 2~e.2) :mod (d2 / distinct~e.6))) # ::id pmid_1177_7939.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All of these predictions were confirmed experimentally ( Fig . 4 , A @–@ C ) . # ::alignments 0-1.1.2 2-1.1.3 3-1.1 3-1.1.1 3-1.1.1.r 5-1 6-1.2 9-1.3.1.1 9-1.3.1.2 9-1.3.1.3 14-1.3.1.1.1 16-1.3.1.3.1 (c / confirm-01~e.5 :ARG1 (t / thing~e.3 :ARG1-of~e.3 (p / predict-01~e.3) :mod (a / all~e.0) :mod (t2 / this~e.2)) :manner (e / experiment-01~e.6) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.9 :mod "A"~e.14) :op2 (f2 / figure~e.9 :mod "B") :op3 (f3 / figure~e.9 :mod "C"~e.16)))) # ::id pmid_1177_7939.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We note that our mapping data are at variance with those recently reported by Fan and Goff ( 2000 ) , who concluded that , in vivo @ , the interaction between Sos @-@ 1 and E3b1 @–@ Abi @-@ 1 is mediated by the NH @₂@ -@ terminal portion of the latter . # ::alignments 0-1.1 1-1 2-1.2.2.1 3-1.2.1.2 3-1.2.1.2.r 4-1.2.1.1 5-1.2.1 5-1.2.2 8-1.2 10-1.2.2.1 11-1.2.2.2.2 12-1.2.2.2 15-1.2.2.2.1.1.1.1.1 16-1.2.2.2.1.1 17-1.2.2.2.1.1.2.1.1 19-1.2.2.2.1.2.1 24-1.2.2.2.1.1.3 25-1.2.2.1 27-1.2.2.2.1.1.3.1.3 28-1.2.2.2.1.1.3.1.3 33-1.2.2.2.1.1.3.1.2 35-1.2.2.2.1.1.3.1.2.1.1.1 37-1.2.2.2.1.1.3.1.2.1.1.1 37-1.2.2.2.1.1.3.1.2.2.1.1 43-1.2.2.2.1.1.3.1.2.1.1.1 43-1.2.2.2.1.1.3.1.2.2.1.1 45-1.2.2.2.1.1.3.1 53-1.2.2.2.1.1.3.1.1.1.1 (n2 / note-02~e.1 :ARG0 (w / we~e.0) :ARG1 (v / vary-01~e.8 :ARG1 (d3 / data~e.5 :topic (m / map-01~e.4) :poss~e.3 w~e.3) :compared-to (d4 / data~e.5 :mod (t / that~e.2,10,25) :ARG1-of (r / report-01~e.12 :ARG0 (p / publication-91 :ARG0 (a / and~e.16 :op1 (p2 / person :name (n / name :op1 "Fan"~e.15)) :op2 (p3 / person :name (n3 / name :op1 "Goff"~e.17)) :ARG0-of (c / conclude-01~e.24 :ARG1 (m2 / mediate-01~e.45 :ARG0 (p6 / protein-segment :name (n7 / name :op1 "NH2-terminus"~e.53) :part-of p4) :ARG1 (i / interact-01~e.33 :ARG0 (p5 / protein :name (n4 / name :op1 "Sos-1"~e.35,37,43)) :ARG1 (p4 / protein :name (n5 / name :op1 "E3b1–Abi-1"~e.37,43))) :manner (i2 / in-vivo~e.27,28)))) :time (d / date-entity :year 2000~e.19)) :time (r2 / recent~e.11))))) # ::id pmid_1177_7939.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistently , Fan and Goff ( 2000 ) did not observe competition in vivo between Grb2 and E3b1 for binding to Sos @-@ 1 . # ::alignments 0-1.4 3-1.2.1.1.1 4-1.2 5-1.2.2.1.1 7-1.2.3.1.1 11-1.1 11-1.1.r 12-1 13-1.3 14-1.5 15-1.5 17-1.3.1.1.1 19-1.3.2.1.1 20-1.3.3.r 21-1.3.3 22-1.3.3.1.r 23-1.3.3.1.1.1 25-1.3.3.1.1.1 (o / observe-01~e.12 :polarity~e.11 -~e.11 :ARG0 (a / and~e.4 :op1 (p2 / person :name (n / name :op1 "Fan"~e.3)) :op2 (p3 / person :name (n2 / name :op1 "Goff"~e.5)) :ARG0-of (p / publication-91 :time (d / date-entity :year 2000~e.7))) :ARG1 (c / compete-01~e.13 :ARG0 (p4 / protein :name (n3 / name :op1 "Grb2"~e.17)) :ARG1 (p5 / protein :name (n4 / name :op1 "E3b1"~e.19)) :ARG2~e.20 (b / bind-01~e.21 :ARG2~e.22 (p6 / protein :name (n5 / name :op1 "Sos-1"~e.23,25)))) :manner (c2 / consistent-02~e.0) :manner (i / in-vivo~e.14,15)) # ::id pmid_1177_7939.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although we cannot exclude that the NH @₂@ -@ terminal region of E3b1 @–@ Abi @-@ 1 participates in binding , in vivo @ , we were not able to observe a high @-@ affinity binding surface in that region by in vitro binding experiments ( Fig . 2 A ; Scita et al. , 1999 ) . # ::alignments 0-1.3.r 1-1.2.1 2-1 2-1.1 2-1.1.r 2-1.3 2-1.3.1 2-1.3.1.r 3-1.3.2 4-1.2.3.1 11-1.3.2.2.1.1.1 12-1.2.3 18-1.3.2.2.1.2.1.1 19-1.3.2.2 20-1.3.2.2.2.r 20-1.3.2.2.3 21-1.3.2.2.2 23-1.3.2.2.3 24-1.3.2.2.3 28-1.3.2.1 30-1.1 30-1.1.r 31-1 33-1.2 35-1.2.2.2.1 37-1.2.2.2 38-1.2.2.1 39-1.2.2 40-1.2.4.2 41-1.2.3.1 42-1.2.3 44-1.2.4.2 45-1.2.4.2 46-1.2.4.1 47-1.2.4 50-1.4.1.2 57-1.4.1.1.1.1.1.1 58-1.4.1 58-1.4.1.1.1 59-1.4.1.1.1.2.1 61-1.4.1.1.2.1 (p / possible-01~e.2,31 :polarity~e.2,30 -~e.2,30 :ARG1 (o / observe-01~e.33 :ARG0 (w / we~e.1) :ARG1 (s / surface~e.39 :location-of (b / bind-01~e.38) :mod (a / affinity~e.37 :ARG1-of (h / high-02~e.35))) :location (r / region~e.12,42 :mod (t / that~e.4,41)) :manner (e / experiment-01~e.47 :ARG1 (b2 / bind-01~e.46) :manner (i / in-vitro~e.40,44,45))) :concession~e.0 (p2 / possible-01~e.2 :polarity~e.2 -~e.2 :ARG1 (e2 / exclude-01~e.3 :ARG0 w~e.28 :ARG1 (p3 / participate-01~e.19 :ARG0 (p4 / protein-segment :name (n / name :op1 "NH2-terminus"~e.11) :part-of (p5 / protein :name (n2 / name :op1 "E3b1–Abi-1"~e.18))) :ARG1~e.20 (b3 / bind-01~e.21) :manner (i2 / in-vivo~e.20,23,24)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.58 :op1 (p6 / publication-91 :ARG0 (a2 / and~e.58 :op1 (p7 / person :name (n4 / name :op1 "Scita"~e.57)) :op2 (p8 / person :mod (o2 / other~e.59))) :time (d / date-entity :year 1999~e.61)) :op2 (f / figure~e.50 :mod "2A")))) # ::id pmid_1177_7939.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , under our conditions of analysis , the efficient competition of the SH3 domains of Grb2 and E3b1 for binding to the same Sos @-@ 1 peptide , coupled to the readily detectable biological competition , strongly suggests that the SH3 @-@ mediated contact is the major determinant of the interaction between Sos @-@ 1 and E3b1 . # ::alignments 3-1.5.2 3-1.5.2.r 4-1.5 4-1.5.r 5-1.5.1.r 6-1.5.1 9-1.1.4 10-1.1 13-1.1.1.1.1 13-1.1.2.1.1 14-1.1.1.1.2 14-1.1.2.1.2 15-1.1.1.r 16-1.1.1.2.1.1 17-1.1.2.r 18-1.1.2.2.1.1 19-1.1.3.r 20-1.1.3 21-1.1.3.1.r 23-1.1.3.1.1 24-1.1.3.1.2.1.1 26-1.1.3.1.2.1.1 27-1.1.3.1 29-1.1.5 30-1.1.5.1.r 32-1.1.5.1.2.2 32-1.1.5.1.2.2.r 33-1.1.5.1.2 34-1.1.5.1.1 35-1.1.5.1 37-1.3 38-1 41-1.2.1.1.1.1.1 43-1.2.1.1 44-1.2.1 47-1.2.3 51-1.2.2 53-1.2.2.1 54-1.2.2.1 55-1.2.2.1 57-1.1.2.2.1.1 (s / suggest-01~e.38 :ARG0 (c / compete-01~e.10 :ARG0~e.15 (p8 / protein-segment :name (n6 / name :op1 "SH3"~e.13 :op2 "domain"~e.14) :part-of (p3 / protein :name (n3 / name :op1 "Grb2"~e.16))) :ARG1~e.17 (p / protein-segment :name (n / name :op1 "SH3"~e.13 :op2 "domain"~e.14) :part-of (p4 / protein :name (n4 / name :op1 "E3b1"~e.18,57))) :ARG2~e.19 (b / bind-01~e.20 :ARG2~e.21 (p5 / peptide~e.27 :ARG1-of (s3 / same-01~e.23) :part-of (p6 / protein :name (n5 / name :op1 "Sos-1"~e.24,26)))) :ARG2-of (e / efficient-01~e.9 :ARG1 p) :ARG1-of (c2 / couple-01~e.29 :ARG2~e.30 (c3 / compete-01~e.35 :mod (b2 / biology~e.34) :ARG1-of (d / detect-01~e.33 :ARG1-of (p7 / possible-01) :manner~e.32 (r / ready~e.32))))) :ARG1 (d2 / determine-01 :ARG0 (c4 / contact~e.44 :ARG1-of (m / mediate-01~e.43 :ARG0 (p2 / protein-segment :name (n8 / name :op1 "SH3"~e.41)))) :ARG1 (i / interact-01~e.51 :ARG0 p6~e.53,54,55 :ARG1 p4) :ARG1-of (m2 / major-02~e.47)) :ARG1-of (s2 / strong-02~e.37) :ARG2-of (c6 / contrast-01) :condition~e.4 (c5 / condition~e.4 :mod~e.5 (a / analyze-01~e.6) :poss~e.3 (w / we~e.3))) # ::id pmid_1177_7939.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E3b1 is a limiting factor in Rac activation # ::alignments 0-1.2.1.1 1-1.2.r 3-1.1 4-1 5-1.1.1.r 6-1.1.1.1.1.1 7-1.1.1 (f / factor~e.4 :ARG0-of (l / limit-01~e.3 :ARG1~e.5 (a / activate-01~e.7 :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"~e.6)))) :domain~e.1 (p / protein :name (n / name :op1 "E3b1"~e.0))) # ::id pmid_1177_7939.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The competition between E3b1 and Grb2 for the same binding site on Sos @-@ 1 implies that an individual Sos @-@ 1 molecule can only be part of one GEF complex at a time . # ::alignments 1-1.1 3-1.1.1.1.1 5-1.1.2.1.1 6-1.1.3.r 8-1.1.3.1 9-1.1.3.2 10-1.1.3 11-1.1.3.3.r 12-1.1.3.3.1.1 14-1.1.3.3.1.1 15-1 16-1.2.r 18-1.2.1.2.2 19-1.2.1.2.1 21-1.1.3.3.1.1 21-1.2.1.1.1 22-1.2.1.1 22-1.2.1.2 23-1.2 24-1.2.1.4 26-1.2.1 26-1.2.1.1.2.r 28-1.2.1.1.1 29-1.2.1.1.2.1.1 30-1.2.1.1 31-1.2.1.3 32-1.2.1.3 33-1.2.1.3 (i / imply-01~e.15 :ARG0 (c / compete-01~e.1 :ARG0 (p / protein :name (n / name :op1 "E3b1"~e.3)) :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2"~e.5)) :ARG2~e.6 (p7 / protein-segment~e.10 :ARG1-of (s2 / same-01~e.8) :ARG1-of (b / bind-01~e.9) :part-of~e.11 (p3 / protein :name (n3 / name :op1 "Sos-1"~e.12,14,21)))) :ARG1~e.16 (p4 / possible-01~e.23 :ARG1 (h / have-part-91~e.26 :ARG1 (m / macro-molecular-complex~e.22,30 :quant 1~e.21,28 :part~e.26 (p6 / protein :name (n4 / name :op1 "GEF"~e.29))) :ARG2 (m2 / molecule~e.22 :mod p3~e.19 :mod (i2 / individual~e.18)) :mod (a / at-a-time~e.31,32,33) :mod (o / only~e.24)))) # ::id pmid_1177_7939.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , different pools of Sos @-@ 1 , either bound to Grb2 or to E3b1 , could exist in vivo . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1.1 4-1.1.1.1.2.r 5-1.1.1.1.2.1.1 7-1.1.1.1.2.1.1 10-1.1.1.1.2 10-1.1.1.1.2.2 10-1.1.1.1.2.2.r 11-1.1.1.1.2.2.1.r 12-1.1.1.1.2.2.1.1.1.1 13-1.1.1.1.2.2.1 15-1.1.1.1.2.2.1.2.1.1 17-1.1 18-1.1.1 19-1.1.2 20-1.1.2 (c2 / contrast-01~e.0 :ARG2 (p / possible-01~e.17 :ARG1 (e / exist-01~e.18 :ARG1 (p2 / pool~e.3 :ARG1-of (d / differ-02~e.2) :consist-of~e.4 (p3 / protein~e.10 :name (n / name :op1 "Sos-1"~e.5,7) :ARG1-of~e.10 (b / bind-01~e.10 :ARG2~e.11 (o / or~e.13 :op1 (p4 / protein :name (n2 / name :op1 "Grb2"~e.12)) :op2 (p5 / protein :name (n3 / name :op1 "E3b1"~e.15))))))) :manner (i / in-vivo~e.19,20))) # ::id pmid_1177_7939.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We tried to gain insight into this issue . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.2 5-1.2.2.1.r 6-1.2.2.1.1 7-1.2.2.1 (t2 / try-01~e.1 :ARG0 (w / we~e.0) :ARG1 (g / gain-02~e.3 :ARG0 w :ARG1 (i2 / insight~e.4 :topic~e.5 (i / issue-02~e.7 :mod (t / this~e.6))))) # ::id pmid_1177_7939.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We showed that BIAcore measurements revealed similar kinetic parameters for the SH3 @-@ mediated S/G and S/E interactions ( Fig . 2 D ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1.1 4-1.2.1 4-1.2.1.1 4-1.2.1.1.r 5-1.2 6-1.2.2.1 7-1.2.2.2 8-1.2.2 11-1.2.2.3.3.1.1.1 13-1.2.2.3.3 15-1.2.2.1.1.1 17-1.2.2.1.1 17-1.2.2.3 20-1.3.1 (s / show-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (r2 / reveal-01~e.5 :ARG0 (t / thing~e.4 :ARG1-of~e.4 (m / measure-01~e.4 :ARG0 (c / company :name (n / name :op1 "BIAcore"~e.3)))) :ARG1 (p / parameter~e.8 :ARG1-of (r / resemble-01~e.6 :ARG2 (i2 / interact-01~e.17 :ARG0 (a / and~e.15 :op1 p5 :op2 (p4 / protein :name (n5 / name :op1 "E3b1"))) :ARG1-of m2)) :mod (k / kinetic~e.7) :topic (i / interact-01~e.17 :ARG0 (p5 / protein :name (n3 / name :op1 "Sos-1")) :ARG1 (p3 / protein :name (n4 / name :op1 "Grb2")) :ARG1-of (m2 / mediate-01~e.13 :ARG0 (p2 / protein-segment :name (n2 / name :op1 "SH3"~e.11)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "2D"))) # ::id pmid_1177_7939.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , when we measured the relative abundance of S/G and S/E complexes within the cell , we found a 10 @-@ fold excess of the former ( Fig . 5 A ) , under conditions in which quantitative immunoprecipitation of the adaptor molecules , Grb2 and E3b1 , was achieved ( Fig . 5 A ) . # ::alignments 0-1 2-1.1.3.r 3-1.1.1 4-1.1.3 6-1.1.3.1.3 7-1.1.3.1 12-1.1.2.1 12-1.1.2.2 15-1.1.3.1.2 17-1.1.1 18-1.1 20-1.1.2.3.1 22-1.1.2.3 23-1.1.2 24-1.1.2.3 29-1.1.2.4.1 29-1.1.2.5.2.1 37-1.1.2.5.r 40-1.1.2.5.1.2 41-1.1.2.5.1 42-1.1.2.5.1.1.r 44-1.1.2.5.1.1.3 45-1.1.2.1 47-1.1.2.1.2.1.1 48-1.1.2.5.1.1 49-1.1.2.2.1.1.1 52-1.1.2.5 55-1.1.2.4.1 55-1.1.2.5.2.1 (c3 / contrast-01~e.0 :ARG2 (f / find-01~e.18 :ARG0 (w / we~e.3,17) :ARG1 (e / exceed-01~e.23 :ARG0 (m / macro-molecular-complex~e.12,45 :part (p5 / protein :name (n / name :op1 "Sos-1")) :part (p / protein :name (n2 / name :op1 "Grb2"~e.47))) :ARG1 (m2 / macro-molecular-complex~e.12 :part (p2 / protein :name (n3 / name :op1 "E3b1"~e.49)) :part p5) :ARG2 (p3 / product-of~e.22,24 :op1 10~e.20) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.29,55 :mod "5A")) :condition~e.37 (a2 / achieve-01~e.52 :ARG1 (i / immunoprecipitate-01~e.41 :ARG1~e.42 (a5 / and~e.48 :op1 p :op2 p2 :mod (a4 / adaptor~e.44)) :mod (q / quantity~e.40)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.29,55 :mod "5A")))) :time~e.2 (m3 / measure-01~e.4 :ARG1 (a / abound-01~e.7 :ARG1 (a6 / and :op1 m :op2 m2) :ARG2 (c / cell~e.15) :ARG2-of (r / relative-05~e.6))))) # ::id pmid_1177_7939.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the data indicate that two pools of Sos @-@ 1 , associated with different adaptors , exist simultaneously in the cell . # ::alignments 3-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.1 7-1.1.2.1 8-1.1.2.1.2.r 9-1.1.2.1.2.1.1 11-1.1.2.1.2.1.1 13-1.1.2.1.3 14-1.1.2.1.3.1.r 15-1.1.2.1.3.1.1 16-1.1.2.1.3.1 18-1.1.2 19-1.1.2.2 19-1.1.2.2.r 20-1.1.2.3.r 22-1.1.2.3 (i / infer-01 :ARG1 (i2 / indicate-01~e.4 :ARG0 (d / data~e.3) :ARG1~e.5 (e / exist-01~e.18 :ARG1 (p / pool~e.7 :quant 2~e.6 :consist-of~e.8 (p2 / protein :name (n / name :op1 "Sos-1"~e.9,11)) :ARG1-of (a / associate-01~e.13 :ARG2~e.14 (a2 / adaptor~e.16 :ARG1-of (d2 / differ-02~e.15)))) :manner~e.19 (s / simultaneous~e.19) :location~e.20 (c / cell~e.22)))) # ::id pmid_1177_7939.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok They further suggest that the pool of E3b1 , available for binding to Sos @-@ 1 , is reduced relative to that of Grb2 , and may be rate @-@ limiting . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.r 5-1.2.1.1 5-1.2.1.2 6-1.2.1.1.1.r 7-1.2.1.1.1.1.1 9-1.2.1.1.1 9-1.2.1.1.1.2 9-1.2.1.1.1.2.r 10-1.2.1.1.1.2.1.r 11-1.2.1.1.1.2.1 12-1.2.1.1.1.2.1.2.r 13-1.2.1.1.1.2.1.2.1.1 15-1.2.1.1.1.2.1.2.1.1 18-1.2.1 22-1.2.1.2.1.r 23-1.2.1.2.1.1.1 25-1.2 26-1.2.2 28-1.2.2.1.2 30-1.2.2.1 (s / suggest-01~e.2 :ARG0 (t / they~e.0) :ARG1~e.3 (a3 / and~e.25 :op1 (r / reduce-01~e.18 :ARG1 (p / pool~e.5 :consist-of~e.6 (p3 / protein~e.9 :name (n / name :op1 "E3b1"~e.7) :ARG2-of~e.9 (a / available-02~e.9 :purpose~e.10 (b / bind-01~e.11 :ARG1 p :ARG2~e.12 (p4 / protein :name (n2 / name :op1 "Sos-1"~e.13,15)))))) :compared-to (p5 / pool~e.5 :consist-of~e.22 (p6 / protein :name (n3 / name :op1 "Grb2"~e.23)))) :op2 (p2 / possible-01~e.26 :ARG1 (l / limit-01~e.30 :ARG0 p :ARG1 (r2 / rate~e.28)))) :degree (f / further~e.1)) # ::id pmid_1177_7939.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , overexpression of E3b1 resulted in increased PAK65 activity , an indicator of Rac activation ( Manser et al. , 1994 ) ( Fig . 5 B ) , which was abrogated by a dominant negative Rac mutant ( Fig . 5 B ) . # ::alignments 0-1.4 2-1.1 3-1.1.1.r 4-1.1.1.1.1 5-1 6-1.2.r 7-1.2.2 8-1.2.1.1.1 9-1.2 12-1.2.3 13-1.2.3.1.r 14-1.2.3.1.1.1.1 15-1.2.3.1 18-1.3.1.1.1.1.1.1 19-1.3.1 19-1.3.1.1.1 20-1.3.1.1.1.2.1 22-1.3.1.1.2.1 27-1.3.1.2 36-1.2.3.1.2 37-1.2.3.1.2.1.r 39-1.2.3.1.2.1 39-1.2.3.1.2.1.2 39-1.2.3.1.2.1.2.r 41-1.2.3.1.2.1.1.1 42-1.2.3.1.2.1.3 45-1.3.1.2 (r / result-01~e.5 :ARG1 (o / overexpress-01~e.2 :ARG1~e.3 (p4 / protein :name (n / name :op1 "E3b1"~e.4))) :ARG2~e.6 (a / activity-06~e.9 :ARG0 (e4 / enzyme :name (n2 / name :op1 "PAK65"~e.8)) :ARG1-of (i2 / increase-01~e.7) :ARG0-of (i / indicate-01~e.12 :ARG1~e.13 (a2 / activate-01~e.15 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Rac"~e.14)) :ARG1-of (a3 / abrogate-01~e.36 :ARG2~e.37 (e3 / enzyme~e.39 :name (n5 / name :op1 "Rac"~e.41) :ARG0-of~e.39 (d4 / dominate-01~e.39) :ARG1-of (m / mutate-01~e.42 :mod "-/-")) :ARG1-of (d5 / describe-01 :ARG0 f2))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.19 :op1 (p / publication-91 :ARG0 (a4 / and~e.19 :op1 (p2 / person :name (n4 / name :op1 "Manser"~e.18)) :op2 (p5 / person :mod (o2 / other~e.20))) :time (d3 / date-entity :year 1994~e.22)) :op2 (f2 / figure~e.27,45 :mod "5B"))) :mod (i3 / indeed~e.0)) # ::id pmid_1177_7939.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , overexpression of Sos @-@ 1 did not lead to increased PAK65 activity . # ::alignments 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1 9-1.1.2.1.1.1 11-1.1.1 11-1.1.1.r 12-1.1 14-1.1.3.2 15-1.1.3.1.1.1 16-1.1.3 (c / contrast-01 :ARG2 (l / lead-03~e.12 :polarity~e.11 -~e.11 :ARG0 (o2 / overexpress-01~e.5 :ARG1~e.6 (p / protein :name (n / name :op1 "Sos-1"~e.7,9))) :ARG2 (a / activity-06~e.16 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PAK65"~e.15)) :ARG1-of (i2 / increase-01~e.14)))) # ::id pmid_1177_7939.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok An additional corollary of this hypothesis is that the overexpression of E3b1 , by facilitating the formation of a trimeric complex with Eps8 and Sos @-@ 1 , should directly lead to activation of Rac . # ::alignments 2-1 4-1.2.1.2 5-1.2.1 5-1.2.1.1 5-1.2.1.1.r 6-1.1.r 9-1.1.1.1 10-1.1.1.1.1.r 11-1.1.1.1.1.1.1 14-1.1.1.4 16-1.1.1.4.2 20-1.1.1.4.2.1 21-1.1.1.4.2.1.2.r 22-1.1.1.4.2.1.2.1.1 24-1.1.1.4.2.1.3.1.1 26-1.1.1.4.2.1.3.1.1 28-1.1 29-1.1.1.3 30-1.1.1 31-1.1.1.2.r 32-1.1.1.2 33-1.1.1.2.1.r 34-1.1.1.2.1.1.1 (c / corollary~e.2 :domain~e.6 (r / recommend-01~e.28 :ARG1 (l / lead-03~e.30 :ARG0 (o / overexpress-01~e.9 :ARG1~e.10 (p2 / protein :name (n2 / name :op1 "E3b1"~e.11))) :ARG2~e.31 (a / activate-01~e.32 :ARG1~e.33 (e / enzyme :name (n / name :op1 "Rac"~e.34))) :ARG1-of (d / direct-02~e.29) :manner (f / facilitate-01~e.14 :ARG0 o :ARG1 (f2 / form-01~e.16 :ARG1 (m / macro-molecular-complex~e.20 :part p2 :part~e.21 (e2 / enzyme :name (n3 / name :op1 "Eps8"~e.22)) :part (p3 / protein :name (n4 / name :op1 "Sos-1"~e.24,26)) :mod (t3 / trimer)))))) :ARG0-of (a2 / add-01 :ARG1 (t2 / thing~e.5 :ARG1-of~e.5 (h / hypothesize-01~e.5) :mod (t / this~e.4)))) # ::id pmid_1177_7939.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this prediction E3b1 or a mutant of E3b1 ( E3b1 @-@ DY ) , bearing alanine substitutions of the DY residues critical for the interaction with Eps8 ( Mongiovi et al. , 1999 ) , were used to infect wild @-@ type and eps8 @^−/− fibroblasts . # ::alignments 1-1.2.3 2-1.2.3.1.2 3-1.2.3.1 3-1.2.3.1.1 3-1.2.3.1.1.r 4-1.1.1.1.1 5-1.1 7-1.1.2 7-1.1.2.2 7-1.1.2.2.r 7-1.2.1.2.1 9-1.1.1.1.1 11-1.1.1.1.1 13-1.1.2.1.1 16-1.1.2.3 17-1.1.2.3.1.1.1.1 18-1.1.2.3.1 19-1.1.2.3.1.2.r 21-1.1.2.3.1.2.1.1.1 22-1.1.2.3.1.2 23-1.1.2.3.1.2.2 24-1.1.2.3.1.2.2.1.r 26-1.1.2.3.1.2.2.1 27-1.1.2.3.1.2.2.1.2.r 28-1.1.2.3.1.2.2.1.2.1.1 31-1.2.3.2.1.1.1.1.1 32-1.2.3.2.1.1 33-1.2.3.2.1.1.2.1 35-1.2.3.2.1.2.1 40-1 40-1.2.3.r 42-1.2 43-1.2.1.1.1 45-1.2.1.1.1 46-1.2.1 47-1.1.2.3.1.2.2.1.2.1.1 51-1.2.1.1 51-1.2.1.2 (u / use-01~e.40 :ARG1 (o / or~e.5 :op1 (p / protein :name (n2 / name :op1 "E3b1"~e.4,9,11)) :op2 (p2 / protein~e.7 :name (n3 / name :op1 "E3b1-DY"~e.13) :ARG2-of~e.7 (m / mutate-01~e.7 :ARG1 p) :ARG0-of (b / bear-01~e.16 :ARG1 (s / substitute-01~e.18 :ARG1 (a / amino-acid :name (n / name :op1 "alanine"~e.17)) :ARG2~e.19 (r / residue~e.22 :mod (p8 / protein-segment :name (n4 / name :op1 "DY"~e.21)) :ARG1-of (c / critical-02~e.23 :ARG3~e.24 (i / interact-01~e.26 :ARG0 p2 :ARG1~e.27 (e2 / enzyme :name (n5 / name :op1 "Eps8"~e.28,47))))))))) :ARG2 (i2 / infect-01~e.42 :ARG1 (a2 / and~e.46 :op1 (f / fibroblast~e.51 :mod (w / wild-type~e.43,45)) :op2 (f2 / fibroblast~e.51 :ARG0-of (m2 / mutate-01~e.7 :ARG1 e2))) :ARG2 o :purpose~e.40 (t2 / test-01~e.1 :ARG1 (t3 / thing~e.3 :ARG1-of~e.3 (p3 / predict-01~e.3) :mod (t4 / this~e.2)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.32 :op1 (p6 / person :name (n7 / name :op1 "Mongiovi"~e.31)) :op2 (p7 / person :mod (o2 / other~e.33))) :time (d3 / date-entity :year 1999~e.35)))))) # ::id pmid_1177_7939.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of GTP @-@ bound Rac were then determined by in vitro binding assays using the immobilized CRIB domain of PAK65 ( Manser et al. , 1994 ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2.1.1.1 5-1.1.1 5-1.1.1.2 5-1.1.1.2.r 6-1.1.1.1.1 8-1.4 9-1 10-1.2.r 11-1.2.3 12-1.2.3 13-1.2.1 14-1.2 15-1.2.2 17-1.2.2.1.3 18-1.2.2.1.1.1 19-1.2.2.1.1.2 21-1.2.2.1.4.1.1 24-1.3.1.1.1.1.1 25-1.3.1.1 26-1.3.1.1.2.1 28-1.3.1.2.1 (d2 / determine-01~e.9 :ARG1 (l / level~e.1 :quant-of~e.2 (e / enzyme~e.5 :name (n / name :op1 "Rac"~e.6) :ARG2-of~e.5 (b / bind-01~e.5 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"~e.3))))) :ARG2~e.10 (a / assay-01~e.14 :ARG1 (b2 / bind-01~e.13) :ARG0-of (u / use-01~e.15 :ARG1 (p5 / protein-segment :name (n6 / name :op1 "CRIB"~e.18 :op2 "domain"~e.19) :ARG1-of (m / mobilize-01 :polarity -) :ARG1-of (i2 / immobilize-01~e.17) :part-of (e2 / enzyme :name (n4 / name :op1 "PAK65"~e.21)))) :manner (i / in-vitro~e.11,12)) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.25 :op1 (p4 / person :name (n3 / name :op1 "Manser"~e.24)) :op2 (p6 / person :mod (o / other~e.26))) :time (d5 / date-entity :year 1994~e.28))) :time (t / then~e.8)) # ::id pmid_1177_7939.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E3b1 , but not the E3b1 mutant impaired in Eps8 binding , caused a readily detectable increase in Rac @-@ GTP levels in wild type , but not in eps8 @^−/− fibroblasts ( Fig . 5 C ) . # ::alignments 0-1.1.1.1.1 0-1.2.2.1.1 2-1 3-1.2.1 3-1.2.1.r 5-1.1.1.1.1 5-1.2.2.1.1 6-1.1.2.3.2.1.3.1 6-1.1.2.3.2.1.3.1.2 6-1.1.2.3.2.1.3.1.2.r 6-1.2.2 6-1.2.2.2 6-1.2.2.2.r 7-1.2.2.3 8-1.2.2.3.1.r 9-1.2.2.3.1.2.1.1 10-1.2.2.3.1 12-1.1 12-1.2 14-1.1.2.2.2 14-1.1.2.2.2.r 15-1.1.2.2 16-1.1.2 17-1.1.2.1.r 18-1.1.2.1.1.1.1.1 20-1.1.2.1.1.2.1.1 21-1.1.2.1 23-1.1.2.3.1.1 24-1.1.2.3.1.1 26-1.1.2.3.2 27-1.1.2.3.2.1.1 27-1.1.2.3.2.1.1.r 29-1.1.2.3.2.1.3.1.1.1 31-1.1.2.3.2.1.3.1.2.1 33-1.1.2.3.1 33-1.1.2.3.2.1.3 36-1.3.1 (c3 / contrast-01~e.2 :ARG1 (c / cause-01~e.12 :ARG0 (p / protein :name (n / name :op1 "E3b1"~e.0,5)) :ARG1 (i / increase-01~e.16 :ARG1~e.17 (l / level~e.21 :quant-of (m3 / macro-molecular-complex :part (e2 / enzyme :name (n2 / name :op1 "Rac"~e.18)) :part (s / small-molecule :name (n6 / name :op1 "GTP"~e.20)))) :ARG1-of (d3 / detect-01~e.15 :ARG1-of (p3 / possible-01) :manner~e.14 (r / ready~e.14)) :ARG1-of (b2 / be-located-at-91 :ARG2 (f4 / fibroblast~e.33 :mod (w2 / wild-type~e.23,24)) :ARG1-of (c2 / contrast-01~e.26 :ARG2 (b3 / be-located-at-91 :polarity~e.27 -~e.27 :ARG1 i :ARG2 (f3 / fibroblast~e.33 :mod (e / enzyme~e.6 :name (n3 / name :op1 "eps8"~e.29) :ARG2-of~e.6 (m2 / mutate-01~e.6 :mod "−/−"~e.31)))))))) :ARG2 (c4 / cause-01~e.12 :polarity~e.3 -~e.3 :ARG0 (p4 / protein~e.6 :name (n4 / name :op1 "E3b1"~e.0,5) :ARG1-of~e.6 (m / mutate-01~e.6) :ARG1-of (i2 / impair-01~e.7 :ARG0~e.8 (b / bind-01~e.10 :ARG1 p4 :ARG2 (e3 / enzyme :name (n5 / name :op1 "Eps8"~e.9))))) :ARG1 i) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.36 :mod "5C"))) # ::id pmid_1177_7939.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the overexpression of E3b1 is sufficient to activate Rac and this effect is strictly dependent on Eps8 @ . # ::alignments 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1.1.1 7-1.1.1 9-1.1.1.2 10-1.1.1.2.2.1.1 11-1.1 12-1.1.2.1.1 13-1.1.2.1 15-1.1.2.3 16-1.1.2 17-1.1.2.2.r 18-1.1.2.2.1.1 (i2 / infer-01 :ARG1 (a2 / and~e.11 :op1 (s / suffice-01~e.7 :ARG0 (o / overexpress-01~e.3 :ARG1~e.4 (p / protein :name (n / name :op1 "E3b1"~e.5))) :ARG1 (a / activate-01~e.9 :ARG0 o :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"~e.10)))) :op2 (d / depend-01~e.16 :ARG0 (e2 / effect~e.13 :mod (t / this~e.12)) :ARG1~e.17 (e3 / enzyme :name (n3 / name :op1 "Eps8"~e.18)) :mod (s2 / strict~e.15)))) # ::id pmid_1177_7939.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The indispensability of E3b1 in the cascade of events leading to Rac activation and Rac @-@ dependent actin reorganization was further analyzed at the biological level . # ::alignments 3-1.1.1.1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1 9-1.1.2.1.1 10-1.1.2.1.1.1.r 11-1.1.2.1.1.1.1.1.1.1 12-1.1.2.1.1.1.1 14-1.1.2.1.1.1.1.1.1.1 16-1.1.2.1.1.1.2.1 16-1.1.2.1.1.1.2.1.2 16-1.1.2.1.1.1.2.1.2.r 17-1.1.2.1.1.1.2.1.1.1 18-1.1.2.1.1.1.2 20-1.2 21-1 22-1.3.r 24-1.3.1 25-1.3 (a / analyze-01~e.21 :ARG1 (i / indispensable-01 :ARG1 (e / enzyme :name (n / name :op1 "E3b1"~e.3)) :ARG2 (c / cascade-01~e.6 :subevent~e.7 (e2 / event~e.8 :ARG0-of (l / lead-03~e.9 :ARG2~e.10 (a4 / and :op1 (a2 / activate-01~e.12 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Rac"~e.11,14))) :op2 (r / reorganize-01~e.18 :ARG1 (p2 / protein~e.16 :name (n3 / name :op1 "actin"~e.17) :ARG0-of~e.16 (d2 / depend-01~e.16 :ARG1 e3)))))))) :time (f / further~e.20) :manner~e.22 (l2 / level~e.25 :mod (b / biology~e.24))) # ::id pmid_1177_7939.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have previously shown that interference with E3b1 functions , by microinjection of anti @-@ E3b1 antibodies , inhibited PDGF @-@ induced ruffles ( Scita et al. 1999 ) . # ::alignments 0-1.1 2-1.3 3-1 4-1.2.r 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.1.1.1 8-1.2.1.1 13-1.2.1.2.1.1 15-1.2.1.2.1.1.1 16-1.2.1.2.1 18-1.2 19-1.2.2.1.1.1.1 21-1.2.2.1 22-1.2.2 25-1.4.1.1.1.1.1 26-1.4.1.1 27-1.4.1.1.2.1 28-1.4.1.2.1 (s / show-01~e.3 :ARG0 (w2 / we~e.0) :ARG1~e.4 (i3 / inhibit-01~e.18 :ARG0 (i / interfere-01~e.5 :ARG1~e.6 (f / function-01~e.8 :ARG0 (p6 / protein :name (n / name :op1 "E3b1"~e.7))) :manner (m / microinject-01 :ARG1 (a / antibody~e.16 :ARG0-of (c / counter-01~e.13 :ARG1 f~e.15)) :ARG2 f)) :ARG1 (r / ruffle-02~e.22 :ARG2-of (i4 / induce-01~e.21 :ARG0 (p5 / protein :name (n3 / name :op1 "PDGF"~e.19))))) :time (p / previous~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and~e.26 :op1 (p2 / person :name (n2 / name :op1 "Scita"~e.25)) :op2 (p3 / person :mod (o / other~e.27))) :time (d3 / date-entity :year 1999~e.28)))) # ::id pmid_1177_7939.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also showed that in eps8 @^−/− cells , ruffling induced by PDGF and activated Ras , but not by activated Rac , was inhibited . # ::alignments 0-1.1 1-1.3 2-1 4-1.4.r 5-1.4.1.1.1 7-1.4.1.2.1 9-1.4 11-1.2.1 12-1.2.1.1 12-1.2.1.1.2.1 13-1.2.1.1.1.r 14-1.2.1.1.1.1.1.1 15-1.2.1.1.1 16-1.2.1.1.1.2.2 17-1.2.1.1.1.2.1.1 19-1.2.1.1.2 20-1.2.1.1.2.1.1 20-1.2.1.1.2.1.1.r 21-1.2.1.1.2.1.2.r 22-1.2.1.1.2.1.2.2 23-1.2.1.1.2.1.2.1.1 26-1.2 (s / show-01~e.2 :ARG0 (w / we~e.0) :ARG1 (i / inhibit-01~e.26 :ARG1 (r / ruffle-02~e.11 :ARG2-of (i2 / induce-01~e.12 :ARG0~e.13 (a2 / and~e.15 :op1 (p / protein :name (n3 / name :op1 "PDGF"~e.14)) :op2 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.17) :ARG1-of (a3 / activate-01~e.16))) :ARG1-of (c2 / contrast-01~e.19 :ARG2 (i3 / induce-01~e.12 :polarity~e.20 -~e.20 :ARG0~e.21 (e3 / enzyme :name (n5 / name :op1 "Rac"~e.23) :ARG1-of a3~e.22) :ARG2 r))))) :mod (a / also~e.1) :location~e.4 (c / cell~e.9 :part (e / enzyme :name (n / name :op1 "eps8"~e.5) :ARG2-of (m / mutate-01 :mod "−/−"~e.7)))) # ::id pmid_1177_7939.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ruffling , however , could be restored upon reexpression of Eps8 , but not of an Eps8 mutant unable to bind to E3b1 ( Scita et al. , 1999 ) , suggesting that the Eps8 @–@ E3b1 @-@ based complex is implicated in the transmission of signal between Ras and Rac . # ::alignments 0-1.1.1.2 2-1 4-1.1 4-1.1.1.1.1.2.1 6-1.1.1 6-1.1.1.1.1.2.1.2 10-1.1.1.1.1.1.1 12-1.1.1.1.1 12-1.1.1.1.1.2 12-1.1.1.1.1.2.r 13-1.1.1.1.1.2.1.1.r 16-1.1.1.1.1.2.1.2.1.1.1.1 17-1.1.1.1.1.2.1.2.1.1 17-1.1.1.1.1.2.1.2.1.1.2 17-1.1.1.1.1.2.1.2.1.1.2.r 18-1.1.1.1.1.2.1.1 18-1.1.1.1.1.2.1.2.1.1.3.2 18-1.1.1.1.1.2.1.2.1.1.3.2.1 18-1.1.1.1.1.2.1.2.1.1.3.2.1.r 20-1.1.1.1.1.2.1.2.1.1.3 21-1.1.1.1.1.2.1.2.1.1.3.1.r 22-1.1.1.1.1.2.1.2.1.1.3.1.1.1 25-1.2.1.1.1.1.1 26-1.2.1.1 27-1.2.1.1.2.1 29-1.2.1.2.1 33-1.1.2 34-1.1.2.1.r 36-1.1.2.1.1.1.1.1 37-1.1.2.1.1.1.1.1 38-1.1.2.1.1.1.1.2 40-1.1.2.1.1.1 41-1.1.2.1.1 43-1.1.2.1 44-1.1.2.1.2.r 46-1.1.2.1.2 47-1.1.2.1.2.2.r 48-1.1.2.1.2.2 50-1.1.2.1.2.1.1.1 52-1.1.2.1.2.3.1.1 (c2 / contrast-01~e.2 :ARG2 (p / possible-01~e.4 :ARG1 (r / restore-01~e.6 :ARG0 (e2 / express-03 :ARG2 (e5 / enzyme~e.12 :name (n2 / name :op1 "Eps8"~e.10) :ARG1-of~e.12 (c4 / contrast-01~e.12 :ARG2 (p6 / possible-01~e.4 :polarity~e.13 -~e.18 :ARG1 (r3 / restore-01~e.6 :ARG0 (e6 / express-03 :ARG2 (e7 / enzyme~e.17 :name (n3 / name :op1 "Eps8"~e.16) :ARG1-of~e.17 (m / mutate-01~e.17) :ARG1-of (b / bind-01~e.20 :ARG2~e.21 (p7 / protein :name (n4 / name :op1 "E3b1"~e.22)) :ARG1-of (p4 / possible-01~e.18 :polarity~e.18 -~e.18)))) :ARG1 r2 :mod a2)))) :mod (a2 / again)) :ARG1 (r2 / ruffle-02~e.0)) :ARG0-of (s / suggest-01~e.33 :ARG1~e.34 (i / implicate-01~e.43 :ARG1 (c / complex~e.41 :ARG1-of (b2 / base-02~e.40 :ARG2 (a / and :op1 e5~e.36,37 :op2 p7~e.38))) :ARG2~e.44 (t / transmit-01~e.46 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.50)) :ARG1~e.47 (s2 / signal-07~e.48) :ARG2 (e4 / enzyme :name (n6 / name :op1 "Rac"~e.52)))))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and~e.26 :op1 (p2 / person :name (n7 / name :op1 "Scita"~e.25)) :op2 (p3 / person :mod (o / other~e.27))) :time (d3 / date-entity :year 1999~e.29)))) # ::id pmid_1177_7939.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , one might predict that a mutant of E3b1 unable to associate to Eps8 should function as a dominant negative on Ras @-@ induced Rac @-@ dependent ruffling . # ::alignments 2-1.1.1.1 3-1.1 4-1.1.1 5-1.1.1.2.r 7-1.1.1.2.1.1 7-1.1.1.2.1.1.2 7-1.1.1.2.1.1.2.r 7-1.1.1.2.1.2 9-1.1.1.2.1.1.1.1 10-1.1.1.2.1.1.3.2 10-1.1.1.2.1.1.3.2.1 10-1.1.1.2.1.1.3.2.1.r 12-1.1.1.2.1.1.3 13-1.1.1.2.1.1.3.1.r 14-1.1.1.2.1.1.3.1.1.1 15-1.1.1.2 16-1.1.1.2.1 17-1.1.1.2.1.2.2.r 17-1.1.1.2.1.2.3.r 19-1.1.1.2.1.2.2 22-1.1.1.2.1.2.3.1.1.1.1 24-1.1.1.2.1.2.3.1 25-1.1.1.2.1.2.3.2.1.1.1 27-1.1.1.2.1.2.3.2 28-1.1.1.2.1.2.3 (i2 / infer-01 :ARG1 (p5 / possible-01~e.3 :ARG1 (p6 / predict-01~e.4 :ARG0 (o / one~e.2) :ARG1~e.5 (r2 / recommend-01~e.15 :ARG1 (f / function-01~e.16 :ARG0 (p2 / protein~e.7 :name (n / name :op1 "E3b1"~e.9) :ARG1-of~e.7 (m / mutate-01~e.7) :ARG1-of (a / associate-01~e.12 :ARG2~e.13 (e2 / enzyme :name (n2 / name :op1 "Eps8"~e.14)) :ARG1-of (p / possible-01~e.10 :polarity~e.10 -~e.10))) :ARG1 (m2 / mutate-01~e.7 :mod "-/-" :ARG0-of~e.17 (d / dominate-01~e.19) :time~e.17 (r3 / ruffle-02~e.28 :ARG2-of (i / induce-01~e.24 :ARG0 (e3 / enzyme :name (n4 / name :op1 "Ras"~e.22))) :ARG0-of (d2 / depend-01~e.27 :ARG1 (e4 / enzyme :name (n5 / name :op1 "Rac"~e.25)))))))))) # ::id pmid_1177_7939.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this , we cotransfected the activated versions of either Ras or Rac , together with E3b1 or the E3b1DY mutant . # ::alignments 1-1.3 2-1.3.2 4-1.1 5-1 7-1.2.1.1.1 7-1.2.1.2.2 8-1.2.1.1 8-1.2.1.2 11-1.2.1.1.2.1.1 12-1.2.1 13-1.2.1.2.1.1.1 16-1.2.r 17-1.2.2.1.1.1 18-1.2.2 20-1.2.2.2.1.1 21-1.2.2.1 21-1.2.2.1.2 21-1.2.2.1.2.r 21-1.2.2.2 21-1.2.2.2.2 21-1.2.2.2.2.r (c / cotransfect-01~e.5 :ARG0 (w / we~e.4) :ARG2~e.16 (a3 / and :op1 (o2 / or~e.12 :op1 (v / version~e.8 :ARG1-of (a / activate-01~e.7) :mod (e4 / enzyme :name (n5 / name :op1 "Ras"~e.11))) :op2 (v2 / version~e.8 :mod (e3 / enzyme :name (n2 / name :op1 "Rac"~e.13)) :ARG1-of (a2 / activate-01~e.7))) :op2 (o / or~e.18 :op1 (p / protein~e.21 :name (n3 / name :op1 "E3b1"~e.17) :ARG1-of~e.21 (m / mutate-01~e.21)) :op2 (p2 / protein~e.21 :name (n4 / name :op1 "E3b1DY"~e.20) :ARG1-of~e.21 (m2 / mutate-01~e.21)))) :purpose (t3 / test-01~e.1 :ARG0 w :ARG1 (t4 / this~e.2))) # ::id pmid_1177_7939.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RasV12 @-@ induced , but not RacQL @-@ induced , ruffles were efficiently inhibited by the coexpression of E3b1DY , but not of E3b1 wild type ( Fig . 6 ) , supporting the contention that the ability of E3b1 to form a complex with Eps8 is required to transmit signals from Ras to Rac . # ::alignments 2-1.2.1.1.3.1 4-1.2.1.1 4-1.2.1.1.3 4-1.2.1.1.3.r 5-1.2.1.1.3.1.1.1 8-1.2.1 10-1.2 12-1.3 13-1 13-1.6.1 20-1.6 21-1.6.1.1 21-1.6.1.1.r 21-1.6.1.2.1 21-1.6.1.2.1.r 23-1.6.1.2.2.2.1 24-1.6.1.2.2.3 25-1.6.1.2.2.3 28-1.4.1 30-1.4.1.1 34-1.5 36-1.5.1 41-1.1.1.2.1 41-1.6.1.2.2.2.1 42-1.5.1.1.r 43-1.5.1.1.1.1 45-1.5.1.1.1.1.1 46-1.5.1.1.1.1.1.2.r 47-1.5.1.1.1.1.1.2.2.1 49-1.5.1.1 51-1.5.1.1.2 52-1.5.1.1.2.2 54-1.2.1.1.2.1 54-1.5.1.1.2.1.2.1 56-1.2.1.1.3.1.1.3.1 56-1.5.1.1.2.3.2.1 (i / inhibit-01~e.13 :ARG0 (c / coexpress-01 :ARG2 (p / protein :wiki - :name (n4 / name :op1 "E3b1"~e.41) :ARG2-of (m4 / mutate-01 :value "DY"))) :ARG1 (r / ruffle-02~e.10 :ARG2-of (i2 / induce-01~e.8 :ARG0 (e3 / enzyme~e.4 :wiki "Ras_subfamily" :name (n2 / name :op1 "Ras"~e.54) :ARG1-of~e.4 (c2 / contrast-01~e.4 :ARG2 (i4 / induce-01~e.2 :ARG0 (e4 / enzyme :polarity -~e.5 :wiki "Rac_(GTPase)" :name (n3 / name :op1 "Rac"~e.56) :ARG2-of (m3 / mutate-01 :value "QL")))) :ARG2-of (m2 / mutate-01 :value "V12")))) :ARG2-of (e / efficient-01~e.12 :ARG1 c) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod 6~e.30)) :ARG0-of (s / support-01~e.34 :ARG1 (c4 / contend-01~e.36 :ARG1~e.42 (r2 / require-01~e.49 :ARG1 (p3 / possible-01 :ARG1 (f2 / form-01~e.43 :ARG1 (m / macro-molecular-complex~e.45 :part p :part~e.46 (e2 / enzyme :wiki "EPS8" :name (n6 / name :op1 "Eps8"~e.47))))) :purpose (t2 / transmit-01~e.51 :ARG0 (e6 / enzyme :wiki "Ras_subfamily" :name (n7 / name :op1 "Ras"~e.54)) :ARG1 (s2 / signal-07~e.52) :ARG2 (e7 / enzyme :wiki "Rac_(GTPase)" :name (n8 / name :op1 "Rac"~e.56)))))) :ARG1-of (c3 / contrast-01~e.20 :ARG2 (i3 / inhibit-01~e.13 :polarity~e.21 -~e.21 :ARG0 (c5 / coexpress-01 :polarity~e.21 -~e.21 :ARG2 (p2 / protein :wiki - :name (n5 / name :op1 "E3b1"~e.23,41) :mod (w / wild-type~e.24,25)))))) # ::id pmid_1177_7939.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In conclusion , our data show that two pools of Sos @-@ 1 exist in the cell , coupled respectively to Grb2 or E3b1 . # ::alignments 1-1 3-1.1.1.1 3-1.1.1.1.r 4-1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.1.1 8-1.1.2.1 9-1.1.2.1.2.r 10-1.1.2.1.2.1.1 12-1.1.2.1.2.1.1 13-1.1.2 14-1.1.2.2.r 16-1.1.2.2 18-1.1.2.1.3 19-1.1.2.1.3.2 20-1.1.2.1.3.1.r 21-1.1.2.1.3.1.1.1.1 22-1.1.2.1.3.1 23-1.1.2.1.3.1.2.1.1 (c / conclude-02~e.1 :ARG1 (s / show-01~e.5 :ARG0 (d / data~e.4 :poss~e.3 (w / we~e.3)) :ARG1~e.6 (e / exist-01~e.13 :ARG1 (p / pool~e.8 :quant 2~e.7 :consist-of~e.9 (p2 / protein :name (n / name :op1 "Sos-1"~e.10,12)) :ARG1-of (c3 / couple-01~e.18 :ARG2~e.20 (o / or~e.22 :op1 (p4 / protein :name (n2 / name :op1 "Grb2"~e.21)) :op2 (p3 / protein :name (n3 / name :op1 "E3b1"~e.23))) :mod (r / respective~e.19))) :location~e.14 (c2 / cell~e.16)))) # ::id pmid_1177_7939.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , the availability of E3b1 , but not of Sos @-@ 1 , is indispensable and rate limiting in the pathway leading to Rac activation . # ::alignments 0-1 0-1.1 1-1 1-1.1 4-1.1.1.1 4-1.1.1.2.1.1 4-1.1.2.3.1.2 5-1.1.1.1.1.r 5-1.1.r 6-1.1.1.1.1.1.1 8-1.1.1.2 8-1.1.2.3 9-1.1.2.3.1.1 9-1.1.2.3.1.1.r 10-1.1.1.2.1.1.1.r 11-1.1.1.2.1.1.1.1.1 13-1.1.1.2.1.1.1.1.1 16-1.1.1 17-1.1 18-1.1.2.2 19-1.1.2 19-1.1.2.3.1 20-1.1.2.4.r 22-1.1.2.4 23-1.1.2.4.1 24-1.1.2.4.1.1.r 25-1.1.2.4.1.1.1.1.1 26-1.1.2.4.1.1 (a / and~e.0,1 :op2~e.5 (a2 / and~e.0,1,17 :op1 (i / indispensable-01~e.16 :ARG1 (a5 / available-02~e.4 :ARG2~e.5 (p / protein :name (n / name :op1 "E3b1"~e.6))) :ARG1-of (c2 / contrast-01~e.8 :ARG2 (d / dispense-01 :ARG1 (a3 / available-02~e.4 :ARG2~e.10 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.11,13)))))) :op2 (l / limit-01~e.19 :ARG0 a5 :ARG1 (r / rate~e.18) :ARG1-of (c / contrast-01~e.8 :ARG2 (l3 / limit-01~e.19 :polarity~e.9 -~e.9 :ARG0 (a6 / available-02~e.4 :ARG2 p2) :ARG1 r)) :location~e.20 (p3 / pathway~e.22 :ARG0-of (l2 / lead-03~e.23 :ARG2~e.24 (a4 / activate-01~e.26 :ARG1 (e / enzyme :name (n3 / name :op1 "Rac"~e.25)))))))) # ::id pmid_1177_7939.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The dual GEF activity of Sos @-@ 1 depends on its presence in distinct complexes # ::alignments 1-1.1.3 2-1.1.2.1.1 3-1.1 4-1.1.1.r 5-1.1.1.1.1 7-1.1.1.1.1 8-1 9-1.2.r 10-1.2.1 10-1.2.1.r 11-1.2 12-1.2.2.r 13-1.2.2.1 14-1.2.2 (d / depend-01~e.8 :ARG0 (a / activity-06~e.3 :ARG0~e.4 (p / protein :name (n / name :op1 "Sos-1"~e.5,7)) :ARG1 (p3 / protein :name (n2 / name :op1 "GEF"~e.2)) :mod (d2 / dual~e.1)) :ARG1~e.9 (p2 / present-02~e.11 :ARG1~e.10 p~e.10 :ARG2~e.12 (c / complex~e.14 :mod (d3 / distinct~e.13)))) # ::id pmid_1177_7939.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The existence of Sos @-@ 1 in two physically and functionally distinct pools suggests the hypothesis that its presence in a S/G or a S/E/E8 complex could dictate its Ras @- or Rac @-@ specific GEF activities , respectively . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.2.r 7-1.1.2.1 8-1.1.2.3 10-1.1.2.2 11-1.1.2.2.1 12-1.1.2 13-1 15-1.2 16-1.2.1.r 17-1.2.1.1.1.1 17-1.2.1.1.1.1.r 18-1.2.1.1.1 22-1.2.1.1.1.2 25-1.2.1.1.1.2.1 25-1.2.1.1.1.2.2 26-1.2.1 27-1.2.1.1 28-1.2.1.1.2.1 28-1.2.1.1.2.1.r 29-1.2.1.1.2.4.1.1.1.1 31-1.2.1.1.2.4.1 32-1.2.1.1.2.4.1.2.1.1 34-1.2.1.1.2.4 35-1.2.1.1.2.2.1.1 36-1.2.1.1.2 38-1.2.1.1.2.3 (s / suggest-01~e.13 :ARG0 (e5 / exist-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "Sos-1"~e.3,5)) :location~e.6 (p2 / pool~e.12 :quant 2~e.7 :ARG0-of (f / function-01~e.10 :manner (d / distinct~e.11)) :mod (p3 / physical~e.8))) :ARG1 (h / hypothesize-01~e.15 :ARG1~e.16 (p4 / possible-01~e.26 :ARG1 (d2 / dictate-01~e.27 :ARG0 (p7 / present-02~e.18 :ARG1~e.17 p~e.17 :ARG2 (o / or~e.22 :op1 (m / macro-molecular-complex~e.25 :part p :part (p5 / protein :name (n2 / name :op1 "Grb2"))) :op2 (m2 / macro-molecular-complex~e.25 :part p :part (p6 / protein :name (n3 / name :op1 "E3b1")) :part (e / enzyme :name (n4 / name :op1 "Eps8"))))) :ARG1 (a / activity-06~e.36 :ARG0~e.28 p~e.28 :ARG1 (p8 / protein :name (n5 / name :op1 "GEF"~e.35)) :mod (r / respective~e.38) :ARG1-of (s2 / specific-02~e.34 :ARG2 (o2 / or~e.31 :op1 (p9 / protein-family :name (n6 / name :op1 "Ras"~e.29)) :op2 (p10 / protein-family :name (n7 / name :op1 "Rac"~e.32))))))))) # ::id pmid_1177_7939.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To explore this possibility , we used an in vitro assay that can score GEF activities in Sos @-@ 1 @–@ containing immunoprecipitates . # ::alignments 1-1.3 2-1.3.2.1 3-1.3.2 5-1.1 6-1 8-1.2.2 9-1.2.2 10-1.2 12-1.2.1.2 13-1.2.1 14-1.2.1.1.1.1.1 15-1.2.1.1 16-1.2.1.1.2.r 16-1.2.2 17-1.2.1.1.2.2.1.1.1 19-1.2.1.1.2.2.1.1.1 22-1.2.1.1.2 22-1.2.1.1.2.1 22-1.2.1.1.2.1.r (u / use-01~e.6 :ARG0 (w / we~e.5) :ARG1 (a / assay-01~e.10 :ARG0-of (s / score-01~e.13 :ARG1 (a2 / activity-06~e.15 :ARG0 (p4 / protein :name (n / name :op1 "GEF"~e.14)) :location~e.16 (m / molecular-physical-entity~e.22 :ARG1-of~e.22 (i / immunoprecipitate-01~e.22) :ARG0-of (c / contain-01 :ARG1 (p / protein :name (n2 / name :op1 "Sos-1"~e.17,19))))) :ARG1-of (p2 / possible-01~e.12)) :manner (i2 / in-vitro~e.8,9,16)) :ARG2 (e2 / explore-01~e.1 :ARG0 w :ARG1 (p3 / possible-01~e.3 :mod (t / this~e.2)))) # ::id pmid_1177_7939.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were transfected with either Sos @-@ 1 alone ( SosTfx ) or a combination of S/E/E8 ( Triple Tfx ) ( Fig . 7 A ) . # ::alignments 0-1.1 2-1 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2.1.2 12-1.2 14-1.2.2 23-1.3.1 (t / transfect-01~e.2 :ARG1 (c / cell~e.0) :ARG2 (o / or~e.12 :op1 (p / protein :name (n / name :op1 "Sos-1"~e.5,7) :mod (a / alone~e.8)) :op2 (c2 / combine-01~e.14 :ARG3 (m / macro-molecular-complex :part p :part (p2 / protein :name (n2 / name :op1 "E3b1")) :part (e / enzyme :name (n3 / name :op1 "Eps8"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "7A"))) # ::id pmid_1177_7939.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When Sos @-@ 1 was immunoprecipitated from SosTfx , it displayed Ras @-@ GEF , but not Rac @-@ GEF , activity ( Fig . 7 B ) . # ::alignments 1-1.1.1.1.1 3-1.1.1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.1.1 10-1.2.1 10-1.2.2 11-1.2.1.2.2.1.1 13-1.2.1.2.1.1.1 15-1.2 16-1.2.2.1 16-1.2.2.1.r 17-1.2.2.3.2.1.1 19-1.2.2.3.1 21-1.2.1.2 21-1.2.2.3 24-1.3.1 (c / cause-01 :ARG0 (i / immunoprecipitate-01~e.5 :ARG1 (p / protein :name (n / name :op1 "Sos-1"~e.1,3)) :ARG2~e.6 (p2 / protein :name (n2 / name :op1 "SosTfx"~e.7))) :ARG1 (c2 / contrast-01~e.15 :ARG1 (d / display-01~e.10 :ARG0 p :ARG1 (a / activity-06~e.21 :ARG0 (p3 / protein :name (n4 / name :op1 "GEF"~e.13)) :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras"~e.11)))) :ARG2 (d3 / display-01~e.10 :polarity~e.16 -~e.16 :ARG0 p :ARG1 (a2 / activity-06~e.21 :ARG0 p3~e.19 :ARG1 (e3 / enzyme :name (n7 / name :op1 "Rac"~e.17))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "7B"))) # ::id pmid_1177_7939.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of note , little E3b1 and no Eps8 could be detected in Sos @-@ 1 immunoprecipitates ( Fig . 7 A ) . # ::alignments 1-1.3 3-1.1.1.1.2 4-1.1.1.1.1.1 5-1 6-1.2.1 6-1.2.1.r 7-1.2.2.1.1.1 8-1.1 8-1.2 10-1.1.1 10-1.2.2 11-1.1.1.2.r 12-1.1.1.2.1.1 14-1.1.1.2.1.1 15-1.1.1.2 15-1.1.1.2.2 15-1.1.1.2.2.r 18-1.4.1 (a2 / and~e.5 :op1 (p / possible-01~e.8 :ARG1 (d / detect-01~e.10 :ARG1 (p2 / protein :name (n / name :op1 "E3b1"~e.4) :quant (l / little~e.3)) :location~e.11 (p3 / protein~e.15 :name (n4 / name :op1 "Sos-1"~e.12,14) :ARG1-of~e.15 (i / immunoprecipitate-01~e.15)))) :op2 (p4 / possible-01~e.8 :polarity~e.6 -~e.6 :ARG1 (d3 / detect-01~e.10 :ARG1 (e / enzyme :name (n2 / name :op1 "Eps8"~e.7)) :location p3)) :ARG1-of (n3 / note-01~e.1 :ARG1-of (r / recommend-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.18 :mod "7A"))) # ::id pmid_1177_7939.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , Grb2 was readily recovered from the same immunoprecipitates ( unpublished data ) . # ::alignments 2-1.1.1.1.1 4-1.1.3 4-1.1.3.r 5-1.1 6-1.1.2.r 8-1.1.2.2 9-1.1.2 9-1.1.2.1 9-1.1.2.1.r 11-1.1.4.1.1.1 12-1.1.4.1 (c / contrast-01 :ARG2 (r / recover-02~e.5 :ARG1 (p / protein :name (n / name :op1 "Grb2"~e.2)) :ARG2~e.6 (m / molecular-physical-entity~e.9 :ARG1-of~e.9 (i / immunoprecipitate-01~e.9) :ARG1-of (s / same-01~e.8)) :manner~e.4 (r2 / ready~e.4) :ARG1-of (d2 / describe-01 :ARG0 (d / data~e.12 :ARG1-of (p2 / publish-01 :polarity -~e.11))))) # ::id pmid_1177_7939.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We then used the Triple Tfx and coimmunoprecipitated Sos @-@ 1 with anti @-@ Eps8 antibodies ( Fig . 7 , A and B ) . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 8-1.1.2.1.1.1 10-1.1.2.1.1.1 12-1.2.2.1 14-1.1.2.3.1.1 15-1.2.2 18-1.3.1.1 18-1.3.1.2 23-1.3.1 (a / and :op1 (u / use-01~e.2 :ARG0 (w / we~e.0) :ARG1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "Sos-1"~e.8,10)) :part (p2 / protein :name (n2 / name :op1 "E3b1")) :part (e / enzyme :name (n4 / name :op1 "Eps8"~e.14)) :ARG2-of (t2 / transfect-01)) :time (t / then~e.1)) :op2 (c / coimmunoprecipitate-01 :ARG1 p :ARG3 (a2 / antibody~e.15 :ARG0-of (c2 / counter-01~e.12 :ARG1 e))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.23 :op1 (f / figure~e.18 :mod "7A") :op2 (f2 / figure~e.18 :mod "7B")))) # ::id pmid_1177_7939.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Under these conditions , all of the coimmunoprecipitated Sos @-@ 1 is present in the S/E/E8 tricomplex ( Scita et al. , 1999 ) . # ::alignments 1-1.2 2-1 4-1.1.1.2 8-1.1.1.1.1 10-1.1.1.1.1 12-1.1 19-1.3.1.1.1.1.1 20-1.3.1.1 21-1.3.1.1.2.1 23-1.3.1.2.1 (h / have-condition-91~e.2 :ARG1 (p6 / present-02~e.12 :ARG1 (p / protein :name (n / name :op1 "Sos-1"~e.8,10) :mod (a / all~e.4) :ARG1-of (c / coimmunoprecipitate-01)) :ARG2 (m / macro-molecular-complex :part p :part (p2 / protein :name (n2 / name :op1 "E3b1")) :part (e / enzyme :name (n3 / name :op1 "Eps8")))) :ARG2 (t / this~e.1) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and~e.20 :op1 (p4 / person :name (n4 / name :op1 "Scita"~e.19)) :op2 (p5 / person :mod (o / other~e.21))) :time (d2 / date-entity :year 1999~e.23)))) # ::id pmid_1177_7939.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite lower levels of Sos @-@ 1 in the coimmunoprecipitate ( with respect to a Sos @-@ 1 immunoprecipitate from SosTfx ) , Rac @-@ GEF activity was now present ( Fig . 7 B ) . # ::alignments 0-1.5.r 1-1.5 1-1.5.2 1-1.5.2.r 2-1.5.1 3-1.5.1.2.r 4-1.5.1.2.1.1 6-1.5.1.2.1.1 7-1.5.1.1.r 9-1.5.1.1 9-1.5.1.1.1 9-1.5.1.1.1.r 15-1.5.1.2.1.1 17-1.5.1.2.1.1 18-1.3 19-1.3.2.r 20-1.3.2.1.1 23-1.1.1.2.1.1 25-1.1.1.1.1.1 26-1.1 28-1.2 29-1 32-1.4.1 (p / present-02~e.29 :ARG1 (a / activity-06~e.26 :ARG0 (m3 / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "GEF"~e.25)) :part (e2 / enzyme :name (n3 / name :op1 "Rac"~e.23)))) :time (n4 / now~e.28) :topic (i / immunoprecipitate-01~e.18 :ARG1 p2 :ARG2~e.19 (p3 / protein :name (n5 / name :op1 "SosTfx"~e.20))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "7B")) :concession~e.0 (l2 / low-04~e.1 :ARG1 (l / level~e.2 :location~e.7 (m2 / molecular-physical-entity~e.9 :ARG1-of~e.9 (c / coimmunoprecipitate-01~e.9)) :quant-of~e.3 (p2 / protein :name (n / name :op1 "Sos-1"~e.4,6,15,17))) :degree~e.1 (m / more~e.1))) # ::id pmid_1177_7939.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , no Ras @-@ GEF activity could be detected ( Fig . 7 B ) . # ::alignments 2-1.1.1 2-1.1.1.r 3-1.1.2.1.2.1.1 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1 9-1.1.2 12-1.1.2.2.1 (c / contrast-01 :ARG2 (p / possible-01~e.7 :polarity~e.2 -~e.2 :ARG1 (d / detect-01~e.9 :ARG1 (a / activity-06~e.6 :ARG0 (p2 / protein :name (n2 / name :op1 "GEF"~e.5)) :beneficiary (e2 / enzyme :name (n3 / name :op1 "Ras"~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.12 :mod "7B"))))) # ::id pmid_1177_7939.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lack of Ras @-@ GEF activity was not due to the low levels of Sos @-@ 1 . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.2.1.1 5-1.3.1.1.1.1 6-1.3.1 8-1.1 8-1.1.r 9-1 10-1 12-1.2.1 13-1.2 14-1.2.1.1.r 15-1.2.1.1.1.1 17-1.2.1.1.1.1 (c / cause-01~e.9,10 :polarity~e.8 -~e.8 :ARG0 (l / level~e.13 :ARG1-of (l2 / low-04~e.12 :quant-of~e.14 (p / protein :name (n / name :op1 "Sos-1"~e.15,17)))) :ARG1 (l3 / lack-01~e.1 :ARG1~e.2 (a / activity-06~e.6 :ARG0 (p2 / protein :name (n3 / name :op1 "GEF"~e.5)) :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.3))))) # ::id pmid_1177_7939.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To prove this point , we immunoprecipitated from SosTfx an amount of Sos @-@ 1 comparable to that present in anti @-@ Eps8 immunoprecipitates from Triple Tfx ( Fig . 7 , A and B , lanes SosTfx1 @/@ 10 ) . # ::alignments 1-1.4 2-1.4.2.1 3-1.4.2 3-1.4.r 5-1.1 6-1 8-1.2.1.1 10-1.3.2 10-1.3.2.1.1.2 11-1.3.2.1.r 12-1.3.2.1.1.1.1 14-1.3.1.1 15-1.3.2.1 17-1.3.2.1.1.2.1.1.3 18-1.3.2.1.1.2.1 20-1.3.2.1.1.2.1.1.2 22-1.3.2.1.1.2.1.1.2.1.1.1 23-1 23-1.3.2.1.1.2.1.1 23-1.3.2.1.1.2.1.1.1 23-1.3.2.1.1.2.1.1.1.r 29-1.5.1.2.1 29-1.5.1.2.2 34-1.5.1.2 38-1.5.1 39-1.5.1.1.1.1 41-1.5.1.1.1.1 (i / immunoprecipitate-01~e.6,23 :ARG0 (w / we~e.5) :ARG1 (p / protein :name (n / name :op1 "SosTfx"~e.8)) :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.14) :quant (a / amount~e.10 :ARG1-of~e.11 (c / comparable-03~e.15 :ARG2 (p3 / protein :name (n3 / name :op1 "Sos-1"~e.12) :quant-of (a2 / amount~e.10 :ARG1-of (p8 / present-02~e.18 :ARG2 (m / molecular-physical-entity~e.23 :ARG1-of~e.23 (i2 / immunoprecipitate-01~e.23 :ARG2 (m2 / macro-molecular-complex :part p3 :part (p4 / protein :name (n5 / name :op1 "E3b1")) :part e :ARG2-of (t3 / transfect-01))) :ARG0-of (c2 / counter-01~e.20 :ARG1 (e / enzyme :name (n4 / name :op1 "Eps8"~e.22))) :mod (t / that~e.17))))) :ARG1-of (p5 / possible-01)))) :purpose~e.3 (p6 / prove-01~e.1 :ARG0 w :ARG1 (p7 / point~e.3 :mod (t2 / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (l2 / lane~e.38 :ARG1-of (l / label-01 :ARG2 (s / string-entity :value "SosTfx1/10"~e.39,41)) :part-of (a3 / and~e.34 :op1 (f / figure~e.29 :mod "7A") :op2 (f2 / figure~e.29 :mod "7B"))))) # ::id pmid_1177_7939.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Under these conditions , Ras @-@ GEF activity was readily detectable ( Fig . 7 B ) . # ::alignments 1-1.2 2-1 4-1.1.2.1.1 6-1.1.1.1.1 7-1.1 9-1.1.3.2 9-1.1.3.2.r 10-1.1.3 13-1.3.1 (h / have-condition-91~e.2 :ARG1 (a / activity-06~e.7 :ARG0 (p / protein :name (n2 / name :op1 "GEF"~e.6)) :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.4)) :ARG1-of (d / detect-01~e.10 :ARG1-of (p2 / possible-01) :manner~e.9 (r / ready~e.9))) :ARG2 (t / this~e.1) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.13 :mod "7B"))) # ::id pmid_1177_7939.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The detection of Rac @-@ specific GEF activity in anti @-@ Eps8 immunoprecipitates strictly required the presence of Sos @-@ 1 , since no GEF activity was detected in Eps8 immunoprecipitates , in the absence of coexpressed Sos @-@ 1 ( Scita et al. , 1999 ; unpublished data ) . # ::alignments 1-1.1 3-1.1.1.3.1.1.1 5-1.1.1.3 6-1.1.1.1.1.1 7-1.1.1 9-1.1.1.2.2 11-1.1.1.2.2.1.1.1 12-1.1.1.2 12-1.1.1.2.1 12-1.1.1.2.1.r 13-1.3 13-1.3.r 14-1 16-1.2 17-1.2.1.r 18-1.2.1.1.1 20-1.2.1.1.1 22-1.4 23-1.4.1.1 23-1.4.1.1.r 24-1.1.1.1.1.1 25-1.1.1 25-1.4.1.2 27-1.1 27-1.4.1 29-1.1.1.2.2.1.1.1 30-1.1.1.2 30-1.1.1.2.1 30-1.1.1.2.1.r 30-1.4.1.4 30-1.4.1.4.1 30-1.4.1.4.1.r 32-1.4.1.3.r 34-1.4.1.3 37-1.4.1.3.1 38-1.4.1.3.1 39-1.4.1.3.1 42-1.5.1.1.1.1.1.1 43-1.5.1 43-1.5.1.1.1 44-1.5.1.1.1.2.1 46-1.5.1.1.2.1 49-1.5.1.2.1.1 50-1.5.1.2 (r / require-01~e.14 :ARG0 (d / detect-01~e.1,27 :ARG1 (a / activity-06~e.7,25 :ARG0 (p7 / protein :name (n2 / name :op1 "GEF"~e.6,24)) :location (m / molecular-physical-entity~e.12,30 :ARG1-of~e.12,30 (i / immunoprecipitate-01~e.12,30) :ARG0-of (c / counter-01~e.9 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Eps8"~e.11,29)))) :ARG1-of (s / specific-02~e.5 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Rac"~e.3))))) :ARG1 (p2 / present-02~e.16 :ARG1~e.17 (p / protein :name (n / name :op1 "Sos-1"~e.18,20) :ARG2-of (c3 / coexpress-01))) :manner~e.13 (s2 / strict~e.13) :ARG1-of (c2 / cause-01~e.22 :ARG0 (d2 / detect-01~e.27 :polarity~e.23 -~e.23 :ARG1 (a2 / activity-06~e.25 :ARG0 p7) :manner~e.32 (a3 / absent-01~e.34 :ARG1 p~e.37,38,39) :location (m2 / molecular-physical-entity~e.30 :ARG1-of~e.30 (i2 / immunoprecipitate-01~e.30 :ARG2 e3)))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.43 :op1 (p3 / publication-91 :ARG0 (a5 / and~e.43 :op1 (p4 / person :name (n6 / name :op1 "Scita"~e.42)) :op2 (p5 / person :mod (o / other~e.44))) :time (d4 / date-entity :year 1999~e.46)) :op2 (d5 / data~e.50 :ARG1-of (p6 / publish-01 :polarity -~e.49))))) # ::id pmid_1177_7939.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , no Rac @-@ GEF activity could be detected in Eps8 immunoprecipitates from lysates of cells transfected with Sos @-@ 1 , E3b1 , and an Eps8 mutant that is impaired in its ability to bind E3b1 and thereby cannot form a trimeric complex ( Scita et al. , 1999 ) . # ::alignments 0-1 2-1.1.1.r 3-1.1.2.1.2.1.1 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1 9-1.1.2 10-1.1.2.3.r 11-1.1.2.3.1.1 12-1.1.2.3 12-1.1.2.3.2 12-1.1.2.3.2.r 13-1.1.2.3.2.1.r 14-1.1.2.3.2.1 15-1.1.2.3.2.1.1.r 16-1.1.2.3.2.1.1 17-1.1.2.3.2.1.2 18-1.1.2.3.2.1.2.1.r 19-1.1.2.3.2.1.2.1.1.1.1 21-1.1.2.3.2.1.2.1.1.1.1 23-1.1.2.3.2.1.2.1.2.1.1 25-1.1.2.3.2.1.2.1 27-1.1.2.3.2.1.2.1.3.1.1 28-1.1.2.3.2.1.2.1.3 28-1.1.2.3.2.1.2.1.3.2 28-1.1.2.3.2.1.2.1.3.2.r 31-1.1.2.3.2.1.2.1.3.3.2.1 35-1.1.2.3.2.1.2.1.3.3.2.1.1 36-1.1.2.3.2.1.2.1.3.3 37-1.1.2.3.2.1.2.1.2.1.1 40-1.1.1 40-1.1.2.3.2.1.2.1.3.3.2 40-1.1.2.3.2.1.2.1.3.3.2.1.1.1 40-1.1.2.3.2.1.2.1.3.3.2.1.1.1.1 40-1.1.2.3.2.1.2.1.3.3.2.1.1.1.1.r 41-1.1.2.3.2.1.2.1.3.3.2.1.1.1.2 44-1.1.2.3.2.1.2.1.3.3.2.1.1.1.2.2 47-1.1.2.2.1.1.1.1.1 48-1.1.2.2.1.1 49-1.1.2.2.1.1.2.1 51-1.1.2.2.1.2.1 (a / and~e.0 :op2 (p / possible-01~e.7 :polarity~e.2 -~e.40 :ARG1 (d / detect-01~e.9 :ARG1 (a2 / activity-06~e.6 :ARG0 (p9 / protein :name (n2 / name :op1 "GEF"~e.5)) :ARG1 (e2 / enzyme :name (n3 / name :op1 "Rac"~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a4 / and~e.48 :op1 (p7 / person :name (n7 / name :op1 "Scita"~e.47)) :op2 (p8 / person :mod (o / other~e.49))) :time (d3 / date-entity :year 1999~e.51))) :location~e.10 (e3 / enzyme~e.12 :name (n4 / name :op1 "Eps8"~e.11) :ARG1-of~e.12 (i / immunoprecipitate-01~e.12 :ARG2~e.13 (l / lysate~e.14 :domain~e.15 (c / cell~e.16) :ARG1-of (t / transfect-01~e.17 :ARG2~e.18 (a3 / and~e.25 :op1 (p2 / protein :name (n / name :op1 "Sos-1"~e.19,21)) :op2 (p3 / protein :name (n5 / name :op1 "E3b1"~e.23,37)) :op3 (e4 / enzyme~e.28 :name (n6 / name :op1 "Eps8"~e.27) :ARG1-of~e.28 (m2 / mutate-01~e.28) :ARG0-of (b / bind-01~e.36 :ARG1 p3 :ARG1-of (p4 / possible-01~e.40 :ARG1-of (i2 / impair-01~e.31 :ARG0-of (c2 / cause-01~e.35 :ARG1 (p5 / possible-01~e.40 :polarity~e.40 -~e.40 :ARG1 (f / form-01~e.41 :ARG0 e4 :ARG1 (m3 / macro-molecular-complex~e.44 :mod (t2 / trimer))))))))))))))))) # ::id pmid_1177_7939.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At this stage , we cannot formally exclude that an unknown GEF , coprecipitating with Sos @-@ 1 , is responsible for the observed activity . # ::alignments 1-1.2.3.1 2-1.2.3 4-1.2.1 5-1 5-1.1 5-1.1.r 5-1.2.2.1.2.1.r 6-1.2.4 6-1.2.4.r 7-1.2 8-1.2.2.r 10-1.2.2.1 10-1.2.2.1.2 10-1.2.2.1.2.1 10-1.2.2.1.2.r 11-1.2.2.1.1.1 14-1.2.2.1.3.r 15-1.2.2.1.3.1.1.1 17-1.2.2.1.3.1.1.1 20-1.2.2 21-1.2.2.2.r 23-1.2.2.2.1 24-1.2.2.2 (p / possible-01~e.5 :polarity~e.5 -~e.5 :ARG1 (e / exclude-01~e.7 :ARG0 (w / we~e.4) :ARG1~e.8 (r / responsible-01~e.20 :ARG0 (p3 / protein~e.10 :name (n2 / name :op1 "GEF"~e.11) :ARG1-of~e.10 (k / know-01~e.10 :polarity~e.5 -~e.10) :op1-of~e.14 (a2 / and :op2 (p2 / protein :name (n3 / name :op1 "Sos-1"~e.15,17)) :ARG1-of (c / coprecipitate-01))) :ARG1~e.21 (a / activity-06~e.24 :ARG1-of (o / observe-01~e.23))) :time (s / stage~e.2 :mod (t / this~e.1)) :manner~e.6 (f / formal~e.6))) # ::id pmid_1177_7939.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , such a hypothetical protein should not only be associated with Sos @-@ 1 , but also be active only in the presence of Eps8 and E3b1 , which are both required for the formation of the trimeric complex endowed with Rac @-@ specific GEF activity ( Scita et al. , 1999 ) , making this possibility unlikely . # ::alignments 0-1 2-1.1.1.1.1.2 4-1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1 7-1.1.3.1.1.r 8-1.1.1.1.3 10-1.1.1.1 11-1.1.1.1.2.r 12-1.1.1.1.2.1.1 14-1.1.1.1.2.1.1 16-1 17-1.1.2.2 19-1.1.2 20-1.1.1.1.3 21-1.1.2.3.r 23-1.1.2.3 24-1.1.2.3.1.r 25-1.1.2.3.1.1.1.1 26-1.1.2.3.1 27-1.1.2.3.1.2.1.1 32-1.1.2.3.1.3 33-1.1.2.3.1.3.1.r 35-1.1.2.3.1.3.1 39-1.1.2.3.1.3.1.1 40-1.1.2.3.1.3.1.1.2 41-1.1.2.3.1.3.1.1.2.1.r 42-1.1.2.3.1.3.1.1.2.1.2.1.1.1 44-1.1.2.3.1.3.1.1.2.1.2 45-1.1.2.3.1.3.1.1.2.1.1.1.1 46-1.1.2.3.1.3.1.1.2.1 49-1.2.1.1.1.1.1 50-1.1 50-1.2.1.1 51-1.2.1.1.2.1 53-1.2.1.2.1 57-1.1.3 58-1.1.3.1.2.2 59-1.1.3.1.2 60-1.1.3.1 60-1.1.3.1.1 (c / contrast-01~e.0,16 :ARG2 (a / and~e.50 :op1 (r / recommend-01~e.6 :ARG1 (a2 / associate-01~e.10 :ARG1 (p / protein~e.5 :ARG1-of (h / hypothetical-02~e.4) :mod (s / such~e.2)) :ARG2~e.11 (p2 / protein :name (n / name :op1 "Sos-1"~e.12,14)) :mod (o / only~e.8,20))) :op2 (a3 / activity-06~e.19 :ARG0 p :mod (a4 / also~e.17) :condition~e.21 (p3 / present-02~e.23 :ARG1~e.24 (a5 / and~e.26 :op1 (e / enzyme :name (n2 / name :op1 "Eps8"~e.25)) :op2 (p4 / protein :name (n3 / name :op1 "E3b1"~e.27)) :ARG1-of (r2 / require-01~e.32 :purpose~e.33 (f / form-01~e.35 :ARG1 (m / macro-molecular-complex~e.39 :mod (t / trimer) :ARG2-of (e2 / endow-01~e.40 :ARG1~e.41 (a6 / activity-06~e.46 :ARG0 (p9 / protein :name (n4 / name :op1 "GEF"~e.45)) :ARG1-of (s2 / specific-02~e.44 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Rac"~e.42))))))))))) :ARG0-of (m2 / make-02~e.57 :ARG1 (l / likely-01~e.60 :polarity~e.7 -~e.60 :ARG1 (p5 / possible-01~e.59 :ARG1 p :mod (t2 / this~e.58))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a7 / and~e.50 :op1 (p7 / person :name (n6 / name :op1 "Scita"~e.49)) :op2 (p8 / person :mod (o2 / other~e.51))) :time (d2 / date-entity :year 1999~e.53)))) # ::id pmid_1177_7939.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is reasonable , therefore , to propose that Sos @-@ 1 alone ( or complexed with proteins , such as Grb2 ) is endowed with Ras @-@ GEF activity . # ::alignments 2-1 2-1.1 2-1.1.r 4-1 6-1 7-1.1.1 8-1.1.1.1.r 9-1.1.1.1.2.1.1.1 11-1.1.1.1.2.1.1.1 12-1.1.1.1.2.1.2 14-1.1.1.1.2 17-1.1.1.1.2.2.2 19-1.1.1.1.2.2.2.1.r 20-1.1.1.1.2.2.2.1.r 21-1.1.1.1.2.2.2.1.1.1 24-1.1.1.1 25-1.1.1.1.1.r 26-1.1.1.1.1.2.1.1 28-1.1.1.1.1.1.1.1 29-1.1.1.1.1 (c / cause-01~e.2,4,6 :ARG1~e.2 (r / reasonable-02~e.2 :ARG1 (p / propose-01~e.7 :ARG1~e.8 (e3 / endow-01~e.24 :ARG1~e.25 (a / activity-06~e.29 :ARG0 (p5 / protein :name (n3 / name :op1 "GEF"~e.28)) :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.26))) :ARG2 (o / or~e.14 :op1 (p2 / protein :name (n / name :op1 "Sos-1"~e.9,11) :mod (a2 / alone~e.12)) :op2 (m / macro-molecular-complex :part p2 :part (p3 / protein~e.17 :example~e.19,20 (p4 / protein :name (n2 / name :op1 "Grb2"~e.21))))))))) # ::id pmid_1177_7939.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , upon interaction with Eps8 and E3b1 , its specificity is switched toward Rac . # ::alignments 0-1 3-1.2 4-1.2.2.r 5-1.2.2.1.1.1 6-1.2.2 7-1.2.2.2.1.1 9-1.1.1.1 9-1.1.1.1.r 10-1.1.1 12-1.1 14-1.1.2.1.1 (h / have-concession-91~e.0 :ARG1 (s / switch-01~e.12 :ARG1 (s2 / specificity~e.10 :poss~e.9 (i2 / it~e.9)) :ARG2 (e3 / enzyme :name (n3 / name :op1 "Rac"~e.14))) :time (i / interact-01~e.3 :ARG0 i2 :ARG1~e.4 (a / and~e.6 :op1 (e / enzyme :name (n / name :op1 "Eps8"~e.5)) :op2 (p3 / protein :name (n2 / name :op1 "E3b1"~e.7))))) # ::id pmid_1177_7939.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A common feature of proteins endowed with GEF catalytic activity is their ability to bind to their specific nucleotide @-@ depleted GTPase with relative high affinities . # ::alignments 1-1.1 2-1 4-1.2.1 5-1.2.1.1 6-1.2.1.1.1.r 7-1.2.1.1.1.1.1.1 8-1.2.1.1.1.2 9-1.2.1.1.1 10-1.2.r 12-1.2 14-1.2.2 15-1.2.2.2.r 16-1.2.2.2.4 16-1.2.2.2.4.r 17-1.2.2.2 17-1.2.2.2.2 17-1.2.2.2.2.r 18-1.2.2.2.3.1 20-1.2.2.2.3 21-1.2.2.2.1.1 22-1.2.2.3.r 23-1.2.2.3.1.1 24-1.2.2.3.1 25-1.2.2.3 (f / feature~e.2 :ARG1-of (s2 / share-01~e.1 :ARG0 p) :domain~e.10 (c / capable-01~e.12 :ARG1 (p / protein~e.4 :ARG2-of (e2 / endow-01~e.5 :ARG1~e.6 (a / activity-06~e.9 :ARG0 (p2 / protein :name (n2 / name :op1 "GEF"~e.7)) :ARG1 (c2 / catalysis~e.8)))) :ARG2 (b / bind-01~e.14 :ARG1 p :ARG2~e.15 (e / enzyme~e.17 :name (n / name :op1 "GTPase"~e.21) :ARG1-of~e.17 (s3 / specific-02~e.17) :ARG1-of (d / deplete-01~e.20 :ARG2 (n3 / nucleotide~e.18)) :poss~e.16 p~e.16) :manner~e.22 (a2 / affinity~e.25 :ARG1-of (h / high-02~e.24 :ARG2-of (r / relative-05~e.23)))))) # ::id pmid_1177_7939.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , one might postulate that Sos @-@ 1 associates with the nucleotide @-@ free form of Rac exclusively when engaged in the S/E/E8 complex . # ::alignments 0-1 2-1.1.1.2.1.1.1 3-1.1 4-1.1.1 6-1.1.1.2.1.1.1 8-1.1.1.2.1.1.1 9-1.1.1.2 10-1.1.1.2.2.r 12-1.1.1.2.2.1.1 14-1.1.1.2.2.1 15-1.1.1.2.2 16-1.1.1.2.2.2.r 17-1.1.1.2.2.2.1.1 18-1.1.1.2.3 19-1.1.1.2.4.r 20-1.1.1.2.4 24-1.1.1.2.4.2 (c / cause-01~e.0 :ARG1 (p8 / possible-01~e.3 :ARG1 (p5 / postulate-01~e.4 :ARG0 (p6 / person) :ARG1 (a / associate-01~e.9 :ARG1 (p7 / protein :name (n / name :op1 "Sos-1"~e.2,6,8)) :ARG2~e.10 (f / form~e.15 :ARG1-of (f2 / free-04~e.14 :ARG2 (n2 / nucleotide~e.12)) :mod~e.16 (e / enzyme :name (n3 / name :op1 "Rac"~e.17))) :ARG0-of (e2 / exclusive-02~e.18) :time~e.19 (e3 / engage-01~e.20 :ARG1 p7 :ARG2 (m / macro-molecular-complex~e.24 :part (p / protein :name (n4 / name :op1 "S")) :part (p3 / protein :name (n5 / name :op1 "E")) :part (p4 / protein :name (n6 / name :op1 "E8")))))))) # ::id pmid_1177_7939.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Purified and nucleotide depleted , GST @-@ Rac and GST @-@ Cdc42 proteins were therefore used to test their ability to interact with Sos @-@ 1 . # ::alignments 0-1.1.1.3 1-1.1.1 2-1.1.1.4.1 3-1.1.1.4 5-1.1.1.1.1.1 5-1.1.1.2.1.1 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.1.1.1 9-1.1.1.2.1.1 11-1.1.1.2.1.1 12-1.1.1.1 12-1.1.1.2 12-1.1.2.1.2.2 14-1 15-1.1 17-1.1.2 18-1.1.2.1.1 18-1.1.2.1.1.r 19-1.1.2.1 21-1.1.2.1.2 23-1.1.2.1.2.2.1.1 25-1.1.2.1.2.2.1.1 (c2 / cause-01~e.14 :ARG1 (u2 / use-01~e.15 :ARG1 (a / and~e.1,8 :op1 (p2 / protein~e.12 :name (n2 / name :op1 "GST-Rac"~e.5,7,9)) :op2 (p3 / protein~e.12 :name (n3 / name :op1 "GST-Cdc42"~e.5,9,11)) :ARG1-of (p / purify-01~e.0) :ARG1-of (d / deplete-01~e.3 :ARG2 (n / nucleotide~e.2))) :ARG2 (t2 / test-01~e.17 :ARG1 (c / capable-01~e.19 :ARG1~e.18 a~e.18 :ARG2 (i / interact-01~e.21 :ARG0 a :ARG1 (p4 / protein~e.12 :name (n4 / name :op1 "Sos-1"~e.23,25))))))) # ::id pmid_1177_7939.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Native Sos @-@ 1 , present in lysates of −/− [ Eps8 myc ] fibroblasts , could be specifically recovered with nucleotide @-@ depleted immobilized GST @-@ Rac , but not with GST @-@ Cdc42 or GST alone ( Fig . 7 C ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1.1 3-1.1.1.1.1.1 5-1.1.1.1 5-1.1.1.1.3 5-1.1.1.1.3.r 6-1.1.1.1.3.1.r 7-1.1.1.1.3.1 8-1.1.1.1.3.1.1.r 9-1.1.1.1.3.1.1.1.2.1 14-1.1.1.1.3.1.1 16-1 18-1.1.1.3 19-1.1.1 19-1.1.2 20-1.1.1.2.r 21-1.1.1.2.3.1 23-1.1.1.2.3 24-1.1.1.2.2 25-1.1.1.2.1.1 27-1.1.1.2.1.1 29-1.1 30-1.1.2.1 30-1.1.2.1.r 31-1.1.2.3.r 32-1.1.2.3.2.1.1 34-1.1.2.3.1.1.1 35-1.1.2.3 36-1.1.2.3.2.1.1 37-1.1.2.3.3 40-1.2.1 (p / possible-01~e.16 :ARG1 (c / contrast-01~e.29 :ARG1 (r / recover-01~e.19 :ARG1 (p2 / protein~e.5 :name (n / name :op1 "Sos-1"~e.1,3) :mod (n2 / native~e.0) :ARG1-of~e.5 (p6 / present-02~e.5 :ARG2~e.6 (l / lysate~e.7 :mod~e.8 (f / fibroblast~e.14 :mod (p5 / protein :name (n3 / name :op1 "Eps8myc") :ARG2-of (m / mutate-01 :mod "−/−"~e.9)))))) :instrument~e.20 (p4 / protein :name (n4 / name :op1 "GST-Rac"~e.25,27) :ARG1-of (i / immobilize-01~e.24) :ARG1-of (d / deplete-01~e.23 :ARG2 (n7 / nucleotide~e.21))) :ARG1-of (s / specific-02~e.18)) :ARG2 (r2 / recover-01~e.19 :polarity~e.30 -~e.30 :ARG1 p2 :instrument~e.31 (o / or~e.35 :op1 (p3 / protein :name (n5 / name :op1 "GST-Cdc42"~e.34)) :op2 (e2 / enzyme :name (n12 / name :op1 "GST"~e.32,36)) :mod (a / alone~e.37)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.40 :mod "7C"))) # ::id pmid_1177_7939.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , no Sos @-@ 1 could be recovered with GST @-@ Rac from lysates of eps8 @^−/− cells . # ::alignments 0-1.2 0-1.2.r 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1.2.1 5-1.1.1.2.1 6-1 8-1.1 9-1.1.3.r 10-1.1.3.1.1 12-1.1.3.1.1 13-1.1.2.r 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1.1.1 18-1.1.2.1.1.2.1 20-1.1.2.1 (p / possible-01~e.6 :ARG1 (r / recover-02~e.8 :ARG1 (p2 / protein :polarity~e.2 -~e.2 :name (n / name :op1 "Sos-1"~e.3,5)) :ARG2~e.13 (l / lysate~e.14 :mod~e.15 (c2 / cell~e.20 :mod (e / enzyme :name (n3 / name :op1 "eps8"~e.16) :ARG2-of (m / mutate-01 :mod "−/−"~e.18)))) :instrument~e.9 (p3 / protein :name (n2 / name :op1 "GST-Rac"~e.10,12))) :manner~e.0 (c / converse~e.0)) # ::id pmid_1177_7939.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , Eps8 is required for the association between Sos @-@ 1 and nucleotide @-@ free Rac . # ::alignments 0-1 2-1.1.1.1.1 4-1.1 5-1.1.2.r 7-1.1.2 9-1.1.2.1.1.1 11-1.1.2.1.1.1 13-1.1.2.2.2.1 15-1.1.2.2 15-1.1.2.2.2 15-1.1.2.2.2.r 16-1.1.2.2.1.1 (c / cause-01~e.0 :ARG1 (r / require-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "Eps8"~e.2)) :purpose~e.5 (a / associate-01~e.7 :ARG1 (p / protein :name (n2 / name :op1 "Sos-1"~e.9,11)) :ARG2 (e2 / enzyme~e.15 :name (n3 / name :op1 "Rac"~e.16) :ARG1-of~e.15 (f / free-04~e.15 :ARG2 (n4 / nucleotide~e.13)))))) # ::id pmid_1177_7939.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , under conditions in which the Eps8 @–@ E3b1 or the E3b1 @–@ Sos @-@ 1 interactions were disrupted by specifically competing peptides , a reduction of > 80 % in the amount of Sos @-@ 1 bound to nucleotide @-@ depleted Rac was observed ( Fig . 7 C ) . # ::alignments 0-1 0-1.1.2.2.1.1 0-1.1.2.2.2.1 3-1.1.2.r 7-1.1.2.2.1.1.1.1.1 9-1.1.2.2.1.1.2.1.1 10-1.1.2.2 12-1.1.2.2.1.1.2.1.1 14-1.1.1.1.1.1.1 16-1.1.1.1.1.1.1 17-1.1.2.2.1 17-1.1.2.2.2 19-1.1.2 20-1.1.2.1.r 21-1.1.2.1.1.1 22-1.1.2.1.1 23-1.1.2.1 26-1.1.1 29-1.1.1.2.1 30-1.1.1.2 33-1.1.1.1 35-1.1.1.1.1.1.1 37-1.1.1.1.1.1.1 38-1.1.1.1.1 38-1.1.1.1.1.2 38-1.1.1.1.1.2.r 39-1.1.1.1.1.2.1.r 40-1.1.1.1.1.2.1.2.1 42-1.1.1.1.1.2.1.2 43-1.1.1.1.1.2.1.1.1 45-1.1 48-1.2.1 (a2 / and~e.0 :op2 (o / observe-01~e.45 :ARG1 (r / reduce-01~e.26 :ARG1 (a / amount~e.33 :quant-of (p3 / protein~e.38 :name (n / name :op1 "Sos-1"~e.14,16,35,37) :ARG1-of~e.38 (b / bind-01~e.38 :ARG2~e.39 (e / enzyme :name (n2 / name :op1 "Rac"~e.43) :ARG1-of (d / deplete-01~e.42 :ARG2 (n3 / nucleotide~e.40)))))) :ARG2 (p / percentage-entity~e.30 :value 80~e.29 :degree (m / more))) :condition~e.3 (d2 / disrupt-01~e.19 :ARG0~e.20 (p2 / peptide~e.23 :ARG0-of (c / compete-01~e.22 :ARG1-of (s / specific-02~e.21))) :ARG1 (o2 / or~e.10 :op1 (i / interact-01~e.17 :ARG0 (a3 / and~e.0 :op1 (e2 / enzyme :name (n4 / name :op1 "Eps8"~e.7)) :op2 (p5 / protein :name (n5 / name :op1 "E3b1"~e.9,12)))) :op2 (i2 / interact-01~e.17 :ARG0 (a4 / and~e.0 :op1 p5 :op2 p3))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.48 :mod "7C"))) # ::id pmid_1177_7939.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This latter result strongly suggests that an intact S/E/E8 complex is required for binding to Rac , providing a molecular basis for the catalytic specificity of the complex . # ::alignments 0-1.1.3 1-1.1.2 2-1.1 2-1.1.1 2-1.1.1.r 3-1.3 4-1 5-1.2.r 7-1.2.1.4 9-1.2.1 11-1.2 12-1.2.2.r 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.1.1 17-1.2.1.5 19-1.2.1.5.1.1 20-1.2.1.5.1 21-1.2.1.5.2.r 23-1.2.1.5.2.1 24-1.2.1.5.2 27-1.2.1 (s / suggest-01~e.4 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2) :mod (l / latter~e.1) :mod (t2 / this~e.0)) :ARG1~e.5 (r2 / require-01~e.11 :ARG1 (m2 / macro-molecular-complex~e.9,27 :part (p2 / protein :name (n / name :op1 "S")) :part (p3 / protein :name (n2 / name :op1 "E")) :part (p4 / protein :name (n3 / name :op1 "E8")) :mod (i / intact~e.7) :ARG0-of (p / provide-01~e.17 :ARG1 (b2 / basis~e.20 :mod (m / molecule~e.19)) :ARG2~e.21 (s3 / specificity~e.24 :mod (c / catalysis~e.23) :poss m2))) :purpose~e.12 (b / bind-01~e.13 :ARG2~e.14 (e / enzyme :name (n4 / name :op1 "Rac"~e.15)))) :ARG1-of (s2 / strong-02~e.3)) # ::id pmid_1177_7939.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RTK activation differentially regulates the S/G and S/E/E8 complexes # ::alignments 0-1.1.1.1.1 1-1.1 2-1.3 2-1.3.r 3-1 6-1.2 8-1.2.1 8-1.2.2 (r / regulate-01~e.3 :ARG0 (a / activate-01~e.1 :ARG0 (e / enzyme :name (n / name :op1 "RTK"~e.0))) :ARG1 (a2 / and~e.6 :op1 (m / macro-molecular-complex~e.8 :part (p / protein :name (n2 / name :op1 "S")) :part (p2 / protein :name (n3 / name :op1 "G"))) :op2 (m2 / macro-molecular-complex~e.8 :part p :part (p3 / protein :name (n4 / name :op1 "E")) :part (p4 / protein :name (n5 / name :op1 "E8")))) :manner~e.2 (d / differential~e.2)) # ::id pmid_1177_7939.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since S/G and S/E complexes are present in the cells simultaneously , then both Sos @-@ 1 @-@ dependent Ras @- and Rac @-@ GEF activities are present at the same time . # ::alignments 0-1.3 2-1.3.1 4-1.1.1 4-1.2.1 4-1.3.1.1 6-1.3.1.2 7-1.3.1.2.1.r 9-1.3.1.2.1 10-1.3.1.2.2 14-1.1.1.3.1.1.1 16-1.1.1.3.1.1.1 18-1.1.1.3 19-1.1.1.1.1.1 21-1 22-1.2.1.1.1.1 24-1.1.1.2.1.1 25-1.1 25-1.2 27-1.4 30-1.4.1.1 31-1.3.1.2.2.r 31-1.4.1 31-1.4.1.r (a5 / and~e.21 :op1 (a2 / activity-06~e.25 :ARG0 (m / macro-molecular-complex~e.4 :part (e / enzyme :name (n / name :op1 "Ras"~e.19)) :part (p5 / protein :name (n2 / name :op1 "GEF"~e.24)) :ARG0-of (d / depend-01~e.18 :ARG1 (p6 / protein :name (n3 / name :op1 "Sos-1"~e.14,16))))) :op2 (a / activity-06~e.25 :ARG0 (m2 / macro-molecular-complex~e.4 :part (e3 / enzyme :name (n4 / name :op1 "Rac"~e.22)) :part p5)) :ARG1-of (c / cause-01~e.0 :ARG0 (a4 / and~e.2 :op1 (m3 / macro-molecular-complex~e.4 :part (p / protein :name (n6 / name :op1 "S")) :part (p2 / protein :name (n7 / name :op1 "G"))) :ARG1-of (p4 / present-02~e.6 :ARG2~e.7 (c2 / cell~e.9) :time~e.31 (s / simultaneous~e.10)))) :ARG1-of (p3 / present-02~e.27 :time~e.31 (t / time~e.31 :ARG1-of (s3 / same-01~e.30)))) # ::id pmid_1177_7939.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The question remains as to how these two complexes , and the ensuing Ras and Rac activities , are coordinated to achieve propagation of signals . # ::alignments 1-1 2-1.2 4-1.1.r 5-1.1.1.r 6-1.1.1.1.1.2 7-1.1.1.1.1.1 8-1.1.1.1.1 10-1.1.1.1 10-1.1.1.1.2 10-1.1.1.1.2.r 12-1.1.1.1.2.3 13-1.1.1.1.2.1.1.1.1 14-1.1.1.1.2 15-1.1.1.1.2.2.1.1.1 16-1.1.1.1.2.2 19-1.1.1 21-1.1.1.2 22-1.1.1.2.2 23-1.1.1.2.2.1.r 24-1.1.1.2.2.1 (q / question-01~e.1 :ARG1~e.4 (t / thing :manner-of~e.5 (c / coordinate-01~e.19 :ARG1 (a2 / and~e.10 :op1 (m / macro-molecular-complex~e.8 :quant 2~e.7 :mod (t2 / this~e.6)) :op2~e.10 (a3 / and~e.10,14 :op1 (a5 / act-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Ras"~e.13))) :op2 (a4 / act-02~e.16 :ARG0 (e4 / enzyme :name (n3 / name :op1 "Rac"~e.15))) :ARG1-of (e2 / ensue-01~e.12))) :purpose (a / achieve-01~e.21 :ARG0 m :ARG1 (p / propagate-01~e.22 :ARG1~e.23 (s / signal~e.24))))) :ARG1-of (r / remain-01~e.2)) # ::id pmid_1177_7939.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore looked for evidence of differential regulation of the S/G and S/E complex upon RTK stimulation . # ::alignments 0-1.1.1 1-1 2-1.1 3-1.1.2.r 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.2 7-1.1.2.1 11-1.1.2.1.1 13-1.1.2.1.1.1 13-1.1.2.1.1.2 15-1.1.2.1.3.1.1.1 16-1.1.2.1.3 (c / cause-01~e.1 :ARG1 (l2 / look-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (e / evidence-01~e.4 :ARG1~e.5 (r / regulate-01~e.7 :ARG1 (a / and~e.11 :op1 (m / macro-molecular-complex~e.13 :part (p / protein :name (n / name :op1 "S")) :part (p2 / protein :name (n2 / name :op1 "G"))) :op2 (m2 / macro-molecular-complex~e.13 :part (p4 / protein :name (n5 / name :op1 "E")) :part p)) :mod (d / differential~e.6) :condition (s / stimulate-01~e.16 :ARG2 (e4 / enzyme :name (n3 / name :op1 "RTK"~e.15))))))) # ::id pmid_1177_7939.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upon PDGF stimulation , we observed decreased coimmunoprecipitation between Grb2 and Sos @-@ 1 and consequently between PDGFR and Sos @-@ 1 ( Fig . 8 , A and B ) , which correlated with the appearance of a mobility @-@ retarded form of Sos @-@ 1 . # ::alignments 1-1.3.1.1.1 2-1.3 4-1.1 5-1 6-1.2.2.3.1 7-1.2.2.3.1 8-1.2.2.3.1 9-1.2.2.3.1 10-1.2.2.3.1 11-1.2.2.3.1 12-1.2.2.3.1 13-1.2.2.3.1 14-1.2 15-1.2.2.3 17-1.2.2.1.1.1 18-1.2.4.1 19-1.2.2.2 20-1.2.2.2 21-1.2.2.2 24-1.2.4.1.1 24-1.2.4.1.2 29-1.2.4.1 35-1.2.3 36-1.2.3.1.r 38-1.2.3.1 39-1.2.3.1.1.r 41-1.2.3.1.1.2.1 43-1.2.3.1.1.2 44-1.2.3.1.1 45-1.2.3.1.1.1.r 46-1.2.3.1.1.1 47-1.2.3.1.1.1 48-1.2.3.1.1.1 (o / observe-01~e.5 :ARG0 (w / we~e.4) :ARG1 (a / and~e.14 :op1 (c / coimmunoprecipitate-01 :ARG1 (p4 / protein :name (n / name :op1 "Grb2")) :ARG2 (p3 / protein :name (n2 / name :op1 "Sos-1")) :ARG1-of (d / decrease-01)) :op2 (c3 / coimmunoprecipitate-01 :ARG1 (p / protein :name (n3 / name :op1 "PDGFR"~e.17)) :ARG2 p3~e.19,20,21 :ARG1-of (c2 / cause-01~e.15 :ARG0 c~e.6,7,8,9,10,11,12,13)) :ARG1-of (c4 / correlate-01~e.35 :ARG2~e.36 (a2 / appear-01~e.38 :ARG1~e.39 (f4 / form~e.44 :mod~e.45 p3~e.46,47,48 :ARG1-of (r / retard-01~e.43 :ARG2 (m / mobility~e.41))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.18,29 :op1 (f / figure~e.24 :mod "8A") :op2 (f2 / figure~e.24 :mod "8B")))) :condition (s / stimulate-01~e.2 :ARG0 (p2 / protein :name (n4 / name :op1 "PDGF"~e.1)))) # ::id pmid_1177_7939.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This likely represents a hyperphosphorylated form of Sos @-@ 1 , as previously demonstrated ( Baltensperger et al. , 1993 ; Cherniack et al. , 1994 ; Pronk et al. , 1994 ) . # ::alignments 0-1.1.1 1-1 2-1.1 4-1.1.2.1 5-1.1.2 6-1.1.2.2.r 7-1.1.2.2.1.1 9-1.1.2.2.1.1 11-1.1.3.1.r 12-1.1.3.1 13-1.1.3 16-1.2.1.1.1.1.1.1 17-1.2.1.1.1 18-1.2.1.1.1.2.1 20-1.2.1.1.2.1 24-1.2.1.2.1.1.1.1 25-1.2.1 25-1.2.1.2.1 25-1.2.1.3.1 26-1.2.1.2.1.2.1 26-1.2.1.3.1.2.1 28-1.2.1.2.2.1 28-1.2.1.3.2.1 32-1.2.1.3.1.1.1.1 33-1.2.1 33-1.2.1.2.1 33-1.2.1.3.1 34-1.2.1.2.1.2.1 34-1.2.1.3.1.2.1 36-1.2.1.2.2.1 36-1.2.1.3.2.1 (l / likely-01~e.1 :ARG1 (r / represent-01~e.2 :ARG0 (t / this~e.0) :ARG1 (f / form~e.5 :ARG3-of (h / hyperphosphorylate-01~e.4) :mod~e.6 (p / protein :name (n / name :op1 "Sos-1"~e.7,9))) :compared-to (d3 / demonstrate-01~e.13 :time~e.11 (p2 / previous~e.12))) :ARG1-of (d4 / describe-01 :ARG0 (a / and~e.25,33 :op1 (p3 / publication-91 :ARG0 (a2 / and~e.17 :op1 (p6 / person :name (n2 / name :op1 "Baltensperger"~e.16)) :op2 (p9 / person :mod (o / other~e.18))) :time (d / date-entity :year 1993~e.20)) :op2 (p4 / publication-91 :ARG0 (a3 / and~e.25,33 :op1 (p7 / person :name (n3 / name :op1 "Cherniack"~e.24)) :op2 (p10 / person :mod (o2 / other~e.26,34))) :time (d2 / date-entity :year 1994~e.28,36)) :op3 (p5 / publication-91 :ARG0 (a4 / and~e.25,33 :op1 (p8 / person :name (n4 / name :op1 "Pronk"~e.32)) :op2 (p11 / person :mod (o3 / other~e.26,34))) :time (d5 / date-entity :year 1994~e.28,36))))) # ::id pmid_1177_7939.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , under identical conditions , the coimmunoprecipitation between E3b1 and Sos @-@ 1 was not affected ( Fig . 8 A ) . # ::alignments 0-1.4 3-1.5.1 4-1.5 4-1.5.r 7-1.2 9-1.2.1.1.1 11-1.2.2.1.1 13-1.2.2.1.1 15-1.1 15-1.1.r 16-1 19-1.3.1 (a / affect-01~e.16 :polarity~e.15 -~e.15 :ARG1 (c4 / coimmunoprecipitate-01~e.7 :ARG1 (p3 / protein :name (n / name :op1 "E3b1"~e.9)) :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.11,13))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "8A")) :mod (c / converse~e.0) :condition~e.4 (c3 / condition~e.4 :ARG1-of (i / identical-01~e.3))) # ::id pmid_1177_7939.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , the stability of the endogenous trimeric complex , Sos @-@ 1/Eps8/E3b1 was not affected by treatment of cells with growth factors ( Fig . 8 C ) . # ::alignments 0-1.5 3-1.3 4-1.3.1.r 6-1.3.1.2 7-1.3.1.1 8-1.3.1 10-1.3.1.3.1.1 14-1.1 14-1.1.r 15-1 16-1.2.r 17-1.2 18-1.2.1.r 19-1.2.1 20-1.2.2.r 21-1.2.2 22-1.2.2 25-1.4.1 (a / affect-01~e.15 :polarity~e.14 -~e.14 :ARG0~e.16 (t / treat-04~e.17 :ARG1~e.18 (c / cell~e.19) :ARG2~e.20 (g / growth-factor~e.21,22)) :ARG1 (s2 / stable-03~e.3 :ARG1~e.4 (m / macro-molecular-complex~e.8 :mod (t2 / trimeric~e.7) :mod (e / endogenous~e.6) :part (p / protein :name (n / name :op1 "Sos-1"~e.10)) :part (e2 / enzyme :name (n2 / name :op1 "Eps8")) :part (p3 / protein :name (n3 / name :op1 "E3b1")))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod "8C")) :ARG1-of (r / resemble-01~e.0)) # ::id pmid_1177_7939.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The above data indicate that , as a consequence of activation of RTKs , the S/G complex is disrupted , whereas the S/E/E8 complex persists in the cell . # ::alignments 1-1.1.1 2-1.1 3-1 6-1.2.3 7-1.2.3 8-1.2.3 9-1.2.3.1.r 10-1.2.3.1 16-1.2.1.1 18-1.2.1 20-1.2 23-1.2.2.1 24-1.2.2 25-1.2.2.2.r 27-1.2.2.2 (i / indicate-01~e.3 :ARG0 (d / data~e.2 :location (a / above~e.1)) :ARG1 (c / contrast-01~e.20 :ARG1 (d2 / disrupt-01~e.18 :ARG1 (m / macro-molecular-complex~e.16 :part (p / protein :name (n / name :op1 "S")) :part (p2 / protein :name (n2 / name :op1 "G")))) :ARG2 (p3 / persist-01~e.24 :ARG1 (m2 / macro-molecular-complex~e.23 :part (p5 / protein :name (n4 / name :op1 "E")) :part (p6 / protein :name (n5 / name :op1 "E8")) :part p) :location~e.25 (c2 / cell~e.27)) :ARG1-of (c3 / cause-01~e.6,7,8 :ARG0~e.9 (a2 / activate-01~e.10 :ARG1 (e / enzyme :name (n6 / name :op1 "RTK")))))) # ::id pmid_1177_7939.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This might lead to a transient peak in Ras activity vis a vis a more prolonged activation of Rac . # ::alignments 0-1.1.1 1-1 2-1.1 5-1.1.2.2 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1.1 9-1.1.2.1 14-1.1.3.2.1 15-1.1.3.2 16-1.1.3 17-1.1.3.1.r 18-1.1.3.1.1.1 (p / possible-01~e.1 :ARG1 (l / lead-03~e.2 :ARG0 (t / this~e.0) :ARG2 (p2 / peak-01~e.6 :ARG1~e.7 (a / activity-06~e.9 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.8))) :ARG1-of (t2 / transient-02~e.5)) :purpose (a2 / activate-01~e.16 :ARG1~e.17 (e2 / enzyme :name (n2 / name :op1 "Rac"~e.18)) :ARG1-of (p3 / prolong-01~e.15 :degree (m / more~e.14))))) # ::id pmid_1177_7939.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we measured the kinetic of RTK @-@ induced activation of Ras and Rac . # ::alignments 0-1 2-1.1.1 3-1.1 7-1.1.2.1.2.1.1.1 9-1.1.2.1.2 10-1.1.2.1 11-1.1.2.1.1.r 12-1.1.2.1.1.1.1.1 13-1.1.2.1.1 14-1.1.2.1.1.2.1.1 (c / cause-01~e.0 :ARG1 (m / measure-01~e.3 :ARG0 (w / we~e.2) :ARG1 (k / kinetics :mod (a / activate-01~e.10 :ARG1~e.11 (a2 / and~e.13 :op1 (e / enzyme :name (n / name :op1 "Ras"~e.12)) :op2 (e2 / enzyme :name (n2 / name :op1 "Rac"~e.14))) :ARG2-of (i / induce-01~e.9 :ARG0 (e3 / enzyme :name (n3 / name :op1 "RTK"~e.7))))))) # ::id pmid_1177_7939.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Fig . 8 D , activation of Ras was rapid and short lived , whereas activation of Rac was sustained over a longer period of time , compatible with the differential regulation of the corresponding activating complexes , S/G and S/E/E8 . # ::alignments 1-1.3 4-1.3.1 10-1.1.1.1 11-1.1.1.1.1.r 12-1.1.1.1.1.1.1 13-1.1.1.1.r 14-1.1.1 15-1.1 16-1.1.2.2 17-1.1.2 19-1 20-1.2.1 21-1.2.1.1.r 22-1.2.1.1.1.1 24-1.2 27-1.2.2 27-1.2.2.1 27-1.2.2.1.r 32-1.2.2.2 33-1.2.2.2.1.r 35-1.2.2.2.1.2 36-1.2.2.2.1 37-1.2.2.2.1.1.r 39-1.2.2.2.1.1.3.1 40-1.2.2.2.1.1.3 41-1.2.2.2.1.1.1 41-1.2.2.2.1.1.2 44-1.2.2.2.1.1 (c / contrast-01~e.19 :ARG1 (a / and~e.15 :op1 (r / rapid~e.14 :domain~e.13 (a2 / activate-01~e.10 :ARG1~e.11 (e / enzyme :name (n / name :op1 "Ras"~e.12)))) :op2 (l / live-01~e.17 :ARG0 a2 :ARG1-of (s / short-07~e.16))) :ARG2 (s2 / sustain-01~e.24 :ARG1 (a3 / activate-01~e.20 :ARG1~e.21 (e2 / enzyme :name (n2 / name :op1 "Rac"~e.22))) :ARG1-of (l2 / long-03~e.27 :degree~e.27 (m / more~e.27) :mod (c2 / compatible~e.32 :prep-with~e.33 (r2 / regulate-01~e.36 :ARG1~e.37 (a4 / and~e.44 :op1 (m2 / macro-molecular-complex~e.41 :part (p2 / protein :name (n3 / name :op1 "S")) :part (p3 / protein :name (n5 / name :op1 "G"))) :op2 (m3 / macro-molecular-complex~e.41 :part (p5 / protein :name (n6 / name :op1 "E")) :part (p6 / protein :name (n7 / name :op1 "E8")) :part p2) :ARG0-of (a5 / activate-01~e.40 :ARG1-of (c3 / correspond-02~e.39))) :ARG1-of (d / differ-02~e.35))))) :ARG1-of (s3 / show-01~e.1 :ARG0 (f / figure~e.4 :mod "8D"))) # ::id pmid_1177_7939.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 1 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 1~e.1) # ::id pmid_1177_7939.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The S/E/E8 complex exists under physiological conditions . # ::alignments 3-1.1 4-1 6-1.2 7-1.2.r (e / exist-01~e.4 :ARG1 (m / macro-molecular-complex~e.3 :part (p2 / protein :name (n / name :op1 "S")) :part (p3 / protein :name (n2 / name :op1 "E")) :part (p4 / protein :name (n3 / name :op1 "E8"))) :condition~e.7 (p / physiology~e.6)) # ::id pmid_1177_7939.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Eps8 @^−/− cells were transfected with a control vector (−/− lanes ) or a vector coding a myc epitope @–@ tagged Eps8 (−/− [ Eps8 myc ] lanes ) , both carrying a hygromicin resistance gene . # ::alignments 1-1.1 3-1.2.1.1.1.1 5-1.3.1.2.1.1.1 7-1.2 7-1.3.2.1.1 9-1 12-1.3.1.1 13-1.3.1 15-1.3.2.2.1 17-1.3 19-1.3.2 20-1.3.2.1 22-1.3.2.1.1.2.1.1.1.1 23-1.3.2.1.1.2.1 25-1.3.2.1.1.2 26-1.3.2.1.1.1.1.1.1 29-1.3.2.1.1.1.1.1.1 30-1.3.2.1.1.2.1.1.1.1 32-1.3.1.2.1 32-1.3.2.2.1 36-1.3.3 38-1.3.3.1.1.1.1.1 39-1.3.3.1.1 40-1.3.3.1 (t / transfect-01~e.9 :li "A"~e.1 :ARG1 (c / cell~e.7 :ARG0-of (c6 / contain-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8"~e.3) :ARG2-of m4))) :ARG2 (o / or~e.17 :op1 (v / vector~e.13 :ARG0-of (c2 / control-01~e.12) :ARG1-of (d / describe-01 :ARG2 (l / lane~e.32 :ARG2-of (m4 / mutate-01 :mod "−/−"~e.5)))) :op2 (v2 / vector~e.19 :ARG0-of (c3 / code-01~e.20 :ARG1 (c4 / cell~e.7 :ARG0-of (c7 / contain-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Eps8"~e.26,29))) :ARG1-of (t2 / tag-01~e.25 :ARG2 (e / epitope~e.23 :mod (p / protein :name (n3 / name :op1 "myc"~e.22,30)))))) :ARG1-of (m2 / mean-01 :ARG2 (l2 / lane~e.15,32 :mod (p2 / protein :name (n5 / name :op1 "Eps8myc") :ARG2-of m4)))) :ARG0-of (c5 / carry-01~e.36 :ARG1 (g / gene~e.40 :ARG0-of (r / resist-01~e.39 :ARG1 (s / small-molecule :name (n4 / name :op1 "hygromicin"~e.38))))))) # ::id pmid_1177_7939.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hygromicin @-@ resistant single @-@ cell clones were established after 10 d of selection with hygromicin ( 0.2 mg/ml ) . # ::alignments 0-1.1.2.1.1.1 2-1.1.2 3-1.1.1 5-1.1 6-1.1.3 8-1 9-1.2 10-1.2.2.1 12-1.2.1.r 13-1.2.1 14-1.2.1.2.r 15-1.2.1.2.2.1 17-1.2.1.2.1 17-1.2.1.2.3.1 (e / establish-01~e.8 :ARG1 (c2 / cell~e.5 :ARG1-of (s / single-02~e.3) :ARG0-of (r / resist-01~e.2 :ARG1 (s4 / small-molecule :name (n / name :op1 "hygromicin"~e.0))) :ARG1-of (c / clone-01~e.6)) :time (a / after~e.9 :op1~e.12 (s2 / select-01~e.13 :ARG1 c2 :instrument~e.14 (s3 / small-molecule :quant 0.2~e.17 :name (n2 / name :op1 "hygromicin"~e.15) :quant (c3 / concentration-quantity :quant 0.2~e.17 :unit (m3 / milligram-per-milliliter)))) :quant (t / temporal-quantity :quant 10~e.10 :unit (d / day)))) # ::id pmid_1177_7939.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of Eps8 , PDGFR , and EGFR in individual clones of eps8 @^−/− , −/− [ Eps8 myc ] , or in wild @-@ type ( WT ) cells were determined by immunoblotting analysis of equal amounts of total cellular lysates ( 50 μg ) using the indicated antibodies ( WB ) , and clones with levels of expression of Eps8 , PDGFR , and EGFR similar to wild @-@ type fibroblasts were used . # ::alignments 1-1.1.2.1 2-1.1.2.1.1.r 3-1.1.2.1.1.1.1 5-1.1.2.2.1.1.1 7-1.1.2 8-1.1.2.3.1.1.1 10-1.1.2.4.1.2 11-1.1.2.4.1 11-1.1.2.4.2 11-1.1.2.4.3 13-1.1.2.4.1.1.1.1.1.1 15-1.1.2.4.1.1.1.1.2.1 18-1.1.2.4.1.1.1.1.2.1 20-1.1.2.4.1.1.1.1.1.1 24-1.1.2.4 26-1.1.2.4.3.1.1 28-1.1.2.4.3.1.1 30-1.1.2.4.3.1.1 30-1.1.2.4.3.1.1.1.1.1 32-1.1.2.4.1.1 32-1.1.2.4.2.1 32-1.1.2.4.3.1 34-1.1 35-1.1.1.r 36-1.1.1.2 37-1.1.1 38-1.1.1.1.r 39-1.1.1.1.1 40-1.1.1.1 41-1.1.1.1.2.r 42-1.1.1.1.2.2 43-1.1.1.1.2.1 44-1.1.1.1.2 46-1.1.1.1.2.2.1.1 47-1.1.1.1.2.2.1.2 49-1.1.1.3 51-1.1.1.3.1.1 52-1.1.1.3.1 54-1.1.1.3.1.2.1.1 57-1 57-1.1.2 58-1.2.1 60-1.1.2.2 60-1.1.2.3 60-1.2.1.1.1 60-1.2.1.1.2 60-1.2.1.1.3 62-1.2.1.1.1.1 62-1.2.1.1.2.1 62-1.2.1.1.3.1 64-1.1.2.1.1.1.1 64-1.1.2.4.1.1.1.1.1.1 66-1.1.2.2.1.1.1 69-1.1.2.3.1.1.1 70-1.2.1.1.4 71-1.2.1.1.4.1.r 72-1.2.1.1.4.1.1 73-1.2.1.1.4.1.1 74-1.2.1.1.4.1.1 75-1.2.1.1.4.1 77-1.2 (a / and~e.57 :op1 (d / determine-01~e.34 :ARG0~e.35 (a3 / analyze-01~e.37 :ARG1~e.38 (a4 / amount~e.40 :ARG1-of (e2 / equal-01~e.39) :quant-of~e.41 (l4 / lysate~e.44 :mod (c3 / cell~e.43) :ARG1-of (t / total-01~e.42 :ARG2 (m / mass-quantity :quant 50~e.46 :unit (m2 / microgram~e.47))))) :manner (i2 / immunoblot-01~e.36) :manner (u / use-01~e.49 :ARG1 (a5 / antibody~e.52 :ARG1-of (i3 / indicate-01~e.51) :ARG1-of (d3 / describe-01 :ARG2 (n6 / name :op1 "WB"~e.54))))) :ARG1 (a2 / and~e.7,57 :op1 (l / level~e.1 :quant-of~e.2 (e8 / enzyme :name (n2 / name :op1 "Eps8"~e.3,64))) :op2 (l2 / level~e.60 :quant-of (e4 / enzyme :name (n3 / name :op1 "PDGFR"~e.5,66))) :op3 (l3 / level~e.60 :quant-of (e3 / enzyme :name (n4 / name :op1 "EGFR"~e.8,69))) :location (o / or~e.24 :op1 (c / clone-01~e.11 :ARG1 (c5 / cell~e.32 :ARG0-of (c6 / contain-01 :ARG1 (e7 / enzyme :name (n5 / name :op1 "Eps8"~e.13,20,64) :ARG2-of (m3 / mutate-01 :mod "−/−"~e.15,18)))) :mod (i / individual~e.10)) :op2 (c7 / clone-01~e.11 :ARG1 (c8 / cell~e.32 :ARG0-of (c9 / contain-01 :ARG1 (p / protein :name (n / name :op1 "Eps8myc") :ARG2-of m3)))) :op3 (c10 / clone-01~e.11 :ARG1 (c2 / cell~e.32 :mod (w / wild-type~e.26,28,30 :ARG1-of (d2 / describe-01 :ARG2 (n7 / name :op1 "WT"~e.30)))))))) :op2 (u2 / use-01~e.77 :ARG1 (c4 / clone~e.58 :poss-of (a6 / and :op1 (l5 / level~e.60 :degree-of (e / express-01~e.62 :ARG1 e8)) :op2 (l6 / level~e.60 :degree-of (e5 / express-01~e.62 :ARG1 e4)) :op3 (l7 / level~e.60 :degree-of (e6 / express-01~e.62 :ARG1 e3)) :ARG1-of (r / resemble-01~e.70 :ARG2~e.71 (f / fibroblast~e.75 :mod w~e.72,73,74)))))) # ::id pmid_1177_7939.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Total cellular lysates ( 10 mg ) , obtained from the transfectants described in A , were immunoprecipitated ( IP ) with the antibody indicated at the bottom ( ctr , irrelevant antibody ) , followed by immunoblot with indicated antibodies ( WB ) . # ::alignments 3-1.1.2 4-1.1.1 5-1.1 7-1.1.2.1.1 8-1.1.2.1.2 11-1.1.3 12-1.1.3.1.r 14-1.1.3.1 14-1.1.3.1.1 14-1.1.3.1.1.r 15-1.1.3.1.2 15-1.2.3 15-1.4 20-1 24-1.2.r 26-1.2 27-1.2.1 28-1.2.1.1.r 30-1.2.1.1 34-1.2.2 34-1.2.2.1 34-1.2.2.1.r 35-1.2 38-1.3 39-1.3.1.r 40-1.3.1 41-1.3.1.2.r 42-1.3.1.2.1 43-1.3.1.2 (i / immunoprecipitate-01~e.20 :ARG1 (l / lysate~e.5 :mod (c / cell~e.4) :ARG1-of (t / total-01~e.3 :ARG2 (m / mass-quantity :quant 10~e.7 :unit (m2 / milligram~e.8))) :ARG1-of (o / obtain-01~e.11 :ARG2~e.12 (m3 / molecular-physical-entity~e.14 :ARG1-of~e.14 (t2 / transfect-01~e.14) :ARG1-of (d / describe-01~e.15 :ARG0 (f3 / figure :mod "1A"))))) :ARG3~e.24 (a2 / antibody~e.26,35 :ARG1-of (i2 / indicate-01~e.27 :location~e.28 (b / bottom~e.30)) :ARG1-of (r / relevant-01~e.34 :polarity~e.34 -~e.34) :ARG1-of (d3 / describe-01~e.15 :ARG2 (c2 / control))) :ARG2-of (f / follow-01~e.38 :ARG1~e.39 (i3 / immunoblot-01~e.40 :ARG2 l :ARG3~e.41 (a3 / antibody~e.43 :ARG1-of (i4 / indicate-01~e.42)))) :ARG1-of (d5 / describe-01~e.15 :ARG0 (f2 / figure :mod "1B"))) # ::id pmid_1177_7939.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The indicated lanes ( lysates ) were loaded with 100 μg of total cellular lysates . # ::alignments 1-1.1.1 2-1.1 4-1.1.2.1 4-1.2 7-1 8-1.2.r 9-1.2.2.1.1 10-1.2.2.1.2 12-1.2.2 13-1.2.1 14-1.1.2.1 14-1.2 (l / load-01~e.7 :ARG1 (l2 / lane~e.2 :ARG1-of (i / indicate-01~e.1) :ARG1-of (d / describe-01 :ARG2 (l4 / lysate~e.4,14))) :ARG2~e.8 (l3 / lysate~e.4,14 :mod (c / cell~e.13) :ARG1-of (t / total-01~e.12 :ARG2 (m / mass-quantity :quant 100~e.9 :unit (m2 / microgram~e.10))))) # ::id pmid_1177_7939.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) Total cellular lysates ( 10 mg ) obtained from −/− [ Eps8 myc ] cells were immunoprecipitated ( IP ) with the antibody indicated at the top ( ctr , irrelevant antibody ) in the presence or absence (−) of 40 ng @/@ ml of the indicated peptides ( peptides ) . # ::alignments 1-1.4.1.1 3-1.1.2 4-1.1.1 5-1.1 7-1.1.2.1.1 8-1.1.2.1.2 10-1.1.3 11-1.1.3.1.r 12-1.1.3.1.1.1.2.1 17-1.1.3.1 19-1 23-1.2.r 25-1.2 26-1.2.1 27-1.2.1.1.r 29-1.2.1.1 33-1.2.2 33-1.2.2.1 33-1.2.2.1.r 34-1.2 36-1.3.r 38-1.3.1 39-1.3 40-1.3.2 42-1.3.1.1.r 43-1.3.1.1.2.1 44-1.3.1.1.2.2 46-1.3.1.1.2.2 47-1.3.1.1.2.r 49-1.3.1.1.1 50-1.3.1.1 52-1.3.1.1 (i / immunoprecipitate-01~e.19 :ARG2 (l / lysate~e.5 :mod (c / cell~e.4) :ARG1-of (t / total-01~e.3 :ARG2 (m / mass-quantity :quant 10~e.7 :unit (m2 / milligram~e.8))) :ARG1-of (o / obtain-01~e.10 :ARG2~e.11 (c2 / cell~e.17 :ARG0-of (c4 / contain-01 :ARG1 (p2 / protein :name (n / name :op1 "EPS8myc") :ARG2-of (m3 / mutate-01 :mod "−/−"~e.12)))))) :ARG3~e.23 (a / antibody~e.25,34 :ARG1-of (i2 / indicate-01~e.26 :location~e.27 (t2 / top~e.29)) :ARG1-of (r / relevant-01~e.33 :polarity~e.33 -~e.33)) :condition~e.36 (o2 / or~e.39 :op1 (p3 / present-02~e.38 :ARG1~e.42 (p / peptide~e.50,52 :ARG1-of (i3 / indicate-01~e.49) :quant~e.47 (c6 / concentration-quantity :quant 40~e.43 :unit (n3 / nanogram-per-milliliter~e.44,46)))) :op2 (a2 / absent-01~e.40 :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"~e.1))) # ::id pmid_1177_7939.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The peptides used were PPPPPVD @ Y @ TEDEE ( PXXDY ) and PPPPPVD @ A @ TEDEE ( PXXDA , used as a control ) . # ::alignments 1-1.1.1 1-1.1.2 2-1.1.2.2 10-1.1.1.2.1.1 12-1.1 19-1.1.2.3.1.1 21-1 21-1.1.2.2 22-1.1.2.2.1.r 24-1.1.2.2.1 (u / use-01~e.21 :ARG1 (a / and~e.12 :op1 (p / peptide~e.1 :name (n / name :op1 "PPPPPVDYTEDEE") :ARG1-of (d / describe-01 :ARG2 (n3 / name :op1 "PXXDY"~e.10))) :op2 (p2 / peptide~e.1 :name (n2 / name :op1 "PPPPPVDATEDEE") :ARG1-of (u2 / use-01~e.2,21 :ARG2~e.22 (c / control-01~e.24 :ARG0 p2)) :ARG1-of (d2 / describe-01 :ARG2 (n4 / name :op1 "PXXDA"~e.19))))) # ::id pmid_1177_7939.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblotting was with the indicated antibodies ( WB ) . # ::alignments 0-1 2-1.1.r 4-1.1.1 5-1.1 7-1.1.2.1.1 (i / immunoblot-01~e.0 :ARG3~e.2 (a / antibody~e.5 :ARG1-of (i2 / indicate-01~e.4) :ARG1-of (d / describe-01 :ARG2 (n / name :op1 "WB"~e.7)))) # ::id pmid_1177_7939.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The indicated lanes ( lysates ) were loaded with 100 μg of total cellular lysates . # ::alignments 1-1.1.1 2-1.1 4-1.1.2.1 4-1.2 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2.1.1.2 12-1.2.1 13-1.2.2 14-1.1.2.1 14-1.2 (l / load-01~e.7 :ARG1 (l2 / lane~e.2 :ARG1-of (i / indicate-01~e.1) :ARG1-of (d / describe-01 :ARG2 (l4 / lysate~e.4,14))) :ARG2~e.8 (l3 / lysate~e.4,14 :ARG1-of (t / total-01~e.12 :ARG2 (m / mass-quantity :quant 100~e.9 :unit (m2 / microgram~e.10))) :mod (c / cell~e.13))) # ::id pmid_1177_7939.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 2 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 2~e.1) # ::id pmid_1177_7939.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro competition between E3b1 and Grb2 for binding to Sos @-@ 1 . # ::alignments 1-1.4 2-1.4 3-1 5-1.1.1.1 7-1.2.1.1 8-1.3.r 9-1.3 10-1.3.1.r 11-1.3.1.1.1 13-1.3.1.1.1 (c / compete-01~e.3 :ARG0 (p / protein :name (n / name :op1 "E3b1"~e.5)) :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2"~e.7)) :ARG2~e.8 (b / bind-01~e.9 :ARG2~e.10 (p3 / protein :name (n3 / name :op1 "Sos-1"~e.11,13))) :manner (i / in-vitro~e.1,2)) # ::id pmid_1177_7939.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A , Top ) schematic of E3b1 . # ::alignments 1-1.2.1.1 3-1.2.1.2 5-1 6-1.1.r 7-1.1.1.1 (s / schematic~e.5 :poss~e.6 (p / protein :name (n / name :op1 "E3b1"~e.7)) :ARG1-of (d / describe-01 :location (f / figure :mod "A"~e.1 :location (t / top~e.3)))) # ::id pmid_1177_7939.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The ruler shows amino acid positions . # ::alignments 1-1.1 2-1 3-1.2.1.1 4-1.2.1.1 5-1.2 5-1.2.1 5-1.2.1.r (s / show-01~e.2 :ARG0 (r / ruler~e.1) :ARG1 (l / location~e.5 :ARG2-of~e.5 (p / position-01~e.5 :ARG1 (a / amino-acid~e.3,4)))) # ::id pmid_1177_7939.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Bottom ) In vitro binding of various fragments of E3b1 ( all engineered as GST fusions , amino acid boundaries are indicated on the top ) to Sos @-@ 1 from lysates of Sos @-@ 1 @–@ transfected Cos @-@ 7 cells . # ::alignments 1-1.1.3 3-1.1.4 4-1.1.4 5-1.1 6-1.1.1.r 7-1.1.1.2 10-1.1.1.1.1.1 12-1.2.1.1 13-1.2.1 14-1.2.1.2.r 15-1.2.1.2.1.1 16-1.2.1.2.1.2 18-1.2.2.1.1 19-1.2.2.1.1 20-1.2.2.1 22-1.2.2 23-1.2.2.2.r 25-1.2.2.2 27-1.1.2.r 28-1.1.2.1.1 30-1.1.2.1.1 31-1.1.2.2.r 32-1.1.2.2 34-1.1.2.1.1 36-1.1.2.1.1 38-1.1.2.2.1.2 39-1.1.2.2.1.1.1 41-1.1.2.2.1.1.1 42-1.1.2.2.1 (m / multi-sentence :snt1 (b / bind-01~e.5 :ARG1~e.6 (p2 / protein-segment :part-of (p / protein :name (n / name :op1 "E3b1"~e.10)) :mod (v / various~e.7)) :ARG2~e.27 (p4 / protein :name (n3 / name :op1 "Sos-1"~e.28,30,34,36) :source~e.31 (l / lysate~e.32 :mod (c / cell-line~e.42 :name (n4 / name :op1 "Cos-7"~e.39,41) :ARG1-of (t / transfect-01~e.38 :ARG2 p4)))) :location (b2 / bottom~e.1) :manner (i / in-vitro~e.3,4)) :snt2 (a2 / and :op1 (e / engineer-01~e.13 :ARG1 (a / all~e.12) :ARG2~e.14 (p3 / protein :name (n2 / name :op1 "GST"~e.15 :op2 "fusion"~e.16))) :op2 (i2 / indicate-01~e.22 :ARG1 (b3 / boundary~e.20 :poss (a3 / amino-acid~e.18,19)) :location~e.23 (t2 / top~e.25)))) # ::id pmid_1177_7939.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detection was with anti @–@ Sos @-@ 1 antibody . # ::alignments 0-1 2-1.1.r 3-1.1.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1 (d / detect-01~e.0 :ARG2~e.2 (a / antibody~e.8 :ARG0-of (c / counter-01~e.3 :ARG1 (p / protein :name (n / name :op1 "Sos-1"~e.5,7))))) # ::id pmid_1177_7939.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lane “ lysate ” was loaded with 50 μg of total cellular lysates . # ::alignments 1-1.1 3-1.1.1.1 3-1.2 6-1 7-1.2.r 8-1.2.2.1.1 9-1.2.2.1.2 11-1.2.2 12-1.2.1 13-1.1.1.1 13-1.2 (l / load-01~e.6 :ARG1 (l2 / lane~e.1 :ARG1-of (d / describe-01 :ARG2 (l4 / lysate~e.3,13))) :ARG2~e.7 (l3 / lysate~e.3,13 :mod (c / cell~e.12) :ARG1-of (t / total-01~e.11 :ARG2 (m / mass-quantity :quant 50~e.8 :unit (m2 / microgram~e.9))))) # ::id pmid_1177_7939.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok P Rich , proline rich region ; SH3 , SH3 domain . # ::alignments 0-1.1.1 1-1.1.2 1-1.1.3.1 3-1.1.3.1.3.1.1 4-1.1.3.1 5-1.1.3.1.2 7-1.2.1 9-1.2.2.1.1.1 10-1.2.2.1.1.2 (a2 / and :op1 (n4 / name :op1 "P"~e.0 :op2 "Rich"~e.1 :ARG2-of (d / describe-01 :ARG1 (r2 / rich~e.1,4 :mod a :domain (r3 / region~e.5) :mod (a / amino-acid :name (n / name :op1 "proline"~e.3))))) :op2 (n5 / name :op1 "SH3"~e.7 :ARG2-of (d2 / describe-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "SH3"~e.9 :op2 "domain"~e.10))))) # ::id pmid_1177_7939.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) A His @-@ tagged COOH @-@ terminal fragment ( His @-@ Sos , aa 1131 @–@ 1333 ) of Sos @-@ 1 ( 10 pmoles ) was bound to 60 pmoles of either immobilized GST ( GST ) or GST @-@ E3b1 @–@ 331 @–@ 480 in the presence of increasing concentrations of the NH @₂@ -@ terminal SH3 domain of Grb2 or of Eps8 ( SH3s , 0 , 10 , 100 , 1,000 pmoles , as indicated on the top ) . # ::alignments 1-1.1.1 6-1.1.2.3 7-1.1.2.1.1 9-1.1.2.1.1 14-1.1.2.2.1.1 17-1.1.2.5.1.1 19-1.1.2.5.1.2 22-1.1.2.2.1.1 24-1.1.2.2.1.1 26-1.1.2.4.1 30-1.1 31-1.1.3.r 32-1.1.3.1.3.1 36-1.1.3.1.2 37-1.1.3.1.1.1 39-1.1.3.1.1.1 41-1.1.3 42-1.1.3.1.1.1 44-1.1.3.2.1.1 46-1.1.3.2.2.1.1 48-1.1.3.2.2.1.2 49-1.1.4.r 51-1.1.4 52-1.1.4.1.r 53-1.1.4.1.2 54-1.1.4.1 62-1.1.4.1.1.1.2.1.1 62-1.1.4.1.1.2.2.1.1 63-1.1.4.1.1.1.1.1 63-1.1.4.1.1.2.1.1 63-1.2.1.1.1 64-1.1.4.1.1.1.1.2 64-1.1.4.1.1.2.1.2 65-1.1.4.1.1.r 66-1.1.4.1.1.1.2.2.1.1 67-1.1.4.1.1 69-1.1.4.1.1.2.2.2.1.1 73-1.2.2.1 75-1.2.3.1 77-1.2.4.1 79-1.2.5.1 83-1.2.6 84-1.2.6.1.r 86-1.2.6.1 (m4 / multi-sentence :snt1 (b / bind-01~e.30 :li "B"~e.1 :ARG1 (p / protein-segment :name (n / name :op1 "COOH-terminus"~e.7,9) :part-of (p2 / protein :name (n2 / name :op1 "Sos-1"~e.14,22,24)) :ARG1-of (t / tag-01~e.6 :ARG2 (a / amino-acid :name (n3 / name :op1 "histidine"))) :quant (m / mass-quantity :quant 10~e.26 :unit (p3 / picomole)) :consist-of (a2 / amino-acid :mod (v / value-interval :op1 1131~e.17 :op2 1333~e.19))) :ARG2~e.31 (o / or~e.41 :op1 (e / enzyme :name (n4 / name :op1 "GST"~e.37,39,42) :ARG1-of (i3 / immobilize-01~e.36) :quant (m3 / mass-quantity :quant 60~e.32 :unit (p4 / picomole))) :op2 (p5 / protein :name (n5 / name :op1 "GST-E3b1"~e.44) :consist-of (a3 / amino-acid :mod (v2 / value-interval :op1 331~e.46 :op2 480~e.48)))) :condition~e.49 (p9 / present-02~e.51 :ARG1~e.52 (c / concentrate-02~e.54 :ARG1~e.65 (o2 / or~e.67 :op1 (p15 / protein-segment :name (n11 / name :op1 "SH3"~e.63 :op2 "domain"~e.64) :part-of (p6 / protein-segment :name (n6 / name :op1 "NH2-terminus"~e.62) :part-of (p7 / protein :name (n7 / name :op1 "Grb2"~e.66)))) :op2 (p16 / protein-segment :name (n12 / name :op1 "SH3"~e.63 :op2 "domain"~e.64) :part-of (p8 / protein-segment :name (n8 / name :op1 "NH2-terminus"~e.62) :part-of (e2 / enzyme :name (n9 / name :op1 "Eps8"~e.69))))) :ARG1-of (i / increase-01~e.53)))) :snt2 (a4 / and :op1 (p10 / protein-segment :name (n10 / name :op1 "SH3"~e.63)) :op2 (m5 / mass-quantity :quant 0~e.73 :unit (p11 / picomole)) :op3 (m6 / mass-quantity :quant 10~e.75 :unit (p12 / picomole)) :op4 (m7 / mass-quantity :quant 100~e.77 :unit (p13 / picomole)) :op5 (m8 / mass-quantity :quant 1000~e.79 :unit (p14 / picomole)) :ARG1-of (i2 / indicate-01~e.83 :location~e.84 (t2 / top~e.86)))) # ::id pmid_1177_7939.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detection was with antihistidine antibody . # ::alignments 0-1 4-1.1 (d / detect-01~e.0 :ARG2 (a / antibody~e.4 :ARG0-of (c / counter-01 :ARG1 (a2 / amino-acid :name (n / name :op1 "histidine"))))) # ::id pmid_1177_7939.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok I , input , 10 pmoles of His @-@ Sos @-@ 1 . # ::alignments 0-1.2.1.1 2-1 4-1.1.3.1 9-1.1.1.1 11-1.1.1.1 (i / input~e.2 :mod (p / protein :name (n / name :op1 "Sos-1"~e.9,11) :ARG1-of (t / tag-01 :ARG2 (a / amino-acid :name (n2 / name :op1 "histidine"))) :quant (m / mass-quantity :quant 10~e.4 :unit (p2 / picomole))) :ARG1-of (d / describe-01 :ARG2 (n3 / name :op1 "I"~e.0))) # ::id pmid_1177_7939.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) His @-@ Sos ( 10 pmoles ) was bound to 60 pmoles of GST fusions encompassing the SH3s of either E3b1 (○ and •) or of Grb2 (□ and ▪) . # ::alignments 1-1.1 5-1.2.1.1 7-1.2.3.1 11-1 12-1.3.r 13-1.3.2.1 16-1.3.1.1 17-1.3.1.2 18-1.3.3 23-1.3.3.1.1.2.1.1 27-1.3.3.1 28-1.3.3.1.r 29-1.3.3.1.2.2.1.1 (b / bind-01~e.11 :li "C"~e.1 :ARG1 (p / protein :name (n2 / name :op1 "Sos"~e.5) :ARG1-of (t / tag-01 :ARG2 (a / amino-acid :name (n / name :op1 "histidine"))) :quant (m2 / mass-quantity :quant 10~e.7 :unit (p2 / picomole))) :ARG2~e.12 (p3 / protein :name (n3 / name :op1 "GST"~e.16 :op2 "fusion"~e.17) :quant (m3 / mass-quantity :quant 60~e.13 :unit (p4 / picomole)) :ARG0-of (e / encompass-01~e.18 :ARG1~e.28 (o / or~e.27 :op1 (p5 / protein-segment :name (n4 / name :op1 "SH3") :part-of (p6 / protein :name (n5 / name :op1 "E3b1"~e.23))) :op2 (p7 / protein-segment :name (n6 / name :op1 "SH3") :part-of (p8 / protein :name (n7 / name :op1 "Grb2"~e.29))))))) # ::id pmid_1177_7939.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Binding was in the presence of the indicated amounts of the competing peptide NH2 @-@ VPVPPPVPPRRR @-@ COOH ( derived from the sequence of Sos @-@ 1 , • and ▪) , or of a scrambled control peptide (○ and □) . # ::alignments 0-1 2-1.1.r 4-1.1 5-1.1.1.r 7-1.1.1.3 8-1.1.1.1 8-1.1.1.2 9-1.1.1.1.1.r 11-1.1.1.1.1.2 12-1.1.1.1.1 13-1.1.1.1.1.1.1 15-1.1.1.1.1.1.1 17-1.1.1.1.1.1.1 19-1.1.1.1.1.3 20-1.1.1.1.1.3.1.r 22-1.1.1.1.1.3.1 23-1.1.1.1.1.3.1.1.r 24-1.1.1.1.1.3.1.1.1.1 26-1.1.1.1.1.3.1.1.1.1 32-1.1.1 33-1.1.1.2.1.r 35-1.1.1.2.1.2 36-1.1.1.2.1.1 37-1.1.1.2.1 (b / bind-01~e.0 :condition~e.2 (p2 / present-02~e.4 :ARG1~e.5 (o / or~e.32 :op1 (a / amount~e.8 :quant-of~e.9 (p / peptide~e.12 :name (n / name :op1 "NH2-VPVPPPVPPRRR-COOH"~e.13,15,17) :ARG0-of (c / compete-01~e.11) :ARG1-of (d / derive-01~e.19 :ARG2~e.20 (s2 / sequence~e.22 :mod~e.23 (p3 / protein :name (n2 / name :op1 "Sos-1"~e.24,26)))))) :op2 (a2 / amount~e.8 :quant-of~e.33 (p4 / peptide~e.37 :ARG0-of (c2 / control-01~e.36) :ARG1-of (s / scramble-02~e.35))) :ARG1-of (i / indicate-01~e.7)))) # ::id pmid_1177_7939.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detection was by immunoblot with anti @-@ His , followed by densitometric scanning . # ::alignments 0-1 2-1.1.r 3-1.1 5-1.1.1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1 12-1.1.2.1 (d / detect-01~e.0 :ARG2~e.2 (i / immunoblot-01~e.3 :ARG3 (a / antibody :ARG0-of (c / counter-01~e.5 :ARG1 (h / histidine))) :ARG2-of (f / follow-01~e.9 :ARG1~e.10 (s / scan-01~e.12 :mod (d2 / densitometric~e.11))))) # ::id pmid_1177_7939.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D ) Kinetic analysis and rate constants for the binding of the SH3 domains of Grb2 and E3b1 to the proline @-@ rich COOH @-@ terminal of Sos @-@ 1 ( aa 1131 @–@ 1333 ) . # ::alignments 1-1.1 4-1.2 5-1 6-1.3.1 7-1.3 10-1.4 13-1.4.1.1.1.1 13-1.4.1.2.1.1 14-1.4.1.1.1.2 14-1.4.1.2.1.2 15-1.4.1.r 16-1.4.1.1.2.1.1 18-1.4.1.2.2.1.1 19-1.4.2.r 21-1.4.2.4.1.1.1 23-1.4.2.4 24-1.4.2.1.1 26-1.4.2.1.1 28-1.4.2.2.1.1 30-1.4.2.2.1.1 33-1.4.2.3.1.1 35-1.4.2.3.1.2 (a / and~e.5 :li "D"~e.1 :op1 (a2 / analyze-01~e.4 :ARG1 (k / kinetics)) :op2 (c / constant~e.7 :mod (r / rate~e.6)) :purpose (b / bind-01~e.10 :ARG1~e.15 (a3 / and :op1 (p / protein-segment :name (n / name :op1 "SH3"~e.13 :op2 "domain"~e.14) :part-of (p2 / protein :name (n2 / name :op1 "Grb2"~e.16))) :op2 (p3 / protein-segment :name (n3 / name :op1 "SH3"~e.13 :op2 "domain"~e.14) :part-of (p4 / protein :name (n4 / name :op1 "E3b1"~e.18)))) :ARG2~e.19 (p5 / protein-segment :name (n5 / name :op1 "COOH-terminus"~e.24,26) :part-of (p6 / protein :name (n6 / name :op1 "Sos-1"~e.28,30)) :consist-of (a4 / amino-acid :mod (b2 / between :op1 1131~e.33 :op2 1333~e.35)) :mod (r2 / rich~e.23 :mod (a5 / amino-acid :name (n7 / name :op1 "proline"~e.21)))))) # ::id pmid_1177_7939.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Increasing concentrations ( 10 @–@ 400 nM ) of His @-@ Sos @-@ 1 were passed over the immobilized GST fusion proteins ( GST @-@ SH3 @-@ Grb2 and GST @-@ SH3 @-@ E3b1 ) for 2.5 min at a flow rate of 50 μl/min . # ::alignments 0-1.1.1 1-1.1 1-1.1.3 1-1.1.3.r 3-1.1.3.1.1 5-1.1.3.1.2 6-1.1.3.2 11-1.1.2.1.1 13-1.1.2.1.1 13-1.4.2.1 15-1 18-1.2.2 19-1.2.1.1 20-1.2.1.2 21-1.1.2 21-1.2 21-1.2.3.1.1 21-1.2.3.1.2 25-1.2.3.1.1.1.1 25-1.2.3.1.2.1.1 27-1.2.3.1.1.1.1 28-1.2.3.1 29-1.2.3.1.1.1.1 29-1.2.3.1.2.1.1 31-1.2.3.1.1.1.1 31-1.2.3.1.2.1.1 33-1.2.3.1.2.1.1 35-1.3.r 36-1.3.1 37-1.3.2 37-1.4.2.2 41-1.4 43-1.4.1.1 (p / pass-08~e.15 :ARG0 (c / concentration~e.1 :ARG1-of (i / increase-01~e.0) :mod (p2 / protein~e.21 :name (n2 / name :op1 "Sos-1"~e.11,13) :ARG1-of (t3 / tag-01 :ARG2 (a / amino-acid :name (n / name :op1 "histidine")))) :quant~e.1 (c2 / concentration-quantity~e.1 :quant (b / between :op1 10~e.3 :op2 400~e.5) :unit (n3 / nanomolar~e.6))) :ARG1 (p3 / protein~e.21 :name (n4 / name :op1 "GST"~e.19 :op2 "fusion"~e.20) :ARG1-of (i2 / immobilize-01~e.18) :ARG0-of (m3 / mean-01 :ARG1 (a2 / and~e.28 :op1 (p4 / protein~e.21 :name (n5 / name :op1 "GST-SH3-Grb2"~e.25,27,29,31)) :op2 (p5 / protein~e.21 :name (n6 / name :op1 "GST-SH3-E3b1"~e.25,29,31,33))))) :duration~e.35 (t / temporal-quantity :quant 2.5~e.36 :unit (m4 / minute~e.37)) :frequency (r / rate-entity-91~e.41 :ARG1 (v / volume-quantity :quant 50~e.43 :unit (m5 / microliter)) :ARG2 (t2 / temporal-quantity :quant 1~e.13 :unit (m6 / minute~e.37)))) # ::id pmid_1177_7939.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The kinetics of binding are shown in the graphs . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1 5-1 6-1.1.r 8-1.1 (s / show-01~e.5 :ARG0~e.6 (g / graph~e.8) :ARG1 (k / kinetics~e.1 :mod~e.2 (b / bind-01~e.3))) # ::id pmid_1177_7939.226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Coupling of equal amounts of the GST fusion proteins was performed with a goat anti @-@ GST antibody covalently linked to CM5 sensor chip according to the manufacturer 's instructions . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 3-1.1.1 4-1.1.1.1.r 6-1.1.1.1.1.1 7-1.1.1.1.1.2 8-1.1.1.1 10-1 11-1.1.2.r 13-1.1.2.1 14-1.1.2.2 16-1.1.2.2.1.1.1 17-1.1.2 19-1.1.2.3 20-1.1.2.3.1.r 21-1.1.2.3.1.1.1 22-1.1.2.3.1.2 23-1.1.2.3.1 24-1.2 25-1.2 27-1.2.1.1 27-1.2.1.1.1 27-1.2.1.1.1.r 28-1.2.1.1.r 29-1.2.1 (p / perform-02~e.10 :ARG1 (c / couple-01~e.0 :ARG1~e.1 (a / amount~e.3 :quant-of~e.4 (p2 / protein~e.8 :name (n / name :op1 "GST"~e.6 :op2 "fusion"~e.7)) :ARG1-of (e / equal-01~e.2)) :ARG2~e.11 (a2 / antibody~e.17 :mod (g / goat~e.13) :ARG0-of (c5 / counter-01~e.14 :ARG1 (e2 / enzyme :name (n2 / name :op1 "GST"~e.16))) :ARG1-of (l / link-01~e.19 :ARG2~e.20 (c3 / chip~e.23 :name (n3 / name :op1 "CM5"~e.21) :mod (s / sensor~e.22)) :manner (c2 / covalent)))) :ARG1-of (s2 / say-01~e.24,25 :ARG0 (i / instruct-01~e.29 :ARG0~e.28 (c4 / company~e.27 :ARG0-of~e.27 (m / manufacture-01~e.27))))) # ::id pmid_1177_7939.227 ::amr-annotator SDL-AMR-09 ::preferred # ::tok k @_on and k @_off kinetic rates were obtained by simple Langmuir fitting model ( biaevaluation software v2.1 ) . # ::alignments 2-1.1.1.1.1 4-1.1 7-1.1.2.1.1 10-1.1.1 10-1.1.2 12-1 13-1.2.r 14-1.2.3 15-1.2.1.1 16-1.2.2 17-1.2 19-1.3.1 20-1.3 (o / obtain-01~e.12 :ARG1 (a / and~e.4 :op1 (r / rate~e.10 :mod (k / kinetics :ARG1-of (o2 / on-01~e.2))) :op2 (r2 / rate~e.10 :mod (k2 / kinetics :mod (o3 / off~e.7)))) :manner~e.13 (m / model~e.17 :name (n / name :op1 "Langmuir"~e.15) :ARG0-of (f / fit-01~e.16) :ARG1-of (s / simple-02~e.14)) :instrument (s2 / software~e.20 :mod (b / biaevaluation~e.19) :mod (v / version :mod 2.1))) # ::id pmid_1177_7939.228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 3 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 3~e.1) # ::id pmid_1177_7939.229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vivo competition between E3b1 and Grb2 for binding to Sos @-@ 1 . # ::alignments 1-1.4 2-1.4 3-1 5-1.1.1.1 7-1.2.1.1 8-1.3.r 9-1.3 10-1.3.1.r 11-1.3.1.1.1 13-1.3.1.1.1 (c / compete-01~e.3 :ARG0 (p / protein :name (n / name :op1 "E3b1"~e.5)) :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2"~e.7)) :ARG2~e.8 (b / bind-01~e.9 :ARG2~e.10 (p3 / protein :name (n3 / name :op1 "Sos-1"~e.11,13))) :manner (i / in-vivo~e.1,2)) # ::id pmid_1177_7939.230 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A , Top ) GST @-@ E3b1 @-@ 331 @–@ 480 , or control GST , was bound to Sos @-@ 1 present in Cos @-@ 7 cells transfected ( Tfx ) with either Sos @-@ 1 or S/G . # ::alignments 1-1.3.1.1 3-1.3.1.2 5-1.1.1.2.1.1 5-1.1.2.1.1 7-1.1.1.3.1.1 9-1.1.1.1.1.1 11-1.1.1.1.1.2 13-1.1 14-1.1.2 14-1.1.2.2 14-1.1.2.2.r 15-1.1.1.2.1.1 15-1.1.2.1.1 18-1 19-1.2.r 20-1.2.1.1 22-1.2.1.1 23-1.2 23-1.2.2 23-1.2.2.r 24-1.2.2.1.r 25-1.2.2.1.1.1 27-1.2.2.1.1.1 28-1.2.2.1 29-1.2.2.1.2 35-1.2.2.1.2.1.1.1.1 37-1.2.2.1.2.1.1.1.1 38-1.2.2.1.2.1 (b / bind-01~e.18 :ARG1 (o / or~e.13 :op1 (m / macro-molecular-complex :consist-of (a / amino-acid :mod (v / value-interval :op1 331~e.9 :op2 480~e.11)) :part (e2 / enzyme :name (n / name :op1 "GST"~e.5,15)) :part (p4 / protein :name (n8 / name :op1 "E3b1"~e.7))) :op2 (e / enzyme~e.14 :name (n2 / name :op1 "GST"~e.5,15) :ARG0-of~e.14 (c / control-01~e.14))) :ARG2~e.19 (p2 / protein~e.23 :name (n3 / name :op1 "Sos-1"~e.20,22) :ARG1-of~e.23 (p5 / present-02~e.23 :ARG2~e.24 (c2 / cell-line~e.28 :name (n4 / name :op1 "Cos-7"~e.25,27) :ARG1-of (t / transfect-01~e.29 :ARG2 (o2 / or~e.38 :op1 (p3 / protein :name (n5 / name :op1 "Sos-1"~e.35,37)) :op2 (m2 / macro-molecular-complex :part p3 :part (p / protein :name (n7 / name :op1 "Grb2")))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "A"~e.1 :location (t2 / top~e.3)))) # ::id pmid_1177_7939.231 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detection was with anti @–@ Sos @-@ 1 . # ::alignments 0-1 3-1.1.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 (d / detect-01~e.0 :ARG2 (a / antibody :ARG0-of (c / counter-01~e.3 :ARG1 (p / protein :name (n / name :op1 "Sos-1"~e.5,7))))) # ::id pmid_1177_7939.232 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Bottom ) The same cellular lysates ( 50 μg ) were detected with anti @-@ Grb2 . # ::alignments 1-1.3 4-1.1.2 5-1.1.1 6-1.1 8-1.1.3.1 9-1.1.3.2 12-1 14-1.2.1 16-1.2.1.1.1.1 (d / detect-01~e.12 :ARG1 (l / lysate~e.6 :mod (c / cell~e.5) :ARG1-of (s / same-01~e.4) :quant (m / mass-quantity :quant 50~e.8 :unit (m2 / microgram~e.9))) :ARG2 (a / antibody :ARG0-of (c2 / counter-01~e.14 :ARG1 (p / protein :name (n / name :op1 "Grb2"~e.16)))) :location (b / bottom~e.1)) # ::id pmid_1177_7939.233 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Lysates , from 293T cells transfected ( Tfx ) with E3b1 or a control vector ( ctr ) , were immunoprecipitated ( IP ) with anti @-@ Grb2 or an irrelevant antibody ( ctr ) , followed by detection ( WB ) with anti @–@ Sos @-@ 1 ( top ) or anti @-@ Grb2 ( middle ) . # ::alignments 1-1.5.1.1 3-1.1 6-1.2.1.1 7-1.2 8-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1.1 14-1.2.2.1 16-1.2.2.1.2.1 17-1.2.2.1.2 23-1 27-1.4.r 28-1.4.1.2.1.1 28-1.4.1.2.2.1 30-1.4.1.2.2.1.1.1.1 31-1.3 31-1.4.1.2 33-1.3.2.1 33-1.3.2.1.1 33-1.3.2.1.1.r 34-1.3.1 34-1.3.2 34-1.4.1.2.1 34-1.4.1.2.2 39-1.4 41-1.4.1 45-1.3.1.1.r 46-1.3.1.1 48-1.4.1.2.1.1.1.1.1 50-1.4.1.2.1.1.1.1.1 52-1.4.1.2.1.2.1 54-1.4.1.2 55-1.3.1.1 57-1.3.1.1.1 59-1.4.1.2.2.2.1 (i / immunoprecipitate-01~e.23 :ARG1 (l / lysate~e.3) :ARG2 (c / cell-line~e.7 :name (n / name :op1 "293T"~e.6) :ARG1-of (t / transfect-01~e.8 :ARG2~e.12 (o / or~e.14 :op1 (p / protein :name (n2 / name :op1 "E3b1"~e.13)) :op2 (v / vector~e.17 :ARG0-of (c2 / control-01~e.16))))) :ARG3 (o2 / or~e.31 :op1 (a / antibody~e.34 :ARG0-of~e.45 (c3 / counter-01~e.46,55 :ARG1 p3~e.57)) :op2 (a2 / antibody~e.34 :ARG1-of (r / relevant-01~e.33 :polarity~e.33 -~e.33))) :ARG2-of~e.27 (f / follow-01~e.39 :ARG1 (d / detect-01~e.41 :ARG1 l :ARG2 (o3 / or~e.31,54 :op1 (a3 / antibody~e.34 :ARG0-of (c4 / counter-01~e.28 :ARG1 (p2 / protein :name (n4 / name :op1 "Sos-1"~e.48,50))) :ARG1-of (d7 / describe-01 :location (t2 / top~e.52))) :op2 (a4 / antibody~e.34 :ARG0-of (c5 / counter-01~e.28 :ARG1 (p3 / protein :name (n10 / name :op1 "Grb2"~e.30))) :ARG1-of (d6 / describe-01 :location (m / middle~e.59)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "B"~e.1))) # ::id pmid_1177_7939.234 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression of E3b1 ( bottom ) was detected with an anti @-@ E3b1 antibody . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.2.1 8-1 9-1.2.r 11-1.2.1 13-1.2.1.1 14-1.2 (d / detect-01~e.8 :ARG1 (e / express-03~e.1 :ARG2~e.2 (p / protein :name (n / name :op1 "E3b1"~e.3)) :ARG1-of (d2 / describe-01 :location (b / bottom~e.5))) :ARG2~e.9 (a / antibody~e.14 :ARG0-of (c / counter-01~e.11 :ARG1 p~e.13))) # ::id pmid_1177_7939.235 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 4 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 4~e.1) # ::id pmid_1177_7939.236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The S/G and the S/E complexes are functionally distinct . # ::alignments 3-1.1 6-1.1.1 6-1.1.2 8-1 9-1.2 (f / function-01~e.8 :ARG0 (a / and~e.3 :op1 (m / macro-molecular-complex~e.6 :part (p / protein :name (n / name :op1 "Sos-1")) :part (p3 / protein :name (n3 / name :op1 "Grb2"))) :op2 (m2 / macro-molecular-complex~e.6 :part p :part (p2 / protein :name (n2 / name :op1 "E3b1")))) :mod (d / distinct~e.9)) # ::id pmid_1177_7939.237 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Cos @-@ 7 cells were transfected with the indicated cDNAs ( Tfx ) , and treated with EGF ( 3 min , +) or mock treated (−) . # ::alignments 1-1.1 3-1.2.1.1.1 5-1.2.1.1.1 6-1.2.1 8-1.2 9-1.2.2.r 11-1.2.2.4 17-1 18-1.3.2 20-1.3.1.2.1.1 22-1.3.1.3.1 23-1.3.1.3.2 26-1.3 27-1.3.2.2 28-1.3.1 28-1.3.2 (a / and~e.17 :li "A"~e.1 :op1 (t / transfect-01~e.8 :ARG1 (c / cell-line~e.6 :name (n / name :op1 "Cos-7"~e.3,5)) :ARG2~e.9 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA") :ARG1-of (c2 / complement-01) :ARG1-of (i / indicate-01~e.11))) :op2 (o / or~e.26 :op1 (t2 / treat-04~e.28 :ARG1 c :ARG2 (p / protein :name (n2 / name :op1 "EGF"~e.20)) :duration (t3 / temporal-quantity :quant 3~e.22 :unit (m / minute~e.23)) :ARG1-of (d2 / describe-01 :ARG2 (s3 / string-entity :value +))) :op2 (t4 / treat-04~e.18,28 :ARG1 c :mod (m2 / mock~e.27) :ARG1-of (d3 / describe-01 :ARG2 (s2 / string-entity :value "−"))))) # ::id pmid_1177_7939.238 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoprecipitates ( IP ) with anti @-@ EGFR or preimmune sera ( ctr ) were analyzed by immunoblotting ( WB ) with anti @–@ EGFR or HA ( for Sos @-@ 1 detection ) . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1.1.1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2.1 15-1 17-1.2.1 17-1.2.2 22-1.1.1.1.1.1 22-1.2.2.1.1 24-1.1.1.1.1.1.1.1.1 25-1.2 26-1.2.2.1.1.1.1.1 28-1.2.r 29-1.2.3.1.1.1 31-1.2.3.1.1.1 32-1.2.3 (a / analyze-01~e.15 :ARG1 (p / protein~e.0 :ARG1-of~e.0 (i / immunoprecipitate-01~e.0 :ARG3~e.4 (o / or~e.8 :op1 (a2 / antibody :ARG0-of (c2 / counter-01~e.5,22 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.7,24)))) :op2 (s2 / serum :mod (p2 / preimmune~e.9))))) :manner~e.28 (o4 / or~e.25 :op1 (i2 / immunoblot-01~e.17 :ARG3 a2) :op2 (i3 / immunoblot-01~e.17 :ARG3 (a3 / antibody :ARG0-of (c / counter-01~e.22 :ARG1 (p4 / protein :name (n2 / name :op1 "HA"~e.26))))) :purpose (d / detect-01~e.32 :ARG1 (p3 / protein :name (n3 / name :op1 "Sos-1"~e.29,31))))) # ::id pmid_1177_7939.239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lysates ( 50 μg ) were analyzed by immunoblotting with anti @-@ EGFR , anti @-@ HA ( for Sos @-@ 1 detection ) , or anti @-@ E3b1 antibody . # ::alignments 0-1.1 2-1.1.1.1 3-1.1.1.2 6-1 7-1.2.r 8-1.2.1 8-1.2.2 8-1.2.3 10-1.2.1.2.1 12-1.2.1.2.1.1.1.1 14-1.2.1.2.1 16-1.2.2.2.1.1.1.1 18-1.2.2.3.r 19-1.2.2.3.1.1.1 21-1.2.2.3.1.1.1 22-1.2.2.3 25-1.2 26-1.2.1.2.1 26-1.2.2.2.1 26-1.2.3.2.1 28-1.2.3.2.1.1.1.1 29-1.2.1.2 29-1.2.2.2 29-1.2.3.2 (a / analyze-01~e.6 :ARG1 (l / lysate~e.0 :quant (m / mass-quantity :quant 50~e.2 :unit (m2 / microgram~e.3))) :manner~e.7 (o5 / or~e.25 :op1 (i / immunoblot-01~e.8 :ARG2 l :ARG3 (a2 / antibody~e.29 :ARG0-of (c / counter-01~e.10,14,26 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.12))))) :op2 (i2 / immunoblot-01~e.8 :ARG2 l :ARG3 (a3 / antibody~e.29 :ARG0-of (c2 / counter-01~e.26 :ARG1 (p / protein :name (n2 / name :op1 "HA"~e.16)))) :purpose~e.18 (d / detect-01~e.22 :ARG1 (p2 / protein :name (n3 / name :op1 "Sos-1"~e.19,21)))) :op3 (i3 / immunoblot-01~e.8 :ARG2 l :ARG3 (a4 / antibody~e.29 :ARG0-of (c3 / counter-01~e.26 :ARG1 (p3 / protein :name (n4 / name :op1 "E3b1"~e.28))))))) # ::id pmid_1177_7939.240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HA @-@ Sos , HA @-@ epitope tagged Sos @-@ 1 # ::alignments 0-1.2.2.1.1.1.1 2-1.1.1.1 4-1.2.2.1.1.1.1 6-1.2.2.1 7-1.2.2 8-1.2.1.1 10-1.2.1.1 (m / mean-01 :ARG1 (p / protein :name (n / name :op1 "HA-Sos"~e.2)) :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.8,10) :ARG1-of (t / tag-01~e.7 :ARG2 (e / epitope~e.6 :mod (p3 / protein :name (n3 / name :op1 "HA"~e.0,4)))))) # ::id pmid_1177_7939.241 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Cos @-@ 7 cells were cotransfected ( Tfx ) with E3b1 ( or a control empty vector , ctr ) and either a myc @-@ tagged Ras ( left ) or HA @-@ tagged MAPK ( right ) , followed by treatment with EGF ( 5 min , +) or mock @-@ treatment (−) . # ::alignments 1-1.4.1.1 3-1.1.1.1 5-1.1.1.1 6-1.1 8-1 12-1.2.r 13-1.2.1.1.1.1 15-1.2.1 15-1.2.2 17-1.2.1.2.2 18-1.2.1.2.1 19-1.2.1.2 23-1.2 26-1.2.2.1.2.1.1.1 28-1.2.2.1.2 29-1.2.2.1.1.1 31-1.2.2.1.3.1 33-1.3.1 34-1.2.2.2.2.1.1.1 36-1.2.2.2.2 37-1.2.2.2.1.1 39-1.2.2.2.3.1 42-1.3 44-1.3.1.2 46-1.3.1.1.1.1.1 48-1.3.1.1.2.1 49-1.3.1.1.2.2 52-1.3.1 53-1.3.1.2.1 55-1.3.1.1 55-1.3.1.2 (c / cotransfect-01~e.8 :ARG1 (c2 / cell-line~e.6 :name (n3 / name :op1 "Cos-7"~e.3,5)) :ARG2~e.12 (a / and~e.23 :op1 (o / or~e.15 :op1 (p2 / protein :name (n4 / name :op1 "E3b1"~e.13)) :op2 (v / vector~e.19 :ARG1-of (e2 / empty-02~e.18) :ARG2-of (c3 / control-01~e.17))) :op2 (o2 / or~e.15 :op1 (e / enzyme :name (n / name :op1 "Ras"~e.29) :ARG1-of (t / tag-01~e.28 :ARG2 (p / protein :name (n2 / name :op1 "myc"~e.26))) :ARG1-of (d / describe-01 :ARG1-of (l / left-20~e.31))) :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK"~e.37) :ARG1-of (t2 / tag-01~e.36 :ARG2 (p4 / protein :name (n6 / name :op1 "HA"~e.34))) :ARG1-of (d2 / describe-01 :ARG1-of (r / right-04~e.39))))) :ARG2-of (f3 / follow-01~e.42 :ARG1 (o3 / or~e.33,52 :op1 (t3 / treat-04~e.55 :ARG2 (p3 / protein :name (n7 / name :op1 "EGF"~e.46)) :duration (t4 / temporal-quantity :quant 5~e.48 :unit (m / minute~e.49)) :ARG1-of (d3 / describe-01 :ARG2 (s3 / string-entity :value +))) :op2 (t5 / treat-04~e.44,55 :mod (m2 / mock~e.53) :ARG1-of (d4 / describe-01 :ARG2 (s2 / string-entity :value "−"))))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure :mod "B"~e.1))) # ::id pmid_1177_7939.242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Top , left ) Ras @-@ GTP was recovered with the GST @-@ RBD of Raf @-@ 1 followed by immunodetection with anti @-@ myc antibodies . # ::alignments 1-1.2.1.1 3-1.2.1.2 5-1.1.1.1.1 7-1.1.2.1.1 9-1 10-1.3.r 12-1.3.1.1 14-1.3.1.1 16-1.3.2.1.1 18-1.3.2.1.1 19-1.3.3 23-1.3.3.1.2.1 25-1.3.3.1.2.1.1.1.1 26-1.3.3.1.2 (r / recover-02~e.9 :ARG1 (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "Ras"~e.5)) :part (s / small-molecule :name (n2 / name :op1 "GTP"~e.7))) :ARG1-of (d / describe-01 :location (a / and :op1 (t / top~e.1) :op2 (l / left-20~e.3))) :manner~e.10 (p / protein-segment :name (n3 / name :op1 "GST-RBD"~e.12,14) :part-of (e2 / enzyme :name (n4 / name :op1 "Raf-1"~e.16,18)) :ARG2-of (f2 / follow-01~e.19 :ARG1 (i2 / immunodetect-01 :ARG1 m :ARG3 (a2 / antibody~e.26 :ARG0-of (c / counter-01~e.23 :ARG1 (p2 / protein :name (n5 / name :op1 "myc"~e.25)))))))) # ::id pmid_1177_7939.243 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Top , right ) Anti @-@ HA immunoprecipitation , followed by immunodetection with an anti @–@ phosphorylated MAPK antibody . # ::alignments 1-1.3.1 3-1.3.2 5-1.1.1 7-1.1.1.1.1.1 8-1 10-1.2 15-1.2.1.1.1 18-1.2.1.1.1.1.1.1 19-1.1 19-1.2.1.1 (i / immunoprecipitate-01~e.8 :ARG3 (a / antibody~e.19 :ARG0-of (c / counter-01~e.5 :ARG1 (p / protein :name (n / name :op1 "HA"~e.7)))) :ARG2-of (f / follow-01~e.10 :ARG1 (i3 / immunodetect-01 :ARG3 (a2 / antibody~e.19 :ARG0-of (c2 / counter-01~e.15 :ARG1 (e / enzyme :name (n2 / name :op1 "MAPK"~e.18) :ARG3-of (p3 / phosphorylate-01)))))) :ARG1-of (d2 / describe-01 :location (t / top~e.1) :ARG1-of (r / right-04~e.3))) # ::id pmid_1177_7939.244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of expression of myc @-@ Ras and HA @-@ MAPK ( middle ) and E3b1 ( bottom ) are also shown . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1.1.1 7-1.1.1.1.1.1.2.1.1 8-1.1.1.1.1 9-1.1.1.1.1.2.1.1.1 11-1.1.1.1.1.2.2.1.1 13-1.1.1.1.1.3.1 15-1.1.1.1 15-1.1.1.1.1 15-1.1.1.1.1.r 16-1.1.1.1.2.1.1 18-1.1.1.1.2.2.1 21-1.2 22-1 (s / show-01~e.22 :ARG1 (l / level~e.1 :mod~e.2 (e / express-03~e.3 :ARG2~e.4 (a / and~e.15 :op1~e.15 (a3 / and~e.8,15 :op1 (m / macro-molecular-complex :part (p / protein :name (n / name :op1 "myc"~e.5)) :part (e2 / enzyme :name (n2 / name :op1 "Ras"~e.7))) :op2 (m2 / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "HA"~e.9)) :part (e3 / enzyme :name (n4 / name :op1 "MAPK"~e.11))) :ARG1-of (d / describe-01 :location (m3 / middle~e.13))) :op2 (p4 / protein :name (n5 / name :op1 "E3b1"~e.16) :ARG1-of (d2 / describe-01 :location (b / bottom~e.18)))))) :mod (a2 / also~e.21)) # ::id pmid_1177_7939.245 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) Quiescent NIH @-@ 3T3 fibroblasts were microinjected with an empty vector together with rabbit IgG ( left ) or with an HA @-@ tagged E3b1 expression vector ( right ) followed by treatment with 10 % serum . # ::alignments 1-1.1 3-1.3.2 4-1.3.1.1.1 6-1.3.1.1.1 7-1.3 9-1 10-1.2.1.2.r 12-1.2.1.1 13-1.2.1 15-1.2.1.2.r 16-1.2.1.2.2 17-1.2.1.2.1.1 19-1.2.1.3.1 21-1.2 22-1.2.1.2.r 22-1.2.r 24-1.2.2.1.1.2.1.1.1 26-1.2.2.1.1.2 27-1.2.2.1.1.1.1 28-1.2.2.1 29-1.2.2 31-1.2.2.2.1 33-1.2.2.3 34-1.2.2.3.1.r 35-1.2.2.3.1 36-1.2.1.2.r 36-1.2.2.3.1.1.r 37-1.2.2.3.1.1.1.1 38-1.2.2.3.1.1.1 39-1.2.2.3.1.1 (m / microinject-01~e.9 :li "C"~e.1 :ARG1~e.22 (o / or~e.21 :op1 (v / vector~e.13 :ARG1-of (e / empty-02~e.12) :accompanier~e.10,15,22,36 (p2 / protein :name (n2 / name :op1 "IgG"~e.17) :mod (r / rabbit~e.16)) :ARG1-of (d / describe-01 :location (l / left-20~e.19))) :op2 (v2 / vector~e.29 :ARG1-of (e2 / express-03~e.28 :ARG2 (p3 / protein :name (n3 / name :op1 "E3b1"~e.27) :ARG1-of (t / tag-01~e.26 :ARG2 (p4 / protein :name (n4 / name :op1 "HA"~e.24))))) :ARG1-of (d2 / describe-01 :ARG1-of (r2 / right-04~e.31)) :ARG2-of (f2 / follow-01~e.33 :ARG1~e.34 (t2 / treat-04~e.35 :ARG2~e.36 (s / serum~e.39 :mod (p / percentage-entity~e.38 :value 10~e.37)))))) :ARG2 (f / fibroblast~e.7 :mod (c / cell-line :name (n / name :op1 "NIH-3T3"~e.4,6)) :mod (q / quiescent~e.3))) # ::id pmid_1177_7939.246 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 15 h , BrdU was added and 3 h later the cells were fixed and stained to detect BrdU incorporation ( top ) , E3b1 ( anti @-@ HA ) , or control ( anti @-@ IgG ) . # ::alignments 0-1.1.2 1-1.1.2.1.1 2-1.1.2.1.2 4-1.1.1.1.1 6-1.1 7-1 8-1.2.4.1.1 9-1.2.4.1.2 10-1.2.4 10-1.2.4.2 10-1.2.4.2.r 12-1.2.1.1 14-1.2.1 15-1.2 16-1.2.2 18-1.2.3 19-1.2.3.1.1.1 20-1.2.3.1.1 22-1.2.3.1.1.2.1 25-1.2.3.1.2.1.1 27-1.2.3.1.2 27-1.2.3.1.2.2 27-1.2.3.1.2.2.r 29-1.2.3.1.2.2.1.1.1 32-1.2.3.1 33-1.2.3.1.3 35-1.2.3.1.3.1 37-1.2.3.1.3.1.1.1.1 (a / and~e.7 :op1 (a2 / add-02~e.6 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"~e.4)) :time (a4 / after~e.0 :op1 (t / temporal-quantity :quant 15~e.1 :unit (h / hour~e.2)))) :op2 (a3 / and~e.15 :op1 (f / fix-02~e.14 :ARG1 (c / cell~e.12)) :op2 (s / stain-01~e.16 :ARG1 c) :purpose (d / detect-01~e.18 :ARG1 (o / or~e.32 :op1 (i / incorporate-02~e.20 :ARG1 s2~e.19 :ARG1-of (d2 / describe-01 :location (t2 / top~e.22))) :op2 (p2 / protein~e.27 :name (n2 / name :op1 "E3b1"~e.25) :ARG0-of~e.27 (c3 / counter-01~e.27 :ARG1 (p3 / protein :name (n3 / name :op1 "HA"~e.29)))) :op3 (c2 / control-01~e.33 :ARG0-of (c4 / counter-01~e.35 :ARG1 (p4 / protein :name (n4 / name :op1 "IgG"~e.37)))))) :time (l2 / late~e.10 :op1 (t3 / temporal-quantity :quant 3~e.8 :unit (h2 / hour~e.9)) :degree~e.10 (m2 / more~e.10)))) # ::id pmid_1177_7939.247 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nuclei were counterstained with Dapi ( bottom ) . # ::alignments 0-1.1 4-1.2.1.1 6-1.4.1 (s / stain-01 :ARG1 (n / nucleus~e.0) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Dapi"~e.4)) :ARG1-of (c / counter-01) :ARG1-of (d / describe-01 :location (b / bottom~e.6))) # ::id pmid_1177_7939.248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A quantitative analysis of BrdU incorporation into control ( empty bar ) and E3b1 ( closed bar ) injected cells is shown on the right . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.r 7-1.1.1.2.1.1 9-1.1.1.2.1.2.1.1 10-1.1.1.2.1.2.1 12-1.1.1.2 13-1.1.1.2.2.2.1.1.1 15-1.1.1.2.2.1.1.1 16-1.1.1.2.2.1.1 18-1.1.1.2.2.2 19-1.1.1.2.1 19-1.1.1.2.2 21-1 22-1.2.r 24-1.2 (s / show-01~e.21 :ARG1 (a / analyze-01~e.2 :ARG1~e.3 (i / incorporate-02~e.5 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"~e.4)) :ARG2~e.6 (a2 / and~e.12 :op1 (c / cell~e.19 :mod (c3 / control-01~e.7) :ARG1-of (m / mean-01 :ARG2 (b / bar~e.10 :ARG1-of (e / empty-02~e.9)))) :op2 (c2 / cell~e.19 :ARG1-of (m2 / mean-01 :ARG2 (b2 / bar~e.16 :ARG1-of (c4 / close-01~e.15))) :ARG2-of (i2 / inject-01~e.18 :ARG1 (p2 / protein :name (n2 / name :op1 "E3b1"~e.13)))))) :mod (q / quantity~e.1)) :ARG1-of~e.22 (r / right-04~e.24)) # ::id pmid_1177_7939.249 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The data are the mean ± SEM of three independent experiments . # ::alignments 1-1.1 4-1.2.1.1.1.1 7-1.2.1.1.1.1.1.r 8-1.2.1.1.1.1.1.1 9-1.2.1.1.1.1.1.2 9-1.2.1.1.1.1.1.2.1 9-1.2.1.1.1.1.1.2.1.r 10-1.2.1.1.1.1.1 (e4 / equal-01 :ARG1 (d / data~e.1) :ARG2 (v / value-interval :op1 (e / error :ARG1-of (s2 / standard-02 :ARG1-of (a / add-02 :ARG2 (m / mean~e.4 :poss~e.7 (e3 / experiment-01~e.10 :quant 3~e.8 :ARG0-of (d2 / depend-01~e.9 :polarity~e.9 -~e.9)))))) :op2 (e2 / error :ARG1-of (s / standard-02) :ARG1-of (s3 / subtract-01 :ARG2 m)))) # ::id pmid_1177_7939.250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results are expressed as a percentage of injected cells incorporating BrdU respect to uninjected ones . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 2-1 3-1.2.r 5-1.2 7-1.2.1.1 7-1.2.2.1 8-1.2.1 8-1.2.2 9-1.2.1.2 9-1.2.2.1.1 10-1.2.1.2.1.1.1 (e / express-01~e.2 :ARG1 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) :manner~e.3 (p / percentage~e.5 :quant-of (c / cell~e.8 :ARG2-of (i / inject-01~e.7) :ARG2-of (i2 / incorporate-02~e.9 :ARG1 (s / small-molecule :name (n / name :op1 "BrdU"~e.10)))) :compared-to (c2 / cell~e.8 :ARG2-of (i3 / inject-01~e.7 :polarity -~e.9)))) # ::id pmid_1177_7939.251 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Serum treatment induces BrdU incorporation in > 95 % of not injected cells . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1.1.1 4-1.2 5-1.2.2.r 6-1.2.2.2 7-1.2.2.2.1.1 8-1.2.2.2.1 9-1.2.2.2.r 10-1.2.2.1.1 10-1.2.2.1.1.r 11-1.2.2.1 12-1.2.2 (i / induce-01~e.2 :ARG0 (t / treat-04~e.1 :ARG2 (s / serum~e.0)) :ARG2 (i2 / incorporate-02~e.4 :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"~e.3)) :ARG2~e.5 (c / cell~e.12 :ARG2-of (i3 / inject-01~e.11 :polarity~e.10 -~e.10) :quant~e.9 (m / more-than~e.6 :op1 (p2 / percentage-entity~e.8 :value 95~e.7))))) # ::id pmid_1177_7939.252 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 5 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 5~e.1) # ::id pmid_1177_7939.253 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E3b1 is a limiting factor in Rac activation . # ::alignments 1-1.2.1.1 2-1.2.r 4-1.1 5-1 6-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1 (f / factor~e.5 :ARG0-of (l / limit-01~e.4 :ARG1~e.6 (a / activate-01~e.8 :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"~e.7)))) :domain~e.2 (p / protein :name (n / name :op1 "E3b1"~e.1))) # ::id pmid_1177_7939.254 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Top , left ) Lysates of Cos @-@ 7 cells were immunoprecipitated ( IP ) with the antibody indicated on the top and immunoblotted with the antibody indicated on the right . # ::alignments 1-1.3.1.1 3-1.3.1.2 5-1.1.1 7-1.1.2.2.1 9-1.1.2.2.1 10-1.1.2 12-1.1 16-1.1.3.r 18-1.1.3 19-1.1.3.1 20-1.1.3.1.1.r 22-1.1.3.1.1 23-1 23-1.3.1 27-1.2.2 28-1.2.2.1 29-1.2.2.1.1.r 31-1.2.2.1.1 (a / and~e.23 :op1 (i / immunoprecipitate-01~e.12 :ARG1 (l / lysate~e.5) :ARG2 (c / cell-line~e.10 :wiki "COS_cells" :name (n / name :op1 "Cos-7"~e.7,9)) :ARG3~e.16 (a2 / antibody~e.18 :ARG1-of (i2 / indicate-01~e.19 :location~e.20 (t / top~e.22)))) :op2 (i3 / immunoblot-01 :ARG1 l :ARG3 (a3 / antibody~e.27 :ARG1-of (i4 / indicate-01~e.28 :ARG1-of~e.29 (r / right-04~e.31)))) :ARG1-of (d / describe-01 :location (a4 / and~e.23 :op1 t~e.1 :op2 (l2 / left-20~e.3)))) # ::id pmid_1177_7939.255 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lysate , 50 μg of total cellular lysate . # ::alignments 0-1 0-1.2.1 2-1.1.1 3-1.1.2 5-1.2.1.2 6-1.2.1.1 7-1 7-1.2.1 (l / lysate~e.0,7 :quant (m / mass-quantity :quant 50~e.2 :unit (m2 / microgram~e.3)) :ARG1-of (i / include-91 :ARG2 (l2 / lysate~e.0,7 :mod (c / cell~e.6) :ARG2-of (t / total-01~e.5)))) # ::id pmid_1177_7939.256 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Top , right ) The efficiency of Grb2 and E3b1 immunoprecipitations was > 95 % , as determined by immunoblot analysis of the supernatants of the immunoprecipitations performed with either the specific antibody with ( Grb2 and E3b1 , respectively , as indicated ) or with an irrelevant ( ctr ) antibody . # ::alignments 1-1.4.1 3-1.4.2 6-1 8-1.1.1.1.1.1 9-1.1.1 10-1.1.1.2.1.1 13-1.2 14-1.2.1.1 15-1.2.1 17-1.3.r 18-1.3 19-1.3.1.r 20-1.3.1.2 21-1.3.1 22-1.3.1.1.r 24-1.3.1.1 28-1.3.1.1.1.1 29-1.3.1.1.1.1.1.r 32-1.3.1.1.1.1.1.1.1 33-1.3.1.1.1.1.1.1 34-1.3.1.1.1.1.1.r 36-1.1.1.1.1.1 37-1.1.1 38-1.1.1.2.1.1 40-1.3.1.1.1.1.1.1.2.2 43-1.3.1.1.1.1.1.1.2.3 45-1.3.1.1.1.1.1 46-1.3.1.1.1.1.1.r 48-1.3.1.1.1.1.1.2.1 48-1.3.1.1.1.1.1.2.1.1 48-1.3.1.1.1.1.1.2.1.1.r 52-1.3.1.1.1.1.1.2 (e / efficient-01~e.6 :ARG1 (i / immunoprecipitate-01 :ARG1 (a / and~e.9,37 :op1 (p2 / protein :name (n / name :op1 "Grb2"~e.8,36)) :op2 (p3 / protein :name (n2 / name :op1 "E3b1"~e.10,38)))) :degree (m / more-than~e.13 :op1 (p / percentage-entity~e.15 :value 95~e.14)) :ARG1-of~e.17 (d / determine-01~e.18 :ARG0~e.19 (a2 / analyze-01~e.21 :ARG1~e.22 (s / supernatant~e.24 :mod (i3 / immunoprecipitate-01 :ARG1-of (p4 / perform-02~e.28 :instrument~e.29,34,46 (o / or~e.45 :op1 (a3 / antibody~e.33 :ARG1-of (s2 / specific-02~e.32) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 p2 :op2 p3) :mod (r / respective~e.40) :ARG1-of (i4 / indicate-01~e.43))) :op2 (a5 / antibody~e.52 :ARG1-of (r2 / relevant-01~e.48 :polarity~e.48 -~e.48) :ARG1-of (m3 / mean-01 :ARG2 (c / control-01))))))) :manner (i2 / immunoblot-01~e.20))) :ARG1-of (d2 / describe-01 :location (t / top~e.1) :ARG1-of (r3 / right-04~e.3))) # ::id pmid_1177_7939.257 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Middle ) Cos @-@ 7 cells were transfected ( Tfx ) with HA @-@ tagged PAK65 ( all lanes ) together with the plasmids indicated on the top ( ctr , empty vector ) and serum starved for 24 h . # ::alignments 1-1.3.1 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.1 8-1.1 12-1.1.2.r 13-1.1.2.1.2.1.1.1 15-1.1.2.1.2 16-1.1.2.1.1.1 18-1.1.2.1.3.1.1 19-1.1.2.1.3.1 25-1.1.2.2.1 26-1.1.2.2.1.1.r 28-1.1.2.2.1.1 32-1.1.2.2.2.1.2 33-1.1.2.2.2.1 35-1 35-1.1.2 36-1.2.2 37-1.2 38-1.2.3.r 39-1.2.3.1 40-1.2.3.2 (a3 / and~e.35 :op1 (t / transfect-01~e.8 :ARG1 (c / cell-line~e.6 :name (n / name :op1 "Cos-7"~e.3,5)) :ARG2~e.12 (a2 / and~e.35 :op1 (e2 / enzyme :name (n2 / name :op1 "PAK65"~e.16) :ARG1-of (t2 / tag-01~e.15 :ARG2 (p2 / protein :name (n3 / name :op1 "HA"~e.13))) :ARG1-of (m / mean-01 :ARG2 (l / lane~e.19 :mod (a / all~e.18)))) :op2 (p3 / plasmid :ARG1-of (i / indicate-01~e.25 :location~e.26 (t3 / top~e.28)) :ARG1-of (m2 / mean-01 :ARG2 (v / vector~e.33 :ARG2-of (c2 / control-01) :ARG1-of (e / empty-02~e.32)))))) :op2 (s / starve-01~e.37 :ARG1 c :ARG2 (s2 / serum~e.36) :duration~e.38 (t4 / temporal-quantity :quant 24~e.39 :unit (h / hour~e.40))) :ARG1-of (d / describe-01 :location (m3 / middle~e.1))) # ::id pmid_1177_7939.258 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Equal amounts of anti @-@ HA immunoprecipitated PAK65 were subjected to an in vitro kinase assay using myelin basic protein ( MBP ) as a substrate . # ::alignments 0-1.1.2.1 1-1.1.2 2-1.1.2.r 3-1.1.3.1.1 5-1.1.3.1.1.1.1.1 6-1.1.3 7-1.1.1.1 9-1 12-1.2.2 13-1.2.2 14-1.2.1 15-1.2 16-1.2.3 17-1.2.3.1.1.1 18-1.2.3.1.1.2 19-1.2.3.1.1.3 23-1.2.3.2.r 25-1.2.3.2 (s / subject-01~e.9 :ARG1 (e2 / enzyme :name (n / name :op1 "PAK65"~e.7) :quant~e.2 (a / amount~e.1 :ARG1-of (e / equal-01~e.0)) :ARG1-of (i / immunoprecipitate-01~e.6 :ARG3 (a3 / antibody :ARG0-of (c / counter-01~e.3 :ARG1 (p2 / protein :name (n2 / name :op1 "HA"~e.5)))))) :ARG2 (a2 / assay-01~e.15 :ARG1 (k / kinase~e.14) :mod (i2 / in-vitro~e.12,13) :ARG0-of (u / use-01~e.16 :ARG1 (p3 / protein :name (n3 / name :op1 "myelin"~e.17 :op2 "basic"~e.18 :op3 "protein"~e.19)) :ARG2~e.23 (s2 / substrate~e.25)))) # ::id pmid_1177_7939.259 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of immunoprecipitated PAK65 and the expression of Sos @-@ 1 , E3b1 , and HARacN17 in the various transfectants are also shown . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2 4-1.1.1.1.1.1 5-1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.1.1 11-1.1.2.1.1.1.1 13-1.1.2.1.2.1.1 16-1.1.2.1.3.1.1 17-1.1.2.2.r 19-1.1.2.2.1 20-1.1.2.2 20-1.1.2.2.2 20-1.1.2.2.2.r 22-1.2 23-1 (s / show-01~e.23 :ARG1 (a / and~e.5 :op1 (l / level~e.1 :quant-of~e.2 (e2 / enzyme :name (n / name :op1 "PAK65"~e.4) :ARG1-of (i / immunoprecipitate-01~e.3))) :op2 (e / express-03~e.7 :ARG2~e.8 (a2 / and :op1 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.9,11)) :op2 (p3 / protein :name (n3 / name :op1 "E3b1"~e.13)) :op3 (p4 / protein :name (n4 / name :op1 "HARacN17"~e.16))) :ARG3~e.17 (c / cell~e.20 :mod (v / various~e.19) :ARG1-of~e.20 (t / transfect-01~e.20)))) :mod (a3 / also~e.22)) # ::id pmid_1177_7939.260 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar results were obtained using Cos @-@ 7 cells . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.2 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2.1 (o / obtain-01~e.3 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (r / result-01~e.1) :ARG1-of (r2 / resemble-01~e.0)) :manner (u / use-01~e.4 :ARG1 (c / cell-line~e.8 :name (n / name :op1 "Cos-7"~e.5,7)))) # ::id pmid_1177_7939.261 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Bottom ) Wild @-@ type (+/+) and eps8 @^−/− (−/−) mouse embryo fibroblasts were infected with retroviral vectors coding for E3b1 ( E3b1 ) or the mutant of E3b1 @-@ DY ( E3b1 @-@ DY ) , or with an empty vector as a control ( ctr ) . # ::alignments 1-1.3.1 3-1.1.1.1 5-1.1.1.1 7-1.1 8-1.1.2.3.1.1.1 10-1.1.2.1.1 10-1.1.2.3.1.2.1 13-1.1.1.2.1 14-1.1.1.2 15-1.1.1 15-1.1.2 17-1 20-1.2.1 21-1.2.1.2 22-1.2.1.2.1.r 23-1.2.1.2.1.1.1 25-1.2.1.2.1.1.1 27-1.2 29-1.1.2.1 29-1.1.2.3.1 29-1.1.2.3.1.2 29-1.1.2.3.1.2.r 29-1.2.2 29-1.2.2.2 29-1.2.2.2.r 31-1.2.1.2.1.1.1 33-1.2.2.1.1 35-1.2.2.1.1 37-1.2.2.1.1 40-1.2 41-1.2.r 43-1.2.3.1 44-1.2.3 45-1.2.3.2.r 47-1.2.3.2 (i / infect-01~e.17 :ARG1 (a / and~e.7 :op1 (f / fibroblast~e.15 :mod (w / wild-type~e.3,5) :source (e / embryo~e.14 :mod (m2 / mouse~e.13))) :op2 (f2 / fibroblast~e.15 :ARG2-of (m / mutate-01~e.29 :mod "−/−"~e.10) :source e :ARG0-of (c3 / contain-01 :ARG1 (e3 / enzyme~e.29 :name (n3 / name :op1 "eps8"~e.8) :ARG2-of~e.29 (m4 / mutate-01~e.29 :mod "−/−"~e.10))))) :ARG2~e.41 (o / or~e.27,40 :op1 (v / vector~e.20 :mod (r / retrovirus) :ARG0-of (c2 / code-01~e.21 :ARG1~e.22 (p / protein :name (n / name :op1 "E3b1"~e.23,25,31)))) :op2 (p2 / protein~e.29 :name (n2 / name :op1 "E3b1-DY"~e.33,35,37) :ARG2-of~e.29 (m3 / mutate-01~e.29)) :op3 (v2 / vector~e.44 :ARG1-of (e2 / empty-02~e.43) :ARG2-of~e.45 (c / control-01~e.47))) :ARG1-of (d / describe-01 :location (b / bottom~e.1))) # ::id pmid_1177_7939.262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok > 95 % of the cells expressed the infected cDNA , as determined by immunostaining with anti @-@ E3b1 ( not shown ) . # ::alignments 0-1.2.1 1-1.2.1.1.1 2-1.2.1.1 3-1.2.1.r 5-1.2 6-1 8-1.1.4 11-1.3.r 12-1.3 13-1.3.1.r 14-1.3.1 16-1.3.1.1.1 18-1.3.1.1.1.1.1.1 20-1.4.1 20-1.4.1.r 21-1.4 (e / express-03~e.6 :ARG2 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA") :ARG1-of (c2 / complement-01) :ARG1-of (i / infect-01~e.8)) :ARG3 (c / cell~e.5 :quant~e.3 (m / more-than~e.0 :op1 (p / percentage-entity~e.2 :value 95~e.1))) :ARG1-of~e.11 (d2 / determine-01~e.12 :ARG2~e.13 (i2 / immunostain-01~e.14 :ARG2 (a / antibody :ARG0-of (c3 / counter-01~e.16 :ARG1 (p2 / protein :name (n / name :op1 "E3b1"~e.18)))))) :ARG1-of (s / show-01~e.21 :polarity~e.20 -~e.20)) # ::id pmid_1177_7939.263 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Equal amounts of lysates were subjected to in vitro binding assays with the immobilized CRIB domain of PAK65 . # ::alignments 0-1.1.1.1.1 1-1.1.1.1 2-1.1.1.1.r 3-1.1.1 5-1 6-1.2.r 7-1.2.2 8-1.2.2 9-1.2.1 10-1.2 11-1.1.r 13-1.1.2.2 14-1.1.2.1.1 15-1.1.2.1.2 17-1.1.2.3.1.1 (s / subject-01~e.5 :ARG1~e.11 (a3 / and :op1 (l / lysate~e.3 :quant~e.2 (a / amount~e.1 :ARG1-of (e / equal-01~e.0))) :op2 (p3 / protein-segment :name (n3 / name :op1 "CRIB"~e.14 :op2 "domain"~e.15) :ARG1-of (i2 / immobilize-01~e.13) :part-of (e2 / enzyme :name (n2 / name :op1 "PAK65"~e.17)))) :ARG2~e.6 (a2 / assay-01~e.10 :ARG1 (b / bind-01~e.9) :manner (i / in-vitro~e.7,8))) # ::id pmid_1177_7939.264 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After washing , bound proteins were resolved by SDS @-@ PAGE and immunoblotted with anti @-@ Rac antibodies ( Rac @-@ GTP ) . # ::alignments 0-1.3 1-1.3.1 3-1.1.1.1 4-1.1.1 6-1.1 7-1.1.2.r 8-1.1.2.1.1 10-1.1.2.1.1 11-1 14-1.2.2.1 16-1.2.2.1.1.1.1 17-1.2.2 19-1.2.2.2.1.1 21-1.2.2.2.1.2.1.1 (a / and~e.11 :op1 (r / resolve-03~e.6 :ARG1 (p / protein~e.4 :ARG1-of (b / bind-01~e.3)) :ARG3~e.7 (t / thing :name (n / name :op1 "SDS-PAGE"~e.8,10))) :op2 (i / immunoblot-01 :ARG1 p :ARG3 (a2 / antibody~e.17 :ARG0-of (c / counter-01~e.14 :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"~e.16))) :ARG1-of (m2 / mean-01 :ARG2 (m3 / macro-molecular-complex :part e~e.19 :part (s / small-molecule :name (n3 / name :op1 "GTP"~e.21)))))) :time (a3 / after~e.0 :op1 (w / wash-01~e.1))) # ::id pmid_1177_7939.265 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of total Rac ( Rac ) and E3b1 proteins are also shown . # ::alignments 1-1.1.1 1-1.1.2 2-1.1.1.1.r 3-1.1.1.1.2 4-1.1.1.1.1.1 6-1.1.1.1.1.1 8-1.1 9-1.1.2.1.1.1 10-1.1.2.1 12-1.2 13-1 (s / show-01~e.13 :ARG1 (a2 / and~e.8 :op1 (l / level~e.1 :quant-of~e.2 (e / enzyme :name (n / name :op1 "Rac"~e.4,6) :mod (t / total~e.3))) :op2 (l2 / level~e.1 :quant-of (p2 / protein~e.10 :name (n2 / name :op1 "E3b1"~e.9)))) :mod (a / also~e.12)) # ::id pmid_1177_7939.266 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 6 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 6~e.1) # ::id pmid_1177_7939.267 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The E3b1DY mutant inhibits actin remodeling induced by activated Ras , but not by activated Rac . # ::alignments 2-1.1.1.1 3-1.1 3-1.1.2 3-1.1.2.r 4-1 5-1.2.1 6-1.2 7-1.2.2 7-1.2.2.2.1 8-1.2.2.1.r 9-1.2.2.1.2 10-1.2.2.1.1.1 12-1.2.2.2 13-1.2.2.2.1.1 13-1.2.2.2.1.1.r 14-1.2.2.2.1.2.r 15-1.2.2.2.1.2.2 16-1.2.2.2.1.2.1.1 (i / inhibit-01~e.4 :ARG0 (p / protein~e.3 :name (n / name :op1 "E3b1DY"~e.2) :ARG2-of~e.3 (m / mutate-01~e.3)) :ARG1 (r / remodel-01~e.6 :ARG1 (a / actin~e.5) :ARG2-of (i2 / induce-01~e.7 :ARG0~e.8 (e / enzyme :name (n2 / name :op1 "Ras"~e.10) :ARG1-of (a2 / activate-01~e.9)) :ARG1-of (c2 / contrast-01~e.12 :ARG2 (i3 / induce-01~e.7 :polarity~e.13 -~e.13 :ARG0~e.14 (e2 / enzyme :name (n3 / name :op1 "Rac"~e.16) :ARG1-of a2~e.15)))))) # ::id pmid_1177_7939.268 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mouse embryo fibroblasts were transfected , as indicated on the top , with expression vectors for either RasV12 or RacQL , together with ECFP @-@ tagged versions of either E3b1 or the E3b1DY mutant . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 4-1 6-1.3.r 7-1.3 8-1.3.1.r 10-1.3.1 12-1.2.2.r 13-1.2.1 14-1.2 17-1.2.1.1.1.1.1 18-1.2.1.1 19-1.2.1.1.2.1.1 22-1.2.2.r 23-1.2.2.3.1.1.1 25-1.2.2.3 29-1.2.2.1.1.1 30-1.2.2 32-1.2.2.2.1.1 33-1.2.2.2 33-1.2.2.2.2 33-1.2.2.2.2.r (t / transfect-01~e.4 :ARG1 (f / fibroblast~e.2 :source (e / embryo~e.1 :mod (m / mouse~e.0))) :ARG2 (v / vector~e.14 :ARG1-of (e2 / express-03~e.13 :ARG2 (o / or~e.18 :op1 (e3 / enzyme :name (n / name :op1 "RasV12"~e.17)) :op2 (e4 / enzyme :name (n2 / name :op1 "RacQL"~e.19)))) :accompanier~e.12,22 (o2 / or~e.30 :op1 (p2 / protein :name (n3 / name :op1 "E3b1"~e.29)) :op2 (p3 / protein~e.33 :name (n4 / name :op1 "E3b1DY"~e.32) :ARG2-of~e.33 (m2 / mutate-01~e.33)) :ARG1-of (t3 / tag-01~e.25 :ARG2 (p4 / protein :name (n5 / name :op1 "ECFP"~e.23))))) :ARG1-of~e.6 (i / indicate-01~e.7 :location~e.8 (t2 / top~e.10))) # ::id pmid_1177_7939.269 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After serum starvation , cells were fixed and stained with rhodamine @-@ conjugated phalloidine to detect F @-@ actin ( top , red ) . # ::alignments 0-1.4 1-1.4.1.2 2-1.4.1 4-1.1.1 6-1.1 7-1 8-1.2 9-1.2.2.r 10-1.2.2.2.1.1.1 12-1.2.2.2 13-1.2.2.1.1 15-1.3 16-1.3.1.1.1 18-1.3.1.1.1 20-1.5.1 22-1.5.2 (a / and~e.7 :op1 (f / fix-02~e.6 :ARG1 (c / cell~e.4)) :op2 (s / stain-01~e.8 :ARG1 c :ARG2~e.9 (s4 / small-molecule :name (n / name :op1 "phalloidine"~e.13) :ARG1-of (c2 / conjugate-02~e.12 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "rhodamine"~e.10))))) :purpose (d / detect-01~e.15 :ARG1 (p / protein :name (n2 / name :op1 "F-actin"~e.16,18))) :time (a2 / after~e.0 :op1 (s2 / starve-01~e.2 :ARG1 c :ARG2 (s3 / serum~e.1))) :ARG1-of (d2 / describe-01 :location (t / top~e.20) :mod (r / red~e.22))) # ::id pmid_1177_7939.270 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of the transfected proteins was detected ( bottom , green ) with either anti @-@ Ras or anti @-@ Rac antibodies or by epifluorescence ( ECFP ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1 4-1.1.1 6-1 8-1.3.1 10-1.4 14-1.2.1.1 16-1.2.1.1.1.1.1 17-1.2 18-1.2.1.1 18-1.2.2.1 20-1.2.2.1.1.1.1 21-1.2.1 21-1.2.2 22-1.2 23-1.2.r 24-1.2.3 (d / detect-01~e.6 :ARG1 (e / express-03~e.0 :ARG2~e.1 (p / protein~e.4 :ARG2-of (t / transfect-01~e.3))) :ARG2~e.23 (o / or~e.17,22 :op1 (a / antibody~e.21 :ARG0-of (c / counter-01~e.14,18 :ARG1 (e2 / enzyme :name (n / name :op1 "Ras"~e.16)))) :op2 (a2 / antibody~e.21 :ARG0-of (c2 / counter-01~e.18 :ARG1 (e4 / enzyme :name (n2 / name :op1 "Rac"~e.20)))) :op3 (e3 / epifluorescence~e.24)) :ARG1-of (d2 / describe-01 :location (b / bottom~e.8)) :ARG1-of (g / green-02~e.10)) # ::id pmid_1177_7939.271 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the cotransfection experiments a molar ratio of 1 @:@ 3 of the activated GTPases to the ECFP @-@ E3b1 constructs was used , such as that all of the epifluorescent cells expressed also the corresponding GTPase ( not shown ) . # ::alignments 2-1.1.1 3-1.1 5-1.2.1 5-1.2.2 6-1.2 7-1.2 8-1.2.3.1 10-1.2.3.1 11-1.2 11-1.2.1.1.r 13-1.2.1.1.2 15-1.2.2.1.r 17-1.2.2.1.1.1.1 19-1.2.2.1.2.1.1 22-1 27-1.3.1.2.1 30-1.3.1.2.2 31-1.3.1.2 32-1.3.1 33-1.3.1.3 35-1.3.1.1 35-1.3.1.1.2 35-1.3.1.1.2.r 36-1.2.1.1.1.1 36-1.3.1.1.1.1 38-1.4.1 38-1.4.1.r 39-1.4 (u / use-01~e.22 :ARG0 (e3 / experiment-01~e.3 :ARG1 (c / cotransfect-01~e.2)) :ARG1 (r / ratio-of~e.6,7,11 :op1 (m2 / molar~e.5 :quant-of~e.11 (e2 / enzyme :name (n2 / name :op1 "GTPase"~e.36) :ARG1-of (a / activate-01~e.13))) :op2 (m3 / molar~e.5 :quant-of~e.15 (m / macro-molecular-complex :part (p / protein :name (n3 / name :op1 "ECFP"~e.17)) :part (p2 / protein :name (n4 / name :op1 "E3b1"~e.19)))) :ARG1-of (e7 / equal-01 :ARG2 "1/3"~e.8,10)) :ARG0-of (c2 / cause-01 :ARG1 (e4 / express-03~e.32 :ARG2 (e6 / enzyme~e.35 :name (n5 / name :op1 "GTPase"~e.36) :ARG1-of~e.35 (c4 / correspond-02~e.35)) :ARG3 (c3 / cell~e.31 :mod (a2 / all~e.27) :mod (e / epifluorescent~e.30)) :mod (a3 / also~e.33))) :ARG1-of (s / show-01~e.39 :polarity~e.38 -~e.38)) # ::id pmid_1177_7939.272 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The percent of transfected cells ( mean ± SEM ) undergoing ruffling was as follow : RasV12 = 65 ± 3 % ; RasV12 + E3b1 WT = 62 ± 4 % ; RasV12 + E3b1DY = 16 ± 2 % ; RacQL = 93 ± 3 % ; RacQL + E3b1 WT = 90 ± 4 % ; RacQL + E3b1DY = 95 ± 5 % . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1 4-1.1.1.1 6-1.1.1.1.3 6-1.1.1.1.3.1 6-1.1.1.1.3.1.r 10-1.1.1.1.2 11-1.1.1.1.2.1 14-1.1 16-1.2.2.1.1 16-1.3.2.1.1.1 16-1.4.2.1.1.1 18-1.2.1.1 20-1.2.1.2.1.1 20-1.2.1.2.2.1 20-1.5.1.2.1.1 20-1.5.1.2.2.1 21-1.2.1.2.1 21-1.2.1.2.2 21-1.5.1.2.1 21-1.5.1.2.2 23-1.2.2.1.1 23-1.3.2.1.1.1 23-1.4.2.1.1.1 24-1.2.1 24-1.3.1 24-1.3.2 24-1.4.2 24-1.6.2 24-1.7.2 25-1.3.2.2.1.1 25-1.6.2.2.1.1 26-1.3.2.2.2 26-1.6.2.2.2 28-1.3.1.1 30-1.3.1.2.1.1 30-1.3.1.2.2.1 30-1.6.1.2.1.1 30-1.6.1.2.2.1 31-1.3.1.2.1 31-1.3.1.2.2 31-1.6.1.2.1 31-1.6.1.2.2 33-1.2.2.1.1 33-1.3.2.1.1.1 33-1.4.2.1.1.1 34-1.3.2 34-1.4.1 34-1.4.2 34-1.6.2 34-1.7.2 35-1.4.2.2.1.1 35-1.7.2.2.1.1 37-1.4.1.1 39-1.4.1.2.1.1 39-1.4.1.2.2.1 40-1.4.1.2.1 40-1.4.1.2.2 42-1.5.2.1.1 42-1.6.2.1.1.1 42-1.7.2.1.1.1 44-1.5.1.1 46-1.2.1.2.1.1 46-1.2.1.2.2.1 46-1.5.1.2.1.1 46-1.5.1.2.2.1 47-1.2.1.2.1 47-1.2.1.2.2 47-1.5.1.2.1 47-1.5.1.2.2 49-1.5.2.1.1 49-1.6.2.1.1.1 49-1.7.2.1.1.1 50-1.3.2 50-1.4.2 50-1.5.1 50-1.6.1 50-1.6.2 50-1.7.2 51-1.3.2.2.1.1 51-1.6.2.2.1.1 52-1.3.2.2.2 52-1.6.2.2.2 54-1.6.1.1 56-1.3.1.2.1.1 56-1.3.1.2.2.1 56-1.6.1.2.1.1 56-1.6.1.2.2.1 57-1.3.1.2.1 57-1.3.1.2.2 57-1.6.1.2.1 57-1.6.1.2.2 59-1.5.2.1.1 59-1.6.2.1.1.1 59-1.7.2.1.1.1 60-1.3.2 60-1.4.2 60-1.6.2 60-1.7.1 60-1.7.2 61-1.4.2.2.1.1 61-1.7.2.2.1.1 63-1.7.1.1 65-1.7.1.2.1.1 65-1.7.1.2.2.1 66-1.7.1.2.1 66-1.7.1.2.2 (m3 / multi-sentence :snt1 (f / follow-04~e.14 :ARG1 (p4 / percentage-entity~e.1 :quant-of~e.2 (c / cell~e.4 :ARG1-of (t / transfect-01~e.3) :ARG1-of (u / undergo-28~e.10 :ARG2 (r / ruffle-02~e.11)) :ARG1-of (m / mean-01~e.6 :ARG2~e.6 (m2 / mean~e.6 :mod (s / slash :op1 (e / error :ARG1-of (s2 / standard-02)) :op2 (e2 / error :polarity - :ARG1-of s2))))))) :snt2 (e3 / equal-01 :ARG1 (s3 / sum-of~e.24 :op1 65~e.18 :op2 (s4 / slash :op1 (p / percentage-entity~e.21,47 :value 3~e.20,46) :op2 (p2 / percentage-entity~e.21,47 :value -3~e.20,46))) :ARG2 (e4 / enzyme :name (n / name :op1 "RasV12"~e.16,23,33))) :snt3 (e5 / equal-01 :ARG1 (s6 / sum-of~e.24 :op1 62~e.28 :op2 (s7 / slash :op1 (p5 / percentage-entity~e.31,57 :value 4~e.30,56) :op2 (p6 / percentage-entity~e.31,57 :value -4~e.30,56))) :ARG2 (s5 / sum-of~e.24,34,50,60 :op1 (e6 / enzyme :name (n2 / name :op1 "RasV12"~e.16,23,33)) :op2 (p3 / protein :name (n3 / name :op1 "E3b1"~e.25,51) :mod (w / wild-type~e.26,52)))) :snt4 (e7 / equal-01 :ARG1 (s9 / sum-of~e.34 :op1 16~e.37 :op2 (s10 / slash :op1 (p8 / percentage-entity~e.40 :value 2~e.39) :op2 (p9 / percentage-entity~e.40 :value -2~e.39))) :ARG2 (s8 / sum-of~e.24,34,50,60 :op1 (e8 / enzyme :name (n4 / name :op1 "RasV12"~e.16,23,33)) :op2 (p7 / protein :name (n5 / name :op1 "E3b1DY"~e.35,61)))) :snt5 (e9 / equal-01 :ARG1 (s11 / sum-of~e.50 :op1 93~e.44 :op2 (s12 / slash :op1 (p11 / percentage-entity~e.21,47 :value 3~e.20,46) :op2 (p12 / percentage-entity~e.21,47 :value -3~e.20,46))) :ARG2 (e14 / enzyme :name (n6 / name :op1 "RacQL"~e.42,49,59))) :snt6 (e10 / equal-01 :ARG1 (s14 / sum-of~e.50 :op1 90~e.54 :op2 (s15 / slash :op1 (p15 / percentage-entity~e.31,57 :value 4~e.30,56) :op2 (p16 / percentage-entity~e.31,57 :value -4~e.30,56))) :ARG2 (s13 / sum-of~e.24,34,50,60 :op1 (e13 / enzyme :name (n7 / name :op1 "RacQL"~e.42,49,59)) :op2 (p14 / protein :name (n8 / name :op1 "E3b1"~e.25,51) :mod (w2 / wild-type~e.26,52)))) :snt7 (e11 / equal-01 :ARG1 (s17 / sum-of~e.60 :op1 95~e.63 :op2 (s18 / slash :op1 (p19 / percentage-entity~e.66 :value 5~e.65) :op2 (p20 / percentage-entity~e.66 :value -5~e.65))) :ARG2 (s16 / sum-of~e.24,34,50,60 :op1 (e12 / enzyme :name (n9 / name :op1 "RacQL"~e.42,49,59)) :op2 (p18 / protein :name (n10 / name :op1 "E3b1DY"~e.35,61))))) # ::id pmid_1177_7939.273 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bar , 10 μm . # ::alignments 0-1 2-1.1.1 3-1.1.2 (b / bar~e.0 :mod (d / distance-quantity :quant 10~e.2 :unit (m / micrometer~e.3))) # ::id pmid_1177_7939.274 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 7 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 7~e.1) # ::id pmid_1177_7939.275 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The bifunctional guanine nucleotide exchange activity of Sos @-@ 1 is regulated by its assembly into distinct molecular complexes . # ::alignments 3-1.2.2.1.1 4-1.2.2.1.2 5-1.2.2.1.3 6-1.2 8-1.1.1.1.1 10-1.1.1.1.1 12-1 15-1.1 16-1.1.2.r 17-1.1.2.1 18-1.1.2.2 19-1.1.2 (r / regulate-01~e.12 :ARG0 (a / assemble-02~e.15 :ARG0 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.8,10)) :ARG1~e.16 (c / complex~e.19 :mod (d / distinct~e.17) :mod (m / molecule~e.18))) :ARG1 (a2 / activity-06~e.6 :ARG0 p2 :ARG1 (p / protein :name (n / name :op1 "guanine"~e.3 :op2 "nucleotide"~e.4 :op3 "exchange"~e.5 :op4 "factor") :ARG0-of (f / function-01 :quant 2)))) # ::id pmid_1177_7939.276 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Cos @-@ 7 cells were transfected with expression vectors for Sos @-@ 1 ( SosTfx ) or for Sos @-@ 1 , E3b1 , and Eps8 ( TripleTfx ) or with the corresponding empty vectors ( mock ) . # ::alignments 1-1.3.1.1 3-1.1.1.1 5-1.1.1.1 6-1.1 8-1 10-1.2.1.1 10-1.2.2.1 11-1.2.1 11-1.2.2 12-1.2.1.1.1.r 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1 17-1.2.1.2.1.1 19-1.2 20-1.2.2.1.1.r 21-1.2.2.1.1.3 22-1.2.2.1.1.3 23-1.2.2.1.1.3 25-1.2.2.1.1.1.1.1 28-1.2.2.1.1.2.1.1 30-1.2.2.2.1.1 32-1.2 33-1.2.r 35-1.2.3.2 36-1.2.3.1 37-1.2.3 39-1.2.3.3.1 (t / transfect-01~e.8 :ARG1 (c / cell-line~e.6 :name (n / name :op1 "Cos-7"~e.3,5)) :ARG2~e.33 (o2 / or~e.19,32 :op1 (v / vector~e.11 :ARG1-of (e / express-03~e.10 :ARG2~e.12 (p4 / protein :name (n5 / name :op1 "Sos-1"~e.13,15))) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :value "SosTfx"~e.17))) :op2 (v3 / vector~e.11 :ARG1-of (e3 / express-03~e.10 :ARG2~e.20 (m2 / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "E3b1"~e.25)) :part (e4 / enzyme :name (n4 / name :op1 "Eps8"~e.28)) :part p4~e.21,22,23)) :ARG1-of (d3 / describe-01 :ARG2 (s2 / string-entity :value "TripleTfx"~e.30))) :op3 (v2 / vector~e.37 :ARG1-of (e2 / empty-02~e.36) :ARG1-of (c2 / correspond-02~e.35) :ARG1-of (d4 / describe-01 :ARG2 (m3 / mock~e.39)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"~e.1))) # ::id pmid_1177_7939.277 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total cellular lysates ( 100 μg , left ) , or immunoprecipitates ( IP , right ) with the antibody indicated on the top ( ctr , irrelevant antibody ) , were immunoblotted ( WB ) with the indicated antibody . # ::alignments 0-1.1.1.4 1-1.1.1.1 2-1.1.1 4-1.1.1.2.1 5-1.1.1.2.2 7-1.1.1.3.1.1 11-1.1.2 11-1.1.2.2 11-1.1.2.2.r 15-1.1.2.1.1.1 17-1.1.2.2.1.r 19-1.1.2.2.1 20-1.1.2.2.1.1 23-1.1.2.2.1.1.1.1 27-1.1.2.2.1.2 27-1.1.2.2.1.2.1 27-1.1.2.2.1.2.1.r 28-1.1.2.2.1 38-1.1.2.2.1.1 39-1.1.2.2.1 (i / immunoblot-01 :ARG1 (a / and :op1 (l / lysate~e.2 :mod (c / cell~e.1) :quant (m / mass-quantity :quant 100~e.4 :unit (m2 / microgram~e.5)) :ARG1-of (d / describe-01 :ARG0 (f / figure :ARG1-of (l2 / left-20~e.7))) :mod (t2 / total~e.0)) :op2 (p / protein~e.11 :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :ARG1-of (r / right-04~e.15))) :ARG1-of~e.11 (i2 / immunoprecipitate-01~e.11 :ARG3~e.17 (a2 / antibody~e.19,28,39 :ARG1-of (i4 / indicate-01~e.20,38 :location (f4 / figure :mod (t / top~e.23))) :ARG1-of (r2 / relevant-01~e.27 :polarity~e.27 -~e.27))))) :ARG3 a2) # ::id pmid_1177_7939.278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 5 mg of total cellular lysates were used for the immunoprecipitations , except in the SosTfx 1 @/@ 10 lanes , in which 0.5 mg were used . # ::alignments 0-1.1.3.1 1-1.1.3.2 2-1.1.3.r 3-1.1.1 4-1.1.2 5-1.1 5-1.3.1.1 7-1 12-1.3 18-1.3.1.2.1.1.1 19-1.3.1.2 23-1.3.1.1.1.1 24-1.3.1.1.1.2 26-1.3.1 (u / use-01~e.7 :ARG1 (l / lysate~e.5 :mod (t / total~e.3) :mod (c / cell~e.4) :quant~e.2 (m / mass-quantity :quant 5~e.0 :unit (m2 / milligram~e.1))) :ARG2 (i / immunoprecipitate-01) :ARG2-of (e / except-01~e.12 :ARG1 (u2 / use-01~e.26 :ARG1 (l3 / lysate~e.5 :quant (m3 / mass-quantity :quant 0.5~e.23 :unit (m4 / milligram~e.24))) :location (l2 / lane~e.19 :ARG1-of (d / describe-01 :ARG2 (n / name :op1 "SosTfx 1/10"~e.18)))))) # ::id pmid_1177_7939.279 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Ras @-@ GEF ( empty bars ) and Rac @-@ GEF ( closed bars ) activities in aliquots of the same immunoprecipitates ( IP ) shown in B. # ::alignments 1-1.3.1.1 3-1.1.2.1.1 7-1.1.3.1.1 8-1.1.3.1 10-1 11-1.2.2.1.1 15-1.2.3.1.1 16-1.2.3.1 18-1.1 18-1.2 19-1.1.4.r 20-1.1.4 23-1.1.4.1.1.2 24-1.1.4.1.1 24-1.1.4.1.1.1 24-1.1.4.1.1.1.r 28-1.3 (a2 / and~e.10 :op1 (a3 / activity-06~e.18 :ARG0 (p / protein :name (n3 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor")) :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.3)) :ARG1-of (d2 / describe-01 :ARG2 (b / bar~e.8 :ARG1-of (e3 / empty-02~e.7))) :location~e.19 (a / aliquot~e.20 :ARG1-of (i / include-91 :ARG2 (p2 / protein~e.24 :ARG1-of~e.24 (i2 / immunoprecipitate-01~e.24) :ARG1-of (s / same-01~e.23))))) :op2 (a4 / activity-06~e.18 :ARG0 p :ARG1 (e2 / enzyme :name (n2 / name :op1 "Rac"~e.11)) :ARG1-of (d3 / describe-01 :ARG2 (b2 / bar~e.16 :ARG1-of (c / close-01~e.15))) :location a) :ARG1-of (s2 / show-01~e.28 :ARG0 (f / figure :mod "B"~e.1))) # ::id pmid_1177_7939.280 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Data are expressed as described in Material and methods . # ::alignments 0-1.1.1 2-1.1 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1 7-1.2.1.1.1 8-1.2.1.1.1.2 (r / resemble-01 :ARG1 (e / express-01~e.2 :ARG1 (d2 / data~e.0)) :ARG2 (d / describe-01~e.4 :ARG0~e.5 (t2 / thing :ARG1-of (t / title-01 :ARG2 (a / and~e.7 :op1 (m / material~e.6) :op2 (m2 / method~e.8)))))) # ::id pmid_1177_7939.281 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) Immobilized , purified GST @-@ Rac ( Rac ) and GST @-@ Cdc42 ( Cdc42 ) were depleted of guanine nucleotide by extensive washing in 10 mM EDTA as described in Material and methods . # ::alignments 1-1.4.1.1 3-1.1.1.2 5-1.1.1.3 6-1.1.1.4.1.1 8-1.1.1.5.1.1 10-1.1.1.5.1.1 13-1.1.1.4.1.1 15-1.1.2.5.1.1 17-1.1.2.5.1.1 20-1 21-1.2.r 22-1.2.1.1.1 23-1.2 24-1.3.r 25-1.3.4 26-1.3 27-1.3.2.r 28-1.3.2.2.1 29-1.3.2.2.2 30-1.3.2.1.1 32-1.1.1.1 32-1.1.2.1 32-1.3.3 32-1.4 33-1.3.3.1.r 34-1.3.3.1.1.1.1 35-1.3.3.1.1.1 36-1.3.3.1.1.1.2 (d2 / deplete-01~e.20 :ARG1 (a / and :op1 (m4 / macro-molecular-complex :ARG1-of (d3 / describe-01~e.32 :ARG2 (n7 / name :op1 "Rac")) :ARG1-of (i / immobilize-01~e.3) :ARG1-of (p / purify-01~e.5) :part (e3 / enzyme :name (n / name :op1 "GST"~e.6,13)) :part (e / enzyme :name (n5 / name :op1 "Rac"~e.8,10))) :op2 (m5 / macro-molecular-complex :ARG1-of (d4 / describe-01~e.32 :ARG2 (n8 / name :op1 "Cdc42")) :ARG1-of i :ARG1-of p :part e3 :part (p2 / protein :name (n2 / name :op1 "Cdc42"~e.15,17)))) :ARG2~e.21 (n6 / nucleotide~e.23 :mod (s / small-molecule :name (n3 / name :op1 "guanine"~e.22))) :manner~e.24 (w / wash-01~e.26 :ARG1 (a2 / and :op1 m4 :op2 m5) :ARG2~e.27 (s2 / small-molecule :name (n4 / name :op1 "EDTA"~e.30) :mod (c / concentration-quantity :quant 10~e.28 :unit (m / millimolar~e.29))) :ARG1-of (d5 / describe-01~e.32 :ARG0~e.33 (t2 / thing :ARG1-of (t / title-01 :ARG2 (a3 / and~e.35 :op1 (m6 / material~e.34) :op2 (m7 / method~e.36))))) :ARG1-of (e2 / extensive-03~e.25)) :ARG1-of (d / describe-01~e.32 :ARG0 (f / figure :mod "C"~e.1))) # ::id pmid_1177_7939.282 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Equal amounts of the nucleotide @-@ free GST @-@ GTPases or GST alone ( GST ) were incubated with total cellular lysates from eps8 @^−/− fibroblasts (−/−) or eps8 @^−/− stably expressing Eps8 myc (−/−[Eps8 myc]) in the presence or absence (−) of the 40 ng @/@ ml of the indicated peptides ( peptides ) . # ::alignments 0-1.2.3 1-1.2.1 1-1.2.2 2-1.2.1.1.r 4-1.2.1.1.3.1 6-1.2.1.1 6-1.2.1.1.3 6-1.2.1.1.3.r 7-1.2.1.1.1.1.1 10-1.3 11-1.2.1.1.1.1.1 14-1.2.1.1.1.1.1 17-1 18-1.1.r 19-1.1.1 20-1.1.2 21-1.1 23-1.1.3.1.1.1.1.1 25-1.1.3.1.1.1.2.1 27-1.1.3.1.1 27-1.1.3.1.2 29-1.1.3.1 30-1.1.3.1.2.3 31-1.1.3.1.2.3 32-1.1.3.1.2.3 34-1.1.3.1.2.1.2 35-1.1.3.1.2.1 36-1.1.3.1.2.3 40-1.3.r 42-1.3.1 43-1.3 44-1.3.2 46-1.3.1.1.r 48-1.3.1.1.3.1 49-1.3.1.1.3.2 51-1.3.1.1.3.2 54-1.3.1.1.1 55-1.3.1.1 55-1.3.1.1.2.1 57-1.3.1.1 57-1.3.1.1.2.1 (i / incubate-01~e.17 :ARG0~e.18 (l / lysate~e.21 :mod (t / total~e.19) :mod (c / cell~e.20) :ARG1-of (o / obtain-01 :ARG2 (o2 / or~e.29 :op1 (f2 / fibroblast~e.27 :part (e6 / enzyme :name (n4 / name :op1 "eps8"~e.23) :ARG2-of (m4 / mutate-01 :mod "−/−"~e.25))) :op2 (f3 / fibroblast~e.27 :ARG3-of (e5 / express-03~e.35 :ARG2 (p3 / protein :name (n5 / name :op1 "Eps8myc")) :ARG1-of (s / stable-03~e.34)) :ARG1-of (d3 / describe-01 :ARG2 (s3 / string-entity :value "−/−[Eps8myc]")) :part e6~e.30,31,32,36)))) :ARG1 (a / and :op1 (a2 / amount~e.1 :quant-of~e.2 (m / macro-molecular-complex~e.6 :part (e / enzyme :name (n / name :op1 "GST"~e.7,11,14)) :part (e2 / enzyme :name (n2 / name :op1 "GTPase")) :ARG1-of~e.6 (f / free-04~e.6 :ARG2 (n6 / nucleotide~e.4)))) :op2 (a4 / amount~e.1 :quant-of e) :ARG1-of (e4 / equal-01~e.0)) :ARG2~e.40 (o3 / or~e.10,43 :op1 (p4 / present-02~e.42 :ARG1~e.46 (p / peptide~e.55,57 :ARG1-of (i2 / indicate-01~e.54) :ARG1-of (d4 / describe-01 :ARG2 (p2 / peptide~e.55,57)) :mod (m3 / mass-quantity :quant 40~e.48 :unit (n7 / nanogram-per-milliliter~e.49,51)))) :op2 (a3 / absent-01~e.44 :ARG1 p :ARG1-of (d5 / describe-01 :ARG2 (s2 / string-entity :value "−"))))) # ::id pmid_1177_7939.283 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The peptide used were PPPPPPVDATEDEE ( PXXDA ) , used as control ( see text and Fig . 1 ) ; PPPPPVDYTEDEE ( PXXDY ) , which corresponds to the E3b1 binding site for the SH3 domain of Eps8 and prevents Eps8 @-@ E3b1 association ( refer to Fig . 1 B ) ; VPVPPPVPPRRR ( PXXP ) , which corresponds to the Sos @-@ 1 binding site for the SH3 domain of E3b1 and readily competes the interaction between Sos @-@ 1 and E3b1 ( refer to Fig . 2 C ) . # ::alignments 1-1.1.1 1-1.1.2 1-1.1.3 2-1 4-1.1.1.1.1 6-1.1.1.2.2.1 9-1 10-1.1.1.3.r 11-1.1.1.3 13-1.1.1.2.1.3 14-1.1.1.2.1.1 15-1.1 15-1.1.1.2.1 17-1.1.1.2.1.2 19-1.1.1.2.1.2.1 23-1.1.2.1.1 25-1.1.2.2.2.1 30-1.1.2.3.r 32-1.1.2.3.1.1.1.1 33-1.1.2.4 33-1.1.3.4 33-1.1.3.4.2.1 34-1.1.3.4.1 37-1.1.3.4.1.1.1 38-1.1.3.4.1.1.2 40-1.1.2.3.1.2.1.1 42-1.1.2.3 43-1.1.2.3.1.2.1.1 45-1.1.2.3.1.1.1.1 46-1.1.2.3.1 48-1.1.2.2.1.2 51-1.1.1.2.1.2 51-1.1.2.2.1 53-1.1.1.2.1.2.1 58-1.1.3.1.1 60-1.1.3.2.2.1 65-1.1.3.3.r 67-1.1.3.3.1.1.1 69-1.1.1.2.1.2.1 69-1.1.3.3.1.1.1 70-1.1.2.4 70-1.1.2.4.2.1 71-1.1.2.4.1 74-1.1.2.4.1.1.1 75-1.1.2.4.1.1.2 76-1.1.2.4.2 77-1.1.2.3.1.1.1.1 78-1.1.3.3.2.1 79-1.1.3.3.3 79-1.1.3.3.3.r 80-1.1.3.3 82-1.1.3.3.2 84-1.1.3.3.2.1.1 85-1.1.3.3.2.1.1 86-1.1.3.3.2.1.1 87-1.1.3.3.2.1 88-1.1.2.3.1.1.1.1 90-1.1.2.2.1.2 93-1.1.2.2.1 93-1.1.3.2.1 (u / use-01~e.2,9 :ARG1 (a / and~e.15 :op1 (p / peptide~e.1 :name (n / name :op1 "PPPPPPVDATEDEE"~e.4) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.15 :op1 (t / text~e.14) :op2 (f / figure~e.17,51 :mod 1~e.19,53,69) :ARG1-of (s / see-01~e.13 :mode imperative :ARG0 y)) :ARG2 (n7 / name :op1 "PXXDA"~e.6)) :ARG0-of~e.10 (c / control-01~e.11)) :op2 (p2 / peptide~e.1 :name (n2 / name :op1 "PPPPPVDYTEDEE"~e.23) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.51,93 :mod "1B" :ARG1-of (r2 / refer-03~e.48,90 :mode imperative :ARG0 (y / you))) :ARG2 (n10 / name :op1 "PXXDY"~e.25)) :ARG0-of~e.30 (p4 / prevent-01~e.42 :ARG1 (a3 / associate-01~e.46 :ARG1 (p6 / protein :name (n5 / name :op1 "E3b1"~e.32,45,77,88)) :ARG2 (e / enzyme :name (n4 / name :op1 "Eps8"~e.40,43)))) :ARG1-of (b2 / bind-01~e.33,70 :ARG2 (p9 / protein-segment~e.71 :name (n8 / name :op1 "SH3"~e.74 :op2 "domain"~e.75) :part-of e) :ARG1-of (i3 / instead-of-91~e.76 :ARG2 (b3 / bind-01~e.70 :ARG1 p6 :ARG2 e)))) :op3 (p3 / peptide~e.1 :name (n3 / name :op1 "VPVPPPVPPRRR"~e.58) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.93 :mod "2C") :ARG2 (n11 / name :op1 "PXXP"~e.60)) :ARG0-of~e.65 (c3 / compete-01~e.80 :ARG1 (p7 / protein :name (n6 / name :op1 "Sos-1"~e.67,69)) :ARG2 (i2 / interact-01~e.82 :ARG0 (a4 / and~e.78,87 :op1 p7~e.84,85,86 :op2 p6)) :manner~e.79 (r / ready~e.79)) :ARG1-of (b4 / bind-01~e.33 :ARG2 (p5 / protein-segment~e.34 :name (n9 / name :op1 "SH3"~e.37 :op2 "domain"~e.38) :part-of p6) :ARG1-of (i4 / instead-of-91 :ARG2 (b5 / bind-01~e.33 :ARG1 p7 :ARG2 p6)))))) # ::id pmid_1177_7939.284 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bound proteins were resolved by SDS @-@ PAGE . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.1.1 7-1.2.1.1 (r / resolve-03~e.3 :ARG1 (p / protein~e.1 :ARG1-of (b / bind-01~e.0)) :ARG3~e.4 (t / thing :name (n / name :op1 "SDS-PAGE"~e.5,7))) # ::id pmid_1177_7939.285 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detection was with anti @–@ Sos @-@ 1 antibody ( Sos @-@ 1 ) . # ::alignments 0-1 2-1.1.r 3-1.1.2 5-1.1.1.1.1 5-1.1.2.1.1.1 7-1.1.1.1.1 7-1.1.2.1.1.1 8-1.1 10-1.1.1.1.1 10-1.1.2.1.1.1 12-1.1.1.1.1 12-1.1.2.1.1.1 (d / detect-01~e.0 :ARG0~e.2 (a / antibody~e.8 :ARG1-of (d2 / describe-01 :ARG2 (n2 / name :op1 "Sos-1"~e.5,7,10,12)) :ARG0-of (c / counter-01~e.3 :ARG1 (p / protein :name (n / name :op1 "Sos-1"~e.5,7,10,12))))) # ::id pmid_1177_7939.286 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The indicted lanes ( lysate ) were loaded with 50 μg of total cellular lysates . # ::alignments 2-1.1 4-1.1.2.1 4-1.2 7-1 8-1.2.r 9-1.2.3.1 10-1.2.3.2 12-1.2.1 13-1.2.2 14-1.1.2.1 14-1.2 (l / load-01~e.7 :ARG1 (l2 / lane~e.2 :ARG1-of (i / indicate-01) :ARG1-of (d / describe-01 :ARG2 (l5 / lysate~e.4,14))) :ARG2~e.8 (l3 / lysate~e.4,14 :mod (t / total~e.12) :mod (c / cell~e.13) :mod (m / mass-quantity :quant 50~e.9 :unit (m2 / microgram~e.10)))) # ::id pmid_1177_7939.287 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 8 . # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 8~e.1) # ::id pmid_1177_7939.288 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The differential regulation of the S/G and S/E/E8 complexes by RTKs correlates with the kinetics of activation of Ras and Rac . # ::alignments 2-1.1.3 3-1.1 4-1.1.2.r 6-1.1.2.1.1.1 7-1.1.2 8-1.1.2.2.1.1 9-1.1.2.1 9-1.1.2.2 12-1 13-1.2.r 15-1.2 16-1.2.1.r 17-1.2.1 18-1.2.1.1.r 19-1.2.1.1.1.1.1 20-1.2.1.1 21-1.2.1.1.2.1.1 (c / correlate-01~e.12 :ARG1 (r / regulate-01~e.3 :ARG0 (e2 / enzyme :name (n2 / name :op1 "RTK")) :ARG1~e.4 (a2 / and~e.7 :op1 (m / macro-molecular-complex~e.9 :name (n3 / name :op1 "S/G"~e.6)) :op2 (m2 / macro-molecular-complex~e.9 :name (n4 / name :op1 "S/E/E8"~e.8))) :ARG1-of (d / differ-02~e.2)) :ARG2~e.13 (k / kinetics~e.15 :mod~e.16 (a / activate-01~e.17 :ARG1~e.18 (a3 / and~e.20 :op1 (e / enzyme :name (n / name :op1 "Ras"~e.19)) :op2 (e3 / enzyme :name (n5 / name :op1 "Rac"~e.21)))))) # ::id pmid_1177_7939.289 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Mouse embryo fibroblasts cells were treated with PDGF for 15 min (+) or mock treated (−) . # ::alignments 1-1.1 3-1.2.1.1.1 4-1.2.1.1 5-1.2.1 8-1.2 9-1.2.2.r 10-1.2.2.1.1 11-1.2.3.r 12-1.2.3.1 13-1.2.3.2 16-1.3.3 17-1.3 (a / and :li "A"~e.1 :op1 (t / treat-03~e.8 :ARG1 (f / fibroblast~e.5 :part-of (e / embryo~e.4 :mod (m / mouse~e.3))) :ARG3~e.9 (p / protein :name (n / name :op1 "PDGF"~e.10) :ARG1-of (d / describe-01 :ARG2 (s2 / string-entity :value +))) :duration~e.11 (t3 / temporal-quantity :quant 15~e.12 :unit (m2 / minute~e.13))) :op2 (t2 / treat-04~e.17 :polarity - :ARG1 f :ARG2 (m3 / mock~e.16) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :value "−")))) # ::id pmid_1177_7939.290 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lysates were immunoprecipitated ( IP ) with anti @-@ Grb2 ( left ) or anti @-@ E3b1 ( right ) antibody and detected with anti @–@ Sos @-@ 1 antibody ( top ) or anti @-@ Grb2 ( bottom , left ) , or anti @-@ E3b1 ( bottom , right ) . # ::alignments 0-1.1.1 2-1.1 6-1.1.2.r 7-1.1.2.1.1 9-1.1.2.1.1.1.1.1 11-1.1.2.1.2 13-1.1.2 14-1.1.2.1.1 16-1.1.2.2.1.1.1.1 18-1.1.2.2.2 20-1.1.2.2 21-1 22-1.2 24-1.1.2.2.1 24-1.2.2.1.1 26-1.2.2.1.1.1.1.1 28-1.2.2.1.1.1.1.1 29-1.1.2.1 29-1.2.2.1 29-1.2.2.2 29-1.2.2.3 31-1.2.2.1.2 33-1.1.2 33-1.2.2 34-1.1.2.1.1 34-1.2.2.2.1 34-1.2.2.3.1 36-1.1.2.1.1.1.1.1 38-1.2.2.2.2 40-1.2.2.2.2.1 43-1.2.2 44-1.1.2.1.1 46-1.1.2.2.1.1.1.1 48-1.2.2.3.2 50-1.2.2.3.2.1 (a / and~e.21 :op1 (i / immunoprecipitate-01~e.2 :ARG1 (l / lysate~e.0) :ARG3~e.6 (o / or~e.13,33 :op1 (a2 / antibody~e.29 :ARG0-of (c / counter-01~e.7,14,34,44 :ARG1 (p3 / protein :name (n / name :op1 "Grb2"~e.9,36))) :ARG1-of (l2 / left-20~e.11)) :op2 (a9 / antibody~e.20 :ARG0-of (c2 / counter-01~e.24 :ARG1 (p4 / protein :name (n2 / name :op1 "E3b1"~e.16,46))) :ARG1-of (r2 / right-04~e.18)))) :op2 (d / detect-01~e.22 :ARG1 l :ARG2 (o2 / or~e.33,43 :op1 (a7 / antibody~e.29 :ARG0-of (c3 / counter-01~e.24 :ARG1 (p / protein :name (n3 / name :op1 "Sos-1"~e.26,28))) :location (t / top~e.31)) :op2 (a10 / antibody~e.29 :ARG0-of (c4 / counter-01~e.34 :ARG1 p3) :location (b / bottom~e.38 :ARG1-of l2~e.40)) :op3 (a4 / antibody~e.29 :ARG0-of (c5 / counter-01~e.34 :ARG1 p4) :location (b2 / bottom~e.48 :ARG1-of r2~e.50))))) # ::id pmid_1177_7939.291 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The indicated lanes ( lysate ) ( 50 μg ) were detected with anti @–@ Sos @-@ 1 antibody to show the mobility shift after PDGF stimulation . # ::alignments 1-1.1.1.1 2-1.1.1 4-1.1.1.3.1.1 7-1.1.1.2.1 8-1.1.1.2.2 11-1.1 12-1.1.2.r 13-1.1.2.1 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 18-1.1.2 20-1.2 22-1.2.1.1 23-1.2.1 24-1.2.1.2 25-1.2.1.2.1.1.1.1 26-1.2.1.2.1 (h / have-purpose-91 :ARG1 (d / detect-01~e.11 :ARG1 (l / lane~e.2 :ARG1-of (i / indicate-01~e.1) :quant (m2 / mass-quantity :quant 50~e.7 :unit (m3 / microgram~e.8)) :ARG1-of (d2 / describe-01 :ARG2 (n3 / name :op1 "lysate"~e.4))) :ARG2~e.12 (a2 / antibody~e.18 :ARG0-of (c / counter-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "Sos-1"~e.15,17))))) :ARG2 (s / show-01~e.20 :ARG1 (s2 / shift-01~e.23 :ARG1 (m / mobility~e.22) :time (a / after~e.24 :op1 (s4 / stimulate-01~e.26 :ARG0 (p / protein :name (n / name :op1 "PDGF"~e.25))))))) # ::id pmid_1177_7939.292 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar results were obtained upon EGF stimulation in Cos @-@ 7 cells ( not shown ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 5-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.r 8-1.1.1.1.2.2.1 10-1.1.1.1.2.1 11-1.1.1.1.2 13-1.2.1 13-1.2.1.r 14-1.2 (o / obtain-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r2 / result-01~e.1 :ARG1 (s / stimulate-01~e.6 :ARG0 (p / protein :name (n / name :op1 "EGF"~e.5)) :location~e.7 (c / cell-line~e.11 :mod 7~e.10 :name (n2 / name :op1 "Cos"~e.8)))) :ARG1-of (r / resemble-01~e.0)) :ARG1-of (s2 / show-01~e.14 :polarity~e.13 -~e.13)) # ::id pmid_1177_7939.293 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Fibroblasts were treated with PDGF for the indicated lengths of time . # ::alignments 1-1.1 3-1.3 5-1 6-1.2.r 7-1.2.1.1 8-1.4.r 10-1.4.1 13-1.4 (t / treat-04~e.5 :li "B"~e.1 :ARG0~e.6 (p / protein :name (n / name :op1 "PDGF"~e.7)) :ARG1 (f / fibroblast~e.3) :duration~e.8 (t2 / temporal-quantity~e.13 :ARG1-of (i / indicate-01~e.10))) # ::id pmid_1177_7939.294 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lysates were immunoprecipitated ( IP ) with anti @-@ PDGFR ( PDGFR ) or an irrelevant antibody as a control ( ctr ) and detected with the indicated antibodies ( WB ) . # ::alignments 0-1.1.1 2-1.1 7-1.2.1.1.1 9-1.2.1.1.1.1.1.1 11-1.2.1.1.1.1.1.1 13-1.2.1 15-1.2.1.2.1 15-1.2.1.2.1.1 15-1.2.1.2.1.1.r 16-1.2.1.1 16-1.2.1.2 19-1.2.1.2.2.1 24-1.2 25-1.2.1.r 27-1.2.1.3 28-1.2.1.2 (a / and :op1 (i / immunoprecipitate-01~e.2 :ARG1 (l / lysate~e.0) :ARG3 o) :op2 (d / detect-01~e.24 :ARG0~e.25 (o / or~e.13 :op1 (a2 / antibody~e.16 :ARG0-of (c2 / counter-01~e.7 :ARG1 (p / protein :name (n / name :op1 "PDGFR"~e.9,11)))) :op2 (a3 / antibody~e.16,28 :ARG1-of (r / relevant-01~e.15 :polarity~e.15 -~e.15) :ARG0-of (a4 / act-01 :ARG1 (c / control-01~e.19))) :ARG1-of (i3 / indicate-01~e.27)) :ARG1 l)) # ::id pmid_1177_7939.295 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) −/− [ Eps8 myc ] cells were treated with 20 ng @/@ ml of PDGF (+) or mock treated (−) , and total cellular lysates were prepared . # ::alignments 1-1.3.1.1 3-1.1.1.2.1.2.1 8-1.1.1.2 10-1.1.1 11-1.1.1.1.r 12-1.1.1.1.2.1 13-1.1.1.1.2.2 15-1.1.1.1.2.2 16-1.1.1.1.2.r 17-1.1.1.1.1.1 19-1.1 20-1.1.2.2 21-1.1.2 24-1 25-1.2.1.1.1 26-1.2.1.1 27-1.2.1 29-1.2 (a / and~e.24 :op1 (o / or~e.19 :op1 (t / treat-04~e.10 :ARG1~e.11 (p / protein :name (n / name :op1 "PDGF"~e.17) :quant~e.16 (c4 / concentration-quantity :quant 20~e.12 :unit (n3 / nanogram-per-milliliter~e.13,15)) :ARG1-of (d2 / describe-01 :ARG2 (s / string-entity :name (n4 / name :op1 +)))) :ARG2 (c / cell~e.8 :part (p3 / protein :name (n2 / name :op1 "Eps8myc") :ARG2-of (m3 / mutate-01 :mod "−/−"~e.3)))) :op2 (t3 / treat-04~e.21 :ARG1 c :manner (m / mock-01~e.20) :ARG1-of (d / describe-01 :ARG2 (s2 / string-entity :name (n5 / name :op1 "−"))))) :op2 (p2 / prepare-01~e.29 :ARG1 (l / lysate~e.27 :mod (c2 / cellular~e.26 :mod (t2 / total~e.25)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "C"~e.1))) # ::id pmid_1177_7939.296 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immmunoprecipitations ( IP ) were performed with anti @-@ myc antibody or with an irrelevant ( ctr ) antibody , followed by immunoblot with the antibody indicated on the right ( WB ) . # ::alignments 5-1 7-1.1.1.1.1 9-1.1.1.1.1.1.1.1 10-1.1.1.1 10-1.1.1.2 11-1.1.1 14-1.1.1.2.1 14-1.1.1.2.1.1 14-1.1.1.2.1.1.r 18-1.1.1.2 20-1.2 21-1.2.1.r 22-1.2.1 23-1.2.1.1.r 25-1.2.1.1 26-1.2.1.1.1 27-1.2.1.1.1.1.r 29-1.2.1.1.1.1 (p / perform-02~e.5 :ARG1 (i / immunoprecipitate-01 :ARG3 (o / or~e.11 :op1 (a / antibody~e.10 :ARG0-of (c3 / counter-01~e.7 :ARG1 (p2 / protein :name (n / name :op1 "myc"~e.9)))) :op2 (a2 / antibody~e.10,18 :ARG2-of (r2 / relevant-01~e.14 :polarity~e.14 -~e.14)))) :ARG2-of (f / follow-01~e.20 :ARG1~e.21 (i3 / immunoblot-01~e.22 :ARG3~e.23 (a3 / antibody~e.25 :ARG1-of (i4 / indicate-01~e.26 :ARG1-of~e.27 (r / right-04~e.29)))))) # ::id pmid_1177_7939.297 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The indicated lanes ( lysates ) were loaded with 100 μg of total cellular lysates . # ::alignments 1-1.1.1 2-1.1 4-1.1.2.1 4-1.2 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2.1.1.2 12-1.2.1 13-1.2.2 14-1.1.2.1 14-1.2 (l / load-01~e.7 :ARG1 (l2 / lane~e.2 :ARG1-of (i / indicate-01~e.1) :ARG1-of (d / describe-01 :ARG2 (l3 / lysate~e.4,14))) :ARG2~e.8 (l4 / lysate~e.4,14 :ARG1-of (t / total-01~e.12 :ARG2 (m / mass-quantity :quant 100~e.9 :unit (m2 / microgram~e.10))) :mod (c / cell~e.13))) # ::id pmid_1177_7939.298 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D ) Fibroblasts were treated with PDGF for the indicated lengths of time . # ::alignments 1-1.1 3-1.2 5-1 6-1.3.r 7-1.3.1.1 8-1.4.r 10-1.4.1 13-1.4 (t / treat-04~e.5 :li "D"~e.1 :ARG1 (f / fibroblast~e.3) :ARG2~e.6 (p / protein :name (n / name :op1 "PDGF"~e.7)) :duration~e.8 (t2 / temporal-quantity~e.13 :ARG1-of (i / indicate-01~e.10))) # ::id pmid_1177_7939.299 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of Ras @-@ GTP and Rac @-@ GTP in total cellular lysates were determined by affinity precipitation using GST @-@ RBD and GST @-@ CRIB , as described in Materials and methods . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.2.1.1 5-1.1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1.1 9-1.1.1.2.2 10-1.1.2.r 11-1.1.2.1 12-1.1.2.2 13-1.1.2 15-1 16-1.2.r 17-1.2.1 18-1.2 19-1.2.2 20-1.2.2.1.1.1.1 20-1.2.2.1.2.1.1 22-1.2.2.1.1.1.1 23-1.2.2.1 24-1.2.2.1.1.1.1 24-1.2.2.1.2.1.1 26-1.2.2.1.2.1.1 28-1.3.r 29-1.3 30-1.3.1.r 31-1.3.1.1 32-1.3.1 33-1.3.1.2 (d / determine-01~e.15 :ARG1 (l / level~e.1 :quant-of~e.2 (a / and~e.6 :op1 (m3 / macro-molecular-complex :part (s2 / small-molecule :name (n3 / name :op1 "GTP"~e.5)) :part (e / enzyme :name (n / name :op1 "Ras"~e.3))) :op2 (m4 / macro-molecular-complex :part (e2 / enzyme :name (n4 / name :op1 "Rac"~e.7)) :part s2~e.9)) :location~e.10 (l3 / lysate~e.13 :quant (t / total~e.11) :source (c / cell~e.12))) :ARG2~e.16 (p / precipitate-01~e.18 :mod (a2 / affinity~e.17) :manner (u / use-01~e.19 :ARG1 (a5 / and~e.23 :op1 (p2 / protein :name (n2 / name :op1 "GST-RBD"~e.20,22,24)) :op2 (p3 / protein :name (n5 / name :op1 "GST-CRIB"~e.20,24,26))))) :ARG1-of~e.28 (d2 / describe-01~e.29 :location~e.30 (a4 / and~e.32 :op1 (m / material~e.31) :op2 (m2 / method~e.33)))) # ::id pmid_1177_7939.300 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Elevated levels of Rac @-@ GTP could be observed ≤ 30 min of RTK stimulation ( not shown ) . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2.1.1 5-1.1.1.1.1.1.1 6-1 8-1.1 10-1.1.2.2.1 11-1.1.2.2.2 13-1.1.2.1.1.1.1 14-1.1.2.1 16-1.2.1 16-1.2.1.r 17-1.2 (p / possible-01~e.6 :ARG1 (o / observe-01~e.8 :ARG1 (l / level~e.1 :degree-of~e.2 (m / macro-molecular-complex :part (s / small-molecule :name (n / name :op1 "GTP"~e.5)) :part (e / enzyme :name (n2 / name :op1 "Rac"~e.3))) :ARG1-of (e2 / elevate-01~e.0)) :time (b2 / before :op1 (s2 / stimulate-01~e.14 :ARG0 (e3 / enzyme :name (n3 / name :op1 "RTK"~e.13))) :duration (t / temporal-quantity :quant 30~e.10 :unit (m2 / minute~e.11)))) :ARG1-of (s3 / show-01~e.17 :polarity~e.16 -~e.16)) # ::id pmid_1177_7939.301 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression levels of Ras ( total Ras ) and Rac ( total Rac ) , in the same lysates , were determined by immunoblotting with anti @-@ Ras and anti @-@ Rac antibodies , respectively . # ::alignments 1-1.1 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1.1.1.2.1 7-1.1.1.1.1.1.1 9-1.1.1.1 10-1.1.1.1.2.1.1 12-1.1.1.1.2.2.1 13-1.1.1.1.2.1.1 16-1.1.2.r 18-1.1.2.1 19-1.1.2 22-1 23-1.2.r 24-1.2 25-1.2.3.r 26-1.2.3.1.1 28-1.2.3.1.1.1 29-1.2.3 30-1.2.3.1.1 30-1.2.3.2.1 32-1.1.1.1.2.1.1 33-1.2.3.1 33-1.2.3.2 (d / determine-01~e.22 :ARG1 (e2 / express-03~e.1 :ARG1 (l / level~e.2 :degree-of~e.3 (a / and~e.9 :op1 (e3 / enzyme :name (n2 / name :op1 "Ras"~e.4,7) :ARG1-of (d2 / describe-01 :ARG2 (t / total-01~e.6 :ARG1 e3))) :op2 (e4 / enzyme :name (n3 / name :op1 "Rac"~e.10,13,32) :ARG1-of (d3 / describe-01 :ARG2 (t2 / total-01~e.12 :ARG1 e4))))) :location~e.16 (l2 / lysate~e.19 :ARG1-of (s / same-01~e.18))) :manner~e.23 (i / immunoblot-01~e.24 :ARG1 e3 :ARG2 l2 :ARG3~e.25 (a2 / and~e.29 :op1 (a3 / antibody~e.33 :ARG0-of (c / counter-01~e.26,30 :ARG1 e3~e.28)) :op2 (a4 / antibody~e.33 :ARG0-of (c2 / counter-01~e.30 :ARG1 e4))))) # ::id pmid_1177_7939.302 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The kinetic of the mobility shift of Sos @-@ 1 , after PDGF stimulation , was determined by immunoblotting with anti @–@ Sos @-@ 1 antibodies . # ::alignments 4-1.1.1.1 5-1.1.1 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1 9-1.1.1.1.1.1.1 11-1.3 12-1.3.1.1.1.1 13-1.3.1 16-1 17-1.2.r 18-1.2 19-1.2.2.r 20-1.2.2.1 22-1.2.2.1.1 23-1.2.2.1.1 24-1.2.2.1.1 25-1.2.2 (d / determine-01~e.16 :ARG1 (k / kinetics :poss (s / shift-01~e.5 :mod (m / mobility~e.4 :poss~e.6 (p / protein :name (n / name :op1 "Sos-1"~e.7,9))))) :ARG2~e.17 (i / immunoblot-01~e.18 :ARG1 p :ARG3~e.19 (a2 / antibody~e.25 :ARG0-of (c / counter-01~e.20 :ARG1 p~e.22,23,24))) :time (a / after~e.11 :op1 (s2 / stimulate-01~e.13 :ARG0 (p2 / protein :name (n2 / name :op1 "PDGF"~e.12))))) # ::id pmid_1563_0473.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A Signaling Pathway Involving TGF-β2 and Snail in Hair Follicle Morphogenesis ( PMID : 15630473 ) # ::alignments 1-1.1.1 2-1.1 3-1 4-1.2.1.1.1 5-1.2 6-1.2.2.1.1 7-1.3.r 8-1.3.1.1 9-1.3.1 10-1.3 (i / involve-01~e.3 :ARG0 (p / pathway~e.2 :ARG0-of (s / signal-07~e.1)) :ARG1 (a / and~e.5 :op1 (p3 / protein :name (n / name :op1 "TGF-β2"~e.4)) :op2 (p4 / protein :name (n2 / name :op1 "Snail"~e.6))) :ARG2~e.7 (m / morphogenesis~e.10 :mod (f / follicle~e.9 :mod (h / hair~e.8))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID15630473"))) # ::id pmid_1563_0473.2 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a common theme of organogenesis , certain cells within a multipotent epithelial sheet exchange signals with their neighbors and develop into a bud structure . # ::alignments 2-1.3.1 3-1.3 7-1.1.1.2 8-1.1.1 8-1.1.3 11-1.1.1.1.1 12-1.1.1.1.2 13-1.1.1.1 14-1.1 15-1.1.2 15-1.1.2.1 15-1.1.2.1.r 16-1.1.3.1.r 17-1.1.3.1.1 17-1.1.3.1.1.r 18-1.1.3.1 19-1 20-1.2 21-1.2.1.r 23-1.2.1.1 24-1.2.1 (a / and~e.19 :op1 (e / exchange-01~e.14 :ARG0 (c / cell~e.8 :location (s / sheet~e.13 :mod (m / multipotent~e.11) :mod (e2 / epithelium~e.12)) :mod (c2 / certain~e.7)) :ARG1 (t2 / thing~e.15 :ARG1-of~e.15 (s2 / signal-07~e.15)) :ARG2 (c4 / cell~e.8 :ARG1-of~e.16 (n / neighbor-01~e.18 :ARG2~e.17 c~e.17))) :op2 (d / develop-02~e.20 :ARG1~e.21 (s3 / structure~e.24 :mod (b / bud~e.23)) :ARG2 c) :subevent-of (t / theme~e.3 :mod (c3 / common~e.2) :purpose (g / genesis :mod (o / organ)))) # ::id pmid_1563_0473.3 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using hair bud morphogenesis as a paradigm , we employed mutant mouse models and cultured keratinocytes to dissect the contributions of multiple extracellular cues in orchestrating adhesion dynamics and proliferation to shape the cluster of cells involved . # ::alignments 0-1.3.r 0-1.4 1-1.4.1.1.1 2-1.4.1.1 3-1.4.1 4-1.4.2.r 6-1.4.2 8-1.1 9-1 10-1.2.1.2 11-1.2.1.1 12-1.2.1 13-1.2 14-1.2.2.2 15-1.2.2.1.1 17-1.3 19-1.3.2 20-1.3.2.1.r 21-1.3.2.1.2 22-1.3.2.1.1 23-1.3.2.1 24-1.3.2.2.r 25-1.3.2.2 26-1.3.2.2.1.1.1 27-1.3.2.2.1.1 28-1.3.2.2.1 29-1.3.2.2.1.2 31-1.3.2.2.2 33-1.3.2.2.2.2 34-1.3.2.2.2.2.1.r 35-1.3.2.2.2.2.1 36-1.3.2.2.2.2.2 (e / employ-02~e.9 :ARG0 (w / we~e.8) :ARG1 (a / and~e.13 :op1 (m / model~e.12 :topic (m2 / mouse~e.11) :ARG1-of (m3 / mutate-01~e.10)) :op2 (c / cell :name (n / name :op1 "keratinocyte"~e.15) :ARG1-of (c2 / culture-01~e.14))) :purpose~e.0 (d / dissect-01~e.17 :ARG0 w :ARG1 (c3 / contribute-01~e.19 :ARG0~e.20 (c6 / cue~e.23 :location (e3 / extracellular~e.22) :quant (m4 / multiple~e.21)) :ARG2~e.24 (o / orchestrate-01~e.25 :ARG1 (a2 / and~e.28 :op1 (d2 / dynamic~e.27 :mod (a3 / adhere-01~e.26)) :op2 (p / proliferate-01~e.29)) :purpose (s / shape-01~e.31 :ARG0 c6 :ARG1 (c4 / cluster~e.33 :consist-of~e.34 (c5 / cell~e.35) :ARG1-of (i / involve-01~e.36)))))) :manner (u / use-01~e.0 :ARG1 (m5 / morphogenesis~e.3 :mod (b / bud~e.2 :mod (h / hair~e.1))) :ARG2~e.4 (p2 / paradigm~e.6))) # ::id pmid_1563_0473.4 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that transforming growth factor β2 signaling is necessary to transiently induce the transcription factor Snail and activate the Ras @-@ mitogen @-@ activated protein kinase ( MAPK ) pathway in the bud . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 4-1.2.1.1.1.2 5-1.2.1.1.1.3 6-1.2.1.1.1.4 7-1.2.1 9-1.2 10-1.2.2.r 11-1.2.2.1.2 12-1.2.2.1 14-1.2.2.1.1.2.1 15-1.2.2.1.1.2 16-1.2.2.1.1.1.1 17-1.2.2 18-1.2.2.2 20-1.2.2.2.1.1.1 22-1.2.2.2.1.1.1 24-1.2.2.2.1.1.1 25-1.2.2.2.1.1.2 26-1.2.2.2.1.1.3 30-1.2.2.2.1 31-1.2.2.2.2.r 33-1.2.2.2.2 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (n2 / need-01~e.9 :ARG1 (s2 / signal-07~e.7 :ARG0 (p2 / protein :name (n / name :op1 "transforming"~e.3 :op2 "growth"~e.4 :op3 "factor"~e.5 :op4 "β2"~e.6))) :purpose~e.10 (a / and~e.17 :op1 (i / induce-01~e.12 :ARG2 (p3 / protein :name (n4 / name :op1 "Snail"~e.16) :mod (f2 / factor~e.15 :ARG0-of (t2 / transcribe-01~e.14))) :ARG1-of (t / transient-02~e.11)) :op2 (a2 / activate-01~e.18 :ARG1 (p / pathway~e.30 :name (n3 / name :op1 "Ras-mitogen-activated"~e.20,22,24 :op2 "protein"~e.25 :op3 "kinase"~e.26)) :location~e.31 (b / bud~e.33))))) # ::id pmid_1563_0473.5 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the epidermis , Snail misexpression leads to hyperproliferation and a reduction in intercellular adhesion . # ::alignments 2-1.3 5-1.1.1.1.1 8-1 9-1.2.r 10-1.2.1 10-1.2.1.1 10-1.2.1.1.r 11-1.2 13-1.2.2 16-1.2.2.1 (l / lead-03~e.8 :ARG0 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.5)) :ARG1-of (w / wrong-04)) :ARG2~e.9 (a / and~e.11 :op1 (p / proliferate-01~e.10 :degree~e.10 (h / hyper~e.10)) :op2 (r / reduce-01~e.13 :ARG1 (a2 / adhere-01~e.16 :ARG1 (c / cell) :ARG2 (c2 / cell)))) :location (e3 / epidermis~e.2)) # ::id pmid_1563_0473.6 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When E @-@ cadherin is transcriptionally down @-@ regulated , associated adhesion proteins with dual functions in signaling are released from cell @-@ cell contacts , a process which we demonstrate leads to Ras @-@ MAPK activation . # ::alignments 0-1.3.r 2-1.3.1.1.1 4-1.3.1.1.1 7-1.3.2 12-1.1.2 13-1.1.1 14-1.1 15-1.1.3.r 16-1.1.3.2 17-1.1.3 18-1.1.3.1.r 19-1.1.3.1 21-1 22-1.2.r 23-1.2.1 25-1.2.1 25-1.2.2 26-1.2 31-1.4.2.1 32-1.4.2 33-1.4 34-1.4.1.r 35-1.4.1.1.1.1 37-1.4.1.1.1.1 38-1.4.1 (r / release-01~e.21 :ARG1 (p / proteins~e.14 :ARG0-of (a / adhere-01~e.13) :ARG1-of (a2 / associate-01~e.12) :ARG0-of~e.15 (f / function-01~e.17 :ARG1~e.18 (s / signal-07~e.19) :mod (d / dual~e.16))) :ARG2~e.22 (c / contact-01~e.26 :ARG0 (c2 / cell~e.23,25) :ARG1 (c3 / cell~e.25)) :time~e.0 (d2 / downregulate-01 :ARG1 (g / gene :name (n / name :op1 "E-cadherin"~e.2,4)) :manner (t / transcribe-01~e.7)) :ARG0-of (l / lead-03~e.33 :ARG1~e.34 (a3 / activate-01~e.38 :ARG1 (p3 / pathway :name (n2 / name :op1 "Ras-MAPK"~e.35,37))) :ARG1-of (d3 / demonstrate-01~e.32 :ARG0 (w / we~e.31)))) # ::id pmid_1563_0473.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These studies provide insights into how multipotent cells within a sheet are stimulated to undergo transcriptional changes that result in proliferation , junctional remodeling , and bud formation . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2 4-1.2.1.r 5-1.2.1.1.r 6-1.2.1.1.1.1 7-1.2.1.1.1 10-1.2.1.1.1.2 12-1.2.1.1 14-1.2.1.1.2 15-1.2.1.1.2.2.1 16-1.2.1.1.2.2 18-1.2.1.1.2.2.2 19-1.2.1.1.2.2.2.1.r 20-1.2.1.1.2.2.2.1.1 23-1.2.1.1.2.2.2.1.2 25-1.2.1.1.2.2.2.1 26-1.2.1.1.2.2.2.1.3.1 27-1.2.1.1.2.2.2.1.3 (p / provide-01~e.2 :ARG0 (s / study~e.1 :mod (t / this~e.0)) :ARG1 (i / insight~e.3 :topic~e.4 (t3 / thing :manner-of~e.5 (s2 / stimulate-01~e.12 :ARG1 (c / cell~e.7 :mod (m2 / multipotent~e.6) :location (s3 / sheet~e.10)) :purpose (u / undergo-28~e.14 :ARG1 c :ARG2 (c2 / change-01~e.16 :ARG1 (t2 / transcribe-01~e.15) :ARG1-of (r / result-01~e.18 :ARG2~e.19 (a / and~e.25 :op1 (p2 / proliferate-01~e.20 :ARG0 c) :op2 (r2 / remodel-01~e.23 :ARG1 c :mod (j / junction)) :op3 (f / form-01~e.27 :ARG1 (b / bud~e.26)))))))))) # ::id pmid_1563_0473.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This novel signaling pathway further weaves together the web of different morphogens and downstream transcriptional events that guide hair bud formation within the developing skin . # ::alignments 0-1.1.3 1-1.1.2 2-1.1.1 3-1.1 4-1.3 5-1 8-1.2 9-1.2.1.r 10-1.2.1.1 10-1.2.1.1.2 10-1.2.1.1.2.r 12-1.2.1 13-1.2.1.2.2 14-1.2.1.2.1 15-1.2.1.2 17-1.2.1.3 18-1.2.1.3.1.1.1 19-1.2.1.3.1.1 20-1.2.1.3.1 23-1.2.1.3.1.2.1 24-1.2.1.3.1.2 (w / weave-01~e.5 :ARG0 (p / pathway~e.3 :ARG0-of (s / signal-07~e.2) :mod (n / novel~e.1) :mod (t / this~e.0)) :ARG1 (w2 / web~e.8 :consist-of~e.9 (a / and~e.12 :op1 (s2 / small-molecule~e.10 :name (n2 / name :op1 "morphogen") :ARG1-of~e.10 (d / differ-02~e.10)) :op2 (e / event~e.15 :mod (t2 / transcribe-01~e.14) :location (d2 / downstream~e.13)) :ARG0-of (g / guide-01~e.17 :ARG1 (f2 / form-01~e.20 :ARG1 (b / bud~e.19 :mod (h / hair~e.18)) :location (s3 / skin~e.24 :ARG1-of (d3 / develop-02~e.23)))))) :degree (f / further~e.4)) # ::id pmid_1563_0473.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The study of hair follicle morphogenesis provides insights into how cells within a sheet can be triggered to proliferate , remodel , and form buds - a recurring theme in development # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1 6-1 7-1.2 8-1.2.1.r 9-1.2.1.1.r 10-1.2.1.1.1.1 13-1.2.1.1.1.1.1 14-1.2.1.1 16-1.2.1.1.1 17-1.2.1.1.1.2.r 18-1.2.1.1.1.2.1 20-1.2.1.1.1.2.2 22-1.2.1.1.1.2 23-1.2.1.1.1.2.3 24-1.2.1.1.1.2.3.2 27-1.2.1.1.1.2.4.1.1 28-1.2.1.1.1.2.4.1 29-1.2.1.1.1.2.4.1.2.r 30-1.2.1.1.1.2.4.1.2 (p / provide-01~e.6 :ARG0 (s / study-01~e.1 :ARG1~e.2 (m / morphogenesis~e.5 :mod (f / follicle~e.4 :mod (h / hair~e.3)))) :ARG1 (i / insight~e.7 :topic~e.8 (t / thing :manner-of~e.9 (p2 / possible-01~e.14 :ARG1 (t4 / trigger-01~e.16 :ARG1 (c / cell~e.10 :location (s2 / sheet~e.13)) :purpose~e.17 (a / and~e.22 :op1 (p3 / proliferate-01~e.18 :ARG0 t4) :op2 (r / remodel-01~e.20 :ARG1 t4) :op3 (f2 / form-01~e.23 :ARG0 t4 :ARG1 (b / bud~e.24)) :ARG1-of (m2 / mean-01 :ARG2 (t3 / theme~e.28 :ARG0-of (r2 / recur-01~e.27) :subevent-of~e.29 (d / develop-02~e.30))))))))) # ::id pmid_1563_0473.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Introduction # ::alignments 0-1 (i / introduce-01~e.0) # ::id pmid_1563_0473.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mammalian development involves the morphogenesis of complex three @-@ dimensional structures from seemingly uniform sheets or masses of cells . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1.2.1 9-1.2.1.2 10-1.2.1 11-1.2.2.r 12-1.2.2.3.1 13-1.2.2.3 14-1.2.2.1 15-1.2.2 16-1.2.2.2 18-1.2.2.4 (i / involve-01~e.2 :ARG0 (d / develop-02~e.1 :ARG1 (m / mammal~e.0)) :ARG1 (m2 / morphogenesis~e.4 :mod~e.5 (s / structure~e.10 :mod (c / complex~e.6) :mod (d2 / dimension~e.9 :quant 3~e.7)) :source~e.11 (o / or~e.15 :op1 (s2 / sheet~e.14) :op2 (m3 / mass~e.16) :ARG1-of (u / uniform-02~e.13 :ARG1-of (s3 / seem-01~e.12)) :consist-of (c2 / cell~e.18)))) # ::id pmid_1563_0473.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A simple bud @-@ like structure initiates the formation of many organs , including lungs , spinal cord , mammary glands , and hair follicles [ @ 1 @ ] . # ::alignments 1-1.1.2 2-1.1.1.1 4-1.1.1 5-1.1 6-1 8-1.2 9-1.2.1.r 10-1.2.1.1 11-1.2.1 13-1.2.1.2 14-1.2.1.2.1.1 17-1.2.1.2.1.2 20-1.2.1.2.1.3 22-1.2.1.2.1 23-1.2.1.2.1.4.1 24-1.2.1.2.1.4 27-1.3.1.1.1 (i / initiate-01~e.6 :ARG0 (s / structure~e.5 :ARG1-of (r / resemble-01~e.4 :ARG2 (b / bud~e.2)) :ARG1-of (s2 / simple-02~e.1)) :ARG1 (f / form-01~e.8 :ARG1~e.9 (o / organ~e.11 :quant (m / many~e.10) :ARG2-of (i2 / include-01~e.13 :ARG1 (a / and~e.22 :op1 (l / lung~e.14) :op2 (c / cord~e.17 :mod (s3 / spine)) :op3 (g / gland~e.20 :source (b2 / breast)) :op4 (f2 / follicle~e.24 :mod (h / hair~e.23)))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG1-of (c2 / cite-01 :ARG2 1~e.27)))) # ::id pmid_1563_0473.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The multipotent , adhering epithelial cells are typically attached to an underlying basal lamina that polarizes the epithelial sheet and separates it from surrounding mesenchyme . # ::alignments 1-1.1.2 3-1.1.3 4-1.1.1 5-1.1 7-1.3 8-1 12-1.2.2 13-1.2 15-1.2.3 17-1.2.3.1.1 18-1.2.3.1 20-1.2.4 22-1.2.4.2.r 23-1.2.4.2.1 24-1.2.4.2 (a / attach-01~e.8 :ARG1 (c / cell~e.5 :part-of (e / epithelium~e.4) :mod (m / multipotent~e.1) :ARG1-of (a2 / adhere-01~e.3)) :ARG2 (l / lamina~e.13 :ARG0-of (u / underlay-01 :ARG1 c) :mod (b / basal~e.12) :ARG0-of (p / polarize-01~e.15 :ARG1 (s / sheet~e.18 :mod e~e.17)) :ARG0-of (s2 / separate-01~e.20 :ARG1 s :ARG2~e.22 (m2 / mesenchyme~e.24 :ARG1-of (s3 / surround-01~e.23 :ARG2 s)))) :ARG1-of (t / typical-02~e.7)) # ::id pmid_1563_0473.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Budding morphogenesis is guided by a reciprocal exchange of signals between epithelium and mesenchyme to specify the identity of the organ that will form and to govern its growth . # ::alignments 0-1.2.1 1-1.2 3-1 4-1.1.r 6-1.1.4 7-1.1 8-1.1.2.r 9-1.1.2 9-1.1.2.1 9-1.1.2.1.r 11-1.1.1 13-1.1.3 14-1.3.r 15-1.3.1 17-1.3.1.1 18-1.3.1.1.1.r 20-1.3.1.1.1 23-1.3.1.1.1.1 24-1.3 26-1.3.2 27-1.3.2.1.1 27-1.3.2.1.1.r 28-1.3.2.1 (g / guide-01~e.3 :ARG0~e.4 (e / exchange-01~e.7 :ARG0 (e2 / epithelium~e.11) :ARG1~e.8 (t / thing~e.9 :ARG0-of~e.9 (s / signal-07~e.9)) :ARG2 (m2 / mesenchyme~e.13) :mod (r / reciprocal~e.6)) :ARG1 (m / morphogenesis~e.1 :ARG1-of (b / bud-01~e.0)) :purpose~e.14 (a / and~e.24 :op1 (s2 / specify-01~e.15 :ARG1 (i / identity~e.17 :mod~e.18 (o / organ~e.20 :ARG1-of (f / form-01~e.23)))) :op2 (g2 / govern-01~e.26 :ARG1 (g3 / grow-01~e.28 :ARG1~e.27 o~e.27)))) # ::id pmid_1563_0473.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the helm of these molecular communication pathways are Wnts , bone morphogenic proteins ( BMPs ) , transforming growth factor βs ( TGF-βs ) , and fibroblast growth factors ( FGFs ) . # ::alignments 0-1 2-1.2 4-1.2.1.1.1 5-1.2.1.1.2.1 6-1.2.1.1.2 7-1.2.1.1 8-1 11-1.1.2.1.1 12-1.1.2.1.2 13-1.1.2.1.3 18-1.1.3.1.1 19-1.1.3.1.2 19-1.1.4.1.2 20-1.1.3.1.3 20-1.1.4.1.3 26-1.1 27-1.1.4.1.1 28-1.1.3.1.2 28-1.1.4.1.2 29-1.1.3.1.3 29-1.1.4.1.3 (b / be-located-at-91~e.0,8 :ARG1 (a / and~e.26 :op1 (p / pathway :name (n2 / name :op1 "Wnt")) :op2 (p2 / protein :name (n / name :op1 "bone"~e.11 :op2 "morphogenic"~e.12 :op3 "protein"~e.13)) :op3 (p4 / protein :name (n3 / name :op1 "transforming"~e.18 :op2 "growth"~e.19,28 :op3 "factor"~e.20,29 :op4 "β")) :op4 (p5 / protein :name (n4 / name :op1 "fibroblast"~e.27 :op2 "growth"~e.19,28 :op3 "factor"~e.20,29))) :ARG2 (h / helm~e.2 :location (r / relative-position :op1 (p3 / pathway~e.7 :mod (t / this~e.4) :path-of (c / communication~e.6 :mod (m / molecule~e.5)))))) # ::id pmid_1563_0473.16 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Through activation of cell surface transmembrane receptors , these external signaling molecules trigger distinct cascades of intracellular events that culminate in changes in gene expression , growth , and differentiation [ @ 2 @ ] . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.2.1 4-1.3.1.2 5-1.3.1.1 6-1.3.1 8-1.1.1 9-1.1.2 10-1.1.3 11-1.1 12-1 13-1.2.2 14-1.2 15-1.2.1.r 16-1.2.1.1 17-1.2.1 19-1.2.3 20-1.2.3.1.r 21-1.2.3.1 22-1.2.3.1.1.r 23-1.2.3.1.1.1.1 24-1.2.3.1.1.1 26-1.2.3.1.1.2 28-1.2.3.1.1 29-1.2.3.1.1.3 32-1.4.1.1.1 (t / trigger-01~e.12 :ARG0 (m / molecule~e.11 :mod (t2 / this~e.8) :mod (e / external~e.9) :ARG0-of (s / signal-07~e.10)) :ARG1 (c / cascade~e.14 :consist-of~e.15 (e2 / event~e.17 :location (c2 / cell~e.16)) :mod (d / distinct~e.13) :ARG1-of (c3 / culminate-01~e.19 :ARG2~e.20 (c4 / change-01~e.21 :ARG1~e.22 (a / and~e.28 :op1 (e3 / express-03~e.24 :ARG1 (g / gene~e.23)) :op2 (g2 / grow-01~e.26 :ARG1 c2) :op3 (d2 / differentiate-01~e.29 :ARG1 c2))))) :ARG2 (a2 / activate-01~e.1 :ARG1~e.2 (r / receptor~e.6 :mod (t3 / transmembrane~e.5) :location (s2 / surface~e.4 :poss (c5 / cell~e.3)))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c6 / cite-01 :ARG2 2~e.32)))) # ::id pmid_1563_0473.17 ::amr-annotator SDL-AMR-09 ::preferred # ::tok How this constellation of signals collaborates in tailoring each budding process so that it executes a distinct morphogenetic program has yet to be comprehensively defined . # ::alignments 0-1.2.1.1.r 0-1.2.2.r 1-1.2.1.1.1.2 2-1.2.1.1.1 3-1.2.1.1.1.1.r 4-1.2.1.1.1.1 4-1.2.1.1.1.1.1 4-1.2.1.1.1.1.1.r 5-1.2.1.1 6-1.2.1.1.2.r 7-1.2.1.1.2 8-1.2.1.1.2.1.2 9-1.2.1.1.2.1.1 10-1.2.1.1.2.1 11-1.2.1.1.3.r 12-1.2.1.1.3.r 13-1.2.1.1.3.1 14-1.2.1.1.3 16-1.2.1.1.3.2.2 18-1.2.1.1.3.2 19-1 20-1.1 23-1.2.2 24-1.2 (h / have-11~e.19 :ARG1 (y / yet~e.20) :ARG2 (d / define-01~e.24 :ARG1 (t / thing :manner-of~e.0 (c2 / collaborate-01~e.5 :ARG0 (c3 / constellation~e.2 :consist-of~e.3 (t3 / thing~e.4 :ARG1-of~e.4 (s / signal-07~e.4)) :mod (t4 / this~e.1)) :ARG2~e.6 (t2 / tailor-01~e.7 :ARG1 (p / process-02~e.10 :ARG1 (b / bud-01~e.9) :mod (e / each~e.8))) :purpose~e.11,12 (e2 / execute-02~e.14 :ARG0 p~e.13 :ARG1 (p2 / program~e.18 :topic (m / morphogenesis) :mod (d2 / distinct~e.16))))) :manner~e.0 (c / comprehensive~e.23))) # ::id pmid_1563_0473.18 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the process appears to be patterned at the initial stages of bud formation , since the relative importance of these pathways and their downstream effectors differ as buds begin to develop and cell fates are specified . # ::alignments 0-1 3-1.1.1 4-1.1 5-1.1.2 7-1.1.1.1 10-1.1.1.1.1.1 11-1.1.1.1.1 12-1.1.1.1.1.2.r 13-1.1.1.1.1.2.1 14-1.1.1.1.1.2 16-1.1.2 18-1.1.2.1.1.1 19-1.1.2.1.1 20-1.1.2.1.1.2.r 21-1.1.2.1.1.2.1 22-1.1.2.1.1.2 23-1.1.2.1.3 24-1.1.2.1.2.2 24-1.1.2.1.2.2.r 25-1.1.2.1.2.1 26-1.1.2.1.2 27-1.1.2.1 28-1.1.1.1.1.r 28-1.1.2.1.3.r 29-1.1.2.1.3.1.1 30-1.1.2.1.3.1 32-1.1.2.1.3.1.2 33-1.1.2.1.3 34-1.1.2.1.3.2.1.1 35-1.1.2.1.3.2.1 37-1.1.2.1.3.2 (c / contrast-01~e.0 :ARG2 (a / appear-02~e.4 :ARG1 (p / process-02~e.3 :ARG1-of (p2 / pattern-01~e.7 :time~e.28 (s / stage~e.11 :mod (i / initial~e.10) :subevent-of~e.12 (f / form-01~e.14 :ARG1 (b / bud~e.13))))) :ARG1-of (c2 / cause-01~e.5,16 :ARG0 (d / differ-02~e.27 :ARG1 (i2 / important~e.19 :ARG2-of (r / relative-05~e.18) :domain~e.20 (p3 / pathway~e.22 :mod (t / this~e.21))) :ARG2 (e / effector~e.26 :location (d2 / downstream~e.25) :poss~e.24 p3~e.24) :condition~e.28 (a3 / and~e.23,33 :op1 (b2 / begin-01~e.30 :ARG0 b~e.29 :ARG1 (d3 / develop-01~e.32 :ARG2 b)) :op2 (s2 / specify-01~e.37 :ARG1 (f2 / fate-01~e.35 :ARG1 (c3 / cell~e.34)))))))) # ::id pmid_1563_0473.19 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The development of a bud requires a number of coordinated changes in the behavior of the targeted cells within an epithelial sheet . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1 5-1 7-1.2.2 9-1.2.3 10-1.2 11-1.2.1.r 13-1.2.1 14-1.2.1.1.r 16-1.2.1.1.1 17-1.2.1.1 18-1.2.2.r 20-1.2.1.1.2.1 21-1.2.1.1.2 (r / require-01~e.5 :ARG0 (d / develop-02~e.1 :ARG1~e.2 (b / bud~e.4)) :ARG1 (c / change-01~e.10 :ARG1~e.11 (b2 / behave-01~e.13 :ARG0~e.14 (c3 / cell~e.17 :ARG1-of (t / target-01~e.16) :location (s / sheet~e.21 :mod (e / epithelium~e.20)))) :quant~e.18 (n / number~e.7) :ARG1-of (c2 / coordinate-01~e.9))) # ::id pmid_1563_0473.20 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The process must be accompanied by alterations in the proliferation , polarity , shape , and adhesiveness of selected cells , as well as by modifications in their underlying basal lamina . # ::alignments 1-1.1.2 2-1 4-1.1 5-1.1.1.r 6-1.1.1.1 7-1.1.1.1.1.r 9-1.1.1.1.1.1 11-1.1.1.1.1.2 13-1.1.1.1.1.3 15-1.1.1.1.1 17-1.1.1.1.1.1.1.r 18-1.1.1.1.1.1.1.1 19-1.1.1.1.1.1.1 21-1.1.1 22-1.1.1 23-1.1.1 25-1.1.1.2 30-1.1.1.2.1 (o / obligate-01~e.2 :ARG2 (a / accompany-01~e.4 :ARG0~e.5 (a5 / and~e.21,22,23 :op1 (a2 / alter-01~e.6 :ARG1~e.7 (a3 / and~e.15 :op1 (p2 / proliferate-01~e.9 :ARG0~e.17 (c / cell~e.19 :ARG1-of (s2 / select-01~e.18))) :op2 (p3 / polarity~e.11 :poss c) :op3 (s / shape~e.13 :poss c) :op4 (c2 / capable-01 :ARG1 c :ARG2 (a4 / adhere-01)))) :op2 (m / modify-01~e.25 :ARG1 (l / lamina~e.30 :ARG0-of (u / underlay-01 :ARG1 c) :mod (b / base)))) :ARG1 (p / process-02~e.1))) # ::id pmid_1563_0473.21 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , extracellular epithelial @-@ mesenchymal crosstalk must be intricately orchestrated to couple the determination of distinct cell fates with the contemporaneous remodeling of the physical and structural properties of the cell . # ::alignments 2-1.1.1.1.1 3-1.1.1.1.2.1 5-1.1.1.1.2.2 6-1.1.1.1 7-1 7-1.1 7-1.1.r 9-1.1.1.2 9-1.1.1.2.r 10-1.1.1 12-1.1.1.3 14-1.1.1.3.1 15-1.1.1.3.1.1.r 16-1.1.1.3.1.1.2 17-1.1.1.3.1.1.1 18-1.1.1.3.1.1 19-1.1.1.3.2.r 21-1.1.1.3.2.2 22-1.1.1.3.2 23-1.1.1.3.2.1.r 25-1.1.1.3.2.1.1.1 26-1.1.1.3.2.1 27-1.1.1.3.2.1.2.1 28-1.1.1.3.2.1.1 28-1.1.1.3.2.1.2 31-1.1.1.3.1.1.1 (i / infer-01~e.7 :ARG1~e.7 (o / obligate-01~e.7 :ARG2 (o2 / orchestrate-01~e.10 :ARG1 (c / crosstalk~e.6 :mod (e / extracellular~e.2) :location (b / between :op1 (e2 / epithelium~e.3) :op2 (m / mesenchyme~e.5))) :manner~e.9 (i2 / intricate~e.9) :purpose (c2 / couple-01~e.12 :ARG1 (d / determine-01~e.14 :ARG1~e.15 (f / fate-01~e.18 :ARG1 (c3 / cell~e.17,31) :mod (d2 / distinct~e.16))) :ARG2~e.19 (r / remodel-01~e.22 :ARG1~e.23 (a / and~e.26 :op1 (p / property~e.28 :mod (p2 / physical~e.25) :poss c3) :op2 (p3 / property~e.28 :mod (s / structure~e.27) :poss c3)) :mod (c4 / contemporaneous~e.21)))))) # ::id pmid_1563_0473.22 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the few dispensable organs , hair follicles offer an excellent model system to study epithelial bud formation . # ::alignments 0-1.1.2 2-1.1.2.1.1 4-1.1.2.1 6-1.1.1 7-1.1 8-1 10-1.2.2 11-1.2.1 12-1.2 14-1.2.2.1 15-1.2.2.1.1.2 16-1.2.2.1.1.1 17-1.2.2.1.1 (o / offer-01~e.8 :ARG0 (f / follicle~e.7 :mod (h / hair~e.6) :ARG1-of (i / include-91~e.0 :ARG2 (o2 / organ~e.4 :quant (f3 / few~e.2) :ARG1-of (d / dispense-01 :ARG1-of (p / possible-01))))) :ARG1 (s / system~e.12 :mod (m / model~e.11) :ARG1-of (e / excellent-02~e.10 :ARG2 (s2 / study-01~e.14 :ARG1 (f2 / form-01~e.17 :ARG1 (b / bud~e.16) :location (e2 / epithelium~e.15)))))) # ::id pmid_1563_0473.23 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mammalian skin epithelium begins as a single sheet of multipotent ectodermal cells . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.r 6-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.1 10-1.2.1.2 11-1.2.1 (b / begin-01~e.3 :ARG1 (e / epithelium~e.2 :part-of (s / skin~e.1 :part-of (m / mammal~e.0))) :ARG2~e.4 (s2 / sheet~e.7 :consist-of~e.8 (c / cell~e.11 :mod (m2 / multipotent~e.9) :part-of (e2 / ectoderm~e.10)) :ARG1-of (s3 / single-02~e.6))) # ::id pmid_1563_0473.24 ::amr-annotator SDL-AMR-09 ::preferred # ::tok During development , specialized mesenchymal cells populate the skin in a spatially defined pattern to initiate the complex epithelial @-@ mesenchymal crosstalk that will specify the bud [ @ 3 @ ] . # ::alignments 0-1.6.r 1-1.6 3-1.2.2 4-1.2.1 5-1.2 6-1 8-1.1 9-1.3.r 11-1.3.1.1 12-1.3.1 13-1.3 15-1.4 17-1.4.2.1 18-1.4.2.2.1 20-1.4.2.2.2 21-1.4.2 24-1.4.2.3 26-1.4.2.3.1 29-1.5.1.1.1 (p / populate-01~e.6 :ARG1 (s2 / skin~e.8) :ARG2 (c / cell~e.5 :part-of (m / mesenchyme~e.4) :ARG0-of (s / specialize-01~e.3)) :manner~e.9 (p2 / pattern~e.13 :ARG1-of (d / define-01~e.12 :mod (s3 / space~e.11))) :purpose (i / initiate-01~e.15 :ARG0 c :ARG1 (c2 / crosstalk~e.21 :mod (c3 / complex~e.17) :location (b / between :op1 (e / epithelium~e.18) :op2 m~e.20) :ARG0-of (s4 / specify-01~e.24 :ARG1 (b2 / bud-01~e.26)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 3~e.29))) :time~e.0 (d3 / develop-02~e.1)) # ::id pmid_1563_0473.25 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Once committed , a small cluster of epithelial cells , the placode , instructs a group of underlying mesenchymal cells to condense and form the nascent dermal papilla , which will be a permanent fixture of the hair follicle . # ::alignments 1-1.4.1 4-1.1.2 5-1.1 6-1.1.1.r 7-1.1.1.1 8-1.1.1 11-1.1.3.1 13-1 15-1.2 18-1.2.1.1 19-1.2.1 20-1.3.r 21-1.3.1 22-1.3 23-1.3.2 26-1.3.2.2.1 27-1.3.2.2 33-1.3.2.2.3.2 37-1.3.2.2.3.1.1 38-1.3.2.2.3.1 (i / instruct-01~e.13 :ARG0 (c / cluster-01~e.5 :ARG1~e.6 (c2 / cell~e.8 :part-of (e / epithelium~e.7)) :mod (s / small~e.4) :ARG1-of (m2 / mean-01 :ARG2 (p3 / placode~e.11))) :ARG1 (g / group~e.15 :consist-of (c3 / cell~e.19 :part-of (m / mesenchyme~e.18) :ARG0-of (u / underlay-01))) :ARG2~e.20 (a / and~e.22 :op1 (c4 / condense-01~e.21 :ARG1 c3) :op2 (f / form-01~e.23 :ARG0 c3 :ARG1 (p / papilla~e.27 :part-of (d / dermis~e.26) :ARG1-of (b / bear-02) :ARG0-of (f2 / fix-03 :ARG1 (f3 / follicle~e.38 :mod (h / hair~e.37)) :manner (p2 / permanent~e.33))))) :time (a2 / after :op1 (c5 / commit-01~e.1 :ARG1 c))) # ::id pmid_1563_0473.26 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Subsequent exchanges between the placode and nascent dermal papilla result in further growth of the follicle into the underlying dermis , or down @-@ growth , and eventual differentiation into the six concentric layers of the mature follicle . # ::alignments 0-1.1.3 0-1.1.3.r 1-1.1 4-1.1.1 5-1.2 7-1.1.2.2 8-1.1.2 9-1 10-1.2.r 11-1.2.1.1.2 12-1.2.1.1 13-1.2.1.1.1.r 15-1.2.1.1.1 19-1.2.1.1.3 21-1.2.1 22-1.2.1.2.2 24-1.2.1.2 26-1.2 27-1.2.2.3 28-1.2.2 29-1.2.2.2.r 31-1.2.2.2.1 32-1.2.2.2.2 33-1.2.2.2 34-1.2.2.2.3.r 36-1.2.2.2.3.1 37-1.2.2.2.3 (r / result-01~e.9 :ARG1 (e / exchange-01~e.1 :ARG0 (p / placode~e.4) :ARG2 (p2 / papilla~e.8 :ARG1-of (b / bear-02) :part-of d~e.7) :time~e.0 (s / subsequent~e.0)) :ARG2~e.10 (a / and~e.5,26 :op1 (o / or~e.21 :op1 (g / grow-01~e.12 :ARG1~e.13 (f2 / follicle~e.15) :ARG2 (f / further~e.11) :direction (d / dermis~e.19 :ARG0-of (u5 / underlay-01))) :op2 (g2 / grow-01~e.24 :ARG1 f2 :ARG1-of (d2 / down-03~e.22))) :op2 (d3 / differentiate-01~e.28 :ARG1 f2 :direction~e.29 (l / layer~e.33 :quant 6~e.31 :mod (c / concentric~e.32) :part-of~e.34 (f3 / follicle~e.37 :ARG1-of (m / mature-02~e.36))) :time (e2 / eventual~e.27)))) # ::id pmid_1563_0473.27 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previously , we delineated how two respective epithelial and mesenchymal signals , Wnts and the BMP @-@ inhibitory factor noggin , function in concert to induce lymphoid enhancer factor @-@ 1/β-catenin ( LEF @-@ 1/β-catenin ) - mediated gene transcription within the follicle placode [ @ 4 @ ] . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.1.2.r 4-1.2.1.r 5-1.2.1.3.1 6-1.2.1.3.1 7-1.2.1.3.1 8-1.2.1.3.1 9-1.2.1.3.1 10-1.2.1.3.1 11-1.2.1.3.1 12-1.2.1.3.1 13-1.2.1.3.1 14-1.2.1.3.1 15-1.2.1.3.1 16-1.2.1.3.1 17-1.2.1.3.1 18-1.2.1.3.2.2.1.1.3 19-1.2.1.1.3.1.2.1.1 21-1.2.1 22-1.2.1.2 23-1.2.1.2 25-1.2.1.3 26-1.2.1.3.2.2.1.1.1 27-1.2.1.3.2.2.1.1.2 28-1.2.1.3.2.2.1.1.3 37-1.2.1.3.2.2 38-1.2.1.3.2.1 39-1.2.1.3.2 40-1.2.1.1.1.r 42-1.2.1.3.2.3.1 43-1.2.1.3.2.3 46-1.4.1.1.1 (d / delineate-01~e.3 :ARG0 (w / we~e.2) :ARG1 (t / thing :manner-of~e.4 (f / function-01~e.21 :ARG0 (t3 / thing :quant~e.40 2 :ARG1-of (s / signal-07) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (p5 / pathway :name (n2 / name :op1 "Wnt") :source (e / epithelium)) :op2 (p / protein :name (n3 / name :op1 "noggin"~e.19) :ARG0-of (i2 / inhibit-01 :ARG1 (p6 / protein :name (n4 / name :op1 "BMP"))) :source (m3 / mesenchyme))) :manner (r / respective))) :manner~e.4 (i3 / in-concert~e.22,23) :purpose (i / induce-01~e.25 :ARG0 t3~e.5,6,7,8,9,10,11,12,13,14,15,16,17 :ARG2 (t2 / transcribe-01~e.39 :ARG1 (g / gene~e.38) :ARG1-of (m2 / mediate-01~e.37 :ARG0 (p7 / pathway :name (n5 / name :op1 "lymphoid"~e.26 :op2 "enhancer"~e.27 :op3 "factor-1/β-catenin"~e.18,28))) :location (p2 / placode~e.43 :part-of (f2 / follicle~e.42)))))) :time (p3 / previous~e.0) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 4~e.46)))) # ::id pmid_1563_0473.28 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The downstream changes elicited through convergence of these two early signaling pathways include down @-@ regulation of the gene encoding E @-@ cadherin , the prototypical epithelial cadherin that forms the transmembrane core of intercellular adherens junctions ( AJs ) [ @ 5 @ ] . # ::alignments 1-1.2.1 2-1.2 3-1.2.2 5-1.2.2.1 6-1.2.2.1.1.r 7-1.2.2.1.1.2 8-1.2.2.1.1.1 9-1.2.2.1.1.3 10-1.2.2.1.1.4 11-1.2.2.1.1 12-1 13-1.1 14-1.1 15-1.1 16-1.1.1.r 18-1.1.1 19-1.1.1.1 20-1.1.1.1.1.1.1 22-1.1.1.1.1.2.1.1.1 26-1.1.1.1.1.2.1.2 27-1.1.1.1.1.2.1.1.1 29-1.1.1.1.1.2.1 29-1.1.1.1.1.2.1.4 29-1.1.1.1.1.2.1.4.r 31-1.1.1.1.1.2.1.4.1.1 32-1.1.1.1.1.2.1.4.1 33-1.1.1.1.1.2.1.4.1.2.r 34-1.1.1.1.1.2.1.4.1.2.2 35-1.1.1.1.1.2.1.4.1.2.1.1 36-1.1.1.1.1.2.1.4.1.2.1.2 42-1.3.1.1.1 (i / include-01~e.12 :ARG1 (d / downregulate-01~e.13,14,15 :ARG1~e.16 (g / gene~e.18 :ARG0-of (e3 / encode-01~e.19 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin"~e.20) :ARG1-of (m / mean-01 :ARG2 (p4 / protein~e.29 :name (n2 / name :op1 "cadherin"~e.22,27) :location (e4 / epithelium~e.26) :mod (p3 / prototype) :ARG0-of~e.29 (f / form-01~e.29 :ARG1 (c3 / core~e.32 :mod (t2 / transmembrane~e.31) :part-of~e.33 (m3 / macro-molecular-complex :name (n4 / name :op1 "adherens"~e.35 :op2 "junction"~e.36) :location (i2 / intercellular~e.34)))))))))) :ARG2 (c / change-01~e.2 :location (d2 / downstream~e.1) :ARG1-of (e / elicit-01~e.3 :ARG0 (c2 / converge-01~e.5 :ARG0~e.6 (p / pathway~e.11 :quant 2~e.8 :mod (t / this~e.7) :time (e2 / early~e.9) :ARG0-of (s / signal-07~e.10))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 5~e.42)))) # ::id pmid_1563_0473.29 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We subsequently showed that when E @-@ cadherin is transgenically elevated in mouse skin , hair follicle morphogenesis is blocked , suggesting that E @-@ cadherin down @-@ regulation is a critical event in governing the adhesion dynamics necessary for budding morphogenesis [ @ 4 @ ] . # ::alignments 0-1.1 1-1.3 1-1.3.r 2-1 4-1.3.r 5-1.2.3.1 6-1.2.3.1 7-1.2.3.1 10-1.2.3 11-1.2.3.3.r 12-1.2.3.3.1 13-1.2.3.3 15-1.2.1.1.1 16-1.2.1.1 17-1.2.1 19-1.2 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1.1.1.1 25-1.2.2.1.1.1.1.1 26-1.2.2.1.1 27-1.2.2.1.1 28-1.2.2.1.1 31-1.2.2.1 33-1.2.2.1.2.r 34-1.2.2.1.2 36-1.2.2.1.2.1.1 37-1.2.2.1.2.1 38-1.2.2.1.2.1.2 39-1.2.2.1.2.1.2.1.r 40-1.2.2.1.2.1.2.1.1 41-1.2.2.1.2.1.2.1 44-1.4.1.1.1 (s / show-01~e.2 :ARG0 (w / we~e.0) :ARG1 (b / block-01~e.19 :ARG1 (m / morphogenesis~e.17 :mod (f / follicle~e.16 :mod (h / hair~e.15))) :ARG0-of (s2 / suggest-01~e.21 :ARG1~e.22 (c / critical-02~e.31 :ARG1 (d / downregulate-01~e.26,27,28 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin"~e.23,25))) :ARG2~e.33 (g / govern-01~e.34 :ARG1 (d2 / dynamic~e.37 :ARG0-of (a / adhere-01~e.36) :ARG1-of (n3 / need-01~e.38 :purpose~e.39 (m2 / morphogenesis~e.41 :ARG1-of (b2 / bud-01~e.40))))))) :time (e2 / elevate-01~e.10 :ARG1 p~e.5,6,7 :manner (t / transgene) :location~e.11 (s4 / skin~e.13 :part-of (m3 / mouse~e.12)))) :time~e.1,4 (s3 / subsequent~e.1) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 4~e.44)))) # ::id pmid_1563_0473.30 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like LEF @-@ 1 , E @-@ cadherin also binds to β-catenin . # ::alignments 0-1.2 0-1.2.2 0-1.2.2.r 1-1.2.2.1.1.1 3-1.2.2.1.1.1 5-1.1.1.1 7-1.1.1.1 8-1.3 9-1 11-1.2.1.1 (b / bind-01~e.9 :ARG1 (p3 / protein :name (n / name :op1 "E-cadherin"~e.5,7)) :ARG2 (p / protein~e.0 :name (n2 / name :op1 "β-catenin"~e.11) :ARG1-of~e.0 (r / resemble-01~e.0 :ARG2 (p2 / protein :name (n3 / name :op1 "LEF-1"~e.1,3)))) :mod (a / also~e.8)) # ::id pmid_1563_0473.31 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At sites of cell @-@ cell contact , however , E @-@ cadherin-β-catenin complexes recruit α-catenin , which in turn coordinates the associated actin polymerization dynamics necessary to stabilize nascent AJs and integrate the cytoskeleton across an epithelial sheet [ @ 6 , 7 , 8 @ ] . # ::alignments 1-1.1.3 2-1.1.3.1.r 3-1.1.3.1.1.1 5-1.1.3.1.1.1 5-1.1.3.1.1.2 6-1.1.3.1 8-1 10-1.1.1.1.1.1 13-1.1.1 14-1.1 15-1.1.2.1.1 18-1.1.4.2 19-1.1.4.2 20-1.1.4 22-1.1.4.1 23-1.1.4.1.1.1.1 24-1.1.4.1.1 24-1.1.4.1.1.2 24-1.1.4.1.1.2.r 25-1.1.4.1.1.3 26-1.1.4.1.2 27-1.1.4.1.2.1.r 28-1.1.4.1.2.1.1 29-1.1.4.1.2.1.1.1.2 31-1.1.4.1.2.1 32-1.1.4.1.2.1.2 34-1.1.4.1.2.1.2.1 35-1.1.4.1.2.1.2.2 37-1.1.4.1.2.1.2.2.1.1 38-1.1.4.1.2.1.2.2.1 41-1.2.1.1.1.1 45-1.2.1.1.1.2 49-1.2.1.1.1.3 (h / have-concession-91~e.8 :ARG2 (r / recruit-01~e.14 :ARG0 (m2 / macro-molecular-complex~e.13 :part (p7 / protein :name (n / name :op1 "E-cadherin"~e.10)) :part (p8 / protein :name (n9 / name :op1 "β-catenin"))) :ARG1 (p / protein :name (n3 / name :op1 "α-catenin"~e.15)) :location (s / site~e.1 :location-of~e.2 (c3 / contact-01~e.6 :ARG1 (a5 / and :op1 (c5 / cell~e.3,5) :op2 (c6 / cell~e.5)))) :ARG0-of (c / coordinate-01~e.20 :ARG1 (a / associate-01~e.22 :ARG1 (p3 / protein~e.24 :name (n4 / name :op1 "actin"~e.23) :ARG1-of~e.24 (p2 / polymerize-01~e.24) :mod (d / dynamic~e.25)) :ARG1-of (n5 / need-01~e.26 :ARG0~e.27 (a2 / and~e.31 :op1 (s2 / stabilize-01~e.28 :ARG1 (p4 / protein :name (n6 / name :op1 "AJ") :mod (n7 / nascent~e.29))) :op2 (i2 / integrate-01~e.32 :ARG1 (c4 / cytoskeleton~e.34) :ARG2 (a3 / across~e.35 :op1 (s3 / sheet~e.38 :consist-of (e / epithelium~e.37))))))) :mod (i / in-turn~e.18,19))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 6~e.41 :op2 7~e.45 :op3 8~e.49))))) # ::id pmid_1563_0473.32 ::amr-annotator SDL-AMR-09 ::preferred # ::tok α-Catenin also binds to the class III Lin @-@ 1 , Isl @-@ 1 , Mec @-@ 3 ( LIM ) protein Ajuba ( a member of the zyxin family of proteins ) , which appears to function dually in both adhesion and in activation of the Ras @-@ mitogen @-@ activated protein kinase ( MAPK ) pathway [ @ 9 , 10 @ ] . # ::alignments 0-1.1.1.1 1-1.4 2-1 3-1.3.r 5-1.3.5 6-1.3.3.1.1 6-1.3.5.1.1 7-1.3.1.1.1 9-1.3.1.1.1 9-1.3.2.1.1 11-1.3.2.1.1 13-1.3.1.1.1 13-1.3.2.1.1 15-1.3.3.1.1 17-1.3.3.1.1 17-1.3.5.1.1 19-1.3.4.1.1 21-1.1 21-1.2 22-1.2.1.1 25-1.2.2.1 28-1.2.2.1.1.1.1.1 29-1.2.2.1.1.1 31-1.2 31-1.2.2.1.1.1 35-1.2.3.2 37-1.2.3 41-1.2.3.1.1 42-1.2.3.1 43-1.2.3.1.r 44-1.2.3.1.2 45-1.2.3.1.2.1.r 47-1.2.3.1.2.1.1.1 49-1.2.3.1.2.1.1.1 51-1.2.3.1.2.1.1.1 52-1.2.3.1.2.1.1.2 53-1.2.3.1.2.1.1.3 57-1.2.3.1.2.1 60-1.5.1.1.1.1 64-1.5.1.1.1.2 (b / bind-01~e.2 :ARG0 (p2 / protein~e.21 :name (n2 / name :op1 "α-Catenin"~e.0)) :ARG1 (p5 / protein~e.21,31 :name (n5 / name :op1 "Ajuba"~e.22) :ARG1-of (m3 / mean-01 :ARG2 (m / member~e.25 :ARG1-of (i / include-91 :ARG2 (p8 / protein-family~e.29,31 :name (n7 / name :op1 "zyxin"~e.28))))) :ARG0-of (f2 / function-01~e.37 :ARG1~e.43 (a4 / and~e.42 :op1 (a5 / adhere-01~e.41) :op2 (a6 / activate-01~e.44 :ARG1~e.45 (p / pathway~e.57 :name (n / name :op1 "Ras-mitogen-activated"~e.47,49,51 :op2 "protein"~e.52 :op3 "kinase"~e.53)))) :ARG1-of (a2 / appear-02~e.35) :manner (d / dual))) :ARG2~e.3 (a / and :op1 (p3 / protein :name (n3 / name :op1 "Lin-1"~e.7,9,13)) :op2 (p4 / protein :name (n4 / name :op1 "Isl-1"~e.9,11,13)) :op3 (p6 / protein :name (n6 / name :op1 "Mec-3"~e.6,15,17)) :ARG1-of (m2 / mean-01 :ARG2 (n10 / name :op1 "LIM"~e.19)) :part-of (c2 / class~e.5 :ord (o / ordinal-entity :value 3~e.6,17))) :mod (a3 / also~e.1) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication :ARG1-of (c / cite-01 :ARG2 (a9 / and :op1 9~e.60 :op2 10~e.64))))) # ::id pmid_1563_0473.33 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Through these links , AJs appear able to couple adhesion with cytoskeletal dynamics as well as with nuclear and cytoplasmic signaling . # ::alignments 1-1.1.1 2-1.1 5-1.2.1.4 6-1.2 8-1.2.1 9-1.2.1.2 12-1.2.1.3.1 13-1.2.1.3 14-1.2.1.3 15-1.2.1.3.2.1 17-1.2.1.3.2.1.1 18-1.2.1.3.2.1 19-1.2.1.3.2.1.2 20-1.2.1.3.2 (h / have-condition-91 :ARG1 (l / link-01~e.2 :mod (t / this~e.1)) :ARG2 (p2 / possible-01~e.6 :ARG1 (c / couple-01~e.8 :ARG0 (p3 / protein :name (n / name :op1 "AJ")) :ARG1 (a / adhere-01~e.9) :ARG2 (a2 / and~e.13,14 :op1 (d / dynamic~e.12 :mod (c3 / cytoskeleton)) :op2 (s / signal-07~e.20 :ARG0 (a3 / and~e.15,18 :op1 (n3 / nucleus~e.17) :op2 (c2 / cytoplasm~e.19)))) :ARG1-of (a4 / appear-02~e.5)))) # ::id pmid_1563_0473.34 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This provides a framework for conceptualizing why E @-@ cadherin levels appear to impact upon a plethora of developmental processes ( reviewed in [ @ 11 @ ]) . # ::alignments 0-1.1 1-1 3-1.2 4-1.3.r 5-1.3 6-1.3.1 6-1.3.1.1 6-1.3.1.1.r 7-1.3.1.1.1.1.1.1.1 9-1.3.1.1.1.1.1.1.1 10-1.3.1.1.1.1 11-1.3.1.1.1 13-1.3.1.1.1.1.2 16-1.3.1.1.1.1.2.1.2 17-1.3.1.1.1.1.2.1.2.r 18-1.3.1.1.1.1.2.1.1 19-1.3.1.1.1.1.2.1 21-1.4 25-1.4.1.1.1 (p / provide-01~e.1 :ARG0 (t / this~e.0) :ARG1 (f / framework~e.3) :ARG2~e.4 (c / conceptualize-00~e.5 :ARG1 (t2 / thing~e.6 :ARG0-of~e.6 (c3 / cause-01~e.6 :ARG1 (a / appear-02~e.11 :ARG1 (l / level~e.10 :quant-of (p5 / protein :name (n / name :op1 "E-cadherin"~e.7,9)) :ARG0-of (i / impact-01~e.13 :ARG1 (p2 / process-02~e.19 :ARG1 (g2 / growth~e.18) :quant~e.17 (p3 / plethora~e.16)))))))) :ARG1-of (r / review-02~e.21 :ARG2 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 11~e.25)))) # ::id pmid_1563_0473.35 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As we probed more deeply into the underlying mechanisms governing E @-@ cadherin promoter activity , we were intrigued by the close proximity of the LEF @-@ 1/β-catenin binding site to a site known to bind the Snail @/@ Slug family of zinc finger transcriptional repressor proteins [ @ 12 , 13 , 14 , 15 @ ] . # ::alignments 1-1.1.1 2-1.1 3-1.1.3.1 4-1.1.3 5-1.1.2.r 7-1.1.2.1 8-1.1.2 9-1.1.2.2 11-1.1.2.2.1.1.1.1.1.1 13-1.1.2.2.1.1.1.1.1.1 15-1.1.2.2.1.1 15-1.1.2.2.1.1.1 15-1.1.2.2.1.1.1.r 16-1.1.2.2.1 18-1.2.2 20-1.2 21-1.2.1.r 23-1.2.1 25-1.2.1.1.r 27-1.2.1.1.1.1.1.1 30-1.2.1.1.1 31-1.2.1.1 31-1.2.1.2 34-1.2.1.1 35-1.2.1.2.1.2 37-1.2.1.2.1 39-1.2.1.2.1.1.2.1.1.1 40-1.2.1.2.1.1.2 41-1.2.1.2.1.1.2.2.1.1 42-1.2.1.2.1.1.2.1 42-1.2.1.2.1.1.2.2 44-1.2.1.2.1.1.1.1.1.1.1 45-1.2.1.2.1.1.1.1.1.1.2 46-1.2.1.2.1.1.1.1 47-1.2.1.2.1.1 47-1.2.1.2.1.1.1 47-1.2.1.2.1.1.1.r 48-1.2.1.2.1.1 51-1.3.1.1.1.1 55-1.3.1.1.1.2 59-1.3.1.1.1.3 63-1.3.1.1.1.4 (c3 / cause-01 :ARG0 (p2 / probe-01~e.2 :ARG0 w2~e.1 :ARG1~e.5 (m / mechanism~e.8 :ARG0-of (u / underlie-01~e.7) :ARG0-of (g / govern-01~e.9 :ARG1 (a / activity-06~e.16 :ARG0 (m3 / molecular-physical-entity~e.15 :ARG0-of~e.15 (p3 / promote-01~e.15 :ARG1 (g2 / gene :name (n / name :op1 "E-cadherin"~e.11,13))))))) :ARG1-of (d / deep-02~e.4 :degree (m2 / more~e.3))) :ARG1 (i2 / intrigue-01~e.20 :ARG0~e.21 (c / close-10~e.23 :ARG1~e.25 (s / site~e.31,34 :location-of (b / bind-01~e.30 :ARG1 (p4 / protein :name (n2 / name :op1 "LEF-1"~e.27)) :ARG2 (p5 / protein :name (n3 / name :op1 "β-catenin")))) :ARG2 (s2 / site~e.31 :location-of (b2 / bind-01~e.37 :ARG1 (p6 / protein~e.47,48 :ARG0-of~e.47 (r2 / repress-01~e.47 :ARG1 (t / transcribe-01~e.46 :ARG1 (p8 / protein :name (n6 / name :op1 "zinc"~e.44 :op2 "finger"~e.45)))) :part-of (s3 / slash~e.40 :op1 (p9 / protein-family~e.42 :name (n4 / name :op1 "Snail"~e.39)) :op2 (p10 / protein-family~e.42 :name (n5 / name :op1 "Slug"~e.41)))) :ARG1-of (k / know-01~e.35)))) :ARG1 (w2 / we~e.18)) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 12~e.51 :op2 13~e.55 :op3 14~e.59 :op4 15~e.63))))) # ::id pmid_1563_0473.36 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both activity of Snail and down @-@ regulation of E @-@ cadherin play pivotal roles in epithelial to mesenchymal transitions ( EMTs ) , typified by the transformation of polarized , adhering epithelial cells into motile mesenchymal cells [ @ 16 , 17 @ ] . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1 5-1.1.2 6-1.1.2 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.1 11-1.1.2.1.1.1 12-1 13-1.2.1 14-1.2 15-1.2.2.r 16-1.2.2.1 18-1.2.2.2 19-1.2.2 24-1.2.2.3 25-1.2.2.3.1.r 27-1.2.2.3.1 28-1.2.2.3.1.1.r 29-1.2.2.3.1.1.2 31-1.2.2.3.1.1.3 32-1.2.2.3.1.1.1 33-1.2.2.3.1.1 34-1.2.2.3.1.2.r 35-1.2.2.3.1.2.1 36-1.2.2.3.1.2.2 37-1.2.2.3.1.2 40-1.3.1.1.1.1 44-1.3.1.1.1.2 (p / play-02~e.12 :ARG0 (a / and~e.4 :op1 (a2 / activity-06~e.1 :ARG0~e.2 (p6 / protein :name (n / name :op1 "Snail"~e.3))) :op2 (d / downregulate-01~e.5,6,7 :ARG1~e.8 (p5 / protein :name (n2 / name :op1 "E-cadherin"~e.9,11)))) :ARG1 (r / role~e.14 :mod (p2 / pivotal~e.13) :topic~e.15 (t / transition-01~e.19 :ARG1 (e / epithelium~e.16) :ARG2 (m / mesenchyme~e.18) :ARG1-of (t2 / typify-01~e.24 :ARG0~e.25 (t3 / transform-01~e.27 :ARG1~e.28 (c / cell~e.33 :mod (e2 / epithelium~e.32) :ARG1-of (p3 / polarize-01~e.29) :ARG1-of (a4 / adhere-01~e.31)) :ARG2~e.34 (c4 / cell~e.37 :mod (m3 / motile~e.35) :part-of m~e.36))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 (a5 / and :op1 16~e.40 :op2 17~e.44))))) # ::id pmid_1563_0473.37 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Bud formation differs from an EMT in that E @-@ cadherin activity needs to be down @-@ regulated but not prevented , so that adhesive junctions are remodeled rather than quantitatively impaired . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2 8-1.3.1.1.1.1.1 10-1.3.1.1.1.1.1 11-1.3.1.1 12-1.3 18-1.3.1.2 19-1.3.1.2.1.1 19-1.3.1.2.1.1.r 20-1.3.1.2.1 22-1.3.1.3.r 23-1.3.1.3.r 24-1.3.1.3.1.1.1 25-1.3.1.3.1.1.2 27-1.3.1.3 28-1.3.1.3.2 30-1.3.1.3.2.1.2 30-1.3.1.3.2.1.2.r 31-1.3.1.3.2.1 (d / differ-02~e.2 :ARG1 (f / form-01~e.1 :ARG1 (b / bud~e.0)) :ARG2~e.3 (t / transition-01~e.5 :ARG2 (c3 / cell :mod (m / mesenchymal)) :ARG3 (c2 / cell :mod (e / epithelial))) :ARG3 (n2 / need-01~e.12 :ARG1 (d2 / downregulate-01 :ARG1 (a / activity-06~e.11 :ARG0 (p / protein :name (n / name :op1 "E-cadherin"~e.8,10))) :ARG1-of (c / contrast-01~e.18 :ARG2 (p2 / prevent-01~e.20 :polarity~e.19 -~e.19 :ARG1 a)) :purpose~e.22,23 (r / remodel-01~e.27 :ARG1 (p3 / protein :name (n3 / name :op1 "adhesive"~e.24 :op2 "junctions"~e.25)) :ARG1-of (i / instead-of-91~e.28 :ARG2 (i2 / impair-01~e.31 :ARG1 p3 :manner~e.30 (q / quantitative~e.30))))))) # ::id pmid_1563_0473.38 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Supportive of an underlying ability to fine @-@ tune cadherin expression at the transcriptional level , Snail seems to have an additive effect with LEF @-@ 1/β-catenin in negatively modulating E @-@ cadherin promoter activity [ @ 4 @ ] . # ::alignments 3-1.1.1.2 4-1.1.1 9-1.1.1.1.1.1.1.1 10-1.1.1.1.1 11-1.1.1.1.1.2.r 13-1.1.1.1.1.2.1 14-1.1.1.1.1.2 16-1.2.1.1.1.1.1 17-1.2 21-1.2.1.3 22-1.2.1 24-1.2.1.1.2.1.1.1 27-1.2.1.2.r 28-1.2.1.2.2 29-1.2.1.2 31-1.2.1.2.1.1.1.1.1.1 33-1.2.1.2.1.1.1.1.1.1 35-1.2.1.2.1.1 35-1.2.1.2.1.1.1 35-1.2.1.2.1.1.1.r 36-1.2.1.2.1 39-1.1.2.1.1.1 (c2 / cause-01 :ARG0 (s / support-01 :ARG1 (c3 / capable-01~e.4 :ARG2 (f / finetune-01 :ARG1 (e / express-03~e.10 :ARG2 (p7 / protein :name (n / name :op1 "cadherin"~e.9)) :ARG3~e.11 (l / level~e.14 :mod (t / transcribe-01~e.13)))) :ARG0-of (u / underlie-01~e.3)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication-91 :ARG0-of (c / cite-01 :ARG2 4~e.39)))) :ARG1 (s2 / seem-01~e.17 :ARG1 (a2 / affect-01~e.22 :ARG0 (a3 / and :op1 (p6 / protein :name (n2 / name :op1 "Snail"~e.16)) :op2 (a4 / and :op1 (p / protein :name (n3 / name :op1 "LEF-1"~e.24)) :op2 (p2 / protein :name (n4 / name :op1 "β-catenin")))) :ARG2~e.27 (m / modulate-01~e.29 :ARG1 (a / activity-06~e.36 :ARG0 (m2 / molecular-physical-entity~e.35 :ARG0-of~e.35 (p3 / promote-01~e.35 :ARG1 (g / gene :name (n5 / name :op1 "E-cadherin"~e.31,33))))) :ARG1-of (n6 / negative-02~e.28)) :mod (a5 / additive~e.21)))) # ::id pmid_1563_0473.39 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the present study , we discovered that Snail is expressed briefly at an early stage of hair bud formation , when E @-@ cadherin down @-@ regulation and activation of proliferation take place . # ::alignments 2-1.3.1 3-1.3 5-1.1 6-1 7-1.2.r 8-1.2.1.1.1 10-1.2 11-1.2.2 12-1.2.3.r 14-1.2.3 15-1.2.3.1 16-1.2.3.1.1.r 17-1.2.3.1.1.1.1 18-1.2.3.1.1.1 19-1.2.3.1.1 21-1.4.r 22-1.4.1.1.1.1 24-1.4.1.1.1.1 25-1.4.1 26-1.4.1 27-1.4.1 28-1.4 29-1.4.2 30-1.4.2.1.r 31-1.4.2.1 (d / discover-01~e.6 :ARG0 (w / we~e.5) :ARG1~e.7 (e / express-03~e.10 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.8)) :duration (b / brief~e.11) :time~e.12 (e2 / early~e.14 :op1 (s / stage~e.15 :part-of~e.16 (f / form-01~e.19 :ARG1 (b2 / bud~e.18 :mod (h2 / hair~e.17)))))) :medium (s2 / study-01~e.3 :time (p / present~e.2)) :time~e.21 (a / and~e.28 :op1 (d2 / downregulate-01~e.25,26,27 :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin"~e.22,24))) :op2 (a2 / activate-01~e.29 :ARG1~e.30 (p3 / proliferate-01~e.31)))) # ::id pmid_1563_0473.40 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thereafter , Snail disappears and remains absent during subsequent follicle down @-@ growth and maturation . # ::alignments 0-1.3 2-1.1.1.1.1 3-1.1 4-1 5-1.2 6-1.2.2 7-1.2.3.r 8-1.2.3.3 8-1.2.3.r 9-1.2.3.1.1 10-1.2.3.1.2 12-1.2.3.1 13-1.2.3 14-1.2.3.2 (a / and~e.4 :op1 (d / disappear-01~e.3 :ARG1 (p / protein :name (n / name :op1 "Snail"~e.2))) :op2 (r / remain-01~e.5 :ARG1 p :ARG3 (a2 / absent-01~e.6 :ARG1 p) :time~e.7,8 (a3 / and~e.13 :op1 (g2 / grow-01~e.12 :ARG1 (f / follicle~e.9) :ARG1-of (d2 / down-03~e.10)) :op2 (m / maturate-03~e.14 :ARG1 f) :mod (s / subsequent~e.8))) :time (t / thereafter~e.0)) # ::id pmid_1563_0473.41 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This exquisite pattern appears to be functionally relevant since altering it in vivo correspondingly affects features associated with hair bud formation , including down @-@ regulation of E @-@ cadherin , increased proliferation , and repressed terminal differentiation . # ::alignments 0-1.2.1.1.1 1-1.2.1.1.2 2-1.2.1.1 3-1.2 6-1.2.1.2 7-1.2.1 8-1 9-1.1 10-1.1.1 11-1.1.2 12-1.1.2 13-1.1.3 14-1.1.4 15-1.1.4.1 16-1.1.4.1.1 17-1.1.4.1.1.1.r 18-1.1.4.1.1.1.1.1 19-1.1.4.1.1.1.1 20-1.1.4.1.1.1 22-1.1.4.1.2 23-1.1.4.1.2.1.1 24-1.1.4.1.2.1.1 25-1.1.4.1.2.1.1 26-1.1.4.1.2.1.1.1.r 27-1.1.4.1.2.1.1.1.1.1 29-1.1.4.1.2.1.1.1.1.1 31-1.1.4.1.2.1.2.1 32-1.1.4.1.2.1.2 34-1.1.4.1.2.1 35-1.1.4.1.2.1.3.2 36-1.1.4.1.2.1.3.1 37-1.1.4.1.2.1.3 (c2 / cause-01~e.8 :ARG0 (a2 / alter-01~e.9 :ARG1 p~e.10 :manner (i / in-vivo~e.11,12) :ARG1-of (c / correspond-02~e.13) :ARG0-of (a3 / affect-01~e.14 :ARG1 (f2 / feature~e.15 :ARG1-of (a4 / associate-01~e.16 :ARG2~e.17 (f3 / form-01~e.20 :ARG1 (b / bud~e.19 :mod (h / hair~e.18)))) :ARG1-of (i2 / include-01~e.22 :ARG2 (a5 / and~e.34 :op1 (d / downregulate-01~e.23,24,25 :ARG1~e.26 (p2 / protein :name (n / name :op1 "E-cadherin"~e.27,29))) :op2 (p3 / proliferate-01~e.32 :ARG1-of (i3 / increase-01~e.31)) :op3 (d2 / differentiate-01~e.37 :ARG1 (t2 / terminus~e.36) :ARG1-of (r2 / repress-01~e.35))))))) :ARG1 (a / appear-02~e.3 :ARG1 (r / relevant-01~e.7 :ARG1 (p / pattern~e.2 :mod (t / this~e.0) :mod (e / exquisite~e.1)) :ARG2 (f / function-01~e.6)))) # ::id pmid_1563_0473.42 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the temporal spike of Snail in the hair bud is reflected at the mRNA level and seems to follow Wnt signaling and BMP inhibition , LEF @-@ 1/β-catenin activation does not appear to induce Snail gene expression in embryonic skin keratinocytes . # ::alignments 0-1.3.r 2-1.1.2.2 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1 6-1.1.2.3.r 8-1.1.2.3.1 9-1.1.2.3 11-1.1 12-1.1.1.r 14-1.1.1.1.1.1 15-1.1.1 16-1 17-1.2 19-1.2.1 20-1.2.1.2.1.1.1.1 21-1.2.1.2.1 22-1.2.1.2 23-1.2.1.2.2.1.1.1 24-1.2.1.2.2 26-1.3.2.1.1.1.1.1 29-1.3.2.1 31-1.3.1 31-1.3.1.r 32-1.3 34-1.3.2 36-1.3.2.2.1 37-1.3.2.2.1 38-1.3.2.2.1 39-1.3.2.2 40-1.3.2.3.r 41-1.3.2.3.2 42-1.3.2.3.3 43-1.3.2.3.1.1 (a / and~e.16 :op1 (r / reflect-01~e.11 :ARG1~e.12 (l / level~e.15 :mod (n8 / nucleic-acid :name (n7 / name :op1 "mRNA"~e.14))) :ARG2 (s / spike-04~e.3 :ARG1~e.4 (g / gene :name (n / name :op1 "Snail"~e.5)) :mod (t / time~e.2) :location~e.6 (b / bud~e.9 :mod (h / hair~e.8)))) :op2 (s2 / seem-01~e.17 :ARG1 (f / follow-01~e.19 :ARG1 s :ARG2 (a2 / and~e.22 :op1 (s3 / signal-07~e.21 :ARG0 (p / pathway :name (n2 / name :op1 "Wnt"~e.20))) :op2 (i / inhibit-01~e.24 :ARG1 (p2 / protein :name (n3 / name :op1 "BMP"~e.23)))))) :concession-of~e.0 (a5 / appear-02~e.32 :polarity~e.31 -~e.31 :ARG1 (i2 / induce-01~e.34 :ARG0 (a3 / activate-01~e.29 :ARG1 (a4 / and :op1 (p3 / protein :name (n4 / name :op1 "LEF-1"~e.26)) :op2 (p4 / protein :name (n5 / name :op1 "β-catenin")))) :ARG2 (e / express-03~e.39 :ARG1 g~e.36,37,38) :location~e.40 (c / cell :name (n6 / name :op1 "keratinocyte"~e.43) :mod (e2 / embryo~e.41) :part-of (s4 / skin~e.42))))) # ::id pmid_1563_0473.43 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , we provide in vitro , transgenic ( Tg ) , and gene targeting evidence to show that TGF-β2 and small phenotype– and mothers against decapentaplegic @–@ related protein 2 ( SMAD2 ) signaling are upstream inducers of Snail gene expression in skin epithelium . # ::alignments 0-1.3 1-1.4 3-1.1 4-1 5-1.3 6-1.3 8-1.2.1.1.1 10-1.2.1.1.1 10-1.2.1.1.1.1.1.1 13-1.2 14-1.2.2.1.1 15-1.2.1.1 15-1.2.2.1 16-1.2.1 16-1.2.2 18-1.5 19-1.5.2.r 20-1.5.2.1.1.1 21-1.5.2 22-1.5.2.2.2.1.1 24-1.5.2 25-1.5.2.3.1.1 26-1.5.2.3.1.2 27-1.5.2.3.1.3 30-1.5.2.2.1.1 31-1.5.2.2.1.2 35-1.5.2.4 37-1.5.2.4.1.2 41-1.5.2.4.1.1.1.1.1 43-1.5.2.4.1.1.1 44-1.5.2.4.1.1 45-1.3 46-1.5.2.4.1.3.1 47-1.5.2.4.1.3 (p / provide-01~e.4 :ARG0 (w / we~e.3) :ARG1 (a / and~e.13 :op1 (e / evidence~e.16 :ARG1-of (t / target-01~e.15 :mod (t2 / transgenic~e.8,10 :ARG1-of (m / mean-01 :ARG2 (n5 / name :op1 "Tg"~e.10))))) :op2 (e2 / evidence~e.16 :ARG1-of (t3 / target-01~e.15 :ARG0 (g / gene~e.14)))) :manner (i / in-vitro~e.0,5,6,45) :ARG2-of (c / contrast-01~e.1) :purpose (s / show-01~e.18 :ARG0 a :ARG1~e.19 (a2 / and~e.21,24 :op1 (p2 / protein :name (n / name :op1 "TGF-β2"~e.20)) :op2 (p5 / protein :name (n3 / name :op1 "protein"~e.30 :op2 2~e.31) :ARG1-of (r / relate-01 :ARG2 (p4 / phenotype :mod (s2 / small~e.22)))) :op3 (p6 / protein :name (n2 / name :op1 "mothers"~e.25 :op2 "against"~e.26 :op3 "decapentaplegic"~e.27 :op4 "protein" :op5 2)) :ARG0-of (s3 / signal-07~e.35 :ARG0-of (i2 / induce-01 :ARG2 (e3 / express-03~e.44 :ARG1 (g2 / gene~e.43 :name (n4 / name :op1 "Snail"~e.41))) :direction (u / upstream~e.37) :location (e4 / epithelium~e.47 :mod (s4 / skin~e.46))))))) # ::id pmid_1563_0473.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the absence of TGF-β2 signaling and Snail gene expression , hair placodes can form , but further follicle down @-@ growth is blocked . # ::alignments 2-1 3-1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1 8-1.1.2.1.1.1 10-1.1.2.1 11-1.1.2 13-1.2.1.1.1 15-1.2 16-1.2.1 18-1.2.2 19-1.2.2.1.1.3 20-1.2.2.1.1.1 21-1.2.2.1.1.2 23-1.2.2.1.1 25-1.2.2.1 (a / absent-01~e.2 :ARG1~e.3 (a2 / and~e.6 :op1 (s / signal-07~e.5 :ARG0 (p / protein :name (n / name :op1 "TGF-β2"~e.4))) :op2 (e / express-03~e.11 :ARG1 (g / gene~e.10 :name (n2 / name :op1 "Snail"~e.8)))) :condition-of (p2 / possible-01~e.15 :ARG1 (f / form-01~e.16 :ARG1 (p3 / placode :mod (h2 / hair~e.13))) :ARG1-of (c / contrast-01~e.18 :ARG2 (b / block-01~e.25 :ARG1 (g2 / grow-01~e.23 :ARG1 (f2 / follicle~e.20) :ARG1-of (d / down-03~e.21) :degree (f3 / further~e.19)))))) # ::id pmid_1563_0473.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our studies point to the view that Snail likely functions downstream of cell fate specification , at a stage where the bud begins to exhibit enhanced proliferation and migration . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1 5-1.2 6-1.2.1.r 7-1.2.1.1.1.1.1 8-1.2.1 9-1.2.1.1 10-1.2.1.1.2.2 12-1.2.1.1.2.1.1.1 13-1.2.1.1.2.1.1 14-1.2.1.1.2.1 16-1.3.r 18-1.3 19-1.2.1.1.2.r 21-1.3.1.1 22-1.3.1 24-1.3.1.2 25-1.3.1.2.2.3 26-1.3.1.2.2.1 27-1.3.1.2.2 28-1.3.1.2.2.2 (p / point-01~e.2 :ARG0 (s / study-01~e.1 :ARG0~e.0 (w / we~e.0)) :ARG1 (v / view-01~e.5 :ARG1~e.6 (l / likely-01~e.8 :ARG1 (f / function-01~e.9 :ARG0 (p3 / protein :name (n / name :op1 "Snail"~e.7)) :location~e.19 (r / relative-position :op1 (s2 / specify-01~e.14 :ARG1 (f2 / fate~e.13 :mod (c / cell~e.12))) :direction (d2 / downstream~e.10))))) :time~e.16 (s3 / stage~e.18 :time-of (b / begin-01~e.22 :ARG0 (b2 / bud~e.21) :ARG1 (e / exhibit-01~e.24 :ARG0 b2 :ARG1 (a / and~e.27 :op1 (p2 / proliferate-01~e.26) :op2 (m / migrate-01~e.28) :ARG1-of (e2 / enhance-01~e.25)))))) # ::id pmid_1563_0473.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 0-1 0-1.1 0-1.1.r (t / thing~e.0 :ARG2-of~e.0 (r2 / result-01~e.0)) # ::id pmid_1563_0473.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Snail mRNA and Protein Are Expressed Transiently at the Hair Bud Stage of Follicle Morphogenesis # ::alignments 1-1.1.1.2.1.1.1 1-1.1.2.1.1 3-1.1.1.1.1 4-1.1 5-1.1.2 7-1 8-1.2 9-1.3.r 11-1.3.2.1 12-1.3.2 13-1.3 14-1.3.1.r 15-1.3.1.1 16-1.3.1 (e / express-03~e.7 :ARG2 (a / and~e.4 :op1 (n3 / nucleic-acid :name (n / name :op1 "mRNA"~e.3) :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n4 / name :op1 "Snail"~e.1)))) :op2 (p / protein~e.5 :name (n2 / name :op1 "Snail"~e.1))) :ARG1-of (t / transient-02~e.8) :time~e.9 (s / stage~e.13 :subevent-of~e.14 (m / morphogenesis~e.16 :mod (f / follicle~e.15)) :mod (b / bud~e.12 :mod (h / hair~e.11)))) # ::id pmid_1563_0473.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although Snail family members are most frequently associated with EMTs , they also participate in many malignant processes involving a down @-@ regulation but not a quantitative abrogation of intercellular junctions [ @ 18 @ ] . # ::alignments 0-1.3.r 1-1.1.1.1.1.1 2-1.1.1.1 3-1.1 5-1.3.3.1 6-1.3.3 7-1.3 11-1.3.1 12-1.5 13-1 14-1.2.r 15-1.2.2 16-1.2.1 17-1.2 18-1.2.3 18-1.2.3.1.2.1 20-1.2.3.1 21-1.2.3.1 22-1.2.3.1 23-1.2.3.1.2 24-1.2.3.1.2.1.1 24-1.2.3.1.2.1.1.r 26-1.2.3.1.2.1.2.2 27-1.2.3.1.2.1.2 28-1.2.3.1.2.1.2.1.r 29-1.2.3.1.2.1.2.1.1 30-1.2.3.1.2.1.2.1 33-1.4.1.1.1 (p / participate-01~e.13 :ARG0 (m3 / member~e.3 :ARG1-of (i / include-91 :ARG2 (p2 / protein-family~e.2 :name (n / name :op1 "Snail"~e.1)))) :ARG1~e.14 (p3 / process-02~e.17 :ARG2-of (m / malignant-02~e.16) :quant (m2 / many~e.15) :ARG2-of (i2 / involve-01~e.18 :ARG1 (d / downregulate-01~e.20,21,22 :ARG1 j :ARG1-of (c2 / contrast-01~e.23 :ARG2 (i4 / involve-01~e.18 :polarity~e.24 -~e.24 :ARG1 (a2 / abrogate-01~e.27 :ARG1~e.28 (j / junction~e.30 :mod (i3 / intercellular~e.29)) :mod (q / quantity~e.26))))))) :concession~e.0 (a / associate-01~e.7 :ARG1 m3~e.11 :ARG2 (t / transition-01 :ARG2 (c3 / cell :mod (m5 / mesenchymal)) :ARG3 (c4 / cell :mod (e / epithelial))) :ARG1-of (f2 / frequent-02~e.6 :degree (m4 / most~e.5))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 18~e.33))) :mod (a3 / also~e.12)) # ::id pmid_1563_0473.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The range of developmental processes in which Snail family members have been implicated thus includes the type of epithelial remodeling that is observed in hair follicle bud formation . # ::alignments 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1.1 4-1.1.2.1 7-1.1.2.1.2.1.1.1.1.1 8-1.1.2.1.2.1.1.1 9-1.1.2.1.2.1 12-1.1.2.1.2 14-1.1 14-1.1.2.1.2.1.1 16-1.1.1.3 18-1.1.1.1 19-1.1.1 22-1.1.1.2 23-1.1.1.2.1.r 24-1.1.1.2.1.1.1.1 25-1.1.1.2.1.1.1 26-1.1.1.2.1.1 27-1.1.1.2.1 (i4 / infer-01 :ARG1 (i / include-01~e.14 :ARG1 (r / remodel-01~e.19 :ARG1 (e / epithelium~e.18) :ARG1-of (o / observe-01~e.22 :time~e.23 (f2 / form-01~e.27 :ARG1 (b / bud~e.26 :part-of (f3 / follicle~e.25 :mod (h / hair~e.24))))) :ARG1-of (t / type-03~e.16)) :ARG2 (r2 / range-01~e.1 :ARG1~e.2 (p / process-02~e.4 :ARG1 (g / growth~e.3) :ARG2-of (i2 / implicate-01~e.12 :ARG1 (m / member~e.9 :ARG1-of (i3 / include-91~e.14 :ARG2 (p2 / protein-family~e.8 :name (n / name :op1 "Snail"~e.7))))))))) # ::id pmid_1563_0473.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given our prior observation that exogenously added Snail can participate with LEF @-@ 1/β-catenin in down @-@ regulating E @-@ cadherin expression in keratinocytes [ @ 4 @ ] , coupled with the established requirement for LEF @-@ 1/β-catenin in hair follicle morphogenesis [ @ 4 , 19 @ ] , we turned to addressing whether Snail @/@ Slug family members might also participate in the process . # ::alignments 1-1.3.1.1.1 1-1.3.1.1.1.r 2-1.3.1.1.3 3-1.3.1.1 6-1.3.1.1.2.1.1.2 7-1.3.1.1.2.1.1.1.1 8-1.3.1.1.2 9-1.3.1.1.2.1 10-1.3.1.1.2.1.1.3.r 11-1.3.1.1.2.1.1.3.1.1.1 19-1.3.1.1.2.1.2.1.1.1.1 21-1.3.1.1.2.1.2.1.1.1.1 23-1.3.1.1.2.1.2.1 24-1.3.1.1.2.1.2.1.2.r 25-1.3.1.1.2.1.2.1.2 28-1.3.1.1.4.1.1.1 33-1.3.1.2.2 35-1.3.1.2.4 36-1.3.1.2 38-1.3.1.2.2 41-1.3.1.2.1.r 42-1.3.1.2.1.1.1 43-1.3.1.2.1.1 44-1.3.1.2.1 47-1.3.1.2.3.1.1.1.1 51-1.3.1.2.3.1.1.1.2 55-1.1 57-1.3 58-1 59-1.2.1 59-1.2.1.r 60-1.2.2.1.1.1.1.1 62-1.2.2.1.1.2.1.1 63-1.2.2.1.1.1 63-1.2.2.1.1.2 63-1.3.1.1.2.1.1 64-1.2.2 65-1.3.1.1.2 66-1.2.4 67-1.2 68-1.2.3.r 70-1.2.3 (a / address-02~e.58 :ARG0 (w / we~e.55) :ARG1 (p2 / participate-01~e.67 :mode~e.59 interrogative~e.59 :ARG0 (m / member~e.64 :ARG1-of (i / include-91 :ARG2 (a2 / and :op1 (p3 / protein-family~e.63 :name (n / name :op1 "Snail"~e.60)) :op2 (p4 / protein-family~e.63 :name (n2 / name :op1 "Slug"~e.62))))) :ARG1~e.68 (p5 / process-02~e.70) :mod (a6 / also~e.66)) :ARG1-of (c / cause-01~e.57 :ARG0 (a4 / and :op1 (o / observe-01~e.3 :ARG0~e.1 (w2 / we~e.1) :ARG1 (p / possible-01~e.8,65 :ARG1 (p7 / participate-01~e.9 :ARG0 (p8 / protein-family~e.63 :name (n3 / name :op1 "Snail"~e.7) :ARG1-of (a3 / add-02~e.6 :manner (e / exogenous)) :accompanier~e.10 (m2 / macro-molecular-complex :part (p12 / protein :name (n6 / name :op1 "LEF-1"~e.11)) :part (p13 / protein :name (n7 / name :op1 "β-catenin")))) :ARG1 (d / downregulate-01 :ARG1 (e2 / express-03~e.23 :ARG1 (g / gene :name (n5 / name :op1 "E-cadherin"~e.19,21)) :ARG3~e.24 (k / keratinocyte~e.25))))) :time (p6 / prior~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.28)))) :op2 (r / require-01~e.36 :ARG0~e.41 (m3 / morphogenesis~e.44 :mod (f2 / follicle~e.43 :mod (h / hair~e.42))) :ARG1 m2~e.33,38 :ARG1-of (d3 / describe-01 :ARG0 (p11 / publication :ARG1-of (c3 / cite-01 :ARG2 (a5 / and :op1 4~e.47 :op2 19~e.51)))) :ARG1-of (e3 / establish-01~e.35))))) # ::id pmid_1563_0473.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PCR analyses identified transient Snail mRNA expression during a period of skin embryogenesis when waves of hair follicles are forming ( unpublished data ) . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 0-1.1.1.2 0-1.1.1.2.r 1-1.1 2-1 3-1.2.2 5-1.2.1.2.1.1 7-1.2.1.1.1 8-1.2 9-1.2.3.2.r 9-1.2.3.r 11-1.2.3 13-1.2.3.1.1 14-1.2.3.1 15-1.2.3.1.r 16-1.2.3.2.1 17-1.2.3.2.1.1.r 18-1.2.3.2.1.1.1 19-1.2.3.2.1.1 21-1.2.3.2 23-1.3.1.1.1 24-1.3.1 (i / identify-01~e.2 :ARG0 (a2 / analyze-01~e.1 :instrument (r / react-01~e.0 :ARG0~e.0 (p3 / polymerase~e.0) :ARG1-of~e.0 (c / chain-01~e.0))) :ARG1 (e / express-03~e.8 :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.7) :mod (g / gene :name (n / name :op1 "Snail"~e.5))) :ARG1-of (t / transient-02~e.3) :time~e.9 (p2 / period~e.11 :time-of~e.15 (e2 / embryogenesis~e.14 :mod (s / skin~e.13)) :time-of~e.9 (f2 / form-01~e.21 :ARG1 (w / wave-04~e.16 :ARG1~e.17 (f / follicle~e.19 :mod (h / hair~e.18)))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.24 :ARG1-of (p / publish-01 :polarity -~e.23)))) # ::id pmid_1563_0473.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To pinpoint specifically where Snail mRNA is expressed in the developing skin , we conducted in situ hybridization using a cRNA probe unique to the Snail 3′ untranslated region ( UTR ) . # ::alignments 1-1.2 2-1.2.3 5-1.3.2.2.1.2.1.1 7-1.2.2.1.1.1.1 9-1.2.2.1 10-1.4 12-1.2.2.2.1 13-1.2.2.2 15-1.1 17-1.4 18-1.4 19-1 20-1.2.r 20-1.3 23-1.3.2 24-1.3.2.2 28-1.3.2.2.1.2.1.1 30-1.3.2.2.1.1.1 31-1.3.2.2.1.1.2 32-1.3.2.2.1.1.3 (h / hybridize-01~e.19 :ARG0 (w / we~e.15) :purpose~e.20 (p / pinpoint-01~e.1 :ARG0 w :ARG1 (l / location :ARG3-of (e / express-03~e.9 :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.7) :ARG0-of (e2 / encode-01 :ARG1 g2))) :part-of (s2 / skin~e.13 :ARG1-of (d / develop-02~e.12))) :ARG1-of (s / specific-02~e.2)) :ARG2-of (u / use-01~e.20 :ARG0 w :ARG1 (p2 / probe~e.23 :mod (n6 / nucleic-acid :name (n2 / name :op1 "complementary" :op2 "RNA")) :mod (u2 / unique~e.24 :topic (d2 / dna-sequence :name (n3 / name :op1 "3′"~e.30 :op2 "untranslated"~e.31 :op3 "region"~e.32) :part-of (g2 / gene :name (n4 / name :op1 "Snail"~e.5,28)))))) :manner (i / in-situ~e.10,17,18)) # ::id pmid_1563_0473.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Embryonic day 17.5 ( E17.5 ) was chosen , since the multiple waves of follicle morphogenesis occurring at this time enabled us to evaluate Snail expression at different stages of the process . # ::alignments 0-1.2.3 1-1.2.2 2-1.2.1 7-1 9-1.3 11-1.3.1.1.2 12-1.3.1.1 13-1.3.1.1.1.r 14-1.3.1.1.1.1 15-1.3.1.1.1 19-1.2 19-1.3.1.1.3.r 20-1.3.1 21-1.3.1.2.1 23-1.3.1.2 24-1.3.1.2.2.1.1.1 25-1.3.1.2.2 26-1.3.1.2.2.2.r 27-1.3.1.2.2.2.2 28-1.3.1.2.2.2 (c / choose-01~e.7 :ARG0 w2 :ARG1 (t / temporal-quantity~e.19 :quant 17.5~e.2 :unit (d2 / day~e.1) :age-of (e / embryo~e.0)) :ARG1-of (c2 / cause-01~e.9 :ARG0 (e2 / enable-01~e.20 :ARG0 (w / wave-04~e.12 :ARG1~e.13 (m2 / morphogenesis~e.15 :mod (f / follicle~e.14)) :quant (m / multiple~e.11) :time~e.19 (a / age-01 :ARG1 e :ARG2 t)) :ARG1 (e3 / evaluate-101~e.23 :ARG0 (w2 / we~e.21) :ARG2 (e4 / express-03~e.25 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.24)) :time~e.26 (s / stage~e.28 :subevent-of m2 :ARG1-of (d3 / differ-02~e.27)))) :ARG2 w2))) # ::id pmid_1563_0473.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 1 @ A , specific hybridization was detected within the epithelium of nascent hair buds . # ::alignments 1-1.3 4-1.3.1 9-1.1.1 10-1.1 12-1 15-1.2 16-1.2.1.r 17-1.2.1.2 18-1.2.1.1 19-1.2.1 (d / detect-01~e.12 :ARG1 (h / hybridize-01~e.10 :ARG1-of (s / specific-02~e.9)) :location (e / epithelium~e.15 :part-of~e.16 (b / bud~e.19 :mod (h2 / hair~e.18) :mod (n / nascent~e.17))) :ARG1-of (s2 / show-01~e.1 :ARG0 (f / figure~e.4 :mod "1A"))) # ::id pmid_1563_0473.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By contrast , as follicles progressed further through their development ( e.g . , germ and peg stages ) , they exhibited no signs of hybridization ( Figure 1 @ A ) . # ::alignments 1-1 3-1.1.4.r 4-1.1.4.1 6-1.1.4.3 9-1.1.4 14-1.1.4.2.1.1 15-1.1.4.2 16-1.1.4.2.2.1 17-1.1.4.2.1 17-1.1.4.2.2 20-1.1.2 21-1.1 22-1.1.1 22-1.1.1.r 23-1.1.3 24-1.1.3.1.r 25-1.1.3.1 28-1.2.1 (c / contrast-01~e.1 :ARG2 (e / exhibit-01~e.21 :polarity~e.22 -~e.22 :ARG0 f~e.20 :ARG1 (s3 / signal-07~e.23 :ARG1~e.24 (h / hybridize-01~e.25)) :time~e.3 (d / develop-02~e.9 :ARG1 (f / follicle~e.4) :example (a / and~e.15 :op1 (s / stage~e.17 :mod (g / germ~e.14)) :op2 (s2 / stage~e.17 :mod (p / peg~e.16))) :degree (f3 / further~e.6))) :ARG1-of (d2 / describe-01 :ARG2 (f2 / figure~e.28 :mod "1A"))) # ::id pmid_1563_0473.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The transient nature of Snail mRNA expression during follicle development was most apparent in hybridized skin sections containing follicles from two different waves of morphogenesis ( as shown in Figure 1 ) . # ::alignments 1-1.2.2 5-1.2.1.2.1.1.1 7-1.2.1.1.1 8-1.2 9-1.2.3.r 10-1.2.3.1 11-1.2.3 12-1.2.r 13-1.1 14-1 15-1.3.r 16-1.3.1.1 17-1.3.1 18-1.3 19-1.3.2 20-1.3.2.1 21-1.3.2.1.1.r 22-1.3.2.1.1.1 23-1.3.2.1.1.3 24-1.3.2.1.1 25-1.3.2.1.1.2.r 26-1.3.2.1.1.2 28-1.2.3.r 28-1.4.r 29-1.4 32-1.4.1 33-1.4.1.1 (a / apparent~e.14 :degree (m / most~e.13) :domain~e.12 (e / express-03~e.8 :ARG1 (n2 / nucleic-acid :name (n / name :op1 "mRNA"~e.7) :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n3 / name :op1 "Snail"~e.5)))) :ARG1-of (t / transient-02~e.1) :time~e.9,28 (d / develop-02~e.11 :ARG1 (f / follicle~e.10))) :location~e.15 (s / section~e.18 :part-of (s2 / skin~e.17 :ARG1-of (h / hybridize-01~e.16)) :ARG0-of (c / contain-01~e.19 :ARG1 (f2 / follicle~e.20 :source~e.21 (w / wave-04~e.24 :quant 2~e.22 :ARG1~e.25 (m2 / morphogenesis~e.26) :ARG1-of (d2 / differ-02~e.23))))) :ARG1-of~e.28 (s3 / show-01~e.29 :ARG0 (f3 / figure~e.32 :mod 1~e.33))) # ::id pmid_1563_0473.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hybridizing hair buds from a later wave appeared juxtaposed with nonhybridizing follicles from an earlier wave . # ::alignments 0-1.1.1.1 0-1.1.2.1 1-1.1.1.2 2-1.1.1 3-1.1.1.3.r 3-1.1.2.2.r 5-1.1.1.3.1 5-1.1.1.3.1.1 5-1.1.1.3.1.1.r 6-1.1.1.3 7-1 8-1.1 11-1.1.2 12-1.1.2.2.r 14-1.1.2.2.1 14-1.1.2.2.1.1 14-1.1.2.2.1.1.r 15-1.1.2.2 (a / appear-01~e.7 :ARG1 (j / juxtapose-01~e.8 :ARG1 (b / bud~e.2 :ARG1-of (h / hybridize-01~e.0) :mod (h2 / hair~e.1) :time~e.3 (w / wave-01~e.6 :mod (l / late~e.5 :degree~e.5 (m / more~e.5)))) :ARG2 (f / follicle~e.11 :ARG1-of (h3 / hybridize-01~e.0 :polarity -) :source~e.3,12 (w2 / wave-04~e.15 :time (e / early~e.14 :degree~e.14 (m2 / more~e.14)))))) # ::id pmid_1563_0473.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether this transient nature of Snail mRNA expression is reflected at the protein level , we generated an antibody against the N @-@ terminal sequence that resides upstream of the more conserved zinc finger domains . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.3.1 4-1.3.2.3.2 5-1.3.2.3 8-1.3.2.3.2.1.1.2.1.1.1 10-1.3.2.3.2.1.1.1.1 11-1.3.2.3.2.1 13-1.3.2 14-1.3.2.2.r 16-1.3.2.2.1 17-1.3.2.2 19-1.1 20-1 22-1.2 23-1.2.1 25-1.2.1.1.1.1.1 27-1.2.1.1.1.1.2 28-1.2.1.1 30-1.2.1.1.1 30-1.2.1.1.1.2 30-1.2.1.1.1.2.r 31-1.2.1.1.1.2.1.2 34-1.2.1.1.1.2.1.1.2.1 35-1.2.1.1.1.2.1.1.2 36-1.2.1.1.1.2.1.1.1.1 37-1.2.1.1.1.2.1.1.1.2 38-1.2.1.1.1.2.1.1.1.3 (g / generate-01~e.20 :ARG0 (w / we~e.19) :ARG1 (a / antibody~e.22 :ARG0-of (o / oppose-01~e.23 :ARG1 (s / sequence~e.28 :mod (p2 / protein-segment~e.30 :name (n2 / name :op1 "N"~e.25 :op2 "terminus"~e.27) :ARG0-of~e.30 (r3 / reside-01~e.30 :ARG1 (r4 / relative-position :op1 (p3 / protein-segment :name (n3 / name :op1 "zinc"~e.36 :op2 "finger"~e.37 :op3 "domain"~e.38) :ARG1-of (c / conserve-01~e.35 :degree (m / more~e.34))) :direction (u / upstream~e.31))))))) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (r / reflect-01~e.13 :mode~e.2 interrogative~e.2 :ARG1~e.14 (l / level~e.17 :mod (p / protein~e.16)) :ARG2 (n4 / nature~e.5 :mod (t2 / this~e.3) :ARG1-of (t / transient-02~e.4 :manner-of (e / express-03~e.11 :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.10) :ARG0-of (e2 / encode-01 :ARG1 (g2 / gene :name (n6 / name :op1 "Snail"~e.8)))))))))) # ::id pmid_1563_0473.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As judged by Western blot analysis , the antibody did not detect endogenous proteins from cultured keratinocytes , but it did yield a band of the expected size from keratinocytes transiently expressing a hemagglutinin ( HA ) - tagged Snail protein ( Figure 1 @ B ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 4-1.3.1 8-1.1.2 10-1.1.1 10-1.1.1.r 11-1.1 12-1.1.3.1 13-1.1.3 14-1.1.4.r 14-1.2.3.r 15-1.1.4.1 16-1.1.4 18-1 21-1.2 23-1.2.2 24-1.2.2.1.r 26-1.2.2.1.1 27-1.2.2.1 28-1.2.3.r 29-1.2.3 30-1.2.3.1.2 31-1.2.3.1 33-1.2.3.1.1.2.1.1.1 38-1.2.3.1.1.2 39-1.2.3.1.1.1.1 40-1.2.3.1.1 43-1.3.2.1 (c / contrast-01~e.18 :ARG1 (d / detect-01~e.11 :polarity~e.10 -~e.10 :ARG0 (a2 / antibody~e.8) :ARG1 (p / protein~e.13 :mod (e / endogenous~e.12)) :ARG2~e.14 (k / keratinocyte~e.16 :ARG1-of (c2 / culture-01~e.15))) :ARG2 (y / yield-01~e.21 :ARG0 a2 :ARG1 (b / band~e.23 :mod~e.24 (s2 / size~e.27 :ARG1-of (e3 / expect-01~e.26))) :source~e.14,28 (k2 / keratinocyte~e.29 :ARG3-of (e2 / express-03~e.31 :ARG2 (p2 / protein~e.40 :name (n3 / name :op1 "Snail"~e.39) :ARG1-of (t2 / tag-01~e.38 :ARG2 (s / small-molecule :name (n4 / name :op1 "hemagglutinin"~e.33)))) :ARG1-of (t / transient-02~e.30)))) :ARG2-of (j / judge-01~e.1 :ARG3~e.2 (i / immunoblot-01~e.3,4) :ARG1-of (d3 / describe-01 :ARG2 (f / figure~e.43 :mod "1B")))) # ::id pmid_1563_0473.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The antibody also recognized a band corresponding to the size of endogenous Snail ( approximately 28 kDa ) in lysates from embryonic mouse skin , the temporal appearance of which corresponded to the waves of hair follicle morphogenesis from E15.5 to newborn when over 90 % of the hair on the mouse is formed ( Figure 1 @ B ) . # ::alignments 1-1.1 2-1.4 3-1 5-1.2 6-1.2.1 7-1.2.1.1.r 9-1.2.1.1 10-1.2.1.1.1.r 11-1.2.1.1.1.2 12-1.2.1.1.1.1.1 14-1.2.1.1.2.1 15-1.2.1.1.2.1.1.1 16-1.2.1.1.2.1.1.2 18-1.3.r 19-1.3 20-1.3.1.r 21-1.2.2.1.1.2.1.1 21-1.3.1.1 22-1.3.1.2 23-1.3.1 26-1.2.2.1.1.2.1.2 26-1.2.2.2 27-1.2.2 30-1.2.2.1 31-1.2.2.1.1.r 33-1.2.2.1.1 34-1.2.2.1.1.1.r 35-1.2.2.1.1.1.1.1 36-1.2.2.1.1.1.1 37-1.2.2.1.1.1 38-1.3.1.r 42-1.2.2.1.1.2.2.2.r 42-1.2.2.1.1.2.3.r 42-1.2.2.1.1.2.r 43-1.2.2.1.1.2.3.1.1.1 44-1.2.2.1.1.2.3.1.1.1.1 45-1.2.2.1.1.2.3.1.1 48-1.2.2.1.1.2.3.1 51-1.2.2.1.1.2.2.1 51-1.2.2.1.1.2.3.1.2 53-1.2.2.1.1.2.3 (r / recognize-02~e.3 :ARG0 (a3 / antibody~e.1) :ARG1 (b / band~e.5 :ARG1-of (c / correspond-02~e.6 :ARG2~e.7 (s / size~e.9 :poss~e.10 (p2 / protein :name (n / name :op1 "Snail"~e.12) :mod (e / endogenous~e.11)) :ARG1-of (e2 / equal-01 :ARG2 (a4 / approximately~e.14 :op1 (m / mass-quantity :quant 28~e.15 :unit (k / kilodalton~e.16)))))) :ARG1-of (a5 / appear-01~e.27 :ARG1-of (c2 / correspond-02~e.30 :ARG2~e.31 (w / wave-04~e.33 :ARG1~e.34 (m3 / morphogenesis~e.37 :mod (f / follicle~e.36 :mod (h / hair~e.35))) :time~e.42 (d / date-interval :op1 (a2 / age-01 :ARG1 (e4 / embryo~e.21) :ARG2 (t2 / temporal-quantity~e.26 :quant 15.5 :unit (d2 / day))) :op2 (b2 / bear-02 :ARG1 (m5 / mouse~e.51) :time~e.42 (n2 / new-01)) :time-of~e.42 (f2 / form-01~e.53 :ARG1 (h2 / hair~e.48 :mod (p / percentage-entity~e.45 :value (o2 / over~e.43 :op1 90~e.44)) :part-of (m4 / mouse~e.51)))))) :mod (t / time~e.26))) :location~e.18 (l / lysate~e.19 :source~e.20,38 (s2 / skin~e.23 :mod (e3 / embryo~e.21) :mod (m2 / mouse~e.22))) :mod (a / also~e.2)) # ::id pmid_1563_0473.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the Western blot data , immunohistochemical analysis did not detect Snail in single @-@ layered E13.5 epidermis ( Figure 1 @ C ) nor in the placode , which is the earliest morphological sign of the commitment of multipotent cells of the embryonic ectoderm to a hair cell fate ( Figure 1 @ D ) . # ::alignments 0-1.4 1-1.4.1.r 3-1.4.1.1.1 4-1.4.1.1.1 5-1.4.1 8-1.2 10-1.1 10-1.1.r 11-1 12-1.3.1.1 13-1.5.r 14-1.5.1.1.1 16-1.5.1.1 18-1.5.1 21-1.5.1.2.1 21-1.5.2.1.1 26-1.1.r 29-1.5.2 34-1.5.2.2.2 34-1.5.2.2.2.1 34-1.5.2.2.2.1.r 35-1.5.2.2.3 36-1.5.2.2 37-1.5.2.2.1.r 39-1.5.2.2.1 40-1.5.2.2.1.1.r 41-1.5.2.2.1.1.1 42-1.5.2.2.1.1 45-1.5.1.3 45-1.5.2.2.1.1.2.1 46-1.5.2.2.1.1.2 47-1.5.2.2.1.2.r 49-1.5.2.2.1.2.1.1 50-1.5.2.2.1.2.1 51-1.5.2.2.1.2 54-1.5.1.2.1 54-1.5.2.1.1 (d / detect-01~e.11 :polarity~e.10,26 -~e.10 :ARG0 (a2 / analyze-01~e.8 :mod (i / immunohistochemistry)) :ARG1 (p / protein :name (n3 / name :op1 "Snail"~e.12)) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (d2 / data~e.5 :ARG2-of (r / result-01 :ARG1 (i2 / immunoblot-01~e.3,4)))) :location~e.13 (a3 / and :op1 (e / epidermis~e.18 :mod (l / layer~e.16 :ARG1-of (s / single-02~e.14)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.21,54 :mod "1C")) :part-of (e2 / embryo~e.45 :age (t / temporal-quantity :quant 13.5 :unit (d3 / day)))) :op2 (p2 / placode~e.29 :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure~e.21,54 :mod "1D")) :ARG0-of (s3 / signal-07~e.36 :ARG1~e.37 (c2 / commit-01~e.39 :ARG1~e.40 (c3 / cell~e.42 :mod (m3 / multipotent~e.41) :part-of (e4 / ectoderm~e.46 :mod (e5 / embryo~e.45))) :ARG2~e.47 (f3 / fate~e.51 :mod (c4 / cell~e.50 :mod (h / hair~e.49)))) :mod (e3 / early~e.34 :degree~e.34 (m / most~e.34)) :mod (m2 / morphology~e.35))))) # ::id pmid_1563_0473.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the in situ hybridization results , anti @-@ Snail antibody labeled only hair buds and not follicles at more mature stages of development ( Figure 1 @ E ) . # ::alignments 0-1.1.3 1-1.1.3.1.r 3-1.1.3.1.1.1.1 4-1.1.3.1.1.1.1 5-1.1.3.1.1.1 6-1.1.3.1 6-1.1.3.1.1 6-1.1.3.1.1.r 8-1.1.1.1 10-1.1.1.1.1.1.1 11-1.1.1 12-1.1 12-1.2 13-1.1.2.2 14-1.1.2.1 15-1.1.2 16-1 17-1.2.1 17-1.2.1.r 18-1.2.3 19-1.2.4.r 20-1.2.4.2.1 21-1.2.4.2 22-1.2.4 23-1.2.4.1.r 24-1.2.4.1 27-1.3.1 (a2 / and~e.16 :op1 (l / label-01~e.12 :ARG0 (a / antibody~e.11 :ARG0-of (c2 / counter-01~e.8 :ARG1 (p / protein :name (n / name :op1 "Snail"~e.10)))) :ARG1 (b / bud~e.15 :mod (h2 / hair~e.14) :mod (o / only~e.13)) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (t / thing~e.6 :ARG2-of~e.6 (r / result-01~e.6 :ARG1 (h / hybridize-01~e.5 :manner (i / in-situ~e.3,4)))))) :op2 (l2 / label-01~e.12 :polarity~e.17 -~e.17 :ARG0 a :ARG1 (f / follicle~e.18) :time~e.19 (s / stage~e.22 :subevent-of~e.23 (d / develop-02~e.24) :ARG1-of (m / mature-02~e.21 :degree (m2 / more~e.20)))) :ARG1-of (d2 / describe-01 :ARG2 (f2 / figure~e.27 :mod "1E"))) # ::id pmid_1563_0473.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , the anti @-@ Snail antibody appeared to be specific for its target protein . # ::alignments 0-1.2.1 1-1.2.1.1 4-1.1.1.1 6-1.1.1.1.1.1.1 7-1.1.1 8-1 9-1.2 11-1.1 12-1.1.2.r 13-1.1.2.1.1 13-1.1.2.1.1.r 14-1.1.2.1 15-1.1.2 (a2 / appear-01~e.8 :ARG1 (s / specific-02~e.11 :ARG1 (a / antibody~e.7 :ARG0-of (c / counter-01~e.4 :ARG1 (p / protein :name (n / name :op1 "Snail"~e.6)))) :ARG2~e.12 (p2 / protein~e.15 :ARG1-of (t / target-01~e.14 :ARG0~e.13 a~e.13))) :ARG1-of (c2 / cause-01~e.9 :ARG0 (t2 / take-01~e.0 :mod (t3 / together~e.1)))) # ::id pmid_1563_0473.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It did not detect other Snail family members known to be expressed in keratinocytes and @/@ or skin ( unpublished data ) . # ::alignments 0-1.2 2-1.1 2-1.1.r 2-1.4.1.1.1 2-1.4.1.1.1.r 3-1 4-1.3.2 5-1.3.1.1.1.1 6-1.3.1.1 7-1.3 8-1.3.1.1.2.2 11-1.3.1.1.2 12-1.3.1.1.2.1.r 13-1.3.1.1.2.1.1 14-1.3.1.1.2.1 16-1.3.1.1.2.1 17-1.3.1.1.2.1.2 19-1.1 19-1.4.1.1.1 20-1.4.1 (d / detect-01~e.3 :polarity~e.2 -~e.2,19 :ARG0 (i / it~e.0) :ARG1 (m / member~e.7 :ARG1-of (i2 / include-91 :ARG2 (p / protein-family~e.6 :name (n / name :op1 "Snail"~e.5) :ARG2-of (e / express-03~e.11 :ARG3~e.12 (a / and-or~e.14,16 :op1 (k2 / keratinocyte~e.13) :op2 (s / skin~e.17)) :ARG1-of (k / know-01~e.8)))) :mod (o / other~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.20 :ARG1-of (p2 / publish-01 :polarity~e.2 -~e.2,19)))) # ::id pmid_1563_0473.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , the immunohistochemical data paralleled our Snail in situ hybridization data revealing transient Snail expression at the hair bud stage ( Figure 1 @ A ) . # ::alignments 0-1 4-1.1.1 4-1.1.2 5-1.1 6-1.1.2.1.1 6-1.1.2.1.1.r 8-1.1.2.1.2.1.1 10-1.1.2.1.3 11-1.1.2.1.3 12-1.1.2.1 13-1.1.2 14-1.1.2.2 15-1.1.2.2.1.2 17-1.1.2.2.1.1 19-1.1.2.2.1 20-1.1.2.2.1.3.r 22-1.1.2.2.1.3.1.1 23-1.1.2.2.1.3.1 24-1.1.2.2.1.3 27-1.1.2.2.1.4.1 (a / and~e.0 :op2 (p / parallel-01~e.5 :ARG0 (d / data~e.4 :mod (i / immunohistochemistry)) :ARG1 (d2 / data~e.4,13 :topic (h / hybridize-01~e.12 :ARG0~e.6 (w / we~e.6) :ARG1 (g / gene :name (n / name :op1 "Snail"~e.8)) :manner (i2 / in-situ~e.10,11)) :ARG0-of (r / reveal-01~e.14 :ARG1 (e / express-03~e.19 :ARG2 g~e.17 :ARG1-of (t / transient-02~e.15) :time~e.20 (s / stage~e.24 :mod (b / bud~e.23 :mod (h2 / hair~e.22))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.27 :mod "1A"))))))) # ::id pmid_1563_0473.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As judged by immunohistochemistry , Snail protein was localized to the nuclei of the hair bud cells ( Figure 1 @ E ) . # ::alignments 1-1 2-1.1.r 3-1.1 5-1.2.1.1.1 6-1.2.1 7-1.2 8-1.2 11-1.2.2 12-1.2.2.1.r 14-1.2.2.1.1.1 15-1.2.2.1.1 16-1.2.2.1 19-1.3.1 (j / judge-01~e.1 :ARG0~e.2 (i / immunohistochemistry~e.3) :ARG1 (b2 / be-located-at-91~e.7,8 :ARG1 (p2 / protein~e.6 :name (n2 / name :op1 "Snail"~e.5)) :ARG2 (n / nucleus~e.11 :poss~e.12 (c2 / cell~e.16 :part-of (b / bud~e.15 :part-of (h2 / hair~e.14))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "1E"))) # ::id pmid_1563_0473.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This feature was consistent with Snail 's known function as a transcriptional repressor [ @ 12 , 13 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2.1.r 7-1.2.3 8-1.2 9-1.2.2.r 11-1.2.2.1 12-1.2.2 15-1.3.1.1.1.1 19-1.3.1.1.1.2 (c / consistent-01~e.3 :ARG1 (f / feature~e.1 :mod (t / this~e.0)) :ARG2~e.4 (f2 / function-01~e.8 :ARG0~e.6 (p2 / protein :name (n / name :op1 "Snail"~e.5)) :ARG1~e.9 (r2 / repress-01~e.12 :ARG1 (t2 / transcribe-01~e.11)) :ARG1-of (k / know-01~e.7)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 12~e.15 :op2 13~e.19))))) # ::id pmid_1563_0473.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , anti @-@ Snail labeling was detected in only three of the four major waves of follicle morphogenesis . # ::alignments 0-1 2-1.1.1.1 4-1.1.1.1.1.1.1 5-1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.3 10-1.1.2.1 13-1.1.2.2.1.1 14-1.1.2.2.1.3 15-1.1.2.2.1 16-1.1.2.2.1.2.r 17-1.1.2.2.1.2.1 18-1.1.2.2.1.2 (a / and~e.0 :op2 (d / detect-01~e.7 :ARG1 (l / label-01~e.5 :ARG0-of (o / oppose-01~e.2 :ARG1 (p / protein :name (n / name :op1 "Snail"~e.4)))) :location~e.8 (t / thing :quant 3~e.10 :ARG1-of (i / include-91 :ARG2 (w2 / wave-04~e.15 :quant 4~e.13 :ARG1~e.16 (m2 / morphogenesis~e.18 :mod (f / follicle~e.17)) :ARG1-of (m / major-02~e.14))) :mod (o2 / only~e.9)))) # ::id pmid_1563_0473.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Snail was not found in the buds of guard hairs that are the earliest of all hairs to form ( at E13.5 ) , and which constitute less than 5 % of the mouse coat ( unpublished data ) . # ::alignments 0-1.2.1.1 2-1.1 2-1.1.r 3-1 4-1.3.r 6-1.3 7-1.3.1.r 8-1.3.1.1 9-1.3.1 13-1.3.1.2.1 14-1.3.1.2.1.2.r 15-1.3.1.2.1.2.1 16-1.3.1.2.1.2 18-1.3.1.2 24-1.3.1.2.2 26-1.3.1.2.2.1 27-1.3.1.3.2 28-1.3.1.3.2 29-1.3.1.3.2.1.1 30-1.3.1.3.2.1 33-1.3.1.3.1.1 34-1.3.1.3.1 36-1.3.1.3.3.1.1.1 37-1.3.1.3.3.1 (f4 / find-01~e.3 :polarity~e.2 -~e.2 :ARG1 (p2 / protein :name (n / name :op1 "Snail"~e.0)) :location~e.4 (b / bud~e.6 :poss~e.7 (h / hair~e.9 :mod (g / guard~e.8) :ARG1-of (f2 / form-01~e.18 :time (e / early~e.13 :mod (m / most) :compared-to~e.14 (h2 / hair~e.16 :mod (a / all~e.15))) :op1-of (a2 / and~e.24 :op2 (c / constitute-01~e.26 :ARG0 h)) :time (a3 / age-01 :ARG1 (e2 / embryo) :ARG2 (t / temporal-quantity :quant 13.5 :unit (d / day)))) :ARG1-of (i / include-91 :ARG2 (c2 / coat~e.34 :poss (m2 / mouse~e.33)) :ARG3 (l2 / less-than~e.27,28 :op1 (p3 / percentage-entity~e.30 :value 5~e.29)) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.37 :ARG1-of (p4 / publish-01 :polarity -~e.36))))))) # ::id pmid_1563_0473.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As judged by immunofluorescence with antibodies against the proliferating nuclear antigen Ki67 , the timing of Snail expression coincided with the stage at which the developing follicle enhanced its proliferation and down @-@ growth ( Figure 1 @ F ) . # ::alignments 0-1.2.2.1.r 1-1 2-1.1.r 3-1.1 4-1.1.1.r 5-1.1.1 6-1.1.1.1 8-1.1.1.1.1 8-1.1.1.1.1.3 8-1.1.1.1.1.3.r 9-1.1.1.1.1.2 10-1.1.1.1.1.4 11-1.1.1.1.1.1.1 14-1.2.1 14-1.2.2.1.r 15-1.2.1.1.r 16-1.2.1.1.1.1.1 17-1.2.1.1 18-1.2 21-1.2.2 25-1.2.2.1.1.1 26-1.2.2.1.1 27-1.2.2.1 29-1.2.2.1.2.1 30-1.2.2.1.2 31-1.2.2.1.2.2.2 33-1.2.2.1.2.2 36-1.3.1 (j / judge-01~e.1 :ARG0~e.2 (i / immunofluoresce-01~e.3 :ARG2~e.4 (a / antibody~e.5 :ARG0-of (o / oppose-01~e.6 :ARG1 (p5 / protein~e.8 :name (n4 / name :op1 "Ki67"~e.11) :mod (n5 / nucleus~e.9) :ARG0-of~e.8 (p / proliferate-01~e.8) :mod (a2 / antigen~e.10))))) :ARG1 (c / coincide-01~e.18 :ARG1 (t / time-02~e.14 :ARG1~e.15 (e / express-03~e.17 :ARG2 (p2 / protein :name (n / name :op1 "Snail"~e.16)))) :ARG2 (s / stage~e.21 :time-of~e.0,14 (e2 / enhance-01~e.27 :ARG0 (f / follicle~e.26 :ARG1-of (d / develop-02~e.25)) :ARG1 (a5 / and~e.30 :op1 (p3 / proliferate-01~e.29 :ARG0 f) :op2 (g / grow-01~e.33 :ARG1 f :ARG1-of (d2 / down-03~e.31)))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.36 :mod "1F"))) # ::id pmid_1563_0473.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunohistochemistry with antibodies against the active ( phosphorylated ) form of MAPK ( pMAPK ) marked a subset of the proliferating ( Ki67 @-@ positive ) cells , and pMAPK @-@ positive cells were enriched in the hair bud ( Figure 1 @ G ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 3-1.1.1.2 5-1.1.1.2.1 5-1.1.1.2.1.2 5-1.1.1.2.1.2.r 7-1.1.1.2.1.3 11-1.1.1.2.1.1.1 13-1.1.1.2.1.3 15-1.1 17-1.1.2 18-1.1.2.1.r 20-1.1.2.1.1 22-1.1.2.1.2.1.1 26-1.1.2.1 29-1.2.1.2 32-1.2.1 34-1.2 35-1.2.1.1.r 37-1.2.1.1.1 38-1.2.1.1 41-1.3.1 (a3 / and :op1 (m / mark-02~e.15 :ARG0 (i / immunohistochemistry~e.0 :mod~e.1 (a / antibody~e.2) :ARG0-of (o2 / oppose-01~e.3 :ARG1 (e2 / enzyme~e.5 :name (n2 / name :op1 "MAPK"~e.11) :ARG0-of~e.5 (a2 / activity-06~e.5) :ARG3-of (p2 / phosphorylate-01~e.7,13)))) :ARG2 (s / subset~e.17 :quant-of~e.18 (c2 / cell~e.26 :ARG0-of (p4 / proliferate-01~e.20) :part (p5 / protein :name (n3 / name :op1 "Ki67"~e.22))))) :op2 (e / enrich-01~e.34 :ARG1 (c3 / cell~e.32 :location~e.35 (b / bud~e.38 :mod (h2 / hair~e.37)) :part e2~e.29)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.41 :mod "1G"))) # ::id pmid_1563_0473.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The timing of Snail induction and Ki67 and pMAPK enrichment in the hair bud appeared to follow closely the induction of LEF @-@ 1/β-catenin activity , known to initiate in the hair placode stage [ @ 20 @ ] . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1.1 4-1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1.1.1 7-1.1.1.1.2.1 8-1.1.1.1.2.1.2.1.1 8-1.1.1.1.2.1.2.2 9-1.1.1.1.2 10-1.1.1.1.2.2.r 12-1.1.1.1.2.2.1 13-1.1.1.1.2.2 14-1 16-1.1 17-1.1.3 19-1.1.2 20-1.1.2.1.r 21-1.1.2.1.1.1.1.1 24-1.1.2.1 26-1.1.2.1.2.2 28-1.1.2.1.2 29-1.1.2.1.2.1.r 31-1.1.2.1.2.1.2 32-1.1.2.1.2.1.1 33-1.1.2.1.2.1 36-1.2.1.1.1 (a / appear-02~e.14 :ARG1 (f / follow-01~e.16 :ARG1 (t / time-02~e.1 :ARG1~e.2 (a5 / and~e.5 :op1 (i / induce-01~e.4 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.3))) :op2 (e / enrich-01~e.9 :ARG1 (a3 / and~e.7 :op1 (p2 / protein :name (n2 / name :op1 "Ki67"~e.6)) :op2 (e2 / enzyme :name (n3 / name :op1 "MAPK"~e.8) :ARG3-of (p7 / phosphorylate-01~e.8))) :location~e.10 (b / bud~e.13 :poss (h / hair~e.12))))) :ARG2 (i2 / induce-01~e.19 :ARG2~e.20 (a2 / activity-06~e.24 :ARG0 (m / macro-molecular-complex :part (p4 / protein :name (n4 / name :op1 "LEF-1"~e.21)) :part (p3 / protein :name (n5 / name :op1 "β-catenin"))) :ARG1-of (i3 / initiate-01~e.28 :time~e.29 (s / stage~e.33 :mod (p5 / placode~e.32) :mod (h2 / hair~e.31)) :ARG1-of (k / know-01~e.26)))) :ARG1-of (c2 / close-10~e.17)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 20~e.36)))) # ::id pmid_1563_0473.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , like placodes , hair buds exhibited down @-@ regulation in E @-@ cadherin expression ( Figure 1 @ H ; see also [ @ 4 @ ]) . # ::alignments 0-1 2-1.1.1.2 5-1.1.1.1 6-1.1.1 7-1.1 8-1.1.2 9-1.1.2 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1.1.1.1 14-1.1.2.1.1.1.1 15-1.1.2.1 18-1.2.1.1 23-1.2.1.2 23-1.2.1.2.2 23-1.2.1.2.2.r 24-1.2.1.2.2.3 27-1.2.1.2.1.1 (c / contrast-01~e.0 :ARG2 (e / exhibit-01~e.7 :ARG0 (b / bud~e.6 :poss (h / hair~e.5) :ARG1-of (r2 / resemble-01~e.2 :ARG2 (p3 / placode))) :ARG1 (d / downregulate-01~e.8,9,10 :ARG1~e.11 (e2 / express-03~e.15 :ARG2 (p / protein :name (n / name :op1 "E-cadherin"~e.12,14))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure~e.18 :mod "1H") :op2 (p2 / publication~e.23 :ARG1-of (c2 / cite-01 :ARG2 4~e.27) :ARG1-of~e.23 (s / see-01~e.23 :mode imperative :ARG0 (y / you) :mod (a2 / also~e.24)))))) # ::id pmid_1563_0473.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sustained Expression of Snail Results in Epidermal Hyperproliferation and Differentiation Defects in Tg Mouse Skin # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1 7-1.2.1 7-1.2.1.2 7-1.2.1.2.r 8-1.2 9-1.2.2.2 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.1.1 13-1.2.2.1.1 14-1.2.2.1 (r / result-01~e.4 :ARG1 (e / express-03~e.1 :ARG2~e.2 (p / protein :name (n / name :op1 "Snail"~e.3)) :ARG1-of (s / sustain-01~e.0)) :ARG2 (a / and~e.8 :op1 (p2 / proliferate-01~e.7 :ARG0 (e2 / epidermis) :degree~e.7 (h / hyper~e.7)) :op2 (d / defect~e.10 :location~e.11 (s2 / skin~e.14 :part-of (m / mouse~e.13 :mod (t / transgenic~e.12))) :mod (d2 / differentiate-01~e.9)))) # ::id pmid_1563_0473.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The striking spike of Snail expression coincident with hair bud formation and enhanced proliferation prompted us to examine the consequences of ectopically expressing Snail elsewhere in mouse skin epidermis . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1 8-1.1.2.1.1.1 9-1.1.2.1.1 10-1.1.2.1 11-1.1.2 12-1.1.2.2.1 13-1.1.2.2 14-1 15-1.2 17-1.3 19-1.3.2 22-1.3.2.1 23-1.3.2.1.1 24-1.3.2.1.2.2 26-1.3.2.1.2.1.1 27-1.3.2.1.2.1 28-1.3.2.1.2 (p / prompt-02~e.14 :ARG0 (c2 / coincide-01 :ARG1 (s3 / spike-04~e.2 :ARG1~e.3 (e / express-03~e.5 :ARG2 (p2 / protein :name (n3 / name :op1 "Snail"~e.4))) :ARG1-of (s / strike-04~e.1)) :ARG2 (a2 / and~e.11 :op1 (f / form-01~e.10 :ARG1 (b / bud~e.9 :poss (h / hair~e.8))) :op2 (p3 / proliferate-01~e.13 :ARG1-of (e2 / enhance-01~e.12)))) :ARG1 (w / we~e.15) :ARG2 (e3 / examine-01~e.17 :ARG0 w :ARG1 (c3 / consequence~e.19 :poss (e4 / express-03~e.22 :ARG2 p2~e.23 :ARG3 (e6 / epidermis~e.28 :part-of (s2 / skin~e.27 :part-of (m / mouse~e.26)) :mod (e7 / elsewhere~e.24)) :manner (e5 / ectopic))))) # ::id pmid_1563_0473.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To distinguish Tg from endogenous Snail , we used the HA @-@ epitope , shown previously not to alter Snail 's transcriptional activity [ @ 12 @ ] . # ::alignments 1-1.3 2-1.3.2.2 3-1.3.3.r 4-1.3.3.2 5-1.3.2.1.1 5-1.3.3.1.1 7-1.1 8-1 8-1.3.r 10-1.2.1.1 12-1.2.1.1 14-1.2.2.3 15-1.2.2.3.1 16-1.2.2.1 16-1.2.2.1.r 18-1.2 18-1.2.2 18-1.2.2.r 19-1.2.2.2.1.1.1 20-1.2.2.2.1.r 21-1.2.2.2.2 22-1.2.2.2 25-1.4.1.1.1 (u / use-01~e.8 :ARG0 (w / we~e.7) :ARG1 (d / dna-sequence~e.18 :name (n / name :op1 "HA-epitope"~e.10,12) :ARG0-of~e.18 (a / alter-01~e.18 :polarity~e.16 -~e.16 :ARG1 (a2 / activity-06~e.22 :ARG0~e.20 (p2 / protein :name (n2 / name :op1 "Snail"~e.19)) :ARG1 (t / transcribe-01~e.21)) :ARG1-of (s / show-01~e.14 :time (p / previous~e.15)))) :purpose~e.8 (d2 / distinguish-01~e.1 :ARG0 w :ARG1 (p5 / protein :name (n4 / name :op1 "Snail"~e.5) :mod (t2 / transgenic~e.2)) :ARG2~e.3 (p3 / protein :name (n3 / name :op1 "Snail"~e.5) :mod (e / endogenous~e.4))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 12~e.25)))) # ::id pmid_1563_0473.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of 20 K14 @-@ Snail[HA ] Tg animals generated , three expressed the transgene and all exhibited analogous phenotypes . # ::alignments 1-1.1.1 3-1.1.3.1.1 9-1.1 9-1.1.4.1 10-1 12-1.1.4.1.1 13-1.1.4.1.2 15-1.1.2 18-1.1.5 20-1.1.5.1 (g / generate-01~e.10 :ARG1 (a / animal~e.9 :quant 20~e.1 :mod (t / transgene~e.15) :part (p / protein :name (n / name :op1 "K14-Snail"~e.3) :part (p2 / protein :name (n2 / name :op1 "HA"))) :ARG2-of (i / include-91 :ARG1 (a2 / animal~e.9 :quant 3~e.12 :ARG1-of (e / express-03~e.13 :ARG2 t))) :ARG0-of (e2 / exhibit-01~e.18 :ARG1 (p3 / phenotype~e.20 :mod (a3 / analogue))))) # ::id pmid_1563_0473.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mice that integrated the transgene at the single @-@ cell stage died at or shortly after birth . # ::alignments 0-1.1 2-1.1.1 4-1.1.1.1 5-1.1.1.2.r 7-1.1.1.2.1.1 9-1.1.1.2.1 10-1.1.1.2 11-1 12-1.2.r 13-1.2 14-1.2.2.2 15-1.2.2 16-1.2.1 (d / die-01~e.11 :ARG1 (m / mouse~e.0 :ARG0-of (i / integrate-01~e.2 :ARG1 (t / transgene~e.4) :time~e.5 (s / stage~e.10 :mod (c / cell~e.9 :ARG1-of (s2 / single-02~e.7))))) :time~e.12 (o / or~e.13 :op1 (b / bear-02~e.16) :op2 (a / after~e.15 :op1 b :quant (s3 / short-07~e.14)))) # ::id pmid_1563_0473.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The three surviving full @-@ Tg founder mice harbored transgene integrations that gave stable transmission of mosaic Snail gene expression through the germline . # ::alignments 1-1.1.1 2-1.1.3 3-1.1.4.1 6-1.1.2 7-1.1 8-1 9-1.1.4 9-1.2.1 10-1.2 12-1.2.2 13-1.2.2.1.3 14-1.2.2.1 15-1.2.2.1.1.r 16-1.2.2.1.1.2 18-1.2.2.1.1.1.1.1 20-1.2.2.1.1.1 21-1.2.2.1.1 24-1.2.2.1.2 (h / harbor-01~e.8 :ARG0 (m / mouse~e.7 :quant 3~e.1 :ARG0-of (f / found-01~e.6) :ARG0-of (s / survive-01~e.2) :mod (t / transgene~e.9 :ARG1-of (f2 / full-09~e.3))) :ARG1 (i / integrate-01~e.10 :ARG1 (t3 / transgene~e.9) :ARG0-of (g / give-01~e.12 :ARG1 (t2 / transmit-01~e.14 :ARG1~e.15 (e / express-03~e.21 :ARG1 (g3 / gene~e.20 :name (n / name :op1 "Snail"~e.18)) :mod (m2 / mosaic~e.16)) :instrument (g2 / germline~e.24) :ARG1-of (s2 / stable-03~e.13))))) # ::id pmid_1563_0473.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Progressively poor health necessitated our sacrificing most offspring from these lines within a year of birth . # ::alignments 2-1.1 3-1 4-1.2.1 4-1.2.1.r 5-1.2 6-1.2.2.1 7-1.2.2 8-1.2.2.2.r 9-1.2.2.2.1 10-1.2.2.2 11-1.2.3 11-1.2.3.2 11-1.2.3.2.1.1.r 11-1.2.3.2.r 12-1.2.3.2.1.1 13-1.2.3.2.1.2 14-1.2.3.1.r 15-1.2.3.1 (n / necessitate-01~e.3 :ARG0 (h / healthy~e.2 :polarity - :ARG1-of (p / progress-01)) :ARG1 (s / sacrifice-01~e.5 :ARG0~e.4 (w / we~e.4) :ARG1 (o / offspring~e.7 :mod (m / most~e.6) :source~e.8 (l / line~e.10 :mod (t2 / this~e.9))) :time (a / after~e.11 :op1~e.14 (b / bear-02~e.15) :quant~e.11 (u / up-to~e.11 :op1 (t3 / temporal-quantity :quant~e.11 1~e.12 :unit (y2 / year~e.13)))))) # ::id pmid_1563_0473.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As Snail Tg animals grew , they became distinguished by their small size , short tails , and flaky skin ( Figure 2 @ A ) . # ::alignments 0-1.3.r 2-1.2.1.1.1 5-1.2 6-1.3 8-1.3.1 10-1 11-1.1.r 12-1.1.1.2 12-1.1.1.2.r 13-1.1.1.1 14-1.1.1 16-1.1.2.1 17-1.1.2 19-1.1 21-1.1.3 24-1.4.1 (d / distinguish-01~e.10 :ARG0~e.11 (a2 / and~e.19 :op1 (s / size~e.14 :mod (s4 / small~e.13) :poss~e.12 a~e.12) :op2 (t2 / tail~e.17 :ARG1-of (s2 / short-07~e.16) :poss a) :op3 (s3 / skin~e.21 :mod (f / flake) :poss a)) :ARG1 (a / animal~e.5 :mod (g3 / gene :name (n / name :op1 "Snail"~e.2)) :mod (t / transgene)) :time~e.0 (g / grow-01~e.6 :ARG1 a~e.8) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.24 :mod "2A"))) # ::id pmid_1563_0473.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histological analyses of 3 @-@ d old ( P3 ) mice revealed mosaic patches marked by epidermal thickening ( Figure 2 @ B ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 6-1.1.1.1.r 10-1.1.1 11-1 12-1.2.1 13-1.2 14-1.2.2 17-1.2.2.1 20-1.3.1 (r / reveal-01~e.11 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (m / mouse~e.10 :age~e.6 (t / temporal-quantity :quant 3~e.3 :unit (d / day))) :mod (h / histology~e.0)) :ARG1 (p / patch~e.13 :mod (m2 / mosaic~e.12) :ARG1-of (m3 / mark-02~e.14 :ARG3 (t2 / thicken-01~e.17 :ARG1 (e / epidermis)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.20 :mod "2B"))) # ::id pmid_1563_0473.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mosaic morphology was reflected at the level of Tg Snail protein , with only the hyperthickened regions expressing nuclear HA @-@ tagged Snail ( Figure 2 @ C ) . # ::alignments 1-1.1.2.1 2-1.1.2 4-1.1 5-1.1.1.r 7-1.1.1 10-1.1.1.1.1.1 11-1.1.1.1 11-1.2.1 11-1.2.1.2.1 14-1.2.2.2 17-1.2.2 18-1.2 19-1.2.1.3 20-1.2.1.2.1.1.1 22-1.2.1.2 23-1.1.1.1.1.1 23-1.2.1.1.1 26-1.1.3.1 (a / and :op1 (r / reflect-01~e.4 :ARG1~e.5 (l / level~e.7 :poss (p / protein~e.11 :name (n / name :op1 "Snail"~e.10,23) :mod (t3 / transgene))) :ARG2 (m / morphology~e.2 :mod (m2 / mosaic~e.1)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "2C"))) :op2 (e / express-03~e.18 :ARG2 (p2 / protein~e.11 :name (n3 / name :op1 "Snail"~e.23) :ARG1-of (t2 / tag-01~e.22 :ARG2 (p3 / protein~e.11 :name (n4 / name :op1 "HA"~e.20))) :mod (n5 / nucleus~e.19)) :ARG3 (r2 / region~e.17 :ARG1-of (t / thicken-01 :degree (h2 / hyper)) :mod (o / only~e.14)))) # ::id pmid_1563_0473.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These hyperthickened areas were marked by excessive proliferation , as revealed by antibodies against the proliferating nuclear antigen Ki67 ( Figure 2 @ D and 2 @ E ) . # ::alignments 0-1.1.2 2-1.1 4-1 5-1.2.r 6-1.2.1 7-1.2 9-1.3.r 10-1.3 11-1.3.1.r 12-1.3.1 13-1.3.1.1 15-1.3.1.1.1 15-1.3.1.1.1.2 15-1.3.1.1.1.2.r 16-1.3.1.1.1.3 17-1.3.1.1.1.4 18-1.3.1.1.1.1.1 21-1.4.1.1 21-1.4.1.2 25-1.4.1 (m / mark-02~e.4 :ARG1 (a / area~e.2 :ARG1-of (t / thicken-01 :degree (h / hyper)) :mod (t2 / this~e.0)) :ARG3~e.5 (p / proliferate-01~e.7 :ARG1-of (e / excessive-02~e.6)) :ARG1-of~e.9 (r / reveal-01~e.10 :ARG0~e.11 (a2 / antibody~e.12 :ARG0-of (o / oppose-01~e.13 :ARG1 (p2 / protein~e.15 :name (n / name :op1 "Ki67"~e.18) :ARG0-of~e.15 (p3 / proliferate-01~e.15) :mod (n2 / nucleus~e.16) :mod (a3 / antigen~e.17))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.25 :op1 (f / figure~e.21 :mod "2D") :op2 (f2 / figure~e.21 :mod "2E")))) # ::id pmid_1563_0473.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated , pMAPK @-@ positive cells were also prevalent in these areas ( Figure 2 @ F and 2 @ G ) , as were cells expressing keratin 6 , a keratin induced in the suprabasal layers of hyperproliferative skin ( Figure 2 @ H and 2 @ I ) . # ::alignments 0-1.1.1.1.2 2-1.1.1.1.1.1 2-1.1.1.1.3 5-1.1.2 7-1.2.2 8-1 10-1.2.1 11-1.2 14-1.1.2.2.1.1 14-1.1.2.2.1.2 14-1.3.1.1 14-1.3.1.2 18-1.1 18-1.1.2.2.1 18-1.3.1 27-1.1.1 27-1.1.2 28-1.1.2.1 29-1.1.2.1.1.1.1 30-1.1.2.1.1.1.1 33-1.1.2.1.1.1.1 34-1.1.2.1.1.2 35-1.1.2.1.1.2.1.r 37-1.1.2.1.1.2.1.1 38-1.1.2.1.1.2.1 39-1.1.2.1.1.2.1.2.r 40-1.1.2.1.1.2.1.2.1 40-1.1.2.1.1.2.1.2.1.1 40-1.1.2.1.1.2.1.2.1.1.r 41-1.1.2.1.1.2.1.2 44-1.1.2.2.1.1 44-1.1.2.2.1.2 44-1.3.1.1 44-1.3.1.2 48-1.1.2.2.1 48-1.3.1 (p5 / prevail-02~e.8 :ARG1 (a4 / and~e.18 :op1 (c / cell~e.27 :part (e2 / enzyme :name (n / name :op1 "MAPK"~e.2) :ARG1-of (a / activate-01~e.0) :ARG3-of (p / phosphorylate-01~e.2))) :op2 (c2 / cell~e.5,27 :ARG3-of (e / express-03~e.28 :ARG2 (p3 / protein :name (n2 / name :op1 "keratin-6"~e.29,30,33) :ARG2-of (i / induce-01~e.34 :location~e.35 (l / layer~e.38 :mod (s3 / suprabasal~e.37) :part-of~e.39 (s2 / skin~e.41 :ARG0-of (p4 / proliferate-01~e.40 :degree~e.40 (h / hyper~e.40))))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.18,48 :op1 (f3 / figure~e.14,44 :mod "2H") :op2 (f4 / figure~e.14,44 :mod "2I"))))) :location (a2 / area~e.11 :mod (t / this~e.10) :mod (a8 / also~e.7)) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.18,48 :op1 (f / figure~e.14,44 :mod "2F") :op2 (f2 / figure~e.14,44 :mod "2G")))) # ::id pmid_1563_0473.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of the Snail transgene did not block terminal differentiation in the hyperproliferative epidermis , but it distorted it markedly ( Figure 3 @ A– @ 3 @ H ) . # ::alignments 0-1.1.2 4-1.1.2.1.1.1.1 6-1.1.2.1 8-1.1.1 8-1.1.1.r 9-1.1 10-1.1.3.2 11-1.1.3 12-1.1.3.1.r 14-1.1.3.1.1 14-1.1.3.1.1.1 14-1.1.3.1.1.1.r 15-1.1.3.1 17-1 19-1.2 21-1.2.3 21-1.2.3.r 24-1.3.1.1 24-1.3.1.2 24-1.3.1.3 24-1.3.1.4 24-1.3.1.5 24-1.3.1.6 24-1.3.1.7 24-1.3.1.8 (c / contrast-01~e.17 :ARG1 (b / block-01~e.9 :polarity~e.8 -~e.8 :ARG0 (e / express-03~e.0 :ARG1 (t2 / transgene~e.6 :mod (g / gene :name (n / name :op1 "Snail"~e.4)))) :ARG1 (d / differentiate-01~e.11 :ARG1~e.12 (e2 / epidermis~e.15 :ARG0-of (p2 / proliferate-01~e.14 :degree~e.14 (h / hyper~e.14))) :mod (t / terminus~e.10))) :ARG2 (d2 / distort-01~e.19 :ARG0 e :ARG1 d :manner~e.21 (m / marked~e.21)) :ARG1-of (d3 / describe-01 :ARG0 (a / and :op1 (f / figure~e.24 :mod "3A") :op2 (f2 / figure~e.24 :mod "3B") :op3 (f3 / figure~e.24 :mod "3C") :op4 (f4 / figure~e.24 :mod "3D") :op5 (f5 / figure~e.24 :mod "3E") :op6 (f6 / figure~e.24 :mod "3F") :op7 (f7 / figure~e.24 :mod "3G") :op8 (f8 / figure~e.24 :mod "3H")))) # ::id pmid_1563_0473.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Typical of most hyperproliferating conditions , Snail expression led to a large expansion in layers with spinous and granular morphology . # ::alignments 0-1.3 2-1.4.2 4-1.4.r 6-1.1.1.1.1 7-1.1 8-1 9-1.2.r 11-1.2.2 12-1.2 13-1.2.1.r 14-1.2.1 19-1.2.1.1 (l / lead-03~e.8 :ARG0 (e / express-03~e.7 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.6))) :ARG2~e.9 (e2 / expand-01~e.12 :location~e.13 (l2 / layer~e.14 :mod (m / morphology~e.19 :mod (s / spine) :mod (g / granule))) :degree (l3 / large~e.11)) :ARG1-of (t / typical-02~e.0) :condition~e.4 (p2 / proliferate-01 :degree (h / hyper) :mod (m2 / most~e.2))) # ::id pmid_1563_0473.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , however , was a marked and variable expansion of keratin 5 ( K5 ) , normally restricted to the innermost basal layer ( see Figure 3 ) . # ::alignments 0-1 2-1.1 6-1.1.1.3 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.1.1 12-1.1.1.1.1.1 17-1.1.1.2.2 18-1.1.1.2 22-1.1.1.2.1.1 23-1.1.1.2.1 25-1.2.1.2 27-1.2.1 28-1.2.1.1 (a2 / and~e.0 :op2 (c / contrast-01~e.2 :ARG2 (e / expand-01~e.9 :ARG1~e.10 (p / protein :name (n / name :op1 "keratin-5"~e.11,12)) :ARG1-of (r / restrict-01~e.18 :ARG2 (l / layer~e.23 :mod (b / basal~e.22) :mod (i / inner :degree (m2 / most))) :ARG1-of (n2 / normal-02~e.17)) :ARG1-of (m / mark-01~e.6) :ARG1-of (v / vary-01))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod 3~e.28 :ARG1-of (s / see-01~e.25 :mode imperative :ARG0 (y / you))))) # ::id pmid_1563_0473.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the failure of Snail @ -@ null mice to develop past gastrulation [ @ 21 @ ] precluded our ability to study the loss of Snail function in skin development , a good correlation emerged between the expression of Snail protein and the extension of K5 , Ki67 , and pMAPK suprabasally ( compare data in Figures 2 and 3 ) . # ::alignments 0-1.1 2-1.1.2.1 5-1.1.2.1.2.1 6-1.1.2.1.2.1 7-1.1.2.1.2.1 8-1.1.2.1.2.1 9-1.1.2.1.2.1 11-1.1.2.1.2 16-1.1.2.1.3.1.1.1 19-1.1.2 20-1.1.2.2.1.1 20-1.1.2.2.1.1.r 23-1.1.2.2.1 25-1.1.2.2.1.2 27-1.1.2.1.1.1.1.1 28-1.1.2.2.1.2.1 29-1.1.2.2.1.2.2.r 30-1.1.2.2.1.2.2.1 31-1.1.2.2.1.2.2 34-1.1.1.1.3 35-1.1.1.1 36-1.1.1 39-1.1.1.1.1 41-1.1.1.1.1.1.1.1 42-1.1.1.1.1.1 42-1.1.1.1.2.1.1 42-1.1.1.1.2.1.2 42-1.1.2.1.1.1 43-1.1.1.1.2.1 45-1.1.1.1.2 47-1.1.1.1.2.1.1.2.1 49-1.1.1.1.2.1.2.1.1 51-1.1.1.1.2.1 52-1.1.1.1.2.1.3.1.1 52-1.1.1.1.2.1.3.2 55-1.2 56-1.2.1 59-1.2.1.1.1.1 59-1.2.1.1.1.2 60-1.2.1.1.1.1.1 62-1.2.1.1.1 64-1.2.1.1.1.2.1 (m / multi-sentence :snt1 (h / have-concession-91~e.0 :ARG1 (e / emerge-02~e.36 :ARG0 (c / correlate-01~e.35 :ARG1 (e2 / express-03~e.39 :ARG2 (p / protein~e.42 :name (n / name :op1 "Snail"~e.41))) :ARG2 (e3 / extend-01~e.45 :ARG1 (a / and~e.43,51 :op1 (p7 / protein~e.42 :mod 7 :name (n2 / name :op1 "K5"~e.47)) :op2 (p2 / protein~e.42 :name (n3 / name :op1 "Ki67"~e.49)) :op3 (e4 / enzyme :name (n4 / name :op1 "MAPK"~e.52) :ARG3-of (p8 / phosphorylate-01~e.52))) :manner (s / suprabasal)) :ARG1-of (g / good-02~e.34))) :ARG2 (p4 / preclude-01~e.19 :ARG0 (f / fail-01~e.2 :ARG1 (m2 / mouse :mod (p9 / protein~e.42 :name (n5 / name :op1 "Snail"~e.27) :ARG2-of (m3 / mutate-01 :mod "−/−"))) :ARG2 (d / develop-02~e.11 :ARG1 m2~e.5,6,7,8,9 :time (a2 / after :op1 (g2 / gastrulate-00))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 21~e.16)))) :ARG1 (p6 / possible-01 :ARG1 (s2 / study-01~e.23 :ARG0~e.20 (w / we~e.20) :ARG1 (l / lose-02~e.25 :ARG1 (f2 / function~e.28 :mod p) :location~e.29 (d2 / develop-01~e.31 :ARG2 (s3 / skin~e.30))))))) :snt2 (c3 / compare-01~e.55 :ARG1 (d3 / data~e.56 :ARG1-of (d4 / describe-01 :ARG0 (a3 / and~e.62 :op1 (f3 / figure~e.59 :mod 2~e.60) :op2 (f4 / figure~e.59 :mod 3~e.64)))))) # ::id pmid_1563_0473.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The changes in hyperproliferation and differentiation were not initially accompanied by gross signs of epithelial invaginations . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1 3-1.2.1.1.1 3-1.2.1.1.1.r 4-1.2.1 5-1.2.1.2 7-1.1 7-1.1.r 8-1.4 9-1 10-1.3.r 11-1.3.2 12-1.3 13-1.3.1.r 14-1.3.1 15-1.3.1.1 (a / accompany-01~e.9 :polarity~e.7 -~e.7 :ARG0 (c / change-01~e.1 :ARG1~e.2 (a2 / and~e.4 :op1 (p / proliferate-01~e.3 :degree~e.3 (h / hyper~e.3)) :op2 (d / differentiate-01~e.5))) :ARG1~e.10 (s / signal-07~e.12 :ARG1~e.13 (e / epithelium~e.14 :ARG1-of (i2 / invaginate-01~e.15)) :ARG1-of (g / gross-04~e.11)) :time (i / initial~e.8)) # ::id pmid_1563_0473.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With age , however , epidermal folds and undulations developed in areas where Snail was expressed , and proliferative markers persisted in these regions ( Figure 3 @ I and 3 @ J ; anti @-@ cyclin D staining ) . # ::alignments 1-1.1.1.1 3-1 6-1.1.1.2.1.1.1 7-1.1.1.2.1.1 9-1.1.1.2.1 10-1.1.1.2.1.2.r 11-1.1.1.2.1.2 12-1.1.1.2.1.2.1.r 13-1.1.1.2.1.2.1.1.1.1 15-1.1.1.2.1.2.1 17-1.1.1.2 19-1.1.1.2.2.1 20-1.1.1.2.2 26-1.2.1.1 26-1.2.1.2 30-1.2.1 36-1.2.2.1 36-1.2.2.1.1 36-1.2.2.1.1.r 38-1.2.2.1.1.1.1.1 39-1.2.2.1.1.1.1.2 40-1.2.2 (h / have-concession-91~e.3 :ARG1 (a2 / and :op1 (c / cause-01 :ARG0 (a / age-01~e.1) :ARG1 (a5 / and~e.17 :op1 (d / develop-02~e.9 :ARG1 (a3 / and~e.7 :op1 (f / fold-03~e.6 :ARG1 (e / epidermis)) :op2 (u / undulate-01 :ARG1 e)) :location~e.10 (a4 / area~e.11 :location-of~e.12 (e2 / express-03~e.15 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.13))))) :op2 (p2 / persist-01~e.20 :ARG0 (m / marker~e.19 :ARG0-of (p3 / proliferate-01)) :location a4)))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and~e.30 :op1 (f2 / figure~e.26 :mod "3I") :op2 (f3 / figure~e.26 :mod "3J")) :ARG2 (s / stain-01~e.40 :ARG2 (m2 / molecular-physical-entity~e.36 :ARG0-of~e.36 (c3 / counter-01~e.36 :ARG1 (p4 / protein :name (n4 / name :op1 "cyclin"~e.38 :op2 "D"~e.39))))))) # ::id pmid_1563_0473.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The undulations were accompanied by partial dissolution of the underlying basement membrane ( Figure 3 @ K and 3 @ L ) . # ::alignments 3-1 5-1.1.2 5-1.1.2.r 9-1.1.1.2 10-1.1.1.1 11-1.1.1 14-1.3.1.1 14-1.3.1.2 18-1.3.1 (a / accompany-01~e.3 :ARG0 (d / dissolute-00 :ARG1 (m / membrane~e.11 :mod (b / basement~e.10) :ARG1-of (u / underlie-01~e.9)) :degree~e.5 (p / part~e.5)) :ARG1 (u2 / undulate-01) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.18 :op1 (f / figure~e.14 :mod "3K") :op2 (f2 / figure~e.14 :mod "3L")))) # ::id pmid_1563_0473.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Aberrant staining was also observed with antibodies against components of the hemidesmosomes , which provide strong adhesion of basal epidermal cells to the underlying basal lamina ( Figure 3 @ M and 3 @ N ) . # ::alignments 0-1.1.2 1-1.1 3-1.2 4-1 5-1.1.1.r 6-1.1.1 7-1.1.1.1 8-1.1.1.1.1 14-1.1.1.1.1.1.1 15-1.1.1.1.1.1.1.1.3 16-1.1.1.1.1.1.1.1 18-1.1.1.1.1.1.1.1.1.1.1 18-1.1.1.1.1.1.1.1.2.1 20-1.1.1.1.1.1.1.1.1 21-1.1.1.1.1.1.1.1.2.r 23-1.1.1.1.1.1.1.1.2.2 24-1.1.1.1.1.1.1.1.2.1 25-1.1.1.1.1.1.1.1.2 28-1.3.1.1 28-1.3.1.2 32-1.3.1 (o / observe-01~e.4 :ARG1 (s / stain-01~e.1 :ARG2~e.5 (a2 / antibody~e.6 :ARG0-of (c / counter-01~e.7 :ARG1 (c2 / component~e.8 :part-of (h / hemidesmosome :ARG0-of (p / provide-01~e.14 :ARG1 (a4 / adhere-01~e.16 :ARG1 (c3 / cell~e.20 :mod (e / epidermis :mod (b / basal~e.18))) :ARG2~e.21 (l2 / lamina~e.25 :mod (b2 / basal~e.18,24) :ARG1-of (u / underlie-01~e.23)) :ARG1-of (s2 / strong-02~e.15))))))) :manner (a / aberrant~e.0)) :mod (a3 / also~e.3) :ARG1-of (d / describe-01 :ARG0 (a5 / and~e.32 :op1 (f / figure~e.28 :mod "3M") :op2 (f2 / figure~e.28 :mod "3N")))) # ::id pmid_1563_0473.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , similar types of alterations occur in the basement membrane in the hair bud of embryonic and newborn mice when Snail is normally expressed . # ::alignments 2-1.3.1 3-1.3 5-1 7-1.1.r 9-1.1.1 10-1.1 11-1.1.2.r 13-1.1.2.1 14-1.1.2 15-1.1.2.2.r 16-1.1.2.2.1 17-1.1.2.2 19-1.1.2.2.1.1 19-1.1.2.2.2 20-1.1.2.2.2.1.1.r 20-1.2.r 21-1.2.1.1.1 23-1.2.2 24-1.2 (a / alter-01~e.5 :location~e.7 (m / membrane~e.10 :mod (b / basement~e.9) :part-of~e.11 (b2 / bud~e.14 :mod (h / hair~e.13) :poss~e.15 (a2 / and~e.17 :op1 (e / embryo~e.16 :mod (m2 / mouse~e.19)) :op2 (m3 / mouse~e.19 :ARG1-of (b3 / bear-02 :time~e.20 (n / new-01)))))) :time~e.20 (e2 / express-03~e.24 :ARG2 (p / protein :name (n2 / name :op1 "Snail"~e.21)) :ARG1-of (n3 / normal-02~e.23)) :ARG2-of (t / type-03~e.3 :ARG1-of (r / resemble-01~e.2)) :ARG2-of (i2 / interest-01)) # ::id pmid_1563_0473.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The fact that the basement membrane separating the epidermis from the dermis is altered only in the adult Tg animals suggests the involvement of intermediary factors not as readily available in the epidermis as they are in the follicle . # ::alignments 4-1.1.1.1 5-1.1.1 6-1.1.1.2 8-1.1.1.2.1 9-1.1.1.2.2.r 11-1.1.1.2.2 13-1.1 14-1.1.3 15-1.1.2.r 17-1.1.2.1 18-1.1.2.2 19-1.1.2 20-1 22-1.2 23-1.2.1.r 24-1.2.1.1 25-1.2.1 26-1.2.1.2.1 26-1.2.1.2.1.r 28-1.2.1.2.2 28-1.2.1.2.2.r 29-1.2.1.2 30-1.2.1.2.3.r 32-1.2.1.2.3 36-1.2.1.2.4.r 38-1.2.1.2.4 (s / suggest-01~e.20 :ARG0 (a / alter-01~e.13 :ARG1 (m / membrane~e.5 :mod (b / basement~e.4) :ARG0-of (s2 / separate-01~e.6 :ARG1 (e / epidermis~e.8) :ARG2~e.9 (d / dermis~e.11))) :location~e.15 (a2 / animal~e.19 :mod (a3 / adult~e.17) :mod (t / transgenic~e.18)) :mod (o / only~e.14)) :ARG1 (i / involve-01~e.22 :ARG1~e.23 (f2 / factor~e.25 :mod (i2 / intermediary~e.24) :ARG2-of (a4 / available-02~e.29 :polarity~e.26 -~e.26 :manner~e.28 (r / ready~e.28) :location~e.30 (e2 / epidermis~e.32) :compared-to~e.36 (f3 / follicle~e.38))))) # ::id pmid_1563_0473.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Possible Links between Epidermal Hyperproliferation and Down @-@ regulation of AJ Proteins in Snail Tg Mice # ::alignments 0-1 1-1.1 2-1.1.1.r 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 6-1.1.2 7-1.1.2 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.1.1 11-1.1.2.1 14-1.1.3.1.1.1 16-1.1.3.2 17-1.1.3 (p / possible-01~e.0 :ARG1 (l / link-01~e.1 :ARG1~e.2 (p4 / proliferate-01~e.4 :ARG0 (e / epidermis) :degree~e.4 (h / hyper~e.4)) :ARG2 (d / downregulate-01~e.6,7,8 :ARG1~e.9 (p3 / protein~e.11 :name (n / name :op1 "AJ"~e.10))) :location (m / mouse~e.17 :mod (g / gene :name (n3 / name :op1 "Snail"~e.14)) :mod (t / transgenic~e.16)))) # ::id pmid_1563_0473.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given that the E @-@ cadherin promoter is a direct target for Snail @-@ mediated repression in vitro [ @ 4 , 12 , 13 @ ] , and that E @-@ cadherin was down @-@ regulated in Snail @-@ expressing hair buds , we examined the status of E @-@ cadherin and other AJ proteins within regions of hyperproliferative epidermis where Tg Snail was present ( Figure 4 @ A ) . # ::alignments 4-1.1.1.2.1.1.1.1 6-1.1.1.2.1.1.1.1 8-1.1.1.2 8-1.1.1.2.1 8-1.1.1.2.1.r 11-1.1.1.3 12-1.1.1 13-1.1.1.1.r 14-1.1.1.1.1.1.1.1 16-1.1.1.1.1 17-1.1.1.1 18-1.1.1.1.2 19-1.1.1.1.2 22-1.1.1.4.1.1.1.1 26-1.1.1.4.1.1.1.2 30-1.1.1.4.1.1.1.3 34-1.1.1.4.1.1.1 36-1.1.1.2.1.1.1.1 38-1.1.1.2.1.1.1.1 43-1.1.1.1.2 44-1.2.2.3.2.1.1.1 46-1.1.2.2.2 47-1.1.2.2.1 48-1.1.2.2 50-1.2.1 51-1.2 53-1.2.2.1 53-1.2.2.2 55-1.1.1.2.1.1.1.1 57-1.1.1.2.1.1.1.1 58-1.2.2 59-1.2.2.2.1.2 60-1.2.2.2.1.1.1 61-1.1.1.1.1.1 61-1.1.1.2.1.1 61-1.2.2.2.1 61-1.2.2.3.2.1 63-1.2.2.3 64-1.2.2.3.1.r 65-1.2.2.3.1.1 65-1.2.2.3.1.1.1 65-1.2.2.3.1.1.1.r 66-1.2.2.3.1 67-1.2.2.3.r 68-1.2.2.3.2.1.2 69-1.2.2.3.2.1.1.1 71-1.2.2.3.2 74-1.2.3.1 75-1.1.1.4.1.1.1.1 (c2 / cause-01 :ARG0 (a / and :op1 (t / target-01~e.12 :ARG0~e.13 (r / repress-01~e.17 :ARG1-of (m / mediate-01~e.16 :ARG0 (p2 / protein~e.61 :name (n2 / name :op1 "Snail"~e.14))) :manner (i / in-vitro~e.18,19,43)) :ARG1 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.8 (p4 / promote-01~e.8 :ARG1 (p / protein~e.61 :name (n / name :op1 "E-cadherin"~e.4,6,36,38,55,57)))) :ARG1-of (d3 / direct-02~e.11) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and~e.34 :op1 4~e.22,75 :op2 12~e.26 :op3 13~e.30))))) :op2 (d / downregulate-01 :ARG1 p :location (b / bud~e.48 :mod (h / hair~e.47) :ARG3-of (e / express-03~e.46 :ARG2 p2)))) :ARG1 (e2 / examine-01~e.51 :ARG0 (w / we~e.50) :ARG1 (a2 / and~e.58 :op1 (s / status~e.53 :poss p) :op2 (s2 / status~e.53 :poss (p3 / protein~e.61 :name (n3 / name :op1 "AJ"~e.60) :mod (o / other~e.59))) :location~e.67 (r2 / region~e.63 :poss~e.64 (e3 / epidermis~e.66 :ARG0-of (p8 / proliferate-01~e.65 :degree~e.65 (h2 / hyper~e.65))) :ARG2-of (p7 / present-02~e.71 :ARG1 (p6 / protein~e.61 :name (n4 / name :op1 "Snail"~e.44,69) :mod (t2 / transgenic~e.68))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.74 :mod "4A")))) # ::id pmid_1563_0473.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In these regions , immunofluorescence staining of E @-@ cadherin and α-catenin were markedly diminished . # ::alignments 1-1.3.1 2-1.3 4-1.1.2 5-1.1 6-1.1.1.r 7-1.1.1.1.1.1 9-1.1.1.1.1.1 10-1.1.1 11-1.1.1.2.1.1 13-1.2 14-1 (d / diminish-01~e.14 :ARG1 (s / stain-01~e.5 :ARG1~e.6 (a2 / and~e.10 :op1 (p / protein :name (n / name :op1 "E-cadherin"~e.7,9)) :op2 (p2 / protein :name (n2 / name :op1 "α-catenin"~e.11))) :ARG2 (i / immunofluoresce-01~e.4)) :degree (m / marked~e.13) :location (r / region~e.2 :mod (t / this~e.1))) # ::id pmid_1563_0473.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the intensity of antibody staining for two other AJ proteins , β-catenin and Ajuba , was still strong . # ::alignments 1-1 4-1.1 5-1.1.1.r 6-1.1.1.2 7-1.1.1 8-1.1.1.1.r 9-1.1.1.1.1 10-1.1.1.1.4 11-1.1.1.1.2.1 12-1.1.1.1 12-1.1.1.1.3.1 12-1.1.1.1.3.2 14-1.1.1.1.3.1.1.1 15-1.1.1.1.3 16-1.1.1.1.3.2.1.1 19-1.1.2.1 20-1.1.2 (c / contrast-01~e.1 :ARG2 (i / intensity~e.4 :degree-of~e.5 (s / stain-01~e.7 :ARG1~e.8 (p / protein~e.12 :quant 2~e.9 :name (n / name :op1 "AJ"~e.11) :example (a2 / and~e.15 :op1 (p2 / protein~e.12 :name (n2 / name :op1 "β-catenin"~e.14)) :op2 (p3 / protein~e.12 :name (n3 / name :op1 "Ajuba"~e.16))) :mod (o / other~e.10)) :ARG2 (a / antibody~e.6)) :ARG1-of (s2 / strong-02~e.20 :mod (s3 / still~e.19)))) # ::id pmid_1563_0473.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , however , despite appreciable immunofluorescence , localization of β-catenin and Ajuba appeared to be largely cytoplasmic rather than at cell @-@ cell borders ( Figure 4 @ A insets ) . # ::alignments 2-1 4-1 5-1.2.1.1 6-1.2 9-1.1.1.2 10-1.1.1.1.1.1.1 11-1.1.1.1 12-1.1.1.1.2.1.1 13-1.1 16-1.1.2 17-1.1.1 18-1.1.1.2 21-1.1.1.2.1.1 23-1.1.1.2.1.1 23-1.1.1.2.1.2 24-1.1.1.2.1 27-1.3.1 (h / have-concession-91~e.2,4 :ARG1 (a / appear-02~e.13 :ARG1 (c / cytoplasmic~e.17 :location-of (a2 / and~e.11 :op1 (p / protein :name (n / name :op1 "β-catenin"~e.10)) :op2 (p2 / protein :name (n2 / name :op1 "Ajuba"~e.12))) :ARG1-of (i / instead-of-91~e.9,18 :ARG2 (b / border-01~e.24 :ARG1 (c2 / cell~e.21,23) :ARG2 (c3 / cell~e.23)))) :degree (l2 / large~e.16)) :ARG2 (i2 / immunofluoresce-01~e.6 :ARG1-of (a3 / appreciate-03 :ARG1-of (p3 / possible-01~e.5))) :ARG1-of (d / describe-01 :ARG2 (f / figure~e.27 :mod "4A" :mod (i4 / inset))) :ARG2-of (i3 / interest-01)) # ::id pmid_1563_0473.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Architectural differences in the epidermis made Western blot analyses somewhat difficult to gauge . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 4-1.1.2 5-1 6-1.2.1.1.1 7-1.2.1.1.1 8-1.2.1.1 9-1.2.2 10-1.2 12-1.2.1 (m / make-02~e.5 :ARG0 (d3 / differ-02~e.1 :ARG3 (a2 / architecture~e.0) :location~e.2 (e / epidermis~e.4)) :ARG1 (d / difficult~e.10 :domain (g / gauge-01~e.12 :ARG1 (a / analyze-01~e.8 :manner (i / immunoblot-01~e.6,7))) :degree (s / somewhat~e.9))) # ::id pmid_1563_0473.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in regions such as ear skin , where the highest levels of Snail protein were expressed , the effects were accentuated . # ::alignments 0-1 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.r 6-1.1.2.1.1 7-1.1.2.1 9-1.1.2.2.r 9-1.1.2.r 11-1.1.2.2.1 11-1.1.2.2.1.1 11-1.1.2.2.1.1.r 12-1.1.2.2 13-1.1.2.2.2.r 14-1.1.2.2.2.1.1 15-1.1.2.2.2 17-1.1.2.2.2.2 20-1.1.1 22-1.1 (h / have-concession-91~e.0 :ARG1 (a / accentuate-01~e.22 :ARG1 (a2 / affect-01~e.20) :location~e.9 (r / region~e.3 :example~e.4,5 (s / skin~e.7 :mod (e / ear~e.6)) :location-of~e.9 (l / level~e.12 :ARG1-of (h2 / high-02~e.11 :degree~e.11 (m2 / most~e.11)) :quant-of~e.13 (p / protein~e.15 :name (n / name :op1 "Snail"~e.14) :ARG2-of (e2 / express-03~e.17)))))) # ::id pmid_1563_0473.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In both back skin and ear skin , overall levels of E @-@ cadherin and α-catenin were reduced , under conditions where β-catenin and Ajuba levels remained unchanged relative to controls ( Figure 4 @ B ) . # ::alignments 2-1.2.1.1 3-1.2.1 3-1.2.2 4-1.2 5-1.2.2.1 6-1.2.2 8-1.1.3 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.1.1 13-1.1.1.1.1.1 14-1.1 15-1.1.2.1.1.1 17-1 20-1.3.r 21-1.2.r 22-1.3.1.2.1.1.1.1 23-1.3.1.2 24-1.3.1.2.2.1.1.1 25-1.1.2 25-1.3.1.2.1 25-1.3.1.2.2 26-1.3 27-1.3.1.1 30-1.3.2.1 33-1.4.1 (r / reduce-01~e.17 :ARG1 (a4 / and~e.14 :op1 (l / level~e.9 :quant-of~e.10 (p / protein :name (n / name :op1 "E-cadherin"~e.11,13))) :op2 (l3 / level~e.25 :quant-of (p2 / protein :name (n2 / name :op1 "α-catenin"~e.15))) :degree (o / overall~e.8)) :location~e.21 (a2 / and~e.4 :op1 (s / skin~e.3 :mod (b / back~e.2)) :op2 (s2 / skin~e.3,6 :mod (e / ear~e.5))) :condition~e.20 (r2 / remain-01~e.26 :ARG1 (c / change-01 :polarity -~e.27 :ARG1 (a / and~e.23 :op1 (l2 / level~e.25 :quant-of (p3 / protein :name (n3 / name :op1 "β-catenin"~e.22))) :op2 (l4 / level~e.25 :quant-of (p4 / protein :name (n4 / name :op1 "Ajuba"~e.24))))) :ARG1-of (r3 / relate-01 :ARG2 (c2 / control-01~e.30))) :ARG1-of (d / describe-01 :ARG2 (f / figure~e.33 :mod "4B"))) # ::id pmid_1563_0473.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these data were consistent with our results obtained from immunofluorescence microscopy . # ::alignments 0-1.2 1-1.2.1 3-1.1.2 4-1.1 6-1.1.1 7-1.1.1.1.r 8-1.1.1.1.2 8-1.1.1.1.2.r 9-1.1.1.1 9-1.1.1.1.1 9-1.1.1.1.1.r 10-1.1.1.1.1.1 11-1.1.1.1.1.1.2.r 12-1.1.1.1.1.1.2.1 13-1.1.1.1.1.1.2 (h / have-condition-91 :ARG1 (d / data~e.4 :ARG1-of (c / consistent-01~e.6 :ARG2~e.7 (t3 / thing~e.9 :ARG2-of~e.9 (r / result-01~e.9 :ARG1-of (o / obtain-01~e.10 :ARG0 w :ARG2~e.11 (m / microscopy~e.13 :mod (i / immunofluoresce-01~e.12)))) :poss~e.8 (w / we~e.8))) :mod (t4 / this~e.3)) :ARG2 (t / take-01~e.0 :mod (t5 / together~e.1))) # ::id pmid_1563_0473.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A priori , the decrease in α-catenin levels could be due to either direct transcriptional repression by Snail or perturbations in AJ formation caused by the decrease in E @-@ cadherin gene expression . # ::alignments 0-1.2 1-1.2 4-1.1 5-1.1.1.r 6-1.1.1.1.1.1 7-1.1.1 8-1 10-1.1.2 11-1.1.2 13-1.1.2.1.1.2.1 14-1.1.2.1.1.2 15-1.1.2.1.1 16-1.1.2.1.1.1.r 17-1.1.2.1.1.1.1.1 18-1.1.2.1 19-1.1.2.1.2 20-1.1.2.1.2.1.r 21-1.1.2.1.2.1.1.1.1 22-1.1.2.1.2.1 23-1.1.2.1.2.2 24-1.1.2.1.2.2.1.r 26-1.1.2.1.2.2.1 29-1.1.2.1.2.2.1.1.1.1.1 31-1.1.2.1.2.2.1.1.1.1.1 33-1.1.2.1.2.2.1.1.1 34-1.1.2.1.2.2.1.1 (p / possible-01~e.8 :ARG1 (d / decrease-01~e.4 :ARG1~e.5 (l / level~e.7 :quant-of (p2 / protein :name (n / name :op1 "α-catenin"~e.6))) :ARG1-of (c / cause-01~e.10,11 :ARG0 (o / or~e.18 :op1 (r / repress-01~e.15 :ARG0~e.16 (p3 / protein :name (n2 / name :op1 "Snail"~e.17)) :ARG2 (t / transcribe-01~e.14 :ARG1-of (d2 / direct-02~e.13))) :op2 (p4 / perturb-01~e.19 :ARG1~e.20 (f / form-01~e.22 :ARG1 (p5 / protein :name (n3 / name :op1 "AJ"~e.21))) :ARG1-of (c2 / cause-01~e.23 :ARG0~e.24 (d3 / decrease-01~e.26 :ARG1 (e / express-03~e.34 :ARG1 (g2 / gene~e.33 :name (n4 / name :op1 "E-cadherin"~e.29,31))))))))) :time (a / a-priori~e.0,1)) # ::id pmid_1563_0473.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To distinguish between these possibilities , we tested whether α-catenin levels could be restored by exogenous expression of E @-@ cadherin in Snail @-@ expressing keratinocytes . # ::alignments 1-1.3 3-1.3.2.1 4-1.3.2 6-1.1 7-1 8-1.2.1.1 8-1.2.1.1.r 9-1.2.1.3.1.1.1 10-1.2.1.3 11-1.2 13-1.2.1 14-1.2.1.4.r 15-1.2.1.4.2 16-1.2.1.4 16-1.2.1.4.3.2 19-1.2.1.4.1.1.1 21-1.2.1.4.1.1.1 23-1.2.1.4.3.r 24-1.2.1.4.3.2.1.1.1 26-1.2.1.4.3.2 27-1.2.1.4.3.1.1 (t / test-01~e.7 :ARG0 (w / we~e.6) :ARG1 (p / possible-01~e.11 :ARG1 (r / restore-01~e.13 :mode~e.8 interrogative~e.8 :ARG0 w :ARG1 (l / level~e.10 :quant-of (p2 / protein :name (n / name :op1 "α-catenin"~e.9))) :manner~e.14 (e / express-03~e.16 :ARG2 (p3 / protein :name (n2 / name :op1 "E-cadherin"~e.19,21)) :mod (e2 / exogenous~e.15) :location~e.23 (c / cell :name (n3 / name :op1 "keratinocyte"~e.27) :ARG3-of (e3 / express-03~e.16,26 :ARG2 (p4 / protein :name (n4 / name :op1 "Snail"~e.24))))))) :purpose (d / distinguish-01~e.1 :ARG0 w :ARG1 (p5 / possible-01~e.4 :mod (t2 / this~e.3)))) # ::id pmid_1563_0473.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 4 @ C , transiently transfected keratinocytes expressing HA @-@ tagged Snail displayed a loss of E @-@ cadherin and α-catenin at cell @-@ cell borders . # ::alignments 1-1.3 4-1.3.1 9-1.1.2.1 10-1.1.2 11-1.1.1.1 12-1.1.3 13-1.1.3.1.2.1.1.1 15-1.1.3.1.2 16-1.1.3.1.1.1 17-1 19-1.2 20-1.2.2.r 21-1.2.2.1.1.1 23-1.2.2.1.1.1 24-1.2.2 25-1.2.2.2.1.1 26-1.2.3.r 27-1.2.3.1 29-1.2.3.1 29-1.2.3.2 30-1.2.3 (d / display-01~e.17 :ARG0 (c / cell :name (n / name :op1 "keratinocyte"~e.11) :ARG1-of (t / transfect-01~e.10 :ARG1-of (t2 / transient-02~e.9)) :ARG3-of (e / express-03~e.12 :ARG2 (p / protein :name (n2 / name :op1 "Snail"~e.16) :ARG1-of (t3 / tag-01~e.15 :ARG2 (p4 / protein :name (n6 / name :op1 "HA"~e.13)))))) :ARG1 (l / lose-02~e.19 :ARG0 c :ARG1~e.20 (a / and~e.24 :op1 (p2 / protein :name (n4 / name :op1 "E-cadherin"~e.21,23)) :op2 (p3 / protein :name (n5 / name :op1 "α-catenin"~e.25))) :location~e.26 (b / border-01~e.30 :ARG1 (c2 / cell~e.27,29) :ARG2 (c3 / cell~e.29))) :ARG1-of (s / show-01~e.1 :ARG0 (f / figure~e.4 :mod "4C"))) # ::id pmid_1563_0473.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Coexpression of exogenous HA @-@ tagged E @-@ cadherin not only enabled cell @-@ cell border localization of E @-@ cadherin protein , but also rescued the cell @-@ cell border staining of α-catenin ( Figure 4 @ C ) . # ::alignments 2-1.1.1.3 3-1.1.1.2.1.1.1 5-1.1.1.2 6-1.1.1.1.1 8-1.1.1.1.1 11-1 12-1.2.1.2.1 14-1.2.1.2.1 14-1.2.1.2.2 15-1.2.1.2 16-1.2.1 18-1.1.1.1.1 20-1.1.1.1.1 21-1.1.1 21-1.1.1.2.1 21-1.2.2.1.1 24-1.2.2.2 25-1.2.2 27-1.2.2.1.2 28-1.2.2.1.2 29-1.2.2.1.2 30-1.2.2.1.2 31-1.2.2.1 33-1.2.2.1.1.1.1 36-1.3.1 (e / enable-01~e.11 :ARG0 (c / coexpress-01 :ARG2 (p / protein~e.21 :name (n / name :op1 "E-cadherin"~e.6,8,18,20) :ARG1-of (t / tag-01~e.5 :ARG2 (p4 / protein~e.21 :name (n5 / name :op1 "HA"~e.3))) :mod (e3 / exogenous~e.2))) :ARG1 (a / and :op1 (b2 / be-located-at-91~e.16 :ARG1 p :mod (b / border-01~e.15 :ARG1 (c2 / cell~e.12,14) :ARG2 (c3 / cell~e.14))) :op2 (r / rescue-01~e.25 :ARG1 (s / stain-01~e.31 :ARG1 (p3 / protein~e.21 :name (n4 / name :op1 "α-catenin"~e.33)) :mod b~e.27,28,29,30) :mod (a2 / also~e.24))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "4C"))) # ::id pmid_1563_0473.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The ability to restore α-catenin expression and localization under these conditions argues against the notion that Snail transcriptionally represses α-catenin . # ::alignments 3-1.1.1 4-1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2 9-1.1.1.2 10-1.1.1.2.r 11-1 12-1.2 14-1.2.1 16-1.2.1.1.1.1.1 17-1.2.1.1.3 18-1.2.1.1 20-1.2.1.1.2.1.1 (a3 / argue-01~e.11 :ARG1 (p / possible-01 :ARG1 (r / restore-01~e.3 :ARG1 (a / and~e.6 :op1 (e / express-03~e.5 :ARG2 p4~e.4) :op2 (l / localize-01~e.7 :ARG1 p4)) :condition~e.10 (t / this~e.9))) :ARG0-of (c / counter-01~e.12 :ARG1 (n2 / notion~e.14 :topic (r2 / repress-01~e.18 :ARG0 (p3 / protein :name (n3 / name :op1 "Snail"~e.16)) :ARG1 (p4 / protein :name (n4 / name :op1 "α-catenin"~e.20)) :ARG2 (t2 / transcribe-01~e.17))))) # ::id pmid_1563_0473.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rather , the findings are consistent with a previous report that E @-@ cadherin is required for the translation of α-catenin mRNA [ @ 22 @ ] . # ::alignments 0-1.3 3-1.1 3-1.1.1 3-1.1.1.r 5-1 6-1.2.r 8-1.2.2 9-1.2 10-1.2.1.r 11-1.2.1.2.1.1 13-1.2.1.2.1.1 15-1.2.1 16-1.2.1.1.r 18-1.2.1.1 21-1.2.1.1.1.2.1.1.1 23-1.2.1.1.1.1.1 26-1.4.1.1.1 (c / consistent-01~e.5 :ARG1 (t / thing~e.3 :ARG1-of~e.3 (f / find-01~e.3)) :ARG2~e.6 (r2 / report-01~e.9 :ARG1~e.10 (r3 / require-01~e.15 :ARG0~e.16 (t2 / translate-02~e.18 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.23) :ARG0-of (e / encode-01 :ARG1 (p3 / protein :name (n3 / name :op1 "α-catenin"~e.21))))) :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin"~e.11,13))) :time (p / previous~e.8)) :mod (r / rather~e.0) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 22~e.26)))) # ::id pmid_1563_0473.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the reductions in AJ markers , Tg skin still displayed sealed membranes and intercellular junctions that were largely intact , as judged by ultrastructural analyses ( unpublished data ) . # ::alignments 0-1.4.r 2-1.4 3-1.4.1.r 4-1.4.1.1.1.1 5-1.4.1 7-1.1.1 8-1.1 9-1.3 10-1 11-1.2.1.1 12-1.2.1 13-1.2 14-1.2.2.1 15-1.2.2 18-1.2.3.1 19-1.2.3 21-1.2.3.2.r 22-1.2.3.2 23-1.2.3.2.1.r 24-1.2.3.2.1.1 25-1.2.3.2.1 27-1.5.1.1.1 28-1.5.1 (d / display-01~e.10 :ARG0 (s / skin~e.8 :mod (t / transgenic~e.7)) :ARG1 (a / and~e.13 :op1 (m / membrane~e.12 :ARG1-of (s3 / seal-01~e.11)) :op2 (j / junction~e.15 :mod (i2 / intercellular~e.14)) :mod (i / intact~e.19 :degree (l / large~e.18) :ARG1-of~e.21 (j2 / judge-01~e.22 :ARG3~e.23 (a2 / analyze-01~e.25 :mod (u / ultrastructural~e.24))))) :mod (s2 / still~e.9) :concession~e.0 (r / reduce-01~e.2 :ARG1~e.3 (m2 / marker~e.5 :mod (p2 / protein :name (n2 / name :op1 "AJ"~e.4)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.28 :ARG1-of (p / publish-01 :polarity -~e.27)))) # ::id pmid_1563_0473.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this respect , the skin epithelium resembled that of the hair bud , where the down @-@ regulation in junction proteins is permissive for cell @-@ cell remodeling without abrogating intercellular adhesion . # ::alignments 0-1.3 1-1.3.1 2-1.3 5-1.1.1 6-1.1 6-1.2 7-1 9-1.2.1.r 11-1.2.1.1 12-1.2.1 14-1.2.2.r 16-1.2.2.1 17-1.2.2.1 18-1.2.2.1 19-1.2.2.1.1.r 19-1.3 20-1.2.2.1.1.1 21-1.2.2.1.1 23-1.2.2 24-1.2.2.2.r 25-1.2.2.2.2.1 25-1.2.2.2.2.2 27-1.2.2.2.2.1 27-1.2.2.2.2.2 28-1.2.2.2 29-1.2.2.3.1 29-1.2.2.3.1.r 30-1.2.2.3 31-1.2.2.3.2.1 32-1.2.2.3.2 (r / resemble-01~e.7 :ARG1 (e / epithelium~e.6 :part-of (s / skin~e.5)) :ARG2 (e2 / epithelium~e.6 :poss~e.9 (b / bud~e.12 :mod (h / hair~e.11)) :location-of~e.14 (p / permissive-02~e.23 :ARG0 (d / downregulate-01~e.16,17,18 :location~e.19 (p2 / protein~e.21 :mod (j / junction~e.20))) :ARG1~e.24 (r3 / remodel-01~e.28 :ARG0 d :ARG1 (a / and :op1 (c / cell~e.25,27) :op2 (c2 / cell~e.25,27))) :ARG0-of (a2 / abrogate-01~e.30 :polarity~e.29 -~e.29 :ARG1 (a3 / adhere-01~e.32 :mod (i / intercellular~e.31))))) :mod (i2 / in-respect~e.0,2,19 :mod (t / this~e.1))) # ::id pmid_1563_0473.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The similarities between Snail Tg epidermis and hair buds extended to the hyperproliferative state , leading us to wonder whether the down @-@ regulation of AJ proteins might contribute to this condition . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 4-1.1.1.1.1.1.1.1 6-1.1.1.1.1.1.2 7-1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2.1 10-1.1.1.1.2 11-1 12-1.2.r 14-1.2.1 14-1.2.1.1 14-1.2.1.1.r 15-1.2 17-1.3 18-1.3.1 20-1.3.2 21-1.3.2.2.1 21-1.3.2.2.1.r 23-1.3.2.2.2.1 24-1.3.2.2.2.1 25-1.3.2.2.2.1 26-1.3.2.2.2.1.1.r 27-1.3.2.2.2.1.1.1.1 28-1.3.2.2.2.1.1 29-1.3.2.2 30-1.3.2.2.2 31-1.3.2.2.2.2.r 32-1.3.2.2.2.2.1 33-1.3.2.2.2.2 (e3 / extend-01~e.11 :ARG0 (t2 / thing~e.1 :ARG1-of~e.1 (r2 / resemble-01~e.1 :ARG2 (a / and~e.8 :op1 (e2 / epidermis~e.7 :mod (g / gene :name (n2 / name :op1 "Snail"~e.4) :mod (t3 / transgenic~e.6))) :op2 (b / bud~e.10 :mod (h / hair~e.9))))) :ARG4~e.12 (s / state~e.15 :mod (p2 / proliferate-01~e.14 :degree~e.14 (h2 / hyper~e.14))) :ARG0-of (l / lead-03~e.17 :ARG1 (w / we~e.18) :ARG2 (w2 / wonder-01~e.20 :ARG0 w :ARG1 (p / possible-01~e.29 :mode~e.21 interrogative~e.21 :ARG1 (c2 / contribute-01~e.30 :ARG0 (d / downregulate-01~e.23,24,25 :ARG1~e.26 (p3 / protein~e.28 :name (n / name :op1 "AJ"~e.27))) :ARG2~e.31 (c3 / condition~e.33 :mod (t / this~e.32))))))) # ::id pmid_1563_0473.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given the increase in pMAPK staining in Snail Tg epidermis ( see Figure 2 @ G ) , we used pMAPK levels as our assay to test whether the loss of E @-@ cadherin contributed to the Snail @-@ mediated increase in proliferation . # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 4-1.1.1.1.3 5-1.1.1 8-1.1.1.1.2.1.1.1 10-1.1.1.1.2.1.2 11-1.1.1.1.2 13-1.1.2 15-1.1.2.1 21-1.2.1 22-1.2 23-1.2.2.1 24-1.2.2 25-1.2.3.r 26-1.2.3.1 26-1.2.3.1.r 27-1.2.3 29-1.2.3.2 30-1.2.3.2.3.1 30-1.2.3.2.3.1.r 32-1.2.3.2.3.2 33-1.2.3.2.3.2.1.r 34-1.2.3.2.3.2.1.1.1 36-1.2.3.2.3.2.1.1.1 37-1.2.3.2.3 38-1 40-1.2.3.2.3.3.2.1 42-1.2.3.2.3.3.2 43-1.2.3.2.3.3 44-1.2.3.2.3.3.1.r 45-1.2.3.2.3.3.1 (c / cause-01~e.38 :ARG0 (i / increase-01~e.2 :ARG1~e.3 (s / stain-01~e.5 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MAPK"~e.4) :location (e / epidermis~e.11 :mod (g / gene :name (n / name :op1 "Snail"~e.8) :mod (t2 / transgenic~e.10))) :ARG3-of (p2 / phosphorylate-01~e.4))) :ARG1-of (s2 / see-01~e.13 :ARG2 (f / figure~e.15 :mod "2G"))) :ARG1 (u / use-01~e.22 :ARG0 (w / we~e.21) :ARG1 (l / level~e.24 :quant-of e2~e.23) :ARG2~e.25 (a / assay-01~e.27 :ARG0~e.26 w~e.26 :purpose (t / test-01~e.29 :ARG0 w :ARG1 l :ARG2 (c2 / contribute-01~e.37 :mode~e.30 interrogative~e.30 :ARG0 (l2 / lose-02~e.32 :ARG1~e.33 (p4 / protein :name (n3 / name :op1 "E-cadherin"~e.34,36))) :ARG2 (i2 / increase-01~e.43 :ARG1~e.44 (p5 / proliferate-01~e.45) :ARG1-of (m / mediate-01~e.42 :ARG0 g~e.40))))))) # ::id pmid_1563_0473.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with our in vivo observations , transfected keratinocytes expressing Snail exhibited a substantial increase in pMAPK levels relative to control cells ( Figure 4 @ D ) . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.1.1 2-1.4.1.1.1.r 3-1.4.1.1.2 4-1.4.1.1.2 5-1.4.1 5-1.4.1.1 5-1.4.1.1.r 7-1.1.1 8-1.1 9-1.1.2 10-1.1.2.1.1.1 11-1 13-1.2.2 14-1.2 15-1.2.1.r 15-1.4.1.1.2 16-1.2.1.1.1.1 16-1.2.1.1.2 17-1.2.1 18-1.2.1.2 19-1.2.1.2.1.r 20-1.2.1.2.1.1 21-1.2.1.2.1 24-1.3.1 (e / exhibit-01~e.11 :ARG0 (k / keratinocyte~e.8 :ARG1-of (t / transfect-01~e.7) :ARG3-of (e2 / express-03~e.9 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.10)))) :ARG1 (i / increase-01~e.14 :ARG1~e.15 (l / level~e.17 :quant-of (e3 / enzyme :name (n2 / name :op1 "MAPK"~e.16) :ARG3-of (p2 / phosphorylate-01~e.16)) :ARG1-of (r / relative-05~e.18 :ARG3~e.19 (c / cell~e.21 :ARG0-of (c2 / control-01~e.20)))) :mod (s / substantial~e.13)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "4D")) :ARG1-of (c3 / consistent-01~e.0 :ARG2~e.1 (t2 / thing~e.5 :ARG1-of~e.5 (o / observe-01~e.5 :ARG0~e.2 (w / we~e.2) :manner (i2 / in-vivo~e.3,4,15))))) # ::id pmid_1563_0473.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Coexpression of E @-@ cadherin with Snail appeared to abrogate this effect . # ::alignments 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 6-1.1.1.1.2.1.1 7-1 9-1.1 10-1.1.2.1 11-1.1.2 (a / appear-02~e.7 :ARG1 (a2 / abrogate-01~e.9 :ARG0 (e2 / express-03 :ARG2 (a3 / and :op1 (p / protein :name (n / name :op1 "E-cadherin"~e.2,4)) :op2 (p2 / protein :name (n2 / name :op1 "Snail"~e.6)))) :ARG1 (a4 / affect-01~e.11 :mod (t / this~e.10)))) # ::id pmid_1563_0473.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these findings raised the possibility that an AJ @-@ associated protein that is normally sequestered at the plasma membrane may participate in a proliferation signaling pathway when AJs are deconstructed . # ::alignments 0-1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 6-1.2 7-1.2.1.r 9-1.2.1.1.1.1.1.1.1 11-1.2.1.1.1.1 12-1.2.1.1.1 15-1.2.1.1.1.2.1 16-1.2.1.1.1.2 17-1.2.1.1.1.2.2.r 19-1.2.1.1.1.2.2.1 20-1.2.1.1.1.2.2 21-1.2.1 22-1.2.1.1 23-1.2.1.1.2.r 25-1.2.1.1.2 26-1.2.1.1.2.1.1 27-1.2.1.1.2.1 28-1.2.1.1.3.r (r / raise-01~e.4 :ARG0 (t / thing~e.3 :ARG1-of~e.3 (f / find-01~e.3) :mod (t2 / this~e.2)) :ARG1 (p6 / possible-01~e.6 :ARG1~e.7 (p2 / possible-01~e.21 :ARG1 (p3 / participate-01~e.22 :ARG0 (p7 / protein~e.12 :ARG1-of (a / associate-01~e.11 :ARG2 (p8 / protein :name (n2 / name :op1 "AJ"~e.9))) :ARG1-of (s2 / sequester-01~e.16 :ARG1-of (n / normal-02~e.15) :location~e.17 (m / membrane~e.20 :part-of (p9 / plasma~e.19)))) :ARG1~e.23 (p4 / proliferate-01~e.25 :ARG0 (p5 / pathway~e.27 :ARG0-of (s / signal-07~e.26))) :time~e.28 (c / construct-01 :polarity - :ARG1 p8)))) :mod (t3 / together~e.0)) # ::id pmid_1563_0473.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Numerous studies have correlated a down @-@ regulation of E @-@ cadherin with a translocation of β-catenin to the nucleus and a transactivation of genes that are regulated by the LEF @-@ 1/T cell factor ( TCF ) family of DNA binding proteins [ @ 23 , 24 , 25 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 5-1.2 6-1.2 7-1.2 8-1.2.1.r 9-1.2.1.1.1 11-1.2.1.1.1 12-1.3.r 14-1.3.1 15-1.3.1.1.r 16-1.3.1.1.1.1 17-1.3.1.2.r 19-1.3.1.2 20-1.3 22-1.3.2 23-1.3.2.1.r 24-1.3.2.1 27-1.3.2.1.1 28-1.3.2.1.1.1.r 30-1.3.2.1.1.1.1.1 33-1.3.2.1.1.1.1.2 34-1.3.2.1.1.1.1.3 38-1.3.2.1.1.1 39-1.3.2.1.1.1.2.r 40-1.3.2.1.1.1.2.1.1.2.1 41-1.3.2.1.1.1.2.1 42-1.3.2.1.1.1.2 45-1.4.1.1.1.1 49-1.4.1.1.1.2 53-1.4.1.1.1.3 (c / correlate-01~e.3 :ARG0 (s / study-01~e.1 :quant (n / numerous~e.0)) :ARG1 (d3 / downregulate-01~e.5,6,7 :ARG1~e.8 (p / protein :name (n2 / name :op1 "E-cadherin"~e.9,11))) :ARG2~e.12 (a / and~e.20 :op1 (t / translocate-01~e.14 :ARG1~e.15 (p2 / protein :name (n3 / name :op1 "β-catenin"~e.16)) :ARG2~e.17 (n4 / nucleus~e.19)) :op2 (t2 / transactivate-01~e.22 :ARG1~e.23 (g / gene~e.24 :ARG1-of (r2 / regulate-01~e.27 :ARG0~e.28 (p5 / protein-family~e.38 :name (n9 / name :op1 "LEF-1/T"~e.30 :op2 "cell"~e.33 :op3 "factor"~e.34) :poss~e.39 (p3 / protein~e.42 :ARG1-of (b / bind-01~e.41 :ARG2 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA"~e.40))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 23~e.45 :op2 24~e.49 :op3 25~e.53))))) # ::id pmid_1563_0473.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The presence of nuclear cyclin D in hyperproliferative Snail Tg epidermis was particularly intriguing since prior studies have reported cyclin D gene as a direct target of TCF/β-catenin transcription [ @ 26 @ ] . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 4-1.1.1.1.1 5-1.1.1.1.2 6-1.1.2.r 7-1.1.2.2 7-1.1.2.2.1 7-1.1.2.2.1.r 9-1.1.2.1.1.1 11-1.1.2.1.2 12-1.1.2 14-1.2 14-1.2.r 15-1 16-1.3 17-1.3.1.1.1 18-1.3.1.1 20-1.3.1 22-1.3.1.2.2.1.1 23-1.3.1.2.2.1.2 25-1.1.2.1 25-1.3.1.2.2 26-1.3.1.1.1.r 28-1.3.1.2.3 29-1.3.1.2 32-1.3.1.2.1 35-1.4.1.1.1 (i / intrigue-01~e.15 :ARG0 (p8 / present-02~e.1 :ARG1~e.2 (p9 / protein :name (n7 / name :op1 "cyclin"~e.4 :op2 "D"~e.5) :mod (n2 / nucleus~e.3)) :ARG2~e.6 (e / epidermis~e.12 :mod (g2 / gene~e.25 :name (n3 / name :op1 "Snail"~e.9) :mod (t3 / transgenic~e.11)) :ARG0-of (p / proliferate-01~e.7 :degree~e.7 (h / hyper~e.7)))) :manner~e.14 (p3 / particular~e.14) :ARG1-of (c5 / cause-01~e.16 :ARG0 (r / report-01~e.20 :ARG0 (s / study-01~e.18 :time~e.26 (p4 / prior~e.17)) :ARG1 (t / target-01~e.29 :ARG0 (t2 / transcribe-01~e.32 :ARG1 (s2 / slash :op1 (p7 / protein :name (n6 / name :op1 "TCF")) :op2 (p5 / protein :name (n5 / name :op1 "β-catenin")))) :ARG1 (g / gene~e.25 :name (n4 / name :op1 "cyclin"~e.22 :op2 "D"~e.23)) :ARG1-of (d / direct-02~e.28)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 26~e.35)))) # ::id pmid_1563_0473.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This said , we did not detect nuclear β-catenin in our Tg epidermis , and mating the Snail Tg mice against the TOPGal reporter mouse [ @ 20 @ ] gave no signs of ectopic LEF @-@ 1/Tcf/β-catenin activity ( unpublished data ) . # ::alignments 0-1.1.1 1-1.1 3-1.2.1.2 5-1.2.1.1 5-1.2.1.1.r 6-1.2.1 7-1.2.1.3.2 8-1.2.1.3.1.1 8-1.2.2.3.1.1.3.1.1 9-1.2.1.4.r 10-1.2.1.4.2 10-1.2.1.4.2.r 11-1.2.1.4.1 12-1.2.1.4 14-1.2 15-1.2.2.2 17-1.2.2.2.2.1.1.1 18-1.2.2.2.2.1.2 19-1.2.2.2.2 19-1.2.2.2.3 22-1.2.2.2.3.1.1 23-1.2.2.2.3.2 24-1.2.2.2.3 27-1.2.2.2.3.3.1.1.1 30-1.2.2 31-1.2.2.1 31-1.2.2.1.r 32-1.2.2.3 33-1.2.2.3.1.r 34-1.2.2.3.1.1.4 35-1.2.2.3.1.1.1.1.1 38-1.2.2.3.1 40-1.2.2.1 40-1.2.3.1.1.1 41-1.2.3.1 (c2 / cause-01 :ARG0 (s2 / say-01~e.1 :ARG1 (t2 / this~e.0)) :ARG1 (a3 / and~e.14 :op1 (d / detect-01~e.6 :polarity~e.5 -~e.5 :ARG0 (w / we~e.3) :ARG1 (p2 / protein :name (n / name :op1 "β-catenin"~e.8) :mod (n7 / nucleus~e.7)) :location~e.9 (e / epidermis~e.12 :mod (t3 / transgenic~e.11) :poss~e.10 w~e.10)) :op2 (g / give-01~e.30 :polarity~e.31 -~e.31,40 :ARG0 (m / mate-02~e.15 :ARG0 w :ARG1 (m2 / mouse~e.19 :mod (p4 / protein :name (n3 / name :op1 "Snail"~e.17) :mod (t / transgenic~e.18))) :ARG2 (m5 / mouse~e.19,24 :name (n9 / name :op1 "TopGal"~e.22) :ARG0-of (r / report-01~e.23) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG0-of (c / cite-01 :ARG2 20~e.27))))) :ARG1 (s / signal-07~e.32 :ARG1~e.33 (a / activity-06~e.38 :ARG0 (m4 / macro-molecular-complex :part (p7 / protein :name (n4 / name :op1 "LEF-1"~e.35)) :part (p5 / protein :name (n5 / name :op1 "Tcf")) :part (p8 / protein :name (n6 / name :op1 "β-catenin"~e.8)) :mod (e2 / ectopic~e.34))))) :ARG1-of (d4 / describe-01 :ARG0 (d5 / data~e.41 :ARG1-of (p6 / publish-01 :polarity -~e.40))))) # ::id pmid_1563_0473.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next turned to the presence of cytoplasmic Ajuba for a possible mechanistic link to the proliferative increase in our Snail Tg epidermis . # ::alignments 0-1.1 1-1.4 2-1 3-1.2.r 5-1.2 6-1.2.1.r 7-1.2.1.2 8-1.2.1.1.1 9-1.3.r 11-1.3.3 12-1.3.4 13-1.3 17-1.3.2 19-1.1 21-1.3.2.1.1.1.1 23-1.3.2.1.1.2 24-1.3.2.1 (t / turn-01~e.2 :ARG1 (w / we~e.0,19) :direction~e.3 (p / present-02~e.5 :ARG1~e.6 (p4 / protein :name (n / name :op1 "Ajuba"~e.8) :mod (c / cytoplasm~e.7))) :purpose~e.9 (l / link-01~e.13 :ARG1 p4 :ARG2 (i / increase-01~e.17 :ARG1 (e / epidermis~e.24 :mod (g / gene :name (n2 / name :op1 "Snail"~e.21) :mod (t2 / transgenic~e.23))) :ARG0-of (p3 / proliferate-01)) :ARG1-of (p2 / possible-01~e.11) :mod (m / mechanistic~e.12)) :time (n3 / next~e.1)) # ::id pmid_1563_0473.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to its documented ability to bind α-catenin [ @ 10 @ ] , Ajuba can also associate with growth factor receptor @-@ bound protein @-@ 2 ( Grb @-@ 2 ) / son of sevenless ( Sos ) , the nucleotide exchange factor for Ras , which is upstream from activation of MAPK [ @ 9 @ ] . # ::alignments 0-1 1-1 3-1.1.1 3-1.1.1.r 4-1.1.3 5-1.1 7-1.1.2 8-1.1.2.2.1.1 11-1.1.4.1.1.1 15-1.2.1.1.1.1 16-1.2 17-1.2.1.4 18-1.2.1 19-1.2.1.2.r 20-1.2.1.2.1.2.1.1 21-1.2.1.2.1.2.1.1 22-1.2.1.2.1.2.1 24-1.2.1.2.1 24-1.2.1.2.1.2 24-1.2.1.2.1.2.r 25-1.2.1.2.1.1.1 27-1.2.1.2.1.1.1 27-1.2.1.2.1.3.1.1.1 29-1.2.1.2.1.3.1.1.1 31-1.2.1.2.1.1.1 31-1.2.1.2.1.3.1.1.1 33-1.2.1.2 34-1.2.1.2.2.1.1 35-1.2.1.2.2.1.2 36-1.2.1.2.2.1.3 38-1.2.1.2.2.2.1.1.1 42-1.2.1.3.1.1 43-1.2.1.3.1 44-1.2.1.3 45-1.2.1.3.2.r 46-1.2.1.3.2.1.1 50-1.2.1.3.3.2 52-1.2.1.3.3.1 53-1.2.1.3.3.1.1.r 54-1.2.1.3.3.1.1.1.1 57-1.2.2.1.1.1 (a / and~e.0,1 :op1 (c3 / capable-01~e.5 :ARG1~e.3 p3~e.3 :ARG2 (b2 / bind-01~e.7 :ARG1 p3 :ARG2 (p8 / protein :name (n / name :op1 "α-catenin"~e.8))) :ARG1-of (d2 / document-01~e.4) :ARG1-of (d3 / describe-01 :ARG0 (p9 / publication :ARG0-of (c4 / cite-01 :ARG2 10~e.11)))) :op2 (p2 / possible-01~e.16 :ARG1 (a2 / associate-01~e.18 :ARG0 (p3 / protein :name (n4 / name :op1 "Ajuba"~e.15)) :ARG1~e.19 (s / slash~e.33 :op1 (p12 / protein~e.24 :name (n10 / name :op1 "protein-2"~e.25,27,31) :ARG1-of~e.24 (b / bind-01~e.24 :ARG2 (r2 / receptor~e.22 :mod (g / growth-factor~e.20,21))) :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n5 / name :op1 "Grb-2"~e.27,29,31)))) :op2 (p4 / protein :name (n9 / name :op1 "son"~e.34 :op2 "of"~e.35 :op3 "sevenless"~e.36) :ARG1-of (m2 / mean-01 :ARG2 (p11 / protein :name (n2 / name :op1 "Sos"~e.38))))) :ARG2 (f / factor~e.44 :mod (e / exchange-01~e.43 :ARG1 (n7 / nucleotide~e.42)) :purpose~e.45 (e2 / enzyme :name (n8 / name :op1 "Ras"~e.46)) :location (r / relative-position :op1 (a4 / activate-01~e.52 :ARG1~e.53 (p / pathway :name (n3 / name :op1 "MAPK"~e.54))) :direction (u / upstream~e.50))) :mod (a3 / also~e.17)) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG0-of (c2 / cite-01 :ARG2 9~e.57))))) # ::id pmid_1563_0473.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given the increase in pMAPK staining in Tg skin , we examined the possibility that Ajuba might have changed its binding partner in Snail @-@ expressing epidermis . # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 4-1.1.1.1.3 5-1.1.1 7-1.1.1.1.2.1 8-1.1.1.1.2 10-1.2.1 11-1.2 13-1.2.2 13-1.2.2.1 13-1.2.2.1.r 15-1.2.2.1.1.1.1.1 16-1.2.2.1 18-1.2.2.1.1 19-1.2.2.1.1.2.1.1 19-1.2.2.1.1.2.1.1.r 20-1.2.2.1.1.2.1 21-1.2.2.1.1.2 22-1.2.2.1.1.2.2.r 23-1.2.2.1.1.2.2.1.1.1.1 25-1.2.2.1.1.2.2.1 26-1.2.2.1.1.2.2 (c2 / cause-01 :ARG0 (i / increase-01~e.2 :ARG1~e.3 (s2 / stain-01~e.5 :ARG1 (e / enzyme :name (n3 / name :op1 "MAPK"~e.4) :location (s / skin~e.8 :mod (t / transgenic~e.7)) :ARG3-of (p / phosphorylate-01~e.4)))) :ARG1 (e4 / examine-01~e.11 :ARG0 (w / we~e.10) :ARG1 (p2 / possible-01~e.13 :ARG1~e.13 (p3 / possible-01~e.13,16 :ARG1 (c / change-01~e.18 :ARG0 (p7 / protein :name (n / name :op1 "Ajuba"~e.15)) :ARG1 (p4 / partner~e.21 :ARG2-of (b / bind-01~e.20 :ARG1~e.19 p4~e.19) :location~e.22 (e2 / epidermis~e.26 :ARG1-of (e3 / express-03~e.25 :ARG2 (p5 / protein :name (n2 / name :op1 "Snail"~e.23)))))))))) # ::id pmid_1563_0473.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , Ajuba was readily detected in anti @-@ Grb @-@ 2 immunoprecipitates of protein lysates from skins of Snail Tg mice but not from the corresponding wild @-@ type ( WT ) animals ( Figure 4 @ E ) . # ::alignments 0-1.3 0-1.3.r 2-1.1.1.1.1 4-1.1.2 4-1.1.2.r 5-1.1 5-1.2 6-1.1.3.r 7-1.1.3.2 12-1.1.3 12-1.1.3.1 12-1.1.3.1.r 13-1.1.3.1.1.r 14-1.1.3.1.1.1 15-1.1.3.1.1 16-1.1.3.1.1.2.r 17-1.1.3.1.1.2 20-1.1.3.1.1.2.1.1.1.1 22-1.1.3.1.1.2.2 23-1.1.3.1.1.2.1 24-1 25-1.2.1 25-1.2.1.r 26-1.2.3.1.r 28-1.2.3.1.2 29-1.2.3.1.1 31-1.2.3.1.1 33-1.2.3.1.1 33-1.2.3.1.1.1.1.1 35-1.2.3.1 38-1.4.1 (c / contrast-01~e.24 :ARG1 (d / detect-01~e.5 :ARG1 (p5 / protein :name (n / name :op1 "Ajuba"~e.2)) :manner~e.4 (r / ready~e.4) :location~e.6 (m2 / molecular-physical-entity~e.12 :ARG1-of~e.12 (i / immunoprecipitate-01~e.12 :ARG2~e.13 (l / lysate~e.15 :mod (p / protein~e.14) :source~e.16 (s / skin~e.17 :part-of (m / mice~e.23 :mod (g / gene :name (n4 / name :op1 "Snail"~e.20))) :mod (t / transgenic~e.22)))) :ARG0-of (c3 / counter-01~e.7 :ARG1 (p2 / protein :name (n3 / name :op1 "Grb2"))))) :ARG2 (d3 / detect-01~e.5 :polarity~e.25 -~e.25 :ARG1 p5 :location (m4 / molecular-physical-entity :source~e.26 (a / animal~e.35 :mod (w / wild-type~e.29,31,33 :ARG1-of (m3 / mean-01 :ARG2 (n2 / name :op1 "WT"~e.33))) :ARG1-of (c2 / correspond-02~e.28)) :ARG1-of i :ARG0-of c3)) :manner~e.0 (i2 / interesting~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.38 :mod "4E"))) # ::id pmid_1563_0473.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When these experiments were repeated with α-catenin @ -@ null epidermis , a similar Grb @-@ 2 @-@ Ajuba association was detected , and again , this interaction was not detected in the protein extracts from control littermate skin ( Figure 4 @ E ) . # ::alignments 0-1.3.r 1-1.3.1.2 2-1.3.1 2-1.3.1.1 2-1.3.1.1.r 4-1.3 7-1.3.1.1.1.2.1.1 10-1.3.1.1.1.3 11-1.3.1.1.1 14-1.1.1.2 15-1.1.1.1.1.1.1 17-1.1.1.1.1.1.1 19-1.1.1.1.2.1.1 20-1.1.1 22-1.1 24-1 25-1.2.4 27-1.2.2.3 28-1.2.2 30-1.2.1 30-1.2.1.r 30-1.3.1.1.1.1 31-1.2 32-1.2.3.r 34-1.2.3.1 35-1.2.3 36-1.2.3.2.r 37-1.2.3.2.2 38-1.2.3.2.1 39-1.2.3.2 42-1.4.1 (a / and~e.24 :op1 (d / detect-01~e.22 :ARG1 (a3 / associate-01~e.20 :ARG1 (m / macro-molecular-complex :part (p2 / protein :name (n3 / name :op1 "Grb-2"~e.15,17)) :part (p3 / protein :name (n2 / name :op1 "Ajuba"~e.19))) :ARG1-of (r2 / resemble-01~e.14))) :op2 (d2 / detect-01~e.31 :polarity~e.30 -~e.30 :ARG1 (i / interact-01~e.28 :ARG0 e2 :ARG1 p3 :mod (t3 / this~e.27)) :location~e.32 (e3 / extract-01~e.35 :ARG1 (p4 / protein~e.34) :ARG2~e.36 (s / skin~e.39 :mod (l / littermate~e.38) :ARG0-of (c / control-01~e.37))) :mod (a2 / again~e.25)) :time~e.0 (r / repeat-01~e.4 :ARG1 (t / thing~e.2 :ARG1-of~e.2 (e / experiment-01~e.2 :ARG2 (e2 / epidermis~e.11 :polarity -~e.30 :mod (p / protein :name (n / name :op1 "α-catenin"~e.7)) :mod (n4 / null~e.10))) :mod (t2 / this~e.1))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.42 :mod "4E"))) # ::id pmid_1563_0473.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these data demonstrate that the reduction in α-catenin levels , either by Snail @-@ mediated down @-@ regulation of E @-@ cadherin or by α-catenin conditional targeting , allows Ajuba to interact with Grb @-@ 2/Sos . # ::alignments 0-1.3 2-1.1.1 3-1.1 4-1 5-1.2.r 7-1.2.1 8-1.2.1.2.r 9-1.2.1.2.1.1.1 10-1.2.1.2 13-1.2.1.1.r 14-1.2.1.1.1.1.2.1.1.1 16-1.2.1.1.1.1.2 17-1.2.1.1.1 18-1.2.1.1.1 19-1.2.1.1.1 22-1.2.1.1.1.1.1.1 24-1.2.1.1.1.1.1.1 26-1.2.1.1 29-1.2.1.1.2.1 31-1.2.1.1.2.2 32-1.2.1.1.2 34-1.2 35-1.2.2.1.1 37-1.2.3 38-1.2.3.2.r 39-1.2.3.2.1.1.1 (d / demonstrate-01~e.4 :ARG0 (d2 / data~e.3 :mod (t / this~e.2)) :ARG1~e.5 (a / allow-02~e.34 :ARG0 (r / reduce-01~e.7 :ARG0~e.13 (o / or~e.26 :op1 (d3 / downregulate-01~e.17,18,19 :ARG1 (g2 / gene :name (n6 / name :op1 "E-cadherin"~e.22,24) :ARG1-of (m2 / mediate-01~e.16 :ARG0 (p5 / protein :name (n5 / name :op1 "Snail"~e.14))))) :op2 (t2 / target-01~e.32 :ARG1 g~e.29 :mod (c2 / conditional~e.31))) :ARG1~e.8 (l / level~e.10 :degree-of (g / gene :name (n4 / name :op1 "α-catenin"~e.9)))) :ARG1 (p / protein :name (n / name :op1 "Ajuba"~e.35)) :ARG2 (i / interact-01~e.37 :ARG0 p :ARG1~e.38 (m / macro-molecular-complex :part (p2 / protein :name (n2 / name :op1 "Grb-2"~e.39)) :part (p3 / protein :name (n3 / name :op1 "Sos"))))) :mod (t3 / together~e.0)) # ::id pmid_1563_0473.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If the competition between Grb @-@ 2/Sos and α-catenin for Ajuba is functionally relevant to the hyperproliferative state of a keratinocyte , then overexpression of Ajuba would be expected to bypass the competition and promote activation of the Ras @-@ MAPK pathway in WT keratinocytes . # ::alignments 0-1.2.r 2-1.2.1 4-1.2.1.1.1.1.1 8-1.2.1.2.1.1 9-1.2.1.3.r 10-1.2.1.3.1.1 12-1.2.3 12-1.2.3.r 13-1.2 14-1.2.2.r 16-1.2.2.1 16-1.2.2.1.1 16-1.2.2.1.1.r 17-1.2.2 18-1.2.2.2.r 20-1.2.2.2 23-1.1.1.1 24-1.1.1.1.1.r 25-1.1.1.1.1 28-1 30-1.1.1 32-1.1.1.2 33-1.1 34-1.1.2 35-1.1.2.2 36-1.1.2.2.1.r 38-1.1.2.2.1.1.1 40-1.1.2.2.1.1.1 41-1.1.2.2.1 42-1.1.2.2.2.r 43-1.1.2.2.2.1 44-1.1.2.2.2 (e / expect-01~e.28 :ARG1 (a / and~e.33 :op1 (b / bypass-01~e.30 :ARG0 (o / overexpress-01~e.23 :ARG1~e.24 p2~e.25) :ARG1 c~e.32) :op2 (p / promote-01~e.34 :ARG0 o :ARG1 (a2 / activate-01~e.35 :ARG1~e.36 (p8 / pathway~e.41 :name (n5 / name :op1 "Ras-MAPK"~e.38,40)) :location~e.42 (k2 / keratinocyte~e.44 :mod (w / wild-type~e.43))))) :condition~e.0 (r / relevant-01~e.13 :ARG1 (c / compete-01~e.2 :ARG0 (m / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "Grb-2"~e.4)) :part (p5 / protein :name (n3 / name :op1 "Sos"))) :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin"~e.8)) :ARG2~e.9 (p2 / protein :name (n / name :op1 "Ajuba"~e.10))) :ARG2~e.14 (s / state~e.17 :mod (p6 / proliferate-01~e.16 :degree~e.16 (h / hyper~e.16)) :mod~e.18 (k / keratinocyte~e.20)) :manner~e.12 (f / functional~e.12))) # ::id pmid_1563_0473.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , when serum @-@ starved keratinocytes were transiently transfected with an Ajuba expression vector , the levels of pMAPK were not only elevated but also comparable to those transfected with the K14 @-@ HASnail transgene ( Figure 4 @ F ) . # ::alignments 0-1.4 2-1.5.r 3-1.5.1.1.1 5-1.5.1.1 6-1.2.2.1 6-1.5.1 8-1.5.3 9-1.5 10-1.5.2.r 12-1.5.2.1.1.1.1 13-1.5.2.1 14-1.5.2 17-1.1.1 17-1.2.2 18-1.1.1.1.r 19-1.1.1.1.1.1 19-1.1.1.1.2 22-1.1.2 23-1.1 26-1.2 29-1.2.2.1.1 33-1.2.2.1.1.1.1.1 35-1.2.2.1.1.1.1.1 37-1.2.2.1.1.1 40-1.3.1 (a / and :op1 (e / elevate-01~e.23 :ARG1 (l / level~e.17 :quant-of~e.18 (e3 / enzyme :name (n / name :op1 "MAPK"~e.19) :ARG3-of (p / phosphorylate-01~e.19))) :mod (o / only~e.22)) :op2 (c / comparable-03~e.26 :ARG1 l :ARG2 (l2 / level~e.17 :location (k2 / keratinocyte~e.6 :ARG1-of (t4 / transfect-01~e.29 :ARG2 (t5 / transgene~e.37 :name (n3 / name :op1 "K14-HASnail"~e.33,35)))) :quant-of e3)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "4F")) :mod (i / indeed~e.0) :time~e.2 (t / transfect-01~e.9 :ARG1 (k / keratinocyte~e.6 :ARG1-of (s / starve-01~e.5 :ARG2 (s2 / serum~e.3))) :ARG2~e.10 (v / vector~e.14 :ARG1-of (e2 / express-03~e.13 :ARG2 (p2 / protein :name (n2 / name :op1 "Ajuba"~e.12)))) :ARG1-of (t2 / transient-02~e.8))) # ::id pmid_1563_0473.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This activation was abolished when cells were treated with a small peptide inhibitor that specifically interrupts the Grb @-@ 2/Sos interaction ( Figure 4 @ F ; see lanes marked “ inh ”) [ @ 27 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.4.r 5-1.4.1 7-1.4 8-1.4.2.r 10-1.4.2.2 11-1.4.2.1.1 12-1.4.2 12-1.4.2.1 12-1.4.2.1.r 14-1.4.2.3.2 15-1.4.2.3 17-1.4.2.3.1.1.1.1 20-1.4.2.3.1 23-1.2.1.1 28-1.2.1.2 29-1.2.1.2.1 30-1.2.1.2.1.1 32-1.2.1.2.1.1.1.1 36-1.3.1.1.1 (a / abolish-01~e.3 :ARG1 (a2 / activate-01~e.1 :mod (t3 / this~e.0)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.23 :mod "4F") :op2 (s3 / see-01~e.28 :ARG1 (l / lane~e.29 :ARG1-of (m / mark-01~e.30 :ARG0 (s4 / string-entity :value "inh"~e.32)))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG0-of (c3 / cite-01 :ARG2 27~e.36))) :time~e.4 (t2 / treat-04~e.7 :ARG1 (c2 / cell~e.5) :ARG2~e.8 (m2 / molecular-physical-entity~e.12 :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (p / peptide~e.11)) :mod (s / small~e.10) :ARG0-of (i2 / interrupt-01~e.15 :ARG1 (i3 / interact-01~e.20 :ARG0 (p2 / protein :name (n / name :op1 "Grb-2"~e.17)) :ARG1 (p3 / protein :name (n2 / name :op1 "Sos"))) :ARG1-of (s2 / specific-02~e.14))))) # ::id pmid_1563_0473.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ajuba 's pre @-@ LIM domain is the segment that associates with Grb @-@ 2 's Src @-@ homology 3 domain [ @ 9 @ ] . # ::alignments 0-1.3.1.1.1 1-1.3.1.r 1-1.3.r 2-1.3.2.1.1 4-1.3.2.1.1 5-1.3 6-1.3.r 8-1 10-1.1 11-1.1.1.r 12-1.1.1.2.1.1 14-1.1.1.2.1.1 15-1.1.1.2.r 16-1.1.1.1.1 18-1.1.1.1.1 19-1.1.1.1.2 20-1.1.1.1.3 20-1.3 23-1.2.1.1.1 (s / segment~e.8 :ARG1-of (a / associate-01~e.10 :ARG2~e.11 (p5 / protein-segment :name (n / name :op1 "Src-homology"~e.16,18 :op2 3~e.19 :op3 "domain"~e.20) :part-of~e.15 (p2 / protein :name (n2 / name :op1 "Grb-2"~e.12,14)))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 9~e.23))) :domain~e.1,6 (d3 / domain~e.5,20 :part-of~e.1 (p3 / protein :name (n3 / name :op1 "Ajuba"~e.0)) :mod (p4 / protein-segment :name (n4 / name :op1 "pre-LIM"~e.2,4)))) # ::id pmid_1563_0473.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When this domain was overexpressed in serum @-@ starved keratinocytes , a comparable elevation in pMAPK was observed ( Figure 4 @ F ) . # ::alignments 0-1.2.r 1-1.2.1.1 2-1.2.1 4-1.2 5-1.2.2.r 6-1.2.2.2.1 8-1.2.2.2 9-1.2.2.1.1 12-1.1.2 13-1.1 14-1.1.1.r 15-1.1.1.1.1 15-1.1.1.2 17-1 20-1.3.1 (o / observe-01~e.17 :ARG1 (e / elevate-01~e.13 :ARG1~e.14 (e2 / enzyme :name (n / name :op1 "MAPK"~e.15) :ARG3-of (p2 / phosphorylate-01~e.15)) :ARG1-of (c / comparable-03~e.12)) :time~e.0 (o2 / overexpress-01~e.4 :ARG1 (d / domain~e.2 :mod (t / this~e.1)) :location~e.5 (c2 / cell :name (n2 / name :op1 "keratinocyte"~e.9) :ARG1-of (s / starve-01~e.8 :ARG2 (s2 / serum~e.6)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.20 :mod "4F"))) # ::id pmid_1563_0473.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , the small peptide inhibitor that interrupts the Grb @-@ 2/Sos association blocked the effects . # ::alignments 1-1.3 4-1.1.1.1.1 5-1.1.1.1 6-1.1 6-1.1.1 6-1.1.1.r 8-1.1.2 10-1.1.2.1.1.1.1 13-1.1.2.1 14-1 16-1.2 (b / block-01~e.14 :ARG0 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6 :ARG1 (p / peptide~e.5 :mod (s / small~e.4))) :ARG0-of (i2 / interrupt-01~e.8 :ARG1 (a / associate-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2"~e.10)) :ARG2 (p3 / protein :name (n3 / name :op1 "Sos"))))) :ARG1 (e / effect~e.16) :ARG1-of (e2 / expect-01~e.1)) # ::id pmid_1563_0473.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggested that by elevating cytosolic Ajuba levels , Ajuba 's pre @-@ LIM domain may associate with Grb @-@ 2/Sos in a manner that stimulates its nucleotide exchange activity and leads to activation of the Ras @-@ MAPK pathway . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.r 5-1.2.1.4 6-1.2.1.4.1.1 7-1.2.1.4.1.1 8-1.2.1.4.1 10-1.2.1.1.2.1.1 11-1.2.1.1.2.r 12-1.2.1.1.1.1 14-1.2.1.1.1.1 16-1.2 17-1.2.1 18-1.2.1.2.r 19-1.2.1.2.1.1.1 24-1.2.1.3.r 24-1.2.1.4.r 26-1.2.1.3.1 28-1.2.1.3.1.2.2.1 29-1.2.1.3.1.2.2 30-1.2.1.3.1.2 31-1.2.1.3 32-1.2.1.3.2 33-1.2.1.3.2.2.r 34-1.2.1.3.2.2 35-1.2.1.3.2.2.1.r 37-1.2.1.3.2.2.1.1.1 39-1.2.1.3.2.2.1.1.1 40-1.2.1.3.2.2.1 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.4 (p / possible-01~e.16 :ARG1 (a / associate-01~e.17 :ARG1 (p2 / protein-segment :name (n / name :op1 "pre-LIM"~e.12,14) :part-of~e.11 (p3 / protein :name (n2 / name :op1 "Ajuba"~e.10) :location (c / cytosol))) :ARG2~e.18 (m / macro-molecular-complex :part (p4 / protein :name (n3 / name :op1 "Grb-2"~e.19)) :part (p5 / protein :name (n4 / name :op1 "Sos"))) :manner~e.24 (a2 / and~e.31 :op1 (s2 / stimulate-01~e.26 :ARG0 a :ARG1 (a3 / activity-06~e.30 :ARG0 p2 :ARG1 (e / exchange-01~e.29 :ARG1 (n5 / nucleotide~e.28)))) :op2 (l / lead-03~e.32 :ARG0 a :ARG2~e.33 (a4 / activate-01~e.34 :ARG1~e.35 (p6 / pathway~e.40 :name (n6 / name :op1 "Ras-MAPK"~e.37,39))))) :manner-of~e.24 (e2 / elevate-01~e.5 :ARG1 (l2 / level~e.8 :degree-of p3~e.6,7))))) # ::id pmid_1563_0473.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although this pathway provides one mechanism by which Snail expression and proliferation may be coupled in skin epithelium , proliferative circuitries involving AJs are known to be complex and often interwoven . # ::alignments 0-1.2.r 1-1.2.1.1 2-1.2.1 3-1.2 4-1.2.2.1.4.1 5-1.2.2.1.4 8-1.2.2.1.1.1.1.1 9-1.2.2.1.1 11-1.1.1.1.1 11-1.2.2.1.2 12-1.2.2 14-1.2.2.1 15-1.2.2.1.3.r 16-1.2.2.1.3.1 17-1.2.2.1.3 20-1.1.1.1 21-1.1.1.1.2 23-1.1.1.1.r 24-1 26-1.1.1.1.r 27-1.1.1 28-1.1 29-1.1.2.2 (k / know-01~e.24 :ARG1 (a / and~e.28 :op1 (c / complex~e.27 :domain~e.23,26 (c2 / circuitry~e.20 :ARG0-of (p / proliferate-01~e.11) :ARG2-of (i / involve-01~e.21 :ARG1 (p2 / protein :name (n / name :op1 "AJ"))))) :op2 (i2 / interweave-01 :ARG1 c2 :frequency (o / often~e.29))) :concession~e.0 (p3 / provide-01~e.3 :ARG0 (p4 / pathway~e.2 :mod (t / this~e.1)) :ARG1 (p5 / possible-01~e.12 :ARG1 (c3 / couple-01~e.14 :ARG1 (e / express-03~e.9 :ARG2 (p6 / protein :name (n2 / name :op1 "Snail"~e.8))) :ARG2 (p7 / proliferate-01~e.11 :ARG0 p6) :location~e.15 (e2 / epithelium~e.17 :part-of (s / skin~e.16)) :instrument (m / mechanism~e.5 :quant 1~e.4))))) # ::id pmid_1563_0473.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Future studies will be needed to systematically dissect these putative intricacies at a molecular level . # ::alignments 0-1.1.1 1-1.1 4-1 6-1.2.2 7-1.2 8-1.2.1.1 9-1.2.1.2 10-1.2.1 11-1.2.3.r 13-1.2.3.1 14-1.2.3 (n / need-01~e.4 :ARG1 (s / study-01~e.1 :time (f / future~e.0)) :purpose (d / dissect-01~e.7 :ARG1 (i / intricacy~e.10 :mod (t / this~e.8) :ARG2-of (t2 / think-01~e.9)) :manner (s2 / systematic~e.6) :location~e.11 (l / level~e.14 :mod (m / molecule~e.13)))) # ::id pmid_1563_0473.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Probing the Regulation of Snail Gene Expression Reveals an Essential Link to TGF-β2 Signaling in the Developing Hair Bud # ::alignments 0-1.1 2-1.1.1 5-1.1.1.1.1.1.1 7-1.1.1.1.1 8-1.1.1.1 9-1 11-1.2.2 12-1.2 13-1.2.1.r 14-1.2.1.1.1.1 15-1.2.1 16-1.2.1.2.r 18-1.2.1.2.1 19-1.2.1.2.2 20-1.2.1.2 (r / reveal-01~e.9 :ARG0 (p / probe-01~e.0 :ARG1 (r2 / regulate-01~e.2 :ARG1 (e / express-03~e.8 :ARG1 (g / gene~e.7 :name (n / name :op1 "Snail"~e.5))))) :ARG1 (l / link-01~e.12 :ARG2~e.13 (s / signal-07~e.15 :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-β2"~e.14)) :location~e.16 (b / bud~e.20 :ARG1-of (d / develop-02~e.18) :mod (h / hair~e.19))) :mod (e2 / essential~e.11))) # ::id pmid_1563_0473.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The temporal spike of Snail mRNA expression in the hair bud prompted us to consider what factor( s ) may be regulating the Snail gene . # ::alignments 1-1.1.2 1-1.1.2.r 2-1.1 5-1.1.1.1.2.1.1.1 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.r 11-1.1.1.2.1 12-1.1.1.2 13-1 14-1.2.1 16-1.2 21-1.2.2.2.2 23-1.2.2.2 26-1.2.2.2.1 27-1.2.2.2.1 28-1.2.2.2.1 (p / prompt-01~e.13 :ARG0 (s / spike-04~e.2 :ARG1 (e / express-03~e.8 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "mRNA"~e.7) :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "Snail"~e.5)))) :location~e.9 (b / bud~e.12 :mod (h / hair~e.11))) :time~e.1 (t / temporal~e.1)) :ARG1 (c / consider-02~e.16 :ARG0 (w / we~e.14) :ARG1 (f / factor :mode interrogative :ARG0-of (r2 / regulate-01~e.23 :ARG1 g~e.26,27,28 :ARG1-of (p2 / possible-01~e.21))))) # ::id pmid_1563_0473.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A variety of extracellular signals have an impact on the cell type @-@ specific expression of different Snail family members , and many of them , including Wnts , BMPs , FGFs , and TGF-βs , also affect hair bud development [ @ 2 , 16 , 28 @ ] . # ::alignments 1-1.1.1.2 3-1.1.1.1 4-1.1.1 4-1.2.1 5-1.1 7-1.1 8-1.1.2.r 10-1.1.2.2.1.1 11-1.1.2.2.1 13-1.1.2.2 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1 17-1.1.2.1.2.1.1.1 18-1.1.2.1.2.1 19-1.1.2.1 21-1.2.1.3.1 22-1.2.1.1 26-1.1.2.1.2 26-1.2.1.2 26-1.2.1.3 36-1.2.3 37-1.2 38-1.2.2.1.1 39-1.2.2.1 40-1.2.2 43-1.3.1.1.1.1 47-1.3.1.1.1.2 51-1.3.1.1.1.3 (a / and :op1 (i / impact-01~e.5,7 :ARG0 (s / signal-07~e.4 :location (e / extracellular~e.3) :mod (v / variety~e.1)) :ARG1~e.8 (e2 / express-03~e.14 :ARG2~e.15 (m3 / member~e.19 :ARG1-of (d / differ-02~e.16) :ARG1-of (i2 / include-91~e.26 :ARG2 (p / protein-family~e.18 :name (n / name :op1 "Snail"~e.17)))) :ARG1-of (s2 / specific-02~e.13 :ARG2 (t / type-03~e.11 :ARG1 (c / cell~e.10))))) :op2 (a2 / affect-01~e.37 :ARG0 (s3 / signal-07~e.4 :quant (m2 / many~e.22) :ARG1-of (i3 / include-91~e.26 :ARG2 s) :ARG2-of (i4 / include-91~e.26 :ARG1 (a3 / and~e.21 :op1 (p2 / protein :name (n2 / name :op1 "Wnt")) :op2 (p3 / protein :name (n3 / name :op1 "BMP")) :op3 (p4 / protein :name (n4 / name :op1 "FGF")) :op4 (p5 / protein :name (n5 / name :op1 "TGF-β"))))) :ARG1 (d2 / develop-02~e.40 :ARG1 (b / bud~e.39 :mod (h / hair~e.38))) :mod (a4 / also~e.36)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 2~e.43 :op2 16~e.47 :op3 28~e.51))))) # ::id pmid_1563_0473.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since Snail is not expressed in cultured skin keratinocytes that secrete active BMPs and FGFs ( see Figure 1 @ B ) , we focused our attention on Wnt and TGF-β signaling as more likely candidates for Snail induction in this cell type . # ::alignments 0-1 1-1.1.2.1.1 3-1.1.1 3-1.1.1.r 4-1.1 5-1.1.3.r 6-1.1.3.2 7-1.1.3.1 8-1.1.3 10-1.1.3.3 11-1.1.3.3.1.3 13-1.1.3.3.1 16-1.1.4 18-1.1.4.1 24-1.2.1 25-1.2 26-1.2.2.1 26-1.2.2.1.r 27-1.2.2 28-1.2.2.2.r 29-1.2.2.2 30-1.2.2.2 31-1.2.2.2 32-1.2.2.2 33-1.2.2.2 34-1.2.2.2 35-1.2.2.2 36-1.2.2.2 38-1.2.3.2.1.1.1.1 39-1.2.3.2.1.1.1 40-1.2.3.2.1.1.1.2.r 41-1.2.3.2.1.1.1.2.2 42-1.2.3.2.1.1.1.2 43-1.2.3.2.1.1.1.2.1 (c / cause-01~e.0 :ARG0 (e / express-03~e.4 :polarity~e.3 -~e.3 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.1)) :ARG3~e.5 (k / keratinocyte~e.8 :mod (s / skin~e.7) :ARG1-of (c2 / culture-01~e.6) :ARG0-of (s2 / secrete-01~e.10 :ARG1 (a / and~e.13 :op1 (p2 / protein :name (n2 / name :op1 "BMP")) :op2 (p3 / protein :name (n3 / name :op1 "FGF")) :ARG0-of (a2 / activity-06~e.11)))) :ARG1-of (s3 / see-01~e.16 :ARG2 (f / figure~e.18 :mod "1B"))) :ARG1 (f2 / focus-01~e.25 :ARG0 (w / we~e.24) :ARG1 (a3 / attend-02~e.27 :ARG0~e.26 w~e.26 :ARG1~e.28 s4~e.29,30,31,32,33,34,35,36) :ARG2 (s4 / signal-07 :ARG0 (a4 / and :op1 (p4 / protein :name (n4 / name :op1 "Wnt")) :op2 (p5 / protein :name (n5 / name :op1 "TGF-β"))) :ARG0-of (a5 / act-01 :ARG1 (l / likely-01 :ARG1 (c3 / candidate :purpose (i / induce-01~e.39 :ARG2 p~e.38 :location~e.40 (c4 / cell~e.42 :ARG1-of (t / type-03~e.43) :mod (t2 / this~e.41)))) :degree (m / more)))))) # ::id pmid_1563_0473.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previously , we showed that effective transmission of a Wnt @-@ 3a signal in cultured keratinocytes can be achieved through their exposure to the BMP inhibitor noggin , which induces LEF @-@ 1 expression [ @ 4 @ ] . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1.2 6-1.2.1.1 7-1.2.1.1.1.r 9-1.2.1.1.1.1.1.1 11-1.2.1.1.1.1.1.1 12-1.2.1.1.1 13-1.2.1.1.1.2.r 14-1.2.1.1.1.2.2 15-1.2.1.1.1.2.1.1 16-1.2 18-1.2.1 20-1.2.1.2.1 20-1.2.1.2.1.r 21-1.2.1.2 22-1.2.1.2.2.r 24-1.2.1.2.2.2.1.1.1 25-1.2.1.2.2 25-1.2.1.2.2.2 25-1.2.1.2.2.2.r 26-1.2.1.2.2.1.1 29-1.2.1.2.2.2.1 29-1.2.1.2.2.2.1.2 29-1.2.1.2.2.2.1.2.r 30-1.2.1.2.2.2.1.2.1.1.1.1 32-1.2.1.2.2.2.1.2.1.1.1.1 33-1.2.1.2.2.2.1.2.1 36-1.4.1.1.1 (s / show-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (p / possible-01~e.16 :ARG1 (a / achieve-01~e.18 :ARG1 (t / transmit-01~e.6 :ARG1~e.7 (s2 / signal-07~e.12 :ARG0 (p2 / protein :name (n / name :op1 "Wnt-3a"~e.9,11)) :location~e.13 (c / cell :name (n2 / name :op1 "keratinocyte"~e.15) :ARG1-of (c2 / culture-01~e.14))) :ARG1-of (e / effective-04~e.5)) :manner (e2 / expose-01~e.21 :ARG1~e.20 c~e.20 :ARG2~e.22 (p3 / protein~e.25 :name (n3 / name :op1 "noggin"~e.26) :ARG0-of~e.25 (i / inhibit-01~e.25 :ARG1 (p4 / protein~e.29 :name (n4 / name :op1 "BMP"~e.24) :ARG0-of~e.29 (i2 / induce-01~e.29 :ARG2 (e3 / express-03~e.33 :ARG2 (p5 / protein :name (n5 / name :op1 "LEF-1"~e.30,32)))))))))) :time (p6 / previous~e.0) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 4~e.36)))) # ::id pmid_1563_0473.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro , these conditions down @-@ regulated the E @-@ cadherin promoter and induced a LEF @-@ 1/β-catenin @-@ sensitive reporter gene , TOPFLASH [ @ 4 @ ] . # ::alignments 0-1.3 1-1.3 3-1.1.1.1 4-1.1.1 10-1.1.2.1.1.1.1 12-1.1.2.1.1.1.1 14-1.1.2 14-1.1.2.1 14-1.1.2.1.r 15-1 16-1.2 18-1.2.2.3.1.1.1.1 22-1.2.2.3 23-1.2.2.2 24-1.2.2 27-1.2.2.1.1 31-1.4.1.1.1 (a / and~e.15 :op1 (d / downregulate-01 :ARG0 (c / condition~e.4 :mod (t / this~e.3)) :ARG1 (m / molecular-physical-entity~e.14 :ARG0-of~e.14 (p / promote-01~e.14 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin"~e.10,12))))) :op2 (i / induce-01~e.16 :ARG0 c :ARG2 (g / gene~e.24 :name (n2 / name :op1 "TOPFLASH"~e.27) :ARG0-of (r / report-01~e.23) :ARG0-of (s / sensitive-03~e.22 :ARG1 (m2 / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "LEF-1"~e.18)) :part (p4 / protein :name (n4 / name :op1 "β-catenin")))))) :manner (i2 / in-vitro~e.0,1) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.31)))) # ::id pmid_1563_0473.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , Snail expression was not induced by these conditions ( Figure 5 @ A ) . # ::alignments 1-1 3-1.1.3.1.1.1 4-1.1.3 6-1.1.1 6-1.1.1.r 7-1.1 8-1.1.2.r 9-1.1.2.1 10-1.1.2 13-1.1.4.1 (c / contrast-01~e.1 :ARG2 (i / induce-01~e.7 :polarity~e.6 -~e.6 :ARG0~e.8 (c2 / condition~e.10 :mod (t / this~e.9)) :ARG2 (e / express-03~e.4 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.3))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13 :mod "5A")))) # ::id pmid_1563_0473.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , despite essential roles for Wnts and noggin in hair follicle specification [ @ 4 , 29 , 30 @ ] , our studies did not support an essential role for these signals in governing Snail expression in keratinocytes . # ::alignments 0-1 2-1.1.4.r 3-1.1.4.1 4-1.1.4 7-1.1.4.2 7-1.1.4.4.1.1.1 8-1.1.4.2.2.2.1 9-1.1.4.3.r 10-1.1.4.3.1.1 11-1.1.4.3.1 12-1.1.4.3 15-1.1.4.4.1.1.1.1 19-1.1.4.4.1.1.1.2 23-1.1.4.4.1.1.1.3 27-1.1.2.1 27-1.1.2.1.r 28-1.1.2 29-1.1.2 30-1.1.1 30-1.1.1.r 31-1.1 33-1.1.3.1 34-1.1.3 35-1.1.3.2.r 36-1.1.3.2.1 37-1.1.3.2 38-1.1.3.3.r 39-1.1.3.3 41-1.1.3.3.1.1.2.1 43-1.1.3.3.1 44-1.1.3.3.1.2.r 45-1.1.3.3.1.2.2.1 (c / cause-01~e.0 :ARG1 (s / support-01~e.31 :polarity~e.30 -~e.30 :ARG0 (s2 / study-01~e.28,29 :ARG0~e.27 (w / we~e.27)) :ARG1 (r / role~e.34 :mod (e / essential~e.33) :beneficiary~e.35 (s3 / signal-07~e.37 :mod (t / this~e.36)) :topic~e.38 (g / govern-01~e.39 :ARG1 (e2 / express-03~e.43 :ARG1 (g2 / gene :wiki - :name (n2 / name :op1 "Snail"~e.41)) :ARG3~e.44 (c2 / cell :wiki "Keratinocyte" :name (n / name :op1 "keratinocyte"~e.45))))) :concession~e.2 (r2 / role~e.4 :mod (e3 / essential~e.3) :beneficiary (a / and~e.7 :op1 (p / protein :wiki - :name (n3 / name :op1 "Wnt")) :op2 (p2 / protein :wiki "Noggin_(protein)" :name (n4 / name :op1 "noggin"~e.8))) :topic~e.9 (s4 / specify-01~e.12 :ARG1 (f / follicle~e.11 :mod (h / hair~e.10))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and~e.7 :op1 4~e.15 :op2 29~e.19 :op3 30~e.23))))))) # ::id pmid_1563_0473.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGF-β1 has been shown to induce Snail family members in hepatocytes and heart [ @ 15 , 31 @ ] . # ::alignments 0-1.1.1.1.1 3-1 5-1.1 6-1.1.2.1.1.1.1 7-1.1.2.1.1 8-1.1.2 9-1.1.3.r 10-1.1.3.1.1.1 11-1.1.3 12-1.1.3.2 15-1.2.1.1.1.1 19-1.2.1.1.1.2 (s / show-01~e.3 :ARG1 (i / induce-01~e.5 :ARG0 (p / protein :name (n / name :op1 "TGF-β1"~e.0)) :ARG2 (m / member~e.8 :ARG1-of (i2 / include-91 :ARG2 (p2 / protein-family~e.7 :name (n2 / name :op1 "Snail"~e.6)))) :location~e.9 (a / and~e.11 :op1 (c / cell :name (n3 / name :op1 "hepatocyte"~e.10)) :op2 (h / heart~e.12))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 15~e.15 :op2 31~e.19))))) # ::id pmid_1563_0473.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In keratinocytes , however , TGF-β1 inhibits keratinocyte growth and seems to be involved in triggering the destructive phase of the cycling hair follicle [ @ 32 @ ] . # ::alignments 3-1 5-1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1.1 8-1.1.1.2 9-1.1 10-1.1.2 13-1.1.2.1 14-1.1.2.1.2.r 15-1.1.2.1.2 17-1.1.2.1.2.2.1 18-1.1.2.1.2.2 19-1.1.2.1.2.2.2.r 21-1.1.2.1.2.2.2.2 22-1.1.2.1.2.2.2.1 23-1.1.2.1.2.2.2 26-1.2.1.1.1 (h / have-concession-91~e.3 :ARG2 (a / and~e.9 :op1 (i / inhibit-01~e.6 :ARG0 (p / protein :name (n / name :op1 "TGF-β1"~e.5)) :ARG1 (g / grow-01~e.8 :ARG1 (c / cell :name (n2 / name :op1 "keratinocyte"~e.7)))) :op2 (s / seem-01~e.10 :ARG1 (i2 / involve-01~e.13 :ARG1 p :ARG2~e.14 (t / trigger-01~e.15 :ARG0 p :ARG1 (p2 / phase~e.18 :ARG0-of (d / destroy-01~e.17) :part-of~e.19 (f / follicle~e.23 :mod (h2 / hair~e.22) :ARG1-of (c2 / cycle-02~e.21)))))) :location c) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 32~e.26)))) # ::id pmid_1563_0473.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the loss @-@ of @-@ function mutations generated in each of the TGF-β genes , only the TGF-β2 null state blocked follicle development at the hair bud stage [ @ 32 @ ] . # ::alignments 2-1.1.4.1.1 6-1.1.4.1.1.1 7-1.1.4.1 8-1.1.4.1.2 10-1.1.4.1.2.1.2 14-1.1.4.1.2.1.1.1 16-1.1.2 16-1.1.4.1.2.1 18-1.1.3 21-1.1.2.1.1 23-1.1.1 24-1.1 25-1 26-1.2 27-1.2.1 28-1.3.r 30-1.3.1.1 31-1.3.1 32-1.3 35-1.4.1.1.1 (b / block-01~e.25 :ARG0 (s / state~e.24 :mod (n / null~e.23) :poss (g / gene~e.16 :name (n2 / name :op1 "TGF-β2"~e.21)) :mod (o / only~e.18) :ARG1-of (i / include-91 :ARG2 (m / mutate-01~e.7 :ARG2 (l / lose-02~e.2 :ARG1 (f2 / function-01~e.6)) :ARG1-of (g2 / generate-01~e.8 :ARG3 (g3 / gene~e.16 :name (n3 / name :op1 "TGF-β"~e.14) :mod (e / each~e.10)))))) :ARG1 (f / follicle~e.26 :ARG1-of (d / develop-02~e.27)) :time~e.28 (s2 / stage~e.32 :mod (b2 / bud~e.31 :mod (h / hair~e.30))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 32~e.35)))) # ::id pmid_1563_0473.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , we turned towards addressing whether TGF-β2 might be involved in regulating Snail expression in keratinocytes isolated from the basal layer of the epidermis . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2 6-1.1.2.2.1 6-1.1.2.2.1.r 7-1.1.2.2.2.1.1.1 8-1.1.2.2 10-1.1.2.2.2 11-1.1.2.2.2.2.r 12-1.1.2.2.2.2 14-1.1.2.2.2.2.2.1.1.1 16-1.1.2.2.2.2.2 17-1.1.2.2.2.2.3.r 18-1.1.2.2.2.2.3.1.1 19-1.1.2.2.2.2.3.2 20-1.1.2.2.2.2.3.2.1.r 22-1.1.2.2.2.2.3.2.1.1 23-1.1.2.2.2.2.3.2.1 24-1.1.2.2.2.2.3.2.1.2.r 26-1.1.2.2.2.2.3.2.1.2 (c / cause-01~e.0 :ARG1 (t / turn-01~e.3 :ARG0 (w / we~e.2) :location (a / address-02~e.5 :ARG0 w :ARG1 (p / possible-01~e.8 :mode~e.6 interrogative~e.6 :ARG1 (i / involve-01~e.10 :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2"~e.7)) :ARG2~e.11 (r / regulate-01~e.12 :ARG0 p2 :ARG1 (e / express-03~e.16 :ARG1 (g / gene :name (n2 / name :op1 "Snail"~e.14))) :location~e.17 (c2 / cell :name (n3 / name :op1 "keratinocyte"~e.18) :ARG1-of (i2 / isolate-01~e.19 :ARG2~e.20 (l / layer~e.23 :mod (b / basal~e.22) :part-of~e.24 (e2 / epidermis~e.26)))))))))) # ::id pmid_1563_0473.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Though there is no cell culture system available to specifically study placodal cells , these keratinocytes are their progenitors and are the closest approximation available to study the behavior of epithelial cells of the placode . # ::alignments 0-1.3.r 3-1.3.1 3-1.3.1.r 4-1.3.2.1.1 5-1.3.2.1 6-1.3.2 7-1.3 9-1.3.3.2 10-1.3.3 12-1.1.2 14-1.1.1.2 15-1.1.1.1.1 17-1.1.3.1 17-1.1.3.1.r 18-1.1.3 19-1 22-1.2.1.2 22-1.2.1.2.1 22-1.2.1.2.1.r 23-1.2.1 24-1.2 26-1.2.1.3 28-1.2.1.3.1 29-1.2.1.3.1.1.r 30-1.2.1.3.1.1.1 31-1.2.1.3.1.1 32-1.1.2.1.r 34-1.1.2.1 (a / and~e.19 :op1 (h / have-rel-role-91 :ARG0 (c / cell :name (n / name :op1 "keratinocyte"~e.15) :mod (t / this~e.14)) :ARG1 (c2 / cell~e.12 :location~e.32 (p2 / placode~e.34)) :ARG2 (p / progenitor~e.18 :poss~e.17 c~e.17)) :op2 (a2 / available-02~e.24 :ARG2 (a3 / approximate-01~e.23 :ARG0 c :ARG1-of (c3 / close-11~e.22 :degree~e.22 (m / most~e.22)) :purpose (s / study-01~e.26 :ARG1 (b / behave-01~e.28 :ARG0~e.29 (c4 / cell~e.31 :location (e / epithelium~e.30) :part-of p2))))) :concession~e.0 (a4 / available-02~e.7 :polarity~e.3 -~e.3 :ARG2 (s2 / system~e.6 :mod (c5 / culture-01~e.5 :ARG1 (c6 / cell~e.4))) :purpose (s3 / study-01~e.10 :ARG1 c2 :ARG1-of (s4 / specific-02~e.9)))) # ::id pmid_1563_0473.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , treatment of cultured keratinocytes with as little as 5 ng @/@ ml of TGF-β2 caused a rapid and transient induction of Snail ( Figure 5 @ B ) . # ::alignments 0-1.3 0-1.3.r 2-1.1 3-1.1.1.r 4-1.1.1.2 5-1.1.1.1.1 7-1.1.2.r 8-1.1.2.2.2 10-1.1.2.2.1 11-1.1.2.2.3 13-1.1.2.2.3 15-1.1.2.1.1 16-1 18-1.2.3 20-1.2.4 21-1.2 22-1.2.2.r 23-1.2.2.1.1 26-1.4.1 27-1.1.2.2.1 (c / cause-01~e.16 :ARG0 (t / treat-04~e.2 :ARG1~e.3 (c2 / cell :name (n / name :op1 "keratinocyte"~e.5) :ARG1-of (c3 / culture-01~e.4)) :ARG2~e.7 (p / protein :name (n2 / name :op1 "TGF-β2"~e.15) :quant (c4 / concentration-quantity :quant 5~e.10,27 :mod (l / little~e.8) :unit (n4 / nanogram-per-milliliter~e.11,13)))) :ARG1 (i / induce-01~e.21 :ARG0 t :ARG2~e.22 (p2 / protein :name (n3 / name :op1 "Snail"~e.23)) :mod (r / rapid~e.18) :ARG1-of (t2 / transient-02~e.20)) :manner~e.0 (i2 / interesting~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "5B"))) # ::id pmid_1563_0473.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following this treatment , Snail protein was detected within 30 min , peaked at 2 h , and then declined thereafter . # ::alignments 0-1 0-1.1.1.2 1-1.1.1.2.1.1 2-1.1.1.2.1 4-1.1.1.1.1.1 5-1.1.1.1 7-1.1.1 8-1.1.1.2 8-1.1.1.2.2 8-1.1.1.2.2.1.1.r 8-1.1.1.2.2.r 8-1.1.2.2 8-1.1.3.2 9-1.1.1.2.2.1.1 10-1.1.1.2.2.1.2 12-1.1.2 13-1.1.2.2.1.r 14-1.1.2.2.1.1 15-1.1.2.2.1.2 17-1.1 19-1.1.3 (f / follow-01~e.0 :ARG1 (a / and~e.17 :op1 (d / detect-01~e.7 :ARG1 (p / protein~e.5 :name (n / name :op1 "Snail"~e.4)) :time (a2 / after~e.0,8 :op1 (t / treat-04~e.2 :mod (t2 / this~e.1)) :quant~e.8 (u / up-to~e.8 :op1 (t3 / temporal-quantity :quant~e.8 30~e.9 :unit (m / minute~e.10))))) :op2 (p2 / peak-01~e.12 :ARG1 p :time (a4 / after~e.8 :op1~e.13 (t4 / temporal-quantity :quant 2~e.14 :unit (h / hour~e.15)))) :op3 (d2 / decline-01~e.19 :ARG1 p :time (a3 / after~e.8 :op1 p2)))) # ::id pmid_1563_0473.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The induction of Snail appeared to be specific for the active form of the growth factor , as pretreatment of TGF-β2 for 10 min at 100 °C obliterated the response [ @ Figure 5 @ B , lanes marked (–)] . # ::alignments 1-1.2.1 2-1.2.1.1.r 3-1.2.1.1.1.1 4-1.2 7-1.2.1.2 8-1.2.1.2.1.r 10-1.2.1.2.1.1 11-1.2.1.2.1 12-1.2.1.2.1.2.r 14-1.2.1.2.1.2 15-1.2.1.2.1.2 18-1.1.1 19-1.1.1.1.r 20-1.1.1.1.1.1 21-1.1.1.3.r 22-1.1.1.3.1 23-1.1.1.3.2 24-1.1.1.2.r 25-1.1.1.2.1 26-1.1.1.2.2 27-1.1 29-1.1.2 32-1.3.1 37-1.3.2.1 38-1.3.2 (c / cause-01 :ARG0 (o / obliterate-01~e.27 :ARG0 (p / pretreat-01~e.18 :ARG1~e.19 (p2 / protein :name (n / name :op1 "TGF-β2"~e.20)) :ARG3~e.24 (t / temperature-quantity :quant 100~e.25 :scale (c2 / celsius~e.26)) :duration~e.21 (t2 / temporal-quantity :quant 10~e.22 :unit (m / minute~e.23))) :ARG1 (r / respond-01~e.29)) :ARG1 (a / appear-02~e.4 :ARG1 (i / induce-01~e.1 :ARG2~e.2 (p3 / protein :name (n2 / name :op1 "Snail"~e.3)) :ARG1-of (s / specific-02~e.7 :ARG2~e.8 (f / form~e.11 :ARG0-of (a2 / activity-06~e.10) :mod~e.12 (g / growth-factor~e.14,15))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.32 :mod "5B") :ARG2-of (m2 / mark-02~e.38 :ARG1 (l / lane~e.37)))) # ::id pmid_1563_0473.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By contrast , although TGF-β receptor activation remained elevated during the duration of the experiment ( as measured by the sustained phosphorylation of the downstream effector SMAD2 ) Snail expression could not be maintained ( Figure 5 @ B ) . # ::alignments 1-1 3-1.1.2.2.r 4-1.1.2.2.1.1.2.1 5-1.1.2.2.1.1 6-1.1.2.2.1 7-1.1.2.2 8-1.1.2.2.1.2.2 9-1.1.2.2.3.r 14-1.1.2.2.3 16-1.1.2.2.3.r 17-1.1.2.2.1.2 18-1.1.2.2.1.2.1.r 20-1.1.2.2.1.2.1.2 21-1.1.2.2.1.2.1 22-1.1.2.2.1.2.1.1.r 24-1.1.2.2.1.2.1.1.2 25-1.1.2.2.1.2.1.1 26-1.1.2.2.1.2.1.1.1.2.1 29-1.1.2.1.1.2.1 31-1.1.2.1 32-1.1 33-1.1.1 33-1.1.1.r 35-1.1.2 38-1.2.1 (c / contrast-01~e.1 :ARG2 (p / possible-01~e.32 :polarity~e.33 -~e.33 :ARG1 (m / maintain-01~e.35 :ARG1 (e / express-03~e.31 :ARG2 (g / gene :wiki - :name (n / name :op1 "Snail"~e.29))) :concession~e.3 (r / remain-01~e.7 :ARG1 (a / activate-01~e.6 :ARG1 (r2 / receptor~e.5 :wiki "TGF_beta_receptors" :name (n2 / name :op1 "TGF-β"~e.4)) :ARG1-of (m2 / measure-01~e.17 :ARG0~e.18 (p2 / phosphorylate-01~e.21 :ARG1~e.22 (e2 / effector~e.25 :mod (p3 / protein :wiki "Mothers_against_decapentaplegic_homolog_2" :name (n3 / name :op1 "SMAD2"~e.26)) :mod (d / downstream~e.24)) :ARG1-of (s / sustain-01~e.20)) :ARG3 (e3 / elevate-01~e.8))) :ARG3 e3 :time~e.9,16 (e4 / experiment-01~e.14)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.38 :mod "5B"))) # ::id pmid_1563_0473.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , although Snail expression correlated with phosphorylated SMAD2 ( pSMAD2 ) induction , its decline seemed to rely on secondary downstream events . # ::alignments 0-1 2-1.1.2.r 4-1.1.1.1.1.1.1.1 6-1.1.1.1.1 7-1.1.2 8-1.1.2.2.r 9-1.1.2.2.1.2 10-1.1.2.2.1.1.1 12-1.1.2.2.1.3.1.1.1 14-1.1.2.2 16-1.1.2.1 16-1.1.2.1.r 17-1.1.1.1 18-1.1 20-1.1.1 21-1.1.1.2.r 22-1.1.1.2.2 23-1.1.1.2.1 24-1.1.1.2 (c / cause-01~e.0 :ARG1 (s / seem-01~e.18 :ARG1 (r / rely-01~e.20 :ARG0 (d / decline-01~e.17 :ARG1 (e / express-03~e.6 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.4)))) :ARG1~e.21 (e2 / event~e.24 :direction (d2 / downstream~e.23) :mod (s2 / secondary~e.22))) :concession~e.2 (c2 / correlate-01~e.7 :ARG1~e.16 e~e.16 :ARG2~e.8 (i / induce-01~e.14 :ARG2 (p / protein :name (n2 / name :op1 "SMAD2"~e.10) :ARG1-of (p2 / phosphorylate-01~e.9) :ARG1-of (d3 / describe-01 :ARG0 (p3 / protein :name (n3 / name :op1 "pSMAD2"~e.12)))))))) # ::id pmid_1563_0473.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The rapid kinetics of Snail expression were reflected at the mRNA level , suggesting that Snail promoter activity in keratinocytes might be sensitive to TGF-β2 signaling ( Figure 5 @ C ) . # ::alignments 1-1.2.1 2-1.2 3-1.2.2.r 4-1.2.2.1.1.1 5-1.2.2 7-1 8-1.1.r 10-1.1.1.1.1 11-1.1 13-1.3 16-1.3.1.1.1.1.1.1 18-1.3.1.1.1.1 18-1.3.1.1.1.1.1 18-1.3.1.1.1.1.1.r 19-1.3.1.1.1 20-1.3.1.1.1.2.r 21-1.3.1.1.1.2 22-1.3.1 24-1.3.1.1 25-1.3.1.1.2.r 26-1.3.1.1.2.1.1.1 27-1.3.1.1.2 30-1.4.1 (r / reflect-01~e.7 :ARG1~e.8 (l / level~e.11 :mod (n4 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.10))) :ARG2 (k / kinetics~e.2 :mod (r2 / rapid~e.1) :poss~e.3 (e / express-03~e.5 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.4)))) :ARG0-of (s / suggest-01~e.13 :ARG1 (p / possible-01~e.22 :ARG1 (s2 / sensitive-03~e.24 :ARG0 (a / activity-06~e.19 :ARG0 (m / molecular-physical-entity~e.18 :ARG0-of~e.18 (p4 / promote-01~e.18 :ARG1 g~e.16)) :location~e.20 (k2 / keratinocyte~e.21)) :ARG1~e.25 (s3 / signal-07~e.27 :ARG0 (p3 / protein :name (n3 / name :op1 "TGF-β2"~e.26)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "5C"))) # ::id pmid_1563_0473.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this possibility , we engineered a transgene driving the β-galactosidase reporter under the control of approximately 2.2 kb of promoter sequence located 5′ from the transcription initiation site of the mouse Snail gene . # ::alignments 1-1.3 2-1.3.2 3-1.3.2.1 5-1.1 6-1 8-1.2 9-1.4 11-1.4.2.1.1 12-1.4.2 12-1.4.2.2 12-1.4.2.2.r 15-1.4.3 16-1.4.3.1.r 17-1.4.3.1.1 18-1.4.3.1.1.1.1 22-1.4.3.1 23-1.4.3.1.2.1.1.r 23-1.4.3.1.2.r 27-1.4.3.1.2.1.1.1 28-1.4.3.1.2.1.1 29-1.4.3.1.2.1 30-1.4.3.1.2.1.2.r 32-1.4.3.1.2.1.2.2 34-1.4.3.1.2.1.2.1.1 36-1.4.3.1.2.1.2 (e / engineer-01~e.6 :ARG0 (w / we~e.5) :ARG1 (t3 / transgene~e.8) :purpose (t / test-01~e.1 :ARG0 w :ARG1 (t2 / this~e.2 :ARG1-of (p / possible-01~e.3))) :manner (d / drive-02~e.9 :ARG0 w :ARG1 (e2 / enzyme~e.12 :name (n / name :op1 "β-galactosidase"~e.11) :ARG0-of~e.12 (r / report-01~e.12)) :ARG2 (c / control-01~e.15 :ARG0~e.16 (s / sequence~e.22 :quant (a / approximately~e.17 :op1 (d2 / distance-quantity :quant 2.2~e.18 :unit (k / kilo-base-pair))) :location~e.23 (r2 / relative-position :op1 (p3 / protein-segment~e.29 :location-of~e.23 (i / initiate-01~e.28 :ARG1 (t4 / transcribe-01~e.27)) :part-of~e.30 (g / gene~e.36 :name (n2 / name :op1 "Snail"~e.34) :mod (m2 / mouse~e.32))) :direction (d3 / dna-sequence :name (n3 / name :op1 "5'"))) :mod (m / molecular-physical-entity :ARG0-of (p2 / promote-02))) :ARG1 e2))) # ::id pmid_1563_0473.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At 2 d after transient transfection , keratinocytes were treated with TGF-β2 ( t = 0 ) and then assayed for transgene activity over the same time course in which we had observed Snail protein induction . # ::alignments 1-1.1.3.2.1 3-1.1.3 4-1.1.3.1.1 5-1.1.3.1 7-1.1.1 9-1.1 11-1.1.2.1.1 15-1.1.4.1 17-1 18-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1.2 22-1.2.1 25-1.2.3.1 26-1.1.3.2 26-1.1.4.2 26-1.2.3.1.1.1.r 26-1.2.3.2 27-1.2.3 27-1.2.3.1.1 30-1.2.3.1.1.1.1 32-1.2.3.1.1.1 33-1.2.3.1.1.1.2.1.1.1 34-1.1.2 34-1.2.3.1.1.1.2.1 35-1.2.3.1.1.1.2 (a / and~e.17 :op1 (t2 / treat-04~e.9 :ARG1 (k / keratinocyte~e.7) :ARG2 (p / protein~e.34 :name (n / name :op1 "TGF-β2"~e.11)) :time (a3 / after~e.3 :op1 (t3 / transfect-01~e.5 :ARG1-of (t4 / transient-02~e.4)) :quant (t5 / temporal-quantity~e.26 :quant 2~e.1 :unit (d / day))) :condition (e / equal-01 :ARG2 0~e.15 :ARG1 (t8 / time~e.26))) :op2 (a2 / assay-01~e.19 :ARG1~e.20 (a4 / activity-06~e.22 :ARG0 k :ARG1 (t7 / transgene~e.21)) :time (t6 / then~e.18) :duration (c2 / course~e.27 :ARG1-of (s / same-01~e.25 :ARG2 (c / course~e.27 :time-of~e.26 (o2 / observe-01~e.32 :ARG0 (w / we~e.30) :ARG1 (i / induce-01~e.35 :ARG2 (p2 / protein~e.34 :name (n2 / name :op1 "Snail"~e.33)))) :mod t)) :mod (t / time~e.26)))) # ::id pmid_1563_0473.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results of this experiment are presented in Figure 5 @ D . # ::alignments 1-1.2 1-1.2.1 1-1.2.1.r 2-1.2.1.1.r 3-1.2.1.1.1 4-1.2.1.1 6-1 9-1.1 10-1.1.1 (p / present-01~e.6 :ARG0 (f / figure~e.9 :mod 5~e.10) :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1 :ARG1~e.2 (e / experiment-01~e.4 :mod (t2 / this~e.3))))) # ::id pmid_1563_0473.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Within 0.5 h of TGF-β2 treatment , Snail promoter activity had increased 3 @-@ fold , and by 2 h , it peaked to approximately 10 @-@ fold over control levels ( Figure 5 @ D ) . # ::alignments 0-1.1.3 0-1.1.3.2 0-1.1.3.2.1.1.r 0-1.1.3.2.r 0-1.2.2 0-1.2.2.2 0-1.2.2.2.1.1.r 0-1.2.2.2.r 1-1.1.3.2.1.1 2-1.1.3.2.1.2 3-1.1.3.1.r 4-1.1.3.1.1.1.1 5-1.1.3.1 8-1.1.1.1.1.1.1.1 10-1.1.1.1 10-1.1.1.1.1 10-1.1.1.1.1.r 11-1.1.1 13-1.1 14-1.1.2.1 16-1.1.2 18-1 19-1.2.2.2.1.r 20-1.2.2.2.1.1 21-1.2.2.2.1.2 24-1.2 25-1.2.1.r 26-1.2.1 27-1.2.1.1.1 29-1.2.1.1 31-1.1.2.2.1 32-1.1.2.2 35-1.3.1 (a / and~e.18 :op1 (i / increase-01~e.13 :ARG1 (a2 / activity-06~e.11 :ARG0 (m / molecular-physical-entity~e.10 :ARG0-of~e.10 (p6 / promote-01~e.10 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.8))))) :ARG4 (p4 / product-of~e.16 :op1 3~e.14 :op2 (l / level~e.32 :mod (c / control~e.31))) :time (a3 / after~e.0 :op1~e.3 (t / treat-04~e.5 :ARG2 (p2 / protein :name (n2 / name :op1 "TGF-β2"~e.4))) :quant~e.0 (u / up-to~e.0 :op1 (t2 / temporal-quantity :quant~e.0 0.5~e.1 :unit (h / hour~e.2))))) :op2 (p3 / peak-01~e.24 :ARG1~e.25 (a4 / approximately~e.26 :op1 (p5 / product-of~e.29 :op1 10~e.27 :op2 l)) :time (a5 / after~e.0 :op1 t :quant~e.0 (u2 / up-to~e.0 :op1~e.19 (t3 / temporal-quantity :quant~e.0 2~e.20 :unit h~e.21)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "5D"))) # ::id pmid_1563_0473.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thereafter , Snail promoter activity rapidly returned to the basal levels seen in unstimulated keratinocytes . # ::alignments 0-1.4 3-1.1.1.1.1.1.1 5-1.1.1 5-1.1.1.1 5-1.1.1.1.r 6-1.1 7-1.3 7-1.3.r 8-1 9-1.2.r 11-1.2.2 12-1.2 13-1.2.1 16-1.2.1.1 (r / return-01~e.8 :ARG1 (a / activity-06~e.6 :ARG0 (m / molecular-physical-entity~e.5 :ARG0-of~e.5 (p2 / promote-01~e.5 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.3))))) :ARG4~e.9 (l / level~e.12 :ARG1-of (s / see-01~e.13 :location (k / keratinocyte~e.16 :ARG1-of (s2 / stimulate-01 :polarity -))) :mod (b / basal~e.11)) :manner~e.7 (r2 / rapid~e.7) :time (t / thereafter~e.0)) # ::id pmid_1563_0473.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The kinetics of Snail promoter activity closely paralleled those observed for Snail protein induction . # ::alignments 1-1.1 1-1.2 4-1.1.1.1.1.1.1.1 6-1.1.1.1 6-1.1.1.1.1 6-1.1.1.1.1.r 7-1.1.1 8-1.3 9-1 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1.1.1 14-1.2.1.1.1 15-1.2.1.1 (p / parallel-01~e.9 :ARG0 (k / kinetics~e.1 :mod (a / activity-06~e.7 :ARG0 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (p4 / promote-01~e.6 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.4)))))) :ARG1 (k2 / kinetics~e.1 :ARG1-of (o / observe-01~e.11 :topic~e.12 (i / induce-01~e.15 :ARG2 (p3 / protein~e.14 :name (n2 / name :op1 "Snail"~e.13))))) :ARG1-of (c / close-10~e.8)) # ::id pmid_1563_0473.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the stimulatory effects appeared to be specific to TGF-β2 , since they were abrogated either by heat inactivation of the TGF-β2 protein or by mutation of a putative SMAD binding element located about 1.8 kb 5′ from the Snail transcription start site ( Figure 5 @ D ) . # ::alignments 0-1 4-1.1.1.1 5-1.1 6-1.1.2 8-1.1.1 10-1.1.1.2.1.1 12-1.1.2 13-1.1.2.1.1 15-1.1.2.1 17-1.1.2.1.2.r 18-1.1.2.1.2.1.3 19-1.1.2.1.2.1 19-1.1.2.1.2.1.1 19-1.1.2.1.2.1.1.r 20-1.1.2.1.2.1.2.r 22-1.1.2.1.2.1.2 23-1.1.1.2 23-1.1.2.1.2.2.1.1.1 24-1.1.2.1.2 26-1.1.2.1.2.2 27-1.1.2.1.2.2.1.r 29-1.1.2.1.2.2.1.1.2 30-1.1.2.1.2.2.1.1.1.1.1 31-1.1.2.1.2.2.1.1 32-1.1.2.1.2.2.1 33-1.1.2.1.2.2.1.2 33-1.1.2.1.2.2.1.2.1.r 35-1.1.2.1.2.2.1.2.1.2.1 41-1.1.2.1.2.2.1.2.1.1.1.1.1.1.1 43-1.1.2.1.2.2.1.2.1.1.1.1 44-1.1.2.1.2.2.1.2.1.1.1 45-1.1.2.1.2.2.1.2.1.1 48-1.2.1 49-1.1.2.1.2.2.1.2.1.3.1.1 (a / and~e.0 :op1 (a2 / appear-02~e.5 :ARG1 (s / specific-02~e.8 :ARG1 (e / effect-03~e.4 :ARG1 (s2 / stimulate-01)) :ARG2 (p / protein~e.23 :name (n / name :op1 "TGF-β2"~e.10))) :ARG1-of (c / cause-01~e.6,12 :ARG0 (a3 / abrogate-01~e.15 :ARG1 e~e.13 :ARG2~e.17 (o / or~e.24 :op1 (a4 / activate-01~e.19 :polarity~e.19 -~e.19 :ARG1~e.20 p~e.22 :mod (h / heat~e.18)) :op2 (m / mutate-01~e.26 :ARG1~e.27 (e2 / element~e.32 :ARG1-of (b / bind-01~e.31 :ARG2 (p2 / protein~e.23 :name (n2 / name :op1 "SMAD"~e.30)) :ARG1-of (t / think-01~e.29)) :ARG1-of (l / locate-01~e.33 :location~e.33 (r / relative-position :op1 (p3 / protein-segment~e.45 :location-of (s3 / start-01~e.44 :ARG1 (t2 / transcribe-01~e.43 :ARG1 (g / gene :name (n3 / name :op1 "Snail"~e.41))))) :quant (d / distance-quantity :quant 1.8~e.35 :unit (k / kilo-base-pair)) :direction (d3 / dna-sequence :name (n4 / name :op1 "5'"~e.49)))))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.48 :mod "5D"))) # ::id pmid_1563_0473.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these results suggested that in keratinocytes , TGF-β2 signaling results in a pSMAD2 @-@ dependent transient activation of the Snail gene , and that maintenance of Snail protein relies , in part , upon sustained promoter activity . # ::alignments 0-1.1.3 1-1.1.3.1 3-1.1.1 4-1.1 4-1.1.2 4-1.1.2.r 4-1.2.1 5-1 7-1.2.r 8-1.2.1.3 10-1.2.1.1.1.1.1 11-1.2.1.1 12-1.2.1 17-1.2.1.2.3 18-1.2.1.2.2 19-1.2.1.2 23-1.2.1.2.1.1.1 25-1.2.1.2.1 27-1.2 28-1.2.r 29-1.2.2.1 31-1.2.2.1.1.1.1 32-1.2.1.1.1 32-1.2.1.2.3.1 32-1.2.2.1.1 33-1.2.2 35-1.2.2.3 35-1.2.2.3.r 36-1.2.2.3.r 39-1.2.2.2.2 40-1.2.2.2.1 40-1.2.2.2.1.1 40-1.2.2.2.1.1.r 41-1.2.2.2 (s / suggest-01~e.5 :ARG0 (t / thing~e.4 :mod (t2 / this~e.3) :ARG2-of~e.4 (r / result-01~e.4) :ARG1-of (t3 / take-01~e.0 :mod (t4 / together~e.1))) :ARG1~e.7,28 (a / and~e.27 :op1 (r2 / result-01~e.4,12 :ARG1 (s2 / signal-07~e.11 :ARG0 (p / protein~e.32 :name (n / name :op1 "TGF-β2"~e.10))) :ARG2 (a2 / activate-01~e.19 :ARG1 (g / gene~e.25 :name (n2 / name :op1 "Snail"~e.23)) :ARG1-of (t5 / transient-02~e.18) :ARG0-of (d / depend-01~e.17 :ARG1 (p2 / protein~e.32 :name (n3 / name :op1 "SMAD2") :ARG1-of (p3 / phosphorylate-01)))) :location (k / keratinocyte~e.8)) :op2 (r3 / rely-01~e.33 :ARG0 (m / maintain-01~e.29 :ARG1 (p4 / protein~e.32 :name (n4 / name :op1 "Snail"~e.31))) :ARG1 (a3 / activity-06~e.41 :ARG0 (m2 / molecular-physical-entity~e.40 :ARG0-of~e.40 (p5 / promote-01~e.40)) :ARG1-of (s3 / sustain-01~e.39)) :degree~e.35,36 (p6 / part~e.35)))) # ::id pmid_1563_0473.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The brevity of Snail gene and protein induction in TGF-β2 treated cultured keratinocytes resembled the temporal appearance of Snail mRNA and protein at the initiation of hair follicle morphogenesis in embryonic mouse skin . # ::alignments 1-1.1.1 4-1.1.1.1.1.1 6-1.1.1.1 7-1.1 8-1.1.2.1 9-1.1.2 10-1.1.2.2.r 11-1.1.2.2.2.1.1.1 12-1.1.2.2.2 13-1.1.2.2.1 14-1.1.2.2 15-1 17-1.2.2 18-1.2 21-1.2.1.1.2 23-1.2.1.1.1.1 24-1.2.1 25-1.2.1.2 26-1.2.3.r 28-1.2.3 29-1.2.3.1.r 30-1.2.3.1.1.1 31-1.2.3.1.1 32-1.2.3.1 33-1.2.3.2.r 34-1.2.3.2.1 35-1.2.3.2.1.1 36-1.2.3.2 (r / resemble-01~e.15 :ARG1 (a / and~e.7 :op1 (b / brevity~e.1 :poss (g / gene~e.6 :name (n / name :op1 "Snail"~e.4))) :op2 (i / induce-01~e.9 :ARG2 (p / protein~e.8) :location~e.10 (k / keratinocyte~e.14 :ARG1-of (c / culture-01~e.13) :ARG1-of (t / treat-04~e.12 :ARG2 (p2 / protein :name (n2 / name :op1 "TGF-β2"~e.11)))))) :ARG2 (a2 / appear-01~e.18 :ARG1 (a3 / and~e.24 :op1 (n3 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.23) :part-of g~e.21) :op2 (p3 / protein~e.25)) :mod (t2 / time~e.17) :time~e.26 (i2 / initiate-01~e.28 :ARG1~e.29 (m2 / morphogenesis~e.32 :mod (f / follicle~e.31 :mod (h / hair~e.30))) :location~e.33 (s / skin~e.36 :part-of (e / embryo~e.34 :mod (m3 / mouse~e.35)))))) # ::id pmid_1563_0473.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test whether TGF-β2 might be required for Snail induction in hair bud formation in vivo , we first analyzed whether TGF-β2 was expressed in or around the hair bud . # ::alignments 1-1.4 2-1.4.2.1 2-1.4.2.1.r 3-1.2.2.1.1 4-1.4.2 6-1.4.2.2 9-1.4.2.2.1.1.1.1 11-1.4.2.2.1 12-1.4.2.2.1.2.2 13-1.2.3.1.1 14-1.2.3.1 15-1.4.2.2.1.2 16-1.4.2.2.1.2.2 17-1.4.2.2.1.2.2 19-1.1 20-1.3 21-1 22-1.2.1 22-1.2.1.r 23-1.2.2.1.1 25-1.2 26-1.4.2.2.1.2.2 27-1.2.3 28-1.2.3.2 30-1.2.3.1.1 31-1.2.3.1 (a / analyze-01~e.21 :ARG0 (w / we~e.19) :ARG1 (e / express-03~e.25 :mode~e.22 interrogative~e.22 :ARG2 (p / protein :name (n / name :op1 "TGF-β2"~e.3,23)) :ARG3 (o / or~e.27 :op1 (b / bud~e.14,31 :mod (h / hair~e.13,30)) :op2 (a2 / around~e.28 :op1 h))) :mod (f / first~e.20) :purpose (t / test-01~e.1 :ARG0 w :ARG1 (p2 / possible-01~e.4 :mode~e.2 interrogative~e.2 :ARG1 (r / require-01~e.6 :ARG0 (i / induce-01~e.11 :ARG2 (g / gene :name (n2 / name :op1 "Snail"~e.9)) :subevent-of (f2 / form-01~e.15 :ARG1 b :manner (i2 / in-vivo~e.12,16,17,26))) :ARG1 p)))) # ::id pmid_1563_0473.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with previous observations [ @ 33 @ ] , an anti @-@ TGF-β2 antibody labeled developing hair buds ( Figure 6 @ A ) . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1.1 3-1.3.1 3-1.3.1.1 3-1.3.1.1.r 6-1.3.1.2.1.1.1 11-1.1.1 13-1.1.1.1.1.1 14-1.1 15-1 16-1.2.2 17-1.2.1 18-1.2 21-1.4.1 (l / label-01~e.15 :ARG0 (a / antibody~e.14 :ARG0-of (c3 / counter-01~e.11 :ARG1 (p3 / protein :name (n / name :op1 "TGF-β2"~e.13)))) :ARG1 (b / bud~e.18 :mod (h / hair~e.17) :ARG1-of (d / develop-01~e.16)) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (t / thing~e.3 :ARG1-of~e.3 (o / observe-01~e.3 :time (p / previous~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 33~e.6))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.21 :mod "6A"))) # ::id pmid_1563_0473.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This labeling appeared to be specific as judged by the lack of staining in follicle buds from mice homozygous for a TGF-β2 null mutation ( Figure 6 @ A ; [ @ 34 @ ]) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 5-1.1 6-1.2.r 7-1.2 11-1.2.1.r 12-1.2.1 13-1.2.1.2.r 14-1.2.1.2.1 15-1.2.1.2 16-1.2.1.2.1.1.r 17-1.2.1.2.1.1 18-1.2.1.2.1.2 22-1.2.1.2.1.2.1.1.1.1 24-1.2.1.2.1.2.1 24-1.2.1.2.1.2.1.1.2 25-1.2.1.2.1.2.1 28-1.3.1.1 35-1.3.1.2.1.1 (a / appear-02~e.2 :ARG1 (s / specific-02~e.5 :ARG1 (l / label-01~e.1 :mod (t / this~e.0))) :ARG2-of~e.6 (j / judge-01~e.7 :ARG3~e.11 (s2 / stain-01~e.12 :polarity - :location~e.13 (b2 / bud~e.15 :mod (f / follicle~e.14 :mod~e.16 (m2 / mouse~e.17) :mod (h / homozygous~e.18 :topic (m / mutate-01~e.24,25 :ARG2 (p / protein :name (n2 / name :op1 "TGF-β2"~e.22) :mod (n / null~e.24)))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure~e.28 :mod "6A") :op2 (p2 / publication :ARG1-of (c / cite-01 :ARG2 34~e.35))))) # ::id pmid_1563_0473.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the downstream effector of TGF-β2 signaling , pSMAD2 , was also expressed in WT , but not TGF-β2 @ -@ null , hair buds ( Figure 6 @ B ) . # ::alignments 0-1 3-1.1.1.1 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1.1 7-1.1.1.2 12-1.1.3 13-1.1 13-1.1.4.1 15-1.1.2.2 17-1.1.4 18-1.1.4.1.1 18-1.1.4.1.1.r 20-1.1.4.1.3.1.1.1 23-1.1.4.1.3.1 23-1.1.4.1.3.1.2 23-1.1.4.1.3.1.2.r 25-1.1.2.1 25-1.1.4.1.3.2 26-1.1.2 26-1.1.4.1.3 29-1.2.1 (a / and~e.0 :op2 (e / express-03~e.13 :ARG2 (e2 / effector~e.4 :location (d / downstream~e.3) :mod~e.5 (s / signal-07~e.7 :ARG0 (p / protein :name (n / name :op1 "TGF-β2"~e.6))) :ARG1-of (m / mean-01 :ARG2 (p2 / protein :name (n2 / name :op1 "SMAD2") :ARG1-of (p3 / phosphorylate-01)))) :ARG3 (b / bud~e.26 :mod (h / hair~e.25) :mod (w / wild-type~e.15)) :mod (a2 / also~e.12) :ARG1-of (c / contrast-01~e.17 :ARG2 (e3 / express-03~e.13 :polarity~e.18 -~e.18 :ARG2 p2 :ARG3 (b2 / bud~e.26 :mod (p5 / protein~e.23 :name (n4 / name :op1 "TGF-β2"~e.20) :ARG2-of~e.23 (m2 / mutate-01~e.23 :mod "−/−")) :mod (h2 / hair~e.25))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod "6B"))) # ::id pmid_1563_0473.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these data underscore the importance of the TGF-β2 isoform despite expression of both TGF-β1 and TGF-β2 in developing hair buds at this stage . # ::alignments 0-1.1.2 2-1.1.1 3-1.1 4-1 6-1.2 7-1.2.1.r 9-1.2.1.1.1.1 10-1.2.1 11-1.2.2.r 12-1.2.2 15-1.2.2.1.1.1.1 16-1.2.2.1 17-1.2.2.1.2 18-1.2.2.2.r 19-1.2.2.2.2 20-1.2.2.2.1 21-1.2.2.2 22-1.2.2.3.r 23-1.2.2.3.1 24-1.2.2.3 (u / underscore-01~e.4 :ARG0 (d / data~e.3 :mod (t / this~e.2) :mod (t2 / together~e.0)) :ARG1 (i / important~e.6 :domain~e.7 (i2 / isoform~e.10 :mod (p / protein :name (n / name :op1 "TGF-β2"~e.9))) :concession~e.11 (e / express-03~e.12 :ARG2 (a / and~e.16 :op1 (p2 / protein :name (n2 / name :op1 "TGF-β1"~e.15)) :op2 p~e.17) :ARG3~e.18 (b / bud~e.21 :mod (h / hair~e.20) :ARG2-of (d2 / develop-01~e.19)) :time~e.22 (s / stage~e.24 :mod (t3 / this~e.23))))) # ::id pmid_1563_0473.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further explore the possible relation between Snail and TGF-β2 , we examined the status of Snail expression in TGF-β2 @ -@ null hair buds . # ::alignments 1-1.3.3 2-1.3 4-1.3.2.3 5-1.3.2 7-1.2.1.1.1.1 9-1.2.1.2.2.1.1 11-1.1 12-1 14-1.2 16-1.2.1.1.1.1 17-1.2.1 20-1.2.1.2.2.1.1 23-1.2.1.2.2.2 24-1.2.1.2.1 25-1.2.1.2 (e / examine-01~e.12 :ARG0 (w / we~e.11) :ARG1 (s / status~e.14 :mod (e2 / express-03~e.17 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.7,16)) :ARG3 (b / bud~e.25 :mod (h / hair~e.24) :mod (p2 / protein :name (n3 / name :op1 "TGF-β2"~e.9,20) :mod (n2 / null~e.23))))) :purpose (e3 / explore-01~e.2 :ARG0 w :ARG1 (r / relation-03~e.5 :ARG0 p :ARG2 p2 :ARG1-of (p3 / possible-01~e.4)) :degree (f / further~e.1))) # ::id pmid_1563_0473.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As judged by immunohistochemistry , Snail protein was absent from E17.5 skin of TGF-β2 @- @ null embryos but not from that of control littermates ( Figure 6 @ C ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 5-1.1.1.1 6-1.1 6-1.2.1.1.1 8-1 8-1.3.1 11-1.2 11-1.3.1.3 14-1.2.1.1.1.1.1 17-1.2.1.1 18-1.2.1 19-1.3 20-1.3.1.1 20-1.3.1.1.r 23-1.3.1.3.1.r 24-1.3.1.3.1.1 25-1.3.1.3.1 28-1.5.1 (a / absent-01~e.8 :ARG1 (p / protein~e.6 :name (n / name :op1 "Snail"~e.5)) :ARG2 (s / skin~e.11 :part-of (e2 / embryo~e.18 :mod (n2 / null~e.17 :mod (p2 / protein~e.6 :name (n3 / name :op1 "TGF-β2"~e.14))) :age (t / temporal-quantity :quant 17.5 :unit (d2 / day)))) :ARG1-of (c / contrast-01~e.19 :ARG2 (a2 / absent-01~e.8 :polarity~e.20 -~e.20 :ARG1 p :ARG2 (s2 / skin~e.11 :part-of~e.23 (l / littermate~e.25 :mod (c2 / control~e.24))))) :ARG2-of (j / judge-01~e.1 :ARG0~e.2 (i / immunohistochemistry~e.3)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod "6C"))) # ::id pmid_1563_0473.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This effect appeared to be exerted at the transcriptional level , since Snail mRNAs were also not found in TGF-β2 null hair buds under conditions in which the signal was readily detected in the hair buds of littermate skin ( Figure 6 @ D ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 3-1.2 5-1.1 6-1.1.2.r 8-1.1.2.1 9-1.1.2 11-1.2 13-1.2.1.2.2.1.1 15-1.2.1.2.1.1 17-1.2.1.3 18-1.2.1.1 18-1.2.1.1.r 19-1.2.1 22-1.2.1.4.2.1.1 24-1.2.1.4.2.2 25-1.2.1.4.1 26-1.2.1.4 28-1.2.1.5.r 32-1.2.1.5.1 34-1.2.1.5.2 34-1.2.1.5.2.r 35-1.2.1.5 36-1.2.1.5.3.r 38-1.2.1.5.3.1 39-1.2.1.5.3 40-1.2.1.5.3.2.r 41-1.2.1.5.3.2.1 42-1.2.1.5.3.2 45-1.3.1 (a / appear-02~e.2 :ARG1 (e2 / exert-01~e.5 :ARG1 (e / effect-03~e.1 :mod (t / this~e.0)) :location~e.6 (l / level~e.9 :mod (t2 / transcribe-01~e.8))) :ARG1-of (c / cause-01~e.3,11 :ARG0 (f / find-01~e.19 :polarity~e.18 -~e.18 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.15) :mod (g / gene :name (n / name :op1 "Snail"~e.13))) :mod (a2 / also~e.17) :location (b / bud~e.26 :mod (h / hair~e.25) :mod (p2 / protein :name (n3 / name :op1 "TGF-β2"~e.22) :mod (n2 / null~e.24))) :condition~e.28 (d / detect-01~e.35 :ARG1 (s / signal-07~e.32) :manner~e.34 (r / ready~e.34) :location~e.36 (b2 / bud~e.39 :mod h~e.38 :part-of~e.40 (s2 / skin~e.42 :part-of (l2 / littermate~e.41)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.45 :mod "6D"))) # ::id pmid_1563_0473.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , in 2 @-@ wk @-@ old K14 @-@ Smad2 Tg mice , which display elevated TGF-β signaling in skin [ @ 35 @ ] , Snail protein was readily detected by Western blot analyses , where it was not found in postnatal skin ( Figure 6 @ E ) . # ::alignments 3-1.1.6.1.1 7-1.1.6.1.r 9-1.1.6.3.1.1.1 11-1.1.6.3.2.1.1 13-1.1.6.2 14-1.1.6 17-1.1.6.4 18-1.1.6.4.1.2 19-1.1.6.4.1.1.1.1 20-1.1.6.4.1 21-1.1.6.4.2.r 22-1.1.6.4.2 25-1.1.6.4.3.1.1.1 29-1.1.1.1.1 30-1.1.1 30-1.1.6.3.1 30-1.1.6.3.2 30-1.1.6.4.1.1 32-1.1.3 32-1.1.3.r 33-1.1 34-1.1.2.r 35-1.1.2.1 36-1.1.2.1 37-1.1.2 39-1.1.4.r 39-1.1.6.r 40-1.1.4.2 42-1.1.4.1 42-1.1.4.1.r 43-1.1.4 44-1.1.4.3.r 45-1.1.4.3.1 46-1.1.4.3 49-1.1.5.1 (c / contrast-01 :ARG2 (d / detect-01~e.33 :ARG1 (p / protein~e.30 :name (n / name :op1 "Snail"~e.29)) :ARG2~e.34 (a / analyze-01~e.37 :manner (i / immunoblot-01~e.35,36)) :manner~e.32 (r / ready~e.32) :location~e.39 (f / find-01~e.43 :polarity~e.42 -~e.42 :ARG1 p~e.40 :location~e.44 (s / skin~e.46 :mod (p2 / postnatal~e.45))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.49 :mod "6A")) :location~e.39 (m / mouse~e.14 :age~e.7 (t / temporal-quantity :quant 2~e.3 :unit (w2 / week)) :mod (t2 / transgenic~e.13) :mod (m2 / macro-molecular-complex :part (p3 / protein~e.30 :name (n2 / name :op1 "K14"~e.9)) :part (p4 / protein~e.30 :name (n3 / name :op1 "Smad2"~e.11))) :ARG0-of (d3 / display-01~e.17 :ARG1 (s2 / signal-07~e.20 :ARG0 (p5 / protein~e.30 :name (n4 / name :op1 "TGF-β"~e.19)) :ARG1-of (e / elevate-01~e.18)) :ARG2~e.21 (s3 / skin~e.22) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 35~e.25))))))) # ::id pmid_1563_0473.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these results provide compelling evidence that TGF-β2 is functionally important for inducing Snail gene expression in a pSMAD @-@ dependent manner in developing hair buds . # ::alignments 0-1.1.3 1-1.1.3.1 3-1.1.1 4-1.1 4-1.1.2 4-1.1.2.r 5-1 6-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.1.1.1 10-1.2.1.1.r 11-1.2.1.2 12-1.2.1 13-1.2.1.3.r 14-1.2.1.3 16-1.2.1.3.1.1.1.1 18-1.2.1.3.1.1 19-1.2.1.3.1 24-1.2.1.3.2 26-1.2.1.3.1.2.r 27-1.2.1.3.1.2.2 28-1.2.1.3.1.2.1 29-1.2.1.3.1.2 (p / provide-01~e.5 :ARG0 (t / thing~e.4 :mod (t2 / this~e.3) :ARG2-of~e.4 (r / result-01~e.4) :ARG1-of (t3 / take-01~e.0 :mod (t4 / together~e.1))) :ARG1 (e / evidence-01~e.7 :ARG1~e.8 (i / important~e.12 :domain~e.10 (p2 / protein :name (n / name :op1 "TGF-β2"~e.9)) :mod (f / function-01~e.11) :purpose~e.13 (i2 / induce-01~e.14 :ARG2 (e2 / express-03~e.19 :ARG1 (g / gene~e.18 :name (n2 / name :op1 "Snail"~e.16)) :ARG3~e.26 (b / bud~e.29 :mod (h / hair~e.28) :ARG2-of (d / develop-01~e.27))) :ARG0-of (d2 / depend-01~e.24 :ARG1 (p3 / protein :name (n3 / name :op1 "SMAD") :ARG1-of (p4 / phosphorylate-01))))) :ARG0-of (c / compel-01~e.6))) # ::id pmid_1563_0473.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whether pMARK activity also contributes to Snail induction was not addressed in the present study [ @ 15 @ ] . # ::alignments 0-1.2.1 0-1.2.1.r 2-1.2.2 3-1.2.4 4-1.2 5-1.2.3.r 6-1.2.3.1.1.1 7-1.2.3 9-1.1 9-1.1.r 10-1 11-1.3.r 13-1.3.1 14-1.3 17-1.4.1.1.1 (a / address-02~e.10 :polarity~e.9 -~e.9 :ARG1 (c / contribute-01~e.4 :mode~e.0 interrogative~e.0 :ARG0 (a3 / activity-06~e.2 :ARG0 (e / enzyme :name (n / name :op1 "MAPK") :ARG1-of (p2 / phosphorylate-01))) :ARG2~e.5 (i / induce-01~e.7 :ARG2 (p3 / protein :name (n2 / name :op1 "Snail"~e.6))) :mod (a2 / also~e.3)) :medium~e.11 (s / study~e.14 :time (p / present~e.13)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 15~e.17)))) # ::id pmid_1563_0473.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although some hair buds still formed in TGF-β2 null skin , their number was reduced by approximately 50 % [ @ 32 @ ] . # ::alignments 0-1 1-1.2.1.2 2-1.2.1.1 3-1.2.1 4-1.2.2 5-1.2 8-1.2.3.1.1.1 10-1.2.3.1 10-1.2.3.1.2 10-1.2.3.1.2.r 11-1.2.3 13-1.1.1.1 13-1.1.1.1.r 14-1.1.1 16-1.1 17-1.1.2.r 18-1.1.2 19-1.1.2.1.1 20-1.1.2.1 23-1.3.1.1.1 (h / have-concession-91~e.0 :ARG1 (r / reduce-01~e.16 :ARG1 (n3 / number~e.14 :quant-of~e.13 b~e.13) :ARG2~e.17 (a / approximately~e.18 :op1 (p2 / percentage-entity~e.20 :value 50~e.19))) :ARG2 (f / form-01~e.5 :ARG1 (b / bud~e.3 :mod (h2 / hair~e.2) :mod (s2 / some~e.1)) :mod (s / still~e.4) :location (s3 / skin~e.11 :mod (p / protein~e.10 :name (n2 / name :op1 "TGF-β2"~e.8) :ARG2-of~e.10 (m / mutate-01~e.10 :mod "−/−")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 32~e.23)))) # ::id pmid_1563_0473.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , although the pathway mediated by TGF-β2 signaling impacts the earliest step of epithelial invagination , it does not appear to be essential for bud morphogenesis . # ::alignments 2-1.1 4-1.1.2.1 5-1.1.2.1.1 6-1.1.2.1.1.1.r 7-1.1.2.1.1.1.1.1.1 8-1.1.2.1.1.1 9-1.1.2 11-1.1.2.2.2 11-1.1.2.2.2.1 11-1.1.2.2.2.1.r 12-1.1.2.2 13-1.1.2.2.1.r 14-1.1.2.2.1.1 15-1.1.2.2.1 19-1.1.1.1 19-1.1.1.1.r 20-1.1.1 21-1.1.1.2.r 22-1.1.1.2.1.r 23-1.1.1.2 24-1.1.1.2.2.r 25-1.1.1.2.2.1 26-1.1.1.2.2 (i / infer-01 :ARG1 (h / have-concession-91~e.2 :ARG1 (a / appear-02~e.20 :polarity~e.19 -~e.19 :ARG1~e.21 (e3 / essential~e.23 :domain~e.22 p :purpose~e.24 (m3 / morphogenesis~e.26 :mod (b / bud~e.25)))) :ARG2 (i2 / impact-01~e.9 :ARG0 (p / pathway~e.4 :ARG1-of (m / mediate-01~e.5 :ARG0~e.6 (s / signal-07~e.8 :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2"~e.7))))) :ARG1 (s2 / step-01~e.12 :ARG1~e.13 (i3 / invaginate-01~e.15 :ARG1 (e2 / epithelium~e.14)) :mod (e / early~e.11 :degree~e.11 (m2 / most~e.11)))))) # ::id pmid_1563_0473.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with this notion , basement membrane remodeling still took place in the TGF-β2 @ -@ null buds , as judged by immunofluorescence with antibodies against β4 integrin , an integral component of keratinocyte @-@ mediated adhesion to its underlying basement membrane ( Figure 6 @ F ) . # ::alignments 0-1 1-1.2.r 2-1.2.1 3-1.2 5-1.1.1.1 6-1.1.1 7-1.1 8-1.1.3 14-1.1.2.1.1.1 17-1.1.2.1.2 18-1.1.2 20-1.1.4.r 21-1.1.4 22-1.1.4.1.r 23-1.1.4.1 24-1.1.4.1.1.r 25-1.1.4.1.1 26-1.1.4.1.1.1 27-1.1.4.1.1.1.1.1.1 28-1.1.4.1.1.1.1.1.2 31-1.1.4.1.1.1.1.2.1.1 32-1.1.4.1.1.1.1.2.1 33-1.1.4.1.1.1.1.2.1.2.r 34-1.1.4.1.1.1.1.2.1.2.2.1 36-1.1.4.1.1.1.1.2.1.2.2 37-1.1.4.1.1.1.1.2.1.2 40-1.1.4.1.1.1.1.2.1.2.1.2 41-1.1.4.1.1.1.1.2.1.2.1.1 42-1.1.4.1.1.1.1.2.1.2.1 45-1.1.5.1 (c / consistent-01~e.0 :ARG1 (r / remodel-01~e.7 :ARG1 (m / membrane~e.6 :mod (b / basement~e.5)) :location (b2 / bud~e.18 :mod (p / protein :name (n2 / name :op1 "TGF-β2"~e.14) :mod (n / null~e.17))) :mod (s / still~e.8) :ARG1-of~e.20 (j / judge-01~e.21 :ARG3~e.22 (i / immunofluoresce-01~e.23 :ARG2~e.24 (a / antibody~e.25 :ARG0-of (c3 / counter-01~e.26 :ARG1 (p2 / protein :name (n4 / name :op1 "β4"~e.27 :op2 "integrin"~e.28) :ARG1-of (m2 / mean-01 :ARG2 (c2 / component~e.32 :mod (i2 / integral~e.31) :mod~e.33 (a2 / adhere-01~e.37 :ARG2 (m4 / membrane~e.42 :mod (b3 / basement~e.41) :ARG1-of (u / underlie-01~e.40)) :ARG1-of (m3 / mediate-01~e.36 :ARG0 (k / keratinocyte~e.34)))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.45 :mod "6F"))) :ARG2~e.1 (n3 / notion~e.3 :mod (t / this~e.2))) # ::id pmid_1563_0473.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , TGF-β2 signaling appeared to be an important factor for the early proliferation that occurs in the developing hair buds , as judged by anti @-@ Ki67 and anti @-@ pMAPK immunofluorescence ( Figure 6 @ F and 6 @ G ) . # ::alignments 1-1 3-1.1.1.3.1.1.1 4-1.1.1.3 5-1.1 7-1.1.1.3.r 9-1.1.1.1 10-1.1.1 11-1.1.1.2.r 13-1.1.1.2.1 14-1.1.1.2 17-1.1.1.2.2.r 19-1.1.1.2.2.2 20-1.1.1.2.2.1 21-1.1.1.2.2 23-1.1.1.4.r 24-1.1.1.4 25-1.1.1.4.1.r 26-1.1.1.4.1.1 28-1.1.1.4.1.1.1.1.1 30-1.1.1.4.1.1 30-1.1.1.4.1.2 32-1.1.1.4.1.2.1.1.1 32-1.1.1.4.1.2.1.2 33-1.1.1.4.1 36-1.2.1.1 36-1.2.1.2 40-1.2.1 (c / contrast-01~e.1 :ARG2 (a / appear-02~e.5 :ARG1 (f / factor~e.10 :mod (i / important~e.9) :mod~e.11 (p / proliferate-01~e.14 :mod (e / early~e.13) :location~e.17 (b / bud~e.21 :mod (h / hair~e.20) :ARG2-of (d / develop-01~e.19))) :domain~e.7 (s / signal-07~e.4 :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2"~e.3))) :ARG1-of~e.23 (j / judge-01~e.24 :ARG3~e.25 (i2 / immunofluoresce-01~e.33 :ARG0-of (c2 / counter-01~e.26,30 :ARG1 (p3 / protein :name (n2 / name :op1 "Ki67"~e.28))) :ARG0-of (c3 / counter-01~e.30 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MAPK"~e.32) :ARG3-of (p4 / phosphorylate-01~e.32))))))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.40 :op1 (f2 / figure~e.36 :mod "6F") :op2 (f3 / figure~e.36 :mod "6G")))) # ::id pmid_1563_0473.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If TGF-β2 stimulates Snail expression in developing buds , loss of this morphogen would be expected to affect the expression of genes that are typically repressed by Snail . # ::alignments 0-1.2.r 1-1.2.1.1.1 2-1.2 4-1.2.2.1.1.1 6-1.2.2 7-1.2.2.2.r 8-1.2.2.2.1 9-1.2.2.2 11-1.1.1 14-1.1.1.1 17-1 19-1.1 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1 26-1.1.2.1.1.2 27-1.1.2.1.1 28-1.1.2.1.1.1.r 29-1.1.2.1.1.1 (e / expect-01~e.17 :ARG1 (a / affect-01~e.19 :ARG0 (l / lose-02~e.11 :ARG1 m2~e.14) :ARG1 (e3 / express-03~e.21 :ARG1~e.22 (g / gene~e.23 :ARG1-of (r / repress-01~e.27 :ARG0~e.28 g2~e.29 :ARG1-of (t / typical-02~e.26))))) :condition~e.0 (s / stimulate-01~e.2 :ARG0 (m2 / morphogen :name (n / name :op1 "TGF-β2"~e.1)) :ARG1 (e2 / express-03~e.6 :ARG1 (g2 / gene :name (n2 / name :op1 "Snail"~e.4)) :ARG3~e.7 (b / bud~e.9 :ARG2-of (d / develop-01~e.8))))) # ::id pmid_1563_0473.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since a major target for Snail @-@ mediated repression is the E @-@ cadherin gene [ @ 12 , 13 @ ] , we investigated the status of E @-@ cadherin in TGF-β2 @ -@ null buds . # ::alignments 0-1.3 2-1.3.1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1.1.1 7-1.3.1.1.1 8-1.3.1.1 12-1.3.1.2 13-1.3.1.2 14-1.3.1.2 15-1.3.1.2 16-1.3.1.2 19-1.3.1.4.1.1.1.1 23-1.3.1.4.1.1.1.2 27-1.1 28-1 30-1.2 31-1.2.1.r 32-1.2.1.1.1 34-1.2.1.1.1 37-1.2.2.1.1.1 40-1.2.2.1 40-1.2.2.1.2 40-1.2.2.1.2.r 41-1.2.2 (i / investigate-01~e.28 :ARG0 (w / we~e.27) :ARG1 (s / status~e.30 :mod~e.31 (g / gene :name (n / name :op1 "E-cadherin"~e.32,34)) :location (b / bud~e.41 :mod (p2 / protein~e.40 :name (n3 / name :op1 "TGF-β2"~e.37) :ARG2-of~e.40 (m3 / mutate-01~e.40 :mod "−/−")))) :ARG1-of (c / cause-01~e.0 :ARG0 (t / target-01~e.3 :ARG0~e.4 (r / repress-01~e.8 :ARG1-of (m2 / mediate-01~e.7 :ARG0 (p / protein :name (n4 / name :op1 "Snail"~e.5)))) :ARG1 g~e.12,13,14,15,16 :ARG1-of (m / major-02~e.2) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 12~e.19 :op2 13~e.23))))))) # ::id pmid_1563_0473.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 6 @ H , hair buds in TGF-β2 null skin displayed elevated immunofluorescence staining relative to their WT counterparts . # ::alignments 1-1.3 4-1.3.1 9-1.1.1 10-1.1 11-1.1.2.r 12-1.1.2.1.1.1 13-1.1.2.1.2 14-1.1.2 15-1 16-1.2.3 17-1.2.2 18-1.2 20-1.2.3.1.r 21-1.2.3.1.1 21-1.2.3.1.1.r 22-1.2.3.1.2 23-1.2.3.1 (d / display-01~e.15 :ARG0 (b / bud~e.10 :mod (h / hair~e.9) :location~e.11 (s / skin~e.14 :mod (p / protein :name (n2 / name :op1 "TGF-β2"~e.12) :mod (n / null~e.13)))) :ARG1 (s2 / stain-01~e.18 :ARG1 b :mod (i / immunofluoresce-01~e.17) :ARG1-of (e / elevate-01~e.16 :compared-to~e.20 (c / counterpart~e.23 :poss~e.21 b~e.21 :mod (w / wild-type~e.22)))) :ARG1-of (s3 / show-01~e.1 :ARG0 (f / figure~e.4 :mod "6H"))) # ::id pmid_1563_0473.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previously we demonstrated that the concerted action of the extracellular signals Wnt and noggin are required for the generation of a LEF @-@ 1/β-catenin transcription complex to repress E @-@ cadherin transcription at the onset of hair fate specification . # ::alignments 0-1.3 1-1.1 2-1 3-1.2.r 5-1.2.2.2 6-1.2.2 7-1.2.2.1.r 9-1.2.2.1.1.2 10-1.2.2.1.3 11-1.2.2.1.1.1.1 12-1.2.2.1 13-1.2.2.1.2.1.1 15-1.2 16-1.2.1.r 18-1.2.1.1 19-1.2.1.1.1.r 21-1.2.1.1.1.2.1.1 24-1.2.1.1.1.1 25-1.2.1.1.1 27-1.2.1 29-1.2.1.2.1.1.1 31-1.2.1.2.1.1.1 33-1.2.1.2 34-1.2.1.2.2.r 36-1.2.1.2.2 37-1.2.1.2.2.1.r 38-1.2.1.2.2.1.1.1 39-1.2.1.2.2.1.1 40-1.2.1.2.2.1 (d / demonstrate-01~e.2 :ARG0 (w / we~e.1) :ARG1~e.3 (r / require-01~e.15 :ARG0~e.16 (r2 / repress-01~e.27 :ARG0 (g / generate-01~e.18 :ARG1~e.19 (m / macro-molecular-complex~e.25 :ARG0-of (t / transcribe-01~e.24) :part (p3 / protein :name (n3 / name :op1 "LEF-1"~e.21)) :part (p4 / protein :name (n4 / name :op1 "β-catenin")))) :ARG1 (t2 / transcribe-01~e.33 :ARG1 (g2 / gene :name (n5 / name :op1 "E-cadherin"~e.29,31)) :time~e.34 (o / onset~e.36 :poss~e.37 (s / specify-01~e.40 :ARG1 (f / fate~e.39 :poss (h / hair~e.38)))))) :ARG1 (a / act-01~e.6 :ARG0~e.7 (a2 / and~e.12 :op1 (p / pathway :name (n6 / name :op1 "Wnt"~e.11) :mod (e / extracellular~e.9)) :op2 (p2 / pathway :name (n / name :op1 "noggin"~e.13) :mod e) :ARG0-of (s2 / signal-07~e.10)) :mod (c / concerted~e.5))) :time (p5 / previous~e.0)) # ::id pmid_1563_0473.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 6 @ I and 6 @ J , both WT and TGF-β2 null buds exhibited nuclear LEF @-@ 1 and β-catenin localization , signs that the Wnt @-@ noggin signaling pathway was intact . # ::alignments 1-1.3 4-1.3.1.1 4-1.3.1.2 7-1.2.1.1.1.1 8-1.3.1 15-1.1.1.1 16-1.1 17-1.1.2.1.1.1 18-1.1.2.1.2 19-1.1.1 19-1.1.2 20-1 21-1.2.2 22-1.2.1.1.1.1 24-1.2.1.1.1.1 25-1.2.1 26-1.2.1.2.1.1 27-1.2 29-1.4 30-1.4.1.r 32-1.4.1.1.1.1 34-1.4.1.1.1.1 35-1.4.1.1.2 36-1.4.1.1 37-1.4.1.1.r 38-1.4.1 (e / exhibit-01~e.20 :ARG0 (a / and~e.16 :op1 (b / bud~e.19 :mod (w / wild-type~e.15)) :op2 (b2 / bud~e.19 :mod (p / protein :name (n2 / name :op1 "TGF-β2"~e.17) :mod (n / null~e.18)))) :ARG1 (b3 / be-located-at-91~e.27 :ARG1 (a3 / and~e.25 :op1 (p2 / protein :name (n3 / name :op1 "LEF-1"~e.7,22,24)) :op2 (p4 / protein :name (n6 / name :op1 "β-catenin"~e.26))) :ARG2 (n4 / nucleus~e.21)) :ARG1-of (s / show-01~e.1 :ARG0 (a2 / and~e.8 :op1 (f / figure~e.4 :mod "6I") :op2 (f2 / figure~e.4 :mod "6J"))) :ARG0-of (s2 / signal-07~e.29 :ARG1~e.30 (i / intact~e.38 :domain~e.37 (p3 / pathway~e.36 :name (n5 / name :op1 "Wnt-noggin"~e.32,34) :ARG0-of (s3 / signal-07~e.35))))) # ::id pmid_1563_0473.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest that during hair follicle morphogenesis , TGF-β2 functions subsequently to Wnt @/@ noggin @-@ mediated determination of hair fate . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.2.r 5-1.2.2.1.1 6-1.2.2.1 7-1.2.2 9-1.2.1.1.1 10-1.2 11-1.2.2.r 11-1.2.3 11-1.2.3.r 12-1.2.3.1.r 13-1.2.3.1.2.1.1.1 15-1.2.3.1.2.1.1.1 17-1.2.3.1.2 18-1.2.3.1 19-1.2.3.1.1.r 20-1.2.3.1.1.1 21-1.2.3.1.1 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (f / function-01~e.10 :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-β2"~e.9)) :time~e.4,11 (m / morphogenesis~e.7 :mod (f2 / follicle~e.6 :mod (h / hair~e.5))) :time~e.11 (s2 / subsequent~e.11 :op1~e.12 (d2 / determine-01~e.18 :ARG1~e.19 (f3 / fate~e.21 :poss (h2 / hair~e.20)) :ARG1-of (m2 / mediate-01~e.17 :ARG0 (p / pathway :name (n / name :op1 "Wnt/noggin"~e.13,15))))))) # ::id pmid_1563_0473.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , through activation of Snail gene expression , TGF-β2 appears to work in tandem with these other morphogens to down @-@ regulate E @-@ cadherin levels , which contributes to the activation of proliferative circuitries . # ::alignments 0-1 0-1.1.1.2.1 3-1.1.2.1 6-1.1.2.1.1.1.1.1 8-1.1.1.2.2.1 8-1.1.2.1.1.1 9-1.1.2.1.1 11-1.1.1.1.1.1 12-1.1 13-1.1.2 14-1.1.1 15-1.1.1.4.r 16-1.1.1.4 18-1.1.1.3.2 19-1.1.1.3.1 25-1.1.1.2.2.1.1.1 27-1.1.1.2.2.1.1.1 28-1.1.1.2.2 31-1.1.1.2.3 32-1.1.1.2.3.1.r 34-1.1.1.2.3.1 37-1.1.1.2.3.1.1 (a / and~e.0 :op2 (a2 / appear-02~e.12 :ARG2 (w / work-01~e.14 :ARG0 (p / protein :name (n / name :op1 "TGF-β2"~e.11)) :ARG1 (d / downregulate-01 :ARG0 (a4 / and~e.0 :op1 p :op2 m) :ARG1 (l / level~e.28 :quant-of (g2 / gene~e.8 :name (n3 / name :op1 "E-cadherin"~e.25,27))) :ARG0-of (c2 / contribute-01~e.31 :ARG2~e.32 (a5 / activate-01~e.34 :ARG1 (c3 / circuitry~e.37 :ARG0-of (p3 / proliferate-01))))) :ARG3 (m / morphogen :mod (o / other~e.19) :mod (t2 / this~e.18)) :mod~e.15 (t / tandem~e.16)) :ARG1-of (c / cause-01~e.13 :ARG0 (a3 / activate-01~e.3 :ARG1 (e / express-03~e.9 :ARG1 (g / gene~e.8 :name (n2 / name :op1 "Snail"~e.6))))))) # ::id pmid_1563_0473.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Discussion # ::alignments 0-1 (d / discuss-01~e.0) # ::id pmid_1563_0473.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok During budding morphogenesis , intersecting signaling networks from the epithelium and mesenchyme govern transcriptional , adhesive , polarity , and motility programs in these select groups of cells . # ::alignments 0-1.4.r 1-1.4.1 2-1.4 4-1.1.2 5-1.1.1 6-1.1 7-1.1.3.r 9-1.1.3.1 10-1.1.3 11-1.1.3.2 12-1 13-1.2.1.1 19-1.2 20-1.2.4.1 21-1.2.1 21-1.2.2 21-1.2.3 21-1.2.4 22-1.3.r 23-1.3.2 24-1.3.3 25-1.3 26-1.3.1.r 27-1.3.1 (g / govern-01~e.12 :ARG0 (n2 / network~e.6 :ARG0-of (s / signal-07~e.5) :ARG0-of (i / intersect-01~e.4) :source~e.7 (a / and~e.10 :op1 (e / epithelium~e.9) :op2 (m / mesenchyme~e.11))) :ARG1 (a4 / and~e.19 :op1 (p3 / program~e.21 :topic (t3 / transcribe-01~e.13)) :op2 (p4 / program~e.21 :topic (a3 / adhere-01)) :op3 (p5 / program~e.21 :topic (p2 / polarize-01)) :op4 (p6 / program~e.21 :topic (m2 / motility~e.20))) :location~e.22 (g2 / group~e.25 :consist-of~e.26 (c / cell~e.27) :mod (t4 / this~e.23) :mod (s2 / select~e.24)) :time~e.0 (m3 / morphogenesis~e.2 :ARG1-of (b / bud-01~e.1))) # ::id pmid_1563_0473.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The dynamic nuclear and cytosolic changes that take place during this time form the cornerstone for organ morphogenesis . # ::alignments 1-1.1.2 2-1.1.1.1 3-1.1.1 4-1.1.1.2 5-1.1 9-1.1.3.r 10-1.1.3 11-1.1.3.r 12-1 14-1.2 15-1.3.r 16-1.3.1 17-1.3 (f / form-01~e.12 :ARG0 (c4 / change-01~e.5 :ARG0 (a2 / and~e.3 :op1 (n / nucleus~e.2) :op2 (c2 / cytosol~e.4)) :mod (d / dynamic~e.1) :time~e.9,11 (t / this~e.10)) :ARG1 (c3 / cornerstone~e.14) :purpose~e.15 (m / morphogenesis~e.17 :mod (o / organ~e.16))) # ::id pmid_1563_0473.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two major challenges in understanding the mechanisms underlying a particular budding process are to order the temporal sequence of external cues involved and then to dissect how the cells of the developing bud translate these signals into the downstream events of cellular remodeling , proliferation , and differentiation . # ::alignments 0-1.3.1 1-1.3.3 2-1.3 3-1.3.2.r 4-1.3.2 6-1.3.2.1 7-1.3.2.1.1 9-1.3.2.1.1.1.2 10-1.3.2.1.1.1.1 11-1.3.2.1.1.1 13-1.3.2 14-1.1 16-1.1.1.1 17-1.1.1 18-1.1.1.2.r 19-1.1.1.2.1 20-1.1.1.2 21-1.1.1.2.2 22-1 23-1.2.2 25-1.2 26-1.2.1.1.r 28-1.2.1.1.1 29-1.2.1.1.1.1.r 31-1.2.1.1.1.1.1 32-1.2.1.1.1.1 33-1.2.1.1 34-1.2.1.1.2.2 35-1.2.1.1.2 35-1.2.1.1.2.1 35-1.2.1.1.2.1.r 36-1.2.1.1.3.r 38-1.2.1.1.3.4 39-1.2.1.1.3.1 39-1.2.1.1.3.2 39-1.2.1.1.3.3 40-1.2.1.1.3.1.1.r 41-1.2.1.1.3.1.1.1 42-1.2.1.1.3.1.1 44-1.2.1.1.3.3.1 46-1.2.1.1.3 47-1.2.1.1.3.2.1 (a / and~e.22 :op1 (o / order-03~e.14 :ARG1 (s / sequence~e.17 :mod (t / time~e.16) :consist-of~e.18 (c / cue~e.20 :source (e / external~e.19) :ARG1-of (i / involve-01~e.21)))) :op2 (d / dissect-01~e.25 :ARG1 (t3 / thing :manner-of~e.26 (t4 / translate-01~e.33 :ARG0 (c2 / cell~e.28 :part-of~e.29 (b / bud~e.32 :ARG1-of (d2 / develop-02~e.31))) :ARG1 (t5 / thing~e.35 :ARG0-of~e.35 (s2 / signal-07~e.35) :mod (t6 / this~e.34)) :ARG2~e.36 (a2 / and~e.46 :op1 (e3 / event~e.39 :mod~e.40 (r / remodel-01~e.42 :ARG1 c2~e.41)) :op2 (e4 / event~e.39 :mod (d4 / differentiate-01~e.47 :ARG1 c2)) :op3 (e5 / event~e.39 :mod (p / proliferate-01~e.44 :ARG0 c2)) :location (d3 / downstream~e.38)))) :time (t2 / then~e.23)) :domain (c3 / challenge-01~e.2 :quant 2~e.0 :ARG2~e.3 (u / understand-01~e.4,13 :ARG1 (m2 / mechanism~e.6 :ARG0-of (u2 / underlie-01~e.7 :ARG1 (p2 / process-02~e.11 :ARG1 (b2 / bud-01~e.10) :mod (p3 / particular~e.9))))) :ARG1-of (m / major-02~e.1))) # ::id pmid_1563_0473.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our studies here provide some insights into how these events are orchestrated during hair bud formation in developing skin . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1.1.2 3-1 4-1.2.1 5-1.2 6-1.2.2.r 7-1.2.2.1.r 8-1.2.2.1.1.1 9-1.2.2.1.1 11-1.2.2.1 12-1.2.2.1.2.r 13-1.2.2.1.2.1.1 14-1.2.2.1.2.1 15-1.2.2.1.2 16-1.2.2.1.2.2.r 17-1.2.2.1.2.2.1 18-1.2.2.1.2.2 (p / provide-01~e.3 :ARG0 (s / study-01~e.1 :ARG0~e.0 (w / we~e.0) :mod (h / here~e.2)) :ARG1 (i / insight~e.5 :quant (s2 / some~e.4) :topic~e.6 (t / thing :manner-of~e.7 (o / orchestrate-01~e.11 :ARG1 (e / event~e.9 :mod (t2 / this~e.8)) :time~e.12 (f / form-01~e.15 :ARG1 (b / bud~e.14 :mod (h2 / hair~e.13)) :location~e.16 (s3 / skin~e.18 :ARG1-of (d / develop-02~e.17))))))) # ::id pmid_1563_0473.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Signaling during Early Hair Follicle Morphogenesis # ::alignments 0-1 1-1.1.r 2-1.1 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1 (s / signal-07~e.0 :time~e.1 (e / early~e.2 :op1 (m / morphogenesis~e.5 :mod (f / follicle~e.4 :mod (h / hair~e.3))))) # ::id pmid_1563_0473.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recent studies on hair bud morphogenesis suggest that Wnt signals likely from the epithelium and BMP inhibitory signals from the underlying mesenchyme converge to produce an active transcription factor complex involving β-catenin and LEF @-@ 1 , which in turn plays a key role in specifying the hair follicle fate [ @ 4 , 29 , 30 , 36 , 37 @ ] . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1 6-1 7-1.2.r 8-1.2.1.1.1.1 9-1.2.1 10-1.2.1.2 11-1.2.1.2.1.r 11-1.2.1.2.r 13-1.2.1.2.1 14-1.2.3.1 15-1.2.2.1.1.1.1 16-1.2.2.1 17-1.2.2 18-1.2.2.2.r 20-1.2.2.2.1 21-1.2.2.2 22-1.2 24-1.2.3 26-1.2.3.2.3 27-1.2.3.2.1.1 28-1.2.3.2.1 29-1.2.3.2 30-1.2.3.2.2 31-1.2.3.2.2.1.1.1.1 32-1.2.3.2.2.1 33-1.2.3.2.2.1.2.1.1 35-1.2.3.2.2.1.2.1.1 38-1.2.3.2.4.2 39-1.2.3.2.4.2 40-1.2.3.2.4 42-1.2.3.2.4.1.1 43-1.2.3.2.4.1 44-1.2.3.2.4.1.1.1.r 44-1.2.3.2.4.2 45-1.2.3.2.4.1.1.1 47-1.2.3.2.4.1.1.1.1.1.1 48-1.2.3.2.4.1.1.1.1.1 49-1.2.3.2.4.1.1.1.1 52-1.3.1.1.1.1 56-1.3.1.1.1.2 60-1.3.1.1.1.3 64-1.3.1.1.1.4 68-1.3.1.1.1.5 (s / suggest-01~e.6 :ARG0 (s2 / study-01~e.1 :ARG1~e.2 (m / morphogenesis~e.5 :mod (b / bud~e.4 :mod (h / hair~e.3))) :time (r / recent~e.0)) :ARG1~e.7 (c / converge-01~e.22 :ARG0 (s6 / signal-07~e.9 :ARG0 (p / pathway :name (n / name :op1 "Wnt"~e.8)) :source~e.11 (l / likely-01~e.10 :ARG1~e.11 (e / epithelium~e.13))) :ARG1 (s3 / signal-07~e.17 :ARG0-of (i / inhibit-01~e.16 :ARG1 (p2 / protein :name (n2 / name :op1 "BMP"~e.15))) :source~e.18 (m2 / mesenchyme~e.21 :ARG0-of (u / underlie-01~e.20))) :purpose (p3 / produce-01~e.24 :ARG0 (a / and~e.14 :op1 s6 :op2 s3) :ARG1 (m3 / macro-molecular-complex~e.29 :part (f / factor~e.28 :ARG0-of (t3 / transcribe-01~e.27)) :ARG0-of (i2 / involve-01~e.30 :ARG1 (a3 / and~e.32 :op1 (p4 / protein :name (n4 / name :op1 "β-catenin"~e.31)) :op2 (p5 / protein :name (n5 / name :op1 "LEF-1"~e.33,35)))) :ARG0-of (a2 / activity-06~e.26) :ARG0-of (p6 / play-02~e.40 :ARG1 (r2 / role~e.43 :ARG1-of (k / key-02~e.42 :ARG2~e.44 (s5 / specify-01~e.45 :ARG1 (f2 / fate-01~e.49 :ARG1 (f3 / follicle~e.48 :mod (h2 / hair~e.47)))))) :mod (i3 / in-turn~e.38,39,44))))) :ARG1-of (d / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 4~e.52 :op2 29~e.56 :op3 30~e.60 :op4 36~e.64 :op5 37~e.68))))) # ::id pmid_1563_0473.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sonic hedgehog ( Shh ) and TGF-β2 signaling also play essential roles in follicle morphogenesis , but in contrast to β-catenin null skin , in which follicle invaginations are absent [ @ 30 @ ] , some hair buds still form in the absence of LEF @-@ 1 , Shh , or TGF-β2 [ @ 32 , 38 @ ] . # ::alignments 0-1.1.1.1.1.1 1-1.1.1.1.1.2 3-1.1.1.1.2.1.1 5-1.1 6-1.1.2.1.1.1 7-1.1.1 7-1.1.2 8-1.3 9-1 10-1.5 12-1.2.r 13-1.2.1 14-1.2 16-1.4.r 18-1.4.4 21-1.4.4.1.2.1.1.1 23-1.4.4.1.2.1 23-1.4.4.1.2.1.2 23-1.4.4.1.2.1.2.r 24-1.4.4.1 28-1.4.4.1.1.1.1 29-1.4.4.1.1.1 31-1.4.4.1.1 34-1.4.4.1.3.1.1.1 38-1.4.1.2 39-1.4.1.1 40-1.4.1 41-1.4.2 42-1.4 43-1.4.3.r 45-1.4.3 46-1.4.3.1.r 47-1.4.3.1.1.1.1 49-1.4.3.1.1.1.1 51-1.4.3.1.2 54-1.1.2.1.1.1 57-1.4.3.2.1.1.1.1 61-1.4.3.2.1.1.1.2 (p / play-08~e.9 :ARG0 (a / and~e.5 :op1 (s2 / signal-07~e.7 :ARG0 (p2 / protein :name (n / name :op1 "Sonic"~e.0 :op2 "hedgehog"~e.1) :ARG1-of (d3 / describe-01 :ARG2 (n5 / name :op1 "Shh"~e.3)))) :op2 (s3 / signal-07~e.7 :ARG0 (p7 / protein :name (n2 / name :op1 "TGF-β2"~e.6,54)))) :ARG1~e.12 (m / morphogenesis~e.14 :mod (f / follicle~e.13)) :mod (a2 / also~e.8) :concession~e.16 (f2 / form-01~e.42 :ARG1 (b / bud~e.40 :mod (h2 / hair~e.39) :quant (s4 / some~e.38)) :mod (s5 / still~e.41) :condition~e.43 (a5 / absent-01~e.45 :ARG1~e.46 (a3 / and :op1 (p3 / protein :name (n3 / name :op1 "LEF-1"~e.47,49)) :op2 p2~e.51 :op3 p7) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 32~e.57 :op2 38~e.61))))) :ARG1-of (c / contrast-01~e.18 :ARG2 (s7 / skin~e.24 :ARG2-of (a6 / absent-01~e.31 :ARG1 (i / invaginate-01~e.29 :ARG1 (f3 / follicle~e.28))) :ARG0-of (c4 / contain-01 :ARG1 (p4 / protein~e.23 :name (n4 / name :op1 "β-catenin"~e.21) :ARG2-of~e.23 (m2 / mutate-01~e.23 :mod "−/−"))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 30~e.34)))))) :mod (e / essential~e.10)) # ::id pmid_1563_0473.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These likely reflect the first wave of follicle ( i.e . , guard hair ) morphogenesis , which accounts for a small number ( fewer than 5 %) of hairs and is under distinct regulatory control . # ::alignments 0-1.1.1 1-1 2-1.1 4-1.1.2.2 4-1.1.2.2.1 4-1.1.2.2.1.r 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1 12-1.1.2.5.1.1 13-1.1.2.5.1 15-1.1.2.1 18-1.1.2.3 19-1.1.2.3.1.r 21-1.1.2.3.1.1.1 22-1.1.2.3.1.1 25-1.1.2.3.1.1.2.1 26-1.1.2.3.1.1.2.1.1.1 29-1.1.2.3.1 33-1.1.2.4.1 34-1.1.2.4.2 35-1.1.2.4 (l / likely-01~e.1 :ARG1 (r / reflect-01~e.2 :ARG1 (t / this~e.0) :ARG2 (w / wave-04~e.5 :ARG1~e.6 (m / morphogenesis~e.15 :mod (f / follicle~e.7)) :ord (o / ordinal-entity~e.4 :value~e.4 1~e.4) :ARG0-of (a / account-01~e.18 :ARG1~e.19 (h3 / hair~e.29 :quant (n / number~e.22 :mod (s / small~e.21) :ARG0-of (m3 / mean-01 :ARG1 (l2 / less-than~e.25 :op1 (p / percentage-entity :value 5~e.26)))))) :ARG1-of (c / control-01~e.35 :mod (d / distinct~e.33) :ARG0-of (r2 / regulate-01~e.34)) :ARG0-of (m2 / mean-01 :ARG1 (h2 / hair~e.13 :mod (g / guard~e.12)))))) # ::id pmid_1563_0473.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Guard hairs form in the absence of LEF @-@ 1 and TGF-β2 , and we have found that they also fail to express Snail at the budding stage of development ( unpublished data ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.r 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1.1 9-1.1.2.1.1.1.1 10-1.1.2.1 11-1.1.2.1.2.1.1 13-1 14-1.2.1 16-1.2 17-1.2.2.r 18-1.2.2.1 19-1.2.2.3 20-1.2.2 22-1.2.2.2 23-1.2.2.2.2.1.1 24-1.2.2.4.r 26-1.2.2.4.2 27-1.2.2.4 28-1.2.2.4.1.r 29-1.2.2.4.1 31-1.3.1.1.1 32-1.3.1 (a / and~e.13 :op1 (f / form-01~e.2 :ARG1 (h / hair~e.1 :mod (g / guard~e.0)) :condition~e.3 (a4 / absent-01~e.5 :ARG1~e.6 (a2 / and~e.10 :op1 (p / protein :name (n / name :op1 "LEF-1"~e.7,9)) :op2 (p3 / protein :name (n2 / name :op1 "TGF-β2"~e.11))))) :op2 (f2 / find-01~e.16 :ARG0 (w / we~e.14) :ARG1~e.17 (f3 / fail-01~e.20 :ARG1 h~e.18 :ARG2 (e / express-03~e.22 :ARG1 h :ARG2 (p4 / protein :name (n3 / name :op1 "Snail"~e.23))) :mod (a3 / also~e.19) :time~e.24 (s2 / stage~e.27 :subevent-of~e.28 (d / develop-02~e.29) :mod (b2 / bud-01~e.26)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.32 :ARG1-of (p2 / publish-01 :polarity -~e.31)))) # ::id pmid_1563_0473.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok How E @-@ cadherin is regulated in guard hairs remains to be determined . # ::alignments 0-1.1.1.1.r 1-1.1.1.1.1.1.1 3-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.r 7-1.1.1.1.2.1 8-1.1.1.1.2 9-1 12-1.1 (r / remain-01~e.9 :ARG1 (d / determine-01~e.12 :ARG1 (t / thing :manner-of~e.0 (r2 / regulate-01~e.5 :ARG1 (p / protein :name (n / name :op1 "E-cadherin"~e.1,3)) :location~e.6 (h / hair~e.8 :mod (g / guard~e.7)))))) # ::id pmid_1563_0473.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several candidates include other Snail family members such as Slug or twist , or alternatively , transcription factors involving β-catenin and a different member of the LEF @-@ 1/TCF/ @ Sry @ -@ type HMG box ( commonly known as SOX ) family [ @ 39 , 40 @ ] . # ::alignments 0-1.2.1 1-1.2 2-1 2-1.1.1.3 2-1.1.2.2.1.2.2 3-1.1.1.1 4-1.1.1.3.1.1.1 5-1.1.1.3.1 6-1.1.1 7-1.1.1.2.r 8-1.1.1.2.r 9-1.1.1.2.1.1.1 10-1.1.1.2 11-1.1.1.2.2.1.1 13-1.1 14-1.1.3 14-1.1.3.r 16-1.1.2.1 17-1.1.2 18-1.1.2.2 19-1.1.2.2.1.1.1.1 20-1.1.2.2.1 22-1.1.2.2.1.2.1 23-1.1.2.2.1.2 26-1.1.2.2.1.2.2.1.1.1.1 30-1.1.2.2.1.2.2.1.3.1.1 33-1.1.2.2.1.2.2.1.3.1.1 34-1.1.2.2.1.2.2.1.3.1.2 35-1.1.2.2.1.2.2.1.3.1.3 37-1.1.2.2.1.2.2.1.3.2.2 37-1.1.2.2.1.2.2.1.3.2.2.r 38-1.1.2.2.1.2.2.1.3.2 39-1.1.2.2.1.2.2.1.3.1.r 40-1.1.2.2.1.2.2.1.3.2.1.1 42-1.1.2.2.1.2.2.1.1 42-1.1.2.2.1.2.2.1.2 42-1.1.2.2.1.2.2.1.3 45-1.3.1.1.1.1 49-1.3.1.1.1.2 (i / include-01~e.2 :ARG1 (o3 / or~e.13 :op1 (m / member~e.6 :mod (o / other~e.3) :example~e.7,8 (o2 / or~e.10 :op1 (p8 / protein :name (n2 / name :op1 "Slug"~e.9)) :op2 (p9 / protein :name (n3 / name :op1 "twist"~e.11))) :ARG1-of (i3 / include-91~e.2 :ARG2 (p4 / protein-family~e.5 :name (n / name :op1 "Snail"~e.4)))) :op2 (f2 / factor~e.17 :ARG0-of (t / transcribe-01~e.16) :ARG2-of (i2 / involve-01~e.18 :ARG1 (a2 / and~e.20 :op1 (p / protein :name (n4 / name :op1 "β-catenin"~e.19)) :op2 (m2 / member~e.23 :ARG1-of (d / differ-02~e.22) :ARG1-of (i4 / include-91~e.2 :ARG2 (s2 / slash :op1 (p2 / protein-family~e.42 :name (n6 / name :op1 "LEF-1"~e.26)) :op2 (p5 / protein-family~e.42 :name (n7 / name :op1 "TCF")) :op3 (p6 / protein-family~e.42 :name~e.39 (n8 / name :op1 "Sry-type"~e.30,33 :op2 "HMG"~e.34 :op3 "box"~e.35) :ARG1-of (k / know-02~e.38 :ARG2 (n5 / name :op1 "SOX"~e.40) :manner~e.37 (c2 / common~e.37))))))))) :manner~e.14 (a / alternative~e.14)) :ARG2 (c / candidate~e.1 :quant (s / several~e.0)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 39~e.45 :op2 40~e.49))))) # ::id pmid_1563_0473.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further investigation will be required to determine whether the signaling pathway we have elucidated here is a theme with multiple variations . # ::alignments 0-1.1.1 1-1.1 4-1 6-1.2 7-1.2.2.1 7-1.2.2.1.r 9-1.2.2.2.1 10-1.2.2.2 11-1.2.2.2.2.1 13-1.2.2.2.2 14-1.2.2.2.2.2 15-1.2.2.2.r 17-1.2.2 18-1.2.2.3.r 19-1.2.2.3.1 20-1.2.2.3 (r / require-01~e.4 :ARG1 (i / investigate-01~e.1 :degree (f / further~e.0)) :purpose (d / determine-01~e.6 :ARG0 w :ARG1 (t / theme~e.17 :mode~e.7 interrogative~e.7 :domain~e.15 (p / pathway~e.10 :ARG0-of (s / signal-07~e.9) :ARG1-of (e / elucidate-01~e.13 :ARG0 (w / we~e.11) :location (h / here~e.14))) :ARG0-of~e.18 (v / vary-01~e.20 :mod (m / multiple~e.19))))) # ::id pmid_1563_0473.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TGF-βs are known to promote withdrawal of keratinocytes from the cell cycle [ @ 41 @ ] . # ::alignments 2-1 4-1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1 8-1.1.2.2.r 10-1.1.2.2.1 11-1.1.2.2 14-1.2.1.1.1 (k / know-01~e.2 :ARG1 (p / promote-02~e.4 :ARG0 (p3 / protein :name (n / name :op1 "TGF-β")) :ARG1 (w / withdraw-01~e.5 :ARG1~e.6 (c / cell :name (n2 / name :op1 "keratinocyte"~e.7)) :ARG2~e.8 (c2 / cycle-02~e.11 :ARG1 (c3 / cell~e.10)))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 41~e.14)))) # ::id pmid_1563_0473.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hence , when TGF-β2 protein was detected at the transition between the growing and destructive phases of the adult hair cycle , research initially and naturally focused on a role for this family member in cessation of growth and @/@ or triggering apoptosis ([ @ 42 @ ] and references therein ) . # ::alignments 0-1 2-1.1.3.r 2-1.1.5.r 2-1.1.6.r 3-1.1.5.1.1.1 4-1.1.5.1 6-1.1.5 9-1.1.6 12-1.1.6.2.1 14-1.1.6.1.1 15-1.1.6.1 15-1.1.6.2 16-1.1.6.1.2.r 18-1.1.6.1.2.1.1 19-1.1.6.1.2.1 20-1.1.6.1.2 22-1.1.1 23-1.1.3 25-1.1.4 26-1.1 27-1.1.2.r 29-1.1.2 30-1.1.2.1.r 31-1.1.2.1.1.1 32-1.1.2.1.1 33-1.1.2.1 34-1.1.2.2.r 35-1.1.2.2.1 36-1.1.2.2.1.1.r 37-1.1.2.2.1.1 38-1.1.2.2 40-1.1.2.2 41-1.1.2.2.2 42-1.1.2.2.2.1 45-1.2.1.1.1.1 48-1.2.1.1.1 49-1.2.1.1.1.2 (i2 / infer-01~e.0 :ARG1 (f / focus-01~e.26 :ARG1 (r / research-01~e.22) :ARG2~e.27 (r2 / role~e.29 :poss~e.30 (m / member~e.33 :part-of (p5 / protein-family~e.32 :mod (t / this~e.31))) :purpose~e.34 (a4 / and-or~e.38,40 :op1 (c / cease-01~e.35 :ARG1~e.36 (g / grow-01~e.37)) :op2 (t2 / trigger-01~e.41 :ARG1 (a / apoptosis~e.42)))) :time~e.2 (i / initial~e.23) :ARG1-of (n / natural-03~e.25) :time~e.2 (d / detect-01~e.6 :ARG1 (p / protein~e.4 :name (n2 / name :op1 "TGF-β2"~e.3))) :time~e.2 (t3 / transition-01~e.9 :ARG2 (p3 / phase~e.15 :mod (d2 / destroy-01~e.14) :subevent-of~e.16 (c2 / cycle-02~e.20 :ARG1 (h / hair~e.19 :mod (a2 / adult~e.18)))) :ARG3 (p2 / phase~e.15 :mod (g2 / grow-01~e.12) :subevent-of c2))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and~e.48 :op1 42~e.45 :op2 (r3 / reference~e.49 :location (h2 / herein))))))) # ::id pmid_1563_0473.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in contrast to TGF-β1 @ -@ null skin , which exhibits an extended growing phase of postnatal hair follicles , TGF-β2 @ -@ null skin displays an embryonic block in follicle bud progression [ @ 32 @ ] . # ::alignments 0-1 0-1.1.3 3-1.1.3 6-1.1.3.1.2.1.1.1 9-1.1.3.1.2.1.2 10-1.1.3.1 13-1.1.3.1.1 15-1.1.3.1.1.1.2 16-1.1.3.1.1.1.1 17-1.1.3.1.1.1 18-1.1.3.1.1.1.1.1.r 19-1.1.3.1.1.1.1.1.2 20-1.1.3.1.1.1.1.1.1 21-1.1.3.1.1.1.1.1 24-1.1.1.1.1.1.1 27-1.1.1.1.1 27-1.1.1.1.1.2 27-1.1.1.1.1.2.r 28-1.1.1 29-1.1 31-1.1.2.1 32-1.1.2 33-1.1.2.2.r 34-1.1.2.2.1.1 35-1.1.2.2.1 36-1.1.2.2 39-1.2.1.1.1 (h2 / have-concession-91~e.0 :ARG2 (d / display-01~e.29 :ARG0 (s / skin~e.28 :ARG0-of (c / contain-01 :ARG1 (p6 / protein~e.27 :name (n / name :op1 "TGF-β2"~e.24) :ARG2-of~e.27 (m / mutate-01~e.27 :mod "−/−")))) :ARG1 (b / block~e.32 :mod (e / embryo~e.31) :time~e.33 (p2 / progress-01~e.36 :ARG1 (b2 / bud~e.35 :mod (f / follicle~e.34)))) :ARG1-of (c2 / contrast-01~e.0,3 :ARG2 (s2 / skin~e.10 :ARG0-of (e2 / exhibit-01~e.13 :ARG1 (p4 / phase~e.17 :mod (g / grow-01~e.16 :ARG1~e.18 (f2 / follicle~e.21 :mod (h / hair~e.20) :mod (p5 / postnatal~e.19))) :ARG1-of (e3 / extend-01~e.15))) :ARG0-of (c3 / contain-01 :ARG1 (p3 / protein :name (n2 / name :op1 "TGF-β1"~e.6) :ARG2-of m~e.9))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 32~e.39)))) # ::id pmid_1563_0473.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although this phenotype is consistent with TGF-β2 's embryonic expression patterns [ @ 33 @ ] , about 50 % of TGF-β2 null buds appear unable to progress to the down @-@ growth phase , a feature that cannot be explained readily on the basis of previously established effects of TGF-βs . # ::alignments 0-1.2.r 1-1.2.1.1 2-1.2.1 4-1.2 5-1.2.2.r 6-1.2.2.1.1 7-1.2.2.1.1.r 8-1.2.2.1.2 9-1.2.2.1 10-1.2.2 13-1.2.3.1.1.1 17-1.1.2 18-1.1.2.1.1 19-1.1.2.1 22-1.1.1.1.1.1.1 24-1.1.1.1.1 24-1.1.1.1.1.2 24-1.1.1.1.1.2.r 25-1.1.1 26-1 27-1.1.3.1 27-1.1.3.3.1.1 27-1.1.3.3.1.1.1 29-1.1.3.2 30-1.1.3.2.1.r 32-1.1.3.2.1.1.1 34-1.1.3.2.1.1 35-1.1.3.2.1 38-1.1.3.3.1 40-1.1.3.3.1.1 40-1.1.3.3.1.1.1 40-1.1.3.3.1.1.1.r 42-1.1.3.3.1.2 43-1.1.3.3.1.2.2 43-1.1.3.3.1.2.2.r 47-1.1.3.3.1.2.1.r 48-1.1.3.3.1.2.1.2.1 49-1.1.3.3.1.2.1.2 50-1.1.3.3.1.2.1 (a / appear-02~e.26 :ARG1 (i / include-91 :ARG2 (b / bud~e.25 :ARG0-of (c4 / contain-01 :ARG1 (p3 / protein~e.24 :name (n / name :op1 "TGF-β2"~e.22) :ARG2-of~e.24 (m / mutate-01~e.24 :mod "−/−")))) :ARG3 (a4 / about~e.17 :op1 (p4 / percentage-entity~e.19 :value 50~e.18)) :ARG1-of (c / capable-01 :polarity -~e.27 :ARG2 (p5 / progress-01~e.29 :ARG4~e.30 (p6 / phase~e.35 :mod (g / grow-01~e.34 :ARG1-of (d / down-03~e.32)))) :ARG0-of (m2 / mean-01 :ARG1 (f / feature~e.38 :ARG1-of (p2 / possible-01~e.27,40 :polarity~e.40 -~e.27,40) :ARG1-of (e / explain-01~e.42 :ARG0~e.47 (a3 / affect-01~e.50 :ARG0 (p10 / protein :name (n2 / name :op1 "TGF-β")) :ARG1-of (e2 / establish-01~e.49 :time (p7 / previous~e.48))) :manner~e.43 (r / ready~e.43)))))) :concession~e.0 (c2 / consistent-01~e.4 :ARG1 (p / phenotype~e.2 :mod (t / this~e.1)) :ARG2~e.5 (p9 / pattern~e.10 :path-of (e3 / express-03~e.9 :ARG2~e.7 p3~e.6 :ARG3 (e4 / embryo~e.8))) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 33~e.13))))) # ::id pmid_1563_0473.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our finding that TGF-β2 is upstream from Ki67 expression and MAPK activation lends further support to the notion that hair follicle keratinocytes at this early stage of development react to TGF-β2 signaling in a fashion opposite to that typically expected for TGF-β factors . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1.1.2.r 3-1.1.2.1.1 5-1.1.2.2.2 7-1.1.2.2.1.1.1.1.1 8-1.1.2.2.1.1 9-1.1.2.2.1 10-1.1.2.2.1.2.1.1.1 11-1.1.2.2.1.2 12-1 13-1.2.2 14-1.2 15-1.3.r 17-1.3 19-1.3.1.1.1.2.1 20-1.3.1.1.1.2 21-1.3.1.1.1.1.1 23-1.3.1.1.4.1.2 24-1.3.1.1.4 25-1.3.1.1.4.1 26-1.3.1.1.4.1.1.r 27-1.3.1.1.4.1.1 28-1.3.1.1 29-1.3.1.1.2.r 30-1.3.1.1.2.1 31-1.3.1.1.2 32-1.3.1.1.3.r 34-1.3.1.1.3 34-1.3.1.1.3.1.1 35-1.3.1.1.3.1 38-1.3.1.1.3.1.1.1.1 39-1.3.1.1.3.1.1.1 40-1.3.1.1.3.1.1.1.2.r 41-1.3.1.1.3.1.1.1.2.1.1 42-1.3.1.1.3.1.1.1.2.1.2 (l / lend-01~e.12 :ARG0 (f5 / find-01~e.1 :ARG0~e.0 (w / we~e.0) :ARG1~e.2 (p2 / protein :name (n2 / name :op1 "TGF-β2"~e.3) :location (r / relative-position :op1 (a / and~e.9 :op1 (e / express-03~e.8 :ARG2 (p3 / protein :name (n3 / name :op1 "Ki67"~e.7))) :op2 (a2 / activate-01~e.11 :ARG1 (p / pathway :name (n / name :op1 "MAPK"~e.10)))) :direction (u / upstream~e.5)))) :ARG1 (s / support-01~e.14 :ARG0 f5 :degree (f2 / further~e.13)) :ARG2~e.15 (n4 / notion~e.17 :ARG0-of (m2 / mean-01 :ARG1 (r2 / react-01~e.28 :ARG0 (c / cell :name (n5 / name :op1 "keratinocyte"~e.21) :part-of (f3 / follicle~e.20 :mod (h / hair~e.19))) :ARG1~e.29 (s3 / signal-07~e.31 :ARG0 p2~e.30) :ARG2~e.32 (f4 / fashion~e.34 :ARG1-of (o / opposite-01~e.35 :ARG2 (f / fashion~e.34 :ARG1-of (e2 / expect-01~e.39 :ARG1-of (t / typical-02~e.38) :topic~e.40 (p4 / protein :name (n6 / name :op1 "TGF-β"~e.41 :op2 "factor"~e.42)))))) :time (e3 / early~e.24 :op1 (s2 / stage~e.25 :subevent-of~e.26 (d / develop-02~e.27) :mod (t4 / this~e.23))))))) # ::id pmid_1563_0473.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This said , based upon pSMAD2 immunohistochemistry , the immediate steps of downstream signaling appeared to be intact . # ::alignments 0-1.2.1.1 1-1.2.1 3-1.3 6-1.3.1 9-1.1.1.2 10-1.1.1 11-1.1.1.1.r 12-1.1.1.1.1 13-1.1.1.1 14-1 16-1.1.1.r 17-1.1 (a / appear-02~e.14 :ARG1 (i2 / intact~e.17 :domain~e.16 (s / step-01~e.10 :ARG1~e.11 (s2 / signal-07~e.13 :location (d / downstream~e.12)) :mod (i / immediate~e.9))) :time (a2 / after :op1 (s3 / say-01~e.1 :ARG1 (t / this~e.0))) :ARG1-of (b / base-02~e.3 :ARG2 (i3 / immunohistochemistry~e.6 :instrument (p2 / protein :name (n2 / name :op1 "SMAD2") :ARG3-of (p / phosphorylate-01))))) # ::id pmid_1563_0473.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , we surmise that the proliferative outcome is likely to be rooted in differences in the repertoire of activated SMAD target genes . # ::alignments 0-1.1.2.1.1.1 2-1.1.1 3-1.1 7-1.1.2.1.1 9-1.1.2 12-1.1.2.1 13-1.1.2.1.2.r 14-1.1.2.1.2 15-1.1.2.1.2.1.r 17-1.1.2.1.2.1 18-1.1.2.1.2.1.1.r 19-1.1.2.1.2.1.1.1 20-1.1.2.1.2.1.1.2.1.1.1 21-1.1.2.1.2.1.1.2 22-1.1.2.1.2.1.1 (i / infer-01 :ARG1 (s / surmise-01~e.3 :ARG0 (w / we~e.2) :ARG1 (l / likely-01~e.9 :ARG1 (r / root-02~e.12 :ARG1 (o / outcome~e.7 :ARG1-of (c / cause-01~e.0 :ARG0 (p / proliferate-01))) :ARG2~e.13 (d / differ-02~e.14 :ARG1~e.15 (r2 / repertoire~e.17 :consist-of~e.18 (g / gene~e.22 :ARG1-of (a / activate-01~e.19) :ARG1-of (t / target-01~e.21 :ARG0 (p2 / protein :name (n / name :op1 "SMAD"~e.20)))))))))) # ::id pmid_1563_0473.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this regard , the positive effects of TGF-β2 on proliferation within the hair bud may be more analogous to what has been seen in progression of squamous cell carcinoma to metastatic carcinoma [ @ 43 @ ] rather than that typically observed for keratinocytes [ @ 44 , 45 , 46 @ ] . # ::alignments 1-1.2 5-1.1.3 6-1.1 7-1.1.1.r 8-1.1.1.1.1 9-1.1.2.r 10-1.1.2 13-1.1.4.1 14-1.1.4 15-1.5 16-1.1.r 17-1.3 18-1 19-1.4.r 20-1.4 23-1.4.1 24-1.4.1.1.r 25-1.4.1.1 26-1.4.1.1.1.r 27-1.4.1.1.1.1.1 28-1.4.1.1.1.1 29-1.4.1.1.1 30-1.4.1.1.2.r 31-1.4.1.1.2.1 32-1.4.1.1.2 35-1.4.2.1.1.1 38-1.4.3 40-1.4.3.1 41-1.4.3.1.1.1 42-1.4.3.1.1 43-1.4.3.1.1.2.r 44-1.4.3.1.1.2.1.1 47-1.4.3.2.1.1.1.1 51-1.4.3.2.1.1.1.2 55-1.4.3.2.1.1.1.3 (a4 / analogous~e.18 :domain~e.16 (a / affect-01~e.6 :ARG0~e.7 (p3 / protein :name (n / name :op1 "TGF-β2"~e.8)) :ARG1~e.9 (p4 / proliferate-01~e.10) :mod (p2 / positive~e.5) :location (b / bud~e.14 :mod (h / hair~e.13))) :purpose (t4 / this~e.1) :degree (m / more~e.17) :prep-to~e.19 (t / thing~e.20 :ARG1-of (s / see-01~e.23 :ARG2~e.24 (p5 / progress-01~e.25 :ARG1~e.26 (c / carcinoma~e.29 :mod (c6 / cell~e.28 :mod (s2 / squamous~e.27))) :ARG4~e.30 (c2 / carcinoma~e.32 :ARG1-of (m2 / metastasize-101~e.31)))) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c5 / cite-01 :ARG2 43~e.35))) :ARG1-of (i / instead-of-91~e.38 :ARG2 (t2 / that~e.40 :ARG1-of (o / observe-01~e.42 :ARG1-of (t3 / typical-02~e.41) :location~e.43 (c3 / cell :name (n2 / name :op1 "keratinocyte"~e.44)))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 (a3 / and :op1 44~e.47 :op2 45~e.51 :op3 46~e.55)))))) :ARG1-of (p / possible-01~e.15)) # ::id pmid_1563_0473.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The prior identification of the Snail gene as a potential target of TGF-β signaling [ @ 15 @ ] was intriguing , given the temporal wave of Snail gene expression that occurs in the developing hair bud . # ::alignments 1-1.1.3 2-1.1 6-1.1.1.1.1 8-1.1.1 9-1.1.2.r 9-1.1.3.r 11-1.1.2.2 12-1.1.2 13-1.1.2.1.r 14-1.1.2.1.1.1.1 15-1.1.2.1 18-1.1.4.1.1.1 22-1 26-1.2.1.2 27-1.2.1 30-1.2.1.1.1 31-1.2.1.1.1 32-1.2.1.1.1 33-1.2.1.1 36-1.2.1.1.2.r 38-1.2.1.1.2.2 39-1.2.1.1.2.1 40-1.2.1.1.2 (i / intrigue-01~e.22 :ARG0 (i2 / identify-01~e.2 :ARG1 (g / gene~e.8 :name (n / name :op1 "Snail"~e.6)) :ARG2~e.9 (t / target-01~e.12 :ARG1-of~e.13 (s / signal-07~e.15 :ARG0 (p4 / protein :name (n2 / name :op1 "TGF-β"~e.14))) :mod (p3 / potential~e.11)) :time~e.9 (p / prior~e.1) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 15~e.18)))) :ARG1-of (c2 / cause-01 :ARG0 (w / wave-04~e.27 :ARG1 (e / express-03~e.33 :ARG1 g~e.30,31,32 :location~e.36 (b / bud~e.40 :mod (h / hair~e.39) :ARG1-of (d2 / develop-02~e.38))) :mod (t2 / time~e.26)))) # ::id pmid_1563_0473.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The additional correlation between epithelial hyperproliferation and Snail transgene expression further fostered our interest in a possible link between TGF-β2 and Snail . # ::alignments 2-1.1 4-1.1.1.1 5-1.1.1 5-1.1.1.2 5-1.1.1.2.r 8-1.1.2.1.1.1 11-1.1.2 12-1.3 13-1 14-1.2.1 14-1.2.1.r 15-1.2 16-1.2.2.r 18-1.2.2.3 19-1.2.2 21-1.2.2.1.1.1 23-1.1.2.1.1.1 23-1.2.2.2.1.1 (f / foster-01~e.13 :ARG0 (c / correlate-01~e.2 :ARG1 (p / proliferate-01~e.5 :ARG0 (e / epithelium~e.4) :degree~e.5 (h / hyper~e.5)) :ARG2 (e2 / express-03~e.11 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.8,23) :ARG2-of (m / mutate-01))) :ARG1-of (a / add-02)) :ARG1 (i / interest-01~e.15 :ARG0~e.14 (w / we~e.14) :ARG2~e.16 (l / link-01~e.19 :ARG1 (p4 / protein :name (n2 / name :op1 "TGF-β2"~e.21)) :ARG2 (p3 / protein :name (n3 / name :op1 "Snail"~e.23)) :ARG1-of (p2 / possible-01~e.18))) :degree (f2 / further~e.12)) # ::id pmid_1563_0473.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our functional studies demonstrate that without TGF-β2 , Snail expression is abolished in the mutant hair buds , and conversely , in K14 @-@ Smad2 skin , Snail is ectopically activated . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1 3-1 5-1.3.1 5-1.3.1.r 6-1.3.2.1.1 9-1.2.1.1.1.1.1 11-1.2.1.1 13-1.2.1 14-1.2.1.2.r 16-1.2.1.2.1 17-1.2.1.2.2 18-1.2.1.2 20-1.2 25-1.2.2.3.1.1.1.1 27-1.2.2.3.1.1.1.1 29-1.2.2.3 32-1.2.2.1 36-1.2.2 (d / demonstrate-01~e.3 :ARG0 (s / study-01~e.2 :ARG0~e.0 (w / we~e.0) :mod (f / function-01~e.1)) :ARG1 (a / and~e.20 :op1 (a2 / abolish-01~e.13 :ARG1 (e / express-03~e.11 :ARG1 (g / gene :name (n / name :op1 "Snail"~e.9))) :location~e.14 (b / bud~e.18 :ARG1-of (m / mutate-01~e.16) :mod (h / hair~e.17))) :op2 (a3 / activate-01~e.36 :ARG1 g~e.32 :manner (e2 / ectopic) :location (s2 / skin~e.29 :ARG0-of (c2 / contain-01 :ARG1 (g2 / gene :name (n3 / name :op1 "K14-Smad2"~e.25,27)))) :ARG2-of (c / contrast-01 :ARG1 a2))) :condition (b2 / be-located-at-91 :polarity~e.5 -~e.5 :ARG1 (p / protein :name (n2 / name :op1 "TGF-β2"~e.6)))) # ::id pmid_1563_0473.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , our in vitro studies indicate that even sustained TGF-β2 exposure may cause only a transient induction of Snail , offering a possible explanation as to why Snail is so briefly expressed during hair follicle morphogenesis . # ::alignments 0-1 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1.2 4-1.1.1.2 5-1.1.1 6-1.1 7-1.1.2.r 8-1.1.2.1.1.3 9-1.1.2.1.1.2 10-1.1.2.1.1.1.1.1 11-1.1.2.1.1 12-1.1.2 13-1.1.2.1 14-1.1.2.1.2.3 16-1.1.2.1.2.2 17-1.1.2.1.2 18-1.1.2.1.2.1.r 19-1.1.2.1.2.1.1.1 21-1.1.3 23-1.1.3.1.2 24-1.1.3.1 25-1.1.3.1.1.1.1.3.r 26-1.1.3.1.1 26-1.1.3.1.1.1 26-1.1.3.1.1.1.r 27-1.1.3.1.1 27-1.1.3.1.1.1 27-1.1.3.1.1.1.r 28-1.1.2.1.2.1.1.1 30-1.1.3.1.1 30-1.1.3.1.1.1 30-1.1.3.1.1.1.1.2.1 30-1.1.3.1.1.1.r 31-1.1.3.1.1.1.1.2 31-1.1.3.1.1.1.1.2.r 32-1.1.3.1.1.1.1 33-1.1.3.1.1.1.1.3.r 34-1.1.3.1.1.1.1.3.1.1 35-1.1.3.1.1.1.1.3.1 36-1.1.3.1.1.1.1.3 (a / and~e.0 :op2 (i / indicate-01~e.6 :ARG0 (s / study-01~e.5 :ARG0~e.2 (w / we~e.2) :manner (i2 / in-vitro~e.3,4)) :ARG1~e.7 (p / possible-01~e.12 :ARG1 (c / cause-01~e.13 :ARG0 (e / expose-01~e.11 :ARG1 (p4 / protein :name (n / name :op1 "TGF-β2"~e.10)) :ARG1-of (s3 / sustain-01~e.9) :mod (e2 / even~e.8)) :ARG1 (i3 / induce-01~e.17 :ARG2~e.18 (p2 / protein :name (n2 / name :op1 "Snail"~e.19,28)) :ARG1-of (t / transient-02~e.16) :mod (o / only~e.14)))) :ARG0-of (o2 / offer-01~e.21 :ARG1 (e3 / explain-01~e.24 :ARG1 (t2 / thing~e.26,27,30 :ARG0-of~e.26,27,30 (c2 / cause-01~e.26,27,30 :ARG1 (e4 / express-03~e.32 :ARG2 p2 :manner~e.31 (b / brief~e.31 :degree (s4 / so~e.30)) :time~e.25,33 (m / morphogenesis~e.36 :mod (f / follicle~e.35 :mod (h / hair~e.34)))))) :ARG1-of (p3 / possible-01~e.23))))) # ::id pmid_1563_0473.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok An additional point worth mentioning is that prolonged expression of Tg Snail in postnatal skin resulted in morphological and biochemical signs of epithelial to mesenchymal transitions ( unpublished data ) , underscoring why transient Snail expression may be so important during normal hair follicle morphogenesis [ @ 18 @ ] . # ::alignments 2-1.1.1 3-1 4-1.1 7-1.1.1.2.1.1.3 8-1.1.1.2.1.1 9-1.1.1.2.1.1.1.r 10-1.1.1.2.1.1.1.2 12-1.1.1.2.1.1.1.1.1 15-1.1.1.2.1.1.1.1.1.r 15-1.1.1.2.1.1.2.1 16-1.1.1.2.1.1.2 17-1.1.1.2.1 18-1.1.1.2.1.2.r 19-1.1.1.2.1.2.1.2 20-1.1.1.2.1.2 21-1.1.1.2.1.2.2.2 22-1.1.1.2.1.2.1 22-1.1.1.2.1.2.2 23-1.1.1.2.1.2.1.1.r 24-1.1.1.2.1.2.1.1.2 26-1.1.1.2.1.2.1.1.1 27-1.1.1.2.1.2.1.1 29-1.1.1.2.1.3.1.1.1 30-1.1.1.2.1.3.1 33-1.1.1.2.1.4 34-1.1.1.2.1.4.1 34-1.1.1.2.1.4.1.1 34-1.1.1.2.1.4.1.1.r 35-1.1.1.2.1.4.1.1.1.1.2.2 36-1.1.1.2.1.4.1.1.1.1.2.1 37-1.1.1.2.1.4.1.1.1.1.2 38-1.1.1.2.1.4.1.1.1 39-1.1.1.2.1.4.1.1.1.1.2.r 40-1.1.1.2.1.4.1.1.1.1.1 41-1.1.1.2.1.4.1.1.1.1 42-1.1.1.2.1.4.1.1.1.1.3.r 43-1.1.1.2.1.4.1.1.1.1.3.1 44-1.1.1.2.1.4.1.1.1.1.3.2.1 45-1.1.1.2.1.4.1.1.1.1.3.2 46-1.1.1.2.1.4.1.1.1.1.3 49-1.1.1.2.1.4.2.1.1.1 (w / worth-02~e.3 :ARG2 (m / mention-01~e.4 :ARG1 (p / point~e.2 :ARG1-of (a / add-02) :ARG0-of (m2 / mean-01 :ARG1 (r / result-01~e.17 :ARG1 (e / express-03~e.8 :ARG1~e.9 (g / gene :name (n / name :op1~e.15 "Snail"~e.12) :mod (t4 / transgenic~e.10)) :ARG3 (s / skin~e.16 :mod (p3 / postnatal~e.15)) :ARG1-of (p2 / prolong-01~e.7)) :ARG2~e.18 (a2 / and~e.20 :op1 (s4 / signal-07~e.22 :ARG1~e.23 (t / transition-01~e.27 :ARG2 (m5 / mesenchyme~e.26) :ARG3 (e2 / epithelium~e.24)) :mod (m3 / morphological~e.19)) :op2 (s5 / signal-07~e.22 :ARG1 t :mod (b / biochemical~e.21))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.30 :ARG1-of (p4 / publish-01 :polarity -~e.29))) :ARG0-of (u / underscore-01~e.33 :ARG1 (t3 / thing~e.34 :ARG0-of~e.34 (c2 / cause-01~e.34 :ARG1 (p5 / possible-01~e.38 :ARG1 (i / important~e.41 :degree (s3 / so~e.40) :domain~e.39 (e3 / express-03~e.37 :ARG1 g~e.36 :ARG1-of (t2 / transient-02~e.35)) :time~e.42 (m6 / morphogenesis~e.46 :ARG1-of (n2 / normal-02~e.43) :mod (f / follicle~e.45 :mod (h / hair~e.44))))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 18~e.49))))))))) # ::id pmid_1563_0473.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At first glance , the sparsity in hair coat of K14 @- @ Snail Tg mice seemed indicative of a defect in follicle formation ( see Figure 2 @ A ) . # ::alignments 1-1.2.1 1-1.2.1.1 1-1.2.1.1.r 2-1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2.r 10-1.1.1.1.2.2.2.1 13-1.1.1.1.2.2.1.1 15-1.1.1.1.2.1 16-1.1.1.1.2 17-1 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1.1 24-1.1.2.1 26-1.3 28-1.3.1 (s / seem-01~e.17 :ARG1 (i / indicate-01 :ARG0 (s2 / sparse~e.5 :domain~e.6 (c / coat~e.8 :mod (h / hair~e.7) :part-of~e.9 (m / mouse~e.16 :mod (t / transgenic~e.15) :mod (p2 / protein :name (n2 / name :op1 "Snail"~e.13) :ARG2-of (m3 / mutate-01 :value "K14"~e.10))))) :ARG1 (d / defect-01~e.21 :ARG1~e.22 (f / form-01~e.24 :ARG1 (f2 / follicle~e.23)))) :time (g / glance-01~e.2 :mod (o / ordinal-entity~e.1 :value~e.1 1~e.1)) :ARG1-of (s3 / see-01~e.26 :ARG2 (f3 / figure~e.28 :mod "2A"))) # ::id pmid_1563_0473.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Closer inspection , however , revealed that not all hairs penetrated the hyperthickened Tg epidermis . # ::alignments 0-1.1.1.1 0-1.1.1.1.1 0-1.1.1.1.1.r 1-1.1.1 3-1 5-1.1 6-1.1.2.r 7-1.1.2.1 7-1.1.2.1.r 8-1.1.2.2.1 9-1.1.2.2 10-1.1.2 13-1.1.2.3.1 14-1.1.2.3 (h3 / have-concession-91~e.3 :ARG1 (r / reveal-01~e.5 :ARG0 (i / inspect-01~e.1 :ARG1-of (c / close-10~e.0 :degree~e.0 (m / more~e.0))) :ARG1~e.6 (p / penetrate-01~e.10 :polarity~e.7 -~e.7 :ARG0 (h / hair~e.9 :mod (a / all~e.8)) :ARG1 (e / epidermis~e.14 :mod (t / transgenic~e.13) :ARG1-of (t2 / thicken-01 :degree (h2 / hyper)))))) # ::id pmid_1563_0473.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several factors may contribute to the seemingly normal follicle development in these mice . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 3-1.1 4-1.1.2.r 6-1.1.2.1.1.1 7-1.1.2.1.1 8-1.1.2.1 9-1.1.2 10-1.1.2.2.r 11-1.1.2.2.1 12-1.1.2.2 (p / possible-01~e.2 :ARG1 (c / contribute-01~e.3 :ARG0 (f / factor~e.1 :quant (s / several~e.0)) :ARG2~e.4 (d2 / develop-02~e.9 :ARG1 (f2 / follicle~e.8 :ARG1-of (n / normal-02~e.7 :ARG1-of (s2 / seem-01~e.6))) :location~e.10 (m / mouse~e.12 :mod (t / this~e.11))))) # ::id pmid_1563_0473.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One obvious factor is the K14 promoter , which is elevated in the basal layer of the epidermis and the outer root sheath ( ORS ) of the hair follicle , but is markedly down @-@ regulated in developing embryonic hair buds as well as in the postnatal hair progenitor cells . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 3-1.1.2.r 5-1.1.2.1.1.1.1 6-1.1.2 6-1.1.2.1 6-1.1.2.1.r 9-1.1.2.r 10-1.1.4 11-1.1.4.1.r 13-1.1.4.1.1.1 14-1.1.4.1.1 15-1.1.4.1.1.2.r 17-1.1.4.1.1.2 18-1.1.4.1 20-1.1.4.1.2.2 21-1.1.4.1.2.1 22-1.1.4.1.2 26-1.1.4.1.2.3.r 28-1.1.4.1.2.3.1 29-1.1.4.1.2.3 31-1 33-1.2.2 33-1.2.2.r 38-1.2.3.1.2 39-1.2.3.1.3 40-1.2.3.1.1 41-1.2.3.1 42-1.2.3 43-1.2.3 44-1.2.3 44-1.2.3.2.3.r 47-1.2.3.1.r 47-1.2.3.2.3 48-1.2.3.2.2 49-1.2.3.2.1 50-1.2.3.2 (c / contrast-01~e.31 :ARG1 (f / factor~e.2 :quant 1~e.0 :domain~e.3,9 (m3 / molecular-physical-entity~e.6 :ARG0-of~e.6 (p / promote-01~e.6 :ARG1 (p2 / protein :name (n / name :op1 "K14"~e.5)))) :ARG1-of (o / obvious-01~e.1) :ARG1-of (e / elevate-01~e.10 :location~e.11 (a / and~e.18 :op1 (l / layer~e.14 :mod (b / basal~e.13) :part-of~e.15 (e2 / epidermis~e.17)) :op2 (s / sheath~e.22 :part-of (r / root~e.21) :mod (o2 / outer~e.20) :part-of~e.26 (f2 / follicle~e.29 :mod (h / hair~e.28)))))) :ARG2 (d / downregulate-01 :ARG1 f :manner~e.33 (m2 / marked~e.33) :location (a2 / and~e.42,43,44 :op1~e.47 (b2 / bud~e.41 :mod (h2 / hair~e.40) :ARG1-of (d2 / develop-02~e.38) :mod (e3 / embryo~e.39)) :op2 (c2 / cell~e.50 :mod (p3 / progenitor~e.49) :part-of (h3 / hair~e.48) :time~e.44 (p4 / postnatal~e.47))))) # ::id pmid_1563_0473.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The K14 promoter is also less active in the ORS than epidermis and hence this might also account for the lack of apparent response of the ORS to ectopic Snail . # ::alignments 1-1.2.1.1 2-1.2.1.1 4-1.2.1.3 5-1.1.2 6-1.1 10-1.1.4.r 11-1.1.4 13-1 15-1.2 16-1.2.1.3 17-1.2.1 18-1.2.1.2.r 20-1.2.1.2 21-1.2.1.2.1.r 22-1.2.1.2.1.3 23-1.2.1.2.1 27-1.2.1.2.1.2.r 28-1.2.1.2.1.2.2 29-1.2.1.2.1.2.1.1 (c / cause-01~e.13 :ARG0 (a / activity-06~e.6 :ARG0 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p2 / protein :name (n / name :op1 "K14")))) :degree (l / less~e.5) :location (s / sheath :part-of (r2 / root :mod (o / outer))) :compared-to~e.10 (e / epidermis~e.11)) :ARG1 (p4 / possible-01~e.15 :ARG1 (a2 / account-01~e.17 :ARG0 a~e.1,2 :ARG1~e.18 (l2 / lack-01~e.20 :ARG1~e.21 (r / respond-01~e.23 :ARG0 s :ARG1~e.27 (p5 / protein :name (n3 / name :op1 "Snail"~e.29) :mod (e2 / ectopic~e.28)) :ARG1-of (a4 / appear-02~e.22))) :mod (a3 / also~e.4,16)))) # ::id pmid_1563_0473.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additional contributing factors could be the multiplicity of Snail family members and their differential expression , the saturation , and @/@ or diversity of regulatory mechanisms that govern AJ formation , migration , and proliferation in the follicle ORS . # ::alignments 1-1.1.3 2-1.1 3-1 4-1.1.1.r 8-1.1.1.1.1.1.1.1.1.1 9-1.1.1.1.1.1.1.1 10-1.1.1.1.1.1 11-1.1.1.1.1 12-1.1.1.2.1 12-1.1.1.2.1.r 13-1.1.1.2.2 14-1.1.1.2 17-1.1.1.3.1 19-1.1.1.3 21-1.1.1.3 22-1.1.1.3.2 23-1.1.1.3.2.1.r 24-1.1.1.3.2.1.1 25-1.1.1.3.2.1 27-1.1.1.3.2.1.2 28-1.1.1.3.2.1.2.1.1.1.1.1 29-1.1.1.3.2.1.2.1.1 31-1.1.1.3.2.1.2.1.2 33-1.1.1.3.2.1.2.1 34-1.1.1.3.2.1.2.1.3 35-1.1.1.3.2.1.2.1.3.2.r 37-1.1.1.3.2.1.2.1.3.2 38-1.1.1.3.2.1.2.1.3.2.1.1 (p / possible-01~e.3 :ARG1 (f / factor~e.2 :domain~e.4 (a / and :op1 (m / multiply-01 :ARG1 (a3 / and~e.11 :op1 (m2 / member~e.10 :ARG1-of (i / include-91 :ARG2 (p2 / protein-family~e.9 :name (n / name :op1 "Snail"~e.8)))))) :op2 (e / express-03~e.14 :ARG1~e.12 m2~e.12 :ARG1-of (d2 / differ-02~e.13)) :op3 (a5 / and-or~e.19,21 :op1 (s / saturate-01~e.17 :ARG1 m3) :op2 (d / diversity~e.22 :domain~e.23 (m3 / mechanism~e.25 :ARG0-of (r / regulate-01~e.24) :ARG0-of (g / govern-01~e.27 :ARG1 (a4 / and~e.33 :op1 (f3 / form-01~e.29 :ARG1 (p4 / protein :name (n2 / name :op1 "AJ"~e.28))) :op2 (m4 / migrate-01~e.31 :ARG0 p4) :op3 (p3 / proliferate-01~e.34 :ARG0 p4 :location~e.35 (f4 / follicle~e.37 :name (n3 / name :op1 "ORS"~e.38))))))))) :ARG1-of (a2 / add-02) :ARG0-of (c / contribute-01~e.1))) # ::id pmid_1563_0473.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Distinguishing between these possibilities must await the generation of mice harboring skin @-@ specific loss @-@ of @-@ function Snail mutations . # ::alignments 0-1.1.1 2-1.1.1.1.2 3-1.1.1.1 3-1.1.1.1.1 3-1.1.1.1.1.r 4-1 5-1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1 10-1.1.2.1.1 11-1.1.2.1.1.1.3.1 13-1.1.2.1.1.1.3 14-1.1.2.1.1.1.2 18-1.1.2.1.1.1.2.1 20-1.1.2.1.1.1.1.1.1 22-1.1.2.1.1.1 (o2 / obligate-01~e.4 :ARG2 (a / await-01~e.5 :ARG1 (d / distinguish-01~e.0 :ARG1 (t / thing~e.3 :ARG1-of~e.3 (p / possible-01~e.3) :mod (t2 / this~e.2))) :ARG2 (g / generation~e.7 :mod~e.8 (m / mouse~e.9 :ARG0-of (h / harbor-01~e.10 :ARG1 (m3 / mutate-01~e.22 :ARG1 (g2 / gene :name (n / name :op1 "Snail"~e.20)) :ARG0-of (l / lose-02~e.14 :ARG1 (f / function~e.18)) :ARG1-of (s2 / specific-02~e.13 :ARG2 (s / skin~e.11)))))))) # ::id pmid_1563_0473.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Links between Signaling , Transcriptional Cascades , Epithelial Remodeling , and Proliferation in the Hair Bud # ::alignments 0-1 1-1.1.r 2-1.1 4-1.2.1.1 5-1.2.1 7-1.2.2.1 8-1.2.2 10-1.2 11-1.2.3 12-1.2.r 14-1.2.4.1 15-1.2.4 (l / link-01~e.0 :ARG1~e.1 (s / signal-07~e.2) :ARG2~e.12 (a / and~e.10 :op1 (c / cascade~e.5 :ARG0-of (t / transcribe-01~e.4)) :op2 (r / remodel-01~e.8 :ARG1 (e / epithelium~e.7)) :op2 (p / proliferate-01~e.11) :location (b / bud~e.15 :mod (h / hair~e.14)))) # ::id pmid_1563_0473.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previously , we discovered that early during hair follicle morphogenesis , E @-@ cadherin gene expression is down @-@ regulated concomitantly with the invagination of developing bud cells into the skin [ @ 4 @ ] . # ::alignments 0-1.3 2-1.1 3-1 5-1.2.3 6-1.2.3.r 7-1.2.3.1.1.1 8-1.2.3.1.1 9-1.2.3.1 12-1.2.1.1.1.1 14-1.2.1.1.1.1 16-1.2.1.1 17-1.2.1 22-1.2.4 22-1.2.4.r 25-1.2.2 26-1.2.2.1.r 27-1.2.2.1.2 28-1.2.2.1.1 29-1.2.2.1 30-1.2.2.2.r 32-1.2.2.2 35-1.4.1.1.1 (d / discover-01~e.3 :ARG0 (w / we~e.2) :ARG1 (d2 / downregulate-01 :ARG1 (e / express-03~e.17 :ARG2 (g / gene~e.16 :name (n / name :op1 "E-cadherin"~e.12,14))) :time (i / invaginate-01~e.25 :ARG1~e.26 (c / cell~e.29 :part-of (b / bud~e.28) :ARG1-of (d3 / develop-02~e.27)) :ARG2~e.30 (s / skin~e.32)) :time~e.6 (e2 / early~e.5 :op1 (m / morphogenesis~e.9 :mod (f / follicle~e.8 :mod (h / hair~e.7)))) :manner~e.22 (c3 / concomitant~e.22)) :time (p / previous~e.0) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.35)))) # ::id pmid_1563_0473.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because the timing of this event correlated with the activation of a LEF @-@ 1/β-catenin transcription factor complex [ @ 20 @ ] , we were intrigued by the presence of a putative LEF @-@ 1/TCF binding site in the E @-@ cadherin promoter . # ::alignments 0-1 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1 5-1.1.1.1 6-1.1 7-1.1.2.r 9-1.1.2 12-1.1.2.1.1 15-1.1.2.1.3.1 16-1.1.2.1.3 17-1.1.2.1 17-1.2.1.2.1 20-1.1.2.2.1.1.1 24-1.2.2 26-1.2 27-1.2.1.r 29-1.2.1.1 32-1.2.1.3 33-1.2.1.2.1.1.1.1 36-1.2.1.2 37-1.2.1 41-1.2.1.1.1.1.1.1.1 43-1.2.1.1.1.1.1.1.1 45-1.2.1.1.1 45-1.2.1.1.1.1 45-1.2.1.1.1.1.r (c / cause-01~e.0 :ARG0 (c2 / correlate-01~e.6 :ARG1 (t2 / time-02~e.2 :ARG1~e.3 (e / event~e.5 :mod (t3 / this~e.4))) :ARG2~e.7 (a / activate-01~e.9 :ARG1 (m2 / macro-molecular-complex~e.17 :part p7~e.12 :part (p5 / protein :name (n4 / name :op1 "β-catenin")) :mod (f / factor~e.16 :ARG0-of (t4 / transcribe-01~e.15))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 20~e.20))))) :ARG1 (i / intrigue-01~e.26 :ARG0~e.27 (p3 / protein-segment~e.37 :ARG1-of (p4 / present-02~e.29 :ARG2 (m4 / molecular-physical-entity~e.45 :ARG0-of~e.45 (p / promote-01~e.45 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin"~e.41,43))))) :ARG1-of (b2 / bind-01~e.36 :ARG2 (m / macro-molecular-complex~e.17 :part (p7 / protein :name (n2 / name :op1 "LEF-1"~e.33)) :part (p8 / protein :name (n3 / name :op1 "TCF")))) :ARG1-of (t5 / think-01~e.32)) :ARG1 (w / we~e.24))) # ::id pmid_1563_0473.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This prompted an investigation that subsequently led to our discovery that LEF @-@ 1/β-catenin can contribute to repression of E @-@ cadherin gene expression in skin keratinocytes [ @ 4 @ ] . # ::alignments 0-1.1 1-1 3-1.2 5-1.2.1.2 5-1.2.1.2.r 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.1 8-1.2.1.1.1.r 9-1.2.1.1 10-1.2.1.1.2.r 11-1.2.1.1.2.1.1.1.1.1 14-1.2.1.1.2 15-1.2.1.1.2.1 16-1.2.1.1.2.1.2.r 17-1.2.1.1.2.1.2 20-1.2.1.1.2.1.2.2.1.1.1 22-1.2.1.1.2.1.2.2.1.1.1 24-1.2.1.1.2.1.2.2.1 25-1.2.1.1.2.1.2.2 26-1.2.1.1.2.1.2.2.2.r 27-1.2.1.1.2.1.2.2.2.1 28-1.2.1.1.2.1.2.2.2 31-1.3.1.1.1 (p / prompt-01~e.1 :ARG0 (t / this~e.0) :ARG1 (i / investigate-01~e.3 :ARG0-of (l / lead-03~e.6 :ARG2~e.7 (d / discover-01~e.9 :ARG0~e.8 (w / we~e.8) :ARG1~e.10 (p5 / possible-01~e.14 :ARG1 (c / contribute-01~e.15 :ARG0 (m / macro-molecular-complex :part (p3 / protein :name (n / name :op1 "LEF-1"~e.11)) :part (p2 / protein :name (n2 / name :op1 "β-catenin"))) :ARG2~e.16 (r / repress-01~e.17 :ARG0 m :ARG1 (e / express-03~e.25 :ARG1 (g2 / gene~e.24 :name (n3 / name :op1 "E-cadherin"~e.20,22)) :ARG3~e.26 (k / keratinocyte~e.28 :part-of (s2 / skin~e.27))))))) :time~e.5 (s / subsequent~e.5))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.31)))) # ::id pmid_1563_0473.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the course of these studies , we also noted that Snail can also contribute to this process in keratinocytes in vitro , and our present studies revealed that Snail is expressed at the right place and time to be physiologically relevant in the process . # ::alignments 0-1.1.2.1.5 4-1.1.3.1 5-1.1.3 7-1.1.1 8-1.1.4 9-1.1 11-1.1.2.1.1.1.1 12-1.1.2 13-1.1.2.1.3 14-1.1.2.1 16-1.1.2.1.2.1 17-1.1.2.1.2 18-1.1.2.1.4.r 18-1.1.2.1.5 19-1.1.2.1.4 20-1.1.2.1.5 21-1.1.2.1.5 24-1.2.1.1 24-1.2.1.1.r 25-1.2.1.2 26-1.2.1 27-1.2 28-1.2.2.r 29-1.2.2.1 31-1.2.2 32-1.2.2.2.r 34-1.2.2.2.1 35-1.2.2.2 37-1.2.2.4 37-1.2.2.4.r 41-1.2.2.3 42-1.1.2.1.5 44-1.1.2.1.2 (a / and :op1 (n / note-01~e.9 :ARG0 (w / we~e.7) :ARG1 (p / possible-01~e.12 :ARG1 (c / contribute-01~e.14 :ARG0 (p2 / protein :name (n2 / name :op1 "Snail"~e.11)) :ARG2 (p3 / process-02~e.17,44 :mod t~e.16) :mod (a2 / also~e.13) :location~e.18 (k / keratinocyte~e.19) :manner (i / in-vitro~e.0,18,20,21,42))) :time (s / study-01~e.5 :mod (t / this~e.4)) :mod (a3 / also~e.8)) :op2 (r / reveal-01~e.27 :ARG0 (s2 / study-01~e.26 :ARG0~e.24 w~e.24 :time (p4 / present~e.25)) :ARG1~e.28 (e / express-03~e.31 :ARG2 p2~e.29 :ARG3~e.32 (p5 / place~e.35 :ARG1-of (r2 / right-03~e.34)) :purpose (r3 / relevant-01~e.41 :ARG1 p2 :ARG2 p3 :manner (p6 / physiological)) :time~e.37 (t2 / time~e.37 :ARG1-of r2)))) # ::id pmid_1563_0473.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In noggin @ -@ null embryonic skin , LEF @-@ 1 expression and subsequent activation of the LEF @-@ 1/β-catenin reporter gene is abrogated in the developing placodes . # ::alignments 2-1.3.2.1.1 5-1.3.2.2 6-1.3.1 7-1.3 9-1.1.1.1.1.1 11-1.1.1.1.1.1 12-1.1.1 13-1.1 14-1.1.2.2 14-1.1.2.2.r 15-1.1.2 16-1.1.2.1.r 18-1.1.2.1.1.1.1 21-1.1.2.1.1 22-1.1.2.1 24-1 27-1.2.1 (a4 / abrogate-01~e.24 :ARG1 (a2 / and~e.13 :op1 (e / express-03~e.12 :ARG2 (p4 / protein :name (n3 / name :op1 "LEF-1"~e.9,11))) :op2 (a3 / activate-01~e.15 :ARG1~e.16 (g2 / gene~e.22 :ARG0-of (r / report-01~e.21 :ARG1 (m / macro-molecular-complex :part p4~e.18 :part (p / protein :name (n4 / name :op1 "β-catenin"))))) :time~e.14 (s2 / subsequent~e.14))) :location (p2 / placode :ARG1-of (d / develop-02~e.27)) :location (s / skin~e.7 :mod (e2 / embryo~e.6) :mod (p3 / protein :name (n / name :op1 "noggin"~e.2) :mod (n2 / null~e.5)))) # ::id pmid_1563_0473.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The corresponding failure of E @-@ cadherin down @-@ regulation underscores the importance of Wnt @/@ noggin signaling in regulating this event in follicle morphogenesis [ @ 4 @ ] . # ::alignments 1-1.1.2 2-1.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1.1 10-1.1.1 11-1.2.2 12-1 14-1.2 15-1.2.1.r 16-1.2.1.1.2.1.1 17-1.2.1.1 18-1.2.1.1.1.1.1 19-1.2.1 21-1.2.2 22-1.2.2.1.1 23-1.2.2.1 24-1.2.2.2.r 25-1.2.2.2.1 26-1.2.2.2 29-1.3.1.1.1 (u2 / underscore-01~e.12 :ARG0 (f / fail-01~e.2 :ARG1 (d / downregulate-01~e.9,10 :ARG1 (p / protein :name (n / name :op1 "E-cadherin"~e.5,7))) :ARG1-of (c2 / correspond-02~e.1)) :ARG1 (i / important~e.14 :domain~e.15 (s / signal-07~e.19 :ARG0 (s2 / slash~e.17 :op1 (p4 / protein :name (n5 / name :op1 "noggin"~e.18)) :op2 (p2 / pathway :name (n2 / name :op1 "Wnt"~e.16)))) :purpose (r / regulate-01~e.11,21 :ARG1 (e / event~e.23 :mod (t / this~e.22)) :location~e.24 (m / morphogenesis~e.26 :mod (f2 / follicle~e.25)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 4~e.29)))) # ::id pmid_1563_0473.226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conditional gene targeting studies will be necessary to establish whether Snail family members also contribute to the down @-@ regulation in E @-@ cadherin gene expression that occurs during follicle formation . # ::alignments 0-1.1.1.2 1-1.1.1.1 2-1.1.1 3-1.1 6-1 8-1.2 9-1.2.1.1 9-1.2.1.1.r 10-1.2.1.2.1.1.1.1 11-1.2.1.2.1.1 12-1.2.1.2 13-1.2.1.4 14-1.2.1 15-1.2.1.3.r 17-1.2.1.3 18-1.2.1.3 19-1.2.1.3 22-1.2.1.3.1.1.1.1 24-1.2.1.3.1.1.1.1 26-1.2.1.3.1.1 27-1.2.1.3.1 30-1.2.1.3.1.2.r 31-1.2.1.3.1.2.1 32-1.2.1.3.1.2 (n / need-01~e.6 :ARG1 (s / study-01~e.3 :ARG1 (t / target-01~e.2 :ARG1 (g / gene~e.1) :mod (c / conditional~e.0))) :purpose (e / establish-01~e.8 :ARG1 (c2 / contribute-01~e.14 :mode~e.9 interrogative~e.9 :ARG0 (m / member~e.12 :ARG1-of (i / include-91 :ARG2 (p / protein-family~e.11 :name (n2 / name :op1 "Snail"~e.10)))) :ARG2~e.15 (d / downregulate-01~e.17,18,19 :ARG1 (e2 / express-03~e.27 :ARG2 (g2 / gene~e.26 :name (n3 / name :op1 "E-cadherin"~e.22,24)) :time~e.30 (f2 / form-01~e.32 :ARG1 (f3 / follicle~e.31)))) :mod (a / also~e.13)))) # ::id pmid_1563_0473.227 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , it is intriguing that K14 @-@ Snail Tg epidermis displayed a marked down @-@ regulation in E @-@ cadherin expression , thereby demonstrating its potential to do so in skin . # ::alignments 0-1 4-1.1.1.3 7-1.1.1.1.2.2.1 9-1.1.1.1.2.1.1 11-1.1.1.1.1 12-1.1.1.1 13-1.1.1 15-1.1.1.2.2 16-1.1.1.2 17-1.1.1.2 18-1.1.1.2 19-1.1.1.2.1.r 20-1.1.1.2.1.1.1.1 22-1.1.1.2.1.1.1.1 23-1.1.1.2.1 26-1.1.2 28-1.1.2.2 29-1.1 31-1.1 32-1.1.2.2.2.r 33-1.1.2.2.2 (h / have-concession-91~e.0 :ARG1 (c2 / cause-01~e.29,31 :ARG0 (d2 / display-01~e.13 :ARG0 (e / epidermis~e.12 :mod (t / transgenic~e.11) :mod (g / gene :name (n2 / name :op1 "Snail"~e.9) :ARG2-of (m / mutate-01 :value "K14"~e.7))) :ARG1 (d3 / downregulate-01~e.16,17,18 :ARG1~e.19 (e2 / express-03~e.23 :ARG2 (p3 / protein :name (n3 / name :op1 "E-cadherin"~e.20,22))) :ARG1-of (m2 / mark-01~e.15)) :ARG0-of (i / intrigue-01~e.4)) :ARG1 (d / demonstrate-01~e.26 :ARG0 e :ARG1 (p4 / potential~e.28 :topic d3 :location~e.32 (s / skin~e.33))))) # ::id pmid_1563_0473.228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our prior findings showed that by elevating E @-@ cadherin levels or by conditionally ablating α-catenin , hair follicle morphogenesis can be impaired [ @ 4 , 7 @ ] . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.3 2-1.1 2-1.1.1 2-1.1.1.r 3-1 3-1.2.1.1.3 5-1.2.r 6-1.2.1.1.1 7-1.2.1.1.1.1.1.1.1 9-1.2.1.1.1.1.1.1.1 10-1.2.1.1.1.1 11-1.2.1.1 13-1.2.1.1.2.2 13-1.2.1.1.2.2.r 14-1.2.1.1.2 16-1.2.1.1.2.1.1.1 19-1.2.1.2.1.1 20-1.2.1.2.1 21-1.2.1.2 22-1.2 24-1.2.1 27-1.4.1.1.1.1 31-1.4.1.2.1.1 (s2 / show-01~e.3 :ARG0 (t / thing~e.2 :ARG1-of~e.2 (f2 / find-01~e.2 :ARG0~e.0 (w / we~e.0))) :ARG1~e.5 (p7 / possible-01~e.22 :ARG1 (i / impair-01~e.24 :ARG0 (o / or~e.11 :op1 (e / elevate-01~e.6 :ARG1 (l / level~e.10 :quant-of (p3 / protein :name (n / name :op1 "E-cadherin"~e.7,9)))) :op2 (a / ablate-01~e.14 :ARG1 (p4 / protein :name (n2 / name :op1 "α-catenin"~e.16)) :manner~e.13 (c / conditional~e.13)) :ARG1-of (s / show-01~e.3)) :ARG1 (m / morphogenesis~e.21 :mod (f / follicle~e.20 :mod (h / hair~e.19))))) :time (p2 / prior~e.1) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.27)) :op2 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 7~e.31))))) # ::id pmid_1563_0473.229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The marked epidermal hyperproliferation seen in the K14 @-@ Snail Tg skin , coupled with the converse suppression of proliferation and Snail in TGF-β2 @ -@ null hair buds led us to wonder whether the down @-@ regulation of E @-@ cadherin during follicle morphogenesis might have a direct impact on elevating the proliferative state of these cells . # ::alignments 1-1.1.2 3-1.1 4-1.1.3 8-1.1.3.1.2.2.1 10-1.1.3.1.2.1.1 12-1.1.3.1.1 13-1.1.3.1 15-1.1.4 16-1.1.4.1.r 18-1.1.4.1.1.2 19-1.1.4.1.1 21-1.1.4.1.1.1 21-1.3.2.1.3.2 22-1.1.4.1 23-1.1.4.1.2 26-1.1.4.1.3.2.1.1 29-1.1.3.1.2 29-1.1.3.1.2.2 29-1.1.3.1.2.2.r 29-1.1.4.1.3.2.2 30-1.1.4.1.3.1 31-1.1.4.1.3 32-1 33-1.2 35-1.3 36-1.3.2.1.1 36-1.3.2.1.1.r 38-1.3.2.1.2 39-1.3.2.1.2 40-1.3.2.1.2 41-1.3.2.1.2.1.r 42-1.3.2.1.2.1.1.1 44-1.3.2.1.2.1.1.1 45-1.3.2.1.2.2.r 46-1.3.2.1.2.2.1 47-1.3.2.1.2.2 48-1.3.2 49-1.3.2.1 51-1.3.2.1.4 52-1.3.2.1 53-1.3.2.1.3.r 54-1.3.2.1.3 58-1.3.2.1.3.2.1.r 59-1.3.2.1.3.2.1.1 60-1.3.2.1.3.2.1 (l / lead-03~e.32 :ARG0 (p8 / proliferate-01~e.3 :ARG0 (e / epidermis) :ARG1-of (m / mark-01~e.1) :ARG1-of (s / see-01~e.4 :location (s2 / skin~e.13 :mod (t / transgenic~e.12) :mod (p2 / protein~e.29 :name (n2 / name :op1 "Snail"~e.10) :ARG2-of~e.29 (m4 / mutate-01~e.29 :value "K14"~e.8)))) :ARG1-of (c / couple-01~e.15 :ARG2~e.16 (a / and~e.22 :op1 (s3 / suppress-01~e.19 :ARG1 (p3 / proliferate-01~e.21) :mod (c2 / converse~e.18)) :op2 p2~e.23 :location (b2 / bud~e.31 :mod (h2 / hair~e.30) :mod (p7 / protein :name (n4 / name :op1 "TGF-β2"~e.26) :mod (n5 / null~e.29)))))) :ARG1 (w / we~e.33) :ARG2 (w2 / wonder-01~e.35 :ARG0 w :ARG1 (p6 / possible-01~e.48 :ARG1 (i / impact-01~e.49,52 :mode~e.36 interrogative~e.36 :ARG0 (d2 / downregulate-01~e.38,39,40 :ARG1~e.41 (p4 / protein :name (n3 / name :op1 "E-cadherin"~e.42,44)) :time~e.45 (m3 / morphogenesis~e.47 :mod (f / follicle~e.46))) :ARG1~e.53 (e2 / elevate-01~e.54 :ARG0 d2 :ARG1 (p5 / proliferate-01~e.21 :ARG0~e.58 (c3 / cell~e.60 :mod (t2 / this~e.59)))) :ARG1-of (d / direct-02~e.51))))) # ::id pmid_1563_0473.230 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our Tg studies suggested that , at least in part through its regulation of E @-@ cadherin , Snail is able to influence the subcellular localization of a variety of AJ @-@ associated proteins . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1 3-1 6-1.2.1.4 7-1.2.1.4 8-1.2.1.4.1 8-1.2.1.4.r 9-1.2.1.4.r 11-1.2.1.3.1.1 11-1.2.1.3.1.1.r 12-1.2.1.3.1 15-1.2.1.3.1.2.1.1 17-1.2.1.3.1.2.1.1 20-1.2.1.1.1.1 22-1.2 23-1.2.1.3 24-1.2.1 26-1.2.1.2.2 27-1.2.1.2 28-1.2.1.2.1.r 30-1.2.1.2.1.2 32-1.2.1.2.1.1.1.1.1 34-1.2.1.2.1.1 35-1.2.1.2.1 (s / suggest-01~e.3 :ARG0 (s2 / study-01~e.2 :ARG0~e.0 (w / we~e.0) :ARG1 (t / transgenic~e.1)) :ARG1 (p2 / possible-01~e.22 :ARG1 (i / influence-01~e.24 :ARG0 (p3 / protein :name (n / name :op1 "Snail"~e.20)) :ARG1 (l / localize-01~e.27 :ARG1~e.28 (p / protein~e.35 :ARG1-of (a / associate-01~e.34 :ARG2 (p6 / protein :name (n3 / name :op1 "AJ"~e.32))) :mod (v2 / variety~e.30)) :mod (s3 / subcellular~e.26)) :ARG1-of (c / cause-01~e.23 :ARG0 (r / regulate-01~e.12 :ARG0~e.11 p3~e.11 :ARG1 (g / gene :name (n2 / name :op1 "E-cadherin"~e.15,17)))) :degree~e.8,9 (a2 / at-least~e.6,7 :op1 (p4 / part~e.8))))) # ::id pmid_1563_0473.231 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One of these appears to be Ajuba , which was previously shown to have the dual capacity to bind Grb @-@ 2 as well as α-catenin [ @ 9 , 10 @ ] . # ::alignments 0-1.1.1 2-1.1.3.1 3-1 6-1.1.2.1 10-1.1.4.2 11-1.1.4.3 15-1.1.4.4 16-1.1 16-1.1.4 16-1.1.4.r 18-1.1.4.1 19-1.1.4.1.2.1.1.1 21-1.1.4.1.2.1.1.1 22-1.1.4.1.2 22-1.1.4.2.r 22-1.2.1 23-1.2.1 23-1.2.1.1.1.1 24-1.1.4.1.2.r 24-1.2.1 24-1.2.1.1.1.1 25-1.1.4.1.2.2.1.1 28-1.2.1.1.1.1.1 32-1.2.1.1.1.1.2 (a / appear-02~e.3 :ARG1 (p / protein~e.16 :quant 1~e.0 :name (n / name :op1 "Ajuba"~e.6) :ARG1-of (i / include-91 :ARG2 (t2 / this~e.2)) :ARG1-of~e.16 (c / capable-01~e.16 :ARG2 (b / bind-01~e.18 :ARG1 p :ARG2~e.24 (a2 / and~e.22 :op1 (p3 / protein :name (n2 / name :op1 "Grb-2"~e.19,21)) :op2 (p4 / protein :name (n3 / name :op1 "α-catenin"~e.25)))) :time~e.22 (p2 / previous~e.10) :ARG1-of (s / show-01~e.11) :mod (d / dual~e.15))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.22,23,24 :op1 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and~e.23,24 :op1 9~e.28 :op2 10~e.32)))))) # ::id pmid_1563_0473.232 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our studies revealed that in skin keratinocytes that either harbor a conditional null mutation in α-catenin or that overexpress Snail , Ajuba develops an interaction with Grb @-@ 2 that is otherwise not observed in WT keratinocytes . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1 4-1.2.r 5-1.2.3.1.2 6-1.2.3.1 6-1.2.3.2 9-1.2.3.1.1 11-1.2.3.1.1.1.3 12-1.2.3.1.1.1 12-1.2.3.1.1.1.2 12-1.2.3.1.1.1.2.r 13-1.2.3.1.1.1 16-1.2.3.1.1.1.1.1.1 18-1.2.3 20-1.2.3.2.1 21-1.2.3.2.1.1.1.1 23-1.2.1.1.1 24-1.2 26-1.2.2 27-1.2.2.2.r 28-1.2.2.2.1.1 30-1.2.2.2.1.1 33-1.2.2.3.2 34-1.2.2.3.1 34-1.2.2.3.1.r 35-1.2.2.3 36-1.2.2.3.3.r 37-1.2.2.3.3.1 38-1.2.2.3.3 (r / reveal-01~e.2 :ARG0 (s / study-01~e.1 :ARG0~e.0 (w2 / we~e.0)) :ARG1~e.4 (d / develop-02~e.24 :ARG0 (p / protein :name (n / name :op1 "Ajuba"~e.23)) :ARG1 (i / interact-01~e.26 :ARG0 p :ARG1~e.27 (p2 / protein :name (n2 / name :op1 "Grb-2"~e.28,30)) :ARG1-of (o / observe-01~e.35 :polarity~e.34 -~e.34 :mod (o2 / otherwise~e.33) :location~e.36 (k2 / keratinocyte~e.38 :mod (w / wild-type~e.37)))) :location (o3 / or~e.18 :op1 (k / keratinocyte~e.6 :ARG0-of (h / harbor-01~e.9 :ARG1 (m / mutate-01~e.12,13 :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin"~e.16)) :mod~e.12 (n3 / null~e.12) :mod (c / conditional~e.11))) :mod (s2 / skin~e.5)) :op2 (k3 / keratinocyte~e.6 :location-of (o4 / overexpress-01~e.20 :ARG1 (p4 / protein :name (n5 / name :op1 "Snail"~e.21))))))) # ::id pmid_1563_0473.233 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The corresponding abilities of either Snail @ -@ transfected or Ajuba @ -@ transfected keratinocytes to exhibit elevated activation of the Ras @-@ MAPK pathway suggest that the Grb @-@ 2 association of Ajuba under conditions of reduced levels of AJ proteins may be directly relevant to the parallel in hyperproliferation . # ::alignments 1-1.1.3 2-1.1 6-1.1.1.1.1.1.1.1 9-1.1.1.1.1 10-1.1.1 12-1.1.1.2.1.1.1.1 15-1.1.1.1.1 15-1.1.1.2.1 16-1.1.1.1 16-1.1.1.2 18-1.1.2 19-1.1.2.2.2 20-1.1.2.2 21-1.1.2.2.1.r 23-1.1.2.2.1.1.1 25-1.1.2.2.1.1.1 26-1.1.2.2.1 27-1 28-1.2.r 30-1.2.1.1.2.1.1 32-1.2.1.1.2.1.1 33-1.2.1.1 34-1.2.1.1.1.r 35-1.2.1.1.1 37-1.2.2.r 39-1.2.2.2 40-1.2.2 42-1.2.2.1.1.1 43-1.2.1.1.2 43-1.2.2.1 44-1.2 46-1.2.1.3 47-1.2.1 48-1.2.1.2.r 50-1.2.1.2 51-1.2.1.2.1.r 52-1.2.1.2.1 52-1.2.1.2.1.1 52-1.2.1.2.1.1.r (s / suggest-01~e.27 :ARG0 (c / capable-01~e.2 :ARG1 (o / or~e.10 :op1 (k / keratinocyte~e.16 :ARG1-of (t / transfect-01~e.9,15 :ARG2 (g / gene :name (n4 / name :op1 "Snail"~e.6)))) :op2 (k2 / keratinocyte~e.16 :ARG1-of (t2 / transfect-01~e.15 :ARG2 (g2 / gene :name (n5 / name :op1 "Ajuba"~e.12))))) :ARG2 (e / exhibit-01~e.18 :ARG0 (a3 / and :op1 k :op2 k2) :ARG1 (a2 / activate-01~e.20 :ARG1~e.21 (p8 / pathway~e.26 :name (n6 / name :op1 "Ras-MAPK"~e.23,25)) :ARG1-of (e2 / elevate-01~e.19))) :ARG1-of (c2 / correspond-02~e.1)) :ARG1~e.28 (p / possible-01~e.44 :ARG1 (r / relevant-01~e.47 :ARG1 (a / associate-01~e.33 :ARG1~e.34 g2~e.35 :ARG2 (p3 / protein~e.43 :name (n2 / name :op1 "Grb-2"~e.30,32))) :ARG2~e.48 (p5 / parallel~e.50 :location~e.51 (p2 / proliferate-01~e.52 :degree~e.52 (h / hyper~e.52))) :ARG1-of (d / direct-02~e.46)) :condition~e.37 (l / level~e.40 :quant-of (p4 / protein~e.43 :name (n3 / name :op1 "AJ"~e.42)) :ARG1-of (r2 / reduce-01~e.39)))) # ::id pmid_1563_0473.234 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In stable epithelial ( i.e . , Madin @-@ Darby canine kidney , or MDCK ) cell lines , Snail has been shown to block cell cycle progression and promote motility and shape changes for invasion [ @ 47 @ ] . # ::alignments 1-1.2.2 2-1.2.1 7-1.2.3.1.1.1 9-1.2.3.1.1.1 10-1.2.3.1.1.2 11-1.2.3.1.1.3 16-1.2 17-1.2 19-1.1.1.1.1.1 22-1 24-1.1.1 25-1.1.1.2.1.1 26-1.1.1.2.1 27-1.1.1.2 28-1.1 29-1.1.2 30-1.1.2.2 31-1.1 32-1.1.3 33-1.1.3.1 34-1.1.3.2.r 35-1.1.3.2 38-1.3.1.1.1 (s / show-01~e.22 :ARG1 (a2 / and~e.28,31 :op1 (b / block-01~e.24 :ARG0 (p2 / protein :name (n / name :op1 "Snail"~e.19)) :ARG1 (p3 / progress-01~e.27 :ARG1 (c2 / cycle-02~e.26 :ARG1 (c / cell~e.25)))) :op2 (p / promote-01~e.29 :ARG0 p2 :ARG1 (m2 / motility~e.30)) :op3 (s3 / shape-01~e.32 :ARG1 (c3 / change-01~e.33) :purpose~e.34 (i / invade-01~e.35))) :location (c6 / cell-line~e.16,17 :mod (e / epithelium~e.2) :ARG1-of (s2 / stable-03~e.1) :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :name (n2 / name :op1 "Madin-Darby"~e.7,9 :op2 "canine"~e.10 :op3 "kidney"~e.11)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 47~e.38)))) # ::id pmid_1563_0473.235 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While our in vivo studies are consistent with a role for Snail in motility and epithelial remodeling , they differ with respect to Snail 's apparent proliferative effects . # ::alignments 1-1.2.1.1 1-1.2.1.1.r 2-1.2.1.2 3-1.2.1.2 4-1.2.1 6-1.2 7-1.2.2.r 9-1.2.2 11-1.1.2.1.1.1 12-1.2.1.2 12-1.2.2.1.r 13-1.2.2.1.1 14-1.2.2.1 15-1.2.2.1.2.1 16-1.2.2.1.2 18-1.2.2.2 19-1.1 23-1.1.2.1.1.1 24-1.1.2.1.r 27-1.1.2 (h / have-concession-91 :ARG1 (d2 / differ-01~e.19 :ARG0 s :ARG2 (a3 / affect-01~e.27 :ARG0~e.24 (p2 / protein :name (n / name :op1 "Snail"~e.11,23)) :ARG2 (p / proliferate-01) :ARG1-of (a / appear-01))) :ARG2 (c / consistent-01~e.6 :ARG1 (s / study-01~e.4 :ARG0~e.1 (w / we~e.1) :manner (i / in-vivo~e.2,3,12)) :ARG2~e.7 (r / role~e.9 :topic~e.12 (a2 / and~e.14 :op1 (m / motility~e.13) :op2 (r2 / remodel-01~e.16 :ARG1 (e2 / epithelium~e.15))) :purpose p2~e.18))) # ::id pmid_1563_0473.236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A priori , this could be simply due to variations in the response of different cell types to Snail expression . # ::alignments 0-1.2 1-1.2 3-1.1.1.2 4-1.1 6-1.1.1.3 7-1.1.1 8-1.1.1 9-1.1.1.1 10-1.1.1.1.1.r 12-1.1.1.1.1 13-1.1.1.1.1.1.r 14-1.1.1.1.1.1.2 15-1.1.1.1.1.1 16-1.1.1.1.1.1.1 17-1.1.1.1.1.2.r 18-1.1.1.1.1.2.1.1.1 19-1.1.1.1.1.2 (i / infer-01 :ARG1 (p / possible-01~e.4 :ARG1 (c / cause-01~e.7,8 :ARG0 (v / vary-01~e.9 :ARG1~e.10 (r / respond-01~e.12 :ARG0~e.13 (c2 / cell~e.15 :ARG1-of (t / type-03~e.16) :ARG1-of (d / differ-02~e.14)) :ARG1~e.17 (e / express-03~e.19 :ARG2 (p2 / protein :name (n / name :op1 "Snail"~e.18))))) :ARG1 (t2 / this~e.3) :ARG1-of (s / simple-02~e.6))) :mod (a / a-priori~e.0,1)) # ::id pmid_1563_0473.237 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternatively , these differences may be relevant to the benefit of using mouse models to reveal functions not always recapitulated in stable cell line models . # ::alignments 0-1.2 0-1.2.r 2-1.1.1.2 3-1.1.1 3-1.1.1.1 3-1.1.1.1.r 4-1 6-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1 12-1.1.2.1.1.1 13-1.1.2.1.1 15-1.1.2.1.2 16-1.1.2.1.2.1 17-1.1.2.1.2.1.1.1.1 17-1.1.2.1.2.1.1.1.1.r 18-1.1.2.1.2.1.1.1 19-1.1.2.1.2.1.1 20-1.1.2.1.2.1.1.2.r 21-1.1.2.1.2.1.1.2.2 22-1.1.2.1.2.1.1.2.1 23-1.1.2.1.2.1.1.2.1 24-1.1.2.1.2.1.1.2 (p / possible-01~e.4 :ARG1 (r / relevant-01~e.6 :ARG1 (t / thing~e.3 :ARG1-of~e.3 (d / differ-02~e.3) :mod (t2 / this~e.2)) :ARG2 (b / benefit-01~e.9 :ARG0~e.10 (u / use-01~e.11 :ARG1 (m / model~e.13 :mod (m2 / mouse~e.12)) :ARG2 (r2 / reveal-01~e.15 :ARG1 (f / function-01~e.16 :ARG1-of (r3 / recapitulate-01~e.19 :time (a2 / always~e.18 :polarity~e.17 -~e.17) :location~e.20 (m3 / model~e.24 :mod (c / cell-line~e.22,23) :ARG1-of (s / stable-03~e.21)))))))) :manner~e.0 (a / alternative~e.0)) # ::id pmid_1563_0473.238 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Future studies should highlight the underlying reasons for these opposing results . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 3-1.1 5-1.1.2.2 6-1.1.2 6-1.1.2.1 6-1.1.2.1.r 7-1.1.2.1.1.r 8-1.1.2.1.1.2 9-1.1.2.1.1.3 10-1.1.2.1.1 10-1.1.2.1.1.1 10-1.1.2.1.1.1.r (r / recommend-01~e.2 :ARG1 (h / highlight-01~e.3 :ARG0 (s / study-01~e.1 :time (f / future~e.0)) :ARG1 (t / thing~e.6 :ARG0-of~e.6 (c / cause-01~e.6 :ARG1~e.7 (t2 / thing~e.10 :ARG2-of~e.10 (r2 / result-01~e.10) :mod (t3 / this~e.8) :ARG0-of (o / oppose-01~e.9))) :ARG0-of (u / underlie-01~e.5)))) # ::id pmid_1563_0473.239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Irrespective of these differences , our in vivo studies do not stand alone , as there are many situations in which a down @-@ regulation in AJ proteins correlate with enhanced proliferation . # ::alignments 0-1.5 2-1.5.1.2 3-1.5.1 3-1.5.1.1 3-1.5.1.1.r 5-1.2.1 5-1.2.1.r 6-1.2.2 7-1.2.2 8-1.2 9-1.2 10-1.1 10-1.1.r 11-1 12-1.3 17-1.4.1.1 18-1.4.1 19-1.2.2 22-1.4.1.2.1 23-1.4.1.2.1 24-1.4.1.2.1 25-1.2.2 25-1.4.1.2.1.1.r 26-1.4.1.2.1.1.1.1 27-1.4.1.2.1.1 28-1.4.1.2 29-1.4.1.2.2.r 30-1.4.1.2.2.1 31-1.4.1.2.2 (s / stand-01~e.11 :polarity~e.10 -~e.10 :ARG1 (s2 / study-01~e.8,9 :ARG0~e.5 (w / we~e.5) :manner (i / in-vivo~e.6,7,19,25)) :manner (a / alone~e.12) :ARG1-of (c / cause-01 :ARG0 (s3 / situation~e.18 :quant (m / many~e.17) :mod (c2 / correlate-01~e.28 :ARG1 (d2 / downregulate-01~e.22,23,24 :ARG1~e.25 (p / protein~e.27 :name (n / name :op1 "AJ"~e.26))) :ARG2~e.29 (p2 / proliferate-01~e.31 :ARG1-of (e / enhance-01~e.30))))) :ARG1-of (r / regardless-91~e.0 :ARG2 (t / thing~e.3 :ARG1-of~e.3 (d / differ-02~e.3) :mod (t2 / this~e.2)))) # ::id pmid_1563_0473.240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In fact , a myriad of diverse mechanisms have been implicated in activating epithelial proliferation upon down @-@ regulation of AJ proteins [ @ 7 , 23 , 24 , 48 @ ] . # ::alignments 0-1.3 1-1.3 4-1.1.2 5-1.1.2.r 6-1.1.1 7-1.1 10-1 11-1.2.r 11-1.3 12-1.2 13-1.2.1.1 14-1.2.1 16-1.2.2 17-1.2.2 18-1.2.2 19-1.2.2.1.r 20-1.2.2.1.1.1 21-1.2.2.1 24-1.4.1.1.1.1 28-1.4.1.1.1.2 32-1.4.1.1.1.3 36-1.4.1.1.1.4 (i / implicate-01~e.10 :ARG1 (m / mechanism~e.7 :mod (d / diverse~e.6) :quant~e.5 (m2 / myriad~e.4)) :ARG2~e.11 (a / activate-01~e.12 :ARG1 (p / proliferate-01~e.14 :ARG0 (e / epithelium~e.13)) :time (d2 / downregulate-01~e.16,17,18 :ARG1~e.19 (p2 / protein~e.21 :name (n / name :op1 "AJ"~e.20)))) :mod (i2 / in-fact~e.0,1,11) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 7~e.24 :op2 23~e.28 :op3 24~e.32 :op4 48~e.36))))) # ::id pmid_1563_0473.241 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sifting through these converging pathways is likely to be a difficult and painstaking process . # ::alignments 0-1.1.1 2-1.1.1.1.2 3-1.1.1.1.1 4-1.1.1.1 6-1 10-1.1.2 12-1.1.3 13-1.1 (l / likely-01~e.6 :ARG1 (p / process-02~e.13 :ARG1 (s / sift-01~e.0 :ARG1 (p3 / pathway~e.4 :ARG0-of (c / converge-01~e.3) :mod (t / this~e.2))) :mod (d / difficult~e.10) :mod (p2 / painstaking~e.12))) # ::id pmid_1563_0473.242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This said , by identifying the status of different players involved in specific cell types and at specific stages in development , our mechanistic understanding of how intercellular remodeling is linked to proliferation in epithelial morphogenesis should begin to surface in the future . # ::alignments 0-1.2.1.1 1-1.2.1 4-1.1.2 6-1.1.2.1 7-1.1.2.1.1.r 8-1.1.2.1.1 8-1.1.2.1.1.1 8-1.1.2.1.1.1.r 9-1.1.2.1.1.3 10-1.1.2.1.1.2 11-1.1.2.1.1.2.1.r 12-1.1.2.1.1.2.1.2 13-1.1.2.1.1.2.1 14-1.1.2.1.1.2.1.1 17-1.1.2.1.1.2.1.2 18-1.1.2.1.1.2.2 19-1.1.2.1.1.2.2.2.r 20-1.1.2.1.1.2.2.2 22-1.1.1.1.1 22-1.1.1.1.1.r 23-1.1.1.1.3 24-1.1.1.1 26-1.1.1.1.2.3 26-1.1.1.1.2.3.r 27-1.1.1.1.2.1.1 28-1.1.1.1.2.1 30-1.1.1.1.2 31-1.1.1.1.2.2.r 32-1.1.1.1.2.2 33-1.1.1.1.2.2.1.r 34-1.1.1.1.2.2.1.1 35-1.1.1.1.2.2.1 36-1 37-1.1 38-1.1.1.1 39-1.1.1 40-1.1.1.2.r 42-1.1.1.2 (r / recommend-01~e.36 :ARG1 (b / begin-01~e.37 :ARG1 (s / surface-01~e.39 :ARG1 (u / understand-01~e.24,38 :ARG0~e.22 (w / we~e.22) :ARG1 (l / link-01~e.30 :ARG1 (r2 / remodel-01~e.28 :mod (i / intercellular~e.27)) :ARG2~e.31 (p / proliferate-01~e.32 :ARG0~e.33 (m / morphogenesis~e.35 :mod (e / epithelium~e.34))) :manner~e.26 (a2 / amr-unknown~e.26)) :mod (m2 / mechanism~e.23)) :time~e.40 (f / future~e.42)) :manner (i2 / identify-01~e.4 :ARG1 (s2 / status~e.6 :poss~e.7 (t / thing~e.8 :ARG1-of~e.8 (d / differ-02~e.8) :ARG1-of (i3 / involve-01~e.10 :ARG2~e.11 (c / cell~e.13 :ARG2-of (t2 / type-03~e.14) :ARG1-of (s3 / specific-02~e.12,17)) :time (s4 / stage~e.18 :ARG1-of s3 :subevent-of~e.19 (d2 / develop-02~e.20))) :ARG0-of (p2 / play-08~e.9))))) :time (a3 / after :op1 (s5 / say-01~e.1 :ARG1 (t3 / this~e.0)))) # ::id pmid_1563_0473.243 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Elucidating the molecular mechanisms through which these networks converge is also a prerequisite for understanding how these processes go awry during tumorigenesis . # ::alignments 0-1.2 2-1.2.1.1 3-1.2.1 5-1.1.1.4 6-1.2.1.2.1.1 7-1.2.1.2.1 8-1.2.1.2 10-1.3 14-1.1 15-1.1.1.4 15-1.1.1.4.r 16-1.1.1.1.1 17-1.1.1.1 18-1.1.1 19-1.1.1.2 20-1.1.1.3.r 21-1.1.1.3 21-1.1.1.3.1 21-1.1.1.3.1.r (r / require-01 :ARG0 (u / understand-01~e.14 :ARG1 (g / go-08~e.18 :ARG1 (p / process-02~e.17 :mod (t / this~e.16)) :ARG2 (a / awry~e.19) :time~e.20 (c / create-01~e.21 :ARG1~e.21 (t2 / tumor~e.21)) :manner~e.15 (a2 / amr-unknown~e.5,15))) :ARG1 (e / elucidate-01~e.0 :ARG1 (m / mechanism~e.3 :mod (m2 / molecule~e.2) :manner-of (c2 / converge-01~e.8 :ARG0 (n / network~e.7 :mod (t3 / this~e.6))))) :mod (a3 / also~e.10)) # ::id pmid_1563_0473.244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Materials and Methods # ::alignments 0-1.1 1-1 2-1.2 (a / and~e.1 :op1 (m / material~e.0) :op2 (m2 / method~e.2)) # ::id pmid_1563_0473.245 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reagents # ::alignments 0-1 (r / reagent~e.0) # ::id pmid_1563_0473.246 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Primary antibodies used were against : E @-@ cadherin ( M . Takeichi , Kyoto University , Japan ) ; α-catenin , β-catenin , pMAPK , tubulin ( Sigma , St. Louis , Missouri , United States ) , Ajuba ( G . Longmore , Washington University , St. Louis , Missouri , United States ) ; β4 integrin @/@ CD104 ( BD Pharmingen , San Diego , California , United States ) , laminin 5 ( R . Burgeson , Harvard University , Cambridge , Massachusetts , United States ) , K5 , K1 , loricrin ( Fuchs Lab ) , involucrin , fillagrin ( Covance , Berkeley , California , United States ) , MAPK , pSMAD2 ( Cell Signaling , Beverly , Massachusetts , United States ) ; Grb @-@ 2 ( Santa Cruz Biotech , Santa Cruz , California , United States ) ; P @-@ cadherin ( Zymed Laboratories , South San Francisco , California , United States ) ; HA ( Roche Biochemicals ) , vimentin ( Chemicon , Temecula , California , United States ) , Ki67 ( Novo Castra , Newcastle Upon Tyne , United Kingdom ) , keratin 6 ( P . Coulombe , John Hopkins University , Baltimore , Maryland , United States ) , cyclin D ( Oncogene , San Diego , California , United States ) , and TGF-β2 ( L . Gold , New York University , New York , New York , United States ) . # ::alignments 0-1.1.1.1 1-1.1.1 1-1.1.10 1-1.1.11 1-1.1.12 1-1.1.13 1-1.1.14 1-1.1.15 1-1.1.16 1-1.1.2 1-1.1.3 1-1.1.4 1-1.1.5 1-1.1.6 1-1.1.7 1-1.1.8 1-1.1.9 2-1 4-1.1.1.2 4-1.1.10.2 4-1.1.11.2 4-1.1.12.2 4-1.1.13.2 4-1.1.14.2 4-1.1.15.2 4-1.1.16.2 4-1.1.2.2 4-1.1.3.2 4-1.1.4.2 4-1.1.5.2 4-1.1.6.2 4-1.1.7.2 4-1.1.8.2 4-1.1.9.2 6-1.1.1.2.1.1.1 8-1.1.1.2.1.1.1 12-1.1.1.2.1.2.1.2 14-1.1.1.2.1.2.2.2.1 15-1.1.1.2.1.2.2.2.2 17-1.1.1.2.1.2.2.3.2.1 20-1.1.2.2.1.1.1.1 22-1.1.2.2.1.2.1.1 24-1.1.2.2.1.3 24-1.1.2.2.1.3.1.1 24-1.1.2.2.1.3.2 24-1.1.2.2.1.3.2.r 26-1.1.2.2.1.4.1.1 28-1.1.2.2.1.5.1.1 30-1.1.2.2.1.5.2.2.1 31-1.1.2.2.1.5.2.2.2 33-1.1.2.2.1.5.2.3.2.1 35-1.1.2.2.1.5.2.3.3.2.1 36-1.1.2.2.1.5.2.3.3.2.2 39-1.1.3.2.1.1.1 43-1.1.3.2.1.2.1.2 45-1.1.3.2.1.2.2.2.1 46-1.1.3.2.1.2.2.2.2 48-1.1.2.2.1.5.2.2.1 49-1.1.2.2.1.5.2.2.2 51-1.1.2.2.1.5.2.3.2.1 53-1.1.2.2.1.5.2.3.3.2.1 54-1.1.2.2.1.5.2.3.3.2.2 57-1.1.4.2.1.1.1 58-1.1.4.2.1.1.1 60-1.1.4.2.1.1.1 62-1.1.4.2.1.2.1.1 63-1.1.4.2.1.2.1.2 65-1.1.4.2.1.2.2.2.1 66-1.1.4.2.1.2.2.2.2 68-1.1.4.2.1.2.2.3.2.1 70-1.1.2.2.1.5.2.3.3.2.1 71-1.1.2.2.1.5.2.3.3.2.2 74-1.1.5.2.1.1.1 75-1.1.5.2.1.1.1 79-1.1.5.2.1.2.1.2 81-1.1.5.2.1.2.2.2.1 82-1.1.5.2.1.2.2.2.2 84-1.1.5.2.1.2.2.3.2.1 86-1.1.5.2.1.2.2.3.3.2.1 88-1.1.2.2.1.5.2.3.3.2.1 89-1.1.2.2.1.5.2.3.3.2.2 92-1.1.6.2.1.1.1.1 94-1.1.6.2.1.2.1.1 96-1.1.6.2.1.3.1.1 98-1.1.6.2.1.4.1.1 99-1.1.6.2.1.4.1.2 102-1.1.7.2.1.1.1.1 104-1.1.7.2.1.2.1.1 106-1.1.7.2.1.3.2.1 108-1.1.7.2.1.3.3.2.1 110-1.1.7.2.1.3.3.3 112-1.1.2.2.1.5.2.3.3.2.1 113-1.1.2.2.1.5.2.3.3.2.2 116-1.1.8.2.1.1 120-1.1.8.2.1.3.1.1 121-1.1.8.2.1.3.1.2 123-1.1.8.2.1.3.2.2.1 125-1.1.8.2.1.3.2.3 127-1.1.5.2.1.2.2.3.3.3 128-1.1.4.2.1.2.2.3 128-1.1.5.2.1.2.2.3.3 131-1.1.9.2.1.1.1 133-1.1.9.2.1.1.1 135-1.1.9.2.1.2.1.1 135-1.1.9.2.1.2.2.2.1 136-1.1.9.2.1.2.1.2 136-1.1.9.2.1.2.2.2.2 137-1.1.9.2.1.2.1.3 139-1.1.9.2.1.2.2.2.1 140-1.1.9.2.1.2.2.2.2 142-1.1.4.2.1.2.2.3.2.1 145-1.1.4.2.1.2.2.3 145-1.1.5.2.1.2.2.3.3 148-1.1.10.2.1.1.1 148-1.1.2.2.1.3 148-1.1.2.2.1.3.2 148-1.1.2.2.1.3.2.r 150-1.1.10.2.1.1.1 152-1.1.10.2.1.2.1.1 153-1.1.10.2.1.2.1.2 155-1.1.10.2.1.2.2.2.1 156-1.1.10.2.1.2.2.2.2 157-1.1.10.2.1.2.2.2.3 159-1.1.10.2.1.2.2.3 162-1.1.4.2.1.2.2.3 162-1.1.5.2.1.2.2.3.3 165-1.1.11.2.1.1.1 167-1.1.11.2.1.2.1.1 168-1.1.11.2.1.2.1.2 171-1.1.12.2.1.1.1 173-1.1.12.2.1.2.1.1 175-1.1.12.2.1.2.2.2.1 177-1.1.12.2.1.2.2.3 180-1.1.4.2.1.2.2.3 180-1.1.5.2.1.2.2.3.3 183-1.1.13.2.1.1.1 185-1.1.13.2.1.2.1.1 186-1.1.13.2.1.2.1.2 188-1.1.13.2.1.2.2.2.1 189-1.1.13.2.1.2.2.2.2 190-1.1.13.2.1.2.2.2.3 192-1.1.13.2.1.2.2.3.2.1 193-1.1.13.2.1.2.2.3.2.2 196-1.1.14.2.1.1.1 197-1.1.14.2.1.1.1 199-1.1.10.2.1.1.1 199-1.1.2.2.1.3 199-1.1.2.2.1.3.2 199-1.1.2.2.1.3.2.r 201-1.1.14.2.1.2.1.2 203-1.1.14.2.1.2.2.2.1 204-1.1.14.2.1.2.2.2.2 205-1.1.14.2.1.2.2.2.3 207-1.1.14.2.1.2.2.3.2.1 209-1.1.14.2.1.2.2.3.3.2.1 212-1.1.14.2.1.2.2.3.3 212-1.1.4.2.1.2.2.3 212-1.1.5.2.1.2.2.3.3 215-1.1.15.2.1.1.1 216-1.1.15.2.1.1.1 218-1.1.15.2.1.2.1.1 220-1.1.4.2.1.2.2.2.1 221-1.1.4.2.1.2.2.2.2 223-1.1.4.2.1.2.2.3.2.1 226-1.1.14.2.1.2.2.3.3 226-1.1.4.2.1.2.2.3 226-1.1.5.2.1.2.2.3.3 229-1.1 229-1.1.2.2.1 229-1.1.6.2.1 229-1.1.7.2.1 229-1.1.8.2.1 230-1.1.16.2.1.1.1 234-1.1.16.2.1.2.1.2 236-1.1.16.2.1.2.2.2.1 236-1.1.16.2.1.2.2.3.2.1 237-1.1.16.2.1.2.2.2.2 237-1.1.16.2.1.2.2.3.2.2 238-1.1.16.2.1.2.2.2.3 240-1.1.16.2.1.2.2.3.2.1 241-1.1.16.2.1.2.2.3.2.2 243-1.1.16.2.1.2.2.3.2.1 244-1.1.16.2.1.2.2.3.2.2 247-1.1.16.2.1.2.2.3.3 (u / use-01~e.2 :ARG1 (a / and~e.229 :op1 (a2 / antibody~e.1 :mod (p / primary~e.0) :ARG0-of (o / oppose-01~e.4 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin"~e.6,8) :source (p3 / person :name (n2 / name :op1 "M." :op2 "Takeichi"~e.12) :location (u2 / university :wiki "Kyoto_University" :name (n3 / name :op1 "Kyoto"~e.14 :op2 "University"~e.15) :location (c / country :wiki "Japan" :name (n4 / name :op1 "Japan"~e.17))))))) :op2 (a7 / antibody~e.1 :mod p :ARG0-of (o2 / oppose-01~e.4 :ARG1 (a3 / and~e.229 :op1 (p4 / protein :name (n5 / name :op1 "α-catenin"~e.20)) :op2 (p5 / protein :name (n6 / name :op1 "β-catenin"~e.22)) :op3 (e / enzyme~e.24,148,199 :name (n7 / name :op1 "MAPK"~e.24) :ARG1-of~e.24,148,199 (p6 / phosphorylate-01~e.24,148,199)) :op4 (p7 / protein :name (n8 / name :op1 "tubulin"~e.26)) :source (c2 / company :name (n9 / name :op1 "Sigma"~e.28) :location (c3 / city :wiki "St._Louis" :name (n10 / name :op1 "St."~e.30,48 :op2 "Louis"~e.31,49) :location (s / state :wiki "Missouri" :name (n11 / name :op1 "Missouri"~e.33,51) :location (c4 / country :wiki "United_States" :name (n12 / name :op1 "United"~e.35,53,70,88,112 :op2 "States"~e.36,54,71,89,113)))))))) :op3 (a8 / antibody~e.1 :mod p :ARG0-of (o3 / oppose-01~e.4 :ARG1 (p8 / protein :name (n13 / name :op1 "Ajuba"~e.39) :source (p9 / person :name (n14 / name :op1 "G." :op2 "Longmore"~e.43) :location (u3 / university :wiki "Washington_University_in_St._Louis" :name (n15 / name :op1 "Washington"~e.45 :op2 "University"~e.46) :location c3))))) :op4 (a9 / antibody~e.1 :mod p :ARG0-of (o4 / oppose-01~e.4 :ARG1 (p10 / protein :name (n16 / name :op1 "β4-integrin/CD104"~e.57,58,60) :source (c5 / company :name (n17 / name :op1 "BD"~e.62 :op2 "Pharmingen"~e.63) :location (c6 / city :wiki "San_Diego" :name (n18 / name :op1 "San"~e.65,220 :op2 "Diego"~e.66,221) :location (s2 / state~e.128,145,162,180,212,226 :wiki "California" :name (n19 / name :op1 "California"~e.68,142,223) :location c4)))))) :op5 (a10 / antibody~e.1 :mod p :ARG0-of (o5 / oppose-01~e.4 :ARG1 (p11 / protein :name (n20 / name :op1 "laminin-5"~e.74,75) :source (p12 / person :name (n21 / name :op1 "R." :op2 "Burgeson"~e.79) :location (u4 / university :wiki "Harvard_University" :name (n22 / name :op1 "Harvard"~e.81 :op2 "University"~e.82) :location (c7 / city :wiki "Cambridge,_Massachusetts" :name (n23 / name :op1 "Cambridge"~e.84) :location (s3 / state~e.128,145,162,180,212,226 :wiki "Massachusetts" :name (n24 / name :op1 "Massachusetts"~e.86) :location c4~e.127))))))) :op6 (a11 / antibody~e.1 :mod p :ARG0-of (o6 / oppose-01~e.4 :ARG1 (a4 / and~e.229 :op1 (p13 / protein :name (n25 / name :op1 "K5"~e.92)) :op2 (p14 / protein :name (n26 / name :op1 "K1"~e.94)) :op3 (p15 / protein :name (n27 / name :op1 "loricrin"~e.96)) :location (r / research-institute :name (n28 / name :op1 "Fuchs"~e.98 :op2 "Lab"~e.99))))) :op7 (a12 / antibody~e.1 :mod p :ARG0-of (o7 / oppose-01~e.4 :ARG1 (a5 / and~e.229 :op1 (p16 / protein :name (n29 / name :op1 "involucrin"~e.102)) :op2 (p17 / protein :name (n30 / name :op1 "fillagrin"~e.104)) :source (c8 / company :wiki "Covance" :name (n31 / name :op1 "Covance"~e.106) :location (c9 / city :wiki "Berkeley,_California" :name (n32 / name :op1 "Berkeley"~e.108) :location s2~e.110))))) :op8 (a13 / antibody~e.1 :mod p :ARG0-of (o8 / oppose-01~e.4 :ARG1 (a6 / and~e.229 :op1 e~e.116 :op2 (p18 / protein :name (n33 / name :op1 "SMAD2") :ARG1-of p6) :source (c10 / company :name (n34 / name :op1 "Cell"~e.120 :op2 "Signaling"~e.121) :location (c11 / city :wiki "Beverly,_Massachusetts" :name (n35 / name :op1 "Beverly"~e.123) :location s3~e.125))))) :op9 (a14 / antibody~e.1 :mod p :ARG0-of (o9 / oppose-01~e.4 :ARG1 (p19 / protein :name (n36 / name :op1 "Grb-2"~e.131,133) :source (c12 / company :name (n37 / name :op1 "Santa"~e.135 :op2 "Cruz"~e.136 :op3 "Biotech"~e.137) :location (c13 / city :wiki "Santa_Cruz,_California" :name (n38 / name :op1 "Santa"~e.135,139 :op2 "Cruz"~e.136,140) :location s2))))) :op10 (a15 / antibody~e.1 :mod p :ARG0-of (o10 / oppose-01~e.4 :ARG1 (p20 / protein :name (n39 / name :op1 "P-cadherin"~e.148,150,199) :source (c14 / company :name (n40 / name :op1 "Zymed"~e.152 :op2 "Laboratories"~e.153) :location (c15 / city :wiki "South_San_Francisco,_California" :name (n41 / name :op1 "South"~e.155 :op2 "San"~e.156 :op3 "Francisco"~e.157) :location s2~e.159))))) :op11 (a16 / antibody~e.1 :mod p :ARG0-of (o11 / oppose-01~e.4 :ARG1 (p21 / protein :name (n42 / name :op1 "HA"~e.165) :source (c16 / company :name (n43 / name :op1 "Roche"~e.167 :op2 "Biochemicals"~e.168))))) :op12 (a17 / antibody~e.1 :mod p :ARG0-of (o12 / oppose-01~e.4 :ARG1 (p22 / protein :name (n44 / name :op1 "vimentin"~e.171) :source (c17 / company :name (n45 / name :op1 "Chemicon"~e.173) :location (c18 / city :wiki "Temecula,_California" :name (n46 / name :op1 "Temecula"~e.175) :location s2~e.177))))) :op13 (a18 / antibody~e.1 :mod p :ARG0-of (o13 / oppose-01~e.4 :ARG1 (p23 / protein :name (n47 / name :op1 "Ki67"~e.183) :source (c19 / company :name (n48 / name :op1 "Novo"~e.185 :op2 "Castra"~e.186) :location (c20 / city :wiki "Newcastle_upon_Tyne" :name (n49 / name :op1 "Newcastle"~e.188 :op2 "Upon"~e.189 :op3 "Tyne"~e.190) :location (c21 / country :wiki "United_Kingdom" :name (n50 / name :op1 "United"~e.192 :op2 "Kingdom"~e.193))))))) :op14 (a19 / antibody~e.1 :mod p :ARG0-of (o14 / oppose-01~e.4 :ARG1 (p24 / protein :name (n51 / name :op1 "keratin-6"~e.196,197) :source (p25 / person :name (n52 / name :op1 "P." :op2 "Coulombe"~e.201) :location (u5 / university :wiki "Johns_Hopkins_University" :name (n53 / name :op1 "John"~e.203 :op2 "Hopkins"~e.204 :op3 "University"~e.205) :location (c22 / city :wiki "Baltimore" :name (n54 / name :op1 "Baltimore"~e.207) :location (s4 / state~e.212,226 :wiki "Maryland" :name (n55 / name :op1 "Maryland"~e.209) :location c4))))))) :op15 (a20 / antibody~e.1 :mod p :ARG0-of (o15 / oppose-01~e.4 :ARG1 (p26 / protein :name (n56 / name :op1 "cyclin-D"~e.215,216) :source (c23 / company :name (n57 / name :op1 "Oncogene"~e.218) :location c6)))) :op16 (a21 / antibody~e.1 :mod p :ARG0-of (o16 / oppose-01~e.4 :ARG1 (p27 / protein :name (n58 / name :op1 "TGF-β2"~e.230) :source (p28 / person :name (n59 / name :op1 "L." :op2 "Gold"~e.234) :location (u6 / university :wiki "New_York_University" :name (n60 / name :op1 "New"~e.236 :op2 "York"~e.237 :op3 "University"~e.238) :location (c24 / city :wiki "New_York" :name (n61 / name :op1 "New"~e.236,240,243 :op2 "York"~e.237,241,244) :location (s5 / state~e.247 :name n61 :location c4))))))))) # ::id pmid_1563_0473.247 ::amr-annotator SDL-AMR-09 ::preferred # ::tok FITC-, Texas Red-, or HRP @-@ conjugated secondary antibodies were from Jackson ImmunoResearch ( West Grove , Pennsylvania , United States ) . # ::alignments 1-1.2.1.2.1.1 3-1.2.1 4-1.2.1.3.1.1 6-1.2 7-1.1 8-1 10-1.3.r 11-1.3.1.1 12-1.3.1.2 14-1.3.2.1.1 15-1.3.2.1.2 17-1.3.2.2.2.1 19-1.3.2.2.3.2.1 20-1.3.2.2.3.2.2 (a / antibody~e.8 :mod (s / secondary~e.7) :ARG1-of (c / conjugate-02~e.6 :ARG2 (o / or~e.3 :op1 (p / product :name (n / name :op1 "FITC")) :op2 (p2 / product :name (n2 / name :op1 "Texas"~e.1 :op2 "Red")) :op3 (e / enzyme :name (n3 / name :op1 "HRP"~e.4)))) :source~e.10 (c2 / company :name (n4 / name :op1 "Jackson"~e.11 :op2 "ImmunoResearch"~e.12) :location (c3 / city :name (n5 / name :op1 "West"~e.14 :op2 "Grove"~e.15) :location (s2 / state :wiki "Pennsylvania" :name (n6 / name :op1 "Pennsylvania"~e.17) :location (c4 / country :wiki "United_States" :name (n7 / name :op1 "United"~e.19 :op2 "States"~e.20)))))) # ::id pmid_1563_0473.248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Biotinylated secondary antibodies were from Vector Labs ( Burlingame , California , United States ) . # ::alignments 1-1.1 2-1 4-1.3.r 5-1.3.1.1 6-1.3.1.2 8-1.3.2.2.1 10-1.3.2.3.2.1 12-1.3.2.3.3.2.1 13-1.3.2.3.3.2.2 (a / antibody~e.2 :mod (s / secondary~e.1) :ARG1-of (b / biotinylate-01) :source~e.4 (c / company :name (n / name :op1 "Vector"~e.5 :op2 "Labs"~e.6) :location (c2 / city :wiki "Burlingame,_California" :name (n2 / name :op1 "Burlingame"~e.8) :location (s2 / state :wiki "California" :name (n3 / name :op1 "California"~e.10) :location (c3 / country :wiki "United_States" :name (n4 / name :op1 "United"~e.12 :op2 "States"~e.13)))))) # ::id pmid_1563_0473.249 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dilutions were according to the manufacturer 's recommendation . # ::alignments 0-1.1 2-1 3-1 5-1.2.1 5-1.2.1.1 5-1.2.1.1.r 6-1.2.1.r 7-1.2 (c / conform-01~e.2,3 :ARG1 (d / dilute-01~e.0) :ARG2 (r / recommend-01~e.7 :ARG0~e.6 (c2 / company~e.5 :ARG0-of~e.5 (m / manufacture-01~e.5)) :ARG4 d)) # ::id pmid_1563_0473.250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Snail antibody was generated in Guinea pigs by inoculating them with the N @-@ terminal sequence of murine Snail fused to GST ( Covance , Princeton , New Jersey , United States ) . # ::alignments 1-1.1.1.1.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1.1 7-1.2.1.2 8-1.3.r 9-1.3 10-1.3.1 11-1.3.2.r 13-1.3.2.1.1 15-1.3.2.1.2 20-1.3.2.2.1.1 22-1.3.2.3 23-1.3.2.3.1.r 24-1.3.2.3.1.1.1 26-1.3.2.3.1.2.2.1 28-1.3.2.3.1.2.3.2.1 30-1.3.2.3.1.2.3.3.2.1 31-1.3.2.3.1.2.3.3.2.2 33-1.3.2.3.1.2.3.3.3.2.1 34-1.3.2.3.1.2.3.3.3.2.2 (g / generate-01~e.4 :ARG1 (a / antibody~e.2 :ARG0-of (c4 / counter-01 :ARG1 (p / protein :name (n / name :op1 "Snail"~e.1)))) :location~e.5 (o2 / organism :name (n2 / name :op1 "Guinea"~e.6 :op2 "pig"~e.7)) :manner~e.8 (i / inoculate-01~e.9 :ARG1 o2~e.10 :ARG3~e.11 (p2 / protein-segment :name (n3 / name :op1 "N"~e.13 :op2 "terminus"~e.15) :part-of (p3 / protein :name (n4 / name :op1 "Snail"~e.20) :mod (m / mouse)) :ARG1-of (f / fuse-01~e.22 :ARG3~e.23 (e / enzyme :name (n6 / name :op1 "GST"~e.24) :source (c / company :wiki "Covance" :name (n7 / name :op1 "Covance"~e.26) :location (c2 / city :wiki "Princeton,_New_Jersey" :name (n8 / name :op1 "Princeton"~e.28) :location (s / state :wiki "New_Jersey" :name (n9 / name :op1 "New"~e.30 :op2 "Jersey"~e.31) :location (c3 / country :wiki "United_States" :name (n10 / name :op1 "United"~e.33 :op2 "States"~e.34)))))))))) # ::id pmid_1563_0473.251 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recombinant human TGF-β2 was purchased from R&D ( Minneapolis , Minnesota , United States ) . # ::alignments 0-1.1.3 1-1.1.2 2-1.1.1.1 4-1 5-1.2.r 6-1.2.1.1 8-1.2.2.2.1 10-1.2.2.3.2.1 12-1.2.2.3.3.2.1 13-1.2.2.3.3.2.2 (p / purchase-01~e.4 :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2"~e.2) :mod (h / human~e.1) :ARG3-of (r / recombine-01~e.0)) :ARG2~e.5 (c / company :name (n2 / name :op1 "R&D"~e.6) :location (c2 / city :wiki "Minneapolis" :name (n3 / name :op1 "Minneapolis"~e.8) :location (s / state :wiki "Minnesota" :name (n4 / name :op1 "Minnesota"~e.10) :location (c3 / country :wiki "United_States" :name (n5 / name :op1 "United"~e.12 :op2 "States"~e.13)))))) # ::id pmid_1563_0473.252 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Heat inactivated TGF-β2 was generated by heating the recombinant protein at 100 °C for 10 min . # ::alignments 0-1.1.2.2 0-1.2 1-1.1.2.1 2-1.1.1.1 4-1 6-1.2 8-1.2.1.1 9-1.2.1 10-1.2.2.r 11-1.2.2.1 12-1.2.2.2 13-1.2.3.r 14-1.2.3.1 15-1.2.3.2 (g / generate-01~e.4 :ARG1 (p / protein :name (n / name :op1 "TGF-β2"~e.2) :ARG1-of (a / activate-01 :polarity -~e.1 :ARG0 (h / heat-01~e.0))) :manner (h2 / heat-01~e.0,6 :ARG1 (p2 / protein~e.9 :ARG3-of (r / recombine-01~e.8)) :destination~e.10 (t / temperature-quantity :quant 100~e.11 :scale (c / celsius~e.12)) :duration~e.13 (t2 / temporal-quantity :quant 10~e.14 :unit (m / minute~e.15)))) # ::id pmid_1563_0473.253 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mice # ::alignments 0-1 (m / mouse~e.0) # ::id pmid_1563_0473.254 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The K14 @-@ Snail Tg mouse was generated by digesting the pcDNA3 @-@ mm Snail @ -@ HA plasmid ( G . de Herreros , Universitat Pompeu , Fabra , Barcelona , Spain ) with BamHI and NotI and subcloned into the K14 vector [ @ 49 @ ] . # ::alignments 2-1.1.1.2.2.1 4-1.1.1.2.1.1 6-1.1.1.1 7-1.1.1 9-1.1 10-1.1.2.r 11-1.1.2 13-1.1.2.1.2.1.1.1 15-1.1.2.1.2.1.1.1 17-1.1.2.1.2.2 20-1.1.2.1.2.3.1.1 21-1.1.2.1.1.1 25-1.1.2.1.3.1.2 26-1.1.2.1.3.1.3 28-1.1.2.1.3.2.2.1 29-1.1.2.1.3.2.2.2 31-1.1.2.1.3.2.2.3 33-1.1.2.1.3.2.3.2.1 35-1.1.2.1.3.2.3.3.2.1 37-1.1.2.2.r 38-1.1.2.2.1.1.1 39-1.1.2.2 40-1.1.2.2.2.1.1 41-1.1.2.2 45-1.1.1.2.2.1 46-1.2.2 49-1.3.1.1.1 (a / and :op1 (g / generate-01~e.9 :ARG1 (m / mouse~e.7 :mod (t / transgenic~e.6) :mod (p2 / protein :name (n2 / name :op1 "Snail"~e.4) :ARG1-of (m5 / mutate-01 :value "K14"~e.2,45))) :manner~e.10 (d / digest-01~e.11 :ARG1 (s / small-molecule :name (n3 / name :op1 "plasmid"~e.21) :mod (m3 / macro-molecular-complex :part (s3 / small-molecule :name (n4 / name :op1 "pcDNA3-mm"~e.13,15)) :part p2~e.17 :part (p3 / protein :name (n5 / name :op1 "HA"~e.20))) :source (p4 / person :name (n6 / name :op1 "G." :op2 "de"~e.25 :op3 "Herreros"~e.26) :location (u / university :wiki "Pompeu_Fabra_University" :name (n7 / name :op1 "Universitat"~e.28 :op2 "Pompeu"~e.29 :op3 "Fabra"~e.31) :location (c / city :wiki "Barcelona" :name (n8 / name :op1 "Barcelona"~e.33) :location (c2 / country :wiki "Spain" :name (n9 / name :op1 "Spain"~e.35)))))) :instrument~e.37 (a2 / and~e.39,41 :op1 (e / enzyme :name (n10 / name :op1 "BamHI"~e.38)) :op2 (e2 / enzyme :name (n11 / name :op1 "NotI"~e.40))))) :op2 (s2 / subclone-01 :ARG1 m :ARG3 (v / vector~e.46 :mod (p / protein))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 49~e.49)))) # ::id pmid_1563_0473.255 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The linearized construct was injected into the nucleus of embryos from CD1 mice . # ::alignments 1-1.1.1 2-1.1 4-1 5-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1 10-1.2.1.1.r 11-1.2.1.1.1.1 12-1.2.1.1.1.2 (i / inject-01~e.4 :ARG1 (c / construct~e.2 :ARG1-of (l / linearize-00~e.1)) :ARG2~e.5 (n / nucleus~e.7 :part-of~e.8 (e / embryo~e.9 :source~e.10 (o / organism :name (n2 / name :op1 "CD1"~e.11 :op2 "mouse"~e.12))))) # ::id pmid_1563_0473.256 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The K14 @-@ Smad 2 Tg mouse was reported in Ito et al. , 2001 . # ::alignments 2-1.2.2.1.1.1 7-1.2.1 8-1.2 10-1 12-1.1.1.1.1.1 13-1.1.1 14-1.1.1.2.1 16-1.1.2.1 (r / report-01~e.10 :ARG0 (p / publication-91 :ARG0 (a / and~e.13 :op1 (p2 / person :name (n / name :op1 "Ito"~e.12)) :op2 (p3 / person :mod (o / other~e.14))) :time (d / date-entity :year 2001~e.16)) :ARG1 (m / mouse~e.8 :mod (t / transgenic~e.7) :mod (m2 / macro-molecular-complex :part (p4 / protein :name (n2 / name :op1 "K14"~e.2)) :part (p5 / protein :name (n3 / name :op1 "SMAD2"))))) # ::id pmid_1563_0473.257 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The TGF-β2 knockout ( KO ) mouse was described in [ @ 34 @ ] . # ::alignments 2-1.2.1.1.1.1 4-1.2.1 8-1.2 10-1 14-1.1.1.1 (d / describe-01~e.10 :ARG0 (p / publication-91 :ARG1-of (c / cite-01 :ARG2 34~e.14)) :ARG1 (m / mouse~e.8 :location-of (k / knock-out-03~e.4 :ARG1 (g / gene :name (n / name :op1 "TGF-β2"~e.2))))) # ::id pmid_1563_0473.258 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The shh KO mouse [ @ 38 @ ] and TOPGal mouse [ @ 20 @ ] have previously been reported . # ::alignments 2-1.1.1.1.1.1.1 5-1.1.1 8-1.1.1.2.1.1.1 11-1.1 12-1.1.2.1.1 13-1.1.2 16-1.1.2.2.1.1.1 20-1.2 22-1 (r / report-01~e.22 :ARG1 (a / and~e.11 :op1 (m / mouse~e.5 :location-of (k / knock-out-03 :ARG1 (g / gene :name (n / name :op1 "shh"~e.2))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 38~e.8)))) :op2 (m4 / mouse~e.13 :name (n3 / name :op1 "TOPGal"~e.12) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 20~e.16))))) :time (p3 / previous~e.20)) # ::id pmid_1563_0473.259 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot and immunoprecipitation # ::alignments 0-1.1 1-1.1 2-1 3-1.2 (a / and~e.2 :op1 (i2 / immunoblot-01~e.0,1) :op2 (i / immunoprecipitate-01~e.3)) # ::id pmid_1563_0473.260 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein extracts from primary keratinocytes were generated either by lysing cells in lysis buffer ( 1 % NP @-@ 40 , 1 % sodium deoxycholate , 20 mM Tris @-@ Cl [ pH 7.4 ] , 140 mM NaCl containing 1 mM sodium vanadate , 2 mM phenylmethylsulfonyl fluoride , and protease inhibitors ) or directly in Laemmli bβuffer and boiled . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1 4-1.1.1.2 6-1.1 10-1.1.2.1.1 13-1.1.2.1.2 13-1.1.2.2.2.1.2 15-1.1.2.1.2.2.1.2.1 16-1.1.2.1.2.2.1.2 17-1.1.2.1.2.2.1.1.1 19-1.1.2.1.2.2.1.1.1 21-1.1.2.1.2.2.1.2.1 22-1.1.2.1.2.2.1.2 23-1.1.2.1.2.2.2.1.1 24-1.1.2.1.2.2.2.1.2 26-1.1.2.1.2.2.3.2.1 27-1.1.2.1.2.2.3.2.2 28-1.1.2.1.2.2.3.1.1 30-1.1.2.1.2.2.3.1.1 32-1.1.2.1.2.2.3.3.2 33-1.1.2.1.2.2.3.3.1 36-1.1.2.1.2.2.4.2.1 37-1.1.2.1.2.2.4.2.2 38-1.1.2.1.2.2.4.1.1 39-1.1.2.1.2.2.4.3 40-1.1.2.1.2.2.1.2.1 40-1.1.2.1.2.2.4.3.1.1.2.1 41-1.1.2.1.2.2.3.2.2 42-1.1.2.1.2.2.4.3.1.1.1.1 43-1.1.2.1.2.2.4.3.1.1.1.2 45-1.1.2.1.2.2.4.3.1.2.2.1 46-1.1.2.1.2.2.4.3.1.2.2.2 47-1.1.2.1.2.2.4.3.1.2.1.1 48-1.1.2.1.2.2.4.3.1.2.1.2 50-1.1.2.1.2.2.4.3.1 51-1.1.2.1.2.2.4.3.1.3.1.1.1.1 52-1.1.2.1.2.2.4.3.1.3 52-1.1.2.1.2.2.4.3.1.3.1 52-1.1.2.1.2.2.4.3.1.3.1.r 54-1.1.2 55-1.1.2.2.3 57-1.1.2.2.2.1.1 59-1 60-1.2 (a / and~e.59 :op1 (g / generate-01~e.6 :ARG1 (e / extract-01~e.1 :ARG1 (p / protein~e.0) :ARG2~e.2 (k / keratinocyte~e.4 :mod (p2 / primary~e.3))) :ARG2 (o / or~e.54 :op1 (l / lyse-01 :ARG1 (c / cell~e.10) :location (b / buffer~e.13 :ARG2-of (l2 / lyse-01) :consist-of (a2 / and :op1 (s / small-molecule :name (n / name :op1 "NP-40"~e.17,19) :quant (p3 / percentage-entity~e.16,22 :value 1~e.15,21,40)) :op2 (s2 / small-molecule :name (n2 / name :op1 "sodium"~e.23 :op2 "deoxycholate"~e.24) :quant p3) :op3 (s5 / small-molecule :name (n3 / name :op1 "Tris-Cl"~e.28,30) :quant (c2 / concentration-quantity :quant 20~e.26 :unit (m4 / millimolar~e.27,41)) :mod (a3 / acidity-quantity :quant 7.4~e.33 :scale (p4 / ph~e.32))) :op4 (s3 / small-molecule :name (n4 / name :op1 "NaCl"~e.38) :quant (c3 / concentration-quantity :quant 140~e.36 :unit m4~e.37) :ARG0-of (c4 / contain-01~e.39 :ARG1 (a4 / and~e.50 :op1 (s6 / small-molecule :name (n5 / name :op1 "sodium"~e.42 :op2 "vanadate"~e.43) :quant (c5 / concentration-quantity :quant 1~e.40 :unit m4)) :op2 (s4 / small-molecule :name (n6 / name :op1 "phenylmethylsulfonyl"~e.47 :op2 "fluoride"~e.48) :quant (c6 / concentration-quantity :quant 2~e.45 :unit m4~e.46)) :op3 (m8 / molecular-physical-entity~e.52 :ARG0-of~e.52 (i / inhibit-01~e.52 :ARG1 (e2 / enzyme :name (n7 / name :op1 "protease"~e.51)))))))))) :op2 (l3 / lyse-01 :ARG1 c :location (t / thing :name (n8 / name :op1 "Laemmli"~e.57 :op2 "buffer"~e.13)) :ARG1-of (d / direct-02~e.55)))) :op2 (b2 / boil-01~e.60 :ARG1 e)) # ::id pmid_1563_0473.261 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For skin tissue : Frozen tissue was pulverized in a liquid nitrogen @-@ cooled Gevebesmascher and the powder scraped into a chilled microcentrifuge tube . # ::alignments 1-1.3.1 2-1.3 4-1.1.1.1 5-1.1.1 7-1.1 8-1.1.2.r 10-1.1.2.3 11-1.1.2.2.1 13-1.1.2.2 14-1.1.2.1.1 15-1 17-1.2.1 18-1.2 19-1.2.2.r 21-1.2.2.2 22-1.2.2.1 23-1.2.2 (a / and~e.15 :op1 (p / pulverize-01~e.7 :ARG1 (t / tissue~e.5 :ARG1-of (f / freeze-01~e.4)) :location~e.8 (s3 / small-molecule :name (n / name :op1 "Gevebesmascher"~e.14) :ARG1-of (c / cool-01~e.13 :instrument (n2 / nitrogen~e.11)) :mod (l / liquid~e.10))) :op2 (s / scrape-02~e.18 :ARG1 (p2 / powder~e.17) :ARG3~e.19 (t2 / tube~e.23 :mod (m2 / microcentrifuge~e.22) :ARG1-of (c2 / chill-01~e.21))) :topic (t3 / tissue~e.2 :part-of (s2 / skin~e.1))) # ::id pmid_1563_0473.262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RIPA buffer ( 1 % Triton X @-@ 100 in PBS with 10 mM EDTA , 150 mN NaCl , 1 % sodium deoxycholate , and 0.1 % SDS ) and protease inhibitors or Laemmli buffer was added . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 3-1.1.1.2.1.1.2.1 4-1.1.1.2.1.1.2 5-1.1.1.2.1.1.1.1 6-1.1.1.2.1.1.1.2 8-1.1.1.2.1.1.1.2 10-1.1.1.2.1.2.1.1 11-1.1.1.2.1.3.r 12-1.1.1.2.1.3.2.1 13-1.1.1.2.1.3.2.2 14-1.1.1.2.1.3.1.1 16-1.1.1.2.2.2.1 18-1.1.1.2.2.1.1 20-1.1.1.2.3.2 21-1.1.1.2.3.2 22-1.1.1.2.3.1.1 23-1.1.1.2.3.1.2 25-1.1.1.2 26-1.1.1.2.4.2.1 27-1.1.1.2.4.2 28-1.1.1.2.4.1.1 30-1.1 30-1.1.1.2 31-1.1.2.1.1.1.1.1 32-1.1.2.1 32-1.1.2.1.1 32-1.1.2.1.1.r 33-1.1.2 34-1.1.2.2.1.1 35-1.1.2.2.1.2 37-1 (a / add-02~e.37 :ARG1 (a2 / and~e.30 :op1 (t / thing :name (n / name :op1 "RIPA"~e.0 :op2 "buffer"~e.1) :consist-of (a3 / and~e.25,30 :op1 (i / include-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "Triton"~e.5 :op2 "X-100"~e.6,8) :quant (p / percentage-entity~e.4 :value 1~e.3)) :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PBS"~e.10)) :accompanier~e.11 (s4 / small-molecule :name (n4 / name :op1 "EDTA"~e.14) :quant (c / concentration-quantity :quant 10~e.12 :unit (m5 / millimolar~e.13)))) :op2 (m6 / molecular-physical-entity :name (n5 / name :op1 "NaCl"~e.18) :quant (c2 / concentration-quantity :quant 150~e.16 :unit m5)) :op3 (s3 / small-molecule :name (n6 / name :op1 "sodium"~e.22 :op2 "deoxycholate"~e.23) :quant p~e.20,21) :op4 (s2 / small-molecule :name (n7 / name :op1 "SDS"~e.28) :quant (p2 / percentage-entity~e.27 :value 0.1~e.26)))) :op2 (o / or~e.33 :op1 (m9 / molecular-physical-entity~e.32 :ARG0-of~e.32 (i2 / inhibit-01~e.32 :ARG1 (e / enzyme :name (n8 / name :op1 "protease"~e.31)))) :op2 (t2 / thing :name (n9 / name :op1 "Laemmli"~e.34 :op2 "buffer"~e.35))))) # ::id pmid_1563_0473.263 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cell suspension was sonicated three times for 15 s and centrifuged at 14,000 rpm at 4 °C . # ::alignments 1-1.1.2.1 2-1.1.2 5-1.1.1 6-1.1.1.r 6-1.1.3 8-1.1.3.1 10-1 11-1.2 12-1.2.3.r 13-1.2.3.1 15-1.2.2.r 16-1.2.2.1 17-1.2.2.2 (a / and~e.10 :op1 (s / sonicate-00 :frequency~e.6 3~e.5 :ARG1 (s2 / suspend-02~e.2 :ARG1 (c / cell~e.1)) :duration (t / temporal-quantity~e.6 :quant 15~e.8 :unit (s3 / second))) :op2 (c2 / centrifuge-00~e.11 :ARG1 s2 :ARG2~e.15 (t2 / temperature-quantity :quant 4~e.16 :scale (c3 / celsius~e.17)) :frequency~e.12 (s4 / speed-quantity :quant 14000~e.13 :unit (r / rotation-per-minute)))) # ::id pmid_1563_0473.264 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The supernatant was separated from the pellet and used in the experiments . # ::alignments 1-1.1.1 3-1.1 4-1.1.2.r 6-1.1.2 7-1 8-1.2 9-1.2.2.r 11-1.2.2 (a / and~e.7 :op1 (s / separate-01~e.3 :ARG1 (s2 / supernatant~e.1) :ARG2~e.4 (p / pellet~e.6)) :op2 (u / use-01~e.8 :ARG1 s2 :ARG2~e.9 (e / experiment-01~e.11))) # ::id pmid_1563_0473.265 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Extracts subjected to immunoprecipitation were precleared with Protein G Sepharose ( Amersham , Piscataway , New York , United States ) and incubated with antibody with rocking overnight at 4 °C . # ::alignments 0-1.1.1 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1 7-1.1.2.1.1 8-1.1.2.1.2 9-1.1.2.1.3 11-1.1.2.2.1.1 13-1.1.2.2.2.1.1 15-1.1.2.2.2.2.2.1 16-1.1.2.2.2.2.2.2 18-1.1.2.2.2.2.3.2.1 19-1.1.2.2.2.2.3.2.2 21-1 22-1.2 23-1.2.2.r 24-1.2.2.1 26-1.2.2.2 27-1.2.3 28-1.2.4.r 29-1.2.4.1 30-1.2.4.2 (a / and~e.21 :op1 (p / preclear-00 :ARG1 (e / extract-01~e.0 :ARG1-of (s2 / subject-01~e.1 :ARG2~e.2 (i / immunoprecipitate-01~e.3))) :ARG2 (p3 / product :name (n6 / name :op1 "Protein"~e.7 :op2 "G"~e.8 :op3 "Sepharose"~e.9) :source (c3 / company :name (n5 / name :op1 "Amersham"~e.11) :location (c5 / city :name (n4 / name :op1 "Piscataway"~e.13) :location (s / state :wiki "New_York" :name (n2 / name :op1 "New"~e.15 :op2 "York"~e.16) :location (c2 / country :wiki "United_States" :name (n3 / name :op1 "United"~e.18 :op2 "States"~e.19))))))) :op2 (i2 / incubate-01~e.22 :ARG1 e :ARG2~e.23 (a2 / and :op1 (a3 / antibody~e.24) :op2 (r / rock-01~e.26 :ARG1 e)) :time (o / overnight~e.27) :mod~e.28 (t / temperature-quantity :quant 4~e.29 :scale (c4 / celsius~e.30)))) # ::id pmid_1563_0473.266 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein G Sepharose was added and samples were incubated for 1 h at 4 °C with rocking . # ::alignments 0-1.1.1.2.1 1-1.1.1.2.2 2-1.1.1.2.3 4-1.1 5-1 6-1.2.1 6-1.2.1.1 6-1.2.1.1.r 8-1.2 9-1.2.3.r 10-1.2.3.1 11-1.2.3.2 12-1.2.4.r 13-1.2.4.1 14-1.2.4.2 15-1.2.2.r 16-1.2.2 (a / and~e.5 :op1 (a2 / add-02~e.4 :ARG1 (p2 / product :wiki - :name (n2 / name :op1 "Protein"~e.0 :op2 "G"~e.1 :op3 "Sepharose"~e.2))) :op2 (i / incubate-01~e.8 :ARG1 (t3 / thing~e.6 :ARG1-of~e.6 (s / sample-01~e.6)) :ARG2~e.15 (r / rock-01~e.16 :ARG1 t3) :duration~e.9 (t / temporal-quantity :quant 1~e.10 :unit (h / hour~e.11)) :mod~e.12 (t2 / temperature-quantity :quant 4~e.13 :scale (c / celsius~e.14)))) # ::id pmid_1563_0473.267 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Samples were washed three times for 5 min each in lysis buffer , and the Protein G Sepharose @-@ antibody @-@ antigen pellet was resuspended in Laemmli buffer and boiled for 10 min . # ::alignments 0-1.1.2 0-1.1.2.2 0-1.1.2.2.r 2-1.1 3-1.1.1 4-1.1.1.r 4-1.1.4 4-1.2.2.2 6-1.1.4.1 7-1.1.4.2 7-1.2.2.2.2 8-1.1.2.1 11-1.1.3 13-1 15-1.2.1.1.3.1.1 16-1.2.1.1.3.1.2 17-1.2.1.1.3.1.3 19-1.2.1.1.2 21-1.2.1.1.1 22-1.2.1.1 26-1.2.1.2.1.1 27-1.2.1.2 28-1.2 29-1.2.2 31-1.2.2.2.1 32-1.1.4.2 (a / and~e.13 :op1 (w / wash-01~e.2 :frequency~e.4 3~e.3 :ARG1 (t3 / thing~e.0 :mod (e / each~e.8) :ARG1-of~e.0 (s / sample-01~e.0)) :ARG2 (b / buffer~e.11 :ARG2-of (l / lyse-01)) :duration (t / temporal-quantity~e.4 :quant 5~e.6 :unit (m / minute~e.7,32))) :op2 (a4 / and~e.28 :op1 (s2 / suspend-02 :ARG1 (p / pellet~e.22 :mod (a2 / antigen~e.21) :mod (a3 / antibody~e.19) :mod (p3 / product :name (n4 / name :op1 "Protein"~e.15 :op2 "G"~e.16 :op3 "Sepharose"~e.17))) :location (b2 / buffer~e.27 :name (n2 / name :op1 "Laemmli"~e.26)) :mod (a5 / again)) :op2 (b3 / boil-01~e.29 :ARG1 p :duration (t2 / temporal-quantity~e.4 :quant 10~e.31 :unit (m2 / minute~e.7))))) # ::id pmid_1563_0473.268 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Samples were run on SDS @-@ PAGE and transferred to nitrocellulose membrane ( Schleicher and Schuell Bioscience , Keene , New Hampshire , United States ) . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 2-1.1 3-1.1.2.r 4-1.1.2.1.1 6-1.1.2.1.1 7-1 8-1.2 9-1.2.2.r 10-1.2.2.1 11-1.2.2 13-1.2.2.2.1.1 14-1.2.2.2.1.2 15-1.2.2.2.1.3 16-1.2.2.2.1.4 18-1.2.2.2.2.1.1 20-1.2.2.2.2.2.2.1 21-1.2.2.2.2.2.2.2 23-1.2.2.2.2.2.3.2.1 24-1.2.2.2.2.2.3.2.2 (a / and~e.7 :op1 (r / run-01~e.2 :ARG1 (t2 / thing~e.0 :ARG1-of~e.0 (s2 / sample-01~e.0)) :manner~e.3 (t3 / thing :name (n7 / name :op1 "SDS-PAGE"~e.4,6))) :op2 (t / transfer-01~e.8 :ARG1 t2 :ARG2~e.9 (m / membrane~e.11 :mod (n4 / nitrocellulose~e.10) :source (c2 / company :name (n5 / name :op1 "Schleicher"~e.13 :op2 "and"~e.14 :op3 "Schuell"~e.15 :op4 "Bioscience"~e.16) :location (c4 / city :name (n6 / name :op1 "Keene"~e.18) :location (s / state :wiki "New_Hampshire" :name (n / name :op1 "New"~e.20 :op2 "Hampshire"~e.21) :location (c / country :wiki "United_States" :name (n2 / name :op1 "United"~e.23 :op2 "States"~e.24)))))))) # ::id pmid_1563_0473.269 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot signals were developed using the enhanced chemiluminescence kit from Amersham # ::alignments 0-1.1.1 1-1.1.1 2-1.1 4-1 5-1.2 7-1.2.1.1 8-1.2.1.2 9-1.2.1 10-1.2.1.3.r 11-1.2.1.3.2.1 (d / develop-02~e.4 :ARG1 (s / signal-07~e.2 :ARG0 (i / immunoblot-01~e.0,1)) :ARG2-of (u / use-01~e.5 :ARG1 (k / kit~e.9 :ARG1-of (e / enhance-01~e.7) :mod (c / chemiluminescence~e.8) :source~e.10 (c2 / company :wiki "Amersham_plc" :name (n2 / name :op1 "Amersham"~e.11))))) # ::id pmid_1563_0473.270 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell culture # ::alignments 0-1.1 1-1 (c / culture~e.1 :mod (c2 / cell~e.0)) # ::id pmid_1563_0473.271 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Primary keratinocytes were culture in low @-@ calcium medium as previously described [ @ 4 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.1 7-1.2.1.1 8-1.2 9-1.3.2.r 10-1.3.2 11-1.3 14-1.3.1.1.1 (c / culture-01~e.3 :ARG1 (k / keratinocyte~e.1 :mod (p / primary~e.0)) :location~e.4 (m / medium~e.8 :ARG1-of (l / low-04~e.5 :ARG2 (c2 / calcium~e.7))) :ARG1-of (d2 / describe-01~e.11 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 4~e.14)) :time~e.9 (p2 / previous~e.10))) # ::id pmid_1563_0473.272 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transient transfections were carried out with FuGENE6 reagent ( Roche , Indianapolis , Indiana , United States ) according to the manufacturer 's protocol . # ::alignments 0-1.1.1 3-1 4-1 5-1.3.r 6-1.3.1.1 7-1.3 9-1.3.2.1.1 11-1.3.2.2.2.1 13-1.3.2.2.3.2.1 15-1.3.2.2.3.3.2.1 16-1.3.2.2.3.3.2.2 18-1.2 19-1.2 21-1.2.1.1 22-1.2.1.1.r 23-1.2.1 (c4 / carry-out-03~e.3,4 :ARG1 (t / transfect-01 :ARG1-of (t2 / transient-02~e.0)) :ARG1-of (s2 / say-01~e.18,19 :ARG0 (p / protocol~e.23 :poss~e.22 c5~e.21)) :instrument~e.5 (r / reagent~e.7 :name (n5 / name :op1 "FuGENE6"~e.6) :source (c5 / company :name (n4 / name :op1 "Roche"~e.9) :location (c / city :wiki "Indianapolis" :name (n / name :op1 "Indianapolis"~e.11) :location (s / state :wiki "Indiana" :name (n2 / name :op1 "Indiana"~e.13) :location (c2 / country :wiki "United_States" :name (n3 / name :op1 "United"~e.15 :op2 "States"~e.16)))) :ARG0-of (m / manufacture-01)))) # ::id pmid_1563_0473.273 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Measurement of β-galactosidase or luciferase levels in promoter activity studies were carried out with the Galacto @-@ Lite assay kit ( TROPIX , Bedford , Massachusetts , United States ) and the Dual luciferase ( Promega , Madison , Wisconsin , United States ) , respectively . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1 5-1.1.1.1 5-1.1.1.2 6-1.1.2.r 7-1.1.2.1.1 7-1.1.2.1.1.1 7-1.1.2.1.1.1.r 8-1.1.2.1 9-1.1.2 11-1 12-1 13-1.3.r 15-1.3.1.1.1 17-1.3.1.1.1 18-1.3.1.2.1 19-1.3.1.2 21-1.3.1.3.1.1 23-1.3.1.3.2.1.1 25-1.3.1.3.2.2.2.1 27-1.3.1.3.2.2.3.2.1 28-1.3.1.3.2.2.3.2.2 30-1.3 32-1.3.2.1.1 33-1.3.2.1.2 35-1.3.2.2.1.1 37-1.3.2.2.2.1.1 39-1.3.2.2.2.2.2.1 41-1.3.2.2.2.2.3 42-1.3.1.3.2.2 42-1.3.2.2.2.2 45-1.2 (c6 / carry-out-03~e.11,12 :ARG1 (m / measure-01~e.0 :ARG1~e.1 (o / or~e.3 :op1 (l3 / level~e.5 :quant-of (e / enzyme :name (n4 / name :op1 "β-galactosidase"~e.2))) :op2 (l / level~e.5 :quant-of (l2 / luciferase~e.4))) :subevent-of~e.6 (s3 / study-01~e.9 :ARG1 (a2 / activity-06~e.8 :ARG0 (m2 / molecular-physical-entity~e.7 :ARG0-of~e.7 (p / promote-01~e.7))))) :mod (r / respective~e.45) :instrument~e.13 (a3 / and~e.30 :op1 (p3 / product :name (n7 / name :op1 "Galacto-Lite"~e.15,17) :mod (k2 / kit~e.19 :instrument-of (a / assay-01~e.18)) :source (c3 / company :name (n5 / name :op1 "TROPIX"~e.21) :location (c4 / city :name (n6 / name :op1 "Bedford"~e.23) :location (s / state~e.42 :wiki "Massachusetts" :name (n / name :op1 "Massachusetts"~e.25) :location (c / country :wiki "United_States" :name (n2 / name :op1 "United"~e.27 :op2 "States"~e.28)))))) :op2 (p2 / product :name (n8 / name :op1 "Dual"~e.32 :op2 "luciferase"~e.33) :source (c2 / company :name (n9 / name :op1 "Promega"~e.35) :location (c5 / city :name (n10 / name :op1 "Madison"~e.37) :location (s2 / state~e.42 :wiki "Wisconsin" :name (n3 / name :op1 "Wisconsin"~e.39) :location c~e.41)))))) # ::id pmid_1563_0473.274 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Runella luciferase was cotransfected into cells to correct for transfection efficiency . # ::alignments 0-1.2.1.1 1-1.2 3-1 4-1.1.r 5-1.1 7-1.3 8-1.3.1.r 9-1.3.1.1 10-1.3.1 (c / cotransfect-01~e.3 :ARG1~e.4 (c2 / cell~e.5) :ARG2 (l / luciferase~e.1 :name (n / name :op1 "Runella"~e.0)) :ARG0-of (c3 / correct-01~e.7 :ARG1~e.8 (e / efficient-01~e.10 :ARG1 (t / transfect-01~e.9)))) # ::id pmid_1563_0473.275 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Experiments were done in triplicate and repeated at least three times . # ::alignments 0-1 3-1.1.r 4-1.1 6-1.2 7-1.2.2 8-1.2.2 9-1.2.1 10-1.2.1.r (e2 / experiment-01~e.0 :quant~e.3 (t / triplicate~e.4) :ARG1-of (r / repeat-01~e.6 :frequency~e.10 3~e.9 :mod (a / at-least~e.7,8))) # ::id pmid_1563_0473.276 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Measurements were done on a luminometer ( MGM Instruments , Hamden , Connecticut , United States ) . # ::alignments 0-1 3-1.1.r 5-1.1 7-1.1.1.1.1 8-1.1.1.1.2 10-1.1.1.2.1.1 12-1.1.1.2.2.2.1 14-1.1.1.2.2.3.2.1 15-1.1.1.2.2.3.2.2 (m2 / measure-01~e.0 :instrument~e.3 (l / luminometer~e.5 :source (c2 / company :name (n3 / name :op1 "MGM"~e.7 :op2 "Instruments"~e.8) :location (c3 / city :name (n4 / name :op1 "Hamden"~e.10) :location (s / state :wiki "Connecticut" :name (n / name :op1 "Connecticut"~e.12) :location (c / country :wiki "United_States" :name (n2 / name :op1 "United"~e.14 :op2 "States"~e.15))))))) # ::id pmid_1563_0473.277 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For experiments measuring phosphorylation of MAPK , keratinocytes were serum starved for 3 h prior to harvesting of cells by incubation in medium lacking serum . # ::alignments 1-1.2.1 2-1.2 3-1.2.2 4-1.2.2.1.r 5-1.2.2.1.1.1 7-1.1.1 9-1.1.2 10-1.1 11-1.1.3.r 12-1.1.3.1 13-1.1.3.2 14-1.1.4 15-1.1.4.1.r 16-1.1.4.1 17-1.1.4.1.1.r 18-1.1.4.1.1 19-1.1.5.r 20-1.1.5 21-1.1.5.2.r 22-1.1.5.2 23-1.1.5.2.1 24-1.1.5.2.1.1 (h / have-purpose-91 :ARG1 (s / starve-01~e.10 :ARG1 (k / keratinocyte~e.7) :ARG2 (s2 / serum~e.9) :duration~e.11 (t / temporal-quantity :quant 3~e.12 :unit (h2 / hour~e.13)) :time (p3 / prior~e.14 :op1~e.15 (h3 / harvest-01~e.16 :ARG1~e.17 (c / cell~e.18))) :manner~e.19 (i / incubate-01~e.20 :ARG1 k :location~e.21 (m / medium~e.22 :ARG0-of (l / lack-01~e.23 :ARG1 s2~e.24)))) :ARG2 (m2 / measure-01~e.2 :ARG0 (e / experiment-01~e.1) :ARG1 (p / phosphorylate-01~e.3 :ARG1~e.4 (e2 / enzyme :name (n / name :op1 "MAPK"~e.5))))) # ::id pmid_1563_0473.278 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of cells with Wnt @- and noggin @-@ conditioned medium was previously described [ @ 4 @ ] . # ::alignments 0-1 1-1.1.r 2-1.1 3-1.2.r 4-1.2.1.1.1.1.1 6-1.2.1.1 7-1.2.1.1.2.1.1 9-1.2.1 10-1.2 12-1.3.2 13-1.3 16-1.3.1.1.1 (t / treat-04~e.0 :ARG1~e.1 (c / cell~e.2) :ARG2~e.3 (m / medium~e.10 :ARG1-of (c2 / condition-01~e.9 :ARG2 (a / and~e.6 :op1 (p / protein :name (n / name :op1 "Wnt"~e.4)) :op2 (p2 / protein :name (n2 / name :op1 "noggin"~e.7))))) :ARG1-of (d2 / describe-01~e.13 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 4~e.16)) :time (p3 / previous~e.12))) # ::id pmid_1563_0473.279 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constructs # ::alignments 0-1 (c / construct-01~e.0) # ::id pmid_1563_0473.280 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The 2.2 @-@ kb murine Snail promoter was generated by PCR using a forward primer with an XbaI linker sequence , 5′-TCTAGAATTGTTTGCTGCTGTATGGTCTTC @-@ 3′ , along with a reverse primer with a BglII linker sequence , 5′-AGATCTGTTGGCCAGAGCGACCTAG @-@ GTAG @-@ 3′ , and mouse genomic DNA as a template . # ::alignments 1-1.2.1.1.2.1 6-1.2.1.1.1.1 8-1.2 8-1.2.1 8-1.2.1.r 10-1 11-1.1.r 12-1.1 12-1.1.1 12-1.1.1.r 12-1.1.2 12-1.1.2.r 13-1.3 15-1.3.1.1.2 16-1.3.1.1 17-1.3.1.1.3.r 19-1.3.1.1.3.1.1 25-1.3.1.1.1 28-1.3.1.r 30-1.3.1.2.2 31-1.3.1.2 32-1.3.1.2.3.r 34-1.3.1.2.3.1.1 42-1.3.1.2.1 44-1.3.1 45-1.3.1.3.1.4 46-1.3.1.3.1.3 47-1.3.1.3.1.2.1 50-1.3.1.3 (g / generate-01~e.10 :ARG0~e.11 (r2 / react-01~e.12 :ARG0~e.12 (p / polymerase~e.12) :ARG1-of~e.12 (c / chain-01~e.12)) :ARG1 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.8 (p2 / promote-01~e.8 :ARG1 (g2 / gene :name (n2 / name :op1 "Snail"~e.6) :quant (d / distance-quantity :quant 2.2~e.1 :unit (k / kilo-base-pair)) :mod (o / organism :name (n7 / name :op1 "Murinae"))))) :ARG2-of (u / use-01~e.13 :ARG1~e.28 (a / and~e.44 :op1 (p3 / primer~e.16 :value "5′-TCTAGAATTGTTTGCTGCTGTATGGTCTTC-3′"~e.25 :ARG1-of (f / forward-01~e.15) :part~e.17 (p5 / protein-segment :name (n8 / name :op1 "XbaI"~e.19) :ARG0-of (l / link-01))) :op2 (p4 / primer~e.31 :value "5′-AGATCTGTTGGCCAGAGCGACCTAGGTAG-3′"~e.42 :ARG1-of (r / reverse-01~e.30) :part~e.32 (p6 / protein-segment :name (n3 / name :op1 "BglII"~e.34) :ARG0-of (l2 / link-01))) :op3 (t / template~e.50 :mod (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.47) :mod (g3 / genome~e.46) :mod (m4 / mouse~e.45)))))) # ::id pmid_1563_0473.281 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PCR product was purified with the Gel Extraction Kit ( Qiagen , Valencia , California , United States ) and ligated into pCRII @-@ TOPO TA vector ( Invitrogen , Carlsbad , California , United States ) . # ::alignments 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 1-1.1.1.2 1-1.1.1.2.r 2-1.2.1 4-1.1 5-1.1.2.r 7-1.1.2.1.1 8-1.1.2.1.2 9-1.1.2.1.3 11-1.1.2.2.1.1 13-1.1.2.2.2.1.1 15-1.1.2.2.2.2.2.1 17-1.1.2.2.2.2.3.2.1 18-1.1.2.2.2.2.3.2.2 20-1 21-1.2 22-1.2.2.r 23-1.2.2.1.1 25-1.2.2.1.1 26-1.2.2.1.2 27-1.2.2.2 29-1.2.2.3.1.1 31-1.2.2.3.2.1.1 33-1.2.2.3.2.2 34-1.2.2.3.2.2 35-1.2.2.3.2.2 36-1.2.2.3.2.2 (a / and~e.20 :op1 (p / purify-01~e.4 :ARG1 (r / react-01~e.1 :ARG0~e.1 (p5 / polymerase~e.1) :ARG1-of~e.1 (c6 / chain-01~e.1)) :instrument~e.5 (p3 / product :name (n4 / name :op1 "Gel"~e.7 :op2 "Extraction"~e.8 :op3 "Kit"~e.9) :source (c2 / company :name (n5 / name :op1 "Qiagen"~e.11) :location (c3 / city :name (n6 / name :op1 "Valencia"~e.13) :location (s / state :wiki "California" :name (n / name :op1 "California"~e.15) :location (c / country :wiki "United_States" :name (n2 / name :op1 "United"~e.17 :op2 "States"~e.18))))))) :op2 (l / ligate-01~e.21 :ARG1 (p2 / product~e.2) :ARG2~e.22 (p4 / product :name (n7 / name :op1 "pCRII-TOPO"~e.23,25 :op2 "TA"~e.26) :mod (v / vector~e.27) :source (c4 / company :name (n8 / name :op1 "Invitrogen"~e.29) :location (c5 / city :name (n9 / name :op1 "Carlsbad"~e.31) :location s~e.33,34,35,36))))) # ::id pmid_1563_0473.282 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The promoter was verified by sequencing and digested with XbaI and BglII and subcloned into the pβ-gal BASIC vector ( BD Biosciences Clontech , Palo Alto , California , United States ) . # ::alignments 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 3-1.1 4-1.1.2.r 5-1.1.2 6-1 7-1.2 8-1.2.2.r 9-1.2.2.1.1.1 11-1.2.2.2.1.1 12-1 16-1.3.2.1.1 17-1.3.2.1.2 18-1.3.2.2 20-1.3.2.3.1.1 21-1.3.2.3.1.2 22-1.3.2.3.1.3 24-1.3.2.3.2.1.1 25-1.3.2.3.2.1.2 27-1.3.2.3.2.2.2.1 29-1.3.2.3.2.2.3.2.1 30-1.3.2.3.2.2.3.2.2 (a / and~e.6,12 :op1 (v / verify-01~e.3 :ARG1 (m / molecular-physical-entity~e.1 :ARG0-of~e.1 (p / promote-01~e.1)) :manner~e.4 (s2 / sequence-01~e.5 :ARG1 m)) :op2 (d / digest-01~e.7 :ARG1 m :instrument~e.8 (a2 / and :op1 (p2 / protein-segment :name (n3 / name :op1 "XbaI"~e.9)) :op2 (p3 / protein-segment :name (n4 / name :op1 "BglII"~e.11)))) :op3 (s3 / subclone-01 :ARG1 m :ARG3 (p4 / product :name (n5 / name :op1 "pβ-gal"~e.16 :op2 "BASIC"~e.17) :mod (v2 / vector~e.18) :source (c2 / company :name (n6 / name :op1 "BD"~e.20 :op2 "Biosciences"~e.21 :op3 "Clontech"~e.22) :location (c3 / city :name (n7 / name :op1 "Palo"~e.24 :op2 "Alto"~e.25) :location (s / state :wiki "California" :name (n / name :op1 "California"~e.27) :location (c / country :wiki "United_States" :name (n2 / name :op1 "United"~e.29 :op2 "States"~e.30)))))))) # ::id pmid_1563_0473.283 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The point mutations in the SMAD binding element was generated with the Quik @-@ Change Kit ( Stratagene , La Jolla , California , United States ) using the forward primer 5′-GGGCGGGCTTAGGTGTTTTCATTTACTCTTGAGGAAAAGCTTGGC @-@ 3′ and the reverse primer 5′-GCTTTT @-@ CCTCAAGAGTAAATGAAAACACCTAAGCCCGCCCTGCCC @-@ 3′ . # ::alignments 1-1.1.1 2-1.1 3-1.1.2.r 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1.2 9-1 10-1.2.r 12-1.2.1.1 14-1.2.1.1 15-1.2.1.2 17-1.2.2.1.1 19-1.2.2.2.1.1 20-1.2.2.2.1.2 22-1.2.2.2.2.2.1 24-1.2.2.2.2.3.2.1 25-1.2.2.2.2.3.2.2 27-1.3 29-1.3.1.1.2 30-1.3.1.1 33-1.3.1.1.1 34-1.3.1 36-1.3.1.2.2 37-1.3.1.2 42-1.3.1.2.1 (g / generate-01~e.9 :ARG1 (m / mutate-01~e.2 :mod (p / point~e.1) :location~e.3 (e / element~e.7 :ARG0-of (b / bind-01~e.6 :ARG1 (p2 / protein :name (n3 / name :op1 "SMAD"~e.5))))) :instrument~e.10 (p3 / product :name (n4 / name :op1 "Quik-Change"~e.12,14 :op2 "Kit"~e.15) :source (c2 / company :name (n5 / name :op1 "Stratagene"~e.17) :location (c3 / city :name (n6 / name :op1 "La"~e.19 :op2 "Jolla"~e.20) :location (s / state :wiki "California" :name (n / name :op1 "California"~e.22) :location (c / country :wiki "United_States" :name (n2 / name :op1 "United"~e.24 :op2 "States"~e.25)))))) :ARG2-of (u / use-01~e.27 :ARG1 (a / and~e.34 :op1 (p4 / primer~e.30 :value "5′-GGGCGGGCTTAGGTGTTTTCATTTACTCTTGAGGAAAAGCTTGGC-3′"~e.33 :ARG1-of (f / forward-01~e.29)) :op2 (p5 / primer~e.37 :value "5′-GCTTTTCCTCAAGAGTAAATGAAAACACCTAAGCCCGCCCTGCCC-3′"~e.42 :ARG1-of (r / reverse-01~e.36))))) # ::id pmid_1563_0473.284 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The probes for the Snail in situ hybridization were generated against the 3′ UTR by PCR using the forward primer 5′-ACCTTCTCCCGCATGTCCTTGCTCC @-@ 3′ and the reverse primer 5′-CTGCTGAGGCATGGTTACAGCTGG @-@ 3′ , and genomic DNA as a template . # ::alignments 1-1.2 5-1.2.1.1.1.1 7-1.2.1.2 8-1.2.1.2 9-1.2.1 11-1 12-1.3.r 14-1.4.1.1.1 16-1.1.r 17-1.1 17-1.1.1 17-1.1.1.r 17-1.1.2 17-1.1.2.r 18-1.4 20-1.4.1.1.2 21-1.4.1.1 24-1.4.1.1.1 25-1.4.1 27-1.4.1.2.2 28-1.4.1.2 31-1.4.1.2.1 33-1.4.1 34-1.4.1.3.1.3 35-1.4.1.3.1.2.1 38-1.4.1.3 (g4 / generate-01~e.11 :ARG0~e.16 (r3 / react-01~e.17 :ARG0~e.17 (p5 / polymerase~e.17) :ARG1-of~e.17 (c / chain-01~e.17)) :ARG1 (p / probe-01~e.1 :ARG2 (h / hybridize-01~e.9 :ARG1 (g2 / gene :name (n / name :op1 "Snail"~e.5)) :manner (i2 / in-situ~e.7,8))) :prep-against~e.12 (r2 / region :value 3 :wiki "Three_prime_untranslated_region" :ARG1-of (t2 / translate-02 :polarity -) :ARG0-of (t3 / trail-01)) :ARG2-of (u / use-01~e.18 :ARG1 (a / and~e.25,33 :op1 (p3 / primer~e.21 :value "5′-ACCTTCTCCCGCATGTCCTTGCTCC-3′"~e.14,24 :ARG1-of (f / forward-01~e.20)) :op2 (p4 / primer~e.28 :value "5′-CTGCTGAGGCATGGTTACAGCTGG-3′"~e.31 :ARG1-of (r / reverse-01~e.27)) :op3 (t / template~e.38 :mod (n3 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.35) :mod (g3 / genomic~e.34)))))) # ::id pmid_1563_0473.285 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PCR product was gel purified and ligated into pCRII @-@ TOPO TA vector . # ::alignments 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 1-1.1.1.2 1-1.1.1.2.r 2-1.2.1 4-1.1.2 5-1.1 6-1 7-1.2 8-1.2.2.r 9-1.2.2.1.1 11-1.2.2.1.1 12-1.2.2.1.2 13-1.2.2.2 (a / and~e.6 :op1 (p / purify-01~e.5 :ARG1 (r / react-01~e.1 :ARG0~e.1 (p4 / polymerase~e.1) :ARG1-of~e.1 (c / chain-01~e.1)) :mod (g / gel~e.4)) :op2 (l / ligate-01~e.7 :ARG1 (p2 / product~e.2) :ARG3~e.8 (p3 / product :name (n2 / name :op1 "pCRII-TOPO"~e.9,11 :op2 "TA"~e.12) :mod (v / vector~e.13)))) # ::id pmid_1563_0473.286 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The pre @-@ LIM domain of Ajuba was generated essentially as described [ @ 9 @ ] , but was fused to GFP by subcloning from the pEGFP @-@ N1 20 vector ( BD Biosciences Clontech ) # ::alignments 1-1.1.1.1.1 3-1.1.1.1.1 6-1.1.1.2.1.1 8-1.1 9-1.1.2.2 11-1.1.2 14-1.1.2.1.1.1 18-1 20-1.2 21-1.2.3.r 22-1.2.3.1.1 25-1.2.1.1.2.r 27-1.2.1.1.1.1 29-1.2.1.1.1.1 30-1.2.1.1.1.2 31-1.2.1.1 33-1.2.1.1.2.1.1 34-1.2.1.1.2.1.2 35-1.2.1.1.2.1.3 (c3 / contrast-01~e.18 :ARG1 (g / generate-01~e.8 :ARG1 (p5 / protein-segment :name (n6 / name :op1 "pre-LIM"~e.1,3) :part-of (p / protein :name (n / name :op1 "Ajuba"~e.6))) :ARG1-of (d3 / describe-01~e.11 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 9~e.14)) :mod (e / essential~e.9))) :ARG2 (f / fuse-01~e.20 :ARG0 (s / subclone-01 :ARG2 (v2 / vector~e.31 :name (n5 / name :op1 "pEGFP-N1"~e.27,29 :op2 20~e.30) :source~e.25 (c2 / company :name (n4 / name :op1 "BD"~e.33 :op2 "Biosciences"~e.34 :op3 "Clontech"~e.35)))) :ARG1 p5 :ARG2~e.21 (p3 / protein :name (n2 / name :op1 "GFP"~e.22)))) # ::id pmid_1563_0473.287 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In situ hybridization # ::alignments 0-1.1 1-1.1 2-1 (h / hybridize-01~e.2 :manner (i / in-situ~e.0,1)) # ::id pmid_1563_0473.288 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The pCRII @-@ TOPO TA vector containing a region of the 3′ UTR of Snail was used as a template to generate digoxigenin @-@ labeled sense and antisense riboprobes ( Roche ) . # ::alignments 1-1.1.1.1 3-1.1.1.1 4-1.1.1.2 5-1.1.2 6-1.1.3 8-1.1.3.1.1.3 11-1.1.3.1.1.1 15-1.1.3.1.2.1.1 18-1 18-1.3.r 19-1.2.r 21-1.2 23-1.3 24-1.3.1.1.2.1 26-1.3.1.1.2 27-1.3.1.1.1 28-1.3.1 29-1.3.1.2.2 32-1.3.1.3.1.1 (u / use-01~e.18 :ARG1 (p / product :name (n / name :op1 "pCRII-TOPO"~e.1,3 :op2 "TA"~e.4) :mod (v / vector~e.5) :ARG0-of (c / contain-01~e.6 :ARG1 (d2 / dna-sequence :name (n4 / name :op1 "3′"~e.11 :op2 "untranslated" :op3 "region"~e.8) :part-of (g / gene :name (n2 / name :op1 "Snail"~e.15))))) :ARG2~e.19 (t / template~e.21) :purpose~e.18 (g2 / generate-01~e.23 :ARG1 (a / and~e.28 :op1 (r2 / riboprobe :mod (s / sense~e.27) :ARG1-of (l / label-01~e.26 :ARG2 (d / digoxigenin~e.24))) :op2 (r3 / riboprobe :ARG1-of l :mod (a3 / antisense~e.29)) :source (c2 / company :name (n3 / name :op1 "Roche"~e.32))))) # ::id pmid_1563_0473.289 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The respective probes were obtained by XhoI and BamH1 digestions . # ::alignments 1-1.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1 9-1.2 (o / obtain-01~e.4 :ARG1 (p / probe-01~e.2 :mod (r / respective~e.1)) :ARG2~e.5 (d / digest-01~e.9 :ARG1 (a / and~e.7 :op1 (p2 / product :name (n / name :op1 "XhoI"~e.6)) :op2 (p3 / product :name (n2 / name :op1 "BamH1"~e.8))))) # ::id pmid_1563_0473.290 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In situ hybridizations were performed on 10-μm thick sections of E17.5 mouse embryos . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 4-1 7-1.2.3 8-1.2 11-1.2.2.1 12-1.2.2 (p / perform-02~e.4 :ARG1 (h / hybridize-01~e.2 :manner (i / in-situ~e.0,1)) :location (s / section-01~e.8 :ARG2 (a / area-quantity :quant 10 :unit (m4 / micrometer)) :ARG3 (e / embryo~e.12 :mod (m3 / mouse~e.11) :age (t2 / temporal-quantity :quant 17.5 :unit (d / day))) :ARG1-of (t / thick-03~e.7))) # ::id pmid_1563_0473.291 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The sections were fixed with 4 % PFA for 10 min at room temperature , prehybridized at room temperature for 4.5 h , hybridized with the probe ( 2 μg/ml ) at 55 °C for 12 @–@ 14 h , blocked with 10 % NGS , and treated with anti @-@ dig Fab @-@ AP antibody ( Roche #1093274 ) at a 1 @:@ 2,500 dilution for 3 h . # ::alignments 1-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.2.1 6-1.1.2.2 7-1.1.2.1.1 8-1.1.3.r 9-1.1.3.1 10-1.1.3.2 12-1.1.4.1 13-1.1.4 17-1.1.4.1 18-1.1.4 18-1.3.3 20-1.2.3.1 21-1.2.3.2 23-1.3 24-1.1.2.r 24-1.3.2.r 26-1.3.2 28-1.3.2.1.1 32-1.3.3.1 33-1.3.3.2 35-1.3.4.1.1 37-1.3.4.2.1 38-1.2.3.2 38-1.3.4.2.2 40-1.4 41-1.1.2.r 42-1.1.3.1 42-1.4.2.2.1 43-1.4.2.2 44-1.4.2.1.1 46-1 46-1.3.4 47-1.5 48-1.1.2.r 48-1.5.2.r 49-1.5.2.1.1 51-1.5.2.1.1 52-1.5.2.1.2 54-1.5.2.1.2 55-1.5.2 57-1.5.2.2.1.1 60-1.5.3.r 62-1.5.3.1.1 64-1.5.3.1.1 65-1.5.3 66-1.5.4.r 67-1.5.4.1 68-1.2.3.2 68-1.3.4.1.2 68-1.3.4.2.2 68-1.5.4.2 (a / and~e.46 :op1 (f / fix-02~e.3 :ARG1 (s2 / section-01~e.1) :instrument~e.4,24,41,48 (p3 / product :name (n / name :op1 "PFA"~e.7) :quant (p / percentage-entity~e.6 :value 4~e.5)) :duration~e.8 (t / temporal-quantity :quant 10~e.9,42 :unit (m / minute~e.10)) :mod (t2 / temperature~e.13,18 :mod (r / room~e.12,17))) :op2 (p4 / prehybridize-00 :ARG1 s2 :mod t2 :duration (t3 / temporal-quantity :quant 4.5~e.20 :unit (h / hour~e.21,38,68))) :op3 (h2 / hybridize-01~e.23 :ARG1 s2 :ARG2~e.24 (p5 / probe-01~e.26 :quant (c / concentration-quantity :quant 2~e.28 :unit (m2 / microgram-per-milliliter))) :manner (t4 / temperature-quantity~e.18 :quant 55~e.32 :scale (c2 / celsius~e.33)) :duration (b2 / between~e.46 :op1 (t6 / temporal-quantity :quant 12~e.35 :unit (h3 / hour~e.68)) :op2 (t7 / temporal-quantity :quant 14~e.37 :unit (h4 / hour~e.38,68)))) :op4 (b / block-01~e.40 :ARG1 s2 :ARG3 (p6 / product :name (n2 / name :op1 "NGS"~e.44) :quant (p2 / percentage-entity~e.43 :value 10~e.42))) :op5 (t8 / treat-04~e.47 :ARG1 s2 :ARG2~e.48 (a2 / antibody~e.55 :name (n3 / name :op1 "anti-dig"~e.49,51 :op2 "Fab-AP"~e.52,54) :source (c3 / company :name (n4 / name :op1 "Roche"~e.57)) :ARG1-of (d2 / describe-01 :ARG2 (s3 / string-entity :value 1093274))) :manner~e.60 (d / dilute-01~e.65 :ARG1-of (e / equal-01 :ARG2 "1/2500"~e.62,64)) :duration~e.66 (t9 / temporal-quantity :quant 3~e.67 :unit (h5 / hour~e.68)))) # ::id pmid_1563_0473.292 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The sections were incubated with NBT and BCIP until adequate signal was detected . # ::alignments 1-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2 7-1.2.2.1.1 8-1.3 9-1.3.1.1.1 10-1.3.1.1 12-1.3.1 (i / incubate-01~e.3 :ARG1 (s / section-01~e.1) :ARG2~e.4 (a / and~e.6 :op1 (p / product :name (n / name :op1 "NBT"~e.5)) :op2 (p2 / product :name (n2 / name :op1 "BCIP"~e.7))) :time (u / until~e.8 :op1 (d / detect-01~e.12 :ARG1 (s2 / signal-07~e.10 :mod (a2 / adequate~e.9))))) # ::id pmid_1563_0473.293 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunofluorescence and immunohistochemistry # ::alignments 0-1.1 1-1 2-1.2 (a / and~e.1 :op1 (i / immunofluoresce-01~e.0) :op2 (i2 / immunohistochemistry~e.2)) # ::id pmid_1563_0473.294 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tissue samples for immunofluorescence were frozen in OCT and sectioned 10 μm thick on a cryostat . # ::alignments 0-1.1.1 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1 5-1.1 8-1 9-1.2 10-1.2.2.1.1 11-1.2.2.1.2 12-1.2.2 13-1.2.3.r 15-1.2.3 (a / and~e.8 :op1 (f / freeze-01~e.5 :ARG1 (t / tissue~e.0 :ARG1-of (s2 / sample-01~e.1 :purpose~e.2 (i / immunofluoresce-01~e.3))) :instrument (t3 / thing :name (n / name :op1 "Optimal" :op2 "Cutting" :op3 "Temperature"))) :op2 (s / section-01~e.9 :ARG1 t :ARG2 (t2 / thick-03~e.12 :mod (d / distance-quantity :quant 10~e.10 :unit (m / micrometer~e.11))) :location~e.13 (c / cryostat~e.15))) # ::id pmid_1563_0473.295 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sections were fixed in 4 % paraformaldehyde for 10 min at room temperature , blocked , and stained with antibodies . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 2-1.1 3-1.1.2.r 4-1.1.2.2.1 5-1.1.2.2 6-1.1.2.1.1 7-1.1.3.r 8-1.1.3.1 9-1.1.3.2 10-1.1.4.r 11-1.1.4.1 12-1.1.4 14-1.2 16-1 17-1.3 18-1.3.2.r 19-1.3.2 (a / and~e.16 :op1 (f / fix-00~e.2 :ARG1 (t / thing~e.0 :ARG2-of~e.0 (s2 / section-01~e.0)) :ARG2~e.3 (s3 / small-molecule :name (n / name :op1 "paraformaldehyde"~e.6) :mod (p / percentage-entity~e.5 :value 4~e.4)) :duration~e.7 (t2 / temporal-quantity :quant 10~e.8 :unit (m2 / minute~e.9)) :mod~e.10 (t3 / temperature~e.12 :poss (r / room~e.11))) :op2 (b / block-01~e.14 :ARG1 t) :op2 (s / stain-01~e.17 :ARG1 t :ARG2~e.18 (a2 / antibody~e.19))) # ::id pmid_1563_0473.296 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tissue samples for immunohistochemistry were fixed in 4 % paraformaldehyde , dehydrated , and embedded in paraffin . # ::alignments 0-1.1.1 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.2.1 8-1.1.2.2 9-1.1.2.1.1 11-1.2 13-1 14-1.3 15-1.3.2.r 16-1.3.2 (a / and~e.13 :op1 (f / fix-03~e.5 :ARG1 (t / tissue~e.0 :ARG1-of (s / sample-01~e.1 :purpose~e.2 (i / immunohistochemistry~e.3))) :ARG2~e.6 (s2 / small-molecule :name (n / name :op1 "paraformaldehyde"~e.9) :mod (p / percentage-entity~e.8 :value 4~e.7))) :op2 (d / dehydrate-01~e.11 :ARG1 t) :op3 (e / embed-01~e.14 :ARG1 t :ARG2~e.15 (p2 / paraffin~e.16))) # ::id pmid_1563_0473.297 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Samples were sectioned on a microtome ( 10 μm thick ) and rehydrated prior to staining with antibody . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 2-1.1 5-1.1.2 7-1.1.1.2.1.1 8-1.1.1.2.1.2 9-1.1.1.2 11-1 13-1.3 14-1.3.1.r 15-1.3.1 16-1.1.2.r 16-1.3.1.2.r 17-1.3.1.2 (a / and~e.11 :op1 (s / section-01~e.2 :ARG1 (t2 / thing~e.0 :ARG1-of~e.0 (s2 / sample-01~e.0) :ARG1-of (t / thick-03~e.9 :mod (d / distance-quantity :quant 10~e.7 :unit (m2 / micrometer~e.8)))) :instrument~e.16 (m / microtome~e.5)) :op2 (h / hydrate-01 :ARG1 t2 :mod (a3 / again)) :time (p / prior~e.13 :op1~e.14 (s3 / stain-01~e.15 :ARG1 t2 :ARG2~e.16 (a2 / antibody~e.17)))) # ::id pmid_1563_0473.298 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Samples stained with Snail , pMAPK , pSmad2 , and cyclin D were antigen unmasked with 10 mM sodium citrate ( pH 6 ) in an Antigen Retriever 2100 ( Pickcell Laboratories , Leiden , Netherlands ) . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.2 2-1.1.2.1.r 2-1.3.r 3-1.1.2.1.1.1.1 5-1.1.2.1.2.1.1 5-1.1.2.1.2.2 9-1.1.2.1 10-1.1.2.1.4.1.1 11-1.1.2.1.4.1.2 13-1.2 14-1 15-1.3.r 16-1.3.2.1 18-1.3.1.1 19-1.3.1.2 21-1.3.3.2 22-1.3.3.1 24-1.4.r 26-1.4.1.1 27-1.4.1.2 28-1.4.1.3 30-1.4.2.1.1.1 31-1.4.2.1.1.2 33-1.4.2.1.2.1.1 35-1.4.2.1.2.2.2.1 (u / unmask-01~e.14 :ARG1 (t / thing~e.0 :ARG1-of~e.0 (s / sample-01~e.0) :ARG1-of (s2 / stain-01~e.1 :ARG2~e.2 (a / and~e.9 :op1 (p / protein :name (n / name :op1 "Snail"~e.3)) :op2 (e / enzyme :name (n2 / name :op1 "MAPK"~e.5) :ARG3-of (p2 / phosphorylate-01~e.5)) :op3 (p3 / protein :name (n3 / name :op1 "Smad2") :ARG1-of p2) :op4 (p4 / protein :name (n4 / name :op1 "cyclin"~e.10 :op2 "D"~e.11))))) :topic (a2 / antigen~e.13) :instrument~e.2,15 (s3 / small-molecule :name (n5 / name :op1 "sodium"~e.18 :op2 "citrate"~e.19) :mod (c / concentration-quantity :quant 10~e.16 :unit (m2 / micromolar)) :mod (a3 / acidity-quantity :quant 6~e.22 :scale (p6 / ph~e.21))) :location~e.24 (p5 / product :name (n6 / name :op1 "Antigen"~e.26 :op2 "Retriever"~e.27 :op3 2100~e.28) :ARG1-of (m3 / manufacture-01 :ARG0 (c2 / company :name (n7 / name :op1 "Pickcell"~e.30 :op2 "Laboratories"~e.31) :location (c3 / city :name (n8 / name :op1 "Leiden"~e.33) :location (c4 / country :wiki "Netherlands" :name (n9 / name :op1 "Netherlands"~e.35))))))) # ::id pmid_1563_0473.299 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The DAB substrate kit ( Vector Labs ) was used according to manufacturer 's instructions to develop the signal . # ::alignments 1-1.1.1.1 2-1.1.3 3-1.1 5-1.1.2.1.1.1 6-1.1.2.1.1.2 9-1 9-1.3.r 12-1.1.2 12-1.1.2.1.r 14-1.2 16-1.3 18-1.3.1 (u / use-01~e.9 :ARG1 (k2 / kit~e.3 :name (n2 / name :op1 "DAB"~e.1) :ARG1-of (m2 / manufacture-01~e.12 :ARG0~e.12 (c2 / company :name (n / name :op1 "Vector"~e.5 :op2 "Labs"~e.6))) :mod (s / substrate~e.2)) :ARG2-of (i / instruct-01~e.14 :ARG0 c2) :purpose~e.9 (d / develop-02~e.16 :ARG1 (s2 / signal-07~e.18))) # ::id pmid_1563_0473.300 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RT @-@ PCR # ::alignments 2-1 2-1.1 2-1.1.r 2-1.2 2-1.2.r (r2 / react-01~e.2 :ARG0~e.2 (p / polymerase~e.2) :ARG1-of~e.2 (c / chain-01~e.2) :mod (t / transcribe-01 :ARG1-of (r3 / reverse-01))) # ::id pmid_1563_0473.301 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RNA was extracted from keratinocytes or skin tissue with Trizol ( Invitrogen ) according to the manufacturer 's protocol . # ::alignments 0-1.1.1.1 2-1 3-1.2.r 4-1.2.1 5-1.2 6-1.2.2.1 7-1.2.2 8-1.3.r 9-1.3.1.1 11-1.3.2.1.1 13-1.4 14-1.4 16-1.4.1.1 16-1.4.1.1.1 16-1.4.1.1.1.r 17-1.4.1.1.r 18-1.4.1 (e / extract-01~e.2 :ARG1 (n / nucleic-acid :name (n4 / name :op1 "RNA"~e.0)) :ARG2~e.3 (o / or~e.5 :op1 (k / keratinocyte~e.4) :op2 (t / tissue~e.7 :part-of (s / skin~e.6))) :instrument~e.8 (s2 / small-molecule :name (n2 / name :op1 "Trizol"~e.9) :mod (c2 / company :name (n3 / name :op1 "Invitrogen"~e.11))) :ARG1-of (s4 / say-01~e.13,14 :ARG0 (p / protocol~e.18 :poss~e.17 (c / company~e.16 :ARG0-of~e.16 (m2 / manufacture-01~e.16))))) # ::id pmid_1563_0473.302 ::amr-annotator SDL-AMR-09 ::preferred # ::tok cDNA was generated using oligo @-@ dT primers and the Superscript II kit ( Invitrogen ) . # ::alignments 2-1 3-1.2 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1.1.1.2 8-1.2.1 10-1.2.1.2.1.1.1 11-1.2.1.2.1.1.2 12-1.2.1.2 14-1.2.1.3.1.1 (g / generate-01~e.2 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA") :ARG1-of (c / complement-01)) :ARG2 (u / use-01~e.3 :ARG1 (a / and~e.8 :op1 (d / dna-sequence :name (n3 / name :op1 "oligo-dT"~e.4,6 :op2 "primer"~e.7)) :op2 (k / kit~e.12 :mod (e / enzyme :name (n / name :op1 "Superscript"~e.10 :op2 "II"~e.11))) :source (c2 / company :name (n2 / name :op1 "Invitrogen"~e.14))))) # ::id pmid_1563_0473.303 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The primers used for PCR were Snail forward : 5′-CAGCTGGCCAGGCTCTCGGT @-@ 3′ ; Snail reverse : 5′-GCGAGGGCCTCCGGAGCA @-@ 3′ ; GAPDH forward 5′-CGTAGACAAAATGGTGAAGGTCGG @-@ 3′ ; and GAPDH reverse : 5′-AAGCAGTTGGTGGTGCAGGATG @-@ 3′ . # ::alignments 1-1.1.1 1-1.1.2 1-1.1.3 1-1.1.4 2-1 3-1.2.r 4-1.2 4-1.2.1 4-1.2.1.r 4-1.2.2 4-1.2.2.r 7-1.1.1.3.1.1 9-1.1.1.2 13-1.1.1.1 13-1.1.2.1 13-1.1.3.1 13-1.1.4.1 16-1.1.2.3 18-1.1.2.2 22-1.1.1.1 24-1.1.3.2.1.1 25-1.1.1.2 28-1.1.1.1 30-1.1 31-1.1.3.2.1.1 32-1.1.2.2 36-1.1.1.1 (u / use-01~e.2 :ARG1 (a / and~e.30 :op1 (p / primer~e.1 :value "5′-CAGCTGGCCAGGCTCTCGGT-3′"~e.13,22,28,36 :ARG1-of (f / forward-01~e.9,25) :part-of (g / gene :name (n2 / name :op1 "Snail"~e.7))) :op2 (p2 / primer~e.1 :value "5′-GCGAGGGCCTCCGGAGCA-3′"~e.13 :ARG1-of (r / reverse-01~e.18,32) :part-of g~e.16) :op3 (p3 / primer~e.1 :value "5′-CGTAGACAAAATGGTGAAGGTCGG-3′"~e.13 :mod (g2 / gene :name (n3 / name :op1 "GAPDH"~e.24,31)) :ARG1-of f) :op4 (p4 / primer~e.1 :value "5′-AAGCAGTTGGTGGTGCAGGATG-3′"~e.13 :ARG1-of r :part-of g2)) :ARG2~e.3 (r2 / react-01~e.4 :ARG0~e.4 (p5 / polymerase~e.4) :ARG1-of~e.4 (c / chain-01~e.4))) # ::id pmid_1563_0473.304 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 1 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 1~e.1) # ::id pmid_1563_0473.305 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Embryos were either frozen in OCT embedding compound ( A , F, and H ) or embedded in paraffin ( C , D, E , and G ) , and then sectioned ( 8 μm ) . # ::alignments 0-1.1.1.1 3-1.1.1 4-1.1.1.3.r 5-1.1.1.3.1.1 6-1.1.1.3.2 7-1.1.1.3 9-1.1.1.2.1.1.1 12-1.1.1.2.1 13-1.1.1.2.1.3.1 15-1.1 16-1.1.2 17-1.1.2.2.r 18-1.1.2.2 20-1.1.2.3.1.1.1 23-1.1.2.3.1.3.1 25-1.1.2.3.1 26-1.1.2.3.1.4.1 29-1 29-1.1.2.3.1 30-1.2.3 31-1.2 33-1.2.2.1 34-1.2.2.2 (a / and~e.29 :op1 (o / or~e.15 :op1 (f / freeze-01~e.3 :ARG1 (e2 / embryo~e.0) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.12 :op1 (f2 / figure :mod "A"~e.9) :op2 (f3 / figure :mod "F") :op3 (f4 / figure :mod "H"~e.13))) :instrument~e.4 (c3 / compound~e.7 :name (n / name :op1 "OCT"~e.5) :ARG2-of (e4 / embed-01~e.6))) :op2 (e / embed-01~e.16 :ARG1 e2 :ARG2~e.17 (p / paraffin~e.18) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.25,29 :op1 (f5 / figure :mod "C"~e.20) :op2 (f6 / figure :mod "D") :op3 (f7 / figure :mod "E"~e.23) :op4 (f8 / figure :mod "G"~e.26))))) :op2 (s / section-01~e.31 :ARG1 e2 :ARG2 (d3 / distance-quantity :quant 8~e.33 :unit (m / micrometer~e.34)) :time (t / then~e.30))) # ::id pmid_1563_0473.306 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) In situ hybridizations with Snail sense or antisense cRNA probes . # ::alignments 1-1.3.1.1 3-1.2 4-1.2 5-1 8-1.1.1.2.1.1 10-1.1.1.3 11-1.1 12-1.1.2.3 13-1.1.1.1.1.1 14-1.1.1 14-1.1.2 (h / hybridize-01~e.5 :ARG2 (o / or~e.11 :op1 (p / probe-01~e.14 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "cRNA"~e.13)) :ARG2 (g / gene :name (n2 / name :op1 "Snail"~e.8)) :mod (s / sense~e.10)) :op2 (p3 / probe-01~e.14 :ARG1 n3 :ARG2 g :mod (a / antisense~e.12))) :manner (i / in-situ~e.3,4) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"~e.1))) # ::id pmid_1563_0473.307 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Black dotted lines demarcate the basement membrane that separates the epidermis ( epi ) from dermis ( der ) . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 3-1 5-1.2.1 6-1.2 8-1.2.2 10-1.2.2.1 12-1.2.2.1.1.1.1 14-1.2.2.2.r 15-1.2.2.2 17-1.2.2.2.1.1.1 (d / demarcate-01~e.3 :ARG0 (l / line~e.2 :ARG1-of (b / black-04~e.0) :ARG1-of (d2 / dot-01~e.1)) :ARG1 (m / membrane~e.6 :mod (b2 / basement~e.5) :ARG0-of (s / separate-01~e.8 :ARG1 (e / epidermis~e.10 :ARG1-of (d5 / describe-01 :ARG2 (s2 / string-entity :value "epi"~e.12))) :ARG2~e.14 (d3 / dermis~e.15 :ARG1-of (d6 / describe-01 :ARG2 (s3 / string-entity :value "der"~e.17)))))) # ::id pmid_1563_0473.308 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Arrows point to Snail RNA expression , restricted to the hair bud stage of follicle morphogenesis . # ::alignments 0-1.1 1-1 4-1.2.1.2.1.1 6-1.2.1.1.1 7-1.2 9-1.2.2 10-1.2.2.1.r 12-1.2.2.1.1.1 13-1.2.2.1.1 14-1.2.2.1 15-1.2.2.1.2.r 16-1.2.2.1.2.1 17-1.2.2.1.2 (p / point-01~e.1 :ARG0 (a / arrow~e.0) :ARG1 (e / express-03~e.7 :ARG2 (n3 / nucleic-acid :name (n / name :op1 "RNA"~e.6) :mod (g / gene :name (n2 / name :op1 "Snail"~e.4))) :ARG1-of (r2 / restrict-01~e.9 :ARG2~e.10 (s / stage~e.14 :mod (b / bud~e.13 :mod (h / hair~e.12)) :subevent-of~e.15 (m / morphogenesis~e.17 :mod (f / follicle~e.16)))))) # ::id pmid_1563_0473.309 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It was not seen in later hair germ or peg stages . # ::alignments 0-1.2 2-1.1 2-1.1.r 3-1 4-1.3.r 5-1.3.1.2 5-1.3.1.2.1 5-1.3.1.2.1.r 6-1.3.1.1 7-1.3.1 8-1.3 9-1.3.2.1 10-1.3.2 (s / see-01~e.3 :polarity~e.2 -~e.2 :ARG1 (i / it~e.0) :topic~e.4 (o / or~e.8 :op1 (g / germ~e.7 :mod (h / hair~e.6) :time (l / late~e.5 :degree~e.5 (m / more~e.5))) :op2 (s2 / stage~e.10 :mod (p / peg~e.9) :time l))) # ::id pmid_1563_0473.310 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Expression of Snail protein coincides with hair development . # ::alignments 1-1.3.1.1 3-1.1 4-1.1.1.r 5-1.1.1.1.1 6-1.1.1 7-1 8-1.2.r 9-1.2.1 10-1.2 (c / coincide-01~e.7 :ARG1 (e / express-03~e.3 :ARG2~e.4 (p / protein~e.6 :name (n / name :op1 "Snail"~e.5))) :ARG2~e.8 (d / develop-01~e.10 :ARG2 (h / hair~e.9)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "B"~e.1))) # ::id pmid_1563_0473.311 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein extracts were prepared from keratinocytes transfected with empty expression vector ( K14 ) , containing the K14 promoter or with the vector driving HA @-@ tagged Snail ( K14 @- @ Snail ) ; or from whole skin from E13.5 to P5 animals , including newborn ( nb ) . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.1 6-1.2.1.1 7-1.2.1.1.1.r 8-1.2.1.1.1.1.2 9-1.2.1.1.1.1.1 10-1.2.1.1.1.1 12-1.2.1.1.1.1.3.1.1.1 15-1.2.1.1.1.1.4 17-1.2.1.1.1.1.4.1.1.1 18-1.2.1.1.1.1.4.1 18-1.2.1.1.1.1.4.1.1 18-1.2.1.1.1.1.4.1.1.r 19-1.2.1.1.1 22-1.2.1.1.1.2 23-1.2.1.1.1.2.1 24-1.2.1.1.1.2.1.1.2.1.1.1 26-1.2.1.1.1.2.1.1.2 28-1.2.1.1.1.2.1.1.1.1 28-1.2.1.1.1.2.2.1.1.1 31-1.2.1.1.1.2.2.1.2.1 34-1.2.1.1.1.2.1.1.1.1 34-1.2.1.1.1.2.2.1.1.1 38-1.2 38-1.2.2.2 40-1.2.2.1 41-1.2.2 46-1.2.2.2.2 46-1.2.2.2.2.1.1 48-1.2.2.2.2.1 (p / prepare-01~e.3 :ARG1 (e / extract-01~e.1 :ARG1 (p2 / protein~e.0)) :ARG2~e.4 (o / or~e.38 :op1 (k / keratinocyte~e.5 :ARG1-of (t / transfect-01~e.6 :ARG2~e.7 (o3 / or~e.19 :op1 (v / vector~e.10 :mod (e2 / express-03~e.9) :ARG1-of (e3 / empty-02~e.8) :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n / name :op1 "K14"~e.12))) :ARG0-of (c / contain-01~e.15 :ARG1 (m4 / molecular-physical-entity~e.18 :ARG0-of~e.18 (p8 / promote-01~e.18 :ARG1 p3~e.17)))) :op2 (v2 / vector~e.22 :ARG0-of (d / drive-02~e.23 :ARG1 (p5 / protein :name (n2 / name :op1 "Snail"~e.28,34) :ARG1-of (t2 / tag-01~e.26 :ARG2 (p6 / protein :name (n3 / name :op1 "HA"~e.24))))) :ARG1-of (m2 / mean-01 :ARG2 (g / gene :name (n4 / name :op1 "Snail"~e.28,34) :ARG1-of (m5 / mutate-01 :value "K14"~e.31))))))) :op2 (s / skin~e.41 :mod (w / whole~e.40) :part-of (o2 / or~e.38 :op1 (e4 / embryo :age (a4 / at-least :op1 (t3 / temporal-quantity :quant 13.5 :unit (d3 / day)))) :op2 (a / animal~e.46 :ARG2-of (i / include-91~e.48 :ARG1 (a2 / animal~e.46 :ARG1-of (b / bear-02 :time (n5 / new-01)))) :age (a5 / at-most :op1 (t4 / temporal-quantity :quant 5 :unit (d4 / day)))))))) # ::id pmid_1563_0473.312 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Equal amounts of proteins were then resolved by SDS @-@ PAGE through 12 % gels and subjected to Western blotting using either an affinity @-@ purified Snail polyclonal antiserum , which we generated , or anti @-@ tubulin ( loading control ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1 2-1.1.1.1.r 3-1.1.1 5-1.1.3 6-1.1 7-1.1.2.r 8-1.1.2.1.1 10-1.1.2.1.1 12-1.1.2.2.1.1 13-1.1.2.2.1 14-1.1.2.2 15-1 16-1.2 17-1.2.2.r 18-1.2.2 19-1.2.2 23-1.2.2.1.1.3.1 25-1.2.2.1.1.3 26-1.2.2.1.1.1.1.1.1 27-1.2.2.1.1.2 31-1.2.2.1.1.4.1 32-1.2.2.1.1.4 34-1.2.2.1 35-1.2.2.1.1.1 35-1.2.2.1.2 35-1.2.2.1.2.1 35-1.2.2.1.2.1.r 37-1.2.2.1.2.1.1.1.1 39-1.2.2.1.2.2.1 40-1.2.2.1.2.2 (a / and~e.15 :op1 (r / resolve-03~e.6 :ARG1 (p / protein~e.3 :quant~e.2 (a2 / amount~e.1 :ARG1-of (e / equal-01~e.0))) :ARG3~e.7 (t2 / thing :name (n / name :op1 "SDS-PAGE"~e.8,10) :instrument (g / gel~e.14 :mod (p2 / percentage-entity~e.13 :value 12~e.12))) :time (t / then~e.5)) :op2 (s / subject-01~e.16 :ARG1 p :ARG2~e.17 (i / immunoblot-01~e.18,19 :ARG3 (o / or~e.34 :op1 (s2 / serum :ARG0-of (c / counter-01~e.35 :ARG1 (p3 / protein :name (n3 / name :op1 "Snail"~e.26))) :mod (p4 / polyclonal~e.27) :ARG1-of (p5 / purify-01~e.25 :ARG2 (a4 / affinity~e.23)) :ARG1-of (g2 / generate-01~e.32 :ARG0 (w / we~e.31))) :op2 (m / molecular-physical-entity~e.35 :ARG0-of~e.35 (c2 / counter-01~e.35 :ARG1 (p6 / protein :name (n4 / name :op1 "tubulin"~e.37))) :ARG0-of (c3 / control-01~e.40 :ARG1 (l / load-01~e.39))))))) # ::id pmid_1563_0473.313 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C @–@ E ) Immunohistochemistry shows expression of Snail protein in the nuclei of cells within the hair and skin . # ::alignments 1-1.3.1.1.1 3-1.3.1.3.1 5-1.1 6-1 7-1.2 8-1.2.1.r 9-1.2.1.1.1 10-1.2.1 11-1.2.2.r 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1 18-1.2.2.1.1.1 19-1.2.2.1.1 20-1.2.2.1.1.2 (s / show-01~e.6 :ARG0 (i / immunohistochemistry~e.5) :ARG1 (e / express-03~e.7 :ARG2~e.8 (p / protein~e.10 :name (n / name :op1 "Snail"~e.9)) :ARG3~e.11 (n2 / nucleus~e.13 :part-of~e.14 (c / cell~e.15 :part-of (a / and~e.19 :op1 (h / hair~e.18) :op2 (s2 / skin~e.20))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "C"~e.1) :op2 (f2 / figure :mod "D") :op3 (f3 / figure :mod "E"~e.3)))) # ::id pmid_1563_0473.314 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) E13.5 skin with a single layered epidermis ( epi ) shows no Snail expression . # ::alignments 1-1.3.1.1 4-1.1 5-1.1.1.r 7-1.1.1.1.1 8-1.1.1.1 9-1.1.1 13-1 14-1.2.1 14-1.2.1.r 15-1.2.2.1.1 16-1.2 (s / show-01~e.13 :ARG0 (s2 / skin~e.4 :part~e.5 (e2 / epidermis~e.9 :mod (l / layer~e.8 :ARG1-of (s3 / single-02~e.7))) :time (d2 / day :mod 13.5 :mod (e3 / embryo))) :ARG1 (e / express-03~e.16 :polarity~e.14 -~e.14 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.15))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"~e.1))) # ::id pmid_1563_0473.315 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D ) The first morphological sign that cells have adopted a hair follicle fate is a cluster of cells called a placode in E16.5 skin . # ::alignments 1-1.5.1.1 4-1.3 4-1.3.1 4-1.3.1.r 5-1.4 6-1 7-1.2.r 8-1.2.1 10-1.2 12-1.2.2.1.1 13-1.2.2.1 14-1.2.2 17-1.1 18-1.1.1.r 19-1.1.1 20-1.1.2 22-1.1.2.1 25-1.1.3 (s / signal-07~e.6 :ARG0 (c / cluster-01~e.17 :ARG1~e.18 (c2 / cell~e.19) :ARG1-of (c3 / call-01~e.20 :ARG2 (p / placode~e.22)) :location (s2 / skin~e.25 :part-of (e / embryo :age (t / temporal-quantity :quant 16.5 :unit (d2 / day))))) :ARG1~e.7 (a / adopt-01~e.10 :ARG0 c2~e.8 :ARG1 (f / fate~e.14 :poss (f2 / follicle~e.13 :mod (h / hair~e.12)))) :ord (o / ordinal-entity~e.4 :value~e.4 1~e.4) :mod (m / morphological~e.5) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "D"~e.1))) # ::id pmid_1563_0473.316 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Snail is not expressed at this stage of development . # ::alignments 0-1.2.1.1 2-1.1 2-1.1.r 3-1 4-1.3.r 5-1.3.1 6-1.3 7-1.3.2.r 8-1.3.2 (e / express-03~e.3 :polarity~e.2 -~e.2 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.0)) :time~e.4 (s / stage~e.6 :mod (t / this~e.5) :subevent-of~e.7 (d / develop-01~e.8))) # ::id pmid_1563_0473.317 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( E ) Snail is expressed in the hair bud of E17.5 skin but not in later stages of development such as the germ or peg . # ::alignments 1-1.4.1.1 3-1.1.1.1 5-1 5-1.3.1 6-1.2.r 8-1.2.1 9-1.2 12-1.2.2 13-1.3 14-1.3.1.1 14-1.3.1.1.r 15-1.3.1.3.r 16-1.3.1.3.1 16-1.3.1.3.1.1 16-1.3.1.3.1.1.r 17-1.3.1.3 18-1.3.1.3.2.r 19-1.3.1.3.2 20-1.3.1.3.3.r 21-1.3.1.3.3.r 23-1.3.1.3.3.1 24-1.3.1.3.3 25-1.3.1.3.3.2 (e / express-03~e.5 :ARG2 (p / protein :name (n / name :op1 "Snail"~e.3)) :ARG3~e.6 (b / bud~e.9 :mod (h / hair~e.8) :part-of (s / skin~e.12 :part-of (e4 / embryo :age (t / temporal-quantity :quant 17.5 :unit (d4 / day))))) :ARG1-of (c / contrast-01~e.13 :ARG2 (e2 / express-03~e.5 :polarity~e.14 -~e.14 :ARG2 p :ARG3~e.15 (s2 / stage~e.17 :time (l / late~e.16 :degree~e.16 (m / more~e.16)) :subevent-of~e.18 (d / develop-01~e.19) :example~e.20,21 (o2 / or~e.24 :op1 (g / germ~e.23) :op2 (p2 / peg~e.25))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "E"~e.1))) # ::id pmid_1563_0473.318 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( F ) Immunofluorescence with anti @-@ Ki67 ( green ) identifies the proliferating cells of the skin , restricted to the basal layer of the epidermis and developing hair follicles . # ::alignments 1-1.3.1.1 3-1.1 5-1.1.1.1 7-1.1.1.1.1.1.1 9-1.1.1.2 11-1 13-1.2.2 14-1.2 15-1.2.1.r 17-1.2.1 19-1.2.3 20-1.2.3.1.r 22-1.2.3.1.1 23-1.2.3.1 24-1.2.3.1.2.r 26-1.2.3.1.2.1 27-1.2.3.1.2 28-1.2.3.1.2.2.2 29-1.2.3.1.2.2.1 30-1.2.3.1.2.2 (i / identify-01~e.11 :ARG0 (i2 / immunofluoresce-01~e.3 :ARG2 (a / antibody :ARG0-of (c / counter-01~e.5 :ARG1 (p / protein :name (n / name :op1 "Ki67"~e.7))) :ARG1-of (g / green-02~e.9))) :ARG1 (c2 / cell~e.14 :part-of~e.15 (s / skin~e.17) :ARG0-of (p2 / proliferate-01~e.13) :ARG1-of (r / restrict-01~e.19 :ARG2~e.20 (l / layer~e.23 :mod (b / basal~e.22) :part-of~e.24 (a2 / and~e.27 :op1 (e / epidermis~e.26) :op2 (f / follicle~e.30 :mod (h / hair~e.29) :ARG2-of (d / develop-01~e.28)))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "F"~e.1))) # ::id pmid_1563_0473.319 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anti-β4 int labeling reveals the presence of the hemidesmosomal integrin β4 , restricted to the base of cells adhering to the underlying basement membrane . # ::alignments 2-1.1 3-1 5-1.2 9-1.1.1.1.1.1.2 9-1.2.1.1.2 10-1.1.1.1.1.1.1 10-1.2.1.1.1 12-1.2.1.3 13-1.2.1.3.1.r 15-1.2.1.3.1 16-1.2.1.3.1.1.r 17-1.2.1.3.1.1 18-1.2.1.3.1.1.1 19-1.2.1.3.1.1.1.1.r 21-1.2.1.3.1.1.1.1.2 22-1.2.1.3.1.1.1.1.1 23-1.2.1.3.1.1.1.1 (r / reveal-01~e.3 :ARG0 (l / label-01~e.2 :ARG0 (a2 / antibody :ARG0-of (c / counter-01 :ARG1 (p2 / protein :name (n / name :op1 "β4"~e.10 :op2 "integrin"~e.9))))) :ARG1 (p3 / present-02~e.5 :ARG1 (p / protein :name (n2 / name :op1 "β4"~e.10 :op2 "integrin"~e.9) :mod (h / hemidesmosome) :ARG1-of (r2 / restrict-01~e.12 :ARG2~e.13 (b2 / base~e.15 :part-of~e.16 (c2 / cell~e.17 :ARG1-of (a / adhere-01~e.18 :ARG2~e.19 (m3 / membrane~e.23 :mod (b3 / basement~e.22) :ARG0-of (u / underlie-01~e.21))))))))) # ::id pmid_1563_0473.320 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The white dotted line marks the outermost surface of the skin . # ::alignments 1-1.1.1 2-1.1.2 3-1.1 4-1 7-1.2 8-1.2.1.r 10-1.2.1 (m / mark-01~e.4 :ARG0 (l / line~e.3 :ARG1-of (w / white-03~e.1) :ARG1-of (d / dot-01~e.2)) :ARG1 (s / surface~e.7 :part-of~e.8 (s2 / skin~e.10 :mod (o / outer :degree (m2 / most))))) # ::id pmid_1563_0473.321 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( G ) Immunohistochemistry with pMAPK marks a subset of proliferating cells within the epidermis and hair bud . # ::alignments 1-1.3.1.1 3-1.1 4-1.1.1.r 5-1.1.1.1.1 5-1.1.1.2 6-1 8-1.2 10-1.2.1.1.1 11-1.2.1.1 14-1.2.1.1.2.1 15-1.2.1.1.2 16-1.2.1.1.2.2.1 17-1.2.1.1.2.2 (m / mark-01~e.6 :ARG0 (i / immunohistochemistry~e.3 :instrument~e.4 (e / enzyme :name (n / name :op1 "MAPK"~e.5) :ARG3-of (p / phosphorylate-01~e.5))) :ARG1 (s / subset~e.8 :ARG1-of (i2 / include-91 :ARG2 (c / cell~e.11 :ARG0-of (p2 / proliferate-01~e.10) :location (a / and~e.15 :op1 (e2 / epidermis~e.14) :op2 (b / bud~e.17 :mod (h / hair~e.16)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "G"~e.1))) # ::id pmid_1563_0473.322 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anti @-@ pMAPK labeling was consistently robust within the hair bud . # ::alignments 0-1.2.1 2-1.2.1.1.1.1 2-1.2.1.1.2 3-1.2 4-1.2.r 5-1.1 6-1 9-1.2.2.1 10-1.2.2 (r / robust~e.6 :manner (c / consistent-02~e.5) :domain~e.4 (l / label-01~e.3 :ARG0-of (c2 / counter-01~e.0 :ARG1 (e / enzyme :name (n / name :op1 "MAPK"~e.2) :ARG3-of (p / phosphorylate-01~e.2))) :location (b / bud~e.10 :mod (h / hair~e.9)))) # ::id pmid_1563_0473.323 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( H ) Immunofluorescence with anti @-@ laminin 5 ( lam5 ) , which demarcates the basement membrane , and anti @-@ E @-@ cadherin ( E @-@ cad ) , a component of AJs . # ::alignments 1-1.2.1.1 3-1 4-1.1.r 5-1.1.1 5-1.1.1.1 5-1.1.1.1.r 5-1.1.2 5-1.1.2.1 5-1.1.2.1.r 7-1.1.1.1.1.1.1 8-1.1.1.1.1.1.2 14-1.1.1.1.1 14-1.1.1.1.1.2 14-1.1.1.1.1.2.r 16-1.1.1.1.1.2.1.1 17-1.1.1.1.1.2.1 19-1.1 20-1.1.1 20-1.1.1.1 20-1.1.1.1.r 20-1.1.2 20-1.1.2.1 20-1.1.2.1.r 22-1.1.2.1.1.1.1 24-1.1.2.1.1.1.1 26-1.1.2.1.1.1.1 (i / immunofluoresce-01~e.3 :ARG2~e.4 (a / and~e.19 :op1 (m / molecular-physical-entity~e.5,20 :ARG0-of~e.5,20 (c / counter-01~e.5,20 :ARG1 (p / protein~e.14 :name (n / name :op1 "laminin"~e.7 :op2 5~e.8) :ARG0-of~e.14 (d / demarcate-01~e.14 :ARG1 (m2 / membrane~e.17 :mod (b / basement~e.16)))))) :op1 (m3 / molecular-physical-entity~e.5,20 :ARG0-of~e.5,20 (c2 / counter-01~e.5,20 :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin"~e.22,24,26) :part-of (m4 / macro-molecular-complex :name (n3 / name :op1 "adherens" :op2 "junction")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "H"~e.1))) # ::id pmid_1563_0473.324 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the leading edge of the growing bud , cell @-@ cell borders show markedly diminished anti @-@ E @-@ cadherin labeling ( arrowheads ) . # ::alignments 2-1.3.1 3-1.3 4-1.3.2.r 6-1.3.2.1 7-1.3.2 9-1.1.1 11-1.1.1 11-1.1.2 12-1.1 13-1 14-1.2.1.1 14-1.2.1.1.r 15-1.2.1 16-1.2.2 18-1.2.2.1.1.1 20-1.2.2.1.1.1 21-1.2 23-1.4.1 (s / show-01~e.13 :ARG0 (b / border-01~e.12 :ARG1 (c / cell~e.9,11) :ARG2 (c2 / cell~e.11)) :ARG1 (l2 / label-01~e.21 :ARG1-of (d / diminish-01~e.15 :manner~e.14 (m / marked~e.14)) :ARG0-of (c3 / counter-01~e.16 :ARG1 (p / protein :name (n / name :op1 "E-cadherin"~e.18,20)))) :location (e / edge~e.3 :ARG0-of (l / lead-01~e.2) :part-of~e.4 (b2 / bud~e.7 :ARG1-of (g / grow-01~e.6))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / arrowhead~e.23))) # ::id pmid_1563_0473.325 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 2 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 2~e.1) # ::id pmid_1563_0473.326 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Three different surviving Tg founder mice harbored a K14 @-@ Snail transgene that was integrated into a locus that resulted in inheritable , mosaic expression of the transgene in skin epidermis . # ::alignments 0-1.1.1 1-1.1.4 2-1.1.5 3-1.1.2 4-1.1.3 5-1.1 6-1 9-1.2.2.2.1 11-1.2.2.1.1 13-1.2 16-1.2.1 17-1.2.1.1.r 19-1.2.1.1 21-1.2.1.1.1 25-1.2.1.1.1.1.4 26-1.2.1.1.1.1 27-1.2.1.1.1.1.1.r 29-1.2.1.1.1.1.1 30-1.2.1.1.1.1.2.r 31-1.2.1.1.1.1.2.1 32-1.2.1.1.1.1.2 (h / harbor-01~e.6 :ARG0 (m / mouse~e.5 :quant 3~e.0 :mod (t / transgenic~e.3) :ARG0-of (f / found-01~e.4) :ARG1-of (d / differ-02~e.1) :ARG0-of (s / survive-01~e.2)) :ARG1 (t2 / transgene~e.13 :ARG1-of (i / integrate-01~e.16 :ARG2~e.17 (l / locus~e.19 :ARG1-of (r / result-01~e.21 :ARG2 (e / express-03~e.26 :ARG1~e.27 (t3 / transgene~e.29) :ARG3~e.30 (e2 / epidermis~e.32 :part-of (s2 / skin~e.31)) :ARG1-of (i2 / inherit-01 :ARG1-of (p3 / possible-01)) :mod (m3 / mosaic~e.25))))) :mod (g / gene :name (n2 / name :op1 "Snail"~e.11) :ARG2-of (m4 / mutate-01 :value "K14"~e.9)))) # ::id pmid_1563_0473.327 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All displayed similar abnormalities , as did their offspring . # ::alignments 0-1.1.1 1-1 2-1.2.1 3-1.2 7-1.1.2.1 7-1.1.2.1.r 8-1.1.2 (d / display-01~e.1 :ARG0 (a3 / and :op1 (a / all~e.0) :op2 (o / offspring~e.8 :poss~e.7 a~e.7)) :ARG1 (a2 / abnormality~e.3 :ARG1-of (r / resemble-01~e.2))) # ::id pmid_1563_0473.328 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) P16 WT and K14 @-@ Snail Tg mice . # ::alignments 1-1.3.1.1 4-1.1.1 5-1 7-1.2.2.2.1 9-1.2.2.1.1 11-1.2.1 12-1.1 12-1.2 (a / and~e.5 :op1 (m3 / mouse~e.12 :mod (w / wild-type~e.4) :time (a3 / after :op1 (b / bear-02) :quant (t2 / temporal-quantity :quant 16 :unit (d3 / day)))) :op2 (m / mouse~e.12 :mod (t / transgenic~e.11) :mod (g / gene :name (n3 / name :op1 "Snail"~e.9) :ARG2-of (m2 / mutate-01 :value "K14"~e.7))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"~e.1))) # ::id pmid_1563_0473.329 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Insets denote magnified tail segments , which displayed a mosaic , flaky appearance in Tg mice . # ::alignments 1-1 2-1.2.2 3-1.2.1 4-1.2 7-1.2.3 9-1.2.3.1.2 12-1.2.3.1 13-1.2.3.1.4.r 14-1.2.3.1.4.1 15-1.2.3.1.4 (d / denote-01~e.1 :ARG0 (i / inset) :ARG1 (s / segment~e.4 :part-of (t / tail~e.3) :ARG1-of (m / magnify-01~e.2) :ARG0-of (d2 / display-01~e.7 :ARG1 (a / appear-02~e.12 :ARG1 s :mod (m2 / mosaic~e.9) :mod (f / flake) :location~e.13 (m3 / mouse~e.15 :mod (t2 / transgenic~e.14)))))) # ::id pmid_1563_0473.330 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Size differences appeared with age , and are likely due to K14 @-@ promoter activity in the tongue and oral epithelium , resulting in progressive defects and reduced food intake . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2 6-1 8-1.2 9-1.2.1 10-1.2.1 11-1.2.1.1.1.1.1.1.1 13-1.2.1.1.1 13-1.2.1.1.1.1 13-1.2.1.1.1.1.r 14-1.2.1.1 15-1.2.1.1.2.r 17-1.2.1.1.2.1 18-1.2.1.1.2 19-1.2.1.1.2.2.1 20-1.2.1.1.2.2 22-1.2.1.1.3 25-1.2.1.1.3.1.1 26-1.2.1.1.3.1 27-1.2.1.1.3.1.2.2 28-1.2.1.1.3.1.2.1 29-1.2.1.1.3.1.2 (a / and~e.6 :op1 (a2 / appear-01~e.2 :ARG1 (d / differ-02~e.1 :ARG3 (s / size~e.0)) :time~e.3 (a3 / age~e.4)) :op2 (l / likely-01~e.8 :ARG1 (c / cause-01~e.9,10 :ARG0 (a4 / activity-06~e.14 :ARG0 (m2 / molecular-physical-entity~e.13 :ARG0-of~e.13 (p4 / promote-01~e.13 :ARG1 (p / protein :name (n / name :op1 "K14"~e.11)))) :location~e.15 (a5 / and~e.18 :op1 (t / tongue~e.17) :op2 (e / epithelium~e.20 :part-of (m / mouth~e.19))) :ARG1-of (r / result-01~e.22 :ARG2 (a6 / and~e.26 :op1 (d2 / defect~e.25 :ARG1-of (p3 / progress-01)) :op2 (i / intake~e.29 :mod (f / food~e.28) :ARG1-of (r2 / reduce-01~e.27))))) :ARG1 d))) # ::id pmid_1563_0473.331 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hence , skin sections from young ( P3 ) mice were analyzed ( B @–@ I ) . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1 3-1.1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.r 5-1.1.1.1.1.1.1 9-1.1.1.1.1.1 11-1.1 13-1.1.2.1.1.1 15-1.1.2.1.8.1 (c / cause-01~e.0 :ARG1 (a / analyze-01~e.11 :ARG1 (t / thing~e.3 :ARG2-of~e.3 (s / section-01~e.3 :ARG1 (s2 / skin~e.2 :source~e.4 (m / mouse~e.9 :mod (y / young~e.5) :ARG1-of (m2 / mean-01 :ARG2 (a2 / after :op1 (b / bear-02) :quant (t2 / temporal-quantity :quant 3 :unit (d3 / day)))))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "B"~e.13) :op2 (f2 / figure :mod "C") :op3 (f3 / figure :mod "D") :op4 (f4 / figure :mod "E") :op5 (f5 / figure :mod "F") :op6 (f6 / figure :mod "G") :op7 (f7 / figure :mod "H") :op8 (f8 / figure :mod "I"~e.15))))) # ::id pmid_1563_0473.332 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Hematoxylin @- and eosin @-@ stained Tg skin section . # ::alignments 1-1.2.1.1 3-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 8-1.1 10-1.3.1 11-1 11-1.3 11-1.3.r (t / thing~e.11 :ARG1-of (s3 / stain-01~e.8 :ARG2 (a / and~e.5 :op1 (s4 / small-molecule :name (n / name :op1 "hematoxylin"~e.3)) :op2 (s5 / small-molecule :name (n2 / name :op1 "eosin"~e.6)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"~e.1)) :ARG2-of~e.11 (s / section-01~e.11 :ARG1 (s2 / skin~e.10))) # ::id pmid_1563_0473.333 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Double arrows demarcate the border of mosaic histology , with seemingly normal epidermis ( epi ) and a mature hair follicle ( hf ) at left and hyperthickened epidermis at right . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1 9-1.2.1.2.r 10-1.2.1.2.1.1 11-1.2.1.2.1 12-1.2.1.2 18-1.2.1.3.2 19-1.2.1.3.1 20-1.2.1.3 24-1.2.1.3.3.r 25-1.2.1.3.3 28-1.2.1.4 29-1.2.1.4.2.r 30-1.2.1.4.2 (d / demarcate-01~e.2 :ARG0 (a / arrow~e.1 :mod (d2 / double~e.0)) :ARG1 (b / border-01~e.4 :ARG1~e.5 (h / histology~e.7 :mod (m / mosaic~e.6) :part~e.9 (e / epidermis~e.12 :ARG1-of (n / normal-02~e.11 :ARG1-of (s / seem-01~e.10))) :part (f / follicle~e.20 :mod (h2 / hair~e.19) :ARG1-of (m2 / mature-02~e.18) :ARG1-of~e.24 (l / left-20~e.25)) :part (e2 / epidermis~e.28 :ARG1-of (t / thicken-01 :degree (h3 / hyper)) :ARG1-of~e.29 (r / right-04~e.30))))) # ::id pmid_1563_0473.334 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) Immunofluorescence of Tg skin section labeled with antibodies as color @-@ coded on frame . # ::alignments 1-1.1.2.1.1 3-1 5-1.1.3.1.1 6-1.1.3.1 7-1.1 7-1.1.3 7-1.1.3.r 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1 11-1.1.1.2.r 12-1.1.1.2.1 14-1.1.1.2 15-1.1.1.2.2.r 16-1.1.1.2.2 (i / immunofluoresce-01~e.3 :ARG1 (t2 / thing~e.7 :ARG1-of (l / label-01~e.8 :ARG2~e.9 (a / antibody~e.10) :ARG1-of~e.11 (c / code-01~e.14 :ARG0 (c2 / color~e.12) :location~e.15 (f / frame~e.16))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "C"~e.1)) :ARG2-of~e.7 (s / section-01~e.7 :ARG1 (s2 / skin~e.6 :mod (t / transgenic~e.5))))) # ::id pmid_1563_0473.335 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Double arrows demarcate the border of mosaic anti @-@ Snail ( green ) , revealing Snail expression coincident with regions of hyperthickened epidermis ( at left ) and absent in regions of normal epidermis ( at right ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.2 7-1.2.1 7-1.2.1.1 7-1.2.1.1.r 9-1.2.1.1.1.1.1 11-1.1.2 14-1.3 15-1.3.1.1.1.1 16-1.3.1.1.1 19-1.3.1.1.2 22-1.3.1.1.2.1 24-1.3.1.1.2.2.r 25-1.3.1.1.2.2 27-1.3.1 28-1.3.1.2 29-1.3.1.2.2.r 30-1.3.1.2.2 31-1.3.1.2.2.1.r 32-1.3.1.2.2.1.1 33-1.3.1.2.2.1 35-1.3.1.2.3.r 36-1.3.1.2.3 (d / demarcate-01~e.2 :ARG0 (a / arrow~e.1 :mod (d2 / double~e.0) :ARG1-of (g / green-02~e.11)) :ARG1 (b / border-01~e.4 :ARG1~e.5 (m / molecular-physical-entity~e.7 :ARG0-of~e.7 (c / counter-01~e.7 :ARG1 (p / protein :name (n / name :op1 "Snail"~e.9))) :mod (m2 / mosaic~e.6))) :ARG0-of (r / reveal-01~e.14 :ARG1 (a2 / and~e.27 :op1 (c2 / coincide-01 :ARG1 (e / express-03~e.16 :ARG2 p~e.15) :ARG2 (r2 / region~e.19 :part-of (e2 / epidermis~e.22 :ARG1-of (t / thicken-01 :degree (h / hyper))) :ARG1-of~e.24 (l / left-20~e.25))) :op2 (a4 / absent-01~e.28 :ARG1 e :ARG2~e.29 (r3 / region~e.30 :part-of~e.31 (e3 / epidermis~e.33 :ARG1-of (n2 / normal-02~e.32))) :ARG1-of~e.35 (r4 / right-04~e.36))))) # ::id pmid_1563_0473.336 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D @–@ I ) Sections of P3 WT or Tg skin ( affected region ) subjected to either immunofluorescence ( D , E, H , and I ) or immunohistochemistry ( F and G ) with antibodies as indicated on the panel . # ::alignments 1-1.2.1.3.1.1.1 3-1.2.1.3.1.4.1 5-1.1 5-1.1.1 5-1.1.1.r 8-1.1.1.1.1.1 9-1.1.1.1 10-1.1.1.1.2.1 11-1.1.1.1.1 11-1.1.1.1.2 13-1.1.1.1.3.1.1 14-1.1.1.1.3.1 16-1 19-1.2.1 21-1.2.1.3.1.1.1 24-1.2.1.3.1.3.1 26-1.2.1.3.1 27-1.2.1.3.1.4.1 29-1.2 30-1.2.2 32-1.2.2.2.1.1.1 33-1.2.2.2.1 34-1.2.2.2.1.2.1 36-1.2.2.1.r 37-1.2.2.1 38-1.1.1.1.1.2.r 38-1.2.2.1.1.r 39-1.2.2.1.1 40-1.2.2.1.1.1.r 42-1.2.2.1.1.1 (s / subject-01~e.16 :ARG1 (t2 / thing~e.5 :ARG2-of~e.5 (s2 / section-01~e.5 :ARG1 (o / or~e.9 :op1 (s3 / skin~e.11 :mod (w / wild-type~e.8) :time~e.38 (a5 / after :op1 (b / bear-02) :quant (t3 / temporal-quantity :quant 3 :unit (d3 / day)))) :op2 (s4 / skin~e.11 :mod (t / transgenic~e.10)) :ARG1-of (m / mean-01 :ARG2 (r / region~e.14 :ARG1-of (a / affect-01~e.13)))))) :ARG2 (o3 / or~e.29 :op1 (i / immunofluoresce-01~e.19 :ARG1 t2 :ARG2 a2 :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.26 :op1 (f3 / figure :mod "D"~e.1,21) :op2 (f4 / figure :mod "E") :op3 (f5 / figure :mod "H"~e.24) :op4 (f6 / figure :mod "I"~e.3,27)))) :op2 (i3 / immunohistochemistry~e.30 :instrument~e.36 (a2 / antibody~e.37 :ARG1-of~e.38 (i4 / indicate-01~e.39 :location~e.40 (p / panel~e.42))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and~e.33 :op1 (f / figure :mod "F"~e.32) :op2 (f7 / figure :mod "G"~e.34))))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 f3 :op2 f4 :op3 f :op4 f7 :op5 f5))) # ::id pmid_1563_0473.337 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anti @-@ keratin 5 indicates K5 , normally restricted to the basal layer of the epidermis ; anti @-@ keratin 6 detects keratin 6 , expressed in postnatal epidermis under conditions such as wounding , in which hyperproliferation occurs . # ::alignments 0-1.1.1.1 0-1.2.1.1 2-1.1.1.1.1.1.1 2-1.2.1.1.1.1.1 3-1.1.2 4-1.1 7-1.1.2 8-1.1.2 9-1.1.2 10-1.1.2 11-1.1.2 12-1.1.2 13-1.1.2 14-1.1.2 15-1.1.2 17-1.1.1.1 17-1.2.1.1 19-1.2.2 20-1.2.2 21-1.2 22-1.2.2 23-1.2.2 24-1.2.2 25-1.2.2 26-1.2.2 27-1.2.2 28-1.2.2 29-1.2.2 30-1.2.2 31-1.2.2 32-1.2.2 33-1.2.2 34-1.2.2 35-1.2.2 36-1.2.2 37-1.2.2 (m / multi-sentence :snt1 (i / indicate-01~e.4 :ARG0 (a / antibody :ARG0-of (c / counter-01~e.0,17 :ARG1 (p / protein :name (n / name :op1 "keratin"~e.2 :op2 5) :ARG1-of (r / restrict-01 :ARG2 (l / layer :part-of (e / epidermis) :mod (b / basal)) :ARG1-of (n2 / normal-02))))) :ARG1 p~e.3,7,8,9,10,11,12,13,14,15) :snt2 (d / detect-01~e.21 :ARG0 (a2 / antibody :ARG0-of (c2 / counter-01~e.0,17 :ARG1 (p2 / protein :name (n3 / name :op1 "keratin"~e.2 :op2 6) :ARG2-of (e2 / express-03 :ARG3 (e3 / epidermis :mod (p3 / postnatal)) :ARG1-of (c3 / condition-01 :example (w / wound-01 :time-of (p4 / proliferate-01 :degree (h / hyper)))))))) :ARG1 p2~e.19,20,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37)) # ::id pmid_1563_0473.338 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All other antibodies are as in the legend to Figure 2 @ . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 2-1.2 5-1.2.1.r 7-1.2.1 10-1.2.1.1 11-1.2.1.1.1 (r / resemble-01 :ARG1 (a / antibody~e.2 :mod (a2 / all~e.0) :mod (o / other~e.1)) :ARG2 (a3 / antibody~e.2 :location~e.5 (l / legend~e.7 :mod (f / figure~e.10 :mod 2~e.11)))) # ::id pmid_1563_0473.339 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Comparison of D and E provide representative examples that illustrate that pMAPK is found in only a subset of all proliferating ( Ki67 @-@ positive ) cells . # ::alignments 0-1.1 2-1.1.1.1 4-1.1.2.1 5-1 6-1.2.1 7-1.2 9-1.2.2 11-1.2.2.1.1.1.1 11-1.2.2.1.1.2 12-1.2.2.1 15-1.2.2.1.2.1 17-1.2.2.1.2 19-1.2.2.1.2.2.1.3 20-1.2.2.1.2.2.1.1 22-1.2.2.1.2.2.1.2.1.1.1 24-1.2.2.1.2.2.1.2 26-1.2.2.1.2.2.1 (p2 / provide-01~e.5 :ARG0 (c / compare-01~e.0 :ARG1 (f / figure :mod "D"~e.2) :ARG2 (f2 / figure :mod "E"~e.4)) :ARG1 (e / example~e.7 :ARG0-of (r2 / represent-01~e.6) :ARG0-of (i / illustrate-01~e.9 :ARG1 (b / be-located-at-91~e.12 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK"~e.11) :ARG3-of (p / phosphorylate-01~e.11)) :ARG2 (s / subset~e.17 :mod (o / only~e.15) :ARG1-of (i2 / include-91 :ARG2 (c2 / cell~e.26 :ARG0-of (p4 / proliferate-01~e.20) :mod (p5 / positive~e.24 :mod (p6 / protein :name (n2 / name :op1 "Ki67"~e.22))) :mod (a / all~e.19)))))))) # ::id pmid_1563_0473.340 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note also the presence of Ki67 @- ( E ) and pMAPK @-@ positive ( G ) cells in some suprabasal areas ; Ki67 @-@ positive cells colabeled with anti @-@ Snail ( E ) . # ::alignments 0-1.1 1-1.1.4 3-1.1.3 5-1.2.1.1.1.1.1 8-1.1.3.1.1.2.1.1 10-1.1.3.1 11-1.1.3.1.2.1.1.1.1 11-1.1.3.1.2.1.1.2 13-1.1.3.1.1.1 15-1.1.3.1.2.2.1.1 17-1.1.3.1.1 18-1.1.3.2.r 19-1.1.3.2.1 20-1.1.3.2.2 21-1.1.3.2 23-1.1.3.1.1.1.1.1.1 23-1.2.1.1.1.1.1 25-1.1.3.1.1.1 25-1.1.3.1.2.1 25-1.2.1.1 26-1.1.3.1.1 26-1.1.3.1.2 26-1.2.1 29-1.2.2.1 31-1.2.2.1.1.1.1 33-1.1.3.1.1.2.1.1 (m / multi-sentence :snt1 (n / note-02~e.0 :mode imperative :ARG0 (y / you) :ARG1 (p8 / present-02~e.3 :ARG1 (a / and~e.10 :op1 (c / cell~e.17,26 :mod (p / positive~e.13,25 :mod (p2 / protein :name (n2 / name :op1 "Ki67"~e.23))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"~e.8,33))) :op2 (c2 / cell~e.26 :mod (p3 / positive~e.25 :mod (e / enzyme :name (n3 / name :op1 "MAPK"~e.11) :ARG3-of (p4 / phosphorylate-01~e.11))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "G"~e.15)))) :ARG2~e.18 (a2 / area~e.21 :quant (s / some~e.19) :mod (s2 / suprabasal~e.20))) :mod (a4 / also~e.1)) :snt2 (c3 / colabel-00 :ARG1 (c5 / cell~e.26 :mod (p6 / positive~e.25 :mod (p7 / protein :name (n5 / name :op1 "Ki67"~e.5,23)))) :ARG2 (a3 / antibody :ARG0-of (c4 / counter-01~e.29 :ARG1 (p5 / protein :name (n4 / name :op1 "Snail"~e.31)))) :ARG1-of (d3 / describe-01 :ARG0 f))) # ::id pmid_1563_0473.341 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 3 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 3~e.1) # ::id pmid_1563_0473.342 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A @–@ H ) Immunofluorescence of skin sections from P3 WT and Tg mice . # ::alignments 1-1.2.1.1.1 3-1.2.1.8.1 5-1 6-1.1.r 7-1.1.1 8-1.1 9-1.1.1.1.r 11-1.1.1.1.1.1 12-1.1.1.1 13-1.1.1.1.2.1 14-1.1.1.1.1 14-1.1.1.1.2 (i / immunofluoresce-01~e.5 :ARG1~e.6 (s2 / section-01~e.8 :ARG1 (s / skin~e.7 :source~e.9 (a / and~e.12 :op1 (m / mouse~e.14 :mod (w / wild-type~e.11)) :op2 (m2 / mouse~e.14 :mod (t2 / transgenic~e.13)) :age (t / temporal-quantity :quant 3 :unit (d / day))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "A"~e.1) :op2 (f2 / figure :mod "B") :op3 (f3 / figure :mod "C") :op4 (f4 / figure :mod "D") :op5 (f5 / figure :mod "E") :op6 (f6 / figure :mod "F") :op7 (f7 / figure :mod "G") :op8 (f8 / figure :mod "H"~e.3)))) # ::id pmid_1563_0473.343 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Shown are affected areas of Tg skin ; in areas where Snail protein was not expressed , stainings were normal . # ::alignments 0-1.1 2-1.1.1.2 3-1.1.1 5-1.1.1.1.1 6-1.1.1.1 9-1.1.1 9-1.2.2 10-1.2.2.r 11-1.2.2.1.2.1.1 12-1.2.2.1.2 14-1.2.2.1.1 14-1.2.2.1.1.r 15-1.2.2.1 17-1.2.1 19-1.2 (m / multi-sentence :snt1 (s / show-01~e.0 :ARG1 (a / area~e.3,9 :mod (s2 / skin~e.6 :mod (t / transgenic~e.5)) :ARG1-of (a2 / affect-01~e.2))) :snt2 (n / normal-02~e.19 :ARG1 (s3 / stain-01~e.17) :location~e.10 (a3 / area~e.9 :ARG3-of (e / express-03~e.15 :polarity~e.14 -~e.14 :ARG2 (p / protein~e.12 :name (n2 / name :op1 "Snail"~e.11)))))) # ::id pmid_1563_0473.344 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sections were labeled with antibodies as indicated and color @-@ coded on each frame . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 2-1 3-1.2.r 4-1.2 5-1.2.1.r 6-1.2.1 8-1.2.2.1 10-1.2.2 11-1.2.1.1.r 12-1.2.1.1.1 13-1.2.1.1 (l / label-01~e.2 :ARG1 (t / thing~e.0 :ARG1-of~e.0 (s / section-01~e.0)) :ARG2~e.3 (a / antibody~e.4 :ARG1-of~e.5 (i / indicate-01~e.6 :location~e.11 (f / frame~e.13 :mod (e / each~e.12))) :ARG1-of (c / code-01~e.10 :ARG0 (c2 / color~e.8) :location f))) # ::id pmid_1563_0473.345 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Antibodies are against markers of normal epidermal differentiation , and include K5 ( a basally expressed keratin ) , K1 ( a suprabasal keratin , expressed in spinous layer cells ) , involucrin ( Inv ; a suprabasally expressed cornified envelope protein found in upper spinous and granular layer cells ) , loricrin ( Lor ; a cornified envelope protein expressed in the granular layer ) , and filaggrin ( Fil ; a protein that bundles keratin filaments in the granular layer and stratum corneum ) . # ::alignments 0-1 2-1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.2 7-1.1.1.1 9-1.2.1 10-1.2 15-1.2.1.1.2.1.1 15-1.2.1.2.2.1.1 16-1.2.1.1.1.1 16-1.2.1.1.2.1 16-1.2.1.2.1.1 16-1.2.1.2.2.1 22-1.2.1.2.2.1.1.2 22-1.2.1.3.2.1.2.2 23-1.2.1.1.1.1 23-1.2.1.2.1.1 23-1.2.1.2.2.1 25-1.2.1.2.2.1.1 27-1.2.1.2.2.1.1.1.1.1 28-1.2.1.2.2.1.1.1.1 28-1.2.1.3.2.1.2.1.2.1 29-1.2.1.2.2.1.1.1 29-1.2.1.3.2.1.2.1.2 32-1.2.1.3.1.1 38-1.2.1.3.2.1.2 40-1.2.1.3.2.1.1 41-1.2.1.3.2.1 43-1.2.1.3.2.1.2.1.2.1.2.r 44-1.2.1.3.2.1.2.1.2.1.2 45-1.2.1.3.2.1.2.1.2.1.1 46-1.2.1.3.2.1.2.1 47-1.2.1.3.2.1.2.1.1.1.1 48-1.2.1.3.2.1.2.1.1.1 49-1.2.1.3.2.1.2.1.1 49-1.2.1.4.2.1.2.1 52-1.2.1.4.1.1 58-1.2.1.3.2.1.1 58-1.2.1.4.2.1.1 59-1.2.1.3.2.1 59-1.2.1.4.2.1 60-1.2.1.3.2.1.2 60-1.2.1.4.2.1.2 63-1.2.1.3.2.1.2.1.1.1.1 64-1.2.1.3.2.1.2.1.1.1 67-1.2.1 68-1.2.1.5.1.1 73-1.2.1.5.2.1 75-1.2.1.5.2.1.1 76-1.2.1.5.2.1.1.1.1.1.1 77-1.2.1.5.2.1.1.1 78-1.2.1.5.2.1.1.2.r 80-1.2.1.5.2.1.1.2.1 81-1.2.1.5.2.1.1.2.1 82-1.2.1.5.2.1.1.2 83-1.2.1.5.2.1.1.2.2.1 84-1.2.1.5.2.1.1.2.2 (a / antibody~e.0 :ARG0-of (c / counter-01~e.2 :ARG1 (m / marker~e.3 :ARG0-of~e.4 (d / differentiate-101~e.7 :ARG1 (e / epidermis) :ARG1-of (n / normal-02~e.5)))) :ARG2-of (i / include-01~e.10 :ARG1 (a2 / and~e.9,67 :op1 (p / protein :name (n2 / name :op1 "keratin"~e.16,23 :op2 5) :ARG1-of (m2 / mean-01 :ARG2 (k / keratin~e.16 :ARG2-of (e2 / express-03~e.15 :manner (b / basal))))) :op2 (p2 / protein :name (n3 / name :op1 "keratin"~e.16,23 :op2 1) :ARG1-of (m3 / mean-01 :ARG2 (k2 / keratin~e.16,23 :ARG2-of (e3 / express-03~e.15,25 :ARG3 (c2 / cell~e.29 :part-of (l / layer~e.28 :mod (s / spinous~e.27))) :manner (s2 / suprabasal~e.22))))) :op3 (p3 / protein :name (n4 / name :op1 "involucrin"~e.32) :ARG1-of (m4 / mean-01 :ARG2 (p7 / protein~e.41,59 :mod (e6 / envelope~e.40,58 :ARG1-of (c6 / cornify-01)) :ARG2-of (e4 / express-03~e.38,60 :ARG3 (a3 / and~e.46 :op1 (c3 / cell~e.49 :part-of (l2 / layer~e.48,64 :mod (g / granular~e.47,63))) :op2 (c4 / cell~e.29 :part-of (l3 / layer~e.28 :mod (s4 / spinous~e.45) :mod~e.43 (u / upper~e.44)))) :manner (s3 / suprabasal~e.22))))) :op4 (p4 / protein :name (n5 / name :op1 "loricrin"~e.52) :ARG1-of (m5 / mean-01 :ARG2 (p8 / protein~e.59 :mod (e7 / envelope~e.58 :ARG1-of (c7 / cornify-01)) :ARG2-of (e5 / express-03~e.60 :ARG3 (c5 / cell~e.49 :part-of l2))))) :op5 (p5 / protein :name (n6 / name :op1 "filaggrin"~e.68) :ARG1-of (m6 / mean-01 :ARG2 (p9 / protein~e.73 :ARG0-of (b2 / bundle-01~e.75 :ARG2 (f / filament~e.77 :mod (p6 / protein :name (n7 / name :op1 "keratin"~e.76))) :location~e.78 (a4 / and~e.82 :op1 l2~e.80,81 :op2 (c8 / corneum~e.84 :mod (s5 / stratum~e.83)))))))))) # ::id pmid_1563_0473.346 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note abnormal extension of anti @-@ K5 suprabasally , often present in anti @-@ K1 positive suprabasal Tg cells . # ::alignments 0-1 1-1.3.3 1-1.3.3.1 1-1.3.3.1.r 2-1.3 4-1.3.1.1 9-1.3.4.2 10-1.3.4 11-1.3.4.1.r 12-1.3.4.1.3.1.1 15-1.3.4.1.3 16-1.3.2 16-1.3.4.1.2 17-1.3.4.1.1 18-1.3.4.1 (n / note-02~e.0 :mode imperative :ARG0 (y / you) :ARG1 (e / extend-01~e.2 :ARG1 (a / antibody :ARG0-of (c / counter-01~e.4 :ARG1 (p / protein :name (n3 / name :op1 "keratin" :op2 5)))) :ARG4 (s / suprabasal~e.16) :ARG1-of (n2 / normal-02~e.1 :polarity~e.1 -~e.1) :ARG1-of (p4 / present-02~e.10 :ARG2~e.11 (c2 / cell~e.18 :mod (t / transgenic~e.17) :mod (s2 / suprabasal~e.16) :mod (p2 / positive~e.15 :mod (a2 / antibody :ARG0-of (c3 / counter-01~e.12 :ARG1 (p3 / protein :name (n4 / name :op1 "keratin" :op2 1)))))) :frequency (o / often~e.9)))) # ::id pmid_1563_0473.347 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( I @–@ N ) Immunohistochemistry ( I and J ) or immunofluorescence ( K @–@ N ) of sections of P30 Wt ( I , K, and M ) and Tg ( J , L, and N ) ( affected areas ) skins using the antibodies indicated . # ::alignments 1-1.1.1.1.1.1 3-1.1.3.1.1.2.2.1.3.1 5-1.1 7-1.1.1.1.1.1 7-1.1.3.1.1.1.2.1.1.1 8-1.1.1.1 8-1.1.3.1.1.1.2.1 8-1.1.3.1.1.2.2.1 9-1.1.1.1.2.1 9-1.1.3.1.1.2.2.1.1.1 12-1.2 14-1.1.3.1.1.1.2.1.2.1 16-1.1.3.1.1.2.2.1.3.1 19-1.1.3 19-1.1.3.1 19-1.1.3.1.r 24-1.1.3.1.1.1.2.1.1.1 27-1.1.3.1.1 27-1.1.3.1.1.1.2.1 27-1.1.3.1.1.2.2.1 28-1.1.3.1.1.1.2.1.3.1 30-1.1.3.1.1 30-1.1.3.1.1.1.2.1 30-1.1.3.1.1.2.2.1 31-1.1.3.1.1.2.1 33-1.1.3.1.1.2.2.1.1.1 36-1.1.3.1.1.2.2.1 37-1.1.3.1.1.2.2.1.3.1 40-1.1.3.1.1.2.4.1.1 41-1.1.3.1.1.2.4.1 43-1.1.3.1.1.1 43-1.1.3.1.1.2 44-1.1.2 46-1.1.2.1 47-1.1.2.1.1 (a / and :op1 (i / immunohistochemistry~e.5 :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.8 :op1 (f2 / figure :mod "I"~e.1,7) :op2 (f6 / figure :mod "J"~e.9))) :manner (u / use-01~e.44 :ARG1 (a8 / antibody~e.46 :ARG1-of (i3 / indicate-01~e.47))) :mod (t3 / thing~e.19 :ARG2-of~e.19 (s / section-01~e.19 :ARG1 (a3 / and~e.27,30 :op1 (s2 / skin~e.43 :mod (w / wild-type) :ARG1-of (d5 / describe-01 :ARG0 (a4 / and~e.8,27,30 :op1 (f4 / figure :mod "I"~e.7,24) :op2 (f7 / figure :mod "K"~e.14) :op3 (f8 / figure :mod "M"~e.28))) :age (t2 / temporal-quantity :quant 30 :unit (d4 / day))) :op2 (s3 / skin~e.43 :mod (t / transgenic~e.31) :ARG1-of (d6 / describe-01 :ARG0 (a5 / and~e.8,27,30,36 :op1 (f5 / figure :mod "J"~e.9,33) :op2 (f9 / figure :mod "L") :op3 (f10 / figure :mod "N"~e.3,16,37))) :age t2 :ARG1-of (d7 / describe-01 :ARG2 (a6 / area~e.41 :ARG1-of (a7 / affect-01~e.40)))))))) :op2 (i2 / immunofluoresce-01~e.12 :ARG1 t3 :ARG2 a8 :ARG1-of (d3 / describe-01 :ARG0 (a11 / and :op1 f7 :op2 f9 :op3 f8 :op4 f10))) :ARG1-of (d / describe-01 :ARG0 (a12 / and :op1 f4 :op2 f5 :op3 f7 :op4 f9 :op5 f8 :op6 f10))) # ::id pmid_1563_0473.348 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note that with age , affected areas of the Tg epidermis became increasingly undulating , often exhibiting papilloma @-@ like invaginations ( J ) . # ::alignments 0-1 2-1.3.r 3-1.3.1.3.1 5-1.3.1.1.2 6-1.3.1.1 7-1.3.1.1.1.r 9-1.3.1.1.1.1 10-1.3.1.1.1 11-1.3.1 12-1.3.1.2.2 13-1.3.1.2 15-1.3.2.3 16-1.3.2 17-1.3.2.2.1.1 19-1.3.2.2.1 20-1.3.2.2 22-1.3.2.1 (n / note-02~e.0 :mode imperative :ARG0 (y / you) :ARG1~e.2 (a5 / and :op1 (b / become-01~e.11 :ARG1 (a / area~e.6 :part-of~e.7 (e / epidermis~e.10 :mod (t / transgenic~e.9)) :ARG1-of (a2 / affect-01~e.5) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "J"))) :ARG2 (u / undulate-01~e.13 :ARG1 a :degree (i / increase-01~e.12)) :ARG1-of (c / cause-01 :ARG0 (a3 / age-01~e.3))) :op2 (e2 / exhibit-01~e.16 :ARG0 a~e.22 :ARG1 (i2 / invaginate-01~e.20 :ARG1-of (r / resemble-01~e.19 :ARG2 (p / papilloma~e.17))) :frequency (o / often~e.15)))) # ::id pmid_1563_0473.349 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Insets in I and J are magnified views of the boxed areas , illustrating the absence ( Wt ) or presence ( Tg ) of nuclear anti @-@ cyclin D staining . # ::alignments 2-1.1.1.1 3-1.1 4-1.1.2.1 5-1.2.r 6-1.2.2 7-1.2 8-1.2.1.r 10-1.2.1.1 11-1.2.1 13-1.2.3 15-1.2.3.1.1 17-1.2.3.1.1.2.1.1 19-1.2.3.1 20-1.2.3.1.2 22-1.2.3.1.2.2.1.1 24-1.2.3.1.1.1.r 25-1.2.3.1.1.1.1 26-1.2.3.1.1.1.2.1 28-1.2.3.1.1.1.2.1.1.1.1 29-1.2.3.1.1.1.2.1.1.1.2 30-1.2.3.1.1.1 (i / inset :location (a / and~e.3 :op1 (f / figure :mod "I"~e.2) :op2 (f2 / figure :mod "J"~e.4)) :domain~e.5 (v / view-01~e.7 :ARG1~e.8 (a2 / area~e.11 :ARG1-of (b / box-02~e.10)) :ARG1-of (m / magnify-01~e.6) :ARG0-of (i2 / illustrate-01~e.13 :ARG1 (o / or~e.19 :op1 (a3 / absent-01~e.15 :ARG1~e.24 (s / stain-01~e.30 :ARG1 (n5 / nucleus~e.25) :ARG2 (a4 / antibody :ARG0-of (c / counter-01~e.26 :ARG1 (p2 / protein :name (n6 / name :op1 "cyclin"~e.28 :op2 "D"~e.29))))) :ARG1-of (d / describe-01 :ARG2 (n / name :op1 "Wt"~e.17))) :op2 (p / present-02~e.20 :ARG1 s :ARG1-of (d2 / describe-01 :ARG2 (n3 / name :op1 "Tg"~e.22))))))) # ::id pmid_1563_0473.350 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With age , affected areas of the Tg epidermis also displayed perturbations within the basement membrane , as judged by antibody labeling against either basement membrane ( K and L ) or hemidesmosomal ( M and N ) components . # ::alignments 0-1.5.1.2.r 1-1.6.1 3-1.1.1 4-1.1 5-1.1.2.r 7-1.1.2.1 8-1.1.2 9-1.4 10-1 11-1.2 14-1.3.1 15-1.3 18-1.5 20-1.5.1.2 21-1.5.1 24-1.5.1.1.1.1 25-1.5.1.1.1 27-1.5.1.1.1.2.1.1.1 28-1.5.1.1.1.2.1 29-1.5.1.1.1.2.1.2.1 31-1.5.1.1 32-1.5.1.1.2.1 34-1.5.1.1.2.2.1.1.1 35-1.5.1.1.2.2.1 36-1.5.1.1.2.2.1.2.1 38-1.5.1.1.2 (d / display-01~e.10 :ARG0 (a / area~e.4 :ARG1-of (a2 / affect-01~e.3) :part-of~e.5 (e / epidermis~e.8 :mod (t / transgenic~e.7))) :ARG1 (p / perturb-01~e.11 :ARG1 a) :ARG2 (m / membrane~e.15 :mod (b / basement~e.14)) :mod (a3 / also~e.9) :ARG2-of (j / judge-01~e.18 :ARG3 (l / label-01~e.21 :ARG1 (o / or~e.31 :op1 (m2 / membrane~e.25 :mod (b2 / basement~e.24) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and~e.28 :op1 (f / figure :mod "K"~e.27) :op2 (f3 / figure :mod "L"~e.29)))) :op2 (c / component~e.38 :mod (h / hemidesmosomal~e.32) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and~e.35 :op1 (f2 / figure :mod "M"~e.34) :op2 (f4 / figure :mod "N"~e.36))))) :instrument~e.0 (a5 / antibody~e.20))) :ARG1-of (c2 / cause-01 :ARG0 (a4 / age-01~e.1))) # ::id pmid_1563_0473.351 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Double arrows in L demarcate mosaic zones , revealing that perturbations were restricted to hyperthickened , i.e. , Snail @-@ positive zones ( to left of double arrows ) . # ::alignments 0-1.1.1 1-1.1 3-1.1.2.1 4-1 5-1.2.1 6-1.2 8-1.1.3 9-1.1.3.1.r 10-1.1.3.1.1 12-1.1.3.1 18-1.1.3.1.2.1.2.1.1.1.1 20-1.1.3.1.2.1.2.1 21-1.1.3.1.2 24-1.1.3.1.2.2.2 26-1.1.1 27-1.1 (d2 / demarcate-01~e.4 :ARG0 (a / arrow~e.1,27 :quant (d / double~e.0,26) :location (f / figure :mod "L"~e.3) :ARG0-of (r / reveal-01~e.8 :ARG1~e.9 (r2 / restrict-01~e.12 :ARG1 (p / perturb-01~e.10) :ARG2 (z2 / zone~e.21 :ARG1-of (t / thicken-01 :degree (h / hyper) :ARG1-of (m2 / mean-01 :ARG2 (p2 / positive~e.20 :mod (p3 / protein :name (n / name :op1 "Snail"~e.18))))) :location (r3 / relative-position :op1 a :direction (l / left-20~e.24)))))) :ARG1 (z / zone~e.6 :mod (m / mosaic~e.5))) # ::id pmid_1563_0473.352 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other abbreviations are as noted in the legend to Figure 2 @ . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 4-1.2 5-1.2.1.r 7-1.2.1 10-1.2.1.1 11-1.2.1.1.1 (r / resemble-01 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (a / abbreviate-01~e.1) :mod (o / other~e.0)) :ARG2 (n / note-01~e.4 :location~e.5 (l / legend~e.7 :mod (f / figure~e.10 :mod 2~e.11)))) # ::id pmid_1563_0473.353 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 4 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 4~e.1) # ::id pmid_1563_0473.354 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Immunofluorescence of skin sections from P30 Wt and Tg mice . # ::alignments 1-1.2.1.1 3-1 4-1.1.r 5-1.1.1.1 6-1.1 6-1.1.1 6-1.1.1.r 7-1.1.1.1.1.r 10-1.1.1.1.1 11-1.1.1.1.1.2.1 12-1.1.1.1.1.1 12-1.1.1.1.1.2 (i / immunofluoresce-01~e.3 :ARG1~e.4 (t3 / thing~e.6 :ARG2-of~e.6 (s / section-01~e.6 :ARG1 (s2 / skin~e.5 :source~e.7 (a / and~e.10 :op1 (m / mouse~e.12 :mod (w / wild-type) :age (t2 / temporal-quantity :quant 30 :unit (d2 / day))) :op2 (m2 / mouse~e.12 :mod (t / transgenic~e.11) :age t2))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "A"~e.1))) # ::id pmid_1563_0473.355 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Shown are affected areas of Tg skin ; in areas where Snail protein was not expressed , stainings were normal . # ::alignments 0-1.1 2-1.1.1.1 3-1.1.1 5-1.1.1.2.1 6-1.1.1.2 9-1.1.1 9-1.2.2 10-1.2.2.r 11-1.2.2.1.2.2.1 12-1.2.2.1.2 14-1.2.2.1.1 14-1.2.2.1.1.r 15-1.2.2.1 17-1.2.1 19-1.2 (m / multi-sentence :snt1 (s / show-01~e.0 :ARG1 (a / area~e.3,9 :ARG1-of (a2 / affect-01~e.2) :mod (s2 / skin~e.6 :mod (t / transgenic~e.5)))) :snt2 (n / normal-02~e.19 :ARG1 (s3 / stain-01~e.17) :location~e.10 (a3 / area~e.9 :ARG3-of (e / express-03~e.15 :polarity~e.14 -~e.14 :ARG2 (p / protein~e.12 :wiki "SNAI1" :name (n2 / name :op1 "Snail"~e.11)))))) # ::id pmid_1563_0473.356 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Antibodies used are against AJ proteins and include E @-@ cadherin ( E @-@ cad ) , the transmembrane core protein ; β-catenin (β-cat ) , which binds E @-@ cadherin at AJs and which can also participate as a transcription cofactor when associated with LEF @-@ 1/TCF proteins in the nucleus ; α-catenin (α-cat ) which binds to both β-catenin and Ajuba , a close relative of zyxin ; and Ajuba , which can associate with proteins that bind to the actin cytoskeleton , as well as with Grb @-@ 2 , a mediator of the GTP nucleotide @-@ exchange protein Sos , involved in activation of the Ras @-@ MAPK signaling cascade . # ::alignments 0-1 1-1.3 3-1.1 5-1.2.1.4.3.1.1 6-1.2.1 6-1.2.1.3.2.1 7-1.2 8-1.2.1.1.1.1 10-1.2.1.1.1.1 12-1.2.1.1.1.1 18-1.2.1.1.2 19-1.2.1.1.3 20-1.2.1.1 22-1.2.1.2.1.1 27-1.2.1.2 27-1.2.1.2.2 27-1.2.1.2.2.r 28-1.2.1.2.2.1 29-1.2.1.2.2.1 30-1.2.1.2.2.1 33-1.2.1.3.2.1 35-1.2.1.2.3.1 36-1.2.1.2.3.4 37-1.2.1.2.3 38-1.2.1.2.3.2.r 40-1.2.1.2.3.2.1 41-1.2.1.2.3.2 43-1.2.1.2.3.3 45-1.2.1.2.3.3.2.1.1 48-1.2.1.4.3.1.2.2.1.3 49-1.2.1.2.3.3.3.r 51-1.2.1.2.3.3.3 53-1.2.1.3.1.1 57-1.2.1.3 57-1.2.1.3.2 57-1.2.1.3.2.r 60-1.2.1.3.2.1.1 61-1.2.1.3.2.1 62-1.2.1.4.1.1 65-1.2.1.4.2.2 68-1.2.1.4.2.1.1.1 71-1.2.1.4.1.1 74-1.2.1.4.3.2 75-1.2.1.4.3 77-1.2.1.2.3.3.2 77-1.2.1.4.2.1 79-1.2.1.4.3.1.1.1 80-1.2.1.4.3.1.1.1.1.r 82-1.2.1.4.3.1.1.1.1.1 83-1.2.1.4.3.1.1.1.1 85-1.2.1 86-1.2.1 87-1.2.1 89-1.2.1.4.3.1.2.1.1 91-1.2.1.4.3.1.2.1.1 94-1.2.1.4.3.1.2 94-1.2.1.4.3.1.2.2 94-1.2.1.4.3.1.2.2.r 97-1.2.1.4.3.1.2.2.1.3.1.1 98-1.2.1.4.3.1.2.2.1.3.1.2 100-1.2.1.4.3.1.2.2.1.3.1.3 101-1.2.1.4.3.1.2.2.1 101-1.2.1.4.3.1.2.2.1.3 101-1.2.1.4.3.1.2.2.1.3.r 102-1.2.1.4.3.1.2.2.1.1.1 104-1.2.1.4.3.1.2.2.1.2 105-1.2.1.4.3.1.2.2.1.2.1.r 106-1.2.1.4.3.1.2.2.1.2.1 107-1.2.1.4.3.1.2.2.1.2.1.1.r 109-1.2.1.4.3.1.2.2.1.2.1.1.1.1 111-1.2.1.4.3.1.2.2.1.2.1.1.1.2 112-1.2.1.4.3.1.2.2.1.2.1.1.2 (a / antibody~e.0 :ARG0-of (c / counter-01~e.3 :ARG1 (m / macro-molecular-complex :name (n10 / name :op1 "adherens" :op2 "junction"))) :ARG2-of (i / include-01~e.7 :ARG1 (a2 / and~e.6,85,86,87 :op1 (p3 / protein~e.20 :name (n3 / name :op1 "E-cadherin"~e.8,10,12) :mod (t / transmembrane~e.18) :mod (c2 / core~e.19)) :op2 (p4 / protein~e.27 :name (n4 / name :op1 "β-catenin"~e.22) :ARG0-of~e.27 (b / bind-01~e.27 :ARG1 p3~e.28,29,30 :ARG2 m) :ARG0-of (p7 / participate-01~e.37 :ARG1-of (p8 / possible-01~e.35) :mod~e.38 (c3 / cofactor~e.41 :ARG0-of (t2 / transcribe-01~e.40)) :condition (a3 / associate-01~e.43 :ARG1 p4 :ARG2 (p16 / protein~e.77 :name (n14 / name :op1 "LEF-1"~e.45 :op2 "TCF")) :location~e.49 (n8 / nucleus~e.51)) :mod (a8 / also~e.36))) :op3 (p5 / protein~e.57 :name (n5 / name :op1 "α-catenin"~e.53) :ARG0-of~e.57 (b2 / bind-01~e.57 :ARG2 (a4 / and~e.6,33,61 :op1 p4~e.60 :op2 p6))) :op4 (p6 / protein :name (n6 / name :op1 "Ajuba"~e.62,71) :ARG1-of (r / relate-01 :ARG2 (p10 / protein~e.77 :name (n9 / name :op1 "zyxin"~e.68)) :ARG1-of (c4 / close-10~e.65)) :ARG1-of (a5 / associate-01~e.75 :ARG2 (a6 / and :op1 (p12 / protein~e.5 :ARG1-of (b3 / bind-01~e.79 :ARG2~e.80 (c5 / cytoskeleton~e.83 :mod (a9 / actin~e.82)))) :op2 (p13 / protein~e.94 :name (n11 / name :op1 "Grb-2"~e.89,91) :ARG0-of~e.94 (m2 / mediate-01~e.94 :ARG1 (p / protein~e.101 :name (n7 / name :op1 "Sos"~e.102) :ARG1-of (i2 / involve-01~e.104 :ARG2~e.105 (a7 / activate-01~e.106 :ARG1~e.107 (p15 / pathway :name (n13 / name :op1 "Ras"~e.109 :op2 "MAPK"~e.111) :ARG0-of (s / signal-07~e.112)))) :mod~e.101 (p9 / protein~e.48,101 :name (n / name :op1 "GTP"~e.97 :op2 "nucleotide"~e.98 :op3 "exchange"~e.100 :op4 "factor")))))) :ARG1-of (p11 / possible-01~e.74))))) :ARG1-of (u / use-01~e.1)) # ::id pmid_1563_0473.357 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In Snail @-@ expressing Tg regions , there was a reduced staining with anti @-@ E @-@ cad and anti-α-cat and a more diffuse staining with anti @-@ Ajuba . # ::alignments 1-1.3.1.1.1.1 3-1.3.1 4-1.3.2 5-1.3 10-1.1.2 11-1.1 13-1.1.1.1.1 13-1.1.1.2.1 15-1.1.1.1.1.1.1.1 18-1 18-1.1.1 20-1 22-1.2.2.1 23-1.2.2 24-1.2 26-1.2.1.1 28-1.2.1.1.1.1.1 (a / and~e.18,20 :op1 (s / stain-01~e.11 :ARG2 (a2 / and~e.18 :op1 (a3 / antibody :ARG0-of (c / counter-01~e.13 :ARG1 (p / protein :name (n / name :op1 "E-cadherin"~e.15)))) :op2 (a4 / antibody :ARG0-of (c2 / counter-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "α-catenin"))))) :ARG1-of (r2 / reduce-01~e.10)) :op2 (s2 / stain-01~e.24 :ARG2 (a5 / antibody :ARG0-of (c3 / counter-01~e.26 :ARG1 (p4 / protein :name (n4 / name :op1 "Ajuba"~e.28)))) :mod (d / diffuse~e.23 :degree (m / more~e.22))) :location (r / region~e.5 :ARG3-of (e / express-03~e.3 :ARG2 (p3 / protein :name (n3 / name :op1 "Snail"~e.1))) :mod (t / transgenic~e.4))) # ::id pmid_1563_0473.358 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Insets in the panels for β-catenin and Ajuba staining are magnified views of the boxed areas . # ::alignments 3-1.1.1 3-1.1.2 5-1.1.1.1.1.1.1 6-1.1 7-1.1.2.1.1.1.1 8-1.1.1.1 8-1.1.2.1 9-1.2.r 10-1.2.2 11-1.2 12-1.2.1.r 14-1.2.1.1 15-1.2.1 (i / inset :location (a / and~e.6 :op1 (p4 / panel~e.3 :purpose (s / stain-01~e.8 :ARG1 (p2 / protein :name (n / name :op1 "β-catenin"~e.5)))) :op2 (p5 / panel~e.3 :purpose (s2 / stain-01~e.8 :ARG1 (p3 / protein :name (n2 / name :op1 "Ajuba"~e.7))))) :domain~e.9 (v / view-01~e.11 :ARG1~e.12 (a2 / area~e.15 :ARG1-of (b / box-02~e.14)) :ARG1-of (m / magnify-01~e.10))) # ::id pmid_1563_0473.359 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Arrows mark membrane localization of the protein and asterisks mark cells with elevated levels of cytoplasmic β-catenin or Ajuba . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.2 3-1.1.2 6-1.1.2.1 7-1 8-1.2.1 9-1.2 10-1.2.2 12-1.2.2.1.1.1 13-1.2.2.1.1 14-1.2.2.1.1.2.r 15-1.2.2.1.1.2.1.2 16-1.2.2.1.1.2.1.1.1 17-1.2.2.1.1.2 18-1.2.2.1.1.2.2.1.1 (a / and~e.7 :op1 (m / mark-01~e.1 :ARG0 (a2 / arrow~e.0) :ARG1 (b / be-located-at-91~e.3 :ARG1 (p / protein~e.6) :ARG2 (m3 / membrane~e.2))) :op2 (m2 / mark-01~e.9 :ARG0 (a3 / asterisk~e.8) :ARG1 (c / cell~e.10 :ARG0-of (h / have-03 :ARG1 (l / level~e.13 :ARG1-of (e / elevate-01~e.12) :quant-of~e.14 (o / or~e.17 :op1 (p2 / protein :name (n / name :op1 "β-catenin"~e.16) :mod (c2 / cytoplasm~e.15)) :op2 (p3 / protein :name (n2 / name :op1 "Ajuba"~e.18) :mod c2))))))) # ::id pmid_1563_0473.360 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) Western blot analyses of protein extracts from P30 Wt and Tg back and ear skins . # ::alignments 1-1.2.1.1 3-1 4-1 6-1.1.r 7-1.1 8-1.1.1 12-1.1.1.1.1.2 13-1.1.1.1.2.1 14-1.1.1.1.1.2.1 15-1.1.1.1.1.2 16-1.1.1.1.1.2.2 17-1.1.1.1.1 17-1.1.1.1.2 (i / immunoblot-01~e.3,4 :ARG1~e.6 (p / protein~e.7 :ARG1-of (e / extract-01~e.8 :ARG2 (a4 / and :op1 (s2 / skin~e.17 :mod (w2 / wild-type) :part-of (a3 / and~e.12,15 :op1 (b / back~e.14) :op2 (e2 / ear~e.16)) :age (t2 / temporal-quantity :quant 30 :unit (d2 / day))) :op2 (s3 / skin~e.17 :mod (t / transgenic~e.13) :part-of a3 :age t2)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"~e.1))) # ::id pmid_1563_0473.361 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Antibodies are as in ( A ) except anti @-@ P @-@ cad , which detects P @-@ cadherin , whose expression in the hair follicle was not affected , and anti @-@ tubulin , which detects tubulin , a control for equal protein loadings . # ::alignments 0-1.1 0-1.2 0-1.3.1.1 0-1.3.1.2 5-1.2.1.1 7-1.3 8-1.3.1.1.1 8-1.3.1.2.1 10-1.3.1.1.2.1 15-1.3.1.1.2 16-1.3.1.1.1.1.2.1 18-1.3.1.1.1.1.2.1 21-1.3.1.1.1.1 21-1.3.1.1.1.1.3 21-1.3.1.1.1.1.3.r 22-1.3.1.1.1.1.3.1.r 24-1.3.1.1.1.1.3.1.1 25-1.3.1.1.1.1.3.1 27-1.3.1.1.1.1.3.2.1 27-1.3.1.1.1.1.3.2.1.r 28-1.3.1.1.1.1.3.2 31-1.3.1.1.1 33-1.3.1.2.2.1 36-1.3.1.2.2 37-1.3.1.2.2.1 38-1.3.1.2.2.1 39-1.3.1.2.2.1 40-1.3.1.2.2.1 41-1.3.1.2.2.1 42-1.3.1.2.2.1 43-1.3.1.2.2.1 44-1.3.1.2.2.1 (r / resemble-01 :ARG1 (a / antibody~e.0) :ARG2 (a6 / antibody~e.0 :location (f / figure :mod "A"~e.5)) :ARG2-of (e / except-01~e.7 :ARG1 (a2 / and :op1 (a3 / antibody~e.0 :ARG0-of (c / counter-01~e.8,31 :ARG1 (p / protein~e.21 :wiki - :name (n / name :op1 "P-cadherin"~e.16,18) :ARG2-of~e.21 (e2 / express-03~e.21 :ARG3~e.22 (f2 / follicle~e.25 :mod (h / hair~e.24)) :ARG1-of (a5 / affect-01~e.28 :polarity~e.27 -~e.27)))) :ARG0-of (d / detect-01~e.15 :ARG1 p~e.10)) :op2 (a4 / antibody~e.0 :ARG0-of (c2 / counter-01~e.8 :ARG1 (p2 / protein :wiki "Tubulin" :name (n2 / name :op1 "tubulin") :ARG0-of (c3 / control-01 :ARG1 (l2 / load-01 :ARG1 (p3 / protein) :ARG1-of (e3 / equal-01))))) :ARG0-of (d2 / detect-01~e.36 :ARG1 p2~e.33,37,38,39,40,41,42,43,44))))) # ::id pmid_1563_0473.362 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note that the reductions seen in E @-@ cadherin and α-catenin are likely to be underestimates of the actual differences in affected regions , since the Tg skin expressed Snail mosaically . # ::alignments 0-1 1-1.3.r 3-1.3.1.1 4-1.3.1.1.2 5-1.3.1.1.1.r 6-1.3.1.1.1.1.1.1 8-1.3.1.1.1.1.1.1 9-1.3.1.1.1 10-1.3.1.1.1.2.1.1 12-1.3 13-1.3.2 15-1.3.1 16-1.3.1.2.r 18-1.3.1.2.1 19-1.3.1.2 20-1.3.1.2.2.r 21-1.3.1.2.2.1 22-1.3.1.2.2 24-1.3.2 26-1.3.2.1.2.1 27-1.3.2.1.2 28-1.3.2.1 29-1.3.2.1.1.1.1 (n / note-02~e.0 :mode imperative :ARG0 (y / you) :ARG1~e.1 (l / likely-01~e.12 :ARG1 (u / underestimate-01~e.15 :ARG0 (r / reduce-01~e.3 :ARG1~e.5 (a / and~e.9 :op1 (p / protein :name (n2 / name :op1 "E-cadherin"~e.6,8)) :op2 (p2 / protein :name (n3 / name :op1 "α-catenin"~e.10))) :ARG1-of (s2 / see-01~e.4)) :ARG1~e.16 (d / differ-02~e.19 :ARG1-of (a2 / actual-02~e.18) :location~e.20 (r2 / region~e.22 :ARG1-of (a3 / affect-01~e.21)))) :ARG1-of (c / cause-01~e.13,24 :ARG0 (e / express-03~e.28 :ARG2 (p3 / protein :name (n4 / name :op1 "Snail"~e.29)) :ARG3 (s / skin~e.27 :mod (t / transgenic~e.26)) :manner (m / mosaical))))) # ::id pmid_1563_0473.363 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) In the presence of elevated Snail , α-catenin levels can be restored by overexpression of E @-@ cadherin . # ::alignments 1-1.3.1.1 5-1.2 6-1.2.1.r 7-1.2.1.2 8-1.2.1.1.1 10-1.1.1.1.1.1 11-1.1.1 12-1 14-1.1 15-1.1.2.r 16-1.1.2 17-1.1.2.1.r 18-1.1.2.1.1.1 20-1.1.2.1.1.1 (p / possible-01~e.12 :ARG1 (r / restore-01~e.14 :ARG1 (l / level~e.11 :quant-of (p2 / protein :name (n / name :op1 "α-catenin"~e.10))) :manner~e.15 (o / overexpress-01~e.16 :ARG1~e.17 (p3 / protein :name (n2 / name :op1 "E-cadherin"~e.18,20)))) :condition (p4 / present-02~e.5 :ARG1~e.6 (p5 / protein :name (n3 / name :op1 "Snail"~e.8) :ARG1-of (e2 / elevate-01~e.7))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"~e.1))) # ::id pmid_1563_0473.364 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Keratinocytes were transfected with either HA @-@ tagged Snail ( Snail[HA ] ; images on the left ) or Snail( HA ) and Ecad( HA ) ( images on the right ) . # ::alignments 0-1.1.1.1 2-1 5-1.2.1.2.1.1.1 7-1.2.1.2 7-1.2.2.2.2 8-1.2.1.1.1 13-1.2.1.3.1 14-1.2.1.3.1.1.r 16-1.2.1.3.1.1 18-1.2 20-1.2.2.1 21-1.2.2.1 22-1.2.2.1 23-1.2.2.1 24-1.2.2.1 27-1.2.2.3.1 28-1.2.2.3.1.1.r 30-1.2.2.3.1.1 (t / transfect-01~e.2 :ARG1 (c / cell :name (n / name :op1 "keratinocyte"~e.0)) :ARG2 (o2 / or~e.18 :op1 (p / protein :name (n2 / name :op1 "Snail"~e.8) :ARG1-of (t2 / tag-01~e.7 :ARG2 (p2 / protein :name (n3 / name :op1 "HA"~e.5))) :ARG1-of (d / describe-01 :ARG0 (i / image~e.13 :ARG1-of~e.14 (l / left-20~e.16)))) :op2 (a / and :op1 p~e.20,21,22,23,24 :op2 (p4 / protein :name (n5 / name :op1 "E-cadherin") :ARG1-of (t4 / tag-01~e.7 :ARG2 p2)) :ARG1-of (d2 / describe-01 :ARG0 (i2 / image~e.27 :ARG1-of~e.28 (r / right-04~e.30)))))) # ::id pmid_1563_0473.365 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 2 d after transfection , cells were switched from low @-@ calcium growth medium to high @-@ calcium medium for 6 h to induce AJ formation . # ::alignments 0-1.6.2.1 2-1.6 3-1.6.1 5-1.1 7-1 9-1.3.2 11-1.2.2 11-1.3.2.1 12-1.2.1 12-1.3.1 13-1.2 13-1.3 15-1.2.2.1 17-1.2.2 18-1.2 19-1.4.r 20-1.4.1 21-1.4.2 23-1.5 24-1.5.1.1.1.1 25-1.5.1 (s / switch-01~e.7 :ARG1 (c / cell~e.5) :ARG2 (m2 / medium~e.13,18 :mod (g2 / grow-01~e.12) :mod (c3 / calcium~e.11,17 :ARG1-of (h / high-02~e.15))) :ARG3 (m / medium~e.13 :mod (g / grow-01~e.12) :ARG1-of (l / low-04~e.9 :ARG2 (c2 / calcium~e.11))) :duration~e.19 (t / temporal-quantity :quant 6~e.20 :unit (h2 / hour~e.21)) :purpose (i / induce-01~e.23 :ARG2 (f / form-01~e.25 :ARG1 (p / protein :name (n / name :op1 "AJ"~e.24)))) :time (a / after~e.2 :op1 (t2 / transfect-01~e.3) :quant (t3 / temporal-quantity :quant 2~e.0 :unit (d / day)))) # ::id pmid_1563_0473.366 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were stained with antibodies as indicated on the panels . # ::alignments 0-1.1 2-1 3-1.2.r 4-1.2 5-1.3.r 6-1.3 7-1.3.1.r 9-1.3.1 (s / stain-01~e.2 :ARG1 (c / cell~e.0) :ARG2~e.3 (a / antibody~e.4) :ARG1-of~e.5 (i / indicate-01~e.6 :location~e.7 (p / panel~e.9))) # ::id pmid_1563_0473.367 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Arrowheads point to sites of intercellular contact between a Snail @-@ transfected keratinocyte and its neighboring untransfected cell . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2 4-1.2.1.r 5-1.2.1.3 6-1.2.1 9-1.2.1.1.2.1.1.1 11-1.2.1.1.2 11-1.2.1.2.1 12-1.2.1.1.1.1 14-1.2.1.2.2.1 14-1.2.1.2.2.1.r 15-1.2.1.2.2 17-1.2.1.2 (p / point-01~e.1 :ARG0 (a / arrowhead~e.0) :ARG2~e.2 (s / site~e.3 :location-of~e.4 (c / contact-01~e.6 :ARG0 (c2 / cell :name (n / name :op1 "keratinocyte"~e.12) :ARG1-of (t / transfect-01~e.11 :ARG2 (p2 / protein :name (n2 / name :op1 "Snail"~e.9)))) :ARG1 (c3 / cell~e.17 :ARG1-of (t2 / transfect-01~e.11 :polarity -) :ARG1-of (n3 / neighbor-01~e.15 :ARG2~e.14 c2~e.14)) :mod (i / intercellular~e.5)))) # ::id pmid_1563_0473.368 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D ) Reintroduction of E @-@ cadherin in keratinocytes expressing Snail returns pMAPK to basal levels . # ::alignments 1-1.4.1.1 6-1.1.1.1.1 8-1.1.1.1.1 11-1.1.2.1.1 12-1.1.2.2 13-1.1.2.2.1.1.1 14-1 15-1.2.1.1 15-1.2.2 16-1.3.r 17-1.3.1 18-1.3 (r / return-04~e.14 :ARG0 (r3 / reintroduce-01 :ARG1 (g / gene :name (n / name :op1 "E-cadherin"~e.6,8)) :ARG2 (c / cell :name (n2 / name :op1 "keratinocyte"~e.11) :ARG1-of (e / express-03~e.12 :ARG2 (p2 / protein :name (n3 / name :op1 "Snail"~e.13))))) :ARG1 (e2 / enzyme :name (n4 / name :op1 "MAPK"~e.15) :ARG3-of (p4 / phosphorylate-01~e.15)) :ARG2~e.16 (l / level~e.18 :mod (b / basal~e.17)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "D"~e.1))) # ::id pmid_1563_0473.369 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Keratinocytes were transfected with control vector ( K14 ) , or Snail( HA ) , or Snail( HA ) + E @-@ cad( HA ) @ . # ::alignments 0-1.1.1.1 2-1 3-1.2.r 4-1.2.1.2 5-1.2.1 7-1.2.1.1.1 10-1.2 17-1.2 23-1.2.3 25-1.2.3.2.1.1 (t / transfect-01~e.2 :ARG1 (c / cell :name (n / name :op1 "keratinocyte"~e.0)) :ARG2~e.3 (o / or~e.10,17 :op1 (v2 / vector~e.5 :name (n2 / name :op1 "K14"~e.7) :ARG0-of (c2 / control-01~e.4)) :op2 (g / gene :name (n3 / name :op1 "Snail(HA)")) :op3 (a / and~e.23 :op1 g :op2 (g2 / gene :name (n4 / name :op1 "E-cad(HA)"~e.25))))) # ::id pmid_1563_0473.370 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 2 d , cells were serum starved for 4 h and whole cell lysates were made and Western blotted with antibodies to pMAPK , HA to recognize the HA @-@ tagged Snail and E @-@ cadherin protein , 20 or tubulin as a loading control . # ::alignments 0-1.4 1-1.4.1.1 4-1.1.1 6-1.1.2 7-1.1 8-1.1.3.r 9-1.1.3.1 10-1.1.3.2 11-1 12-1.2.1.1 13-1.2.1.2 14-1.2.1 16-1.2 17-1 20-1.3.2.3.r 21-1.3.2.1 23-1.3.2.1.1.1.1.1 23-1.3.2.1.1.1.2 25-1.3.2.2.1.1 27-1.3.2.2.2 29-1.3.2.2.1.1 31-1.3.2.2.2.1.1.2 32-1.3.2.2.2.1.1.1.1 33-1.3.2.2.2.1 34-1.3.2.2.2.1.2.1.1 36-1.3.2.2.2.1.2.1.1 37-1.3.2.2 37-1.3.2.2.2.1.1 37-1.3.2.2.2.1.2 37-1.3.2.3 41-1.3.2.3.1.1 42-1.3.2.3.2.r 42-1.4.r 44-1.3.2.3.2.1 45-1.3.2.3.2 (a / and~e.11,17 :op1 (s / starve-01~e.7 :ARG1 (c / cell~e.4) :ARG2 (s2 / serum~e.6) :duration~e.8 (t / temporal-quantity :quant 4~e.9 :unit (h / hour~e.10))) :op2 (m / make-01~e.16 :ARG1 (l / lysate~e.14 :mod (w2 / whole~e.12) :mod (c2 / cell~e.13))) :op3 (i / immunoblot-01 :ARG2 l :ARG3 (a2 / and :op1 (a3 / antibody~e.21 :ARG0-of (o / oppose-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MAPK"~e.23) :ARG3-of (p2 / phosphorylate-01~e.23)))) :op2 (p6 / protein~e.37 :name (n3 / name :op1 "HA"~e.25,29) :purpose (r / recognize-02~e.27 :ARG1 (a4 / and~e.33 :op1 (p3 / protein~e.37 :name (n4 / name :op1 "Snail"~e.32) :ARG1-of (t2 / tag-01~e.31 :ARG2 p6)) :op2 (p4 / protein~e.37 :name (n5 / name :op1 "E-cadherin"~e.34,36) :ARG1-of t2)))) :accompanier~e.20 (p5 / protein~e.37 :name (n6 / name :op1 "tubulin"~e.41) :ARG0-of~e.42 (c3 / control-01~e.45 :ARG0-of (l2 / load-01~e.44))))) :time~e.42 (a5 / after~e.0 :quant (t3 / temporal-quantity :quant 2~e.1 :unit (d2 / day)))) # ::id pmid_1563_0473.371 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( E ) Ajuba interacts with Grb @-@ 2 under conditions where α-catenin levels are reduced . # ::alignments 1-1.4.1.1 3-1.1.1.1 4-1 5-1.2.r 6-1.2.1.1 8-1.2.1.1 10-1.3.r 12-1.3.1.1.1.1 13-1.3.1 15-1.3 (i / interact-01~e.4 :ARG0 (p3 / protein :name (n / name :op1 "Ajuba"~e.3)) :ARG1~e.5 (p / protein :name (n2 / name :op1 "Grb-2"~e.6,8)) :condition~e.10 (r / reduce-01~e.15 :ARG1 (l / level~e.13 :quant-of (p2 / protein :name (n3 / name :op1 "α-catenin"~e.12)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"~e.1))) # ::id pmid_1563_0473.372 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein extracts were made from skins of P30 Wt and K14 @-@ Snail Tg P30 mice ( blots on the left ) and of newborn Wt and K14 @-@ Cre/α-catenin ( fl/fl ) conditionally null animals ( blots on the right ) [ @ 7 @ ] . # ::alignments 0-1.1 1-1 4-1.2.r 5-1.2.1.1 5-1.2.1.2 5-1.2.2.1 5-1.2.2.2 9-1.2 9-1.2.1 9-1.2.1.r 9-1.2.2 9-1.2.2.r 11-1.2.1.2.1.2.2.1 11-1.2.2.2.1.1.1.1.1 13-1.2.1.2.1.2.1.1 15-1.2.1.2.1.1 17-1.2.1.1.1 17-1.2.1.2.1 19-1.2.1.3.1 20-1.2.1.3.1.1.r 22-1.2.1.3.1.1 24-1.2 28-1.2 30-1.2.2.2.1.1.1.1.1 37-1.2.2.2.1.1.3.2 38-1.2.1.2.1.2 38-1.2.1.2.1.2.2 38-1.2.1.2.1.2.2.r 38-1.2.2.2.1.1 38-1.2.2.2.1.1.3 38-1.2.2.2.1.1.3.r 39-1.2.2.1.1 39-1.2.2.2.1 41-1.2.2.3.1 42-1.2.2.3.1.1.r 44-1.2.2.3.1.1 48-1.3.1.1.1 (e / extract-01~e.1 :ARG1 (p / protein~e.0) :ARG2~e.4 (a2 / and~e.9,24,28 :op1~e.9 (a6 / and~e.9 :op1 (s / skin~e.5 :part-of (m / mouse~e.17 :mod (w / wild-type) :age (t / temporal-quantity :quant 30 :unit (d / day)))) :op2 (s2 / skin~e.5 :part-of (m2 / mouse~e.17 :mod (t2 / transgenic~e.15) :mod (g / gene~e.38 :name (n / name :op1 "Snail"~e.13) :ARG2-of~e.38 (m5 / mutate-01~e.38 :value "K14"~e.11)) :age (t3 / temporal-quantity :quant 30 :unit (d2 / day)))) :ARG1-of (d4 / describe-01 :ARG0 (b2 / blot~e.19 :ARG1-of~e.20 (l / left-20~e.22)))) :op2~e.9 (a7 / and~e.9 :op1 (s3 / skin~e.5 :part-of (a4 / animal~e.39 :mod (w2 / wild-type) :ARG1-of (b / bear-02 :time (n4 / new-01)))) :op2 (s4 / skin~e.5 :part-of (a5 / animal~e.39 :mod (m3 / macro-molecular-complex~e.38 :part (p3 / protein :name (n2 / name :op1 "K14-Cre"~e.11,30)) :part (p4 / protein :name (n3 / name :op1 "α-catenin")) :ARG2-of~e.38 (m4 / mutate-01~e.38 :mod "−/−" :mod (c2 / conditional~e.37))))) :ARG1-of (d5 / describe-01 :ARG0 (b3 / blot~e.41 :ARG1-of~e.42 (r / right-04~e.44))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 7~e.48)))) # ::id pmid_1563_0473.373 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Equal amounts of protein extracts were treated with anti @-@ Grb @-@ 2 antibody (+) or control isotype antibody (–) , and following centrifugation , immunoprecipitates were subjected to SDS @-@ PAGE and Western blot analysis with anti @-@ Ajuba and anti @-@ Grb @-@ 2 antibodies . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 4-1.1.1.2 4-1.1.1.2.1 4-1.1.1.2.1.r 6-1.1 8-1.1.2.1.1 8-1.2.2.2.2.2.2.1 10-1.1.2.1.1.1.1.1 12-1.1.2.1.1.1.1.1 13-1.1.2.1 13-1.1.2.2 15-1.1.2 16-1.1.2.2.1.1 17-1.1.2.2.1 18-1.1.2.2 18-1.2.2.2.2.2.2 22-1.2.3 23-1.2.3.1 25-1.2.1 25-1.2.1.1 25-1.2.1.1.r 27-1.2 28-1.2.2.r 29-1.2.2.1.2.1.1 31-1.2.2.1.2.1.1 32-1.2.2 33-1.2.2.2.2 34-1.2.2.2.2 35-1.2.2.1 35-1.2.2.2 36-1.2.2.2.2.2.r 37-1.2.2.2.2.2.1.1 39-1.2.2.2.2.2.1.1.1.1.1 41-1.2.2.2.2.2.1.1 43-1.1.2.1.1.1.1.1 45-1.1.2.1.1.1.1.1 46-1.2.2.2.2.2.1 (a4 / and :op1 (t / treat-04~e.6 :ARG1 (a / amount~e.1 :ARG1-of (e2 / equal-01~e.0) :quant-of~e.2 (t2 / thing~e.4 :ARG1-of~e.4 (e / extract-01~e.4 :ARG2 (p4 / protein~e.3)))) :ARG2 (o2 / or~e.15 :op1 (a2 / antibody~e.13 :ARG0-of (o / oppose-01~e.8 :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2"~e.10,12,43,45)))) :op2 (a3 / antibody~e.13,18 :mod (i / isotype~e.17 :ARG1-of (c / control-01~e.16))))) :op2 (s / subject-01~e.27 :ARG1 (m / molecular-physical-entity~e.25 :ARG1-of~e.25 (i2 / immunoprecipitate-01~e.25)) :ARG2~e.28 (a9 / and~e.32 :op1 (a5 / analyze-01~e.35 :ARG1 m :mod (t5 / thing :name (n / name :op1 "SDS-PAGE"~e.29,31))) :op2 (a8 / analyze-01~e.35 :ARG1 m :manner (i3 / immunoblot-01~e.33,34 :ARG1 m :ARG3~e.36 (a10 / and :op1 (a6 / antibody~e.46 :ARG0-of (o3 / oppose-01~e.37,41 :ARG1 (p3 / protein :name (n3 / name :op1 "Ajuba"~e.39)))) :op2 (a7 / antibody~e.18 :ARG0-of (o4 / oppose-01~e.8 :ARG1 p2)))))) :ARG1-of (f / follow-01~e.22 :ARG2 (c2 / centrifugate~e.23)))) # ::id pmid_1563_0473.374 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note the presence of Ajuba only under conditions where levels of α-catenin and other AJ proteins were aberrantly low or absent . # ::alignments 0-1 2-1.2 4-1.2.1.1.1 5-1.2.3 7-1.2.2.r 9-1.2.2.1.1.1 9-1.2.2.1.1.2 11-1.2.2.1.1.1.1.1.1 12-1.2.2.1.1 13-1.2.2.1.1.2.1.2 14-1.2.2.1.1.2.1.1.1 15-1.2.1 15-1.2.2.1.1.1.1 15-1.2.2.1.1.2.1 18-1.2.2.1 19-1.2.2 20-1.2.2.2 (n / note-02~e.0 :ARG0 (y / you) :ARG1 (p / present-02~e.2 :ARG1 (p2 / protein~e.15 :name (n2 / name :op1 "Ajuba"~e.4)) :condition~e.7 (o / or~e.19 :op1 (l / low-04~e.18 :ARG1 (a4 / and~e.12 :op1 (l2 / level~e.9 :quant-of (p3 / protein~e.15 :name (n3 / name :op1 "α-catenin"~e.11))) :op2 (l3 / level~e.9 :quant-of (p4 / protein~e.15 :name (n4 / name :op1 "AJ"~e.14) :mod (o2 / other~e.13)))) :mod (a2 / aberrant)) :op2 (a / absent-01~e.20 :ARG1 a4)) :mod (o3 / only~e.5))) # ::id pmid_1563_0473.375 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( F ) Transgene expression of excess Ajuba or the Grb @-@ 2 @-@ interacting domain ( pre @-@ LIM ) of Ajuba in keratinocytes results in the activation of the Ras @-@ MAPK pathway . # ::alignments 1-1.3.1.1 3-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1.1 6-1.1.1.1.2 6-1.1.1.1.2.r 7-1.1.1.1.1.1 8-1.1.1 10-1.1.1.2.2.1.1.1 12-1.1.1.2.2.1.1.1 14-1.1.1.2.2 17-1.1.1.2.1.1 19-1.1.1.2.1.1 22-1.1.1.2.4 24-1.1.1.2.3.1.1 25-1 26-1.2.r 28-1.2 29-1.2.1.r 31-1.2.1.1.1 33-1.2.1.1.1 34-1.2.1 (r / result-01~e.25 :ARG1 (e / express-03~e.4 :ARG2~e.5 (o / or~e.8 :op1 (p / protein~e.6 :name (n / name :op1 "Ajuba"~e.7) :ARG0-of~e.6 (e3 / exceed-01~e.6)) :op2 (p5 / protein-segment :name (n6 / name :op1 "pre-LIM"~e.17,19) :ARG0-of (i2 / interact-01~e.14 :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2"~e.10,12))) :location (c / cell :name (n3 / name :op1 "keratinocyte"~e.24)) :part-of p~e.22)) :mod (t / transgene~e.3)) :ARG2~e.26 (a / activate-01~e.28 :ARG1~e.29 (p3 / pathway~e.34 :name (n4 / name :op1 "Ras-MAPK"~e.31,33))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "F"~e.1))) # ::id pmid_1563_0473.376 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Primary newborn mouse keratinocytes were transfected with either the empty K14 expression vector ( K14 ) , or the expression vector driving Snail , full length Ajuba , or the pre @-@ LIM domain of Ajuba in the absence or presence of a peptide inhibitor ( inh ) that disrupts the interaction between Grb @-@ 2 and Sos . # ::alignments 0-1.1.2.1 2-1.1.2 3-1.1.1.1 5-1 9-1.2.1.2 10-1.2.1.1.1.1.1 11-1.2.1.1 12-1.2.1 14-1.2.1.1.1.1.1 17-1.2 19-1.2.2.1 20-1.2.2 21-1.2.2.2 22-1.2.2.2.1.1.1 24-1.2.3.2.1 25-1.2.3 25-1.2.3.2 25-1.2.3.2.r 26-1.2.3.1.1 28-1.2 30-1.2.4.1.1 32-1.2.4.1.1 35-1.2.4.2 36-1.3.r 38-1.3.1 39-1.3 40-1.3.2 41-1.3.1.1.r 43-1.3.1.1.1.1.1.1 44-1.3.1.1 44-1.3.1.1.1 44-1.3.1.1.1.r 49-1.3.1.1.1.2 51-1.3.1.1.1.2.1 53-1.3.1.1.1.2.1.1.1.1 55-1.3.1.1.1.2.1.1.1.1 57-1.3.1.1.1.2.1.2.1.1 (t2 / transfect-01~e.5 :ARG1 (c / cell :name (n / name :op1 "keratinocyte"~e.3) :part-of (m / mouse~e.2 :mod (p / primary~e.0) :ARG1-of (b / bear-02 :time (n2 / new-01)))) :ARG2 (o / or~e.17,28 :op1 (v / vector~e.12 :ARG1-of (e / express-03~e.11 :ARG2 (p8 / protein :name (n3 / name :op1 "K14"~e.10,14))) :ARG1-of (e3 / empty-02~e.9)) :op2 (v2 / vector~e.20 :ARG1-of (e4 / express-03~e.19) :ARG0-of (d / drive-02~e.21 :ARG1 (p2 / protein :name (n4 / name :op1 "Snail"~e.22)))) :op3 (p7 / protein~e.25 :name (n5 / name :op1 "Ajuba"~e.26) :ARG1-of~e.25 (l / long-03~e.25 :degree (f2 / full~e.24))) :op4 (p6 / protein-segment :name (n10 / name :op1 "pre-LIM"~e.30,32) :part-of p7~e.35)) :condition~e.36 (o2 / or~e.39 :op1 (a / absence~e.38 :domain~e.41 (m2 / molecular-physical-entity~e.44 :ARG0-of~e.44 (i2 / inhibit-01~e.44 :ARG1 (s / small-molecule :name (n7 / name :op1 "peptide"~e.43)) :ARG0-of (d3 / disrupt-01~e.49 :ARG1 (i3 / interact-01~e.51 :ARG0 (p4 / protein :name (n8 / name :op1 "Grb-2"~e.53,55)) :ARG1 (p5 / protein :name (n9 / name :op1 "Sos"~e.57))))))) :op2 (p3 / present-02~e.40 :ARG1 m2))) # ::id pmid_1563_0473.377 ::amr-annotator SDL-AMR-09 ::preferred # ::tok 48 h posttransfection , protein extracts were prepared and subjected to SDS @-@ PAGE and Western blot analyses with antibodies against pMAPK , total MAPK , Ajuba ( also recognizing the smaller , pre @-@ LIM domain ) , and Snail . # ::alignments 0-1.3.2.1 1-1.3.2.2 4-1.1.1.1.1 5-1.1.1 5-1.1.1.1 5-1.1.1.1.r 7-1.1 8-1 9-1.2 10-1.2.2.r 11-1.2.2.1.2.1.1 13-1.2.2.1.2.1.1 14-1.2.2 15-1.2.2.2.2 16-1.2.2.2.2 17-1.2.2.1 17-1.2.2.2 18-1.2.2.2.2.2.r 19-1.2.2.2.2.2 20-1.2.2.2.2.2.1 21-1.2.2.2.2.2.1.1.1.2 23-1.2.2.2.2.2.1.1.2.2 24-1.2.2.2.2.2.1.1.1.1.1 24-1.2.2.2.2.2.1.1.2.1.1 26-1.2.2.2.2.2.1.1.3.1.1 28-1.2.2.2.2.2.2.2 29-1.2.2.2.2.2.2 31-1.2.2.2.2.2.2.1.2 31-1.2.2.2.2.2.2.1.2.1 31-1.2.2.2.2.2.2.1.2.1.r 33-1.2.2.2.2.2.2.1.1.1 35-1.2.2.2.2.2.2.1.1.1 40-1.2.2.2.2.2.1.1.4.1.1 (a / and~e.8 :op1 (p2 / prepare-02~e.7 :ARG1 (t4 / thing~e.5 :ARG1-of~e.5 (e2 / extract-01~e.5 :ARG2 (p8 / protein~e.4)))) :op2 (s / subject-01~e.9 :ARG1 t4 :ARG2~e.10 (a2 / and~e.14 :op1 (a3 / analyze-01~e.17 :ARG1 t4 :mod (t5 / thing :name (n / name :op1 "SDS-PAGE"~e.11,13))) :op2 (a4 / analyze-01~e.17 :ARG1 t4 :manner (i / immunoblot-01~e.15,16 :ARG1 t4 :ARG3~e.18 (a5 / antibody~e.19 :ARG0-of (o / oppose-01~e.20 :ARG1 (a6 / and :op1 (e / enzyme :name (n2 / name :op1 "MAPK"~e.24) :ARG3-of (p4 / phosphorylate-01~e.21)) :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK"~e.24) :mod (t / total~e.23)) :op3 (p6 / protein :name (n6 / name :op1 "Ajuba"~e.26)) :op4 (p7 / protein :name (n7 / name :op1 "Snail"~e.40)))) :ARG0-of (r / recognize-02~e.29 :ARG1 (p9 / protein-segment :name (n9 / name :op1 "pre-LIM"~e.33,35) :mod (s2 / small~e.31 :degree~e.31 (m / more~e.31))) :mod (a8 / also~e.28))))))) :time (a7 / after :op1 (t2 / transfect-01) :quant (t3 / temporal-quantity :quant 48~e.0 :unit (h / hour~e.1)))) # ::id pmid_1563_0473.378 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 5 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 5~e.1) # ::id pmid_1563_0473.379 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A ) Failure of Wnt and noggin signaling to induce Snail in cultured keratinocytes . # ::alignments 1-1.3.1.1 3-1 4-1.1.r 5-1.1.1.1.1.1 6-1.1 7-1.1.2.1.1.1 8-1.1.1 8-1.1.2 10-1.2 11-1.2.2.1.1 12-1.2.3.r 13-1.2.3.2 14-1.2.3.1.1 (f / fail-01~e.3 :ARG1~e.4 (a / and~e.6 :op1 (s / signal-07~e.8 :ARG0 (p / pathway :name (n / name :op1 "Wnt"~e.5))) :op2 (s2 / signal-07~e.8 :ARG0 (p2 / protein :name (n2 / name :op1 "noggin"~e.7)))) :ARG2 (i / induce-01~e.10 :ARG0 a :ARG2 (p3 / protein :name (n3 / name :op1 "Snail"~e.11)) :location~e.12 (c / cell :name (n4 / name :op1 "keratinocyte"~e.14) :ARG1-of (c2 / culture-01~e.13))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "A"~e.1))) # ::id pmid_1563_0473.380 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Primary mouse keratinocytes were treated with Wnt @- and @/@ or noggin @-@ conditioned medium (+) or the corresponding control medium (–) . # ::alignments 0-1.1.3 1-1.1.2 2-1.1.1.1 4-1 5-1.2.r 6-1.2.1.1.1.1.1.1 8-1.2.1.1.1 10-1.2.1.1.1 11-1.2.1.1.1.2.1.1 13-1.2.1.1 14-1.2.1 16-1.2 18-1.2.2.1 19-1.2.2.2 20-1.2.2 (t / treat-04~e.4 :ARG1 (c / cell :name (n / name :op1 "keratinocyte"~e.2) :part-of (m / mouse~e.1) :mod (p / primary~e.0)) :ARG2~e.5 (o3 / or~e.16 :op1 (m2 / medium~e.14 :ARG1-of (c2 / condition-02~e.13 :ARG2 (a2 / and-or~e.8,10 :op1 (p2 / pathway :name (n2 / name :op1 "Wnt"~e.6)) :op2 (p3 / protein :name (n3 / name :op1 "noggin"~e.11))))) :op2 (m3 / medium~e.20 :ARG2-of (c3 / correspond-02~e.18) :ARG0-of (c4 / control-01~e.19)))) # ::id pmid_1563_0473.381 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These conditions are known to activate the LEF @-@ 1/β-catenin reporter TOPGal and down @-@ regulate the E @-@ cadherin promoter ( see [ @ 4 @ ] for details ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1 3-1 5-1.1.1 7-1.1.1.2.2.1.1.1.1 10-1.1.1.2 10-1.1.1.2.2 10-1.1.1.2.2.r 11-1.1.1.2.1.1 12-1.1 18-1.1.2.1.1.1.1.1 20-1.1.2.1.1.1.1.1 22-1.1.2.1 22-1.1.2.1.1 22-1.1.2.1.1.r 24-1.2 27-1.2.3.1.1 30-1.2.2.r 31-1.2.2 (k / know-01~e.3 :ARG1 (a2 / and~e.12 :op1 (a / activate-01~e.5 :ARG0 (c / condition~e.1 :mod (t / this~e.0)) :ARG1 (t2 / thing~e.10 :name (n3 / name :op1 "TOPGal"~e.11) :ARG0-of~e.10 (r2 / report-01~e.10 :ARG1 (m3 / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "LEF-1"~e.7)) :part (p3 / protein :name (n2 / name :op1 "β-catenin")))))) :op2 (d4 / downregulate-01 :ARG1 (m / molecular-physical-entity~e.22 :ARG0-of~e.22 (p4 / promote-01~e.22 :ARG1 (g / gene :name (n4 / name :op1 "E-cadherin"~e.18,20)))))) :ARG1-of (s2 / see-01~e.24 :ARG0 (y / you) :purpose~e.30 (d / detail-01~e.31) :location (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 4~e.27)))) # ::id pmid_1563_0473.382 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using Western blot analyses , cellular proteins were then analyzed for Snail , LEF @-@ 1 , β-catenin , and tubulin . # ::alignments 0-1.2.r 0-1.3 1-1.3.1 2-1.3.1 3-1 5-1.1.1 6-1.1 9-1 11-1.2.1.1.1.1 13-1.2.1.2.1.1 15-1.2.1.2.1.1 17-1.2.1.3.1.1 19-1.2.1 20-1.2.1.4.1.1 (a / analyze-01~e.3,9 :ARG1 (p / protein~e.6 :mod (c / cell~e.5)) :purpose~e.0 (f / find-01 :ARG1 (a2 / and~e.19 :op1 (p2 / protein :name (n2 / name :op1 "Snail"~e.11)) :op2 (p3 / protein :name (n3 / name :op1 "LEF-1"~e.13,15)) :op3 (p4 / protein :name (n4 / name :op1 "β-catenin"~e.17)) :op4 (p5 / protein :name (n5 / name :op1 "tubulin"~e.20)))) :ARG0-of (u / use-01~e.0 :ARG1 (i / immunoblot-01~e.1,2))) # ::id pmid_1563_0473.383 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Proteins from keratinocytes transfected with K14 @- @ Snail were used as a positive control for Snail expression . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1.2 4-1.1.1.2.1.r 5-1.1.1.2.1.2.1 8-1.1.1.2.1.1.1 11-1 12-1.2.r 14-1.2.3 15-1.2 16-1.2.2.r 17-1.2.2.1.1.1 18-1.2.2 (u / use-01~e.11 :ARG1 (p / protein~e.0 :source~e.1 (c / cell :name (n / name :op1 "keratinocyte"~e.2) :ARG1-of (t / transfect-01~e.3 :ARG2~e.4 (g / gene :name (n2 / name :op1 "Snail"~e.8) :ARG2-of (m / mutate-01 :value "K14"~e.5))))) :ARG2~e.12 (c2 / control-01~e.15 :ARG0 p :ARG1~e.16 (e2 / express-03~e.18 :ARG2 (p4 / protein :name (n4 / name :op1 "Snail"~e.17))) :mod (p3 / positive~e.14))) # ::id pmid_1563_0473.384 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( B ) TGF-β2 can induce Snail protein . # ::alignments 1-1.2.1.1 3-1.1.1.1.1 4-1 5-1.1 6-1.1.2.1.1 7-1.1.1 7-1.1.2 (p / possible-01~e.4 :ARG1 (i / induce-01~e.5 :ARG0 (p2 / protein~e.7 :name (n / name :op1 "TGF-β2"~e.3)) :ARG2 (p3 / protein~e.7 :name (n2 / name :op1 "Snail"~e.6))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"~e.1))) # ::id pmid_1563_0473.385 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Primary keratinocytes were treated for the indicated times with recombinant TGF-β2 (+) or heat inactivated TGF-β2 (–) . # ::alignments 0-1.1.2 1-1.1.1.1 3-1 4-1.3.r 6-1.3.1 7-1.3 8-1.2.r 9-1.2.1 9-1.2.1.2 9-1.2.1.2.r 10-1.2.1.1.1 10-1.2.2.1.1 12-1.2 13-1.2.2.2.2 14-1.2.2.2.1 14-1.2.2.3.1.1 15-1.2.1.1.1 15-1.2.2.1.1 (t / treat-04~e.3 :ARG1 (c / cell :name (n / name :op1 "keratinocyte"~e.1) :mod (p / primary~e.0)) :ARG2~e.8 (o / or~e.12 :op1 (p2 / protein~e.9 :name (n2 / name :op1 "TGF-β2"~e.10,15) :ARG1-of~e.9 (r / recombine-01~e.9) :ARG1-of (d / describe-01 :ARG2 (s / string-entity :value +))) :op2 (p3 / protein :name (n3 / name :op1 "TGF-β2"~e.10,15) :ARG1-of (a2 / activate-01 :polarity -~e.14 :ARG0 (h / heat~e.13)) :ARG1-of (d2 / describe-01 :ARG2 (s2 / string-entity :value -~e.14)))) :time~e.4 (t2 / time~e.7 :ARG1-of (i / indicate-01~e.6))) # ::id pmid_1563_0473.386 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total cellular proteins were then isolated and analyzed by Western blot for Snail , pSMAD2 ( reflective of activated TGF @- signaling ) , and tubulin . # ::alignments 0-1.1.1.2 1-1.1.1.1 2-1.1.1 4-1.3 5-1.1 6-1 7-1.2 8-1.2.2.r 9-1.2.2 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.1.1.1 18-1.2.2.1.2.3.1.2 19-1.2.2.1.2.3.1.1.1.1 21-1.2.2.1.2.3.1 24-1.2.2.1 25-1.2.2.1.3.1.1 (a / and~e.6 :op1 (i / isolate-01~e.5 :ARG1 (p / protein~e.2 :mod (c / cell~e.1) :mod (t / total~e.0))) :op2 (a2 / analyze-01~e.7 :ARG1 p :manner~e.8 (i2 / immunoblot-01~e.9,10 :ARG1~e.11 (a3 / and~e.24 :op1 (p2 / protein :name (n2 / name :op1 "Snail"~e.12)) :op2 (p5 / protein :name (n3 / name :op1 "SMAD2") :ARG3-of (p3 / phosphorylate-01) :ARG1-of (r / reflect-01 :ARG2 (s / signal-07~e.21 :ARG1 (p6 / protein :name (n4 / name :op1 "TGF"~e.19)) :ARG1-of (a5 / activate-01~e.18)))) :op3 (p4 / protein :name (n5 / name :op1 "tubulin"~e.25))) :ARG2 p)) :time (t2 / then~e.4)) # ::id pmid_1563_0473.387 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note the activation of Snail expression , peaking at 2 h post @-@ TGF-β2 treatment and then disappearing thereafter . # ::alignments 0-1 2-1.2.1.1 3-1.2.1.1.1.r 4-1.2.1.1.1.1.1.1 5-1.2.1.1.1 7-1.2.1 8-1.2.1.2.r 9-1.2.1.2.2.1 10-1.2.1.2.2.2 11-1.2.1.2 13-1.2.1.2.1.1.1.1 14-1.2.1.2.1 15-1.2 16-1.2.2.2 17-1.2.2 (n2 / note-02~e.0 :ARG0 (y / you) :ARG1 (a / and~e.15 :op1 (p / peak-01~e.7 :ARG1 (a2 / activate-01~e.2 :ARG1~e.3 (e / express-03~e.5 :ARG1 (p2 / protein :name (n / name :op1 "Snail"~e.4)))) :time~e.8 (a3 / after~e.11 :op1 (t / treat-04~e.14 :ARG2 (p3 / protein :name (n3 / name :op1 "TGF-β2"~e.13))) :quant (t3 / temporal-quantity :quant 2~e.9 :unit (h / hour~e.10)))) :op2 (d / disappear-01~e.17 :ARG1 a2 :time (t2 / then~e.16)))) # ::id pmid_1563_0473.388 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( C ) Snail mRNA expression is transiently induced by TGF-β2 . # ::alignments 1-1.4.1.1 4-1.2.1.2.1.1.1 6-1.2.1.1.1 7-1.2 9-1.3 10-1 11-1.1.r 12-1.1.1.1 (i / induce-01~e.10 :ARG0~e.11 (p2 / protein :name (n3 / name :op1 "TGF-β2"~e.12)) :ARG2 (e / express-03~e.7 :ARG2 (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.6) :ARG0-of (e2 / encode-01 :ARG1 (g / gene :name (n2 / name :op1 "Snail"~e.4))))) :ARG1-of (t / transient-02~e.9) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "C"~e.1))) # ::id pmid_1563_0473.389 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The experiment in ( B ) was repeated , and this time , total RNAs were isolated from keratinocytes treated with TGF-β2 for the indicated times . # ::alignments 1-1.1.1 4-1.1.1.1.1.1 7-1.1 9-1 10-1.2.3.1 11-1.2.3 11-1.2.3.r 13-1.2.1.2 16-1.2 17-1.2.2.r 18-1.2.2.1.1 19-1.2.2.2 20-1.2.2.2.1.r 21-1.2.2.2.1.1.1 22-1.2.2.2.2.r 24-1.2.2.2.2.1 25-1.2.2.2.2 (a / and~e.9 :op1 (r / repeat-01~e.7 :ARG1 (e / experiment-01~e.1 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "B"~e.4)))) :op2 (i / isolate-01~e.16 :ARG1 (n4 / nucleic-acid :name (n / name :op1 "RNA") :mod (t / total~e.13)) :ARG2~e.17 (c / cell :name (n2 / name :op1 "keratinocyte"~e.18) :ARG1-of (t2 / treat-04~e.19 :ARG2~e.20 (p / protein :name (n3 / name :op1 "TGF-β2"~e.21)) :duration~e.22 (t3 / time~e.25 :ARG1-of (i2 / indicate-01~e.24)))) :time~e.11 (t4 / time~e.11 :mod (t5 / this~e.10)))) # ::id pmid_1563_0473.390 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RT @-@ PCR was then used with (+) or without (–) reverse transcriptase ( RT ) and with primer sets specific for Snail and GAPDH mRNAs . # ::alignments 0-1.1.1.1 2-1.1.1.1 4-1.2 5-1 8-1.1.2.1 9-1.1.2.1.2.1 9-1.1.2.1.2.1.r 11-1.1.2.1.1.1 11-1.1.2.1.1.1.2 11-1.1.2.1.1.1.2.r 12-1.1.2.1.1.1.1.1 14-1.1.1.1 16-1.1.2 18-1.1.2.2.1.1.1.1 19-1.1.2.2.1 20-1.1.2.2.1.2 23-1.1.2.2.1.2.1.1.1.1 25-1.1.2.2.1.2.1 26-1.1.2.2.1.2.1.2.2.1.1 27-1.1.2.2.1.2.1.2.1.1 (u / use-01~e.5 :ARG1 (t2 / thing :name (n / name :op1 "RT-PCR"~e.0,2,14) :manner (a6 / and~e.16 :op1 (o / or~e.8 :op1 (a / accompany-01 :ARG0 (e / enzyme~e.11 :name (n2 / name :op1 "transcriptase"~e.12) :ARG1-of~e.11 (r / reverse-01~e.11))) :op2 (a2 / accompany-01 :polarity~e.9 -~e.9 :ARG0 e)) :op2 (a3 / accompany-01 :ARG0 (s / set~e.19 :mod (d / dna-sequence :name (n3 / name :op1 "primer"~e.18)) :ARG1-of (s2 / specific-02~e.20 :ARG2 (a4 / and~e.25 :op1 (g / gene :name (n4 / name :op1 "Snail"~e.23)) :op2 (n7 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.27) :part-of (e2 / enzyme :name (n6 / name :op1 "GAPDH"~e.26))))))))) :time (t / then~e.4)) # ::id pmid_1563_0473.391 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note that Snail mRNA expression also peaked at 2 h , paralleling Snail protein . # ::alignments 0-1 3-1.2.1.1.2.1.1 5-1.2.1.1.1.1 6-1.2.1 6-1.2.1.2.1 7-1.2.2 8-1.2 10-1.3.1.1 11-1.3.1.2 13-1.2.1.2 14-1.2.1.2.1.1 15-1.2.1.2.1.1 (n3 / note-02~e.0 :ARG0 (y / you) :ARG1 (p / peak-01~e.8 :ARG1 (e / express-03~e.6 :ARG2 (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.5) :part (p2 / protein :name (n2 / name :op1 "Snail"~e.3))) :ARG0-of (p3 / parallel-01~e.13 :ARG1 (e2 / express-03~e.6 :ARG2 p2~e.14,15))) :mod (a / also~e.7)) :time (a2 / after :op1 (t / temporal-quantity :quant 2~e.10 :unit (h / hour~e.11)))) # ::id pmid_1563_0473.392 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( D ) TGF-β2 treatment results in enhanced activity of a Snail promoter-β-galactosidase reporter . # ::alignments 1-1.3.1.1 3-1.1.1.1.1 4-1.1 5-1 6-1.2.r 7-1.2.2 8-1.2 12-1.2.1.1.1.1.1 15-1.2.1 15-1.2.1.2 15-1.2.1.2.r (r2 / result-01~e.5 :ARG1 (t / treat-04~e.4 :ARG2 (p2 / protein :name (n / name :op1 "TGF-β2"~e.3))) :ARG2~e.6 (a / activity-06~e.8 :ARG0 (m / molecular-physical-entity~e.15 :ARG0-of (p3 / promote-01 :ARG1 (g / gene :name (n2 / name :op1 "Snail"~e.12))) :ARG0-of~e.15 (r3 / report-01~e.15 :ARG1 (e2 / enzyme :name (n3 / name :op1 "β-galactosidase") :ARG0-of p3))) :ARG1-of (e / enhance-01~e.7)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "D"~e.1))) # ::id pmid_1563_0473.393 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Keratinocytes were transfected with a β-galactosidase reporter driven by a Snail promoter that is either WT ( wt prom ) or harbors a mutation in a putative pSMAD2 @/@ pSMAD4 binding site ( mt prom ) . # ::alignments 0-1.1.2.1 2-1 3-1.2.r 5-1.2.1.1.2.1 6-1.2 6-1.2.1 6-1.2.1.r 7-1.2.2 11-1.2.2.1.1.1.1.2.1 13-1.2.2.1.1 13-1.2.2.1.1.1 13-1.2.2.1.1.1.r 13-1.2.2.1.2 13-1.2.2.1.2.1 13-1.2.2.1.2.1.r 17-1.2.2.1.1.1.1.3 19-1.2.2.1.1.1.1.3 22-1.2.2.1 23-1.2.2.1.1.2 25-1.2.2.1.1.2.1 26-1.2.2.1.1.2.1.1.r 28-1.2.2.1.1.2.1.1.3 32-1.2.2.1.1.2.1.1.1 33-1.2.2.1.1.2.1.1 (t / transfect-01~e.2 :ARG1 (c / cell :wiki "Keratinocyte" :name (n / name :op1 "keratinocyte"~e.0)) :ARG2~e.3 (m2 / molecular-physical-entity~e.6 :ARG0-of~e.6 (r2 / report-01~e.6 :ARG1 (e / enzyme :wiki "Beta-galactosidase" :name (n2 / name :op1 "β-galactosidase"~e.5))) :ARG1-of (d / drive-02~e.7 :ARG0 (o / or~e.22 :op1 (m3 / molecular-physical-entity~e.13 :ARG0-of~e.13 (p2 / promote-01~e.13 :ARG1 (g / gene :wiki - :name (n3 / name :op1 "Snail"~e.11) :mod (w / wild-type~e.17,19))) :ARG0-of (h / harbor-01~e.23 :ARG1 (m / mutate-01~e.25 :ARG2~e.26 (p6 / protein-segment~e.33 :ARG1-of (b / bind-01~e.32 :ARG2 (p8 / protein :wiki "Mothers_against_decapentaplegic_homolog_4" :name (n5 / name :op1 "SMAD4") :ARG1-of (p5 / phosphorylate-01))) :part-of (p7 / protein :wiki "Mothers_against_decapentaplegic_homolog_2" :name (n6 / name :op1 "SMAD2") :ARG1-of (p4 / phosphorylate-01)) :ARG1-of (t2 / think-01~e.28))))) :op2 (m4 / molecular-physical-entity~e.13 :ARG0-of~e.13 (p / promote-01~e.13 :ARG1 g) :ARG0-of h))))) # ::id pmid_1563_0473.394 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At 2 d posttransfection , cells were treated with either TGF-β or heat @-@ inactivated TGF-β2 ( inact ) for the times indicated . # ::alignments 1-1.4.2.1 5-1.1 7-1 10-1.2.1.1.1 10-1.2.2.1.1 11-1.2 12-1.2.2.2.2 14-1.2.2.2.1 21-1.3 21-1.4.2 21-1.4.r 22-1.3.1 (t / treat-04~e.7 :ARG1 (c / cell~e.5) :ARG2 (o / or~e.11 :op1 (p / protein :name (n / name :op1 "TGF-β"~e.10)) :op2 (p2 / protein :name (n2 / name :op1 "TGF-β"~e.10) :ARG1-of (a3 / activate-01 :polarity -~e.14 :ARG0 (h / heat~e.12)))) :duration (t2 / temporal-quantity~e.21 :ARG1-of (i / indicate-01~e.22)) :time~e.21 (a2 / after :op1 (t3 / transfect-01) :quant (t4 / temporal-quantity~e.21 :quant 2~e.1 :unit (d / day)))) # ::id pmid_1563_0473.395 ::amr-annotator SDL-AMR-09 ::preferred # ::tok β-galactosidase assays were then conducted , and results are reported as fold increase over a basal level of activity of 1 . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1.2 4-1.1 6-1 7-1.2.1 7-1.2.1.1 7-1.2.1.1.r 9-1.2 10-1.1.2.r 10-1.2.2.r 11-1.2.2.2 12-1.2.2 15-1.2.2.1.1 16-1.2.2.1 17-1.2.2.1.2.r 18-1.2.2.1.2 20-1.2.2.1.3.1 (a / and~e.6 :op1 (c / conduct-01~e.4 :ARG1 (a2 / assay-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "β-galactosidase"~e.0))) :time~e.10 (t / then~e.3)) :op2 (r / report-01~e.9 :ARG1 (t2 / thing~e.7 :ARG2-of~e.7 (r2 / result-01~e.7)) :manner~e.10 (i / increase-01~e.12 :ARG3 (l / level~e.16 :mod (b / basal~e.15) :degree-of~e.17 (a3 / activity-06~e.18) :ARG1-of (e2 / equal-01 :ARG2 1~e.20)) :mod (f / fold~e.11)))) # ::id pmid_1563_0473.396 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The experiment was repeated three times in triplicate , and error bars reflect variations in the results . # ::alignments 1-1.1.2 3-1.1 4-1.1.2.1 4-1.1.1 9-1 10-1.2.1.1 11-1.2.1 12-1.2 13-1.2.2 14-1.2.2.1.r 16-1.2.2.1 16-1.2.2.1.1 16-1.2.2.1.1.r (a / and~e.9 :op1 (r / repeat-01~e.3 :ARG3 3~e.4 :ARG1 (e / experiment-01~e.1 :quant 3~e.4)) :op2 (r2 / reflect-01~e.12 :ARG1 (b / bar~e.11 :mod (e2 / error~e.10)) :ARG2 (v / vary-01~e.13 :ARG1~e.14 (t / thing~e.16 :ARG2-of~e.16 (r3 / result-01~e.16))))) # ::id pmid_1563_0473.397 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 6 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 6~e.1) # ::id pmid_1563_0473.398 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( A @–@ D ) Skins from TGF-β2 WT or KO E17.5 embryos were analyzed for expression of TGF-β2 protein ( A ) , which is present in the epidermis and dermis as previously described [ @ 33 @ ] and in the hair bud , pSMAD2 ( B ) , Snail ( C ) , and Snail mRNA ( D ) . # ::alignments 1-1.1.3.1.1 3-1.1.2.1.1.2.1.2.4.3.1.1 5-1.1.1.1 5-1.1.1.2 6-1.1.1.1.1.r 6-1.1.1.2.1.r 7-1.1.1.1.1.1.1.1 8-1.1.1.1.1.1.2 9-1.1.1 10-1.1.1.2.1.1.1.1 12-1.1.1.1.1 12-1.1.1.2.1 14-1.1 16-1.1.2.1 18-1.1.2.1.1.1.1 19-1.1.1.1.1.1 19-1.1.2.1.1 19-1.1.2.1.1.2.1.2.2 19-1.1.2.1.1.2.1.2.3 21-1.1.3.1.1 26-1.1.2.1.1.2 27-1.1.2.1.1.2.1.r 29-1.1.2.1.1.2.1.1.1 30-1.1.2.1.1.2.1.1 31-1.1.2.1.1.2.1.1.2 32-1.1.2.1.1.2.1.1.3.2.r 33-1.1.2.1.1.2.1.1.3.2 34-1.1.2.1.1.2.1.1.3 34-1.1.2.1.1.2.1.2.2.3 34-1.1.2.1.1.2.1.2.3.2 34-1.1.2.1.1.2.1.2.4.3 34-1.1.3 34-1.2 37-1.1.2.1.1.2.1.1.3.1.1.1 40-1.1.2.1.1.2.1.2 43-1.1.2.1.1.2.1.2.1.1 44-1.1.2.1.1.2.1.2.1 48-1.1.2.1.1.2.1.2.2.3.1.1 51-1.1.2.1.1.2.1.2.3.1.1 53-1.1.2.1.1.2.1.2.3.2.1.1 58-1.1.2.1.1.2.1.2.3.1.1 60-1.1.2.1.1.2.1.2.4.1.1 62-1.1.2.1.1.2.1.2.4.3.1.1 (a3 / and :op1 (a / analyze-01~e.14 :ARG1 (o2 / or~e.9 :op1 (s / skin~e.5 :source~e.6 (e / embryo~e.12 :mod (p / protein~e.19 :name (n / name :op1 "TGF-β2"~e.7) :mod (w / wild-type~e.8)))) :op2 (s3 / skin~e.5 :source~e.6 (e5 / embryo~e.12 :mod (e3 / enzyme :name (n2 / name :op1 "KO"~e.10)) :age (t / temporal-quantity :quant 17.5 :unit (d4 / day))))) :purpose (f / find-01 :ARG1 (e4 / express-03~e.16 :ARG2 (p2 / protein~e.19 :name (n3 / name :op1 "TGF-β2"~e.18) :ARG1-of (p8 / present-02~e.26 :ARG2~e.27 (a2 / and :op1 (a5 / and~e.30 :op1 (e2 / epidermis~e.29) :op2 (d / dermis~e.31) :ARG1-of (d2 / describe-01~e.34 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 33~e.37)) :time~e.32 (p3 / previous~e.33))) :op2 (a6 / and~e.40 :op1 (b / bud~e.44 :mod (h / hair~e.43)) :op2 (p7 / protein~e.19 :name (n4 / name :op1 "SMAD2") :ARG1-of (p5 / phosphorylate-01) :ARG1-of (d6 / describe-01~e.34 :ARG0 (f4 / figure :mod "B"~e.48))) :op3 (p6 / protein~e.19 :name (n5 / name :op1 "Snail"~e.51,58) :ARG1-of (d7 / describe-01~e.34 :ARG0 (f5 / figure :mod "C"~e.53))) :op4 (n7 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.60) :part p6 :ARG1-of (d8 / describe-01~e.34 :ARG0 (f6 / figure :mod "D"~e.3,62))))))))) :ARG1-of (d5 / describe-01~e.34 :ARG0 (f3 / figure :mod "A"~e.1,21))) :ARG1-of (d3 / describe-01~e.34 :ARG0 (a4 / and :op1 f3 :op2 f4 :op3 f5 :op4 f6))) # ::id pmid_1563_0473.399 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Arrows point to the hair buds . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.1 5-1.2 (p / point-01~e.1 :ARG0 (a / arrow~e.0) :ARG2~e.2 (b / bud~e.5 :mod (h / hair~e.4))) # ::id pmid_1563_0473.400 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( E ) Western blot analyses of Snail expression in the skins of 2 @-@ wk @-@ old K14 @-@ Smad2 transgenic ( SMAD2 TG ) and WT littermate ( WT ) mice . # ::alignments 1-1.2.1.1 3-1 4-1 6-1.1.r 7-1.1.1.1.1 8-1.1 9-1.1.2.r 11-1.1.2.1 11-1.1.2.2 13-1.1.2.1.1.2.1 17-1.1.2.1.1.2.r 19-1.1.2.1.1.1.1.1 21-1.1.2.1.1.1.1.1 23-1.1.2.1.1.3 28-1.1.2 29-1.1.2.2.1.2 30-1.1.2.2.1.1 32-1.1.2.2.1.2 34-1.1.2.1.1 34-1.1.2.2.1 (i / immunoblot-01~e.3,4 :ARG1~e.6 (e / express-03~e.8 :ARG2 (p / protein :name (n2 / name :op1 "Snail"~e.7)) :ARG3~e.9 (a / and~e.28 :op1 (s / skin~e.11 :mod (m / mouse~e.34 :mod (g / gene :name (n3 / name :op1 "K14-Smad2"~e.19,21)) :age~e.17 (t / temporal-quantity :quant 2~e.13 :unit (w2 / week)) :mod (t2 / transgenic~e.23))) :op2 (s2 / skin~e.11 :mod (m2 / mouse~e.34 :mod (l / littermate~e.30) :mod (w / wild-type~e.29,32))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "E"~e.1))) # ::id pmid_1563_0473.401 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Antibody to tubulin was used as a control for equal protein loadings . # ::alignments 0-1.1 2-1.1.1.1.1.1 4-1 5-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.2 10-1.2.1.1 11-1.2.1 (u / use-01~e.4 :ARG1 (a / antibody~e.0 :ARG0-of (o / oppose-01 :ARG1 (p / protein :name (n / name :op1 "tubulin"~e.2)))) :ARG2~e.5 (c / control-01~e.7 :ARG1~e.8 (l / load-01~e.11 :ARG1 (p2 / protein~e.10) :ARG1-of (e / equal-01~e.9)) :ARG2 a)) # ::id pmid_1563_0473.402 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The K14 @-@ Smad2 Tg mouse was previously shown to possess activated TGF-β signaling [ @ 35 @ ] . # ::alignments 1-1.1.1.1.1.1 3-1.1.1.1.1.1 4-1.1.1.2 5-1.1.1 7-1.3 8-1 10-1.1 11-1.1.2.1.2 12-1.1.2.1.1.1 13-1.1.2 16-1.2.1.1.1 (s / show-01~e.8 :ARG1 (p / possess-01~e.10 :ARG0 (m / mouse~e.5 :mod (e / enzyme :name (n2 / name :op1 "K14-Smad2"~e.1,3)) :mod (t / transgenic~e.4)) :ARG1 (s2 / signal-07~e.13 :ARG0 (p2 / protein :name (n3 / name :op1 "TGF-β"~e.12) :ARG1-of (a / activate-01~e.11)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 35~e.16))) :time (p4 / previous~e.7)) # ::id pmid_1563_0473.403 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( F @–@ G ) Proliferation markers Ki67 ( F ) and pMAPK ( G ) are diminished in TGF-β2 @ -@ null hair relative to its WT counterpart . # ::alignments 1-1.1.1.2.1.1 3-1.1.2.3.1.1 5-1.1.3.1 7-1.1.1.1.1 9-1.1.1.2.1.1 11-1.1 12-1.1.2.1.1 12-1.1.2.2 14-1.1.2.3.1.1 17-1 20-1.2.1.1.1 23-1.2.1 23-1.2.1.2 23-1.2.1.2.r 24-1.2 28-1.3.1.1 29-1.3.1 (d / diminish-01~e.17 :ARG1 (a2 / and~e.11 :op1 (p / protein :name (n5 / name :op1 "Ki67"~e.7) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "F"~e.1,9))) :op2 (e / enzyme :name (n6 / name :op1 "MAPK"~e.12) :ARG3-of (p4 / phosphorylate-01~e.12) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure :mod "G"~e.3,14))) :ARG0-of (m4 / mark-01 :ARG1 (p2 / proliferate-01~e.5))) :location (h / hair~e.24 :mod (p5 / protein~e.23 :name (n3 / name :op1 "TGF-β2"~e.20) :ARG2-of~e.23 (m / mutate-01~e.23 :mod "−/−"))) :ARG1-of (c / compare-01 :ARG2 (c2 / counterpart~e.29 :mod (w / wild-type~e.28))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 f2 :op2 f3))) # ::id pmid_1563_0473.404 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( H @–@ J ) TGF-β2 @ -@ null hair fails to down @-@ regulate E @-@ cadherin ( H ) . # ::alignments 1-1.4.1.1.1 3-1.4.1.3.1 6-1.2.1.1.1 9-1.2.1 9-1.2.1.2 9-1.2.1.2.r 10-1.2 16-1.3.1.1 18-1.3.1.1 20-1.4.1.1.1 (d3 / downregulate-01 :polarity - :ARG0 (h / hair~e.10 :mod (p / protein~e.9 :name (n / name :op1 "TGF-β2"~e.6) :ARG2-of~e.9 (m / mutate-01~e.9 :mod "−/−"))) :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin"~e.16,18)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "H"~e.1,20) :op2 (f3 / figure :mod "I") :op3 (f4 / figure :mod "J"~e.3)))) # ::id pmid_1563_0473.405 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Wnt and noggin signaling pathways are still intact in the TGF-β2 null hair as nuclear LEF @-@ 1 ( I ) and nuclear β-catenin ( J ) are still expressed . # ::alignments 0-1.3.1.1.1 1-1.3 2-1.3.2.1.1 3-1.3.1.2 4-1.3.1 4-1.3.2 5-1.3.r 6-1.3.3 7-1 8-1.1.r 10-1.1.1.1.1 11-1.1.1 11-1.1.1.2 11-1.1.1.2.r 12-1.1 14-1.2.1.1.1.2 14-1.2.1.1.2.2 15-1.2.1.1.1.1.1 17-1.2.1.1.1.1.1 19-1.2.1.1.1.1.1 19-1.2.1.1.1.3.1.1 21-1.2.1.1 22-1.2.1.1.1.2 22-1.2.1.1.2.2 23-1.2.1.1.2.1.1 25-1.2.1.1.2.3.1.1 27-1.3.r 28-1.2.1.2 29-1.2.1 (i / intact~e.7 :location~e.8 (h / hair~e.12 :mod (p2 / protein~e.11 :name (n / name :op1 "TGF-β2"~e.10) :ARG2-of~e.11 (m / mutate-01~e.11 :mod "−/−"))) :ARG1-of (c / cause-01 :ARG0 (e / express-03~e.29 :ARG2 (a2 / and~e.21 :op1 (p3 / protein :name (n2 / name :op1 "LEF-1"~e.15,17,19) :mod (n3 / nucleus~e.14,22) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "I"~e.19))) :op2 (p4 / protein :name (n4 / name :op1 "β-catenin"~e.23) :mod (n5 / nucleus~e.14,22) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "J"~e.25)))) :mod s2~e.28)) :domain~e.5,27 (a3 / and~e.1 :op1 (p5 / pathway~e.4 :name (n7 / name :op1 "Wnt"~e.0) :ARG0-of (s3 / signal-07~e.3)) :op2 (p6 / pathway~e.4 :name (n8 / name :op1 "noggin"~e.2) :ARG0-of s3) :mod (s2 / still~e.6))) # ::id pmid_1627_1139.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transformation of human bronchial epithelial cells alters responsiveness to inflammatory cytokines ( PMID : 16271139 ) # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.2 4-1.1.1.3 5-1.1.1 6-1 9-1.2.1.1 10-1.2.1 (a / alter-01~e.6 :ARG0 (t / transform-01~e.0 :ARG1~e.1 (c / cell~e.5 :mod (h / human~e.2) :mod (b / bronchus~e.3) :mod (e / epithelium~e.4))) :ARG1 (r / responsive-02 :ARG1 (c2 / cytokine~e.10 :ARG0-of (i / inflame-01~e.9))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID16271139"))) # ::id pmid_1627_1139.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1627_1139.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Normal epithelial cells respond strongly to OSM , IFNγ and EGF , and respond moderately to IL @-@ 6 , and do not exhibit a detectable response to LIF . # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1.1.1 3-1.1 4-1.1.3 6-1.1.2.1.1.1 8-1.1.2.2.1.1 10-1.1.2.3.1.1 12-1 12-1.1.2 13-1.1 13-1.2 14-1.2.3 14-1.2.3.r 15-1.2.2.r 16-1.2.2.1.1 18-1.2.2.1.1 20-1 22-1.3.1 22-1.3.1.r 23-1.3 25-1.3.3.3 26-1.3.3 27-1.3.3.2.r 28-1.3.3.2.1.1 (a / and~e.12,20 :op1 (r / respond-01~e.3,13 :ARG0 (c / cell~e.2 :mod (n / normal~e.0) :source (e / epithelium~e.1)) :ARG1 (a2 / and~e.12 :op1 (p / protein :name (n2 / name :op1 "OSM"~e.6)) :op2 (p2 / protein :name (n3 / name :op1 "IFNγ"~e.8)) :op3 (p6 / protein :name (n4 / name :op1 "EGF"~e.10))) :ARG1-of (s / strong-02~e.4)) :op2 (r2 / respond-01~e.13 :ARG0 c :ARG1~e.15 (p3 / protein :name (n5 / name :op1 "IL-6"~e.16,18)) :manner~e.14 (m / moderate~e.14)) :op3 (e2 / exhibit-01~e.23 :polarity~e.22 -~e.22 :ARG0 c :ARG1 (r3 / respond-01~e.26 :ARG0 c :ARG1~e.27 (p5 / protein :name (n6 / name :op1 "LIF"~e.28)) :ARG1-of (d / detect-01~e.25 :ARG1-of (p4 / possible-01))))) # ::id pmid_1627_1139.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In preneoplastic cells , the aberrant signaling that was detected most frequently was an elevated activation of ERK , a reduced or increased IL @-@ 6 and EGF response , and an increased LIF response . # ::alignments 2-1.4.3 5-1.4.1 6-1.4 8-1.4.r 9-1.4.2 10-1.4.2.1.1 11-1.4.2.1 12-1.4.r 14-1.1.2 15-1.1 16-1.1.1.r 17-1.1.1.1.1 20-1.2.1.1.2 21-1.2.1 21-1.2.2 22-1.2.1.2.2 23-1.2.1.1.1.1.1 25-1.2.1.1.1.1.1 26-1.2 27-1.2.2.1.1.1.1 28-1.2.1.1 28-1.2.2.1 32-1.3.2 33-1.3.1.1.1 34-1.2.1.2 34-1.2.2.2 34-1.3 (a / and :op1 (a2 / activate-01~e.15 :ARG1~e.16 (e2 / enzyme :name (n / name :op1 "ERK"~e.17)) :ARG1-of (e / elevate-01~e.14)) :op2 (a3 / and~e.26 :op1 (o / or~e.21 :op1 (r2 / respond-01~e.28 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"~e.23,25)) :ARG1-of (r / reduce-01~e.20)) :op2 (r3 / respond-01~e.34 :ARG1 p2 :ARG1-of (i / increase-01~e.22))) :op2 (o2 / or~e.21 :op1 (r4 / respond-01~e.28 :ARG1 (p / protein :name (n4 / name :op1 "EGF"~e.27)) :ARG1-of r) :op2 (r5 / respond-01~e.34 :ARG1 p :ARG1-of i))) :op3 (r6 / respond-01~e.34 :ARG1 (p3 / protein :name (n3 / name :op1 "LIF"~e.33)) :ARG1-of i~e.32) :domain~e.8,12 (s2 / signal-07~e.6 :mod (a4 / aberrant~e.5) :ARG1-of (d / detect-01~e.9 :ARG1-of (f / frequent-02~e.11 :degree (m / most~e.10))) :location (c / cell~e.2 :mod (p4 / preneoplasm)))) # ::id pmid_1627_1139.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Some of these changes in preneoplastic cell signaling approach those observed in established lung cancer cell lines . # ::alignments 0-1.1.1.2 2-1.1.2 3-1.1 3-1.1.1.1 3-1.2 6-1.1.1.1.1.1 7-1.1.1.1.1 8-1 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.3 13-1.2.1.1.1.2.1 14-1.2.1.1.1.2.2 15-1.2.1.1 16-1.2.1.1 (a / approach-02~e.8 :ARG0 (c / change-01~e.3 :ARG1-of (i / include-91 :ARG2 (c2 / change-01~e.3 :ARG1 (s / signal-07~e.7 :ARG0 (c3 / cell~e.6 :mod (p / preneoplasm)))) :ARG3 (s2 / some~e.0)) :mod (t / this~e.2)) :ARG1 (c4 / change-01~e.3 :ARG1-of (o / observe-01~e.10 :location~e.11 (c5 / cell-line~e.15,16 :mod (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung"~e.13 :op2 "cancer"~e.14) :ARG1-of (e / establish-01~e.12)))))) # ::id pmid_1627_1139.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Epigenetic control of LIF receptor expression by histone acetylation can account for the gain of LIF responsiveness . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.r 7-1.1.1.1.2.1.1.1 8-1.1.1.1.2 9-1 10-1.1 11-1.1.2.r 13-1.1.2 15-1.1.2.1.1.1.1 (p / possible-01~e.9 :ARG1 (a / account-01~e.10 :ARG0 (c / control-01~e.1 :ARG1~e.2 (e2 / express-03~e.5 :ARG2 (r2 / receptor~e.4 :mod p2~e.3) :ARG3-of~e.6 (a2 / acetylate-01~e.8 :ARG1 (p3 / protein :name (n3 / name :op1 "histone"~e.7)))) :mod (e / epigenetic~e.0)) :ARG1~e.11 (g / gain-02~e.13 :ARG1 (r / responsive-02 :ARG1 (p2 / protein :name (n / name :op1 "LIF"~e.15)))))) # ::id pmid_1627_1139.16 ::amr-annotator SDL-AMR-09 ::preferred # ::tok OSM and macrophage @-@ derived cytokines suppressed proliferation of normal epithelial cells , but reduced inhibition or even stimulated proliferation was noted for preneoplastic cells . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 4-1.1.1.2.1 5-1.1.1.1 5-1.1.1.2 6-1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1 10-1.1.2.1.2 11-1.1.2.1 13-1 14-1.2.1.1.1 15-1.2.1.1 16-1.2.1 17-1.2.1.2.2 18-1.2.1.2.1 19-1.2.1.2 21-1.2 24-1.2.2 (c / contrast-01~e.13 :ARG1 (s / suppress-01~e.6 :ARG0 (a / and~e.1 :op1 (c6 / cytokine~e.5 :name (n / name :op1 "OSM"~e.0)) :op2 (c3 / cytokine~e.5 :ARG1-of (d / derive-01~e.4 :ARG0 (m / macrophage~e.2)))) :ARG1 (p2 / proliferate-01~e.7 :ARG0~e.8 (c4 / cell~e.11 :mod (n2 / normal~e.9) :source (e / epithelium~e.10)))) :ARG2 (n3 / note-01~e.21 :ARG1 (o / or~e.16 :op1 (i / inhibit-01~e.15 :ARG1-of (r / reduce-01~e.14)) :op2 (p3 / proliferate-01~e.19 :ARG1-of (s2 / stimulate-01~e.18) :mod (e2 / even~e.17))) :location (c5 / cell~e.24 :mod (p4 / preneoplasm)))) # ::id pmid_1627_1139.17 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These alterations likely contribute to the supporting effects that inflammation has on lung tumor progression . # ::alignments 0-1.1.1 1-1.1 2-1.3 3-1 4-1.2.r 6-1.2.3 7-1.2 9-1.2.1 11-1.2.2.r 12-1.2.2.1.1 13-1.2.2.1 14-1.2.2 (c / contribute-01~e.3 :ARG0 (a / alter-01~e.1 :mod (t / this~e.0)) :ARG2~e.4 (a2 / affect-01~e.7 :ARG0 (i / inflame-01~e.9) :ARG1~e.11 (p / progress-01~e.14 :ARG1 (t2 / tumor~e.13 :mod (l2 / lung~e.12))) :ARG0-of (s / support-01~e.6)) :ARG1-of (l / likely-01~e.2)) # ::id pmid_1627_1139.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1627_1139.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transformed lung epithelial cell lines have grossly abnormal patterns of cytokine responsiveness # ::alignments 1-1.1.3 2-1.1.2 3-1.1.1 4-1.1 5-1.1 6-1 7-1.2.2.2 8-1.2.2 8-1.2.2.1 8-1.2.2.1.r 9-1.2 11-1.2.1.1 (h / have-03~e.6 :ARG0 (c / cell-line~e.4,5 :source (e / epithelium~e.3) :mod (l / lung~e.2) :ARG1-of (t / transform-01~e.1)) :ARG1 (p / pattern-01~e.9 :ARG1 (r / responsive-02 :ARG1 (c2 / cytokine~e.11)) :ARG1-of (n / normal-02~e.8 :polarity~e.8 -~e.8 :ARG1-of (g / gross-06~e.7)))) # ::id pmid_1627_1139.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We predicted that if oncogenic transformation of lung epithelial cells is associated with altered responsiveness to inflammation and reduced growth @-@ inhibition , then the most prominent deviations from the regulatory phenotype should be seen in advanced lung cancer cells . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.2.r 4-1.2.2.1.2 4-1.2.2.1.2.1.2.1 5-1.2.2.1 7-1.2.2.1.1.1 8-1.2.2.1.1.2 9-1.2.2.1.1 11-1.2.2 12-1.2.2.2.r 13-1.2.2.2.1.2 16-1.2.2.2.1.1 17-1.2.2.2 18-1.2.2.2.2.2 19-1.2.2.2.2.1 21-1.2.2.2.2 25-1.2.1.1.2.1 26-1.2.1.1.2 27-1.2.1.1 28-1.2.1.1.1.r 28-1.2.2.1.1.2.r 30-1.2.1.1.1.1 31-1.2.1.1.1 32-1.2 34-1.2.1 36-1.2.1.2.1.3 37-1.2.1.2.1.2.1 38-1.2.1.2.1.2.2 39-1.2.1.2 39-1.2.2.1.1 (p / predict-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (r / recommend-01~e.32 :ARG1 (s / see-01~e.34 :ARG1 (d / deviate-01~e.27 :ARG1~e.28 (p3 / phenotype~e.31 :ARG0-of (r2 / regulate-01~e.30)) :mod (p2 / prominent~e.26 :degree (m / most~e.25))) :location (c / cell~e.39 :mod (d2 / disease :wiki "Lung_cancer" :name (n / name :op1 "lung"~e.37 :op2 "cancer"~e.38) :ARG1-of (a / advance-01~e.36)))) :condition~e.3 (a2 / associate-01~e.11 :ARG1 (t / transform-01~e.5 :ARG1 (c3 / cell~e.9,39 :mod (l2 / lung~e.7) :source~e.28 (e / epithelium~e.8)) :ARG0-of (c4 / cause-01~e.4 :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.4)))) :ARG2~e.12 (a3 / and~e.17 :op1 (r3 / responsive-02 :ARG1 (i / inflame-01~e.16) :ARG1-of (a4 / alter-01~e.13)) :op2 (i2 / inhibit-01~e.21 :ARG1 (g / grow-01~e.19) :ARG1-of (r4 / reduce-01~e.18)))))) # ::id pmid_1627_1139.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , as first step , we determined if responsiveness to members of the IL @-@ 6 family ( IL @-@ 6 , OSM and LIF ) were detectable in established @ lines of malignant human non @-@ small cell lung carcinoma cells . # ::alignments 0-1 2-1.1.r 3-1.1.3.1 3-1.1.3.1.1 3-1.1.3.1.1.r 4-1.1.3 6-1.1.1 7-1.1 10-1.1.2.r 11-1.1.2.1.1 14-1.1.2.1.1.1.1.1.1 14-1.1.2.1.1.2.1.1.1 16-1.1.2.1.1.1.1.1.1 16-1.1.2.1.1.2.1.1.1 17-1.1.2.1.1.1.1 19-1.1.2.1.1.1.1.1.1 19-1.1.2.1.1.2.1.1.1 21-1.1.2.1.1.1.1.1.1 21-1.1.2.1.1.2.1.1.1 23-1.1.2.1.1.2.2.1.1 24-1.1.2.1.1.2 25-1.1.2.1.1.2.3.1.1 28-1.1.2 31-1.1.2.3.1 33-1.1.2.3 34-1.1.2.3.2.r 35-1.1.2.3.2.2.1.3 36-1.1.2.3.2.2.1.1 37-1.1.2.3.2.2.1.2.1 37-1.1.2.3.2.2.1.2.1.r 39-1.1.2.3.2.2.1.2 40-1.1.2.3.2.2.1 41-1.1.2.3.2.2 42-1.1.2.3.2.1.1 43-1.1.2.3.2.2.1 (c / cause-01~e.0 :ARG1~e.2 (d / determine-01~e.7 :ARG0 (w / we~e.6) :ARG1~e.10 (d2 / detect-01~e.28 :ARG1 (r / responsive-02 :ARG1 (m / member~e.11 :ARG1-of (i / include-91 :ARG2 (p2 / protein-family~e.17 :name (n / name :op1 "IL-6"~e.14,16,19,21))) :example (a / and~e.24 :op1 (p3 / protein :name (n2 / name :op1 "IL-6"~e.14,16,19,21)) :op2 (p4 / protein :name (n3 / name :op1 "OSM"~e.23)) :op3 (p5 / protein :name (n4 / name :op1 "LIF"~e.25))))) :ARG1-of (p / possible-01 :mode interrogative) :location (c4 / cell-line~e.33 :ARG1-of (e / establish-01~e.31) :mod~e.34 (m3 / medical-condition :name (n5 / name :op1 "carcinoma"~e.42) :mod (l2 / lung~e.41 :mod (c3 / cell~e.40,43 :mod (h / human~e.36) :mod (s2 / small~e.39 :polarity~e.37 -~e.37) :ARG1-of (m2 / malignant-02~e.35)))))) :ARG4-of (s / step-01~e.4 :ord (o / ordinal-entity~e.3 :value~e.3 1~e.3)))) # ::id pmid_1627_1139.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The responsiveness to the cytokines was defined by measurable phosphorylation of STAT and ERK . # ::alignments 4-1.2.1 6-1 7-1.1.r 8-1.1.2 9-1.1 10-1.1.1.r 11-1.1.1.1.1.1 12-1.1.1 13-1.1.1.2.1.1 (d / define-01~e.6 :ARG0~e.7 (p / phosphorylate-01~e.9 :ARG1~e.10 (a / and~e.12 :op1 (p3 / protein :name (n / name :op1 "STAT"~e.11)) :op2 (e / enzyme :name (n2 / name :op1 "ERK"~e.13))) :ARG1-of (m / measure-01~e.8 :ARG1-of (p2 / possible-01))) :ARG1 (r / responsive-02 :ARG1 (c / cytokine~e.4))) # ::id pmid_1627_1139.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is a treatment reaction that is a measure for the level of active cytokine receptors and downstream signaling pathways in the target cells [ @ 14 , 16 @ ] . # ::alignments 0-1.2 1-1.2.r 3-1.1 4-1 6-1.2.r 8-1.3 9-1.3.1.r 11-1.3.1.1 11-1.3.1.2 12-1.3.1.1.1.r 13-1.3.1.1.1.2 14-1.3.1.1.1.1 15-1.3.1.1.1 16-1.3.1 17-1.3.1.2.1.1.1 18-1.3.1.2.1.1 19-1.3.1.2.1 20-1.3.2.r 22-1.3.2.1 23-1.3.2 26-1.4.1.1.1.1 30-1.4.1.1.1.2 (r / react-01~e.4 :ARG1 (t2 / treat-04~e.3) :domain~e.1,6 (t / this~e.0) :ARG0-of (m / measure-01~e.8 :ARG1~e.9 (a2 / and~e.16 :op1 (l / level~e.11 :degree-of~e.12 (r2 / receptor~e.15 :mod (c / cytokine~e.14) :ARG0-of (a / activity-06~e.13))) :op2 (l2 / level~e.11 :degree-of (p / pathway~e.19 :ARG0-of (s / signal-07~e.18 :source (d / downstream~e.17))))) :location~e.20 (c2 / cell~e.23 :ARG1-of (t3 / target-01~e.22))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 14~e.26 :op2 16~e.30))))) # ::id pmid_1627_1139.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Normal type II epithelial cells and pulmonary fibroblasts were included in the analyses to gauge cell type @-@ specific differences in signaling reactions ( Fig . 1 ) . # ::alignments 0-1.1.1.2 1-1.1.1.3 2-1.1.1.3.1.1 3-1.1.1.1 4-1.1.1 5-1.1 7-1.1.2 9-1 10-1.2.r 12-1.2 14-1.3 15-1.3.1.1 16-1.3.1.3.1 18-1.3.1.3 19-1.3.1 20-1.3.1.2.r 21-1.3.1.2.1 22-1.3.1.2 24-1.4.1 27-1.4.1.1 (i / include-01~e.9 :ARG1 (a / and~e.5 :op1 (c / cell~e.4 :source (e / epithelium~e.3) :mod (n / normal~e.0) :mod (t / type~e.1 :name (n2 / name :op1 "II"~e.2))) :op2 (f / fibroblast~e.7 :part-of (l / lung))) :ARG2~e.10 (a2 / analyze-01~e.12) :purpose (g / gauge-01~e.14 :ARG1 (d / differ-02~e.19 :ARG1 (c2 / cell~e.15) :ARG3~e.20 (r / react-01~e.22 :ARG0-of (s2 / signal-07~e.21)) :ARG1-of (s / specific-02~e.18 :ARG2 (t2 / type~e.16)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.24 :mod 1~e.27))) # ::id pmid_1627_1139.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of STAT3 and ERK was sufficient for identifying responsiveness to cytokines in specific cell types ( Fig . 1A shows representative immunoblots and Fig. 1B presents the quantitative data from independently performed experiments involving 5 separate matched cultures of type II epithelial cells and fibroblasts ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 6-1 7-1.2.r 8-1.2 11-1.2.1.1 12-1.2.2.r 13-1.2.2.2 14-1.2.2 15-1.2.2.1 17-1.3.1.1 20-1.3.1.1.1 22-1.3.1.1.2 23-1.3.1.1.2.1.1 25-1.3.1 26-1.3.1.1 26-1.3.1.2 28-1.3.1.2.1 30-1.3.1.2.2 32-1.3.1.2.2.1.1 33-1.3.1.2.2.1 34-1.3.1.2.2.1.2.r 35-1.3.1.2.2.1.2.1.1.1 36-1.3.1.2.2.1.2.1 37-1.3.1.2.2.1.2 38-1.3.1.2.2.1.2.2 39-1.3.1.2.2.1.2.2.1.1 40-1.3.1.2.2.1.2.2.1.2 41-1.3.1.2.2.1.2.2.1.3 42-1.3.1.2.2.1.2.2.1 43-1.3.1.2.2.1.2.2.1.4.r 44-1.3.1.2.2.1.2.2.1.4.1.2 45-1.3.1.2.2.1.2.2.1.4.1.2.1.1 46-1.3.1.2.2.1.2.2.1.4.1.1 47-1.3.1.2.2.1.2.2.1.4.1 48-1.3.1.2.2.1.2.2.1.4 49-1.3.1.2.2.1.2.2.1.4.2 (s / suffice-01~e.6 :ARG0 (p / phosphorylate-01~e.0 :ARG1~e.1 (a / and~e.3 :op1 (p2 / protein :name (n / name :op1 "STAT3"~e.2)) :op2 (e3 / enzyme :name (n2 / name :op1 "ERK"~e.4)))) :ARG1~e.7 (i / identify-01~e.8 :ARG1 (r / responsive-02 :ARG1 (c / cytokine~e.11)) :location~e.12 (c2 / cell~e.14 :mod (t / type~e.15) :ARG1-of (s2 / specific-02~e.13))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.25 :op1 (f / figure~e.17,26 :mod "1A"~e.20 :ARG0-of (s3 / show-01~e.22 :ARG1 (i2 / immunoblot-01 :ARG0-of (r2 / represent-01~e.23)))) :op2 (f2 / figure~e.26 :mod "1B"~e.28 :ARG0-of (p4 / present-01~e.30 :ARG1 (d2 / data~e.33 :mod (q / quantity~e.32) :source~e.34 (e / experiment-01~e.37 :ARG1-of (p5 / perform-02~e.36 :ARG0-of (d3 / depend-01 :polarity -~e.35)) :ARG2-of (i4 / involve-01~e.38 :ARG1 (c3 / culture~e.42 :quant 5~e.39 :ARG1-of (s4 / separate-02~e.40) :ARG1-of (m / match-01~e.41) :consist-of~e.43 (a3 / and~e.48 :op1 (c4 / cell~e.47 :source (e2 / epithelium~e.46) :mod (t2 / type~e.44 :name (n3 / name :op1 "II"~e.45))) :op2 (f3 / fibroblast~e.49))))))))))) # ::id pmid_1627_1139.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In brief , normal type II epithelial cells showed the following features ( Fig . 1A , top panel ) : OSM strongly activated phosphorylation of STAT3 and ERK , while IL @-@ 6 was less effective , and LIF did not produce any detectable response . # ::alignments 1-1.4 3-1.1.3 4-1.1.1 5-1.1.1.1.1 6-1.1.2 7-1.1 8-1 10-1.2.1 11-1.2 13-1.3.1 16-1.3.1.1 19-1.3.1.2.1 20-1.3.1.2 23-1.2.2.1.1.1.1 24-1.2.2.1.3 25-1.2.2.1 26-1.2.2.1.2 27-1.2.2.1.2.1.r 28-1.2.2.1.2.1.1.1.1 29-1.2.2.1.2.1 30-1.2.2.1.2.1.2.1.1 32-1.2.2 33-1.2.2.2.1.1.1.1 35-1.2.2.2.1.1.1.1 37-1.2.2.2.1.2 38-1.2.2.2.1 40-1.2.2.2 41-1.2.2.2.2.2.1.1 43-1.2.2.2.2.1 43-1.2.2.2.2.1.r 44-1.2.2.2.2 46-1.2.2.2.2.3.1 47-1.2.2.2.2.3 (s / show-01~e.8 :ARG0 (c / cell~e.7 :mod (t / type~e.4 :name (n / name :op1 "II"~e.5)) :source (e / epithelium~e.6) :ARG1-of (n2 / normal-02~e.3)) :ARG1 (f / feature~e.11 :ARG1-of (f2 / follow-04~e.10) :example (c2 / contrast-01~e.32 :ARG1 (a2 / activate-01~e.25 :ARG0 (p / protein :name (n3 / name :op1 "OSM"~e.23)) :ARG1 (p2 / phosphorylate-01~e.26 :ARG1~e.27 (a3 / and~e.29 :op1 (p3 / protein :name (n4 / name :op1 "STAT3"~e.28)) :op2 (e4 / enzyme :name (n5 / name :op1 "ERK"~e.30)))) :ARG1-of (s2 / strong-02~e.24)) :ARG2 (a4 / and~e.40 :op1 (e3 / effective-04~e.38 :ARG0 (p5 / protein :name (n6 / name :op1 "IL-6"~e.33,35)) :degree (l / less~e.37)) :op2 (p6 / produce-01~e.44 :polarity~e.43 -~e.43 :ARG0 (p7 / protein :name (n7 / name :op1 "LIF"~e.41)) :ARG1 (r / respond-01~e.47 :ARG1-of (d / detect-01~e.46 :ARG1-of (p8 / possible-01))))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.13 :mod "1A"~e.16 :location (p9 / panel~e.20 :mod (t2 / top~e.19)))) :ARG2-of (b / brief-01~e.1)) # ::id pmid_1627_1139.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF stimulated phosphorylation of ERK in the range of OSM , while insulin was minimally effective . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1.1 5-1.1.2.2.r 7-1.1.2.2 8-1.1.2.2.1.r 9-1.1.2.2.1.1.1 11-1 12-1.2.1.1.1 14-1.2.2 15-1.2 (c / contrast-01~e.11 :ARG1 (s / stimulate-01~e.1 :ARG0 (p2 / protein :name (n / name :op1 "EGF"~e.0)) :ARG1 (p / phosphorylate-01~e.2 :ARG1~e.3 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.4)) :part-of~e.5 (r / range-01~e.7 :ARG1~e.8 (p3 / protein :name (n3 / name :op1 "OSM"~e.9))))) :ARG2 (e / effective-04~e.15 :ARG0 (p4 / protein :name (n4 / name :op1 "insulin"~e.12)) :degree (m / minimal-02~e.14))) # ::id pmid_1627_1139.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fibroblasts exhibited a prominent LIF response and a several @-@ fold higher activation of ERK relative to STAT3 by IL @-@ 6 cytokines ( Fig . 1A , bottom panel ) , in contrast to normal epithelial cells . # ::alignments 0-1.1 1-1.1.1 3-1.1.1.1.1.3 4-1.1.1.1.1.2.1.1 5-1.1.1.1.1 6-1.1.1.1 8-1.1.1.1.2.3.1.1.1 10-1.1.1.1.2.3.1.1 11-1.1.1.1.2.3 11-1.1.1.1.2.3.1 11-1.1.1.1.2.3.1.r 12-1.1.1.1.2 13-1.1.1.1.2.2.r 13-1.1.1.1.2.3.1.1 14-1.1.1.1.2.2.1.1 15-1.1.1.1.2.3.2 16-1.1.1.1.2.3.2.1.r 17-1.1.1.1.2.3.2.1.1.1 18-1.1.1.1.2.1.r 19-1.1.1.1.2.1.1.1 21-1.1.1.1.2.1.1.1 22-1.1.1.1.2.1 24-1.1.2.1 27-1.1.2.1.1 30-1.1.2.2.1 31-1.1.2.2 35-1 36-1.2.r 37-1.2.1 38-1.2.2 39-1.2 (c / contrast-01~e.35 :ARG1 (f / fibroblast~e.0 :ARG0-of (e / exhibit-01~e.1 :ARG1 (a / and~e.6 :op1 (r / respond-01~e.5 :ARG0 f :ARG1 (p2 / protein :name (n / name :op1 "LIF"~e.4)) :mod (p / prominent~e.3)) :op2 (a2 / activate-01~e.12 :ARG0~e.18 (c4 / cytokine~e.22 :name (n5 / name :op1 "IL-6"~e.19,21)) :ARG1~e.13 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.14)) :ARG1-of (h / high-02~e.11 :degree~e.11 (m / more~e.11 :quant (p4 / product-of~e.10,13 :op1 (s / several~e.8))) :ARG1-of (r2 / relative-05~e.15 :ARG3~e.16 (p5 / protein :name (n6 / name :op1 "STAT3"~e.17))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.24 :mod "1A"~e.27) :location (p6 / panel~e.31 :mod (b / bottom~e.30)))) :ARG2~e.36 (c2 / cell~e.39 :ARG1-of (n4 / normal-02~e.37) :source (e3 / epithelium~e.38))) # ::id pmid_1627_1139.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The maximal level of receptor action in epithelial cells was reached after 15 min agonist treatment ( Fig . 1D , example of OSM on normal type II epithelial cells ) . # ::alignments 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1 5-1.1.2 6-1.1.3.r 7-1.1.3.1 8-1.1.3 10-1 11-1.2 12-1.2.1.2.1 13-1.2.1.2.2 14-1.2.1.1 15-1.2.1 17-1.3.1 20-1.3.1.1 23-1.3.1.2.r 25-1.3.1.2.1.1 27-1.3.1.2.2.1 28-1.3.1.2.2.2 29-1.3.1.2.2.2.1.1 30-1.3.1.2.2.3 31-1.3.1.2.2 (r / reach-01~e.10 :ARG1 (l / level~e.2 :degree (m / maximal~e.1) :degree-of~e.3 (a / act-02~e.5 :ARG0 (r2 / receptor~e.4)) :location~e.6 (c / cell~e.8 :source (e / epithelium~e.7))) :time (a2 / after~e.11 :op1 (t / treat-04~e.15 :ARG2 (a3 / agonist~e.14) :duration (t2 / temporal-quantity :quant 15~e.12 :unit (m2 / minute~e.13)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod "1D"~e.20 :example-of~e.23 (p / protein :name (n / name :op1 "OSM"~e.25) :location (c2 / cell~e.31 :ARG1-of (n2 / normal-02~e.27) :mod (t3 / type~e.28 :name (n3 / name :op1 "II"~e.29)) :source (e3 / epithelium~e.30)))))) # ::id pmid_1627_1139.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Deviations from the normal regulatory phenotype of epithelial cells were already evident in immortalized bronchial epithelial cells , HBE4 ( Fig . 1A ) and HBE137 ( not shown ) . # ::alignments 0-1.1 1-1.1.1.3.1.r 3-1.1.1.1 4-1.1.1.2 5-1.1.1 7-1.1.1.3.1 8-1.1.1.3 8-1.3 10-1.2 11-1 12-1.3.r 13-1.3.3 14-1.3.2 15-1.3.1 16-1.3 18-1.3.4.1.1.1.1 20-1.3.4.1.1.2.1 23-1.3.4.1.1.2.1.1 26-1.3.4.1 27-1.3.4.1.2.1.1 29-1.3.4.1.2.2.1 29-1.3.4.1.2.2.1.r 30-1.3.4.1.2 30-1.3.4.1.2.2 30-1.3.4.1.2.2.r (e / evidence-01~e.11 :ARG1 (d / deviate-01~e.0 :ARG1 (p / phenotype~e.5 :ARG1-of (n / normal-02~e.3) :ARG0-of (r / regulate-01~e.4) :poss (c / cell~e.8 :source~e.1 (e2 / epithelium~e.7)))) :time (a / already~e.10) :location~e.12 (c2 / cell~e.8,16 :source (e3 / epithelium~e.15) :mod (b / bronchus~e.14) :ARG1-of (i / immortalize-03~e.13) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.26 :op1 (c3 / cell-line :name (n2 / name :op1 "HBE4"~e.18) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.20 :mod "1A"~e.23))) :op2 (c4 / cell-line~e.30 :name (n3 / name :op1 "HBE137"~e.27) :ARG1-of~e.30 (s / show-01~e.30 :polarity~e.29 -~e.29)))))) # ::id pmid_1627_1139.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These cell lines responded to IL @-@ 6 cytokines like normal epithelial cells , but showed a detectable STAT3 signaling by LIF and a ~ 2 @-@ fold higher ERK activation by OSM and IL @-@ 6 . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1 3-1.1 3-1.1.3.1 4-1.1.2.r 5-1.1.2.1.1 7-1.1.2.1.1 8-1.1.2 9-1.1.3 10-1.1.3.1.1.1 11-1.1.3.1.1.2 12-1.1.3.1.1 14-1 15-1.2 17-1.2.2.1.3 18-1.2.2.1.1.1.1 19-1.2.2.1 20-1.2.2.1.2.r 21-1.2.2.1.2.1.1 22-1.2.2 24-1.2.2.2.3.1.1 25-1.2.2.2.3.1.1.1.1 27-1.2.2.2.3.1.1.1 28-1.2.2.2.3 28-1.2.2.2.3.1 28-1.2.2.2.3.1.r 29-1.2.2.2.2.1.1 30-1.2.2.2 31-1.2.2.2.1.r 32-1.2.2.2.1.1.1.1 33-1.2.2 33-1.2.2.2.1 34-1.2.2.2.1.2 35-1.2.2.2.1.2 36-1.2.2.2.1.2 (c / contrast-01~e.14 :ARG1 (r / respond-01~e.3 :ARG0 (c2 / cell-line~e.1,2 :mod (t / this~e.0)) :ARG1~e.4 (c3 / cytokine~e.8 :name (n / name :op1 "IL-6"~e.5,7)) :ARG1-of (r2 / resemble-01~e.9 :ARG2 (r3 / respond-01~e.3 :ARG0 (c4 / cell~e.12 :ARG1-of (n2 / normal-02~e.10) :source (e / epithelium~e.11))))) :ARG2 (s / show-01~e.15 :ARG0 c2 :ARG1 (a / and~e.22,33 :op1 (s2 / signal-07~e.19 :ARG0 (p / protein :name (n3 / name :op1 "STAT3"~e.18)) :ARG2~e.20 (p3 / protein :name (n4 / name :op1 "LIF"~e.21)) :ARG1-of (d / detect-01~e.17 :ARG1-of (p2 / possible-01))) :op2 (a2 / activate-01~e.30 :ARG0~e.31 (a3 / and~e.33 :op1 (p4 / protein :name (n5 / name :op1 "OSM"~e.32)) :op2 c3~e.34,35,36) :ARG1 (e2 / enzyme :name (n7 / name :op1 "ERK"~e.29)) :ARG1-of (h / high-02~e.28 :degree~e.28 (m / more~e.28 :quant (a4 / approximately~e.24 :op1 (p6 / product-of~e.27 :op1 2~e.25)))))))) # ::id pmid_1627_1139.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More profound differences were detected in carcinoma lines ( Fig . 1A and not shown ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2 9-1.3.1.1 12-1.3.1.1.1 14-1.3.1 15-1.3.1.2.1.1 15-1.3.1.2.1.1.r 16-1.3.1.2.1 (d / detect-01~e.4 :ARG1 (d2 / differ-02~e.2 :mod (p / profound~e.1 :degree (m / more~e.0))) :location~e.5 (l / line~e.7 :source (m2 / medical-condition :name (n / name :op1 "carcinoma"~e.6))) :ARG1-of (d4 / describe-01 :ARG0 (a / and~e.14 :op1 (f / figure~e.9 :mod "1A"~e.12) :op2 (d5 / data :ARG1-of (s / show-01~e.16 :polarity~e.15 -~e.15))))) # ::id pmid_1627_1139.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In carcinoma cell lines , the major trends included a strong STAT3 activation by LIF ( ADLC , H125 ) , an increased ( ADLC , H23 ) or decreased STAT3 activation by IL @-@ 6 ( H125 , H324 ) , a decreased ERK activation by EGF ( H522 ) , and a treatment @-@ independent , constitutive activation of the ERK pathway ( H23 ) . # ::alignments 1-1.3.1.1.1 2-1.3 3-1.3 6-1.2.1 7-1.2 8-1 10-1.1.1.3 11-1.1.1.2.1.1 12-1.1.1 13-1.1.1.1.r 14-1.1.1.1.1.1 16-1.1.1.1.2.1.1.1 18-1.1.1.1.2.2.1.1 22-1.1.2.1.3 24-1.1.2.1.1.2.1 26-1.1.2.1.1.2.2.1.1 28-1.1.2 29-1.1.2.2.3 30-1.1.1.2.1.1 31-1.1.2.1 31-1.1.2.2 33-1.1.2.1.1.1.1 33-1.1.2.2.1.1.1 35-1.1.2.1.1.1.1 35-1.1.2.2.1.1.1 37-1.1.2.2.1.2.1 39-1.1.2.2.1.2.2.1.1 43-1.1.2.2.3 44-1.1.3.2.1.1 44-1.1.4.1.1.1 45-1.1.3 46-1.1.3.1.r 47-1.1.3.1.1.1 49-1.1.3.1.2.1.1 52-1.1 52-1.1.1.1.2 52-1.1.2.1.1.2 54-1.1.4.3.2 56-1.1.4.3 56-1.1.4.3.1 56-1.1.4.3.1.r 58-1.1.4.2 59-1.1.4 62-1.1.3.2.1.1 62-1.1.4.1.1.1 63-1.1.3.2 63-1.1.4.1 65-1.1.2.1.1.2.2.1.1 (i / include-91~e.8 :ARG1 (a / and~e.52 :op1 (a2 / activate-01~e.12 :ARG0~e.13 (p / protein :name (n2 / name :op1 "LIF"~e.14) :location (a3 / and~e.52 :op1 (c3 / cell-line :name (n4 / name :op1 "ADLC"~e.16)) :op2 (c8 / cell-line :name (n5 / name :op1 "H125"~e.18)))) :ARG1 (p2 / protein :name (n3 / name :op1 "STAT3"~e.11,30)) :ARG1-of (s / strong-02~e.10)) :op2 (o2 / or~e.28 :op1 (a4 / activate-01~e.31 :ARG0 (p5 / protein :name (n6 / name :op1 "IL-6"~e.33,35) :location (a7 / and~e.52 :op1 c3~e.24 :op2 (c4 / cell-line :name (n11 / name :op1 "H23"~e.26,65)))) :ARG1 p2 :ARG1-of (i2 / increase-01~e.22)) :op2 (a5 / activate-01~e.31 :ARG0 (p3 / protein :name (n18 / name :op1 "IL-6"~e.33,35) :location (a6 / and :op1 c8~e.37 :op2 (c5 / cell-line :name (n8 / name :op1 "H324"~e.39)))) :ARG1 p2 :ARG1-of (d2 / decrease-01~e.29,43))) :op3 (a8 / activate-01~e.45 :ARG0~e.46 (p4 / protein :name (n14 / name :op1 "EGF"~e.47) :location (c7 / cell-line :name (n15 / name :op1 "H522"~e.49))) :ARG1 (p12 / pathway~e.63 :name (n13 / name :op1 "ERK"~e.44,62)) :ARG1-of d2) :op4 (a9 / activate-01~e.59 :ARG1 (p13 / pathway~e.63 :name (n16 / name :op1 "ERK"~e.44,62) :location c4) :mod (c2 / constitutive~e.58) :ARG0-of (d4 / depend-01~e.56 :polarity~e.56 -~e.56 :ARG1 (t2 / treat-04~e.54)))) :ARG2 (t / trend-01~e.7 :ARG1-of (m / major-02~e.6)) :location (c / cell-line~e.2,3 :source (m2 / medical-condition :name (n / name :op1 "carcinoma"~e.1)))) # ::id pmid_1627_1139.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the substantial changes in response patterns , STAT and ERK signaling in response to OSM was consistently high in all analyzed lung cancer cell lines . # ::alignments 0-1.4.r 2-1.4.2 3-1.4 4-1.4.1.r 5-1.4.1.1 6-1.4.1 8-1.1.1.1.1.1 9-1.1.1 10-1.1.1.2.1.1 11-1.1 12-1.1.2.r 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 17-1.2 18-1 19-1.3.r 20-1.3.1 21-1.3.2 22-1.3.3.2.1 23-1.3.3.2.2 24-1.3 25-1.3 (h / high-02~e.18 :ARG1 (s / signal-07~e.11 :ARG0 (a / and~e.9 :op1 (p / protein :name (n / name :op1 "STAT"~e.8)) :op2 (e / enzyme :name (n2 / name :op1 "ERK"~e.10))) :ARG0-of~e.12 (r / respond-01~e.13 :ARG1~e.14 (p3 / protein :name (n3 / name :op1 "OSM"~e.15)))) :manner (c / consistent-02~e.17) :location~e.19 (c2 / cell-line~e.24,25 :mod (a2 / all~e.20) :ARG1-of (a3 / analyze-01~e.21) :mod (d / disease :wiki "Lung_cancer" :name (n4 / name :op1 "lung"~e.22 :op2 "cancer"~e.23))) :concession~e.0 (c4 / change-01~e.3 :ARG1~e.4 (p4 / pattern~e.6 :ARG1-of (r2 / respond-01~e.5)) :degree (s2 / substantial~e.2))) # ::id pmid_1627_1139.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the cell @-@ type and line specific differences in STAT3 and ERK signaling were not due different expression of the signaling proteins as demonstrated by the comparable expression level of total STAT3 and ERK proteins among the cell types ( Fig . 1C ) . # ::alignments 0-1.1.3 3-1.1.3.1.1.1 5-1.1.3.1.1 6-1.1.3 7-1.1.3.2.2.1 8-1.1.3.2.2 9-1.1.3.1 9-1.1.3.2 10-1.1.3.1.2.r 11-1.1.3.1.2.1.1.1.1 12-1.1.3 13-1.1.3.1.2.1.2.1.1 14-1.1.3.1.2 16-1.1.1 16-1.1.1.r 17-1.1 18-1.1.1 18-1.1.1.r 18-1.1.2.2 19-1.1.2 20-1.1.2.1.r 22-1.1.2.1.1 23-1.1.2.1 24-1.1.4.r 25-1.1.4 26-1.1.4.1.r 28-1.1.4.1.2 29-1.1.4.1.1 30-1.1.4.1 32-1.1.4.1.1.1.1.2 33-1.1.3.1.2.1.1.1.1 33-1.1.4.1.1.1.1.1.1 34-1.1.3.1.2.1 34-1.1.4.1.1.1 35-1.1.3.1.2.1.2.1.1 35-1.1.4.1.1.1.2.1.1 36-1.1.3.1.2.1.1 36-1.1.4.1.1.1.1 39-1.1.3.1.1.1 40-1.1.3.1.1 42-1.2.1 45-1.2.1.1 (a4 / and :op2 (c / cause-01~e.17 :polarity~e.16,18 -~e.16,18 :ARG0 (e / express-03~e.19 :ARG2~e.20 (p3 / protein~e.23 :ARG0-of (s3 / signal-07~e.22)) :ARG1-of (d3 / differ-02~e.18)) :ARG1 (a2 / and~e.0,6,12 :op1 (d / differ-02~e.9 :ARG1 (t / type~e.5,40 :mod (c2 / cell~e.3,39)) :ARG3~e.10 (s2 / signal-07~e.14 :ARG0 (a / and~e.34 :op1 (p / protein~e.36 :name (n / name :op1 "STAT3"~e.11,33)) :op2 (e4 / enzyme :name (n2 / name :op1 "ERK"~e.13,35))))) :op2 (d2 / differ-02~e.9 :ARG3 s2 :ARG1-of (s / specific-02~e.8 :ARG2 (l / line~e.7)))) :ARG1-of~e.24 (d4 / demonstrate-01~e.25 :ARG0~e.26 (l2 / level~e.30 :degree-of (e2 / express-03~e.29 :ARG2 (a3 / and~e.34 :op1 (p4 / protein~e.36 :name (n3 / name :op1 "STAT3"~e.33) :mod (t2 / total~e.32)) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK"~e.35) :mod t2))) :ARG1-of (c3 / comparable-03~e.28) :location t))) :ARG1-of (d5 / describe-01 :ARG0 (f / figure~e.42 :mod "1C"~e.45))) # ::id pmid_1627_1139.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell line @-@ specific effect of cytokines on proliferation # ::alignments 1-1.3.1 2-1.3.1 4-1.3 5-1 6-1.1.r 7-1.1 8-1.2.r 9-1.2 (a / affect-01~e.5 :ARG0~e.6 (c / cytokine~e.7) :ARG1~e.8 (p / proliferate-01~e.9) :ARG1-of (s2 / specific-02~e.4 :ARG2 (c2 / cell-line~e.1,2))) # ::id pmid_1627_1139.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To relate cytokine signaling with effects on cell proliferation , representative lung cell types were cultured for 6 days in growth medium containing in addition increasing concentrations of OSM , IL @-@ 6 or LIF ( Fig . 2 ) . # ::alignments 1-1.5 2-1.5.1.1 3-1.5.1 4-1.5.2.r 5-1.5.2 6-1.5.2.2.r 7-1.5.2.2.1 8-1.5.2.2 10-1.1.2 11-1.1.1.1 12-1.1.1 13-1.1 15-1 16-1.2.r 17-1.2.1 18-1.2.2 19-1.3.r 20-1.3.1 21-1.3 22-1.3.2 23-1.3.2.1.r 24-1.3.2.1.3 25-1.3.2.1.2 26-1.3.2.1 27-1.3.2.1.1.r 28-1.3.2.1.1.1.1.1 30-1.3.2.1.1.2.1.1 32-1.3.2.1.1.2.1.1 33-1.3.2.1.1 34-1.3.2.1.1.3.1.1 36-1.4.1 39-1.4.1.1 (c / culture-01~e.15 :ARG1 (t / type~e.13 :mod (c2 / cell~e.12 :mod (l / lung~e.11)) :ARG0-of (r / represent-01~e.10)) :duration~e.16 (t2 / temporal-quantity :quant 6~e.17 :unit (d / day~e.18)) :location~e.19 (m / medium~e.21 :mod (g / grow-01~e.20) :ARG0-of (c3 / contain-01~e.22 :ARG1~e.23 (c4 / concentrate-02~e.26 :ARG1~e.27 (o / or~e.33 :op1 (p / protein :name (n / name :op1 "OSM"~e.28)) :op2 (p2 / protein :name (n2 / name :op1 "IL-6"~e.30,32)) :op3 (p3 / protein :name (n3 / name :op1 "LIF"~e.34))) :ARG1-of (i / increase-01~e.25) :ARG1-of (a / add-02~e.24)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.36 :mod 2~e.39)) :purpose (r2 / relate-01~e.1 :ARG1 (s / signal-07~e.3 :ARG0 (c5 / cytokine~e.2)) :ARG2~e.4 (a2 / affect-01~e.5 :ARG0 s :ARG1~e.6 (p4 / proliferate-01~e.8 :ARG0 (c6 / cell~e.7))))) # ::id pmid_1627_1139.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In all cell types , OSM reduced in a dose @-@ dependent manner proliferation , with maximal effect at a concentration of 20 to 100 ng/ml . # ::alignments 1-1.3.2 2-1.3.1 3-1.3 5-1.1.1.1 6-1 9-1.4.1 11-1.4 12-1.4.r 13-1.2 15-1.5.r 16-1.5.1 17-1.5 18-1.5.1.1.r 20-1.5.1.1 21-1.5.1.1.2.r 22-1.5.1.1.2.1 24-1.5.1.1.2.2 (r / reduce-01~e.6 :ARG0 (p / protein :name (n / name :op1 "OSM"~e.5)) :ARG1 (p2 / proliferate-01~e.13) :location (t / type~e.3 :mod (c / cell~e.2) :mod (a / all~e.1)) :manner~e.12 (d / depend-01~e.11 :ARG1 (d2 / dose~e.9)) :ARG1-of~e.15 (a2 / affect-01~e.17 :degree (m / maximal~e.16 :quant~e.18 (c2 / concentration-quantity~e.20 :unit (n2 / nanogram-per-milliliter) :quant~e.21 (v / value-interval :op1 20~e.22 :op2 100~e.24))))) # ::id pmid_1627_1139.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Maximal inhibition varied among the cell types and ranged from > 80 % ( normal primary epithelial cells ) to ~ 40 % ( HBE137 , A549 , fibroblasts ) and ~ 20 % ( H23 ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 5-1.1.2.1 6-1.1.2 7-1 8-1.2 9-1.2.2.1.2.3.r 10-1.2.2 11-1.2.2.1.1 12-1.2.2.1 14-1.2.2.1.2.1 15-1.2.2.1.2.2 16-1.2.2.1.2.3 17-1.2.2.1.2 19-1.2.3.r 20-1.2.3.1 21-1.2.3.1.1.1 22-1.2.3.1.1 24-1.2.3.1.1.2.1.1.1 26-1.2.3.1.1.2.2.1.1 28-1.2.3.1.1.2.3 30-1.2.3 31-1.2.3.1 31-1.2.3.2 32-1.2.3.2.1.1 33-1.2.3.2.1 35-1.2.3.2.1.2.1.1 (a / and~e.7 :op1 (v / vary-01~e.2 :ARG1 (i / inhibit-01~e.1 :degree (m / maximal~e.0)) :ARG5 (t / type~e.6 :mod (c / cell~e.5))) :op2 (r / range-01~e.8 :ARG1 i :ARG3 (m2 / more-than~e.10 :op1 (p / percentage-entity~e.12 :value 80~e.11 :location (c2 / cell~e.17 :ARG1-of (n / normal-02~e.14) :mod (p2 / primary~e.15) :source~e.9 (e / epithelium~e.16)))) :ARG4~e.19 (a2 / and~e.30 :op1 (a3 / approximately~e.20,31 :op1 (p3 / percentage-entity~e.22 :value 40~e.21 :location (a4 / and :op1 (c3 / cell-line :name (n2 / name :op1 "HBE137"~e.24)) :op2 (c4 / cell-line :name (n3 / name :op1 "A549"~e.26)) :op3 (f / fibroblast~e.28)))) :op2 (a5 / approximately~e.31 :op1 (p4 / percentage-entity~e.33 :value 20~e.32 :location (c5 / cell-line :name (n4 / name :op1 "H23"~e.35))))))) # ::id pmid_1627_1139.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 6 and LIF did not appreciably alter proliferation of epithelial or fibroblastic cells . # ::alignments 0-1.2.1.2.1 2-1.2.1.2.1 3-1.2 4-1.2.2.2.1 6-1.1 6-1.1.r 8-1 9-1.3 10-1.3.1.r 11-1.3.1.1.1 12-1.3.1 14-1.3.1.1 14-1.3.1.2 (a / alter-01~e.8 :polarity~e.6 -~e.6 :ARG0 (a2 / and~e.3 :op1 (p / protein :wiki "Interleukin_6" :name (n / name :op1 "IL-6"~e.0,2)) :op2 (p2 / protein :wiki "Leukemia_inhibitory_factor" :name (n2 / name :op1 "LIF"~e.4))) :ARG1 (p3 / proliferate-01~e.9 :ARG0~e.10 (o / or~e.12 :op1 (c / cell~e.14 :mod (e / epithelium~e.11)) :op2 (c2 / cell~e.14 :mod (f / fibroblast)))) :ARG1-of (a4 / appreciate-03 :ARG1-of (p4 / possible-01))) # ::id pmid_1627_1139.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The comparative analyses also indicated that immortalization of epithelial cells with the E6E7 gene ( HBE4 or HBE137 ) or constitutive activation of ERK pathway ( H23 ) correlated with a lower growth inhibition by OSM . # ::alignments 1-1.1.1 2-1.1 3-1.3 4-1 7-1.2.r 8-1.2.1.1.1 9-1.2.1.1 12-1.2.1.2.1.1 13-1.2.1.2 15-1.2.1.1.2.1.1.1.1 16-1.2.1.1.2.1 17-1.2.1.1.2.1.2.1.1 19-1.2 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1.1 24-1.2.2.1 26-1.2.2.3.1.1 28-1.2.3 29-1.2.3.1.r 31-1.2.3.1.3 31-1.2.3.1.3.1 31-1.2.3.1.3.1.r 32-1.2.3.1.2 33-1.2.3.1 34-1.2.3.1.1.r 35-1.2.3.1.1.1.1 (i / indicate-01~e.4 :ARG0 (a / analyze-01~e.2 :ARG0-of (c / compare-01~e.1)) :ARG1~e.7 (o / or~e.19 :op1 (i2 / immortalize-03 :ARG1 (c3 / cell~e.9 :mod (e / epithelium~e.8) :ARG1-of (m2 / mean-01 :ARG2 (o2 / or~e.16 :op1 (c5 / cell-line :name (n4 / name :op1 "HBE4"~e.15)) :op2 (c6 / cell-line :name (n5 / name :op1 "HBE137"~e.17))))) :ARG2 (g / gene~e.13 :name (n / name :op1 "E6E7"~e.12))) :op2 (a4 / activate-01~e.21 :ARG1~e.22 (p / pathway~e.24 :name (n3 / name :op1 "ERK"~e.23)) :ARG0-of (c4 / constitute-01) :location (c7 / cell-line :name (n6 / name :op1 "H23"~e.26))) :ARG1-of (c2 / correlate-01~e.28 :ARG2~e.29 (i3 / inhibit-01~e.33 :ARG0~e.34 (p2 / protein :name (n2 / name :op1 "OSM"~e.35)) :ARG1-of (g2 / grow-01~e.32) :ARG1-of (l2 / low-04~e.31 :degree~e.31 (m / more~e.31))))) :mod (a2 / also~e.3)) # ::id pmid_1627_1139.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The same cells were tested for growth in the presence of conditioned medium from lipopolysaccaride ( LPS ) activated macrophages . # ::alignments 1-1.1.1 2-1.1 4-1 5-1.2.r 6-1.2 7-1.2.1.r 9-1.2.1 11-1.2.1.1.2 12-1.2.1.1 13-1.2.1.1.1.r 14-1.2.1.1.1.1.1.1.1 18-1.2.1.1.1.1 19-1.2.1.1.1 (t / test-01~e.4 :ARG1 (c / cell~e.2 :ARG1-of (s / same-01~e.1)) :ARG2~e.5 (g / grow-01~e.6 :condition~e.7 (p / present-02~e.9 :ARG1 (m / medium~e.12 :source~e.13 (m2 / macrophage~e.19 :ARG1-of (a / activate-01~e.18 :ARG0 (m4 / molecular-physical-entity :name (n / name :op1 "lipopolysaccaride"~e.14)))) :ARG1-of (c2 / condition-02~e.11))))) # ::id pmid_1627_1139.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Such medium is considered to contain a physiologically relevant mixture of inflammatory mediators ( Table 1 ) . # ::alignments 0-1.1.1.1 1-1.1.1 3-1 5-1.1 8-1.1.2.2 11-1.1.2.1 11-1.1.2.1.1 11-1.1.2.1.1.r 12-1.1.2.1.2 14-1.2.1 16-1.2.1.1 (c / consider-01~e.3 :ARG1 (c2 / contain-01~e.5 :ARG0 (m / medium~e.1 :mod (s / such~e.0)) :ARG1 (m2 / mix-01 :ARG1 (m4 / molecular-physical-entity~e.11 :ARG1-of~e.11 (i / inflame-01~e.11) :ARG0-of (m3 / mediate-01~e.12)) :ARG1-of (r2 / relevant-01~e.8 :mod (p / physiological)))) :ARG1-of (d / describe-01 :ARG0 (t / table~e.14 :mod 1~e.16))) # ::id pmid_1627_1139.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The LPS macrophage medium suppressed the proliferation of epithelial cells in a dose @-@ dependent fashion ( Fig . 2 ) . # ::alignments 1-1.1.1.1.1 2-1.1.1.2 3-1.1 4-1 6-1.2 7-1.2.1.r 8-1.2.1.1 9-1.2.1 10-1.2.2.r 12-1.2.2.1.1 14-1.2.2.1 15-1.2.2 17-1.3.1 20-1.3.1.1 (s / suppress-01~e.4 :ARG0 (m / medium~e.3 :mod (m2 / molecular-physical-entity :name (n / name :op1 "LPS"~e.1) :mod (m3 / macrophage~e.2))) :ARG1 (p / proliferate-01~e.6 :ARG0~e.7 (c / cell~e.9 :mod (e / epithelium~e.8)) :manner~e.10 (f / fashion~e.15 :ARG0-of (d / depend-01~e.14 :ARG1 (d2 / dose~e.12)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.17 :mod 2~e.20))) # ::id pmid_1627_1139.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Suppression ranged from > 80 % ( primary epithelial cells and A549 ) to < 20 % in HBE137 and H23 . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2 4-1.2.1.1 5-1.2.1 7-1.2.1.2.1.1.1 8-1.2.1.2.1.1 9-1.2.1.2.1 10-1.2.1.2 11-1.2.1.2.2.1.1 13-1.3.r 14-1.3 15-1.3.1.1 16-1.3.1 17-1.3.1.2.r 18-1.3.1.2.1.1.1 20-1.3.1.2.2.1.1 (r / range-01~e.1 :ARG1 (s / suppress-01~e.0) :ARG3~e.2 (m2 / more-than~e.3 :op1 (p / percentage-entity~e.5 :value 80~e.4 :location (a / and~e.10 :op1 (c / cell~e.9 :mod (e / epithelium~e.8 :mod (p3 / primary~e.7))) :op2 (c2 / cell-line :name (n / name :op1 "A549"~e.11))))) :ARG4~e.13 (l2 / less-than~e.14 :op1 (p2 / percentage-entity~e.16 :value 20~e.15 :location~e.17 (a2 / and :op1 (c3 / cell-line :name (n2 / name :op1 "HBE137"~e.18)) :op2 (c4 / cell-line :name (n3 / name :op1 "H23"~e.20)))))) # ::id pmid_1627_1139.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the same treatment led to enhanced proliferation of fibroblasts . # ::alignments 1-1 4-1.1.1.1 5-1.1.1 6-1.1 7-1.1.2.r 8-1.1.2.2 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1 (c / contrast-01~e.1 :ARG2 (l / lead-03~e.6 :ARG0 (t / treat-04~e.5 :ARG1-of (s / same-01~e.4)) :ARG2~e.7 (p / proliferate-01~e.9 :ARG0~e.10 (f / fibroblast~e.11) :ARG1-of (e / enhance-01~e.8)))) # ::id pmid_1627_1139.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these data indicated that cytokine responsiveness and growth regulation by OSM and inflammatory mediators are indeed subject to alterations in lung epithelial cells in part as a function of immortalization and transformation . # ::alignments 0-1.1.2 1-1.1.2.1 3-1.1.1 4-1.1 5-1 6-1.2.r 7-1.2.1.1.1 9-1.2.1 10-1.2.1.2.2 11-1.2.1.2 12-1.2.1.2.1.r 13-1.2.1.2.1.1.1.1 15-1.2.1.2.1.2.2 16-1.2.1.2.1.2 16-1.2.1.2.1.2.1 16-1.2.1.2.1.2.1.r 18-1.2.3 19-1.2 20-1.2.2.r 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.2 24-1.2.2.1.1 25-1.2.2.1 26-1.2.4.2 27-1.2.4.2 30-1.2.4 33-1.2.4.1 34-1.2.4.1.2 (i / indicate-01~e.5 :ARG0 (d / data~e.4 :mod (t / this~e.3) :ARG1-of (t2 / take-01~e.0 :mod (t3 / together~e.1))) :ARG1~e.6 (s / subject-02~e.19 :ARG1 (a2 / and~e.9 :op1 (r / responsive-02 :ARG1 (c2 / cytokine~e.7)) :op2 (r2 / regulate-01~e.11 :ARG0~e.12 (a3 / and :op1 (p3 / protein :name (n2 / name :op1 "OSM"~e.13)) :op2 (m3 / molecular-physical-entity~e.16 :ARG0-of~e.16 (m / mediate-01~e.16) :ARG0-of (i3 / inflame-01~e.15))) :ARG1 (g / grow-01~e.10))) :ARG2~e.20 (a / alter-01~e.21 :location~e.22 (c / cell~e.25 :mod (e2 / epithelium~e.24) :mod (l / lung~e.23))) :mod (i2 / indeed~e.18) :ARG1-of (f / function-01~e.30 :ARG0 (a4 / and~e.33 :op1 (i4 / immortalize-03) :op2 (t5 / transform-01~e.34)) :mod (p2 / part~e.26,27)))) # ::id pmid_1627_1139.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Characteristic changes in the cellular response patterns may serve as markers for the transformation process or may even contribute functionally to tumorigenesis . # ::alignments 0-1.1.1.1.2 1-1.1.1.1 2-1.1.1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1.1.1 7-1 8-1.1.1 9-1.1.1.2.r 10-1.1.1.2 11-1.1.1.2.1.r 13-1.1.1.2.1.1 14-1.1.1.2.1 15-1.1 16-1 17-1.1.2.4 18-1.1.2 19-1.1.2.3 20-1.1.2.2.r 21-1.1.2.2 21-1.1.2.2.1 21-1.1.2.2.1.r (p / possible-01~e.7,16 :ARG1 (o / or~e.15 :op1 (s / serve-01~e.8 :ARG0 (c / change-01~e.1 :ARG1~e.2 (p2 / pattern-01~e.6 :ARG1 (r / respond-01~e.5 :ARG0 (c3 / cell~e.4))) :ARG1-of (c2 / characteristic-02~e.0)) :ARG1~e.9 (m2 / marker~e.10 :purpose~e.11 (p3 / process-02~e.14 :ARG1 (t3 / transform-01~e.13)))) :op2 (c4 / contribute-01~e.18 :ARG0 c :ARG2~e.20 (c5 / create-01~e.21 :ARG1~e.21 (t / tumor~e.21)) :manner (f / function-01~e.19) :mod (e / even~e.17)))) # ::id pmid_1627_1139.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One of the key questions is at what stage in the transformation of lung epithelial cells are these changes established . # ::alignments 0-1.1 3-1.3.1.1 4-1 4-1.3.1 6-1.2.r 7-1.2.1 8-1.2 9-1.2.2.r 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1 14-1.2.2.1.2 15-1.2.2.1 17-1.2.3.1 18-1.2.3 19-1.2.3.2 (q / question-01~e.4 :quant 1~e.0 :ARG1~e.6 (s / stage-02~e.8 :time (a / amr-unknown~e.7) :subevent-of~e.9 (t / transform-01~e.11 :ARG1~e.12 (c / cell~e.15 :mod (l / lung~e.13) :mod (e / epithelium~e.14))) :time-of (c2 / change-01~e.18 :mod (t2 / this~e.17) :ARG1-of (e2 / establish-01~e.19))) :ARG1-of (i / include-91 :ARG2 (q2 / question~e.4 :ARG2-of (k / key-02~e.3)))) # ::id pmid_1627_1139.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To address this question , we used short @-@ term primary cultures of non @-@ immortalized epithelial cells derived from normal and pathologically distinct stages of premalignant lesions sampled by brushing during bronchoscopy of patients . # ::alignments 1-1.3 2-1.3.2.1 3-1.3.2 5-1.1 6-1 6-1.3.r 7-1.2.3.1 9-1.2.3 10-1.2.2 11-1.2 12-1.2.1.r 13-1.2.1.3.1 13-1.2.1.3.1.r 15-1.2.1.3 16-1.2.1.1 17-1.2.1 18-1.2.1.2 20-1.2.1.2.1.1.1 21-1.2.1.2.1 22-1.2.1.2.1.3.1 23-1.2.1.2.1.3 24-1.2.1.2.1.1 24-1.2.1.2.1.2 25-1.2.1.2.1.r 26-1.2.1.2.1.4.1 27-1.2.1.2.1.4 28-1.2.1.2.1.4.2 29-1.2.1.2.1.4.2.2.r 30-1.2.1.2.1.4.2.2 31-1.2.1.2.1.4.2.1.r 32-1.2.1.2.1.4.2.1 33-1.2.1.2.1.4.2.1.1.r 34-1.2.1.2.1.4.2.1.1.1.1 (u / use-01~e.6 :ARG0 (w / we~e.5) :ARG1 (c / culture-01~e.11 :ARG1~e.12 (c2 / cell~e.17 :mod (e / epithelium~e.16) :ARG1-of (d / derive-01~e.18 :ARG2~e.25 (a2 / and~e.21 :op1 (s2 / stage~e.24 :ARG1-of (n / normal-02~e.20)) :op2 (s3 / stage~e.24) :mod (d2 / distinct~e.23 :mod (p3 / pathology~e.22)) :topic (l / lesion~e.27 :mod (p2 / premalignant~e.26) :ARG1-of (s4 / sample-01~e.28 :time~e.31 (b2 / bronchoscopy~e.32 :beneficiary~e.33 (p5 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.34)))) :manner~e.29 (b / brush-01~e.30))))) :ARG1-of (i / immortalize-03~e.15 :polarity~e.13 -~e.13)) :mod (p / primary~e.10) :mod (t2 / term~e.9 :ARG1-of (s / short-07~e.7))) :purpose~e.6 (a / address-01~e.1 :ARG0 w :ARG1 (q / question-01~e.3 :mod (t / this~e.2)))) # ::id pmid_1627_1139.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The experimental approach also allowed us to establish the more basic information of what is the cytokine responsiveness of normal epithelial cells and what is the range among individuals . # ::alignments 1-1.1.1 2-1.1 3-1.3 4-1 5-1.2.1 7-1.2 9-1.2.2.1.1 10-1.2.2.1 11-1.2.2 12-1.2.2.2.r 13-1.2.2.2.1.3 13-1.2.2.2.2.1 16-1.2.2.2.1.2 19-1.2.2.2.1.1.2 20-1.2.2.2.1.1.1 21-1.2.2.2.1.1 22-1.2.2.2 23-1.2.2.2.1.3 23-1.2.2.2.2.1 26-1.2.2.2.2 27-1.2.2.2.2.2.1 28-1.2.2.2.2.2 28-1.2.2.2.2.2.1.1 (a / allow-01~e.4 :ARG0 (a2 / approach-02~e.2 :ARG1-of (e / experiment-01~e.1)) :ARG1 (e2 / establish-01~e.7 :ARG0 (w / we~e.5) :ARG1 (i / information~e.11 :mod (b / basic~e.10 :degree (m / more~e.9)) :topic~e.12 (a4 / and~e.22 :op1 (r / responsive-02 :ARG0 (c / cell~e.21 :mod (e3 / epithelium~e.20) :ARG1-of (n2 / normal-02~e.19)) :ARG1 (c2 / cytokine~e.16) :degree (a5 / amr-unknown~e.13,23)) :op2 (r2 / range-01~e.26 :ARG2 (a6 / amr-unknown~e.13,23) :ARG5 (i2 / individual~e.28 :ARG1-of (i3 / include-91~e.27 :ARG2 (i4 / individual~e.28))))))) :mod (a3 / also~e.3)) # ::id pmid_1627_1139.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Application of primary epithelial cells derived from bronchial brushing # ::alignments 1-1 2-1.1.r 3-1.1.1 4-1.1.2 5-1.1 6-1.1.3 7-1.1.3.1.r 8-1.1.3.1.1 9-1.1.3.1 (a2 / apply-02~e.1 :ARG1~e.2 (c / cell~e.5 :mod (p / primary~e.3) :mod (e / epithelium~e.4) :ARG1-of (d / derive-01~e.6 :ARG2~e.7 (b / brush-01~e.9 :mod (b2 / bronchus~e.8))))) # ::id pmid_1627_1139.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Epithelial cell cultures were established from the brushed bronchial epithelium . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 4-1 5-1.2.r 7-1.2.2 8-1.2.1 9-1.2 (e / establish-01~e.4 :ARG1 (c / culture-01~e.2 :ARG1 (c2 / cell~e.1 :mod (e2 / epithelium~e.0))) :source~e.5 (e3 / epithelium~e.9 :mod (b / bronchus~e.8) :ARG1-of (b2 / brush-01~e.7))) # ::id pmid_1627_1139.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Biopsies of the same sites were processed for pathological and cytological evaluation . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1 4-1.1.1 6-1 7-1.2.r 8-1.2.1.1 9-1.2 10-1.2.2.1 11-1.2.1 11-1.2.2 (p / process-01~e.6 :ARG1 (b / biopsy-101~e.0 :ARG1~e.1 (s / site~e.4 :ARG1-of (s2 / same-01~e.3))) :purpose~e.7 (a / and~e.9 :op1 (e / evaluate-01~e.11 :mod (p2 / pathology~e.8)) :op2 (e2 / evaluate-01~e.11 :mod (c / cytology~e.10)))) # ::id pmid_1627_1139.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The pathological findings ( normal , metaplasia , dysplasia or non @-@ invasive carcinoma in situ ) were subsequently applied in the interpretation of the signaling data ( Table 2 ) . # ::alignments 1-1.1.2 2-1.1 2-1.1.1 2-1.1.1.r 4-1.1.3.1 6-1.1.3.2 8-1.1.3.3 9-1.1.3 10-1.1.3.4.1.1 10-1.1.3.4.1.1.r 12-1.1.3.4.1 13-1.1.3.4 15-1.1.3.4.1.2.r 16-1.1.3.4.1.2 20-1.3 20-1.3.r 21-1 22-1.2.r 24-1.2 25-1.2.1.r 27-1.2.1.1 28-1.2.1 30-1.4.1 32-1.4.1.1 (a / apply-02~e.21 :ARG1 (t2 / thing~e.2 :ARG1-of~e.2 (f / find-01~e.2) :mod (p / pathology~e.1) :example (o / or~e.9 :op1 (n / normal-02~e.4) :op2 (m / metaplasia~e.6) :op3 (d / dysplasia~e.8) :op4 (c / carcinoma~e.13 :ARG0-of (i / invade-01~e.12 :polarity~e.10 -~e.10 :ARG1~e.15 (s / situ~e.16))))) :ARG2~e.22 (i2 / interpret-01~e.24 :ARG1~e.25 (d2 / data~e.28 :ARG0-of (s3 / signal-07~e.27))) :manner~e.20 (s2 / subsequent~e.20) :ARG1-of (d3 / describe-01 :ARG0 (t / table~e.30 :mod 2~e.32))) # ::id pmid_1627_1139.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No cases of invasive carcinoma or advanced lung cancer were included . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 0-1.1.2.1 0-1.1.2.1.r 1-1.1.1 1-1.1.2 2-1.1.1.2.r 3-1.1.1.2.1 4-1.1.1.2 5-1.1 6-1.1.2.2.3 7-1.1.2.2.2.1 8-1.1.2.2.2.2 10-1 (i / include-01~e.10 :ARG1 (o2 / or~e.5 :op1 (c / case-04~e.1 :polarity~e.0 -~e.0 :ARG1~e.2 (c2 / carcinoma~e.4 :ARG0-of (i3 / invade-01~e.3))) :op2 (c3 / case-04~e.1 :polarity~e.0 -~e.0 :ARG1 (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung"~e.7 :op2 "cancer"~e.8) :ARG1-of (a / advance-01~e.6))))) # ::id pmid_1627_1139.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok From May 2000 to March 2005 , 192 separate brushings were taken from 96 patients ( EC @-@ 1 to EC @-@ 96 ) . # ::alignments 0-1.3.1.r 1-1.3.1.1 1-1.3.1.1.r 2-1.3.1.2 3-1.3.2.r 4-1.3.2.1 4-1.3.2.1.r 5-1.3.2.2 7-1.1.1 8-1.1.2 9-1.1 11-1 13-1.2.1 13-1.4.2.1.1 14-1.2.2.1 16-1.4.1.1.1 16-1.4.2.1.1 18-1.4.1.1.1 20-1.4.1.1.1 20-1.4.2.1.1 22-1.2.1 22-1.4.2.1.1 (t / take-01~e.11 :ARG1 (b / brush-01~e.9 :quant 192~e.7 :ARG1-of (s / separate-02~e.8)) :ARG2 (p / person :quant 96~e.13,22 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.14))) :time (d / date-interval :op1~e.0 (d2 / date-entity :month~e.1 5~e.1 :year 2000~e.2) :op2~e.3 (d3 / date-entity :month~e.4 3~e.4 :year 2005~e.5)) :mod (v / value-interval :op1 (c / cell-line :name (n / name :op1 "EC-1"~e.16,18,20)) :op2 (c2 / cell-line :name (n2 / name :op1 "EC-96"~e.13,16,20,22)))) # ::id pmid_1627_1139.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok From these , 113 brushings ( 59 %) yielded sufficient epithelial cells that expanded to cultures suitable for functional analyses . # ::alignments 1-1.1.2.1.1 3-1.1.1 4-1.1 4-1.1.2.1 6-1.1.2.2.1 8-1 9-1.2.2 10-1.2.1 11-1.2 13-1.2.3 14-1.2.3.1.r 15-1.2.3.1 16-1.2.3.1.1 17-1.2.3.1.1.1.r 18-1.2.3.1.1.1.1 19-1.2.3.1.1.1 (y / yield-01~e.8 :ARG0 (b / brush-01~e.4 :quant 113~e.3 :ARG1-of (i / include-91 :ARG2 (b2 / brush-01~e.4 :mod (t / this~e.1)) :ARG3 (p / percentage-entity :value 59~e.6))) :ARG1 (c / cell~e.11 :mod (e / epithelium~e.10) :ARG0-of (s / suffice-01~e.9) :ARG1-of (e2 / expand-01~e.13 :ARG4~e.14 (c2 / culture~e.15 :ARG1-of (s2 / suitable-04~e.16 :ARG2~e.17 (a / analyze-01~e.19 :ARG1-of (f2 / function-01~e.18))))))) # ::id pmid_1627_1139.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Approximately 50 % of sites initially judged to be abnormal by bronchoscopy proved to be normal by histology . # ::alignments 0-1.2.1.1.2 1-1.2.1.1.2.1.1 2-1.2.1.1.2.1 4-1.2.1 4-1.2.1.1.1 5-1.2.1.1.1.1.3 6-1.2.1.1.1.1 9-1.2.1.1.1.1.2 9-1.2.1.1.1.1.2.1 9-1.2.1.1.1.1.2.1.r 10-1.2.1.1.1.1.1.r 11-1.2.1.1.1.1.1 12-1 15-1.2 16-1.1.r 17-1.1 (p2 / prove-01~e.12 :ARG0~e.16 (h / histology~e.17) :ARG1 (n2 / normal-02~e.15 :ARG1 (s / site~e.4 :ARG1-of (i / include-91 :ARG2 (s2 / site~e.4 :ARG1-of (j / judge-01~e.6 :ARG0~e.10 (b / bronchoscopy~e.11) :ARG2 (n / normal-02~e.9 :polarity~e.9 -~e.9 :ARG1 s2) :time (i2 / initial~e.5))) :ARG3 (a2 / approximately~e.0 :op1 (p / percentage-entity~e.2 :value 50~e.1)))))) # ::id pmid_1627_1139.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Based on immunostaining , every cell preparation consisted of > 95 % cytokeratin @-@ positive epithelial cells . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1 4-1.1.2 5-1.1.1 6-1.1 7-1 8-1.2.r 9-1.2.3 10-1.2.3.1.1 11-1.2.3.1 12-1.2.2.1.1.1 14-1.2.2 15-1.2.1 16-1.2 (c / consist-01~e.7 :ARG1 (p / prepare-01~e.6 :ARG1 (c2 / cell~e.5) :mod (e / every~e.4)) :ARG2~e.8 (c3 / cell~e.16 :mod (e2 / epithelium~e.15) :mod (p3 / positive~e.14 :topic (p4 / protein :name (n / name :op1 "cytokeratin"~e.12))) :quant (m2 / more-than~e.9 :op1 (p2 / percentage-entity~e.11 :value 95~e.10))) :ARG1-of (b / base-02~e.0 :ARG0~e.1 (i / immunostain-01~e.2))) # ::id pmid_1627_1139.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All cultures derived from normal and abnormal sites showed essentially the same epithelial cell morphology . # ::alignments 0-1.1.1 1-1.1 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.2.1 5-1.1.2.1 6-1.1.2.1.1.1 6-1.1.2.1.2.1 6-1.1.2.1.2.1.1 6-1.1.2.1.2.1.1.r 7-1.1.2.1.1 7-1.1.2.1.2 8-1 9-1.3 9-1.3.r 11-1.2.2 12-1.2.1.1 13-1.2.1 14-1.2 (s / show-01~e.8 :ARG0 (c / culture~e.1 :mod (a / all~e.0) :ARG1-of (d / derive-01~e.2 :ARG2~e.3 (a2 / and~e.5 :op1 (s2 / site~e.7 :ARG1-of (n / normal-02~e.6)) :op2 (s3 / site~e.7 :ARG1-of (n2 / normal-02~e.4,6 :polarity~e.6 -~e.6))))) :ARG1 (m / morphology~e.14 :poss (c2 / cell~e.13 :mod (e2 / epithelium~e.12)) :ARG1-of (s4 / same-01~e.11)) :manner~e.9 (e / essential~e.9)) # ::id pmid_1627_1139.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether or not the primary cultures demonstrated any gross chromosomal abnormalities , cells were analyzed by SKY . # ::alignments 1-1.3 2-1.3.1.1 2-1.3.1.1.r 4-1.3.1.3.1 4-1.3.1.3.1.r 6-1.3.1.2.1 7-1.3.1.2 8-1.3.1 10-1.3.1.3.3 11-1.3.1.3.2 14-1.1 16-1 (a / analyze-01~e.16 :ARG1 (c / cell~e.14) :manner (k / karyotype :mod (s / spectrum)) :purpose (d / determine-01~e.1 :ARG1 (d2 / demonstrate-01~e.8 :mode~e.2 interrogative~e.2 :ARG0 (c2 / culture~e.7 :mod (p / primary~e.6)) :ARG1 (n2 / normal-02 :polarity~e.4 -~e.4 :ARG1 (c3 / chromosome~e.11) :ARG1-of (g2 / gross-06~e.10))))) # ::id pmid_1627_1139.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With the exception of one carcinoma , the cells showed normal karyotypes . # ::alignments 2-1.3 3-1.3.1.r 4-1.3.1.1 5-1.3.1 8-1.1 9-1 10-1.2.1 (s / show-01~e.9 :ARG0 (c / cell~e.8) :ARG1 (k / karyotype :ARG1-of (n / normal-02~e.10)) :ARG2-of (e / except-01~e.2 :ARG1~e.3 (c2 / carcinoma~e.5 :quant 1~e.4))) # ::id pmid_1627_1139.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The carcinoma cell culture carried a chromosome 10 deletion ( q11.2 @-@ q22 ) in all metaphase spreads . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1 4-1 6-1.2.1 7-1.2.1.1 8-1.2 10-1.2.1.2.1.1.1.1 12-1.2.1.2.1.2.1.1 14-1.2.2.r 15-1.2.2.1 16-1.2.2.2 17-1.2.2 (c / carry-01~e.4 :ARG0 (c2 / culture~e.3 :mod (c3 / cell~e.2 :mod (c4 / carcinoma~e.1))) :ARG1 (d / delete-01~e.8 :ARG1 (c5 / chromosome~e.6 :mod 10~e.7 :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (d2 / dna-sequence :name (n / name :op1 "q11.2"~e.10)) :op2 (d3 / dna-sequence :name (n2 / name :op1 "q22"~e.12))))) :location~e.14 (s / spread-02~e.17 :mod (a / all~e.15) :mod (m / metaphase~e.16)))) # ::id pmid_1627_1139.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Paired epithelial cell cultures indicate the occurrence of altered cytokine responsiveness at early stage of transformation # ::alignments 1-1.1.1.2 1-1.1.1.3 2-1.1.1.1 3-1.1.1 4-1.1 5-1 9-1.2.1.1 10-1.2.1 13-1.2.2.1 14-1.2.2 15-1.2.2.2.r 16-1.2.2.2 (i / indicate-01~e.5 :ARG0 (c / culture~e.4 :mod (c2 / cell~e.3 :mod (e / epithelium~e.2) :mod (p / paired~e.1) :ARG1-of (p2 / pair-01~e.1))) :ARG1 (r / responsive-02 :ARG1 (c3 / cytokine~e.10 :ARG1-of (a / alter-01~e.9)) :time (s / stage~e.14 :mod (e2 / early~e.13) :poss~e.15 (t / transform-01~e.16)))) # ::id pmid_1627_1139.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cytokine responsiveness of the epithelial cells was determined by the activation of signaling and by the effect on DNA synthesis . # ::alignments 1-1.2.2 5-1.2.1.1 6-1.2.1 8-1 9-1.1.r 11-1.1.1 12-1.1.1.1.r 13-1.1.1.1 14-1.1 17-1.1.2 18-1.1.2.1.r 19-1.1.2.1.1.2.1 20-1.1.2.1 (d / determine-01~e.8 :ARG0~e.9 (a2 / and~e.14 :op1 (a / activate-01~e.11 :ARG1~e.12 (s2 / signal-07~e.13)) :op2 (a3 / affect-01~e.17 :ARG1~e.18 (s / synthesize-01~e.20 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"~e.19))))) :ARG1 (r / responsive-02 :ARG0 (c2 / cell~e.6 :mod (e / epithelium~e.5)) :ARG1 (c / cytokine~e.1))) # ::id pmid_1627_1139.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Signaling was measured in first passage subcultures by treatment with cytokines and growth factors for 15 min followed by immunodetection of the phosphorylated signaling proteins ( representative example in Fig. 3 ) . # ::alignments 0-1.1 2-1 3-1.3.r 4-1.3.2 4-1.3.2.1 4-1.3.2.1.r 5-1.3 6-1.3.1 7-1.2.r 8-1.2 9-1.2.1.r 10-1.2.1.1 11-1.2.1 14-1.2.2.r 15-1.2.2.1 16-1.2.2.2 17-1.2.3 22-1.2.3.1.1.1.1 23-1.2.3.1.1 24-1.2.3.1.1.1 26-1.4.1.1 27-1.4.1 28-1.4.1.2.r 29-1.4.1.2 31-1.4.1.2.1 (m / measure-01~e.2 :ARG1 (s / signal-07~e.0) :ARG2~e.7 (t / treat-04~e.8 :ARG2~e.9 (a / and~e.11 :op1 (c / cytokine~e.10) :op2 (s4 / small-molecule :name (n / name :op1 "growth_factor"))) :duration~e.14 (t2 / temporal-quantity :quant 15~e.15 :unit (m2 / min~e.16)) :ARG2-of (f2 / follow-01~e.17 :ARG1 (i / immunodetect-01 :ARG1 (s3 / signal-07~e.23 :ARG0 (p2 / protein~e.24 :ARG3-of (p3 / phosphorylate-01~e.22)))))) :location~e.3 (p / pass-03~e.5 :ARG1 (s2 / subculture~e.6) :mod (o / ordinal-entity~e.4 :value~e.4 1~e.4)) :ARG1-of (d / describe-01 :ARG0 (e / example~e.27 :ARG0-of (r / represent-01~e.26) :mod~e.28 (f3 / figure~e.29 :mod 3~e.31)))) # ::id pmid_1627_1139.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The level of phosphorylated STAT1 , STAT3 and ERK1 @/@ 2 were quantified and expressed relative to the level of these proteins in OSM @-@ treated normal cultures in each pair ( Fig . 4A @–@ F ) . # ::alignments 1-1.1.1.1 3-1.1.1.1.1.2 4-1.1.1.1.1.1.1 6-1.1.1.2.1.1.1 7-1.1.1 8-1.1.1.3.1.1.1 10-1.1.1.3.1.1.1 12-1.1 13-1 13-1.1.1 13-1.4.1 14-1.2 15-1.3 18-1.1.1.1 18-1.1.1.2 18-1.1.1.3 21-1.1.1.1.1 21-1.1.1.2.1 21-1.3.1.4.2.1 22-1.3.1.r 23-1.3.1.4.2.1.1.1 25-1.3.1.4.2 26-1.3.1.4.1 27-1.3.1.4 28-1.3.1.4.2.2.r 29-1.3.1.4.2.2.1 30-1.3.1.4.2.2 32-1.4.1.1 32-1.4.1.2 32-1.4.1.3 32-1.4.1.4 32-1.4.1.5 32-1.4.1.6 35-1.4.1.1.1 (a3 / and~e.13 :op1 (q / quantify-01~e.12 :ARG1 (a / and~e.7,13 :op1 (l3 / level~e.1,18 :quant-of (p / protein~e.21 :name (n / name :op1 "STAT1"~e.4) :ARG3-of (p3 / phosphorylate-01~e.3))) :op2 (l4 / level~e.18 :quant-of (p2 / protein~e.21 :name (n2 / name :op1 "STAT3"~e.6) :ARG3-of p3)) :op3 (l5 / level~e.18 :quant-of (e4 / enzyme :name (n3 / name :op1 "ERK1/2"~e.8,10) :ARG3-of p3)))) :op2 (e2 / express-01~e.14 :ARG2 a) :ARG1-of (r / relative-05~e.15 :ARG3~e.22 (a4 / and :op1 l3 :op2 l4 :op3 l5 :location (c / culture~e.27 :ARG1-of (n4 / normal-02~e.26) :ARG1-of (t / treat-04~e.25 :ARG2 (p4 / protein~e.21 :name (n5 / name :op1 "OSM"~e.23)) :location~e.28 (p5 / pair~e.30 :mod (e / each~e.29)))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.13 :op1 (f / figure~e.32 :mod "4A"~e.35) :op2 (f2 / figure~e.32 :mod "4B") :op3 (f3 / figure~e.32 :mod "4C") :op4 (f4 / figure~e.32 :mod "4D") :op5 (f5 / figure~e.32 :mod "4E") :op6 (f6 / figure~e.32 :mod "4F")))) # ::id pmid_1627_1139.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The analyses of normal bronchial epithelial cells defined the following response pattern . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.3 4-1.1.1.1 5-1.1.1.2 6-1.1.1 7-1 9-1.2.1.1 10-1.2.1 11-1.2 (d / define-01~e.7 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (c / cell~e.6 :mod (b / bronchus~e.4) :mod (e / epithelium~e.5) :ARG1-of (n / normal-02~e.3))) :ARG1 (p / pattern-01~e.11 :ARG1 (r / respond-01~e.10 :ARG1-of (f / follow-04~e.9)))) # ::id pmid_1627_1139.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The reaction to cytokine treatment ( Fig . 3 ) was comparable to that of type II epithelial cells ( Fig . 1A ) . # ::alignments 1-1.1 1-1.2 2-1.1.1.r 3-1.1.1.1 4-1.1.1 6-1.1.2.1 9-1.1.2.1.1 13-1 16-1.2.1.r 17-1.2.1.2 18-1.2.1.2.1 19-1.2.1.1 20-1.2.1 22-1.2.2.1 25-1.2.2.1.1 (c / comparable-03~e.13 :ARG1 (r / react-01~e.1 :ARG1~e.2 (t / treat-04~e.4 :ARG2 (c3 / cytokine~e.3)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.6 :mod 3~e.9))) :ARG2 (r2 / react-01~e.1 :ARG0~e.16 (c2 / cell-line~e.20 :mod (e / epithelium~e.19) :mod (t2 / type~e.17 :mod "II"~e.18)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.22 :mod "1A"~e.25)))) # ::id pmid_1627_1139.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Data from 63 separate preparations of normal bronchial epithelial cell cultures indicated that basal level of phosphorylated ERK was consistently low ( 7.5 ± 5.6 % of OSM level ; mean ± SD ) and the basal levels of phosphorylated STAT3 and STAT1 were generally low to non @-@ detectable . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.3 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.3 7-1.1.1.2.1.2 8-1.1.1.2.1.1 9-1.1.1.2.1 10-1.1.1.2 11-1 12-1.2.r 13-1.2.1.1.2 14-1.2.1.1 15-1.2.1.1.1.r 16-1.2.1.1.1.2 17-1.2.1.1.1.1.1 19-1.2.1.2 20-1.2.1 22-1.2.1.1.3.1.1.1.1 22-1.2.1.1.3.1.2.1.1 24-1.2.1.1.3.1.1.1.2.1.1 25-1.2.1.1.3.1.1.1 25-1.2.1.1.3.1.1.1.2.1 25-1.2.1.1.3.1.2.1 26-1.2.1.1.3.1.1 27-1.2.1.1.3.1.1.2.1.1.1 28-1.2.1.1.3.1.1.2 30-1.2.1.1.3.1.3.1 36-1.2.2.3.2 37-1.2.2.3 38-1.2.2.3.1.r 39-1.2.2.3.1.1.2 40-1.2.2.3.1.1.1.1 42-1.2.2.3.1.2.1.1 43-1.2.2.3.r 44-1.2.2.4 45-1.2.2.1 47-1.2.2.2.1.1 47-1.2.2.2.1.1.r 49-1.2.2.2 (i / indicate-01~e.11 :ARG0 (d / data~e.0 :source~e.1 (p / prepare-01~e.4 :quant 63~e.2 :ARG1~e.5 (c / culture-01~e.10 :ARG1 (c2 / cell~e.9 :mod (e / epithelium~e.8) :mod (b / bronchus~e.7) :ARG1-of (n / normal-02~e.6))) :ARG1-of (s3 / separate-01~e.3))) :ARG1~e.12 (a / and :op1 (l / low-04~e.20 :ARG1 (l2 / level~e.14 :quant-of~e.15 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.17) :ARG3-of (p2 / phosphorylate-01~e.16)) :mod (b2 / basal~e.13) :ARG1-of (e3 / equal-01 :ARG2 (v2 / value-interval :op1 (p3 / product-of~e.26 :op1 (p4 / percentage-entity~e.25 :value 7.5~e.22 :ARG2-of (a2 / add-02 :ARG1 (p5 / percentage-entity~e.25 :value 5.6~e.24))) :op2 (l3 / level~e.28 :quant-of (p6 / protein :name (n3 / name :op1 "OSM"~e.27)))) :op2 (p8 / product-of :op1 (p11 / percentage-entity~e.25 :value 7.5~e.22 :ARG2-of (s / subtract-01 :ARG1 p5)) :op2 l3) :condition (d3 / deviate-01 :mod (m / mean~e.30) :ARG1-of (s2 / standard-02))))) :manner (c3 / consistent-02~e.19)) :op2 (v / value-interval :op1 (l5 / low-04~e.45) :op2 (d2 / detect-01~e.49 :ARG1-of (p10 / possible-01 :polarity~e.47 -~e.47)) :domain~e.43 (l4 / level~e.37 :quant-of~e.38 (a3 / and :op1 (p7 / protein :name (n4 / name :op1 "STAT3"~e.40) :ARG3-of p2~e.39) :op2 (p9 / protein :name (n5 / name :op1 "STAT1"~e.42) :ARG3-of p2)) :mod b2~e.36) :ARG1-of (g / general-02~e.44)))) # ::id pmid_1627_1139.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok OSM prominently activated ERK ( Fig . 4A & @ 4B ) and STAT3 ( Fig . 4C & @ 4D ) . # ::alignments 0-1.1.1.1.1 1-1.3 1-1.3.r 2-1.1 2-1.2 3-1.1.2.1.1 5-1.1.3.1.1 8-1.1.3.1.1.1 10-1 10-1.1.3.1 12-1.1.3.1.2.1 15-1.1.3.1 16-1.2.2.1.1 18-1.1.3.1.2 18-1.2.3.1.1 18-1.2.3.1.2 21-1.2.3.1.1.1 23-1.1.3.1 25-1.2.3.1.2.1 (a / and~e.10 :op1 (a2 / activate-01~e.2 :ARG0 (p / protein :name (n / name :op1 "OSM"~e.0)) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.3)) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.10,15,23 :op1 (f / figure~e.5 :mod "4A"~e.8) :op2 (f2 / figure~e.18 :mod "4B"~e.12)))) :op2 (a4 / activate-01~e.2 :ARG0 p :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3"~e.16)) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure~e.18 :mod "4C"~e.21) :op2 (f4 / figure~e.18 :mod "4D"~e.25)))) :manner~e.1 (p2 / prominent~e.1)) # ::id pmid_1627_1139.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The response was uniformly high among cultures from different individuals . # ::alignments 1-1.1 3-1.2 3-1.2.r 4-1 6-1.3 7-1.3.1.r 8-1.3.1.1 9-1.3.1 (h / high-02~e.4 :ARG1 (r / respond-01~e.1) :manner~e.3 (u / uniform~e.3) :location (c / culture-01~e.6 :source~e.7 (i / individual~e.9 :ARG1-of (d / differ-02~e.8)))) # ::id pmid_1627_1139.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IL @-@ 6 response , although quite variable among individuals , was consistently below that of OSM . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 3-1.1.2.1.1 5-1 6-1.2.3 9-1.2.2 12-1.2.1 13-1.2.1 14-1.2.1 15-1.2.1 16-1.2.1 (h / have-concession-91~e.5 :ARG1 (r / respond-01~e.3 :ARG0 (p / protein :name (n / name :op1 "IL-6"~e.0,2)) :ARG1-of (e / equal-01 :ARG2 (b / below :op1 (r2 / respond-01~e.3 :ARG0 (p2 / protein :name (n2 / name :op1 "OSM"))) :manner (c / consistent-02)))) :ARG2 (v / vary-01 :ARG1 r~e.12,13,14,15,16 :location (i / individual~e.9) :degree (q / quite~e.6))) # ::id pmid_1627_1139.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The level of activated ERK was 37 ± 18 % of OSM ( Fig . 4A & @ 4B ) and activated STAT3 was 63 ± + 27 % ( Fig . 4C & @ 4D ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 4-1.1.1.1.1 6-1.1.1.3.1.1.1.1 6-1.1.1.3.1.2.1.1 8-1.1.1.3.1.1.1.2.1.1 9-1.1.1.3.1.1.1 9-1.1.1.3.1.1.1.2.1 9-1.1.1.3.1.2.1 9-1.2.4.1.1.1 9-1.2.4.1.2.1 10-1.1.1.3.1.1 11-1.1.1.3.1.1.2.1.1 13-1.1.2.1.1 13-1.1.2.1.2 16-1.1.2.1.1.1 18-1 18-1.1.2.1 20-1.1.2.1.2.1 23-1.1.2.1 24-1.2.2 25-1.2.1.1 27-1.2.4.1.1.1.1 27-1.2.4.1.2.1.1 29-1.2.3.1 30-1.2.4.1.1.1.2.1.1 31-1.2.4.1.1.1.2.1 33-1.2.3.1.1 33-1.2.3.1.2 36-1.2.3.1.1.1 38-1.2.3.1 40-1.2.3.1.2.1 (a / and~e.18 :op1 (l / level~e.1 :quant-of~e.2 (e / enzyme :name (n / name :op1 "ERK"~e.4) :ARG1-of (a2 / activate-01~e.3) :ARG1-of (e2 / equal-01 :ARG2 (v / value-interval :op1 (p / product-of~e.10 :op1 (p2 / percentage-entity~e.9 :value 37~e.6 :ARG2-of (a3 / add-02 :ARG1 (p3 / percentage-entity~e.9 :value 18~e.8))) :op2 (p4 / protein :name (n3 / name :op1 "OSM"~e.11))) :op2 (p6 / product-of :op1 (p7 / percentage-entity~e.9 :value 37~e.6 :ARG2-of (s / subtract-01 :ARG1 p3)) :op2 p4)))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.18,23 :op1 (f / figure~e.13 :mod "4A"~e.16) :op2 (f2 / figure~e.13 :mod "4B"~e.20)))) :op2 (p5 / protein :name (n2 / name :op1 "STAT3"~e.25) :ARG1-of a2~e.24 :ARG1-of (d2 / describe-01 :ARG0 (a6 / and~e.29,38 :op1 (f3 / figure~e.33 :mod "4C"~e.36) :op2 (f4 / figure~e.33 :mod "4D"~e.40))) :ARG1-of (e3 / equal-01 :ARG2 (v2 / value-interval :op1 (p10 / product-of :op1 (p8 / percentage-entity~e.9 :value 63~e.27 :ARG2-of (a5 / add-02 :ARG1 (p9 / percentage-entity~e.31 :value 27~e.30))) :op2 p4) :op2 (p11 / product-of :op1 (p12 / percentage-entity~e.9 :value 63~e.27 :ARG2-of (s2 / subtract-01 :ARG1 p9)) :op2 p4))))) # ::id pmid_1627_1139.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The two @-@ fold lower activation of ERK relative to STAT3 by IL @-@ 6 is due to the difference in signaling by the IL @-@ 6 and OSM receptor [ @ 16 , 22 @ ] . # ::alignments 1-1.2.4.1 3-1.2.4 4-1.2.3 4-1.2.3.1 4-1.2.3.1.r 5-1.2 6-1.2.2.r 6-1.2.4 7-1.2.2.1.1 8-1.2.3.2 9-1.2.3.2.1.r 10-1.2.3.2.1.1.1 11-1.2.1.r 12-1.2.1.1.1 14-1.2.1.1.1 16-1 17-1 19-1.1 21-1.1.1 21-1.1.2 24-1.2.1.1.1 26-1.2.1.1.1 27-1.3.1.1.1 28-1.1.2.1.1.1.1 29-1.1.1.1 29-1.1.2.1 32-1.3.1.1.1.1 36-1.3.1.1.1.2 (c / cause-01~e.16,17 :ARG0 (d / differ-02~e.19 :ARG1 (s / signal-07~e.21 :ARG0 (r2 / receptor~e.29 :mod p)) :ARG2 (s2 / signal-07~e.21 :ARG0 (r3 / receptor~e.29 :mod (p4 / protein :name (n4 / name :op1 "OSM"~e.28))))) :ARG1 (a / activate-01~e.5 :ARG0~e.11 (p / protein :name (n2 / name :op1 "IL-6"~e.12,14,24,26)) :ARG1~e.6 (e / enzyme :name (n / name :op1 "ERK"~e.7)) :ARG1-of (l / low-04~e.4 :degree~e.4 (m / more~e.4) :ARG2-of (r / relative-05~e.8 :ARG3~e.9 (p2 / protein :name (n3 / name :op1 "STAT3"~e.10)))) :degree (p3 / product-of~e.3,6 :op1 2~e.1)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and~e.27 :op1 16~e.32 :op2 22~e.36))))) # ::id pmid_1627_1139.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LIF did not elicit a measurable ERK and STAT3 signaling in any of normal epithelial cell culture . # ::alignments 0-1.2.1.1 2-1.1 2-1.1.r 3-1 5-1.3.2 6-1.3.1.1.1.1 7-1.3.1 8-1.3.1.2.1.1 9-1.3 10-1.4.r 11-1.4.1.3 13-1.4.1.2 14-1.4.1.1 15-1.4.1 16-1.4 (e / elicit-01~e.3 :polarity~e.2 -~e.2 :ARG0 (p / protein :name (n / name :op1 "LIF"~e.0)) :ARG1 (s / signal-07~e.9 :ARG0 (a / and~e.7 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.6)) :op2 (p3 / protein :name (n3 / name :op1 "STAT3"~e.8))) :ARG1-of (m / measure-01~e.5 :ARG1-of (p2 / possible-01))) :location~e.10 (c / culture-01~e.16 :ARG1 (c2 / cell~e.15 :mod (e3 / epithelium~e.14) :ARG1-of (n4 / normal-02~e.13) :mod (a2 / any~e.11)))) # ::id pmid_1627_1139.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF activated ERK to 90 ± 29 % of OSM level ( Fig . 4A & @ 4B ) . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1 4-1.2.2.1.1.1.1 4-1.2.2.1.2.1.1 6-1.2.2.1.1.1.2.1.1 7-1.2.2.1.1.1 7-1.2.2.1.1.1.2.1 7-1.2.2.1.2.1 8-1.2.2.1.1 9-1.2.2.1.1.2.1.1.1 10-1.2.2.1.1.2 12-1.3.1.1 12-1.3.1.2 15-1.3.1.1.1 17-1.3.1 19-1.3.1.2.1 (a / activate-01~e.1 :ARG0 (p / protein :name (n / name :op1 "EGF"~e.0)) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.2) :ARG1-of (e2 / equal-01 :ARG2 (v / value-interval :op1 (p2 / product-of~e.8 :op1 (p3 / percentage-entity~e.7 :value 90~e.4 :ARG2-of (a3 / add-02 :ARG1 (p4 / percentage-entity~e.7 :value 29~e.6))) :op2 (l / level~e.10 :quant-of (p5 / protein :name (n3 / name :op1 "OSM"~e.9)))) :op2 (p6 / product-of :op1 (p7 / percentage-entity~e.7 :value 90~e.4 :ARG2-of (s / subtract-01 :ARG1 p4)) :op2 l)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.17 :op1 (f / figure~e.12 :mod "4A"~e.15) :op2 (f2 / figure~e.12 :mod "4B"~e.19)))) # ::id pmid_1627_1139.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF generally had no measurable effect on STAT3 even when the cells were treated with EGF for longer than 15 minutes ( not shown ) . # ::alignments 0-1.2.1.1 1-1.5 3-1.1 3-1.1.r 4-1.4 5-1 6-1.3.r 7-1.3.1.1 8-1.6 9-1.6 11-1.6.1.1 13-1.6.1 14-1.6.1.2.r 15-1.6.1.2 17-1.6.1.3.r 18-1.6.1.3 19-1.6.1.3.1.1 20-1.6.1.3.1.2 22-1.7.1 22-1.7.1.r 23-1.7 (a / affect-01~e.5 :polarity~e.3 -~e.3 :ARG0 (p / protein :name (n / name :op1 "EGF"~e.0)) :ARG1~e.6 (p2 / protein :name (n2 / name :op1 "STAT3"~e.7)) :ARG1-of (m / measure-01~e.4 :ARG1-of (p3 / possible-01)) :ARG1-of (g / general-02~e.1) :concession (e / even-when~e.8,9 :op1 (t / treat-04~e.13 :ARG1 (c / cell~e.11) :ARG2~e.14 p~e.15 :duration~e.17 (m2 / more-than~e.18 :op1 (t2 / temporal-quantity :quant 15~e.19 :unit (m3 / minute~e.20))))) :ARG1-of (s / show-01~e.23 :polarity~e.22 -~e.22)) # ::id pmid_1627_1139.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In all cases , IFNγ did not appreciably activate ERK and STAT3 , but yielded highest level of STAT1 phosphorylation ( 2441 ± 2073 % of OSM level ( Fig . 4E & @ 4F ) . # ::alignments 1-1.4.1 2-1.4 4-1.1.2.1.1 6-1.1.1 6-1.1.1.r 8-1.1 9-1.1.3.1.1.1 10-1.1.3 11-1.1.3.2.1.1 13-1 14-1.2 15-1.2.2.1 15-1.2.2.1.1 15-1.2.2.1.1.r 16-1.2.2 17-1.2.2.2.r 18-1.2.2.2.1.1.1 19-1.2.2.2 21-1.2.2.3.1.1.1.1 21-1.2.2.3.1.2.1.1 23-1.2.2.3.1.1.1.2.1.1 24-1.2.2.3.1.1.1 24-1.2.2.3.1.1.1.2.1 24-1.2.2.3.1.2.1 25-1.2.2.3.1.1 26-1.2.2.3.1.1.2.1.1.1 27-1.2.2.3.1.1.2 29-1.3.1.1 29-1.3.1.2 32-1.3.1.1.1 34-1.3.1 36-1.3.1.2.1 (c / contrast-01~e.13 :ARG1 (a / activate-01~e.8 :polarity~e.6 -~e.6 :ARG0 (p / protein :name (n / name :op1 "IFNγ"~e.4)) :ARG1 (a2 / and~e.10 :op1 (e / enzyme :name (n2 / name :op1 "ERK"~e.9)) :op2 (p2 / protein :name (n3 / name :op1 "STAT3"~e.11))) :degree (a3 / appreciate-03 :ARG1-of (p3 / possible-01))) :ARG2 (y / yield-01~e.14 :ARG0 p :ARG1 (l / level~e.16 :ARG1-of (h / high-02~e.15 :degree~e.15 (m / most~e.15)) :degree-of~e.17 (p4 / phosphorylate-01~e.19 :ARG1 (p5 / protein :name (n4 / name :op1 "STAT1"~e.18))) :ARG1-of (e2 / equal-01 :ARG2 (v / value-interval :op1 (p6 / product-of~e.25 :op1 (p7 / percentage-entity~e.24 :value 2441~e.21 :ARG2-of (a4 / add-02 :ARG1 (p8 / percentage-entity~e.24 :value 2073~e.23))) :op2 (l2 / level~e.27 :quant-of (p9 / protein :name (n5 / name :op1 "OSM"~e.26)))) :op2 (p10 / product-of :op1 (p11 / percentage-entity~e.24 :value 2441~e.21 :ARG2-of (s / subtract-01 :ARG1 p8)) :op2 l2))))) :ARG1-of (d / describe-01 :ARG0 (a5 / and~e.34 :op1 (f / figure~e.29 :mod "4E"~e.32) :op2 (f2 / figure~e.29 :mod "4F"~e.36))) :mod (c2 / case-04~e.2 :mod (a6 / all~e.1))) # ::id pmid_1627_1139.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The IFNγ response from patient to patient showed the highest variability among the cytokine responses , even though paired cultures from individual patients exhibited highly consistent levels of STAT1 activation by IFNγ. # ::alignments 1-1.1.1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.1 6-1.1.2.1.1 7-1 9-1.2 9-1.2.2 9-1.2.2.r 11-1.2.1.1.2 13-1.2.1.1.2.1.1 14-1.2.1.1 14-1.2.1.1.2.1 16-1.3.r 17-1.3.r 18-1.3.1.1 19-1.3.1 20-1.3.1.2.r 21-1.3.1.2.1 22-1.3.1.2.2 23-1.3 24-1.3.2.2.1 25-1.3.2.2 26-1.3.2 27-1.3.2.1.r 28-1.3.2.1.2.1.1 29-1.3.2.1 (s / show-01~e.7 :ARG0 (r / respond-01~e.2 :ARG0 (p / protein :name (n / name :op1 "IFNγ"~e.1)) :source~e.3 (p7 / person :ARG0-of (h5 / have-org-role-91 :ARG2 (p5 / patient~e.4,6)))) :ARG1 (h / high-02~e.9 :ARG1 (v / vary-01 :ARG1 (r2 / respond-01~e.14 :ARG0 p :ARG1-of (i / include-91~e.11 :ARG2 (r3 / respond-01~e.14 :ARG1 (c3 / cytokine~e.13))))) :degree~e.9 (m / most~e.9)) :concession~e.16,17 (e / exhibit-01~e.23 :ARG0 (c / culture-01~e.19 :ARG1-of (p3 / pair-01~e.18) :source~e.20 (p4 / person :mod (i2 / individual~e.21) :ARG0-of h5~e.22)) :ARG1 (l / level~e.26 :degree-of~e.27 (a / activate-01~e.29 :ARG0 p :ARG1 (p6 / protein :name (n3 / name :op1 "STAT1"~e.28))) :ARG1-of (c2 / consistent-02~e.25 :ARG1-of (h4 / high-02~e.24))))) # ::id pmid_1627_1139.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The reproducibility of detecting comparable patterns in independently derived cell cultures was assessed in those paired cultures in which the samples were initially classified as " abnormal " ( or " suspicious ") by autofluorescence bronchoscopy but proved normal by subsequent pathological analysis ( Fig . 4A , C & @ 4E ) . # ::alignments 3-1.1.1 4-1.1.1.1.1 5-1.1.1.1 7-1.1.3.2.1.1 8-1.1.3.2 9-1.1.3.1 10-1.1.3 12-1 13-1.2.r 14-1.2.3 15-1.2.1 16-1.2 20-1.2.2.2 20-1.2.2.2.1 20-1.2.2.2.1.r 22-1.2.2.5 23-1.2.2 24-1.2.2.5.r 26-1.2.2.3.1 26-1.2.2.3.1.1 26-1.2.2.3.1.1.r 29-1.2.2.3 31-1.2.2.3.2 33-1.2.2.1.r 34-1.2.2.1.1 35-1.2.2.1 36-1.2.2.4 37-1.2.2.4.1 38-1.2.2.4.1.2 39-1.2.2.4.1.1.r 40-1.2.2.4.1.1.2 41-1.2.2.4.1.1.1 42-1.2.2.4.1.1 44-1.3.1.1 44-1.3.1.2 44-1.3.1.3 47-1.3.1.1.1 51-1.3.1 53-1.3.1.3.1 (a / assess-01~e.12 :ARG1 (r / reproduce-01 :ARG0 (d / detect-01~e.3 :ARG1 (p2 / pattern~e.5 :ARG1-of (c / comparable-03~e.4))) :ARG1-of (p / possible-01) :location (c2 / culture-01~e.10 :ARG1 (c3 / cell~e.9) :ARG1-of (d2 / derive-01~e.8 :ARG1-of (d4 / depend-01 :polarity -~e.7)))) :location~e.13 (c4 / culture-01~e.16 :ARG1-of (p3 / pair-01~e.15) :location-of (c5 / classify-01~e.23 :ARG0~e.33 (b / bronchoscopy~e.35 :mod (a3 / autofluorescence~e.34)) :ARG1 (t / thing~e.20 :ARG1-of~e.20 (s / sample-01~e.20)) :ARG2 (o / or~e.29 :op1 (n / normal-02~e.26 :polarity~e.26 -~e.26 :ARG1 c4) :op2 (s2 / suspicious~e.31)) :ARG1-of (c6 / contrast-01~e.36 :ARG2 (p5 / prove-01~e.37 :ARG0~e.39 (a4 / analyze-01~e.42 :mod (p6 / pathology~e.41) :mod (s3 / subsequent~e.40)) :ARG2 (n2 / normal-02~e.38 :ARG1 c4))) :time~e.24 (i / initial~e.22)) :mod (t2 / that~e.14)) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and~e.51 :op1 (f / figure~e.44 :mod "4A"~e.47) :op2 (f2 / figure~e.44 :mod "4C") :op3 (f3 / figure~e.44 :mod "4E"~e.53)))) # ::id pmid_1627_1139.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When cell cultures were derived from histologically normal areas with abnormal fluorescence , the level and range of signaling reactions elicited by the treatments were essentially identical to those with normal histology and normal fluorescence . # ::alignments 1-1.2.1.1 2-1.1.2 2-1.2.1 4-1.2 7-1.2.2.1.1.1 8-1.2.2 10-1.2.2.1.1.1 10-1.2.2.1.1.1.1 10-1.2.2.1.1.1.1.r 11-1.2.2.1.1 14-1.1.1.1 15-1.1.1 16-1.1.1.2 17-1.1.1.1.1.r 18-1.1.1.1.1.2 19-1.1.1.1.1 20-1.1.1.3 21-1.1.1.3.1.r 23-1.1.1.3.1 25-1.1.3 26-1.1 30-1.1.2.2.1.1.1 31-1.1.2.2.1.1 33-1.1.2.2.1.1.1 34-1.1.2.2.1.2 (h / have-condition-91 :ARG1 (i / identical-01~e.26 :ARG1 (a2 / and~e.15 :op1 (l / level~e.14 :degree-of~e.17 (r2 / react-01~e.19 :ARG0 c :ARG2 (s / signal-07~e.18))) :op2 (r / range-01~e.16 :ARG1 r2) :ARG1-of (e / elicit-01~e.20 :ARG0~e.21 (t / treat-04~e.23))) :ARG2 (c3 / culture-01~e.2 :ARG1 c2 :ARG0-of (h4 / have-03 :ARG1 (a3 / and :op1 (h5 / histology~e.31 :ARG1-of (n / normal-02~e.30,33)) :op2 (f2 / fluorescence~e.34 :ARG1-of n)))) :mod (e2 / essential~e.25)) :ARG2 (d / derive-01~e.4 :ARG1 (c / culture-01~e.2 :ARG1 (c2 / cell~e.1)) :ARG2 (a / area~e.8 :ARG0-of (h3 / have-03 :ARG1 (f / fluorescence~e.11 :ARG1-of (n2 / normal-02~e.7,10 :polarity~e.10 -~e.10))) :poss h5))) # ::id pmid_1627_1139.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK activation by OSM was 108 ± 35 % , by IL @-@ 6 was 31 ± 15 % , and by EGF was 85 ± 40 % . # ::alignments 0-1.1.2.1.1 1-1.1 1-1.2 1-1.3 2-1.1.1.r 3-1.1.1.1.1 5-1.1.3.1.1.1 5-1.1.3.1.2.1 7-1.1.3.1.1.2.1.1 8-1.1.3.1.1 8-1.1.3.1.1.2.1 8-1.1.3.1.2 10-1.2.1.r 11-1.2.1.1.1 13-1.2.1.1.1 15-1.2.3.1.1.1 17-1.2.3.1.1.2.1.1 18-1.2.3.1.1 18-1.2.3.1.1.2.1 18-1.2.3.1.2 20-1 21-1.3.1.r 22-1.3.1.1.1 24-1.3.3.1.1.1 24-1.3.3.1.2.1 26-1.3.3.1.1.2.1.1 27-1.2.3.1.2 27-1.3.3.1.1 27-1.3.3.1.1.2.1 27-1.3.3.1.2 (a / and~e.20 :op1 (a2 / activate-01~e.1 :ARG0~e.2 (p / protein :name (n / name :op1 "OSM"~e.3)) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.0)) :ARG1-of (e2 / equal-01 :ARG2 (v3 / value-interval :op1 (p2 / percentage-entity~e.8 :value 108~e.5 :ARG2-of (a4 / add-02 :ARG1 (p3 / percentage-entity~e.8 :value 35~e.7))) :op2 (p4 / percentage-entity~e.8 :value 108~e.5 :ARG2-of (s / subtract-01 :ARG1 p3))))) :op2 (a3 / activate-01~e.1 :ARG0~e.10 (p5 / protein :name (n3 / name :op1 "IL-6"~e.11,13)) :ARG1 p :ARG1-of (e3 / equal-01 :ARG2 (v2 / value-interval :op1 (p6 / percentage-entity~e.18 :value 31~e.15 :ARG2-of (a5 / add-02 :ARG1 (p7 / percentage-entity~e.18 :value 15~e.17))) :op2 (p8 / percentage-entity~e.18,27 :ARG2-of (s2 / subtract-01 :ARG1 p7))))) :op3 (a6 / activate-01~e.1 :ARG0~e.21 (p9 / protein :name (n4 / name :op1 "EGF"~e.22)) :ARG1 p :ARG1-of (e4 / equal-01 :ARG2 (v / value-interval :op1 (p10 / percentage-entity~e.27 :value 85~e.24 :ARG2-of (a7 / add-02 :ARG1 (p11 / percentage-entity~e.27 :value 40~e.26))) :op2 (p12 / percentage-entity~e.27 :value 85~e.24 :ARG2-of (s3 / subtract-01 :ARG1 p11)))))) # ::id pmid_1627_1139.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAT3 activation by OSM was 97 ± 31 % and by IL @-@ 6 was 63 ± 27 % . # ::alignments 0-1.1.2.1.1 1-1.1 1-1.2 2-1.1.1.r 3-1.1.1.1.1 5-1.1.3.1.1.1 5-1.1.3.1.2.1 7-1.1.3.1.1.2.1.1 8-1.1.3.1.1 8-1.1.3.1.1.2.1 8-1.1.3.1.2 9-1 10-1.2.1.r 11-1.2.1.1.1 13-1.2.1.1.1 15-1.2.3.1.1.1 15-1.2.3.1.2.1 17-1.2.3.1.1.2.1.1 18-1.2.3.1.1 18-1.2.3.1.1.2.1 18-1.2.3.1.2 (a / and~e.9 :op1 (a2 / activate-01~e.1 :ARG0~e.2 (p / protein :name (n / name :op1 "OSM"~e.3)) :ARG1 (p2 / protein :name (n2 / name :op1 "STAT3"~e.0)) :ARG1-of (e / equal-01 :ARG2 (v / value-interval :op1 (p3 / percentage-entity~e.8 :value 97~e.5 :ARG2-of (a3 / add-02 :ARG1 (p4 / percentage-entity~e.8 :value 31~e.7))) :op2 (p5 / percentage-entity~e.8 :value 97~e.5 :ARG2-of (s / subtract-01 :ARG1 p4))))) :op2 (a4 / activate-01~e.1 :ARG0~e.10 (p6 / protein :name (n3 / name :op1 "IL-6"~e.11,13)) :ARG1 p2 :ARG1-of (e2 / equal-01 :ARG2 (v2 / value-interval :op1 (p7 / percentage-entity~e.18 :value 63~e.15 :ARG2-of (a5 / add-02 :ARG1 (p8 / percentage-entity~e.18 :value 27~e.17))) :op2 (p9 / percentage-entity~e.18 :value 63~e.15 :ARG2-of (s2 / subtract-01 :ARG1 p8)))))) # ::id pmid_1627_1139.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cytokine @-@ induced activation of ERK and STAT3 in paired cultures indicated highly consistent response patterns ( Fig . 4G and 4H , left side panels ) . # ::alignments 1-1.1.2.1 3-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1.1.1.1 7-1.1.1 8-1.1.1.2.1.1 9-1.1.3.r 10-1.1.3.1 11-1.1.3 12-1 13-1.2.2.1 14-1.2.2 15-1.2.1 16-1.2 18-1.3.1.1 18-1.3.1.2 21-1.3.1.1.1 23-1.3.1 25-1.3.1.2.1 28-1.3.1.3.1.1 29-1.3.1.3.1 30-1.3.1.3 (i / indicate-01~e.12 :ARG0 (a / activate-01~e.4 :ARG1~e.5 (a2 / and~e.7 :op1 (e / enzyme :name (n / name :op1 "ERK"~e.6)) :op2 (p / protein :name (n2 / name :op1 "STAT3"~e.8))) :ARG2-of (i2 / induce-01~e.3 :ARG0 (c3 / cytokine~e.1)) :location~e.9 (c / culture~e.11 :ARG1-of (p3 / pair-01~e.10))) :ARG1 (p4 / pattern-01~e.16 :ARG1 (r / respond-01~e.15) :ARG1-of (c2 / consistent-02~e.14 :ARG1-of (h / high-02~e.13))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.23 :op1 (f / figure~e.18 :mod "4G"~e.21) :op2 (f2 / figure~e.18 :mod "4H"~e.25) :location (p5 / panel~e.30 :location (s / side~e.29 :ARG1-of (l / left-20~e.28)))))) # ::id pmid_1627_1139.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Confirmed premalignant epithelial cells ( metaplasia , dysplasia and carcinoma ) exhibited two recurring aberrant phenotypes when compared with normal cells . # ::alignments 0-1.1.3 1-1.1.2 2-1.1.1 3-1.1 5-1.1.4.1.1 7-1.1.4.1.2 8-1.1.4.1 9-1.1.4.1.3 11-1 12-1.2.1 13-1.2.2 14-1.2.3 15-1.2 17-1.3 18-1.3.2.r 19-1.3.2.1 20-1.3.2 (e / exhibit-01~e.11 :ARG0 (c / cell~e.3 :mod (e2 / epithelium~e.2) :mod (p / premalignant~e.1) :ARG1-of (c2 / confirm-01~e.0) :ARG1-of (m2 / mean-01 :ARG2 (a / and~e.8 :op1 (m / metaplasia~e.5) :op2 (d / dysplasia~e.7) :op3 (c3 / carcinoma~e.9)))) :ARG1 (p2 / phenotype~e.15 :quant 2~e.12 :ARG0-of (r / recur-01~e.13) :mod (a2 / aberrant~e.14)) :condition (c4 / compare-01~e.17 :ARG1 c :ARG2~e.18 (c5 / cell~e.20 :ARG1-of (n / normal-02~e.19)))) # ::id pmid_1627_1139.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The first aberrancy was the elevated basal or cytokine @-@ stimulated level of phosphorylated ERK ( Fig . 4B and 4G , right panel ) and the second was the reactivation of LIFR function ( Fig . 4D and 4H , right panel ) . # ::alignments 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1 2-1.2 3-1.1.2.r 5-1.1.2.1.2 6-1.1.2.1.3 7-1.1.2 8-1.1.2.2.1.1 10-1.1.2.2.1 11-1.1.2.1 11-1.1.2.2 12-1.1.2.1.1.r 13-1.1.2.1.1.2 14-1.1.2.1.1.1.1 16-1.1.3.1.1 16-1.1.3.1.2 19-1.1.3.1.1.1 21-1.1.3.1 23-1.1.3.1.2.1 26-1.1.3.1.3.1 27-1.1.3.1.3 29-1.1.3.1 31-1.2.1 31-1.2.1.1 31-1.2.1.1.r 32-1.2.2.r 34-1.2.2 35-1.2.2.1.r 36-1.2.2.1.1.1.1 37-1.2.2.1 39-1.2.3.1.1 39-1.2.3.1.2 42-1.2.3.1.1.1 46-1.2.3.1.2.1 49-1.2.3.1.3 50-1.2.3.1.3 (a / and :op1 (a2 / aberrancy~e.2 :ord (o / ordinal-entity~e.1 :value~e.1 1~e.1) :domain~e.3 (o2 / or~e.7 :op1 (l / level~e.11 :quant-of~e.12 (e / enzyme :name (n / name :op1 "ERK"~e.14) :ARG3-of (p / phosphorylate-01~e.13)) :ARG1-of (e2 / elevate-01~e.5) :mod (b / basal~e.6)) :op2 (l2 / level~e.11 :ARG1-of (s / stimulate-01~e.10 :ARG0 (c / cytokine~e.8)) :quant-of e :ARG1-of e2)) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.21,29 :op1 (f / figure~e.16 :mod "4B"~e.19) :op2 (f2 / figure~e.16 :mod "4G"~e.23) :location (p3 / panel~e.27 :ARG1-of (r / right-04~e.26))))) :op2 (a4 / aberrancy~e.2 :ord (o3 / ordinal-entity~e.31 :value~e.31 2~e.31) :domain~e.32 (r2 / reactivate-01~e.34 :ARG1~e.35 (f3 / function-01~e.37 :ARG0 (p4 / protein :name (n3 / name :op1 "LIFR"~e.36)))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f4 / figure~e.39 :mod "4D"~e.42) :op2 (f5 / figure~e.39 :mod "4H"~e.46) :location p3~e.49,50)))) # ::id pmid_1627_1139.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the 23 preneoplastic cell cultures , the basal level of phosphorylated ERK was increased to 22 ± 27 % of the OSM value ( p = 0.07 ) . # ::alignments 2-1.3.1 3-1.3.3 4-1.3.2 5-1.3 8-1.1.1 9-1.1 10-1.1.2.r 11-1.1.2.2 12-1.1.2.1.1 14-1 15-1.2.r 16-1.2.1.1.1 16-1.2.2.1.1 18-1.2.1.1.2.1.1 19-1.2.1.1 19-1.2.1.1.2.1 19-1.2.2.1 20-1.2.1 22-1.2.1.2.1.1.1 23-1.2 23-1.2.1.2 25-1.4 27-1.4.1 (i / increase-01~e.14 :ARG1 (l / level~e.9 :mod (b / basal~e.8) :quant-of~e.10 (e / enzyme :name (n / name :op1 "ERK"~e.12) :ARG3-of (p / phosphorylate-01~e.11))) :ARG4~e.15 (v2 / value-interval~e.23 :op1 (p2 / product-of~e.20 :op1 (p3 / percentage-entity~e.19 :value 22~e.16 :ARG2-of (a / add-02 :ARG1 (p4 / percentage-entity~e.19 :value 27~e.18))) :op2 (v / value~e.23 :quant-of (p5 / protein :name (n2 / name :op1 "OSM"~e.22)))) :op2 (p8 / product-of :op1 (p9 / percentage-entity~e.19 :value 22~e.16 :ARG2-of (s / subtract-01 :ARG1 p4)) :op2 v)) :location (c / culture-01~e.5 :quant 23~e.2 :ARG1 (c2 / cell~e.4) :mod (p7 / preneoplastic~e.3)) :ARG1-of (s2 / statistical-test-91~e.25 :ARG2 0.07~e.27)) # ::id pmid_1627_1139.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Based on two @-@ sample Kolmogorov @-@ Smirnov test , two cases that were cultured from metaplastic foci were above the 95 % confidence interval . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1.1 4-1.3.1.1 4-1.3.1.1.2 4-1.3.1.1.2.r 5-1.3.1.2.1.1 7-1.3.1.2.1.1 8-1.3.1 10-1.2.1 11-1.2 13-1.2.r 14-1.2.2 15-1.2.2.1.r 16-1.2.2.1.1 17-1.2.2.1 18-1.2.r 19-1 21-1.1.1 22-1.1 23-1.1.2.1 24-1.1.2 (a / above~e.19 :op1 (p / percentage-entity~e.22 :value 95~e.21 :quant-of (i / interval~e.24 :mod (c / confidence~e.23))) :domain~e.13,18 (c2 / case-04~e.11 :quant 2~e.10 :ARG1-of (c3 / culture-01~e.14 :source~e.15 (f / focus~e.17 :mod (m / metaplastic~e.16)))) :ARG1-of (b / base-02~e.0 :ARG2~e.1 (t / test~e.8 :mod (t2 / thing~e.4 :quant 2~e.2 :ARG1-of~e.4 (s / sample-01~e.4)) :mod (t3 / thing :name (n / name :op1 "Kolmogorov-Smirnov"~e.5,7))))) # ::id pmid_1627_1139.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Preneoplastic cells showed also an overall trend of increased ERK signaling when treated with OSM ( 133 ± 66 % ; p = 0.17 ) or IL @-@ 6 ( 53 ± 38 % ; p = 0.01 ) but not with EGF ( 85 ± 67 % ; p = 0.46 ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.4 5-1.3 6-1.2 7-1.2.1.r 8-1.2.1.1 8-1.2.1.2 8-1.2.1.3.1 9-1.2.1.1.1.1.1.1 10-1.2.1.1.1 12-1.2.1.1.3 12-1.2.1.2.3 12-1.2.1.3.1.3 13-1.2.1.1.3.2.r 14-1.2.1.1.3.2.1.1 16-1.2.1.1.2.1.1 16-1.2.1.1.2.2.1 18-1.2.1.1.2.1.2.1.1 19-1.2.1.1.2.1 19-1.2.1.1.2.1.2.1 19-1.2.1.1.2.2 21-1.2.1.1.4 23-1.2.1.1.4.1 25-1.2.1 26-1.2.1.2.3.2.1.1 28-1.2.1.2.3.2.1.1 30-1.2.1.2.2.1.1 30-1.2.1.2.2.2.1 32-1.2.1.2.2.1.2.1.1 33-1.2.1.2.2.1 33-1.2.1.2.2.1.2.1 33-1.2.1.2.2.2 35-1.2.1.2.4 37-1.2.1.2.4.1 39-1.2.1.3 41-1.2.1.3.1.3.2.r 42-1.2.1.3.1.3.2.1.1 44-1.2.1.3.1.2.1.1 44-1.2.1.3.1.2.2.1 46-1.2.1.3.1.2.1.2.1.1 47-1.2.1.3.1.2.1 47-1.2.1.3.1.2.1.2.1 47-1.2.1.3.1.2.2 49-1.2.1.3.1.4 51-1.2.1.3.1.4.1 (s / show-01~e.2 :ARG0 (c / cell~e.1 :mod (p / preneoplastic~e.0)) :ARG1 (t / trend-01~e.6 :ARG1~e.7 (o4 / or~e.25 :op1 (i / increase-01~e.8 :ARG1 (s2 / signal-07~e.10 :ARG0 (e / enzyme :name (n5 / name :op1 "ERK"~e.9))) :ARG2 (v3 / value-interval :op1 (p3 / percentage-entity~e.19 :value 133~e.16 :ARG2-of (a2 / add-02 :ARG1 (p4 / percentage-entity~e.19 :value 66~e.18))) :op2 (p5 / percentage-entity~e.19 :value 133~e.16 :ARG2-of (s3 / subtract-01 :ARG1 p4))) :condition (t2 / treat-04~e.12 :ARG1 c :ARG2~e.13 (p2 / protein :name (n2 / name :op1 "OSM"~e.14))) :ARG1-of (s6 / statistical-test-91~e.21 :ARG2 0.17~e.23)) :op2 (i2 / increase-01~e.8 :ARG1 s2 :ARG2 (v / value-interval :op1 (p6 / percentage-entity~e.33 :value 53~e.30 :ARG2-of (a / add-02 :ARG1 (p7 / percentage-entity~e.33 :value 38~e.32))) :op2 (p8 / percentage-entity~e.33 :value 53~e.30 :ARG2-of (s4 / subtract-01 :ARG1 p7))) :condition (t3 / treat-04~e.12 :ARG1 c :ARG2 (p9 / protein :name (n3 / name :op1 "IL-6"~e.26,28))) :ARG1-of (s7 / statistical-test-91~e.35 :ARG2 0.01~e.37)) :ARG1-of (c2 / contrast-01~e.39 :ARG2 (i3 / increase-01~e.8 :ARG1 s2 :ARG2 (v2 / value-interval :op1 (p13 / percentage-entity~e.47 :value 85~e.44 :ARG2-of (a3 / add-02 :ARG1 (p14 / percentage-entity~e.47 :value 67~e.46))) :op2 (p15 / percentage-entity~e.47 :value 85~e.44 :ARG2-of (s5 / subtract-01 :ARG1 p14))) :condition (t4 / treat-04~e.12 :ARG1 c :ARG2~e.41 (p12 / protein :name (n4 / name :op1 "EGF"~e.42) :ARG1-of (e4 / equal-01))) :ARG1-of (s8 / statistical-test-91~e.49 :ARG2 0.46~e.51))))) :mod (o / overall~e.5) :mod (a4 / also~e.3)) # ::id pmid_1627_1139.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The ERK signaling by IL @-@ 6 and EGF included several cases that lie outside of the 95 % confidence interval . # ::alignments 1-1.2.2.1.1 2-1.2 3-1.2.1.r 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1 9-1 10-1.1.1 11-1.1 13-1.1.2 14-1.1.2.1 15-1.1.2.1.1.r 17-1.1.2.1.1.1 18-1.1.2.1.1 19-1.1.2.1.1.2.1 20-1.1.2.1.1.2 (i / include-01~e.9 :ARG1 (c / case-04~e.11 :quant (s2 / several~e.10) :ARG1-of (l / lie-07~e.13 :ARG2 (o / outside~e.14 :op1~e.15 (p3 / percentage-entity~e.18 :value 95~e.17 :quant-of (i2 / interval~e.20 :mod (c2 / confidence~e.19)))))) :ARG2 (s / signal-07~e.2 :ARG0~e.3 (a / and~e.7 :op1 (p / protein :name (n / name :op1 "IL-6"~e.4,6)) :op2 (p2 / protein :name (n2 / name :op1 "EGF"~e.8))) :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"~e.1)))) # ::id pmid_1627_1139.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For the IL @-@ 6 response , 3 @/@ 23 cases were above and 5 @/@ 23 cases below the 95 % confidence interval , and for EGF response , 4 @/@ 23 cases were above and 3 @/@ 23 cases below . # ::alignments 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1 7-1.1.3.1 9-1.1.3.2.1.1 10-1.1.3 10-1.1.3.2.1 12-1.1.2 13-1 14-1.2.3.1 16-1.2.3.2 17-1.1.3.2.1 17-1.2.3 18-1.2.2 20-1.3.2 21-1.3.2 22-1.3.2 23-1.3.2 25-1 27-1.3.1.1.1 28-1.2 28-1.3 28-1.4 30-1.3.3.1 32-1.3.3.2 33-1.1.3.2.1 33-1.3.3 35-1.1.2 37-1.1.3.1 39-1.1.3.2.1.1 40-1.1.3.2.1 41-1.2.2 (a / and~e.13,25 :op1 (r / respond-01~e.5 :ARG0 (p / protein :name (n / name :op1 "IL-6"~e.2,4)) :ARG2 (a2 / above~e.12,35 :op1 (p2 / percentage-entity :value 95 :quant-of (i / interval :mod (c / confidence)))) :location (c2 / case-04~e.10 :quant 3~e.7,37 :ARG1-of (i2 / include-91 :ARG2 (c3 / case-04~e.10,17,33,40 :quant 23~e.9,39)))) :op2 (r2 / respond-01~e.28 :ARG0 p :ARG2 (b / below~e.18,41 :op1 p2) :location (c4 / case-04~e.17 :quant 5~e.14 :ARG1-of i2~e.16)) :op3 (r3 / respond-01~e.28 :ARG0 (p3 / protein :name (n2 / name :op1 "EGF"~e.27)) :ARG2 a2~e.20,21,22,23 :location (c5 / case-04~e.33 :quant 4~e.30 :ARG1-of i2~e.32)) :op4 (r4 / respond-01~e.28 :ARG0 p3 :ARG2 b :location c2)) # ::id pmid_1627_1139.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok STAT3 phosphorylation by OSM and IL @-@ 6 , and STAT1 phosphorylation by OSM , IL @-@ 6 and IFNγ did not show significant differences among the cases tested ( Fig . 4C @–@ F ) , in contrast to ERK phosphorylation . # ::alignments 0-1.2.1.1.1.1 1-1.2.1 3-1.2.1.2.1.1.1 5-1.2.1.2.2.1.1 7-1.2.1.2.2.1.1 9-1.2 9-1.2.1.2 10-1.2.2.1.1.1 11-1.2.1 11-1.2.2 13-1.2.1.2.1.1.1 15-1.2.1.2.2.1.1 17-1.2.1.2.2.1.1 18-1.2 19-1.2.2.2.3.1.1 21-1.1 21-1.1.r 22-1 23-1.3.1 24-1.3 27-1.4 28-1.4.1 30-1.4.2.1.1 30-1.4.2.1.2 30-1.4.2.1.3 30-1.4.2.1.4 33-1.4.2.1.1.1 39-1.2.r 40-1.2.3 41-1.2.3.1.r 42-1.2.3.1.1.1.1 43-1.2.3.1 (s / show-01~e.22 :polarity~e.21 -~e.21 :ARG0~e.39 (a / and~e.9,18 :op1 (p / phosphorylate-01~e.1,11 :ARG1 (p2 / protein :name (n / name :op1 "STAT3"~e.0)) :ARG2 (a2 / and~e.9 :op1 (p3 / protein :name (n2 / name :op1 "OSM"~e.3,13)) :op3 (p4 / protein :name (n3 / name :op1 "IL-6"~e.5,7,15,17)))) :op2 (p5 / phosphorylate-01~e.11 :ARG1 (p6 / protein :name (n4 / name :op1 "STAT1"~e.10)) :ARG2 (a3 / and :op1 p3 :op2 p4 :op3 (p7 / protein :name (n5 / name :op1 "IFNγ"~e.19)))) :ARG1-of (c2 / contrast-01~e.40 :ARG2~e.41 (p8 / phosphorylate-01~e.43 :ARG1 (e / enzyme :name (n6 / name :op1 "ERK"~e.42))))) :ARG1 (d / differ-01~e.24 :ARG1-of (s2 / significant-02~e.23)) :location (c / case-04~e.27 :ARG1-of (t / test-01~e.28) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.30 :mod "4C"~e.33) :op2 (f2 / figure~e.30 :mod "4D") :op3 (f3 / figure~e.30 :mod "4E") :op4 (f4 / figure~e.30 :mod "4F"))))) # ::id pmid_1627_1139.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the abnormal epithelial cells with elevated basal ERK phosphorylation ( Fig . 4B ) , the two cell cultures from metaplastic foci in the airway were distinct because the basal ERK phosphorylation that was equivalent to the OSM @-@ treated control culture ( Fig . 5A ) . # ::alignments 0-1 2-1.2.2 2-1.2.2.1 2-1.2.2.1.r 3-1.2.1 4-1.2 6-1.2.3.1.2 7-1.2.3.1.3 8-1.2.3.1.1.1.1 9-1.2.3.1 11-1.2.4.1 14-1.2.4.1.1 19-1.1.1 20-1.1.2 21-1.1 22-1.1.3.r 23-1.1.3.1 24-1.1.3 25-1.1.4.r 27-1.1.4 29-1.1.5 30-1.1.5.1 32-1.2.3.1.3 33-1.2.3.1.1.1.1 34-1.1.5.1.1.1 34-1.2.3.1 37-1.1.5.1.1 38-1.1.5.1.1.2.r 40-1.1.5.1.1.2.2.1.1.1 42-1.1.5.1.1.2.2 43-1.1.5.1.1.2.1 44-1.1.5.1.1.2 46-1.1.6.1 49-1.1.6.1.1 (i / include-91~e.0 :ARG1 (c2 / culture-01~e.21 :quant 2~e.19 :ARG1 (c3 / cell~e.20) :source~e.22 (f2 / focus~e.24 :mod (m / metaplastic~e.23)) :location~e.25 (a / airway~e.27) :mod (d3 / distinct~e.29 :ARG0-of (c4 / cause-01~e.30 :ARG1 (e4 / equal-01~e.37 :ARG1 (p2 / phosphorylate-01~e.34 :ARG1 e2 :mod b) :ARG2~e.38 (c5 / culture~e.44 :mod (c6 / control~e.43) :ARG1-of (t / treat-04~e.42 :ARG2 (p3 / protein :name (n3 / name :op1 "OSM"~e.40))))))) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure~e.46 :mod "5A"~e.49))) :ARG2 (c / cell~e.4 :mod (e / epithelium~e.3) :ARG1-of (n / normal-02~e.2 :polarity~e.2 -~e.2) :ARG0-of (h / have-03 :ARG1 (p / phosphorylate-01~e.9,34 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.8,33)) :ARG1-of (e3 / elevate-01~e.6) :mod (b / basal~e.7,32))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "4B"~e.14)))) # ::id pmid_1627_1139.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The increased phosphorylation of ERK , but not of STATs in these metaplastic cells was similar to the regulatory phenotype of NCI H23 tumor cell line ( Fig . 1A ) . # ::alignments 1-1.1.2 2-1.1 2-1.1.4.1 3-1.1.1.r 4-1.1.1.1.1 6-1.1.4 10-1.1.3.r 11-1.1.3.2 12-1.1.3.1 13-1.1.3 15-1 16-1.2.r 18-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1.1.1 22-1.2.1.1.2 23-1.2.1.2 24-1.2.1 25-1.2.1 27-1.3.1 30-1.3.1.1 (r / resemble-01~e.15 :ARG1 (p / phosphorylate-01~e.2 :ARG1~e.3 (e / enzyme :name (n / name :op1 "ERK"~e.4)) :ARG1-of (i / increase-01~e.1) :location~e.10 (c / cell~e.13 :mod (m / metaplastic~e.12) :mod (t2 / this~e.11)) :ARG1-of (c3 / contrast-01~e.6 :ARG2 (p3 / phosphorylate-01~e.2 :ARG1 (p4 / protein :name (n3 / name :op1 "STAT"))))) :ARG2~e.16 (p2 / phenotype~e.19 :poss~e.20 (c2 / cell-line~e.24,25 :name (n2 / name :op1 "NCI"~e.21 :op2 "H23"~e.22) :mod (t / tumor~e.23)) :ARG0-of (r2 / regulate-01~e.18)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "1A"~e.30))) # ::id pmid_1627_1139.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Due to the elevated ERK phosphorylation , the response to EGF was obscured , even though a normal or even enhanced level of EGFR could be demonstrated ( Fig . 5B ) . # ::alignments 0-1.2 1-1.2 3-1.2.1 4-1.2.1.1.1.1.1 5-1.2.1.1 8-1.1 9-1.1.1.r 10-1.1.1.1.1 12-1 14-1.3.r 15-1.3.r 17-1.3.1.1.1.2 18-1.3.1.1 19-1.3.1.1.2.2.1 20-1.3.1.1.2.2 21-1.3.1.1.1 21-1.3.1.1.2 22-1.3.1.1.1.1.r 23-1.3.1.1.1.1.1.1 24-1.3 26-1.3.1 28-1.4.1 31-1.4.1.1 (o / obscure-02~e.12 :ARG1 (r / respond-01~e.8 :ARG1~e.9 (p / protein :name (n / name :op1 "EGF"~e.10))) :ARG1-of (c / cause-01~e.0,1 :ARG0 (e / elevate-01~e.3 :ARG1 (p2 / phosphorylate-01~e.5 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.4))))) :concession~e.14,15 (p3 / possible-01~e.24 :ARG1 (d / demonstrate-01~e.26 :ARG1 (o2 / or~e.18 :op1 (l / level~e.21 :quant-of~e.22 (e3 / enzyme :name (n3 / name :op1 "EGFR"~e.23)) :ARG1-of (n4 / normal-02~e.17)) :op2 (l2 / level~e.21 :quant-of e3 :ARG1-of (e4 / enhance-01~e.20 :mod (e5 / even~e.19)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.28 :mod "5B"~e.31))) # ::id pmid_1627_1139.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The high basal level phosphorylation of ERK was abrogated by treatment with U0126 , an inhibitor for MEK1 ( Fig . 5C ) , suggesting a constitutive activation of the MAPK pathway upstream of ERK in these metaplastic cells . # ::alignments 1-1.1.3 2-1.1.2 3-1.1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1 9-1.2.r 10-1.2 11-1.2.2.r 12-1.2.2.1.1 15-1.2.2.2.1 15-1.2.2.2.1.1 15-1.2.2.2.1.1.r 16-1.2.2.2.1.1.1.r 17-1.2.2.2.1.1.1.1.1 19-1.3.1 22-1.3.1.1 26-1.4 28-1.4.1.2 29-1.4.1 30-1.4.1.1.r 32-1.4.1.1.1.1 33-1.4.1.1 34-1.4.1.3 35-1.4.1.3.1.r 36-1.4.1.3.1 39-1.4.1.4.1 40-1.4.1.4 (a / abrogate-01~e.8 :ARG1 (l / level~e.3 :degree-of (p / phosphorylate-01~e.4 :ARG1~e.5 (e / enzyme :name (n / name :op1 "ERK"~e.6))) :mod (b / basal~e.2) :ARG1-of (h / high-02~e.1)) :ARG2~e.9 (t / treat-04~e.10 :ARG1 l :ARG2~e.11 (s / small-molecule :name (n2 / name :op1 "U0126"~e.12) :ARG1-of (m / mean-01 :ARG2 (s2 / small-molecule~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1~e.16 (e2 / enzyme :name (n3 / name :op1 "MEK1"~e.17))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "5C"~e.22)) :ARG0-of (s3 / suggest-01~e.26 :ARG1 (a2 / activate-01~e.29 :ARG1~e.30 (p2 / pathway~e.33 :name (n4 / name :op1 "MAPK"~e.32)) :mod (c / constitutive~e.28) :location (u / upstream~e.34 :op1~e.35 e~e.36) :location (c2 / cell~e.40 :mod (m2 / metaplastic~e.39))))) # ::id pmid_1627_1139.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The pair @-@ wise comparison also revealed that 5 @/@ 23 of the abnormal cases ( 4 metaplasia and 1 carcinoma ) had a LIF response detectable by the activation of ERK and STAT3 ( Fig . 3 , Fig. 4B , D,G and 4H ) . # ::alignments 4-1.1 5-1.3 6-1 7-1.2.r 8-1.2.1.1 10-1.2.1.2.1.1 13-1.2.1.2.1.2 13-1.2.1.2.1.2.1 13-1.2.1.2.1.2.1.r 14-1.2.1 14-1.2.1.2.1 16-1.2.1.3.1.1.1 17-1.2.1.3.1.1 18-1.2.1.3.1 19-1.2.1.3.1.2.1 20-1.2.1.3.1.2 22-1.2 24-1.2.2.1.1.1 25-1.2.2 26-1.4 27-1.4.1.r 29-1.4.1 30-1.4.1.1.r 31-1.4.1.1.1.1.1 32-1.4.1.1 33-1.4.1.1.2.1.1 35-1.5.1.1 35-1.5.1.3 35-1.5.1.4 35-1.5.1.5 38-1.5.1.1.1 41-1.5.1.2 43-1.5.1.2.1 47-1.5.1 49-1.5.1.5.1 (r / reveal-01~e.6 :ARG0 (c / compare-01~e.4 :mod (p / pairwise)) :ARG1~e.7 (h / have-03~e.22 :ARG0 (c2 / case-04~e.14 :quant 5~e.8 :ARG1-of (i / include-91 :ARG2 (c3 / case-04~e.14 :quant 23~e.10 :ARG1-of (n4 / normal-02~e.13 :polarity~e.13 -~e.13))) :ARG1-of (m / mean-01 :ARG2 (a4 / and~e.18 :op1 (m2 / metaplasia~e.17 :quant 4~e.16) :op2 (c4 / carcinoma~e.20 :quant 1~e.19)))) :ARG1 (r2 / respond-01~e.25 :ARG0 (p2 / protein :name (n / name :op1 "LIF"~e.24)))) :mod (a / also~e.5) :ARG1-of (d / detect-01~e.26 :ARG2~e.27 (a2 / activate-01~e.29 :ARG1~e.30 (a3 / and~e.32 :op1 (e / enzyme :name (n2 / name :op1 "ERK"~e.31)) :op2 (p4 / protein :name (n3 / name :op1 "STAT3"~e.33)))) :ARG1-of (p3 / possible-01)) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.47 :op1 (f / figure~e.35 :mod 3~e.38) :op2 (f2 / figure~e.41 :mod "4B"~e.43) :op3 (f3 / figure~e.35 :mod "4D") :op4 (f4 / figure~e.35 :mod "4G") :op5 (f5 / figure~e.35 :mod "4H"~e.49)))) # ::id pmid_1627_1139.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Three cases ( 2 metaplasia and 1 carcinoma ) produced a signaling that lied outside of the 95 % confidence interval . # ::alignments 0-1.1.1 1-1.1 3-1.1.2.1.1.1 4-1.1.2.1.1 5-1.1.2.1 7-1.1.2.1.2.1.1 9-1 11-1.2 14-1.2.1.1 15-1.2.1.1.1.r 17-1.2.1.1.1.2.1 18-1.2.1.1.1.2 19-1.2.1.1.1.1 20-1.2.1.1.1 (p / produce-01~e.9 :ARG0 (c / case-04~e.1 :quant 3~e.0 :ARG1-of (m / mean-01 :ARG2 (a / and~e.5 :op1 (m2 / metaplasia~e.4 :quant 2~e.3) :op2 (m3 / medical-condition :name (n / name :op1 "carcinoma"~e.7))))) :ARG1 (s / signal-07~e.11 :ARG1-of (l / lay-01 :ARG2 (o / outside~e.14 :op1~e.15 (i / interval~e.20 :mod (c2 / confidence~e.19) :mod (p2 / percentage-entity~e.18 :value 95~e.17)))))) # ::id pmid_1627_1139.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The carcinoma case also included a prominent reduction of IL @-@ 6 receptor function ( Fig . 6 ) , which resulted in an overall cytokine response pattern comparable to that of the NCI H125 tumor cell line ( Fig . 1A ) . # ::alignments 1-1.2.1.1.1 2-1.2 3-1.4 4-1 6-1.1.2 7-1.1 8-1.1.1.r 9-1.1.1.1.1.1 11-1.1.1.1.1.1 12-1.1.1.1 13-1.1.1 15-1.3.1 18-1.3.1.1 23-1.1.3 24-1.1.3.1.r 26-1.1.3.1.1.2 27-1.1.3.1.1.1 28-1.1.3.1.1 28-1.1.3.1.2.1.1 29-1.1.3.1 29-1.1.3.1.2.1 30-1.1.3.1.2 33-1.1.3.1.2.1.1.1.r 35-1.1.3.1.2.1.1.1.1.1 36-1.1.3.1.2.1.1.1.1.2 37-1.1.3.1.2.1.1.1.2 38-1.1.3.1.2.1.1.1 39-1.1.3.1.2.1.1.1 41-1.1.3.2.1 44-1.1.3.2.1.1 (i / include-01~e.4 :ARG1 (r / reduce-01~e.7 :ARG1~e.8 (f / function-01~e.13 :ARG0 (r2 / receptor~e.12 :name (n2 / name :op1 "IL-6"~e.9,11))) :mod (p / prominent~e.6) :ARG1-of (r3 / result-01~e.23 :ARG2~e.24 (p2 / pattern~e.29 :ARG1-of (r4 / respond-01~e.28 :ARG0 (c2 / cytokine~e.27) :mod (o / overall~e.26)) :ARG1-of (c3 / comparable-03~e.30 :ARG2 (p3 / pattern~e.29 :ARG1-of (r5 / respond-01~e.28 :ARG0~e.33 (c4 / cell-line~e.38,39 :name (n3 / name :op1 "NCI"~e.35 :op2 "H125"~e.36) :mod (t / tumor~e.37)))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.41 :mod "1A"~e.44)))) :ARG2 (c / case-04~e.2 :ARG1 (m / medical-condition :name (n / name :op1 "carcinoma"~e.1))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.15 :mod 6~e.18)) :mod (a / also~e.3)) # ::id pmid_1627_1139.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The changes in signaling reactions correlated with receptor expression . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1 6-1.2.r 7-1.2.1 8-1.2 (c / correlate-01~e.5 :ARG1 (c2 / change-01~e.1 :ARG1~e.2 (r / react-01~e.4 :ARG1 (s / signal-07~e.3))) :ARG2~e.6 (e / express-03~e.8 :ARG2 (r2 / receptor~e.7))) # ::id pmid_1627_1139.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression of LIFRα in normal cells was undetectable by immunoblotting whereas expression was observed in the 5 cultures of abnormal cells with LIF response . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1.1.2.r 5-1.1.1.2.1 6-1.1.1.2 8-1.1 8-1.1.3.1 9-1.1.2.r 10-1.1.2 11-1 12-1.2.1 14-1.2 15-1.2.1.2.r 17-1.2.1.2.1 18-1.2.1.2 19-1.2.1.2.2.r 20-1.2.1.2.2.1 20-1.2.1.2.2.1.1 20-1.2.1.2.2.1.1.r 21-1.2.1.2.2 22-1.2.1.2.2.2.r 23-1.2.1.2.2.2.1.1.1 24-1.2.1.2.2.2 (c / contrast-01~e.11 :ARG1 (d / detect-01~e.8 :ARG1 (e / express-03~e.1 :ARG2~e.2 (p2 / protein :name (n / name :op1 "LIFRα"~e.3)) :ARG3~e.4 (c2 / cell~e.6 :ARG1-of (n3 / normal-02~e.5))) :ARG2~e.9 (i / immunoblot-01~e.10) :ARG1-of (p / possible-01 :polarity -~e.8)) :ARG2 (o / observe-01~e.14 :ARG1 (e2 / express-03~e.12 :ARG2 p2 :ARG3~e.15 (c3 / culture-01~e.18 :quant 5~e.17 :ARG1~e.19 (c4 / cell~e.21 :ARG1-of (n2 / normal-02~e.20 :polarity~e.20 -~e.20) :ARG0-of~e.22 (r / respond-01~e.24 :ARG1 (p3 / protein :name (n4 / name :op1 "LIF"~e.23)))))))) # ::id pmid_1627_1139.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The re @-@ expression of LIFR in various cell types is controlled by an epigenetic process that depends on histone acetylation within CpG islands of the LIFR promoter region [ @ 22 @ ] . # ::alignments 3-1.1 4-1.1.1.r 5-1.1.1.1.1 6-1.1.2.r 7-1.1.2.1.1 8-1.1.2.1 9-1.1.2 11-1 12-1.2.r 14-1.2.1 15-1.2 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1.1.1.1 20-1.2.2.1 22-1.2.2.1.2.1.1.1 23-1.2.2.1.2 24-1.2.2.1.2.2.r 26-1.2.2.1.2.2.1.1 27-1.2.2.1.2.2.1 28-1.2.2.1.2.2 31-1.3.1.1.1 (c / control-01~e.11 :ARG1 (e / express-03~e.3 :ARG2~e.4 (p / protein :name (n / name :op1 "LIFR"~e.5)) :ARG3~e.6 (t / type~e.9 :mod (c2 / cell~e.8 :mod (v / various~e.7))) :mod (a / again)) :ARG2~e.12 (p2 / process~e.15 :mod (e2 / epigenetic~e.14) :ARG0-of (d / depend-01~e.17 :ARG1~e.18 (a2 / acetylate-01~e.20 :ARG1 (p3 / protein :name (n2 / name :op1 "histone"~e.19)) :location (i / island~e.23 :mod (d2 / dna-sequence :name (n3 / name :op1 "CpG"~e.22)) :location~e.24 (r / region~e.28 :ARG1-of (p4 / promote-01~e.27 :ARG0 p~e.26)))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 22~e.31)))) # ::id pmid_1627_1139.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether altered protein acetylation could account for the switch in LIF responsiveness from normal to carcinoma cells , the normal epithelial cells were treated for 6 h with the histone deacetylase inhibitor FR901228 . # ::alignments 1-1.4 2-1.4.1.1 2-1.4.1.1.r 3-1.4.1.2.1.1.1 4-1.4.1.2.1.1 5-1.4.1.2.1 6-1.4.1 7-1.4.1.2 8-1.4.1.2.2.r 10-1.4.1.2.2 12-1.4.1.2.2.1.1.1.1 14-1.1.1.r 15-1.1.2 17-1.4.1.2.2.2.1.1.1 18-1.1 18-1.4.1.2.2.2 21-1.1.2 22-1.1.1 23-1.1 23-1.4.1.2.2.3 25-1 26-1.3.r 27-1.3.1 28-1.3.2 29-1.2.r 31-1.2.2.1.1.1 33-1.2 33-1.2.2 33-1.2.2.r 34-1.2.1.1 (t / treat-04~e.25 :ARG1 (c / cell~e.18,23 :source~e.14 (e / epithelium~e.22) :ARG1-of (n / normal-02~e.15,21)) :ARG2~e.29 (s2 / small-molecule~e.33 :name (n2 / name :op1 "FR901228"~e.34) :ARG0-of~e.33 (i / inhibit-01~e.33 :ARG1 (p4 / protein :name (n4 / name :op1 "histone"~e.31) :ARG1-of (d3 / deacetylate-01)))) :duration~e.26 (t2 / temporal-quantity :quant 6~e.27 :unit (h / hour~e.28)) :purpose (d / determine-01~e.1 :ARG1 (p2 / possible-01~e.6 :mode~e.2 interrogative~e.2 :ARG1 (a4 / account-01~e.7 :ARG0 (a2 / acetylate-01~e.5 :ARG1 (p / protein~e.4 :ARG1-of (a3 / alter-01~e.3))) :ARG1~e.8 (s / switch-01~e.10 :ARG1 (r / responsive-02 :ARG1 (p3 / protein :name (n3 / name :op1 "LIF"~e.12))) :ARG2 (c3 / cell~e.18 :mod (m / medical-condition :name (n5 / name :op1 "carcinoma"~e.17))) :ARG3 (c2 / cell~e.23 :ARG1-of n)))))) # ::id pmid_1627_1139.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The treatment induced the expression of LIFRα and established a LIF @-@ dependent STAT3 and ERK signaling that was comparable to the level observed in the carcinoma cells ( Fig . 6 ) . # ::alignments 1-1.1.1 2-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 7-1 8-1.2 10-1.2.2.1.2.1.1.1 12-1.2.2.1.2 13-1.2.2.1.1.1.1 14-1.2.2 15-1.2.2.2.1.1.1 16-1.2.2.1 16-1.2.2.2 19-1.2.2.3 20-1.2.2.3.1.r 22-1.2.2.3.1 23-1.2.2.3.1.1 24-1.2.2.3.1.1.1.r 26-1.2.2.3.1.1.1.1.1.1 27-1.2.2.3.1.1.1 29-1.3.1 32-1.3.1.1 (a / and~e.7 :op1 (i / induce-01~e.2 :ARG0 (t / treat-04~e.1) :ARG2 (e / express-03~e.4 :ARG2~e.5 (p / protein :name (n / name :op1 "LIFRα"~e.6)))) :op2 (e2 / establish-01~e.8 :ARG0 t :ARG1 (a2 / and~e.14 :op1 (s / signal-07~e.16 :ARG0 (p2 / protein :name (n3 / name :op1 "STAT3"~e.13)) :ARG0-of (d / depend-01~e.12 :ARG1 (p3 / protein :name (n4 / name :op1 "LIF"~e.10)))) :op2 (s2 / signal-07~e.16 :ARG0 (e3 / enzyme :name (n2 / name :op1 "ERK"~e.15)) :ARG0-of d) :ARG1-of (c2 / comparable-03~e.19 :ARG2~e.20 (l / level~e.22 :ARG1-of (o / observe-01~e.23 :location~e.24 (c / cell~e.27 :mod (m / medical-condition :name (n5 / name :op1 "carcinoma"~e.26)))))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.29 :mod 6~e.32))) # ::id pmid_1627_1139.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A similar FR901228 treatment of the carcinoma cells further enhanced LIFR expression and LIF @-@ dependent signaling ( Fig . 6 ) . # ::alignments 1-1.2.3 2-1.2.2.1.1 3-1.2 4-1.2.1.r 6-1.2.1.1.1.1 7-1.2.1 8-1.3 9-1 10-1.1.1.1.1.1 11-1.1.1 12-1.1 13-1.1.2.1.1.1.1 15-1.1.2.1 16-1.1.2 18-1.4.1 21-1.4.1.1 (e / enhance-01~e.9 :ARG1 (a / and~e.12 :op1 (e2 / express-03~e.11 :ARG2 (p / protein :name (n3 / name :op1 "LIFR"~e.10))) :op2 (s2 / signal-07~e.16 :ARG0-of (d2 / depend-01~e.15 :ARG1 (p2 / protein :name (n4 / name :op1 "LIF"~e.13))))) :ARG2 (t / treat-04~e.3 :ARG1~e.4 (c / cell~e.7 :mod (m / medical-condition :name (n2 / name :op1 "carcinoma"~e.6))) :ARG2 (s / small-molecule :name (n / name :op1 "FR901228"~e.2)) :ARG1-of (r / resemble-01~e.1)) :mod (f / further~e.8) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.18 :mod 6~e.21))) # ::id pmid_1627_1139.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the same treatment reduced he expression of IL @-@ 6R in normal cells resulting in a response pattern as found in the corresponding carcinoma cells from the same patient ( Fig . 6 ) . # ::alignments 0-1.5 3-1.1.1 4-1.1 5-1 7-1.2 8-1.2.1.r 9-1.2.1.1.1 11-1.2.1.1.1 12-1.2.2.r 13-1.2.2.1 14-1.2.2 15-1.3 16-1.3.1.r 18-1.3.1.1 19-1.3.1 19-1.3.1.2.1 20-1.3.1.2.1.1.r 21-1.3.1.2.1.1 22-1.3.1.2.1.1.1.r 24-1.3.1.2.1.1.1.2 25-1.3.1.2.1.1.1.1.1.1 26-1.3.1.2.1.1.1 27-1.3.1.2.1.1.1.3.r 29-1.3.1.2.1.1.1.3.2 30-1.3.1.2.1.1.1.3.1.1 32-1.4.1 35-1.4.1.1 (r / reduce-01~e.5 :ARG0 (t / treat-04~e.4 :ARG1-of (s / same-01~e.3)) :ARG1 (e / express-03~e.7 :ARG2~e.8 (p / protein :name (n / name :op1 "IL-6R"~e.9,11)) :ARG3~e.12 (c / cell~e.14 :ARG1-of (n2 / normal-02~e.13))) :ARG1-of (r2 / result-01~e.15 :ARG2~e.16 (p2 / pattern~e.19 :ARG1-of (r3 / respond-01~e.18) :ARG1-of (r4 / resemble-01 :ARG2 (p3 / pattern~e.19 :ARG1-of~e.20 (f / find-01~e.21 :location~e.22 (c2 / cell~e.26 :mod (m / medical-condition :name (n3 / name :op1 "carcinoma"~e.25)) :ARG2-of (c3 / correspond-02~e.24 :ARG1 c) :source~e.27 (p4 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient~e.30)) :ARG1-of s~e.29))))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.32 :mod 6~e.35)) :ARG2-of (i2 / interest-01~e.0)) # ::id pmid_1627_1139.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok OSM and secreted macrophage factors attenuate proliferation of bronchial epithelial cells # ::alignments 1-1.1.1.1.1 2-1.1 3-1.1.2.2 4-1.1.2.1 5-1.1.2 6-1 7-1.2 8-1.2.1.r 9-1.2.1.2 10-1.2.1.1 11-1.2.1 (a / attenuate-01~e.6 :ARG0 (a2 / and~e.2 :op1 (p / protein :name (n / name :op1 "OSM"~e.1)) :op2 (f / factor~e.5 :mod (m / macrophage~e.4) :ARG1-of (s / secrete-01~e.3))) :ARG1 (p2 / proliferate-01~e.7 :ARG0~e.8 (c / cell~e.11 :source (e / epithelium~e.10) :mod (b / bronchus~e.9)))) # ::id pmid_1627_1139.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok DNA synthesis of the epithelial cells was inhibited by OSM and LPS conditioned medium from of activated macrophages in a dose @-@ dependent fashion ( Fig . 7 ) . # ::alignments 0-1.2.1.2.1 1-1.2 2-1.2.2.r 4-1.2.2.1 5-1.2.2 7-1 8-1.1.r 9-1.1.1.1.1.1.1 10-1.1.1.1 11-1.1.1.1.2.1.1 12-1.1.1 13-1.1 14-1.1.2.r 16-1.1.2.1 17-1.1.2 18-1.3.r 20-1.3.1 22-1.3 25-1.4.1 28-1.4.1.1 (i / inhibit-01~e.7 :ARG0~e.8 (m / medium~e.13 :ARG1-of (c2 / condition-01~e.12 :ARG2 (a / and~e.10 :op1 (p / protein :name (n / name :op1 "OSM"~e.9)) :op2 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS"~e.11)))) :source~e.14 (m3 / macrophage~e.17 :ARG1-of (a2 / activate-01~e.16))) :ARG1 (s / synthesize-01~e.1 :ARG0 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.0)) :ARG1~e.2 (c / cell~e.5 :source (e / epithelium~e.4))) :manner~e.18 (d2 / depend-01~e.22 :ARG1 (d3 / dose~e.20)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.25 :mod 7~e.28))) # ::id pmid_1627_1139.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The data for all cultures identified as normal cells ( Fig . 7A ) indicated that low concentrations of OSM (≤ 0.1 ng/ml ) or LPS conditioned macrophage medium (< 10 @^{-@ 3}@ dilution ) had no appreciable modulating effects . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1.1.1.2 6-1.1.1.2.1.r 7-1.1.1.2.1.1 8-1.1.1.2.1 10-1.1.1.2.2.1 13-1.1.1.2.2.1.1 16-1 17-1.2.r 18-1.2.2.2 19-1.2.2 19-1.2.2.1.2.1.1.2 20-1.2.2.1.r 21-1.2.2.1.2.1.1.1.1 23-1.2.2.1.2.1.1.2.1.1 23-1.2.2.1.2.1.1.2.1.2.1 26-1.2.2.1.2.1 26-1.2.2.1.2.1.1.2.1 27-1.2.2.1.2.1.2.1.1 28-1.2.2.1.2 29-1.2.2.1.1 30-1.2.2.1 37-1.2.2.3 39-1.2 40-1.2.1 40-1.2.1.r 41-1.2.3.2 41-1.2.3.2.1 41-1.2.3.2.1.r 42-1.2.3.1 43-1.2.3 (i / indicate-01~e.16 :ARG0 (d / data~e.1 :topic~e.2 (c / culture~e.4 :mod (a / all~e.3) :ARG1-of (i2 / identify-01~e.5 :ARG2~e.6 (c2 / cell~e.8 :ARG1-of (n / normal-02~e.7)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.10 :mod "7A"~e.13))))) :ARG1~e.17 (h / have-03~e.39 :polarity~e.40 -~e.40 :ARG0 (c3 / concentrate-02~e.19 :ARG1~e.20 (m / medium~e.30 :mod (m2 / macrophage~e.29) :ARG1-of (c4 / condition-01~e.28 :ARG2 (o / or~e.26 :op1 (p / protein :name (n2 / name :op1 "OSM"~e.21) :quant (c5 / concentration-quantity~e.19 :quant (o2 / or~e.26 :op1 0.1~e.23 :op2 (l2 / less-than :op1 0.1~e.23)) :unit (n4 / nanogram-per-milliliter))) :op2 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS"~e.27))))) :ARG1-of (l / low-04~e.18) :ARG1-of (d4 / dilute-01~e.37 :ARG2 (l4 / less-than :op1 0.001))) :ARG1 (a2 / affect-01~e.43 :ARG0-of (m4 / modulate-01~e.42) :ARG1-of (a3 / appreciate-02~e.41 :ARG1-of~e.41 (p2 / possible-01~e.41))))) # ::id pmid_1627_1139.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only at higher concentrations , suppression of DNA synthesis became evident ( p < 0.05 ) . # ::alignments 0-1.2.1.1.1 2-1.2.1 2-1.2.1.1 2-1.2.1.1.r 3-1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.2.1 8-1.1.1.1 10-1.1 12-1.1.2 13-1.1.2.1 14-1.1.2.1.1 (h / have-condition-91 :ARG1 (e / evidence-01~e.10 :ARG1 (s / suppress-01~e.5 :ARG1~e.6 (s2 / synthesize-01~e.8 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"~e.7)))) :ARG1-of (s3 / statistical-test-91~e.12 :ARG2 (l / less-than~e.13 :op1 0.05~e.14))) :ARG2 (c / concentrate-02~e.3 :ARG1-of (h2 / high-02~e.2 :degree~e.2 (m / more~e.2 :mod (o / only~e.0))))) # ::id pmid_1627_1139.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , several cultures of metaplastic and dysplastic cells exhibited the trend , in which the cells responded to low doses of OSM or conditioned medium from macrophages by a stimulation of DNA synthesis ( Fig . 7B ) . # ::alignments 1-1 3-1.1.1.2 4-1.1.1 7-1.1.1.1 8-1.1.1.1.2.1 9-1.1.1.1.1 9-1.1.1.1.2 10-1.1 12-1.1.2 17-1.1.2.1.2.1.1 18-1.1.2.1 20-1.1.2.1.2.1.3 21-1.1.2.1.2.1 22-1.1.2.1.2.1.2.r 23-1.1.2.1.2.1.2.1.1 24-1.1.2.1.2 25-1.1.2.1.2.2.1 26-1.1.2.1.2.2 27-1.1.2.1.2.2.2.r 28-1.1.2.1.2.2.2 29-1.1.2.1.3.r 31-1.1.2.1.3 32-1.1.2.1.3.1.r 33-1.1.2.1.3.1.1.2.1 34-1.1.2.1.3.1 36-1.1.3.1 39-1.1.3.1.1 (c / contrast-01~e.1 :ARG2 (e / exhibit-01~e.10 :ARG0 (c2 / culture-01~e.4 :ARG1 (a / and~e.7 :op1 (c3 / cell~e.9 :mod (m / metaplasia)) :op2 (c4 / cell~e.9 :mod (d / dysplasia~e.8))) :quant (s / several~e.3)) :ARG1 (t / trend-01~e.12 :ARG2 (r / respond-01~e.18 :ARG0 a :ARG1 (o / or~e.24 :op1 (d2 / dose-01~e.21 :ARG1 (c5 / cell~e.17) :ARG2~e.22 (p / protein :name (n / name :op1 "OSM"~e.23)) :ARG1-of (l / low-04~e.20)) :op2 (m2 / medium~e.26 :ARG1-of (c6 / condition-01~e.25) :source~e.27 (m3 / macrophage~e.28))) :ARG2~e.29 (s2 / stimulate-01~e.31 :ARG1~e.32 (s3 / synthesize-01~e.34 :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.33)))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.36 :mod "7B"~e.39)))) # ::id pmid_1627_1139.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The exact sign test using the paired samples ( normal and abnormal ) indicated a significant increase of DNA synthesis by low dose ( 10 @^{-@ 3}@ dilution ) of macrophage medium ( p = 0.016 ) . # ::alignments 1-1.1.3 2-1.1.2 3-1.1 4-1.1.1 6-1.1.1.1.3 7-1.1.1.1.1.2 9-1.1.1.1.1 9-1.1.1.1.1.1 9-1.1.1.1.1.1.r 9-1.1.1.1.2 9-1.1.1.1.2.1 9-1.1.1.1.2.1.r 10-1.1.1.1 11-1.1.1.1.1 11-1.1.1.1.1.1 11-1.1.1.1.1.1.r 11-1.1.1.1.2 11-1.1.1.1.2.1 11-1.1.1.1.2.1.1 11-1.1.1.1.2.1.1.r 11-1.1.1.1.2.1.r 13-1 15-1.2.3 16-1.2 17-1.2.2.r 18-1.2.2.1.2.1 19-1.2.2 20-1.2.1.r 21-1.2.1.3 22-1.2.1 29-1.2.1.4 31-1.2.1.2.r 32-1.2.1.2.1 33-1.2.1.2 35-1.2.4 37-1.2.4.1 (i / indicate-01~e.13 :ARG0 (t2 / test-01~e.3 :ARG0-of (u / use-01~e.4 :ARG1 (a / and~e.10 :op1 (t / thing~e.9,11 :ARG1-of~e.9,11 (n2 / normal-02~e.9,11) :ARG1-of (s / sample-01~e.7)) :op2 (t3 / thing~e.9,11 :ARG1-of~e.9,11 (n3 / normal-02~e.9,11 :polarity~e.11 -~e.11) :ARG1-of s) :ARG1-of (p / pair-01~e.6))) :mod (s6 / sign~e.2) :mod (e / exact~e.1)) :ARG1 (i2 / increase-01~e.16 :ARG0~e.20 (d2 / dose-01~e.22 :ARG1 s3 :ARG2~e.31 (m / medium~e.33 :mod (m2 / macrophage~e.32)) :ARG1-of (l / low-04~e.21) :ARG1-of (d4 / dilute-01~e.29 :ARG2 (l2 / less-than :op1 0.001))) :ARG1~e.17 (s3 / synthesize-01~e.19 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.18))) :ARG1-of (s4 / significant-02~e.15) :ARG1-of (s2 / statistical-test-91~e.35 :ARG2 0.016~e.37))) # ::id pmid_1627_1139.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The comparison of the data from paired cultures by the Wilcoxon two @-@ sample test also indicated that DNA synthesis in the abnormal epithelial cells was significantly increased at lowest concentration of OSM ( p = 0.02 ) and macrophage medium ( p = 0.005 ) relative to the normal cells . # ::alignments 1-1.1 2-1.1.2.r 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1 7-1.1.2.1 8-1.1.1.r 10-1.1.1.2.1.1 11-1.1.1.1.1 13-1.1.1.1 13-1.1.1.1.2 13-1.1.1.1.2.r 14-1.1.1 15-1.3 16-1 17-1.2.r 18-1.2.1.2.1.2.1 19-1.2.1.2 22-1.2.4.2 22-1.2.4.2.1 22-1.2.4.2.1.r 23-1.2.4.1 24-1.2.4 26-1.2.3 27-1.2.1 27-1.2.2 28-1.2.1.1.r 29-1.2.1.1.2 29-1.2.1.1.2.1 29-1.2.1.1.2.1.r 30-1.2.1.1 30-1.2.2.1 31-1.2.1.1.1.r 32-1.2.1.1.1.1.1 34-1.2.1.3 36-1.2.1.3.1 38-1.2 39-1.2.2.1.1.1 40-1.2.2.1.1 42-1.2.2.3 44-1.2.2.3.1 46-1.2.3.1 47-1.2.3.1.1.r 49-1.2.3.1.1.1 50-1.2.3.1.1 (i / indicate-01~e.16 :ARG0 (c / compare-01~e.1 :ARG0~e.8 (t2 / test-01~e.14 :mod (t3 / thing~e.13 :quant 2~e.11 :ARG1-of~e.13 (s3 / sample-01~e.13)) :mod (p5 / person :name (n / name :op1 "Wilcoxon"~e.10))) :ARG1~e.2 (d / data~e.4 :source~e.5 (c2 / culture~e.7 :ARG1-of (p / pair-01~e.6)))) :ARG1~e.17 (a / and~e.38 :op1 (i2 / increase-01~e.27 :ARG0~e.28 (c4 / concentrate-02~e.30 :ARG1~e.31 (p2 / protein :name (n3 / name :op1 "OSM"~e.32)) :ARG1-of (l / low-04~e.29 :degree~e.29 (m / most~e.29))) :ARG1 (s / synthesize-01~e.19 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.18))) :ARG1-of (s4 / statistical-test-91~e.34 :ARG2 0.02~e.36)) :op2 (i3 / increase-01~e.27 :ARG0 (c6 / concentrate-02~e.30 :ARG1 (m2 / medium~e.40 :mod (m3 / macrophage~e.39))) :ARG1 s :ARG1-of (s5 / statistical-test-91~e.42 :ARG2 0.005~e.44)) :ARG1-of (s2 / significant-02~e.26 :ARG1-of (r / relative-05~e.46 :ARG3~e.47 (c5 / cell~e.50 :ARG1-of (n4 / normal-02~e.49)))) :location (c3 / cell~e.24 :source (e / epithelium~e.23) :ARG1-of (n2 / normal-02~e.22 :polarity~e.22 -~e.22))) :mod (a2 / also~e.15)) # ::id pmid_1627_1139.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The reduced sensitivity for inhibited DNA synthesis in all cases could be correlated with metaplasia which shows enhanced ERK phosphorylation in response to cytokine treatment ( example of dysplastic cells in Fig. 7C ) . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.3 5-1.1.1.1.1.2.1 6-1.1.1.1 7-1.1.1.3.r 8-1.1.1.3.1 9-1.1.1.3 10-1 12-1.1 13-1.1.2.r 14-1.1.2 16-1.1.2.1 17-1.1.2.1.1.2 18-1.1.2.1.1.1.1.1 19-1.1.2.1.1 20-1.1.2.1.1.3.r 21-1.1.2.1.1.3 22-1.1.2.1.1.3.1.r 23-1.1.2.1.1.3.1.1 24-1.1.2.1.1.3.1 28-1.1.3.2.1 29-1.1.3.2 31-1.1.3.1 33-1.1.3.1.1 (p3 / possible-01~e.10 :ARG1 (c / correlate-01~e.12 :ARG1 (s / sensitive-03~e.2 :ARG0~e.3 (s2 / synthesize-01~e.6 :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.5) :ARG1-of (i / inhibit-01~e.4))) :ARG1-of (r / reduce-01~e.1) :condition~e.7 (c2 / case-04~e.9 :mod (a / all~e.8))) :ARG2~e.13 (m / metaplasia~e.14 :ARG0-of (s3 / show-01~e.16 :ARG1 (p2 / phosphorylate-01~e.19 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.18)) :ARG1-of (e2 / enhance-01~e.17) :ARG2-of~e.20 (r2 / respond-01~e.21 :ARG1~e.22 (t / treat-04~e.24 :ARG2 (c3 / cytokine~e.23)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "7C"~e.33) :ARG2 (c4 / cell~e.29 :mod (d3 / dysplasia~e.28))))) # ::id pmid_1627_1139.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , we noted that in premalignant cells the basal ERK phosphorylation approached the level of OSM @-@ treated cells or EGF @-@ treated cells ( Fig . 4B ) . # ::alignments 0-1 1-1 3-1.1.1 4-1.1 6-1.1.2.r 7-1.1.2.3.1 8-1.1.2.3 10-1.1.2.1.2 11-1.1.2.1.1.1.1 12-1.1.2.1 13-1.1.2 15-1.1.2.2 16-1.1.2.2.1.r 17-1.1.2.2.1.1.1.1.1.1 19-1.1.2.2.1.1.1 19-1.1.2.2.1.2.1 20-1.1.2.2.1.1 20-1.1.2.2.1.2 21-1.1.2.2.1 22-1.1.2.2.1.2.1.1.1.1 24-1.1.2.2.1.1.1 25-1.1.2.2.1.1 27-1.1.3.1 30-1.1.3.1.1 (a / and~e.0,1 :op2 (n / note-01~e.4 :ARG0 (w / we~e.3) :ARG1~e.6 (a2 / approach-01~e.13 :ARG1 (p / phosphorylate-01~e.12 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.11)) :mod (b / basal~e.10)) :ARG2 (l / level~e.15 :quant-of~e.16 (o / or~e.21 :op1 (c / cell~e.20,25 :ARG1-of (t / treat-04~e.19,24 :ARG2 (p2 / protein :name (n3 / name :op1 "OSM"~e.17)))) :op2 (c2 / cell~e.20 :ARG1-of (t2 / treat-04~e.19 :ARG2 (p4 / protein :name (n4 / name :op1 "EGF"~e.22)))))) :location (c3 / cell~e.8 :mod (p3 / premalignant~e.7))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "4B"~e.30)))) # ::id pmid_1627_1139.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , the thymidine incorporation by premalignant cells maintained in growth medium was close to two @-@ fold higher than in the corresponding normal cultures ( Fig . 5D ) . # ::alignments 0-1 1-1 4-1.1.1.2.1.1 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1 8-1.1.1.1 9-1.1.1.3 10-1.1.1.3.1.r 11-1.1.1.3.1.1 12-1.1.1.3.1 14-1.1 15-1.1.2.r 16-1.1.2.2.1 18-1.1.2.2 19-1.1.2 19-1.1.2.1 19-1.1.2.1.r 20-1.1.2.3.r 23-1.1.2.3.2 24-1.1.2.3.1 25-1.1.2.3 27-1.2.1 30-1.2.1.1 (a / and~e.0,1 :op2 (c / close-06~e.14 :ARG1 (i / incorporate-02~e.5 :ARG0~e.6 (c2 / cell~e.8 :mod (p / premalignant~e.7)) :ARG1 (s / small-molecule :name (n / name :op1 "thymidine"~e.4)) :ARG1-of (m2 / maintain-01~e.9 :location~e.10 (m3 / medium~e.12 :mod (g / grow-01~e.11)))) :ARG2~e.15 (h / high-02~e.19 :degree~e.19 (m4 / more~e.19) :degree (p2 / product-of~e.18 :op1 2~e.16) :compared-to~e.20 (c3 / culture~e.25 :ARG1-of (n2 / normal-02~e.24) :ARG1-of (c4 / correspond-02~e.23 :ARG2 m3)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "5D"~e.30))) # ::id pmid_1627_1139.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , the ERK activity was reduced by treatment in both normal and carcinoma cells with U0126 which correlates with the suppression of DNA synthesis observed ( Fig . 5C ) . # ::alignments 1-1.4 4-1.1.1.1.1 5-1.1 7-1 9-1.2 12-1.3.1.1 13-1.3 14-1.3.2.1.1.1 15-1.3.1 15-1.3.2 16-1.2.1.r 16-1.2.r 17-1.2.1.1.1 19-1.5 20-1.2.r 20-1.5.1.r 22-1.5.1 23-1.5.1.1.r 24-1.5.1.1.1.2.1 25-1.5.1.1 26-1.5.1.2 28-1.6.1 31-1.6.1.1 (r / reduce-01~e.7 :ARG1 (a / activity-06~e.5 :ARG0 (e / enzyme :name (n / name :op1 "ERK"~e.4))) :instrument~e.16,20 (t / treat-04~e.9 :ARG2~e.16 (s / small-molecule :name (n2 / name :op1 "U0126"~e.17))) :location (a2 / and~e.13 :op1 (c / cell~e.15 :ARG1-of (n3 / normal-02~e.12)) :op2 (c2 / cell~e.15 :mod (m / medical-condition :name (n4 / name :op1 "carcinoma"~e.14)))) :ARG1-of (e2 / expect-01~e.1) :ARG1-of (c3 / correlate-01~e.19 :ARG2~e.20 (s2 / suppress-01~e.22 :ARG1~e.23 (s3 / synthesize-01~e.25 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.24))) :ARG1-of (o / observe-01~e.26))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.28 :mod "5C"~e.31))) # ::id pmid_1627_1139.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High concentrations of OSM or macrophage factors were effective to reduce this intrinsically stimulated DNA synthesis in both normal and premalignant epithelial cell cultures . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1 5-1.1.2.1 6-1.1.2 8-1 10-1.2 11-1.2.2.3 12-1.2.2.2.1 13-1.2.2.2 14-1.2.2.1.2.1 15-1.2.2 18-1.2.3.1.1.2 19-1.2.3.1 20-1.2.3.1.2.1 21-1.2.3.1.1.1 22-1.2.3.1.1 22-1.2.3.1.2 23-1.2.3 (e / effective-04~e.8 :ARG0 (o / or~e.4 :op1 (c / concentrate-02~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "OSM"~e.3)) :ARG1-of (h / high-02~e.0)) :op2 (f / factor~e.6 :mod (m / macrophage~e.5))) :ARG1 (r / reduce-01~e.10 :ARG0 o :ARG1 (s / synthesize-01~e.15 :ARG0 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.14)) :ARG1-of (s2 / stimulate-01~e.13 :manner (i / intrinsic~e.12)) :mod (t / this~e.11)) :location (c2 / culture-01~e.23 :ARG1 (a / and~e.19 :op1 (c3 / cell~e.22 :source (e2 / epithelium~e.21) :ARG1-of (n2 / normal-02~e.18)) :op2 (c4 / cell~e.22 :mod (p2 / premalignant~e.20) :source e2))))) # ::id pmid_1859_7688.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TDAG51 is an ERK signaling target that opposes ERK @-@ mediated HME16C mammary epithelial cell transformation ( PMID : 18597688 ) # ::alignments 0-1.1.1.1 3-1.1.2.1.1.1 4-1.1.2.1.2 5-1.1 5-1.1.2 5-1.1.2.r 7-1 8-1.2.2.1.1.1 10-1.2.2 11-1.2.1.1.1 12-1.2.1.2.1 13-1.2.1.2 14-1.2.1 15-1.2 (o / oppose-01~e.7 :ARG0 (p / protein~e.5 :name (n / name :op1 "TDAG51"~e.0) :ARG1-of~e.5 (t / target-01~e.5 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.3) :ARG0-of (s / signal-07~e.4)))) :ARG1 (t2 / transform-01~e.15 :ARG1 (c / cell-line~e.14 :name (n4 / name :op1 "HME16C"~e.11) :mod (e3 / epithelium~e.13 :mod (m2 / mammary~e.12))) :ARG1-of (m / mediate-01~e.10 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK"~e.8)))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID18597688"))) # ::id pmid_1859_7688.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 0-1 0-1.1 0-1.1.r (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) # ::id pmid_1859_7688.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of both the ERK and PI3K signaling pathways was sufficient to induce cellular transformation , which was accompanied by up @-@ regulation of EGFR ligands , suggesting autocrine EGFR stimulation during the transformation process . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.3 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 7-1.1.1.4 8-1.1.1.1 8-1.1.1.2 10-1.1.2 12-1.1.2.1 13-1.1.2.1.2.1 14-1.1.2.1.2 18-1.1.2.1.2.2 19-1.1.2.1.2.2.1.r 20-1.1.2.1.2.2.1 21-1.1.2.1.2.2.1 22-1.1.2.1.2.2.1 23-1.1.2.1.2.2.1.1.r 24-1.1.2.1.2.2.1.1.1.1.1 25-1.1.2.1.2.2.1.1 27-1 28-1.2.2 29-1.2.1 30-1.2 31-1.2.3.r 33-1.2.3.1 34-1.2.3 (s / suggest-01~e.27 :ARG0 (a / activate-01~e.0 :ARG1~e.1 (a2 / and~e.5 :op1 (p / pathway~e.8 :name (n / name :op1 "ERK"~e.4)) :op2 (p2 / pathway~e.8 :name (n2 / name :op1 "PI3K"~e.6)) :mod (b / both~e.2) :ARG0-of (s2 / signal-07~e.7)) :ARG0-of (s3 / suffice-01~e.10 :ARG1 (i / induce-01~e.12 :ARG0 a :ARG2 (t / transform-01~e.14 :ARG1 (c / cell~e.13) :ARG1-of (a3 / accompany-01~e.18 :ARG0~e.19 (u / upregulate-01~e.20,21,22 :ARG1~e.23 (l / ligand~e.25 :mod (e / enzyme :name (n3 / name :op1 "EGFR"~e.24))))))))) :ARG1 (s4 / stimulate-01~e.30 :ARG1 e~e.29 :mod (a4 / autocrine~e.28) :time~e.31 (p3 / process-02~e.34 :ARG1 (t2 / transform-01~e.33)))) # ::id pmid_1859_7688.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only activation of the ERK pathway was sufficient to transform cells in the presence of EGFR inhibition and was sufficient for tumorigenesis in xenografts . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 4-1.1.1.1.1 5-1.1.1 7-1 9-1.2.1 10-1.2.1.1 15-1.2.1.1.1.1.1.1 16-1.2.1.1.1.1 16-1.2.1.1.1.1.2 16-1.2.1.1.1.1.2.r 18-1.2.1.1.1 19-1 20-1.2.r 21-1.2.2 21-1.2.2.1 21-1.2.2.1.r 22-1.2.2.2.r 23-1.2.2.2 (s / suffice-01~e.7,19 :ARG0 (a / activate-01~e.1 :ARG1~e.2 (p / pathway~e.5 :name (n / name :op1 "ERK"~e.4)) :mod (o / only~e.0)) :ARG1~e.20 (a2 / and :op1 (t / transform-01~e.9 :ARG1 (c / cell~e.10 :condition (b / be-located-at-91~e.18 :ARG1 (e / enzyme~e.16 :name (n2 / name :op1 "EGFR"~e.15) :ARG1-of~e.16 (i / inhibit-01~e.16))))) :op2 (c2 / create-01~e.21 :ARG1~e.21 (t2 / tumor~e.21) :location~e.22 (x / xenograft~e.23)))) # ::id pmid_1859_7688.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Up @-@ regulation of the PHLDA1 gene product , TDAG51 , was found to correlate with persistent ERK activation and anchorage @-@ independent growth in the absence or presence of EGFR inhibition . # ::alignments 0-1.1.1 1-1.1.1 2-1.1.1 3-1.1.1.1.r 5-1.1.1.1.1.1.1 6-1.1.1.1.1 7-1.1.1.1 9-1.1.1.1.2.1.1 12-1 14-1.1 15-1.1.2.r 16-1.1.2.1.2 17-1.1.2.1.1.1.1 18-1.1.2.1 19-1.1.2 20-1.1.2.2.1.2 22-1.1.2.2.1 22-1.1.2.2.1.1 22-1.1.2.2.1.1.r 23-1.1.2.2 24-1.1.3.r 26-1.1.3.1 27-1.1.3 28-1.1.3.2 29-1.1.3.1.1.r 30-1.1.3.1.1.1.1.1 31-1.1.3.1.1 (f / find-01~e.12 :ARG1 (c / correlate-01~e.14 :ARG1 (u / upregulate-01~e.0,1,2 :ARG1~e.3 (p / produce-01~e.7 :ARG0 (g / gene~e.6 :name (n / name :op1 "PHLDA1"~e.5)) :ARG1 (p3 / protein :name (n2 / name :op1 "TDAG51"~e.9)))) :ARG2~e.15 (a / and~e.19 :op1 (a2 / activate-01~e.18 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"~e.17)) :ARG1-of (p2 / persist-01~e.16)) :op2 (g3 / grow-01~e.23 :ARG0-of (d / depend-01~e.22 :polarity~e.22 -~e.22 :ARG1 (a3 / anchorage~e.20)))) :condition~e.24 (o / or~e.27 :op1 (a4 / absent-01~e.26 :ARG1~e.29 (i / inhibit-01~e.31 :ARG1 (e2 / enzyme :name (n4 / name :op1 "EGFR"~e.30)))) :op2 (p4 / present-02~e.28 :ARG1 i)))) # ::id pmid_1859_7688.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Knockdown of this putative breast cancer tumor @-@ suppressor gene resulted in increased ERK pathway activation and enhanced matrix @-@ detached cellular proliferation of Ras @/@ Raf transformed cells . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 3-1.1.1.1 4-1.1.1.1.1.2.1.2.1 5-1.1.1.1.1.2.1.2.2 6-1.1.1.1.1.2 8-1.1.1.1.1 9-1.1.1 10-1 11-1.2.r 12-1.2.1 13-1.2.1.1.1.1.1 14-1.2.1.1.1 15-1.2.1.1 16-1.2 17-1.2.2 18-1.2.2.1.1.2.1 20-1.2.2.1.1.2 21-1.2.2.1.1 22-1.2.2.1 24-1.2.2.1.1.1.1.1.1.1 25-1.2.2.1.1.1.1 26-1.2.2.1.1.1.1.2.1.1 27-1.2.2.1.1.1 28-1.2.2.1.1 (r / result-01~e.10 :ARG1 (k / knock-down-02~e.0 :ARG1~e.1 (g / gene~e.9 :ARG1-of (t3 / think-01~e.3 :ARG2 (s / suppress-01~e.8 :ARG0 g :ARG1 (t / tumor~e.6 :source (d2 / disease :wiki "Breast_cancer" :name (n4 / name :op1 "breast"~e.4 :op2 "cancer"~e.5))))) :mod (t4 / this~e.2))) :ARG2~e.11 (a / and~e.16 :op1 (i / increase-01~e.12 :ARG1 (a2 / activate-01~e.15 :ARG1 (p2 / pathway~e.14 :name (n / name :op1 "ERK"~e.13)))) :op2 (e / enhance-01~e.17 :ARG1 (p3 / proliferate-01~e.22 :ARG0 (c2 / cell~e.21,28 :ARG1-of (t2 / transform-01~e.27 :ARG0 (s2 / slash~e.25 :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.24)) :op2 (e3 / enzyme :name (n3 / name :op1 "Raf"~e.26)))) :ARG1-of (d / detach-01~e.20 :ARG2 (m / matrix~e.18))))))) # ::id pmid_1859_7688.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 0-1 0-1.1 0-1.1.r (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) # ::id pmid_1859_7688.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Generation of H @-@ Ras @- and Rlf @-@ CAAX @-@ expressing HME16C cell lines # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1 9-1.1.1.2.1.1 11-1.1 12-1.1.2.1.1 13-1.1.2 14-1.1.2 (g / generate-01~e.0 :ARG1~e.1 (e / express-03~e.11 :ARG2 (a / and~e.6 :op1 (e2 / enzyme :name (n / name :op1 "H-Ras"~e.2,4)) :op2 (e3 / enzyme :name (n2 / name :op1 "Rlf-CAAX"~e.7,9))) :ARG3 (c / cell-line~e.13,14 :name (n3 / name :op1 "HME16C"~e.12)))) # ::id pmid_1859_7688.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Retroviral vectors coding for amino terminal HA @-@ tagged activated H @-@ RasV12 , the H @-@ RasV12 effector domain mutants ( EDM ) H @-@ RasV12G37 , H @-@ RasV12S35 , and H @-@ RasV12C40 , and the constitutively activated version of a RalGEF , Rlf @-@ CAAX , were used to infect telomerase immortalized HME16C human mammary epithelial cells . # ::alignments 1-1.1.1 2-1.1.1.2 3-1.1.1.2.1.r 4-1.1.1.2.1.1.1 5-1.1.1.2.1.1.1 8-1.1.1.2.1.2.3 9-1.1.1.2.1.2.4 9-1.1.3.2 10-1.1.1.2.1.2.1.1 10-1.1.2.2.1.1 10-1.1.2.3.1.1.1.1 10-1.1.2.3.1.2.1.1 10-1.1.2.3.1.3.1.1 15-1.1.1.2.1.2.1.1 15-1.1.2.2.1.1 15-1.1.2.3.1.1.1.1 15-1.1.2.3.1.2.1.1 15-1.1.2.3.1.3.1.1 18-1.1.2.1 19-1.1.2 20-1.1.1.2.1.2 20-1.1.1.2.1.2.2 20-1.1.1.2.1.2.2.r 20-1.1.2.2 20-1.1.2.2.2 20-1.1.2.2.2.r 20-1.1.2.3.1.1 20-1.1.2.3.1.1.2 20-1.1.2.3.1.1.2.r 20-1.1.2.3.1.2 20-1.1.2.3.1.2.2 20-1.1.2.3.1.2.2.r 20-1.1.2.3.1.3 20-1.1.2.3.1.3.2 20-1.1.2.3.1.3.2.r 24-1.1.1.2.1.2.1.1 24-1.1.2.2.1.1 24-1.1.2.3.1.1.1.1 24-1.1.2.3.1.2.1.1 24-1.1.2.3.1.3.1.1 28-1.1.1.2.1.2.1.1 28-1.1.2.2.1.1 28-1.1.2.3.1.1.1.1 28-1.1.2.3.1.2.1.1 28-1.1.2.3.1.3.1.1 32-1.1 32-1.1.2.3.1 33-1.1.1.2.1.2.1.1 33-1.1.2.2.1.1 33-1.1.2.3.1.1.1.1 33-1.1.2.3.1.2.1.1 33-1.1.2.3.1.3.1.1 37-1.1 37-1.1.2.3.1 39-1.1.3.2.1 40-1.1.1.2.1.2.4 40-1.1.3.2 42-1.1.1.2.1.2.3.1.r 43-1.1.1.2.1.2.3.1.1.2 44-1.1.3.1.1 46-1.1.3.2.2.1.1.1 48-1.1.3.2.2.1.1.1 51-1 53-1.2 54-1.2.2.3.1 55-1.2.2.3 56-1.2.2.1.1 57-1.2.2.2.1.1 58-1.2.2.2.1 59-1.2.2.2 60-1.2.2 (u2 / use-01~e.51 :ARG1 (a4 / and~e.32,37 :op1 (v / vector~e.1 :mod (r / retrovirus) :ARG0-of (c / code-01~e.2 :ARG1~e.3 (p4 / protein-segment :name (n12 / name :op1 "amino-terminus"~e.4,5) :part-of (e / enzyme~e.20 :name (n2 / name :op1 "H-Ras"~e.10,15,24,28,33) :ARG2-of~e.20 (m / mutate-01~e.20 :value "V12") :ARG1-of (t2 / tag-01~e.8 :ARG2~e.42 (p3 / protein :name (n10 / name :op1 "haemagglutinin" :op2 "A"~e.43))) :ARG1-of (a / activate-01~e.9,40))))) :op2 (d / domain~e.19 :mod (e9 / effector~e.18) :mod (e3 / enzyme~e.20 :name (n3 / name :op1 "H-Ras"~e.10,15,24,28,33) :ARG2-of~e.20 (m2 / mutate-01~e.20 :value "V12")) :ARG1-of (m7 / mean-01 :ARG2 (a6 / and~e.32,37 :op1 (e4 / enzyme~e.20 :name (n4 / name :op1 "H-Ras"~e.10,15,24,28,33) :ARG2-of~e.20 (m3 / mutate-01~e.20 :value "V12G37")) :op2 (e5 / enzyme~e.20 :name (n5 / name :op1 "H-Ras"~e.10,15,24,28,33) :ARG2-of~e.20 (m4 / mutate-01~e.20 :value "V12S35")) :op3 (e6 / enzyme~e.20 :name (n6 / name :op1 "H-Ras"~e.10,15,24,28,33) :ARG2-of~e.20 (m5 / mutate-01~e.20 :value "V12C40"))))) :op3 (p2 / pathway :name (n7 / name :op1 "RalGEF"~e.44) :ARG1-of (a5 / activate-01~e.9,40 :mod (c2 / constitutive~e.39) :ARG1-of (m6 / mean-01 :ARG2 (e7 / enzyme :name (n8 / name :op1 "Rlf-CAAX"~e.46,48)))))) :ARG2 (i / infect-01~e.53 :ARG0 a4 :ARG1 (c3 / cell-line~e.60 :name (n9 / name :op1 "HME16C"~e.56) :mod (e2 / epithelium~e.59 :mod (m8 / mammary~e.58 :mod (h / human~e.57))) :ARG1-of (i2 / immortalize-03~e.55 :ARG2 (t / telomerase~e.54))))) # ::id pmid_1859_7688.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anti @-@ Ras and anti @-@ HA western blotting demonstrated approximately equal levels of ectopic Ras expression among Ras @-@ infected cells , with slightly lower levels in HME16C RasV12 @-@ infected cells relative to EDM @-@ infected cells ( Figure 1A ) . # ::alignments 0-1.1.1.1.1 0-1.1.2.1.1 2-1.2.2.1.1.1 2-1.2.2.2.1.1.1.1 2-1.2.3.3.2.1.1.1 3-1.1 4-1.1.1.1.1 4-1.1.2.1.1 6-1.1.2.1.1.1.1.1 7-1.1.1 7-1.1.2 8-1.1.1 9-1 10-1.2.1.1 11-1.2.1 12-1.2 13-1.2.2.r 14-1.2.2.1.2 15-1.2.2.1.1.1 15-1.2.2.2.1.1.1.1 16-1.2.2 18-1.2.2.2.1.1.1.1 20-1.2.2.2.1 20-1.2.3.3.2 21-1.2.2.2 23-1.2.3.r 24-1.2.3.1.1.1 25-1.2.3.1 25-1.2.3.1.1 25-1.2.3.1.1.r 26-1.2.3 26-1.2.3.2.1 27-1.2.3.3.r 28-1.2.3.3.1.1 31-1.2.3.2.1.1.1 32-1.2.3.2.1.1 33-1.2.3.2 35-1.2.3.2.1.1.1.1.1.1 37-1.2.3.2.1.1.1 38-1.2.3.2.1.1 40-1.3.1 41-1.3.1.1 (d / demonstrate-01~e.9 :ARG0 (a / and~e.3 :op1 (i4 / immunoblot-01~e.7,8 :ARG3 (a3 / antibody :ARG0-of (c3 / counter-01~e.0,4 :ARG1 e5))) :op2 (i5 / immunoblot-01~e.7 :ARG3 (a4 / antibody :ARG0-of (c5 / counter-01~e.0,4 :ARG1 (p / protein :name (n2 / name :op1 "HA"~e.6)))))) :ARG1 (l / level~e.12 :ARG1-of (e / equal-01~e.11 :ARG0-of (a2 / approximate-01~e.10)) :degree-of~e.13 (e2 / express-03~e.16 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras"~e.2,15) :mod (e3 / ectopic~e.14)) :ARG3 (c / cell~e.21 :ARG1-of (i / infect-01~e.20 :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras"~e.2,15,18))))) :prep-with~e.23 (l2 / level~e.26 :ARG1-of (l3 / low-04~e.25 :degree~e.25 (m / more~e.25 :degree (s / slight~e.24))) :ARG1-of (r / relative-05~e.33 :ARG2 (l4 / level~e.26 :mod (c4 / cell~e.32,38 :ARG1-of (i3 / infect-01~e.31,37 :ARG2 (e7 / enzyme :name (n8 / name :op1 "EDM"~e.35)))))) :location~e.27 (c2 / cell-line :name (n / name :op1 "HME16C"~e.28) :ARG1-of (i2 / infect-01~e.20 :ARG2 (e6 / enzyme :name (n7 / name :op1 "Ras"~e.2) :ARG2-of (m2 / mutate-01 :value "V12")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.40 :mod "1A"~e.41))) # ::id pmid_1859_7688.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of activated , GTP @-@ bound Ral A demonstrated highly elevated levels of activated Ral A only in Rlf @-@ CAAX @-@ expressing cells and not in Ras @-@ infected cells grown under standard culture conditions ( Figure 1B ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 4-1.1.1.3.1.1.1 6-1.1.1 6-1.1.1.3 6-1.1.1.3.r 7-1.1.1.1.1 8-1.1.1.1.2 9-1 10-1.2.1.2 11-1.2.1 11-1.2.2 12-1.2.1.1 14-1.1.1.2 14-1.2.1.1.1 15-1.1.1.1.1 16-1.1.1.1.2 17-1.2.1.4 18-1.2.1.3.r 19-1.2.1.3.1.1.1.1 21-1.2.1.3.1.1.1.1 23-1.2.1.3.1 24-1.2.1.3 25-1.2 26-1.2.2.1 26-1.2.2.1.r 27-1.2.2.3.r 28-1.2.2.3.1.1.1.1 30-1.2.2.3.1 31-1.2.2.3 32-1.2.2.3.2 34-1.2.2.3.2.1.1 35-1.2.2.3.2.1 36-1.2.2.3.2.1.r 38-1.3.1 39-1.3.1.1 (d / demonstrate-01~e.9 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (e2 / enzyme~e.6 :name (n2 / name :op1 "Ral"~e.7,15 :op2 "A"~e.8,16) :ARG1-of (a2 / activate-01~e.2,14) :ARG2-of~e.6 (b / bind-01~e.6 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.4))))) :ARG1 (a4 / and~e.25 :op1 (e3 / elevate-01~e.11 :ARG1 (l / level~e.12 :mod (a3 / activate-01~e.14 :ARG1 e2)) :ARG1-of (h / high-02~e.10) :location~e.18 (c / cell~e.24 :ARG3-of (e4 / express-03~e.23 :ARG2 (e5 / enzyme :name (n3 / name :op1 "Rlf-CAAX"~e.19,21)))) :mod (o / only~e.17)) :op2 (e6 / elevate-01~e.11 :polarity~e.26 -~e.26 :ARG1 l :location~e.27 (c2 / cell~e.31 :ARG1-of (i / infect-01~e.30 :ARG2 (e7 / enzyme :name (n4 / name :op1 "Ras"~e.28))) :ARG1-of (g / grow-03~e.32 :condition~e.36 (c5 / culture-01~e.35 :mod (s2 / standard~e.34)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.38 :mod "1B"~e.39))) # ::id pmid_1859_7688.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess activation of the ERK pathway , anti @-@ phospho Erk western blotting was performed and showed significantly elevated Erk phosphoprotein in RasV12 @- and RasV12S35 @-@ infected HME16C cells relative to control pLRT @-@ infected cells ( Figure 1A ) . # ::alignments 1-1.1.2 2-1.1.2.1 3-1.1.2.1.1.r 5-1.1.2.1.1.1.1 6-1.1.2.1.1 8-1.1.1.1 10-1.1.1.1.1.2 10-1.2.2.3.1.1.1.2 11-1.1.1.1.1.1.1 12-1.1.1 13-1.1.1 15-1.1 16-1 17-1.2 18-1.2.2.4 19-1.2.2 20-1.1.2.1.1.1.1 25-1.2.2.2.2.1 28-1.2.2.2.2 29-1.2.2.2.1.1 30-1.2.2.3.1 31-1.2.2.3 33-1.2.2.3.1.2 36-1.2.2.3.1.1 37-1.2.2.3.1 39-1.3.1 40-1.3.1.1 (a / and~e.16 :op1 (p / perform-01~e.15 :ARG1 (i3 / immunoblot-01~e.12,13 :ARG0-of (c / counter-01~e.8 :ARG1 (e4 / enzyme :name (n2 / name :op1 "Erk"~e.11) :ARG3-of (p2 / phosphorylate-01~e.10)))) :purpose (a2 / assess-01~e.1 :ARG1 (a3 / activate-01~e.2 :ARG1~e.3 (p3 / pathway~e.6 :name (n3 / name :op1 "ERK"~e.5,20))))) :op2 (s / show-01~e.17 :ARG0 i3 :ARG1 (e2 / elevate-01~e.19 :ARG1 e4 :location (c3 / cell-line :name (n4 / name :op1 "HME16C"~e.29) :ARG1-of (i / infect-01~e.28 :ARG2 (a4 / and~e.25 :op1 (e / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12")) :op2 (e3 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35"))))) :ARG1-of (r / relative-05~e.31 :ARG2 (c2 / cell~e.30,37 :ARG1-of (i2 / infect-01~e.36 :ARG2 (p4 / protein :name (n7 / name :op1 "LRT") :ARG3-of (p5 / phosphorylate-01~e.10))) :ARG0-of (c4 / control-01~e.33))) :ARG1-of (s2 / significant-02~e.18))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod "1A"~e.40))) # ::id pmid_1859_7688.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Elevated levels of phosphorylated Erk were also observed in RasV12G37 @- and RasV12C40 @-@ infected cells , although at a much lower level than that found in RasV12 @- and RasV12S35 @-@ infected cells . # ::alignments 0-1.1.1 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1.2 4-1.1.1.1.1.1.1 6-1.1.2 7-1.1 11-1.1.1.1.2.1.1 14-1.1.1.1.2.1 14-1.2.3.1.2.1 15-1.1.1.1.2 15-1.2.3.1.2 17-1 20-1.2.4 21-1.2 21-1.2.2 21-1.2.2.r 22-1.2.3.1 25-1.2.3.1.1 29-1.2.1 30-1.2.1 31-1.2.1 32-1.2.1 33-1.2.1 (h / have-concession-91~e.17 :ARG1 (o / observe-01~e.7 :ARG1 (e / elevate-01~e.0 :ARG1 (l / level~e.1 :quant-of~e.2 (e6 / enzyme :name (n / name :op1 "Erk"~e.4) :ARG3-of (p / phosphorylate-01~e.3)) :location (c / cell~e.15 :ARG1-of (i / infect-01~e.14 :ARG2 (a / and~e.11 :op1 (e5 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37")) :op2 (e4 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40"))))))) :mod (a2 / also~e.6)) :ARG2 (l3 / low-04~e.21 :ARG1 l~e.29,30,31,32,33 :degree~e.21 (m3 / more~e.21) :ARG1-of (c2 / compare-01 :ARG2 (l2 / level~e.22 :ARG1-of (f2 / find-01~e.25) :location (c3 / cell~e.15 :ARG1-of (i2 / infect-01~e.14 :ARG2 (a3 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12")) :op2 (e3 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12S35"))))))) :degree (m6 / much~e.20))) # ::id pmid_1859_7688.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess activation of the PI3K signaling pathway , anti @-@ phosphoAkt ( Ser473 ) western blotting was performed to detect activated , phosphorylated Akt . # ::alignments 1-1.3 2-1.3.1 5-1.3.1.1.1.1 6-1.3.1.1.2 7-1.3.1.1 15-1.1 16-1.1 18-1 20-1.2 21-1.2.1.1 21-1.3.1 23-1.1.1.3.2 24-1.1.1.3.1.1 (p / perform-01~e.18 :ARG1 (i / immunoblot-01~e.15,16 :ARG1 (a / amino-acid :mod 473 :name (n3 / name :op1 "Serine") :part-of (e / enzyme :name (n2 / name :op1 "Akt"~e.24) :ARG3-of (p2 / phosphorylate-01~e.23)))) :purpose (d / detect-01~e.20 :ARG1 (a2 / and :op1 (a3 / activate-01~e.21 :ARG1 e) :op2 e)) :purpose (a4 / assess-01~e.1 :ARG1 (a5 / activate-01~e.2,21 :ARG1 (p3 / pathway~e.7 :name (n4 / name :op1 "PI3K"~e.5) :ARG0-of (s / signal-07~e.6))))) # ::id pmid_1859_7688.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In cells that were serum starved for 24 hours and matrix detached for 6 hours , elevated levels of phosphorylated Akt were observed in RasV12-, RasV12C40-, and RasV12G37 @-@ infected HME16C , with highest levels present in RasV12 @-@ infected cells ( Figure 1C ) . # ::alignments 1-1.2 4-1.2.1.1 5-1.2.1 6-1.2.1.2.r 7-1.2.1.2.1 8-1.2.1.2.2 10-1.2.2.1 11-1.2.2 12-1.2.2.2.r 13-1.2.2.2.1 14-1.2.2.2.2 16-1.1 17-1.1.1 19-1.1.1.1.2 20-1.1.1.1.1.1 22-1 26-1.1.1.2.2.1 29-1.1.1.2.2 30-1.1.1.2.1.1 33-1.1.1.3 33-1.1.1.3.1 33-1.1.1.3.1.r 34-1.1.1 39-1.1.1.3.2.1 40-1.1.1.3.2 42-1.3.1 43-1.3.1.1 (o / observe-01~e.22 :ARG1 (e / elevate-01~e.16 :ARG1 (l / level~e.17,34 :quant-of (e2 / enzyme :name (n / name :op1 "Akt"~e.20) :ARG3-of (p / phosphorylate-01~e.19)) :location (c2 / cell-line :name (n2 / name :op1 "HME16C"~e.30) :ARG1-of (i / infect-01~e.29 :ARG2 (a / and~e.26 :op1 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12")) :op2 (e4 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12C40")) :op3 (e5 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12G37"))))) :ARG1-of (h / high-02~e.33 :degree~e.33 (m5 / most~e.33) :location (c3 / cell~e.40 :ARG1-of (i2 / infect-01~e.39 :ARG2 e3))))) :location (c / cell~e.1 :ARG1-of (s / starve-01~e.5 :ARG2 (s2 / serum~e.4) :duration~e.6 (t / temporal-quantity :quant 24~e.7 :unit (h4 / hour~e.8))) :ARG1-of (d / detach-01~e.11 :ARG2 (m / matrix~e.10) :duration~e.12 (t2 / temporal-quantity :quant 6~e.13 :unit h4~e.14))) :ARG1-of (d2 / describe-01 :ARG2 (f / figure~e.42 :mod "1C"~e.43))) # ::id pmid_1859_7688.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anchorage @-@ independent growth of mammary epithelial cell lines # ::alignments 0-1.2.2 2-1.2 2-1.2.1 2-1.2.1.r 3-1 4-1.1.r 5-1.1.1.1 6-1.1.1 7-1.1 8-1.1 (g / grow-01~e.3 :ARG1~e.4 (c / cell-line~e.7,8 :mod (e / epithelium~e.6 :mod (m / mammary~e.5))) :ARG0-of (d / depend-01~e.2 :polarity~e.2 -~e.2 :ARG1 (a / anchorage~e.0))) # ::id pmid_1859_7688.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess transformation by different Ras signaling pathways , anchorage @-@ independent growth assays were performed in soft agar and in ultra @-@ low attachment tissue culture plates . # ::alignments 1-1.3 2-1.3.1 3-1.3.1.1.r 4-1.3.1.1.3 5-1.3.1.1.1.1 6-1.3.1.1.2 7-1.3.1.1 9-1.1.1.1.2 11-1.1.1.1 11-1.1.1.1.1 11-1.1.1.1.1.r 12-1.1.1 13-1.1 15-1 16-1.2.r 17-1.2.1.2.1 18-1.2.1.2 21-1.2.1.1.1.1.1 23-1.2.1.1.1.1 24-1.2.1.1.1 25-1.2.1.1 26-1.2.1 27-1.2 (p / perform-01~e.15 :ARG1 (a / assay-01~e.13 :ARG1 (g / grow-01~e.12 :ARG0-of (d / depend-01~e.11 :polarity~e.11 -~e.11 :mod (a2 / anchorage~e.9)))) :ARG2~e.16 (p2 / plate~e.27 :mod (c / culture-01~e.26 :ARG1 (t / tissue~e.25 :ARG3-of (a5 / attach-01~e.24 :ARG1-of (l / low-04~e.23 :degree (u / ultra~e.21)))) :instrument (a4 / agar~e.18 :ARG1-of (s / soft-02~e.17)))) :purpose (a6 / assess-01~e.1 :ARG1 (t2 / transform-01~e.2 :ARG0~e.3 (p3 / pathway~e.7 :name (n / name :op1 "Ras"~e.5) :ARG0-of (s2 / signal-07~e.6) :ARG1-of (d2 / differ-02~e.4))))) # ::id pmid_1859_7688.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras @- and Ras EDM @-@ infected HME16C cells formed significantly more soft agar colonies > 100 μm in diameter than pLRT vector @-@ infected cells ( Figure 2A ) . # ::alignments 0-1.1.2.1.1.1.1 2-1.1.2.1 3-1.1.2.1.1.1.1 3-1.1.2.1.2.1.1 4-1.1.2.1.2.1.2 6-1.1.2 7-1.1.1.1 8-1.1 9-1 10-1.2.3.1 11-1.2.3 12-1.2.1.1 13-1.2.1 14-1.2 15-1.2.2.1 16-1.2.2.1.1.1 17-1.2.2.1.1.2 19-1.2.2 20-1.2.2.1 22-1.2.3.2.1.1.1 24-1.2.3.2.1.1 25-1.2.3.2.1 27-1.3.1 28-1.3.1.1 (f / form-01~e.9 :ARG0 (c / cell-line~e.8 :name (n / name :op1 "HME16C"~e.7) :ARG1-of (i / infect-01~e.6 :ARG2 (a / and~e.2 :op1 (e / enzyme :name (n2 / name :op1 "Ras"~e.0,3)) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.3 :op2 "EDM"~e.4))))) :ARG1 (c2 / colony~e.14 :mod (a2 / agar~e.13 :ARG1-of (s / soft-02~e.12)) :mod (d / diameter~e.19 :mod (m2 / more-than~e.15,20 :op1 (d2 / distance-quantity :quant 100~e.16 :unit (m / micrometer~e.17)))) :quant (m3 / more~e.11 :ARG1-of (s2 / significant-02~e.10) :ARG1-of (c3 / compare-01 :ARG2 (c4 / cell~e.25 :ARG1-of (i2 / infect-01~e.24 :ARG2 (v / vector~e.22 :name (n4 / name :op1 "LRT") :ARG3-of (p2 / phosphorylate-01))))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.27 :mod "2A"~e.28))) # ::id pmid_1859_7688.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The RasV12 @-@ infected cells formed large colonies , many exceeding 1000 μm , although the total number exceeding 100 μm was typically less than that for the Ras EDM ( Figure 2B ) . # ::alignments 3-1.1.1 4-1.1 5-1 6-1.2.1 7-1.2 9-1.2.2 10-1.2.3 11-1.2.3.1.1 12-1.2.3.1.2 14-1.3.r 16-1.3.1 17-1.3 17-1.3.4.1 18-1.3.2 19-1.3.2.1.1 20-1.3.2.1.2 22-1.3.3.1 23-1.3.3 28-1.1.1.1.1.1 28-1.3.4.1.1.1.1 29-1.3.4.1.1.1.2 31-1.4.1 32-1.4.1.1 (f / form-01~e.5 :ARG0 (c / cell~e.4 :ARG1-of (i / infect-01~e.3 :ARG2 (e / enzyme :name (n / name :op1 "Ras"~e.28) :ARG2-of (m / mutate-01 :value "V12")))) :ARG1 (c2 / colony~e.7 :mod (l / large~e.6) :quant (m2 / many~e.9) :ARG0-of (e4 / exceed-01~e.10 :ARG1 (d / distance-quantity :quant 1000~e.11 :unit (m3 / micrometer~e.12)))) :concession~e.14 (n2 / number~e.17 :mod (t / total~e.16) :ARG0-of (e2 / exceed-01~e.18 :ARG1 (d2 / distance-quantity :quant 100~e.19 :unit m3~e.20)) :quant (l2 / less~e.23 :ARG1-of (t2 / typical-02~e.22)) :ARG1-of (c3 / compare-01 :ARG2 (n4 / number~e.17 :condition (e3 / enzyme :name (n3 / name :op1 "Ras"~e.28 :op2 "EDM"~e.29))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.31 :mod "2B"~e.32))) # ::id pmid_1859_7688.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the Ras EDM @-@ infected cells , the RasV12S35 @-@ infected cells formed the largest colonies . # ::alignments 0-1.1.2 2-1.1.1.1.1.1 2-1.1.2.1.1.1.1.1 3-1.1.2.1.1.1.1.2 5-1.1.1 5-1.1.2.1.1 6-1.1 6-1.1.2.1 11-1.1.1 12-1.1 13-1 15-1.2.1 15-1.2.1.1 15-1.2.1.1.r 16-1.2 (f / form-01~e.13 :ARG0 (c / cell~e.6,12 :ARG1-of (i / infect-01~e.5,11 :ARG2 (e / enzyme :name (n / name :op1 "Ras"~e.2) :ARG2-of (m / mutate-01 :value "V12S35"))) :ARG1-of (i2 / include-91~e.0 :ARG2 (c2 / cell~e.6 :ARG1-of (i3 / infect-01~e.5 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.2 :op2 "EDM"~e.3)))))) :ARG1 (c3 / colony~e.16 :mod (l / large~e.15 :degree~e.15 (m2 / most~e.15)))) # ::id pmid_1859_7688.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These were similar to , but smaller than , the RasV12 @-@ infected cells . # ::alignments 0-1.1.1 2-1.1 5-1 6-1.2 6-1.2.2 6-1.2.2.r 12-1.1.2.1 13-1.1.2 (c3 / contrast-01~e.5 :ARG1 (r / resemble-01~e.2 :ARG1 (t / this~e.0) :ARG2 (c / cell~e.13 :ARG1-of (i / infect-01~e.12 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12"))))) :ARG2 (s / small~e.6 :domain t :degree~e.6 (m2 / more~e.6) :ARG1-of (c2 / compare-01 :ARG2 c))) # ::id pmid_1859_7688.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For colonies above 100 μm in diameter , RasV12C40 @-@ infected cells were the most efficient at colony formation , despite the smaller mean size of colonies . # ::alignments 1-1.3 2-1.3.1.1 3-1.3.1.1.1.1 4-1.3.1.1.1.2 6-1.3.1 10-1.1.1.1 11-1.1.1 14-1.1.3 15-1.1 17-1.3 18-1.1.2 20-1 22-1.2.2 22-1.2.2.1 22-1.2.2.1.r 23-1.2.3 24-1.2 25-1.1.2.1.r 26-1.1.2.1 (h / have-concession-91~e.20 :ARG1 (e / efficient-01~e.15 :ARG1 (c / cell~e.11 :ARG1-of (i / infect-01~e.10 :ARG2 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12C40")))) :ARG2 (f / form-01~e.18 :ARG1~e.25 (c2 / colony~e.26)) :degree (m2 / most~e.14)) :ARG2 (s / size-01~e.24 :ARG1 c2 :ARG2 (s2 / small~e.22 :degree~e.22 (m4 / more~e.22)) :mod (m3 / mean~e.23)) :condition (c3 / colony~e.1,17 :mod (d2 / diameter~e.6 :mod (a / above~e.2 :op1 (d / distance-quantity :quant 100~e.3 :unit (m5 / micrometer~e.4)))))) # ::id pmid_1859_7688.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rlf @-@ CAAX @-@ infected cells formed slightly more colonies above 100 μm than vector @-@ transfected control cells , but these were significantly smaller than those formed by Ras @- and Ras EDM @-@ infected cells . # ::alignments 0-1.1.1.1.1.1.1 2-1.1.1.1.1.1.1 4-1.1.1.1 4-1.2.4.1.1.1 5-1.1.1 5-1.2.4.1.1 6-1.1 6-1.2.4.1 7-1.1.2.1.1 8-1.1.2.1 8-1.2.1 9-1.1.2 9-1.2.4 10-1.1.2.3 11-1.1.2.3.1.1 12-1.1.2.3.1.2 13-1.1.2.2.r 14-1.1.2.2.2.1 16-1.1.2.2.2 17-1.1.2.2.1 18-1.1.2.2 20-1 22-1.2.3.r 23-1.2.2 24-1.2 24-1.2.1 24-1.2.1.r 25-1.2.4.r 27-1.1 28-1.2.4.1.1.1.1.r 29-1.2.4.1.1.1.1.1.1.1 31-1.2.4.1.1.1.1 32-1.2.4.1.1.1.1.1.1.1 32-1.2.4.1.1.1.1.2.1.1 33-1.2.4.1.1.1.1.2.1.2 35-1.2.3 36-1.2.3 (c / contrast-01~e.20 :ARG1 (f / form-01~e.6,27 :ARG0 (c2 / cell~e.5 :ARG1-of (i / infect-01~e.4 :ARG2 (e / enzyme :name (n / name :op1 "Rlf-CAAX"~e.0,2)))) :ARG1 (c3 / colony~e.9 :quant (m2 / more~e.8 :degree (s3 / slight~e.7)) :compared-to~e.13 (c4 / cell~e.18 :ARG0-of (c5 / control-01~e.17) :ARG1-of (t / transfect-01~e.16 :ARG2 (v / vector~e.14))) :mod (a / above~e.10 :op1 (d / distance-quantity :quant 100~e.11 :unit (m / micrometer~e.12))))) :ARG2 (s / small~e.24 :degree~e.24 (m3 / more~e.8,24) :ARG1-of (s2 / significant-02~e.23) :domain~e.22 c2~e.35,36 :compared-to~e.25 (c7 / colony~e.9 :ARG1-of (f2 / form-01~e.6 :ARG0 (c6 / cell~e.5 :ARG1-of (i2 / infect-01~e.4 :ARG2~e.28 (a2 / and~e.31 :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.29,32)) :op2 (e3 / enzyme :name (n3 / name :op1 "Ras"~e.32 :op2 "EDM"~e.33))))))))) # ::id pmid_1859_7688.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When grown under anchorage @-@ independent conditions in ultra @-@ low attachment plates , the accumulation of cells for the various infected cell lines roughly paralleled the total cell masses seen in soft agar growth assays ( Figure 2C ) . # ::alignments 1-1.4 3-1.4.1.2 5-1.4.1 5-1.4.1.1 5-1.4.1.1.r 6-1.4.r 7-1.4.2.r 8-1.4.2.1.1.1 10-1.4.2.1.1 11-1.4.2.1 12-1.4.2 15-1.1 17-1.1.1 17-1.1.2 20-1.1.2.2 21-1.1.2.1 22-1.1.2 23-1.1.2 24-1.3 25-1 27-1.2.1.1 28-1.2.1 29-1.2 30-1.2.2 31-1.2.2.1.r 32-1.2.2.1.1.1.1 33-1.2.2.1.1.1 34-1.2.2.1.1 35-1.2.2.1 37-1.5.1 38-1.5.1.1 (p / parallel-01~e.25 :ARG0 (a / accumulate-01~e.15 :ARG1 (c / cell~e.17) :mod (c2 / cell-line~e.17,22,23 :ARG1-of (i / infect-01~e.21) :mod (v / various~e.20))) :ARG1 (m / mass-01~e.29 :ARG0 (c3 / cell~e.28 :mod (t / total~e.27)) :ARG1-of (s / see-01~e.30 :location~e.31 (a2 / assay-01~e.35 :ARG1 (g / grow-01~e.34 :condition (a3 / agar~e.33 :ARG1-of (s2 / soft-02~e.32)))))) :degree (r / rough~e.24) :condition~e.6 (g2 / grow-01~e.1 :ARG0-of (d / depend-01~e.5 :polarity~e.5 -~e.5 :ARG1 (a4 / anchorage~e.3)) :location~e.7 (p2 / plate~e.12 :ARG3-of (a5 / attach-01~e.11 :ARG1-of (l / low-04~e.10 :degree (u / ultra~e.8))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.37 :mod "2C"~e.38))) # ::id pmid_1859_7688.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The RasV12 @- and RasV12 EDM @-@ expressing cells grew well , while the growth of the Rlf @-@ CAAX @-@ expressing cells was significantly less . # ::alignments 3-1.1.1.1.1 5-1.1.1.1.1.2.1.2 7-1.1.1.1 7-1.2.1.1 8-1.1.1 8-1.2.1 9-1.1 9-1.2 10-1.1.2 12-1 14-1.2.3 15-1.2.1.1.1.r 17-1.2.1.1.1.1.1 19-1.2.1.1.1.1.1 21-1.2.3 22-1.2.3 24-1.2.2.1 25-1.2.2 (c / contrast-01~e.12 :ARG1 (g / grow-01~e.9 :ARG1 (c2 / cell~e.8 :ARG3-of (e / express-03~e.7 :ARG2 (a / and~e.3 :op1 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12")) :op2 (e3 / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM"~e.5) :ARG2-of (m2 / mutate-01 :value "V12"))))) :ARG1-of (w / well-09~e.10)) :ARG2 (g2 / grow-01~e.9 :ARG1 (c3 / cell~e.8 :ARG3-of (e4 / express-03~e.7 :ARG2~e.15 (e5 / enzyme :name (n3 / name :op1 "Rlf-CAAX"~e.17,19)))) :mod (l / less~e.25 :ARG1-of (s / significant-02~e.24)) :compared-to g~e.14,21,22)) # ::id pmid_1859_7688.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The HME16C cells maintained viability but did not increase in number . # ::alignments 1-1.1.1.1.1 2-1.1.1 3-1.1 4-1.1.2 5-1 7-1.2.1 7-1.2.1.r 8-1.2 9-1.2.3.r 10-1.2.3 (c / contrast-01~e.5 :ARG1 (m / maintain-01~e.3 :ARG0 (c2 / cell-line~e.2 :name (n / name :op1 "HME16C"~e.1)) :ARG1 (v / viability~e.4)) :ARG2 (i / increase-01~e.8 :polarity~e.7 -~e.7 :ARG1 c2 :mod~e.9 (n2 / number~e.10))) # ::id pmid_1859_7688.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To compare our results to others , we verified the function of pLRT vector driven Ras EDM mutants and Rlf @-@ CAAX in HEK @-@ HT cells , which previously have been reported to form colonies in soft agar upon expression of H @-@ RasV12G37 and Rlf @-@ CAAX [ 27 ] . # ::alignments 1-1.4 2-1.4.2.2 2-1.4.2.2.r 3-1.4.2 3-1.4.2.1 3-1.4.2.1.r 4-1.4.3.r 5-1.4.3.3 7-1.4.1 8-1 10-1.2 13-1.2.1.3.1 14-1.2.1.3 15-1.2.1.1.1.1 16-1.2.1.1.1.2 17-1.2.1.1 17-1.2.1.1.2 17-1.2.1.1.2.r 17-1.2.2.2.3.1.1 17-1.2.2.2.3.1.1.2 17-1.2.2.2.3.1.1.2.r 18-1.2.1 19-1.2.1.2.1.1 21-1.2.1.2.1.1 22-1.2.2.r 23-1.2.2.1.1 25-1.2.2.1.1 26-1.2.2 29-1.2.2.2.4.1 32-1.2.2.2.4 34-1.2.2.2 35-1.2.2.2.1 36-1.2.2.2.2.r 37-1.2.2.2.2.1 38-1.2.2.2.2 40-1.2.2.2.3 41-1.2.2.2.3.1.r 42-1.2.2.2.3.1.1.1.1 45-1.2.2.2.3.1 46-1.2.2.2.3.1.2 47-1.2.2.2.3.1.2 48-1.2.2.2.3.1.2 50-1.3.1.1.1 (v / verify-01~e.8 :ARG0 (w / we) :ARG1 (f / function-01~e.10 :ARG0 (a / and~e.18 :op1 (e / enzyme~e.17 :name (n2 / name :op1 "Ras"~e.15 :op2 "EDM"~e.16) :ARG2-of~e.17 (m / mutate-01~e.17)) :op2 (e2 / enzyme :name (n3 / name :op1 "Rlf-CAAX"~e.19,21)) :ARG1-of (d / drive-02~e.14 :ARG0 (v2 / vector~e.13 :name (n / name :op1 "LRT") :ARG3-of (p4 / phosphorylate-01)))) :location~e.22 (c / cell-line~e.26 :name (n4 / name :op1 "HEK-HT"~e.23,25) :ARG0-of (f2 / form-01~e.34 :ARG1 (c2 / colony~e.35) :location~e.36 (a2 / agar~e.38 :ARG1-of (s / soft-02~e.37)) :condition (e3 / express-03~e.40 :ARG2~e.41 (a3 / and~e.45 :op1 (e4 / enzyme~e.17 :name (n5 / name :op1 "H-Ras"~e.42) :ARG2-of~e.17 (m2 / mutate-01~e.17 :value "V12G37")) :op2 e2~e.46,47,48)) :ARG1-of (r / report-01~e.32 :time (p2 / previous~e.29))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 27~e.50))) :purpose (c4 / compare-01~e.1 :ARG0 w~e.7 :ARG1 (t2 / thing~e.3 :ARG2-of~e.3 (r2 / result-01~e.3) :poss~e.2 w~e.2) :ARG2~e.4 (t / thing :ARG2-of r2 :poss (p5 / person) :mod (o / other~e.5)))) # ::id pmid_1859_7688.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In our hands , expression of H @-@ RasV12 , H @-@ RasV12G37 , and Rlf @-@ CAAX from the pLRT vector induced efficient soft agar colony growth , and H @-@ RasV12S35 and H @-@ RasV12C40 did not ( not shown ) , identical to previously reported results [ 27 ] . # ::alignments 1-1.3.1 1-1.3.1.r 2-1.3 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1.1 6-1.1.1.1.2.1.1 10-1.1.1.1.1.1.1 10-1.1.1.1.2.1.1 14-1.1.1.1 15-1.1.1.1.3.1.1 17-1.1.1.1.3.1.1 18-1.1.1.1.4.r 21-1.1.1.1.4 22-1.1 22-1.2 23-1.1.2.2 24-1.1.2.1.1.1 25-1.1.2.1.1 26-1.1.2.1 27-1.1.2 29-1.2.2 30-1.2.2.1.1.1 30-1.2.2.2.1.1 33-1.2.2 34-1.2.2.1.1.1 34-1.2.2.2.1.1 38-1.2.1 38-1.2.1.r 40-1.2.4.1 40-1.2.4.1.r 41-1.2.4 44-1.4 45-1.4.1.r 46-1.4.1.1.1.1 47-1.4.1.1.1 48-1.4.1 48-1.4.1.1 48-1.4.1.1.r 50-1.5.1.1.1 (c / contrast-01 :ARG1 (i / induce-01~e.22 :ARG0 (e / express-03~e.4 :ARG2~e.5 (a / and~e.14 :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.6,10) :ARG2-of (m / mutate-01 :value "V12")) :op2 (e3 / enzyme :name (n3 / name :op1 "H-Ras"~e.6,10) :ARG2-of (m2 / mutate-01 :value "V12G37")) :op3 (e4 / enzyme :name (n4 / name :op1 "Rlf-CAAX"~e.15,17)) :source~e.18 (v / vector~e.21 :name (n / name :op1 "LRT") :ARG3-of (p4 / phosphorylate-01)))) :ARG2 (g / grow-01~e.27 :ARG2 (c2 / colony~e.26 :location (a2 / agar~e.25 :ARG1-of (s / soft-02~e.24))) :ARG1-of (e5 / efficient-01~e.23))) :ARG2 (i3 / induce-01~e.22 :polarity~e.38 -~e.38 :ARG0 (a3 / and~e.29,33 :op1 (e6 / enzyme :name (n5 / name :op1 "H-ras"~e.30,34) :ARG2-of (m3 / mutate-01 :value "V12S35")) :op2 (e7 / enzyme :name (n6 / name :op1 "H-ras"~e.30,34) :ARG2-of (m4 / mutate-01 :value "V12C40"))) :ARG2 g :ARG1-of (s2 / show-01~e.41 :polarity~e.40 -~e.40)) :location (h / hand~e.2 :part-of~e.1 (w / we~e.1)) :ARG1-of (i2 / identical-01~e.44 :ARG2~e.45 (t / thing~e.48 :ARG2-of~e.48 (r / result-01~e.48 :ARG1-of (r2 / report-01~e.47 :time (p2 / previous~e.46))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 27~e.50)))) # ::id pmid_1859_7688.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of exogenous H @-@ Ras and Rlf @-@ CAAX , and activation of endogenous RalA , in this cell line was similar to that observed in HME16C cells ( not shown ) . # ::alignments 0-1.1.1 3-1.1.1.1.1.1.1 5-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.1.1 9-1.1.1.1.2.1.1 11-1.1 12-1.1.2 15-1.1.2.1.1.1 17-1.1.1.2.r 18-1.1.1.2.1 19-1.1.1.2 20-1.1.1.2 22-1 25-1.2 26-1.2.2.r 27-1.2.2.1.1 28-1.2.2 30-1.2.2.2.1 30-1.2.2.2.1.r 31-1.2.2.2 (r / resemble-01~e.22 :ARG1 (a / and~e.11 :op1 (e / express-03~e.0 :ARG2 (a3 / and~e.6 :op1 (e2 / enzyme :name (n / name :op1 "H-Ras"~e.3,5)) :op2 (e3 / enzyme :name (n2 / name :op1 "Rlf-CAAX"~e.7,9)) :mod (e4 / exogene)) :ARG3~e.17 (c / cell-line~e.19,20 :mod (t / this~e.18))) :op2 (a2 / activate-01~e.12 :ARG1 (p / protein :name (n3 / name :op1 "RalA"~e.15) :mod (e6 / endogene)) :location c)) :ARG2 (o / observe-01~e.25 :ARG1 (a4 / and :op1 e :op2 a2) :location~e.26 (c2 / cell-line~e.28 :name (n4 / name :op1 "HME16C"~e.27) :ARG1-of (s / show-01~e.31 :polarity~e.30 -~e.30)))) # ::id pmid_1859_7688.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , expression of Rlf @-@ CAAX and subsequent RalA activation did not appear to be sufficient to induce anchorage @-@ independent growth in the HME16C mammary epithelial cell line in contrast to HEK @-@ HT and various other immortalized human cell types [ 27 ] . # ::alignments 0-1 2-1.1.2.1 3-1.1.2.1.1.r 4-1.1.2.1.1.1.1 6-1.1.2.1.1.1.1 7-1.1.2 8-1.1.2.2.2 9-1.1.2.2.1.1.1 10-1.1.2.2 12-1.1.1 12-1.1.1.r 13-1.1 16-1.1.3 18-1.1.3.1 19-1.1.3.1.2.1.2 21-1.1.3.1.2.1 21-1.1.3.1.2.1.1 21-1.1.3.1.2.1.1.r 22-1.1.3.1.2 23-1.1.3.1.3.r 25-1.1.3.1.3.1.1 26-1.1.3.1.3.2.1 27-1.1.3.1.3.2 28-1.1.3.1.3 29-1.1.3.1.3 30-1.1.3.2.r 31-1.1.3.2 32-1.1.3.2.1.r 33-1.1.3.2.1.1.1.1 35-1.1.3.2.1.1.1.1 36-1.1.3.2.1 37-1.1.3.2.1.2.3 38-1.1.3.2.1.2.2 39-1.1.3.2.1.2.1.2 40-1.1.3.2.1.2.1.1 41-1.1.3.2.1.2.1 42-1.1.3.2.1.2 44-1.2.1.1.1 (i / infer-01~e.0 :ARG1 (a / appear-01~e.13 :polarity~e.12 -~e.12 :ARG1 (a2 / and~e.7 :op1 (e / express-03~e.2 :ARG2~e.3 (e2 / enzyme :name (n / name :op1 "Rlf-CAAX"~e.4,6))) :op1 (a3 / activate-01~e.10 :ARG1 (p2 / protein :name (n2 / name :op1 "RalA"~e.9)) :mod (s / subsequent~e.8))) :ARG0-of (s2 / suffice-01~e.16 :ARG1 (i2 / induce-01~e.18 :ARG0 a2 :ARG2 (g / grow-01~e.22 :ARG0-of (d / depend-01~e.21 :polarity~e.21 -~e.21 :ARG1 (a4 / anchorage~e.19))) :location~e.23 (c / cell-line~e.28,29 :name (n3 / name :op1 "HME16C"~e.25) :mod (e4 / epithelium~e.27 :mod (m / mammary~e.26)))) :ARG1-of~e.30 (c2 / contrast-01~e.31 :ARG2~e.32 (a5 / and~e.36 :op1 (c3 / cell-line :name (n4 / name :op1 "HEK-HT"~e.33,35)) :op2 (t / type-03~e.42 :ARG1 (c4 / cell~e.41 :mod (h / human~e.40) :ARG1-of (i3 / immortalize-03~e.39)) :mod (o / other~e.38) :mod (v / various~e.37)))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 27~e.44)))) # ::id pmid_1859_7688.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumorigenesis of HME16C cell lines in nude mice # ::alignments 0-1 0-1.1 0-1.1.r 1-1.2.r 2-1.2.1.1 3-1.2 4-1.2 5-1.3.r 6-1.3.1 7-1.3 (c / create-01~e.0 :ARG1~e.0 (t / tumor~e.0) :mod~e.1 (c2 / cell-line~e.3,4 :name (n / name :op1 "HME16C"~e.2)) :location~e.5 (m / mouse~e.7 :mod (n2 / nude~e.6))) # ::id pmid_1859_7688.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anchorage @-@ independent growth often predicts the ability of cells to grow as xenografted tumors in immuno @-@ compromised mice . # ::alignments 0-1.1.1.2 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 3-1.1 4-1.3 5-1 7-1.2 8-1.2.1.r 9-1.2.1 11-1.2.2 14-1.2.2.2 18-1.2.2.2.2.1.1 19-1.2.2.2.2 (p / predict-01~e.5 :ARG0 (g / grow-01~e.3 :ARG0-of (d / depend-01~e.2 :polarity~e.2 -~e.2 :ARG1 (a / anchorage~e.0))) :ARG1 (c / capable-01~e.7 :ARG1~e.8 (c2 / cell~e.9) :ARG2 (g2 / grow-01~e.11 :ARG1 c2 :manner (t / tumor~e.14 :mod (x / xenograft) :location (m / mouse~e.19 :ARG1-of (i / immune-02 :ARG1-of (c3 / compromise-02~e.18)))))) :frequency (o / often~e.4)) # ::id pmid_1859_7688.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumor formation was assessed following subcutaneous inoculation . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2 5-1.2.1.1 6-1.2.1 (a / assess-01~e.3 :ARG1 (f / form-01~e.1 :ARG1 (t / tumor~e.0)) :ARG1-of (f2 / follow-01~e.4 :ARG2 (i / inoculate-01~e.6 :mod (s / subcutaneous~e.5)))) # ::id pmid_1859_7688.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The RasV12 @-@ infected HME16C cells formed rapidly growing , fluid @-@ filled tumors with an average latency of 4 weeks and a mean tumor volume of 808.8 mm3 at 6 weeks ( Table 1 ) . # ::alignments 3-1.1.2 4-1.1.1.1 5-1.1 6-1 7-1.2.1.1 7-1.2.1.1.r 8-1.2.1 10-1.2.2.1 12-1.2.2 13-1.2 14-1.2.3.r 16-1.2.3.1 17-1.2.3 18-1.2.3.1.1.r 19-1.2.3.1.1.1 20-1.2.3.1.1.2 23-1.2.4.2.1 24-1.2.4.2 25-1.2.4 27-1.2.4.1 28-1.2.4.3 30-1.2.4.4.1.1 31-1.2.4.4.1.2 33-1.3.1 34-1.3.1.1 (f / form-01~e.6 :ARG0 (c / cell-line~e.5 :name (n / name :op1 "HME16C"~e.4) :ARG1-of (i / infect-01~e.3 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12")))) :ARG1 (t / tumor~e.13 :ARG1-of (g / grow-01~e.8 :manner~e.7 (r2 / rapid~e.7)) :ARG1-of (f2 / fill-01~e.12 :ARG2 (f3 / fluid~e.10)) :mod~e.14 (l / latency~e.17 :ARG1-of (a / average-01~e.16 :ARG2~e.18 (t2 / temporal-quantity :quant 4~e.19 :unit (w / week~e.20)))) :mod (v / volume-quantity~e.25 :quant 808.8~e.27 :mod (t3 / tumor~e.24 :mod (m2 / mean~e.23)) :unit (c2 / cubic-millimeter~e.28) :time (a2 / after :op1 (t4 / temporal-quantity :quant 6~e.30 :unit w~e.31)))) :ARG1-of (d / describe-01 :ARG0 (t5 / table~e.33 :mod 1~e.34))) # ::id pmid_1859_7688.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Approximately one @-@ half of the tumors were aspirated prior to sacrifice , and a sero @-@ sanguinous fluid was observed , on average accounting for roughly one @-@ third of the measured tumor volume . # ::alignments 0-1.1.1.1.1 1-1.2.1.2.1.3.1 3-1.1.1.1 4-1.1.1.1.r 6-1.1.1 8-1.1 9-1.1.2 11-1.1.2.1 13-1 15-1.2.1.1 18-1.2.1 20-1.2 23-1.2.1.2.2 24-1.2.1.2 26-1.2.1.2.1.3 27-1.2.1.2.1.3.1 29-1.2.1.2.1.3.1 30-1.2.1.2.1.3.r 32-1.2.1.2.1.2 33-1.2.1.2.1.1 34-1.2.1.2.1 (a / and~e.13 :op1 (a2 / aspirate-101~e.8 :ARG1 (t / tumor~e.6 :quant~e.4 (h / half~e.3 :ARG1-of (a3 / approximate-01~e.0))) :time (p / prior~e.9 :op1 (s / sacrifice-01~e.11))) :op2 (o2 / observe-01~e.20 :ARG1 (f / fluid~e.18 :mod (s2 / sero-sanguine~e.15) :ARG0-of (a4 / account-01~e.24 :ARG1 (v / volume~e.34 :mod (t2 / tumor~e.33) :ARG1-of (m / measure-01~e.32) :quant~e.30 (r2 / roughly~e.26 :op1 "1/3"~e.1,27,29)) :ARG1-of (a5 / average-01~e.23))))) # ::id pmid_1859_7688.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histological analysis of H&E stained tumor sections revealed poorly differentiated spindle @-@ shaped tumor cells with prominent squamous cell differentiation and extracellular keratin deposition ( not shown ) . # ::alignments 0-1.1.2 1-1.1 4-1.1.1.2 5-1.1.1.1 6-1.1.1 7-1 8-1.2.3.1 9-1.2.3 10-1.2.2.1 12-1.2.2 13-1.2.1 14-1.2 16-1.2.4.1.1.2 17-1.2.4.1.1.1.1 18-1.2.4.1.1.1 19-1.2.4.1.1 20-1.2.4.1 21-1.2.4.1.2.2 22-1.2.4.1.2.1 25-1.3.1 25-1.3.1.r 26-1.3 (r / reveal-01~e.7 :ARG0 (a / analyze-01~e.1 :ARG1 (s / section-01~e.6 :ARG1 (t / tumor~e.5) :ARG1-of (s2 / stain-01~e.4 :ARG2 (a2 / and :op1 (s7 / small-molecule :name (n / name :op1 "hematoxylin")) :op2 (s8 / small-molecule :name (n2 / name :op1 "eosin"))))) :mod (h / histology~e.0)) :ARG1 (c / cell~e.14 :mod t~e.13 :ARG1-of (s3 / shape-01~e.12 :ARG2 (s4 / spindle~e.10)) :ARG1-of (d / differentiate-101~e.9 :degree (p / poor~e.8)) :ARG0-of (h2 / have-03 :ARG1 (a3 / and~e.20 :op1 (d2 / differentiate-101~e.19 :ARG1 (c2 / cell~e.18 :mod (s5 / squamous~e.17)) :degree (p2 / prominent~e.16)) :op2 (d3 / deposit-01 :ARG1 (k / keratin~e.22) :mod (e / extracellular~e.21))))) :ARG1-of (s6 / show-01~e.26 :polarity~e.25 -~e.25)) # ::id pmid_1859_7688.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumors also contained a strong inflammatory component . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.2 5-1.2.1 6-1.2 (c / contain-01~e.2 :ARG0 (t / tumor~e.0) :ARG1 (c2 / component~e.6 :ARG0-of (i / inflame-01~e.5) :ARG1-of (s / strong-02~e.4)) :mod (a / also~e.1)) # ::id pmid_1859_7688.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the other cell lines tested , only the RasV12S35 @-@ infected HME16C cells formed palpable tumors in 50 % of injected animals with an average latency of approximately 12 weeks and a mean tumor volume of 109.0 mm3 at 16 weeks , considerably smaller than RasV12 @-@ expressing tumors ( Table 1 ) . # ::alignments 2-1.2.3.1.2 3-1.2.3.1 4-1.2.3.1 5-1.2.3.1.1 7-1.2.4 11-1.2.2 12-1.2.1.1 13-1.2 14-1 15-1.1.1 16-1.1 17-1.3.r 18-1.3.1.2.1 19-1.3.1.2 21-1.3.1.1.1 22-1.3 22-1.3.1.1 25-1.1.2.1.2.2 26-1.1.2.1.1 27-1.1.2.1.1.1.r 28-1.1.2.1.1.1 29-1.1.2.1.1.1.1.1 30-1.1.2.1.1.1.1.2 31-1.1.2.1 34-1.1 35-1.1.2.1.2 37-1.1.2.1.2.2.1 38-1.1.2.1.2.2.2 40-1.1.2.1.2.3.1.1 41-1.1.2.1.2.3.1.2 43-1.1.2.1.2.4.2 44-1.1.2.1.2.4 44-1.1.2.1.2.4.1 44-1.1.2.1.2.4.1.r 45-1.1.2.1.2.4.3.r 48-1.1.2.1.2.4.3.1 49-1.1.2.1.2.4.3 51-1.4.1 52-1.4.1.1 (f / form-01~e.14 :ARG1 (t / tumor~e.16,34 :mod (p / palpable~e.15) :ARG0-of (h / have-03 :ARG1 (a3 / and~e.31 :op1 (l / latency~e.26 :duration~e.27 (a4 / approximately~e.28 :op1 (t3 / temporal-quantity :quant 12~e.29 :unit (w / week~e.30)))) :op2 (v / volume~e.35 :mod t :ARG1-of (a5 / average-01~e.25 :ARG2 109.0~e.37 :ARG3 (c3 / cubic-millimeter~e.38)) :time (a6 / after :quant (t4 / temporal-quantity :quant 16~e.40 :unit w~e.41)) :degree (s / small~e.44 :degree~e.44 (m2 / more~e.44) :mod (c4 / considerable~e.43) :compared-to~e.45 (t5 / tumor~e.49 :ARG3-of (e2 / express-03~e.48 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12"))))))))) :ARG2 (c / cell-line~e.13 :name (n / name :op1 "HME16C"~e.12) :ARG1-of (i / infect-01~e.11 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35"))) :ARG1-of (i2 / include-01 :ARG2 (c2 / cell-line~e.3,4 :ARG1-of (t2 / test-01~e.5) :mod (o / other~e.2))) :mod (o2 / only~e.7)) :location~e.17 (a / animal~e.22 :ARG1-of (i3 / include-91 :ARG2 (a2 / animal~e.22 :ARG2-of (i4 / inject-01~e.21)) :ARG3 (p2 / percentage-entity~e.19 :value 50~e.18))) :ARG1-of (d / describe-01 :ARG0 (t6 / table~e.51 :mod 1~e.52))) # ::id pmid_1859_7688.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells within RasV12S35 @-@ infected tumors resembled the histology of RasV12 tumor cells but with less keratin deposition and without the formation of fluid @-@ filled spaces ( not shown ) . # ::alignments 0-1.1 1-1.3.1.1.2.2.r 4-1.1.1.1 4-1.2.1.1.1 5-1.1.1 5-1.2.1.1 6-1 8-1.2 11-1.1.1 11-1.2.1.1 12-1.1 12-1.2.1 13-1.3 15-1.3.1.1.2.2 16-1.3.1.1.2.1 18-1.3.1 19-1.3.1.2.1 19-1.3.1.2.1.r 21-1.3.1.2 22-1.3.1.2.2.r 23-1.3.1.2.2.1.1 25-1.3.1.2.2.1 26-1.3.1.2.2 28-1.4.1 28-1.4.1.r 29-1.4 (r / resemble-01~e.6 :ARG1 (c / cell~e.0,12 :location (t / tumor~e.5,11 :ARG1-of (i / infect-01~e.4 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35"))))) :ARG2 (h / histology~e.8 :poss (c2 / cell~e.12 :mod (t2 / tumor~e.5,11 :ARG1-of (i2 / infect-01~e.4 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12")))))) :ARG1-of (c3 / contrast-01~e.13 :ARG2 (a / and~e.18 :op1 (h2 / have-03 :ARG0 c :ARG1 (d / deposit-01 :ARG1 (k / keratin~e.16) :quant~e.1 (l / less~e.15))) :op2 (f / form-01~e.21 :polarity~e.19 -~e.19 :ARG1~e.22 (s / space~e.26 :ARG1-of (f2 / fill-01~e.25 :ARG2 (f3 / fluid~e.23))) :ARG2 c))) :ARG1-of (s2 / show-01~e.29 :polarity~e.28 -~e.28)) # ::id pmid_1859_7688.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Empty vector-, RasV12G37-, RasV12C40-, and Rlf @-@ CAAX @-@ infected cells failed to form palpable tumors four months after injection . # ::alignments 0-1.1.1.1.1.1 4-1.1 5-1.1.4.1.1.1.1 7-1.1.4.1.1.1.1 9-1.1.1.1 9-1.1.2.1 9-1.1.3.1 9-1.1.4.1 10-1.1.1 10-1.1.2 10-1.1.3 10-1.1.4 11-1 13-1.2 14-1.2.2.1 15-1.2.2 16-1.3.2.1 17-1.3.2.2 18-1.3 19-1.3.1 (f / fail-01~e.11 :ARG1 (a / and~e.4 :op1 (c / cell~e.10 :ARG1-of (i / infect-01~e.9 :ARG2 (v / vector :ARG2-of (e / empty-01~e.0)))) :op2 (c2 / cell~e.10 :ARG1-of (i2 / infect-01~e.9 :ARG2 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37")))) :op3 (c3 / cell~e.10 :ARG1-of (i3 / infect-01~e.9 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40")))) :op4 (c4 / cell~e.10 :ARG1-of (i4 / infect-01~e.9 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Rlf-CAAX"~e.5,7))))) :ARG2 (f2 / form-01~e.13 :ARG0 c :ARG1 (t / tumor~e.15 :mod (p2 / palpable~e.14))) :time (a2 / after~e.18 :op1 (i5 / inject-01~e.19) :quant (t2 / temporal-quantity :quant 4~e.16 :unit (m3 / month~e.17)))) # ::id pmid_1859_7688.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The metastatic potential of RasV12 @- and RasV12G37 @-@ expressing cell lines was tested by tail @-@ vein injection in nude mice , but no metastatic lesions were observed by histological analysis in lungs , liver , spleen , or kidneys at 16 weeks post injection ( not shown ) . # ::alignments 1-1.1.1.1 2-1.1.1 6-1.1.1.1.1 9-1.1.1.1.1.1.1 9-1.1.1.1.1.2.1 10-1.1.1.1.1.1 10-1.1.1.1.1.2 11-1.1.1.1.1.1 13-1.1 14-1.1.2.r 15-1.1.2.1.1 17-1.1.2.1 18-1.1.2 19-1.1.2.1.1.1.r 20-1.1.2.1.1.1.1 21-1.1.2.1.1.1 23-1 24-1.2.1 24-1.2.1.r 25-1.2.2.1 26-1.2.2 28-1.2 29-1.2.3.r 30-1.2.3.1 31-1.2.3 32-1.2.4.r 33-1.2.4.1 35-1.2.4.2 37-1.2.4.3 39-1.2.4 40-1.2.4.4 41-1.2.5.r 42-1.2.5.2.1 43-1.2.5.2.2 44-1.2.5 45-1.2.5.1 47-1.3.1 47-1.3.1.r 48-1.3 (c / contrast-01~e.23 :ARG1 (t / test-01~e.13 :ARG1 (p / potential~e.2 :mod (m / metastasize-101~e.1 :ARG2 (a / and~e.6 :op1 (c2 / cell-line~e.10,11 :ARG3-of (e / express-03~e.9 :ARG2 (e2 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12")))) :op2 (c3 / cell-line~e.10 :ARG3-of (e3 / express-03~e.9 :ARG2 (e4 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37"))))))) :manner~e.14 (i / inject-01~e.18 :ARG2 (v / vein~e.17 :part-of (t2 / tail~e.15 :part-of~e.19 (m4 / mouse~e.21 :mod (n3 / nude~e.20)))))) :ARG2 (o / observe-01~e.28 :polarity~e.24 -~e.24 :ARG1 (l / lesion~e.26 :mod m~e.25) :manner~e.29 (a2 / analyze-01~e.31 :mod (h / histology~e.30)) :location~e.32 (o2 / or~e.39 :op1 (l2 / lung~e.33) :op2 (l3 / liver~e.35) :op3 (s / spleen~e.37) :op4 (k / kidney~e.40)) :time~e.41 (a3 / after~e.44 :op1 (i2 / inject-01~e.45) :quant (t3 / temporal-quantity :quant 16~e.42 :unit (w / week~e.43)))) :ARG1-of (s2 / show-01~e.48 :polarity~e.47 -~e.47)) # ::id pmid_1859_7688.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Autocrine EGFR signaling is required for RasV12G37 @- and RasV12C40 @-@ mediated , but not RasV12S35 @-@ mediated , HME16C cell anchorage @- independent growth # ::alignments 0-1.2.1 1-1.2.2.1.1 2-1.2 4-1 4-1.3.1 8-1.1.2.1 11-1.1.2 13-1.3 14-1.1.1.1.r 14-1.3.1.1 14-1.3.1.1.r 17-1.1.2 17-1.3.1.2.2 19-1.1.1.2.1.1.1 20-1.1.1.2.1 23-1.1.1 23-1.1.1.1 24-1.1 24-1.3.1.2 (r / require-01~e.4 :ARG0 (g / grow-01~e.24 :ARG0-of (d / depend-01~e.23 :polarity~e.14 -~e.23 :ARG1 (a / anchor-01 :ARG1 (c / cell-line~e.20 :name (n / name :op1 "HME16C"~e.19)))) :ARG1-of (m / mediate-01~e.11,17 :ARG0 (a2 / and~e.8 :op1 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12G37")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12C40"))))) :ARG1 (s / signal-07~e.2 :ARG0 (a3 / autocrine~e.0) :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGFR"~e.1))) :ARG1-of (c2 / contrast-01~e.13 :ARG2 (r2 / require-01~e.4 :polarity~e.14 -~e.14 :ARG0 (g2 / grow-01~e.24 :ARG0-of d :ARG1-of (m4 / mediate-01~e.17 :ARG0 (e3 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12S35")))) :ARG1 s))) # ::id pmid_1859_7688.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGFR signaling is frequently altered in breast cancer , where EGFR and ErbB2 over @-@ expression are common events . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.2 4-1 5-1.3.r 6-1.3.2.1 7-1.3.2.2 9-1.3.3.r 10-1.3.3.2.1.1 11-1.3.3.2.1 12-1.3.3.2.1.2.1.1 16-1.3.3.2.r 17-1.3.3.1 18-1.3.3 (a / alter-01~e.4 :ARG1 (s / signal-07~e.1 :ARG1 (e2 / enzyme :name (n / name :op1 "EGFR"~e.0))) :ARG1-of (f / frequent-02~e.3) :location~e.5 (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast"~e.6 :op2 "cancer"~e.7) :location-of~e.9 (e / event~e.18 :mod (c2 / common~e.17) :domain~e.16 (o / overexpress-01 :ARG1 (a2 / and~e.11 :op1 e2~e.10 :op2 (p / protein :name (n3 / name :op1 "ErbB2"~e.12))))))) # ::id pmid_1859_7688.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok cDNA microarray and real @-@ time RT @-@ PCR analysis of HME16C RasV12 @- and Ras EDM @-@ infected cells ( Additional file 1 ) revealed increased levels of mRNAs for EGFR ligands , including epiregulin , amphiregulin , and TGFa ( Table 2 ) . # ::alignments 0-1.1.1.2.1.1.1 1-1.1.1.2 2-1.1.1.1 3-1.1.2.2.4 5-1.1.2.2.4 8-1.1.2.2 8-1.1.2.2.1 8-1.1.2.2.1.r 9-1.1.1 9-1.1.2 10-1.1.1.1.r 11-1.1.1.1.1.1.1 11-1.1.1.1.2.1.1 14-1.1.1.1 15-1.1.1.1.1.2.1.1.1 15-1.1.1.1.2.2.1.1.1 16-1.1.1.1.2.2.1.1.2 18-1.1.1.1.1.2 18-1.1.1.1.2.2 19-1.1.1.1.1 19-1.1.1.1.2 22-1.1.3.1 23-1.1.3.1.1 25-1 26-1.2.2 27-1.2 28-1.2.1.r 29-1.2.1.1.1 30-1.3.r 31-1.3.1.1 32-1.3 32-1.3.2.1.1 32-1.3.2.1.2 32-1.3.2.1.3 34-1.3.2 35-1.3.2.1.1.1.1 37-1.3.2.1.2.1.1 39-1.3.2.1 40-1.3.2.1.3.1.1 42-1.4.1 43-1.4.1.1 (r / reveal-01~e.25 :ARG0 (a / and :op1 (a2 / analyze-01~e.9 :ARG1~e.10 (a3 / and~e.2,14 :op1 (c / cell-line~e.19 :name (n / name :op1 "HME16C"~e.11) :ARG1-of (i / infect-01~e.18 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras"~e.15) :ARG2-of (m / mutate-01 :value "V12")))) :op2 (c2 / cell-line~e.19 :name (n3 / name :op1 "HME16C"~e.11) :ARG1-of (i2 / infect-01~e.18 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.15 :op2 "EDM"~e.16))))) :instrument (m2 / microarray~e.1 :consist-of (n5 / nucleic-acid :name (n13 / name :op1 "cDNA"~e.0)))) :op2 (a4 / analyze-01~e.9 :ARG1 a3 :mod (r3 / react-01~e.8 :ARG0~e.8 (p / polymerase~e.8) :mod (c3 / chain) :subevent (t / transcribe-01 :ARG1-of (r4 / reverse-01)) :mod (r2 / real-time~e.3,5))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.22 :mod 1~e.23 :ARG1-of (a5 / add-02)))) :ARG1 (l / level~e.27 :quant-of~e.28 (n12 / nucleic-acid :name (n7 / name :op1 "mRNA"~e.29)) :ARG1-of (i3 / increase-01~e.26)) :location~e.30 (l2 / ligand~e.32 :name (n8 / name :op1 "EGFR"~e.31) :ARG2-of (i4 / include-91~e.34 :ARG1 (a6 / and~e.39 :op1 (l3 / ligand~e.32 :name (n9 / name :op1 "epiregulin"~e.35)) :op2 (l4 / ligand~e.32 :name (n10 / name :op1 "amphiregulin"~e.37)) :op3 (l5 / ligand~e.32 :name (n11 / name :op1 "TGFa"~e.40))))) :ARG1-of (d2 / describe-01 :ARG0 (t3 / table~e.42 :mod 2~e.43))) # ::id pmid_1859_7688.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , increased levels of phospho @-@ Erk were unexpectedly seen in RasV12G37 @- and RasV12C40 @-@ infected cells , possibly the result of autocrine activation of endogenous EGFR by secreted EGFR ligands . # ::alignments 0-1.1.3 1-1.1.3 3-1.1.1.2 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.2 8-1.1.1.1.1.1 10-1.1.2.1 11-1.1 15-1.1.3 18-1.1.3.1.1 18-1.1.3.2.1 19-1.1.3.1 19-1.1.3.2 21-1.1.4.2 23-1.1.4 24-1.1.4.1.r 25-1.1.4.1.3 26-1.1.4.1 27-1.1.4.1.2.r 28-1.1.4.1.2.2 29-1.1.4.1.1.1.1 29-1.1.4.1.2.1.1 30-1.1.4.1.1.r 31-1.1.4.1.1.2 32-1.1.4.1.1.1.1 33-1.1.4.1.1 (a / and :op2 (s / see-01~e.11 :ARG1 (l / level~e.4 :quant-of~e.5 (e4 / enzyme :name (n / name :op1 "Erk"~e.8) :ARG3-of (p / phosphorylate-01~e.6)) :ARG1-of (i / increase-01~e.3)) :ARG1-of (e2 / expect-01 :polarity -~e.10) :location (a2 / and~e.0,1,15 :op1 (c / cell~e.19 :ARG1-of (i2 / infect-01~e.18 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37")))) :op2 (c2 / cell~e.19 :ARG1-of (i3 / infect-01~e.18 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40"))))) :ARG2-of (r / result-01~e.23 :ARG1~e.24 (a3 / activate-01~e.26 :ARG0~e.30 (l2 / ligand~e.33 :name (n4 / name :op1 "EGFR"~e.29,32) :ARG1-of (s2 / secrete-01~e.31)) :ARG1~e.27 (e5 / enzyme :name (n5 / name :op1 "EGFR"~e.29) :mod (e6 / endogenous~e.28)) :mod (a4 / autocrine~e.25)) :ARG1-of (p2 / possible-01~e.21)))) # ::id pmid_1859_7688.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The presence of EGFR was established using Western blots ( not shown ) . # ::alignments 3-1.1.1.1.1 4-1.1 5-1 6-1.2 7-1.2.1 8-1.2.1 10-1.3.1 10-1.3.1.r 11-1.3 (e / establish-01~e.5 :ARG1 (b / be-located-at-91~e.4 :ARG1 (e2 / enzyme :name (n / name :op1 "EGFR"~e.3))) :ARG2-of (u / use-01~e.6 :ARG1 (i / immunoblot-01~e.7,8)) :ARG1-of (s / show-01~e.11 :polarity~e.10 -~e.10)) # ::id pmid_1859_7688.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we sought to determine if autocrine signaling by the EGFR was required for the anchorage @-@ independent growth of Ras @- or Ras EDM @-@ infected cells . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2 7-1.1.2.2.3.2 8-1.1.2.2.3 9-1.1.2.2.3.1.r 11-1.1.2.2.3.1.1.1 13-1.1.2.2 18-1.1.2.2.2.2 18-1.1.2.2.2.2.1 18-1.1.2.2.2.2.1.r 19-1.1.2.2.2 20-1.1.2.2.2.1.r 21-1.1.2.2.2.1.1.1.1.1.1 23-1.1.2.2.2.1 24-1.1.2.2.2.1.1.1.1.1.1 24-1.1.2.2.2.1.2.1.1.1.1 25-1.1.2.2.2.1.2.1.1.1.2 27-1.1.2.2.2.1.1.1 27-1.1.2.2.2.1.2.1 28-1.1.2.2.2.1.1 28-1.1.2.2.2.1.2 (c / cause-01~e.0 :ARG1 (s / seek-01~e.3 :ARG0 (w / we~e.2) :ARG1 (d / determine-01~e.5 :ARG0 w :ARG1 (r / require-01~e.13 :mode interrogative :ARG0 (g / grow-01~e.19 :ARG1~e.20 (o / or~e.23 :op1 (c2 / cell~e.28 :ARG1-of (i / infect-01~e.27 :ARG2 (e / enzyme :name (n / name :op1 "Ras"~e.21,24)))) :op2 (c3 / cell~e.28 :ARG1-of (i2 / infect-01~e.27 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.24 :op2 "EDM"~e.25))))) :ARG0-of (d2 / depend-01~e.18 :polarity~e.18 -~e.18 :ARG1 (a / anchor-01))) :ARG1 (s2 / signal-07~e.8 :ARG0~e.9 (e3 / enzyme :name (n3 / name :op1 "EGFR"~e.11)) :mod (a2 / autocrine~e.7)))))) # ::id pmid_1859_7688.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RasV12 @- and Ras EDM @-@ infected HME16C cells were grown in soft agar in the presence or absence of the EGFR @-@ specific inhibitors , PD153035 and PD168393 . # ::alignments 2-1.1 3-1.1.1.2.1.1.1 3-1.1.2.2.1.1.1 4-1.1.2.2.1.1.2 6-1.1.1.2 6-1.1.2.2 7-1.1.1.1.1 7-1.1.2.1.1 8-1.1.1 8-1.1.2 10-1 11-1.2.r 12-1.2.1 13-1.2 17-1.3 18-1.3.2 21-1.3.1.1.4.1.1.1 23-1.3.1.1.4 24-1.3.1.1.3 26-1.3.1.1.1.1.1 27-1.3.1.1 28-1.3.1.1.2.1.1 (g / grow-01~e.10 :ARG1 (a / and~e.2 :op1 (c / cell-line~e.8 :name (n / name :op1 "HME16C"~e.7) :ARG1-of (i / infect-01~e.6 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras"~e.3) :ARG2-of (m / mutate-01 :value "V12")))) :op2 (c2 / cell-line~e.8 :name (n3 / name :op1 "HME16C"~e.7) :ARG1-of (i2 / infect-01~e.6 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.3 :op2 "EDM"~e.4))))) :location~e.11 (a2 / agar~e.13 :ARG1-of (s / soft-02~e.12)) :manner (o / or~e.17 :op1 (b / be-located-at-91 :ARG1 (a3 / and~e.27 :op1 (s2 / small-molecule :name (n5 / name :op1 "PD153035"~e.26)) :op2 (s3 / small-molecule :name (n6 / name :op1 "PD168393"~e.28)) :ARG0-of (i3 / inhibit-01~e.24) :ARG1-of (s4 / specific-02~e.23 :ARG2 (e3 / enzyme :name (n7 / name :op1 "EGFR"~e.21))))) :op2 (a4 / absent-01~e.18 :ARG1 a3))) # ::id pmid_1859_7688.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Complete inhibition of colony formation for RasV12G37 @-@ infected and RasV12C40 @-@ infected cells was observed at 0.25 μM PD153035 , a concentration that specifically inhibits EGFR [ 28 ] , whereas both the RasV12 @- and RasV12S35 @-@ infected cells formed colonies efficiently at this same concentration of inhibitor ( Figure 3A and 3B ) . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2 4-1.1.1.1 8-1.1.1.1.1.1.1 9-1.1.1.1.1 12-1.1.1.1.1.1.1 12-1.1.1.1.1.2.1 13-1.1.1.1.1.1 13-1.1.1.1.1.2 15-1.1 16-1.1.2.r 17-1.1.2.2.1 18-1.1.2.2.2 19-1.1.2.1.1 22-1.1.2.2 24-1.1.2.2.3.2 25-1.1.2.2.3 26-1.1.2.2.3.1.1.1 28-1.1.3.1.1.1 31-1 36-1.2.1 39-1.2.1.1.1 39-1.2.1.2.1 40-1.2.1.1 40-1.2.1.2 41-1.2 42-1.2.2 43-1.2.3 47-1.2.4 48-1.2.4 49-1.2.4 51-1.3.1.1 51-1.3.1.2 52-1.3.1.1.1 53-1.3.1 54-1.3.1.2.1 (c / contrast-01~e.31 :ARG1 (o / observe-01~e.15 :ARG1 (i / inhibit-01~e.1 :ARG1~e.2 (f / form-01~e.4 :ARG0 (a / and~e.9 :op1 (c2 / cell~e.13 :ARG1-of (i2 / infect-01~e.8,12 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37")))) :op2 (c3 / cell~e.13 :ARG1-of (i3 / infect-01~e.12 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40"))))) :ARG1 (c4 / colony~e.3)) :degree (c5 / complete-01~e.0)) :manner~e.16 (s / small-molecule :name (n3 / name :op1 "PD153035"~e.19) :quant (c6 / concentration-quantity~e.22 :quant 0.25~e.17 :unit (m3 / micromolar~e.18) :ARG0-of (i4 / inhibit-01~e.25 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR"~e.26)) :ARG1-of (s2 / specific-02~e.24)))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c7 / cite-01 :ARG2 28~e.28)))) :ARG2 (f2 / form-01~e.41 :ARG0 (a2 / and~e.36 :op1 (c8 / cell~e.40 :ARG1-of (i5 / infect-01~e.39 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12")))) :op2 (c9 / cell~e.40 :ARG1-of (i6 / infect-01~e.39 :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12S35"))))) :ARG1 c4~e.42 :ARG2-of (e6 / efficient-01~e.43) :manner s~e.47,48,49) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.53 :op1 (f3 / figure~e.51 :mod "3A"~e.52) :op2 (f4 / figure~e.51 :mod "3B"~e.54)))) # ::id pmid_1859_7688.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Identical results were found for the EGFR @-@ specific inhibitor PD168393 used at 0.1 μM , a concentration that specifically inhibits EGFR and Her @-@ 2 receptors [ 29]( not shown ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.2.r 6-1.2.3.1.1.1 8-1.2.3 9-1.2 9-1.2.2 9-1.2.2.r 10-1.2.1.1 11-1.2.4 12-1.2.4.1.r 13-1.2.4.1.1 14-1.2.4.1.2 17-1.2.4.1 19-1.2.4.1.3.2 20-1.2.4.1.3 21-1.2.4.1.3.1.1.1.1 22-1.2.4.1.3.1 23-1.2.4.1.3.1.2.1.1 25-1.2.4.1.3.1.2.1.1 26-1.2.4.1.3.1.2 29-1.4.1 29-1.4.1.r 30-1.4 (f / find-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :ARG2-of (i / identical-01~e.0)) :ARG2~e.4 (s / small-molecule~e.9 :name (n / name :op1 "PD168393"~e.10) :ARG0-of~e.9 (i2 / inhibit-01~e.9) :ARG1-of (s2 / specific-02~e.8 :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR"~e.6))) :ARG1-of (u / use-01~e.11 :manner~e.12 (c / concentration-quantity~e.17 :quant 0.1~e.13 :unit (m / micromolar~e.14) :ARG0-of (i3 / inhibit-01~e.20 :ARG1 (a / and~e.22 :op1 (e2 / enzyme :name (n3 / name :op1 "EGFR"~e.21)) :op2 (r3 / receptor~e.26 :name (n4 / name :op1 "Her-2"~e.23,25))) :ARG1-of (s3 / specific-02~e.19))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 29))) :ARG1-of (s4 / show-01~e.30 :polarity~e.29 -~e.29)) # ::id pmid_1859_7688.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , treatment of cells grown in ultra @-@ low @-@ attachment plates also demonstrated that EGFR inhibition substantially inhibited growth of RasV12G37 @-@ and RasV12C40 @-@ expressing cells relative to that of RasV12 @- and RasV12S35 @-@ expressing HME16C ( Figure 2C ) . # ::alignments 0-1.4 2-1.1 3-1.1.1.r 4-1.1.1 5-1.1.1.1 5-1.2.4.1 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1.1 9-1.1.1.1.1.1.1 11-1.1.1.1.1.1 12-1.1.1.1.1 13-1.3 14-1 15-1.2.r 16-1.2.1.1.1.1 17-1.2 17-1.2.1 17-1.2.1.r 18-1.2.3 19-1.2 19-1.2.1 19-1.2.1.r 20-1.2.2 24-1.2.2.1.1.1 27-1.2.2.1.1 27-1.2.4.1.1.2 28-1.2.2.1 29-1.2.4 35-1.2.2.1.1.1 38-1.2.2.1.1 39-1.2.4.1.1.1.1 41-1.5.1 42-1.5.1.1 (d / demonstrate-01~e.14 :ARG0 (t / treat-04~e.2 :ARG1~e.3 (c / cell~e.4 :ARG1-of (g / grow-01~e.5 :location~e.6 (p / plate~e.12 :ARG2-of (a / attach-01~e.11 :ARG1-of (l / low-04~e.9 :degree (u / ultra~e.7))))))) :ARG1~e.15 (i / inhibit-01~e.17,19 :ARG0~e.17,19 (i2 / inhibit-01~e.17,19 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.16))) :ARG1 (g2 / grow-01~e.20 :ARG1 (c2 / cell~e.28 :ARG3-of (e2 / express-03~e.27,38 :ARG2 (a2 / and~e.24,35 :op1 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37")) :op2 (e4 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40")))))) :degree (s / substantial~e.18) :ARG1-of (r / relative-05~e.29 :ARG3 (g3 / grow-01~e.5 :ARG1 (c3 / cell-line :name (n4 / name :op1 "HME16C"~e.39) :ARG3-of (e5 / express-03~e.27 :ARG2 (a3 / and :op1 (e6 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12")) :op2 (e7 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35")))))))) :mod (a4 / also~e.13) :ARG1-of (r2 / resemble-01~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.41 :mod "2C"~e.42))) # ::id pmid_1859_7688.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blotting of cellular lysates from cells treated with 0.25 μM PD153035 showed that high levels of phosphorylated Erk were maintained only in RasV12 @- and RasV12S35 @-@ infected cells , but were significantly reduced in RasV12G37 @- or RasV12C40 @-@ infected cells treated with the inhibitor ( Figure 3C ) , while phoshorylated Akt was minimally affected ( not shown ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1 3-1.1.1.1.2 4-1.1.1.1 5-1.1.1.1.2.r 6-1.1.1.1.2 7-1.1.1.1.2.1 8-1.1.1.1.2.1.1.r 9-1.1.1.1.2.1.1.2.1 10-1.1.1.1.2.1.1.2.2 11-1.1.1.1.2.1.1.1.1 12-1.1 14-1.1.2.1.1.2 15-1.1.2.1.1 16-1.1.2.1.1.1.r 17-1.1.2.1.1.1.2 18-1.1.2.1.1.1.1.1 20-1.1.2.1 21-1.1.2.1.2.3 25-1.1.2.1.2 28-1.1.2.1.2.1.1 28-1.1.2.1.2.2.1 29-1.1.2.1.2.1 29-1.1.2.1.2.2 31-1.1.2 33-1.1.2.2.2 34-1.1.2.2 38-1.1.2.2.3 41-1.1.2.2.3.1.1 41-1.1.2.2.3.2.1 42-1.1.2.2.3.1 42-1.1.2.2.3.2 43-1.1.2.2.3.3 44-1.1.2.2.3.3.1.r 46-1.1.2.2.3.3.1 48-1.1.3.1 49-1.1.3.1.1 52-1 54-1.2.1.1.1 56-1.2.2 57-1.2 59-1.2.3.1 59-1.2.3.1.r 60-1.1 60-1.2.3 (c / contrast-01~e.52 :ARG1 (s / show-01~e.12,60 :ARG0 (i6 / immunoblot-01~e.0,1 :ARG1~e.2 (l / lysate~e.4 :mod (c2 / cell~e.3) :source~e.5 (c3 / cell~e.3,6 :ARG1-of (t / treat-04~e.7 :ARG2~e.8 (s2 / small-molecule :name (n / name :op1 "PD153035"~e.11) :quant (c4 / concentration-quantity :quant 0.25~e.9 :unit (m / micromolar~e.10)) :ARG0-of (i / inhibit-01)))))) :ARG1 (c5 / contrast-01~e.31 :ARG1 (m2 / maintain-01~e.20 :ARG1 (l2 / level~e.15 :quant-of~e.16 (e / enzyme :name (n3 / name :op1 "Erk"~e.18) :ARG3-of (p / phosphorylate-01~e.17)) :ARG1-of (h / high-02~e.14)) :location (a2 / and~e.25 :op1 (c6 / cell~e.29 :ARG1-of (i2 / infect-01~e.28 :ARG2 (e5 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12")))) :op2 (c7 / cell~e.29 :ARG1-of (i3 / infect-01~e.28 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35")))) :mod (o / only~e.21))) :ARG2 (r / reduce-01~e.34 :ARG1 l2 :ARG2 (s3 / significant-02~e.33) :location (o2 / or~e.38 :op1 (c8 / cell~e.42 :ARG1-of (i4 / infect-01~e.41 :ARG2 (e2 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12G37")))) :op2 (c9 / cell~e.42 :ARG1-of (i5 / infect-01~e.41 :ARG2 (e3 / enzyme :name (n7 / name :op1 "Ras") :ARG2-of (m6 / mutate-01 :value "V12C40")))) :ARG1-of (t3 / treat-04~e.43 :ARG2~e.44 s2~e.46)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.48 :mod "3C"~e.49))) :ARG2 (a3 / affect-01~e.57 :ARG1 (e6 / enzyme :name (n8 / name :op1 "Akt"~e.54) :ARG3-of p) :ARG1-of (m7 / minimal-02~e.56) :ARG1-of (s4 / show-01~e.60 :polarity~e.59 -~e.59))) # ::id pmid_1859_7688.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anchorage @-@ independent growth therefore correlated with maintenance of high Erk activity in HME16C cells . # ::alignments 2-1.1.1.1 2-1.1.1.1.1 2-1.1.1.1.1.r 3-1.1.1 4-1 5-1.1 6-1.1.2.r 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.2 10-1.1.2.1.1.1.1 11-1.1.2.1 12-1.1.2.2.r 13-1.1.2.2.1.1 14-1.1.2.2 (c / cause-01~e.4 :ARG1 (c2 / correlate-01~e.5 :ARG1 (g / grow-01~e.3 :ARG0-of (d / depend-01~e.2 :polarity~e.2 -~e.2 :ARG1 (a / anchor-01))) :ARG2~e.6 (m / maintain-01~e.7 :ARG1~e.8 (a2 / activity-06~e.11 :ARG0 (e / enzyme :name (n / name :op1 "Erk"~e.10)) :ARG1-of (h / high-02~e.9)) :location~e.12 (c3 / cell-line~e.14 :name (n2 / name :op1 "HME16C"~e.13))))) # ::id pmid_1859_7688.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with this observation , inhibition of MEK , and therefore ERK signaling , using the MEK @-@ specific inhibitor PD98059 at 10 μM , significantly inhibited soft agar colony formation by all cell lines ( not shown ) . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.1 3-1.4.1 5-1.1.1 5-1.1.2 6-1.1.2.2.r 7-1.1.2.2.1 9-1.1 10-1.1.2.2 11-1.1.2.1.1.1.1 12-1.1.1.1 12-1.1.2.1 14-1.1.3 16-1.1.3.1.3.1 18-1.1.3.1 18-1.1.3.1.3 18-1.1.3.1.3.r 19-1.1.3.1.2 20-1.1.3.1.1.1 21-1.1.3.1.4.r 22-1.1.3.1.4.1 23-1.1.3.1.4.2 25-1.3 26-1 26-1.1.3.1.2 27-1.2.1.1.1 28-1.2.1.1 29-1.2.1 30-1.2 31-1.2.2.r 32-1.2.2.1 33-1.2.2 34-1.2.2 36-1.5.1 36-1.5.1.r 37-1.5 (i / inhibit-01~e.26 :ARG0 (a / and~e.9 :op1 (i2 / inhibit-01~e.5 :ARG1 (s / signal-07~e.12 :ARG0 (e / enzyme :name (n / name :op1 "MEK")))) :op2 (i3 / inhibit-01~e.5 :ARG1 (s2 / signal-07~e.12 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Erk"~e.11))) :ARG1-of~e.6 (c / cause-01~e.10 :ARG0 i2~e.7)) :ARG2-of (u / use-01~e.14 :ARG1 (s3 / small-molecule~e.18 :name (n3 / name :op1 "PD98059"~e.20) :ARG0-of (i4 / inhibit-01~e.19,26 :ARG1 e) :ARG1-of~e.18 (s4 / specific-02~e.18 :ARG2 e~e.16) :quant~e.21 (c2 / concentration-quantity :quant 10~e.22 :unit (m / micromolar~e.23))))) :ARG1 (f / form-01~e.30 :ARG1 (c3 / colony~e.29 :mod (a2 / agar~e.28 :ARG1-of (s5 / soft-02~e.27))) :ARG2~e.31 (c4 / cell-line~e.33,34 :mod (a3 / all~e.32))) :ARG1-of (s6 / significant-02~e.25) :ARG1-of (c5 / consistent-01~e.0 :ARG2~e.1 (o / observe-01~e.3 :mod (t / this~e.2))) :ARG1-of (s7 / show-01~e.37 :polarity~e.36 -~e.36)) # ::id pmid_1859_7688.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Microarray analysis of gene expression changes in RasV12-, RasV12G37-, RasV12S35-, and RasV12C40 @-@ infected HME16C cells # ::alignments 0-1.2 1-1 2-1.1.r 3-1.1.1.1 4-1.1.1 5-1.1 10-1.3 13-1.3.1.3 13-1.3.2.3 13-1.3.3.3 13-1.3.4.3 14-1.3.1.2.1 14-1.3.2.2.1 14-1.3.3.2.1 14-1.3.4.2.1 15-1.3.1 15-1.3.2 15-1.3.3 15-1.3.4 (a / analyze-01~e.1 :ARG1~e.2 (c / change-01~e.5 :ARG1 (e / express-03~e.4 :ARG1 (g / gene~e.3))) :mod (m / microarray~e.0) :location (a2 / and~e.10 :op1 (c2 / cell-line~e.15 :wiki - :name (n / name :op1 "HME16C"~e.14) :ARG1-of (i / infect-01~e.13 :ARG2 (e2 / enzyme :wiki "Ras_subfamily" :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12")))) :op2 (c3 / cell-line~e.15 :wiki - :name (n3 / name :op1 "HME16C"~e.14) :ARG1-of (i2 / infect-01~e.13 :ARG2 (e3 / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37")))) :op3 (c4 / cell-line~e.15 :wiki - :name (n5 / name :op1 "HME16C"~e.14) :ARG1-of (i3 / infect-01~e.13 :ARG2 (e4 / enzyme :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35")))) :op4 (c5 / cell-line~e.15 :wiki - :name (n7 / name :op1 "HME16C"~e.14) :ARG1-of (i4 / infect-01~e.13 :ARG2 (e5 / enzyme :wiki "Ras_subfamily" :name (n8 / name :op1 "Ras") :ARG2-of (m5 / mutate-01 :value "V12C40")))))) # ::id pmid_1859_7688.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of the Ras oncogene is accompanied by the stimulation of multiple signal transduction pathways leading to the activation or repression of numerous transcription factors as well as changes in mRNA translation and stability , and thus , the modulation of gene expression . # ::alignments 0-1.2 3-1.2.1.1.1 6-1 7-1.1.r 9-1.1 10-1.1.1.r 11-1.1.1.2 12-1.1.1.1.1 13-1.1.1.1 14-1.1.1 15-1.3 16-1.3.1.r 18-1.3.1.1.1.1 19-1.3.1.1.1 20-1.3.1.1.1.2 21-1.3.1.1.1.1.1.r 22-1.3.1.1.1.1.1.2 23-1.3.1.1.1.1.1.1 24-1.3.1.1.1.1.1 25-1.3.1.1 26-1.3.1.1 27-1.3.1.1.2.1 28-1.3.1.1.2 29-1.3.1.1.2.1.r 30-1.3.1.1.2.1.1.1.1.1 31-1.3.1.1.2.1.1 32-1.3.1.1.2.1 33-1.3.1.1.2.1.2 35-1.3.1 35-1.3.1.1 35-1.3.1.1.r 36-1.2.1 36-1.2.1.2 36-1.2.1.2.r 36-1.3.1.2 39-1.3.1.2.2 40-1.3.1.2.2.1.r 41-1.3.1.2.2.1.1 42-1.3.1.2.2.1 (a / accompany-01~e.6 :ARG0~e.7 (s / stimulate-01~e.9 :ARG1~e.10 (p / pathway~e.14 :ARG2-of (t / transduce-01~e.13 :ARG1 (s2 / signal-07~e.12)) :quant (m / multiple~e.11))) :ARG1 (a2 / activate-01~e.0 :ARG1 (e2 / enzyme~e.36 :name (n / name :op1 "Ras"~e.3) :ARG0-of~e.36 (c3 / cause-01~e.36 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))) :ARG0-of (l / lead-03~e.15 :ARG2~e.16 (a3 / and~e.35 :op1~e.35 (a4 / and~e.25,26,35 :op1 (o2 / or~e.19 :op1 (a5 / activate-01~e.18 :ARG1~e.21 (f / factor~e.24 :ARG0-of (t2 / transcribe-01~e.23) :quant (n2 / numerous~e.22))) :op2 (r / repress-01~e.20 :ARG1 f)) :op2 (c / change-01~e.28 :ARG1~e.29 (a6 / and~e.27,32 :op1 (t3 / translate-02~e.31 :ARG1 (n4 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.30))) :op2 (s3 / stable-03~e.33 :ARG1 n4)))) :op2 (c2 / cause-01~e.36 :ARG0 a4 :ARG1 (m2 / modulate-01~e.39 :ARG1~e.40 (e / express-03~e.42 :ARG1 (g / gene~e.41))))))) # ::id pmid_1859_7688.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine which gene expression changes accompany the transformation of HME16C human epithelial cells by activated Ras , we examined our transformed HME16C cells by cDNA microarray analysis . # ::alignments 1-1.3 3-1.3.2.1.1.1 4-1.3.2.1.1 5-1.3.2.1 6-1.3.2 8-1.3.2.2 9-1.3.2.2.2.r 10-1.3.2.2.2.1.1 11-1.3.2.2.2.2.1 12-1.3.2.2.2.2 13-1.3.2.2.2 14-1.3.2.2.1.r 15-1.3.2.2.1.2 16-1.3.2.2.1.1.1 18-1.3.1 19-1 20-1.2.4 20-1.2.4.r 21-1.2.2 22-1.2.1.1 23-1.2 24-1.2.3.r 25-1.2.3.1.1.1.1 26-1.2.3.1 27-1.2.3 (e / examine-01~e.19 :ARG0 (w / we) :ARG1 (c / cell-line~e.23 :name (n / name :op1 "HME16C"~e.22) :ARG1-of (t / transform-01~e.21) :ARG1-of~e.24 (a / analyze-01~e.27 :instrument (m / microarray~e.26 :consist-of (n2 / nucleic-acid :name (n5 / name :op1 "cDNA"~e.25)))) :poss~e.20 w~e.20) :purpose (d / determine-01~e.1 :ARG0 w~e.18 :ARG1 (a2 / accompany-01~e.6 :ARG0 (c2 / change-01~e.5 :ARG1 (e2 / express-03~e.4 :ARG1 (g / gene~e.3))) :ARG1 (t3 / transform-01~e.8 :ARG0~e.14 (e3 / enzyme :name (n3 / name :op1 "Ras"~e.16) :ARG1-of (a3 / activate-01~e.15)) :ARG1~e.9 (c3 / cell-line~e.13 :name (n4 / name :op1 "HME16C"~e.10) :mod (e4 / epithelium~e.12 :part-of (h / human~e.11))))))) # ::id pmid_1859_7688.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To do this , RNA was isolated from H @-@ RasV12 and H @-@ RasV12 EDM expressing cells after treatment with doxycycline to fully induce gene expression and compared to RNA from identically treated pLRT vector @-@ infected control cells . # ::alignments 1-1.3 2-1.3.1 4-1.2.1 5-1.2.1 6-1.2.1 7-1.2.1 8-1.2.1 9-1.2.1 10-1.2.1 11-1.2.1 12-1.2.1 13-1.2.1 14-1.2.1 15-1.2.1 16-1.2.1 17-1.2.1 18-1.2.1 19-1.2.1 20-1.2.1 21-1.2.1 22-1.2.1 23-1.2.1 24-1.2.1 25-1.2.1 26-1.2.1 27-1 28-1.2 30-1.2.2.1 32-1.2.2.2.3.2 33-1.2.2.2.3 35-1.2.2.2.2.1 37-1.2.2.2.2 38-1.2.2.2.1 39-1.2.2.2 (a / and~e.27 :op1 (i / isolate-01 :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "RNA")) :ARG2 (a2 / and :op1 (c / cell :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "H-Ras") :ARG2-of (m / mutate-01 :value "V12")))) :op2 (c2 / cell :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n2 / name :op1 "H-Ras" :op2 "EDM") :ARG2-of m)))) :time (a3 / after :op1 (t / treat-04 :ARG1 a2 :ARG2 (d / doxycycline))) :purpose (i2 / induce-01 :ARG0 n4 :ARG2 (e5 / express-03 :ARG1 (g / gene)) :degree (f / full))) :op2 (c3 / compare-01~e.28 :ARG1 i~e.4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26 :ARG2 (i3 / isolate-01 :ARG1 n4~e.30 :ARG2 (c4 / cell~e.39 :ARG2-of (c5 / control-01~e.38) :ARG1-of (i4 / infect-01~e.37 :ARG2 (v / vector~e.35 :name (n3 / name :op1 "LRT") :ARG3-of (p / phosphorylate-01))) :ARG1-of (t2 / treat-04~e.33 :ARG2 d :ARG2-of (i5 / identical-01~e.32))))) :purpose (d2 / do-02~e.1 :ARG1 (t3 / this~e.2))) # ::id pmid_1859_7688.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Statistical analysis of microarray ( SAM ) data analysis was performed for the datasets , and a delta value of 0.4 was chosen for each dataset , which maintains the estimated false discovery rate ( FDR ) below 1 % for each . # ::alignments 0-1.1.1.3 1-1.1.1 3-1.1.1.1.1 7-1.1.1.1 8-1.1.1 10-1.1 15-1 17-1.2.1.2 18-1.2.1 20-1.2.1.1 22-1.2 23-1.2.2.r 24-1.2.2.1 25-1.1.1.2 25-1.2.2 28-1.2.3 30-1.2.3.1.3 31-1.2.3.1.2 32-1.2.3.1.1 33-1.2.3.1 37-1.2.3.2 38-1.2.3.2.1.1 39-1.2.3.2.1 41-1.2.2.1 (a / and~e.15 :op1 (p / perform-01~e.10 :ARG1 (a2 / analyze-01~e.1,8 :ARG1 (d5 / data~e.7 :topic (m2 / microarray~e.3)) :purpose (d / dataset~e.25) :mod (s / statistics~e.0))) :op2 (c / choose-01~e.22 :ARG1 (v / value~e.18 :quant 0.4~e.20 :mod (d2 / delta~e.17)) :ARG3~e.23 (d3 / dataset~e.25 :mod (e / each~e.24,41)) :ARG0-of (m / maintain-01~e.28 :ARG1 (r / rate~e.33 :mod (d4 / discover-01~e.32) :mod (f / false~e.31) :ARG1-of (e2 / estimate-01~e.30)) :ARG2 (b / below~e.37 :quant (p2 / percentage-entity~e.39 :value 1~e.38))) :beneficiary d3)) # ::id pmid_1859_7688.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A summary of the genes up @- or down @-@ regulated greater than 2 @-@ fold in the H @-@ RasV12 @- and Ras effector domain mutant @-@ infected HME16C cell lines is presented in Additional file 1 , organized according to broad categories of gene function . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.1 4-1.1.1.2 7-1.1.1 12-1.1.1.3 13-1.1.1.3.1.1 15-1.1.1.3.1 16-1.1.1.4.r 18-1.1.1.4.1.2.1.1.1 22-1.1.1.4 23-1.1.1.4.2.2.1.1.1.1.1 24-1.1.1.4.2.2.1.1 25-1.1.1.4.2.2.1 26-1.1.1.4.1.2.1 26-1.1.1.4.1.2.1.2 26-1.1.1.4.1.2.1.2.r 26-1.1.1.4.2.2.1.2 28-1.1.1.4.1.2 28-1.1.1.4.2.2 29-1.1.1.4.1.1.1 29-1.1.1.4.2.1.1 30-1.1.1.4.1 30-1.1.1.4.2 31-1.1.1.4.1 33-1 36-1.2 37-1.2.1 39-1.1.2 42-1.1.2.1.1.2 45-1.1.2.1.1.1.1 46-1.1.2.1.1.1 (p / present-01~e.33 :ARG1 (s / summarize-01~e.1 :ARG1~e.2 (o / or~e.7 :op1 (g / gene~e.4 :ARG1-of (u / upregulate-01)) :op2 (g2 / gene~e.4 :ARG1-of (d / downregulate-01)) :quant (m2 / more-than~e.12 :op1 (p2 / product-of~e.15 :quant 2~e.13)) :location~e.16 (a / and~e.22 :op1 (c / cell-line~e.30,31 :name (n / name :op1 "HME16C"~e.29) :ARG1-of (i / infect-01~e.28 :ARG2 (e / enzyme~e.26 :name (n2 / name :op1 "H-Ras"~e.18) :ARG2-of~e.26 (m / mutate-01~e.26 :value "V12")))) :op2 (c2 / cell-line~e.30 :name (n3 / name :op1 "HME16C"~e.29) :ARG1-of (i2 / infect-01~e.28 :ARG2 (d2 / domain~e.25 :part-of (e2 / effector~e.24 :mod (p3 / protein-family :name (n4 / name :op1 "Ras"~e.23))) :ARG2-of (m3 / mutate-01~e.26)))))) :ARG1-of (o2 / organize-01~e.39 :ARG1-of (c3 / consistent-01 :ARG2 (c4 / categorize-01 :ARG1 (f / function~e.46 :mod (g4 / gene~e.45)) :ARG1-of (b / broad-02~e.42))))) :location (f2 / file~e.36 :mod 1~e.37 :ARG1-of (a2 / add-02))) # ::id pmid_1859_7688.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To validate gene expression changes identified by cDNA microarray analysis , quantitative RT @-@ PCR was performed using RNA from the same samples used in microarray analysis , and is presented in Additional file 2 . # ::alignments 1-1.3 2-1.3.1.1.1 3-1.3.1.1 4-1.3.1 5-1.3.1.2 6-1.3.1.2.1.r 7-1.3.1.2.1 8-1.3.1.2.1 9-1.3.1.2.1 11-1.1.1.2 14-1.1.1 14-1.1.1.1 14-1.1.1.1.r 16-1.1 17-1.1.2 18-1.1.2.1.1.1 19-1.1.2.1.2.r 21-1.1.2.1.2.2 22-1.1.2.1.2 22-1.1.2.1.2.1 22-1.1.2.1.2.1.r 22-1.1.2.1.2.2.1 22-1.1.2.1.2.2.1.1 22-1.1.2.1.2.2.1.1.r 23-1.1.2.1.2.2.1.2 24-1.1.2.1.2.2.1.2.1.r 25-1.1.2.1.2.2.1.2.1.1 26-1.1.2.1.2.2.1.2.1 28-1 30-1.2 33-1.2.2 34-1.2.2.1 (a / and~e.28 :op1 (p / perform-01~e.16 :ARG1 (r / react-01~e.14 :ARG0~e.14 (p3 / polymerase~e.14) :mod (q / quantitative~e.11) :mod (c2 / chain) :subevent (t / transcribe-01 :ARG1-of (r2 / reverse-01))) :ARG2-of (u / use-01~e.17 :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "RNA"~e.18) :source~e.19 (t2 / thing~e.22 :ARG1-of~e.22 (s / sample-01~e.22) :ARG1-of (s2 / same-01~e.21 :ARG2 (t3 / thing~e.22 :ARG1-of~e.22 (s3 / sample-01~e.22) :ARG1-of (u2 / use-01~e.23 :ARG2~e.24 (a2 / analyze-01~e.26 :mod (m / microarray~e.25 :consist-of (n5 / nucleic-acid :name (n6 / name :op1 "cDNA"))))))))))) :op2 (p2 / present-01~e.30 :ARG1 r :location (f / file~e.33 :mod 2~e.34 :ARG1-of (a3 / add-02))) :purpose (v / validate-01~e.1 :ARG1 (c / change-01~e.4 :ARG1 (e / express-03~e.3 :ARG1 (g / gene~e.2)) :ARG1-of (i / identify-01~e.5 :ARG0~e.6 a2~e.7,8,9)))) # ::id pmid_1859_7688.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results for 22 of 26 genes chosen to reflect genes up @- or down @-@ regulated both strongly or weakly showed strong agreement with microarray data , demonstrating that the microarray dataset represents a reliable quantification of gene expression changes . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.1.1.r 2-1.1.1.1.1 4-1.1.1.1.2.1.1 5-1.1.1.1.2.1 6-1.1.1.1.2.1.2 8-1.1.1.1.2.1.2.2 9-1.1.1.1.2.1.2.2.2.1 9-1.1.1.1.2.1.2.2.2.2 12-1.1.1.1.2.1.2.2.2 17-1.1.1.1.2.1.2.2.2.1.1.1.1 18-1.1.1.1.2.1.2.2.2.1.1.1 19-1.1.1.1.2.1.2.2.2.1.1.1.2 20-1 21-1.2.3 22-1.2 23-1.2.2.r 24-1.2.2.1 25-1.2.2 27-1.3 28-1.3.1.r 30-1.3.1.1.1 31-1.3.1.1 32-1.3.1 34-1.3.1.2.2 34-1.3.1.2.2.1 34-1.3.1.2.2.1.r 35-1.3.1.2 37-1.1.1.1 38-1.3.1.2.1.1 39-1.3.1.2.1 (s / show-01~e.20 :ARG0 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0 :ARG1~e.1 (g / gene~e.37 :quant 22~e.2 :ARG1-of (i / include-91 :ARG2 (g2 / gene~e.5 :quant 26~e.4 :ARG2-of (c / choose-01~e.6 :ARG1 g :ARG4 (r2 / reflect-01~e.8 :ARG1 g :ARG2 (o / or~e.12 :op1 (g3 / gene~e.9 :ARG1-of (u / upregulate-01 :degree (o2 / or~e.18 :op1 (s2 / strong-02~e.17) :op2 (w / weak-02~e.19)))) :op2 (g4 / gene~e.9 :ARG1-of (d / downregulate-01 :degree o2)))))))))) :ARG1 (a / agree-01~e.22 :ARG0 t :ARG1~e.23 (d2 / data~e.25 :mod (m / microarray~e.24)) :degree s2~e.21) :ARG0-of (d3 / demonstrate-01~e.27 :ARG1~e.28 (r3 / represent-01~e.32 :ARG0 (d4 / dataset~e.31 :mod m~e.30) :ARG1 (q / quantify-01~e.35 :ARG1 (c2 / change-01~e.39 :ARG1 (e / express-03~e.38 :ARG1 o)) :ARG1-of (r4 / rely-01~e.34 :ARG1-of~e.34 (p / possible-01~e.34)))))) # ::id pmid_1859_7688.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To evaluate the effect of EGFR inhibition on gene expression , RasV12-, RasV12S35-, and RasV12G37 @-@ infected cells were induced with doxycycline and subsequently incubated either in the presence or absence of 0.25 μM PD153035 , and microarray analysis comparisons were made to vehicle @-@ treated pLRT @-@ infected cells . # ::alignments 1-1.3 3-1.3.1 5-1.3.1.1.1.1.1 6-1.1.2.2.1.1 6-1.1.2.2.1.1.2 6-1.1.2.2.1.1.2.r 6-1.3.1.1 7-1.3.1.2.r 8-1.3.1.2.1 9-1.3.1.2 13-1 13-1.1 13-1.1.r 16-1.1.1.2.1.1 16-1.1.1.2.2.1 16-1.1.1.2.3.1 17-1.1.1.2.1 17-1.1.1.2.2 17-1.1.1.2.3 19-1.1.1 20-1.1.1.1.r 21-1.1.1.1 22-1.1.1.2 23-1.1.2.3 23-1.1.2.3.r 24-1.1.2 25-1.1.2.2.3 29-1.1.2.2 30-1.1.2.2.2 31-1.1.2.2.1.1.3.r 32-1.1.2.2.1.1.3.1 33-1.1.2.2.1.1.3.2 34-1.1.2.2.1.1.1.1 37-1.2.1.3 39-1.2.1 41-1.2 42-1.2.1.2.r 43-1.2.1.2.2.1 45-1.2.1.2.2 48-1.2.1.2.1 49-1.2.1.2 (a / and~e.13 :op1~e.13 (a2 / and~e.13 :op1 (i / induce-01~e.19 :ARG0~e.20 (d / doxycycline~e.21) :ARG2 (a3 / and~e.22 :op1 (c / cell~e.17 :ARG1-of (i2 / infect-01~e.16 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12")))) :op2 (c2 / cell~e.17 :ARG1-of (i3 / infect-01~e.16 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35")))) :op3 (c3 / cell~e.17 :ARG1-of (i4 / infect-01~e.16 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37")))))) :op2 (i5 / incubate-01~e.24 :ARG1 a3 :ARG2 (o / or~e.29 :op1 (b / be-located-at-91 :ARG1 (s / small-molecule~e.6 :name (n4 / name :op1 "PD153035"~e.34) :ARG0-of~e.6 (i6 / inhibit-01~e.6) :quant~e.31 (c4 / concentration-quantity :quant 0.25~e.32 :unit (m4 / micromolar~e.33)))) :op2 (a4 / absent-01~e.30 :ARG1 s) :mod (e4 / either~e.25)) :time~e.23 (s2 / subsequent~e.23))) :op2 (m5 / make-01~e.41 :ARG1 (c5 / compare-01~e.39 :ARG1 a3 :ARG2~e.42 (c6 / cell~e.49 :ARG1-of (i7 / infect-01~e.48 :ARG2 (p2 / protein :name (n5 / name :op1 "LRT") :ARG3-of (p / phosphorylate-01))) :ARG1-of (t / treat-04~e.45 :ARG2 (v / vehicle~e.43))) :mod (m7 / microarray~e.37))) :purpose (e5 / evaluate-01~e.1 :ARG1 (a5 / affect-01~e.3 :ARG0 (i8 / inhibit-01~e.6 :ARG1 (e7 / enzyme :name (n6 / name :op1 "EGFR"~e.5))) :ARG1~e.7 (e6 / express-03~e.9 :ARG1 (g / gene~e.8))))) # ::id pmid_1859_7688.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Almost all Ras and Ras EDM @-@ induced upregulated transcriptional responses were blocked by pharmacological inhibition of EGFR , consistent with previous reports for inhibition of Raf @-@ regulated transcription [ 30 ] . # ::alignments 0-1.2.5.1 1-1.2.5 2-1.2.4.1.1.1.1 3-1.2.4.1 4-1.2.4.1.1.1.1 4-1.2.4.1.2.1.1 5-1.2.4.1.2.1.2 7-1.2.4 8-1.2.3 9-1.2.2 10-1.2 10-1.2.1 10-1.2.1.r 12-1 13-1.1.r 14-1.1.2 15-1.1 16-1.1.1.r 17-1.1.1.1.1 19-1.3 20-1.3.1.r 21-1.3.1.2 22-1.3.1 23-1.3.1.1.r 24-1.3.1.1 26-1.3.1.1.1.1.1.1.1 28-1.3.1.1.1.1 29-1.2.2 29-1.3.1.1.1 31-1.4.1.1.1 (b / block-01~e.12 :ARG0~e.13 (i / inhibit-01~e.15 :ARG1~e.16 (e4 / enzyme :name (n / name :op1 "EGFR"~e.17)) :mod (p2 / pharmacology~e.14)) :ARG1 (t / thing~e.10 :ARG2-of~e.10 (r / respond-01~e.10) :ARG1-of (t2 / transcribe-01~e.9,29) :ARG1-of (u / upregulate-01~e.8) :ARG2-of (i2 / induce-01~e.7 :ARG0 (a / and~e.3 :op1 (e / enzyme :name (n2 / name :op1 "Ras"~e.2,4)) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.4 :op2 "EDM"~e.5)))) :mod (a2 / all~e.1 :degree (a3 / almost~e.0))) :ARG1-of (c / consistent-01~e.19 :ARG2~e.20 (r2 / report-01~e.22 :ARG1~e.23 (i3 / inhibit-01~e.24 :ARG1 (t3 / transcribe-01~e.29 :ARG1-of (r3 / regulate-01~e.28 :ARG0 (e3 / enzyme :name (n4 / name :op1 "Raf"~e.26))))) :time (p3 / previous~e.21))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 30~e.31)))) # ::id pmid_1859_7688.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our analysis identified PHLDA1 as an up @-@ regulated gene in both vehicle @-@ treated and PD153035 @-@ treated RasV12 and RasV12S35 cells , although the relative fold increase was reduced following EGFR inhibition . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1 2-1.1 3-1.1.2.2.1 6-1.2.1 9-1.1.3 12-1.1.4.2.1.1 14-1.1.4.2.1 15-1.1.4 16-1.1.4.1.1.1.2.1 18-1.1.4.1.1 18-1.1.4.2.1 20-1.1.4 22-1.1.4.1 22-1.1.4.2 24-1 26-1.2.1.2 27-1.2.1.1 28-1.2.1 30-1.2 31-1.2.2 32-1.2.2.1.1.2.1 33-1.2.2.1 (h / have-concession-91~e.24 :ARG1 (i / identify-01~e.2 :ARG0 (a / analyze-01~e.1 :ARG0~e.0 (w / we~e.0)) :ARG1 (g2 / gene :wiki - :name (n2 / name :op1 "PHLDA1"~e.3)) :ARG2 (g3 / gene~e.9 :ARG1-of (u / upregulate-01)) :location (a2 / and~e.15,20 :op1 (c2 / cell~e.22 :ARG1-of (t2 / treat-04~e.18 :ARG2 (s / small-molecule :wiki - :name (n3 / name :op1 "PD153035"~e.16))) :mod (e / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12"))) :op2 (c3 / cell~e.22 :ARG1-of (t / treat-04~e.14,18 :ARG0 (v / vehicle~e.12)) :mod (e2 / enzyme :wiki "Ras_subfamily" :name (n5 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12S35"))))) :ARG2 (r / reduce-01~e.30 :ARG1 (i2 / increase-01~e.6,28 :ARG2 (p / product-of~e.27) :ARG1-of (r2 / relative-05~e.26)) :ARG1-of (f2 / follow-01~e.31 :ARG2 (i3 / inhibit-01~e.33 :ARG1 (e3 / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n / name :op1 "EGFR"~e.32)))))) # ::id pmid_1859_7688.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By comparison , PHLDA1 was down @-@ regulated in PD153035 @-@ treated RasV12G37 relative to vehicle @-@ treated cells ( not shown ) . # ::alignments 1-1.2 3-1.1.1.1 9-1.3.1.2.1.1.1 11-1.3.1.2 13-1.3.2 15-1.3.2.1.1.1 17-1.3.1.2 17-1.3.2.1.1 18-1.3 18-1.3.2.1 20-1.4.1 20-1.4.1.r 21-1.4 (d / downregulate-01 :ARG1 (g / gene :name (n / name :op1 "PHLDA1"~e.3)) :ARG1-of (c / compare-01~e.1) :location (c3 / cell~e.18 :mod (e / enzyme :ARG2-of (m / mutate-01 :value "V12G37") :ARG1-of (t / treat-04~e.11,17 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD153035"~e.9)))) :ARG1-of (r / relative-05~e.13 :ARG3 (c2 / cell~e.18 :ARG1-of (t2 / treat-04~e.17 :ARG0 (v / vehicle~e.15))))) :ARG1-of (s / show-01~e.21 :polarity~e.20 -~e.20)) # ::id pmid_1859_7688.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , PHLDA1 represents a Raf @/@ ERK @-@ responsive gene whose expression parallels EGFR @-@ independent HME16C mammary epithelial cell transformation . # ::alignments 0-1 2-1.1.1.1.1 3-1.1 5-1.1.2.1.1 7-1.1.2.1.1 9-1.1.2 9-1.1.2.2 9-1.1.2.2.r 10-1.1.1 12-1.1.2.3 13-1.1.2.3.1 14-1.1.2.3.1.1.1.4.2.1.1 16-1.1.2.3.1.1.1.4 16-1.1.2.3.1.1.1.4.1 16-1.1.2.3.1.1.1.4.1.r 17-1.1.2.3.1.1.1.1.1 18-1.1.2.3.1.1.1.3 19-1.1.2.3.1.1.1.2 20-1.1.2.3.1.1.1 21-1.1.2.3.1.1 (c2 / cause-01~e.0 :ARG1 (r / represent-01~e.3 :ARG0 (g / gene~e.10 :name (n / name :op1 "PHLDA1"~e.2)) :ARG1 (p2 / pathway~e.9 :name (n2 / name :op1 "Raf/ERK"~e.5,7) :ARG0-of~e.9 (r2 / responsive-02~e.9) :ARG1-of (e / express-01~e.12 :ARG0-of (p / parallel-01~e.13 :ARG1 (t / transform-01~e.21 :ARG1 (c / cell-line~e.20 :name (n3 / name :op1 "HME16C"~e.17) :location (e2 / epithelium~e.19) :mod (m / mammary~e.18) :ARG0-of (d / depend-01~e.16 :polarity~e.16 -~e.16 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR"~e.14)))))))))) # ::id pmid_1859_7688.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TDAG51 expression is up @-@ regulated by Ras signaling in a ERK @-@ dependent manner , and is associated with EGFR @-@ independent transformation # ::alignments 0-1.1.1.1.1.1 1-1.1.1 7-1.1.2.1.1.1 8-1.1.2 11-1.1.2.2.1.1.1 13-1.1.2.2 14-1.1.2.2.r 16-1 18-1.2 19-1.2.2.r 20-1.2.2.1.1.1.1 22-1.2.2.1 23-1.2.2 (a / and~e.16 :op1 (u2 / upregulate-01 :ARG1 (e / express-03~e.1 :ARG2 (p2 / protein :name (n / name :op1 "TDAG51"~e.0))) :ARG2 (s / signal-07~e.8 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.7)) :manner~e.14 (d / depend-01~e.13 :ARG1 (e4 / enzyme :name (n3 / name :op1 "ERK"~e.11))))) :op2 (a2 / associate-01~e.18 :ARG1 e :ARG2~e.19 (t / transform-01~e.23 :ARG0-of (d2 / depend-01~e.22 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR"~e.20)))))) # ::id pmid_1859_7688.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PHLDA1 gene is of interest as it has been suggested to be a tumor suppressor in breast adenocarcinoma and melanoma [ 17,18 ] . # ::alignments 1-1.2.1.1.1 2-1.2.1 5-1.2 10-1.1 14-1.1.1.2 15-1.1.1 16-1.1.1.3.r 17-1.1.1.3.3 18-1.1.1.3.1.1.1 19-1.1.1.3 20-1.1.1.3.2.1.1 (c / cause-01 :ARG0 (s / suggest-01~e.10 :ARG1 (s2 / suppress-01~e.15 :ARG0 g :ARG1 (t / tumor~e.14) :location~e.16 (a / and~e.19 :op1 (m2 / medical-condition :name (n2 / name :op1 "adenocarcinoma"~e.18)) :op2 (m / medical-condition :name (n3 / name :op1 "melanoma"~e.20)) :mod (b / breast~e.17)))) :ARG1 (i / interest-01~e.5 :ARG0 (g / gene~e.2 :name (n / name :op1 "PHLDA1"~e.1))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 17 :op2 18))))) # ::id pmid_1859_7688.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We further analyzed the signal dependent expression of the PHLDA1 gene and its protein product , TDAG51 . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.1.1.2.1 5-1.2.1.1.2 6-1.2.1 9-1.2.1.1.1.1 10-1.2.1.1 11-1.2 13-1.2.2 14-1.2.2.2 16-1.2.2.1.1 (a / analyze-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a2 / and~e.11 :op1 (e / express-03~e.6 :ARG1 (g / gene~e.10 :name (n2 / name :op1 "PHLDA1"~e.9) :ARG0-of (d / depend-01~e.5 :ARG1 (s / signal~e.4)))) :op2 (p2 / protein~e.13 :name (n / name :op1 "TDAG51"~e.16) :ARG1-of (p / produce-01~e.14 :ARG0 g))) :degree (f / further~e.1)) # ::id pmid_1859_7688.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Microarray analysis identified the PHLDA1 gene as being dramatically up @-@ regulated in RasV12 @- and Ras EDM @-@ infected cells to levels that correlated with the level of ERK activation and the extent of anchorage @-@ independent growth ( Additional file 1 ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.1.1.1 5-1.2.1 8-1.2.3 15-1.2.2 16-1.2.2.1.1.1.1.1 17-1.2.2.2.1.1.1.1 19-1.2.2.1.1 19-1.2.2.2.1 20-1.2.2.1 20-1.2.2.2 22-1.2.4 24-1.2.4.1 25-1.2.4.1.1.r 27-1.2.4.1.1.1 28-1.2.4.1.1.1.1.r 29-1.2.4.1.1.1.1.1.1.1 30-1.2.4.1.1.1.1 31-1.2.4.1.1 33-1.2.4.1.1.2 34-1.2.4.1.1.2.1.r 35-1.2.4.1.1.2.1.1.2 37-1.2.4.1.1.2.1.1 37-1.2.4.1.1.2.1.1.1 37-1.2.4.1.1.2.1.1.1.r 38-1.2.4.1.1.2.1 40-1.3.1.2 41-1.3.1 42-1.3.1.1 (i / identify-01~e.2 :ARG0 (a2 / analyze-01~e.1 :ARG1 (m / microarray~e.0)) :ARG1 (u / upregulate-01 :ARG1 (g / gene~e.5 :name (n / name :op1 "PHLDA1"~e.4)) :location (a3 / and~e.15 :op1 (c / cell~e.20 :ARG1-of (i2 / infect-01~e.19 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras"~e.16) :ARG2-of (m2 / mutate-01 :value "V12")))) :op2 (c2 / cell~e.20 :ARG1-of (i3 / infect-01~e.19 :ARG0 (e2 / enzyme :name (n3 / name :op1 "EDM"~e.17))))) :manner (d2 / dramatic~e.8) :degree (l / level~e.22 :ARG1-of (c3 / correlate-01~e.24 :ARG2~e.25 (a5 / and~e.31 :op1 (l2 / level~e.27 :degree-of~e.28 (a4 / activate-01~e.30 :ARG1 (e3 / enzyme :name (n4 / name :op1 "ERK"~e.29)))) :op2 (e4 / extent~e.33 :degree-of~e.34 (g2 / grow-01~e.38 :ARG0-of (d3 / depend-01~e.37 :polarity~e.37 -~e.37 :ARG1 (a6 / anchorage~e.35)))))))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.41 :mod 1~e.42 :mod (a / additional~e.40)))) # ::id pmid_1859_7688.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blotting confirmed that TDAG51 was also upregulated in a similar manner ( Figure 4A ) . # ::alignments 0-1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1 6-1.2.2 7-1.2 8-1.2.3.r 10-1.2.3 11-1.2.3.1 13-1.3.1 14-1.3.1.1 (c / confirm-01~e.2 :ARG0 (i / immunoblot-01~e.0,1) :ARG1~e.3 (u / upregulate-01~e.7 :ARG1 (p / protein :name (n2 / name :op1 "TDAG51"~e.4)) :mod (a2 / also~e.6) :ARG1-of~e.8 (r / resemble-01~e.10 :ARG2 (m / manner~e.11))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13 :mod "4A"~e.14))) # ::id pmid_1859_7688.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PHLDA1 gene was elevated in PD153035 @-@ treated RasV12 @- and RasV12S35 @-@ infected cells but was significantly dependent upon EGFR tyrosine kinase activity for upregulation in RasV12G37 @- and RasV12C40 @-@ infected cells ( not shown ) , and the expression of the encoded TDAG51 protein approximately paralleled PHLDA1 RNA expression ( Figure 4B ) . # ::alignments 1-1.1.1.1.2.1 2-1.1.1.1 2-1.2.2.1.3.1 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2.3.1.2.1 8-1.1.1.2.3 11-1.1.1.2 14-1.1.1.2.1.1 14-1.1.1.2.2.1 15-1.1.1.2.1 15-1.1.1.2.2 16-1.1 18-1.1.2.3 19-1.1.2 21-1.1.2.2.1.1.2.1 22-1.1.2.2.1.2 23-1.1.2.2.1 24-1.1.2.2 25-1.1.2.2.2.r 26-1.1.2.2.2 30-1.1.2.2.2.1 33-1.1.2.2.2.1.1.1 33-1.1.2.2.2.1.2.1 34-1.1.2.2.2.1.1 34-1.1.2.2.2.1.2 36-1.1.2.2.2.2.1 36-1.1.2.2.2.2.1.r 37-1.1.2.2.2.2 40-1.1.2.2.2.1 42-1.2.1 45-1.2.1.1.3 45-1.2.2.1.3 46-1.2.1.1.2.1 47-1.2.1.1 48-1.2.3 49-1.2 50-1.2.2.1.3.1.2.1 51-1.2.2.1.2.1 52-1.2.1 52-1.2.2 54-1.3.1 55-1.3.1.1 (a / and :op1 (c / contrast-01~e.16 :ARG1 (e4 / elevate-01~e.4 :ARG1 (g2 / gene~e.2 :wiki - :name (n7 / name :op1 "PHLDA1"~e.1)) :location~e.5 (a3 / and~e.11 :op1 (c2 / cell~e.15 :ARG1-of (i / infect-01~e.14 :ARG2 (e6 / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12")))) :op2 (c3 / cell~e.15 :ARG1-of (i2 / infect-01~e.14 :ARG2 (e7 / enzyme :wiki "Ras_subfamily" :name (n5 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35")))) :ARG1-of (t / treat-04~e.8 :ARG2 (s / small-molecule :wiki - :name (n6 / name :op1 "PD153035"~e.6))))) :ARG2 (d2 / depend-01~e.19 :ARG0 g2 :ARG1 (a4 / activity-06~e.24 :ARG0 (k / kinase~e.23 :mod (e10 / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n11 / name :op1 "EGFR"~e.21)) :mod (t2 / tyrosine~e.22)) :ARG1~e.25 (u / upregulate-01~e.26 :ARG1 (a5 / and~e.30,40 :op1 (c4 / cell~e.34 :ARG1-of (i3 / infect-01~e.33 :ARG2 (e8 / enzyme :wiki "Ras_subfamily" :name (n9 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12G37")))) :op2 (c5 / cell~e.34 :ARG1-of (i4 / infect-01~e.33 :ARG2 (e9 / enzyme :wiki "Ras_subfamily" :name (n10 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12C40"))))) :ARG1-of (s3 / show-01~e.37 :polarity~e.36 -~e.36))) :ARG1-of (s2 / significant-02~e.18))) :op2 (p / parallel-01~e.49 :ARG0 (e3 / express-03~e.42,52 :ARG2 (p2 / protein~e.47 :wiki "PHLDA1" :name (n / name :op1 "TDAG51"~e.46) :ARG1-of (e2 / encode-01~e.45))) :ARG1 (e / express-03~e.52 :ARG1 (n8 / nucleic-acid :wiki "RNA" :name (n3 / name :op1 "RNA"~e.51) :ARG0-of (e5 / encode-01~e.45 :ARG1 (g / gene~e.2 :wiki - :name (n2 / name :op1 "PHLDA1"~e.50))))) :degree (a2 / approximate~e.48)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.54 :mod "4B"~e.55))) # ::id pmid_1859_7688.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 3C , EGFR inhibition significantly reduced ERK signaling in RasV12G37 @- and RasV12C40 @-@ infected cells without affecting RasV12 @- and RasV12S35 @-@ infected cells . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 4-1.4.1.1 6-1.1.1.1.1 7-1.1 8-1.3 9-1 10-1.2.1.1.1 11-1.2 15-1.2.2 18-1.2.2.1.1 18-1.2.2.2.1 19-1.2.2.1 19-1.2.2.2 20-1.5.1 20-1.5.1.r 21-1.5 24-1.5.2 27-1.5.2.1.1 27-1.5.2.2.1 28-1.5.2.1 28-1.5.2.2 (r / reduce-01~e.9 :ARG0 (i / inhibit-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.6))) :ARG1 (s3 / signal-07~e.11 :ARG0 (e6 / enzyme :name (n2 / name :op1 "ERK"~e.10)) :location (a / and~e.15 :op1 (c2 / cell~e.19 :ARG1-of (i2 / infect-01~e.18 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12G37")))) :op2 (c / cell~e.19 :ARG1-of (i5 / infect-01~e.18 :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12C40")))))) :ARG2 (s2 / significant-02~e.8) :ARG1-of (s / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "3C"~e.4)) :ARG0-of (a2 / affect-01~e.21 :polarity~e.20 -~e.20 :ARG1 (a3 / and~e.24 :op1 (c3 / cell~e.28 :ARG1-of (i3 / infect-01~e.27 :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12")))) :op2 (c4 / cell~e.28 :ARG1-of (i4 / infect-01~e.27 :ARG2 (e2 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m4 / mutate-01 :value "V12S35"))))))) # ::id pmid_1859_7688.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm that TDAG51 up @-@ regulation was induced specifically by ERK activation , we treated pLRT-, RasV12-, and RasV12S35 @-@ infected cells with the MEK @-@ specific inhibitor PD98059 . # ::alignments 1-1.4 2-1.4.2.r 3-1.4.2.2.1.1.1 4-1.4.2.2 5-1.4.2.2 6-1.4.2.2 8-1.4.2 9-1.4.2.3 10-1.4.2.1.r 11-1.4.2.1.1.1.1 12-1.4.2.1 14-1.4.1 15-1 18-1.2 21-1.2.2.1 21-1.2.3.1 22-1.2.1 22-1.2.2 22-1.2.3 23-1.3.r 25-1.3.2.1.1.1 27-1.3.3 28-1.3 28-1.3.2 28-1.3.2.r 29-1.3.1.1 (t / treat-04~e.15 :ARG0 w :ARG1 (a2 / and~e.18 :op1 (c2 / cell~e.22 :mod (p4 / protein :name (n5 / name :op1 "LRT") :ARG1-of (p2 / phosphorylate-01))) :op2 (c3 / cell~e.22 :ARG1-of (i4 / infect-01~e.21 :ARG2 (e / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12")))) :op3 (c4 / cell~e.22 :ARG1-of (i5 / infect-01~e.21 :ARG2 (e5 / enzyme :name (n7 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12S35"))))) :ARG2~e.23 (s2 / small-molecule~e.28 :name (n3 / name :op1 "PD98059"~e.29) :ARG0-of~e.28 (i2 / inhibit-01~e.28 :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK"~e.25))) :ARG1-of (s / specific-02~e.27)) :purpose (c / confirm-01~e.1 :ARG0 (w / we~e.14) :ARG1~e.2 (i / induce-01~e.8 :ARG0~e.10 (a / activate-01~e.12 :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK"~e.11))) :ARG2 (u / upregulate-01~e.4,5,6 :ARG1 (p / protein :name (n / name :op1 "TDAG51"~e.3))) :ARG1-of s~e.9))) # ::id pmid_1859_7688.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PD98059 used at 20 μM appears to be specific for MEK1 as it does not nonspecifically inhibit a variety of other protein kinases that have been assayed . # ::alignments 0-1.1.1.1.1 1-1.1.1.2 2-1.1.1.2.1.r 3-1.1.1.2.1.1 5-1 6-1.2 8-1.1 9-1.1.2.r 10-1.1.2.1.1 11-1.2.1.r 12-1.2.1.2 14-1.2.1.1.r 14-1.2.1.4.1 14-1.2.1.4.1.r 15-1.2.1.1 15-1.2.1.4 15-1.2.1.4.1 16-1.2.1 18-1.2.1.3.3 20-1.2.1.3.1 21-1.2.1.3.4 22-1.2.1.3 26-1.2.1.3.2 (a3 / appear-02~e.5 :ARG1 (s / specific-02~e.8 :ARG1 (s3 / small-molecule :name (n / name :op1 "PD98059"~e.0) :ARG1-of (u / use-01~e.1 :ARG2~e.2 (c2 / concentration-quantity :quant 20~e.3 :unit (n2 / nanomolar)))) :ARG2~e.9 (e / enzyme :name (n3 / name :op1 "MEK1"~e.10))) :ARG1-of (c3 / cause-01~e.6 :ARG0~e.11 (i / inhibit-01~e.16 :polarity~e.14 -~e.15 :ARG0 s3~e.12 :ARG1 (k / kinase~e.22 :mod (o / other~e.20) :ARG1-of (a2 / assay-01~e.26) :mod (v / variety~e.18) :mod (p / protein~e.21)) :ARG1-of (s2 / specific-02~e.15 :polarity~e.14 -~e.14,15)))) # ::id pmid_1859_7688.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok [ 31 ] . # ::alignments 1-1.1.1 (p / publication :ARG1-of (c / cite-01 :ARG2 31~e.1)) # ::id pmid_1859_7688.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TDAG51 up @-@ regulation was attenuated by MEK inhibition ( Figure 5 ) . # ::alignments 0-1.2.1.1.1 1-1.2 2-1.2 3-1.2 5-1 6-1.1.r 7-1.1.1.1.1 8-1.1 10-1.3.1 11-1.3.1.1 (a / attenuate-01~e.5 :ARG0~e.6 (i / inhibit-01~e.8 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK"~e.7))) :ARG1 (u / upregulate-01~e.1,2,3 :ARG1 (p / protein :name (n / name :op1 "TDAG51"~e.0))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.10 :mod 5~e.11))) # ::id pmid_1859_7688.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TDAG51 therefore represents an ERK @-@ inducible gene whose up @-@ regulation in HME16C is correlated with an EGFR @-@ independent , ERK @-@ mediated transformation . # ::alignments 0-1.1.1.1.1 1-1 2-1.1 4-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1.2 9-1.1.2.2 10-1.1.2.2 11-1.1.2.2 12-1.1.2.2.1.r 13-1.1.2.2.1.1.1 15-1.1.2.2.2 16-1.1.2.2.2.1.r 18-1.1.2.2.2.1.1.2.1.1 20-1.1.2.2.2.1.1 20-1.1.2.2.2.1.1.1 20-1.1.2.2.2.1.1.1.r 22-1.1.2.2.2.1.2.1 24-1.1.2.2.2.1.2 25-1.1.2.2.2.1 (c2 / cause-01~e.1 :ARG1 (r2 / represent-01~e.2 :ARG0 (g2 / gene :name (n / name :op1 "TDAG51"~e.0)) :ARG1 (g / gene~e.7 :ARG2-of (i / induce-01~e.6 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.4)) :ARG1-of (p / possible-01)) :ARG1-of (u / upregulate-01~e.9,10,11 :location~e.12 (c3 / cell-line :name (n3 / name :op1 "HME16C"~e.13)) :ARG1-of (c / correlate-01~e.15 :ARG2~e.16 (t / transform-01~e.25 :ARG0-of (d / depend-01~e.20 :polarity~e.20 -~e.20 :ARG1 (e2 / enzyme :name (n4 / name :op1 "EGFR"~e.18))) :ARG1-of (m2 / mediate-01~e.24 :ARG0 e~e.22))))))) # ::id pmid_1859_7688.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TDAG51 up @-@ regulation opposes ERK @-@ mediated HME16C transformation # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1 3-1.1 4-1 5-1.2.1.2.1.1.1 7-1.2.1.2 8-1.2.1.1.1 9-1.2 (o / oppose-01~e.4 :ARG0 (u / upregulate-01~e.1,2,3 :ARG1 (p / protein :name (n / name :op1 "TDAG51"~e.0))) :ARG1 (t / transform-01~e.9 :ARG1 (c / cell-line :name (n2 / name :op1 "HME16C"~e.8) :ARG1-of (m2 / mediate-01~e.7 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK"~e.5)))))) # ::id pmid_1859_7688.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To analyze the role of TDAG51 in ERK @-@ dependent growth , we reduced TDAG51 expression in RasV12 @- and RasV12S35 @-@ infected cells to a level comparable to that in non @-@ transformed vector @-@ infected control cells using stably expressed TDAG51 @-@ specific shRNA ( Figure 6A ) . # ::alignments 1-1.6 3-1.6.2 4-1.6.2.1.r 5-1.6.2.1.1.1 6-1.6.2.2.r 7-1.6.2.2.1.1.1.1 9-1.6.2.2.1 10-1.6.2.2 12-1.6.1 13-1 14-1.2.1 15-1.2 19-1.2.2 22-1.2.2.1.1 22-1.2.2.3 23-1.2.2.1 23-1.2.2.2 24-1.3.r 26-1.3 26-1.3.1.1 27-1.3.1 30-1.3.1.1.1.r 31-1.3.1.1.1.3.1 31-1.3.1.1.1.3.1.r 33-1.3.1.1.1.3 34-1.3.1.1.1.1.1 36-1.3.1.1.1.1 37-1.3.1.1.1.2 38-1.3.1.1.1 39-1.4 39-1.6.r 40-1.4.2.3.1 41-1.4.2.3 42-1.4.2.2.1 44-1.4.2 44-1.4.2.2 44-1.4.2.2.r 45-1.4.2.1.1 47-1.5.1 48-1.5.1.1 (r / reduce-01~e.13 :ARG0 w :ARG1 (e2 / express-03~e.15 :ARG2 p~e.14 :ARG3 (a2 / and~e.19 :op1 (c / cell~e.23 :ARG1-of (i3 / infect-01~e.22 :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12")))) :op2 (c2 / cell~e.23) :ARG1-of (i / infect-01~e.22 :ARG2 (e4 / enzyme :name n3 :ARG2-of (m2 / mutate-01 :value "V12S35"))))) :ARG4~e.24 (l / level~e.26 :ARG1-of (c3 / comparable-03~e.27 :ARG2 (l2 / level~e.26 :location~e.30 (c4 / cell~e.38 :ARG1-of (i2 / infect-01~e.36 :ARG2 (v / vector~e.34)) :ARG0-of (c5 / control-01~e.37) :ARG1-of (t / transform-01~e.33 :polarity~e.31 -~e.31))))) :manner (u / use-01~e.39 :ARG0 w :ARG1 (n5 / nucleic-acid~e.44 :name (n4 / name :op1 "shRNA"~e.45) :ARG1-of~e.44 (s / specific-02~e.44 :ARG2 p~e.42) :ARG2-of (e5 / express-03~e.41 :ARG1-of (s2 / stable-03~e.40)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.47 :mod "6A"~e.48)) :purpose~e.39 (a / analyze-01~e.1 :ARG0 (w / we~e.12) :ARG1 (r2 / role~e.3 :poss~e.4 (p / protein :name (n / name :op1 "TDAG51"~e.5)) :topic~e.6 (g / grow-01~e.10 :ARG0-of (d2 / depend-01~e.9 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.7))))))) # ::id pmid_1859_7688.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell proliferation of attached cells grown on tissue culture plastic was unaffected by lowered TDAG51 protein levels ( not shown ) . # ::alignments 0-1.3.1 1-1.3 3-1.3.1.1 4-1.3.1 5-1.3.1.2 6-1.3.1.2.1.r 7-1.3.1.2.1.1.1 8-1.3.1.2.1.1 9-1.3.1.2.1 11-1 11-1.1 12-1.2.r 13-1.2.2 14-1.2.1.1.1 15-1.2.1 16-1.2 18-1.1.r 18-1.4.1 18-1.4.1.r 19-1.4 (a / affect-01~e.11 :polarity~e.18 -~e.11 :ARG0~e.12 (l / level~e.16 :quant-of (p3 / protein~e.15 :name (n / name :op1 "TDAG51"~e.14)) :ARG1-of (l2 / low-04~e.13)) :ARG1 (p / proliferate-01~e.1 :ARG0 (c / cell~e.0,4 :ARG1-of (a2 / attach-01~e.3) :ARG1-of (g / grow-01~e.5 :location~e.6 (p2 / plastic~e.9 :mod (c3 / culture~e.8 :source (t / tissue~e.7)))))) :ARG1-of (s / show-01~e.19 :polarity~e.18 -~e.18)) # ::id pmid_1859_7688.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , cell growth under anchorage @-@ independent conditions in ultra @-@ low attachment plates was significantly enhanced by TDAG51 knock @-@ down in RasV12S35 @-@ infected cells ( Figure 6B ) . # ::alignments 0-1 2-1.1.1.1 3-1.1.1 5-1.1.1.3.2 7-1.1.1.3 7-1.1.1.3.1 7-1.1.1.3.1.r 8-1.1.1.3.r 9-1.1.1.2.r 10-1.1.1.2.2.1 12-1.1.1.2.2 13-1.1.1.2.1 14-1.1.1.2 16-1.1.3 17-1.1 18-1.1.2.r 19-1.1.2.1.1.1 20-1.1.2 22-1.1.2 26-1.1.4.1 27-1.1.4 29-1.2.1 30-1.2.1.1 (c / contrast-01~e.0 :ARG2 (e / enhance-01~e.17 :ARG1 (g / grow-01~e.3 :ARG1 (c3 / cell~e.2) :location~e.9 (p / plate~e.14 :ARG3-of (a2 / attach-01~e.13) :ARG1-of (l / low-04~e.12 :degree (u / ultra~e.10))) :condition~e.8 (d2 / depend-01~e.7 :polarity~e.7 -~e.7 :ARG1 (a / anchorage~e.5))) :ARG2~e.18 (k / knock-down-02~e.20,22 :ARG1 (p2 / protein :name (n / name :op1 "TDAG51"~e.19))) :ARG1-of (s / significant-02~e.16) :location (c5 / cell~e.27 :ARG1-of (i / infect-01~e.26 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "6B"~e.30))) # ::id pmid_1859_7688.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , results with RasV12 @-@ infected cells stably infected with TDAG51 @-@ targeting shRNA also showed enhanced growth relative to vector @-@ infected control cells , although to a lesser extent than that seen with RasV12S35 @-@ infected cells ( Figure 6C ) . # ::alignments 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 6-1.1.1.1.1.1 6-1.1.1.1.1.2 7-1.1.1.1.1 8-1.1.1.1.1.2.2 9-1.1.1.1.1.2 10-1.1.1.1.1.2.1.r 11-1.1.1.1.1.2.1.3.1.2.1 13-1.1.1.1.1.2.1.3 14-1.1.1.1.1.2.1.2.1 15-1.1.3 16-1.1 16-1.2 17-1.1.2.1 18-1.1.2 18-1.2.2 18-1.2.2.2 19-1.1.2.2 20-1.1.2.2.1.r 21-1.1.2.2.1.2.1 23-1.1.2.2.1.2 24-1.1.2.2.1.1 25-1.1.2.2.1 28-1.2.2.1.r 30-1.2.2.1 30-1.2.2.1.1 30-1.2.2.1.1.r 32-1.2.2.2.r 34-1.2.2.2.1 38-1.2.2.2.1.1.1 39-1.2.2.2.1.1 41-1.4.1 42-1.4.1.1 (c / contrast-01 :ARG1 (s / show-01~e.16 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r2 / result-01~e.2 :ARG1 (c4 / cell~e.7 :ARG1-of (i2 / infect-01~e.6 :ARG2 (e2 / enzyme :wiki "Ras_subfamily" :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12"))) :ARG1-of (i3 / infect-01~e.6,9 :ARG2~e.10 (n5 / nucleic-acid :wiki "Small_hairpin_RNA" :name (n2 / name :op1 "shRNA"~e.14) :ARG0-of (t2 / target-01~e.13 :ARG1 (p / protein :wiki "PHLDA1" :name (n3 / name :op1 "TDAG51"~e.11)))) :ARG1-of (s3 / stable-03~e.8))))) :ARG1 (g / grow-01~e.18 :ARG1-of (e / enhance-01~e.17) :ARG1-of (r3 / relative-05~e.19 :ARG2~e.20 (c2 / cell~e.25 :ARG0-of (c3 / control-01~e.24) :ARG1-of (i / infect-01~e.23 :ARG0 (v / vector~e.21))))) :mod (a / also~e.15)) :ARG2 (s2 / show-01~e.16 :ARG0 t :ARG1 (g2 / grow-01~e.18 :degree~e.28 (l / less~e.30 :degree~e.30 (m2 / more~e.30)) :compared-to~e.32 (g3 / grow-01~e.18 :ARG1-of (s4 / see-01~e.34 :location (c5 / cell~e.39 :ARG1-of (i4 / infect-01~e.38 :ARG2 (e3 / enzyme :wiki "Ras_subfamily" :name (n4 / name :op1 "Ras") :ARG2-of (m3 / mutate-01 :value "V12S35")))))))) :ARG1-of (r / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.41 :mod "6C"~e.42))) # ::id pmid_1859_7688.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This suggests that Ras signaling pathways other than ERK compensate partially for the negative growth effects of TDAG51 , or that RasV12 @-@ infected cells are already close to maximally transformed under anchorage @-@ independent growth conditions . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 3-1.2.2.1.1.1.1.1 4-1.2.1.1.2 5-1.2.1.1 5-1.2.1.1.3.1 8-1.2.1.1.3.1.1.1 9-1.2.1 10-1.2.1.3 10-1.2.1.3.r 11-1.2.1.2.r 13-1.2.1.2.2 14-1.2.1.2.1 15-1.2.1.2 16-1.2.1.2.1.1.r 17-1.2.1.2.1.1.1.1 19-1.2 23-1.2.2.1.1 24-1.2.2.1 26-1.2.2.3 27-1.2.2 28-1.2.2.2.r 29-1.2.2.2.2 30-1.2.2.2 32-1.2.2.4.1.2 34-1.2.2.4.1 34-1.2.2.4.1.1 34-1.2.2.4.1.1.r 35-1.2.2.4 36-1.2.2.4.r (s / suggest-01~e.1 :ARG0 (t / this~e.0) :ARG1~e.2 (o / or~e.19 :op1 (c / compensate-01~e.9 :ARG0 (p2 / pathway~e.5 :name (n / name :op1 "Ras"~e.3) :ARG0-of (s2 / signal-07~e.4) :ARG2-of (e2 / except-01 :ARG1 (p3 / pathway~e.5 :name (n2 / name :op1 "ERK"~e.8)))) :ARG1~e.11 (a2 / affect-01~e.15 :ARG0 (g / grow-01~e.14 :ARG1~e.16 (p4 / protein :name (n4 / name :op1 "TDAG51"~e.17))) :ARG2-of (n3 / negative-05~e.13)) :degree~e.10 (p / part~e.10)) :op2 (c2 / close-10~e.27 :ARG1 (c4 / cell~e.24 :ARG1-of (i / infect-01~e.23 :ARG2 (e / enzyme :name (n5 / name :op1 "Ras"~e.3) :ARG2-of (m2 / mutate-01 :value "V12")))) :ARG2~e.28 (t2 / transform-01~e.30 :ARG1 c4 :degree (m / maximal~e.29)) :time (a3 / already~e.26) :condition~e.36 (g2 / grow-01~e.35 :ARG0-of (d / depend-01~e.34 :polarity~e.34 -~e.34 :ARG1 (a / anchorage~e.32)))))) # ::id pmid_1859_7688.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Loss of TDAG51 expression in transformed cells stimulates both cell cycle progression and apoptosis # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.r 5-1.1.1.2.1 6-1.1.1.2 7-1 9-1.2.1.1.1 10-1.2.1.1 11-1.2.1 12-1.2 13-1.2.2 (s / stimulate-01~e.7 :ARG0 (l / lose-02~e.0 :ARG1~e.1 (e / express-03~e.3 :ARG1 (p / protein :name (n / name :op1 "TDAG51"~e.2)) :ARG3~e.4 (c / cell~e.6 :ARG1-of (t / transform-01~e.5)))) :ARG1 (a / and~e.12 :op1 (p2 / progress-01~e.11 :ARG1 (c2 / cycle-02~e.10 :ARG1 (c3 / cell~e.9))) :op2 (a2 / apoptosis~e.13 :mod c3))) # ::id pmid_1859_7688.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To characterize the effect of TDAG51 on cell proliferation under anchorage @-@ independent conditions , cell cycle analysis and cell proliferation assays for RasV12S35 @- and RasV12 @-@ infected cells were performed . # ::alignments 1-1.2 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.1.1 6-1.2.1.2.r 7-1.2.1.2.1 8-1.2.1.2 10-1.2.1.2.2.1 12-1.2.1.2.2 13-1.2.1.2.2.r 15-1.1.1.1.1 16-1.1.1.1 17-1.1.1 19-1.1.2.1.1 20-1.1.2.1 21-1.1.2 25-1.1.3 28-1.1.3.1.1 28-1.1.3.2.1 29-1.1.3.1 29-1.1.3.2 31-1 (p / perform-01~e.31 :ARG1 (a / and :op1 (a2 / analyze-01~e.17 :ARG1 (c2 / cycle-02~e.16 :ARG1 (c3 / cell~e.15))) :op2 (a3 / assay-01~e.21 :ARG1 (p2 / proliferate-01~e.20 :ARG0 c3~e.19)) :purpose (a4 / and~e.25 :op1 (c4 / cell~e.29 :ARG1-of (i2 / infect-01~e.28 :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35")))) :op2 (c5 / cell~e.29 :ARG1-of (i / infect-01~e.28 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12")))))) :purpose (c / characterize-01~e.1 :ARG1 (a5 / affect-01~e.3 :ARG0~e.4 (p3 / protein :name (n3 / name :op1 "TDAG51"~e.5)) :ARG1~e.6 (p4 / proliferate-01~e.8 :ARG0 c3~e.7 :condition~e.13 (d / depend-01~e.12 :ARG1 (a6 / anchorage~e.10)))))) # ::id pmid_1859_7688.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both RasV12S35 @- and RasV12 @- TDAG51 shRNA @-@ expressing cells demonstrated an increased S @-@ phase fraction versus pLVTHM vector control cells at various time points during anchorage @-@ independent growth ( Figure 7A ) . # ::alignments 3-1.1 6-1.1.1.1.1.2.1.1.1 7-1.1.1.1.1.1.1 9-1.1.1.1 9-1.1.2.1 10-1.1.1 10-1.1.2 11-1 13-1.2.1 16-1.2.2 17-1.2 20-1.4.2 21-1.4.1 22-1.4 25-1.5.1 25-1.5.r 26-1.5 27-1.5.r 27-1.6.r 28-1.6.1.2 30-1.6.1 30-1.6.1.1 30-1.6.1.1.r 31-1.6 33-1.3.1 34-1.3.1.1 (d / demonstrate-01~e.11 :ARG0 (a / and~e.3 :op1 (c / cell~e.10 :ARG3-of (e / express-03~e.9 :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA"~e.7) :ARG0-of (e5 / encode-01 :ARG1 (p4 / protein :name (n5 / name :op1 "TDAG51"~e.6) :ARG1-of (i2 / infect-01 :ARG2 (e3 / enzyme :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35")))))))) :op2 (c2 / cell~e.10 :ARG3-of (e2 / express-03~e.9 :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12")) :ARG2 n4))) :ARG1 (f2 / fraction~e.17 :ARG1-of (i / increase-01~e.13) :part-of (p / phase~e.16 :mod (s / synthesize-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.33 :mod "7A"~e.34)) :compared-to (c3 / cell~e.22 :ARG0-of (c4 / control-01~e.21) :mod (v / vector~e.20 :name (n3 / name :op1 "LVTHM") :ARG3-of (p2 / phosphorylate-01))) :time~e.25,27 (p3 / point~e.26 :mod (t / time~e.25) :ARG1-of (v2 / vary-01)) :time~e.27 (g / grow-01~e.31 :ARG0-of (d3 / depend-01~e.30 :polarity~e.30 -~e.30 :ARG1 (a2 / anchorage~e.28)))) # ::id pmid_1859_7688.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In concordance with these results , RasV12S35 and RasV12 cells expressing the TDAG51 @-@ specific shRNA showed enhanced incorporation of 5 @-@ ethynyl @-@ 2 ' @-@ deoxyuridine ( EdU ) in cell proliferation assays , indicating a higher rate of DNA synthesis in cells with reduced TDAG51 protein ( Figure 7C ) . # ::alignments 3-1.5.1.2 4-1.5.1 4-1.5.1.1 4-1.5.1.1.r 7-1.1 9-1.1.1 9-1.1.2 10-1.1.3 12-1.1.3.1.3.1.2.1 14-1.1.3.1 14-1.1.3.1.3 14-1.1.3.1.3.r 15-1.1.3.1.2.1 16-1 17-1.2.3 18-1.2 19-1.2.2.r 20-1.2.2.2.1 22-1.2.2.2.1 27-1.2.2.2.1 31-1.2.4.r 32-1.2.4.1.1 33-1.2.4.1 34-1.2.4 36-1.3 38-1.3.1.2 38-1.3.1.2.1 38-1.3.1.2.1.r 39-1.3.1 41-1.3.1.1.1.2.1 42-1.3.1.1 43-1.3.2.r 44-1.3.2 46-1.3.2.1.1.3 47-1.3.2.1.1.2.1 48-1.1.3.1.3.1 48-1.3.2.1.1 50-1.4.1 51-1.4.1.1 (s / show-01~e.16 :ARG0 (a / and~e.7 :op1 (c2 / cell~e.9 :mod (e / enzyme :wiki "Ras_subfamily" :name (n / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35"))) :op2 (c3 / cell~e.9 :mod (e5 / enzyme :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12"))) :ARG3-of (e3 / express-03~e.10 :ARG1 (n7 / nucleic-acid~e.14 :wiki "Small_hairpin_RNA" :name (n2 / name :op1 "shRNA"~e.15) :ARG1-of~e.14 (s2 / specific-02~e.14 :ARG2 (p / protein~e.48 :wiki "PHLDA1" :name (n3 / name :op1 "TDAG51"~e.12)))))) :ARG1 (i2 / incorporate-01~e.18 :ARG0 n7 :ARG1~e.19 (s4 / small-molecule :wiki "5-Ethynyl-2'-deoxyuridine" :name (n4 / name :op1 "5-ethynyl-2'-deoxyuridine"~e.20,22,27)) :ARG1-of (e4 / enhance-01~e.17) :location~e.31 (a2 / assay-01~e.34 :ARG1 (p2 / proliferate-01~e.33 :ARG0 (c4 / cell~e.32)))) :ARG0-of (i / indicate-01~e.36 :ARG1 (r3 / rate-entity-91~e.39 :ARG4 (s3 / synthesize-01~e.42 :ARG1 (n8 / nucleic-acid :wiki "DNA" :name (n9 / name :op1 "DNA"~e.41))) :ARG1-of (h / high-02~e.38 :degree~e.38 (m4 / more~e.38))) :location~e.43 (c5 / cell~e.44 :ARG0-of (h2 / have-03 :ARG1 (p4 / protein~e.48 :wiki "PHLDA1" :name (n5 / name :op1 "TDAG51"~e.47) :ARG1-of (r4 / reduce-01~e.46))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.50 :mod "7C"~e.51)) :ARG1-of (r5 / resemble-01 :ARG2 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :mod (t2 / this~e.3)))) # ::id pmid_1859_7688.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since cell growth under anchorage @-@ independent conditions is a balance between cell proliferation and cell death , we sought to evaluate the effect upon cellular death of TDAG51 knock @-@ down . # ::alignments 0-1 1-1.1.1.1 2-1.1.1 4-1.1.1.2.2 6-1.1.1.2 6-1.1.1.2.1 6-1.1.1.2.1.r 7-1.1.1.2.r 10-1.1 12-1.1.2.1.1 13-1.1.2.1 15-1.1.2.1.1 16-1.1.2.2 18-1.2.1 19-1.2 21-1.2.2 23-1.2.2.2 25-1.2.2.2.2.1 26-1.2.2.2.2 27-1.2.2.2.1.r 28-1.2.2.2.1.1.1.1 29-1.2.2.2.1 31-1.2.2.2.1 (c / cause-01~e.0 :ARG0 (b / balance-01~e.10 :ARG0 (g / grow-01~e.2 :ARG1 (c3 / cell~e.1) :condition~e.7 (d3 / depend-01~e.6 :polarity~e.6 -~e.6 :ARG1 (a2 / anchorage~e.4))) :ARG1 (a3 / and :op1 (p2 / proliferate-01~e.13 :ARG0 (c5 / cell~e.12,15)) :op2 (d2 / die-01~e.16 :ARG1 c5))) :ARG1 (s / seek-01~e.19 :ARG0 (w / we~e.18) :ARG1 (e / evaluate-01~e.21 :ARG0 w :ARG1 (a / affect-01~e.23 :ARG0~e.27 (k / knock-down-02~e.29,31 :ARG1 (p / protein :name (n / name :op1 "TDAG51"~e.28))) :ARG1 (d / die-01~e.26 :ARG1 (c2 / cell~e.25)))))) # ::id pmid_1859_7688.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We used an assay of cellular cytotoxicity that measures the release of the lactose deydrogenase enzyme , LDH . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1 6-1.2.1 8-1.2.2 10-1.2.2.1 11-1.2.2.1.1.r 13-1.2.2.1.1.1.1 14-1.2.2.1.1.1.2 15-1.2.2.1.1 (u / use-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / assay-01~e.3 :ARG1~e.4 (c / cytotoxicity~e.6 :mod (c2 / cell~e.5)) :ARG0-of (m / measure-01~e.8 :ARG1 (r / release-01~e.10 :ARG1~e.11 (e / enzyme~e.15 :name (n / name :op1 "lactose"~e.13 :op2 "deydrogenase"~e.14)))))) # ::id pmid_1859_7688.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LDH release was increased by TDAG51 shRNA @-@ expressing RasV12S35 cells relative to pLVTHM @-@ infected cells at various time points after the initiation of matrix @-@ detached growth ( Figure 8 ) . # ::alignments 0-1.2.1.1.1 1-1.2 3-1 4-1.1.r 5-1.1.1.1.2.1.1.1 6-1.1.1.1.1.1 8-1.1.1 10-1.1 11-1.4 15-1.4.1.1 16-1.4.1 19-1.5.1 19-1.5.r 19-1.6.r 20-1.5 21-1.6 23-1.6.1 24-1.6.1.1.r 25-1.6.1.1.1.1 27-1.6.1.1.1 28-1.6.1.1 30-1.3.1 31-1.3.1.1 (i / increase-01~e.3 :ARG0~e.4 (c / cell~e.10 :ARG3-of (e2 / express-03~e.8 :ARG2 (n6 / nucleic-acid :name (n5 / name :op1 "shRNA"~e.6) :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "TDAG51"~e.5))))) :mod (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35"))) :ARG1 (r / release-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "LDH"~e.0))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod 8~e.31)) :ARG1-of (r2 / relative-05~e.11 :ARG3 (c2 / cell~e.16 :ARG1-of (i2 / infect-01~e.15 :ARG2 (v2 / vector :name (n4 / name :op1 "LVTHM") :ARG3-of (p2 / phosphorylate-01))))) :time~e.19 (p3 / point~e.20 :mod (t / time~e.19) :ARG1-of (v / vary-01)) :time~e.19 (a / after~e.21 :op1 (i3 / initiate-01~e.23 :ARG1~e.24 (g / grow-01~e.28 :ARG1-of (d2 / detach-01~e.27 :ARG2 (m3 / matrix~e.25)))))) # ::id pmid_1859_7688.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The difference in LDH release for TDAG51 shRNA @-@ expressing RasV12 cells was minimal and rarely approached statistical significance . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.2.1.1 4-1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1.2.1.1.1 7-1.1.1.1.1.1.1.1.1 9-1.1.1.1.1.1 11-1.1.1.1.1 13-1.1 14-1 15-1.2.3 16-1.2 17-1.2.2.2 18-1.2.2 (a / and~e.14 :op1 (m / minimal-02~e.13 :ARG1 (d / differ-02~e.1 :ARG1~e.2 (r2 / release-01~e.4 :ARG0~e.5 (c / cell~e.11 :ARG3-of (e2 / express-03~e.9 :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.7) :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "TDAG51"~e.6))))) :mod (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12"))) :ARG1 (e / enzyme :name (n / name :op1 "LDH"~e.3))))) :op2 (a2 / approach-01~e.16 :ARG1 d :ARG2 (s / significant-02~e.18 :ARG1 d :mod (s2 / statistics~e.17)) :ARG1-of (r / rare-02~e.15))) # ::id pmid_1859_7688.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sub @-@ G1 peaks indicative of dead cells were sometimes seen with cell cycle analysis at late time points , but varied from experiment to experiment . # ::alignments 0-1.1.2 3-1.1 6-1.1.1.1.1 7-1.1.1.1 9-1.2 10-1 11-1.3.r 12-1.3.1.1 13-1.3.1 14-1.3 15-1.4.r 16-1.4.1.1 17-1.4.1 17-1.4.1.1.r 18-1.4 20-1.5 21-1.5.1 22-1.5.1.2.r 23-1.5.1.2 25-1.5.1.2 (s / see-01~e.10 :ARG1 (p / peak~e.3 :ARG0-of (i / indicate-01 :ARG1 (c / cell~e.7 :ARG1-of (d / die-01~e.6))) :mod (s4 / sub~e.0 :op1 (p2 / phase :mod 1 :mod (g / grow-01)))) :frequency (s2 / sometimes~e.9) :instrument~e.11 (a / analyze-01~e.14 :ARG1 (c2 / cycle-02~e.13 :ARG1 (c3 / cell~e.12))) :time~e.15 (p3 / point~e.18 :mod (t / time~e.17 :time~e.17 (l / late~e.16))) :ARG1-of (c4 / contrast-01~e.20 :ARG2 (v / vary-01~e.21 :ARG1 p :ARG3~e.22 (e / experiment-01~e.23,25) :ARG4 e))) # ::id pmid_1859_7688.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , for RasV12S35 @-@ infected cells , the differences in cell growth after TDAG51 reduction under anchorage @-@ independent conditions resulted from an enhanced rate of cellular proliferation that exceeded a concomitant increase in cell death . # ::alignments 0-1 5-1.1.2.2.1.1 6-1.1.2.2.1 9-1.1.2 11-1.1.2.1 11-1.1.2.2.1 12-1.1.2.2 13-1.1.2.2.2 14-1.1.2.2.2.1.1.1.1 15-1.1.2.2.2.1 17-1.1.2.2.2.1.2.2 19-1.1.2.2.2.1.2 19-1.1.2.2.2.1.2.1 19-1.1.2.2.2.1.2.1.r 20-1.1.2.2.2.1.2.r 21-1.1 22-1.1.1.r 24-1.1.1.1 25-1.1.1 26-1.1.1.3.r 27-1.1.1.3.1 28-1.1.1.3 30-1.1.1.2 32-1.1.1.2.1.2 33-1.1.1.2.1 34-1.1.1.2.1.1.r 35-1.1.1.2.1.1.1 36-1.1.1.2.1.1 (c7 / cause-01~e.0 :ARG1 (r / result-01~e.21 :ARG1~e.22 (r2 / rate~e.25 :ARG1-of (e / enhance-01~e.24) :ARG0-of (e2 / exceed-01~e.30 :ARG1 (i / increase-01~e.33 :ARG1~e.34 (d / die-01~e.36 :ARG1 (c3 / cell~e.35)) :time (c2 / concomitant~e.32))) :degree-of~e.26 (p / proliferate-01~e.28 :ARG0 (c / cell~e.27))) :ARG2 (d2 / differ-02~e.9 :ARG1 (c6 / cell~e.11) :ARG3 (g / grow-01~e.12 :ARG1 (c4 / cell~e.6,11 :ARG1-of (i2 / infect-01~e.5 :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "V12S35")))) :time (a / after~e.13 :op1 (r3 / reduce-01~e.15 :ARG1 (p2 / protein :name (n / name :op1 "TDAG51"~e.14)) :condition~e.20 (d3 / depend-01~e.19 :polarity~e.19 -~e.19 :ARG1 (a2 / anchorage~e.17)))))))) # ::id pmid_1859_7688.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reduction of TDAG51 in transformed cells enhances proximal ERK signaling # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 4-1.1.2.1 5-1.1.2 6-1 7-1.2.1.2 8-1.2.1.1.1 9-1.2 (e / enhance-01~e.6 :ARG0 (r / reduce-01~e.0 :ARG1~e.1 (p2 / protein :name (n / name :op1 "TDAG51"~e.2)) :location~e.3 (c / cell~e.5 :ARG1-of (t / transform-01~e.4))) :ARG1 (s / signal-07~e.9 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.8) :mod (p / proximal~e.7)))) # ::id pmid_1859_7688.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reducing TDAG51 protein levels in ERK @-@ driven cellular transformation enhanced cell growth under anchorage @-@ independent , but not attached , conditions . # ::alignments 0-1.1 1-1.1.1.1.1.1 2-1.1.1.1 3-1.1.1 4-1.1.2.r 5-1.1.2.2.1.1.1 7-1.1.2.2 8-1.1.2.1 9-1.1.2 10-1 11-1.2.1 12-1.2 14-1.3.2 16-1.3 16-1.3.1 16-1.3.1.r 18-1.3.3 19-1.3.3.1.1 19-1.3.3.1.1.r 20-1.3.3.1 22-1.3.r (e / enhance-01~e.10 :ARG0 (r / reduce-01~e.0 :ARG1 (l / level~e.3 :quant-of (p / protein~e.2 :name (n / name :op1 "TDAG51"~e.1))) :time~e.4 (t / transform-01~e.9 :ARG1 (c / cell~e.8) :ARG1-of (d / drive-02~e.7 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.5))))) :ARG1 (g / grow-01~e.12 :ARG1 c~e.11) :condition~e.22 (d2 / depend-01~e.16 :polarity~e.16 -~e.16 :ARG1 (a / anchorage~e.14) :ARG1-of (c2 / contrast-01~e.18 :ARG2 (a2 / attach-01~e.20 :polarity~e.19 -~e.19)))) # ::id pmid_1859_7688.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test whether TDAG51 might affect proximal ERK signaling , we examined the activation status of Erk in cells expressing TDAG51 @-@ specific shRNA . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.2.1.2.1.1.2.1.1.1 4-1.3.2 5-1.3.2.2 6-1.3.2.2.2.2 7-1.3.2.2.2.1 8-1.3.2.2.2 10-1.1 11-1 13-1.2.1 14-1.2 15-1.2.1.1.r 16-1.2.1.1.1.1 18-1.2.1.2 19-1.2.1.2.1 20-1.2.1.2.1.1.2.1.1.1 22-1.2.1.2.1.1 22-1.2.1.2.1.1.2 22-1.2.1.2.1.1.2.r 23-1.2.1.2.1.1.1.1 (e / examine-01~e.11 :ARG0 (w / we~e.10) :ARG1 (s / status~e.14 :mod (a / activate-01~e.13 :ARG1~e.15 (e2 / enzyme :name (n / name :op1 "Erk"~e.16)) :location (c / cell~e.18 :ARG3-of (e3 / express-03~e.19 :ARG1 (n4 / nucleic-acid~e.22 :name (n2 / name :op1 "shRNA"~e.23) :ARG1-of~e.22 (s2 / specific-02~e.22 :ARG2 (p / protein :name (n3 / name :op1 "TDAG51"~e.3,20)))))))) :purpose (t / test-01~e.1 :ARG0 w :ARG1 (p2 / possible-01~e.4 :mode~e.2 interrogative~e.2 :ARG1 (a2 / affect-01~e.5 :ARG0 p :ARG1 (s3 / signal-07~e.8 :ARG1 e2~e.7 :mod (p3 / proximal~e.6)))))) # ::id pmid_1859_7688.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the levels of phosphorylated Erk were enhanced when TDAG51 protein levels were reduced in RasV12S35 and RasV12 cells grown under anchorage @-@ independent , but not attached , conditions ( Figure 9 ) . # ::alignments 0-1.4 3-1.1 4-1.1.1.r 5-1.1.1.2 6-1.1.1.1.1 8-1 9-1.2.r 10-1.2.1.1.1.1 11-1.2.1.1 12-1.2.1 14-1.2 17-1.2.2 19-1.2.2.1 19-1.2.2.2 20-1.2.2.3 22-1.2.2.3.1.2 24-1.2.2.3.1 24-1.2.2.3.1.1 24-1.2.2.3.1.1.r 26-1.2.2.3.1.3 27-1.2.2.3.1.3.1.1 27-1.2.2.3.1.3.1.1.r 28-1.2.2.3.1.3.1 30-1.2.2.3.1.r 32-1.3.1 33-1.3.1.1 (e / enhance-01~e.8 :ARG1 (l / level~e.3 :quant-of~e.4 (e2 / enzyme :name (n / name :op1 "Erk"~e.6) :ARG3-of (p / phosphorylate-01~e.5))) :time~e.9 (r / reduce-01~e.14 :ARG1 (l2 / level~e.12 :quant-of (p2 / protein~e.11 :name (n2 / name :op1 "TDAG51"~e.10))) :location (a / and~e.17 :op1 (c4 / cell~e.19 :mod (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "V12S35"))) :op2 (c5 / cell~e.19 :mod (e4 / enzyme :name n3 :ARG2-of (m / mutate-01 :value "V12"))) :ARG1-of (g / grow-01~e.20 :condition~e.30 (d / depend-01~e.24 :polarity~e.24 -~e.24 :ARG1 (a2 / anchorage~e.22) :ARG1-of (c / contrast-01~e.26 :ARG2 (a3 / attach-01~e.28 :polarity~e.27 -~e.27)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.32 :mod 9~e.33)) :ARG0-of (i / interest-01~e.0)) # ::id pmid_1859_7688.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The fact that the activation status of Erk was unchanged in cells grown under attached conditions suggests that reducing TDAG51 expression had no selective effect with regard to ERK activation in these cells . # ::alignments 4-1.1.2.1 5-1.1.2 6-1.1.2.1.1.r 7-1.1.2.1.1.1.1 9-1.1 9-1.1.1 9-1.1.1.r 10-1.1.3.r 11-1.1.3 12-1.1.3.1 14-1.1.3.2 15-1.1.3.2.r 16-1 17-1.2.r 18-1.2.2 19-1.2.2.1.1.1.1 20-1.2.2.1 22-1.2.1 22-1.2.1.r 23-1.2.3 24-1.2 27-1.2.4.r 28-1.2.4.1.1.1 29-1.2.4 32-1.1.3 (s / suggest-01~e.16 :ARG0 (c2 / change-01~e.9 :polarity~e.9 -~e.9 :ARG1 (s3 / status~e.5 :mod (a3 / activate-01~e.4 :ARG1~e.6 (e2 / enzyme :name (n3 / name :op1 "Erk"~e.7)))) :location~e.10 (c3 / cell~e.11,32 :ARG1-of (g / grow-01~e.12) :condition~e.15 (a4 / attach-01~e.14))) :ARG1~e.17 (a / affect-01~e.24 :polarity~e.22 -~e.22 :ARG0 (r / reduce-01~e.18 :ARG1 (e / express-03~e.20 :ARG2 (p / protein :name (n / name :op1 "TDAG51"~e.19)))) :manner (s2 / selective~e.23) :topic~e.27 (a2 / activate-01~e.29 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK"~e.28) :location c3)))) # ::id pmid_1859_7688.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rather , the enhanced activation of Erk was specific to anchorage @-@ independent growth conditions . # ::alignments 0-1 3-1.1.1.2 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 8-1.1 9-1.1.2.r 10-1.1.2.2.2 12-1.1.2.2 12-1.1.2.2.1 12-1.1.2.2.1.r 13-1.1.2.1 14-1.1.2 (i / instead-of-91~e.0 :ARG1 (s / specific-02~e.8 :ARG1 (a / activate-01~e.4 :ARG1~e.5 (e2 / enzyme :name (n / name :op1 "Erk"~e.6)) :ARG1-of (e / enhance-01~e.3)) :ARG2~e.9 (c / condition~e.14 :mod (g / grow-01~e.13) :ARG0-of (d / depend-01~e.12 :polarity~e.12 -~e.12 :ARG1 (a2 / anchorage~e.10))))) # ::id pmid_1901_4680.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors ( PMID : 19014680 ) # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1.1 5-1.1.1.1 5-1.1.1.2 7-1 8-1.2.r 9-1.2.1.3 10-1.2.1 11-1.2.1.2.1.1 12-1.2.1.2.1 13-1.2.1.2 14-1.2 15-1.2.2 17-1.2.2.2 18-1.2.2.2.1.r 19-1.2.2.2.1.1 20-1.2.2.2.1 (s / suffice-01~e.7 :ARG0 (a / activate-01~e.0 :ARG1~e.1 (o / or~e.3 :op1 (i / isoform~e.5 :mod (e / enzyme :name (n / name :op1 "MEK1"~e.2))) :op2 (i2 / isoform~e.5 :mod (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.4))))) :ARG1~e.8 (a2 / and~e.14 :op1 (t / transform-01~e.10 :ARG0 a :ARG1 (c / cell~e.13 :part-of (e3 / epithelium~e.12 :part-of (i3 / intestine~e.11))) :degree (f / full~e.9)) :op2 (i4 / induce-01~e.15 :ARG0 a :ARG2 (f2 / form-01~e.17 :ARG2~e.18 (t2 / tumor~e.20 :mod (m / metastasis~e.19))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID19014680"))) # ::id pmid_1901_4680.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1901_4680.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that expression of activated MEK1 or MEK2 is sufficient to morphologically transform intestinal epithelial cells , dysregulate cell proliferation and induce the formation of high @-@ grade adenocarcinomas after orthotopic transplantation in mice . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.3 6-1.2.1.1.1.1.1 7-1.2.1.1 8-1.2.1.1.2.1.1 10-1.2 11-1.2.2.r 12-1.2.2.1.3 12-1.2.2.1.3.r 13-1.2.2.1 14-1.2.2.1.2.1.1 15-1.2.2.1.2.1 16-1.2.2.1.2 18-1.2.2.2 19-1.2.2.2.2.1 20-1.2.2.2.2 21-1.2.2 22-1.2.2.3 24-1.2.2.3.2 25-1.2.2.3.2.1.r 26-1.2.2.3.2.1.2.1 28-1.2.2.3.2.1.2 29-1.2.2.3.2.1.1.1 31-1.2.3.2 32-1.2.3 33-1.2.3.1.r 34-1.2.3.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (s / suffice-01~e.10 :ARG0 (e / express-03~e.3 :ARG2~e.4 (o / or~e.7 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.6)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.8)) :ARG1-of (a / activate-01~e.5))) :ARG1~e.11 (a2 / and~e.21 :op1 (t / transform-01~e.13 :ARG0 e :ARG1 (c / cell~e.16 :part-of (e4 / epithelium~e.15 :part-of (i / intestine~e.14))) :manner~e.12 (m / morphological~e.12)) :op2 (d / dysregulate-01~e.18 :ARG0 e :ARG1 (p / proliferate-01~e.20 :ARG0 (c2 / cell~e.19))) :op3 (i2 / induce-01~e.22 :ARG0 e :ARG2 (f2 / form-01~e.24 :ARG1~e.25 (m3 / medical-condition :name (n3 / name :op1 "adenocarcinoma"~e.29) :mod (g / grade~e.28 :ARG1-of (h / high-02~e.26)))))) :condition (t2 / transplant-01~e.32 :ARG2~e.33 (m2 / mouse~e.34) :mod (o2 / orthotopic~e.31)))) # ::id pmid_1901_4680.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A large proportion of these intestinal tumors metastasize to the liver and lung . # ::alignments 1-1.1.2.1 2-1.1.2 3-1.1.2.r 4-1.1.3 5-1.1.1 6-1.1 7-1 8-1.2.r 10-1.2.1 11-1.2 12-1.2.2 (m / metastasize-101~e.7 :ARG1 (t / tumor~e.6 :mod (i / intestine~e.5) :quant~e.3 (p / proportion~e.2 :mod (l / large~e.1)) :mod (t2 / this~e.4)) :ARG2~e.8 (a / and~e.11 :op1 (l2 / liver~e.10) :op2 (l3 / lung~e.12))) # ::id pmid_1901_4680.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mechanistically , activation of MEK1 or MEK2 up @-@ regulates the expression of matrix metalloproteinases , promotes invasiveness and protects cells from undergoing anoikis . # ::alignments 0-1.4 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1.1.1 5-1.1.2.1 6-1.1.2.1.2.1.1 11-1.1.1 12-1.1.1.1.r 13-1.1.1.1.1.1 16-1.2 18-1 19-1.3 20-1.3.2 21-1.3.3.r 22-1.3.3 23-1.3.3.2 (a / and~e.18 :op1 (u / upregulate-01 :ARG1 (e3 / express-03~e.11 :ARG2~e.12 (e4 / enzyme :name (n3 / name :op1 "matrix"~e.13 :op2 "metalloproteinase"))) :ARG2 (a2 / activate-01~e.2 :ARG1~e.3 (o / or~e.5 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.6))))) :op2 (p / promote-01~e.16 :ARG0 a2 :ARG1 (i / invade-01)) :op3 (p2 / protect-01~e.19 :ARG0 a2 :ARG1 (c / cell~e.20) :ARG2~e.21 (u2 / undergo-28~e.22 :ARG1 c :ARG2 (a3 / anoikis~e.23))) :manner (m / mechanistic~e.0)) # ::id pmid_1901_4680.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , we show that silencing of MEK2 expression completely suppresses the proliferation of human colon carcinoma cell lines , whereas inactivation of MEK1 has a much weaker effect . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1 6-1.2.1.1.1.r 7-1.2.1.1.1.1.1.1 8-1.2.1.1.1 9-1.2.1.3 10-1.2.1 12-1.2.1.2 13-1.2.1.2.1.r 14-1.2.1.2.1.2 15-1.2.1.2.1.1.2 16-1.2.1.2.1.1.1.1 17-1.2.1.2.1 18-1.2.1.2.1 20-1.2 21-1.2.2.1 21-1.2.2.1.1 21-1.2.2.1.1.r 22-1.2.2.1.2.r 23-1.2.2.1.2.1.1 26-1.2.2.3.1.1 27-1.2.2.3 27-1.2.2.3.1 27-1.2.2.3.1.r 28-1.2.2 (s / show-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (c / contrast-01~e.20 :ARG1 (s2 / suppress-01~e.10 :ARG0 (s3 / silence-01~e.5 :ARG1~e.6 (e / express-03~e.8 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"~e.7)))) :ARG1 (p / proliferate-01~e.12 :ARG0~e.13 (c3 / cell-line~e.17,18 :mod (m3 / medical-condition :name (n2 / name :op1 "carcinoma"~e.16) :mod (c4 / colon~e.15)) :mod (h / human~e.14))) :degree (c2 / complete~e.9)) :ARG2 (a / affect-01~e.28 :ARG0 (a2 / activate-01~e.21 :polarity~e.21 -~e.21 :ARG1~e.22 (e3 / enzyme :name (n3 / name :op1 "MEK1"~e.23))) :ARG1 p :ARG1-of (w2 / weak-02~e.27 :degree~e.27 (m / more~e.27 :degree (m2 / much~e.26))))) :mod (i / important~e.0)) # ::id pmid_1901_4680.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1901_4680.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutive activation of MEK1 or MEK2 is sufficient for transformation of intestinal epithelial cells and formation of tumors in vivo @ # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 8-1 9-1.2.r 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.1 13-1.2.1.1.1 14-1.2.1.1 15-1.2 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1 20-1.2.2.2 21-1.2.2.2 (s / suffice-01~e.8 :ARG0 (a / activate-01~e.2 :ARG1~e.3 (o / or~e.5 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.6))) :mod (c / constitutive~e.1)) :ARG1~e.9 (a2 / and~e.15 :op1 (t / transform-01~e.10 :ARG1~e.11 (c2 / cell~e.14 :part-of (e3 / epithelium~e.13 :part-of (i / intestine~e.12)))) :op2 (f / form-01~e.16 :ARG1~e.17 (t2 / tumor~e.18) :manner (i2 / in-vivo~e.20,21)))) # ::id pmid_1901_4680.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunohistochemistry analysis of a colorectal cancer tissue microarray containing over 400 colorectal cancer and 50 normal colon tissue biopsies revealed that 44 % of colorectal cancers display high cytoplasmic expression of phosphorylated MEK1 @/@ MEK2 as compared to 10 % of normal tissues ( analysis to be published elsewhere ) . # ::alignments 0-1.1.2 1-1.1 4-1.1.1.1.1.2.1 5-1.1.1.1.1.2.2 6-1.1.1.1 7-1.1.1 8-1.1.1.2 9-1.1.1.2.1.1.2 10-1.1.1.2.1.1.2.1 11-1.1.1.2.1.1.1 12-1.1.1.2.1.1.1 13-1.1.1.2.1 14-1.1.1.2.1.2.1 15-1.1.1.2.1.2.2.2 16-1.1.1.2.1.2.2.1 17-1.1.1.2.1.2.2 17-1.2.1.4 18-1.1.1.2.1.1 18-1.1.1.2.1.2 19-1 20-1.2.r 21-1.2.1.3.2.1 22-1.2.1.3.2 24-1.1.1.2.1.2.2.1 25-1.2.1.2.1 26-1.2 26-1.2.1.4.1 27-1.2.2.3 28-1.2.2.2 29-1.2.2 30-1.2.2.1.r 31-1.2.2.1.3 32-1.2.2.1.1.1.1 34-1.2.2.1.2.1.1 36-1.2.1.4.r 38-1.2.1.4.2.2.1 39-1.2.1.4.2.2 41-1.1.1.2.1.2.2.2 42-1.1.1.2.1.2.2 42-1.2.1.4.2.1 44-1.1 47-1.1.3.1 48-1.1.3.1.2 (r / reveal-01~e.19 :ARG0 (a / analyze-01~e.1,44 :ARG1 (m / microarray~e.7 :mod (t2 / tissue~e.6 :mod (d6 / disease :wiki "Colorectal_cancer" :name (n10 / name :op1 "colorectal"~e.4 :op2 "cancer"~e.5))) :ARG0-of (c2 / contain-01~e.8 :ARG1 (a2 / and~e.13 :op1 (b / biopsy~e.18 :mod t2~e.11,12 :quant (o / over~e.9 :op1 400~e.10)) :op2 (b2 / biopsy~e.18 :quant 50~e.14 :mod (t3 / tissue~e.17,42 :part-of (c3 / colon~e.16,24) :ARG1-of (n2 / normal-02~e.15,41)))))) :instrument (i3 / immunohistochemistry~e.0) :ARG1-of (s / suppose-02 :ARG2 (p4 / publish-01~e.47 :ARG1 a :location (e4 / elsewhere~e.48)))) :ARG1~e.20 (d2 / display-01~e.26 :ARG0 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.25) :ARG1-of (i / include-91 :ARG2 d6 :ARG3 (p / percentage-entity~e.22 :value 44~e.21)) :compared-to~e.36 (t / tissue~e.17 :ARG0-of (d4 / display-01~e.26 :ARG1 e) :ARG1-of (i2 / include-91 :ARG2 (t4 / tissue~e.42 :ARG1-of n2) :ARG3 (p3 / percentage-entity~e.39 :value 10~e.38)))) :ARG1 (e / express-03~e.29 :ARG2~e.30 (a4 / and :op1 (e2 / enzyme :name (n5 / name :op1 "MEK1"~e.32)) :op2 (e3 / enzyme :name (n6 / name :op1 "MEK2"~e.34)) :ARG3-of (p2 / phosphorylate-01~e.31)) :ARG3 (c5 / cytoplasm~e.28) :ARG1-of (h / high-02~e.27)))) # ::id pmid_1901_4680.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the functional significance of MEK1 @/@ MEK2 activation in colorectal cancer , we ectopically expressed wild type and constitutively active ( DD mutant ) versions of MEK1 and MEK2 by retroviral gene transfer in the normal undifferentiated intestinal epithelial cell line IEC @-@ 6 [ @ 27 @ ] . # ::alignments 0-1.6 1-1.3 3-1.3.2.2 4-1.3.2 5-1.3.2.1.r 6-1.3.2.1.1.1.1.1 8-1.3.2.1.1.2.1.1 9-1.1.2 9-1.1.2.2 9-1.1.2.2.r 9-1.3.2.1 10-1.3.2.1.2.r 11-1.3.2.1.2.2.1 12-1.3.2.1.2.2.2 14-1.6.1 16-1 17-1.1.1.2 17-1.1.3.2 18-1.1.1.2 18-1.1.3.2 19-1.1 20-1.1.2.2.1 20-1.1.2.2.1.r 23-1.1.2.2.2.1.1.1 24-1.1.2.2.2.1 24-1.1.2.2.2.1.2 24-1.1.2.2.2.1.2.r 28-1.1.1.1.1 28-1.1.2.1.1 29-1.1 30-1.1.3.1.1 30-1.1.4.1.1 30-1.3.2.1.1.2.1.1 31-1.4.r 32-1.4.2 33-1.4.1 34-1.4 35-1.3.2.1.2.r 35-1.4.3.r 37-1.4.3.3 39-1.4.3.2.1 40-1.4.3.2 41-1.4.3 42-1.4.3 43-1.4.3.1.1 45-1.4.3.1.1 48-1.5.1.1.1 (e / express-03~e.16 :ARG2 (a / and~e.19,29 :op1 (e3 / enzyme :name (n / name :op1 "MEK1"~e.28) :mod (w2 / wild-type~e.17,18)) :op2 (e4 / enzyme~e.9 :name (n2 / name :op1 "MEK1"~e.28) :ARG1-of~e.9 (a5 / activate-01~e.9 :manner~e.20 (c4 / constitutive~e.20) :ARG1-of (m / mean-01 :ARG2 (p2 / protein-segment~e.24 :name (n10 / name :op1 "DD"~e.23) :ARG2-of~e.24 (m2 / mutate-01~e.24))))) :op3 (e5 / enzyme :name (n3 / name :op1 "MEK2"~e.30) :mod (w3 / wild-type~e.17,18)) :op4 (e6 / enzyme :name (n4 / name :op1 "MEK2"~e.30) :ARG0-of a5)) :manner (e2 / ectopic) :purpose (a2 / assess-01~e.1 :ARG0 w :ARG1 (s / significant-02~e.4 :ARG1~e.5 (a3 / activate-01~e.9 :ARG1 (a4 / and :op1 (e7 / enzyme :name (n5 / name :op1 "MEK1"~e.6)) :op2 (e8 / enzyme :name (n6 / name :op1 "MEK2"~e.8,30))) :prep-in~e.10,35 (d4 / disease :wiki "Colorectal_cancer" :name (n11 / name :op1 "colorectal"~e.11 :op2 "cancer"~e.12))) :ARG0-of (f / function-01~e.3))) :manner~e.31 (t / transfer-01~e.34 :ARG1 (g / gene~e.33) :mod (r / retroviral~e.32) :location~e.35 (c2 / cell-line~e.41,42 :name (n8 / name :op1 "IEC-6"~e.43,45) :part-of (e9 / epithelium~e.40 :part-of (i / intestine~e.39)) :ARG1-of (n7 / normal-02~e.37) :ARG1-of (d2 / differentiate-01 :polarity -))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 27~e.48))) :ARG1-of (c5 / cause-01~e.0 :ARG0 (w / we~e.14))) # ::id pmid_1901_4680.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Polyclonal populations of infected clones were selected in puromycin and used for subsequent experiments . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1 4-1.1.1.1 6-1.1 7-1.1.2.r 8-1.1.2.1.1 9-1 10-1.2 11-1.2.2.r 12-1.2.2.1 12-1.2.2.1.r 13-1.2.2 (a / and~e.9 :op1 (s / select-01~e.6 :ARG1 (p / population~e.1 :mod~e.2 (c / clone~e.4 :ARG1-of (i / infect-01~e.3)) :mod (p2 / polyclonal~e.0)) :location~e.7 (s2 / small-molecule :name (n / name :op1 "puromycin"~e.8))) :op2 (u / use-01~e.10 :ARG1 p :purpose~e.11 (e / experiment-01~e.13 :time~e.12 (s3 / subsequent~e.12)))) # ::id pmid_1901_4680.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblot analysis confirmed that ectopic MEK isoforms are expressed at comparable levels in IEC @-@ 6 transduced populations ( Fig . 1A ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.1.1.1.1.2 5-1.2.1.1.1.1.1.1.1 6-1.2.1.1.1.1 8-1.2.1.1.1 11-1.2.1.1 12-1.2.1.1.1.2.r 13-1.2.1.1.1.2.1.1.1.1 15-1.2.1.1.1.2.1.1.1.1 16-1.2.1.1.1.2.1 17-1.2.1.1.1.2 19-1.3.1 22-1.3.1.1 (c / confirm-01~e.2 :ARG0 (a2 / analyze-01~e.1 :manner (i2 / immunoblot-01~e.0)) :ARG1 (p / possible-01 :ARG1 (c2 / compare-01 :ARG1 (l / level~e.11 :quant-of (e2 / express-03~e.8 :ARG2 (i / isoform~e.6 :mod (e / enzyme :name (n / name :op1 "MEK"~e.5)) :mod (e3 / ectopic~e.4)) :ARG3~e.12 (p2 / population~e.17 :ARG1-of (t / transduce-01~e.16 :ARG2 (c3 / cell-line :name (n3 / name :op1 "IEC-6"~e.13,15)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "1A"~e.22))) # ::id pmid_1901_4680.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of wild type MEK1 or MEK2 did not affect the expression of endogenous MEK isoforms . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.3 3-1.2.1.3 4-1.2.1.1.1.1 5-1.2.1 6-1.2.1.2.1.1 8-1.1 8-1.1.r 9-1 11-1.3 12-1.3.1.r 13-1.3.1.2 14-1.3.1.1.1.1 15-1.3.1 (a / affect-01~e.9 :polarity~e.8 -~e.8 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (o2 / or~e.5 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.6)) :mod (w / wild-type~e.2,3))) :ARG1 (e3 / express-03~e.11 :ARG2~e.12 (i / isoform~e.15 :mod (e4 / enzyme :name (n3 / name :op1 "MEK"~e.14)) :mod (e5 / endogenous~e.13)))) # ::id pmid_1901_4680.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , ectopic expression or MEK2DD slightly increased the steady @-@ state levels of endogenous MEK1 , while overexpression of MEK1DD had a similar effect on MEK2 levels ( Fig . 1B ) . # ::alignments 0-1 0-1.1 0-1.1.r 2-1.1.1.1.2 3-1.1.1.1 5-1.1.1.1.1.1.1 6-1.1.1.3 7-1.1.1 9-1.1.1.2.2.1 11-1.1.1.2.2 12-1.1.1.2 13-1.1.1.2.1.r 14-1.1.1.2.1.2 15-1.1.1.2.1.1.1 17-1.1 18-1.1.2.1.1 19-1.1.2.1.1.1.r 20-1.1.2.1.1.1.1.1 23-1.1.2 24-1.1.2.1 25-1.1.2.1.2.r 26-1.1.2.1.2.1.1.1 27-1.1.2.1.2 29-1.1.3.1 32-1.1.3.1.1 (c2 / contrast-01~e.0 :ARG2~e.0 (c / contrast-01~e.0,17 :ARG1 (i / increase-01~e.7 :ARG0 (e / express-03~e.3 :ARG2 (e3 / enzyme :name (n / name :op1 "MEK2DD"~e.5)) :mod (e2 / ectopic~e.2)) :ARG1 (l / level~e.12 :quant-of~e.13 (e4 / enzyme :name (n2 / name :op1 "MEK1"~e.15) :mod (e5 / endogenous~e.14)) :mod (s / state~e.11 :mod (s2 / steady~e.9))) :ARG2 (s3 / slight~e.6)) :ARG2 (r / resemble-01~e.23 :ARG1 (a / affect-01~e.24 :ARG0 (o / overexpress-01~e.18 :ARG1~e.19 (e6 / enzyme :name (n3 / name :op1 "MEK1DD"~e.20))) :ARG1~e.25 (l2 / level~e.27 :quant-of (e7 / enzyme :name (n4 / name :op1 "MEK2"~e.26)))) :ARG2 i) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "1B"~e.32)))) # ::id pmid_1901_4680.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , substitution of the activation loop Ser phosphorylation sites by Asp residues strongly potentiated the enzymatic activity of MEK1 and MEK2 , but no reproducible difference in activity was observed between the two isoforms ( Fig . 1C ) . # ::alignments 1-1.1.4 3-1.1.2 4-1.1.2.2.r 6-1.1.2.2.2.1 7-1.1.2.2.2 8-1.1.2.2.1.1.1.1 9-1.1.2.2.1 10-1.1.2.2 13-1.1.2.1 14-1.1.3 14-1.1.3.r 17-1.1.1.1.3 18-1.1.1 19-1.1.1.1.r 20-1.1.1.1.1.1.1 21-1.1.1.1 22-1.1.1.1.2.1.1 24-1 25-1.2.1.r 27-1.2.1 27-1.2.1.r 27-1.2.2 28-1.2.2.3.r 29-1.2.2.3 31-1.2 37-1.3.1 40-1.3.1.1 (c / contrast-01~e.24 :ARG1 (p2 / potentiate-01 :ARG1 (a / activity-06~e.18 :ARG0~e.19 (a2 / and~e.21 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.20)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.22)) :mod (e3 / enzyme~e.17))) :ARG2 (s / substitute-01~e.3 :ARG1 (r / residue~e.13 :mod (a6 / amino-acid :name (n3 / name :op1 "aspartic" :op2 "acid"))) :ARG2~e.4 (s4 / site~e.10 :location-of (p / phosphorylate-01~e.9 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "serine"~e.8))) :mod (l / loop~e.7 :mod (a4 / activate-01~e.6)))) :manner~e.14 (s2 / strong~e.14) :ARG1-of (e4 / expect-01~e.1)) :ARG2 (o / observe-01~e.31 :polarity~e.25,27 -~e.27 :ARG1 (d / differ-02~e.27 :ARG1 e :ARG2 e2 :ARG3~e.28 (a5 / activity-06~e.29) :ARG1-of (r2 / reproduce-01 :ARG1-of (p3 / possible-01)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.37 :mod "1C"~e.40))) # ::id pmid_1901_4680.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IEC @-@ 6 cells grow as a monolayer and display a typical epithelial morphology with organized cell @-@ cell adhesions ( Fig . 1D ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1.1 4-1.1 5-1.1.2.r 7-1.1.2 8-1 9-1.2 11-1.2.2.1 12-1.2.2.2 13-1.2.2 14-1.2.2.3.r 15-1.2.2.3.3 16-1.2.2.3.1 18-1.2.2.3.1 18-1.2.2.3.2 19-1.2.2.3 21-1.3.1 24-1.3.1.1 (a / and~e.8 :op1 (g / grow-01~e.4 :ARG1 (c / cell-line~e.3 :name (n / name :op1 "IEC-6"~e.0,2)) :manner~e.5 (m / monolayer~e.7)) :op2 (d / display-01~e.9 :ARG0 c :ARG1 (m2 / morphology~e.13 :ARG1-of (t / typical-02~e.11) :mod (e / epithelium~e.12) :accompanier~e.14 (a2 / adhere-01~e.19 :ARG1 (c2 / cell~e.16,18) :ARG2 (c3 / cell~e.18) :ARG1-of (o / organize-01~e.15)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.21 :mod "1D"~e.24))) # ::id pmid_1901_4680.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of wild type MEK isoforms had no noticeable effect on the morphology of IEC @-@ 6 cells . # ::alignments 0-1.2.1.1 1-1.2.1.1.1.r 2-1.2.1.1.1.1.2 3-1.2.1.1.1.1.2 4-1.2.1.1.1.1.1.1 5-1.2.1.1.1 7-1.1 7-1.1.r 9-1.2.1 10-1.2.1.2.r 12-1.2.1.2 13-1.2.1.2.1.r 14-1.2.1.2.1.1.1 16-1.2.1.2.1.1.1 17-1.2.1.2.1 (p / possible-01 :polarity~e.7 -~e.7 :ARG1 (n3 / notice-01 :ARG1 (a / affect-01~e.9 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (i / isoform~e.5 :mod (e / enzyme :name (n / name :op1 "MEK"~e.4) :mod (w / wild-type~e.2,3)))) :ARG1~e.10 (m / morphology~e.12 :mod~e.13 (c / cell-line~e.17 :name (n2 / name :op1 "IEC-6"~e.14,16)))))) # ::id pmid_1901_4680.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , expression of activated MEK1 or MEK2 led to drastic morphological changes accompanied by loss of cell @-@ cell contacts ; the cells adopted a spindle @-@ like fibroblast morphology , were more refractile and formed multilayers . # ::alignments 1-1.1 3-1.1.1.1 4-1.1.1.1.1.r 5-1.1.1.1.1.3 6-1.1.1.1.1.1.1.1 7-1.1.1.1.1 8-1.1.1.1.1.2.1.1 9-1.1.1 10-1.1.1.2.r 11-1.1.1.2.2 12-1.1.1.2.1 13-1.1.1.2 14-1.1.1.2.3 15-1.1.1.2.3.1.r 16-1.1.1.2.3.1 17-1.1.1.2.3.1.1.r 18-1.1.1.2.3.1.1.1 20-1.1.1.2.3.1.1.1 20-1.1.1.2.3.1.1.2 21-1.1.1.2.3.1.1 24-1.2.1.1 25-1.2.1 27-1.2.1.2.2.1 29-1.2.1.2.2 30-1.2.1.2.1 31-1.2.1.2 33-1.2.2.1.r 34-1.2.2.2 35-1.2.2 36-1.2 37-1.2.3 (m / multi-sentence :snt1 (c / contrast-01~e.1 :ARG2 (l / lead-03~e.9 :ARG0 (e / express-03~e.3 :ARG2~e.4 (o / or~e.7 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.6)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.8)) :ARG1-of (a / activate-01~e.5))) :ARG2~e.10 (c2 / change-01~e.13 :ARG1 (m2 / morphology~e.12) :mod (d / drastic~e.11) :ARG1-of (a2 / accompany-01~e.14 :ARG0~e.15 (l2 / lose-02~e.16 :ARG1~e.17 (c3 / contact-01~e.21 :ARG0 (c4 / cell~e.18,20) :ARG1 (c5 / cell~e.20))))))) :snt2 (a3 / and~e.36 :op1 (a4 / adopt-01~e.25 :ARG0 (c6 / cell~e.24) :ARG1 (m3 / morphology~e.31 :mod (f / fibroblast~e.30) :ARG1-of (r / resemble-01~e.29 :ARG2 (s / spindle~e.27)))) :op2 (r2 / refractile~e.35 :domain~e.33 c6 :degree (m4 / more~e.34)) :op3 (f2 / form-01~e.37 :ARG0 c6 :ARG1 (m5 / multilayer)))) # ::id pmid_1901_4680.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These changes are characteristic of epithelial @-@ mesenchymal transitions ( EMT ) that play an important role in tumor progression [ @ 39 @ ] . # ::alignments 0-1.2.1 1-1.2 3-1 4-1.1.r 5-1.1.1.1 7-1.1.1.1 8-1.1.1.2 10-1.1.1.1 10-1.1.1.2 13-1.1 13-1.1.2 13-1.1.2.r 15-1.1.2.1.2 16-1.1.2.1 17-1.1.2.1.1.r 18-1.1.2.1.1.1 19-1.1.2.1.1 22-1.3.1.1.1 (c / characteristic-02~e.3 :ARG1~e.4 (e / event~e.13 :name (n / name :op1 "epithelial-mesenchymal"~e.5,7,10 :op2 "transition"~e.8,10) :ARG0-of~e.13 (p / play-02~e.13 :ARG1 (r / role~e.16 :prep-in~e.17 (p2 / progress-01~e.19 :ARG1 (t2 / tumor~e.18)) :mod (i / important~e.15)))) :ARG2 (c2 / change-01~e.1 :mod (t / this~e.0)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 39~e.22)))) # ::id pmid_1901_4680.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether MEK1DD @- and MEK2DD @-@ expressing cells undergo an EMT , we examined the localization and measured the expression levels of various epithelial and mesenchymal markers . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.2.1.1.1.1.1 5-1.3.2.2 6-1.3.2.2.2.1.1.1.1 8-1.3.2.2.1.1 8-1.3.2.2.2.1 9-1.3.2.2.1 9-1.3.2.2.2 10-1.3.2 12-1.3.2.3.1.1 12-1.3.2.3.1.2 14-1.1.1 15-1.1 17-1.1.2 18-1 19-1.2 21-1.2.2.1 22-1.2.2 23-1.2.2.1.1.r 24-1.2.2.1.1.3 25-1.2.2.1.1.1.1 26-1.2.2.1.1 27-1.2.2.1.1.2.1 28-1.2.2.1.1.1 28-1.2.2.1.1.2 (a / and~e.18 :op1 (e / examine-01~e.15 :ARG0 (w / we~e.14) :ARG1 (b / be-located-at-91~e.17 :ARG1 a3)) :op2 (m / measure-01~e.19 :ARG0 w :ARG1 (l2 / level~e.22 :quant-of (e7 / express-03~e.21 :ARG2~e.23 (a3 / and~e.26 :op1 (m2 / marker~e.28 :mod (e8 / epithelium~e.25)) :op2 (m3 / marker~e.28 :mod (m4 / mesenchymal~e.27)) :mod (v / various~e.24))))) :purpose (d / determine-01~e.1 :ARG0 w :ARG1 (u / undergo-28~e.10 :mode~e.2 interrogative~e.2 :ARG1 (a2 / and~e.5 :op1 (c / cell~e.9 :ARG3-of (e2 / express-03~e.8 :ARG2 (e3 / enzyme :name (n / name :op1 "MEK1DD"~e.3)))) :op2 (c2 / cell~e.9 :ARG3-of (e4 / express-03~e.8 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MEK2DD"~e.6))))) :ARG2 (e6 / event :name (n3 / name :op1 "epithelial-mesenchymal"~e.12 :op2 "transition"~e.12))))) # ::id pmid_1901_4680.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Parental and vector @-@ infected IEC @-@ 6 cells showed a polarized basolateral membrane distribution of the epithelial marker E @-@ cadherin , with basal expression of the fibroblast marker vimentin ( Fig . 1E ) . # ::alignments 0-1.1.1.2 1-1.1 2-1.1.2.2.1 4-1.1.2.2 5-1.1.1.1.1 5-1.1.2.1.1 7-1.1.1.1.1 7-1.1.2.1.1 8-1.1.1 8-1.1.2 9-1 11-1.2.3 12-1.2.2.1 13-1.2.2 14-1.2 15-1.2.1.r 17-1.2.1.2 18-1.2.1 19-1.2.1.1.1 21-1.2.1.1.1 23-1.2.4.r 24-1.2.4.2 25-1.2.4 26-1.2.4.1.r 28-1.2.4.1.1 29-1.2.4.1 30-1.2.4.1.2.1.1 32-1.3.1 35-1.3.1.1 (s / show-01~e.9 :ARG0 (a / and~e.1 :op1 (c / cell-line~e.8 :name (n / name :op1 "IEC-6"~e.5,7) :mod (p / parent~e.0)) :op2 (c2 / cell-line~e.8 :name (n2 / name :op1 "IEC-6"~e.5,7) :ARG1-of (i / infect-01~e.4 :ARG2 (v / vector~e.2)))) :ARG1 (d / distribute-01~e.14 :ARG1~e.15 (m4 / marker~e.18 :name (n3 / name :op1 "E-cadherin"~e.19,21) :mod (e / epithelium~e.17)) :ARG2 (m / membrane~e.13 :mod (b / basolateral~e.12)) :ARG1-of (p2 / polarize-01~e.11) :accompanier~e.23 (e2 / express-03~e.25 :ARG2~e.26 (m3 / marker~e.29 :mod (f / fibroblast~e.28) :mod (p4 / protein :name (n4 / name :op1 "vimentin"~e.30))) :mod (b2 / basal~e.24))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.32 :mod "1E"~e.35))) # ::id pmid_1901_4680.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ectopic expression of MEK1DD or MEK2DD resulted in the loss of E @-@ cadherin staining at the plasma membrane ( Fig . 1E ) , concomitant with a marked reduction of E @-@ cadherin protein and mRNA levels ( Fig . 1F and 1G ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1 7-1.2.r 9-1.2 10-1.2.1.r 11-1.2.1.1.1.1 13-1.2.1.1.1.1 14-1.2.1 15-1.2.1.2.r 17-1.2.1.2.1 18-1.2.1.2 20-1.2.2.1 23-1.2.2.1.1 27-1.2.3.3 30-1.2.3.2 31-1.2.3 33-1.2.1.1.1.1 35-1.2.1.1.1.1 36-1.2.1.1 37-1.2.3.1 37-1.2.3.4.1 38-1.2.3.1.2.1.1.1 39-1.2.3.1.1 39-1.2.3.1.2 41-1.2.3.4.1.1 41-1.2.3.4.1.2 44-1.2.3.4.1.1.1 46-1.2.3.4.1 48-1.2.3.4.1.2.1 (r / result-01~e.6 :ARG1 (e / express-03~e.1 :ARG2~e.2 (o / or~e.4 :op1 (e3 / enzyme :name (n / name :op1 "MEK1DD"~e.3)) :op2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD"~e.5))) :mod (e2 / ectopic~e.0)) :ARG2~e.7 (l / lose-02~e.9 :ARG1~e.10 (s / stain-01~e.14 :ARG1 (p / protein~e.36 :name (n3 / name :op1 "E-cadherin"~e.11,13,33,35)) :location~e.15 (m / membrane~e.18 :mod (p2 / plasma~e.17))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "1E"~e.23)) :time (r2 / reduce-01~e.31 :ARG1 (a / and~e.37 :op1 (l2 / level~e.39 :quant-of p) :op2 (l3 / level~e.39 :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.38)))) :ARG2 (m2 / mark-01~e.30) :manner (c / concomitant~e.27) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.37,46 :op1 (f2 / figure~e.41 :mod "1F"~e.44) :op2 (f3 / figure~e.41 :mod "1G"~e.48)))))) # ::id pmid_1901_4680.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No significant change in the expression of keratins and no induction of the mesenchymal proteins vimentin and smooth muscle α-actin ( we instead observed a decreased expression ) were observed in these cells ( Fig . 1F ) . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1.1.1.r 5-1.1.1.1 7-1.1.1.1.1.1.1 8-1.1 10-1.1.2 11-1.1.2.1.r 13-1.1.2.1.3 14-1.1.1.1.1 14-1.1.2.1.1 14-1.1.2.1.2 15-1.1.2.1.1.1.1 16-1.1.2.1 17-1.1.2.1.2.1.1 18-1.1.2.1.2.1.2 19-1.1.2.1.2.1.3 21-1.4.1.1 22-1.4 23-1 23-1.4.1 25-1.4.1.2.1 26-1.4.1.2 29-1.4.1 30-1.2.r 31-1.2.1 32-1.2 34-1.3.1 37-1.3.1.1 (o / observe-01~e.23 :ARG1 (a / and~e.8 :op1 (c / change-01~e.2 :ARG1~e.3 (e / express-03~e.5 :ARG2 (p / protein~e.14 :name (n / name :op1 "keratin"~e.7))) :ARG1-of (s / significant-02~e.1)) :op2 (i / induce-01~e.10 :ARG2~e.11 (a2 / and~e.16 :op1 (p2 / protein~e.14 :name (n2 / name :op1 "vimentin"~e.15)) :op2 (p3 / protein~e.14 :name (n3 / name :op1 "smooth"~e.17 :op2 "muscle"~e.18 :op3 "α-actin"~e.19)) :mod (m / mesenchymal~e.13)))) :location~e.30 (c2 / cell~e.32 :mod (t / this~e.31)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "1F"~e.37)) :ARG2-of (i2 / instead-of-91~e.22 :ARG1 (o2 / observe-01~e.23,29 :ARG0 (w / we~e.21) :ARG1 (e2 / express-03~e.26 :ARG1-of (d2 / decrease-01~e.25))))) # ::id pmid_1901_4680.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that constitutive activation of MEK1 or MEK2 , while disrupting normal epithelial morphology and polarization , is not sufficient to induce a full EMT in intestinal epithelial cells . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.2.2.2 5-1.2.2.2 6-1.2.2.2.1.r 7-1.2.2.2.1.1.1.1 8-1.2.2.2.1 9-1.2.2.2.1.2.1.1 11-1.2 12-1.2.1 13-1.2.1.2.1.1 14-1.2.1.2.1.2 15-1.2.1.2.1 16-1.2.1.2 17-1.2.1.2.2 20-1.2.2.1 20-1.2.2.1.r 21-1.2.2 23-1.2.2.3 25-1.2.2.3.3 25-1.2.2.3.3.2 25-1.2.2.3.3.2.r 26-1.2.2.3.3.1.1 26-1.2.2.3.3.1.2 27-1.2.2.3.2.r 28-1.2.2.3.2.1.1 29-1.2.2.3.2.1 30-1.2.2.3.2 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (c3 / contrast-01~e.11 :ARG1 (d / disrupt-01~e.12 :ARG0 a :ARG1 (a2 / and~e.16 :op1 (m / morphology~e.15 :ARG1-of (n4 / normal-02~e.13) :mod (e5 / epithelium~e.14)) :op2 (p / polarize-01~e.17 :ARG1 e5))) :ARG2 (s / suffice-01~e.21 :polarity~e.20 -~e.20 :ARG0 (a / activate-01~e.5 :ARG1~e.6 (o / or~e.8 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.7)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.9))) :mod (c / constitutive~e.4)) :ARG1 (i2 / induce-01~e.23 :ARG0 a :ARG1~e.27 (c2 / cell~e.30 :part-of (e4 / epithelium~e.29 :part-of (i3 / intestine~e.28))) :ARG2 (e3 / event~e.25 :name (n3 / name :op1 "epithelial-mesenchymal"~e.26 :op2 "transition"~e.26) :ARG1-of~e.25 (f / full-09~e.25)))))) # ::id pmid_1901_4680.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This epithelial plasticity change has been referred to as scattering and is distinct from EMT [ @ 40 @ ] . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 2-1.1.1.1 3-1.1.1 9-1.1.2 10-1 11-1.2.1.r 12-1.2 13-1.2.2.r 14-1.2.2.1.1 14-1.2.2.1.2 17-1.3.1.1.1 (a / and~e.10 :op1 (r / reference-04 :ARG1 (c / change-01~e.3 :ARG1 (p / plasticity~e.2 :mod (e / epithelium~e.1)) :mod (t / this~e.0)) :ARG2 (s / scatter-01~e.9)) :op2 (d / distinct~e.12 :domain~e.11 c :compared-to~e.13 (e3 / event :name (n2 / name :op1 "epithelial-mesenchymal"~e.14 :op2 "transition"~e.14))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 40~e.17)))) # ::id pmid_1901_4680.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We examined whether constitutive activation of MEK1 or MEK2 was conferring some proliferation advantage to intestinal epithelial cells . # ::alignments 0-1.1 1-1 2-1.2.1 2-1.2.1.r 3-1.2.2.1.3 4-1.2.2 5-1.2.2.1.r 6-1.2.2.1.1.1.1 7-1.2.2.1 8-1.2.2.1.2.1.1 10-1.2 11-1.2.3.2 12-1.2.3.1 13-1.2.3 14-1.2.4.r 15-1.2.4.1.1 16-1.2.4.1 17-1.2.4 (e / examine-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / confer-02~e.10 :mode~e.2 interrogative~e.2 :ARG0 (a / activate-01~e.4 :ARG1~e.5 (o / or~e.7 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.6)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.8)) :mod (c2 / constitutive~e.3))) :ARG1 (a2 / advantage~e.13 :mod (p / proliferate-01~e.12) :mod (s / some~e.11)) :ARG2~e.14 (c3 / cell~e.17 :part-of (e4 / epithelium~e.16 :part-of (i / intestine~e.15))))) # ::id pmid_1901_4680.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ectopic expression of either activated MEK1 or MEK2 significantly increased the proliferation rate of IEC @-@ 6 cells grown in 10 % serum containing @-@ medium when compared to vector @-@ infected cells or cells overexpressing wild type MEK isoforms ( Fig . 2A ) . # ::alignments 0-1.1.2 1-1.1 4-1.1.1.3 5-1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1 8-1.3 9-1 11-1.2.1 12-1.2 13-1.2.1.1.r 14-1.2.1.1.1.1 16-1.2.1.1.1.1 17-1.2.1.1 18-1.2.1.1.2 19-1.2.1.1.2.1.r 20-1.2.1.1.2.1.1.1.1.1 21-1.2.1.1.2.1.1.1.1 22-1.2.1.1.2.1.1.1 23-1.2.1.1.2.1.1 25-1.2.1.1.2.1 27-1.2.1.1.3.r 29-1.2.1.1.3.1.1.1 31-1.2.1.1.3.1.1 32-1.2.1.1.3.1 33-1.2.1.1.3 34-1.2.1.1.3.2 35-1.2.1.1.3.2.1 36-1.2.1.1.3.2.1.1.1.2 37-1.2.1.1.3.2.1.1.1.2 38-1.2.1.1.3.2.1.1.1.1.1 39-1.2.1.1.3.2.1.1 41-1.4.1 44-1.4.1.1 (i / increase-01~e.9 :ARG0 (e2 / express-03~e.1 :ARG2 (o / or~e.6 :op1 (e4 / enzyme :name (n2 / name :op1 "MEK1"~e.5)) :op2 (e5 / enzyme :name (n3 / name :op1 "MEK2"~e.7)) :ARG1-of (a / activate-01~e.4)) :mod (e3 / ectopic~e.0)) :ARG1 (r / rate~e.12 :mod (p2 / proliferate-01~e.11 :ARG0~e.13 (c / cell-line~e.17 :name (n4 / name :op1 "IEC-6"~e.14,16) :ARG1-of (g / grow-01~e.18 :location~e.19 (m / medium~e.25 :ARG0-of (c2 / contain-01~e.23 :ARG1 (s2 / serum~e.22 :mod (p / percentage-entity~e.21 :value 10~e.20))))) :compared-to~e.27 (o2 / or~e.33 :op1 (c3 / cell~e.32 :ARG1-of (i2 / infect-01~e.31 :ARG2 (v / vector~e.29))) :op2 (c4 / cell~e.34 :location-of (o3 / overexpress-01~e.35 :ARG1 (i3 / isoform~e.39 :mod (e / enzyme :name (n / name :op1 "MEK"~e.38) :mod (w / wild-type~e.36,37))))))))) :ARG2 (s / significant-02~e.8) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.41 :mod "2A"~e.44))) # ::id pmid_1901_4680.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This increase in proliferation was not observed in low serum ( 2 %) containing @-@ medium ( data not shown ) . # ::alignments 0-1.2.2 1-1.2 2-1.2.1.r 3-1.2.1 5-1.1 5-1.1.r 6-1 7-1.2.3.r 8-1.2.3.1.1.2 9-1.2.3.1.1 11-1.2.3.1.1.1.1 13-1.2.3.1 15-1.2.3 17-1.3.1 18-1.3.1.1.1 18-1.3.1.1.1.r 19-1.3.1.1 (o / observe-01~e.6 :polarity~e.5 -~e.5 :ARG1 (i / increase-01~e.1 :ARG1~e.2 (p2 / proliferate-01~e.3) :mod (t / this~e.0) :location~e.7 (m / medium~e.15 :ARG0-of (c / contain-01~e.13 :ARG1 (s / serum~e.9 :mod (p / percentage-entity :value 2~e.11) :ARG1-of (l / low-04~e.8))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.17 :ARG1-of (s2 / show-01~e.19 :polarity~e.18 -~e.18)))) # ::id pmid_1901_4680.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both activated MEK1 and MEK2 conferred anchorage @-@ independence growth to IEC @-@ 6 cells ( Fig . 2B ) . # ::alignments 1-1.1.3 2-1.1.1.1.1 3-1.1 4-1.1.2.1.1 5-1 6-1.2.1.2 8-1.2.1 8-1.2.1.1 8-1.2.1.1.r 9-1.2 10-1.3.r 11-1.3.1.1 13-1.3.1.1 14-1.3 16-1.4.1 19-1.4.1.1 (c / confer-02~e.5 :ARG0 (a / and~e.3 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.2)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.4)) :ARG1-of (a2 / activate-01~e.1)) :ARG1 (g / grow-01~e.9 :ARG0-of (d / depend-01~e.8 :polarity~e.8 -~e.8 :ARG1 (a3 / anchorage~e.6))) :ARG2~e.10 (c2 / cell-line~e.14 :name (n3 / name :op1 "IEC-6"~e.11,13)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.16 :mod "2B"~e.19))) # ::id pmid_1901_4680.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test the tumorigenic potential of IEC @-@ 6 transduced cell populations in vivo , the cells were injected subcutaneously into athymic mice . # ::alignments 0-1.4.1.1 1-1.4 3-1.4.1.1.2 4-1.4.1 5-1.4.1.1.1.r 6-1.4.1.1.1.1.1.1.1 8-1.4.1.1.1.1.1.1.1 9-1.4.1.1.1.1 10-1.4.1.1.1.1.1 11-1.4.1.1.1 13-1.4.1.2 14-1.4.1.2 18-1.1 20-1 21-1.3 21-1.3.r 22-1.2.r 23-1.2.1 24-1.2 (i / inject-01~e.20 :ARG1 (c / cell~e.18) :ARG2~e.22 (m / mouse~e.24 :mod (a / athymic~e.23)) :manner~e.21 (s / subcutaneous~e.21) :purpose (t / test-01~e.1 :ARG1 (p / potential~e.4 :mod (c2 / cause-01~e.0 :ARG0~e.5 (p2 / population~e.11 :ARG1-of (t2 / transduce-01~e.9 :ARG2 (c3 / cell-line~e.10 :name (n / name :op1 "IEC-6"~e.6,8)))) :ARG1 (t3 / tumor~e.3)) :mod (i2 / in-vivo~e.13,14)))) # ::id pmid_1901_4680.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells infected with vector or wild type MEK isoforms never formed any tumor ( Fig . 2C ) . # ::alignments 0-1.2 1-1.2.1 2-1.2.1.1.r 3-1.2.1.1.1 4-1.2.1.1 5-1.2.1.1.2.1.2 6-1.2.1.1.2.1.2 7-1.2.1.1.2.1.1.1 8-1.2.1.1.2 9-1.1 9-1.1.r 9-1.4 10-1 11-1.3.1 12-1.3 14-1.5.1 17-1.5.1.1 (f / form-01~e.10 :polarity~e.9 -~e.9 :ARG0 (c / cell~e.0 :ARG1-of (i / infect-01~e.1 :ARG2~e.2 (o / or~e.4 :op1 (v / vector~e.3) :op2 (i2 / isoform~e.8 :mod (e / enzyme :name (n / name :op1 "MEK"~e.7) :mod (w / wild-type~e.5,6)))))) :ARG1 (t / tumor~e.12 :mod (a / any~e.11)) :time (e2 / ever~e.9) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.14 :mod "2C"~e.17))) # ::id pmid_1901_4680.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , both MEK1DD @- and MEK2DD @-@ expressing cells generated rapidly growing tumors in all injected mice . # ::alignments 1-1 4-1.1.1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1.1.1 9-1.1.1.1.1 9-1.1.1.2.1 10-1.1.1.1 10-1.1.1.2 11-1.1 12-1.1.2.1.1 12-1.1.2.1.1.r 13-1.1.2.1 14-1.1.2 15-1.1.3.r 16-1.1.3.2 17-1.1.3.1 18-1.1.3 (c / contrast-01~e.1 :ARG2 (g / generate-01~e.11 :ARG0 (a / and~e.6 :op1 (c2 / cell~e.10 :ARG3-of (e / express-03~e.9 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK1DD"~e.4)))) :op2 (c3 / cell~e.10 :ARG3-of (e3 / express-03~e.9 :ARG2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD"~e.7))))) :ARG1 (t / tumor~e.14 :ARG1-of (g2 / grow-01~e.13 :manner~e.12 (r / rapid~e.12))) :location~e.15 (m / mouse~e.18 :ARG2-of (i / inject-01~e.17) :mod (a2 / all~e.16)))) # ::id pmid_1901_4680.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Injection of as low as 3 × 10 @⁴@ cells produced tumors of ~ 1,000 mm @³@ after 2 weeks . # ::alignments 0-1.1 2-1.1.1.r 2-1.3.r 3-1.1.1.2 4-1.3.r 11-1.1.1 12-1 13-1.2 14-1.2.1.r 15-1.2.1 16-1.2.1.1.1 17-1.2.1.1.2 21-1.3 22-1.3.1.1 23-1.3.1.2 (p / produce-01~e.12 :ARG0 (i / inject-01~e.0 :ARG1~e.2 (c / cell~e.11 :quant 30000 :ARG3-of (l / low-04~e.3))) :ARG1 (t2 / tumor~e.13 :mod~e.14 (a / approximately~e.15 :op1 (v / volume-quantity :quant 1000~e.16 :unit (c2 / cubic-millimeter~e.17)))) :time~e.2,4 (a2 / after~e.21 :op1 (t / temporal-quantity :quant 2~e.22 :unit (w / week~e.23)))) # ::id pmid_1901_4680.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No major difference was observed in the growth rate of tumors expressing activated MEK1 or MEK2 ( Fig . 2D ) . # ::alignments 0-1.1.1.r 1-1.1.3 2-1.1 2-1.1.1 2-1.1.1.r 4-1 5-1.1.2.r 7-1.1.2.1 8-1.1.2 9-1.1.2.1.1.r 10-1.1.2.1.1 11-1.1.2.1.1.1 12-1.1.2.1.1.1.1.3 13-1.1.2.1.1.1.1.1.1.1 14-1.1.2.1.1.1.1 15-1.1.2.1.1.1.1.2.1.1 17-1.2.1 20-1.2.1.1 (o / observe-01~e.4 :ARG1 (d / differ-02~e.2 :polarity~e.0,2 -~e.2 :ARG1~e.5 (r / rate~e.8 :mod (g / grow-01~e.7 :ARG1~e.9 (t / tumor~e.10 :ARG3-of (e / express-03~e.11 :ARG2 (o2 / or~e.14 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.13)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.15)) :ARG1-of (a / activate-01~e.12)))))) :ARG1-of (m / major-02~e.1)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod "2D"~e.20))) # ::id pmid_1901_4680.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To analyze the impact of active MEK isoforms on tumorigenesis in a more pathologically relevant model , IEC @-@ 6 transduced cells were orthotopically transplanted into the caecum of athymic mice . # ::alignments 1-1.4 3-1.4.1 6-1.4.1.1.1.1.1 7-1.4.1.1 9-1.4.1.2.1 10-1.4.2.r 12-1.4.2.1.2 13-1.4.2.1.1 14-1.4.2.1 15-1.4.2 17-1.1.1.1.1.1 19-1.1.1.1.1.1 20-1.1.1 21-1.1 24-1 25-1.2.r 27-1.2 28-1.2.1.r 29-1.2.1.1 30-1.2.1 (t / transplant-01~e.24 :ARG1 (c / cell~e.21 :ARG1-of (t2 / transduce-01~e.20 :ARG2 (c4 / cell-line :name (n2 / name :op1 "IEC-6"~e.17,19)))) :ARG2~e.25 (c2 / caecum~e.27 :part-of~e.28 (m / mouse~e.30 :mod (a / athymic~e.29))) :manner (o / orthotopic) :purpose (a2 / analyze-01~e.1 :ARG1 (i / impact-01~e.3 :ARG0 (i2 / isoform~e.7 :mod (e / enzyme :name (n / name :op1 "MEK"~e.6)) :ARG1-of (a3 / activate-01)) :ARG1 (c3 / cause-01 :ARG1 (t3 / tumor~e.9))) :prep-in~e.10 (m2 / model~e.15 :ARG1-of (r / relevant-01~e.14 :ARG2 (p / pathology~e.13) :degree (m3 / more~e.12))))) # ::id pmid_1901_4680.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This model more closely recapitulates human colorectal cancer progression , in particular the spontaneous metastatic process that is highly dependent on the host environment [ @ 41 @ ] . # ::alignments 0-1.1.1 1-1.1 2-1.3.1 3-1.3 4-1 5-1.2.1.1.3 6-1.2.1.1.2.1 7-1.2.1.1.2.2 8-1.2.1 10-1.2.r 11-1.2.2.3 13-1.2.2.2 14-1.2.2.1 15-1.2.2 18-1.2.2.4.2 19-1.2.2.4 20-1.2.2.4.1.r 22-1.2.2.4.1.1 23-1.2.2.4.1 26-1.4.1.1.1 (r / recapitulate-01~e.4 :ARG0 (m / model~e.1 :mod (t / this~e.0)) :ARG1~e.10 (a / and :op1 (p / progress-01~e.8 :ARG1 (d3 / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal"~e.6 :op2 "cancer"~e.7) :mod (h / human~e.5))) :op2 (p2 / process-02~e.15 :ARG1 (m3 / metastasize-101~e.14) :mod (s / spontaneous~e.13) :mod (p3 / particular~e.11) :ARG0-of (d / depend-01~e.19 :ARG1~e.20 (e / environment~e.23 :ARG0-of (h3 / host-01~e.22)) :ARG1-of (h2 / high-02~e.18)))) :ARG1-of (c / close-10~e.3 :degree (m2 / more~e.2)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 41~e.26)))) # ::id pmid_1901_4680.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Strikingly , 100 % of the mice transplanted with 10 @⁵@ IEC @-@ 6 cells expressing either MEK1DD or MEK2DD developed massive intestinal tumors , while the control group remained tumor @-@ free ( Fig . 2C and 2E ) . # ::alignments 0-1.4 2-1.1.1.1.2.1 3-1.1.1.1.2 6-1.1.1 6-1.1.1.1.1 7-1.1.1.1.1.1 13-1.1.1.1.1.1.1.2.1 15-1.1.1.1.1.1.1.2.1 16-1.1.1.1.1.1.1 17-1.1.1.1.1.1.1.3 19-1.1.1.1.1.1.1.3.1.1.1.1 20-1.1.1.1.1.1.1.3.1 21-1.1.1.1.1.1.1.3.1.2.1.1 22-1.1 23-1.1.2.2 24-1.1.2.1 25-1.1.2 27-1 29-1.2.1.1 30-1.2.1 31-1.2 32-1.2.2.2 34-1.2.2 36-1.3.1.1 36-1.3.1.2 39-1.3.1.1.1 41-1.3.1 43-1.3.1.2.1 (c / contrast-01~e.27 :ARG1 (d / develop-02~e.22 :ARG0 (m / mouse~e.6 :ARG1-of (i2 / include-91 :ARG2 (m3 / mouse~e.6 :ARG2-of (t / transplant-01~e.7 :ARG1 (c2 / cell-line~e.16 :quant 100000 :name (n / name :op1 "IEC-6"~e.13,15) :ARG3-of (e / express-03~e.17 :ARG2 (o / or~e.20 :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"~e.19)) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD"~e.21))))))) :ARG3 (p / percentage-entity~e.3 :value 100~e.2))) :ARG1 (t2 / tumor~e.25 :mod (i / intestine~e.24) :mod (m2 / massive~e.23))) :ARG2 (r / remain-01~e.31 :ARG1 (g / group~e.30 :mod (c3 / control~e.29)) :ARG3 (f / free-04~e.34 :ARG1 g :ARG2 t2~e.32)) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.41 :op1 (f2 / figure~e.36 :mod "2C"~e.39) :op2 (f3 / figure~e.36 :mod "2E"~e.43))) :ARG1-of (s / strike-04~e.0)) # ::id pmid_1901_4680.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mice were sacrificed when they became moribund or presented symptoms of weight loss , respiratory distress , or a palpable abdominal mass. # ::alignments 1-1.1 3-1 4-1.2.r 5-1.2.1.1 6-1.2.1 7-1.2.1.2 8-1.2 9-1.2.2 10-1.2.2.2.1 10-1.2.2.2.2 10-1.2.2.2.3 11-1.2.2.2.1.1.r 12-1.2.2.2.1.1.1 13-1.2.2.2.1.1 15-1.2.2.2.2.1.1 16-1.2.2.2.2.1 18-1.2.2.2 21-1.2.2.2.3.1.2 (s / sacrifice-01~e.3 :ARG1 (m / mouse~e.1) :time~e.4 (o / or~e.8 :op1 (b / become-01~e.6 :ARG1 m~e.5 :ARG2 (m2 / moribund~e.7)) :op2 (p / present-102~e.9 :ARG0 m :ARG1 (o2 / or~e.18 :op1 (s2 / symptom~e.10 :mod~e.11 (l / lose-02~e.13 :ARG1 (w / weight~e.12))) :op2 (s3 / symptom~e.10 :mod (d / distress-01~e.16 :ARG1 (r / respiration~e.15))) :op3 (s4 / symptom~e.10 :mod (m3 / mass :ARG1-of (p2 / palpate-00 :ARG1-of (p3 / possible-01)) :mod (a2 / abdomen~e.21))))))) # ::id pmid_1901_4680.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Microscopic examination of the tumors revealed a poorly differentiated morphology with occasional signet @-@ ring cells ( inset ) corresponding to a high @-@ grade adenocarcinoma ( Fig . 2E ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 4-1.1.1 5-1 7-1.2.1.1 7-1.2.1.1.r 8-1.2.1 9-1.2 10-1.2.2.r 11-1.2.2.4 12-1.2.2.1.1 14-1.2.2.1.1 15-1.2.2 17-1.2.2.2.1 19-1.2.2.3 20-1.2.2.3.1.r 22-1.2.2.3.1.2.1 24-1.2.2.3.1.2 25-1.2.2.3.1.1.1 27-1.3.1 30-1.3.1.1 (r / reveal-01~e.5 :ARG0 (e / examine-01~e.1 :ARG1~e.2 (t / tumor~e.4) :mod (m / microscopic~e.0)) :ARG1 (m2 / morphology~e.9 :ARG1-of (d / differentiate-01~e.8 :manner~e.7 (p / poor~e.7)) :consist-of~e.10 (c / cell-line~e.15 :name (n / name :op1 "signet-ring"~e.12,14) :ARG1-of (m3 / mean-01 :ARG2 (i / inset~e.17)) :ARG1-of (c2 / correspond-02~e.19 :ARG2~e.20 (m4 / medical-condition :name (n2 / name :op1 "adenocarcinoma"~e.25) :mod (g / grade~e.24 :ARG1-of (h / high-02~e.22)))) :frequency (o / occasional~e.11))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.27 :mod "2E"~e.30))) # ::id pmid_1901_4680.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The tumors are invasive and diffusely infiltrate the lamina propria and the underlying muscular layers ( muscularis propria and muscularis mucosae ) . # ::alignments 1-1.1.1 3-1.1 4-1 5-1.2.3 5-1.2.3.r 6-1.2 8-1.2.2.1 9-1.2.2.1 10-1.2.2 12-1.2.2.2.2 13-1.2.2.2.1 14-1.2.2.2 14-1.2.2.2.3.1.1 14-1.2.2.2.3.1.2 16-1.2.2.2.3.1.1.1.1 17-1.2.2.2.3.1.1.1.2 18-1.2.2.2.3.1 19-1.2.2.2.3.1.2.1.1 20-1.2.2.2.3.1.2.1.2 (a / and~e.4 :op1 (i / invade-01~e.3 :ARG0 (t / tumor~e.1)) :op2 (i2 / infiltrate-01~e.6 :ARG0 t :ARG1 (a2 / and~e.10 :op1 (l / lamina-propria~e.8,9) :op2 (l2 / layer~e.14 :mod (m / muscle~e.13) :ARG1-of (u / underlie-01~e.12) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and~e.18 :op1 (l3 / layer~e.14 :name (n / name :op1 "muscularis"~e.16 :op2 "propria"~e.17)) :op2 (l4 / layer~e.14 :name (n2 / name :op1 "muscularis"~e.19 :op2 "mucosae"~e.20)))))) :manner~e.5 (d / diffuse~e.5))) # ::id pmid_1901_4680.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these data demonstrate that constitutive activation of MEK1 or MEK2 is sufficient to transform intestinal epithelial cells and induce the formation of invasive colon adenocarcinomas . # ::alignments 0-1.1.2 2-1.1.1 3-1.1 4-1 5-1.2.r 6-1.2.1.2 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1.1.1 11-1.2.1.1.2.1.1 13-1.2 14-1.2.2.r 15-1.2.2.1 16-1.2.2.1.2.2 17-1.2.2.1.2.1 18-1.2.2.1.2 19-1.2.2 20-1.2.2.2 22-1.2.2.2.2 23-1.2.2.2.2.1.r 24-1.2.2.2.2.1 24-1.2.2.2.2.1.3 24-1.2.2.2.2.1.3.r 25-1.2.2.2.2.1.2 26-1.2.2.2.2.1.1.1 (d / demonstrate-01~e.4 :ARG0 (d2 / data~e.3 :mod (t / this~e.2) :mod (t2 / together~e.0)) :ARG1~e.5 (s / suffice-01~e.13 :ARG0 (a / activate-01~e.7 :ARG1~e.8 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.9)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.11))) :mod (c3 / constitutive~e.6)) :ARG1~e.14 (a3 / and~e.19 :op1 (t3 / transform-01~e.15 :ARG0 a :ARG1 (c / cell~e.18 :mod (e3 / epithelium~e.17) :part-of (i2 / intestine~e.16))) :op2 (i / induce-01~e.20 :ARG0 a :ARG2 (f / form-01~e.22 :ARG1~e.23 (m / medical-condition~e.24 :name (n3 / name :op1 "adenocarcinoma"~e.26) :mod (c2 / colon~e.25) :ARG0-of~e.24 (i3 / invade-01~e.24))))))) # ::id pmid_1901_4680.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutive activation of MEK1 or MEK2 confers metastatic properties to transformed intestinal epithelial cells # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 6-1.1.1.2.1.1 7-1 8-1.2.1 9-1.2 10-1.3.r 11-1.3.3 12-1.3.2 13-1.3.1 14-1.3 (c / confer-02~e.7 :ARG0 (a / activate-01~e.2 :ARG1~e.3 (a2 / and :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.6))) :mod (c2 / constitutive~e.1)) :ARG1 (p / property~e.9 :mod (m / metastasize-101~e.8)) :ARG2~e.10 (c3 / cell~e.14 :mod (e3 / epithelium~e.13) :part-of (i / intestine~e.12) :ARG1-of (t / transform-01~e.11))) # ::id pmid_1901_4680.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of the ERK1 @/@ 2 MAP kinase pathway has been implicated in the regulation of cell motility and invasion [ @ 42 @ ] . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1.2 7-1.1.1.1.2 8-1.1.1 11-1 12-1.2.r 14-1.2 15-1.2.2.r 16-1.2.2.1.1 17-1.2.2.1 18-1.2.2 19-1.2.2.2 22-1.3.1.1.1 (i / implicate-01~e.11 :ARG1 (a / activate-01~e.0 :ARG1~e.1 (p / pathway~e.8 :name (n / name :op1 "ERK1/2"~e.3,5 :op2 "MAP-kinase"~e.6,7))) :ARG2~e.12 (r / regulate-01~e.14 :ARG0 a :ARG1~e.15 (a2 / and~e.18 :op1 (m / motility~e.17 :mod (c / cell~e.16)) :op2 (i2 / invade-01~e.19 :ARG0 c))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 42~e.22)))) # ::id pmid_1901_4680.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , treatment of colon carcinoma cells with the MEK1 @/@ 2 inhibitor PD184352 was shown to inhibit HGF @-@ induced cell scattering and to reduce their invasive properties [ @ 20 @ ] . # ::alignments 0-1.2 2-1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.2 5-1.1.1.1.1.1.1.1 6-1.1.1.1.1 7-1.1.1.1.2.r 9-1.1.1.1.2.2.1.1.1 11-1.1.1.1.2.2.1.1.1 12-1.1.1.1.2 12-1.1.1.1.2.2 12-1.1.1.1.2.2.r 13-1.1.1.1.2.1.1 15-1 17-1.1.1 18-1.1.1.2.2.1.1.1 20-1.1.1.2.2 21-1.1.1.2.1 22-1.1.1.2 23-1.1 25-1.1.2 26-1.1.2.2.2 26-1.1.2.2.2.r 27-1.1.2.2.1 28-1.1.2.2 31-1.3.1.1.1 (s / show-01~e.15 :ARG1 (a / and~e.23 :op1 (i2 / inhibit-01~e.17 :ARG0 (t / treat-04~e.2 :ARG1~e.3 (c / cell~e.6 :mod (m / medical-condition :name (n / name :op1 "carcinoma"~e.5)) :part-of (c2 / colon~e.4)) :ARG2~e.7 (s2 / small-molecule~e.12 :name (n2 / name :op1 "PD184352"~e.13) :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (e / enzyme :name (n3 / name :op1 "MEK1/2"~e.9,11))))) :ARG1 (s3 / scatter-01~e.22 :ARG1 (c3 / cell~e.21) :ARG2-of (i3 / induce-01~e.20 :ARG0 (p / protein :name (n4 / name :op1 "HGF"~e.18))))) :op2 (r / reduce-01~e.25 :ARG0 t :ARG1 (p2 / property~e.28 :mod (i4 / invade-01~e.27 :ARG0 c3) :poss~e.26 c3~e.26))) :ARG1-of (n5 / notable-04~e.0) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 20~e.31)))) # ::id pmid_1901_4680.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We examined the impact of MEK1 or MEK2 activation on the motility of IEC @-@ 6 cells using two different cell migration assays . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1.1.1.1 6-1.2.1.1 7-1.2.1.1.2.1.1 8-1.2.1 9-1.2.2.r 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1 15-1.2.2.1.1.1 16-1.2.2.1 17-1.3 18-1.3.2.1 19-1.3.2.3 20-1.3.2.2.1 21-1.3.2.2 22-1.3.2 (e / examine-01~e.1 :ARG0 (w / we~e.0) :ARG1 (i / impact-01~e.3 :ARG0~e.4 (a / activate-01~e.8 :ARG1 (o / or~e.6 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.5)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.7)))) :ARG1~e.9 (m / motility~e.11 :poss~e.12 (c / cell-line~e.16 :name (n3 / name :op1 "IEC-6"~e.13,15)))) :ARG2-of (u / use-01~e.17 :ARG0 w :ARG1 (a2 / assay-01~e.22 :quant 2~e.18 :ARG1 (m2 / migrate-01~e.21 :ARG0 (c2 / cell~e.20)) :ARG1-of (d / differ-02~e.19)))) # ::id pmid_1901_4680.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No difference in the migration rate of the different IEC @-@ 6 transduced populations was observed in a standard chemotaxis assay with serum as chemoattractant ( Fig . 3A ) . # ::alignments 0-1.1.1.r 1-1.1.1.r 4-1.1.2.1 5-1.1.2 8-1.1 8-1.1.1 8-1.1.1.r 9-1.1.2.1.1.1.1.1.1 11-1.1.2.1.1.1.1.1.1 12-1.1.2.1.1.1 13-1.1.2.1.1 15-1 16-1.2.r 18-1.2.2 19-1.2.1 20-1.2 21-1.2.3.r 22-1.2.3 23-1.2.3.1.r 24-1.2.3.1 26-1.3.1 29-1.3.1.1 (o / observe-01~e.15 :ARG1 (d / differ-02~e.8 :polarity~e.0,1,8 -~e.8 :ARG1 (r / rate~e.5 :mod (m / migrate-01~e.4 :ARG1 (p / population~e.13 :ARG1-of (t / transduce-01~e.12 :ARG2 (c / cell-line :name (n / name :op1 "IEC-6"~e.9,11))))))) :location~e.16 (a / assay-01~e.20 :ARG1 (c2 / chemotaxis~e.19) :mod (s / standard~e.18) :instrument~e.21 (s2 / serum~e.22 :purpose~e.23 (c3 / chemoattractant~e.24))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26 :mod "3A"~e.29))) # ::id pmid_1901_4680.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar results were obtained using a wound @-@ healing assay ( data not shown ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.2 6-1.2.1.1.1 8-1.2.1.1 9-1.2.1 11-1.3.1 12-1.3.1.1.1 12-1.3.1.1.1.r 13-1.3.1.1 (o / obtain-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :ARG1-of (r2 / resemble-01~e.0)) :ARG2-of (u / use-01~e.4 :ARG1 (a / assay-01~e.9 :ARG1 (h / heal-01~e.8 :ARG2 (w / wound~e.6)))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.11 :ARG1-of (s / show-01~e.13 :polarity~e.12 -~e.12)))) # ::id pmid_1901_4680.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next analyzed the ability of the cells to migrate through a Matrigel @-@ coated membrane as a reflection of their invasive properties . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 7-1.2.1 9-1.2.2 12-1.2.2.2.1.1.1.1 14-1.2.2.2.1 15-1.2.2.2 16-1.2.3.r 16-1.3.r 18-1.2.3 19-1.2.3.1.r 20-1.2.3.1.2 20-1.2.3.1.2.r 21-1.2.3.1.1 22-1.2.3.1 (a / analyze-01~e.2 :ARG0 (w / we~e.0) :ARG1 (c / capable-01~e.4 :ARG1~e.5 (c2 / cell~e.7) :ARG2 (m / migrate-01~e.9 :ARG0 c2 :ARG1 (m2 / membrane~e.15 :ARG1-of (c3 / coat-01~e.14 :ARG2 (p3 / protein :name (n3 / name :op1 "Matrigel"~e.12))))) :ARG1-of~e.16 (r / reflect-01~e.18 :ARG2~e.19 (p2 / property~e.22 :mod (i / invade-01~e.21 :ARG0 c2) :poss~e.20 c2~e.20))) :time~e.16 (n2 / next~e.1)) # ::id pmid_1901_4680.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ectopic expression of activated MEK1 or MEK2 significantly enhanced the invasive capacity of IEC @-@ 6 cells , while the wild type MEK isoforms had no effect ( Fig . 3B ) . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.2 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1 7-1.1.3 8-1.1 10-1.1.2.2 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1 15-1.1.2.1.1.1 16-1.1.2.1 18-1 20-1.2.2.2 21-1.2.2.2 22-1.2.2.1.1.1 23-1.2.2 25-1.2.1 25-1.2.1.r 26-1.2 28-1.3.1 31-1.3.1.1 (c / contrast-01~e.18 :ARG1 (e / enhance-01~e.8 :ARG0 (e2 / express-03~e.1 :ARG2~e.2 (o / or~e.5 :op1 (e4 / enzyme :name (n / name :op1 "MEK1"~e.4) :ARG1-of (a / activate-01~e.3)) :op2 (e5 / enzyme :name (n2 / name :op1 "MEK2"~e.6) :ARG1-of a)) :mod (e3 / ectopic~e.0)) :ARG1 (c2 / capable-01~e.11 :ARG1~e.12 (c3 / cell-line~e.16 :name (n3 / name :op1 "IEC-6"~e.13,15)) :ARG2 (i / invade-01~e.10)) :ARG1-of (s / significant-02~e.7)) :ARG2 (a2 / affect-01~e.26 :polarity~e.25 -~e.25 :ARG0 (i2 / isoform~e.23 :mod (e6 / enzyme :name (n4 / name :op1 "MEK"~e.22)) :mod (w / wild-type~e.20,21))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod "3B"~e.31))) # ::id pmid_1901_4680.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the MEK2DD @-@ transduced cells appeared more invasive than cells expressing MEK1DD in this assay . # ::alignments 0-1.2 3-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1 7-1 8-1.1.2 9-1.1 10-1.1.3.r 11-1.1.3 12-1.1.3.1 13-1.1.3.1.1.1.1 14-1.3.r 15-1.3.1 16-1.3 (a / appear-02~e.7 :ARG1 (i / invade-01~e.9 :ARG0 (c / cell~e.6 :ARG1-of (t / transduce-01~e.5 :ARG2 (e / enzyme :name (n / name :op1 "MEK2DD"~e.3)))) :degree (m / more~e.8) :compared-to~e.10 (c2 / cell~e.11 :ARG3-of (e2 / express-03~e.12 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK1DD"~e.13))))) :mod (i2 / interesting~e.0) :location~e.14 (a2 / assay-01~e.16 :mod (t2 / this~e.15))) # ::id pmid_1901_4680.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The invasive properties of the cells in vitro @ and the histology of the intestinal tumors suggest that MEK1DD @- and MEK2DD @-@ expressing IEC @-@ 6 cells may have metastatic properties in vivo @ . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1.1.1.1.r 5-1.1.1.1.1 7-1.1.1.1.2 8-1.1.1.1.2 10-1.1 12-1.1.2 13-1.1.2.1.r 15-1.1.2.1.1 16-1.1.2.1 17-1 18-1.2.r 19-1.2.1.1.2.1.1.1.1 21-1.2.1.1.2.1 22-1.2.1.1.2.1.2.1.1 24-1.2.1.1.2 25-1.2.1.1.1.1 27-1.2.1.1.1.1 28-1.2.1.1 29-1.2 30-1.2.1 31-1.2.1.2.1 32-1.2.1.2 34-1.2.1.3 35-1.2.1.3 (s / suggest-01~e.17 :ARG0 (a / and~e.10 :op1 (p / property~e.2 :mod (i / invade-01~e.1 :ARG0~e.3 (c / cell~e.5) :manner (i2 / in-vitro~e.7,8))) :op2 (h / histology~e.12 :poss~e.13 (t / tumor~e.16 :location (i3 / intestine~e.15)))) :ARG1~e.18 (p2 / possible-01~e.29 :ARG1 (h2 / have-03~e.30 :ARG0 (c2 / cell-line~e.28 :name (n / name :op1 "IEC-6"~e.25,27) :ARG3-of (e / express-03~e.24 :ARG2 (a2 / and~e.21 :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"~e.19)) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD"~e.22))))) :ARG1 (p3 / property~e.32 :mod (m / metastasize-101~e.31)) :manner (i4 / in-vivo~e.34,35)))) # ::id pmid_1901_4680.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detailed histological examination of a subset of mice that develop orthotopic tumors revealed the presence of metastasis in the lymph nodes , the lungs and the liver in both the MEK1DD and MEK2DD groups ( Fig . 3C and 3D ) . # ::alignments 0-1.1.2 1-1.1.3 2-1.1 3-1.1.1.r 5-1.1.1 7-1.1.1.1.1 9-1.1.1.1.1.1 10-1.1.1.1.1.1.1.1 11-1.1.1.1.1.1.1 12-1 15-1.2.r 16-1.2 17-1.2.1.r 19-1.2.1.1.1 20-1.2.1.1 23-1.2.1.2 24-1.2.1 26-1.2.1.3 30-1.3.1.1.1.1 31-1.3 32-1.3.2.1.1.1 33-1.3.1 33-1.3.2 35-1.4.1.1 35-1.4.1.2 38-1.4.1.1.1 40-1.4.1 42-1.4.1.2.1 (r / reveal-01~e.12 :ARG0 (e / examine-01~e.2 :ARG1~e.3 (s / subset~e.5 :ARG1-of (i / include-91 :ARG2 (m / mouse~e.7 :ARG1-of (d2 / develop-01~e.9 :ARG2 (t / tumor~e.11 :mod (o / orthotopic~e.10)))))) :ARG1-of (d / detail-01~e.0) :mod (h / histology~e.1)) :ARG1~e.15 (m2 / metastasize-101~e.16 :ARG2~e.17 (a / and~e.24 :op1 (n / node~e.20 :mod (l / lymph~e.19)) :op2 (l2 / lung~e.23) :op3 (l3 / liver~e.26))) :location (a2 / and~e.31 :op1 (g / group~e.33 :mod (e2 / enzyme :name (n2 / name :op1 "MEK1DD"~e.30))) :op2 (g2 / group~e.33 :mod (e3 / enzyme :name (n3 / name :op1 "MEK2DD"~e.32)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.40 :op1 (f / figure~e.35 :mod "3C"~e.38) :op2 (f2 / figure~e.35 :mod "3D"~e.42)))) # ::id pmid_1901_4680.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These observations indicate that constitutive activation of either MEK1 or MEK2 is sufficient to confer a metastatic phenotype to intestinal tumor cells . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.2 5-1.2.1 8-1.2.1.1.1.1.1 9-1.2.1.1 10-1.2.1.1.2.1.1 12-1.2 14-1.2.2 16-1.2.2.2.1 17-1.2.2.2 18-1.2.2.3.r 19-1.2.2.3.2 20-1.2.2.3.1 21-1.2.2.3 (i / indicate-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1~e.3 (s / suffice-01~e.12 :ARG0 (a / activate-01~e.5 :ARG1 (o2 / or~e.9 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.8)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.10))) :mod (c3 / constitutive~e.4)) :ARG1 (c / confer-02~e.14 :ARG0 a :ARG1 (p / phenotype~e.17 :mod (m / metastasize-101~e.16)) :ARG2~e.18 (c2 / cell~e.21 :mod (t2 / tumor~e.20) :part-of (i2 / intestine~e.19))))) # ::id pmid_1901_4680.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The acquisition of invasiveness does not result from changes in cellular motility . # ::alignments 1-1.3 5-1.1 5-1.1.r 6-1 7-1.2.r 8-1.2 9-1.2.1.r 10-1.2.1.1 11-1.2.1 (r / result-01~e.6 :polarity~e.5 -~e.5 :ARG1~e.7 (c / change-01~e.8 :ARG1~e.9 (m / motility~e.11 :mod (c2 / cell~e.10))) :ARG2 (a / acquire-01~e.1 :ARG1 (i / invade-01))) # ::id pmid_1901_4680.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To identify downstream targets of MEK1 @/@ MEK2 involved in intestinal tumor progression , we analyzed the transcriptional profile of MEK1DD @- and MEK2DD @-@ expressing IEC @-@ 6 cells using Affymetrix GeneChip arrays . # ::alignments 1-1.4 2-1.4.2.2 3-1.4.2 4-1.4.2.1.r 5-1.4.2.1.1.1.1 6-1.4.2.1 7-1.4.2.1.2.1.1 8-1.4.2.3 9-1.4.2.3.1.r 10-1.4.2.3.1.1.1 11-1.4.2.3.1.1 12-1.4.2.3.1 14-1.1 15-1 17-1.2.2 18-1.2 19-1.2.1.r 20-1.2.1.2.1.1.1.1 22-1.2.1.2.1 23-1.2.1.2.1.2.1.1 25-1.2.1.2 26-1.2.1.1.1 28-1.2.1.1.1 29-1.2.1 30-1.3 30-1.4.r 31-1.3.1.1.1.1 32-1.3.1.1.1.2 33-1.3.1 (a / analyze-01~e.15 :ARG0 (w / we~e.14) :ARG1 (p / profile-01~e.18 :ARG1~e.19 (c / cell-line~e.29 :name (n / name :op1 "IEC-6"~e.26,28) :ARG3-of (e / express-03~e.25 :ARG2 (a3 / and~e.22 :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"~e.20)) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD"~e.23))))) :mod (t4 / transcribe-01~e.17 :ARG0 c)) :ARG2-of (u / use-01~e.30 :ARG1 (a2 / array-01~e.33 :mod (t / thing :name (n4 / name :op1 "Affymetrix"~e.31 :op2 "GeneChip"~e.32)))) :purpose~e.30 (i / identify-01~e.1 :ARG0 w :ARG1 (t2 / target-01~e.3 :ARG0~e.4 (s / slash~e.6 :op1 (e4 / enzyme :name (n5 / name :op1 "MEK1"~e.5)) :op2 (e5 / enzyme :name (n6 / name :op1 "MEK2"~e.7))) :location (d / downstream~e.2) :ARG1-of (i2 / involve-01~e.8 :ARG2~e.9 (p2 / progress-01~e.12 :ARG1 (t3 / tumor~e.11 :location (i3 / intestine~e.10))))))) # ::id pmid_1901_4680.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of the gene expression data identified several genes that were up @-@ regulated or down @-@ regulated in MEK1DD @- and MEK2DD @-@ expressing cells as compared to control IEC @-@ 6 cells ( Additional files 1 and 2 ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1 4-1.1.1.1.1 5-1.1.1 6-1 7-1.2.1.1 8-1.2.1 8-1.2.2 14-1.2 18-1.2.r 19-1.2.3.1.1.1.1.1 21-1.2.3.1.1 22-1.2.3.1.1.2.1.1 24-1.2.3.1 25-1.2.3 26-1.2.3.2.r 27-1.2.3.2 28-1.2.3.2.1.r 29-1.2.3.2.1.2 30-1.2.3.2.1.1.1 32-1.2.3.2.1.1.1 33-1.2.3.2.1 36-1.3.1.1 36-1.3.1.2 38-1.3.1.1.1 40-1.3.1 42-1.3.1.2.1 (i / identify-01~e.6 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (d / data~e.5 :topic (g / gene~e.3 :ARG1-of (e / express-03~e.4)))) :ARG1~e.18 (o / or~e.14 :op1 (g2 / gene~e.8 :quant (s / several~e.7) :ARG1-of (u / upregulate-01)) :op2 (g3 / gene~e.8 :quant s :ARG1-of (d2 / downregulate-01)) :location (c / cell~e.25 :ARG3-of (e2 / express-03~e.24 :ARG2 (a2 / and~e.21 :op1 (e3 / enzyme :name (n / name :op1 "MEK1DD"~e.19)) :op2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD"~e.22)))) :ARG1-of~e.26 (c2 / compare-01~e.27 :ARG2~e.28 (c3 / cell-line~e.33 :name (n3 / name :op1 "IEC-6"~e.30,32) :mod (c4 / control-01~e.29))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.40 :op1 (f / file~e.36 :mod 1~e.38 :ARG1-of (a4 / add-02)) :op2 (f2 / file~e.36 :mod 2~e.42 :ARG1-of a4)))) # ::id pmid_1901_4680.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The list of modulated genes included growth factors , signaling molecules , drug metabolism enzymes and , interestingly , several proteases . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1 4-1.2.1 5-1 6-1.1.1 7-1.1.1 9-1.1.2.1 10-1.1.2 12-1.1.3.1.1 14-1.1.3 15-1.1 17-1.3 19-1.1.4.1 20-1.1.4 (i / include-01~e.5 :ARG1 (a / and~e.15 :op1 (g2 / growth-factor~e.6,7) :op2 (m2 / molecule~e.10 :ARG0-of (s2 / signal-07~e.9)) :op3 (e / enzyme~e.14 :ARG0-of (m3 / metabolize-01 :ARG1 (d / drug~e.12))) :op4 (p / protease~e.20 :quant (s3 / several~e.19))) :ARG2 (l / list~e.1 :consist-of~e.2 (g / gene~e.4 :ARG1-of (m / modulate-01~e.3))) :mod (i2 / interesting~e.17)) # ::id pmid_1901_4680.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The matrix metalloproteinases ( MMPs ) MMP @-@ 3 and MMP @-@ 13 were up @-@ regulated in both MEK1DD @- and MEK2DD @-@ expressing cells , while up @-@ regulation of MMP @-@ 10 reached significance only in MEK2DD cells . # ::alignments 1-1.1.1.3.1.1.1 6-1.1.1.1.1.1 6-1.1.1.2.1.1 8-1.1.1.1.1.1 10-1.1.1.1.1.1 10-1.1.1.2.1.1 12-1.1.1.2.1.1 19-1.1.2.1.1.1.1.1 21-1.1.2.1.1 22-1.1.2.1.1.2.1.1 24-1.1.2.1 25-1.1.2 27-1 28-1.1 29-1.1 30-1.1 30-1.2.1 32-1.1.1.2.1.1 32-1.2.1.1.1.1 34-1.2.1.1.1.1 35-1.2 36-1.2.2 37-1.2.4 38-1.2.3.r 39-1.2.3.1 40-1.2.3 (c / contrast-01~e.27 :ARG1 (u / upregulate-01~e.28,29,30 :ARG1 (a / and :op1 (e5 / enzyme :name (n / name :op1 "MMP-3"~e.6,8,10)) :op2 (e6 / enzyme :name (n2 / name :op1 "MMP-13"~e.6,10,12,32)) :ARG1-of (i / include-91 :ARG2 (e7 / enzyme :name (n7 / name :op1 "matrix"~e.1 :op2 "metalloproteinase")))) :location (c2 / cell~e.25 :ARG3-of (e / express-03~e.24 :ARG2 (a2 / and~e.21 :op1 (e2 / enzyme :name (n3 / name :op1 "MEK1DD"~e.19)) :op2 (e3 / enzyme :name (n4 / name :op1 "MEK2DD"~e.22)))))) :ARG2 (r / reach-01~e.35 :ARG0 (u2 / upregulate-01~e.30 :ARG1 (e8 / enzyme :name (n5 / name :op1 "MMP-10"~e.32,34))) :ARG1 (s / significant-02~e.36) :location~e.38 (c3 / cell~e.40 :mod e3~e.39) :mod (o / only~e.37))) # ::id pmid_1901_4680.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of the urokinase receptor was also up @-@ regulated in IEC @-@ 6 cells expressing activated MEK2 . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 6-1.2 11-1.3.1.1 13-1.3.1.1 14-1.3 15-1.3.2 16-1.3.2.1.2 17-1.3.2.1.1.1 (u / upregulate-01 :ARG1 (e / express-03~e.0 :ARG2~e.1 (r / receptor~e.4 :mod (e2 / enzyme :name (n / name :op1 "urokinase"~e.3)))) :mod (a / also~e.6) :location (c / cell-line~e.14 :name (n2 / name :op1 "IEC-6"~e.11,13) :ARG1-of (e3 / express-03~e.15 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MEK2"~e.17) :ARG1-of (a2 / activate-01~e.16))))) # ::id pmid_1901_4680.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because of the importance of MMPs and urokinase receptor in tumor progression [ @ 43 , 44 @ ] , we further validated the regulation of these genes by MEK1 and MEK2 signaling to confirm the data from the arrays . # ::alignments 0-1.5 3-1.5.1 6-1.5.1.1 7-1.5.1.1.2.1.1.1 8-1.5.1.1.2 9-1.5.1.2.r 10-1.5.1.2.1 11-1.5.1.2 14-1.5.2.1.1.1.1 18-1.5.2.1.1.1.2 22-1.1 23-1.3 24-1 26-1.2 27-1.2.2.r 28-1.2.2.1 29-1.2.2 30-1.2.1.r 31-1.2.1.1.1.1.1 32-1.2.1.1 33-1.2.1.1.2.1.1 34-1.2.1 35-1.5 36-1.4 38-1.4.2 39-1.4.2.1.r 41-1.4.2.1 (v / validate-01~e.24 :ARG0 (w / we~e.22) :ARG1 (r / regulate-01~e.26 :ARG0~e.30 (s / signal-07~e.34 :ARG0 (a / and~e.32 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.31)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.33)))) :ARG1~e.27 (g / gene~e.29 :mod (t / this~e.28))) :time (f / further~e.23) :purpose (c / confirm-01~e.36 :ARG0 w :ARG1 (d / data~e.38 :source~e.39 (a2 / array~e.41))) :ARG1-of (c2 / cause-01~e.0,35 :ARG0 (i / important~e.3 :domain (a3 / and~e.6 :op1 (e3 / enzyme :name (n3 / name :op1 "MMP")) :op2 (r2 / receptor~e.8 :mod (e4 / enzyme :name (n4 / name :op1 "urokinase"~e.7)))) :purpose~e.9 (p / progress-01~e.11 :ARG1 (t2 / tumor~e.10))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 43~e.14 :op2 44~e.18)))))) # ::id pmid_1901_4680.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No expression or activity of MMPs could be detected in empty vector @-@ infected IEC @-@ 6 cells . # ::alignments 0-1.1.1.1.1 0-1.1.1.1.1.r 0-1.1.1.2.1 0-1.1.1.2.1.r 1-1.1.1.1 2-1.1.1 3-1.1.1.2 6-1 8-1.1 9-1.1.2.r 10-1.1.2.2.1.1 11-1.1.2.2.1 13-1.1.2.2 14-1.1.2.1.1 16-1.1.2.1.1 17-1.1.2 (p / possible-01~e.6 :ARG1 (d / detect-01~e.8 :ARG1 (o / or~e.2 :op1 (e / express-03~e.1 :polarity~e.0 -~e.0 :ARG2 (e2 / enzyme :name (n / name :op1 "MMP"))) :op2 (a / activity-06~e.3 :polarity~e.0 -~e.0 :ARG0 e2)) :location~e.9 (c / cell-line~e.17 :name (n2 / name :op1 "IEC-6"~e.14,16) :ARG1-of (i / infect-01~e.13 :ARG2 (v / vector~e.11 :ARG1-of (e3 / empty-01~e.10)))))) # ::id pmid_1901_4680.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , activation of either MEK1 or MEK2 markedly up @-@ regulated the expression of MMP @-@ 13 protein ( Fig . 4A ) . # ::alignments 0-1 2-1.1.1 5-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.1.1 8-1.1.3 8-1.1.3.r 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 17-1.1.2.1.1.1 20-1.2.1 23-1.2.1.1 (c / contrast-01~e.0 :ARG2 (u / upregulate-01 :ARG0 (a / activate-01~e.2 :ARG1 (o / or~e.6 :op2 (e2 / enzyme :name (n2 / name :op1 "MEK1"~e.5)) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2"~e.7)))) :ARG1 (e / express-03~e.13 :ARG2~e.14 (e4 / enzyme :name (n / name :op1 "MMP-13"~e.15,17))) :manner~e.8 (m / marked~e.8)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "4A"~e.23))) # ::id pmid_1901_4680.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , higher levels of MMP @-@ 13 protein were detected in IEC @-@ 6 cells expressing the activated MEK2 isoform . # ::alignments 0-1.3 2-1.1.2 2-1.1.2.1 2-1.1.2.1.r 3-1.1 4-1.1.1.r 5-1.1.1.1.1 7-1.1.1.1.1 10-1 11-1.2.r 12-1.2.1.1 14-1.2.1.1 15-1.2 16-1.2.2 18-1.2.2.1.1 19-1.2.2.1.2.1.1 20-1.2.2.1 (d / detect-01~e.10 :ARG1 (l / level~e.3 :quant-of~e.4 (e3 / enzyme :name (n / name :op1 "MMP-13"~e.5,7)) :ARG1-of (h / high-02~e.2 :degree~e.2 (m / more~e.2))) :location~e.11 (c / cell-line~e.15 :name (n2 / name :op1 "IEC-6"~e.12,14) :ARG3-of (e / express-03~e.16 :ARG2 (i / isoform~e.20 :ARG1-of (a / activate-01~e.18) :mod (e2 / enzyme :name (n3 / name :op1 "MEK2"~e.19))))) :ARG1-of (n4 / notable-04~e.0)) # ::id pmid_1901_4680.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression of MMP @-@ 3 @/@ 10 was analyzed by measuring their activity by zymography in casein @-@ containing gels . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 7-1.1.1.1.1 9-1 10-1.2.r 11-1.2 12-1.2.1.1 12-1.2.1.1.r 13-1.2.1 14-1.2.2.r 15-1.2.2 16-1.2.3.r 17-1.2.3.1.1.1.1 19-1.2.3.1 20-1.2.3 (a / analyze-01~e.9 :ARG1 (e / express-03~e.1 :ARG2~e.2 (e2 / enzyme :name (n / name :op1 "MMP-3/10"~e.3,5,7))) :manner~e.10 (m / measure-01~e.11 :ARG1 (a2 / activity-06~e.13 :ARG0~e.12 e2~e.12) :ARG2~e.14 (z / zymography~e.15) :location~e.16 (g / gel~e.20 :ARG0-of (c / contain-01~e.19 :ARG1 (p / protein :name (n3 / name :op1 "casein"~e.17)))))) # ::id pmid_1901_4680.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Again , we observed that MEK2DD increased MMP @-@ 3 @/@ 10 enzymatic activity more robustly than MEK1DD ( Fig . 4A ) . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2 7-1.2.2.1.1.1 9-1.2.2.1.1.1 11-1.2.2.1.1.1 12-1.2.2.2 13-1.2.2 14-1.2.3.1 15-1.2.3 15-1.2.3.r 16-1.2.3.2.r 17-1.2.3.2.1.1 19-1.4.1 22-1.4.1.1 (o / observe-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (i / increase-01~e.6 :ARG0 (e / enzyme :name (n / name :op1 "MEK2DD"~e.5)) :ARG1 (a / activity-06~e.13 :ARG0 (e2 / enzyme :name (n2 / name :op1 "MMP-3/10"~e.7,9,11)) :mod (e3 / enzyme~e.12)) :manner~e.15 (r / robust~e.15 :degree (m / more~e.14) :compared-to~e.16 (e4 / enzyme :name (n3 / name :op1 "MEK1DD"~e.17)))) :mod (a2 / again~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "4A"~e.22))) # ::id pmid_1901_4680.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Quantitative PCR analysis confirmed that constitutive activation of MEK1 or MEK2 induces the expression of urokinase receptor mRNA ( Fig . 4B ) . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.1 1-1.1.1.1.1.r 1-1.1.1.1.r 2-1.1 3-1 4-1.2.r 5-1.2.1.2 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.1.1.1 9-1.2.1.1 10-1.2.1.1.2.1.1 11-1.2 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.2.1.1.1 16-1.2.2.1.2 17-1.2.2.1.1.1 19-1.3.1 22-1.3.1.1 (c / confirm-01~e.3 :ARG0 (a / analyze-01~e.2 :manner (r2 / react-01~e.1 :ARG0~e.1 (p / polymerase~e.1 :ARG1-of~e.1 (c3 / chain-01~e.1)) :mod (q / quantitative~e.0))) :ARG1~e.4 (i / induce-01~e.11 :ARG0 (a2 / activate-01~e.6 :ARG1~e.7 (o / or~e.9 :op1 (e / enzyme :name (n2 / name :op1 "MEK1"~e.8)) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2"~e.10))) :mod (c2 / constitutive~e.5)) :ARG2 (e3 / express-03~e.13 :ARG2~e.14 (n6 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.17) :mod (r / receptor~e.16 :mod (e4 / enzyme :name (n4 / name :op1 "urokinase"~e.15)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "4B"~e.22))) # ::id pmid_1901_4680.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As observed for the MMPs , the extent of induction of the urokinase receptor gene was higher in MEK2DD @-@ expressing cells . # ::alignments 1-1.4 7-1.1 8-1.1.1.r 9-1.1.1 10-1.1.1.1.r 12-1.1.1.1.1.1.1.1 13-1.1.1.1.1 14-1.1.1.1 16-1 16-1.2 16-1.2.r 17-1.3.r 18-1.3.1.1.1.1 20-1.3.1 21-1.3 (h / high-02~e.16 :ARG1 (e / extent~e.7 :extent-of~e.8 (i / induce-01~e.9 :ARG2~e.10 (g / gene~e.14 :mod (r / receptor~e.13 :mod (e2 / enzyme :name (n / name :op1 "urokinase"~e.12)))))) :degree~e.16 (m / more~e.16) :location~e.17 (c / cell~e.21 :ARG3-of (e3 / express-03~e.20 :ARG2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD"~e.18)))) :ARG1-of (o / observe-01~e.1 :topic (e5 / enzyme :name (n3 / name :op1 "MMP")))) # ::id pmid_1901_4680.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a previous study , Komatsu et al. [ @ 45 @ ] have used oligonucleotide microarrays to analyze the gene expression profile of intestinal epithelial cells expressing a conditional allele of activated MEK1 . # ::alignments 2-1.4.1.1 3-1.4 3-1.4.1 3-1.4.1.r 5-1.1.1.1.1 6-1.1 7-1.1.2.1 10-1.5.1.1.1 14-1 15-1.2.1 16-1.2 18-1.3 20-1.3.2.2 21-1.3.2.1 22-1.3.2 24-1.3.2.1.2.2 25-1.3.2.1.2.1 26-1.3.2.1.2 27-1.3.2.1 29-1.3.2.1.1.1 30-1.3.2.1.1 31-1.3.2.1.1.2.r 32-1.3.2.1.1.2.2 33-1.3.2.1.1.2.1.1 (u / use-01~e.14 :ARG0 (a / and~e.6 :op1 (p / person :name (n / name :op1 "Komatsu"~e.5)) :op2 (p2 / person :mod (o / other~e.7))) :ARG1 (m / microarray~e.16 :mod (o2 / oligonucleotide~e.15)) :ARG2 (a4 / analyze-01~e.18 :ARG0 a :ARG1 (p3 / profile-01~e.22 :ARG1 (e3 / express-03~e.21,27 :ARG2 (a2 / allele~e.30 :mod (c2 / conditional~e.29) :part-of~e.31 (e4 / enzyme :name (n3 / name :op1 "MEK1"~e.33) :ARG1-of (a3 / activate-01~e.32))) :ARG3 (c / cell~e.26 :mod (e2 / epithelium~e.25) :part-of (i / intestine~e.24))) :mod (g / gene~e.20))) :location (t / thing~e.3 :ARG1-of~e.3 (s2 / study-01~e.3 :time (p4 / previous~e.2))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 45~e.10)))) # ::id pmid_1901_4680.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have compared the results of our transcriptional profiling analysis with this study . # ::alignments 0-1.1 2-1 4-1.2 4-1.2.1 4-1.2.1.r 5-1.2.1.1.r 6-1.2.1.1.1 6-1.2.1.1.1.r 7-1.2.1.1.3 8-1.2.1.1.2 9-1.2.1.1 10-1.3.r 11-1.3.1 12-1.3 (c / compare-01~e.2 :ARG0 (w / we~e.0) :ARG1 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4 :ARG1~e.5 (a / analyze-01~e.9 :ARG0~e.6 w~e.6 :ARG0-of (p / profile-01~e.8) :mod (t2 / transcribe-01~e.7)))) :ARG2~e.10 (s / study-01~e.12 :mod (t4 / this~e.11))) # ::id pmid_1901_4680.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the 69 gene transcripts that showed altered expression in the study of Komatsu , 18 ( 26 %) were found to be modulated in IEC @-@ 6 cells expressing constitutively active MEK1 or MEK2 . # ::alignments 2-1.1.1.3.1.1 3-1.1.1.2 3-1.1.1.3.1.2 6-1.1.1.3.1.3 7-1.1.1.3.1.3.1.1 8-1.1.1.3.1.3.1 9-1.1.1.3.1.3.2.r 11-1.1.1.3.1.3.2 12-1.1.1.3.1.3.2.1.r 13-1.1.1.3.1.3.2.1.1.1 15-1.1.1.1 17-1.1.1.3.2.1 20-1 23-1.1 24-1.1.2.r 25-1.1.2.1.1 27-1.1.2.1.1 28-1.1.2 29-1.1.2.2 30-1.1.2.2.1.1.2.1 30-1.1.2.2.1.1.2.1.r 32-1.1.2.2.1.1.1.1 33-1.1.2.2.1 34-1.1.2.2.1.2.1.1 (f / find-01~e.20 :ARG1 (m / modulate-01~e.23 :ARG1 (t3 / transcribe-01 :quant 18~e.15 :ARG1 (g2 / gene~e.3) :ARG1-of (i / include-91 :ARG2 (t / transcribe-01 :quant 69~e.2 :ARG1 (g / gene~e.3) :ARG0-of (s / show-01~e.6 :ARG1 (e / express-03~e.8 :ARG1-of (a / alter-01~e.7)) :location~e.9 (s2 / study-01~e.11 :ARG0~e.12 (p / person :name (n / name :op1 "Komatsu"~e.13))))) :ARG3 (p2 / percentage-entity :value 26~e.17))) :location~e.24 (c / cell-line~e.28 :name (n2 / name :op1 "IEC-6"~e.25,27) :ARG3-of (e2 / express-03~e.29 :ARG2 (o / or~e.33 :op1 (e3 / enzyme :name (n3 / name :op1 "MEK1"~e.32) :ARG1-of (a2 / activate-01 :manner~e.30 (c2 / constitutive~e.30))) :op2 (e4 / enzyme :name (n4 / name :op1 "MEK2"~e.34) :ARG1-of a2 :manner c2)))))) # ::id pmid_1901_4680.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , the two studies converge on a series of genes involved in cell proliferation , cell invasion , tumor suppression and drug metabolism . # ::alignments 0-1.3 3-1.1.1 4-1.1 5-1 6-1.2.r 8-1.2.1 9-1.2.1.r 10-1.2 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1 14-1.2.2.1.1 16-1.2.2.1.1.1 17-1.2.2.1.2 19-1.2.2.1.3.1 20-1.2.2.1.3 21-1.2.2.1 22-1.2.2.1.4.1 (c / converge-01~e.5 :ARG0 (s / study-01~e.4 :quant 2~e.3) :ARG2~e.6 (g / gene~e.10 :quant~e.9 (s2 / series~e.8) :ARG1-of (i / involve-01~e.11 :ARG2~e.12 (a / and~e.21 :op1 (p / proliferate-01~e.14 :ARG0 (c2 / cell~e.13,16)) :op2 (i2 / invade-01~e.17 :ARG0 c2) :op3 (s3 / suppress-01~e.20 :ARG1 (t2 / tumor~e.19)) :op4 (m / metabolize-01 :ARG1 (d / drug~e.22))))) :mod (i3 / important~e.0)) # ::id pmid_1901_4680.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutive activation of MEK1 or MEK2 protects intestinal epithelial cells against anoikis # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 7-1 8-1.2.2 9-1.2.1 10-1.2 11-1.3.r 12-1.3 (p / protect-01~e.7 :ARG0 (a / activate-01~e.2 :ARG1~e.3 (o / or~e.5 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.6))) :mod (c / constitutive~e.1)) :ARG1 (c2 / cell~e.10 :mod (e3 / epithelium~e.9) :part-of (i / intestine~e.8)) :ARG2~e.11 (a2 / anoikis~e.12)) # ::id pmid_1901_4680.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Epithelial cancer progression and metastasis is associated with the acquisition of resistance to anoikis [ @ 46 @ ] . # ::alignments 0-1.1.1.1.3 1-1.1.1.1.2.1 2-1.1.1 3-1.1 4-1.1.2 6-1 7-1.2.r 9-1.2 10-1.2.1.r 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1 16-1.3.1.1.1 (a / associate-01~e.6 :ARG1 (a2 / and~e.3 :op1 (p / progress-01~e.2 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.1) :mod (e / epithelium~e.0))) :op2 (m / metastasize-101~e.4 :ARG1 d)) :ARG2~e.7 (a3 / acquire-01~e.9 :ARG1~e.10 (r / resist-01~e.11 :ARG1~e.12 (a4 / anoikis~e.13))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 46~e.16)))) # ::id pmid_1901_4680.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further explore the mechanism by which MEK1 and MEK2 promote tumor metastasis , we asked whether activated MEK isoforms protect intestinal epithelial cells from cell death induced by loss of adhesion . # ::alignments 1-1.3.3 2-1.3 4-1.3.2 7-1.3.2.1.1.1.1.1 8-1.3.2.1.1 9-1.3.2.1.1.2.1.1 10-1.3.2.1 11-1.3.2.1.2.1 12-1.3.2.1.2 14-1.1 15-1 16-1.2.1 16-1.2.1.r 17-1.2.2.2 18-1.2.2.1.1.1 19-1.2.2 20-1.2 21-1.2.4.1 22-1.2.4.1 23-1.2.4.1 24-1.2.4.r 25-1.2.4.1 26-1.2.4 27-1.2.4.2 28-1.2.4.2.1.r 29-1.2.4.2.1 30-1.2.4.2.1.1.r 31-1.2.4.2.1.1 (a / ask-01~e.15 :ARG0 (w / we~e.14) :ARG1 (p / protect-01~e.20 :mode~e.16 interrogative~e.16 :ARG0 (i / isoform~e.19 :mod (e / enzyme :name (n / name :op1 "MEK"~e.18)) :ARG1-of (a2 / activate-01~e.17)) :ARG1 (c / cell :mod (e2 / epithelium :mod (i2 / intestine))) :ARG2~e.24 (d / die-01~e.26 :ARG1 c~e.21,22,23,25 :ARG2-of (i3 / induce-01~e.27 :ARG0~e.28 (l / lose-02~e.29 :ARG1~e.30 (a3 / adhere-01~e.31))))) :purpose (e3 / explore-01~e.2 :ARG0 w :ARG1 (m / mechanism~e.4 :instrument-of (p2 / promote-01~e.10 :ARG0 (a4 / and~e.8 :op1 (e4 / enzyme :name (n2 / name :op1 "MEK1"~e.7)) :op2 (e5 / enzyme :name (n3 / name :op1 "MEK2"~e.9))) :ARG1 (m2 / metastasize-101~e.12 :ARG1 (t / tumor~e.11)))) :mod (f / further~e.1))) # ::id pmid_1901_4680.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok IEC @-@ 6 @-@ transduced populations were placed on poly @-@ HEMA @-@ coated plates in normal growth medium and the extent of apoptosis was measured at different times by TUNEL . # ::alignments 0-1.1.1.1.1.1.1 2-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.1.1.1.1 11-1.1.2.1.1.1.1 13-1.1.2.1 14-1.1.2 15-1.1.3.r 16-1.1.3.2 17-1.1.3.1 18-1.1.3 19-1 21-1.2.1 22-1.2.1.1.r 23-1.2.1.1 25-1.2 26-1.2.2.r 27-1.2.2.1 28-1.2.2 29-1.2.3.r 30-1.2.3.1.1 (a / and~e.19 :op1 (p / place-01~e.7 :ARG1 (p2 / population~e.5 :ARG1-of (t / transduce-01~e.4 :ARG2 (c / cell-line :name (n / name :op1 "IEC-6"~e.0,2)))) :ARG2~e.8 (p3 / plate~e.14 :ARG1-of (c2 / coat-01~e.13 :ARG2 (s / small-molecule :name (n2 / name :op1 "poly-HEMA"~e.9,11)))) :location~e.15 (m2 / medium~e.18 :mod (g / grow-01~e.17) :ARG1-of (n3 / normal-02~e.16))) :op2 (m3 / measure-01~e.25 :ARG1 (e / extent~e.21 :degree-of~e.22 (a2 / apoptosis~e.23)) :frequency~e.26 (t2 / time~e.28 :ARG1-of (d / differ-02~e.27)) :instrument~e.29 (t3 / thing :name (n4 / name :op1 "TUNEL"~e.30)))) # ::id pmid_1901_4680.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Detachment from matrix induced high levels of apoptosis of control IEC @-@ 6 cells , which was already detectable at 6 h and increased up to 24 h ( Fig . 5A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1 3-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.2 10-1.2.1.1.1.1 12-1.2.1.1.1.1 13-1.2.1.1 17-1.3.3 18-1.3 20-1.3.2.1.1 21-1.3.2.1.2 23-1.4 24-1.4 24-1.4.1.1 25-1.4.1.1 26-1.4.1.1.1.1 27-1.4.1.1.1.2 29-1.5.1 32-1.5.1.1 (i / induce-01~e.3 :ARG0 (d / detach-01~e.0 :ARG2~e.1 (m / matrix~e.2)) :ARG2 (l / level~e.5 :quant-of~e.6 (a / apoptosis~e.7 :poss~e.8 (c / cell-line~e.13 :name (n / name :op1 "IEC-6"~e.10,12) :ARG2-of (c2 / control-01~e.9))) :ARG1-of (h / high-02~e.4)) :ARG1-of (d2 / detect-01~e.18 :ARG1-of (p / possible-01) :time (a2 / after :quant (t / temporal-quantity :quant 6~e.20 :unit (h2 / hour~e.21))) :time (a3 / already~e.17)) :ARG1-of (i2 / increase-01~e.23,24 :time (a4 / after :quant (u / up-to~e.24,25 :op1 (t2 / temporal-quantity :quant 24~e.26 :unit h2~e.27)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.29 :mod "5A"~e.32))) # ::id pmid_1901_4680.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Strikingly , expression of either MEK1DD or MEK2DD almost completely protected IEC @-@ 6 cells from undergoing anoikis . # ::alignments 0-1.5 2-1.1 5-1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1 8-1.4.1 9-1.4 10-1 11-1.2.1.1 13-1.2.1.1 14-1.2 15-1.3.r 16-1.3 17-1.3.2 (p / protect-01~e.10 :ARG0 (e / express-03~e.2 :ARG2 (o / or~e.6 :op1 (e2 / enzyme :name (n / name :op1 "MEK1DD"~e.5)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2DD"~e.7)))) :ARG1 (c / cell-line~e.14 :name (n3 / name :op1 "IEC-6"~e.11,13)) :ARG2~e.15 (u / undergo-28~e.16 :ARG1 c :ARG2 (a / anoikis~e.17)) :degree (c2 / complete-01~e.9 :degree (a2 / almost~e.8)) :ARG1-of (s / strike-04~e.0)) # ::id pmid_1901_4680.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a step to understand the molecular mechanism by which activated MEK isoforms suppress anoikis , we monitored the expression of Bcl @-@ 2 anti @-@ apoptotic and pro @-@ apoptotic family proteins . # ::alignments 2-1.3 3-1.3.1 4-1.3.1 6-1.3.1.2.1 7-1.3.1.2 10-1.3.1.2.2.1.2 11-1.3.1.2.2.1.1.1.1 12-1.3.1.2.2.1 13-1.3.1.2.2 14-1.3.1.2.2.2 16-1.1 17-1 19-1.2 20-1.2.1.r 21-1.2.1.1.1.1 21-1.2.1.2.1.1 23-1.2.1.1.1.1 23-1.2.1.2.1.1 24-1.2.1.1.3 26-1.2.1.1.3.1 27-1.2.1 28-1.2.1.2.3 30-1.2.1.2.3.1 31-1.2.1.1.2 32-1.2.1.1 32-1.2.1.2 (m / monitor-01~e.17 :ARG0 (w / we~e.16) :ARG1 (e / express-03~e.19 :ARG2~e.20 (a / and~e.27 :op1 (p / protein~e.32 :name (n / name :op1 "Bcl-2"~e.21,23) :mod (f / family~e.31) :ARG0-of (c / counter-01~e.24 :ARG1 (a2 / apoptosis~e.26))) :op2 (p2 / protein~e.32 :name (n2 / name :op1 "Bcl-2"~e.21,23) :mod f :ARG0-of (f2 / favor-01~e.28 :ARG1 a2~e.30)))) :ARG4-of (s / step-01~e.2 :ARG2 (u / understand-01~e.3,4 :ARG0 w :ARG1 (m2 / mechanism~e.7 :mod (m3 / molecule~e.6) :instrument-of (s2 / suppress-01~e.13 :ARG0 (i / isoform~e.12 :mod (e2 / enzyme :name (n3 / name :op1 "MEK"~e.11)) :ARG1-of (a3 / activate-01~e.10)) :ARG1 (a4 / anoikis~e.14)))))) # ::id pmid_1901_4680.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutive activation of MEK1 or MEK2 resulted in the up @-@ regulation of the pro @-@ survival proteins Mcl @-@ 1 , Bcl @-@ 2 and , to a lesser extent , Bcl @-@ x @_L@ in IEC @-@ 6 cells ( Fig . 5B ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1 7-1.2.r 9-1.2 10-1.2 11-1.2 12-1.2.1.r 14-1.2.1.4 16-1.2.1.4.1 17-1.2.1.1 17-1.2.1.2 17-1.2.1.3 18-1.2.1.1.1.1 20-1.2.1.1.1.1 22-1.2.1.2.1.1 22-1.2.1.3.1.1 24-1.2.1.2.1.1 25-1.2.1 27-1.2.1.3.2.r 29-1.2.1.3.2.1 29-1.2.1.3.2.1.1 29-1.2.1.3.2.1.1.r 30-1.2.1.3.2 32-1.2.1.2.1.1 32-1.2.1.3.1.1 38-1.2.2.r 39-1.2.2.1.1 41-1.2.2.1.1 42-1.2.2 44-1.3.1 47-1.3.1.1 (r / result-01~e.6 :ARG1 (a / activate-01~e.1 :ARG1~e.2 (o / or~e.4 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.3)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.5))) :mod (c / constitutive~e.0)) :ARG2~e.7 (u / upregulate-01~e.9,10,11 :ARG1~e.12 (a2 / and~e.25 :op1 (p / protein~e.17 :name (n3 / name :op1 "Mcl-1"~e.18,20)) :op2 (p2 / protein~e.17 :name (n4 / name :op1 "Bcl-2"~e.22,24,32)) :op3 (p3 / protein~e.17 :name (n5 / name :op1 "Bcl-xL"~e.22,32) :degree~e.27 (e3 / extent~e.30 :quant (l / less~e.29 :degree~e.29 (m / more~e.29)))) :ARG0-of (f / favor-01~e.14 :ARG1 (s / survive-01~e.16))) :location~e.38 (c2 / cell-line~e.42 :name (n6 / name :op1 "IEC-6"~e.39,41))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.44 :mod "5B"~e.47))) # ::id pmid_1901_4680.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our results confirm and extend previous observations [ @ 47 , 48 @ ] by demonstrating that both MEK1 and MEK2 isoforms share the property to induce the accumulation of Bcl @-@ 2 family pro @-@ survival members . # ::alignments 0-1.1.1.2 0-1.1.1.2.r 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1 3-1 3-1.3.1.1.1 4-1.2 5-1.1.2.1 6-1.1.2 9-1.3.1.1.1.1 13-1.3.1.1.1.2 17-1.4 20-1.4.2.1.1.1.1.1 21-1.4.2.1 22-1.4.2.1.2.1.1.1 23-1.4.2.1.1 23-1.4.2.1.2 24-1.4.2 26-1.4.2.2 28-1.4.2.2.1 30-1.4.2.2.1.2 31-1.4.2.2.1.2.1.r 32-1.4.2.2.1.2.1.1.1.1.1 34-1.4.2.2.1.2.1.1.1.1.1 35-1.4.2.2.1.2.1.1.1 36-1.4.2.2.1.2.1.2 38-1.4.2.2.1.2.1.2.1 39-1.4.2.2.1.2.1 (a / and~e.3 :op1 (c / confirm-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :poss~e.0 (w / we~e.0)) :ARG1 (o / observe-01~e.6 :mod (p / previous~e.5))) :op2 (e / extend-01~e.4 :ARG0 t :ARG1 o) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and~e.3 :op1 47~e.9 :op2 48~e.13)))) :manner (d2 / demonstrate-01~e.17 :ARG0 t :ARG1 (s / share-01~e.24 :ARG0 (a3 / and~e.21 :op1 (i / isoform~e.23 :mod (e2 / enzyme :name (n / name :op1 "MEK1"~e.20))) :op2 (i2 / isoform~e.23 :mod (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.22)))) :ARG1 (p3 / property~e.26 :mod (i3 / induce-01~e.28 :ARG0 a3 :ARG2 (a4 / accumulate-01~e.30 :ARG1~e.31 (m / member~e.39 :ARG1-of (i4 / include-91 :ARG2 (p4 / protein-family~e.35 :name (n3 / name :op1 "Bcl-2"~e.32,34))) :ARG0-of (f2 / favor-01~e.36 :ARG1 (s2 / survive-01~e.38))))))))) # ::id pmid_1901_4680.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Reciprocally , induction of the BH3 @-@ only pro @-@ apoptotic protein Bim was completely suppressed in cells expressing MEK1DD or MEK2DD ( Fig . 5C ) . # ::alignments 0-1.4 0-1.4.r 2-1.1 3-1.1.1.r 5-1.1.1.1.1 7-1.1.1.1.1 8-1.1.1 8-1.1.1.2 8-1.1.1.2.r 10-1.1.1.2.1 11-1.1.1.1.2 12-1.1.1.1.3 14-1.3 15-1 16-1.2.r 17-1.2 18-1.2.1 19-1.2.1.1.1.1.1 20-1.2.1.1 21-1.2.1.1.2.1.1 23-1.5.1 26-1.5.1.1 (s / suppress-01~e.15 :ARG1 (i / induce-01~e.2 :ARG2~e.3 (p / protein~e.8 :name (n / name :op1 "BH3-only"~e.5,7 :op2 "protein"~e.11 :op3 "Bim"~e.12) :ARG0-of~e.8 (f / favor-01~e.8 :ARG1 (a / apoptosis~e.10)))) :location~e.16 (c / cell~e.17 :ARG3-of (e / express-03~e.18 :ARG2 (o / or~e.20 :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"~e.19)) :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD"~e.21))))) :degree (c2 / complete-01~e.14) :manner~e.0 (r / reciprocal~e.0) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.23 :mod "5C"~e.26))) # ::id pmid_1901_4680.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This finding is consistent with previous reports documenting the role of the ERK1 @/@ 2 MAP kinase pathway in promoting the degradation of Bim [ @ 49 , 50 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.2 6-1.2 6-1.2.1 6-1.2.1.r 7-1.2.3 9-1.2.3.1 10-1.2.3.1.1.r 12-1.2.3.1.1.1.1 14-1.2.3.1.1.1.1 15-1.2.3.1.1.1.2 16-1.2.3.1.1.1.2 17-1.2.3.1.1 18-1.2.3.1.2.r 19-1.2.3.1.2 21-1.2.3.1.2.2 22-1.2.3.1.2.2.1.r 23-1.2.3.1.2.2.1.1.1 26-1.3.1.1.1.1 30-1.3.1.1.1.2 (c / consistent-01~e.3 :ARG1 (f / find-01~e.1 :mod (t / this~e.0)) :ARG2~e.4 (t2 / thing~e.6 :ARG1-of~e.6 (r / report-01~e.6) :mod (p / previous~e.5) :ARG0-of (d / document-01~e.7 :ARG1 (r2 / role~e.9 :poss~e.10 (p2 / pathway~e.17 :name (n / name :op1 "ERK1/2"~e.12,14 :op2 "MAP-kinase"~e.15,16)) :topic~e.18 (p3 / promote-01~e.19 :ARG0 p2 :ARG1 (d2 / degrade-01~e.21 :ARG1~e.22 (p4 / protein :name (n2 / name :op1 "Bim"~e.23))))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 49~e.26 :op2 50~e.30))))) # ::id pmid_1901_4680.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK1 or MEK2 activation had no significant effect on the expression of the pro @-@ apoptotic proteins Bax and Bak in these cells ( data not shown ) . # ::alignments 0-1.2.1.1.1.1 1-1.2.1 2-1.2.1.2.1.1 3-1.2 5-1.1 5-1.1.r 6-1.4 7-1 8-1.3.r 10-1.3 11-1.3.1.r 13-1.3.1.3 15-1.3.1.3.1 16-1.3.1.1 16-1.3.1.2 17-1.3.1.1.1.1 18-1.3.1 19-1.3.1.2.1.1 20-1.3.2.r 21-1.3.2.1 22-1.3.2 24-1.5.1 25-1.5.1.1.1 25-1.5.1.1.1.r 26-1.5.1.1 (a / affect-01~e.7 :polarity~e.5 -~e.5 :ARG0 (a2 / activate-01~e.3 :ARG1 (o / or~e.1 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.0)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.2)))) :ARG1~e.8 (e3 / express-03~e.10 :ARG2~e.11 (a3 / and~e.18 :op1 (p / protein~e.16 :name (n3 / name :op1 "Bax"~e.17)) :op2 (p2 / protein~e.16 :name (n4 / name :op1 "Bak"~e.19)) :ARG0-of (f / favor-01~e.13 :ARG1 (a4 / apoptosis~e.15))) :ARG3~e.20 (c / cell~e.22 :mod (t / this~e.21))) :ARG1-of (s / significant-02~e.6) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.24 :ARG1-of (s2 / show-01~e.26 :polarity~e.25 -~e.25)))) # ::id pmid_1901_4680.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Silencing of MEK2 expression markedly inhibits the proliferation of human colon cancer cells # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.3 6-1 8-1.2 9-1.2.1.r 10-1.2.1.1.3 11-1.2.1.1.2.1 12-1.2.1.1.2.2 13-1.2.1 (i / inhibit-01~e.6 :ARG0 (s / silence-01~e.1 :ARG1~e.2 (e / express-03~e.4 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"~e.3)))) :ARG1 (p / proliferate-01~e.8 :ARG0~e.9 (c / cell~e.13 :mod (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon"~e.11 :op2 "cancer"~e.12) :mod (h / human~e.10)))) :degree (m / marked~e.5)) # ::id pmid_1901_4680.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results presented above clearly demonstrate that constitutive activation of either MEK isoform , MEK1 or MEK2 , is sufficient to fully transform intestinal epithelial cells to the metastatic stage . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1.1.2 3-1.1.2.1 4-1.3 5-1 6-1.2.r 7-1.2.1.2 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.4 11-1.2.1.1.3.1.1.1.1 12-1.2.1.1.3.1 14-1.2.1.1.1.1.1 15-1.2.1.1 16-1.2.1.1.2.1.1 19-1.2 21-1.2.2.4 22-1.2.2 23-1.2.2.2.1.1 24-1.2.2.2.1 25-1.2.2.2 28-1.2.2.3.1 29-1.2.2.3 (d / demonstrate-01~e.5 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :ARG1-of (p / present-01~e.2 :location (a / above~e.3))) :ARG1~e.6 (s / suffice-01~e.19 :ARG0 (a2 / activate-01~e.8 :ARG1~e.9 (o / or~e.15 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.14)) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2"~e.16)) :ARG1-of (m / mean-01 :ARG2 (i / isoform~e.12 :mod (e3 / enzyme :name (n2 / name :op1 "MEK"~e.11)))) :mod (e4 / either~e.10)) :mod (c / constitutive~e.7)) :ARG1 (t2 / transform-01~e.22 :ARG0 a2 :ARG1 (c2 / cell~e.25 :mod (e5 / epithelium~e.24 :mod (i2 / intestine~e.23))) :ARG2 (s2 / stage-02~e.29 :ARG2 (m2 / metastasize-101~e.28)) :degree (f / full~e.21))) :ARG1-of (c3 / clear-06~e.4)) # ::id pmid_1901_4680.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next wanted to determine if human colon cancer cells depend on the activity of MEK isoforms for cell proliferation . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 6-1.2.2.2.1.3 7-1.2.2.2.1.2.1 8-1.2.2.2.1.2.2 9-1.2.2.2 10-1.2.2 11-1.2.2.3.r 13-1.2.2.3 14-1.2.2.3.1.r 15-1.2.2.3.1.1.1.1 16-1.2.2.3.1 17-1.2.2.4.r 18-1.2.2.4.1 19-1.2.2.4 (w / want-01~e.2 :ARG0 (w2 / we~e.0) :ARG1 (d / determine-01~e.4 :ARG0 w2 :ARG1 (d2 / depend-01~e.10 :mode interrogative :ARG0 (c / cell~e.9 :mod (d4 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colon"~e.7 :op2 "cancer"~e.8) :mod (h / human~e.6))) :ARG1~e.11 (a / activity-06~e.13 :ARG0~e.14 (i / isoform~e.16 :mod (e / enzyme :name (n2 / name :op1 "MEK"~e.15)))) :purpose~e.17 (p / proliferate-01~e.19 :ARG0 c~e.18))) :time (n3 / next~e.1)) # ::id pmid_1901_4680.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several human colon carcinoma cell lines display constitutive phosphorylation of ERK1 @/@ ERK2 MAP kinases [ @ 20 @ ] , likely resulting from activation of MEK1/MEK2 . # ::alignments 0-1.1.2 1-1.1.1.1.1 2-1.1.1.1 3-1.1.1 4-1.1 5-1.1 6-1 7-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1.1.1 12-1.2.1.1.1 13-1.2.1.1.2 14-1.2.1.1.2 17-1.3.1.1.1 21-1.4.2 22-1.4 23-1.4.1.r 24-1.4.1 25-1.4.1.1.r 26-1.4.1.1.1.1 (d / display-01~e.6 :ARG0 (c / cell-line~e.4,5 :mod (c2 / carcinoma~e.3 :mod (c3 / colon~e.2 :part-of (h / human~e.1))) :quant (s / several~e.0)) :ARG1 (p / phosphorylate-01~e.8 :ARG1~e.9 (e / enzyme :name (n / name :op1 "ERK1/ERK2"~e.10,12 :op2 "MAP-kinase"~e.13,14)) :mod (c4 / constitutive~e.7)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 20~e.17))) :ARG2-of (r / result-01~e.22 :ARG1~e.23 (a / activate-01~e.24 :ARG1~e.25 (e2 / enzyme :name (n2 / name :op1 "MEK1/MEK2"~e.26))) :ARG1-of (l / likely-01~e.21))) # ::id pmid_1901_4680.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The HCT116 cell line , which represents one of the best studied model of colorectal cancer cells , display constitutive activation of the two MEK isoforms ( Fig . 6A ) . # ::alignments 1-1.1.1.1 2-1.1 3-1.1 6-1.1.2 7-1.1.2.1.1 11-1.1.2.1.2.1.1 12-1.1.2.1 12-1.1.2.1.2.1 13-1.1.2.1.2.1.2.r 14-1.1.2.1.2.1.2.1.2.1 15-1.1.2.1.2.1.2.1.2.2 16-1.1.2.1.2.1.2 18-1 19-1.2.2 20-1.2 21-1.2.1.r 23-1.2.1.1 24-1.2.1.2.1.1 25-1.2.1 27-1.3.1 30-1.3.1.1 (d / display-01~e.18 :ARG0 (c / cell-line~e.2,3 :name (n / name :op1 "HCT116"~e.1) :ARG0-of (r / represent-01~e.6 :ARG1 (m / model~e.12 :quant 1~e.7 :ARG1-of (i / include-91 :ARG2 (m2 / model~e.12 :ARG1-of (s / study-01~e.11 :ARG1-of (w / well-09)) :mod~e.13 (c2 / cell~e.16 :mod (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal"~e.14 :op2 "cancer"~e.15)))))))) :ARG1 (a / activate-01~e.20 :ARG1~e.21 (i2 / isoform~e.25 :quant 2~e.23 :mod (e / enzyme :name (n3 / name :op1 "MEK"~e.24))) :mod (c4 / constitutive~e.19)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.27 :mod "6A"~e.30))) # ::id pmid_1901_4680.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the individual roles of MEK1 and MEK2 , we expressed short @-@ hairpin ( sh ) RNAs specifically targeting MEK1 or MEK2 gene in HCT116 cells using VSV @-@ pseudotyped lentiviral vectors . # ::alignments 1-1.4 3-1.4.2.2 4-1.4.2 6-1.1.2.1.1.1.1 8-1.1.2.1.2.1.1 10-1.3.1 11-1 12-1.1.1.1 14-1.1.1.1 19-1.1.2.2 20-1.1.2 21-1.1.2.1.1.1.1 22-1.1.2.1 23-1.1.2.1.2.1.1 24-1.1.2.1.1 24-1.1.2.1.2 25-1.2.r 26-1.2.1.1 27-1.2 28-1.3 28-1.4.r 29-1.3.2.1.1 31-1.3.2.1.1 32-1.3.2.1.2 33-1.3.2 33-1.3.2.1.3 (e / express-03~e.11 :ARG1 (n6 / nucleic-acid :name (n / name :op1 "short-hairpin"~e.12,14 :op2 "RNA") :ARG0-of (t / target-01~e.20 :ARG1 (o / or~e.22 :op1 (g / gene~e.24 :name (n2 / name :op1 "MEK1"~e.6,21)) :op2 (g2 / gene~e.24 :name (n3 / name :op1 "MEK2"~e.8,23))) :ARG1-of (s / specific-02~e.19))) :ARG3~e.25 (c / cell-line~e.27 :name (n4 / name :op1 "HCT116"~e.26)) :manner (u / use-01~e.28 :ARG0 (w / we~e.10) :ARG1 (v / vector~e.33 :name (n5 / name :op1 "VSV-pseudotyped"~e.29,31 :op2 "lentiviral"~e.32 :op3 "vector"~e.33))) :purpose~e.28 (a / assess-01~e.1 :ARG0 w :ARG1 (r2 / role~e.4 :poss (a2 / and :op1 g :op2 g2) :mod (i / individual~e.3)))) # ::id pmid_1901_4680.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We tested the effect of 5 distinct shRNAs for MEK1 and 3 shRNAs for MEK2 , using as control a GFP @-@ encoding vector . # ::alignments 0-1.1 1-1 3-1.2.1 3-1.2.2 4-1.2.1.1.r 5-1.2.1.1.1 6-1.2.1.1.3 7-1.2.1.1.2.1 8-1.2.1.2.r 9-1.2.1.2.1.1 10-1.2 11-1.2.2.1.1 12-1.2.2.1.2.1 13-1.2.2.2.r 14-1.2.2.2.1.1 16-1.3 17-1.3.2.r 18-1.3.2.2 20-1.3.2.1.1.1.1 22-1.3.2.1 23-1.3.2 (t / test-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / and~e.10 :op1 (a2 / affect-01~e.3 :ARG0~e.4 (n6 / nucleic-acid :quant 5~e.5 :name (n / name :op1 "shRNA"~e.7) :mod (d / distinct~e.6)) :ARG1~e.8 (g / gene :name (n2 / name :op1 "MEK1"~e.9))) :op2 (a3 / affect-01~e.3 :ARG0 (n7 / nucleic-acid :quant 3~e.11 :name (n3 / name :op1 "shRNA"~e.12)) :ARG1~e.13 (g2 / gene :name (n4 / name :op1 "MEK2"~e.14)))) :manner (u / use-01~e.16 :ARG0 w :ARG1~e.17 (v / vector~e.23 :ARG0-of (e / encode-01~e.22 :ARG1 (p / protein :name (n5 / name :op1 "GFP"~e.20))) :ARG2-of (c / control-01~e.18)))) # ::id pmid_1901_4680.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We selected the two most efficient shRNAs to MEK1 and MEK2 genes ( Additional file 3 ) . # ::alignments 0-1.1 1-1 3-1.2.1 4-1.2.3.1 5-1.2 5-1.2.3 5-1.2.3.r 6-1.2.2.1 8-1.2.4.1.1.1.1 9-1.2.4.1 10-1.2.4.1.2.1.1 11-1.2.4.1.1 11-1.2.4.1.2 14-1.3.1 16-1.3.1.1 (s / select-01~e.1 :ARG0 (w / we~e.0) :ARG1 (n4 / nucleic-acid~e.5 :quant 2~e.3 :name (n / name :op1 "shRNA"~e.6) :ARG1-of~e.5 (e / efficient-01~e.5 :degree (m / most~e.4)) :ARG0-of (a / affect-01 :ARG1 (a2 / and~e.9 :op1 (g / gene~e.11 :name (n2 / name :op1 "MEK1"~e.8)) :op2 (g2 / gene~e.11 :name (n3 / name :op1 "MEK2"~e.10))))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.14 :mod 3~e.16 :ARG1-of (a3 / add-02)))) # ::id pmid_1901_4680.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A non @-@ silencing inactive MEK1 shRNA was used as additional negative control in these experiments . # ::alignments 1-1.1.3.1 1-1.1.3.1.r 1-1.1.4.1.r 3-1.1.4 4-1.1.3.1 4-1.1.4.1 5-1.1.2.1.1 6-1.1.1.1 8-1 11-1.1.5.1 12-1.1 12-1.1.5 12-1.1.5.r 13-1.2.r 14-1.2.1 15-1.2 (u / use-01~e.8 :ARG1 (n4 / nucleic-acid~e.12 :name (n / name :op1 "shRNA"~e.6) :mod (g / gene :name (n2 / name :op1 "MEK1"~e.5)) :ARG1-of (a / activate-01 :polarity~e.1 -~e.1,4) :ARG0-of (s / silence-01~e.3 :polarity~e.1 -~e.4) :ARG2-of~e.12 (c / control-01~e.12 :ARG2-of (n3 / negative-01~e.11)) :ARG1-of (a2 / add-02)) :location~e.13 (e / experiment-01~e.15 :mod (t / this~e.14))) # ::id pmid_1901_4680.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The efficiency of transduction estimated by GFP immunofluorescence was over 90 % , and therefore the experiments were performed without cellular selection . # ::alignments 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1 4-1.1 5-1.1.1.r 6-1.1.1.1.1.1 7-1.1.1 9-1.1.3 10-1.1.3.1.1 11-1.1.3.1 14-1 16-1.2.1 18-1.2 19-1.2.2.1 19-1.2.2.1.r 20-1.2.2.2 21-1.2.2 (c / cause-01~e.14 :ARG0 (e / estimate-01~e.4 :ARG0~e.5 (i / immunofluoresce-01~e.7 :ARG2 (p / protein :name (n2 / name :op1 "GFP"~e.6))) :ARG1 (e2 / efficient-01~e.1 :ARG1~e.2 (t / transduce-01~e.3)) :ARG2 (o / over~e.9 :quant (p2 / percentage-entity~e.11 :value 90~e.10))) :ARG1 (p3 / perform-01~e.18 :ARG1 (e3 / experiment-01~e.16) :manner (s / select-01~e.21 :polarity~e.19 -~e.19 :ARG1 (c2 / cell~e.20)))) # ::id pmid_1901_4680.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown by immunoblot analysis , lentivirus @-@ mediated delivery of MEK1 shRNAs resulted in complete silencing of MEK1 expression with no effect on MEK2 , whereas the two MEK2 shRNAs markedly knocked @-@ down MEK2 expression without affecting MEK1 isoform ( Fig . 6B ) . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1.1 4-1.3.1 6-1.1.1.2.1 8-1.1.1.2 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.2.1.1 12-1.1.1.1.1.1 13-1.1 14-1.1.2.r 15-1.1.2.2 16-1.1.2 17-1.1.2.1.r 18-1.1.2.1.1.1.1 19-1.1.2.1 20-1.1.2.3.r 21-1.1.2.3.1 21-1.1.2.3.1.r 22-1.1.2.3 24-1.1.2.3.2.1.1 24-1.2.1.3.1.1 26-1 28-1.2.1.1 29-1.2.1.3.1.1 30-1.2.1.2.1 31-1.2.4 32-1.2 34-1.2 35-1.2.1.3.1.1 36-1.2.2 37-1.2.3.1 37-1.2.3.1.r 38-1.2.3 39-1.2.3.2.1.1 40-1.2.3.2.2 42-1.4.1 45-1.4.1.1 (c / contrast-01~e.26 :ARG1 (r / result-01~e.13 :ARG1 (d / deliver-01~e.9 :ARG1~e.10 (n8 / nucleic-acid :name (n / name :op1 "shRNA"~e.12) :mod (g / gene :name (n2 / name :op1 "MEK1"~e.11))) :ARG1-of (m / mediate-01~e.8 :ARG0 (l / lentivirus~e.6))) :ARG2~e.14 (s / silence-01~e.16 :ARG1~e.17 (e / express-03~e.19 :ARG2 (e2 / enzyme :name (n3 / name :op1 "MEK1"~e.18))) :degree (c2 / complete-01~e.15) :ARG0-of~e.20 (a / affect-01~e.22 :polarity~e.21 -~e.21 :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK2"~e.24))))) :ARG2 (k / knock-down-02~e.32,34 :ARG0 (n9 / nucleic-acid :quant 2~e.28 :name (n5 / name :op1 "shRNA"~e.30) :mod (g2 / gene :name (n6 / name :op1 "MEK2"~e.24,29,35))) :ARG1 (e4 / express-03~e.36 :ARG2 e3) :ARG0-of (a2 / affect-01~e.38 :polarity~e.37 -~e.37 :ARG1 (e5 / enzyme :name (n10 / name :op1 "MEK1"~e.39) :mod (i / isoform~e.40))) :degree (m2 / marked~e.31)) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (a3 / analyze-01~e.4 :manner (i2 / immunoblot-01~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.42 :mod "6B"~e.45))) # ::id pmid_1901_4680.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We then analyzed the functional consequence of MEK1 or MEK2 silencing on the proliferation rate of the cells . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.3 5-1.2 5-1.2.1 5-1.2.1.r 6-1.2.1.1.r 7-1.2.1.1.1.1.1.1 8-1.2.1.1.1 9-1.2.1.1.1.2.1.1 10-1.2.1.1 11-1.2.2.r 13-1.2.2.1 14-1.2.2 15-1.2.2.1.1.r 17-1.2.2.1.1 (a / analyze-01~e.2 :ARG0 (w / we~e.0) :ARG1 (c / consequence~e.5 :ARG1-of~e.5 (c2 / cause-01~e.5 :ARG0~e.6 (s / silence-01~e.10 :ARG1 (o / or~e.8 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.7)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.9))))) :topic~e.11 (r / rate~e.14 :degree-of (p / proliferate-01~e.13 :ARG0~e.15 (c3 / cell~e.17))) :mod (f / function-01~e.4)) :mod (t / then~e.1)) # ::id pmid_1901_4680.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Strikingly , lowering of MEK2 expression with the two shRNAs completely suppressed the proliferation of HCT116 cells , whereas MEK1 shRNAs exerted a significant but much weaker effect ( Fig . 6B ) . # ::alignments 0-1.3 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.r 8-1.1.1.1.2.1 9-1.1.1.1.2.2.1 10-1.1.3 11-1.1 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 16-1.1.2.1 18-1 19-1.2.1.2.1.1 20-1.2.1.1.1 21-1.2 23-1.2.2.1 24-1.2.2.1.1 25-1.2.2.1.1.1.1.1 26-1.2.2.1.1.1 26-1.2.2.1.1.1.1 26-1.2.2.1.1.1.1.r 27-1.2.2 29-1.4.1 32-1.4.1.1 (c / contrast-01~e.18 :ARG1 (s / suppress-01~e.11 :ARG0 (l / lower-05~e.2 :ARG1~e.3 (e / express-03~e.5 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"~e.4)) :instrument~e.6 (n7 / nucleic-acid :quant 2~e.8 :name (n2 / name :op1 "shRNA"~e.9)))) :ARG1 (p / proliferate-01~e.13 :ARG0~e.14 (c2 / cell-line~e.16 :name (n3 / name :op1 "HCT116"~e.15))) :degree (c3 / complete~e.10)) :ARG2 (e3 / exert-01~e.21 :ARG0 (n6 / nucleic-acid :name (n4 / name :op1 "shRNA"~e.20) :mod (g / gene :name (n5 / name :op1 "MEK1"~e.19))) :ARG1 (a / affect-01~e.27 :ARG1-of (s2 / significant-02~e.23 :ARG1-of (c4 / contrast-01~e.24 :ARG2 (w / weak-02~e.26 :degree~e.26 (m / more~e.26 :degree (m2 / much~e.25))))))) :manner (s3 / strike-04~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "6B"~e.32))) # ::id pmid_1901_4680.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The extent of inhibition observed with MEK2 shRNAs was similar to that obtained by treating cells with the non @-@ selective MEK1 @/@ 2 inhibitor U0126 . # ::alignments 1-1.1 1-1.2 2-1.1.1.r 3-1.1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.2.1.1 7-1.1.2.1.1.1 9-1 12-1.2.2 13-1.2.2.1.r 14-1.2.2.1 15-1.2.2.1.1 16-1.2.2.1.2.r 18-1.2.2.1.2.3.1 18-1.2.2.1.2.3.1.r 21-1.2.2.1.2.2.1.1.1 23-1.2.2.1.2.2.1.1.1 24-1.2.2.1.2 24-1.2.2.1.2.2 24-1.2.2.1.2.2.r 25-1.2.2.1.2.1.1 (r / resemble-01~e.9 :ARG1 (e / extent~e.1 :degree-of~e.2 (i / inhibit-01~e.3) :ARG1-of (o / observe-01~e.4 :topic~e.5 (n5 / nucleic-acid :name (n / name :op1 "shRNA"~e.7) :mod (g / gene :name (n2 / name :op1 "MEK2"~e.6))))) :ARG2 (e2 / extent~e.1 :degree-of i :ARG1-of (o2 / obtain-01~e.12 :manner~e.13 (t / treat-04~e.14 :ARG1 (c / cell~e.15) :ARG2~e.16 (s2 / small-molecule~e.24 :name (n3 / name :op1 "U0126"~e.25) :ARG0-of~e.24 (i2 / inhibit-01~e.24 :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK1/2"~e.21,23))) :ARG0-of (s / select-01 :polarity~e.18 -~e.18)))))) # ::id pmid_1901_4680.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also showed that silencing of MEK1 or MEK2 expression significantly reduces the extent of ERK1 and ERK2 activating phosphorylation ( Fig . 7 ) . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.r 4-1.2.1 5-1.2.1.1.r 6-1.2.1.1.1.1.1.1 7-1.2.1.1.1 8-1.2.1.1.1.2.1.1 9-1.2.1.1 10-1.2.3 11-1.2 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.1.1.1.1.1 16-1.2.2.1.1.1 17-1.2.2.1.1.1.2.1.1 18-1.2.2.1.1 19-1.2.2.1 21-1.4.1 24-1.4.1.1 (s / show-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (r / reduce-01~e.11 :ARG0 (s2 / silence-01~e.4 :ARG1~e.5 (e / express-03~e.9 :ARG2 (o / or~e.7 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.6)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.8))))) :ARG1 (e4 / extent~e.13 :degree-of~e.14 (p / phosphorylate-01~e.19 :ARG0-of (a / activate-01~e.18 :ARG1 (a2 / and~e.16 :op1 (e5 / enzyme :name (n3 / name :op1 "ERK1"~e.15)) :op2 (e6 / enzyme :name (n4 / name :op1 "ERK2"~e.17)))))) :ARG2 (s3 / significant-02~e.10)) :mod (a3 / also~e.1) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod 7~e.24))) # ::id pmid_1901_4680.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To verify whether this differential contribution of MEK isoforms could be generalized to other colorectal cancer cells , we examined the impact of MEK1 or MEK2 silencing on the proliferation of two other human colon cancer cell lines . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.2.1.3 4-1.3.2.2.1.2 5-1.3.2.2.1 6-1.3.2.2.1.1.r 7-1.3.2.2.1.1.1.1.1 8-1.3.2.2.1.1 9-1.3.2 11-1.3.2.2 13-1.2.2.1.2 14-1.2.2.1.3.2.1 15-1.2.2.1.3.2.2 16-1.2.2.1 16-1.3.2.2.2 18-1.1 19-1 21-1.2 22-1.2.1.r 23-1.2.1.1.1.1.1 24-1.2.1.1 25-1.2.1.1.2.1.1 26-1.2.1 29-1.2.2 31-1.2.2.1.1 32-1.2.2.1.2 33-1.2.2.1.3.3 36-1.2.2.1 37-1.2.2.1 (e / examine-01~e.19 :ARG0 (w / we~e.18) :ARG1 (i / impact-01~e.21 :ARG0~e.22 (s / silence-01~e.26 :ARG1 (o / or~e.24 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.23)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"~e.25)))) :ARG1 (p / proliferate-01~e.29 :ARG0 (c / cell-line~e.16,36,37 :quant 2~e.31 :mod (o2 / other~e.13,32) :mod (d4 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colorectal"~e.14 :op2 "cancer"~e.15) :mod (h / human~e.33))))) :purpose (v / verify-01~e.1 :ARG0 w :ARG1 (p2 / possible-01~e.9 :mode~e.2 interrogative~e.2 :ARG1 (g / generalize-01~e.11 :ARG1 (c3 / contribute-01~e.5 :ARG0~e.6 (i2 / isoform~e.8 :mod (e4 / enzyme :name (n4 / name :op1 "MEK"~e.7))) :mod (d2 / differential~e.4) :mod (t / this~e.3)) :ARG2 (c4 / cell~e.16 :mod d4))))) # ::id pmid_1901_4680.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We specifically chose the human colon carcinoma cell lines SW480 ( which harbors a KRAS @ mutation like HCT116 ) and HT @-@ 29 ( harboring a BRAF @ mutation ) . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.3.1.1 5-1.2.3.1 6-1.2.3 7-1.2.1 8-1.2.1 8-1.2.1.3.1 8-1.2.2 9-1.2.1.1.1 12-1.2.1.2 12-1.2.2.2 15-1.2.1.2.1.1.1.1 17-1.2.1.2.1 17-1.2.2.2.1 18-1.2.1.3 19-1.2.1.3.1.1.1 21-1.2 22-1.2.2.1.1 24-1.2.2.1.1 26-1.2.1.2 29-1.2.2.2.1.1.1.1 31-1.2.1.2.1 (c / choose-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / and~e.21 :op1 (c2 / cell-line~e.7,8 :name (n / name :op1 "SW480"~e.9) :ARG0-of (h / harbor-01~e.12,26 :ARG1 (m / mutate-01~e.17,31 :ARG2 (e / enzyme :name (n2 / name :op1 "KRAS"~e.15)))) :ARG1-of (r / resemble-01~e.18 :ARG2 (c3 / cell-line~e.8 :name (n3 / name :op1 "HCT116"~e.19)))) :op2 (c4 / cell-line~e.8 :name (n4 / name :op1 "HT-29"~e.22,24) :ARG0-of (h2 / harbor-01~e.12 :ARG1 (m2 / mutate-01~e.17 :ARG2 (g / gene :name (n5 / name :op1 "BRAF"~e.29))))) :mod (c5 / carcinoma~e.6 :mod (c6 / colon~e.5 :part-of (h3 / human~e.4)))) :ARG1-of (s / specific-02~e.1)) # ::id pmid_1901_4680.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SW480 cells display a comparable expression pattern of MEK1 and MEK2 proteins as HCT116 cells ( Fig . 6A ) . # ::alignments 0-1.1.1.1 1-1.1 2-1 5-1.2.1 6-1.2 7-1.2.1.1.r 8-1.2.1.1.1.1.1 9-1.2.1.1 10-1.2.1.1.2.1.1 13-1.2.2.1.1.1 14-1.1 14-1.2.2.1 16-1.3.1 19-1.3.1.1 (d / display-01~e.2 :ARG0 (c / cell-line~e.1,14 :name (n / name :op1 "SW480"~e.0)) :ARG1 (p / pattern-01~e.6 :ARG1 (e3 / express-03~e.5 :ARG2~e.7 (a / and~e.9 :op1 (e / enzyme :name (n2 / name :op1 "MEK1"~e.8)) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2"~e.10)))) :ARG1-of (c2 / compare-01 :ARG2 (c3 / cell-line~e.14 :name (n4 / name :op1 "HCT116"~e.13)) :ARG1-of (p2 / possible-01))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.16 :mod "6A"~e.19))) # ::id pmid_1901_4680.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to HCT116 cells , knock @-@ down of MEK2 expression dramatically suppressed the proliferation of SW480 cells , whereas MEK1 silencing induced a significant but much lower decrease of cell proliferation ( Fig . 6C ) . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1.1 3-1.3.1 5-1.1.1 7-1.1.1 8-1.1.1.1.r 9-1.1.1.1.1.1.1 10-1.1.1.1 11-1.1.3 12-1.1 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1.1 17-1.1.2.1 19-1 20-1.2.1.1.1.1 21-1.2.1 22-1.2 24-1.2.2.2 25-1.2.2.2.1 26-1.2.2.2.1.1.1.1 27-1.2.2.2.1.1 27-1.2.2.2.1.1.1 27-1.2.2.2.1.1.1.r 28-1.2.2 29-1.2.2.1.r 30-1.2.2.1 31-1.2.2.1 33-1.4.1 36-1.4.1.1 (c / contrast-01~e.19 :ARG1 (s / suppress-01~e.12 :ARG0 (k / knock-down-02~e.5,7 :ARG1~e.8 (e / express-03~e.10 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"~e.9)))) :ARG1 (p / proliferate-01~e.14 :ARG0~e.15 (c2 / cell-line~e.17 :name (n2 / name :op1 "SW480"~e.16))) :degree (d / dramatic~e.11)) :ARG2 (i / induce-01~e.22 :ARG0 (s2 / silence-01~e.21 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK1"~e.20))) :ARG2 (d2 / decrease-01~e.28 :ARG1~e.29 p~e.30,31 :ARG1-of (s3 / significant-02~e.24 :ARG1-of (c3 / contrast-01~e.25 :ARG2 (l / low-04~e.27 :degree~e.27 (m / more~e.27 :quant (m2 / much~e.26))))))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (c4 / cell-line~e.3 :name (n4 / name :op1 "HCT116"~e.2))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.33 :mod "6C"~e.36))) # ::id pmid_1901_4680.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar results were obtained in HT @-@ 29 cells , except that the inhibitory effect of MEK1 shRNAs on proliferation was quantitatively more important than on HCT116 and SW480 cells ( Fig . 6D ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.2.r 5-1.2.1.1 7-1.2.1.1 8-1.2 10-1.3 11-1.3.1.r 13-1.3.1.3 14-1.3.1 14-1.3.1.5 15-1.3.1.1.r 16-1.3.1.1.2.1.1 17-1.3.1.1.1.1 18-1.3.1.2.r 19-1.3.1.2 21-1.3.1.4.2 21-1.3.1.4.2.r 22-1.3.1.4.1 23-1.3.1.4 24-1.3.1.5.r 25-1.3.1.5.2.r 26-1.3.1.5.2.1.1.1 27-1.3.1.5.2 28-1.3.1.5.2.2.1.1 29-1.3.1.5.2.1 29-1.3.1.5.2.2 31-1.4.1 34-1.4.1.1 (o / obtain-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :ARG1-of (r2 / resemble-01~e.0)) :location~e.4 (c / cell-line~e.8 :name (n / name :op1 "HT-29"~e.5,7)) :ARG2-of (e / except-01~e.10 :ARG1~e.11 (a / affect-01~e.14 :ARG0~e.15 (n6 / nucleic-acid :name (n2 / name :op1 "shRNA"~e.17) :mod (g / gene :name (n3 / name :op1 "MEK1"~e.16))) :ARG1~e.18 (p / proliferate-01~e.19) :ARG2 (i / inhibit-01~e.13) :mod (i2 / important~e.23 :degree (m / more~e.22) :manner~e.21 (q / quantitative~e.21)) :compared-to~e.24 (a2 / affect-01~e.14 :ARG0 n6 :ARG1~e.25 (a3 / and~e.27 :op1 (c2 / cell-line~e.29 :name (n4 / name :op1 "HCT116"~e.26)) :op2 (c3 / cell-line~e.29 :name (n5 / name :op1 "SW480"~e.28)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "6D"~e.34))) # ::id pmid_1901_4680.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This observation could be explained by the much higher expression of MEK1 in the HT @-@ 29 cell line as compared to HCT116 or SW480 cells ( Fig . 6A ) , which may have a more important contribution to total MEK1 @/@ 2 signaling . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1 4-1.1 5-1.1.2.r 7-1.1.2.5.1.1 8-1.1.2.5 8-1.1.2.5.1 8-1.1.2.5.1.r 9-1.1.2 9-1.1.2.3 10-1.1.2.1.r 11-1.1.2.1.2.1 14-1.1.2.2.2.1 16-1.1.2.2.2.1 17-1.1.2.2 17-1.1.2.3.2.1 18-1.1.2.3.2.1 20-1.1.2.3.r 22-1.1.2.3.2.1.2.1 23-1.1.2.3.2 24-1.1.2.3.2.2.2.1 25-1.1.2.3.2.1 25-1.1.2.3.2.2 27-1.2.1 30-1.2.1.1 35-1.1.2.4.3 36-1.1.2.4.2 38-1.1.2.4.2.1 38-1.1.2.5.1 39-1.1.2.4.2 40-1.1.2.4 41-1.1.2.4.1.r 42-1.1.2.4.1.2 43-1.1.2.4.1.1.2.1 45-1.1.2.4.1.1.2.1 46-1.1.2.4.1 (p / possible-01~e.2 :ARG1 (e / explain-01~e.4 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (o / observe-01~e.1) :mod (t2 / this~e.0)) :manner~e.5 (e2 / express-03~e.9 :ARG2~e.10 (e3 / enzyme :wiki "MAP2K1" :name (n / name :op1 "MEK1"~e.11)) :ARG3 (c / cell-line~e.17 :wiki - :name (n2 / name :op1 "HT-29"~e.14,16)) :compared-to~e.20 (e4 / express-03~e.9 :ARG2 e3 :ARG3 (o2 / or~e.23 :op1 (c2 / cell-line~e.17,18,25 :wiki - :name (n3 / name :op1 "HCT116"~e.22)) :op2 (c3 / cell-line~e.25 :wiki - :name (n4 / name :op1 "SW480"~e.24)))) :ARG0-of (c4 / contribute-01~e.40 :ARG2~e.41 (s / signal-07~e.46 :ARG0 (e5 / enzyme :wiki "Mitogen-activated_protein_kinase_kinase" :name (n5 / name :op1 "MEK1/2"~e.43,45)) :mod (t3 / total-01~e.42)) :mod (i / important~e.36,39 :degree (m / more~e.38)) :ARG1-of (p2 / possible-01~e.35)) :ARG1-of (h / high-02~e.8 :degree~e.8 (m2 / more~e.8,38 :quant (m3 / much~e.7))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "6A"~e.30))) # ::id pmid_1901_4680.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the single inactivation of MEK2 was still capable of abolishing the proliferation of HT @-@ 29 cells even in the presence of high MEK1 levels . # ::alignments 0-1 3-1.1.1.3 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1.1.1.2.r 6-1.1.1.2.1.1 8-1.1.4 9-1.1 10-1.1.2.r 11-1.1.2 13-1.1.2.2 14-1.1.2.2.1.r 15-1.1.2.2.1.1.1 17-1.1.2.2.1.1.1 18-1.1.2.2.1 23-1.1.3.r 24-1.1.3.2 25-1.1.3.1.1.1 26-1.1.3 (c / contrast-01~e.0 :ARG2 (c2 / capable-01~e.9 :ARG1 (a / activate-01~e.4 :polarity~e.4 -~e.4 :ARG1~e.5 (e / enzyme :name (n / name :op1 "MEK2"~e.6)) :ARG1-of (s / single-02~e.3)) :ARG2~e.10 (a2 / abolish-01~e.11 :ARG0 a :ARG1 (p / proliferate-01~e.13 :ARG0~e.14 (c3 / cell-line~e.18 :name (n2 / name :op1 "HT-29"~e.15,17)))) :concession~e.23 (l / level~e.26 :quant-of (e2 / enzyme :name (n3 / name :op1 "MEK1"~e.25)) :ARG1-of (h / high-02~e.24)) :mod (s2 / still~e.8))) # ::id pmid_1901_4680.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For all colorectal cancer cell lines tested , the inhibition of proliferation seen with MEK2 shRNAs was comparable to that achieved with the MEK1 @/@ 2 inhibitor U0126 . # ::alignments 1-1.2.2 2-1.2.3.2.1 3-1.2.3.2.2 4-1.2 5-1.2 6-1.2.1 9-1.1.1 9-1.1.2 10-1.1.1.2.r 11-1.1.1.2 12-1.1.1.3 13-1.1.1.1.r 13-1.1.2.2.1.r 14-1.1.1.1.2.1.1 15-1.1.1.1.1.1 20-1.1.2.2 21-1.1.2.2.1.r 23-1.1.2.2.1.2.1.1.1 25-1.1.2.2.1.2.1.1.1 26-1.1.2.2.1 26-1.1.2.2.1.2 26-1.1.2.2.1.2.r 27-1.1.2.2.1.1.1 (p / possible-01 :ARG1 (c / compare-01 :ARG1 (i / inhibit-01~e.9 :ARG0~e.13 (n6 / nucleic-acid :name (n / name :op1 "shRNA"~e.15) :mod (g / gene :name (n2 / name :op1 "MEK2"~e.14))) :ARG1~e.10 (p2 / proliferate-01~e.11) :ARG1-of (s / see-01~e.12)) :ARG2 (i2 / inhibit-01~e.9 :ARG1 p2 :ARG1-of (a / achieve-01~e.20 :instrument~e.13,21 (s2 / small-molecule~e.26 :name (n3 / name :op1 "U0126"~e.27) :ARG0-of~e.26 (i3 / inhibit-01~e.26 :ARG1 (e / enzyme :name (n4 / name :op1 "MEK1/2"~e.23,25))))))) :location (c2 / cell-line~e.4,5 :ARG1-of (t / test-01~e.6) :mod (a2 / all~e.1) :mod (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal"~e.2 :op2 "cancer"~e.3)))) # ::id pmid_1901_4680.226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further extend our investigation to non @-@ colorectal carcinomas , we tested the effect of MEK1 and MEK2 shRNAs on the human breast adenocarcinoma cell line MDA @-@ MB @-@ 231 , which exhibit strong constitutive activation of MEK1 @/@ MEK2 signaling ( Fig . 6A ) . # ::alignments 1-1.3.3 2-1.3 3-1.3.2.1 3-1.3.2.1.r 4-1.3.2 5-1.3.2.2.r 6-1.3.2.2.1.1 6-1.3.2.2.1.1.r 8-1.3.2.2.1 9-1.3.2.2 11-1.1 12-1 14-1.2 15-1.2.1.r 16-1.2.1.1.2.1.1 17-1.2.1 18-1.2.1.2.2.1.1 19-1.2.1.1.1.1 19-1.2.1.2.1.1 20-1.2.2.r 22-1.2.2.2.1.1 23-1.2.2.2.1 24-1.2.2.2 25-1.2.2 26-1.2.2 27-1.2.2.1.1 29-1.2.2.1.1 31-1.2.2.1.1 34-1.2.2.3 35-1.2.2.3.1.3 36-1.2.2.3.1.2 37-1.2.2.3.1 38-1.2.2.3.1.1.r 39-1.2.2.3.1.1.1.1.1 41-1.2.2.3.1.1.1.1.1 42-1.2.2.3.1.1 44-1.4.1 47-1.4.1.1 (t / test-01~e.12 :ARG0 (w / we~e.11) :ARG1 (a / affect-01~e.14 :ARG0~e.15 (a2 / and~e.17 :op1 (n7 / nucleic-acid :name (n / name :op1 "shRNA"~e.19) :mod (g / gene :name (n2 / name :op1 "MEK1"~e.16))) :op2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.19) :mod (g2 / gene :name (n4 / name :op1 "MEK2"~e.18)))) :ARG1~e.20 (c / cell-line~e.25,26 :name (n5 / name :op1 "MDA-MB-231"~e.27,29,31) :mod (a3 / adenocarcinoma~e.24 :mod (b / breast~e.23 :part-of (h / human~e.22))) :ARG0-of (e / exhibit-01~e.34 :ARG1 (a4 / activate-01~e.37 :ARG1~e.38 (s / signal-07~e.42 :ARG0 (e2 / enzyme :name (n6 / name :op1 "MEK1/MEK2"~e.39,41))) :mod (c2 / constitutive~e.36) :degree (s2 / strong~e.35))))) :purpose (e3 / extend-01~e.2 :ARG0 w :ARG1 (i / investigate-01~e.4 :ARG0~e.3 w~e.3 :ARG1~e.5 (c3 / carcinoma~e.9 :mod (c4 / colorectal~e.8 :polarity~e.6 -~e.6))) :mod (f / further~e.1)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.44 :mod "6A"~e.47))) # ::id pmid_1901_4680.227 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the MEK2 shRNA @-@ 06 completely inhibited the proliferation of MDA @-@ MB @-@ 231 cells to the same extent as the drug inhibitor U0126 ( Additional file 4 ) . # ::alignments 0-1.5 0-1.5.r 3-1.1.2.1.1 4-1.1.1.1 6-1.1.1.1 7-1.4 8-1 8-1.3.1.1.1 10-1.2 11-1.2.1.r 12-1.2.1.1.1 14-1.2.1.1.1 16-1.2.1.1.1 17-1.2.1 18-1.3.r 20-1.3.1 21-1.3 21-1.3.1.1 22-1.3.1.1.1.1.r 24-1.3.1.1.1.1.2.1 25-1.3.1.1.1.1 25-1.3.1.1.1.1.2 25-1.3.1.1.1.1.2.r 26-1.3.1.1.1.1.1.1 29-1.6.1 31-1.6.1.1 (i / inhibit-01~e.8 :ARG0 (n5 / nucleic-acid :name (n / name :op1 "shRNA-06"~e.4,6) :mod (g / gene :name (n2 / name :op1 "MEK2"~e.3))) :ARG1 (p / proliferate-01~e.10 :ARG0~e.11 (c / cell-line~e.17 :name (n3 / name :op1 "MDA-MB-231"~e.12,14,16))) :degree~e.18 (e / extent~e.21 :ARG1-of (s / same-01~e.20 :ARG2 (e2 / extent~e.21 :degree-of (i2 / inhibit-01~e.8 :ARG0~e.22 (s2 / small-molecule~e.25 :name (n4 / name :op1 "U0126"~e.26) :ARG0-of~e.25 (i3 / inhibit-01~e.25 :ARG1 (d / drug~e.24))) :ARG1 p)))) :degree (c2 / complete~e.7) :manner~e.0 (i4 / interesting~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / file~e.29 :mod 4~e.31 :ARG1-of (a / add-02)))) # ::id pmid_1901_4680.228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The other MEK2 shRNA @-@ 08 also markedly but not completely inhibited cell proliferation , consistent with its lower silencing activity in these cells . # ::alignments 1-1.1.3 2-1.1.2.1.1 3-1.1.1.1 5-1.1.1.1 6-1.4 7-1.3 8-1.3.1 9-1.3.1.1.1 9-1.3.1.1.1.r 10-1.3.1.1 11-1 12-1.2.1 13-1.2 15-1.5 16-1.5.1.r 17-1.5.1.1 17-1.5.1.1.r 18-1.5.1.3 18-1.5.1.3.1 18-1.5.1.3.1.r 19-1.5.1.2 20-1.5.1 21-1.5.1.4.r 22-1.5.1.4.1 23-1.5.1.4 (i / inhibit-01~e.11 :ARG0 (n3 / nucleic-acid :name (n / name :op1 "shRNA-08"~e.3,5) :mod (g / gene :name (n2 / name :op1 "MEK2"~e.2)) :mod (o / other~e.1)) :ARG1 (p / proliferate-01~e.13 :ARG0 (c2 / cell~e.12)) :degree (m / marked~e.7 :ARG1-of (c / contrast-01~e.8 :ARG2 (c3 / complete~e.10 :polarity~e.9 -~e.9))) :mod (a / also~e.6) :ARG1-of (c4 / consistent-01~e.15 :ARG2~e.16 (a2 / activity-06~e.20 :ARG0~e.17 n3~e.17 :ARG1 (s / silence-01~e.19) :ARG1-of (l / low-04~e.18 :degree~e.18 (m2 / more~e.18)) :location~e.21 (c5 / cell~e.23 :mod (t / this~e.22))))) # ::id pmid_1901_4680.229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of MEK1 shRNAs suppressed cell proliferation by approximately 50 % . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2.1.1 3-1.1.1.1.1 4-1 5-1.2.1 6-1.2 7-1.3.r 8-1.3 9-1.3.1.1 10-1.3.1 (s / suppress-01~e.4 :ARG0 (e / express-03~e.0 :ARG1~e.1 (n3 / nucleic-acid :name (n / name :op1 "shRNA"~e.3) :mod (g / gene :name (n2 / name :op1 "MEK1"~e.2)))) :ARG1 (p / proliferate-01~e.6 :ARG0 (c / cell~e.5)) :quant~e.7 (a / approximately~e.8 :op1 (p2 / percentage-entity~e.10 :value 50~e.9))) # ::id pmid_1943_2991.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Identification of the B @-@ Raf/Mek/Erk MAP kinase pathway as a target for all @-@ trans retinoic acid during skin cancer promotion ( PMID : 19432991 ) # ::alignments 0-1 1-1.1.r 3-1.1.1.1 6-1.1.2.1.1 7-1.1.2 8-1.1 9-1.2.3.r 11-1.2 12-1.2.1.r 13-1.2.1.1.1 15-1.2.1.1.1 16-1.2.1.1.1 17-1.2.1.1.1 18-1.2.3.r 19-1.2.3.1.2.1 20-1.2.3.1.2.2 21-1.2.3 (i / identify-01~e.0 :ARG1~e.1 (p / pathway~e.8 :name (n2 / name :op1 "B-Raf/Mek/Erk"~e.3) :mod (k / kinase~e.7 :name (n3 / name :op1 "MAP"~e.6))) :ARG2 (t / target-01~e.11 :ARG0~e.12 (s3 / small-molecule :name (n5 / name :op1 "all-trans-retinoic-acid"~e.13,15,16,17)) :ARG1 p :time~e.9,18 (p2 / promote-01~e.21 :ARG1 (d / disease :wiki "Skin_cancer" :name (n / name :op1 "skin"~e.19 :op2 "cancer"~e.20)))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID19432991"))) # ::id pmid_1943_2991.6 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1943_2991.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have used the 2 @-@ stage dimethylbenzanthracene ( DMBA ) / 12 @- @ O @ -@ tetradecanoylphorbol @-@ 13 @-@ acetate ( TPA ) mouse skin carcinogenesis model to investigate the chemopreventive effects of ATRA . # ::alignments 0-1.1 2-1 4-1.2.2.1.2.1 6-1.2.2.1.2 7-1.2.2.1.1.1 11-1.2.2 12-1.2.2.2.1.1 15-1.2.2.2.1.1 18-1.2.2.2.1.1 20-1.2.2.2.1.1 22-1.2.2.2.1.1 26-1.2.1.1.1 27-1.2.1.1 28-1.2.1 29-1.2 31-1.3 34-1.3.2 35-1.3.2.1.r 36-1.3.2.1.1.1 (u / use-01~e.2 :ARG0 (w / we~e.0) :ARG1 (m / model~e.29 :mod (c / carcinogenesis~e.28 :mod (s / skin~e.27 :poss (m2 / mouse~e.26))) :mod (s2 / slash~e.11 :op1 (s4 / small-molecule :name (n / name :op1 "dimethylbenzanthracene"~e.7) :mod (s3 / stage~e.6 :quant 2~e.4)) :op2 (s5 / small-molecule :name (n2 / name :op1 "12-O-tetradecanoylphorbol-13-acetate"~e.12,15,18,20,22)))) :ARG2 (i / investigate-01~e.31 :ARG0 w :ARG1 (a / affect-01~e.34 :ARG0~e.35 (s6 / small-molecule :name (n4 / name :op1 "ATRA"~e.36)) :ARG2 (p / prevent-01 :ARG1 (d / disease :wiki "Breast_cancer" :name (n3 / name :op1 "breast" :op2 "cancer")) :mod (c2 / chemistry))))) # ::id pmid_1943_2991.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have compared the gene expression profiles of control skin to skin subjected to the 2 @-@ stage protocol , with or without ATRA , using Affymetrix 430 2.0 DNA microarrays . # ::alignments 0-1.1 2-1 4-1.2.2.1 5-1.2.2 6-1.2 6-1.3 7-1.2.1.r 8-1.2.1.1 9-1.2.1 10-1.3.1.r 11-1.3.1 12-1.3.1.1 13-1.3.1.1.1.r 15-1.3.1.1.1.1.1.1 17-1.3.1.1.1.1.1 18-1.3.1.1.1.1 20-1.3.1.1.1.1.2.r 21-1.3.1.1.1 23-1.3.1.1.1.1.2.1.1 26-1.4.4.1.1 27-1.4.1 28-1.4.2 29-1.4.3.2.1 30-1.4 (c / compare-01~e.2 :ARG0 (w / we~e.0) :ARG1 (p / profile-01~e.6 :ARG1~e.7 (s / skin~e.9 :ARG0-of (c2 / control-01~e.8)) :topic (e / express-03~e.5 :ARG2 (g / gene~e.4))) :ARG2 (p2 / profile-01~e.6 :ARG1~e.10 (s2 / skin~e.11 :ARG1-of (s3 / subject-01~e.12 :ARG2~e.13 (o / or~e.21 :op1 (p3 / protocol~e.18 :mod (s4 / stage~e.17 :quant 2~e.15) :accompanier~e.20 (s5 / small-molecule :name (n / name :op1 "ATRA"~e.23))) :op2 p3))) :topic e) :instrument (m / microarray~e.30 :mod 430~e.27 :mod 2.0~e.28 :mod (n2 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.29)) :mod (c3 / company :name (n3 / name :op1 "Affymetrix"~e.26)))) # ::id pmid_1943_2991.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Approximately 49 % of the genes showing altered expression with TPA treatment are conversely affected when ATRA is co @-@ administered . # ::alignments 0-1.1.1.2.2 1-1.1.1.1 2-1.1.1 5-1.1 5-1.1.1.2.1 6-1.1.1.2.1.1 7-1.1.1.2.1.1.1.1 8-1.1.1.2.1.1.1 9-1.1.1.2.1.1.2.r 10-1.1.1.2.1.1.2.1.1.1 11-1.1.1.2.1.1.2 13-1.2 13-1.2.r 14-1 16-1.3.1.2.1.1 20-1.3 (a3 / affect-01~e.14 :ARG1 (g / gene~e.5 :quant (p2 / percentage-entity~e.2 :value 49~e.1 :ARG1-of (i / include-91 :ARG2 (g2 / gene~e.5 :ARG0-of (s / show-01~e.6 :ARG1 (e / express-03~e.8 :ARG1-of (a2 / alter-01~e.7)) :condition~e.9 (t / treat-04~e.11 :ARG2 (s3 / small-molecule :name (n / name :op1 "TPA"~e.10))))) :ARG3 (a / approximate-01~e.0)))) :manner~e.13 (c / converse~e.13) :condition (a4 / administer-01~e.20 :ARG1 (a5 / and :op1 s3 :op2 (s2 / small-molecule :name (n2 / name :op1 "ATRA"~e.16))))) # ::id pmid_1943_2991.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activity of these genes , which we refer to as ' counter @-@ regulated ', may contribute to chemoprevention by ATRA . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1 4-1.1.1.1 7-1.1.1.2.1 8-1.1.1.2 12-1.1.1.2.2.2 14-1.1.1.2.2 16-1 17-1.1 21-1.1.2.2.1.1 (p / possible-01~e.16 :ARG1 (c / contribute-01~e.17 :ARG1 (a / activity-06~e.1 :ARG0~e.2 (g / gene~e.4 :mod (t / this~e.3)) :ARG1-of (r / refer-01~e.8 :ARG0 (w / we~e.7) :ARG2 (r2 / regulate-01~e.14 :ARG1 a :ARG1-of (c2 / counter-01~e.12)))) :ARG2 (p2 / prevent-01 :ARG1 (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")) :ARG3 (s / small-molecule :name (n2 / name :op1 "ATRA"~e.21)) :mod (c3 / chemistry)))) # ::id pmid_1943_2991.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The counter @-@ regulated genes have been clustered into functional categories and bioinformatic analysis has identified the B @-@ Raf/Mek/Erk branch of the MAP kinase pathway as one containing several genes whose upregulation by TPA is blocked by ATRA . # ::alignments 1-1.1.1.1.1 3-1.1.1.1 4-1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.1 10-1.1.2 11-1 12-1.2.1.1 13-1.2.1 15-1.2 17-1.2.2.1.1.1.1 20-1.2.2 21-1.2.2.2.r 23-1.2.2.2.1.1 24-1.2.2.2.1.2 25-1.2.2.2 28-1.2.3 29-1.2.3.2.1 30-1.2.3.2 32-1.2.3.2.2 33-1.2.3.2.2.1.r 34-1.2.3.2.2.1.1.1 36-1.2.3.2.2.2 37-1.2.3.2.2.2.1.r 38-1.2.3.2.2.2.1.1.1 (a / and~e.11 :op1 (c / cluster-01~e.7 :ARG1 (g / gene~e.4 :ARG1-of (r / regulate-01~e.3 :ARG1-of (c2 / counter-01~e.1))) :ARG2~e.8 (c3 / category~e.10 :ARG0-of (f / function-01~e.9))) :op2 (i / identify-01~e.15 :ARG0 (a2 / analyze-01~e.13 :mod (b / bioinformatic~e.12)) :ARG1 (b2 / branch~e.20 :mod (s / slash :op1 (e / enzyme :name (n / name :op1 "B-Raf"~e.17)) :op2 (e2 / enzyme :name (n2 / name :op1 "Mek")) :op3 (e3 / enzyme :name (n3 / name :op1 "Erk"))) :part-of~e.21 (p / pathway~e.25 :name (n4 / name :op1 "MAP"~e.23 :op2 "kinase"~e.24))) :ARG2 (c4 / contain-01~e.28 :ARG0 b2 :ARG1 (g2 / gene~e.30 :quant (s2 / several~e.29) :ARG1-of (u / upregulate-01~e.32 :ARG2~e.33 (s3 / small-molecule :name (n5 / name :op1 "TPA"~e.34)) :ARG1-of (b3 / block-01~e.36 :ARG0~e.37 (s4 / small-molecule :name (n6 / name :op1 "ATRA"~e.38)))))))) # ::id pmid_1943_2991.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also show that ATRA blocks signaling through this pathway , as revealed by immunohistochemistry and Western blotting . # ::alignments 0-1.1 1-1.4 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2 6-1.2.2 8-1.2.2.1.1 9-1.2.2.1 11-1.3.r 12-1.3 13-1.3.1.r 14-1.3.1.1 15-1.3.1 16-1.3.1.2 17-1.3.1.2 (s / show-01~e.2 :ARG0 (w2 / we~e.0) :ARG1~e.3 (b / block-01~e.5 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "ATRA"~e.4)) :ARG1 (s2 / signal-07~e.6 :ARG0 (p / pathway~e.9 :mod (t / this~e.8)))) :ARG1-of~e.11 (r / reveal-01~e.12 :ARG0~e.13 (a2 / and~e.15 :op1 (i / immunohistochemistry~e.14) :op2 (i2 / immunoblot-01~e.16,17))) :mod (a / also~e.1)) # ::id pmid_1943_2991.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , we found that blocking the B @-@ Raf/Mek/Erk pathway with a pharmacological inhibitor , Sorafenib ( BAY43 @-@ 9006 ) , induces squamous differentiation of existing skin SCCs formed in the 2 @-@ stage model . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.r 5-1.2.1 7-1.2.1.1.1.1 10-1.2.1.1 11-1.2.1.2.r 13-1.2.1.2.3 14-1.2.1.2 14-1.2.1.2.2 14-1.2.1.2.2.r 16-1.2.1.2.1.1 18-1.2.1.2.4.1.1 20-1.2.1.2.4.1.1 23-1.2 24-1.2.2.1.3 24-1.2.2.2 25-1.2.2 28-1.2.2.1.4 30-1.2.2.1.5 31-1.2.2.1.5.1.r 33-1.2.2.1.5.1.1.1.1 35-1.2.2.1.5.1.1.1 36-1.2.2.1.5.1 (f4 / find-01~e.3 :ARG0 (w / we~e.2) :ARG1~e.4 (i2 / induce-01~e.23 :ARG0 (b / block-01~e.5 :ARG1 (p / pathway~e.10 :name (n / name :op1 "B-Raf/Mek/Erk"~e.7)) :ARG3~e.11 (s5 / small-molecule~e.14 :name (n2 / name :op1 "Sorafenib"~e.16) :ARG0-of~e.14 (i / inhibit-01~e.14) :mod (p2 / pharmacology~e.13) :ARG1-of (n4 / name-01 :ARG2 (n6 / name :op1 "BAY43-9006"~e.18,20)))) :ARG2 (d / differentiate-01~e.25 :ARG1 (m2 / medical-condition :name (n3 / name :op1 "carcinoma") :mod (c / cell) :mod (s2 / squamous~e.24) :mod (s3 / skin~e.28) :ARG1-of (f3 / form-01~e.30 :location~e.31 (m / model~e.36 :ARG0-of (h / have-03 :ARG1 (s4 / stage~e.35 :quant 2~e.33))))) :mod (s / squamous~e.24))) :time (f5 / final~e.0)) # ::id pmid_1943_2991.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1943_2991.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ATRA reverses many of the gene expression changes caused by TPA in mouse skin : microarray @-@ based analysis # ::alignments 1-1.1.1.2.1 2-1.1 3-1.1.2.3 6-1.1.2.1.1 6-1.1.2.4.1.1.1 7-1.1.2.1 7-1.1.2.4.1.1 8-1.1.2 8-1.1.2.4.1 9-1.1.2.2 10-1.1.2.2.1.r 11-1.1.2.2.1.2.1 12-1.1.2.2.2.r 13-1.1.2.2.2.1 14-1.1.2.2.2 16-1.2.1.1 18-1.2.1 19-1.2 (m2 / multi-sentence :snt1 (r / reverse-01~e.2 :ARG0 (s2 / small-molecule :wiki "Tretinoin" :name (n / name :op1 "ATRA"~e.1)) :ARG1 (c / change-01~e.8 :ARG1 (e / express-03~e.7 :ARG2 (g / gene~e.6)) :ARG1-of (c2 / cause-01~e.9 :ARG0~e.10 (s3 / small-molecule :wiki "12-O-Tetradecanoylphorbol-13-acetate" :name (n2 / name :op1 "TPA"~e.11)) :location~e.12 (s / skin~e.14 :mod (m / mouse~e.13))) :mod (m3 / many~e.3) :ARG1-of (i / include-91 :ARG2 (c3 / change-01~e.8 :ARG1 (e2 / express-03~e.7 :ARG2 (g3 / gene~e.6)))))) :snt2 (a2 / analyze-01~e.19 :ARG1-of (b / base-02~e.18 :ARG2 (m4 / microarray~e.16)))) # ::id pmid_1943_2991.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our group and others have shown that ATRA can suppress tumor promotion by TPA in the 2 @-@ stage model , but only as long as it is being co @-@ administered with TPA [ @ 9 , 20 @ ] . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1 2-1.1 3-1.1.2 5-1 6-1.2.r 7-1.2.1.1.1.1 8-1.2 9-1.2.1 10-1.2.1.2.2 11-1.2.1.2 12-1.2.1.2.1.r 13-1.2.1.2.1.1.1 14-1.2.1.3.r 16-1.2.1.3.1.1.1 18-1.2.1.3.1.1 19-1.2.1.3 22-1.2.1.4.1.2 23-1.2.1.4 24-1.2.1.4 25-1.2.1.4 31-1.2.1.4.1 33-1.2.1.2.1.1.1 36-1.3.1.1.1.1 40-1.3.1.1.1.2 (s / show-01~e.5 :ARG0 (a2 / and~e.2 :op1 (g / group~e.1 :poss~e.0 (w / we~e.0)) :op2 (o / other~e.3)) :ARG1~e.6 (p / possible-01~e.8 :ARG1 (s2 / suppress-01~e.9 :ARG0 (s4 / small-molecule :name (n / name :op1 "ATRA"~e.7)) :ARG1 (p2 / promote-01~e.11 :ARG0~e.12 (s5 / small-molecule :name (n2 / name :op1 "TPA"~e.13,33)) :ARG1 (t / tumor~e.10)) :location~e.14 (m / model~e.19 :ARG0-of (h / have-03 :ARG1 (s3 / stage~e.18 :quant 2~e.16))) :condition (a / as-long-as~e.23,24,25 :op1 (a4 / administer-01~e.31 :ARG1 (a5 / and :op1 s4 :op2 s5) :mod (o2 / only~e.22))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a6 / and :op1 9~e.36 :op2 20~e.40))))) # ::id pmid_1943_2991.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If ATRA treatment is discontinued while TPA treatment is maintained , the mice showed a linear increase in tumor multiplicity with time after stopping the last treatment [ @ 20 @ ] . # ::alignments 0-1.3.r 1-1.3.1.1.1.1.1 2-1.3.1.1 4-1.3.1 5-1.2.3.1.1.r 6-1.3.2.1.1.1.1 7-1.3.2.1 9-1.3.2 12-1.1 13-1 15-1.2.2 16-1.2 18-1.2.1.1 21-1.2.3.1 21-1.2.3.1.1.r 22-1.2.3.1.1 23-1.2.3.1.1.1 25-1.2.3.1.1.1.1.1 26-1.2.3.1.1.1.1 29-1.4.1.1.1 (s / show-01~e.13 :ARG0 (m / mouse~e.12) :ARG1 (i / increase-01~e.16 :ARG1 (m2 / multiply-01 :ARG1 (t / tumor~e.18)) :mod (l / linear~e.15) :ARG0-of (h / have-03 :ARG1 (t2 / time~e.21 :time~e.5,21 (a / after~e.22 :op1 (s2 / stop-01~e.23 :ARG1 (t3 / treat-04~e.26 :mod (l2 / last~e.25))))))) :condition~e.0 (a2 / and :op1 (d / discontinue-01~e.4 :ARG1 (t4 / treat-04~e.2 :ARG2 (s3 / small-molecule :name (n / name :op1 "ATRA"~e.1)))) :op2 (m3 / maintain-01~e.9 :ARG1 (t5 / treat-04~e.7 :ARG2 (s4 / small-molecule :name (n2 / name :op1 "TPA"~e.6))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 20~e.29)))) # ::id pmid_1943_2991.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This suggests that ATRA may be primarily acting to suppress promotion by TPA , but has little apparent effect on initiation . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1.1.1 4-1.1.2 6-1.1.2.1.3 7-1.1.2.1 9-1.1.2.1.2 10-1.1.2.1.2.2 11-1.1.2.1.2.2.1.r 12-1.1.2.1.2.2.1.1.1 14-1 16-1.2.3 18-1.2 19-1.2.2.r 20-1.2.2 (c / contrast-01~e.14 :ARG1 (s / suggest-01~e.1 :ARG0 (t / this~e.0) :ARG1~e.2 (p / possible-01~e.4 :ARG1 (a / act-01~e.7 :ARG0 (s3 / small-molecule :name (n / name :op1 "ATRA"~e.3)) :purpose (s2 / suppress-01~e.9 :ARG0 s3 :ARG1 (p2 / promote-01~e.10 :ARG0~e.11 (s4 / small-molecule :name (n2 / name :op1 "TPA"~e.12)))) :mod (p4 / primary~e.6)))) :ARG2 (a3 / affect-01~e.18 :ARG0 s3 :ARG1~e.19 (i / initiate-01~e.20 :ARG1 p2) :degree (l / little~e.16) :ARG1-of (a4 / appear-01))) # ::id pmid_1943_2991.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to explore the mechanism of the chemopreventive effect of ATRA at an early step during TPA @-@ induced tumor promotion , we performed Affymetrix DNA microarray analyses for mouse skin subjected to the 2 @-@ stage protocol for 3 weeks , with and without co @-@ administration of ATRA . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 5-1.3.2 9-1.3.2.1 10-1.3.2.1.1.r 11-1.3.2.1.1 14-1.3.2.1.3.1 15-1.3.2.1.3 16-1.3.2.1.3.r 17-1.3.2.1.3.2.2.1.1.1 19-1.3.2.1.3.2.2 20-1.3.2.1.3.2.1 21-1.3.2.1.3.2 23-1.1 24-1 25-1.2.1.1.2.2.1.1 26-1.2.1.1.2.1.2.1 27-1.2.1.1.2 28-1.2.1.1 29-1.2.1.1.1.r 30-1.2.1.1.1.1 31-1.2.1.1.1 32-1.2.1.1.1.2 33-1.2.1.1.1.2.1.r 35-1.2.1.1.1.2.1.1.1.1 37-1.2.1.1.1.2.1.1.1 38-1.2.1.1.1.2.1 39-1.2.1.1.1.2.2.r 40-1.2.1.1.1.2.2.1 41-1.2.1.1.1.2.2.2 44-1.2.1 44-1.2.2 45-1.2.2.2.1 45-1.2.2.2.1.r 48-1.2.1.2 48-1.2.2.2 49-1.2.1.2.1.r 50-1.2.1.2.1.1.1 (p / perform-01~e.24 :ARG0 (w2 / we~e.23) :ARG1 (o / or :op1 (a2 / and~e.44 :op1 (a / analyze-01~e.28 :ARG1~e.29 (s / skin~e.31 :mod (m / mouse~e.30) :ARG1-of (s2 / subject-01~e.32 :ARG2~e.33 (p2 / protocol~e.38 :ARG0-of (h / have-03 :ARG1 (s3 / stage~e.37 :quant 2~e.35))) :duration~e.39 (t2 / temporal-quantity :quant 3~e.40 :unit (w3 / week~e.41)))) :mod (m3 / microarray~e.27 :mod (n / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.26)) :source (c / company :name (n2 / name :op1 "Affymetrix"~e.25)))) :op2 (a3 / administer-01~e.48 :ARG1~e.49 (s5 / small-molecule :name (n3 / name :op1 "ATRA"~e.50)))) :op2 (a5 / and~e.44 :op1 a :op2 (a6 / administer-01~e.48 :polarity~e.45 -~e.45 :ARG1 s5))) :purpose~e.0,1,2 (e / explore-01~e.3 :ARG0 w2 :ARG1 (m2 / mechanism~e.5 :poss (a7 / affect-01~e.9 :ARG0~e.10 s5~e.11 :ARG2 (p3 / prevent-01 :ARG1 (d / disease :wiki "Breast_cancer" :name (n7 / name :op1 "breast" :op2 "cancer")) :mod (c2 / chemistry)) :time~e.16 (s4 / step~e.15 :mod (e2 / early~e.14) :subevent-of (p4 / promote-01~e.21 :ARG1 (t / tumor~e.20) :ARG2-of (i / induce-01~e.19 :ARG0 (s6 / small-molecule :name (n5 / name :op1 "TPA"~e.17))))))))) # ::id pmid_1943_2991.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We chose the 3 week time point because this precedes the appearance of tumors but is after the TPA treated skin exhibits pronounced hyperplasia ( Fig . 1 ) ; and this time point proved to be advantageous for identifying genes regulated by TPA plus retinoid combinations in mouse skin in a previous study from our laboratory [ @ 20 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1.1.2.1.1.1.1 4-1.1.2.1.1.1.2 5-1.1.2.1 5-1.1.2.1.1.1 6-1.1.2 7-1.1.3 9-1.1.3.1.1 11-1.1.3.1.1.2 12-1.1.3.1.1.2.1.r 13-1.1.3.1.1.2.1 14-1.1.3.1 15-1.1.3.1.2.2.r 16-1.1.3.1.2 18-1.1.3.1.2.1.1.1.1.1.1 19-1.1.3.1.2.1.1.1 20-1.1.3.1.2.1.1 21-1.1.3.1.2.1 22-1.1.3.1.2.1.2.2 23-1.1.3.1.2.1.2.1.1 25-1.1.4.1 28-1.1.4.1.1 32-1 35-1.2.1 36-1.2 39-1.2.2 40-1.2.2.1.r 41-1.2.2.1 42-1.2.2.1.1 43-1.2.2.1.1.1 44-1.2.2.1.1.1.1.r 45-1.2.2.1.1.1.1.1 46-1.2.2.1.1.1.1 47-1.2.2.1.1.1.1.2.1.1.1 48-1.2.2.1.1.1.1.2 49-1.2.2.1.1.1.1.2.3.r 50-1.2.2.1.1.1.1.2.3.1 51-1.2.2.1.1.1.1.2.3 52-1.2.2.1.1.1.1.2.2.r 54-1.2.2.1.1.1.1.2.2.1 55-1.2.2.1.1.1.1.2.2 56-1.2.2.1.1.1.1.2.2.2.r 57-1.2.2.1.1.1.1.2.2.2.1 57-1.2.2.1.1.1.1.2.2.2.1.r 58-1.2.2.1.1.1.1.2.2.2 61-1.2.3.1.1.1 (a3 / and~e.32 :op1 (c / choose-01~e.1 :ARG0 (w2 / we~e.0) :ARG1 (p / point~e.6 :mod (t2 / time~e.5 :ARG1-of (e / equal-01 :ARG2 (t3 / temporal-quantity~e.5 :quant 3~e.3 :unit (w3 / week~e.4))))) :ARG1-of (c2 / cause-01~e.7 :ARG0 (c3 / contrast-01~e.14 :ARG1 (p2 / precede-01~e.9 :ARG1 p :ARG2 (a / appear-01~e.11 :ARG1~e.12 (t4 / tumor~e.13))) :ARG2 (a2 / after~e.16 :op1 (e2 / exhibit-01~e.21 :ARG0 (s / skin~e.20 :ARG1-of (t5 / treat-04~e.19 :ARG2 (s5 / small-molecule :name (n / name :op1 "TPA"~e.18)))) :ARG1 (m / medical-condition :name (n2 / name :op1 "hyperplasia"~e.23) :ARG1-of (p4 / pronounced-02~e.22))) :domain~e.15 p))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.25 :mod 1~e.28))) :op2 (p5 / prove-01~e.36 :ARG0 p~e.35 :ARG1 (a4 / advantageous~e.39 :purpose~e.40 (i / identify-01~e.41 :ARG1 (g / gene~e.42 :ARG1-of (r / regulate-01~e.43 :ARG0~e.44 (a5 / and~e.46 :op1 s5~e.45 :op2 (c4 / combine-01~e.48 :ARG1 (s4 / small-molecule :name (n3 / name :op1 "retinoid"~e.47)) :time~e.52 (s2 / study-01~e.55 :mod (p6 / previous~e.54) :location~e.56 (l / laboratory~e.58 :poss~e.57 (w4 / we~e.57))) :location~e.49 (s3 / skin~e.51 :mod (m2 / mouse~e.50)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c5 / cite-01 :ARG2 20~e.61))))) # ::id pmid_1943_2991.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We reason that at least a portion of important TPA @-@ induced promotion events will have taken place by this time . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 4-1.2.1 6-1.2 7-1.2.2.r 8-1.2.2.3 9-1.2.2.2.1.1.1 11-1.2.2.2 12-1.2.2.1 13-1.2.2 15-1.2.2.3 19-1.2.3.1.1 20-1.2.3.1 20-1.2.3.r (r / reason-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (p3 / portion~e.6 :mod (a / at-least~e.3,4) :part-of~e.7 (e / event~e.13 :ARG0-of (p / promote-01~e.12) :ARG1-of (i / induce-01~e.11 :ARG0 (s / small-molecule :name (n / name :op1 "TPA"~e.9))) :mod (i3 / important~e.8,15)) :time~e.20 (u / up-to :op1 (t / time~e.20 :mod (t2 / this~e.19))))) # ::id pmid_1943_2991.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the ~ 45,000 probe sets ( representing ~ 39,000 transcripts and variants from over 34,000 characterized mouse genes ) on the 430 2.0 GeneChip , expression of 3,948 were altered by TPA , upwards or downwards , relative to untreated controls ( fold changes between treatment groups ≥ 1.5 , with p ≤ 0.05 ) . # ::alignments 2-1.1.2.1.3.1.2 3-1.1.2.1.3.1.2.1 4-1.1.2.1.2 4-1.1.2.1.3.1.1 5-1.1.2.1 5-1.1.2.1.3.1 7-1.1.2.1.3.1.3 8-1.1.2.1.3.1.3.1.3 9-1.1.2.1.3.1.3.1.3.1 11-1.1.2.1.3.1.3.1 14-1.1.2.1.3.1.3.1.1.1.3 14-1.2.3.1 15-1.1.2.1.3.1.3.1.1.1.3.1 16-1.1.2.1.3.1.3.1.1.1.2 17-1.1.2.1.3.1.3.1.1.1.1 18-1.1.2.1.3.1.3.1.1.1 20-1.1.2.1.3.1.4.r 22-1.1.2.1.3.1.4.2 23-1.1.2.1.3.1.4.1 24-1.1.2.1.3.1.4.3.1 26-1.1.2 28-1.1.2.1.1 30-1.1 31-1.1.1.r 32-1.1.1.1.1 35-1.1.3 35-1.2.4.1 40-1.1.4.1.1 40-1.1.4.1.1.1 40-1.1.4.1.1.1.r 41-1.1.4.1 43-1.2.1 44-1.2 45-1.2.2 46-1.2.2.1.1 47-1.2.2.1 49-1.2.3.1.1 52-1.2.4 54-1.2.4.1.1 54-1.2.4.1.2.1 (m2 / multi-sentence :snt1 (a / alter-01~e.30 :ARG0~e.31 (s3 / small-molecule :name (n2 / name :op1 "TPA"~e.32)) :ARG1 (e / express-03~e.26 :ARG2 (s / set~e.5 :quant 3948~e.28 :mod (p / probe~e.4) :ARG1-of (i / include-91 :ARG2 (s2 / set~e.5 :mod (p2 / probe~e.4) :quant (a2 / approximately~e.2 :op1 45000~e.3) :ARG0-of (r / represent-01~e.7 :ARG1 (a3 / and~e.11 :op1 (t / transcribe-01 :ARG1 (g / gene~e.18 :mod (m / mouse~e.17) :ARG1-of (c / characterize-01~e.16) :quant (o / over~e.14 :op1 34000~e.15))) :op2 (v / vary-01 :ARG1 g) :quant (a4 / approximately~e.8 :op1 39000~e.9))) :location~e.20 (t2 / thing :mod 2.0~e.23 :mod 430~e.22 :name (n / name :op1 "GeneChip"~e.24)))))) :direction (o2 / or~e.35 :op1 (u / upward) :op2 (d / downward)) :ARG1-of (r2 / relate-01 :ARG2 (c2 / control-01~e.41 :ARG1-of (t3 / treat-04~e.40 :polarity~e.40 -~e.40)))) :snt2 (c3 / change-01~e.44 :mod (f / fold~e.43) :location (b2 / between~e.45 :op1 (g2 / group~e.47 :mod (t4 / treat-04~e.46))) :ARG1-of (e2 / equal-01 :ARG2 (o3 / over~e.14 :op1 1.5~e.49)) :ARG1-of (s4 / statistical-test-91~e.52 :ARG2 (o4 / or~e.35 :op1 0.05~e.54 :op2 (l / less-than :op1 0.05~e.54))))) # ::id pmid_1943_2991.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This group of genes was divided into clusters as described in Materials and Methods . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1 5-1 6-1.2.r 7-1.2 8-1.3.r 9-1.3 10-1.3.1.r 11-1.3.1.1 12-1.3.1 13-1.3.1.2 (d / divide-02~e.5 :ARG1 (g / group~e.1 :consist-of~e.2 (g2 / gene~e.3) :mod (t / this~e.0)) :ARG2~e.6 (c / cluster~e.7) :ARG1-of~e.8 (d2 / describe-01~e.9 :medium~e.10 (a / and~e.12 :op1 (m / material~e.11) :op2 (m2 / method~e.13)))) # ::id pmid_1943_2991.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The heatmap in figure 2 represents the genes that fall into each subcluster , with expression patterns produced by normalized raw scores for the subcluster indicated in the panels on the right . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 5-1.1.1.1 7-1 9-1.2 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1 14-1.2.1.1 17-1.2.2.1.1 18-1.2.2.1 19-1.2.2.1.2 20-1.2.2.1.2.1.r 21-1.2.2.1.2.1.2 22-1.2.2.1.2.1.1 23-1.2.2.1.2.1 24-1.2.2.1.2.2.r 26-1.2.2.1.2.2 27-1.2.2.1.2.2.1 28-1.2.2.1.2.2.1.1.r 30-1.2.2.1.2.2.1.1 31-1.2.2.1.2.2.1.1.1.r 33-1.2.2.1.2.2.1.1.1 (r / represent-01~e.7 :ARG0 (h / heatmap~e.1 :location~e.2 (f / figure~e.3 :mod 2~e.5)) :ARG1 (g / gene~e.9 :ARG1-of (f2 / fall-01~e.11 :ARG4~e.12 (s / subcluster~e.14 :mod (e / each~e.13))) :ARG0-of (h2 / have-03 :ARG1 (p / pattern~e.18 :topic (e2 / express-03~e.17) :ARG1-of (p2 / produce-01~e.19 :ARG0~e.20 (s2 / score~e.23 :mod (r2 / raw~e.22) :ARG1-of (n / normalize-01~e.21)) :ARG3~e.24 (s3 / subcluster~e.26 :ARG1-of (i / indicate-01~e.27 :location~e.28 (p3 / panel~e.30 :ARG1-of~e.31 (r3 / right-04~e.33))))))))) # ::id pmid_1943_2991.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Amongst the 3,948 total TPA regulated genes , 49.5 % were found to be in the C1A and C2A subclusters . # ::alignments 2-1.1.1.1.1 3-1.1.1.1.2 4-1.1.1.1.3.1.1.1 5-1.1.1.1.3 6-1.1 6-1.1.1.1 8-1.1.1.2.1 9-1.1.1.2 11-1 14-1.2.r 16-1.2.1.1.1.1 17-1.2 18-1.2.2.1.1.1 (f / find-01~e.11 :ARG1 (g / gene~e.6 :ARG1-of (i / include-91 :ARG2 (g2 / gene~e.6 :quant 3948~e.2 :mod (t / total~e.3) :ARG1-of (r / regulate-01~e.5 :ARG0 (s3 / small-molecule :name (n / name :op1 "TPA"~e.4)))) :ARG3 (p / percentage-entity~e.9 :value 49.5~e.8))) :location~e.14 (a / and~e.17 :op1 (s / subcluster :part-of (g3 / gene :name (n2 / name :op1 "C1A"~e.16))) :op2 (s2 / subcluster :part-of (g4 / gene :name (n3 / name :op1 "C2A"~e.18))))) # ::id pmid_1943_2991.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We are calling these genes ' counter @-@ regulated ' because their direction of expression ( increase or decrease ) in TPA + ATRA treated skin compared to TPA treated skin is opposite to that of TPA treated skin compared to control skin . # ::alignments 0-1.1 2-1 3-1.2.1 4-1.2 4-1.3 6-1.3.1.1 8-1.3.1 10-1.4 12-1.4.1.1 13-1.4.1.1.1.r 14-1.4.1.1.1 16-1.4.1.1.2.1.1 17-1.4.1.1.2.1 18-1.4.1.1.2.1.2 20-1.4.1.1.1.2.r 21-1.4.1.1.1.2.1.1.1.1.1 22-1.4.1.1.1.2.1.1 23-1.4.1.1.1.2.1.1.2.1.1 24-1.4.1.1.1.2.1 24-1.4.1.1.1.2.2.1 25-1.4.1.1.1.2 25-1.4.1.1.1.2.2 26-1.4.1.1.1.2.2.r 28-1.4.1.1.1.2.2.1.1 29-1.4.1.1.1.2.1 29-1.4.1.1.1.2.2.1 30-1.4.1.1.1.2 30-1.4.1.1.1.2.2 32-1.4.1 35-1.4.1.2.r 36-1.4.1.2.1.1 37-1.4.1.2.1 38-1.4.1.2 38-1.4.1.2.2 39-1.4.1.2.2.r 41-1.4.1.2.2.1 42-1.4.1.2.2 (c / call-01~e.2 :ARG0 (w / we~e.0) :ARG1 (g / gene~e.4 :mod (t / this~e.3)) :ARG2 (g2 / gene~e.4 :ARG1-of (r / regulate-01~e.8 :ARG1-of (c2 / counter-01~e.6))) :ARG1-of (c3 / cause-01~e.10 :ARG0 (o / opposite-01~e.32 :ARG1 (d / direct-01~e.12 :ARG1~e.13 (e / express-03~e.14 :ARG2 g :ARG3~e.20 (s / skin~e.25,30 :ARG1-of (t2 / treat-04~e.24,29 :ARG2 (a / and~e.22 :op1 (s5 / small-molecule :name (n / name :op1 "TPA"~e.21)) :op2 (s6 / small-molecule :name (n2 / name :op1 "ATRA"~e.23)))) :compared-to~e.26 (s2 / skin~e.25,30 :ARG1-of (t3 / treat-04~e.24,29 :ARG2 s5~e.28)))) :ARG1-of (m / mean-01 :ARG2 (o2 / or~e.17 :op1 (i / increase-01~e.16) :op2 (d2 / decrease-01~e.18)))) :ARG2~e.35 (s3 / skin~e.38 :ARG1-of (t4 / treat-04~e.37 :ARG2 s5~e.36) :compared-to~e.39 (s4 / skin~e.38,42 :ARG0-of (c4 / control-01~e.41)))))) # ::id pmid_1943_2991.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This data can also be represented graphically as scatterplots ( Fig . S1 , additional file 1 ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 3-1.1.4 5-1.1 6-1.1.3 10-1.2.1.1 12-1.2.1.1.1 15-1.2.1.2 17-1.2.1.2.1 (p / possible-01~e.2 :ARG1 (r / represent-01~e.5 :ARG1 (d / data~e.1 :mod (t / this~e.0)) :ARG2 (s / scatterplot) :mod (g / graphic~e.6) :mod (a3 / also~e.3)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure~e.10 :mod "S1"~e.12) :op2 (f2 / file~e.15 :mod 1~e.17 :ARG1-of (a2 / add-02))))) # ::id pmid_1943_2991.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We note that when comparing control skin with TPA + ATRA skin , the majority of counter @-@ regulated genes lie close the x = y diagonal , indicating that ATRA can suppress TPA effects on expression of these genes completely or near completely ( Fig . S1C , additional file 1 , see C1A and C2A subclusters ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.3.r 4-1.1.2.3 5-1.1.2.3.2.1 6-1.1.2.3.2 6-1.1.2.3.3 8-1.1.2.3.3.1.1.1.1.1 9-1.1.2.3.3.1.1 10-1.1.2.3.3.1.1.2.1.1 11-1.1.2.3.2 14-1.1.2.1.1 15-1.1.2.1.1.r 16-1.1.2.1.2.1.1.1 18-1.1.2.1.2.1.1 19-1.1.2.1 19-1.1.2.1.2.1 20-1.1.2 21-1.1.2.2 23-1.1.2.2.2.1.1.1 25-1.1.2.2.2.1.2.1 26-1.1.2.2.2 28-1.1.2.4 30-1.1.2.3.3.1.1.2.1.1 31-1.1.2.4.1 32-1.1.2.4.1.1.1 32-1.1.2.4.1.1.2 33-1.1.2.4.1.1.1.1.1 34-1.1.2.4.1.1.1.1 35-1.1.2.4.1.1.1.1.2.r 36-1.1.2.4.1.1.1.1.2 39-1.1.2.1 40-1.1.2.4.1.1.1.2 40-1.1.2.4.1.1.2.2 41-1.1.2.4.1.1 42-1.1.2.4.1.1.2.2.1 43-1.1.2.4.1.1.2.2 45-1.1.3.1.1 47-1.1.3.1.1.1 50-1.1.3.1.2 52-1.1.3.1.2.1 55-1.2 56-1.2.2.1.1.1.1 57-1.2.2 58-1.2.2.2.1.1.1 (m2 / multi-sentence :snt1 (n / note-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (l / lie-07~e.20 :ARG1 (g / gene~e.19,39 :quant~e.15 (m / majority~e.14) :ARG1-of (i / include-91 :ARG2 (g2 / gene~e.19 :ARG1-of (r / regulate-01~e.18 :ARG1-of (c2 / counter-01~e.16))))) :ARG2 (c / close-10~e.21 :ARG1 g :ARG2 (d / diagonal~e.26 :location-of (e2 / equal-01 :ARG1 (s10 / string-entity :value "x"~e.23) :ARG2 (s11 / string-entity :value "y"~e.25)))) :time~e.3 (c3 / compare-01~e.4 :ARG0 w :ARG1 (s / skin~e.6,11 :ARG0-of (c4 / control-01~e.5)) :ARG2 (s2 / skin~e.6 :ARG1-of (t / treat-04 :ARG2 (a / and~e.9 :op1 (s8 / small-molecule :name (n3 / name :op1 "TPA"~e.8)) :op2 (s9 / small-molecule :name (n4 / name :op1 "ATRA"~e.10,30)))))) :ARG0-of (i2 / indicate-01~e.28 :ARG1 (p / possible-01~e.31 :ARG1 (o / or~e.41 :op1 (s3 / suppress-01~e.32 :ARG1 (a3 / affect-01~e.34 :ARG0 s8~e.33 :ARG1~e.35 (e / express-03~e.36 :ARG2 g)) :ARG1-of (c6 / complete-02~e.40)) :op2 (s4 / suppress-01~e.32 :ARG1 a3 :ARG1-of (c7 / complete-02~e.40,43 :degree (n5 / near~e.42))))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.45 :mod "S1C"~e.47) :op2 (f2 / file~e.50 :mod 1~e.52 :ARG1-of (a5 / add-02))))) :snt2 (s5 / see-01~e.55 :ARG0 (y / you) :ARG1 (a6 / and~e.57 :op1 (s6 / subcluster :part-of (g3 / gene :name (n2 / name :op1 "C1A"~e.56))) :op2 (s7 / subcluster :part-of (g4 / gene :name (n6 / name :op1 "C2A"~e.58)))))) # ::id pmid_1943_2991.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A subset of the C1A and C2A genes are listed in Table S1 in additional file 2 , sorted according to their known function in cellular signaling pathways , using the GeneSifter program . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 7-1.1.1.1 7-1.1.1.2 9-1 10-1.2.r 11-1.2 12-1.2.1 15-1.2.2 17-1.2.2.1 20-1.1.2 23-1.1.2.1.1 23-1.1.2.1.1.r 24-1.1.2.1.3 25-1.1.2.1 26-1.1.2.1.2.r 27-1.1.2.1.2.1.1 28-1.1.2.1.2.1 29-1.1.2.1.2 31-1.3 33-1.3.1.1.1 34-1.3.1 (l / list-01~e.9 :ARG1 (s / subset~e.1 :consist-of~e.2 (a / and~e.5 :op1 (g / gene~e.7 :name (n / name :op1 "C1A"~e.4)) :op2 (g2 / gene~e.7 :name (n2 / name :op1 "C2A"~e.6))) :ARG1-of (s2 / sort-01~e.20 :ARG2 (f2 / function-01~e.25 :ARG0~e.23 a~e.23 :ARG1~e.26 (p / pathway~e.29 :ARG0-of (s4 / signal-07~e.28 :mod (c / cell~e.27))) :ARG1-of (k / know-01~e.24)))) :ARG2~e.10 (t / table~e.11 :mod "S1"~e.12 :location (f / file~e.15 :mod 2~e.17)) :manner (u / use-01~e.31 :ARG1 (p2 / program~e.34 :name (n5 / name :op1 "GeneSifter"~e.33)))) # ::id pmid_1943_2991.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The table lists genes in the major signaling pathways in epithelial cells that have the highest Z @-@ scores . # ::alignments 1-1.1 2-1 3-1.2 4-1.2.1.r 6-1.2.1.2 7-1.2.1.1 8-1.2.1 9-1.2.1.3.r 10-1.2.1.3.1 11-1.2.1.3 13-1.2.1.3.2 15-1.2.1.3.2.1.2 15-1.2.1.3.2.1.2.1 15-1.2.1.3.2.1.2.1.r 16-1.2.1.3.2.1.1.1 18-1.2.1.3.2.1 (l / list-01~e.2 :ARG0 (t / table~e.1) :ARG1 (g / gene~e.3 :location~e.4 (p / pathway~e.8 :ARG0-of (s / signal-07~e.7) :ARG1-of (m2 / major-02~e.6) :location~e.9 (c / cell~e.11 :mod (e / epithelium~e.10) :ARG0-of (h2 / have-03~e.13 :ARG1 (s2 / score~e.18 :name (n / name :op1 "Z"~e.16) :ARG1-of (h / high-02~e.15 :degree~e.15 (m / most~e.15)))))))) # ::id pmid_1943_2991.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Z @-@ score is a measure of the significance of over @-@ representation for a particular gene list within an ontology group [ @ 21 @ ] . # ::alignments 0-1.2.1.1 2-1.2 5-1 6-1.1.r 8-1.1 9-1.1.1.r 10-1.1.1.2 12-1.1.1 13-1.1.1.1.r 15-1.1.1.1.3 16-1.1.1.1.1 17-1.1.1.1 20-1.1.1.1.2.1 21-1.1.1.1.2 24-1.3.1.1.1 (m / measure-01~e.5 :ARG1~e.6 (s2 / significant-02~e.8 :ARG1~e.9 (r / represent-01~e.12 :ARG2~e.13 (l / list~e.17 :topic (g / gene~e.16) :location (g2 / group~e.21 :mod (o2 / ontology~e.20)) :mod (p2 / particular~e.15)) :degree (o / over~e.10))) :ARG2 (s / score~e.2 :name (n / name :op1 "Z"~e.0)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 21~e.24)))) # ::id pmid_1943_2991.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also identified several counter @-@ regulated genes that were previously determined to be TPA regulated ( Table S2 , additional file 3 ) . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 4-1.2.2.1 6-1.2.2 7-1.2 10-1.2.3.2 11-1.2.3 14-1.2.3.1.1.1.1 15-1.2.3.1 17-1.4.1.1 18-1.4.1.1.1 21-1.4.1.2 23-1.4.1.2.1 (i / identify-01~e.2 :ARG0 (w / we~e.0) :ARG1 (g / gene~e.7 :quant (s / several~e.3) :ARG1-of (r / regulate-01~e.6 :ARG1-of (c / counter-01~e.4)) :ARG1-of (d / determine-01~e.11 :ARG3 (r2 / regulate-01~e.15 :ARG0 (s2 / small-molecule :name (n / name :op1 "TPA"~e.14)) :ARG1 g) :time (p / previous~e.10))) :mod (a / also~e.1) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (t / table~e.17 :mod "S2"~e.18) :op2 (f / file~e.21 :mod 3~e.23 :ARG1-of (a3 / add-02))))) # ::id pmid_1943_2991.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This abrogation of TPA effect on gene expression by ATRA is consistent with the findings of numerous investigators who have shown that TPA activates the AP @-@ 1 transcription factor complex , and that AP @-@ 1 activity is inhibited by ATRA through the retinoid receptors [ @ 10 @ ] for review and [ @ 14 , 22 @ ] . # ::alignments 0-1.1.3 1-1.1 2-1.1.2.r 3-1.1.2.1.1.1 4-1.1.2 5-1.1.2.2.r 6-1.1.2.2.1 7-1.1.2.2 8-1.1.1.r 9-1.1.1.1.1 11-1 12-1.2.1.3.1.2.3.r 14-1.2 16-1.2.1.2 17-1.2.1 17-1.2.1.1 17-1.2.1.1.r 20-1.2.1.3 21-1.2.1.3.1.r 22-1.2.1.3.1.1.1 23-1.2.1.3.1.1 25-1.2.1.3.1.1.2.2.1.1.1 27-1.2.1.3.1.1.2.2.1.1.1 28-1.2.1.3.1.1.2.1.1 29-1.2.1.3.1.1.2.1 30-1.2.1.3.1.1.2 34-1.2.1.3.1.2.2.1 35-1.2.1.3.1.2.2.1 36-1.2.1.3.1.2.2.1 37-1.2.1.3.1.2.2 39-1.2.1.3.1.2 41-1.1.1.1.1 44-1.2.1.3.1.2.3.1 45-1.2.1.3.1.2.3 48-1.2.1.3.1.2.4.1.1.1.1 53-1.2.1.3.1.2.4.1.1.1 56-1.2.1.3.1.2.4.1.1.1.2 60-1.2.1.3.1.2.4.1.1.1.3 (c / consistent-01~e.11 :ARG1 (a / abrogate-01~e.1 :ARG0~e.8 (s2 / small-molecule :name (n3 / name :op1 "ATRA"~e.9,41)) :ARG1~e.2 (a2 / affect-01~e.4 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA"~e.3)) :ARG1~e.5 (e / express-03~e.7 :ARG2 (g / gene~e.6))) :mod (t / this~e.0)) :ARG2 (f / find-01~e.14 :ARG0 (p3 / person~e.17 :ARG0-of~e.17 (i / investigate-01~e.17) :quant (n4 / numerous~e.16) :ARG0-of (s / show-01~e.20 :ARG1~e.21 (a5 / and :op1 (a4 / activate-01~e.23 :ARG0 s3~e.22 :ARG1 (c2 / complex~e.30 :mod (f2 / factor~e.29 :ARG0-of (t2 / transcribe-01~e.28)) :ARG1-of (m / mean-01 :ARG2 (p4 / protein :name (n5 / name :op1 "AP-1"~e.25,27))))) :op2 (i2 / inhibit-01~e.39 :ARG0 s2 :ARG1 (a3 / activity-06~e.37 :ARG0 p4~e.34,35,36) :instrument~e.12 (r / receptor~e.45 :mod (r2 / retinoid~e.44)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 (a7 / and~e.53 :op1 10~e.48 :op2 14~e.56 :op3 22~e.60)))))))))) # ::id pmid_1943_2991.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ATRA suppresses B @-@ Raf/Mek/Erk signaling in early and late tumor progression times in the 2 @-@ stage skin carcinogenesis model # ::alignments 1-1.1.1.1 2-1 3-1.2.1.1.1 6-1.2 8-1.3.1.2 9-1.3 10-1.3.2.2 11-1.3.1.1 12-1.3.1 12-1.3.2 13-1.3.r 14-1.4.r 16-1.4.1.1.1 18-1.4.1.1 19-1.4.2.1 20-1.4.2 21-1.4 (s / suppress-01~e.2 :ARG0 (s5 / small-molecule :name (n / name :op1 "ATRA"~e.1)) :ARG1 (s2 / signal-07~e.6 :ARG0 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk"~e.3))) :time~e.13 (a2 / and~e.9 :op1 (p2 / progress-01~e.12 :ARG1 (t2 / tumor~e.11) :mod (e / early~e.8)) :op2 (p3 / progress-01~e.12 :ARG1 t2 :mod (l / late~e.10))) :location~e.14 (m / model~e.21 :ARG0-of (h / have-03 :ARG1 (s4 / stage~e.18 :quant 2~e.16)) :mod (c / carcinogenesis~e.20 :mod (s3 / skin~e.19)))) # ::id pmid_1943_2991.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Examination of the above microarray results revealed altered expression of a disproportionate number of genes involved in the MAP kinase signaling pathway , in particular the B @-@ Raf/Mek/Erk pathway ( Table S1 , additional file 2 ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.2 4-1.1.1 5-1.1.1.1 6-1 7-1.2.2 8-1.2 9-1.2.1.r 11-1.2.1.2 12-1.2.1 13-1.2.1.1.r 14-1.2.1.1 15-1.2.1.1.1 18-1.2.1.1.1.1.1.1.1 19-1.2.1.1.1.1.1.1.2 20-1.2.1.1.1.1.1.2 21-1.2.1.1.1.1.1 21-1.2.1.1.1.1.2 24-1.2.1.1.1.1.2.2 26-1.2.1.1.1.1.2.1.1 29-1.2.1.1.1.1.2 31-1.3.1.1 32-1.3.1.1.1 35-1.3.1.2 37-1.3.1.2.1 (r / reveal-01~e.6 :ARG0 (e / examine-01~e.0 :ARG1~e.1 (m / microarray~e.4 :ARG1-of (r2 / result-01~e.5) :location (a / above~e.3))) :ARG1 (e2 / express-03~e.8 :ARG2~e.9 (n2 / number~e.12 :quant-of~e.13 (g / gene~e.14 :ARG1-of (i / involve-01~e.15 :ARG2 (a3 / and :op1 (p4 / pathway~e.21 :name (n / name :op1 "MAP"~e.18 :op2 "kinase"~e.19) :ARG0-of (s / signal-07~e.20)) :op2 (p2 / pathway~e.21,29 :name (n4 / name :op1 "B-Raf/Mek/Erk"~e.26) :mod (p3 / particular~e.24))))) :mod (d / disproportionate~e.11)) :ARG1-of (a2 / alter-01~e.7)) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (t2 / table~e.31 :mod "S1"~e.32) :op2 (f / file~e.35 :mod 2~e.37 :ARG1-of (a5 / add-02))))) # ::id pmid_1943_2991.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next performed a 2 @-@ stage skin carcinogenesis experiment as above , except that in this study the protocol was carried out for 30 weeks . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 4-1.1.2.2.1.1 6-1.1.2.2.1 7-1.1.2.1.1 9-1.1.2 10-1.1.3.r 11-1.1.2.3.1 16-1.2.4.1 17-1.2.4 19-1.2.2 21-1.2 22-1.2 23-1.2.3.r 24-1.2.3.1 25-1.2.3.2 (c / contrast-01 :ARG1 (p / perform-02~e.2 :ARG0 (w2 / we~e.0) :ARG1 (e / experiment-01~e.9 :ARG1 (c3 / carginogenesis :mod (s / skin~e.7)) :ARG0-of (h / have-03 :ARG1 (s2 / stage~e.6 :quant 2~e.4)) :ARG1-of (r / resemble-01 :ARG2 (a / above~e.11))) :time~e.10 (n / next~e.1)) :ARG2 (c2 / carry-out-03~e.21,22 :ARG0 w2 :ARG1 (p2 / protocol~e.19) :duration~e.23 (t2 / temporal-quantity :quant 30~e.24 :unit (w3 / week~e.25)) :location (s3 / study~e.17 :mod (t3 / this~e.16)))) # ::id pmid_1943_2991.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumor counts were recorded each week and mice were sacrificed at multiple time points ( 6 hours , 3 , 7 , 10 , and 30 weeks of treatment ) , for subsequent analysis of B @-@ Raf/Mek/Erk pathway signaling . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 5-1.2.2.3.1.3.1.1.2 5-1.2.2.3.1.4.1.1.2 5-1.2.2.3.1.5.1.1.2 6-1 7-1.2.1 9-1.2 10-1.2.2.r 11-1.2.2.2 12-1.2.2.1 12-1.2.2.3.1.1.1.1 12-1.2.2.3.1.2.1.1 12-1.2.2.3.1.3.1.1 12-1.2.2.3.1.4.1.1 12-1.2.2.3.1.5.1.1 13-1.2.2 15-1.2.2.3.1.1.1.1.1 16-1.2.2.3.1.1.1.1.2 18-1.2.2.3.1.2.1.1.1 20-1.2.2.3.1.3.1.1.1 22-1.2.2.3.1.4.1.1.1 24-1.2.2.3.1 25-1.2.2.3.1.5.1.1.1 26-1.2.2.3.1.2.1.1.2 27-1.2.2.3.1.2.1.1.r 28-1.2.2.3.1.1.1 28-1.2.2.3.1.2.1 28-1.2.2.3.1.3.1 28-1.2.2.3.1.4.1 28-1.2.2.3.1.5.1 32-1.2.2.3.1.1 32-1.2.2.3.1.2 32-1.2.2.3.1.3 32-1.2.2.3.1.4 32-1.2.2.3.1.5 32-1.2.3.2 32-1.2.3.2.r 33-1.2.3 34-1.2.3.1.r 35-1.2.3.1.1.1.1 38-1.2.3.1.1 39-1.2.3.1 (a / and~e.6 :op1 (r / record-01~e.3 :ARG1 (c / count-01~e.1 :ARG1 (t3 / tumor~e.0)) :time (w2 / week~e.5 :mod (e / each~e.4))) :op2 (s / sacrifice-01~e.9 :ARG1 (m / mouse~e.7) :time~e.10 (p / point~e.13 :mod (t4 / time~e.12) :quant (m2 / multiple~e.11) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and~e.24 :op1 (a4 / after~e.32 :op1 (t7 / treat-04~e.28 :quant (t / temporal-quantity~e.12 :quant 6~e.15 :unit (h / hour~e.16)))) :op2 (a5 / after~e.32 :op1 (t8 / treat-04~e.28 :quant~e.27 (t5 / temporal-quantity~e.12 :quant 3~e.18 :unit (w3 / week~e.26)))) :op3 (a6 / after~e.32 :op1 (t9 / treat-04~e.28 :quant (t6 / temporal-quantity~e.12 :quant 7~e.20 :unit (w4 / week~e.5)))) :op4 (a7 / after~e.32 :op1 (t10 / treat-04~e.28 :quant (t11 / temporal-quantity~e.12 :quant 10~e.22 :unit (w5 / week~e.5)))) :op5 (a8 / after~e.32 :op1 (t12 / treat-04~e.28 :quant (t13 / temporal-quantity~e.12 :quant 30~e.25 :unit (w6 / week~e.5))))))) :purpose (a3 / analyze-01~e.33 :ARG1~e.34 (s2 / signal-07~e.39 :ARG0 (p2 / pathway~e.38 :name (n / name :op1 "B-Raf/Mek/Erk"~e.35))) :time~e.32 (s3 / subsequent~e.32)))) # ::id pmid_1943_2991.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The reduced tumor multiplicity and increased tumor latency for mice treated with TPA+ATRA , compared to mice treated with TPA alone , indicated the potent tumor suppressive activity of ATRA , in agreement with previous results ( Fig . 3A , compare black line with blue line ) [ @ 8 , 9 @ ] . # ::alignments 1-1.1.1.1.2 2-1.1.1.1.1 4-1.1.1 5-1.1.1.2.2 6-1.1.1.2.1 7-1.1.1.2 9-1.1.1.3 10-1.1.1.3.1 14-1.1.1.4.r 16-1.1.1.4 17-1.1.1.4.1 18-1.1.1.3.1.1.r 19-1.1.1.3.1.1.1.1.1 20-1.1.1.4.1.2 22-1.1 24-1.1.2.3 25-1.1.1.1.1 27-1.1.2 29-1.1.1.3.1.1.2.1.1 31-1.1.2.4.r 32-1.1.2.4 33-1.1.2.4.1.r 34-1.1.2.4.1.1.1 35-1.1.2.4.1 35-1.1.2.4.1.1 35-1.1.2.4.1.1.r 37-1.1.3.1 40-1.1.3.1.1 43-1.2 44-1.2.2.1 45-1.2.2 46-1.2.3.r 47-1.2.3.1 48-1.2.3 52-1.3.1.1.1.1 56-1.3.1.1.1.2 (m4 / multi-sentence :snt1 (i / indicate-01~e.22 :ARG0 (a / and~e.4 :op1 (m / multiply-01 :ARG1 (t / tumor~e.2,25) :ARG1-of (r / reduce-01~e.1)) :op2 (l / latent~e.7 :domain t~e.6 :ARG1-of (i2 / increase-01~e.5)) :location (m2 / mouse~e.9 :ARG1-of (t2 / treat-04~e.10 :ARG2~e.18 (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "TPA"~e.19)) :op2 (s3 / small-molecule :name (n2 / name :op1 "ATRA"~e.29))))) :compared-to~e.14 (m3 / mouse~e.16 :ARG1-of (t3 / treat-04~e.17 :ARG2 s2 :mod (a4 / alone~e.20)))) :ARG1 (a3 / activity-06~e.27 :ARG0 s3 :ARG1 (s / suppress-01 :ARG1 t) :mod (p2 / potent~e.24) :ARG0-of~e.31 (a6 / agree-01~e.32 :ARG2~e.33 (t5 / thing~e.35 :ARG2-of~e.35 (r2 / result-01~e.35 :time (p3 / previous~e.34))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.37 :mod "3A"~e.40))) :snt2 (c / compare-01~e.43 :ARG0 (y / you) :ARG1 (l2 / line~e.45 :ARG1-of (b / black-04~e.44)) :ARG2~e.46 (l3 / line~e.48 :mod (b2 / blue~e.47))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 (a7 / and :op1 8~e.52 :op2 9~e.56))))) # ::id pmid_1943_2991.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However a small number of tumors were observed in the mice treated with TPA+ATRA . # ::alignments 0-1 2-1.1.1.2 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1 7-1.1 8-1.1.2.r 10-1.1.2 11-1.1.2.1 (h / have-concession-91~e.0 :ARG1 (o / observe-01~e.7 :ARG1 (n / number~e.3 :quant-of~e.4 (t / tumor~e.5) :mod (s / small~e.2)) :location~e.8 (m / mouse~e.10 :ARG1-of (t2 / treat-04~e.11 :ARG2 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "TPA")) :op2 (s3 / small-molecule :name (n3 / name :op1 "ATRA"))))))) # ::id pmid_1943_2991.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , histological examination of these ATRA resistant tumors revealed a less differentiated phenotype than for the tumors that arose in the mice treated with TPA alone ( Fig . 3B ) . # ::alignments 0-1.3 2-1.1.2 3-1.1 4-1.1.1.r 5-1.1.1.1.1.2 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1 9-1 11-1.2.1.1 12-1.2.1 13-1.2 14-1.2.1.2.r 17-1.2.1.2 19-1.2.1.2.1 20-1.2.1.2.1.1.r 22-1.2.1.2.1.1 23-1.2.1.2.1.1.1 24-1.2.1.2.1.1.1.1.r 25-1.2.1.2.1.1.1.1.1.1 26-1.2.1.2.1.1.1.1.2 28-1.4.1 31-1.4.1.1 (r / reveal-01~e.9 :ARG0 (e / examine-01~e.3 :ARG1~e.4 (t / tumor~e.8 :ARG0-of (r2 / resist-01~e.7 :ARG1 (s / small-molecule :name (n / name :op1 "ATRA"~e.6) :mod (t2 / this~e.5)))) :mod (h / histology~e.2)) :ARG1 (p / phenotype~e.13 :ARG1-of (d / differentiate-01~e.12 :degree (l / less~e.11) :compared-to~e.14 (t3 / tumor~e.17 :ARG1-of (a2 / arise-02~e.19 :location~e.20 (m / mouse~e.22 :ARG1-of (t4 / treat-04~e.23 :ARG2~e.24 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.25) :mod (a3 / alone~e.26)))))))) :ARG2-of (i / interest-01~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.28 :mod "3B"~e.31))) # ::id pmid_1943_2991.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These tumors closely resembled advanced SCC , while the tumors in the TPA mice were papillary , with a high degree of keratinization as confirmed by a immunohistochemical ( IHC ) staining for cytokeratin 10 ( Fig . 3B , lower panels ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.3 3-1.1 4-1.1.2.4 5-1.1.2.1.1 5-1.1.2.2 5-1.1.2.3 7-1 9-1.2.1 10-1.2.1.1.r 12-1.2.1.1.1.1.1.1 13-1.2.1.1 14-1.2.1.r 15-1.2 19-1.2.1.2.1.2 20-1.2.1.2.1 20-1.2.1.2.1.1.r 24-1.2.1.2.2 25-1.2.1.2.2.1.r 27-1.2.1.2.2.1.1 31-1.2.1.2.2.1 32-1.2.1.2.2.1.2.r 33-1.2.1.2.2.1.2.1.1 34-1.2.1.2.2.1.2.1.2 36-1.3.1.1 39-1.3.1.1.1 42-1.3.1.2.1 42-1.3.1.2.1.1 42-1.3.1.2.1.1.r 43-1.3.1.2 (c3 / contrast-01~e.7 :ARG1 (r / resemble-01~e.3 :ARG1 (t / tumor~e.1 :mod (t2 / this~e.0)) :ARG2 (m / medical-condition :name (n / name :op1 "carcinoma"~e.5) :mod (c2 / cell~e.5) :mod (s / squamous~e.5) :ARG1-of (a / advance-01~e.4)) :ARG1-of (c / close-10~e.2)) :ARG2 (p / papilla~e.15 :domain~e.14 (t3 / tumor~e.9 :location~e.10 (m2 / mouse~e.13 :ARG1-of (t4 / treat-04 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "TPA"~e.12)))) :ARG0-of (h / have-03 :ARG1 (d2 / degree~e.20 :degree-of~e.20 (k / keratinize-00) :ARG1-of (h2 / high-02~e.19)) :ARG1-of (c4 / confirm-01~e.24 :ARG0~e.25 (s2 / stain-01~e.31 :mod (i / immunohistochemical~e.27) :purpose~e.32 (p3 / protein :name (n3 / name :op1 "cytokeratin"~e.33 :op2 10~e.34))))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.36 :mod "3B"~e.39) :op2 (p4 / panel~e.43 :ARG1-of (l / low-04~e.42 :degree~e.42 (m3 / more~e.42)))))) # ::id pmid_1943_2991.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to investigate the effects of ATRA on TPA @-@ induced activation of the B @-@ Raf/Mek/Erk pathway , we performed IHC staining of paraffin sections from mouse skin treated with TPA , ATRA , TPA+ATRA , or acetone solvent , with phosphorylation site @-@ specific antibodies to B @-@ Raf ( phospho @-@ Ser 445 ) , Mek1 @/@ 2 ( phospho @-@ Ser 217 @/@ 221 ) , and Erk1 @/@ 2 ( phospho @-@ Thr202 @/@ Tyr 204 ) . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 5-1.3.2 7-1.2.1.1.2.1.2.1.1 8-1.3.2.2.r 9-1.3.2.2.2.1 11-1.3.2.2.2 12-1.3.2.2 13-1.3.2.2.1.r 15-1.3.2.2.1.1.1 18-1.3.2.2.1 20-1.1 21-1 23-1.2 25-1.2.1.2 26-1.2.1 27-1.2.1.1.r 28-1.2.1.1.1 29-1.2.1.1 30-1.2.1.1.2 31-1.2.1.1.2.1.r 32-1.2.1.1.2.1.1.1.1 34-1.2.1.1.2.1.2.1.1 38-1.2.1.1.2.1 39-1.2.1.1.2.1.4.1 40-1.2.1.1.2.1.4 42-1.2.2.r 43-1.2.2.1.1.1.1 43-1.2.2.1.1.1.2.1.3 44-1.2.2.1.1.1 44-1.2.2.2.2.1 44-1.2.2.3.2.1 46-1.2.2.1.1 46-1.2.2.2.2 46-1.2.2.3.2 47-1.2.2.1 47-1.2.2.2 47-1.2.2.3 49-1.2.2.1.2.1.1.1 51-1.2.2.1.2.1.1.1 53-1.2.2.1.1.1.1 53-1.2.2.1.1.1.2.1.3 55-1.2.2.1.1.1.2.1.2.1 56-1.2.2.1.1.1.2.1.1 59-1.2.2.2.1.1.1.1.1 60-1.2.2.2.1.1 60-1.2.2.2.2.1.1.1 63-1.2.2.2.2.1.1.1.1.3 65-1.2.2.2.2.1.1.1.1.2.1 65-1.2.2.2.2.1.1.1.2.2.1 66-1.2.2.2.2.1.1.1.1.1 67-1.2.2.2.2.1.1.1 68-1.2.2.2.2.1.1.1.2.1 71-1.2.2 72-1.2.2.3.1.1.1.1.1 73-1.2.2.2.2.1.1.1 73-1.2.2.3.1.1 73-1.2.2.3.2.1.1.1 76-1.2.2.1.1.1.1 76-1.2.2.1.1.1.2.1.3 79-1.2.2.2.2.1.1.1 79-1.2.2.3.1.1 79-1.2.2.3.2.1.1.1 80-1.2.2.3.2.1.1.1.2.2.1 81-1.2.2.3.2.1.1.1.2.1 (p2 / perform-02~e.21 :ARG0 (w / we~e.20) :ARG1 (s / stain-01~e.23 :ARG1 (s2 / section~e.26 :source~e.27 (s3 / skin~e.29 :mod (m / mouse~e.28) :ARG1-of (t2 / treat-04~e.30 :ARG2~e.31 (o / or~e.38 :op1 (s11 / small-molecule :name (n4 / name :op1 "TPA"~e.32)) :op2 (s12 / small-molecule :name (n5 / name :op1 "ATRA"~e.7,34)) :op3 (a3 / and :op1 s11 :op2 s12) :op4 (s4 / solvent~e.40 :mod (a / acetone~e.39))))) :mod (p3 / paraffin~e.25)) :ARG2~e.42 (a5 / and~e.71 :op1 (a4 / antibody~e.47 :ARG1-of (s5 / specific-02~e.46 :ARG2 (s6 / site~e.44 :ARG1-of (p / phosphorylate-01~e.43,53,76) :ARG1-of (m2 / mean-01 :ARG2 (a7 / amino-acid :mod 445~e.56 :name (n8 / name :op1 "serine"~e.55) :ARG3-of (p4 / phosphorylate-01~e.43,53,76))))) :ARG0-of (c / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"~e.49,51)))) :op2 (a6 / antibody~e.47 :ARG0-of (c2 / counter-01 :ARG1 (s7 / slash~e.60 :op1 (e3 / enzyme :name (n6 / name :op1 "Mek1"~e.59)) :op2 (e4 / enzyme :name (n7 / name :op1 "Mek2")))) :ARG1-of (s13 / specific-02~e.46 :ARG2 (s14 / site~e.44 :ARG1-of (m3 / mean-01 :ARG2 (s10 / slash~e.60,67,73,79 :op1 (a12 / amino-acid :mod 217~e.66 :name (n9 / name :op1 "serine"~e.65) :ARG3-of (p5 / phosphorylate-01~e.63)) :op2 (a13 / amino-acid :mod 221~e.68 :name (n14 / name :op1 "serine"~e.65))))))) :op3 (a9 / antibody~e.47 :ARG0-of (c3 / counter-01 :ARG1 (s8 / slash~e.73,79 :op1 (e5 / enzyme :name (n10 / name :op1 "Erk1"~e.72)) :op2 (e6 / enzyme :name (n11 / name :op1 "Erk2")))) :ARG1-of (s15 / specific-02~e.46 :ARG2 (s16 / site~e.44 :ARG1-of (m4 / mean-01 :ARG2 (s9 / slash~e.73,79 :op1 (a10 / amino-acid :mod 202 :name (n12 / name :op1 "threonine")) :op2 (a11 / amino-acid :mod 204~e.81 :name (n13 / name :op1 "tyrosine"~e.80)))))))) :mod (i / immunohistochemistry)) :purpose~e.0,1,2 (i2 / investigate-01~e.3 :ARG0 w :ARG1 (a14 / affect-01~e.5 :ARG0 s12 :ARG1~e.8 (a15 / activate-01~e.12 :ARG1~e.13 (p6 / pathway~e.18 :name (n15 / name :op1 "B-Raf/Mek/Erk"~e.15)) :ARG2-of (i3 / induce-01~e.11 :ARG0 s11~e.9)) :ARG1-of p))) # ::id pmid_1943_2991.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The 6 h , 3 , 7 , 10 and 30 week time points were selected for sample isolation in order to obtain data prior to tumor formation ( 6 h and 3 weeks ) , just as tumors are beginning to be detectable ( 7 weeks ) , after the majority of mice have tumors ( 10 weeks ) , and after tumors had grown substantially ( 30 weeks ) . # ::alignments 1-1.1.1.1.1.1.1 2-1.1.1.1.1.1.2 4-1.1.2.1.1.1.1 6-1.1.3.1.1.1.1 8-1.1.4.1.1.1.1 9-1.1 10-1.1.5.1.1.1.1 11-1.1.2.1.1.1.2 11-1.1.3.1.1.1.2 11-1.1.4.1.1.1.2 11-1.1.5.1.1.1.2 12-1.1.1.1 12-1.1.1.1.1.1 12-1.1.2.1 12-1.1.2.1.1.1 12-1.1.3.1 12-1.1.3.1.1.1 12-1.1.4.1 12-1.1.4.1.1.1 12-1.1.5.1 12-1.1.5.1.1.1 13-1.1.1 13-1.1.2 13-1.1.3 13-1.1.4 13-1.1.5 15-1 16-1.2.r 17-1.2.1 17-1.2.1.1 17-1.2.1.1.r 18-1.2 19-1.2.2.r 20-1.2.2.r 21-1.2.2.r 22-1.2.2 23-1.2.2.1.1 23-1.2.2.1.2 23-1.2.2.1.3 23-1.2.2.1.4 24-1.2.2.1.1.1 25-1.2.2.1.1.1.1.r 26-1.2.2.1.1.1.1.1 27-1.2.2.1.1.1.1 29-1.1.1.1.1.1.1 30-1.1.1.1.1.1.2 32-1.1.2.1.1.1.1 33-1.1.2.1.1.1.2 37-1.2.2.1.2.1.r 37-1.2.2.1.3.1.r 38-1.2.2.1.2.1.1 40-1.2.2.1.2.1 43-1.2.2.1.2.1.2 45-1.1.3.1.1.1.1 46-1.1.2.1.1.1.2 49-1.2.2.1.3.1 51-1.2.2.1.3.1.1.1.1 52-1.2.2.1.3.1.1.1.1.r 53-1.2.2.1.3.1.1.1 53-1.2.2.1.3.1.1.1.2.1 54-1.2.2.1.3.1.1 55-1.2.2.1.3.1.1.2 57-1.1.4.1.1.1.1 58-1.1.2.1.1.1.2 61-1.2.2.1 62-1.2.2.1.3.1 62-1.2.2.1.4.1 63-1.2.2.1.4.1.1.1 64-1.2.2.1.3.1.1 65-1.2.2.1.4.1.1 66-1.2.2.1.4.1.1.2 68-1.1.5.1.1.1.1 69-1.1.2.1.1.1.2 (s / select-01~e.15 :ARG1 (a / and~e.9 :op1 (p / point~e.13 :mod (t5 / time~e.12 :ARG1-of (e2 / equal-01 :ARG2 (t6 / temporal-quantity~e.12 :quant 6~e.1,29 :unit (h / hour~e.2,30))))) :op2 (p2 / point~e.13 :mod (t7 / time~e.12 :ARG1-of (e3 / equal-01 :ARG2 (t2 / temporal-quantity~e.12 :quant 3~e.4,32 :unit (w2 / week~e.11,33,46,58,69))))) :op3 (p3 / point~e.13 :mod (t8 / time~e.12 :ARG1-of (e4 / equal-01 :ARG2 (t3 / temporal-quantity~e.12 :quant 7~e.6,45 :unit (w3 / week~e.11) :ARG1-of (e / equal-01))))) :op4 (p4 / point~e.13 :mod (t9 / time~e.12 :ARG1-of (e5 / equal-01 :ARG2 (t4 / temporal-quantity~e.12 :quant 10~e.8,57 :unit (w4 / week~e.11))))) :op5 (p5 / point~e.13 :mod (t10 / time~e.12 :ARG1-of (e6 / equal-01 :ARG2 (t / temporal-quantity~e.12 :quant 30~e.10,68 :unit (w / week~e.11)))))) :ARG3~e.16 (i / isolate-01~e.18 :ARG1 (t13 / thing~e.17 :ARG1-of~e.17 (s2 / sample-01~e.17)) :purpose~e.19,20,21 (o / obtain-01~e.22 :ARG1 (a4 / and~e.61 :op1 (d / data~e.23 :time (p6 / prior~e.24 :op1~e.25 (f / form-01~e.27 :ARG1 (t11 / tumor~e.26)) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 t6 :op2 t2)))) :op2 (d3 / data~e.23 :time~e.37 (b / begin-01~e.40 :ARG0 t11~e.38 :ARG1 (d2 / detect-01~e.43 :ARG1 t11) :ARG1-of (m5 / mean-01 :ARG2 t3))) :op3 (d4 / data~e.23 :time~e.37 (a5 / after~e.49,62 :op1 (h3 / have-03~e.54,64 :ARG0 (m2 / mouse~e.53 :quant~e.52 (m3 / majority~e.51) :ARG1-of (i2 / include-91 :ARG2 (m7 / mouse~e.53))) :ARG1 t11~e.55) :ARG1-of (m6 / mean-01 :ARG2 t4))) :op4 (d5 / data~e.23 :time (a3 / after~e.62 :op1 (g / grow-01~e.65 :ARG1 t11~e.63 :degree (s3 / substantial~e.66)) :ARG1-of (m4 / mean-01 :ARG2 t))))))) # ::id pmid_1943_2991.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the TPA treated skin , hyperproliferation was correlated with increased levels of activated ( phosphorylated ) B @-@ Raf , Mek1 @/@ 2 , and Erk1 @/@ 2 , as detected by increased red fluorescence from the Alexa 546 @-@ coupled secondary antibody . # ::alignments 2-1.4.1.1.1.1 3-1.4.1 4-1.4 8-1 9-1.2.r 10-1.2.1.1 11-1.2.1 11-1.2.2 11-1.2.3 12-1.2.1.2.r 13-1.2.1.2.2 15-1.2.1.2.2.1.1 17-1.2.1.2.1.1 19-1.2.1.2.1.1 21-1.2.2.2.1.1.1 22-1.2.2.2 22-1.2.3.2 25-1.2 26-1.2.3.2.1.1.1 27-1.2.2.2 30-1.3.r 31-1.3 33-1.3.1.3 34-1.3.1.2 38-1.3.1.1.2.1.1.1 39-1.3.1.1.2.1.1.2 41-1.3.1.1.2 42-1.3.1.1.1 43-1.3.1.1 (c / correlate-01~e.8 :ARG1 (h / hyperproliferate-01) :ARG2~e.9 (a / and~e.25 :op1 (l / level~e.11 :ARG1-of (i / increase-01~e.10) :quant-of~e.12 (e3 / enzyme :name (n3 / name :op1 "B-Raf"~e.17,19) :ARG1-of (a2 / activate-01~e.13 :ARG1-of (m / mean-01 :ARG2 (p / phosphorylate-01~e.15))))) :op2 (l2 / level~e.11 :ARG1-of i :quant-of (s / slash~e.22,27 :op1 (e4 / enzyme :name (n4 / name :op1 "Mek1"~e.21) :ARG1-of a2) :op2 (e5 / enzyme :name (n5 / name :op1 "Mek2") :ARG1-of a2))) :op3 (l3 / level~e.11 :ARG1-of i :quant-of (s2 / slash~e.22 :op1 (e6 / enzyme :name (n6 / name :op1 "Erk1"~e.26) :ARG1-of a2) :op2 (e7 / enzyme :name (n7 / name :op1 "Erk2") :ARG1-of a2)))) :ARG1-of~e.30 (d / detect-01~e.31 :ARG0 (f / fluoresce-01 :ARG1 (a3 / antibody~e.43 :mod (s3 / secondary~e.42) :ARG1-of (c2 / couple-01~e.41 :ARG2 (s6 / small-molecule :name (n8 / name :op1 "Alexa"~e.38 :op2 546~e.39)))) :ARG1-of (r / red-02~e.34) :ARG1-of i~e.33)) :location (s4 / skin~e.4 :ARG1-of (t2 / treat-04~e.3 :ARG2 (s5 / small-molecule :name (n9 / name :op1 "TPA"~e.2))))) # ::id pmid_1943_2991.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results are shown for a representative ( 3 week ) time point ( Fig . 4A ; compare TPA panels to Control panels for all 3 rows ) . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 2-1.1 3-1.1.2.r 5-1.1.2.2 7-1.1.2.3.1.1.1 8-1.1.2.3.1.1.2 10-1.1.2.1 10-1.1.2.3.1.1 11-1.1.2 13-1.1.3.1 16-1.1.3.1.1 19-1.2 20-1.2.2.1.1.1 21-1.2.2 21-1.2.3 23-1.2.3.1 24-1.2.3 25-1.2.4.r 26-1.2.4.2 27-1.2.4.1 28-1.2.4 (m2 / multi-sentence :snt1 (s / show-01~e.2 :ARG1 (t2 / thing~e.0 :ARG2-of~e.0 (r2 / result-01~e.0)) :purpose~e.3 (p2 / point~e.11 :mod (t3 / time~e.10) :ARG0-of (r3 / represent-01~e.5) :ARG1-of (m / mean-01 :ARG2 (a2 / after :op1 (t / temporal-quantity~e.10 :quant 3~e.7 :unit (w / week~e.8))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13 :mod "4A"~e.16))) :snt2 (c / compare-01~e.19 :ARG0 (y / you) :ARG1 (p3 / panel~e.21 :consist-of (s2 / small-molecule :name (n / name :op1 "TPA"~e.20))) :ARG2 (p5 / panel~e.21,24 :ARG0-of (c2 / control-01~e.23)) :purpose~e.25 (r4 / row~e.28 :quant 3~e.27 :mod (a / all~e.26)))) # ::id pmid_1943_2991.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Skin treated with a single application of TPA , ATRA or TPA+ATRA showed no notable changes in staining for any of the phosphoproteins ( data not shown ) . # ::alignments 0-1.1 1-1.1.1 2-1.1.1.1.r 4-1.1.1.1.1.2 5-1.1.1.1.1 5-1.1.1.1.2 5-1.1.1.1.3 6-1.1.1.1.1.1.r 7-1.1.1.1.1.1.1.1 9-1.1.1.1.2.1.1.1 10-1.1.1.1 12-1 12-1.3.1.1 13-1.3.1.1.1 13-1.3.1.1.1.r 14-1.2.2 15-1.2 16-1.2.1.r 17-1.2.1 18-1.2.1.1.r 19-1.2.1.1.1 24-1.3.1 25-1.3.1.1.1 25-1.3.1.1.1.r 26-1.3.1.1 (s5 / show-01~e.12 :ARG0 (s2 / skin~e.0 :ARG1-of (t / treat-04~e.1 :ARG2~e.2 (o / or~e.10 :op1 (a / apply-02~e.5 :ARG1~e.6 (s6 / small-molecule :name (n / name :op1 "TPA"~e.7)) :ARG1-of (s3 / single-02~e.4)) :op2 (a2 / apply-02~e.5 :ARG1 (s7 / small-molecule :name (n2 / name :op1 "ATRA"~e.9)) :ARG1-of s3) :op3 (a4 / apply-02~e.5 :ARG1 (a5 / and :op1 s6 :op2 s7) :ARG1-of s3)))) :ARG1 (c / change-01~e.15 :ARG1~e.16 (s4 / stain-01~e.17 :ARG1~e.18 (p2 / protein :mod (a6 / any~e.19) :ARG1-of (p3 / phosphorylate-01))) :ARG1-of (n3 / notable-04~e.14)) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.24 :ARG1-of (s / show-01~e.12,26 :polarity~e.13,25 -~e.13,25)))) # ::id pmid_1943_2991.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok pB @-@ Raf was expressed predominantly in the cytoplasm in TPA treated skin at all time points , and this effect was blocked with co @-@ administration of ATRA with TPA ( Fig . 4A , upper rows and data not shown ) . # ::alignments 2-1.1.1.1.1 4-1.1 5-1.1.3 6-1.1.2.r 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.1.1.1.1 11-1.1.2.1.1 12-1.1.2.1 13-1.1.4.r 14-1.1.4.2 15-1.1.4.1 16-1.1.4 18-1 19-1.2.1.1 20-1.2.1 22-1.2 26-1.2.2 27-1.2.2.1.r 28-1.2.2.1.1.1.1 30-1.2.2.1.2 32-1.3.1.1 35-1.3.1.1.1 39-1.3.1.1.2 40-1.3.1 41-1.3.1.2 42-1.3.1.2.1.1 42-1.3.1.2.1.1.r 43-1.3.1.2.1 (a / and~e.18 :op1 (e / express-03~e.4 :ARG2 (e2 / enzyme :name (n / name :op1 "B-Raf"~e.2) :ARG3-of (p / phosphorylate-01)) :ARG3~e.6 (c / cytoplasm~e.8 :location~e.9 (s / skin~e.12 :ARG1-of (t / treat-04~e.11 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "TPA"~e.10))))) :ARG1-of (p2 / predominate-01~e.5) :time~e.13 (p4 / point~e.16 :mod (t2 / time~e.15) :mod (a2 / all~e.14))) :op2 (b / block-01~e.22 :ARG1 (a4 / affect-01~e.20 :mod (t3 / this~e.19)) :ARG3 (a5 / administer-01~e.26 :ARG1~e.27 (a6 / and :op1 (s4 / small-molecule :name (n3 / name :op1 "ATRA"~e.28)) :op2 s3~e.30))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.40 :op1 (f / figure~e.32 :mod "4A"~e.35 :location (r / row~e.39)) :op2 (d2 / data~e.41 :ARG1-of (s2 / show-01~e.43 :polarity~e.42 -~e.42))))) # ::id pmid_1943_2991.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We did not observe any changes in phosphorylation of c @-@ Raf ( RAF1 ) , the other Raf family member present in skin , with any of the treatments using an antibody to phospho @-@ serine 338 ( Fig . S2 , additional file 4 ) . # ::alignments 0-1.2 2-1.1 2-1.1.r 3-1 4-1.3.2 5-1.3 6-1.3.1.r 7-1.3.1 8-1.3.1.1.r 9-1.3.1.1.1.1 11-1.3.1.1.1.1 17-1.4.2.2 18-1.4.2.1.1.1.1 19-1.4.2.1.1 20-1.4.2 21-1.4 22-1.4.1.r 23-1.4.1 25-1.5.r 26-1.5.1 29-1.5 30-1.5.2 32-1.5.2.1 34-1.5.2.1.1.1.3 36-1.5.2.1.1.1.2.1 37-1.5.2.1.1.1.1 39-1.6.1.1 41-1.6.1.1.1 44-1.6.1.2 46-1.6.1.2.1 (o / observe-01~e.3 :polarity~e.2 -~e.2 :ARG0 (w / we~e.0) :ARG1 (c / change-01~e.5 :ARG1~e.6 (p / phosphorylate-01~e.7 :ARG1~e.8 (e / enzyme :name (n / name :op1 "c-Raf"~e.9,11))) :mod (a6 / any~e.4)) :condition (p3 / present~e.21 :location~e.22 (s / skin~e.23) :domain (m2 / member~e.20 :ARG1-of (i / include-91 :ARG2 (p2 / protein-family~e.19 :name (n3 / name :op1 "Raf"~e.18) :ARG1-of (m / mean-01 :ARG2 e))) :mod (o2 / other~e.17))) :condition~e.25 (t / treat-04~e.29 :mod (a / any~e.26) :ARG0-of (u / use-01~e.30 :ARG1 (a2 / antibody~e.32 :ARG0-of (c2 / counter-01 :ARG1 (a3 / amino-acid :mod 338~e.37 :name (n5 / name :op1 "serine"~e.36) :ARG3-of (p4 / phosphorylate-01~e.34)))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.39 :mod "S2"~e.41) :op2 (f2 / file~e.44 :mod 4~e.46 :ARG1-of (a5 / add-02))))) # ::id pmid_1943_2991.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok pMek1 @/@ 2 levels were increased and expression was localized predominantly to the inner surface of the cell membrane in TPA treated skin ( Fig . 4A , middle rows ) . # ::alignments 1-1.1.1 3-1.1.1.1 3-1.1.1.2 5-1.1 6-1 7-1.2.1 9-1.2 10-1.2.2 11-1.2.3.r 13-1.2.3.1 14-1.2.3 15-1.2.3.2.r 17-1.2.3.2.1 18-1.2.3.2 19-1.2.3.2.2.r 20-1.2.3.2.2.1.1.1.1 21-1.2.3.2.2.1 22-1.2.3.2.2 24-1.3.1 27-1.3.1.1 30-1.3.1.2.1 31-1.3.1.2 (a / and~e.6 :op1 (i / increase-01~e.5 :ARG1 (s / slash~e.1 :op1 (l / level~e.3 :quant-of (e / enzyme :name (n / name :op1 "Mek1") :ARG3-of (p / phosphorylate-01))) :op2 (l2 / level~e.3 :quant-of (e2 / enzyme :name (n2 / name :op1 "Mek2")) :ARG3-of p))) :op2 (l3 / localize-01~e.9 :ARG1 (e3 / express-03~e.7) :ARG1-of (p2 / predominate-01~e.10) :location~e.11 (s2 / surface~e.14 :mod (i2 / inner~e.13) :part-of~e.15 (m / membrane~e.18 :mod (c / cell~e.17) :location~e.19 (s3 / skin~e.22 :ARG1-of (t / treat-04~e.21 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "TPA"~e.20))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "4A"~e.27 :part (r / row~e.31 :location (m2 / middle~e.30))))) # ::id pmid_1943_2991.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This observation is notable since it has been shown that the translocation of pMek to the cell membrane results in lowering the threshold for activation of MAP kinase signal output [ @ 23 @ ] . # ::alignments 0-1.2.1.2 1-1.2.1 1-1.2.1.1 1-1.2.1.1.r 3-1.2 4-1 8-1.1 9-1.1.1.r 11-1.1.1.1 14-1.1.1.1.2.r 16-1.1.1.1.2.1 17-1.1.1.1.2 18-1.1.1 19-1.1.1.2.r 20-1.1.1.2 22-1.1.1.2.1 23-1.1.1.2.1.1.r 24-1.1.1.2.1.1 25-1.1.1.2.1.1.1.r 26-1.1.1.2.1.1.1.1.1.1.1 27-1.1.1.2.1.1.1.1.1 28-1.1.1.2.1.1.1.1 29-1.1.1.2.1.1.1 32-1.3.1.1.1 (c / cause-01~e.4 :ARG0 (s / show-01~e.8 :ARG1~e.9 (r / result-01~e.18 :ARG1 (t / translocate-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "Mek") :ARG3-of (p / phosphorylate-01)) :ARG2~e.14 (m / membrane~e.17 :mod (c2 / cell~e.16))) :ARG2~e.19 (l / lower-05~e.20 :ARG1 (t2 / threshold~e.22 :degree-of~e.23 (a / activate-01~e.24 :ARG1~e.25 (o / output~e.29 :mod (s2 / signal-07~e.28 :ARG0 (k / kinase~e.27 :name (n2 / name :op1 "MAP"~e.26))))))))) :ARG1 (n3 / notable-04~e.3 :ARG1 (t3 / thing~e.1 :ARG1-of~e.1 (o2 / observe-01~e.1) :mod (t4 / this~e.0))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 23~e.32)))) # ::id pmid_1943_2991.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As was observed for pB @-@ Raf , the increased levels of pMek1 @/@ 2 was blocked with co @-@ administration of ATRA . # ::alignments 2-1.3.1 6-1.3.1.1.1.1 9-1.1.2 10-1.1 14-1.1.1.1.1 16-1 22-1.2.1.1.1 (b / block-01~e.16 :ARG1 (l / level~e.10 :quant-of (e / enzyme :name (n / name :op1 "Mek1/2"~e.14) :ARG3-of (p / phosphorylate-01)) :ARG1-of (i / increase-01~e.9)) :ARG3 (c / coadminister-00 :ARG1 (s / small-molecule :name (n2 / name :op1 "ATRA"~e.22))) :ARG2-of (r / resemble-01 :ARG1 (o / observe-01~e.2 :ARG1 (e2 / enzyme :name (n3 / name :op1 "B-Raf"~e.6) :ARG3-of p)))) # ::id pmid_1943_2991.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Staining for pErk1 @/@ 2 was observed in pairs of scattered nuclei in control skin , with an increase in staining intensity for TPA treated skin , as would be predicted accompanying hyperproliferation . # ::alignments 0-1.1 4-1.1.1.2.1 6-1 7-1.2.r 8-1.2 9-1.2.1.r 10-1.2.1.1 11-1.2.1 12-1.2.1.2.r 13-1.2.1.2.1 14-1.2.1.2 18-1.1.2.1.1 20-1.1 21-1.1.2.1 22-1.1.2.1.1.1.r 23-1.1.2.1.1.1.1.1.2.1 24-1.1.2.1.1.1.1 25-1.1.2.1.1.1 30-1.1.2.1.1.2.1 31-1.1.2.1.1.2.1.2.1 (o / observe-01~e.6 :ARG1 (s / stain-01~e.0,20 :purpose (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n / name :op1 "Erk1/2"~e.4) :ARG3-of (p / phosphorylate-01)) :ARG0-of (h3 / have-03 :ARG1 (i / intensity~e.21 :ARG1-of (i2 / increase-01~e.18 :location~e.22 (s4 / skin~e.25 :ARG1-of (t / treat-04~e.24 :ARG2 (s5 / small-molecule :wiki "12-O-Tetradecanoylphorbol-13-acetate" :name (n3 / name :op1 "TPA"~e.23)))) :ARG1-of (c2 / cause-01 :ARG0 (p3 / predict-01~e.30 :ARG0 i2 :ARG1 (h2 / hyperproliferate-01 :ARG0-of (a / accompany-01~e.31)))))))) :location~e.7 (p2 / pair-01~e.8 :ARG1~e.9 (n2 / nucleus~e.11 :ARG1-of (s2 / scatter-01~e.10) :location~e.12 (s3 / skin~e.14 :mod (c / control~e.13))))) # ::id pmid_1943_2991.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fewer nuclei were stained for TPA+ATRA treated skin than for TPA treatment alone ( Fig . 4A , bottom rows ) . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 1-1.1 3-1 6-1.3.1 7-1.3 8-1.1.1.2.r 9-1.3.1.1.r 10-1.3.1.1.1.1.1 11-1.1.1.2 12-1.1.1.2.2 14-1.2.1 17-1.2.1.1 20-1.2.1.2.1 21-1.2.1.2 (s / stain-01~e.3 :ARG1 (n / nucleus~e.1 :quant (f / few~e.0 :degree~e.0 (m / more~e.0) :compared-to~e.8 (t2 / treat-04~e.11 :ARG2 s3 :mod (a2 / alone~e.12)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.14 :mod "4A"~e.17 :location (r / row~e.21 :location (b / bottom~e.20)))) :purpose (s2 / skin~e.7 :ARG1-of (t / treat-04~e.6 :ARG2~e.9 (a / and :op1 (s3 / small-molecule :name (n2 / name :op1 "TPA"~e.10)) :op2 (s4 / small-molecule :name (n3 / name :op1 "ATRA")))))) # ::id pmid_1943_2991.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We attempted to quantitate pErk1 @/@ 2 levels by determining the percent positive nuclei in the treated skin . # ::alignments 0-1.1 1-1 3-1.2 6-1.2.2.1.1.1 7-1.2.2 8-1.3.r 9-1.3 11-1.3.2 12-1.3.2.1.1 13-1.3.2.1 14-1.3.2.2.r 16-1.3.2.2.1 17-1.3.2.2 (a / attempt-01~e.1 :ARG0 (w / we~e.0) :ARG1 (q / quantitate-01~e.3 :ARG0 w :ARG1 (l / level~e.7 :quant-of (e / enzyme :name (n / name :op1 "Erk1/2"~e.6) :ARG3-of (p / phosphorylate-01)))) :instrument~e.8 (d / determine-01~e.9 :ARG0 w :ARG1 (p2 / percent~e.11 :quant-of (n2 / nucleus~e.13 :mod (p3 / positive~e.12)) :location~e.14 (s / skin~e.17 :ARG1-of (t / treat-04~e.16))))) # ::id pmid_1943_2991.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At all time points except 30 weeks , the percent positive pErk staining nuclei actually decreased in TPA treated skin compared to controls and TPA+ATRA skin ( data not shown ) . # ::alignments 1-1.4.2 2-1.4.1 2-1.4.3.1 2-1.4.r 3-1.4 4-1.4.3 5-1.4.3.1.1 6-1.4.3.1.2 9-1.1 10-1.1.1 12-1.1.2.1 13-1.1.2 14-1.2 15-1 16-1.3.r 17-1.3.1.1.1.1 18-1.3.1 19-1.3 20-1.6.r 22-1.6.1.1 23-1.6 25-1.6.1 25-1.6.2 27-1.5.1 28-1.5.1.1.1 28-1.5.1.1.1.r 29-1.5.1.1 (d / decrease-01~e.15 :ARG1 (p / percent~e.9 :mod (p2 / positive~e.10) :quant-of (n / nucleus~e.13 :ARG1-of (s6 / stain-01~e.12 :purpose (e / enzyme :name (n4 / name :op1 "Erk") :ARG3-of (p3 / phosphorylate-01))))) :ARG1-of (a / actual-02~e.14) :location~e.16 (s / skin~e.19 :ARG1-of (t / treat-04~e.18 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.17)))) :time~e.2 (p4 / point~e.3 :mod (t2 / time~e.2) :mod (a3 / all~e.1) :ARG2-of (e2 / except-01~e.4 :ARG1 (t3 / temporal-quantity~e.2 :quant 30~e.5 :unit (w / week~e.6)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.27 :ARG1-of (s7 / show-01~e.29 :polarity~e.28 -~e.28))) :compared-to~e.20 (a2 / and~e.23 :op1 (s3 / skin~e.25 :mod (c / control~e.22)) :op2 (s4 / skin~e.25 :mod (s5 / small-molecule :name (n3 / name :op1 "ATRA")) :mod s2))) # ::id pmid_1943_2991.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was due to the far greater number of total cells in the hyperplastic TPA treated skin . # ::alignments 0-1.2 2-1 3-1 5-1.1.2.1.1 6-1.1.2 6-1.1.2.1 6-1.1.2.1.r 7-1.1 8-1.1.1.r 9-1.1.1.1 10-1.1.1 11-1.1.1.2.r 13-1.1.1.2.1 14-1.1.1.2.2.1.1.1 15-1.1.1.2.2 16-1.1.1.2 (c / cause-01~e.2,3 :ARG0 (n / number~e.7 :quant-of~e.8 (c2 / cell~e.10 :mod (t / total~e.9) :location~e.11 (s / skin~e.16 :mod (h / hyperplasia~e.13) :ARG1-of (t2 / treat-04~e.15 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.14))))) :mod (g / great~e.6 :degree~e.6 (m / more~e.6 :degree (f / far~e.5)))) :ARG1 (t3 / this~e.0)) # ::id pmid_1943_2991.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To more precisely measure the levels of phosphorylation of the MAP kinase signaling proteins in this model , we performed Western blot analysis on epidermal lysates pooled from 5 mice per treatment group for each time point , from skin adjacent to the tissue that was embedded for sectioning and IHC . # ::alignments 1-1.3.4.1 2-1.3.4 2-1.3.4.r 3-1.3 5-1.3.2 6-1.3.2.1.r 7-1.3.2.1 8-1.3.2.1.1.r 10-1.3.2.1.1.1.1 11-1.3.2.1.1.1.2 12-1.3.2.1.1.2 14-1.3.3.r 15-1.3.3.1 16-1.3.3 18-1.1 19-1 20-1.2 21-1.2 25-1.2.1 26-1.2.1.2 27-1.2.1.2.1.r 28-1.2.1.2.1.1 29-1.2.1.2.1 30-1.2.1.2.1.2 31-1.2.1.2.1.2.1.1 32-1.2.1.2.1.2.1 33-1.2.1.2.2.r 34-1.2.1.2.2.2 35-1.2.1.2.2.1 36-1.2.1.2.2 38-1.2.1.3.r 39-1.2.1.3 43-1.2.1.3.1.1 46-1.2.1.3.1.1.1 47-1.2.1.3.1.1.1.1.r 48-1.2.1.3.1.1.1.1.1 49-1.2.1.3.1.1.1.1 (p / perform-02~e.19 :ARG0 (w / we~e.18) :ARG1 (i / immunoblot-01~e.20,21 :ARG2 (l / lysate~e.25 :mod (e / epidermis) :ARG1-of (p2 / pool-01~e.26 :source~e.27 (m / mouse~e.29 :quant 5~e.28 :ARG1-of (r / rate-entity-91~e.30 :ARG2 (g / group~e.32 :ARG1-of (t2 / treat-04~e.31)))) :time~e.33 (p3 / point~e.36 :mod (t3 / time~e.35) :mod (e2 / each~e.34))) :source~e.38 (s / skin~e.39 :ARG2-of (b / border-01 :ARG1 (t4 / tissue~e.43 :ARG1-of (e3 / embed-01~e.46 :purpose~e.47 (a2 / and~e.49 :op1 (s2 / section-01~e.48) :op2 (i2 / immunohistochemistry)))))))) :purpose (m2 / measure-01~e.3 :ARG0 w :ARG1 (l2 / level~e.5 :degree-of~e.6 (p4 / phosphorylate-01~e.7 :ARG1~e.8 (e4 / enzyme :name (n3 / name :op1 "MAP"~e.10 :op2 "kinase"~e.11) :ARG0-of (s3 / signal-07~e.12)))) :location~e.14 (m3 / model~e.16 :mod (t6 / this~e.15)) :manner~e.2 (p6 / precise~e.2 :degree (m4 / more~e.1)))) # ::id pmid_1943_2991.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using 10 weeks as a representative time point , co @-@ administration of ATRA with TPA resulted in a lower level of pB @-@ Raf , pMek1 @/@ 2 and pErk1 @/@ 2 , than with TPA treatment alone ( Fig . 4B compare TPA and TPA+ATRA lanes ) . # ::alignments 0-1.3 1-1.3.1.1 2-1.3.1.2 5-1.3.1.3 6-1.3.1 6-1.3.1.3.1.1 7-1.3.1.3.1 13-1.1.1.1.1.1 15-1.1.1.2.1.1 16-1 17-1.2.r 19-1.2 19-1.2.2 19-1.2.2.r 20-1.2.1.1 20-1.2.1.2 20-1.2.1.3 24-1.2.1.1.1.1.1 28-1.2.1.2.1.1.1 28-1.2.1.3.1.1.1 29-1.2.1 32-1.2.1.2.1.1.1 32-1.2.1.3.1.1.1 34-1.2.3.r 36-1.2.3.1.1.1 37-1.2.3 38-1.2.3.1.2 40-1.4.1 43-1.4.1.1 45-1.4.1.2 46-1.1.1.2.1.1 46-1.2.3.1.1.1 47-1.1.1 49-1.4.1.2.1 49-1.4.1.2.2 (r / result-01~e.16 :ARG1 (c / coadminister-00 :ARG1 (a / and~e.47 :op1 (s / small-molecule :name (n / name :op1 "ATRA"~e.13)) :op2 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.15,46)))) :ARG2~e.17 (l / low-04~e.19 :ARG1 (a2 / and~e.29 :op1 (l2 / level~e.20 :quant-of (e / enzyme :name (n3 / name :op1 "B-Raf"~e.24) :ARG3-of (p / phosphorylate-01)) :mod (s4 / small-molecule)) :op2 (l3 / level~e.20 :quant-of (e2 / enzyme :name (n4 / name :op1 "Mek1/2"~e.28,32) :ARG3-of p)) :op3 (l4 / level~e.20 :quant-of (e3 / enzyme :name (n5 / name :op1 "Erk1/2"~e.28,32) :ARG3-of p))) :degree~e.19 (m / more~e.19) :compared-to~e.34 (t / treat-04~e.37 :ARG2 (s3 / small-molecule :name (n6 / name :op1 "TPA"~e.36,46) :mod (a3 / alone~e.38)))) :ARG2-of (u / use-01~e.0 :ARG1 (t2 / temporal-quantity~e.6 :quant 10~e.1 :unit (w / week~e.2) :ARG0-of (r2 / represent-01~e.5 :ARG1 (p2 / point~e.7 :mod (t3 / time~e.6))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "4B"~e.43 :ARG0-of (c2 / compare-01~e.45 :ARG1 (l5 / lane~e.49 :mod s2) :ARG2 (l7 / lane~e.49 :mod s :mod s2))))) # ::id pmid_1943_2991.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the same time there is an increase in the protein levels of total Erk1 @/@ 2 with TPA treatment that is suppressed by ATRA . # ::alignments 2-1.3.1 3-1.3 3-1.3.r 7-1 11-1.1 12-1.1.1.r 13-1.1.1.2 14-1.1.1.1.1 16-1.1.1.1.1 17-1.2.r 18-1.2.1.1.1 19-1.2 22-1.4 23-1.4.1.r 24-1.4.1.1.1 (i / increase-01~e.7 :ARG1 (l / level~e.11 :quant-of~e.12 (e / enzyme :name (n / name :op1 "Erk1/2"~e.14,16) :mod (t3 / total~e.13))) :condition~e.17 (t / treat-04~e.19 :ARG2 (s / small-molecule :name (n2 / name :op1 "TPA"~e.18))) :time~e.3 (t2 / time~e.3 :ARG1-of (s4 / same-01~e.2)) :ARG1-of (s2 / suppress-01~e.22 :ARG0~e.23 (s3 / small-molecule :name (n3 / name :op1 "ATRA"~e.24)))) # ::id pmid_1943_2991.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results from both IHC and Western blot analysis indicate that suppression of pB @-@ Raf , pMek1 @/@ 2 , and pErk1 @/@ 2 levels by ATRA . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1.1.2.r 5-1.1.2 6-1.1.2.2.1 7-1.1.2.2.1 8-1.1.2.1 8-1.1.2.2 9-1 10-1.2.r 11-1.2 15-1.2.2.1.1.1.1 19-1.2.2.2.1.1.1 19-1.2.2.3.1.1.1 21-1.2.2 24-1.2.2.2.1.1.1 24-1.2.2.3.1.1.1 25-1.2.2.1 25-1.2.2.2 25-1.2.2.3 26-1.2.1.r 27-1.2.1.1.1 (i / indicate-01~e.9 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :source~e.2 (a / and~e.5 :op1 (a3 / analyze-01~e.8 :mod (i3 / immunohistochemistry)) :op2 (a2 / analyze-01~e.8 :manner (i2 / immunoblot-01~e.6,7)))) :ARG1~e.10 (s / suppress-01~e.11 :ARG0~e.26 (s2 / small-molecule :name (n3 / name :op1 "ATRA"~e.27)) :ARG1 (a4 / and~e.21 :op1 (l / level~e.25 :quant-of (e / enzyme :name (n4 / name :op1 "B-Raf"~e.15) :ARG3-of (p / phosphorylate-01))) :op2 (l2 / level~e.25 :quant-of (e2 / enzyme :name (n5 / name :op1 "Mek1/2"~e.19,24) :ARG3-of p)) :op3 (l3 / level~e.25 :quant-of (e3 / enzyme :name (n6 / name :op1 "Erk1/2"~e.19,24) :ARG3-of p))))) # ::id pmid_1943_2991.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok P38 and JNK branches of the MAP Kinase cascade are not suppressed by ATRA treatment # ::alignments 1-1.3.1.1.1.1 2-1.3 3-1.3.2.1.1.1 4-1.3.1 4-1.3.2 7-1.3.3.1.1 8-1.3.3.1.2 11-1.1 11-1.1.r 12-1 13-1.2.r 14-1.2.1.1.1 15-1.2 (s / suppress-01~e.12 :polarity~e.11 -~e.11 :ARG0~e.13 (t / treat-04~e.15 :ARG2 (s2 / small-molecule :name (n / name :op1 "ATRA"~e.14))) :ARG1 (a / and~e.2 :op1 (b / branch~e.4 :mod (e / enzyme :name (n2 / name :op1 "P38"~e.1))) :op2 (b2 / branch-01~e.4 :mod (e2 / enzyme :name (n3 / name :op1 "JNK"~e.3))) :part-of (p / pathway :name (n4 / name :op1 "MAP"~e.7 :op2 "Kinase"~e.8)))) # ::id pmid_1943_2991.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The two other major MAP kinase signaling pathways besides the B @-@ Raf/Mek/Erk pathway are the Jun N @-@ terminal kinase ( JNK ) and p38 MAP kinase pathways . # ::alignments 1-1.1 2-1.4 3-1.5 4-1.2.1 5-1.2.2 6-1.3 7-1 7-1.6.1 8-1.6 10-1.6.1.1.1 13-1 14-1.7.r 16-1.7.1.1.1 17-1.7.1.1.2 19-1.7.1.1.2 20-1.7.1.1.3 24-1.7 25-1.7.2.1.1 26-1.2.1 26-1.7.2.1.2 27-1.2.2 27-1.7.2.1.3 28-1 28-1.7.1 28-1.7.2 (p3 / pathway~e.7,13,28 :quant 2~e.1 :name (n3 / name :op1 "MAP"~e.4,26 :op2 "kinase"~e.5,27) :ARG0-of (s / signal-07~e.6) :mod (o / other~e.2) :ARG1-of (m / major-02~e.3) :ARG2-of (e / except-01~e.8 :ARG1 (p4 / pathway~e.7 :name (n4 / name :op1 "B-Raf/Mek/Erk"~e.10))) :domain~e.14 (a / and~e.24 :op1 (p / pathway~e.28 :name (n / name :op1 "Jun"~e.16 :op2 "N-terminal"~e.17,19 :op3 "kinase"~e.20)) :op2 (p2 / pathway~e.28 :name (n2 / name :op1 "p38"~e.25 :op2 "MAP"~e.26 :op3 "kinase"~e.27)))) # ::id pmid_1943_2991.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to confirm our previous microarray results , which suggested that these pathways were less important in regards to ATRA suppression of TPA induced tumor promotion , we performed IHC on tissue sections taken at the 7 week time point from the same 2 @-@ stage skin carcinogenesis experiment as above . # ::alignments 0-1.4.r 1-1.4.r 2-1.4.r 3-1.4 4-1.4.2.4 4-1.4.2.4.r 5-1.4.2.2 6-1.4.2.3 7-1.4.2 7-1.4.2.1 7-1.4.2.1.r 10-1.4.2.5 11-1.4.2.5.1.r 12-1.4.2.5.1.2.1 13-1.4.2.5.1.2 14-1.4.2.5.1.2.r 15-1.4.2.5.1.1 16-1.4.2.5.1 19-1.4.2.5.1.3.r 20-1.4.2.5.1.3.1.1.1 21-1.4.2.5.1.3 22-1.4.2.5.1.3.2.r 23-1.4.2.5.1.3.2.1.1.1.1.1 24-1.4.2.5.1.3.2.1.1 25-1.4.2.5.1.3.2.1 26-1.4.2.5.1.3.2 28-1.1 29-1 31-1.3.r 32-1.3.1 33-1.3 34-1.3.2 37-1.3.2.2.2.1 38-1.3.2.2.2.2 39-1.3.2.2.1 39-1.3.2.2.2 39-1.3.2.2.r 40-1.3.2.2 41-1.3.2.1.r 43-1.3.2.1.4 44-1.3.2.1.2.1 46-1.3.2.1.2 47-1.3.2.1.1.1 48-1.3.2.1.1 49-1.3.2.1 50-1.3.2.2.r 51-1.3.2.1.3.1 (p / perform-02~e.29 :ARG0 (w / we~e.28) :ARG1 (i3 / immunohistochemistry) :location~e.31 (s / section-01~e.33 :ARG1 (t2 / tissue~e.32) :ARG1-of (t3 / take-01~e.34 :ARG2~e.41 (e / experiment-01~e.49 :ARG1 (c / carcinogenesis~e.48 :mod (s2 / skin~e.47)) :mod (s3 / stage~e.46 :mod 2~e.44) :ARG1-of (r / resemble-01 :ARG2 (a / above~e.51)) :ARG1-of (s8 / same-01~e.43)) :time~e.39,50 (p2 / point~e.40 :mod (t4 / time~e.39) :mod (t5 / temporal-quantity~e.39 :quant 7~e.37 :unit (w2 / week~e.38))))) :purpose~e.0,1,2 (c2 / confirm-01~e.3 :ARG0 w :ARG1 (t6 / thing~e.7 :ARG2-of~e.7 (r2 / result-01~e.7) :time (p3 / previous~e.5) :mod (m / microarray~e.6) :poss~e.4 w~e.4 :ARG0-of (s4 / suggest-01~e.10 :ARG1~e.11 (i / important~e.16 :degree (l / less~e.15) :domain~e.14 (p4 / pathway~e.13 :mod (t7 / this~e.12)) :topic~e.19 (s5 / suppress-01~e.21 :ARG0 (s6 / small-molecule :name (n2 / name :op1 "ATRA"~e.20)) :ARG1~e.22 (p5 / promote-01~e.26 :ARG1 (t8 / tumor~e.25 :ARG2-of (i2 / induce-01~e.24 :ARG0 (s7 / small-molecule :name (n3 / name :op1 "TPA"~e.23))))))))))) # ::id pmid_1943_2991.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using antibodies to phosphorylated ( activated ) p38 ( Thr180/Tyr182 ) , and JNK ( Thr183/Tyr185 ) we observed that , unlike the B @-@ Raf , Mek1 @/@ 2 and Erk1 @/@ 2 proteins , neither p38 nor JNK were increased in phosphorylation upon TPA treatment ( Fig . 5A , compare TPA panels to Control ) . # ::alignments 0-1.3 1-1.3.1 3-1.2.2 5-1.3.1.1.1.1.2.2.1 7-1.2.2.1.1.1.1 7-1.3.1.1.1.1.1.1 12-1.2.2.1 12-1.3.1.1.1 13-1.2.2.1.2.1.1 13-1.3.1.1.1.2.1.1 17-1.1 18-1 21-1.2.2.2 21-1.2.2.2.1 23-1.2.2.2.2.1.1.1 25-1.2.2.2.2.1.1.1 27-1.2.2.2.2.2.1.1 28-1.3.1.1.1.1.2.1 29-1.2.2.2.2.2.1.1 29-1.2.2.2.2.3.1.1 30-1.2.2.2.2 31-1.2.2.2.2.3.1.1 32-1.3.1.1.1.1.2.1 32-1.3.1.1.1.2.2.1 33-1.2.2.2.2.2.1.1 33-1.2.2.2.2.3.1.1 36-1.2.1.r 36-1.2.2.2.1.r 37-1.2.2.1.1.1.1 38-1.2.1 38-1.2.1.r 39-1.2.2.1.2.1.1 41-1.2 43-1.2.2 43-1.3.1.1.1.1.2 43-1.3.1.1.1.2.2 45-1.2.3.2.1.1 46-1.2.3 48-1.4.1 51-1.4.1.1 54-1.4.1.2 55-1.4.1.2.1.1 56-1.4.1.2.1 57-1.4.1.2.2.r 58-1.4.1.2.2 (o / observe-01~e.18 :ARG0 (w / we~e.17) :ARG1 (i / increase-01~e.41 :polarity~e.36,38 -~e.38 :ARG1 (p / phosphorylate-01~e.3,43 :ARG1 (a3 / and~e.12 :op1 (e / enzyme :name (n / name :op1 "p38"~e.7,37)) :op2 (e2 / enzyme :name (n2 / name :op1 "JNK"~e.13,39))) :ARG1-of (r / resemble-01~e.21 :polarity~e.36 -~e.21 :ARG2 (a2 / and~e.30 :op1 (e5 / enzyme :name (n4 / name :op1 "B-Raf"~e.23,25)) :op2 (e6 / enzyme :name (n5 / name :op1 "Mek1/2"~e.27,29,33)) :op3 (e7 / enzyme :name (n6 / name :op1 "Erk1/2"~e.29,31,33))))) :condition (t / treat-04~e.46 :ARG0 a3 :ARG2 (s / small-molecule :name (n3 / name :op1 "TPA"~e.45)))) :ARG2-of (u / use-01~e.0 :ARG1 (a / antibody~e.1 :ARG0-of (c3 / counter-01 :ARG1 (a7 / and~e.12 :op1 (e3 / enzyme :name (n7 / name :op1 "p38"~e.7) :ARG3-of (p2 / phosphorylate-01~e.43 :ARG1 (s3 / slash~e.28,32 :op1 (a5 / amino-acid :mod 180 :name (n8 / name :op1 "threonine")) :op2 (a6 / amino-acid :mod 182 :name (n9 / name :op1 "threonine"))) :ARG1-of (m / mean-01 :ARG2 (a11 / activate-01~e.5)))) :op2 (e4 / enzyme :name (n10 / name :op1 "JNK"~e.13) :ARG3-of (p6 / phosphorylate-01~e.43 :ARG1 (s2 / slash~e.32 :op1 (a9 / amino-acid :mod 183 :name (n11 / name :op1 "threonine")) :op2 (a10 / amino-acid :mod 185 :name (n12 / name :op1 "threonine"))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.48 :mod "5A"~e.51 :ARG0-of (c / compare-01~e.54 :ARG1 (p7 / panel~e.56 :mod s~e.55) :ARG2~e.57 (c2 / control~e.58))))) # ::id pmid_1943_2991.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , the phosphorylation levels of p38 and JNK were not suppressed by co @-@ administration of ATRA with TPA ( Fig . 5A , compare TPA and TPA+ATRA panels ) . # ::alignments 0-1.5 3-1.3.1 4-1.3 5-1.3.1.1.r 6-1.3.1.1.1.1.1 7-1.3.1.1 8-1.3.1.1.2.1.1 10-1.1 10-1.1.r 11-1 17-1.2.1.1.1.1 19-1.2.1.2.1.1 21-1.4.1 24-1.4.1.1 27-1.4.1.2 28-1.2.1.2.1.1 29-1.2.1 29-1.4.1.2.2 31-1.4.1.2.1 31-1.4.1.2.2.1 31-1.4.1.2.2.2 (s / suppress-01~e.11 :polarity~e.10 -~e.10 :ARG0 (c / coadminister-00 :ARG1 (a / and~e.29 :op1 (s2 / small-molecule :name (n / name :op1 "ATRA"~e.17)) :op2 (s3 / small-molecule :name (n2 / name :op1 "TPA"~e.19,28)))) :ARG1 (l / level~e.4 :degree-of (p / phosphorylate-01~e.3 :ARG1~e.5 (a2 / and~e.7 :op1 (e / enzyme :name (n3 / name :op1 "p38"~e.6)) :op2 (e2 / enzyme :name (n4 / name :op1 "JNK"~e.8))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "5A"~e.24 :ARG0-of (c2 / compare-01~e.27 :ARG1 (p2 / panel~e.31 :mod s3) :ARG2 (a3 / and~e.29 :op1 (p3 / panel~e.31 :mod s3) :op2 (p4 / panel~e.31 :mod s2))))) :mod (i / important~e.0)) # ::id pmid_1943_2991.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This observation was confirmed by Western blotting using the same phospho @-@ specific antibodies , as well as antibodies to total p38 and total JNK ( Fig . 5B ) . # ::alignments 0-1.2.1 1-1.2 3-1 4-1.1.r 5-1.1 6-1.1 7-1.3 9-1.3.1.1.2 10-1.3.1.1.1.1 12-1.3.1.1.1 13-1.3.1.1 15-1.3.1 15-1.3.1.2.1.1 16-1.3.1 16-1.3.1.2.1.1 17-1.3.1 17-1.3.1.2.1.1 18-1.3.1.1 18-1.3.1.2 20-1.3.1.2.1.1.1.2 21-1.3.1.2.1.1.1.1.1 23-1.3.1.2.1.1.1.2 24-1.3.1.2.1.1.2.1.1 26-1.3.1.2.2.1 29-1.3.1.2.2.1.1 (c / confirm-01~e.3 :ARG0~e.4 (i / immunoblot-01~e.5,6) :ARG1 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG2-of (u / use-01~e.7 :ARG1 (a / and~e.15,16,17 :op1 (a2 / antibody~e.13,18 :ARG1-of (s / specific-02~e.12 :ARG2 (p / phosphorylate-01~e.10)) :ARG1-of (s2 / same-01~e.9)) :op2 (a3 / antibody~e.18 :ARG0-of (c2 / counter-01 :ARG1 (a4 / and~e.15,16,17 :op1 (e / enzyme :name (n2 / name :op1 "p38"~e.21) :mod (t3 / total~e.20,23)) :op2 (e2 / enzyme :name (n3 / name :op1 "JNK"~e.24) :mod t3))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "5B"~e.29)))))) # ::id pmid_1943_2991.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly we observed a modest increase in p38 phosphorylation in the skin treated with ATRA alone , suggesting that the p38 pathway could play a role in mediating retinoid effects in skin . # ::alignments 0-1.3 1-1.1 2-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1 8-1.2.1 9-1.2.3.r 11-1.2.3 12-1.2.3.1 13-1.2.3.1.1.r 14-1.2.3.1.1.1.1 15-1.2.3.1.1.2 17-1.2.4 18-1.2.4.1.r 20-1.2.4.1.1.1.1.1 21-1.2.4.1.1.1 22-1.2.4.1 23-1.2.4.1.1 26-1.2.4.1.1.2.r 27-1.2.4.1.1.2 28-1.2.4.1.1.2.1.1.1.1 29-1.2.4.1.1.2.1 30-1.2.4.1.1.2.1.2.r 31-1.2.4.1.1.2.1.2 (o / observe-01~e.2 :ARG0 (w / we~e.1) :ARG1 (i / increase-01~e.5 :ARG1~e.6 (p / phosphorylate-01~e.8 :ARG1 p4~e.7) :ARG2 (m / modest~e.4) :location~e.9 (s / skin~e.11 :ARG1-of (t / treat-04~e.12 :ARG2~e.13 (s2 / small-molecule :name (n2 / name :op1 "ATRA"~e.14) :mod (a2 / alone~e.15)))) :ARG0-of (s3 / suggest-01~e.17 :ARG1~e.18 (p2 / possible-01~e.22 :ARG1 (p3 / play-02~e.23 :ARG0 (p4 / pathway~e.21 :name (n3 / name :op1 "p38"~e.20)) :ARG1~e.26 (m2 / mediate-01~e.27 :ARG1 (a / affect-01~e.29 :ARG0 (s4 / small-molecule :name (n4 / name :op1 "retinoid"~e.28)) :ARG1~e.30 (s5 / skin~e.31))))))) :ARG2-of (i2 / interest-01~e.0)) # ::id pmid_1943_2991.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sorafenib suppresses cell growth in TPA @-@ induced tumors # ::alignments 1-1.1.1.1 2-1 3-1.2.1 4-1.2 5-1.3.r 6-1.3.1.1.1.1 8-1.3.1 9-1.3 (s / suppress-01~e.2 :ARG0 (s2 / small-molecule :name (n / name :op1 "Sorafenib"~e.1)) :ARG1 (g / grow-01~e.4 :ARG1 (c / cell~e.3)) :location~e.5 (t / tumor~e.9 :ARG2-of (i / induce-01~e.8 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA"~e.6))))) # ::id pmid_1943_2991.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We hypothesize that ATRA exerts its tumor suppressive effect by blocking B @-@ Raf/Mek/Erk signaling . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1 4-1.2 6-1.2.2.2.2 8-1.2.2 9-1.2.3.r 10-1.2.3 11-1.2.3.1.1.1.1 14-1.2.3.1 (h / hypothesize-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (e / exert-01~e.4 :ARG0 (s / small-molecule :name (n / name :op1 "ATRA"~e.3)) :ARG1 (a / affect-01~e.8 :ARG0 s :ARG2 (s2 / suppress-01 :ARG0 s :ARG1 (t / tumor~e.6))) :instrument~e.9 (b / block-01~e.10 :ARG1 (s3 / signal-07~e.14 :ARG0 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk"~e.11))) :ARG3 s))) # ::id pmid_1943_2991.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This predicts that blocking this pathway through another means should also suppress tumorigenesis and @/@ or the growth of tumors . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1 4-1.2.1.1.1.1 5-1.2.1.1.1 7-1.2.1.1.2.1 8-1.2.1.1.2 9-1.2 10-1.2.1.3 11-1.2.1 12-1.2.1.2.1 12-1.2.1.2.1.1 12-1.2.1.2.1.1.r 13-1.2.1.2 15-1.2.1.2 17-1.2.1.2.2 18-1.2.1.2.2.1.r 19-1.2.1.2.2.1 (p / predict-01~e.1 :ARG0 (t / this~e.0) :ARG1~e.2 (r / recommend-01~e.9 :ARG1 (s / suppress-01~e.11 :ARG0 (b / block-01~e.3 :ARG1 (p2 / pathway~e.5 :mod t~e.4) :manner (m / mean~e.8 :mod (a2 / another~e.7))) :ARG1 (a / and-or~e.13,15 :op1 (c / create-01~e.12 :ARG1~e.12 (t2 / tumor~e.12)) :op2 (g / grow-01~e.17 :ARG1~e.18 (t3 / tumor~e.19))) :mod (a3 / also~e.10)))) # ::id pmid_1943_2991.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this prediction we have used a novel Raf inhibiting bi @-@ aryl urea compound from Bayer Pharmaceuticals called BAY 43 @-@ 9006 , or Sorafenib [ @ 24 @ ] . # ::alignments 1-1.3 2-1.3.2.1 3-1.3.2 4-1.1 6-1 9-1.2.3.1.2.1 10-1.2.3 14-1.2.1 15-1.2 16-1.2.2.r 17-1.2.2.2.1 18-1.2.2.2.2 19-1.2.2.2.r 19-1.2.5 19-1.2.5.1.1.2.r 20-1.2.5.1.1.2.1 21-1.2.5.1.1.2.2 23-1.2.5.1.1.2.2 25-1.2.5.1 26-1.2.5.1.2.2.1 29-1.4.1.1.1 (u / use-01~e.6 :ARG0 (w / we~e.4) :ARG1 (c / compound~e.15 :mod (u2 / urea~e.14) :source~e.16 (c2 / company :wiki "Bayer" :name~e.19 (n2 / name :op1 "Bayer"~e.17 :op2 "Pharmaceuticals"~e.18)) :ARG0-of (i / inhibit-01~e.10 :ARG1 (e / enzyme :wiki "RAF_kinase" :name (n5 / name :op1 "Raf"~e.9))) :mod (b / biaryl) :ARG1-of (c3 / call-01~e.19 :ARG2 (o / or~e.25 :op1 (s / small-molecule :wiki - :name~e.19 (n / name :op1 "BAY"~e.20 :op2 "43-9006"~e.21,23)) :op2 (s2 / small-molecule :wiki "Sorafenib" :name (n3 / name :op1 "Sorafenib"~e.26))))) :ARG2 (t / test-01~e.1 :ARG0 w :ARG1 (p / predict-01~e.3 :mod (t2 / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG0-of (c4 / cite-01 :ARG2 24~e.29)))) # ::id pmid_1943_2991.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This compound has been shown to inhibit MAP kinase signaling in colon , pancreatic and breast cancer cell lines , as well as inhibit tumor growth in colon , breast and non @-@ small @-@ cell lung cancer mouse xenograft models . # ::alignments 0-1.1.1.1.1 1-1.1.1.1 4-1 6-1.1.1 7-1.1.1.2.1.1.1 8-1.1.1.2.1 9-1.1.1.2 11-1.1.1.3.2.1.2.1 13-1.1.1.3.1.1.2.1 14-1.1.1.3 15-1.1.1.3.3.1.2.1 16-1.1.1.3.3.1.2.2 17-1.1.1.3.1 18-1.1.1.3.1 18-1.1.1.3.2 18-1.1.1.3.3 20-1.1.1.3 21-1.1.1.3 22-1.1 22-1.1.1.3 22-1.1.2.3 23-1.1.1 23-1.1.2 24-1.1.2.2.1 25-1.1.2.2 27-1.1.1.3.2.1.2.1 30-1.1.1.3 31-1.1.2.3.3.3.3.1.1 31-1.1.2.3.3.3.3.1.1.r 33-1.1.2.3.3.3.3.1 35-1.1.2.3.3.3.3 36-1.1.2.3.3.3.2.1 37-1.1.2.3.3.3.2.2 38-1.1.2.3.1.1 39-1.1.2.3.1.2 40-1.1.2.3.1 40-1.1.2.3.2 40-1.1.2.3.3 (s / show-01~e.4 :ARG1 (a / and~e.22 :op1 (i / inhibit-01~e.6,23 :ARG0 (c / compound~e.1 :mod (t / this~e.0)) :ARG1 (s2 / signal-07~e.9 :ARG0 (k / kinase~e.8 :name (n / name :op1 "MAP"~e.7))) :location (a2 / and~e.14,20,21,22,30 :op1 (c2 / cell-line~e.17,18 :mod (d / disease :wiki "Pancreatic_cancer" :name (n2 / name :op1 "pancreatic"~e.13 :op2 "cancer"))) :op2 (c4 / cell-line~e.18 :mod (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon"~e.11,27 :op2 "cancer"))) :op3 (c7 / cell-line~e.18 :mod (d3 / disease :wiki "Breast_cancer" :name (n4 / name :op1 "breast"~e.15 :op2 "cancer"~e.16))))) :op2 (i2 / inhibit-01~e.23 :ARG0 c :ARG1 (g / grow-01~e.25 :ARG1 (t2 / tumor~e.24)) :location (a3 / and~e.22 :op1 (m / model~e.40 :mod (m2 / mouse~e.38) :mod (x / xenograft~e.39) :mod d2) :op2 (m3 / model~e.40 :mod m2 :mod x :mod d3) :op3 (m4 / model~e.40 :mod m2 :mod x :mod (d4 / disease :wiki "Lung_cancer" :name (n5 / name :op1 "lung"~e.36 :op2 "cancer"~e.37) :mod (c10 / cell~e.35 :mod (s3 / small~e.33 :polarity~e.31 -~e.31)))))))) # ::id pmid_1943_2991.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumor @-@ bearing SENCAR mice that had been treated topically with TPA , twice weekly for 27 weeks , were treated with Sorafenib either topically or by gavage , as described in the Materials and Methods . # ::alignments 0-1.1.1.1 2-1.1.1 4-1.1 8-1 8-1.1.2 9-1.1.2.4 11-1.1.2.1.1.1 13-1.1.2.3.1 13-1.1.2.3.r 14-1.1.2.3 14-1.1.2.3.2.1 16-1.1.2.2.1 17-1.1.2.2.2 20-1.1.2 21-1.2.r 22-1.2.1.1 24-1.3.1 25-1.3 26-1.3.r 27-1.3.2 29-1.4.r 30-1.4 33-1.4.1.1.1 34-1.4.1.1 35-1.4.1.1.2 (t / treat-04~e.8 :ARG1 (m / mouse~e.4 :ARG0-of (b / bear-01~e.2 :ARG1 (t3 / tumor~e.0)) :ARG1-of (t4 / treat-04~e.8,20 :ARG2 (s / small-molecule :name (n2 / name :op1 "TPA"~e.11)) :duration (t5 / temporal-quantity :quant 27~e.16 :unit (w / week~e.17)) :frequency~e.13 (r / rate-entity-91~e.14 :ARG1 2~e.13 :ARG2 (t6 / temporal-quantity :quant 1~e.14 :unit w)) :manner (t7 / topic~e.9)) :ARG0-of (s3 / sensitive-03 :ARG1 (c / carcinogen))) :ARG2~e.21 (s2 / small-molecule :name (n3 / name :op1 "Sorafenib"~e.22)) :manner~e.26 (o / or~e.25 :op1 t7~e.24 :op2 (g / gavage~e.27)) :ARG1-of~e.29 (d / describe-01~e.30 :ARG0 (t9 / title-01 :ARG1 (a / and~e.34 :op1 (m2 / material~e.33) :op2 (m3 / method~e.35))))) # ::id pmid_1943_2991.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mice were photographed twice weekly to monitor tumor morphology and size . # ::alignments 0-1.1 2-1 3-1.2.1 3-1.2.r 4-1.2 4-1.2.2.1 4-1.2.2.2 6-1.3 7-1.3.1.1.1 8-1.3.1.1 9-1.3.1 10-1.3.1.2 (p / photograph-01~e.2 :ARG1 (m / mouse~e.0) :frequency~e.3 (r / rate-entity-91~e.4 :ARG1 2~e.3 :ARG2 (t / temporal-quantity :quant 1~e.4 :unit (w / week~e.4))) :purpose (m2 / monitor-01~e.6 :ARG1 (a / and~e.9 :op1 (m3 / morphology~e.8 :mod (t2 / tumor~e.7)) :op2 (s / size~e.10 :mod t2)))) # ::id pmid_1943_2991.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumors that received only topical acetone solvent , along with the TPA treatment , displayed the exophytic papilloma morphology normally observed in TPA @-@ treated mice in this model ( Fig . 6A ) . # ::alignments 0-1.1 2-1.1.1 3-1.1.1.2 4-1.1.1.1.1.1 6-1.1.1.1.1 6-1.1.1.1.1.2 6-1.1.1.1.1.2.r 9-1.1.1.1.r 11-1.1.1.1.2.2.1.1 12-1.1.1.1.2 14-1 16-1.2.2 17-1.2.1 18-1.2 19-1.2.3.2 20-1.2.3 21-1.2.3.1.r 22-1.2.3.1.1.1 24-1.2.3.1.1 25-1.2.3.1 26-1.2.3.3.r 27-1.2.3.3.1 28-1.2.3.3 30-1.3.1 33-1.3.1.1 (d / display-01~e.14 :ARG0 (t / tumor~e.0 :ARG0-of (r / receive-01~e.2 :ARG1~e.9 (a / and :op1 (s / solvent~e.6 :mod (t2 / topic~e.4) :mod~e.6 (s3 / solvent~e.6)) :op2 (t3 / treat-04~e.12 :ARG1 t :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.11)))) :mod (o / only~e.3))) :ARG1 (m / morphology~e.18 :mod (p / papilloma~e.17) :mod (e / exophytic~e.16) :ARG1-of (o2 / observe-01~e.20 :location~e.21 (m2 / mouse~e.25 :ARG1-of (t4 / treat-04~e.24 :ARG2 s2~e.22)) :ARG1-of (n3 / normal-02~e.19) :location~e.26 (m3 / model~e.28 :mod (t5 / this~e.27)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.30 :mod "6A"~e.33))) # ::id pmid_1943_2991.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The histological appearance of these tumors was also typical of TPA @-@ induced papillomas ( Fig . 6E ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1 5-1.1.1 7-1.3 8-1 10-1.2.1.1.1.1 12-1.2.1 15-1.4.1 18-1.4.1.1 (t / typical-02~e.8 :ARG1 (a / appear-01~e.2 :ARG1~e.3 (t2 / tumor~e.5 :mod (t3 / this~e.4)) :mod (h / histology~e.1)) :ARG2 (p / papilloma :ARG2-of (i / induce-01~e.12 :ARG0 (s / small-molecule :name (n / name :op1 "TPA"~e.10)))) :mod (a2 / also~e.7) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod "6E"~e.18))) # ::id pmid_1943_2991.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumors receiving topical Sorafenib at either concentration displayed a dried and darkened appearance that was reminiscent of human keratoacanthoma ( Fig . 6 , compare A to B and data not shown ) . # ::alignments 0-1.1 1-1.1.1 3-1.1.1.1.1.1 5-1.1.1.1.2.1 6-1.1.1.1 6-1.1.1.1.2 6-1.1.1.1.2.r 7-1 9-1.2.2 12-1.2 17-1.2.4.1.1 18-1.2.4.1 20-1.3.1.1 20-1.3.1.1.2.1 20-1.3.1.1.2.2 23-1.3.1.1.1 26-1.3.1.1.2 30-1.3.1 31-1.3.1.2 32-1.3.1.2.1.1 32-1.3.1.2.1.1.r 33-1.3.1.2.1 (d / display-01~e.7 :ARG0 (t / tumor~e.0 :ARG0-of (r / receive-01~e.1 :ARG1 (s / small-molecule~e.6 :name (n / name :op1 "Sorafenib"~e.3) :ARG1-of~e.6 (c / concentrate-02~e.6 :mod (e / either~e.5))))) :ARG1 (a2 / appear-01~e.12 :ARG1 t :ARG1-of (d2 / dry-08~e.9) :ARG1-of (d3 / dark-02) :ARG0-of (r2 / reminisce-01 :ARG1 (k / keratoacanthoma~e.18 :mod (h / human~e.17)))) :ARG1-of (d4 / describe-01 :ARG0 (a4 / and~e.30 :op1 (f / figure~e.20 :mod 6~e.23 :ARG0-of (c2 / compare-01~e.26 :ARG1 (f2 / figure~e.20 :mod "6A") :ARG2 (f3 / figure~e.20 :mod "6B"))) :op2 (d5 / data~e.31 :ARG1-of (s2 / show-01~e.33 :polarity~e.32 -~e.32))))) # ::id pmid_1943_2991.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histological analysis of these tumors revealed that the bulk of the tumor mass was non @-@ cellular keratin , indicating a greatly enhanced level of squamous differentiation compared to the control TPA @-@ induced tumors ( Fig . 6 , compare E to F ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1 6-1.2.r 8-1.2.3.2 9-1.2.3.2.r 11-1.2.3.1 12-1.2.3 13-1.2.3.r 14-1.2.2.1 14-1.2.2.1.r 16-1.2.2 17-1.2.1.1 19-1.2.4 21-1.2.4.1.2.2 22-1.2.4.1.2 23-1.2.4.1 24-1.2.4.1.1.r 25-1.2.4.1.1.1 26-1.2.4.1.1 27-1.2.4.1.2.1.r 30-1.2.4.1.2.1.1 31-1.2.4.1.2.1.2.1.1.1 33-1.2.4.1.2.1.2 34-1.2.4.1.2.1 36-1.3.1 36-1.3.1.2.1 36-1.3.1.2.2 39-1.3.1.1 42-1.3.1.2 (r / reveal-01~e.5 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (t / tumor~e.4 :mod (t2 / this~e.3)) :mod (h / histology~e.0)) :ARG1~e.6 (p / protein :name (n / name :op1 "keratin"~e.17) :mod (c / cell~e.16 :polarity~e.14 -~e.14) :domain~e.13 (m / mass~e.12 :mod (t3 / tumor~e.11) :quant~e.9 (b / bulk~e.8)) :ARG0-of (i / indicate-01~e.19 :ARG1 (l / level~e.23 :degree-of~e.24 (d / differentiate-101~e.26 :mod (s / squamous~e.25)) :ARG1-of (e / enhance-01~e.22 :compared-to~e.27 (t4 / tumor~e.34 :mod (c2 / control~e.30) :ARG2-of (i2 / induce-01~e.33 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.31)))) :degree (g / great~e.21))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.36 :mod 6~e.39 :ARG0-of (c3 / compare-01~e.42 :ARG1 (f2 / figure~e.36 :mod "6E") :ARG2 (f3 / figure~e.36 :mod "6F"))))) # ::id pmid_1943_2991.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the tumors of mice treated with Sorafenib by oral gavage did not differ drastically in outward appearance from the control TPA @-@ induced tumors . # ::alignments 0-1.6 3-1.2 4-1.2.1.r 5-1.2.1 6-1.2.1.1 7-1.2.1.1.1.r 8-1.2.1.1.1.1.1 9-1.2.1.1.2.r 10-1.2.1.1.2.1 11-1.2.1.1.2 13-1.1 13-1.1.r 14-1 15-1.5 16-1.4.r 17-1.4.1 18-1.4 19-1.3.r 21-1.3.1 22-1.3.2.1.1.1 24-1.3.2 25-1.3 (d / differ-02~e.14 :polarity~e.13 -~e.13 :ARG1 (t / tumor~e.3 :poss~e.4 (m / mouse~e.5 :ARG1-of (t2 / treat-04~e.6 :ARG2~e.7 (s / small-molecule :name (n / name :op1 "Sorafenib"~e.8)) :manner~e.9 (g / gavage~e.11 :mod (o / oral~e.10))))) :ARG2~e.19 (t3 / tumor~e.25 :mod (c / control~e.21) :ARG2-of (i / induce-01~e.24 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA"~e.22)))) :ARG3~e.16 (a / appear-01~e.18 :mod (o2 / outward~e.17)) :mod (d2 / drastic~e.15) :ARG2-of (i2 / interest-01~e.0)) # ::id pmid_1943_2991.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However upon histological examination these tumors appear very similar to the tumors that received topical Sorafenib ( Fig . 6C and 6G ) . # ::alignments 0-1 2-1.1.2.1 3-1.1.2 4-1.1.1.1.1 5-1.1.1.1 6-1.1 7-1.1.1.3 8-1.1.1 9-1.1.1.2.r 11-1.1.1.2 13-1.1.1.2.1 14-1.1.1.2.1.1.2 15-1.1.1.2.1.1.1.1 17-1.2.1.1 17-1.2.1.2 20-1.2.1.1.1 22-1.2.1 24-1.2.1.2.1 (h2 / have-concession-91~e.0 :ARG2 (a / appear-02~e.6 :ARG1 (r / resemble-01~e.8 :ARG1 (t / tumor~e.5 :mod (t2 / this~e.4)) :ARG2~e.9 (t3 / tumor~e.11 :ARG0-of (r2 / receive-01~e.13 :ARG1 (s / small-molecule :name (n / name :op1 "Sorafenib"~e.15) :mod (t4 / topic~e.14)))) :degree (v / very~e.7)) :condition (e / examine-01~e.3 :mod (h / histology~e.2))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.22 :op1 (f / figure~e.17 :mod "6C"~e.20) :op2 (f2 / figure~e.17 :mod "6G"~e.24)))) # ::id pmid_1943_2991.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It was previously shown in the breast and colon tumor xenograft models that inhibition of tumor growth was closely associated with suppression of Erk1 @/@ 2 phosphorylation [ @ 24 @ ] . # ::alignments 2-1.3 3-1 4-1.1.r 6-1.1.1.2 7-1.1 8-1.1.2.2 9-1.2.1.1.1 10-1.1.1.1 11-1.1.1 11-1.1.2 13-1.2.1 15-1.2.1.1.1 16-1.2.1.1 18-1.2.3 19-1.2 20-1.2.2.r 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1.1.1 25-1.2.2.1.1.1.1 26-1.2.2.1 29-1.4.1.1.1 (s / show-01~e.3 :ARG0~e.4 (a / and~e.7 :op1 (m / model~e.11 :mod (x / xenograft~e.10) :mod (b / breast~e.6)) :op2 (m2 / model~e.11 :mod x :mod (c / colon~e.8))) :ARG1 (a2 / associate-01~e.19 :ARG1 (i / inhibit-01~e.13 :ARG1 (g / grow-01~e.16 :ARG1 (t / tumor~e.9,15))) :ARG2~e.20 (s2 / suppress-01~e.21 :ARG1~e.22 (p2 / phosphorylate-01~e.26 :ARG1 (e / enzyme :name (n / name :op1 "Erk1/2"~e.23,25)))) :ARG1-of (c2 / close-10~e.18)) :time (p / previous~e.2) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 24~e.29)))) # ::id pmid_1943_2991.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore stained paraffin @-@ embedded sections of the TPA @-@ induced tumors , with and without Sorafenib treatment , with the pErk1 @/@ 2 antibody . # ::alignments 0-1.1.1 1-1 2-1.1 3-1.1.2.2.1 5-1.1.2.2 6-1.1.2 7-1.1.2.1.r 9-1.1.2.1.1.1.1.1.1 11-1.1.2.1.1.1 12-1.1.2.1.1 12-1.1.2.1.2 15-1.1.2.1 16-1.1.2.1.2.1.1 16-1.1.2.1.2.1.1.r 17-1.1.2.1.1.2.1.1.1 18-1.1.2.1.1.2 18-1.1.2.1.2.1 24-1.1.3.1.1.1.1 25-1.1.3 (c / cause-01~e.1 :ARG1 (s / stain-01~e.2 :ARG0 (w / we~e.0) :ARG1 (s2 / section-01~e.6 :ARG1~e.7 (a2 / and~e.15 :op1 (t / tumor~e.12 :ARG2-of (i / induce-01~e.11 :ARG0 (s3 / small-molecule :name (n / name :op1 "TPA"~e.9))) :ARG1-of (t2 / treat-04~e.18 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "Sorafenib"~e.17)))) :op2 (t3 / tumor~e.12 :ARG1-of (t4 / treat-04~e.18 :polarity~e.16 -~e.16 :ARG2 s4) :ARG2-of i)) :ARG1-of (e / embed-01~e.5 :ARG2 (p / paraffin~e.3))) :ARG2 (a / antibody~e.25 :ARG0-of (c2 / counter-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk1/2"~e.24) :ARG3-of (p2 / phosphorylate-01)))))) # ::id pmid_1943_2991.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The number of nuclei and intensity of staining was reduced for Sorafenib treated tumors compared to the TPA only @-@ treated tumors ( Fig . 6H ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1 4-1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1 9-1 10-1.2.r 11-1.2.1.1.1.1 12-1.2.1 12-1.4.1 13-1.2 13-1.4 14-1.4.r 15-1.4.1.1.r 17-1.4.1.1.1.1 18-1.4.1.2 20-1.2.1 21-1.2 23-1.3.1 26-1.3.1.1 (r / reduce-01~e.9 :ARG1 (a / and~e.4 :op1 (n / number~e.1 :quant-of~e.2 (n2 / nucleus~e.3)) :op2 (i / intensity~e.5 :degree-of~e.6 (s / stain-01~e.7))) :location~e.10 (t / tumor~e.13,21 :ARG1-of (t2 / treat-04~e.12,20 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "Sorafenib"~e.11)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "6H"~e.26)) :compared-to~e.14 (t3 / tumor~e.13 :ARG1-of (t4 / treat-04~e.12 :ARG2~e.15 (s3 / small-molecule :name (n4 / name :op1 "TPA"~e.17)) :mod (o / only~e.18)))) # ::id pmid_1965_4571.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combination of cetuximab with chemoradiation , trastuzumab or MAPK inhibitors : mechanisms of sensitisation of cervical cancer cells ( PMID : 19654571 ) # ::alignments 0-1 1-1.1.r 2-1.1.1.1 3-1.3.1.1.r 6-1.2.2.1.1 7-1.2 8-1.2.3.1.1.1.1 9-1.2.3 9-1.2.3.1 9-1.2.3.1.r 11-1.3.1 15-1.3.1.1.1.1.2.1 16-1.3.1.1.1.1.2.2 17-1.3.1.1.1 (c / combine-01~e.0 :ARG1~e.1 (s2 / small-molecule :name (n3 / name :op1 "cetuximab"~e.2)) :ARG2 (o / or~e.7 :op1 (c4 / chemoradiate-00) :op2 (s3 / small-molecule :name (n5 / name :op1 "trastuzumab"~e.6)) :op3 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (i2 / inhibit-01~e.9 :ARG1 (p2 / protein-family :name (n6 / name :op1 "MAPK"~e.8))))) :ARG1-of (m2 / mean-01 :ARG2 (m3 / mechanism~e.11 :instrument-of~e.3 (s / sensitize-01 :ARG1 (c2 / cell~e.17 :mod (d2 / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical"~e.15 :op2 "cancer"~e.16)))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID19654571"))) # ::id pmid_1965_4571.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results : # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1965_4571.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab with cisplatin and radiation achieved maximum cytotoxic effects for A431 , Caski and C33A cells ( high , intermediate and low EGFR expression , respectively ) in CA . # ::alignments 0-1.1.1.1.1 2-1.1.2.1.1 3-1.1 4-1.1.3 5-1 6-1.2.4 7-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1.1.1.1 12-1.2.1.2.1.1 13-1.2.1 14-1.2.1.3.1.1 15-1.2.1.1 15-1.2.1.2 15-1.2.1.3 17-1.2.3.1.1.2 19-1.2.3.1.2.2 20-1.2.3.1 21-1.2.3.1.3.2 22-1.2.3.1.1.1.1.1 23-1.2.3.1.1 23-1.2.3.1.2 23-1.2.3.1.3 25-1.2.3.1.4 (a / achieve-01~e.5 :ARG0 (a6 / and~e.3 :op1 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.0)) :op2 (s2 / small-molecule :name (n4 / name :op1 "cisplatin"~e.2)) :op3 (r2 / radiate-01~e.4)) :ARG1 (a3 / affect-01~e.8 :ARG1~e.9 (a4 / and~e.13 :op1 (c2 / cell-line~e.15 :name (n5 / name :op1 "A431"~e.10)) :op2 (c3 / cell-line~e.15 :name (n6 / name :op1 "Caski"~e.12)) :op3 (c4 / cell-line~e.15 :name (n7 / name :op1 "C33A"~e.14))) :mod (c / cytotoxic~e.7) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and~e.20 :op1 (e2 / express-03~e.23 :ARG2 (e / enzyme :name (n / name :op1 "EGFR"~e.22)) :ARG1-of (h2 / high-02~e.17)) :op2 (e3 / express-03~e.23 :ARG2 e :degree (i / intermediate~e.19)) :op3 (e4 / express-03~e.23 :ARG2 e :ARG1-of (l2 / low-04~e.21)) :mod (r3 / respective~e.25))) :degree (m / maximum~e.6) :time (a2 / assay-01 :mod (c5 / clonogenic)))) # ::id pmid_1965_4571.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab efficiently decreased MAPK and AKT phosphorylation in A431 cells but slightly less in Caski and C33A cells . # ::alignments 0-1.1.1.1.1 1-1.1.3 2-1.1 2-1.2 3-1.1.2.1.1.1.1 4-1.1.2.1 5-1.1.2.1.2.1.1 6-1.1.2 7-1.1.4.r 8-1.1.4.1.1 9-1.1.4 10-1 11-1.2.3.1 12-1.2.3 13-1.2.4.r 14-1.2.4.1.1.1 15-1.2.4 16-1.2.4.2.1.1 17-1.2.4.1 17-1.2.4.2 (c2 / contrast-01~e.10 :ARG1 (d / decrease-01~e.2 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"~e.0)) :ARG1 (p2 / phosphorylate-01~e.6 :ARG1 (a3 / and~e.4 :op1 (e3 / enzyme :name (n / name :op1 "MAPK"~e.3)) :op2 (e2 / enzyme :name (n3 / name :op1 "AKT"~e.5)))) :manner (e / efficient-01~e.1) :location~e.7 (c / cell-line~e.9 :name (n4 / name :op1 "A431"~e.8))) :ARG2 (d2 / decrease-01~e.2 :ARG0 s2 :ARG1 a3 :ARG2 (l / less~e.12 :mod (s / slight~e.11)) :location~e.13 (a2 / and~e.15 :op1 (c3 / cell-line~e.17 :name (n5 / name :op1 "Caski"~e.14)) :op2 (c4 / cell-line~e.17 :name (n6 / name :op1 "C33A"~e.16))) :compared-to d)) # ::id pmid_1965_4571.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To check whether further EGFR , HER2 or MAPK inhibition would improve cetuximab 's cytotoxicity , we combined it with an EGFR tyrosine kinase inhibitor ( TKI ) , trastuzumab or a MEK1 @/@ 2 inhibitor ( PD98059 ) . # ::alignments 1-1.4 2-1.4.2.1 2-1.4.2.1.r 3-1.4.2.2 4-1.4.2.2 5-1.4.2.2 6-1.4.2.2 7-1.4.2.2 8-1.4.2.2 9-1.2 9-1.3.1 9-1.3.1.1 9-1.3.1.1.r 11-1.4.2 12-1.4.2.3.1.1.1 13-1.4.2.3.1.r 16-1.1 17-1 21-1.2.1.1.1.1 24-1.2 24-1.3.1 24-1.3.1.1 24-1.3.1.1.r 29-1.3.2.1.1 30-1.2.1 32-1.3.3.1.1.1.1 34-1.3.3.1.1.1.1 35-1.3.3 35-1.3.3.1 35-1.3.3.1.r 37-1.3.3.2.1.1.1 (c / combine-01~e.17 :ARG0 (w / we~e.16) :ARG1 (i / inhibit-01~e.9,24 :ARG1 (o / or~e.30 :op1 (e3 / enzyme :name (n4 / name :op1 "EGFR"~e.21)) :op2 (e4 / enzyme :name (n5 / name :op1 "HER2")) :op3 (e / enzyme :name (n6 / name :op1 "MAPK"))) :degree (f / further)) :ARG2 (o2 / or :op1 (m / molecular-physical-entity~e.9,24 :ARG0-of~e.9,24 (i2 / inhibit-01~e.9,24 :ARG1 e3)) :op2 (s / small-molecule :name (n8 / name :op1 "trastuzumab"~e.29)) :op3 (m2 / molecular-physical-entity~e.35 :ARG0-of~e.35 (i3 / inhibit-01~e.35 :ARG1 (e2 / enzyme :name (n9 / name :op1 "MEK1/2"~e.32,34))) :ARG1-of (m3 / mean-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "PD98059"~e.37))))) :purpose (c2 / check-01~e.1 :ARG0 w :ARG1 (i4 / improve-01~e.11 :mode~e.2 interrogative~e.2 :ARG0 i~e.3,4,5,6,7,8 :ARG1 (c3 / cytotoxic :domain~e.13 (s2 / small-molecule :name (n10 / name :op1 "cetuximab"~e.12)))))) # ::id pmid_1965_4571.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In Caski , but not in C33A cells , cetuximab cooperated with the TKI , reducing cell survival and AKT and MAPK phosphorylation . # ::alignments 1-1.1.4.1.1 3-1 4-1.2.1 4-1.2.1.r 6-1.2.4.1.1 7-1.1.4 7-1.2.4 9-1.1.1.1.1 10-1.1 10-1.2 15-1.1.3 16-1.1.3.2.1.1 17-1.1.3.2.1 18-1.1.3.2 19-1.1.3.2.2.1.1.1.1 20-1.1.3.2.2.1 21-1.1.3.2.2.1.2.1.1 22-1.1.3.2.2 (c3 / contrast-01~e.3 :ARG1 (c / cooperate-01~e.10 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"~e.9)) :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (k / kinase :mod (t / tyrosine)))) :ARG2 (r2 / reduce-01~e.15 :ARG0 s2 :ARG1 (a / and~e.18 :op1 (s / survive-01~e.17 :ARG0 (c6 / cell~e.16)) :op2 (p2 / phosphorylate-01~e.22 :ARG1 (a2 / and~e.20 :op1 (e / enzyme :name (n6 / name :op1 "AKT"~e.19)) :op2 (e2 / enzyme :name (n / name :op1 "MAPK"~e.21)))))) :location (c2 / cell-line~e.7 :name (n4 / name :op1 "Caski"~e.1))) :ARG2 (c4 / cooperate-01~e.10 :polarity~e.4 -~e.4 :ARG0 s2 :ARG1 m :location (c5 / cell-line~e.7 :name (n5 / name :op1 "C33A"~e.6)))) # ::id pmid_1965_4571.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , cetuximab with trastuzumab or PD98059 reduced survival and MAPK phosphorylation of both cell lines . # ::alignments 0-1 2-1.1.1.1.1.1 4-1.1.1.2.1.1.1 5-1.1.1.2 6-1.1.1.2.2.1.1 7-1.1 8-1.1.2.1 9-1.1.2 10-1.1.2.2.1.1.1 11-1.1.2.2 12-1.1.2.1.1.r 13-1.1.2.1.1.1 14-1.1.2.1.1 15-1.1.2.1.1 (h / have-concession-91~e.0 :ARG2 (r / reduce-01~e.7 :ARG0 (a2 / and :op1 (s3 / small-molecule :name (n2 / name :op1 "cetuximab"~e.2)) :op2 (o / or~e.5 :op1 (s4 / small-molecule :name (n3 / name :op1 "trastuzumab"~e.4)) :op2 (s / small-molecule :name (n4 / name :op1 "PD98059"~e.6)))) :ARG1 (a / and~e.9 :op1 (s2 / survive-01~e.8 :ARG0~e.12 (c / cell-line~e.14,15 :mod (b / both~e.13))) :op2 (p2 / phosphorylate-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "MAPK"~e.10)) :location c)))) # ::id pmid_1965_4571.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_1965_4571.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Differential effects of RxT , cisplatin and cetuximab on cell proliferation and cell @-@ cycle kinetics # ::alignments 1-1.3 2-1 6-1.1.2.1.1 7-1.1 8-1.1.3.1.1 9-1.2.r 10-1.2.1.1 11-1.2.1 12-1.2 13-1.2.2.1.1 15-1.2.2.1 16-1.2.2 (a / affect-01~e.2 :ARG0 (a2 / and~e.7 :op1 (r2 / radiotherapy) :op2 (s / small-molecule :name (n2 / name :op1 "cisplatin"~e.6)) :op3 (s2 / small-molecule :name (n3 / name :op1 "cetuximab"~e.8))) :ARG1~e.9 (a3 / and~e.12 :op1 (p2 / proliferate-01~e.11 :ARG0 (c / cell~e.10)) :op2 (k / kinetics~e.16 :mod (c2 / cycle-02~e.15 :ARG1 (c3 / cell~e.13)))) :mod (d / differential~e.1)) # ::id pmid_1965_4571.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We examined the antiproliferative effects of isolated RxT , cisplatin and cetuximab treatments on A431 , Caski and C33A cells ( Figures 1A @–@ F ) , which express high to low EGFR levels , respectively ( see Figures 3A and 5A ) . # ::alignments 0-1.1 1-1 3-1.2.3 3-1.2.3.1 3-1.2.3.1.r 4-1.2 5-1.2.1.r 6-1.2.1.1.1 9-1.2.1.2.1.1.1 10-1.2.1 11-1.2.1.3.1.1.1 12-1.2.1.2 12-1.2.1.3 13-1.2.2.r 14-1.2.2.1.1.1 16-1.2.2.2.1.1 17-1.2.2 18-1.2.2.3.1.1 19-1.2.2.1 19-1.2.2.2 19-1.2.2.3 22-1.3.1.1 22-1.3.1.2 23-1.3.1.1.1 30-1.2.2.4 31-1.2.2.4.1.1.2 33-1.2.2.4.1.2.2 34-1.2.2.4.1.1.1.1.1 35-1.2.2.4.1.1 35-1.2.2.4.1.2 37-1.2.2.4.2 39-1.2.2.4.3.1.3 40-1.2.2.4.3.1.1 40-1.2.2.4.3.1.2 41-1.2.2.4.3.1.1.1 42-1.2.2.4.3.1 43-1.2.2.4.3.1.2.1 (e2 / examine-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / affect-01~e.4 :ARG0~e.5 (a2 / and~e.10 :op1 (r3 / radiotherapy :ARG1-of (i / isolate-01~e.6)) :op2 (t3 / treat-04~e.12 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "cisplatin"~e.9))) :op3 (t2 / treat-04~e.12 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "cetuximab"~e.11)))) :ARG1~e.13 (a3 / and~e.17 :op1 (c / cell-line~e.19 :name (n5 / name :op1 "A431"~e.14)) :op2 (c2 / cell-line~e.19 :name (n6 / name :op1 "Caski"~e.16)) :op3 (c3 / cell-line~e.19 :name (n7 / name :op1 "C33A"~e.18)) :ARG3-of (e3 / express-03~e.30 :ARG2 (v2 / value-interval :op1 (l / level~e.35 :quant-of (e / enzyme :name (n / name :op1 "EGFR"~e.34)) :ARG1-of (h / high-02~e.31)) :op2 (l2 / level~e.35 :quant-of e :ARG1-of (l3 / low-04~e.33))) :mod (r2 / respective~e.37) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.42 :op1 (f3 / figure~e.40 :mod "3A"~e.41) :op2 (f4 / figure~e.40 :mod "5A"~e.43) :ARG1-of (s / see-01~e.39 :ARG0 (y / you)))))) :ARG0-of (o / oppose-01~e.3 :ARG1~e.3 (p / proliferate-01~e.3))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.22 :mod "1A"~e.23) :op2 (f2 / figure~e.22 :mod "1F")))) # ::id pmid_1965_4571.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A431 growth is impaired by EGFR inhibitors ( Janmaat et al , 2003 ) , so we used this cell line for comparison with the CC cell lines . # ::alignments 0-1.2.1.1.1 1-1.2 3-1 4-1.1.r 5-1.1.1.1.1.1 6-1.1 6-1.1.1 6-1.1.1.r 9-1.3.1.1.1.1.1 11-1.3.1.1 12-1.3.1.1.2.1 15-1.3.1.2.1 19-1.4 20-1.4.1.1 21-1.4.1 23-1.4.1.2 24-1.4.1.3.2 26-1.4.1.3 30-1.4.1.3.1 31-1.4.1.3.1 (i2 / impair-01~e.3 :ARG0~e.4 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i3 / inhibit-01~e.6 :ARG1 (e2 / enzyme :name (n2 / name :op1 "EGFR"~e.5)))) :ARG1 (g / grow-01~e.1 :ARG1 (c / cell-line :name (n3 / name :op1 "A431"~e.0))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and~e.11 :op1 (p2 / person :name (n4 / name :op1 "Janmaat"~e.9)) :op2 (p3 / person :mod (o / other~e.12))) :time (d / date-entity :year 2003~e.15))) :ARG0-of (c2 / cause-01~e.19 :ARG1 (u / use-01~e.21 :ARG0 (w / we~e.20) :ARG1 c~e.23 :ARG2 (c4 / compare-01~e.26 :ARG1 c~e.30,31 :ARG2 (c5 / cell-line~e.24 :mod (d3 / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer"))))))) # ::id pmid_1965_4571.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A431 and Caski cells showed similar resistance to RxT and low cisplatin concentrations ( IC @₃₀ ) in CA and MTT assays ( Figures 1A and B ) , but Caski cells showed increased resistance at higher cisplatin concentrations ( IC @₅₀ and IC @₈₀ ; Figure 1B ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1.1.1 3-1.1.1.2 4-1.1 5-1.1.2.1.3 6-1.1.2.1 9-1.1.2 10-1.1.2.2.3 11-1.1.2.2.2.1.1 12-1.1.2.2 12-1.1.2.2.5.1 14-1.1.2.2 16-1.1.2.2.1 16-1.1.2.2.5.1.1.1.1 21-1.1.2.2.4 22-1.1.2.2.4.2.1.1.1 23-1.1.2.2.4.1 23-1.1.2.2.4.2 26-1.1.3.1.1 27-1.1.3.1.1.1 28-1.1.3.1 33-1 34-1.2.1 35-1.2.1 36-1.2 37-1.2.2.2 38-1.2.2 39-1.2.3.r 40-1.2.3.3 40-1.2.3.3.1 40-1.2.3.3.1.r 41-1.2.3.1 42-1.1.2.2.5.1 42-1.2.3 44-1.2.3.2.1.1 46-1.2.3.2.1.1.1 48-1.2.3.2.1 49-1.2.3.2.1.1 49-1.2.3.2.1.2 51-1.2.3.2.1.2.1 55-1.1.3.1.2 55-1.2.4.1 56-1.1.3.1.2.1 56-1.2.4.1.1 (c4 / contrast-01~e.33 :ARG1 (s2 / show-01~e.4 :ARG0 (a / and~e.1 :op1 (c / cell-line~e.3 :name (n2 / name :op1 "A431"~e.0)) :op2 (c2 / cell-line~e.3 :name (n3 / name :op1 "Caski"~e.2))) :ARG1 (a2 / and~e.9 :op1 (r2 / resist-01~e.6 :ARG0 a :ARG1 (r / radiotherapy) :ARG1-of (r3 / resemble-01~e.5)) :op2 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.12,14 :ARG2 30~e.16 :ARG1 (s / small-molecule :name (n5 / name :op1 "cisplatin"~e.11)) :ARG1-of (l / low-04~e.10) :time (a3 / and~e.21 :op1 (a4 / assay-01~e.23 :mod (c5 / clonogenic)) :op2 (a5 / assay-01~e.23 :instrument (s4 / small-molecule :name (n / name :op1 "MTT"~e.22)))) :ARG1-of (m4 / mean-01 :ARG2 (c7 / concentrate-02~e.12,42 :mod (i2 / inhibit-01 :degree (p / percentage-entity :value 30~e.16)))))) :ARG1-of (d / describe-01 :ARG0 (a6 / and~e.28 :op1 (f / figure~e.26 :mod "1A"~e.27) :op2 (f2 / figure~e.55 :mod "1B"~e.56)))) :ARG2 (s3 / show-01~e.36 :ARG0 c2~e.34,35 :ARG1 (r4 / resist-01~e.38 :ARG0 c2 :ARG1-of (i / increase-01~e.37)) :condition~e.39 (c6 / concentrate-02~e.42 :ARG1 s~e.41 :ARG1-of (m / mean-01 :ARG2 (a7 / and~e.48 :op1 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.44,49 :ARG2 50~e.46 :ARG1 s) :op2 (h4 / have-percentage-maximal-inhibitory-concentration-01~e.49 :ARG2 80~e.51 :ARG1 s))) :ARG1-of (h / high-02~e.40 :degree~e.40 (m2 / more~e.40))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.55 :mod "1B"~e.56)))) # ::id pmid_1965_4571.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C33A cells were , in turn , quite sensitive to both treatments ( Figures 1A and B ) . # ::alignments 0-1.1.1.1 1-1.1 4-1.4 5-1.4 7-1.3 8-1 9-1.2.r 10-1.2.1 11-1.2 14-1.5.1.1 14-1.5.1.2 15-1.5.1.1.1 16-1.5.1 (s / sensitive-03~e.8 :ARG0 (c / cell-line~e.1 :name (n / name :op1 "C33A"~e.0)) :ARG1~e.9 (t / treat-04~e.11 :mod (b / both~e.10)) :degree (q / quite~e.7) :mod (i / in-turn~e.4,5) :ARG1-of (d / describe-01 :ARG0 (a / and~e.16 :op1 (f / figure~e.14 :mod "1A"~e.15) :op2 (f2 / figure~e.14 :mod "1B")))) # ::id pmid_1965_4571.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab treatment decreased the viability of all cell lines in CA and MTT experiments at all concentrations tested ( Figures 1C and D ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 6-1.2.1.1 7-1.2.1 8-1.2.1 11-1.2.1.2.1 12-1.2.1.2.1.2.1.1.1 13-1.2.1.2 14-1.3.r 15-1.3.2 16-1.3 17-1.3.1 20-1.4.1.1 20-1.4.1.2 21-1.4.1.1.1 22-1.4.1 (d / decrease-01~e.2 :ARG0 (t / treat-04~e.1 :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.0))) :ARG1 (v / viable :mod (c / cell-line~e.7,8 :mod (a2 / all~e.6) :time (e / experiment-01~e.13 :ARG1 (a3 / and~e.11 :op1 (a4 / assay-01 :mod (c3 / clonogenic)) :op2 (a5 / assay-01 :instrument (s2 / small-molecule :name (n / name :op1 "MTT"~e.12))))))) :condition~e.14 (c2 / concentrate-02~e.16 :ARG1-of (t2 / test-01~e.17) :mod (a6 / all~e.15)) :ARG1-of (d2 / describe-01 :ARG0 (a7 / and~e.22 :op1 (f / figure~e.20 :mod "1C"~e.21) :op2 (f2 / figure~e.20 :mod "1D")))) # ::id pmid_1965_4571.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These effects were related to an increase of 14.1 , 12.6 and 6.5 % in cell number at G @₀@ /G @₁ for A431 , Caski and C33A cells on cetuximab treatment , respectively ( Figure 1E ) and a decrease in the population of cells at S and G @₂@ /M phases when compared to controls ( CT ; Figure 1E ) . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 6-1.2.1 6-1.2.2 6-1.2.3 8-1.2.1.2.1.1 10-1.2.2.2.1 11-1.2.1.2 12-1.2.3.2.1 13-1.2.1.2.1 13-1.2.2.2 13-1.2.3.2 15-1.2.1.1.1 15-1.2.2.1.1 15-1.2.3.1.1 16-1.2.1.1 16-1.2.2.1 16-1.2.3.1 27-1.2.1.1.1.1.1 29-1.2.2.1.1.1.1 30-1.2 31-1.2.3.1.1.1.1 32-1.2.1.1.1 33-1.2.1.4.r 34-1.2.1.4.1.1.1 35-1.2.1.4 40-1.2.4.3.1 41-1.2.4.3.1.1 44-1.2 46-1.2.4 47-1.2.4.1.r 49-1.2.4.1 50-1.2.4.1.1.r 51-1.2.4.1.1 54-1.2.4.2 60-1.2.4.2.1 60-1.2.4.2.2.1.1.1.2 60-1.2.4.2.2.1.2.1.2 61-1.2.4.2.r 62-1.2.4.4 63-1.2.4.4.1.r 64-1.2.4.4.1 69-1.2.4.3.1 69-1.3.1 70-1.2.4.3.1.1 70-1.3.1.1 (r / relate-01~e.3 :ARG1 (a5 / affect-01~e.1 :mod (t / this~e.0)) :ARG2~e.4 (a3 / and~e.30,44 :op1 (i / increase-01~e.6 :ARG1 (n / number~e.16 :quant-of (c2 / cell-line~e.15,32 :name (n2 / name :op1 "A431"~e.27))) :ARG2 (a / and~e.11 :op1 (p / percentage-entity~e.13 :value 14.1~e.8)) :time (s / slash :op1 (e / event :name (n8 / name :op1 "G0")) :op2 (e2 / event :name (n9 / name :op1 "G1"))) :condition~e.33 (t2 / treat-04~e.35 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "cetuximab"~e.34)))) :op2 (i2 / increase-01~e.6 :ARG1 (n6 / number~e.16 :quant-of (c3 / cell-line~e.15 :name (n3 / name :op1 "Caski"~e.29))) :ARG2 (p2 / percentage-entity~e.13 :value 12.6~e.10) :time s :condition t2) :op3 (i3 / increase-01~e.6 :ARG1 (n7 / number~e.16 :quant-of (c4 / cell-line~e.15 :name (n4 / name :op1 "C33A"~e.31))) :ARG2 (p3 / percentage-entity~e.13 :value 6.5~e.12) :time s :condition t2) :op4 (d2 / decrease-01~e.46 :ARG1~e.47 (p5 / population~e.49 :mod~e.50 (c5 / cell~e.51)) :time~e.61 (a4 / and~e.54 :op1 (p7 / phase~e.60 :mod (s4 / synthesize-01)) :op2 (t3 / time :mod (s2 / slash :op1 (e3 / event :name (n10 / name :op1 "G2" :op2 "phase"~e.60)) :op2 (e4 / event :name (n11 / name :op1 "M" :op2 "phase"~e.60))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.40,69 :mod "1E"~e.41,70)) :condition (c / compare-01~e.62 :ARG1~e.63 (c6 / control~e.64)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.69 :mod "1E"~e.70))) # ::id pmid_1965_4571.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Apoptotic cells are usually found in the sub @-@ G @₁ phases and , accordingly , 24 @-@ h cetuximab treatment increased this cell population by 4.6 , 3.9 and 2.9 % in A431 , Caski and C33A cells , respectively ( Figure 1E ) . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1.2 4-1.1 5-1.1.3.r 7-1.1.3.1.1 13-1.1.3.1.2 14-1 14-1.2 14-1.2.r 18-1.2.1.1.2.1 20-1.2.1.1.2.2 21-1.2.1.1.1.1.1 22-1.2.1.1 23-1.2.1 23-1.2.2 23-1.2.3 25-1.2.1.2.1 25-1.2.2.2.1 25-1.2.3.2.1 26-1.2.1.2 26-1.2.2.2 26-1.2.3.2 28-1.2.1.3.1 30-1.2.2.3.1 31-1.2 32-1.2.3.3.1 33-1.2.1.3 33-1.2.2.3 33-1.2.3.3 35-1.2.1.2.1.1.1 37-1.2.2.2.1.1.1 38-1.2 39-1.2.3.2.1.1.1 40-1.2.1.2.1 45-1.3.1 46-1.3.1.1 (a2 / and~e.14 :op1 (f / find-01~e.4 :ARG1 (c / cell~e.1 :mod (a / apoptotic~e.0)) :time (u / usual~e.3) :location~e.5 (e / event :name (n / name :op1 "sub-G1"~e.7 :op2 "phase"~e.13))) :op2~e.14 (a5 / and~e.14,31,38 :op1 (i / increase-01~e.23 :ARG0 (t / treat-04~e.22 :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.21)) :duration (t2 / temporal-quantity :quant 24~e.18 :unit (h / hour~e.20))) :ARG1 (p2 / population~e.26 :mod (c3 / cell-line~e.25,40 :name (n3 / name :op1 "A431"~e.35))) :ARG2 (p3 / percentage-entity~e.33 :value 4.6~e.28)) :op2 (i2 / increase-01~e.23 :ARG0 t :ARG1 (p6 / population~e.26 :mod (c4 / cell-line~e.25 :name (n4 / name :op1 "Caski"~e.37))) :ARG2 (p4 / percentage-entity~e.33 :value 3.9~e.30)) :op3 (i3 / increase-01~e.23 :ARG0 t :ARG1 (p7 / population~e.26 :mod (c2 / cell-line~e.25 :name (n5 / name :op1 "C33A"~e.39))) :ARG2 (p5 / percentage-entity~e.33 :value 2.9~e.32))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.45 :mod "1E"~e.46))) # ::id pmid_1965_4571.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , apoptotic cells were also observed by Hoechst staining in all cell lines after cetuximab treatment ( Figure 1F ) and , even in C33A cells , which express low EGFR levels , a reduction of 21 % in cell proliferation was obtained , especially at high MAb concentration ( 100 μ @ g ml @⁻¹ ; Figure 1D ) . # ::alignments 0-1 0-1.1 0-1.1.r 2-1.1.1.1.1.1 3-1.1.1.1.1 5-1.1.1.1.6 6-1.1.1.1 7-1.1.1.1.2.r 8-1.1.1.1.2.1.1.1 9-1.1.1.1.2 10-1.1.1.1.5.r 11-1.1.1.1.5.1 12-1.1.1.1.5 13-1.1.1.1.5 14-1.1.1.1.3 15-1.1.1.1.3.1.1.1.1 16-1.1.1.1.3.1 19-1.1.1.1.4.1 20-1.1.1.1.4.1.1 23-1.1 25-1.1.2.2.3 27-1.1.2.2.1.1 28-1.1.2.2 31-1.1.2.2.2 32-1.1.2.2.2.1.2 33-1.1.2.2.2.1.1.1.1 34-1.1.2.2.2.1 37-1.1.2.1 38-1.1.2.1.2.r 39-1.1.2.1.2.1 40-1.1.2.1.2 41-1.1.2.1.1.r 42-1.1.2.1.1.1 43-1.1.2.1.1 45-1.1.2 47-1.1.2.3.2 49-1.1.2.3.4 51-1.1.2.3 51-1.1.2.3.3.1 53-1.1.2.3.3.1.1 58-1.1.2.3.3.1.2 64-1.1.2.4.1 65-1.1.2.4.1.1 (a6 / and~e.0 :op2~e.0 (a7 / and~e.0,23 :op1 (a / add-01 :ARG1 (o / observe-01~e.6 :ARG1 (c / cell~e.3 :mod (a2 / apoptotic~e.2)) :instrument~e.7 (s / stain-01~e.9 :ARG2 (p3 / product :name (n5 / name :op1 "Hoechst"~e.8))) :time (a4 / after~e.14 :op1 (t / treat-04~e.16 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"~e.15)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "1F"~e.20)) :location~e.10 (c2 / cell-line~e.12,13 :mod (a3 / all~e.11)) :mod (a8 / also~e.5))) :op2 (o2 / obtain-01~e.45 :ARG1 (r2 / reduce-01~e.37 :ARG1~e.41 (p2 / proliferate-01~e.43 :ARG0 (c4 / cell~e.42)) :ARG2~e.38 (p / percentage-entity~e.40 :value 21~e.39)) :location (c3 / cell-line~e.28 :name (n3 / name :op1 "C33A"~e.27) :ARG1-of (e2 / express-03~e.31 :ARG2 (l / level~e.34 :quant-of (e / enzyme :name (n / name :op1 "EGFR"~e.33)) :ARG1-of (l3 / low-04~e.32))) :mod (e5 / even~e.25)) :condition (c5 / concentrate-02~e.51 :ARG1 (a5 / antibody :mod (m2 / monoclone)) :degree (e3 / especially~e.47) :ARG1-of (e4 / equal-01 :ARG2 (c6 / concentration-quantity~e.51 :quant 100~e.53 :unit (m / microgram-per-milliliter~e.58))) :ARG1-of (h2 / high-02~e.49)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.64 :mod "1D"~e.65))))) # ::id pmid_1965_4571.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab induces chemo @/@ radiosensitisation of CC cells # ::alignments 1-1.1.1.1 2-1 4-1.2 8-1.2.1.1 (i / induce-01~e.2 :ARG0 (s2 / small-molecule :name (n / name :op1 "cetuximab"~e.1)) :ARG1 (s / slash~e.4 :op1 (c / chemosensitize-00 :ARG1 (c2 / cell-line~e.8 :mod (d / disease :wiki "Cervical_cancer" :name (n2 / name :op1 "cervical" :op2 "cancer")))) :op2 (r / radiosensitize-00 :ARG1 c2))) # ::id pmid_1965_4571.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We evaluated whether the combination of cetuximab ( 100 μ @ g ml @⁻¹ ) with RxT and @/@ or cisplatin could enhance the cytotoxic effects observed in CA . # ::alignments 0-1.1 1-1 2-1.2.1.1 2-1.2.1.1.r 4-1.2.1.2 5-1.2.1.2.1.r 6-1.2.1.2.1.1.1 8-1.2.1.2.1.2.1 13-1.2.1.2.1.2.2 20-1.2.1.2.2 22-1.2.1.2.2 23-1.2.1.2.2.2.1.1 24-1.2 25-1.2.1 27-1.2.1.3.1 28-1.2.1.3 29-1.2.1.3.2 (e / evaluate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (p / possible-01~e.24 :ARG1 (e2 / enhance-01~e.25 :mode~e.2 interrogative~e.2 :ARG0 (c / combine-01~e.4 :ARG1~e.5 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.6) :quant (c2 / concentration-quantity :quant 100~e.8 :unit (m / microgram-per-milliliter~e.13))) :ARG2 (a / and-or~e.20,22 :op1 (r / radiotherapy) :op2 (s2 / small-molecule :name (n4 / name :op1 "cisplatin"~e.23)))) :ARG1 (a2 / affect-01~e.28 :ARG2 (c3 / cytotoxic~e.27) :ARG1-of (o / observe-01~e.29 :time (a3 / assay-01 :mod (c4 / clonogenic))))))) # ::id pmid_1965_4571.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Isolated cetuximab , cisplatin and RxT treatments decreased the survival of all cell lines ( Figures 2A @–@ D ) but the combination of cetuximab with either RxT or cisplatin enhanced these effects ( P @ < 0.05 ) . # ::alignments 0-1.1.1.1.1.2 1-1.1.1.1.1.1.1 3-1.1.1.2.1.1.1 4-1.1.1 6-1.1.1.1 6-1.1.1.2 6-1.1.1.3 7-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1 12-1.1.2.1 13-1.1.2.1 16-1.1.3.1.1 16-1.1.3.1.2 17-1.1.3.1.1.1 22-1 24-1.2.1 25-1.2.1.1.r 26-1.2.1.1 30-1.2.1.2 31-1.2.1.2.2 32-1.2 33-1.2.2.1 34-1.2.2 37-1.2.3 39-1.2.3.1 40-1.2.3.1.1 (c2 / contrast-01~e.22 :ARG1 (d / decrease-01~e.7 :ARG0 (a / and~e.4 :op1 (t2 / treat-04~e.6 :ARG2 (s2 / small-molecule :name (n / name :op1 "cetuximab"~e.1) :ARG1-of (i / isolate-01~e.0))) :op2 (t3 / treat-04~e.6 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "cisplatin"~e.3))) :op3 (t4 / treat-04~e.6 :ARG2 (r / radiotherapy))) :ARG1 (s / survive-01~e.9 :ARG0~e.10 (c / cell-line~e.12,13 :mod (a2 / all~e.11))) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.16 :mod "2A"~e.17) :op2 (f2 / figure~e.16 :mod "2D")))) :ARG2 (e / enhance-01~e.32 :ARG0 (c3 / combine-01~e.24 :ARG1~e.25 s2~e.26 :ARG2 (o / or~e.30 :op1 r :op2 s3~e.31)) :ARG1 (a3 / affect-01~e.34 :mod (t5 / this~e.33)) :ARG1-of (s4 / statistical-test-91~e.37 :ARG2 (l2 / less-than~e.39 :op1 0.05~e.40)))) # ::id pmid_1965_4571.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , the triple combination of cetuximab , cisplatin and RxT achieved maximum effects for all cell lines in CA ( demonstrative pictures of A431 cells are shown in Figure 2D ) . # ::alignments 0-1.1.1.1.2 3-1.1.1.1.3 4-1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1 8-1.1.1.1.2.1.1.1 11-1.1.1 12-1.1.1.2.1 13-1.1.1.2 14-1.1.1.3.r 15-1.1.1.3.1 16-1.1.1.3 17-1.1.1.3 22-1.2.1 24-1.2.1.1.1.1.1 25-1.2.1.1.1 27-1.2 30-1.2.2 31-1.2.2.1 (m2 / multi-sentence :snt1 (a / and :op2 (a2 / achieve-01~e.11 :ARG0 (c / combine-01~e.4 :ARG1~e.5 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.6)) :ARG2 (a3 / and~e.0 :op1 (s2 / small-molecule :name (n3 / name :op1 "cisplatin"~e.8)) :op2 (r / radiotherapy)) :mod (t / triple~e.3)) :ARG1 (a4 / affect-01~e.13 :degree (m / maximum~e.12)) :location~e.14 (c2 / cell-line~e.16,17 :mod (a5 / all~e.15)) :ARG1-of (d / describe-01) :time (a6 / assay-01 :mod (c4 / clonogenic)))) :snt2 (s3 / show-01~e.27 :ARG1 (p / picture~e.22 :ARG0-of (d2 / demonstrate-01 :ARG1 (c3 / cell-line~e.25 :name (n6 / name :op1 "A431"~e.24)))) :location (f / figure~e.30 :mod "2D"~e.31))) # ::id pmid_1965_4571.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Caski cells are HPV @-@ positive and express intermediate levels of EGFR and HER2 , resembling typical CC tumours . # ::alignments 0-1.1.2.1.1 1-1.1.2 2-1.1.2.r 3-1.1.1.1.1 5-1.1 6-1 7-1.2 8-1.2.1.1.2 9-1.2.1.1 9-1.2.1.2 10-1.2.1.1.1.r 11-1.2.1.1.1.1.1 12-1.2.1 13-1.2.1.2.1.1.1 15-1.2.2 16-1.2.2 17-1.2.2 18-1.2.2 (a / and~e.6 :op1 (p / positive~e.5 :topic (d / disease :name (n3 / name :op1 "HPV"~e.3)) :domain~e.2 (c / cell-line~e.1 :name (n4 / name :op1 "Caski"~e.0) :ARG1-of (r / resemble-01 :ARG2 (t / tumor :ARG0-of (t2 / typify-01) :mod (d2 / disease :wiki "Cervical_cancer" :name (n5 / name :op1 "cervical" :op2 "cancer")))))) :op2 (e3 / express-03~e.7 :ARG2 (a2 / and~e.12 :op1 (l / level~e.9 :quant-of~e.10 (e / enzyme :name (n / name :op1 "EGFR"~e.11)) :degree (i / intermediate~e.8)) :op2 (l2 / level~e.9 :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2"~e.13)) :degree i)) :ARG3 c~e.15,16,17,18)) # ::id pmid_1965_4571.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this cell line , the triple combination reached up to 70 % inhibition in CA ( Figure 2B ) whereas in C33A cells , an inhibition of 60 % was observed ( Figure 2C ) . # ::alignments 1-1.1.3.1 2-1.1.3 3-1.1.3 6-1.1.1.1 7-1.1.1 8-1.1 10-1.1.2.r 11-1.1.2.1.1 12-1.1.2.1 13-1.1.2 18-1.1.4.1 19-1.1.4.1.1 22-1 23-1.2.r 24-1.2.3.1.1 25-1.2.3 28-1.2.1 29-1.2.1.1.r 30-1.2.1.1.1 31-1.2.1.1 33-1.2 36-1.2.2.1 37-1.2.2.1.1 (c3 / contrast-01~e.22 :ARG1 (r / reach-01~e.8 :ARG0 (c2 / combine-01~e.7 :mod (t2 / triple~e.6)) :ARG1~e.10 (i / inhibit-01~e.13 :degree (p / percentage-entity~e.12 :value 70~e.11)) :location (c / cell-line~e.2,3 :mod (t / this~e.1)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "2B"~e.19)) :time (a / assay-01 :mod (c4 / clonogenic))) :ARG2~e.23 (o / observe-01~e.33 :ARG1 (i2 / inhibit-01~e.28 :degree~e.29 (p2 / percentage-entity~e.31 :value 60~e.30)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.36 :mod "2C"~e.37)) :location (c5 / cell-line~e.25 :name (n / name :op1 "C33A"~e.24)))) # ::id pmid_1965_4571.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The CC cell lines express different basal levels of total and phosphorylated EGFR , HER @-@ 2 , AKT and ERK1 @/@ 2 # ::alignments 3-1.2 4-1.2 5-1 6-1.1.1.1.1 7-1.1.1.1.3 8-1.1.1.1 8-1.1.1.2 8-1.1.2.1 8-1.1.2.2 8-1.1.3.1 8-1.1.3.2 8-1.1.4.1 8-1.1.4.2 9-1.1.1.1.2.r 10-1.1.1.1.2.2 11-1.1.1 12-1.1.1.2.1.2 13-1.1.1.1.2.1.1 13-1.1.1.2.1.1.1 15-1.1.2.1.1.1.1 15-1.1.2.2.1.1.1 17-1.1.2.1.1.1.1 17-1.1.2.2.1.1.1 19-1.1.3.1.1.1.1 19-1.1.3.2.1.1.1 20-1.1 21-1.1.4.1.1.1.1.1 21-1.1.4.2.1.1.1.1 22-1.1.4.1.1 22-1.1.4.2.1 23-1.1.2.1.1.1.1 23-1.1.2.2.1.1.1 (e2 / express-03~e.5 :ARG2 (a2 / and~e.20 :op1 (a / and~e.11 :op1 (l / level~e.8 :ARG0-of (d / differ-01~e.6) :quant-of~e.9 (e / enzyme :name (n / name :op1 "EGFR"~e.13) :mod (t / total~e.10)) :mod (b / basal~e.7)) :op2 (l2 / level~e.8 :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR"~e.13) :ARG3-of (p / phosphorylate-01~e.12)) :mod b :ARG0-of d)) :op2 (a3 / and :op1 (l3 / level~e.8 :quant-of (e4 / enzyme :name (n4 / name :op1 "HER-2"~e.15,17,23) :mod t) :mod b :ARG0-of d) :op2 (l4 / level~e.8 :quant-of (e5 / enzyme :name (n5 / name :op1 "HER-2"~e.15,17,23) :ARG3-of p) :mod b)) :op3 (a4 / and :op1 (l5 / level~e.8 :quant-of (e6 / enzyme :name (n6 / name :op1 "AKT"~e.19) :mod t) :mod b :ARG0-of d) :op2 (l6 / level~e.8 :quant-of (e7 / enzyme :name (n7 / name :op1 "AKT"~e.19) :ARG3-of p) :mod b :ARG0-of d)) :op4 (a5 / and :op1 (l7 / level~e.8 :quant-of (s / slash~e.22 :op1 (e8 / enzyme :name (n8 / name :op1 "ERK1"~e.21) :mod t) :op2 (e9 / enzyme :name (n9 / name :op1 "ERK2") :mod t)) :mod b :ARG0-of d) :op2 (l8 / level~e.8 :quant-of (s2 / slash~e.22 :op1 (e10 / enzyme :name (n10 / name :op1 "ERK1"~e.21) :ARG3-of p) :op2 (e11 / enzyme :name (n11 / name :op1 "ERK2") :ARG3-of p)) :mod b :ARG0-of d))) :ARG3 (c / cell-line~e.3,4 :mod (d2 / disease :wiki "Cervical_cancer" :name (n2 / name :op1 "cervical" :op2 "cancer")))) # ::id pmid_1965_4571.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A431 cells strongly express EGFR ( Janmaat et al , 2003 ) whereas Caski and C33A cells show moderate and low expression levels , respectively ( Figure 3A ) . # ::alignments 0-1.1.2.1.1 1-1.1.2 2-1.1.3 2-1.1.3.r 3-1.1 4-1.1.1.1.1 7-1.1.4.1.1.1.1.1 9-1.1.4.1.1 10-1.1.4.1.1.2.1 13-1.1.4.1.2.1 16-1 17-1.2.1.1.1.1 18-1.2.1 19-1.2.1.2.1.1 20-1.2.1.1 20-1.2.1.2 21-1.2 22-1.2.2.1.1.1 23-1.2.2 24-1.2.2.2.1.1 25-1.2.2.1.1 25-1.2.2.2.1 26-1.2.2.1 26-1.2.2.2 28-1.2.3 31-1.2.4.1 32-1.2.4.1.1 (c2 / contrast-01~e.16 :ARG1 (e2 / express-03~e.3 :ARG2 (e / enzyme :name (n / name :op1 "EGFR"~e.4)) :ARG3 (c / cell-line~e.1 :name (n2 / name :op1 "A431"~e.0)) :manner~e.2 (s / strong~e.2) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and~e.9 :op1 (p2 / person :name (n3 / name :op1 "Janmaat"~e.7)) :op2 (p3 / person :mod (o / other~e.10))) :time (d3 / date-entity :year 2003~e.13)))) :ARG2 (s2 / show-01~e.21 :ARG0 (a2 / and~e.18 :op1 (c3 / cell-line~e.20 :name (n4 / name :op1 "Caski"~e.17)) :op2 (c4 / cell-line~e.20 :name (n5 / name :op1 "C33A"~e.19))) :ARG1 (a3 / and~e.23 :op1 (l / level~e.26 :degree-of (e3 / express-03~e.25 :ARG1-of (m / moderate-03~e.22))) :op2 (l2 / level~e.26 :degree-of (e4 / express-03~e.25 :ARG1-of (l3 / low-04~e.24)))) :mod (r / respective~e.28) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.31 :mod "3A"~e.32)))) # ::id pmid_1965_4571.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , we confirmed EGFR expression by real @-@ time RT @-@ PCR and by FACS analysis . # ::alignments 0-1 2-1.1.1 3-1.1 4-1.1.2.1.1.1 5-1.1.2 6-1.1.3.r 7-1.1.3.1.1 9-1.1.3.1.1 12-1.1.3.1.2 12-1.1.3.1.2.1 12-1.1.3.1.2.1.r 13-1.1.3 16-1.1.3.1 16-1.1.3.2 (a / and~e.0 :op2 (c / confirm-01~e.3 :ARG0 (w / we~e.2) :ARG1 (e2 / express-03~e.5 :ARG2 (e / enzyme :name (n / name :op1 "EGFR"~e.4))) :instrument~e.6 (a3 / and~e.13 :op1 (a2 / analyze-01~e.16 :manner (r / real-time~e.7,9) :mod (r3 / react-01~e.12 :ARG0~e.12 (p / polymerase~e.12) :mod (c2 / chain) :subevent (t / transcribe-01 :ARG1-of (r2 / reverse-01)))) :op2 (a4 / analyze-01~e.16 :mod r :mod (s / sort-01 :ARG1 (c3 / cell) :ARG1-of (a5 / activate-01 :ARG0 (f / fluorescence))))))) # ::id pmid_1965_4571.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The relative EGFR mRNA level of A431 is high and Caski cells express two times more EGFR than C33A ( Figure 5A ) . # ::alignments 1-1.1.1.3 3-1.1.1.1.2.1.1.1 3-1.2.1.1.1 5-1.1.1.1.1.1 6-1.1.1 8-1.1.1.2.1.1 10-1.1 11-1 12-1.2.2.1.1 13-1.1.1.2 13-1.2.1.2.2.1.2.1 13-1.2.2 14-1.2 14-1.2.1.2.2.1 14-1.2.1.2.2.1.2 14-1.2.1.2.2.1.2.r 15-1.2.1.2.1 16-1.2.1.2 19-1.2.1.2.2.1.1.1 22-1.2.1.2.2.1.2.1.1.1 24-1.3.1 25-1.3.1.1 (a / and~e.11 :op1 (h / high-02~e.10 :ARG1 (l / level~e.6 :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.5) :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.3)))) :quant-of (c / cell-line~e.13 :name (n3 / name :op1 "A431"~e.8)) :ARG1-of (r2 / relative-05~e.1))) :op2 (e2 / express-03~e.14 :ARG2 (e3 / enzyme :name (n5 / name :op1 "EGFR"~e.3) :quant (p / product-of~e.16 :op1 2~e.15 :op2 (m / mass-quantity :quant-of (e5 / enzyme~e.14 :name (n8 / name :op1 "EGFR"~e.19) :ARG2-of~e.14 (e6 / express-03~e.14 :ARG3 (c3 / cell-line~e.13 :name (n6 / name :op1 "C33A"~e.22))))))) :ARG3 (c2 / cell-line~e.13 :name (n4 / name :op1 "Caski"~e.12))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "5A"~e.25))) # ::id pmid_1965_4571.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , FACS analysis showed that both a murine anti @-@ EGFR MAb and cetuximab could detect high EGFR expression on the surface of A431 cells and intermediate and low levels in Caski and C33A cells , respectively ( Figure 5B ) . # ::alignments 0-1 3-1.1.1 4-1.1 9-1.1.2.1.1.1.1 11-1.1.2.1.1.1.1.1.1.1 13-1.1.2.1.1 14-1.1.2.1.1.2.1.1 15-1.1.2 16-1.1.2.1 17-1.1.2.1.2.1.3 18-1.1.2.1.2.1.1 19-1.1.2.1.2.1 20-1.1.2.1.2.1.2.r 22-1.1.2.1.2.1.2 23-1.1.2.1.2.1.2.1.r 24-1.1.2.1.2.1.2.1.1.1 25-1.1.2.1.2.1.2.1 26-1.1.2.1.2 26-1.1.2.1.2.2 26-1.1.2.1.2.2.r 27-1.1.2.1.2.2.1.1 28-1.1.2.1.2.2 29-1.1.2.1.2.2.2.1 30-1.1.2.1.2.2.1 30-1.1.2.1.2.2.2 31-1.1.2.1.2.2.1.2.r 32-1.1.2.1.2.2.1.2.1.1 33-1.1.2.1.2.2 34-1.1.2.1.2.2.2.2.1.1 35-1.1.1.1.1 37-1.1.2.1.2.2.3 39-1.2.1 40-1.2.1.1 (a / and~e.0 :op2 (s / show-01~e.4 :ARG0 (a2 / analyze-01~e.3 :mod (s4 / sort-01 :ARG1 (c4 / cell~e.35) :ARG1-of (a4 / activate-01 :ARG0 (f2 / fluorescence)))) :ARG1 (p / possible-01~e.15 :ARG1 (d / detect-01~e.16 :ARG0 (a3 / and~e.13 :op1 (a7 / antibody :ARG0-of (o / oppose-01~e.9 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.11))) :mod (m / mouse)) :op2 (s3 / small-molecule :name (n3 / name :op1 "cetuximab"~e.14))) :ARG1 (a5 / and~e.26 :op1 (e2 / express-03~e.19 :ARG2 e~e.18 :ARG3~e.20 (s2 / surface~e.22 :poss~e.23 (c / cell-line~e.25 :name (n4 / name :op1 "A431"~e.24))) :ARG1-of (h2 / high-02~e.17)) :op2~e.26 (a6 / and~e.26,28,33 :op1 (l / level~e.30 :degree (i / intermediate~e.27) :location~e.31 (c2 / cell-line :name (n5 / name :op1 "Caski"~e.32))) :op2 (l2 / level~e.30 :ARG1-of (l3 / low-04~e.29) :location (c3 / cell-line :name (n6 / name :op1 "C33A"~e.34))) :mod (r2 / respective~e.37)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.39 :mod "5B"~e.40)) :mod (m2 / monoclone)) # ::id pmid_1965_4571.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok HER2 expression was more homogenous among the cell lines with Caski and C33A cells expressing 20 and 40 % more HER2 than A431 cells , respectively . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.r 3-1.2 4-1 7-1.3.1 8-1.3.1 10-1.3.1.1.1 11-1.3 12-1.3.2.1.1 13-1.3.1 13-1.3.2 14-1.3.1.2 14-1.3.2.2 15-1.3.1.2.1.2.1 16-1.3 17-1.3.2.2.1.2.1 18-1.3.1.2.1.2 18-1.3.2.2.1.2 19-1.3.1.2.1.2.2 19-1.3.2.2.1.2.2 20-1.3.1.2.1.1.1 20-1.3.2.2.1.1.1 21-1.3.1.2.1.2.3.r 21-1.3.2.2.1.2.3.r 22-1.3.1.2.1.2.3.1.1 23-1.3.1.2.1.2.3 (h / homogenous~e.4 :domain~e.2 (e2 / express-03~e.1 :ARG2 (e3 / enzyme :name (n2 / name :op1 "HER2"~e.0))) :degree (m / more~e.3) :location (a / and~e.11,16 :op1 (c / cell-line~e.7,8,13 :name (n3 / name :op1 "Caski"~e.10) :ARG3-of (e4 / express-03~e.14 :ARG2 (e5 / enzyme :name (n5 / name :op1 "HER2"~e.20) :quant (p2 / percentage-entity~e.18 :value 20~e.15 :mod (m2 / more~e.19) :compared-to~e.21 (c3 / cell-line~e.23 :name (n6 / name :op1 "A431"~e.22)))))) :op2 (c2 / cell-line~e.13 :name (n4 / name :op1 "C33A"~e.12) :ARG3-of (e6 / express-03~e.14 :ARG2 (e7 / enzyme :name (n7 / name :op1 "HER2"~e.20) :quant (p3 / percentage-entity~e.18 :value 40~e.17 :mod (m3 / more~e.19) :compared-to~e.21 c3)))))) # ::id pmid_1965_4571.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The basal phosphorylation status of EGFR and HER2 was inversely correlated , with higher levels of p @-@ EGFR in A431 cells and higher levels of p @-@ HER2 in C33A and Caski cells ( Figure 3A ) . # ::alignments 1-1.1.2 2-1.1.1 3-1.1 3-1.2 5-1.1.3.1.1 5-1.5.1.1.2.1.1 6-1.5.1 7-1.2.3.1.1 9-1.3 9-1.3.r 10-1 13-1.5.1.1.1 13-1.5.1.1.1.1 13-1.5.1.1.1.1.r 14-1.5.1.1 16-1.1.1 18-1.1.3.1.1 18-1.5.1.1.2.1.1 20-1.5.1.1.3.1.1 21-1.5.1.1.3 21-1.5.1.2.3.2 23-1.5.1.1.1 23-1.5.1.1.1.1 23-1.5.1.1.1.1.r 24-1.5.1.1 24-1.5.1.2 26-1.1.1 28-1.2.3.1.1 28-1.5.1.2.2.1.1 29-1.5.1.2.3.r 30-1.5.1.2.3.1.1.1 31-1.5.1.2.3 32-1.5.1.2.3.2.1.1 33-1.5.1.2.3.1 36-1.4.1 37-1.4.1.1 (c / correlate-01~e.10 :ARG1 (s / status~e.3 :topic (p / phosphorylate-01~e.2,16,26) :mod (b / basal~e.1) :poss (e / enzyme :name (n / name :op1 "EGFR"~e.5,18))) :ARG2 (s2 / status~e.3 :topic p :mod b :poss (e2 / enzyme :name (n2 / name :op1 "HER2"~e.7,28))) :manner~e.9 (i / inverse~e.9) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "3A"~e.37)) :ARG0-of (h2 / have-03 :ARG1 (a / and~e.6 :op1 (l / level~e.14,24 :ARG1-of (h / high-02~e.13,23 :degree~e.13,23 (m / more~e.13,23)) :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR"~e.5,18) :ARG3-of p) :location (c2 / cell-line~e.21 :name (n4 / name :op1 "A431"~e.20))) :op2 (l2 / level~e.24 :ARG1-of h :quant-of (e4 / enzyme :name (n5 / name :op1 "HER2"~e.28) :ARG3-of p) :location~e.29 (a3 / and~e.31 :op1 (c3 / cell-line~e.33 :name (n6 / name :op1 "C33A"~e.30)) :op2 (c4 / cell-line~e.21 :name (n7 / name :op1 "Caski"~e.32))))))) # ::id pmid_1965_4571.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On EGF binding , the major signalling pathways activated are the MAPK and AKT cascades ( Citri and Yarden , 2006 ) . # ::alignments 1-1.2.1.1.1.1 2-1.2.1 5-1.3 6-1.1 7-1 8-1.2 9-1.4.r 11-1.4.1.1.1 12-1.4 13-1.4.2.1.1 17-1.2.2.1.1.1.1.1 18-1.2.2.1.1 19-1.2.2.1.1.2.1.1 21-1.2.2.1.2.1 (p / pathway~e.7 :ARG0-of (s / signal-07~e.6) :ARG1-of (a / activate-01~e.8 :condition (b / bind-01~e.2 :ARG1 (p4 / protein :name (n2 / name :op1 "EGF"~e.1))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and~e.18 :op1 (p6 / person :name (n5 / name :op1 "Citri"~e.17)) :op2 (p7 / person :name (n6 / name :op1 "Yarden"~e.19))) :time (d3 / date-entity :year 2006~e.21)))) :mod (m / major~e.5) :domain~e.9 (a2 / and~e.12 :op1 (p2 / pathway :name (n / name :op1 "MAPK"~e.11)) :op2 (p3 / pathway :name (n3 / name :op1 "AKT"~e.13)))) # ::id pmid_1965_4571.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A431 and Caski cells show low basal levels of p @-@ AKT whereas C33A cells have a much higher level . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1.1.1 3-1.1.1.2 4-1.1 5-1.1.2.1 6-1.1.2.2 7-1.1.2 8-1.1.2.3.r 9-1.1.2.3.2 11-1.1.2.3.1.1 12-1 13-1.2.1.1.1 14-1.2.1 15-1.2 17-1.2.2.1.1.1 18-1.2.2.1 18-1.2.2.1.1 18-1.2.2.1.1.r 19-1.2.2 (c3 / contrast-01~e.12 :ARG1 (s / show-01~e.4 :ARG0 (a / and~e.1 :op1 (c / cell-line~e.3 :name (n / name :op1 "A431"~e.0)) :op2 (c2 / cell-line~e.3 :name (n2 / name :op1 "Caski"~e.2))) :ARG1 (l / level~e.7 :ARG1-of (l2 / low-04~e.5) :mod (b / basal~e.6) :quant-of~e.8 (e / enzyme :name (n3 / name :op1 "AKT"~e.11) :ARG3-of (p / phosphorylate-01~e.9)))) :ARG2 (h2 / have-03~e.15 :ARG0 (c4 / cell-line~e.14 :name (n4 / name :op1 "C33A"~e.13)) :ARG1 (l3 / level~e.19 :ARG1-of (h / high-02~e.18 :degree~e.18 (m / more~e.18 :mod (m2 / much~e.17)))))) # ::id pmid_1965_4571.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A431 and C33A cells had higher levels of activated ERK1 @/@ 2 ( p @-@ p44 @/@ 42 MAPK ) but no significant differences in total MAPK were observed among the cell lines ( Figure 3A ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1 3-1.1.1.1 3-1.1.1.2 4-1.1 5-1.1.2.1 5-1.1.2.1.1 5-1.1.2.1.1.r 6-1.1.2 8-1.1.2.2.1.2 9-1.1.2.2.1.1.1 10-1.1.2.2 10-1.1.2.3.1 13-1.1.2.3.1.1.2 15-1.1.2.3.1.1.1.1 16-1.1.2.2 16-1.1.2.3.1 18-1.2.2.1.1.1 20-1 21-1.2.1 21-1.2.1.r 22-1.2.2.2 23-1.2.2 25-1.2.2.1.2 26-1.2.2.1.1.1 28-1.2 31-1.2.3 32-1.2.3 35-1.3.1 36-1.3.1.1 (c / contrast-01~e.20 :ARG1 (h2 / have-03~e.4 :ARG0 (a / and~e.1 :op1 (c2 / cell-line~e.3 :name (n2 / name :op1 "A431"~e.0)) :op2 (c3 / cell-line~e.3 :name (n3 / name :op1 "C33A"~e.2))) :ARG1 (l / level~e.6 :ARG1-of (h / high-02~e.5 :degree~e.5 (m / more~e.5)) :quant-of (s / slash~e.10,16 :op1 (e / enzyme :name (n4 / name :op1 "ERK1"~e.9) :ARG1-of (a2 / activate-01~e.8)) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2") :ARG1-of a2)) :ARG1-of (m2 / mean-01 :ARG2 (s2 / slash~e.10,16 :op1 (e3 / enzyme :name (n8 / name :op1 "p44"~e.15 :op2 "MAPK") :ARG3-of (p2 / phosphorylate-01~e.13)) :op2 (e4 / enzyme :name (n / name :op1 "p42" :op2 "MAPK") :ARG3-of p2))))) :ARG2 (o / observe-01~e.28 :polarity~e.21 -~e.21 :ARG1 (d / differ-02~e.23 :ARG1 (e5 / enzyme :name (n7 / name :op1 "MAPK"~e.18,26) :mod (t / total~e.25)) :ARG1-of (s3 / significant-02~e.22)) :location (c4 / cell-line~e.31,32)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.35 :mod "3A"~e.36))) # ::id pmid_1965_4571.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab inhibits EGFR and HER2 phosphorylation # ::alignments 1-1.1.1.1 2-1 3-1.2.1.1.1.1 4-1.2.1 5-1.2.1.2.1.1 6-1.2 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.1)) :ARG1 (p2 / phosphorylate-01~e.6 :ARG1 (a / and~e.4 :op1 (e / enzyme :name (n / name :op1 "EGFR"~e.3)) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2"~e.5))))) # ::id pmid_1965_4571.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the molecular determinants for cetuximab 's effects in MTT and CA , we analysed EGFR phosphorylation by WB in cells treated with cetuximab ( 100 μ @ g ml @⁻¹ ) alone or in the presence of EGF . # ::alignments 1-1.4 3-1.4.2.2 6-1.3.1.1.1.1.1 6-1.3.1.1.2.1.1 8-1.4.2.1.1 9-1.4.2.1.1.2.r 10-1.4.2.1.1.2.1.1.1.1 11-1.4.2.1.1.2 14-1.1 15-1 16-1.2.1.1.1 17-1.2 21-1.3 22-1.3.1 23-1.4.2.1.1.2.1.1.r 24-1.3.1.1.1.1.1 24-1.3.1.1.2.1.1 26-1.3.1.1.1.2.1 31-1.3.1.1.1.2.2 36-1.3.1.1.1.3 37-1.3.1.1 38-1.3.1.1.r 40-1.3.1.1.2.3 41-1.3.1.1.2.3.1.r 42-1.3.1.1.2.3.1.1.1 (a / analyze-01~e.15 :ARG0 (w / we~e.14) :ARG1 (p / phosphorylate-01~e.17 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR"~e.16))) :location (c / cell~e.21 :ARG1-of (t / treat-04~e.22 :ARG2~e.38 (o / or~e.37 :op1 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.6,24) :quant (c2 / concentration-quantity :quant 100~e.26 :unit (m / microgram-per-milliliter~e.31)) :mod (a2 / alone~e.36)) :op2 (s2 / small-molecule :name (n4 / name :op1 "cetuximab"~e.6,24) :quant c2 :condition (p2 / present-02~e.40 :ARG1~e.41 (p3 / protein :name (n5 / name :op1 "EGF"~e.42))))))) :purpose (i / investigate-01~e.1 :ARG0 w :ARG1 (t2 / thing :ARG0-of (d / determine-01 :ARG1 (a3 / affect-01~e.8 :ARG0 s :time~e.9 (a4 / and~e.11 :op1 (a5 / assay-01 :instrument~e.23 (s3 / small-molecule :name (n / name :op1 "MTT"~e.10))) :op2 (a6 / assay-01 :mod (c3 / clonogenic))))) :mod (m2 / molecule~e.3))) :manner (i2 / immunoblot-01 :ARG0 w)) # ::id pmid_1965_4571.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Receptor phosphorylation was increased by EGF in A431 and Caski cells , whereas cetuximab reduced it ( Figures 3B and C ) . # ::alignments 0-1.1.2.1 1-1.1.2 3-1.1 4-1.1.1.r 5-1.1.1.1.1 6-1.1.3.r 7-1.1.3.1.1.1 8-1.1.3 9-1.1.3.2.1.1 10-1.1.3.1 10-1.1.3.2 12-1 13-1.2.1.1.1 14-1.2 15-1.2.2 18-1.3.1.1 18-1.3.1.2 19-1.3.1.1.1 20-1.3.1 (c3 / contrast-01~e.12 :ARG1 (i / increase-01~e.3 :ARG0~e.4 (p2 / protein :name (n / name :op1 "EGF"~e.5)) :ARG1 (p / phosphorylate-01~e.1 :ARG1 (r / receptor~e.0)) :location~e.6 (a / and~e.8 :op1 (c / cell-line~e.10 :name (n2 / name :op1 "A431"~e.7)) :op2 (c2 / cell-line~e.10 :name (n3 / name :op1 "Caski"~e.9)))) :ARG2 (r2 / reduce-01~e.14 :ARG0 (s2 / small-molecule :name (n4 / name :op1 "cetuximab"~e.13)) :ARG1 p~e.15) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.20 :op1 (f / figure~e.18 :mod "3B"~e.19) :op2 (f2 / figure~e.18 :mod "3C")))) # ::id pmid_1965_4571.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Epidermal growth factor and cetuximab also induced a slight decrease in the total amount of EGFR in these cells ( Figures 3B and C ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1.1.1.3 3-1.1 4-1.1.2.1.1 5-1.3 6-1 8-1.2.2 9-1.2 10-1.2.1.r 12-1.2.1.1 13-1.2.1 14-1.2.1.2.r 15-1.2.1.2.1.1 16-1.2.3.r 17-1.2.3.1 18-1.2.3 21-1.4.1.1 21-1.4.1.2 22-1.4.1.1.1 23-1.4.1 (i / induce-01~e.6 :ARG0 (a / and~e.3 :op1 (p / protein :name (n4 / name :op1 "epidermal"~e.0 :op2 "growth"~e.1 :op3 "factor"~e.2)) :op2 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.4))) :ARG2 (d / decrease-01~e.9 :ARG1~e.10 (a3 / amount~e.13 :mod (t / total~e.12) :quant-of~e.14 (e / enzyme :name (n2 / name :op1 "EGFR"~e.15))) :degree (s2 / slight~e.8) :location~e.16 (c / cell~e.18 :mod (t2 / this~e.17))) :mod (a2 / also~e.5) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.23 :op1 (f / figure~e.21 :mod "3B"~e.22) :op2 (f2 / figure~e.21 :mod "3C")))) # ::id pmid_1965_4571.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Epidermal growth factor receptor can interact with another member of the ErbB family , HER2 , to form heterodimers that are very potent in activating signal transduction pathways ( Citri and Yarden , 2006 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1.1.1.3 3-1.1.1.1.4 4-1 5-1.1 6-1.1.2.r 7-1.1.2.1 8-1.1.2 11-1.1.2.2.1.1.1 12-1.1.2.2.1 14-1.1.2.3.1.1.1 17-1.1.3 18-1.1.3.2 21-1.1.3.2.1.2 24-1.1.3.2.1.1 25-1.1.3.2.1.1.1.1.1 26-1.1.3.2.1.1.1.1 27-1.1.3.2.1.1.1 30-1.2.1.1.1.1.1 31-1.2.1.1 32-1.2.1.1.2.1.1 34-1.2.1.1.3.1 (p / possible-01~e.4 :ARG1 (i / interact-01~e.5 :ARG0 (e / enzyme :name (n3 / name :op1 "epidermal"~e.0 :op2 "growth"~e.1 :op3 "factor"~e.2 :op4 "receptor"~e.3)) :ARG1~e.6 (m / member~e.8 :mod (a / another~e.7) :ARG1-of (i2 / include-91 :ARG2 (p2 / protein-family~e.12 :name (n4 / name :op1 "ErbB"~e.11))) :ARG1-of (m2 / mean-01 :ARG2 (e3 / enzyme :name (n5 / name :op1 "HER2"~e.14)))) :purpose (f2 / form-01~e.17 :ARG0 e :ARG1 (h / heterodimer~e.18 :ARG1-of (c / capable-01 :ARG2 (a2 / activate-01~e.24 :ARG1 (p3 / pathway~e.27 :ARG2-of (t / transduce-01~e.26 :ARG1 (s2 / signal-07~e.25)))) :degree (v / very~e.21))) :ARG2 (a4 / and :op1 e :op2 m))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.31 :op1 (p5 / person :name (n7 / name :op1 "Citri"~e.30)) :op2 (p6 / person :name (n8 / name :op1 "Yarden"~e.32)) :time (d / date-entity :year 2006~e.34))))) # ::id pmid_1965_4571.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On cetuximab treatment there were no changes in total HER2 in the CC cell lines , whereas EGF @-@ induced HER2 phosphorylation was inhibited in A431 and Caski cells ( Figures 3B and C ) . # ::alignments 1-1.1.2.1.1.1 2-1.1.2 5-1.1.1.1 5-1.1.1.1.r 6-1.1.1 7-1.1.1.2.r 8-1.1.1.2.2 9-1.1.1.2.1.1 13-1.1.1.3 14-1.1.1.3 16-1 17-1.2.1.2.1.1.1 19-1.2.1.2 20-1.2.1.1 21-1.2.1 23-1.2 24-1.2.2.r 25-1.2.2.1.1.1 26-1.2.2 27-1.2.2.2.1.1 28-1.2.2.1 28-1.2.2.2 31-1.3.1.1 31-1.3.1.2 32-1.3.1.1.1 33-1.3.1 (c / contrast-01~e.16 :ARG1 (h / have-condition-91 :ARG1 (c2 / change-01~e.6 :polarity~e.5 -~e.5 :ARG1~e.7 (e / enzyme :name (n / name :op1 "HER2"~e.9) :mod (t2 / total~e.8)) :location (c3 / cell-line~e.13,14 :mod (d / disease :wiki "Cervical_cancer" :name (n3 / name :op1 "cervical" :op2 "cancer")))) :ARG2 (t / treat-04~e.2 :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.1)))) :ARG2 (i / inhibit-01~e.23 :ARG1 (p / phosphorylate-01~e.21 :ARG1 e~e.20 :ARG2-of (i2 / induce-01~e.19 :ARG0 (p2 / protein :name (n4 / name :op1 "EGF"~e.17)))) :location~e.24 (a / and~e.26 :op1 (c4 / cell-line~e.28 :name (n5 / name :op1 "A431"~e.25)) :op2 (c5 / cell-line~e.28 :name (n6 / name :op1 "Caski"~e.27)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.33 :op1 (f / figure~e.31 :mod "3B"~e.32) :op2 (f2 / figure~e.31 :mod "3C")))) # ::id pmid_1965_4571.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , in C33A cells , which express more HER2 than EGFR ( Fig 3A ) , cetuximab markedly reduced EGF @-@ induced HER2 phosphorylation ( Figure 3D ) . # ::alignments 0-1.6 3-1.4.1.1 4-1.4 7-1.4.2 8-1.4.2.3 9-1.4.2.1 10-1.4.2.4.r 11-1.4.2.4.1.1 14-1.4.2.2.1 15-1.4.2.2.1.1 19-1.1.1.1 20-1.3 20-1.3.r 21-1 22-1.2.2.1.1.1 24-1.2.2 25-1.2.1.1.1 26-1.2 29-1.5.1 30-1.5.1.1 (r / reduce-01~e.21 :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.19)) :ARG1 (p / phosphorylate-01~e.26 :ARG1 (e / enzyme :name (n / name :op1 "HER2"~e.25)) :ARG2-of (i / induce-01~e.24 :ARG0 (p2 / protein :name (n2 / name :op1 "EGF"~e.22)))) :manner~e.20 (m / marked~e.20) :location (c / cell-line~e.4 :name (n4 / name :op1 "C33A"~e.3) :ARG3-of (e3 / express-03~e.7 :ARG2 e~e.9 :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "3A"~e.15)) :degree (m2 / more~e.8) :compared-to~e.10 (e2 / enzyme :name (n5 / name :op1 "EGFR"~e.11)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.29 :mod "3D"~e.30)) :mod (i2 / interesting~e.0)) # ::id pmid_1965_4571.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There were no changes in total AKT and MAPK proteins in all cell lines on cetuximab treatment ( Figures 3B @–@ D ) . # ::alignments 2-1.1 2-1.1.r 3-1 4-1.2.r 5-1.2.3 6-1.2.1.1.1 7-1.2 8-1.2.2.1.1 9-1.2.1 9-1.2.2 10-1.3.r 11-1.3.1 12-1.3 13-1.3 14-1.3.2.r 15-1.3.2.1.1.1 16-1.3.2 19-1.4.1.1 19-1.4.1.2 20-1.4.1.1.1 (c / change-01~e.3 :polarity~e.2 -~e.2 :ARG1~e.4 (a / and~e.7 :op1 (p2 / protein-family~e.9 :name (n2 / name :op1 "AKT"~e.6)) :op2 (p / protein-family~e.9 :name (n / name :op1 "MAPK"~e.8)) :mod (t2 / total~e.5)) :location~e.10 (c2 / cell-line~e.12,13 :mod (a2 / all~e.11) :ARG1-of~e.14 (t / treat-04~e.16 :ARG2 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.15)))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.19 :mod "3B"~e.20) :op2 (f2 / figure~e.19 :mod "3D")))) # ::id pmid_1965_4571.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Epidermal growth factor increased AKT and ERK1 @/@ 2 phosphorylation in A431 and Caski cells but in C33A cells there was only a slight increase . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1.1.1.3 3-1.1 4-1.1.2.1.1.1.1 5-1.1.2 6-1.1.2.2.1.1.1 8-1.1.2.2.1.1.1 9-1.1.2.1 9-1.1.2.2 10-1.1.3.r 11-1.1.3.1.1.1 12-1.1.3 13-1.1.3.2.1.1 14-1.1.3.1 14-1.1.3.2 15-1 16-1.2.r 17-1.2.3.1.1 18-1.2.3 21-1.2.4 23-1.2.5 24-1.2 (c / contrast-01~e.15 :ARG1 (i / increase-01~e.3 :ARG0 (p2 / protein :name (n2 / name :op1 "epidermal"~e.0 :op2 "growth"~e.1 :op3 "factor"~e.2)) :ARG1 (a / and~e.5 :op1 (p / phosphorylate-01~e.9 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT"~e.4))) :op1 (p3 / phosphorylate-01~e.9 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"~e.6,8)))) :location~e.10 (a2 / and~e.12 :op1 (c2 / cell-line~e.14 :name (n5 / name :op1 "A431"~e.11)) :op2 (c3 / cell-line~e.14 :name (n6 / name :op1 "Caski"~e.13)))) :ARG2~e.16 (i2 / increase-01~e.24 :ARG0 p2 :ARG1 a :location (c4 / cell-line~e.18 :name (n7 / name :op1 "C33A"~e.17)) :mod (o / only~e.21) :degree (s2 / slight~e.23))) # ::id pmid_1965_4571.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was not unexpected , because both pathways are activated in this cell line ( Figure 3A ) . # ::alignments 0-1.2.2 2-1.2.1 2-1.2.1.r 3-1.2 3-1.2.1 5-1 6-1.1.1.1 7-1.1.1 9-1.1 10-1.1.2.r 11-1.1.2.1 12-1.1.2 13-1.1.2 16-1.3.1 17-1.3.1.1 (c / cause-01~e.5 :ARG0 (a / activate-01~e.9 :ARG1 (p / pathway~e.7 :mod (b / both~e.6)) :location~e.10 (c2 / cell-line~e.12,13 :mod (t / this~e.11))) :ARG1 (e / expect-01~e.3 :polarity~e.2 -~e.2,3 :ARG1 (t2 / this~e.0)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "3A"~e.17))) # ::id pmid_1965_4571.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab inhibited EGF @-@ induced AKT phosphorylation more strongly in A431 cells and less so in Caski and C33A cells . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.2 2-1.1.2.2.1.1.1 4-1.1.2.2 5-1.1.2.1.1.1 6-1.1.2 7-1.1.3.1 8-1.1.3 10-1.1.4.1.1 11-1.1.4 11-1.2.4.2 12-1 13-1.2.3 15-1.2.4.r 16-1.2.4.1.1.1 17-1.2.4 18-1.2.4.2.1.1 19-1.2.4.1 (a2 / and~e.12 :op1 (i / inhibit-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"~e.0)) :ARG1 (p / phosphorylate-01~e.6 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT"~e.5)) :ARG2-of (i2 / induce-01~e.4 :ARG0 (p2 / protein :name (n3 / name :op1 "EGF"~e.2)))) :ARG1-of (s2 / strong-02~e.8 :degree (m / more~e.7)) :location (c / cell-line~e.11 :name (n4 / name :op1 "A431"~e.10))) :op2 (i3 / inhibit-01~e.1 :ARG0 s :ARG1 p :degree (l / less~e.13) :location~e.15 (a / and~e.17 :op1 (c2 / cell-line~e.19 :name (n5 / name :op1 "Caski"~e.16)) :op2 (c3 / cell-line~e.11 :name (n6 / name :op1 "C33A"~e.18))))) # ::id pmid_1965_4571.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , it markedly reduced EGF @-@ induced ERK1 @/@ 2 phosphorylation in A431 cells , but in Caski and C33A cells the reduction was more modest ( 60 and 20 % inhibition , respectively ; Figures 3B @–@ D ) , suggesting that persistent signalling through these pathways led to increased survival of Caski and C33A cells , when compared to A431 cells in the presence of cetuximab . # ::alignments 0-1.4 2-1.1.1 3-1.1.4 3-1.1.4.r 4-1.1 5-1.1.2.2.1.1.1 7-1.1.2.2 8-1.1.2.1.1.1 10-1.1.2.1.1.1 11-1.1.2 13-1.1.3.1.1 14-1.2.3.1 16-1 18-1.2.3.1.1.1 19-1.2.3 20-1.2.3.2.1.1 21-1.1.3 21-1.2.3.1 23-1.2 25-1.2.2.1 26-1.2.2 28-1.2.4.1.1.1.1 29-1.2.4.1 30-1.2.4.1.2.1.1 31-1.2.4.1.1.1 31-1.2.4.1.2.1 32-1.2.4.1.1 32-1.2.4.1.2 34-1.2.4.1.3 37-1.5.1.1 37-1.5.1.2 38-1.5.1.1.1 44-1.3 45-1.3.1.r 46-1.3.1.1.2 47-1.3.1.1 49-1.3.1.1.1.1 50-1.3.1.1.1 51-1.3.1 52-1.3.1.2.r 53-1.3.1.2.2 54-1.3.1.2 56-1.2.3.1.1.1 57-1.2.3 58-1.2.3.2.1.1 59-1.2.3.1 59-1.2.3.2 61-1.3.1.3.r 62-1.3.1.3 63-1.3.1.3.1.r 64-1.3.1.3.1.1.1 65-1.3.1.3.1 66-1.3.1.3.1.2.r 68-1.3.1.3.1.2 69-1.3.1.3.1.2.1.r 70-1.3.1.3.1.2.1.1.1 (c / contrast-01~e.16 :ARG1 (r / reduce-01~e.4 :ARG0 (i / it~e.2) :ARG1 (p2 / phosphorylate-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.8,10)) :ARG2-of (i2 / induce-01~e.7 :ARG0 (p3 / protein :name (n2 / name :op1 "EGF"~e.5)))) :location (c2 / cell-line~e.21 :name (n3 / name :op1 "A431"~e.13)) :manner~e.3 (m4 / marked~e.3)) :ARG2 (r3 / reduce-01~e.23 :ARG1 p2 :mod (m / modest~e.26 :degree (m2 / more~e.25)) :location (a / and~e.19,57 :op1 (c3 / cell-line~e.14,21,59 :name (n4 / name :op1 "Caski"~e.18,56)) :op2 (c4 / cell-line~e.59 :name (n5 / name :op1 "C33A"~e.20,58))) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and~e.29 :op1 (i3 / inhibit-01~e.32 :quant (p4 / percentage-entity~e.31 :value 60~e.28) :location c3) :op2 (i4 / inhibit-01~e.32 :quant (p / percentage-entity~e.31 :value 20~e.30) :location c4) :mod (r2 / respective~e.34)))) :ARG0-of (s / suggest-01~e.44 :ARG1~e.45 (l / lead-03~e.51 :ARG0 (s2 / signal-07~e.47 :ARG0 (p6 / pathway~e.50 :mod (t / this~e.49)) :ARG1-of (p5 / persist-01~e.46)) :ARG2~e.52 (s3 / survive-01~e.54 :ARG1 (a3 / and :op1 c3 :op2 c4) :ARG1-of (i5 / increase-01~e.53)) :time~e.61 (c5 / compare-01~e.62 :ARG2~e.63 (c6 / cell-line~e.65 :name (n6 / name :op1 "A431"~e.64) :ARG2-of~e.66 (p7 / present-02~e.68 :ARG1~e.69 (s4 / small-molecule :name (n7 / name :op1 "cetuximab"~e.70))))))) :mod (i6 / indeed~e.0) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.37 :mod "3B"~e.38) :op2 (f2 / figure~e.37 :mod "3D")))) # ::id pmid_1965_4571.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab combined with trastuzumab synergistically reduces cell proliferation and activation of downstream signalling pathways in CC cells # ::alignments 1-1.1.1.1 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1.1 5-1.4 6-1 7-1.3 8-1.2.1 9-1.2 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.1.1 13-1.2.2.1.1 14-1.2.2.1 17-1.2.1.1 (r / reduce-01~e.6 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"~e.1) :ARG1-of (c / combine-01~e.2 :ARG2~e.3 (s2 / small-molecule :name (n2 / name :op1 "trastuzumab"~e.4)))) :ARG1 (a / and~e.9 :op1 (p / proliferate-01~e.8 :ARG0 (c2 / cell~e.17)) :op2 (a2 / activate-01~e.10 :ARG1~e.11 (p2 / pathway~e.14 :ARG0-of (s3 / signal-07~e.13 :location (d / downstream~e.12))))) :location (c3 / cell-line~e.7 :mod (d2 / disease :wiki "Cervical_cancer" :name (n3 / name :op1 "cervical" :op2 "cancer"))) :manner (s4 / synergize-01~e.5)) # ::id pmid_1965_4571.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We speculated that cells expressing higher EGFR @/@ HER2 ratios , such as A431 cells , rely more on EGFR signalling for MAPK pathway activation and cell proliferation , whereas cells with a lower EGFR @/@ HER2 ratio , such as C33A cells , depend more on EGFR @/@ HER2 heterodimer signalling . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1 4-1.2.1.1.1 5-1.2.1.1.1.1.2 5-1.2.1.1.1.1.2.1 5-1.2.1.1.1.1.2.1.r 6-1.2.1.1.1.1.1.1.1.1 8-1.2.1.1.1.1.1.2.1.1 9-1.2.1.1.1.1 11-1.2.1.1.2.r 12-1.2.1.1.2.r 13-1.2.1.1.2.1.1 14-1.2.1.1 16-1.2.1 17-1.2.1.1.1.1.2.1 18-1.2.1.2.r 19-1.2.1.2.1.1.2.1 20-1.2.1.2.1.1.2 22-1.2.1.2.1.1.1.1 23-1.2.1.2.1.1 24-1.2.1.2.1 25-1.2.1.2 26-1.2.1.2.2.1 27-1.2.1.2.2 29-1.2 30-1.2.1.1 31-1.2.2.r 33-1.2.2.1.1.1.2 34-1.2.2.1.1.1.1 35-1.2.2.1.1.1.1 36-1.2.2.1.1.1.3 37-1.2.2.1.1.1 39-1.2.2.1.2.r 40-1.2.2.1.2.r 41-1.2.2.1.2.1.1 42-1.2.2.1 44-1.2.2 45-1.2.2.3 47-1.2.1.1.1.1.1.1.1.1 49-1.2.1.1.1.1.1.2.1.1 50-1.2.2.2.1 51-1.2.2.2 (s / speculate-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (c / contrast-01~e.29 :ARG1 (r / rely-01~e.16 :ARG0 (c2 / cell-line~e.3,14,30 :ARG3-of (e2 / express-03~e.4 :ARG2 (r2 / ratio-of~e.9 :op1 (m3 / macro-molecular-complex :part (e3 / enzyme :name (n3 / name :op1 "EGFR"~e.6,47)) :part (e4 / enzyme :name (n4 / name :op1 "HER2"~e.8,49))) :ARG1-of (h2 / high-02~e.5 :degree~e.5 (m4 / more~e.5,17)) :part e3)) :example~e.11,12 (c3 / cell-line :name (n5 / name :op1 "A431"~e.13))) :ARG1~e.18 (a / and~e.25 :op1 (a2 / activate-01~e.24 :ARG1 (p2 / pathway~e.23 :name (n6 / name :op1 "MAPK"~e.22) :ARG0-of (s2 / signal-07~e.20 :ARG1 e3~e.19))) :op2 (p3 / proliferate-01~e.27 :ARG0 (c4 / cell~e.26))) :degree m4) :ARG2~e.31 (d / depend-01~e.44 :ARG0 (c5 / cell-line~e.42 :ARG0-of (h3 / have-03 :ARG1 (r3 / ratio-of~e.37 :op1 m3~e.34,35 :ARG1-of (l2 / low-04~e.33 :degree m4) :part e4~e.36)) :example~e.39,40 (c6 / cell-line :name (n7 / name :op1 "C33A"~e.41))) :ARG1 (s3 / signal-07~e.51 :ARG1 (h / heterodimer~e.50 :mod m3)) :degree m4~e.45))) # ::id pmid_1965_4571.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Based on this assumption , the inhibition of the EGFR @/@ HER2 heterodimer by anti @-@ EGFR ( cetuximab ) and anti @-@ HER2 ( trastuzumab ) MAbs should interfere with C33A cell proliferation . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1 3-1.2.1 6-1.1.1 7-1.1.1.2.r 9-1.1.1.2.1.1.1 11-1.1.1.2.2.1.1 12-1.1.1.2 14-1.1.1.1.2.1.1 14-1.1.1.1.2.1.1.2 14-1.1.1.1.2.1.1.2.r 14-1.1.1.1.2.1.2 14-1.1.1.1.2.1.2.2 14-1.1.1.1.2.1.2.2.r 16-1.1.1.2.1.1.1 18-1.1.1.1.2.1.1.1.1 20-1.1.1.1.2.1 21-1.1.1.1.2.1.1 21-1.1.1.1.2.1.1.2 21-1.1.1.1.2.1.1.2.r 21-1.1.1.1.2.1.2 21-1.1.1.1.2.1.2.2 21-1.1.1.1.2.1.2.2.r 23-1.1.1.2.2.1.1 25-1.1.1.1.2.1.2.1.1 29-1.1 30-1.1.2.r 31-1.1.2.1.1.1 32-1.1.2.1 33-1.1.2 (p / possible-01 :ARG1 (i / interfere-01~e.29 :ARG0 (i2 / inhibit-01~e.6 :ARG0 (a3 / antibody :mod (m3 / monoclone) :ARG1-of (m / mean-01 :ARG2 (a / and~e.20 :op1 (s / small-molecule~e.14,21 :name (n / name :op1 "cetuximab"~e.18) :ARG0-of~e.14,21 (c / counter-01~e.14,21 :ARG1 e)) :op2 (s2 / small-molecule~e.14,21 :name (n5 / name :op1 "trastuzumab"~e.25) :ARG0-of~e.14,21 (c2 / counter-01~e.14,21 :ARG1 e2))))) :ARG1~e.7 (h / heterodimer~e.12 :part (e / enzyme :name (n2 / name :op1 "EGFR"~e.9,16)) :part (e2 / enzyme :name (n3 / name :op1 "HER2"~e.11,23)))) :ARG1~e.30 (p2 / proliferate-01~e.33 :ARG0 (c3 / cell-line~e.32 :name (n7 / name :op1 "C33A"~e.31)))) :ARG1-of (b / base-02~e.0 :ARG2~e.1 (a2 / assume-02~e.3 :mod (t / this~e.2)))) # ::id pmid_1965_4571.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , this combination markedly reduced C33A cell colony formation leading to a synergistic interaction ( R @ = 0.58 ; Figures 4A and B ) , with concomitant reduction of MAPK and AKT phosphorylation ( Figure 4D ) . # ::alignments 1-1.6 3-1.1.1 4-1.1 5-1.3 5-1.3.r 6-1 7-1.2.1.1.1.1 8-1.2.1.1 9-1.2.1 10-1.2 11-1.4 12-1.4.1.r 14-1.4.1.1 15-1.4.1 18-1.4.1.3.1.1 21-1.4.1.3.1.2.1 24-1.5.1.1 24-1.5.1.2 25-1.5.1.1.1 26-1.5.1 32-1.4.1.2.1.2 33-1.4.1.2.1 34-1.4.1.2.1.1.r 35-1.4.1.2.1.1.1.1.1.1 36-1.4.1.2.1.1 37-1.4.1.2.1.1.2.1.1.1 38-1.4.1.2.1.1.1 38-1.4.1.2.1.1.2 41-1.4.1.2.1.3.1 42-1.4.1.2.1.3.1.1 (r / reduce-01~e.6 :ARG0 (c / combine-01~e.4 :mod (t / this~e.3)) :ARG1 (f / form-01~e.10 :ARG1 (c2 / colony~e.9 :mod (c3 / cell-line~e.8 :name (n2 / name :op1 "C33A"~e.7)))) :manner~e.5 (m / marked~e.5) :ARG0-of (l / lead-03~e.11 :ARG2~e.12 (i / interact-01~e.15 :ARG0-of (s / synergize-01~e.14) :ARG0-of (h / have-03 :ARG1 (r3 / reduce-01~e.33 :ARG1~e.34 (a3 / and~e.36 :op1 (p2 / phosphorylate-01~e.38 :ARG1 (e4 / enzyme :name (n / name :op1 "MAPK"~e.35))) :op2 (p3 / phosphorylate-01~e.38 :ARG1 (e / enzyme :name (n3 / name :op1 "AKT"~e.37)))) :mod (c4 / concomitant~e.32) :ARG1-of (d2 / describe-01 :ARG0 (f4 / figure~e.41 :mod "4D"~e.42)))) :ARG1-of (m2 / mean-01 :ARG2 (s2 / string-entity :value "R"~e.18 :ARG1-of (e3 / equal-01 :ARG2 0.58~e.21))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.26 :op1 (f2 / figure~e.24 :mod "4A"~e.25) :op2 (f3 / figure~e.24 :mod "4B"))) :ARG1-of (e2 / expect-01~e.1)) # ::id pmid_1965_4571.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , an additive effect ( R @ = 0.84 ) was also noted for Caski cells , that express intermediate levels of EGFR and HER2 ( Figure 3A ) , with a decrease of almost 60 % in cell survival ( Figures 4A and B ) and inhibition of downstream signalling pathways ( MAPK and AKT ; Figure 4C ) . # ::alignments 0-1.4 3-1.1.1 4-1.1 7-1.1.2.1.1 10-1.1.2.1.2.1 13-1.3 14-1 15-1.2.r 16-1.2.1.1 17-1.2 20-1.2.2 21-1.2.2.1.3 22-1.2.2.1.1 22-1.2.2.1.2 23-1.2.2.1.1.1.r 24-1.2.2.1.1.1.1.1 25-1.2.2.1 26-1.2.2.1.2.1.1.1 29-1.2.2.2.1 30-1.2.2.2.1.1 36-1.2.3.1 37-1.2.3.1.2.r 38-1.2.3.1.2.2 39-1.2.3.1.2.1 40-1.2.3.1.2 41-1.2.3.1.1.r 42-1.2.3.1.1.1.1 43-1.2.3.1.1.1 46-1.2.3.1.1.1.2.1.1 46-1.2.3.1.1.1.2.1.2 47-1.2.3.1.1.1.2.1.1.1 48-1.2.3.1.1.1.2.1 52-1.2.3.1.1 53-1.2.3.1.1.2 54-1.2.3.1.1.2.1.r 55-1.2.3.1.1.2.1.1.1 56-1.2.3.1.1.2.1.1 57-1.2.3.1.1.2.1 59-1.2.3.1.1.2.1.2.1.1.1.1 60-1.2.3.1.1.2.1.2.1 61-1.2.3.1.1.2.1.2.1.2.1.1 64-1.2.3.1.1.2.2.1 65-1.2.3.1.1.2.2.1.1 (n4 / note-02~e.14 :ARG1 (a / affect-01~e.4 :ARG1-of (a2 / add-02~e.3) :ARG1-of (m2 / mean-01 :ARG2 (s3 / string-entity :value "R"~e.7 :ARG1-of (e4 / equal-01 :ARG2 0.84~e.10)))) :ARG2~e.15 (c / cell-line~e.17 :name (n5 / name :op1 "Caski"~e.16) :ARG3-of (e3 / express-03~e.20 :ARG2 (a4 / and~e.25 :op1 (l / level~e.22 :quant-of~e.23 (e / enzyme :name (n / name :op1 "EGFR"~e.24))) :op2 (l2 / level~e.22 :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2"~e.26))) :mod (i2 / intermediate~e.21)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "3A"~e.30))) :ARG0-of (h / have-03 :ARG1 (d2 / decrease-01~e.36 :ARG1~e.41 (a5 / and~e.52 :op1 (s / survive-01~e.43 :ARG1 (c2 / cell~e.42) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and~e.48 :op1 (f2 / figure~e.46 :mod "4A"~e.47) :op2 (f3 / figure~e.46 :mod "4B")))) :op2 (i3 / inhibit-01~e.53 :ARG1~e.54 (p3 / pathway~e.57 :ARG0-of (s2 / signal-07~e.56 :location (d4 / downstream~e.55)) :ARG1-of (m / mean-01 :ARG2 (a7 / and~e.60 :op1 (p2 / pathway :name (n3 / name :op1 "MAPK"~e.59)) :op2 (p4 / pathway :name (n6 / name :op1 "AKT"~e.61))))) :ARG1-of (d5 / describe-01 :ARG0 (f4 / figure~e.64 :mod "4C"~e.65)))) :ARG2~e.37 (p / percentage-entity~e.40 :value 60~e.39 :mod (a8 / almost~e.38))))) :mod (a3 / also~e.13) :mod (i / indeed~e.0)) # ::id pmid_1965_4571.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There were no changes in total AKT and MAPK proteins in Caski and C33A cell lines on treatments ( data not shown ) . # ::alignments 2-1.1 2-1.1.r 3-1 4-1.2.r 5-1.2.1.2 6-1.2.1.1.1 7-1.2 8-1.2.2.1.1 9-1.2.1 9-1.2.2 10-1.3.r 11-1.3.1.1.1 12-1.3 13-1.3.2.1.1 14-1.3.1 14-1.3.2 15-1.3.1 17-1.3.3 19-1.4.1 20-1.4.1.1.1 20-1.4.1.1.1.r 21-1.4.1.1 (c / change-01~e.3 :polarity~e.2 -~e.2 :ARG1~e.4 (a / and~e.7 :op1 (p2 / protein-family~e.9 :name (n2 / name :op1 "AKT"~e.6) :mod (t / total~e.5)) :op2 (p / protein-family~e.9 :name (n / name :op1 "MAPK"~e.8))) :location~e.10 (a2 / and~e.12 :op1 (c2 / cell-line~e.14,15 :name (n3 / name :op1 "Caski"~e.11)) :op2 (c3 / cell-line~e.14 :name (n4 / name :op1 "C33A"~e.13)) :ARG1-of (t2 / treat-04~e.17)) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.19 :ARG1-of (s / show-01~e.21 :polarity~e.20 -~e.20)))) # ::id pmid_1965_4571.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The combination of cetuximab with a TKI inhibits cell proliferation and MAPK phosphorylation in Caski but not in C33A cells # ::alignments 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.2.r 7-1.1.1.2.1.1 8-1.1 8-1.2 9-1.1.3 9-1.2.4 10-1.1.2.1 11-1.1.2 12-1.1.2.2.1.1.1 13-1.1.2.2 15-1.1.3.1.1 16-1 17-1.2.1 17-1.2.1.r 19-1.2.4.1.1 20-1.2.3 (c / contrast-01~e.16 :ARG1 (i / inhibit-01~e.8 :ARG0 (c2 / combine-01~e.2 :ARG1~e.3 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.4)) :ARG2~e.5 (s2 / small-molecule :name (n3 / name :op1 "TKI"~e.7))) :ARG1 (a / and~e.11 :op1 (p3 / proliferate-01~e.10 :ARG0 (c3 / cell)) :op2 (p2 / phosphorylate-01~e.13 :ARG1 (e / enzyme :name (n / name :op1 "MAPK"~e.12)))) :location (c4 / cell-line~e.9 :name (n4 / name :op1 "Caski"~e.15))) :ARG2 (i2 / inhibit-01~e.8 :polarity~e.17 -~e.17 :ARG0 c2 :ARG1 a~e.20 :location (c5 / cell-line~e.9 :name (n5 / name :op1 "C33A"~e.19)))) # ::id pmid_1965_4571.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Based on the idea of an EGFR @/@ HER2 heterodimer signalling dependency of C33A cells , we investigated whether further EGFR inhibition with another targeted drug , such as TKIs , affected more Caski than C33A cells . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1 4-1.3.1.1.r 6-1.3.1.1.2.1.1 8-1.3.1.1.2.1.2.2.1 9-1.3.1.1.2.1 10-1.3.1.1.2 11-1.3.1.1 12-1.3.1.1.1.r 13-1.3.1.1.1 14-1.3.1.1.1 16-1.1 17-1 18-1.2.1 18-1.2.1.r 19-1.2.2.3 20-1.2.2.2.2.1 21-1.2.2 22-1.2.2.1.r 23-1.2.2.1.1 24-1.2.2.1.2 25-1.2.2.1 27-1.2.2.1.3.r 28-1.2.2.1.3.r 31-1.2 32-1.2.4 33-1.2.3.2.1 34-1.2.5.r 35-1.2.5.2.1 36-1.2.3 36-1.2.5 (i / investigate-01~e.17 :ARG0 (w / we~e.16) :ARG1 (a / affect-01~e.31 :mode~e.18 interrogative~e.18 :ARG0 (i2 / inhibit-01~e.21 :ARG0~e.22 (d / drug~e.25 :mod (a2 / another~e.23) :ARG1-of (t / target-01~e.24) :example~e.27,28 (s / small-molecule :wiki "Tyrosine-kinase_inhibitor" :name (n2 / name :op1 "TKI"))) :ARG1 (e / enzyme :wiki "Epidermal_growth_factor_receptor" :name (n / name :op1 "EGFR"~e.20)) :degree (f / further~e.19)) :ARG1 (c / cell-line~e.36 :wiki - :name (n3 / name :op1 "Caski"~e.33)) :degree (m2 / more~e.32) :compared-to~e.34 (c2 / cell-line~e.36 :wiki - :name (n4 / name :op1 "C33A"~e.35))) :ARG1-of (b / base-02~e.0 :ARG0~e.1 (i3 / idea~e.3 :topic~e.4 (d2 / depend-01~e.11 :ARG0~e.12 c2~e.13,14 :ARG1 (s2 / signal-07~e.10 :ARG1 (h / heterodimer~e.9 :part e~e.6 :part (e2 / enzyme :wiki "HER2/neu" :name (n6 / name :op1 "HER2"~e.8)))))))) # ::id pmid_1965_4571.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we tested the combination of cetuximab with a specific EGFR TKI ( PD153035 ) . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1 8-1.1.2.2.r 10-1.1.2.2.2 11-1.1.2.2.3.1.1.1 12-1.1.2.2.1.1 14-1.1.2.2.4.1.1.1 (c / cause-01~e.0 :ARG1 (t / test-01~e.3 :ARG0 (w / we~e.2) :ARG1 (c2 / combine-01~e.5 :ARG1~e.6 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.7)) :ARG2~e.8 (s2 / small-molecule :name (n3 / name :op1 "TKI"~e.12) :mod (s3 / specific~e.10) :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.11))) :ARG1-of (m / mean-01 :ARG2 (s4 / small-molecule :name (n4 / name :op1 "PD153035"~e.14))))))) # ::id pmid_1965_4571.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , combined treatments reduced Caski cell survival leading to an additive interaction ( R @ = 0.94 ) when compared to treatments alone ( Figure 4E ) . # ::alignments 1-1.5 3-1.1.1 4-1.1 5-1 6-1.2.1.1.1 7-1.2.1 8-1.2 9-1.3 10-1.3.1.r 12-1.3.1.1 13-1.3.1 16-1.3.1.2.1.1 19-1.3.1.2.1.2.1 22-1.3.2 23-1.3.2.2.r 24-1.3.2.2 25-1.3.2.2.1 28-1.4.1 29-1.4.1.1 (r / reduce-01~e.5 :ARG0 (t / treat-04~e.4 :ARG1-of (c / combine-01~e.3)) :ARG1 (s / survive-01~e.8 :ARG1 (c2 / cell-line~e.7 :name (n / name :op1 "Caski"~e.6))) :ARG0-of (l / lead-03~e.9 :ARG2~e.10 (i / interact-01~e.13 :ARG1-of (a / add-02~e.12) :ARG1-of (m / mean-01 :ARG2 (s2 / string-entity :value "R"~e.16 :ARG1-of (e2 / equal-01 :ARG2 0.94~e.19)))) :condition (c3 / compare-01~e.22 :ARG1 t :ARG2~e.23 (t2 / treat-04~e.24 :mod (a2 / alone~e.25)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod "4E"~e.29)) :ARG1-of (e / expect-01~e.1)) # ::id pmid_1965_4571.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , the double treatment in Caski cells was accompanied by a greater reduction of EGFR , HER2 , AKT and MAPK phosphorylation ( Figure 4G ) . # ::alignments 0-1 3-1.1.2.2 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 7-1.1.2.1 9-1.1 10-1.1.1.r 12-1.1.1.2 12-1.1.1.2.1 12-1.1.1.2.1.r 13-1.1.1 14-1.1.1.1.r 15-1.1.1.1.1.1.1.1 17-1.1.1.1.2.1.1.1 19-1.1.1.1.3.1.1.1 20-1.1.1.1 21-1.1.1.1.4.1.1.1 22-1.1.1.1.1 22-1.1.1.1.2 22-1.1.1.1.3 22-1.1.1.1.4 25-1.2.1 26-1.2.1.1 (a / and~e.0 :op2 (a2 / accompany-01~e.9 :ARG0~e.10 (r / reduce-01~e.13 :ARG1~e.14 (a3 / and~e.20 :op1 (p2 / phosphorylate-01~e.22 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.15))) :op2 (p3 / phosphorylate-01~e.22 :ARG1 (e2 / enzyme :name (n2 / name :op1 "HER2"~e.17))) :op3 (p4 / phosphorylate-01~e.22 :ARG1 (e3 / enzyme :name (n5 / name :op1 "AKT"~e.19))) :op4 (p5 / phosphorylate-01~e.22 :ARG1 (e4 / enzyme :name (n3 / name :op1 "MAPK"~e.21)))) :mod (g / great~e.12 :degree~e.12 (m / more~e.12))) :ARG1 (t / treat-04~e.4 :ARG1~e.5 (c / cell-line~e.7 :name (n4 / name :op1 "Caski"~e.6)) :mod (d / double~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.25 :mod "4G"~e.26))) # ::id pmid_1965_4571.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Isolated cetuximab or PD153035 treatments reduced the survival of C33A cells in CA by the same proportion , reaching a more modest inhibition of HER2 , AKT and MAPK phosphorylation than in Caski cells ( Figures 4E and G ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1.1 2-1.1 3-1.1.2.1.1.1 4-1.1.1 4-1.1.2 5-1 7-1.2 8-1.2.1.r 9-1.2.1.1.1 10-1.2.1 13-1.3.r 15-1.3.1 16-1.3 18-1.4.1 20-1.4.1.1.2.1 21-1.4.1.1.2 22-1.4.1.1 23-1.4.1.1.1.r 24-1.4.1.1.1.1.1.1.1 26-1.4.1.1.1.2.1.1.1 27-1.4.1.1.1 28-1.4.1.1.1.3.1.1.1 29-1.4.1.1.1.1 29-1.4.1.1.1.2 29-1.4.1.1.1.3 30-1.4.1.1.3.r 32-1.4.1.1.3.1.1 33-1.4.1.1.3 36-1.5.1.1 36-1.5.1.2 37-1.5.1.1.1 38-1.5.1 (r / reduce-01~e.5 :ARG0 (o / or~e.2 :op1 (t / treat-04~e.4 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "cetuximab"~e.1) :ARG1-of (i / isolate-01~e.0))) :op2 (t2 / treat-04~e.4 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "PD153035"~e.3)))) :ARG1 (s4 / survive-01~e.7 :ARG1~e.8 (c / cell-line~e.10 :name (n6 / name :op1 "C33A"~e.9))) :ARG2~e.13 (p3 / proportion-01~e.16 :ARG1-of (s5 / same-01~e.15)) :ARG0-of (c2 / cause-01 :ARG1 (r2 / reach-01~e.18 :ARG1 (i2 / inhibit-01~e.22 :ARG1~e.23 (a / and~e.27 :op1 (p2 / phosphorylate-01~e.29 :ARG1 (e / enzyme :name (n2 / name :op1 "HER2"~e.24))) :op2 (p4 / phosphorylate-01~e.29 :ARG1 (e2 / enzyme :name (n8 / name :op1 "AKT"~e.26))) :op3 (p5 / phosphorylate-01~e.29 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MAPK"~e.28)))) :mod (m / modest~e.21 :degree (m2 / more~e.20)) :compared-to~e.30 (c3 / cell-line~e.33 :name (n9 / name :op1 "Caski"~e.32))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.38 :op1 (f / figure~e.36 :mod "4E"~e.37) :op2 (f2 / figure~e.36 :mod "4G"))) :time (a3 / assay-01 :mod (c4 / clonogenic))) # ::id pmid_1965_4571.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the combined treatment proved to be antagonistic ( R @ = 1.28 ) , with no decrease in phosphorylated proteins when compared to either drug alone ( Figures 4E and G ) . # ::alignments 1-1 4-1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1 12-1.1.1.1.2.1.1 15-1.1.1.1.2.1.2.1 18-1.1.r 19-1.1.2.1 19-1.1.2.1.r 20-1.1.2 21-1.1.2.2.r 22-1.1.2.2.1 23-1.1.2.2 24-1.1.2.3.r 25-1.1.2.3 26-1.1.2.3.2.r 27-1.1.2.3.2.1 28-1.1.2.3.2 29-1.1.2.3.2.2 32-1.2.1.1 32-1.2.1.2 33-1.2.1.1.1 34-1.1 34-1.2.1 (c / contrast-01~e.1 :ARG2~e.18 (a2 / and~e.34 :op1 (p / prove-01~e.6 :ARG1 (a / antagonize-01 :ARG0 (t / treat-04~e.5 :ARG1-of (c2 / combine-01~e.4)) :ARG1-of (m / mean-01 :ARG2 (s / string-entity :value "R"~e.12 :ARG1-of (e2 / equal-01 :ARG2 1.28~e.15))))) :op2 (d / decrease-01~e.20 :polarity~e.19 -~e.19 :ARG1~e.21 (p2 / protein~e.23 :ARG3-of (p3 / phosphorylate-01~e.22)) :time~e.24 (c3 / compare-01~e.25 :ARG1 t :ARG2~e.26 (d2 / drug~e.28 :mod (e / either~e.27) :mod (a3 / alone~e.29))))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.34 :op1 (f / figure~e.32 :mod "4E"~e.33) :op2 (f2 / figure~e.32 :mod "4G")))) # ::id pmid_1965_4571.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Altogether , these data corroborate with our hypothesis that C33A cells are not so dependent on EGFR signalling for proliferation , as double EGFR inhibition with different drugs did not enhance the toxicity achieved by either agent alone . # ::alignments 0-1.3 2-1.1.1.1 3-1.1.1 4-1 5-1.1.r 6-1.1.2.1.1 6-1.1.2.1.1.r 7-1.1.2 7-1.1.2.1 7-1.1.2.1.r 8-1.2.r 9-1.2.2.1.1 10-1.2.2 12-1.2.1 12-1.2.1.r 13-1.2.5 13-1.2.6 14-1.2 15-1.2.3.r 16-1.2.3.1.1.1 17-1.2.3 18-1.2.4.r 19-1.2.4 21-1.2.5.1.r 22-1.2.5.1.2.3 23-1.2.5.1.2.2 24-1.2.5.1.2 25-1.2.5.1.2.1.r 26-1.2.5.1.2.1.1 27-1.2.5.1.2.1 29-1.2.5.1.1 29-1.2.5.1.1.r 30-1.2.5.1 32-1.2.5.1.3 33-1.2.5.1.3.1 34-1.2.5.1.3.1.1.r 35-1.2.5.1.3.1.1.1 36-1.2.5.1.3.1.1 37-1.2.5.1.3.1.1.2 (c / corroborate-01~e.4 :ARG0~e.5 (a / and :op1 (d / data~e.3 :mod (t2 / this~e.2)) :op2 (t / thing~e.7 :ARG1-of~e.7 (h / hypothesize-01~e.7 :ARG0~e.6 (w / we~e.6)))) :ARG1~e.8 (d2 / depend-01~e.14 :polarity~e.12 -~e.12 :ARG0 (c2 / cell-line~e.10 :name (n2 / name :op1 "C33A"~e.9)) :ARG1~e.15 (s / signal-07~e.17 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.16))) :purpose~e.18 (p / proliferate-01~e.19) :ARG1-of (c3 / cause-01~e.13 :ARG0~e.21 (e2 / enhance-01~e.30 :polarity~e.29 -~e.29 :ARG0 (i / inhibit-01~e.24 :ARG0~e.25 (d3 / drug~e.27 :ARG1-of (d4 / differ-02~e.26)) :ARG1 e~e.23 :mod (d5 / double~e.22)) :ARG1 (t3 / toxicity~e.32 :ARG1-of (a2 / achieve-01~e.33 :ARG0~e.34 (a3 / agent~e.36 :mod (e3 / either~e.35) :mod (a4 / alone~e.37)))))) :mod (s2 / so~e.13)) :mod (a5 / altogether~e.0)) # ::id pmid_1965_4571.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , the targeting of EGFR and HER2 with two different MAbs showed synergistic inhibitory effects ( Figures 4A and B ) demonstrating that heterodimer signalling is necessary for C33A cell proliferation . # ::alignments 0-1.1.1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.1.1 10-1.1.1.2.1 12-1.1 13-1.1.2.1 14-1.1.2.2 15-1.1.2 18-1.1.3.1.1 18-1.1.3.1.2 19-1.1.3.1.1.1 20-1.1.3.1 24-1.1.4 25-1.1.4.1.r 26-1.1.4.1.1.1 27-1.1.4.1.1 29-1.1.4.1 30-1.1.4.1.2.r 31-1.1.4.1.2.1.1.1 32-1.1.4.1.2.1 33-1.1.4.1.2 (a / and :op2 (s / show-01~e.12 :ARG0 (t / target-01~e.3 :ARG1~e.4 (a2 / and~e.0,6 :op1 (e / enzyme :name (n / name :op1 "EGFR"~e.5)) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2"~e.7))) :ARG2 (a5 / antibody :ARG1-of (d / differ-02~e.10))) :ARG1 (a3 / affect-01~e.15 :ARG2 (s2 / synergize-01~e.13) :ARG0-of (i / inhibit-01~e.14)) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.20 :op1 (f / figure~e.18 :mod "4A"~e.19) :op2 (f2 / figure~e.18 :mod "4B"))) :ARG0-of (d3 / demonstrate-01~e.24 :ARG1~e.25 (n3 / need-01~e.29 :ARG1 (s4 / signal-07~e.27 :ARG1 (h / heterodimer~e.26)) :purpose~e.30 (p / proliferate-01~e.33 :ARG0 (c / cell-line~e.32 :name (n6 / name :op1 "C33A"~e.31))))))) # ::id pmid_1965_4571.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , these data indicate that the successful inhibition of the MAPK and @/@ or AKT pathways is a determinant factor for cetuximab efficacy in all CC cell lines . # ::alignments 0-1 2-1.1.1.1 3-1.1.1 4-1.1 5-1.1.2.r 7-1.1.2.1.2 8-1.1.2.1 9-1.1.2.1.1.r 11-1.1.2.1.1.1.1.1 12-1.1.2.1.1 14-1.1.2.1.1 15-1.1.2.1.1.2.1.1 16-1.1.2.1.1.1 16-1.1.2.1.1.2 17-1.1.2.1.r 20-1.1.2 22-1.1.2.2.1.1.1.1 25-1.1.2.2.1.2.2 26-1.1.2.2.1.2.1.1.1 27-1.1.2.2.1.2 28-1.1.2.2.1.2 (a / and~e.0 :op2 (i / indicate-01~e.4 :ARG0 (d / data~e.3 :mod (t / this~e.2)) :ARG1~e.5 (f / factor~e.20 :domain~e.17 (i2 / inhibit-01~e.8 :ARG1~e.9 (a3 / and-or~e.12,14 :op1 (p / pathway~e.16 :name (n / name :op1 "MAPK"~e.11)) :op2 (p2 / pathway~e.16 :name (n2 / name :op1 "AKT"~e.15))) :ARG0-of (s / succeed-01~e.7)) :ARG1-of (d2 / determine-01 :ARG3 (e / efficient-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "cetuximab"~e.22)) :location (c / cell-line~e.27,28 :mod (d3 / disease :name (n4 / name :op1 "CC"~e.26)) :mod (a2 / all~e.25))))))) # ::id pmid_1965_4571.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab combined with PD98059 synergistically reduces cell proliferation and MAPK pathway activation in CC cells # ::alignments 1-1.1.1.1 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1.1 5-1.3 6-1 7-1.4 8-1.2.1 9-1.2 10-1.2.2.1.1.1 11-1.2.2.1 12-1.2.2 13-1.4.1.r 14-1.4.1.1.1 15-1.2.1.1 (r / reduce-01~e.6 :ARG0 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.1) :ARG1-of (c / combine-01~e.2 :ARG2~e.3 (s2 / small-molecule :name (n3 / name :op1 "PD98059"~e.4)))) :ARG1 (a / and~e.9 :op1 (p2 / proliferate-01~e.8 :ARG0 (c2 / cell~e.15)) :op2 (a2 / activate-01~e.12 :ARG1 (p / pathway~e.11 :name (n / name :op1 "MAPK"~e.10)))) :manner (s3 / synergize-01~e.5) :location (c3 / cell-line~e.7 :mod~e.13 (d / disease :name (n4 / name :op1 "CC"~e.14)))) # ::id pmid_1965_4571.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm that the MAPK pathway is relevant for cetuximab response , drug combination experiments with PD98059 ( MEK1 @/@ 2 inhibitor ) were performed . # ::alignments 1-1.2 2-1.2.1.r 4-1.2.1.1.1.1 5-1.2.1.1 7-1.2.1 8-1.2.1.2.r 9-1.2.1.2.1.1.1 10-1.2.1.2 12-1.1.2.1 13-1.1.2 14-1.1 15-1.1.1.r 16-1.1.1.1.1 18-1.1.1.2.1.1.1 20-1.1.1.2.1.1.1 21-1.1.1 21-1.1.1.2 21-1.1.1.2.r 24-1 (p2 / perform-01~e.24 :ARG1 (e / experiment-01~e.14 :ARG1~e.15 (s / small-molecule~e.21 :name (n2 / name :op1 "PD98059"~e.16) :ARG0-of~e.21 (i / inhibit-01~e.21 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1/2"~e.18,20)))) :ARG2 (c / combine-01~e.13 :ARG1 (d / drug~e.12))) :purpose (c2 / confirm-01~e.1 :ARG1~e.2 (r / relevant-01~e.7 :ARG1 (p / pathway~e.5 :name (n / name :op1 "MAPK"~e.4)) :ARG2~e.8 (r2 / respond-01~e.10 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "cetuximab"~e.9)))))) # ::id pmid_1965_4571.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both treatments inhibited Caski and C33A cell proliferation by the same magnitude , with a reduction of 50 % and an additive effect for the combination over single @-@ drug treatment in both cell lines ( R @ = 0.88 and R @ = 0.92 , respectively ; Figure 4F ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1.1.1.1 4-1.2 5-1.2.2.1.1.1 6-1.2.1.1 6-1.2.2.1 7-1.2.1 7-1.2.2 8-1.3.r 10-1.3.1 11-1.3 15-1.4.1.1 16-1.4.1.1.1.r 17-1.4.1.1.1.1 18-1.4.1.1.1 19-1.4.1 21-1.4.1.2.2 22-1.4.1.2 23-1.4.1.2.1.r 25-1.4.1.2.1 27-1.4.1.2.1.1.2.1 29-1.4.1.2.1.1.2 30-1.4.1.2.1.1 32-1.1.1 33-1.4.1.2.1.1.1 34-1.4.1.2.1.1.1 37-1.4.1.1.2.1.1 37-1.4.1.2.3.1.1 40-1.4.1.1.2.1.2.1 41-1.4.1 43-1.4.1.1.2.1.1 43-1.4.1.2.3.1.1 46-1.4.1.2.3.1.2.1 48-1.4.1.3 51-1.5.1 52-1.5.1.1 (i / inhibit-01~e.2 :ARG0 (t / treat-04~e.1 :mod (b / both~e.0,32)) :ARG1 (a / and~e.4 :op1 (p2 / proliferate-01~e.7 :ARG0 (c / cell-line~e.6 :name (n / name :op1 "Caski"~e.3))) :op2 (p3 / proliferate-01~e.7 :ARG0 (c2 / cell-line~e.6 :name (n2 / name :op1 "C33A"~e.5)))) :manner~e.8 (m / magnitude~e.11 :ARG1-of (s / same-01~e.10)) :ARG0-of (c3 / cause-01 :ARG1 (a2 / and~e.19,41 :op1 (r / reduce-01~e.15 :ARG2~e.16 (p / percentage-entity~e.18 :value 50~e.17) :ARG1-of (m2 / mean-01 :ARG2 (s3 / string-entity :value "R"~e.37,43 :ARG1-of (e / equal-01 :ARG2 0.88~e.40)))) :op2 (a3 / affect-01~e.22 :ARG1~e.23 (c4 / combine-01~e.25 :compared-to (t2 / treat-01~e.30 :ARG1 (c5 / cell-line~e.33,34) :ARG2 (d / drug~e.29 :ARG1-of (s2 / single-02~e.27)))) :ARG1-of (a4 / add-02~e.21) :ARG1-of (m3 / mean-01 :ARG2 (s4 / string-entity :value "R"~e.37,43 :ARG1-of (e2 / equal-01 :ARG2 0.92~e.46)))) :mod (r2 / respective~e.48))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.51 :mod "4F"~e.52))) # ::id pmid_1965_4571.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , Figure 4H shows that a strong inhibition of MAPK phosphorylation was seen in both cell lines on treatment with PD98059 alone or in combination with cetuximab . # ::alignments 1-1.3 4-1.1 5-1.1.1 7-1 8-1.2.r 10-1.2.1.2 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1.1.1 14-1.2.1.1 16-1.2 17-1.2.2.r 18-1.2.2.1 19-1.2.2 20-1.2.2 21-1.2.2.2.r 22-1.2.2.2 24-1.2.2.2.1.1.1.1 24-1.2.2.2.1.2.1.1.1 25-1.2.2.2.1.1.2 26-1.2.2.2.1 27-1.2.2.2.1.r 28-1.2.2.2.1.2 29-1.2.2.2.1.2.2.r 30-1.2.2.2.1.2.2.1.1 (s / show-01~e.7 :ARG0 (f / figure~e.4 :mod "4H"~e.5) :ARG1~e.8 (s2 / see-01~e.16 :ARG1 (i / inhibit-01~e.11 :ARG1~e.12 (p2 / phosphorylate-01~e.14 :ARG1 (e2 / enzyme :name (n5 / name :op1 "MAPK"~e.13))) :ARG1-of (s3 / strong-02~e.10)) :location~e.17 (c / cell-line~e.19,20 :mod (b / both~e.18) :ARG1-of~e.21 (t / treat-04~e.22 :ARG2~e.27 (o / or~e.26 :op1 (s4 / small-molecule :name (n2 / name :op1 "PD98059"~e.24) :mod (a / alone~e.25)) :op2 (c2 / combine-01~e.28 :ARG1 (s5 / small-molecule :name (n3 / name :op1 "PD98059"~e.24)) :ARG2~e.29 (s6 / small-molecule :name (n4 / name :op1 "cetuximab"~e.30))))))) :ARG1-of (e / expect-01~e.1)) # ::id pmid_1965_4571.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As the combination of both treatments led to a near complete MAPK cascade blockage , accompanied by a significant reduction of CC cell proliferation , we confirmed that the inhibition of this pathway plays an important role in cetuximab 's efficacy . # ::alignments 2-1.3.1.1 3-1.3.1.1.1.r 4-1.3.1.1.1.1 5-1.3.1.1.1 6-1.3.1 7-1.3.1.2.r 9-1.3.1.2.2.1 10-1.3.1.2.2 11-1.3.1.2.1.1.1 13-1.3.1.2 15-1.3.1.2.3 16-1.3.1.2.3.1.r 18-1.3.1.2.3.1.2 19-1.3.1.2.3.1 22-1.3.1.2.3.1.1.1 23-1.3.1.2.3.1.1 25-1.1 26-1 27-1.2.r 29-1.2.1 32-1.2.1.1 33-1.2 35-1.2.2.2 36-1.2.2 38-1.2.2.1.1.1.1 39-1.2.2.2 (c / confirm-01~e.26 :ARG0 (w / we~e.25) :ARG1~e.27 (p2 / play-02~e.33 :ARG0 (i / inhibit-01~e.29 :ARG1 p~e.32) :ARG1 (r / role~e.36 :topic (e / efficient-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.38))) :mod (i2 / important~e.35,39))) :ARG1-of (c2 / cause-01 :ARG0 (l / lead-03~e.6 :ARG0 (c3 / combine-01~e.2 :ARG1~e.3 (t / treat-04~e.5 :mod (b / both~e.4))) :ARG2~e.7 (b2 / block-01~e.13 :ARG1 (p / pathway :name (n / name :op1 "MAPK"~e.11)) :ARG1-of (c5 / complete-01~e.10 :degree (n3 / near~e.9)) :ARG1-of (a / accompany-01~e.15 :ARG0~e.16 (r2 / reduce-01~e.19 :ARG1 (p3 / proliferate-01~e.23 :ARG0 (c6 / cell-line~e.22 :mod (d / disease :wiki "Cervical_cancer" :name (n4 / name :op1 "cervical" :op2 "cancer")))) :ARG1-of (s2 / significant-02~e.18))))))) # ::id pmid_1965_4571.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab induces ADCC in A431 and Caski , but not in C33A cells # ::alignments 1-1.1.1.1.1 2-1.1 2-1.2 4-1.1.3.r 5-1.1.3.1.1.1 6-1.1.3 7-1.1.3.2.1.1 9-1 10-1.2.1 10-1.2.1.r 11-1.2.4.r 12-1.2.4.1.1 13-1.1.2.1 (c3 / contrast-01~e.9 :ARG1 (i / induce-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"~e.1)) :ARG1 (c5 / cytotoxicity :mod (c6 / cellular~e.13) :ARG0-of (d / depend-01 :ARG1 (a2 / antibody))) :location~e.4 (a / and~e.6 :op1 (c / cell-line :name (n3 / name :op1 "A431"~e.5)) :op2 (c2 / cell-line :name (n4 / name :op1 "Caski"~e.7)))) :ARG2 (i2 / induce-01~e.2 :polarity~e.10 -~e.10 :ARG0 s :ARG2 (t / thing) :location~e.11 (c4 / cell-line :name (n5 / name :op1 "C33A"~e.12)))) # ::id pmid_1965_4571.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Antibody @-@ dependent cellular cytotoxicity response is dependent on the number of EGFR molecules per cell and on how efficiently cetuximab recognises its target ( Vincenzi et al , 2008 ) . # ::alignments 0-1.1.1.2.1 2-1.1.1.2 3-1.1.1.1 4-1.1.1 5-1.1 7-1 8-1.2.r 10-1.2.1.1 11-1.2.1.1.1.r 12-1.2.1.1.1.1.1.1 13-1.2.1.1.1 14-1.2.1 15-1.2.1.2 16-1.2 19-1.2.2.3 20-1.2.2.1.1.1 22-1.2.2.2.1.1 22-1.2.2.2.1.1.r 23-1.2.2.2 23-1.2.2.2.1 23-1.2.2.2.1.r 26-1.3.1.1.1.1.1 28-1.3.1.1 29-1.3.1.1.2.1 32-1.3.1.2.1 (d2 / depend-01~e.7 :ARG0 (r / respond-01~e.5 :ARG2 (c / cytotoxicity~e.4 :mod (c2 / cell~e.3) :ARG0-of (d3 / depend-01~e.2 :ARG1 (a / antibody~e.0)))) :ARG1~e.8 (a2 / and~e.16 :op1 (r2 / rate-entity-91~e.14 :ARG1 (n2 / number~e.10 :quant-of~e.11 (m / molecule~e.13 :mod (e / enzyme :name (n / name :op1 "EGFR"~e.12)))) :ARG2 (c3 / cell~e.15)) :op2 (r3 / recognize-02 :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.20)) :ARG1 (t2 / thing~e.23 :ARG1-of~e.23 (t / target-01~e.23 :ARG0~e.22 s~e.22)) :ARG1-of (e2 / efficient-01~e.19))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and~e.28 :op1 (p2 / person :name (n4 / name :op1 "Vincenzi"~e.26)) :op2 (p3 / person :mod (o / other~e.29))) :time (d / date-entity :year 2008~e.32)))) # ::id pmid_1965_4571.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok FACS analysis showed that cetuximab detected even more cell surface receptors in A431 and Caski cells ( P @ < 0.05 ) , when compared to a commercially available murine anti @-@ EGFR MAb , although the same was not observed for C33A cells ( Figure 5B ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2 6-1.2.2.2.1 7-1.2.2.2 8-1.2.2.1.1 9-1.2.2.1 10-1.2.2 11-1.2.3.r 12-1.2.3.1.1.1 13-1.2.3 14-1.2.3.2.1.1 15-1.2.3.1 15-1.2.3.2 18-1.2.6 20-1.2.6.1 21-1.2.6.1.1 24-1.2.4.r 25-1.2.4 28-1.2.4.2.2.1 29-1.2.4.2.2 30-1.2.4.2.3.1.1 31-1.2.4.2.1 33-1.2.4.2.1.1.1.1 36-1.2.5.r 38-1.2.5.2 40-1.2.5.1 40-1.2.5.1.r 41-1.2.5 42-1.2.5.3.r 43-1.2.5.3.1.1 44-1.2.5.3 47-1.3.1 48-1.3.1.1 (s / show-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (t / thing :name (n / name :op1 "FACS"~e.0))) :ARG1~e.3 (d / detect-01~e.5 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"~e.4)) :ARG1 (r / receptor~e.10 :mod (s3 / surface~e.9 :mod (c / cell~e.8)) :degree (m2 / more~e.7 :mod (e3 / even~e.6))) :location~e.11 (a2 / and~e.13 :op1 (c2 / cell-line~e.15 :name (n3 / name :op1 "A431"~e.12)) :op2 (c3 / cell-line~e.15 :name (n4 / name :op1 "Caski"~e.14))) :time~e.24 (c4 / compare-01~e.25 :ARG1 s2 :ARG2 (a4 / antibody :ARG0-of (c5 / counter-01~e.31 :ARG1 (e2 / enzyme :name (n6 / name :op1 "EGFR"~e.33))) :ARG2-of (a3 / available-02~e.29 :manner (c6 / commerce~e.28)) :mod (o2 / organism :name (n8 / name :op1 "Muridae"~e.30)) :mod (m / monoclone))) :concession~e.36 (o / observe-01~e.41 :polarity~e.40 -~e.40 :ARG1 (s5 / same-01~e.38) :location~e.42 (c7 / cell-line~e.44 :name (n7 / name :op1 "C33A"~e.43))) :ARG1-of (s6 / statistical-test-91~e.18 :ARG2 (l / less-than~e.20 :op1 0.05~e.21))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.47 :mod "5B"~e.48))) # ::id pmid_1965_4571.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Accordingly , at E/T ratios of 20 : 1 , cetuximab mediated ADCC in 26.4 and 15.1 % of A431 and Caski cells , respectively , but not in C33A cells ( 1.75 % ; Figure 5C ) . # ::alignments 0-1.1.4 4-1.3.1 4-1.3.2 5-1.3.1 5-1.3.2 6-1.3.2.1 8-1.3.2.2 10-1.1.1.1.1 11-1.1 11-1.2 13-1.1.3.r 14-1.1.3.1.2.1 15-1.1.3 16-1.1.3.2.2.1 17-1.1.3.1.2 17-1.1.3.2.2 19-1.1.3.1.1.1 20-1.1.3 21-1.1.3.2.1.1 22-1.1.3.1 22-1.1.3.2 24-1.1.3.3 26-1 27-1.2.1 27-1.2.1.r 28-1.2.4.r 29-1.2.4.1.1 30-1.1.2.1 32-1.2.4.2.1 33-1.2.4.2 36-1.4.1 37-1.4.1.1 (c3 / contrast-01~e.26 :ARG1 (m / mediate-01~e.11 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"~e.10)) :ARG1 (c5 / cytotoxicity :mod (c6 / cellular~e.30) :ARG0-of (d2 / depend-01 :ARG1 (a3 / antibody))) :location~e.13 (a / and~e.15,20 :op1 (c / cell-line~e.22 :name (n3 / name :op1 "A431"~e.19) :quant (p3 / percentage-entity~e.17 :value 26.4~e.14)) :op2 (c2 / cell-line~e.22 :name (n4 / name :op1 "Caski"~e.21) :quant (p / percentage-entity~e.17 :value 15.1~e.16)) :mod (r / respective~e.24)) :manner (a2 / accordingly~e.0)) :ARG2 (m2 / mediate-01~e.11 :polarity~e.27 -~e.27 :ARG0 s :ARG1 (t / thing) :location~e.28 (c4 / cell-line :name (n5 / name :op1 "C33A"~e.29) :quant (p2 / percentage-entity~e.33 :value 1.75~e.32))) :condition (e / equal-01 :ARG1 (r3 / ratio-of~e.4,5 :op1 (e2 / effector) :op2 (t2 / target-01)) :ARG2 (r4 / ratio-of~e.4,5 :op1 20~e.6 :op2 1~e.8)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "5C"~e.37))) # ::id pmid_1965_4571.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab and RxT cooperate in an additive manner to inhibit VEGF secretion # ::alignments 1-1.1.1.1 2-1.3.1 4-1 7-1.4 8-1.4.r 10-1.3 11-1.3.2.1.1.1 12-1.3.2 (c / cooperate-01~e.4 :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"~e.1)) :ARG1 (r / radiotherapy) :ARG2 (i / inhibit-01~e.10 :ARG0 (a2 / and~e.2 :op1 s :op2 r) :ARG1 (s3 / secrete-01~e.12 :ARG1 (p / protein :name (n3 / name :op1 "VEGF"~e.11)))) :manner~e.8 (a / additive~e.7)) # ::id pmid_1965_4571.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anti @-@ EGFR MAbs show suppressive effects on VEGF expression in vitro and in vivo ( Vincenzi et al , 2008 ; Meira et al , 2009 ) . # ::alignments 0-1.1 0-1.1.2 0-1.1.2.r 2-1.1.2.1.1.1 3-1.1.1.1 4-1 6-1.2 7-1.2.1.r 8-1.2.1.1.1.1 9-1.2.1 11-1.2.1.2.1 12-1.2.1.2.1 14-1.2.1.2 16-1.2.1.2.1 16-1.2.1.2.2 17-1.2.1.2.2 21-1.3.1.1.1.1.1.1 23-1.3.1.1.1 24-1.3.1.1.1.2.1 27-1.3.1.1.2.1 31-1.3.1.2.1.1.1.1 33-1.3.1 33-1.3.1.1.1 33-1.3.1.2.1 34-1.3.1.1.1.2.1 37-1.3.1.2.2.1 (s / show-01~e.4 :ARG0 (s2 / small-molecule~e.0 :name (n / name :op1 "MAbs"~e.3) :ARG0-of~e.0 (c / counter-01~e.0 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR"~e.2)))) :ARG1 (a / affect-01~e.6 :ARG1~e.7 (e2 / express-03~e.9 :ARG2 (p / protein :name (n3 / name :op1 "VEGF"~e.8)) :manner (a2 / and~e.14 :op1 (i / in-vitro~e.11,12,16) :op2 (i2 / in-vivo~e.16,17))) :ARG0-of (s3 / suppress-01)) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.33 :op1 (p2 / publication-91 :ARG0 (a4 / and~e.23,33 :op1 (p3 / person :name (n4 / name :op1 "Vincenzi"~e.21)) :op2 (p4 / person :mod (o / other~e.24,34))) :time (d / date-entity :year 2008~e.27)) :op2 (p5 / publication-91 :ARG0 (a5 / and~e.33 :op1 (p6 / person :name (n5 / name :op1 "Meira"~e.31)) :op2 p4) :time (d2 / date-entity :year 2009~e.37))))) # ::id pmid_1965_4571.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine whether cetuximab ( 100 μ @ g ml @⁻¹ ) had this effect in CC cells , we tested it alone or combined with RxT ( 5 Gy ) and VEGF expression was analysed by ELISA . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.2.1.1 5-1.3.2.2.2.1 10-1.3.2.2.2.2 15-1.3.2 17-1.3.2.3 20-1.3.2.3.1 22-1.1.1 23-1.1 24-1.1.2.1 26-1.1.2 27-1.1.2.2 31-1.1.2.2.2.1.1 34-1 35-1.2.2.1.1.1 36-1.2.2 38-1.2 39-1.2.1.r 40-1.2.1.1.1 (a / and~e.34 :op1 (t / test-01~e.23 :ARG0 (w / we~e.22) :ARG1 (o / or~e.26 :op1 s4~e.24 :op2 (c / combine-01~e.27 :ARG1 s4 :ARG2 (r2 / radiotherapy :quant (r / radiation-quantity :quant 5~e.31 :unit (g / gray)))))) :op2 (a3 / analyze-01~e.38 :ARG0~e.39 (t2 / thing :name (n5 / name :op1 "ELISA"~e.40)) :ARG1 (e / express-03~e.36 :ARG2 (p / protein :name (n4 / name :op1 "VEGF"~e.35)))) :purpose (e2 / examine-01~e.1 :ARG0 w :ARG1 (h / have-03~e.15 :mode~e.2 interrogative~e.2 :ARG0 (s4 / small-molecule :name (n7 / name :op1 "cetuximab"~e.3) :quant (v / volume-quantity :quant 100~e.5 :unit (m / microgram-per-milliliter~e.10))) :ARG1 (a4 / affect-01~e.17 :location (c2 / cell-line~e.20 :mod (d / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer"))))))) # ::id pmid_1965_4571.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab or RxT treatments decreased VEGF secretion in all cell lines ( Figures 5D @–@ F ; P @ < 0.05 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1 3-1.1.1 3-1.1.2 4-1 5-1.2.1.1.1 6-1.2 7-1.3.r 8-1.3.1 9-1.3 10-1.3 13-1.4.1.1 13-1.4.1.2 14-1.4.1.1.1 20-1.5 22-1.5.1 23-1.5.1.1 (d / decrease-01~e.4 :ARG0 (o / or~e.1 :op1 (t / treat-04~e.3 :ARG2 (s / small-molecule :name (n / name :op1 "cetuximab"~e.0))) :op2 (t2 / treat-04~e.3 :ARG2 (r / radiotherapy))) :ARG1 (s3 / secrete-01~e.6 :ARG1 (p / protein :name (n3 / name :op1 "VEGF"~e.5))) :location~e.7 (c / cell-line~e.9,10 :mod (a / all~e.8)) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.13 :mod "5D"~e.14) :op2 (f2 / figure~e.13 :mod "5F"))) :ARG1-of (s2 / statistical-test-91~e.20 :ARG2 (l / less-than~e.22 :op1 0.05~e.23))) # ::id pmid_1965_4571.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The combination of cetuximab with RxT for 24 h had an additive effect and , after 48 h of treatment , a further reduction was observed ( Figures 5D @–@ F ) , suggesting that these treatments have the potential of interfering with angiogenesis even in cells that do not express high EGFR levels . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 6-1.1.1.3.r 7-1.1.1.3.1 8-1.1.1.3.2 9-1.1 11-1.1.2.1 12-1.1.2 13-1 15-1.2.3 16-1.2.3.2.1 17-1.2.3.2.2 18-1.2.3.1.r 19-1.2.3.1 22-1.2.1.1 23-1.2.1 25-1.2 28-1.2.2.1.1 28-1.2.2.1.2 28-1.2.2.1.3 29-1.2.2.1.1.1 35-1.2.1.2 37-1.2.1.2.1.1.1 38-1.2.1.2.1.1 43-1.2.1.2.1.2 44-1.2.1.2.1.2.2.r 45-1.2.1.2.1.2.2 46-1.2.1.2.1.2.3.1 48-1.2.1.2.1.2.3 51-1.2.1.2.1.2.3.2.1 51-1.2.1.2.1.2.3.2.1.r 52-1.2.1.2.1.2.3.2 53-1.2.1.2.1.2.3.2.2.2 54-1.2.1.2.1.2.3.2.2.1.1.1 55-1.2.1.2.1.2.3.2.2 (a / and~e.13 :op1 (h / have-03~e.9 :ARG0 (c / combine-01~e.1 :ARG1~e.2 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.3)) :ARG2 (r2 / radiotherapy) :duration~e.6 (t / temporal-quantity :quant 24~e.7 :unit (h2 / hour~e.8))) :ARG1 (a2 / affect-01~e.12 :ARG1-of (a3 / add-02~e.11))) :op2 (o / observe-01~e.25 :ARG1 (r / reduce-01~e.23 :degree (f / further~e.22) :ARG0-of (s3 / suggest-01~e.35 :ARG1 (c2 / capable-01 :ARG1 (t2 / treat-04~e.38 :mod (t3 / this~e.37)) :ARG2 (i / interfere-01~e.43 :ARG0 t2 :ARG1~e.44 (a4 / angiogenesis~e.45) :location (c3 / cell-line~e.48 :mod (e2 / even~e.46) :ARG3-of (e3 / express-03~e.52 :polarity~e.51 -~e.51 :ARG2 (l / level~e.55 :quant-of (e4 / enzyme :name (n4 / name :op1 "EGFR"~e.54)) :ARG1-of (h3 / high-02~e.53)))))))) :ARG1-of (d / describe-01 :ARG0 (a6 / and :op1 (f2 / figure~e.28 :mod "5D"~e.29) :op2 (f3 / figure~e.28 :mod "5E") :op3 (f4 / figure~e.28 :mod "5F"))) :time (a5 / after~e.15 :op1~e.18 (t4 / treat-04~e.19) :quant (t5 / temporal-quantity :quant 48~e.16 :unit (h4 / hour~e.17))))) # ::id pmid_2023_3444.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A rapid , sensitive , reproducible and cost @-@ effective method for mutation profiling of colon cancer and metastatic lymph nodes ( PMID : 20233444 ) # ::alignments 1-1.2.2 3-1.2.3 7-1.2.5.1 10-1.2 11-1.2.6.r 12-1.2.6.1 13-1.2.6 14-1.2.6.1.1.r 15-1.2.6.1.1.1.2.1 16-1.2.6.1.1.1.2.2 17-1.2.6.1.1 18-1.2.6.1.1.2.2 19-1.2.6.1.1.2.1 20-1.2.6.1.1.2 (p3 / publication-91 :ARG8 "PMID20233444" :ARG1 (m / method~e.10 :ARG1-of (d / describe-01) :mod (r / rapid~e.1) :ARG0-of (s / sensitive-03~e.3) :ARG1-of (r2 / reproduce-01 :ARG1-of (p2 / possible-01)) :ARG0-of (a2 / affect-01 :ARG1 (c / cost~e.7)) :purpose~e.11 (p / profile-01~e.13 :ARG0 (m2 / mutate-01~e.12 :ARG1~e.14 (a3 / and~e.17 :op1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon"~e.15 :op2 "cancer"~e.16)) :op2 (n / node~e.20 :mod (l / lymph~e.19) :ARG1-of (m3 / metastasize-101~e.18))))))) # ::id pmid_2023_3444.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2023_3444.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the 238 common hot @-@ spot cancer mutations in 19 genes interrogated by the OncoCarta panel , mutations were detected in 7 different genes at 26 different nucleotide positions in our colon cancer samples . # ::alignments 0-1.1.2 2-1.1.2.1.1 3-1.1.2.1.3 8-1.1.2.1 9-1.1.2.1.2.r 10-1.1.2.1.2.1 11-1.1.2.1.2 12-1.1.2.1.2.2 13-1.1.2.1.2.2.1.r 15-1.1.2.1.2.2.1.1.1 16-1.1.2.1.2.2.1 18-1.1 20-1 21-1.1.1.r 22-1.1.1.1 23-1.1.1.2 24-1.1.1 25-1.1.1.3.r 26-1.1.1.3.1 27-1.1.1.2 28-1.1.1.3.2 29-1.1.1.3 30-1.1.1.3.4.r 31-1.1.1.3.4.3.1 31-1.1.1.3.4.3.1.r 32-1.1.1.3.4.2.1 33-1.1.1.3.4.2.2 34-1.1.1.3.4 34-1.1.1.3.4.3 34-1.1.1.3.4.3.r (d / detect-01~e.20 :ARG1 (m / mutate-01~e.18 :ARG1~e.21 (g / gene~e.24 :quant 7~e.22 :ARG1-of (d2 / differ-02~e.23,27) :part~e.25 (p / position~e.29 :quant 26~e.26 :mod (n / nucleotide~e.28) :ARG1-of d2 :location~e.30 (d3 / disease~e.34 :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon"~e.32 :op2 "cancer"~e.33) :ARG1-of~e.34 (s / sample-01~e.34 :ARG0~e.31 (w / we~e.31))))) :ARG1-of (i2 / include-91~e.0 :ARG2 (m2 / mutate-01~e.8 :quant 238~e.2 :ARG1~e.9 (g2 / gene~e.11 :quant 19~e.10 :ARG1-of (i / interrogate-01~e.12 :ARG0~e.13 (p2 / panel~e.16 :name (n2 / name :op1 "OncoCarta"~e.15)))) :ARG1-of (s2 / share-01~e.3 :degree (m3 / most)) :mod (h / hotspot))))) # ::id pmid_2023_3444.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Twenty @-@ four assays that detected mutations in more than 1 % of the samples were reconfigured into a new multiplexed panel , termed here as ColoCarta . # ::alignments 3-1.1 5-1.1.2 6-1.1.2.1 7-1.1.2.2.r 8-1.1.2.2.1 9-1.1.2.2.1 10-1.1.2.2.1.1.1 11-1.1.2.2.1.1 12-1.1.2.2.1.r 14-1.1.2.2 14-1.1.2.2.2 14-1.1.2.2.2.r 19-1.2.1 21-1.2 21-1.2.3.1 23-1.2.3 24-1.2.3.2 26-1.2.3.1.1.1 (c / configure-01 :ARG1 (a / assay-01~e.3 :quant 24 :ARG0-of (d / detect-01~e.5 :ARG1 (m / mutate-01~e.6) :location~e.7 (t2 / thing~e.14 :quant~e.12 (m2 / more-than~e.8,9 :op1 (p / percentage-entity~e.11 :value 1~e.10)) :ARG1-of~e.14 (s / sample-01~e.14)))) :ARG4 (p2 / panel~e.21 :ARG1-of (n / new-01~e.19) :mod (m3 / multiplex) :ARG1-of (t / term-01~e.23 :ARG3 (p3 / panel~e.21 :name (n2 / name :op1 "ColoCarta"~e.26)) :location (h / here~e.24))) :mod (a2 / again)) # ::id pmid_2023_3444.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation profiling was repeated on 32 mutant samples using ColoCarta and the results were identical to results with OncoCarta , demonstrating that this methodology was reproducible . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1 6-1.1.2 7-1.1.2.2 8-1.1.3 9-1.1.3.1.1.1 10-1 12-1.2.1 12-1.2.1.1 12-1.2.1.1.r 12-1.2.2 12-1.2.2.1 12-1.2.2.1.r 14-1.2 16-1.2.1 16-1.2.1.1 16-1.2.1.1.r 16-1.2.2 16-1.2.2.1 16-1.2.2.1.r 17-1.2.2.2.r 18-1.2.2.2.1.1 20-1.2.3 22-1.2.3.1.1.1.1 23-1.2.3.1.1.1 (a / and~e.10 :op1 (r4 / repeat-01~e.3 :ARG1 (p2 / profile-01~e.1 :ARG1 (m2 / mutate-01~e.0)) :ARG3~e.4 (m4 / mutate-01~e.6 :quant 32~e.5 :ARG1-of (s / sample-01~e.7)) :manner (u / use-01~e.8 :ARG1 (p3 / panel :name (n2 / name :op1 "ColoCarta"~e.9)))) :op2 (i / identical-01~e.14 :ARG1 (t / thing~e.12,16 :ARG2-of~e.12,16 (r / result-01~e.12,16)) :ARG2 (t2 / thing~e.12,16 :ARG2-of~e.12,16 (r2 / result-01~e.12,16) :instrument~e.17 (p / product :name (n / name :op1 "OncoCarta"~e.18))) :ARG0-of (d / demonstrate-01~e.20 :ARG1 (p4 / possible-01 :ARG1 (r3 / reproduce-01 :ARG0 (m / methodology~e.23 :mod (t3 / this~e.22))))))) # ::id pmid_2023_3444.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further evidence demonstrating the validity of the data was the fact that the mutation frequencies of the most common colon cancer mutations were similar to the COSMIC ( Catalog of Somatic Mutations in Cancer ) database . # ::alignments 0-1.2 1-1 2-1.3 4-1.3.1 5-1.3.1.1.r 7-1.3.1.1 13-1.1.1.1 13-1.1.1.2 14-1.1.1 15-1.1.1.1.2.r 17-1.1.1.1.2.1 18-1.1.1.1.2 19-1.1.1.1.1.2.1 20-1.1.1.1.1.2.2 21-1.1.2 23-1.1 26-1.1.2.1.1.1 31-1.1.2 35-1.1.2.1 (e / evidence-01~e.1 :ARG0 (r / resemble-01~e.23 :ARG1 (h / have-frequency-91~e.14 :ARG1 (m2 / mutate-01~e.13 :ARG1 (d4 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon"~e.19 :op2 "cancer"~e.20)) :ARG1-of~e.15 (s / share-01~e.18 :degree (m3 / most~e.17))) :mod (m / mutate-01~e.13)) :ARG2 (m4 / mutate-01~e.21,31 :source (d / database~e.35 :name (n / name :op1 "COSMIC"~e.26)))) :degree (f / further~e.0) :ARG0-of (d2 / demonstrate-01~e.2 :ARG1 (v / valid-02~e.4 :ARG1~e.5 (d3 / data~e.7)))) # ::id pmid_2023_3444.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The frequencies were 43.5 % for KRAS , 20.1 % for PIK3CA , and 12.1 % for BRAF @ . # ::alignments 1-1.1 1-1.2 1-1.3 3-1.1.2.1 4-1.1.2 7-1.1.1.1.1 10-1.2.2.1 11-1.2.2 14-1.2.1.1.1 17-1 18-1.3.2.1 19-1.3.2 22-1.3.1.1.1 (a2 / and~e.17 :op1 (h / have-frequency-91~e.1 :ARG1 (g2 / gene :name (n2 / name :op1 "KRAS"~e.7)) :ARG2 (p / percentage-entity~e.4 :value 43.5~e.3)) :op2 (h2 / have-frequency-91~e.1 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.14)) :ARG2 (p2 / percentage-entity~e.11 :value 20.1~e.10)) :op3 (h3 / have-frequency-91~e.1 :ARG1 (g3 / gene :name (n3 / name :op1 "BRAF"~e.22)) :ARG2 (p3 / percentage-entity~e.19 :value 12.1~e.18))) # ::id pmid_2023_3444.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , infrequent mutations in NRAS , AKT1 , ABL1 , and MET @ were detected . # ::alignments 0-1.1.1.1 1-1.1.1.1 3-1.1.1.2 3-1.1.1.2.1 3-1.1.1.2.1.r 4-1.1.1 7-1.1.1.1.1.1.1 11-1.1.1.1.2.1.1 15-1.1.1.1.3.1.1 20-1.1.1.1.4.1.1 23-1.1 (a / and :op2 (d / detect-01~e.23 :ARG1 (m / mutate-01~e.4 :ARG1 (a2 / and~e.0,1 :op1 (g4 / gene :name (n / name :op1 "NRAS"~e.7)) :op2 (g / gene :name (n2 / name :op1 "AKT1"~e.11)) :op3 (g2 / gene :name (n3 / name :op1 "ABL1"~e.15)) :op4 (g3 / gene :name (n4 / name :op1 "MET"~e.20))) :ARG1-of (f / frequent-02~e.3 :polarity~e.3 -~e.3)))) # ::id pmid_2023_3444.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation profiling of metastatic lymph nodes and their corresponding primary tumors showed that they were 89.7 % concordant . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1.1.1 6-1.1 7-1.1.2.2.1 7-1.1.2.2.1.r 8-1.1.2.2 9-1.1.2.1 10-1.1.2 11-1 12-1.2.r 13-1.2.1 14-1.2.1.r 15-1.2.2.1 16-1.2.2 17-1.2 (s / show-01~e.11 :ARG0 (a / and~e.6 :op1 (p2 / profile-01~e.1 :ARG1 (m / mutate-01~e.0 :ARG1~e.2 (n / node~e.5 :mod (l / lymph~e.4 :mod (m2 / metastasis~e.3))))) :op2 (t / tumor~e.10 :mod (p3 / primary~e.9) :ARG1-of (c / correspond-02~e.8 :ARG2~e.7 n~e.7))) :ARG1~e.12 (c2 / concordant~e.17 :domain~e.14 a~e.13 :mod (p / percentage-entity~e.16 :value 89.7~e.15))) # ::id pmid_2023_3444.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All mutations found in the lymph nodes were also found in the corresponding primary tumors , but in 4 cases a mutation was present in the primary tumor only . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1 3-1.1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.1.1 8-1.1.3 9-1.1 10-1.1.2.r 12-1.1.2.2 13-1.1.2.1 14-1.1.2 16-1 17-1.2.r 18-1.2.2.1 19-1.2.2 21-1.2 24-1.2.3.r 26-1.2.3.1 27-1.2.3 28-1.2.3.2 (c / contrast-01~e.16 :ARG1 (f2 / find-01~e.9 :ARG1 (m / mutate-01~e.1 :ARG1-of (f / find-01~e.2 :location~e.3 (n / node~e.6 :mod (l / lymph~e.5))) :mod (a / all~e.0)) :location~e.10 (t / tumor~e.14 :mod (p / primary~e.13) :ARG1-of (c2 / correspond-02~e.12)) :mod (a2 / also~e.8)) :ARG2~e.17 (m2 / mutate-01~e.21 :quant 1 :mod (c3 / case-04~e.19 :quant 4~e.18) :location~e.24 (t2 / tumor~e.27 :mod p~e.26 :mod (o / only~e.28)))) # ::id pmid_2023_3444.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2023_3444.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutations were detected in control DNAs from intact and FFPETsamples # ::alignments 1-1.1 3-1 4-1.2.r 5-1.2 5-1.2.3 5-1.2.3.r 6-1.2.2.1 7-1.2.4.r 8-1.2.4.1.1 9-1.2.4 (d / detect-01~e.3 :ARG1 (m / mutate-01~e.1) :location~e.4 (n2 / nucleic-acid~e.5 :wiki "DNA" :name (n3 / name :op1 "DNA"~e.6) :ARG0-of~e.5 (c / control-01~e.5) :source~e.7 (a / and~e.9 :op1 (t2 / thing :mod (i / intact~e.8) :ARG1-of (s / sample-01)) :op2 (t3 / thing :name (n / name :op1 "FFPET") :ARG1-of s)))) # ::id pmid_2023_3444.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previously described mutations in control cell lines were detected . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1 5-1.1.2 6-1.1.2 8-1 (d / detect-01~e.8 :ARG1 (m / mutate-01~e.2 :ARG1-of (d2 / describe-01~e.1 :time (p / previous~e.0)) :location~e.3 (c / cell-line~e.5,6 :ARG0-of (c2 / control-01~e.4)))) # ::id pmid_2023_3444.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @ _V600E , HRAS @ _G12D , NRAS @ _Q61L , PIK3CA @ _E545K , KRAS @ _G13D , NRAS @ _Q61K , EGFR @ 1_S125L , and PIK3CA @ _H1047R were detected in the appropriate cell lines ( A2058 , HS578T , HL60 , MCF7 , MDAMB231 , NCI @-@ H1299 , NCI @-@ H1395 , and UACC @-@ 893 , respectively ) . # ::alignments 1-1.1.1.2.1 6-1.1.2.2.1 11-1.1.3.2.1 11-1.1.6.2.1 16-1.1.4.2.1 16-1.1.8.2.1 21-1.1.5.2.1 26-1.1.3.2.1 26-1.1.6.2.1 31-1.1.7.2.1 35-1.1 37-1.1.4.2.1 37-1.1.8.2.1 41-1 42-1.2.r 44-1.2.1 45-1.2 46-1.2 48-1.2.2.1.1.2.1 50-1.2.2.1.2.2.1 52-1.2.2.1.3.2.1 54-1.2.2.1.4.2.1 56-1.2.2.1.5.2.1 58-1.2.2.1.6.2.1 58-1.2.2.1.7.2.1 60-1.2.2.1.6.2.1 62-1.2.2.1.6.2.1 62-1.2.2.1.7.2.1 64-1.2.2.1.7.2.1 66-1.2.2.1 67-1.2.2.1.8.2.1 69-1.2.2.1.8.2.1 (d / detect-01~e.41 :ARG1 (a3 / and~e.35 :op1 (g2 / gene :wiki "BRAF_(gene)" :name (n3 / name :op1 "BRAF"~e.1) :ARG1-of (m2 / mutate-01 :value "V600E")) :op2 (g3 / gene :wiki - :name (n4 / name :op1 "HRAS"~e.6) :ARG1-of (m3 / mutate-01 :value "G12D")) :op3 (g4 / gene :wiki - :name (n5 / name :op1 "NRAS"~e.11,26) :ARG1-of (m4 / mutate-01 :value "Q61L")) :op4 (g5 / gene :wiki - :name (n6 / name :op1 "PIK3CA"~e.16,37) :ARG1-of (m5 / mutate-01 :value "E545K")) :op5 (g6 / gene :wiki - :name (n7 / name :op1 "KRAS"~e.21) :ARG1-of (m6 / mutate-01 :value "G13D")) :op6 (g7 / gene :wiki - :name (n8 / name :op1 "NRAS"~e.11,26) :ARG1-of (m7 / mutate-01 :value "Q61K")) :op7 (g / gene :wiki - :name (n2 / name :op1 "EGFR"~e.31) :ARG1-of (m9 / mutate-01 :value "S125L")) :op8 (g8 / gene :wiki - :name (n / name :op1 "PIK3CA"~e.16,37) :ARG1-of (m8 / mutate-01 :value "H1047R"))) :location~e.42 (c / cell-line~e.45,46 :ARG1-of (a / appropriate-02~e.44) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.66 :op1 (c2 / cell-line :wiki - :name (n9 / name :op1 "A2058"~e.48)) :op2 (c3 / cell-line :wiki - :name (n16 / name :op1 "HS578T"~e.50)) :op3 (c4 / cell-line :wiki "HL60" :name (n12 / name :op1 "HL60"~e.52)) :op4 (c5 / cell-line :wiki "MCF-7" :name (n15 / name :op1 "MCF7"~e.54)) :op5 (c6 / cell-line :wiki - :name (n13 / name :op1 "MDAMB231"~e.56)) :op6 (c7 / cell-line :wiki - :name (n11 / name :op1 "NCI-H1299"~e.58,60,62)) :op7 (c8 / cell-line :wiki - :name (n14 / name :op1 "NCI-H1395"~e.58,62,64)) :op8 (c9 / cell-line :wiki - :name (n10 / name :op1 "UACC-893"~e.67,69)))))) # ::id pmid_2023_3444.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The appropriate mutation was found in MCF @-@ 7 ( PIK3CA @ _E545K ) from both intact DNA and DNA isolated from FFPET . # ::alignments 1-1.1.1 2-1.1 2-1.2.2.1 2-1.2.2.1.2 2-1.2.2.1.2.r 4-1 5-1.2.r 6-1.2.1.1 8-1.2.1.1 11-1.2.2.1.1.1 17-1.2.3.1.3 18-1.2.3.1.2.1 18-1.2.3.2.2.1 19-1.2.3 20-1.2.3.1.2.1 20-1.2.3.2.2.1 21-1.2.3.2.3 22-1.2.3.2.3.1.r 23-1.2.3.2.3.1.1.1 (f / find-01~e.4 :ARG1 (m / mutate-01~e.2 :ARG1-of (a / appropriate-02~e.1)) :location~e.5 (c / cell-line :name (n / name :op1 "MCF-7"~e.6,8) :ARG1-of (m2 / mean-01 :ARG2 (g / gene~e.2 :name (n2 / name :op1 "PIK3CA"~e.11) :ARG1-of~e.2 (m3 / mutate-01~e.2 :value "E545K"))) :location (a3 / and~e.19 :op1 (n3 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.18,20) :mod (i / intact~e.17)) :op2 (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA"~e.18,20) :ARG1-of (i2 / isolate-01~e.21 :ARG2~e.22 (t / thing :name (n4 / name :op1 "FFPET"~e.23))))))) # ::id pmid_2023_3444.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok DNAs from clinical samples , control cell lines , and cell lines formalin @-@ fixed , paraffin @-@ embedded cell lines showed the same rates of primer extension and performance on mass spectrometer . # ::alignments 0-1.1.2.1 1-1.1.3.r 2-1.1.3.1.1 3-1.1.3.1 3-1.1.3.1.2 3-1.1.3.1.2.r 5-1.1.3.2.1 6-1.1.3.2 7-1.1.3.2 9-1.1.3 10-1.1.3.3 10-1.1.3.4 11-1.1.3.3 12-1.1.3.3.1.1 14-1.1.3.3.1 16-1.1.3.4.1.1 18-1.1.3.4.1 19-1.1.3.4 20-1.1.3.4 21-1 23-1.2.2 24-1.2 26-1.2.1.1.2 27-1.2.1.1 28-1.2.1 29-1.2.1.2 31-1.2.1.1.1.1 (s / show-01~e.21 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"~e.0) :source~e.1 (a2 / and~e.9 :op1 (t / thing~e.3 :mod (c / clinic~e.2) :ARG1-of~e.3 (s4 / sample-01~e.3)) :op2 (c2 / cell-line~e.6,7 :ARG1-of (c3 / control-01~e.5)) :op3 (c4 / cell-line~e.10,11 :ARG0-of (f / fix-01~e.14 :ARG1 (f2 / formalin~e.12))) :op4 (c5 / cell-line~e.10,19,20 :ARG1-of (e2 / embed-01~e.18 :ARG2 (p3 / paraffin~e.16))))) :ARG1 (r / rate-entity-91~e.24 :ARG1 (a / and~e.28 :op1 (e / extend-01~e.27 :instrument (s3 / spectometer :mod (m / mass~e.31)) :mod (p / primer~e.26)) :op2 (p2 / perform-01~e.29 :instrument s3)) :ARG1-of (s2 / same-01~e.23))) # ::id pmid_2023_3444.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The proportion of the mutated alleles in each cell line , as observed from the area under the mutant peak on the spectra , ranged from 0.4 @-@ 0.6 , as expected for a pure clonal population with a heterozygote mutation . # ::alignments 1-1.3 2-1.3.1.r 4-1.3.1.1 5-1.3.1 6-1.3.1.2.r 7-1.3.1.2.1 8-1.3.1.2 9-1.3.1.2 11-1.3.2.r 12-1.3.2 13-1.3.2.1.r 15-1.3.2.1 16-1.3.2.1.1 18-1.3.2.1.1.1.1 19-1.3.2.1.1.1 24-1 26-1.1 28-1.2 30-1.4.r 31-1.4 32-1.4.1.r 34-1.4.1.3 35-1.4.1.1 36-1.4.1 37-1.4.1.2.r 39-1.4.1.2.1 40-1.4.1.2 (r / range-01~e.24 :ARG3 0.4~e.26 :ARG4 0.6~e.28 :ARG1 (p2 / proportion-01~e.1 :ARG1~e.2 (a / allele~e.5 :ARG1-of (m2 / mutate-01~e.4) :location~e.6 (c2 / cell-line~e.8,9 :mod (e2 / each~e.7))) :ARG1-of~e.11 (o / observe-01~e.12 :location~e.13 (a2 / area~e.15 :location (u / under~e.16 :op1 (p3 / peak~e.19 :ARG0-of (m3 / mutate-01~e.18) :location (s / spectrum)))))) :ARG1-of~e.30 (e / expect-01~e.31 :prep-for~e.32 (p / population~e.36 :mod (c / clone~e.35) :ARG1-of~e.37 (m / mutate-01~e.40 :ARG3 (h / heterozygote~e.39)) :mod (p4 / pure~e.34)))) # ::id pmid_2023_3444.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Spectra for cell line UACC @-@ 893 had equal fractions of mutant and wt alleles ( Fig . 2A ) . # ::alignments 2-1.1.1 3-1.1.1 4-1.1.1.1.1 6-1.1.1.1.1 7-1 8-1.2 9-1.2.1 9-1.2.2 11-1.2.1.1.1 13-1.2.2.1.1 14-1.2.1.1 14-1.2.2.1 16-1.3.1 19-1.3.1.1 (h / have-03~e.7 :ARG0 (s / spectrum :mod (c / cell-line~e.2,3 :name (n / name :op1 "UACC-893"~e.4,6))) :ARG1 (e / equal-01~e.8 :ARG1 (f / fraction-01~e.9 :ARG1 (a / allele~e.14 :ARG1-of (m / mutate-01~e.11))) :ARG2 (f2 / fraction-01~e.9 :ARG1 (a2 / allele~e.14 :mod (w / wild-type~e.13)))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure~e.16 :mod "2A"~e.19))) # ::id pmid_2023_3444.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One exception to this distribution among cell lines was seen in A2058 , which showed spectra consistent with 2 copies of the WT allele and one mutant BRAF @ mutant allele ( Fig . 2B ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1.1.1.1.r 3-1.1.1.1.2 4-1.1.1.1 6-1.1.1.1.1 7-1.3 9-1 11-1.3.1.1 14-1.3.2 15-1.3.2.1 16-1.3.2.1.1 17-1.3.2.1.1.1.r 18-1.3.2.1.1.1.1.1 19-1.3.2.1.1.1.1 19-1.3.2.1.1.1.2 20-1.3.2.1.1.1.1.2.r 22-1.3.2.1.1.1.1.2.1 23-1.3.2.1.1.1.1.2 24-1.3.2.1.1.1 26-1.3.2.1.1.1.2.1.1 28-1.3.2.1.1.1.2.1.1.1.1.1 30-1.3.2.1.1.1.2.1.1 31-1.3.2.1.1.1.2.1 33-1.2.1 36-1.2.1.1 (s / see-01~e.9 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (e / except-01~e.1 :ARG2~e.2 (d2 / distribute-01~e.4 :ARG1 (c2 / cell-line~e.6) :mod (t2 / this~e.3)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.33 :mod "2B"~e.36)) :location (c / cell-line~e.7 :name (n / name :op1 "A2058"~e.11) :ARG0-of (s2 / show-01~e.14 :ARG1 (s3 / spectra~e.15 :ARG1-of (c3 / consistent-01~e.16 :ARG2~e.17 (a / and~e.24 :op1 (c4 / copy-01~e.19 :quant 2~e.18 :ARG1~e.20 (a2 / allele~e.23 :mod (w / wild-type~e.22))) :op2 (c5 / copy-01~e.19 :ARG1 (a3 / allele~e.31 :ARG3-of (m / mutate-01~e.26,30 :ARG1 (g / gene :name (n2 / name :op1 "BRAF"~e.28))))))))))) # ::id pmid_2023_3444.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The 3 alleles of BRAF @ in A2058 are consistent with the observation that there are 3 copies of chromosome 7 in this cell line ( COSMIC in the SNP Array Based LOH and Copy Number Analysis data base ) [ @ 21 @ ] . # ::alignments 1-1.1.1 2-1.1 5-1.1.2.1.1 7-1.1.3.r 8-1.1.3.1.1 10-1 11-1.2.r 13-1.2 16-1.2.1 17-1.2.1.1.1 18-1.2.1.1 19-1.2.1.1.2.r 20-1.2.1.1.2 21-1.2.1.1.2.1 23-1.2.1.2.1 24-1.2.1.2 25-1.2.1.2 27-1.3.1.1.1 30-1.3.1.2.1.1.1 31-1.3.1.2.1.1.2 32-1.3.1.2.1.1.3 33-1.3.1.2.1.1.4 34-1.3.1.2 35-1.3.1.2.2.1.1 36-1.3.1.2.2.1.2 37-1.3.1.2.2.1.3 43-1.4.1.1.1 (c / consistent-01~e.10 :ARG1 (a / allele~e.2 :quant 3~e.1 :mod (g / gene :name (n / name :op1 "BRAF"~e.5)) :location~e.7 (c2 / cell-line :name (n2 / name :op1 "A2058"~e.8))) :ARG2~e.11 (o / observe-01~e.13 :ARG1 (b / be-located-at-91~e.16 :ARG1 (c3 / copy-01~e.18 :quant 3~e.17 :ARG1~e.19 (c4 / chromosome~e.20 :mod 7~e.21)) :ARG2 (c5 / cell-line~e.24,25 :mod (t / this~e.23)))) :ARG1-of (d / describe-01 :ARG0 (d2 / database :name (n3 / name :op1 "COSMIC"~e.27) :location (a3 / and~e.34 :op1 (d5 / database :name (n6 / name :op1 "SNP"~e.30 :op2 "Array"~e.31 :op3 "Based"~e.32 :op4 "LOH"~e.33)) :op2 (d3 / database :name (n5 / name :op1 "Copy"~e.35 :op2 "Number"~e.36 :op3 "Analysis"~e.37))))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG0-of (c6 / cite-01 :ARG1 21~e.43)))) # ::id pmid_2023_3444.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Sequenom platform was sensitive and quantitative # ::alignments 2-1.1.1.1.1 3-1.1.1 5-1.1 6-1 7-1.2 (a / and~e.6 :op1 (s / sensitive-03~e.5 :ARG0 (p / platform~e.3 :name (n / name :op1 "Sequenom"~e.2))) :op2 (q / quantitative~e.7 :domain p)) # ::id pmid_2023_3444.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pilot studies demonstrated that the assays worked with as little as 1 ng of DNA ( Fig . 3 ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.1 6-1.2 8-1.2.1.1.r 9-1.2.1.1.3 11-1.2.1.1.1 12-1.2.1.1.2 13-1.2.1.1.3.1.r 14-1.2.1.1.3.1.2.1 16-1.3.1 19-1.3.1.1 (d / demonstrate-01~e.2 :ARG0 (s / study-01~e.1 :mod (p / pilot~e.0)) :ARG1~e.3 (w / work-09~e.6 :ARG1 (a / assay-01~e.5 :mod~e.8 (c / concentration-quantity :quant 1~e.11 :unit (n / nanogram~e.12) :mod (l / little~e.9 :compared-to~e.13 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.14)))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.16 :mod 3~e.19))) # ::id pmid_2023_3444.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The fraction of unextended primer was .09 even when the input DNA was between 1 @-@ 3 ng , When concentrations of the amount of DNA was between 3 @-@ 14 ng , the fraction of unextended primer was similar , .07 . # ::alignments 1-1.1 4-1.1.2 10-1.1.3.3 11-1.1.3.2.1 13-1.1.3.4 14-1.1.3.4.1.1 16-1.1.3.4.2.1 16-1.2.2.1.2.1.1 17-1.1.3.4.1.2 17-1.2.2.1.2.2.2 20-1.1.3.4.1 20-1.1.3.4.2 20-1.2.2 20-1.2.2.1.2.1 20-1.2.2.1.2.2 21-1.2.2.1.r 23-1.2.2.1 25-1.1.3.2.1 25-1.2.2.1.1.2.1 27-1.1.3.4 27-1.2.2.1.2 28-1.1.3.4.2.1 30-1.2.2.1.2.2.1 31-1.1.3.4.1.2 34-1.1 34-1.2 37-1.2.1 39-1.2.3 (m / multi-sentence :snt1 (f4 / fraction~e.1,34 :quant 0.09 :part-of (p / primer~e.4 :ARG1-of (e / extend-01 :polarity -)) :condition (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.11,25) :mod (i / input~e.10) :quant (b / between~e.13,27 :op1 (c / concentration-quantity~e.20 :quant 1~e.14 :unit (n / nanogram~e.17,31)) :op2 (c2 / concentration-quantity~e.20 :quant 3~e.16,28 :unit n)))) :snt2 (f5 / fraction~e.34 :part-of (p2 / primer~e.37 :quant 0.07 :ARG1-of (e2 / extend-01 :polarity -)) :condition (c3 / concentrate-02~e.20 :ARG1~e.21 (a / amount-01~e.23 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.25)) :ARG2 (b2 / between~e.27 :op1 (c4 / concentration-quantity~e.20 :quant 3~e.16 :unit n2) :op2 (c5 / concentration-quantity~e.20 :quant 14~e.30 :unit (n2 / nanogram~e.17))))) :ARG1-of (r / resemble-01~e.39))) # ::id pmid_2023_3444.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the assays worked well even when only 1 ng of DNA was used . # ::alignments 0-1 3-1.1.1 4-1.1 5-1.1.2 6-1.1.3 7-1.1.3 8-1.1.3.1.1.3.3 9-1.1.3.1.1.3.1 10-1.1.3.1.1.3.2 11-1.1.3.1.1.3.r 12-1.1.3.1.1.2.1 14-1.1.3.1 (c3 / cause-01~e.0 :ARG1 (w / work-09~e.4 :ARG1 (a / assay-01~e.3) :manner (w2 / well~e.5) :concession (e / even-when~e.6,7 :op1 (u / use-01~e.14 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.12) :quant~e.11 (c2 / concentration-quantity :quant 1~e.9 :unit (n / nanogram~e.10) :mod (o / only~e.8)))))) :ARG2-of (c / contrast-01)) # ::id pmid_2023_3444.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In clinical samples with some assays it was possible to detect mutations that only represented 5 % of the total 2 peak areas . # ::alignments 1-1.1.2.1.2 2-1.1.2 2-1.1.2.1 2-1.1.2.1.r 3-1.1.2.1.1.r 4-1.1.2.1.1.1 5-1.1.2.1.1 8-1 10-1.1 11-1.1.1 13-1.1.1.1.2 14-1.1.1.1 15-1.1.1.1.1.1 16-1.1.1.1.1 19-1.1.1.1.1.2.1.2 20-1.1.1.1.1.2.1.1 21-1.1.1.1.1.2.1.3 22-1.1.1.1.1.2.1 (p2 / possible-01~e.8 :ARG1 (d / detect-01~e.10 :ARG1 (m / mutate-01~e.11 :ARG0-of (r / represent-01~e.14 :ARG1 (p / percentage-entity~e.16 :value 5~e.15 :ARG3-of (i / include-91 :ARG1 (a2 / area~e.22 :quant 2~e.20 :mod (t / total~e.19) :mod (p3 / peak~e.21)))) :mod (o / only~e.13))) :location (t2 / thing~e.2 :ARG1-of~e.2 (s / sample-01~e.2 :manner~e.3 (a / assay-01~e.5 :quant (s2 / some~e.4)) :mod (c / clinic~e.1))))) # ::id pmid_2023_3444.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The spectra in Fig. 4 show a small but clear peak at the expected size for a PIK3CA @ 1047R mutation in a lymph node . # ::alignments 1-1.1 3-1.1.1.1 5-1.1.1.1.1 7-1 9-1.2.1 10-1.2.1.1 11-1.2.1.1.1.1 12-1.2 12-1.2.1.1.1 15-1.2.1.1.1.2.1.2 16-1.2.1.1.1.2.1 20-1.2.1.1.1.2.1.1.2.1.1 22-1.2.1.1.1.2.1.1.1 23-1.2.1.1.1.2.1.1 24-1.2.1.1.1.2.1.1.3.r 26-1.2.1.1.1.2.1.1.3.1 27-1.2.1.1.1.2.1.1.3 (s / show-01~e.7 :ARG0 (s2 / spectra~e.1 :ARG1-of (d / describe-01 :ARG0 (f / figure~e.3 :mod 4~e.5))) :ARG1 (p / peak~e.12 :mod (s3 / small~e.9 :ARG1-of (c / contrast-01~e.10 :ARG2 (p2 / peak~e.12 :mod (c2 / clear~e.11) :ARG0-of (h / have-03 :ARG1 (s4 / size-01~e.16 :ARG1 (m / mutate-01~e.23 :value "1047R"~e.22 :ARG2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.20)) :location~e.24 (n4 / node~e.27 :mod (l / lymph~e.26))) :ARG1-of (e / expect-01~e.15)))))))) # ::id pmid_2023_3444.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also were able to demonstrate the sensitivity of the platform by performing a cell mixing experiment . # ::alignments 0-1.1.1 1-1.1.3 3-1 5-1.1 7-1.1.2 8-1.1.2.1.r 10-1.1.2.1 11-1.1.4.r 12-1.1.4 14-1.1.4.2.1.1 15-1.1.4.2.1 16-1.1.4.2 (p2 / possible-01~e.3 :ARG1 (d / demonstrate-01~e.5 :ARG0 (w / we~e.0) :ARG1 (s / sensitive-03~e.7 :ARG0~e.8 (p3 / platform~e.10)) :mod (a / also~e.1) :manner~e.11 (p / perform-02~e.12 :ARG0 w :ARG1 (e / experiment-01~e.16 :ARG1 (m / mix-01~e.15 :ARG1 (c / cell~e.14)))))) # ::id pmid_2023_3444.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation analysis was done using MCF @-@ 7 cell line DNA alone or mixed with SKBR3 at various percentages . # ::alignments 0-1.1 1-1 4-1.2.1 4-1.2.2 5-1.2.1.1.3.1.1 7-1.2.1.1.3.1.1 8-1.2.1.1.3 9-1.2.1.1.3 9-1.2.2.1.2 10-1.2.1.1.2.1 11-1.2.1.1.4 12-1.2 13-1.2.2.1 15-1.2.2.1.2.1.1 18-1.2.2.2 (a / analyze-01~e.1 :ARG1 (m / mutate-01~e.0) :manner (o / or~e.12 :op1 (u / use-01~e.4 :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"~e.10) :mod (c / cell-line~e.8,9 :name (n / name :op1 "MCF-7"~e.5,7)) :mod (a2 / alone~e.11))) :op2 (u2 / use-01~e.4 :ARG1 (m2 / mix-01~e.13 :ARG1 n3 :ARG2 (c2 / cell-line~e.9 :name (n2 / name :op1 "SKBR3"~e.15))) :degree (p / percentage~e.18 :ARG1-of (v / vary-01))))) # ::id pmid_2023_3444.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MCF @-@ 7 cells contain a PIK3CA mutation , and SKBR3 cells do not . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1.1 3-1.2.2 4-1.1 4-1.2 6-1.1.2.1.1.1 7-1.1.2 9-1 10-1.2.2.1.1 11-1.1.1 13-1.2.1 13-1.2.1.r (a / and~e.9 :op1 (c / contain-01~e.4 :ARG0 (c3 / cell-line~e.3,11 :name (n2 / name :op1 "MCF-7"~e.0,2)) :ARG1 (m / mutate-01~e.7 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.6)))) :op2 (c2 / contain-01~e.4 :polarity~e.13 -~e.13 :ARG0 (c4 / cell-line~e.3 :name (n3 / name :op1 "SKBR3"~e.10)) :ARG1 g)) # ::id pmid_2023_3444.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fig. 5 demonstrates that the mutation was detectable even when the MCF @-@ 7 cells represented only 5 to 10 % of the total DNA and only 5 to 2.5 % of the alleles . # ::alignments 0-1.1 2-1.1.1 4-1 9-1.2.1.1 13-1.2.2.1.1.1 15-1.2.2.1.1.1 16-1.2.2.1 17-1.2.2 18-1.2.2.2.2.3 19-1.2.2.2.1.1.1 19-1.2.2.2.2.1.1 21-1.2.2.2.1.2.1 22-1.2.2.2.1.1 22-1.2.2.2.1.2 25-1.2.2.2.1.3.1.3 26-1.2.2.2.1.3.1.2.1 27-1.2.2.2 27-1.2.2.2.1 27-1.2.2.2.1.r 27-1.2.2.2.2 27-1.2.2.2.2.r 28-1.2.2.2.2.3 29-1.2.2.2.2.1.1 31-1.2.2.2.2.2.1 32-1.2.2.2.2.1 32-1.2.2.2.2.2 35-1.2.2.2.2.4.1 (d / demonstrate-01~e.4 :ARG0 (f / figure~e.0 :mod 5~e.2) :ARG1 (h / have-concession-91 :ARG1 (p3 / possible-01 :ARG1 (d2 / detect-01~e.9)) :ARG2 (r / represent-01~e.17 :ARG0 (c / cell-line~e.16 :name (n / name :op1 "MCF-7"~e.13,15)) :ARG1 (a / and~e.27 :op1~e.27 (b / between~e.27 :op1 (p4 / percentage-entity~e.22 :value 5~e.19) :op2 (p / percentage-entity~e.22 :value 10~e.21) :ARG3-of (i / include-91 :ARG2 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.26) :mod (t / total~e.25)))) :op2~e.27 (b2 / between~e.27 :op1 (p6 / percentage-entity~e.32 :value 5~e.19,29) :op2 (p5 / percentage-entity~e.32 :value 2.5~e.31) :mod (o / only~e.18,28) :ARG3-of (i2 / include-91 :ARG2 (a2 / allele~e.35))))))) # ::id pmid_2023_3444.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This sensitivity is important for mutation detection in clinical cancer samples , which usually contain some amount of normal tissue , which dilutes the number of tumor cells . # ::alignments 0-1.1.1 1-1.1 2-1.1.r 3-1 4-1.2.r 5-1.2.1 6-1.2 7-1.2.2.r 8-1.2.2.3 9-1.2.2.1.2.1 10-1.2.2 13-1.2.2.2.2 13-1.2.2.2.2.r 14-1.2.2.2 15-1.2.2.2.1.1 16-1.2.2.2.1 17-1.2.2.2.1.3.r 18-1.2.2.2.1.3 19-1.2.2.2.1.2 22-1.2.2.2.1.4 24-1.2.2.2.1.4.1 25-1.2.2.2.1.4.1.1.r 26-1.2.2.2.1.4.1.1.1 27-1.2.2.2.1.4.1.1 (i / important~e.3 :domain~e.2 (s / sensitive-03~e.1 :mod (t3 / this~e.0)) :purpose~e.4 (d / detect-01~e.6 :ARG1 (m / mutate-01~e.5) :location~e.7 (s2 / sample-01~e.10 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.9)) :ARG0-of (c / contain-01~e.14 :ARG1 (a2 / amount~e.16 :mod (s3 / some~e.15) :quant-of (t / tissue~e.19) :ARG1-of~e.17 (n2 / normal-02~e.18) :ARG0-of (d3 / dilute-01~e.22 :ARG1 (n / number~e.24 :quant-of~e.25 (c2 / cell~e.27 :mod (t2 / tumor~e.26))))) :manner~e.13 (u / usual~e.13)) :mod (c4 / clinic~e.8)))) # ::id pmid_2023_3444.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is of particular concern when profiling lymph nodes , which may contain a minority of tumor cells . # ::alignments 0-1.1 3-1.3 4-1 5-1.2.r 6-1.2 7-1.2.1.1 8-1.2.1 11-1.2.1.2.2 12-1.2.1.2 14-1.2.1.2.1.2 15-1.2.1.2.1.2.r 16-1.2.1.2.1.1 17-1.2.1.2.1 (c / concern-01~e.4 :ARG0 (t2 / this~e.0) :time~e.5 (p / profile-01~e.6 :ARG1 (n / node~e.8 :mod (l / lymph~e.7) :ARG0-of (c2 / contain-01~e.12 :ARG1 (c3 / cell~e.17 :mod (t / tumor~e.16) :quant~e.15 (m / minority~e.14)) :ARG1-of (p2 / possible-01~e.11)))) :mod (p3 / particular~e.3)) # ::id pmid_2023_3444.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Frequencies of C @-@ 07 mutations in KRAS , NRAS , PIK3CA , and BRAF @ detected with OncoCarta and the Sequenom platform were similar to previous reports # ::alignments 1-1.1 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1 9-1.1.1.2.1.1.1 13-1.1.1.2.2.1.1 17-1.1.1.2.3.1.1 20-1.1.1.2 22-1.1.1.2.4.1.1 24-1.1.2 25-1.1.2.1.r 26-1.1.2.1.1.1.1 27-1.1.2.1 29-1.1.2.1.2.1.1 30-1.1.2.1.1 30-1.1.2.1.2 32-1 33-1.2.r 34-1.2.1.1 35-1.2 35-1.2.1 35-1.2.1.r (r2 / resemble-01~e.32 :ARG1 (h / have-frequency-91~e.1 :ARG1 (m / mutate-01~e.6 :ARG0 (c / cell-line :name (n8 / name :op1 "C-07"~e.3,5)) :ARG1 (a2 / and~e.20 :op1 (g2 / gene :name (n4 / name :op1 "KRAS"~e.9)) :op2 (g3 / gene :name (n5 / name :op1 "NRAS"~e.13)) :op3 (g4 / gene :name (n6 / name :op1 "PIK3CA"~e.17)) :op4 (g5 / gene :name (n7 / name :op1 "BRAF"~e.22)))) :ARG1-of (d / detect-01~e.24 :ARG2~e.25 (a / and~e.27 :op1 (p2 / platform~e.30 :name (n / name :op1 "OncoCarta"~e.26)) :op2 (p3 / platform~e.30 :name (n3 / name :op1 "Sequenom"~e.29))))) :ARG2~e.33 (t / thing~e.35 :ARG1-of~e.35 (r3 / report-01~e.35 :time (p / previous~e.34)))) # ::id pmid_2023_3444.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this preliminary assessment of the feasibility of using the Sequenom platform to do large @-@ scale mutation profiling of colon cancer samples isolated from FFPET , it was essential to determine if our data yielded frequencies typical of what has been seen previously . # ::alignments 1-1.1.2.3 2-1.1.2.2 3-1.1.2 8-1.1.2.1.1 10-1.1.2.1.1.1.1.1 11-1.1.2.1.1.1 14-1.1.2.1.1.2.1.1 16-1.1.2.1.1.2.1.1 17-1.1.2.1.1.2.1 18-1.1.2.1.1.2 19-1.1.2.1.1.2.2.r 20-1.1.2.1.1.2.2.1.2.1 21-1.1.2.1.1.2.2.1.2.2 22-1.1.2.1.1.2.2 23-1.1.2.1.1.2.2.2 24-1.1.2.1.1.2.2.2.1.r 25-1.1.2.1.1.2.2.2.1.1.1 28-1.1.r 29-1 31-1.1 33-1.1.1.2.1 33-1.1.1.2.1.r 34-1.1.1.2 35-1.1.1 36-1.1.1.3 39-1.1.1.3.1.1 42-1.1.1.3.1.1.1 43-1.1.1.3.1.1.1.1 (e / essential~e.29 :domain~e.28 (d3 / determine-01~e.31 :ARG1 (y / yield-01~e.35 :mode interrogative :ARG0 (d2 / data~e.34 :poss~e.33 (w / we~e.33)) :ARG1 (f / frequency~e.36 :ARG0-of (t / typify-01 :ARG1 (t2 / thing~e.39 :ARG1-of (s / see-01~e.42 :time (p / previous~e.43)))))) :time (a / assess-01~e.3 :ARG1 (f2 / feasible :mod (u / use-01~e.8 :ARG1 (p3 / platform~e.11 :name (n / name :op1 "Sequenom"~e.10)) :ARG2 (p4 / profile-01~e.18 :ARG0 (m / mutate-01~e.17 :mod (l / large-scale~e.14,16)) :ARG1~e.19 (s2 / sample-01~e.22 :ARG1 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon"~e.20 :op2 "cancer"~e.21)) :ARG1-of (i / isolate-01~e.23 :ARG2~e.24 (t3 / thing :name (n2 / name :op1 "FFPET"~e.25))))))) :mod (p2 / preliminary~e.2) :mod (t4 / this~e.1)))) # ::id pmid_2023_3444.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 2 shows the mutation frequencies obtained here and from the COSMIC ( Catalog of Somatic Mutations in Cancer ) database [ @ 21 @ ] . # ::alignments 0-1.1 2-1.1.1 4-1 6-1.2.1 7-1.2 8-1.2.2 9-1.2.2.1 11-1.2.2.2.r 13-1.2.2.2.1.1 17-1.2.2.2.2.1.1.1.1 18-1.2.2.2.2.1.1.1 19-1.2.2.2.2.1.1.1.2.r 20-1.2.2.2.2.1.1.1.2.2.1 22-1.2.2.2 25-1.3.1.1.1 (s / show-01~e.4 :ARG0 (t / table~e.0 :mod 2~e.2) :ARG1 (h2 / have-frequency-91~e.7 :ARG1 (m / mutate-01~e.6) :ARG1-of (o / obtain-01~e.8 :location (h / here~e.9) :source~e.11 (d2 / database~e.22 :name (n / name :op1 "COSMIC"~e.13) :ARG1-of (m2 / mean-01 :ARG2 (t2 / thing :ARG2-of (c2 / catalogue-01 :ARG1 (m3 / mutate-01~e.18 :mod (s2 / somatic~e.17) :location~e.19 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.20))))))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c / cite-01 :ARG1 21~e.25)))) # ::id pmid_2023_3444.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The COSMIC frequencies seen in Table 2 are based only on those mutations that are detectable with OncoCarta . # ::alignments 1-1.1.2.1.1 2-1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1 7-1.1.1.1.1 10-1 11-1.3 14-1.2 17-1.2.2 18-1.2.2.2.r 19-1.2.2.2.1.1 (b / base-02~e.10 :ARG1 (h / have-frequency-91~e.2 :ARG1-of (s / see-01~e.3 :location~e.4 (t / table~e.5 :mod 2~e.7)) :mod (t4 / thing :name (n / name :op1 "COSMIC"~e.1))) :ARG2 (m / mutate-01~e.14 :mod (t2 / this) :ARG1-of (d / detect-01~e.17 :ARG1-of (p / possible-01) :instrument~e.18 (p2 / product :name (n2 / name :op1 "OncoCarta"~e.19)))) :mod (o / only~e.11)) # ::id pmid_2023_3444.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok OncoCarta assays interrogate 99 % , 98 % , and 78 % of the known colon cancer mutations in BRAF , KRAS , and PIK3CA , respectively , based on a large number of colon cancer samples that have been sequenced in BRAF @ ( n = 4628 ) , KRAS @ ( n = 858 ) and PIK3CA @ ( n = 247 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2.4.2.1.1 4-1.2.4.2.1 6-1.2.4.2.2.1 7-1.2.4.2.2 9-1.2.4.2 10-1.2.4.2.3.1 11-1.2.4.2.3 14-1.2.3 15-1.2.5.2.1 16-1.2.5.2.2 17-1.2 17-1.2.4.1 20-1.2.1.1.1.1 24-1.2.1.2.1.1 27-1.2.1 29-1.2.1.3.1.1 32-1.2.2 32-1.2.2.r 34-1.3 35-1.3.1.r 37-1.3.1.1 38-1.3.1 40-1.2.5.2.1 41-1.2.5.2.2 42-1.3.1.2.1 42-1.3.1.2.1.2 42-1.3.1.2.1.2.r 42-1.3.1.2.2 42-1.3.1.2.2.2 42-1.3.1.2.2.2.r 42-1.3.1.2.3 42-1.3.1.2.3.2 42-1.3.1.2.3.2.r 46-1.3.1.2.1.3 46-1.3.1.2.2.3 46-1.3.1.2.3.3 49-1.2.1.1.1.1 54-1.3.1.2.1.1 58-1.2.1.2.1.1 63-1.3.1.2.2.1 65-1.3.1.2 67-1.2.1.3.1.1 72-1.3.1.2.3.1 (i / interrogate-01~e.2 :ARG0 (a / assay-01~e.1 :instrument (p4 / product :name (n / name :op1 "OncoCarta"~e.0))) :ARG1 (m / mutate-01~e.17 :ARG1 (a2 / and~e.27 :op1 (g / gene :name (n2 / name :op1 "BRAF"~e.20,49)) :op2 (g2 / gene :name (n3 / name :op1 "KRAS"~e.24,58)) :op3 (g3 / gene :name (n4 / name :op1 "PIK3CA"~e.29,67))) :manner~e.32 (r / respective~e.32) :ARG1-of (k / know-02~e.14) :ARG2-of (i2 / include-91 :ARG1 (m2 / mutate-01~e.17 :ARG1 a2 :ARG1-of k :mod d) :ARG3 (a4 / and~e.9 :op1 (p / percentage-entity~e.4 :value 99~e.3) :op2 (p2 / percentage-entity~e.7 :value 98~e.6) :op3 (p3 / percentage-entity~e.11 :value 78~e.10))) :mod (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colon"~e.15,40 :op2 "cancer"~e.16,41))) :ARG1-of (b / base-02~e.34 :ARG2~e.35 (n8 / number~e.38 :mod (l / large~e.37) :quant-of (a3 / and~e.65 :op1 (t / thing~e.42 :quant 4628~e.54 :ARG1-of~e.42 (s / sample-01~e.42 :ARG2 d) :ARG1-of (s2 / sequence-01~e.46 :location g)) :op2 (t2 / thing~e.42 :quant 858~e.63 :ARG1-of~e.42 (s3 / sample-01~e.42 :ARG2 d) :ARG1-of (s4 / sequence-01~e.46 :location g2)) :op3 (t3 / thing~e.42 :quant 247~e.72 :ARG1-of~e.42 (s5 / sample-01~e.42 :ARG2 d) :ARG1-of (s6 / sequence-01~e.46 :location g3)))))) # ::id pmid_2023_3444.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The OncoCarta panel found that the most frequent mutations in C @-@ 07 were KRAS @ ( 43.5 %) , PIK3CA @ ( 20.1 %) , and BRAF @ ( 12.1 %) , which are similar to what is seen in COSMIC . # ::alignments 1-1.1.1.1 2-1.1 3-1 4-1.2.r 6-1.2.2 7-1.2 8-1.2.1.1 8-1.2.1.2 8-1.2.1.3 9-1.2.1.r 10-1.2.1.5.1.1 12-1.2.1.5.1.1 15-1.2.1.1.1.1.1 18-1.2.1.1.1.2.1 22-1.2.1.2.1.1.1 25-1.2.1.2.1.2.1 28-1.2.1 30-1.2.1.3.1.1.1 33-1.2.1.3.1.2.1 38-1.2.1.4 39-1.2.1.4.1.r 40-1.2.1.4.1 42-1.2.1.4.1.1 43-1.2.1.4.1.1.1.r 44-1.2.1.4.1.1.1.1.1 (f / find-01~e.3 :ARG0 (p / panel~e.2 :name (n / name :op1 "OncoCarta"~e.1)) :ARG1~e.4 (f2 / frequent-02~e.7 :ARG1~e.9 (a3 / and~e.28 :op1 (m / mutate-01~e.8 :ARG1 (g / gene :name (n2 / name :op1 "KRAS"~e.15) :frequency (p2 / percentage-entity :value 43.5~e.18))) :op2 (m3 / mutate-01~e.8 :ARG1 (g2 / gene :name (n3 / name :op1 "PIK3CA"~e.22) :frequency (p3 / percentage-entity :value 20.1~e.25))) :op3 (m4 / mutate-01~e.8 :ARG1 (g3 / gene :name (n4 / name :op1 "BRAF"~e.30) :frequency (p4 / percentage-entity :value 12.1~e.33))) :ARG1-of (r / resemble-01~e.38 :ARG2~e.39 (t3 / thing~e.40 :ARG1-of (s / see-01~e.42 :location~e.43 (t2 / thing :name (n6 / name :op1 "COSMIC"~e.44))))) :location (c / cell-line :name (n5 / name :op1 "C-07"~e.10,12))) :degree (m2 / most~e.6))) # ::id pmid_2023_3444.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NRAS @ mutations , while infrequent , were detected in codons 12 , 13 and 61 and represent a sizable minority of the C0 @-@ 7 samples ( 3.8 %) . # ::alignments 1-1.1.1.1.2.1 3-1.1.1 6-1.1.1.2 6-1.1.1.2.1 6-1.1.1.2.1.r 9-1.1 10-1.1.2.r 11-1.1.2.1 11-1.1.2.2 11-1.1.2.3 12-1.1.2.1.1 14-1.1.2.2.1 15-1.1.2 16-1.1.2.3.1 17-1 18-1.2 20-1.2.2.1 21-1.2.2 22-1.2.2.2.r 24-1.2.2.2.2.1.1 26-1.2.2.2.2.1.1 27-1.2.2.2 27-1.2.2.2.1 27-1.2.2.2.1.r 29-1.2.2.3.1.1 (a / and~e.17 :op1 (d / detect-01~e.9 :ARG1 (m / mutate-01~e.3 :ARG1 (g / gene :wiki - :name (n / name :op1 "NRAS"~e.1)) :concession (f / frequent-02~e.6 :polarity~e.6 -~e.6 :ARG1 m)) :location~e.10 (a2 / and~e.15 :op1 (c / codon~e.11 :mod 12~e.12) :op2 (c2 / codon~e.11 :mod 13~e.14) :op3 (c3 / codon~e.11 :mod 61~e.16))) :op2 (r / represent-01~e.18 :ARG0 m :ARG1 (m2 / minority~e.21 :mod (s / sizable~e.20) :poss~e.22 (t2 / thing~e.27 :ARG1-of~e.27 (s2 / sample-01~e.27) :ARG1-of (l / label-01 :ARG2 (s3 / string-entity :value "C0-7"~e.24,26))) :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value 3.8~e.29))))) # ::id pmid_2023_3444.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest that FFPET samples can be interrogated with the technology described here and yield accurate data . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.1.1.1 5-1.2.1.1.1 5-1.2.1.1.1.2 5-1.2.1.1.1.2.r 6-1.2.1 8-1.2.1.1 9-1.2.1.1.2.r 11-1.2.1.1.2 12-1.2.1.1.2.1 13-1.2.1.1.2.1.1 14-1.2 15-1.2.2 16-1.2.2.2.1 17-1.2.2.2 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (a / and~e.14 :op1 (p / possible-01~e.6 :ARG1 (i / interrogate-01~e.8 :ARG2 (t3 / thing~e.5 :name (n / name :op1 "FFPET"~e.4) :ARG1-of~e.5 (s2 / sample-01~e.5)) :instrument~e.9 (t2 / technology~e.11 :ARG1-of (d3 / describe-01~e.12 :location (h / here~e.13))))) :op2 (y / yield-01~e.15 :ARG0 t3 :ARG1 (d2 / data~e.17 :mod (a2 / accurate~e.16))))) # ::id pmid_2023_3444.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While most of the specific amino acid mutations mirror what is seen on the COSMIC database , some unique colon cancer gene mutations were found , which include ABL1 @ -@ F359V , AKT1 @- @ E17K , MET @- @ R970C , and MET @ -@ T992I . # ::alignments 1-1.2.2.3.2 4-1.2.2.2 5-1.2.2.1 6-1.2.2.1 6-1.2.2.3.1.1 7-1.2.2 7-1.2.2.3.1 8-1.2 9-1.2.1 11-1.2.1.1 12-1.2.1.1.1.r 14-1.2.1.1.1.1.1 15-1.2.1.1.1 17-1.1.1.4 18-1.1.1.2 19-1.1.1.1.1.2.1 20-1.1.1.1.1.2.2 21-1.1.1.1 22-1.1.1 22-1.1.1.3.1.1 22-1.1.1.3.1.1.2 22-1.1.1.3.1.1.2.r 22-1.1.1.3.1.2 22-1.1.1.3.1.2.2 22-1.1.1.3.1.2.2.r 22-1.1.1.3.1.3 22-1.1.1.3.1.3.2 22-1.1.1.3.1.3.2.r 22-1.1.1.3.1.4 22-1.1.1.3.1.4.2 22-1.1.1.3.1.4.2.r 24-1.1 27-1.1.1.3 27-1.2.2.3 29-1.1.1.3.1.1.1.1 32-1.1.1.3.1.1.2.1 35-1.1.1.3.1.2.1.1 38-1.1.1.3.1.2.2.1 41-1.1.1.3.1.3.1.1 41-1.1.1.3.1.4.1.1 44-1.1.1.3.1.3.2.1 46-1.1.1.3.1 48-1.1.1.3.1.3.1.1 48-1.1.1.3.1.4.1.1 51-1.1.1.3.1.4.2.1 (h / have-concession-91 :ARG1 (f / find-01~e.24 :ARG1 (m / mutate-01~e.22 :ARG1 (g / gene~e.21 :mod (d2 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colon"~e.19 :op2 "cancer"~e.20))) :mod (u / unique~e.18) :ARG2-of (i / include-01~e.27 :ARG1 (a / and~e.46 :op1 (g2 / gene~e.22 :name (n2 / name :op1 "ABL1"~e.29) :ARG2-of~e.22 (m7 / mutate-01~e.22 :value "F359V"~e.32)) :op2 (g3 / gene~e.22 :name (n3 / name :op1 "AKT1"~e.35) :ARG2-of~e.22 (m2 / mutate-01~e.22 :value "E17K"~e.38)) :op3 (g4 / gene~e.22 :name (n4 / name :op1 "MET"~e.41,48) :ARG2-of~e.22 (m3 / mutate-01~e.22 :value "R970C"~e.44)) :op3 (g5 / gene~e.22 :name (n5 / name :op1 "MET"~e.41,48) :ARG2-of~e.22 (m8 / mutate-01~e.22 :value "T992I"~e.51)))) :mod (s3 / some~e.17))) :ARG2 (m4 / mirror-01~e.8 :ARG1 (t / thing~e.9 :ARG1-of (s2 / see-01~e.11 :location~e.12 (d / database~e.15 :name (n / name :op1 "COSMIC"~e.14)))) :ARG2 (m5 / mutate-01~e.7 :ARG1 (a4 / amino-acid~e.5,6) :ARG1-of (s / specific-02~e.4) :ARG1-of (i2 / include-91~e.27 :ARG2 (m9 / mutate-01~e.7 :ARG1 (a2 / amino-acid~e.6) :ARG1-of s) :ARG3 (m6 / most~e.1))))) # ::id pmid_2023_3444.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other amino acid changes that were not in the COSMIC database were amino acid changes R88Q , H701P , and C420R in PIK3CA , BRAF @ -@ 594V/G , and KRAS @ -@ Q61R , and several in NRAS , including G12C , G12D , G13R , G13V , Q61H and Q61K ( Table 2 ) . # ::alignments 0-1.2 1-1.1 2-1.1 3-1 5-1.3 5-1.5.r 6-1.3.1 6-1.3.1.r 9-1.3.2.1.1 10-1.3.2 11-1.3 12-1.1 13-1.1 13-1.5.1.1 13-1.5.2.1 13-1.5.3.1 13-1.5.4.1 13-1.5.5.1 13-1.5.6.1 14-1 14-1.5.1 14-1.5.2 14-1.5.3 14-1.5.4 14-1.5.5 14-1.5.6 15-1.5.1.1.1.2.1 17-1.5.2.1.1.2.1 19-1.5 20-1.5.3.1.1.2.1 23-1.5.1.1.1.1.1 23-1.5.2.1.1.1.1 23-1.5.3.1.1.1.1 27-1.5.4.1.1.1.1 30-1.5.4.1.1.2.1 32-1.5 34-1.5.5.1.1.1.1 37-1.5.5.1.1.2.1 40-1.5.6.2 43-1.5.6.1.1.1.1 46-1.5.6.1.1.2.1 47-1.5.6.1.1.2.1.1.1.1 49-1.5.6.1.1.2.1.1.2.1 51-1.5.6.1.1.2.1.1.3.1 53-1.5.6.1.1.2.1.1.4.1 55-1.5.6.1.1.2.1.1.5.1 56-1.5.6.1.1.2.1.1 57-1.5.6.1.1.2.1.1.6.1 59-1.4.1 61-1.4.1.1 (c / change-01~e.3,14 :ARG1 (a / amino-acid~e.1,2,12,13) :mod (o / other~e.0) :ARG1-of (b / be-located-at-91~e.5,11 :polarity~e.6 -~e.6 :ARG2 (d / database~e.10 :name (n16 / name :op1 "COSMIC"~e.9))) :ARG1-of (d2 / describe-01 :ARG0 (t / table~e.59 :mod 2~e.61)) :domain~e.5 (a6 / and~e.19,32 :op1 (c3 / change-01~e.14 :ARG1 (a7 / amino-acid~e.13 :part-of (g / gene :name (n4 / name :op1 "PIK3CA"~e.23) :ARG2-of (m / mutate-01 :value "R88Q"~e.15)))) :op2 (c4 / change-01~e.14 :ARG1 (a8 / amino-acid~e.13 :part-of (g5 / gene :name (n / name :op1 "PIK3CA"~e.23) :ARG2-of (m2 / mutate-01 :value "H701P"~e.17)))) :op3 (c5 / change-01~e.14 :ARG1 (a9 / amino-acid~e.13 :part-of (g6 / gene :name (n2 / name :op1 "PIK3CA"~e.23) :ARG2-of (m3 / mutate-01 :value "C420R"~e.20)))) :op4 (c6 / change-01~e.14 :ARG1 (a10 / amino-acid~e.13 :part-of (g2 / gene :name (n6 / name :op1 "BRAF"~e.27) :ARG2-of (m4 / mutate-01 :value "594V/G"~e.30)))) :op5 (c7 / change-01~e.14 :ARG1 (a11 / amino-acid~e.13 :part-of (g3 / gene :name (n8 / name :op1 "KRAS"~e.34) :ARG2-of (m5 / mutate-01 :value "Q61R"~e.37)))) :op6 (c8 / change-01~e.14 :ARG1 (a12 / amino-acid~e.13 :part-of (g4 / gene :name (n9 / name :op1 "NRAS"~e.43) :ARG2-of (m6 / mutate-01 :ARG2-of (i / include-01~e.46 :ARG1 (a4 / and~e.56 :op1 (m7 / mutate-01 :value "G12C"~e.47) :op2 (m8 / mutate-01 :value "G12D"~e.49) :op3 (m9 / mutate-01 :value "G13R"~e.51) :op4 (m10 / mutate-01 :value "G13V"~e.53) :op5 (m11 / mutate-01 :value "Q61H"~e.55) :op6 (m12 / mutate-01 :value "Q61K"~e.57)))))) :quant (s / several~e.40)))) # ::id pmid_2023_3444.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MET mutations were found in C0 @-@ 7 and amplified in sometumors # ::alignments 1-1.1.1.1.1.1 2-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.1 8-1.1.2.1.1 9-1 10-1.2 (a / and~e.9 :op1 (f / find-01~e.4 :ARG1 (m / mutate-01~e.2 :ARG1 (p / protein :name (n / name :op1 "MET"~e.1))) :location~e.5 (t / thing :name (n2 / name :op1 "C0-7"~e.6,8))) :op2 (a2 / amplify-01~e.10 :ARG1 m :location (t2 / tumor :quant (s / some)))) # ::id pmid_2023_3444.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MET @ mutations were found in 3.3 % of C @-@ 07 samples . # ::alignments 1-1.1.1.1.1 3-1.1 5-1 6-1.2.r 7-1.2.1.2.1 8-1.2.1.2 10-1.2.1.1.2.1.1.1 12-1.2.1.1.2.1.1.1 13-1.2 13-1.2.1.1 13-1.2.1.1.2 13-1.2.1.1.2.r 13-1.2.2 13-1.2.2.r (f / find-01~e.5 :ARG1 (m / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "MET"~e.1))) :location~e.6 (t2 / thing~e.13 :ARG1-of (i / include-91 :ARG2 (t3 / thing~e.13 :source c :ARG1-of~e.13 (s2 / sample-01~e.13 :source (c / cell-line :name (n2 / name :op1 "C-07"~e.10,12)))) :ARG3 (p / percentage-entity~e.8 :value 3.3~e.7)) :ARG1-of~e.13 (s / sample-01~e.13))) # ::id pmid_2023_3444.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , these mutations were not only unexpected in their appearance within the colon cancer population but also the frequency within the samples was unexpected . # ::alignments 0-1.3 2-1.1.2.1.1 3-1.1.2.1 5-1.1.1.r 7-1.1 7-1.1.1 10-1.1.2 13-1.1.2.2.1.2.1 14-1.1.2.2.1.2.2 15-1.1.2.2 17-1.2.3 19-1.2.2 22-1.2.2.1 22-1.2.2.1.1 22-1.2.2.1.1.r 24-1.2 24-1.2.1 24-1.2.1.r (a2 / and :op1 (e / expect-01~e.7 :polarity~e.5 -~e.7 :ARG1 (a / appear-01~e.10 :ARG1 (m / mutate-01~e.3 :mod (t / this~e.2)) :location (p / population~e.15 :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colon"~e.13 :op2 "cancer"~e.14))))) :op2 (e2 / expect-01~e.24 :polarity~e.24 -~e.24 :ARG1 (f / frequent-02~e.19 :ARG1 (t2 / thing~e.22 :ARG1-of~e.22 (s / sample-01~e.22))) :mod (a3 / also~e.17)) :ARG2-of (i / interest-01~e.0)) # ::id pmid_2023_3444.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In four of the eight samples with MET @ mutations , the mutant alleles were present at 58 @-@ 70 % , suggesting an amplification of the mutant allele or a loss of the wt gene ( Fig . 6 ) . # ::alignments 1-1.2.1 4-1.2.3.1.1 5-1.2 5-1.2.3.1 8-1.2.2.1.1.1 10-1.2.2 13-1.1.1 14-1.1 15-1 17-1 17-1.1.2.r 18-1.1.2.1.1 20-1.1.2.2.1 21-1.1.2.1 21-1.1.2.2 23-1.3 25-1.3.1.1 26-1.3.1.1.1.r 28-1.3.1.1.1.1 29-1.3.1.1.1 30-1.3.1 32-1.3.1.2 33-1.3.1.2.1.r 35-1.3.1.2.1.1 36-1.3.1.2.1 38-1.4.1 41-1.4.1.1 (b / be-located-at-91~e.15,17 :ARG1 (a / allele~e.14 :ARG2-of (m / mutate-01~e.13) :quant~e.17 (v / value-interval :op1 (p / percentage-entity~e.21 :value 58~e.18) :op2 (p2 / percentage-entity~e.21 :value 70~e.20))) :ARG2 (s / sample-01~e.5 :quant 4~e.1 :ARG1 (m2 / mutate-01~e.10 :ARG1 (g / gene :name (n / name :op1 "MET"~e.8))) :ARG1-of (i / include-91 :ARG2 (s2 / sample-01~e.5 :quant 8~e.4 :ARG1 m2))) :ARG0-of (s3 / suggest-01~e.23 :ARG1 (o / or~e.30 :op1 (a2 / amplify-01~e.25 :ARG1~e.26 (a3 / allele~e.29 :ARG2-of m~e.28)) :op2 (l / lose-02~e.32 :ARG1~e.33 (g2 / gene~e.36 :mod (w / wild-type~e.35))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.38 :mod 6~e.41))) # ::id pmid_2023_3444.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Amplification may represent the best explanation , in that amplification of the MET @ genomic region , 7q31 , has been observed in the Progenetix CGH Database in 23 % of colorectal cancers [ @ 22 @ ] # ::alignments 0-1.1.1 1-1 2-1.1 4-1.1.2.1 4-1.1.2.1.1 4-1.1.2.1.1.r 5-1.1.2 9-1.2.1.1 13-1.2.1.1.1.3.1.1 15-1.2.1.1.1.2 16-1.2.1.1.1.1.2 18-1.2.1.1.1.1.1 22-1.2.1 23-1.2.1.2.r 25-1.2.1.2.1.1 26-1.2.1.2.1.2 27-1.2.1.2 28-1.2.1.3.r 29-1.2.1.3.3.2.1 30-1.2.1.3.3.2 32-1.2.1.3.3.1.2.1 33-1.2.1.3.2.1 33-1.2.1.3.3.1.2.2 36-1.3.1.1.1 (p / possible-01~e.1 :ARG1 (r / represent-01~e.2 :ARG0 (a2 / amplify-01~e.0) :ARG1 (e / explain-01~e.5 :ARG2-of (g / good-03~e.4 :degree~e.4 (m / most~e.4)))) :ARG0-of (c / cause-01 :ARG1 (o / observe-01~e.22 :ARG1 (a / amplify-01~e.9 :ARG1 (d5 / dna-sequence :name (n5 / name :op1 "7q31"~e.18 :op2 "region"~e.16) :mod (g2 / genome~e.15) :mod (g3 / gene :name (n / name :op1 "MET"~e.13)))) :location~e.23 (d / database~e.27 :name (n2 / name :op1 "Progenetix"~e.25 :op2 "CGH"~e.26)) :location~e.28 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.33) :ARG1-of (i / include-91 :ARG2 (d3 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal"~e.32 :op2 "cancer"~e.33)) :ARG3 (p2 / percentage-entity~e.30 :value 23~e.29))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 22~e.36)))) # ::id pmid_2023_3444.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sequenom data was reproducible # ::alignments 1-1.1.1.1.1.1 2-1.1.1 (p / possible-01 :ARG1 (r / reproduce-01 :ARG1 (d / data~e.2 :source (c / company :name (n / name :op1 "Sequenom"~e.1))))) # ::id pmid_2023_3444.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Most of the assays in the OncoCarta panel did not detect mutations or the frequency of mutations was very low ( below 1 %) in our colon cancer samples . # ::alignments 0-1.1.2.1 1-1.1.2.1.r 3-1.1.2 3-1.1.2.2.1 4-1.1.2.2.1.1.r 6-1.1.2.2.1.1.1.1 7-1.1.2.2.1.1 9-1.1.1 9-1.1.1.r 10-1.1 11-1.1.3 12-1 14-1.2.1 15-1.2.1.1.r 16-1.2.1.1 18-1.2.3 19-1.2 21-1.2.2 22-1.2.2.1.1 24-1.2.1.1.1.r 25-1.2.1.1.1.1 25-1.2.1.1.1.1.r 26-1.2.1.1.1.2.2.1 27-1.2.1.1.1.2.2.2 28-1.2.1.1.1 (o / or~e.12 :op1 (d / detect-01~e.10 :polarity~e.9 -~e.9 :ARG0 (a / assay-01~e.3 :quant~e.1 (m / most~e.0) :ARG1-of (i / include-91 :ARG2 (a2 / assay-01~e.3 :location~e.4 (p / panel~e.7 :name (n / name :op1 "OncoCarta"~e.6))))) :ARG1 (m2 / mutate-01~e.11)) :op2 (l / low-04~e.19 :ARG1 (f / frequent-02~e.14 :ARG1~e.15 (m3 / mutate-01~e.16 :location~e.24 (s / sample-01~e.28 :ARG0~e.25 (w / we~e.25) :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon"~e.26 :op2 "cancer"~e.27))))) :ARG3 (b / below~e.21 :op1 (p2 / percentage-entity :value 1~e.22)) :degree (v / very~e.18))) # ::id pmid_2023_3444.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok OncoCarta assays interrogate mutations in these 19 genes listed in Table 1 @ . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2 4-1.3.r 5-1.3.2 6-1.3.1 7-1.3 8-1.3.3 9-1.3.3.1.r 10-1.3.3.1 12-1.3.3.1.1 (i / interrogate-01~e.2 :ARG0 (a / assay-01~e.1 :instrument (p / product :name (n / name :op1 "OncoCarta"~e.0))) :ARG1 (m / mutate-01~e.3) :location~e.4 (g / gene~e.7 :quant 19~e.6 :mod (t / this~e.5) :ARG1-of (l / list-01~e.8 :ARG2~e.9 (t2 / table~e.10 :mod 1~e.12)))) # ::id pmid_2023_3444.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To reduce the cost , time and the amount of DNA required for profiling , only 24 assays , which detected mutations at a frequency of 1 % or greater in C @-@ 07 , were selected , resorted in 6 pools and included in a new panel , termed ColoCarta ( Table 3 ) . # ::alignments 1-1.4 3-1.4.1.1 5-1.4.1.2 6-1.4.1 8-1.4.1.3 9-1.4.1.3.1.r 10-1.4.1.3.1.2.1 11-1.4.1.4 12-1.4.1.4.1.r 13-1.4.1.4.1 15-1.1.1.2 16-1.1.1.1 17-1.1.1 20-1.1.1.3 21-1.1.1.3.1 24-1.1.1.3.1.1 26-1.1.1.3.1.1.1.1.1 27-1.1.1.3.1.1.1.1 28-1.1.1.3.1.1.1 31-1.1.1.3.1.1.2.1.1 33-1.1.1.3.1.1.2.1.1 36-1.1 38-1.2 39-1.2.2.r 40-1.2.2.1 41-1.2.2 42-1 43-1.3 44-1.3.2.r 46-1.3.2.1 47-1.3.2 49-1.3.2.2 50-1.3.2.2.1.1.1 52-1.5.1 54-1.5.1.1 (a / and~e.42 :op1 (s / select-01~e.36 :ARG1 (a2 / assay-01~e.17 :quant 24~e.16 :mod (o / only~e.15) :ARG0-of (d / detect-01~e.20 :ARG1 (m / mutate-01~e.21 :ARG1-of (h / have-frequency-91~e.24 :ARG2 (o2 / or~e.28 :op1 (p / percentage-entity~e.27 :value 1~e.26) :op2 (m2 / more-than :op1 p)) :location (c / cell-line :name (n / name :op1 "C-07"~e.31,33))))))) :op2 (r / resort-00~e.38 :ARG1 a2 :location~e.39 (p2 / pool~e.41 :quant 6~e.40)) :op3 (i / include-01~e.43 :ARG1 a2 :ARG2~e.44 (p3 / panel~e.47 :ARG1-of (n2 / new-01~e.46) :ARG1-of (t2 / term-01~e.49 :ARG3 (t5 / thing :name (n3 / name :op1 "ColoCarta"~e.50))))) :purpose (r2 / reduce-01~e.1 :ARG1 (a3 / and~e.6 :op1 (c2 / cost~e.3) :op2 (t3 / time~e.5) :op3 (a4 / amount~e.8 :quant-of~e.9 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.10))) :ARG1-of (r3 / require-01~e.11 :ARG0~e.12 (p4 / profile-01~e.13)))) :ARG1-of (d3 / describe-01 :ARG0 (t4 / table~e.52 :mod 3~e.54))) # ::id pmid_2023_3444.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation profiles of 32 mutant samples with 41 mutations were repeated with the ColoCarta . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 5-1.1.1.4 6-1.2.r 7-1.1.1.3.1.1 8-1.1.1.3.1 10-1 11-1.2.r 13-1.2.1.1 (r / repeat-01~e.10 :ARG1 (p / profile-01~e.1 :ARG1~e.2 (t2 / thing~e.4 :quant 32~e.3 :ARG2-of~e.4 (m / mutate-01~e.4) :ARG0-of (h / have-03 :ARG1 (m2 / mutate-01~e.8 :quant 41~e.7)) :ARG1-of (s / sample-01~e.5)) :mod m~e.0) :instrument~e.6,11 (t / thing :name (n / name :op1 "ColoCarta"~e.13))) # ::id pmid_2023_3444.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mutations detected by the 2 panels ( OncoCarta and ColoCarta ) were identical , demonstrating the reproducibility of the methodology . # ::alignments 1-1.1 2-1.1.1 3-1.1.1.1.r 5-1.1.1.1.1 6-1.1.1.1 6-1.1.1.1.2.1.1 6-1.1.1.1.2.1.2 8-1.1.1.1.2.1.1.1.1 9-1.1.1.1.2.1 10-1.1.1.1.2.1.2.1.1 13-1 15-1.2 20-1.2.1.1.1 (i / identical-01~e.13 :ARG1 (m / mutate-01~e.1 :ARG1-of (d / detect-01~e.2 :ARG0~e.3 (p / panel~e.6 :quant 2~e.5 :ARG1-of (m3 / mean-01 :ARG2 (a / and~e.9 :op1 (p3 / panel~e.6 :name (n / name :op1 "OncoCarta"~e.8)) :op2 (p4 / panel~e.6 :name (n2 / name :op1 "ColoCarta"~e.10))))))) :ARG0-of (d2 / demonstrate-01~e.15 :ARG1 (p2 / possible-01 :ARG1 (r / reproduce-01 :ARG1 (m2 / methodology~e.20))))) # ::id pmid_2023_3444.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Multiple mutation frequencies suggest an order to the acquisition of different mutations # ::alignments 1-1.1.2 2-1.1.1 3-1.1 4-1 6-1.2 7-1.2.1.r 9-1.2.1 10-1.2.1.1.r 11-1.2.1.1.1 12-1.2.1.1 (s / suggest-01~e.4 :ARG0 (h / have-frequency-91~e.3 :ARG1 (m / mutate-01~e.2) :mod (m2 / multiple~e.1)) :ARG1 (o / order-03~e.6 :ARG1~e.7 (a / acquire-01~e.9 :ARG1~e.10 (m3 / mutate-01~e.12 :ARG1-of (d / differ-02~e.11))))) # ::id pmid_2023_3444.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A majority of the tumors ( 64 %) contained at least one or more mutations in the following genes : BRAF , KRAS , NRAS , MET , or PIK3CA , and 18 % had 2 or more mutations . # ::alignments 1-1.1.1.1 4-1.1.1 4-1.2.1 6-1.1.1.1.1.1.1 8-1.1 9-1.1.2.1 10-1.1.2.1 11-1.1.2.1.1.1 11-1.1.2.1.1.2.1 12-1.1.2.1.1 12-1.1.3.2.1 13-1.1.2.1 13-1.1.2.1.1.2 14-1.1.2 15-1.1.3.r 17-1.1.3.1 18-1.1.3 21-1.1.3.2.1.1.1.1 25-1.1.3.2.1.2.1.1 29-1.1.3.2.1.3.1.1 33-1.1.3.2.1.4.1.1 36-1.2.2.1 38-1.1.3.2.1.5.1.1 41-1 42-1.2.1.1.2.1 43-1.1.1.1.1.1 43-1.2.1.1.2 44-1.2 45-1.2.2.1.1 45-1.2.2.1.2.1 46-1.2.2.1 47-1.2.2.1.2 48-1.2.2 (a / and~e.41 :op1 (c / contain-01~e.8 :ARG0 (t / tumor~e.4 :quant (m / majority~e.1 :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity~e.43 :value 64~e.6)))) :ARG1 (m3 / mutate-01~e.14 :quant (a2 / at-least~e.9,10,13 :op1 (o / or~e.12 :op1 1~e.11 :op2 (m4 / more-than~e.13 :op1 1~e.11)))) :location~e.15 (g / gene~e.18 :ARG1-of (f / follow-04~e.17) :ARG1-of (m7 / mean-01 :ARG2 (o2 / or~e.12 :op1 (g2 / gene :name (n / name :op1 "BRAF"~e.21)) :op2 (g3 / gene :name (n2 / name :op1 "KRAS"~e.25)) :op3 (g4 / gene :name (n3 / name :op1 "NRAS"~e.29)) :op4 (g5 / gene :name (n4 / name :op1 "MET"~e.33)) :op5 (g6 / gene :name (n5 / name :op1 "PIK3CA"~e.38)))))) :op2 (h / have-03~e.44 :ARG0 (t2 / tumor~e.4 :ARG1-of (i / include-91 :ARG2 t :ARG3 (p2 / percentage-entity~e.43 :value 18~e.42))) :ARG1 (m5 / mutate-01~e.48 :quant (o3 / or~e.36,46 :op1 2~e.45 :op2 (m6 / more-than~e.47 :op1 2~e.45))))) # ::id pmid_2023_3444.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The most common double mutation was in KRAS @ and PIK3CA , followed by PIK3CA @ and BRAF @ ( Table 4 ) . # ::alignments 1-1.2.1 2-1.2 3-1.1 4-1 8-1.3.1.1.1 10-1.3 12-1.3.2.1.1 15-1.3.3 18-1.3.3.1.1 20-1.3 20-1.3.3.1 22-1.3.3.1.2.1.1 25-1.4.1 27-1.4.1.1 (m / mutate-01~e.4 :ARG1-of (d / double-01~e.3) :mod (c / common~e.2 :degree (m2 / most~e.1)) :location (a / and~e.10,20 :op1 (g / gene :name (n / name :op1 "KRAS"~e.8)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.12)) :ARG2-of (f / follow-01~e.15 :ARG1 (a2 / and~e.20 :op1 g2~e.18 :op2 (g3 / gene :name (n3 / name :op1 "BRAF"~e.22))))) :ARG1-of (d2 / describe-01 :ARG0 (t / table~e.25 :mod 4~e.27))) # ::id pmid_2023_3444.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Most samples with PIK3CA @ mutations ( 80 %) also had mutations in other genes , the most frequent of which was KRAS ; other mutated genes were BRAF , MET , NRAS , and a second PIK3CA @ mutation ( Table 2 , last column ) . # ::alignments 0-1.1.1.1.2 1-1.1.1 1-1.1.1.1.1 1-1.1.1.1.1.1 1-1.1.1.1.1.1.r 1-1.1.1.2 1-1.1.1.2.r 4-1.1.1.1.1.2.1.1.1.1 6-1.1.1.1.1.2.1 8-1.1.1.1.2.1.1.1 10-1.1.3 11-1.1 11-1.1.1.1.1.2 12-1.1.1.1.1.2.1 12-1.1.2 14-1.2.3 15-1.1.2.1 15-1.2 18-1.1.1.1.2 19-1.1.2.1.2.1 19-1.1.2.1.2.1.2 19-1.1.2.1.2.1.2.r 24-1.1.2.1.2.1.1.1 27-1.1.2.1.1 28-1.2.1 29-1.1.1.1.1.2.1.1 29-1.2.2.1.1 29-1.2.2.1.2 29-1.2.2.1.3 29-1.2.2.1.4 32-1.2.2.1.1.1.1 36-1.2.2.1.2.1.1 40-1.2.2.1.3.1.1 43-1.2.2.1 45-1.2.2.1.4.2.1 45-1.2.2.1.4.2.1.1 45-1.2.2.1.4.2.1.1.r 47-1.2.2.1.4.1.1 49-1.2.2.1.4.2 51-1.3.1 53-1.3.1.1 56-1.3.1.2.1 57-1.3.1.2 (m / multi-sentence :snt1 (h / have-03~e.11 :ARG0 (t2 / thing~e.1 :ARG1-of (i / include-91 :ARG2 (t3 / thing~e.1 :ARG1-of~e.1 (s2 / sample-01~e.1) :ARG0-of (h2 / have-03~e.11 :ARG1 (m3 / mutate-01~e.6,12 :ARG1 (g2 / gene~e.29 :name (n2 / name :op1 "PIK3CA"~e.4))))) :ARG3 (m4 / most~e.0,18 :ARG1-of (m5 / mean-01 :ARG2 (p / percentage-entity :value 80~e.8)))) :ARG1-of~e.1 (s / sample-01~e.1)) :ARG1 (m6 / mutate-01~e.12 :location (g3 / gene~e.15 :mod (o / other~e.27) :ARG2-of (i2 / include-91 :ARG1 (g4 / gene~e.19 :name (n3 / name :op1 "KRAS"~e.24) :ARG1-of~e.19 (f / frequent-02~e.19))))) :mod (a / also~e.10)) :snt2 (g5 / gene~e.15 :ARG2-of (m7 / mutate-01~e.28) :ARG1-of (i3 / include-91 :ARG2 (a2 / and~e.43 :op1 (g6 / gene~e.29 :name (n4 / name :op1 "BRAF"~e.32)) :op2 (g7 / gene~e.29 :name (n5 / name :op1 "MET"~e.36)) :op3 (g8 / gene~e.29 :name (n6 / name :op1 "NRAS"~e.40)) :op4 (g9 / gene~e.29 :name (n7 / name :op1 "PIK3CA"~e.47) :ARG1-of (m8 / mutate-01~e.49 :ord (o2 / ordinal-entity~e.45 :value~e.45 2~e.45))))) :mod (o3 / other~e.14)) :ARG1-of (d / describe-01 :ARG0 (t / table~e.51 :mod 2~e.53 :part (c / column~e.57 :mod (l / last~e.56))))) # ::id pmid_2023_3444.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumors with MET @ and NRAS @ mutations also have an unexpectedly high frequency of co @-@ occurring mutations , which suggests that they occur as a second mutation and perhaps later in the etiology of the tumor . # ::alignments 0-1.1.1 3-1.1.1.1.1.1.1.1.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1.2.1.1 9-1.1 9-1.1.1.1.1 10-1.3 11-1 13-1.2.1.1 14-1.2 15-1 20-1.4.1 23-1.4 25-1.4.1.2 29-1.4.1.1 29-1.4.1.1.1 29-1.4.1.1.1.r 30-1.4.1 32-1.4.1.3.2 33-1.4.1.3.1 33-1.4.1.3.1.2 33-1.4.1.3.1.2.r 34-1.4.1.3.1.1.r 36-1.4.1.3.1.1 37-1.4.1.3.1.1.1.r 39-1.4.1.3.1.1.1 (h / have-frequency-91~e.11,15 :ARG1 (m / mutate-01~e.9 :location (t / tumor~e.0 :ARG0-of (h3 / have-03 :ARG1 (m2 / mutate-01~e.9 :ARG1 (a / and~e.5 :op1 (g / gene :name (n / name :op1 "MET"~e.3)) :op2 (g2 / gene :name (n2 / name :op1 "NRAS"~e.7)))))) :ARG1-of (c / cooccur-00)) :ARG2 (h2 / high~e.14 :ARG1-of (e / expect-01 :polarity -~e.13)) :mod (a2 / also~e.10) :ARG0-of (s / suggest-01~e.23 :ARG1 (m3 / mutate-01~e.20,30 :ord (o / ordinal-entity~e.29 :value~e.29 2~e.29) :domain t~e.25 :ARG1-of (b / be-temporally-at-91 :ARG2 (l / late~e.33 :op1~e.34 (e2 / etiology~e.36 :poss~e.37 (t3 / tumor~e.39)) :degree~e.33 (m4 / more~e.33)) :ARG1-of (p / possible-01~e.32))))) # ::id pmid_2023_3444.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Many tumors contain only a KRAS @ or BRAF @ mutation , which is consistent with previous reports finding these mutations in earlier stages of colon cancer [ @ 23 , 24 @ ] . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.2 6-1.2.1.1.1.1 10-1.2.1.2.1.1 12-1.2 16-1.3 17-1.3.1.r 18-1.3.1.1 19-1.3.1 20-1.3.1.2 22-1.3.1.2.1 23-1.3.1.2.2.r 24-1.3.1.2.2 24-1.3.1.2.2.2 24-1.3.1.2.2.2.r 25-1.3.1.2.2.1 26-1.3.1.2.2.1.1.r 27-1.3.1.2.2.1.1.2.1 28-1.3.1.2.2.1.1.2.2 31-1.4.1.1.1.1 35-1.4.1.1.1.2 (c / contain-01~e.2 :ARG0 (t / tumor~e.1 :quant (m / many~e.0)) :ARG1 (m2 / mutate-01~e.12 :ARG1 (a / and :op1 (g / gene :name (n / name :op1 "KRAS"~e.6)) :op2 (g2 / gene :name (n2 / name :op1 "BRAF"~e.10))) :mod (o / only~e.3)) :ARG1-of (c2 / consistent-01~e.16 :ARG2~e.17 (r / report~e.19 :time (p / previous~e.18) :ARG0-of (f / find-01~e.20 :ARG2 m2~e.22 :time~e.23 (e / early~e.24 :op1 (s / stage~e.25 :subevent-of~e.26 (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon"~e.27 :op2 "cancer"~e.28))) :degree~e.24 (m4 / more~e.24))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 (a2 / and :op1 23~e.31 :op2 24~e.35))))) # ::id pmid_2023_3444.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The multiple mutation frequencies for tumors with KRAS @ and PIK3CA @ or with PIK3CA @ and BRAF @ were slightly higher and lower , respectively , than expected based on their individual frequencies ( Table 4 ) . # ::alignments 1-1.1.1.1.1 2-1.1.1.1 2-1.2.1.1 3-1.1.1 3-1.2.1 5-1.1.1.2 5-1.2.1.2 8-1.1.1.2.1.1.1.1.1 10-1.1.1.2.1.1 12-1.1.1.2.1.1.2.1.1 17-1.1.1.2.1.1.2.1.1 19-1 19-1.1.1.2.1.1 19-1.2.1.2.1.1 21-1.2.1.2.1.1.2.1.1 24-1.4 24-1.4.r 25-1.1 26-1 26-1.1.1.2.1.1 26-1.2.1.2.1.1 27-1.2 29-1.3 31-1.1.2.r 31-1.2.2.r 32-1.1.2 33-1.1.1.3 34-1.1.1.3.1.r 35-1.1.1.3.1.1 35-1.1.1.3.1.1.r 36-1.1.1.3.1.2 37-1.1.1.3.1 39-1.5.1 41-1.5.1.1 (a / and~e.19,26 :op1 (h / high-02~e.25 :ARG1 (h3 / have-frequency-91~e.3 :ARG1 (m / mutate-01~e.2 :mod (m2 / multiple~e.1)) :location (t / tumor~e.5 :ARG0-of (h2 / have-03 :ARG1 (a4 / and~e.10,19,26 :op1 (g / gene :name (n / name :op1 "KRAS"~e.8)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.12,17))))) :ARG1-of (b / base-02~e.33 :ARG2~e.34 (f2 / frequent-02~e.37 :ARG1~e.35 t~e.35 :mod (i / individual~e.36)))) :compared-to~e.31 (e / expect-01~e.32)) :op2 (l / low-04~e.27 :ARG1 (h4 / have-frequency-91~e.3 :ARG1 (m3 / mutate-01~e.2) :location (t3 / tumor~e.5 :ARG0-of (h5 / have-03 :ARG1 (a3 / and~e.19,26 :op1 g2 :op2 (g3 / gene :name (n3 / name :op1 "BRAF"~e.21))))) :ARG1-of b) :compared-to~e.31 e) :mod (r / respective~e.29) :manner~e.24 (s / slight~e.24) :ARG1-of (d / describe-01 :ARG0 (t2 / table~e.39 :mod 4~e.41))) # ::id pmid_2023_3444.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , the expected double mutation frequency of BRAF @ and KRAS @ would be 5.1 % , based on our data , but this combination was not found , also in agreement with previous reports [ @ 24 @ ] ( Table 4 ) . # ::alignments 0-1.7 0-1.7.r 3-1.1.3 4-1.1.2 5-1.1 6-1 9-1.1.1.1.1.1 11-1.1.1 13-1.1.1.2.1.1 17-1.2.1 18-1.2 20-1.3 21-1.3.1.r 22-1.3.1.1 22-1.3.1.1.r 23-1.3.1 25-1.4.r 26-1.4.2.1 27-1.4.2 29-1.4.1 29-1.4.1.r 30-1.4 32-1.4.3.2 34-1.4.3 35-1.4.3.1.r 36-1.4.3.1.1 37-1.4.3.1 40-1.5.1.1.1 44-1.6.1 46-1.6.1.1 (h / have-frequency-91~e.6 :ARG1 (m / mutate-01~e.5 :ARG1 (a / and~e.11 :op1 (g / gene :name (n / name :op1 "BRAF"~e.9)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS"~e.13))) :ARG1-of (d / double-01~e.4) :ARG1-of (e / expect-01~e.3)) :ARG2 (p / percentage-entity~e.18 :value 5.1~e.17) :ARG1-of (b / base-02~e.20 :ARG2~e.21 (d2 / data~e.23 :poss~e.22 (w / we~e.22))) :concession~e.25 (f / find-01~e.30 :polarity~e.29 -~e.29 :ARG1 (c / combine-01~e.27 :mod (t / this~e.26)) :ARG0-of (a2 / agree-01~e.34 :ARG2~e.35 (r / report~e.37 :time (p2 / previous~e.36)) :mod (a3 / also~e.32))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 24~e.40))) :ARG1-of (d4 / describe-01 :ARG0 (t2 / table~e.44 :mod 4~e.46)) :manner~e.0 (c3 / converse~e.0)) # ::id pmid_2023_3444.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Primary tumors with KRAS and PIK3CA mutations vary with respect to the frequency of these mutant alleles # ::alignments 1-1.2.1 2-1.2 4-1.2.2.1.1.1.1.1 5-1.2.2.1.1 6-1.2.2.1.1.2.1.1 7-1.2.2.1 8-1 13-1.1 15-1.1.1.1 16-1.1.1.2 17-1.1.1 (v / vary-01~e.8 :ARG0 (h2 / have-frequency-91~e.13 :ARG1 (a2 / allele~e.17 :mod (t2 / this~e.15) :ARG2-of (m2 / mutate-01~e.16))) :ARG1 (t / tumor~e.2 :mod (p / primary~e.1) :ARG0-of (h / have-03 :ARG1 (m / mutate-01~e.7 :ARG1 (a / and~e.5 :op1 (g / gene :name (n / name :op1 "KRAS"~e.4)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.6))))))) # ::id pmid_2023_3444.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the samples with co @-@ occurring mutations , the ratios of KRAS @ mutation ratio ( KRAS @ mutation peak area @/@ total peak area ) to the PIK3CA @ mutation ratio ( PIK3CA @ mutation peak area @/@ total peak area ) was determined . # ::alignments 2-1.2 7-1.2.1 10-1.1.1 13-1.1.1.1.1.1.1 15-1.1.1.1 16-1.1.1 16-1.1.1.2.1 19-1.1.1.2.1.1.2 20-1.1.1.2.1.1.2 21-1.1.1.2.1.1.2 22-1.1.1.2.1.1.1 23-1.1.1.2.1.1 23-1.1.1.2.1.2 25-1.1.1.2.1.2.2 26-1.1.1.2.1.2.1 26-1.1.2.2.1.1.1 27-1.1.1.2.1.2 27-1.1.2.2.1.1 32-1.1.2.1.1.1.1 34-1.1.2.1 35-1.1 35-1.1.2 35-1.1.2.2.1 35-1.1.2.r 38-1.1.2.1.1.1.1 40-1.1.1.1 41-1.1.1.2.1.1.1 41-1.1.1.2.1.2.1 42-1.1.1.2.1.1 42-1.1.1.2.1.2 44-1.1.1.2.1.2.2 45-1.1.1.2.1.2.1 46-1.1.1.2.1.2 49-1 (d / determine-01~e.49 :ARG1 (r / ratio-of~e.35 :op1 (r2 / ratio-of~e.10,16 :op1 (m / mutate-01~e.15,40 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.13))) :ARG1-of (m2 / mean-01 :ARG2 (r4 / ratio-of~e.16 :op1 (a / area~e.23,42 :ARG1-of (p / peak-01~e.22,41) :mod m~e.19,20,21) :op2 (a2 / area~e.23,27,42,46 :ARG1-of (p2 / peak-01~e.26,41,45) :mod (t / total~e.25,44))))) :op2~e.35 (r3 / ratio-of~e.35 :op1 (m3 / mutate-01~e.34 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.32,38))) :ARG1-of (m4 / mean-01 :ARG2 (r5 / ratio-of~e.35 :op1 (a3 / area~e.27 :ARG1-of (p3 / peak-01~e.26) :mod m3) :op2 a2)))) :location (s / sample-01~e.2 :ARG1 (m5 / mutate-01~e.7 :ARG1-of (c / cooccur-00)))) # ::id pmid_2023_3444.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Twenty @-@ two out of 31 samples ( 71 %) had KRAS @ / @ PIK3CA @ ratios above 1.25 ( Table 5 ) . # ::alignments 4-1.2 5-1.1.2.1.1 6-1.1 6-1.1.2.1 6-1.1.2.1.2 6-1.1.2.1.2.r 6-1.1.3 6-1.1.3.r 8-1.1.2.2.1 10-1 12-1.2.1.1.1 16-1.2.2.1.1 18-1.2 19-1.2.3.1 20-1.2.3.1.1 22-1.3.1 24-1.3.1.1 (h / have-03~e.10 :ARG0 (t3 / thing~e.6 :quant 22 :ARG1-of (i / include-91 :ARG2 (t2 / thing~e.6 :quant 31~e.5 :ARG1-of~e.6 (s2 / sample-01~e.6)) :ARG3 (p / percentage-entity :value 71~e.8)) :ARG1-of~e.6 (s / sample-01~e.6)) :ARG1 (r / ratio-of~e.4,18 :op1 (g / gene :name (n / name :op1 "KRAS"~e.12)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.16)) :ARG1-of (e / equal-01 :ARG3 (a / above~e.19 :op1 1.25~e.20))) :ARG1-of (d / describe-01 :ARG0 (t / table~e.22 :mod 5~e.24))) # ::id pmid_2023_3444.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PIK3CA @ mutations were more prevalent in only 2 out of 31 samples . # ::alignments 1-1.1.1.1.1 3-1.1 5-1.2 6-1 7-1.3.r 8-1.3.3 9-1.3.1 12-1.3.2.1.1 13-1.3 13-1.3.2.1 13-1.3.2.1.2 13-1.3.2.1.2.r 13-1.3.4 13-1.3.4.r (p / prevail-02~e.6 :ARG1 (m2 / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.1))) :degree (m / more~e.5) :location~e.7 (t2 / thing~e.13 :quant 2~e.9 :ARG1-of (i / include-91 :ARG2 (t / thing~e.13 :quant 31~e.12 :ARG1-of~e.13 (s2 / sample-01~e.13))) :mod (o / only~e.8) :ARG1-of~e.13 (s / sample-01~e.13))) # ::id pmid_2023_3444.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These differences demonstrate that in a majority of primary tumors with double mutations in KRAS @ and PIK3CA , the KRAS @ mutations are more prevalent than the PIK3CA @ . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.r 6-1.2.3.1 7-1.2.3.1.r 8-1.2.3.2 9-1.2.3 11-1.2.3.3.1.2 12-1.2.3.3.1 15-1.2.1.1.1.1 17-1.2.3.3.1.1 19-1.2.4.1.1 24-1.2.1.1.1.1 26-1.2.1 28-1.2.2 29-1.2 30-1.2.4.r 33-1.2.4.1.1 (d / demonstrate-01~e.2 :ARG0 (d2 / differ-02~e.1 :mod (t / this~e.0)) :ARG1~e.4 (p / prevail-02~e.29 :ARG1 (m / mutate-01~e.26 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.15,24))) :mod (m2 / more~e.28) :location (t2 / tumor~e.9 :quant~e.7 (m3 / majority~e.6) :mod (p2 / primary~e.8) :ARG0-of (h / have-03 :ARG1 (m4 / mutate-01~e.12 :ARG1 (a / and~e.17 :op1 g :op2 g2) :ARG1-of (d3 / double-01~e.11)))) :compared-to~e.30 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.19,33)))) # ::id pmid_2023_3444.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This unequal distribution of mutant alleles within a tumor may be due to the fact that a majority of the tumor cells have only the KRAS @ mutation , and cells with a PIK3CA @ mutation are in the minority , or it could be due to copy number variations in the KRAS @ and PIK3CA @ loci . # ::alignments 0-1.1.3 1-1.1.2 1-1.1.2.1 1-1.1.2.1.r 2-1.1 3-1.1.1.r 4-1.1.1.1 5-1.1.1 6-1.2.1.2.1.1.r 8-1.1.4 9-1 11-1.2 12-1.2 17-1.2.1.1.1.1.2.2 20-1.2.1.1.1.1.1 21-1.2.1.1.1.1 21-1.2.1.1.1.1.2.1 22-1.2.1.1.1 23-1.2.1.1.1.3 26-1.2.1.1.1.2.1.1.1 28-1.2.1.1.1.2 28-1.2.1.1.2.1 30-1.2.1.1 31-1.2.1.1.2 35-1.2.1.1.2.1.1.1.1 37-1.2.1.1.2.1 39-1.2.1.1.2.2.r 41-1.2.1.1.2.2 43-1.2.1 45-1 47-1.2 48-1.2 49-1.2.1.2.1.1 49-1.2.1.2.1.1.1 49-1.2.1.2.1.1.1.r 50-1.2.1.2.1 51-1.2.1.2 55-1.2.1.1.1.2.1.1.1 59-1.2.1.1.2.1.1.1.1 (p / possible-01~e.9,45 :ARG1 (d / distribute-01~e.2 :ARG1~e.3 (a / allele~e.5 :ARG2-of (m / mutate-01~e.4)) :mod (e / equal~e.1 :polarity~e.1 -~e.1) :mod (t / this~e.0) :location (t2 / tumor~e.8)) :ARG1-of (c / cause-01~e.11,12,47,48 :ARG0 (o / or~e.43 :op1 (a2 / and~e.30 :op1 (h / have-03~e.22 :ARG0 (c2 / cell~e.21 :mod (t3 / tumor~e.20) :ARG1-of (i / include-91 :ARG2 (c3 / cell~e.21) :ARG3 (m2 / majority~e.17))) :ARG1 (m3 / mutate-01~e.28 :ARG1 (g2 / gene :name (n / name :op1 "KRAS"~e.26,55))) :mod (o2 / only~e.23)) :op2 (c4 / cell~e.31 :location-of (m4 / mutate-01~e.28,37 :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA"~e.35,59))) :quant~e.39 (m5 / minority~e.41))) :op2 (v / vary-01~e.51 :ARG1 (n3 / number~e.50 :quant-of~e.6 (d2 / dna-sequence~e.49 :ARG2-of~e.49 (c7 / copy-01~e.49))) :location (a3 / and :op1 (l / locus :ARG0-of (c5 / contain-01 :ARG1 g2)) :op2 (l2 / locus :ARG0-of (c6 / contain-01 :ARG1 g))))))) # ::id pmid_2023_3444.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF mutations were correlated with poorly differentiated tumors and with mucinous tumors # ::alignments 1-1.1.1.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1 6-1.2.1.1.1.r 7-1.2.1.1 8-1.2.1 8-1.2.2 9-1.2 10-1.2.2.1.r 11-1.2.2.1.1.1 12-1.2.1 (c / correlate-01~e.4 :ARG1 (m / mutate-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "BRAF"~e.1))) :ARG2~e.5 (a / and~e.9 :op1 (t / tumor~e.8,12 :ARG1-of (d / differentiate-101~e.7 :manner~e.6 (p / poor~e.6))) :op2 (t2 / tumor~e.8 :mod~e.10 (p2 / protein :name (n2 / name :op1 "mucin"~e.11))))) # ::id pmid_2023_3444.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The frequency of mutations for KRAS , PIK3CA , and BRAF @ were tested for correlation to the degree of differentiation and to the prevalence of mucin in the tumor . # ::alignments 1-1.1.1 1-1.1.2 1-1.1.3 3-1.1.1.1 3-1.1.2.1 3-1.1.3.1 6-1.1.1.1.1.1.1 10-1.1.2.1.1.1.1 13-1.1 15-1.1.3.1.1.1.1 18-1 19-1.2.r 20-1.2 21-1.2.2.r 23-1.2.2.1 24-1.2.2.1.1.r 25-1.2.2.1.1 26-1.2.2 31-1.2.2.2.1.1.1 34-1.2.2.2.2 (t / test-01~e.18 :ARG1 (a / and~e.13 :op1 (h / have-frequency-91~e.1 :ARG1 (m / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.6)))) :op2 (h2 / have-frequency-91~e.1 :ARG1 (m2 / mutate-01~e.3 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.10)))) :op3 (h3 / have-frequency-91~e.1 :ARG1 (m3 / mutate-01~e.3 :ARG1 (g3 / gene :name (n3 / name :op1 "BRAF"~e.15))))) :ARG2~e.19 (c / correlate-01~e.20 :ARG1 a :ARG2~e.21 (a2 / and~e.26 :op1 (d / degree~e.23 :degree-of~e.24 (d2 / differentiate-101~e.25)) :op2 (p / prevail-01 :ARG1 (p2 / protein :name (n4 / name :op1 "mucin"~e.31)) :location (t2 / tumor~e.34))))) # ::id pmid_2023_3444.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @ mutations were found in 26.2 % of the poorly differentiated tumors and in 8.2 % of the moderate and well differentiated . # ::alignments 1-1.1.1.1.1 3-1.1 5-1 6-1.2.r 7-1.2.1.1.2.1 8-1.2.1.1.2 11-1.2.1.1.1.1.1 11-1.2.1.1.1.1.1.r 12-1.2.1.1.1.1 12-1.2.2.1.1.1.1 13-1.2.1 13-1.2.1.1.1 13-1.2.2 13-1.2.2.1.1.1 13-1.2.2.1.1.2 14-1.2 16-1.2.2.1.2.1 17-1.2.2.1.2 18-1.2.2.1.1.1.1.1.r 20-1.2.2.1.1.1.1.1 22-1.2.2.1.1.2.1.1 23-1.2.2.1.1.2.1 (f / find-01~e.5 :ARG1 (m / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.1))) :location~e.6 (a / and~e.14 :op1 (t2 / tumor~e.13 :ARG1-of (i / include-91 :ARG2 (t / tumor~e.13 :ARG1-of (d / differentiate-01~e.12 :manner~e.11 (p / poor~e.11))) :ARG3 (p2 / percentage-entity~e.8 :value 26.2~e.7))) :op2 (t3 / tumor~e.13 :ARG1-of (i2 / include-91 :ARG2 (a2 / and :op1 (t4 / tumor~e.13 :ARG1-of (d2 / differentiate-01~e.12 :manner~e.18 (m2 / moderate~e.20))) :op2 (t5 / tumor~e.13 :ARG1-of (d3 / differentiate-01~e.23 :ARG1-of (w / well-09~e.22)))) :ARG3 (p3 / percentage-entity~e.17 :value 8.2~e.16))))) # ::id pmid_2023_3444.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These frequencies were significantly different by Chi square test ( p value = 0.001 ) . # ::alignments 0-1.1.1 1-1.1 3-1.2 4-1 6-1.3.2.2.1 7-1.3.2.2.2 8-1.3.2.2.3 10-1.3 13-1.3.1 (d / differ-02~e.4 :ARG1 (h / have-frequency-91~e.1 :mod (t / this~e.0)) :ARG1-of (s / significant-02~e.3) :ARG1-of (s3 / statistical-test-91~e.10 :ARG2 0.001~e.13 :ARG4 (t3 / thing :wiki "Chi-squared_test" :name (n / name :op1 "Chi"~e.6 :op2 "square"~e.7 :op3 "test"~e.8)))) # ::id pmid_2023_3444.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @ mutations were also associated with mucinous tumors : BRAF @ mutations occurred in 28 % of grade 3 mucinous tumors (> 50 % mucinous tumor cells ) but in only 9.4 % of the non @-@ mucinous tumors ( grade 1 and 2 ) . # ::alignments 1-1.1.1.1.1 3-1.1 3-1.4.1.1 4-1.4.1 5-1.3 6-1 7-1.2.r 8-1.2.1.1.1 9-1.2 12-1.1.1.1.1 14-1.1 17-1.4.1.2.1.1.2.1 18-1.4.1.2.1.1.2 20-1.4.1.2.1.1.1.1 21-1.4.1.2.1.1.1.1.1 22-1.4.1.2.2.1.1.2.2.1.1 23-1.4.1.2.1.1.1 25-1.4.1.2.1.1.2.2.1.1.1 26-1.4.1.2.1.1.2.2.1.1 27-1.4.1.2.2.1.1.2.2.1.1 28-1.4.1.2.2.1.1 29-1.4.1.2.1.1.2.2.1.2 33-1.4.1.2.2.2 34-1.4.1.2.2.1.2.1 35-1.4.1.2.2.1.2 38-1.4.1.2.2.1.1.2.1 38-1.4.1.2.2.1.1.2.1.r 40-1.4.1.2.2.1.1.2.2.1.1 41-1.4.1.2.1 41-1.4.1.2.2 41-1.4.1.2.2.1.1 43-1.4.1.2.2.1.1.1.1.1 43-1.4.1.2.2.1.1.1.1.2 44-1.4.1.2.2.1.1.1.1.1.1 45-1.4.1.2.2.1.1.1.1 46-1.4.1.2.2.1.1.1.1.2.1 (a / associate-01~e.6 :ARG1 (m / mutate-01~e.3,14 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.1,12))) :ARG2~e.7 (t / tumor~e.9 :mod (p4 / protein :name (n3 / name :op1 "mucin"~e.8))) :mod (a2 / also~e.5) :ARG1-of (m3 / mean-01 :ARG2 (b3 / be-located-at-91~e.4 :ARG1 (m4 / mutate-01~e.3 :ARG1 g) :ARG2 (a3 / and :op1 (t2 / tumor~e.41 :ARG1-of (i / include-91 :ARG2 (t3 / tumor~e.23 :mod (g3 / grade~e.20 :mod 3~e.21) :mod p4) :ARG3 (p2 / percentage-entity~e.18 :value 28~e.17 :ARG1-of (m6 / mean-01 :ARG2 (m2 / more-than :op1 (p / percentage-entity~e.26 :value 50~e.25) :quant-of (c / cell~e.29 :mod t)))))) :op2 (t5 / tumor~e.41 :ARG1-of (i2 / include-91 :ARG2 (t6 / tumor~e.28,41 :ARG1-of (m9 / mean-01 :ARG2 (a4 / and~e.45 :op1 (g5 / grade~e.43 :mod 1~e.44) :op2 (g6 / grade~e.43 :mod 2~e.46))) :ARG1-of (h / have-mod-91 :polarity~e.38 -~e.38 :ARG2 (p5 / protein :name (n4 / name :op1 "mucin"~e.22,27,40)))) :ARG3 (p3 / percentage-entity~e.35 :value 9.4~e.34)) :mod (o / only~e.33)))))) # ::id pmid_2023_3444.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was significant by the Chi square test at p value = 0.006 . # ::alignments 0-1.1 2-1 5-1.2.2.2.1 6-1.2.2.2.2 7-1.2.2.2.3 9-1.2 12-1.2.1 (s / significant-02~e.2 :ARG1 (t / this~e.0) :ARG1-of (s3 / statistical-test-91~e.9 :ARG2 0.006~e.12 :ARG4 (t2 / thing :wiki "Chi-squared_test" :name (n / name :op1 "Chi"~e.5 :op2 "square"~e.6 :op3 "test"~e.7)))) # ::id pmid_2023_3444.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar data have been reported previously [ @ 25 , 26 @ ] . # ::alignments 0-1.1.1 1-1.1 4-1 5-1.2 8-1.3.1.1.1.1 12-1.3.1.1.1.2 (r / report-01~e.4 :ARG1 (d / data~e.1 :ARG1-of (r2 / resemble-01~e.0)) :time (p / previous~e.5) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 25~e.8 :op2 26~e.12))))) # ::id pmid_2023_3444.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KRAS @ and PIK3CA @ mutations did not correlate with either the degree of differentiation or with prevalence of mucinous cells . # ::alignments 1-1.2.1.1.1.1 3-1.2.1 5-1.2.1.2.1.1 7-1.2 9-1.1 9-1.1.r 10-1 14-1.3.1 15-1.3.1.1.r 16-1.3.1.1 17-1.3 21-1.3.2.1.1.1.1 22-1.3.2.1 (c / correlate-01~e.10 :polarity~e.9 -~e.9 :ARG1 (m / mutate-01~e.7 :ARG1 (a / and~e.3 :op1 (g / gene :name (n / name :op1 "KRAS"~e.1)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.5)))) :ARG2 (o / or~e.17 :op1 (d / degree~e.14 :degree-of~e.15 (d2 / differentiate-01~e.16)) :op2 (p / prevail-01 :ARG0 (c2 / cell~e.22 :mod (p2 / protein :name (n3 / name :op1 "mucin"~e.21)))))) # ::id pmid_2023_3444.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation profiling demonstrated a majority of primary and lymph node samples were concordant but differences were detected # ::alignments 1-1.1.1 2-1.1 3-1 5-1.2.1.1.2 5-1.2.1.2.2 7-1.2.1.1.1.1 8-1.2.1 9-1.2.1.2.1.1 10-1.2.1.1.1 10-1.2.1.2.1 11-1.2.1.1 11-1.2.1.2 12-1.2.1.r 13-1.2 14-1.3 15-1.3.1.1 17-1.3.1 (d / demonstrate-01~e.3 :ARG0 (p / profile-01~e.2 :ARG1 (m / mutate-01~e.1)) :ARG1 (c / concordant~e.13 :domain~e.12 (a / and~e.8 :op1 (s / sample-01~e.11 :ARG1 (n / node~e.10 :mod (p2 / primary~e.7)) :quant (m2 / majority~e.5)) :op2 (s2 / sample-01~e.11 :ARG1 (n2 / node~e.10 :mod (l / lymph~e.9)) :quant (m3 / majority~e.5)))) :ARG1-of (c2 / contrast-01~e.14 :ARG2 (d2 / detect-01~e.17 :ARG1 (d3 / differ-02~e.15)))) # ::id pmid_2023_3444.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lymph node metastases were not routinely collected in C @-@ 07 but as a pilot study to determine the feasibility of using lymph nodes for mutation profiling was conducted . # ::alignments 0-1.1.2.1.1 1-1.1.2.1 2-1.1.2 4-1.1.1 4-1.1.1.r 5-1.1.3 5-1.1.3.r 6-1.1 7-1.1.4.r 8-1.1.4.1.1 10-1.1.4.1.1 11-1 12-1.2.r 14-1.2.1.1 15-1.2.1 17-1.2.2 19-1.2.2.1 20-1.2.2.1.1.r 21-1.2.2.1.1 22-1.2.2.1.1.1.1 23-1.2.2.1.1.1 24-1.2.2.1.1.2.r 25-1.2.2.1.1.2.1 26-1.2.2.1.1.2 28-1.2 (c2 / contrast-01~e.11 :ARG1 (c / collect-01~e.6 :polarity~e.4 -~e.4 :ARG1 (m / metastasize-101~e.2 :ARG2 (n / node~e.1 :mod (l / lymph~e.0))) :manner~e.5 (r / routine~e.5) :location~e.7 (c4 / cell-line :name (n3 / name :op1 "C-07"~e.8,10))) :ARG2~e.12 (c3 / conduct-01~e.28 :ARG1 (s / study-01~e.15 :ARG1-of (p / pilot-01~e.14)) :purpose (d / determine-01~e.17 :ARG1 (f / feasibility~e.19 :poss~e.20 (u / use-01~e.21 :ARG1 (n2 / node~e.23 :mod (l2 / lymph~e.22)) :ARG2~e.24 (p2 / profile-01~e.26 :ARG1 (m2 / mutate-01~e.25))))))) # ::id pmid_2023_3444.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We isolated DNA from 39 lymph nodes containing tumor cells and their corresponding primary tumors . # ::alignments 0-1.1 1-1 2-1.2.2.1 3-1.3.r 4-1.3.1.1 5-1.3.1.2 6-1.3.1 7-1.3.1.3 8-1.3.1.3.1.1 9-1.3.1.3.1 10-1.3 11-1.3.2.2.1 11-1.3.2.2.1.r 12-1.3.2.2 13-1.3.2.1 14-1.3.2 (i / isolate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.2)) :ARG2~e.3 (a / and~e.10 :op1 (n / node~e.6 :quant 39~e.4 :mod (l / lymph~e.5) :ARG0-of (c / contain-01~e.7 :ARG1 (c2 / cell~e.9 :mod (t / tumor~e.8)))) :op2 (t2 / tumor~e.14 :mod (p / primary~e.13) :ARG2-of (c3 / correspond-02~e.12 :ARG1~e.11 n~e.11)))) # ::id pmid_2023_3444.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These primary and lymph nodes samples were profiled with the entire OncoCarta panel . # ::alignments 0-1.1.1.2 1-1.1.2.1.1 2-1.1 3-1.1.1.1.1 4-1.1.1.1 4-1.1.2.1 5-1.1.1 5-1.1.2 7-1 8-1.2.r 11-1.2.1.1 12-1.2 (p / profile-01~e.7 :ARG1 (a / and~e.2 :op1 (s / sample-01~e.5 :ARG1 (n / node~e.4 :mod (l / lymph~e.3)) :mod (t / this~e.0)) :op2 (s2 / sample-01~e.5 :ARG1 (n2 / node~e.4 :mod (p2 / primary~e.1)) :mod t)) :instrument~e.8 (p3 / panel~e.12 :name (n3 / name :op1 "OncoCarta"~e.11))) # ::id pmid_2023_3444.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The majority of lymph nodes and their corresponding primary tumors ( 89.7 %) were concordant . # ::alignments 1-1.1.1.1.2 3-1.1.1.1.1.1 4-1.1.1 4-1.1.1.1.1 5-1.1 6-1.1.2.2.1 6-1.1.2.2.1.r 7-1.1.2.2 8-1.1.2.1 9-1.1.2 11-1.1.2.3.1 13-1.1.r 14-1 (c2 / concordant~e.14 :domain~e.13 (a / and~e.5 :op1 (n2 / node~e.4 :ARG1-of (i / include-91 :ARG2 (n / node~e.4 :mod (l / lymph~e.3)) :ARG3 (m / majority~e.1))) :op2 (t / tumor~e.9 :mod (p / primary~e.8) :ARG2-of (c / correspond-02~e.7 :ARG1~e.6 n~e.6) :quant (p2 / percentage-entity :value 89.7~e.11)))) # ::id pmid_2023_3444.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A total of 26 mutations were detected in lymph nodes , including KRAS , BRAF , PIK3CA , and NRAS @ . # ::alignments 1-1.1.1 3-1.1.1.1 4-1.1 6-1 7-1.2.r 8-1.2.1 9-1.2 11-1.1.2 13-1.1.2.1.1.1.1 17-1.1.2.1.2.1.1 21-1.1.2.1.3.1.1 24-1.1.2.1 26-1.1.2.1.4.1.1 (d / detect-01~e.6 :ARG1 (m / mutate-01~e.4 :ARG1-of (t / total-01~e.1 :ARG2 26~e.3) :ARG2-of (i / include-91~e.11 :ARG1 (a / and~e.24 :op1 (g / gene :name (n2 / name :op1 "KRAS"~e.13)) :op2 (g2 / gene :name (n3 / name :op1 "BRAF"~e.17)) :op3 (g3 / gene :name (n4 / name :op1 "PIK3CA"~e.21)) :op4 (g4 / gene :name (n5 / name :op1 "NRAS"~e.26))))) :location~e.7 (n / node~e.9 :mod (l / lymph~e.8))) # ::id pmid_2023_3444.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thirty @-@ five out of 39 lymph nodes had identical mutation profiles , but in 4 cases mutations in the primary tumors were not found in the corresponding lymph nodes ( BRAF @ [ @ 2 @ ] , PIK3CA @ [ @ 1 @ ] and KRAS @ [ @ 1 @ ]) . # ::alignments 5-1.1.1.3.1.1 6-1.1.1.3.1.2 7-1.1.1 7-1.1.1.3.1 8-1.1 9-1.1.2.2 10-1.1.2.1 11-1.1.2 13-1 14-1.2.r 15-1.2.3.1 16-1.2.3 17-1.2.2 18-1.2.2.1.r 20-1.2.2.1.1 21-1.2.2.1 23-1.2.1 23-1.2.1.r 24-1.2 25-1.2.4.r 27-1.2.4.2 28-1.2.4.3 29-1.2.4 32-1.2.4.1.1.1.1.1 36-1.2.4.1.1.1.2.1.1.1 41-1.2.4.1.1.2.1.1 45-1.2.4.1.1.2.2.1.1.1 48-1.2.4.1.1 50-1.2.4.1.1.3.1.1 54-1.2.4.1.1.3.2 (c / contrast-01~e.13 :ARG1 (h / have-03~e.8 :ARG0 (n / node~e.7 :quant 35 :mod (l / lymph) :ARG1-of (i / include-91 :ARG2 (n2 / node~e.7 :quant 39~e.5 :mod l~e.6))) :ARG1 (p / profile-01~e.11 :ARG1 (m / mutate-01~e.10) :ARG1-of (i2 / identical-01~e.9))) :ARG2~e.14 (f / find-01~e.24 :polarity~e.23 -~e.23 :ARG1 (m2 / mutate-01~e.17 :location~e.18 (t / tumor~e.21 :mod (p2 / primary~e.20))) :mod (c2 / case-04~e.16 :quant 4~e.15) :location~e.25 (n3 / node~e.29 :ARG1-of (m3 / mean-01 :ARG2 (a / and~e.48 :op1 (g / gene :name (n4 / name :op1 "BRAF"~e.32) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 2~e.36)))) :op2 (g2 / gene :name (n5 / name :op1 "PIK3CA"~e.41) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 1~e.45)))) :op3 (g3 / gene :name (n6 / name :op1 "KRAS"~e.50) :ARG1-of d2~e.54))) :ARG2-of (c6 / correspond-02~e.27 :ARG1 t) :mod l~e.28))) # ::id pmid_2023_3444.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation profiles demonstrate that tumor cell populations may be different in lymph nodes and in the primary tumors # ::alignments 1-1.1.1 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2.1.1 7-1.2.1 8-1.2.2 10-1.2 11-1.2.3.r 12-1.2.3.1.1 13-1.2.3.1 14-1.2.3 17-1.2.3.2.1 18-1.2.3.2 (d / demonstrate-01~e.3 :ARG0 (p / profile-01~e.2 :ARG1 (m / mutate-01~e.1)) :ARG1~e.4 (d2 / differ-02~e.10 :ARG1 (p3 / population~e.7 :mod (c / cell~e.6 :mod (t / tumor~e.5))) :ARG1-of (p2 / possible-01~e.8) :location~e.11 (a / and~e.14 :op1 (n / node~e.13 :mod (l / lymph~e.12)) :op2 (t2 / tumor~e.18 :mod (p4 / primary~e.17))))) # ::id pmid_2023_3444.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Peak area evaluation of tumors that had 2 mutations and for which a metastatic lymph node was available demonstrated differences between the primary and lymph node samples . # ::alignments 0-1.1.2.1 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1 6-1.1.1.1 7-1.1.1.1.1.1 8-1.1.1.1.1 13-1.1.1.2.1.2 14-1.1.1.2.1.1 15-1.1.1.2.1 17-1.1.1.2 18-1 19-1.2 22-1.2.1.1.1 24-1.2.2.1.1 25-1.2.1.1 25-1.2.2.1 26-1.2.1 26-1.2.2 (d / demonstrate-01~e.18 :ARG0 (e / evaluate-01~e.2 :ARG1~e.3 (t / tumor~e.4 :ARG0-of (h / have-03~e.6 :ARG1 (m / mutate-01~e.8 :quant 2~e.7)) :ARG1-of (a2 / available-02~e.17 :ARG2 (n / node~e.15 :mod (l / lymph~e.14) :ARG1-of (m2 / metastasize-101~e.13)))) :location (a / area~e.1 :mod (p / peak~e.0))) :ARG1 (d2 / differ-02~e.19 :ARG1 (s / sample-01~e.26 :ARG1 (n2 / node~e.25 :mod (p2 / primary~e.22))) :ARG2 (s2 / sample-01~e.26 :ARG1 (n3 / node~e.25 :mod (l2 / lymph~e.24))))) # ::id pmid_2023_3444.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 6 details the frequency of mutant and wt alleles based on the peak areas for 5 such samples . # ::alignments 0-1.1 2-1.1.1 4-1 6-1.2 8-1.2.1.1.1 9-1.2.1 10-1.2.1.2.1 11-1.2.1.1 11-1.2.1.2 12-1.3 13-1.3.1.r 15-1.3.1.1 16-1.3.1 17-1.4.r 18-1.4.1 19-1.4.2 20-1.4 (d / detail-01~e.4 :ARG0 (t / table~e.0 :mod 6~e.2) :ARG1 (h / have-frequency-91~e.6 :ARG1 (a / and~e.9 :op1 (a2 / allele~e.11 :ARG2-of (m / mutate-01~e.8)) :op2 (a3 / allele~e.11 :mod (w / wild-type~e.10)))) :ARG1-of (b / base-02~e.12 :ARG2~e.13 (a4 / area~e.16 :mod (p / peak~e.15))) :beneficiary~e.17 (s / sample~e.20 :quant 5~e.18 :mod (s2 / such~e.19))) # ::id pmid_2023_3444.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KRAS @ to PIK3CA @ ratios demonstrated that there were more KRAS @ mutations than PIK3CA @ mutations in 4 of 4 primary samples , and in 3 of the 4 lymph node samples . # ::alignments 1-1.1.1.1.1 5-1.1.2.1.1 7-1.1 8-1 12-1.2.2 14-1.1.1.1.1 16-1.2 16-1.2.2.1 17-1.2.2 19-1.2.2.1.1 21-1.2 22-1.2.3.r 23-1.2.3.1.1 25-1.2.3.1.1 25-1.2.3.1.2.1.1 26-1.2.3.1.2.1.2 27-1.2.3.1 27-1.2.3.1.2.1 29-1.2.3 31-1.2.3.2.1 34-1.2.3.2.3.1.1 35-1.2.3.2.2.1 36-1.2.3.2.2 37-1.2.3.2 37-1.2.3.2.3.1 (d / demonstrate-01~e.8 :ARG0 (r / ratio-of~e.7 :op1 (g / gene :name (n / name :op1 "KRAS"~e.1,14)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.5))) :ARG1 (m / mutate-01~e.16,21 :ARG1 g :quant (m2 / more-than~e.12,17 :op1 (m3 / mutate-01~e.16 :ARG1 g2~e.19)) :location~e.22 (a / and~e.29 :op1 (s / sample-01~e.27 :quant 4~e.23,25 :ARG1-of (i / include-91 :ARG2 (s2 / sample-01~e.27 :quant 4~e.25 :mod (p2 / primary~e.26)))) :op2 (s3 / sample-01~e.37 :quant 3~e.31 :ARG1 (n5 / node~e.36 :mod (l2 / lymph~e.35)) :ARG1-of (i2 / include-91 :ARG2 (s4 / sample-01~e.37 :quant 4~e.34 :ARG1 n5)))))) # ::id pmid_2023_3444.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , it is also notable that the ratio of KRAS @ /PIK3A was lower in the lymph node compared to their primary tumor in 3 out of 4 samples . # ::alignments 0-1 4-1.1.4 5-1.1 6-1.1.1.r 8-1.1.1 9-1.1.1 11-1.1.1.1.1.1 15-1.1.2 16-1.1.2.2.r 18-1.1.2.2.1 19-1.1.2.2 20-1.1.2.3.r 22-1.1.2.3.2 22-1.1.2.3.2.r 23-1.1.2.3.1 24-1.1.2.3 25-1.1.3.r 26-1.1.3.1 29-1.1.3.2.1.1 30-1.1.3 30-1.1.3.2.1 (c / contrast-01~e.0 :ARG2 (n / notable-04~e.5 :ARG1~e.6 (r / ratio-of~e.8,9 :op1 (g / gene :name (n2 / name :op1 "KRAS"~e.11)) :op2 (g2 / gene :name (n3 / name :op1 "PIK3A"))) :ARG2 (l / low-04~e.15 :ARG1 r :location~e.16 (n4 / node~e.19 :mod (l2 / lymph~e.18)) :compared-to~e.20 (t / tumor~e.24 :mod (p / primary~e.23) :poss~e.22 n4~e.22)) :location~e.25 (s / sample~e.30 :quant 3~e.26 :ARG1-of (i / include-91 :ARG2 (s2 / sample~e.30 :quant 4~e.29))) :mod (a / also~e.4))) # ::id pmid_2023_3444.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In sample 0940 , the KRAS @ / @ PIK3CA @ mutation decreased by almost 1 @/@ 2 in the lymph node tumor compared to the primary . # ::alignments 1-1.4 2-1.4.1 6-1.1.1.1.1.1 8-1.1.1 10-1.1.1.2.1.1 12-1.1 13-1 14-1.2.r 15-1.2 16-1.2.1.1 17-1.1.1 18-1.2.1.1 19-1.3.r 21-1.3.1.1 22-1.3.1 23-1.3 23-1.3.2 24-1.3.2.r 25-1.3.2.1.r 27-1.3.2.1 (d / decrease-01~e.13 :ARG1 (m / mutate-01~e.12 :ARG1 (s / slash~e.8,17 :op1 (g / gene :name (n / name :op1 "KRAS"~e.6)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.10)))) :ARG2~e.14 (a / almost~e.15 :op1 (p2 / product-of :op1 "1/2"~e.16,18)) :location~e.19 (t / tumor~e.23 :mod (n4 / node~e.22 :mod (l / lymph~e.21)) :compared-to~e.24 (t2 / tumor~e.23 :mod~e.25 (p / primary~e.27))) :location (s2 / sample~e.1 :mod 0940~e.2)) # ::id pmid_2023_3444.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , in these samples there is either a loss of KRAS @ mutations or an accumulation of PIK3CA @ mutations , suggesting that PIK3CA @ mutations may impart a selective advantage in the lymph node . # ::alignments 3-1.1.1.2.1 4-1.1.1.2 9-1.1.1 12-1.1.1.1.1.1.1 14-1.1.1.1 15-1.1 17-1.1.2 20-1.1.2.1.1.1.1 22-1.1.2.1 24-1.2 27-1.2.1.1 28-1.2.1.1 29-1.2.1.1 30-1.2.1.4 31-1.2.1 33-1.2.1.2.1 34-1.2.1.2 35-1.2.1.3.r 37-1.2.1.3.1 38-1.2.1.3 (i / infer-01 :ARG1 (o / or~e.15 :op1 (l / lose-01~e.9 :ARG1 (m / mutate-01~e.14 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.12))) :location (s / sample~e.4 :mod (t / this~e.3))) :op2 (a / accumulate-01~e.17 :ARG1 (m2 / mutate-01~e.22 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.20))) :location s)) :ARG0-of (s2 / suggest-01~e.24 :ARG1 (i2 / impart-01~e.31 :ARG0 m2~e.27,28,29 :ARG1 (a2 / advantage~e.34 :mod (s3 / selective~e.33)) :ARG2~e.35 (n4 / node~e.38 :mod (l2 / lymph~e.37)) :ARG1-of (p / possible-01~e.30)))) # ::id pmid_2023_3444.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , two other samples have a less frequent occurrence of their PIK3CA @ mutation in the lymph node than in the primary tumor . # ::alignments 1-1 3-1.1.1.2.1 4-1.1.1.2.2 5-1.1.1.2 6-1.1 8-1.1.2 9-1.1 14-1.1.1.1.1.1 16-1.1.1 19-1.1.3.1 20-1.1.3 21-1.1.3.2.r 24-1.1.3.2.1 25-1.1.3.2 (c / contrast-01~e.1 :ARG2 (h / have-frequency-91~e.6,9 :ARG1 (m / mutate-01~e.16 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.14)) :location (s / sample~e.5 :quant 2~e.3 :mod (o / other~e.4))) :ARG2 (l / less~e.8) :location (n2 / node~e.20 :mod (l2 / lymph~e.19) :compared-to~e.21 (t / tumor~e.25 :mod (p / primary~e.24))))) # ::id pmid_2023_3444.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In sample 2244 , the PIK3CA @ mutation was undetectable in the lymph node ( Table 6 ) . # ::alignments 1-1.3 2-1.3.1 6-1.1.1.1.1 8-1.1 10-1 10-1.5.1 11-1.2.r 13-1.2.1 14-1.2 16-1.4.1 18-1.4.1.1 (d / detect-01~e.10 :ARG1 (m / mutate-01~e.8 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.6))) :location~e.11 (n2 / node~e.14 :mod (l / lymph~e.13)) :location (s / sample~e.1 :mod 2244~e.2) :ARG1-of (d2 / describe-01 :ARG0 (t / table~e.16 :mod 6~e.18)) :ARG1-of (p / possible-01 :polarity -~e.10)) # ::id pmid_2023_3444.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In fact , if there was a selection for both mutations in the lymph node , then the PIK3CA @ mutation frequency would have been the same as that of the KRAS @ mutation ( 0.15 ) . # ::alignments 0-1.3 1-1.3 3-1 7-1.2 8-1.2.1.r 9-1.2.1.1 10-1.2.1 11-1.2.2.r 11-1.3 13-1.2.2.1 14-1.2.2 16-1 19-1.1.1.1.1.1.1 21-1.1.1.1 21-1.1.2.1 22-1.1.1 22-1.1.2 22-1.1.2.2 22-1.1.2.2.r 24-1.1.2 27-1.1 33-1.1.2.1.1.1.1 35-1.1.1.1 37-1.1.2.2.1 (h / have-condition-91~e.3,16 :ARG1 (s2 / same-01~e.27 :ARG1 (h2 / have-frequency-91~e.22 :ARG1 (m2 / mutate-01~e.21,35 :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA"~e.19))) :ARG2 f3) :ARG2 (h3 / have-frequency-91~e.22,24 :ARG1 (m3 / mutate-01~e.21 :ARG1 (g2 / gene :name (n3 / name :op1 "KRAS"~e.33))) :ARG2~e.22 (f3 / frequency-quantity~e.22 :value 0.15~e.37))) :ARG2 (s / select-01~e.7 :ARG1~e.8 (m / mutate-01~e.10 :mod (b / both~e.9)) :location~e.11 (n / node~e.14 :mod (l / lymph~e.13))) :mod (i / in-fact~e.0,1,11)) # ::id pmid_2023_3444.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , if the PIK3CA @ / @ KRAS @ ratio were the same in the primary and lymph node tumor , then the PIK3CA @ mutation frequency would have been .08 , which is still detectable with this technology ( Fig . 3 ) . # ::alignments 5-1.1 8-1.1.2.1.1.1.1 12-1.1.2.1.2.1.1 14-1.1.2.1 14-1.1.2.2 17-1.1.2 20-1.1.2.1.3.1.1 22-1.1.2.2.3.1.1 23-1.1.2.1.3.1 23-1.1.2.2.3.1 24-1.1.2.1.3 24-1.1.2.2.3 26-1.1 29-1.1.1.1.1 31-1.1.1.1 32-1.1.1 32-1.1.1.2 32-1.1.1.2.r 34-1.1.1 40-1.1.1.3.2 41-1.1.1.3 42-1.1.1.3.1.r 43-1.1.1.3.1.1 44-1.1.1.3.1 46-1.2.1 49-1.2.1.1 (c / contrast-01 :ARG2 (h / have-condition-91~e.5,26 :ARG1 (h2 / have-frequency-91~e.32,34 :ARG1 (m / mutate-01~e.31 :ARG1 g~e.29) :ARG2~e.32 (f2 / frequency-quantity~e.32 :value 0.08) :ARG1-of (d / detect-01~e.41 :ARG2~e.42 (t3 / technology~e.44 :mod (t4 / this~e.43)) :mod (s2 / still~e.40) :ARG1-of (p2 / possible-01))) :ARG2 (s / same-01~e.17 :ARG1 (r / ratio-of~e.14 :op1 (g / gene :name (n / name :op1 "PIK3CA"~e.8)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS"~e.12)) :location (t / tumor~e.24 :mod (n3 / node~e.23 :mod (p / primary~e.20)))) :ARG2 (r2 / ratio-of~e.14 :op1 g :op2 g2 :location (t2 / tumor~e.24 :mod (n4 / node~e.23 :mod (l / lymph~e.22)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.46 :mod 3~e.49))) # ::id pmid_2023_3444.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , in sample 2244 there were fewer PIK3CA @ mutant alleles in the lymph node than in the primary tumor . # ::alignments 3-1.1.4 4-1.1.4.1 7-1.1 9-1.1.1.1.1.1.1 11-1.1.1.1 12-1.1.1 13-1.1.2.r 15-1.1.2.1 16-1.1.2 17-1.1.3.r 20-1.1.3.1 21-1.1.3 (i / infer-01 :ARG1 (f / few~e.7 :quant-of (a / allele~e.12 :ARG2-of (m / mutate-01~e.11 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.9)))) :location~e.13 (n2 / node~e.16 :mod (l / lymph~e.15)) :compared-to~e.17 (t / tumor~e.21 :mod (p / primary~e.20)) :location (s / sample~e.3 :mod 2244~e.4))) # ::id pmid_2023_3444.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In sample 1837 , mutations in both BRAF @ and PIK3CA @ were detected and the BRAF @ / @ PIK3CA @ ratio was 1.67 , but increased to 4.4 in the metastatic lymph node . # ::alignments 1-1.3 2-1.3.1 4-1.1.1.1 8-1.1.1.1.1.1.1.1 10-1.1.1.1.1 12-1.1.1.1.1.2.1.1 15-1.1.1 19-1.1.1.1.1.1.1.1 23-1.1.1.1.1.2.1.1 25-1.1.2.2 27-1.1.2.1 29-1 30-1.2 32-1.2.1 33-1.2.3.r 35-1.2.3.2 36-1.2.3.1 37-1.2.3 (c / contrast-01~e.29 :ARG1 (a / and :op1 (d / detect-01~e.15 :ARG1 (m / mutate-01~e.4 :ARG1 (a2 / and~e.10 :op1 (g / gene :name (n / name :op1 "BRAF"~e.8,19)) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.12,23))))) :op2 (e / equal-01 :ARG2 1.67~e.27 :ARG1 (r / ratio-of~e.25 :op1 g :op2 g2))) :ARG2 (i / increase-01~e.30 :ARG4 4.4~e.32 :ARG1 r :location~e.33 (n5 / node~e.37 :mod (l / lymph~e.36) :ARG2-of (m2 / metastasize-101~e.35))) :location (s / sample~e.1 :mod 1837~e.2)) # ::id pmid_2112_2157.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Signal transducer and activator of transcription 3 activation up @-@ regulates interleukin @-@ 6 autocrine production : a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells ( PMID : 21122157 ) # ::alignments 0-1.2.1.1.1 1-1.2.1.1.2 2-1.2.1.1.3 3-1.2.1.1.4 4-1.2.1.1.5 5-1.2.1.1.6 6-1.2.1.1.6 7-1.2 11-1.1.1.1.1 13-1.1.1.1.1 14-1.1.1.2 15-1.1 18-1.3.1.2 19-1.3.1.1 20-1.3.1.3 21-1.3.1 22-1.3.1.1.r 23-1.3.1.1.1.2 24-1.3.1.1.1.1.2.1 25-1.3.1.1.1 26-1.3.1.1.1 27-1.3.1.1 28-1.3.1.1.2.3.1 29-1.3.1.1.2.3 30-1.3.1.1.2.2 31-1.3.1.1.2.1 32-1.3.1.1.2 (u / upregulate-01 :ARG1 (p / produce-01~e.15 :ARG1 (p2 / protein :name (n / name :op1 "interleukin-6"~e.11,13) :mod (a / autocrine~e.14))) :ARG2 (a2 / activate-01~e.7 :ARG1 (p3 / protein :name (n2 / name :op1 "Signal"~e.0 :op2 "transducer"~e.1 :op3 "and"~e.2 :op4 "activator"~e.3 :op5 "of"~e.4 :op6 "transcription-3"~e.5,6))) :ARG1-of (m / mean-01 :ARG2 (s / study-01~e.21 :ARG1~e.22 (a3 / and~e.19,27 :op1 (c / cell-line~e.25,26 :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.24)) :ARG1-of (e / establish-01~e.23)) :op2 (c2 / cell~e.32 :mod d~e.31 :mod (h / human~e.30) :ARG1-of (i / isolate-01~e.29 :manner (c3 / clinic~e.28)))) :mod (b / biochemistry~e.18) :mod (g / genetics~e.20))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID21122157"))) # ::id pmid_2112_2157.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 0-1 0-1.1 0-1.1.r (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) # ::id pmid_2112_2157.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibitors of Jak2/Stat3 , MEK @/@ Erk and PI3 @-@ K/Akt pathways down @-@ regulated IL @-@ 6 secretion in the lung adenocarcinoma PC14PE6 @/@ AS2 ( AS2 ) cells , which spontaneously secreted IL @-@ 6 and possessed constitutively activated Stat3 . # ::alignments 0-1.2 0-1.2.1 0-1.2.1.r 1-1.2.1.1.r 2-1.2.1.1.1.1.1 4-1.2.1.1.2.1.1 6-1.2.1.1.2.1.1 7-1.2.1.1 8-1.2.1.1.3.1.1 11-1.2.1.1.1 11-1.2.1.1.2 11-1.2.1.1.3 15-1.1.1.1.1 17-1.1.1.1.1 18-1.1 21-1.3.2 22-1.3.5.1.1 23-1.3.1.1 25-1.3.1.1 27-1.3.1.1 29-1.3 32-1.3.3.2 32-1.3.3.2.r 33-1.1 33-1.3.3 34-1.1.1.1.1 36-1.1.1.1.1 37-1.2.1.1 38-1.3.4 39-1.3.4.1.2.1 39-1.3.4.1.2.1.r 40-1.3.4.1.2 41-1.3.4.1.1.1 (d / downregulate-01 :ARG1 (s / secrete-01~e.18,33 :ARG1 (p / protein :name (n / name :op1 "IL-6"~e.15,17,34,36))) :ARG2 (m / molecular-physical-entity~e.0 :ARG0-of~e.0 (i / inhibit-01~e.0 :ARG1~e.1 (a / and~e.7,37 :op1 (p2 / pathway~e.11 :name (n2 / name :op1 "Jak2/Stat3"~e.2)) :op2 (p3 / pathway~e.11 :name (n3 / name :op1 "MEK/Erk"~e.4,6)) :op3 (p4 / pathway~e.11 :name (n4 / name :op1 "PI3-K/Akt"~e.8))))) :location (c / cell~e.29 :name (n5 / name :op1 "PC14PE6/AS2"~e.23,25,27) :part-of (l / lung~e.21) :ARG0-of (s2 / secrete-01~e.33 :ARG1 p :manner~e.32 (s3 / spontaneous~e.32)) :ARG0-of (p5 / possess-01~e.38 :ARG1 (p6 / protein :name (n6 / name :op1 "Stat3"~e.41) :ARG1-of (a3 / activate-01~e.40 :manner~e.39 (c2 / constitutive~e.39)))) :mod (m2 / medical-condition :name (n7 / name :op1 "adenocarcinoma"~e.22)))) # ::id pmid_2112_2157.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Transfection with dominant @-@ negative Stat3 , Stat3 siRNA , or Stat3 shRNA decreased IL @-@ 6 expression in AS2 cells . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.4 5-1.1.1.2.2 6-1.1.1.2.2 7-1.1.1.2.2 8-1.1.1.2.1.1 10-1.1.1 11-1.1.1.3.2 12-1.1.1.3.1.1 13-1 14-1.2.1.1.1 16-1.2.1.1.1 17-1.2 18-1.3.r 19-1.3.1.1 20-1.3 (d / decrease-01~e.13 :ARG0 (t / transfect-01~e.0 :ARG2~e.1 (o / or~e.10 :op1 (p / protein :name (n / name :op1 "Stat3")) :op2 (n6 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.8) :mod p~e.5,6,7) :op3 (n7 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.12) :mod p~e.11) :ARG0-of (d2 / dominate-01~e.2) :ARG2-of (m / mutate-01 :mod "-/-"))) :ARG1 (e / express-03~e.17 :ARG2 (p2 / protein :name (n4 / name :op1 "IL-6"~e.14,16))) :location~e.18 (c / cell-line~e.20 :name (n5 / name :op1 "AS2"~e.19))) # ::id pmid_2112_2157.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , transfection with constitutively @-@ activated Stat3 increased the production of IL @-@ 6 . # ::alignments 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.2.1 4-1.1.1.1.2.1.r 6-1.1.1.1.2 7-1.1.1.1.1.1 8-1.1 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1.1.1 14-1.1.2.1.1.1 (c / contrast-01 :ARG2 (i / increase-01~e.8 :ARG0 (t / transfect-01~e.2 :ARG2~e.3 (p / protein :name (n / name :op1 "Stat3"~e.7) :ARG1-of (a / activate-01~e.6 :manner~e.4 (c2 / constitutive~e.4)))) :ARG1 (p2 / produce-01~e.10 :ARG1~e.11 (p3 / protein :name (n2 / name :op1 "IL-6"~e.12,14))))) # ::id pmid_2112_2157.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In AS2 derived cells , resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL @-@ 6 , which is commonly secreted in drug resistant cancer cells . # ::alignments 1-1.4.1.1.1.1 2-1.4.1 3-1.4 5-1.1 6-1.1.1.r 7-1.1.1.1.1 9-1.3 9-1.3.r 10-1 11-1.2.r 12-1.2.1.1.1.1.1 13-1.2.1.1 14-1.2.1 15-1.2 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1.1.1 21-1.2.2.1.1.1 25-1.2.2.1.2.1 25-1.2.2.1.2.1.r 26-1.2.2.1.2 27-1.2.2.1.2.2.r 28-1.2.2.1.2.2.2.1 29-1.2.2.1.2.2.2 30-1.2.2.1.2.2.1.2.1 31-1.2.2.1.2.2 (c / correlate-01~e.10 :ARG1 (r / resist-01~e.5 :ARG1~e.6 (s / small-molecule :name (n / name :op1 "paclitaxel"~e.7))) :ARG2~e.11 (a / and~e.15 :op1 (s2 / status~e.14 :mod (a2 / activate-01~e.13 :ARG1 (p / protein :name (n2 / name :op1 "Stat3"~e.12)))) :op2 (e / express-03~e.17 :ARG2~e.18 (p2 / protein :name (n3 / name :op1 "IL-6"~e.19,21) :ARG1-of (s3 / secrete-01~e.26 :manner~e.25 (c2 / common~e.25) :location~e.27 (c3 / cell~e.31 :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.30)) :ARG0-of (r2 / resist-01~e.29 :ARG1 (d2 / drug-01~e.28))))))) :manner~e.9 (p3 / positive~e.9) :location (c4 / cell~e.3 :ARG1-of (d3 / derive-01~e.2 :ARG2 (c5 / cell-line :name (n5 / name :op1 "AS2"~e.1))))) # ::id pmid_2112_2157.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The pharmacological inhibition of NF-?B , PI3 @-@ K/Akt and MEK @/@ Erk and the pharmacological inhibition and genetic inhibition ( Stat3 siRNA ) of Jak2 @/@ Stat3 pathway decreased IL @-@ 6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL @-@ 6 autocrine production in clinically isolated lung cancer cells . # ::alignments 1-1.1.1.2.1.2 2-1.1.1.2.1 6-1.1.1.1.1.2.1.1 10-1.1.1.1.1.3.1.1 12-1.1.1.1.1.3.1.1 15-1.1.1.1.2 16-1.1.1.1 16-1.1.1.2.1 17-1.1.1 17-1.1.1.2 17-1.1.1.2.r 18-1.1.1.2.2.3 19-1.1.1.2.2 21-1.1.1.2.2.1.2.1.1 22-1.1.1.2.2.1.1.1 25-1.1.1.2.1.1.1.1 27-1.1.1.2.2.1.2.1.1 28-1.1.1.1.1.1 28-1.1.1.1.1.2 28-1.1.1.1.1.3 28-1.1.1.2.1.1 29-1.2 30-1.1.2.1.1.1 32-1.1.2.1.1.1 33-1.1.2.2 34-1.1.2 36-1.1.3.3 37-1.1.3.2.1 38-1.1.3.2 39-1.1.3.1.2.1 40-1.1.3 41-1.1.3 42-1 42-1.1.1 43-1.2.4 44-1.1 44-1.2 45-1.2.2 46-1.2.2 47-1.2.2 48-1.2.2 49-1.2.2 50-1.2.3.r 51-1.2.3.3.1 52-1.2.3.3 53-1.2.3.2 54-1.2.3.1 55-1.2.3 (a / and~e.42 :op1 (d / decrease-01~e.44 :ARG0 (a2 / and~e.17,42 :op1 (i / inhibit-01~e.16 :ARG1 (a3 / and :op1 (p / pathway~e.28 :name (n / name :op1 "NF-κB")) :op2 (p2 / pathway~e.28 :name (n2 / name :op1 "PI3-K/Akt"~e.6)) :op3 (p3 / pathway~e.28 :name (n3 / name :op1 "MEK/Erk"~e.10,12))) :mod (p4 / pharmacology~e.15)) :op2~e.17 (a4 / and~e.17 :op1 (i2 / inhibit-01~e.2,16 :ARG1 (p5 / pathway~e.28 :name (n4 / name :op1 "Jak2/Stat3"~e.25)) :mod p4~e.1) :op2 (i3 / inhibit-01~e.19 :ARG0 (n9 / nucleic-acid :name (n5 / name :op1 "siRNA"~e.22) :mod (p6 / protein :name (n6 / name :op1 "Stat3"~e.21,27))) :ARG1 p5 :mod (g / genetics~e.18)))) :ARG1 (p7 / produce-01~e.34 :ARG1 (p8 / protein :name (n7 / name :op1 "IL-6"~e.30,32)) :mod (a5 / autocrine~e.33)) :location (c / cell-line~e.40,41 :mod (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.39)) :ARG0-of (r2 / resist-01~e.38 :ARG1 (d3 / drug~e.37)) :quant (v / various~e.36))) :op2 (d4 / decrease-01~e.29,44 :ARG0 a2 :ARG1 p7~e.45,46,47,48,49 :location~e.50 (c2 / cell~e.55 :mod d2~e.54 :part-of (l / lung~e.53) :ARG1-of (i4 / isolate-01~e.52 :manner (c3 / clinic~e.51))) :ARG1-of (r3 / resemble-01~e.43))) # ::id pmid_2112_2157.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 0-1 0-1.1 0-1.1.r (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0)) # ::id pmid_2112_2157.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Autocrine IL @-@ 6 induced Stat3 activation and paclitaxel resistance in AS2 cells # ::alignments 0-1.1.2.1.2 1-1.1.2.1.1.1 3-1.1.2.1.1.1 4-1.1.2 5-1.1.1.1.1 6-1.1 7-1 8-1.2.1.1.1 9-1.2 11-1.3.1.1 12-1.3 (a / and~e.7 :op1 (a2 / activate-01~e.6 :ARG1 (p / protein :name (n / name :op1 "Stat3"~e.5)) :ARG2-of (i / induce-01~e.4 :ARG0 (p2 / protein :name (n2 / name :op1 "IL-6"~e.1,3) :mod (a3 / autocrine~e.0)))) :op2 (r / resist-01~e.9 :ARG1 (s / small-molecule :name (n4 / name :op1 "paclitaxel"~e.8))) :location (c / cell-line~e.12 :name (n3 / name :op1 "AS2"~e.11))) # ::id pmid_2112_2157.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We previously demonstrated that AS2 cells produced autocrine IL @-@ 6 and the secreted IL @-@ 6 induced Stat3 activation and subsequently promoted tumor progression [ 2 ] . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.r 4-1.2.1.1.1.1 5-1.2.1.1 6-1.2.1 7-1.2.1.2.1.2 8-1.2.1.2.1.1.1 8-1.2.1.2.2.1.1.1 10-1.2.1.2.1.1.1 10-1.2.1.2.2.1.1.1 11-1.2.1.2 13-1.2.1.2.2.1.2 14-1.2.1.2.2.1.1.1 16-1.2.1.2.2.1.1.1 17-1.2.1.2.2 18-1.2.1.2.2.2.1.1.1 19-1.2.1.2.2.2 20-1.2 20-1.2.1.2 21-1.2.2.3 21-1.2.2.3.r 22-1.2.2 23-1.2.2.2.1 24-1.2.2.2 26-1.4.1.1.1 (d / demonstrate-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (a / and~e.20 :op1 (p / produce-01~e.6 :ARG0 (c / cell-line~e.5 :name (n / name :op1 "AS2"~e.4)) :ARG1 (a2 / and~e.11,20 :op1 (p2 / protein :name (n2 / name :op1 "IL-6"~e.8,10) :mod (a3 / autocrine~e.7)) :op2 (i / induce-01~e.17 :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6"~e.8,10,14,16) :ARG1-of (s / secrete-01~e.13)) :ARG2 (a4 / activate-01~e.19 :ARG1 (p3 / protein :name (n3 / name :op1 "Stat3"~e.18)))))) :op2 (p5 / promote-01~e.22 :ARG0 c :ARG1 (p6 / progress-01~e.24 :ARG1 (t / tumor~e.23)) :time~e.21 (s2 / subsequent~e.21))) :time (p7 / previous~e.1) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 2~e.26)))) # ::id pmid_2112_2157.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We used ELISA and Western blot analysis to measure IL @-@ 6 secretion and Stat3 activation ( phosphorylation ) after medium replacement to remove the existing IL @-@ 6 in the old medium and make it possible to measure the amount of newly secreted IL @-@ 6 time @-@ dependently in AS2 cells , respectively . # ::alignments 0-1.1 1-1 2-1.2.1.1.1.1 3-1.2 4-1.2.2.1 5-1.2.2.1 6-1.2.1 6-1.2.2 8-1.3 9-1.3.2.1.1.1.1 11-1.3.2.1.1.1.1 12-1.3.2.1 13-1.3.2 14-1.3.2.2.1.1.1 15-1.3.2.2 17-1.3.2.2.2.1 19-1.4 20-1.4.1.1 21-1.4.1 22-1.5.r 23-1.5.1 25-1.5.1.1 25-1.5.1.1.2 25-1.5.1.1.2.r 26-1.5.1.1.1.1 28-1.5.1.1.1.1 29-1.5.1.2.r 31-1.5.1.2.1 32-1.5.1.2 33-1.5 34-1.5.2 35-1.5.2.1 36-1.5.2.2 38-1.5.2.2.1 40-1.5.2.2.1.1 41-1.5.2.2.1.1.1.r 42-1.5.2.2.1.1.1.2.1 43-1.5.2.2.1.1.1.2 44-1.5.2.2.1.1.1.1.1 46-1.5.2.2.1.1.1.1.1 47-1.5.2.2.1.2.1 49-1.5.2.2.1.2 50-1.5.2.2.1.3.r 51-1.5.2.2.1.3.1.1 52-1.5.2.2.1.3 54-1.5.3 (u / use-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / and~e.3 :op1 (a2 / analyze-01~e.6 :instrument (t2 / thing :name (n / name :op1 "ELISA"~e.2))) :op2 (a3 / analyze-01~e.6 :manner (i / immunoblot-01~e.4,5 :ARG0 w))) :ARG2 (m / measure-01~e.8 :ARG0 w :ARG1 (a4 / and~e.13 :op1 (s / secrete-01~e.12 :ARG1 (p / protein :name (n3 / name :op1 "IL-6"~e.9,11))) :op2 (a5 / activate-01~e.15 :ARG1 (p2 / protein :name (n4 / name :op1 "Stat3"~e.14)) :ARG1-of (m2 / mean-01 :ARG2 (p3 / phosphorylate-01~e.17 :ARG1 p2))))) :time (a6 / after~e.19 :op1 (r / replace-01~e.21 :ARG1 (m3 / medium~e.20))) :purpose~e.22 (a7 / and~e.33 :op1 (r2 / remove-01~e.23 :ARG1 (p4 / protein~e.25 :name (n5 / name :op1 "IL-6"~e.26,28) :ARG1-of~e.25 (e / exist-01~e.25)) :location~e.29 (m4 / medium~e.32 :mod (o / old~e.31))) :op2 (m5 / make-02~e.34 :ARG0 w~e.35 :ARG1 (p5 / possible-01~e.36 :ARG1 (m6 / measure-01~e.38 :ARG1 (a8 / amount-01~e.40 :ARG1~e.41 (p6 / protein :name (n6 / name :op1 "IL-6"~e.44,46) :ARG1-of (s2 / secrete-01~e.43 :ARG1-of (n7 / new-01~e.42)))) :ARG0-of (d / depend-01~e.49 :ARG1 (t / time~e.47)) :location~e.50 (c / cell-line~e.52 :name (n8 / name :op1 "AS2"~e.51))))) :mod (r3 / respective~e.54))) # ::id pmid_2112_2157.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found the constitutive secretion of IL @-@ 6 at hours 1 to 24 and the activation of Stat3 peaked at hours 3 and 8 , confirming the autocrine production of IL @-@ 6 and the subsequent activation of Stat3 in AS2 cells ( Figure 1A and 1B ) . # ::alignments 0-1.1 1-1 3-1.2.1.2 4-1.2.1 5-1.2.1.1.r 6-1.2.1.1.1.1 8-1.2.1.1.1.1 10-1.2.1.3.1.2 11-1.2.1.3.1.1.1 13-1.2.1.3.1.1.2 16-1.2.2.1 17-1.2.2.1.1.r 18-1.2.2.1.1.1.1 19-1.2.2 21-1.2.2.2.1.1.2 22-1.2.2.2.1.1.1 24-1.2.2.2.1.2.1 26-1.2.3 28-1.2.3.1.1.2 29-1.2.3.1.1 30-1.2.3.1.1.1.r 31-1.2.3.1.1.1 32-1.2.3.1.1.1 33-1.2.3.1.1.1 34-1.2.2.2.1 36-1.2.1.3 36-1.2.2.2 36-1.2.2.2.r 36-1.2.3.1.2.2 36-1.2.3.1.2.2.r 37-1.2.3.1.2 38-1.2.3.1.2.1.r 39-1.2.3.1.2.1 40-1.2.3.1.r 41-1.2.3.1.3.1.1 42-1.2.3.1.3 44-1.3.1.1 44-1.3.1.2 45-1.3.1.1.1 46-1.3.1 47-1.3.1.2.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / and :op1 (s / secrete-01~e.4 :ARG1~e.5 (p / protein :name (n / name :op1 "IL-6"~e.6,8)) :mod (c / constitutive~e.3) :time (a2 / after~e.36 :op1 (t / temporal-quantity :quant (v / value-interval :op1 1~e.11 :op2 24~e.13) :unit (h / hour~e.10)))) :op2 (p2 / peak-01~e.19 :ARG1 (a3 / activate-01~e.16 :ARG1~e.17 (p3 / protein :name (n2 / name :op1 "Stat3"~e.18))) :time~e.36 (a4 / after~e.36 :op1 (a5 / and~e.34 :op1 (t2 / temporal-quantity :quant 3~e.22 :unit h~e.21) :op2 (t3 / temporal-quantity :quant 8~e.24 :unit h)))) :ARG0-of (c2 / confirm-01~e.26 :ARG1~e.40 (a6 / and :op1 (p4 / produce-01~e.29 :ARG1~e.30 p~e.31,32,33 :mod (a7 / autocrine~e.28)) :op2 (a8 / activate-01~e.37 :ARG1~e.38 p3~e.39 :time~e.36 (s2 / subsequent~e.36)) :location (c3 / cell-line~e.42 :name (n3 / name :op1 "AS2"~e.41))))) :ARG1-of (d / describe-01 :ARG0 (a9 / and~e.46 :op1 (f2 / figure~e.44 :mod "1A"~e.45) :op2 (f3 / figure~e.44 :mod "1B"~e.47)))) # ::id pmid_2112_2157.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been shown that cancer cells resistant to chemotherapeutic agents express elevated levels of IL @-@ 6 , and the IL @-@ 6 contributes to the drug resistance of cancer cells [ 30,39 ] . # ::alignments 3-1 4-1.1.r 5-1.1.1.2.1.2.1 6-1.1.1.2 7-1.1.1.2.2 8-1.1.1.2.2.1.r 9-1.1.1.2.2.1.1 10-1.1.1.2.2.1 11-1.1.1 12-1.1.1.1.2 13-1.1.1.1 14-1.1.1.1.1.r 15-1.1.1.1.1.1.1 17-1.1.1.1.1.1.1 21-1.1.1.1.1.1.1 23-1.1.1.1.1.1.1 24-1.1.2 25-1.1.2.2.r 27-1.1.2.2.2 28-1.1.2.2 29-1.1.2.2.1.r 30-1.1.2.2.1.1 31-1.1.2.2.1 (s / show-01~e.3 :ARG1~e.4 (a / and :op1 (e / express-03~e.11 :ARG2 (l / level~e.13 :quant-of~e.14 (p / protein :name (n / name :op1 "IL-6"~e.15,17,21,23)) :ARG1-of (e2 / elevate-01~e.12)) :ARG3 (c / cell~e.6 :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.5)) :ARG0-of (r / resist-01~e.7 :ARG1~e.8 (a2 / agent~e.10 :mod (c2 / chemotherapy~e.9))))) :op2 (c3 / contribute-01~e.24 :ARG0 p :ARG2~e.25 (r2 / resist-01~e.28 :ARG0~e.29 (c4 / cell~e.31 :mod d~e.30) :ARG1 (d2 / drug~e.27)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 (a3 / and :op1 30 :op2 39))))) # ::id pmid_2112_2157.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In our MTT assay of the effect of IL @-@ 6 on paclitaxel sensitivity in AS2 cells , we found a significant increase ( about 15 %) in cell viability in cells pre @-@ treated with exogenous IL @-@ 6 and a significant decrease ( about 15 %) in cell viability in cells treated with anti @-@ IL @-@ 6R , compared to the un @-@ pretreated cells ( both p < 0.001 ) , indicating that autocrine IL @-@ 6 contributed to the paclitaxel resistance in AS2 cells ( Figure 1C ) . # ::alignments 1-1.5.1 1-1.5.1.r 2-1.5.3.1.1 3-1.5 4-1.5.2.r 6-1.5.2 8-1.3.1.1.1.1 10-1.3.1.1.1.1 11-1.5.2.2.r 12-1.5.2.2.1.1.1 13-1.5.2.2 14-1.5.2.3.r 15-1.5.2.3.1.1 16-1.5.2.3 18-1.1 19-1 21-1.2.1.2 22-1.2.1 24-1.2.1.2.1.1 25-1.2.1.2.1.1.1.1 28-1.2.1.1.1 28-1.2.1.3 29-1.2.1.1 31-1.2.1.1.1 31-1.2.3.1 34-1.2.3.2.1 35-1.5.3.r 36-1.2.1.3.1.1.2 37-1.2.1.3.1.1.1.1 39-1.2.1.3.1.1.1.1 42-1.2.2.2 43-1.2.2 45-1.2.2.2 46-1.2.2.2 49-1.2.1.1.1 50-1.2.1.1 52-1.2.2.3 52-1.2.3.2 53-1.2.2.3.1 53-1.2.3.2.1 54-1.2.2.3.1.1.r 54-1.5.3.r 55-1.2.2.3.1.1 55-1.2.2.3.1.1.1 55-1.2.2.3.1.1.1.r 57-1.3.1.1.1.1 61-1.2.3.r 67-1.2.2.3 70-1.2.4 71-1.2.4.1 72-1.2.4.1.1 75-1.3 77-1.3.1.1.2 78-1.3.1.1.1.1 80-1.3.1.1.1.1 81-1.3.1 82-1.3.1.2.r 84-1.3.1.2.1 85-1.3.1.2 86-1.3.1.3.r 87-1.3.1.3 88-1.2.2.3 90-1.4.1 91-1.4.1.1 (f / find-01~e.19 :ARG0 (w / we~e.18) :ARG1 (a / and :op1 (i / increase-01~e.22 :ARG1 (v / viability~e.29,50 :mod (c / cell~e.28,31,49)) :ARG2 (s / significant-02~e.21 :ARG1-of (m / mean-01 :ARG2 (a2 / about~e.24 :op1 (p / percentage-entity :value 15~e.25)))) :location (c2 / cell~e.28 :ARG1-of (p2 / pretreat-01 :ARG3 (p3 / protein :name (n / name :op1 "IL-6"~e.37,39) :mod (e / exogenous~e.36))))) :op2 (d / decrease-01~e.43 :ARG1 v :ARG1-of s~e.42,45,46 :location (c3 / cell~e.52,67,88 :ARG1-of (t / treat-04~e.53 :ARG2~e.54 (m2 / molecular-physical-entity~e.55 :ARG0-of~e.55 (c8 / counter-01~e.55 :ARG1 p3))))) :compared-to~e.61 (a3 / and :op1 (c4 / cell~e.31 :ARG1-of (p4 / pretreat-01 :polarity - :ARG3 p3)) :op2 (c5 / cell~e.52 :ARG1-of (t2 / treat-04~e.34,53 :polarity - :ARG2 m2))) :ARG1-of (s4 / statistical-test-91~e.70 :ARG2 (l / less-than~e.71 :op1 0.001~e.72))) :ARG0-of (i2 / indicate-01~e.75 :ARG1 (c7 / contribute-01~e.81 :ARG0 (p6 / protein :name (n6 / name :op1 "IL-6"~e.8,10,57,78,80) :mod (a6 / autocrine~e.77)) :ARG2~e.82 (r / resist-01~e.85 :ARG1 s3~e.84) :location~e.86 c6~e.87)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.90 :mod "1C"~e.91)) :time (a4 / assay-01~e.3 :ARG0~e.1 w~e.1 :ARG1~e.4 (a5 / affect-01~e.6 :ARG0 p3 :ARG1~e.11 (s2 / sensitive-03~e.13 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "paclitaxel"~e.12))) :location~e.14 (c6 / cell-line~e.16 :name (n5 / name :op1 "AS2"~e.15))) :instrument~e.35,54 (s5 / small-molecule :name (n2 / name :op1 "MTT"~e.2)))) # ::id pmid_2112_2157.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Jak2 @/@ Stat3 pathway positively regulated IL @-@ 6 autocrine production in AS2 cells # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1.1 4-1.4 4-1.4.r 5-1 6-1.2.1.1.1 8-1.2.1.1.1 9-1.2.2 10-1.2 11-1.3.r 12-1.3.1.1 13-1.3 (r / regulate-01~e.5 :ARG0 (p / pathway~e.3 :name (n / name :op1 "Jak2/Stat3"~e.0,2)) :ARG1 (p2 / produce-01~e.10 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"~e.6,8)) :mod (a / autocrine~e.9)) :location~e.11 (c / cell-line~e.13 :name (n3 / name :op1 "AS2"~e.12)) :manner~e.4 (p4 / positive~e.4)) # ::id pmid_2112_2157.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate whether Jak2 @/@ Stat3 as well as the other three IL @-@ 6 downstream pathways ( PI3 @-@ K/Akt , MEK/Erk , and NF-?B ) known to be involved in IL @-@ 6 expression in various cells would act as an upstream regulator of IL @-@ 6 autocrine production in AS2 cells , we used ELISA to measure IL @-@ 6 secretion in one control AS2 group and in four different AS2 treatment groups each with one pathway ( Jak2/Stat3 , PI3 @-@ K/Akt , MEK/Erk , or NF-?B ) pharmacologically inhibited by the inhibitors AG490 , LY294002 , U0126 , or BAY11 @-@ 7082 , respectively . # ::alignments 1-1.5 2-1.5.2.1 2-1.5.2.1.r 3-1.5.2.2.1 4-1.5.2.2.1 5-1.5.2.2.1 6-1.5.2.2.2.4.1 7-1.5.2.2.2.4.1 8-1.5.2.2.2.4.1 10-1.5.2.2.2.2 11-1.5.2.2.2.1 12-1.5.2.2.2.3.1 13-1.5.2.2.2.3.1 14-1.5.2.2.2.3.1 15-1.5.2.2.2.3 16-1.5.2.2.2 18-1.4.2.4.2.1.2.1.1 22-1.4.2.4.2.1.3.1.1 24-1.5.2.2 27-1.5.2.2.3.2 30-1.5.2.2.3 31-1.5.2.2.3.1.r 32-1.5.2.2.3.1.1 33-1.5.2.2.3.1.1 34-1.5.2.2.3.1.1 35-1.5.2.2.3.1 36-1.5.2.2.3.1.2.r 37-1.5.2.2.3.1.2.1 38-1.5.2.2.3.1.2 40-1.5.2 41-1.5.2.3.r 43-1.5.2.3.3 44-1.5.2.3 45-1.5.2.3.2.r 46-1.5.2.3.2.1 47-1.5.2.3.2.1 48-1.5.2.3.2.1 49-1.5.2.3.2.2 50-1.5.2.3.2 51-1.5.2.4.r 52-1.5.2.4 53-1.5.2.4 55-1.1 56-1 56-1.5.r 57-1.2.1.1 59-1.3 60-1.3.2.1.1.1 62-1.3.2.1.1.1 63-1.3.2 64-1.4.r 65-1.4.1.1 66-1.4.1.3 67-1.4.1.2.1.1 68-1.4.1 69-1.4 71-1.4.2.1 72-1.4.2.3 73-1.4.2.2.1 74-1.4.2.2 75-1.4.2 76-1.4.2.5 78-1.4.2.4.1 79-1.4.2.4 81-1.4.2.4.2.1.1.1.1 83-1.4.2.4.2.1.2.1.1 87-1.4.2.4.2.1.3.1.1 89-1.4.2.4.2.1 92-1.4.2.4.2.1.1.2.2 93-1.4.2.4.2.1.1.2 93-1.4.2.4.2.1.2.2 93-1.4.2.4.2.1.3.2 93-1.4.2.4.2.1.4.2 96-1.4.2.4.2.1.1.2 97-1.4.2.4.2.1.1.2.1.1.1 99-1.4.2.4.2.1.2.2.1.1.1 101-1.4.2.4.2.1.3.2.1.1.1 103-1.4.2.4.2.1 104-1.4.2.4.2.1.4.2.1.1.1 106-1.4.2.4.2.1.4.2.1.1.1 (u / use-01~e.56 :ARG0 (w / we~e.55) :ARG1 (t / thing :name (n / name :op1 "ELISA"~e.57)) :ARG2 (m / measure-01~e.59 :ARG0 w :ARG1 (s / secrete-01~e.63 :ARG1 (p / protein :name (n2 / name :op1 "IL-6"~e.60,62)))) :location~e.64 (a / and~e.69 :op1 (g / group-01~e.68 :quant 1~e.65 :ARG2 (c / cell-line :name (n3 / name :op1 "AS2"~e.67)) :ARG2-of (c2 / control-01~e.66)) :op2 (g2 / group-01~e.75 :quant 4~e.71 :mod (t2 / treat-04~e.74 :ARG1 c~e.73) :ARG1-of (d / differ-02~e.72) :mod (p2 / pathway~e.79 :quant 1~e.78 :ARG1-of (m2 / mean-01 :ARG2 (o / or~e.89,103 :op1 (p3 / pathway :name (n4 / name :op1 "Jak2/Stat3"~e.81) :ARG1-of (i / inhibit-01~e.93,96 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "AG490"~e.97)) :manner (p4 / pharmacology~e.92))) :op2 (p5 / pathway :name (n6 / name :op1 "PI3-K/Akt"~e.18,83) :ARG1-of (i2 / inhibit-01~e.93 :ARG0 (s3 / small-molecule :name (n7 / name :op1 "LY294002"~e.99)) :manner p4)) :op3 (p6 / pathway :name (n8 / name :op1 "MEK/Erk"~e.22,87) :ARG1-of (i3 / inhibit-01~e.93 :ARG0 (s4 / small-molecule :name (n9 / name :op1 "U0126"~e.101)) :manner p4)) :op4 (p7 / pathway :name (n10 / name :op1 "NF-κB") :ARG1-of (i4 / inhibit-01~e.93 :ARG0 (s5 / small-molecule :name (n11 / name :op1 "BAY11-7082"~e.104,106)) :manner p4))))) :mod (e / each~e.76))) :purpose~e.56 (i5 / investigate-01~e.1 :ARG0 w :ARG1 (a2 / act-01~e.40 :mode~e.2 interrogative~e.2 :ARG0 (a3 / and~e.24 :op1 p3~e.3,4,5 :op2 (p8 / pathway~e.16 :quant 3~e.11 :mod (o2 / other~e.10) :direction (d2 / downstream~e.15 :mod p~e.12,13,14) :ARG1-of (m3 / mean-01 :ARG2 (a4 / and~e.6,7,8 :op1 p5 :op2 p6 :op3 p7))) :ARG1-of (i6 / involve-01~e.30 :ARG2~e.31 (e2 / express-03~e.35 :ARG2 p~e.32,33,34 :ARG3~e.36 (c3 / cell~e.38 :mod (v / various~e.37))) :ARG1-of (k / know-01~e.27))) :ARG1~e.41 (r / regulate-01~e.44 :ARG0 a3 :ARG1~e.45 (p9 / produce-01~e.50 :ARG1 p~e.46,47,48 :mod (a5 / autocrine~e.49)) :direction (u2 / upstream~e.43)) :location~e.51 c~e.52,53))) # ::id pmid_2112_2157.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that , compared to the controls , MEK @/@ Erk inhibitor and PI3 @-@ K/Akt inhibitor reduced IL @-@ 6 secretion in AS2 cells by about 80 % and 90 % ( both p < 0.01 ) , but NF-?B inhibitor decreased it by only 20 % ( p < 0.05 ) ( Figure 2A ) . # ::alignments 0-1.1 1-1 4-1.2.3 5-1.2.3.1.r 7-1.2.3.1 7-1.2.3.1.1 7-1.2.3.1.1.r 9-1.2.1.1.1.1.1.1.1 11-1.2.1.1.1.1.1.1.1 12-1.2.1.1.1 12-1.2.1.1.1.1 12-1.2.1.1.1.1.r 12-1.2.1.1.2 12-1.2.1.1.2.1 12-1.2.1.1.2.1.r 13-1.2.1.1 14-1.2.1.1.2.1.1.1.1 17-1.2.1.1.2 17-1.2.1.1.2.1 17-1.2.1.1.2.1.r 18-1.2.1 19-1.2.1.2.1.1.1 21-1.2.1.2.1.1.1 22-1.2.1.2 23-1.2.1.4.r 24-1.2.1.4.1.1 25-1.2.1.4 26-1.2.1.3.r 27-1.2.1.3 28-1.2.1.3.1.1.1 29-1.2.1.3.1.1 29-1.2.1.3.1.2 30-1.2.1.3.1 31-1.2.1.3.1.2.1 32-1.2.1.3.1.2 35-1.2.1.5 36-1.2.1.5.1 37-1.2.1.5.1.1 40-1.2 42-1.2.2.1 42-1.2.2.1.1 42-1.2.2.1.1.r 43-1.2.2 44-1.2.2.2 45-1.2.2.4.r 46-1.2.2.4 47-1.2.2.3.1 48-1.2.2.3 50-1.2.2.5 51-1.2.2.5.1 52-1.2.2.5.1.1 55-1.3.1 56-1.3.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (c / contrast-01~e.40 :ARG1 (r / reduce-01~e.18 :ARG0 (a / and~e.13 :op1 (m / molecular-physical-entity~e.12 :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (p / pathway :name (n / name :op1 "MEK/Erk"~e.9,11)))) :op2 (m2 / molecular-physical-entity~e.12,17 :ARG0-of~e.12,17 (i2 / inhibit-01~e.12,17 :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3-K/Akt"~e.14))))) :ARG1 (s / secrete-01~e.22 :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6"~e.19,21))) :ARG2~e.26 (a2 / about~e.27 :op1 (a3 / and~e.30 :op1 (p4 / percentage-entity~e.29 :value 80~e.28) :op2 (p5 / percentage-entity~e.29,32 :value 90~e.31))) :location~e.23 (c2 / cell-line~e.25 :name (n4 / name :op1 "AS2"~e.24)) :ARG1-of (s2 / statistical-test-91~e.35 :ARG2 (l / less-than~e.36 :op1 0.01~e.37))) :ARG2 (d / decrease-01~e.43 :ARG0 (m3 / molecular-physical-entity~e.42 :ARG0-of~e.42 (i3 / inhibit-01~e.42 :ARG1 (p7 / pathway :name (n5 / name :op1 "NF-κB")))) :ARG1 s~e.44 :ARG2 (p8 / percentage-entity~e.48 :value 20~e.47) :mod~e.45 (o / only~e.46) :ARG1-of (s3 / statistical-test-91~e.50 :ARG2 (l2 / less-than~e.51 :op1 0.05~e.52))) :ARG1-of (c3 / compare-01~e.4 :ARG2~e.5 (m4 / molecular-physical-entity~e.7 :ARG2-of~e.7 (c4 / control-01~e.7)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.55 :mod "2A"~e.56))) # ::id pmid_2112_2157.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , Jak2 @/@ Stat3 inhibitor also reduced IL @-@ 6 secretion by more than 60 % ( p < 0.01 ) . # ::alignments 0-1.5 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1 5-1.1.1 5-1.1.1.r 6-1.4 7-1 8-1.2.1.1.1 10-1.2.1.1.1 11-1.2 12-1.3.r 13-1.3 14-1.3 15-1.3.1.1 16-1.3.1 18-1.6 19-1.6.1 20-1.6.1.1 (r / reduce-01~e.7 :ARG0 (m / molecular-physical-entity~e.5 :ARG0-of~e.5 (i / inhibit-01~e.5 :ARG1 (p / pathway :name (n / name :op1 "Jak2/Stat3"~e.2,4)))) :ARG1 (s / secrete-01~e.11 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"~e.8,10))) :ARG2~e.12 (m2 / more-than~e.13,14 :op1 (p3 / percentage-entity~e.16 :value 60~e.15)) :mod (a / also~e.6) :mod (i2 / important~e.0) :ARG1-of (s2 / statistical-test-91~e.18 :ARG2 (l / less-than~e.19 :op1 0.01~e.20))) # ::id pmid_2112_2157.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Though Jak2 @/@ Stat3 inhibitor was not the most efficient , Jak2 @/@ Stat3 pathway clearly participates in the regulation of IL @-@ 6 and should be significant an upstream regulator of IL @-@ 6 secretion in AS2 cells ( Figure 2A ) . # ::alignments 0-1.3.r 1-1.3.2.1.1 2-1.3.2.1.1 3-1.3.2.1.1 4-1.3.2 4-1.3.2.1 4-1.3.2.1.r 6-1.3.1 6-1.3.1.r 8-1.3.3 9-1.3 11-1.1.1.1.1 13-1.1.1.1.1 14-1.1.1 15-1.1.3 16-1.1 17-1.1.2.r 19-1.1.2 20-1.1.2.1.r 21-1.1.2.1.1.1 23-1.1.2.1.1.1 24-1 25-1.2 27-1.2.1 29-1.2.1.2.1.3 30-1.2.1.2.1 31-1.2.1.2.1.2.r 32-1.2.1.2.1.2.1 33-1.2.1.2.1.2.1 34-1.2.1.2.1.2.1 35-1.2.1.2.1.2 36-1.2.2.r 37-1.2.2.1.1 38-1.2.2 40-1.4.1 41-1.4.1.1 (a / and~e.24 :op1 (p / participate-01~e.16 :ARG0 (p2 / pathway~e.14 :name (n / name :op1 "Jak2/Stat3"~e.11,13)) :ARG1~e.17 (r / regulate-01~e.19 :ARG1~e.20 (p3 / protein :name (n2 / name :op1 "IL-6"~e.21,23))) :ARG1-of (c / clear-06~e.15)) :op2 (r2 / recommend-01~e.25 :ARG1 (s / significant-02~e.27 :ARG1 p2 :ARG1-of (c3 / cause-01 :ARG0 (r3 / regulate-01~e.30 :ARG0 p2 :ARG1~e.31 (s2 / secrete-01~e.35 :ARG1 p3~e.32,33,34) :location (u / upstream~e.29)))) :location~e.36 (c2 / cell-line~e.38 :name (n4 / name :op1 "AS2"~e.37))) :concession~e.0 (e / efficient-01~e.9 :polarity~e.6 -~e.6 :ARG1 (m / molecular-physical-entity~e.4 :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 p2~e.1,2,3)) :degree (m2 / most~e.8)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "2A"~e.41))) # ::id pmid_2112_2157.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To exclude the possibility that the reduction of IL @-@ 6 secretion was mainly caused by the reduction of cell survival , cell viability was measured by MTT assay after being treated with each one of four inhibitors . # ::alignments 1-1.4 3-1.4.1 4-1.4.1.1.r 6-1.4.1.1.2 8-1.4.1.1.2.1.1.1.1 10-1.4.1.1.2.1.1.1.1 11-1.4.1.1.2.1 13-1.4.1.1.3 14-1.4.1.1 17-1.4.1.1.1 17-1.4.1.1.2 18-1.4.1.1.1.1.r 19-1.4.1.1.1.1.1 20-1.4.1.1.1.1 22-1.1.1 23-1.1 25-1 26-1.2.r 27-1.2.1.1.1 28-1.2 29-1.3 31-1.3.1 32-1.2.1.r 32-1.3.1.2.r 33-1.3.1.2.3 36-1.3.1.2.1 37-1.3.1.2 37-1.3.1.2.2 37-1.3.1.2.2.r (m / measure-01~e.25 :ARG1 (v / viability~e.23 :mod (c / cell~e.22)) :manner~e.26 (a / assay-01~e.28 :instrument~e.32 (s3 / small-molecule :name (n / name :op1 "MTT"~e.27))) :time (a2 / after~e.29 :op1 (t / treat-04~e.31 :ARG1 c :ARG2~e.32 (m2 / molecular-physical-entity~e.37 :quant 4~e.36 :ARG0-of~e.37 (i / inhibit-01~e.37) :mod (e / each~e.33)))) :purpose (e2 / exclude-01~e.1 :ARG1 (p / possible-01~e.3 :ARG1~e.4 (c2 / cause-01~e.14 :ARG0 (r / reduce-01~e.17 :ARG1~e.18 (s / survive-01~e.20 :ARG0 (c3 / cell~e.19))) :ARG1 (r2 / reduce-01~e.6,17 :ARG1 (s2 / secrete-01~e.11 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"~e.8,10)))) :mod (m3 / main~e.13))))) # ::id pmid_2112_2157.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok None of these inhibitors compromised the viability of AS2 cells during the treatment period at the indicated doses ( Additional file 1 , Figure S1A ) . # ::alignments 2-1.2.2 3-1.2 3-1.2.1 3-1.2.1.r 4-1 6-1.3 7-1.3.1.r 8-1.3.1.1.1 9-1.3.1 10-1.4.r 12-1.4.1 13-1.4 14-1.2.3.r 16-1.2.3.1 17-1.2.3 20-1.5.1.1.1 23-1.5.1.2 24-1.5.1.2.1 (c / compromise-02~e.4 :polarity - :ARG0 (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (i / inhibit-01~e.3) :mod (t / this~e.2) :ARG1-of~e.14 (d / dose-01~e.17 :ARG1-of (i2 / indicate-01~e.16))) :ARG1 (v / viability~e.6 :poss~e.7 (c2 / cell-line~e.9 :name (n / name :op1 "AS2"~e.8))) :time~e.10 (p / period~e.13 :mod (t2 / treat-04~e.12)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (a2 / add-02 :ARG1 (f / file~e.20)) :op2 (f2 / figure~e.23 :mod "S1A"~e.24)))) # ::id pmid_2112_2157.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm our findings , we performed inhibition experiments on AS2 cells using increasing doses of Jak2 @/@ Stat3 inhibitor . # ::alignments 1-1.4 2-1.4.2.1.1 3-1.4.2 3-1.4.2.1 3-1.4.2.1.r 5-1.4.2.1.1 6-1 7-1.2.3 8-1.2 9-1.2.2.r 10-1.2.2.1.1 11-1.2.2 12-1.4.r 13-1.3.3 14-1.3 16-1.3.2.1.1.1.1 18-1.3.2.1.1.1.1 19-1.2.3 19-1.3.2 19-1.3.2.1 19-1.3.2.1.r (p / perform-01~e.6 :ARG0 (w / we) :ARG1 (e / experiment-01~e.8 :ARG0 w :ARG1~e.9 (c / cell-line~e.11 :name (n / name :op1 "AS2"~e.10)) :ARG2 (i / inhibit-01~e.7,19)) :ARG2 (d / dose-01~e.14 :ARG1 c :ARG2 (m / molecular-physical-entity~e.19 :ARG0-of~e.19 (i2 / inhibit-01~e.19 :ARG1 (p2 / pathway :name (n2 / name :op1 "Jak2/Stat3"~e.16,18)))) :ARG1-of (i3 / increase-01~e.13)) :purpose~e.12 (c2 / confirm-01~e.1 :ARG0 w :ARG1 (t / thing~e.3 :ARG1-of~e.3 (f / find-01~e.3 :ARG0 w~e.2,5)))) # ::id pmid_2112_2157.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Decrease in Stat3 phosphorylation was confirmed by Western blot analysis , and IL @-@ 6 secretion was measured by ELISA . # ::alignments 0-1.1.2 1-1.1.2.1.r 2-1.1.2.1.1.1.1 3-1.1.2.1 5-1.1 6-1.1.1.r 7-1.1.1.1 8-1.1.1.1 9-1.1.1 11-1 12-1.2.1.1.1.1 14-1.2.1.1.1.1 15-1.2.1 17-1.2 18-1.2.2.r 19-1.2.2.1.1 (a / and~e.11 :op1 (c / confirm-01~e.5 :ARG0~e.6 (a2 / analyze-01~e.9 :manner (i / immunoblot-01~e.7,8)) :ARG1 (d / decrease-01~e.0 :ARG1~e.1 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein :name (n / name :op1 "Stat3"~e.2))))) :op2 (m / measure-01~e.17 :ARG1 (s / secrete-01~e.15 :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6"~e.12,14))) :manner~e.18 (t / thing :name (n4 / name :op1 "ELISA"~e.19)))) # ::id pmid_2112_2157.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found the Jak2 @/@ Stat3 inhibitor dose @-@ dependently decreased Stat3 phosphorylation ( Figure 2B ) and IL @-@ 6 secretion ( p < 0.05 at doses higher than 20 �M ) ( Figure 2C ) . # ::alignments 0-1.1 1-1 3-1.2.1.1.1.1.1 5-1.2.1.1.1.1.1 6-1.2.1 6-1.2.1.1 6-1.2.1.1.r 7-1.2.3.1 9-1.2.3 10-1.2 11-1.2.2.1.1.1.1 12-1.2.2.1 14-1.2.2.1.2.1 15-1.2.2.1.2.1.1 17-1.2.2 18-1.2.2.2.1.1.1 20-1.2.2.2.1.1.1 21-1.2.2.2 23-1.2.4 24-1.2.4.1 25-1.2.4.1.1 26-1.2.2.2.2.r 27-1.2.2.2.2 29-1.2.2.2.2.1 30-1.2.2.2.2.1.1.1 34-1.2.2.2.3.1 35-1.2.2.2.3.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (d / decrease-01~e.10 :ARG0 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6 :ARG1 (p / pathway :name (n / name :op1 "Jak2/Stat3"~e.3,5)))) :ARG1 (a / and~e.17 :op1 (p2 / phosphorylate-01~e.12 :ARG1 (p3 / protein :name (n2 / name :op1 "Stat3"~e.11)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.14 :mod "2B"~e.15))) :op2 (s / secrete-01~e.21 :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6"~e.18,20)) :ARG1-of~e.26 (d3 / dose-01~e.27 :quant (m3 / more-than~e.29 :op1 (c / concentration-quantity :quant 20~e.30 :unit (m2 / micromolar)))) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure~e.34 :mod "2C"~e.35)))) :ARG0-of (d5 / depend-01~e.9 :ARG1 d3~e.7) :ARG1-of (s2 / statistical-test-91~e.23 :ARG2 (l / less-than~e.24 :op1 0.05~e.25)))) # ::id pmid_2112_2157.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also used MTT assay to analyze the effect of the increasing doses of AG490 on cell viability and showed that only a minor reduction in cell survival ( about 15 %) was found when cells exposed to 80 �M AG490 ( Additional file 1 , Figure S1B ) . # ::alignments 0-1.1.1 1-1.1.4 2-1.1 3-1.1.2.1.1.1 4-1.1.2 6-1.1.3 8-1.1.3.2 9-1.1.3.2.1.r 11-1.1.3.2.1.2 12-1.1.3.2.1 13-1.1.3.2.1.1.r 14-1.1.3.2.1.1.1.1 15-1.1.3.2.2.r 16-1.1.3.2.2.1 17-1.1.3.2.2 18-1 18-1.3.1 19-1.2 20-1.2.2.r 21-1.2.2.2.3 23-1.2.2.2.2 24-1.2.2.2 25-1.2.2.2.1.r 26-1.2.2.2.1.1 27-1.2.2.2.1 29-1.2.2.2.2.1.1 30-1.2.2.2.2.1.1.1.1 33-1.2.2 34-1.2.2.3.r 35-1.2.2.3.2 36-1.2.2.3 37-1.2.2.3.3.r 38-1.2.2.3.3.2.1 40-1.2.2.3.3.1.1 43-1.3.1.1.1 44-1.3.1.1.1.1 46-1.3.1.2 47-1.3.1.2.1 (a / and~e.18 :op1 (u / use-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a2 / assay-01~e.4 :instrument (s5 / small-molecule :name (n / name :op1 "MTT"~e.3))) :ARG2 (a3 / analyze-01~e.6 :ARG0 w :ARG1 (a4 / affect-01~e.8 :ARG0~e.9 (d / dose-01~e.12 :ARG1~e.13 (s3 / small-molecule :name (n2 / name :op1 "AG490"~e.14)) :ARG1-of (i / increase-01~e.11)) :ARG1~e.15 (v / viability~e.17 :mod (c / cell~e.16)))) :mod (a5 / also~e.1)) :op2 (s / show-01~e.19 :ARG0 w :ARG1~e.20 (f / find-01~e.33 :ARG0 w :ARG1 (r / reduce-01~e.24 :ARG1~e.25 (s2 / survive-01~e.27 :ARG0 (c2 / cell~e.26)) :ARG1-of (m / minor-01~e.23 :ARG1-of (m3 / mean-01 :ARG2 (a6 / about~e.29 :op1 (p / percentage-entity :value 15~e.30)))) :mod (o / only~e.21)) :time~e.34 (e / expose-01~e.36 :ARG0 w :ARG1 (c3 / cell~e.35) :ARG2~e.37 (s4 / small-molecule :name (n3 / name :op1 "AG490"~e.40) :quant (c4 / concentration-quantity :quant 80~e.38 :unit (m5 / micromolar)))))) :ARG1-of (d2 / describe-01 :ARG0 (a7 / and~e.18 :op1 (a8 / add-02 :ARG1 (f2 / file~e.43 :mod 1~e.44)) :op2 (f3 / figure~e.46 :mod "S1B"~e.47)))) # ::id pmid_2112_2157.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , we showed that treatment with AG490 ( 40 �M ) significantly decreased IL @-@ 6 promoter activity ( Figure 2D ) . # ::alignments 0-1 1-1 3-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1 7-1.1.2.1.1.r 8-1.1.2.1.1.1.1 10-1.1.2.1.1.2.1 13-1.1.2.3 14-1.1.2 15-1.1.2.2.1.1.1.1.1 17-1.1.2.2.1.1.1.1.1 18-1.1.2.2.1 18-1.1.2.2.1.1 18-1.1.2.2.1.1.r 19-1.1.2.2 21-1.2.1 22-1.2.1.1 (a / and~e.0,1 :op1 (s / show-01~e.4 :ARG0 (w / we~e.3) :ARG1~e.5 (d / decrease-01~e.14 :ARG0 (t / treat-04~e.6 :ARG2~e.7 (s2 / small-molecule :name (n / name :op1 "AG490"~e.8) :quant (c / concentration-quantity :quant 40~e.10 :unit (m / micromolar)))) :ARG1 (a2 / activity-06~e.19 :ARG0 (m2 / molecular-physical-entity~e.18 :ARG0-of~e.18 (p / promote-01~e.18 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"~e.15,17))))) :ARG2 (s3 / significant-02~e.13))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.21 :mod "2D"~e.22))) # ::id pmid_2112_2157.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our results suggest that Jak2 @/@ Stat3 pathway may regulate the autocrine production of IL @-@ 6 in AS2 cells . # ::alignments 0-1.1.2 0-1.1.2.r 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1.1 8-1.2 9-1.2.1 11-1.2.1.2.2 12-1.2.1.2 13-1.2.1.2.1.r 14-1.2.1.2.1.1.1 16-1.2.1.2.1.1.1 17-1.2.1.2.3.r 18-1.2.1.2.3.1.1 19-1.2.1.2.3 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :poss~e.0 (w / we~e.0)) :ARG1~e.3 (p / possible-01~e.8 :ARG1 (r2 / regulate-01~e.9 :ARG0 (p2 / pathway~e.7 :name (n / name :op1 "Jak2/Stat3"~e.4,6)) :ARG1 (p3 / produce-01~e.12 :ARG1~e.13 (p4 / protein :name (n2 / name :op1 "IL-6"~e.14,16)) :mod (a / autocrine~e.11) :location~e.17 (c / cell-line~e.19 :name (n3 / name :op1 "AS2"~e.18)))))) # ::id pmid_2112_2157.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stat3 activation status was positively correlated with IL @-@ 6 expression and paclitaxel resistance in AS2 @-@ derived cells # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1 4-1.4 4-1.4.r 5-1 6-1.2.r 7-1.2.1.1.1.1 9-1.2.1.1.1.1 10-1.2.1 11-1.2 12-1.2.2.1.1.1 13-1.2.2 14-1.3.r 15-1.3.1.1.1.1 17-1.3.1 18-1.3 (c / correlate-01~e.5 :ARG1 (s / status~e.2 :mod (a / activate-01~e.1 :ARG1 (p / protein :name (n / name :op1 "Stat3"~e.0)))) :ARG2~e.6 (a2 / and~e.11 :op1 (e / express-03~e.10 :ARG2 (p2 / protein :name (n2 / name :op1 "IL-6"~e.7,9))) :op2 (r / resist-01~e.13 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "paclitaxel"~e.12)))) :location~e.14 (c2 / cell~e.18 :ARG1-of (d / derive-01~e.17 :ARG2 (c3 / cell-line :name (n3 / name :op1 "AS2"~e.15)))) :manner~e.4 (p3 / positive~e.4)) # ::id pmid_2112_2157.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To clarify the role of Stat3 on IL @-@ 6 autocrine production proposed by the biochemical studies , we performed genetic studies to investigate the effect of varying degrees of Stat3 activation and inactivation on the mRNA expression and the secretion of IL @-@ 6 using parental AS2 cells and various previously established AS2 @-@ derived cell lines with different Stat3 activation status : vector control cells , two AS2 @/@ S3C cells , two AS2 @/@ S3D cells , and two AS2 @/@ S3F cells [ 2,10 ] . # ::alignments 1-1.2 3-1.2.1 5-1.1.3.2.3.2.1.3.1.1.1.1.1 7-1.1.3.2.2.2.1.1.1 9-1.1.3.2.2.2.1.1.1 10-1.2.1.1.2.2 11-1.2.1.1 11-1.2.1.1.2 11-1.2.1.1.2.r 12-1.2.1.1.3 16-1.1.2 16-1.2.1.1.3.1 18-1.1.1 19-1.1 20-1.1.2.1 21-1.1.2 23-1.1.3 25-1.1.3.2 27-1.1.3.2.1.3.1 27-1.1.3.2.3.2.1.2 28-1.1.3.2.1.3 28-1.1.3.2.1.3.r 30-1.1.3.2.3.2.1.3.1.1.1.1.1 31-1.1.3.2.1.1 31-1.1.3.2.1.2 32-1.1.3.2.1 33-1.1.3.2.1.1 33-1.1.3.2.1.2 33-1.1.3.2.1.2.1 33-1.1.3.2.1.2.1.r 34-1.1.3.2.2.r 36-1.1.3.2.2.1.1.1.1 37-1.1.3.2.2.1 38-1.1.3.2.2 40-1.1.3.2.2.2 42-1.1.3.2.2.2.1.1.1 44-1.1.3.2.2.2.1.1.1 45-1 45-1.1.3.r 46-1.1.3.2.3.1.2 47-1.1.3.2.3.1.1.1 48-1.1.3.2.3.2.1.4.1.1 49-1.1.3.2.3 49-1.1.3.2.3.2.1.4.1 51-1.1.3.2.3.2.2 52-1.1.3.2.3.2 53-1.1.3.2.3.2.1.4.1.4.2.1 55-1.1.3.2.3.2.1.1 56-1.1.3.2.3.2.1 57-1.1.3.2.3.2.1 59-1.1.3.2.3.2.1.3.1.2 60-1.1.3.2.3.2.1.3.1.1.1.1.1 61-1.1.3.2.3.2.1.3.1.1 62-1.1.3.2.3.2.1.3.1 64-1.1.3.2.3.2.1.4.1.1.1.1 65-1.1.3.2.3.2.1.4.1.1.1 66-1.1.3.2.3.2.1.4.1.1 68-1.1.3.2.3.2.1.4.1.3.1 68-1.1.3.2.3.2.1.4.1.4.1 69-1.1.3.2.3.2.1.4.1.2.2.1 69-1.1.3.2.3.2.1.4.1.3.2.1 69-1.1.3.2.3.2.1.4.1.4.2.1 71-1.1.3.2.3.2.1.4.1.2.2.1 72-1.1.3.2.3.2.1.4.1.2 74-1.1.3.2.3.2.1.4.1.2.1 75-1.1.3.2.3.2.1.4.1.2.2.1 75-1.1.3.2.3.2.1.4.1.3.2.1 75-1.1.3.2.3.2.1.4.1.4.2.1 77-1.1.3.2.3.2.1.4.1.3.2.1 78-1.1.3.2.3.2.1.4.1.2 80-1.3.1.1.1 81-1.3.1.1.1.1 82-1.1.3.2.3.1.1.1 84-1.1.3.2.3.2.1.4.1.4.2.1 85-1.1.3.2.3.2.1.4.1.2 (h / have-purpose-91~e.45 :ARG1 (p4 / perform-01~e.19 :ARG0 (w / we~e.18) :ARG1 (s2 / study-01~e.16,21 :mod (g / genetic~e.20)) :purpose~e.45 (i / investigate-01~e.23 :ARG0 w :ARG1 (a2 / affect-01~e.25 :ARG0 (a3 / and~e.32 :op1 (a4 / activate-01~e.31,33 :ARG1 p) :op2 (a5 / activate-01~e.31,33 :polarity~e.33 -~e.33 :ARG1 p) :degree~e.28 (d / degree~e.28 :ARG1-of (v / vary-01~e.27))) :ARG1~e.34 (a6 / and~e.38 :op1 (e2 / express-03~e.37 :ARG2 (n / nucleic-acid :name (n3 / name :op1 "mRNA"~e.36))) :op2 (s3 / secrete-01~e.40 :ARG1 (p10 / protein :name (n4 / name :op1 "IL-6"~e.7,9,42,44)))) :ARG2 (a7 / and~e.49 :op1 (c2 / cell-line :name (n5 / name :op1 "AS2"~e.47,82) :mod (p5 / parent~e.46)) :op2 (e4 / establish-01~e.52 :ARG1 (c3 / cell-line~e.56,57 :ARG1-of (d2 / derive-01~e.55 :ARG2 c2) :ARG1-of (v2 / vary-01~e.27) :ARG0-of (h3 / have-03 :ARG1 (s4 / status~e.62 :mod (a8 / activate-01~e.61 :ARG1 (p7 / protein :name (n6 / name :op1 "Stat3"~e.5,30,60))) :ARG1-of (d3 / differ-02~e.59))) :ARG1-of (m / mean-01 :ARG2 (a9 / and~e.49 :op1 (c4 / cell~e.48,66 :ARG1-of (c5 / control-01~e.65 :ARG0 (v3 / vector~e.64))) :op2 (c6 / cell-line~e.72,78,85 :quant 2~e.74 :name (n7 / name :op1 "AS2/S3C"~e.69,71,75)) :op3 (c7 / cell-line :quant 2~e.68 :name (n8 / name :op1 "AS2/S3D"~e.69,75,77)) :op4 (c8 / cell-line :quant 2~e.68 :name (n9 / name :op1 "AS2/S3F"~e.53,69,75,84))))) :time (p6 / previous~e.51)))))) :ARG2 (c / clarify-10~e.1 :ARG1 (r / role~e.3 :poss (p / protein~e.11 :name n6 :ARG0-of~e.11 (p2 / produce-01~e.11 :ARG1 (p9 / protein :name n4) :mod (a / autocrine~e.10)) :ARG1-of (p3 / propose-01~e.12 :ARG0 (s / study-01~e.16 :mod (b / biochimic)))))) :ARG1-of (d4 / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c9 / cite-01 :ARG2 (a10 / and~e.80 :op1 2~e.81 :op2 10))))) # ::id pmid_2112_2157.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this current study , we used S3C as active form Stat3 , and S3D and S3F as inactivated forms of Stat3 . # ::alignments 1-1.3.2 2-1.3.1 3-1.3 5-1.1 6-1 7-1.2.1.1.1 9-1.2.1.2.1 9-1.2.1.2.1.2 9-1.2.1.2.1.2.r 9-1.2.2.3.1 9-1.2.2.3.1.2 9-1.2.2.3.1.2.r 11-1.2.1.2.1.1.1 13-1.2 13-1.2.2 13-1.2.2.r 14-1.2.2.1.1.1 15-1.2.2 16-1.2.2.2.1.1 18-1.2.2.3.1.2.1 21-1.2.1.2.1.1.1 21-1.2.2.3.1.1.1 (u / use-01~e.6 :ARG0 (w / we~e.5) :ARG1 (a / and~e.13 :op1 (p / protein :name (n / name :op1 "S3C"~e.7) :mod (c / consider-01 :ARG1 (p2 / protein~e.9 :name (n2 / name :op1 "Stat3"~e.11,21) :ARG0-of~e.9 (a5 / activity-06~e.9)))) :op2~e.13 (a3 / and~e.13,15 :op1 (p3 / protein :name (n3 / name :op1 "S3D"~e.14)) :op2 (p4 / protein :name (n4 / name :op1 "S3F"~e.16)) :mod (c2 / consider-01 :ARG1 (p5 / protein~e.9 :name (n5 / name :op1 "Stat3"~e.21) :ARG0-of~e.9 (a2 / activity-06~e.9 :polarity -~e.18))))) :medium (s / study-01~e.3 :mod (c3 / current~e.2) :mod (t / this~e.1))) # ::id pmid_2112_2157.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis showed increased expression of Stat3 protein in all mutant cells , in the AS2 @/@ S3C cells ( AS2/S3C @-@ A and AS2 @/@ S3C @-@ C ) , in the AS2 @/@ S3D cells ( AS2/S3D @-@ 8 and AS2 @/@ S3D @-@ 9 ) and in the AS2 @/@ S3F cells ( AS2/S3F @-@ 3 and AS2 @/@ S3F @-@ 7 ) , compared to the parental cells ( AS2 ) and vector control cells ( AS2/Vec @-@ 11 ) ( Figure 3A ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.3 5-1.2 6-1.2.1.r 7-1.2.1.1.1 8-1.2.1 9-1.2.2.r 10-1.2.2.2 11-1.2.2.1 12-1.2.2 14-1.2.3.1.r 16-1.2.3.1.1.2.1.1 18-1.2.2.3.1.1.2.1.1.1.1 19-1.2.2.3.1.1 21-1.2.2.3.1.1.1.1 23-1.2.2.3.1.1.2.1.1.1.1 25-1.2.2.3.1.1.2.1.1.1.1 25-1.2.2.3.1.1.2.1.2.1.1 27-1.2.2.3.1.1.2.1.1.1.1 27-1.2.2.3.1.1.2.1.2.1.1 29-1.2.2.3.1.1.2.1.2.1.1 34-1.2.2.3.1.1.2.1.2.1.1 36-1.2.2.3.1.2.2.1.1.1.1 37-1.2.2.3.1.1 39-1.2.2.3.1.2.1.1 41-1.2.2.3.1.2.2.1.1.1.1 43-1.2.2.3.1.2.2.1.1.1.1 43-1.2.2.3.1.2.2.1.2.1.1 45-1.2.2.3.1.2.2.1.1.1.1 45-1.2.2.3.1.2.2.1.2.1.1 47-1.2.2.3.1.2.2.1.2.1.1 49-1.2.2.3.1 52-1.2.2.3.1.1.2.1.2.1.1 52-1.2.2.3.1.2.2.1.2.1.1 54-1.2.2.3.1.3.2.1.1.1.1 55-1.2.2.3.1.1 57-1.2.2.3.1.3.1.1 59-1.2.2.3.1.3.2.1.1.1.1 61-1.2.2.3.1.3.2.1.1.1.1 61-1.2.2.3.1.3.2.1.2.1.1 63-1.2.2.3.1.3.2.1.1.1.1 63-1.2.2.3.1.3.2.1.2.1.1 65-1.2.2.3.1.3.2.1.2.1.1 68-1.2.3.1 69-1.2.3.1.1.r 71-1.2.3.1.1.1.2 72-1.2.3.1.1.1 74-1.2.3.1.1.1.1.1 76-1.2.3.1.1 77-1.2.3.1.1.2.2.1 78-1.2.3.1.1.2.2 79-1.2.2.3.1.1.2.1.1 79-1.2.2.3.1.1.2.1.2 79-1.2.2.3.1.2 79-1.2.2.3.1.2.2.1.1 79-1.2.2.3.1.2.2.1.2 79-1.2.2.3.1.3 79-1.2.2.3.1.3.2.1.1 79-1.2.2.3.1.3.2.1.2 79-1.2.3.1.1.2 83-1.2.3.1.1.2.1.1 86-1.3.1 87-1.3.1.1 (s / show-01~e.3 :ARG0 (a / analyze-01~e.2 :manner (i2 / immunoblot-01~e.0,1)) :ARG1 (e / express-03~e.5 :ARG2~e.6 (p / protein~e.8 :name (n2 / name :op1 "Stat3"~e.7)) :ARG3~e.9 (c14 / cell~e.12 :ARG2-of (m4 / mutate-01~e.11) :mod (a7 / all~e.10) :ARG1-of (m5 / mean-01 :ARG2 (a3 / and~e.49 :op1 (c5 / cell-line~e.19,37,55 :name (n3 / name :op1 "AS2/S3C"~e.21) :ARG1-of (m / mean-01 :ARG2 (a4 / and :op1 (c6 / cell-line~e.79 :name (n4 / name :op1 "AS2/S3C-A"~e.18,23,25,27)) :op2 (c7 / cell-line~e.79 :name (n5 / name :op1 "AS2/S3C-C"~e.25,27,29,34,52))))) :op2 (c8 / cell-line~e.79 :name (n6 / name :op1 "AS2/S3D"~e.39) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (c9 / cell-line~e.79 :name (n7 / name :op1 "AS2/S3D-8"~e.36,41,43,45)) :op2 (c10 / cell-line~e.79 :name (n8 / name :op1 "AS2/S3D-9"~e.43,45,47,52))))) :op3 (c11 / cell-line~e.79 :name (n9 / name :op1 "AS2/S3F"~e.57) :ARG1-of (m3 / mean-01 :ARG2 (a6 / and :op1 (c12 / cell-line~e.79 :name (n10 / name :op1 "AS2/S3F-3"~e.54,59,61,63)) :op2 (c13 / cell-line~e.79 :name (n11 / name :op1 "AS2/S3F-7"~e.61,63,65)))))))) :ARG1-of (i / increase-01~e.4 :ARG1-of~e.14 (c / compare-01~e.68 :ARG2~e.69 (a2 / and~e.76 :op1 (c2 / cell-line~e.72 :name (n12 / name :op1 "AS2"~e.74) :mod (p2 / parent~e.71)) :op2 (c3 / cell-line~e.79 :name (n13 / name :op1 "AS2/Vec-11"~e.16,83) :mod (c4 / control-01~e.78 :ARG0 (v / vector~e.77))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.86 :mod "3A"~e.87))) # ::id pmid_2112_2157.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , only AS2 @/@ S3F cells but not AS2 @/@ S3C or AS2 @/@ S3D cells were found to have decreases in Stat3 phosphorylation ( Figure 3A ) . # ::alignments 0-1.1.2 2-1.1.1.1.2 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1.1.1 7-1 7-1.1.2 9-1.1.2.1.1.1.1 11-1.1.2.1.1.1.1 12-1.1.2.1 13-1.1.2.1.1.1.1 13-1.1.2.1.2.1.1 15-1.1.2.1.2.1.1 16-1.1.1.1 16-1.1.2.1.1 16-1.1.2.1.2 18-1.1 20-1.1.1 21-1.1.1.2 22-1.1.1.2.1.r 23-1.1.1.2.1.1.1 24-1.1.1.2.1 24-1.1.1.2.1.2 24-1.1.1.2.1.2.r 26-1.1.3.1 27-1.1.3.1.1 (c5 / contrast-01~e.7 :ARG2 (f2 / find-01~e.18 :ARG1 (h / have-03~e.20 :ARG0 (c2 / cell-line~e.6,16 :name (n / name :op1 "AS2/S3F"~e.3,5) :mod (o2 / only~e.2)) :ARG1 (d2 / decrease-01~e.21 :ARG1~e.22 (p / protein~e.24 :name (n2 / name :op1 "Stat3"~e.23) :ARG1-of~e.24 (p2 / phosphorylate-01~e.24)))) :ARG1-of (c3 / contrast-01~e.0,7 :ARG2 (o / or~e.12 :op1 (c4 / cell-line~e.16 :name (n3 / name :op1 "AS2/S3C"~e.9,11,13)) :op2 (c / cell-line~e.16 :name (n4 / name :op1 "AS2/S3D"~e.13,15)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "3A"~e.27)))) # ::id pmid_2112_2157.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RT @-@ PCR showed that the AS2 @/@ S3C cells expressed 3 to 4 times more IL @-@ 6 mRNA than the parental and vector control cells and that AS2 @/@ S3D and AS2 @/@ S3F cells expressed 30 to 70 percent less IL @-@ 6 mRNA ( Figure 3B ) . # ::alignments 2-1.1 2-1.1.1 2-1.1.1.r 3-1 6-1.2.1.2.1.1 6-1.2.2.2.1.1.1 8-1.2.1.2.1.1 9-1.2.1.2 10-1.2.1 11-1.2.1.3.1.1 13-1.2.1.3.1.2 14-1.2.1.3 15-1.2.1.4 16-1.2.1.1.2.1.1.1 18-1.2.1.1.2.1.1.1 19-1.2.1.1.1.1 20-1.2.1.5.r 22-1.2.1.5.1.1 23-1.2.1.5 24-1.2.1.5.2.1.1 25-1.2.1.5.2.1 26-1.2.1.5.1 26-1.2.1.5.2 27-1.2.1.5 27-1.2.2.2 29-1.2.1.2.1.1 29-1.2.2.2.1.1.1 31-1.2.2.2.1.1.1 32-1.2.2.2 33-1.2.2.2.1.1.1 33-1.2.2.2.2.1.1 35-1.2.2.2.2.1.1 36-1.2.1.2 37-1.2.1 37-1.2.2 38-1.2.2.3.1.1 40-1.2.2.3.1.2 41-1.2.2.3 42-1.2.2.3.2 43-1.2.2.1 44-1.2.2.1 45-1.2.2.1 46-1.2.2.1 48-1.3.1 49-1.3.1.1 (s / show-01~e.3 :ARG0 (r / react-01~e.2 :ARG0~e.2 (p5 / polymerase~e.2) :mod (c7 / chain) :subevent (t / transcribe-01 :ARG1-of (r2 / reverse-01))) :ARG1 (a / and :op1 (e / express-03~e.10,37 :ARG2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.19) :ARG0-of (e2 / encode-01 :ARG1 (p4 / protein :name (n4 / name :op1 "IL-6"~e.16,18)))) :ARG3 (c / cell-line~e.9,36 :name (n2 / name :op1 "AS2/S3C"~e.6,8,29)) :quant (p / product-of~e.14 :op1 (v2 / value-interval :op1 3~e.11 :op2 4~e.13)) :degree (m / more~e.15) :compared-to~e.20 (a2 / and~e.23,27 :op1 (c2 / cell~e.26 :mod (p2 / parent~e.22)) :op2 (c3 / cell~e.26 :mod (c4 / control-01~e.25 :ARG0 (v / vector~e.24))))) :op2 (e3 / express-03~e.37 :ARG2 n7~e.43,44,45,46 :ARG3 (a3 / and~e.27,32 :op1 (c5 / cell-line :name (n5 / name :op1 "AS2/S3D"~e.6,29,31,33)) :op2 (c6 / cell-line :name (n6 / name :op1 "AS2/S3F"~e.33,35))) :quant (p3 / percentage-entity~e.41 :op1 (v3 / value-interval :op1 30~e.38 :op2 70~e.40) :mod (l / less~e.42)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.48 :mod "3B"~e.49))) # ::id pmid_2112_2157.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , transient transfection with S3C plasmid increased IL @-@ 6 promoter luciferase activity by more than 70 % and transient transfection with S3F plasmid decreased IL @-@ 6 promoter luciferase activity by more than 40 % compared with the mock and vector control groups ( both p < 0.001 ) ( Figure 3C ) . # ::alignments 0-1.4 2-1.1.1.2 3-1.1.1 5-1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.3 8-1.1.1.3.1.1.1.1.1 10-1.1.1.3.1.1.1.1.1 11-1.1.1.3.1 11-1.1.1.3.1.1 11-1.1.1.3.1.1.r 12-1.1.1.3.1.1.1.2.1 13-1.1.1.3.1.1.1 13-1.1.1.3.1.1.1.2 13-1.1.1.3.1.1.1.2.r 14-1.1.1.3.2.r 15-1.1.1.3.2 16-1.1.1.3.2 17-1.1.1.3.2.1.1 18-1.1.1.3.2.1 20-1.1.1.2 21-1.1.1 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1.1.1.1 24-1.1.2.1 25-1.1.2.2 26-1.1.1.3.1.1.1.1.1 28-1.1.1.3.1.1.1.1.1 29-1.1.1.3.1.1.r 30-1.1.1.3.1.1.1.2.1 31-1.1.1.3.1.1.1 31-1.1.1.3.1.1.1.2 31-1.1.1.3.1.1.1.2.r 32-1.1.2.2.2.r 33-1.1.2.2.2 34-1.1.2.2.2 35-1.1.2.2.2.1.1 36-1.1.2.2.2.1 37-1 38-1.2.r 40-1.2.1.1 41-1.2 42-1.2.2.1.1 43-1.2.2.1 44-1.2.1 44-1.2.2 47-1.1.3 48-1.1.3.1 49-1.1.3.1.1 52-1.3.1 53-1.3.1.1 (c / compare-01~e.37 :ARG1 (a / and :op1 (t / transfect-01~e.3,21 :ARG2 (p9 / plasmid~e.6 :mod (p / protein :name (n2 / name :op1 "S3C"~e.5))) :ARG1-of (t2 / transient-02~e.2,20) :ARG0-of (i / increase-01~e.7 :ARG1 (m2 / molecular-physical-entity~e.11 :ARG0-of~e.11,29 (p10 / promote-01~e.11 :ARG1 (p7 / protein~e.13,31 :name (n3 / name :op1 "IL-6"~e.8,10,26,28) :ARG0-of~e.13,31 (a2 / activity-06~e.13,31 :ARG1 (l / luciferase~e.12,30))))) :ARG2~e.14 (m4 / more-than~e.15,16 :op1 (p3 / percentage-entity~e.18 :value 70~e.17)))) :op2 (t3 / transfect-01~e.21 :ARG2~e.22 (p8 / plasmid~e.24 :mod (p4 / protein :name (n5 / name :op1 "S3F"~e.23))) :ARG0-of (d / decrease-01~e.25 :ARG1 p7 :ARG2~e.32 (m / more-than~e.33,34 :op1 (p5 / percentage-entity~e.36 :value 40~e.35))) :ARG1-of t2) :ARG1-of (s / statistical-test-91~e.47 :ARG2 (l2 / less-than~e.48 :op1 0.001~e.49))) :ARG2~e.38 (a3 / and~e.41 :op1 (g / group~e.44 :mod (m3 / mock~e.40)) :op2 (g2 / group~e.44 :mod (c2 / control-01~e.43 :ARG0 (v / vector~e.42)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.52 :mod "3C"~e.53)) :ARG1-of (r / resemble-01~e.0)) # ::id pmid_2112_2157.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ELISA showed that AS2 @/@ S3C cells secreted 5 to 10 times more IL @-@ 6 than the parental and vector control cells ( both p < 0.001 ) ( Figure 3D ) and AS2 @/@ S3D and AS2 @/@ S3F cells secreted 40 to 80 percent less IL @-@ 6 ( both p < 0.01 in AS2 @/@ S3D cells and both p < 0.001 in S3F cells ) ( Figure 3E ) . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1.1.1.1 3-1.2.2.1.1.1.1 5-1.2.1.1.1.1 6-1.2.1.1 7-1.2.1 8-1.2.1.3.1.1 10-1.2.1.3.1.2 11-1.2.1.3 12-1.2.1.4 13-1.2.1.2.1.1 15-1.2.1.2.1.1 16-1.2.1.5.r 18-1.2.1.5.1.1 20-1.2.1.5.2.1.1 21-1.2.1.5.2.1 22-1.2.1.5.2 25-1.2.1.7 26-1.2.1.7.1 27-1.2.1.7.1.1 30-1.2.1.6.1 31-1.2.1.3.r 31-1.2.1.6.1.1 33-1.2 34-1.2.1.1.1.1 34-1.2.2.1.1.1.1 36-1.2.2.1.1.1.1 38-1.2.2.1.1.1.1 38-1.2.2.1.2.1.1 40-1.2.2.1.2.1.1 41-1.2.1.1 42-1.2.1 42-1.2.2 43-1.2.2.3.1.1 45-1.2.2.3.1.2 46-1.2.2.3 47-1.2.2.3.2 48-1.2.1.2.1.1 50-1.2.1.2.1.1 53-1.2.2.5 54-1.2.2.5.1.1 55-1.2.2.5.1.1.1 57-1.2.2.1.1.1.1 57-1.2.2.1.2.1.1 59-1.2.2.1.1.1.1 60-1.2.1.5.1 61-1.2.2.1 61-1.2.2.5.1 63-1.2.2.5 64-1.2.2.5.1.2 65-1.2.2.5.1.2.1 66-1.2.2.5.1.2.2.r 67-1.2.2.5.1.2.2 68-1.2.2.1.1 71-1.2.2.4.1 72-1.2.2.4.1.1 (s / show-01~e.1 :ARG0 (t / thing :name (n / name :op1 "ELISA"~e.0)) :ARG1~e.2 (a / and~e.33 :op1 (s2 / secrete-01~e.7,42 :ARG0 (c / cell-line~e.6,41 :name (n2 / name :op1 "AS2/S3C"~e.3,5,34)) :ARG1 (p / protein :name (n3 / name :op1 "IL-6"~e.13,15,48,50)) :quant~e.31 (p2 / product-of~e.11 :op1 (v3 / value-interval :op1 5~e.8 :op2 10~e.10)) :degree (m / more~e.12) :compared-to~e.16 (a2 / and :op1 (c2 / cell~e.60 :mod (p3 / parent~e.18)) :op2 (c3 / cell~e.22 :mod (c4 / control-01~e.21 :ARG0 (v / vector~e.20)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "3D"~e.31)) :ARG1-of (s4 / statistical-test-91~e.25 :ARG2 (l / less-than~e.26 :op1 0.001~e.27))) :op2 (s3 / secrete-01~e.42 :ARG0 (a3 / and~e.61 :op1 (c5 / cell-line~e.68 :name (n4 / name :op1 "AS2/S3D"~e.3,34,36,38,57,59)) :op2 (c6 / cell-line :name (n5 / name :op1 "AS2/S3F"~e.38,40,57))) :ARG1 p :quant (p5 / percentage-entity~e.46 :op1 (v2 / value-interval :op1 40~e.43 :op2 80~e.45) :mod (l2 / less~e.47)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.71 :mod "3E"~e.72)) :ARG1-of (s5 / statistical-test-91~e.53,63 :ARG2 (a4 / and~e.61 :op1 (l3 / less-than~e.54 :op1 0.01~e.55 :location c5) :op2 (l4 / less-than~e.64 :op1 0.001~e.65 :location~e.66 c6~e.67)))))) # ::id pmid_2112_2157.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results show that Stat3 may positively regulate the expression of IL @-@ 6 mRNA expression and the secretion of IL @-@ 6 in AS2 cells . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1.1 5-1.2 6-1.2.1.3 7-1.2.1 9-1.2.1.2.1 11-1.2.1.2.1.1.2.1.1 13-1.2.1.2.1.1.2.1.1 14-1.2.1.2.1.1.1.1 15-1.2.1.2.1 16-1.2.1.2 18-1.2.1.2.2 19-1.2.1.2.2.2.r 20-1.2.1.2.2.2 21-1.2.1.2.2.2 22-1.2.1.2.2.2 23-1.2.1.2.1.2.r 24-1.2.1.2.1.2.1.1 25-1.2.1.2.1.2 (s / show-01~e.2 :ARG0 (t2 / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t / this~e.0)) :ARG1~e.3 (p / possible-01~e.5 :ARG1 (r2 / regulate-01~e.7 :ARG0 (p3 / protein :name (n / name :op1 "Stat3"~e.4)) :ARG1 (a / and~e.16 :op1 (e / express-03~e.9,15 :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.14) :mod (p4 / protein :name (n3 / name :op1 "IL-6"~e.11,13))) :ARG3~e.23 (c / cell-line~e.25 :name (n4 / name :op1 "AS2"~e.24))) :op2 (s2 / secrete-01~e.18 :ARG0 c :ARG1~e.19 p4~e.20,21,22)) :mod (p2 / positive~e.6)))) # ::id pmid_2112_2157.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To evaluate drug resistance , we treated the parental AS2 cells , vector control cells ( AS2/Vec @-@ 11 ) , the AS2 @/@ S3C cells ( AS2/S3C @-@ C ) , the AS2 @/@ S3D cells ( AS2/S3D @-@ 9 ) , and the AS2 @/@ S3F cells ( AS2/S3F @-@ 3 ) with paclitaxel for 72 hours . # ::alignments 1-1.2 2-1.2.2.1 3-1.2.2 5-1.1.1 6-1.1 8-1.1.2.1.2 9-1.1.2.1.1.1 10-1.1.2.1 12-1.1.2.2.2.1 13-1.1.2.2.2 14-1.1.2.2 18-1.1.2.2.1.1 22-1.1.2.1.1.1 24-1.1.2.3.2.1.1.1 25-1.1.2.3.2.1 27-1.1.2.3.1.1 29-1.1.2.3.2.1.1.1 33-1.1.2.1.1.1 35-1.1.2.4.2.1.1.1 36-1.1.2.4.2.1 38-1.1.2.4.1.1 40-1.1.2.4.2.1.1.1 43-1.1.2 45-1.1.2.1.1.1 47-1.1.2.5.2.1.1.1 48-1.1.2.3 48-1.1.2.4 48-1.1.2.5 48-1.1.2.5.2.1 50-1.1.2.5.1.1 52-1.1.2.5.2.1.1.1 54-1.1.3.r 55-1.1.3.1.1 56-1.1.4.r 57-1.1.4.1 58-1.1.4.2 (h / have-purpose-91 :ARG1 (t / treat-04~e.6 :ARG0 (w / we~e.5) :ARG1 (a / and~e.43 :op1 (c / cell-line~e.10 :name (n / name :op1 "AS2"~e.9,22,33,45) :mod (p2 / parent~e.8)) :op2 (c2 / cell-line~e.14 :name (n2 / name :op1 "AS2/Vec-11"~e.18) :mod (c3 / control-01~e.13 :ARG0 (v / vector~e.12))) :op3 (c4 / cell-line~e.48 :name (n3 / name :op1 "AS2/S3C"~e.27) :ARG1-of (m / mean-01 :ARG2 (c5 / cell-line~e.25 :name (n4 / name :op1 "AS2/S3C-C"~e.24,29)))) :op4 (c6 / cell-line~e.48 :name (n5 / name :op1 "AS2/S3D"~e.38) :ARG1-of (m2 / mean-01 :ARG2 (c8 / cell-line~e.36 :name (n7 / name :op1 "AS2/S3D-9"~e.35,40)))) :op5 (c7 / cell-line~e.48 :name (n6 / name :op1 "AS2/S3F"~e.50) :ARG1-of (m3 / mean-01 :ARG2 (c9 / cell-line~e.48 :name (n8 / name :op1 "AS2/S3F-3"~e.47,52))))) :ARG2~e.54 (s / small-molecule :name (n9 / name :op1 "paclitaxel"~e.55)) :duration~e.56 (t2 / temporal-quantity :quant 72~e.57 :unit (h2 / hour~e.58))) :ARG2 (e / evaluate-01~e.1 :ARG0 w :ARG1 (r / resist-01~e.3 :ARG1 (d / drug~e.2)))) # ::id pmid_2112_2157.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using MTT assay to access cell viability , we found AS2 cells with increased Stat3 activity ( AS2/S3C @-@ C ) to be more resistant to paclitaxel than AS2 and AS2 @/@ Vec @-@ 11 cells ( p < 0.05 ) , and AS2 cells with decreased Stat3 activity ( AS2/S3D @-@ 9 and AS2 @/@ S3F @-@ 3 ) to be less resistant to paclitaxel ( p < 0.05 ) ( Figure 3F ) . # ::alignments 0-1.3 1-1.3.2.1.1.1 2-1.3.2 4-1.3.3 5-1.3.3.2.1 6-1.3.3.2 8-1.1 9-1 10-1.2.1.1.1.1 11-1.3.3.2.1 12-1.3.2.1.r 13-1.2.1.1.2.1 14-1.2.1.1.2.1.1.1.1.1 15-1.2.1.1.2.1.1 19-1.2.1.1.3.1.1.1 23-1.2.1.3 24-1.2.1 25-1.2.1.2.r 26-1.2.1.2.1.1 27-1.2.1.4.r 28-1.2.1.4.2.1.1 29-1.2.1.4 30-1.2.1.4.2.1.1 32-1.2.1.4.2.1.1 34-1.2.1.4.2.1.1 35-1.2.1.4.1 37-1.2.1.5 38-1.2.1.5.1 39-1.2.1.5.1.1 42-1.2.1.4 43-1.2.1.1.1.1 44-1.2.1.4.1 44-1.2.2.1 45-1.2.r 45-1.3.2.1.r 46-1.2.2.1.2.1 47-1.2.2.1.2.1.1 48-1.2.2.1.2.1.1 52-1.2.2.1.3.1.1.1.1 54-1.2.2.1.3.1.1.1.1 54-1.2.2.1.3.1.2.1.1 56-1.2.2.1.3.1.2.1.1 58-1.2.2.1.3.1.2.1.1 62-1.2.2.3 63-1.2.2 64-1.2.2.2.r 65-1.2.2.2 67-1.2.2.4 68-1.2.2.4.1 69-1.2.2.4.1 72-1.4.1 73-1.4.1.1 (f / find-01~e.9 :ARG0 (w / we~e.8) :ARG1~e.45 (a3 / and :op1 (r / resist-01~e.24 :ARG0 (c2 / cell-line :name (n / name :op1 "AS2"~e.10,43) :ARG0-of (h / have-03 :ARG1 (i / increase-01~e.13 :ARG1 (a4 / activity-06~e.15 :ARG0 (p / protein :name (n2 / name :op1 "Stat3"~e.14))))) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :name (n3 / name :op1 "AS2/S2C-C"~e.19)))) :ARG1~e.25 (s / small-molecule :name (n4 / name :op1 "paclitaxel"~e.26)) :degree (m2 / more~e.23) :compared-to~e.27 (a5 / and~e.29,42 :op1 (c4 / cell~e.35,44 :name n) :op2 (c5 / cell-line :name (n5 / name :op1 "AS2/Vec-11"~e.28,30,32,34))) :ARG1-of (s2 / statistical-test-91~e.37 :ARG2 (l / less-than~e.38 :op1 0.05~e.39))) :op2 (r2 / resist-01~e.63 :ARG0 (c6 / cell~e.44 :name n :ARG0-of (h2 / have-03 :ARG1 (d / decrease-01~e.46 :ARG1 a4~e.47,48)) :ARG1-of (m3 / mean-01 :ARG2 (a6 / and :op1 (c7 / cell-line :name (n7 / name :op1 "AS2/S3D-9"~e.52,54)) :op2 (c8 / cell-line :name (n8 / name :op1 "AS2/S3F-3"~e.54,56,58))))) :ARG1~e.64 s~e.65 :degree (l2 / less~e.62) :ARG1-of (s3 / statistical-test-91~e.67 :ARG2 l~e.68,69))) :manner (u / use-01~e.0 :ARG0 w :ARG1 (a7 / assay-01~e.2 :instrument~e.12,45 (s4 / small-molecule :name (n6 / name :op1 "MTT"~e.1))) :ARG2 (a2 / access-01~e.4 :ARG0 w :ARG1 (v / viability~e.6 :mod (c / cell~e.5,11)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.72 :mod "3F"~e.73))) # ::id pmid_2112_2157.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these findings suggest that the activation of Stat3 may contribute to the regulation of IL @-@ 6 autocrine production and resistance to paclitaxel in AS2 cells . # ::alignments 0-1.1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 5-1.2.r 7-1.2.1.1 8-1.2.1.1.1.r 9-1.2.1.1.1.1.1 10-1.2 11-1.2.1 12-1.2.1.2.r 14-1.2.1.2.1 15-1.2.1.2.1.1.r 16-1.2.1.2.1.1.1.1.1 18-1.2.1.2.1.1.1.1.1 19-1.2.1.2.1.1.2 20-1.2.1.2.1.1 21-1.2.1.2 22-1.2.1.2.2 23-1.2.1.2.2.1.r 24-1.2.1.2.2.1.1.1 26-1.2.1.2.3.1.1 27-1.2.1.2.3 (s / suggest-01~e.4 :ARG0 (t3 / thing~e.3 :ARG1-of~e.3 (f / find-01~e.3) :mod (t / this~e.2) :mod (t2 / together~e.0)) :ARG1~e.5 (p / possible-01~e.10 :ARG1 (c / contribute-01~e.11 :ARG0 (a / activate-01~e.7 :ARG1~e.8 (p2 / protein :name (n / name :op1 "Stat3"~e.9))) :ARG2~e.12 (a2 / and~e.21 :op1 (r / regulate-01~e.14 :ARG1~e.15 (p3 / produce-01~e.20 :ARG1 (p5 / protein :name (n2 / name :op1 "IL-6"~e.16,18)) :mod (a3 / autocrine~e.19))) :op2 (r2 / resist-01~e.22 :ARG1~e.23 (s2 / small-molecule :name (n4 / name :op1 "paclitaxel"~e.24))) :location (c2 / cell-line~e.27 :name (n3 / name :op1 "AS2"~e.26)))))) # ::id pmid_2112_2157.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Knocking @-@ down Stat3 by transient transfection with synthetic siRNA decreased IL @-@ 6 expression in AS2 cells # ::alignments 0-1.1 2-1.1 3-1.1.1.1.1 4-1.1.2.r 5-1.1.2.3 6-1.1.2 7-1.1.2.2.r 8-1.1.2.2.2 9-1.1.2.2.1.1 10-1 11-1.2.1.1.1 13-1.2.1.1.1 14-1.2 15-1.1.2.1.r 16-1.1.2.1.1.1 17-1.1.2.1 (d / decrease-01~e.10 :ARG0 (k / knock-down-02~e.0,2 :ARG1 (p / protein :name (n / name :op1 "Stat3"~e.3)) :ARG5~e.4 (t / transfect-01~e.6 :ARG1~e.15 (c / cell-line~e.17 :name (n4 / name :op1 "AS2"~e.16)) :ARG2~e.7 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.9) :mod (s / synthetic~e.8)) :ARG1-of (t2 / transient-02~e.5))) :ARG1 (e2 / express-03~e.14 :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6"~e.11,13)) :ARG3 c)) # ::id pmid_2112_2157.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm that Stat3 regulated IL @-@ 6 expression in cancer cells , we transiently transfected AS2 cells with Stat3 siRNA to knock @-@ down the expression of Stat3 . # ::alignments 1-1.2 2-1.2.2.r 3-1.2.2.1 4-1.2.2 5-1.2.2.2.1.1 7-1.2.2.2.1.1 8-1.2.2.2 8-1.2.2.2.2 8-1.2.2.2.2.r 9-1.2.2.2.2.1.r 10-1.2.2.2.2.1.1.2.1 11-1.2.2.2.2.1 13-1.1.1 14-1.1.4 15-1.1 16-1.1.2.1.1 17-1.1.2 18-1.1.3.r 19-1.1.3.2.1.1.1 20-1.1.3.1.1 21-1.1.5.r 22-1.1.5 24-1.1.5 26-1.1.5.1 27-1.1.5.1.1.r 28-1.1.5.1.1 (h / have-purpose-91 :ARG1 (t / transfect-01~e.15 :ARG0 (w / we~e.13) :ARG1 (c / cell-line~e.17 :name (n / name :op1 "AS2"~e.16)) :ARG2~e.18 (n6 / nucleic-acid :name (n2 / name :op1 "siRNA"~e.20) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "Stat3"~e.19)))) :ARG1-of (t2 / transient-02~e.14) :purpose~e.21 (k / knock-down-02~e.22,24 :ARG1 (e / express-03~e.26 :ARG2~e.27 p~e.28))) :ARG2 (c2 / confirm-01~e.1 :ARG0 w :ARG1~e.2 (r2 / regulate-01~e.4 :ARG0 p~e.3 :ARG1 (p2 / protein~e.8 :name (n4 / name :op1 "IL-6"~e.5,7) :ARG2-of~e.8 (e3 / express-03~e.8 :ARG3~e.9 (c3 / cell~e.11 :mod (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.10)))))))) # ::id pmid_2112_2157.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis showed transfection with Stat3 siRNA ( Stat3#1 ) dose @-@ dependently decreased the total amount of Stat3 protein and phosphorylated Stat3 ( Figure 4A ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1 4-1.2 5-1.2.2.r 6-1.2.2.2.1.1 7-1.2.2.2.1.1 8-1.2.2.2.1.1 9-1.2.2.2.1.1 11-1.2.2.2.1 13-1.2.2.2 14-1.2.2 16-1.2.2.1.2 17-1.2.2.1 18-1.2.1.r 19-1.2.1.2.1.1 20-1.2.2.1.1.1 20-1.2.2.1.1.2 21-1.2.2.1.1 22-1.2.2.1.1.2.2 23-1.2.2.1.1.2.1 25-1.3.1 26-1.3.1.1 (s / show-01~e.3 :ARG0 (a / analyze-01~e.2 :manner (i / immunoblot-01~e.0,1)) :ARG1 (t / transfect-01~e.4 :ARG2~e.18 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA") :mod (p / protein :name (n3 / name :op1 "Stat3"~e.19)) :ARG1-of (l / label-01 :ARG2 (n7 / name :op1 "Stat3#1"))) :ARG0-of~e.5 (d3 / decrease-01~e.14 :ARG1 (a2 / amount-01~e.17 :ARG1 (a3 / and~e.21 :op1 (p2 / protein~e.20 :name n3) :op2 (p3 / protein~e.20 :name n3~e.23 :ARG3-of (p4 / phosphorylate-01~e.22))) :ARG2 (t2 / total~e.16)) :ARG0-of (d2 / depend-01~e.13 :ARG1 (d / dose-01~e.11 :ARG1 n5~e.6,7,8,9)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.25 :mod "4A"~e.26))) # ::id pmid_2112_2157.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RT @-@ PCR and ELISA showed transfection with Stat3#1 reduced the expression of IL @-@ 6 mRNA ( Figure 4B ) and the secretion of IL @-@ 6 at 3 , 8 , and 24 hours after medium replacement ( p < 0.01 in the lower dose and p < 0.001 in the higher doses ) ( Figure 4C ) . # ::alignments 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 3-1.1 5-1 6-1.2 7-1.1.2.1.r 7-1.2.1.r 8-1.2.1.1.1 9-1.2.2 11-1.2.2.1.1 12-1.2.2.1.1.1.r 13-1.2.2.1.1.1.2.1.1.1 15-1.2.2.1.1.1.2.1.1.1 16-1.2.2.1.1.1.1.1 18-1.2.2.1.1.2.1 19-1.2.2.1.1.2.1.1 21-1.2.2.1 23-1.2.2.1.2 24-1.2.2.1.2.1.r 25-1.2.2.1.2.1 26-1.2.2.1.2.1 27-1.2.2.1.2.1 28-1.2.2.1.2.2.r 29-1.2.2.1.2.2.1.2.1 31-1.2.2.1.2.2.2.2.1 33-1.2.2.1.2.2 34-1.2.2.1.2.2.3.2.1 35-1.2.2.1.2.2.1.2.2 36-1.2.2.1.2.2.1 36-1.2.2.1.2.2.2 36-1.2.2.1.2.2.3 37-1.2.2.1.2.2.1.1.1 38-1.2.2.1.2.2.1.1 40-1.2.2.1.2.4 41-1.2.2.1.2.4.1.1 42-1.2.2.1.2.4.1.1.1 43-1.2.2.1.2.4.1.1.2.r 45-1.2.2.1.2.4.1.1.2.1 45-1.2.2.1.2.4.1.1.2.1.1 45-1.2.2.1.2.4.1.1.2.1.1.r 46-1.2.2.1.2.4.1.1.2 47-1.2.2.1.2.4.1 48-1.2.2.1.2.4 49-1.2.2.1.2.4.1.2 50-1.2.2.1.2.4.1.2.1 51-1.2.2.1.2.4.1.2.2.r 53-1.2.2.1.2.4.1.2.2.1 53-1.2.2.1.2.4.1.2.2.1.1 53-1.2.2.1.2.4.1.2.2.1.1.r 54-1.2.2.1.2.4.1.2.2 57-1.2.2.1.2.3.1 58-1.2.2.1.2.3.1.1 (s / show-01~e.5 :ARG0 (a / and~e.3 :op1 (r3 / react-01~e.2 :ARG0~e.2 (p3 / polymerase~e.2) :mod (c / chain) :subevent (t / transcribe-01) :ARG1-of (r / reverse-01)) :op2 (a9 / assay-01 :instrument~e.7 (i / immunosorbent) :ARG1-of (l4 / link-01 :ARG2 (e2 / enzyme)))) :ARG1 (t3 / transfect-01~e.6 :ARG2~e.7 (p / protein :name (n3 / name :op1 "Stat3#1"~e.8)) :ARG0-of (r2 / reduce-01~e.9 :ARG1 (a2 / and~e.21 :op1 (e / express-03~e.11 :ARG2~e.12 (n6 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.16) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "IL-6"~e.13,15)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "4B"~e.19))) :op2 (s2 / secrete-01~e.23 :ARG1~e.24 p2~e.25,26,27 :time~e.28 (a4 / and~e.33 :op1 (a5 / after~e.36 :op1 (r4 / replace-01~e.38 :ARG1 (m / medium~e.37)) :quant (t4 / temporal-quantity :quant 3~e.29 :unit (h / hour~e.35))) :op2 (a6 / after~e.36 :op1 r4 :quant (t5 / temporal-quantity :quant 8~e.31 :unit h)) :op3 (a7 / after~e.36 :op1 r4 :quant (t6 / temporal-quantity :quant 24~e.34 :unit h))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.57 :mod "4C"~e.58)) :ARG1-of (s3 / statistical-test-91~e.40,48 :ARG2 (a8 / and~e.47 :op1 (l / less-than~e.41 :op1 0.01~e.42 :condition~e.43 (d2 / dose-01~e.46 :ARG1-of (l2 / low-04~e.45 :degree~e.45 (m2 / more~e.45)))) :op2 (l3 / less-than~e.49 :op1 0.001~e.50 :condition~e.51 (d3 / dose-01~e.54 :ARG1-of (h2 / high-02~e.53 :degree~e.53 (m3 / more~e.53))))))))))) # ::id pmid_2112_2157.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To make sure our results were not confounded by differences in cell viability , we performed MTT assay of the transfected and untransfected cells , and found that these siRNAs did not affect the viability of AS2 cells ( Figure 4D ) . # ::alignments 1-1.1.3 2-1.1.3 3-1.1.3.2.2.2 3-1.1.3.2.2.2.r 4-1.1.3.2.2 4-1.1.3.2.2.1 4-1.1.3.2.2.1.r 6-1.1.2.1.2.1.1.r 7-1.1.3.2 8-1.1.3.2.1.r 9-1.1.3.2.1 10-1.1.3.2.1.1.r 11-1.1.3.2.1.1.1 12-1.1.3.2.1.1 14-1.1.3.1 15-1.1 16-1.1.2.2.1.1 17-1.1.2 20-1.1.2.1.1.1 20-1.1.2.1.2.1 21-1.1.2.1 23-1.1.2.1.1 23-1.1.2.1.2 25-1 26-1.2 27-1.2.2.r 28-1.2.2.2.2 31-1.1.2.1.2.1.1 31-1.2.2.1 31-1.2.2.1.r 32-1.2.2 34-1.2.2.3.2 36-1.2.2.3.1.1 37-1.2.2.3 39-1.3.1 40-1.3.1.1 (a / and~e.25 :op1 (p / perform-01~e.15 :ARG0 (w / we) :ARG1 (a5 / assay-01~e.17 :ARG1 (a3 / and~e.21 :op1 (c5 / cell~e.23 :ARG1-of (t4 / transfect-01~e.20)) :op2 (c6 / cell~e.23 :ARG1-of (t5 / transfect-01~e.20 :polarity~e.6 -~e.31))) :instrument (s / small-molecule :name (n3 / name :op1 "MTT"~e.16))) :purpose (e / ensure-01~e.1,2 :ARG0 w~e.14 :ARG1 (c2 / confound-01~e.7 :ARG0~e.8 (d / differ-02~e.9 :ARG3~e.10 (v / viability~e.12 :mod (c3 / cell~e.11))) :ARG1 (t / thing~e.4 :ARG2-of~e.4 (r3 / result-01~e.4) :poss~e.3 w~e.3)))) :op2 (f / find-01~e.26 :ARG0 w :ARG1~e.27 (a4 / affect-01~e.32 :polarity~e.31 -~e.31 :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA") :mod (t3 / this~e.28)) :ARG1 (c / cell-line~e.37 :name (n2 / name :op1 "AS2"~e.36) :mod (v2 / viability~e.34)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.39 :mod "4D"~e.40))) # ::id pmid_2112_2157.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The findings suggested that the suppression of IL @-@ 6 production by knocking @-@ down Stat3 was not likely a result of a decrease in cell number . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.2.2 6-1.2.2.2.1.r 7-1.2.2.2.1.1.1 9-1.2.2.2.1.1.1 10-1.2.2.2.1 10-1.2.2.2.1.2 10-1.2.2.2.1.2.r 11-1.2.2.2.2.r 12-1.2.2.2.2 14-1.2.2.1 15-1.2.2.2.2.1.1.1 17-1.2.1 17-1.2.1.r 18-1.2 20-1.2.2 23-1.2.2.1 24-1.2.2.1.1.r 25-1.2.2.1.1.1 26-1.2.2.1.1 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1)) :ARG1~e.3 (l / likely-01~e.18 :polarity~e.17 -~e.17 :ARG1 (r / result-01~e.20 :ARG1 (d / decrease-01~e.14,23 :ARG1~e.24 (n / number-01~e.26 :ARG1 (c / cell~e.25))) :ARG2 (s2 / suppress-01~e.5 :ARG1~e.6 (p3 / protein~e.10 :name (n2 / name :op1 "IL-6"~e.7,9) :ARG1-of~e.10 (p / produce-01~e.10)) :manner~e.11 (k / knock-down-02~e.12 :ARG1 (p2 / protein :name (n3 / name :op1 "Stat3"~e.15))))))) # ::id pmid_2112_2157.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As can be seen in Figures S2A and S2B in Additional file 2 , the other Stat3 siRNA ( Stat3#2 ) with a different targeting sequence also knocked @-@ down Stat3 expression and reduced IL @-@ 6 secretion but did not compromise cell proliferation ( Additional file 3 , Figure S3A ) , a further confirmation of our findings . # ::alignments 1-1.4.1 3-1.4 5-1.4.2.1 5-1.4.2.2 6-1.4.2.1.1 7-1.4.2 8-1.4.2.2.1 9-1.4.2.r 10-1.4.2.3.2 11-1.4.2.3 12-1.4.2.3.1 15-1.1.1.1.4 16-1.1.1.1.2.1.1 17-1.1.1.1.1.1 19-1.1.1.1.3.1.1.1 23-1.1.1.1.5.1.1.1 24-1.1.1.1.5.1.1 25-1.1.1.1.5.1 26-1.1.3 27-1.1.1 29-1.1.1 30-1.1.1.2.1 31-1.1.1.2 31-1.1.1.2.2 31-1.1.1.2.2.r 32-1.1 33-1.1.2 34-1.1.2.2.1.1 36-1.1.2.2.1.1 37-1.1.2.2 37-1.1.2.2.2 37-1.1.2.2.2.r 38-1 40-1.2.1 40-1.2.1.r 41-1.2 42-1.2.3 43-1.2.3.1 45-1.2.4.1.2.2 46-1.2.4.1.2 47-1.2.4.1.2.1 49-1.2.4.1 50-1.2.4.1.1 54-1.3.2 55-1.3 56-1.3.1.r 57-1.3.1.1.1 57-1.3.1.1.1.r 58-1.3.1 58-1.3.1.1 58-1.3.1.1.r (c / contrast-01~e.38 :ARG1 (a3 / and~e.32 :op1 (k / knock-down-02~e.27,29 :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA"~e.17) :mod (p / protein :name (n2 / name :op1 "Stat3"~e.16)) :ARG1-of (m / mean-01 :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "Stat3#2"~e.19))) :mod (o / other~e.15) :ARG0-of (h / have-03 :ARG1 (s / sequence~e.25 :ARG0-of (t / target-01~e.24 :ARG1-of (d2 / differ-02~e.23))))) :ARG1 (p2 / protein~e.31 :name n2~e.30 :ARG2-of~e.31 (e / express-03~e.31))) :op2 (r4 / reduce-01~e.33 :ARG0 n4 :ARG1 (p5 / protein~e.37 :name (n5 / name :op1 "IL-6"~e.34,36) :ARG1-of~e.37 (s2 / secrete-01~e.37))) :mod (a / also~e.26)) :ARG2 (c2 / compromise-02~e.41 :polarity~e.40 -~e.40 :ARG0 n4 :ARG1 (c3 / cell~e.42 :ARG0-of (p3 / proliferate-01~e.43)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.49 :mod "S3A"~e.50 :part-of (f2 / file~e.46 :mod 3~e.47 :mod (a2 / additional~e.45))))) :ARG0-of (c4 / confirm-01~e.55 :ARG1~e.56 (t2 / thing~e.58 :ARG1-of~e.58 (f3 / find-01~e.58 :ARG0~e.57 (w / we~e.57))) :ARG1-of (f4 / further-01~e.54)) :ARG1-of (s3 / see-01~e.3 :ARG1-of (p4 / possible-01~e.1) :location~e.9 (a5 / and~e.7 :op1 (f7 / figure~e.5 :mod "S2A"~e.6) :op2 (f8 / figure~e.5 :mod "S2B"~e.8) :part-of (f6 / file~e.11 :mod 2~e.12 :mod (a4 / additional~e.10))))) # ::id pmid_2112_2157.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Knocking @-@ down Stat3 by stable transfection with shRNA decreased the expression of IL @-@ 6 in AS2 cells # ::alignments 0-1.1 2-1.1 3-1.1.1.1.1 4-1.1.2.r 5-1.1.2.2 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1 9-1 11-1.2 12-1.2.1.r 13-1.2.1.1.1 15-1.2.1.1.1 16-1.2.2.r 17-1.2.2.1.1 18-1.2.2 (d / decrease-01~e.9 :ARG0 (k / knock-down-02~e.0,2 :ARG1 (p / protein :name (n / name :op1 "Stat3"~e.3)) :manner~e.4 (t / transfect-01~e.6 :ARG2~e.7 (n5 / nucleic-acid :name (n2 / name :op1 "shRNA"~e.8)) :ARG1-of (s / stable-03~e.5))) :ARG1 (e / express-03~e.11 :ARG2~e.12 (p2 / protein :name (n3 / name :op1 "IL-6"~e.13,15)) :ARG3~e.16 (c / cell-line~e.18 :name (n4 / name :op1 "AS2"~e.17)))) # ::id pmid_2112_2157.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further investigate the possible role of Stat3 in the regulation of IL @-@ 6 , we stably transfected AS2 cells with the control vector from which we selected one cell line ( AS2/shVec ) and the vector expressing Stat3 shRNA from which we selected two cell lines ( AS2/shStat3 @-@ 1 and AS2 @/@ shStat3 @-@ 2 ) . # ::alignments 1-1.2.3 2-1.2 4-1.2.2.1 5-1.2.2 7-1.1.2.2.1.1.2.1.1.1 8-1.2.2.2.r 10-1.2.2.2 11-1.2.2.2.1.r 12-1.2.2.2.1.1.1 14-1.2.2.2.1.1.1 16-1.2.1 18-1.1 19-1.1.1.1.1 20-1.1.1 21-1.1.2.r 23-1.1.2.1 24-1.1.2.1.1 27-1.1.2.1.2.1 28-1.1.2.1.2 29-1.1.2.1.2.2.1 30-1.1.2.1.2.2 31-1.1.2.1.2.2 31-1.1.2.2.2.2.2 31-1.1.2.2.2.2.3 33-1.1.2.1.2.2.2.1 35-1.1.2 35-1.1.2.2.2.2 37-1.1.2.2 38-1.1.2.2.1 39-1.1.2.2.1.1.2.1.1.1 40-1.1.2.2.1.1.1.1 43-1.1.2.1.2.1 44-1.1.2.1.2 44-1.1.2.2.2 45-1.1.2.2.2.2.1 45-1.1.2.2.2.2.3.1.1 46-1.1.2.1.2.2 47-1.1.2.1.2.2 51-1.1.2.1.2.2.1 51-1.1.2.2.2.2.2.1.1 52-1.1.2.2.2.2 53-1.1.2.2.2.2.2.1.1 53-1.1.2.2.2.2.3.1.1 55-1.1.2.2.2.2.2.1.1 55-1.1.2.2.2.2.3.1.1 57-1.1.2.2.2.2.1 57-1.1.2.2.2.2.3.1.1 (h / have-purpose-91 :ARG1 (t / transfect-01~e.18 :ARG1 (c / cell-line~e.20 :name (n / name :op1 "AS2"~e.19)) :ARG2~e.21 (a / and~e.35 :op1 (c2 / control-01~e.23 :ARG0 (v / vector~e.24) :ARG2-of (s / select-01~e.28,44 :ARG0 (w / we~e.27,43) :ARG1 (c3 / cell-line~e.30,31,46,47 :quant 1~e.29,51 :name (n2 / name :op1 "AS2/shVec"~e.33)))) :op2 (v2 / vector~e.37 :ARG1-of (e / express-03~e.38 :ARG2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.40) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n4 / name :op1 "Stat3"~e.7,39))))) :ARG2-of (s2 / select-01~e.44 :ARG0 w :ARG1 (a2 / and~e.35,52 :quant 2~e.45,57 :op1 (c6 / cell-line~e.31 :name (n5 / name :op1 "AS2/shStat3-1"~e.51,53,55)) :op2 (c7 / cell-line~e.31 :name (n7 / name :op1 "AS2/shStat3-2"~e.45,53,55,57))))))) :ARG2 (i / investigate-01~e.2 :ARG0 w~e.16 :ARG1 (r2 / role~e.5 :ARG1-of (p3 / possible-01~e.4) :topic~e.8 (r3 / regulate-01~e.10 :ARG1~e.11 (p4 / protein :name (n6 / name :op1 "IL-6"~e.12,14))) :poss (p2 / protein :name n4)) :ARG1-of (f / further-01~e.1))) # ::id pmid_2112_2157.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis showed a lower expression of Stat3 protein and a lower level of Stat3 phosphorylation in both cell lines expressing Stat3 shRNA than in either the parental cells or the vector control cells ( Figure 5A ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1 5-1.2.1 5-1.2.1.2 5-1.2.1.2.r 6-1.2.1.1 7-1.2.1.1.1.r 8-1.2.1.1.1.1.1 9-1.2.1.1.1 10-1.2 12-1.2.2 13-1.2.2.1 14-1.2.2.1.1.r 15-1.2.2.1.1.1 16-1.2.2.1.1 17-1.3.r 18-1.3.1 19-1.3 20-1.3 21-1.3.2 22-1.3.2.1.2 23-1.3.2.1.1.1 24-1.3.3.r 26-1.3.3.1.2 28-1.3.3.1.1 29-1.3.3.1 30-1.3.3 32-1.3.3.2.1 33-1.3.3.2.2 34-1.3.3.2 36-1.4.1 38-1.4.1.1 (s / show-01~e.3 :ARG0 (a / analyze-01~e.2 :manner (i / immunoblot-01~e.0,1)) :ARG1 (a2 / and~e.10 :op1 (l / low-04~e.5 :ARG1 (e / express-03~e.6 :ARG2~e.7 (p / protein~e.9 :name (n2 / name :op1 "Stat3"~e.8))) :degree~e.5 (m / more~e.5)) :op2 (l3 / low-04~e.12 :ARG1 (l2 / level~e.13 :quant-of~e.14 (p2 / phosphorylate-01~e.16 :ARG3 p~e.15)) :degree m)) :location~e.17 (c / cell-line~e.19,20 :mod (b / both~e.18) :ARG3-of (e2 / express-03~e.21 :ARG2 (n4 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.23) :mod p~e.22)) :compared-to~e.24 (o / or~e.30 :op1 (c2 / cell~e.29 :mod (p3 / parent~e.28) :mod (e3 / either~e.26)) :op2 (c3 / cell~e.34 :mod (v / vector~e.32) :mod (c4 / control~e.33)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "5A"~e.38))) # ::id pmid_2112_2157.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RT @-@ PCR showed a continuing decrease in the expression of IL @-@ 6 mRNA in both cell lines expressing Stat3 shRNA ( Figure 5B ) . # ::alignments 2-1.1 2-1.1.1 2-1.1.1.r 3-1 5-1.2.2 6-1.2 7-1.2.1.r 9-1.2.1 10-1.2.1.1.r 11-1.2.1.1.2.1.1 13-1.2.1.1.2.1.1 14-1.2.1.1.1.1 15-1.2.3.r 16-1.2.3.2 17-1.2.3 18-1.2.3 19-1.2.3.1 20-1.2.3.1.1.2.1.1 21-1.2.3.1.1.1.1 23-1.3.1 25-1.3.1.1 (s / show-01~e.3 :ARG0 (r3 / react-01~e.2 :ARG0~e.2 (p3 / polymerase~e.2) :mod (c3 / chain) :subevent (t / transcribe-01 :ARG1-of (r / reverse-01))) :ARG1 (d / decrease-01~e.6 :ARG1~e.7 (e / express-03~e.9 :ARG2~e.10 (n / nucleic-acid :name (n2 / name :op1 "mRNA"~e.14) :mod (p / protein :name (n3 / name :op1 "IL-6"~e.11,13)))) :ARG1-of (c / continue-01~e.5) :location~e.15 (c2 / cell-line~e.17,18 :ARG3-of (e2 / express-03~e.19 :ARG2 (n6 / nucleic-acid :name (n4 / name :op1 "shRNA"~e.21) :mod (p2 / protein :name (n5 / name :op1 "Stat3"~e.20)))) :mod (b / both~e.16))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.23 :mod "5B"~e.25))) # ::id pmid_2112_2157.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ELISA also showed a continuing decrease IL @-@ 6 secretion in both cell lines expressing Stat3 shRNA compared to the parental AS2 ( 90 % in AS2 @/@ shStat3 @-@ 1 and 95 % AS2 @/@ shStat3 @-@ 2 at 24 hours ) ( p < 0.001 ) ( Figure 5C ) . # ::alignments 0-1.1.1.1 1-1.4 2-1 4-1.2.4 5-1.2 6-1.2.1.1.1.1 8-1.2.1.1.1.1 9-1.2.1 10-1.2.2.r 11-1.2.2.1 12-1.2.2 13-1.2.2 14-1.2.2.2 15-1.2.2.2.1.2.1.1 16-1.2.2.2.1.1.1 17-1.2.2.3.r 20-1.2.2.3.2 21-1.2.2.3.1.1 23-1.2.3.1.1.2.1 24-1.2.3.1.1.2 26-1.2.3.1.1.1.1 28-1.2.3.1.1.1.1 30-1.2.3.1.1.1.1 31-1.2.3.1 32-1.2.3.1.2.2.1 33-1.2.3.1.2.2 34-1.2.3.1.2.1.1 36-1.2.3.1.2.1.1 38-1.2.3.1.2.1.1 40-1.2.3.1.3.1.1 41-1.2.3.1.3.1.2 44-1.2.5 45-1.2.5.1 46-1.2.5.1.1 49-1.3.1 51-1.3.1.1 (s / show-01~e.2 :ARG0 (t / thing :name (n / name :op1 "ELISA"~e.0) :mod (i / immunosorbent) :ARG1-of (l2 / link-01 :ARG2 (e2 / enzyme))) :ARG1 (d / decrease-01~e.5 :ARG1 (s2 / secrete-01~e.9 :ARG1 (p / protein :name (n2 / name :op1 "IL-6"~e.6,8))) :location~e.10 (c / cell-line~e.12,13 :mod (b / both~e.11) :ARG3-of (e / express-03~e.14 :ARG2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.16) :mod (p8 / protein :name (n7 / name :op1 "Stat3"~e.15)))) :compared-to~e.17 (c2 / cell-line :name (n4 / name :op1 "AS2"~e.21) :mod (p2 / parent~e.20))) :ARG1-of (m / mean-01 :ARG2 (a / and~e.31 :op1 (c3 / cell-line :name (n5 / name :op1 "AS2/shStat3-1"~e.26,28,30) :quant (p4 / percentage-entity~e.24 :value 90~e.23)) :op2 (c4 / cell-line :name (n6 / name :op1 "AS2/shStat3-2"~e.34,36,38) :quant (p6 / percentage-entity~e.33 :value 95~e.32)) :time (a3 / after :op1 (t2 / temporal-quantity :quant 24~e.40 :unit (h / hour~e.41))))) :ARG1-of (c5 / continue-01~e.4) :ARG1-of (s3 / statistical-test-91~e.44 :ARG2 (l / less-than~e.45 :op1 0.001~e.46))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.49 :mod "5C"~e.51)) :mod (a2 / also~e.1)) # ::id pmid_2112_2157.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also analyzed the drug resistance of these cells to paclitaxel by MTT assay . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.3 5-1.2 6-1.2.1.r 7-1.2.1.1 8-1.2.1 9-1.2.2.r 10-1.2.2.1.1 11-1.4.r 12-1.4.1.1.1 13-1.4 (a / analyze-01~e.2 :ARG0 (w / we~e.0) :ARG1 (r / resist-01~e.5 :ARG0~e.6 (c / cell~e.8 :mod (t / this~e.7)) :ARG1~e.9 (s / small-molecule :name (n / name :op1 "paclitaxel"~e.10)) :mod (d / drug~e.4)) :mod (a2 / also~e.1) :manner~e.11 (a3 / assay-01~e.13 :instrument (s2 / small-molecule :name (n2 / name :op1 "MTT"~e.12)))) # ::id pmid_2112_2157.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MTT assay showed that the permanent knock @-@ down of Stat3 in AS2 @/@ shStat3 @-@ 1 and AS2 @/@ shStat3 @-@ 2 cells significantly reduced their resistance to paclitaxel ( p < 0.001 ) ( Figure 5D ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.1.3 6-1.2.1 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.1.1 11-1.2.1.2.r 12-1.2.1.2.1.1.1 12-1.2.1.2.2.1.1 14-1.2.1.2.1.1.1 14-1.2.1.2.2.1.1 16-1.2.1.2.1.1.1 17-1.2.1.2 18-1.2.1.2.1.1.1 18-1.2.1.2.2.1.1 20-1.2.1.2.1.1.1 20-1.2.1.2.2.1.1 22-1.2.1.2.2.1.1 23-1.2.1.2.1 23-1.2.1.2.2 24-1.2.3 25-1.2 26-1.2.2.1 26-1.2.2.1.r 27-1.2.2 28-1.2.2.2.r 29-1.2.2.2.1.1 31-1.2.4 32-1.2.4.1 33-1.2.4.1.1 36-1.3.1 38-1.3.1.1 (s / show-01~e.2 :ARG0 (a / assay-01~e.1 :instrument (s5 / small-molecule :name (n / name :op1 "MTT"~e.0))) :ARG1~e.3 (r / reduce-01~e.25 :ARG0 (k / knock-down-02~e.6,8 :ARG1~e.9 (p / protein :name (n2 / name :op1 "Stat3"~e.10)) :location~e.11 (a2 / and~e.17 :op1 (c / cell-line~e.23 :name (n3 / name :op1 "AS2/shStat3-1"~e.12,14,16,18,20)) :op2 (c2 / cell-line~e.23 :name (n4 / name :op1 "AS2/shStat3-2"~e.12,14,18,20,22))) :mod (p3 / permanent~e.5)) :ARG1 (r2 / resist-01~e.27 :ARG0~e.26 a2~e.26 :ARG1~e.28 (s3 / small-molecule :name (n5 / name :op1 "paclitaxel"~e.29))) :ARG2 (s2 / significant-02~e.24) :ARG1-of (s4 / statistical-test-91~e.31 :ARG2 (l / less-than~e.32 :op1 0.001~e.33))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.36 :mod "5D"~e.38))) # ::id pmid_2112_2157.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pretreatment with exogenous IL @-@ 6 modestly restored the resistance ( p < 0.01 ) ( Figure 5D ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 3-1.1.1.1.1 5-1.1.1.1.1 6-1.3 7-1 9-1.2 11-1.5 12-1.5.1 13-1.5.1.1 16-1.4.1 18-1.4.1.1 (r / restore-01~e.7 :ARG0 (p / pretreat-01~e.0 :ARG3~e.1 (p2 / protein :name (n / name :op1 "IL-6"~e.3,5) :mod (e / exogenous~e.2))) :ARG1 (r2 / resist-01~e.9) :degree (m / modest~e.6) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "5D"~e.18)) :ARG1-of (s / statistical-test-91~e.11 :ARG2 (l / less-than~e.12 :op1 0.01~e.13))) # ::id pmid_2112_2157.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest that the IL @-@ 6 @-@ induced paclitaxel resistance is mediated by both Stat3 @-@ dependent and Stat3 @-@ independent pathways . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.2.2.1.1.1 7-1.2.2.2.1.1.1 9-1.2.2.2 10-1.2.2.1.1.1 11-1.2.2 13-1.2 16-1.2.1.2.1.2.1.1 18-1.2.1.2.1 20-1.2.1.2.1.2.1.1 22-1.2.1.1.1 22-1.2.1.2.1 22-1.2.1.2.1.1 22-1.2.1.2.1.1.r 23-1.2.1.1 23-1.2.1.2 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (m / mediate-01~e.13 :ARG0 (a / and :op1 (p2 / pathway~e.23 :ARG0-of (d2 / depend-01~e.22 :ARG1 p5)) :op2 (p4 / pathway~e.23 :ARG0-of (d3 / depend-01~e.18,22 :polarity~e.22 -~e.22 :ARG1 (p5 / protein :name (n4 / name :op1 "Stat3"~e.16,20))))) :ARG1 (r / resist-01~e.11 :ARG1 (s2 / small-molecule :name (n / name :op1 "paclitaxel"~e.10)) :ARG2-of (i / induce-01~e.9 :ARG0 (p / protein :name (n2 / name :op1 "IL-6"~e.5,7)))))) # ::id pmid_2112_2157.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stat3 contributed to the elevation of IL @-@ 6 in drug resistant cancer cells # ::alignments 1-1.1.1.1 2-1 3-1.2.r 5-1.2 6-1.2.1.r 7-1.2.1.1.1 9-1.2.1.1.1 10-1.3.r 11-1.3.1.3.1 12-1.3.1 12-1.3.1.3 12-1.3.1.3.r 13-1.3.1.2.1 14-1.3 (c / contribute-01~e.2 :ARG0 (p / protein :name (n / name :op1 "Stat3"~e.1)) :ARG1~e.3 (e / elevate-01~e.5 :ARG1~e.6 (p2 / protein :name (n2 / name :op1 "IL-6"~e.7,9))) :ARG2~e.10 (c2 / cell~e.14 :mod (d2 / disease~e.12 :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.13) :ARG0-of~e.12 (r / resist-01~e.12 :ARG1 (d / drug~e.11))))) # ::id pmid_2112_2157.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been shown that cancer cells resistant to chemotherapeutic agents express elevated levels of IL @-@ 6 [ @ 30 , 39 @ ] . # ::alignments 3-1 4-1.1.r 5-1.1.2.1.2.1 6-1.1.2 7-1.1.2.1 7-1.1.2.1.3 7-1.1.2.1.3.r 8-1.1.2.1.3.1.r 9-1.1.2.1.3.1.1 10-1.1.2.1.3.1 11-1.1 12-1.1.1.1 13-1.1.1 14-1.1.1.2.r 15-1.1.1.2.1.1 17-1.1.1.2.1.1 20-1.2.1.1.1.1 24-1.2.1.1.1.2 (s / show-01~e.3 :ARG1~e.4 (e / express-03~e.11 :ARG2 (l / level~e.13 :ARG1-of (e2 / elevate-01~e.12) :quant-of~e.14 (p / protein :name (n / name :op1 "IL-6"~e.15,17))) :ARG3 (c / cell~e.6 :mod (d2 / disease~e.7 :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.5) :ARG0-of~e.7 (r / resist-01~e.7 :ARG1~e.8 (a / agent~e.10 :mod (c3 / chemotherapy~e.9)))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 (a2 / and :op1 30~e.20 :op2 39~e.24))))) # ::id pmid_2112_2157.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , drug resistant cancer cells are ideal models for studying IL @-@ 6 autocrine production . # ::alignments 2-1.1.2.1.3.1 3-1.1.2.1 3-1.1.2.1.3 3-1.1.2.1.3.r 4-1.1.2.1.2.1 5-1.1.2 6-1.1.2.r 7-1.1.1 8-1.1 9-1.1.3.r 10-1.1.3 11-1.1.3.1.1.1.1 13-1.1.3.1.1.1.1 14-1.1.3.1.2 15-1.1.3.1 (i / infer-01 :ARG1 (m / model~e.8 :mod (i2 / ideal~e.7) :domain~e.6 (c / cell~e.5 :mod (d2 / disease~e.3 :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.4) :ARG0-of~e.3 (r / resist-01~e.3 :ARG1 (d / drug~e.2)))) :purpose~e.9 (s / study-01~e.10 :ARG1 (p / produce-01~e.15 :ARG1 (p2 / protein :name (n / name :op1 "IL-6"~e.11,13)) :mod (a / autocrine~e.14))))) # ::id pmid_2112_2157.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To find out whether IL @-@ 6 would be regulated by Stat3 in cancer cell lines other than AS2 , we performed genetic siRNA experiments on two drug resistant cancer cell lines ( KB @-@ CPT100 and MCF @-@ 7/ADR ) . # ::alignments 1-1.3 2-1.3 3-1.3.2.1 3-1.3.2.1.r 4-1.3.2.3.1.1 6-1.3.2.3.1.1 9-1.3.2 10-1.3.2.2.r 11-1.3.2.2.1.1 12-1.3.2.4.r 13-1.3.2.4.2.2.1 14-1.3.2.4 15-1.3.2.4 18-1.3.2.4.1.1.1.1 20-1.1 21-1 22-1.2.3 23-1.2.4.1.1 24-1.2 25-1.2.2.r 26-1.2.2.1 27-1.2.2.3.3.1 28-1.2.2.3 28-1.2.2.3.3 28-1.2.2.3.3.r 29-1.2.2.3.2.1 30-1.2.2 31-1.2.2 33-1.2.2.2.1.1.1.1 35-1.2.2.2.1.1.1.1 36-1.2.2.2.1 37-1.2.2.2.1.2.1.1 (p / perform-02~e.21 :ARG0 (w / we~e.20) :ARG1 (e / experiment-01~e.24 :ARG0 w :ARG1~e.25 (c / cell-line~e.30,31 :quant 2~e.26 :ARG1-of (m / mean-01 :ARG2 (a / and~e.36 :op1 (c2 / cell-line :name (n2 / name :op1 "KB-CPT100"~e.33,35)) :op2 (c4 / cell-line :name (n3 / name :op1 "MCF-7/ADR"~e.37)))) :mod (d2 / disease~e.28 :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.29) :ARG0-of~e.28 (r / resist-01~e.28 :ARG1 (d / drug~e.27)))) :mod (g / genetic~e.22) :mod (n7 / nucleic-acid :name (n / name :op1 "siRNA"~e.23))) :purpose (f / find-out-03~e.1,2 :ARG0 w :ARG1 (r3 / regulate-01~e.9 :mode~e.3 interrogative~e.3 :ARG0~e.10 (p2 / protein :name (n4 / name :op1 "Stat3"~e.11)) :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6"~e.4,6)) :location~e.12 (c5 / cell-line~e.14,15 :ARG2-of (e2 / except-01 :ARG1 (c7 / cell-line :name (n6 / name :op1 "AS2"~e.18))) :mod (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer"~e.13)))))) # ::id pmid_2112_2157.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MTT assay revealed that KB @-@ CPT100 cells were more resistant to the chemotherapeutic agent camptothecin than the parental KB cells ( Figure 6A ) and MCF @-@ 7/ADR cells were much more resistant to the chemotherapeutic agent epirubicin than the parental MCF @-@ 7 cells ( p < 0.001 ) ( Figure 6B ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1.2.1.1 6-1.2.1.1.1.1 7-1.2.2.1 9-1.2.2.3 10-1.2.2 13-1.2.1.2.2.1.1 14-1.2.1.2.2.1 15-1.2.1.2.1.1 16-1.2.2.1.2.r 18-1.2.2.1.2.2 19-1.2.1.1.2.1.1 20-1.2.2.1 20-1.2.2.1.2 22-1.2.1.3.1 24-1.2.1.3.1.1 27-1.2 28-1.2.2.1.1.1 28-1.2.2.1.2.1.1 31-1.2.2.1 33-1.2.2.3.1 34-1.2.1.4 34-1.2.2.3 35-1.2.1 35-1.2.2 38-1.2.1.2.2.1.1 39-1.2.1.2.2.1 40-1.2.2.2.1.1 41-1.2.1.1.2.r 43-1.2.1.1.2.2 44-1.2.2.1.1.1 44-1.2.2.1.2.1.1 46-1.2.2.1.1.1 46-1.2.2.1.2.1.1 47-1.2.1.1 47-1.2.1.1.2 49-1.2.2.5 50-1.2.2.5.1 51-1.2.2.5.1.1 54-1.2.2.4.1 56-1.2.2.4.1.1 (r / reveal-01~e.2 :ARG0 (a / assay-01~e.1 :instrument (s4 / small-molecule :name (n / name :op1 "MTT"~e.0))) :ARG1~e.3 (a2 / and~e.27 :op1 (r2 / resist-01~e.35 :ARG0 (c / cell-line~e.47 :name (n2 / name :op1 "KB-CPT100"~e.6) :compared-to~e.41 (c3 / cell-line~e.47 :name (n4 / name :op1 "KB"~e.4,19) :mod (p / parent~e.43))) :ARG1 (s / small-molecule :name (n3 / name :op1 "camptothecin"~e.15) :ARG1-of (m / mean-01 :ARG2 (a3 / agent~e.14,39 :mod (c2 / chemotherapy~e.13,38)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.22 :mod "6A"~e.24)) :degree (m2 / more~e.34)) :op2 (r3 / resist-01~e.10,35 :ARG0 (c4 / cell-line~e.7,20,31 :name (n5 / name :op1 "MCF-7/ADR"~e.28,44,46) :compared-to~e.16 (c6 / cell-line~e.20 :name (n7 / name :op1 "MCF-7"~e.28,44,46) :mod p~e.18)) :ARG1 (s2 / small-molecule :name (n6 / name :op1 "epirubicin"~e.40) :ARG1-of (m5 / mean-01 :ARG2 a3)) :degree (m3 / more~e.9,34 :mod (m4 / much~e.33)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.54 :mod "6B"~e.56)) :ARG1-of (s3 / statistical-test-91~e.49 :ARG2 (l / less-than~e.50 :op1 0.001~e.51))))) # ::id pmid_2112_2157.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The two drug resistant cell lines were found by ELISA to secrete more IL @-@ 6 than their parental cells ( Figures 6C and 6D ) . # ::alignments 1-1.2.1.1 2-1.2.1.2.1 3-1.2.1.2 4-1.2.1 5-1.2.1 7-1 8-1.1.r 9-1.1.1.1 11-1.2 12-1.2.2.2 13-1.2.2.1.1 15-1.2.2.1.1 16-1.2.2.3.r 17-1.2.2.3.2 17-1.2.2.3.2.r 18-1.2.2.3.1 19-1.2.2.3 21-1.3.1.1 21-1.3.1.2 23-1.3.1.1.1 25-1.3.1 27-1.3.1.2.1 (f / find-01~e.7 :ARG0~e.8 (t / thing :name (n / name :op1 "ELISA"~e.9)) :ARG1 (s / secrete-01~e.11 :ARG0 (c / cell-line~e.4,5 :quant 2~e.1 :ARG0-of (r / resist-01~e.3 :ARG1 (d / drug~e.2))) :ARG1 (p / protein :name (n2 / name :op1 "IL-6"~e.13,15) :quant (m / more~e.12) :compared-to~e.16 (c2 / cell~e.19 :mod (p2 / parent~e.18) :poss~e.17 c~e.17))) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.25 :op1 (f2 / figure~e.21 :mod "6C"~e.23) :op2 (f3 / figure~e.21 :mod "6D"~e.27)))) # ::id pmid_2112_2157.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We transiently transfected the two drug resistant cells with Stat3#1 to knock @-@ down Stat3 . # ::alignments 0-1.1 1-1.4 2-1 4-1.2.1 5-1.2.2.1 6-1.2.2 7-1.2 8-1.3.r 9-1.3.1.1 10-1.5.r 11-1.5 13-1.5 14-1.5.1.1.1 (t / transfect-01~e.2 :ARG0 (w / we~e.0) :ARG1 (c / cell~e.7 :quant 2~e.4 :ARG0-of (r / resist-01~e.6 :ARG1 (d / drug~e.5))) :ARG2~e.8 (p / protein :name (n / name :op1 "Stat3#1"~e.9)) :ARG1-of (t2 / transient-02~e.1) :purpose~e.10 (k / knock-down-02~e.11,13 :ARG1 (p2 / protein :name (n2 / name :op1 "Stat3"~e.14)))) # ::id pmid_2112_2157.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis confirmed that the total amount of Stat3 protein and phosphorylated Stat3 had been knocked @-@ down in both resistant cells ( Figures 6E and 6F ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.r 6-1.2.1.2 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1.2.1 9-1.2.1.1.2.2.1 10-1.2.1.1.1 10-1.2.1.1.2 11-1.2.1.1 12-1.2.1.1.2.3 13-1.2.1.1.1.2.1 13-1.2.1.1.2.2.1 16-1.2 18-1.2 19-1.2.2.r 20-1.2.2.1 21-1.2.2.2 22-1.2.2 24-1.3.1.1 24-1.3.1.2 26-1.3.1.1.1 28-1.3.1 30-1.3.1.2.1 (c / confirm-01~e.3 :ARG0 (a / analyze-01~e.2 :manner (i / immunoblot-01~e.0,1)) :ARG1~e.4 (k / knock-down-02~e.16,18 :ARG1 (a2 / amount~e.7 :quant-of~e.8 (a3 / and~e.11 :op1 (p / protein~e.10 :wiki "STAT3" :name (n2 / name :op1 "Stat3"~e.9,13)) :op2 (p2 / protein~e.10 :wiki "STAT3" :name (n3 / name :op1 "Stat3"~e.9,13) :ARG3-of (p3 / phosphorylate-01~e.12))) :mod (t / total~e.6)) :location~e.19 (c2 / cell~e.22 :mod (b / both~e.20) :ARG0-of (r / resist-01~e.21))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.28 :op1 (f / figure~e.24 :mod "6E"~e.26) :op2 (f2 / figure~e.24 :mod "6F"~e.30)))) # ::id pmid_2112_2157.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MTT assay found no change in cell viability ( Additional file 3 , Figure S3B and S3C ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2.1 3-1.2.1.r 4-1.2 5-1.2.2.r 6-1.2.2.1 7-1.2.2 10-1.3.1 12-1.3.1.1 15-1.3.1.3.1.1 15-1.3.1.3.1.2 16-1.3.1.3.1.1.1 17-1.3.1.3.1 18-1.3.1.3.1.2.1 (f / find-01~e.2 :ARG0 (a / assay-01~e.1 :instrument (s / small-molecule :name (n / name :op1 "MTT"~e.0))) :ARG1 (c / change-01~e.4 :polarity~e.3 -~e.3 :ARG1~e.5 (v / viability~e.7 :mod (c2 / cell~e.6))) :ARG1-of (d / describe-01 :ARG0 (f2 / file~e.10 :mod 3~e.12 :ARG1-of (a3 / add-02) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.17 :op1 (f3 / figure~e.15 :mod "S3B"~e.16) :op2 (f4 / figure~e.15 :mod "S3C"~e.18)))))) # ::id pmid_2112_2157.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ELISA revealed that knocking @-@ down Stat3 decreased the secretion of IL @-@ 6 in KB @-@ CPT100 cells by one @-@ third ( p < 0.001 ) ( Figure 6G ) and by one @-@ half in MCF @-@ 7/ADR cells ( p < 0.001 ) ( Figure 6H ) . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1.1 5-1.2.1.1 5-1.2.2 6-1.2.1.1.1.1.1 7-1.2.1 9-1.2.1.2 10-1.2.1.2.1.r 11-1.2.1.2.1.1.1 13-1.2.1.2.1.1.1 14-1.2.1.4.r 15-1.2.1.4.1.1 17-1.2.1.4.1.1 18-1.2.1.4 18-1.2.2.4 20-1.2.1.3.1 22-1.2.1.3.1 24-1.2.1.6 24-1.2.2.6 25-1.2.1.6.1 26-1.2.1.6.1.1 29-1.2.1.5.1 31-1.2.1.5.1.1 36-1.2.1.3.1 38-1.2.2.3.1 40-1.2.2.4.1.1 43-1.2.1.4 45-1.2.1.6 46-1.2.1.6.1 47-1.2.1.6.1.1 50-1.2.2.5.1 52-1.2.2.5.1.1 (r / reveal-01~e.1 :ARG0 (t / thing :name (n / name :op1 "ELISA"~e.0)) :ARG1~e.2 (a / and :op1 (d / decrease-01~e.7 :ARG0 (k / knock-down-02~e.3,5 :ARG1 (p / protein :name (n2 / name :op1 "Stat3"~e.6))) :ARG1 (s / secrete-01~e.9 :ARG1~e.10 (p2 / protein :name (n3 / name :op1 "IL-6"~e.11,13))) :ARG2 (p5 / product-of :op1 "1/3"~e.20,22,36) :location~e.14 (c / cell-line~e.18,43 :name (n4 / name :op1 "KB-CPT100"~e.15,17)) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.29 :mod "6G"~e.31)) :ARG1-of (s2 / statistical-test-91~e.24,45 :ARG2 (l / less-than~e.25,46 :op1 0.001~e.26,47))) :op2 (d2 / decrease-01~e.5 :ARG0 k :ARG1 s :ARG2 (p6 / product-of :op1 "1/2"~e.38) :location (c2 / cell-line~e.18 :name (n5 / name :op1 "MCF-7/ADR"~e.40)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.50 :mod "6H"~e.52)) :ARG1-of (s3 / statistical-test-91~e.24 :ARG2 l)))) # ::id pmid_2112_2157.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that the Stat3 also contributes to the elevation of IL @-@ 6 in drug resistant cancer cells . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1.1.1 6-1.2.4 7-1.2 8-1.2.2.r 10-1.2.2 11-1.2.2.2.r 12-1.2.2.2.1.1 14-1.2.2.2.1.1 15-1.2.3.r 16-1.2.3.1.3.1 17-1.2.3.1 17-1.2.3.1.3 17-1.2.3.1.3.r 18-1.2.3.1.2.1 19-1.2.3 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (c / contribute-01~e.7 :ARG0 (p / protein :name (n / name :op1 "Stat3"~e.5)) :ARG1~e.8 (e / elevate-01~e.10 :ARG0 p :ARG1~e.11 (p2 / protein :name (n2 / name :op1 "IL-6"~e.12,14))) :ARG2~e.15 (c2 / cell~e.19 :mod (d2 / disease~e.17 :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.18) :ARG0-of~e.17 (r2 / resist-01~e.17 :ARG1 (d / drug~e.16)))) :mod (a / also~e.6))) # ::id pmid_2112_2157.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Jak2 @/@ Stat3 pathway regulated the expression of IL @-@ 6 in cooperation with other IL @-@ 6 downstream pathways # ::alignments 1-1.1.1.1 3-1.1.1.1 4-1.1 5-1 7-1.2 8-1.2.1.r 9-1.2.1.1.1 11-1.2.1.1.1 12-1.1.2.r 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1 16-1.1.2.1.3 17-1.1.2.1.3 18-1.1.2.1.3 19-1.1.2.1.2 20-1.1.2.1 (r / regulate-01~e.5 :ARG0 (p / pathway~e.4 :name (n / name :op1 "Jak2/Stat3"~e.1,3) :ARG0-of~e.12 (c / cooperate-01~e.13 :ARG1~e.14 (p3 / pathway~e.20 :mod (o / other~e.15) :mod (d / downstream~e.19) :mod p2~e.16,17,18))) :ARG1 (e / express-03~e.7 :ARG2~e.8 (p2 / protein :name (n2 / name :op1 "IL-6"~e.9,11)))) # ::id pmid_2112_2157.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To find out whether IL @-@ 6 could be regulated by different combinations of its downstream pathways including Jak2 @/@ Stat3 in various cancer cells , we pharmacologically inhibited the four IL @-@ 6 downstream pathways in six drug resistant cancer cell lines derived from cervical cancer , breast cancer , and lung cancer cells . # ::alignments 1-1.5 2-1.5 3-1.5.2.1 3-1.5.2.1.r 4-1.5.2.2.2.1.1 6-1.5.2.2.2.1.1 7-1.5.2 9-1.5.2.2 10-1.5.2.2.1.r 11-1.5.2.2.1.2 12-1.5.2.2.1 14-1.2.4 14-1.2.4.r 15-1.2.3 16-1.5.2.2.1.1 17-1.5.2.2.1.1.1 18-1.5.2.2.1.1.1.1.1.1 20-1.5.2.2.1.1.1.1.1.1 21-1.5.2.2.1.1.1.2.r 22-1.5.2.2.1.1.1.2.1 23-1.5.2.2.1.1.1.2.2.2.1 24-1.5.2.2.1.1.1.2 26-1.1 27-1.3 27-1.3.r 28-1 30-1.2.1 31-1.2.2.1 33-1.2.2.1 34-1.2.3 35-1.2 37-1.2.2.1 37-1.4.1 37-1.5.2.2.2.1.1 38-1.4.2.1 39-1.4.2 40-1.5.2.2.1.1.1.2.2.2.1 41-1.4 42-1.4 43-1.4.3 44-1.4.3.1.r 45-1.4.3.1.1.1.2.1 46-1.4.3.1.1.1.2.2 48-1.4.3.1.2.1.2.1 49-1.4.3.1.2.1.2.2 51-1.4.3.1 52-1.4.3.1.3.1.2.1 53-1.4.3.1.3.1.2.2 54-1.4.3.1.1 54-1.4.3.1.2 54-1.4.3.1.3 (i / inhibit-01~e.28 :ARG0 (w / we~e.26) :ARG1 (p2 / pathway~e.35 :quant 4~e.30 :name (n / name :op1 "IL-6"~e.31,33,37) :mod (d4 / downstream~e.15,34) :mod~e.14 p4~e.14) :manner~e.27 (p / pharmacological~e.27) :location (c / cell-line~e.41,42 :quant 6~e.37 :ARG0-of (r / resist-01~e.39 :ARG1 (d / drug~e.38)) :ARG1-of (d2 / derive-01~e.43 :ARG2~e.44 (a / and~e.51 :op1 (c10 / cell~e.54 :mod (d5 / disease :wiki "Cervical_cancer" :name (n4 / name :op1 "cervical"~e.45 :op2 "cancer"~e.46))) :op2 (c11 / cell~e.54 :mod (d6 / disease :wiki "Breast_cancer" :name (n5 / name :op1 "breast"~e.48 :op2 "cancer"~e.49))) :op3 (c5 / cell~e.54 :mod (d7 / disease :wiki "Lung_cancer" :name (n6 / name :op1 "lung"~e.52 :op2 "cancer"~e.53)))))) :purpose (f / find-out-03~e.1,2 :ARG0 w :ARG1 (p3 / possible-01~e.7 :mode~e.3 interrogative~e.3 :ARG1 (r2 / regulate-01~e.9 :ARG0~e.10 (c7 / combine-01~e.12 :ARG1 (p5 / pathway~e.16 :ARG2-of (i2 / include-01~e.17 :ARG1 (p6 / pathway :name (n3 / name :op1 "Jak2/Stat3"~e.18,20)) :location~e.21 (c8 / cell~e.24 :mod (v / various~e.22) :mod (d8 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"~e.23,40)))) :mod d4) :ARG1-of (d3 / differ-02~e.11)) :ARG1 (p4 / protein :name (n2 / name :op1 "IL-6"~e.4,6,37)))))) # ::id pmid_2112_2157.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ELISA revealed that all drug resistant cells secreted more IL @-@ 6 than their parental cells . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1.2 4-1.2.1.1.1 5-1.2.1.1 6-1.2.1 6-1.2.3 7-1.2 8-1.2.2.2 9-1.2.2.1.1 11-1.2.2.1.1 12-1.2.3.r 13-1.2.3.2 13-1.2.3.2.r 14-1.2.3.1 15-1.2.3 (r / reveal-01~e.1 :ARG0 (t / thing :name (n / name :op1 "ELISA"~e.0)) :ARG1~e.2 (s / secrete-01~e.7 :ARG0 (c / cell~e.6 :ARG0-of (r2 / resist-01~e.5 :ARG1 (d / drug~e.4)) :mod (a / all~e.3)) :ARG1 (p / protein :name (n2 / name :op1 "IL-6"~e.9,11) :quant (m / more~e.8)) :compared-to~e.12 (c2 / cell~e.6,15 :mod (p2 / parent~e.14) :poss~e.13 c~e.13))) # ::id pmid_2112_2157.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Different cells used different combinations of signaling pathways , including Jak2/Stat3 , to regulate secretion of IL @-@ 6 ( Figures 7A to 7F ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.1.1 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1 9-1.2.1.2 10-1.2.1.2.1.1.1 13-1.3 14-1.3.2 15-1.3.2.1.r 16-1.3.2.1.1.1 18-1.3.2.1.1.1 20-1.4.1.1 20-1.4.1.2 22-1.4.1.1.1 26-1.4.1.2.1 (u / use-01~e.2 :ARG0 (c / cell~e.1 :ARG1-of (d / differ-02~e.0,3)) :ARG1 (c2 / combine-01~e.4 :ARG1~e.5 (p / pathway~e.7 :ARG0-of (s / signal-07~e.6) :ARG2-of (i / include-01~e.9 :ARG1 (p2 / pathway :name (n / name :op1 "Jak2/Stat3"~e.10))))) :ARG2 (r / regulate-01~e.13 :ARG0 c :ARG1 (s2 / secrete-01~e.14 :ARG1~e.15 (p3 / protein :name (n2 / name :op1 "IL-6"~e.16,18)))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure~e.20 :mod "7A"~e.22) :op2 (f2 / figure~e.20 :mod "7F"~e.26)))) # ::id pmid_2112_2157.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To exclude the possibility that the reduction of IL @-@ 6 secretion was caused by the reduction of cell survival , we used MTT assay to analyze the effect of these inhibitors on cell viability ( Additional file 1 , Figure S1C to S1H ) . # ::alignments 1-1.4 3-1.4.2 6-1.4.2.1.2 8-1.4.2.1.2.1.1.1.1 10-1.4.2.1.2.1.1.1.1 11-1.4.2.1.2.1 13-1.4.2.1 16-1.4.2.1.1 16-1.4.2.1.2 17-1.4.2.1.1.1.r 18-1.4.2.1.1.1.1 19-1.4.2.1.1.1 21-1.1 22-1 22-1.4.r 23-1.2.1.1.1 24-1.2 25-1.4.2.1 26-1.3 28-1.3.2 29-1.3.2.1.r 30-1.3.2.1.2 31-1.3.2.1 31-1.3.2.1.1 31-1.3.2.1.1.r 32-1.3.2.2.r 33-1.3.2.2.1 34-1.3.2.2 37-1.5.1 39-1.5.1.1 42-1.5.1.3.1.1 42-1.5.1.3.1.2 43-1.5.1.3.1.1.1 45-1.5.1.3.1.2.1 (u / use-01~e.22 :ARG0 (w / we~e.21) :ARG1 (a / assay-01~e.24 :instrument (s3 / small-molecule :name (n / name :op1 "MTT"~e.23))) :ARG2 (a2 / analyze-01~e.26 :ARG0 w :ARG1 (a3 / affect-01~e.28 :ARG0~e.29 (m / molecular-physical-entity~e.31 :ARG0-of~e.31 (i / inhibit-01~e.31) :mod (t / this~e.30)) :ARG1~e.32 (v / viability~e.34 :mod (c / cell~e.33)))) :purpose~e.22 (e / exclude-01~e.1 :ARG0 w :ARG1 (p / possible-01~e.3 :ARG1 (c2 / cause-01~e.13,25 :ARG0 (r / reduce-01~e.16 :ARG1~e.17 (s / survive-01~e.19 :ARG0 (c3 / cell~e.18))) :ARG1 (r2 / reduce-01~e.6,16 :ARG1 (s2 / secrete-01~e.11 :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"~e.8,10))))))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.37 :mod 1~e.39 :ARG1-of (a5 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (v2 / value-interval :op1 (f2 / figure~e.42 :mod "S1C"~e.43) :op2 (f3 / figure~e.42 :mod "S1H"~e.45)))))) # ::id pmid_2112_2157.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We showed that the majority of inhibitors had only limited suppressive effect on cell viability ( below 25 %) ( Additional file 1 , Figure S1C @-@ S1H ) except that the PI3 @-@ K/Akt pathway inhibitor LY294002 had more suppressive activity on the cellular viability by 30 to 50 % ( Additional file 1 , Figure S1C @-@ S1F ) . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.1.2 5-1.2.1.2.r 6-1.2.1 6-1.2.1.1 6-1.2.1.1.r 8-1.2.4.1 9-1.2.4 11-1.2 13-1.2.2.1 14-1.2.2 16-1.2.2.2 17-1.2.2.2.1.1 21-1.2.5.1 21-1.2.6.2.1 23-1.2.5.1.1 23-1.2.6.2.1.1 26-1.2.5.1.3.1.1 27-1.2.5.1.3.1.1.1 31-1.2.6 32-1.2.6.1.r 34-1.2.6.1.1.2.1.1.1 37-1.2.6.1.1.2.1 38-1.2.6.1.1 38-1.2.6.1.1.2 38-1.2.6.1.1.2.r 39-1.2.6.1.1.1.1 41-1.2.6.1.2.2 43-1.2.6.1 46-1.2.2.1 47-1.2.2 47-1.2.6.1.2.1 48-1.2.6.1.2.1.2.r 49-1.2.6.1.2.1.2.1.1 51-1.2.6.1.2.1.2.2.1 52-1.2.2.2.1 52-1.2.6.1.2.1.2.1 52-1.2.6.1.2.1.2.2 55-1.2.5.1 55-1.2.6.2.1 57-1.2.5.1.1 57-1.2.6.2.1.1 60-1.2.5.1.3.1.1 60-1.2.5.1.3.1.2 60-1.2.6.2.1.2.1.2 61-1.2.5.1.3.1.1.1 63-1.2.5.1.3.1.2.1 63-1.2.6.2.1.2.1.2.1 (s / show-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (a / affect-01~e.11 :ARG0 (s2 / small-molecule~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6) :quant~e.5 (m / majority~e.4)) :ARG1 (v / viability~e.14,47 :mod (c / cell~e.13,46) :quant (b / below~e.16 :op1 (p / percentage-entity~e.52 :value 25~e.17))) :ARG2 (s3 / suppress-01) :ARG1-of (l / limit-01~e.9 :mod (o / only~e.8)) :ARG1-of (d / describe-01 :ARG0 (f / file~e.21,55 :mod 1~e.23,57 :ARG1-of (a2 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (v2 / value-interval :op1 (f2 / figure~e.26,60 :mod "S1C"~e.27,61) :op2 (f3 / figure~e.60 :mod "S1F"~e.63))))) :ARG2-of (e / except-01~e.31 :ARG1~e.32 (a3 / activity-06~e.43 :ARG0 (s4 / small-molecule~e.38 :name (n / name :op1 "LY294002"~e.39) :ARG0-of~e.38 (i2 / inhibit-01~e.38 :ARG1 (p2 / pathway~e.37 :name (n2 / name :op1 "PI3-K/Akt"~e.34)))) :ARG1 (s5 / suppress-01 :ARG1 (v3 / viability~e.47 :mod c :quant~e.48 (v4 / value-interval :op1 (p3 / percentage-entity~e.52 :value 30~e.49) :op2 (p4 / percentage-entity~e.52 :value 50~e.51))) :degree (m3 / more~e.41))) :ARG1-of (d2 / describe-01 :ARG0 (f4 / file~e.21,55 :mod 1~e.23,57 :ARG1-of (m4 / mean-01 :ARG2 (v5 / value-interval :op1 f2 :op2 (f5 / figure~e.60 :mod "S1F"~e.63))) :ARG1-of a2))))) # ::id pmid_2112_2157.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , LY294002 induced much greater ( 75 to 90 %) decrease of IL @-@ 6 in these cells ( Figure 7A to 7D ) . # ::alignments 0-1 2-1.1.1.1.1 3-1.1 4-1.1.2.4.1.1 5-1.1.2.4 5-1.1.2.4.1 5-1.1.2.4.1.r 7-1.1.2.2.1.1 9-1.1.2.2.2.1 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1 15-1.1.2.1.1.1 16-1.1.2.3.r 17-1.1.2.3.1 18-1.1.2.3 20-1.2.1.1 20-1.2.1.2 22-1.2.1.1.1 26-1.2.1.2.1 (c2 / contrast-01~e.0 :ARG2 (i / induce-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "LY294002"~e.2)) :ARG2 (d / decrease-01~e.11 :ARG1~e.12 (p / protein :name (n2 / name :op1 "IL-6"~e.13,15)) :ARG2 (v / value-interval :op1 (p2 / percentage-entity :value 75~e.7) :op2 (p3 / percentage-entity :value 90~e.9)) :location~e.16 (c / cell~e.18 :mod (t / this~e.17)) :mod (g / great~e.5 :degree~e.5 (m / more~e.5 :mod (m2 / much~e.4))))) :ARG1-of (d2 / describe-01 :ARG0 (v2 / value-interval :op1 (f / figure~e.20 :mod "7A"~e.22) :op2 (f2 / figure~e.20 :mod "7D"~e.26)))) # ::id pmid_2112_2157.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There is only one exception that the AG490 @-@ induced reductions of cell survival and IL @-@ 6 secretion were both about 30 % in KB @-@ 7D cells ( Additional file 1 , Figure S1F and Figure 7D ) . # ::alignments 2-1.5.2 3-1.5.1 4-1.5 7-1.1.2.1.1.1 9-1.1.2 10-1.1 11-1.1.1.r 12-1.1.1.1 13-1.1.1 14-1 15-1.2.1.1.1 17-1.2.1.1.1 18-1.2 21-1.3 22-1.3.1.1 23-1.3.1 25-1.4.1.1 27-1.4.1.1 28-1.4 31-1.6.1 33-1.6.1.1 36-1.6.1.3.1.1 37-1.6.1.3.1.1.1 38-1.6.1.3.1 39-1.6.1.3.1.1 39-1.6.1.3.1.2 41-1.6.1.3.1.2.1 (a / and~e.14 :op1 (r / reduce-01~e.10 :ARG1~e.11 (s / survive-01~e.13 :ARG0 (c / cell~e.12)) :ARG2-of (i / induce-01~e.9 :ARG0 (s2 / small-molecule :name (n / name :op1 "AG490"~e.7)))) :op2 (s3 / secrete-01~e.18 :ARG1 (p / protein :name (n2 / name :op1 "IL-6"~e.15,17))) :quant (a2 / about~e.21 :op1 (p2 / percentage-entity~e.23 :value 30~e.22)) :location (c2 / cell-line~e.28 :name (n3 / name :op1 "KB-7D"~e.25,27)) :ARG1-of (e / except-01~e.4 :mod 1~e.3 :mod (o / only~e.2)) :ARG1-of (d / describe-01 :ARG0 (f / file~e.31 :mod 1~e.33 :ARG1-of (a3 / add-02) :ARG1-of (m / mean-01 :ARG2 (a4 / and~e.38 :op1 (f2 / figure~e.36,39 :mod "S1F"~e.37) :op2 (f3 / figure~e.39 :mod "7D"~e.41)))))) # ::id pmid_2112_2157.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Jak2 @/@ Stat3 pathway contributed to IL @-@ 6 autocrine production in clinically isolated lung cancer cells # ::alignments 1-1.1.1.1 3-1.1.1.1 4-1.1 5-1 6-1.2.r 7-1.2.1.1.1 9-1.2.1.1.1 10-1.2.2 11-1.2 12-1.3.r 13-1.3.1.1 13-1.3.1.1.r 14-1.3.1 15-1.3.2.2.1 16-1.3.2.2.2 17-1.3 (c / contribute-01~e.5 :ARG0 (p / pathway~e.4 :name (n / name :op1 "Jak2/Stat3"~e.1,3)) :ARG1~e.6 (p2 / produce-01~e.11 :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"~e.7,9)) :mod (a / autocrine~e.10)) :ARG2~e.12 (c2 / cell~e.17 :ARG1-of (i / isolate-01~e.14 :manner~e.13 (c4 / clinical~e.13)) :mod (d / disease :wiki "Lung_cancer" :name (n3 / name :op1 "lung"~e.15 :op2 "cancer"~e.16)))) # ::id pmid_2112_2157.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because previous studies suggesting Stat3 on IL @-@ 6 were all in vitro @ cell line studies , not clinical studies , we also wanted to find out whether IL @-@ 6 could be regulated by different combinations of pathways including Jak2 @/@ Stat3 in not just cell lines but also in the human body . # ::alignments 0-1.3 1-1.3.1.3.2 2-1.3.1.3 3-1.3.1.3.1 4-1.3.1.3.1.1.1.1.1 6-1.3.1.3.1.1.2 7-1.3.1.3.1.1.2 8-1.3.1.3.1.1.2 9-1.3.1.3.r 10-1.3.1.3.3 12-1.3.1.2 13-1.3.1.2 15-1.3.1.1 16-1.3.1.1 17-1.3.1 19-1.2.2.2.3.1.1.1.r 20-1.3.1.2.1.1.1 21-1.3.1.2.1.1 23-1.1 24-1.2.2.2.3.2.2 25-1 26-1.3 27-1.2 28-1.2 29-1.2.2.1 29-1.2.2.1.r 30-1.2.2.2.2.1.1 32-1.2.2.2.2.1.1 33-1.2.2 35-1.2.2.2 35-1.3.1.3.1.1 36-1.2.2.2.1.r 37-1.2.2.2.1.2 38-1.2.2.2.1 39-1.2.2.2.1.1.r 40-1.2.2.2.1.1 41-1.2.2.2.1.1.1 42-1.2.2.2.1.1.1.1.1.1 44-1.2.2.2.1.1.1.1.1.1 45-1.3.1.2 46-1.2.2.2.3.1.1.1 46-1.2.2.2.3.1.1.1.r 47-1.2.2.2.3.1.1 48-1.2.2.2.3.1 49-1.2.2.2.3.1 50-1.3.1.2.1 51-1.2.2.2.3.2.2 52-1.3.1.2 54-1.2.2.2.3.2.1 55-1.2.2.2.3.2 (w / want-01~e.25 :ARG0 (w2 / we~e.23) :ARG1 (f / find-out-03~e.27,28 :ARG0 w2 :ARG1 (p4 / possible-01~e.33 :mode~e.29 interrogative~e.29 :ARG1 (r / regulate-01~e.35 :ARG0~e.36 (c / combine-01~e.38 :ARG1~e.39 (p2 / pathway~e.40 :ARG2-of (i / include-01~e.41 :ARG1 (p3 / pathway :name (n2 / name :op1 "Jak2/Stat3"~e.42,44)))) :ARG1-of (d / differ-02~e.37)) :ARG1 (p / protein :name (n / name :op1 "IL-6"~e.30,32)) :location (a / and :op1 (c2 / cell-line~e.48,49 :mod (j / just~e.47 :polarity~e.19,46 -~e.46)) :op2 (b / body~e.55 :mod (h / human~e.54) :mod (a2 / also~e.24,51)))))) :ARG1-of (c3 / cause-01~e.0,26 :ARG0 (s / study-01~e.17 :ARG1 (c5 / cell-line~e.15,16) :mod (i2 / in-vitro~e.12,13,45,52 :ARG1-of (c6 / contrast-01~e.50 :ARG2 (s4 / study-01~e.21 :mod (c4 / clinical~e.20)))) :domain~e.9 (s2 / study-01~e.2 :ARG0-of (s3 / suggest-01~e.3 :ARG1 (r2 / regulate-01~e.35 :ARG0 (p5 / protein :name (n3 / name :op1 "Stat3"~e.4)) :ARG1 p~e.6,7,8)) :time (p6 / previous~e.1) :mod (a3 / all~e.10)))) :mod a2) # ::id pmid_2112_2157.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We had previously found IL @-@ 6 levels to be increased in MPE of patients with lung cancer [ @ 2 @ ] . # ::alignments 0-1.1 2-1.3 3-1 4-1.2.1.1.1.1 6-1.2.1.1.1.1 7-1.2.1 10-1.2 13-1.2.2.r 14-1.2.2.3 15-1.2.2.3.1.r 16-1.2.2.3.1.2.1 17-1.2.2.3.1.2.2 (f / find-01~e.3 :ARG0 (w / we~e.0) :ARG1 (i / increase-01~e.10 :ARG1 (l / level~e.7 :quant-of (p / protein :name (n / name :op1 "IL-6"~e.4,6))) :location~e.13 (m2 / medical-condition :wiki "Malignant_pleural_effusion" :name (n3 / name :op1 "malignant" :op2 "pleural" :op3 "effusion") :poss (p2 / patient~e.14 :mod~e.15 (d / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung"~e.16 :op2 "cancer"~e.17))))) :time (p3 / previous~e.2)) # ::id pmid_2112_2157.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To do this , we pharmacologically inhibited the four IL @-@ 6 downstream pathways in 20 clinical samples of human lung cancer obtained from MPE . # ::alignments 1-1.5 2-1.5.2 4-1.1 5-1.3 5-1.3.r 6-1 8-1.2.1 9-1.2.2.1 11-1.2.2.1 12-1.2.3 13-1.2 14-1.4.r 15-1.4.1 16-1.4.3 17-1.4 18-1.4.2.r 19-1.4.2.3 20-1.4.2.2.1 21-1.4.2.2.2 22-1.4.4 (i / inhibit-01~e.6 :ARG0 (w / we~e.4) :ARG1 (p2 / pathway~e.13 :mod 4~e.8 :name (n / name :op1 "IL-6"~e.9,11) :mod (d / downstream~e.12)) :manner~e.5 (p / pharmacological~e.5) :location~e.14 (s / sample-01~e.17 :quant 20~e.15 :ARG1~e.18 (d3 / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung"~e.20 :op2 "cancer"~e.21) :mod (h / human~e.19)) :mod (c / clinical~e.16) :ARG1-of (o / obtain-01~e.22 :ARG2 (m / medical-condition :wiki "Malignant_pleural_effusion" :name (n3 / name :op1 "malignant" :op2 "pleural" :op3 "effusion")))) :purpose (d2 / do-02~e.1 :ARG0 w :ARG1 (t / this~e.2))) # ::id pmid_2112_2157.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ELISA revealed that IL @-@ 6 was expressed in the conditioned medium of all samples , ranging from 16.58 ± 0.21 to 1016.47 ± 12.45 pg @/@ ml ( Figure 8A ) , with a mean of 393.14 pg/ml . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1.1.1 5-1.2.1.1.1 7-1.2 8-1.2.2.r 10-1.2.2.1 11-1.2.2 12-1.2.2.2.r 13-1.2.2.2.1 14-1.2.2.2 14-1.2.2.2.3 14-1.2.2.2.3.r 16-1.2.1.2 17-1.2.1.2.1.r 18-1.2.1.2.1.1.1.1 18-1.2.1.2.1.1.2.2 20-1.2.1.2.1.1.1.2 20-1.2.1.2.1.1.2.1 21-1.2.1.2.2.r 22-1.2.1.2.2.1.1.1 22-1.2.1.2.2.1.2.2 24-1.2.1.2.2.1.1.2 24-1.2.1.2.2.1.2.1 27-1.2.1.2.1.2 29-1.3.1 31-1.3.1.1 35-1.2.2.2.2.r 37-1.2.2.2.2.3 39-1.2.2.2.2.1 (r / reveal-01~e.1 :ARG0 (t / thing :name (n / name :op1 "ELISA"~e.0)) :ARG1~e.2 (e / express-03~e.7 :ARG2 (p / protein :name (n2 / name :op1 "IL-6"~e.3,5) :ARG1-of (r2 / range-01~e.16 :ARG3~e.17 (c2 / concentration-quantity :quant (v / value-interval :op1 (a2 / add-02 :ARG1 16.58~e.18 :ARG2 0.21~e.20) :op2 (s2 / subtract-01 :ARG1 0.21~e.20 :ARG2 16.58~e.18)) :unit (p3 / picogram-per-milliliter~e.27)) :ARG4~e.21 (c3 / concentration-quantity :quant (v2 / value-interval :op1 (a3 / add-02 :ARG1 1016.47~e.22 :ARG2 12.45~e.24) :op2 (s3 / subtract-01 :ARG1 12.45~e.24 :ARG2 1016.47~e.22)) :unit p3))) :ARG3~e.8 (m / medium~e.11 :ARG1-of (c / condition-01~e.10) :poss~e.12 (t2 / thing~e.14 :mod (a / all~e.13) :mod~e.35 (c4 / concentration-quantity :quant 393.14~e.39 :unit p3 :mod (m2 / mean~e.37)) :ARG1-of~e.14 (s / sample-01~e.14)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "8A"~e.31))) # ::id pmid_2112_2157.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The four aforementioned inhibitors significantly decreased IL @-@ 6 secretion in the clinically isolated cancer cells differently ( U0126 , p < 0.01 ; AG490 , LY294002 and BAY11 @-@ 7082 , all p < 0.001 ) ( Figure 8A ) . # ::alignments 1-1.1.1 3-1.1 3-1.1.2 3-1.1.2.r 4-1.3 5-1 5-1.6.1.1 5-1.6.1.2 6-1.2.1.1.1 8-1.2.1.1.1 9-1.2 10-1.4.r 12-1.4.1 12-1.4.1.r 13-1.4.2.3 14-1.4.2.2.1 15-1.4 16-1.5 18-1.6.1.1.1.1.1 20-1.6.1.1.4 21-1.6.1.1.4.1 22-1.6.1.1.4.1.1 24-1.6.1.2.1.1.1.1 26-1.6.1.2.1.2.1.1 27-1.6.1.2.1 28-1.6.1.2.1.3.1.1 30-1.6.1.2.1.3.1.1 32-1.6.1.2.1.4 33-1.6.1.2.3 34-1.6.1.2.3.1 35-1.6.1.2.3.1.1 38-1.7.1 40-1.7.1.1 (d / decrease-01~e.5 :ARG0 (s / small-molecule~e.3 :quant 4~e.1 :ARG1-of~e.3 (i / inhibit-01~e.3) :ARG1-of (m / mention-01 :time (b / before))) :ARG1 (s3 / secrete-01~e.9 :ARG1 (p / protein :name (n / name :op1 "IL-6"~e.6,8))) :ARG2 (s2 / significant-02~e.4) :location~e.10 (c / cell~e.15 :manner~e.12 (c3 / clinical~e.12) :mod (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.14) :ARG1-of (i2 / isolate-01~e.13))) :ARG1-of (d2 / differ-02~e.16) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (d5 / decrease-01~e.5 :ARG0 (s7 / small-molecule :name (n2 / name :op1 "U0126"~e.18)) :ARG1 s3 :location c :ARG1-of (s8 / statistical-test-91~e.20 :ARG2 (l / less-than~e.21 :op1 0.01~e.22)) :location c) :op2 (d6 / decrease-01~e.5 :ARG0 (a2 / and~e.27 :op1 (s4 / small-molecule :name (n3 / name :op1 "AG490"~e.24)) :op2 (s5 / small-molecule :name (n4 / name :op1 "LY294002"~e.26)) :op2 (s6 / small-molecule :name (n5 / name :op1 "BAY11-7082"~e.28,30)) :mod (a3 / all~e.32)) :ARG1 s3 :ARG1-of (s9 / statistical-test-91~e.33 :ARG2 (l2 / less-than~e.34 :op1 0.001~e.35))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.38 :mod "8A"~e.40))) # ::id pmid_2112_2157.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We further analyzed the percent of inhibition by each inhibitor on IL @-@ 6 secretion . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 6-1.2.1 8-1.2.1.1.2 9-1.2.1 10-1.2.1.2.r 11-1.2.1.2.1.1.1 13-1.2.1.2.1.1.1 14-1.2.1.2 (a / analyze-01~e.2 :ARG0 (w / we~e.0) :ARG1 (p / percent~e.4 :quant-of~e.5 (i / inhibit-01~e.6,9 :ARG0 (s / small-molecule :ARG1-of i :mod (e / each~e.8)) :ARG1~e.10 (s2 / secrete-01~e.14 :ARG1 (p2 / protein :name (n / name :op1 "IL-6"~e.11,13))))) :time (f / further~e.1)) # ::id pmid_2112_2157.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BAY11 @-@ 7082 had the greatest inhibitory activity on the autocrine production of IL @-@ 6 in the clinical samples ( BAY11 @-@ 7082 > LY294002 > AG490 > U0126 ) ( Figure 8B ) . # ::alignments 0-1.1.1.1 0-1.4.1.1.1 2-1.1.1.1 2-1.4.1.1.1 3-1 5-1.2.2 5-1.2.2.1 5-1.2.2.1.r 6-1.2.1 7-1.2 8-1.2.1.1.r 10-1.2.1.1.2 11-1.2.1.1 12-1.2.1.1.1.r 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1 16-1.3.r 18-1.3.1 19-1.3 19-1.3.2 19-1.3.2.r 21-1.1.1.1 21-1.4.1.1.1 23-1.1.1.1 23-1.4.1.1.1 24-1.4.1.2 25-1.4.1.2.1.1.1 26-1.4.1.2.1.2 27-1.4.1.2.1.2.1.1.1 28-1.4.1.2.1.2.1.2 29-1.4.1.2.1.2.1.2.1.1.1 32-1.5.1 34-1.5.1.1 (h / have-03~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "BAY11-7082"~e.0,2,21,23)) :ARG1 (a / activity-06~e.7 :ARG1 (i / inhibit-01~e.6 :ARG1~e.8 (p / produce-01~e.11 :ARG1~e.12 (p2 / protein :name (n2 / name :op1 "IL-6"~e.13,15)) :mod (a2 / autocrine~e.10))) :mod (g / great~e.5 :degree~e.5 (m / most~e.5))) :location~e.16 (t / thing~e.19 :mod (c / clinical~e.18) :ARG1-of~e.19 (s2 / sample-01~e.19)) :ARG1-of (m2 / mean-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "BAY11-7082"~e.0,2,21,23) :quant (m3 / more-than~e.24 :op1 (s4 / small-molecule :name (n4 / name :op1 "LY294002"~e.25) :quant (m4 / more-than~e.26 :op1 (s5 / small-molecule :name (n5 / name :op1 "AG490"~e.27) :quant (m5 / more-than~e.28 :op1 (s6 / small-molecule :name (n6 / name :op1 "U0126"~e.29))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "8B"~e.34))) # ::id pmid_2155_9022.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Upregulation of MAPK pathway is associated with survival in castrate @-@ resistant prostate cancer ( PMID : 21559022 ) # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1 5-1 6-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.3.1 11-1.2.1 11-1.2.1.3 11-1.2.1.3.r 12-1.2.1.2.1 13-1.2.1.2.2 (a / associate-01~e.5 :ARG1 (u / upregulate-01~e.0 :ARG1~e.1 (p / pathway~e.3 :name (n / name :op1 "MAPK"~e.2))) :ARG2~e.6 (s / survive-01~e.7 :ARG1~e.8 (d2 / disease~e.11 :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate"~e.12 :op2 "cancer"~e.13) :ARG0-of~e.11 (r / resist-01~e.11 :ARG1 (c2 / castrate-01~e.9)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID21559022"))) # ::id pmid_2155_9022.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results : # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2155_9022.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse ( 1.40 vs 3.00 years , P @ = 0.0255 ) as well as reduced disease @-@ specific survival when compared with those whose expression fell or remained unchanged ( 1.16 vs 2.62 years , P @ = 0.0005 ) . # ::alignments 0-1.1.1.1 0-1.1.3.1.1.1 2-1.1.2.2 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1 6-1.1.2.3 9-1.1.2.3.1 10-1.1.2.3.1.1.r 11-1.1.2.3.1.1.1.1 12-1 12-1.1.1 12-1.1.3.1.1 14-1.2.1.2.2 15-1.2.1.2 15-1.2.1.2.1 15-1.2.1.2.1.r 16-1.2.1.1 17-1.1.3.1.2.3.1 17-1.1.3.1.2.3.1.2 17-1.2.1 17-1.2.1.4.1 17-1.2.1.4.1.2 17-1.2.1.4.1.2.r 18-1.2.1.3.r 19-1.2.1.3 20-1.2.1.3.1 21-1.2.1.3.1.1.1 22-1.2.1.3.1.1 24-1.2.1.4.1.1 28-1.2.1.4.1.2.1 29-1.1.3.1.2.3.1.3 32-1.2.1.2.3 35-1.2.1.2.3.1 37-1.2 38-1.2 39-1.2 39-1.2.r 40-1.2.2.1 41-1.2.2.2.1 43-1.2.2.2 44-1.2.2 45-1.1.2.3.1.r 46-1.1.3 46-1.1.3.1.2.3.1.2.r 50-1.1.3.1.2.1 50-1.1.3.1.2.2 51-1.1.3.1.2.1.1 52-1.1.3.1.2 54-1.1.3.1.2.2.1 54-1.1.3.1.2.2.1.1 54-1.1.3.1.2.2.1.1.r 56-1.1.3.1.2.3.1.1 60-1.1.3.1.2.3.1.2.1 61-1.1.3.1.2.3.1.2.2 64-1.1.3.1.2.4 (h / have-03~e.12 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91~e.12 :ARG2 (p2 / patient~e.0)) :ARG3-of (e / express-03~e.3 :ARG2~e.4 (e2 / enzyme :name (n2 / name :op1 "MAPK"~e.5)) :mod (n / nucleus~e.2) :ARG1-of (r / rise-01~e.6 :time~e.45 (d / develop-01~e.9 :ARG2~e.10 (d4 / disease :name (n3 / name :op1 "CRPC"~e.11))))) :ARG1-of (c / compare-01~e.46 :ARG2 (p3 / person :ARG0-of (h3 / have-rel-role-91~e.12 :ARG2 (p4 / patient~e.0)) :poss (o2 / or~e.52 :op1 (e4 / express-03~e.50 :ARG1-of (f2 / fall-01~e.51)) :op2 (e5 / express-03~e.50 :ARG1-of (c3 / change-01~e.54 :polarity~e.54 -~e.54)) :ARG1-of (m5 / mean-01 :ARG2 (t2 / temporal-quantity~e.17 :quant 1.16~e.56 :compared-to~e.46 (t3 / temporal-quantity~e.17 :quant 2.62~e.60 :unit y3~e.61) :unit (y3 / year~e.29))) :ARG1-of (s6 / statistical-test-91~e.64 :ARG2 0.005))))) :ARG1~e.39 (a / and~e.37,38,39 :op1 (t / time~e.17 :mod (m / median~e.16) :ARG1-of (s / short-07~e.15 :degree~e.15 (m2 / more~e.15) :ARG1-of (s2 / significant-02~e.14) :ARG1-of (s5 / statistical-test-91~e.32 :ARG2 0.0255~e.35)) :mod~e.18 (d2 / die-01~e.19 :ARG1-of (f / follow-01~e.20 :ARG2 (r2 / relapse-01~e.22 :mod (b / biochemistry~e.21)))) :ARG1-of (m3 / mean-01 :ARG2 (t4 / temporal-quantity~e.17 :quant 1.40~e.24 :compared-to~e.17 (t5 / temporal-quantity~e.17 :quant 3.00~e.28 :unit y3) :unit y3))) :op2 (s3 / survive-01~e.44 :ARG1-of (r3 / reduce-01~e.40) :ARG1-of (s4 / specific-02~e.43 :ARG2 (d3 / disease~e.41))))) # ::id pmid_2155_9022.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significant correlations were observed between protein expression of Raf @-@ 1 and MAPK with the type 1 receptor tyrosine kinases , Her2 and epidermal growth factor receptor , as well as the transcription factor AP @-@ 1 in CRPC tumours . # ::alignments 0-1.1.3 1-1.1 3-1 5-1.1.2.4 6-1.1.1 7-1.1.1.1.r 8-1.1.1.1.1.1.1 10-1.1.1.1.1.1.1 11-1.1.1.1 12-1.1.1.1.2.1.1 13-1.1.2.r 15-1.1.2.1.2 16-1.1.2.1.2.1 17-1.1.2.1.1.1 18-1.1.2.1.1.2 19-1.1.2.1.1.3 21-1.1.2.2.1.1 22-1.1.2 23-1.1.2.3.1.1 24-1.1.2.3.1.2 25-1.1.2.3.1.3 26-1.1.2.3.1.4 28-1.1.2 29-1.1.2 30-1.1.2 30-1.1.2.4.2.r 32-1.1.2.4.2 33-1.1.2.4.3 34-1.1.2.4.1.1 36-1.1.2.4.1.1 37-1.1.1.2.r 38-1.1.1.2.1.1.1 39-1.1.1.2 (o / observe-01~e.3 :ARG1 (c / correlate-01~e.1 :ARG1 (e / express-03~e.6 :ARG2~e.7 (a / and~e.11 :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"~e.8,10)) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK"~e.12))) :location~e.37 (t3 / tumor~e.39 :mod (d / disease :name (n7 / name :op1 "CRPC"~e.38)))) :ARG2~e.13 (a2 / and~e.22,28,29,30 :op1 (e4 / enzyme :name (n5 / name :op1 "receptor"~e.17 :op2 "tyrosine"~e.18 :op3 "kinase"~e.19) :mod (t / type~e.15 :mod 1~e.16)) :op2 (e5 / enzyme :name (n3 / name :op1 "Her2"~e.21)) :op3 (e6 / enzyme :name (n4 / name :op1 "epidermal"~e.23 :op2 "growth"~e.24 :op3 "factor"~e.25 :op4 "receptor"~e.26)) :op4 (p / protein~e.5 :name (n6 / name :op1 "AP-1"~e.34,36) :ARG0-of~e.30 (t2 / transcribe-01~e.32) :mod (f / factor~e.33))) :ARG1-of (s / significant-02~e.0))) # ::id pmid_2155_9022.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2155_9022.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patient cohort characteristics # ::alignments 1-1.1.1.1.1.1 2-1.1 3-1 (c / characteristic-02~e.3 :ARG1 (c2 / cohort~e.2 :ARG2-of (i / include-91 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.1)))))) # ::id pmid_2155_9022.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The clinical data collected and recorded for each patient included age ( median : 70 years ; inter @-@ quartile range : 66 @–@ 74 years ) , PSA level at diagnosis ( median : 31 ng ml @⁻¹ ; inter @-@ quartile range : 7.8 @–@ 109 ng ml @⁻¹ ) , PSA level at relapse ( median : 10 ng ml @⁻¹ ; inter @-@ quartile range : 4 @–@ 11 ng ml @⁻¹ ) and Gleason grade at diagnosis ( median : 8 , inter @-@ quartile range : 7 @–@ 9 ) . # ::alignments 1-1.2.1 2-1.2 3-1.2.2 5-1.2.3 6-1.2.2.1.r 7-1.2.2.1.1 8-1.2.2.1.2.1 9-1 10-1.1.1 12-1.1.1.1.1.1.1 14-1.1.1.1.1.1.2.1.1 15-1.1.1.1.1.1.2.1.2 17-1.1.1.1.1.2.3 19-1.1.4.2.1.2.3 20-1.1.4.2.1.2 22-1.1.1.1.1.2.1.1 24-1.1.1.1.1.2.2.1 25-1.1.1.1.1.2.2.2 28-1.1.2.1.1.1 29-1.1.2 29-1.1.3 33-1.1.2.3.1.1.2 35-1.1.2.3.1.1.1 36-1.1.2.3.1.1.3 37-1.1.2.3.1.1.3 42-1.1.1.1.1.2.3 44-1.1.1.1.1.2.3 45-1.1.1.1.1.2 47-1.1.2.3.1.2.1.1 49-1.1.2.3.1.2.2.1 50-1.1.2.3.1.2.2.2 51-1.1.2.3.1.2.2.2 57-1.1.3.1 58-1.1.3 59-1.1.3.2.r 60-1.1.3.2 62-1.1.3.3.1.1.2 64-1.1.3.3.1.1.1 65-1.1.3.3.1.1.3 66-1.1.3.3.1.1.3 71-1.1.1.1.1.2.3 73-1.1.1.1.1.2.3 73-1.1.2.3.1.2.3 73-1.1.3.3.1.2.3 73-1.1.4.2.1.2.3 74-1.1.1.1.1.2 74-1.1.2.3.1.2 74-1.1.3.3.1.2 74-1.1.4.2.1.2 76-1.1.3.3.1.2.1.1 78-1.1.3.3.1.2.2.1 79-1.1.3.3.1.2.2.2 80-1.1.3.3.1.2.2.2 85-1.1 85-1.1.1.1.1 85-1.1.2.3.1 85-1.1.3.3.1 85-1.1.4.2.1 86-1.1.4.3.1.1 87-1.1.4 91-1.1.1.1.1.1.1 93-1.1.4.2.1.1.1 95-1.1.1.1.1.2.3 97-1.1.1.1.1.2.3 98-1.1.1.1.1.2 100-1.1.4.2.1.2.1.1 102-1.1.4.2.1.2.2.1 (i / include-91~e.9 :ARG1 (a2 / and~e.85 :op1 (a / age~e.10 :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.85 :op1 (t / time :mod (m2 / median~e.12,91) :ARG1-of (m3 / mean-01 :ARG2 (t2 / temporal-quantity :quant 70~e.14 :unit (y / year~e.15)))) :op2 (r3 / range-01~e.45,74,98 :ARG3 (t3 / temporal-quantity :quant 66~e.22 :unit y) :ARG4 (t4 / temporal-quantity :quant 74~e.24 :unit y~e.25) :mod (i2 / inter-quartile~e.17,42,44,71,73,95,97))))) :op2 (l / level~e.29 :degree-of (e2 / enzyme :name (n / name :op1 "PSA"~e.28)) :time (d2 / diagnose-01) :ARG1-of (m5 / mean-01 :ARG2 (a4 / and~e.85 :op1 (c3 / concentration-quantity :quant 31~e.35 :mod m2~e.33 :unit (n2 / nanogram-per-milliliter~e.36,37)) :op2 (r4 / range-01~e.74 :ARG3 (c4 / concentration-quantity :quant 7.8~e.47 :unit n2) :ARG4 (c5 / concentration-quantity :quant 109~e.49 :unit n2~e.50,51) :mod (i3 / inter-quartile~e.73))))) :op3 (l2 / level~e.29,58 :degree-of e2~e.57 :time~e.59 (r2 / relapse-01~e.60) :ARG1-of (m6 / mean-01 :ARG2 (a5 / and~e.85 :op1 (c6 / concentration-quantity :quant 10~e.64 :mod m2~e.62 :unit n2~e.65,66) :op2 (r5 / range-01~e.74 :ARG3 (c8 / concentration-quantity :quant 4~e.76 :unit n2) :ARG4 (c9 / concentration-quantity :quant 11~e.78 :unit n2~e.79,80) :mod (i4 / inter-quartile~e.73))))) :op4 (g / grade~e.87 :time d2 :ARG1-of (m7 / mean-01 :ARG2 (a6 / and~e.85 :op1 (c7 / concentration-quantity :quant 8~e.93 :unit n2) :op2 (r6 / range-01~e.20,74 :ARG3 (c10 / concentration-quantity :quant 7~e.100 :unit n2) :ARG4 (c11 / concentration-quantity :quant 9~e.102 :unit n2) :mod (i5 / inter-quartile~e.19,73)))) :mod (p3 / person :name (n3 / name :op1 "Gleason"~e.86)))) :ARG2 (d / data~e.2 :mod (c / clinic~e.1) :ARG1-of (c2 / collect-01~e.3 :topic~e.6 (p / person :mod (e / each~e.7) :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.8)))) :ARG1-of (r / record-01~e.5 :topic p))) # ::id pmid_2155_9022.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All patients underwent biochemical relapse ( median time to relapse : 2.54 years ; inter @-@ quartile range : 1.51 @–@ 4.62 years ) . # ::alignments 0-1.1.2 1-1.1.1.1 2-1 3-1.2.2 4-1.2 6-1.2.3.1.1.1 7-1.2.3.1.1 7-1.2.3.1.1.3.1 7-1.2.3.1.2.1 7-1.2.3.1.2.2 9-1.2.3.1.1.2 11-1.2.3.1.1.3.1.1 12-1.2.3.1.1.3.1.2 14-1.2.3.1.2.3 16-1.2.3.1.2.3 17-1.2.3.1.2 19-1.2.3.1.2.1.1 21-1.2.3.1.2.2.1 22-1.2.3.1.2.2.2 (u / undergo-28~e.2 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.1)) :mod (a / all~e.0)) :ARG2 (r / relapse-01~e.4 :ARG1 p :mod (b / biochemistry~e.3) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (t / time~e.7 :mod (m2 / median~e.6) :mod (r3 / relapse-01~e.9) :ARG1-of (m3 / mean-01 :ARG2 (t2 / temporal-quantity~e.7 :quant 2.54~e.11 :unit (y / year~e.12)))) :op2 (r2 / range-01~e.17 :ARG3 (t3 / temporal-quantity~e.7 :quant 1.51~e.19 :unit y) :ARG4 (t4 / temporal-quantity~e.7 :quant 4.62~e.21 :unit y~e.22) :mod (i / inter-quartile~e.14,16)))))) # ::id pmid_2155_9022.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All patients included in this study were deceased ( median time to death after relapse : 1.37 years ; inter @-@ quartile range : 0.82 @–@ 2.69 ) . # ::alignments 0-1.1.2 1-1.1.1.1 2-1.1.3 3-1.1.3.1.r 4-1.1.3.1.1 5-1.1.3.1 7-1 9-1.2.1.1.1 10-1.2.1.1 10-1.2.1.1.3.r 10-1.2.1.1.4.1 10-1.2.1.2.1 10-1.2.1.2.2 11-1.2.1.1.2.r 12-1.2.1.1.2 13-1.2.1.1.3 14-1.2.1.1.3.1 16-1.2.1.1.4.1.1 17-1.2.1.1.4.1.2 19-1.2.1.2.3 21-1.2.1.2.3 22-1.2.1.2 24-1.2.1.2.1.1 26-1.2.1.2.2.1 (d / decease-01~e.7 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.1)) :mod (a / all~e.0) :ARG1-of (i / include-01~e.2 :ARG2~e.3 (s / study~e.5 :mod (t / this~e.4)))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (t2 / time~e.10 :mod (m2 / median~e.9) :mod~e.11 (d2 / die-01~e.12) :time~e.10 (a3 / after~e.13 :op1 (r / relapse-01~e.14)) :ARG1-of (m3 / mean-01 :ARG2 (t3 / temporal-quantity~e.10 :quant 1.37~e.16 :unit (y / year~e.17)))) :op2 (r2 / range-01~e.22 :ARG3 (t4 / temporal-quantity~e.10 :quant 0.82~e.24 :unit y) :ARG4 (t5 / temporal-quantity~e.10 :quant 2.69~e.26 :unit y) :mod (i2 / inter-quartile~e.19,21))))) # ::id pmid_2155_9022.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This resulted in an overall median survival time of 4.5 years ( inter @-@ quartile range : 3.00 @–@ 7.01 ) . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.2 5-1.2.3 6-1.2.1 7-1.2 7-1.2.4 7-1.2.4.r 7-1.3.1.1 7-1.3.1.2 9-1.2.4.1 10-1.2.4.2 10-1.3.1.1.2 12-1.3.1.3 14-1.3.1.3 15-1.3.1 17-1.3.1.1.1 19-1.3.1.2.1 (r / result-01~e.1 :ARG1 (t / this~e.0) :ARG2~e.2 (t2 / time~e.7 :mod (s / survive-01~e.6) :mod (o / overall~e.4) :mod (m / median~e.5) :duration~e.7 (t3 / temporal-quantity~e.7 :quant 4.5~e.9 :unit (y / year~e.10))) :ARG1-of (m2 / mean-01 :ARG2 (r2 / range-01~e.15 :ARG3 (t4 / temporal-quantity~e.7 :quant 3.00~e.17 :unit (y2 / year~e.10)) :ARG4 (t5 / temporal-quantity~e.7 :quant 7.01~e.19 :unit y) :mod (i / inter-quartile~e.12,14)))) # ::id pmid_2155_9022.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients were diagnosed with locally advanced ( 46 patients ) or metastatic ( 19 patients ) prostate cancer , and at the time of relapse the number of patients presenting with metastatic disease had risen ( 40 patients ) . # ::alignments 0-1.1.2.1.3.2.1.2.1 2-1.1 4-1.1.2.1.3.1 5-1.1.2.1.3 7-1.1.2.1.3.2.1.1 8-1.1.2.1.3.2.1.2.1 10-1.1.2 11-1.1.2.2.3 13-1.1.2.2.3.1.1.1 14-1.1.2.2.3.1.1.2 16-1.1.2.1.2.1 17-1.1.2.1.2.2 17-1.1.2.2.2.1 19-1 22-1.2.2.r 24-1.2.2 26-1.2.1 27-1.2.1.1.r 28-1.2.1.1.2 29-1.2.1.1.1 30-1.2.1.1.1.1.r 31-1.2.1.1.1.1.1 32-1.2.1.1.1.1 33-1.1.2.1.3.2.1.2 34-1.2 36-1.2.3.1.1 37-1.2.3.1.2 (a / and~e.19 :op1 (d / diagnose-01~e.2 :ARG1 p4 :ARG2 (o / or~e.10 :op1 (d3 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate"~e.16 :op2 "cancer"~e.17) :ARG1-of (a2 / advanced-02~e.5 :ARG1-of (l / local-02~e.4) :ARG1-of (m2 / mean-01 :ARG2 (p2 / person :quant 46~e.7 :ARG0-of (h / have-rel-role-91~e.33 :ARG2 (p3 / patient~e.0,8)))))) :op2 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.17) :ARG1-of (m / metastasize-101~e.11 :ARG1-of (m3 / mean-01 :ARG2 (p7 / person :quant 19~e.13 :ARG0-of h~e.14)))))) :op2 (r / rise-01~e.34 :ARG1 (n / number~e.26 :quant-of~e.27 (p4 / person :ARG0-of (p / present-102~e.29 :ARG1~e.30 (d2 / disease~e.32 :ARG1-of m~e.31)) :ARG0-of h~e.28)) :time~e.22 (r2 / relapse-01~e.24) :ARG1-of (m4 / mean-01 :ARG2 (p9 / person :quant 40~e.36 :ARG0-of h~e.37)))) # ::id pmid_2155_9022.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At diagnosis , patients either underwent surgery ( 27 orchidectomy ) or androgen deprivation therapy ( 59 GnRH analogue and @/@ or anti @-@ androgen deprivation therapy ) . # ::alignments 3-1.1.1.1 5-1 6-1.2.1 8-1.2.1.2.1.1 9-1.2.1.2.1 11-1.2 12-1.2.2.1.1 13-1.2.2.1 14-1.2.2 16-1.2.2.2.1.1.1 17-1.2.2.2.1.1.2.1 18-1.2.2.2.1.1.3 19-1.2.2.2.1 21-1.2.2.2.1 22-1.2.2.2.1.2.2 24-1.2.2.2.1.2.2.1 25-1.2.2.2.1.2.1 26-1.2.2.2.1.2 (u / undergo-28~e.5 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.3))) :ARG2 (o / or~e.11 :op1 (s / surgery-01~e.6 :ARG1 p :ARG1-of (m / mean-01 :ARG2 (o2 / orchidectomy~e.9 :mod 27~e.8))) :op2 (t / therapy~e.14 :ARG0-of (d2 / deprive-01~e.13 :ARG1 (a / androgen~e.12)) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and-or~e.19,21 :op1 (e / enzyme :mod 59~e.16 :name (n / name :op1 "GnRH"~e.17) :mod (a3 / analogue~e.18)) :op2 (t2 / therapy~e.26 :ARG1-of (d3 / deprive-01~e.25) :ARG0-of (o3 / oppose-01~e.22 :ARG1 (a4 / androgen~e.24))))))) :time (d / diagnose-01)) # ::id pmid_2155_9022.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Most patients were deceased during the course of follow @-@ up ( 46 patients ) , although some survived beyond follow @-@ up ( 19 patients ) . # ::alignments 0-1.1.2 1-1.1.1.1 3-1 4-1.2.r 8-1.2 10-1.2 12-1.1.2.1.1.1 13-1.1.2.1.1.2 16-1.3.r 17-1.3.1 18-1.3 19-1.3.2 20-1.3.2.1 21-1.3.2.1 22-1.3.2.1 24-1.3.1.1.1.1 25-1.3.1.1.1.2 (d / decease-01~e.3 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.1)) :mod (m / most~e.0 :ARG1-of (m2 / mean-01 :ARG2 (p3 / person :quant 46~e.12 :ARG0-of h~e.13)))) :time~e.4 (f / follow-up-03~e.8,10) :concession~e.16 (s / survive-01~e.18 :ARG1 (s2 / some~e.17 :ARG1-of (m3 / mean-01 :ARG2 (p5 / person :quant 19~e.24 :ARG0-of h~e.25))) :mod (b / beyond~e.19 :op1 f~e.20,21,22))) # ::id pmid_2155_9022.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The presence of metastatic disease at diagnosis was associated with reduced time to biochemical relapse ( P @ = 0.037 ) and a trend in overall patient survival ( P @ = 0.06 ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 8-1 9-1.2.r 10-1.2.1.1 11-1.2.1 13-1.2.1.2.1 14-1.2.1.2 17-1.2.1.2.2 20-1.2.1.2.2.1 22-1.2 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1.2 27-1.2.2.1.1.1.1 28-1.2.2.1 31-1.2.2.2 34-1.2.2.2.1 (a / associate-01~e.8 :ARG1 (p / present-02~e.1 :ARG1~e.2 (d / disease~e.4 :ARG1-of (m / metastasize-101~e.3)) :ARG2 (d2 / diagnose-01)) :ARG2~e.9 (a2 / and~e.22 :op1 (t / time~e.11 :ARG1-of (r / reduce-01~e.10) :mod (r2 / relapse-01~e.14 :mod (b / biochemistry~e.13) :ARG1-of (s2 / statistical-test-91~e.17 :ARG2 0.037~e.20))) :op2 (t2 / trend-01~e.24 :ARG1~e.25 (s / survive-01~e.28 :ARG0 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.27))) :mod (o / overall~e.26)) :ARG1-of (s3 / statistical-test-91~e.31 :ARG2 0.06~e.34)))) # ::id pmid_2155_9022.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High Gleason scores were associated with more rapid biochemical relapse ( P @ = 0.002 ) , time to death after biochemical relapse ( P @ = 0.02 ) and disease @-@ specific survival ( P @ = 0.001 ) , confirming the association of these clinical parameters with the progression of prostate cancer . # ::alignments 0-1.1.1 1-1.1.2.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2.1.1 8-1.2.1.2 9-1.2.1 12-1.1.3 15-1.1.3.1 18-1.2.2 18-1.2.2.2.r 19-1.2.2.1.r 20-1.2.2.1 21-1.2.2.2 22-1.2.2.2.1 23-1.2.2.2.1 26-1.2.2.3 29-1.2.2.3.1 31-1.2 32-1.2.3.1.1 34-1.2.3.1 35-1.2.3 38-1.2.3.2 41-1.2.3.2.1 44-1.3 46-1.3.1 51-1.3.1.2.r 53-1.3.1.2 54-1.3.1.2.1.r 55-1.3.1.2.1.2.1 56-1.3.1.2.1.2.2 (a / associate-01~e.4 :ARG1 (s / score~e.2 :ARG1-of (h / high-02~e.0) :mod (p6 / person :name (n / name :op1 "Gleason"~e.1)) :ARG1-of (s4 / statistical-test-91~e.12 :ARG2 0.002~e.15)) :ARG2~e.5 (a2 / and~e.31 :op1 (r / relapse-01~e.9 :mod (r2 / rapid~e.7 :degree (m / more~e.6)) :mod (b / biochemistry~e.8)) :op2 (t / time~e.18 :mod~e.19 (d / die-01~e.20) :time~e.18 (a3 / after~e.21 :op1 r~e.22,23) :ARG1-of (s5 / statistical-test-91~e.26 :ARG2 0.02~e.29)) :op3 (s2 / survive-01~e.35 :ARG1-of (s3 / specific-02~e.34 :ARG2 (d2 / disease~e.32)) :ARG1-of (s6 / statistical-test-91~e.38 :ARG2 0.001~e.41))) :ARG0-of (c / confirm-01~e.44 :ARG1 (a4 / associate-01~e.46 :ARG1 a2 :ARG2~e.51 (p / progress-01~e.53 :ARG1~e.54 (d3 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate"~e.55 :op2 "cancer"~e.56)))))) # ::id pmid_2155_9022.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression and localisation of Raf @-@ 1 and MAPK # ::alignments 1-1.1 2-1.1.1 4-1.1.1.r 5-1.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1.1.2.1.1 (a / and :op1 (e / express-03~e.1 :ARG2~e.4 (a2 / and~e.2 :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"~e.5,7)) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK"~e.9)))) :op2 (l / localize-01 :ARG1 a2)) # ::id pmid_2155_9022.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Raf @-@ 1 was observed in the cytoplasm and peri @-@ membrane areas ( Figure 1A ) , and the inactive form of Raf @-@ 1 was found only in the peri @-@ membrane region ( Figure 1B ) ; however , the activated form of Raf @-@ 1 was observed in the cytoplasm , nucleus and the cell membrane ( Figure 1C ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 4-1.1.1 5-1.1.1.3.r 7-1.1.1.3.1.1 8-1.1.1.3 9-1.1.1.3.2.1 11-1.1.1.3.2.1 12-1.1.1.3.1 12-1.1.1.3.2 15-1.1.1.2.1 16-1.1.1.2.1.1 20-1.1 22-1.1.2.1.2.1 22-1.1.2.1.2.1.1 22-1.1.2.1.2.1.1.r 23-1.1.2.1.2 24-1.1.2.1.2.r 25-1.1.2.1.1.1 27-1.1.2.1.1.1 29-1.1.2 30-1.1.2.2.1 33-1.1.2.2.2 34-1.1.2.2.2 35-1.1.2.2.2 36-1.1.2.2 39-1.1.2.3.1 40-1.1.2.3.1.1 44-1.2 47-1.2.1.1.2.1 48-1.2.1.1.2 49-1.2.1.1.2.r 50-1.2.1.1.1.1 52-1.2.1.1.1.1 54-1.2.1 57-1.2.2.1 59-1.2.2.2 60-1.2.2 62-1.2.2.3.1 63-1.2.2.3 66-1.2.3.1 67-1.2.3.1.1 (a / and :op1 (a2 / and~e.20 :op1 (o / observe-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"~e.0,2)) :ARG0-of (d / describe-01 :ARG1 (f4 / figure~e.15 :mod "1A"~e.16)) :location~e.5 (a8 / and~e.8 :op1 (a4 / area~e.12 :part-of (c / cytoplasm~e.7)) :op2 (a9 / area~e.12 :part-of (p / peri-membrane~e.9,11)))) :op2 (f / find-01~e.29 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf-1"~e.25,27) :mod~e.24 (f2 / form~e.23 :ARG0-of (a3 / activity-06~e.22 :polarity~e.22 -~e.22))) :location (r / region~e.36 :mod (o3 / only~e.30) :part-of p~e.33,34,35) :ARG0-of (d2 / describe-01 :ARG1 (f5 / figure~e.39 :mod "1B"~e.40)))) :op2 (h / have-concession-91~e.44 :ARG1 (o2 / observe-01~e.54 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Raf-1"~e.50,52) :mod~e.49 (f3 / form~e.48 :ARG0-of (a5 / activate-01~e.47)))) :location (a7 / and~e.60 :op1 c~e.57 :op2 (n4 / nucleus~e.59) :op3 (m / membrane~e.63 :part-of (c3 / cell~e.62))) :ARG0-of (d3 / describe-01 :ARG1 (f6 / figure~e.66 :mod "1C"~e.67)))) # ::id pmid_2155_9022.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mitogen @-@ activated protein kinase and phosphorylated MAPK ( pMAPK ) ( Thr202 @/@ 204 ) were observed in the nucleus and cytoplasm ( Figure 1D ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1.1.1.2 4-1.1.1.1.3 6-1.1.2.3 7-1.1.2.2.1.1 9-1.1.2.3 13-1.1.2.4 14-1.1.2.4.2 17-1 18-1.2.r 20-1.2.1 21-1.2 22-1.2.2 25-1.3.1 26-1.3.1.1 (o / observe-01~e.17 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "mitogen-activated"~e.0,2 :op2 "protein"~e.3 :op3 "kinase"~e.4)) :op2 (a2 / amino-acid :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n3 / name :op1 "MAPK"~e.7)) :ARG3-of (p / phosphorylate-01~e.6,9) :mod (s / slash~e.13 :op1 202 :op2 204~e.14))) :location~e.18 (a3 / and~e.21 :op1 (n5 / nucleus~e.20) :op2 (c / cytoplasm~e.22)) :ARG0-of (d / describe-01 :ARG1 (f / figure~e.25 :mod "1D"~e.26))) # ::id pmid_2155_9022.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overall , comparison of HNPC tumours and CRPC tumours revealed no differences in total or average expression levels of either Raf @-@ 1 ( and all phosphorylated forms ) ( Table 1 ) or MAPK ( activated or inactivate , nuclear or cytoplasmic ) ( Table 2 ) . # ::alignments 0-1.3 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 5-1.1.2 7-1.1.2.1.1.1 8-1.1.1 9-1 10-1.2.1 10-1.2.1.r 11-1.2 12-1.2.2.r 13-1.2.2.2 14-1.2.2.1.1 14-1.2.2.1.1.2 14-1.2.2.1.1.2.r 15-1.2.2.3 16-1.2.2.1 17-1.2.2 20-1.2.2.1.1.1.1.1.1 20-1.2.2.1.1.1.2.1.1 22-1.2.2.1.1.1.1.1.1 22-1.2.2.1.1.1.2.1.1 22-1.2.2.1.1.1.3.1.1 24-1.2.2.1.1.1 26-1.2.2.1.1.1.2.2 31-1.2.2.1.1.1.3.1 32-1.2.2.1.1.1.1.1.1 32-1.2.2.1.1.1.2.1.1 32-1.2.2.1.1.1.3.1.1 35-1.2.2.1.1.2 35-1.2.2.1.1.2.1 35-1.2.2.1.1.2.1.r 35-1.2.2.1.1.2.2 35-1.2.2.1.1.2.2.r 36-1.2.2.1.1.2.1.1.1.1 36-1.2.2.1.1.2.1.2.1.1 36-1.2.2.1.1.2.2.1.1.1 36-1.2.2.1.1.2.2.2.1.1 38-1.2.2.1.1.2.1.1.3 38-1.2.2.1.1.2.1.2.2 39-1.2.2.1.1.2.1 40-1.2.2.1.1.2.1.2.2.1 42-1.2.2.1.1.2.2.1.2 43-1.2.2.1.1.2.2 44-1.2.2.1.1.2.2.2.2 48-1.2.2.1.1.2.1.1.2.1 49-1.2.2.1.1.2.1.1.2.1.1 (r / reveal-01~e.9 :ARG0 (c / compare-01~e.2 :ARG1~e.3 (t / tumor~e.5,8 :mod (d4 / disease :name (n / name :op1 "HNPC"~e.4))) :ARG2 (t2 / tumor~e.5 :mod (d5 / disease :name (n2 / name :op1 "CRPC"~e.7)))) :ARG1 (d / differ-02~e.11 :polarity~e.10 -~e.10 :ARG1~e.12 (l / level~e.17 :degree-of (e / express-03~e.16 :ARG2 (o3 / or~e.14 :op1 (a2 / and~e.24 :op1 (e2 / enzyme :name (n3 / name :op1 "Raf-1"~e.20,22,32)) :op2 (e3 / enzyme :name (n4 / name :op1 "Raf-1"~e.20,22,32) :ARG3-of (p / phosphorylate-01~e.26)) :ARG1-of (d2 / describe-01 :ARG0 (t4 / table~e.31 :mod 1~e.22,32))) :op2~e.14 (o7 / or~e.14,35 :op1~e.35 (o8 / or~e.35,39 :op1 (e7 / enzyme :name (n5 / name :op1 "MAPK"~e.36) :ARG1-of (d3 / describe-01 :ARG0 (t5 / table~e.48 :mod 2~e.49)) :ARG0-of (a3 / activate-01~e.38)) :op2 (e4 / enzyme :name (n7 / name :op1 "MAPK"~e.36) :ARG0-of (a4 / activate-01~e.38 :polarity -~e.40))) :op2~e.35 (o9 / or~e.35,43 :op1 (e6 / enzyme :name (n8 / name :op1 "MAPK"~e.36) :location (n9 / nucleus~e.42)) :op2 (e5 / enzyme :name (n10 / name :op1 "MAPK"~e.36) :location (c3 / cytoplasm~e.44)))))) :ARG1-of (t3 / total-01~e.13) :ARG1-of (a / average-01~e.15))) :mod (o / overall~e.0)) # ::id pmid_2155_9022.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , analysis of matched pairs revealed a subgroup that showed significant increases in Raf @-@ 1 and MAPK levels in CRPC tumours . # ::alignments 0-1 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1 5-1.1.1.1 6-1.1 8-1.1.2 10-1.1.2.1 11-1.1.2.1.1.2 12-1.1.2.1.1 13-1.1.2.1.1.1.r 14-1.1.2.1.1.1.1.1.1.1 16-1.1.2.1.1.1.1.1.1.1 17-1.1.2.1.1.1 18-1.1.2.1.1.1.2.1.1.1 19-1.1.2.1.1.1.1 19-1.1.2.1.1.1.2 20-1.1.2.1.2.r 21-1.1.2.1.2.1.1.1 22-1.1.2.1.2 (h / have-concession-91~e.0 :ARG1 (r / reveal-01~e.6 :ARG0 (a / analyze-01~e.2 :ARG1~e.3 (p / pair~e.5 :ARG1-of (m / match-01~e.4))) :ARG1 (s / subgroup~e.8 :ARG0-of (s2 / show-01~e.10 :ARG1 (i / increase-01~e.12 :ARG1~e.13 (a3 / and~e.17 :op1 (l / level~e.19 :quant-of (e3 / enzyme :name (n3 / name :op1 "Raf-1"~e.14,16))) :op2 (l2 / level~e.19 :quant-of (e / enzyme :name (n2 / name :op1 "MAPK"~e.18)))) :ARG1-of (s3 / significant-02~e.11)) :location~e.20 (t / tumor~e.22 :mod (d / disease :name (n / name :op1 "CRPC"~e.21))))))) # ::id pmid_2155_9022.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We have previously reported that patients whose Raf @-@ 1 expression rose in this cohort with the development of CRPC had a significantly shorter time to relapse than those patients who had a fall or no change ( P @ = 0.0005 ) ( Mukherjee et al , 2005 ) . # ::alignments 0-1.1 1-1.2 2-1.4 3-1 4-1.2.1.3.1.2 5-1.2.1.3.1.1.1 7-1.2.1.2.1.1.1 9-1.2.1.2.1.1.1 10-1.2.1.2 11-1.2.1.2.2 12-1.2.1.2.2.1.r 13-1.2.1.2.2.1.1 14-1.2.1.2.2.1 15-1.2.1.2.2.2.r 17-1.2.1.2.2.2 18-1.2.1.2.2.2.1.r 19-1.2.1.2.2.2.1.1.1 20-1.2 22-1.2.2.2 23-1.2.2.1 23-1.2.2.1.1 23-1.2.2.1.1.r 24-1.2.2 26-1.2.2.3 28-1.2.1.3.1.2 29-1.2.1.1.1 29-1.2.1.3.1.1.1 31-1.2.1.3.1 31-1.2.1.3.1.1 31-1.2.1.3.1.1.r 31-1.2.1.3.1.3 31-1.2.1.3.1.3.r 33-1.2.1.3.1.3.1.1 34-1.2.1.3.1.3.1 35-1.2.1.3.1.3.1.2.1 35-1.2.1.3.1.3.1.2.1.r 36-1.2.1.3.1.3.1.2 39-1.2.3 42-1.2.3.1 46-1.3.1.1.1.1.1 48-1.3.1.1 49-1.3.1.1.2.1 52-1.3.1.2.1 (r / report-01~e.3 :ARG0 (w / we~e.0) :ARG1 (h / have-03~e.1,20 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.29)) :poss (e / express-03~e.10 :ARG2 (e2 / enzyme :name (n / name :op1 "Raf-1"~e.7,9)) :ARG1-of (r2 / rise-01~e.11 :location~e.12 (c / cohort~e.14 :mod (t3 / this~e.13)) :time~e.15 (d / develop-01~e.17 :ARG2~e.18 (d4 / disease :name (n2 / name :op1 "CRPC"~e.19))))) :ARG1-of (c3 / compare-01 :ARG2 (p3 / person~e.31 :ARG0-of~e.31 (h3 / have-rel-role-91~e.31 :ARG2 (p4 / patient~e.5,29)) :mod (t2 / that~e.4,28) :ARG0-of~e.31 (h4 / have-06~e.31 :ARG1 (o / or~e.34 :op1 (f / fall-01~e.33) :op2 (c4 / change-01~e.36 :polarity~e.35 -~e.35)))))) :ARG1 (t / time~e.24 :ARG1-of (s / short-07~e.23 :degree~e.23 (m / more~e.23)) :ARG1-of (s2 / significant-02~e.22) :mod (r3 / relapse-01~e.26)) :ARG1-of (s3 / statistical-test-91~e.39 :ARG2 0.0005~e.42)) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a / and~e.48 :op1 (p7 / person :name (n3 / name :op1 "Mukherjee"~e.46)) :op2 (p8 / person :mod (o2 / other~e.49))) :time (d3 / date-entity :year 2005~e.52))) :time (p9 / previous~e.2)) # ::id pmid_2155_9022.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with this observation , patients with rising levels of nuclear pRaf ( Ser338 , activated Raf @-@ 1 ) had a significantly shorter time to biochemical relapse ( 2.2 years ; range : 1.84 @–@ 2.56 years ) by 2.4 years when compared with patients who showed a fall in levels ( 4.6 years ; range : 3.4 @–@ 5.8 years ) ( P @ = 0.01 ) ( Figure 2 ) . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1 3-1.3.1 5-1.1.1.1 7-1.1.2.1.2 8-1.1.2.1 9-1.1.2.1.1.r 10-1.1.2.1.1.3.3 11-1.1.2.1.1.3.1.1 11-1.1.2.1.1.3.2 15-1.1.2.1.1.3.4.1.2 16-1.1.2.1.1.3.4.1.1.1 18-1.1.2.1.1.3.4.1.1.1 20-1 20-1.1 20-1.1.1 20-1.1.1.r 20-1.1.2 20-1.1.2.r 20-1.1.r 22-1.2.1.2 23-1.2.1 23-1.2.1.1 23-1.2.1.1.r 24-1.2 24-1.2.2.2 24-1.2.3.1.1 24-1.2.3.1.2.1 24-1.2.3.1.2.2 24-1.5.2.1.1.1.1.1.1 24-1.5.2.1.1.1.1.1.2.1 24-1.5.2.1.1.1.1.1.2.2 26-1.2.2.1 27-1.2.2 29-1.2.3.1.1.1 30-1.2.3.1.1.2 32-1.2.3.1.2 32-1.5.2.1.1.1.1.1.2 34-1.2.3.1.2.1.1 36-1.2.3.1.2.2.1 37-1.2.2.2.2 40-1.2.2.2.1 41-1.2.2.2.2 43-1.5 44-1.5.2.r 45-1.5.2.2 47-1.5.2.1 49-1.5.2.1.1 50-1.5.2.1.1.1.r 51-1.5.2.1.1.1 53-1.5.2.1.1.1.1.1.1.1 54-1.5.2.1.1.1.1.1.1.2 56-1.2.3.1.2 58-1.5.2.1.1.1.1.1.2.1.1 60-1.5.2.1.1.1.1.1.2.2.1 61-1.5.2.1.1.1.1.1.2.2.2 65-1.2.1.3 68-1.2.1.3.1 72-1.4.1 73-1.4.1.1 (h / have-03~e.20 :ARG0~e.20 (p / person~e.20 :ARG0-of~e.20 (h2 / have-rel-role-91~e.20 :ARG2 (p2 / patient~e.5)) :ARG0-of~e.20 (h4 / have-03~e.20 :ARG1 (l / level~e.8 :quant-of~e.9 (a / amino-acid :mod 338 :name (n / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "Raf"~e.11) :ARG3-of (p3 / phosphorylate-01~e.11) :mod (n3 / nucleus~e.10) :ARG1-of (m2 / mean-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Raf-1"~e.16,18) :ARG1-of (a2 / activate-01~e.15))))) :ARG1-of (r2 / rise-01~e.7)))) :ARG1 (t5 / time~e.24 :ARG1-of (s / short-07~e.23 :degree~e.23 (m / more~e.23) :ARG1-of (s2 / significant-02~e.22) :ARG1-of (s4 / statistical-test-91~e.65 :ARG2 0.01~e.68)) :mod (r / relapse-01~e.27 :mod (b / biochemistry~e.26) :duration (t7 / temporal-quantity~e.24 :quant 2.4~e.40 :unit (y5 / year~e.37,41))) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (t / temporal-quantity~e.24 :quant 2.2~e.29 :unit y5~e.30) :op2 (r3 / range-01~e.32,56 :ARG3 (t2 / temporal-quantity~e.24 :quant 1.84~e.34 :unit y5) :ARG4 (t3 / temporal-quantity~e.24 :quant 2.56~e.36 :unit y5))))) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (o / observe-01~e.3 :mod (t6 / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.72 :mod 2~e.73)) :condition (c2 / compare-01~e.43 :ARG1 p :ARG2~e.44 (p4 / person :ARG0-of (s3 / show-01~e.47 :ARG1 (f / fall-01~e.49 :ARG1~e.50 (l2 / level~e.51 :ARG1-of (m5 / mean-01 :ARG2 (a4 / and :op1 (t4 / temporal-quantity~e.24 :quant 4.6~e.53 :unit y5~e.54) :op2 (r4 / range-01~e.32 :ARG3 (t8 / temporal-quantity~e.24 :quant 3.4~e.58 :unit y5) :ARG4 (t9 / temporal-quantity~e.24 :quant 5.8~e.60 :unit y5~e.61))))))) :ARG0-of h2~e.45))) # ::id pmid_2155_9022.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients whose nuclear MAPK expression rose with the development of CRPC had a significantly shorter time to death from relapse ( 1.40 ( 1.20 @–@ 1.61 ) years ) compared with samples that showed a fall or no change in expression ( 3.00 ( 1.43 @–@ 4.57 ) years ) , P @ = 0.0255 ( Figure 3A ) . # ::alignments 0-1.1.1.1 2-1.1.2.2 3-1.1.2.1.1.1 4-1.1.2 5-1.1.2.3 6-1.1.2.3.1.r 8-1.1.2.3.1 9-1.1.2.3.1.1.r 10-1.1.2.3.1.1.1.1 11-1 11-1.1.1 13-1.2.1.2 14-1.2.1 14-1.2.1.1 14-1.2.1.1.r 15-1.1.3.1.1.2.1 15-1.1.3.1.1.2.1.3.1.1 15-1.1.3.1.1.2.1.3.1.2 15-1.2 15-1.2.3.1 15-1.2.3.1.3.1.1 15-1.2.3.1.3.1.2 16-1.2.2.r 17-1.2.2 19-1.2.2.1.1 21-1.2.3.1.1 23-1.2.3.1.3.1.1.1 25-1.2.3.1.3.1.2.1 27-1.2.3.1.3.1.2.2 29-1.1.3 30-1.1.3.1.r 31-1.1.3.1 31-1.1.3.1.1 31-1.1.3.1.1.r 33-1.1.3.1.1.1 35-1.1.3.1.1.1.1.1 36-1.1.3.1.1.1.1 37-1.1.3.1.1.1.1.2.1 37-1.1.3.1.1.1.1.2.1.r 38-1.1.3.1.1.1.1.2 39-1.1.3.1.1.1.1.2.2.r 40-1.1.3.1.1.1.1.2.2 42-1.1.3.1.1.2.1.1 44-1.1.3.1.1.2.1.3.1.1.1 46-1.1.3.1.1.2.1.3.1.2.1 48-1.1.3.1.1.2.1.3.1.2.2 52-1.2.1.3 55-1.2.1.3.1 58-1.3.1 59-1.3.1.1 (h / have-03~e.11 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91~e.11 :ARG2 (p2 / patient~e.0)) :poss (e / express-03~e.4 :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK"~e.3)) :mod (n2 / nucleus~e.2) :ARG1-of (r / rise-01~e.5 :time~e.6 (d / develop-01~e.8 :ARG2~e.9 (d4 / disease :name (n3 / name :op1 "CRPC"~e.10))))) :ARG1-of (c2 / compare-01~e.29 :ARG2~e.30 (t8 / thing~e.31 :ARG1-of~e.31 (s3 / sample-01~e.31 :ARG0-of (s4 / show-01~e.33 :ARG1 (o / or~e.36 :op1 (f / fall-01~e.35 :ARG1 e3) :op2 (c3 / change-01~e.38 :polarity~e.37 -~e.37 :ARG1~e.39 (e3 / express-03~e.40)))) :ARG1-of (m4 / mean-01 :ARG2 (t5 / temporal-quantity~e.15 :quant 3.00~e.42 :unit y :ARG1-of (m5 / mean-01 :ARG2 (v2 / value-interval :op1 (t6 / temporal-quantity~e.15 :quant 1.43~e.44 :unit y) :op2 (t7 / temporal-quantity~e.15 :quant 4.57~e.46 :unit y~e.48))))))))) :ARG1 (t / time~e.15 :ARG1-of (s / short-07~e.14 :degree~e.14 (m / more~e.14) :ARG1-of (s2 / significant-02~e.13) :ARG1-of (s5 / statistical-test-91~e.52 :ARG2 0.0255~e.55)) :mod~e.16 (d2 / die-01~e.17 :time (a / after :op1 (r2 / relapse-01~e.19))) :ARG1-of (m2 / mean-01 :ARG2 (t2 / temporal-quantity~e.15 :quant 1.40~e.21 :unit (y / year) :ARG1-of (m3 / mean-01 :ARG2 (v / value-interval :op1 (t3 / temporal-quantity~e.15 :quant 1.20~e.23 :unit y) :op2 (t4 / temporal-quantity~e.15 :quant 1.61~e.25 :unit y~e.27)))))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.58 :mod "3A"~e.59))) # ::id pmid_2155_9022.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This translated into a shorter disease @-@ specific survival of 3.37 ( 1.58 @–@ 5.16 ) years compared with 6.89 ( 5.70 @–@ 8.08 ) years , P @ = 0.0068 ( Figure 3B ) . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.1 4-1.2.1.1 4-1.2.1.1.r 5-1.2.2.1 7-1.2.2 8-1.2 9-1.2.3.r 10-1.2.3.1 12-1.2.3.4.1.1.1 14-1.2.3.4.1.2.1 16-1.2.3.2 17-1.2.3.3.r 19-1.2.3.3.1 21-1.2.3.3.3.1.1.1 23-1.2.3.3.3.1.2.1 25-1.2.3.2 28-1.4 31-1.4.1 34-1.3.1 35-1.3.1.1 (t / translate-01~e.1 :ARG1 (t2 / this~e.0) :ARG2~e.2 (s / survive-01~e.8 :ARG1-of (s2 / short-07~e.4 :degree~e.4 (m / more~e.4)) :ARG1-of (s3 / specific-02~e.7 :ARG2 (d / disease~e.5)) :duration~e.9 (t3 / temporal-quantity :quant 3.37~e.10 :unit (y / year~e.16,25) :compared-to~e.17 (t4 / temporal-quantity :quant 6.89~e.19 :unit y :ARG1-of (m3 / mean-01 :ARG2 (v2 / value-interval :op1 (t5 / temporal-quantity :quant 5.70~e.21 :unit y) :op2 (t6 / temporal-quantity :quant 8.08~e.23 :unit y)))) :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (t7 / temporal-quantity :quant 1.58~e.12 :unit y) :op2 (t8 / temporal-quantity :quant 5.16~e.14 :unit y))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.34 :mod "3B"~e.35)) :ARG1-of (s4 / statistical-test-91~e.28 :ARG2 0.0068~e.31)) # ::id pmid_2155_9022.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , there was also an association seen between rising cytoplasmic pMAPK ( Thr202 @/@ 204 ) expression and reduced time to biochemical relapse ( P @ = 0.06 ) . # ::alignments 0-1.2 4-1.1.3 6-1.1 7-1 9-1.1.1.2 10-1.1.1.1.5 11-1.1.1.1.3.1.1 11-1.1.1.1.4 14-1.1.1.1.2 15-1.1.1.1.2.2 17-1.1.1 19-1.1.2.1 20-1.1.2 22-1.1.2.2.1 23-1.1.2.2 26-1.1.4 29-1.1.4.1 (s / see-01~e.7 :ARG1 (a / associate-01~e.6 :ARG1 (e / express-03~e.17 :ARG2 (a2 / amino-acid :name (n / name :op1 "threonine") :mod (s2 / slash~e.14 :op1 202 :op2 204~e.15) :part-of (e2 / enzyme :name (n2 / name :op1 "MAPK"~e.11)) :ARG3-of (p / phosphorylate-01~e.11) :mod (c / cytoplasm~e.10)) :ARG1-of (r / rise-01~e.9)) :ARG2 (t / time~e.20 :ARG1-of (r2 / reduce-01~e.19) :mod (r3 / relapse-01~e.23 :mod (b / biochemistry~e.22))) :mod (a3 / also~e.4) :ARG1-of (s3 / statistical-test-91~e.26 :ARG2 0.06~e.29)) :ARG2-of (i / interest-01~e.0)) # ::id pmid_2155_9022.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Relative protein expression levels in hormone @-@ naïve prostate cancer # ::alignments 1-1.1 2-1.2.1 3-1.2 4-1 5-1.3.r 6-1.3.1.1 8-1.3.1.1 9-1.3.1.2 10-1.3.1.3 (l / level~e.4 :ARG1-of (r / relative-05~e.1) :degree-of (e / express-03~e.3 :ARG2 (p / protein~e.2)) :location~e.5 (d / disease :name (n / name :op1 "hormone-naive"~e.6,8 :op2 "prostate"~e.9 :op3 "cancer"~e.10))) # ::id pmid_2155_9022.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In HNPC tumours , Raf @-@ 1 correlated with the inactive form , pRaf ( Ser259 ) , before relapse ( P @ = 0.0041 , r @ ²@ = 0.1201 ) . # ::alignments 1-1.4.1.1.1 2-1.4 4-1.2.3.1.1 6-1.1.1.1 7-1 10-1.2.5.1 10-1.2.5.1.1 10-1.2.5.1.1.r 11-1.2.5 13-1.1.1.1 13-1.2.4 18-1.3 19-1.3.1 22-1.2.4 22-1.5 25-1.5.1 34-1.5.2 (c / correlate-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"~e.6,13)) :ARG2 (a / amino-acid :mod 259 :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf"~e.4)) :ARG3-of (p / phosphorylate-01~e.13,22) :mod (f / form~e.11 :ARG1-of (a2 / activity-06~e.10 :polarity~e.10 -~e.10))) :time (b / before~e.18 :op1 (r / relapse-01~e.19)) :location (t / tumor~e.2 :mod (d / disease :name (n4 / name :op1 "HNPC"~e.1))) :ARG1-of (s / statistical-test-91~e.22 :ARG2 0.0041~e.25 :ARG3 0.1201~e.34)) # ::id pmid_2155_9022.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nuclear pRaf ( Ser338 ) and cytoplasmic pRaf ( Ser338 ) strongly correlated with each other ( P @ = 0.0035 , r @ ²@ = 0.1381 ) . # ::alignments 0-1.1.3.2 1-1.1.3.1.1 1-1.1.4 1-1.2.3.1.1 6-1.2.3.2 7-1.1.3.1.1 7-1.1.4 7-1.2.3.1.1 11-1.3 12-1 18-1.1.4 18-1.4 21-1.4.1 30-1.4.2 (c / correlate-01~e.12 :ARG1 (a2 / amino-acid :mod 338 :name (n / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "Raf"~e.1,7) :mod (n3 / nucleus~e.0)) :ARG3-of (p / phosphorylate-01~e.1,7,18)) :ARG2 (a / amino-acid :mod 338 :name (n4 / name :op1 "serine") :part-of (e2 / enzyme :name (n5 / name :op1 "Raf"~e.1,7) :mod (c2 / cytoplasm~e.6) :ARG3-of p)) :ARG1-of (s / strong-02~e.11) :ARG1-of (s2 / statistical-test-91~e.18 :ARG2 0.0035~e.21 :ARG3 0.1381~e.30)) # ::id pmid_2155_9022.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No correlations between total Raf @-@ 1 and cytoplasmic pRaf ( Ser338 ) or nuclear pRaf ( Ser338 ) expression were evident . # ::alignments 0-1.1 0-1.1.r 1-1.2 3-1.2.1.2 4-1.2.1.1.1 6-1.2.1.1.1 8-1.2.2.1.1.5 9-1.2.2.1.1.3.1.1 9-1.2.2.1.1.4 9-1.2.2.2.1.3.1.1 13-1.2.2 14-1.2.2.2.2 15-1.2.2.1.1.3.1.1 15-1.2.2.1.1.4 15-1.2.2.2.1.3.1.1 19-1.2.2.1 19-1.2.2.2 21-1 (e / evidence-01~e.21 :polarity~e.0 -~e.0 :ARG1 (c / correlate-01~e.1 :ARG1 (e2 / enzyme :name (n / name :op1 "Raf-1"~e.4,6) :mod (t / total~e.3)) :ARG2 (o / or~e.13 :op1 (e3 / express-03~e.19 :ARG2 (a / amino-acid :mod 338 :name (n2 / name :op1 "serine") :part-of (e4 / enzyme :name (n3 / name :op1 "Raf"~e.9,15)) :ARG3-of (p / phosphorylate-01~e.9,15) :mod (c2 / cytoplasm~e.8))) :op2 (e5 / express-03~e.19 :ARG2 (a3 / amino-acid :mod 338 :name (n4 / name :op1 "serine") :part-of (e6 / enzyme :name (n6 / name :op1 "Raf"~e.9,15) :ARG3-of p)) :mod (n5 / nucleus~e.14))))) # ::id pmid_2155_9022.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition no correlations were observed between the inactive form of pRaf ( Ser259 ) and nuclear pRaf ( Ser338 ) or cytoplasmic pRaf ( Ser338 ) . # ::alignments 0-1 1-1 2-1.1.1 2-1.1.1.r 3-1.1.2 5-1.1 8-1.1.1 8-1.1.2.1.5.1 8-1.1.2.1.5.1.1 8-1.1.2.1.5.1.1.r 9-1.1.2.1.5 11-1.1.2.1.3.1.1 11-1.1.2.1.4 11-1.1.2.2.1.3.1.1 16-1.1.2.2.1.4 17-1.1.2.2.1.3.1.1 17-1.1.2.2.2.3.1.1 21-1.1.2.2 22-1.1.2.2.2.4 23-1.1.2.1.3.1.1 23-1.1.2.1.4 23-1.1.2.2.2.3.1.1 (a / and~e.0,1 :op2 (o / observe-01~e.5 :polarity~e.2 -~e.2,8 :ARG1 (c / correlate-01~e.3 :ARG1 (a4 / amino-acid :mod 259 :name (n / name :op1 "serine") :part-of (e / enzyme :name (n4 / name :op1 "Raf"~e.11,23)) :ARG3-of (p / phosphorylate-01~e.11,23) :mod (f / form~e.9 :ARG0-of (a2 / activity-06~e.8 :polarity~e.8 -~e.8))) :ARG2 (o3 / or~e.21 :op1 (a5 / amino-acid :mod 338 :name (n3 / name :op1 "serine") :part-of (e2 / enzyme :name (n5 / name :op1 "Raf"~e.11,17) :ARG3-of p) :mod (n2 / nucleus~e.16)) :op2 (a3 / amino-acid :mod 338 :name (n6 / name :op1 "serine") :part-of (e3 / enzyme :name (n7 / name :op1 "Raf"~e.17,23) :ARG3-of p) :mod (c2 / cytoplasm~e.22)))))) # ::id pmid_2155_9022.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total cytoplasmic expression of MAPK correlated with total nuclear expression of MAPK ( P @ = 0.0126 , r @ ²@ = 0.1009 ) , activated MAPK ( Thr202 @/@ 204 ) ( P @ = 0.0152 , r @ ²@ = 0.1044 ) and the cytoplasmic expression of MAPK ( Thr202 @/@ 204 ) ( P @ < 0.0001 , r @ ²@ = 0.3391 ) . # ::alignments 0-1.1.2.1.3 1-1.1.1.2 2-1.1.1 2-1.1.2 2-1.3.2 4-1.1.1.1.1.1 4-1.1.2.1.1.1 5-1.1 5-1.2 5-1.3 7-1.1.2.1.3 8-1.1.2.1.2 9-1.1.1 11-1.1.1.1.1.1 11-1.1.2.1.1.1 14-1.1.3 17-1.1.3.1 26-1.1.3.2 30-1.1.1.1.1.1 30-1.1.2.1.1.1 30-1.2.2.2.1.1 33-1.2.2.3 34-1.2.2.3.2 38-1.2.3 41-1.2.3.1 50-1.2.3.2 52-1 54-1.1.1.2 55-1.1.1 57-1.1.1.1.1.1 57-1.2.2.2.1.1 60-1.2.2.3 61-1.2.2.3.2 65-1.3.3 67-1.3.3.2 68-1.3.3.2.1 77-1.3.3.1 (a2 / and~e.52 :op1 (c / correlate-01~e.5 :ARG1 (e / express-03~e.2,9,55 :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK"~e.4,11,30,57)) :mod (c2 / cytoplasm~e.1,54)) :ARG2 (e3 / express-03~e.2 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MAPK"~e.4,11,30) :mod (n3 / nucleus~e.8) :mod (t / total~e.0,7))) :ARG1-of (s2 / statistical-test-91~e.14 :ARG2 0.0126~e.17 :ARG3 0.1009~e.26)) :op2 (c3 / correlate-01~e.5 :ARG1 e :ARG2 (a3 / amino-acid :name (n5 / name :op1 "threonine") :part-of (e4 / enzyme :name (n4 / name :op1 "MAPK"~e.30,57)) :mod (s / slash~e.33,60 :op1 202 :op2 204~e.34,61)) :ARG1-of (s3 / statistical-test-91~e.38 :ARG2 0.0152~e.41 :ARG3 0.1044~e.50)) :op3 (c4 / correlate-01~e.5 :ARG1 e :ARG2 (e6 / express-03~e.2 :ARG2 (a4 / amino-acid :name (n6 / name :op1 "threonine") :mod s :part-of e2) :mod c2) :ARG1-of (s4 / statistical-test-91~e.65 :ARG3 0.3391~e.77 :ARG2 (l / less-than~e.67 :op1 0.0001~e.68)))) # ::id pmid_2155_9022.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total nuclear MAPK expression correlated very strongly with the activated form of MAPK ( Thr202 @/@ 204 ) in the nucleus ( P @ < 0.0001 , r @ ²@ = 0.3447 ) and pMAPK ( Thr202 @/@ 204 ) in the cytoplasm ( P @ = 0.0075 , r @ ²@ = 0.1250 ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.2 2-1.1.1.1.1.1 3-1.1.1 4-1.1 4-1.2 5-1.3.1 6-1.3 7-1.1.2.r 9-1.1.2.3.2 12-1.1.2.3.1.1 15-1.1.2.2 16-1.1.2.2.2 18-1.1.3.r 20-1.1.3 23-1.1.4 26-1.1.4.1 35-1.1.4.2 38-1.2.2.2.1.1 41-1.1.2.2 42-1.1.2.2.2 44-1.2.3.r 46-1.2.3 49-1.2.2.2.2 49-1.2.4 52-1.2.4.1 61-1.2.4.2 (a5 / and :op1 (c / correlate-01~e.4 :ARG1 (e / express-03~e.3 :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK"~e.2) :mod (t / total~e.0)) :mod (n2 / nucleus~e.1)) :ARG2~e.7 (a / amino-acid :name (n3 / name :op1 "threonine") :mod (s2 / slash~e.15,41 :op1 202 :op2 204~e.16,42) :part-of (e3 / enzyme :name (n4 / name :op1 "MAPK"~e.12) :ARG1-of (a2 / activate-01~e.9))) :location~e.18 (n5 / nucleus~e.20) :ARG1-of (s3 / statistical-test-91~e.23 :ARG2 0.0001~e.26 :ARG3 0.3447~e.35)) :op2 (c3 / correlate-01~e.4 :ARG1 e :ARG2 (a4 / amino-acid :name (n6 / name :op1 "threonine") :part-of (e4 / enzyme :name (n7 / name :op1 "MAPK"~e.38) :ARG3-of (p / phosphorylate-01~e.49)) :mod s2) :location~e.44 (c2 / cytoplasm~e.46) :ARG1-of (s4 / statistical-test-91~e.49 :ARG2 0.0075~e.52 :ARG3 0.1250~e.61)) :ARG1-of (s / strong-02~e.6 :degree (v / very~e.5))) # ::id pmid_2155_9022.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated cytoplasmic MAPK ( Thr202 @/@ 204 ) also very strongly associated with its activated expression ( MAPK pThr202 ) in the nucleus ( P @ < 0.0001 , r @ ²@ = 0.5210 ) . # ::alignments 0-1.1.2.3 0-1.2.5.2 1-1.1.2.2 2-1.1.2.1.1 5-1.1.3 6-1.1.3.2 8-1.4 9-1.3.1 10-1.3 11-1 14-1.2.5.2 15-1.2 15-1.2.5 15-1.2.5.r 17-1.2.4.1.1 20-1.2.5.1.r 22-1.2.5.1 25-1.2.3 25-1.5 27-1.5.2 28-1.5.2.1 37-1.5.1 (a / associate-01~e.11 :ARG1 (a3 / amino-acid :name (n / name :op1 "threonine") :part-of (e2 / enzyme :name (n2 / name :op1 "MAPK"~e.2) :mod (c / cytoplasm~e.1) :ARG1-of (a4 / activate-01~e.0)) :mod (s2 / slash~e.5 :op1 202 :op2 204~e.6)) :ARG2 (a5 / amino-acid~e.15 :mod 202 :name (n3 / name :op1 "threonine") :ARG3-of (p / phosphorylate-01~e.25) :part-of (e / enzyme :name (n4 / name :op1 "MAPK"~e.17)) :ARG2-of~e.15 (e3 / express-03~e.15 :ARG3~e.20 (n5 / nucleus~e.22) :ARG1-of (a6 / activate-01~e.0,14))) :ARG1-of (s / strong-02~e.10 :degree (v / very~e.9)) :mod (a2 / also~e.8) :ARG1-of (s3 / statistical-test-91~e.25 :ARG3 0.5210~e.37 :ARG2 (l / less-than~e.27 :op1 0.0001~e.28))) # ::id pmid_2155_9022.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , Raf @-@ 1 and pRaf ( Ser259 ) both correlated with the cytoplasmic expression of MAPK ( P @ < 0.0001 , r @ ²@ = 0.2979 and P @ = 0.0005 , r @ ²@ = 0.1879 , respectively ) and activated cytoplasmic MAPK ( Thr202 @/@ 204 ) ( P @ = 0.0007 , r @ ²@ = 0.1826 and P @ = 0.0069 , r @ ²@ = 0.1214 , respectively ) . # ::alignments 0-1 0-1.1 0-1.1.r 1-1 1-1.1 1-1.1.r 3-1.1.1.2.1.3.1.1 5-1.1.1.1.1.1.1 7-1.1.1.1.1.1.1 12-1.1.1.1 12-1.1.1.2 12-1.1.2.1 12-1.1.2.2 13-1.1.1.1.2.r 15-1.1.1.1.2.2 16-1.1.1.1.2 17-1.1.1.1.2.1.r 18-1.1.1.1.2.1.1.1 21-1.1.1.1.3 23-1.1.1.1.3.2 24-1.1.1.1.3.2.1 33-1.1.1.1.3.1 36-1.1.1.2.1.4 36-1.1.1.2.3 39-1.1.1.2.3.1 48-1.1.1.2.3.2 52-1.1 53-1.1.2.1.2.4 54-1.1.1.1.2.2 55-1.1.1.1.2.1.1.1 55-1.1.2.1.2.3.1.1 58-1.1.2.1.2.2 59-1.1.2.1.2.2.2 63-1.1.2.1.3 66-1.1.2.1.3.1 75-1.1.2.1.3.2 78-1.1.2.1.3 78-1.1.2.2.3 81-1.1.2.2.3.1 90-1.1.2.2.3.2 (a / and~e.0,1 :op2~e.0,1 (a4 / and~e.0,1,52 :op1 (a7 / and :op1 (c / correlate-01~e.12 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"~e.5,7)) :ARG2~e.13 (e14 / express-03~e.16 :ARG2~e.17 (e4 / enzyme :name (n4 / name :op1 "MAPK"~e.18,55)) :ARG3 (c2 / cytoplasm~e.15,54)) :ARG1-of (s2 / statistical-test-91~e.21 :ARG3 0.2979~e.33 :ARG2 (l / less-than~e.23 :op1 0.0001~e.24))) :op2 (c3 / correlate-01~e.12 :ARG1 (a5 / amino-acid :mod 259 :name (n2 / name :op1 "serine") :part-of (e3 / enzyme :name (n3 / name :op1 "Raf"~e.3)) :ARG3-of (p / phosphorylate-01~e.36)) :ARG2 e14 :ARG1-of (s3 / statistical-test-91~e.36 :ARG2 0.0005~e.39 :ARG3 0.1879~e.48))) :op2 (a8 / and :op1 (c4 / correlate-01~e.12 :ARG1 e :ARG2 (a2 / amino-acid :name (n5 / name :op1 "threonine") :mod (s / slash~e.58 :op1 202 :op2 204~e.59) :part-of (e2 / enzyme :name (n6 / name :op1 "MAPK"~e.55) :mod c2) :ARG1-of (a3 / activate-01~e.53)) :ARG1-of (s4 / statistical-test-91~e.63,78 :ARG2 0.0007~e.66 :ARG3 0.1826~e.75)) :op2 (c5 / correlate-01~e.12 :ARG1 a5 :ARG2 a2 :ARG1-of (s5 / statistical-test-91~e.78 :ARG2 0.0069~e.81 :ARG3 0.1214~e.90))))) # ::id pmid_2155_9022.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Raf @-@ 1 also correlated with nuclear activated MAPK ( Thr202 @/@ 204 ) ( P @ = 0.0022 , r @ ²@ = 0.1525 ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1.3 4-1 5-1.2.r 6-1.2.3 7-1.2.2 8-1.2.1.1 11-1.2.4.2 12-1.2.4.2.2 16-1.4 19-1.4.1 28-1.4.2 (c / correlate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"~e.0,2)) :ARG2~e.5 (e2 / enzyme :name (n2 / name :op1 "MAPK"~e.8) :ARG1-of (a / activate-01~e.7) :mod (n3 / nucleus~e.6) :part (a2 / amino-acid :name (n4 / name :op1 "threonine") :mod (s / slash~e.11 :op1 202 :op2 204~e.12))) :mod (a4 / also~e.3) :ARG1-of (s2 / statistical-test-91~e.16 :ARG2 0.0022~e.19 :ARG3 0.1525~e.28)) # ::id pmid_2155_9022.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There were no correlations seen between pRaf ( Ser338 ) and MAPK or pMAPK ( Thr202 @/@ 204 ) . # ::alignments 2-1.1 2-1.1.r 3-1.2 4-1 6-1.2.1.3.1.1 6-1.2.1.3.2 11-1.2.2.1.1.1 11-1.2.2.2.3.1.1 12-1.2.2 16-1.2.2.2.2 17-1.2.2.2.2.2 (s / see-01~e.4 :polarity~e.2 -~e.2 :ARG1 (c / correlate-01~e.3 :ARG1 (a / amino-acid :mod 338 :name (n / name :op1 "serine") :part-of (e2 / enzyme :name (n2 / name :op1 "Raf"~e.6) :ARG3-of (p / phosphorylate-01~e.6))) :ARG2 (o / or~e.12 :op1 (e3 / enzyme :name (n3 / name :op1 "MAPK"~e.11)) :op2 (a2 / amino-acid :name (n4 / name :op1 "threonine") :mod (s2 / slash~e.16 :op1 202 :op2 204~e.17) :part-of (e / enzyme :name (n5 / name :op1 "MAPK"~e.11) :ARG3-of p))))) # ::id pmid_2155_9022.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Relative protein expression levels in CRPC # ::alignments 1-1.2 2-1.1 3-1.1.1 4-1 (l / level~e.4 :quant-of (p / protein~e.2 :ARG2-of (e / express-03~e.3 :ARG3 (d2 / disease :name (n2 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")))) :ARG2-of (r / relative-05~e.1)) # ::id pmid_2155_9022.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In CRPC tumours , Raf @-@ 1 correlated with pRaf ( Ser259 ) strongly ( P @ = 0.0003 , r @ ²@ = 0.1778 ) . # ::alignments 2-1.4 4-1.2.4.2.1 6-1.1.2.1 7-1 9-1.1.2.1 9-1.2.4.3 13-1.3 16-1.2.4.3 16-1.5 19-1.5.1 28-1.5.2 (c / correlate-01~e.7 :ARG1 (e / enzyme :wiki "C-Raf" :name (n / name :op1 "Raf-1"~e.6,9)) :ARG2 (a2 / amino-acid :mod 259 :wiki "Serine" :name (n4 / name :op1 "serine") :part-of (e2 / enzyme :wiki "RAF_kinase" :name (n2 / name :op1 "Raf"~e.4) :ARG3-of (p / phosphorylate-01~e.9,16))) :manner (s / strong-02~e.13) :location (t / tumor~e.2 :mod (d3 / disease :wiki - :name (n5 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))) :ARG1-of (s2 / statistical-test-91~e.16 :ARG2 0.0003~e.19 :ARG3 0.1778~e.28)) # ::id pmid_2155_9022.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The nuclear and cytoplasmic forms of pRaf ( Ser338 ) also strongly correlated with each other ( P @ < 0.0001 , r @ ²@ = 0.6009 ) . # ::alignments 1-1.1.3 3-1.2.3 6-1.1.4.1.1 6-1.1.4.2 10-1.4 11-1.3 12-1 18-1.1.4.2 18-1.5 20-1.5.2 21-1.5.2.1 30-1.5.1 (c / correlate-01~e.12 :ARG1 (a3 / amino-acid :mod 338 :name (n5 / name :op1 "serine") :mod (n2 / nucleus~e.1) :part-of (e / enzyme :name (n / name :op1 "Raf"~e.6) :ARG3-of (p / phosphorylate-01~e.6,18))) :ARG2 (a / amino-acid :mod 338 :name (n3 / name :op1 "serine") :mod (c2 / cytoplasm~e.3) :part-of e) :manner (s / strong-02~e.11) :mod (a2 / also~e.10) :ARG1-of (s2 / statistical-test-91~e.18 :ARG3 0.6009~e.30 :ARG2 (l / less-than~e.20 :op1 0.0001~e.21))) # ::id pmid_2155_9022.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly to HNPC , protein expression of the inactive form of pRaf ( Ser259 ) and the active forms of pRaf ( Ser338 ) did not correlate in the cell cytoplasm or nucleus . # ::alignments 0-1.5 5-1.2 5-1.3 8-1.2.1 8-1.2.1.5 8-1.2.1.5.1 8-1.2.1.5.r 8-1.3.1 8-1.3.1.4 8-1.3.1.4.r 10-1.2.1.r 11-1.2.1.4.2.1 11-1.2.1.4.3 17-1.2.1 17-1.2.1.5 17-1.2.1.5.r 20-1.2.1.4.2.1 20-1.2.1.4.3 25-1.1 25-1.1.r 25-1.2.1.5.1.r 26-1 27-1.4.r 29-1.4.1.1 30-1.4.1 31-1.4 32-1.4.2 (c / correlate-01~e.26 :polarity~e.25 -~e.25 :ARG1 (e / express-03~e.5 :ARG2~e.10 (a2 / amino-acid~e.8,17 :mod 259 :wiki "Serine" :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :wiki "RAF_kinase" :name (n / name :op1 "Raf"~e.11,20) :ARG3-of (p2 / phosphorylate-01~e.11,20)) :ARG0-of~e.8,17 (a / activity-06~e.8,17 :polarity~e.25 -~e.8))) :ARG2 (e3 / express-03~e.5 :ARG2 (a4 / amino-acid~e.8 :mod 338 :wiki "Serine" :name (n4 / name :op1 "serine") :ARG0-of~e.8 (a3 / activity-06~e.8) :part-of e2)) :location~e.27 (o / or~e.31 :op1 (c2 / cytoplasm~e.30 :part-of (c3 / cell~e.29)) :op2 (n5 / nucleus~e.32 :part-of c3)) :ARG1-of (r / resemble-01~e.0 :ARG2 (d / disease :wiki - :name (n3 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer")))) # ::id pmid_2155_9022.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After the development of CRPC , cytoplasmic expression of total MAPK became strongly associated with the expression of total MAPK in the nucleus ( P @ =< 0.0001 , r @ ²@ = 0.2564 ) and more weakly with its activated form , pMAPK ( Thr202 @/@ 204 ) , in the nucleus ( P @ = 0.0194 , r @ ²@ = 0.0864 ) . # ::alignments 0-1.3 2-1.3.1 6-1.1.1.2 7-1.1.1 9-1.1.1.1 9-1.1.1.1.2 9-1.1.1.1.2.r 10-1.1.1.1.1.1 12-1.1.3 13-1.1 13-1.2 16-1.1.1 16-1.1.2 16-1.2.2 17-1.1.2.1.r 18-1.1.2.1 19-1.1.2.1 20-1.1.2.2.r 22-1.1.2.2 25-1.1.4 28-1.1.4.2.1 28-1.1.4.2.2.1 37-1.1.4.1 39-1 41-1.2.3 44-1.2.2.1.3 47-1.2.2.1.2.1.1 47-1.2.2.1.5 50-1.2.2.1.4 51-1.2.2.1.4.2 54-1.2.2.2.r 56-1.2.2.2 59-1.2.2.1.5 59-1.2.4 62-1.2.4.1 71-1.2.4.2 (a2 / and~e.39 :op1 (a / associate-01~e.13 :ARG1 (e / express-03~e.7,16 :ARG2 (e5 / enzyme~e.9 :name (n / name :op1 "MAPK"~e.10) :ARG1-of~e.9 (t / total-01~e.9)) :ARG3 (c / cytoplasm~e.6)) :ARG2 (e2 / express-03~e.16 :ARG2~e.17 e5~e.18,19 :ARG3~e.20 (n5 / nucleus~e.22)) :manner (s / strong-02~e.12) :ARG1-of (s3 / statistical-test-91~e.25 :ARG3 0.2564~e.37 :ARG2 (o / or :op1 0.0001~e.28 :op2 (l / less-than :op1 0.0001~e.28)))) :op2 (a3 / associate-01~e.13 :ARG1 e :ARG2 (e3 / express-03~e.16 :ARG2 (a5 / amino-acid :name (n4 / name :op1 "threonine") :part-of (e4 / enzyme :name (n3 / name :op1 "MAPK"~e.47)) :ARG1-of (a4 / activate-01~e.44) :mod (s2 / slash~e.50 :op1 202 :op2 204~e.51) :ARG3-of (p / phosphorylate-01~e.47,59)) :ARG3~e.54 n5~e.56) :manner (w / weak-02~e.41) :ARG1-of (s4 / statistical-test-91~e.59 :ARG2 0.0194~e.62 :ARG3 0.0864~e.71)) :time (a6 / after~e.0 :op1 (d / develop-02~e.2 :ARG1 (d4 / disease :name (n2 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytoplasmic expression of total MAPK continued to show a correlation with its activated form in the cytoplasm ( MAPK pThr202 @/@ 204 ) ( P @ = 0.0004 , r @ ²@ = 0.1861 ) . # ::alignments 0-1.2.2.2.2 1-1.1 1-1.2.2.2 2-1.1.1.r 3-1.1.1.2 4-1.1.1.1.1 5-1 7-1.2 9-1.2.2 10-1.2.2.1.r 11-1.2.2.1 12-1.2.2.2.1.2.2 14-1.1.2.r 16-1.1.2 18-1.2.2.2.1.2.1.1 20-1.2.2.2.1.3 21-1.2.2.2.1.3.2 25-1.2.2.3 28-1.2.2.3.1 37-1.2.2.3.2 (c / continue-01~e.5 :ARG0 (e / express-03~e.1 :ARG2~e.2 (e3 / enzyme :name (n / name :op1 "MAPK"~e.4) :mod (t / total~e.3)) :ARG3~e.14 (c2 / cytoplasm~e.16)) :ARG1 (s / show-01~e.7 :ARG0 e :ARG1 (c3 / correlate-01~e.9 :ARG1~e.10 e~e.11 :ARG2 (e2 / express-03~e.1 :ARG2 (a2 / amino-acid :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n2 / name :op1 "MAPK"~e.18) :ARG1-of (a / activate-01~e.12)) :mod (s2 / slash~e.20 :op1 202 :op2 204~e.21)) :ARG3 (c4 / cytoplasm~e.0)) :ARG1-of (s3 / statistical-test-91~e.25 :ARG2 0.0004~e.28 :ARG3 0.1861~e.37)))) # ::id pmid_2155_9022.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated cytoplasmic MAPK ( Thr202 @/@ 204 ) remained strongly associated with activated nuclear MAPK ( Thr202 @/@ 204 ) ( P @ < 0.0001 , r @ ²@ = 0.5350 ) . # ::alignments 0-1.1.4 1-1.1.3 2-1.1.2.1.1 5-1.1.5 6-1.1.5.2 8-1 9-1.2.3 10-1.2 11-1.2.2.r 12-1.2.2.4 13-1.2.2.3 14-1.2.2.2 17-1.1.5 17-1.2.2.5 18-1.1.5.2 18-1.2.2.5.2 22-1.2.4 24-1.2.4.2 25-1.2.4.2.1 34-1.2.4.1 (r / remain-01~e.8 :ARG1 (a / amino-acid :name (n / name :op1 "threonine") :part-of (e / enzyme :name (n2 / name :op1 "MAPK"~e.2)) :mod (c / cytoplasm~e.1) :ARG1-of (a2 / activate-01~e.0) :mod (s2 / slash~e.5,17 :op1 202 :op2 204~e.6,18)) :ARG2 (a3 / associate-01~e.10 :ARG1 a :ARG2~e.11 (a4 / amino-acid :name (n3 / name :op1 "threonine") :part-of e~e.14 :mod (n4 / nucleus~e.13) :ARG1-of a2~e.12 :mod (s3 / slash~e.17 :op1 202 :op2 204~e.18)) :ARG1-of (s / strong-02~e.9) :ARG1-of (s4 / statistical-test-91~e.22 :ARG3 0.5350~e.34 :ARG2 (l / less-than~e.24 :op1 0.0001~e.25)))) # ::id pmid_2155_9022.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Raf @-@ 1 showed similar associations with cytoplasmic and nuclear MAPK expression ( P @ < 0.0001 , r @ ²@ = 0.2141 and P @ = 0.0016 , r @ ²@ = 0.1426 , respectively ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2.1.3 5-1.2.1 5-1.2.2 7-1.2.1.2.2 8-1.2 9-1.2.2.2.2 10-1.2.1.2.1.1.1 11-1.2.1.2 11-1.2.2.2 14-1.2.1.4 16-1.2.1.4.2 17-1.2.1.4.2.1 26-1.2.1.4.1 27-1.2 29-1.2.2.4 32-1.2.2.4.1 41-1.2.2.4.2 (s / show-01~e.3 :ARG0 (e / enzyme :name (n / name :op1 "Raf-1"~e.0,2)) :ARG1 (a5 / and~e.8,27 :op1 (a / associate-01~e.5 :ARG1 e :ARG2 (e2 / express-03~e.11 :ARG2 (e4 / enzyme :name (n2 / name :op1 "MAPK"~e.10)) :ARG3 (c / cytoplasm~e.7)) :ARG1-of (r / resemble-01~e.4) :ARG1-of (s2 / statistical-test-91~e.14 :ARG3 0.2141~e.26 :ARG2 (l / less-than~e.16 :op1 0.0001~e.17))) :op2 (a6 / associate-01~e.5 :ARG1 e :ARG2 (e3 / express-03~e.11 :ARG2 e4 :ARG3 (n3 / nucleus~e.9)) :ARG1-of r :ARG1-of (s3 / statistical-test-91~e.29 :ARG2 0.0016~e.32 :ARG3 0.1426~e.41)))) # ::id pmid_2155_9022.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cytoplasmic MAPK also correlated with pRaf ( Ser259 ) ( P @ = 0.0026 , r @ ²@ = 0.1329 ) . # ::alignments 0-1.1.2 1-1.1.1.1 2-1.3 3-1 4-1.2.r 5-1.2.3.1.1 5-1.2.3.2 11-1.2.3.2 11-1.4 14-1.4.1 23-1.4.2 (c / correlate-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "MAPK"~e.1) :mod (c2 / cytoplasm~e.0)) :ARG2~e.4 (a2 / amino-acid :mod 259 :name (n2 / name :op1 "serine") :part-of (p3 / protein-family :name (n3 / name :op1 "Raf"~e.5) :ARG3-of (p2 / phosphorylate-01~e.5,11))) :mod (a / also~e.2) :ARG1-of (s / statistical-test-91~e.11 :ARG2 0.0026~e.14 :ARG3 0.1329~e.23)) # ::id pmid_2155_9022.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly to HNPC tumours , no correlations were noted between pRaf ( Ser338 ) and MAPK in any location or form . # ::alignments 0-1.3 3-1.3.1 5-1.1 5-1.1.r 6-1.2 8-1 10-1.2.1.3.1.1 10-1.2.1.3.2 15-1.2.2.1.1 16-1.2.3.r 17-1.2.3.1 17-1.2.4.1 18-1.2.3 20-1.2.4 (n / note-01~e.8 :polarity~e.5 -~e.5 :ARG1 (c / correlate-01~e.6 :ARG1 (a / amino-acid :mod 338 :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf"~e.10) :ARG3-of (p / phosphorylate-01~e.10))) :ARG2 (e / enzyme :name (n4 / name :op1 "MAPK"~e.15)) :location~e.16 (l / location~e.18 :mod (a2 / any~e.17)) :manner (f / form~e.20 :mod (a3 / any~e.17))) :ARG1-of (r / resemble-01~e.0 :ARG2 (t / tumor~e.3 :mod (d / disease :name (n5 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Relative expression levels of Raf @-@ 1 and MAPK compared with upstream and downstream targets in hormone @-@ naïve prostate cancer # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1 7-1.1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2.1.1 10-1 11-1.2.r 12-1.2.1.1 13-1.2 14-1.2.2.1 15-1.2.1 15-1.2.2 16-1.3.r 17-1.3.1.1 19-1.3.1.1 20-1.3.1.2 21-1.3.1.3 (c / compare-01~e.10 :ARG1 (l / level~e.3 :degree-of (e / express-03~e.2 :ARG2~e.4 (a / and~e.8 :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"~e.5,7)) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK"~e.9))) :ARG2-of (r / relative-05~e.1))) :ARG2~e.11 (a3 / and~e.13 :op1 (t / target-01~e.15 :location (u / upstream~e.12)) :op2 (t2 / target-01~e.15 :location (d / downstream~e.14))) :location~e.16 (d2 / disease :name (n3 / name :op1 "hormone-naïve"~e.17,19 :op2 "prostate"~e.20 :op3 "cancer"~e.21))) # ::id pmid_2155_9022.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of the upstream activators EGFR and Her2 , as well as the downstream targets AR and AP @-@ 1 , has previously been carried out on the same cohort of patients ( Edwards et al , 2003a , 2004 ; Bartlett et al , 2005 ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.2 4-1.1.1.1 5-1.1.1.1.1.1.1.1 6-1.1.1.1.1 7-1.1.1.1.1.2.1.1 9-1.4.1 9-1.4.1.1.1 9-1.4.1.2.1 10-1.1.1 10-1.4.1 10-1.4.1.1.1 10-1.4.1.2.1 11-1.2.r 11-1.4.1 11-1.4.1.1.1 11-1.4.1.2.1 13-1.1.1.2.2 14-1.1.1.2 15-1.1.1.2.1.1.1.1 16-1.1.1.2.1 17-1.1.1.2.1.2.1.1 19-1.1.1.2.1.2.1.1 22-1.2 24-1 25-1 26-1.3.r 28-1.3.2 29-1.3 30-1.3.1.r 31-1.3.1.1.1 34-1.4.1.1.1.1.1.1 36-1.4.1.1.1 37-1.4.1.1.1.2.1 44-1.4.1.1.2.2.1 48-1.4.1.2.1.1.1.1 50-1.4.1 50-1.4.1.1.1 50-1.4.1.1.2 50-1.4.1.2.1 51-1.4.1.1.1.2.1 54-1.4.1.2.2.1 (c / carry-out-03~e.24,25 :ARG1 (a / analyze-01~e.0 :ARG1~e.1 (a4 / and~e.10 :op1 (a2 / activate-01~e.4 :ARG0 (a3 / and~e.6 :op1 (e / enzyme :name (n / name :op1 "EGFR"~e.5)) :op2 (e2 / enzyme :name (n4 / name :op1 "Her2"~e.7))) :mod (u / upstream~e.3)) :op2 (t / target-01~e.14 :ARG1 (a5 / and~e.16 :op1 (e3 / enzyme :name (n2 / name :op1 "AR"~e.15)) :op2 (p2 / protein :name (n3 / name :op1 "AP-1"~e.17,19))) :mod (d / downstream~e.13)))) :time~e.11 (p3 / previous~e.22) :instrument~e.26 (c2 / cohort~e.29 :consist-of~e.30 (p4 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient~e.31))) :ARG1-of (s / same-01~e.28)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and~e.9,10,11,50 :op1 (p6 / publication-91 :ARG0 (a7 / and~e.9,10,11,36,50 :op1 (p7 / person :name (n5 / name :op1 "Edwards"~e.34)) :op2 (p8 / person :mod (o / other~e.37,51))) :time (a8 / and~e.50 :op1 (d4 / date-entity :year 2003) :op2 (d5 / date-entity :year 2004~e.44))) :op2 (p9 / publication-91 :ARG0 (a9 / and~e.9,10,11,50 :op1 (p10 / person :name (n9 / name :op1 "Bartlett"~e.48)) :op2 p8) :time (d3 / date-entity :year 2005~e.54))))) # ::id pmid_2155_9022.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore correlated Raf @-@ 1 and MAPK expression with these previous results , to determine the differences in the entire pathway in the transition from HNPC to CRPC . # ::alignments 0-1.1.1 1-1 2-1.1 3-1.1.2.1.1.1.1 5-1.1.2.1.1.1.1 6-1.1.2 7-1.1.2.2.1.1.1 8-1.1.2.1 8-1.1.2.2 9-1.1.3.r 10-1.1.3.2 11-1.1.3.1 12-1.1.3 12-1.1.3.3 12-1.1.3.3.r 15-1.1.4 17-1.1.4.2 18-1.1.4.2.1.r 20-1.1.4.2.1.1 21-1.1.4.2.1 22-1.1.4.2.2.r 24-1.1.4.2.2 27-1 (c / cause-01~e.1,27 :ARG1 (c2 / correlate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / and~e.6 :op1 (e / express-03~e.8 :ARG2 (e2 / enzyme :name (n / name :op1 "Raf-1"~e.3,5))) :op2 (e3 / express-03~e.8 :ARG2 (e5 / enzyme :name (n2 / name :op1 "MAPK"~e.7)))) :ARG2~e.9 (t3 / thing~e.12 :time (p2 / previous~e.11) :mod (t / this~e.10) :ARG2-of~e.12 (r / result-01~e.12)) :purpose (d / determine-01~e.15 :ARG0 w :ARG1 (d2 / differ-02~e.17 :ARG3~e.18 (p3 / pathway~e.21 :mod (e4 / entire~e.20)) :time~e.22 (t2 / transition-01~e.24 :ARG2 (d4 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")) :ARG3 (d3 / disease :name (n4 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer"))))))) # ::id pmid_2155_9022.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In hormone @-@ naïve tumours , expression of the putative growth factor receptor Her2 correlated with Raf @-@ 1 expression ( P @ = 0.0099 , r @ ²@ = 0.1333 ) and the nuclear and cytoplasmic expression of pMAPK ( Thr202 @/@ 204 ) ( P @ = 0.0150 , r @ ²@ = 0.1300 and P @ = 0.0017 , r @ ²@ = 0.2074 , respectively ) . # ::alignments 1-1.3.1 3-1.3.1 4-1.3 6-1.1 10-1.1.1.1.1 11-1.1.1.1.2 12-1.1.1.1.3 13-1.1.1.1.4 14-1 16-1.2.1.1.1.1 18-1.2.1.1.1.1 19-1.1 22-1.2.1.2 25-1.2.1.2.1 34-1.2.1.2.2 36-1.2.2 38-1.2.2.1.2 39-1.2.2 40-1.2.2.2.2 41-1.2.1 41-1.2.2.1 41-1.2.2.2 42-1.2.2.1.1.r 43-1.2.2.1.1.2.1.1 43-1.2.2.1.1.2.2 46-1.2.2.1.1.3 47-1.2.2.1.1.3.2 51-1.2.2.1.3 54-1.2.2.1.3.1 54-1.2.2.1.3.2 64-1.2.2 66-1.2.2.2.3 69-1.2.2.2.3.1 78-1.2.2.2.3.2 (c / correlate-01~e.14 :ARG1 (e / express-03~e.6,19 :ARG2 (e10 / enzyme :name (n7 / name :op1 "growth"~e.10 :op2 "factor"~e.11 :op3 "receptor"~e.12 :op4 "Her2"~e.13))) :ARG2 (a / and :op1 (e3 / express-03~e.41 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Raf-1"~e.16,18)) :ARG1-of (s2 / statistical-test-91~e.22 :ARG2 0.0099~e.25 :ARG3 0.1333~e.34)) :op2 (a2 / and~e.36,39,64 :op1 (e5 / express-03~e.41 :ARG2~e.42 (a3 / amino-acid :name (n5 / name :op1 "threonine") :part-of (e2 / enzyme :name (n6 / name :op1 "MAPK"~e.43) :ARG3-of (p3 / phosphorylate-01~e.43)) :mod (s / slash~e.46 :op1 202 :op2 204~e.47)) :ARG3 (n4 / nucleus~e.38) :ARG1-of (s3 / statistical-test-91~e.51 :ARG2 0.0150~e.54 :ARG3 0.0150~e.54)) :op2 (e6 / express-03~e.41 :ARG2 a3 :ARG3 (c2 / cytoplasm~e.40) :ARG1-of (s4 / statistical-test-91~e.66 :ARG2 0.0017~e.69 :ARG3 0.2074~e.78)))) :location (t / tumor~e.4 :mod (h / hormone-naive~e.1,3))) # ::id pmid_2155_9022.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Once activated , the phosphorylated form of Her2 ( pHer2 ) showed moderate correlations with Raf @-@ 1 ( P @ = 0.0056 , r @ ²@ = 0.1435 ) , pRaf ( Ser259 ) ( P @ = 0.0052 , r @ ²@ = 0.1459 ) and cytoplasmic MAPK expression ( P @ = 0.0123 , r @ ²@ = 0.1211 ) ( Figure 4 ) , but not the activated forms of Raf or MAPK . # ::alignments 0-1.1.2.1.2.1.1 1-1.1.4 4-1.1.1.2 7-1.1.1.1.1 11-1.1 11-1.2 12-1.1.2.1.3 13-1.1.2.1 13-1.1.2.2 13-1.1.2.3 13-1.2.3 15-1.1.2.1.2.1.1 17-1.1.2.1.2.1.1 20-1.1.2.1.4 23-1.1.2.1.4.1 32-1.1.2.1.4.2 35-1.1.2.2.2.3.1.1 41-1.1.2.2.3 44-1.1.2.2.3.1 53-1.1.2.2.3.2 55-1.1.2 56-1.1.2.3.2.2 57-1.1.2.3.2.1.1.1 58-1.1.2.3.2 61-1.1.2.3.3 64-1.1.2.3.3.1 73-1.1.2.3.3.2 77-1.1.3.1 78-1.1.3.1.1 82-1 83-1.2.1 83-1.2.1.r 85-1.1.4 85-1.2.3.2.1.2 87-1.2.3.2.r 88-1.2.3.2.1.1.1 90-1.2.3.2.2.1.1 (c3 / contrast-01~e.82 :ARG1 (s / show-01~e.11 :ARG0 (e / enzyme :name (n / name :op1 "Her2"~e.7) :ARG3-of (p / phosphorylate-01~e.4)) :ARG1 (a6 / and~e.55 :op1 (c / correlate-01~e.13 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf-1"~e.0,15,17)) :ARG1-of (m / moderate-03~e.12) :ARG1-of (s3 / statistical-test-91~e.20 :ARG2 0.0056~e.23 :ARG3 0.1435~e.32)) :op2 (c6 / correlate-01~e.13 :ARG1 e :ARG2 (a3 / amino-acid :mod 259 :name (n4 / name :op1 "serine") :part-of (e3 / enzyme :name (n3 / name :op1 "Raf"~e.35) :ARG3-of p)) :ARG1-of (s4 / statistical-test-91~e.41 :ARG2 0.0052~e.44 :ARG3 0.1459~e.53)) :op3 (c7 / correlate-01~e.13 :ARG1 e :ARG2 (e4 / express-03~e.58 :ARG2 (e7 / enzyme :name (n5 / name :op1 "MAPK"~e.57)) :ARG3 (c2 / cytoplasm~e.56)) :ARG1-of (s5 / statistical-test-91~e.61 :ARG2 0.0123~e.64 :ARG3 0.1211~e.73))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.77 :mod 4~e.78)) :time (a / activate-01~e.1,85 :ARG1 e)) :ARG2 (s2 / show-01~e.11 :polarity~e.83 -~e.83 :ARG0 e :ARG1 (c4 / correlate-01~e.13 :ARG1 e :ARG2~e.87 (a4 / and :op1 (e5 / enzyme :name (n6 / name :op1 "Raf"~e.88) :ARG1-of (a5 / activate-01~e.85)) :op2 (e6 / enzyme :name (n7 / name :op1 "MAPK"~e.90) :ARG1-of a5))))) # ::id pmid_2155_9022.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No correlations were seen with EGFR in HNPC tumours , except weak correlations with Raf @-@ 1 ( P @ = 0.0439 , r @ ²@ = 0.06008 ) and pMAPK ( Thr202 @/@ 204 ) ( nuclear ) ( P @ = 0.0243 , r @ ²@ = 0.0844 ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 3-1 4-1.1.2.r 5-1.1.2.1.1 8-1.2 10-1.1.3 11-1.1.3.1.3 12-1.1.3.1.1 12-1.1.3.1.2 13-1.1.3.1.1.2.r 14-1.1.3.1.1.2.1.1 16-1.1.3.1.1.2.1.1 19-1.1.3.1.1.3 22-1.1.3.1.1.3.1 31-1.1.3.1.1.3.2 33-1.1.3.1 34-1.1.3.1.2.2.2.1.1 34-1.1.3.1.2.2.2.2 37-1.1.3.1.2.2.4 38-1.1.3.1.2.2.4.2 41-1.1.3.1.2.2.3 45-1.1.3.1.2.3 48-1.1.3.1.2.3.1 57-1.1.3.1.2.3.2 (s / see-01~e.3 :ARG1 (c / correlate-01~e.1 :polarity~e.0 -~e.0 :ARG2~e.4 (e / enzyme :name (n / name :op1 "EGFR"~e.5)) :ARG2-of (e2 / except-01~e.10 :ARG1 (a3 / and~e.33 :op1 (c2 / correlate-01~e.12 :ARG1 e :ARG2~e.13 (e3 / enzyme :name (n2 / name :op1 "Raf-1"~e.14,16)) :ARG1-of (s3 / statistical-test-91~e.19 :ARG2 0.0439~e.22 :ARG3 0.06008~e.31)) :op2 (c4 / correlate-01~e.12 :ARG1 e :ARG2 (a2 / amino-acid :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n4 / name :op1 "MAPK"~e.34) :ARG3-of (p3 / phosphorylate-01~e.34)) :mod (n5 / nucleus~e.41) :mod (s2 / slash~e.37 :op1 202 :op2 204~e.38)) :ARG1-of (s4 / statistical-test-91~e.45 :ARG2 0.0243~e.48 :ARG3 0.0844~e.57)) :ARG1-of (w / weak-02~e.11)))) :location (t / tumor~e.8 :mod (d / disease :name (n6 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer")))) # ::id pmid_2155_9022.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the mutant variant , EGFR vIII , did correlate strongly with cytoplasmic expression of MAPK ( P @ < 0.0001 , r @ ²@ = 0.2617 ) and to a weaker extent with Raf @-@ 1 ( P @ = 0.025 , r @ ²@ = 0.07965 ) and pRaf ( Ser259 ) ( P @ = 0.0323 , r @ ²@ = 0.07295 ) . # ::alignments 0-1 3-1.1.1.1.1 4-1.1.1.1 6-1.1.1.1.2.1.1.1 7-1.1.1.1.2.1.1.2 10-1.1.1 10-1.1.2 11-1.1.1.3 12-1.1.1.2.r 13-1.1.1.2.2 14-1.1.1.2 15-1.1.1.2.1.r 16-1.1.1.2.1.1.1 19-1.1.1.4 21-1.1.1.4.2 22-1.1.1.4.2.1 31-1.1.1.4.1 33-1.1 34-1.1.2.3.r 36-1.1.2.3.1 37-1.1.2.3 38-1.1.2.2.r 39-1.1.2.2.2.3.1.1 41-1.1.2.2.1.1.1 44-1.1.2.2.1.2 47-1.1.2.2.1.2.1 56-1.1.2.2.1.2.2 59-1.1.2.2.2.3.2 65-1.1.2.2.2.3.2 65-1.1.2.2.2.4 68-1.1.2.2.2.4.1 77-1.1.2.2.2.4.2 (c4 / contrast-01~e.0 :ARG2 (a / and~e.33 :op1 (c / correlate-01~e.10 :ARG1 (v / variant~e.4 :ARG2-of (m / mutate-01~e.3) :ARG1-of (d / describe-01 :ARG2 (e / enzyme :name (n / name :op1 "EGFR"~e.6 :op2 "vIII"~e.7)))) :ARG2~e.12 (e2 / express-03~e.14 :ARG2~e.15 (e6 / enzyme :name (n2 / name :op1 "MAPK"~e.16)) :ARG3 (c2 / cytoplasm~e.13)) :manner (s / strong-02~e.11) :ARG1-of (s2 / statistical-test-91~e.19 :ARG3 0.2617~e.31 :ARG2 (l / less-than~e.21 :op1 0.0001~e.22))) :op2 (c3 / correlate-01~e.10 :ARG1 v :ARG2~e.38 (a2 / and :op1 (e4 / enzyme :name (n3 / name :op1 "Raf-1"~e.41) :ARG1-of (s3 / statistical-test-91~e.44 :ARG2 0.025~e.47 :ARG3 0.07965~e.56)) :op2 (a3 / amino-acid :mod 259 :name (n4 / name :op1 "serine") :part-of (e5 / enzyme :name (n5 / name :op1 "Raf"~e.39) :ARG3-of (p4 / phosphorylate-01~e.59,65)) :ARG1-of (s4 / statistical-test-91~e.65 :ARG2 0.0323~e.68 :ARG3 0.07295~e.77))) :degree~e.34 (e3 / extent~e.37 :ARG1-of (w / weak-02~e.36))))) # ::id pmid_2155_9022.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further downstream , activated pRaf ( Ser338 ) in the cytoplasm strongly correlated with phosphorylated c @-@ jun ( P @ = 0.0009 , r @ ²@ = 0.2673 ) and total MAPK ( cytoplasmic ) correlated weakly with c @-@ Fos ( P @ = 0.0453 , r @ ²@ = 0.09418 ) ( Figure 5 ) . # ::alignments 0-1.3.1 1-1.3 3-1.1.1.3.3 4-1.1.1.3.1.1 4-1.1.1.3.2 8-1.1.1.3.3.1.r 10-1.1.1.3.3.1 11-1.1.3 12-1.1 14-1.1.1.3.2 15-1.1.2.1.1 17-1.1.2.1.1 20-1.1.1.3.2 20-1.1.4 23-1.1.4.1 32-1.1.4.2 34-1 35-1.2.1.3 36-1.2.1.1.1 38-1.2.1.2 40-1.2 41-1.2.3 42-1.2.2.r 43-1.2.2.1.1 45-1.2.2.1.1 48-1.2.4 51-1.2.4.1 60-1.2.4.2 64-1.4.1 65-1.4.1.1 (a3 / and~e.34 :op1 (c / correlate-01~e.12 :ARG1 (a / amino-acid :mod 338 :name (n2 / name :op1 "serine") :part-of (e / enzyme :name (n / name :op1 "Raf"~e.4) :ARG3-of (p / phosphorylate-01~e.4,14,20) :ARG1-of (a2 / activate-01~e.3 :location~e.8 (c2 / cytoplasm~e.10)))) :ARG2 (p2 / protein :name (n3 / name :op1 "c-jun"~e.15,17) :ARG3-of p) :manner (s / strong-02~e.11) :ARG1-of (s2 / statistical-test-91~e.20 :ARG2 0.0009~e.23 :ARG3 0.2673~e.32)) :op2 (c3 / correlate-01~e.40 :ARG1 (e4 / enzyme :name (n4 / name :op1 "MAPK"~e.36) :mod (c4 / cytoplasm~e.38) :mod (t / total~e.35)) :ARG2~e.42 (p5 / protein :name (n5 / name :op1 "c-Fos"~e.43,45)) :ARG1-of (w / weak-02~e.41) :ARG1-of (s3 / statistical-test-91~e.48 :ARG2 0.0453~e.51 :ARG3 0.09418~e.60)) :location (d / downstream~e.1 :degree (f / further~e.0)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.64 :mod 5~e.65))) # ::id pmid_2155_9022.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There were no correlations seen between MAPK and its activated form with c @-@ jun , phospho c @-@ Jun or c @-@ Fos . # ::alignments 2-1.1.1 2-1.1.1.r 3-1.1 4-1 6-1.1.2.1.1.1 6-1.1.2.2.1.1 7-1.1.2 9-1.1.2.2.2 11-1.1.3.r 12-1.1.3.1.1.1 12-1.1.3.2.1.1 12-1.1.3.3.1.1 14-1.1.3.1.1.1 14-1.1.3.2.1.1 16-1.1.3.2.2 17-1.1.3.1.1.1 17-1.1.3.2.1.1 17-1.1.3.3.1.1 19-1.1.3.1.1.1 19-1.1.3.2.1.1 20-1.1.3 21-1.1.3.1.1.1 21-1.1.3.2.1.1 21-1.1.3.3.1.1 23-1.1.3.3.1.1 (s / see-01~e.4 :ARG1 (c / correlate-01~e.3 :polarity~e.2 -~e.2 :ARG1 (a / and~e.7 :op1 (e / enzyme :name (n / name :op1 "MAPK"~e.6)) :op2 (e2 / enzyme :name (n2 / name :op1 "MAPK"~e.6) :ARG1-of (a2 / activate-01~e.9))) :ARG2~e.11 (o / or~e.20 :op1 (p3 / protein :name (n3 / name :op1 "c-jun"~e.12,14,17,19,21)) :op2 (p4 / protein :name (n4 / name :op1 "c-Jun"~e.12,14,17,19,21) :ARG3-of (p5 / phosphorylate-01~e.16)) :op3 (p6 / protein :name (n5 / name :op1 "c-Fos"~e.12,17,21,23))))) # ::id pmid_2155_9022.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , PSA showed weak correlations with Raf @-@ 1 ( P @ = 0.0142 , r @ ²@ = 0.09604 ) , pRaf ( Ser259 ) ( P @ = 0.043 , r @ ²@ = 0.06547 ) , and showed links to overall MAPK levels , MAPK ( nuclear ) ( P @ = 0.0029 , r @ ²@ = 0.1502 ) and MAPK ( cytoplasmic ) ( P @ < 0.0001 , r @ ²@ = 0.2467 ) , with strong ties to the activated forms , pMAPK ( Thr202 @/@ 204 ) ( cytoplasmic ) ( P @ < 0.0001 , r @ ²@ = 0.2891 ) and pMAPK ( Thr202 @/@ 204 ) ( nuclear ) ( P @ = 0.0001 , r @ ²@ = 0.2233 ) ( Figure 6 ) , whereas AR showed no correlations with Raf , MAPK or any of their forms . # ::alignments 0-1.1.1.2 1-1.1.1.2 1-1.1.1.2.1.2 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.3 6-1.1.1.2.1 7-1.1.1.2.1.2.r 8-1.1.1.2.1.2.1.1.1 10-1.1.1.2.1.2.1.1.1 13-1.1.1.2.1.2.1.2 16-1.1.1.2.1.2.1.2.1 25-1.1.1.2.1.2.1.2.2 28-1.1.1.2.1.2.2.3.1.1 28-1.1.1.2.1.2.2.3.2 34-1.1.1.2.1.2.2.3.2 34-1.1.1.2.1.2.2.4 37-1.1.1.2.1.2.2.4.1 46-1.1.1.2.1.2.2.4.2 49-1.1.1.2 50-1.1.1 51-1.1.1.2.2 52-1.1.1.2.2.2.r 53-1.1.1.2.2.2.1.2 54-1.1.1.2.2.2.1.1.1.1 55-1.1.1.2.2.2.1 57-1.1.1.2.2.2.1.1.1.1 57-1.1.1.2.2.2.2.1.1 57-1.1.1.2.2.2.3.1.1 59-1.1.1.2.2.2.2.2 63-1.1.1.2.2.2.2.3 66-1.1.1.2.2.2.2.3.1 75-1.1.1.2.2.2.2.3.2 78-1.1.1.2.2.2.1.1.1.1 78-1.1.1.2.2.2.2.1.1 78-1.1.1.2.2.2.3.1.1 80-1.1.1.2.2.2.3.2 84-1.1.1.2.2.2.3.3 86-1.1.1.2.2.2.3.3.2 87-1.1.1.2.2.2.3.3.2.1 96-1.1.1.2.2.2.3.3.1 99-1.1.1.2.r 100-1.1.1.2.3.3 101-1.1.1.2.3 102-1.1.1.2.3.2.r 104-1.1.1.2.3.2.3 105-1.1.2.2.3.3 107-1.1.1.2.1.2.2.3.2 107-1.1.1.2.3.2.1.2.2.1 107-1.1.1.2.3.2.1.2.3 110-1.1.1.2.3.2.1.4 111-1.1.1.2.3.2.1.4.2 114-1.1.1.2.3.2.1.3 118-1.1.1.2.3.2.1.2.3 118-1.1.1.2.3.2.1.5 120-1.1.1.2.3.2.1.5.2 121-1.1.1.2.3.2.1.5.2.1 130-1.1.1.2.3.2.1.5.1 133-1.1.1.2.3.2.1.2.2.1 133-1.1.1.2.3.2.1.2.3 136-1.1.1.2.3.2.1.4 137-1.1.1.2.3.2.1.4.2 140-1.1.1.2.3.2.2.3 144-1.1.1.2.3.2.1.2.3 144-1.1.1.2.3.2.2.5 147-1.1.1.2.3.2.1.2.1 147-1.1.1.2.3.2.2.5.1 156-1.1.1.2.3.2.2.5.2 160-1.1.1.3.1 161-1.1.1.3.1.1 165-1.1 166-1.1.2.1.1.1 167-1.1.2 168-1.1.2.2.1 168-1.1.2.2.1.r 169-1.1.2.2 170-1.1.2.2.3.r 171-1.1.2.2.3.1.1.1 173-1.1.2.2.3.2.1.1 174-1.1.2.2.3 175-1.1.2.2.3.3.1 178-1.1.2.2.3.3 (a / and :op2 (c4 / contrast-01~e.165 :ARG1 (s / show-01~e.4,50 :ARG0 (e4 / enzyme :name (n14 / name :op1 "PSA"~e.3)) :ARG1~e.99 (a3 / and~e.0,1,49 :op1 (c / correlate-01~e.6 :ARG1 e4 :ARG2~e.7 (a5 / and~e.1 :op1 (e / enzyme :name (n / name :op1 "Raf-1"~e.8,10) :ARG1-of (s5 / statistical-test-91~e.13 :ARG2 0.0142~e.16 :ARG3 0.09604~e.25)) :op2 (a6 / amino-acid :mod 259 :name (n2 / name :op1 "serine") :part-of (e6 / enzyme :name (n3 / name :op1 "Raf"~e.28) :ARG3-of (p2 / phosphorylate-01~e.28,34,107)) :ARG1-of (s6 / statistical-test-91~e.34 :ARG2 0.043~e.37 :ARG3 0.06547~e.46))) :ARG1-of (w / weak-02~e.5)) :op2 (l / link-01~e.51 :ARG1 e4 :ARG2~e.52 (a13 / and :op1 (l2 / level~e.55 :quant-of (e2 / enzyme :name (n4 / name :op1 "MAPK"~e.54,57,78)) :mod (o / overall~e.53)) :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK"~e.57,78) :mod (n6 / nucleus~e.59) :ARG1-of (s7 / statistical-test-91~e.63 :ARG2 0.0029~e.66 :ARG3 0.1502~e.75)) :op3 (e10 / enzyme :name (n7 / name :op1 "MAPK"~e.57,78) :mod (c2 / cytoplasm~e.80) :ARG1-of (s8 / statistical-test-91~e.84 :ARG3 0.2467~e.96 :ARG2 (l3 / less-than~e.86 :op1 0.0001~e.87))))) :op3 (t / tie-01~e.101 :ARG1 e4 :ARG2~e.102 (a8 / and :op1 (a9 / amino-acid :name (n8 / name :op1 "threonine") :part-of (e9 / enzyme :quant 0.0001~e.147 :name (n9 / name :op1 "MAPK"~e.107,133) :ARG3-of (p11 / phosphorylate-01~e.107,118,133,144)) :mod (c3 / cytoplasm~e.114) :mod (s4 / slash~e.110,136 :op1 202 :op2 204~e.111,137) :ARG1-of (s9 / statistical-test-91~e.118 :ARG3 0.2891~e.130 :ARG2 (l4 / less-than~e.120 :op1 0.0001~e.121))) :op2 (a10 / amino-acid :name (n10 / name :op1 "threonine") :part-of e9 :mod (n11 / nucleus~e.140) :mod s4 :ARG1-of (s10 / statistical-test-91~e.144 :ARG2 0.0001~e.147 :ARG3 0.2233~e.156)) :ARG1-of (a7 / activate-01~e.104)) :ARG1-of (s2 / strong-02~e.100))) :ARG1-of (d3 / describe-01 :ARG2 (f2 / figure~e.160 :mod 6~e.161))) :ARG2 (s3 / show-01~e.167 :ARG0 (e5 / enzyme :name (n15 / name :op1 "AR"~e.166)) :ARG2 (c5 / correlate-01~e.169 :polarity~e.168 -~e.168 :ARG1 e5 :ARG2~e.170 (o2 / or~e.174 :op1 (e8 / enzyme :name (n12 / name :op1 "Raf"~e.171)) :op2 (e7 / enzyme :name (n13 / name :op1 "MAPK"~e.173)) :op3 (f3 / form~e.105,178 :mod (a11 / any~e.175) :poss (a12 / and :op1 e8 :op2 e7))))))) # ::id pmid_2155_9022.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Relative expression levels of Raf @-@ 1 and MAPK compared with upstream and downstream targets in CRPC # ::alignments 1-1.1.1 2-1.1.2 3-1.1 4-1.1.2.1.r 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 8-1.1.2.1 9-1.1.2.1.2.1.1 10-1 11-1.2.r 12-1.2.1.1 13-1.2 14-1.2.2.1 15-1.2.1 15-1.2.2 (c / compare-01~e.10 :ARG1 (l / level~e.3 :ARG2-of (r / relative-05~e.1) :degree-of (e / express-03~e.2 :ARG2~e.4 (a / and~e.8 :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"~e.5,7)) :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK"~e.9))))) :ARG2~e.11 (a2 / and~e.13 :op1 (t / target-01~e.15 :mod (u / upstream~e.12)) :op2 (t2 / target-01~e.15 :mod (d / downstream~e.14))) :location (d2 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))) # ::id pmid_2155_9022.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After the development of CRPC , Her2 no longer showed a correlation with Raf @-@ 1 nor a negative association became evident between pRaf ( Ser338 ) both in the cytoplasm ( P @ = 0.0035 , r @ ²@ = 0.1854 ) and nucleus ( P @ = 0.0068 , r @ ²@ = 0.1581 ) with Her2 . # ::alignments 0-1.3 2-1.3.1 6-1.1.1.1.1 7-1.2.1.r 8-1.1.3 9-1.1 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2.1.1 15-1.1.2.2.1.1 16-1.2.1 16-1.2.1.r 18-1.2.2.3 19-1.2.2 21-1.2 23-1.2.2.1.3.1.1 23-1.2.2.1.3.2 30-1.2.2.1.4.1 33-1.2.2.1.4.1.1 36-1.2.2.1.4.1.1.1 45-1.2.2.1.4.1.1.2 47-1.2.2.1.4 48-1.2.2.1.4.2 51-1.2.2.1.4.2.1 54-1.2.2.1.4.2.1.1 63-1.2.2.1.4.2.1.2 65-1.2.2.2.r 66-1.2.2.2 (a / and :op1 (s / show-01~e.9 :ARG0 (e / enzyme :name (n / name :op1 "Her2"~e.6)) :ARG1 (c / correlate-01~e.11 :ARG1 e :ARG2~e.12 (e2 / enzyme :name (n3 / name :op1 "Raf-1"~e.13,15))) :time (n2 / no-longer~e.8)) :op2 (e3 / evident~e.21 :polarity~e.7,16 -~e.16 :domain (a2 / associate-01~e.19 :ARG1 (a3 / amino-acid :mod 338 :name (n5 / name :op1 "serine") :part-of (e4 / enzyme :name (n6 / name :op1 "Raf"~e.23) :ARG3-of (p / phosphorylate-01~e.23)) :location (a4 / and~e.47 :op1 (c2 / cytoplasm~e.30 :ARG1-of (s2 / statistical-test-91~e.33 :ARG2 0.0035~e.36 :ARG3 0.1854~e.45)) :op2 (n7 / nucleus~e.48 :ARG1-of (s3 / statistical-test-91~e.51 :ARG2 0.0068~e.54 :ARG3 0.1581~e.63)))) :ARG2~e.65 e~e.66 :ARG2-of (n4 / negative-01~e.18))) :time (a5 / after~e.0 :op1 (d / develop-01~e.2 :ARG2 (d2 / disease :name (n9 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , the activated form ( pHer2 ) correlated with pRaf ( Ser259 ) ( P @ = 0.0008 , r @ ²@ = 0.2011 ) . # ::alignments 0-1 1-1 4-1.1.1.1 5-1.1.1 9-1.1 11-1.1.1.2.1.2 11-1.1.2.3.1.1 17-1.1.1.2.1.2 17-1.1.3 20-1.1.3.1 (a / and~e.0,1 :op2 (c / correlate-01~e.9 :ARG1 (f / form~e.5 :ARG1-of (a2 / activate-01~e.4) :ARG1-of (d / describe-01 :ARG2 (e / enzyme :name (n / name :op1 "Her2") :ARG3-of (p / phosphorylate-01~e.11,17)))) :ARG2 (a3 / amino-acid :mod 259 :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf"~e.11) :ARG3-of p)) :ARG1-of (s / statistical-test-91~e.17 :ARG2 0.0008~e.20 :ARG3 0.02011))) # ::id pmid_2155_9022.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the activated cytoplasmic form of Raf showed a positive weak correlation with the pHer2 ( P @ = 0.0363 , r @ ²@ = 0.09376 ) ( Figure 7 ) . # ::alignments 0-1.4 3-1.1.3 4-1.1.2 7-1.1.1.1 8-1 10-1.2.3 11-1.2.4 12-1.2 18-1.2.2.2 18-1.2.5 21-1.2.5.1 30-1.2.5.2 34-1.3.1 35-1.3.1.1 (s / show-01~e.8 :ARG0 (e / enzyme :name (n / name :op1 "Raf"~e.7) :mod (c / cytoplasm~e.4) :ARG1-of (a / activate-01~e.3)) :ARG1 (c2 / correlate-01~e.12 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "Her2") :ARG3-of (p2 / phosphorylate-01~e.18)) :mod (p / positive~e.10) :ARG1-of (w / weak-02~e.11) :ARG1-of (s2 / statistical-test-91~e.18 :ARG2 0.0363~e.21 :ARG3 0.09376~e.30)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.34 :mod 7~e.35)) :ARG0-of (i / interest-01~e.0)) # ::id pmid_2155_9022.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , no correlations were evident between Her2 or pHer2 with MAPK in any form . # ::alignments 0-1 0-1.1.1.2 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1 4-1.1.1.r 5-1.1 7-1.1.1.2.1.1.1 7-1.1.1.2.2.1.1 10-1.1.1.3.r 11-1.1.1.3.2.1.1 13-1.1.1.3.1 14-1.1.1.3 (a3 / and~e.0 :op2 (e / evident~e.5 :domain~e.4 (c / correlate-01~e.3 :polarity~e.2 -~e.2 :ARG1 (a / and~e.0 :op1 (e2 / enzyme :name (n / name :op1 "Her2"~e.7)) :op2 (e3 / enzyme :name (n2 / name :op1 "Her2"~e.7) :ARG3-of (p / phosphorylate-01))) :ARG2~e.10 (f / form~e.14 :mod (a2 / any~e.13) :mod (e4 / enzyme :name (n3 / name :op1 "MAPK"~e.11)))))) # ::id pmid_2155_9022.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All associations between EGFR and EGFR vIII disappeared after progression to CRPC . # ::alignments 0-1.1.3 1-1.1 3-1.1.1.1.1 5-1.1.1.1.1 5-1.1.2.1.1 6-1.1.2.1.2 7-1 8-1.2 9-1.2.1 (d / disappear-01~e.7 :ARG1 (a / associate-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.3,5)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "EGFR"~e.5 :op2 "vIII"~e.6)) :mod (a2 / all~e.0)) :time (a3 / after~e.8 :op1 (p / progress-01~e.9 :ARG4 (d2 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))))) # ::id pmid_2155_9022.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A moderate positive correlation was seen between pRaf ( Ser259 ) and AR ( P @ = 0.0035 , r @ ²@ = 0.1154 ) , whereas a negative correlation is evident between nuclear MAPK and AR ( P @ = 0.0429 , r @ ²@ = 0.06066 ) . # ::alignments 1-1.1.1.3 2-1.1.1.4 3-1.1.1 5-1.1 7-1.1.1.1.3.1.1 7-1.1.1.1.3.2 12-1.1.1.2.1.1 15-1.1.1.1.3.2 15-1.1.1.5 18-1.1.1.5.1 27-1.1.1.5.2 30-1 32-1.2.1.3 33-1.2.1 35-1.2 37-1.2.1.1.2 38-1.2.1.1.1.1 40-1.2.1.2 43-1.2.1.4 46-1.2.1.4.1 55-1.2.1.4.2 (c / contrast-01~e.30 :ARG1 (s / see-01~e.5 :ARG1 (c2 / correlate-01~e.3 :ARG1 (a / amino-acid :mod 259 :name (n2 / name :op1 "serine") :part-of (e4 / enzyme :name (n / name :op1 "Raf"~e.7) :ARG3-of (p2 / phosphorylate-01~e.7,15))) :ARG2 (e3 / enzyme :name (n3 / name :op1 "AR"~e.12)) :ARG1-of (m / moderate-03~e.1) :mod (p / positive~e.2) :ARG1-of (s2 / statistical-test-91~e.15 :ARG2 0.0035~e.18 :ARG3 0.1154~e.27))) :ARG2 (e2 / evidence-01~e.35 :ARG1 (c3 / correlate-01~e.33 :ARG1 (e / enzyme :name (n5 / name :op1 "MAPK"~e.38) :mod (n6 / nucleus~e.37)) :ARG2 e3~e.40 :ARG2-of (n4 / negative-01~e.32) :ARG1-of (s3 / statistical-test-91~e.43 :ARG2 0.0429~e.46 :ARG3 0.06066~e.55)))) # ::id pmid_2155_9022.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There was no correlation ( positive or negative ) shown between total Raf @-@ 1 expression and AR . # ::alignments 2-1.1.1 2-1.1.1.r 3-1.1 5-1.1.4.1 6-1.1.4 7-1.1.4.2 9-1 11-1.1.2.1.2 12-1.1.2.1.1.1 14-1.1.2.1.1.1 15-1.1.2 17-1.1.3.1.1 (s / show-01~e.9 :ARG1 (c / correlate-01~e.3 :polarity~e.2 -~e.2 :ARG1 (e / express-03~e.15 :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf-1"~e.12,14) :mod (t / total~e.11))) :ARG2 (e3 / enzyme :name (n3 / name :op1 "AR"~e.17)) :mod (o / or~e.6 :op1 (p / positive~e.5) :op2 (n / negative-01~e.7)))) # ::id pmid_2155_9022.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , there were no correlations noted between either Raf @-@ 1 ( any form ) or MAPK ( any form ) and PSA level . # ::alignments 0-1 1-1 5-1.1.1.1 5-1.1.1.1.r 6-1.1.1 7-1.1 10-1.1.1.2.1.2.1.1 12-1.1.1.2.1.2.1.1 14-1.1.1.2.1.1 14-1.1.1.2.2.1 15-1.1.1.2.1 15-1.1.1.2.2 17-1.1.1.2 18-1.1.1.2.2.2.1.1 20-1.1.1.2.1.1 21-1.1.1.2.1 24-1.1.1.3.1.1.1 25-1.1.1.3 (a / and~e.0,1 :op2 (n / note-01~e.7 :ARG1 (c / correlate-01~e.6 :polarity~e.5 -~e.5 :ARG1 (o / or~e.17 :op1 (f / form~e.15,21 :mod (a2 / any~e.14,20) :mod (e / enzyme :name (n2 / name :op1 "Raf-1"~e.10,12))) :op2 (f2 / form~e.15 :mod (a3 / any~e.14) :mod (e3 / enzyme :name (n3 / name :op1 "MAPK"~e.18)))) :ARG2 (l / level~e.25 :quant-of (e2 / enzyme :name (n4 / name :op1 "PSA"~e.24)))))) # ::id pmid_2155_9022.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More correlations were noted with components of the downstream transcription factor AP @-@ 1 . # ::alignments 0-1.1.2 1-1.1 3-1 4-1.1.1.r 5-1.1.1 6-1.1.1.1.r 8-1.1.1.1.2 9-1.1.1.1 9-1.1.1.1.4 9-1.1.1.1.4.r 10-1.1.1.1.3 11-1.1.1.1.1.1 13-1.1.1.1.1.1 (n / note-01~e.3 :ARG1 (c / correlate-01~e.1 :ARG2~e.4 (c2 / component~e.5 :part-of~e.6 (p / protein~e.9 :name (n2 / name :op1 "AP-1"~e.11,13) :location (d / downstream~e.8) :mod (f / factor~e.10) :ARG1-of~e.9 (t / transcribe-01~e.9))) :quant (m / more~e.0))) # ::id pmid_2155_9022.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Correlations were evident between phosphorylated c @-@ jun and cytoplasmic pRaf ( Ser338 ) ( P @ = 0.0026 , r @ ²@ = 0.2192 ) and pRaf ( Ser259 ) ( P @ = 0.0278 , r @ ²@ = 0.1077 ) . # ::alignments 0-1.1.1 0-1.1.2 2-1 4-1.1.1.1.2 4-1.1.1.2.3.2 5-1.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1.1.2.4 10-1.1.1.1.2 10-1.1.1.2.3.1.1 10-1.1.1.2.3.2 16-1.1.1.1.2 16-1.1.1.2.3.2 16-1.1.1.3 19-1.1.1.3.1 28-1.1.1.3.2 31-1.1.1.1.2 31-1.1.1.2.3.1.1 31-1.1.1.2.3.2 37-1.1.2.3 40-1.1.2.3.1 49-1.1.2.3.2 (e / evidence-01~e.2 :ARG1 (a4 / and :op1 (c / correlate-01~e.0 :ARG1 (p / protein :name (n / name :op1 "c-jun"~e.5,7) :ARG3-of (p2 / phosphorylate-01~e.4,10,16,31)) :ARG2 (a2 / amino-acid :mod 338 :name (n2 / name :op1 "serine") :part-of (e2 / enzyme :name (n3 / name :op1 "Raf"~e.10,31) :ARG3-of (p3 / phosphorylate-01~e.4,10,16,31)) :mod (c2 / cytoplasm~e.9)) :ARG1-of (s / statistical-test-91~e.16 :ARG2 0.0026~e.19 :ARG3 0.2192~e.28)) :op2 (c4 / correlate-01~e.0 :ARG1 p :ARG2 (a3 / amino-acid :mod 259 :name (n4 / name :op1 "serine") :part-of e2) :ARG1-of (s2 / statistical-test-91~e.37 :ARG2 0.0278~e.40 :ARG3 0.1077~e.49)))) # ::id pmid_2155_9022.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There was also a correlation seen between Raf @-@ 1 and c @-@ Fos ( P @ = 0.0131 , r @ ²@ = 0.1512 ) , and between the nuclear and cytoplasmic expression of pMAPK ( Thr202 @/@ 204 ) and c @-@ jun ( P @ = 0.0146 , r @ ²@ = 0.1368 and P @ = 0.0178 , r @ ²@ = 0.1295 , respectively ) ( Figure 8 ) . # ::alignments 2-1.2 4-1.1.1 4-1.1.2 5-1 7-1.1.1.1.1.1 9-1.1.1.1.1.1 11-1.1.1.2.1.1 13-1.1.1.2.1.1 16-1.1.1.3 19-1.1.1.3.1 28-1.1.1.3.2 31-1.1.2.1 34-1.1.2.1.1.2 35-1.1.2.1 36-1.1.2.1.2.2 37-1.1.2.1.1 37-1.1.2.1.2 38-1.1.2.1.1.1.r 39-1.1.2.1.1.1.2.1.1 39-1.1.2.1.1.1.2.2 42-1.1.2.1.1.1.3 43-1.1.2.1.1.1.3.2 45-1.1.2.1 46-1.1.2.2.1.1 48-1.1.2.2.1.1 51-1.1.2.1.1.3 54-1.1.2.1.1.3.1 63-1.1.2.1.1.3.2 64-1.1.2.1 66-1.1.2.1.1.3 66-1.1.2.1.2.3 69-1.1.2.1.2.3.1 78-1.1.2.1.2.3.2 84-1.1.3.1 85-1.1.3.1.1 (s / see-01~e.5 :ARG1 (a / and :op1 (c / correlate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"~e.7,9)) :ARG2 (p / protein :name (n2 / name :op1 "c-Fos"~e.11,13)) :ARG1-of (s3 / statistical-test-91~e.16 :ARG2 0.0131~e.19 :ARG3 0.1512~e.28)) :op2 (c3 / correlate-01~e.4 :ARG1 (a2 / and~e.31,35,45,64 :op1 (e2 / express-03~e.37 :ARG2~e.38 (a3 / amino-acid :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n5 / name :op1 "MAPK"~e.39) :ARG3-of (p4 / phosphorylate-01~e.39)) :mod (s2 / slash~e.42 :op1 202 :op2 204~e.43)) :ARG3 (n4 / nucleus~e.34) :ARG1-of (s4 / statistical-test-91~e.51,66 :ARG2 0.0146~e.54 :ARG3 0.1368~e.63)) :op2 (e3 / express-03~e.37 :ARG2 a3 :ARG3 (c2 / cytoplasm~e.36) :ARG1-of (s5 / statistical-test-91~e.66 :ARG2 0.0178~e.69 :ARG3 0.1295~e.78))) :ARG2 (p5 / protein :name (n6 / name :op1 "c-jun"~e.46,48))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.84 :mod 8~e.85))) :mod (a6 / also~e.2)) # ::id pmid_2246_3874.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Prognostic value of RKIP and p @-@ ERK in gastric cancer ( PMID : 22463874 ) # ::alignments 0-1.2 1-1 2-1.1.r 3-1.1.1.1.1 4-1.1 5-1.1.2.2 7-1.1.2.1.1 8-1.4.r 9-1.4.2.1 10-1.4.2.2 (v / value-01~e.1 :ARG1~e.2 (a / and~e.4 :op1 (p2 / protein :name (n / name :op1 "RKIP"~e.3)) :op2 (e / enzyme :name (n2 / name :op1 "ERK"~e.7) :ARG3-of (p3 / phosphorylate-01~e.5))) :mod (p / prognostic~e.0) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID22463874")) :location~e.8 (d2 / disease :wiki "Stomach_cancer" :name (n3 / name :op1 "stomach"~e.9 :op2 "cancer"~e.10))) # ::id pmid_2246_3874.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2246_3874.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of RKIP , p @-@ MEK , and p @-@ ERK was found in 69 ( 66 %) , 54 ( 51 %) , and 64 ( 61 %) of all tumours , respectively . # ::alignments 0-1.1.1 0-1.1.2 0-1.1.3 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.2.1.2 6-1.1.2.1.1.1 9-1.1.2.1.2 11-1.1.3.1.1.1 13-1 15-1.1.1.2.1 17-1.1.1.2.2.2.1 20-1.1.2.2.1 22-1.1.2.2.2.2.1 25-1.1 26-1.1.3.2.1 28-1.1.3.2.2.2.1 31-1.1.1.2.2.1.1 32-1.1.1.2 32-1.1.1.2.2.1 32-1.1.2.2 32-1.1.3.2 (f / find-01~e.13 :ARG1 (a2 / and~e.25 :op1 (e / express-03~e.0 :ARG2~e.1 (p / protein :name (n / name :op1 "RKIP"~e.2)) :ARG3 (t / tumor~e.32 :quant 69~e.15 :ARG1-of (i / include-91 :ARG2 (t2 / tumor~e.32 :mod (a / all~e.31)) :ARG3 (p2 / percentage-entity :value 66~e.17)))) :op2 (e2 / express-03~e.0 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK"~e.6) :ARG3-of (p3 / phosphorylate-01~e.4,9)) :ARG3 (t3 / tumor~e.32 :quant 54~e.20 :ARG1-of (i2 / include-91 :ARG2 t2 :ARG3 (p4 / percentage-entity :value 51~e.22)))) :op3 (e4 / express-03~e.0 :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK"~e.11) :ARG3-of p3) :ARG3 (t4 / tumor~e.32 :quant 64~e.26 :ARG1-of (i3 / include-91 :ARG2 t2 :ARG3 (p6 / percentage-entity :value 61~e.28)))))) # ::id pmid_2246_3874.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RKIP expression negatively correlated with the depth of invasion ( p < 0.001 ) , lymph node involvement ( p = 0.028 ) , and Union for International Cancer Control ( UICC ) stage ( p = 0.007 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.3 3-1.1 3-1.2 3-1.3 4-1.1.2.r 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1 10-1.1.4 11-1.1.4.1 12-1.1.4.1.1 15-1.2.2.1.1 16-1.2.2.1 17-1.2.2 19-1.2.3 21-1.2.3.1 24-1 31-1.3.2.1.1.1 33-1.3.2 35-1.3.3 37-1.3.3.1 (a2 / and~e.24 :op1 (c / correlate-01~e.3 :ARG1 (e / express-03~e.1 :ARG2 (p / protein :name (n2 / name :op1 "RKIP"~e.0))) :ARG2~e.4 (d / depth~e.6 :mod~e.7 (i / invade-01~e.8)) :ARG2-of (n / negative-01~e.2) :ARG1-of (s / statistical-test-91~e.10 :ARG2 (l / less-than~e.11 :value 0.001~e.12))) :op2 (c2 / correlate-01~e.3 :ARG1 e :ARG2 (i2 / involve-01~e.17 :ARG1 (n3 / node~e.16 :mod (l2 / lymph~e.15))) :ARG1-of (s3 / statistical-test-91~e.19 :ARG2 0.028~e.21)) :op3 (c3 / correlate-01~e.3 :ARG1 e :ARG2 (s2 / stage~e.33 :mod (o / organization :name (n5 / name :op1 "UICC"~e.31))) :ARG1-of (s4 / statistical-test-91~e.35 :ARG2 0.007~e.37))) # ::id pmid_2246_3874.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RKIP expression was associated with significantly longer relapse @-@ free survival ( RFS ) ( p = 0.0033 ) , whereas p @-@ MEK was not ( p = 0.79 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1 3-1.2 4-1.1.2.r 5-1.1.2.2.2 6-1.1.2.2 6-1.1.2.2.1 6-1.1.2.2.1.r 7-1.1.2.1.1 9-1.1.2.1 10-1.1.2 15-1.1.3 17-1.1.3.1 20-1 21-1.1.3 21-1.2.2.2 23-1.2.2.1.1 25-1.2.1 25-1.2.1.r 27-1.2.2.2 27-1.2.4 29-1.2.4.1 (c / contrast-01~e.20 :ARG1 (a / associate-01~e.3 :ARG1 (e / express-03~e.1 :ARG2 (p / protein :name (n / name :op1 "RKIP"~e.0))) :ARG2~e.4 (s / survive-01~e.10 :ARG1-of (f / free-04~e.9 :ARG2 (r / relapse-01~e.7)) :ARG1-of (l / long-03~e.6 :degree~e.6 (m / more~e.6) :ARG1-of (s2 / significant-02~e.5))) :ARG1-of (s3 / statistical-test-91~e.15,21 :ARG2 0.0033~e.17)) :ARG2 (a2 / associate-01~e.3 :polarity~e.25 -~e.25 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK"~e.23) :ARG3-of (p4 / phosphorylate-01~e.21,27)) :ARG2 s :ARG1-of (s4 / statistical-test-91~e.27 :ARG2 0.79~e.29))) # ::id pmid_2246_3874.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with p @-@ ERK expression had slightly , but not significantly shorter RFS than those without such expression ( p = 0.054 ) . # ::alignments 0-1.1.1.1 2-1.1.2.1.2 4-1.1.2.1.1.1 5-1.1.2 6-1 7-1.2.2.1 9-1.2.2.1.1 10-1.2.2.1.1.1.1 10-1.2.2.1.1.1.1.r 11-1.2.2.1.1.1 12-1.2.2 14-1.2.3.r 16-1.2.3.2.1 16-1.2.3.2.1.r 18-1.2.3.2 20-1.2.4 22-1.2.4.1 (h / have-03~e.6 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.0)) :ARG3-of (e / express-03~e.5 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK"~e.4) :ARG3-of (p3 / phosphorylate-01~e.2)))) :ARG1 (s / survive-01 :ARG1-of (f / free-04 :ARG2 (r / relapse-01)) :ARG1-of (s2 / short-07~e.12 :degree (s5 / slight~e.7 :ARG1-of (c / contrast-01~e.9 :ARG2 (s4 / significant-02~e.11 :polarity~e.10 -~e.10))) :degree (m / more)) :compared-to~e.14 (p4 / person :ARG0-of h2 :ARG3-of (e3 / express-03~e.18 :polarity~e.16 -~e.16 :ARG2 e2)) :ARG1-of (s3 / statistical-test-91~e.20 :ARG2 0.054~e.22))) # ::id pmid_2246_3874.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with positive p @-@ ERK and negative RKIP expression had significantly shorter RFS than the other patients ( p < 0.001 ) . # ::alignments 0-1.1.1.1 2-1.1.3.2 3-1.1.3.1.2 5-1.1.3.1.1.1 8-1.1.4.1.1.1 9-1.1.3 9-1.1.4 10-1 10-1.1.1 11-1.2.2.1 12-1.2.2 14-1.1.2.r 14-1.2.2.2.1 16-1.1.2.1 17-1.1.2.2 19-1.2.2.2 20-1.2.2.2.1 21-1.2.2.2.1.1 (h / have-03~e.10 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91~e.10 :ARG2 (p2 / patient~e.0)) :compared-to~e.14 (p6 / person :mod (o / other~e.16) :ARG0-of h2~e.17) :ARG3-of (e2 / express-03~e.9 :ARG2 (e / enzyme :name (n / name :op1 "ERK"~e.5) :ARG3-of (p3 / phosphorylate-01~e.3)) :mod (p4 / positive~e.2)) :ARG3-of (e3 / express-03~e.9 :ARG2 (p5 / protein :name (n2 / name :op1 "RKIP"~e.8) :ARG2-of (m / mutate-01 :mod "-/-")))) :ARG1 (s / survive-01 :ARG1-of (f / free-04 :ARG2 (r / relapse-01)) :ARG1-of (s2 / short-07~e.12 :ARG1-of (s3 / significant-02~e.11) :ARG1-of (s4 / statistical-test-91~e.19 :ARG2 (l / less-than~e.14,20 :value 0.001~e.21))))) # ::id pmid_2246_3874.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The combination of RKIP and p @-@ ERK expression was an independent prognostic factor ( hazard ratio , 2.4 ; 95 % confidence interval , 1.3 - 4.6 ; p = 0.008 ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.2 7-1.1.1.1.2.1.1 8-1.1.1 9-1.1.r 11-1.3 11-1.3.1 11-1.3.1.r 12-1.2 13-1 15-1.4.2 16-1.4 18-1.4.1 20-1.5.3.1 21-1.5.3 22-1.5.1 23-1.5 23-1.5.2 23-1.5.2.r 25-1.5.2.1 27-1.5.2.2 29-1.6 31-1.6.1 (f / factor~e.13 :domain~e.9 (c / combine-01~e.1 :ARG3~e.2 (e / express-03~e.8 :ARG2 (a / and~e.4 :op1 (p / protein :name (n / name :op1 "RKIP"~e.3)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.7) :ARG3-of (p2 / phosphorylate-01~e.5))))) :mod (p3 / prognostic~e.12) :ARG0-of (d / depend-01~e.11 :polarity~e.11 -~e.11) :mod (r / ratio~e.16 :quant 2.4~e.18 :mod (h / hazard~e.15)) :mod (i / interval~e.23 :mod (c2 / confidence~e.22) :value~e.23 (v / value-interval~e.23 :op1 1.3~e.25 :op2 4.6~e.27) :mod (p4 / percentage-entity~e.21 :value 95~e.20)) :ARG1-of (s / statistical-test-91~e.29 :ARG2 0.008~e.31)) # ::id pmid_2246_3874.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2246_3874.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RKIP , p @-@ MEK , and p @-@ ERK were respectively expressed by 69 ( 66 %) , 54 ( 51 %) , and 64 ( 61 %) of all tumours ( Figure 1a @-@ c ) . # ::alignments 0-1.1.1.1.1 2-1.2.1.2 4-1.2.1.1.1 7-1.2.1.2 9-1.3.1.1.1 12-1.1 12-1.2 12-1.3 14-1.1.2.1 16-1.1.2.2.2.1 19-1.2.2.1 21-1.2.2.2.2.1 24-1.4.1 25-1.3.2.1 27-1.3.2.2.2.1 30-1.1.2.2.1.1 31-1.1.2 31-1.1.2.2.1 31-1.2.2 31-1.3.2 33-1.4.1.1 33-1.4.1.2 33-1.4.1.3 35-1.4.1.1.1 (a / and :op1 (e / express-03~e.12 :ARG2 (p / protein :name (n / name :op1 "RKIP"~e.0)) :ARG3 (t / tumor~e.31 :quant 69~e.14 :ARG1-of (i / include-91 :ARG2 (t4 / tumor~e.31 :mod (a2 / all~e.30)) :ARG3 (p4 / percentage-entity :value 66~e.16)))) :op2 (e2 / express-03~e.12 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK"~e.4) :ARG3-of (p2 / phosphorylate-01~e.2,7)) :ARG3 (t2 / tumor~e.31 :quant 54~e.19 :ARG1-of (i2 / include-91 :ARG2 t4 :ARG3 (p5 / percentage-entity :value 51~e.21)))) :op3 (e4 / express-03~e.12 :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK"~e.9) :ARG3-of p2) :ARG3 (t3 / tumor~e.31 :quant 64~e.25 :ARG1-of (i3 / include-91 :ARG2 t4 :ARG3 (p6 / percentage-entity :value 61~e.27)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.24 :op1 (f / figure~e.33 :mod "1a"~e.35) :op2 (f2 / figure~e.33 :mod "1b") :op3 (f3 / figure~e.33 :mod "1c")))) # ::id pmid_2246_3874.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RKIP expression was mainly observed in the cytoplasm of tumour or non @-@ tumour cells . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.3 3-1.3.r 4-1 5-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.2.1 10-1.2.1 11-1.2.1.2.1.1 11-1.2.1.2.1.1.r 13-1.2.1.1.1 13-1.2.1.2.1 14-1.2.1.1 14-1.2.1.2 (o / observe-01~e.4 :ARG1 (e / express-03~e.1 :ARG2 (p / protein :name (n / name :op1 "RKIP"~e.0))) :location~e.5 (c / cytoplasm~e.7 :part-of~e.8 (o2 / or~e.10 :op1 (c2 / cell~e.14 :mod (t / tumor~e.13)) :op2 (c3 / cell~e.14 :mod (t2 / tumor~e.9,13 :polarity~e.11 -~e.11)))) :manner~e.3 (m / main~e.3)) # ::id pmid_2246_3874.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expressions of p @-@ MEK and p @-@ ERK were found in both the cytoplasm and nucleus . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.2 4-1.1.1.1.1.1 6-1.1.1.1.2 8-1.1.1.2.1.1 10-1 11-1.2.r 12-1.2.3 14-1.2.1 15-1.2 16-1.2.2 (f / find-01~e.10 :ARG1 (e / express-03~e.0 :ARG2~e.1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "MEK"~e.4) :ARG3-of (p / phosphorylate-01~e.2,6)) :op2 (e3 / enzyme :name (n2 / name :op1 "ERK"~e.8) :ARG3-of p))) :location~e.11 (a2 / and~e.15 :op1 (c / cytoplasm~e.14) :op2 (n3 / nucleus~e.16) :mod (b / both~e.12))) # ::id pmid_2246_3874.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expressions of RKIP , p @-@ MEK , and p @-@ ERK were respectively detected in 5 ( 19 %) , 9 ( 35 %) , and 21 ( 81 %) of 26 metastatic lymph nodes obtained from patients with recurrent disease ( Figure 1d @-@ f ) . # ::alignments 0-1.1.1 0-1.1.2 0-1.1.3 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.2.1.2 6-1.1.2.1.1.1 9-1.1.2.1.2 11-1.1.3.1.1.1 14-1 15-1.1.1.2.r 16-1.1.1.2.1 18-1.1.1.2.2.2.1 21-1.1.2.2.1 23-1.1.2.2.2.2.1 26-1.1 27-1.1.3.2.1 29-1.1.3.2.2.2.1 32-1.1.1.2.2.1.1 33-1.1.1.2.2.1.3 34-1.1.1.2.2.1.2 35-1.1.1.2 35-1.1.1.2.2.1 35-1.1.2.2 35-1.1.3.2 36-1.1.1.2.2.1.4 37-1.1.1.2.2.1.4.1.r 38-1.1.1.2.2.1.4.1.1.1 41-1.1.1.2.2.1.4.1.2 43-1.2.1.1 43-1.2.1.2 43-1.2.1.3 45-1.2.1.1.1 (d / detect-01~e.14 :ARG1 (a / and~e.26 :op1 (e / express-03~e.0 :ARG2~e.1 (p / protein :name (n / name :op1 "RKIP"~e.2)) :ARG3~e.15 (n2 / node~e.35 :quant 5~e.16 :ARG1-of (i / include-91 :ARG2 (n7 / node~e.35 :quant 26~e.32 :mod (l / lymph~e.34) :mod (m / metastasis~e.33) :ARG1-of (o / obtain-01~e.36 :ARG2~e.37 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.38)) :mod (d2 / disease~e.41 :ARG1-of (r / reoccur-01))))) :ARG3 (p5 / percentage-entity :value 19~e.18)))) :op2 (e2 / express-03~e.0 :ARG2 (e3 / enzyme :name (n3 / name :op1 "MEK"~e.6) :ARG3-of (p4 / phosphorylate-01~e.4,9)) :ARG3 (n4 / node~e.35 :quant 9~e.21 :ARG1-of (i2 / include-91 :ARG2 n7 :ARG3 (p6 / percentage-entity :value 35~e.23)))) :op3 (e5 / express-03~e.0 :ARG2 (e4 / enzyme :name (n5 / name :op1 "ERK"~e.11) :ARG3-of p4) :ARG3 (n6 / node~e.35 :quant 21~e.27 :ARG1-of (i3 / include-91 :ARG2 n7 :ARG3 (p7 / percentage-entity :value 81~e.29))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.43 :mod "1d"~e.45) :op2 (f2 / figure~e.43 :mod "1e") :op3 (f3 / figure~e.43 :mod "1f")))) # ::id pmid_2246_3874.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of p @-@ ERK was found mainly in the nuclei of metastatic tumour cells . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.2 4-1.1.1.1.1 6-1 7-1.2 7-1.2.r 8-1.3.r 10-1.3 11-1.3.1.r 12-1.3.1.1.1 13-1.3.1.1 14-1.3.1 (f / find-01~e.6 :ARG1 (e / express-03~e.0 :ARG2~e.1 (e2 / enzyme :name (n / name :op1 "ERK"~e.4) :ARG3-of (p / phosphorylate-01~e.2))) :manner~e.7 (m / main~e.7) :location~e.8 (n2 / nucleus~e.10 :part-of~e.11 (c / cell~e.14 :mod (t / tumor~e.13 :ARG1-of (m2 / metastasize-101~e.12))))) # ::id pmid_2246_3874.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These proteins were also detected in tumour cells associated with venous invasion ( Figure 1g @-@ i ) . # ::alignments 0-1.1.1 1-1.1 3-1.2 4-1 5-1.3.r 6-1.3.1 7-1.3 8-1.3.2 9-1.3.2.1.r 10-1.3.2.1.1 11-1.3.2.1 13-1.4.1.1 13-1.4.1.2 13-1.4.1.3 15-1.4.1.1.1 (d / detect-01~e.4 :ARG1 (p / protein~e.1 :mod (t / this~e.0)) :mod (a / also~e.3) :location~e.5 (c / cell~e.7 :mod (t2 / tumor~e.6) :ARG1-of (a2 / associate-01~e.8 :ARG2~e.9 (i / invade-01~e.11 :ARG1 (v / vein~e.10)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.13 :mod "1g"~e.15) :op2 (f2 / figure~e.13 :mod "1h") :op3 (f3 / figure~e.13 :mod "1i")))) # ::id pmid_2246_3874.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No p @-@ ERK or p @-@ MEK staining was detected in normal gastric mucosa . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2.1.2 3-1.1.2.1.1.1 4-1.1.2 5-1.1.2.2.2 7-1.1.2.2.1.1 8-1.1 10-1 11-1.2.r 12-1.2.2 13-1.2.1 14-1.2 (d / detect-01~e.10 :ARG1 (s / stain-01~e.8 :polarity~e.0 -~e.0 :ARG2 (o / or~e.4 :op1 (e / enzyme :name (n / name :op1 "ERK"~e.3) :ARG3-of (p / phosphorylate-01~e.1)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK"~e.7) :ARG3-of p~e.5))) :location~e.11 (m / mucosa~e.14 :mod (s2 / stomach~e.13) :ARG1-of (n3 / normal-02~e.12))) # ::id pmid_2246_3874.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression of p @-@ MEK positively correlated with the expressions of RKIP ( p = 0.042 ) and p @-@ ERK ( p = 0.007 ) , whereas there was no relation between RKIP and p @-@ ERK expressions ( p = 0.98 ) ( Table 1 ) . # ::alignments 1-1.1.1.1 3-1.1.1.1.1.2 5-1.1.1.1.1.1.1 6-1.1.1.3 6-1.1.1.3.r 7-1.1.1 7-1.1.2 10-1.1.1.1 10-1.1.1.2 11-1.1.1.2.1.r 12-1.1.1.2.1.1.1 14-1.1.1.1.1.2 14-1.1.1.4 16-1.1.1.4.1 19-1.1.1.1.1.2 19-1.1.1.4 21-1.1.2.2.1.1 23-1.1.2.3 25-1.1.2.3.1 28-1 31-1.2.1 31-1.2.1.r 32-1.2 34-1.1.1.2.1.1.1 35-1.1 36-1.2.4 38-1.1.2.2.1.1 39-1.2.2 39-1.2.3 41-1.2.4 46-1.3.1 48-1.3.1.1 (c / contrast-01~e.28 :ARG1 (a2 / and~e.35 :op1 (c2 / correlate-01~e.7 :ARG1 (e / express-03~e.1,10 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK"~e.5) :ARG3-of (p / phosphorylate-01~e.3,14,19))) :ARG2 (e3 / express-03~e.10 :ARG2~e.11 (p2 / protein :name (n2 / name :op1 "RKIP"~e.12,34))) :manner~e.6 (p6 / positive~e.6) :ARG1-of (s / statistical-test-91~e.14,19 :ARG2 0.042~e.16)) :op2 (c3 / correlate-01~e.7 :ARG1 e :ARG2 (e4 / enzyme :name (n3 / name :op1 "ERK"~e.21,38) :ARG3-of p) :ARG1-of (s2 / statistical-test-91~e.23 :ARG2 0.007~e.25))) :ARG2 (r / relate-01~e.32 :polarity~e.31 -~e.31 :ARG1 (e5 / express-03~e.39 :ARG2 p2) :ARG2 (e6 / express-03~e.39 :ARG2 e4) :ARG1-of (s3 / statistical-test-91~e.36,41 :ARG2 0.098)) :ARG1-of (d / describe-01 :ARG0 (t / table~e.46 :mod 1~e.48))) # ::id pmid_2246_3874.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RKIP expression negatively correlated with the depth of invasion ( p < 0.001 ) , lymph node involvement ( p = 0.028 ) , and UICC stage ( p = 0.007 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1.3 3-1.1 3-1.2 3-1.3 4-1.1.2.r 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1 10-1.1.4 11-1.1.4.1 12-1.1.4.1.1 15-1.2.2.1.1 16-1.2.2.1 17-1.2.2 19-1.2.3 21-1.2.3.1 24-1 25-1.3.2.1.1.1 26-1.3.2 28-1.3.3 30-1.3.3.1 (a2 / and~e.24 :op1 (c / correlate-01~e.3 :ARG1 (e / express-03~e.1 :ARG2 (p / protein :name (n / name :op1 "RKIP"~e.0))) :ARG2~e.4 (d / depth~e.6 :mod~e.7 (i / invade-01~e.8)) :ARG2-of (n3 / negative-01~e.2) :ARG1-of (s / statistical-test-91~e.10 :ARG2 (l2 / less-than~e.11 :op1 0.001~e.12))) :op2 (c2 / correlate-01~e.3 :ARG1 e :ARG2 (i2 / involve-01~e.17 :ARG1 (n2 / node~e.16 :mod (l / lymph~e.15))) :ARG1-of (s3 / statistical-test-91~e.19 :ARG2 0.028~e.21)) :op3 (c3 / correlate-01~e.3 :ARG1 e :ARG2 (s2 / stage~e.26 :mod (o / organization :name (n5 / name :op1 "UICC"~e.25))) :ARG1-of (s4 / statistical-test-91~e.28 :ARG2 0.007~e.30))) # ::id pmid_2246_3874.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RKIP was more commonly found in differentiated type than in undifferentiated type tumours ( p = 0.042 ) . # ::alignments 0-1.1.1.1 2-1.3.1 3-1.3 3-1.3.r 4-1 5-1.2.r 6-1.2.1.1 6-1.2.2.1.1 7-1.2.1 7-1.2.2.1 8-1.2.2.r 11-1.2.1 11-1.2.2.1 12-1.2 12-1.2.2 14-1.4 16-1.4.1 (f / find-01~e.4 :ARG1 (p / protein :name (n / name :op1 "RKIP"~e.0)) :location~e.5 (t / tumor~e.12 :mod (t2 / type~e.7,11 :ARG1-of (d / differentiate-01~e.6)) :compared-to~e.8 (t3 / tumor~e.12 :mod (t4 / type~e.7,11 :ARG1-of (d2 / differentiate-01~e.6 :polarity -)))) :manner~e.3 (c / common~e.3 :degree (m / more~e.2)) :ARG1-of (s / statistical-test-91~e.14 :ARG2 0.042~e.16)) # ::id pmid_2246_3874.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expressions of p @-@ ERK and p @-@ MEK significantly correlated with gender ( p = 0.027 , p = 0.036 , respectively ) , but were not related to any other clinicopathological factor ( Table 2 ) . # ::alignments 1-1.1.1.1 1-1.1.2.1 3-1.1.1.1.1.2 3-1.1.1.4 5-1.1.1.1.1.1.1 7-1.1.1.1.1.2 7-1.1.1.4 9-1.1.2.1.1.1.1 10-1.1.1.3 11-1.1.1 11-1.1.2 12-1.1.1.2.r 13-1.1.1.2 15-1.1.1.1.1.2 15-1.1.1.4 17-1.1.1.4.1 19-1.1.1.4 19-1.1.2.3 21-1.1.2.3.1 26-1 28-1.2.1 28-1.2.1.r 29-1.2 30-1.2.3.r 31-1.2.3.2.1 32-1.2.3.2 34-1.2.3 36-1.3.1 38-1.3.1.1 (c / contrast-01~e.26 :ARG1 (a3 / and :op1 (c2 / correlate-01~e.11 :ARG1 (e / express-03~e.1 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK"~e.5) :ARG3-of (p / phosphorylate-01~e.3,7,15))) :ARG2~e.12 (g / gender~e.13) :ARG1-of (s / significant-02~e.10) :ARG1-of (s2 / statistical-test-91~e.3,7,15,19 :ARG2 0.027~e.17)) :op2 (c4 / correlate-01~e.11 :ARG1 (e4 / express-03~e.1 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK"~e.9) :ARG3-of p)) :ARG2 g :ARG1-of (s3 / statistical-test-91~e.19 :ARG2 0.036~e.21))) :ARG2 (r / relate-01~e.29 :polarity~e.28 -~e.28 :ARG1 e :ARG2~e.30 (f / factor~e.34 :mod (c3 / clinicopathology) :mod (o / other~e.32 :mod (a2 / any~e.31)))) :ARG1-of (d / describe-01 :ARG0 (t / table~e.36 :mod 2~e.38))) # ::id pmid_2246_3874.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RKIP expression was associated with significantly longer RFS ( p = 0.003 ) , whereas p @-@ MEK was not ( p = 0.79 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 1-1.2.2 3-1.1 3-1.2 5-1.1.2.1.2 6-1.1.2.1 6-1.1.2.1.1 6-1.1.2.1.1.r 9-1.1.3 11-1.1.3.1 14-1 15-1.1.3 15-1.2.2.1.2 17-1.2.2.1.1.1 19-1.2.1 19-1.2.1.r 21-1.2.2.1.2 21-1.2.4 23-1.2.4.1 (c / contrast-01~e.14 :ARG1 (a / associate-01~e.3 :ARG1 (e / express-03~e.1 :ARG2 (p / protein :name (n / name :op1 "RKIP"~e.0))) :ARG2 (s / survive-01 :ARG1-of (l / long-03~e.6 :degree~e.6 (m / more~e.6) :ARG1-of (s2 / significant-02~e.5)) :ARG1-of (f / free-04 :ARG2 (r / relapse-01))) :ARG1-of (s3 / statistical-test-91~e.9,15 :ARG2 0.003~e.11)) :ARG2 (a2 / associate-01~e.3 :polarity~e.19 -~e.19 :ARG1 (e2 / express-03~e.1 :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK"~e.17) :ARG3-of (p3 / phosphorylate-01~e.15,21))) :ARG2 s :ARG1-of (s4 / statistical-test-91~e.21 :ARG2 0.79~e.23))) # ::id pmid_2246_3874.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The presence of p @-@ ERK expression was associated with slightly , but not significantly shorter RFS than the absence of such expression ( p = 0.054 ) ( Table 3 ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.2 5-1.1.1.1.1.1 6-1.1.1 8-1 10-1.2.1.2 12-1.2.1.2.1 13-1.2.1.2.1.1.1 13-1.2.1.2.1.1.1.r 14-1.2.1.2.1.1 15-1.2.1 15-1.2.1.1 15-1.2.1.1.r 17-1.1.2.r 19-1.1.2 22-1.1.2.1 24-1.4 26-1.4.1 29-1.3.1 31-1.3.1.1 (a / associate-01~e.8 :ARG1 (p / present-02~e.1 :ARG1~e.2 (e / express-03~e.6 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK"~e.5) :ARG3-of (p2 / phosphorylate-01~e.3))) :compared-to~e.17 (a2 / absent-01~e.19 :ARG1 e~e.22)) :ARG2 (s / survive-01 :ARG1-of (s2 / short-07~e.15 :degree~e.15 (m / more~e.15) :degree (s3 / slight~e.10 :ARG1-of (c / contrast-01~e.12 :ARG2 (s4 / significant-02~e.14 :polarity~e.13 -~e.13)))) :ARG1-of (f / free-04 :ARG2 (r / relapse-01))) :ARG1-of (d / describe-01 :ARG0 (t / table~e.29 :mod 3~e.31)) :ARG1-of (s5 / statistical-test-91~e.24 :ARG2 0.054~e.26)) # ::id pmid_2246_3874.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with positive p @-@ ERK and negative RKIP expression had significantly shorter RFS than the other patients ( p < 0.001 ) ( Figure 2 ) . # ::alignments 0-1.1.1.1 2-1.1.3.2 3-1.1.3.1.2 5-1.1.3.1.1.1 8-1.1.4.1.1.1 9-1.1.3 9-1.1.4 10-1 10-1.1.1 11-1.2.1.1 12-1.2.1 12-1.2.1.2 12-1.2.1.2.r 14-1.1.2.r 14-1.2.1.3.1 16-1.1.2.1 17-1.1.2.2 19-1.2.1.3 20-1.2.1.3.1 21-1.2.1.3.1.1 24-1.3.1 26-1.3.1.1 (h / have-03~e.10 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91~e.10 :ARG2 (p2 / patient~e.0)) :compared-to~e.14 (p6 / person :mod (o / other~e.16) :ARG0-of h2~e.17) :ARG3-of (e / express-03~e.9 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK"~e.5) :ARG3-of (p3 / phosphorylate-01~e.3)) :mod (p4 / positive~e.2)) :ARG3-of (e3 / express-03~e.9 :ARG2 (p5 / protein :name (n2 / name :op1 "RKIP"~e.8) :ARG2-of (m2 / mutate-01 :mod "-/-")))) :ARG1 (s / survive-01 :ARG1-of (s2 / short-07~e.12 :ARG1-of (s3 / significant-02~e.11) :degree~e.12 (m / more~e.12) :ARG1-of (s4 / statistical-test-91~e.19 :ARG2 (l / less-than~e.14,20 :op1 0.001~e.21))) :ARG1-of (f / free-04 :ARG2 (r / relapse-01))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.24 :mod 2~e.26))) # ::id pmid_2246_3874.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The prognostic relevance of positive p @-@ ERK expression combined with negative RKIP expression was therefore assessed using a multivariate proportional @-@ hazards model adjusted for established clinical prognostic factors ( i.e . , age , gender , histopathology , depth of invasion , lymph node involvement ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.3 5-1.1.1.1.2 7-1.1.1.1.1.1 8-1.1.1 8-1.1.1.2.1 9-1.1.1.2 10-1.2.r 12-1.1.1.2.1.1.1.1 13-1.1.1 15-1.3 16-1 19-1.2.3 20-1.2.2.1 22-1.2.2 23-1.2 24-1.2.1 25-1.2.1.1.r 26-1.2.1.1.2 27-1.2.1.1.1 28-1.2.1.1.3 29-1.2.1.1 34-1.2.1.1.4.1 36-1.2.1.1.4.2 38-1.2.1.1.4.3 40-1.2.1.1.4.4 41-1.2.1.1.4.4.1.r 42-1.2.1.1.4.4.1 44-1.2.1.1.4.5.1.1 45-1.2.1.1.4.5.1 46-1.2.1.1.4.5 (a / assess-01~e.16 :ARG1 (r / relevant-01~e.2 :ARG1~e.3 (e / express-03~e.8,13 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK"~e.7) :ARG3-of (p / phosphorylate-01~e.5)) :ARG1-of (c / combine-01~e.9 :ARG2 (e3 / express-03~e.8 :ARG2 (p2 / protein :name (n2 / name :op1 "RKIP"~e.12) :ARG2-of (m3 / mutate-01 :mod "-/-")))) :mod (p3 / positive~e.4)) :mod (p4 / prognostic~e.1)) :instrument~e.10 (m / model-01~e.23 :ARG1-of (a2 / adjust-01~e.24 :ARG2~e.25 (f / factor~e.29 :mod (c2 / clinic~e.27) :ARG1-of (e4 / establish-01~e.26) :mod p4~e.28 :example (a3 / and :op1 (a4 / age~e.34) :op2 (g / gender~e.36) :op3 (h / histopathology~e.38) :op4 (d / depth~e.40 :mod~e.41 (i2 / invade-01~e.42)) :op5 (i3 / involve-01~e.46 :ARG1 (n4 / node~e.45 :mod (l / lymph~e.44)))))) :mod (h2 / hazard~e.22 :mod (p5 / proportional~e.20)) :mod (m2 / multivariate~e.19)) :ARG1-of (c3 / cause-01~e.15)) # ::id pmid_2246_3874.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The combination of RKIP and p @-@ ERK expression was found to be an independent prognostic factor ( hazard ratio [ HR ] , 2.4 ; 95 % confidence interval [ CI ] , 1.3 - 4.6 ; p = 0.008 ) . # ::alignments 1-1.1.3 2-1.1.3.1.r 3-1.1.3.1.1.1.1.1 4-1.1.3.1.1 5-1.1.3.1.1.2.2 7-1.1.3.1.1.2.1.1 8-1.1.3.1 9-1.1.3.r 10-1 12-1.1.3.r 14-1.1.2 14-1.1.2.1 14-1.1.2.1.r 15-1.1.1 16-1.1 18-1.2.2 19-1.2 21-1.2.2 24-1.2.1 26-1.3.2.1 27-1.3.2 28-1.3.1 29-1.3 31-1.3 31-1.3.1 31-1.3.1.r 31-1.3.3 31-1.3.3.r 34-1.3.3.1 36-1.3.3.2 38-1.1.4 40-1.1.4.1 (f / find-01~e.10 :ARG1 (f2 / factor~e.16 :mod (p3 / prognostic~e.15) :ARG0-of (d / depend-01~e.14 :polarity~e.14 -~e.14) :domain~e.9,12 (c / combine-01~e.1 :ARG1~e.2 (e / express-03~e.8 :ARG2 (a / and~e.4 :op1 (p / protein :name (n / name :op1 "RKIP"~e.3)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.7) :ARG3-of (p2 / phosphorylate-01~e.5))))) :ARG1-of (s / statistical-test-91~e.38 :ARG2 0.008~e.40)) :mod (r / ratio~e.19 :value 2.4~e.24 :mod (h / hazard~e.18,21)) :mod (i / interval~e.29,31 :mod~e.31 (c2 / confidence~e.28,31) :mod (p4 / percentage-entity~e.27 :value 95~e.26) :value~e.31 (v / value-interval~e.31 :op1 1.3~e.34 :op2 4.6~e.36))) # ::id pmid_2246_3874.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histopathological type and depth of invasion were also independent prognostic factors ( HR , 2.1 ; 95 % CI , 1.0 - 4.2 ; p = 0.043 and HR , 4.7 ; 95 % CI , 1.0 @-@ 22 ; p = 0.048 , respectively ) ( Table 3 ) . # ::alignments 0-1.3.1.1 1-1.3.1 2-1.3 3-1.3.2 4-1.3.2.1.r 5-1.3.2.1 6-1.3.r 7-1.5 8-1.2 8-1.2.1 8-1.2.1.r 9-1.1 10-1 12-1.3.1.2.2 12-1.3.2.2.2 14-1.3.1.2.1 16-1.3.1.3.2.1 17-1.3.1.3.2 18-1.3.1.3 18-1.3.1.3.1 18-1.3.1.3.1.r 20-1.3.1.3.3.1 22-1.3.1.3.3.2 24-1.3.1.4 26-1.3.1.4.1 27-1.3.1.3.3 28-1.3.2.2.2 30-1.3.2.2.1 32-1.3.2.3.2.1 33-1.3.2.3.2 34-1.3.2.3 34-1.3.2.3.1 34-1.3.2.3.1.r 34-1.3.2.3.3 34-1.3.2.3.3.r 36-1.3.2.3.3.1 38-1.3.2.3.3.2 40-1.3.2.4 42-1.3.2.4.1 47-1.4.1 49-1.4.1.1 (f / factor~e.10 :mod (p / prognostic~e.9) :ARG0-of (d / depend-01~e.8 :polarity~e.8 -~e.8) :domain~e.6 (a / and~e.2 :op1 (t / type~e.1 :mod (h / histopathological~e.0) :mod (r / ratio :value 2.1~e.14 :mod (h2 / hazard~e.12)) :mod (i2 / interval~e.18 :mod~e.18 (c / confidence~e.18) :mod (p2 / percentage-entity~e.17 :value 95~e.16) :value (b / between~e.27 :op1 1.0~e.20 :op2 4.2~e.22)) :ARG1-of (s / statistical-test-91~e.24 :ARG2 0.043~e.26)) :op2 (d2 / depth~e.3 :mod~e.4 (i / invade-01~e.5) :mod (r2 / ratio :value 4.7~e.30 :mod (h3 / hazard~e.12,28)) :mod (i3 / interval~e.34 :mod~e.34 (c2 / confidence~e.34) :mod (p4 / percentage-entity~e.33 :value 95~e.32) :value~e.34 (v / value-interval~e.34 :op1 1.0~e.36 :op2 22~e.38)) :ARG1-of (s2 / statistical-test-91~e.40 :ARG2 0.048~e.42))) :ARG1-of (d3 / describe-01 :ARG0 (t2 / table~e.47 :mod 3~e.49)) :mod (a2 / also~e.7)) # ::id pmid_2247_5322.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines ( PMID : 22475322 ) # ::alignments 0-1 2-1.1.1.1 3-1.1.1.1 4-1.1.1.2 5-1.1.1 8-1.1.2.3 9-1.1.2.1.2 10-1.1.2.1.1 11-1.1.2 12-1.1.2.2.1.1.1 13-1.1.2.1 13-1.1.2.2 14-1.1.2.1 (c / compare-01~e.0 :ARG1 (u / utilize-01 :ARG1 (p / pathway~e.5 :mod (g / growth-factor~e.2,3) :ARG0-of (s2 / signal-07~e.4)) :location (a / and~e.11 :op1 (c2 / cell-line~e.13,14 :source (m2 / melanocyte~e.10) :ARG1-of (n3 / normal-02~e.9)) :op2 (c3 / cell-line~e.13 :source (m / medical-condition :name (n / name :op1 "melanoma"~e.12))) :ARG1-of (c4 / culture-01~e.8))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID22475322"))) # ::id pmid_2247_5322.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2247_5322.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum , but could be distinguished upon serum starvation , where signalling protein phosphorylation was generally abrogated . # ::alignments 0-1.1.2.1.1 1-1.1.2.1 2-1.1 3-1.1.1 3-1.1.1.r 5-1.1.2 6-1.1.2.2.1.r 7-1.1.2.2.1.1.1 8-1.1.2.2 13-1.1.2.3.1 15-1.1.2.4.r 16-1.1.2.4 17-1.1.2.4.2.r 19-1.1.2.4.2 20-1.1.2.4.2.1.r 21-1.1.2.4.2.1 23-1 24-1.1 24-1.2 26-1.1.2 26-1.2.1 28-1.2.1.2.1.2 29-1.2.1.2.1 32-1.2.1.3.1.1.1 33-1.2.1.3.1.1 34-1.2.1.3.1 36-1.2.1.3.2 37-1.2.1.3 (c / contrast-01~e.23 :ARG1 (p2 / possible-01~e.2,24 :polarity~e.3 -~e.3 :ARG1 (d / distinguish-01~e.5,26 :ARG1 (m / melanocyte~e.1 :ARG1-of (n / normal-02~e.0)) :ARG2 (c2 / cell~e.8 :source~e.6 (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.7))) :instrument (u / utilize-01 :ARG1 (p / pathway~e.13)) :time~e.15 (g / grow-01~e.16 :ARG1 m :manner~e.17 (p3 / present-02~e.19 :ARG1~e.20 (s / serum~e.21))))) :ARG2 (p4 / possible-01~e.24 :ARG1 (d2 / distinguish-01~e.26 :ARG1 m :ARG1-of (c3 / cause-01 :ARG0 (s2 / starve-01~e.29 :ARG1 m :ARG2 s~e.28)) :time (a / abrogate-01~e.37 :ARG1 (p5 / phosphorylate-01~e.34 :ARG1 (p6 / protein~e.33 :ARG0-of (s3 / signal-07~e.32))) :ARG1-of (g2 / general-02~e.36))))) # ::id pmid_2247_5322.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Surprisingly , the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways . # ::alignments 0-1.4 3-1.2.2 6-1.2.1.1 7-1.2.1 9-1.1 9-1.1.r 10-1.5 11-1 12-1.3.r 14-1.3 15-1.3.1.r 17-1.3.1.1.2 17-1.3.1.1.2.1.2.1 18-1.3.1 19-1.3.1.2.1.2 20-1.3.1.1.1 20-1.3.1.1.1.1 20-1.3.1.1.1.1.r 20-1.3.1.2.1 20-1.3.1.2.1.1 20-1.3.1.2.1.1.r 21-1.3.1.1 21-1.3.1.2 22-1.3.1.2.1.1.1.r 23-1.3.1.2.1.1.1 26-1.3.1.3 (a / associate-01~e.11 :polarity~e.9 -~e.9 :ARG1 (u / utilize-01 :ARG1 (p / pathway~e.7 :mod (i / individual~e.6)) :ARG1-of (d / differentiate-01~e.3)) :ARG2~e.12 (p2 / present-02~e.14 :ARG1~e.15 (o / or~e.18 :op1 (m / mutate-01~e.21 :ARG1 (m3 / molecular-physical-entity~e.20 :ARG0-of~e.20 (s3 / suppress-01~e.20 :ARG1 g)) :ARG0-of (c2 / cause-01~e.17 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.17)))) :op2 (m2 / mutate-01~e.21 :ARG1 (m4 / molecular-physical-entity~e.20 :ARG0-of~e.20 (s2 / suppress-01~e.20 :ARG1~e.22 (g / gene~e.23)) :mod (t / tumor~e.19))) :location p~e.26)) :ARG1-of (s / surprise-01~e.0) :manner (c / consistent-02~e.10)) # ::id pmid_2247_5322.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2247_5322.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NZM cell line mutations in the PI3K and MAPK pathways # ::alignments 1-1.1.1.1 2-1.1 3-1.1 4-1 5-1.2.r 7-1.2.1.1.1 8-1.2 9-1.2.2.1.1 10-1.2.1 10-1.2.2 (m / mutate-01~e.4 :ARG1 (c / cell-line~e.2,3 :name (n4 / name :op1 "NZM"~e.1)) :location~e.5 (a / and~e.8 :op1 (p2 / pathway~e.10 :name (n2 / name :op1 "PI3K"~e.7)) :op2 (p3 / pathway~e.10 :name (n3 / name :op1 "MAPK"~e.9)))) # ::id pmid_2247_5322.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to determine whether the presence of activating mutations in the PI3K and MAPK signalling pathways correlated with increased utilisation of downstream signalling pathways , we first determined the mutational status of PIK3CA , PTEN , NRAS @ and BRAF @ genes in the NZM cell line collection . # ::alignments 0-1.4.r 1-1.4.r 2-1.4.r 3-1 4-1.4.2.1 4-1.4.2.1.r 6-1.4.2.2 7-1.4.2.2.1.r 8-1.4.2.2.1.1 9-1.4.2.2.1 10-1.4.2.2.2.r 12-1.4.2.2.2.1.1.1 13-1.4.2.2.2 14-1.4.2.2.2.2.1.1 15-1.4.2.2.2.3 16-1.4.2.2.2.1 16-1.4.2.2.2.2 17-1.4.2 19-1.4.2.3.2 22-1.4.2.3.1.1.1 23-1.4.2.3.1.1 24-1.4.2.3.1 26-1.1 27-1.3 28-1 28-1.4 30-1.2.1.1 30-1.2.2.1 30-1.2.3.1 30-1.2.4.1 31-1.2.1 31-1.2.2 31-1.2.3 31-1.2.4 34-1.2.1.1.1.1.1 36-1.2.2.1.1.1.1 38-1.2.3.1.1.1.1 40-1.2 42-1.2.4.1.1.1.1 44-1.2.1.1.1 44-1.2.2.1.1 44-1.2.3.1.1 44-1.2.4.1.1 45-1.2.r 47-1.2.5.1.1.1 48-1.2.5.1 49-1.2.5.1 50-1.2.5 (d / determine-01~e.3,28 :ARG0 (w / we~e.26) :ARG1~e.45 (a4 / and~e.40 :op1 (s / status~e.31 :topic (m / mutate-01~e.30 :ARG1 (g / gene~e.44 :name (n2 / name :op1 "PIK3CA"~e.34)))) :op2 (s4 / status~e.31 :topic (m3 / mutate-01~e.30 :ARG1 (g2 / gene~e.44 :name (n3 / name :op1 "PTEN"~e.36)))) :op3 (s5 / status~e.31 :topic (m4 / mutate-01~e.30 :ARG1 (g3 / gene~e.44 :name (n4 / name :op1 "NRAS"~e.38)))) :op4 (s6 / status~e.31 :topic (m5 / mutate-01~e.30 :ARG1 (g4 / gene~e.44 :name (n5 / name :op1 "BRAF"~e.42)))) :location (c / collect-01~e.50 :ARG1 (c2 / cell-line~e.48,49 :name (n / name :op1 "NZM"~e.47)))) :time (f / first~e.27) :purpose~e.0,1,2 (d2 / determine-01~e.28 :ARG0 w :ARG1 (c3 / correlate-01~e.17 :mode~e.4 interrogative~e.4 :ARG1 (p / present-02~e.6 :ARG1~e.7 (m2 / mutate-01~e.9 :ARG0-of (a2 / activate-01~e.8)) :ARG2~e.10 (a3 / and~e.13 :op1 (p2 / pathway~e.16 :name (n6 / name :op1 "PI3K"~e.12)) :op2 (p3 / pathway~e.16 :name (n7 / name :op1 "MAPK"~e.14)) :ARG0-of (s2 / signal-07~e.15))) :ARG2 (u / utilize-01 :ARG1 (p4 / pathway~e.24 :ARG0-of (s3 / signal-07~e.23 :direction (d3 / downstream~e.22))) :ARG1-of (i / increase-01~e.19))))) # ::id pmid_2247_5322.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Representative DNA sequences for PTEN , PIK3CA , BRAF @ and NRAS @ are provided in Figure 1 @ . # ::alignments 0-1.2.1 1-1.2 2-1.2 5-1.2.1.1.1.1.1 7-1.2.1.1.2.1.1 9-1.2.1.1.3.1.1 11-1.2.1.1 13-1.2.1.1.4.1.1 16-1 17-1.1.r 18-1.1 20-1.1.1 (p2 / provide-01~e.16 :ARG0~e.17 (f / figure~e.18 :mod 1~e.20) :ARG1 (d2 / dna-sequence~e.1,2 :ARG0-of (r / represent-01~e.0 :ARG1 (a / and~e.11 :op1 (g4 / gene :name (n / name :op1 "PTEN"~e.5)) :op2 (g / gene :name (n2 / name :op1 "PIK3CA"~e.7)) :op3 (g2 / gene :name (n3 / name :op1 "BRAF"~e.9)) :op4 (g3 / gene :name (n4 / name :op1 "NRAS"~e.13)))))) # ::id pmid_2247_5322.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Table 1 , we selected cell lines that were characterised by a number of genetic mutations . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 5-1.3.1.1 8-1.1 9-1 10-1.2 11-1.2 17-1.2.1.1.2 18-1.2.1.1.2.r 20-1.2.1.1 (s / select-01~e.9 :ARG0 (w / we~e.8) :ARG1 (c / cell-line~e.10,11 :ARG1-of (c2 / characterize-01 :ARG2 (m / mutate-01~e.20 :ARG1 (g / gene) :quant~e.18 (n / number~e.17)))) :ARG1-of (s2 / show-01~e.1 :ARG0~e.2 (t / table~e.3 :mod 1~e.5))) # ::id pmid_2247_5322.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All of the selected cell lines harboured either oncogenic V600E or V600K BRAF @ or Q61H NRAS @ mutations . # ::alignments 0-1.1.1 3-1.1.2.1.1 4-1.1.2.1 5-1.1 6-1 8-1.2.4 8-1.2.4.1.2.1 9-1.2.1.2.1 10-1.2 11-1.2.2.2.1 13-1.2.1.1.1 13-1.2.2.1.1 15-1.2 16-1.2.3.2.1 18-1.2.3.1.1 20-1.2.1 20-1.2.1.2 20-1.2.1.2.r 20-1.2.2 20-1.2.2.2 20-1.2.2.2.r 20-1.2.3 20-1.2.3.2 20-1.2.3.2.r (h / harbor-01~e.6 :ARG0 (c / cell-line~e.5 :mod (a / all~e.0) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.4 :ARG1-of (s / select-01~e.3)))) :ARG1 (o / or~e.10,15 :op1 (g2 / gene~e.20 :name (n2 / name :op1 "BRAF"~e.13) :ARG1-of~e.20 (m / mutate-01~e.20 :value "V600E"~e.9)) :op2 (g / gene~e.20 :name (n / name :op1 "BRAF"~e.13) :ARG1-of~e.20 (m3 / mutate-01~e.20 :value "V600K"~e.11)) :op3 (g3 / gene~e.20 :name (n3 / name :op1 "NRAS"~e.18) :ARG1-of~e.20 (m2 / mutate-01~e.20 :value "Q61H"~e.16)) :ARG0-of (c3 / cause-01~e.8 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.8))))) # ::id pmid_2247_5322.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since the tumour suppressor gene PTEN @ can be functionally lost during melanoma development through both mutation and epigenetic mechanisms [ @ 32 @ ] , we measured PTEN protein expression in the NZM cell lines ( Figure 2 ) . # ::alignments 0-1 2-1.1.1.1.2.1 3-1.1.1.1.2 4-1.1.1.1 6-1.1.1.1.1.1 8-1.1 10-1.1.1.2 11-1.1.1 12-1.1.1.3.r 13-1.1.1.3.1.1.1 14-1.1.1.3 17-1.1.1.3.2.1 18-1.1.1.3.2 19-1.1.1.3.2.2.1 20-1.1.1.3.2.2 23-1.1.2.1.1.1 27-1.2.1 28-1.2 29-1.2.2.1.1.1 30-1.2.2.1 31-1.2.2 32-1.2.2.2.r 34-1.2.2.2.1.1 35-1.2.2.2 36-1.2.2.2 38-1.3.1 40-1.3.1.1 (c / cause-01~e.0 :ARG0 (p2 / possible-01~e.8 :ARG1 (l / lose-02~e.11 :ARG1 (g / gene~e.4 :name (n3 / name :op1 "PTEN"~e.6) :ARG0-of (s / suppress-01~e.3 :ARG1 (t / tumor~e.2))) :ARG1-of (f2 / function-01~e.10) :time~e.12 (d2 / develop-01~e.14 :ARG2 (m2 / medical-condition :name (n4 / name :op1 "melanoma"~e.13)) :manner (a / and~e.18 :op1 (m3 / mutate-01~e.17) :op2 (m4 / mechanism~e.20 :mod (e2 / epigenetic~e.19))))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG0-of (c3 / cite-01 :ARG1 32~e.23)))) :ARG1 (m / measure-01~e.28 :ARG0 (w / we~e.27) :ARG1 (e / express-03~e.31 :ARG1 (p / protein~e.30 :name (n / name :op1 "PTEN"~e.29)) :ARG3~e.32 (c2 / cell-line~e.35,36 :name (n2 / name :op1 "NZM"~e.34)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.38 :mod 2~e.40))) # ::id pmid_2247_5322.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation of the PTEN @ gene led to loss of functional PTEN protein expression , as seen in Figure 2 @ . # ::alignments 0-1.1 4-1.1.1.1.1 6-1.1.1 7-1 8-1.2.r 9-1.2 10-1.2.1.r 11-1.2.1.1.2 12-1.2.1.1.1.1 13-1.2.1.1 14-1.2.1 16-1.3.r 17-1.3 18-1.3.1.r 19-1.3.1 21-1.3.1.1 (l / lead-03~e.7 :ARG0 (m / mutate-01~e.0 :ARG1 (g / gene~e.6 :name (n / name :op1 "PTEN"~e.4))) :ARG2~e.8 (l2 / lose-02~e.9 :ARG1~e.10 (e / express-03~e.14 :ARG2 (p / protein~e.13 :name (n2 / name :op1 "PTEN"~e.12) :ARG0-of (f / function-01~e.11)))) :ARG1-of~e.16 (s / see-01~e.17 :location~e.18 (f2 / figure~e.19 :mod 2~e.21))) # ::id pmid_2247_5322.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cell lines NZM40 , NZM46 and NZM52 , which all harbour the oncogenic H1047R PIK3CA @ mutation , had concurrent BRAF @ or NRAS @ mutations ( Table 1 ) . # ::alignments 1-1.1.1 2-1.1.1 2-1.1.2 2-1.1.3 3-1.1.1.1.1 5-1.1.2.1.1 6-1.1 7-1.1.3.1.1 13-1.1.4.1.3 13-1.1.4.1.3.1.2.1 14-1.1.4.1.1 16-1.1.4.1.2.1.1 18-1.1.4.1 20-1 21-1.2.3 23-1.2.1.1.1.1 25-1.2 27-1.2.2.1.1.1 29-1.2.1 29-1.2.2 31-1.3.1 33-1.3.1.1 (h / have-03~e.20 :ARG0 (a / and~e.6 :op1 (c / cell-line~e.1,2 :name (n2 / name :op1 "NZM40"~e.3)) :op2 (c2 / cell-line~e.2 :name (n3 / name :op1 "NZM46"~e.5)) :op3 (c3 / cell-line~e.2 :name (n4 / name :op1 "NZM52"~e.7)) :ARG0-of (h2 / harbor-01 :ARG1 (m / mutate-01~e.18 :value "H1047R"~e.14 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.16)) :ARG0-of (c5 / cause-01~e.13 :ARG1 (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"~e.13)))))) :ARG1 (o / or~e.25 :op1 (m2 / mutate-01~e.29 :ARG1 (g2 / gene :name (n6 / name :op1 "BRAF"~e.23))) :op2 (m3 / mutate-01~e.29 :ARG1 (g3 / gene :name (n5 / name :op1 "NRAS"~e.27))) :ARG1-of (c4 / concurrent-02~e.21)) :ARG1-of (d / describe-01 :ARG0 (t / table~e.31 :mod 1~e.33))) # ::id pmid_2247_5322.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of particular interest was the high degree of expression of PTEN protein in the NZM46 cell line , compared to other cell lines harbouring the PIK3CA @ oncogenic mutation . # ::alignments 1-1.2 2-1 5-1.1.2 6-1.1 7-1.1.1.r 8-1.1.1 9-1.1.1.1.r 10-1.1.1.1.1.1 11-1.1.1.1 12-1.1.1.2.r 14-1.1.1.2.1.1 15-1.1.3 16-1.1.3 18-1.1.3.r 20-1.1.3.2 21-1.1.3 22-1.1.3 23-1.1.3.1 26-1.1.3.1.1.1.1.1 28-1.1.3.1.1.2 28-1.1.3.1.1.2.1.2.1 29-1.1.3.1.1 (i / interest-01~e.2 :ARG2 (d / degree~e.6 :degree-of~e.7 (e / express-03~e.8 :ARG2~e.9 (p2 / protein~e.11 :name (n2 / name :op1 "PTEN"~e.10)) :ARG3~e.12 (c / cell-line :name (n3 / name :op1 "NZM46"~e.14))) :ARG1-of (h / high-02~e.5) :compared-to~e.18 (c2 / cell-line~e.15,16,21,22 :ARG0-of (h2 / harbor-01~e.23 :ARG1 (m / mutate-01~e.29 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.26)) :ARG0-of (c3 / cause-01~e.28 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.28))))) :mod (o2 / other~e.20))) :mod (p / particular~e.1)) # ::id pmid_2247_5322.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since the presence of an oncogenic mutation or a loss of tumour suppressor function does not dictate whether the cell uses all of the downstream signalling molecules for pathway activation [ @ 33 , 34 @ ] , we determined the phosphorylation status of the immediate downstream substrates of the PI3K , mTOR and MAPK pathways . # ::alignments 0-1.1.2.1.1.1 2-1.1.2.1 5-1 5-1.1.2.1.1.1 5-1.1.2.1.1.1.1.2.1 6-1.1.2.1.1 7-1.1.2 9-1.1.2.2 10-1.1.2.2.1.r 11-1.1.2.2.1.1.1 12-1.1.2.2.1.1 13-1.1.2.2.1 15-1.1.1 15-1.1.1.r 16-1.1 19-1.1.3.1 20-1.1.3 22-1.1.3.2.r 24-1.1.3.2.1.1 25-1.1.3.2.1 26-1.1.3.2 27-1.1.3.3.r 28-1.1.3.3.2 29-1.1.3.3 32-1.1.4.1.1.1.1 36-1.1.4.1.1.1.2 40-1.2.1 41-1.2 43-1.2.2.1 44-1.2.2 45-1.2.2.2.r 47-1.2.2.2.1.1 48-1.2.2.2.1 49-1.2.2.2 50-1.2.2.2.2.r 52-1.2.2.2.2.1.1.1 54-1.2.2.2.2.2.1.1 55-1.2.2.2.2 56-1.2.2.2.2.3.1.1 57-1.2.2.2.2.1 57-1.2.2.2.2.2 57-1.2.2.2.2.3 (c / cause-01~e.5 :ARG0 (d3 / dictate-01~e.16 :polarity~e.15 -~e.15 :ARG0 (o2 / or~e.7 :op1 (p5 / present-02~e.2 :ARG1 (m / mutate-01~e.6 :ARG0-of (c4 / cause-01~e.0,5 :ARG1 (d5 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.5))))) :op1 (l / lose-02~e.9 :ARG1~e.10 (f / function-01~e.13 :ARG1 (s3 / suppress-01~e.12 :ARG1 (t / tumor~e.11))))) :ARG1 (u / use-01~e.20 :ARG0 (c2 / cell~e.19) :ARG1~e.22 (m2 / molecule~e.26 :ARG0-of (s4 / signal-07~e.25 :mod d2~e.24)) :ARG2~e.27 (a2 / activate-01~e.29 :ARG0 c2 :ARG1 (p6 / pathway~e.28))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG0-of (c3 / cite-01 :ARG1 (a3 / and :op1 33~e.32 :op2 34~e.36))))) :ARG1 (d / determine-01~e.41 :ARG0 (w / we~e.40) :ARG1 (s / status~e.44 :topic (p / phosphorylate-01~e.43) :poss~e.45 (s2 / substrate~e.49 :direction (d2 / downstream~e.48 :mod (i / immediate~e.47)) :poss~e.50 (a / and~e.55 :op1 (p2 / pathway~e.57 :name (n / name :op1 "PI3K"~e.52)) :op2 (p3 / pathway~e.57 :name (n2 / name :op1 "mTOR"~e.54)) :op3 (p4 / pathway~e.57 :name (n3 / name :op1 "MAPK"~e.56))))))) # ::id pmid_2247_5322.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blots for phosphorylated molecules were used as surrogate markers for pathway activation . # ::alignments 0-1.1 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 6-1 7-1.3.r 8-1.3.2 10-1.2.r 11-1.2.1 12-1.2 (u / use-01~e.6 :ARG1 (i / immunoblot-01~e.0,1 :ARG1~e.2 (m / molecule~e.4 :ARG1-of (p2 / phosphorylate-01~e.3))) :ARG2~e.10 (a / activate-01~e.12 :ARG1 (p / pathway~e.11)) :manner~e.7 (t / thing :ARG1-of (m2 / mark-02) :mod (s / surrogate~e.8))) # ::id pmid_2247_5322.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of PKB in melanoma and melanocytes # ::alignments 1-1 2-1.1.r 3-1.1.1.1 4-1.2.r 5-1.2.1.1.1 6-1.2 7-1.2.2 (p2 / phosphorylate-01~e.1 :ARG1~e.2 (e / enzyme :name (n / name :op1 "PKB"~e.3)) :location~e.4 (a / and~e.6 :op1 (m / medical-condition :name (n2 / name :op1 "melanoma"~e.5)) :op2 (m2 / melanocyte~e.7))) # ::id pmid_2247_5322.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to establish whether PIK3CA , PTEN , NRAS @ and BRAF @ mutations resulted in constitutive activation of the downstream signalling pathways , we measured PKB activation by western blotting for phosphorylation at two sites , Ser473 and Thr308 . # ::alignments 0-1.4.r 1-1.4.r 2-1.4.r 3-1.4 4-1.4.2.1 4-1.4.2.1.r 6-1.4.2.2.1.1.1.1 8-1.4.2.2.2.1.1.1 10-1.4.2.2.3.1.1.1 12-1.4.2.2 14-1.4.2.2.4.1.1.1 16-1.4.2.2.1 16-1.4.2.2.2 16-1.4.2.2.3 16-1.4.2.2.4 17-1.4.2 18-1.4.2.3.r 19-1.4.2.3.2 20-1.4.2.3 21-1.4.2.3.1.r 23-1.4.2.3.1.1.1 24-1.4.2.3.1.1 25-1.4.2.3.1 27-1.1 28-1 29-1.2.1.1.1 30-1.2 31-1.3.r 32-1.3.2 33-1.3 34-1.3.1.r 35-1.3.1 36-1.3.1.1.r 37-1.3.1.1.1 38-1.3.1.1 41-1.3.1.1.2.1 (m / measure-01~e.28 :ARG0 (w / we~e.27) :ARG1 (a / activate-01~e.30 :ARG1 (e2 / enzyme :name (n / name :op1 "PKB"~e.29))) :ARG2~e.31 (b / blot~e.33 :purpose~e.34 (p / phosphorylate-01~e.35 :ARG1~e.36 (s / site~e.38 :quant 2~e.37 :ARG1-of (m6 / mean-01 :ARG2 (a3 / and~e.41 :op1 (a4 / amino-acid :mod 473 :name (n3 / name :op1 "serine")) :op2 (a5 / amino-acid :mod 308 :name (n4 / name :op1 "threonine")))))) :mod (w2 / western~e.32)) :purpose~e.0,1,2 (e / establish-01~e.3 :ARG0 w :ARG1 (r / result-01~e.17 :mode~e.4 interrogative~e.4 :ARG1 (a6 / and~e.12 :op1 (m2 / mutate-01~e.16 :ARG1 (g / gene :name (n5 / name :op1 "PIK3CA"~e.6))) :op2 (m3 / mutate-01~e.16 :ARG1 (g4 / gene :name (n6 / name :op1 "PTEN"~e.8))) :op3 (m4 / mutate-01~e.16 :ARG1 (g2 / gene :name (n7 / name :op1 "NRAS"~e.10))) :op4 (m5 / mutate-01~e.16 :ARG1 (g3 / gene :name (n8 / name :op1 "BRAF"~e.14)))) :ARG2~e.18 (a7 / activate-01~e.20 :ARG1~e.21 (p2 / pathway~e.25 :ARG0-of (s2 / signal-07~e.24 :direction (d / downstream~e.23))) :manner (c / constitutive~e.19))))) # ::id pmid_2247_5322.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Equal amounts of protein from NZM cell lines were loaded onto the same gel , but for clarity , western blots were segmented to show results for individual NZM cell lines . # ::alignments 0-1.1.2.2 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1 4-1.1.2.1.1.r 5-1.1.2.1.1 6-1.1.2.1.1 7-1.1.2.1.1 9-1.1 12-1.1.1.1 13-1.1.1 15-1 19-1.2.1 20-1.2.1 22-1.2 24-1.2.3 25-1.2.3.2 25-1.2.3.2.1 25-1.2.3.2.1.r 26-1.2.3.2.1.1.r 27-1.2.3.2.1.1.2 28-1.2.3.2.1.1.1.1 29-1.2.3.2.1.1 30-1.2.3.2.1.1 (c / contrast-01~e.15 :ARG1 (l / load-01~e.9 :ARG1 (g / gel~e.13 :ARG1-of (s3 / same-01~e.12)) :ARG2 (a / amount-01~e.1 :ARG1~e.2 (p / protein~e.3 :source~e.4 c3~e.5,6,7) :ARG1-of (e / equal-01~e.0))) :ARG2 (s / segment-01~e.22 :ARG1 (i2 / immunoblot-01~e.19,20) :purpose (c2 / clear-06) :purpose (s2 / show-01~e.24 :ARG0 i2 :ARG1 (t / thing~e.25 :ARG2-of~e.25 (r / result-01~e.25 :ARG1~e.26 (c3 / cell-line~e.29,30 :name (n2 / name :op1 "NZM"~e.28) :mod (i / individual~e.27))))))) # ::id pmid_2247_5322.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In melanocytes , phosphorylation of PKB on both Ser473 and Thr308 was strongly serum dependent while most of the NZM cell lines in this study showed serum independent phosphorylation . # ::alignments 1-1.1.1.1.3 3-1.1.1 5-1.1.1.1.1.3.1.1 9-1.1.1.1 12-1.2.2.1.3 13-1.2.2.1.2 14-1.2.2.1 16-1.2.1.2 17-1.2.1.2.r 19-1.2.1.1.1.1.1 20-1.2.1 21-1.2.1 23-1.2.1.1.1.2.1 24-1.2.1.1.1 24-1.2.1.1.1.2 24-1.2.1.1.1.2.r 25-1.2 26-1.2.2.1.2 27-1.1 27-1.2.2.1 27-1.2.2.1.1 27-1.2.2.1.1.r 28-1.1.1 28-1.2.2 (h / have-concession-91 :ARG1 (d2 / depend-01~e.27 :ARG0 (p / phosphorylate-01~e.3,28 :ARG1 (a / and~e.9 :op1 (a2 / amino-acid :mod 473 :name (n3 / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "PKB"~e.5))) :op2 (a3 / amino-acid :mod 308 :name (n4 / name :op1 "threonine") :part-of e) :location (m2 / melanocyte~e.1))) :ARG1 s2 :manner s3) :ARG2 (s / show-01~e.25 :ARG0 (c / cell-line~e.20,21 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.24 :name (n / name :op1 "NZM"~e.19) :ARG1-of~e.24 (s4 / study-01~e.24 :mod (t / this~e.23)))) :quant~e.17 (m / most~e.16)) :ARG1 (p2 / phosphorylate-01~e.28 :ARG0-of (d / depend-01~e.14,27 :polarity~e.27 -~e.27 :ARG1 (s2 / serum~e.13,26) :ARG1-of (s3 / strong-02~e.12))))) # ::id pmid_2247_5322.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PKB was phosphorylated independently of serum at the mTORC2 dependent Ser473 site in most of the cell lines , although NZM46 and NZM3 surprisingly had very low levels of phosphorylation even in the presence of serum ( Figure 3 ) . # ::alignments 0-1.1.1.1.3.1.1 2-1.1 3-1.1.2.1 5-1.1.2.2 8-1.1.1.2.1.1.1 9-1.1.1.2 9-1.1.2 11-1.1.1 12-1.1.3.r 13-1.1.3.1 14-1.1.3.1.r 16-1.1.3 16-1.1.3.2.1 17-1.1.3 17-1.1.3.2.1 19-1 20-1.2.1.1.1.1 21-1.2.1 22-1.2.1.2.1.1 23-1.2.4 24-1.2 25-1.2.2.1.1 26-1.2.2.1 27-1.2.2 28-1.2.2.2.r 29-1.2.2.2 31-1.2.3.r 33-1.2.3 34-1.2.3.1.r 35-1.2.3.1 37-1.3.1 39-1.3.1.1 (h / have-concession-91~e.19 :ARG1 (p / phosphorylate-01~e.2 :ARG1 (s3 / site~e.11 :mod (a2 / amino-acid :mod 473 :name (n4 / name :op1 "serine") :part-of (e / enzyme :name (n3 / name :op1 "PKB"~e.0))) :ARG0-of (d3 / depend-01~e.9 :ARG1 (m / macro-molecular-complex :name (n5 / name :op1 "mTORC2"~e.8)))) :ARG0-of (d2 / depend-01~e.9 :polarity -~e.3 :ARG1 s~e.5) :location~e.12 (c3 / cell-line~e.16,17 :quant~e.14 (m2 / most~e.13) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line~e.16,17)))) :ARG2 (h2 / have-03~e.24 :ARG0 (a / and~e.21 :op1 (c / cell-line :name (n / name :op1 "NZM46"~e.20)) :op2 (c2 / cell-line :name (n2 / name :op1 "NZM3"~e.22))) :ARG1 (l / level~e.27 :ARG1-of (l2 / low-04~e.26 :degree (v / very~e.25)) :degree-of~e.28 (p2 / phosphorylate-01~e.29)) :concession~e.31 (p3 / present-02~e.33 :ARG1~e.34 (s / serum~e.35)) :ARG0-of (s2 / surprise-01~e.23)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.37 :mod 3~e.39))) # ::id pmid_2247_5322.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , phosphorylation at the PIP @₃@ -@ PDK1 dependent Thr308 site tended to be low in the serum starved state in most cell lines and increased with serum ( Figure 3 ) . # ::alignments 1-1 3-1.1.1.1 8-1.2.1.1 11-1.1.1.1.1.2.1.1.1 12-1.1.1.1.1.2 14-1.1.1.1.1 15-1.1.1 18-1.1.1.2 19-1.1.1.2.2.r 21-1.1.1.2.2.1.2 22-1.1.1.2.2.1 23-1.1.1.2.2 24-1.1.1.2.2.1.1.r 25-1.1.1.2.2.1.1.1 26-1.1.1.2.2.1.1 27-1.1.1.2.2.1.1 28-1.1 29-1.1.2 31-1.1.1.2.2.1.2 33-1.2.1 35-1.2.1.1 (c / contrast-01~e.1 :ARG2 (a / and~e.28 :op1 (t / tend-02~e.15 :ARG1 (p2 / phosphorylate-01~e.3 :ARG1 (s / site~e.14 :mod (a2 / amino-acid :mod 308 :name (n / name :op1 "threonine")) :ARG0-of (d / depend-01~e.12 :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "PIP3-PDK1"~e.11))))) :ARG2 (l / low-04~e.18 :ARG1 p2 :location~e.19 (s2 / state~e.23 :topic (s3 / starve-01~e.22 :ARG1~e.24 (c2 / cell-line~e.26,27 :quant (m2 / most~e.25)) :ARG2 (s4 / serum~e.21,31))))) :op2 (i / increase-01~e.29 :ARG1 p2 :ARG1-of (c3 / cause-01 :ARG0 s4))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.33 :mod 3~e.8,35))) # ::id pmid_2247_5322.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The notable exceptions were cell lines NZM12 , NZM40 and NZM52 which have comparatively high Thr308 phosphorylation in serum starved cells . # ::alignments 1-1.2 2-1 4-1.1.1 5-1.1.1 5-1.1.2 5-1.1.3 6-1.1.1.1.1 8-1.1.2.1.1 9-1.1 10-1.1.3.1.1 12-1.1.4 14-1.1.4.1.1 14-1.1.4.1.1.3 14-1.1.4.1.1.3.r 16-1.1.4.1 17-1.1.4.1.2.r 18-1.1.4.1.2.1.1 19-1.1.4.1.2.1 20-1.1.4.1.2 (e / except-01~e.2 :ARG1 (a / and~e.9 :op1 (c / cell-line~e.4,5 :name (n2 / name :op1 "NZM12"~e.6)) :op2 (c2 / cell-line~e.5 :name (n3 / name :op1 "NZM40"~e.8)) :op3 (c3 / cell-line~e.5 :name (n4 / name :op1 "NZM52"~e.10)) :ARG0-of (h / have-03~e.12 :ARG1 (p3 / phosphorylate-01~e.16 :ARG1 (a2 / amino-acid~e.14 :mod 308 :name (n5 / name :op1 "threonine") :ARG1-of~e.14 (h2 / high-02~e.14 :ARG1-of (c4 / comparable-03))) :location~e.17 (c5 / cell~e.20 :ARG1-of (s / starve-01~e.19 :ARG2 (s2 / serum~e.18)))))) :ARG1-of (n / notable-04~e.1 :ARG1-of (p2 / possible-01))) # ::id pmid_2247_5322.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of Thr308 in the NZM40 and NZM52 cell lines may be explained by the activating PIK3CA @ mutation in these cells . # ::alignments 0-1.1.2 3-1.1.2.2.r 5-1.1.2.2.1.1.1 6-1.1.2.2 7-1.1.2.2.2.1.1 8-1.1.2.2.1 8-1.1.2.2.2 9-1.1.2.2.1 10-1 12-1.1 13-1.1.1.r 15-1.1.1 17-1.1.1.1.1.1.1 19-1.1.1.1 22-1.1.1.2 (p2 / possible-01~e.10 :ARG1 (e / explain-01~e.12 :ARG0~e.13 (a / activate-01~e.15 :ARG1 (m / mutate-01~e.19 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.17))) :location a3~e.22) :ARG1 (p / phosphorylate-01~e.0 :ARG1 (a2 / amino-acid :mod 308 :name (n3 / name :op1 "threonine")) :location~e.3 (a3 / and~e.6 :op1 (c / cell-line~e.8,9 :name (n / name :op1 "NZM40"~e.5)) :op2 (c2 / cell-line~e.8 :name (n4 / name :op1 "NZM52"~e.7)))))) # ::id pmid_2247_5322.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These two cell lines also have a very low level of total PKB suggesting some feedback regulation of PKB gene expression in these cells . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 3-1.1 4-1.3 5-1 7-1.2.1.1 8-1.2.1 9-1.2 10-1.2.2.r 11-1.2.2 11-1.2.2.2 11-1.2.2.2.r 12-1.2.2.1.1 13-1.4 14-1.4.1.1.1 15-1.4.1.1 16-1.4.1 17-1.4.1.2.r 18-1.4.1.2.1.1.1 19-1.4.1.2.1 20-1.4.1.2 21-1.4.1.2.2.r 22-1.4.1.2.2 23-1.4.1.2.2 (h / have-03~e.5 :ARG0 (c / cell-line~e.2,3 :quant 2~e.1 :mod (t / this~e.0)) :ARG1 (l / level~e.9 :ARG1-of (l2 / low-04~e.8 :degree (v / very~e.7)) :quant-of~e.10 (e / enzyme~e.11 :name (n / name :op1 "PKB"~e.12) :ARG2-of~e.11 (t2 / total-01~e.11))) :mod (a / also~e.4) :ARG0-of (s / suggest-01~e.13 :ARG1 (r / regulate-01~e.16 :ARG0 (f / feedback~e.15 :quant (s2 / some~e.14)) :ARG1~e.17 (e2 / express-03~e.20 :ARG1 (g / gene~e.19 :name (n2 / name :op1 "PKB"~e.18)) :ARG3~e.21 c~e.22,23)))) # ::id pmid_2247_5322.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In support of this , NZM46 , which also has a PIK3CA @ mutation ( Figure 3 ) , also has very high PTEN levels ( Figure 2 ) which could explain the low Thr308 phosphorylation in these cells and the higher levels of total PKB compared to NZM40 and NZM52 , as PIP @₃@ levels would be predicted to be low despite the PIK3CA @ mutation . # ::alignments 1-1 2-1.2.r 3-1.2 5-1.1.1.1.1 8-1.1.4 9-1.1 9-1.1.1.2 12-1.1.1.2.1.1 14-1.1.1.2.1 16-1.1.1.2.1.2.1 18-1.1.1.2.1.2.1.1 22-1.1.4 23-1.1 24-1.1.2.1.1 25-1.1.2.1 26-1.1.2.2.1.1 27-1.1.2 29-1.1.2.1.2.1 31-1.1.2.1.2.1.1 35-1.1.3.2 36-1.1.3 38-1.1.3.4 40-1.1.3.1.1 42-1.2 43-1.1.1 43-1.1.3.1.2.1.2.1 43-1.1.3.1.2.1.2.2 44-1.1.3.1 46-1.1.3.1.2.1 46-1.1.3.1.2.1.1 46-1.1.3.1.2.1.1.r 47-1.1.3.1.2 48-1.1.3.1.2.2.r 49-1.1.3.1.2.2 49-1.1.3.1.2.2.2 49-1.1.3.1.2.2.2.r 50-1.1.3.1.2.2.1.1 51-1.1.3.1.2.1.2.r 53-1.1.3.1.2.1.2.1.1.1 54-1.1.3.1.2.1.2 55-1.1.3.1.2.1.2.2.1.1 60-1.1.1.2.1.2.1.1 62-1.1.3.3.1.1.1 65-1.1.3.3.1 68-1.1.3.3.1.1 69-1.1.3.3.1.1.2.r 72-1.1.3.3.1.1.2.1.1.1 74-1.1.3.3.1.1.2 (s / support-01~e.1 :ARG0 (h / have-03~e.9,23 :ARG0 (c5 / cell-line~e.43 :name (n7 / name :op1 "NZM46"~e.5) :ARG0-of (h5 / have-03~e.9 :ARG1 (m3 / mutate-01~e.14 :ARG1 g~e.12 :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod 3~e.18,60))) :mod a4)) :ARG1 (l5 / level~e.27 :ARG1-of (h4 / high-02~e.25 :degree (v / very~e.24) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.29 :mod 2~e.31))) :quant-of (p5 / protein :name (n8 / name :op1 "PTEN"~e.26))) :ARG0-of (e / explain-01~e.36 :ARG1 (a / and~e.44 :op1 (p2 / phosphorylate-01~e.40 :ARG1 (a2 / amino-acid :mod 308 :name (n / name :op1 "threonine")) :location c5) :op2 (l2 / level~e.47 :ARG1-of (h2 / high-02~e.46 :degree~e.46 (m / more~e.46) :compared-to~e.51 (a3 / and~e.54 :op1 (c2 / cell-line~e.43 :name (n3 / name :op1 "NZM40"~e.53)) :op2 (c3 / cell-line~e.43 :name (n4 / name :op1 "NZM52"~e.55)))) :quant-of~e.48 (e2 / enzyme~e.49 :name (n2 / name :op1 "PKB"~e.50) :ARG1-of~e.49 (t2 / total-01~e.49)))) :ARG1-of (p / possible-01~e.35) :ARG1-of (c4 / cause-01 :ARG0 (p3 / predict-01~e.65 :ARG1 (l3 / low-04~e.68 :ARG1 (l4 / level~e.62 :quant-of (p4 / protein :name (n5 / name :op1 "PIP3"))) :concession~e.69 (m2 / mutate-01~e.74 :ARG1 (g / gene :name (n6 / name :op1 "PIK3CA"~e.72)))))) :ARG1-of (l / low-04~e.38)) :mod (a4 / also~e.8,22)) :ARG1~e.2 (t / this~e.3,42)) # ::id pmid_2247_5322.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NZM46 shows suppression of phosphorylation by serum in the Thr308 site ( as with the Ser473 site ) . # ::alignments 0-1.1.1.1 1-1 2-1.2 3-1.2.1.r 4-1.2.1 5-1.2.1.1.r 6-1.2.1.1 10-1.2.1.2 10-1.3.1 16-1.2.1.2 16-1.3.1 (s / show-01~e.1 :ARG0 (c / cell-line :name (n2 / name :op1 "NZM46"~e.0)) :ARG1 (s2 / suppress-01~e.2 :ARG1~e.3 (p2 / phosphorylate-01~e.4 :ARG0~e.5 (s3 / serum~e.6) :ARG1 (s4 / site~e.10,16 :mod (a / amino-acid :mod 308 :name (n / name :op1 "threonine"))))) :ARG1-of (m / mean-01 :ARG2 (s5 / site~e.10,16 :mod (a2 / amino-acid :mod 473 :name (n3 / name :op1 "serine"))))) # ::id pmid_2247_5322.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of components of the mTOR pathway in melanoma cells and melanocytes # ::alignments 1-1 2-1.1.r 3-1.1 4-1.1.1.r 6-1.1.1.1.1 7-1.1.1 8-1.2.r 9-1.2.1.1.1.1 10-1.2.1 11-1.2 12-1.2.2 (p2 / phosphorylate-01~e.1 :ARG1~e.2 (c / component~e.3 :poss~e.4 (p / pathway~e.7 :name (n / name :op1 "mTOR"~e.6))) :location~e.8 (a / and~e.11 :op1 (c2 / cell~e.10 :source (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.9))) :op1 (m / melanocyte~e.12))) # ::id pmid_2247_5322.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of components of the protein translation machinery has been observed in a large percentage of melanomas and is predictive of a poor prognosis [ @ 35 @ ] . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1 3-1.1.1.1.1.r 5-1.1.1.1.1.1.1 6-1.1.1.1.1.1 7-1.1.1.1.1 10-1.1 11-1.1.2.r 13-1.1.2.1 14-1.1.2 15-1.1.2.2.r 16-1.1.2.2.1.1 17-1 19-1.2 20-1.2.2.r 22-1.2.2.1 23-1.2.2 26-1.3.1.1.1 (a2 / and~e.17 :op1 (o2 / observe-01~e.10 :ARG1 (a / activate-01~e.0 :ARG1~e.1 (c2 / component~e.2 :poss~e.3 (m / machinery~e.7 :ARG0-of (t / translate-02~e.6 :ARG2 (p2 / protein~e.5))))) :location~e.11 (p3 / percentage~e.14 :mod (l / large~e.13) :quant-of~e.15 (m2 / medical-condition :name (n / name :op1 "melanoma"~e.16)))) :op2 (p4 / predict-01~e.19 :ARG0 a :ARG1~e.20 (p5 / prognosis~e.23 :mod (p6 / poor~e.22))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c / cite-01 :ARG1 35~e.26)))) # ::id pmid_2247_5322.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PI3K signalling pathway can regulate protein translation machinery through mTORC1 and subsequent activation of p70S6K and phosphorylation of ribosomal protein S6 ( rpS6 ) . # ::alignments 1-1.1.1.1.1 2-1.1.1.2 3-1.1.1 4-1 5-1.1 6-1.1.2.1.1 7-1.1.2.1 8-1.1.2 10-1.1.3.1.1.1 11-1.1.3 12-1.1.3.2.2 12-1.1.3.2.2.r 13-1.1.3.2 14-1.1.3.2.1.r 15-1.1.3.2.1.1.1 16-1.1.3 17-1.1.3.3 18-1.1.3.3.1.r 19-1.1.3.3.1.1.1 20-1.1.3.3.1.1.2 21-1.1.3.3.1.1.3 (p2 / possible-01~e.4 :ARG1 (r / regulate-01~e.5 :ARG0 (p6 / pathway~e.3 :name (n5 / name :op1 "PI3K"~e.1) :ARG0-of (s / signal-07~e.2)) :ARG1 (m / machinery~e.8 :ARG0-of (t / translate-02~e.7 :ARG2 (p3 / protein~e.6))) :instrument (a / and~e.11,16 :op1 (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC1"~e.10)) :op2 (a2 / activate-01~e.13 :ARG1~e.14 (e / enzyme :name (n3 / name :op1 "p70S6K"~e.15)) :time~e.12 (s2 / subsequent~e.12)) :op3 (p / phosphorylate-01~e.17 :ARG1~e.18 (p5 / protein :name (n4 / name :op1 "ribosomal"~e.19 :op2 "protein"~e.20 :op3 "S6"~e.21)))))) # ::id pmid_2247_5322.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore we next determined the phosphorylation status of p70S6K ( Figure 4 ) . # ::alignments 0-1 1-1.1.1 2-1.1.3 3-1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.1.1.r 8-1.1.2.1.1.1.1 10-1.2.1 12-1.2.1.1 (c / cause-01~e.0 :ARG1 (d2 / determine-01~e.3 :ARG0 (w / we~e.1) :ARG1 (s2 / status~e.6 :mod (p2 / phosphorylate-01~e.5 :ARG1~e.7 (e / enzyme :name (n / name :op1 "p70S6K"~e.8)))) :time (n2 / next~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.10 :mod 4~e.12))) # ::id pmid_2247_5322.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The p70S6K was strongly expressed in all cell lines as well as in normal melanocytes but the pattern of phosphorylation of p70S6K and p85S6K at Thr389 did not correlate with the phosphorylation status of PKB nor did it correlate with genotypes ( Figure 4 ) . # ::alignments 1-1.1.1.1 3-1.1.1.3 4-1.1.1 4-1.1.2 5-1.1.1.2.r 6-1.1.1.2.1 7-1.1.1.2 8-1.1.1.2 9-1.1 10-1.1 11-1.1 12-1.1.2.1.r 13-1.1.2.1.1 14-1.1.2.1 15-1 17-1.2.1.2 18-1.2.1.2.1.r 19-1.2.1.2.1 20-1.2.1.2.1.1.r 21-1.2.1.2.1.1.1.3.1.1 22-1.2.1.2.1.1 23-1.2.1.2.1.1.2.3.1.1 27-1.2.1.1 27-1.2.1.1.r 27-1.2.2.1 28-1.2.1 29-1.2.1.3.r 31-1.2.1.3 33-1.2.1.3.1.r 34-1.2.1.3.1.1.1 35-1.2.2.1.r 37-1.2.2.2 38-1.2.2 39-1.2.2.3.r 40-1.2.2.3 42-1.3.1 (c / contrast-01~e.15 :ARG1 (a / and~e.9,10,11 :op1 (e / express-03~e.4 :ARG1 e3~e.1 :ARG3~e.5 (c4 / cell-line~e.7,8 :mod (a5 / all~e.6)) :manner (s / strong-02~e.3)) :op2 (e2 / express-03~e.4 :ARG3~e.12 (m / melanocyte~e.14 :ARG1-of (n4 / normal-02~e.13)))) :ARG2 (a2 / and :op1 (c2 / correlate-01~e.28 :polarity~e.27 -~e.27 :ARG1 (p / pattern-01~e.17 :ARG1~e.18 (p2 / phosphorylate-01~e.19 :ARG1~e.20 (a3 / and~e.22 :op1 (a6 / amino-acid :mod 389 :name (n6 / name :op1 "threonine") :part-of (e3 / enzyme :name (n / name :op1 "p70S6K"~e.21))) :op2 (a4 / amino-acid :mod 389 :name (n3 / name :op1 "threonine") :part-of (e4 / enzyme :name (n2 / name :op1 "p85S6K"~e.23)))))) :ARG2~e.29 (p3 / phosphorylate-01~e.31 :ARG1~e.33 (e5 / enzyme :name (n5 / name :op1 "PKB"~e.34)))) :op2 (c3 / correlate-01~e.38 :polarity~e.35 -~e.27 :ARG1 p~e.37 :ARG2~e.39 (g / genotype~e.40))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.42 :mod "f4"))) # ::id pmid_2247_5322.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In melanocytes , the observed phosphorylation of Ser235 @/@ 236 was serum dependent while Ser240 @/@ 244 site , which is phosphorylated by p70S6K , was phosphorylated even in the absence of serum . # ::alignments 1-1.1.1.2.1 4-1.1.1.2 5-1.1.1 8-1.1.1.1 9-1.1.1.1.2.1 11-1.1.2 12-1.1 13-1 15-1.2.1.1.2 16-1.2.1.1.2.2.1 17-1.2.1.1 21-1.2.1.1.1 22-1.2.1.1.1.1.r 23-1.2.1.1.1.1.1.1 26-1.2.1 30-1.2.2 31-1.2.2.1.r 32-1.2.2.1 (c / contrast-01~e.13 :ARG1 (d / depend-01~e.12 :ARG0 (p2 / phosphorylate-01~e.5 :ARG1 (s3 / slash~e.8 :op1 (a2 / amino-acid :mod 235 :name (n / name :op1 "serine")) :op2 (a3 / amino-acid :mod 236~e.9 :name (n4 / name :op1 "serine"))) :ARG1-of (o / observe-01~e.4 :location (m / melanocyte~e.1))) :ARG1 (s2 / serum~e.11)) :ARG2 (h / have-concession-91 :ARG1 (p / phosphorylate-01~e.26 :ARG1 (s / site~e.17 :ARG1-of (p5 / phosphorylate-01~e.21 :ARG2~e.22 (e / enzyme :name (n3 / name :op1 "p70S6K"~e.23))) :mod (s4 / slash~e.15 :op1 (a4 / amino-acid :mod 240 :name (n2 / name :op1 "serine")) :op2 (a5 / amino-acid :mod 244~e.16 :name (n5 / name :op1 "serine"))))) :ARG2 (a / absent-01~e.30 :ARG1~e.31 s2~e.32))) # ::id pmid_2247_5322.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In most of the cell lines , we observed serum independent phosphorylation of rpS6 while in NZM43 and to some degree , NZM10 and NZM15 showed serum dependent phosphorylation . # ::alignments 1-1.1.3.1.1.1 2-1.1.3.1.1.1.r 4-1.1.3.1.1 5-1.1.3 7-1.1.1 8-1.1 9-1.1.2.2.2 10-1.1.2.2 10-1.1.2.2.1 10-1.1.2.2.1.r 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1 14-1 15-1.2.r 16-1.2.2.1.1.1 17-1.2.2.2 19-1.2.2.2.3 20-1.2.2.2.3.r 22-1.2.2.2.1.1.1 23-1.2.2.2 24-1.2.2.2.2.1.1 25-1.2 26-1.2.1.1.1 27-1.2.1.1 28-1.2.1 (c6 / contrast-01~e.14 :ARG1 (o / observe-01~e.8 :ARG0 (w / we~e.7) :ARG1 (p / phosphorylate-01~e.11 :ARG1~e.12 (p3 / protein :name (n3 / name :op1 "rpS6"~e.13)) :ARG0-of (d2 / depend-01~e.10 :polarity~e.10 -~e.10 :ARG1 s2~e.9)) :location (c3 / cell-line~e.5 :ARG1-of (i / include-91 :ARG2 (c4 / cell-line~e.4 :quant~e.2 (m / most~e.1))))) :ARG2~e.15 (s / show-01~e.25 :ARG1 (p2 / phosphorylate-01~e.28 :ARG0-of (d / depend-01~e.27 :ARG1 (s2 / serum~e.26))) :location (a2 / and :op1 (c5 / cell-line :name (n4 / name :op1 "NZM43"~e.16)) :op2 (a3 / and~e.17,23 :op1 (c / cell-line :name (n / name :op1 "NZM10"~e.22)) :op2 (c2 / cell-line :name (n2 / name :op1 "NZM15"~e.24)) :degree~e.20 (s3 / some~e.19))))) # ::id pmid_2247_5322.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , we observed little phosphorylation of rpS6 at both sites in BRAF @ mutant cell lines , NZM3 and NZM12 ( Figure 5 ) . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1.1 8-1.2.3.r 9-1.2.3.2 10-1.2.3 13-1.2.3.1.3.1.1.1 15-1.2.3.1.3 16-1.2.3.1.1 17-1.2.3.1.1 17-1.2.3.1.2 19-1.2.3.1.1.1.1 20-1.2.3.1 21-1.2.3.1.2.1.1 23-1.4.1 25-1.4.1.1 (o / observe-01~e.3 :ARG0 (w / we~e.2) :ARG1 (p / phosphorylate-01~e.5 :ARG1~e.6 (p2 / protein :name (n / name :op1 "rpS6"~e.7)) :degree (l / little~e.4) :location~e.8 (s / site~e.10 :location (a / and~e.20 :op1 (c / cell-line~e.16,17 :name (n3 / name :op1 "NZM3"~e.19)) :op2 (c2 / cell-line~e.17 :name (n4 / name :op1 "NZM12"~e.21)) :mod (m / mutate-01~e.15 :ARG3 (g / gene :name (n2 / name :op1 "BRAF"~e.13)))) :mod (b / both~e.9))) :ARG2-of (i / interest-01~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod 5~e.25))) # ::id pmid_2247_5322.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , phosphorylation of rpS6 is independent of PI3K pathway activation in these melanoma cell lines . # ::alignments 0-1 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1.1 6-1.1 6-1.1.1 6-1.1.1.r 7-1.1.3.r 8-1.1.3.1.1.1 9-1.1.3.1 10-1.1.3 11-1.1.3.2.r 12-1.1.3.2.1 13-1.1.3.2.2.1.1 14-1.1.3.2 15-1.1.3.2 (c2 / cause-01~e.0 :ARG1 (d2 / depend-01~e.6 :polarity~e.6 -~e.6 :ARG0 (p / phosphorylate-01~e.2 :ARG1~e.3 (p3 / protein :name (n / name :op1 "rpS6"~e.4))) :ARG1~e.7 (a / activate-01~e.10 :ARG1 (p2 / pathway~e.9 :name (n2 / name :op1 "PI3K"~e.8)) :location~e.11 (c / cell-line~e.14,15 :mod (t / this~e.12) :source (m / medical-condition :name (n3 / name :op1 "melanoma"~e.13)))))) # ::id pmid_2247_5322.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In these cells the phosphorylation of rpS6 is likely due to input from the ERK signalling cascade as can be seen in other cell types [ @ 36 @ ] . # ::alignments 1-1.1.2.2.1 2-1.1.2.2 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 8-1 9-1.1 10-1.1 11-1.1.1 12-1.1.1.1.r 14-1.1.1.1.1.1 15-1.1.1.1.2 17-1.3.r 18-1.3.1 20-1.3 21-1.3.2.r 22-1.3.2.2 23-1.3.2.1 24-1.3.2 27-1.2.1.1.1 (l / likely-01~e.8 :ARG1 (c / cause-01~e.9,10 :ARG0 (i / input~e.11 :source~e.12 (p5 / pathway :name (n / name :op1 "ERK"~e.14) :ARG0-of (s / signal-07~e.15))) :ARG1 (p3 / phosphorylate-01~e.4 :ARG1~e.5 (p4 / protein :name (n2 / name :op1 "rpS6"~e.6)) :ARG3 (c2 / cell~e.2 :mod (t / this~e.1)))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c5 / cite-01 :ARG1 36~e.27))) :ARG1-of~e.17 (s3 / see-01~e.20 :ARG1-of (p2 / possible-01~e.18) :location~e.21 (t2 / type-03~e.24 :ARG2 (c4 / cell~e.23) :mod (o / other~e.22)))) # ::id pmid_2247_5322.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation of components of the ERK pathway in melanoma cells and melanocytes # ::alignments 1-1 2-1.1.r 3-1.1 4-1.1.1.r 6-1.1.1.1.1 7-1.1.1 8-1.2.r 9-1.2.1.1.1.1 10-1.2.1 11-1.2 12-1.2.2 (p / phosphorylate-01~e.1 :ARG1~e.2 (c / component~e.3 :part-of~e.4 (p2 / pathway~e.7 :name (n / name :op1 "ERK"~e.6))) :location~e.8 (a / and~e.11 :op1 (c2 / cell~e.10 :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.9))) :op2 (m / melanocyte~e.12))) # ::id pmid_2247_5322.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also analysed the activation status of the MAPK pathway in NZM cell lines with NRAS @ or BRAF @ mutations and cell lines which additionally harbour PTEN @ or PIK3CA @ mutations . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.1 5-1.2 6-1.2.1.2.r 8-1.2.1.2.1.1 9-1.2.1.2 10-1.2.1.2.2.r 11-1.2.1.2.2.1.1 12-1.2.1.2.2 13-1.2.1.2.2 16-1.2.1.1.1.1.1.1.1 18-1.2.1.1.1 20-1.2.1.1.1.2.1.1.1 22-1.2.1.1.1.2 23-1.2.1.1 24-1.2.1.1.2 25-1.2.1.1.2 27-1.2.1.1.2.1.2 27-1.2.1.1.2.1.2.r 30-1.2.1.1.2.1.1.1.1.1.1 32-1.2.1.1.2.1.1 34-1.2.1.1.2.1.1.2.1.1.1 36-1.2.1.1.1.1 36-1.2.1.1.1.2 36-1.2.1.1.2.1.1.1 36-1.2.1.1.2.1.1.2 (a / analyze-01~e.2 :ARG0 (w / we~e.0) :ARG1 (s / status~e.5 :mod (a3 / activate-01~e.4 :ARG0 (a4 / and~e.23 :op1 (o / or~e.18 :op1 (m / mutate-01~e.36 :ARG1 (g2 / gene :name (n6 / name :op1 "NRAS"~e.16))) :op2 (m2 / mutate-01~e.22,36 :ARG1 (g3 / gene :name (n5 / name :op1 "BRAF"~e.20)))) :op2 (c2 / cell-line~e.24,25 :ARG0-of (h / harbor-01 :ARG1 (o2 / or~e.32 :op1 (m4 / mutate-01~e.36 :ARG1 (g / gene :name (n / name :op1 "PTEN"~e.30))) :op2 (m3 / mutate-01~e.36 :ARG1 (g4 / gene :name (n2 / name :op1 "PIK3CA"~e.34)))) :manner~e.27 (a5 / additional~e.27)))) :ARG1~e.6 (p2 / pathway~e.9 :name (n3 / name :op1 "MAPK"~e.8) :location~e.10 (c / cell-line~e.12,13 :name (n4 / name :op1 "NZM"~e.11))))) :mod (a2 / also~e.1)) # ::id pmid_2247_5322.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activation of MEK and then ERK in response to oncogenic NRAS @ and BRAF @ mutations is proposed to be the basis of a MAPK pathway addiction by these cells [ @ 37 @ ] . # ::alignments 1-1.1.1 1-1.1.2 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1 5-1.1.2.1 6-1.1.2.2.1.1 8-1.1.3 9-1.1.3.1.3 10-1.1.3.1.3 10-1.1.3.1.3.1.2.1 12-1.1.3.1.1.1.1.1 14-1.1.3.1 16-1.1.3.1.2.1.1.1 18-1.1.3.1.1 18-1.1.3.1.2 20-1 24-1.2 25-1.2.1.r 27-1.2.1.2.1.1 28-1.2.1.2 29-1.2.1 30-1.2.1.1.r 31-1.2.1.1.1 32-1.2.1.1 35-1.3.1.1.1 (p4 / propose-01~e.20 :ARG1 (a / and~e.4 :op1 (a2 / activate-01~e.1 :ARG1~e.2 (e / enzyme :name (n / name :op1 "MEK"~e.3))) :op2 (a3 / activate-01~e.1 :time (t / then~e.5) :mod (e2 / enzyme :name (n2 / name :op1 "ERK"~e.6))) :ARG2-of (r / respond-01~e.8 :ARG1 (a4 / and~e.14 :op1 (m / mutate-01~e.18 :ARG1 (g / gene :name (n4 / name :op1 "NRAS"~e.12))) :op2 (m2 / mutate-01~e.18 :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF"~e.16))) :ARG0-of (c3 / cause-01~e.9,10 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.10)))))) :ARG2 (b / base-02~e.24 :ARG0~e.25 (a5 / addictive-02~e.29 :ARG0~e.30 (c / cell~e.32 :mod (t2 / this~e.31)) :ARG1 (p3 / pathway~e.28 :name (n3 / name :op1 "MAPK"~e.27))) :ARG1 a2) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG0-of (c2 / cite-01 :ARG1 37~e.35)))) # ::id pmid_2247_5322.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Total MEK protein was abundantly expressed in all NZM cell lines as well as melanocytes ( Figure 6 ) . # ::alignments 0-1.1.2 1-1.1.1.1 4-1.3 5-1 6-1.2.r 7-1.2.1.2 8-1.2.1.1.1 9-1.2.1 10-1.2.1 11-1.2 12-1.2 13-1.2 14-1.2.2 16-1.4.1 18-1.4.1.1 (e / express-03~e.5 :ARG2 (e2 / enzyme :name (n / name :op1 "MEK"~e.1) :mod (t / total~e.0)) :ARG3~e.6 (a3 / and~e.11,12,13 :op1 (c / cell-line~e.9,10 :name (n2 / name :op1 "NZM"~e.8) :mod (a2 / all~e.7)) :op2 (m / melanocyte~e.14)) :ARG1-of (a / abound-01~e.4) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.16 :mod 6~e.18))) # ::id pmid_2247_5322.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However levels of MEK phosphorylation varied considerably and were not directly related to genotype ( Figure 6 ) . # ::alignments 0-1 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1.1.1.1 4-1.1.1.1.1 5-1.1.1 6-1.1.1.2 7-1.1 9-1.1.2.1 9-1.1.2.1.r 10-1.1.2.4 11-1.1.2 12-1.1.2.3.r 13-1.1.2.3 15-1.2.1 17-1.2.1.1 (h / have-concession-91~e.0 :ARG1 (a2 / and~e.7 :op1 (v / vary-01~e.5 :ARG1 (l / level~e.1 :degree-of~e.2 (p / phosphorylate-01~e.4 :ARG2 (e / enzyme :name (n / name :op1 "MEK"~e.3)))) :ARG2 (c3 / considerable~e.6)) :op2 (r / relate-01~e.11 :polarity~e.9 -~e.9 :ARG1 l :ARG2~e.12 (g / genotype~e.13) :ARG1-of (d2 / direct-02~e.10))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod 6~e.17))) # ::id pmid_2247_5322.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , NRAS @- @ only mutant NZM cell lines , NZM10 , NZM15 and NZM42 showed very low levels of MEK phosphorylation ( Figure 6 ) . # ::alignments 0-1.1.1.3.1 3-1.1.1.2.1.1.1 6-1.1.1.4 7-1.1.1.2 8-1.1.1.1.1 9-1.1.1 10-1.1.1 10-1.1.1.3.1.1 10-1.1.1.3.1.2 10-1.1.1.3.1.3 12-1.1.1.3.1.1.1.1 14-1.1.1.3.1.2.1.1 15-1.1.1.3.1 16-1.1.1.3.1.3.1.1 17-1.1 18-1.1.2.1.1 19-1.1.2.1 20-1.1.2 21-1.1.2.2.r 22-1.1.2.2.1.1.1 23-1.1.2.2 25-1.2.1 27-1.2.1.1 (a2 / and :op1 (s2 / show-01~e.17 :ARG0 (c / cell-line~e.9,10 :name (n / name :op1 "NZM"~e.8) :mod (m / mutate-01~e.7 :ARG1 (g / gene :name (n2 / name :op1 "NRAS"~e.3))) :ARG1-of (m2 / mean-01 :ARG2 (a / and~e.0,15 :op1 (c2 / cell-line~e.10 :name (n3 / name :op1 "NZM10"~e.12)) :op2 (c3 / cell-line~e.10 :name (n4 / name :op1 "NZM15"~e.14)) :op3 (c4 / cell-line~e.10 :name (n5 / name :op1 "NZM42"~e.16)))) :mod (o / only~e.6)) :ARG1 (l / level~e.20 :ARG1-of (l2 / low-04~e.19 :degree (v / very~e.18)) :degree-of~e.21 (p / phosphorylate-01~e.23 :ARG1 (e / enzyme :name (n6 / name :op1 "MEK"~e.22))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod 6~e.27))) # ::id pmid_2247_5322.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK was constitutively phosphorylated in almost all cell lines , and unlike melanocytes , NZM cell lines showed serum independent MEK and ERK phosphorylation patterns ( Figures 6 and 7 ) . # ::alignments 0-1.1.1.1.1 2-1.1.2 2-1.1.2.r 3-1.1 4-1.1.3.r 5-1.1.3.1.1 6-1.1.3.1 7-1.1.3 8-1.1.3 10-1.2.2 11-1.2.3 11-1.2.3.1 11-1.2.3.1.r 12-1.2.3.2 14-1.2.1.1.1 15-1.2.1 16-1.2.1 17-1.2 18-1.2.2.3.2 19-1.2.2.3 19-1.2.2.3.1 19-1.2.2.3.1.r 20-1.2.2.1.1.1.1.1 21-1 21-1.2.2 22-1.1.1.1.1 23-1.2.2.1.1 23-1.2.2.2.1 24-1.2.2.1 24-1.2.2.2 26-1.3.1.1 26-1.3.1.2 28-1.3.1.1.1 30-1.3.1 32-1.3.1.2.1 (a / and~e.21 :op1 (p4 / phosphorylate-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.0,22)) :manner~e.2 (c / constitutive~e.2) :location~e.4 (c2 / cell-line~e.7,8 :mod (a2 / all~e.6 :degree (a3 / almost~e.5)))) :op2 (s / show-01~e.17 :ARG0 (c3 / cell-line~e.15,16 :name (n3 / name :op1 "NZM"~e.14)) :ARG1 (a4 / and~e.10,21 :op1 (p5 / pattern-01~e.24 :ARG1 (p7 / phosphorylate-01~e.23 :ARG1 (e2 / enzyme :name (n4 / name :op1 "MEK"~e.20)))) :op2 (p6 / pattern-01~e.24 :ARG1 (p8 / phosphorylate-01~e.23 :ARG1 e)) :ARG0-of (d / depend-01~e.19 :polarity~e.19 -~e.19 :ARG1 (s2 / serum~e.18))) :ARG1-of (r2 / resemble-01~e.11 :polarity~e.11 -~e.11 :ARG2 (m / melanocyte~e.12))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.30 :op1 (f / figure~e.26 :mod 6~e.28) :op2 (f2 / figure~e.26 :mod 7~e.32)))) # ::id pmid_2247_5322.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , MEK phosphorylation status did not correlate with ERK phosphorylation patterns . # ::alignments 0-1 2-1.1.2.1.1.1.1 3-1.1.2.1 4-1.1.2 6-1.1.1 6-1.1.1.r 7-1.1 8-1.1.3.r 9-1.1.3.1.1.1.1 10-1.1.3.1 11-1.1.3 (a / and~e.0 :op2 (c / correlate-01~e.7 :polarity~e.6 -~e.6 :ARG1 (s / status~e.4 :mod (p4 / phosphorylate-01~e.3 :ARG1 (e2 / enzyme :name (n / name :op1 "MEK"~e.2)))) :ARG2~e.8 (p5 / pattern-01~e.11 :ARG1 (p6 / phosphorylate-01~e.10 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"~e.9)))))) # ::id pmid_2282_9094.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma ( PMID : 22829094 ) # ::alignments 1-1.1.2.1.1.1 2-1.1 2-1.1.2 2-1.1.2.r 3-1.1.1.1 4-1 5-1.2.1 6-1.2 7-1.2.2 8-1.4.r 9-1.4.1.1 10-1.4.1.2 (r / regulate-01~e.4 :ARG0 (s / small-molecule~e.2 :name (n / name :op1 "AZD1480"~e.3) :ARG0-of~e.2 (i2 / inhibit-01~e.2 :ARG1 (e / enzyme :name (n2 / name :op1 "JAK"~e.1)))) :ARG1 (a / and~e.6 :op1 (p / proliferate-01~e.5) :op2 (i3 / immunity~e.7)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID22829094")) :location~e.8 (d2 / disease :name (n4 / name :op1 "Hodgkin"~e.9 :op2 "lymphoma"~e.10))) # ::id pmid_2282_9094.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2282_9094.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression of activated JAK2 in cultured HL cells # ::alignments 1-1 2-1.1.r 3-1.1.2 4-1.1.1.1 5-1.2.r 6-1.2.1 7-1.2.2.1.1 8-1.2 (e / express-03~e.1 :ARG2~e.2 (e2 / enzyme :name (n / name :op1 "JAK2"~e.4) :ARG1-of (a / activate-01~e.3)) :ARG3~e.5 (c / cell~e.8 :ARG1-of (c2 / culture-01~e.6) :mod (d / disease :name (n2 / name :op1 "HL"~e.7)))) # ::id pmid_2282_9094.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To explore the potential therapeutic value of the JAK2 inhibitor AZD1480 in HL , we initially examined the expression pattern of its protein target , the active , phosphorylated form of JAK2 Y1007 @/@ 1008 , in cultured HL cells . # ::alignments 1-1.4 3-1.4.3.3 4-1.4.3.2 5-1.4.3 6-1.4.3.1.r 8-1.4.3.1.2.1 9-1.4.3.1 9-1.4.3.1.2 9-1.4.3.1.2.r 10-1.4.3.1.1.1 11-1.4.2.r 12-1.4.2 14-1.1 15-1.3 16-1 18-1.2.1 19-1.2 23-1.2.1.1 28-1.2.1.1.2.4 29-1.2.1.1.2.3.2 30-1.2.1.1.2.3.2.r 31-1.2.1.1.2.3.1.1 34-1.2.1.1.2.1 36-1.2.1.2.r 37-1.2.1.2.1 38-1.2.1.2.2.1.1 39-1.2.1.2 (e / examine-01~e.16 :ARG0 (w / we~e.14) :ARG1 (p / pattern-01~e.19 :ARG1 (e2 / express-03~e.18 :ARG2 (t2 / target-01~e.23 :ARG0 s :ARG1 (a / amino-acid :mod "1007/1008"~e.34 :name (n2 / name :op1 "tyrosine") :part-of (e3 / enzyme :name (n / name :op1 "JAK2"~e.31) :mod~e.30 (f / form~e.29)) :ARG3-of (p3 / phosphorylate-01~e.28) :ARG1-of (a2 / activate-01))) :ARG3~e.36 (c / cell~e.39 :ARG1-of (c2 / culture-01~e.37) :mod (d / disease :name (n4 / name :op1 "HL"~e.38))))) :time (i2 / initial~e.15) :purpose (e4 / explore-01~e.1 :ARG0 w :ARG1~e.11 c~e.12 :ARG2 (v / value-01~e.5 :ARG1~e.6 (s / small-molecule~e.9 :name (n3 / name :op1 "AZD1480"~e.10) :ARG0-of~e.9 (i / inhibit-01~e.9 :ARG1 e3~e.8)) :mod (t3 / therapy~e.4) :mod (p4 / potential~e.3)))) # ::id pmid_2282_9094.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We hypothesized that cells with high levels of p @-@ JAK2 would be more sensitive to the antiproliferative effect of AZD1480 than cells with lower levels of p @-@ JAK2 . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1 5-1.2.1.1.1.2 6-1.2.1.1.1 7-1.2.1.1.1.1.r 8-1.2.1.1.1.1.2 10-1.2.1.1.1.1.1.1 13-1.2.3 13-1.2.4.1.1.2.1 14-1.2 15-1.2.2.r 17-1.2.2.2 17-1.2.2.2.1 17-1.2.2.2.1.r 18-1.2.2 19-1.2.2.1.r 20-1.2.2.1.1.1 21-1.2.4.r 22-1.2.4 24-1.2.4.1.1.2 24-1.2.4.1.1.2.1 24-1.2.4.1.1.2.1.r 25-1.2.4.1.1 26-1.2.4.1.1.1.r 27-1.2.4.1.1.1 28-1.2.4.1.1.1 29-1.2.4.1.1.1 (h / hypothesize-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (s / sensitive-03~e.14 :ARG0 (c / cell~e.3 :ARG0-of (h2 / have-03 :ARG1 (l2 / level~e.6 :quant-of~e.7 (e2 / enzyme :name (n / name :op1 "JAK2"~e.10) :ARG3-of (p / phosphorylate-01~e.8)) :ARG1-of (h3 / high-02~e.5)))) :ARG1~e.15 (a / affect-01~e.18 :ARG0~e.19 (s2 / small-molecule :name (n2 / name :op1 "AZD1480"~e.20)) :ARG0-of (c2 / counter-01~e.17 :ARG1~e.17 (p2 / proliferate-01~e.17))) :degree (m2 / more~e.13) :compared-to~e.21 (c3 / cell~e.22 :ARG0-of (h4 / have-03 :ARG1 (l3 / level~e.25 :quant-of~e.26 e2~e.27,28,29 :ARG1-of (l / low-04~e.24 :degree~e.24 (m / more~e.13,24))))))) # ::id pmid_2282_9094.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found p @-@ JAK2 to be expressed in two of the four HL cell lines ( Figure 1a ) . # ::alignments 0-1.1 1-1 2-1.2.1.2 4-1.2.1.1.1 7-1.2 8-1.2.2.r 9-1.2.2.1 12-1.2.2.2.1.1 13-1.2.2.2.1.2.1.1 14-1.2.2 14-1.2.2.2.1 15-1.2.2.2.1 18-1.3.1 19-1.3.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.7 :ARG2 (e2 / enzyme :name (n / name :op1 "JAK2"~e.4) :ARG3-of (p / phosphorylate-01~e.2)) :ARG3~e.8 (c / cell-line~e.14 :quant 2~e.9 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.14,15 :quant 4~e.12 :mod (d2 / disease :name (n2 / name :op1 "HL"~e.13)))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.18 :mod "1a"~e.19))) # ::id pmid_2282_9094.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok None of the HL cell lines expressed p @-@ JAK1 Y1022 @/@ 1023 , two cell lines expressed p @-@ TYK2 Y1054 @/@ 1055 , and only one cell line ( L @-@ 540 ) expressed p @-@ JAK3 Y980 ( Figure 1a ) . # ::alignments 0-1.1.2.1 1-1.1.2.1.r 3-1.1.2.2.1.1 4-1.1.2 5-1.1.2 6-1.1 7-1.1.1.2 7-1.2.1.2 9-1.1.1.1.1 12-1.1.1.2.1.1 14-1.2.2.1 15-1.2.2 16-1.2.2 17-1.2 18-1.3.1.2 20-1.2.1.1.1 23-1.2.1.2.1.1 25-1 26-1.3.2.2 27-1.3.2.1 28-1.3.2 29-1.3.2 31-1.3.2.3.1.1.1 33-1.3.2.3.1.1.1 35-1.3 36-1.3.1.2 38-1.3.1.1.1 42-1.4.1 43-1.4.1.1 (a / and~e.25 :op1 (e / express-03~e.6 :ARG2 (e2 / enzyme :name (n2 / name :op1 "JAK1"~e.9) :ARG3-of (p / phosphorylate-01~e.7 :ARG1 (a2 / amino-acid :mod "1022/1023"~e.12 :name (n3 / name :op1 "tyrosine")))) :ARG3 (c / cell-line~e.4,5 :quant~e.1 (n / none~e.0) :mod (d2 / disease :name (n9 / name :op1 "HL"~e.3)))) :op2 (e3 / express-03~e.17 :ARG2 (e4 / enzyme :name (n4 / name :op1 "TYK2"~e.20) :ARG3-of (p2 / phosphorylate-01~e.7 :ARG1 (a3 / amino-acid :mod "1054/1055"~e.23 :name (n5 / name :op1 "tyrosine")))) :ARG3 (c2 / cell-line~e.15,16 :quant 2~e.14)) :op3 (e5 / express-03~e.35 :ARG2 (e6 / enzyme :name (n7 / name :op1 "JAK3"~e.38) :ARG3-of (p3 / phosphorylate-01~e.18,36 :ARG1 (a4 / amino-acid :mod 980 :name (n8 / name :op1 "tyrosine")))) :ARG3 (c3 / cell-line~e.28,29 :quant 1~e.27 :mod (o / only~e.26) :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :name (n6 / name :op1 "L-540"~e.31,33))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.42 :mod "1a"~e.43))) # ::id pmid_2282_9094.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the activation pattern of the JAK family members is rather heterogeneous in the HL cell lines . # ::alignments 0-1 3-1.1.1.1 4-1.1.1 5-1.1.1.1.1.r 7-1.1.1.1.1.1.1.1.1 8-1.1.1.1.1.1.1 9-1.1.1.1.1 10-1.1.1.r 12-1.1 13-1.1.1.2.r 15-1.1.1.2.1.1.1 16-1.1.1.2 17-1.1.1.2 (c / cause-01~e.0 :ARG1 (h / heterogeneity~e.12 :domain~e.10 (p / pattern-01~e.4 :ARG1 (a / activate-01~e.3 :ARG1~e.5 (m / member~e.9 :ARG1-of (i / include-91 :ARG2 (p2 / protein-family~e.8 :name (n / name :op1 "JAK"~e.7))))) :location~e.13 (c2 / cell-line~e.16,17 :mod (d / disease :name (n2 / name :op1 "HL"~e.15)))))) # ::id pmid_2282_9094.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Next , we investigated the expression pattern of the active phosphorylated form of downstream ( p @-@ STATs ) . # ::alignments 0-1.3 2-1.1 3-1 5-1.2.1 6-1.2 10-1.2.1.1.2 11-1.2.1.1.1 12-1.2.1.1.1.r 13-1.2.1.1 15-1.2.1.1.2 (i / investigate-01~e.3 :ARG0 (w / we~e.2) :ARG1 (p / pattern-01~e.6 :ARG1 (e / express-03~e.5 :ARG2 (d / downstream~e.13 :mod~e.12 (f / form~e.11) :ARG3-of (p2 / phosphorylate-01~e.10,15) :ARG1-of (a / activate-01) :ARG1-of (m / mean-01 :ARG2 (p3 / protein :name (n2 / name :op1 "STAT") :ARG3-of p2))))) :time (n / next~e.0)) # ::id pmid_2282_9094.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found p @-@ STAT3 , p @-@ STAT5 and p @-@ STAT6 to be expressed in the three cell lines that expressed at least one active phosphorylated member of the JAK family : HD @-@ LM2 , L @-@ 428 and L @-@ 540 ( Figure 1a ) . # ::alignments 0-1.1 1-1 2-1.2.1.1.2 4-1.2.1.1.1.1 6-1.2.1.1.2 8-1.2.1.2.1.1 9-1.2.1 10-1.2.1.1.2 12-1.2.1.3.1.1 15-1.2 16-1.2.2.r 18-1.2.2.1 19-1.2.2 20-1.2.2 22-1.2.2.2 23-1.2.2.2.1.2 24-1.2.2.2.1.2 25-1.2.2.2.1.2.1 27-1.2.2.2.1.4 28-1.2.2.2.1 31-1.2.2.2.1.3.1.1.1 32-1.2.2.2.1.3.1 34-1.2.2.3.1.1.1.1 36-1.2.2.3.1.1.1.1 38-1.2.2.3.1.2.1.1 38-1.2.2.3.1.3.1.1 40-1.2.2.3.1.2.1.1 41-1.2.2.3.1 42-1.2.2.3.1.2.1.1 42-1.2.2.3.1.3.1.1 44-1.2.2.3.1.3.1.1 47-1.3.1 48-1.3.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.15 :ARG2 (a3 / and~e.9 :op1 (p / protein :name (n / name :op1 "STAT3"~e.4) :ARG3-of (p2 / phosphorylate-01~e.2,6,10)) :op2 (p3 / protein :name (n2 / name :op1 "STAT5"~e.8) :ARG3-of p2) :op3 (p5 / protein :name (n3 / name :op1 "STAT6"~e.12) :ARG3-of p2)) :ARG3~e.16 (c / cell-line~e.19,20 :quant 3~e.18 :ARG1-of (e2 / express-03~e.22 :ARG2 (m / member~e.28 :ARG1-of (a4 / activate-01) :quant (a / at-least~e.23,24 :op1 1~e.25) :ARG1-of (i / include-91 :ARG2 (p4 / protein-family~e.32 :name (n4 / name :op1 "JAK"~e.31))) :ARG3-of p2~e.27)) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and~e.41 :op1 (c2 / cell-line :name (n5 / name :op1 "HD-LM2"~e.34,36)) :op2 (c3 / cell-line :name (n6 / name :op1 "L-428"~e.38,40,42)) :op3 (c4 / cell-line :name (n7 / name :op1 "L-540"~e.38,42,44)))))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure~e.47 :mod "1a"~e.48))) # ::id pmid_2282_9094.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with a previous report , the KM @-@ H2 cell line did not express p @-@ JAKs or p @-@ STAT3 , pSTAT5 or pSTAT6 proteins ; ^{19 @} neither did the three samples of PBMCs isolated from healthy donors . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1.1 4-1.3.1 7-1.1.3.1.1 9-1.1.3.1.1 10-1.2.2 11-1.1.3 13-1.1.1 13-1.1.1.r 13-1.2.1 14-1.1 14-1.2 15-1.1.2.1.2 17-1.1.2.1.1.1 18-1.1.2 19-1.1.2.2.2 21-1.1.2.2.1.1 24-1.1.2 26-1.1.2.2 26-1.1.2.3 26-1.1.2.4 30-1.1.4.1.1.1 33-1.2.1.r 36-1.2.2.1 37-1.2.2.3 40-1.2.2.4 41-1.2.2.4.1.r 42-1.2.2.4.1.2 43-1.2.2.4.1 43-1.2.2.4.1.1 43-1.2.2.4.1.1.r (a / and :op1 (e / express-03~e.14 :polarity~e.13 -~e.13 :ARG2 (o / or~e.18,24 :op1 (e2 / enzyme :name (n2 / name :op1 "JAK"~e.17) :ARG3-of (p2 / phosphorylate-01~e.15)) :op2 (p3 / protein~e.26 :name (n3 / name :op1 "STAT3"~e.21) :ARG3-of p2~e.19) :op3 (p5 / protein~e.26 :name (n4 / name :op1 "STAT5") :ARG3-of p2) :op4 (p7 / protein~e.26 :name (n5 / name :op1 "STAT6") :ARG3-of p2)) :ARG3 (c / cell-line~e.11 :name (n / name :op1 "KM-H2"~e.7,9)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 19~e.30)))) :op2 (e3 / express-03~e.14 :polarity~e.33 -~e.13 :ARG3 (c2 / cell~e.10 :quant 3~e.36 :name (n6 / name :op1 "PBMC") :ARG1-of (s / sample-01~e.37) :ARG1-of (i / isolate-01~e.40 :ARG2~e.41 (p / person~e.43 :ARG0-of~e.43 (d / donate-01~e.43) :mod (h / healthy~e.42))))) :ARG1-of (c3 / consistent-01~e.0 :ARG2~e.1 (r / report-01~e.4 :time (p10 / previous~e.3)))) # ::id pmid_2282_9094.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found p @-@ STAT1 to be expressed in all HL cell lines and in only one PBMC sample from a healthy donor . # ::alignments 0-1.1 1-1 2-1.2.1.2 4-1.2.1.1.1 7-1.2 8-1.2.2.r 9-1.2.2.1.1 11-1.2.2.1 12-1.2.2.1 13-1.2.2 15-1.2.2.2.4 16-1.2.2.2.1 17-1.2.2.2.2.1.1 18-1.2.2.2 19-1.2.2.2.3.r 21-1.2.2.2.3.2 22-1.2.2.2.3 22-1.2.2.2.3.1 22-1.2.2.2.3.1.r (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.7 :ARG2 (p2 / protein :name (n / name :op1 "STAT1"~e.4) :ARG3-of (p3 / phosphorylate-01~e.2)) :ARG3~e.8 (a / and~e.13 :op1 (c / cell-line~e.11,12 :mod (a2 / all~e.9) :mod (d2 / disease :name (n3 / name :op1 "Hodgkin's" :op2 "lymphoma"))) :op2 (s / sample-01~e.18 :quant 1~e.16 :ARG1 (c2 / cell :name (n2 / name :op1 "PBMC"~e.17)) :ARG2~e.19 (p / person~e.22 :ARG0-of~e.22 (d / donate-01~e.22) :mod (h2 / healthy~e.21)) :mod (o / only~e.15))))) # ::id pmid_2282_9094.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD1480 inhibits STAT3 , STAT5 and STAT6 phosphorylation in HL cells # ::alignments 1-1.1.1.1 2-1 3-1.2.1.1.1.1 5-1.2.2.1.1.1 6-1.2 7-1.2.3.1.1.1 8-1.2.1 8-1.2.2 8-1.2.3 11-1.3 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.1)) :ARG1 (a / and~e.6 :op1 (p2 / phosphorylate-01~e.8 :ARG1 (p3 / protein :name (n2 / name :op1 "STAT3"~e.3))) :op2 (p4 / phosphorylate-01~e.8 :ARG1 (p5 / protein :name (n3 / name :op1 "STAT5"~e.5))) :op3 (p6 / phosphorylate-01~e.8 :ARG1 (p7 / protein :name (n4 / name :op1 "STAT6"~e.7)))) :location (c / cell~e.11 :mod (d / disease :name (n5 / name :op1 "Hodgkin's" :op2 "lymphoma")))) # ::id pmid_2282_9094.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The differential expression of JAK @/@ STAT family members in HL cell lines gave us an opportunity to determine the biological effect of AZD1480 in cells that have thee different patterns of expression : HD @-@ LM2 and L @-@ 428 ( which expressed p @-@ JAK2 and p @-@ TYK2 ) , L @-@ 540 ( which expressed p @-@ JAK3 ) , and KM @-@ H2 ( which lacked p @-@ JAKs expression ) . # ::alignments 1-1.1.3 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1.1.2.1.1 7-1.1.1.1.1.1 7-1.1.1.1.1.2 8-1.1.1 9-1.1.2.r 10-1.1.2.1.1.1 11-1.1.2 12-1.1.2 13-1 14-1.3 16-1.2 18-1.2.1 20-1.2.1.2.2 21-1.2.1.2 22-1.2.1.2.1.r 23-1.2.1.2.1.1.1 24-1.2.1.2.3.r 25-1.2.1.2.3 27-1.2.1.2.3.1 29-1.2.1.2.3.1.1.3 30-1.2.1.2.3.1.1 32-1.2.1.2.3.1.1.2 32-1.2.1.2.3.2.1.2.2 34-1.2.1.2.3.2.1.1.1.1.1 36-1.2.1.2.3.2.1.1.1.1.1 37-1.2.1.2.3.2.1.1 38-1.2.1.2.3.2.1.1.2.1.1 40-1.2.1.2.3.2.1.1.2.1.1 43-1.2.1.2.3.2.1.1.3 44-1.2.1.2.3.2.1.1.3.1.1.2 46-1.2.1.2.3.2.1.1.3.1.1.1.1 48-1.2.1.2.3.2.1.1.3.1.1.2 50-1.2.1.2.3.2.1.1.3.1.2.1.1 53-1.2.1.2.3.2.1.1.2.1.1 53-1.2.1.2.3.2.1.2.1.1 55-1.2.1.2.3.2.1.2.1.1 58-1.2.1.2.3.2.1.1.3 59-1.2.1.2.3.2.1.2.2.1.2 61-1.2.1.2.3.2.1.2.2.1.1.1 64-1.2.1.2.3.2.1.1 65-1.2.1.2.3.2.1.3.1.1 67-1.2.1.2.3.2.1.3.1.1 70-1.2.1.2.3.2.1.3.2 71-1.2.1.2.3.2.1.3.2.1.1.2 73-1.2.1.2.3.2.1.3.2.1.1.1.1 74-1.2.1.2.3.2.1.3.2.1 (g / give-01~e.13 :ARG0 (e / express-03~e.2 :ARG2~e.3 (m / member~e.8 :ARG1-of (i / include-91 :ARG2 (s / slash~e.5 :op1 (p4 / protein-family~e.7 :name (n2 / name :op1 "JAK"~e.4)) :op2 (p / protein-family~e.7 :name (n3 / name :op1 "STAT"~e.6))))) :ARG3~e.9 (c2 / cell-line~e.11,12 :mod (d3 / disease :name (n / name :op1 "HL"~e.10))) :ARG1-of (d / differ-02~e.1)) :ARG1 (o / opportunity~e.16 :purpose (d2 / determine-01~e.18 :ARG0 w :ARG1 (a / affect-01~e.21 :ARG0~e.22 (s2 / small-molecule :name (n4 / name :op1 "AZD1480"~e.23)) :mod (b / biology~e.20) :location~e.24 (c3 / cell~e.25 :ARG0-of (h2 / have-03~e.27 :ARG1 (p2 / pattern-01~e.30 :quant 3 :ARG1 (e3 / express-03~e.32) :ARG1-of d~e.29)) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (a3 / and~e.37,64 :op1 (c4 / cell-line :name (n5 / name :op1 "HD-LM2"~e.34,36)) :op2 (c5 / cell-line :name (n6 / name :op1 "L-428"~e.38,40,53)) :ARG3-of (e4 / express-03~e.43,58 :ARG2 (a4 / and :op1 (e5 / enzyme :name (n7 / name :op1 "JAK2"~e.46) :ARG3-of (p3 / phosphorylate-01~e.44,48)) :op2 (e6 / enzyme :name (n8 / name :op1 "TYK2"~e.50) :ARG3-of p3)))) :op2 (c6 / cell-line :name (n9 / name :op1 "L-540"~e.53,55) :ARG3-of (e7 / express-03~e.32 :ARG2 (e8 / enzyme :name (n10 / name :op1 "JAK3"~e.61) :ARG3-of p3~e.59))) :op3 (c7 / cell-line :name (n11 / name :op1 "KM-H2"~e.65,67) :ARG0-of (l / lack-01~e.70 :ARG1 (e9 / express-03~e.74 :ARG2 (e10 / enzyme :name (n12 / name :op1 "JAK"~e.73) :ARG3-of p3~e.71)))))))))) :ARG2 (w / we~e.14)) # ::id pmid_2282_9094.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Increasing concentrations of AZD1480 ( 0.1 @–@ 5 μ) inhibited STAT1 , STAT3 , STAT5 and STAT6 phosphorylation in all three cell lines that showed evidence of full JAK @/@ STAT activation : HD @-@ LM2 , L @-@ 428 and L @-@ 540 ( Figure 1b ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.2.1.1 1-1.1.2.1.2 2-1.1.1.r 3-1.1.1.1.1 5-1.1.2.1.1.1 7-1.1.2.1.2.1 9-1 10-1.2.1.1.1.1 12-1.2.2.1.1.1 14-1.2.3.1.1.1 15-1.2 16-1.2.4.1.1.1 17-1.2.1 17-1.2.2 17-1.2.3 17-1.2.4 18-1.3.r 19-1.3.4 20-1.3.1 21-1.3 22-1.3 24-1.3.2 25-1.3.2.1 26-1.3.2.1.1.r 27-1.3.2.1.1.2 28-1.3.2.1.1.1.1.1.1 30-1.3.2.1.1.1.2.1.1 31-1.3.2.1.1 35-1.3.3.1.1.1.1 37-1.3.3.1.2.1.1 37-1.3.3.1.3.1.1 39-1.3.3.1.2.1.1 41-1.3.3.1.2.1.1 41-1.3.3.1.3.1.1 43-1.3.3.1.3.1.1 46-1.4.1 47-1.4.1.1 (i / inhibit-01~e.9 :ARG0 (c / concentrate-02~e.1 :ARG1~e.2 (s / small-molecule :name (n / name :op1 "AZD1480"~e.3)) :ARG1-of (i2 / increase-01~e.0 :ARG2 (v / value-interval :op1 (c2 / concentration-quantity~e.1 :quant 0.1~e.5 :unit (m / micromolar)) :op2 (c3 / concentration-quantity~e.1 :quant 5~e.7 :unit m)))) :ARG1 (a / and~e.15 :op1 (p / phosphorylate-01~e.17 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT1"~e.10))) :op2 (p3 / phosphorylate-01~e.17 :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3"~e.12))) :op3 (p5 / phosphorylate-01~e.17 :ARG1 (p6 / protein :name (n4 / name :op1 "STAT5"~e.14))) :op4 (p7 / phosphorylate-01~e.17 :ARG1 (p8 / protein :name (n5 / name :op1 "STAT6"~e.16)))) :location~e.18 (c4 / cell-line~e.21,22 :quant 3~e.20 :ARG0-of (s2 / show-01~e.24 :ARG1 (e / evidence-01~e.25 :ARG1~e.26 (a2 / activate-01~e.31 :ARG1 (a3 / and :op1 (e2 / enzyme :name (n6 / name :op1 "JAK"~e.28)) :op2 (p9 / protein :name (n7 / name :op1 "STAT"~e.30))) :degree (f2 / full~e.27)))) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and :op1 (c5 / cell-line :name (n8 / name :op1 "LM2"~e.35)) :op2 (c6 / cell-line :name (n9 / name :op1 "L-428"~e.37,39,41)) :op3 (c7 / cell-line :name (n10 / name :op1 "L-540"~e.37,41,43)))) :mod (a5 / all~e.19)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.46 :mod "1b"~e.47))) # ::id pmid_2282_9094.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that in addition to JAK2 , AZD1480 may also inhibit JAK3 activity in HL cell lines . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 4-1.2.r 5-1.2.1.2.1 5-1.2.1.2.1.2 5-1.2.1.2.1.2.r 6-1.2.1.2.1.2.1.r 7-1.2.1.2.1.2.1.1.1 9-1.2.1.1.1.1 10-1.2 11-1.2.1.3 12-1.2.1 13-1.2.1.2.1.1.1 14-1.2.1.2 15-1.2.1.2.2.r 16-1.2.1.2.2.1.1.1 17-1.2.1.2.2 18-1.2.1.2.2 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.4 (p / possible-01~e.10 :ARG1 (i / inhibit-01~e.12 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.9)) :ARG1 (a2 / activity-06~e.14 :ARG0 (e / enzyme~e.5 :name (n2 / name :op1 "JAK3"~e.13) :ARG1-of~e.5 (a3 / add-02~e.5 :ARG2~e.6 (e2 / enzyme :name (n3 / name :op1 "JAK2"~e.7)))) :location~e.15 (c / cell-line~e.17,18 :mod (d / disease :name (n4 / name :op1 "HL"~e.16)))) :mod (a / also~e.11)))) # ::id pmid_2282_9094.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Potent inhibition of STAT3 phosphorylation was observed as soon as after 30 min of incubation with AZD1480 and was maintained up to 72 h ( Supplementary Figure S1A and B ) . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 6-1.1 7-1.1.2 7-1.1.2.r 8-1.1.2 9-1.1.2 10-1.1.2.1 11-1.1.2.1.2.1 12-1.1.2.1.2.2 13-1.1.2.1.1.r 14-1.1.2.1.1 15-1.1.2.1.1.2.r 16-1.1.2.1.1.2.1.1 17-1 19-1.2 20-1.2.2 21-1.2.2 22-1.2.2.1.1 23-1.2.2.1.2 26-1.3.1.3 27-1.3.1.1 27-1.3.1.2 28-1.3.1.1.1 29-1.3.1 (a3 / and~e.17 :op1 (o / observe-01~e.6 :ARG1 (i / inhibit-01~e.1 :ARG1~e.2 (p / phosphorylate-01~e.4 :ARG1 (p2 / protein :name (n / name :op1 "STAT3"~e.3))) :mod (p3 / potent~e.0)) :time~e.7 (a / as-soon-as~e.7,8,9 :op1 (a2 / after~e.10 :op1~e.13 (i2 / incubate-01~e.14 :ARG1 i :ARG2~e.15 (s / small-molecule :name (n2 / name :op1 "AZD1480"~e.16))) :quant (t / temporal-quantity :quant 30~e.11 :unit (m / minute~e.12))))) :op2 (m2 / maintain-01~e.19 :ARG1 i :duration (u / up-to~e.20,21 :op1 (t2 / temporal-quantity :quant 72~e.22 :unit (h / hour~e.23)))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.29 :op1 (f / figure~e.27 :mod "S1A"~e.28) :op2 (f2 / figure~e.27 :mod "S1B") :ARG2-of (s2 / supplement-01~e.26)))) # ::id pmid_2282_9094.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Antiproliferative effects of AZD1480 in HL cell lines # ::alignments 1-1.2 1-1.2.1 1-1.2.1.r 2-1 3-1.1.r 4-1.1.1.1 5-1.3.r 6-1.3.1.1.1 7-1.3 8-1.3 (a / affect-01~e.2 :ARG0~e.3 (s / small-molecule :name (n / name :op1 "AZD1480"~e.4)) :ARG2 (c2 / counter-01~e.1 :ARG1~e.1 (p / proliferate-01~e.1)) :location~e.5 (c / cell-line~e.7,8 :mod (d / disease :name (n2 / name :op1 "HL"~e.6)))) # ::id pmid_2282_9094.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Previous studies have demonstrated that HL cell lines are addicted to the JAK @/@ STAT pathway , and selective inhibition of STAT proteins by RNA interference has been shown to result in antiproliferative effects in HL cell lines . @^{2 @} # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1.2.1 9-1.1.2 10-1.1.2.2.r 12-1.1.2.2.1.1 14-1.1.2.2.1.1 15-1.1.2.2 17-1 18-1.2.1.3 19-1.2.1 20-1.2.1.2.r 21-1.2.1.2.1.1 22-1.2.1.2 23-1.2.1.1.r 24-1.2.1.1.1.1.1 25-1.2.1.1 28-1.2 30-1.2.1.4 31-1.2.1.4.1.r 32-1.2.1.4.1.1 32-1.2.1.4.1.1.1 32-1.2.1.4.1.1.1.r 33-1.2.1.4.1 34-1.2.1.4.1.2.r 35-1.2.1.4.1.2 36-1.2.1.4.1.2 37-1.2.1.4.1.2 41-1.3.1.1.1 (a / and~e.17 :op1 (d / demonstrate-01~e.3 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (s / study-01~e.1) :time (p / previous~e.0)) :ARG1~e.4 (a2 / addict-01~e.9 :ARG1 (c / cell-line~e.6,7 :mod (d3 / disease :name (n4 / name :op1 "HL"~e.5))) :ARG2~e.10 (p2 / pathway~e.15 :name (n / name :op1 "JAK/STAT"~e.12,14)))) :op2 (s2 / show-01~e.28 :ARG1 (i / inhibit-01~e.19 :ARG0~e.23 (i3 / interfere-01~e.25 :ARG1 (n5 / nucleic-acid :name (n2 / name :op1 "RNA"~e.24))) :ARG1~e.20 (p3 / protein~e.22 :name (n3 / name :op1 "STAT"~e.21)) :manner (s3 / selective~e.18) :ARG1-of (r2 / result-01~e.30 :ARG2~e.31 (a3 / affect-01~e.33 :ARG2 (c2 / counter-01~e.32 :ARG1~e.32 (p4 / proliferate-01~e.32)) :location~e.34 c~e.35,36,37)))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 2~e.41)))) # ::id pmid_2282_9094.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because AZD1480 inhibited p @-@ STAT3 , p @-@ STAT5 and p @-@ STAT6 , we investigated the antiproliferative effect of AZD1480 in HL cells by using the MTS assay . # ::alignments 0-1.3 1-1.3.1.1.1.1 2-1.3.1 3-1.3.1.2.1.2 5-1.3.1.2.1.1.1 7-1.3.1.2.1.2 9-1.3.1.2.2.1.1 10-1.3.1.2 11-1.3.1.2.1.2 13-1.3.1.2.3.1.1 15-1.1 16-1 18-1.2.2 18-1.2.2.1 18-1.2.2.1.r 19-1.2 20-1.2.1.r 21-1.2.1 22-1.2.3.r 23-1.2.3.1.1.1 24-1.2.3 25-1.4.r 26-1.4 28-1.4.1.1.1.1 29-1.4.1 (i2 / investigate-01~e.16 :ARG0 (w / we~e.15) :ARG1 (a2 / affect-01~e.19 :ARG0~e.20 s~e.21 :ARG2 (c3 / counter-01~e.18 :ARG1~e.18 (p7 / proliferate-01~e.18)) :location~e.22 (c2 / cell~e.24 :mod (d / disease :name (n5 / name :op1 "HL"~e.23)))) :ARG1-of (c / cause-01~e.0 :ARG0 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.1)) :ARG1 (a / and~e.10 :op1 (p / protein :name (n2 / name :op1 "STAT3"~e.5) :ARG3-of (p2 / phosphorylate-01~e.3,7,11)) :op2 (p3 / protein :name (n3 / name :op1 "STAT5"~e.9) :ARG3-of p2) :op3 (p5 / protein :name (n4 / name :op1 "STAT6"~e.13) :ARG3-of p2)))) :manner~e.25 (u / use-01~e.26 :ARG1 (a3 / assay-01~e.29 :instrument (s2 / small-molecule :name (n6 / name :op1 "MTS"~e.28))))) # ::id pmid_2282_9094.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD1480 induced antiproliferative effects in a time @- and dose @-@ dependent manner ( Figure 1c ) . # ::alignments 0-1.1.1.1 1-1 2-1.2.1 2-1.2.1.1 2-1.2.1.1.r 3-1.2 6-1.3.1.1 8-1.3.1 9-1.3.1.2 11-1.3 12-1.3.r 15-1.4.1 16-1.4.1.1 (i / induce-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.0)) :ARG2 (a / affect-01~e.3 :ARG2 (c / counter-01~e.2 :ARG1~e.2 (p / proliferate-01~e.2))) :manner~e.12 (d / depend-01~e.11 :ARG1 (a2 / and~e.8 :op1 (t / time~e.6) :op2 (d2 / dose-01~e.9))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.15 :mod "1c"~e.16))) # ::id pmid_2282_9094.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After 72 h of incubation , the half maximal inhibitory concentration ( IC @₅₀ ) values for AZD1480 ranged from 1 to 8 μ; L @-@ 540 cells were the most sensitive to AZD1480 ( Figure 1c and d ) . # ::alignments 0-1.1.4 1-1.1.4.2.1 2-1.1.4.2.2 3-1.1.4.1.r 4-1.1.4.1 8-1.1.1.1 9-1.1.1.1 10-1.1.1 10-1.1.1.1 10-1.1.1.1.r 10-1.1.2 10-1.1.3 12-1.1.1.1 14-1.1.1.1.1 18-1.1.1.1.2.r 19-1.1.1.1.2.1.1 20-1.1 22-1.1.2.1 24-1.1.3.1 26-1.1.1.1.1 26-1.2.1.1.1 28-1.2.1.1.1 29-1.2.1 32-1.2.3 33-1.2 34-1.2.2.r 35-1.2.2 38-1.3.1.1 38-1.3.1.2 39-1.3.1.1.1 40-1 40-1.3.1 (a / and~e.40 :op1 (r / range-01~e.20 :ARG1 (c5 / concentration-quantity~e.10 :ARG4-of~e.10 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.8,9,10,12 :ARG2 50~e.14,26 :ARG1~e.18 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.19)))) :ARG3 (c2 / concentration-quantity~e.10 :quant 1~e.22 :unit (m2 / micromolar)) :ARG4 (c3 / concentration-quantity~e.10 :quant 8~e.24 :unit m2) :time (a2 / after~e.0 :op1~e.3 (i2 / incubate-01~e.4) :quant (t / temporal-quantity :quant 72~e.1 :unit (h2 / hour~e.2)))) :op2 (s / sensitive-03~e.33 :ARG0 (c4 / cell-line~e.29 :name (n2 / name :op1 "L-540"~e.26,28)) :ARG1~e.34 s2~e.35 :degree (m4 / most~e.32)) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.40 :op1 (f / figure~e.38 :mod "1c"~e.39) :op2 (f2 / figure~e.38 :mod "1d")))) # ::id pmid_2282_9094.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , although submicromolar concentrations of AZD1480 inhibited STAT phosphorylation , these low concentrations were not sufficient to induce a significant antiproliferative activity , especially in the HD @-@ LM2 and L @-@ 428 cells . # ::alignments 0-1 2-1.1 3-1.1.2.1.2 4-1.1.2.1 5-1.1.2.1.1.r 6-1.1.2.1.1.1.1 7-1.1.2 8-1.1.2.2.1.1.1 9-1.1.2.2 11-1.1.1.2.2 12-1.1.1.2.1 13-1.1.1.2 15-1.1.1.1 15-1.1.1.1.r 16-1.1.1 18-1.1.1.3 20-1.1.1.3.2.2 21-1.1.1.3.2.1 21-1.1.1.3.2.1.1 21-1.1.1.3.2.1.1.r 22-1.1.1.3.2 24-1.1.1.3.3.3 27-1.1.1.3.3.1.1.1 29-1.1.1.3.3.1.1.1 30-1.1.1.3.3 31-1.1.1.3.3.2.1.1 33-1.1.1.3.3.2.1.1 34-1.1.1.3.3.1 34-1.1.1.3.3.2 (c / cause-01~e.0 :ARG1 (h / have-concession-91~e.2 :ARG1 (s3 / suffice-01~e.16 :polarity~e.15 -~e.15 :ARG0 (c3 / concentrate-02~e.13 :ARG1-of (l / low-04~e.12) :mod (t / this~e.11)) :ARG1 (i2 / induce-01~e.18 :ARG0 c3 :ARG2 (a / activity-06~e.22 :ARG0-of (c4 / counter-01~e.21 :ARG1~e.21 (p3 / proliferate-01~e.21)) :ARG1-of (s4 / significant-02~e.20)) :location (a2 / and~e.30 :op1 (c5 / cell-line~e.34 :name (n3 / name :op1 "HD-LM2"~e.27,29)) :op2 (c6 / cell-line~e.34 :name (n4 / name :op1 "L-428"~e.31,33)) :mod (e / especially~e.24)))) :ARG2 (i / inhibit-01~e.7 :ARG0 (c2 / concentrate-01~e.4 :ARG1~e.5 (s / small-molecule :name (n / name :op1 "AZD1480"~e.6)) :mod (s2 / submicromolar~e.3)) :ARG1 (p / phosphorylate-01~e.9 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT"~e.8)))))) # ::id pmid_2282_9094.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , at a higher concentration ( 5 μ) , AZD1480 had a stronger effect in all cell lines , including KM @-@ H2 , which lacked active JAK @/@ STAT proteins . # ::alignments 1-1 5-1.1.2.1 5-1.1.2.1.1 5-1.1.2.1.1.r 6-1.1.2 6-1.1.2.2 6-1.1.2.2.r 8-1.1.2.2.1 11-1.1.1.1.1.1 14-1.1.1.2 14-1.1.1.2.1 14-1.1.1.2.1.r 15-1.1.1 16-1.1.1.3.r 17-1.1.1.3.2 18-1.1.1.3 19-1.1.1.3 21-1.1.1.3.1 22-1.1.1.3.1.1.1.1 24-1.1.1.3.1.1.1.1 27-1.1.1.3.1.1.2 29-1.1.1.3.1.1.2.1.1.1.1 30-1.1.1.3.1.1.2.1 31-1.1.1.3.1.1.2.1.2.1.1 32-1.1.1.3.1.1.2.1.2 (c / contrast-01~e.1 :ARG2 (h2 / have-condition-91 :ARG1 (a / affect-01~e.15 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.11)) :ARG1-of (s / strong-02~e.14 :degree~e.14 (m2 / more~e.14)) :location~e.16 (c2 / cell-line~e.18,19 :ARG2-of (i / include-01~e.21 :ARG1 (c3 / cell-line :name (n2 / name :op1 "KM-H2"~e.22,24) :ARG0-of (l / lack-01~e.27 :ARG1 (s3 / slash~e.30 :op1 (e / enzyme :name (n3 / name :op1 "JAK"~e.29)) :op2 (p / protein~e.32 :name (n4 / name :op1 "STAT"~e.31)) :ARG1-of (a3 / activate-01))))) :mod (a5 / all~e.17))) :ARG2 (c4 / concentrate-02~e.6 :ARG1-of (h / high-02~e.5 :degree~e.5 (m / more~e.5)) :quant~e.6 (c5 / concentration-quantity~e.6 :quant 5~e.8 :unit (m3 / micromolar))))) # ::id pmid_2282_9094.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest that at this higher concentration ( 5 μ) , AZD1480 induced antiproliferative effects in HL cell lines in a JAK @/@ STAT @-@ independent manner . # ::alignments 0-1.1.1 1-1.1 2-1 5-1.1.1 6-1.2.4.2 6-1.2.4.2.1 6-1.2.4.2.1.r 7-1.2.4 7-1.2.4.3 7-1.2.4.3.r 9-1.2.4.3.1 12-1.2.1.1.1 13-1.2 14-1.2.2.1 14-1.2.2.1.1 14-1.2.2.1.1.r 15-1.2.2 16-1.2.2.2.r 17-1.2.2.2.1.1.1 18-1.2.2.2 19-1.2.2.2 22-1.2.3.2.1.1.1 23-1.2.3.2 24-1.2.3.2.2.1.1 26-1.2.3 26-1.2.3.1 26-1.2.3.1.r 27-1.2.3.r (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0,5)) :ARG1 (i / induce-01~e.13 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.12)) :ARG2 (a / affect-01~e.15 :ARG2 (c / counter-01~e.14 :ARG1~e.14 (p / proliferate-01~e.14)) :location~e.16 (c2 / cell-line~e.18,19 :mod (d3 / disease :name (n4 / name :op1 "HL"~e.17)))) :manner~e.27 (d2 / depend-01~e.26 :polarity~e.26 -~e.26 :ARG1 (s3 / slash~e.23 :op1 (e / enzyme :name (n2 / name :op1 "JAK"~e.22)) :op2 (p2 / protein :name (n3 / name :op1 "STAT"~e.24)))) :condition (c3 / concentrate-02~e.7 :ARG1 s2 :ARG1-of (h / high-02~e.6 :degree~e.6 (m / more~e.6)) :quant~e.7 (c4 / concentration-quantity~e.7 :quant 5~e.9 :unit (m2 / micromolar))))) # ::id pmid_2282_9094.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further investigate the mechanisms of the antiproliferative activity of AZD1480 , we determined the inhibitor 's effect on apoptosis . # ::alignments 1-1.3.3 2-1.3 4-1.3.2 5-1.3.2.1.r 7-1.3.2.1.2 7-1.3.2.1.2.1 7-1.3.2.1.2.1.r 8-1.3.2.1 9-1.3.2.1.1.r 10-1.3.2.1.1.1.1 12-1.1 13-1 15-1.2.1 15-1.2.1.1 15-1.2.1.1.r 16-1.2.1.r 17-1.2 18-1.2.2.r 19-1.2.2 (d / determine-01~e.13 :ARG0 (w / we~e.12) :ARG1 (a / affect-01~e.17 :ARG0~e.16 (m / molecular-physical-entity~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15)) :ARG1~e.18 (a2 / apoptosis~e.19)) :purpose (i2 / investigate-01~e.2 :ARG0 w :ARG1 (m2 / mechanism~e.4 :poss~e.5 (a3 / activity-06~e.8 :ARG0~e.9 (s / small-molecule :name (n / name :op1 "AZD1480"~e.10)) :ARG0-of (c / counter-01~e.7 :ARG1~e.7 (p / proliferate-01~e.7)))) :degree (f / further~e.1))) # ::id pmid_2282_9094.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the MTS data in Figure 1c , we found that AZD1480 induced apoptotic cell death in a dose @-@ dependent manner ( Figure 2a and b ) . # ::alignments 0-1.3 1-1.3.1.2.1.r 3-1.3.1.2.1.1.1 4-1.3.1 7-1.3.1.1 8-1.3.1.1.1 11-1.1 12-1 13-1.2.r 14-1.2.1.1.1 15-1.2 16-1.2.2.1.1 17-1.2.2.1 18-1.2.2 21-1.2.3.1 23-1.2.3 24-1.2.3.r 27-1.4.1.1 27-1.4.1.2 28-1.4.1.1.1 29-1.4.1 (f / find-01~e.12 :ARG0 (w / we~e.11) :ARG1~e.13 (i / induce-01~e.15 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.14)) :ARG2 (d / die-01~e.18 :ARG1 (c / cell~e.17 :mod (a / apoptotic~e.16))) :manner~e.24 (d2 / depend-01~e.23 :ARG1 (d3 / dose-01~e.21))) :ARG1-of (c2 / consistent-01~e.0 :ARG2 (d4 / data~e.4 :location (f2 / figure~e.7 :mod "1c"~e.8) :source (a3 / assay-01 :instrument~e.1 (s2 / small-molecule :name (n2 / name :op1 "MTS"~e.3))))) :ARG1-of (d5 / describe-01 :ARG0 (a2 / and~e.29 :op1 (f3 / figure~e.27 :mod "2a"~e.28) :op2 (f4 / figure~e.27 :mod "2b")))) # ::id pmid_2282_9094.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the lower concentration of AZD1480 ( 1 μ) , L @-@ 540 cells were the most sensitive ( 43.3 % cell death after 72 h of incubation ) and L @-@ 428 cells were modestly sensitive ( 27.6 % cell death ) . # ::alignments 2-1.2.2 2-1.2.2.1 2-1.2.2.1.r 3-1.2 3-1.2.3 3-1.2.3.r 4-1.2.1.r 5-1.2.1.1.1 7-1.2.3.1 10-1.1.1.1.1.1 10-1.1.2.1.1.1 12-1.1.1.1.1.1 13-1.1.1.1 16-1.1.1.2 17-1.1.1 19-1.1.1.3.1.1.1.1 20-1.1.1.3.1.1.1 21-1.1.1.3.1.1 22-1.1.1.3.1 23-1.1.1.3.1.2 24-1.1.1.3.1.2.2.1 25-1.1.1.3.1.2.2.2 26-1.1.1.3.1.2.1.r 27-1.1.1.3.1.2.1 29-1.1 30-1.1.2.1.1.1 32-1.1.2.1.1.1 33-1.1.2.1 35-1.1.2.3 36-1.1.2 38-1.1.2.2.1.1.1.1 39-1.1.2.2.1.1.1 40-1.1.2.2.1.1 41-1.1.2.2.1 (h / have-condition-91 :ARG1 (a / and~e.29 :op1 (s / sensitive-03~e.17 :ARG0 (c / cell-line~e.13 :name (n / name :op1 "L-540"~e.10,12)) :degree (m2 / most~e.16) :ARG1-of (m3 / mean-01 :ARG2 (d / die-01~e.22 :ARG1 (c2 / cell~e.21 :quant (p / percentage-entity~e.20 :value 43.3~e.19)) :time (a2 / after~e.23 :op1~e.26 (i / incubate-01~e.27) :quant (t / temporal-quantity :quant 72~e.24 :unit (h2 / hour~e.25)))))) :op2 (s2 / sensitive-03~e.36 :ARG0 (c3 / cell-line~e.33 :name (n2 / name :op1 "L-428"~e.10,30,32)) :ARG1-of (m4 / mean-01 :ARG2 (d2 / die-01~e.41 :ARG1 (c4 / cell~e.40 :quant (p2 / percentage-entity~e.39 :value 27.6~e.38)))) :degree (m6 / modest~e.35))) :ARG2 (c5 / concentrate-02~e.3 :ARG1~e.4 (s3 / small-molecule :name (n3 / name :op1 "AZD1480"~e.5)) :ARG1-of (l / low-04~e.2 :degree~e.2 (m / more~e.2)) :quant~e.3 (c6 / concentration-quantity~e.3 :quant 1~e.7 :unit (m5 / micromolar)))) # ::id pmid_2282_9094.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the higher concentration ( 5 μ) , AZD1480 induced apoptosis in all four cell lines , but L @-@ 540 cells remained the most sensitive . # ::alignments 2-1.3.2 2-1.3.2.1 2-1.3.2.1.r 3-1.3 3-1.3.1 3-1.3.1.r 5-1.3.1.1 8-1.1.1.1.1 9-1.1 10-1.1.2 11-1.1.3.r 12-1.1.3.2 13-1.1.3.1 14-1.1.3 15-1.1.3 17-1 18-1.2.1.1.1 20-1.2.1.1.1 21-1.2.1 22-1.2 24-1.2.2.1 25-1.2.2 (c / contrast-01~e.17 :ARG1 (i / induce-01~e.9 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.8)) :ARG2 (a / apoptosis~e.10) :location~e.11 (c2 / cell-line~e.14,15 :quant 4~e.13 :mod (a2 / all~e.12))) :ARG2 (r / remain-01~e.22 :ARG1 (c3 / cell-line~e.21 :name (n2 / name :op1 "L-540"~e.18,20)) :ARG3 (s2 / sensitive-03~e.25 :degree (m2 / most~e.24))) :condition (c4 / concentrate-02~e.3 :quant~e.3 (c5 / concentration-quantity~e.3 :quant 5~e.5 :unit (m3 / micromolar)) :ARG1-of (h / high-02~e.2 :degree~e.2 (m / more~e.2)))) # ::id pmid_2282_9094.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with induction of apoptosis , AZD1480 activated caspases 9 and 3 , and induced poly ( adenosine diphosphate ribose ) polymerase cleavage . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1 3-1.3.1.1.r 4-1.3.1.1 6-1.1.1.1.1 7-1.1 9-1.1.2.1.1.2 10-1.1.2 11-1.1.2.2.1.2 13-1 14-1.2 15-1.2.2.1.1.1 17-1.2.2.1.1.2 18-1.2.2.1.1.3 19-1.2.2.1.1.4 21-1.2.2.1.1.5 22-1.2.2 (a / and~e.13 :op1 (a2 / activate-01~e.7 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.6)) :ARG1 (a3 / and~e.10 :op1 (p2 / protein :name (n3 / name :op1 "caspase" :op2 9~e.9)) :op2 (p3 / protein :name (n4 / name :op1 "caspase" :op2 3~e.11)))) :op2 (i / induce-01~e.14 :ARG0 s :ARG2 (c3 / cleave-01~e.22 :ARG1 (p / protein :name (n2 / name :op1 "poly"~e.15 :op2 "adenosine"~e.17 :op3 "diphosphate"~e.18 :op4 "ribose"~e.19 :op5 "polymerase"~e.21)))) :ARG1-of (c4 / consistent-01~e.0 :ARG2~e.1 (i2 / induce-01~e.2 :ARG2~e.3 (a4 / apoptosis~e.4)))) # ::id pmid_2282_9094.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Figure 2c ) . # ::alignments 2-1 3-1.1 (f / figure~e.2 :mod "2c"~e.3) # ::id pmid_2282_9094.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was observed as soon as after 24 h of incubation with AZD1480 in all cell lines , when high doses ( 5 μ) were used ( Supplementary Figure S1C ) . # ::alignments 0-1.1 2-1 3-1.2 3-1.2.r 3-1.3.r 4-1.2 5-1.2 6-1.2.1 7-1.2.1.2.1 8-1.2.1.2.2 9-1.2.1.1.r 10-1.2.1.1 11-1.2.1.1.1.r 12-1.2.1.1.1.1.1 13-1.2.1.1.2.r 14-1.2.1.1.2.1 15-1.2.1.1.2 16-1.2.1.1.2 18-1.3.r 19-1.3.1.2 20-1.3.1 22-1.3.1.1.1 25-1.3 28-1.4.1.2 29-1.4.1 30-1.4.1.1 (o / observe-01~e.2 :ARG1 (t / this~e.0) :time~e.3 (a / as-soon-as~e.3,4,5 :op1 (a2 / after~e.6 :op1~e.9 (i / incubate-01~e.10 :ARG2~e.11 (s / small-molecule :name (n / name :op1 "AZD1480"~e.12)) :location~e.13 (c / cell-line~e.15,16 :mod (a3 / all~e.14))) :quant (t2 / temporal-quantity :quant 24~e.7 :unit (h / hour~e.8)))) :time~e.3,18 (u / use-01~e.25 :ARG1 (d / dose-01~e.20 :quant (c2 / concentration-quantity :quant 5~e.22 :unit (m / micromolar)) :ARG1-of (h2 / high-02~e.19))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod "S1C"~e.30 :ARG2-of (s2 / supplement-01~e.28)))) # ::id pmid_2282_9094.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD1480 induces paradoxical hyperphosphorylation of JAK2 and TYK2 at the activation loop in HL cells # ::alignments 1-1.1.1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1 9-1.3.r 11-1.3.1 12-1.3 13-1.3.2.r 14-1.3.2.1.1.1 15-1.3.2 (i / induce-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.1)) :ARG2 (h / hyperphosphorylate-01~e.4 :ARG1~e.5 (a / and~e.7 :op1 (e / enzyme :name (n2 / name :op1 "JAK2"~e.6)) :op2 (e2 / enzyme :name (n3 / name :op1 "TYK2"~e.8))) :manner (p / paradox)) :location~e.9 (l / loop~e.12 :ARG0-of (a2 / activate-01~e.11) :location~e.13 (c / cell~e.15 :mod (d / disease :name (n4 / name :op1 "HL"~e.14))))) # ::id pmid_2282_9094.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although AZD1480 inhibited phosphorylation of STATs , its effect on the phosphorylation of the JAK family members in HL cells is unknown . # ::alignments 0-1 1-1.2.1.1.1 2-1.2 3-1.2.2 7-1.1.2.1 7-1.1.2.1.r 8-1.1.2 9-1.1.2.2.r 11-1.1.2.2 12-1.1.2.2.1.r 14-1.1.2.2.1.1.1.1.1 15-1.1.2.2.1.1.1 16-1.1.2.2.1 17-1.1.2.3.r 18-1.1.2.3.1.1.1 19-1.1.2.3 21-1.1 21-1.1.1 21-1.1.1.r (h / have-concession-91~e.0 :ARG1 (k / know-01~e.21 :polarity~e.21 -~e.21 :ARG1 (a / affect-01~e.8 :ARG0~e.7 s~e.7 :ARG1~e.9 (p3 / phosphorylate-01~e.11 :ARG1~e.12 (m / member~e.16 :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family~e.15 :name (n3 / name :op1 "JAK"~e.14))))) :location~e.17 (c / cell~e.19 :mod (d / disease :name (n4 / name :op1 "HL"~e.18))))) :ARG2 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.1)) :ARG1 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein :name (n2 / name :op1 "STAT"))))) # ::id pmid_2282_9094.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only the Tyr @-@ phosphorylated forms of JAKs are known to exhibit kinase activity , and phosphorylation at two tandem Tyr residues in the activation loop appears to be required for enzymatic activity . @^{20 @} # ::alignments 0-1.1.1.4 2-1.1.1.2.1.1.1 4-1.2.1.1 5-1.1.1.3 6-1.1.1.3.r 7-1.1.1.1.1 9-1.1 11-1.1.1 11-1.1.1.5 11-1.1.1.5.r 12-1.1.1.5.1.1 13-1.1.1.5.1 15-1 16-1.1.1.2 16-1.2.1.1 17-1.2.1.1.1.r 18-1.2.1.1.1.2.1 19-1.2.1.1.1.2 20-1.2.1.1.1.1.1.1 21-1.2.1.1.1 22-1.2.1.1.2.r 24-1.2.1.1.2.1 25-1.2.1.1.2 26-1.2 29-1.2.1 30-1.2.1.2.r 31-1.2.1.2.1 32-1.2.1.2 36-1.3.1.1.1 (a / and~e.15 :op1 (k / know-01~e.9 :ARG1 (e / enzyme~e.11 :name (n / name :op1 "JAK"~e.7) :ARG3-of (p / phosphorylate-01~e.16 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine"~e.2))) :mod~e.6 (f2 / form~e.5) :mod (o / only~e.0) :ARG0-of~e.11 (e2 / exhibit-01~e.11 :ARG1 (a3 / activity-06~e.13 :ARG0 (k2 / kinase~e.12))))) :op2 (a4 / appear-01~e.26 :ARG1 (r2 / require-01~e.29 :ARG1 (p2 / phosphorylate-01~e.4,16 :ARG1~e.17 (r / residue~e.21 :mod (a5 / amino-acid :name (n3 / name :op1 "tyrosine"~e.20)) :mod (t / tandem~e.19 :quant 2~e.18)) :location~e.22 (l / loop~e.25 :ARG0-of (a6 / activate-01~e.24))) :purpose~e.30 (a7 / activity-06~e.32 :ARG0 (e3 / enzyme~e.31)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 20~e.36)))) # ::id pmid_2282_9094.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As levels of baseline p @-@ JAK2 expression and p @-@ STATs inhibition did not predict sensitivity to AZD1480 in HD @-@ LM2 and L @-@ 428 cells , we investigated the effect of AZD1480 on the phosphorylation status of the JAK family members at the activation loop . # ::alignments 1-1.3.1.2.1 1-1.3.1.2.2 2-1.3.1.2.1.1.r 3-1.3.1.2.1.1.1.3 4-1.3.1.2.1.1.1.2 6-1.3.1.2.1.1.1.1.1 7-1.3.1.2.1.1 8-1.3.1.2 9-1.3.1.2.2.1.1.2 12-1.3.1.2.2.1 14-1.3.1.1 14-1.3.1.1.r 15-1.3.1 16-1.3.1.3 17-1.3 17-1.3.1.3.1.r 18-1.3.1.3.1 19-1.3.1.3.2.r 20-1.3.1.3.2.1.1.1 22-1.3.1.3.2.1.1.1 23-1.3.1.3.2 24-1.3.1.3.2.2.1.1 26-1.3.1.3.2.2.1.1 27-1.3.1.3.2.1 27-1.3.1.3.2.2 29-1.1 30-1 32-1.2 33-1.2.1.r 34-1.2.1.1.1 35-1.2.2.r 37-1.2.2.2 38-1.2.2 39-1.2.2.1.r 41-1.2.2.1.1.1.1.1 42-1.2.2.1.1.1 43-1.2.2.1 44-1.2.3.r 46-1.2.3.1 47-1.2.3 (i / investigate-01~e.30 :ARG0 (w / we~e.29) :ARG1 (a / affect-01~e.32 :ARG0~e.33 (s / small-molecule :name (n / name :op1 "AZD1480"~e.34)) :ARG1~e.35 (s2 / status~e.38 :poss~e.39 (m / member~e.43 :ARG1-of (i3 / include-91 :ARG2 (p5 / protein-family~e.42 :name (n2 / name :op1 "JAK"~e.41)))) :mod (p / phosphorylate-01~e.37)) :location~e.44 (l / loop~e.47 :ARG0-of (a2 / activate-01~e.46))) :ARG1-of (c3 / cause-01~e.17 :ARG0 (p2 / predict-01~e.15 :polarity~e.14 -~e.14 :ARG0 (a3 / and~e.8 :op1 (l2 / level~e.1 :degree-of~e.2 (e2 / express-03~e.7 :ARG2 (e3 / enzyme :name (n3 / name :op1 "JAK2"~e.6) :ARG3-of (p3 / phosphorylate-01~e.4) :mod (b / baseline~e.3)))) :op2 (l3 / level~e.1 :degree-of (i2 / inhibit-01~e.12 :ARG1 (p4 / protein :name (n4 / name :op1 "STAT") :ARG3-of p3~e.9)))) :ARG1 (s3 / sensitive-03~e.16 :ARG1~e.17 s~e.18 :location~e.19 (a4 / and~e.23 :op1 (c / cell-line~e.27 :name (n6 / name :op1 "HD-LM2"~e.20,22)) :op2 (c2 / cell-line~e.27 :name (n7 / name :op1 "L-428"~e.24,26))))))) # ::id pmid_2282_9094.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine the effect of AZD1480 on p @-@ JAKs , we focused our experiments on the three cell lines that expressed active JAK @/@ STAT proteins : HD @-@ LM2 , L @-@ 428 and L @-@ 540 ( Figure 3a ) . # ::alignments 1-1.3 3-1.3.2 4-1.3.2.1.r 5-1.3.2.1.1.1 6-1.3.2.2.r 7-1.3.2.2.2 9-1.3.2.2.1.1 11-1.3.1 12-1 13-1.2.1 13-1.2.1.r 14-1.2 15-1.2.2.r 17-1.2.2.1 18-1.2.2 19-1.2.2 21-1.2.2.2 23-1.2.2.2.1.1.1.1 24-1.2.2.2.1 25-1.2.2.2.1.2.1.1 26-1.2.2.2.1.2 28-1.2.2.3.1.1.1.1 30-1.2.2.3.1.1.1.1 32-1.2.2.3.1.2.1.1 32-1.2.2.3.1.3.1.1 34-1.2.2.3.1.2.1.1 35-1.2.2.3.1 36-1.2.2.3.1.2.1.1 36-1.2.2.3.1.3.1.1 38-1.2.2.3.1.3.1.1 41-1.4.1 42-1.4.1.1 (f / focus-01~e.12 :ARG0 (w / we) :ARG1 (e / experiment-01~e.14 :ARG0~e.13 w~e.13 :ARG1~e.15 (c / cell-line~e.18,19 :quant 3~e.17 :ARG3-of (e2 / express-03~e.21 :ARG2 (s / slash~e.24 :op1 (e3 / enzyme :name (n / name :op1 "JAK"~e.23)) :op2 (p / protein~e.26 :name (n2 / name :op1 "STAT"~e.25)) :ARG1-of (a / activate-01))) :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.35 :op1 (c2 / cell-line :name (n3 / name :op1 "HD-LM2"~e.28,30)) :op2 (c3 / cell-line :name (n4 / name :op1 "L-428"~e.32,34,36)) :op3 (c4 / cell-line :name (n5 / name :op1 "L-540"~e.32,36,38)))))) :purpose (d / determine-01~e.1 :ARG0 w~e.11 :ARG1 (a4 / affect-01~e.3 :ARG0~e.4 (s2 / small-molecule :name (n6 / name :op1 "AZD1480"~e.5)) :ARG1~e.6 (e4 / enzyme :name (n7 / name :op1 "JAK"~e.9) :ARG3-of (p2 / phosphorylate-01~e.7)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.41 :mod "3a"~e.42))) # ::id pmid_2282_9094.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In L @-@ 540 , which was the most sensitive cell line and which expressed only p @-@ JAK3 , increasing concentrations of AZD1480 ( 0.1 @–@ 5 μ) completely inhibited JAK3 Y980 phosphorylation . # ::alignments 1-1.4.1.1 3-1.4.1.1 8-1.4.2.1 9-1.4.2 10-1.4 11-1.4 14-1.4.3 15-1.4.3.2 16-1.2 16-1.4.3.1.2 18-1.2.1.3.1.1 18-1.4.3.1.1.1 20-1.1.2 21-1.1 21-1.1.2.1.1 21-1.1.2.1.2 22-1.1.1.r 23-1.1.1.1.1 25-1.1.2.1.1.1 27-1.1.2.1.2.1 29-1.3 29-1.3.r 30-1 31-1.2.1.3.1.1 31-1.4.3.1.1.1 33-1.2 33-1.4.3.1.2 (i / inhibit-01~e.30 :ARG0 (c / concentrate-02~e.21 :ARG1~e.22 (s / small-molecule :name (n / name :op1 "AZD1480"~e.23)) :ARG1-of (i2 / increase-01~e.20 :ARG2 (v / value-interval :op1 (c2 / concentration-quantity~e.21 :quant 0.1~e.25 :unit (m / micromolar)) :op2 (c3 / concentration-quantity~e.21 :quant 5~e.27 :unit m)))) :ARG1 (p2 / phosphorylate-01~e.16,33 :ARG1 (a / amino-acid :mod 980 :name (n2 / name :op1 "tyrosine") :part-of (e / enzyme :name (n3 / name :op1 "JAK3"~e.18,31)))) :manner~e.29 (c4 / complete~e.29) :location (c5 / cell-line~e.10,11 :name (n4 / name :op1 "L-540"~e.1,3) :ARG0-of (s2 / sensitive-03~e.9 :degree (m3 / most~e.8)) :ARG3-of (e2 / express-03~e.14 :ARG2 (e3 / enzyme :name (n5 / name :op1 "JAK3"~e.18,31) :ARG3-of (p3 / phosphorylate-01~e.16,33)) :mod (o / only~e.15)))) # ::id pmid_2282_9094.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , when HD @-@ LM2 and L @-@ 428 cells were incubated with AZD1480 , a paradoxical increase in JAK2 Y1007 @/@ 1008 and TYK2 Y1054 @/@ 1055 phosphorylation was observed after 72 h of incubation ( Figure 3a ) . # ::alignments 1-1 3-1.1.2.r 4-1.1.2.1 5-1.1.2.1 6-1.1.2.1 7-1.1.2.1 8-1.1.2.1 9-1.1.2.1 10-1.1.2.1 11-1.1.2.1 12-1.1.2.1 13-1.1.2.1 14-1.1.2.1 15-1.1.2.1 19-1.1.1.1 20-1.1.1.1.1.r 21-1.1.1.1.1.3.1.1 24-1.1.1.1.1.1 25-1.1.1 26-1.1.1.2.1.3.1.1 29-1.1.1.2.1.1 30-1.1.1.2 32-1.1 33-1.1.2 34-1.1.2.2.1 35-1.1.2.2.2 37-1.1.2.1 40-1.2.1 41-1.2.1.1 (c / contrast-01~e.1 :ARG2 (o / observe-01~e.32 :ARG1 (a / and~e.25 :op1 (i / increase-01~e.19 :ARG1~e.20 (a2 / amino-acid :mod "1007/1008"~e.24 :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "JAK2"~e.21))) :manner (p2 / paradox)) :op2 (p / phosphorylate-01~e.30 :ARG1 (a3 / amino-acid :mod "1054/1055"~e.29 :name (n3 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n4 / name :op1 "TYK2"~e.26))))) :time~e.3 (a4 / after~e.33 :op1 i3~e.4,5,6,7,8,9,10,11,12,13,14,15,37 :quant (t / temporal-quantity :quant 72~e.34 :unit (h / hour~e.35))) :condition (i3 / incubate-01 :ARG1 (a5 / and :op1 (c2 / cell-line :name (n5 / name :op1 "HD-LM2")) :op2 (c3 / cell-line :name (n6 / name :op1 "L-428"))) :ARG2 (s / small-molecule :name (n7 / name :op1 "AZD1480")))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "3a"~e.41))) # ::id pmid_2282_9094.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The hyperphosphorylation of JAK2 at the activation loop was confirmed using two antibodies obtained from different clones . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.2.r 6-1.1.2.1 7-1.1.2 9-1 10-1.2 11-1.2.1.1 12-1.2.1 13-1.2.1.2 14-1.2.1.2.1.r 15-1.2.1.2.1.1 16-1.2.1.2.1 (c / confirm-01~e.9 :ARG1 (h / hyperphosphorylate-01~e.1 :ARG1~e.2 (e / enzyme :name (n / name :op1 "JAK2"~e.3)) :location~e.4 (l / loop~e.7 :ARG0-of (a / activate-01~e.6))) :manner (u / use-01~e.10 :ARG1 (a2 / antibody~e.12 :quant 2~e.11 :ARG1-of (o / obtain-01~e.13 :ARG2~e.14 (c2 / clone-01~e.16 :ARG1-of (d / differ-02~e.15)))))) # ::id pmid_2282_9094.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The phosphorylation of the immediate downstream target STAT3 was abrogated at the same time point in all the three cell lines ( Figure 1b ) , suggesting that the function of the JAKs was effectively inhibited by AZD1480 . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.3 5-1.1.1.2 6-1.1.1 7-1.1.1.1.1.1 9-1 10-1.2.r 12-1.2.1 13-1.2.2 14-1.2 15-1.3.r 16-1.3.2 18-1.3.1 19-1.3 20-1.3 23-1.4.1 24-1.4.1.1 28-1.5 29-1.5.1.r 31-1.5.1.2 32-1.5.1.2.1.r 34-1.5.1.2.1.1.1 36-1.5.1.3 37-1.5.1 38-1.5.1.1.r 39-1.5.1.1.1.1 (a / abrogate-01~e.9 :ARG1 (p / phosphorylate-01~e.1 :ARG1~e.2 (t2 / target-01~e.6 :ARG1 (p2 / protein :name (n / name :op1 "STAT3"~e.7)) :mod (d / downstream~e.5) :mod (i / immediacy~e.4))) :time~e.10 (p3 / point~e.14 :ARG1-of (s / same-01~e.12) :mod (t3 / time~e.13)) :location~e.15 (c / cell-line~e.19,20 :quant 3~e.18 :mod (a2 / all~e.16)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.23 :mod "1b"~e.24)) :ARG0-of (s3 / suggest-01~e.28 :ARG1~e.29 (i2 / inhibit-01~e.37 :ARG0~e.38 (s4 / small-molecule :name (n3 / name :op1 "AZD1480"~e.39)) :ARG1 (f2 / function-01~e.31 :ARG0~e.32 (e / enzyme :name (n2 / name :op1 "JAK"~e.34))) :ARG1-of (e2 / effective-04~e.36)))) # ::id pmid_2282_9094.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When JAKs phosphorylation was analyzed over a shorter time period , a strong increase in JAK2 Y1007 @/@ 1008 phosphorylation was observed in HD @-@ LM2 and L @-@ 428 cells after 30 min of incubation with 1 μ AZD1480 ( Supplementary Figure S1A ) , whereas JAK3 Y980 phosphorylation was abrogated in L @-@ 540 cells ( Supplementary Figure S1A ) . # ::alignments 0-1.3.r 1-1.3.1.1.1.1 2-1.3.1 4-1.3 7-1.3.2 7-1.3.2.1 7-1.3.2.1.r 8-1.1.3.2 8-1.3.r 12-1.1.1.2 13-1.1.1 14-1.1.1.1.r 15-1.1.1.1.1.3.1.1 18-1.1.1.1.1.1 19-1.1.1.1 21-1.1 22-1.1.2.r 23-1.1.2.1.1.1 25-1.1.2.1.1.1 26-1.1.2 27-1.1.2.2.1.1 29-1.1.2.2.1.1 30-1.1.2.1 30-1.1.2.2 31-1.1.3 32-1.1.3.2.1 33-1.1.3.2.2 34-1.1.3.1.r 35-1.1.3.1 36-1.1.3.1.1.r 37-1.1.3.1.1.2.1 39-1.1.3.1.1.1.1 42-1.1.4.1.2 42-1.2.3.1.2 43-1.1.4.1 43-1.2.3.1 44-1.1.4.1.1 44-1.2.3.1.1 48-1 49-1.2.1.1.3.1.1 51-1.2.1 53-1.2 54-1.2.2.r 55-1.2.2.1.1 57-1.2.2.1.1 58-1.2.2 61-1.1.4.1.2 61-1.2.3.1.2 62-1.1.4.1 62-1.2.3.1 63-1.1.4.1.1 63-1.2.3.1.1 (c / contrast-01~e.48 :ARG1 (o / observe-01~e.21 :ARG1 (i / increase-01~e.13 :ARG1~e.14 (p / phosphorylate-01~e.19 :ARG1 (a / amino-acid :mod "1007/1008"~e.18 :name (n / name :op1 "tyrosine") :part-of (e / enzyme :name (n2 / name :op1 "JAK2"~e.15)))) :ARG1-of (s / strong-02~e.12)) :location~e.22 (a2 / and~e.26 :op1 (c2 / cell-line~e.30 :name (n3 / name :op1 "HD-LM2"~e.23,25)) :op2 (c3 / cell-line~e.30 :name (n4 / name :op1 "L-428"~e.27,29))) :time (a3 / after~e.31 :op1~e.34 (i2 / incubate-01~e.35 :ARG2~e.36 (s2 / small-molecule :name (n5 / name :op1 "AZD1480"~e.39) :quant (c4 / concentration-quantity :quant 1~e.37 :unit (m2 / micromolar)))) :quant (t / temporal-quantity~e.8 :quant 30~e.32 :unit (m / minute~e.33))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.43,62 :mod "S1A"~e.44,63 :ARG2-of (s3 / supplement-01~e.42,61)))) :ARG2 (a4 / abrogate-01~e.53 :ARG1 (p2 / phosphorylate-01~e.51 :ARG1 (a5 / amino-acid :mod 980 :name (n6 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n7 / name :op1 "JAK3"~e.49)))) :location~e.54 (c5 / cell-line~e.58 :name (n8 / name :op1 "L-540"~e.55,57)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.43,62 :mod "S1A"~e.44,63 :ARG2-of (s4 / supplement-01~e.42,61)))) :time~e.0,8 (a6 / analyze-01~e.4 :ARG1 (p3 / phosphorylate-01~e.2 :ARG1 (e3 / enzyme :name (n9 / name :op1 "JAK"~e.1))) :duration (s5 / short-07~e.7 :degree~e.7 (m3 / more~e.7)))) # ::id pmid_2282_9094.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The phosphorylation of the immediate downstream target STAT3 was abrogated at the same time point ( 30 min ) in all the three cell lines , suggesting that the function of the JAKs was effectively inhibited after 30 min of incubation with AZD1480 ( Supplementary Figure S1A ) . # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.3 5-1.1.1.2 6-1.1.1 7-1.1.1.1.1.1 9-1 10-1.2.r 12-1.2.2 13-1.2.1 13-1.2.3.1 14-1.2 16-1.2.3.1.1 17-1.2.3.1.2 19-1.3.r 20-1.3.2 22-1.3.1 23-1.3 24-1.3 26-1.4 27-1.4.1.r 29-1.4.1.1 30-1.4.1.1.1.r 32-1.4.1.1.1.1.1 34-1.4.1.2 35-1.4.1 36-1.4.1.3 37-1.4.1.3.2 38-1.4.1.3.2 39-1.4.1.3.1.r 40-1.4.1.3.1 41-1.4.1.3.1.1.r 42-1.4.1.3.1.1.1.1 45-1.5.1.2 46-1.5.1 47-1.5.1.1 (a / abrogate-01~e.9 :ARG1 (p / phosphorylate-01~e.1 :ARG1~e.2 (t2 / target-01~e.6 :ARG1 (p2 / protein :name (n / name :op1 "STAT3"~e.7)) :mod (d / downstream~e.5) :mod (i / immediacy~e.4))) :time~e.10 (p3 / point~e.14 :mod (t3 / time~e.13) :ARG1-of (s2 / same-01~e.12) :ARG1-of (m3 / mean-01 :ARG2 (t4 / temporal-quantity~e.13 :quant 30~e.16 :unit (m / minute~e.17)))) :location~e.19 (c / cell-line~e.23,24 :quant 3~e.22 :mod (a2 / all~e.20)) :ARG0-of (s3 / suggest-01~e.26 :ARG1~e.27 (i2 / inhibit-01~e.35 :ARG1 (f / function-01~e.29 :ARG0~e.30 (e / enzyme :name (n2 / name :op1 "JAK"~e.32))) :ARG1-of (e2 / effective-04~e.34) :time (a3 / after~e.36 :op1~e.39 (i3 / incubate-01~e.40 :ARG2~e.41 (s4 / small-molecule :name (n3 / name :op1 "AZD1480"~e.42))) :quant t4~e.37,38))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.46 :mod "S1A"~e.47 :ARG2-of (s5 / supplement-01~e.45)))) # ::id pmid_2282_9094.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD1480 induces a negative @-@ feedback loop involving phosphorylation ERK1 @/@ 2 and p38 # ::alignments 1-1.1.1.1 2-1 4-1.2.1.1 6-1.2.1 7-1.2 8-1.2.2 9-1.2.2.1.1 9-1.2.2.1.2 10-1.2.2.1.1.1.1.1 12-1.2.2.1.1.1.1.1 13-1.2.2.1 14-1.2.2.1.2.1.1.1 (i / induce-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.1)) :ARG2 (l / loop~e.7 :mod (f / feedback~e.6 :ARG0-of (n2 / negative-03~e.4)) :ARG2-of (i2 / involve-01~e.8 :ARG1 (a / and~e.13 :op1 (p / phosphorylate-01~e.9 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2"~e.10,12))) :op2 (p2 / phosphorylate-01~e.9 :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38"~e.14))))))) # ::id pmid_2282_9094.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As AZD1480 inhibition of STATs activity did not translate into antiproliferative activity in two cell lines , we hypothesized that these cells may depend on other signaling pathways to promote their survival . # ::alignments 1-1.3.1.2.1.1.1 2-1.3.1.2 5-1.3.1.2.2 5-1.3.1.3 7-1.3.1.1 7-1.3.1.1.r 8-1.3.1 9-1.3.1.3.r 10-1.3.1.3.1 10-1.3.1.3.1.1 10-1.3.1.3.1.1.r 11-1.3.1.3 12-1.3.1.4.r 13-1.3.1.4.1 14-1.3.1.4 15-1.3.1.4 17-1.1 18-1 19-1.2.r 20-1.2.1.1.1 21-1.2.1.1 22-1.2 23-1.2.1 24-1.2.1.2.r 25-1.2.1.2.2 26-1.2.1.2.1 27-1.2.1.2 29-1.2.1.3 31-1.2.1.3.2 (h / hypothesize-01~e.18 :ARG0 (w / we~e.17) :ARG1~e.19 (p / possible-01~e.22 :ARG1 (d2 / depend-01~e.23 :ARG0 (c / cell~e.21 :mod (t / this~e.20)) :ARG1~e.24 (p2 / pathway~e.27 :ARG0-of (s / signal-07~e.26) :mod (o / other~e.25)) :purpose (p3 / promote-01~e.29 :ARG0 p2 :ARG1 (s2 / survive-01~e.31 :ARG1 c)))) :ARG1-of (c4 / cause-01 :ARG0 (t2 / translate-01~e.8 :polarity~e.7 -~e.7 :ARG1 (i / inhibit-01~e.2 :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD1480"~e.1)) :ARG1 (a / activity-06~e.5 :ARG0 (p4 / protein :name (n2 / name :op1 "STAT")))) :ARG2~e.9 (a2 / activity-06~e.5,11 :ARG0-of (c2 / counter-01~e.10 :ARG1~e.10 (p5 / proliferate-01~e.10))) :location~e.12 (c3 / cell-line~e.14,15 :quant 2~e.13)))) # ::id pmid_2282_9094.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this hypothesis , we examined the effect of AZD1480 on ERK , p38 and phosphatidylinositol @-@ 3 kinase @/@ AKT signaling pathways , which are known to promote HL survival . # ::alignments 1-1.3 2-1.3.2.2 3-1.3.2 3-1.3.2.1 3-1.3.2.1.r 5-1.1 6-1 8-1.2 9-1.2.1.r 10-1.2.1.1.1 11-1.2.2.r 12-1.2.2.1.1.1 14-1.2.2.2.1.1 15-1.2.2 16-1.2.2.3.1.1 18-1.2.2.3.1.1 19-1.2.2.3.1.2 21-1.2.2.3.1.2 22-1.2.2.1.2 23-1.2.2.1 23-1.2.2.2 23-1.2.2.3 27-1.2.2.4.2 29-1.2.2.4 30-1.2.2.4.1.1.1.1 31-1.2.2.4.1 (e2 / examine-01~e.6 :ARG0 (w / we~e.5) :ARG1 (a / affect-01~e.8 :ARG0~e.9 (s / small-molecule :name (n2 / name :op1 "AZD1480"~e.10)) :ARG1~e.11 (a2 / and~e.15 :op1 (p / pathway~e.23 :name (n3 / name :op1 "ERK"~e.12) :ARG0-of (s2 / signal-07~e.22)) :op2 (p2 / pathway~e.23 :name (n4 / name :op1 "p38"~e.14) :ARG0-of s2) :op3 (p3 / pathway~e.23 :name (n5 / name :op1 "phosphatidylinositol-3"~e.16,18 :op2 "kinase/AKT"~e.19,21) :ARG0-of s2) :ARG0-of (p4 / promote-01~e.29 :ARG1 (s5 / survive-01~e.31 :ARG1 (d / disease :name (n / name :op1 "HL"~e.30))) :ARG1-of (k / know-01~e.27)))) :purpose (t2 / test-01~e.1 :ARG0 w :ARG1 (t / thing~e.3 :ARG1-of~e.3 (h / hypothesize-01~e.3) :mod (t3 / this~e.2)))) # ::id pmid_2282_9094.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that AZD1480 had no effect on phosphatidylinositol @-@ 3 kinase @/@ AKT signaling in any of these cell lines ( data not shown ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.2.1.1 5-1.2.1 5-1.2.1.r 6-1.2 7-1.2.3.r 8-1.2.3.1.1.1 10-1.2.3.1.1.1 11-1.2.3.1.1.2 13-1.2.3.1.1.2 14-1.2.3 15-1.2.4.r 16-1.2.4.1 18-1.2.4.2 19-1.2.4 20-1.2.4 22-1.3.1 23-1.3.1.1.1 23-1.3.1.1.1.r 24-1.3.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (a / affect-01~e.6 :polarity~e.5 -~e.5 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.3)) :ARG1~e.7 (s2 / signal-07~e.14 :ARG0 (p / pathway :name (n2 / name :op1 "phosphatidylinositol-3"~e.8,10 :op2 "kinase/AKT"~e.11,13))) :location~e.15 (c / cell-line~e.19,20 :mod (a2 / any~e.16) :mod (t / this~e.18))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.22 :ARG1-of (s3 / show-01~e.24 :polarity~e.23 -~e.23)))) # ::id pmid_2282_9094.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , AZD1480 increased the levels of ERK and p38 phosphorylation in the resistant HD @-@ LM2 and L @-@ 428 cells , whereas it inhibited ERK and p38 phosphorylation in the sensitive L @-@ 540 cells ( Figure 3b ) . # ::alignments 1-1 1-1.1 1-1.1.r 3-1.1.1.1.1.1 4-1.1.1 6-1.1.1.2.1 6-1.1.1.2.2 8-1.1.1.2.1.1.1.1.1 9-1.1.1.2 10-1.1.1.2.2.1.1.1.1 11-1.1.1.2.1.1 11-1.1.1.2.2.1 12-1.1.1.3.r 14-1.1.1.3.3 15-1.1.1.3.1.1.1 17-1.1.1.3.1.1.1 18-1.1.1.3 19-1.1.1.3.2.1.1 21-1.1.1.3.2.1.1 22-1.1.1.3.1 22-1.1.1.3.2 24-1.1 26-1.1.2 27-1.1.2.2 28-1.1.2.2 29-1.1.2.2 30-1.1.2.2 31-1.1.2.3.r 33-1.1.2.3.2 34-1.1.2.3.1.1 36-1.1.2.3.1.1 37-1.1.2.3 40-1.2.1 41-1.2.1.1 (c / contrast-01~e.1 :ARG2~e.1 (c2 / contrast-01~e.1,24 :ARG1 (i / increase-01~e.4 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480"~e.3)) :ARG1 (a / and~e.9 :op1 (l / level~e.6 :degree-of (p / phosphorylate-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.8)))) :op2 (l2 / level~e.6 :degree-of (p2 / phosphorylate-01~e.11 :ARG1 (e2 / enzyme :name (n3 / name :op1 "p38"~e.10))))) :location~e.12 (a2 / and~e.18 :op1 (c3 / cell-line~e.22 :name (n4 / name :op1 "HD-LM2"~e.15,17)) :op2 (c4 / cell-line~e.22 :name (n5 / name :op1 "L-428"~e.19,21)) :ARG0-of (r / resist-01~e.14))) :ARG2 (i2 / inhibit-01~e.26 :ARG0 s :ARG1 a~e.27,28,29,30 :location~e.31 (c5 / cell-line~e.37 :name (n6 / name :op1 "L-540"~e.34,36) :ARG0-of (s2 / sensitive-03~e.33)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "3b"~e.41))) # ::id pmid_2282_9094.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To define the mechanism of ERK and p38 activation in the two resistant cell lines , we first assessed the expression and activation levels of the Src homology 2 domain @-@ containing protein phosphatase 2 ( SHP @-@ 2 ) and SOCS @-@ 3 ( a STAT3 target gene @^{21 @} ) , two known regulators of JAK @/@ STAT and mitogen @-@ activated protein kinase ( MAPK ) signaling . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.1.r 5-1.4.2.1.1.1.1.1 6-1.4.2.1.1 7-1.4.2.1.1.2.1.1 8-1.4.2.1 9-1.4.2.1.2.r 11-1.4.2.1.2.1 12-1.4.2.1.2.2 13-1.4.2.1.2 14-1.4.2.1.2 16-1.1 17-1.3 18-1 20-1.2.1.1 21-1.2 21-1.2.1.1.1 22-1.2.2.1 23-1.2.1 23-1.2.2 24-1.2.1.1.1.r 26-1.2.1.1.1.3.1.1.1 27-1.2.1.1.1.3.1.1.2 28-1.2.1.1.1.3.1.1.3 29-1.2.1.1.1.3.1.1.4 31-1.2.1.1.1.3 32-1.2.1.1.1.1.1.1 33-1.2.1.1.1.1.1.2 34-1.2.1.1.1.1.1.3 40-1.2.1.1.1 41-1.2.1.1.1.2.1.1 43-1.2.1.1.1.2.1.1 46-1.2.1.1.1.2.2.1.1.1 47-1.2.1.1.1.2 47-1.2.1.1.1.2.2 47-1.2.1.1.1.2.2.r 51-1.2.1.1.1.2.2.2.1.1 57-1.2.1.1.1.4.2 58-1.2.1.1.1.4 59-1.2.1.1.1.4.1.r 60-1.2.1.1.1.4.1.1.1.1.1 62-1.2.1.1.1.4.1.1.1.1.1 63-1.2.1.1.1.4.1 64-1.2.1.1.1.4.1.2.1.1.1 66-1.2.1.1.1.4.1.2.1.1.1 67-1.2.1.1.1.4.1.2.1.1.2 68-1.2.1.1.1.4.1.2.1.1.3 72-1.2.1.1.1.4.1.1 72-1.2.1.1.1.4.1.2 (a / assess-01~e.18 :ARG0 (w / we~e.16) :ARG1 (a2 / and~e.21 :op1 (l / level~e.23 :degree-of (e / express-03~e.20 :ARG2~e.24 (a8 / and~e.21,40 :op1 (e5 / enzyme :name (n4 / name :op1 "protein"~e.32 :op2 "phosphatase"~e.33 :op3 2~e.34)) :op2 (p4 / protein~e.47 :name (n5 / name :op1 "SOCS-3"~e.41,43) :ARG0-of~e.47 (t / target-01~e.47 :ARG1 (p5 / protein :name (n6 / name :op1 "STAT3"~e.46)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :mod 21~e.51)))) :ARG0-of (c / contain-01~e.31 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "Src"~e.26 :op2 "homology"~e.27 :op3 2~e.28 :op4 "domain"~e.29))) :ARG0-of (r2 / regulate-01~e.58 :ARG1~e.59 (a5 / and~e.63 :op1 (s / signal-07~e.72 :ARG0 (p7 / pathway :name (n7 / name :op1 "JAK-STAT"~e.60,62))) :op2 (s2 / signal-07~e.72 :ARG0 (p / pathway :name (n8 / name :op1 "mitogen-activated"~e.64,66 :op2 "protein"~e.67 :op3 "kinase"~e.68)))) :ARG1-of (k / know-01~e.57))))) :op2 (l2 / level~e.23 :ARG1-of (a4 / activate-01~e.22) :quant-of p2)) :time (f / first~e.17) :purpose (d2 / define-01~e.1 :ARG0 w :ARG1 (m / mechanism~e.3 :poss~e.4 (a6 / activate-01~e.8 :ARG1 (a7 / and~e.6 :op1 (e2 / enzyme :name (n9 / name :op1 "ERK"~e.5)) :op2 (e4 / enzyme :name (n10 / name :op1 "p38"~e.7))) :location~e.9 (c2 / cell-line~e.13,14 :quant 2~e.11 :ARG0-of (r3 / resist-01~e.12)))))) # ::id pmid_2282_9094.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In fact , SHP @-@ 2 has been reported to be a negative regulator of the JAK @/@ STAT activation , whereas having a positive effect on ERK activation . @^{22 , 23 , 24 , 25 @} # ::alignments 0-1.2 1-1.2 3-1.1.2.1.1 5-1.1.2.1.1 8-1 12-1.1 13-1.1 14-1.1.1.r 16-1.1.1.1.1.1 18-1.1.1.1.1.1 19-1.1.1 21-1.3 24-1.3.1.3 25-1.3.1 26-1.3.1.2.r 27-1.3.1.2.1.1.1 28-1.3.1.2 32-1.4.1.1.1.1 36-1.4.1.1.1.2 40-1.4.1.1.1.3 44-1.4.1.1.1.4 (r / report-01~e.8 :ARG1 (d / downregulate-01~e.12,13 :ARG1~e.14 (a / activate-01~e.19 :ARG1 (p2 / pathway :name (n2 / name :op1 "JAK/STAT"~e.16,18))) :ARG2 (p / protein :name (n / name :op1 "SHP-2"~e.3,5))) :manner (i / in-fact~e.0,1) :ARG1-of (c / contrast-01~e.21 :ARG2 (a2 / affect-01~e.25 :ARG0 p :ARG1~e.26 (a3 / activate-01~e.28 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"~e.27))) :mod (p3 / positive~e.24))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG0 (a4 / and :op1 22~e.32 :op2 23~e.36 :op3 24~e.40 :op4 25~e.44))))) # ::id pmid_2282_9094.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , numerous studies have described enhanced SHP @-@ 2 and ERK activation after SOCS @-@ 3 deletion in both in vitro and in vivo models , postulating a negative @-@ feedback loop between SOCS @-@ 3 and SHP @-@ 2 . @^{22 , 23 , 26 @} # ::alignments 0-1 2-1.1.1.1 3-1.1.1 5-1.1 5-1.2 6-1.1.2.3 7-1.1.1.2.1.1.2.1.1 9-1.1.1.2.1.1.2.1.1 10-1.1.2 11-1.1.2.2.1.1.1 12-1.1.2.1 12-1.1.2.2 13-1.1.2.2.2 15-1.1.2.2.2.1.1.1.1 17-1.1.2.2.2.1.1.1.1 19-1.1.2.2.2.1 20-1.1.2.2.2.1.2.1.1 23-1.1.2.2.2.1.2.1.1 24-1.1.2.2.2.1.2.2.1 26-1.1.2.2.2.1.2 28-1.1.2.2.2.1.2.1.1 28-1.1.2.2.2.1.2.2.1 29-1.1.2.2.2.1.2.1.1 31-1.1.2.2.2.1.2.1 31-1.1.2.2.2.1.2.2 33-1.1.1.2 35-1.1.1.2.1.2.1 37-1.1.1.2.1.2 38-1.1.1.2.1 39-1.1.1.2.1.1 40-1.1.2.2.2.1.1.1.1 42-1.1.2.2.2.1.1.1.1 43-1.1.1.2.1.1 44-1.1.1.2.1.1.2.1.1 46-1.1.1.2.1.1.2.1.1 50-1.2.1.1.1.1 54-1.2.1.1.1.2 58-1.2.1.1.1.3 (a / and~e.0 :op2 (d / describe-01~e.5 :ARG0 (s / study-01~e.3 :mod (n4 / numerous~e.2) :ARG0-of (p / postulate-01~e.33 :ARG1 (l / loop-01~e.38 :ARG2 (b / between~e.39,43 :op1 p4 :op2 (p3 / protein :name (n3 / name :op1 "SHP-2"~e.7,9,44,46))) :mod (f / feedback~e.37 :ARG0-of (n / negative-03~e.35))))) :ARG1 (a2 / and~e.10 :op1 (a3 / activate-01~e.12 :ARG1 p3) :op2 (a4 / activate-01~e.12 :ARG1 (e / enzyme :name (n5 / name :op1 "ERK"~e.11)) :time (a5 / after~e.13 :op1 (d2 / delete-01~e.19 :ARG1 (p4 / protein :name (n6 / name :op1 "SOCS-3"~e.15,17,40,42)) :ARG2 (a6 / and~e.26 :op1 (m / model~e.31 :mod (i / in-vivo~e.20,23,28,29)) :op2 (m2 / model~e.31 :mod (i2 / in-vitro~e.24,28)))))) :ARG1-of (e2 / enhance-01~e.6))) :ARG1-of (d3 / describe-01~e.5 :ARG0 (p5 / publication :ARG0-of (c / cite-01 :ARG1 (a7 / and :op1 22~e.50 :op2 23~e.54 :op3 26~e.58))))) # ::id pmid_2282_9094.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the described changes in ERK phosphorylation status , after 72 h of incubation with increasing doses of AZD1480 ( 0.1 @–@ 5 μ) , an increase in SHP @-@ 2 phosphorylation on Tyr542 ( the major site of SHP @-@ 2 activation ) coupled with SOCS3 downregulation was observed in the HD @-@ LM2 and L @-@ 428 cell lines , but not in the L @-@ 540 cells ( Figure 3b ) . # ::alignments 0-1.1.2 3-1.1.2.1.2 3-1.1.4 4-1.1.2.1 5-1.1.2.1.1.r 6-1.1.2.1.1.1.1.1.1 7-1.1.2.1.1.1 8-1.1.2.1.1 10-1.1.3 11-1.1.3.2.1 12-1.1.3.2.2 13-1.1.3.1.r 14-1.1.3.1 15-1.1.3.1.1.r 16-1.1.3.1.1.2 17-1.1.3.1.1 18-1.1.3.1.1.1.r 19-1.1.3.1.1.1.1.1 21-1.1.3.1.1.3.1.1 23-1.1.3.1.1.3.2.1 27-1.1.1 28-1.1.1.1.r 29-1.1.1.1.2.1.1 31-1.1.1.1.2.1.1 32-1.1.1.1 33-1.1.1.1.1.r 34-1.1.1.1.1.1.1 37-1.1.1.1.1.2.1.2 38-1.1.1.1.1.2.1 39-1.1.1.1.1.2.1.1.r 40-1.1.1.1.1.2.1.1.1 41-1.1.1.1.1.2.1.1.1 42-1.1.1.1.1.2.1.1.1 43-1.1.1.1.1.2.1.1 45-1.1.1.1.3 46-1.1.1.1.3.1.r 47-1.1.1.1.3.1.1.1.1 48-1.1.1.1.3.1 50-1.1 50-1.2 51-1.1.5.r 53-1.1.5.1.1.1 55-1.1.5.1.1.1 56-1.1.5 57-1.1.5.2.1.1 59-1.1.5.2.1.1 60-1.1.5.1 60-1.1.5.2 60-1.2.3 61-1.1.5.1 63-1 64-1.2.1 64-1.2.1.r 67-1.2.3.1.1 69-1.2.3.1.1 70-1.1.5.1 73-1.1.4.1 74-1.1.4.1.1 (c8 / contrast-01~e.63 :ARG1 (o3 / observe-01~e.50 :ARG1 (i3 / increase-01~e.27 :ARG1~e.28 (p2 / phosphorylate-01~e.32 :ARG1~e.33 (a2 / amino-acid :name (n4 / name :op1 "Tyr542"~e.34) :ARG1-of (m3 / mean-01 :ARG2 (s2 / site-01~e.38 :ARG1~e.39 (a3 / activate-01~e.43 :ARG1 p3~e.40,41,42) :ARG1-of (m4 / major-02~e.37)))) :ARG2 (p3 / protein :name (n3 / name :op1 "SHP-2"~e.29,31)) :ARG1-of (c5 / couple-01~e.45 :ARG2~e.46 (d4 / downregulate-01~e.48 :ARG1 (p4 / protein :name (n5 / name :op1 "SOCS3"~e.47)))))) :ARG1-of (c / consistent-01~e.0 :ARG2 (c2 / change-01~e.4 :ARG1~e.5 (s / status~e.8 :topic (p / phosphorylate-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.6)))) :ARG1-of (d / describe-01~e.3))) :time (a / after~e.10 :op1~e.13 (i / incubate-01~e.14 :ARG2~e.15 (d2 / dose-01~e.17 :ARG2~e.18 (s3 / small-molecule :name (n2 / name :op1 "AZD1480"~e.19)) :ARG1-of (i2 / increase-01~e.16) :quant (b / between :op1 (c3 / concentration-quantity :quant 0.1~e.21 :unit (m / micromolar)) :op2 (c4 / concentration-quantity :quant 5~e.23 :unit m)))) :quant (t / temporal-quantity :quant 72~e.11 :unit (h / hour~e.12))) :ARG1-of (d3 / describe-01~e.3 :ARG0 (f / figure~e.73 :mod "3b"~e.74)) :location~e.51 (a4 / and~e.56 :op1 (c6 / cell-line~e.60,61,70 :name (n6 / name :op1 "HD-LM2"~e.53,55)) :op2 (c7 / cell-line~e.60 :name (n7 / name :op1 "L-428"~e.57,59)))) :ARG2 (o2 / observe-01~e.50 :polarity~e.64 -~e.64 :ARG1 i3 :location (c9 / cell-line~e.60 :name (n8 / name :op1 "L-540"~e.67,69)))) # ::id pmid_2282_9094.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , in the L @-@ 540 cells , SOCS3 downregulation was not coupled with SHP @-@ 2 hyperphosphorylation , and ERK phosphorylation was in fact inhibited after treatment with AZD1480 , suggesting a different model of MAPK activation in this cell line . # ::alignments 5-1.1.2.3 7-1.1.1.2.2.1.1 9-1.1.1.2.2.1.1 10-1.1.1.2.2 12-1.1.1.2.1.1.1 13-1.1.1.2 15-1.1.1.1 15-1.1.1.1.r 16-1.1.1 17-1.1.1.3.r 18-1.1.1.3.1.1.1 20-1.1.1.3.1.1.1 21-1.1.1.3 23-1.1 24-1.1.2.1.1.1.1 25-1.1.2.1 27-1.1.2.3 28-1.1.2.3 29-1.1.2 30-1.1.2.2 31-1.1.2.2.1 32-1.1.2.2.1.1.r 33-1.1.2.2.1.1.1.1 35-1.1.3 37-1.1.3.1.1 38-1.1.3.1 39-1.1.3.1.2.r 40-1.1.3.1.2.1.1.1 41-1.1.3.1.2 42-1.1.2.3 44-1.1.1.2.2 45-1.1.1.2.2 (c / contrast-01 :ARG2 (a / and~e.23 :op1 (c2 / couple-01~e.16 :polarity~e.15 -~e.15 :ARG1 (d2 / downregulate-01~e.13 :ARG1 (p3 / protein :name (n4 / name :op1 "SOCS3"~e.12)) :location (c3 / cell-line~e.10,44,45 :name (n6 / name :op1 "L-540"~e.7,9))) :ARG2~e.17 (h / hyperphosphorylate-01~e.21 :ARG1 (p4 / protein :name (n5 / name :op1 "SHP-2"~e.18,20)))) :op2 (i / inhibit-01~e.29 :ARG1 (p / phosphorylate-01~e.25 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.24))) :time (a2 / after~e.30 :op1 (t / treat-04~e.31 :ARG2~e.32 (s2 / small-molecule :name (n3 / name :op1 "AZD1480"~e.33)))) :mod (i2 / in-fact~e.5,27,28,42)) :ARG0-of (s / suggest-01~e.35 :ARG1 (m / model~e.38 :ARG1-of (d / differ-02~e.37) :mod~e.39 (a3 / activate-01~e.41 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK"~e.40)) :location c3))))) # ::id pmid_2282_9094.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activation of p38 signaling observed in the HD @-@ LM2 and L @-@ 428 cell lines after incubation with AZD1480 was probably related to the activity of autocrine and paracrine chemokine and cytokine loops , triggered by SHP @-@ 2/ERK activation . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2 6-1.1.1.2.1.r 8-1.1.1.2.1.1.1.1 10-1.1.1.2.1.1.1.1 11-1.1.1.2.1 12-1.1.1.2.1.2.1.1 14-1.1.1.2.1.2.1.1 15-1.1.1.2.1.1 15-1.1.1.2.1.2 16-1.1.1.2.1.1 17-1.1.1.2.2 18-1.1.1.2.2.1 19-1.1.1.2.2.1.1.r 20-1.1.1.2.2.1.1.1.1 22-1.3 23-1 26-1.2 27-1.2.1.r 28-1.2.1.1.1.1 29-1.2.1 30-1.2.1.4.1.1 31-1.2.1.1.1 31-1.2.1.2.1 32-1.2.1 33-1.2.1.3.1 33-1.2.1.4.1 34-1.2.1.1 34-1.2.1.2 34-1.2.1.3 34-1.2.1.4 36-1.2.1.5 37-1.2.1.5.1.r 38-1.2.1.5.1.1.1.1 41-1.2.1.5.1 (r / relate-01~e.23 :ARG1 (a5 / activate-01~e.1 :ARG1~e.2 (s / signal-07~e.4 :ARG0 (e / enzyme :name (n2 / name :op1 "p38"~e.3)) :ARG1-of (o / observe-01~e.5 :location~e.6 (a6 / and~e.11 :op1 (c3 / cell-line~e.15,16 :name (n3 / name :op1 "HD-LM2"~e.8,10)) :op2 (c4 / cell-line~e.15 :name (n4 / name :op1 "L-428"~e.12,14))) :time (a7 / after~e.17 :op1 (i / incubate-01~e.18 :ARG2~e.19 (s2 / small-molecule :name (n5 / name :op1 "AZD1480"~e.20))))))) :ARG2 (a / activity-06~e.26 :ARG0~e.27 (a2 / and~e.29,32 :op1 (l3 / loop~e.34 :mod (c / chemokine~e.31 :mod (a3 / autocrine~e.28))) :op2 (l / loop~e.34 :mod (c5 / chemokine~e.31 :mod p2)) :op3 (l2 / loop~e.34 :mod (c6 / cytokine~e.33 :mod a3)) :op4 (l4 / loop~e.34 :mod (c2 / cytokine~e.33 :mod (p2 / paracrine~e.30))) :ARG1-of (t / trigger-01~e.36 :ARG2~e.37 (a4 / activate-01~e.41 :ARG1 (p3 / pathway :name (n / name :op1 "SHP-2/ERK"~e.38)))))) :mod (p / probable~e.22)) # ::id pmid_2282_9094.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Over a shorter time period , we observed a strong correlation between SOCS @-@ 3 downregulation and SHP @-@ 2/ERK activation in the HD @-@ LM2 cell line after 6 h of incubation with AZD1480 , whereas in the L @-@ 540 cell line , ERK phosphorylation was inhibited without an increase in SHP @-@ 2 phosphorylation or a decrease in SOCS @-@ 3 levels ( Supplementary Figure S1D ) . # ::alignments 0-1.1.3 2-1.1.3.1.1 2-1.1.3.1.1.1 2-1.1.3.1.1.1.r 3-1.1.3.r 3-1.1.5.1.2 4-1.1.3.1 6-1.1.1 7-1.1 9-1.1.2.3 10-1.1.2 12-1.1.2.1.1.1.1 14-1.1.2.1.1.1.1 15-1.1.2.1 17-1.1.2.2.1.1.1 20-1.1.2.2 21-1.1.4.r 23-1.1.4.1.1 25-1.1.4.1.1 26-1.1.4 27-1.1.4 28-1.1.5 29-1.1.5.1.2.1 30-1.1.5.1.2.2 32-1.1.5.1 33-1.1.5.1.1.r 34-1.1.5.1.1.1.1 36-1 37-1.2.r 39-1.2.4.1.1 41-1.2.4.1.1 42-1.2.4 43-1.2.4 45-1.2.2.1.1.1 46-1.2.2 48-1.2 49-1.2.1 49-1.2.1.r 49-1.2.3.1 49-1.2.3.1.r 49-1.2.5.1 49-1.2.5.1.r 51-1.2.3 52-1.2.3.2.r 53-1.2.3.2.1.1.1.1 55-1.2.3.2.1.1.1.1 56-1.2.3.2.1 57-1.2.3.2 59-1.2.5 60-1.2.5.2.r 61-1.2.5.2.1 62-1.2.5.2.1 63-1.2.5.2.1 64-1.2.5.2 67-1.3.1.2 68-1.3.1 69-1.3.1.1 (c / contrast-01~e.36 :ARG1 (o / observe-01~e.7 :ARG0 (w / we~e.6) :ARG1 (c2 / correlate-01~e.10 :ARG1 (d / downregulate-01~e.15 :ARG1 (p / protein :name (n / name :op1 "SOCS-3"~e.12,14))) :ARG2 (a / activate-01~e.20 :ARG1 (p3 / pathway :name (n2 / name :op1 "SHP-2/ERK"~e.17))) :ARG1-of (s2 / strong-02~e.9)) :time~e.3 (o2 / over~e.0 :op1 (p2 / period~e.4 :ARG1-of (s / short-07~e.2 :degree~e.2 (m / more~e.2)))) :location~e.21 (c3 / cell-line~e.26,27 :name (n3 / name :op1 "HD-LM2"~e.23,25)) :time (a2 / after~e.28 :op1 (i / incubate-01~e.32 :ARG2~e.33 (s4 / small-molecule :name (n4 / name :op1 "AZD1480"~e.34)) :duration (t2 / temporal-quantity~e.3 :quant 6~e.29 :unit (h / hour~e.30))))) :ARG2~e.37 (i2 / inhibit-01~e.48 :polarity~e.49 -~e.49 :ARG1 (p4 / phosphorylate-01~e.46 :ARG1 (p7 / protein-family :name (n5 / name :op1 "ERK"~e.45))) :ARG0-of (i3 / increase-01~e.51 :polarity~e.49 -~e.49 :ARG1~e.52 (o3 / or~e.57 :op1 (p5 / phosphorylate-01~e.56 :ARG1 (p6 / protein :name (n6 / name :op1 "SHP-2"~e.53,55))))) :location (c4 / cell-line~e.42,43 :name (n8 / name :op1 "L-540"~e.39,41)) :ARG0-of (d2 / decrease-01~e.59 :polarity~e.49 -~e.49 :ARG1~e.60 (l / level~e.64 :quant-of p~e.61,62,63))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.68 :mod "S1D"~e.69 :ARG2-of (s3 / supplement-01~e.67)))) # ::id pmid_2282_9094.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD1480 determines increased production of the chemokines IP @-@ 10 , IL @-@ 8 and RANTES in HL cells # ::alignments 1-1.1.1.1 2-1 3-1.2.2 4-1.2 7-1.2.1.1 7-1.2.1.2 7-1.2.1.3 8-1.2.1.1.1.1 10-1.2.1.1.1.1 12-1.2.1.2.1.1 14-1.2.1.2.1.1 15-1.2.1 16-1.2.1.3.1.1 17-1.2.1.r 18-1.2.1.4.1.1.1 19-1.2.1.4 (d2 / determine-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"~e.1)) :ARG1 (p / produce-01~e.4 :ARG1~e.17 (a / and~e.15 :op1 (c / chemokine~e.7 :name (n3 / name :op1 "IP-10"~e.8,10)) :op2 (c2 / chemokine~e.7 :name (n4 / name :op1 "IL-8"~e.12,14)) :op3 (c3 / chemokine~e.7 :name (n5 / name :op1 "RANTES"~e.16)) :location (c4 / cell-line~e.19 :mod (d / disease :name (n2 / name :op1 "HL"~e.18)))) :ARG1-of (i / increase-01~e.3))) # ::id pmid_2282_9094.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The interaction between HRS cells and the surrounding reactive infiltrate provides an environment that supports the growth and survival of HRS cells through a complex network of autocrine and paracrine loops involving a variety of cytokines and chemokines . @^{1 , 27 @} # ::alignments 1-1.1 3-1.1.1.1.1 4-1.1.1 7-1.1.2.2 9-1.1.2 10-1 12-1.2 14-1.2.1 16-1.2.1.1.1 17-1.2.1.1 18-1.2.1.1.2 19-1.2.1.1.2.1.r 20-1.2.1.1.2.1 21-1.2.1.1.2.1 24-1.2.1.2.4 25-1.2.1.2 27-1.2.1.2.1.1 29-1.2.1.2.2.1 30-1.2.1.2.1 30-1.2.1.2.2 31-1.2.1.2.3 35-1.2.1.2.3.1.1.1 37-1.2.1.2.3.1.2.1 41-1.3.1.1.1.1 45-1.3.1.1.1.2 (p / provide-01~e.10 :ARG0 (i / interact-01~e.1 :ARG0 (c / cell-line~e.4 :name (n / name :op1 "HRS"~e.3)) :ARG1 (i2 / infiltrate~e.9 :ARG0-of (r / react-01) :ARG1-of (s / surround-01~e.7))) :ARG1 (e / environment~e.12 :ARG0-of (s2 / support-01~e.14 :ARG1 (a / and~e.17 :op1 (g / grow-01~e.16 :ARG1 c) :op2 (s3 / survive-01~e.18 :ARG0~e.19 c~e.20,21)) :manner (n2 / network-01~e.25 :ARG1 (l / loop-01~e.30 :ARG1 (a2 / autocrine~e.27)) :ARG2 (l2 / loop-01~e.30 :ARG1 (p2 / paracrine~e.29)) :ARG2-of (i3 / involve-01~e.31 :ARG1 (a3 / and :op1 (v / vary-01 :ARG1 (c2 / cytokine~e.35)) :op2 (v2 / vary-01 :ARG1 (c3 / chemokine~e.37)))) :mod (c4 / complex~e.24)))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG0-of (c5 / cite-01 :ARG1 (a4 / and :op1 1~e.41 :op2 27~e.45))))) # ::id pmid_2282_9094.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The chemokines IP @-@ 10 , RANTES and IL @-@ 8 are known to be upregulated by MAPK ( ERK and p38 ) activation and have previously been reported to have a role in tumorigenesis and Hodgkin lymphomagenesis by promoting cell proliferation and survival . @^{1 , 27 , 28 , 29 , 30 , 31 @} # ::alignments 1-1.1.1.1.1 1-1.1.1.1.2 1-1.1.1.1.3 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 6-1.1.1.1.2.1.1 7-1.1.1.1 8-1.1.1.1.3.1.1 10-1.1.1.1.3.1.1 12-1.1 15-1.1.1 16-1.1.1.2.r 17-1.1.1.2.1.1.1 19-1.1.1.2.1.2.1.1.1.1 20-1.1.1.2.1.2.1 21-1.1.1.2.1.2.1.2.1.1 23-1.1.1.2 24-1 25-1.2.1 26-1.2.2 28-1.2 30-1.2.1 32-1.2.1.2 33-1.2.1.2.1.r 34-1.2.1.2.1 34-1.2.1.2.1.1.1 35-1.2.1.2.1.1 36-1.2.1.2.1.1.2.1.1 38-1.2.1.3.r 39-1.2.1.3 40-1.2.1.3.2.1.1 41-1.2.1.3.2.1 42-1.2.1.3.2 43-1.2.1.3.2.2 47-1.3.1.1.1.1 51-1.3.1.1.1.2 55-1.3.1.1.1.3 59-1.3.1.1.1.4 63-1.3.1.1.1.5 67-1.3.1.1.1.6 (a / and~e.24 :op1 (k / know-01~e.12 :ARG1 (u / upregulate-01~e.15 :ARG1 (a3 / and~e.7 :op1 (c2 / chemokine~e.1 :name (n3 / name :op1 "IP-10"~e.2,4)) :op2 (c3 / chemokine~e.1 :name (n4 / name :op1 "RANTES"~e.6)) :op3 (c4 / chemokine~e.1 :name (n5 / name :op1 "IL-8"~e.8,10))) :ARG2~e.16 (a5 / activate-01~e.23 :ARG1 (p3 / pathway :name (n6 / name :op1 "MAPK"~e.17) :ARG1-of (m / mean-01 :ARG2 (a4 / and~e.20 :op1 (e / enzyme :name (n / name :op1 "ERK"~e.19)) :op2 (e2 / enzyme :name (n2 / name :op1 "p38"~e.21)))))))) :op2 (r / report-01~e.28 :ARG1 (h / have-03~e.25,30 :ARG0 a3 :ARG1 (r2 / role~e.32 :prep-in~e.33 (c6 / create-01~e.34 :ARG1 (a8 / and~e.35 :op1 (t2 / tumor~e.34) :op2 (d2 / disease :name (n8 / name :op1 "Hodgkin"~e.36 :op2 "lymphoma"))))) :manner~e.38 (p4 / promote-01~e.39 :ARG0 a3 :ARG1 (a7 / and~e.42 :op1 (p5 / proliferate-01~e.41 :ARG0 (c5 / cell~e.40)) :op2 (s / survive-01~e.43 :ARG0 c5)))) :time (p / previous~e.26)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG0-of (c / cite-01 :ARG1 (a2 / and :op1 1~e.47 :op2 27~e.51 :op3 28~e.55 :op4 29~e.59 :op5 30~e.63 :op6 31~e.67))))) # ::id pmid_2282_9094.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the observed changes in SHP2 , ERK and p38 phosphorylation , AZD1480 increased the production of IP @-@ 10 , RANTES and IL @-@ 8 in the supernatants of the resistant HD @-@ LM2 and L @-@ 428 , and not the sensitive L @-@ 540 cells . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1.2 4-1.3.1 5-1.3.1.1.r 6-1.3.1.1.1.1.1.1 8-1.3.1.1.1.2.1.1 9-1.3.1.1.1 10-1.3.1.1.1.3.1.1 11-1.3.1.1 13-1.1.1.1 14-1 16-1.2 17-1.2.1.r 18-1.2.1.1.1.1 20-1.2.1.1.1.1 22-1.2.1.2.1.1 23-1.2.1 24-1.2.1.3.1.1 26-1.2.1.3.1.1 27-1.2.2.r 29-1.2.2 30-1.2.2.1.r 32-1.2.2.1.3 33-1.2.2.1.1.1.1 35-1.2.2.1.1.1.1 36-1.2.2.1 37-1.2.2.1.2.1.1 39-1.2.2.1.2.1.1 41-1.2.2.1 44-1.2.2.2.1.2 45-1.2.2.2.1.1.1 47-1.2.2.2.1.1.1 48-1.2.2.1.1 48-1.2.2.1.2 48-1.2.2.2.1 (i / increase-01~e.14 :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD1480"~e.13)) :ARG1 (p / produce-01~e.16 :ARG1~e.17 (a2 / and~e.23 :op1 (p2 / protein :name (n5 / name :op1 "IP-10"~e.18,20)) :op2 (p3 / protein :name (n6 / name :op1 "RANTES"~e.22)) :op3 (p4 / protein :name (n7 / name :op1 "IL-8"~e.24,26))) :location~e.27 (s / supernatant~e.29 :poss~e.30 (a3 / and~e.36,41 :op1 (c3 / cell-line~e.48 :name (n9 / name :op1 "HD-LM2"~e.33,35)) :op2 (c4 / cell-line~e.48 :name (n10 / name :op1 "L-428"~e.37,39)) :ARG0-of (r / resist-01~e.32)) :ARG1-of (c5 / contrast-01 :ARG2 (c6 / cell-line~e.48 :name (n8 / name :op1 "L-540"~e.45,47) :ARG0-of (s2 / sensitive-03~e.44))))) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (c2 / change-01~e.4 :ARG1~e.5 (p5 / phosphorylate-01~e.11 :ARG1 (a / and~e.9 :op1 (e2 / enzyme :name (n2 / name :op1 "SHP2"~e.6)) :op2 (e / enzyme :name (n3 / name :op1 "ERK"~e.8)) :op3 (e4 / enzyme :name (n4 / name :op1 "p38"~e.10)))) :ARG1-of (o / observe-01~e.3)))) # ::id pmid_2282_9094.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ( Figure 3c ) . # ::alignments 2-1 3-1.1 (f / figure~e.2 :mod "3c"~e.3) # ::id pmid_2282_9094.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This data suggest that the efficacy of AZD1480 may have been attenuated in the HD @-@ LM2 and L @-@ 428 cells by an autocrine negative @-@ feedback loop involving cytokines that activate ERK @/@ p38 survival signaling pathway . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.1.2 6-1.2.1.2.1.r 7-1.2.1.2.1.1.1 8-1.2 11-1.2.1 12-1.2.1.3.r 14-1.2.1.3.1.1.1 16-1.2.1.3.1.1.1 17-1.2.1.3 18-1.2.1.3.2.1.1 20-1.2.1.3.2.1.1 21-1.2.1.3.1 21-1.2.1.3.2 22-1.2.1.1.r 24-1.2.1.1.1.1 25-1.2.1.1.1.2 27-1.2.1.1.1 28-1.2.1.1 29-1.2.1.1.1.3 30-1.2.1.1.1.3.1 32-1.2.1.1.1.3.1.1 33-1.2.1.1.1.3.1.1.1.1.1 35-1.2.1.1.1.3.1.1.1.1.1 36-1.2.1.1.1.3.1.1.1.2.1 37-1.2.1.1.1.3.1.1.1.2 38-1.2.1.1.1.3.1.1.1 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.3 (p / possible-01~e.8 :ARG1 (a / attenuate-01~e.11 :ARG0~e.22 (l2 / loop-01~e.28 :mod (f / feedback~e.27 :mod (a3 / autocrine~e.24) :ARG0-of (n3 / negative-03~e.25) :ARG2-of (i / involve-01~e.29 :ARG1 (c3 / cytokine~e.30 :ARG0-of (a4 / activate-01~e.32 :ARG1 (p2 / pathway~e.38 :name (n4 / name :op1 "ERK/p38"~e.33,35) :ARG0-of (s2 / signal-07~e.37 :ARG1 (s3 / survive-01~e.36)))))))) :ARG1 (e / efficacy~e.5 :poss~e.6 (s4 / small-molecule :name (n5 / name :op1 "AZD1480"~e.7))) :location~e.12 (a2 / and~e.17 :op1 (c / cell-line~e.21 :name (n / name :op1 "HD-LM2"~e.14,16)) :op2 (c2 / cell-line~e.21 :name (n2 / name :op1 "L-428"~e.18,20)))))) # ::id pmid_2282_9094.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK inhibitors enhance the efficacy of AZD1480 in the HD @-@ LM2 and L @-@ 428 cell lines # ::alignments 1-1.1.1.1.1.1 2-1.1 2-1.1.1 2-1.1.1.r 3-1 5-1.2 6-1.2.1.r 7-1.2.1.1.1 8-1.3.r 10-1.3.1.1.1 12-1.3.1.1.1 13-1.3 14-1.3.2.1.1 16-1.3.2.1.1 17-1.3.1 17-1.3.2 18-1.3.1 (e2 / enhance-01~e.3 :ARG0 (m / molecular-physical-entity~e.2 :ARG0-of~e.2 (i / inhibit-01~e.2 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"~e.1)))) :ARG1 (e / efficacy~e.5 :poss~e.6 (s / small-molecule :name (n / name :op1 "AZD1480"~e.7))) :location~e.8 (a / and~e.13 :op1 (c / cell-line~e.17,18 :name (n3 / name :op1 "HD-LM2"~e.10,12)) :op2 (c2 / cell-line~e.17 :name (n4 / name :op1 "L-428"~e.14,16)))) # ::id pmid_2282_9094.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess whether the observed activation of the SHP @-@ 2/ERK pathway is involved in the resistance to JAK @/@ STAT inhibition , HL cells were treated with 1 μ AZD1480 in combination with two commercially available MEK inhibitors ( UO126 and PD98059 ) . # ::alignments 1-1.3 2-1.3.1.1 2-1.3.1.1.r 4-1.3.1.2.2 5-1.3.1.2 8-1.3.1.2.1.1.1 11-1.3.1.2.1 11-1.3.1.3.1.1 13-1.3.1 14-1.3.1.3.r 16-1.3.1.3 17-1.3.1.3.1.r 18-1.3.1.3.1.1.1.1 20-1.3.1.3.1.1.1.1 21-1.3.1.3.1 23-1.1.1.1.1 24-1.1 26-1 27-1.2.r 28-1.2.2.1 30-1.2.1.1 32-1.2 32-1.2.3 32-1.2.3.r 33-1.2.3.1.r 34-1.2.3.1.1 35-1.2.3.1.3.1 35-1.2.3.1.3.1.r 36-1.2.3.1.3 37-1.2.3.1.2.1.1.1 38-1.2.3.1 38-1.2.3.1.2 38-1.2.3.1.2.r 40-1.2.3.1.4.1.1.1.1 41-1.2.3.1.4.1 42-1.2.3.1.4.1.2.1.1 (t2 / treat-04~e.26 :ARG1 (c2 / cell-line~e.24 :mod (d / disease :name (n / name :op1 "HL"~e.23))) :ARG2~e.27 (s / small-molecule~e.32 :name (n4 / name :op1 "AZD1480"~e.30) :quant (c / concentration-quantity :quant 1~e.28 :unit (m / micromolar)) :ARG1-of~e.32 (c3 / combine-01~e.32 :ARG2~e.33 (m2 / molecular-physical-entity~e.38 :quant 2~e.34 :ARG0-of~e.38 (i / inhibit-01~e.38 :ARG1 (p / protein-family :name (n5 / name :op1 "MEK"~e.37))) :ARG2-of (a3 / available-02~e.36 :manner~e.35 (c4 / commercial~e.35)) :ARG1-of (m3 / mean-01 :ARG2 (a4 / and~e.41 :op1 (s2 / small-molecule :name (n6 / name :op1 "UO126"~e.40)) :op2 (s3 / small-molecule :name (n7 / name :op1 "PD98059"~e.42))))))) :purpose (a / assess-01~e.1 :ARG1 (i2 / involve-01~e.13 :mode~e.2 interrogative~e.2 :ARG1 (a2 / activate-01~e.5 :ARG1 (p2 / pathway~e.11 :name (n2 / name :op1 "SHP-2/ERK"~e.8)) :ARG1-of (o / observe-01~e.4)) :ARG2~e.14 (r / resist-01~e.16 :ARG1~e.17 (i3 / inhibit-01~e.21 :ARG1 (p3 / pathway~e.11 :name (n3 / name :op1 "JAK/STAT"~e.18,20))))))) # ::id pmid_2282_9094.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were incubated with increasing concentrations of UO126 or PD98059 ( 10 @–@ 100 μ) , with or without 1 μ AZD1480 for 24 , 48 and 72 h , and cell viability was assessed using the MTS assay . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 3-1.2.2.1.1.r 4-1.1.2.2 5-1.1.2 5-1.1.2.1.3.1 5-1.1.2.1.3.2 5-1.1.3.1.2 6-1.1.2.1.r 7-1.1.2.1.1.1.1 8-1.1.2.1 8-1.1.3 9-1.1.2.1.2.1.1 11-1.1.2.1.3.1.1 13-1.1.2.1.3.2.1 16-1.2.2.1.1.r 17-1.1.2.1 18-1.1.3.2.1 18-1.1.3.2.1.r 19-1.1.3.1.2.1 21-1.1.3.1.1.1 21-1.1.3.2.2.1 22-1.1.4.r 23-1.1.4.1.1 25-1.1.4.2.1 26-1.1.4 27-1.1.4.3.1 28-1.1.4.1.2 28-1.1.4.2.2 28-1.1.4.3.2 30-1 31-1.2.1.1 32-1.2.1 34-1.2 35-1.2.2 37-1.2.2.1.1.1.1 38-1.2.2.1 (a / and~e.30 :op1 (i / incubate-01~e.2 :ARG1 (c2 / cell~e.0) :ARG2~e.3 (c3 / concentrate-01~e.5 :ARG1~e.6 (o / or~e.8,17 :op1 (s2 / small-molecule :name (n2 / name :op1 "UO126"~e.7)) :op2 (s3 / small-molecule :name (n3 / name :op1 "PD98059"~e.9)) :quant (b / between :op1 (c4 / concentration-quantity~e.5 :quant 10~e.11 :unit (m2 / micromolar)) :op2 (c5 / concentration-quantity~e.5 :quant 100~e.13 :unit m2))) :ARG1-of (i2 / increase-01~e.4)) :manner (o2 / or~e.8 :op1 (s / small-molecule :name (n4 / name :op1 "AZD1480"~e.21) :quant (c6 / concentration-quantity~e.5 :quant 1~e.19 :unit m2)) :op2 (s4 / small-molecule :polarity~e.18 -~e.18 :name (n5 / name :op1 "AZD1480"~e.21))) :duration~e.22 (a4 / and~e.26 :op1 (t2 / temporal-quantity :quant 24~e.23 :unit (h / hour~e.28)) :op2 (t3 / temporal-quantity :quant 48~e.25 :unit (h2 / hour~e.28)) :op3 (t4 / temporal-quantity :quant 72~e.27 :unit (h3 / hour~e.28)))) :op2 (a2 / assess-01~e.34 :ARG1 (v2 / viability~e.32 :poss (c / cell~e.31)) :ARG2-of (u / use-01~e.35 :ARG1 (a3 / assay-01~e.38 :instrument~e.3,16 (s5 / small-molecule :name (n / name :op1 "MTS"~e.37)))))) # ::id pmid_2282_9094.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both UO126 and PD98059 enhanced the effect of AZD1480 in the HD @-@ LM2 and L @-@ 428 cells at 72 h ( Figure 3d ) . # ::alignments 1-1.1.1.1.1 2-1.1 3-1.1.2.1.1 4-1 6-1.2 7-1.2.1.r 8-1.2.1.1.1 9-1.3.r 11-1.3.1.1.1 13-1.3.1.1.1 14-1.3 15-1.3.2.1.1 17-1.3.2.1.1 18-1.3.1 18-1.3.2 20-1.3.3.1.1 21-1.3.3.1.2 24-1.4.1 25-1.4.1.1 (e / enhance-01~e.4 :ARG0 (a / and~e.2 :op1 (s / small-molecule :name (n2 / name :op1 "UO126"~e.1)) :op2 (s2 / small-molecule :name (n / name :op1 "PD98059"~e.3))) :ARG1 (a2 / affect-01~e.6 :ARG0~e.7 (s3 / small-molecule :name (n3 / name :op1 "AZD1480"~e.8))) :location~e.9 (a3 / and~e.14 :op1 (c / cell-line~e.18 :name (n4 / name :op1 "HD-LM2"~e.11,13)) :op2 (c2 / cell-line~e.18 :name (n5 / name :op1 "L-428"~e.15,17)) :time (a4 / after :op1 (t / temporal-quantity :quant 72~e.20 :unit (h / hour~e.21)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "3d"~e.25))) # ::id pmid_2282_9094.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This effect was associated with inhibition of AZD1480 @-@ induced ERK phosphorylation ( Figure 3e ) . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2 6-1.2.1.r 7-1.2.1.2.1.1.1 9-1.2.1.2 10-1.2.1.1.1.1 11-1.2.1 14-1.3.1 15-1.3.1.1 (a / associate-01~e.3 :ARG1 (a2 / affect-01~e.1 :mod (t / this~e.0)) :ARG2~e.4 (i / inhibit-01~e.5 :ARG1~e.6 (p2 / phosphorylate-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.10)) :ARG2-of (i2 / induce-01~e.9 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480"~e.7))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "3e"~e.15))) # ::id pmid_2282_9094.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoregulatory effects of AZD1480 in HL cells # ::alignments 2-1 3-1.1.r 4-1.1.1.1 5-1.2.r 6-1.2.1.1.1 7-1.2 (a / affect-01~e.2 :ARG0~e.3 (s / small-molecule :name (n2 / name :op1 "AZD1480"~e.4)) :ARG1~e.5 (c / cell-line~e.7 :mod (d / disease :name (n / name :op1 "HL"~e.6))) :ARG2 (i / immunoregulate-00)) # ::id pmid_2282_9094.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PD @-@ L1 and PD @-@ L2 are members of the B7 family , which inhibit T @-@ cell function by interacting with the programmed cell death 1 receptor expressed on T cells . # ::alignments 0-1.2.1.1.1 0-1.2.2.1.1 2-1.2.1.1.1 3-1.2 4-1.2.1.1.1 4-1.2.2.1.1 6-1.2.2.1.1 7-1.2.r 8-1 11-1.1.1.1.1.1 12-1.1.1 15-1.3 16-1.3.1.1.1.1 18-1.3.1.1 19-1.3.1 20-1.3.2.r 21-1.3.2 22-1.3.2.2.r 24-1.3.2.2.1.1 25-1.3.2.2.1.2 26-1.3.2.2.1.3 27-1.3.2.2.1.4 28-1.3.2.2.1.5 29-1.3.2.2.2 30-1.3.2.2.2.1.r 31-1.3.2.2.2.1 32-1.3.2.2.2.1 (m / member~e.8 :ARG1-of (i3 / include-91 :ARG2 (f / family~e.12 :mod (p4 / protein :name (n5 / name :op1 "B7"~e.11)))) :domain~e.7 (a / and~e.3 :op1 (p2 / protein :name (n / name :op1 "PD-L1"~e.0,2,4)) :op2 (p3 / protein :name (n2 / name :op1 "PD-L2"~e.0,4,6))) :ARG0-of (i / inhibit-01~e.15 :ARG1 (f2 / function-01~e.19 :ARG0 (c3 / cell~e.18 :name (n3 / name :op1 "T"~e.16))) :manner~e.20 (i2 / interact-01~e.21 :ARG0 a :ARG1~e.22 (p / protein :name (n4 / name :op1 "programmed"~e.24 :op2 "cell"~e.25 :op3 "death"~e.26 :op4 1~e.27 :op5 "receptor"~e.28) :ARG2-of (e / express-03~e.29 :ARG3~e.30 c3~e.31,32))))) # ::id pmid_2282_9094.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PD @-@ L1 and PD @-@ L2 have been reported to be regulated by the JAK @/@ STAT pathway or the MAPK pathway , depending on the cellular context . @^{9 , 11 , 13 @} # ::alignments 0-1.1.2.1.1.1 0-1.1.2.2.1.1 2-1.1.2.1.1.1 3-1.1.2 4-1.1.2.1.1.1 4-1.1.2.2.1.1 6-1.1.2.2.1.1 9-1 12-1.1 13-1.1.1.r 15-1.1.1.1.1.1 17-1.1.1.1.1.1 18-1.1.1.1 18-1.1.1.2 19-1.1.1 21-1.1.1.2.1.1 22-1.1.1.1 24-1.1.3 25-1.1.3.1.r 27-1.1.3.1.1 28-1.1.3.1 32-1.2.1.1.1.1 36-1.2.1.1.1.2 40-1.2.1.1.1.3 (r / report-01~e.9 :ARG1 (r2 / regulate-01~e.12 :ARG0~e.13 (o / or~e.19 :op1 (p4 / pathway~e.18,22 :name (n4 / name :op1 "JAK/STAT"~e.15,17)) :op2 (p5 / pathway~e.18 :name (n5 / name :op1 "MAPK"~e.21))) :ARG1 (a / and~e.3 :op1 (p2 / protein :name (n2 / name :op1 "PD-L1"~e.0,2,4)) :op2 (p3 / protein :name (n3 / name :op1 "PD-L2"~e.0,4,6))) :ARG0-of (d / depend-01~e.24 :ARG1~e.25 (c / context~e.28 :mod (c2 / cell~e.27)))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG0 (a2 / and :op1 9~e.32 :op2 11~e.36 :op3 13~e.40))))) # ::id pmid_2282_9094.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we assessed the effect of AZD1480 on PD @-@ L1 and PD @-@ L2 expression in HL cells by flow cytometry . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2.1 5-1.1.2.2 6-1.1.2.1.1.r 7-1.1.2.1.1.1.1 9-1.1.2.1.2.1.1.1 11-1.1.2.1.2.1.1.1 12-1.1.2 13-1.1.2.1.2.1.1.1 13-1.1.2.2.1.1.1.1 15-1.1.2.2.1.1.1.1 16-1.1.2.1.2 16-1.1.2.2.1 17-1.1.2.2.1.2.r 18-1.1.2.2.1.2.1.1.1 19-1.1.2.2.1.2 20-1.1.3.r 21-1.1.3.1 22-1.1.3 (c / cause-01~e.0 :ARG1 (a / assess-01~e.3 :ARG0 (w / we~e.2) :ARG1 (a2 / and~e.12 :op1 (a3 / affect-01~e.5 :ARG0~e.6 (s / small-molecule :name (n / name :op1 "AZD1480"~e.7)) :ARG1 (e2 / express-03~e.16 :ARG1 (p / protein :name (n2 / name :op1 "PD-L1"~e.9,11,13)))) :op2 (a4 / affect-01~e.5 :ARG1 (e / express-03~e.16 :ARG2 (p2 / protein :name (n3 / name :op1 "PD-L2"~e.13,15)) :ARG3~e.17 (c2 / cell-line~e.19 :mod (d / disease :name (n4 / name :op1 "HL"~e.18)))))) :instrument~e.20 (c3 / cytometry~e.22 :mod (f / flow~e.21)))) # ::id pmid_2282_9094.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After incubation with AZD1480 1 μ for 72 h , we observed a significant downregulation of PD @-@ L1 and PD @-@ L2 in the PD @-@ L1 @/@ PD @-@ L2 @-@ positive HL cell lines HD @-@ LM2 and L @-@ 540 ( Figure 4a and b ) . # ::alignments 0-1.4 1-1.4.1 2-1.4.1.1.r 3-1.4.1.1.1.1 4-1.4.1.1.2.1 6-1.4.1.2.r 7-1.4.1.2.1 8-1.4.1.2.2 10-1.1 11-1 13-1.2.2 14-1.2 15-1.2.1.r 16-1.2.1.1.1.1 16-1.2.1.2.1.1 18-1.2.1.1.1.1 19-1.2.1 20-1.2.1.1.1.1 20-1.2.1.2.1.1 22-1.2.1.2.1.1 25-1.2.1.1.1.1 25-1.2.1.2.1.1 27-1.2.1.1.1.1 29-1.2.1.1.1.1 29-1.2.1.2.1.1 31-1.2.1.2.1.1 33-1.2.3.2 34-1.2.3.3.1.1 35-1.2.3 36-1.2.3 37-1.2.3.1.1.1.1.1 39-1.2.3.1.1.1.1.1 40-1.2.3.1.1 41-1.2.3.1.1.2.1.1 43-1.2.3.1.1.2.1.1 46-1.3.1.1 46-1.3.1.2 47-1.3.1.1.1 48-1.3.1 (o / observe-01~e.11 :ARG0 (w / we~e.10) :ARG1 (d2 / downregulate-01~e.14 :ARG1~e.15 (a3 / and~e.19 :op1 (p / protein :name (n4 / name :op1 "PD-L1"~e.16,18,20,25,27,29)) :op2 (p2 / protein :name (n5 / name :op1 "PD-L2"~e.16,20,22,25,29,31))) :ARG1-of (s / significant-02~e.13) :location (c4 / cell-line~e.35,36 :ARG1-of (m2 / mean-01 :ARG0 (a4 / and~e.40 :op1 (c2 / cell-line :name (n2 / name :op1 "HD-LM2"~e.37,39)) :op2 (c3 / cell-line :name (n3 / name :op1 "L-540"~e.41,43)))) :mod (p4 / positive~e.33 :topic p2) :mod (d3 / disease :name (n6 / name :op1 "HL"~e.34)))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.48 :op1 (f / figure~e.46 :mod "4a"~e.47) :op2 (f2 / figure~e.46 :mod "4b"))) :time (a2 / after~e.0 :op1 (i / incubate-01~e.1 :ARG2~e.2 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.3) :quant (c / concentration-quantity :quant 1~e.4 :unit (m / micromolar))) :duration~e.6 (t / temporal-quantity :quant 72~e.7 :unit (h / hour~e.8))))) # ::id pmid_2282_9094.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No significant dowregulation was detected following incubation with MEK inhibitors ( UO126 and PD98059 25 μ for 72 h ) in the L @-@ 540 cell line ( data not shown ) . # ::alignments 0-1.1 0-1.1.r 1-1.2.1 4-1 5-1.3 6-1.3.1 7-1.3.1.1.r 8-1.3.1.1.1.1.1.1 9-1.3.1.1 9-1.3.1.1.1 9-1.3.1.1.1.r 11-1.3.1.1.3.1.1.1.1 12-1.3.1.1.3.1 13-1.3.1.1.3.1.2.1.1 14-1.3.1.1.3.1.3.1 16-1.3.1.2.r 17-1.3.1.2.1 18-1.3.1.2.2 20-1.3.1.1.2.r 22-1.3.1.1.2.1.1 24-1.3.1.1.2.1.1 25-1.3.1.1.2 26-1.3.1.1.2 28-1.4.1 29-1.4.1.1.1 29-1.4.1.1.1.r 30-1.4.1.1 (d / detect-01~e.4 :polarity~e.0 -~e.0 :ARG1 (d2 / downregulate-01 :ARG1-of (s / significant-02~e.1)) :ARG1-of (f / follow-01~e.5 :ARG2 (i2 / incubate-01~e.6 :ARG2~e.7 (m3 / molecular-physical-entity~e.9 :ARG0-of~e.9 (i / inhibit-01~e.9 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.8))) :location~e.20 (c / cell-line~e.25,26 :name (n2 / name :op1 "L-540"~e.22,24)) :ARG1-of (m / mean-01 :ARG2 (a / and~e.12 :op1 (s3 / small-molecule :name (n3 / name :op1 "UO126"~e.11)) :op2 (s4 / small-molecule :name (n4 / name :op1 "PD98059"~e.13)) :quant (c2 / concentration-quantity :quant 25~e.14 :unit (m2 / micromolar))))) :duration~e.16 (t2 / temporal-quantity :quant 72~e.17 :unit (h / hour~e.18)))) :ARG1-of (d3 / describe-01 :ARG0 (d4 / data~e.28 :ARG1-of (s2 / show-01~e.30 :polarity~e.29 -~e.29)))) # ::id pmid_2282_9094.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , in the HD @-@ LM2 cell line , an increase in the activation of ERK was observed after incubation with AZD1480 , ruling out a role of this pathway in the regulation of PD ligands expression in this cell line ( Figure 3b ) . # ::alignments 7-1.1.1.2.2.1 9-1.1.1.2.2.1 10-1.1.1.2 11-1.1.1.2 14-1.1.1 15-1.1.1.1.r 17-1.1.1.1 18-1.1.1.1.1.r 19-1.1.1.1.1.2.1 21-1.1 22-1.1.2 23-1.1.2.1 24-1.1.2.1.1.r 25-1.1.2.1.1.2.1 27-1.1.3 28-1.1.3 30-1.1.3.1 34-1.1.3.2.r 36-1.1.3.2 37-1.1.3.2.2.r 38-1.1.3.2.2.1.2.1 39-1.1.3.2.2.1.2.1 40-1.1.3.2.2 43-1.1.3.2.2.2 44-1.1.3.2.2.2 47-1.2.1 48-1.2.1.1 (c2 / contrast-01 :ARG2 (o / observe-01~e.21 :ARG1 (i / increase-01~e.14 :ARG1~e.15 (a / activate-01~e.17 :ARG1~e.18 (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n2 / name :op1 "ERK"~e.19))) :location (c / cell-line~e.10,11 :wiki - :name (n3 / name :op1 "HD-LM2"~e.7,9))) :time (a2 / after~e.22 :op1 (i2 / incubate-01~e.23 :ARG2~e.24 (s / small-molecule :wiki - :name (n / name :op1 "AZD1480"~e.25)))) :ARG0-of (r / rule-out-02~e.27,28 :ARG1 (r2 / role~e.30 :poss e) :ARG2~e.34 (r3 / regulate-01~e.36 :ARG0 e :ARG1~e.37 (e2 / express-03~e.40 :ARG2 (p / protein :wiki "PD-L1" :name (n4 / name :op1 "PD-ligand"~e.38,39)) :ARG3 c~e.43,44)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.47 :mod "3b"~e.48))) # ::id pmid_2282_9094.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given the potent inhibition of STAT proteins phosphorylation observed with low doses AZD1480 ( 0.1 @–@ 1 μ) , we also assessed the effect of AZD1480 on the expression of STAT @-@ regulated cytokines and chemokines involved in HL cell survival ( IL @-@ 6 ) and immune escape ( IL @-@ 13 , TARC ) , focusing on the three cell lines with baseline JAK @/@ STAT activation . # ::alignments 2-1.3.1.4 3-1.3.1 5-1.5.1.2.1.1.1 6-1.2.1.2.1.3.1 6-1.2.1.2.1.4.1.1 6-1.2.1.2.1.4.1.2 6-1.2.1.2.1.5.1 7-1.3.1.2 8-1.3.1.3 9-1.3.1.1.r 10-1.3.1.1.2.1 11-1.3.1.1 11-1.3.1.1.2 11-1.3.1.1.2.r 12-1.3.1.1.1.1 14-1.3.1.1.2.2.1.1 16-1.3.1.1.2.2.2.1 19-1.1 20-1.4 21-1 23-1.2.1 25-1.3.1.1.1.1 28-1.2.1.2 29-1.2.1.2.1.r 30-1.2.1.2.1.3.1.1.1 32-1.2.1.2.1.3 33-1.2.1.2.1.1 34-1.2.1.2.1 34-1.2.1.2.1.4.1 35-1.2.1.2.1.2 36-1.2.1.2.1.4.1.3 36-1.2.1.2.1.5.1.2 37-1.2.1.2.1.5.1.2.1.r 38-1.2.1.2.1.5.1.2.1.1.1.1.1 39-1.2.1.2.1.5.1.2.1.1 40-1.2.1.2.1.5.1.2.1 42-1.2.1.2.1.5.1.1.1 44-1.2.1.2.1.5.1.1.1 46-1.2.1.2.1 47-1.2.1.2.1.4.1.3.1.1 48-1.2.1.2.1.4.1.3.1 50-1.2.1.2.1.4.1.1.1.1 52-1.2.1.2.1.4.1.1.1.1 54-1.2.1.2.1.4.1.2.1.1 57-1.5 60-1.5.1.1 61-1.5.1 62-1.5.1 64-1.5.1.2.2 65-1.5.1.2.1.1.1 67-1.5.1.2.1.1.1 68-1.5.1.2 (a / assess-01~e.21 :ARG0 (w / we~e.19) :ARG1 (a4 / and :op1 (a5 / affect-01~e.23 :ARG0 s2 :ARG1 (e3 / express-03~e.28 :ARG2~e.29 (a7 / and~e.34,46 :op1 (c4 / cytokine~e.33) :op2 (c6 / chemokine~e.35) :ARG1-of (r / regulate-01~e.32 :ARG0 (p4 / protein~e.6 :name (n3 / name :op1 "STAT"~e.30))) :ARG1-of (m3 / mean-01 :ARG2 (a9 / and~e.34 :op1 (p6 / protein~e.6 :name (n6 / name :op1 "IL-13"~e.50,52)) :op2 (p7 / protein~e.6 :name (n7 / name :op1 "TARC"~e.54)) :ARG1-of (i4 / involve-01~e.36 :ARG2 (e2 / escape-01~e.48 :ARG1 (i3 / immune-02~e.47))))) :ARG1-of (m2 / mean-01 :ARG2 (p8 / protein~e.6 :name (n8 / name :op1 "IL-6"~e.42,44) :ARG1-of (i2 / involve-01~e.36 :ARG2~e.37 (s / survive-01~e.40 :ARG0 (c5 / cell-line~e.39 :mod (d2 / disease :name (n / name :op1 "HL"~e.38))))))))))) :ARG1-of (c / cause-01 :ARG0 (i / inhibit-01~e.3 :ARG0~e.9 (s2 / small-molecule~e.11 :name (n2 / name :op1 "AZD1480"~e.12,25) :ARG2-of~e.11 (d / dose-01~e.11 :ARG1-of (l / low-04~e.10) :quant (a2 / and :op1 (c2 / concentration-quantity :quant 0.1~e.14 :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant 1~e.16 :unit m)))) :ARG1 (p / phosphorylate-01~e.7 :ARG1 p4) :ARG1-of (o / observe-01~e.8) :mod (p3 / potent~e.2))) :mod (a3 / also~e.20) :ARG1-of (f / focus-01~e.57 :ARG2 (c7 / cell-line~e.61,62 :quant 3~e.60 :mod (a8 / activate-01~e.68 :ARG1 (p5 / pathway :name (n5 / name :op1 "JAK/STAT"~e.5,65,67)) :mod (b / baseline~e.64))))) # ::id pmid_2282_9094.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following incubation with AZD1480 1 μ for 72 h , cell culture supernatants were analyzed by enzyme @-@ linked immunosorbent assay ; consistent with the inhibition of STAT3 and STAT6 phosphorylation , decreased levels of IL @-@ 6 , IL @-@ 13 and TARC were observed in HD @-@ LM2 , L @-@ 428 and L @-@ 540 ( Figure 4b ) . # ::alignments 0-1.1.3 1-1.1.3.1 2-1.1.1.1.r 2-1.1.3.1.1.r 3-1.1.3.1.1.1.1 4-1.1.3.1.1.2.1 6-1.1.3.1.2.r 7-1.1.3.1.2.1 8-1.1.3.1.2.2 10-1.1.2.2 11-1.1.2.1 12-1.1.2 14-1.1 16-1.1.1.2.1 18-1.1.1.2 19-1.1.1.1 20-1.1.1 22-1.3 23-1.1.1.1.r 23-1.3.2.r 25-1.3.2 26-1.3.2.1.r 27-1.3.2.1.1.1.1.1 28-1.3.2.1.1 29-1.3.2.1.1.2.1.1 30-1.3.2.1 32-1.3.1.1.2 33-1.3.1.1 35-1.3.1.1.1.1.1.1 35-1.3.1.1.1.2.1.1 37-1.3.1.1.1.1.1.1 39-1.3.1.1.1.1.1.1 39-1.3.1.1.1.2.1.1 41-1.3.1.1.1.2.1.1 43-1.3.1.1.1.3.1.1 45-1.3.1 46-1.3.1.2.r 47-1.3.1.2.1.1.1 49-1.3.1.2.1.1.1 51-1.3.1.2.2.1.1 51-1.3.1.2.3.1.1 53-1.3.1.2.2.1.1 54-1.3.1.2 55-1.3.1.2.2.1.1 55-1.3.1.2.3.1.1 57-1.3.1.2.3.1.1 60-1.2.1 61-1.2.1.1 (m / multi-sentence :snt1 (a / analyze-01~e.14 :ARG0 (a6 / assay-01~e.20 :instrument~e.2,23 (i / immunosorbent~e.19) :ARG1-of (l / link-01~e.18 :ARG2 (e / enzyme~e.16))) :ARG1 (s / supernatant~e.12 :ARG0-of (c / culture-01~e.11) :mod (c8 / cell~e.10)) :ARG1-of (f / follow-01~e.0 :ARG2 (i2 / incubate-01~e.1 :ARG2~e.2 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.3) :quant (c3 / concentration-quantity :quant 1~e.4 :unit (m2 / micromolar))) :duration~e.6 (t / temporal-quantity :quant 72~e.7 :unit (h / hour~e.8))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.60 :mod "4b"~e.61)) :snt2 (c4 / consistent-01~e.22 :ARG1 (o / observe-01~e.45 :ARG1 (l2 / level~e.33 :quant-of (a4 / and :op1 (p4 / protein :name (n4 / name :op1 "IL-6"~e.35,37,39)) :op2 (p5 / protein :name (n5 / name :op1 "IL-13"~e.35,39,41)) :op3 (p6 / protein :name (n6 / name :op1 "TARC"~e.43))) :ARG1-of (d2 / decrease-01~e.32)) :location~e.46 (a5 / and~e.54 :op1 (c5 / cell-line :name (n7 / name :op1 "HD-LM2"~e.47,49)) :op2 (c6 / cell-line :name (n8 / name :op1 "L-428"~e.51,53,55)) :op3 (c7 / cell-line :name (n9 / name :op1 "L-540"~e.51,55,57)))) :ARG2~e.23 (i3 / inhibit-01~e.25 :ARG1~e.26 (p / phosphorylate-01~e.30 :ARG1 (a3 / and~e.28 :op1 (p2 / protein :name (n2 / name :op1 "STAT3"~e.27)) :op2 (p3 / protein :name (n3 / name :op1 "STAT6"~e.29))))))) # ::id pmid_2282_9094.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High concentrations of AZD1480 promote early G2/M arrest and cell death in HL cells by inhibiting Aurora kinases # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1 5-1 7-1.2.1.1.1.1 8-1.2.1 9-1.2 10-1.2.3 11-1.2.2 12-1.2.3.1.r 13-1.2.3.1.1.1 14-1.2.2.1 15-1.3.r 16-1.3 17-1.3.2.1.1 18-1.3.2 (p / promote-01~e.5 :ARG0 (c / concentrate-02~e.2 :ARG1~e.3 (s / small-molecule :name (n / name :op1 "AZD1480"~e.4)) :ARG1-of (h / high-02~e.1)) :ARG1 (a2 / and~e.9 :op1 (a / arrest-02~e.8 :time (e / event :name (n4 / name :op1 "G2/M"~e.7))) :op2 (d / die-01~e.11 :ARG1 (c2 / cell~e.14)) :location (c3 / cell-line~e.10 :mod~e.12 (d2 / disease :name (n2 / name :op1 "HL"~e.13)))) :manner~e.15 (i / inhibit-01~e.16 :ARG0 c :ARG1 (k / kinase~e.18 :name (n3 / name :op1 "Aurora"~e.17)))) # ::id pmid_2282_9094.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Higher concentrations ( 5 μ) of AZD1480 promoted a marked increase in the G2/M fraction in all four cell lines after 24 h of incubation , especially pronounced in HD @-@ LM2 and L @-@ 428 cells ( Figure 5a and b ) . # ::alignments 0-1.1.2 0-1.1.2.1 0-1.1.2.1.r 1-1.1 1-1.1.3.1 3-1.1.3.1.1 5-1.1.1.r 6-1.1.1.1.1 7-1 9-1.2.4 10-1.2 11-1.2.1.r 13-1.2.1.1.1.1 14-1.2.1 17-1.2.2.1 18-1.2.2 19-1.2.2 20-1.2.5 22-1.2.5.1.1.2 24-1.2.5.1 26-1.2.3.1 27-1.2.3 28-1.2.3.2.r 29-1.2.3.2.1.1.1 31-1.2.3.2.1.1.1 32-1.2.3.2 33-1.2.3.2.2.1.1 35-1.2.3.2.2.1.1 36-1.2.3.2.1 36-1.2.3.2.2 39-1.3.1.1 39-1.3.1.2 40-1.3.1.1.1 41-1.3.1 (p / promote-01~e.7 :ARG0 (c / concentrate-02~e.1 :ARG1~e.5 (s / small-molecule :name (n / name :op1 "AZD1480"~e.6)) :ARG1-of (h / high-02~e.0 :degree~e.0 (m / more~e.0)) :ARG1-of (m2 / mean-01 :ARG2 (c2 / concentration-quantity~e.1 :quant 5~e.3 :unit (m3 / micromolar)))) :ARG1 (i / increase-01~e.10 :ARG1~e.11 (f3 / fraction-01~e.14 :time (e2 / event :name (n2 / name :op1 "G2/M"~e.13))) :location (c3 / cell-line~e.18,19 :quant 4~e.17) :ARG1-of (p3 / pronounced-02~e.27 :mod (e / especially~e.26) :location~e.28 (a3 / and~e.32 :op1 (c4 / cell-line~e.36 :name (n3 / name :op1 "HD-LM2"~e.29,31)) :op2 (c5 / cell-line~e.36 :name (n4 / name :op1 "L-428"~e.33,35)))) :ARG1-of (m4 / mark-01~e.9) :time (a2 / after~e.20 :op1 (i2 / incubate-01~e.24 :duration (t / temporal-quantity :quant 72 :unit (h2 / hour~e.22))))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.41 :op1 (f / figure~e.39 :mod "5a"~e.40) :op2 (f2 / figure~e.39 :mod "5b")))) # ::id pmid_2282_9094.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , treatment with a lower AZD1480 concentration ( 1 μ) for 24 h did not significantly affect the cell cycle fractions ( Figure 5a and b ) . # ::alignments 1-1 3-1.1.2 4-1.1.2.1.r 6-1.1.2.1.2 6-1.1.2.1.2.1 6-1.1.2.1.2.1.r 7-1.1.2.1.1.1.1 8-1.1.2.1 8-1.1.2.1.3 8-1.1.2.1.3.r 10-1.1.2.1.3.1 12-1.1.2.2.r 13-1.1.2.2.1 14-1.1.2.2.2 16-1.1.1 16-1.1.1.r 17-1.1.4 18-1.1 20-1.1.3.1.1 21-1.1.3.1 22-1.1.3 25-1.2.1.1 25-1.2.1.2 26-1.2.1.1.1 27-1.2.1 (c / contrast-01~e.1 :ARG2 (a / affect-01~e.18 :polarity~e.16 -~e.16 :ARG0 (t / treat-04~e.3 :ARG2~e.4 (c4 / concentrate-02~e.8 :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.7)) :ARG1-of (l / low-04~e.6 :degree~e.6 (m2 / more~e.6)) :quant~e.8 (c5 / concentration-quantity~e.8 :quant 1~e.10 :unit (m / micromolar))) :duration~e.12 (t2 / temporal-quantity :quant 24~e.13 :unit (h / hour~e.14))) :ARG1 (f / fraction-01~e.22 :ARG1 (c2 / cycle-02~e.21 :ARG1 (c3 / cell~e.20))) :ARG1-of (s / significant-02~e.17)) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.27 :op1 (f2 / figure~e.25 :mod "5a"~e.26) :op2 (f3 / figure~e.25 :mod "5b")))) # ::id pmid_2282_9094.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As AZD1480 was reported to inhibit Aurora A kinase in enzymatic assays , ^{14 @} we assessed whether the significant increase in the G2/M fraction observed in HL cell lines after incubation with 5 μ AZD1480 was related to the inhibition of Aurora A. # ::alignments 0-1.2.2.3.2.r 1-1.2.2.3.2.1.1.1.1 3-1.3.1 5-1.3.1.1 6-1.3.1.1.2.1.1 7-1.3.1.1.2.1.2 8-1.3.1.1.2 9-1.3.1.1.3.r 10-1.3.1.1.3.1 11-1.3.1.1.3 18-1.1 19-1 20-1.2.1 20-1.2.1.r 22-1.2.2.2 23-1.2.2 24-1.2.2.1.r 26-1.2.2.1.1.1.1 27-1.2.2.1 28-1.2.2.3 29-1.2.2.3.1.r 30-1.2.2.3.1.1.1.1 31-1.2.2.3.1 32-1.2.2.3.1 33-1.2.2.3.2 34-1.2.2.3.2.1 36-1.2.2.3.2.1.1.2.1 38-1.2.2.3.2.1.1.1.1 40-1.2 41-1.2.3.r 43-1.2.3 44-1.2.3.1.r 45-1.2.3.1 (a / assess-01~e.19 :ARG0 (w / we~e.18) :ARG1 (r / relate-01~e.40 :mode~e.20 interrogative~e.20 :ARG1 (i / increase-01~e.23 :ARG1~e.24 (f / fraction-01~e.27 :time (e / event :name (n / name :op1 "G2/M"~e.26))) :ARG2 (s / significant-02~e.22) :ARG1-of (o / observe-01~e.28 :location~e.29 (c / cell-line~e.31,32 :mod (d / disease :name (n2 / name :op1 "HL"~e.30))) :time~e.0 (a2 / after~e.33 :op1 (i2 / incubate-01~e.34 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "AZD1480"~e.1,38) :quant (c2 / concentration-quantity :quant 5~e.36 :unit (m / micromolar))))))) :ARG2~e.41 (i3 / inhibit-01~e.43 :ARG1~e.44 k~e.45)) :ARG0-of (c3 / cause-01 :ARG1 (r2 / report-01~e.3 :ARG1 (i4 / inhibit-01~e.5 :ARG0 s2 :ARG1 (k / kinase~e.8 :name (n5 / name :op1 "Aurora"~e.6 :op2 "A"~e.7)) :time~e.9 (a3 / assay-01~e.11 :ARG1 (e2 / enzyme~e.10)))))) # ::id pmid_2282_9094.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok First , we analyzed the baseline expression of Aurora A and B kinases in exponentially growing HL cells by western blotting . # ::alignments 0-1.3 0-1.3.1 0-1.3.1.r 2-1.1 3-1 5-1.2.4 6-1.2 7-1.2.1.r 8-1.2.1.1.1.1 9-1.2.1.1.1.2 10-1.2.1 11-1.2.1.2.1.2 12-1.2.1.1 12-1.2.1.2 13-1.2.2.r 14-1.2.2.1.1 14-1.2.2.1.1.r 15-1.2.2.1 16-1.2.2.2.1.1 17-1.2.2 18-1.2.3.r 19-1.2.3 20-1.2.3 (a / analyze-01~e.3 :ARG0 (w / we~e.2) :ARG1 (e / express-03~e.6 :ARG2~e.7 (a2 / and~e.10 :op1 (k / kinase~e.12 :name (n3 / name :op1 "Aurora"~e.8 :op2 "A"~e.9)) :op2 (k2 / kinase~e.12 :name (n4 / name :op1 "Aurora" :op2 "B"~e.11))) :ARG3~e.13 (c / cell-line~e.17 :ARG1-of (g / grow-01~e.15 :manner~e.14 (e2 / exponential~e.14)) :mod (d / disease :name (n / name :op1 "HL"~e.16))) :manner~e.18 (i / immunoblot-01~e.19,20) :mod (b / baseline~e.5)) :ord (o / ordinal-entity~e.0 :value~e.0 1~e.0)) # ::id pmid_2282_9094.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All four cell lines showed overexpression of Aurora A and B , and histone H3 , compared with PBMCs from healthy donors ( Figure 5c ) . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 3-1.1 4-1 5-1.2 6-1.2.1.r 7-1.2.1.1.1.1 8-1.2.1.1.1.2 9-1.2.1 10-1.2.1.2.1.2 12-1.2.1 13-1.2.1.3.1.1 14-1.2.1.3.1.2 16-1.3 19-1.3.1.2.r 20-1.3.1.2.1 21-1.3.1.2 21-1.3.1.2.2 21-1.3.1.2.2.r 24-1.4.1 25-1.4.1.1 (s / show-01~e.4 :ARG0 (c2 / cell-line~e.2,3 :quant 4~e.1 :mod (a / all~e.0)) :ARG1 (o / overexpress-01~e.5 :ARG1~e.6 (a2 / and~e.9,12 :op1 (e / enzyme :name (n / name :op1 "Aurora"~e.7 :op2 "A"~e.8)) :op2 (e2 / enzyme :name (n2 / name :op1 "Aurora" :op2 "B"~e.10)) :op3 (p3 / protein :name (n3 / name :op1 "histone"~e.13 :op2 "H3"~e.14)))) :ARG1-of (c / compare-01~e.16 :ARG2 (c3 / cell :name (n4 / name :op1 "PBMC") :source~e.19 (p / person~e.21 :mod (h / healthy~e.20) :ARG0-of~e.21 (d / donate-01~e.21)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "5c"~e.25))) # ::id pmid_2282_9094.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Aurora A kinase activity depends on autophosphorylation at Thr288 in the activation loop . # ::alignments 0-1.1.1.1.1 2-1.1.1 3-1.1 4-1 5-1.2.r 6-1.2 9-1.2.3.r 11-1.2.3.1 12-1.2.3 (d / depend-01~e.4 :ARG0 (a / activity-06~e.3 :ARG0 (k / kinase~e.2 :name (n / name :op1 "Aurora"~e.0))) :ARG1~e.5 (p2 / phosphorylate-01~e.6 :ARG1 (a3 / amino-acid :mod 288 :name (n2 / name :op1 "threonine") :part-of k) :ARG2 k :location~e.9 (l / loop-01~e.12 :ARG0-of (a4 / activate-01~e.11 :ARG1 k)))) # ::id pmid_2282_9094.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , to determine the effect of AZD1480 on Aurora A kinase , we evaluated the levels of autophosphorylation at Thr288 by western blotting . # ::alignments 0-1 2-1 3-1.2 5-1.2.2 6-1.2.2.1.r 7-1.2.2.1.1.1 8-1.2.2.2.r 9-1.2.2.2.1.1 10-1.2.2.2.1.2 11-1.2.2.2 13-1.1.1 14-1.1 16-1.1.2 17-1.1.2.1.r 18-1.1.2.1 21-1.1.3.r 22-1.1.3 23-1.1.3 (c / cause-01~e.0,2 :ARG1 (e2 / evaluate-01~e.14 :ARG0 (w / we~e.13) :ARG2 (l / level~e.16 :degree-of~e.17 (p2 / phosphorylate-01~e.18 :ARG1 (a2 / amino-acid :mod 288 :name (n / name :op1 "threonine") :part-of k) :ARG2 k)) :manner~e.21 (i / immunoblot-01~e.22,23)) :purpose (d / determine-01~e.3 :ARG0 w :ARG1 (a3 / affect-01~e.5 :ARG0~e.6 (s / small-molecule :name (n3 / name :op1 "AZD1480"~e.7)) :ARG1~e.8 (k / kinase~e.11 :name (n4 / name :op1 "Aurora"~e.9 :op2 "A"~e.10))))) # ::id pmid_2282_9094.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were pretreated with nocodazole ( 400 ng/ml ) for 18 h , to achieve a mitotic block , and then exposed to AZD1480 ( 1 or 5 μ) with or without the proteasome inhibitor MG132 ( 20 μ; to prevent a potential override of the nocodazole @-@ induced mitotic block by proteasome @-@ dependent mechanisms ) for 3 h ( Figure 5d ) . # ::alignments 0-1.1.1 3-1.2.2.3.r 4-1.1.2.1.1 6-1.1.2.2.1 10-1.1.3.1 11-1.1.3.2 14-1.1.4 16-1.1.4.2.1 17-1.1.4.2 19-1 20-1.2.3 21-1.2 23-1.2.2.1.1 25-1.2.2.2.1.1 26-1.2.2.2 27-1.2.2.2.2.1 29-1.2.2.3.r 30-1.2.2.3 31-1.2.2.3.2.1 31-1.2.2.3.2.1.r 33-1.2.2.3.1.3.1 34-1.2.2.3.1 34-1.2.2.3.1.3 34-1.2.2.3.1.3.r 35-1.2.2.3.1.1.1 35-1.2.2.3.2.2.1 37-1.2.2.3.1.2.1 40-1.2.2.3.1.4 42-1.2.2.3.1.4.1.3 43-1.2.2.3.1.4.1 44-1.2.2.3.1.4.1.2.r 46-1.2.2.3.1.4.1.2.2.1 48-1.2.2.3.1.4.1.2.2 49-1.2.2.3.1.4.1.2.1 50-1.2.2.3.1.4.1.2 51-1.2.2.3.1.4.1.1.r 52-1.2.2.3.1.4.1.1.1.1.1.1 54-1.2.2.3.1.4.1.1.1 55-1.2.2.3.1.4.1.1 57-1.2.4.r 58-1.2.4.1 59-1.2.4.2 62-1.3.1 63-1.3.1.1 (a / and~e.19 :op1 (p / pretreat-01 :ARG1 (c / cell~e.0) :ARG3 (s2 / small-molecule :name (n / name :op1 "nocodazole"~e.4) :quant (c2 / concentration-quantity :quant 400~e.6 :unit (n2 / nanogram-per-milliliter))) :duration (t / temporal-quantity :quant 18~e.10 :unit (h / hour~e.11)) :purpose (a2 / achieve-01~e.14 :ARG0 c :ARG1 (b / block~e.17 :mod (m / mitosis~e.16)))) :op2 (e / expose-01~e.21 :ARG1 c :ARG2 (s / small-molecule :name (n3 / name :op1 "AZD1480"~e.23) :quant (o / or~e.26 :op1 (c3 / concentration-quantity :quant 1~e.25 :unit (m2 / micromolar)) :op2 (c4 / concentration-quantity :quant 5~e.27 :unit m2)) :accompanier~e.3,29 (o2 / or~e.30 :op1 (s3 / small-molecule~e.34 :name (n4 / name :op1 "MG132"~e.35) :mod (c5 / concentration-quantity :quant 20~e.37 :unit m2) :ARG0-of~e.34 (i / inhibit-01~e.34 :ARG1 (p2 / proteasome~e.33)) :purpose (p3 / prevent-01~e.40 :ARG1 (o3 / override-01~e.43 :ARG0~e.51 (m7 / mechanism~e.55 :ARG0-of (d2 / depend-01~e.54 :ARG1 (m3 / macro-molecular-complex :name (n6 / name :op1 "proteasome"~e.52)))) :ARG1~e.44 (b2 / block~e.50 :mod (m8 / mitosis~e.49) :ARG2-of (i2 / induce-01~e.48 :ARG0 s2~e.46)) :mod (p5 / potential~e.42)))) :op2 (s4 / small-molecule :polarity~e.31 -~e.31 :name (n5 / name :op1 "MG132"~e.35)))) :time (t2 / then~e.20) :duration~e.57 (t3 / temporal-quantity :quant 3~e.58 :unit (h2 / hour~e.59))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.62 :mod "5d"~e.63))) # ::id pmid_2282_9094.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dose @-@ dependent inhibition of Aurora A was detected after 3 h of incubation in all the four cell lines , and Thr288 autophosphorylation was abrogated when a higher dose of AZD1480 ( 5 μ) was used ( Figure 5d ) . # ::alignments 0-1.1.1.2.1 2-1.1.1.2 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.1.1.2 8-1.1 9-1.1.2 10-1.1.2.2.1 11-1.1.2.2.2 12-1.1.2.1.r 13-1.1.2.1 14-1.1.2.1.1.r 15-1.1.2.1.1.2 17-1.1.2.1.1.1 18-1.1.2.1.1 19-1.1.2.1.1 21-1 23-1.2.1 25-1.2 26-1.1.2.r 26-1.2.2.r 28-1.2.2.1.2 28-1.2.2.1.2.1 28-1.2.2.1.2.1.r 29-1.2.2.1 30-1.2.2.1.1.r 31-1.2.2.1.1.1.1 33-1.2.2.1.3.1 36-1.2.2 39-1.3.1 40-1.3.1.1 (a / and~e.21 :op1 (d2 / detect-01~e.8 :ARG1 (i / inhibit-01~e.3 :ARG1~e.4 (e / enzyme :name (n2 / name :op1 "Aurora"~e.5 :op2 "A"~e.6)) :ARG0-of (d4 / depend-01~e.2 :ARG1 (d5 / dose-01~e.0))) :time~e.26 (a3 / after~e.9 :op1~e.12 (i2 / incubate-01~e.13 :location~e.14 (c2 / cell-line~e.18,19 :quant 4~e.17 :mod (a4 / all~e.15))) :quant (t / temporal-quantity :quant 3~e.10 :unit (h2 / hour~e.11)))) :op2 (a2 / abrogate-01~e.25 :ARG1 (p / phosphorylate-01~e.23 :ARG1 (a6 / amino-acid :mod 288 :name (n3 / name :op1 "Threonine") :part-of e) :ARG2 e) :time~e.26 (u / use-01~e.36 :ARG1 (d3 / dose-01~e.29 :ARG2~e.30 (s / small-molecule :name (n / name :op1 "AZD1480"~e.31)) :ARG1-of (h / high-02~e.28 :degree~e.28 (m / more~e.28)) :quant (c / concentration-quantity :quant 5~e.33 :unit (m2 / micromolar))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod "5d"~e.40))) # ::id pmid_2282_9094.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings are consistent with the analysis of the cell cycle fractions , showing major dose @-@ dependent changes in the cell cycle after incubation with AZD1480 . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 4-1.2.r 6-1.2 7-1.2.1.r 9-1.2.1.1 10-1.2.1.1 11-1.2.1 13-1.1.3 14-1.1.3.1.3 15-1.1.3.1.2.1 17-1.1.3.1.2 18-1.1.3.1 19-1.1.3.1.1.r 21-1.1.3.1.1.1 22-1.1.3.1.1 23-1.1.3.1.4 24-1.1.3.1.4.1 25-1.1.3.1.4.1.2.r 26-1.1.3.1.4.1.2.1.1 (c / consistent-01~e.3 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :mod (t2 / this~e.0) :ARG0-of (s / show-01~e.13 :ARG1 (c4 / change-01~e.18 :ARG1~e.19 (c5 / cycle-02~e.22 :ARG1 (c6 / cell~e.21)) :ARG0-of (d / depend-01~e.17 :ARG1 (d2 / dose~e.15)) :ARG1-of (m / major-02~e.14) :time (a2 / after~e.23 :op1 (i / incubate-01~e.24 :ARG1 c6 :ARG2~e.25 (s2 / small-molecule :name (n / name :op1 "AZD1480"~e.26))))))) :ARG2~e.4 (a / analyze-01~e.6 :ARG1~e.7 (f2 / fraction~e.11 :mod c5~e.9,10))) # ::id pmid_2282_9094.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In L @-@ 428 and L @-@ 540 cells , a dose @-@ dependent inhibition of the phosphorylation of histone H3 at Ser10 was observed , suggesting a dual inhibition of Aurora A and B in these cell lines . # ::alignments 1-1.2.1.2 2-1.2.1.2 3-1.2.1.2 4-1.2.1.2 5-1.2.1.2 6-1.2.1.2 7-1.2.1.2 8-1.2.1.2 11-1.1.2.1 13-1.1.2 14-1.1 15-1.1.1.r 17-1.1.1 18-1.1.1.1.r 19-1.1.1.1.3.1.1 20-1.1.1.1.3.1.2 24-1 26-1.2 28-1.2.1.3 29-1.2.1 30-1.2.1.1.r 31-1.2.1.1.1.1.1 32-1.2.1.1.1.1.2 33-1.2.1.1 34-1.2.1.1.2.1.2 37-1.2.1.2 38-1.2.1.2 (o / observe-01~e.24 :ARG1 (i2 / inhibit-01~e.14 :ARG1~e.15 (p / phosphorylate-01~e.17 :ARG1~e.18 (a2 / amino-acid :mod 10 :name (n4 / name :op1 "Serine") :part-of (p4 / protein :name (n3 / name :op1 "histone"~e.19 :op2 "H3"~e.20)))) :ARG0-of (d2 / depend-01~e.13 :ARG1 (d3 / dose~e.11))) :ARG0-of (s / suggest-01~e.26 :ARG1 (i / inhibit-01~e.29 :ARG1~e.30 (a / and~e.33 :op1 (e / enzyme :name (n / name :op1 "Aurora"~e.31 :op2 "A"~e.32)) :op2 (e2 / enzyme :name (n2 / name :op1 "Aurora" :op2 "B"~e.34))) :location a3~e.1,2,3,4,5,6,7,8,37,38 :mod (d / dual~e.28))) :location (a3 / and :op1 (c / cell-line :name (n5 / name :op1 "L-428")) :op2 (c2 / cell-line :name (n6 / name :op1 "L-540")))) # ::id pmid_2290_9976.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan @- or oxaliplatin @-@ based chemotherapy ( PMID : 22909976 ) # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1.1 4-1.1 5-1 6-1.2.r 8-1.2.1 10-1.2.2 11-1.2 12-1.2.3.r 13-1.2.3.1.1 15-1.2.3.2.1.2.1 16-1.2.3.2.1.2.2 17-1.2.3.3 18-1.2.3.3.1.1.1.1.1.1 20-1.2.3.3.1.1.1 21-1.2.3.3.1.1.1.2.1.1 23-1.2.3.3.1.1 24-1.2.3.3.1 (s / status~e.5 :mod (m / mutate-01~e.4 :ARG1 (g / gene~e.3 :name (n / name :op1 "K-Ras"~e.0,2))) :condition~e.6 (f / factor~e.11 :mod (p / prognostic~e.8) :ARG0-of (p2 / predict-01~e.10) :location~e.12 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.13)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal"~e.15 :op2 "cancer"~e.16))) :ARG1-of (u / undergo-28~e.17 :ARG2 (c3 / chemotherapy~e.24 :ARG1-of (b / base-02~e.23 :ARG2 (o / or~e.20 :op1 (s2 / small-molecule :name (n3 / name :op1 "irinotecan"~e.18)) :op2 (s3 / small-molecule :name (n4 / name :op1 "oxaliplatin"~e.21)))))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication-91 :ARG8 "PMID2909976"))) # ::id pmid_2290_9976.28 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2290_9976.29 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patient characteristics # ::alignments 1-1.1.1.1.1 2-1 2-1.1 2-1.1.r (t / thing~e.2 :ARG2-of~e.2 (c / characteristic-02~e.2 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.1))))) # ::id pmid_2290_9976.30 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patient characteristics are summarized in Table 1 @ . # ::alignments 0-1.1.1.1.1.1 1-1.1 1-1.1.1 1-1.1.1.r 3-1 6-1.2 7-1.2.1 (s / summarize-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (c / characteristic-02~e.1 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0))))) :ARG2 (t2 / table~e.6 :mod 1~e.7)) # ::id pmid_2290_9976.31 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The median age of the patients included in this study was 65 y ( 181 women , 92 men ) . # ::alignments 1-1.3 2-1 3-1.1.r 5-1.1.1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1 9-1.1.2.1 11-1.2.1 14-1.1.3.1.1.1 15-1.1.3.1.1 17-1.1.3.1.2.1 18-1.1.3.1.2 (a / age-01~e.2 :ARG1~e.3 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.5)) :ARG1-of (i / include-01~e.6 :ARG2~e.7 (s / study-01~e.9 :mod (t2 / this~e.8))) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (w / woman~e.15 :quant 181~e.14) :op2 (m3 / man~e.18 :quant 92~e.17)))) :ARG2 (t / temporal-quantity :quant 65~e.11 :unit (y / year)) :mod (m / median~e.1)) # ::id pmid_2290_9976.32 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Most underwent primary tumor resection ( 260 @/@ 273 patients , 95.2 %) , while secondary metastatic disease was diagnosed in 194 patients ( 71.1 %) , of whom 70 ( 36.1 %) underwent resection and 22 ( 11.3 %) underwent thermoablation . # ::alignments 0-1.1.1.2 1-1.1 2-1.1.2.1.1 3-1.1.2.1 4-1.1.2 6-1.1.1.3.1.1.1 8-1.1.1.3.1.2.1 9-1.1.1.3.1.2.2 11-1.1.1.3.1.3.1 14-1 15-1.2.2.1 16-1.2.2.2 17-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1.1 22-1.2.1.2 24-1.2.1.3.1.1 29-1.2.1.4.1.1.1 31-1.2.1.4.1.1.3.1.1 33-1.2.1.4.1.1 33-1.2.1.4.1.1.4 33-1.2.1.4.1.1.4.r 34-1.2.1.4.1.1.4.1 35-1.2.1.4.1 36-1.2.1.4.1.2.1 38-1.2.1.4.1.2.4.1.1 40-1.2.1.4.1.2 40-1.2.1.4.1.2.3 40-1.2.1.4.1.2.3.r 41-1.2.1.4.1.2.3.1 (c / contrast-01~e.14 :ARG1 (u / undergo-28~e.1 :ARG1 (p5 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient)) :quant (m / most~e.0) :ARG1-of (m2 / mean-01 :ARG2 (i / include-91 :ARG1 (p8 / person :quant 260~e.6 :ARG0-of h) :ARG2 (p9 / person :quant 273~e.8 :ARG0-of h~e.9) :ARG3 (p / percentage-entity :value 95.2~e.11)))) :ARG2 (r / resection~e.4 :mod (t / tumor~e.3 :mod (p7 / primary~e.2)))) :ARG2 (d / diagnose-01~e.19 :ARG1~e.20 (p10 / person :quant 194~e.21 :ARG0-of h~e.22 :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value 71.1~e.24)) :ARG2-of (i2 / include-91 :ARG1 (a / and~e.35 :op1 (p11 / person~e.33 :quant 70~e.29 :ARG0-of h :ARG1-of (m5 / mean-01 :ARG2 (p3 / percentage-entity :value 36.1~e.31)) :ARG1-of~e.33 (u2 / undergo-28~e.33 :ARG2 (r2 / resection~e.34))) :op2 (p12 / person~e.40 :quant 22~e.36 :ARG0-of h :ARG1-of~e.40 (u3 / undergo-28~e.40 :ARG2 (t2 / thermoablation~e.41)) :ARG1-of (m6 / mean-01 :ARG2 (p4 / percentage-entity :value 11.3~e.38)))))) :ARG2 (d2 / disease~e.17 :mod (s / secondary~e.15) :ARG1-of (m3 / metastasize-101~e.16)))) # ::id pmid_2290_9976.33 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The primary tumor was located in the colon in 112 patients ( 41.1 %) , sigmoid colon in 100 patients ( 36.6 %) and rectum in 61 patients ( 22.3 %) . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.3.r 7-1.1.2 9-1.1.3.1 10-1.1.3.2.1 12-1.1.3.3.1.1 15-1.2.2.1 16-1.2.2 18-1.2.3.1 19-1.2.3.2 21-1.2.3.3.1.1 23-1 24-1.3.2 26-1.3.3.1 27-1.3.3.2 29-1.3.3.3.1.1 (a / and~e.23 :op1 (b / be-located-at-91~e.3 :ARG1 (t / tumor~e.2 :mod (p4 / primary~e.1)) :ARG2 (c / colon~e.7) :location~e.4 (p5 / person :quant 112~e.9 :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient~e.10)) :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value 41.1~e.12)))) :op2 (b2 / be-located-at-91 :ARG1 t :ARG2 (c2 / colon~e.16 :mod (s / sigmoid~e.15)) :location (p7 / person :quant 100~e.18 :ARG0-of h~e.19 :ARG1-of (m2 / mean-01 :ARG2 (p2 / percentage-entity :value 36.6~e.21)))) :op3 (b3 / be-located-at-91 :ARG1 t :ARG2 (r / rectum~e.24) :location (p8 / person :quant 61~e.26 :ARG0-of h~e.27 :ARG1-of (m3 / mean-01 :ARG2 (p3 / percentage-entity :value 22.3~e.29))))) # ::id pmid_2290_9976.34 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The metastases were located in the liver in 129 ( 66.5 % of patients with metastases ) , in the lungs in 39 ( 20.1 %) , and in other organs in 126 patients ( 64.9 %) . # ::alignments 1-1.1.1 2-1.1 3-1.1.3.r 6-1.1.2 8-1.1.3.1 10-1.1.3.3.1.1 11-1.1.3.3.1 11-1.2.3.3.1 11-1.3.3.3.1 13-1.1.3.2.1 15-1.2.1 20-1.2.2 22-1.2.3.1 24-1.2.3.3.1.1 27-1 29-1.3.2.1 30-1.3.2 32-1.3.3.1 33-1.3.3.2 35-1.3.3.3.1.1 (a / and~e.27 :op1 (b / be-located-at-91~e.2 :ARG1 (m / metastasize-101~e.1) :ARG2 (l2 / liver~e.6) :location~e.3 (p4 / person :quant 129~e.8 :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient~e.13)) :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity~e.11 :value 66.5~e.10 :ARG3-of (i / include-91 :ARG2 (p6 / person :ARG0-of h :ARG0-of (h2 / have-03 :ARG1 m))))))) :op2 (b2 / be-located-at-91 :ARG1 m~e.15 :ARG2 (l4 / lung~e.20) :location (p7 / person :quant 39~e.22 :ARG0-of h :ARG1-of (m5 / mean-01 :ARG2 (p2 / percentage-entity~e.11 :value 20.1~e.24)))) :op3 (b3 / be-located-at-91 :ARG1 m :ARG2 (o / organ~e.30 :mod (o2 / other~e.29)) :location (p8 / person :quant 126~e.32 :ARG0-of h~e.33 :ARG1-of (m7 / mean-01 :ARG2 (p3 / percentage-entity~e.11 :value 64.9~e.35))))) # ::id pmid_2290_9976.35 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pretreatment carcinoembryonic antigen ( CEA ) levels were elevated above the normal range in 89 patients ( 32.6 %) . # ::alignments 1-1.1.1.1.1 2-1.1.1.1.2 6-1.1 8-1 9-1.2 11-1.2.1.1 12-1.2.1 13-1.3.r 14-1.3.1 15-1.3.2.1 17-1.3.3.1.1 (e / elevate-01~e.8 :ARG1 (l / level~e.6 :quant-of (p2 / protein :name (n / name :op1 "carcinoembryonic"~e.1 :op2 "antigen"~e.2)) :time (b / before :op1 (t / treat-04))) :ARG2 (a / above~e.9 :op1 (r / range~e.12 :ARG1-of (n2 / normal-02~e.11))) :location~e.13 (p3 / person :quant 89~e.14 :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.15)) :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value 32.6~e.17)))) # ::id pmid_2290_9976.36 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 1 . Patient and tumor characteristics # ::alignments 2-1.1 3-1.1.1 6-1.2.1.1.1.1 7-1.2 8-1.2.2.1 9-1.2.1 9-1.2.2 (d / describe-01 :ARG0 (t / table~e.2 :mod 1~e.3) :ARG1 (a / and~e.7 :op1 (c / characteristic-02~e.9 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.6)))) :op2 (c2 / characteristic-02~e.9 :ARG1 (t2 / tumor~e.8)))) # ::id pmid_2290_9976.37 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras and B @-@ Raf gene mutation status # ::alignments 2-1.1.1.1.1.1 4-1.1.1.1.1.1 6-1 8-1.2.1.1.1.1 10-1.2.1.1.1.1 12-1.1.1.1 12-1.2.1.1 13-1.1.1 13-1.2.1 14-1.1 14-1.2 (a / and~e.6 :op1 (s / status~e.14 :mod (m / mutate-01~e.13 :ARG1 (g / gene~e.12 :name (n / name :op1 "K-Ras"~e.2,4)))) :op2 (s2 / status~e.14 :mod (m2 / mutate-01~e.13 :ARG1 (g2 / gene~e.12 :name (n3 / name :op1 "B-Raf"~e.8,10))))) # ::id pmid_2290_9976.38 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras gene mutations were present in 89 patients ( 32.6 %) , of whom 76 ( 85.4 %) had mutations in codon 12 and 10 ( 11.2 %) had mutations in codon 13 . # ::alignments 1-1.2.1.1.1 3-1.2.1.1.1 5-1.2.1 6-1.2 8-1 9-1.1.r 10-1.1.1 11-1.1.2.1 13-1.1.3.1.1 18-1.1.4.1.1.1 20-1.1.4.1.1.3.1.1 22-1.1.4.1.1 22-1.1.4.1.1.4 22-1.1.4.1.1.4.r 23-1.1.4.1.1.4.1 24-1.1.4.1.1.4.1.1.r 25-1.1.4.1.1.4.1.1 26-1.1.4.1.1.4.1.1.1 27-1.1.4.1 28-1.1.4.1.2.1 30-1.1.4.1.2.3.1.1 32-1.1.4.1.2 32-1.1.4.1.2.4 32-1.1.4.1.2.4.r 33-1.1.4.1.2.4.1 34-1.1.4.1.2.4.1.1.r 35-1.1.4.1.2.4.1.1 36-1.1.4.1.2.4.1.1.1 (p4 / present-102~e.8 :ARG0~e.9 (p5 / person :quant 89~e.10 :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient~e.11)) :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value 32.6~e.13)) :ARG2-of (i / include-91 :ARG1 (a / and~e.27 :op1 (p7 / person~e.22 :quant 76~e.18 :ARG0-of h :ARG1-of (m3 / mean-01 :ARG2 (p2 / percentage-entity :value 85.4~e.20)) :ARG0-of~e.22 (h2 / have-03~e.22 :ARG1 (m4 / mutate-01~e.23 :ARG1~e.24 (c / codon~e.25 :mod 12~e.26)))) :op2 (p8 / person~e.32 :quant 10~e.28 :ARG0-of h :ARG1-of (m5 / mean-01 :ARG2 (p3 / percentage-entity :value 11.2~e.30)) :ARG0-of~e.32 (h3 / have-03~e.32 :ARG1 (m6 / mutate-01~e.33 :ARG1~e.34 (c2 / codon~e.35 :mod 13~e.36))))))) :ARG1 (m / mutate-01~e.6 :ARG1 (g / gene~e.5 :name (n / name :op1 "K-Ras"~e.1,3)))) # ::id pmid_2290_9976.39 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Women showed a higher incidence of K @-@ Ras gene mutations relative to men ( p = 0.0290 ) . # ::alignments 0-1.1 1-1 3-1.2.1 3-1.2.1.1 3-1.2.1.1.r 4-1.2 7-1.2.2.1.1.1 9-1.2.2.1.1.1 11-1.2.2.1 12-1.2.2 14-1.2.1.2.r 15-1.2.1.2 17-1.2.1.3 19-1.2.1.3.1 (s / show-01~e.1 :ARG0 (w / woman~e.0) :ARG1 (i / incidence~e.4 :ARG1-of (h / high-02~e.3 :degree~e.3 (m / more~e.3) :compared-to~e.14 (m3 / man~e.15) :ARG1-of (s2 / statistical-test-91~e.17 :ARG2 0.0290~e.19)) :frequency-of (m2 / mutate-01~e.12 :ARG1 (g / gene~e.11 :name (n / name :op1 "K-Ras"~e.7,9))))) # ::id pmid_2290_9976.40 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No significant differences were observed with respect to tumor size , lymph node involvement grade , histological grade , histopathological type , primary tumor localization , performance status , age , or pretreatment CEA level . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.3 2-1.1 4-1 7-1.1.2.r 8-1.1.2.1.1 9-1.1.2.1 11-1.1.2.2.1.1.1 12-1.1.2.2.1.1 13-1.1.2.2.1 14-1.1.2.2 16-1.1.2.3.1 17-1.1.2.3 20-1.1.2.4 22-1.1.2.5.1.1 23-1.1.2.5.1 24-1.1.2.5 26-1.1.2.6.1 27-1.1.2.6 29-1.1.2.7 31-1.1.2 33-1.1.2.8.1.1.1 34-1.1.2.8 (o / observe-01~e.4 :ARG1 (d / differ-02~e.2 :polarity~e.0 -~e.0 :ARG3~e.7 (o2 / or~e.31 :op1 (s2 / size~e.9 :poss (t / tumor~e.8)) :op2 (g / grade~e.14 :extent-of (i / involve-01~e.13 :ARG1 (n / node~e.12 :mod (l / lymph~e.11)))) :op3 (g2 / grade~e.17 :mod (h / histology~e.16)) :op4 (t2 / type~e.20 :mod (h2 / histopathology)) :op5 (b2 / be-located-at-91~e.24 :ARG1 (t3 / tumor~e.23 :mod (p / primary~e.22))) :op6 (s3 / status~e.27 :mod (p2 / perform-02~e.26)) :op7 (a / age-01~e.29) :op8 (l3 / level~e.34 :quant-of (p3 / protein :name (n2 / name :op1 "CEA"~e.33)) :time (b / before :op1 (t4 / treat-03)))) :ARG1-of (s / significant-02~e.1))) # ::id pmid_2290_9976.41 ::amr-annotator SDL-AMR-09 ::preferred # ::tok B @-@ Raf gene mutations were present in 17 patients ( 6.9 %) , of whom 6 ( 35.3 %) had mutations in exon 15 . # ::alignments 1-1.2.1.1.1 3-1.2.1.1.1 5-1.2.1 6-1.2 8-1 9-1.1.r 10-1.1.1 11-1.1.2.1 13-1.1.3.1.1 18-1.1.4.1.1 20-1.1.4.2.1 22-1.1.4.1 22-1.1.4.1.3 22-1.1.4.1.3.r 23-1.1.4.1.3.1 24-1.1.4.1.3.1.1.r 25-1.1.4.1.3.1.1 26-1.1.4.1.3.1.1.1 (p3 / present-102~e.8 :ARG0~e.9 (p4 / person :quant 17~e.10 :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient~e.11)) :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value 6.9~e.13)) :ARG2-of (i / include-91 :ARG1 (p6 / person~e.22 :quant 6~e.18 :ARG0-of h :ARG0-of~e.22 (h2 / have-03~e.22 :ARG1 (m4 / mutate-01~e.23 :ARG1~e.24 (e / exon~e.25 :mod 15~e.26)))) :ARG3 (p2 / percentage-entity :value 35.3~e.20))) :ARG1 (m / mutate-01~e.6 :ARG1 (g / gene~e.5 :name (n2 / name :op1 "B-Raf"~e.1,3)))) # ::id pmid_2290_9976.42 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One patient had a mutation in exon 11 , while mutation status was not determined in 10 patients ( 58.8 %) . # ::alignments 0-1.1.1.1 1-1.1.1.2.1 2-1.1 2-1.1.1.2 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1 7-1.1.2.1.1 9-1 10-1.2.2.1 11-1.2.2 13-1.2.1 13-1.2.1.r 14-1.2 15-1.2.3.r 16-1.2.3.1 17-1.2.3.2 19-1.2.3.3.1.1 (c / contrast-01~e.9 :ARG1 (h / have-03~e.2 :ARG0 (p2 / person :quant 1~e.0 :ARG0-of (h2 / have-rel-role-91~e.2 :ARG2 (p3 / patient~e.1))) :ARG1 (m / mutate-01~e.4 :ARG1~e.5 (e / exon~e.6 :mod 11~e.7))) :ARG2 (d2 / determine-01~e.14 :polarity~e.13 -~e.13 :ARG1 (s / status~e.11 :mod (m2 / mutate-01~e.10)) :location~e.15 (p4 / person :quant 10~e.16 :ARG0-of h2~e.17 :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value 58.8~e.19))))) # ::id pmid_2290_9976.43 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A higher incidence of B @-@ Raf gene mutations was detected in patients with low @-@ grade neoplasm ( p < 0.0001 ) , primary tumor localization outside the sigmoid colon ( p = 0.0467 ) and with non @-@ tubular neoplasms ( p = 0.0468 ) . # ::alignments 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1 5-1.1.2.1.1.1 7-1.1.2.1.1.1 9-1.1.2.1 10-1.1.2 12-1 13-1.2.r 14-1.2.1.1.1 16-1.2.1.2.1.1.1 18-1.2.1.2.1.1 19-1.2.1.2.1 21-1.2.1.2.1.2 22-1.2.1.2.1.2.1 23-1.2.1.2.1.2.1.1 26-1.2.2.2.1.1.1 27-1.2.2.2.1.1 28-1.2.2.2.1 29-1.2.2.2.1.2 31-1.2.2.2.1.2.1.1 32-1.2.2.2.1.2.1 34-1.2.2.2.1.1.2 36-1.2.2.2.1.1.2.1 38-1.2 40-1.2.3.2.1.1.1 40-1.2.3.2.1.1.1.r 42-1.2.3.2.1.1 43-1.2.3.2.1 45-1.2.3.2.1.2 47-1.2.3.2.1.2.1 (d / detect-01~e.12 :ARG1 (i / incidence~e.2 :ARG1-of (h / high-02~e.1 :degree~e.1 (m / more~e.1)) :frequency-of (m2 / mutate-01~e.10 :ARG1 (g / gene~e.9 :name (n / name :op1 "B-Raf"~e.5,7)))) :location~e.13 (a / and~e.38 :op1 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.14)) :ARG0-of (h3 / have-03 :ARG1 (n2 / neoplasm~e.19 :mod (g2 / grade~e.18 :ARG1-of (l / low-04~e.16)) :ARG1-of (s2 / statistical-test-91~e.21 :ARG2 (l2 / less-than~e.22 :op1 0.0001~e.23))))) :op2 (p4 / person :ARG0-of h2 :ARG0-of (h4 / have-03 :ARG1 (b / be-located-at-91~e.28 :ARG1 (t / tumor~e.27 :mod (p5 / primary~e.26) :ARG1-of (s3 / statistical-test-91~e.34 :ARG2 0.0467~e.36)) :ARG2 (o / outside~e.29 :op1 (c / colon~e.32 :mod (s / sigmoid~e.31)))))) :op3 (p7 / person :ARG0-of h2 :ARG0-of (h5 / have-03 :ARG1 (n3 / neoplasm~e.43 :mod (t2 / tubular~e.42 :polarity~e.40 -~e.40) :ARG1-of (s4 / statistical-test-91~e.45 :ARG2 0.0468~e.47)))))) # ::id pmid_2290_9976.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other parameters assessed were not statistically different . # ::alignments 0-1.2.1 1-1.2 2-1.2.2 4-1.1.r 6-1 6-1.1 6-1.1.r (d / differ-02~e.6 :polarity~e.4,6 -~e.6 :ARG1 (p / parameter~e.1 :mod (o / other~e.0) :ARG1-of (a / assess-01~e.2)) :manner (s / statistic)) # ::id pmid_2290_9976.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Prognostic significance of K @-@ Ras and B @-@ Raf gene mutation status # ::alignments 1-1.2 5-1.1.1.1.1.1.1 7-1.1.1.1.1.1.1 9-1.1 11-1.1.2.1.1.1.1 13-1.1.2.1.1.1.1 15-1.1.1.1.1 15-1.1.2.1.1 16-1.1.1.1 16-1.1.2.1 17-1.1.1 17-1.1.2 (s / signify-01 :ARG0 (a / and~e.9 :op1 (s2 / status~e.17 :mod (m / mutate-01~e.16 :ARG1 (g / gene~e.15 :name (n / name :op1 "K-Ras"~e.5,7)))) :op2 (s3 / status~e.17 :mod (m2 / mutate-01~e.16 :ARG1 (g2 / gene~e.15 :name (n2 / name :op1 "B-Raf"~e.11,13))))) :mod (p / prognostic~e.1)) # ::id pmid_2290_9976.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There were no significant differences in OS rates between patients with K @-@ Ras mutations and wild @-@ type K @-@ Ras genes ( p = 0.6869 ; Fig . 1 ) . # ::alignments 2-1.1 2-1.1.r 3-1.4 4-1 7-1.2 7-1.3 9-1.2.1.1.1.1 12-1.2.1.1.2.1.1.1.1 14-1.2.1.1.2.1.1.1.1 16-1.2.1.1.2.1 18-1.3.1.1.2.1.2 20-1.3.1.1.2.1.2 22-1.2.1.1.2.1.1.1.1 22-1.3.1.1.2.1.1.1 24-1.2.1.1.2.1.1.1.1 24-1.3.1.1.2.1.1.1 26-1.2.1.1.2.1.1 26-1.3.1.1.2.1 28-1.6 30-1.6.1 33-1.5.1 35-1.5.1.1 (d / differ-02~e.4 :polarity~e.2 -~e.2 :ARG1 (r / rate~e.7 :mod (s2 / survive-01 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.9)) :ARG0-of (h2 / have-03 :ARG1 (m / mutate-01~e.16 :ARG1 (g / gene~e.26 :name (n / name :op1 "K-Ras"~e.12,14,22,24))))) :mod (o2 / overall))) :ARG2 (r2 / rate~e.7 :mod (s3 / survive-01 :ARG1 (p3 / person :ARG0-of h :ARG0-of (h3 / have-03 :ARG1 (g2 / gene~e.26 :name (n2 / name :op1 "K-Ras"~e.22,24) :mod (w / wild-type~e.18,20)))) :mod o2)) :ARG1-of (s / significant-02~e.3) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.33 :mod 1~e.35)) :ARG1-of (s4 / statistical-test-91~e.28 :ARG2 0.6869~e.30)) # ::id pmid_2290_9976.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A perceptible trend to prolongation of OS was apparent when K @-@ Ras mutations were present in codon 13 relative to codon 12 ( p = 0.0830 ; Fig . 2 ) . # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1 8-1 9-1.2.r 11-1.2.1.1.2.1.1 13-1.2.1.1.2.1.1 15-1.2.1 15-1.2.2.1.1 17-1.2 17-1.2.2.1 19-1.2.1.1 20-1.2.1.1.1 21-1.2.2 22-1.2.2.1.1.1.r 23-1.2.2.1.1.1 24-1.2.2.1.1.1.1 26-1.4 28-1.4.1 31-1.3.1 33-1.3.1.1 (a / appear-02~e.8 :ARG1 (t / trend-01~e.2 :ARG1~e.3 (p / prolong-01~e.4 :ARG1 (s / survive-01 :mod (o2 / overall))) :ARG1-of (p2 / perceptive-02 :ARG1-of (p5 / possible-01))) :time~e.9 (p3 / present-102~e.17 :ARG1 (m / mutate-01~e.15 :ARG1 (c / codon~e.19 :mod 13~e.20 :part-of (g / gene :name (n3 / name :op1 "K-Ras"~e.11,13)))) :ARG1-of (r / relative-05~e.21 :ARG3 (p4 / present-102~e.17 :ARG1 (m2 / mutate-01~e.15 :ARG1~e.22 (c2 / codon~e.23 :mod 12~e.24 :part-of g))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.31 :mod 2~e.33)) :ARG1-of (s2 / statistical-test-91~e.26 :ARG2 0.0830~e.28)) # ::id pmid_2290_9976.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , mutations in the B @-@ Raf gene showed no prognostic significance ( Fig . 3 ) . # ::alignments 0-1.4 2-1.1 6-1.1.1.1.1 8-1.1.1.1.1 10-1.1.1 11-1 12-1.2.1 12-1.2.1.r 13-1.2.3 14-1.2 17-1.3.1 19-1.3.1.1 (s / show-01~e.11 :ARG0 (m / mutate-01~e.2 :ARG1 (g / gene~e.10 :name (n2 / name :op1 "B-Raf"~e.6,8))) :ARG1 (s2 / significant-02~e.14 :polarity~e.12 -~e.12 :ARG1 m :mod (p / prognostic~e.13)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod 3~e.19)) :ARG1-of (r / resemble-01~e.0)) # ::id pmid_2290_9976.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with disseminated CRC ( M+) and B @-@ Raf gene mutations tended toward shorter OS relative to those with wild @-@ type B @-@ Raf genes ( p = 0.06723 ) . # ::alignments 0-1.1.1.1 2-1.1.2.1.1.3 6-1.1.2.1 8-1.1.2.1.2.1.1.1 10-1.1.2.1.2.1.1.1 12-1.1.2.1.2.1 13-1.1.2.1.2 14-1 16-1.2 16-1.2.2 16-1.2.2.r 18-1.2.3 21-1.2.3.1.r 22-1.2.3.1.2.1.2 24-1.2.3.1.2.1.2 26-1.2.3.1.2.1.1.1 28-1.2.3.1.2.1.1.1 30-1.2.3.1.2.1 32-1.3 34-1.3.1 (t / tend-02~e.14 :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0)) :ARG0-of (h2 / have-03 :ARG1 (a / and~e.6 :op1 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal" :op2 "cancer") :ARG1-of (d2 / disseminate-01~e.2) :ARG1-of (l / label-01 :ARG2 (s4 / string-entity :value "M+"))) :op2 (m2 / mutate-01~e.13 :ARG1 (g / gene~e.12 :name (n2 / name :op1 "B-Raf"~e.8,10)))))) :ARG2 (s / short-07~e.16 :ARG1 (s2 / survive-01 :ARG0 p :mod (o2 / overall)) :degree~e.16 (m3 / more~e.16) :ARG1-of (r / relative-05~e.18 :ARG3~e.21 (p3 / person :ARG0-of h :ARG0-of (h4 / have-03 :ARG1 (g2 / gene~e.30 :name (n / name :op1 "B-Raf"~e.26,28) :mod (w / wild-type~e.22,24)))))) :ARG1-of (s3 / statistical-test-91~e.32 :ARG2 0.06723~e.34)) # ::id pmid_2290_9976.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Clinical and pathological variables identified by univariate analysis as potential prognostic factors for OS rate # ::alignments 1-1.1.1 2-1 3-1.2.1 4-1.1 4-1.2 5-1.3 6-1.3.1.r 7-1.3.1.1 8-1.3.1 9-1.3.2.r 10-1.3.2.2 11-1.3.2.1 12-1.3.2 15-1.3.2.3 (a / and~e.2 :op1 (v / variable~e.4 :mod (c / clinic~e.1)) :op2 (v2 / variable~e.4 :mod (p / pathology~e.3)) :ARG1-of (i / identify-01~e.5 :ARG0~e.6 (a2 / analyze-01~e.8 :mod (u / univariate~e.7)) :ARG2~e.9 (f / factor~e.12 :mod (p2 / prognostic~e.11) :mod (p3 / potential~e.10) :topic (r / rate~e.15 :mod (s / survive-01 :mod (o2 / overall)))))) # ::id pmid_2290_9976.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are summarized in Table 2 @ . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1 6-1.2 7-1.2.1 (s / summarize-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG2 (t3 / table~e.6 :mod 2~e.7)) # ::id pmid_2290_9976.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Univariate analysis identified the following prognostic factors as influencing OS rate in this patient cohort : Age , patients 75 y and older lived for 36.7 mo relative to those younger than 75 ( 58.9 mo ) ( p = 0.0472 ) ; Gender , female patients lived for 62.7 mo relative to 42.6 mo for male patients ( p = 0.0328 ) ; Primary tumor localization , patients with primary tumors in the sigmoid colon lived for 68.0 mo compared with 43.5 mo in patients with primary tumors located in the colon or rectum ( p = 0.0039 ) ; Performance status , patients with a good performance score e.g. , WHO 0 @–@ 1 ( 58.4 mo ) and Karnofsky status 81 @–@ 100 % ( 58.1 mo ) lived longer relative to those with poor performance status ( 19.0 and 19.4 mo for patients with WHO 2 @–@ 3 and Karnofsky status ≤ 80 % , respectively ) ( p = 0.0027 and p = 0.0036 , respectively ) ; Lymph node involvement grade , survival in patients without lymph node metastases was 65.3 mo relative to 46.3 mo in patients presenting with metastases ( p = 0.0031 ) ; Pretreatment CEA level , median time to progression in patients with normal pretreatment CEA level ≤ 5 ng @/@ ml was 76.3 mo relative to 25.6 mo in patients with increased pretreatment CEA level ( p < 0.0001 ; Table 2 ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.1 5-1.2.2 6-1.2 7-1.2.3.r 7-1.2.4.1.6.1.r 7-1.2.4.1.6.3.1.3.2.1.2.r 8-1.2.3 10-1.2.3.1 11-1.2.3.2.r 12-1.2.3.2.1 13-1.2.3.2.2.1.1 14-1.2.3.2 16-1.2.4.1.1 18-1.2.4.1.1.1.1.1.1 19-1.2.4.1.1.1.1.1.2.1.1 21-1.2.4.1.1.1.1.1.2 22-1.2.4.1.1.1.1.1.2.r 23-1.2.4.1.1.1.1 25-1.2.4.1.1.1.1.2.1 26-1.2.4.1.1.1.1.2.2 27-1.2.4.1.1.1.1.2.3 31-1.2.4.1.1.1.1.1.2.2 31-1.2.4.1.1.1.1.2.3.1.2 31-1.2.4.1.4.2.1.2.2.1.3.1.2.3.1.2.1.1.1 32-1.2.4.1.1.1.1.1.2.1.1 34-1.2.4.1.1.1.1.2.3.1.3.1.1 35-1.2.4.1.1.1.1.2.3.1.3.1.2 38-1.2.4.1.1.2 40-1.2.4.1.1.2.1 43-1.2.4.1.2 45-1.2.4.1.2.1.1.1.1 46-1.2.4.1.2.1.1.1.2 47-1.2.4.1.1.1.1 47-1.2.4.1.1.1.1.2.3.1.3 47-1.2.4.1.2.1.1 49-1.2.4.1.2.1.1.2.1 50-1.2.4.1.2.1.1.2.2 51-1.2.4.1.1.1.1.2.3 51-1.2.4.1.2.1.1.2.3 53-1.2.4.1.2.1.1.2.3.1.1 54-1.2.4.1.2.1.1.2.3.1.2 56-1.2.4.1.2.1.1.2.3.1.3.1.1 57-1.2.4.1.2.1.1.2.3.1.3.1.2 59-1.2.4.1.2.2 61-1.2.4.1.2.2.1 64-1.2.4.1.3.1.1 65-1.2.4.1.3.1 66-1.2.4.1.3 68-1.2.3.2.2.1.1 70-1.2.4.1.3.2.1.1.2.1 71-1.2.4.1.3.2.1.1.2.1 74-1.2.4.1.3.2.1.1.2.2.1 75-1.2.4.1.3.2.1.1.2.2 76-1.2.4.1.2.1.1.2.3.1.3 76-1.2.4.1.3.2.1 76-1.2.4.1.3.2.1.2.3.3 76-1.2.4.1.4.2.1.2.2.1.3.1.1.3 76-1.2.4.1.4.2.1.2.2.1.3.1.2.3 78-1.2.4.1.3.2.1.2.1 79-1.2.4.1.3.2.1.2.3.2 80-1.2.4.1.3.2.1.2.3.r 82-1.2.4.1.3.2.1.2.3.1 83-1.2.4.1.3.2.1.2.3.2 85-1.2.3.2.2.1.1 87-1.2.4.1.3.1.1 88-1.2.4.1.3.1 89-1.2.4.1.3 89-1.2.4.1.3.2.1.1.2.2.r 89-1.2.4.1.3.2.1.2.3.3.1.2.2.r 90-1.2.4.1.3.2.1.2.3.3.1.r 92-1.2.4.1.3.2.1.2.3.3.1.2.2.1 93-1.2.4.1.3.2.1.2.3.3.1.2.2 93-1.2.4.1.4.2.1.2.2.1.3.1.2.3.1.2.1.1 93-1.2.4.1.6.3.1.3.2.1.3 94-1.2.4.1.3.2.1.2.3.3.1.2.2.2 96-1.2.4.1.3.3 98-1.2.4.1.3.3.1 101-1.2.4.1.4.1 102-1.2.4.1.4 102-1.2.4.1.4.2.1.2.2.1.3.1.2.3.1.2.1 104-1.2.4.1.4.2.1.1.1 107-1.2.4.1.4.2.1.1.2.3 108-1.2.4.1.4.2.1.1.2.2 109-1.2.4.1.4.2.1.1 109-1.2.4.1.4.2.1.1.2 109-1.2.4.1.4.2.1.1.2.r 112-1.2.4.1.4.2.1.2.3.1.1.3 113-1.2.4.1.4.2.1.2.3.1.1.3 114-1.2.4.1.4.2.1.2.3.1.1.3 115-1.2.4.1.4.2.1.2.3.1.1.3 117-1.2.4.1.4.2.1.2.3.1.1.1 118-1.2.4.1.4.2.1.2.3.1.1.2 120-1.2.4.1.4.2.1.1.2.1 120-1.2.4.1.4.2.1.1.2.1.1.1 120-1.2.4.1.4.2.1.2.3.1 121-1.2.4.1.4.2.1.2.3.1.2.3 122-1.2.4.1.4.2.1.2.3.1.2.3 123-1.2.4.1.4.2.1.2.3.1.2.3 124-1.2.4.1.4.2.1.2.3.1.2.3 125-1.2.4.1.4.2.1.2.3.1.2.3 126-1.2.4.1.4.2.1.2.3.1.2.3 128-1.2.4.1.4.2.1.2.3.1.2.1 129-1.2.4.1.4.2.1.2.3.1.2.2 131-1.2.4.1.1.1.1 131-1.2.4.1.1.1.1.2.3.1.3 131-1.2.4.1.4.2.1 132-1.2.4.1.1.1.1.2.3.1.3.1.r 132-1.2.4.1.1.1.1.2.r 132-1.2.4.1.4.2.1.2 133-1.2.4.1.1.1.1.2.3 133-1.2.4.1.4.2.1.2.2 136-1.2.4.1.4.2.1.2.2.1.r 137-1.2.4.1.4.2.1.2.2.1.2.1.2 138-1.2.4.1.4.2.1.2.2.1.2.1.1 139-1.2.4.1.4 139-1.2.4.1.4.2.1.2.2.1.2.1 141-1.2.4.1.4.2.1.2.2.1.3.1.1.1 142-1.2.4.1.4.2.1.2.2.1.3.1 143-1.2.4.1.4.2.1.2.2.1.3.1.2.1 144-1.2.4.1.4.2.1.2.2.1.3.1.2.2 146-1.2.3.2.2.1.1 147-1.2.4.1.4.2.1.2.2.1.3.1.1.3.1.r 148-1.2.4.1.4.2.1.2.2.1.3.1.1.3.1.2.1.2 149-1.2.4.1.4.2.1.2.2.1.3.1.1.3.1.2.1.1.1 151-1.2.4.1.4.2.1.2.2.1.3.1.1.3.1.2.1.1.2 152-1.2.4.1.4.2.1.2.2.1.3.1 152-1.2.4.1.4.2.1.2.2.1.3.1.1.3.1.2.1.1 152-1.2.4.1.4.2.1.2.3.1 153-1.2.4.1.4.2.1.1.2.1.2.2.1.1 154-1.2.4.1.4.2.1.2.2.1.3.1.1.3.1.2.1 156-1.2.4.1.4.2.1.2.2.1.3.1.2.3.1.2.1.1.1.1.1 157-1.2.4.1.4.2.1.2.2.1.3.1.2.3.1.2.1.1.1.1 162-1.2.4.1.4.2.1.2.2.1.3.1.1.4 164-1.2.4.1.4.2.1.2.2.1.3.1.1.4.1 165-1.2.4.1.4.2.1.2.2.1.3.1 166-1.2.4.1.4.2.1.2.2.1.3.1.1.4 166-1.2.4.1.4.2.1.2.2.1.3.1.2.4 168-1.2.4.1.4.2.1.2.2.1.3.1.2.4.1 173-1.2.4.1.5.1.1.1 174-1.2.4.1.5.1.1 175-1.2.4.1.5.1 176-1.2.4.1.5 178-1.2.3.1.1 178-1.2.4.1.5.2.1 178-1.2.4.1.5.2.1.2.3.1.3 179-1.2.4.1.5.2.1.1.r 180-1.2.4.1.5.2.1.1.1 181-1.2.4.1.5.2.1.1.2.1 181-1.2.4.1.5.2.1.1.2.1.r 182-1.2.4.1.5.2.1.1.2.2.1 183-1.2.4.1.5.2.1.1.2.2.1 184-1.2.4.1.5.2.1.1.2.2 186-1.2.4.1.5.2.1.2.1 187-1.2.4.1.5.2.1.2.2 188-1.2.4.1.1.1.1.2.3 188-1.2.4.1.5.2.1.2.3 190-1.2.4.1.5.2.1.2.3.1.1 191-1.2.4.1.5.2.1.2.3.1.2 192-1.2.4.1.5.2.1.2.3.1.3.1.r 193-1.2.4.1.5.2.1.2.3.1.3.1.1 194-1.2.4.1.5.2.1.2.3.1.3.1.2 195-1.2.4.1.5.2.1.2.3.1.3.1.2.1.r 196-1.2.4.1.5.2.1.2.3.1.3.1.2.1 198-1.2.4.1.5.3 200-1.2.4.1.5.3.1 204-1.2.4.1.6.3.1.3.2.1.4 205-1.2.4.1.6.3.1.3.2.1 207-1.2.4.1.6.3.1.2 208-1.2.4.1.1.1.1.1.2.1 208-1.2.4.1.1.1.1.2 208-1.2.4.1.1.1.1.2.3.1.3.1 208-1.2.4.1.2.1.1.2 208-1.2.4.1.2.1.1.2.3.1 208-1.2.4.1.3.2.1.2 208-1.2.4.1.3.2.1.2.3 208-1.2.4.1.4.2.1.2.2.1.3.1.1 208-1.2.4.1.4.2.1.2.2.1.3.1.2 208-1.2.4.1.4.2.1.2.3.1.1 208-1.2.4.1.4.2.1.2.3.1.2 208-1.2.4.1.5.2.1.2 208-1.2.4.1.5.2.1.2.3.1 208-1.2.4.1.6.3.1 208-1.2.4.1.6.3.1.1.r 208-1.2.4.1.6.3.1.3.2.1.2.r 208-1.2.4.1.6.3.1.4 208-1.2.4.1.6.3.1.4.3.1 208-1.2.4.1.6.3.1.4.3.1.3 208-1.2.4.1.6.3.1.4.3.1.3.r 208-1.2.4.1.6.3.1.4.r 210-1.2.4.1.6.3.1.1.1 212-1.2.3.2.2.1.1 214-1.2.4.1.6.3.1.3.2.1.1 216-1.2.4.1.6.3.1.3.2.1.4 217-1.2.4.1.6.3.1.3.2.1 219-1.2.4.1.6.3.1.3.2.1.3.1.1 220-1.2.4.1.6.3.1.3.2.1.3.1.2 222-1.2.4.1.6.3.1.3.2.1.3.1.2 224-1.2.4.1.6.3.1.4.1 225-1.2.4.1.6.3.1.4.2 226-1.2.4.1.1.1.1.2.3 226-1.2.4.1.6.3.1.4.3 228-1.2.4.1.6.3.1.4.3.1.1 229-1.2.4.1.6.3.1.4.3.1.2 230-1.2.4.1.6.3.1.4.3.1.3.1.r 231-1.2.4.1.6.3.1.4.3.1.3.1.1 233-1.2.4.1.6.3.1.4.3.1.3.1.2.1.1 235-1.2.4.1.6.3.1.4.3.1.3.1.2.1.2 236-1.2.4.1.6 236-1.2.4.1.6.3.1.4.3.1.3.1.2.1 238-1.2.4.1.6.5 239-1.2.4.1.6.3.1.3.2.1.3.2 240-1.2.4.1.6.5.1 243-1.2.4.1.6.4.1 244-1.2.4.1.6.4.1.1 (i / identify-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (u / univariate~e.0)) :ARG1 (f / factor~e.6 :ARG1-of (f2 / follow-04~e.4) :mod (p / prognostic~e.5) :ARG0-of~e.7 (i2 / influence-01~e.8 :ARG1 (r / rate~e.10 :mod (s11 / survive-01~e.178 :mod (o6 / overall))) :location~e.11 (c / cohort~e.14 :mod (t / this~e.12) :consist-of (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.13,68,85,146,212))))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (a3 / age-01~e.16 :ARG1-of (m2 / mean-01 :ARG2 (l / live-01~e.23,47,131 :ARG0 (p4 / person :ARG0-of h~e.18 :age~e.22 (a5 / and~e.21 :op1 (t2 / temporal-quantity~e.208 :quant 75~e.19,32 :unit (y / year)) :op2 (m3 / more-than~e.31 :op1 t2))) :duration~e.132 (t3 / temporal-quantity~e.208 :quant 36.7~e.25 :unit (m4 / month~e.26) :ARG1-of (r2 / relative-05~e.27,51,133,188,226 :ARG3 (p5 / person :ARG0-of h :age (l2 / less-than~e.31 :op1 t2) :ARG0-of (l3 / live-01~e.47,131 :duration~e.132 (t4 / temporal-quantity~e.208 :quant 58.9~e.34 :unit m4~e.35))))))) :ARG1-of (s12 / statistical-test-91~e.38 :ARG2 0.0472~e.40)) :op2 (g / gender~e.43 :ARG1-of (m5 / mean-01 :ARG2 (l4 / live-01~e.47 :ARG0 (p7 / person :mod (f3 / female~e.45) :ARG0-of h~e.46) :duration (t5 / temporal-quantity~e.208 :quant 62.7~e.49 :unit m4~e.50 :ARG1-of (r3 / relative-05~e.51 :ARG3 (t6 / temporal-quantity~e.208 :quant 42.6~e.53 :unit m4~e.54 :duration-of (l5 / live-01~e.76 :ARG0 (p8 / person :mod (m6 / male~e.56) :ARG0-of h~e.57))))))) :ARG1-of (s13 / statistical-test-91~e.59 :ARG2 0.0328~e.61)) :op3 (b6 / be-located-at-91~e.66,89 :ARG1 (t7 / tumor~e.65,88 :mod (p10 / primary~e.64,87)) :ARG1-of (m7 / mean-01 :ARG2 (l7 / live-01~e.76 :ARG0 (p11 / person :ARG0-of h :ARG0-of (h2 / have-03 :ARG1 t7~e.70,71 :location~e.89 (c2 / colon~e.75 :mod (s / sigmoid~e.74)))) :duration (t8 / temporal-quantity~e.208 :quant 68.0~e.78 :unit m4 :compared-to~e.80 (t9 / temporal-quantity~e.208 :quant 43.5~e.82 :unit m4~e.79,83 :duration-of (l8 / live-01~e.76 :ARG0~e.90 (p12 / person :ARG0-of h :ARG0-of (h3 / have-03 :ARG1 t7 :location~e.89 (o2 / or~e.93 :op1 (c3 / colon~e.92) :op2 (r4 / rectum~e.94))))))))) :ARG1-of (s14 / statistical-test-91~e.96 :ARG2 0.0039~e.98)) :op4 (s2 / status~e.102,139 :mod (p14 / perform-01~e.101) :ARG1-of (m8 / mean-01 :ARG2 (l9 / live-01~e.131 :ARG0 (p15 / person~e.109 :ARG0-of h~e.104 :ARG1-of~e.109 (s3 / score-01~e.109 :ARG2 (a7 / and~e.120 :op1 (s4 / status :value (b / between~e.120 :op1 0 :op2 1) :mod (o / organization :wiki "World_Health_Organization" :name (n6 / name :op1 "World" :op2 "Health" :op3 "Organization"))) :op2 (s5 / status :value (b2 / between :op1 (p16 / percentage-entity :value 81) :op2 (p17 / percentage-entity :value 100)) :mod (p34 / person :name (n / name :op1 "Karnofsky"~e.153)))) :ARG3 p14~e.108 :ARG1-of (g2 / good-02~e.107))) :ARG1-of (l10 / long-03~e.132 :ARG2 (m9 / more) :ARG1-of (r5 / relative-05~e.133 :ARG3~e.136 (p18 / person :ARG0-of h :ARG0-of (h4 / have-03 :ARG1 (s6 / status~e.139 :mod p14~e.138 :mod (p19 / poor~e.137))) :ARG1-of (m10 / mean-01 :ARG2 (a8 / and~e.142,152,165 :op1 (t12 / temporal-quantity~e.208 :quant 19.0~e.141 :unit m4 :duration-of (l11 / live-01~e.76 :ARG0~e.147 (p20 / person :ARG0-of h :ARG0-of (h5 / have-03 :ARG1 (s7 / status~e.154 :value (b3 / between~e.152 :op1 2~e.149 :op2 3~e.151) :mod o~e.148)))) :ARG1-of (s15 / statistical-test-91~e.162,166 :ARG2 0.0027~e.164)) :op2 (t13 / temporal-quantity~e.208 :quant 19.4~e.143 :unit m4~e.144 :duration-of (l12 / live-01~e.76 :ARG0 (p21 / person :ARG0-of h :ARG0-of (h6 / have-03 :ARG1 (s8 / status~e.102 :value (o4 / or~e.93 :op1 (l13 / less-than~e.31 :op1 (p22 / percentage-entity~e.157 :value 80~e.156)) :op2 p22) :mod p34)))) :ARG1-of (s16 / statistical-test-91~e.166 :ARG2 0.0036~e.168)))))) :ARG1-of (m15 / mean-01 :ARG2 (a9 / and~e.120,152 :op1 (t10 / temporal-quantity~e.208 :quant 58.4~e.117 :unit m4~e.118 :condition s4~e.112,113,114,115) :op2 (t11 / temporal-quantity~e.208 :quant 58.1~e.128 :unit m4~e.129 :condition s5~e.121,122,123,124,125,126))))))) :op5 (g3 / grade~e.176 :degree-of (i3 / involve-01~e.175 :ARG1 (n2 / node~e.174 :mod (l14 / lymph~e.173))) :ARG1-of (m11 / mean-01 :ARG2 (s9 / survive-01~e.178 :ARG0~e.179 (p25 / person :ARG0-of h~e.180 :ARG0-of (h7 / have-03 :polarity~e.181 -~e.181 :ARG1 (m12 / metastasize-101~e.184 :ARG2 n2~e.182,183))) :duration (t14 / temporal-quantity~e.208 :quant 65.3~e.186 :unit m4~e.187 :ARG1-of (r6 / relative-05~e.188 :ARG3 (t15 / temporal-quantity~e.208 :quant 46.3~e.190 :unit m4~e.191 :duration-of (s10 / survive-01~e.178 :ARG0~e.192 (p26 / person :ARG0-of h~e.193 :ARG0-of (p27 / present-102~e.194 :ARG1~e.195 m12~e.196)))))))) :ARG1-of (s17 / statistical-test-91~e.198 :ARG2 0.0031~e.200)) :op6 (l15 / level~e.236 :time~e.7 (b4 / before :op1 (t16 / treat-03)) :quant-of (p29 / protein :name (n3 / name :op1 "CEA")) :ARG1-of (m13 / mean-01 :ARG2 (t17 / time~e.208 :time~e.208 (b5 / before :op1 (p30 / progress-01~e.210)) :mod (m14 / median~e.207) :location (p31 / person :ARG0-of h :ARG0-of (h8 / have-03 :ARG1 (l16 / level~e.205,217 :ARG1-of (n4 / normal-02~e.214) :time~e.7,208 b4 :quant (o5 / or~e.93 :op1 (c4 / concentration-quantity :quant 5~e.219 :unit (n5 / nanogram-per-milliliter~e.220,222)) :op2 (l17 / less-than~e.239 :op1 c4)) :quant-of p29~e.204,216))) :duration~e.208 (t18 / temporal-quantity~e.208 :quant 76.3~e.224 :unit m4~e.225 :ARG1-of (r7 / relative-05~e.226 :ARG3 (t19 / temporal-quantity~e.208 :quant 25.6~e.228 :unit m4~e.229 :duration-of~e.208 (t20 / time~e.208 :location~e.230 (p32 / person :ARG0-of h~e.231 :ARG0-of (h9 / have-03 :ARG1 (l18 / level~e.236 :ARG1-of (i4 / increase-01~e.233) :quant-of p29~e.235 :time b4))) :mod m14 :time b5)))))) :ARG1-of (d / describe-01 :ARG0 (t21 / table~e.243 :mod 2~e.244)) :ARG1-of (s18 / statistical-test-91~e.238 :ARG2 0.0001~e.240)))))) # ::id pmid_2290_9976.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 2 . Univariate and multivariate analysis of OS rate ( log @-@ rank test ) # ::alignments 2-1.1 3-1.1.1 6-1.2.1.2 7-1.2 8-1.2.2.2 9-1.2.1 9-1.2.2 12-1.2.1.1 14-1.2.3.1.1 16-1.2.3.1.1 17-1.2.3.1 (d / describe-01 :ARG0 (t / table~e.2 :mod 2~e.3) :ARG1 (a / and~e.7 :op1 (a2 / analyze-01~e.9 :ARG1 (r / rate~e.12 :mod (s / survive-01 :mod (o2 / overall))) :mod (u / univariate~e.6)) :op2 (a3 / analyze-01~e.9 :ARG1 r :mod (m / multivariate~e.8)) :ARG1-of (m2 / mean-01 :ARG2 (t2 / test-01~e.17 :mod (l / log-rank~e.14,16))))) # ::id pmid_2290_9976.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other clinical parameters such as histological differentiation grade and primary tumor size showed no significant differences between groups . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 3-1.1.3.r 4-1.1.3.r 5-1.1.3.1.1.1 6-1.1.3.1.1 7-1.1.3.1 8-1.1.3 9-1.1.3.2.1.1 10-1.1.3.2.1 11-1.1.3.2 12-1 13-1.2.1 13-1.2.1.r 14-1.2.4 15-1.2 17-1.2.2 (s / show-01~e.12 :ARG0 (p / parameter~e.2 :mod (o / other~e.0) :mod (c / clinic~e.1) :example~e.3,4 (a / and~e.8 :op1 (g / grade~e.7 :degree-of (d / differentiate-01~e.6 :mod (h / histology~e.5))) :op2 (s2 / size~e.11 :poss (t / tumor~e.10 :mod (p2 / primary~e.9))))) :ARG1 (d2 / differ-02~e.15 :polarity~e.13 -~e.13 :ARG1 (g2 / group~e.17) :ARG3 p :ARG1-of (s3 / significant-02~e.14))) # ::id pmid_2290_9976.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Clinical and pathological variables identified by multivariate analysis as potential prognostic factors for OS rate # ::alignments 1-1.1.1 2-1 3-1.2.1 4-1.1 4-1.2 5-1.3 6-1.3.1.r 7-1.3.1.1 8-1.3.1 9-1.3.2.r 10-1.3.2.1 11-1.3.2.2 12-1.3.2 15-1.3.2.3 (a / and~e.2 :op1 (v / variable~e.4 :mod (c / clinic~e.1)) :op2 (v2 / variable~e.4 :mod (p / pathology~e.3)) :ARG1-of (i / identify-01~e.5 :ARG0~e.6 (a2 / analyze-01~e.8 :mod (m / multivariate~e.7)) :ARG2~e.9 (f / factor~e.12 :mod (p2 / potential~e.10) :mod (p3 / prognostic~e.11) :topic (r / rate~e.15 :mod (s / survive-01 :mod (o2 / overall)))))) # ::id pmid_2290_9976.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are summarized in Table 2 @ . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 3-1 6-1.2 7-1.2.1 (s / summarize-01~e.3 :ARG1 (t / thing~e.1 :mod (t2 / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG2 (t3 / table~e.6 :mod 2~e.7)) # ::id pmid_2290_9976.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Multivariate analysis identified the following independent prognostic factors affecting OS rates : Primary tumor localization ( HR 0.53 ; p = 0.0032 ) ; Pretreatment CEA level ( HR 2.68 ; p < 0.0001 ) ; WHO performance status ( HR 0.34 ; p = 0.0008 ) ; Lymph node involvement grade ( HR 1.94 ; p = 0.0107 ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.1 5-1.2.2 5-1.2.2.1 5-1.2.2.1.r 6-1.2.3 7-1.2 8-1.2.4 10-1.2.4.1 12-1.2.5.1.1.1.1 13-1.2.5.1.1.1 14-1.2.5.1.1 16-1.2.5.1.1.2.1 17-1.2.5.1.1.2.1.1 19-1.2.5.1.1.3 21-1.2.5.1.1.3.1 25-1.2.5.1.2.1.1.1 26-1.2.5.1.2 28-1.2.5.1.1.2.1.2 28-1.2.5.1.2.3.1 29-1.2.5.1.2.3.1.1 31-1.2.5.1.2.4 32-1.2.5.1.2.4.1 33-1.2.5.1.2.4.1.1 36-1.2.5.1.3.1.1.2.1 36-1.2.5.1.3.1.1.2.2 36-1.2.5.1.3.1.1.2.3 37-1.2.5.1.3.1 38-1.2.5.1.3 40-1.2.5.1.3.2.1 41-1.2.5.1.3.2.1.1 43-1.2.5.1.3.3 45-1.2.5.1.3.3.1 48-1.2.5.1.4.1.1.1 49-1.2.5.1.4.1.1 50-1.2.5.1.4.1 51-1.2.5.1.4 53-1.2.5.1.4.2.1 54-1.2.5.1.4.2.1.1 56-1.2.5.1.4.3 (i / identify-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (m / multivariate~e.0)) :ARG1 (f / factor~e.7 :ARG1-of (f2 / follow-04~e.4) :ARG0-of (d / depend-01~e.5 :polarity~e.5 -~e.5) :mod (p / prognostic~e.6) :ARG0-of (a2 / affect-01~e.8 :ARG1 (r / rate~e.10 :mod (s2 / survive-01 :mod (o3 / overall)))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (b2 / be-located-at-91~e.14 :ARG1 (t / tumor~e.13 :mod (p2 / primary~e.12)) :ARG1-of (m3 / mean-01 :ARG2 (r2 / ratio-of~e.16 :quant 0.53~e.17 :op1 (h / hazard~e.28))) :ARG1-of (s3 / statistical-test-91~e.19 :ARG2 0.0032~e.21)) :op2 (l2 / level~e.26 :quant-of (p4 / protein :name (n / name :op1 "CEA"~e.25)) :time (b / before :op1 (t2 / treat-03)) :ARG1-of (m4 / mean-01 :ARG2 (r3 / ratio-of~e.28 :quant 2.68~e.29 :op1 h)) :ARG1-of (s4 / statistical-test-91~e.31 :ARG2 (l3 / less-than~e.32 :op1 0.0001~e.33))) :op3 (s / status~e.38 :mod (p6 / perform-02~e.37 :ARG2 (o2 / organization :wiki "World_Health_Organization" :name (n2 / name :op1 "World"~e.36 :op2 "Health"~e.36 :op3 "Organization"~e.36))) :ARG1-of (m5 / mean-01 :ARG2 (r4 / ratio-of~e.40 :quant 0.34~e.41 :op1 h)) :ARG1-of (s5 / statistical-test-91~e.43 :ARG2 0.0008~e.45)) :op4 (g / grade~e.51 :degree-of (i2 / involve-01~e.50 :ARG1 (n3 / node~e.49 :mod (l4 / lymph~e.48))) :ARG1-of (m6 / mean-01 :ARG2 (r5 / ratio-of~e.53 :quant 1.94~e.54 :op1 h)) :ARG1-of (s6 / statistical-test-91~e.56 :ARG2 0.01077)))))) # ::id pmid_2290_9976.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other clinical parameters such as age , gender , and Karnofsky performance status showed no significant differences in this analysis . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 3-1.1.3.r 4-1.1.3.r 5-1.1.3.1 7-1.1.3.2 9-1.1.3 10-1.1.3.3.2.1.1 11-1.1.3.3.1 12-1.1.3.3 13-1 14-1.2.1 14-1.2.1.r 15-1.2.4 16-1.2 17-1.2.3.r 18-1.2.3.1 19-1.2.3 (s / show-01~e.13 :ARG0 (p / parameter~e.2 :mod (o / other~e.0) :mod (c / clinic~e.1) :example~e.3,4 (a / and~e.9 :op1 (a2 / age-01~e.5) :op2 (g / gender~e.7) :op3 (s2 / status~e.12 :mod (p2 / perform-02~e.11) :mod (p3 / person :name (n / name :op1 "Karnofsky"~e.10))))) :ARG1 (d / differ-02~e.16 :polarity~e.14 -~e.14 :ARG1 p :time~e.17 (a3 / analyze-01~e.19 :mod (t / this~e.18)) :ARG1-of (s3 / significant-02~e.15))) # ::id pmid_2290_9976.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Predictive roles of K @-@ Ras and B @-@ Raf mutations on time to progression in CRC patients treated with irinotecan @-@ based first @-@ line palliative chemotherapy on the basis of univariate analysis # ::alignments 1-1.2 2-1.3.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1 11-1.1.2.1.1.1 13-1.1.2.1.1.1 15-1.1.1 15-1.1.2 16-1.2.2.r 17-1.2.2 17-1.2.2.1.r 19-1.2.2.1.1 22-1.3.1.1 23-1.3.2 24-1.3.2.2.r 25-1.3.2.2.2.1.1.1 27-1.3.2.2.2 28-1.3.2.2.3.1 28-1.3.2.2.3.1.1 28-1.3.2.2.3.1.1.r 30-1.3.2.2.3 31-1.3.2.2.1 32-1.3.2.2 35-1.4 36-1.4.1.r 37-1.4.1.1 38-1.4.1 (p / play-02 :ARG0 (a / and~e.9 :op1 (m / mutate-01~e.15 :ARG1 (g / gene :name (n / name :op1 "K-Ras"~e.5,7))) :op2 (m2 / mutate-01~e.15 :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf"~e.11,13)))) :ARG1 (p2 / predict-01~e.1 :ARG0 a :ARG1~e.16 (t2 / time~e.17 :time~e.17 (b2 / before :op1 (p6 / progress-01~e.19 :ARG1 (d / disease))))) :location (p3 / person :ARG0-of (h / have-rel-role-91~e.2 :ARG2 (p4 / patient~e.22)) :ARG1-of (t / treat-03~e.23 :ARG2 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer")) :ARG3~e.24 (c / chemotherapy~e.32 :mod (p5 / palliative~e.31) :ARG1-of (b / base-02~e.27 :ARG2 (s / small-molecule :name (n4 / name :op1 "irinotecan"~e.25))) :mod (l / line~e.30 :ord (o / ordinal-entity~e.28 :value~e.28 1~e.28))))) :ARG1-of (b3 / base-02~e.35 :ARG2~e.36 (a2 / analyze-01~e.38 :mod (u / univariate~e.37)))) # ::id pmid_2290_9976.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are summarized in Table 3 @ . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 3-1 6-1.2 7-1.2.1 (s / summarize-01~e.3 :ARG1 (t / thing~e.1 :mod (t2 / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG2 (t3 / table~e.6 :mod 3~e.7)) # ::id pmid_2290_9976.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with higher pretreatment levels of CEA (> 5 ng/ml ) showed a median time to progression of 9.0 mo relative to 13.0 mo in patients with normal levels (≤ 5 ng/ml , p = 0.0085 ) . # ::alignments 0-1.1.1.1 2-1.1.2.1.1 2-1.1.2.1.1.1 2-1.1.2.1.1.1.r 4-1.1.2.1 5-1.1.2.1.2.r 6-1.1.2.1.2.1.1 8-1.1.2.1.3.1.1.1 11-1 11-1.2.3.1.1 13-1.2.2 14-1.2 14-1.2.1.r 14-1.2.3.1 14-1.2.3.1.2 14-1.2.3.1.2.r 14-1.2.4 14-1.2.4.r 16-1.2.1.1 19-1.2.4.2 20-1.2.3 23-1.2.4.2 24-1.2.3.1.1.1.r 25-1.2.3.1.1.1.1 27-1.2.3.1.1.1.2.1.1 28-1.2.3.1.1.1.2.1 30-1.1.2.1.3.1.1.1 33-1.2.3.1.1.1.2.1.3 35-1.2.3.1.1.1.2.1.3.1 (s / show-01~e.11 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0)) :ARG0-of (h2 / have-03 :ARG1 (l / level~e.4 :ARG1-of (h3 / high-02~e.2 :degree~e.2 (m / more~e.2)) :quant-of~e.5 (p3 / protein :name (n / name :op1 "CEA"~e.6)) :ARG1-of (m2 / mean-01 :ARG2 (m3 / more-than :op1 (c / concentration-quantity :quant 5~e.8,30 :unit (n2 / nanogram-per-milliliter)))) :time (b / before :op1 (t / treat-03))))) :ARG1 (t2 / time~e.14 :time~e.14 (b2 / before :op1 (p4 / progress-01~e.16)) :mod (m4 / median~e.13) :ARG1-of (r / relative-05~e.20 :ARG3 (t4 / time~e.14 :ARG1-of (s2 / show-01~e.11 :ARG0~e.24 (p5 / person :ARG0-of h~e.25 :ARG0-of (h4 / have-03 :ARG1 (l2 / level~e.28 :ARG1-of (n3 / normal-02~e.27) :ARG1-of (m6 / mean-01 :ARG2 (o / or :op1 (l3 / less-than :op1 c) :op2 c)) :ARG1-of (s3 / statistical-test-91~e.33 :ARG2 0.0085~e.35))))) :duration~e.14 (t5 / temporal-quantity~e.14 :quant 13 :unit m5) :time b2)) :duration~e.14 (t3 / temporal-quantity~e.14 :quant 9 :unit (m5 / month~e.19,23)))) # ::id pmid_2290_9976.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients without resection of metastases showed a median time to progression of 9.0 mo relative to 14.0 mo in patients who underwent resection ( p = 0.0131 ) . # ::alignments 0-1.1.1.1 1-1.1.2.1 1-1.1.2.1.r 2-1.1.2.2 4-1.1.2.2.1 5-1 5-1.2.3.1.1 7-1.2.1 8-1.2 8-1.2.2.r 8-1.2.3.1 8-1.2.3.1.2 8-1.2.3.1.2.r 8-1.2.3.1.3.r 8-1.2.4 8-1.2.4.r 10-1.2.2.1 13-1.2.4.2 14-1.2.3 17-1.2.4.2 19-1.1.1.1 21-1.1 21-1.1.2 21-1.1.2.r 21-1.2.3.1.1.1 21-1.2.3.1.1.1.2 21-1.2.3.1.1.1.2.r 22-1.1.2.2 24-1.3 26-1.3.1 (s / show-01~e.5 :ARG0 (p / person~e.21 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0,19)) :ARG1-of~e.21 (u / undergo-28~e.21 :polarity~e.1 -~e.1 :ARG2 (r / resection~e.2,22 :mod (m / metastasize-101~e.4)))) :ARG1 (t / time~e.8 :mod (m2 / median~e.7) :time~e.8 (b / before :op1 (p3 / progress-01~e.10)) :ARG1-of (r2 / relative-05~e.14 :ARG3 (t3 / time~e.8 :ARG1-of (s2 / show-01~e.5 :ARG0 (p4 / person~e.21 :ARG0-of h :ARG1-of~e.21 (u2 / undergo-28~e.21 :ARG2 r))) :duration~e.8 (t4 / temporal-quantity~e.8 :quant 14 :unit m3) :time~e.8 b)) :duration~e.8 (t2 / temporal-quantity~e.8 :quant 9 :unit (m3 / month~e.13,17))) :ARG1-of (s3 / statistical-test-91~e.24 :ARG2 0.0131~e.26)) # ::id pmid_2290_9976.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with K @-@ Ras gene mutations showed a median time to progression of 9.0 mo relative to 11.0 mo in those with the wild @-@ type K @-@ Ras gene ( p = 0.05883 ) . # ::alignments 0-1.1.1.1 3-1.1.2.1.1.1.1 5-1.1.2.1.1.1.1 7-1.1.2.1.1 8-1.1.2.1 9-1 9-1.2.3.1.1 11-1.2.1 12-1.2 12-1.2.2.r 12-1.2.3.1 12-1.2.3.1.2 12-1.2.3.1.2.r 12-1.2.4 12-1.2.4.r 14-1.2.2.1 17-1.2.4.2 18-1.2.3 21-1.2.4.2 24-1.2.3.1.1.1.r 26-1.2.3.1.1.1.2.1.2 28-1.2.3.1.1.1.2.1.2 30-1.2.3.1.1.1.2.1.1.1 32-1.2.3.1.1.1.2.1.1.1 34-1.2.3.1.1.1.2.1 36-1.3 38-1.3.1 (s / show-01~e.9 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0)) :ARG0-of (h2 / have-03 :ARG1 (m / mutate-01~e.8 :ARG1 (g / gene~e.7 :name (n / name :op1 "K-Ras"~e.3,5))))) :ARG1 (t / time~e.12 :mod (m2 / median~e.11) :time~e.12 (b / before :op1 (p3 / progress-01~e.14)) :ARG1-of (r / relative-05~e.18 :ARG3 (t3 / time~e.12 :ARG1-of (s2 / show-01~e.9 :ARG0~e.24 (p4 / person :ARG0-of h :ARG0-of (h3 / have-03 :ARG1 (g2 / gene~e.34 :name (n2 / name :op1 "K-Ras"~e.30,32) :mod (w / wild-type~e.26,28))))) :duration~e.12 (t4 / temporal-quantity~e.12 :quant 11 :unit m3) :time b)) :duration~e.12 (t2 / temporal-quantity~e.12 :quant 9 :unit (m3 / month~e.17,21))) :ARG1-of (s3 / statistical-test-91~e.36 :ARG2 0.05883~e.38)) # ::id pmid_2290_9976.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other clinical parameters including histological differentiation grade , primary tumor location and size , lymph node involvement grade , and B @-@ Raf gene mutation status showed no predictive significance in this analysis . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 3-1.1.3 4-1.1.3.1.1.1.1 5-1.1.3.1.1.1 6-1.1.3.1.1 8-1.1.3.1.2.1.1 9-1.1.3.1.2.1 11-1.1.3.1 12-1.1.3.1.3 14-1.1.3.1.4.1.1.1 15-1.1.3.1.4.1.1 16-1.1.3.1.4.1 17-1.1.3.1.4 19-1.1.3.1 21-1.1.3.1.5.1.1.1.1 23-1.1.3.1.5.1.1.1.1 25-1.1.3.1.5.1.1 26-1.1.3.1.5.1 27-1.1.3.1.5 28-1 29-1.2.1 29-1.2.1.r 30-1.2.3 31-1.2 32-1.3.r 33-1.3.1 34-1.3 (s / show-01~e.28 :ARG0 (p / parameter~e.2 :mod (o / other~e.0) :mod (c / clinic~e.1) :ARG2-of (i / include-91~e.3 :ARG1 (a / and~e.11,19 :op1 (g / grade~e.6 :degree-of (d / differentiate-01~e.5 :mod (h / histology~e.4))) :op2 (b / be-located-at-91 :ARG1 (t / tumor~e.9 :mod (p2 / primary~e.8))) :op3 (s2 / size~e.12 :poss t) :op4 (g2 / grade~e.17 :degree-of (i2 / involve-01~e.16 :ARG1 (n3 / node~e.15 :mod (l2 / lymph~e.14)))) :op5 (s3 / status~e.27 :mod (m / mutate-01~e.26 :ARG1 (g3 / gene~e.25 :name (n2 / name :op1 "B-Raf"~e.21,23))))))) :ARG1 (s4 / significant-02~e.31 :polarity~e.29 -~e.29 :ARG1 p :ARG0-of (p3 / predict-01~e.30)) :time~e.32 (a2 / analyze-01~e.34 :mod (t2 / this~e.33))) # ::id pmid_2290_9976.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 3 . Univariate and multivariate analysis of time to progression ( log @-@ rank test ) for irinotecan @-@ based chemotherapy # ::alignments 2-1.1 3-1.1.1 6-1.2.1.2 7-1.2 8-1.2.2.2 9-1.2.1 9-1.2.2 10-1.2.1.1.r 11-1.2.1.1 11-1.2.1.1.1.r 13-1.2.1.1.1.1 15-1.2.3.1.1 17-1.2.3.1.1 18-1.2.3.1 21-1.2.4.1.1.1.1 23-1.2.4.1 24-1.2.4 (d / describe-01 :ARG0 (t / table~e.2 :mod 3~e.3) :ARG1 (a / and~e.7 :op1 (a2 / analyze-01~e.9 :ARG1~e.10 (t2 / time~e.11 :time~e.11 (b / before :op1 (p / progress-01~e.13))) :mod (u / univariate~e.6)) :op2 (a3 / analyze-01~e.9 :ARG1 t2 :mod (m / multivariate~e.8)) :ARG1-of (m2 / mean-01 :ARG2 (t3 / test-01~e.18 :mod (l / log-rank~e.15,17))) :condition (c / chemotherapy~e.24 :ARG1-of (b2 / base-02~e.23 :ARG2 (s / small-molecule :name (n / name :op1 "irinotecan"~e.21)))))) # ::id pmid_2290_9976.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Predictive roles of K @-@ Ras and B @-@ Raf mutations on time to progression in CRC patients treated with irinotecan @-@ based first @-@ line palliative chemotherapy on the basis of multivariate analysis # ::alignments 1-1.2 2-1.3.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1 11-1.1.2.1.1.1 13-1.1.2.1.1.1 15-1.1.1 15-1.1.2 16-1.2.2.r 17-1.2.2 17-1.2.2.1.r 19-1.2.2.1.1 22-1.3.1.1 23-1.3.3 24-1.3.3.1.r 25-1.3.3.1.1.1.1.1 27-1.3.3.1.1 28-1.3.3.1.3.1 28-1.3.3.1.3.1.1 28-1.3.3.1.3.1.1.r 30-1.3.3.1.3 31-1.3.3.1.2 32-1.3.3.1 35-1.4 36-1.4.1.r 37-1.4.1.1 38-1.4.1 (p / play-02 :ARG0 (a / and~e.9 :op1 (m / mutate-01~e.15 :ARG1 (g / gene :name (n / name :op1 "K-Ras"~e.5,7))) :op2 (m2 / mutate-01~e.15 :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf"~e.11,13)))) :ARG1 (p2 / predict-01~e.1 :ARG0 a :ARG1~e.16 (t / time~e.17 :time~e.17 (b / before :op1 (p3 / progress-01~e.19 :ARG1 (d / disease))))) :location (p4 / person :ARG0-of (h / have-rel-role-91~e.2 :ARG2 (p5 / patient~e.22)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (t2 / treat-03~e.23 :ARG2~e.24 (c / chemotherapy~e.32 :ARG1-of (b2 / base-02~e.27 :ARG2 (s / small-molecule :name (n4 / name :op1 "irinotecan"~e.25))) :mod (p6 / palliative~e.31) :mod (l / line~e.30 :ord (o / ordinal-entity~e.28 :value~e.28 1~e.28))))) :ARG1-of (b3 / base-02~e.35 :ARG2~e.36 (a2 / analyze-01~e.38 :mod (m3 / multivariate~e.37)))) # ::id pmid_2290_9976.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are summarized in Table 3 @ . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 3-1 6-1.2 7-1.2.1 (s / summarize-01~e.3 :ARG1 (t / thing~e.1 :mod (t2 / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG2 (t3 / table~e.6 :mod 3~e.7)) # ::id pmid_2290_9976.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Multivariate analysis identified the following independent favorable predictive factors in patients with disseminated CRC treated with irinotecan @-@ based first @-@ line palliative chemotherapy : Wild @-@ type K @-@ Ras gene ( HR 0.59 ; p = 0.0459 ) and normal pretreatment CEA levels ( HR 0.52 ; p = 0.0065 ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.1 5-1.2.2 5-1.2.2.1 5-1.2.2.1.r 6-1.2.5 7-1.2.3 8-1.2 9-1.3.r 10-1.3.1.1 12-1.3.2.1.3 14-1.2.4.1.2.2.1 14-1.3.3 15-1.3.3.1.r 16-1.3.3.1.1.1.1.1 18-1.3.3.1.1 19-1.3.3.1.2.1 19-1.3.3.1.2.1.1 19-1.3.3.1.2.1.1.r 21-1.3.3.1.2 22-1.3.3.1.3 23-1.3.3.1 25-1.2.4.1.1.2 27-1.2.4.1.1.2 29-1.2.4.1.1.1.1 31-1.2.4.1.1.1.1 33-1.2.4.1.1 35-1.2.4.1.1.3.1 36-1.2.4.1.1.3.1.1 38-1.2.4.1.1.4 40-1.2.4.1.1.4.1 42-1.2.4.1 43-1.2.4.1.2.1 45-1.2.4.1.2.3.1.1 46-1.2.4.1.2 48-1.2.4.1.1.3.1.2 48-1.2.4.1.2.4.1 49-1.2.4.1.2.4.1.1 51-1.2.4.1.2.5 (i / identify-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (m / multivariate~e.0)) :ARG1 (f / factor~e.8 :ARG1-of (f2 / follow-04~e.4) :ARG0-of (d / depend-01~e.5 :polarity~e.5 -~e.5) :ARG0-of (p / predict-01~e.7) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.42 :op1 (g / gene~e.33 :name (n3 / name :op1 "K-Ras"~e.29,31) :mod (w / wild-type~e.25,27) :ARG1-of (m3 / mean-01 :ARG2 (r / ratio-of~e.35 :quant 0.59~e.36 :op1 (h3 / hazard~e.48))) :ARG1-of (s2 / statistical-test-91~e.38 :ARG2 0.0459~e.40)) :op2 (l2 / level~e.46 :ARG1-of (n4 / normal-02~e.43) :time (b2 / before :op1 (t2 / treat-03~e.14)) :quant-of (p6 / protein :name (n5 / name :op1 "CEA"~e.45)) :ARG1-of (m4 / mean-01 :ARG2 (r2 / ratio-of~e.48 :quant 0.52~e.49 :op1 h3)) :ARG1-of (s3 / statistical-test-91~e.51 :ARG2 0.065)))) :mod (f3 / favorable~e.6)) :location~e.9 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.10)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer") :ARG1-of (d3 / disseminate-01~e.12))) :ARG1-of (t / treat-03~e.14 :ARG2~e.15 (c / chemotherapy~e.23 :ARG1-of (b / base-02~e.18 :ARG2 (s / small-molecule :name (n2 / name :op1 "irinotecan"~e.16))) :mod (l / line~e.21 :ord (o / ordinal-entity~e.19 :value~e.19 1~e.19)) :mod (p4 / palliative~e.22))))) # ::id pmid_2290_9976.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , this analysis did not reveal any significant differences between patients with and without resection of metastases , with different histological types of neoplasms and B @-@ Raf gene mutation status . # ::alignments 0-1 2-1.1.2.1 3-1.1.2 5-1.1.1 5-1.1.1.r 6-1.1 8-1.1.3.3 9-1.1.3 11-1.1.3.1.1.1.1 13-1.1.3.1 14-1.1.3.1.2.2.1 14-1.1.3.1.2.2.1.r 15-1.1.3.1.1.2.1 16-1.1.3.1.1.2.1.1.r 17-1.1.3.1.1.2.1.1 19-1.1.3.2.r 20-1.1.3.2.1.2.1.3 21-1.1.3.2.1.2.1.2 22-1.1.3.2.1.2.1 23-1.1.3.2.1.2.1.1.r 24-1.1.3.2.1.2.1.1 27-1.1.3.2.2.2.1.2.1.1.1 29-1.1.3.2.2.2.1.2.1.1.1 31-1.1.3.2.2.2.1.2.1 32-1.1.3.2.2.2.1.2 33-1.1.3.2.2.2.1 (c / contrast-01~e.0 :ARG2 (r / reveal-01~e.6 :polarity~e.5 -~e.5 :ARG0 (a / analyze-01~e.3 :mod (t2 / this~e.2)) :ARG1 (d / differ-02~e.9 :ARG1 (a2 / and~e.13 :op1 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.11)) :ARG0-of (h3 / have-03 :ARG1 (r2 / resection~e.15 :mod~e.16 (m / metastasize-101~e.17)))) :op2 (p3 / person :ARG0-of h2 :ARG0-of (h4 / have-03 :polarity~e.14 -~e.14 :ARG1 r2))) :ARG2~e.19 (a3 / and :op1 (p4 / person :ARG0-of h2 :ARG0-of (h5 / have-03 :ARG1 (t / type~e.22 :mod~e.23 (n3 / neoplasm~e.24) :mod (h6 / histology~e.21) :ARG1-of (d2 / differ-02~e.20)))) :op2 (p5 / person :ARG0-of h2 :ARG0-of (h7 / have-03 :ARG1 (s2 / status~e.33 :ARG1-of d2 :mod (m2 / mutate-01~e.32 :ARG1 (g / gene~e.31 :name (n2 / name :op1 "B-Raf"~e.27,29))))))) :ARG1-of (s / significant-02~e.8)))) # ::id pmid_2290_9976.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Predictive roles of K @-@ Ras and B @-@ Raf mutations on time to progression in CRC patients treated with oxaliplatin @-@ based first @-@ line palliative chemotherapy on the basis of univariate analysis # ::alignments 1-1.2 2-1.3.1 5-1.1.1.1.2.1 7-1.1.1.1.2.1 9-1.1 11-1.1.2.1.2.1 13-1.1.2.1.2.1 15-1.1.1 15-1.1.2 16-1.2.2.r 17-1.2.2 17-1.2.2.1.r 19-1.2.2.1.1 22-1.3.1.1 23-1.3.3 24-1.3.3.1.r 25-1.3.3.1.2.1.2.1 27-1.3.3.1.2 28-1.3.3.1.3.1 28-1.3.3.1.3.1.1 28-1.3.3.1.3.1.1.r 30-1.3.3.1.3 31-1.3.3.1.1 32-1.3.3.1 35-1.4 36-1.4.1.r 37-1.4.1.1 38-1.4.1 (p / play-02 :ARG0 (a / and~e.9 :op1 (m / mutate-01~e.15 :ARG1 (g / gene :wiki - :name (n / name :op1 "K-Ras"~e.5,7))) :op2 (m2 / mutate-01~e.15 :ARG2 (g2 / gene :wiki "BRAF_(gene)" :name (n3 / name :op1 "B-Raf"~e.11,13)))) :ARG1 (p2 / predict-01~e.1 :ARG0 a :ARG1~e.16 (t / time~e.17 :time~e.17 (b / before :op1 (p3 / progress-01~e.19 :ARG1 (d / disease))))) :location (p4 / person :ARG0-of (h / have-rel-role-91~e.2 :ARG2 (p5 / patient~e.22)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (t2 / treat-03~e.23 :ARG2~e.24 (c / chemotherapy~e.32 :mod (p6 / palliative~e.31) :ARG1-of (b2 / base-02~e.27 :ARG2 (s / small-molecule :wiki "Oxaliplatin" :name (n4 / name :op1 "oxaliplatin"~e.25))) :mod (l / line~e.30 :ord (o / ordinal-entity~e.28 :value~e.28 1~e.28))))) :ARG1-of (b3 / base-02~e.35 :ARG2~e.36 (a2 / analyze-01~e.38 :mod (u / univariate~e.37)))) # ::id pmid_2290_9976.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are summarized in Table 4 @ . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 3-1 6-1.2 7-1.2.1 (s / summarize-01~e.3 :ARG1 (t / thing~e.1 :mod (t2 / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG2 (t3 / table~e.6 :mod 4~e.7)) # ::id pmid_2290_9976.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Univariate analysis of time to progression in patients treated with oxaliplatin @-@ based first @-@ line chemotherapy regimens reveals that increased CEA levels and resection of metastases exerted significant influences on median time to progression . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1 3-1.1.1.1.r 5-1.1.1.1.1 7-1.3.1.1 8-1.3.2 9-1.3.2.1.r 10-1.3.2.1.1.1.1.1.1 12-1.3.2.1.1.1 13-1.3.2.1.1.2.1 13-1.3.2.1.1.2.1.1 13-1.3.2.1.1.2.1.1.r 15-1.3.2.1.1.2 16-1.3.2.1.1 17-1.3.2.1 18-1 19-1.2.r 20-1.2.1.1.2 21-1.2.1.1.1.1.1 22-1.2.1.1 23-1.2.1 24-1.2.1.2 25-1.2.1.2.1.r 26-1.2.1.2.1 27-1.2 28-1.2.2.1 29-1.2.2 30-1.2.3.r 31-1.2.3.2 32-1.2.3 33-1.2.3.1.r 34-1.2.3.1 (r / reveal-01~e.18 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (t / time~e.3 :time~e.3 (b / before :op1 (p / progress-01~e.5))) :mod (u / univariate~e.0)) :ARG1~e.19 (e / exert-01~e.27 :ARG0 (a2 / and~e.23 :op1 (l2 / level~e.22 :quant-of (p4 / protein :name (n2 / name :op1 "CEA"~e.21)) :ARG1-of (i / increase-01~e.20)) :op2 (r3 / resection~e.24 :mod~e.25 (m / metastasize-101~e.26))) :ARG1 (i2 / influence-01~e.29 :ARG1-of (s2 / significant-02~e.28)) :ARG2~e.30 (t3 / time~e.32 :time~e.33 b~e.34 :mod (m2 / median~e.31))) :location (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.7)) :ARG1-of (t2 / treat-03~e.8 :ARG2~e.9 (r2 / regimen~e.17 :mod (c / chemotherapy~e.16 :ARG1-of (b2 / base-02~e.12 :ARG2 (s / small-molecule :name (n / name :op1 "oxaliplatin"~e.10))) :mod (l / line~e.15 :ord (o / ordinal-entity~e.13 :value~e.13 1~e.13))))))) # ::id pmid_2290_9976.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with increased pretreatment CEA levels had a time to progression of 8.0 mo compared with 13.0 mo in patients with normal CEA levels ( p = 0.0084 ) . # ::alignments 0-1.1.1.1 2-1.1.2.1.2 4-1.1.2.1.1.1.1 5-1.1.2.1 6-1 6-1.1 6-1.1.1 6-1.1.1.r 6-1.1.2 6-1.1.2.r 6-1.1.r 8-1.1.2.1.3.r 8-1.2 8-1.2.1.r 8-1.2.2 8-1.2.2.r 8-1.2.3 8-1.2.3.2 8-1.2.3.2.r 10-1.2.1.1 13-1.2.2.2 14-1.2.3.r 17-1.2.2.2 19-1.2.3.3.1.1 21-1.2.3.3.1.2.1.1 22-1.2.3.3.1.2.1.2 23-1.2.3.3.1.2.1 25-1.3 27-1.3.1 (h / have-03~e.6 :ARG0~e.6 (p / person~e.6 :ARG0-of~e.6 (h2 / have-rel-role-91~e.6 :ARG2 (p2 / patient~e.0)) :ARG0-of~e.6 (h3 / have-03~e.6 :ARG1 (l / level~e.5 :quant-of (p3 / protein :name (n / name :op1 "CEA"~e.4)) :ARG1-of (i / increase-01~e.2) :time~e.8 (b / before :op1 (t / treat-03))))) :ARG1 (t2 / time~e.8 :time~e.8 (b2 / before :op1 (p4 / progress-01~e.10)) :duration~e.8 (t3 / temporal-quantity~e.8 :quant 8 :unit (m / month~e.13,17)) :compared-to~e.14 (t4 / time~e.8 :time b2 :duration~e.8 (t5 / temporal-quantity~e.8 :quant 13 :unit m) :ARG1-of (h4 / have-03 :ARG0 (p5 / person :ARG0-of h2~e.19 :ARG0-of (h5 / have-03 :ARG1 (l2 / level~e.23 :ARG1-of (n2 / normal-02~e.21) :quant-of p3~e.22)))))) :ARG1-of (s / statistical-test-91~e.25 :ARG2 0.0084~e.27)) # ::id pmid_2290_9976.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients without resection of metastases had a time to progression of 9.0 mo relative to 16.0 mo in patients who underwent resection ( p = 0.0226 ) . # ::alignments 0-1.1.1.1 1-1.1.2.1 1-1.1.2.1.r 2-1.1.2.2 4-1.1.2.2.1 5-1 5-1.1.1 7-1.2 7-1.2.1.r 7-1.2.2 7-1.2.2.r 7-1.2.3.1 7-1.2.3.1.1.r 7-1.2.3.1.2 7-1.2.3.1.2.r 9-1.2.1.1 12-1.2.2.2 13-1.2.3 16-1.2.2.2 18-1.1.1.1 20-1.1 20-1.1.2 20-1.1.2.r 20-1.2.3.1.3.1 20-1.2.3.1.3.1.2 20-1.2.3.1.3.1.2.r 21-1.1.2.2 23-1.3 25-1.3.1 (h / have-03~e.5 :ARG0 (p / person~e.20 :ARG0-of (h2 / have-rel-role-91~e.5 :ARG2 (p2 / patient~e.0,18)) :ARG1-of~e.20 (u / undergo-28~e.20 :polarity~e.1 -~e.1 :ARG2 (r / resection~e.2,21 :mod (m / metastasize-101~e.4)))) :ARG1 (t / time~e.7 :time~e.7 (b / before :op1 (p3 / progress-01~e.9)) :duration~e.7 (t2 / temporal-quantity~e.7 :quant 9 :unit (m2 / month~e.12,16)) :ARG1-of (r2 / relative-05~e.13 :ARG3 (t3 / time~e.7 :time~e.7 b :duration~e.7 (t4 / temporal-quantity~e.7 :quant 16 :unit m2) :ARG1-of (h3 / have-03 :ARG0 (p4 / person~e.20 :ARG0-of h2 :ARG1-of~e.20 (u2 / undergo-28~e.20 :ARG2 r)))))) :ARG1-of (s / statistical-test-91~e.23 :ARG2 0.0226~e.25)) # ::id pmid_2290_9976.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with tubular tumors showed a time to progression of 9.0 mo compared with 13.0 mo in those with other histological types ( p = 0.0462 ) . # ::alignments 0-1.1.1.1 2-1.1.2.1.1 3-1.1.2.1 4-1 4-1.2.3.3 6-1.2 6-1.2.1.r 6-1.2.2 6-1.2.2.r 6-1.2.3 6-1.2.3.1.r 6-1.2.3.2 6-1.2.3.2.r 8-1.2.1.1 11-1.2.2.2 12-1.2.3.r 15-1.2.2.2 18-1.2.3.3.1.r 19-1.2.3.3.1.2.2 20-1.2.3.3.1.2.1 21-1.2.3.3.1.2 23-1.3 25-1.3.1 (s / show-01~e.4 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0)) :ARG0-of (h2 / have-03 :ARG1 (t / tumor~e.3 :mod (t2 / tubular~e.2)))) :ARG1 (t3 / time~e.6 :time~e.6 (b / before :op1 (p3 / progress-01~e.8)) :duration~e.6 (t4 / temporal-quantity~e.6 :quant 9 :unit (m / month~e.11,15)) :compared-to~e.12 (t5 / time~e.6 :time~e.6 b :duration~e.6 (t6 / temporal-quantity~e.6 :quant 13 :unit m) :ARG1-of (s2 / show-01~e.4 :ARG0~e.18 (p4 / person :ARG0-of h :mod (t7 / type~e.21 :mod (h3 / histology~e.20) :mod (o / other~e.19)))))) :ARG1-of (s3 / statistical-test-91~e.23 :ARG2 0.0462~e.25)) # ::id pmid_2290_9976.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with K @-@ Ras gene mutations did not show a significant difference in time to progression when treated with oxaliplatin chemotherapy , when compared with those with the wild @-@ type K @-@ Ras gene ( Fig . 4 ) . # ::alignments 0-1.2.1.1 3-1.2.2.1.1.1.1 5-1.2.2.1.1.1.1 7-1.2.2.1.1 8-1.2.2.1 10-1.1 10-1.1.r 11-1 13-1.3.2 14-1.3 15-1.3.1.r 16-1.3.1 16-1.3.1.1.r 18-1.3.1.1.1 19-1.4.r 20-1.4 21-1.4.2.r 22-1.4.2.1.1.1 23-1.4.2 25-1.4.r 26-1.5.r 31-1.5.2.2 33-1.5.2.2 35-1.5.2.1.1 37-1.5.2.1.1 39-1.5.2 42-1.6.1 44-1.6.1.1 (s / show-01~e.11 :polarity~e.10 -~e.10 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.0)) :ARG0-of (h2 / have-03 :ARG1 (m / mutate-01~e.8 :ARG1 (g / gene~e.7 :name (n / name :op1 "K-Ras"~e.3,5))))) :ARG1 (d / differ-02~e.14 :ARG1~e.15 (t / time~e.16 :time~e.16 (b / before :op1 (p3 / progress-01~e.18))) :ARG1-of (s2 / significant-02~e.13)) :time~e.19,25 (t2 / treat-03~e.20 :ARG1 p :ARG2~e.21 (c / chemotherapy~e.23 :mod (s3 / small-molecule :name (n2 / name :op1 "oxaliplatin"~e.22)))) :compared-to~e.26 (p4 / person :ARG0-of h :mod (g2 / gene~e.39 :name (n3 / name :op1 "K-Ras"~e.35,37) :mod (w / wild-type~e.31,33))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.42 :mod 4~e.44))) # ::id pmid_2290_9976.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The significance of B @-@ Raf gene status , WHO performance status , and Karnofsky performance status could not be assessed . # ::alignments 4-1.2.1.1.1.1.1.1 8-1.2.1.1.1.1 9-1.2.1.1.1 11-1.2.1.1.2.2.2.1 11-1.2.1.1.2.2.2.2 11-1.2.1.1.2.2.2.3 12-1.2.1.1.2.1 12-1.2.1.1.3.1 13-1.2.1.1.2 13-1.2.1.1.3 15-1.2.1.1 16-1.2.1.1.3.2.1.1 17-1.2.1.1.2.1 18-1.2.1.1.2 19-1 20-1.1 20-1.1.r 22-1.2 (p2 / possible-01~e.19 :polarity~e.20 -~e.20 :ARG1 (a / assess-01~e.22 :ARG1 (s / signify-01 :ARG0 (a2 / and~e.15 :op1 (s2 / status~e.9 :mod (g / gene~e.8 :name (n / name :op1 "B-RAF"~e.4))) :op2 (s3 / status~e.13,18 :mod (p3 / perform-02~e.12,17) :mod (o / organization :wiki "World_Health_Organization" :name (n2 / name :op1 "World"~e.11 :op2 "Health"~e.11 :op3 "Organization"~e.11))) :op3 (s4 / status~e.13 :mod (p4 / perform-02~e.12) :mod (p / person :name (n3 / name :op1 "Karnofsky"~e.16))))))) # ::id pmid_2290_9976.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Table 4 . Univariate and multivariate analysis of time to progression ( log @-@ rank test ) for oxaliplatin @-@ based chemotherapy # ::alignments 2-1.1 3-1.1.1 6-1.2.1.2 7-1.2 8-1.2.2.2 9-1.2.1 9-1.2.2 10-1.2.1.1.r 11-1.2.1.1 11-1.2.1.1.1.r 13-1.2.1.1.1.1 15-1.2.3.1.1 17-1.2.3.1.1 18-1.2.3.1 21-1.2.4.1.1.1.1 23-1.2.4.1 24-1.2.4 (d / describe-01 :ARG0 (t / table~e.2 :mod 4~e.3) :ARG1 (a / and~e.7 :op1 (a2 / analyze-01~e.9 :ARG1~e.10 (t2 / time~e.11 :time~e.11 (b / before :op1 (p / progress-01~e.13))) :mod (u / univariate~e.6)) :op2 (a3 / analyze-01~e.9 :ARG1 t2 :mod (m / multivariate~e.8)) :ARG1-of (m2 / mean-01 :ARG2 (t3 / test-01~e.18 :mod (l / log-rank~e.15,17))) :condition (c / chemotherapy~e.24 :ARG1-of (b2 / base-02~e.23 :ARG2 (s / small-molecule :name (n / name :op1 "oxaliplatin"~e.21)))))) # ::id pmid_2290_9976.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Predictive roles of K @-@ Ras and B @-@ Raf mutations on time to progression in CRC patients treated with oxaliplatin @-@ based first @-@ line palliative chemotherapy on the basis of multivariate analysis # ::alignments 1-1.2 2-1.3.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1 11-1.1.2.1.1.1 13-1.1.2.1.1.1 15-1.1.1 15-1.1.2 16-1.2.2.r 17-1.2.2 17-1.2.2.1.r 19-1.2.2.1.1 22-1.3.1.1 23-1.3.3 24-1.3.3.1.r 25-1.3.3.1.2.1.1.1 27-1.3.3.1.2 28-1.3.3.1.3.1 28-1.3.3.1.3.1.1 28-1.3.3.1.3.1.1.r 30-1.3.3.1.3 31-1.3.3.1.1 32-1.3.3.1 35-1.4 36-1.4.1.r 37-1.4.1.1 38-1.4.1 (p / play-02 :ARG0 (a / and~e.9 :op1 (m / mutate-01~e.15 :ARG1 (g / gene :name (n / name :op1 "K-Ras"~e.5,7))) :op2 (m2 / mutate-01~e.15 :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf"~e.11,13)))) :ARG1 (p2 / predict-01~e.1 :ARG0 a :ARG1~e.16 (t / time~e.17 :time~e.17 (b / before :op1 (p3 / progress-01~e.19 :ARG1 (d / disease))))) :location (p4 / person :ARG0-of (h / have-rel-role-91~e.2 :ARG2 (p5 / patient~e.22)) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (t2 / treat-03~e.23 :ARG2~e.24 (c / chemotherapy~e.32 :mod (p6 / palliative~e.31) :ARG1-of (b2 / base-02~e.27 :ARG2 (s / small-molecule :name (n4 / name :op1 "oxaliplatin"~e.25))) :mod (l / line~e.30 :ord (o / ordinal-entity~e.28 :value~e.28 1~e.28))))) :ARG1-of (b3 / base-02~e.35 :ARG2~e.36 (a2 / analyze-01~e.38 :mod (m3 / multivariate~e.37)))) # ::id pmid_2290_9976.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are summarized in Table 4 @ . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 3-1 6-1.2 7-1.2.1 (s / summarize-01~e.3 :ARG1 (t / thing~e.1 :mod (t2 / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG2 (t3 / table~e.6 :mod 4~e.7)) # ::id pmid_2290_9976.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Multivariate analysis identified resection of metastases ( HR 0.43 ; p = 0.0249 ) and wild @-@ type K @-@ Ras gene ( HR 0.49 ; p = 0.0451 ) as independent favorable predictive factors in patients with disseminated CRC who were treated with oxaliplatin @-@ based first @-@ line palliative chemotherapy regimens . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1 4-1.2.1.1.r 4-1.2.1.2.1 5-1.2.1.1 7-1.2.1.2.1 8-1.2.1.2.1.1 10-1.2.1.3 12-1.2.1.3.1 14-1.2 15-1.2.2.2 17-1.2.2.2 19-1.2.2.1.1 21-1.2.2.1.1 23-1.2.2 25-1.2.1.2.1.2 25-1.2.2.3.1 26-1.2.2.3.1.1 28-1.2.2.4 30-1.2.2.4.1 32-1.3.r 33-1.3.1 33-1.3.1.1 33-1.3.1.1.r 34-1.3.3 35-1.3.2 36-1.3 37-1.4.r 38-1.4.1.1 40-1.4.2.1.3 44-1.4.3 45-1.4.3.1.r 46-1.4.3.1.1.1.1.1.1 48-1.4.3.1.1.1 49-1.4.3.1.1.2.1 49-1.4.3.1.1.2.1.1 49-1.4.3.1.1.2.1.1.r 51-1.4.3.1.1.2 52-1.4.3.1.1.3 53-1.4.3.1.1 54-1.4.3.1 (i / identify-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (m / multivariate~e.0)) :ARG1 (a2 / and~e.14 :op1 (r / resection~e.3 :mod~e.4 (m2 / metastasize-101~e.5) :ARG1-of (m3 / mean-01 :ARG2 (r2 / ratio-of~e.4,7 :quant 0.43~e.8 :op1 (h / hazard~e.25))) :ARG1-of (s2 / statistical-test-91~e.10 :ARG2 0.0249~e.12)) :op2 (g / gene~e.23 :name (n / name :op1 "K-Ras"~e.19,21) :mod (w / wild-type~e.15,17) :ARG1-of (m4 / mean-01 :ARG2 (r3 / ratio-of~e.25 :quant 0.49~e.26 :op1 h)) :ARG1-of (s3 / statistical-test-91~e.28 :ARG2 0.0451~e.30))) :ARG2~e.32 (f / factor~e.36 :ARG0-of (d / depend-01~e.33 :polarity~e.33 -~e.33) :ARG0-of (p3 / predict-01~e.35) :mod (f3 / favorable~e.34)) :location~e.37 (p4 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p5 / patient~e.38)) :ARG0-of (h3 / have-03 :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer") :ARG1-of (d3 / disseminate-01~e.40))) :ARG1-of (t / treat-03~e.44 :ARG2~e.45 (r4 / regimen~e.54 :mod (c / chemotherapy~e.53 :ARG1-of (b / base-02~e.48 :ARG2 (s / small-molecule :name (n3 / name :op1 "oxaliplatin"~e.46))) :mod (l / line~e.51 :ord (o / ordinal-entity~e.49 :value~e.49 1~e.49)) :mod (p6 / palliative~e.52)))))) # ::id pmid_2290_9976.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , no statistically significant effects of CEA levels and types of neoplasm could be seen . # ::alignments 0-1 2-1.1.1.1.1 2-1.1.1.1.1.r 4-1.1.1.1.3 5-1.1.1.1 6-1.1.1.1.2.r 7-1.1.1.1.2.1.1.1.1 8-1.1.1.1.2.1 9-1.1.1.1.2 10-1.1.1.1.2.2 11-1.1.1.1.2.2.1.r 12-1.1.1.1.2.2.1 13-1.1 15-1.1.1 (h / have-concession-91~e.0 :ARG1 (p / possible-01~e.13 :ARG1 (s / see-01~e.15 :ARG1 (a / affect-01~e.5 :polarity~e.2 -~e.2 :ARG0~e.6 (a2 / and~e.9 :op1 (l / level~e.8 :quant-of (p2 / protein :name (n / name :op1 "CEA"~e.7))) :op2 (t / type~e.10 :mod~e.11 (n2 / neoplasm~e.12))) :ARG1-of (s2 / significant-02~e.4 :manner (s3 / statistic)))))) # ::id pmid_2290_9976.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The significance of B @-@ Raf gene status , WHO performance status , and Karnofsky performance status could not be assessed due to the small number of patients . # ::alignments 4-1.2.1.1.1.1.1.1 6-1.2.1.1.1.1.1.1 8-1.2.1.1.1.1 9-1.2.1.1.1 11-1.2.1.1.2.2.2.1 11-1.2.1.1.2.2.2.2 11-1.2.1.1.2.2.2.3 12-1.2.1.1.2.1 12-1.2.1.1.3.1 13-1.2.1.1.2 13-1.2.1.1.3 15-1.2.1.1 16-1.2.1.1.3.2.1.1 17-1.2.1.1.2.1 18-1.2.1.1.2 19-1 20-1.1 20-1.1.r 22-1.2 23-1.3 24-1.3 26-1.3.1.1 27-1.3.1 28-1.3.1.2.r 29-1.3.1.2.1.1 (p2 / possible-01~e.19 :polarity~e.20 -~e.20 :ARG1 (a / assess-01~e.22 :ARG1 (s2 / signify-01 :ARG0 (a2 / and~e.15 :op1 (s / status~e.9 :mod (g / gene~e.8 :name (n2 / name :op1 "B-Raf"~e.4,6))) :op2 (s3 / status~e.13,18 :mod (p3 / perform-02~e.12,17) :mod (o / organization :wiki "World_Health_Organization" :name (n3 / name :op1 "World"~e.11 :op2 "Health"~e.11 :op3 "Organization"~e.11))) :op3 (s4 / status~e.13 :mod (p4 / perform-02~e.12) :mod (p / person :name (n4 / name :op1 "Karnofsky"~e.16)))))) :ARG1-of (c / cause-01~e.23,24 :ARG0 (n / number~e.27 :mod (s5 / small~e.26) :quant-of~e.28 (p5 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p6 / patient~e.29)))))) # ::id pmid_2303_9341.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status ( PMID : 23039341 ) # ::alignments 0-1.1 1-1.1.2.r 3-1.1.2.3.1.2.1 4-1.1.2 4-1.1.2.3 4-1.1.2.3.r 5-1.1.2.2.1 6-1.1.1.r 7-1.1.1.1.2.1 8-1.1.1 10-1 11-1.2.r 12-1.2.1.1 12-1.2.1.1.3 12-1.2.1.1.3.r 14-1.2.1.1.2.1 16-1.2 17-1.2.2.1.3 19-1.2.2.1.2.1 21-1.2.1 21-1.2.2 (a / associate-01~e.10 :ARG1 (s / sensitive-03~e.0 :ARG0~e.6 (c / cell~e.8 :mod (m2 / medical-condition :wiki "Melanoma" :name (n3 / name :op1 "melanoma"~e.7))) :ARG1~e.1 (s4 / small-molecule~e.4 :wiki - :name (n / name :op1 "E6201"~e.5) :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (p2 / protein-family :wiki "Mitogen-activated_protein_kinase_kinase" :name (n2 / name :op1 "MEK"~e.3))))) :ARG2~e.11 (a2 / and~e.16 :op1 (s2 / status~e.21 :mod (g / gene~e.12 :wiki "BRAF_(gene)" :name (n4 / name :op1 "BRAF"~e.14) :ARG2-of~e.12 (m / mutate-01~e.12))) :op2 (s3 / status~e.21 :mod (g2 / gene :wiki "PTEN_(gene)" :name (n5 / name :op1 "PTEN"~e.19) :mod (w / wild-type~e.17)))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23039341"))) # ::id pmid_2303_9341.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2303_9341.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The majority of melanoma cell lines were either sensitive ( IC50 < 500 nM , 24 @/@ 31 ) or hypersensitive ( IC50 < 100 nM , 18 @/@ 31 ) to E6201 . # ::alignments 1-1.1.1.2 1-1.2.1.4 3-1.1.1.3.1.2.1.1 4-1.1.1 5-1.1.1.3.1 5-1.2.1 8-1.2 11-1.1.1.4.1.2 11-1.2.1.3.1.2 12-1.1.1.4.1.2.1.1 13-1.1.1.4.1.2.1.2 15-1.1.1.1 17-1.1.1.3.1.1 19-1 20-1.1 20-1.1.1.4.1.1.1.1.r 20-1.1.1.4.1.1.1.r 20-1.2 20-1.2.3 20-1.2.3.r 23-1.1.1.4.1.2 23-1.2.1.3.1.2 24-1.2.1.3.1.2.1.1 25-1.2.1.3.1.2.1.2 27-1.2.1.1 29-1.1.1.3.1.1 31-1.1.2.r 32-1.1.2.1.1 (o / or~e.19 :op1 (s / sensitive-03~e.20 :ARG0 (c / cell-line~e.4 :quant 24~e.15 :quant (m / majority~e.1) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.5 :quant 31~e.17,29 :mod (m2 / medical-condition :name (n / name :op1 "melanoma"~e.3)))) :ARG0-of (h2 / have-03 :ARG1 (c6 / concentrate-02 :mod (i3 / inhibit-01 :degree~e.20 (p / percentage-entity :degree~e.20 50)) :quant (l3 / less-than~e.11,23 :op1 (c2 / concentration-quantity :quant 500~e.12 :unit (n3 / nanomolar~e.13)))))) :ARG1~e.31 (s3 / small-molecule :name (n2 / name :op1 "E6201"~e.32))) :op2 (s2 / sensitive-03~e.8,20 :ARG0 (c4 / cell-line~e.5 :quant 18~e.27 :ARG1-of (i2 / include-91 :ARG2 c3) :ARG0-of (h3 / have-03 :ARG1 (c7 / concentrate-02 :mod i3 :quant (l / less-than~e.11,23 :op1 (c5 / concentration-quantity :quant 100~e.24 :unit n3~e.25)))) :quant (m3 / majority~e.1) :mod m2) :ARG1 s3 :degree~e.20 (h / hyper~e.20))) # ::id pmid_2303_9341.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This sensitivity correlated with wildtype PTEN and mutant BRAF status , whereas mutant RAS and PI3K pathway activation were associated with resistance . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.1.2 6-1.1.2.1.1.1.1 8-1.1.2 9-1.1.2.2.1 9-1.1.2.2.1.2 9-1.1.2.2.1.2.r 11-1.1.2.2.1.1.1 13-1.1.2.1 13-1.1.2.2 15-1 16-1.2.1.1 16-1.2.1.1.2 16-1.2.1.1.2.r 18-1.2.1.1.1.1 20-1.2.1 21-1.2.1.2.1.1 22-1.2.1.2 23-1.2.1.2.2 25-1.2 26-1.2.2.r 27-1.2.2 (c / contrast-01~e.15 :ARG1 (c2 / correlate-01~e.2 :ARG1 (s / sensitive-03~e.1 :mod (t / this~e.0)) :ARG2~e.3 (a / and~e.8 :op1 (s2 / status~e.13 :mod (g / gene :name (n2 / name :op1 "PTEN"~e.6) :mod (w / wild-type~e.4))) :op2 (s3 / status~e.13 :mod (g2 / gene~e.9 :name (n / name :op1 "BRAF"~e.11) :ARG2-of~e.9 (m / mutate-01~e.9))))) :ARG2 (a2 / associate-01~e.25 :ARG1 (a6 / and~e.20 :op1 (g3 / gene~e.16 :name (n3 / name :op1 "RAS"~e.18) :ARG2-of~e.16 (m2 / mutate-01~e.16)) :op2 (p / pathway~e.22 :name (n4 / name :op1 "PI3K"~e.21) :ARG1-of (a7 / activate-01~e.23))) :ARG2~e.26 (r / resist-01~e.27))) # ::id pmid_2303_9341.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although MEK inhibitors predominantly exert a cytostatic effect , E6201 elicited a potent cytocidal effect on most of the sensitive lines studied , as evidenced by Annexin positivity and cell death ELISA . # ::alignments 0-1.3.r 1-1.3.1.1.1.1.1 2-1.3.1 2-1.3.1.1 2-1.3.1.1.r 3-1.3.2.3 4-1.3 6-1.3.2.2 7-1.2 7-1.3.2 9-1.1.1.1 10-1 12-1.2.3.1 14-1.2 15-1.2.2.r 16-1.2.2.2 17-1.2.2.2.r 19-1.2.2.1 19-1.2.2.3.1.1 20-1.2.2 20-1.2.2.3.1 21-1.2.2.3.1.2 23-1.4.r 24-1.4 25-1.4.1.r 26-1.4.1.1.1.1.1 27-1.4.1.1 28-1.4.1 29-1.4.1.2 30-1.4.1.2.1 31-1.4.2.1.1 (e2 / elicit-01~e.10 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "E6201"~e.9)) :ARG1 (a / affect-01~e.7,14 :ARG0 s4 :ARG1~e.15 (l / line~e.20 :ARG0-of (s / sensitive-03~e.19) :quant~e.17 (m / most~e.16) :ARG1-of (i2 / include-91 :ARG2 (l2 / line~e.20 :ARG0-of (s2 / sensitive-03~e.19) :ARG1-of (s3 / study-01~e.21)))) :ARG2 (c / cytocide :mod (p / potent~e.12))) :concession~e.0 (e3 / exert-01~e.4 :ARG0 (m2 / molecular-physical-entity~e.2 :ARG0-of~e.2 (i3 / inhibit-01~e.2 :ARG1 (p5 / protein-family :name (n3 / name :op1 "MEK"~e.1)))) :ARG2 (a2 / affect-01~e.7 :ARG0 m2 :ARG2 (c2 / cytostatic~e.6) :ARG1-of (p4 / predominate-01~e.3))) :ARG1-of~e.23 (e5 / evidence-01~e.24 :ARG0~e.25 (a3 / and~e.28 :op1 (p2 / positive~e.27 :domain (p3 / protein :name (n4 / name :op1 "Annexin"~e.26))) :op2 (c3 / cell~e.29 :ARG1-of (d / die-01~e.30))) :instrument (t / thing :name (n / name :op1 "ELISA"~e.31)))) # ::id pmid_2303_9341.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , E6201 did not induce cell death in the two resistant melanoma cell lines tested . # ::alignments 2-1.1.2.1.1 4-1.1.1 4-1.1.1.r 5-1.1 6-1.1.3 6-1.1.4.1 7-1.1.4 8-1.1.3.r 10-1.1.3.1 11-1.1.3.3 12-1.1.3.2.1.1 13-1.1.3 14-1.1.3 15-1.1.3.4 (c3 / contrast-01 :ARG2 (i / induce-01~e.5 :polarity~e.4 -~e.4 :ARG0 (s / small-molecule :name (n / name :op1 "E6201"~e.2)) :ARG1~e.8 (c / cell-line~e.6,13,14 :quant 2~e.10 :mod (m / medical-condition :name (n2 / name :op1 "melanoma"~e.12)) :ARG0-of (r / resist-01~e.11) :ARG1-of (t2 / test-01~e.15)) :ARG2 (d2 / die-01~e.7 :ARG1 (c2 / cell~e.6)))) # ::id pmid_2303_9341.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees , but a more pronounced anti @-@ tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro @ . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1.1.2.1 4-1.1.2 5-1.1.3.r 5-1.2.1.1.1.2 6-1.1.3.3 7-1.1.3.1 8-1.1.3.2.1.1 9-1.1.3 10-1.1.3 11-1.1.3.4 13-1.1.4.1 14-1.1.4 14-1.1.4.r 14-1.2.1.3.1.r 16-1 18-1.2.1.3.1 19-1.2.1.3 20-1.2.1.2 22-1.2.1.2.1 23-1.2.1 25-1.2 27-1.2.1.1 28-1.2.1.1 30-1.2.1.1.1.3 31-1.2.1.1.1 34-1.2.1.1.1.1 36-1.2.1.1.1.2 37-1.2.1.1.1.2 (c / contrast-01~e.16 :ARG1 (i / inhibit-01~e.1 :ARG0 (s2 / small-molecule :name (n / name :op1 "E6201"~e.0)) :ARG1 (g / grow-01~e.4 :ARG1 (t2 / tumor~e.3 :mod (x / xenograft~e.2))) :location~e.5 (c2 / cell-line~e.9,10 :quant 4~e.7 :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.8)) :mod (a / all~e.6) :ARG1-of (s / study-01~e.11)) :degree~e.14 (d3 / degree~e.14 :ARG1-of (v / vary-01~e.13))) :ARG2 (o / observe-01~e.25 :ARG1 (a2 / affect-01~e.23 :ARG1 (c3 / cell-line~e.27,28 :ARG0-of (d2 / demonstrate-01~e.31 :ARG1 (r / respond-01~e.34 :ARG0 c3 :ARG2 (c4 / cytocide)) :manner (i2 / in-vitro~e.5,36,37) :time (p2 / previous~e.30))) :ARG2 (c5 / counter-01~e.20 :ARG1 (t3 / tumor~e.22)) :ARG1-of (p / pronounce-01~e.19 :degree~e.14 (m / more~e.18))))) # ::id pmid_2303_9341.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested , as defined by a mean combination index < 1 . # ::alignments 1-1.1.2 2-1.1.2 4-1.1 5-1.1.1.1 5-1.1.1.2 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.1.1.1 10-1 11-1.2 12-1.1.2 12-1.3.r 13-1.3.4 14-1.3.1 15-1.3.2.1.1 16-1.3 17-1.3 18-1.3.3 20-1.1.3.r 21-1.1.3 22-1.1.3.1.r 24-1.1.3.1.1.1 25-1.1.3.1.1 26-1.1.3.1 27-1.1.3.1.2 28-1.1.3.1.2.1 (s / show-01~e.10 :ARG0 (c / combine-01~e.4 :ARG1 (a2 / and~e.8 :op1 (s4 / study-01~e.5 :ARG1~e.6 (s2 / small-molecule :name (n / name :op1 "E6201"~e.7))) :op2 (s5 / study-01~e.5 :ARG1 (s6 / small-molecule :name (n2 / name :op1 "LY294002"~e.9)))) :manner (i3 / in-vitro~e.1,2,12) :ARG1-of~e.20 (d2 / define-01~e.21 :ARG0~e.22 (i / index~e.26 :mod (c3 / combine-01~e.25 :mod (m / mean~e.24)) :value (l / less-than~e.27 :op1 1~e.28)))) :ARG1 (s3 / synergism~e.11) :location~e.12 (c2 / cell-line~e.16,17 :quant 6~e.14 :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma"~e.15)) :ARG1-of (t3 / test-01~e.18) :mod (a / all~e.13))) # ::id pmid_2303_9341.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG1-of~e.1 (r / result-01~e.1)) # ::id pmid_2303_9341.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity to E6201 in a melanoma cell line panel # ::alignments 1-1 2-1.2.r 3-1.2.1.1 4-1.1.r 6-1.1.1.1.1.1 7-1.1.1 8-1.1.1 9-1.1 (s / sensitive-03~e.1 :ARG0~e.4 (p / panel~e.9 :consist-of (c / cell-line~e.7,8 :mod (m / medical-condition :name (n2 / name :op1 "melanoma"~e.6)))) :ARG1~e.2 (s2 / small-molecule :name (n / name :op1 "E6201"~e.3))) # ::id pmid_2303_9341.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sensitivity to E6201 was assessed in a panel of 31 cell lines for which the mutation status of common melanoma genes was known ( Table 1 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 4-1 5-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.1 10-1.2.1 11-1.2.1 15-1.2.1.2.1.1 16-1.2.1.2.1 17-1.2.1.2.1.1.1.r 18-1.2.1.2.1.1.1.2 19-1.2.1.2.1.1.1.1.1.1 20-1.2.1.2.1.1.1 22-1.2.1.2 24-1.3.1 26-1.3.1.1 (a / assess-01~e.4 :ARG1 (s / sensitive-03~e.0 :ARG1~e.1 (s3 / small-molecule :name (n / name :op1 "E6201"~e.2))) :location~e.5 (p / panel~e.7 :consist-of~e.8 (c / cell-line~e.10,11 :quant 31~e.9 :mod (k / know-01~e.22 :ARG1 (s2 / status~e.16 :mod (m / mutate-01~e.15 :ARG1~e.17 (g / gene~e.20 :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.19)) :mod (c2 / common~e.18))))))) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table~e.24 :mod 1~e.26))) # ::id pmid_2303_9341.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These lines were chosen to represent different mutational profiles from a larger panel of more than one hundred melanoma cell lines . # ::alignments 0-1.1.1 1-1.1 3-1 5-1.3 6-1.3.2.2 7-1.3.2.1 8-1.3.2 9-1.2.r 11-1.2.1 11-1.2.1.1 11-1.2.1.1.r 12-1.2 14-1.2.1.1 14-1.2.2.2 15-1.2.2.2 16-1.2.2.2.1 17-1.2.2.2.1 18-1.2.2.1.1.1 19-1.2.2 20-1.2.2 (c / choose-01~e.3 :ARG1 (l / line~e.1 :mod (t / this~e.0)) :ARG2~e.9 (p2 / panel~e.12 :mod (l2 / large~e.11 :degree~e.11 (m3 / more~e.11,14)) :consist-of (c2 / cell-line~e.19,20 :mod (m2 / medical-condition :name (n / name :op1 "melanoma"~e.18)) :quant (m4 / more-than~e.14,15 :op1 100~e.16,17))) :ARG4 (r / represent-01~e.5 :ARG0 l :ARG1 (p / profile~e.8 :mod (m / mutate-01~e.7) :ARG1-of (d / differ-02~e.6)))) # ::id pmid_2303_9341.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blots in Additional file 1 : Figure S1 confirm that E6201 efficiently inhibits MEK1 @/@ 2 activity by virtue of its ability to abrogate phosphorylation of ERK1 @/@ 2 in our entire panel of melanoma cell lines . # ::alignments 0-1.1 1-1.1 4-1.1.1.1.2.2 5-1.1.1.1.2 6-1.1.1.1.2.1 8-1.1.1.1 9-1.1.1.1.1 11-1 12-1.2.r 13-1.2.1.1.1 14-1.2.3 15-1.2 16-1.2.2.1.1.1 18-1.2.2.1.1.1 19-1.2.2 23-1.2.4.1.1 23-1.2.4.1.1.r 24-1.2.4.1 26-1.2.4.1.2 27-1.2.4.1.2.2 28-1.2.4.1.2.2.1.r 29-1.2.4.1.2.2.1.1.1 31-1.2.4.1.2.2.1.1.1 32-1.2.4.1.2.3.r 33-1.2.4.1.2.3.3 33-1.2.4.1.2.3.3.r 34-1.2.4.1.2.3.2 35-1.2.4.1.2.3 36-1.2.4.1.2.3.1.r 37-1.2.4.1.2.3.1.1.1.1 38-1.2.4.1.2.3.1 39-1.2.4.1.2.3.1 (c / confirm-01~e.11 :ARG0 (i2 / immunoblot-01~e.0,1 :ARG1-of (d / describe-01 :ARG0 (f / figure~e.8 :mod "S1"~e.9 :location (f2 / file~e.5 :mod 1~e.6 :mod (a / additional~e.4))))) :ARG1~e.12 (i / inhibit-01~e.15 :ARG0 (s / small-molecule :name (n3 / name :op1 "E6201"~e.13)) :ARG1 (a2 / activity-06~e.19 :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEK1/2"~e.16,18))) :ARG2-of (e / efficient-01~e.14 :ARG1 s) :ARG1-of (c4 / cause-01 :ARG0 (c3 / capable-01~e.24 :ARG1~e.23 s~e.23 :ARG2 (a4 / abrogate-01~e.26 :ARG0 s :ARG1 (p2 / phosphorylate-01~e.27 :ARG1~e.28 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"~e.29,31))) :location~e.32 (p3 / panel~e.35 :consist-of~e.36 (c2 / cell-line~e.38,39 :mod (m / medical-condition :name (n6 / name :op1 "melanoma"~e.37))) :mod (e4 / entire~e.34) :poss~e.33 (w2 / we~e.33))))))) # ::id pmid_2303_9341.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The majority ( 24 @/@ 31 ) of the melanoma cell lines were sensitive to E6201 ( IC50 < 500 nM ) ( Figure 1 ) . # ::alignments 1-1.1.2.2 3-1.1.1 5-1.1.2.1.1 9-1.1.2.1.2.1.1 10-1.1 10-1.1.2.1 11-1.1 13-1 14-1.2.r 15-1.2.1.1 18-1.1.3.2 19-1.1.3.2.1.1 20-1.1.3.2.1.2 23-1.3.1 25-1.3.1.1 (s / sensitive-03~e.13 :ARG0 (c / cell-line~e.10,11 :quant 24~e.3 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.10 :quant 31~e.5 :mod (m2 / medical-condition :name (n / name :op1 "melanoma"~e.9))) :ARG3 (m / majority~e.1)) :mod (c4 / concentrate-02 :mod (i2 / inhibit-01 :degree (p / percentage-entity :value 50)) :quant (l2 / less-than~e.18 :op1 (c3 / concentration-quantity :quant 500~e.19 :unit (n3 / nanomolar~e.20))))) :ARG1~e.14 (s2 / small-molecule :name (n2 / name :op1 "E6201"~e.15)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.23 :mod 1~e.25))) # ::id pmid_2303_9341.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MAPK activation due to mutations in BRAF and NRAS was not significantly associated with increased sensitivity to E6201 . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2 3-1.1.2 4-1.1.2.1 7-1.1.2.1.1.1.1.1 9-1.1.2.1.1 11-1.1.2.1.1.2.1.1 14-1.3.1 14-1.3.1.r 15-1.3 16-1 17-1.2.r 18-1.2.2 19-1.2 20-1.2.1.r 21-1.2.1.1.1 (a / associate-01~e.16 :ARG1 (a2 / activate-01~e.1 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK"~e.0)) :ARG1-of (c / cause-01~e.2,3 :ARG0 (m / mutate-01~e.4 :ARG1 (a3 / and~e.9 :op1 (g / gene :name (n3 / name :op1 "BRAF"~e.7)) :op2 (g2 / gene :name (n4 / name :op1 "NRAS"~e.11)))))) :ARG2~e.17 (s2 / sensitive-03~e.19 :ARG1~e.20 (s3 / small-molecule :name (n5 / name :op1 "E6201"~e.21)) :ARG1-of (i / increase-01~e.18)) :ARG1-of (s / significant-02~e.15 :polarity~e.14 -~e.14)) # ::id pmid_2303_9341.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the 26 cell lines carrying mutations in BRAF , NRAS , or HRAS , sensitivity to E6201 was statistically associated with wildtype PTEN status ( p = 0.02 ) . # ::alignments 2-1.4.1 3-1.4 4-1.4 5-1.4.2 6-1.4.2.1 9-1.4.2.1.1.1.1.1 13-1.4.2.1.1.2.1.1 16-1.4.2.1.1 18-1.4.2.1.1.3.1.1 21-1.1 22-1.1.1.r 23-1.1.1.1.1 25-1.5 26-1 27-1.2.r 28-1.2.1.2 30-1.2.1.1.1 32-1.2 34-1.5 36-1.5.1 (a / associate-01~e.26 :ARG1 (s / sensitive-03~e.21 :ARG1~e.22 (s4 / small-molecule :name (n / name :op1 "E6201"~e.23))) :ARG2~e.27 (s3 / status~e.32 :mod (g / gene :name (n2 / name :op1 "PTEN"~e.30) :mod (w / wild-type~e.28))) :mod (s2 / statistic) :location (c / cell-line~e.3,4 :quant 26~e.2 :ARG0-of (c2 / carry-01~e.5 :ARG1 (m / mutate-01~e.6 :ARG1 (o / or~e.16 :op1 (g2 / gene :name (n3 / name :op1 "BRAF"~e.9)) :op2 (g3 / gene :name (n4 / name :op1 "NRAS"~e.13)) :op3 (g4 / gene :name (n5 / name :op1 "HRAS"~e.18)))))) :ARG1-of (s5 / statistical-test-91~e.25,34 :ARG2 0.02~e.36)) # ::id pmid_2303_9341.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Specifically , of the 18 cell lines with wildtype PTEN , 17 were sensitive whereas in the 8 cell lines with mutant PTEN , only 4 were sensitive . # ::alignments 0-1.3 4-1.1.1.2.1.1 5-1.1.1.2.1 6-1.1.1.2.1 8-1.1.1.2.1.2.1.2 10-1.1.1.2.1.2.1.1.1 13-1.1.1.1 15-1.1 15-1.2 16-1 17-1.2.1.r 19-1.2.1.2.1.1 20-1.1.1 20-1.2.1 20-1.2.1.2.1 21-1.2.1.2.1 23-1.2.1.2.1.2.1 23-1.2.1.2.1.2.1.2 23-1.2.1.2.1.2.1.2.r 25-1.2.1.2.1.2.1.1.1 28-1.2.1.3 29-1.2.1.1 31-1.1 (c / contrast-01~e.16 :ARG1 (s / sensitive-03~e.15,31 :ARG0 (c2 / cell-line~e.20 :quant 17~e.13 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.5,6 :quant 18~e.4 :ARG0-of (h / have-03 :ARG1 (g / gene :name (n / name :op1 "PTEN"~e.10) :mod (w / wild-type~e.8))))))) :ARG2 (s2 / sensitive-03~e.15 :ARG0~e.17 (c4 / cell-line~e.20 :quant 4~e.29 :ARG1-of (i2 / include-91 :ARG2 (c5 / cell-line~e.20,21 :quant 8~e.19 :ARG0-of (h2 / have-03 :ARG1 (g2 / gene~e.23 :name (n2 / name :op1 "PTEN"~e.25) :ARG2-of~e.23 (m / mutate-01~e.23))))) :mod (o / only~e.28))) :ARG1-of (s3 / specific-02~e.0)) # ::id pmid_2303_9341.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , even if PTEN status alone is examined , E6201 sensitivity is associated , albeit non @-@ significantly , with wildtype PTEN status ; 23 @/@ 31 cell lines are wildtype for PTEN and of these 20 are sensitive ( whereas only 4 @/@ 8 cell lines with mutant PTEN are sensitive ) ( p = 0.053 ) . # ::alignments 0-1.1 2-1.1.1.4 3-1.1.1.4 5-1.1.1.4.1.1.1.1.1 7-1.1.1.4.1.1 8-1.1.1.4.1.1.2 10-1.1.1.4.1 12-1.1.1.1.1.1.1 13-1.1.1.1 15-1.1.1 18-1.1.1.3.1 18-1.1.1.3.1.r 20-1.1.1.3 22-1.1.1.2.r 23-1.1.1.2.1.2 25-1.1.1.2.1.1.1 27-1.1.1.2 29-1.2.1.1.1 31-1.2.1.1.3.1.1 32-1.2.1.1 32-1.2.1.1.3.1 33-1.2.1.1.3.1 35-1.2.1.1.2.2 38-1.2.1.1.2.1.1 40-1.2.1 43-1.2.1.2.1.1 45-1.2.1.2 45-1.2.2 47-1.2 48-1.2.2.1.3 49-1.2.2.1.1 51-1.2.2.1.2.1.1 52-1.2.1.2.1 52-1.2.2.1 52-1.2.2.1.2.1 53-1.2.2.1.2.1 55-1.2.2.1.2.1.2.1 57-1.2.1.1.2.1.1 57-1.2.2.1.2.1.2.1.1.1.1 60-1.2.1.2 63-1.2.3 65-1.2.3.1 (m / multi-sentence :snt1 (a / and~e.0 :op2 (a2 / associate-01~e.15 :ARG1 (s / sensitive-03~e.13 :ARG1 (s7 / small-molecule :name (n / name :op1 "E6201"~e.12))) :ARG2~e.22 (s2 / status~e.27 :mod (g4 / gene :name (n2 / name :op1 "PTEN"~e.25) :mod (w / wild-type~e.23))) :ARG1-of (s3 / significant-02~e.20 :polarity~e.18 -~e.18 :concession-of a2) :concession (e2 / even-if~e.2,3 :op1 (e3 / examine-01~e.10 :ARG1 (s4 / status~e.7 :mod (g3 / gene :name (n3 / name :op1 "PTEN"~e.5)) :mod (a3 / alone~e.8)))))) :snt2 (c / contrast-01~e.47 :ARG1 (a4 / and~e.40 :op1 (c2 / cell-line~e.32 :quant 23~e.29 :mod (g2 / gene :name (n4 / name :op1 "PTEN"~e.38,57) :mod (w2 / wild-type~e.35)) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.32,33 :quant 31~e.31))) :op2 (s5 / sensitive-03~e.45,60 :ARG0 (c4 / cell-line~e.52 :quant 20~e.43 :ARG1-of (i2 / include-91 :ARG2 c2)))) :ARG2 (s6 / sensitive-03~e.45 :ARG0 (c5 / cell-line~e.52 :quant 4~e.49 :ARG1-of (i3 / include-91 :ARG2 (c6 / cell-line~e.52,53 :quant 8~e.51 :ARG0-of (h2 / have-03 :ARG1 (m2 / mutate-01~e.55 :ARG2 (g / gene :name (n5 / name :op1 "PTEN"~e.57)))))) :mod (o / only~e.48))) :ARG1-of (s8 / statistical-test-91~e.63 :ARG2 0.053~e.65))) # ::id pmid_2303_9341.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , 18 of the 24 sensitive cell lines also demonstrated hypersensitivity to E6201 , with an IC50 < 100 nM . # ::alignments 0-1.4 2-1.1.1 5-1.1.2.1.1 6-1.1.2.1.2 7-1.1 7-1.1.2.1 8-1.1 9-1.3 10-1 11-1.1.3.1.1.1.r 11-1.2 11-1.2.3 11-1.2.3.r 12-1.2.2.r 13-1.2.2.1.1 18-1.2.1 19-1.2.1 20-1.2.1 (d / demonstrate-01~e.10 :ARG0 (c / cell-line~e.7,8 :quant 18~e.2 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.7 :quant 24~e.5 :ARG0-of (s2 / sensitive-03~e.6))) :ARG0-of (h2 / have-03 :ARG1 (c4 / concentrate-02 :mod (i3 / inhibit-01 :degree~e.11 (p / percentage-entity :value 50)) :mod (l2 / less-than :op1 (c3 / concentration-quantity :quant 100 :unit (n2 / nanomolar)))))) :ARG1 (s3 / sensitive-03~e.11 :ARG0 c~e.18,19,20 :ARG1~e.12 (s4 / small-molecule :name (n / name :op1 "E6201"~e.13)) :degree~e.11 (h / hyper~e.11)) :mod (a / also~e.9) :ARG0-of (i2 / interest-01~e.0)) # ::id pmid_2303_9341.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Using this criterion , BRAF mutation status correlated with E6201 hypersensitivity ( p < 0.03 ) , with 15 out of the 18 hypersensitive cell lines possessing a BRAF mutation . # ::alignments 0-1.3 1-1.3.1.1 2-1.3.1 5-1.1.1.1.1 7-1.1.1 7-1.1.1.2 7-1.1.1.2.r 8-1.1 9-1 10-1.2.r 10-1.4.r 11-1.2.1.1.1 12-1.2 12-1.2.2 12-1.2.2.r 14-1.5 15-1.5.1 16-1.5.1.1 19-1.4.r 20-1.4.1 24-1.4.3.1.1 25-1.4.3.1.2 25-1.4.3.1.2.1 25-1.4.3.1.2.1.r 26-1.4.3.1 27-1.4 28-1.4.2 31-1.4.2.1 32-1.4.2.1 33-1.4.2.1 (c / correlate-01~e.9 :ARG1 (s / status~e.8 :mod (g / gene~e.7 :name (n / name :op1 "BRAF"~e.5) :ARG1-of~e.7 (m / mutate-01~e.7))) :ARG2~e.10 (s2 / sensitive-03~e.12 :ARG1 (s5 / small-molecule :name (n2 / name :op1 "E6201"~e.11)) :degree~e.12 (h / hyper~e.12)) :condition (u / use-01~e.0 :ARG1 (c2 / criterion~e.2 :mod (t2 / this~e.1))) :prep-with~e.10,19 (c3 / cell-line~e.27 :quant 15~e.20 :ARG0-of (p2 / possess-01~e.28 :ARG1 g~e.31,32,33) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line~e.26 :quant 18~e.24 :ARG0-of (s4 / sensitive-03~e.25 :degree~e.25 (h3 / hyper~e.25))))) :ARG1-of (s3 / statistical-test-91~e.14 :ARG2 (l / less-than~e.15 :op1 0.03~e.16))) # ::id pmid_2303_9341.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , of the 11 cell lines with wildtype BRAF , only 3 were hypersensitive . # ::alignments 1-1 3-1.1.r 5-1.1.3.1.1 6-1.1 6-1.1.3.1 7-1.1.3.1 9-1.1.3.1.2.1.2 11-1.1.3.1.2.1.1.1 14-1.1.4 15-1.1.1 17-1.1.2 17-1.1.2.1 17-1.1.2.1.r (c / contrast-01~e.1 :ARG2~e.3 (c2 / cell-line~e.6 :quant 3~e.15 :ARG0-of (s / sensitive-03~e.17 :degree~e.17 (h / hyper~e.17)) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.6,7 :quant 11~e.5 :ARG0-of (h2 / have-03 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.11) :mod (w / wild-type~e.9))))) :mod (o / only~e.14))) # ::id pmid_2303_9341.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In those cell lines carrying mutations in BRAF ( 21 cell lines ) , sensitivity to E6201 was not statistically associated with wildtype PTEN status . # ::alignments 1-1.5.3 2-1.5 3-1.5 4-1.5.2 5-1.5.2.1 8-1.5.2.1.1.1.1 11-1.5.1 12-1.5 13-1.5 16-1.2 17-1.2.1.r 18-1.2.1.1.1 20-1.1 20-1.1.r 22-1 23-1.3.r 24-1.3.1.2 26-1.3.1.1.1 28-1.3 (a / associate-01~e.22 :polarity~e.20 -~e.20 :ARG1 (s / sensitive-03~e.16 :ARG1~e.17 (s4 / small-molecule :name (n / name :op1 "E6201"~e.18))) :ARG2~e.23 (s2 / status~e.28 :mod (g2 / gene :name (n2 / name :op1 "PTEN"~e.26) :mod (w / wild-type~e.24))) :mod (s3 / statistic) :location (c / cell-line~e.2,3,12,13 :quant 21~e.11 :ARG0-of (c2 / carry-01~e.4 :ARG1 (m / mutate-01~e.5 :ARG1 (g / gene :name (n3 / name :op1 "BRAF"~e.8)))) :mod (t / that~e.1))) # ::id pmid_2303_9341.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NRAS @/@ HRAS mutation status correlated with E6201 resistance , where none of the 5 NRAS @ / @ HRAS mutant cell lines were hypersensitive to E6201 and 18 of the 26 NRAS @/@ HRAS wildtype cell lines were hypersensitive ( p < 0.01 ) . # ::alignments 1-1.1.1.1.1.1.1 2-1.1.1.1 3-1.1.1.1.2.1.1 5-1.1.1 6-1.1 7-1 8-1.2.r 9-1.2.1.1.1 10-1.2 14-1.3.r 16-1.3.1.2.1.1 18-1.3.1.2.1.2.1.1 20-1.3.1.2.1.2.1 22-1.3.1.2.1.2.1.2 24-1.3.1.2.1.2 25-1.3.1.2.1 26-1.3.1 26-1.3.2 28-1.3.1.3 28-1.3.1.3.2 28-1.3.1.3.2.r 29-1.3.1.3.1.r 30-1.3.1.3.1 31-1.3 32-1.3.2.1 35-1.3.2.2.1.1 37-1.3.2.2.1.2.1 38-1.3.2.2.1.2 39-1.3.2.2.1.2.2 41-1.3.2.2.1.2.3 42-1.3.2.2.1 43-1.3.2.2.1 45-1.3.2.3 47-1.4 48-1.4.1 49-1.4.1.1 (c / correlate-01~e.7 :ARG1 (s / status~e.6 :mod (m / mutate-01~e.5 :ARG1 (s2 / slash~e.2 :op1 (g5 / gene :name (n2 / name :op1 "NRAS"~e.1)) :op2 (g6 / gene :name (n3 / name :op1 "HRAS"~e.3))))) :ARG2~e.8 (r / resist-01~e.10 :ARG1 (s8 / small-molecule :name (n / name :op1 "E6201"~e.9))) :example~e.14 (a / and~e.31 :op1 (c2 / cell-line~e.26 :quant 0 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.25 :quant 5~e.16 :mod (m2 / mutate-01~e.24 :ARG2 (s3 / slash~e.20 :op1 g5~e.18 :op2 g6~e.22)))) :ARG0-of (s4 / sensitive-03~e.28 :ARG1~e.29 s8~e.30 :degree~e.28 (h / hyper~e.28))) :op2 (c4 / cell-line~e.26 :quant 18~e.32 :ARG1-of (i2 / include-91 :ARG2 (c5 / cell-line~e.42,43 :quant 26~e.35 :mod (s5 / slash~e.38 :op1 g5~e.37 :op2 g6~e.39 :mod (w / wild-type~e.41)))) :ARG0-of s4~e.45)) :ARG1-of (s6 / statistical-test-91~e.47 :ARG2 (l / less-than~e.48 :op1 0.01~e.49))) # ::id pmid_2303_9341.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neither CDKN2A , CDK4 or TP53 mutational status in our panel of melanoma cell lines , irrespective of their BRAF and RAS mutational status , was associated with E6201 sensitivity . # ::alignments 0-1.1.2 2-1.1.1.1.1.1.1 6-1.1.1.1.2.1.1 8-1.1.1.1 10-1.1.1.1.3.1.1 12-1.1.1 13-1.1 14-1.1.3.r 15-1.1.3.1 15-1.1.3.1.r 16-1.1.3 17-1.1.3.2.r 18-1.1.3.2.1.1.1 19-1.1.3.2 20-1.1.3.2 22-1.3 24-1.3.1.2 24-1.3.1.2.r 26-1.3.1.1.1.1.1.1 28-1.3.1.1.1 30-1.3.1.1.1.2.1.1 32-1.3.1.1 33-1.3.1 36-1 37-1.2.r 38-1.2.1.1.1 39-1.2 (a / associate-01~e.36 :ARG1 (s / status~e.13 :mod (m / mutate-01~e.12 :ARG1 (o / or~e.8 :op1 (g / gene :name (n3 / name :op1 "CDKN2A"~e.2)) :op2 (g2 / gene :name (n4 / name :op1 "CDK4"~e.6)) :op3 (g3 / gene :name (n5 / name :op1 "TP53"~e.10)))) :mod (n6 / neither~e.0) :location~e.14 (p / panel~e.16 :poss~e.15 (w / we~e.15) :consist-of~e.17 (c / cell-line~e.19,20 :mod (m3 / medical-condition :name (n7 / name :op1 "melanoma"~e.18))))) :ARG2~e.37 (s2 / sensitive-03~e.39 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "E6201"~e.38))) :ARG1-of (r / regardless-91~e.22 :ARG2 (s3 / status~e.33 :mod (m2 / mutate-01~e.32 :ARG1 (a2 / and~e.28 :op1 (g4 / gene :name (n8 / name :op1 "BRAF"~e.26)) :op2 (g5 / gene :name (n9 / name :op1 "RAS"~e.30)))) :poss~e.24 c~e.24))) # ::id pmid_2303_9341.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 sensitivity and downstream pathway activation # ::alignments 1-1.1.1.1 2-1.1 2-1.1.2 2-1.1.2.r 3-1 4-1.2.1.1 5-1.2.1 6-1.2 (a / and~e.3 :op1 (s2 / small-molecule~e.2 :name (n / name :op1 "E6201"~e.1) :ARG1-of~e.2 (s / sensitive-03~e.2)) :op2 (a2 / activate-01~e.6 :ARG1 (p / pathway~e.5 :mod (d / downstream~e.4)))) # ::id pmid_2303_9341.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether E6201 responsiveness correlated with direct Akt or ERK1 @/@ 2 activation , the phosphorylation status of Akt and ERK1 @/@ 2 proteins was evaluated following serum starvation ( Figure 2 ) . # ::alignments 1-1.3 2-1.3.1.1 2-1.3.1.1.r 3-1.3.1.2.1.1.1 5-1.3.1 6-1.3.1.3.r 7-1.3.1.3.2 8-1.1.1.1.1.1.1 10-1.1.2.1.1.1.1 12-1.1.2.1.1.1.1 12-1.4.1.1 13-1.3.1.3 16-1.1.1.1 16-1.1.2.1 17-1.1.1 17-1.1.2 19-1.1.1.1.1.1.1 20-1.1 21-1.1.2.1.1.1.1 23-1.1.2.1.1.1.1 23-1.4.1.1 26-1 27-1.2 28-1.2.1.1 29-1.2.1 31-1.4.1 33-1.1.2.1.1.1.1 33-1.4.1.1 (e / evaluate-01~e.26 :ARG1 (a / and~e.20 :op1 (s / status~e.17 :mod (p / phosphorylate-01~e.16 :ARG1 (e3 / enzyme :name (n / name :op1 "Akt"~e.8,19)))) :op2 (s2 / status~e.17 :mod (p3 / phosphorylate-01~e.16 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.10,12,21,23,33))))) :ARG1-of (f / follow-01~e.27 :ARG2 (s3 / starve-01~e.29 :ARG2 (s4 / serum~e.28))) :purpose (d / determine-01~e.1 :ARG1 (c / correlate-01~e.5 :mode~e.2 interrogative~e.2 :ARG1 (r / respond-01 :ARG1 (s5 / small-molecule :name (n3 / name :op1 "E6201"~e.3))) :ARG2~e.6 (a2 / activate-01~e.13 :ARG1 (a3 / and :op1 e3 :op2 e2) :ARG1-of (d2 / direct-02~e.7)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.31 :mod 2~e.12,23,33))) # ::id pmid_2303_9341.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylated ( p ) Akt ( Ser473 ) was detectable in 7 @/@ 7 cell lines with mutant PTEN . # ::alignments 0-1.1.3.2 2-1.1.3.2 4-1.1.3.1.1 9-1 10-1.2.r 11-1.2.1 13-1.2.1 13-1.2.2.1.1 14-1.2 14-1.2.2.1 15-1.2 17-1.2.2.1.2.1 18-1.2.2.1.2.1.1.1.1 (d / detect-01~e.9 :ARG1 (a / amino-acid :mod 473 :name (n2 / name :op1 "serine") :part-of (e / enzyme :name (n4 / name :op1 "Akt"~e.4) :ARG3-of (p / phosphorylate-01~e.0,2))) :location~e.10 (c / cell-line~e.14,15 :quant 7~e.11,13 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.14 :quant 7~e.13 :ARG0-of (h / have-03 :ARG1 (m2 / mutate-01~e.17 :ARG2 (p3 / protein :name (n3 / name :op1 "PTEN"~e.18))))))) :ARG1-of (p2 / possible-01)) # ::id pmid_2303_9341.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , pAkt was present in 5 @/@ 23 cell lines with wildtype PTEN although the mechanism responsible for phosphorylation of Akt in these cell lines is unknown . # ::alignments 0-1 1-1 3-1.1.2.2.1.1 5-1.1.1 6-1.1.1.2.r 7-1.1.1.2.1 9-1.1.1.2.2.1.1 10-1.1.1.2 10-1.1.1.2.2.1 11-1.1.1.2.2.1 13-1.1.1.2.2.1.2.1.2 15-1.1.1.2.2.1.2.1.1.1 17-1.1 19-1.1.2.2 20-1.1.2.2.1 22-1.1.1.1.2 22-1.1.2.2.1.1 23-1.1.1.1.r 24-1.1.1.1.1.1 27-1.1.1.2.2.1 28-1.1.1.2.2.1 30-1.1.2 30-1.1.2.1 30-1.1.2.1.r (a / and~e.0,1 :op2 (h2 / have-concession-91~e.17 :ARG1 (p / present-02~e.5 :ARG1~e.23 (e / enzyme :name (n / name :op1 "Akt"~e.24) :ARG3-of (p3 / phosphorylate-01~e.22)) :ARG2~e.6 (c2 / cell-line~e.10 :quant 5~e.7 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.10,11,27,28 :quant 23~e.9 :ARG0-of (h / have-03 :ARG1 (g / gene :name (n2 / name :op1 "PTEN"~e.15) :mod (w / wild-type~e.13))))))) :ARG2 (k / know-01~e.30 :polarity~e.30 -~e.30 :ARG1 (m / mechanism~e.19 :ARG0-of (r / responsible-01~e.20 :ARG1 (p5 / phosphorylate-01~e.3,22 :ARG1 (p4 / protein) :location c3)))))) # ::id pmid_2303_9341.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylated ( p ) ERK1 @/@ 2 was detected in all cell lines with mutant BRAF ( 20 @/@ 20 ) . # ::alignments 0-1.1.2 2-1.1.2 4-1.1.1.1 6-1.1.1.1 8-1 9-1.2.r 10-1.2.3 11-1.2 12-1.2 12-1.2.2.1 14-1.2.2.1.2.1 16-1.2.2.1.2.1.1.1.1 19-1.2.1 19-1.2.2.1.1 21-1.2.1 (d / detect-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.4,6) :ARG3-of (p / phosphorylate-01~e.0,2)) :location~e.9 (c / cell-line~e.11,12 :quant 20~e.19,21 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.12 :quant 20~e.19 :ARG0-of (h / have-03 :ARG1 (m / mutate-01~e.14 :ARG2 (g / gene :name (n2 / name :op1 "BRAF"~e.16)))))) :mod (a / all~e.10))) # ::id pmid_2303_9341.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with previous reports [ @ 13 , 26 @ ] , elevated pERK1 @/@ 2 was detected in 3 @/@ 5 cell lines with mutant NRAS or HRAS @ . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1 3-1.3.1 6-1.3.2.1.1.1.1 10-1.3.2.1.1.1.2 14-1.1.3 17-1.1.1.1 19-1 20-1.2.r 21-1.2.1 23-1.2.2.1.1 24-1.2 24-1.2.2.1 25-1.2.2.1 27-1.2.2.1.2.1 29-1.2.2.1.2.1.1.1.1.1 31-1.2.2.1.2.1.1 33-1.2.2.1.2.1.1.2.1.1 (d / detect-01~e.19 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.17) :ARG3-of (p / phosphorylate-01) :ARG1-of (e2 / elevate-01~e.14)) :location~e.20 (c / cell-line~e.24 :quant 3~e.21 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.24,25 :quant 5~e.23 :ARG0-of (h / have-03 :ARG1 (m / mutate-01~e.27 :ARG2 (o / or~e.31 :op1 (g2 / gene :name (n2 / name :op1 "NRAS"~e.29)) :op2 (g / gene :name (n3 / name :op1 "HRAS"~e.33)))))))) :ARG1-of (c3 / consistent-01~e.0 :ARG2~e.1 (r / report-01~e.3 :time (p2 / previous~e.2)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 (a / and :op1 13~e.6 :op2 26~e.10)))))) # ::id pmid_2303_9341.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All five cell lines with wildtype BRAF and NRAS also had elevated ERK1 @/@ 2 phosphorylation , as reported previously [ @ 26 , 27 @ ] , although the mechanism responsible for ERK1 @/@ 2 activation in these cell lines is unknown . # ::alignments 0-1.1.4 1-1.1.1 2-1.1 3-1.1 5-1.1.2.1.3 7-1.1.2.1.1.1.1 9-1.1.2.1 11-1.1.2.1.2.1.1 13-1.1.2.2 14-1.1.2 14-1.1.3 15-1.1.3.1.2 16-1.1.3.1.1.1.1 18-1.1.3.1.1.1.1 19-1.1.3.1 21-1.1.5.1.r 22-1.1.5 23-1.1.5.1 26-1.1.5.2.1.1.1.1 30-1.1.5.2.1.1.1.2 34-1 36-1.2.2 37-1.2.2.1 38-1.2.2.1.1.r 39-1.2.2.1.1.1 40-1.2.2.1.1.1 41-1.2.2.1.1.1 42-1.2.2.1.1 43-1.2.2.2.r 44-1.2.2.2.1 45-1.2.2.2 46-1.2.2.2 48-1.2 48-1.2.1 48-1.2.1.r (h3 / have-concession-91~e.34 :ARG1 (c2 / cell-line~e.2,3 :quant 5~e.1 :ARG0-of (h / have-03~e.14 :ARG1 (a / and~e.9 :op1 (g / gene :name (n / name :op1 "BRAF"~e.7)) :op2 (g2 / gene :name (n2 / name :op1 "NRAS"~e.11)) :mod (w / wild-type~e.5)) :mod (a3 / also~e.13)) :ARG0-of (h2 / have-03~e.14 :ARG1 (p3 / phosphorylate-01~e.19 :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2"~e.16,18)) :ARG1-of (e4 / elevate-01~e.15))) :mod (a2 / all~e.0) :ARG1-of (r / report-01~e.22 :time~e.21 (p2 / previous~e.23) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 26~e.26 :op2 27~e.30)))))) :ARG2 (k / know-01~e.48 :polarity~e.48 -~e.48 :ARG1 (m / mechanism~e.36 :ARG0-of (r2 / responsible-01~e.37 :ARG1~e.38 (a5 / activate-01~e.42 :ARG1 e3~e.39,40,41)) :location~e.43 (c4 / cell-line~e.45,46 :mod (t / this~e.44))))) # ::id pmid_2303_9341.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When the cell lines were classified based on phospho @-@ ERK levels rather than BRAF mutation status , there was no correlation with the degree of cell growth inhibition . # ::alignments 2-1.3.1 3-1.3.1 5-1.3 6-1.3.2 7-1.3.2.1.r 8-1.3.2.1.1 10-1.3.2.1.1.1.1.1 11-1.3.2.1 12-1.3.2.1.2 15-1.3.2.1.2.1.1.1.1 17-1.3.2.1.2.1.1 17-1.3.2.1.2.1.1.2 17-1.3.2.1.2.1.1.2.r 18-1.3.2.1.2.1 22-1.1 22-1.1.r 23-1 24-1.2.r 26-1.2 27-1.2.1.r 28-1.2.1.1.1 29-1.2.1.1 30-1.2.1 (c / correlate-01~e.23 :polarity~e.22 -~e.22 :ARG2~e.24 (d / degree~e.26 :degree-of~e.27 (i / inhibit-01~e.30 :ARG1 (g / grow-01~e.29 :ARG1 (c2 / cell~e.28)))) :condition (c3 / classify-01~e.5 :ARG1 (c4 / cell-line~e.2,3) :ARG1-of (b / base-02~e.6 :ARG2~e.7 (l / level~e.11 :quant-of (p / phosphorylate-01~e.8 :ARG2 (e / enzyme :name (n / name :op1 "ERK"~e.10))) :ARG1-of (i2 / instead-of-91~e.12 :ARG2 (s / status~e.18 :mod (g2 / gene~e.17 :name (n2 / name :op1 "BRAF"~e.15) :ARG1-of~e.17 (m / mutate-01~e.17)))))))) # ::id pmid_2303_9341.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , high levels of pAkt ( 3+) in BRAF @/@ RAS mutant cell lines were strongly suggestive of insensitivity to E6201 ( p = 0.057 ) . # ::alignments 1-1 3-1.1.1.1 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2 6-1.1.1.2.1.1.1 11-1.1.1.3.1.1.1.1.1 13-1.1.1.3.1.1.2.1.1 15-1.1.1.3.1 16-1.1.1.3 17-1.1.1.3 19-1.1.3 22-1.1.2 22-1.1.2.1 22-1.1.2.1.r 23-1.1.2.2.r 24-1.1.2.2.1.1 26-1.1.4 28-1.1.4.1 (c / contrast-01~e.1 :ARG2 (s / suggest-01 :ARG0 (l / level~e.4 :ARG1-of (h / high-02~e.3) :quant-of~e.5 (p / phosphorylate-01~e.6 :ARG2 (e / enzyme :name (n / name :op1 "Akt"~e.6))) :location (c2 / cell-line~e.16,17 :mod (m / mutate-01~e.15 :ARG2 (a / and :op1 (g / gene :name (n2 / name :op1 "BRAF"~e.11)) :op2 (g2 / gene :name (n3 / name :op1 "RAS"~e.13))))) :value (m2 / more-than :op1 3)) :ARG1 (s4 / sensitive-03~e.22 :polarity~e.22 -~e.22 :ARG1~e.23 (s3 / small-molecule :name (n4 / name :op1 "E6201"~e.24))) :ARG1-of (s2 / strong-02~e.19) :ARG1-of (s5 / statistical-test-91~e.26 :ARG2 0.057~e.28))) # ::id pmid_2303_9341.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , high levels of pAkt ( 3+) significantly correlated with E6201 insensitivity independent of BRAF or PTEN status ( p < 0.02 ) . # ::alignments 0-1 0-1.1.3.2 2-1.1.1.2 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1 5-1.1.1.1.1.1.1 8-1.1.4 9-1.1 11-1.1.2.2.1.1 12-1.1.2 12-1.1.2.1 12-1.1.2.1.r 12-1.1.3.1 13-1.1.2.1 13-1.1.3 13-1.1.3.1 13-1.1.3.1.r 16-1.1.3.2.1.1.1.1 20-1.1.3.2.2.1.1.1 22-1.1.3.2.1 22-1.1.3.2.2 24-1.1.5 25-1.1.5.1 26-1.1.5.1.1 (a / and~e.0 :op2 (c / correlate-01~e.9 :ARG1 (l / level~e.3 :quant-of~e.4 (p / phosphorylate-01~e.5 :ARG2 (e / enzyme :name (n / name :op1 "Akt"~e.5))) :ARG1-of (h / high-02~e.2) :value (m / more-than :op1 3)) :ARG2 (s5 / sensitive-03~e.12 :polarity~e.12 -~e.12,13 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "E6201"~e.11))) :ARG0-of (d / depend-01~e.13 :polarity~e.13 -~e.12,13 :ARG1 (a2 / and~e.0 :op1 (s2 / status~e.22 :mod (g / gene :name (n3 / name :op1 "BRAF"~e.16))) :op2 (s3 / status~e.22 :mod (g2 / gene :name (n4 / name :op1 "PTEN"~e.20))))) :ARG1-of (s / significant-02~e.8) :ARG1-of (s6 / statistical-test-91~e.24 :ARG2 (l2 / less-than~e.25 :op1 0.02~e.26)))) # ::id pmid_2303_9341.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PTEN protein was present in 20 of the melanoma cell lines tested with a lack of the tumour suppressor being suggestive of resistance to E6201 in not only BRAF @/@ RAS mutant lines ( p = 0.12 ) but also if all lines are considered ( p = 0.14 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1 8-1.1.2.2.1.1 9-1.1.2 9-1.1.2.3.1 10-1.1.2.3.1 11-1.1.2.3.1.1 14-1.2.1 15-1.2.1.1.r 17-1.2.1.1.1.1 18-1.2.1.1 18-1.2.1.1.1 18-1.2.1.1.1.r 22-1.2.2 29-1.2.2.1.1.1.1.1.1.1 30-1.2.2.1.1.1.1 31-1.2.2.1.1.1.1.2.1.1 33-1.2.2.1.1.1 34-1.2.2.1.1 36-1.2.2.1.1.2 38-1.2.2.1.1.2.1 41-1.2.2.1.2.3 43-1.2.2.1.2.2 44-1.2.2.1.2 46-1.2.2.1.2.1 48-1.2.2.1.2.4 50-1.2.2.1.2.4.1 (a3 / and :op1 (p4 / present-02~e.3 :ARG1 (p2 / protein~e.1 :name (n / name :op1 "PTEN"~e.0)) :ARG2~e.4 (c / cell-line~e.9 :quant 20~e.5 :mod (m3 / medical-condition :name (n2 / name :op1 "melanoma"~e.8)) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.9,10 :ARG1-of (t / test-01~e.11))))) :op2 (s / suggest-01 :ARG0 (l / lack-01~e.14 :ARG1~e.15 (m2 / molecular-physical-entity~e.18 :ARG0-of~e.18 (s5 / suppress-01~e.18 :ARG1 (t3 / tumor~e.17)))) :ARG1 (r / resist-01~e.22 :ARG0 (a4 / and :op1 (l2 / line~e.34 :mod (m / mutate-01~e.33 :ARG2 (s3 / slash~e.30 :op1 (g / gene :name (n4 / name :op1 "BRAF"~e.29)) :op2 (g2 / gene :name (n5 / name :op1 "RAS"~e.31)))) :ARG1-of (s2 / statistical-test-91~e.36 :ARG2 0.12~e.38)) :op2 (l3 / line~e.44 :ARG1-of (c3 / consider-01~e.46) :mod (a5 / all~e.43) :mod (a / also~e.41) :ARG1-of (s6 / statistical-test-91~e.48 :ARG2 0.14~e.50))) :ARG1 (s4 / small-molecule :name (n3 / name :op1 "E3201"))))) # ::id pmid_2303_9341.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Characterization of E6201 response in vitro @ # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1 4-1.1 6-1.1.2 7-1.1.2 (c / characterize-01~e.1 :ARG1~e.2 (r / respond-01~e.4 :ARG1 (s / small-molecule :name (n / name :op1 "E6201"~e.3)) :manner (i / in-vitro~e.6,7))) # ::id pmid_2303_9341.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK inhibitors have been previously shown to have a predominantly cytostatic effect on melanoma cells , although some clinically relevant inhibitors , such as CI @-@ 1040 , PD0325901 and AZD6244 , have been shown to induce cell death [ @ 10 , 12 , 13 @ ] . # ::alignments 0-1.1.1.1.1.1.1.1 1-1.1.1.1 1-1.1.1.1.1 1-1.1.1.1.1.r 4-1.1.2 5-1.1 9-1.1.1.4 11-1.1.1 12-1.1.1.2.r 13-1.1.1.2.1.1.1 14-1.1.1.2 17-1.2.1.1.2 18-1.2.1.1.1.1 18-1.2.1.1.1.1.r 19-1.2.1.1 19-1.2.1.1.1 19-1.2.1.1.1.r 20-1.2.1.1.3 22-1.2.1.1.4.r 23-1.2.1.1.4.r 24-1.2.1.1.4.1.1.1 26-1.2.1.1.4.1.1.1 28-1.2.1.1.4.2.1.1 29-1.2.1.1.4 30-1.2.1.1.4.3.1.1 34-1.2 36-1.2.1 37-1.2.1.2.1 38-1.2.1.2 41-1.3.1.1.1.1 45-1.3.1.1.1.2 49-1.3.1.1.1.3 (c / contrast-01 :ARG1 (s5 / show-01~e.5 :ARG1 (a3 / affect-01~e.11 :ARG0 (m2 / molecular-physical-entity~e.1 :ARG0-of~e.1 (i3 / inhibit-01~e.1 :ARG1 (p4 / protein-family :name (n4 / name :op1 "MEK"~e.0)))) :ARG1~e.12 (c5 / cell~e.14 :source (m / medical-condition :name (n5 / name :op1 "melanoma"~e.13))) :ARG2 (c6 / cytostasis) :ARG1-of (p2 / predominate-01~e.9)) :time (p3 / previous~e.4)) :ARG2 (s / show-01~e.34 :ARG1 (i / induce-01~e.36 :ARG0 (m3 / molecular-physical-entity~e.19 :ARG1-of~e.19 (r / relevant-01~e.19 :manner~e.18 (c4 / clinical~e.18)) :mod (s6 / some~e.17) :ARG0-of i3~e.20 :example~e.22,23 (a2 / and~e.29 :op1 (s2 / small-molecule :name (n / name :op1 "CI-1040"~e.24,26)) :op2 (s3 / small-molecule :name (n2 / name :op1 "PD0325901"~e.28)) :op3 (s4 / small-molecule :name (n3 / name :op1 "AZD6244"~e.30)))) :ARG2 (d2 / die-01~e.38 :ARG1 (c3 / cell~e.37)))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 10~e.41 :op2 12~e.45 :op3 13~e.49))))) # ::id pmid_2303_9341.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We sought to further evaluate the mechanism of sensitivity to E6201 , as an equivocal cytocidal response in vitro may equate to the poor clinical response observed with current MEK inhibitors . # ::alignments 0-1.2.1 1-1.2 3-1.2.2.3 4-1.2.2 6-1.2.2.2 7-1.2.2.2.1.r 8-1.2.2.2.1 9-1.2.2.2.1.1.r 10-1.2.2.2.1.1.1.1 12-1.1.1.2.1.1.1.2.r 14-1.1.1.2.4 15-1.1.1.1.2 16-1.1.1.1 16-1.1.1.1.1 16-1.1.1.1.1.r 18-1.1.1.1.1.1 19-1.1.1.1.1.1 21-1.1 22-1.1.1 25-1.1.1.2.2 26-1.1.1.2.3 27-1.1.1.2 27-1.1.1.2.1 27-1.1.1.2.1.r 28-1.1.1.2.1.1 29-1.1.1.2.1.1.1.r 30-1.1.1.2.1.1.1.2 31-1.1.1.2.1.1.1.1.1.1.1 32-1.1.1.2.1.1.1 32-1.1.1.2.1.1.1.1 32-1.1.1.2.1.1.1.1.r (c / cause-01 :ARG0 (p / possible-01~e.21 :ARG1 (e3 / equate-01~e.22 :ARG1 (t2 / thing~e.16 :ARG2-of~e.16 (r / respond-01~e.16 :manner (i2 / in-vitro~e.18,19)) :mod (c2 / cytocidal~e.15)) :ARG2 (t3 / thing~e.27 :ARG2-of~e.27 (r2 / respond-01~e.27 :ARG1-of (o / observe-01~e.28 :prep-with~e.29 (m3 / molecular-physical-entity~e.32 :ARG0-of~e.32 (i3 / inhibit-01~e.32 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.31))) :time~e.12 (c4 / current~e.30)))) :mod (p2 / poor~e.25) :mod (c3 / clinic~e.26) :mod (e4 / equivocal~e.14)))) :ARG1 (s / seek-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e2 / evaluate-01~e.4 :ARG0 w :ARG1 (m / mechanism~e.6 :ARG0-of~e.7 (s2 / sensitive-03~e.8 :ARG1~e.9 (s3 / small-molecule :name (n2 / name :op1 "E6201"~e.10)))) :degree (f / further~e.3)))) # ::id pmid_2303_9341.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fifteen melanoma cell lines were selected such that 13 cell lines demonstrated sensitivity to E6201 and 2 cell lines were insensitive to E6201 . # ::alignments 0-1.1.1 1-1.1.2.1.1 2-1.1 3-1.1 5-1 6-1.2.r 7-1.2.r 8-1.2.1.1.1 9-1.2.1.1 10-1.2.1.1 11-1.2.1 12-1.2.1.2 13-1.2.1.2.2.r 14-1.2.1.2.2.1.1 15-1.2 16-1.2.2.2.1 17-1.2.2.2 18-1.2.2.2 20-1.2.2 20-1.2.2.1 20-1.2.2.1.r 21-1.2.2.3.r 22-1.2.2.3 (s / select-01~e.5 :ARG1 (c / cell-line~e.2,3 :quant 15~e.0 :source (m / medical-condition :name (n2 / name :op1 "melanoma"~e.1))) :purpose~e.6,7 (a / and~e.15 :op1 (d / demonstrate-01~e.11 :ARG0 (c2 / cell-line~e.9,10 :quant 13~e.8) :ARG1 (s3 / sensitive-03~e.12 :ARG0 c2 :ARG1~e.13 (s4 / small-molecule :name (n / name :op1 "E6201"~e.14)))) :op2 (s2 / sensitive-03~e.20 :polarity~e.20 -~e.20 :ARG0 (c3 / cell-line~e.17,18 :quant 2~e.16) :ARG1~e.21 s4~e.22))) # ::id pmid_2303_9341.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of these cell lines , seven were mutant for BRAF but wildtype for PTEN , five were mutant for both BRAF @ / @ NRAS and PTEN , and three were wildtype for both BRAF and PTEN @ . # ::alignments 1-1.4.1.1 2-1.4.1 3-1.1 3-1.2 3-1.3 5-1.1.1 7-1.1.2 7-1.1.2.2 7-1.1.2.2.r 10-1.1.2.1.1 12-1.1.2.3 13-1.1.2.3.1.2 13-1.3.2.2 16-1.1.2.3.1.1.1 19-1.2.1 21-1.2.2.4 25-1.2.2.1.1.1 27-1.2.2 29-1.2.2.2.1.1 31-1 33-1.1.2.3.1.1.1 33-1.2.2.3.1.1 36-1 37-1.3.1 39-1.1.2.3.1.2 39-1.3.2.2 43-1.1.2.1.1 43-1.2.2.1.1.1 43-1.3.2.1.1 45-1 47-1.1.2.3.1.1.1 47-1.2.2.3.1.1 (a / and~e.31,36,45 :op1 (c / cell-line~e.3 :quant 7~e.5 :mod (g4 / gene~e.7 :name (n / name :op1 "BRAF"~e.10,43) :ARG2-of~e.7 (m2 / mutate-01~e.7) :ARG1-of (c5 / contrast-01~e.12 :ARG2 (g5 / gene :name (n2 / name :op1 "PTEN"~e.16,33,47) :mod (w / wild-type~e.13,39))))) :op2 (c2 / cell-line~e.3 :quant 5~e.19 :mod (s / slash~e.27 :op1 (g / gene :name (n4 / name :op1 "BRAF"~e.25,43)) :op2 (g2 / gene :name (n3 / name :op1 "NRAS"~e.29)) :op3 (g3 / gene :name (n5 / name :op1 "PTEN"~e.33,47)) :ARG2-of (m / mutate-01~e.21))) :op3 (c3 / cell-line~e.3 :quant 3~e.37 :mod (e3 / enzyme :name (n6 / name :op1 "BRAF"~e.43) :mod (w2 / wild-type~e.13,39)) :mod g5) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line~e.2 :mod (t / this~e.1)))) # ::id pmid_2303_9341.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 treatment induced G1 arrest in all of the sensitive cell lines and had little to no effect on cell cycle progression in the two insensitive cell lines ( Figure 3 @ A ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.1.1.1 4-1.1.2 5-1.1.3.r 6-1.1.3.1 9-1.1.3.2 10-1.1.3 11-1.1.3 12-1 14-1.2.1.3 16-1.2.2.1 17-1.2.1 17-1.2.2 18-1.2.1.2.r 19-1.2.1.2.1.1 20-1.2.1.2.1 21-1.2.1.2 22-1.2.1.2.2.r 24-1.2.1.2.2.1 25-1.2.1.2.2.2 25-1.2.1.2.2.2.1 25-1.2.1.2.2.2.1.r 26-1.2.1.2.2 27-1.2.1.2.2 29-1.3.1 (a / and~e.12 :op1 (i / induce-01~e.2 :ARG0 (t / treat-04~e.1 :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201"~e.0))) :ARG2 (a2 / arrest-02~e.4 :time (e / event :name (n2 / name :op1 "G1"~e.3))) :location~e.5 (c / cell-line~e.10,11 :mod (a3 / all~e.6) :ARG0-of (s / sensitive-03~e.9))) :op2 (o2 / or :op1 (a4 / affect-01~e.17 :ARG0 t :ARG1~e.18 (p3 / progress-01~e.21 :ARG1 (c2 / cycle-02~e.20 :ARG1 (c3 / cell~e.19)) :location~e.22 (c4 / cell-line~e.26,27 :quant 2~e.24 :ARG0-of (s2 / sensitive-03~e.25 :polarity~e.25 -~e.25))) :degree (l / little~e.14)) :op2 (a5 / affect-01~e.17 :polarity -~e.16 :ARG0 t :ARG1 p3)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "3A"))) # ::id pmid_2303_9341.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 treatment resulted in a greater than 2 @-@ fold increase in Annexin @-@ positive staining in eleven out of fifteen cell lines , including eleven out of thirteen sensitive cell lines ( Figure 3 @ B ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1 6-1.2.2 7-1.2.2.1.1 9-1.2.2.1 10-1.2 11-1.2.1.r 12-1.2.1.1.1.1 14-1.2.1.2 15-1.2.1 16-1.2.3.r 17-1.2.3.1 20-1.2.3.2.1.1 21-1.2.3.2.1 22-1.2.3 22-1.2.3.2.2.1 24-1.2.3.2 24-1.2.3.2.2 24-1.2.3.2.2.1.2 24-1.2.3.2.2.r 25-1.2.3.2.2.1.1 28-1.2.3.2.2.1.2.1.1 29-1.2.3.2.2.1.2.1.2 30-1.2.3.2.2.1.2.1 31-1.2.3.2.2.1.2.1 33-1.3.1 (r / result-01~e.2 :ARG1 (t / treat-04~e.1 :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201"~e.0))) :ARG2 (i2 / increase-01~e.10 :ARG1~e.11 (s / stain-01~e.15 :ARG2 (p / protein :name (n2 / name :op1 "Annexin"~e.12)) :mod (p2 / positive~e.14)) :ARG2 (m / more-than~e.6 :op1 (p3 / product-of~e.9 :op1 2~e.7)) :location~e.16 (c / cell-line~e.22 :quant 11~e.17 :ARG1-of (i3 / include-91~e.24 :ARG2 (c2 / cell-line~e.21 :quant 15~e.20) :ARG2-of~e.24 (i4 / include-91~e.24 :ARG1 (c3 / cell-line~e.22 :quant 11~e.25 :ARG1-of (i5 / include-91~e.24 :ARG2 (c4 / cell-line~e.30,31 :quant 13~e.28 :ARG0-of (s2 / sensitive-03~e.29)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.33 :mod "3B"))) # ::id pmid_2303_9341.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two sensitive cell lines , SKMEL13 and BL , did not demonstrate E6201 @-@ induced Annexin staining although both of these cell lines underwent cell cycle arrest with E6201 treatment and were hypersensitive to E6201 ( IC50 < 100 nM ) . # ::alignments 0-1.1.2.1 1-1.1.2.2 2-1.1.2 3-1.1.2 5-1.1.2.3.1.1.1.1 6-1.1.2.3.1 7-1.1.2.3.1.2.1.1 10-1.1.1 10-1.1.1.r 11-1.1 12-1.1.3.2.1 14-1.1.3.2 15-1.1.3.1.1.1 16-1.1.3 17-1 21-1.2.1.2.2.1 22-1.1.2.3.1.1 23-1.2.1 24-1.2.1.2.2.1 25-1.2.1.2.2 26-1.2.1.2 27-1.2.1.2.1.r 28-1.2.1.2.1.1 29-1.2.1.2.1 30-1.2 32-1.2.2 32-1.2.2.3 32-1.2.2.3.r 32-1.2.2.4.2.1.r 33-1.2.2.2.r 34-1.2.2.2.1.1 37-1.2.2.4.1 38-1.2.2.4.1.1.1 39-1.2.2.4.1.1.2 (h2 / have-concession-91~e.17 :ARG1 (d / demonstrate-01~e.11 :polarity~e.10 -~e.10 :ARG0 (c2 / cell-line~e.2,3 :quant 2~e.0 :ARG0-of (s2 / sensitive-03~e.1) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.6 :op1 (c3 / cell-line~e.22 :name (n2 / name :op1 "SKMEL13"~e.5)) :op2 (c4 / cell-line :name (n3 / name :op1 "BL"~e.7))))) :ARG1 (s3 / stain-01~e.16 :ARG2 (p / protein :name (n4 / name :op1 "Annexin"~e.15)) :ARG2-of (i / induce-01~e.14 :ARG0 s4~e.12))) :ARG2 (a / and~e.30 :op1 (u / undergo-28~e.23 :ARG1 a2 :ARG2 (a3 / arrest-02~e.26 :ARG0~e.27 (t / treat-04~e.29 :ARG2 s4~e.28) :ARG1 (c5 / cycle-02~e.25 :ARG1 (c6 / cell~e.21,24)))) :op2 (s / sensitive-03~e.32 :ARG0 a2 :ARG1~e.33 (s4 / small-molecule :name (n / name :op1 "E6201"~e.34)) :degree~e.32 (h / hyper~e.32) :mod (c7 / concentrate-02 :quant (l / less-than~e.37 :op1 (c / concentration-quantity :quant 100~e.38 :unit (n5 / nanomolar~e.39))) :mod (i2 / inhibit-01 :degree~e.32 (p2 / percentage-entity :value 50)))))) # ::id pmid_2303_9341.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These experiments were repeated in duplicate to confirm this finding . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2 7-1.3 8-1.1.1 9-1.3.2 9-1.3.2.1 9-1.3.2.1.r (r / repeat-01~e.3 :ARG1 (e / experiment-01~e.1 :mod (t / this~e.0,8)) :ARG3~e.4 (d / duplicate-01~e.5 :ARG1 e) :purpose (c / confirm-01~e.7 :ARG0 r :ARG1 (t2 / thing~e.9 :ARG1-of~e.9 (f / find-01~e.9)))) # ::id pmid_2303_9341.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 induced a less than two @-@ fold increase in Annexin staining in the E6201 @-@ insensitive cell lines ( IC50 > 500 nM ) ( Figure 3 @ B ) . # ::alignments 0-1.1.1.1 1-1 3-1.2.2 4-1.2.2 5-1.2.2.1.1 7-1.2.2.1 8-1.2 9-1.2.1.r 10-1.2.1.1.1.1 11-1.2.1 12-1.2.3.r 14-1.2.3.1.2 16-1.2.3.1 16-1.2.3.1.1 16-1.2.3.1.1.r 17-1.2.3 18-1.2.3 21-1.2.3.2.1.1 22-1.2.3.2.1.1.1.1 23-1.2.3.2.1.1.1.2 26-1.3.1 (i / induce-01~e.1 :ARG0 (s3 / small-molecule :name (n / name :op1 "E6201"~e.0)) :ARG2 (i2 / increase-01~e.8 :ARG1~e.9 (s / stain-01~e.11 :ARG2 (p2 / protein :name (n2 / name :op1 "Annexin"~e.10))) :ARG2 (l / less-than~e.3,4 :op1 (p / product-of~e.7 :op1 2~e.5)) :location~e.12 (c / cell-line~e.17,18 :ARG0-of (s2 / sensitive-03~e.16 :polarity~e.16 -~e.16 :ARG1 s3~e.14) :ARG1-of (m2 / mean-01 :ARG2 (c3 / concentrate-02 :quant (m / more-than~e.21 :op1 (c2 / concentration-quantity :quant 500~e.22 :unit (n3 / nanomolar~e.23))) :mod (i3 / inhibit-01 :degree (p3 / percentage-entity :value 50)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "3B"))) # ::id pmid_2303_9341.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Three of the five PTEN @ -@ mutant cell lines exhibited a cytocidal response to E6201 , demonstrating that PTEN mutation does not preclude a cytocidal response to E6201 . # ::alignments 0-1.1.1.1 3-1.1.1.2.1.1 5-1.1.1.2.1.2.1.1 8-1.1.1.2.1.2 8-1.1.1.2.1.2.2 8-1.1.1.2.1.2.2.r 9-1.1.1 9-1.1.1.2.1 10-1.1.1 11-1.1 13-1.1.2.1 14-1.1.2 14-1.1.2.2 14-1.1.2.2.r 15-1.1.2.2.2.r 16-1.1.2.2.2.1.1 18-1.2 21-1.2.2.2 22-1.2.2.2 23-1.2.2.2 25-1.2.2.1 25-1.2.2.1.r 26-1.2.2 28-1.2.2.3 29-1.2.2.3 30-1.2.2.3 31-1.2.2.3 (c / cause-01 :ARG0 (e / exhibit-01~e.11 :ARG0 (c2 / cell-line~e.9,10 :quant 3~e.0 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.9 :quant 5~e.3 :mod (g / gene~e.8 :name (n / name :op1 "PTEN"~e.5) :ARG2-of~e.8 (m / mutate-01~e.8))))) :ARG1 (t / thing~e.14 :mod (c4 / cytocidal~e.13) :ARG2-of~e.14 (r / respond-01~e.14 :ARG0 c2 :ARG1~e.15 (s / small-molecule :name (n2 / name :op1 "E6201"~e.16))))) :ARG1 (d / demonstrate-01~e.18 :ARG0 c2 :ARG1 (p2 / preclude-01~e.26 :polarity~e.25 -~e.25 :ARG0 g~e.21,22,23 :ARG1 t~e.28,29,30,31))) # ::id pmid_2303_9341.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 also induced cell cycle arrest and cell death in cell lines with constitutively active Akt , suggesting that although high pAkt correlates with E6201 insensitivity , cell lines with high pAkt can still undergo a cytocidal response to E6201 . # ::alignments 0-1.1.1.1 1-1.4 2-1 3-1.2.1.1.1 4-1.2.1.1 5-1.2.1 6-1.2 7-1.2.3 8-1.2.2 10-1.2.3 11-1.2.3 12-1.2.3.1.r 13-1.2.3.1.2.1 13-1.2.3.1.2.1.r 14-1.2.3.1 14-1.2.3.1.2 14-1.2.3.1.2.r 15-1.2.3.1.1.1 17-1.3 19-1.3.1 20-1.3.1.2.1 20-1.3.1.2.1.3 20-1.3.1.2.1.3.r 21-1.3.1.2.1.2 22-1.3.1.2 23-1.3.1.2.2.r 24-1.3.1.2.2.2 25-1.3.1.2.2 25-1.3.1.2.2.1 25-1.3.1.2.2.1.r 27-1.3.1.1.1.1 28-1.3.1.1.1.1 29-1.3.1.1.1.1.1.r 30-1.3.1.1.1.1.1 31-1.3.1.1.1.1.1 32-1.3.1.1 33-1.3.1.1.1.3 34-1.3.1.1.1 36-1.3.1.1.1.2.1.3 37-1.3.1.1.1.2 37-1.3.1.1.1.2.1 37-1.3.1.1.1.2.1.r 38-1.3.1.1.1.2.1.2.r 39-1.3.1.1.1.2.1.2 (i / induce-01~e.2 :ARG0 (s4 / small-molecule :name (n / name :op1 "E6201"~e.0)) :ARG2 (a2 / and~e.6 :op1 (a3 / arrest-02~e.5 :ARG1 (c / cycle-02~e.4 :ARG1 (c2 / cell~e.3))) :op2 (d / die-01~e.8 :ARG1 c) :location (c3 / cell-line~e.7,10,11 :mod~e.12 (e / enzyme~e.14 :name (n2 / name :op1 "Akt"~e.15) :ARG0-of~e.14 (a4 / activity-06~e.14 :manner~e.13 (c4 / constitutive~e.13))))) :ARG0-of (s / suggest-01~e.17 :ARG1 (h2 / have-concession-91~e.19 :ARG1 (p / possible-01~e.32 :ARG1 (u / undergo-28~e.34 :ARG1 (c7 / cell-line~e.27,28 :mod~e.29 e2~e.30,31) :ARG2 (t / thing~e.37 :ARG2-of~e.37 (r / respond-01~e.37 :ARG0 c7 :ARG1~e.38 s4~e.39 :mod (c5 / cytocidal~e.36))) :mod (s3 / still~e.33))) :ARG2 (c6 / correlate-01~e.22 :ARG1 (e2 / enzyme~e.20 :name n2 :ARG3-of (p2 / phosphorylate-01~e.21) :ARG1-of~e.20 (h / high-02~e.20)) :ARG2~e.23 (s2 / sensitive-03~e.25 :polarity~e.25 -~e.25 :ARG1 s4~e.24)))) :mod (a / also~e.1)) # ::id pmid_2303_9341.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm our Annexin V results we also performed an enzyme @-@ linked immunosorbent assay ( ELISA ) to determine the degree of DNA fragmentation as an indicator of cell death with E6201 treatment ( Figure 3 @ C ) . # ::alignments 1-1.3 2-1.3.1 3-1.3.2.1.1.1.1 4-1.3.2.1.1.1.2 5-1.3.2 5-1.3.2.1 5-1.3.2.1.r 6-1.3.1 7-1.4 8-1 10-1.2.2.1.1 12-1.2.2.1 13-1.2.2 14-1.2 16-1.2.3.1.1.1 19-1.2.1 21-1.2.1.2 22-1.2.1.2.1.r 23-1.2.1.2.1.1.2.1 24-1.2.1.2.1 25-1.2.1.2.2.r 27-1.2.1.2.2 28-1.2.1.2.2.1.r 29-1.2.1.2.2.1.1 30-1.2.1.2.2.1 31-1.2.2.r 32-1.2.1.2.2.1.2.1.1.1.1 33-1.2.1.2.2.1.2.1 35-1.5.1 (p / perform-01~e.8 :ARG0 (w / we) :ARG1 (a2 / assay-01~e.14 :purpose (d / determine-01~e.19 :ARG0 w :ARG1 (d2 / degree~e.21 :degree-of~e.22 (f / fragment-01~e.24 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.23))) :ARG0-of~e.25 (i / indicate-01~e.27 :ARG1~e.28 (d4 / die-01~e.30 :ARG1 (c2 / cell~e.29) :ARG0-of (c3 / cause-01 :ARG1 (t3 / treat-04~e.33 :ARG2 (s / small-molecule :name (n3 / name :op1 "E6201"~e.32)))))))) :instrument~e.31 (i2 / immunosorbent~e.13 :ARG1-of (l / link-01~e.12 :ARG2 (e / enzyme~e.10))) :ARG1-of (d3 / describe-01 :ARG2 (t / thing :name (n2 / name :op1 "ELISA"~e.16)))) :purpose (c / confirm-01~e.1 :ARG0 w~e.2,6 :ARG1 (t2 / thing~e.5 :ARG2-of~e.5 (r / result-01~e.5 :ARG1 (p2 / protein :name (n / name :op1 "Annexin"~e.3 :op2 "V"~e.4))))) :mod (a / also~e.7) :ARG1-of (d5 / describe-01 :ARG0 (f2 / figure~e.35 :mod "3C"))) # ::id pmid_2303_9341.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results from the cell death ELISA were very similar to that obtained from the Annexin studies with 10 out of 13 sensitive melanoma lines demonstrating a greater than two @-@ fold increase in DNA fragmentation with E6201 . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 1-1.2 1-1.2.1 1-1.2.1.r 2-1.1.1.1.r 2-1.2.1.1.1.1.2.2.1.3.r 4-1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1.1 8-1.3 9-1 12-1.2.1.1 13-1.2.1.1.1.1.2.2.1.3.r 15-1.2.1.1.1.1.1.1 16-1.2.1.1.1 17-1.2.1.1.1.1.2.r 18-1.2.1.1.1.1.2.1 21-1.2.1.1.1.1.2.2.1.1 22-1.2.1.1.1.1.2.2.1.2 23-1.2.1.1.1.1.2.2.1.3.1.1 24-1.2.1.1.1.1.2 24-1.2.1.1.1.1.2.2.1 25-1.4 28-1.4.1.2 29-1.4.1.2.1.1 31-1.4.1.2.1 32-1.4.1 33-1.4.1.1.r 34-1.4.1.1.2.2.1 35-1.4.1.1 36-1.2.1.1.1.1.2.r 36-1.4.1.1.1.r 37-1.4.1.1.1.1.1 (r2 / resemble-01~e.9 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1 :ARG1~e.2 (d / die-01~e.5 :ARG1 (c / cell~e.4) :mod (a / assay-01 :mod (t2 / thing :name (n / name :op1 "ELISA"~e.6)))))) :ARG2 (t3 / thing~e.1 :ARG2-of~e.1 (r3 / result-01~e.1 :ARG1-of (o / obtain-01~e.12 :ARG2 (s / study-01~e.16 :ARG1 (p / protein :name (n2 / name :op1 "Annexin"~e.15) :prep-with~e.17,36 (c2 / cell-line~e.24 :quant 10~e.18 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.24 :quant 13~e.21 :ARG0-of (s2 / sensitive-03~e.22) :source~e.2,13 (m / medical-condition :name (n6 / name :op1 "melanoma"~e.23)))))))))) :degree (v / very~e.8) :ARG0-of (d2 / demonstrate-01~e.25 :ARG1 (i2 / increase-01~e.32 :ARG1~e.33 (f / fragment-01~e.35 :ARG0~e.36 (s3 / small-molecule :name (n3 / name :op1 "E6201"~e.37)) :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"~e.34))) :ARG2 (m2 / more-than~e.28 :op1 (p2 / product-of~e.31 :op1 2~e.29))))) # ::id pmid_2303_9341.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the three sensitive lines that did not exhibit a cytocidal response by ELISA , SKMEL13 and BL also demonstrated no induction of cell death with E6201 by Annexin positivity , as stated previously . # ::alignments 2-1.1.3.1.1 3-1.1.3.1.2 4-1.1.3.1 7-1.1.3.1.3.1 7-1.1.3.1.3.1.r 8-1.1.3.1.3 10-1.1.3.1.3.2.2 11-1.1.3.1.3.2 13-1.1.3.1.3.3.1.1.1 15-1.1.1.1.1 16-1.1 17-1.1.2.1.1 18-1.5 19-1 20-1.2.1 20-1.2.1.r 21-1.2 22-1.2.3.r 23-1.2.3.1 24-1.2.3 25-1.2.2.r 26-1.2.2.1.1 27-1.3.r 28-1.3.1.1.1 29-1.3 31-1.4.1.r 32-1.4 33-1.4.1 (d3 / demonstrate-01~e.19 :ARG0 (a4 / and~e.16 :op1 (c2 / cell-line :name (n2 / name :op1 "SKMEL13"~e.15)) :op2 (c3 / cell-line :name (n3 / name :op1 "BL"~e.17)) :ARG1-of (i / include-91 :ARG2 (c4 / cell-line~e.4 :quant 3~e.2 :ARG0-of (s2 / sensitive-03~e.3) :ARG0-of (e / exhibit-01~e.8 :polarity~e.7 -~e.7 :ARG1 (r / respond-01~e.11 :ARG0 c4 :mod (c5 / cytocidal~e.10)) :manner (a / assay-01 :mod (t / thing :name (n / name :op1 "ELISA"~e.13))))))) :ARG1 (i2 / induce-01~e.21 :polarity~e.20 -~e.20 :ARG0~e.25 (s3 / small-molecule :name (n4 / name :op1 "E6201"~e.26)) :ARG2~e.22 (d2 / die-01~e.24 :ARG1 (c6 / cell~e.23))) :manner~e.27 (p2 / positive~e.29 :domain (p3 / protein :name (n5 / name :op1 "Annexin"~e.28))) :ARG1-of (s / state-01~e.32 :time~e.31 (p / previous~e.33)) :mod (a3 / also~e.18)) # ::id pmid_2303_9341.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There was no significant induction of DNA fragmentation in any of the E6201 @-@ resistant melanoma cell lines . # ::alignments 2-1.3.1 2-1.3.1.r 3-1.3 4-1 5-1.1.r 6-1.1.1.2.1 7-1.1 8-1.2.r 9-1.2.1 12-1.2.2.1.1.1 14-1.2.2 15-1.2.3.1.1 16-1.2 17-1.2 (i / induce-01~e.4 :ARG2~e.5 (f / fragment-01~e.7 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"~e.6))) :location~e.8 (c / cell-line~e.16,17 :mod (a / any~e.9) :ARG0-of (r / resist-01~e.14 :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201"~e.12))) :source (m / medical-condition :name (n4 / name :op1 "melanoma"~e.15))) :ARG1-of (s / significant-02~e.3 :polarity~e.2 -~e.2)) # ::id pmid_2303_9341.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Characterization of E6201 response in vivo in melanoma xenografts # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1 4-1.1 6-1.1.3 7-1.1.3 9-1.1.2.r 9-1.1.3 10-1.1.2.1.1.1 11-1.1.2 (c / characterize-01~e.1 :ARG1~e.2 (r / respond-01~e.4 :ARG1 (s / small-molecule :name (n / name :op1 "E6201"~e.3)) :location~e.9 (x / xenograft~e.11 :source (m / medical-condition :name (n2 / name :op1 "melanoma"~e.10))) :manner (i / in-vivo~e.6,7,9))) # ::id pmid_2303_9341.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We evaluated the in vivo activity of E6201 in two melanoma cell lines that exhibited a cytocidal response ( MM540 , MM604 ) and two melanoma cell lines that exhibited a cytostatic response ( SKMEL13 , BL ) to E6201 in vitro ( Figure 4 ) . # ::alignments 0-1.1 1-1 4-1.2.2 5-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.1.1 10-1.2.2 10-1.2.3.r 11-1.2.3.2.1 12-1.2.3.2.2 13-1.2.3.2 14-1.2.3.2 16-1.2.3.2.3 18-1.2.3.1.2.1.1.2 19-1.2.3.1.2.1 19-1.2.3.1.2.1.1 19-1.2.3.1.2.1.1.r 21-1.2.3.1.3.1.1.1.1 23-1.2.3.1.3.1.2.1.1 25-1.2.3 25-1.2.3.1.3.1 25-1.2.3.2.4.1 26-1.2.3.1.1 26-1.2.3.2.1 27-1.2.3.1.4.1.1 28-1.2.3.1 28-1.2.3.2 29-1.2.3.2 31-1.2.3.1.2 31-1.2.3.2.3 34-1.2.3.2.3.1 36-1.2.3.2.4.1.1.1.1 38-1.2.3.2.4.1.2.1.1 40-1.2.3.2.3.1.1.r 41-1.2.3.2.3.1.1 43-1.2.3.2.3.1.3 44-1.2.3.2.3.1.3 47-1.3.1 49-1.3.1.1 (e / evaluate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a2 / activity-06~e.7 :ARG0~e.8 (s / small-molecule :name (n / name :op1 "E6201"~e.9)) :manner (i / in-vivo~e.4,5,10) :location~e.10 (a5 / and~e.25 :op1 (c / cell-line~e.28 :quant 2~e.26 :ARG0-of (e2 / exhibit-01~e.31 :ARG1 (t / thing~e.19 :ARG2-of~e.19 (r / respond-01~e.19 :ARG1 s :mod (c2 / cytocidal~e.18)))) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and~e.25 :op1 (c3 / cell-line :name (n2 / name :op1 "MM540"~e.21)) :op2 (c4 / cell-line :name (n3 / name :op1 "MM604"~e.23)))) :source (m / medical-condition :name (n6 / name :op1 "melanoma"~e.27))) :op2 (c5 / cell-line~e.13,14,28,29 :quant 2~e.11,26 :source (m2 / melanoma~e.12) :ARG0-of (e3 / exhibit-01~e.16,31 :ARG1 (r2 / respond-01~e.34 :ARG1~e.40 s~e.41 :ARG2 (c6 / cytostasis) :manner (i2 / in-vitro~e.43,44))) :ARG1-of (m4 / mean-01 :ARG2 (a4 / and~e.25 :op1 (c7 / cell-line :name (n4 / name :op1 "SKMEL13"~e.36)) :op2 (c8 / cell-line :name (n5 / name :op1 "BL"~e.38))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.47 :mod 4~e.49))) # ::id pmid_2303_9341.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given that the majority of sensitive melanoma cell lines in our cell line panel exhibited a cytocidal response to E6201 in vitro , we hypothesized that E6201 would induce tumour regression in a xenograft model of these cell lines as well , and to a greater extent in those cell lines that demonstrated a cytocidal response to E6201 in vitro compared to those with a cytostatic response . # ::alignments 0-1.2.2.3.2 1-1.2.2.3.1 3-1.3.1.1.1.2 5-1.3.1.1.1.1.2 6-1.3.1.1.1.1.3.1.1 7-1.2.2.3 8-1.2.2.3 9-1.3.1.2.1.2 10-1.3.1.1.1.1.1.2 11-1.3.1.1 12-1.3.1.1 12-1.3.1.1.1.1 13-1.3.1.1.1.1.1 14-1.3.1 16-1.2.2.3.2.1.3 17-1.2.2.3.2.1 17-1.3.1.2 17-1.3.1.2.1 17-1.3.1.2.1.r 18-1.3 19-1.3.1.2.1.1.1.1 21-1.3.1.2.1.2 22-1.3.1.2.1.2 25-1.3.1.1.1.1.1.2 26-1 27-1.2.2.3.1 28-1.3.1.2.1.1.1.1 30-1.2.1 30-1.2.2 31-1.2.1.2.1 33-1.2.1.4.r 33-1.3.1.2.1.2 35-1.2.1.4.1 36-1.2.1.4 39-1.2.2.3 40-1.2.2.3 41-1.2.1.3 42-1.2.1.3 44-1.2 45-1.2.2.2.r 47-1.2.2.2.1 47-1.2.2.2.1.1 47-1.2.2.2.1.1.r 48-1.2.2.2 49-1.3.1.2.1.2 50-1.2.2.3.1 51-1.2.2.3 52-1.2.2.3 52-1.2.2.3.3 53-1.2.2.3.1 54-1.2.2.3.2 56-1.2.2.3.2.1.3 57-1.2.2.3.2.1 57-1.2.2.3.3.1 57-1.3.1.2 57-1.3.1.2.1 57-1.3.1.2.1.r 58-1.3 59-1.3.1.2.1.1.1.1 61-1.3.1.2.1.2 62-1.3.1.2.1.2 64-1.2.2.3.3.r 66-1.2.2.3.1 70-1.3.1.2 70-1.3.1.2.1 70-1.3.1.2.1.r (h / hypothesize-01~e.26 :ARG0 w :ARG1 (a / and~e.44 :op1 (i2 / induce-01~e.30 :ARG0 s2 :ARG2 (r2 / regress-01 :ARG1 (t2 / tumor~e.31)) :manner (a2 / as-well~e.41,42) :location~e.33 (m4 / model~e.36 :mod (x / xenograft~e.35) :source c2)) :op2 (i3 / induce-01~e.30 :ARG0 s2 :degree~e.45 (e2 / extent~e.48 :mod (g / great~e.47 :degree~e.47 (m5 / more~e.47))) :location (c3 / cell-line~e.7,8,39,40,51,52 :mod (t3 / that~e.1,27,50,53,66) :ARG0-of (d / demonstrate-01~e.0,54 :ARG1 (r3 / respond-01~e.17,57 :ARG0 c2 :ARG1 s2 :mod (c4 / cytocidal~e.16,56) :manner i)) :compared-to~e.64 (c5 / cell-line~e.52 :ARG0-of (r4 / respond-01~e.57 :ARG2 (c6 / cytostasis)))))) :ARG1-of (c / cause-01~e.18,58 :ARG0 (e / exhibit-01~e.14 :ARG0 (c2 / cell-line~e.11,12 :ARG1-of (i4 / include-91 :ARG2 (c7 / cell-line~e.12 :location (p / panel~e.13 :mod c2 :poss (w / we~e.10,25)) :ARG0-of (s / sensitive-03~e.5) :source (m / medical-condition :name (n2 / name :op1 "melanoma"~e.6))) :ARG3 (m2 / majority~e.3))) :ARG1 (t / thing~e.17,57,70 :ARG2-of~e.17,57,70 (r / respond-01~e.17,57,70 :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201"~e.19,28,59)) :manner (i / in-vitro~e.9,21,22,33,49,61,62)) :mod c4)))) # ::id pmid_2303_9341.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Administration of E6201 at all doses ( 10 , 20 and 40 mg/kg ) to MM540 tumour @-@ bearing mice completely abrogated tumour growth and caused transient , partial tumour regression for the two weeks of drug treatment , although tumour growth recommenced following drug withdrawal , indicating not all cells were killed in this two week period ( Figure 4 @ A ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.1.2.1 5-1.1.1.1 5-1.1.1.1.2 5-1.1.1.1.2.r 7-1.1.1.1.3.1.1 9-1.1.1.1.3.1.2 10-1.1.1.1.3.1 11-1.1.1.1.3.1.3 14-1.1.1.2.r 15-1.1.1.2.1.1.1.1.1 16-1.1.1.2.1.1 18-1.1.1.2.1 19-1.1.1.2 20-1.1.3 21-1.1 22-1.1.2 23-1.1.2 25-1.2 26-1.2.2.2 28-1.2.2.3 28-1.2.2.3.r 29-1.2.2.1 33-1.2.2.4.1 34-1.2.2.4.2 36-1.2.2.4.3.1 37-1.2.2.4.3 39-1.2.3.r 40-1.2.3.1.1 41-1.2.3.1 42-1.2.3 43-1.2.3.3 44-1.2.3.3.1.1 45-1.2.3.3.1 47-1.2.3.2 48-1.2.3.2.1.1.1.1 48-1.2.3.2.1.1.1.1.r 49-1.2.3.2.1.1.1 50-1.2.3.2.1.1 52-1.2.3.2.1 55-1.2.2.4.1 56-1.2.2.4.2 59-1.3.1 (a / and :op1 (a2 / abrogate-01~e.21 :ARG0 (a4 / administer-01~e.0 :ARG1~e.1 (s / small-molecule~e.5 :name (n / name :op1 "E6201"~e.2) :ARG2-of~e.5 (d3 / dose-01~e.5 :mod (a5 / all~e.4)) :quant (c6 / concentration-quantity :quant (a6 / and~e.10 :op1 10~e.7 :op2 20~e.9 :op3 40~e.11) :unit (m / milligram-per-kilogram))) :ARG2~e.14 (m2 / mouse~e.19 :ARG0-of (b / bear-01~e.18 :ARG1 (t4 / tumor~e.16 :mod (c5 / cell-line :name (n2 / name :op1 "MM540"~e.15)))))) :ARG1 g~e.22,23 :degree (c4 / complete~e.20)) :op2 (c2 / cause-01~e.25 :ARG0 a4 :ARG1 (r2 / regress-01 :ARG1 t~e.29 :ARG1-of (t2 / transient-02~e.26) :degree~e.28 (p / part~e.28) :duration (t3 / temporal-quantity :quant 2~e.33,55 :unit (w2 / week~e.34,56) :time-of (t5 / treat-04~e.37 :ARG2 d2~e.36))) :concession~e.39 (r / recommence-01~e.42 :ARG1 (g / grow-01~e.41 :ARG1 (t / tumor~e.40)) :ARG0-of (i / indicate-01~e.47 :ARG1 (k / kill-01~e.52 :ARG1 (c3 / cell~e.50 :mod (a3 / all~e.49 :polarity~e.48 -~e.48)))) :ARG1-of (f2 / follow-01~e.43 :ARG2 (w / withdraw-01~e.45 :ARG1 (d2 / drug~e.44))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.59 :mod "4A"))) # ::id pmid_2303_9341.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 at 40 mg @/@ kg in MM604 and SKMEL13 xenografts prevented tumour progression for the two weeks of drug treatment , with tumour growth recommencing following drug removal , while lower doses of drug ( 10 and 20 mg/kg ) only attenuated , rather than prevented , tumour growth in vivo ( Figure 4 @ B and C ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.2.1 3-1.1.1.1.2.2 5-1.1.1.1.2.2 5-1.2.1.1.3.1.2 5-1.2.1.1.3.2.2 6-1.2.2.2.2 7-1.1.1.1.3.1.1.1.1 8-1.1.1.1.3 9-1.1.1.1.3.2.1.1.1 10-1.1.1.1.3.1 10-1.1.1.1.3.2 11-1.1.1 12-1.1.1.2.1 13-1.1.1.2 14-1.1.1.3.r 16-1.1.1.3.2.1 17-1.1.1.3.2.2 19-1.1.1.3.1 20-1.1.1.3 23-1.1.2.1.1 24-1.1.2.1 25-1.1.2 26-1.1.2.2 27-1.1.2.2.1.1 28-1.1.2.2.1 30-1 31-1.2.1.1.2 31-1.2.1.1.2.1 31-1.2.1.1.2.1.r 32-1.2.1.1 33-1.2 33-1.2.1.1.1.r 34-1.2.1.1.1 36-1.2.1.1.3.1.1 37-1.2.1.1.3 38-1.2.1.1.3.2.1 41-1.2.1.2 42-1.2.1 44-1.2 46-1.2.2 48-1.1.2.1.1 49-1.2.2.2 51-1.2.2.2.2 52-1.2.2.2.2 55-1.3.1.1 55-1.3.1.2 60-1.3.1 (c / contrast-01~e.30 :ARG1 (a4 / and :op1 (p / prevent-01~e.11 :ARG0 (s / small-molecule :name (n / name :op1 "E6201"~e.0) :quant (c2 / concentration-quantity :quant 40~e.2 :unit (m2 / milligram-per-kilogram~e.3,5)) :location (a / and~e.8 :op1 (x / xenograft~e.10 :mod (c3 / cell-line :name (n2 / name :op1 "MM604"~e.7))) :op2 (x2 / xenograft~e.10 :mod (c4 / cell-line :name (n3 / name :op1 "SKMEL13"~e.9))))) :ARG1 (p2 / progress-01~e.13 :ARG1 t3~e.12) :time~e.14 (t2 / treat-04~e.20 :ARG2 (d / drug~e.19) :duration (t / temporal-quantity :quant 2~e.16 :unit (w / week~e.17)))) :op2 (r / recommence-01~e.25 :ARG1 (g / grow-01~e.24 :ARG1 (t3 / tumor~e.23,48)) :ARG1-of (f / follow-01~e.26 :ARG2 (r2 / remove-01~e.28 :ARG1 d~e.27)))) :ARG2 (i2 / instead-of-91~e.33,44 :ARG1 (a2 / attenuate-01~e.42 :ARG0 (d2 / dose-01~e.32 :ARG2~e.33 d~e.34 :ARG1-of (l / low-04~e.31 :degree~e.31 (m / more~e.31)) :quant (a5 / and~e.37 :op1 (c5 / concentration-quantity :quant 10~e.36 :unit (m3 / milligram-per-kilogram~e.5)) :op2 (c6 / concentration-quantity :quant 20~e.38 :unit (m4 / milligram-per-kilogram~e.5)))) :mod (o / only~e.41)) :ARG2 (p3 / prevent-01~e.46 :ARG0 d2 :ARG1 (g2 / grow-01~e.49 :ARG1 t3 :manner (i / in-vivo~e.6,51,52)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.60 :op1 (f2 / figure~e.55 :mod "4B") :op2 (f3 / figure~e.55 :mod "4C")))) # ::id pmid_2303_9341.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only the highest dose of E6201 ( 40 mg/kg ) had any significant inhibitory effect on tumour growth in BL tumour @-@ bearing mice , while lower drug doses had little or no effect on tumour progression ( Figure 4 @ D ) . # ::alignments 0-1.1.1.3 2-1.1.1.2 2-1.1.1.2.1 2-1.1.1.2.1.r 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1.1.1.2.1 11-1.1.4 12-1.1.3 13-1.1.2 14-1.1 15-1.1.2.1.r 16-1.1.2.1.2.1.1 17-1.1.2.1 19-1.1.2.1.2.1.1.1.1.1 20-1.1.2.1.2.1.1 22-1.1.2.1.2.1 23-1.1.2.1.2 25-1 26-1.2.1.1.2 26-1.2.1.1.2.1 26-1.2.1.1.2.1.r 27-1.2.1.1.1 28-1.2.1.1 30-1.2.1.3 31-1.2 32-1.2.2.1 32-1.2.2.1.r 33-1.2.1 33-1.2.2 34-1.2.1.2.r 35-1.2.1.2.1 36-1.2.1.2 38-1.3.1 (c / contrast-01~e.25 :ARG1 (a / affect-01~e.14 :ARG0 (d4 / dose-01~e.3 :ARG2~e.4 (s3 / small-molecule :name (n / name :op1 "E6201"~e.5) :quant (c3 / concentration-quantity :quant 40~e.7 :unit (m3 / milligram-per-kilogram))) :ARG1-of (h / high-02~e.2 :degree~e.2 (m2 / most~e.2)) :mod (o2 / only~e.0)) :ARG2 (i / inhibit-01~e.13 :ARG1~e.15 (g / grow-01~e.17 :ARG1 t :location (m4 / mouse~e.23 :ARG0-of (b / bear-01~e.22 :ARG1 (t2 / tumor~e.16,20 :mod (c2 / cell-line :name (n2 / name :op1 "BL"~e.19))))))) :ARG1-of (s2 / significant-02~e.12) :mod (a4 / any~e.11)) :ARG2 (o / or~e.31 :op1 (a2 / affect-01~e.33 :ARG0 (d2 / dose-01~e.28 :ARG1 (d3 / drug~e.27) :ARG1-of (l2 / low-04~e.26 :degree~e.26 (m / more~e.26))) :ARG1~e.34 (p / progress-01~e.36 :ARG1 (t / tumor~e.35)) :mod (l / little~e.30)) :op2 (a3 / affect-01~e.33 :polarity~e.32 -~e.32 :ARG0 d2 :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.38 :mod "4D"))) # ::id pmid_2303_9341.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As such our hypothesis was confirmed , with E6201 inhibiting xenograft tumour growth in all four melanoma cell lines studied , and enhanced in vivo activity observed for those cell lines that demonstrated a cytocidal response in vitro @ . # ::alignments 0-1.3 1-1.3 2-1.2.1.1 2-1.2.1.1.r 3-1.2 3-1.2.1 3-1.2.1.r 5-1 7-1.1.r 8-1.1.1.1.1.1 9-1.1.1 10-1.1.1.2.1.1 11-1.1.1.2.1 12-1.1.1.2 13-1.1.1.3.r 13-1.1.2.1.1 14-1.1.1.3.2 15-1.1.1.3.1 16-1.1.1.3.5.1.1 17-1.1.1.3 18-1.1.1.3 19-1.1.1.3.3 21-1.1 22-1.1.2 24-1.1.2.1.1 25-1.1.2.1.1 27-1.1.2.1 28-1.1.2.1.2 29-1.1.1.3.4.r 30-1.1.1.3.4 31-1.1.2.1.2.1 32-1.1.2.1.2.1 33-1.1.2.1.2.1.2 34-1.1.2.1.2.1.1 36-1.1.2.1.2.1.1.1.1.1 37-1.1.2.1.2.1.1.1 37-1.1.2.1.2.1.1.1.1 37-1.1.2.1.2.1.1.1.1.r 39-1.1.2.1.2.1.1.1.1.2 40-1.1.2.1.2.1.1.1.1.2 (c / confirm-01~e.5 :ARG0~e.7 (a2 / and~e.21 :op1 (i / inhibit-01~e.9 :ARG0 (s2 / small-molecule :name (n / name :op1 "E6201"~e.8)) :ARG1 (g / grow-01~e.12 :ARG1 (t2 / tumor~e.11 :mod (x / xenograft~e.10))) :location~e.13 (c2 / cell-line~e.17,18 :quant 4~e.15 :mod (a3 / all~e.14) :ARG1-of (s / study-01~e.19) :mod~e.29 (t4 / that~e.30) :source (m / medical-condition :name (n2 / name :op1 "melanoma"~e.16)))) :op2 (e / enhance-01~e.22 :ARG1 (a4 / activity-06~e.27 :manner (i2 / in-vivo~e.13,24,25) :ARG1-of (o / observe-01~e.28 :location (c3 / cell-line~e.31,32 :ARG0-of (d / demonstrate-01~e.34 :ARG1 (t3 / thing~e.37 :ARG2-of~e.37 (r / respond-01~e.37 :mod (c4 / cytocidal~e.36) :manner (i3 / in-vitro~e.39,40)))) :mod (t5 / that~e.33)))))) :ARG1 (t / thing~e.3 :ARG1-of~e.3 (h / hypothesize-01~e.3 :ARG0~e.2 (w / we~e.2))) :mod (a / as-such~e.0,1)) # ::id pmid_2303_9341.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok E6201 and LY294002 # ::alignments 1-1.1.1.1 2-1 3-1.2.1.1 (a / and~e.2 :op1 (s / small-molecule :name (n / name :op1 "E6201"~e.1)) :op2 (s2 / small-molecule :name (n2 / name :op1 "LY294002"~e.3))) # ::id pmid_2303_9341.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given our previous data suggesting that E6201 resistance is associated with mutation of PTEN and high levels of pAkt , we hypothesized that combining E6201 with an inhibitor of the PI3K pathway in these cell lines might result in either an additive or synergistic effect . # ::alignments 0-1.3.1.3 1-1.3.1.1 1-1.3.1.1.r 2-1.3.1.2 3-1.3.1 4-1.3.1.3 5-1.3.1.3.1.r 6-1.3.1.3.1.1 7-1.3.1.3.1 9-1.3.1.3.1.2 10-1.3.1.3.1.2.1.r 11-1.3.1.3.1.2.1.1 14-1.3.1.3.1.2.1.1.1.1.1 16-1.3.1.3.1.2.1 17-1.3.1.3.1.2.1.2.1 18-1.3.1.3.1.2.1.2 19-1.3.1.3.1.2.1.2.2.r 20-1.3.1.3.1.2.1.2.2.1.1 20-1.3.1.3.1.2.1.2.2.2 22-1.1 23-1 24-1.2.r 25-1.2.1 26-1.2.1.1.1.1 27-1.2.1.2.r 29-1.2.1.2 29-1.2.1.2.1 29-1.2.1.2.1.r 30-1.2.1.2.1.1.r 32-1.2.1.2.1.1.1.1 33-1.2.1.2.1.1 34-1.2.1.3.r 35-1.2.1.3.1 36-1.2.1.3 37-1.2.1.3 38-1.2.3 39-1.2 43-1.2.2.1.1 44-1.2.2.1 45-1.2.2.1.2 46-1.2.2 (h3 / hypothesize-01~e.23 :ARG0 (w2 / we~e.22) :ARG1~e.24 (r2 / result-01~e.39 :ARG1 (c / combine-01~e.25 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "E6201"~e.26)) :ARG2~e.27 (m / molecular-physical-entity~e.29 :ARG0-of~e.29 (i2 / inhibit-01~e.29 :ARG1~e.30 (p4 / pathway~e.33 :name (n5 / name :op1 "PI3K"~e.32)))) :location~e.34 (c2 / cell-line~e.36,37 :mod (t / this~e.35))) :ARG2 (a3 / affect-01~e.46 :ARG2 (o / or~e.44 :op1 (a4 / add-02~e.43) :op2 (s2 / synergize-01~e.45))) :ARG1-of (p5 / possible-01~e.38)) :ARG1-of (i / infer-01 :ARG2 (d / data~e.3 :poss~e.1 (w / we~e.1) :time (p / previous~e.2) :ARG0-of (s / suggest-01~e.0,4 :ARG1~e.5 (r / resist-01~e.7 :ARG0 s3~e.6 :ARG1-of (a / associate-01~e.9 :ARG2~e.10 (a2 / and~e.16 :op1 (m2 / mutate-01~e.11 :ARG1 (g / gene :name (n2 / name :op1 "PTEN"~e.14))) :op2 (l / level~e.18 :ARG1-of (h / high-02~e.17) :quant-of~e.19 (e / enzyme :name (n3 / name :op1 "Akt"~e.20) :ARG3-of (p6 / phosphorylate-01~e.20)))))))))) # ::id pmid_2303_9341.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additional file 2 : Figure S2 demonstrates that LY294002 effectively inhibits PI3K by evidence of reduced phosphorylated AKT protein levels in the four PTEN @ -@ mutant melanoma cell lines that normally express high levels of pAKT ( UACC647 , UACC558 , UACC903 and MM622 ) . # ::alignments 1-1.1.1.2 2-1.1.1 3-1.1.1.1 3-1.1.2.1 5-1.1.2 8-1 9-1.2.r 10-1.2.1.1.1 11-1.2.3 12-1.2 13-1.2.2.1.1 14-1.3.r 15-1.3 16-1.3.1.r 17-1.3.1.2 18-1.3.1.1.2 19-1.3.1.1.1.1 21-1.3.1 22-1.3.2.r 24-1.3.2.1 26-1.3.2.4.2.1.1 29-1.3.2.4.2 29-1.3.2.4.2.2 29-1.3.2.4.2.2.r 30-1.3.2.4.1.1 31-1.3.2 32-1.3.2 34-1.3.2.2.2 35-1.3.2.2 36-1.3.2.2.1.1 37-1.3.2.2.1 38-1.3.2.2.1.2.r 39-1.3.2.2.1.2 41-1.3.2.3.1.1.1 43-1.3.2.3.2.1.1 45-1.3.2.3.3.1.1 46-1.3.2.3 47-1.3.2.3.4.1.1 (d / demonstrate-01~e.8 :ARG0 (a2 / and :op1 (f / file~e.2 :mod 2~e.3 :mod (a3 / additional~e.1)) :op2 (f2 / figure~e.5 :mod 2~e.3)) :ARG1~e.9 (i / inhibit-01~e.12 :ARG0 (s / small-molecule :name (n / name :op1 "LY294002"~e.10)) :ARG1 (e6 / enzyme :name (n2 / name :op1 "PI3K"~e.13)) :ARG1-of (e / effective-04~e.11)) :ARG1-of~e.14 (e2 / evidence-01~e.15 :ARG0~e.16 (l / level~e.21 :mod (e7 / enzyme :name (n3 / name :op1 "AKT"~e.19) :ARG3-of (p3 / phosphorylate-01~e.18)) :ARG1-of (r / reduce-01~e.17)) :location~e.22 (c / cell-line~e.31,32 :quant 4~e.24 :ARG3-of (e3 / express-03~e.35 :ARG2 (l2 / level~e.37 :ARG1-of (h / high-02~e.36) :quant-of~e.38 e7~e.39) :ARG1-of (n5 / normal-02~e.34)) :example (a / and~e.46 :op1 (c2 / cell-line :name (n7 / name :op1 "UACC647"~e.41)) :op2 (c3 / cell-line :name (n8 / name :op1 "UACC558"~e.43)) :op3 (c4 / cell-line :name (n9 / name :op1 "UACC903"~e.45)) :op4 (c5 / cell-line :name (n10 / name :op1 "MM622"~e.47))) :source (m / medical-condition :name (n6 / name :op1 "melanoma"~e.30) :mod (g / gene~e.29 :name (n4 / name :op1 "PTEN"~e.26) :ARG2-of~e.29 (m4 / mutate-01~e.29)))))) # ::id pmid_2303_9341.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , Additional file 3 : Figures S3 and Additional file 4 : Figure S4 show the concentration @-@ effect curves for single @-@ agent LY294002 and E6201 respectively , where both drugs were added 24 hours following plating . # ::alignments 0-1.1.2 0-1.1.2.3.1 1-1.1.2 1-1.1.2.3 1-1.1.2.3.1 1-1.1.2.3.1.r 4-1.1.1.1.2.2 5-1.1.1.1.2 6-1.1.1.1.2.1 8-1.1.1.1 9-1.1.1.1.1 13-1.1.1.2.2.2 14-1.1.1.2.2 15-1.1.1.2.2.1 17-1.1.1.2 18-1.1.1.2.1 20-1.1 22-1.1.2.1.2.1 24-1.1.2.1.2 25-1.1.2.1 25-1.1.2.2 26-1.1.2.1.1.r 27-1.1.2.1.1.1 29-1.1.2.1.1 29-1.1.2.2.1 30-1.1.2.1.1.2.1.1 31-1.1.2 32-1.1.2.2.1.1.1.1 35-1.1.2.3.r 39-1.1.2.3 40-1.1.2.3.2.2.1 41-1.1.2.3.2.2.2 42-1.1.2.3.2 43-1.1.2.3.2.1 (a / and :op2 (s / show-01~e.20 :ARG0 (a2 / and :op1 (f / figure~e.8 :mod "S3"~e.9 :location (f3 / file~e.5 :mod 3~e.6 :mod (a7 / additional~e.4))) :op2 (f2 / figure~e.17 :mod "S4"~e.18 :location (f4 / file~e.14 :mod 4~e.15 :mod a7~e.13))) :ARG1 (a8 / and~e.0,1,31 :op1 (c / curve~e.25 :beneficiary~e.26 (a4 / agent~e.29 :ARG1-of (s2 / single-02~e.27) :mod (s3 / small-molecule :name (n / name :op1 "LY294002"~e.30))) :topic (a3 / affect-01~e.24 :ARG0 (c2 / concentrate-02~e.22))) :op2 (c3 / curve~e.25 :beneficiary (a5 / agent~e.29 :mod (s5 / small-molecule :name (n2 / name :op1 "E6201"~e.32))) :topic a3) :location-of~e.35 (a6 / add-on-05~e.1,39 :ARG1~e.1 (a10 / and~e.0,1 :op1 s3 :op2 s5) :ARG1-of (f5 / follow-01~e.42 :ARG2 (p / plate-00~e.43) :quant (t / temporal-quantity :quant 24~e.40 :unit (h / hour~e.41))))))) # ::id pmid_2303_9341.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The six melanoma cell lines tested displayed similar trends in E6201 sensitivity compared to our previous experiments , with MM622 , MM540 , UACC903 , and WM35 being the most sensitive ( IC50 = 40 @-@ 61 nM ) and UACC558 and UACC647 being less sensitive ( 302 and 2310 nM , respectively ) . # ::alignments 1-1.1.1 2-1.1.3.1.1 3-1.1 4-1.1 5-1.1.2 6-1 7-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1.2.1.1 11-1.2.1 12-1.2.3 13-1.2.3.1.r 14-1.2.3.1.1 14-1.2.3.1.1.r 15-1.2.3.1.2 16-1.2.3.1 18-1.2.1.1.r 19-1.2.1.1.1.1.1 21-1.2.1.1.2.1.1 23-1.2.1.1.3.1.1 25-1.2.1.1.5.1 26-1.2.1.1.4.1.1 29-1.3 30-1.2.1.1.5.1.3 34-1.2.1.1.6.2.1.1 36-1.2.1.1.6.2.1.2 37-1.2.1.1.5.1.4.1.1.1 37-1.2.1.1.6.2.2 39-1.2.1.1 40-1.2.1.1.5.1.1.1.1 42-1.2.1.1.5.1.2.1.1 44-1.2.1.1.5.1.3.1 45-1.2.1.1.5.1.3 47-1.2.1.1.5.1.4.1.1.2.1 48-1.2.1.1.5.1.4.1.1.2 49-1.2.1.1.5.1.4.1.1.2.2 50-1.2.1.1.5.1.4.1.1.1 50-1.2.1.1.6.2.2 (d / display-01~e.6 :ARG0 (c / cell-line~e.3,4 :quant 6~e.1 :ARG1-of (t / test-01~e.5) :mod (m / medical-condition :name (n12 / name :op1 "melanoma"~e.2))) :ARG1 (t2 / trend-01~e.8 :ARG2~e.9 (s / sensitive-03~e.11 :ARG0~e.18 (a / and~e.39 :op1 (c4 / cell-line :name (n2 / name :op1 "MM622"~e.19)) :op2 (c5 / cell-line :name (n3 / name :op1 "MM540"~e.21)) :op3 (c6 / cell-line :name (n4 / name :op1 "UACC903"~e.23)) :op4 (c9 / cell-line :name (n5 / name :op1 "WM35"~e.26)) :ARG1-of (c3 / contrast-01 :ARG2 (a2 / and~e.25 :op1 (c8 / cell-line :name (n6 / name :op1 "UACC558"~e.40)) :op1 (c7 / cell-line :name (n7 / name :op1 "UACC647"~e.42)) :ARG1-of (s2 / sensitive-03~e.30,45 :degree (l / less~e.44)) :mod (c12 / concentrate-02 :ARG1-of (e3 / equal-01 :ARG2 (c11 / concentration-quantity :unit (n9 / nanomolar~e.37,50) :quant (a3 / and~e.48 :op1 302~e.47 :op2 2310~e.49))) :mod (i / inhibit-01 :degree (p2 / percentage-entity :value 50))))) :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (c10 / concentration-quantity :quant (v / value-interval :op1 40~e.34 :op2 61~e.36) :unit (n8 / nanomolar~e.37,50)))) :ARG1 (s3 / small-molecule :name (n / name :op1 "E6201"~e.10))) :ARG1-of (r / resemble-01~e.7) :ARG1-of (c2 / compare-01~e.12 :ARG2~e.13 (e / experiment-01~e.16 :ARG0~e.14 (w / we~e.14) :time (p / previous~e.15)))) :degree (m2 / most~e.29)) # ::id pmid_2303_9341.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Surprisingly , all cell lines showed similar sensitivity to LY294002 , with IC50 ranging from 11 μM to 17 μM . # ::alignments 0-1.3 2-1.1.1 3-1.1 4-1.1 5-1 6-1.2.3 7-1.2 8-1.2.2.r 9-1.2.2.1.1 13-1.2.1 14-1.2.1 15-1.2.1 16-1.2.1 17-1.2.1 18-1.2.1 19-1.1.2.1.1.2.2 (s / show-01~e.5 :ARG0 (c / cell-line~e.3,4 :mod (a / all~e.2) :ARG0-of (h / have-03 :ARG1 (c4 / concentrate-02 :ARG1-of (r2 / range-01 :ARG3 (c2 / concentration-quantity :quant 11 :unit (m / micromolar)) :ARG4 (c3 / concentration-quantity :quant 17 :unit m~e.19)) :mod (i / inhibit-01 :degree (p / percentage-entity :value 50))))) :ARG1 (s2 / sensitive-03~e.7 :ARG0 c~e.13,14,15,16,17,18 :ARG1~e.8 (s4 / small-molecule :name (n / name :op1 "LY294002"~e.9)) :ARG1-of (r / resemble-01~e.6)) :ARG0-of (s3 / surprise-01~e.0)) # ::id pmid_2303_9341.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was unexpected , as one would predict MM540 and WM35 cells to be relatively resistant to PI3K inhibition given the lack of detectable levels of pAkt indicating no constitutive PI3K activation in these cell lines . # ::alignments 0-1.2 2-1 2-1.1 2-1.1.r 7-1.3.1 8-1.3.1.2.1.1.1.1 9-1.3.1.2.1 10-1.3.1.2.1.2.1.1 11-1.3.1.2.1.1 11-1.3.1.2.1.2 12-1.3.1.2.4 14-1.3.1.2.3 15-1.3.1.2 16-1.3.1.2.2.r 16-1.3.1.2.4 17-1.3.1.2.2.1.1.1 18-1.3.1.2.2 21-1.3.1.2.4.1 22-1.3.1.2.4.1.1.r 23-1.3.1.2.4.1.1.1 24-1.3.1.2.4.1.1 25-1.3.1.2.4.1.1.2.r 26-1.3.1.2.4.1.1.2.1.1 26-1.3.1.2.4.1.1.2.2 27-1.3.1.2.4.1.2 28-1.3.1.2.4.1.2.1.1 28-1.3.1.2.4.1.2.1.1.r 29-1.3.1.2.4.1.2.1.3 30-1.3.1.2.4.1.2.1.2 31-1.3.1.2.4.1.2.1 33-1.2 34-1.3.1.2.1.1 35-1.3.1.2.1.1 (e / expect-01~e.2 :polarity~e.2 -~e.2 :ARG1 (t / this~e.0,33) :ARG0-of (c / cause-01 :ARG1 (p / predict-01~e.7 :ARG0 (p2 / person) :ARG1 (r / resist-01~e.15 :ARG0 (a / and~e.9 :op1 (c2 / cell-line~e.11,34,35 :name (n / name :op1 "MM540"~e.8)) :op2 (c3 / cell-line~e.11 :name (n2 / name :op1 "WM35"~e.10))) :ARG1~e.16 (i / inhibit-01~e.18 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PI3K"~e.17))) :ARG2-of (r2 / relative-05~e.14) :ARG1-of (c4 / cause-01~e.12,16 :ARG0 (l / lack-01~e.21 :ARG1~e.22 (l2 / level~e.24 :ARG1-of (d / detect-01~e.23 :ARG1-of (p4 / possible-01)) :quant-of~e.25 (e3 / enzyme :name (n4 / name :op1 "Akt"~e.26) :ARG3-of (p3 / phosphorylate-01~e.26))) :ARG0-of (i2 / indicate-01~e.27 :ARG1 (a2 / activate-01~e.31 :polarity~e.28 -~e.28 :ARG1 e2~e.30 :manner (c5 / constitutive~e.29) :location a)))))))) # ::id pmid_2303_9341.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A previous study by Smalley and others [ @ 26 @ ] , however , reported a similar sensitivity of WM35 cells to LY294002 . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1 9-1.1.3.1.1.1 13-1.3 15-1 17-1.2.3 18-1.2 19-1.2.1.r 20-1.2.1.1.1 21-1.2.1 22-1.2.2.r 23-1.2.2.1.1 (r / report-01~e.15 :ARG0 (s / study-01~e.2 :ARG0~e.3 (a / and~e.5 :op1 (p2 / person :name (n / name :op1 "Smalley"~e.4)) :op2 (p4 / person :mod (o / other~e.6))) :time (p / previous~e.1) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0-of (c / cite-01 :ARG2 26~e.9)))) :ARG1 (s2 / sensitive-03~e.18 :ARG0~e.19 (c2 / cell-line~e.21 :name (n2 / name :op1 "WM35"~e.20)) :ARG1~e.22 (s3 / small-molecule :name (n3 / name :op1 "LY294002"~e.23)) :ARG1-of (r2 / resemble-01~e.17)) :ARG2-of (c3 / contrast-01~e.13)) # ::id pmid_2303_9341.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The concentration response curves for E6201 and LY294002 combinations , normalized to a dimethyl sulfoxide ( DMSO ) control are given in Additional file 4 : Figure S4 @ . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.1.1.1.r 5-1.1.1.1.1.1.1.1 7-1.1.1.1.1.2.1.1 8-1.1.1.1.1 10-1.1.2 16-1.1.2.1.1.1.1 18-1.1.2.1 20-1 23-1.2.2.2 24-1.2.2 25-1.2.2.1 27-1.2 28-1.2.1 (g / give-01~e.20 :ARG1 (c / curve~e.3 :mod (r / respond-01~e.2 :ARG1 (c2 / concentrate-02~e.1 :ARG1~e.4 (c3 / combine-01~e.8 :ARG1 (s / small-molecule :name (n / name :op1 "E6201"~e.5)) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "LY294002"~e.7))))) :ARG1-of (n3 / normalize-01~e.10 :topic (c4 / control-01~e.18 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "DMSO"~e.16))))) :location (f / figure~e.27 :mod "S4"~e.28 :location (f2 / file~e.24 :mod 4~e.25 :mod (a / additional~e.23)))) # ::id pmid_2303_9341.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As differences in synergy may exist at different drug effect levels , we graphed individual combination index values for LY294002 with increasing concentrations of E6201 for each cell line ( Figure 5 @ A ) . # ::alignments 1-1.1.1.1 3-1.1.1.1.1 4-1.1 5-1.1.1 7-1.1.1.1 7-1.1.1.2.1 8-1.1.1.2.2.1 9-1.1.1.2.2 10-1.1.1.2 12-1.2.1 13-1.2 14-1.2.2.1 15-1.2.2.2 16-1.2.2.3 17-1.2.2 18-1.2.3.r 19-1.2.3.1.1 20-1.2.4.r 21-1.2.4.2 22-1.2.4 23-1.2.4.1.r 24-1.2.4.1.1.1 25-1.2.5.r 26-1.2.5.1 27-1.2.5 28-1.2.5 30-1.2.6.1 (c / cause-01 :ARG0 (p / possible-01~e.4 :ARG1 (e / exist-01~e.5 :ARG1 (d / differ-02~e.1,7 :ARG2 (s / synergize-01~e.3)) :location (l / level~e.10 :ARG1-of (d2 / differ-02~e.7) :degree-of (a / affect-01~e.9 :ARG0 (d3 / drug~e.8))))) :ARG1 (g / graph-00~e.13 :ARG0 (w / we~e.12) :ARG1 (v / value~e.17 :mod (i / individual~e.14) :mod (c2 / combine-01~e.15) :mod (i2 / index~e.16)) :value-of~e.18 (s2 / small-molecule :name (n / name :op1 "LY294002"~e.19)) :accompanier~e.20 (c3 / concentrate-02~e.22 :ARG1~e.23 (s3 / small-molecule :name (n2 / name :op1 "E6201"~e.24)) :ARG1-of (i3 / increase-01~e.21)) :location~e.25 (c4 / cell-line~e.27,28 :mod (e2 / each~e.26)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.30 :mod "5A")))) # ::id pmid_2303_9341.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 5 @ A , evaluating the individual combination index for all combinations tested revealed that E6201 and LY294002 exhibit synergistic activity in all six melanoma cell lines , irrespective of E6201 sensitivity or PTEN or pAkt status . # ::alignments 1-1.3 2-1.3.1.r 3-1.3.1 9-1.1 11-1.1.1.1.1 12-1.1.1.1 13-1.1.1 14-1.1.1.2.r 15-1.1.1.2.1 16-1.1.1.2 17-1.1.1.2.2 18-1 19-1.2.r 20-1.2.1.1.1.1 21-1.2.1 22-1.2.1.2.1.1 23-1.2 24-1.2.2.1 25-1.2.2 26-1.2.2.2.r 27-1.2.2.2.3 28-1.2.2.2.1 29-1.2.2.2.2.1.1 30-1.2.2.2 31-1.2.2.2 33-1.2.2.3 35-1.2.2.3.1.1.1 36-1.2.2.3.1.1 37-1.2.2.3.1 39-1.2.2.3.1.2.1.1.1.1 41-1.2.2.3.1 42-1.2.2.3.1.2.1.2.1.1 42-1.2.2.3.1.2.1.2.2 43-1.2.2.3.1.2 (r / reveal-01~e.18 :ARG0 (e / evaluate-01~e.9 :ARG1 (i / index~e.13 :mod (c / combine-01~e.12 :manner (i2 / individual~e.11)) :beneficiary~e.14 (c2 / combine-01~e.16 :mod (a / all~e.15) :ARG1-of (t / test-01~e.17)))) :ARG1~e.19 (e2 / exhibit-01~e.23 :ARG0 (a2 / and~e.21 :op1 (s5 / small-molecule :name (n / name :op1 "E6201"~e.20)) :op2 (s6 / small-molecule :name (n2 / name :op1 "LY294002"~e.22))) :ARG1 (a3 / activity-06~e.25 :ARG1 (s / synergize-01~e.24) :location~e.26 (c3 / cell-line~e.30,31 :quant 6~e.28 :mod (m / medical-condition :name (n3 / name :op1 "melanoma"~e.29)) :mod (a4 / all~e.27)) :ARG1-of (r2 / regardless-91~e.33 :ARG2 (o / or~e.37,41 :op1 (s2 / sensitive-03~e.36 :ARG1 s5~e.35) :op2 (s3 / status~e.43 :poss (a5 / and :op1 (p / protein :name (n5 / name :op1 "PTEN"~e.39)) :op2 (e3 / enzyme :name (n6 / name :op1 "Akt"~e.42) :ARG3-of (p2 / phosphorylate-01~e.42)))))))) :ARG1-of (s4 / show-01~e.1 :ARG0~e.2 (f / figure~e.3 :mod "5A"))) # ::id pmid_2303_9341.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , different patterns of synergy were observed among the groups of cell lines tested . # ::alignments 0-1.2 2-1.1.2 3-1.1 4-1.1.1.r 5-1.1.1 7-1 8-1.1.3 10-1.1.3.1 11-1.1.3.1.1.r 12-1.1.3.1.1 13-1.1.3.1.1 14-1.1.3.1.1.1 (o / observe-01~e.7 :ARG1 (p / pattern-01~e.3 :ARG1~e.4 (s / synergize-01~e.5) :ARG1-of (d / differ-02~e.2) :ARG1-of (i / include-91~e.8 :ARG2 (g / group~e.10 :consist-of~e.11 (c / cell-line~e.12,13 :ARG1-of (t / test-01~e.14))))) :ARG2-of (i2 / interest-01~e.0)) # ::id pmid_2303_9341.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While most ( 4 @/@ 6 ) of the cell lines showed an increasing combination index ( and thus decreasing synergy ) at higher concentrations of E6201 , UACC647 and UACC558 cells showed a decreasing combination index or enhanced synergy with increasing concentrations of E6201 . # ::alignments 0-1 1-1.1.1.2.2 3-1.1.1.1 5-1.1.1.2.1.1 9-1.1.1 9-1.1.1.2.1 10-1.1.1 11-1.1 13-1.1.2.1.1 14-1.1.2.1 15-1.1.2 18-1.1.3 19-1.1.3.1 20-1.1.3.1.1 22-1.1.4.r 23-1.1.4.2 24-1.1.4 25-1.1.4.1.r 26-1.1.4.1.1.1 28-1.2.1.1.1.1 29-1.2.1 30-1.2.1.2.1.1 31-1.2.1.1 31-1.2.1.2 32-1.2 34-1.2.2.1.1.1 35-1.2.2.1.1 36-1.2.2.1 37-1.2.2 38-1.2.2.2.1 39-1.2.2.2 40-1.2.2.2.2.r 41-1.2.2.2.2.2 42-1.2.2.2.2 43-1.2.2.2.2.1.r 44-1.2.2.2.2.1 (c / contrast-01~e.0 :ARG1 (s / show-01~e.11 :ARG0 (c2 / cell-line~e.9,10 :quant 4~e.3 :ARG1-of (i5 / include-91 :ARG2 (c8 / cell-line~e.9 :quant 6~e.5) :ARG3 (m / most~e.1))) :ARG1 (i / index~e.15 :mod (c3 / combine-01~e.14 :ARG1-of (i2 / increase-01~e.13))) :ARG0-of (c4 / cause-01~e.18 :ARG1 (d2 / decrease-01~e.19 :ARG1 (s2 / synergize-01~e.20))) :condition~e.22 (c5 / concentrate-02~e.24 :ARG1~e.25 (s5 / small-molecule :name (n / name :op1 "E6201"~e.26)) :ARG1-of (h / high-02~e.23))) :ARG2 (s3 / show-01~e.32 :ARG0 (a / and~e.29 :op1 (c9 / cell-line~e.31 :name (n2 / name :op1 "UACC647"~e.28)) :op2 (c10 / cell-line~e.31 :name (n3 / name :op1 "UACC558"~e.30))) :ARG1 (o / or~e.37 :op1 (i3 / index~e.36 :mod (c6 / combine-01~e.35 :ARG1-of (d / decrease-01~e.34))) :op2 (s4 / synergize-01~e.39 :ARG1-of (e / enhance-01~e.38) :condition~e.40 (c7 / concentrate-02~e.42 :ARG1~e.43 s5~e.44 :ARG1-of (i4 / increase-01~e.41)))))) # ::id pmid_2303_9341.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , this pattern observed for UACC647 and UACC558 cells occurs within the context of high pAkt and relative resistance to E6201 , supporting the hypothesis that administration of a PI3K inhibitor can sensitize E6201 @-@ resistant cells with high pAkt levels to E6201 . # ::alignments 0-1.1 2-1.2 3-1 4-1.3 5-1.4.r 6-1.4.1.1.1 7-1.4 8-1.4.2.1.1 9-1.4.1 9-1.4.2 11-1.6.1.1.2.2.1.r 13-1.5 14-1.5.1.r 15-1.5.1.1 15-1.5.1.1.3 15-1.5.1.1.3.r 16-1.5.1.1.1.1 16-1.5.1.1.2 17-1.5.1 18-1.5.1.2.2 19-1.5.1.2 20-1.5.1.2.1.r 21-1.5.1.2.1.1.1 23-1.6 25-1.6.1 27-1.6.1.1.1 28-1.6.1.1.1.1.r 30-1.6.1.1.1.1.1.1.1.1 31-1.6.1.1.1.1 31-1.6.1.1.1.1.1 31-1.6.1.1.1.1.1.r 32-1.6.1.1.4 33-1.6.1.1 34-1.6.1.1.2.1.1 36-1.6.1.1.2.1 37-1.6.1.1.2 39-1.6.1.1.2.2.1 40-1.6.1.1.2.2.1 41-1.6.1.1.2.2 42-1.6.1.1.3.r 43-1.6.1.1.3 (p3 / pattern~e.3 :ARG1-of (n6 / notable-04~e.0) :mod (t / this~e.2) :ARG1-of (o2 / observe-01~e.4) :topic~e.5 (a / and~e.7 :op1 (c3 / cell-line~e.9 :name (n / name :op1 "UACC647"~e.6)) :op2 (c4 / cell-line~e.9 :name (n2 / name :op1 "UACC558"~e.8))) :time (c / context~e.13 :poss~e.14 (a2 / and~e.17 :op1 (e / enzyme~e.15 :name (n3 / name :op1 "Akt"~e.16) :ARG3-of (p6 / phosphorylate-01~e.16) :ARG1-of~e.15 (h2 / high-02~e.15)) :op2 (r / resist-01~e.19 :ARG1~e.20 (s3 / small-molecule :name (n4 / name :op1 "E6201"~e.21)) :ARG2-of (r2 / relative-05~e.18)))) :ARG0-of (s / support-01~e.23 :ARG1 (h / hypothesize-01~e.25 :ARG1 (s2 / sensitize-01~e.33 :ARG0 (a3 / administer-01~e.27 :ARG1~e.28 (m / molecular-physical-entity~e.31 :ARG0-of~e.31 (i / inhibit-01~e.31 :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K"~e.30))))) :ARG1 (c2 / cell~e.37 :ARG0-of (r3 / resist-01~e.36 :ARG1 s3~e.34) :mod (l / level~e.41 :quant-of~e.11 e~e.39,40 :degree h2)) :ARG2~e.42 s3~e.43 :ARG1-of (p4 / possible-01~e.32))))) # ::id pmid_2303_9341.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In summary , the combination of E6201 and LY294002 resulted in synergistic activity in all six melanoma cell lines tested , as defined by a combination index < 1 . # ::alignments 1-1.5 4-1.1 5-1.1.1.r 6-1.1.1.1.1 8-1.1.2.1.1 9-1 10-1.2.r 11-1.2.1 12-1.2 13-1.3.r 14-1.3.2 15-1.3.1 16-1.3.4.1.1 17-1.3 18-1.3 19-1.3.3 21-1.4.r 22-1.4 23-1.4.1.r 25-1.4.1.1 26-1.4.1 27-1.4.1.2 28-1.4.1.2.1 (r / result-01~e.9 :ARG1 (c / combine-01~e.4 :ARG1~e.5 (s2 / small-molecule :name (n / name :op1 "E6201"~e.6)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "LY294002"~e.8))) :ARG2~e.10 (a / activity-06~e.12 :ARG1 (s / synergize-01~e.11)) :location~e.13 (c2 / cell-line~e.17,18 :quant 6~e.15 :mod (a2 / all~e.14) :ARG1-of (t / test-01~e.19) :mod (m / medical-condition :name (n3 / name :op1 "melanoma"~e.16))) :ARG1-of~e.21 (d / define-01~e.22 :ARG0~e.23 (i / index~e.26 :mod (c3 / combine-01~e.25) :value (l / less-than~e.27 :op1 1~e.28))) :ARG2-of (s4 / summarize-01~e.1)) # ::id pmid_2303_9341.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , enhanced synergy of E6201 with LY294002 treatment in the E6201 @-@ resistant cell lines UACC647 and UACC558 was observed at high concentrations of E6201 . # ::alignments 0-1.3 2-1.1.3 3-1.1 4-1.1.2.r 5-1.1.2.1.1.1 7-1.1.1.1.1.1 8-1.1.1 8-1.1.2 11-1.1.2.1.1.1 13-1.1.4.1 14-1.1.4 15-1.1.4 16-1.1.4.2.1.1.1.1 17-1.1.4.2.1 18-1.1.4.2.1.2.1.1 20-1 21-1.2.r 22-1.2.2 23-1.2 24-1.2.1.r 25-1.2.1 (o / observe-01~e.20 :ARG1 (s / synergize-01~e.3 :ARG0 (t / treat-04~e.8 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "LY294002"~e.7))) :ARG1~e.4 (t2 / treat-04~e.8 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "E6201"~e.5,11))) :ARG1-of (e / enhance-01~e.2) :location (c / cell-line~e.14,15 :ARG0-of (r / resist-01~e.13) :ARG2-of (i / include-91 :ARG1 (a / and~e.17 :op1 (c3 / cell-line :name (n4 / name :op1 "UACC647"~e.16)) :op2 (c4 / cell-line :name (n5 / name :op1 "UACC558"~e.18)))))) :condition~e.21 (c2 / concentrate-02~e.23 :ARG1~e.24 s3~e.25 :ARG1-of (h / high-02~e.22)) :ARG2-of (i2 / interest-01~e.0)) # ::id pmid_2325_9591.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternative dosing of dual PI3K and MEK inhibition in cancer therapy ( PMID : 23259591 ) # ::alignments 0-1.2 1-1 2-1.1.r 3-1.1.2 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1.1 7-1.1 8-1.3.r 9-1.3.1.2.1 10-1.3 (d2 / dose-01~e.1 :ARG1~e.2 (i / inhibit-01~e.7 :ARG1 (a3 / and~e.5 :op1 (e / enzyme :name (n3 / name :op1 "PI3K"~e.4)) :op2 (e2 / enzyme :name (n / name :op1 "MEK"~e.6))) :mod (d3 / dual~e.3)) :mod (a / alternative~e.0) :location~e.8 (t / therapy~e.10 :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.9))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID23259591"))) # ::id pmid_2325_9591.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2325_9591.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two of the 12 NSCLC cell lines tested , H3122 ( ALK translocated ) and H1437 ( triple @-@ negative ) , showed increased cytotoxicity upon dual MEK and PI3K inhibition . # ::alignments 0-1.1.1 3-1.1.2.1.1 4-1.1.2.1.3.1.1 5-1.1 5-1.1.2.1 6-1.1.2.1 7-1.1.2.1.2 9-1.1.3.1.1.1.1 11-1.1.3.1.1.2.1.1.1 12-1.1.3.1.1.2 14-1.1.3.1 15-1.1.3.1.2.1.1 17-1.1.3.1.2.2.1 19-1.1.3.1.2 19-1.1.3.1.2.2 19-1.1.3.1.2.2.r 22-1 23-1.2.1 24-1.2 26-1.2.1.1.1.2 27-1.2.1.1.1.1.1.1.1 28-1.2.1.1.1.1 29-1.2.1.1.1.1.2.1.1 30-1.2.1.1.1 (s / show-01~e.22 :ARG0 (c / cell-line~e.5 :quant 2~e.0 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.5,6 :quant 12~e.3 :ARG1-of (t / test-01~e.7) :mod (d2 / disease :name (n2 / name :op1 "NSCLC"~e.4)))) :ARG1-of (m / mean-01 :ARG2 (a / and~e.14 :op1 (c3 / cell-line :name (n4 / name :op1 "H3122"~e.9) :ARG2-of (t2 / translocate-01~e.12 :ARG1 (e / enzyme :name (n5 / name :op1 "ALK"~e.11)))) :op2 (c4 / cell-line~e.19 :name (n6 / name :op1 "H1437"~e.15) :ARG1-of~e.19 (n3 / negative-01~e.19 :ARG1-of (t3 / triple-01~e.17)))))) :ARG1 (c5 / cytotoxicity~e.24 :ARG1-of (i2 / increase-01~e.23 :time (a2 / after :op1 (i3 / inhibit-01~e.30 :ARG1 (a3 / and~e.28 :op1 (e2 / enzyme :name (n / name :op1 "MEK"~e.27)) :op2 (e3 / enzyme :name (n8 / name :op1 "PI3K"~e.29))) :mod (d / dual~e.26)))))) # ::id pmid_2325_9591.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , MDA @-@ MB231 ( breast ) and HCT116 ( colon ) , showed increased cytotoxicity upon dual inhibition , as in previous studies . # ::alignments 0-1 2-1.1.1.1.1.1 4-1.1.1.1.1.1 6-1.1.1.1.2 8-1.1.1 9-1.1.1.2.1.1 11-1.1.1.2.2 14-1.1 15-1.1.2.1 16-1.1.2 18-1.1.2.1.2.1.1 19-1.1.2.1.2.1 21-1.1.2.1.1.1.1.r 21-1.1.2.1.2.r 23-1.1.2.1.1.1.1 24-1.1.2.1.1.1 (a / and~e.0 :op2 (s / show-01~e.14 :ARG0 (a2 / and~e.8 :op1 (c / cell-line :name (n / name :op1 "MDA-MB231"~e.2,4) :mod (b / breast~e.6)) :op2 (c2 / cell-line :name (n2 / name :op1 "HCT116"~e.9) :mod (c3 / colon~e.11))) :ARG1 (c4 / cytotoxicity~e.16 :ARG1-of (i / increase-01~e.15 :ARG1-of (r / resemble-01 :ARG2 (s2 / study-01~e.24 :time~e.21 (p / previous~e.23))) :time~e.21 (a3 / after :op1 (i2 / inhibit-01~e.19 :mod (d / dual~e.18))))))) # ::id pmid_2325_9591.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of parallel pathways in the dual inhibition @-@ sensitive lines was also noted in response to single inhibitor treatment . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1 4-1.1.2.r 6-1.1.2.1.1.1 7-1.1.2.1.1 9-1.1.2.1 10-1.1.2 12-1.2 13-1 14-1.3.r 15-1.3 16-1.3.1.r 17-1.3.1.1.2 18-1.3.1.1 18-1.3.1.1.1 18-1.3.1.1.1.r 19-1.3.1 (n / note-01~e.13 :ARG1 (a2 / activate-01~e.0 :ARG1~e.1 (p / pathway~e.3 :ARG1-of (p2 / parallel-01~e.2)) :location~e.4 (c / cell-line~e.10 :ARG0-of (s / sensitive-03~e.9 :ARG1 (i2 / inhibit-01~e.7 :mod (d / dual~e.6))))) :mod (a / also~e.12) :ARG2-of~e.14 (r / respond-01~e.15 :ARG1~e.16 (t2 / treat-04~e.19 :ARG2 (s2 / small-molecule~e.18 :ARG0-of~e.18 (i / inhibit-01~e.18) :ARG1-of (s3 / single-02~e.17))))) # ::id pmid_2325_9591.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Otherwise , no significant differences in downstream intracellular pathway activity ( S6 and 4E @-@ BPI ) were noted between PI3K alone and dual inhibition other than the increased cytotoxicity of the latter . # ::alignments 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1.5 4-1.1.1 5-1.1.1.4.r 6-1.1.1.4.1.2 7-1.1.1.4.1.1 8-1.1.1.4.1 9-1.1.1.4 9-1.1.1.4.1.3.1 11-1.1.1.4.1.3.1.1.1.1.1 12-1.1.1.4.1.3.1.1 13-1.1.1.4.1.3.1.1.2.1.1 15-1.1.1.4.1.3.1.1.2.1.1 18-1.1 20-1.1.1.2.1.1 21-1.1.1.2.2 22-1.1.1.4.1.3.1.1 23-1.1.1.3.1 24-1.1.1.3 28-1.1.1.6.1.1 29-1.1.1.6.1 (h2 / have-condition-91 :ARG1 (n / note-01~e.18 :ARG1 (d / differ-02~e.4 :polarity~e.2 -~e.2 :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K"~e.20) :mod (a3 / alone~e.21)) :ARG2 (i2 / inhibit-01~e.24 :mod (d3 / dual~e.23)) :ARG3~e.5 (a / activity-06~e.9 :ARG0 (p / pathway~e.8 :mod (i / intracellular~e.7) :location (d2 / downstream~e.6) :ARG1-of (m / mean-01 :ARG2 (a4 / activity-06~e.9 :ARG0 (a2 / and~e.12,22 :op1 (p2 / protein :name (n2 / name :op1 "S6"~e.11)) :op2 (p3 / protein :name (n3 / name :op1 "4E-BPI"~e.13,15))))))) :ARG1-of (s / significant-02~e.3) :ARG2-of (e2 / except-01 :ARG1 (c / cytotoxicity~e.29 :ARG1-of (i3 / increase-01~e.28) :topic i2))))) # ::id pmid_2325_9591.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the alternative dosing schedules two out of the four dual inhibition @-@ sensitive cell lines showed similar cytotoxicity to continuous PI3K and short ( 15 min ) MEK inhibition treatment . # ::alignments 2-1.4.1.1 3-1.4.1 4-1.4 5-1.1.1 9-1.1.2.1.1 10-1.1.2.1.2.1.1 11-1.1.2.1.2.1 13-1.1.2.1.2 14-1.1.2.1 15-1.1 16-1 17-1.2.1 18-1.2 19-1.3.r 20-1.3.1.1.1.2 21-1.3.1.1.1.1.1.1 22-1.3.1 23-1.3.1.2.1.2 25-1.3.1.2.1.2.1.1 26-1.3.1.2.1.2.1.2 28-1.3.1.2.1.1.1.1 29-1.3.1.1 29-1.3.1.1.1 29-1.3.1.1.1.r 29-1.3.1.2 29-1.3.1.2.1 29-1.3.1.2.1.r 30-1.3 (s / show-01~e.16 :ARG0 (c / cell-line~e.15 :quant 2~e.5 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.14 :quant 4~e.9 :ARG0-of (s2 / sensitive-03~e.13 :ARG1 (i2 / inhibit-01~e.11 :mod (d / dual~e.10)))))) :ARG1 (c3 / cytotoxicity~e.18 :ARG1-of (r2 / resemble-01~e.17)) :ARG2~e.19 (t / treat-04~e.30 :ARG2 (a2 / and~e.22 :op1 (s4 / small-molecule~e.29 :ARG0-of~e.29 (i3 / inhibit-01~e.29 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"~e.21)) :mod (c4 / continuity~e.20))) :op2 (s6 / small-molecule~e.29 :ARG0-of~e.29 (i4 / inhibit-01~e.29 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.28)) :ARG1-of (s5 / short-07~e.23 :duration (t2 / temporal-quantity :quant 15~e.25 :unit (m / minute~e.26))))))) :location (s3 / schedule-01~e.4 :ARG1 (d2 / dose-01~e.3 :mod (a / alternative~e.2)))) # ::id pmid_2325_9591.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2325_9591.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dual inhibition of PI3K and MEK in cancer cell lines # ::alignments 1-1.2 2-1 3-1.1.r 4-1.1.1.1.1 5-1.1 6-1.1.2.1.1 7-1.3.r 8-1.3.1.2.1 9-1.3 10-1.3 (i / inhibit-01~e.2 :ARG1~e.3 (a / and~e.5 :op1 (e / enzyme :name (n3 / name :op1 "PI3K"~e.4)) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK"~e.6))) :mod (d2 / dual~e.1) :location~e.7 (c / cell-line~e.9,10 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.8)))) # ::id pmid_2325_9591.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The inhibitors used were ZSTK474 ( PI3K inhibitor ) and PI @-@ 103 ( PI3K and mTOR inhibitor ) and CI @-@ 1040 ( MEK inhibitor ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 4-1.1.2.1.1.1.1 6-1.1.2.1.1.2.1.1.1 7-1.1.2.1.1 7-1.1.2.1.1.2 7-1.1.2.1.1.2.r 9-1.1.2.1 10-1.1.2.1.2.1.1 12-1.1.2.1.2.1.1 14-1.1.2.1.2.2.1.1 15-1.1.2.1 15-1.1.2.1.2.2.1 16-1.1.2.1.2.2.1.2.1.1 17-1.1.2.1.1 17-1.1.2.1.1.2 17-1.1.2.1.1.2.r 17-1.1.2.1.2 17-1.1.2.1.2.2 17-1.1.2.1.2.2.r 19-1.1.2.1 19-1.1.2.1.2.2.1 20-1.1.2.1.3.1.1 22-1.1.2.1.3.1.1 24-1.1.2.1.3.2.1.1.1 25-1.1 25-1.1.1 25-1.1.1.r 25-1.1.2.1.3 25-1.1.2.1.3.2 25-1.1.2.1.3.2.r (u / use-01~e.2 :ARG1 (s / small-molecule~e.1,25 :ARG0-of~e.1,25 (i2 / inhibit-01~e.1,25) :ARG1-of (m / mean-01 :ARG2 (a / and~e.9,15,19 :op1 (s2 / small-molecule~e.7,17 :name (n2 / name :op1 "ZSTK474"~e.4) :ARG0-of~e.7,17 (i3 / inhibit-01~e.7,17 :ARG1 (p2 / protein-family :name (n3 / name :op1 "PI3K"~e.6)))) :op2 (s3 / small-molecule~e.17 :name (n4 / name :op1 "PI-103"~e.10,12) :ARG0-of~e.17 (i4 / inhibit-01~e.17 :ARG1 (a2 / and~e.15,19 :op1 p2~e.14 :op2 (p3 / protein :name (n5 / name :op1 "mTOR"~e.16))))) :op3 (s4 / small-molecule~e.25 :name (n6 / name :op1 "CI-1040"~e.20,22) :ARG0-of~e.25 (i5 / inhibit-01~e.25 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.24)))))))) # ::id pmid_2325_9591.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We first addressed the effects of these inhibitors alone in the NSCLC lines A549 ( K @ - @ Ras mutant ) , HCC827 ( EGFR mutant ) and H3122 ( EML4 @ - @ ALK translocated ) , representing the three most frequent oncogenic genotypes of the disease , to establish concentration frames for the target inhibition . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1 7-1.2.1.3 7-1.2.1.3.r 8-1.2.1.2 9-1.2.2.r 11-1.2.2.2.1.1 12-1.2.2 13-1.2.2.1.1.1.1.1 16-1.2.2.1.1.1.2.1.1 20-1.2.2.1.1.1.2.1.1 22-1.2.2.1.1.1.2 22-1.2.2.1.1.1.2.2 22-1.2.2.1.1.1.2.2.r 25-1.2.2.1.1.2.1.1 28-1.2.2.1.1.2.2.1.1 30-1.2.2.1.1.1.2 30-1.2.2.1.1.1.2.2 30-1.2.2.1.1.1.2.2.r 30-1.2.2.1.1.2.2 30-1.2.2.1.1.2.2.2 30-1.2.2.1.1.2.2.2.r 32-1.2.2.1.1 33-1.2.2.1.1.3.1.1 36-1.2.2.1.1.3.2.1.1.1 40-1.2.2.1.1.3.2.1.1.1 42-1.2.2.1.1.3.2 45-1.2.2.1.1.4 47-1.2.2.1.1.4.1.1 48-1.2.2.1.1.4.1.2.1.1.1 49-1.2.2.1.1.4.1.2.1.1 50-1.2.2.1.1.4.1.2.1.3 50-1.2.2.1.1.4.1.2.1.3.1.2.1 51-1.2.2.1.1.4.1 51-1.2.2.1.1.4.1.2.1 52-1.2.2.1.1.4.1.2.1.2.r 54-1.2.2.1.1.4.1.2.1.2 56-1.2.2.1.1.4.1.2.1.3 57-1.4 58-1.4.2.1 59-1.4.2 60-1.4.3.r 62-1.4.3.1 63-1.4.3 (a / address-02~e.2 :ARG0 (w / we~e.0) :ARG1 (a2 / affect-01~e.4 :ARG0~e.5 (s / small-molecule~e.7 :mod (t2 / this~e.6) :mod (a3 / alone~e.8) :ARG0-of~e.7 (i2 / inhibit-01~e.7)) :location~e.9 (c / cell-line~e.12 :ARG1-of (m / mean-01 :ARG2 (a4 / and~e.32 :op1 (c3 / cell-line :name (n5 / name :op1 "A549"~e.13) :mod (g / gene~e.22,30 :name (n4 / name :op1 "K-Ras"~e.16,20) :ARG2-of~e.22,30 (m2 / mutate-01~e.22,30))) :op2 (c2 / cell-line :name (n6 / name :op1 "HCC827"~e.25) :mod (g2 / gene~e.30 :name (n7 / name :op1 "EGFR"~e.28) :ARG2-of~e.30 (m3 / mutate-01~e.30))) :op3 (c4 / cell-line :name (n8 / name :op1 "H3122"~e.33) :ARG2-of (t3 / translocate-01~e.42 :ARG1 (e2 / enzyme :name (n9 / name :op1 "EML4-ALK"~e.36,40)))) :ARG1-of (r / represent-01~e.45 :ARG2 (g3 / genotype~e.51 :quant 3~e.47 :ARG1-of (i3 / include-91 :ARG2 (g4 / genotype~e.51 :ARG1-of (f2 / frequent-02~e.49 :degree (m4 / most~e.48)) :poss~e.52 (d / disease~e.54) :ARG0-of (c6 / cause-01~e.50,56 :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.50))))))))) :mod (d2 / disease :name (n / name :op1 "NSCLC"~e.11)))) :time (f / first~e.1) :purpose (e3 / establish-01~e.57 :ARG0 w :ARG1 (f3 / frame~e.59 :mod (c5 / concentrate-02~e.58)) :ARG3~e.60 (i4 / inhibit-01~e.63 :ARG1-of (t4 / target-01~e.62)))) # ::id pmid_2325_9591.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the Western blots ZSTK474 at a 3.3μM concentration induced complete downregulation of pAKT , an immediate downstream target of PI3K , while PI @-@ 103 induced a similar inhibition at concentrations of 1 to 3.3 μM ( Figure 1A ) . # ::alignments 2-1.1.3 3-1.1.3 4-1.1.1.1.1.1 8-1.1.1 8-1.1.1.2 8-1.1.1.2.r 8-1.2.3 9-1.1 10-1.1.2.2 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1 13-1.1.2.1.2 16-1.1.2.3.3 17-1.1.2.3.2 18-1.1.2.3 19-1.1.2.3.1.r 20-1.1.2.3.1.1.1 22-1 23-1.2.1.1.1 25-1.2.1.1.1 26-1.2 28-1.2.2.1 29-1.2.2 30-1.2.3.2.r 31-1.2.3.2.1 33-1.2.3.2.1.1 35-1.1.1.2.1 36-1.1.1.2.2 38-1.3.1 40-1.3.1.1 (c / contrast-01~e.22 :ARG1 (i / induce-01~e.9 :ARG0 (c3 / concentrate-02~e.8 :ARG1 (s / small-molecule :name (n / name :op1 "ZSTK474"~e.4)) :quant~e.8 (c2 / concentration-quantity~e.8 :quant 3.3~e.35 :unit (m / micromolar~e.36))) :ARG2 (d / downregulate-01~e.11 :ARG1~e.12 (e / enzyme :name (n3 / name :op1 "AKT"~e.13) :ARG3-of (p / phosphorylate-01~e.13)) :ARG1-of (c4 / complete-02~e.10) :ARG1-of (t2 / target-01~e.18 :ARG0~e.19 (p2 / protein-family :name (n4 / name :op1 "PI3K"~e.20)) :location (d2 / downstream~e.17) :time (i2 / immediate~e.16))) :location (i5 / immunoblot-01~e.2,3)) :ARG2 (i3 / induce-01~e.26 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PI-103"~e.23,25)) :ARG2 (i4 / inhibit-01~e.29 :ARG1-of (r / resemble-01~e.28)) :condition (c5 / concentrate-02~e.8 :ARG1 s2 :quant~e.30 (v / value-interval :op1 (c6 / concentration-quantity~e.31 :quant 1~e.33 :unit m) :op2 c2))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.38 :mod "1A"~e.40))) # ::id pmid_2325_9591.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok pS6 downregulation correlated highly with pAKT downregulation ( Figure 1A ) . # ::alignments 1-1.1 1-1.2 2-1 3-1.3 5-1.1.1.2 5-1.2.1.1.1 6-1.1 8-1.4.1 10-1.4.1.1 (c / correlate-01~e.2 :ARG1 (d / downregulate-01~e.1,6 :ARG1 (p / protein :name (n / name :op1 "S6") :ARG3-of (p2 / phosphorylate-01~e.5))) :ARG2 (d2 / downregulate-01~e.1 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT"~e.5) :ARG3-of p2)) :ARG1-of (h / high-02~e.3) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.8 :mod "1A"~e.10))) # ::id pmid_2325_9591.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MTS cytotoxicity assay showed a major reduction in the number of viable cells in all the cell lines with similar concentrations of both inhibitors , which were closely correlated with the concentrations inducing complete inhibition of pAKT in Western blot analysis ( Figure 1A , C ) . # ::alignments 1-1.1.2.1.1 2-1.1.1 3-1.1 4-1 6-1.2.2 7-1.2 8-1.2.1.r 10-1.2.1 12-1.2.1.1.1 13-1.2.1.1 13-1.2.3 15-1.2.3.2 17-1.2.3 18-1.2.3 20-1.2.3.1.1.2 21-1.2.3.1.1 22-1.2.3.1.1.1.r 23-1.2.3.1.1.1.2 24-1.2.3.1.1.1 24-1.2.3.1.1.1.1 24-1.2.3.1.1.1.1.r 28-1.2.3.1.1.3.2 29-1.2.3.1.1.3 30-1.2.3.1.1.3.1.r 32-1.2.3.1.1.3.1 33-1.2.3.1.1.3.1.1 34-1.2.3.1.1.3.1.1.1.2 35-1.2.3.1.1.3.1.1.1 36-1.2.3.1.1.3.1.1.1.1.r 37-1.2.3.1.1.3.1.1.1.1.1.1 37-1.2.3.1.1.3.1.1.1.1.2 38-1.2.3.1.1.3.1.1.2.r 39-1.2.3.1.1.3.1.1.2.1 40-1.2.3.1.1.3.1.1.2.1 41-1.2.3.1.1.3.1.1.2 43-1.3.1.1 43-1.3.1.2 45-1.3.1.1.1 (s / show-01~e.4 :ARG0 (a / assay-01~e.3 :ARG1 (c / cytotoxicity~e.2) :mod (s3 / small-molecule :name (n2 / name :op1 "MTS"~e.1))) :ARG1 (r2 / reduce-01~e.7 :ARG1~e.8 (n / number~e.10 :quant-of (c2 / cell~e.13 :mod (v / viable~e.12))) :ARG1-of (m / major-02~e.6) :location (c3 / cell-line~e.13,17,18 :ARG0-of (h / have-03 :ARG1 (c4 / concentrate-02~e.21 :ARG1~e.22 (s2 / small-molecule~e.24 :ARG0-of~e.24 (i2 / inhibit-01~e.24) :mod (b / both~e.23)) :ARG1-of (r3 / resemble-01~e.20) :ARG1-of (c5 / correlate-01~e.29 :ARG2~e.30 (c6 / concentrate-02~e.32 :ARG0-of (i3 / induce-01~e.33 :ARG2 (i4 / inhibit-01~e.35 :ARG1~e.36 (e / enzyme :name (n4 / name :op1 "AKT"~e.37) :ARG3-of (p / phosphorylate-01~e.37)) :ARG1-of (c7 / complete-02~e.34)) :time~e.38 (a2 / analyze-01~e.41 :manner (i / immunoblot-01~e.39,40)))) :ARG1-of (c8 / close-10~e.28)))) :mod (a4 / all~e.15))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.43 :mod "1A"~e.45) :op2 (f2 / figure~e.43 :mod "1C")))) # ::id pmid_2325_9591.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CI @-@ 1040 induced complete inhibition of ERK1 @/@ 2 , an immediate downstream target of MEK , at a 1 μM concentration ( Figure 1B ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1.1 9-1.2.1.1.1 12-1.2.1.2.3 13-1.2.1.2.2 14-1.2.1 14-1.2.1.2 14-1.2.1.2.r 15-1.2.1.2.1.r 16-1.2.1.2.1.1.1 20-1.1.2.1.1 21-1.1.2.1.2 22-1.1 22-1.1.2 22-1.1.2.1 22-1.1.2.1.r 22-1.1.2.r 24-1.3.1 26-1.3.1.1 (i / induce-01~e.3 :ARG0 (s / small-molecule~e.22 :name (n2 / name :op1 "CI-1040"~e.0,2) :ARG1-of~e.22 (c2 / concentrate-02~e.22 :quant~e.22 (c3 / concentration-quantity~e.22 :quant 1~e.20 :unit (m / micromolar~e.21)))) :ARG2 (i2 / inhibit-01~e.5 :ARG1~e.6 (e / enzyme~e.14 :name (n3 / name :op1 "ERK1/2"~e.7,9) :ARG1-of~e.14 (t / target-01~e.14 :ARG0~e.15 (e2 / enzyme :name (n / name :op1 "MEK"~e.16)) :location (d / downstream~e.13) :time (i3 / immediate~e.12))) :ARG1-of (c / complete-02~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "1B"~e.26))) # ::id pmid_2325_9591.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only the H3122 line showed any marked reduction in cell viability in the MTS assays in response to increasing concentrations of the inhibitor , correlating with maximal target inhibition , while the other lines displayed minor changes in viability , except for the 10 μM treatment in HCC827 , despite the achieving of complete inhibition of pERK1 @/@ 2 in all the lines tested at 1 μM ( Figure 1C ) . # ::alignments 0-1.1.1.2 2-1.1.1.1.1 3-1.1.1 4-1.1 5-1.1.2.3 6-1.1.2.2 7-1.1.2 9-1.1.2.1.1 10-1.2.2.1 13-1.1.2.1.2.1.1.1 14-1.1.2.1.2 15-1.1.2.4.r 16-1.1.2.4 17-1.1.2.4.1.r 18-1.1.2.4.1.2 19-1.1.2.4.1 19-1.2.1.2.1.2.1 19-1.2.3.1.3.2.1 22-1.1.2.4.1.1 22-1.1.2.4.1.1.1 22-1.1.2.4.1.1.1.r 24-1.1.2.4.1.3 26-1.1.2.4.1.3.1.2 27-1.1.2.4.1.3.1.1 28-1.1.2.4.1.1 28-1.1.2.4.1.1.1 28-1.1.2.4.1.1.1.r 28-1.1.2.4.1.3.1 30-1 32-1.2.1.1 33-1.2.1 34-1.2 35-1.2.2.2 36-1.2.2 38-1.2.2.1 40-1.2.1.2 41-1.2.1.2.1.r 43-1.2.1.2.1.2.1.1 44-1.2.1.2.1.2.1.2 44-1.2.3.1.3.2.1.2 45-1.2.1.2.1 46-1.2.1.2.1.1.r 47-1.2.1.2.1.1.1.1 49-1.2.3.r 51-1.2.3 52-1.2.3.1.r 53-1.2.3.1.2 54-1.2.3.1 58-1.2.3.1.1.1.1 59-1.2.3.1.3.r 60-1.2.3.1.3.1 62-1.2.3.1.3 63-1.2.3.1.3.2 65-1.2.3.1.3.2.1.1 66-1.2.1.2.1.2.1.2 68-1.3.1 70-1.3.1.1 (c13 / contrast-01~e.30 :ARG1 (s / show-01~e.4 :ARG0 (c / cell-line~e.3 :name (n / name :op1 "H3122"~e.2) :mod (o / only~e.0)) :ARG1 (r / reduce-01~e.7 :ARG1 (v / viable :mod (c2 / cell~e.9) :location (a / assay-01~e.14 :mod (s4 / small-molecule :name (n2 / name :op1 "MTS"~e.13)))) :manner (m / marked~e.6) :mod (a2 / any~e.5) :ARG2-of~e.15 (r2 / respond-01~e.16 :ARG1~e.17 (c3 / concentrate-02~e.19 :ARG1 (s2 / small-molecule~e.22,28 :ARG0-of~e.22,28 (i3 / inhibit-01~e.22,28)) :ARG1-of (i2 / increase-01~e.18) :ARG1-of (c4 / correlate-01~e.24 :ARG2 (i4 / inhibit-01~e.28 :ARG1-of (t3 / target-01~e.27) :degree (m2 / maximum~e.26))))))) :ARG2 (d / display-01~e.34 :ARG0 (c6 / cell-line~e.33 :mod (o2 / other~e.32) :ARG2-of (e / except-01~e.40 :ARG1~e.41 (t4 / treat-04~e.45 :ARG1~e.46 (c8 / cell-line :name (n3 / name :op1 "HCC827"~e.47)) :ARG2 (s3 / small-molecule :quant (c9 / concentration-quantity~e.19 :quant 10~e.43 :unit (m4 / micromolar~e.44,66)))))) :ARG1 (c7 / change-01~e.36 :ARG1 (v2 / viability~e.10,38) :ARG1-of (m3 / minor-01~e.35)) :concession~e.49 (a3 / achieve-01~e.51 :ARG1~e.52 (i5 / inhibit-01~e.54 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"~e.58) :ARG3-of (p / phosphorylate-01)) :ARG1-of (c10 / complete-02~e.53) :location~e.59 (c11 / cell-line~e.62 :mod (a4 / all~e.60) :ARG1-of (t5 / test-01~e.63 :manner (c12 / concentration-quantity~e.19 :quant 1~e.65 :unit (m5 / micromolar~e.44))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.68 :mod "1C"~e.70))) # ::id pmid_2325_9591.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dual inhibition of PI3K and MEK was tested in a panel of NSCLC lines ( n= 12 ) with the K @ - @ Ras ( n= 3 ) , EGFR ( n= 3 ) , ALK ( n= 3 ) , or triple @-@ negative ( n= 3 ) oncogenic genotypes . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 7-1 8-1.2.r 10-1.2 11-1.2.1.r 12-1.2.1.3.1.1 13-1.2.1 16-1.2.1.2.1 21-1.2.1.1.1.1.1.1.1 25-1.2.1.1.1.1.1.1.1 29-1.2.1.1.1.1.2.1 29-1.2.1.1.1.2.2.1 29-1.2.1.1.1.3.2.1 29-1.2.1.1.1.4.2.1 33-1.2.1.1.1.2.1.1.1 37-1.2.1.1.1.1.2.1 37-1.2.1.1.1.2.2.1 37-1.2.1.1.1.3.2.1 37-1.2.1.1.1.4.2.1 41-1.2.1.1.1.3.1.1.1 45-1.2.1.1.1.1.2.1 45-1.2.1.1.1.2.2.1 45-1.2.1.1.1.3.2.1 45-1.2.1.1.1.4.2.1 48-1.2.1.1.1 49-1.2.1.1.1.4.1.1 51-1.2.1.1.1.4.1 54-1.2.1.1.1.1.2.1 54-1.2.1.1.1.2.2.1 54-1.2.1.1.1.3.2.1 54-1.2.1.1.1.4.2.1 56-1.2.1.1.1.5 56-1.2.1.1.1.5.1.2.1 57-1.2.1.1.1.1 57-1.2.1.1.1.2 57-1.2.1.1.1.3 57-1.2.1.1.1.4 (t / test-01~e.7 :ARG1 (i / inhibit-01~e.1 :ARG1~e.2 (a / and~e.4 :op1 (e / enzyme :name (n4 / name :op1 "PI3K"~e.3)) :op2 (e2 / enzyme :name (n / name :op1 "MEK"~e.5))) :mod (d / dual~e.0)) :location~e.8 (p4 / panel~e.10 :consist-of~e.11 (c / cell-line~e.13 :ARG0-of (h / have-03 :ARG1 (o / or~e.48 :op1 (g4 / genotype~e.57 :mod (g / gene :name (n6 / name :op1 "K-Ras"~e.21,25)) :ARG1-of (n3 / number-01 :ARG2 3~e.29,37,45,54)) :op2 (g5 / genotype~e.57 :mod (g2 / gene :name (n7 / name :op1 "EGFR"~e.33)) :ARG1-of (n10 / number-01 :ARG2 3~e.29,37,45,54)) :op3 (g6 / genotype~e.57 :mod (g3 / gene :name (n8 / name :op1 "ALK"~e.41)) :ARG1-of (n11 / number-01 :ARG2 3~e.29,37,45,54)) :op4 (g7 / genotype~e.57 :ARG1-of (n9 / negative-01~e.51 :ARG1-of (t2 / triple-01~e.49)) :ARG1-of (n12 / number-01 :ARG2 3~e.29,37,45,54)) :ARG0-of (c2 / cause-01~e.56 :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.56))))) :ARG1-of (n2 / number-01 :ARG2 12~e.16) :mod (d2 / disease :name (n13 / name :op1 "NSCLC"~e.12))))) # ::id pmid_2325_9591.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analogously to the cell lines in the preliminary experiments , all the cell lines tested here showed a major reduction in cell growth in response to the PI3K inhibitors alone , with no significant differences between ZSTK474 or PI @-@ 103 ( Figure 2A , eight of the twelve lines presented graphically ) . # ::alignments 3-1.1.3.1 4-1.1.3.1 7-1.1.3.1.1.1 8-1.1.3.1.1 10-1.1.1 12-1.1 12-1.1.3.1 13-1.1 14-1.1.2 15-1.1.2.1 16-1 18-1.2.1.2 19-1.2.1 20-1.2.1.1.r 21-1.2.1.1.1 22-1.2.1.1 23-1.2.1.3.r 24-1.2.1.3 25-1.2.1.3.1.r 27-1.2.1.3.1.2.1.1.1 28-1.2.1.3.1 28-1.2.1.3.1.2 28-1.2.1.3.1.2.r 29-1.2.1.3.1.1 31-1.2.r 32-1.2.2.1 32-1.2.2.1.r 33-1.2.2.4 34-1.2.2 36-1.2.2.2.1.1 38-1.2.2.3.1.1 40-1.2.2.3.1.1 42-1.3.1.1 44-1.3.1.1.1 47-1.3.1.2.1 50-1.3.1.2.2.1.1 51-1.3.1.2 51-1.3.1.2.2.1 52-1.3.1.2.2.1.2 53-1.3.1.2.2.1.2.1 (s / show-01~e.16 :ARG0 (c / cell-line~e.12,13 :mod (a / all~e.10) :ARG1-of (t2 / test-01~e.14 :location (h / here~e.15)) :ARG1-of (r3 / resemble-01 :ARG2 (c3 / cell-line~e.3,4,12 :location (e / experiment-01~e.8 :mod (p2 / preliminary~e.7))))) :ARG1~e.31 (a3 / and :op1 (r / reduce-01~e.19 :ARG1~e.20 (g / grow-01~e.22 :ARG1 (c2 / cell~e.21)) :ARG1-of (m / major-02~e.18) :ARG2-of~e.23 (r2 / respond-01~e.24 :ARG1~e.25 (s2 / small-molecule~e.28 :mod (a2 / alone~e.29) :ARG0-of~e.28 (i2 / inhibit-01~e.28 :ARG1 (p / protein-family :name (n / name :op1 "PI3K"~e.27)))))) :op2 (d / differ-02~e.34 :polarity~e.32 -~e.32 :ARG1 (s4 / small-molecule :name (n2 / name :op1 "ZSTK474"~e.36)) :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PI-103"~e.38,40)) :ARG1-of (s3 / significant-02~e.33))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.42 :mod "2A"~e.44) :op2 (c4 / cell-line~e.51 :quant 8~e.47 :ARG1-of (i3 / include-01 :ARG2 (c5 / cell-line~e.51 :quant 12~e.50 :ARG1-of (p3 / present-02~e.52 :manner (g2 / graphic~e.53)))))))) # ::id pmid_2325_9591.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MEK inhibitor CI @-@ 1040 elicited variable responses with the majority of cell lines , showing only minor inhibition of growth or none at all . # ::alignments 1-1.1.2.1.1.1 2-1.1 2-1.1.2 2-1.1.2.r 3-1.1.1.1 5-1.1.1.1 6-1 8-1.2 9-1.2.1.r 11-1.2.1.2 12-1.2.1.2.r 13-1.2.1 13-1.2.1.1.1 14-1.2.1 14-1.2.1.1.1 16-1.3 17-1.3.1.1.2 18-1.3.1.1.1 19-1.3.1.1 19-1.3.1.2 22-1.3.1 24-1.3.1.2.2 25-1.3.1.2.2 (e / elicit-01~e.6 :ARG0 (s / small-molecule~e.2 :name (n2 / name :op1 "CI-1040"~e.3,5) :ARG0-of~e.2 (i2 / inhibit-01~e.2 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.1)))) :ARG1 (r / respond-01~e.8 :ARG1~e.9 (c / cell-line~e.13,14 :ARG1-of (i3 / include-91 :ARG2 (c2 / cell-line~e.13,14)) :quant~e.12 (m / majority~e.11)) :ARG1-of (v2 / vary-01)) :ARG0-of (s2 / show-01~e.16 :ARG1 (o / or~e.22 :op1 (i4 / inhibit-01~e.19 :ARG1-of (m2 / minor-01~e.18) :mod (o2 / only~e.17)) :op2 (i5 / inhibit-01~e.19 :polarity - :mod (a / at-all~e.24,25))))) # ::id pmid_2325_9591.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When the cell lines were exposed to dual , concurrent inhibition of PI3K and MEK , two out of 12 tested cell lines , H3122 and H1437 , showed marked additional cytotoxicity compared with treatment with a single agent ( Figure 2A ) . # ::alignments 0-1.3.r 2-1.3.1 3-1.3.1 5-1.3 6-1.3.2.r 7-1.3.2.3 9-1.3.2.2 10-1.3.2 11-1.3.2.1.r 12-1.3.2.1.1.1.1 13-1.3.2.1 14-1.3.2.1.2.1.1 16-1.1.1 19-1.1.2.1.1 20-1.1.2.1.2 21-1.1 21-1.1.2.1 22-1.1.2.1 24-1.1.3.1.1.1.1 25-1.1.3.1 26-1.1.3.1.2.1.1 28-1 29-1.2.2 31-1.2 32-1.2.3.r 34-1.2.3 35-1.2.3.1.r 37-1.2.3.1.1 38-1.2.3.1 40-1.4.1 42-1.4.1.1 (s / show-01~e.28 :ARG0 (c / cell-line~e.21 :quant 2~e.16 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.21,22 :quant 12~e.19 :ARG1-of (t / test-01~e.20))) :ARG1-of (m / mean-01 :ARG2 (a / and~e.25 :op1 (c3 / cell-line :name (n2 / name :op1 "H3122"~e.24)) :op2 (c4 / cell-line :name (n3 / name :op1 "H1437"~e.26))))) :ARG1 (c5 / cytotoxicity~e.31 :ARG1-of (a2 / add-02) :mod (m2 / marked~e.29) :compared-to~e.32 (t2 / treat-04~e.34 :ARG2~e.35 (a3 / agent~e.38 :ARG1-of (s2 / single-02~e.37)))) :time~e.0 (e / expose-01~e.5 :ARG1 c2~e.2,3 :ARG2~e.6 (i2 / inhibit-01~e.10 :ARG1~e.11 (a4 / and~e.13 :op1 (e2 / enzyme :name (n4 / name :op1 "PI3K"~e.12)) :op2 (e3 / enzyme :name (n / name :op1 "MEK"~e.14))) :ARG1-of (c6 / concurrent-02~e.9) :mod (d / dual~e.7))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.40 :mod "2A"~e.42))) # ::id pmid_2325_9591.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results were submitted to combination index ( CI ) analysis and average CI values were calculated based on combinations of ZSTK474 and PI @-@ 103 . # ::alignments 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 3-1.1 4-1.1.2.r 5-1.1.2.1.1 6-1.1.2.1 10-1.1.2 11-1 12-1.2.1 14-1.2.1.1 16-1.2 17-1.2.2 18-1.2.2.1.r 19-1.2.2.1 20-1.2.2.1.1.r 21-1.2.2.1.1.1.1 23-1.2.2.1.2.1.1 25-1.2.2.1.2.1.1 (a / and~e.11 :op1 (s / submit-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG2~e.4 (a2 / analyze-01~e.10 :ARG1 (i / index-01~e.6 :mod (c / combine-01~e.5)))) :op2 (c2 / calculate-01~e.16 :ARG1 (a3 / average-01~e.12 :ARG1 (v / value-01~e.14 :ARG1 i)) :ARG1-of (b / base-02~e.17 :ARG2~e.18 (c3 / combine-01~e.19 :ARG1~e.20 (s2 / small-molecule :name (n / name :op1 "ZSTK474"~e.21)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "PI-103"~e.23,25)))))) # ::id pmid_2325_9591.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This analysis grouped the cell lines into three categories : antagonism ( n= 5 , CI 1.10 @-@ 3.3 ) , nearly additive or slight synergy ( n= 5 , CI 0.7 @-@ 1.10 ) , and synergy or strong synergy ( n= 2 , CI < 0.7 ) ( Table 1 ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2 6-1.3.r 7-1.3.1 8-1.3 13-1.3.2.1.1.1.1 13-1.3.2.1.2.3.1 16-1.3.2.1.1.2.1.1 18-1.3.2.1.1.2.1.2 21-1.3.2.1.2.1.1 22-1.3.2.1.2.1 23-1.3.2.1.2 24-1.3.2.1.2.2.1 25-1.3.2.1.2.2 28-1.3.2.1.2.3.1 31-1.3.2.1.2.4.1.1 33-1.3.2.1.2.4.1.2 36-1.3.2.1 36-1.3.2.1.1.2.1 36-1.3.2.1.2.4.1 37-1.3.2.1.3.1 37-1.3.2.1.3.2 38-1.3.2.1.3 39-1.3.2.1.3.2.1 40-1.3.2.1.3.2 43-1.3.2.1.3.3.1 46-1.3.2.1.3.4.1 47-1.3.2.1.3.4.1.1 50-1.4.1 52-1.4.1.1 (g / group-01~e.2 :ARG0 (a / analyze-01~e.1 :mod (t / this~e.0)) :ARG1 (c / cell-line~e.4,5) :ARG2~e.6 (c2 / category~e.8 :quant 3~e.7 :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.36 :op1 (a3 / antagonize-01 :ARG1-of (n / number-01 :ARG2 5~e.13) :ARG1-of (i / index-01 :ARG2 (b / between~e.36 :op1 1.10~e.16 :op2 3.3~e.18) :mod (c3 / combine-01))) :op2 (o / or~e.23 :op1 (a4 / additive~e.22 :mod (n2 / near~e.21)) :op2 (s / synergize-01~e.25 :mod (s2 / slight~e.24)) :ARG1-of (n3 / number-01 :ARG2 5~e.13,28) :ARG1-of (i2 / index-01 :ARG2 (b2 / between~e.36 :op1 0.7~e.31 :op2 1.10~e.33))) :op2 (o2 / or~e.38 :op1 (s3 / synergize-01~e.37) :op2 (s4 / synergize-01~e.37,40 :ARG1-of (s5 / strong-02~e.39)) :ARG1-of (n4 / number-01 :ARG2 2~e.43) :ARG1-of (i3 / index-01 :ARG2 (l / less-than~e.46 :op1 0.7~e.47)))))) :ARG1-of (d / describe-01 :ARG0 (t2 / table~e.50 :mod 1~e.52))) # ::id pmid_2325_9591.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Visual assessment of the dual inhibition in MTS curves did not suggest any major antagonism of treatment in any of the lines tested , however , since the combination treatment curves in the cell lines with antagonistic CI values closely followed the single PI3K inhibitor treatment curves ( Figure 2A ) . # ::alignments 0-1.1.2.2 1-1.1.2 2-1.1.2.1.r 4-1.1.2.1.1 5-1.1.2.1 6-1.1.2.1.2.r 7-1.1.2.1.2.1.1.1 8-1.1.2.1.2 10-1.1.1 10-1.1.1.r 11-1.1 12-1.1.3.2.1 13-1.1.3.3 16-1.1.3.1 18-1.1.3.2.1 21-1.1.3.2 22-1.1.3.2.2 24-1 28-1.2.1.2.1.1.1 28-1.2.1.3.1 29-1.2.1.3 30-1.2.1 31-1.2.1.1.r 33-1.2.1.1 34-1.2.1.1 38-1.2.1.2.1 39-1.2.3 40-1.2 42-1.2.2.1.1.2 43-1.2.2.1.1.1.1.1.1 44-1.2.2.1.1 44-1.2.2.1.1.1 44-1.2.2.1.1.1.r 45-1.1.3.1 45-1.2.2.1 46-1.2.2 48-1.3.1 50-1.3.1.1 (h / have-concession-91~e.24 :ARG1 (s / suggest-01~e.11 :polarity~e.10 -~e.10 :ARG0 (a / assess-01~e.1 :ARG1~e.2 (i2 / inhibit-01~e.5 :mod (d / dual~e.4) :location~e.6 (c / curve-01~e.8 :mod (t2 / thing :name (n / name :op1 "MTS"~e.7)))) :mod (v / visual~e.0)) :ARG1 (a2 / antagonize-01 :ARG1 (t3 / treat-04~e.16,45) :location (c2 / cell-line~e.21 :mod (a3 / any~e.12,18) :ARG1-of (t4 / test-01~e.22)) :ARG1-of (m / major-02~e.13))) :ARG2 (f / follow-01~e.40 :ARG1 (c4 / curve-01~e.30 :location~e.31 (c5 / cell-line~e.33,34) :ARG0-of (h2 / have-03 :ARG1 (v2 / value-01~e.38 :mod (i3 / index-01 :mod (c6 / combine-01~e.28) :ARG0-of (a4 / antagonize-01)))) :ARG1-of (t5 / treat-04~e.29 :mod (c3 / combine-01~e.28))) :ARG2 (c7 / curve-01~e.46 :ARG1-of (t6 / treat-04~e.45 :ARG2 (s2 / small-molecule~e.44 :ARG0-of~e.44 (i4 / inhibit-01~e.44 :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K"~e.43))) :ARG1-of (s3 / single-02~e.42)))) :ARG1-of (c8 / close-10~e.39)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.48 :mod "2A"~e.50))) # ::id pmid_2325_9591.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There was no correlation between the cancer genotypes in responsiveness to the dual inhibition , since an ALK translocated line ( H3122 ) and a triple @-@ negative negative line ( H1437 ) showed synergistic responses to dual inhibition ( Figure 2A , Table 1 ) . # ::alignments 2-1.1 2-1.1.r 3-1 6-1.2.1.2.1 7-1.2 10-1.3.r 10-1.5 12-1.3.1.1 13-1.3.1 15-1.5 18-1.5.1.1.1.1.1.1.1 20-1.5.1.1.1.1 21-1.5.1.1.1 23-1.5.1.1.1.2.1.1.1 25-1.5.1.1 27-1.5.1.1.2.1.1 29-1.5.1.1.2.1 30-1.5.1.1.2.1 31-1.5.1.1.2 33-1.5.1.1.2.2.1.1.1 35-1.5.1 36-1.5.1.2.2 37-1.3 37-1.5.1.2 37-1.5.1.2.1 37-1.5.1.2.1.r 38-1.5 39-1.3.1.1 40-1.3.1 42-1.4.1.1 44-1.4.1.1.1 47-1.4.1.2 49-1.4.1.2.1 (c / correlate-01~e.3 :polarity~e.2 -~e.2 :ARG1 (g / genotype~e.7 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.6))) :ARG2-of~e.10 (r / respond-01~e.37 :ARG1 (i / inhibit-01~e.13,40 :mod (d2 / dual~e.12,39))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.42 :mod "2A"~e.44) :op2 (t4 / table~e.47 :mod 1~e.49))) :ARG1-of (c7 / cause-01~e.10,15,38 :ARG0 (s / show-01~e.35 :ARG0 (a / and~e.25 :op1 (c3 / cell-line~e.21 :ARG2-of (t / translocate-01~e.20 :ARG1 (g2 / gene :name (n2 / name :op1 "ALK"~e.18))) :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :name (n3 / name :op1 "H3122"~e.23)))) :op2 (c5 / cell-line~e.31 :ARG1-of (n4 / negative-01~e.29,30 :ARG1-of (t2 / triple-01~e.27)) :ARG1-of (m2 / mean-01 :ARG2 (c6 / cell-line :name (n5 / name :op1 "H1437"~e.33))))) :ARG1 (t3 / thing~e.37 :ARG2-of~e.37 (r2 / respond-01~e.37 :ARG1 i) :ARG0-of (s2 / synergize-01~e.36))))) # ::id pmid_2325_9591.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The NSCLC lines showing synergistic responses to dual inhibition seemed to be more responsive to low concentrations (< 1 μM ) of the MEK inhibitor alone ( Figure 2A ) . # ::alignments 1-1.1.1.2.1.1 2-1.1.1 3-1.1.1.1 4-1.1.1.1.1.2 5-1.1.1.1.1 5-1.1.1.1.1.1 5-1.1.1.1.1.1.r 6-1.1.1.1.1.1.1.r 7-1.1.1.1.1.1.1.1 8-1.1.1.1.1.1.1 9-1 13-1.1 14-1.1.2.r 15-1.1.2.2 16-1.1.2 16-1.1.2.3.1 18-1.1.2.3.1.1 19-1.1.2.3.1.2 21-1.1.2.1.r 23-1.1.2.1.1.1.1.1 24-1.1.2.1 24-1.1.2.1.1 24-1.1.2.1.1.r 25-1.1.2.1.2 27-1.2.1 29-1.2.1.1 (s / seem-01~e.9 :ARG1 (r2 / responsive-02~e.13 :ARG0 (c / cell-line~e.2 :ARG0-of (s2 / show-01~e.3 :ARG1 (t2 / thing~e.5 :ARG2-of~e.5 (r / respond-01~e.5 :ARG1~e.6 (i2 / inhibit-01~e.8 :mod (d / dual~e.7))) :ARG0-of (s3 / synergize-01~e.4))) :mod (d3 / disease :name (n3 / name :op1 "NSCLC"~e.1))) :ARG1~e.14 (c2 / concentrate-02~e.16 :ARG1~e.21 (s4 / small-molecule~e.24 :ARG0-of~e.24 (i3 / inhibit-01~e.24 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.23))) :mod (a / alone~e.25)) :ARG1-of (l / low-04~e.15) :quant (l2 / less-than :op1 (c3 / concentration-quantity~e.16 :quant 1~e.18 :unit (m / micromolar~e.19))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.27 :mod "2A"~e.29))) # ::id pmid_2325_9591.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analogously to the single inhibitor results , the lines sensitive to dual inhibition showed only a minor difference between the activities of the different PI3K inhibitors in combination with the MEK inhibitor . # ::alignments 3-1.3.1.1.1.2 4-1.3.1.1.1 4-1.3.1.1.1.1 4-1.3.1.1.1.1.r 5-1.3.1 5-1.3.1.1 5-1.3.1.1.r 8-1.1 9-1.1.1 11-1.1.1.1.1 12-1.1.1.1 13-1 16-1.2.2 17-1.2 17-1.3 20-1.2.1 21-1.2.1.1.r 23-1.2.1.1.2 24-1.2.1.1.1.1.1.1 25-1.2.1.1 25-1.2.1.1.1 25-1.2.1.1.1.r 26-1.2.1.1.3.r 27-1.2.1.1.3 30-1.2.1.1.3.1.1.1.1.1 31-1.1.1.1 31-1.2.1.1.3.1 31-1.2.1.1.3.1.1 31-1.2.1.1.3.1.1.r (s / show-01~e.13 :ARG0 (c / cell-line~e.8 :ARG0-of (s2 / sensitive-03~e.9 :ARG1 (i2 / inhibit-01~e.12,31 :mod (d / dual~e.11)))) :ARG1 (d2 / differ-02~e.17 :ARG1 (a / activity-06~e.20 :ARG0~e.21 (s3 / small-molecule~e.25 :ARG0-of~e.25 (i3 / inhibit-01~e.25 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"~e.24))) :ARG1-of (d3 / differ-02~e.23) :ARG1-of~e.26 (c2 / combine-01~e.27 :ARG2 (s4 / small-molecule~e.31 :ARG0-of~e.31 (i4 / inhibit-01~e.31 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.30))))))) :ARG1-of (m / minor-01~e.16)) :ARG1-of (r / resemble-01~e.17 :ARG2 (t / thing~e.5 :ARG2-of~e.5 (r2 / result-01~e.5 :ARG1 (s5 / small-molecule~e.4 :ARG0-of~e.4 (i / inhibit-01~e.4) :ARG1-of (s6 / single-02~e.3)))))) # ::id pmid_2325_9591.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Based on a literature search [ @ 4 , 7 @ ] , additional cell lines known to be responsive to dual PI3K and MEK inhibition were studied . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1.1 4-1.2.1 7-1.2.1.2.1.1.1.1 11-1.2.1.2.1.1.1.2 16-1.1 17-1.1 18-1.1.2.2 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1.2 24-1.1.2.1.1.1.1.1 25-1.1.2.1.1 26-1.1.2.1.1.2.1.1 27-1.1.2.1 29-1 (s / study-01~e.29 :ARG1 (c / cell-line~e.16,17 :ARG1-of (a / add-02) :ARG0-of (r / responsive-02~e.21 :ARG1~e.22 (i / inhibit-01~e.27 :ARG1 (a2 / and~e.25 :op1 (e / enzyme :name (n2 / name :op1 "PI3K"~e.24)) :op2 (e2 / enzyme :name (n / name :op1 "MEK"~e.26))) :mod (d / dual~e.23)) :ARG1-of (k / know-01~e.18))) :ARG1-of (b / base-02~e.0 :ARG2~e.1 (s2 / search-01~e.4 :ARG1 (l / literature~e.3) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 4~e.7 :op2 7~e.11))))))) # ::id pmid_2325_9591.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MDA @-@ MB231 , a basal @-@ like breast cancer line , and HCT116 , a K @ Ras mutant colorectal line , were exposed to single inhibitors or dual inhibition and analyzed with the MTS assay . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 5-1.1.1.1.2.1.1 7-1.1.1.1 7-1.1.1.1.2 7-1.1.1.1.2.r 8-1.1.1.1.2.1.2.2.1 9-1.1.1.1.2.1.2.2.2 10-1.1.1.1.2.1 12-1.1.1 13-1.1.1.2.1.1 22-1.1.1.2.2.1.2 22-1.1.1.2.2.1.2.2 22-1.1.1.2.2.1.2.2.r 23-1.1.1.2.2.1.1 24-1.1.1.2.2.1 27-1.1 28-1.1.2.r 29-1.1.2.1 29-1.1.2.1.1 29-1.1.2.1.1.r 30-1.1.2.1.2 30-1.1.2.2 31-1.1.2 32-1.1.2.2.1 33-1.1.2.1.2 33-1.1.2.2 34-1 35-1.2 36-1.2.2.r 38-1.2.2.1.1.1 39-1.2.2 (a2 / and~e.34 :op1 (e / expose-01~e.27 :ARG1 (a / and~e.12 :op1 (c / cell-line~e.7 :name (n3 / name :op1 "MDA-MB231"~e.0,2) :ARG1-of~e.7 (r / resemble-01~e.7 :ARG2 (c3 / cell-line~e.10 :mod (b2 / basal~e.5) :mod (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast"~e.8 :op2 "cancer"~e.9))))) :op2 (c4 / cell-line :name (n4 / name :op1 "HCT116"~e.13) :ARG1-of (m / mean-01 :ARG2 (c5 / cell-line~e.24 :mod (c6 / colon~e.23) :mod (g / gene~e.22 :name (n5 / name :op1 "KRas") :ARG2-of~e.22 (m2 / mutate-01~e.22)))))) :ARG2~e.28 (o / or~e.31 :op1 (s / small-molecule~e.29 :ARG1-of~e.29 (s2 / single-02~e.29) :ARG0-of (i2 / inhibit-01~e.30,33)) :op2 (i3 / inhibit-01~e.30,33 :mod (d2 / dual~e.32)))) :op2 (a3 / analyze-01~e.35 :ARG1 a :instrument~e.36 (a4 / assay-01~e.39 :mod (s3 / small-molecule :name (n / name :op1 "MTS"~e.38))))) # ::id pmid_2325_9591.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As in the previous work , both the cell lines showed synergistic responses to dual inhibition ( Figure 2B , Table 1 ) . # ::alignments 0-1.3.1.1.r 3-1.3.1.1 4-1.3.1 6-1.1.1 8-1.1 9-1.1 10-1 11-1.2.2 12-1.2 12-1.2.1 12-1.2.1.r 13-1.2.1.1.r 14-1.2.1.1.1 15-1.2.1.1 17-1.4.1.1 19-1.4.1.1.1 22-1.4.1.2 24-1.4.1.2.1 (s / show-01~e.10 :ARG0 (c / cell-line~e.8,9 :mod (b / both~e.6)) :ARG1 (t / thing~e.12 :ARG2-of~e.12 (r / respond-01~e.12 :ARG1~e.13 (i / inhibit-01~e.15 :mod (d / dual~e.14))) :ARG0-of (s2 / synergize-01~e.11)) :ARG1-of (r2 / resemble-01 :ARG2 (w / work-01~e.4 :time~e.0 (p / previous~e.3))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure~e.17 :mod "2B"~e.19) :op2 (t2 / table~e.22 :mod 1~e.24)))) # ::id pmid_2325_9591.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PI @-@ 103 was markedly less effective than ZSTK474 in the HCT116 cell line , while , like all the NSCLC cell lines , MDA @-@ MB231 responded similarly to both PI3K inhibitors ( Figure 2B , Table 1 ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 4-1.1.3 4-1.1.3.r 5-1.1.2 7-1.1.4.r 8-1.1.4.1.1 11-1.1.5.1.1 12-1.1.5 13-1.1.5 15-1 17-1.2.1 17-1.2.1.2 17-1.2.1.2.r 18-1.2.1.2.1.1 20-1.2.1.2.1.2.1.1 21-1.2.1.2.1 22-1.2.1.2.1 24-1.2.1.1.1 26-1.2.1.1.1 27-1.2 28-1.2.3 29-1.2.2.r 30-1.2.2.2 31-1.2.2.1.1.1.1 32-1.2.2 32-1.2.2.1 32-1.2.2.1.r 34-1.3.1.1 36-1.3.1.1.1 39-1.3.1.2 41-1.3.1.2.1 (c / contrast-01~e.15 :ARG1 (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "PI-103"~e.0,2)) :degree (l / less~e.5) :manner~e.4 (m / marked~e.4) :compared-to~e.7 (s2 / small-molecule :name (n2 / name :op1 "ZSTK474"~e.8)) :location (c2 / cell-line~e.12,13 :name (n3 / name :op1 "HCT116"~e.11))) :ARG2 (r / respond-01~e.27 :ARG1 (c3 / cell-line~e.17 :name (n4 / name :op1 "MDA-MB231"~e.24,26) :ARG1-of~e.17 (r2 / resemble-01~e.17 :ARG2 (c4 / cell-line~e.21,22 :mod (a2 / all~e.18) :mod (d2 / disease :name (n7 / name :op1 "NSCLC"~e.20))))) :ARG2~e.29 (s3 / small-molecule~e.32 :ARG0-of~e.32 (i2 / inhibit-01~e.32 :ARG1 (p / protein-family :name (n6 / name :op1 "PI3K"~e.31))) :mod (b / both~e.30)) :ARG1-of (r3 / resemble-01~e.28)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.34 :mod "2B"~e.36) :op2 (t2 / table~e.39 :mod 1~e.41)))) # ::id pmid_2325_9591.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , we did not see any differences in target inhibition between ZSTK474 and PI @-@ 103 in the HCT116 line ( Figure 3A ) , so that the mechanism of differential efficiency remains unknown . # ::alignments 0-1.5 2-1.2 4-1.1 4-1.1.r 5-1 6-1.3.4 7-1.3 8-1.3.3.r 9-1.3.3.1 10-1.3.3 12-1.3.1.1.1 14-1.3.2.1.1 16-1.3.2.1.1 17-1.3.5.r 19-1.3.5.1.1 20-1.3.5 22-1.4.1 24-1.4.1.1 28-1.6 29-1.6.1.r 31-1.6.1.1 32-1.6.1.1.1.r 33-1.6.1.1.1.1 34-1.6.1.1.1 35-1.6.1 36-1.6.1.2 36-1.6.1.2.1 36-1.6.1.2.1.r (s / see-01~e.5 :polarity~e.4 -~e.4 :ARG0 (w / we~e.2) :ARG1 (d / differ-02~e.7 :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474"~e.12)) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "PI-103"~e.14,16)) :ARG3~e.8 (i / inhibit-01~e.10 :ARG1-of (t / target-01~e.9)) :mod (a / any~e.6) :location~e.17 (c / cell-line~e.20 :name (n3 / name :op1 "HCT116"~e.19))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.22 :mod "3A"~e.24)) :ARG2-of (i3 / interest-01~e.0) :ARG0-of (c2 / cause-01~e.28 :ARG1~e.29 (r / remain-01~e.35 :ARG1 (m / mechanism~e.31 :ARG1-of~e.32 (e / efficient-01~e.34 :mod (d3 / differential~e.33))) :ARG3 (k / know-01~e.36 :polarity~e.36 -~e.36 :ARG1 m)))) # ::id pmid_2325_9591.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lines H3122 , H1437 , MDA @-@ MB231 , and HCT116 , which were sensitive to dual inhibition , were further analyzed with Western blot analysis for cleaved PARP , a well @-@ characterized marker of apoptosis . # ::alignments 1-1.1.1 1-1.1.2 1-1.1.3 1-1.1.4 2-1.1.1.1.1 4-1.1.2.1.1 6-1.1.3.1.1 8-1.1.3.1.1 10-1.1 11-1.1.4.1.1 15-1.1.5 16-1.1.5.1.r 17-1.1.5.1.1 18-1.1.5.1 21-1.2 22-1 24-1.3 25-1.3 26-1 27-1.3.1.r 28-1.3.1.2 29-1.3.1.1.1 32-1.3.1.3.3 34-1.3.1.3.2 37-1.3.1.3.1 (a / analyze-01~e.22,26 :ARG1 (a2 / and~e.10 :op1 (c / cell-line~e.1 :name (n2 / name :op1 "H3122"~e.2)) :op2 (c2 / cell-line~e.1 :name (n3 / name :op1 "H1437"~e.4)) :op3 (c3 / cell-line~e.1 :name (n4 / name :op1 "MDA-MB231"~e.6,8)) :op4 (c4 / cell-line~e.1 :name (n5 / name :op1 "HCT116"~e.11)) :ARG0-of (s / sensitive-03~e.15 :ARG1~e.16 (i / inhibit-01~e.18 :mod (d / dual~e.17)))) :degree (f / further~e.21) :manner (i2 / immunoblot-01~e.24,25 :ARG1~e.27 (p / protein :name (n7 / name :op1 "PARP"~e.29) :ARG1-of (c5 / cleave-01~e.28) :ARG0-of (m / mark-02 :ARG1 (a4 / apoptosis~e.37) :ARG1-of (c6 / characterize-01~e.34) :ARG1-of (w / well-09~e.32))) :ARG2 a2)) # ::id pmid_2325_9591.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No cleaved PARP was detected in any of the cell lines following the single agent treatments ( Figure 4A ) , but when dual inhibition with either ZSTK474 or PI @-@ 103 was administered , marked PARP cleavage was seen in the H3122 line but not in the other lines tested ( Figure 4A ) . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1.2.2 2-1.1.2.1.1 4-1.1 5-1.1.3.r 6-1.1.3.1 9-1.1.3 10-1.1.3 11-1.1.5 13-1.1.5.1.1.1 14-1.1.5.1.1 15-1.1.5.1 17-1.1.4.1 19-1.1.4.1.1 23-1.2.3 24-1.2.4.r 25-1.2.4.1.2 26-1.2.4.1 29-1.2.4.1.1.1.1.1 30-1.2.4.1.1 31-1.2.4.1.1.2.1.1 33-1.2.4.1.1.2.1.1 35-1.2.4 37-1.2.1.2.1 38-1.2.1.1.1 39-1.2.1 39-1.2.1.2 39-1.2.1.2.r 41-1.2 41-1.2.3.1 42-1.2.2.r 44-1.2.2.1.1 45-1.2.2 46-1 46-1.2.3 47-1.2.3.1.1 47-1.2.3.1.1.r 48-1.2.3.1.3.r 50-1.2.3.1.3.1 51-1.2.3.1.3 52-1.2.3.1.3.2 54-1.2.5 55-1.2.5 56-1.2.5 (c / contrast-01~e.46 :ARG1 (d / detect-01~e.4 :polarity~e.0 -~e.0 :ARG1 (p / protein :name (n / name :op1 "PARP"~e.2) :ARG1-of (c2 / cleave-01~e.1)) :location~e.5 (c3 / cell-line~e.9,10 :mod (a / any~e.6)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.17 :mod "4A"~e.19)) :ARG1-of (f / follow-01~e.11 :ARG2 (t / treat-04~e.15 :ARG2 (a2 / agent~e.14 :ARG1-of (s / single-02~e.13))))) :ARG2 (s2 / see-01~e.41 :ARG1 (p2 / protein~e.39 :name (n2 / name :op1 "PARP"~e.38) :ARG1-of~e.39 (c4 / cleave-01~e.39 :ARG1-of (m / mark-01~e.37))) :location~e.42 (c5 / cell-line~e.45 :name (n3 / name :op1 "H3122"~e.44)) :ARG1-of (c6 / contrast-01~e.23,46 :ARG2 (s3 / see-01~e.41 :polarity~e.47 -~e.47 :ARG1 p2 :location~e.48 (c7 / cell-line~e.51 :mod (o / other~e.50) :ARG1-of (t2 / test-01~e.52)))) :time~e.24 (a3 / administer-01~e.35 :ARG1 (i / inhibit-01~e.26 :ARG0 (o2 / or~e.30 :op1 (s4 / small-molecule :name (n4 / name :op1 "ZSTK474"~e.29)) :op2 (s5 / small-molecule :name (n5 / name :op1 "PI-103"~e.31,33))) :mod (d3 / dual~e.25))) :ARG1-of d2~e.54,55,56)) # ::id pmid_2325_9591.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effect of dual inhibition on cell signaling # ::alignments 1-1 2-1.1.r 3-1.1.1 4-1.1 5-1.2.r 6-1.2.1 7-1.2 (a / affect-01~e.1 :ARG0~e.2 (i / inhibit-01~e.4 :mod (d / dual~e.3)) :ARG1~e.5 (s / signal-07~e.7 :ARG1 (c / cell~e.6))) # ::id pmid_2325_9591.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The NSCLC ( H3122 and H1437 ) , breast cancer ( MDA @-@ MB231 ) and colon cancer ( HCT116 ) lines , which showing major synergy upon dual inhibition , were further studied for cell signaling in response to the inhibitors . # ::alignments 1-1.1.1.2.1.1 3-1.1.1.1.1.1.1.1 5-1.1.1.1.1.2.1.1 8-1.1.2.2.2.1 9-1.1.2.2.2.2 11-1.1.2.1.1.1.1 13-1.1.2.1.1.1.1 15-1.1 15-1.1.1.1.1 16-1.1.3.2.2.1 17-1.1.3.2.2.2 19-1.1.3.1.1.1.1 21-1.1.1 21-1.1.2 21-1.1.3 24-1.1.4 25-1.1.4.1.1 26-1.1.4.1 28-1.1.4.2.1.1 29-1.1.4.2.1 32-1.2 33-1 34-1.3.r 35-1.3.1 36-1.3 37-1.3.2.r 38-1.3.2 41-1.1.4.2.1 41-1.3.2.1 41-1.3.2.1.1 41-1.3.2.1.1.r (s / study-01~e.33 :ARG1 (a / and~e.15 :op1 (c / cell-line~e.21 :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.15 :op1 (c2 / cell-line :name (n3 / name :op1 "H3122"~e.3)) :op2 (c3 / cell-line :name (n4 / name :op1 "H1437"~e.5)))) :mod (d / disease :name (n / name :op1 "NSCLC"~e.1))) :op2 (c4 / cell-line~e.21 :ARG1-of (m2 / mean-01 :ARG2 (c6 / cell-line :name (n5 / name :op1 "MDA-MB231"~e.11,13))) :mod (d3 / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast"~e.8 :op2 "cancer"~e.9))) :op3 (c7 / cell-line~e.21 :ARG1-of (m3 / mean-01 :ARG2 (c10 / cell-line :name (n6 / name :op1 "HCT116"~e.19))) :mod (d4 / disease :wiki "Colorectal_cancer" :name (n7 / name :op1 "colon"~e.16 :op2 "cancer"~e.17))) :ARG0-of (s2 / show-01~e.24 :ARG1 (s3 / synergize-01~e.26 :ARG1-of (m4 / major-02~e.25)) :time (a3 / after :op1 (i2 / inhibit-01~e.29,41 :mod (d2 / dual~e.28))))) :degree (f / further~e.32) :purpose~e.34 (s4 / signal-07~e.36 :ARG1 (c11 / cell~e.35) :ARG2-of~e.37 (r / respond-01~e.38 :ARG1 (s5 / small-molecule~e.41 :ARG0-of~e.41 (i3 / inhibit-01~e.41))))) # ::id pmid_2325_9591.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All the cell lines downregulated pAKT and its downstream target pS6 completely in response to 6h of treatment with the PI3K inhibitor ZSTK474 or PI @-@ 103 ( 3.3 μM ) ( Figure 3A ) . # ::alignments 0-1.1.1 2-1.1 3-1.1 4-1 5-1.2.1.1.1 5-1.2.1.2 6-1.2 8-1.2.2.3.2 9-1.2.2 9-1.2.2.3 9-1.2.2.3.r 11-1.3.2 13-1.3 16-1.3.1.r 17-1.3.1 18-1.3.1.1.r 20-1.3.1.1.3.1.1.1 21-1.3.1.1.3 22-1.3.1.1.1.1.1 23-1.3.1.1 24-1.3.1.1.2.1.1 26-1.3.1.1.2.1.1 28-1.3.1.1.1.2.1 29-1.3.1.1.1.2.2 32-1.4.1 34-1.4.1.1 (d / downregulate-01~e.4 :ARG0 (c / cell-line~e.2,3 :mod (a / all~e.0)) :ARG1 (a2 / and~e.6 :op1 (e / enzyme :name (n / name :op1 "AKT"~e.5) :ARG3-of (p / phosphorylate-01~e.5)) :op2 (p3 / protein~e.9 :name (n2 / name :op1 "S6") :ARG3-of p :ARG1-of~e.9 (t2 / target-01~e.9 :ARG0 e :location (d2 / downstream~e.8)))) :ARG2-of (r / respond-01~e.13 :ARG1~e.16 (t3 / treat-04~e.17 :ARG2~e.18 (o / or~e.23 :op1 (s / small-molecule :name (n3 / name :op1 "ZSTK474"~e.22) :quant (c3 / concentration-quantity :quant 3.3~e.28 :unit (m / micromolar~e.29))) :op2 (s2 / small-molecule :name (n4 / name :op1 "PI-103"~e.24,26) :quant c3) :ARG0-of (i2 / inhibit-01~e.21 :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K"~e.20)))) :duration (t4 / temporal-quantity :quant 6 :unit (h / hour))) :ARG1-of (c2 / complete-02~e.11)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.32 :mod "3A"~e.34))) # ::id pmid_2325_9591.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Downregulation of p4E @-@ BP1 was also noted with all the cell lines tested , but it was complete only in the H3122 cell line ( Figure 3A ) . # ::alignments 0-1.1.1 4-1.1.1.1.1.1 7-1.1 11-1.1.1.2 12-1.1.1.2 13-1.1.1.2.1 15-1 16-1.2.1 18-1.2 19-1.2.2.2 22-1.2.2.1.1 23-1.2.2 24-1.2.2 26-1.3.1 28-1.3.1.1 (c2 / contrast-01~e.15 :ARG1 (n / note-01~e.7 :ARG1 (d / downregulate-01~e.0 :ARG1 (p / protein :name (n2 / name :op1 "4E-BP1"~e.4) :ARG3-of (p2 / phosphorylate-01)) :location (c / cell-line~e.11,12 :ARG1-of (t / test-01~e.13)))) :ARG2 (c3 / complete-02~e.18 :ARG1 d~e.16 :location (c4 / cell-line~e.23,24 :name (n3 / name :op1 "H3122"~e.22) :mod (o / only~e.19))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26 :mod "3A"~e.28))) # ::id pmid_2325_9591.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , concurrent activation of pERK1 @/@ 2 was recognized in the H3122 , MDA @-@ MB231 and HCT116 cell lines during PI3K inhibitor treatment ( Figure 3A ) . # ::alignments 0-1.1.2 2-1.1.1.2 3-1.1.1 7-1.1.1.1.1.1 9-1.1 10-1.1.2.r 12-1.1.2.1.1.1 14-1.1.2.2.1.1 16-1.1.2.2.1.1 17-1.1.2 18-1.1.2.3.1.1 19-1.1.2.1 19-1.1.2.2 19-1.1.2.3 20-1.1.2.1 21-1.1.3.r 22-1.1.3.1.1.1.1.1 23-1.1.3.1 23-1.1.3.1.1 23-1.1.3.1.1.r 24-1.1.3 26-1.2.1 28-1.2.1.1 (a / and :op2 (r / recognize-01~e.9 :ARG1 (a2 / activate-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.7) :ARG3-of (p / phosphorylate-01)) :ARG1-of (c / concurrent-02~e.2)) :location~e.10 (a3 / and~e.0,17 :op1 (c2 / cell-line~e.19,20 :name (n2 / name :op1 "H3122"~e.12)) :op2 (c3 / cell-line~e.19 :name (n3 / name :op1 "MDA-MB231"~e.14,16)) :op3 (c4 / cell-line~e.19 :name (n4 / name :op1 "HCT116"~e.18))) :time~e.21 (t2 / treat-04~e.24 :ARG2 (s / small-molecule~e.23 :ARG0-of~e.23 (i2 / inhibit-01~e.23 :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K"~e.22)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "3A"~e.28))) # ::id pmid_2325_9591.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When the cell lines were treated with the MEK inhibitor CI @-@ 1040 ( 1 μM , 6 h ) , complete ( H3122 , H1437 ) or marked ( MDA @-@ MB231 , HCT116 ) downregulation of pERK1 @/@ 2 was seen ( Figure 3A ) . # ::alignments 0-1.2.r 2-1.2.1 3-1.2.1 5-1.2 6-1.2.2.r 8-1.2.2.2.1.1.1 9-1.2.2 9-1.2.2.2 9-1.2.2.2.r 10-1.2.2.1.1 12-1.2.2.1.1 14-1.2.2.3.1 15-1.2.2.3.2 17-1.2.3.1 18-1.2.3.2 21-1.1.1.2 23-1.1.1.3.1.1.1 25-1.1.1.3.2.1.1 27-1.1 28-1.1.2.3 30-1.1.2.2.1.1.1 32-1.1.2.2.1.1.1 34-1.1.2.2.2.1.1 36-1.1.1 36-1.1.2 40-1.1.1.1.1.1 42-1 44-1.3.1 46-1.3.1.1 (s / see-01~e.42 :ARG1 (o / or~e.27 :op1 (d / downregulate-01~e.36 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"~e.40) :ARG3-of (p2 / phosphorylate-01)) :ARG1-of (c3 / complete-02~e.21) :location (a / and :op1 (c4 / cell-line :name (n4 / name :op1 "H3122"~e.23)) :op2 (c5 / cell-line :name (n5 / name :op1 "H1437"~e.25)))) :op2 (d2 / downregulate-01~e.36 :ARG1 e :location (a2 / and :op1 (c6 / cell-line :name (n6 / name :op1 "MDA-MB231"~e.30,32)) :op2 (c7 / cell-line :name (n7 / name :op1 "HCT116"~e.34))) :degree (m3 / marked~e.28))) :time~e.0 (t2 / treat-04~e.5 :ARG1 (c / cell-line~e.2,3) :ARG2~e.6 (s2 / small-molecule~e.9 :name (n3 / name :op1 "CI-1040"~e.10,12) :ARG0-of~e.9 (i2 / inhibit-01~e.9 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.8))) :quant (c2 / concentration-quantity :quant 1~e.14 :unit (m / micromolar~e.15))) :duration (t3 / temporal-quantity :quant 6~e.17 :unit (h / hour~e.18))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.44 :mod "3A"~e.46))) # ::id pmid_2325_9591.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was accompanied by upregulation of pAKT in the H3122 and MDA @-@ MB231 lines , but not by upregulation of pS6 or p4E @-@ BP1 ( H3122 ) ( Figure 3A ) . # ::alignments 0-1.1.2 2-1.1 2-1.2 3-1.1.1.r 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 6-1.1.1.1.2 7-1.1.1.2.r 9-1.1.1.2.1.1.1 10-1.1.1.2 11-1.1.1.2.2.1.1 13-1.1.1.2.2.1.1 14-1.1.1.2.1 14-1.1.1.2.2 16-1 17-1.2.1 17-1.2.1.r 18-1.2.2.r 19-1.2.2 22-1.2.2.1 25-1.2.2.1.2.1.1 27-1.2.2.2 30-1.3.1 32-1.3.1.1 (c / contrast-01~e.16 :ARG1 (a / accompany-01~e.2 :ARG0~e.3 (u / upregulate-01~e.4 :ARG1~e.5 (e / enzyme :name (n / name :op1 "AKT"~e.6) :ARG3-of (p / phosphorylate-01~e.6)) :location~e.7 (a2 / and~e.10 :op1 (c2 / cell-line~e.14 :name (n2 / name :op1 "H3122"~e.9)) :op2 (c3 / cell-line~e.14 :name (n3 / name :op1 "MDA-MB231"~e.11,13)))) :ARG1 (t / this~e.0)) :ARG2 (a3 / accompany-01~e.2 :polarity~e.17 -~e.17 :ARG0~e.18 (u2 / upregulate-01~e.19 :ARG1 (o / or~e.22 :op1 (p3 / protein :name (n4 / name :op1 "S6") :ARG3-of p) :op2 (p2 / protein :name (n5 / name :op1 "4E-BP1"~e.25) :ARG3-of p)) :location c2~e.27) :ARG1 t) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "3A"~e.32))) # ::id pmid_2325_9591.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok p4E @-@ BP1 was markedly upregulated in the MDA @-@ MB231 line in response to CI @-@ 1040 treatment ( Figure 3A ) . # ::alignments 2-1.1.1.1 4-1.2 4-1.2.r 5-1 6-1.3.r 8-1.3.1.1 10-1.3.1.1 11-1.3 12-1.4.r 13-1.4 14-1.4.1.r 15-1.4.1.1.1.1 17-1.4.1.1.1.1 18-1.4.1 20-1.5.1 22-1.5.1.1 (u / upregulate-01~e.5 :ARG1 (p / protein :name (n / name :op1 "4E-BP1"~e.2) :ARG3-of (p2 / phosphorylate-01)) :manner~e.4 (m / marked~e.4) :location~e.6 (c / cell-line~e.11 :name (n2 / name :op1 "MDA-MB231"~e.8,10)) :ARG2-of~e.12 (r / respond-01~e.13 :ARG1~e.14 (t / treat-04~e.18 :ARG2 (s / small-molecule :name (n3 / name :op1 "CI-1040"~e.15,17)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "3A"~e.22))) # ::id pmid_2325_9591.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When the PI3K and MEK inhibitors were administered simultaneously the inhibition of the targets was similar to that seen with single inhibitor treatment ( Figure 3A ) . # ::alignments 0-1.3.r 2-1.3.1.1.1.1.1.1 3-1.3.1 4-1.3.1.2.1.1.1.1 5-1.3.1.1 5-1.3.1.1.1 5-1.3.1.1.1.r 5-1.3.1.2 5-1.3.1.2.1 5-1.3.1.2.1.r 7-1.3 8-1.3.2 8-1.3.2.r 10-1.1 10-1.2 11-1.1.1.r 13-1.1.1 13-1.1.1.1 13-1.1.1.1.r 15-1 18-1.2.1 19-1.2.2.r 20-1.2.2.1.2 21-1.2.2.1 21-1.2.2.1.1 21-1.2.2.1.1.r 22-1.2.2 24-1.4.1 26-1.4.1.1 (r2 / resemble-01~e.15 :ARG1 (i2 / inhibit-01~e.10 :ARG1~e.11 (t / thing~e.13 :ARG1-of~e.13 (t2 / target-01~e.13))) :ARG2 (i3 / inhibit-01~e.10 :ARG1-of (s / see-01~e.18) :time~e.19 (t3 / treat-04~e.22 :ARG2 (s2 / small-molecule~e.21 :ARG0-of~e.21 (i4 / inhibit-01~e.21) :ARG1-of (s3 / single-02~e.20)))) :time~e.0 (a / administer-01~e.7 :ARG1 (a2 / and~e.3 :op1 (s5 / small-molecule~e.5 :ARG0-of~e.5 (i5 / inhibit-01~e.5 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"~e.2)))) :op2 (s6 / small-molecule~e.5 :ARG0-of~e.5 (i6 / inhibit-01~e.5 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.4))))) :manner~e.8 (s4 / simultaneous~e.8)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "3A"~e.26))) # ::id pmid_2325_9591.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dual inhibition was able to overcome the single inhibitor @-@ induced stimulation of parallel pathway activation ( Figure 3A ) . # ::alignments 0-1.1.1 1-1.1 3-1 5-1.2 7-1.2.2.2.1 7-1.2.2.2.1.1 7-1.2.2.2.1.1.r 8-1.2.2.2.1.2 10-1.2.2.2 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1 14-1.2.2.1.1 15-1.2.2.1 17-1.3.1 19-1.3.1.1 (c / capable-01~e.3 :ARG1 (i / inhibit-01~e.1 :mod (d / dual~e.0)) :ARG2 (o / overcome-01~e.5 :ARG0 i :ARG1 (s3 / stimulate-01~e.11 :ARG1~e.12 (a / activate-01~e.15 :ARG1 (p2 / pathway~e.14 :ARG1-of (p3 / parallel-01~e.13))) :ARG2-of (i3 / induce-01~e.10 :ARG0 (s / small-molecule~e.7 :ARG1-of~e.7 (s2 / single-02~e.7) :ARG0-of (i2 / inhibit-01~e.8))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod "3A"~e.19))) # ::id pmid_2325_9591.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We were not able to detect any significant difference in the activity of either pS6 or p4E @-@ BP1 following dual inhibitor treatment as compared with the single PI3K inhibitor treatments ( Figure 3A ) . # ::alignments 0-1.2 2-1.1 2-1.1.r 3-1 5-1.3 6-1.3.2.2 7-1.3.2.3 8-1.3.2 9-1.3.2.1.r 11-1.3.2.1 15-1.3.2.1.1 18-1.3.2.1.1.2.1.1 19-1.3.2.1.2 20-1.3.2.1.2.1.1.1.1 21-1.3.2.1.2.1.1 21-1.3.2.1.2.1.1.1 21-1.3.2.1.2.1.1.1.r 22-1.3.2.1.2.1 22-1.3.2.1.2.1.2 24-1.3.2.1.2.1.2.r 27-1.3.2.1.2.1.2.1 27-1.3.2.1.2.1.2.1.1 27-1.3.2.1.2.1.2.1.1.r 28-1.3.2.1.2.1.2.1.2.1.1.1 29-1.3.2.1.2.1.1 29-1.3.2.1.2.1.1.1 29-1.3.2.1.2.1.1.1.r 29-1.3.2.1.2.1.2.1.2 30-1.3.2.1.2.1 30-1.3.2.1.2.1.2 32-1.4.1 34-1.4.1.1 (c / capable-01~e.3 :polarity~e.2 -~e.2 :ARG1 (w / we~e.0) :ARG2 (d / detect-01~e.5 :ARG0 w :ARG1 (d2 / differ-02~e.8 :ARG3~e.9 (a2 / activity-06~e.11 :ARG0 (o / or~e.15 :op1 (p / protein :name (n / name :op1 "S6") :ARG3-of (p2 / phosphorylate-01)) :op2 (p3 / protein :name (n2 / name :op1 "4E-BP1"~e.18) :ARG3-of p2)) :ARG1-of (f / follow-01~e.19 :ARG2 (t2 / treat-04~e.22,30 :ARG2 (s2 / small-molecule~e.21,29 :ARG0-of~e.21,29 (i2 / inhibit-01~e.21,29 :mod (d3 / dual~e.20))) :compared-to~e.24 (t3 / treat-04~e.22,30 :ARG2 (s3 / small-molecule~e.27 :ARG1-of~e.27 (s4 / single-02~e.27) :ARG0-of (i3 / inhibit-01~e.29 :ARG1 (p4 / protein-family :name (n3 / name :op1 "PI3K"~e.28)))))))) :mod (a / any~e.6) :ARG1-of (s / significant-02~e.7))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.32 :mod "3A"~e.34))) # ::id pmid_2325_9591.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further analysis of the dual inhibition of the central RTKs and signaling nodes was carried out with the PathScan Antibody Array , which investigates the phosphorylation status of 28 RTKs and 11 signaling nodes concurrently . # ::alignments 0-1.2.1.2 1-1.2.1 2-1.2.1.1.r 4-1.2.1.1.1.2 5-1.2.1.1.1 6-1.2.1.1.1.1.r 8-1.2.1.1.1.1.2 10-1.1.2.1.1.1 10-1.2 10-1.2.1.1 11-1.1.2.1.1.1.2.2 12-1.1.2.1.1.1.2 12-1.2.1.1.2 14-1 15-1 18-1.1.1.1 19-1.1.1.2 20-1.1.1.3 23-1.1 23-1.1.2 23-1.1.2.r 25-1.1.2.1.1 26-1.1.2.1 27-1.1.2.1.1.1.r 28-1.1.2.1.1.1.1.1 30-1.1.2.1.1.1 31-1.1.2.1.1.1.2.1 32-1.1.2.1.1.1.2.2 33-1.1.2.1.1.1.2 34-1.1.2.2 (c / carry-out-03~e.14,15 :ARG0 (p3 / product~e.23 :name (n3 / name :op1 "PathScan"~e.18 :op2 "Antibody"~e.19 :op3 "Array"~e.20) :ARG0-of~e.23 (i2 / investigate-01~e.23 :ARG1 (s2 / status~e.26 :mod (p4 / phosphorylate-01~e.25 :ARG1~e.27 (a4 / and~e.10,30 :op1 (p5 / protein :quant 28~e.28 :ARG1-of (i3 / include-91 :ARG2 (p6 / protein-family :name (n4 / name :op1 "RTK")))) :op2 (n5 / node~e.12,33 :quant 11~e.31 :ARG0-of (s3 / signal-07~e.11,32))))) :ARG1-of (c3 / concurrent-02~e.34))) :ARG1 (a / and~e.10 :op1 (a2 / analyze-01~e.1 :ARG1~e.2 (a3 / and~e.10 :op1 (i / inhibit-01~e.5 :ARG1~e.6 (p / protein :name (n / name :op1 "RTK") :mod (c2 / central~e.8)) :mod (d / dual~e.4)) :op2 (n2 / node~e.12 :ARG0-of s3)) :degree (f / further~e.0)))) # ::id pmid_2325_9591.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Attention was focused on the dual inhibition @-@ sensitive H1437 and MDA @-@ MB231 lines . # ::alignments 0-1.1 2-1 3-1.2.r 5-1.2.1.2.1.1 6-1.2.1.2.1 8-1.2.1.2 9-1.2.1.1.1 10-1.2 11-1.2.2.1.1 13-1.2.2.1.1 14-1.2.1 14-1.2.2 (f / focus-01~e.2 :ARG1 (a / attend-02~e.0 :ARG1 a2) :ARG2~e.3 (a2 / and~e.10 :op1 (c / cell-line~e.14 :name (n / name :op1 "H1437"~e.9) :ARG0-of (s / sensitive-03~e.8 :ARG1 (i / inhibit-01~e.6 :mod (d / dual~e.5)))) :op2 (c2 / cell-line~e.14 :name (n2 / name :op1 "MDA-MB231"~e.11,13) :ARG0-of s))) # ::id pmid_2325_9591.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A low level of RTK activation was noted in untreated cells of both cell lines , H1437 showing some activity with c @-@ MET ( Figure 5 ) , while in the signaling nodes , pAKT , S6 and ERK1 @/@ 2 showed activity in both cell lines and Src activity was also noted in H1437 . # ::alignments 1-1.1.1.1 2-1.1.1 5-1.1.1.2 7-1.1 8-1.1.2.r 9-1.1.2.1 9-1.1.2.1.1 9-1.1.2.1.1.r 9-1.1.2.3.1.2.1.1 10-1.1.2 12-1.1.2.2 13-1.1.2 14-1.1.2 16-1.1.2.3.1.1.1 17-1.1.2.3.1.2 18-1.1.2.3.1.2.1.2 19-1.1.2.3.1.2.1 20-1.1.2.3.1.2.1.1.2.r 21-1.1.2.3.1.2.1.1.2.1.1 23-1.1.2.3.1.2.1.1.2.1.1 25-1.1.2.3.1.2.2.1 27-1.1.2.3.1.2.2.1.1 31-1 32-1.2.r 34-1.2.1.3.1 35-1.2.1.3 37-1.2.1.1.1.1.1 37-1.2.1.1.1.2 39-1.2.1.1.2.1.1 40-1.2.1.1 41-1.2.1.1.3.1.1.1 42-1.2.1.1.3 44-1.2.1 45-1.2.1.2 46-1.2.1.2.1.r 47-1.2.1.2.1 48-1.2.1.2.1 49-1.2.1.2.1 50-1.2 51-1.2.2.1.1.1.1 52-1.2.2.1 54-1.2.2.3 55-1.2.2 56-1.2.2.2.r 57-1.2.2.2 (c3 / contrast-01~e.31 :ARG1 (n / note-02~e.7 :ARG1 (l / level~e.2 :ARG1-of (l2 / low-04~e.1) :degree-of (a2 / activate-01~e.5 :ARG1 (e / enzyme :name (n2 / name :op1 "RKT")))) :location~e.8 (c / cell-line~e.10,13,14 :ARG1-of (t / treat-04~e.9 :polarity~e.9 -~e.9) :mod (b / both~e.12) :ARG1-of (m / mean-01 :ARG2 (c2 / cell-line :name (n3 / name :op1 "H1437"~e.16) :ARG0-of (s / show-01~e.17 :ARG1 (a / activity-06~e.19 :condition (t2 / treat-04~e.9 :ARG1 c2 :ARG2~e.20 (p / protein :name (n4 / name :op1 "c-MET"~e.21,23))) :mod (s5 / some~e.18)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25 :mod 5~e.27))))))) :ARG2~e.32 (a5 / and~e.50 :op1 (s2 / show-01~e.44 :ARG0 (a4 / and~e.40 :op1 (e2 / enzyme :name (n5 / name :op1 "AKT"~e.37) :ARG3-of (p2 / phosphorylate-01~e.37)) :op2 (p4 / protein :name (n6 / name :op1 "S6"~e.39)) :op3 (s3 / slash~e.42 :op1 (e4 / enzyme :name (n7 / name :op1 "ERK1"~e.41)) :op2 (e5 / enzyme :name (n8 / name :op1 "ERK2")))) :ARG1 (a3 / activity-06~e.45 :location~e.46 c~e.47,48,49) :location (n9 / node~e.35 :ARG0-of (s4 / signal-07~e.34))) :op2 (n10 / note-02~e.55 :ARG1 (a6 / activity-06~e.52 :ARG0 (p3 / protein :name (n11 / name :op1 "Src"~e.51))) :location~e.56 c2~e.57 :mod (a7 / also~e.54)))) # ::id pmid_2325_9591.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the drug @-@ treated cells , ZSTK474 ( 24 h ) was able to inhibit both AKT and S6 phosphorylation , S6 showing a more pronounced effect ( Figure 5 ) . # ::alignments 2-1.3.1.1 4-1.3.1 5-1.3 7-1.1.1.1 9-1.2.2.1.1 10-1.2.2.1.2 13-1 15-1.2 17-1.2.1.1.1.1.1 18-1.2.1.1 19-1.2.1.1.2.1.1 20-1.2.1 22-1.2.1.1.2.1.1 23-1.2.1.1.2.2 26-1.2.1.1.2.2.1.1 27-1.2.1.1.2.2.1 29-1.2.1.1.2.2.2.1 31-1.2.1.1.2.2.2.1.1 (c / capable-01~e.13 :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474"~e.7)) :ARG2 (i / inhibit-01~e.15 :ARG1 (p2 / phosphorylate-01~e.20 :ARG1 (a / and~e.18 :op1 (e2 / enzyme :name (n2 / name :op1 "AKT"~e.17)) :op2 (p / protein :name (n3 / name :op1 "S6"~e.19,22) :ARG0-of (s / show-01~e.23 :ARG1 (a2 / affect-01~e.27 :ARG1-of (p3 / pronounced-02~e.26)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod 5~e.31)))))) :time (a3 / after :op1 (t / temporal-quantity :quant 24~e.9 :unit (h / hour~e.10)))) :location (c2 / cell~e.5 :ARG1-of (t2 / treat-04~e.4 :ARG2 (d / drug~e.2)))) # ::id pmid_2325_9591.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , ZSTK474 induced a marked broad feedback RTK activation in the H1437 cell line ( Figure 5 ) . # ::alignments 0-1 2-1.1.1.1.1 3-1.1 5-1.1.2.4 6-1.1.2.3 7-1.1.2.2 8-1.1.2.1.1.1 9-1.1.2 10-1.1.3.r 12-1.1.3.1.1 13-1.1.3 14-1.1.3 16-1.1.4.1 18-1.1.4.1.1 (a / and~e.0 :op2 (i / induce-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "ZSTK474"~e.2)) :ARG2 (a2 / activate-01~e.9 :ARG1 (e2 / enzyme :name (n2 / name :op1 "RTK"~e.8)) :mod (f / feedback~e.7) :mod (b / broad~e.6) :ARG1-of (m / mark-01~e.5)) :location~e.10 (c / cell-line~e.13,14 :name (n3 / name :op1 "H1437"~e.12)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.16 :mod 5~e.18)))) # ::id pmid_2325_9591.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CI @-@ 1040 ( 24 h ) effects were limited to the inhibition of ERK1 @/@ 2 activity . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 4-1.1.2.1.1 5-1.1.2.1.2 7-1.1 9-1 10-1.2.r 12-1.2 13-1.2.1.r 14-1.2.1.1.1.1.1 15-1.2.1.1 17-1.2.1 (l / limit-01~e.9 :ARG1 (a / affect-01~e.7 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "CI-1040"~e.0,2)) :time (a3 / after :op1 (t / temporal-quantity :quant 24~e.4 :unit (h / hour~e.5)))) :ARG2~e.10 (i / inhibit-01~e.12 :ARG1~e.13 (a2 / activity-06~e.17 :ARG0 (s / slash~e.15 :op1 (e / enzyme :name (n / name :op1 "ERK1"~e.14)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2")))))) # ::id pmid_2325_9591.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When dual inhibition with ZSTK474 and CI @-@ 1040 was administered , downregulation of both pAKT @/@ S6 and ERK1 @/@ 2 was noted , but otherwise no marked difference was evident relative to the single agent treatments ( Figure 5 ) . # ::alignments 2-1.1.2.1 3-1.1.2.1.1.r 4-1.1.2.1.1.1.1.1 5-1.1.2.1.1 6-1.1.2.1.1.2.1.1 8-1.1.2.1.1.2.1.1 10-1.1.2 12-1.1.1 15-1.1.1.1.1.1.1.1 15-1.1.1.1.1.1.2 16-1.1.1.1.1 17-1.1.1.1.1.2.1.1 18-1.1.1.1 19-1.1.1.1.2.1.1.1 20-1.1.1.1.1 20-1.1.1.1.2 23-1.1 25-1 27-1.2.1.r 28-1.2.2.1 29-1.2.1 29-1.2.1.r 29-1.2.2 31-1.2 32-1.2.3 37-1.2.3.1 39-1.3.1 41-1.3.1.1 (c / contrast-01~e.25 :ARG1 (n / note-02~e.23 :ARG1 (d / downregulate-01~e.12 :ARG1 (a / and~e.18 :op1 (s / slash~e.16,20 :op1 (e / enzyme :name (n2 / name :op1 "AKT"~e.15) :ARG3-of (p / phosphorylate-01~e.15)) :op2 (p2 / protein :name (n3 / name :op1 "S6"~e.17))) :op2 (s2 / slash~e.20 :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1"~e.19)) :op2 (e4 / enzyme :name (n5 / name :op1 "ERK2"))))) :condition (a2 / administer-01~e.10 :ARG1 (i / inhibit-01~e.2 :ARG0~e.3 (a3 / and~e.5 :op1 (s3 / small-molecule :name (n6 / name :op1 "ZSTK474"~e.4)) :op2 (s4 / small-molecule :name (n7 / name :op1 "CI-1040"~e.6,8)))))) :ARG2 (e7 / evidence-01~e.31 :polarity~e.27,29 -~e.29 :ARG1 (d2 / differ-02~e.29 :ARG1-of (m / mark-01~e.28)) :ARG1-of (r / relative-05~e.32 :ARG3 (t / treat-04~e.37 :ARG2 (o / or :op1 s3 :op2 s4)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.39 :mod 5~e.41))) # ::id pmid_2325_9591.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results suggest specificity of the inhibitors for their targets and the existence of broad feedback activation . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 6-1.2.1.1 6-1.2.1.1.1 6-1.2.1.1.1.r 8-1.2.1.2.1.1 8-1.2.1.2.1.1.r 9-1.2.1.2 9-1.2.1.2.1 9-1.2.1.2.1.r 10-1.2 13-1.2.r 14-1.2.2.2 15-1.2.2.1 16-1.2.2 (s2 / suggest-01~e.2 :ARG0 (t2 / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.13 (a / and~e.10 :op1 (s / specific-02 :ARG1 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6)) :ARG2 (m2 / molecular-physical-entity~e.9 :ARG1-of~e.9 (t / target-01~e.9 :ARG0~e.8 m~e.8))) :op2 (a2 / activate-01~e.16 :mod (f / feedback~e.15) :mod (b / broad~e.14)))) # ::id pmid_2325_9591.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternative dosing of dual inhibition # ::alignments 1-1.2 2-1 3-1.1.r 4-1.1.1 5-1.1 (d / dose-01~e.2 :ARG1~e.3 (i / inhibit-01~e.5 :mod (d2 / dual~e.4)) :mod (a / alternative~e.1)) # ::id pmid_2325_9591.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Even though dual inhibition of PI3K and MEK was identified as an effective form of cancer therapy based on the in vitro models , administration of both drugs at doses inducing major downregulation of the target for long periods of time may be too toxic in a clinical setting . # ::alignments 0-1 1-1 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.1.1.1 6-1.2.1.1 7-1.2.1.1.2.1.1 9-1.2 10-1.1.1.2.1.2.1.1.2.r 10-1.2.2.r 12-1.2.2.2 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.1.2.1 16-1.2.2.1 17-1.2.3 21-1.2.3.1.1 22-1.2.3.1.1 24-1.2.3.1 26-1.1.1.2 28-1.1.1.2.1.1 29-1.1.1.2.1 31-1.1.1.2.1.2 32-1.1.1.2.1.2.1 33-1.1.1.2.1.2.1.1.3 34-1.1.1.2.1.2.1.1 35-1.1.1.2.1.2.1.1.1.r 37-1.1.1.2.1.2.1.1.1 37-1.1.1.2.1.2.1.1.1.1 37-1.1.1.2.1.2.1.1.1.1.r 39-1.1.1.2.1.2.1.1.2.1 40-1.1.1.2.1.2.1.1.2 42-1.1.1.2.1.2.1.1.2.r 43-1.1 44-1.1.1.2.r 45-1.1.1.1 46-1.1.1 47-1.1.1.3.r 47-1.2.3.1.1 49-1.1.1.3.1 50-1.1.1.3 (h / have-concession-91~e.0,1 :ARG1 (p2 / possible-01~e.43 :ARG1 (t2 / toxic~e.46 :degree (t3 / too~e.45) :domain~e.44 (a3 / administer-01~e.26 :ARG1 (d3 / drug~e.29 :mod (b2 / both~e.28) :ARG1-of (d4 / dose-01~e.31 :ARG0-of (i4 / induce-01~e.32 :ARG2 (d5 / downregulate-01~e.34 :ARG1~e.35 (m3 / molecular-physical-entity~e.37 :ARG1-of~e.37 (t4 / target-01~e.37)) :time~e.10,42 (p3 / period~e.40 :ARG1-of (l / long-03~e.39)) :ARG1-of (m2 / major-02~e.33)))))) :condition~e.47 (s / setting~e.50 :mod (c / clinical~e.49)))) :ARG2 (i / identify-01~e.9 :ARG1 (i2 / inhibit-01~e.3 :ARG1~e.4 (a2 / and~e.6 :op1 (e / enzyme :name (n3 / name :op1 "PI3K"~e.5)) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK"~e.7)))) :ARG2~e.10 (f / form~e.13 :topic~e.14 (t / therapy~e.16 :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.15))) :ARG0-of (e3 / effective-04~e.12)) :ARG1-of (b / base-02~e.17 :ARG2 (m / model~e.24 :mod (i3 / in-vitro~e.21,22,47))))) # ::id pmid_2325_9591.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore set out to investigate concurrent administration of PI3K and MEK inhibitors to cell lines sensitive to dual inhibition with alternative dosing schedules . # ::alignments 0-1.1 1-1.3 2-1 3-1 4-1.3 5-1.2 6-1.2.2.3 7-1.2.2 8-1.2.2.1.r 9-1.2.2.1.1.1.1.1.1 10-1.2.2.1 11-1.2.2.1.2.1.1.1.1 12-1.2.2.1.2 12-1.2.2.1.2.1 12-1.2.2.1.2.1.r 13-1.2.2.2.r 14-1.2.2.2 15-1.2.2.2 16-1.2.2.2.1 17-1.2.2.2.1.1.r 18-1.2.2.2.1.1.2 19-1.2.2.1.1 19-1.2.2.1.1.1 19-1.2.2.1.1.1.r 19-1.2.2.2.1.1 22-1.2.2.2.1.1.1.1 23-1.2.2.2.1.1.1 (s / set-out-07~e.2,3 :ARG0 (w / we~e.0) :ARG1 (i2 / investigate-01~e.5 :ARG0 w :ARG1 (a2 / administer-01~e.7 :ARG1~e.8 (a3 / and~e.10 :op1 (m / molecular-physical-entity~e.19 :ARG0-of~e.19 (i / inhibit-01~e.19 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"~e.9)))) :op2 (m2 / molecular-physical-entity~e.12 :ARG0-of~e.12 (i3 / inhibit-01~e.12 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"~e.11))))) :ARG2~e.13 (c3 / cell-line~e.14,15 :ARG0-of (s2 / sensitive-03~e.16 :ARG1~e.17 (i4 / inhibit-01~e.19 :ARG0 (s3 / schedule-01~e.23 :ARG1 (d2 / dose-01~e.22) :ARG1-of (a4 / alternate-01)) :mod (d / dual~e.18)))) :ARG1-of (c2 / concurrent-02~e.6))) :ARG1-of (c / cause-01~e.1,4)) # ::id pmid_2325_9591.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MTS assays showed that for maximal reduction in the number of living cells in all the lines , dual inhibition needed to be administered for longer periods of time . # ::alignments 1-1.1.1.1.1 2-1.1 3-1 5-1.2.r 6-1.2.1.2 7-1.2.1 8-1.2.1.1.r 10-1.2.1.1 11-1.2.1.1.1.r 12-1.2.1.1.1.1 13-1.2.1.1.1 13-1.2.1.1.1.2 13-1.2.1.1.1.2.r 15-1.2.1.1.1.2.1 17-1.2.1.1.1.2 19-1.2.2.1.1 20-1.2.2.1 21-1.2 24-1.2.2 25-1.2.2.2.r 26-1.2.2.2.1 26-1.2.2.2.1.1 26-1.2.2.2.1.1.r 27-1.2.2.2 (s / show-01~e.3 :ARG0 (a / assay-01~e.2 :instrument (s2 / small-molecule :name (n3 / name :op1 "MTS"~e.1))) :ARG1~e.5 (n / need-01~e.21 :ARG0 (r / reduce-01~e.7 :ARG1~e.8 (n2 / number~e.10 :quant-of~e.11 (c / cell~e.13 :ARG0-of (l2 / live-01~e.12) :part-of~e.13 (c2 / cell-line~e.13,17 :mod (a3 / all~e.15)))) :ARG2 (m3 / maximum~e.6)) :ARG1 (a2 / administer-01~e.24 :ARG1 (i / inhibit-01~e.20 :mod (d / dual~e.19)) :duration~e.25 (p / period~e.27 :ARG1-of (l / long-03~e.26 :degree~e.26 (m2 / more~e.26)))))) # ::id pmid_2325_9591.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The therapy was significantly more effective when it was administered throughout the 72 h experiment as compared with 15 min , 4 h or 24 h periods ( Figure 6 ) . # ::alignments 1-1.1 3-1.2 4-1.4 5-1 6-1.3.2.r 9-1.3 12-1.3.2.1.1 13-1.3.2.1.2 14-1.3.2 15-1.3.2.r 16-1.3.2.1.3.r 18-1.3.2.1.3.1.1.1 19-1.3.2.1.3.1.1.2 21-1.3.2.1.3.2.1.1 22-1.3.2.1.3.2.1.2 22-1.3.2.1.3.3.1.2 23-1.3.2.1.3 24-1.3.2.1.3.3.1.1 25-1.3.2.1.3.2.1.2 25-1.3.2.1.3.3.1.2 26-1.3.2.1.3.1 26-1.3.2.1.3.2 26-1.3.2.1.3.3 28-1.5.1 30-1.5.1.1 (e / effective-04~e.5 :ARG0 (t / therapy~e.1) :ARG1-of (s / significant-02~e.3) :condition (a / administer-01~e.9 :ARG1 t :time~e.6,15 (e2 / experiment-01~e.14 :duration (t2 / temporal-quantity :quant 72~e.12 :unit (h / hour~e.13) :compared-to~e.16 (o / or~e.23 :op1 (p / period~e.26 :consist-of (t3 / temporal-quantity :quant 15~e.18 :unit (m2 / minute~e.19))) :op2 (p2 / period~e.26 :consist-of (t4 / temporal-quantity :quant 4~e.21 :unit (h2 / hour~e.22,25))) :op3 (p3 / period~e.26 :consist-of (t5 / temporal-quantity :quant 24~e.24 :unit (h3 / hour~e.22,25))))))) :degree (m / more~e.4) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod 6~e.30))) # ::id pmid_2325_9591.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , maximal cytotoxicity was seen in the ALK translocated H3122 line even with short courses of ALK inhibition ( 15 min ) , while similar cytotoxicity was seen with 72 h inhibition of PI3K and MEK concurrently ( Figure 6 ) , even though both approaches induced major inhibition of phosphorylated AKT and ERK in Western blots after 6 h treatments ( Figure 3A ) . # ::alignments 0-1.1.1.2 2-1.1.1.1.1 5-1.1.1 9-1.1.1.3.2.1.1.1 11-1.1.1.3.2 12-1.1.1.3.1.1 13-1.1.1.3 16-1.1.1.1.2.1 17-1.1.1.1.2 18-1.1.1.1.2.2.r 19-1.1.1.1.2.2.1 20-1.1.1.1.2.2 22-1.1.1.1.2.3.1.1 23-1.1.1.1.2.3.1.2 26-1.1 27-1.1.2.1.1 30-1.1.2 31-1.1.2.2.r 32-1.1.2.2.2.1 33-1.1.2.2.2.2 34-1.1.2.2 35-1.1.2.2.1.r 36-1.1.2.2.1.1.1.1 37-1.1.2.2.1 38-1.1.2.2.1.2.1.1 39-1.1.2.2.1.3 41-1.1.2.3.1 43-1.1.2.3.1.1 47-1 48-1 49-1.2.1.1 50-1.2.1 51-1.2 52-1.2.2.2 53-1.2.2 54-1.2.2.1.r 55-1.2.2.1.1.2 56-1.2.2.1.1.1.1 57-1.2.2.1 58-1.2.2.1.2.1.1 59-1.2.5.r 60-1.2.5 61-1.2.5 62-1.2.3 63-1.2.3.1.1.1 64-1.2.3.1.1.2 65-1.2.3.1 67-1.2.4.1 69-1.2.4.1.1 (h2 / have-concession-91~e.47,48 :ARG1 (c3 / contrast-01~e.26 :ARG1 (s / see-01~e.5 :ARG1 (c4 / cytotoxic :degree (m / maximal~e.2) :condition (c2 / course-01~e.17 :ARG1-of (s2 / short-07~e.16) :consist-of~e.18 (i2 / inhibit-01~e.20 :ARG1 e5~e.19) :ARG1-of (m2 / mean-01 :ARG2 (t3 / temporal-quantity :quant 15~e.22 :unit (m3 / minute~e.23))))) :ARG2-of (i / interest-01~e.0) :location (c / cell-line~e.13 :name (n4 / name :op1 "H3122"~e.12) :ARG1-of (t2 / translocate-01~e.11 :ARG0 (e5 / enzyme :name (n5 / name :op1 "ALK"~e.9))))) :ARG2 (s3 / see-01~e.30 :ARG1 (c5 / cytotoxic :ARG1-of (r2 / resemble-01~e.27 :ARG2 c4)) :concession~e.31 (i3 / inhibit-01~e.34 :ARG1~e.35 (a / and~e.37 :op1 (e / enzyme :name (n6 / name :op1 "PI3K"~e.36)) :op2 (e2 / enzyme :name (n7 / name :op1 "MEK"~e.38)) :ARG1-of (c6 / concurrent-02~e.39)) :duration (t / temporal-quantity :quant 72~e.32 :unit (h / hour~e.33))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.41 :mod 6~e.43)))) :ARG2 (i4 / induce-01~e.51 :ARG0 (a2 / approach-02~e.50 :mod (b / both~e.49)) :ARG2 (i5 / inhibit-01~e.53 :ARG1~e.54 (a3 / and~e.57 :op1 (e3 / enzyme :name (n8 / name :op1 "AKT"~e.56) :ARG3-of (p3 / phosphorylate-01~e.55)) :op2 (e4 / enzyme :name (n9 / name :op1 "ERK"~e.58) :ARG3-of p3)) :ARG1-of (m4 / major-02~e.52)) :time (a4 / after~e.62 :op1 (t4 / treat-04~e.65 :duration (t5 / temporal-quantity :quant 6~e.63 :unit (h3 / hour~e.64)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.67 :mod "3A"~e.69)) :location~e.59 (i6 / immunoblot-01~e.60,61))) # ::id pmid_2325_9591.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since the results showed that dual inhibition needed to be administered for longer periods of time for maximal cytotoxicity , we turned next to investigating whether both inhibitors are required throughout the period of exposure . # ::alignments 0-1 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 3-1.1 4-1.1.2.r 5-1.1.2.1.1 6-1.1.2.1 7-1.1.2 10-1.1.2.2 11-1.1.2.2.2.r 12-1.1.2.2.2.2 12-1.1.2.2.2.2.1 12-1.1.2.2.2.2.1.r 13-1.1.2.2.2 14-1.1.2.2.2.1.r 15-1.1.2.2.2.1 17-1.1.2.3.1 20-1.2.1 21-1.2 22-1.2.3 23-1.2.2.r 24-1.2.2 25-1.2.2.2.1 25-1.2.2.2.1.r 26-1.2.2.2.2.2 27-1.2.2.2.2 27-1.2.2.2.2.1 27-1.2.2.2.2.1.r 29-1.2.2.2 32-1.2.2.2.3 33-1.2.2.2.3.1.r 34-1.2.2.2.3.1 (c / cause-01~e.0 :ARG0 (s / show-01~e.3 :ARG0 (t2 / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2)) :ARG1~e.4 (n / need-01~e.7 :ARG0 (i / inhibit-01~e.6 :mod (d / dual~e.5)) :ARG1 (a / administer-01~e.10 :ARG1 i :duration~e.11 (p / period~e.13 :consist-of~e.14 (t3 / time~e.15) :ARG1-of (l / long-03~e.12 :degree~e.12 (m / more~e.12)))) :purpose (c2 / cytotoxic :degree (m2 / maximal~e.17)))) :ARG1 (t / turn-02~e.21 :ARG1 (w / we~e.20) :ARG2~e.23 (i2 / investigate-01~e.24 :ARG0 w :ARG1 (r2 / require-01~e.29 :mode~e.25 interrogative~e.25 :ARG1 (m3 / molecular-physical-entity~e.27 :ARG0-of~e.27 (i3 / inhibit-01~e.27) :mod (b / both~e.26)) :time (p2 / period~e.32 :duration-of~e.33 (e / expose-01~e.34)))) :time (n2 / next~e.22))) # ::id pmid_2325_9591.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The dual inhibition @-@ sensitive cell lines were exposed to one inhibitor throughout the treatment period ( 72 h ) while the other inhibitor was administered concurrently for 15 min , 4 h or 24 h at the beginning of the drug exposure . # ::alignments 1-1.1.1.1.1.1 2-1.1.1.1.1 4-1.1.1.1 5-1.1.1 6-1.1.1 8-1.1 9-1.1.2.r 10-1.1.2.1 11-1.1.2 11-1.1.2.2 11-1.1.2.2.r 14-1.1.3 17-1.1.3.1.1.1 18-1.1.3.1.1.2 20-1 23-1.1.2 23-1.1.2.2 23-1.1.2.2.r 25-1.2 26-1.2.2 27-1.2.3.r 28-1.2.3.1.1 29-1.2.3.1.2 31-1.2.3.2.1 32-1.2.3.2.2 32-1.2.3.3.2 33-1.2.3 34-1.2.3.3.1 35-1.2.3.3.2 36-1.2.4.r 38-1.2.4 39-1.2.4.1.r 41-1.2.4.1.1 42-1.2.4.1 (c2 / contrast-01~e.20 :ARG1 (e / expose-01~e.8 :ARG1 (c / cell-line~e.5,6 :ARG0-of (s / sensitive-03~e.4 :ARG1 (i2 / inhibit-01~e.2 :mod (d / dual~e.1)))) :ARG2~e.9 (m / molecular-physical-entity~e.11,23 :quant 1~e.10 :ARG0-of~e.11,23 (i / inhibit-01~e.11,23)) :duration (t2 / treat-04~e.14 :ARG1-of (m2 / mean-01 :ARG2 (t3 / temporal-quantity :quant 72~e.17 :unit (h / hour~e.18))))) :ARG2 (a / administer-01~e.25 :ARG1 (m3 / molecular-physical-entity :ARG0-of i) :ARG1-of (c3 / concurrent-02~e.26) :duration~e.27 (o / or~e.33 :op1 (t4 / temporal-quantity :quant 15~e.28 :unit (m4 / minute~e.29)) :op2 (t5 / temporal-quantity :quant 4~e.31 :unit (h2 / hour~e.32)) :op3 (t6 / temporal-quantity :quant 24~e.34 :unit (h3 / hour~e.32,35))) :time~e.36 (b / begin-01~e.38 :ARG1~e.39 (e2 / expose-01~e.42 :ARG2 (d2 / drug~e.41))))) # ::id pmid_2325_9591.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results varied significantly between the cell lines tested . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.3 6-1.2 7-1.2 8-1.2.1 (v / vary-01~e.2 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG5 (c / cell-line~e.6,7 :ARG1-of (t2 / test-01~e.8)) :ARG1-of (s / significant-02~e.3)) # ::id pmid_2325_9591.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the H1437 and MDA @-@ MB231 lines concurrent inhibition of PI3K and MEK for 15 min with continued PI3K inhibition for 72 h achieved similar cytotoxicity to concurrent inhibition for 72 h ( Figure 6 ) . # ::alignments 2-1.1.1.4.1.1.1 3-1.1.1.4 4-1.1.1.4.2.1.1 6-1.1.1.4.2.1.1 7-1.1.1.4.1 7-1.1.1.4.2 8-1.1.1.2 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.1.1.1 12-1.1.1.1 13-1.1.1.1.2.1.1 14-1.1.1.3.r 15-1.1.1.3.1 16-1.1.1.3.2 18-1.1.2.3 19-1.1.2.1 20-1.1.2 21-1.1.2.2.r 22-1.1.2.2.1 23-1.1.2.2.2 24-1 25-1.2.1 27-1.2.1.1.r 28-1.2.1.1.1 29-1.2.1.1 30-1.2.1.1.2.r 31-1.2.1.1.2.1 32-1.2.1.1.2.2 34-1.3.1 36-1.3.1.1 (a / achieve-01~e.24 :ARG0 (a2 / and :op1 (i / inhibit-01~e.9 :ARG1~e.10 (a3 / and~e.12 :op1 (e / enzyme :name (n2 / name :op1 "PI3K"~e.11)) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK"~e.13))) :ARG1-of (c / concurrent-02~e.8) :duration~e.14 (t / temporal-quantity :quant 15~e.15 :unit (m / minute~e.16)) :location (a4 / and~e.3 :op1 (c2 / cell-line~e.7 :name (n4 / name :op1 "H1437"~e.2)) :op2 (c3 / cell-line~e.7 :name (n5 / name :op1 "MDA-MB231"~e.4,6)))) :op2 (i2 / inhibit-01~e.20 :ARG1 e~e.19 :duration~e.21 (t2 / temporal-quantity :quant 72~e.22 :unit (h / hour~e.23)) :ARG1-of (c4 / continue-01~e.18))) :ARG1 (c5 / cytotoxic :ARG1-of (r / resemble-01~e.25 :ARG2~e.27 (i3 / inhibit-01~e.29 :ARG1-of c~e.28 :duration~e.30 (t3 / temporal-quantity :quant 72~e.31 :unit (h2 / hour~e.32))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod 6~e.36))) # ::id pmid_2325_9591.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , when these lines were exposed to the MEK inhibitor throughout the treatment period , short concurrent exposures ( 15 min , 4 h or 24 h ) to PI3K inhibitors did not induce any comparable cytotoxicity ( Figure 6 ) . # ::alignments 2-1.2.r 3-1.2.1.1 4-1.2.1 6-1.2 7-1.2.2.r 9-1.2.2.1.1.1.1 10-1.2.2 10-1.2.2.1 10-1.2.2.1.r 13-1.2.3.1 14-1.2.3 16-1.1.2.3 17-1.1.2.2 18-1.1.2 20-1.1.2.4.1.1 21-1.1.2.4.1.2 23-1.1.2.4.2.1 24-1.1.2.4.2.2 25-1.1.2.4 26-1.1.2.4.3.1 27-1.1.2.4.3.2 29-1.1.2.1.r 30-1.1.2.1.1.1.1.1 31-1.1.2.1 31-1.1.2.1.1 31-1.1.2.1.1.r 33-1.1.1 33-1.1.1.r 34-1.1 35-1.1.3.2 36-1.1.3.1 39-1.3.1 41-1.3.1.1 (c / contrast-01 :ARG2 (i2 / induce-01~e.34 :polarity~e.33 -~e.33 :ARG0 (e / expose-01~e.18 :ARG2~e.29 (m2 / molecular-physical-entity~e.31 :ARG0-of~e.31 (i / inhibit-01~e.31 :ARG1 (p3 / protein-family :name (n2 / name :op1 "PI3K"~e.30)))) :ARG1-of (c2 / concurrent-02~e.17) :ARG1-of (s / short-07~e.16) :duration (o / or~e.25 :op1 (t2 / temporal-quantity :quant 15~e.20 :unit (m / minute~e.21)) :op2 (t3 / temporal-quantity :quant 4~e.23 :unit (h / hour~e.24)) :op3 (t4 / temporal-quantity :quant 24~e.26 :unit h~e.27))) :ARG2 (c3 / cytotoxic :ARG1-of (c4 / comparable-03~e.36) :mod (a / any~e.35))) :time~e.2 (e3 / expose-01~e.6 :ARG1 (c5 / cell-line~e.4 :mod (t5 / this~e.3)) :ARG2~e.7 (m3 / molecular-physical-entity~e.10 :ARG0-of~e.10 (i3 / inhibit-01~e.10 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"~e.9)))) :duration (p2 / period~e.14 :duration-of (t7 / treat-04~e.13))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod 6~e.41))) # ::id pmid_2325_9591.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , the effects of dual inhibition with PI @-@ 103 occurred faster in the H1437 line than with ZSTK474 , since shorter exposures to the drug ( 24 h ) seemed to be sufficient for maximal cytotoxicity as compared with 72h of ZSTK474 ( Figure 6 ) . # ::alignments 6-1.1 7-1.1.1.r 8-1.1.1.2 9-1.1.1 9-1.1.3.2 10-1.1.1.1.r 11-1.1.1.1.1.1 13-1.1.1.1.1.1 15-1.1.3 15-1.1.3.1 15-1.1.3.1.r 16-1.1.2.r 18-1.1.2.1.1 19-1.1.2 20-1.1.3.2.r 21-1.1.3.2.1.r 22-1.1.3.2.1.1.1 24-1.2 25-1.2.1.1.1.2 25-1.2.1.1.1.2.1 25-1.2.1.1.1.2.1.r 26-1.2.1.1.1 26-1.2.1.1.1.4 31-1.2.1.1.1.3.1.1 32-1.2.1.1.1.3.1.2 32-1.2.1.1.1.4.2.2 34-1.2.1 37-1.2.1.1 39-1.2.1.1.2.1 42-1.2.1.1.1.4.r 45-1.2.1.1.1.4.1.r 46-1.2.1.1.1.4.1 48-1.3.1 50-1.3.1.1 (c / contrast-01 :ARG2 (a / affect-01~e.6 :ARG0~e.7 (i / inhibit-01~e.9 :ARG0~e.10 (s / small-molecule :name (n / name :op1 "PI-103"~e.11,13)) :mod (d / dual~e.8)) :location~e.16 (c2 / cell-line~e.19 :name (n2 / name :op1 "H1437"~e.18)) :ARG1-of (f / fast-02~e.15 :degree~e.15 (m / more~e.15) :compared-to~e.20 (i2 / inhibit-01~e.9 :ARG0~e.21 (s2 / small-molecule :name (n3 / name :op1 "ZSTK474"~e.22))))) :ARG1-of (c3 / cause-01~e.24 :ARG0 (s5 / seem-01~e.34 :ARG1 (s3 / suffice-01~e.37 :ARG0 (e / expose-01~e.26 :ARG2 s :ARG1-of (s4 / short-07~e.25 :degree~e.25 (m2 / more~e.25)) :ARG1-of (m3 / mean-01 :ARG2 (t / temporal-quantity :quant 24~e.31 :unit (h / hour~e.32))) :compared-to~e.42 (e2 / expose-01~e.26 :ARG2~e.45 s2~e.46 :duration (t2 / temporal-quantity :quant 72 :unit (h2 / hour~e.32)))) :ARG1 (c4 / cytotoxic :mod (m4 / maximal~e.39))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.48 :mod 6~e.50))) # ::id pmid_2325_9591.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the case of the H3122 and HCT116 lines , both the PI3K and MEK inhibitors needed to be administered throughout the treatment period for maximal cytotoxicity ( Figure 6 ) . # ::alignments 5-1.3.1.1.1 6-1.3 7-1.3.2.1.1 8-1.3.1 8-1.3.2 12-1.2.1.1.1.1.1.1 13-1.2.1 14-1.2.1.2.1.1.1.1 15-1.2.1.1 15-1.2.1.1.1 15-1.2.1.1.1.r 15-1.2.1.2 15-1.2.1.2.1 15-1.2.1.2.1.r 16-1 19-1.2 22-1.2.2.1 23-1.2.2 24-1.1.r 25-1.1.1 26-1.1 28-1.4.1 30-1.4.1.1 (n2 / need-01~e.16 :ARG0~e.24 (c / cytotoxicity~e.26 :mod (m3 / maximal~e.25)) :ARG1 (a2 / administer-01~e.19 :ARG1 (a / and~e.13 :op1 (m / molecular-physical-entity~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1 (p3 / protein-family :name (n3 / name :op1 "PI3K"~e.12)))) :op2 (m2 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i2 / inhibit-01~e.15 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"~e.14))))) :duration (p2 / period~e.23 :duration-of (t2 / treat-04~e.22))) :location (a3 / and~e.6 :op1 (c2 / cell-line~e.8 :name (n5 / name :op1 "H3122"~e.5)) :op2 (c3 / cell-line~e.8 :name (n6 / name :op1 "HCT116"~e.7))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod 6~e.30))) # ::id pmid_2325_9591.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next investigated alternative dosing of the dual inhibition of cell signaling . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 7-1.2.1.2 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.1 11-1.2.1.1 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (d / dose-01~e.4 :ARG1~e.5 (i2 / inhibit-01~e.8 :ARG1~e.9 (s / signal-07~e.11 :ARG0 (c / cell~e.10)) :mod (d2 / dual~e.7)) :ARG1-of (a / alternate-01)) :time (n / next~e.1)) # ::id pmid_2325_9591.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The dual inhibition @-@ sensitive lines were exposed to the PI3K inhibitors and MEK inhibitor concurrently for 15 min , after which treatment was continued with a single inhibitor for the remainder of the 6 h period . # ::alignments 1-1.3.1.1.1.1.1 2-1.3.1.1.1.1 4-1.3.1.1.1 5-1.3.1.1 7-1.3.1 8-1.3.1.2.r 10-1.3.1.2.1.1.1.1.1 11-1.3.1.2.1 11-1.3.1.2.1.1 11-1.3.1.2.1.1.r 11-1.3.1.2.2 11-1.3.1.2.2.1 11-1.3.1.2.2.1.r 12-1.3.1.2 13-1.3.1.2.2.1.1.1.1 14-1.3.1.2.2 14-1.3.1.2.2.1 14-1.3.1.2.2.1.r 15-1.3.1.3 16-1.3.1.4.r 17-1.3.1.4.1 18-1.3.1.4.2 20-1.3 22-1.1 24-1 25-1.1.1.r 27-1.1.1 27-1.1.1.1 27-1.1.1.1.r 28-1.1.1.2 32-1.2.r 34-1.2.2.1.1 35-1.2.2.1.2 36-1.2 (c3 / continue-01~e.24 :ARG1 (t3 / treat-04~e.22 :ARG2~e.25 (m4 / molecular-physical-entity~e.27 :ARG1-of~e.27 (s2 / single-02~e.27) :ARG0-of (i4 / inhibit-01~e.28))) :duration~e.32 (p / period~e.36 :ARG1-of (r / remain-01) :ARG1-of (m5 / mean-01 :ARG2 (t4 / temporal-quantity :quant 6~e.34 :unit (h / hour~e.35)))) :time (a2 / after~e.20 :op1 (e / expose-01~e.7 :ARG1 (c / cell-line~e.5 :ARG0-of (s / sensitive-03~e.4 :ARG1 (i2 / inhibit-01~e.2 :mod (d / dual~e.1)))) :ARG2~e.8 (a / and~e.12 :op1 (m / molecular-physical-entity~e.11 :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"~e.10)))) :op2 (m2 / molecular-physical-entity~e.11,14 :ARG0-of~e.11,14 (i3 / inhibit-01~e.11,14 :ARG1 (p3 / protein-family :name (n3 / name :op1 "MEK"~e.13))))) :ARG1-of (c2 / concurrent-02~e.15) :duration~e.16 (t2 / temporal-quantity :quant 15~e.17 :unit (m3 / minute~e.18))))) # ::id pmid_2325_9591.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok pAKT downregulation was complete or nearly complete when the cells were treated for only 15 min and with PI3K inhibitors for 6 h ( Figure 3B ) , while conversely , pERK1 @/@ 2 recovered completely in 6 h when the cells were treated with the MEK inhibitor for 15 min ( Figure 3B ) . # ::alignments 0-1.1.1.1.1.1.1 0-1.1.1.1.1.2 0-1.2.1.1.2 1-1.1.1.1 3-1.1.1 3-1.1.2 4-1.1 5-1.1.2.2 6-1.1.2 7-1.2.3.r 9-1.1.1.2.1.1 11-1.1.1.2.1 11-1.1.1.2.2 12-1.1.1.2.1.2.r 13-1.1.1.2.1.2.3 14-1.1.1.2.1.2.1 15-1.1.1.2.1.2.2 16-1.1.1.2 17-1.1.1.2.2.2.r 18-1.1.1.2.2.2.1.1.1.1 19-1.1.1.2.2.2 19-1.1.1.2.2.2.1 19-1.1.1.2.2.2.1.r 20-1.1.1.2.2.3.r 21-1.1.1.2.2.3.1 22-1.1.1.2.2.3.2 24-1.1.3.1 24-1.2.5.1 26-1.1.3.1.1 26-1.2.5.1.1 30-1 34-1.2.1 36-1.2 37-1.2.2 39-1.2.3.1 40-1.2.3.1 41-1.2.3.r 43-1.2.4.1 45-1.2.4 46-1.2.4.2.r 48-1.2.4.2.1.1.1.1 49-1.2.4.2 49-1.2.4.2.1 49-1.2.4.2.1.r 50-1.2.4.3.r 51-1.2.4.3 52-1.2.4.3 54-1.1.3.1 54-1.2.5.1 56-1.1.3.1.1 56-1.2.5.1.1 (c4 / contrast-01~e.30 :ARG1 (o / or~e.4 :op1 (c / complete-02~e.3 :ARG1 (d / downregulate-01~e.1 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT"~e.0) :ARG3-of (p2 / phosphorylate-01~e.0))) :condition (a / and~e.16 :op1 (t2 / treat-04~e.11 :ARG1 (c3 / cell~e.9) :duration~e.12 (t3 / temporal-quantity :quant 15~e.14 :unit (m / minute~e.15) :mod (o2 / only~e.13))) :op2 (t4 / treat-04~e.11 :ARG1 c3 :ARG2~e.17 (m2 / molecular-physical-entity~e.19 :ARG0-of~e.19 (i / inhibit-01~e.19 :ARG1 (p / protein-family :name (n4 / name :op1 "PI3K"~e.18)))) :duration~e.20 (t5 / temporal-quantity :quant 6~e.21 :unit (h / hour~e.22))))) :op2 (c2 / complete-02~e.3,6 :ARG1 d :ARG1-of (n3 / near-01~e.5) :condition a) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24,54 :mod "3B"~e.26,56))) :ARG2 (r / recover-01~e.36 :ARG1 (s / slash~e.34 :op1 (e3 / enzyme :name (n5 / name :op1 "ERK1") :ARG3-of (p3 / phosphorylate-01~e.0)) :op2 (e4 / enzyme :name (n6 / name :op1 "ERK2") :ARG3-of p3)) :ARG1-of (c5 / complete-02~e.37) :time~e.7,41 (a2 / after :op1 t5~e.39,40) :condition (t6 / treat-04~e.45 :ARG1 (c6 / cell~e.43) :ARG2~e.46 (m3 / molecular-physical-entity~e.49 :ARG0-of~e.49 (i2 / inhibit-01~e.49 :ARG1 (p4 / protein-family :name (n7 / name :op1 "MEK"~e.48)))) :duration~e.50 t3~e.51,52) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.24,54 :mod "3B"~e.26,56)))) # ::id pmid_2325_9591.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , we were able to see some recovery in the activity of the downstream targets of AKT when the PI3K inhibitors were administered for 15 min despite the remaining pAKT downregulation . # ::alignments 0-1.4 2-1.1 4-1 6-1.2 7-1.2.2.2 8-1.2.2 9-1.2.2.1.r 11-1.2.2.1 12-1.2.2.1.1.r 14-1.2.2.1.1.2 15-1.2.2.1.1 15-1.2.2.1.1.1 15-1.2.2.1.1.1.r 16-1.2.2.1.1.1.1.r 17-1.2.2.1.1.1.1.1.1 20-1.2.3.1.1.1.1.1 21-1.2.3.1 21-1.2.3.1.1 21-1.2.3.1.1.r 23-1.2.3 24-1.2.3.2.r 25-1.2.3.2.1 26-1.2.3.2.2 27-1.3.r 29-1.3.2 30-1.3.1.1.1 30-1.3.1.2 31-1.3 (c2 / capable-01~e.4 :ARG1 (w / we~e.2) :ARG2 (s / see-01~e.6 :ARG0 w :ARG1 (r / recover-02~e.8 :ARG1~e.9 (a / activity-06~e.11 :ARG0~e.12 (m3 / molecular-physical-entity~e.15 :ARG1-of~e.15 (t2 / target-01~e.15 :ARG0~e.16 (e / enzyme :name (n / name :op1 "AKT"~e.17))) :mod (d / downstream~e.14))) :mod (s2 / some~e.7)) :condition (a2 / administer-01~e.23 :ARG1 (m / molecular-physical-entity~e.21 :ARG0-of~e.21 (i / inhibit-01~e.21 :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K"~e.20)))) :duration~e.24 (t3 / temporal-quantity :quant 15~e.25 :unit (m2 / minute~e.26)))) :concession~e.27 (d2 / downregulate-01~e.31 :ARG1 (e3 / enzyme :name (n3 / name :op1 "AKT"~e.30) :ARG3-of (p2 / phosphorylate-01~e.30)) :ARG1-of (r2 / remain-01~e.29)) :ARG2-of (i2 / interest-01~e.0)) # ::id pmid_2325_9591.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The pS6 signal was able to recovery in the MDA @-@ MB231 ( with ZSTK474 ) and HCT116 ( with both PI3K inhibitors ) lines after short PI3K administration ( Figure 3B ) . # ::alignments 2-1.1.1 4-1.1 4-1.2 6-1.1.2 6-1.2.2 9-1.1.2.2.1.1 11-1.1.2.2.1.1 14-1.1.2.3.1.1.1 16-1 17-1.2.2.1.1.1 20-1.2.2.2.1.2 21-1.2.2.2.1.1.1.1.1 22-1.2.2.2.1 22-1.2.2.2.1.1 22-1.2.2.2.1.1.r 24-1.1.2.2 24-1.2.2.1 25-1.3 26-1.3.1.2 27-1.3.1.1 28-1.3.1 30-1.4.1 32-1.4.1.1 (a2 / and~e.16 :op1 (c / capable-01~e.4 :ARG1 (s / signal-07~e.2 :ARG0 (p3 / protein :name (n / name :op1 "S6") :ARG3-of (p2 / phosphorylate-01))) :ARG2 (r / recover-01~e.6 :ARG1 s :location (c2 / cell-line~e.24 :name (n2 / name :op1 "MDA-MB231"~e.9,11)) :condition (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "ZSTK474"~e.14))))) :op2 (c3 / capable-01~e.4 :ARG1 s :ARG2 (r2 / recover-01~e.6 :location (c4 / cell-line~e.24 :name (n4 / name :op1 "HCT116"~e.17)) :condition (t3 / treat-04 :ARG2 (m / molecular-physical-entity~e.22 :ARG0-of~e.22 (i / inhibit-01~e.22 :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K"~e.21))) :mod (b / both~e.20))))) :time (a3 / after~e.25 :op1 (a4 / administer-01~e.28 :ARG1 p~e.27 :ARG1-of (s3 / short-07~e.26))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "3B"~e.32))) # ::id pmid_2325_9591.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , p4E @-@ BP1 recovery was noted in the H3122 ( with ZSTK474 ) , MDA @-@ MB231 ( with ZSTK474 ) , and HCT116 ( with both PI3K inhibitors ) lines ( Figure 3B ) . # ::alignments 0-1 0-1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1 5-1.1.1.2 5-1.1.1.3 7-1.1 10-1.1.1.1.2.1.1 13-1.1.1.1.3.1.1.1 16-1.1.1.2.2.1.1 18-1.1.1.2.2.1.1 20-1.1.1.2.3.r 21-1.1.1.2.3 24-1.1.1 25-1.1.1.3.2.1.1 28-1.1.1.3.3.1.2 29-1.1.1.3.3.1.1.1.1.1 30-1.1.1.3.3.1 30-1.1.1.3.3.1.1 30-1.1.1.3.3.1.1.r 32-1.1.1.1.2 32-1.1.1.2.2 32-1.1.1.3.2 34-1.1.2.1 36-1.1.2.1.1 (a / and~e.0 :op2 (n / note-02~e.7 :ARG1 (a2 / and~e.0,24 :op1 (r / recover-01~e.5 :ARG1 (p2 / protein :name (n2 / name :op1 "4E-BP1"~e.4) :ARG3-of (p / phosphorylate-01)) :location (c / cell-line~e.32 :name (n3 / name :op1 "H3122"~e.10)) :condition (t2 / treat-04 :ARG2 (s / small-molecule :name (n4 / name :op1 "ZSTK474"~e.13)))) :op2 (r2 / recover-01~e.5 :ARG1 p2 :location (c2 / cell-line~e.32 :name (n5 / name :op1 "MDA-MB231"~e.16,18)) :condition~e.20 t2~e.21) :op3 (r3 / recover-01~e.5 :ARG1 p2 :location (c3 / cell-line~e.32 :name (n6 / name :op1 "HCT116"~e.25)) :condition (t3 / treat-04 :ARG2 (m / molecular-physical-entity~e.30 :ARG0-of~e.30 (i / inhibit-01~e.30 :ARG1 (p3 / protein-family :name (n7 / name :op1 "PI3K"~e.29))) :mod (b / both~e.28))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "3B"~e.36)))) # ::id pmid_2325_9591.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , MEK inhibitor treatment induced upregulation of p4E @-@ BP1 in the MDA @-@ MB231 line ( Figure 3A ) , and marked downregulation p4E @-@ BP1 was noted only with PI @-@ 103 ( PI3K and mTOR inhibitor ) in the alternative dosing experiments , but not with ZSTK474 ( with a PI3K inhibitor alone ) ( Figure 5 ) , suggesting mTOR @-@ mediated activation of 4E @-@ BP1 in response to MEK inhibition . # ::alignments 0-1.1.3 2-1.1.1.1.1.1.1.1 3-1.2.2.3.1.2.1 3-1.2.2.3.1.2.1.1 3-1.2.2.3.1.2.1.1.r 4-1.1.1 4-1.2.1.2 4-1.2.2.3 5-1.1 6-1.1.2 10-1.1.2.1.1.1 11-1.1.2.2.r 13-1.1.2.2.1.1 15-1.1.2.2.1.1 16-1.1.2.2 18-1.1.4.1 20-1.1.4.1.1 24-1 25-1.2.1.1.2 26-1.2.1.1 29-1.2.1.1.1 31-1.2.1 31-1.2.2 32-1.2.1.2.2 34-1.2.1.2.1.1.1 36-1.2.1.2.1.1.1 38-1.2.1.2.1.2.1.1.1.1 39-1.2.1.2.1.2.1 40-1.2.1.2.1.2.1.2.1.1 41-1.2.1.2.1 41-1.2.1.2.1.2 41-1.2.1.2.1.2.r 46-1.1.5.1 47-1.1.5 49-1.2 50-1.2.2.1 50-1.2.2.1.r 52-1.2.2.3.1.1.1 56-1.2.1.2.1.2.1.1.1.1 57-1.2.1.2.1 57-1.2.1.2.1.2 57-1.2.1.2.1.2.r 57-1.2.2.3.1.2.1 57-1.2.2.3.1.2.1.1 57-1.2.2.3.1.2.1.1.r 58-1.2.2.3.1.2.1.2 61-1.2.3.1 63-1.2.3.1.1 67-1.3 68-1.3.1.2.1 70-1.3.1.2 71-1.3.1 72-1.3.1.1.r 73-1.3.1.1.1.1 75-1.3.1.1.1.1 76-1.3.1.3.r 77-1.3.1.3 78-1.3.1.3.1.r 79-1.3.1.3.1 80-1.3.1.3.1 (a / and~e.24 :op1 (i2 / induce-01~e.5 :ARG0 (t2 / treat-04~e.4 :ARG2 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK"~e.2))))) :ARG2 (u / upregulate-01~e.6 :ARG1 (p4 / protein :name (n3 / name :op1 "4E-BP1"~e.10) :ARG3-of (p2 / phosphorylate-01)) :location~e.11 (c / cell-line~e.16 :name (n4 / name :op1 "MDA-MB231"~e.13,15))) :ARG2-of (i3 / interest-01~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "3A"~e.20)) :location (e4 / experiment-01~e.47 :ARG2 (d3 / dose-01~e.46 :ARG1-of (a3 / alternate-01)))) :op2 (c2 / contrast-01~e.49 :ARG1 (n5 / note-02~e.31 :ARG1 (d2 / downregulate-01~e.26 :ARG1 p4~e.29 :ARG1-of (m2 / mark-01~e.25)) :condition (t3 / treat-04~e.4 :ARG2 (s / small-molecule~e.41,57 :name (n6 / name :op1 "PI-103"~e.34,36) :ARG0-of~e.41,57 (i4 / inhibit-01~e.41,57 :ARG1 (a2 / and~e.39 :op1 (p5 / protein-family :name (n7 / name :op1 "PI3K"~e.38,56)) :op2 (p3 / protein :name (n8 / name :op1 "mTOR"~e.40))))) :mod (o / only~e.32)) :location e4) :ARG2 (n9 / note-02~e.31 :polarity~e.50 -~e.50 :ARG1 d2 :condition (t4 / treat-04~e.4 :ARG2 (s2 / small-molecule :name (n10 / name :op1 "ZSTK474"~e.52) :ARG1-of (m3 / mean-01 :ARG2 (m4 / molecular-physical-entity~e.3,57 :ARG0-of~e.3,57 (i5 / inhibit-01~e.3,57 :ARG1 p5) :mod (a4 / alone~e.58)))))) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.61 :mod 5~e.63))) :ARG0-of (s3 / suggest-01~e.67 :ARG1 (a5 / activate-01~e.71 :ARG1~e.72 (p / protein :name (n11 / name :op1 "4E-BP1"~e.73,75)) :ARG1-of (m5 / mediate-01~e.70 :ARG0 p3~e.68) :ARG2-of~e.76 (r / respond-01~e.77 :ARG1~e.78 i~e.79,80)))) # ::id pmid_2325_9591.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TAE684 , an ALK inhibitor , treatment was also included in the experiments conducted with the H3122 line , and this induced comparable pAKT , pERK1 @/@ 2 , and pS6 downregulation to that achieved with dual inhibition , whereas no change in p4E @-@ BPI was noted ( Figure 3B ) . # ::alignments 0-1.1.1.1.1.1.1 3-1.1.1.1.1.2.1.1.1 4-1.1.1.1.1 4-1.1.1.1.1.2 4-1.1.1.1.1.2.r 6-1.1.1.1 8-1.1.1.1.2 9-1.1.1 10-1.1.1.2.r 12-1.1.1.2 13-1.1.1.2.2 14-1.1.1.2.1.r 16-1.1.1.2.1.1.1 17-1.1.1.2.1 19-1.1 21-1.1.2 22-1.1.2.2.2 23-1.1.2.2.1.1.1.1 23-1.1.2.2.1.1.2 26-1.1.2.2.1.2 29-1.1.2.2.1 31-1.1.2.2 31-1.1.2.2.2.1 34-1.1.2.2.2.1.2 35-1.1.2.2.2.1.2.1.r 36-1.1.2.2.2.1.2.1.1 37-1.1.2.2.2.1.2.1 39-1 40-1.2.1 40-1.2.1.r 41-1.2.2 45-1.2.2.1.1.1 47-1.2 49-1.3.1 51-1.3.1.1 (c4 / contrast-01~e.39 :ARG1 (a / and~e.19 :op1 (i2 / include-01~e.9 :ARG1 (t2 / treat-04~e.6 :ARG2 (s / small-molecule~e.4 :name (n / name :op1 "TAE684"~e.0) :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (e6 / enzyme :name (n2 / name :op1 "ALK"~e.3)))) :mod (a4 / also~e.8)) :ARG2~e.10 (e / experiment-01~e.12 :ARG1~e.14 (c2 / cell-line~e.17 :name (n3 / name :op1 "H3122"~e.16)) :ARG1-of (c / conduct-01~e.13))) :op2 (i3 / induce-01~e.21 :ARG0 i2 :ARG2 (d / downregulate-01~e.31 :ARG1 (a2 / and~e.29 :op1 (e2 / enzyme :name (n4 / name :op1 "AKT"~e.23) :ARG3-of (p / phosphorylate-01~e.23)) :op2 (s2 / slash~e.26 :op1 (e3 / enzyme :name (n5 / name :op1 "ERK1") :ARG3-of p) :op2 (e4 / enzyme :name (n6 / name :op1 "ERK2") :ARG3-of p)) :op3 (p3 / protein :name (n7 / name :op1 "S6") :ARG3-of p)) :ARG1-of (c3 / comparable-03~e.22 :ARG2 (d2 / downregulate-01~e.31 :ARG1 a2 :ARG1-of (a3 / achieve-01~e.34 :ARG0~e.35 (i4 / inhibit-01~e.37 :mod (d3 / dual~e.36)))))))) :ARG2 (n8 / note-02~e.47 :polarity~e.40 -~e.40 :ARG1 (c5 / change-01~e.41 :ARG1 (p2 / protein :name (n9 / name :op1 "4E-BPI"~e.45) :ARG3-of p))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.49 :mod "3B"~e.51))) # ::id pmid_2325_9591.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Some recovery of pAKT and pS6 was seen after a short treatment with TAE684 ( Figure 3B ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 3-1.1.1.1.2 4-1.1.1 7-1 8-1.2 10-1.2.1.2 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1.1 15-1.3.1 17-1.3.1.1 (s / see-01~e.7 :ARG1 (r / recover-02~e.1 :ARG1~e.2 (a / and~e.4 :op1 (e / enzyme :name (n / name :op1 "AKT"~e.3) :ARG3-of (p / phosphorylate-01~e.3)) :op2 (p2 / protein :name (n2 / name :op1 "S6") :ARG3-of p)) :degree (s4 / some~e.0)) :time (a2 / after~e.8 :op1 (t / treat-04~e.11 :ARG2~e.12 (s3 / small-molecule :name (n3 / name :op1 "TAE684"~e.13)) :ARG1-of (s2 / short-07~e.10))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod "3B"~e.17))) # ::id pmid_2325_9591.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We went on further to analyze whether the alternative dosing could also result in apoptosis in the H3122 cell line , the only line identified as inducing apoptosis in response to dual inhibition . # ::alignments 0-1.1 1-1 2-1.3.r 3-1.3 5-1.2 6-1.2.2.1 6-1.2.2.1.r 9-1.2.2.2.1 10-1.2.2 11-1.2.2.2.4 12-1.2.2.2 13-1.2.2.2.2.r 14-1.2.2.2.2 15-1.2.2.2.3.r 17-1.2.2.2.3.1.1 18-1.2.2.2.3 19-1.2.2.2.3 22-1.2.2.2.3.3 23-1.2.2.2.3 24-1.2.2.2.3.2 25-1.2.2.2.3.2.1.r 26-1.2.2.2.3.2.1 27-1.2.2.2.3.2.1.2 28-1.2.2.2.3.2.1.3.r 29-1.2.2.2.3.2.1.3 30-1.2.2.2.3.2.1.3.1.r 31-1.2.2.2.3.2.1.3.1.1 32-1.2.2.2.3.2.1.3.1 (g / go-06~e.1 :ARG0 (w / we~e.0) :ARG1 (a / analyze-01~e.5 :ARG0 w :ARG1 (p2 / possible-01~e.10 :mode~e.6 interrogative~e.6 :ARG1 (r / result-01~e.12 :ARG1 (d / dose-01~e.9 :ARG1-of (a2 / alternate-01)) :ARG2~e.13 (a3 / apoptosis~e.14) :location~e.15 (c / cell-line~e.18,19,23 :name (n / name :op1 "H3122"~e.17) :ARG1-of (i / identify-01~e.24 :ARG2~e.25 (i2 / induce-01~e.26 :ARG0 c :ARG2 a3~e.27 :ARG2-of~e.28 (r2 / respond-01~e.29 :ARG1~e.30 (i3 / inhibit-01~e.32 :mod (d2 / dual~e.31))))) :mod (o / only~e.22)) :mod (a4 / also~e.11)))) :ARG2~e.2 (f / further~e.3)) # ::id pmid_2325_9591.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When the cells was treated for 15 min with dual inhibition and treatment with either the PI3K inhibitors or the MEK inhibitor was continued for 48 h , marked PARP cleavage was seen in all the treatments ( Figure 4B ) . # ::alignments 2-1.2.1.1 4-1.2.1 6-1.2.1.3.1 7-1.2.1.3.2 9-1.2.1.2.1 10-1.2.1.2 10-1.2.2.1.1.1 10-1.2.2.1.1.1.1 10-1.2.2.1.1.1.1.r 11-1.2 12-1.2.1 12-1.2.2.1 16-1.2.2.1.1.1.1.1.1.1 17-1.2.2.1.1.1 17-1.2.2.1.1.1.1 17-1.2.2.1.1.1.1.r 17-1.2.2.1.1.2 17-1.2.2.1.1.2.1 17-1.2.2.1.1.2.1.r 18-1.2.2.1.1 20-1.2.2.1.1.2.1.1.1.1 21-1.2.2.1.1.2 21-1.2.2.1.1.2.1 21-1.2.2.1.1.2.1.r 23-1.2.2 24-1.2.2.2.r 25-1.2.2.2.1 26-1.2.2.2.2 28-1.1.2 29-1.1.1.1.1 30-1.1 32-1 33-1.1.3.r 34-1.1.3.1 36-1.1.3 38-1.3.1 40-1.3.1.1 (s / see-01~e.32 :ARG1 (c / cleave-01~e.30 :ARG1 (p2 / protein :name (n2 / name :op1 "PARP"~e.29)) :ARG1-of (m / mark-01~e.28) :location~e.33 (t3 / treat-04~e.36 :mod (a / all~e.34))) :condition (a2 / and~e.11 :op1 (t2 / treat-04~e.4,12 :ARG1 (c2 / cell~e.2) :ARG2 (i2 / inhibit-01~e.10 :mod (d / dual~e.9)) :duration (t4 / temporal-quantity :quant 15~e.6 :unit (m2 / minute~e.7))) :op2 (c3 / continue-01~e.23 :ARG1 (t5 / treat-04~e.12 :ARG2 (o / or~e.18 :op1 (m3 / molecular-physical-entity~e.10,17 :ARG0-of~e.10,17 (i3 / inhibit-01~e.10,17 :ARG1 (p / protein-family :name (n3 / name :op1 "PI3K"~e.16)))) :op2 (m4 / molecular-physical-entity~e.17,21 :ARG0-of~e.17,21 (i4 / inhibit-01~e.17,21 :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK"~e.20)))))) :duration~e.24 (t6 / temporal-quantity :quant 48~e.25 :unit (h / hour~e.26)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.38 :mod "4B"~e.40))) # ::id pmid_2325_9591.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , 15 min treatment with an ALK inhibitor resulted in marked PARP cleavage ( Figure 4B ) . # ::alignments 0-1 2-1.1.1.2.1 3-1.1.1.2.2 4-1.1.1 5-1.1.1.1.r 7-1.1.1.1.1.1.1.1 8-1.1.1.1 8-1.1.1.1.1 8-1.1.1.1.1.r 9-1.1 10-1.1.2.r 11-1.1.2.2 12-1.1.2.1.1.1 13-1.1.2 15-1.1.3.1 17-1.1.3.1.1 (a / and~e.0 :op2 (r / result-01~e.9 :ARG1 (t2 / treat-04~e.4 :ARG2~e.5 (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (i / inhibit-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "ALK"~e.7)))) :duration (t3 / temporal-quantity :quant 15~e.2 :unit (m2 / minute~e.3))) :ARG2~e.10 (c / cleave-01~e.13 :ARG1 (p / protein :name (n2 / name :op1 "PARP"~e.12)) :ARG1-of (m3 / mark-01~e.11)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.15 :mod "4B"~e.17)))) # ::id pmid_2325_9591.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cleaved PARP results were further verified with western blot analysis for cleaved caspase @-@ 3 , another marker for apoptosis . # ::alignments 0-1.1.1.2 0-1.3.1.2 1-1.1.1.1.1 2-1.1 4-1.2 5-1 6-1.4.r 7-1.4.1 8-1.4.1 9-1.4 11-1.3.1.2 12-1.3.1.1.1 14-1.3.1.1.1 16-1.3.1.3.1.2 19-1.3.1.3.1.1.1 (v / verify-01~e.5 :ARG1 (r / result-01~e.2 :ARG1 (p / protein :name (n2 / name :op1 "PARP"~e.1) :ARG1-of (c / cleave-01~e.0))) :mod (f / further~e.4) :purpose (f2 / find-01 :ARG1 (p2 / protein :name (n3 / name :op1 "caspase-3"~e.12,14) :ARG1-of (c2 / cleave-01~e.0,11) :ARG1-of (m2 / mean-01 :ARG2 (t / thing :ARG0-of (m / mark-01 :ARG1 (a2 / apoptosis~e.19)) :mod (a3 / another~e.16))))) :instrument~e.6 (a / analyze-01~e.9 :manner (i / immunoblot-01~e.7,8))) # ::id pmid_2325_9591.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cleaved caspase @-@ 3 was detected with concurrent PI3K and MEK , or ALK inhibition while no signal was seen in PI3K or MEK inhibitor treatments . # ::alignments 0-1.1.1.2 1-1.1.1.1.1 3-1.1.1.1.1 5-1.1 7-1.1.2.2 8-1.1.2.1.1.1.1.1.1.1 9-1.1.2.1.1 10-1.1.2.1.1.2.1.1.1.1 12-1.1.2.1 13-1.1.2.1.2.1.1.1.1 14-1.1.2.1.1.1 14-1.1.2.1.1.1.1 14-1.1.2.1.1.1.1.r 14-1.1.2.1.1.2 14-1.1.2.1.1.2.1 14-1.1.2.1.1.2.1.r 14-1.1.2.1.2 14-1.1.2.1.2.1 14-1.1.2.1.2.1.r 15-1 16-1.2.1 16-1.2.1.r 17-1.2.2 19-1.2 21-1.1.2.1.1.1.1.1.1.1 22-1.1.2.1 22-1.2.3.1 23-1.1.2.1.1.2.1.1.1.1 24-1.1.2.1.1.2 24-1.1.2.1.1.2.1 24-1.1.2.1.1.2.1.r 24-1.1.2.1.2 24-1.1.2.1.2.1 24-1.1.2.1.2.1.r 25-1.1.2 25-1.2.3 (c2 / contrast-01~e.15 :ARG1 (d / detect-01~e.5 :ARG1 (p2 / protein :name (n2 / name :op1 "caspase-3"~e.1,3) :ARG1-of (c / cleave-01~e.0)) :condition (t2 / treat-04~e.25 :ARG2 (o / or~e.12,22 :op1 (a / and~e.9 :op1 (m / molecular-physical-entity~e.14 :ARG0-of~e.14 (i / inhibit-01~e.14 :ARG1 (p3 / protein-family :name (n3 / name :op1 "PI3K"~e.8,21)))) :op2 (m2 / molecular-physical-entity~e.14,24 :ARG0-of~e.14,24 (i2 / inhibit-01~e.14,24 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"~e.10,23))))) :op2 (m3 / molecular-physical-entity~e.14,24 :ARG0-of~e.14,24 (i3 / inhibit-01~e.14,24 :ARG1 (e3 / enzyme :name (n5 / name :op1 "ALK"~e.13))))) :ARG1-of (c3 / concurrent-02~e.7))) :ARG2 (s / see-01~e.19 :polarity~e.16 -~e.16 :ARG1 (s2 / signal-07~e.17) :condition (t3 / treat-04~e.25 :ARG2 (o2 / or~e.22 :op1 m :op2 m2)))) # ::id pmid_2325_9591.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely to cleaved PARP , the cleaved caspase @-@ 3 signal was much lower in alternative dosing schedules compared to continuous , concurrent PI3K and MEK inhibition ( Figure 4C ) . # ::alignments 2-1.1.1.1.2 2-1.2.2 3-1.2.1.1 6-1.1.1.1.2 6-1.2.2 7-1.1.1.1.1.1 9-1.1.1.1.1.1 10-1.1.1 12-1.1.2.1 13-1.1 13-1.1.2 13-1.1.2.r 16-1.1.3.1 17-1.1.3 18-1.1.4.r 20-1.1.4.2 22-1.1.4.3 23-1.1.4.1.1.1.1 24-1.1.4.1 25-1.1.4.1.2.1.1 26-1.1.4 28-1.3.1 30-1.3.1.1 (c / contrast-01 :ARG1 (l2 / low-04~e.13 :ARG1 (s / signal-07~e.10 :ARG0 (p3 / protein :name (n3 / name :op1 "caspase-3"~e.7,9) :ARG1-of (c3 / cleave-01~e.2,6))) :degree~e.13 (m2 / more~e.13 :mod (m3 / much~e.12)) :location (s2 / schedule-01~e.17 :mod (d / dose-01~e.16 :ARG1-of (a / alternate-01))) :compared-to~e.18 (i / inhibit-01~e.26 :ARG1 (a2 / and~e.24 :op1 (e / enzyme :name (n4 / name :op1 "PI3K"~e.23)) :op2 (e2 / enzyme :name (n5 / name :op1 "MEK"~e.25))) :ARG1-of (c4 / continue-01~e.20) :ARG1-of (c5 / concurrent-02~e.22))) :ARG2 (p2 / protein :name (n2 / name :op1 "PARP"~e.3) :ARG1-of (c2 / cleave-01~e.2,6)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.28 :mod "4C"~e.30))) # ::id pmid_2337_4602.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Biomarkers of benefit from cetuximab @-@ based therapy in metastatic colorectal cancer : interaction of EGFR ligand expression with RAS/RAF , PIK3CA genotypes ( PMID : 23374602 ) # ::alignments 2-1.1 4-1.2.1.1.1.1 6-1.2.1 7-1.2 9-1.5.3 10-1.5.2.1 11-1.5.2.2 13-1.3.1 14-1.3.1.1.r 15-1.3.1.1.1.1.1 16-1.3.1.1.1 17-1.3.1.1 19-1.3.1.2.1.1.1.1 21-1.3.1.2.2.1.1.1 22-1.3.1.2.1 22-1.3.1.2.2 (b4 / biomarker :ARG0-of (b / benefit-01~e.2) :topic (t / therapy~e.7 :ARG1-of (b3 / base-02~e.6 :ARG2 (s / small-molecule :name (n / name :op1 "cetuximab"~e.4)))) :ARG1-of (m2 / mean-01 :ARG2 (i / interact-01~e.13 :ARG0~e.14 (e2 / express-03~e.17 :ARG2 (l / ligand~e.16 :name (n2 / name :op1 "EGFR"~e.15))) :ARG1 (a / and :op1 (g2 / genotype~e.22 :mod (p2 / pathway :name (n4 / name :op1 "RAS/RAF"~e.19))) :op2 (g4 / genotype~e.22 :mod (g / gene :name (n3 / name :op1 "PIK3CA"~e.21)))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23374602")) :location (d2 / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal"~e.10 :op2 "cancer"~e.11) :ARG1-of (m / metastasize-101~e.9))) # ::id pmid_2337_4602.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2337_4602.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only PIK3CA mutations occasionally coexisted with other gene mutations . # ::alignments 0-1.1.2 1-1.1.1.1.1 2-1.1 3-1.3 4-1 6-1.2.1.1 7-1.2.1 8-1.1 8-1.2 (c / coexist-01~e.4 :ARG1 (m / mutate-01~e.2,8 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.1)) :mod (o / only~e.0)) :ARG2 (m2 / mutate-01~e.8 :ARG2 (g2 / gene~e.7 :mod (o3 / other~e.6))) :frequency (o2 / occasional~e.3)) # ::id pmid_2337_4602.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In univariate analysis , prognostic significance for survival ( from metastases until death ) was seen for BRAF mutations ( Hazard Ratio HR 8.1 , 95 % CI 3.4 @-@ 19 ) , codon 12 @-@ only KRAS mutations ( HR 1.62 , 95 % CI 1.1 @-@ 2.4 ) , high AREG mRNA expression only in KRAS wild type CRC ( HR 0.47 , 95 % CI 0.3 @-@ 0.7 ) and high EREG mRNA expression irrespective of KRAS mutation status ( HR 0.45 , 95 % CI 0.28 @-@ 0.7 ) . # ::alignments 1-1.2.1 2-1.2 4-1.1.3 7-1.1.2 10-1.1.2.1.1 11-1.1.2.2 12-1.1.2.2.1 15-1 17-1.1.1.1.1.1.1 18-1.1.1.2 20-1.1.1.1.2.1.1.2 21-1.1.1.1.2.1.1 22-1.1.1.1.2.1.1 23-1.1.1.1.2.1.1.1 25-1.1.1.2.2.1.2.2 26-1.1.1.2.2.1.2.2 27-1.1.1.2.2.1.2 28-1.1.1.1.2.1.2.1.1 30-1.1.1.1.2.1.2.1.2 33-1.1.1.2.1 34-1.1.1.2.1.1 36-1.1.1.2.1.2 37-1.1.1.2.1.3.1.1 38-1.1.1.2 40-1.1.1.2.2.1.1 41-1.1.1.2.2.1.1.1 43-1.1.1.4.2.1.2.2 44-1.1.1.4.2.1.2.2 45-1.1.1.4.2.1.2 46-1.1.1.2.2.1.2.1.1 48-1.1.1.2.2.1.2.1.2 51-1.1.1.3.3 52-1.1.1.3.1.2.1.1.1 53-1.1.1.3.1.1.1 53-1.1.1.4.1.1.1 54-1.1.1.4 55-1.1.1.2.1.2 57-1.1.1.2.1.3.1.1 57-1.1.1.3.2.3.1.1 58-1.1.1.3.2.3.2 59-1.1.1.3.2.3.2 60-1.1.1.3.2.1.1 62-1.1.1.3.4.1.1 63-1.1.1.3.4.1.1.1 65-1.1.1.1.2.1.2.2.1 66-1.1.1.1.2.1.2.2 67-1.1.1.1.2.1.2 67-1.1.1.1.2.1.2.3 67-1.1.1.1.2.1.2.3.r 67-1.1.1.3.4.1.2 67-1.1.1.4.2.1.2 68-1.1.1.3.4.1.2.1.1 70-1.1.1.3.4.1.2.1.2 70-1.1.1.4.2.1.2.1.2 72-1.1.1.3.4.1 72-1.1.1.3.4.1.2.1 73-1.1.1.3.3 74-1.1.1.4.1.2.1.1.1 75-1.1.1.4.1.1.1 76-1.1.1.3 76-1.1.1.4 77-1.1.1.4.4 78-1.1.1.4.2.1.1 79-1.1.1.2.1.3.1.1 80-1.1.1.1 80-1.1.1.4.4.1.1 81-1.1.1.4.4.1 83-1.1.1.4.2.1.1 84-1.1.1.4.2.1.1.1 86-1.1.1.1.2.1.2.2.1 87-1.1.1.1.2.1.2.2 88-1.1.1.3.4.1.2 89-1.1.1.4.2.1.2.1.1 91-1.1.1.3.4.1.2.1.2 (s / see-01~e.15 :ARG1 (s2 / signify-01 :ARG0 (a / and :op1 (m2 / mutate-01~e.80 :ARG1 (e5 / enzyme :name (n / name :op1 "BRAF"~e.17)) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and :op1 (r4 / ratio-of~e.21,22 :quant 8.1~e.23 :op1 (h2 / hazard~e.20)) :op2 (i / interval~e.67 :value (b / between :op1 3.4~e.28 :op2 19~e.30) :quant (p / percentage-entity~e.66,87 :value 95~e.65,86) :mod~e.67 (c2 / confidence~e.67))))) :op2 (m3 / mutate-01~e.18,38 :ARG1 (c / codon~e.33 :mod 12~e.34 :mod (o / only~e.36,55) :part-of (e6 / enzyme :name (n3 / name :op1 "KRAS"~e.37,57,79))) :ARG1-of (m6 / mean-01 :ARG2 (a3 / and :op1 (r5 / ratio-of~e.40 :quant 1.62~e.41 :op1 h2) :op2 (i2 / interval~e.27 :value (b2 / between :op1 1.1~e.46 :op2 2.4~e.48) :quant p~e.25,26 :mod c2)))) :op3 (e / express-03~e.76 :ARG2 (n10 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.53) :ARG0-of (e2 / encode-01 :ARG1 (p3 / protein :name (n5 / name :op1 "AREG"~e.52)))) :ARG3 (d / disease :name (n6 / name :op1 "CRC"~e.60) :mod o :mod (e7 / enzyme :name (n7 / name :op1 "KRAS"~e.57) :mod (w / wild-type~e.58,59))) :ARG1-of (h / high-02~e.51,73) :ARG1-of (m7 / mean-01 :ARG2 (a4 / and~e.72 :op1 (r6 / ratio-of~e.62 :quant 0.47~e.63 :op1 h2) :op2 (i3 / interval~e.67,88 :value (b3 / between~e.72 :op1 0.3~e.68 :op2 0.7~e.70,91) :quant p :mod c2)))) :op4 (e3 / express-03~e.54,76 :ARG2 (n11 / nucleic-acid :name (n8 / name :op1 "mRNA"~e.53,75) :ARG0-of (e4 / encode-01 :ARG1 (p4 / protein :name (n9 / name :op1 "EREG"~e.74)))) :ARG1-of (m8 / mean-01 :ARG2 (a5 / and :op1 (r7 / ratio-of~e.78,83 :quant 0.45~e.84 :op1 h2) :op2 (i4 / interval~e.45,67 :value (b4 / between :op1 0.28~e.89 :op2 0.7~e.70) :quant p~e.43,44 :mod c2))) :ARG1-of h :ARG1-of (r / regardless-91~e.77 :ARG2 (s4 / status~e.81 :mod (m4 / mutate-01~e.80 :ARG2 e6))))) :ARG1 (s3 / survive-01~e.7 :time (a6 / after :op1 (m / metastasize-101~e.10)) :time (u2 / until~e.11 :op1 (d2 / die-01~e.12))) :mod (p2 / prognostic~e.4)) :time (a7 / analyze-01~e.2 :mod (u / univariate~e.1))) # ::id pmid_2337_4602.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EREG tumoural mRNA expression was significantly associated with a 2.26 @-@ fold increased likelihood of objective response to cetuximab therapy ( RECIST 1.1 ) . # ::alignments 0-1.1.1.2.1.1.1 2-1.1.1.1.1 3-1.1 5-1.3 6-1 9-1.2.2.1.1 11-1.2.2.1 12-1.2.2 14-1.2.2.1 15-1.2.1.2 16-1.2.1 16-1.2.1.1 16-1.2.1.1.r 17-1.2.1.1.1.r 18-1.2.1.1.1.1.1.1 19-1.2.1.1.1 21-1.2.3.1.2.1 22-1.2.3.1.1 (a / associate-01~e.6 :ARG1 (e / express-03~e.3 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.2) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "EREG"~e.0)))) :ARG0-of (c / cause-01 :ARG1 (t / tumor))) :ARG2 (l / likely-01 :ARG1 (t2 / thing~e.16 :ARG2-of~e.16 (r2 / respond-01~e.16 :ARG1~e.17 (t3 / therapy~e.19 :mod (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.18)))) :mod (o / objective~e.15)) :ARG1-of (i / increase-01~e.12 :ARG2 (p2 / product-of~e.11,14 :op1 2.26~e.9)) :ARG1-of (m / mean-01 :ARG2 (t4 / thing :value 1.1~e.22 :name (n4 / name :op1 "RECIST"~e.21)))) :ARG1-of (s2 / significant-02~e.5)) # ::id pmid_2337_4602.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In multivariate analysis , favourable predictive factors were high AREG mRNA in KRAS wild type tumours , high EREG mRNA , low Ephrin A2 receptor mRNA . # ::alignments 1-1.5.1 2-1.5 5-1.4.1 6-1.4 7-1.4.r 8-1.1 8-1.1.3 8-1.1.3.r 9-1.1.2.1.1.1 10-1.1.1.1 12-1.1.4.1.1.1 13-1.1.4.1.2 14-1.1.4.1.2 15-1.1.4 17-1.1 17-1.1.3 17-1.1.3.r 18-1.2.2.1.1.1 19-1.1.1.1 19-1.2.1.1 19-1.3.1.1 21-1.3 21-1.3.3 21-1.3.3.r 22-1.3.2.1.1.1 23-1.3.2.1.1.2 24-1.3.2.1.1.3 25-1.1.1.1 25-1.2.1.1 25-1.3.1.1 (a / and :op1 (n8 / nucleic-acid~e.8,17 :name (n / name :op1 "mRNA"~e.10,19,25) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG"~e.9))) :ARG1-of~e.8,17 (h / high-02~e.8,17) :location (t / tumor~e.15 :mod (g / gene :name (n3 / name :op1 "KRAS"~e.12) :mod (w / wild-type~e.13,14)))) :op2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.19,25) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "EREG"~e.18))) :ARG1-of h) :op3 (n10 / nucleic-acid~e.21 :name (n6 / name :op1 "mRNA"~e.19,25) :ARG0-of (e4 / encode-01 :ARG1 (p3 / protein :name (n7 / name :op1 "Ephrin"~e.22 :op2 "A2"~e.23 :op3 "receptor"~e.24))) :ARG1-of~e.21 (l / low-04~e.21)) :domain~e.7 (f / factor~e.6 :ARG0-of (p4 / predict-01~e.5) :ARG0-of (f2 / favor-01)) :time (a2 / analyze-01~e.2 :mod (m / multivariate~e.1))) # ::id pmid_2337_4602.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab @-@ treated patients with AREG @-@ low KRAS wild type CRC fared very poorly , their survival being similar to KRAS mutant CRC . # ::alignments 0-1.1.2.1.1.1 2-1.1.2 3-1.1.1.1 5-1.1.3.1.3.1.1.1 7-1.1.3.1 7-1.1.3.1.3 7-1.1.3.1.3.r 8-1.1.3.1.2.1.1 9-1.1.3.1.2.2 10-1.1.3.1.2.2 11-1.1.3.1.1.1 12-1 13-1.2.1 14-1.2 14-1.2.r 17-1.3.1.1 17-1.3.1.2 19-1.3.1 20-1.3.1.2.1.r 21-1.3.1.2.1.2.1.1 22-1.3.1.2.1.2 22-1.3.1.2.1.2.2 22-1.3.1.2.1.2.2.r 23-1.1.3.1.1.1 23-1.3.1.2.1.1.1 (f / fare-01~e.12 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.3)) :ARG1-of (t / treat-03~e.2 :ARG3 (s / small-molecule :name (n / name :op1 "cetuximab"~e.0))) :ARG0-of (h2 / have-03 :ARG1 (d / disease~e.7 :name (n2 / name :op1 "CRC"~e.11,23) :mod (g / gene :name (n3 / name :op1 "KRAS"~e.8) :mod (w / wild-type~e.9,10)) :ARG1-of~e.7 (l / low-04~e.7 :ARG2 (p3 / protein :name (n4 / name :op1 "AREG"~e.5)))))) :manner~e.14 (p4 / poor~e.14 :degree (v / very~e.13)) :ARG1-of (c / cause-01 :ARG0 (r / resemble-01~e.19 :ARG1 (s2 / survive-01~e.17 :ARG0 p) :ARG2 (s3 / survive-01~e.17 :ARG1~e.20 (d2 / disease :name (n5 / name :op1 "CRC"~e.23) :mod (g2 / gene~e.22 :name (n6 / name :op1 "KRAS"~e.21) :ARG2-of~e.22 (m / mutate-01~e.22))))))) # ::id pmid_2337_4602.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with KRAS codon 13 or other non @-@ codon 12 mutations had a median survival ( 30 months , 95 % CI 20 @–@ 35 ) similar to that of patients with KRAS wild @-@ type ( median survival 29 months , 95 % CI 25 @–@ 35 ) , in contrast to patients with KRAS codon 12 mutations who fared worse ( median survival 19 months , 95 % CI 15 @–@ 26 ) . # ::alignments 0-1.1.1.1 2-1.1.2.1.1.1.2.1.1 3-1.1.2.1.1.1 4-1.1.2.1.1.1.1 5-1.1.2.1 6-1.1.2.1.2.2 7-1.1.2.1.2.1.2 7-1.1.2.1.2.1.2.r 9-1.1.2.1.2.1 9-1.4.1.2.1.1 10-1.1.2.1.2.1.1 10-1.4.1.2.1.1.1 11-1.1.2.1.1 11-1.1.2.1.2 11-1.4.1.2.1 12-1 12-1.1 12-1.1.1 12-1.1.1.r 12-1.1.2 12-1.1.2.r 12-1.1.r 14-1.2.2 15-1.2 17-1.3.1.1.1 18-1.3.1.1.2 20-1.3.1.2.2.1 21-1.3.1.2.2 22-1.3.1.2 23-1.3.1.2.1.1.1 25-1.3.1.2.1.2.1 27-1.2.3 31-1.1.1.1 33-1.1.2.1.1.1.2.1.1 33-1.2.3.1.1.2.1.1.1 34-1.2.3.1.1.2.1.2 36-1.2.3.1.1.2.1.2 38-1.2.2 39-1.2 39-1.2.3.1 39-1.2.3.1.2.1.1 40-1.2.3.1.2.1.1.1.1 41-1.2.3.1.2.1.1.1.2 43-1.3.1.2.2.1 44-1.3.1.2.2 45-1.2.3.1.2.1.2 45-1.2.3.1.2.1.2.3 45-1.2.3.1.2.1.2.3.r 45-1.3.1.2 46-1.2.3.1.2.1.2.1.1.1 48-1.2.3.1.2.1.2.1.2 51-1.4.r 52-1.4 54-1.1.1.1 56-1.1.2.1.2.1.3 57-1.1.2.1.2.1 58-1.1.2.1.2.1.1 59-1.1.2.1.2 61-1.4.1.3 62-1.4.1.3.1 62-1.4.1.3.1.1 62-1.4.1.3.1.1.r 64-1.2.2 65-1.2 65-1.4.1.3.1.2.1.1 66-1.4.1.3.1.2.1.1.1.1 67-1.4.1.3.1.2.1.1.1.2 69-1.3.1.2.2.1 70-1.3.1.2.2 71-1.3.1.2 71-1.4.1.3.1.2.1.2 72-1.4.1.3.1.2.1.2.1.1.1 74-1.4.1.3.1.2.1.2.1.2.1 (h3 / have-03~e.12 :ARG0~e.12 (p2 / person~e.12 :ARG0-of~e.12 (h / have-rel-role-91~e.12 :ARG2 (p3 / patient~e.0,31,54)) :ARG0-of~e.12 (h2 / have-03~e.12 :ARG1 (o / or~e.5 :op1 (m / mutate-01~e.11 :ARG1 (c2 / codon~e.3 :mod 13~e.4 :part-of (g / gene :name (n3 / name :op1 "KRAS"~e.2,33)))) :op2 (m2 / mutate-01~e.11,59 :ARG1 (c4 / codon~e.9,57 :mod 12~e.10,58 :polarity~e.7 -~e.7 :part-of g~e.56) :mod (o2 / other~e.6))))) :ARG1 (s / survive-01~e.15,39,65 :ARG0 p2 :mod (m3 / median~e.14,38,64) :ARG1-of (r / resemble-01~e.27 :ARG2 (s2 / survive-01~e.39 :ARG0 (p4 / person :ARG0-of h :ARG0-of (h4 / have-03 :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS"~e.33) :mod (w / wild-type~e.34,36)))) :ARG1-of (m6 / mean-01 :ARG2 (a2 / and :op1 (s3 / survive-01~e.39 :duration (t2 / temporal-quantity :quant 29~e.40 :unit m5~e.41) :mod m3) :op2 (i / interval~e.45 :value (b3 / between :op1 (t6 / temporal-quantity :quant 25~e.46 :unit m5) :op2 t5~e.48) :quant p :mod~e.45 (c3 / confidence~e.45))))))) :ARG1-of (m4 / mean-01 :ARG2 (a / and :op1 (t / temporal-quantity :quant 30~e.17 :unit (m5 / month~e.18)) :op2 (i2 / interval~e.22,45,71 :value (b2 / between :op1 (t4 / temporal-quantity :quant 20~e.23 :unit m5) :op2 (t5 / temporal-quantity :quant 35~e.25 :unit m5)) :quant (p / percentage-entity~e.21,44,70 :value 95~e.20,43,69) :mod c3))) :ARG1-of~e.51 (c / contrast-01~e.52 :ARG2 (p5 / person :ARG0-of h :ARG0-of (h5 / have-03 :ARG1 (m8 / mutate-01~e.11 :ARG1 (c5 / codon~e.9 :mod 12~e.10 :part-of g))) :ARG0-of (f / fare-01~e.61 :ARG1-of (b / bad-07~e.62 :degree~e.62 (m9 / more~e.62) :ARG1-of (m10 / mean-01 :ARG2 (a3 / and :op1 (s4 / survive-01~e.65 :duration (t3 / temporal-quantity :quant 19~e.66 :unit m5~e.67) :mod m3) :op2 (i3 / interval~e.71 :value (b4 / between :op1 (t7 / temporal-quantity :quant 15~e.72 :unit m5) :op2 (t8 / temporal-quantity :quant 26~e.74 :unit m5)) :quant p :mod c3)))))))) # ::id pmid_2337_4602.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2337_4602.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patient and tumour demographics # ::alignments 1-1.1.1.1.1 2-1 3-1.2.1 (a / and~e.2 :op1 (d / demographic :mod (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.1)))) :op2 (d2 / demographic :mod (t / tumor~e.3))) # ::id pmid_2337_4602.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A total of 226 patients of a median age of 62.6 years ( range 26 @–@ 85 ) underwent excisional or incisional biopsy of colorectal adenocarcinoma , of whom 83 ( 36.8 %) were diagnosed with localised ( stage I @-@ III ) colon cancer and 137 ( 60.6 %) with metastatic disease ( Table 1 ) . # ::alignments 1-1.1 1-1.1.2 1-1.1.2.r 3-1.1.2.1 4-1.1.1.1 5-1.1.3.r 7-1.1.3.2 8-1.1.3 9-1.1.3.1.r 10-1.1.3.1.1 11-1.1.3.1.2 13-1.1.3.3 13-1.1.4.1.1.4.1 13-1.1.4.1.1.4.1.4 13-1.1.4.1.1.4.1.4.r 14-1.1.3.3.1.1 16-1.1.3.3.2.1 18-1 20-1.2 22-1.2.1 22-1.2.2 23-1.2.1.1.r 24-1.2.1.1.2 25-1.2.1.1.1.1 29-1.1.4.1.1.1 31-1.1.4.1.1.3.1.1 34-1.1.4.1.1.4 34-1.1.4.1.2.4 38-1.1.4.1.1.4.1.4.1 38-1.1.4.1.1.4.1.4.2 39-1.1.4.1.1.4.1.4.1.1.1 41-1.1.4.1.1.4.1.4.2.1.1 43-1.1.4.1.1.4.1.3.1 44-1.1.4.1.1.4.1.2.1 45-1.1.4.1 46-1.1.4.1.2.1 48-1.1.4.1.2.3.1.1 50-1.1.4.1.2.4.1.r 51-1.1.4.1.2.4.1.1 52-1.1.4.1.2.4.1 54-1.3.1 56-1.3.1.1 (u / undergo-28~e.18 :ARG1 (p3 / person~e.1 :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.4)) :ARG1-of~e.1 (t / total-01~e.1 :ARG2 226~e.3) :ARG1-of~e.5 (a / age-01~e.8 :ARG2~e.9 (t2 / temporal-quantity :quant 62.6~e.10 :unit (y / year~e.11)) :mod (m / median~e.7) :ARG1-of (r / range-01~e.13 :ARG3 (t3 / temporal-quantity :quant 26~e.14 :unit y) :ARG4 (t4 / temporal-quantity :quant 85~e.16 :unit y))) :ARG2-of (i2 / include-91 :ARG1 (a3 / and~e.45 :op1 (p5 / person :quant 83~e.29 :ARG0-of h :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value 36.8~e.31)) :ARG1-of (d2 / diagnose-01~e.34 :ARG2 (d5 / disease~e.13 :wiki "Cancer" :name (n / name :op1 "cancer"~e.44) :ARG1-of (l / local-02 :ARG2 (c3 / colon~e.43)) :ARG1-of~e.13 (r2 / range-01~e.13 :ARG3 (s / stage~e.38 :ord (o / ordinal-entity :value 1~e.39)) :ARG4 (s2 / stage~e.38 :ord (o3 / ordinal-entity :value 3~e.41)))))) :op2 (p6 / person :quant 137~e.46 :ARG0-of h :ARG1-of (m3 / mean-01 :ARG2 (p2 / percentage-entity :value 60.6~e.48)) :ARG1-of (d3 / diagnose-01~e.34 :ARG2~e.50 (d4 / disease~e.52 :ARG1-of (m4 / metastasize-101~e.51))))))) :ARG2 (o2 / or~e.20 :op1 (b / biopsy-101~e.22 :ARG1~e.23 (m5 / medical-condition :name (n2 / name :op1 "adenocarcinoma"~e.25) :mod (c / colorectal~e.24)) :ARG0-of (e / excise-01)) :op2 (b2 / biopsy-101~e.22 :ARG1 (a2 / adenocarcinoma) :ARG0-of (i / incise-01))) :ARG1-of (d / describe-01 :ARG0 (t5 / table~e.54 :mod 1~e.56))) # ::id pmid_2337_4602.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The primary tumour was located in the left colon ( distal transverse to rectum ) in 165 ( 73.0 %) of cases and in the right colon ( caecum to proximal transverse ) in 60 ( 26.6 %) . # ::alignments 1-1.1.1.1 2-1.1.1 4-1.1 4-1.1.3.r 4-1.2 5-1.1.2.r 7-1.1.2.1 8-1.1.2 10-1.1.2.2.1.1.1 11-1.1.2.2.1.1 13-1.1.2.2.1.2 16-1.1.3.1 18-1.1.3.2.1.1 21-1.1.3 21-1.2.3 22-1 23-1.2.2.r 25-1.2.2.2 26-1.2.2 28-1.2.2.1.1.1 30-1.2.2.1.1.2.1 31-1.2.2.1.1.2 34-1.2.3.1 36-1.2.3.2.1.1 (a / and~e.22 :op1 (l / locate-02~e.4 :ARG1 (t / tumor~e.2 :mod (p3 / primary~e.1)) :location~e.5 (c / colon~e.8 :ARG1-of (l2 / left-20~e.7) :ARG1-of (m / mean-01 :ARG2 (b / between :op1 (t2 / transverse~e.11 :mod (d / distal~e.10)) :op2 (r / rectum~e.13)))) :location~e.4 (c2 / case-04~e.21 :quant 165~e.16 :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value 73.0~e.18)))) :op2 (l3 / locate-02~e.4 :ARG1 t :location~e.23 (c3 / colon~e.26 :ARG1-of (m2 / mean-01 :ARG2 (b2 / between :op1 (c4 / caecum~e.28) :op2 (t3 / transverse~e.31 :mod (p4 / proximal~e.30)))) :ARG1-of (r2 / right-04~e.25)) :location (c5 / case-04~e.21 :quant 60~e.34 :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value 26.6~e.36))))) # ::id pmid_2337_4602.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rectal tumours accounted for 71 cases ( 31 %) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1 5-1.2 7-1.2.2.1.1 (a / account-01~e.2 :ARG0 (t / tumor~e.1 :mod (r / rectum~e.0)) :ARG1~e.3 (c / case-04~e.5 :quant 71~e.4 :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value 31~e.7)))) # ::id pmid_2337_4602.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok From May 2004 until December 2008 , cetuximab had been administered as an intravenous infusion according to standard regimens ( loading dose 400 mg @/@ m2 followed by weekly 250 mg/m2 ) as monotherapy ( 42 , 13.4 %) or with regimes based on irinotecan ( 153 , 48.7 %) , oxaliplatin ( 84 , 26.7 %) or both agents ( 29 , 9.2 %) . # ::alignments 0-1.5.1.r 1-1.5.1.1 1-1.5.1.1.r 2-1.5.1.2 4-1.5.2.1 4-1.5.2.1.r 5-1.5.2.2 7-1.1.1.1.1 10-1.1 10-1.2 10-1.3 10-1.4 11-1.1.3.r 11-1.5.r 13-1.1.3.1 14-1.1.3 15-1.1.4 16-1.1.4.1.r 17-1.1.4.1.1 18-1.1.4.1 18-1.2.4 18-1.3.4 18-1.4.4 20-1.1.4.1.2.1.1 21-1.1.4.1.2.1 21-1.1.4.1.2.1.3.1 22-1.1.4.1.2.1.2.1 23-1.1.4.1.2.1.2.2 26-1.1.4.1.2.1.3 27-1.1.4.1.2.1.3.1.1.r 28-1.1.4.1.2.1.3.1.1 29-1.1.4.1.2.1.3.1.2.1 32-1.1.5.r 32-1.5.r 33-1.1.5 35-1.1.2.1 37-1.1.2.2.1.1 39-1 40-1.2.4.r 40-1.3.4.r 40-1.4.4.r 42-1.2.4.1 42-1.3.4.1 42-1.4.4.1 43-1.2.4.1.1.r 44-1.2.4.1.1.1.1 46-1.2.2.1 48-1.2.2.2.1.1 51-1.3.4.1.1.1.1 53-1.3.2.1 55-1.3.2.2.1.1 57-1 61-1.4.2.1 63-1.4.2.2.1.1 (o / or~e.39,57 :op1 (a / administer-01~e.10 :ARG1 (s / small-molecule :name (n / name :op1 "cetuximab"~e.7)) :ARG2 (c3 / case-04 :quant 42~e.35 :ARG1-of (m4 / mean-01 :ARG2 (p / percentage-entity :value 13.4~e.37))) :ARG1-of~e.11 (i / infuse-01~e.14 :mod (i2 / intravenous~e.13)) :ARG1-of (a2 / accord-02~e.15 :ARG2~e.16 (r / regimen~e.18 :ARG1-of (s2 / standard-02~e.17) :ARG1-of (m / mean-01 :ARG2 (d3 / dose-01~e.21 :ARG2-of (l / load-01~e.20) :quant (c / concentration-quantity :quant 400~e.22 :unit (m2 / milligram-per-square-meter~e.23)) :ARG2-of (f / follow-01~e.26 :ARG1 (d4 / dose-01~e.21 :frequency~e.27 (w / week~e.28) :quant (c2 / concentration-quantity :quant 250~e.29 :unit m2))))))) :manner~e.32 (m3 / monotherapy~e.33)) :op2 (a3 / administer-01~e.10 :ARG1 s :ARG2 (c4 / case-04 :quant 153~e.46 :ARG1-of (m5 / mean-01 :ARG2 (p2 / percentage-entity :value 48.7~e.48))) :ARG1-of i :prep-with~e.40 (r2 / regimen~e.18 :ARG1-of (b / base-02~e.42 :ARG2~e.43 (s3 / small-molecule :name (n2 / name :op1 "irinotecan"~e.44)))) :ARG1-of a2) :op3 (a4 / administer-01~e.10 :ARG1 s :ARG2 (c5 / case-04 :quant 84~e.53 :ARG1-of (m6 / mean-01 :ARG2 (p3 / percentage-entity :value 26.7~e.55))) :ARG1-of i :prep-with~e.40 (r3 / regimen~e.18 :ARG1-of (b2 / base-02~e.42 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "oxaliplatin"~e.51)))) :ARG1-of a2) :op4 (a5 / administer-01~e.10 :ARG1 s :ARG2 (c6 / case-04 :quant 29~e.61 :ARG1-of (m7 / mean-01 :ARG2 (p4 / percentage-entity :value 9.2~e.63))) :ARG1-of i :prep-with~e.40 (r4 / regimen~e.18 :ARG1-of (b3 / base-02~e.42 :ARG2 (a6 / and :op1 s3 :op2 s4))) :ARG1-of a2) :time~e.11,32 (d5 / date-interval :op1~e.0 (d / date-entity :month~e.1 5~e.1 :year 2004~e.2) :op2 (d2 / date-entity :month~e.4 12~e.4 :year 2008~e.5))) # ::id pmid_2337_4602.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lines of therapy during which cetuximab was administered were 1 st line in 38 ( 16.8 %) , 2 nd line in 108 ( 47.8 %) , 3 rd and beyond in 80 ( 35.4 %) ( Table 1 ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 4-1.4.2.r 6-1.4.2.1.1.1 8-1.4.2 9-1.4.r 10-1.1.1 10-1.1.1.1 10-1.1.1.1.r 11-1.1.1 12-1.1 14-1.1.2.1 16-1.1.2.2.1.1 19-1.2.1 19-1.2.1.1 19-1.2.1.1.r 20-1.2.1 21-1.2 21-1.3.1 21-1.3.2 23-1.2.2.1 25-1.2.2.2.1.1 28-1.3.1.1 28-1.3.1.1.1 28-1.3.1.1.1.r 29-1.3.1.1 30-1.3 31-1.3.2.1 33-1.3.3.1 35-1.3.3.2.1.1 38-1.5.1 40-1.5.1.1 (a / and :op1 (l2 / line~e.12 :ord (o / ordinal-entity~e.10,11 :value~e.10 1~e.10) :location (c / case-04 :quant 38~e.14 :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value 16.8~e.16)))) :op2 (l3 / line~e.21 :ord (o2 / ordinal-entity~e.19,20 :value~e.19 2~e.19) :location (c2 / case-04 :quant 108~e.23 :ARG1-of (m2 / mean-01 :ARG2 (p2 / percentage-entity :value 47.8~e.25)))) :op3 (a3 / and~e.30 :op1 (l4 / line~e.21 :ord (o3 / ordinal-entity~e.28,29 :value~e.28 3~e.28)) :op2 (l5 / line~e.21 :mod (b / beyond~e.31 :op1 l4)) :location (c3 / case-04 :quant 80~e.33 :ARG1-of (m3 / mean-01 :ARG2 (p3 / percentage-entity :value 35.4~e.35)))) :domain~e.9 (l / line~e.1 :mod~e.2 (t / therapy~e.3) :time-of~e.4 (a2 / administer-01~e.8 :ARG1 (s / small-molecule :name (n / name :op1 "cetuximab"~e.6)))) :ARG1-of (d / describe-01 :ARG0 (t2 / table~e.38 :mod 1~e.40))) # ::id pmid_2337_4602.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of note , as the period of therapy extended from 2004 until December 2008 , an unselected patient population received cetuximab @-@ based therapies , irrespective of KRAS mutational status . # ::alignments 1-1.3 5-1.4.1.1 6-1.4.1.1.1.r 7-1.4.1.1.1 8-1.4.1 9-1.4.1.2.r 10-1.4.1.2.1 12-1.4.1.3.1 12-1.4.1.3.1.r 13-1.4.1.3.2 16-1.1.1.2 16-1.1.1.2.1 16-1.1.1.2.1.r 17-1.1.1.1.1 18-1.1 19-1 20-1.2.1.1.1.1 22-1.2.1 23-1.2 25-1.5 27-1.5.1.1.1.1.1 28-1.5.1.1 29-1.5.1 (r / receive-01~e.19 :ARG0 (p / population~e.18 :consist-of (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.17)) :ARG1-of (s / select-01~e.16 :polarity~e.16 -~e.16))) :ARG1 (t / therapy~e.23 :ARG1-of (b / base-02~e.22 :ARG2 (s2 / small-molecule :name (n / name :op1 "cetuximab"~e.20)))) :ARG1-of (n3 / note-02~e.1) :ARG1-of (c / cause-01 :ARG0 (e2 / extend-01~e.8 :ARG1 (p4 / period~e.5 :duration-of~e.6 t~e.7) :ARG3~e.9 (d / date-entity :year 2004~e.10) :ARG4 (d2 / date-entity :month~e.12 12~e.12 :year 2008~e.13))) :ARG1-of (r2 / regardless-91~e.25 :ARG2 (s3 / status~e.29 :mod (m / mutate-01~e.28 :ARG2 (g / gene :name (n2 / name :op1 "KRAS"~e.27)))))) # ::id pmid_2337_4602.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok mRNA markers and somatic genotypes # ::alignments 1-1.1.1.1.1 2-1.1 3-1 4-1.2.1 5-1.2 (a / and~e.3 :op1 (m / marker~e.2 :mod (n2 / nucleic-acid :name (n / name :op1 "mRNA"~e.1))) :op2 (g / genotype~e.5 :mod (s / somatic~e.4))) # ::id pmid_2337_4602.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Out of the 199 samples tested for mRNA expression , three were found not eligible for all targets . # ::alignments 3-1.1.4.1.1 4-1.1 4-1.1.2 4-1.1.2.r 5-1.1.4.1.3 6-1.1.4.1.3.1.r 7-1.1.4.1.3.1.1.1.1 8-1.1.4.1.3.1 10-1.1.1 12-1 13-1.1.3.1 13-1.1.3.1.r 14-1.1.3 15-1.1.3.2.r 16-1.1.3.2.2 17-1.1.3.2 17-1.1.3.2.1 17-1.1.3.2.1.r (f / find-02~e.12 :ARG1 (t / thing~e.4 :quant 3~e.10 :ARG1-of~e.4 (s / sample-01~e.4) :ARG1-of (q / qualify-02~e.14 :polarity~e.13 -~e.13 :ARG2~e.15 (t3 / thing~e.17 :ARG1-of~e.17 (t2 / target-01~e.17) :mod (a / all~e.16))) :ARG1-of (i / include-91 :ARG2 (t4 / thing :quant 199~e.3 :ARG1-of s :ARG1-of (t5 / test-01~e.5 :ARG2~e.6 (e2 / express-03~e.8 :ARG2 (n2 / nucleic-acid :name (n / name :op1 "mRNA"~e.7)))))))) # ::id pmid_2337_4602.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In total , 84.4 % of samples were eligible for AREG analysis ; 83.9 % for EGF ; 84.4 % for EGFR ; 80.4 % for EREG ; and 81.4 % for TGFa . # ::alignments 1-1.2 3-1.1.1.1.2.2.1 4-1.1.1.1.2.2 6-1.1.1.1 6-1.1.1.1.1 6-1.1.1.1.1.r 8-1.1.1 8-1.1.2 8-1.1.3 8-1.1.4 8-1.1.5 10-1.1.1.2.1.1.1 11-1.1.1.2 11-1.1.2.2 11-1.1.3.2 11-1.1.4.2 11-1.1.5.2 13-1.1.2.1.2.2.1 14-1.1.2.1.2.2 15-1.1.2.2.1.r 16-1.1.2.2.1.1.1 18-1.1.3.1 19-1.1.3.1 20-1.1.3.2.1.r 21-1.1.3.2.1.1.1 23-1.1.4.1.2.2.1 24-1.1.4.1.2.2 25-1.1.4.2.1.r 26-1.1.4.2.1.1.1 28-1.1 29-1.1.5.1.2.2.1 30-1.1.5.1.2.2 31-1.1.5.2.1.r 32-1.1.5.2.1.1.1 (p7 / possible-01 :ARG1 (a / and~e.28 :op1 (q / qualify-02~e.8 :ARG1 (t / thing~e.6 :ARG1-of~e.6 (s / sample-01~e.6) :ARG1-of (i / include-91 :ARG2 (t7 / thing :ARG1-of s) :ARG3 (p / percentage-entity~e.4 :value 84.4~e.3))) :ARG2 (a2 / analyze-01~e.11 :ARG1 (p6 / protein :name (n2 / name :op1 "AREG"~e.10)))) :op2 (q2 / qualify-02~e.8 :ARG1 (t2 / thing :ARG1-of s :ARG1-of (i2 / include-91 :ARG2 t7 :ARG3 (p2 / percentage-entity~e.14 :value 83.9~e.13))) :ARG2 (a3 / analyze-01~e.11 :ARG1~e.15 (p9 / protein :name (n3 / name :op1 "EGF"~e.16)))) :op3 (q3 / qualify-02~e.8 :ARG1 t~e.18,19 :ARG2 (a4 / analyze-01~e.11 :ARG1~e.20 (e / enzyme :name (n / name :op1 "EGFR"~e.21)))) :op4 (q4 / qualify-02~e.8 :ARG1 (t4 / thing :ARG1-of s :ARG1-of (i3 / include-91 :ARG2 t7 :ARG3 (p4 / percentage-entity~e.24 :value 80.4~e.23))) :ARG2 (a5 / analyze-01~e.11 :ARG1~e.25 (p3 / protein :name (n4 / name :op1 "EREG"~e.26)))) :op5 (q5 / qualify-02~e.8 :ARG1 (t5 / thing :ARG1-of s :ARG1-of (i4 / include-91 :ARG2 t7 :ARG3 (p5 / percentage-entity~e.30 :value 81.4~e.29))) :ARG2 (a6 / analyze-01~e.11 :ARG1~e.31 (p8 / protein :name (n5 / name :op1 "TGFa"~e.32))))) :ARG1-of (t6 / total-01~e.1)) # ::id pmid_2337_4602.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Out of the 226 DNA samples screened for the presence of mutations , genotyping was successful in 205 samples for KRAS ( 90.8 %) , 159 ( 70.4 %) for NRAS , 220 for BRAF and 220 for PIK3CA ( 97.3 % in each case ) ( Table 2 ) . # ::alignments 3-1.1.3.3.1.1 4-1.1.3.3.1.2.2.1 5-1.1.3.3.1 5-1.2.3 5-1.3.3 5-1.4.3 6-1.1.3.3.1.3 7-1.1.3.3.1.3.1.r 9-1.1.3.3.1.3.1 10-1.1.3.3.1.3.1.1.r 11-1.1.3.3.1.3.1.1 13-1.1.1 15-1.1 15-1.2 15-1.3 15-1.4 17-1.1.3.1 18-1.1.3 19-1.1.2.r 20-1.1.2.1.1 22-1.1.3.3.2.1 25-1.2.3.1 27-1.2.3.3.2.1 29-1.2.2.r 30-1.2.2.1.1 32-1.4.3.1 33-1.3.2.r 34-1.3.2.1.1 36-1.3.3.1 37-1.4.2.r 38-1.4.2.1.1 40-1.3.3.3.2.1 41-1.1.3.3.2 41-1.2.3.3.2 41-1.3.3.3.2 47-1.5.1 49-1.5.1.1 (a2 / and :op1 (s / succeed-01~e.15 :ARG0 (g5 / genotyping~e.13) :ARG1~e.19 (e4 / enzyme :name (n3 / name :op1 "KRAS"~e.20)) :location (s7 / sample-01~e.18 :quant 205~e.17 :ARG2 n2 :ARG1-of (i / include-91 :ARG2 (s6 / sample-01~e.5 :quant 226~e.3 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.4)) :ARG1-of (s8 / screen-01~e.6 :ARG2~e.7 (p4 / present-02~e.9 :ARG1~e.10 (m / mutate-01~e.11)))) :ARG3 (p / percentage-entity~e.41 :value 90.8~e.22)))) :op2 (s3 / succeed-01~e.15 :ARG0 g5 :ARG1~e.29 (e / enzyme :name (n4 / name :op1 "NRAS"~e.30)) :location (s9 / sample-01~e.5 :quant 159~e.25 :ARG2 n2 :ARG1-of (i2 / include-91 :ARG2 s6 :ARG3 (p2 / percentage-entity~e.41 :value 70.4~e.27)))) :op3 (s4 / succeed-01~e.15 :ARG0 g5 :ARG1~e.33 (e3 / enzyme :name (n5 / name :op1 "BRAF"~e.34)) :location (s10 / sample-01~e.5 :quant 220~e.36 :ARG2 n2 :ARG1-of (i3 / include-91 :ARG2 s6 :ARG3 (p3 / percentage-entity~e.41 :value 97.3~e.40)))) :op4 (s5 / succeed-01~e.15 :ARG0 g5 :ARG1~e.37 (g / gene :name (n / name :op1 "PIK3CA"~e.38)) :location (s2 / sample-01~e.5 :quant 220~e.32 :ARG2 n2 :ARG1-of i3)) :ARG1-of (d / describe-01 :ARG0 (t6 / table~e.47 :mod 2~e.49))) # ::id pmid_2337_4602.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KRAS mutations were detected in 72 tumours ( 31.9 %) , mostly in exon 2 , in codon 12 in 45 cases ( 20.0 %) and in codon 13 in 16 cases ( 7.0 %) , while BRAF V600E mutations were found in 6 cases ( 2.6 %) . # ::alignments 0-1.1.1.1.2.1.1 1-1.1.1 1-1.1.2.3.1.1.3.1 3-1.1 4-1.1.2.r 5-1.1.2.1 6-1.1.2 8-1.1.2.2.1.1 11-1.1.1.1.3 13-1.1.1.1 14-1.1.1.1.1 16-1.1.2.3.1.1.3.1.1.r 17-1.1.2.3.1.1.3.1.1 18-1.1.2.3.1.1.3.1.1.1 20-1.1.2.3.1.1.1 21-1.1.2.3.1.1 23-1.1.2.3.1.1.2.1.1 25-1.1.2.3.1 27-1.1.2.3.1.2.3.1.1 28-1.1.2.3.1.2.3.1.1.1 30-1.1.2.3.1.2.1 31-1.1.2.3.1.2 33-1.1.2.3.1.2.2.1.1 36-1 37-1.2.1.2.1.1 38-1.2.1.1 39-1.1.2.3.1.2.3.1 39-1.2.1 41-1.2 42-1.2.2.r 43-1.2.2.1 44-1.2.2 46-1.2.2.2.1.1 (c / contrast-01~e.36 :ARG1 (d / detect-01~e.3 :ARG1 (m / mutate-01~e.1 :ARG2 (e / exon~e.13 :mod 2~e.14 :part-of (g / gene :name (n / name :op1 "KRAS"~e.0)) :degree (m2 / most~e.11))) :location~e.4 (t / tumor~e.6 :quant 72~e.5 :ARG1-of (m6 / mean-01 :ARG2 (p / percentage-entity :value 31.9~e.8)) :ARG2-of (i / include-91 :ARG1 (a2 / and~e.25 :op1 (c2 / case-04~e.21 :quant 45~e.20 :ARG1-of (m7 / mean-01 :ARG2 (p2 / percentage-entity :value 20.0~e.23)) :ARG0-of (h / have-03 :ARG1 (m3 / mutate-01~e.1 :ARG2~e.16 (c5 / codon~e.17 :mod 12~e.18 :part-of g)))) :op2 (c3 / case-04~e.31 :quant 16~e.30 :ARG1-of (m8 / mean-01 :ARG2 (p3 / percentage-entity :value 7.0~e.33)) :ARG0-of (h2 / have-03 :ARG1 (m4 / mutate-01~e.39 :ARG2 (c6 / codon~e.27 :mod 13~e.28)))))))) :ARG2 (f / find-01~e.41 :ARG1 (m5 / mutate-01~e.39 :value "V600E"~e.38 :ARG2 (e2 / enzyme :name (n5 / name :op1 "BRAF"~e.37))) :location~e.42 (c4 / case-04~e.44 :quant 6~e.43 :ARG1-of (m9 / mean-01 :ARG2 (p4 / percentage-entity :value 2.6~e.46))))) # ::id pmid_2337_4602.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok NRAS mutations were also quite rare , found only in 7 cases ( 3.1 %) . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2 4-1.2 5-1 7-1.3.1 8-1.3.1.2 9-1.3.1.3.r 10-1.3.1.3.1 11-1.3.1.3 13-1.3.1.3.2.1.1 (r / rare-02~e.5 :ARG1 (m / mutate-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "NRAS"~e.0)) :mod (a / also~e.3)) :degree (q / quite~e.4) :ARG1-of (i / infer-01 :ARG2 (f / find-01~e.7 :ARG1 m :mod (o / only~e.8) :location~e.9 (c / case-04~e.11 :quant 7~e.10 :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value 3.1~e.13)))))) # ::id pmid_2337_4602.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PIK3CA mutations were detected in 37 tumours ( 16.4 %) , 20 in exon 9 ( 8.8 %) and only five in exon 20 ( 2.2 %) . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.2.3.1.1.2.1 1-1.2.3.1.2.3.1 3-1 4-1.2.r 5-1.2.1 6-1.2 6-1.2.3.1.1 6-1.2.3.1.2 8-1.2.2.1.1 11-1.2.3.1.1.1 12-1.2.3.1.1.2.1.1.r 13-1.2.3.1.1.2.1.1 14-1.2.3.1.1.2.1.1.1 16-1.2.3.1.1.3.1.1 18-1.2.3.1 19-1.2.3.1.2.2 20-1.2.3.1.2.1 21-1.2.3.1.2.3.1.1.r 22-1.2.3.1.2.3.1.1 23-1.2.3.1.2.3.1.1.1 25-1.2.3.1.2.4.1.1 (d2 / detect-01~e.3 :ARG1 (m / mutate-01~e.1 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.0))) :location~e.4 (t / tumor~e.6 :quant 37~e.5 :ARG1-of (m2 / mean-01 :ARG2 (p / percentage-entity :value 16.4~e.8)) :ARG2-of (i / include-91 :ARG1 (a / and~e.18 :op1 (t2 / tumor~e.6 :quant 20~e.11 :ARG0-of (h / have-03 :ARG1 (m3 / mutate-01~e.1 :ARG1~e.12 (e / exon~e.13 :mod 9~e.14))) :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value 8.8~e.16))) :op2 (t3 / tumor~e.6 :quant 5~e.20 :mod (o / only~e.19) :ARG0-of (h2 / have-03 :ARG1 (m5 / mutate-01~e.1 :ARG1~e.21 (e2 / exon~e.22 :mod 20~e.23))) :ARG1-of (m6 / mean-01 :ARG2 (p3 / percentage-entity :value 2.2~e.25))))))) # ::id pmid_2337_4602.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This genotypic analysis was included in a previous publication [ @ 8 @ ] . # ::alignments 0-1.1.2 2-1.1 4-1 5-1.2.r 7-1.2.1 8-1.2 8-1.2.2.1 8-1.2.3 8-1.2.3.r 11-1.2.2.1.1.1 (i / include-01~e.4 :ARG1 (a / analyze-01~e.2 :ARG1 (g / genotype) :mod (t / this~e.0)) :ARG2~e.5 (t2 / thing~e.8 :time (p2 / previous~e.7) :ARG1-of (d / describe-01 :ARG0 (p3 / publication~e.8 :ARG1-of (c / cite-01 :ARG2 8~e.11))) :ARG1-of~e.8 (p / publish-01~e.8))) # ::id pmid_2337_4602.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Correlation analysis revealed that mutations in KRAS , BRAF , NRAS genes were mutually exclusive in all evaluable cases . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.1.1 4-1.2.1.2 4-1.2.1.3 6-1.2.1.1.1.1.1 8-1.2.1.2.1.1.1 10-1.2.1.3.1.1.1 11-1.2.1.1.1 11-1.2.1.2.1 11-1.2.1.3.1 13-1.2.2 13-1.2.2.r 16-1.2.3.2 18-1.2.3 (r / reveal-01~e.2 :ARG0 (a / analyze-01~e.1 :ARG1 (c / correlate-01~e.0)) :ARG1 (e / exclude-01 :ARG1 (a2 / and :op1 (m / mutate-01~e.4 :ARG1 (g / gene~e.11 :name (n / name :op1 "KRAS"~e.6))) :op2 (m2 / mutate-01~e.4 :ARG1 (g2 / gene~e.11 :name (n2 / name :op1 "BRAF"~e.8))) :op3 (m3 / mutate-01~e.4 :ARG1 (g3 / gene~e.11 :name (n3 / name :op1 "NRAS"~e.10)))) :manner~e.13 (m4 / mutual~e.13) :location (c2 / case-04~e.18 :ARG1-of (e2 / evaluate-101 :ARG1-of (p / possible-01)) :mod (a3 / all~e.16)))) # ::id pmid_2337_4602.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the contrary , mutations in the PIK3CA gene co @-@ existed with KRAS mutations in 17 cases and with NRAS mutations in two . # ::alignments 2-1 4-1.1.1.1 4-1.1.1.2 4-1.1.2.2 7-1.1.1.1.1.1.1 8-1.1.1.1.1 8-1.1.1.2.1 8-1.1.2.2.1 13-1.1.1.2.1.1.1 14-1.1.1.1 16-1.1.1.3.1.1 17-1.1.1.3 17-1.1.1.3.1 17-1.1.1.3.1.r 17-1.1.2.3 17-1.1.2.3.1 17-1.1.2.3.1.r 18-1.1 20-1.1.2.2.1.1.1 21-1.1.2.1 23-1.1.2.3.1.1 (c / contrast-01~e.2 :ARG2 (a / and~e.18 :op1 (c2 / coexist-01 :ARG1 (m / mutate-01~e.4,14 :ARG1 (g / gene~e.8 :name (n / name :op1 "PIK3CA"~e.7))) :ARG2 (m2 / mutate-01~e.4 :ARG1 (g2 / gene~e.8 :name (n2 / name :op1 "KRAS"~e.13))) :location (t / thing~e.17 :ARG1-of~e.17 (c3 / case-04~e.17 :quant 17~e.16))) :op2 (c4 / coexist-01 :ARG1 m~e.21 :ARG2 (m3 / mutate-01~e.4 :ARG1 (g3 / gene~e.8 :name (n3 / name :op1 "NRAS"~e.20))) :location (t2 / thing~e.17 :ARG1-of~e.17 (c5 / case-04~e.17 :quant 2~e.23))))) # ::id pmid_2337_4602.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Statistically significant associations at the 2 @-@ sided p< 0.05 level were seen between wild type status of KRAS , BRAF genes and high AREG , EREG , EGFR mRNA levels . # ::alignments 0-1.3 1-1.1.2 2-1.1 5-1.3.2.1 7-1.3.2 9-1.3.1.1 10-1.2.1 12-1 14-1.1.1.3 15-1.1.1.3 18-1.1.1.1.1.1 20-1.1.1.2.1.1 21-1.1.1.1 21-1.1.1.2 22-1.1.1 22-1.2 23-1.2.4 24-1.2.1.1.2.1.1.1 26-1.2.2.1.2.1.1.1 28-1.2.3.1.2.1.1.1 29-1.2.1.1.1.1 29-1.2.2.1.1.1 29-1.2.3.1.1.1 30-1.2.1 30-1.2.2 30-1.2.3 (s / see-01~e.12 :ARG1 (a / associate-01~e.2 :ARG1 (a2 / and~e.22 :op1 (g / gene~e.21 :name (n2 / name :op1 "KRAS"~e.18)) :op2 (g2 / gene~e.21 :name (n3 / name :op1 "BRAF"~e.20)) :mod (w / wild-type~e.14,15)) :ARG1-of (s2 / significant-02~e.1 :manner (s3 / statistic))) :ARG2 (a4 / and~e.22 :op1 (l / level~e.10,30 :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.29) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n7 / name :op1 "AREG"~e.24))))) :op2 (l4 / level~e.30 :quant-of (n10 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.29) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n8 / name :op1 "EREG"~e.26))))) :op3 (l5 / level~e.30 :quant-of (n11 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.29) :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"~e.28))))) :ARG1-of (h / high-02~e.23)) :condition (s5 / statistical-test-91~e.0 :ARG2 (l3 / less-than :op1 0.05~e.9) :mod (s4 / side~e.7 :quant 2~e.5))) # ::id pmid_2337_4602.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among KRAS @-@ wild type cases , 81.4 % were seen in AREG @-@ high and 57.4 % in EREG @-@ high tumours , while of KRAS @-@ mutated cases only 63.9 % were observed in AREG @-@ high and only 35.7 % in EREG @-@ high tumours . # ::alignments 0-1.1.1.1.1 0-1.1.2.1.1 0-1.2.1.1.1 0-1.2.2.1.1 1-1.1.1.1.1.1.1.1.1 1-1.2.1.1.1.1.1.1.1 3-1.1.1.1.1.1.1.2 4-1.1.1.1.1.1.1.2 5-1.1.1.1 5-1.1.1.1.1.1 5-1.1.2.1 5-1.2.1.1.1.1 5-1.2.2.1 7-1.1.1.1.1.2.1 8-1.1.1.1.1.2 10-1.1.1 10-1.1.2 11-1.1.1.2.r 12-1.1.1.2.1.1.1.1 14-1.1.1.2.1 15-1.1 16-1.1.2.1.1.2.1 17-1.1.2.1.1.2 19-1.1.2.2.1.1.1.1 21-1.1.1.2.1 21-1.1.2.2.1 22-1.1.1.2 22-1.1.2.2 24-1 25-1.2.1.1.1.1.1.r 25-1.2.r 26-1.2.1.1.1.1.1.1.1 28-1.2.1.1.1.1.1.2 29-1.2.1.1 30-1.2.1.1.1.2.2 31-1.2.1.1.1.2.1 32-1.2.1.1.1.2 34-1.2.1 34-1.2.2 36-1.1.1.2.1.1.1.1 38-1.1.1.2.1 39-1.2 40-1.2.2.1.1.2.2 41-1.2.2.1.1.2.1 42-1.2.2.1.1.2 43-1.2.2.2.r 44-1.2.2.2 46-1.1.1.2.1 47-1.1.1.2 (c / contrast-01~e.24 :ARG1 (a / and~e.15 :op1 (s / see-01~e.10 :ARG1 (c2 / case-04~e.5 :ARG1-of (i / include-91~e.0 :ARG2 (c4 / case-04~e.5 :ARG1 (g / gene :name (n3 / name :op1 "KRAS"~e.1) :mod (w / wild-type~e.3,4))) :ARG3 (p / percentage-entity~e.8 :value 81.4~e.7))) :location~e.11 (t / tumor~e.22,47 :ARG1-of (h / high-02~e.14,21,38,46 :ARG2 (p5 / protein :name (n / name :op1 "AREG"~e.12,36))))) :op2 (s2 / see-01~e.10 :ARG1 (c3 / case-04~e.5 :ARG1-of (i3 / include-91~e.0 :ARG2 c4 :ARG3 (p2 / percentage-entity~e.17 :value 57.4~e.16))) :location (t2 / tumor~e.22 :ARG1-of (h2 / high-02~e.21 :ARG2 (p6 / protein :name (n2 / name :op1 "EREG"~e.19)))))) :ARG2~e.25 (a2 / and~e.39 :op1 (o / observe-01~e.34 :ARG1 (c5 / case-04~e.29 :ARG1-of (i2 / include-91~e.0 :ARG2 (c6 / case-04~e.5 :ARG1~e.25 (g2 / gene :name (n4 / name :op1 "KRAS"~e.1,26) :ARG2-of (m / mutate-01~e.28))) :ARG3 (p3 / percentage-entity~e.32 :value 63.9~e.31 :mod (o2 / only~e.30)))) :location t) :op2 (o3 / observe-01~e.34 :ARG1 (c7 / case-04~e.5 :ARG1-of (i4 / include-91~e.0 :ARG2 c6 :ARG3 (p4 / percentage-entity~e.42 :value 35.7~e.41 :mod o2~e.40))) :location~e.43 t2~e.44))) # ::id pmid_2337_4602.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , among BRAF @-@ wild type cases , 76.1 % were seen in AREG @-@ high and 50.7 % in EREG @-@ high tumours , while of BRAF @-@ mutated cases only two out of six ( 33.3 %) were observed in AREG @-@ high and none in EREG @-@ high tumours . # ::alignments 0-1.3 2-1.1.1.1.1 2-1.1.2.1.1 2-1.2.1.1.2 3-1.1.1.1.1.1.1.1.1 3-1.2.1.1.2.1.2.1.1 5-1.1.1.1.1.1.1.2 6-1.1.1.1.1.1.1.2 7-1.1.1.1 7-1.1.1.1.1.1 7-1.1.2.1 7-1.2.2.1 9-1.1.1.1.1.2.1 10-1.1.1.1.1.2 10-1.2.1.1.2.2 12-1.1.1 12-1.1.2 13-1.1.1.2.r 14-1.1.1.2.1.1.1.1 16-1.1.1.2.1 17-1.1 18-1.1.2.1.1.2.1 19-1.1.2.1.1.2 20-1.1.2.2.r 21-1.1.2.2.1.1.1.1 23-1.1.1.2.1 23-1.1.2.2.1 24-1.1.1.2 24-1.1.2.2 26-1 28-1.2.1.1.2.1.2.1.1 30-1.2.1.1.2.1.2.2 31-1.2.1.1 31-1.2.1.1.2.1 32-1.2.1.1.3 33-1.2.1.1.1 36-1.2.1.1.2.1.1 38-1.2.1.1.2.2.1 41-1.2.1 41-1.2.2 43-1.1.1.2.1.1.1.1 45-1.1.1.2.1 49-1.1.2.2.1.1.1.1 51-1.1.1.2.1 52-1.1.1.2 (c / contrast-01~e.26 :ARG1 (a / and~e.17 :op1 (s / see-01~e.12 :ARG1 (c2 / case-04~e.7 :ARG1-of (i / include-91~e.2 :ARG2 (c3 / case-04~e.7 :ARG1 (e / enzyme :name (n / name :op1 "BRAF"~e.3) :mod (w / wild-type~e.5,6))) :ARG3 (p / percentage-entity~e.10 :value 76.1~e.9))) :location~e.13 (t / tumor~e.24,52 :ARG1-of (h / high-02~e.16,23,45,51 :ARG2 (p4 / protein :name (n2 / name :op1 "AREG"~e.14,43))))) :op2 (s2 / see-01~e.12 :ARG1 (c4 / case-04~e.7 :ARG1-of (i3 / include-91~e.2 :ARG2 c3 :ARG3 (p2 / percentage-entity~e.19 :value 50.7~e.18))) :location~e.20 (t2 / tumor~e.24 :ARG1-of (h2 / high-02~e.23 :ARG2 (p5 / protein :name (n3 / name :op1 "EREG"~e.21,49)))))) :ARG2 (a2 / and :op1 (o / observe-01~e.41 :ARG1 (c5 / case-04~e.31 :quant 2~e.33 :ARG1-of (i2 / include-91~e.2 :ARG2 (c6 / case-04~e.31 :quant 6~e.36 :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF"~e.3,28) :ARG2-of (m / mutate-01~e.30))) :ARG3 (p3 / percentage-entity~e.10 :value 33.3~e.38)) :mod (o2 / only~e.32)) :location t) :op2 (o3 / observe-01~e.41 :ARG1 (c7 / case-04~e.7 :polarity - :ARG1-of i2) :location t2)) :ARG1-of (r / resemble-01~e.0)) # ::id pmid_2337_4602.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regarding the primary location , 64.8 % of KRAS mutations ( p= 0.07 ) and 58 % of PIK3CA mutations ( p= 0.036 ) occurred in left @-@ sided colorectal tumours , whereas four ( 66.7 %) of BRAF mutations in right @-@ sided colon carcinomas ( p= 0.024 ) . # ::alignments 0-1.3.r 2-1.3.1 3-1.3 5-1.1.1.1.2.1 6-1.1.1.1.2 8-1.1.1.1.1.1.1.1 9-1.1.1 9-1.1.1.1.1 11-1.1.1.2 12-1.1.1.2.1 14-1.1 15-1.1.2.1.2.1 16-1.1.2.1.2 16-1.2.3.2 18-1.1.2.1.1.1.1.1 19-1.1.2 19-1.1.2.1.1 21-1.1.2.2 22-1.1.2.2.1 26-1.1.3.2.1 28-1.1.3.2 29-1.1.3.1 30-1.1.3 32-1 33-1.2.1 35-1.2.3.2.1 38-1.2.3.1.1.1.1 39-1.2 39-1.2.3.1 40-1.2.2.r 41-1.2.2.1.2 43-1.2.2.1 44-1.2.2.1.1 45-1.2.2 47-1.2.4 48-1.2.4.1 (c / contrast-01~e.32 :ARG1 (a2 / and~e.14 :op1 (m2 / mutate-01~e.9 :ARG1-of (i / include-91 :ARG2 (m / mutate-01~e.9 :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS"~e.8))) :ARG3 (p / percentage-entity~e.6 :value 64.8~e.5)) :ARG1-of (s3 / statistical-test-91~e.11 :ARG2 0.07~e.12)) :op2 (m9 / mutate-01~e.19 :ARG1-of (i2 / include-91 :ARG2 (m3 / mutate-01~e.19 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.18))) :ARG3 (p2 / percentage-entity~e.16 :value 58~e.15)) :ARG1-of (s4 / statistical-test-91~e.21 :ARG2 0.036~e.22)) :location (t / tumor~e.30 :mod (c2 / colorectal~e.29) :location (s / side~e.28 :ARG1-of (l / left-20~e.26)))) :ARG2 (m7 / mutate-01~e.39 :quant 4~e.33 :location~e.40 (c3 / carcinoma~e.45 :location (s2 / side~e.43 :poss (c4 / colon~e.44) :ARG1-of (r / right-04~e.41))) :ARG1-of (i3 / include-91 :ARG2 (m6 / mutate-01~e.39 :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF"~e.38))) :ARG3 (p3 / percentage-entity~e.16 :value 66.7~e.35)) :ARG1-of (s5 / statistical-test-91~e.47 :ARG2 0.024~e.48)) :topic~e.0 (l2 / location~e.3 :mod (p7 / primary~e.2))) # ::id pmid_2337_4602.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok mRNA RQ values were examined as continuous variables and significant correlations at Spearmann ’s R> 0.4 were found between AREG and EREG mRNA ( R= 0.63 , 95 % CI 0.53 @-@ 0.72 , p= 0.0005 ) . # ::alignments 0-1.1.1.2.1.1 2-1.1.1 2-1.2.2 4-1.1 5-1.1.2.r 6-1.1.2.1 7-1.1.2 8-1 9-1.2.1.3 10-1.2.1 11-1.2.2.1.r 12-1.2.2.1.1.1 15-1.2.2.2.1 17-1.2 18-1.2.1.4.1.2.1 19-1.2.1.1.2.1.1.1 20-1.2.1.4.1 20-1.2.1.4.1.2.1 21-1.2.1.2.2.1.1.1 22-1.2.1.1.1.1 22-1.2.1.2.1.1 25-1.2.1.4.1.1.1 27-1.2.1.4.1.2.2.1 28-1.2.1.4.1.2.2 29-1.2.1.4.1.2 29-1.2.1.4.1.2.3 29-1.2.1.4.1.2.3.r 30-1.2.1.4.1.2.1.1 32-1.2.1.4.1.2.1.2 34-1.3 35-1.3.1 (a / and~e.8 :op1 (e / examination-02~e.4 :ARG1 (v / value~e.2 :ARG2-of (r / result-01 :ARG1 (q / quantify-01 :ARG1-of (r6 / relative-05))) :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.0))) :manner~e.5 (v2 / variable~e.7 :ARG1-of (c / continue-01~e.6))) :op2 (f / find-01~e.17 :ARG1 (c2 / correlate-01~e.10 :ARG1 (n8 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.22) :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "AREG"~e.19)))) :ARG2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.22) :ARG0-of (e3 / encode-01 :ARG1 (p3 / protein :name (n6 / name :op1 "EREG"~e.21)))) :ARG1-of (s / significant-02~e.9) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.20 :op1 (r5 / rho :value 0.63~e.25) :op2 (i / interval~e.29 :value (b2 / between~e.18,20 :op1 0.53~e.30 :op2 0.72~e.32) :quant (p / percentage-entity~e.28 :value 95~e.27) :mod~e.29 (c3 / confidence~e.29))))) :manner (v3 / value~e.2 :mod~e.11 (p5 / person :name (n / name :op1 "Spearmann"~e.12)) :value (m2 / more-than :op1 0.4~e.15) :mod (s3 / string-entity :value "R"))) :ARG1-of (s2 / statistical-test-91~e.34 :ARG2 0.0005~e.35)) # ::id pmid_2337_4602.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Factors with predictive significance at univariate analysis # ::alignments 1-1 2-1.1.r 3-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1 7-1.1.2 (f / factor~e.1 :ARG1-of~e.2 (s / significant-02~e.4 :ARG0-of (p / predict-01~e.3) :time~e.5 (a / analyze-01~e.7 :mod (u / univariate~e.6)))) # ::id pmid_2337_4602.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At a median follow @-@ up of 73.6 months , 215 patients ( 95.1 %) had experienced disease progression and 163 ( 93.1 %) had died . # ::alignments 2-1.3.1 3-1.3 3-1.3.2 3-1.3.2.r 5-1.3 6-1.3.2.1.r 7-1.3.2.1.1 8-1.3.2.1.2 10-1.1.1.1 11-1.1.1.2.1 13-1.1.1.3.1.1 15-1.1 16-1.1 17-1.1.2.1 18-1.1.2 19-1 20-1.2.1.1 22-1.2.1.3.1.1 25-1.2 (a / and~e.19 :op1 (e / experience-01~e.15,16 :ARG0 (p3 / person :quant 215~e.10 :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.11)) :ARG1-of (m3 / mean-01 :ARG2 (p / percentage-entity :value 95.1~e.13))) :ARG1 (p5 / progress-01~e.18 :ARG1 (d / disease~e.17))) :op2 (d2 / die-01~e.25 :ARG1 (p6 / person :quant 163~e.20 :ARG0-of h :ARG1-of (m4 / mean-01 :ARG2 (p2 / percentage-entity :value 93.1~e.22)))) :time (f / follow-up-03~e.3,5 :mod (m / median~e.2) :time~e.3 (a2 / after~e.3 :op1~e.6 (t / temporal-quantity :quant 73.6~e.7 :unit (m2 / month~e.8))))) # ::id pmid_2337_4602.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The median survival was was 27 months ( 95 % CI 25 @–@ 31 ) . # ::alignments 1-1.3.1 2-1.3 3-1.3.r 4-1.3.r 5-1.1 6-1.2 8-1.4.2.1 9-1.4.2 10-1.4 10-1.4.3 10-1.4.3.r 11-1.4.1.1.1 13-1.4.1.2.1 (t2 / temporal-quantity :quant 27~e.5 :unit (m / month~e.6) :domain~e.3,4 (s / survive-01~e.2 :mod (m2 / median~e.1)) :condition (i / interval~e.10 :value (b / between :op1 (t / temporal-quantity :quant 25~e.11 :unit m) :op2 (t3 / temporal-quantity :quant 31~e.13 :unit m)) :quant (p / percentage-entity~e.9 :value 95~e.8) :mod~e.10 (c / confidence~e.10))) # ::id pmid_2337_4602.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At univariate analysis , in the present cohort of patients treated with cetuximab the presence of BRAF mutations was significantly associated with an 8.1 @-@ fold increased risk of death compared to patients harbouring BRAF @-@ wild type tumours . # ::alignments 1-1.5.1 2-1.5 6-1.1 6-1.1.2.1 7-1.1.2 8-1.1.2.2.r 9-1.1.2.2.1.1 10-1.1.2.2.2 11-1.1.2.2.2.1.r 12-1.1.2.2.2.1.1.1 14-1.1 15-1.1.1.r 16-1.1.1.1.1.1 17-1.1.1 19-1.3 20-1 21-1.2.r 23-1.2.2.1.1 25-1.2.2.1 26-1.2.2 27-1.2 28-1.2.1.r 29-1.2.1 30-1.4.r 32-1.4.1 33-1.4.2 34-1.4.2.1.1.1.1 36-1.4.2.1.1.2 37-1.4.2.1.1.2 38-1.4.2.1 (a / associate-01~e.20 :ARG1 (p / present-02~e.6,14 :ARG1~e.15 (m / mutate-01~e.17 :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF"~e.16))) :ARG2 (c / cohort~e.7 :ARG1-of (p2 / present-02~e.6) :consist-of~e.8 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.9)) :ARG1-of (t / treat-03~e.10 :ARG3~e.11 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"~e.12)))))) :ARG2~e.21 (r / risk-01~e.27 :ARG1~e.28 (d / die-01~e.29) :ARG1-of (i / increase-01~e.26 :ARG2 (p5 / product-of~e.25 :op1 8.1~e.23))) :ARG1-of (s / significant-02~e.19) :compared-to~e.30 (p6 / person :ARG0-of h~e.32 :ARG0-of (h2 / harbor-01~e.33 :ARG1 (t2 / tumor~e.38 :mod (e / enzyme :name (n3 / name :op1 "BRAF"~e.34) :mod (w / wild-type~e.36,37))))) :time (a2 / analyze-01~e.2 :mod (u / univariate~e.1))) # ::id pmid_2337_4602.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When all types of mutations were pooled for each gene , KRAS ( HR 1.28 , p= 0.14 ) , NRAS ( HR 1.43 , p= 0.36 ) and PIK3CA ( HR 1.27 , p= 0.25 ) mutations did not have prognostic @/@ predictive utility . # ::alignments 0-1.4.r 1-1.4.1.1.1 2-1.4.1.1 3-1.4.1.1.r 4-1.2.2 4-1.4.1 6-1.4 7-1.4.2.r 8-1.4.2.1 9-1.4.2 11-1.2.1.1.1.1 13-1.2.1.1.2 14-1.2.1.1.2.1 16-1.2.1.2 17-1.2.1.2.1 20-1.2.2.1.1.1 22-1.2.2.2 23-1.2.2.2.1 25-1.2.2.3 26-1.2.2.3.1 28-1.2 29-1.2.3.1.1.1 31-1.2.1.1.2.2 31-1.2.3.2 32-1.2.3.2.1 34-1.2.3.3 35-1.2.3.3.1 37-1.2.1 37-1.2.3 39-1.1 39-1.1.r 40-1 41-1.3.1 43-1.3.2 44-1.3 (h / have-03~e.40 :polarity~e.39 -~e.39 :ARG0 (a2 / and~e.28 :op1 (m / mutate-01~e.37 :ARG2 (e2 / enzyme :name (n / name :op1 "KRAS"~e.11) :mod (r / ratio-of~e.13 :quant 1.28~e.14 :op1 (h2 / hazard~e.31))) :ARG1-of (s / statistical-test-91~e.16 :ARG2 0.14~e.17)) :op2 (m3 / mutate-01~e.4 :ARG2 (e3 / enzyme :name (n2 / name :op1 "NRAS"~e.20)) :mod (r2 / ratio-of~e.22 :quant 1.43~e.23 :op1 h2) :ARG1-of (s2 / statistical-test-91~e.25 :ARG2 0.36~e.26)) :op3 (m4 / mutate-01~e.37 :ARG2 (g2 / gene :name (n3 / name :op1 "PIK3CA"~e.29)) :mod (r3 / ratio-of~e.31 :quant 1.27~e.32 :op1 h2) :ARG1-of (s3 / statistical-test-91~e.34 :ARG2 0.25~e.35))) :ARG1 (u / utility~e.44 :mod (p / prognostic~e.41) :ARG0-of (p2 / predict-01~e.43)) :time~e.0 (p3 / pool-01~e.6 :ARG1 (m2 / mutate-01~e.4 :mod~e.3 (t / type~e.2 :mod (a / all~e.1))) :topic~e.7 (g / gene~e.9 :mod (e / each~e.8)))) # ::id pmid_2337_4602.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , when types of mutations were analysed separately for each gene , KRAS codon 12 mutations were predictive for increased risk of death ( HR 1.62 , p= 0.014 ) . # ::alignments 0-1 2-1.1.3.r 3-1.1.3.1.1 4-1.1.3.1.1.r 5-1.1.3.1 7-1.1.3 8-1.1.3.2 9-1.1.3.2.1.r 10-1.1.3.2.1.1 11-1.1.3.2.1 13-1.1.1.1.2.1.1 14-1.1.1.1 15-1.1.1.1.1 16-1.1.1 18-1.1 21-1.1.2 22-1.1.2.1.r 23-1.1.2.1 25-1.1.1.2 25-1.1.1.2.2 25-1.1.1.2.2.r 26-1.1.1.2.1 28-1.1.4 29-1.1.4.1 (c / contrast-01~e.0 :ARG2 (p / predict-01~e.18 :ARG0 (m / mutate-01~e.16 :ARG1 (c2 / codon~e.14 :mod 12~e.15 :part-of (e / enzyme :name (n / name :op1 "KRAS"~e.13))) :mod (r2 / ratio-of~e.25 :quant 1.62~e.26 :op1~e.25 (h / hazard~e.25))) :ARG1 (r / risk-01~e.21 :ARG2~e.22 (d / die-01~e.23)) :time~e.2 (a / analyze-01~e.7 :ARG1 (m2 / mutate-01~e.5 :mod~e.4 (t / type~e.3)) :manner (s / separate-02~e.8 :ARG1~e.9 (g / gene~e.11 :mod (e2 / each~e.10)))) :ARG1-of (s2 / statistical-test-91~e.28 :ARG2 0.014~e.29))) # ::id pmid_2337_4602.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among parameters studied for gene expression , only the 25 th percentile of AREG mRNA values and the 75 th percentile of EREG mRNA values dichotomized cases into groups with different outcome and were selected as optimal cut @-@ offs . # ::alignments 0-1.1.1.1.1.1 0-1.1.1.2.1.1 0-1.1.1.3 1-1.1.1.3.1 2-1.1.1.3.1.1 3-1.1.1.3.1.1.1.r 4-1.1.1.3.1.1.1.1 5-1.1.1.3.1.1.1 7-1.1.1.1.1.2 7-1.1.1.2.1.2 9-1.1.1.1.1.3.1 11-1.1.1.1.1 11-1.1.1.2.1 13-1.1.1.1.1.1.1.2.1.1.1 14-1.1.1.1.1.1.1.1.1 15-1.1.1.1 15-1.1.1.2 16-1.1.1 18-1.1.1.2.1.3.1 20-1.1.1.1.1 22-1.1.1.2.1.1.1.2.1.1.1 23-1.1.1.2.1.1.1.1.1 24-1.1.1.1 25-1.1 26-1.1.2 27-1.1.3.r 28-1.1.3 30-1.1.3.1.1.1 31-1.1.3.1.1 32-1 34-1.2 35-1.2.2.r 36-1.2.2.1 37-1.2.2.2 39-1.2.2.2 (a / and~e.32 :op1 (d / dichotomize-00~e.25 :ARG0 (a2 / and~e.16 :op1 (v / value~e.15,24 :mod (p / percentile~e.11,20 :ARG3-of (i / include-91~e.0 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.14) :ARG0-of (e2 / encode-01 :ARG1 (p5 / protein :name (n3 / name :op1 "AREG"~e.13))))) :mod (o2 / only~e.7) :ord (o5 / ordinal-entity :value 25~e.9))) :op2 (v2 / value~e.15 :mod (p2 / percentile~e.11 :ARG3-of (i2 / include-91~e.0 :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.23) :ARG0-of (e3 / encode-01 :ARG1 (p4 / protein :name (n4 / name :op1 "EREG"~e.22))))) :mod (o3 / only~e.7) :ord (o6 / ordinal-entity :value 75~e.18))) :ARG1-of (i3 / include-91~e.0 :ARG2 (p3 / parameter~e.1 :ARG1-of (s2 / study-01~e.2 :purpose~e.3 (e / express-03~e.5 :ARG1 (g2 / gene~e.4)))))) :ARG1 (c / case-04~e.26) :ARG2~e.27 (g / group~e.28 :ARG0-of (h / have-03 :ARG1 (o / outcome~e.31 :ARG1-of (d2 / differ-02~e.30))))) :op2 (s / select-01~e.34 :ARG1 a2 :ARG3~e.35 (t / thing :mod (o4 / optimal~e.36) :ARG3-of (c2 / cut-off-04~e.37,39)))) # ::id pmid_2337_4602.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok None of EGF , TGFa , EGFR mRNA levels disclosed cut @-@ off points of prognostic significance . # ::alignments 0-1.1.4 1-1.1.4.r 2-1.1.1.1.2.1.1.1 4-1.1.2.1.2.1.1.1 6-1.1.3.1.2.1.1.1 7-1.1.1.1.1.1 7-1.1.2.1.1.1 7-1.1.3.1.1.1 8-1.1.1 8-1.1.2 8-1.1.3 9-1 10-1.2.1 12-1.2.1 13-1.2 15-1.2.2.1.1 16-1.2.2.1 16-1.2.2.1.2 16-1.2.2.1.2.r (d / disclose-01~e.9 :ARG0 (a / and :op1 (l / level~e.8 :quant-of (n / nucleic-acid :name (n2 / name :op1 "mRNA"~e.7) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n3 / name :op1 "EGF"~e.2))))) :op2 (l2 / level~e.8 :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.7) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n5 / name :op1 "TGFa"~e.4))))) :op3 (l3 / level~e.8 :quant-of (n10 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.7) :ARG0-of (e4 / encode-01 :ARG1 (e / enzyme :name (n7 / name :op1 "EGFR"~e.6))))) :quant~e.1 (n8 / none~e.0)) :ARG1 (p4 / point~e.13 :mod (c / cut-off-04~e.10,12) :ARG0-of (h / have-03 :ARG1 (t / thing~e.16 :mod (p5 / prognostic~e.15) :ARG1-of~e.16 (s / significant-02~e.16))))) # ::id pmid_2337_4602.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cetuximab therapy in patients harbouring AREG @-@ high ( HR 0.47 , p= 0.0002 ) or EREG @-@ high ( HR 0.45 , p= 0.0009 ) tumours resulted in reduced risk of death . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.2.1 4-1.1.2.1 5-1.1.2.1.1.1.1.1.1.1 7-1.1.2.1.1.1.1 9-1.1.2.1.1.1.2 9-1.1.2.1.1.1.2.2 9-1.1.2.1.1.1.2.2.r 10-1.1.2.1.1.1.2.1 12-1.1.2.1.1.1.3 13-1.1.2.1.1.1.3.1 15-1.1.2.1.1 16-1.1.2.1.1.2.1.1.1.1 18-1.1.2.1.1.2.1 20-1.1.2.1.1.2.2 20-1.1.2.1.1.2.2.2 20-1.1.2.1.1.2.2.2.r 21-1.1.2.1.1.2.2.1 23-1.1.2.1.1.2.3 24-1.1.2.1.1.2.3.1 26-1.1.2.1.1.1 26-1.1.2.1.1.2 27-1 28-1.2.r 29-1.2.2 30-1.2 31-1.2.1.r 32-1.2.1 (r / result-01~e.27 :ARG1 (t / therapy~e.1 :mod (s / small-molecule :name (n / name :op1 "Cetuximab"~e.0)) :location~e.2 (p / person :ARG0-of (h / harbor-01~e.4 :ARG1 (o / or~e.15 :op1 (t2 / tumor~e.26 :ARG1-of (h2 / high-02~e.7 :ARG2 (p2 / protein :name (n2 / name :op1 "AREG"~e.5))) :mod (r4 / ratio-of~e.9 :quant 0.47~e.10 :op1~e.9 (h5 / hazard~e.9)) :ARG1-of (s2 / statistical-test-91~e.12 :ARG2 0.0002~e.13)) :op2 (t3 / tumor~e.26 :ARG1-of (h3 / high-02~e.18 :ARG2 (p3 / protein :name (n3 / name :op1 "EREG"~e.16))) :mod (r5 / ratio-of~e.20 :quant 0.45~e.21 :op1~e.20 (h6 / hazard~e.20)) :ARG1-of (s3 / statistical-test-91~e.23 :ARG2 0.0009~e.24)))) :ARG0-of (h4 / have-rel-role-91 :ARG2 (p6 / patient~e.3)))) :ARG2~e.28 (r2 / risk-01~e.30 :ARG2~e.31 (d / die-01~e.32) :ARG1-of (r3 / reduce-01~e.29))) # ::id pmid_2337_4602.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGFR , EGF , TGFa mRNA expression had no significant prognostic @/@ predictive value , either in the entire cohort or in the KRAS @-@ wild type versus KRAS mutant cases . # ::alignments 0-1.2.1.2.1.1.1.1 2-1.2.1.2.1.2.1.1 4-1.2.1.2.1.3.1.1 5-1.2.1.1.1 6-1.2 7-1 8-1.1 8-1.1.r 9-1.3.1 10-1.3.2 12-1.3.3 13-1.3 16-1.4.r 18-1.4.1.1 19-1.4.1 20-1.4 23-1.4.2.1.1.1 23-1.4.2.2.1.1 25-1.4.2.1.2 26-1.4.2.1.2 28-1.4.2.1.1.1 28-1.4.2.2.1.1 29-1.4.2.2 29-1.4.2.2.2 29-1.4.2.2.2.r (h / have-03~e.7 :polarity~e.8 -~e.8 :ARG0 (e2 / express-03~e.6 :ARG1 (n / nucleic-acid :name (n2 / name :op1 "mRNA"~e.5) :ARG0-of (e3 / encode-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "EGFR"~e.0)) :op2 (p4 / protein :name (n4 / name :op1 "EGF"~e.2)) :op3 (p5 / protein :name (n5 / name :op1 "TGFa"~e.4)))))) :ARG1 (v / value~e.13 :ARG1-of (s / significant-02~e.9) :mod (p / prognostic~e.10) :ARG0-of (p2 / predict-01~e.12)) :location~e.16 (o2 / or~e.20 :op1 (c / cohort~e.19 :mod (e4 / entire~e.18)) :op2 (c2 / compare-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "KRAS"~e.23,28) :mod (w / wild-type~e.25,26)) :ARG2 (e6 / enzyme~e.29 :name (n7 / name :op1 "KRAS"~e.23,28) :ARG2-of~e.29 (m / mutate-01~e.29))))) # ::id pmid_2337_4602.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regarding objective tumour response to any line of cetuximab @-@ based therapy , tumoural AREG and EREG mRNA expression levels were associated with tumour shrinkage as continuous variables . # ::alignments 0-1.4.r 1-1.4.3 2-1.4.1 3-1.4 4-1.4.2.r 5-1.4.2.1 6-1.4.2 7-1.4.2.2.r 8-1.4.2.2.1.1.1.1 10-1.4.2.2.1 11-1.4.2.2 14-1.1.1.1.1.2.1.1.1 15-1.1.1.1 16-1.1.1.1.2.2.1.1.1 17-1.1.1.1.1.1.1 17-1.1.1.1.2.1.1 18-1.1.1 19-1.1 21-1 22-1.2.r 23-1.2.1 24-1.2 25-1.3.r 26-1.3.1 27-1.3 (a / associate-01~e.21 :ARG1 (l / level~e.19 :quant-of (e / express-03~e.18 :ARG1 (a2 / and~e.15 :op1 (n6 / nucleic-acid :name (n / name :op1 "mRNA"~e.17) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG"~e.14)))) :op2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.17) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "EREG"~e.16)))))) :location (t / tumor)) :ARG2~e.22 (s / shrink-01~e.24 :ARG1 t~e.23) :purpose~e.25 (v / variable~e.27 :ARG1-of (c / continue-01~e.26)) :topic~e.0 (r3 / respond-01~e.3 :ARG0 t~e.2 :ARG1~e.4 (l2 / line~e.6 :mod (a3 / any~e.5) :part-of~e.7 (t2 / therapy~e.11 :ARG1-of (b / base-02~e.10 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "cetuximab"~e.8))))) :mod (o / objective~e.1))) # ::id pmid_2337_4602.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AREG was not statistically significant as categorical variable but EREG mRNA at the 75 th percentile was associated with a 2.26 @-@ fold increased likelihood of tumour response to cetuximab compared to tumours with lower EREG mRNA expression . # ::alignments 0-1.1.1.1 2-1.1.2.1 2-1.1.2.1.r 4-1.1 4-1.1.2 4-1.1.2.r 5-1.1.2.3.r 6-1.1.2.3.1 7-1.1.2.3 8-1 9-1.2.2.1.1.1 10-1.2.1.1 13-1.2.3.1.1 15-1.2.3 17-1.2.4 20-1.2.4.1.2.1.1 22-1.2.4.1.2.1 23-1.2.4.1.2 25-1.2.4.1.2.1 26-1.2.4.1.1.1 27-1.2.4.1.1 28-1.2.4.1.1.2.r 29-1.2.4.1.1.2.1.1 30-1.2.4.1.3.r 32-1.2.4.1.3 33-1.2.4.1.3.1.r 34-1.2.4.1.3.1.3 34-1.2.4.1.3.1.3.1 34-1.2.4.1.3.1.3.1.r 35-1.2.4.1.3.1.2.1.1 36-1.2.4.1.3.1.1.1.1 37-1.2.4.1.3.1 (c / contrast-01~e.8 :ARG1 (p / protein~e.4 :name (n2 / name :op1 "AREG"~e.0) :ARG1-of~e.4 (s / significant-02~e.4 :polarity~e.2 -~e.2 :mod (s2 / statistic) :purpose~e.5 (v / variable~e.7 :mod (c2 / categorical~e.6)))) :ARG2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.10) :ARG0-of (e2 / encode-01 :ARG1 (p2 / protein :name (n4 / name :op1 "EREG"~e.9))) :location (p3 / percentile~e.15 :ord (o / ordinal-entity :value 75~e.13)) :ARG1-of (a / associate-01~e.17 :ARG2 (l / likely-01 :ARG1 (r / respond-01~e.27 :ARG0 (t / tumor~e.26) :ARG1~e.28 (s3 / small-molecule :name (n / name :op1 "cetuximab"~e.29))) :ARG1-of (i / increase-01~e.23 :ARG2 (p4 / product-of~e.22,25 :op1 2.26~e.20)) :compared-to~e.30 (t2 / tumor~e.32 :ARG3-of~e.33 (e / express-03~e.37 :ARG1 (n8 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.36)) :ARG2 (p5 / protein :name (n6 / name :op1 "EREG"~e.35)) :ARG2-of (l2 / low-04~e.34 :degree~e.34 (m / more~e.34)))))))) # ::id pmid_2337_4602.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AREG failed to predict response in either KRAS wild type or mutated cases . # ::alignments 0-1.1.1.1 1-1 3-1.2 4-1.2.2 5-1.2.2.1.r 7-1.2.2.1.1.1.1.1 7-1.2.2.1.2.1.1.1 8-1.2.2.1.1.1.2 9-1.2.2.1.1.1.2 10-1.2.2.1 11-1.2.2.1.2.1.2 12-1.2.2.1.1 12-1.2.2.1.2 (f / fail-01~e.1 :ARG1 (p / protein :name (n / name :op1 "AREG"~e.0)) :ARG2 (p2 / predict-01~e.3 :ARG0 p :ARG1 (r / respond-01~e.4 :prep-in~e.5 (o / or~e.10 :op1 (c / case-04~e.12 :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS"~e.7) :mod (w / wild-type~e.8,9))) :op2 (c2 / case-04~e.12 :ARG1 (e2 / enzyme :name (n3 / name :op1 "KRAS"~e.7) :ARG2-of (m / mutate-01~e.11))))))) # ::id pmid_2337_4602.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression levels of EREG in the tumours of responding and non @-@ responding patients by KRAS gene status is depicted in a waterfall plot ( Figure 1 ) . # ::alignments 1-1.1.1 2-1.1 3-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.2.r 7-1.1.1.2 8-1.1.1.2.1.r 9-1.1.1.2.1.1.1 9-1.1.1.2.1.2.1 10-1.1.1.2.1 11-1.1.1.2.1.2.1.1 11-1.1.1.2.1.2.1.1.r 13-1.1.1.2.1.1.1 13-1.1.1.2.1.2.1 14-1.1.1.2.1.1.2.1 16-1.1.1.2.1.3.1.1.1.1 17-1.1.1.2.1.3.1.1 18-1.1.1.2.1.3.1 20-1 21-1.2.r 23-1.2.1 24-1.2 26-1.3.1 28-1.3.1.1 (d / depict-01~e.20 :ARG1 (l / level~e.2 :quant-of (e / express-03~e.1 :ARG2~e.3 (p / protein :name (n / name :op1 "EREG"~e.4)) :ARG3~e.5 (t / tumor~e.7 :source~e.8 (a / and~e.10 :op1 (p2 / person :ARG0-of (r / respond-01~e.9,13) :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient~e.14))) :op2 (p3 / person :ARG0-of (r2 / respond-01~e.9,13 :polarity~e.11 -~e.11) :ARG0-of h) :ARG1-of (s / say-01 :ARG0 (s2 / status~e.18 :poss (g / gene~e.17 :name (n2 / name :op1 "KRAS"~e.16)))))))) :location~e.21 (p4 / plot~e.24 :mod (w / waterfall~e.23)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.26 :mod 1~e.28))) # ::id pmid_2337_4602.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of note , in an exploratory analysis , the predictive significance for objective response was maintained only in KRAS mutated CRC , in which EREG had an odds ratio for response of 5.4 ( 95 % CI 1.2 @-@ 23.8 , p= 0.024 ) . # ::alignments 1-1 3-1.1.r 5-1.1.3.2 6-1.1.3 9-1.1.1.2 10-1.1.1 11-1.1.1.1.r 12-1.1.1.1.1 13-1.1.1.1 15-1.1 16-1.1.2.4 18-1.1.2.2.1.1.1 19-1.1.2.2 20-1.1.2.1.1 24-1.1.2.3.1.1.1 25-1.1.2.3 27-1.1.2.3.2.1.1 28-1.1.2.3.2.1 29-1.1.2.3.2.1.2.r 30-1.1.2.3.2.1.2 31-1.1.2.3.2.2 32-1.1.2.3.2.2.1 34-1.1.2.3.2.3.2.1 35-1.1.2.3.2.3.2 36-1.1.2.3.2.3 36-1.1.2.3.2.3.1 36-1.1.2.3.2.3.1.r 36-1.1.2.3.2.3.3 36-1.1.2.3.2.3.3.r 37-1.1.2.3.2.3.1.1 39-1.1.2.3.2.3.1.2 41-1.1.4 42-1.1.4.1 (n / note-02~e.1 :ARG1~e.3 (m / maintain-01~e.15 :ARG1 (s / significant-02~e.10 :ARG1~e.11 (r / respond-01~e.13 :mod (o / objective~e.12)) :ARG0-of (p2 / predict-01~e.9)) :location (d / disease :name (n2 / name :op1 "CRC"~e.20) :mod (m2 / mutate-01~e.19 :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS"~e.18))) :location-of (h / have-03~e.25 :ARG0 (p3 / protein :name (n4 / name :op1 "EREG"~e.24)) :ARG1 (e3 / equal-01 :ARG1 (r2 / ratio~e.28 :mod (o2 / odds~e.27) :prep-for~e.29 (r3 / respond-01~e.30)) :ARG2 (r4 / ratio-of~e.31 :op1 5.4~e.32) :mod (i / interval~e.36 :quant~e.36 (v / value-interval~e.36 :op1 1.2~e.37 :op2 23.8~e.39) :mod (p4 / percentage-entity~e.35 :quant 95~e.34) :mod~e.36 (c / confidence~e.36)))) :mod (o3 / only~e.16)) :time (a / analyze-01~e.6 :quant 1 :ARG0-of (e2 / explore-01~e.5)) :ARG1-of (s2 / statistical-test-91~e.41 :ARG2 0.024~e.42))) # ::id pmid_2337_4602.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By contrast , in KRAS @-@ wild type tumours EREG failed to significantly predict for response to therapy ( OR 2.2 , 95 % CI 0.83 @-@ 5.86 , p= 0.11 ) . # ::alignments 1-1 3-1.1.r 4-1.1.3.1.1.1 6-1.1.3.1.2 7-1.1.3.1.2 8-1.1.3 9-1.1.1.1.1 10-1.1 12-1.1.2.3 13-1.1.2 14-1.1.2.2.r 15-1.1.2.2 16-1.1.2.2.1.r 17-1.1.2.2.1 20-1.1.5.1 22-1.1.4.1.1 23-1.1.4.1 24-1.1.4 24-1.1.4.2 24-1.1.4.2.r 24-1.1.4.3 24-1.1.4.3.r 25-1.1.4.2.1 27-1.1.4.2.2 29-1.1.6 30-1.1.6.1 (c / contrast-01~e.1 :ARG2~e.3 (f / fail-01~e.10 :ARG1 (p2 / protein :name (n / name :op1 "EREG"~e.9)) :ARG2 (p3 / predict-01~e.13 :ARG0 p2 :ARG1~e.14 (r / respond-01~e.15 :ARG1~e.16 (t / therapy~e.17)) :ARG1-of (s / significant-02~e.12)) :location (t2 / tumor~e.8 :mod (e / enzyme :name (n2 / name :op1 "KRAS"~e.4) :mod (w / wild-type~e.6,7))) :mod (i / interval~e.24 :mod (p4 / percentage-entity~e.23 :quant 95~e.22) :quant~e.24 (v / value-interval~e.24 :op1 0.83~e.25 :op2 5.86~e.27) :mod~e.24 (c2 / confidence~e.24)) :mod (r2 / ratio :quant 2.2~e.20 :mod (o / odds)) :ARG1-of (s2 / statistical-test-91~e.29 :ARG2 0.11~e.30))) # ::id pmid_2337_4602.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok EGF , TGFa and EGFR mRNA expression had no predictive utility for response to cetuximab in the whole cohort , neither in KRAS wild @-@ type or KRAS mutated cases . # ::alignments 0-1.2.1.2.1.1.1.1 2-1.2.1.2.1.2.1.1 3-1.2.1.2.1 4-1.2.1.2.1.3.1.1 5-1.2.1.1.1 6-1.2 7-1 8-1.1 8-1.1.r 9-1.3.1 10-1.3 11-1.3.1.1.r 12-1.3.1.1 13-1.3.1.1.1.r 14-1.3.1.1.1.1.1 15-1.4.r 17-1.4.1 18-1.4 20-1.1.r 21-1.5.r 22-1.5.1.1.1.1 22-1.5.2.1.1.1 23-1.5.1.1.2 25-1.5.1.1.2 26-1.5 27-1.5.1.1.1.1 27-1.5.2.1.1.1 28-1.5.2.1.2 29-1.5.1 29-1.5.2 (h / have-03~e.7 :polarity~e.8,20 -~e.8 :ARG0 (e2 / express-03~e.6 :ARG1 (n / nucleic-acid :name (n2 / name :op1 "mRNA"~e.5) :ARG0-of (e3 / encode-01 :ARG1 (a / and~e.3 :op1 (p / protein :name (n3 / name :op1 "EGF"~e.0)) :op2 (p2 / protein :name (n4 / name :op1 "TGFa"~e.2)) :op2 (e / enzyme :name (n5 / name :op1 "EGFR"~e.4)))))) :ARG1 (u / utility~e.10 :ARG0-of (p4 / predict-01~e.9 :ARG1~e.11 (r2 / respond-01~e.12 :ARG1~e.13 (s / small-molecule :name (n6 / name :op1 "cetuximab"~e.14))))) :location~e.15 (c2 / cohort~e.18 :mod (w / whole~e.17)) :topic~e.21 (o / or~e.26 :op1 (c / case-04~e.29 :ARG1 (e4 / enzyme :name (n7 / name :op1 "KRAS"~e.22,27) :mod (w2 / wild-type~e.23,25))) :op2 (c3 / case-04~e.29 :ARG1 (e5 / enzyme :name (n8 / name :op1 "KRAS"~e.22,27) :ARG2-of (m / mutate-01~e.28))))) # ::id pmid_2337_4602.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All factors with potential predictive utility for cetuximab benefit are summarized in Table 3 @ . # ::alignments 0-1.1.1 1-1.1 4-1.1.2.1 5-1.1.2 6-1.1.2.1.1.r 7-1.1.2.1.1.1.1.1 8-1.1.2.1.1 10-1 12-1.2.1 14-1.2.1.1 (s / summarize-01~e.10 :ARG1 (f / factor~e.1 :mod (a / all~e.0) :poss (u / utility~e.5 :ARG0-of (p / predict-01~e.4 :ARG1~e.6 (b / benefit-01~e.8 :ARG0 (s2 / small-molecule :name (n / name :op1 "cetuximab"~e.7)))))) :ARG1-of (d / describe-01 :ARG0 (t / table~e.12 :mod 3~e.14))) # ::id pmid_2337_4602.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interactions and factors with predictive utility at multivariate analysis # ::alignments 1-1.1.1 2-1.1 3-1.1.2 5-1.2.1 6-1.2 8-1.3.1 9-1.3 (h / have-03 :ARG0 (a / and~e.2 :op1 (i / interact-01~e.1) :op2 (f / factor~e.3)) :ARG1 (u / utility~e.6 :ARG0-of (p / predict-01~e.5)) :location (a2 / analyze-01~e.9 :mod (m / multivariate~e.8))) # ::id pmid_2337_4602.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Significant interactions ( at the 1 % significance level ) between study variables for prognostic @/@ predictive utility ( survival , ORR ) were sought . # ::alignments 0-1.1.2 1-1.1 3-1.1.3.r 5-1.1.3.2.1 6-1.1.3.2 7-1.1.3.1 8-1.1.3 11-1.1.1.1 12-1.1.1 13-1.1.4.r 14-1.1.4.2 16-1.1.4.1 17-1.1.4 19-1.1.4.3.1.1 24-1 (s / seek-01~e.24 :ARG1 (i / interact-01~e.1 :ARG0 (v / variable~e.12 :mod (s4 / study-01~e.11)) :ARG1-of (s2 / significant-02~e.0) :prep-at~e.3 (l / level~e.8 :ARG1-of (s3 / significant-02~e.7) :mod (p / percentage-entity~e.6 :value 1~e.5)) :purpose~e.13 (u / utility~e.17 :ARG0-of (p2 / predict-01~e.16) :mod (p3 / prognostic~e.14) :ARG1-of (m / mean-01 :ARG2 (a / and :op1 (s5 / survive-01~e.19) :op2 (r / rate :mod (r2 / respond-01) :mod (o / overall))))))) # ::id pmid_2337_4602.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In terms of impact on survival , significant interactions were found between AREG mRNA levels and mutational status of the KRAS gene ( p= 0.0033 ) . # ::alignments 3-1.2 4-1.2.1.r 5-1.2.1 7-1.1.3 8-1.1 10-1 12-1.1.1.1.2.1.1.1 13-1.1.1.1.1.1 14-1.1.1 16-1.1.2.1 17-1.1.2 18-1.1.2.2.r 20-1.1.2.2.1.1 21-1.1.2.2 23-1.3 24-1.3.1 (f / find-01~e.10 :ARG1 (i / interact-01~e.8 :ARG0 (l / level~e.14 :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.13) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG"~e.12))))) :ARG1 (s2 / status~e.17 :mod (m / mutate-01~e.16) :poss~e.18 (g / gene~e.21 :name (n3 / name :op1 "KRAS"~e.20))) :ARG1-of (s / significant-02~e.7)) :topic (i2 / impact-01~e.3 :ARG1~e.4 (s3 / survive-01~e.5)) :ARG1-of (s4 / statistical-test-91~e.23 :ARG2 0.0033~e.24)) # ::id pmid_2337_4602.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High mRNA levels of AREG predicted for longer survival in patients with KRAS wild @-@ type ( median survival 33 vs. 15 months , p= 0.0005 , Figure 2 ) , but not in KRAS mutant tumours ( median survival 22 vs. 17 months , p= 0.64 ) . # ::alignments 0-1.1.1.2 1-1.1.1.1.1.1 2-1.1.1 4-1.1.1.1.2.1.1.1 5-1.1 5-1.2 6-1.1.2.r 7-1.1.2.2 7-1.1.2.2.1 7-1.1.2.2.1.r 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.2.1 12-1.1.2.1.1.1.1.1 13-1.1.2.1.1.1.2 15-1.1.2.1.1.1.2 17-1.1.2.3.1.1 18-1.1.2.3.1 18-1.1.2.3.2 19-1.1.2.3.1.2.1 20-1 20-1.1.2.3 21-1.1.2.3.2.1.1 22-1.1.2.3.2.1.2 24-1.1.2.4 25-1.1.2.4.1 27-1.1.2.3.3.1 29-1.1.2.3.3.1.1 33-1.2.3.2 34-1.2.1 34-1.2.1.r 36-1.2.3.1.1.1.1.1.1 37-1.2.3.1.1.1 38-1.1.2.1.1 38-1.2.3.1.1 40-1.1.2.3.1.1 41-1.2.3 41-1.2.3.2.1 41-1.2.3.2.2 42-1.2.3.2.1.1.1 43-1.2.3.2 44-1.2.3.2.2.2.1 45-1.2.3.2.2.2.2 47-1.2.3.3 48-1.2.3.3.1 (c / contrast-01~e.20 :ARG1 (p / predict-01~e.5 :ARG0 (l / level~e.2 :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.1) :ARG0-of (e3 / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "AREG"~e.4)))) :ARG1-of (h / high-02~e.0)) :ARG1~e.6 (s / survive-01~e.8 :ARG0~e.9 (p3 / person :poss (t / tumor~e.38 :mod (e / enzyme :name (n3 / name :op1 "KRAS"~e.12) :mod (w / wild-type~e.13,15))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p8 / patient~e.10))) :ARG1-of (l2 / long-03~e.7 :degree~e.7 (m / more~e.7)) :mod (c2 / contrast-01~e.20 :ARG1 (s3 / survive-01~e.18 :mod (m3 / median~e.17,40) :duration (t3 / temporal-quantity :quant 33~e.19 :unit (m5 / month))) :ARG2 (s4 / survive-01~e.18 :duration (t4 / temporal-quantity :quant 15~e.21 :unit m5~e.22) :mod m3) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod 2~e.29))) :ARG1-of (s7 / statistical-test-91~e.24 :ARG2 0.0005~e.25))) :ARG2 (p4 / predict-01~e.5 :polarity~e.34 -~e.34 :ARG0 l :ARG1 (s2 / survive-01~e.41 :ARG0 (p5 / person :poss (t2 / tumor~e.38 :mod (m2 / mutate-01~e.37 :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS"~e.36)))) :ARG0-of h2) :mod (c3 / contrast-01~e.33,43 :ARG1 (s5 / survive-01~e.41 :duration (t5 / temporal-quantity :quant 22~e.42 :unit m5) :mod m3) :ARG2 (s6 / survive-01~e.41 :mod m3 :duration (t6 / temporal-quantity :quant 17~e.44 :unit m5~e.45))) :ARG1-of (s8 / statistical-test-91~e.47 :ARG2 0.64~e.48)))) # ::id pmid_2337_4602.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , high mRNA levels of EREG were associated with favourable prognosis irrespective of KRAS mutational status . # ::alignments 1-1 3-1.1.1.2 4-1.1.1.1.1.1 5-1.1.1 7-1.1.1.1.2.1.1.1 9-1.1 10-1.1.2.r 11-1.1.2.1 12-1.1.2 13-1.1.3 15-1.1.3.1.1.1.1.1 16-1.1.3.1.1 17-1.1.3.1 (c / contrast-01~e.1 :ARG2 (a / associate-01~e.9 :ARG1 (l / level~e.5 :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA"~e.4) :ARG0-of (e2 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "EREG"~e.7)))) :ARG1-of (h / high-02~e.3)) :ARG2~e.10 (p2 / prognosis~e.12 :mod (f / favourable~e.11)) :ARG1-of (r / regardless-91~e.13 :ARG2 (s / status~e.17 :mod (m / mutate-01~e.16 :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS"~e.15))))))) # ::id pmid_2337_4602.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In KRAS wild type cases , the median survival was 37 months for EREG @-@ high as compared to 23 months for EREG @-@ low expressing tumours ( p= 0.01 ) , while in KRAS mutated tumours median survival was 33 versus 19 months ( p= 0.02 ) in EREG @-@ high vs. low cases ( Figure 3 ) . # ::alignments 1-1.1.3.1.2.1 2-1.1.3.1.3 3-1.1.3.1.3 4-1.2.1.3 4-1.2.2.3 7-1.1.1.2 8-1.2.1 8-1.2.2 10-1.1.1.3.1 11-1.1.1.3.2 13-1.1.1.1.1.1.2.1 15-1.1.1.1.1.1 15-1.1.1.1.1.1.3 15-1.1.1.1.1.1.3.r 17-1.2 19-1.1.2.3.1 20-1.1.2.3.2 22-1.1.1.1.1.1.2.1 22-1.1.2.1.1.1.2.1 24-1.1.2.1.1.1 24-1.1.2.1.1.1.3 24-1.1.2.1.1.1.3.r 25-1.1.1.1.1 25-1.1.2.1.1 26-1.1.1.1 26-1.1.2.1 26-1.2.3 28-1.1.1.4 29-1.1.1.4.1 32-1 34-1.1.3.1.2.1 34-1.2.3.1.2.1 35-1.2.3.1.3 36-1.1.1.1 37-1.1.1.2 38-1.1.1 38-1.1.2 40-1.2.1.2.1 42-1.2.2.2.1 43-1.2.2.2.2 45-1.2.1.4 46-1.2.1.4.1 49-1.1.1.1.1.1.2.1 49-1.1.2.1.1.1.2.1 51-1.1.1.1.1.1 51-1.1.1.1.1.1.3 51-1.1.1.1.1.1.3.r 52-1.1 53-1.1.2.1.1.1 53-1.1.2.1.1.1.3 53-1.1.2.1.1.1.3.r 54-1.1.3 56-1.3.1 58-1.3.1.1 (c / contrast-01~e.32 :ARG1 (c2 / compare-01~e.52 :ARG1 (s / survive-01~e.38 :condition (t / tumor~e.26,36 :ARG3-of (e / express-03~e.25 :ARG2 (p / protein~e.15,51 :wiki "Epiregulin" :name (n / name :op1 "EREG"~e.13,22,49) :ARG1-of~e.15,51 (h / high-02~e.15,51)))) :mod (m / median~e.7,37) :duration (t2 / temporal-quantity :quant 37~e.10 :unit (m2 / month~e.11)) :ARG1-of (s5 / statistical-test-91~e.28 :ARG2 0.01~e.29)) :ARG2 (s2 / survive-01~e.38 :condition (t3 / tumor~e.26 :ARG3-of (e2 / express-03~e.25 :ARG2 (p2 / protein~e.24,53 :wiki "Epiregulin" :name (n2 / name :op1 "EREG"~e.22,49) :ARG1-of~e.24,53 (l / low-04~e.24,53)))) :mod m :duration (t4 / temporal-quantity :quant 23~e.19 :unit m2~e.20)) :topic (c3 / case-04~e.54 :ARG1 (e3 / enzyme :wiki "KRAS" :name (n3 / name :op1 "KRAS"~e.1,34) :mod (w / wild-type~e.2,3)))) :ARG2 (c4 / compare-01~e.17 :ARG1 (s3 / survive-01~e.8 :mod m :duration (t6 / temporal-quantity :quant 33~e.40 :unit m2) :condition (c5 / case-04~e.4 :ARG1 p) :ARG1-of (s6 / statistical-test-91~e.45 :ARG2 0.02~e.46)) :ARG2 (s4 / survive-01~e.8 :mod m :duration (t7 / temporal-quantity :quant 19~e.42 :unit m2~e.43) :condition (c6 / case-04~e.4 :ARG1 p2)) :condition (t5 / tumor~e.26 :mod (e4 / enzyme :wiki "KRAS" :name (n4 / name :op1 "KRAS"~e.34) :ARG2-of (m3 / mutate-01~e.35)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.56 :mod 3~e.58))) # ::id pmid_2337_4602.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar findings for EREG high vs. low were seen when we examined complex cancer genotypes : a ) KRAS+BRAF , both wild type vs. any mutant , b ) KRAS+BRAF+PIK3CA+NRAS , all wild type vs. any mutant . # ::alignments 0-1.1.3 1-1.1 1-1.1.1 1-1.1.1.r 2-1.1.2.r 3-1.1.2.1.1.1 3-1.1.2.2.1.1 4-1.1.2.1 4-1.1.2.1.2 4-1.1.2.1.2.r 5-1.1.2 6-1.1.2.2 6-1.1.2.2.2 6-1.1.2.2.2.r 8-1 9-1.2.r 10-1.2.1 11-1.2 12-1.2.2.1 13-1.2.2.3.2.1 14-1.2.2 16-1.2.2.2.1.1.1 21-1.2.2.2.1.1.2.1.2 22-1.2.2.2.1.1.2.1.2 23-1.2.2.2.1.1 24-1.2.2.2.1.2.3 25-1.2.2.2.1.2.3 27-1.2.2.2.1.2.1 32-1.2.2.2.1.1.2.1.2 33-1.2.2.2.1.1.2.1.2 34-1.2.2.2.1.2 35-1.2.2.2.1.2.3 36-1.2.2.2.1.2.3 (s / see-01~e.8 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :topic~e.2 (c / compare-01~e.5 :ARG1 (p / protein~e.4 :name (n2 / name :op1 "EREG"~e.3) :ARG1-of~e.4 (h / high-02~e.4)) :ARG2 (p2 / protein~e.6 :name (n3 / name :op1 "EREG"~e.3) :ARG1-of~e.6 (l / low-04~e.6))) :ARG1-of (r / resemble-01~e.0)) :time~e.9 (e / examine-01~e.11 :ARG0 (w / we~e.10) :ARG1 (g / genotype~e.14 :mod (c3 / complex~e.12) :ARG1-of (m / mean-01 :ARG2 (a3 / and :op1 (c4 / compare-01~e.23 :li "a"~e.16 :ARG1 (a / and :op1 (g5 / gene :name (n4 / name :op1 "KRAS") :mod (w2 / wild-type~e.21,22,32,33)) :op2 (g4 / gene :name (n5 / name :op1 "BRAF") :mod w2)) :ARG2 (m2 / molecular-physical-entity :ARG2-of (m3 / mutate-01) :mod (a2 / any))) :op2 (c5 / compare-01~e.34 :li "b"~e.27 :ARG1 (a5 / and :op1 g5 :op2 g4 :op3 (g2 / gene :name (n8 / name :op1 "PIK3CA") :mod w2) :op4 (g3 / gene :name (n9 / name :op1 "NRAS") :mod w2)) :ARG2 m2~e.24,25,35,36))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.13))))) # ::id pmid_2337_4602.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AREG mRNA had a favourable predictive significance in wild type cases only , whereas EREG mRNA preserved its significance in wild type as well as in mutant cases . # ::alignments 0-1.1.2.1.1.1 1-1.1.1.1 4-1.1.3.1 5-1.1.3.2 6-1.1 6-1.1.3 6-1.1.3.r 7-1.1.3.3.r 8-1.1.3.3.1 9-1.1.3.3.1 10-1.1.3.3 10-1.2.3.2.1 11-1.1.3.3.2 13-1 14-1.2.2.1.1.1 15-1.2.1.1 16-1.2.3 17-1.2.3.1.1 17-1.2.3.1.1.r 18-1.2.3.1 20-1.1.3.3.1 21-1.1.3.3.1 22-1.2.3.2 23-1.2.3.2 24-1.2.3.2 25-1.2.3.2.r 26-1.2.3.2.2.1 27-1.2.3.2.2 (c / contrast-01~e.13 :ARG1 (n5 / nucleic-acid~e.6 :name (n / name :op1 "mRNA"~e.1) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "AREG"~e.0))) :ARG1-of~e.6 (s / significant-02~e.6 :mod (f / favourable~e.4) :ARG0-of (p2 / predict-01~e.5) :topic~e.7 (c2 / case-04~e.10 :mod (w / wild-type~e.8,9,20,21) :mod (o / only~e.11)))) :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA"~e.15) :ARG0-of (e2 / encode-01 :ARG1 (p3 / protein :name (n4 / name :op1 "EREG"~e.14))) :ARG0-of (p4 / preserve-01~e.16 :ARG1 (s2 / significant-02~e.18 :ARG1~e.17 n6~e.17) :topic~e.25 (a / and~e.22,23,24 :op1 (c3 / case-04~e.10 :mod w) :op2 (c4 / case-04~e.27 :ARG2-of (m / mutate-01~e.26)))))) # ::id pmid_2337_4602.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A multivariate analysis was performed in the context of a broader mRNA profiling project of several biomarkers ( IGFBP2 , IGF1R , cMET , EGFR , TGFa , EphA2 , HER2 , HER3 , HER4 , Table 4 ) . # ::alignments 1-1.1.1 2-1.1 4-1 8-1.3.r 10-1.3.2 10-1.3.2.1 10-1.3.2.1.r 11-1.3.1.2.1.1 12-1.3.1 13-1.3 15-1.3.1.1.2 18-1.3.1.1.1.1.1.1.1 20-1.3.1.1.1.1.2.1.1 22-1.3.1.1.1.1.3.1.1 24-1.3.1.1.1.1.4.1.1 26-1.3.1.1.1.1.5.1.1 28-1.3.1.1.1.1.6.1.1 30-1.3.1.1.1.1.7.1.1 32-1.3.1.1.1.1.8.1.1 34-1.3.1.1.1.1.9.1.1 36-1.2.1 38-1.2.1.1 (p / perform-02~e.4 :ARG1 (a / analyze-01~e.2 :mod (m / multivariate~e.1)) :ARG1-of (d / describe-01 :ARG0 (t / table~e.36 :mod 4~e.38)) :time~e.8 (p2 / project~e.13 :ARG0-of (p3 / profile-01~e.12 :ARG1 (b2 / biomarker :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (p4 / protein :name (n5 / name :op1 "IGFBP2"~e.18)) :op2 (p5 / protein :name (n6 / name :op1 "IGF1R"~e.20)) :op3 (p6 / protein :name (n7 / name :op1 "cMET"~e.22)) :op4 (e / enzyme :name (n / name :op1 "EGFR"~e.24)) :op5 (p8 / protein :name (n9 / name :op1 "TGFa"~e.26)) :op6 (p9 / protein :name (n10 / name :op1 "EphA2"~e.28)) :op7 (e2 / enzyme :name (n11 / name :op1 "HER2"~e.30)) :op8 (e3 / enzyme :name (n12 / name :op1 "HER3"~e.32)) :op9 (e4 / enzyme :name (n13 / name :op1 "HER4"~e.34)))) :quant (s / several~e.15)) :instrument (n2 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.11))) :ARG1-of (b / broad-02~e.10 :degree~e.10 (m3 / more~e.10)))) # ::id pmid_2337_4602.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the presence of wild @-@ type KRAS , high AREG mRNA levels were independently associated with 83.0 % reduction in the risk of death compared to patients with AREG @-@ low tumours . # ::alignments 2-1.4 3-1.4.1.r 4-1.4.1.2 6-1.4.1.2 7-1.4.1.1.1 9-1.1.2 10-1.1.1.2.1.1.1 11-1.1.1.1.1 12-1.1 14-1.3.1 15-1 18-1.2.2 19-1.2 20-1.2.1.r 22-1.2.1 23-1.2.1.1.r 24-1.2.1.1 25-1.2.3.r 27-1.2.3.2.1 29-1.2.3.1.1.1 31-1.2.3.1.1 32-1.2.3.1 (a / associate-01~e.15 :ARG1 (l / level~e.12 :quant-of (n3 / nucleic-acid :name (n / name :op1 "mRNA"~e.11) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "AREG"~e.10)))) :ARG1-of (h / high-02~e.9)) :ARG2 (r2 / reduce-01~e.19 :ARG1~e.20 (r3 / risk-01~e.22 :ARG2~e.23 (d / die-01~e.24)) :ARG2 (p3 / percentage-entity~e.18 :value 83) :compared-to~e.25 (p4 / person :poss (t / tumor~e.32 :ARG1-of (l2 / low-04~e.31 :ARG2 p2~e.29)) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p / patient~e.27)))) :ARG0-of (d2 / depend-01 :polarity -~e.14) :condition (p5 / present-02~e.2 :ARG1~e.3 (e2 / enzyme :name (n4 / name :op1 "KRAS"~e.7) :mod (w / wild-type~e.4,6)))) # ::id pmid_2337_4602.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High EREG tumoural mRNA was a favourable outcome predictor for cetuximab @-@ treated patients , irrespective of KRAS mutation status . # ::alignments 0-1.2.3 1-1.2.2.1.1.1 3-1.2.1.1 4-1.2.r 6-1.3 7-1.1.1 10-1.4.1.1.1.1 12-1.4.1 13-1.4 15-1.5 17-1.5.1.1.1.1.1 18-1.5.1.1 19-1.5.1 (t / thing :ARG0-of (p / predict-01 :ARG1 (o / outcome~e.7)) :domain~e.4 (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.3) :ARG0-of (e / encode-01 :ARG1 (p2 / protein :name (n2 / name :op1 "EREG"~e.1))) :mod (h / high~e.0)) :mod (f / favourable~e.6) :topic (p3 / patient~e.13 :ARG1-of (t2 / treat-03~e.12 :ARG3 (s / small-molecule :name (n3 / name :op1 "cetuximab"~e.10)))) :ARG1-of (r / regardless-91~e.15 :ARG2 (s2 / status~e.19 :mod (m / mutate-01~e.18 :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS"~e.17)))))) # ::id pmid_2337_4602.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High Ephrin A2 ( EphA2 ) mRNA and advanced age were adverse independent prognosticators . # ::alignments 0-1.1.1.2.1 0-1.1.1.2.1.2 0-1.1.1.2.1.2.r 1-1.1.1.2.1.1.1 2-1.1.1.2.1.1.2 6-1.1.1.1.1 7-1.1 8-1.1.2.1 9-1.1.2 10-1.1.r 11-1.3 12-1.2 12-1.2.1 12-1.2.1.r 13-1 (p / prognosticator~e.13 :domain~e.10 (a / and~e.7 :op1 (n3 / nucleic-acid :name (n / name :op1 "mRNA"~e.6) :ARG0-of (e / encode-01 :ARG1 (p2 / protein~e.0 :name (n2 / name :op1 "Ephrin"~e.1 :op2 "A2"~e.2) :ARG1-of~e.0 (h / high-02~e.0)))) :op2 (a2 / age~e.9 :ARG1-of (a3 / advance-01~e.8))) :ARG0-of (d / depend-01~e.12 :polarity~e.12 -~e.12) :mod (a4 / adverse~e.11)) # ::id pmid_2337_4602.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , among cetuximab @-@ treated patients with AREG @-@ low tumours , those with mutant KRAS fared significantly better than patients harbouring colon cancer with KRAS wild type ( 81 % decreased risk of death ) . # ::alignments 0-1.4 2-1.1.1 3-1.1.1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1.3.1 8-1.1.1.1.2.1.1.1 10-1.1.1.1.2.1 10-1.1.1.1.2.1.2 10-1.1.1.1.2.1.2.r 11-1.1.1.1.2 15-1.1.2 15-1.1.2.2 15-1.1.2.2.r 16-1.1.2.1.1 17-1 18-1.2.2 19-1.2 19-1.2.1 19-1.2.1.r 19-1.2.4 19-1.2.4.r 20-1.3.r 21-1.3.2 22-1.3.1 23-1.3.1.1.2.1 24-1.3.1.1.2.2 26-1.3.1.1.3.1.1 27-1.3.1.1.3.2 28-1.3.1.1.3.2 30-1.2.3.1.2.1.1 31-1.2.3.1.2.1 32-1.2.3.1.2 33-1.2.3.1 34-1.2.3.1.1.r 35-1.2.3.1.1 (f / fare-01~e.17 :ARG0 (p6 / person :ARG1-of (i / include-91~e.2 :ARG2 (p / person :ARG1-of (t2 / treat-03~e.5 :ARG3 (s2 / small-molecule :name (n3 / name :op1 "cetuximab"~e.3))) :poss (t / tumor~e.11 :mod (p5 / protein~e.10 :name (n4 / name :op1 "AREG"~e.8) :ARG1-of~e.10 (l / low-04~e.10))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient~e.6)))) :mod (e2 / enzyme~e.15 :name (n / name :op1 "KRAS"~e.16) :ARG2-of~e.15 (m4 / mutate-01~e.15))) :ARG1-of (w2 / well-09~e.19 :mod~e.19 (m2 / more~e.19) :ARG1-of (s / significant-02~e.18) :ARG1-of (m3 / mean-01 :ARG2 (r / risk-01~e.33 :ARG2~e.34 (d2 / die-01~e.35) :ARG1-of (d3 / decrease-01~e.32 :ARG2 (p3 / percentage-entity~e.31 :value 81~e.30)))) :degree~e.19 (m / more~e.19)) :compared-to~e.20 (p2 / person :ARG0-of (h / harbor-01~e.22 :ARG1 (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colon"~e.23 :op2 "cancer"~e.24) :mod (e / enzyme :name (n2 / name :op1 "KRAS"~e.26) :mod (w / wild-type~e.27,28)))) :ARG0-of h2~e.21) :time (f2 / final~e.0)) # ::id pmid_2337_4602.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Impact of distinct types of KRAS and PIK3CA mutations on outcome of cetuximab @-@ treated patients # ::alignments 1-1 2-1.1.r 3-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1.1.1.1 7-1.1.2.1 8-1.1.2.1.2.1.1 9-1.1.2 10-1.2.r 11-1.2 12-1.2.1.r 13-1.2.1.1.1.1.1 15-1.2.1.1 16-1.2.1.2.1 (i / impact-01~e.1 :ARG0~e.2 (t / type~e.4 :mod (d / distinct~e.3) :mod~e.5 (m / mutate-01~e.9 :ARG1 (a / and~e.7 :op1 (g2 / gene :name (n2 / name :op1 "KRAS"~e.6)) :op2 (g3 / gene :name (n3 / name :op1 "PIK3CA"~e.8))))) :ARG1~e.10 (o / outcome~e.11 :topic~e.12 (p / person :ARG1-of (t2 / treat-03~e.15 :ARG3 (s / small-molecule :name (n4 / name :op1 "cetuximab"~e.13))) :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.16))))) # ::id pmid_2337_4602.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We examined different types of KRAS and PIK3CA mutations for potentially distinct impact on patient survival . # ::alignments 0-1.1 1-1 2-1.2.2 3-1.2 4-1.2.1.r 5-1.2.1.1.1.1.1 6-1.2.1.1 7-1.2.1.1.2.1.1 8-1.2.1 9-1.3.r 10-1.3.3.1 11-1.3.3 12-1.3 13-1.3.2.r 14-1.3.2.1.1.1 15-1.3.2 (e / examine-01~e.1 :ARG0 (w / we~e.0) :ARG1 (t / type~e.3 :mod~e.4 (m / mutate-01~e.8 :ARG2 (a / and~e.6 :op1 (g2 / gene :name (n2 / name :op1 "KRAS"~e.5)) :op2 (g3 / gene :name (n3 / name :op1 "PIK3CA"~e.7)))) :ARG1-of (d / differ-02~e.2)) :ARG2~e.9 (i / impact-01~e.12 :ARG0 t :ARG1~e.13 (s / survive-01~e.15 :ARG0 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.14)))) :mod (d2 / distinct~e.11 :mod (p2 / potential~e.10)))) # ::id pmid_2337_4602.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Regarding KRAS , cetuximab @-@ treated patients with codon 12 mutations had a median survival of 19 months ( 95 % CI 15 @–@ 26 ) , significantly lower ( p= 0.033 ) than the median survival of patients with other KRAS mutations ( 30 months , 95 % CI 20 @–@ 35 ) and that of patients with wild @-@ type KRAS ( 29 months , 95 % CI 25 @–@ 35 ) . # ::alignments 0-1.3.r 1-1.3.1.1 3-1.1.1.1.1.1 5-1.1.1 6-1.1.3.1 8-1.1.2.1 9-1.1.2.1.1 10-1.1.2 11-1 11-1.1.3 13-1.2.1 14-1.2 16-1.2.2.1 17-1.2.2.2 19-1.2.3.1.1.1 20-1.2.3.1.1 21-1.2.3.1 21-1.2.3.1.2 21-1.2.3.1.2.r 22-1.2.3.1.2.1 24-1.2.3.1.2.2 27-1.2.4.2 28-1.2.4 28-1.2.4.1 28-1.2.4.1.r 30-1.2.4.4 31-1.2.4.4.1 33-1.2.4.3.r 35-1.2.1 36-1.2 36-1.2.4.3.1 36-1.2.4.3.2 37-1.2.4.3.1.1.r 38-1.2.4.3.1.1.2 40-1.2.4.3.1.1.1.2 41-1.2.4.3.2.1.1.1.1 42-1.2.4.3.1.1.1 44-1.2.4.3.1.3.2.1 45-1.2.4.3.1.3.2.2 47-1.2.3.1.1.1 48-1.2.3.1.1 49-1.2.3.1.3 49-1.2.4.3.1.3.1 49-1.2.4.3.1.3.1.1 49-1.2.4.3.1.3.1.1.r 50-1.2.4.3.1.3.1.1.1 52-1.2.4.3.1.3.1.1.2 54-1.2.4.3 57-1.1.3.1 59-1.2.4.3.2.1.1.2 61-1.2.4.3.2.1.1.2 62-1.2.4.3.2.1.1.1.1 64-1.2.4.3.2.2.2.1 65-1.2.4.3.2.2.2.2 67-1.2.3.1.1.1 68-1.2.3.1.1 69-1.2.4.3.2.2.1 69-1.2.4.3.2.2.1.1 69-1.2.4.3.2.2.1.1.r 70-1.2.4.3.2.2.1.1.1 72-1.2.4.3.2.2.1.1.2 (h / have-03~e.11 :ARG0 (p / person :ARG1-of (t / treat-03~e.5 :ARG3 (s / small-molecule :name (n2 / name :op1 "cetuximab"~e.3))) :poss (m2 / mutate-01~e.10 :ARG1 (c / codon~e.8 :mod 12~e.9)) :ARG0-of (h2 / have-rel-role-91~e.11 :ARG2 (p2 / patient~e.6,57))) :ARG1 (s2 / survive-01~e.14,36 :mod (m3 / median~e.13,35) :duration (t2 / temporal-quantity :quant 19~e.16 :unit (m4 / month~e.17)) :ARG1-of (m5 / mean-01 :ARG2 (i / interval~e.21 :mod (p3 / percentage-entity~e.20,48,68 :value 95~e.19,47,67) :mod~e.21 (v / value-interval~e.21 :op1 15~e.22 :op2 26~e.24) :mod (c2 / confidence~e.49))) :ARG1-of (l / low-04~e.28 :degree~e.28 (m6 / more~e.28) :ARG1-of (s3 / significant-02~e.27) :compared-to~e.33 (a / and~e.54 :op1 (s4 / survive-01~e.36 :ARG0~e.37 (p5 / person :poss (m8 / mutate-01~e.42 :ARG1 g :mod (o / other~e.40)) :ARG0-of h2~e.38) :mod m3 :ARG1-of (m9 / mean-01 :ARG2 (i2 / interval~e.49 :mod~e.49 (v2 / value-interval~e.49 :op1 20~e.50 :op2 35~e.52) :mod p3 :mod c2) :duration (t3 / temporal-quantity :quant 30~e.44 :unit m4~e.45))) :op2 (s5 / survive-01~e.36 :ARG0 (p6 / person :poss (g2 / gene :name (n3 / name :op1 "KRAS"~e.41,62) :mod (w / wild-type~e.59,61)) :ARG0-of h2) :ARG1-of (m10 / mean-01 :ARG2 (i3 / interval~e.69 :mod~e.69 (v3 / value-interval~e.69 :op1 25~e.70 :op2 35~e.72) :mod c2) :duration (t4 / temporal-quantity :quant 29~e.64 :unit m4~e.65)))) :ARG1-of (s6 / statistical-test-91~e.30 :ARG2 0.033~e.31))) :topic~e.0 (g / gene :name (n / name :op1 "KRAS"~e.1))) # ::id pmid_2337_4602.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further subgroup analyses showed that the median survival in patients with codon 12 KRAS mutations was also lower than the median survival of all other patient subgroups ( other KRAS mutations or KRAS wild @-@ type ) . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 3-1 4-1.2.r 6-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.2.1 11-1.2.1.1.1 12-1.2.1.1.1.1 13-1.2.1.1.1.2.1.1 14-1.2.1.1 16-1.2.3.3 17-1.2.3 17-1.2.3.1 17-1.2.3.1.r 18-1.2.3.2.r 20-1.2.3.2.2 21-1.2.3.2 22-1.2.3.2.1.r 23-1.2.3.2.1.2 24-1.2.3.2.1.1 25-1.2.1.2.1 26-1.2.3.2.1 28-1.2.3.2.1.1 28-1.2.3.2.1.3.1.1.2 29-1.2.3.2.1.3.1.2.1.1 30-1.2.3.2.1.3.1.1 31-1.2.3.2.1.3.1 32-1.2.3.2.1.3.1.2.1.1 33-1.2.3.2.1.3.1.2.2 35-1.2.3.2.1.3.1.2.2 (s / show-01~e.3 :ARG0 (a / analyze-01~e.2 :ARG1 (s2 / subgroup~e.1) :degree (f / further~e.0)) :ARG1~e.4 (s3 / survive-01~e.7 :ARG0~e.8 (p / person :poss (m3 / mutate-01~e.14 :ARG1 (c / codon~e.11 :mod 12~e.12 :part-of (g / gene :name (n / name :op1 "KRAS"~e.13)))) :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.9,25))) :mod (m2 / median~e.6) :ARG1-of (l / low-04~e.17 :degree~e.17 (m4 / more~e.17) :compared-to~e.18 (s4 / survive-01~e.21 :ARG0~e.22 (s5 / subgroup~e.26 :mod (o / other~e.24,28) :mod (a2 / all~e.23) :ARG1-of (m5 / mean-01 :ARG2 (o2 / or~e.31 :op1 (m6 / mutate-01~e.30 :ARG2 g :mod (o3 / other~e.28)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS"~e.29,32) :mod (w / wild-type~e.33,35)))) :consist-of (p3 / person :ARG0-of h)) :mod m2~e.20) :mod (a3 / also~e.16)))) # ::id pmid_2337_4602.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Specifically , patients with codon 13 mutations reached a median survival of 28 months ( 95 % CI 16 @–@ 39 ) , those with other rarer KRAS mutations a median survival of 33 months ( 95 % CI 16 @–@ 42 ) and patients with KRAS wild @-@ type tumours a median survival of 29 months ( 95 % CI 25 @–@ 35 ) . # ::alignments 0-1.4 2-1.1.3.1 4-1.1.1.1 5-1.1.1.1.1 6-1.1.1 7-1.1.2 7-1.2.2 7-1.3.2 9-1.1.2.1.1 10-1.1.2.1 10-1.2.2.1 10-1.3.2.1 12-1.1.2.1.2.1 13-1.1.2.1.2.2 15-1.2.2.1.3.1.2 16-1.2.2.1.3.1.2 17-1.2.2.1.3.1 18-1.2.2.1.3.1.1.1 20-1.1.2.1.3.1.2.2 25-1.2.1.2 26-1.2.1.3 26-1.2.1.3.1 26-1.2.1.3.1.r 27-1.2.1.1.1.1 28-1.2.1 30-1.1.2.1.1 31-1.1.2.1 32-1.2.2.1.2.r 33-1.2.2.1.2.1 34-1.2.2.1.2.2 36-1.1.2.1.3.1.1.1 37-1.1.2.1.3.1.1 38-1.1.2.1.3.1 38-1.1.2.1.3.1.2 38-1.1.2.1.3.1.2.r 38-1.1.2.1.3.1.3 38-1.1.2.1.3.1.3.r 38-1.2.2.1.3.1 38-1.2.2.1.3.1.1 38-1.2.2.1.3.1.1.r 39-1.1.2.1.3.1.2.1 39-1.2.2.1.3.1.1.1 41-1.2.2.1.3.1.1.2 43-1 44-1.1.3.1 46-1.3.1.1.1.1 47-1.3.1.1.2 49-1.3.1.1.2 50-1.3.1 52-1.1.2.1.1 53-1.1.2.1 54-1.3.2.1.2.r 55-1.3.2.1.2.1 56-1.3.2.1.2.2 58-1.3.2.1.3.1.2 59-1.3.2.1.3.1.2 60-1.3.2.1.3.1 60-1.3.2.1.3.1.1 60-1.3.2.1.3.1.1.r 61-1.3.2.1.3.1.1.1 63-1.3.2.1.3.1.1.2 (a / and~e.43 :op1 (p / person :poss (m / mutate-01~e.6 :ARG1 (c / codon~e.4 :mod 13~e.5)) :ARG0-of (r / reach-01~e.7 :ARG1 (s2 / survive-01~e.10,31,53 :mod (m2 / median~e.9,30,52) :duration (t / temporal-quantity :quant 28~e.12 :unit (m3 / month~e.13)) :ARG1-of (m4 / mean-01 :ARG2 (i / interval~e.38 :mod (p3 / percentage-entity~e.37 :value 95~e.36) :mod~e.38 (v / value-interval~e.38 :op1 16~e.39 :op2 39~e.20) :mod~e.38 (c2 / confidence~e.38))))) :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient~e.2,44))) :op2 (p2 / person :poss (m5 / mutate-01~e.28 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.27)) :mod (o / other~e.25) :ARG1-of (r4 / rare-02~e.26 :degree~e.26 (m8 / more~e.26))) :ARG0-of (r2 / reach-01~e.7 :ARG1 (s3 / survive-01~e.10 :mod m2 :duration~e.32 (t2 / temporal-quantity :quant 33~e.33 :unit m3~e.34) :ARG1-of (m6 / mean-01 :ARG2 (i2 / interval~e.17,38 :mod~e.38 (v2 / value-interval~e.38 :op1 16~e.18,39 :op2 42~e.41) :mod p3~e.15,16 :mod c2)))) :ARG0-of h) :op3 (p4 / person :poss (t3 / tumor~e.50 :mod (g2 / gene :name (n2 / name :op1 "KRAS"~e.46) :mod (w / wild-type~e.47,49))) :ARG0-of (r3 / reach-01~e.7 :ARG1 (s4 / survive-01~e.10 :mod m2 :duration~e.54 (t4 / temporal-quantity :quant 29~e.55 :unit m3~e.56) :ARG1-of (m7 / mean-01 :ARG2 (i3 / interval~e.60 :mod~e.60 (v3 / value-interval~e.60 :op1 25~e.61 :op2 35~e.63) :mod p3~e.58,59 :mod c2)))) :ARG0-of h) :ARG1-of (s / specific-02~e.0)) # ::id pmid_2337_4602.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the rather small size of compared subgroups , a trend for statistical significance was evident ( p= 0.068 , Figure 4 ) . # ::alignments 0-1.2.r 2-1.2.2.1 3-1.2.2 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1 10-1.1 12-1.4 15-1 17-1.4 18-1.4.1 20-1.3.1 22-1.3.1.1 (e / evidence-01~e.15 :ARG1 (t / trend-01~e.10 :ARG2 (s / signify-01 :mod (s2 / statistic))) :concession~e.0 (s3 / size-01~e.4 :ARG1~e.5 (s5 / subgroup~e.7 :ARG1-of (c / compare-01~e.6)) :ARG2 (s4 / small~e.3 :degree (r / rather~e.2))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod 4~e.22)) :ARG1-of (s6 / statistical-test-91~e.12,17 :ARG2 0.068~e.18)) # ::id pmid_2337_4602.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No difference in patient outcomes was found when we compared tumours with PIK3CA exon 9 versus exon 20 mutations versus PIK3CA wild @-@ type status , as survival times clustered from 25 to 29 months ( p= 0.31 ) . # ::alignments 0-1.1.r 1-1.1 1-1.1.r 1-1.2 2-1.2.1.r 3-1.2.1.1.1.1 4-1.2.1 6-1 7-1.3.r 8-1.3.1 9-1.3 10-1.3.2 12-1.3.2.1.1.1.2.1.1 12-1.3.2.1.3.1.1 13-1.3.2.1.1.1 14-1.3.2.1.1.1.1 16-1.3.2.1.2.1 17-1.3.2.1.2.1.1 18-1.3.2.1.1 18-1.3.2.1.2 20-1.3.2.1.1.1.2.1.1 20-1.3.2.1.3.1.1 21-1.3.2.1.3.2.1 23-1.3.2.1.3.2.1 24-1.3.2.1.3.2 26-1.3.r 27-1.4.1.1 28-1.4.1 28-1.4.1.2.1.1 28-1.4.1.2.1.2 29-1.4.1.2 30-1.4.1.2.1.r 31-1.4.1.2.1.1.1 33-1.4.1.2.1.2.1 34-1.4.1.2.1.1.2 36-1.5 37-1.5.1 (f / find-01~e.6 :polarity~e.0,1 -~e.1 :ARG1 (d / differ-02~e.1 :ARG1~e.2 (o / outcome~e.4 :poss-of (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.3))))) :time~e.7,26 (c / compare-01~e.9 :ARG0 (w / we~e.8) :ARG1 (t / tumor~e.10 :poss (a / and :op1 (m / mutate-01~e.18 :ARG2 (e / exon~e.13 :mod 9~e.14 :part-of (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.12,20)))) :op2 (m2 / mutate-01~e.18 :ARG2 (e2 / exon~e.16 :mod 20~e.17 :part-of g2)) :op3 (g3 / gene :name (n3 / name :op1 "PIK3CA"~e.12,20) :poss (s / status~e.24 :mod (w2 / wild-type~e.21,23)))))) :ARG1-of (c2 / cause-01 :ARG0 (t2 / time~e.28 :duration-of (s2 / survive-01~e.27) :ARG1-of (c3 / cluster-01~e.29 :duration~e.30 (v / value-interval :op1 (t3 / temporal-quantity~e.28 :quant 25~e.31 :unit (m3 / month~e.34)) :op2 (t4 / temporal-quantity~e.28 :quant 29~e.33 :unit m3))))) :ARG1-of (s3 / statistical-test-91~e.36 :ARG2 0.31~e.37)) # ::id pmid_2337_4602.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The only complex genotype that harboured significance for cetuximab benefit was CG3 ( p= 0.019 ) : Patients with tumours wild @-@ type for all PIK3CA , KRAS , BRAF reached a median survival of 32 months ( 95 % CI 25 @–@ 36 ) , those with a PIK3CA mutation along with KRAS or BRAF mutation had a median survival of 26 months ( 95 % CI 16 @–@ 32 ) while patients with any single mutation in KRAS , BRAF or PIK3CA genes had a median survival of 22 months ( 95 % CI 19 @–@ 28 ) . # ::alignments 1-1.1.1.2 2-1.1.1.1 3-1.1.1 5-1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.1.3.r 11-1.1.1.3.1.1 13-1.1.2.2 14-1.1.2.2.1 17-1.2.1.1.2.1 19-1.2.1.1.1 19-1.2.1.1.3 19-1.2.1.1.4 20-1.2.1.1.1.1.2 22-1.2.1.1.1.1.2 25-1.2.1.1.1.1.1.1 27-1.2.1.1.3.1.1.1 29-1.2.1.1.4.1.1.1 30-1.2.1 32-1.2.1.2.2 33-1.2.1.2 34-1.2.1.2.3.r 35-1.2.1.2.3.1 36-1.2.1.2.3.2 38-1.2.1.2.4.1.1.1 39-1.2.1.2.4.1.1 40-1.2.1.2.4.1 40-1.2.1.2.4.1.2 40-1.2.1.2.4.1.2.r 41-1.2.1.2.4.1.2.1 43-1.2.1.2.4.1.2.2 49-1.2.1.1.1.1.1.1 50-1.2.3.1.1 53-1.2.1.1.3.1.1.1 54-1.2.2.1.1.2 55-1.2.1.1.4.1.1.1 56-1.2.2.1.1.2.1 56-1.2.2.1.1.2.2 57-1.2.2 57-1.2.3 59-1.2.1.2.2 60-1.2.2.2 60-1.2.3.2 62-1.2.2.2.3.1 63-1.2.2.2.3.2 65-1.2.1.2.4.1.1.1 66-1.2.1.2.4.1.1 67-1.2.1.2.4.1.3 67-1.2.2.2.4.1 67-1.2.2.2.4.1.1 67-1.2.2.2.4.1.1.r 68-1.2.2.2.4.1.1.1 70-1.2.1.2.3.1 70-1.2.2.2.4.1.1.2 73-1.2.1.1.2.1 76-1.2.3.1.1.2 77-1.2.2.1.1.1 77-1.2.3.1.1 79-1.2.1.1.3.1.1.1 81-1.2.3.1.1.1.3 82-1.2.3.1.1.1 83-1.2.3.1.1.1.1 84-1.2.3.1.1.1.1 87-1.2.1.2.2 88-1.2.2.2 88-1.2.3.2 89-1.2.3.2.3.r 90-1.2.3.2.3.1 91-1.2.3.2.3.2 93-1.2.3.2.4.1.2 94-1.2.3.2.4.1.2 95-1.2.3.2.4.1 95-1.2.3.2.4.1.1 95-1.2.3.2.4.1.1.r 96-1.2.3.2.4.1.1.1 98-1.2.3.2.4.1.1.2 (m / multi-sentence :snt1 (h / harbor-01~e.5 :ARG0 (g2 / genotype~e.3 :mod (c / complex~e.2) :mod (o / only~e.1) :domain~e.10 (d / dna-sequence :name (n / name :op1 "CG3"~e.11))) :ARG1 (s / significant-02~e.6 :ARG1~e.7 (b / benefit-01~e.9 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"~e.8))) :ARG1-of (s7 / statistical-test-91~e.13 :ARG2 0.019~e.14))) :snt2 (a / and :op1 (r / reach-01~e.30 :ARG0 (p / person :poss (t / tumor~e.19 :mod (g / gene :name (n3 / name :op1 "PIK3CA"~e.25,49) :mod (w / wild-type~e.20,22))) :ARG0-of (h4 / have-rel-role-91 :ARG2 (p5 / patient~e.17,73)) :poss (t6 / tumor~e.19 :mod (e2 / enzyme :name (n4 / name :op1 "KRAS"~e.27,53,79) :mod w)) :poss (t7 / tumor~e.19 :mod (e3 / enzyme :name (n5 / name :op1 "BRAF"~e.29,55) :mod w))) :ARG1 (s3 / survive-01~e.33 :ARG0 p :mod (m2 / median~e.32,59,87) :duration~e.34 (t2 / temporal-quantity :quant 32~e.35,70 :unit (m3 / month~e.36)) :ARG1-of (m4 / mean-01 :ARG2 (i / interval~e.40 :mod (p4 / percentage-entity~e.39,66 :value 95~e.38,65) :mod~e.40 (v / value-interval~e.40 :op1 25~e.41 :op2 36~e.43) :mod (c2 / confidence~e.67))))) :op2 (h2 / have-03~e.57 :ARG0 (p7 / person :poss (a4 / and :op1 (m5 / mutate-01~e.77 :ARG2 g) :op2 (o2 / or~e.54 :op1 (m6 / mutate-01~e.56 :ARG2 e2) :op2 (m7 / mutate-01~e.56 :ARG2 e3))) :ARG0-of h4) :ARG1 (s4 / survive-01~e.60,88 :ARG0 p7 :mod m2 :duration (t3 / temporal-quantity :quant 26~e.62 :unit m3~e.63) :ARG1-of (m8 / mean-01 :ARG2 (i2 / interval~e.67 :mod~e.67 (v2 / value-interval~e.67 :op1 16~e.68 :op2 32~e.70) :mod p4 :mod c2)))) :op3 (h3 / have-03~e.57 :ARG0 (p3 / person :poss (m9 / mutate-01~e.50,77 :ARG2 (o3 / or~e.82 :op1 g~e.83,84 :op2 e2 :op3 e3~e.81) :ARG1-of (s5 / single-02~e.76)) :ARG0-of h4) :ARG1 (s6 / survive-01~e.60,88 :ARG0 p3 :mod m2 :duration~e.89 (t5 / temporal-quantity :quant 22~e.90 :unit m3~e.91) :ARG1-of (m10 / mean-01 :ARG2 (i3 / interval~e.95 :mod~e.95 (v3 / value-interval~e.95 :op1 19~e.96 :op2 28~e.98) :mod p4~e.93,94 :mod c2)))))) # ::id pmid_2337_4602.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Apparently , concurrent mutations in PIK3CA along with KRAS or BRAF mutations carried rather weak additional adverse prediction . # ::alignments 0-1.3 0-1.3.r 2-1.1.1.2 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2.1.2.1.1 11-1.1.2 12-1 13-1.2.3.1 14-1.2.3 15-1.2.2 16-1.2.1 17-1.2 (c / carry-01~e.12 :ARG0 (a4 / and :op1 (m / mutate-01~e.3 :ARG2~e.4 (e3 / enzyme :name (n2 / name :op1 "PIK3CA"~e.5)) :ARG1-of (c2 / concurrent-02~e.2)) :op2 (m2 / mutate-01~e.11 :ARG2 (o / or~e.9 :op1 (e / enzyme :name (n3 / name :op1 "KRAS"~e.8)) :op2 (e2 / enzyme :name (n4 / name :op1 "BRAF"~e.10))))) :ARG1 (p / predict-01~e.17 :mod (a2 / adverse~e.16) :mod (a3 / additional~e.15) :ARG1-of (w / weak-02~e.14 :degree (r / rather~e.13))) :manner~e.0 (a / apparent~e.0)) # ::id pmid_2352_4590.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK inhibitors as a chemotherapeutic intervention in multiple myeloma ( PMID : 23524590 ) # ::alignments 0-1.2.1.1 1-1 2-1.1.1.r 4-1.1.1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 8-1.1.1.1.1.2 (i / inhibit-01~e.1 :ARG0 (m / molecular-physical-entity :prep-as~e.2 (i2 / intervene-01~e.5 :ARG1~e.6 (d / disease :name (n2 / name :op1 "multiple"~e.7 :op2 "myeloma"~e.8)) :mod (c / chemotherapy~e.4))) :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.0)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23524590"))) # ::id pmid_2352_4590.2 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ras/Raf/MEK/extracellular signal regulated kinase ( ERK ) ( Ras/mitogen @-@ activated protein kinases ( MAPK )) signal transduction pathway is a crucial mediator of many fundamental biological processes , including cellular proliferation , survival , angiogenesis and migration . # ::alignments 2-1.1.2.1 15-1.1.1.1 17-1.1.2.1 18-1.1.2 19-1.1 22-1.1.3 23-1 24-1.2.r 25-1.2.3 26-1.2.2 27-1.2.1 28-1.2 30-1.2.4 31-1.2.4.1.1.1 32-1.2.4.1.1 34-1.2.4.1.2 36-1.2.4.1.3 37-1.2.4.1 38-1.2.4.1.4 (m / mediate-01~e.23 :ARG0 (p3 / pathway~e.19 :name (n / name :op1 "MAPK"~e.15) :ARG0-of (t / transduce-01~e.18 :ARG1 (s2 / signal-07~e.2,17)) :mod (c2 / crucial~e.22)) :ARG1~e.24 (p / process-02~e.28 :ARG1 (b / biology~e.27) :mod (f / fundamental~e.26) :mod (m2 / many~e.25) :ARG2-of (i / include-91~e.30 :ARG1 (a / and~e.37 :op1 (p2 / proliferate-01~e.32 :ARG0 (c / cell~e.31)) :op2 (s / survive-01~e.34 :ARG0 c) :op3 (a2 / angiogenesis~e.36 :mod c) :op4 (m3 / migrate-01~e.38 :ARG0 c))))) # ::id pmid_2352_4590.3 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Aberrant signalling through the Ras @/@ MAPK cascade is common in a wide array of malignancies , including multiple myeloma ( MM ) , making it an appealing candidate for the development of novel targeted therapies . # ::alignments 0-1.1.2 1-1.1 4-1.1.1.1.1 6-1.1.1.1.1 8-1.1.r 9-1 10-1.2.r 12-1.2.1 13-1.2 14-1.2.2.r 15-1.2.2 17-1.2.2.1 18-1.2.2.1.1.1.1 19-1.2.2.1.1.1.2 24-1.3 25-1.3.1.3 27-1.3.1.1 28-1.3.1 29-1.3.1.2.r 31-1.3.1.2 32-1.3.1.2.1.r 33-1.3.1.2.1.2 34-1.3.1.2.1.1 35-1.3.1.2.1 (c / common~e.9 :domain~e.8 (s / signal-07~e.1 :ARG0 (p / pathway :name (n / name :op1 "Ras/MAPK"~e.4,6)) :mod (a / aberrant~e.0)) :location~e.10 (a2 / array~e.13 :ARG1-of (w / wide-02~e.12) :consist-of~e.14 (m / malignancy~e.15 :ARG2-of (i / include-91~e.17 :ARG1 (d / disease :name (n2 / name :op1 "multiple"~e.18 :op2 "myeloma"~e.19))))) :ARG0-of (m2 / make-02~e.24 :ARG1 (c3 / candidate~e.28 :ARG0-of (a3 / appeal-03~e.27) :purpose~e.29 (d2 / develop-02~e.31 :ARG1~e.32 (t / therapy~e.35 :ARG0-of (t2 / target-01~e.34) :mod (n3 / novel~e.33))) :domain s~e.25))) # ::id pmid_2352_4590.4 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this review , we explore our current understanding of the Ras @/@ MAPK pathway and its role in MM . # ::alignments 1-1.3.1 2-1.3 4-1.1 5-1 6-1.2.1 6-1.2.1.r 7-1.2.3 8-1.2 9-1.2.2.r 11-1.2.2.1.1.1 13-1.2.2.1.1.1 14-1.2.2.1 15-1.2.2 16-1.2.2.2.2 16-1.2.2.2.2.r 17-1.2.2.2 18-1.2.2.2.1.r 19-1.2.2.2.1.1.1 19-1.2.2.2.1.1.2 (e / explore-01~e.5 :ARG0 (w / we~e.4) :ARG1 (u / understand-01~e.8 :ARG0~e.6 w~e.6 :ARG1~e.9 (a / and~e.15 :op1 (p / pathway~e.14 :name (n / name :op1 "Ras/MAPK"~e.11,13)) :op2 (r / role~e.17 :topic~e.18 (d / disease :name (n2 / name :op1 "multiple"~e.19 :op2 "myeloma"~e.19)) :poss~e.16 p~e.16)) :mod (c / current~e.7)) :medium (r2 / review~e.2 :mod (t / this~e.1))) # ::id pmid_2352_4590.5 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , we summarise the current status of small molecule inhibitors of MEK under clinical evaluation , and discuss future approaches required to optimise their use . # ::alignments 0-1 0-1.3 0-1.3.r 2-1.1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.2.r 8-1.1.2.2 8-1.1.2.2.2.1 9-1.1.2.2 9-1.1.2.2.2 9-1.1.2.2.2.r 10-1.1.2.2.1 11-1.1.2.2.1.1.r 12-1.1.2.2.1.1.1.1 14-1.1.2.2.3.1 15-1.1.2.2.3 17-1 18-1.2 19-1.2.2.1 20-1.2.2 21-1.2.2.2 24-1.2.2.2.1.1.1 24-1.2.2.2.1.1.1.r 25-1.2.2.2.1.1 (a / and~e.0,17 :op1 (s / summarize-01 :ARG0 (w / we~e.2) :ARG2 (s2 / status~e.6 :mod (c / current~e.5) :mod~e.7 (s4 / small-molecule~e.8,9 :ARG0-of (i / inhibit-01~e.10 :ARG1~e.11 (p / protein-family :name (n / name :op1 "MEK"~e.12))) :mod~e.9 (m2 / molecule~e.9 :mod (s3 / small~e.8)) :ARG1-of (e2 / evaluate-01~e.15 :mod (c2 / clinic~e.14))))) :op2 (d / discuss-01~e.18 :ARG0 w :ARG1 (a2 / approach-02~e.20 :mod (f / future~e.19) :ARG1-of (r / require-01~e.21 :ARG0 (o / optimize-01 :ARG1 (u / use-01~e.25 :ARG1~e.24 s4~e.24))))) :manner~e.0 (a3 / additional~e.0)) # ::id pmid_2352_4590.6 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Introduction # ::alignments 1-1 (i / introduce-01~e.1) # ::id pmid_2352_4590.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mitogen @-@ activated protein kinases ( MAPKs ) are a family of ubiquitously expressed serine @/@ threonine kinases that transmit diverse cell surface signals throughout the cell . # ::alignments 0-1.2.1.1 2-1.2.1.1 3-1.2.1.2 4-1.2.1.3 8-1.2.r 10-1 13-1.1.3 14-1.1.1.1.1 16-1.1.2.1.1 17-1.1.1.1.2 17-1.1.2.1.2 19-1.1.4 20-1.1.4.1.2 21-1.1.4.1.1.1 22-1.1.4.1.1 23-1.1.4.1 24-1.1.4.2 26-1.1.4.2.1 (p / protein-family~e.10 :mod (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "serine"~e.14 :op2 "kinase"~e.17)) :op2 (e3 / enzyme :name (n3 / name :op1 "threonine"~e.16 :op2 "kinase"~e.17)) :ARG2-of (e / express-03~e.13 :manner (u / ubiquitous)) :ARG0-of (t2 / transmit-01~e.19 :ARG1 (s2 / signal-07~e.23 :mod (s3 / surface~e.22 :mod (c / cell~e.21)) :mod (d / diverse~e.20)) :ARG2 (t3 / throughout~e.24 :op1 (c2 / cell~e.26)))) :domain~e.8 (e4 / enzyme :name (n4 / name :op1 "Mitogen-activated"~e.0,2 :op2 "protein"~e.3 :op3 "kinase"~e.4))) # ::id pmid_2352_4590.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MAPK pathways consist of a three @-@ tiered signalling module activated via a phosphorylation cascade . # ::alignments 0-1.1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.3.1 8-1.2.1 9-1.2 10-1.2.2 13-1.2.2.1.1 14-1.2.2.1 (c / consist-01~e.2 :ARG1 (p / pathway~e.1 :name (n / name :op1 "MAPK"~e.0)) :ARG2~e.3 (m / module~e.9 :ARG0-of (s / signal-07~e.8) :ARG1-of (a / activate-01~e.10 :instrument (c2 / cascade~e.14 :mod (p2 / phosphorylate-01~e.13))) :mod (t / tier :quant 3~e.5))) # ::id pmid_2352_4590.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The most proximal kinase in these pathways , the MAPK kinase kinase ( MAPKKK or MAP3k ) , engaged by extracellular signals , phosphorylates a dual specificity MAPK kinase ( MAPKK or MAP2K ) , which in turn phosphorylates and actives the distil effector MAPK . # ::alignments 1-1.2.4.1 2-1.2.4 3-1.1.3.1.1.2 3-1.1.3.1.1.3 4-1.1.4.2 5-1.2.2.1.1 6-1.2.2.1 9-1.2.1.1 10-1.2.1.2 11-1.2.1.3 18-1.2.3 19-1.2.3.1.r 20-1.2.3.1.1 21-1.2.3.1 23-1 23-1.1 23-1.1.4 23-1.1.4.r 23-1.1.r 25-1.1.2.1 26-1.1.2 27-1.1.1.1 27-1.1.4.1.2.1.1 28-1.1.3.1.1.2 28-1.1.3.1.1.3 36-1.1.4.2 37-1.1.4.2 38-1.1 38-1.1.4 38-1.1.4.r 43-1.1.4.1 44-1.1.1.1 44-1.1.4.1.2.1.1 (p / phosphorylate-01~e.23 :ARG1~e.23 (e6 / enzyme~e.23,38 :name (n2 / name :op1 "MAPK"~e.27,44) :mod (s2 / specificity~e.26 :mod (d / dual~e.25)) :ARG1-of (m2 / mean-01 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MAPK" :op2 "kinase"~e.3,28 :op3 "kinase"~e.3,28))) :ARG2-of~e.23,38 (p8 / phosphorylate-01~e.23,38 :ARG1 (e7 / effector~e.43 :mod (d2 / distal) :mod (e3 / enzyme :name (n / name :op1 "MAPK"~e.27,44))) :mod (i3 / in-turn~e.4,36,37)) :ARG0-of (a / activate-01 :ARG1 e7 :manner i3)) :ARG2 (e5 / enzyme :name (n4 / name :op1 "MAPK"~e.9 :op2 "kinase"~e.10 :op3 "kinase"~e.11) :ARG1-of (i / include-91 :ARG2 (p3 / pathway~e.6 :mod (t / this~e.5))) :ARG1-of (e / engage-01~e.18 :ARG0~e.19 (s / signal-07~e.21 :mod (e2 / extracellular~e.20))) :mod (p4 / proximal~e.2 :degree (m / most~e.1)))) # ::id pmid_2352_4590.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mammalian MAPK pathways are represented by the Extracellular Signal Regulated Kinase ( ERK ) , c @-@ Jun N @-@ terminal kinase , p38 , ERK 5 , ERK 3 @/@ 4 and ERK 7 @/@ 8 pathways . @^{1 @} # ::alignments 0-1.2.2 1-1.2.1.1 2-1.2 4-1 10-1.1.2.1.3 12-1.1.1.1.1 15-1.1.2.1.1 17-1.1.2.1.1 18-1.1.2.1.2 20-1.1.2.1.2 21-1.1.2.1.3 23-1.1.3.1.1 25-1.1.1.1.1 28-1.1.1.1.1 31-1.1.5.1.1 32-1.1 33-1.1.1.1.1 36-1.1.6.1.1 37-1.1.1 37-1.1.2 37-1.1.3 37-1.1.4 37-1.1.5 37-1.1.6 41-1.3.1.1.1 (r / represent-01~e.4 :ARG0 (a / and~e.32 :op1 (p2 / pathway~e.37 :name (n2 / name :op1 "ERK"~e.12,25,28,33)) :op2 (p3 / pathway~e.37 :name (n3 / name :op1 "c-Jun"~e.15,17 :op2 "N-terminal"~e.18,20 :op3 "kinase"~e.10,21)) :op3 (p4 / pathway~e.37 :name (n4 / name :op1 "p38"~e.23)) :op4 (p5 / pathway~e.37 :name (n5 / name :op1 "ERK5")) :op5 (p6 / pathway~e.37 :name (n6 / name :op1 "ERK3/4"~e.31)) :op6 (p7 / pathway~e.37 :name (n7 / name :op1 "ERK7/8"~e.36))) :ARG1 (p / pathway~e.2 :name (n / name :op1 "MAPK"~e.1) :mod (m / mammal~e.0)) :ARG1-of (d / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c / cite-01 :ARG2 1~e.41)))) # ::id pmid_2352_4590.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ras @/@ MAPK pathway is the best characterised of the mammalian MAPK signal transduction networks , consisting of the Ras proteins , a family of small G @-@ coupled molecules , the Raf kinases ( MAP3K ) , the MAP2K kinases ( MEK1 and MEK2 ) and the pathway distil kinases ERK1 and ERK2 . # ::alignments 1-1.1.1.1 3-1.1.2.1.2.1.1 4-1.1 4-1.1.2.1.2 7-1.2 7-1.2.1 7-1.2.1.r 11-1.1.2.1.3 12-1.1.2.1.2.1.1 13-1.1.2.1.1.1 14-1.1.2.1.1 15-1.1.2.1 17-1.1.2.1.4 18-1.1.2.1.4.1.r 20-1.1.2.1.4.1.1.1.1 21-1.1.2.1.4.1.2.1.1.2.1 24-1.1.2.1.4.1.2 26-1.1.2.1.4.1.2.1.1.1 27-1.1.2.1.4.1.2.1.1.2.1.1.1 29-1.1.2.1.4.1.2.1.1.2 30-1.1.2.1.4.1.2.1.1 33-1.1.2.1.4.1.3.1.1 34-1.1.2.1.4.1.3.2.1 36-1.1.2.1.4.1.3.2.1.1.1 40-1.1.2.1.4.1.4.1.1 41-1.1.2.1.4.1.3.2.1 43-1.1.2.1.4.1.4.2.1.1.1.1 45-1.1.2.1.4.1.4.2.1.2.1.1 47-1.1.2.1.4.1.5 49-1.1.2.1.4.1.5.1.3 51-1.1.2.1.4.1.4 51-1.1.2.1.4.1.4.2.1.1 51-1.1.2.1.4.1.4.2.1.2 51-1.1.2.1.4.1.5.1 51-1.1.2.1.4.1.5.2 52-1.1.2.1.4.1.5.1.1.1 53-1.1.2.1.4.1.5 54-1.1.2.1.4.1.5.2.1.1 (c / characterize-01 :ARG1 (p / pathway~e.4 :name (n / name :op1 "Ras/MAPK"~e.1) :ARG1-of (i / include-91 :ARG2 (n2 / network~e.15 :ARG2-of (t / transduce-01~e.14 :ARG1 (s / signal-07~e.13)) :mod (p2 / pathway~e.4 :name (n3 / name :op1 "MAPK"~e.3,12)) :mod (m2 / mammal~e.11) :ARG1-of (c2 / consist-01~e.17 :ARG2~e.18 (a / and :op1 (p3 / protein-family :name (n4 / name :op1 "Ras"~e.20)) :op2 (f / family~e.24 :ARG2-of (i3 / include-91 :ARG1 (m3 / molecule~e.30 :mod (s2 / small~e.26) :ARG1-of (c3 / couple-01~e.29 :ARG2 (p4 / protein~e.21 :name (n5 / name :op1 "G"~e.27)))))) :op3 (p6 / protein-family :name (n6 / name :op1 "Raf"~e.33) :ARG2-of (i4 / include-91 :ARG1 (k7 / kinase~e.34,41 :name (n12 / name :op1 "MAP3K"~e.36)))) :op4 (k2 / kinase~e.51 :name (n7 / name :op1 "MAP2K"~e.40) :ARG2-of (i2 / include-91 :ARG1 (a2 / and :op1 (k3 / kinase~e.51 :name (n8 / name :op1 "MEK1"~e.43)) :op2 (k4 / kinase~e.51 :name (n9 / name :op1 "MEK2"~e.45))))) :op5 (a3 / and~e.47,53 :op1 (k5 / kinase~e.51 :name (n10 / name :op1 "ERK1"~e.52) :mod (d / distal) :mod (p5 / pathway~e.49)) :op2 (k6 / kinase~e.51 :name (n11 / name :op1 "ERK2"~e.54) :mod d :mod p5))))))) :ARG1-of (g / good-02~e.7 :degree~e.7 (m / most~e.7))) # ::id pmid_2352_4590.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ras @/@ MAPK network is frequently deregulated in malignancy and contributes to many of the hallmarks of oncogenesis , including abnormal cellular proliferation , impaired apoptosis , enhanced angiogenesis , metastasis and the development of drug resistance . @^{2 @} # ::alignments 1-1.1.1.1.1 3-1.1.1.1.1 6-1.1.2 7-1.1 8-1.1.3.r 9-1.1.3 10-1 11-1.2 12-1.2.2.r 13-1.2.2.1 14-1.2.2.1.r 16-1.2.2 20-1.2.2.2 21-1.2.2.2.1.1.2 22-1.2.2.2.1.1.1 23-1.2.2.2.1.1 25-1.2.2.2.1.2.1 26-1.2.2.2.1.2 28-1.2.2.2.1.3.1 29-1.2.2.2.1.3 31-1.2.2.2.1.4 32-1.2.2.2.1 34-1.2.2.2.1.5 35-1.2.2.2.1.5.1.r 36-1.2.2.2.1.5.1.1 37-1.2.2.2.1.5.1 41-1.3.1.1.1 (a / and~e.10 :op1 (d / deregulate-01~e.7 :ARG1 (p3 / pathway :name (n2 / name :op1 "Ras/MAPK"~e.1,3)) :ARG1-of (f / frequent-02~e.6) :location~e.8 (m / malignancy~e.9)) :op2 (c / contribute-01~e.11 :ARG0 p3 :ARG2~e.12 (h / hallmark~e.16 :quant~e.14 (m2 / many~e.13) :ARG2-of (i / include-91~e.20 :ARG1 (a2 / and~e.32 :op1 (p / proliferate-01~e.23 :ARG0 (c3 / cell~e.22) :mod (a3 / abnormal~e.21)) :op2 (a4 / apoptosis~e.26 :ARG1-of (i2 / impair-01~e.25)) :op3 (a5 / angiogenesis~e.29 :ARG1-of (e / enhance-01~e.28)) :op4 (m3 / metastasis~e.31) :op5 (d2 / develop-01~e.34 :ARG2~e.35 (r / resist-01~e.37 :ARG1 (d3 / drug~e.36))))) :mod (d5 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer") :ARG1-of (o / originate-01)))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 2~e.41)))) # ::id pmid_2352_4590.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK lies at a critical juncture within the Ras @/@ MAPK pathway , having a limited number of direct upstream MAP3K activators and ERK1 @/@ 2 as its only known cellular targets , thereby making it an attractive target for cancer therapy . # ::alignments 0-1.1.1.1 1-1 2-1.2.r 4-1.2.1 5-1.2 6-1.1.2.1.1.2.r 8-1.2.2.1.1 10-1.2.2.1.1 11-1.2.2 13-1.1.2 15-1.1.2.1.1.1 16-1.1.2.1.1 18-1.1.2.1.1.2.2 19-1.1.2.1.1.2.3 20-1.1.2.1.1.2.1.1.1.1 21-1.1.2.1.1.2 21-1.1.2.1.1.2.1 21-1.1.2.1.1.2.1.r 22-1.1.2.1 23-1.1.2.1.2.1.1 25-1.1.2.1.2.1.1 28-1.1.2.1.3.2 29-1.1.2.1.3.1 30-1.1.2.1.3.3 31-1.1.2.1.3 34-1.3 35-1.3.1.2 37-1.3.1.3 38-1.3.1 39-1.3.1.1.r 40-1.3.1.1.1.2.1 41-1.3.1.1 (l / lie-07~e.1 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.0) :ARG0-of (h / have-03~e.13 :ARG1 (a2 / and~e.22 :op1 (n3 / number~e.16 :ARG1-of (l2 / limit-01~e.15) :quant-of~e.6 (m / molecular-physical-entity~e.21 :ARG0-of~e.21 (a / activate-01~e.21 :ARG1 (e2 / enzyme :name (n4 / name :op1 "MAP3K"~e.20))) :ARG1-of (d / direct-02~e.18) :mod (u / upstream~e.19))) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"~e.23,25)) :ARG1-of (t / target-01~e.31 :ARG1-of (k / know-01~e.29) :mod (o / only~e.28) :mod (c2 / cell~e.30))))) :ARG2~e.2 (j / juncture~e.5 :ARG1-of (c / critical-02~e.4) :location (p / pathway~e.11 :name (n2 / name :op1 "Ras/MAPK"~e.8,10))) :ARG0-of (m2 / make-02~e.34 :ARG1 (t2 / target-01~e.38 :ARG0~e.39 (t4 / therapy~e.41 :mod (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.40))) :ARG1 e~e.35 :ARG0-of (a3 / attract-01~e.37)))) # ::id pmid_2352_4590.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several MEK inhibitors have been developed and investigated in preclinical and clinical models . # ::alignments 0-1.1.1.2 1-1.1.1.1.1.1.1 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 5-1.1 6-1 6-1.3 6-1.3.r 7-1.2 9-1.3.1.1 10-1.3 11-1.3.2.1 12-1.3.1 12-1.3.2 (a / and~e.6 :op1 (d / develop-02~e.5 :ARG1 (m / molecular-physical-entity~e.2 :ARG0-of~e.2 (i / inhibit-01~e.2 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.1))) :quant (s / several~e.0))) :op2 (i2 / investigate-01~e.7 :ARG1 m) :location~e.6 (a2 / and~e.6,10 :op1 (m2 / model~e.12 :mod (p / preclinical~e.9)) :op2 (m3 / model~e.12 :mod (c / clinic~e.11)))) # ::id pmid_2352_4590.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results from these studies have been promising and suggest that MEK inhibitors , whether alone or in combination with other anticancer therapies , may have a significant role to play in the future management of malignancy . # ::alignments 0-1.1.1 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1.1.1.r 2-1.1.1.1.1.1 3-1.1.1.1.1 6-1.1 7-1 8-1.2 9-1.2.2.r 10-1.2.2.1.1.1.1.1.1 11-1.2.2.1.1 11-1.2.2.1.1.1 11-1.2.2.1.1.1.r 14-1.2.2.1.4.1 15-1.2.2.1.4 17-1.2.2.1.4.2 18-1.2.2.1.4.2.2.r 19-1.2.2.1.4.2.2.2 21-1.2.2.1.4.2.2 23-1.2.2 26-1.2.2.1.3 29-1.2.2.1 30-1.2.2.1.2.r 32-1.2.2.1.2.2 33-1.2.2.1.2 34-1.2.2.1.2.1.r 35-1.2.2.1.2.1 (a / and~e.7 :op1 (p / promise-01~e.6 :ARG0 (t / thing~e.0 :ARG2-of~e.0 (r / result-01~e.0 :ARG1~e.1 (s / study-01~e.3 :mod (t2 / this~e.2))))) :op2 (s2 / suggest-01~e.8 :ARG0 t :ARG1~e.9 (p2 / possible-01~e.23 :ARG1 (p3 / play-08~e.29 :ARG0 (m / molecular-physical-entity~e.11 :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"~e.10)))) :ARG1~e.30 (m2 / manage-01~e.33 :ARG1~e.34 (m3 / malignancy~e.35) :mod (f / future~e.32)) :ARG1-of (s3 / significant-02~e.26) :manner (o / or~e.15 :op1 (a2 / alone~e.14) :op2 (c / combine-01~e.17 :ARG1 m :ARG2~e.18 (t3 / therapy~e.21 :ARG0-of (c2 / counter-01 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :mod (o2 / other~e.19)))))))) # ::id pmid_2352_4590.16 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Current management strategies for multiple myeloma ( MM ) involve conventional chemotherapeutics and novel anti @-@ MM agents ( thalidomide , lenalidomide and bortezomib ) , with or without subsequent autologous stem cell transplantation . @^{3 @} # ::alignments 0-1.2.2 1-1.2.1 2-1.2 3-1.2.3.r 4-1.2.3.1.1 5-1.2.3.1.2 9-1 10-1.1.1.2 12-1.1 13-1.1.2.1 14-1.1.2.2 16-1.1.2.2.1 17-1.1.2 19-1.1.2.3.1.1.1.1 21-1.1.2.3.1.2.1.1 22-1.1.2.3.1 23-1.1.2.3.1.3.1.1 26-1.4.r 27-1.4 28-1.4.2.1 28-1.4.2.1.r 29-1.4.1.3 30-1.4.1.1.2 31-1.4.1.1.1.1 32-1.4.1.1.1 33-1.4.1.1 37-1.3.1.1.1 (i / involve-01~e.9 :ARG1 (a / and~e.12 :op1 (t / thing :mod (c2 / chemotherapy) :mod (c3 / conventional~e.10)) :op2 (a2 / agent~e.17 :mod (n2 / novel~e.13) :ARG0-of (c4 / counter-01~e.14 :ARG1 d~e.16) :ARG2-of (i2 / include-91 :ARG1 (a3 / and~e.22 :op1 (s4 / small-molecule :name (n3 / name :op1 "thalidomide"~e.19)) :op2 (s5 / small-molecule :name (n4 / name :op1 "lenalidomide"~e.21)) :op3 (s6 / small-molecule :name (n5 / name :op1 "bortezomib"~e.23)))))) :ARG2 (s / strategy~e.2 :mod (m / manage-01~e.1) :mod (c / current~e.0) :prep-for~e.3 (d / disease :name (n / name :op1 "multiple"~e.4 :op2 "myeloma"~e.5))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG1-of (c6 / cite-01 :ARG2 3~e.37))) :manner~e.26 (o / or~e.27 :op1 (a4 / accompany-01 :ARG0 (t3 / transplant-01~e.33 :ARG1 (c5 / cell~e.32 :mod (s2 / stem~e.31)) :mod (a5 / autologous~e.30)) :ARG1 a :mod (s3 / subsequent~e.29)) :op2 (a6 / accompany-01 :polarity~e.28 -~e.28 :ARG0 t3 :ARG1 a))) # ::id pmid_2352_4590.17 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although these anticancer therapies are typically effective initially , MM remains a fatal and largely incurable disease . # ::alignments 0-1 1-1.2.1.2 3-1.2.1 5-1.2.3 6-1.2 7-1.2.2 9-1.1.1.1.1 9-1.1.1.1.2 10-1.1 12-1.1.2.1.1 13-1.1.2 14-1.1.2.2.1.1 14-1.1.2.2.1.1.r 15-1.1.2.2.1.2.1 16-1.1.2.1 16-1.1.2.2 (h / have-concession-91~e.0 :ARG1 (r / remain-01~e.10 :ARG1 (d / disease :name (n / name :op1 "multiple"~e.9 :op2 "myeloma"~e.9)) :ARG3 (a / and~e.13 :op1 (d2 / disease~e.16 :mod (f / fatal~e.12)) :op2 (d3 / disease~e.16 :ARG2-of (c3 / cure-01 :manner~e.14 (l / large~e.14) :ARG1-of (p / possible-01 :polarity -~e.15))))) :ARG2 (e / effective-04~e.6 :ARG0 (t / therapy~e.3 :ARG0-of (c / counter-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))) :mod (t2 / this~e.1)) :time (i / initial~e.7) :ARG1-of (t3 / typical-02~e.5))) # ::id pmid_2352_4590.18 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is due to the high frequency of relapse and the eventual development of drug resistance . # ::alignments 0-1.2 2-1 3-1 5-1.1.1.2 6-1.1.1 7-1.1.1.1.r 8-1.1.1.1 9-1.1 11-1.1.2.2 12-1.1.2 13-1.1.2.1.r 14-1.1.2.1.1 15-1.1.2.1 (c / cause-01~e.2,3 :ARG0 (a / and~e.9 :op1 (f / frequent-02~e.6 :ARG1~e.7 (r / relapse-01~e.8) :ARG1-of (h / high-02~e.5)) :op2 (d / develop-01~e.12 :ARG2~e.13 (r2 / resist-01~e.15 :ARG1 (d2 / drug~e.14)) :mod (e / eventual~e.11))) :ARG1 (t / this~e.0)) # ::id pmid_2352_4590.19 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Accumulative genetic changes within malignant plasma cells , together with MM interplay with the bone marrow microenvironment ( BMME ) , potentiate disease progression by promoting the deregulation of multiple signal transduction networks , one of which is the Ras @/@ MAPK pathway . @^{4 , 5 @} # ::alignments 0-1.3.1 1-1.3.1 2-1.3.1 3-1.3.2.1.1.r 4-1.2.1.3.2 5-1.2.1.3.1 6-1.2.1.3 9-1.2.2.2.r 10-1.2.2.1.1.1 10-1.2.2.1.1.2 11-1.2.2 12-1.2.2.2.r 14-1.2.2.2.1.1 15-1.2.2.2.1 16-1.2.2.2 21-1 22-1.1.1 23-1.1 25-1.3 27-1.3.2 29-1.3.2.1.1 30-1.3.2.1.2.1 31-1.3.2.1.2 32-1.3.2.1 39-1.3.2.1.3.1.1.1 41-1.3.2.1.3.1.1.1 42-1.3.2.1.3.1 46-1.4.1.1.1.1 50-1.4.1.1.1.2 (p / potentiate-01~e.21 :ARG1 (p3 / progress-01~e.23 :ARG1 (d2 / disease~e.22)) :ARG2 (a / and :op1 (c / change-01 :ARG1-of (a2 / accumulate-01) :mod (g / genetics) :location (c2 / cell~e.6 :mod (p2 / plasma~e.5) :ARG1-of (m / malignant-02~e.4))) :op2 (i / interplay-00~e.11 :mod (d / disease :name (n / name :op1 "multiple"~e.10 :op2 "myeloma"~e.10)) :prep-with~e.9,12 (m2 / microenvironment~e.16 :mod (m3 / marrow~e.15 :mod (b / bone~e.14))))) :manner (p4 / promote-01~e.25 :ARG0 a~e.0,1,2 :ARG1 (d3 / deregulate-01~e.27 :ARG1 (n2 / network~e.32 :quant~e.3 (m4 / multiple~e.29) :ARG2-of (t / transduce-01~e.31 :ARG1 (s / signal-07~e.30)) :ARG2-of (i2 / include-91 :ARG1 (p5 / pathway~e.42 :name (n3 / name :op1 "Ras/MAPK"~e.39,41)))))) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 4~e.46 :op2 5~e.50))))) # ::id pmid_2352_4590.20 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This suggests that MM patients may benefit from the abrogation of this kinase network through the administration of a MEK inhibitor . # ::alignments 0-1.2.1 1-1.2 3-1.1.2.2.1.1 3-1.1.2.2.1.2 4-1.1.2.1.1 5-1 6-1.1 7-1.1.1.r 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1.2 12-1.1.1.1.1 13-1.1.1.1 16-1.1.1.2 17-1.1.1.2.1.r 19-1.1.1.2.1.1.1.1.1 20-1.1.1.2.1 20-1.1.1.2.1.1 20-1.1.1.2.1.1.r (p / possible-01~e.5 :ARG1 (b / benefit-01~e.6 :ARG0~e.7 (a / abrogate-01~e.9 :ARG1~e.10 (n2 / network~e.13 :mod (k / kinase~e.12) :mod (t / this~e.11)) :manner (a2 / administer-01~e.16 :ARG1~e.17 (m / molecular-physical-entity~e.20 :ARG0-of~e.20 (i / inhibit-01~e.20 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK"~e.19)))))) :ARG1 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.4)) :mod (d / disease :name (n / name :op1 "multiple"~e.3 :op2 "myeloma"~e.3)))) :ARG1-of (s / suggest-01~e.1 :ARG0 (t2 / this~e.0))) # ::id pmid_2352_4590.21 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here , we discuss the Ras @/@ MAPK pathway , its involvement in MM and the role of MEK inhibitors in the future management of the disease . # ::alignments 0-1.3 2-1.1 3-1 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2.1 10-1.2.2.1 10-1.2.2.1.r 11-1.2.2 12-1.2.2.2.r 13-1.2.2.2.1.1 13-1.2.2.2.1.2 14-1.2 16-1.2.3 17-1.2.3.1.r 18-1.2.3.1.1.1.1.1 19-1.2.3.1 19-1.2.3.1.1 19-1.2.3.1.1.r 20-1.2.3.2.r 22-1.2.3.2.2 23-1.2.3.2 24-1.2.3.2.1.r 26-1.2.3.2.1 (d / discuss-01~e.3 :ARG0 (w / we~e.2) :ARG1 (a / and~e.14 :op1 (p / pathway~e.8 :name (n / name :op1 "Ras/MAPK"~e.5,7)) :op2 (i / involve-01~e.11 :ARG1~e.10 p~e.10 :ARG2~e.12 (d2 / disease :name (n4 / name :op1 "multiple"~e.13 :op2 "myeloma"~e.13))) :op3 (r / role~e.16 :poss~e.17 (m / molecular-physical-entity~e.19 :ARG0-of~e.19 (i2 / inhibit-01~e.19 :ARG1 (p2 / protein-family :name (n3 / name :op1 "MEK"~e.18)))) :purpose~e.20 (m2 / manage-01~e.23 :ARG1~e.24 d2~e.26 :mod (f / future~e.22)))) :medium (h / here~e.0)) # ::id pmid_2352_4590.22 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overview of the Ras/Raf/MEK/ERK pathway # ::alignments 1-1 2-1.1.r 4-1.1.1.1 5-1.1 (o / overview~e.1 :poss~e.2 (p / pathway~e.5 :name (n / name :op1 "Ras/Raf/MEK/ERK"~e.4))) # ::id pmid_2352_4590.23 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Members of the Ras protein subfamily ( H-, K @- and N @-@ Ras ) function as molecular switches in cellular signal transduction . # ::alignments 0-1.1 3-1.1.1.1.1.1 4-1.1.1.1 8-1.1.2.1.2.1.1 10-1.1.2.1 11-1.1.2.1.3.1.1 13-1.1.1.1.1.1 15-1 16-1.2.r 16-1.3.r 17-1.2.1 18-1.2 20-1.3.1.1 21-1.3.1 22-1.3 (f / function-01~e.15 :ARG0 (m / member~e.0 :ARG1-of (i2 / include-91 :ARG2 (p / protein-family~e.4 :name (n / name :op1 "Ras"~e.3,13))) :ARG1-of (m3 / mean-01 :ARG2 (a / and~e.10 :op1 (e / enzyme :name (n2 / name :op1 "H-Ras")) :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras"~e.8)) :op3 (e3 / enzyme :name (n4 / name :op1 "N-Ras"~e.11))))) :ARG1~e.16 (s2 / switch-01~e.18 :mod (m2 / molecule~e.17)) :time~e.16 (t / transduce-01~e.22 :ARG1 (s3 / signal-07~e.21 :location (c / cell~e.20)))) # ::id pmid_2352_4590.24 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Diverse growth factor , mitogen and cytokine engagement of cognate receptors leads to the recruitment of the GDP @/@ GTP exchange factors , growth @-@ factor @-@ receptor bound protein 2 ( Grp2 ) and Sons of Sevenless ( SOS ) to the plasma membrane where Ras resides . # ::alignments 0-1.1.3 1-1.1.1.1 2-1.1.1.1 4-1.1.1.2 5-1.1.1 6-1.1.1.3 7-1.1 8-1.1.2.r 9-1.1.2.1 10-1.1.2 11-1 12-1.2.r 14-1.2 15-1.2.1.r 17-1.2.1.1.1.1.1.1 19-1.2.1.1.1.2.1.1 20-1.2.1.1.1 21-1.2.1.1 21-1.2.1.2.1.1 23-1.2.1.2.1.1 25-1.2.1.1 25-1.2.1.2.1.1 27-1.2.1.2.1.1 28-1.2.1.2.1.2 29-1.2.1.2 29-1.2.1.3 34-1.2.1 35-1.2.1.3.1.1 36-1.2.1.3.1.2 37-1.2.1.3.1.3 41-1.2.2.r 43-1.2.2.1 44-1.2.2 46-1.2.2.2.1.1.1 47-1.2.2.2 (l / lead-03~e.11 :ARG0 (e / engage-01~e.7 :ARG0 (a / and~e.5 :op1 (g / growth-factor~e.1,2) :op2 (m / mitogen~e.4) :op3 (c / cytokine~e.6)) :ARG1~e.8 (r / receptor~e.10 :mod (c2 / cognate~e.9)) :mod (d / diverse~e.0)) :ARG2~e.12 (r2 / recruit-01~e.14 :ARG1~e.15 (a2 / and~e.34 :op1 (f / factor~e.21,25 :ARG0-of (e3 / exchange-01~e.20 :ARG1 (s / small-molecule :name (n2 / name :op1 "GDP"~e.17)) :ARG3 (s2 / small-molecule :name (n6 / name :op1 "GTP"~e.19)))) :op2 (p / protein~e.29 :name (n3 / name :op1 "growth-factor-receptor"~e.21,23,25,27 :op2 "bound"~e.28 :op3 "protein2")) :op3 (p3 / protein~e.29 :name (n4 / name :op1 "Sons"~e.35 :op2 "of"~e.36 :op3 "Sevenless"~e.37))) :ARG2~e.41 (m2 / membrane~e.44 :mod (p2 / plasma~e.43) :ARG1-of (r3 / reside-01~e.47 :ARG0 (e4 / enzyme :name (n5 / name :op1 "Ras"~e.46)))))) # ::id pmid_2352_4590.25 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The grp2 @/@ SOS complex then promotes inactive Ras to exchange GDP with GTP and enters an activated state . @^{6 @} # ::alignments 1-1.1.1.1.1 3-1.1.2.1.1 4-1.1 5-1.4 6-1 7-1.2.2.1 8-1.2.1.1 9-1.3.r 10-1.3.1 11-1.3.1.1.1.1 12-1.3.1.2.r 13-1.3.1.2.1.1 14-1.3 15-1.3.2 17-1.2.2 17-1.3.2.2.1 18-1.3.2.2 22-1.5.1.1.1 (p / promote-01~e.6 :ARG0 (m / macro-molecular-complex~e.4 :part (p3 / protein :name (n / name :op1 "grp2"~e.1)) :part (p4 / protein :name (n5 / name :op1 "SOS"~e.3))) :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.8) :ARG1-of (a2 / activate-01~e.17 :polarity -~e.7)) :ARG2~e.9 (a / and~e.14 :op1 (e2 / exchange-01~e.10 :ARG1 (s / small-molecule :name (n3 / name :op1 "GDP"~e.11)) :ARG3~e.12 (s2 / small-molecule :name (n4 / name :op1 "GTP"~e.13))) :op2 (e3 / enter-01~e.15 :ARG0 e :ARG1 (s3 / state~e.18 :ARG1-of (a3 / activate-01~e.17)))) :time (t / then~e.5) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c / cite-01 :ARG2 6~e.22)))) # ::id pmid_2352_4590.26 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated Ras then recruits Raf to the cell membrane , where it is activated by phosphorylation . # ::alignments 0-1.1.2 1-1.1.1.1 2-1.4 3-1 4-1.2.1.1 5-1.3.r 7-1.3.1 8-1.3 10-1.3.2.r 11-1.3.2.1 13-1.3.2 14-1.3.2.2.r 15-1.3.2.2 (r / recruit-01~e.3 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.1) :ARG1-of (a / activate-01~e.0)) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf"~e.4)) :ARG2~e.5 (m / membrane~e.8 :mod (c / cell~e.7) :location-of~e.10 (a2 / activate-01~e.13 :ARG1 e2~e.11 :manner~e.14 (p / phosphorylate-01~e.15))) :time (t / then~e.2)) # ::id pmid_2352_4590.27 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This process is antagonised by GTPase @-@ activating proteins , which promote GTP hydrolysis and the formation of inactive Ras @-@ GDP complexes . @^{7 @} # ::alignments 0-1.2.1 1-1.2 5-1.1.1.1.1.1 7-1.1.1 7-1.1.2.1.2.1.1 8-1.1 11-1.1.2 12-1.1.2.1.1.1.1.1 13-1.1.2.1.1 14-1.1.2.1 16-1.1.2.1.2 17-1.1.2.1.2.1.r 18-1.1.2.1.2.1.1.1 19-1.1.2.1.2.1.2.1.1 21-1.1.2.1.2.1.3.1.1 22-1.1.2.1.2.1 26-1.3.1.1.1 (a / antagonize-02 :ARG1 (p2 / protein~e.8 :ARG0-of (a2 / activate-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "GTPase"~e.5))) :ARG0-of (p3 / promote-01~e.11 :ARG1 (a3 / and~e.14 :op1 (h / hydrolyze-01~e.13 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"~e.12))) :op2 (f / form-01~e.16 :ARG1~e.17 (m / macro-molecular-complex~e.22 :ARG1-of (a4 / activate-01~e.7 :polarity -~e.18) :part (e2 / enzyme :name (n3 / name :op1 "Ras"~e.19)) :part (s2 / small-molecule :name (n4 / name :op1 "GDP"~e.21))))))) :ARG2 (p / process-02~e.1 :mod (t / this~e.0)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 7~e.26)))) # ::id pmid_2352_4590.28 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Approximately 30 % of malignancies contain activating mutations in a Ras proto @-@ oncogene , with pancreatic ( 90 %) , colon ( 50 %) and thyroid ( 50 %) carcinomas demonstrating the highest prevalence . # ::alignments 0-1.1.2.2 1-1.1.2.2.1.1 2-1.1.1.1.1.1 2-1.1.1.1.2.1 2-1.1.1.1.3.1 2-1.1.2.2.1 4-1.1 4-1.1.2.1 5-1 6-1.2.2 7-1.2 8-1.2.1.r 10-1.2.1.1.1.1.1 11-1.2.1 13-1.2.1 16-1.1.1.1.1.2 18-1.1.1.1.1.1.1 21-1.1.1.1.2.2 23-1.1.1.1.2.1.1 23-1.1.1.1.3.1.1 25-1.1.1.1 26-1.1.1.1.3.2 28-1.1.1.1.2.1.1 30-1.1.1.1.1 30-1.1.1.1.2 30-1.1.1.1.3 31-1.1.1.1.4 33-1.1.1.1.4.1.1 33-1.1.1.1.4.1.1.1 33-1.1.1.1.4.1.1.1.r 34-1.1.1.1.4.1 (c / contain-01~e.5 :ARG0 (m / malignancy~e.4 :ARG2-of (i2 / include-91 :ARG1 (a2 / and~e.25 :op1 (c5 / carcinoma~e.30 :value (p4 / percentage-entity~e.2 :value 90~e.18) :mod (p3 / pancreas~e.16)) :op2 (c4 / carcinoma~e.30 :value (p5 / percentage-entity~e.2 :value 50~e.23,28) :mod (c6 / colon~e.21)) :op3 (c7 / carcinoma~e.30 :value (p6 / percentage-entity~e.2 :value 50~e.23) :mod (t2 / thyroid~e.26)) :ARG0-of (d / demonstrate-01~e.31 :ARG1 (p7 / prevalence~e.34 :ARG1-of (h / high-02~e.33 :degree~e.33 (m3 / most~e.33)))))) :ARG1-of (i3 / include-91 :ARG2 (m4 / malignancy~e.4) :ARG3 (a3 / approximately~e.0 :op1 (p / percentage-entity~e.2 :value 30~e.1)))) :ARG1 (m2 / mutate-01~e.7 :ARG1~e.8 (p8 / proto-oncogene~e.11,13 :ARG1-of (i / include-91 :ARG2 (p2 / protein-family :name (n / name :op1 "Ras"~e.10)))) :ARG0-of (a / activate-01~e.6))) # ::id pmid_2352_4590.29 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutations typically affect K @-@ Ras and N @-@ Ras , but rarely H @-@ Ras , and occur in a mutually exclusive manner . @^{8 @} # ::alignments 0-1.1.1 1-1.1.3 2-1.1 2-1.1.2.3.1 2-1.1.2.3.1.3 2-1.1.2.3.1.3.r 3-1.1.2.1.2.1 5-1.1.2.1.2.1 5-1.1.2.2.2.1 6-1.1.2 7-1.1.2.2.2.1 9-1.1.2.1.2.1 9-1.1.2.2.2.1 11-1.1.2.3 12-1.1.2.3.1.3.2 13-1.1.2.3.1.2.1 15-1.1.2.1.2.1 15-1.1.2.2.2.1 15-1.1.2.3.1.2.1 17-1.1.2 21-1.2.1 23-1.2.1.r 23-1.2.2.r 27-1.3.1.1.1 (a / and :op1 (a2 / affect-01~e.2 :ARG0 (m / mutate-01~e.0) :ARG1 (a3 / and~e.6,17 :op1 (e / enzyme :wiki "KRAS" :name (n / name :op1 "K-Ras"~e.3,5,9,15)) :op2 (e2 / enzyme :wiki "Neuroblastoma_RAS_viral_oncogene_homolog" :name (n2 / name :op1 "N-Ras"~e.5,7,9,15)) :ARG1-of (c / contrast-01~e.11 :ARG2 (e3 / enzyme~e.2 :wiki "HRAS" :name (n3 / name :op1 "H-Ras"~e.13,15) :ARG1-of~e.2 (a4 / affect-01~e.2 :ARG0 m :ARG1-of (r / rare-02~e.12))))) :ARG1-of (t / typical-02~e.1)) :op2 (e4 / exclude-01 :manner~e.23 (m2 / mutual~e.21) :manner-of~e.23 m) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG1-of (c2 / cite-01 :ARG2 8~e.27)))) # ::id pmid_2352_4590.30 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Raf family of serine @/@ threonine kinases ( A-, B @- and c @-@ Raf ( Raf @-@ 1 )) lie at the apex of the MEK @/@ ERK pathway . # ::alignments 1-1.1.1.1 2-1.1 4-1.1.2.1.1.1.1 6-1.1.2.1.2.1.1 7-1.1.2.1.1.1.2 7-1.1.2.1.2.1.2 10-1.1.2.1.3.1.2.1.1 12-1.1.2.1.3.1 13-1.1.2.1.3.1.3.1.1 15-1.1.1.1 17-1.1.1.1 21-1 22-1.2.r 24-1.2 25-1.2.1.r 27-1.2.1.1.1 29-1.2.1.1.1 30-1.2.1 (l / lie-07~e.21 :ARG1 (p2 / protein-family~e.2 :name (n / name :op1 "Raf"~e.1,15,17) :ARG2-of (i2 / include-91 :ARG1 (o / or :op1 (e7 / enzyme :name (n2 / name :op1 "serine"~e.4 :op2 "kinase"~e.7)) :op2 (e2 / enzyme :name (n3 / name :op1 "threonine"~e.6 :op2 "kinase"~e.7)) :ARG2-of (i / include-91 :ARG1 (a / and~e.12 :op1 (e4 / enzyme :name (n4 / name :op1 "A-Raf")) :op2 (e5 / enzyme :name (n5 / name :op1 "B-Raf"~e.10)) :op3 (e6 / enzyme :name (n6 / name :op1 "c-Raf"~e.13))))))) :ARG2~e.22 (a2 / apex~e.24 :poss~e.25 (p / pathway~e.30 :name (n7 / name :op1 "MEK/ERK"~e.27,29)))) # ::id pmid_2352_4590.31 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All three Raf isoforms share similar structural characteristics . # ::alignments 0-1.1.2 1-1.1.1 2-1.1.3.1.1 3-1.1 4-1 5-1.2.2 6-1.2.1.1 7-1.2 7-1.2.1 7-1.2.1.r (s / share-01~e.4 :ARG0 (i / isoform~e.3 :quant (t / three~e.1) :mod (a / all~e.0) :mod (e / enzyme :name (n / name :op1 "Raf"~e.2))) :ARG1 (t2 / thing~e.7 :ARG2-of~e.7 (c / characteristic-02~e.7 :ARG1 (s2 / structure~e.6)) :ARG1-of (r / resemble-01~e.5))) # ::id pmid_2352_4590.32 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , they differ in their ability to phosphorylate and activate MEK , with B @-@ Raf demonstrating higher basal kinase activity compared with Raf @-@ 1 and A @-@ Raf . @^{9 , 10 @} # ::alignments 0-1 2-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.1 5-1.1.2.1.r 6-1.1.2 7-1.1.2.2.r 8-1.1.2.2.1 9-1.1.2.2 10-1.1.2.2.2 11-1.1.2.2.1.1.1.1 13-1.1.3.r 14-1.1.3.1.1.1 16-1.1.3.1.1.1 17-1.1.3 18-1.1.3.2.2 18-1.1.3.2.2.1 18-1.1.3.2.2.1.r 19-1.1.3.2.1.1 20-1.1.3.2.1 21-1.1.3.2 22-1.1.3.2.3.r 24-1.1.3.2.3.1.1.1 24-1.1.3.2.3.2.1.1 26-1.1.3.2.3.1.1.1 27-1.1.3.2.3 28-1.1.3.2.3.2.1.1 30-1.1.3.1.1.1 30-1.1.3.2.3.2.1.1 34-1.2.1.1.1.1 38-1.2.1.1.1.2 (c3 / contrast-01~e.0 :ARG2 (d / differ-02~e.3 :ARG1 (t / they~e.2) :ARG3~e.4 (c / capable-01~e.6 :ARG1~e.5 t~e.5 :ARG2~e.7 (a / and~e.9 :op1 (p / phosphorylate-01~e.8 :ARG1 (e4 / enzyme :name (n4 / name :op1 "MEK"~e.11))) :op2 (a2 / activate-01~e.10 :ARG1 e4))) :manner~e.13 (d2 / demonstrate-01~e.17 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf"~e.14,16,30)) :ARG1 (a3 / activity-06~e.21 :ARG0 (k / kinase~e.20 :mod (b / basal~e.19)) :ARG1-of (h / high-02~e.18 :degree~e.18 (m / more~e.18)) :compared-to~e.22 (a4 / and~e.27 :op1 (e2 / enzyme :name (n2 / name :op1 "Raf-1"~e.24,26)) :op2 (e3 / enzyme :name (n3 / name :op1 "A-Raf"~e.24,28,30)))))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a5 / and :op1 9~e.34 :op2 10~e.38))))) # ::id pmid_2352_4590.33 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activating B @-@ Raf mutations have been described in 66 % of melanomas and to a lesser degree in other solid tumours . @^{11 @} # ::alignments 0-1.1.2 1-1.1.1.1.1 3-1.1.1.1.1 4-1.1 7-1 7-1.2 7-1.2.r 8-1.3.r 9-1.3.1.2.1.1 10-1.3.1.2.1 12-1.3.1.1.1 13-1.3 16-1.3.2.3.1 16-1.3.2.3.1.1 16-1.3.2.3.1.1.r 17-1.3.2.3 17-1.3.2.3.1.1.r 19-1.3.2.1 20-1.3.2.2 21-1.3.2 25-1.2.1.1.1 (d / describe-01~e.7 :ARG1 (m / mutate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"~e.1,3)) :ARG0-of (a / activate-01~e.0)) :ARG1-of~e.7 (d3 / describe-01~e.7 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 11~e.25))) :location~e.8 (a2 / and~e.13 :op1 (m5 / medical-condition :name (n2 / name :op1 "melanoma"~e.12) :ARG1-of (i / include-91 :ARG3 (p / percentage-entity~e.10 :value 66~e.9))) :op2 (t / tumor~e.21 :mod (o / other~e.19) :ARG1-of (s / solid-02~e.20) :quant (d2 / degree~e.17 :mod (l / less~e.16 :degree~e.16,17 (m4 / more~e.16)) :compared-to p)))) # ::id pmid_2352_4590.34 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The clinical relevance of this association is reinforced by the exquisite sensitivity of these B @-@ Raf mutated tumours to MEK inhibition . @^{12 @} # ::alignments 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1 5-1.1.2 7-1 8-1.2.r 10-1.2.3 11-1.2 12-1.2.1.r 13-1.2.1.2 14-1.2.1.1.1.1.1 16-1.2.1.1.1.1.1 17-1.2.1.1 18-1.2.1 19-1.2.2.r 20-1.2.2.1.1.1 21-1.2.2 25-1.3.1.1.1 (r / reinforce-01~e.7 :ARG1 (r2 / relevance~e.2 :mod (c / clinical~e.1) :poss~e.3 (a / associate-01~e.5 :mod (t / this~e.4))) :ARG2~e.8 (s / sensitive-03~e.11 :ARG0~e.12 (t2 / tumor~e.18 :ARG2-of (m / mutate-01~e.17 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf"~e.14,16))) :mod t~e.13) :ARG1~e.19 (i / inhibit-01~e.21 :ARG1 (e3 / enzyme :name (n2 / name :op1 "MEK"~e.20))) :mod (e / exquisite~e.10)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 12~e.25)))) # ::id pmid_2352_4590.35 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite a high prevalence of activating B @-@ Raf mutations in melanoma and solid tumours , these mutations are infrequent in MM . @^{13 @} # ::alignments 0-1 2-1.2.2 3-1.2 4-1.2.1.r 5-1.2.1.2 6-1.2.1.1.1.1 8-1.2.1.1.1.1 9-1.2.1 10-1.2.3.r 11-1.2.3.1.1.1 12-1.2.3 13-1.2.3.2.1 14-1.2.3.2 16-1.2.1.3 17-1.2.1 19-1.1 19-1.1.1 19-1.1.1.r 20-1.1.3.r 21-1.1.3.1.1 21-1.1.3.1.2 25-1.3.1.1.1 (h / have-concession-91~e.0 :ARG1 (f2 / frequent-02~e.19 :polarity~e.19 -~e.19 :ARG1 m :location~e.20 (d3 / disease :name (n3 / name :op1 "multiple"~e.21 :op2 "myeloma"~e.21))) :ARG2 (p / prevail-02~e.3 :ARG1~e.4 (m / mutate-01~e.9,17 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"~e.6,8)) :ARG0-of (a / activate-01~e.5) :mod (t2 / this~e.16)) :ARG1-of (h2 / high-02~e.2) :location~e.10 (a2 / and~e.12 :op1 (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.11)) :op2 (t / tumor~e.14 :ARG1-of (s / solid-02~e.13)))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 13~e.25)))) # ::id pmid_2352_4590.36 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This suggests that molecules other than B @-@ Raf or alternative kinase pathways may have a crucial role in MM tumourigenesis . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1 6-1.2.1.1.1.1.1.1.1 8-1.2.1.1.1.1.1.1.1 9-1.2.1.1.1.1 10-1.2.1.1.1.1.2.2 11-1.2.1.1.1.1.2.1 12-1.2.1.1.1.1.2 13-1.2 14-1.2.1 16-1.2.1.2.1 17-1.2.1.2 18-1.2.1.2.2.r 19-1.2.1.2.2.1.1.1 19-1.2.1.2.2.1.1.2 20-1.2.1.2.2 (s / suggest-01~e.1 :ARG0 (t / this~e.0) :ARG1~e.2 (p / possible-01~e.13 :ARG1 (h / have-03~e.14 :ARG0 (m / molecule~e.3 :ARG2-of (e2 / except-01 :ARG1 (o / or~e.9 :op1 (e / enzyme :name (n / name :op1 "B-Raf"~e.6,8)) :op2 (p2 / pathway~e.12 :mod (k / kinase~e.11) :mod (a / alternative~e.10))))) :ARG1 (r / role~e.17 :mod (c / crucial~e.16) :topic~e.18 (t3 / tumourigenesis~e.20 :mod (d2 / disease :name (n3 / name :op1 "multiple"~e.19 :op2 "myeloma"~e.19))))))) # ::id pmid_2352_4590.37 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK is a unique dual specificity kinase that phosphorylates both serine @/@ threonine and tyrosine residues . @^{14 @} # ::alignments 0-1.2.1.1 1-1.2.r 3-1.1.2 4-1.1.1 5-1.1 6-1 8-1.3 9-1.3.1.3 10-1.3.1.1.1.1.1 11-1.3.1.1 12-1.3.1.1.2.1.1 13-1.3.1 14-1.3.1.2.1.1.1 15-1.3.1.2 19-1.4.1.1.1 (k / kinase~e.6 :mod (s / specificity~e.5 :mod (d / dual~e.4) :mod (u / unique~e.3)) :domain~e.1 (e / enzyme :name (n / name :op1 "MEK"~e.0)) :ARG2-of (p / phosphorylate-01~e.8 :ARG1 (a / and~e.13 :op1 (s2 / slash~e.11 :op1 (a2 / amino-acid :name (n2 / name :op1 "serine"~e.10)) :op2 (a3 / amino-acid :name (n3 / name :op1 "threonine"~e.12))) :op2 (r / residue~e.15 :mod (a4 / amino-acid :name (n4 / name :op1 "tyrosine"~e.14))) :mod (b / both~e.9))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 14~e.19)))) # ::id pmid_2352_4590.38 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK consists of two isoforms , MEK1 and MEK2 , which in turn phosphorylate ERK1 and ERK2 . @^{15 @} # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.1 4-1.2 6-1.2.3.1.1.1.1 7-1.2.3.1 8-1.2.3.1.2.1.1 11-1.2.2 12-1.2.2 13-1.2.3.1.1 13-1.2.3.1.1.2 13-1.2.3.1.1.2.r 13-1.2.3.1.2 13-1.2.3.1.2.2 13-1.2.3.1.2.2.r 14-1.2.3.1.1.2.1.1.1 15-1.2.3.1 16-1.2.3.1.2.2.1.1.1 20-1.3.1.1.1 (c / consist-01~e.1 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"~e.0)) :ARG2~e.2 (i / isoform~e.4 :quant 2~e.3 :mod (i2 / in-turn~e.11,12) :ARG1-of (m / mean-01 :ARG2 (a / and~e.7,15 :op1 (e3 / enzyme~e.13 :name (n2 / name :op1 "MEK1"~e.6) :ARG2-of~e.13 (p2 / phosphorylate-01~e.13 :ARG1 (e5 / enzyme :name (n4 / name :op1 "ERK1"~e.14)))) :op2 (e4 / enzyme~e.13 :name (n3 / name :op1 "MEK2"~e.8) :ARG1-of~e.13 (p3 / phosphorylate-01~e.13 :ARG2 (e6 / enzyme :name (n5 / name :op1 "ERK2"~e.16))))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 15~e.20)))) # ::id pmid_2352_4590.39 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated ERK1 @/@ 2 control a diverse range of cellular processes through their many substrates (> 160 ) that are located in cellular membranes , the cytoplasm and nucleus . # ::alignments 0-1.1.3 1-1.1.1.1.1 4-1 6-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.1 10-1.2.1 12-1.3.1 12-1.3.1.r 13-1.3.2 14-1.3 16-1.3.4.1 20-1.3.3 21-1.3.3.1.r 22-1.3.3.1.1.1 23-1.3.3.1.1 26-1.3.3.1.2 27-1.3.3.1 28-1.3.3.1.3 (c / control-01~e.4 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "ERK1"~e.1)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2")) :ARG1-of (a2 / activate-01~e.0)) :ARG1 (r / range-01~e.7 :ARG1~e.8 (p / process~e.10 :mod (c2 / cell~e.9)) :mod (d / diverse~e.6)) :ARG2 (s / substrate~e.14 :poss~e.12 a~e.12 :quant (m2 / many~e.13) :ARG1-of (l / locate-01~e.20 :location~e.21 (a4 / and~e.27 :op1 (m4 / membrane~e.23 :mod (c3 / cell~e.22)) :op2 (c4 / cytoplasm~e.26) :op3 (n4 / nucleus~e.28))) :quant (m3 / more-than :op1 160~e.16))) # ::id pmid_2352_4590.40 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Many of these are transcription factors that are important in cellular proliferation , differentiation , survival , angiogenesis and migration . @^{16 @} # ::alignments 0-1.5 1-1.5.r 2-1.4.1 4-1.1 5-1 8-1.2 9-1.2.1.r 10-1.2.1.1.1 11-1.2.1.1 13-1.2.1.2 15-1.2.1.3 17-1.2.1.4 18-1.2.1 19-1.2.1.5 23-1.3.1.1.1 (f / factor~e.5 :ARG0-of (t / transcribe-01~e.4) :mod (i / important~e.8 :topic~e.9 (a / and~e.18 :op1 (p / proliferate-01~e.11 :ARG0 (c / cell~e.10)) :op2 (d / differentiate-01~e.13 :ARG1 c) :op3 (s / survive-01~e.15 :ARG0 c) :op4 (a2 / angiogenesis~e.17) :op5 (m2 / migrate-01~e.19 :ARG0 c))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 16~e.23))) :ARG1-of (i2 / include-91 :ARG2 (t3 / this~e.2)) :quant~e.1 (m / many~e.0)) # ::id pmid_2352_4590.41 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Physiological activation of the Ras @/@ MAPK pathway is also influenced by multiple mechanisms . # ::alignments 0-1.2.2 1-1.2 2-1.2.1.r 4-1.2.1.1.1 6-1.2.1.1.1 7-1.2.1 9-1.3 10-1 11-1.1.r 12-1.1.1 13-1.1 (i / influence-01~e.10 :ARG0~e.11 (m / mechanism~e.13 :quant (m2 / multiple~e.12)) :ARG1 (a / activate-01~e.1 :ARG1~e.2 (p2 / pathway~e.7 :name (n / name :op1 "Ras/MAPK"~e.4,6)) :mod (p / physiology~e.0)) :mod (a2 / also~e.9)) # ::id pmid_2352_4590.42 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibitory molecules , such as Sprouty proteins ( SPRY ) and MAPK phosphatases ( MKP or DUSPs ) , engage the pathway at different points to negatively regulate signalling . @^{17 , 18 @} # ::alignments 0-1.1.1 1-1.1 3-1.1.2.r 4-1.1.2.r 5-1.1.2.1.1.1 6-1.1.2.1 10-1.1.2 11-1.1.2.2.2.1.1 12-1.1.2.2.1.1 14-1.1.2.2.3.1.1.1.1 15-1.1.2.2.3.1 19-1 21-1.2 22-1.2.2.r 23-1.2.2 24-1.2.1 25-1.3.r 26-1.3 27-1.3 28-1.3.1 32-1.4.1.1.1.1 36-1.4.1.1.1.2 (e / engage-01~e.19 :ARG0 (m / molecule~e.1 :ARG0-of (i / inhibit-01~e.0) :example~e.3,4 (a / and~e.10 :op1 (p5 / protein~e.6 :name (n5 / name :op1 "Sprouty"~e.5)) :op2 (e6 / enzyme :name (n2 / name :op1 "phosphatase"~e.12) :mod (e4 / enzyme :name (n6 / name :op1 "MAPK"~e.11)) :ARG1-of (m3 / mean-01 :ARG0 (o / or~e.15 :op1 (e3 / enzyme :name (n / name :op1 "MKP"~e.14)) :op2 (e5 / enzyme :name (n7 / name :op1 "DUSP"))))))) :ARG1 (p3 / pathway~e.21 :location (p4 / point~e.24) :ARG1-of~e.22 (d / differ-02~e.23)) :ARG2~e.25 (d3 / downregulate-01~e.26,27 :ARG1 (s3 / signal-07~e.28) :ARG2 p3) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 17~e.32 :op2 18~e.36))))) # ::id pmid_2352_4590.43 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated ERK induces the expression of these inhibitory factors . # ::alignments 0-1.1.2 1-1.1.1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.2 7-1.2.1.1 8-1.2.1 (i / induce-01~e.2 :ARG0 (e / enzyme :name (n / name :op1 "ERK"~e.1) :ARG1-of (a / activate-01~e.0)) :ARG2 (e2 / express-03~e.4 :ARG1~e.5 (f / factor~e.8 :ARG1-of (i2 / inhibit-01~e.7) :mod (t / this~e.6)))) # ::id pmid_2352_4590.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , certain DUSPs , induced by ERK @-@ regulated transcription factors , dephosphorylate ERK . @^{19 @} # ::alignments 0-1 1-1 3-1.1.2.2 6-1.1.2.3 7-1.1.2.3.1.r 8-1.1.2.3.1.2.1 10-1.1.2.3.1.2 11-1.1.2.3.1.1 12-1.1.2.3.1 14-1.1 15-1.1.1.1.1 19-1.2.1.1.1 (e / exemplify-01~e.0,1 :ARG0 (d / dephosphorylate-01~e.14 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK"~e.15)) :ARG2 (e3 / enzyme :name (n3 / name :op1 "DUSP") :mod (c / certain~e.3) :ARG2-of (i / induce-01~e.6 :ARG0~e.7 (f / factor~e.12 :ARG0-of (t / transcribe-01~e.11) :ARG1-of (r / regulate-01~e.10 :ARG0 e2~e.8))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 19~e.19)))) # ::id pmid_2352_4590.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Downstream signalling from B @-@ Raf , Raf @-@ 1 and MEK1 may also be diminished following ERK @-@ mediated phosphorylation . @^{20 , 21 @} # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 5-1.1.1.1.1.1.1 5-1.1.1.1.2.1.1 7-1.1.1.1.1.1.1 7-1.1.1.1.2.1.1 9-1.1.1.1.2.1.1 10-1.1.1.1 11-1.1.1.1.3.1.1 12-1 13-1.2 15-1.1 16-1.4 17-1.4.1.1.1.1.1 19-1.4.1.1 20-1.4.1 24-1.3.1.1.1.1 28-1.3.1.1.1.2 (p / possible-01~e.12 :ARG1 (d / diminish-01~e.15 :ARG1 (s / signal-07~e.1 :ARG0~e.2 (a2 / and~e.10 :op1 (e / enzyme :name (n / name :op1 "B-Raf"~e.3,5,7)) :op2 (e2 / enzyme :name (n2 / name :op1 "Raf-1"~e.5,7,9)) :op3 (e3 / enzyme :name (n3 / name :op1 "MEK1"~e.11))) :direction (d2 / downstream~e.0))) :mod (a / also~e.13) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 20~e.24 :op2 21~e.28)))) :ARG1-of (f / follow-01~e.16 :ARG2 (p2 / phosphorylate-01~e.20 :ARG1-of (m / mediate-01~e.19 :ARG0 (e4 / enzyme :name (n4 / name :op1 "ERK"~e.17)))))) # ::id pmid_2352_4590.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These various mechanisms fine tune the activity of the Ras @/@ MAPK cascade through the creation of a negative @-@ feedback loop . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 6-1.2 7-1.2.1.r 9-1.2.1.1.1.1 11-1.2.1.1.1.1 12-1.2.1 15-1.2.2 16-1.2.2.1.r 18-1.2.2.1.1.1 20-1.2.2.1.1 21-1.2.2.1 (f / finetune-01 :ARG0 (m / mechanism~e.2 :mod (v / various~e.1) :mod (t / this~e.0)) :ARG1 (a / activity-06~e.6 :ARG0~e.7 (c / cascade-01~e.12 :ARG1 (p / pathway :name (n3 / name :op1 "Ras/MAPK"~e.9,11))) :manner (c2 / create-01~e.15 :ARG1~e.16 (l / loop-01~e.21 :mod (f2 / feedback~e.20 :ARG0-of (n / negative-03~e.18)))))) # ::id pmid_2352_4590.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As will be discussed later , this mode of regulation has implications for inhibitors targeting the pathway . # ::alignments 0-1.2.r 3-1 4-1.2 4-1.2.1 4-1.2.1.r 6-1.1.1.1.1 7-1.1.1.1 9-1.1.1 11-1.1 12-1.1.2.r 13-1.1.2 13-1.1.2.1 13-1.1.2.1.r 14-1.1.2.2 16-1.1.2.2.1 (d / discuss-01~e.3 :ARG1 (i / implicate-01~e.11 :ARG0 (r / regulate-01~e.9 :mod (m2 / mode~e.7 :mod (t / this~e.6))) :ARG1~e.12 (m3 / molecular-physical-entity~e.13 :ARG0-of~e.13 (i2 / inhibit-01~e.13) :ARG0-of (t3 / target-01~e.14 :ARG1 (p / pathway~e.16)))) :time~e.0 (l / late~e.4 :degree~e.4 (m / more~e.4))) # ::id pmid_2352_4590.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ras @/@ MAPK pathway and MM # ::alignments 2-1.1.1.1 4-1.1.1.1 5-1.1 6-1 7-1.2.1.1 7-1.2.1.2 (a / and~e.6 :op1 (p / pathway~e.5 :name (n / name :op1 "Ras/MAPK"~e.2,4)) :op2 (d2 / disease :name (n2 / name :op1 "multiple"~e.7 :op2 "myeloma"~e.7))) # ::id pmid_2352_4590.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The genetic changes associated with MM are complex and heterogeneous . # ::alignments 1-1.3.2 2-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1 5-1.3.1.1.1.2 6-1.3.r 7-1.1 8-1 9-1.2 (a / and~e.8 :op1 (c / complex~e.7) :op2 (h / heterogeneous~e.9) :domain~e.6 (c2 / change-01~e.2 :ARG1-of (a2 / associate-01~e.3 :ARG2~e.4 (d2 / disease :name (n / name :op1 "multiple"~e.5 :op2 "myeloma"~e.5))) :mod (g2 / genetic~e.1))) # ::id pmid_2352_4590.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Increasing evidence suggests that the disease evolves through a multistep transformation process , involving the gain or loss of whole chromosomes , nonrandom chromosomal translocations involving the IgH locus and point mutations . @^{4 @} # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 5-1.2.1 6-1.2 9-1.2.2.1.1 10-1.2.2.1 11-1.2.2 13-1.2.2.2 15-1.2.2.2.1.1.1 16-1.2.2.2.1.1 17-1.2.2.2.1.1.2 18-1.2.2.2.1.1.1.1.r 19-1.2.2.2.1.1.1.1.1 20-1.2.2.2.1.1.1.1 22-1.2.2.2.1.2.2 22-1.2.2.2.1.2.2.1 22-1.2.2.2.1.2.2.1.r 23-1.2.2.2.1.2.1 24-1.2.2.2.1.2 25-1.2.2.2.1.2.3 27-1.2.2.2.1.2.3.1.1.1.1.1 28-1.2.2.2.1.2.3.1.1 29-1.2.2.2.1.2.3.1 30-1.2.2.2.1.2.3.1.2.1 31-1.2.2.2.1.2.3.1.2 35-1.3.1.1.1 (s / suggest-01~e.2 :ARG0 (e / evidence~e.1 :ARG1-of (i / increase-01~e.0)) :ARG1~e.3 (e2 / evolve-01~e.6 :ARG1 (d / disease~e.5) :manner (p / process-01~e.11 :ARG1 (t / transform-01~e.10 :mod (m / multistep~e.9)) :ARG0-of (i2 / involve-01~e.13 :ARG1 (a / and :op1 (o / or~e.16 :op1 (g / gain-02~e.15 :ARG1~e.18 (c / chromosome~e.20 :mod (w / whole~e.19))) :op2 (l / lose-02~e.17 :ARG1 c)) :op2 (t2 / translocate-01~e.24 :ARG1 (c2 / chromosome~e.23) :mod (r / random~e.22 :polarity~e.22 -~e.22) :ARG0-of (i3 / involve-01~e.25 :ARG1 (a2 / and~e.29 :op1 (l3 / locus~e.28 :location-of (g2 / gene :name (n2 / name :op1 "IgH"~e.27))) :op2 (m2 / mutate-01~e.31 :ARG1 (p2 / point~e.30))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 4~e.35)))) # ::id pmid_2352_4590.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These aberrations , which influence the clinical and pathological features of MM are manifest in variable disease progression and therapeutic outcomes . # ::alignments 0-1.1.1 1-1.1 4-1.1.2 6-1.1.2.1.2 8-1.1.2.1.3 9-1.1.2.1 10-1.1.2.1.1.r 11-1.1.2.1.1.1.1 11-1.1.2.1.1.1.2 13-1 14-1.2.r 15-1.2.1.1.1 16-1.2.1.1 17-1.2.1 18-1.2 19-1.2.2.1 20-1.2.2 (m / manifest-01~e.13 :ARG1 (a / aberration~e.1 :mod (t / this~e.0) :ARG0-of (i / influence-01~e.4 :ARG1 (f / feature-01~e.9 :ARG1~e.10 (d3 / disease :name (n2 / name :op1 "multiple"~e.11 :op2 "myeloma"~e.11)) :mod (c2 / clinic~e.6) :mod (p2 / pathology~e.8)))) :ARG3~e.14 (a2 / and~e.18 :op1 (p / progress-01~e.17 :ARG1 (d / disease~e.16 :mod (v / variable~e.15))) :op2 (o / outcome~e.20 :mod (t2 / therapy~e.19)))) # ::id pmid_2352_4590.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several of these molecular alterations lead to deregulated activation of the Ras @/@ MAPK pathway . # ::alignments 0-1.1.1 1-1.1.1.r 2-1.1.2.1.2 3-1.1.2.1.1 4-1.1 4-1.1.2.1 5-1 6-1.2.r 7-1.2.2 8-1.2 9-1.2.1.r 11-1.2.1.1.1 13-1.2.1.1.1 14-1.2.1 (l / lead-03~e.5 :ARG0 (a / alter-01~e.4 :quant~e.1 (s / several~e.0) :ARG1-of (i / include-91 :ARG2 (a3 / alter-01~e.4 :ARG1 (m / molecule~e.3) :mod (t2 / this~e.2)))) :ARG2~e.6 (a2 / activate-01~e.8 :ARG1~e.9 (p / pathway~e.14 :name (n / name :op1 "Ras/MAPK"~e.11,13)) :ARG1-of (d / deregulate-01~e.7))) # ::id pmid_2352_4590.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The t( 4;14 ) translocation that juxtaposes the fibroblast growth factor receptor 3 gene and a strong IgH enhancer , resulting in fibroblast growth factor receptor 3 overexpression , stimulates the Ras @/@ MAPK pathway , an outcome typically associated with abnormal cellular proliferation and apoptosis . @^{22 @} # ::alignments 4-1.1 6-1.1.3 8-1.1.3.1.1.1.1 9-1.1.3.1.1.1.2 10-1.1.3.1.1.1.3 11-1.1.3.1.1.1.4 12-1.1.3.1.1.1.5 13-1.1.3.1.1 13-1.1.3.1.2.1.1 14-1.1.3.1 16-1.1.3.1.2.1.2 17-1.1.3.1.2.1.1.1.1 20-1.1.3.2 21-1.1.3.2.1.r 22-1.1.3.2.1.1 23-1.1.3.2.1.1 24-1.1.3.2.1.1 25-1.1.3.2.1.1 26-1.1.3.2.1.1 27-1.1.3.2.1 29-1 31-1.2.1.1 33-1.2.1.1 34-1.2 37-1.2.2.1 38-1.2.2.1.1.2 39-1.2.2.1.1 40-1.2.2.1.1.1.r 41-1.2.2.1.1.1.1.2 41-1.2.2.1.1.1.1.2.1 41-1.2.2.1.1.1.1.2.1.r 42-1.2.2.1.1.1.1.1 43-1.2.2.1.1.1.1 44-1.2.2.1.1.1 45-1.2.2.1.1.1.2 49-1.3.1.1.1 (s / stimulate-01~e.29 :ARG0 (t / translocate-01~e.4 :ARG2 14 :ARG3 4 :ARG0-of (j / juxtapose-01~e.6 :ARG1 (a / and~e.14 :op1 (g / gene~e.13 :name (n / name :op1 "fibroblast"~e.8 :op2 "growth"~e.9 :op3 "factor"~e.10 :op4 "receptor"~e.11 :op5 3~e.12)) :op2 (t3 / thing :ARG0-of (e / enhance-01 :ARG1 (g2 / gene~e.13 :name (n5 / name :op1 "IgH"~e.17)) :ARG1-of (s2 / strong-02~e.16)))) :ARG1-of (r / result-01~e.20 :ARG2~e.21 (o / overexpress-01~e.27 :ARG1 g~e.22,23,24,25,26)))) :ARG1 (p / pathway~e.34 :name (n3 / name :op1 "Ras/MAPK"~e.31,33) :ARG1-of (m2 / mean-01 :ARG2 (o2 / outcome~e.37 :ARG1-of (a2 / associate-01~e.39 :ARG2~e.40 (a3 / and~e.44 :op1 (p2 / proliferate-01~e.43 :ARG0 (c / cell~e.42) :ARG1-of (n4 / normal-02~e.41 :polarity~e.41 -~e.41)) :op2 (a4 / apoptosis~e.45)) :ARG1-of (t2 / typical-02~e.38))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 22~e.49)))) # ::id pmid_2352_4590.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activating Ras mutations , which have a reported incidence varying between 32 @–@ 50 % in MM , are also thought to deregulate this pathway . @^{23 , 24 , 25 @} # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1.1 2-1.1.1 5-1.1.1.2 7-1.1.1.2.1.1 8-1.1.1.2.1 9-1.1.1.2.1.2 11-1.1.1.2.1.2.1.1 13-1.1.1.2.1.2.2.1 14-1.1.1.2.1.2.1 14-1.1.1.2.1.2.2 15-1.1.1.2.1.2.3.r 16-1.1.1.2.1.2.3.1.1 16-1.1.1.2.1.2.3.1.2 19-1.2 20-1 22-1.1 23-1.1.2.1 24-1.1.2 28-1.3.1.1.1.1 32-1.3.1.1.1.2 36-1.3.1.1.1.3 (t / think-01~e.20 :ARG1 (d3 / deregulate-01~e.22 :ARG0 (m / mutate-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.1) :ARG0-of (a2 / activate-01~e.0)) :ARG0-of (h / have-03~e.5 :ARG1 (i / incidence~e.8 :ARG1-of (r / report-01~e.7) :ARG1-of (v / vary-01~e.9 :ARG3 (p2 / percentage-entity~e.14 :value 32~e.11) :ARG4 (p3 / percentage-entity~e.14 :value 50~e.13) :location~e.15 (d / disease :name (n2 / name :op1 "multiple"~e.16 :op2 "myeloma"~e.16)))))) :ARG1 (p / pathway~e.24 :mod (t2 / this~e.23))) :mod (a / also~e.19) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 23~e.28 :op2 24~e.32 :op3 25~e.36))))) # ::id pmid_2352_4590.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras and N @- Ras are the most frequently mutated , with oncogenic H @-@ Ras being a rare phenomenon . @^{25 @} # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 2-1.1.2.1.1 3-1.1 4-1.1.2.1.1 6-1.1.2.1.1 7-1.2.1.r 9-1.4.1 10-1.4 11-1 13-1.2.r 14-1.2.1 14-1.2.1.2 14-1.2.1.2.1.2.1 14-1.2.1.2.r 15-1.2.1.1.1 17-1.2.1.1.1 18-1.2.1.r 20-1.2.2 21-1.2 25-1.3.1.1.1 (m / mutate-01~e.11 :ARG1 (a / and~e.3 :op1 (e / enzyme :name (n / name :op1 "K-Ras"~e.0,2)) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"~e.2,4,6))) :manner~e.13 (p / phenomenon~e.21 :domain~e.7,18 (e3 / enzyme~e.14 :name (n3 / name :op1 "H-Ras"~e.15,17) :ARG0-of~e.14 (c3 / cause-01~e.14 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.14)))) :ARG1-of (r / rare-02~e.20)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 25~e.25))) :ARG1-of (f2 / frequent-02~e.10 :degree (m2 / most~e.9))) # ::id pmid_2352_4590.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While certain genetic lesions common to MM ( for example , t( 14;16 ) , t( 4;14 ) and hyperdiploidy ) are also present in the asymptomatic precursor to MM , monoclonal gammopathy of unknown significance , ^{26 @} Ras mutations occur almost exclusively in MM . # ::alignments 1-1.2.1.2 2-1.2.1.1 3-1.2.1 4-1.2.1.3 5-1.2.1.3.1.r 6-1.2.1.3.1 8-1.2.1.4.r 9-1.2.1.4.r 18-1.2.1.4 19-1.2.1.4.3 22-1.2.3 23-1.2 24-1.2.2.r 26-1.2.2.1 26-1.2.2.1.1 26-1.2.2.1.1.r 27-1.2.2 28-1.2.2.2.r 29-1.2.2.2 32-1.2.4.1 34-1.2.4.1.1.1 34-1.2.4.1.1.1.1 34-1.2.4.1.1.1.1.r 39-1.2.5.1.1.1 42-1.1.1.1.1 43-1.1 45-1.1.3.1 46-1.1.3 47-1.1.2.r 48-1.1.2.1.1 48-1.1.2.1.2 (h / have-concession-91 :ARG1 (m3 / mutate-01~e.43 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.42)) :location~e.47 (d / disease :name (n3 / name :op1 "multiple"~e.48 :op2 "myeloma"~e.48)) :ARG0-of (e4 / exclusive-02~e.46 :mod (a / almost~e.45))) :ARG2 (p / present-02~e.23 :ARG1 (l / lesion~e.3 :mod (g / genetics~e.2) :mod (c2 / certain~e.1) :ARG1-of (s / share-01~e.4 :ARG2~e.5 d~e.6) :example~e.8,9 (a3 / and~e.18 :op1 (t / translocate-01 :ARG2 16 :ARG3 14) :op2 (t2 / translocate-01 :ARG2 14 :ARG3 4) :op3 (h3 / hyperdiploidy~e.19))) :ARG2~e.24 (p2 / precursor~e.27 :mod (s2 / symptom~e.26 :polarity~e.26 -~e.26) :location~e.28 d~e.29) :mod (a2 / also~e.22) :ARG1-of (m2 / mean-01 :ARG2 (g2 / gammopathy~e.32 :ARG0-of (s3 / signify-01 :ARG1-of (k / know-01~e.34 :polarity~e.34 -~e.34)) :mod (m4 / monoclone))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 26~e.39))))) # ::id pmid_2352_4590.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This indicates that Ras mutations are likely to contribute to the transition of the disease from a premalignant state . @^{27 @} # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1.1 4-1.2.1.1 6-1.2 8-1.2.1 11-1.2.1.2 12-1.2.1.2.1.r 14-1.2.1.2.1 15-1.2.1.2.2.r 17-1.2.1.2.2.1 18-1.2.1.2.2 22-1.3.1.1.1 (i / indicate-01~e.1 :ARG0 (t / this~e.0) :ARG1~e.2 (l / likely-01~e.6 :ARG1-of (c / contribute-01~e.8 :ARG0 (m / mutate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.3))) :ARG2 (t2 / transition-01~e.11 :ARG1~e.12 (d / disease~e.14) :ARG3~e.15 (s / state~e.18 :mod (p / premalignant~e.17))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 27~e.22)))) # ::id pmid_2352_4590.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the case of the t( 4 @:@ 14 ) lesion that can activate the Ras @/@ MAPK pathway , this raises the interesting possibility that deregulation of the Ras @/@ MAPK pathway in monoclonal gammopathy of unknown significance precedes constitutive MAPK activation associated with Ras mutations . # ::alignments 2-1.3.r 3-1.3.r 6-1.3.1.2 8-1.3.1.1 10-1.3 12-1.3.2.2 13-1.3.2 15-1.3.2.1.1.1 17-1.3.2.1.1.1 18-1.3.2.1 20-1.1 21-1 23-1.2.2 24-1.2 25-1.2.1.r 26-1.2.1.1 27-1.2.1.1.1.r 29-1.2.1.1.1 31-1.2.1.2.1.1.1 32-1.2.1.2.1 33-1.2.1.1.2.r 34-1.2.1.1.2.1 35-1.2.1.1.2 37-1.2.1.1.2.2.1 37-1.2.1.1.2.2.1.1 37-1.2.1.1.2.2.1.1.r 39-1.2.1 40-1.2.1.2.3 41-1.2.1.2.1.1.1 42-1.2.1.2 43-1.2.1.2.2 44-1.2.1.2.2.1.r 45-1.2.1.2.2.1.1.1.1 46-1.2.1.2.2.1 (r / raise-01~e.21 :ARG0 (t2 / this~e.20) :ARG1 (p / possible-01~e.24 :ARG1~e.25 (p4 / precede-01~e.39 :ARG1 (d / deregulate-01~e.26 :ARG1~e.27 p3~e.29 :location~e.33 (g / gammopathy~e.35 :mod (m / monoclonal~e.34) :ARG0-of (s / signify-01 :ARG1-of (k / know-01~e.37 :polarity~e.37 -~e.37)))) :ARG2 (a2 / activate-01~e.42 :ARG1 (p5 / pathway~e.32 :name (n3 / name :op1 "MAPK"~e.31,41)) :ARG1-of (a3 / associate-01~e.43 :ARG2~e.44 (m2 / mutate-01~e.46 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Ras"~e.45)))) :mod (c2 / constitutive~e.40))) :ARG2-of (i / interest-01~e.23)) :condition~e.2,3 (l / lesion~e.10 :mod (t / translocate-01 :ARG2 14~e.8 :ARG3 4~e.6) :ARG0-of (a / activate-01~e.13 :ARG1 (p3 / pathway~e.18 :name (n / name :op1 "Ras/MAPK"~e.15,17)) :ARG1-of (p2 / possible-01~e.12)))) # ::id pmid_2352_4590.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients with MM harbouring oncogenic K @-@ Ras often have a worse clinical outcomes compared with those with N @-@ Ras mutations or wild @-@ type Ras ^{24 @} This link is exemplified by Ras mutations being associated with the evolution of MM from an intermedullary disease to a more advanced extramedullary phenotype . @^{28 @} # ::alignments 0-1.1.1.1.1 0-1.1.2.3.1.2.1 2-1.1.1.2.1.1.1 2-1.1.1.2.1.1.2 3-1.1.1.2.1.2 4-1.1.1.2.1.2.1 4-1.1.1.2.1.2.1.2 4-1.1.1.2.1.2.1.2.1.2.1 4-1.1.1.2.1.2.1.2.r 5-1.1.1.2.1.2.1.1.1 7-1.1.1.2.1.2.1.1.1 8-1.1.3 9-1.1 9-1.1.1 9-1.1.1.1 9-1.1.1.1.r 9-1.1.1.2 9-1.1.1.2.r 9-1.1.1.r 11-1.1.2.2 11-1.1.2.2.1 11-1.1.2.2.1.r 12-1.1.2.1 13-1.1.2 14-1.1.2.3 17-1.1.2.3.1.r 18-1.1.2.3.1.1.1.1.1.1.1 20-1.1.2.3.1.1.1.1.1.1.1 21-1.1.2.3.1.1.1.1 22-1.1.2.3.1.1.1 23-1.1.2.3.1.1.1.2.2 25-1.1.2.3.1.1.1.2.2 26-1.1.2.3.1.1.1.2.1.1 29-1.1.4.1.1.1 32-1.2.2.1 33-1.2.2 35-1.2 36-1.2.1.r 37-1.2.1.1.1.1 38-1.2.1 40-1.2.1.2 41-1.2.1.2.1.r 43-1.2.1.2.1 44-1.2.1.2.1.1.r 45-1.2.1.2.1.1.1.1 45-1.2.1.2.1.1.1.2 46-1.2.1.2.1.3.r 48-1.2.1.2.1.3.1 49-1.2.1.2.1.3 50-1.2.1.2.1.2.r 52-1.2.1.2.1.2.2.1 53-1.2.1.2.1.2.2 54-1.2.1.2.1.2.1 55-1.2.1.2.1.2 59-1.2.3.1.1.1 (m3 / multi-sentence :snt1 (h / have-03~e.9 :ARG0~e.9 (p / person~e.9 :ARG0-of~e.9 (h2 / have-rel-role-91~e.9 :ARG2 (p2 / patient~e.0)) :ARG0-of~e.9 (h3 / have-03~e.9 :ARG1 (d6 / disease :name (n7 / name :op1 "multiple"~e.2 :op2 "myeloma"~e.2) :ARG0-of (h5 / harbor-01~e.3 :ARG1 (e / enzyme~e.4 :name (n / name :op1 "K-Ras"~e.5,7) :ARG0-of~e.4 (c6 / cause-01~e.4 :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.4)))))))) :ARG1 (o / outcome~e.13 :mod (c2 / clinical~e.12) :ARG1-of (b / bad-07~e.11 :degree~e.11 (m / more~e.11)) :ARG1-of (c3 / compare-01~e.14 :ARG2~e.17 (p3 / person :ARG0-of (h6 / have-03 :ARG1 (o3 / or~e.22 :op1 (m2 / mutate-01~e.21 :ARG1 (e2 / enzyme :name (n3 / name :op1 "N-Ras"~e.18,20))) :op2 (e3 / enzyme :name (n4 / name :op1 "Ras"~e.26) :mod (w / wild-type~e.23,25)))) :ARG0-of (h7 / have-rel-role-91 :ARG2 (p4 / patient~e.0))))) :frequency (o2 / often~e.8) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 24~e.29)))) :snt2 (e4 / exemplify-01~e.35 :ARG0~e.36 (m4 / mutate-01~e.38 :ARG1 (e5 / enzyme :name (n5 / name :op1 "Ras"~e.37)) :ARG1-of (a / associate-01~e.40 :ARG2~e.41 (e6 / evolve-01~e.43 :ARG1~e.44 (d / disease :name (n2 / name :op1 "multiple"~e.45 :op2 "myeloma"~e.45)) :ARG2~e.50 (p5 / phenotype~e.55 :mod (e7 / extramedullary~e.54) :ARG1-of (a2 / advance-01~e.53 :degree (m5 / more~e.52))) :ARG3~e.46 (d4 / disease~e.49 :mod (i / intermedullary~e.48))))) :ARG1 (l / link-01~e.33 :mod (t / this~e.32)) :ARG1-of (d5 / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 28~e.59))))) # ::id pmid_2352_4590.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These observations suggest that aberrant MEK @/@ ERK signalling has an important role in MM disease progression and prognosis . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.2.1 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2.1.2 9-1.2 11-1.2.2.1 12-1.2.2 13-1.2.2.2.r 14-1.2.2.2.1.1.1.1 14-1.2.2.2.1.1.1.2 15-1.2.2.2.1.1 16-1.2.2.2.1 17-1.2.2.2 18-1.2.2.2.2 (s / suggest-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1~e.3 (h / have-03~e.9 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK"~e.5,7) :ARG0-of (s2 / signal-07~e.8 :manner (a / aberrant~e.4))) :ARG1 (r / role~e.12 :mod (i / important~e.11) :topic~e.13 (a2 / and~e.17 :op1 (p2 / progress-01~e.16 :ARG1 (d2 / disease~e.15 :name (n3 / name :op1 "multiple"~e.14 :op2 "myeloma"~e.14))) :op2 (p3 / prognosis~e.18 :mod d2))))) # ::id pmid_2352_4590.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Malignant plasma cell and BMME interactions are thought to contribute to disease progression through the induction of various cytokines and growth factors , a number of which mediate their effects through the Ras @/@ MAPK cascade . @^{5 , 29 , 30 @} # ::alignments 0-1.1.1.1.2 1-1.1.1.1.1 2-1.1.1.1 3-1.1.1 5-1.1.1.2 7-1 9-1.1 10-1.1.2.r 11-1.1.2.1 12-1.1.2 15-1.1.2.2 16-1.1.2.2.1.r 17-1.1.2.2.1.1.1 18-1.1.2.2.1.1 19-1.1.2.2.1 20-1.1.2.2.1.2.1 21-1.1.2.2.1.2 24-1.1.2.2.1.3 27-1.1.2.2.1.3.1 28-1.1.2.2.1.3.1.1.1 28-1.1.2.2.1.3.1.1.1.r 29-1.1.2.2.1.3.1.1 32-1.1.2.2.1.3.1.1.2.1.1.1 34-1.1.2.2.1.3.1.1.2.1.1.1 35-1.1.2.2.1.3.1.1.2 39-1.2.1.1.1.1 43-1.2.1.1.1.2 47-1.2.1.1.1.3 (t / think-01~e.7 :ARG1 (c / contribute-01~e.9 :ARG0 (a / and~e.3 :op1 (c2 / cell~e.2 :mod (p / plasma~e.1) :ARG1-of (m / malignant-02~e.0)) :op2 (i / interact-01~e.5 :ARG0 (m2 / microenvironment :mod (m4 / marrow :part-of (b / bone))))) :ARG2~e.10 (p2 / progress-01~e.12 :ARG1 (d / disease~e.11) :manner (i2 / induce-01~e.15 :ARG2~e.16 (a2 / and~e.19 :op1 (c3 / cytokine~e.18 :mod (v / various~e.17)) :op2 (f / factor~e.21 :mod (g / growth~e.20)) :quant (n2 / number~e.24 :ARG0-of (m3 / mediate-01~e.27 :ARG1 (a3 / affect-01~e.29 :ARG0~e.28 a2~e.28 :ARG2 (c4 / cascade-01~e.35 :ARG1 (p3 / pathway :name (n3 / name :op1 "Ras/MAPK"~e.32,34)))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 (a4 / and :op1 5~e.39 :op2 29~e.43 :op3 30~e.47))))) # ::id pmid_2352_4590.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to a number of these cytokines being able to activate MEK @/@ ERK via the classical Ras @/@ Raf link , another MAP3K , Tpl2 ( Cot , MAP3K8 ) , a known oncogene , has emerged as being important in the cytokine @-@ induced activation of ERK in various cell types , in particular hemopoietic cells . @^{31 @} # ::alignments 1-1 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1 9-1.2.1.2.3 11-1.2.1.2 12-1.2.1.2.1.1.1 14-1.2.1.2.1.1.1 17-1.2.1.2.2.3 18-1.2.1.2.2.1.1.1 20-1.2.1.2.2.2.1.1 21-1.2.1.2.2 23-1.1.2 24-1.1.1.1 26-1.1.4.1.1.1 34-1.1.3.1 35-1.1.3 37-1.1.5.1 38-1.1.5 40-1.1.5.1.2.r 41-1.1.5.1 42-1.1.5.1.1.r 44-1.1.5.1.1.4.1 46-1.1.5.1.1.4 47-1.1.5.1.1 48-1.1.5.1.1.1.r 49-1.1.5.1.1.1.1.1 50-1.1.5.1.1.2.r 51-1.1.5.1.1.2.1.1 52-1.1.5.1.1.2 53-1.1.5.1.1.2.1 55-1.1.5.1.1.3.r 56-1.1.5.1.1.3 58-1.1.5.1.1.3.1 62-1.3.1.1.1 (a / add-02~e.1 :ARG1 (g / gene :name (n6 / name :op1 "MAP3K"~e.24) :mod (a3 / another~e.23) :domain (o / oncogene~e.35 :ARG1-of (k / know-01~e.34)) :ARG1-of (m / mean-01 :ARG2 (g2 / gene :name (n8 / name :op1 "Tpl2"~e.26))) :ARG0-of (e4 / emerge-02~e.38 :ARG1 (i / important~e.37,41 :topic~e.42 (a4 / activate-01~e.47 :ARG1~e.48 (e5 / enzyme :name (n7 / name :op1 "ERK"~e.49)) :location~e.50 (c4 / cell~e.52 :ARG1-of (t2 / type-03~e.53 :mod (v / various~e.51))) :manner~e.55 (p3 / particular~e.56 :location (c5 / cell~e.58 :mod (h / hematopoiesis))) :ARG2-of (i2 / induce-01~e.46 :ARG0 (c3 / cytokine~e.44))) :domain~e.40 g))) :ARG2 (n5 / number-01~e.4 :ARG1~e.5 (c / cytokine~e.7 :mod (t / this~e.6) :ARG0-of (a2 / activate-01~e.11 :ARG1 (p2 / pathway :name (n / name :op1 "MEK/ERK"~e.12,14)) :manner (l / link-01~e.21 :ARG1 (e / enzyme :name (n3 / name :op1 "Ras"~e.18)) :ARG2 (e2 / enzyme :name (n4 / name :op1 "Raf"~e.20)) :mod (c2 / classical~e.17)) :ARG1-of (p / possible-01~e.9)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 31~e.62)))) # ::id pmid_2352_4590.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The observation that the tumour necrosis factor receptor superfamily cytokines ( tumour necrosis factor-α, BAFF ) , CD40 and RANK ligands , all of which have been implicate in MM , activate MEK @/@ ERK via Tpl2 raises the likelihood that the MEK @/@ ERK arm of this MAPK pathway can be activated through different MAP3K . @^{32 @} # ::alignments 1-1.1 2-1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1.1.1.2 6-1.1.1.1.1.1.3 7-1.1.1.1.1.1.4 9-1.1.1.1.1.2.1.1 9-1.1.1.1.1.2.1.2 11-1.1.1.1.1.2.1.1.1.1 12-1.1.1.1.1.2.1.1.1.2 14-1.1.1.1.1.2.1.2.1.1 17-1.1.1.1.2.1.1 18-1.1.1.1 18-1.1.1.1.1.2.1 19-1.1.1.1.3.1.1 20-1.1.1.1.2 20-1.1.1.1.3 22-1.1.1.1.4 27-1.1.1.1.4.1 28-1.1.1.1.4.1.1.r 29-1.1.1.1.4.1.1.1.1 29-1.1.1.1.4.1.1.1.2 31-1.1.1 32-1.2.1.1.2.1.1.1.1 33-1.2.1.1.2.1 34-1.2.1.1.2.1.2.1.1 36-1.1.1.3.1.1 37-1 42-1.2.1.1.2.1.1.1.1 43-1.2.1.1.2.1 44-1.2.1.1.2.1.2.1.1 45-1.2.1.1.2 49-1.1.1.2 50-1.2.1 52-1.2.1.1 54-1.2.1.1.1 54-1.2.1.1.1.2 54-1.2.1.1.1.2.r 55-1.2.1.1.1.1.1 59-1.3.1.1.1 (r / raise-01~e.37 :ARG0 (o / observe-02~e.1 :ARG1~e.2 (a3 / activate-01~e.31 :ARG0 (a4 / and~e.18 :op1 (p4 / protein-family :name (n6 / name :op1 "tumour"~e.4 :op2 "necrosis"~e.5 :op3 "factor"~e.6 :op4 "receptor"~e.7) :ARG2-of (i2 / include-91 :ARG1 (a5 / and~e.18 :op1 (c4 / cytokine~e.9 :name (n7 / name :op1 "tumour"~e.11 :op2 "necrosis"~e.12 :op3 "factor-α")) :op2 (c5 / cytokine~e.9 :name (n8 / name :op1 "BAFF"~e.14))))) :op2 (l2 / ligand~e.20 :name (n9 / name :op1 "CD40"~e.17)) :op3 (l3 / ligand~e.20 :name (n10 / name :op1 "RANK"~e.19)) :mod (a6 / all~e.22 :ARG1-of (i / implicate-01~e.27 :ARG2~e.28 (d4 / disease :name (n13 / name :op1 "multiple"~e.29 :op2 "myeloma"~e.29))))) :ARG1 (p / pathway~e.49 :name (n / name :op1 "MEK/ERK")) :instrument (e4 / enzyme :name (n12 / name :op1 "Tpl2"~e.36)))) :ARG1 (l / likely-01 :ARG1 (p3 / possible-01~e.50 :ARG1 (a2 / activate-01~e.52 :ARG0 (e3 / enzyme~e.54 :name (n5 / name :op1 "MAP3K"~e.55) :ARG1-of~e.54 (d / differ-02~e.54)) :ARG1 (a / arm~e.45 :consist-of (s / slash~e.33,43 :op1 (e / enzyme :name (n3 / name :op1 "MEK"~e.32,42)) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK"~e.34,44))) :part-of p)))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 32~e.59)))) # ::id pmid_2352_4590.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With aberrant MEK @/@ ERK signalling thought to be important in regulating the growth , survival , migration and drug resistance of MM , it will be interesting to determine if specific MAP3Ks differentially control these particular features of the disease . # ::alignments 1-1.1.1.1.2 2-1.1.1.1.1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1 8-1.1.1.1.r 9-1.1.1 10-1.1.1.2.r 11-1.1.1.2 13-1.1.1.2.1.1 15-1.1.1.2.1.2 17-1.1.1.2.1.3 18-1.1.1.2.1 19-1.1.1.2.1.4.2 20-1.1.1.2.1.4 21-1.1.1.2.1.4.1.r 22-1.1.1.2.1.4.1 26-1.1.1.1.r 27-1 29-1.2 31-1.2.1.2 31-1.2.1.2.2 31-1.2.1.2.2.r 33-1.2.1.4 33-1.2.1.4.r 34-1.2.1 35-1.2.1.3.1 36-1.2.1.3.2 37-1.2.1.3 38-1.2.1.3.3.r 40-1.2.1.3.3 (i / interest-01~e.27 :ARG0 (t2 / think-01~e.6 :ARG1 (i2 / important~e.9 :domain~e.8,26 (s2 / signal-07~e.5 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK"~e.2,4)) :mod (a / aberrant~e.1)) :purpose~e.10 (r / regulate-01~e.11 :ARG1 (a2 / and~e.18 :op1 (g / grow-01~e.13 :ARG1 (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :op2 (s3 / survive-01~e.15 :ARG0 d3) :op3 (m / migrate-01~e.17 :ARG0 d3) :op3 (r2 / resist-01~e.20 :ARG0~e.21 d3~e.22 :ARG1 (d5 / drug~e.19)))))) :ARG2 (d / determine-01~e.29 :ARG1 (c / control-01~e.34 :mode interrogative :ARG0 (e / enzyme~e.31 :name (n2 / name :op1 "MAP3K") :ARG1-of~e.31 (s / specific-02~e.31)) :ARG1 (f / feature~e.37 :mod (t / this~e.35) :mod (p2 / particular~e.36) :poss~e.38 d3~e.40) :manner~e.33 (d2 / differential~e.33)))) # ::id pmid_2352_4590.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interactions between Bcl @-@ 2 @-@ like prosurvival and BH3 @-@ only pro @-@ apoptotic family members play an integral role in controlling the balance between cell survival and death though the intrinsic apoptosis pathway . # ::alignments 0-1.1 2-1.1.1.2.1.1.1.1 4-1.1.1.2.1.1.1.1 6-1.1.1.2.1 9-1.1.2.1.1.1 11-1.1.2.1.2 12-1.1.1.1 12-1.1.2.2 14-1.1.2.2.1 15-1.1.1.2 16-1.1.1 16-1.1.2 17-1 19-1.3 21-1.2.r 22-1.2 24-1.2.2 26-1.2.2.1.1 27-1.1.1.1.1 27-1.2.2.1 29-1.2.2.2 32-1.2.3.1 33-1.2.3.2 34-1.2.3 (p / play-08~e.17 :ARG0 (i / interact-01~e.0 :ARG0 (m / member~e.16 :ARG0-of (f2 / favor-01~e.12 :ARG1 (s / survive-01~e.27)) :part-of (f4 / family~e.15 :ARG1-of (r / resemble-01~e.6 :ARG2 (p2 / protein :name (n / name :op1 "Bcl-2"~e.2,4))))) :ARG1 (m2 / member~e.16 :part-of (p4 / protein-family :name (n2 / name :op1 "BH3"~e.9) :mod (o / only~e.11)) :ARG0-of (f3 / favor-01~e.12 :ARG1 (a2 / apoptosis~e.14)))) :ARG1~e.21 (c / control-01~e.22 :ARG0 i :ARG1 (b2 / balance-01~e.24 :ARG1 (s2 / survive-01~e.27 :ARG0 (c2 / cell~e.26)) :ARG2 (d / die-01~e.29 :ARG1 c2)) :ARG2 (p3 / pathway~e.34 :mod (i3 / intrinsic~e.32) :mod a2~e.33)) :mod (i2 / integral~e.19)) # ::id pmid_2352_4590.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Aberrant expression of these apoptotic regulatory molecules in diverse cancers , including MM , contributes to drug resistance . # ::alignments 0-1.1.3 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1.2.1 5-1.1.1.2 6-1.1.1 7-1.1.2.r 8-1.1.2.3 9-1.1.2.2.1 11-1.1.2.4 12-1.1.2.4.1.1.1 12-1.1.2.4.1.1.2 14-1 15-1.2.r 16-1.2.1 17-1.2 (c / contribute-01~e.14 :ARG0 (e / express-03~e.1 :ARG2~e.2 (m / molecule~e.6 :mod (t / this~e.3) :ARG0-of (r / regulate-01~e.5 :ARG1 (a2 / apoptosis~e.4))) :ARG3~e.7 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.9) :mod (d / diverse~e.8) :ARG2-of (i / include-01~e.11 :ARG1 (d4 / disease :name (n2 / name :op1 "multiple"~e.12 :op2 "myeloma"~e.12)))) :mod (a / aberrant~e.0)) :ARG2~e.15 (r2 / resist-01~e.17 :ARG1 (d3 / drug~e.16))) # ::id pmid_2352_4590.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , the activity of a number of these proteins is modulated by MEK @/@ ERK signalling . # ::alignments 0-1.3 3-1.2 4-1.2.1.r 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.1 9-1.2.1.1 11-1 12-1.1.r 13-1.1.1.1.1 15-1.1.1.1.1 16-1.1 (m / modulate-01~e.11 :ARG0~e.12 (s / signal-07~e.16 :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK"~e.13,15))) :ARG1 (a / activity-06~e.3 :ARG0~e.4 (n2 / number~e.6 :quant-of~e.7 (p2 / protein~e.9 :mod (t / this~e.8)))) :mod (i / important~e.0)) # ::id pmid_2352_4590.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , ERK @-@ mediated phosphorylation of the antiapoptotic molecule , Mcl @-@ 1 , decreases its degradation , thereby promoting cell survival . @^{33 @} # ::alignments 0-1.4 1-1.4 3-1.1.2.1.1.1 5-1.1.2 6-1.1 12-1.1.1.1.1 14-1.1.1.1.1 16-1 17-1.2.1 17-1.2.1.r 18-1.2 21-1.3.1 22-1.3.1.2.1 23-1.3.1.2 27-1.5.1.1.1 (d / decrease-01~e.16 :ARG0 (p2 / phosphorylate-01~e.6 :ARG1 (p4 / protein :name (n2 / name :op1 "Mcl-1"~e.12,14) :ARG0-of (c / counter-01 :ARG1 (a / apoptosis))) :ARG1-of (m / mediate-01~e.5 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK"~e.3)))) :ARG1 (d2 / degrade-01~e.18 :ARG1~e.17 p4~e.17) :ARG0-of (c2 / cause-01 :ARG1 (p3 / promote-02~e.21 :ARG0 p2 :ARG1 (s / survive-01~e.23 :ARG0 (c3 / cell~e.22)))) :ARG0-of (e / exemplify-01~e.0,1) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 33~e.27)))) # ::id pmid_2352_4590.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With the overexpression of Mcl @-@ 1 , a common feature of MM associated with greater relapse and shorter survival , ^{34 @} constitutive MEK @/@ ERK activity almost certainly contributes to elevated Mcl @-@ 1 expression in those MM with lesions in the Ras @/@ ERK pathway . # ::alignments 2-1.2 3-1.2.1.r 4-1.2.1 5-1.2.1 6-1.2.1 9-1.2.2.1 10-1.2.2 11-1.2.2.4.r 12-1.2.2.4 13-1.2.2.2 14-1.2.2.2.1.r 15-1.2.2.2.1.1.1 15-1.2.2.2.1.1.1.1 15-1.2.2.2.1.1.1.1.r 16-1.2.2.2.1.1 17-1.2.2.2.1 18-1.2.2.2.1.2.1 18-1.2.2.2.1.2.1.1 18-1.2.2.2.1.2.1.1.r 19-1.2.2.2.1.2 23-1.2.2.3.1.1.1 26-1.1.2 27-1.1.1.1.1 29-1.1.1.1.1 30-1.1 31-1.4.1 32-1.4 32-1.4.r 33-1 34-1.3.r 35-1.3.3 36-1.3.1.1.1 38-1.3.1.1.1 39-1.3 40-1.3.2.r 41-1.3.2.2 42-1.3.2.1.1 42-1.3.2.1.2 44-1.3.2.3 47-1.3.2.3.1.1.1 49-1.3.2.3.1.1.1 50-1.1.1 50-1.3.2.3.1 (c / contribute-01~e.33 :ARG0 (a2 / activity-06~e.30 :ARG0 (p / pathway~e.50 :name (n / name :op1 "MEK/ERK"~e.27,29)) :mod (c3 / constitutive~e.26)) :ARG1 (o / overexpress-01~e.2 :ARG1~e.3 p2~e.4,5,6 :mod (f / feature~e.10 :mod (c4 / common~e.9) :ARG1-of (a3 / associate-01~e.13 :ARG2~e.14 (a4 / and~e.17 :op1 (r / relapse-01~e.16 :mod (g2 / great~e.15 :degree~e.15 (m2 / more~e.15))) :op2 (s / survive-01~e.19 :ARG1-of (s2 / short-07~e.18 :degree~e.18 (m3 / more~e.18))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 34~e.23))) :poss~e.11 d3~e.12)) :ARG2~e.34 (e / express-03~e.39 :ARG1 (p2 / protein :name (n2 / name :op1 "Mcl-1"~e.36,38)) :ARG3~e.40 (d3 / disease :name (n5 / name :op1 "multiple"~e.42 :op2 "myeloma"~e.42) :mod (t / that~e.41) :mod (l / lesion~e.44 :mod (p3 / pathway~e.50 :name (n4 / name :op1 "Ras/ERK"~e.47,49)))) :ARG1-of (e2 / elevate-01~e.35)) :manner~e.32 (c2 / certain~e.32 :degree (a / almost~e.31))) # ::id pmid_2352_4590.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , Bim , a proapoptotic Bcl @-@ 2 family member that can bind to and neutralize Mcl @-@ 1 , is targeted by ERK phosphorylation for proteasome @-@ dependent degradation . @^{35 @} # ::alignments 1-1 3-1.1.2.1.1 7-1.1.2.5.1.1.1 9-1.1.2.5.1.1.1 10-1.1.2.5.1 13-1.1.2.3.2 14-1.1.2.3 17-1.1.2 17-1.1.2.4 17-1.1.2.4.r 18-1.1.2.3.1.1.1 20-1.1.2.3.1.1.1 23-1.1 24-1.1.1.r 25-1.1.1.1.1.1 26-1.1.1 27-1.1.3.r 28-1.1.3.1.1.1.1 30-1.1.3.1 31-1.1.3 35-1.2.1.1.1 (c / contrast-01~e.1 :ARG2 (t / target-01~e.23 :ARG0~e.24 (p / phosphorylate-01~e.26 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.25))) :ARG1 (p2 / protein~e.17 :name (n2 / name :op1 "Bim"~e.3) :ARG0-of (f2 / favor-01 :ARG1 (a / apoptosis)) :ARG1-of (b / bind-01~e.14 :ARG2 (p5 / protein :name (n5 / name :op1 "Mcl-1"~e.18,20)) :ARG1-of (p6 / possible-01~e.13)) :ARG0-of~e.17 (n6 / neutralize-01~e.17 :ARG1 p5 :ARG1-of p6) :ARG1-of (i / include-91 :ARG2 (p4 / protein-family~e.10 :name (n4 / name :op1 "Bcl-2"~e.7,9)))) :purpose~e.27 (d / degrade-01~e.31 :ARG0-of (d2 / depend-01~e.30 :ARG1 (m / macro-molecular-complex :name (n3 / name :op1 "proteasome"~e.28))))) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 35~e.35)))) # ::id pmid_2352_4590.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hence , constitutive ERK signalling is likely to contribute significantly to MM survival by stabilising Mcl @-@ 1 and diminishing Bim expression . # ::alignments 0-1 2-1.1.1.1.2 3-1.1.1.1.1.1.1 4-1.1.1.1 6-1.1 8-1.1.1 9-1.1.1.4 10-1.1.1.3.r 11-1.1.1.3.1.1.1 11-1.1.1.3.1.1.2 12-1.1.1.3 15-1.1.1.2.1.2.1.1 17-1.1.1.2.1.2.1.1 18-1.1.1.2 19-1.1.1.2.2 20-1.1.1.2.2.2.1.1.1 21-1.1.1.2.2.2 (i / infer-01~e.0 :ARG1 (l / likely-01~e.6 :ARG1 (c / contribute-01~e.8 :ARG0 (s / signal-07~e.4 :ARG0 (e / enzyme :name (n / name :op1 "ERK"~e.3)) :mod (c2 / constitutive~e.2)) :ARG1 (a / and~e.18 :op1 (s4 / stabilize-01 :ARG0 s :ARG1 (p / protein :name (n3 / name :op1 "Mcl-1"~e.15,17))) :op2 (d2 / diminish-01~e.19 :ARG0 s :ARG1 (e2 / express-03~e.21 :ARG2 (p2 / protein :name (n4 / name :op1 "Bim"~e.20))))) :ARG2~e.10 (s2 / survive-01~e.12 :ARG0 (d3 / disease :name (n5 / name :op1 "multiple"~e.11 :op2 "myeloma"~e.11))) :ARG1-of (s3 / significant-02~e.9)))) # ::id pmid_2352_4590.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activity of other prosurvival ( Bcl @-@ 2 and Bcl @-@ xL ) and proapoptotic ( Bad ) Bcl @-@ 2 @-@ like proteins , that are also known to be regulated by ERK signalling , represent additional candidates that may contribute to the enhanced survival of MM cells . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.3 6-1.1.1.1.2.1.1.1.1 6-1.1.1.1.2.1.2.1.1 8-1.1.1.1.2.1.1.1.1 10-1.1.1.1.2.1.1.1.1 10-1.1.1.1.2.1.2.1.1 12-1.1.1.1.2.1.2.1.1 14-1.1.1 14-1.1.1.1.2.1 17-1.1.1.2.2.1.1.1 19-1.1.1.1.2.1.1.1.1 19-1.1.1.1.2.1.2.1.1 21-1.1.1.1.2.1.1.1.1 23-1.1.1.2.3 24-1.1.1.1 24-1.1.1.2 28-1.1.1.4.2.1 29-1.1.1.4.2 32-1.1.1.4 33-1.1.1.4.1.r 34-1.1.1.4.1.1.1.1 35-1.1.1.4.1 37-1 38-1.2.1 39-1.2 41-1.2.2.2 42-1.2.2 43-1.2.2.1.r 45-1.2.2.1.2 46-1.1.1.1.1.1 46-1.2.2.1 47-1.2.2.1.1.r 48-1.2.2.1.1.1.1.1 48-1.2.2.1.1.1.1.2 49-1.2.2.1.1 (r / represent-01~e.37 :ARG0 (a / activity-06~e.1 :ARG0~e.2 (a2 / and~e.14 :op1 (p / protein~e.24 :ARG0-of (f / favor-01 :ARG1 (s / survive-01~e.46)) :ARG1-of (m / mean-01 :ARG2 (a3 / and~e.14 :op1 (p2 / protein :name (n2 / name :op1 "Bcl-2"~e.6,8,10,19,21)) :op2 (p3 / protein :name (n3 / name :op1 "Bcl-xL"~e.6,10,12,19))))) :op2 (p4 / protein~e.24 :ARG0-of (f2 / favor-01 :ARG1 (a4 / apoptosis)) :ARG1-of (m2 / mean-01 :ARG2 (p5 / protein :name (n4 / name :op1 "Bad"~e.17))) :ARG1-of (r2 / resemble-01~e.23 :ARG2 p2)) :mod (o / other~e.3) :ARG1-of (r3 / regulate-01~e.32 :ARG0~e.33 (s2 / signal-07~e.35 :ARG0 (e / enzyme :name (n / name :op1 "ERK"~e.34))) :ARG1-of (k / know-01~e.29 :mod (a5 / also~e.28))))) :ARG1 (c / candidate~e.39 :mod (a6 / additional~e.38) :ARG0-of (c2 / contribute-01~e.42 :ARG2~e.43 (s3 / survive-01~e.46 :ARG0~e.47 (c3 / cell~e.49 :mod (d / disease :name (n6 / name :op1 "multiple"~e.48 :op2 "myeloma"~e.48))) :ARG1-of (e2 / enhance-01~e.45)) :ARG1-of (p6 / possible-01~e.41)))) # ::id pmid_2352_4590.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK inhibitors # ::alignments 1-1.1.1.1.1 2-1 2-1.1 2-1.1.r (m / molecular-physical-entity~e.2 :ARG0-of~e.2 (i / inhibit-01~e.2 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.1)))) # ::id pmid_2352_4590.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK1 and MEK2 are homologous dual specificity kinases that share ERK as their only known catalytic substrate , ^{15 @} making MEK an appealing target for cancer drug development . # ::alignments 0-1.2.1.1.1 1-1.2 2-1.2.2.1.1 3-1.2.r 4-1.1 5-1.4.1 6-1.4 7-1 7-1.2.1 7-1.2.2 9-1.3 10-1.3.1.1.1 12-1.3.1.2.1.4 12-1.3.1.2.1.4.r 13-1.3.1.2.1.3 14-1.3.1.2.1.2 15-1.3.1.2.1.1 16-1.3.1.2.1 20-1.3.2.1.1.1 23-1.3.3 24-1.3.3.1.1.1 26-1.3.3.1.2.1 27-1.3.3.1 27-1.3.3.1.2 27-1.3.3.1.2.r 28-1.3.3.1.2.1.1.r 29-1.3.3.1.2.1.1.1.1.2.1 30-1.3.3.1.2.1.1.1 31-1.3.3.1.2.1.1 (k / kinase~e.7 :mod (h / homologous~e.4) :domain~e.3 (a / and~e.1 :op1 (k2 / kinase~e.7 :name (n5 / name :op1 "MEK1"~e.0)) :op2 (k3 / kinase~e.7 :name (n6 / name :op1 "MEK2"~e.2))) :ARG0-of (s / share-01~e.9 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.10) :ARG0-of (h2 / have-rel-role-91 :ARG2 (s2 / substrate~e.16 :ARG0-of (c / catalyze-01~e.15) :ARG1-of (k4 / know-01~e.14) :mod (o / only~e.13) :poss~e.12 a~e.12))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 15~e.20))) :ARG0-of (m / make-02~e.23 :ARG1 (e2 / enzyme~e.27 :name (n2 / name :op1 "MEK"~e.24) :ARG1-of~e.27 (t / target-01~e.27 :ARG0-of (a2 / appeal-03~e.26 :ARG1~e.28 (d4 / develop-02~e.31 :ARG1 (d5 / drug~e.30 :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.29))))))))) :mod (s3 / specificity~e.6 :mod (d / dual~e.5))) # ::id pmid_2352_4590.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although many kinase inhibitors target the ATP @-@ binding region of an enzyme , MEK contains a hydrophobic allosteric pocket adjacent to the ATP @-@ binding site that is not shared with other kinases . @^{36 @} # ::alignments 0-1 1-1.2.1.2 2-1.2.1.1.1 3-1.2.1 3-1.2.1.1 3-1.2.1.1.r 4-1.2 6-1.2.2.1.1.1.1 8-1.2.2.1 9-1.2.2 10-1.2.2.2.r 12-1.2.2.2 14-1.1.1.1.1 15-1.1 17-1.1.2.2 18-1.1.2.1 19-1.1.2 23-1.1.2.4.1.1 24-1.1.2.4.1.1 25-1.1.2.4.1.1 26-1.1.2.4.1 29-1.1.2.3.1 29-1.1.2.3.1.r 30-1.1.2.3 31-1.1.2.3.3.r 32-1.1.2.3.3.1 33-1.1.2.3.3 37-1.3.1.1.1 (h / have-concession-91~e.0 :ARG1 (c / contain-01~e.15 :ARG0 (e / enzyme :name (n / name :op1 "MEK"~e.14)) :ARG1 (p / pocket~e.19 :mod (a / allosteric~e.18) :mod (h2 / hydrophobic~e.17) :ARG1-of (s3 / share-01~e.30 :polarity~e.29 -~e.29 :ARG0 e :ARG2~e.31 (k2 / kinase~e.33 :mod (o / other~e.32))) :ARG1-of (b2 / border-01 :ARG2 (s2 / site~e.26 :ARG2-of b~e.23,24,25)))) :ARG2 (t2 / target-01~e.4 :ARG0 (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (i / inhibit-01~e.3 :ARG1 (k / kinase~e.2)) :quant (m2 / many~e.1)) :ARG1 (r / region~e.9 :ARG2-of (b / bind-01~e.8 :ARG1 (s / small-molecule :name (n2 / name :op1 "ATP"~e.6))) :part-of~e.10 (e2 / enzyme~e.12))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 36~e.37)))) # ::id pmid_2352_4590.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This offers the opportunity to design highly selective inhibitors of MEK that do not simply target the conserved ATP region of the kinase . # ::alignments 0-1.1 1-1 3-1.2 5-1.2.1 6-1.2.1.1.2.1 8-1.2.1.1 8-1.2.1.1.1 8-1.2.1.1.1.r 9-1.2.1.1.1.1.r 10-1.2.1.1.1.1.1.1 13-1.2.1.1.3.1 13-1.2.1.1.3.1.r 14-1.2.1.1.3.3 15-1.2.1.1.3 17-1.2.1.1.3.2.3 18-1.2.1.1.3.2.2.1.1 19-1.2.1.1.3.2 20-1.2.1.1.3.2.1.r 22-1.2.1.1.3.2.1 (o / offer-01~e.1 :ARG0 (t2 / this~e.0) :ARG1 (o2 / opportunity~e.3 :topic (d / design-01~e.5 :ARG1 (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (i / inhibit-01~e.8 :ARG1~e.9 (p / protein-family :name (n / name :op1 "MEK"~e.10))) :ARG0-of (s / select-01 :ARG1-of (h / high-02~e.6)) :ARG0-of (t / target-01~e.15 :polarity~e.13 -~e.13 :ARG1 (r / region~e.19 :part-of~e.20 (k / kinase~e.22) :mod (s3 / small-molecule :name (n2 / name :op1 "ATP"~e.18)) :ARG1-of (c / conserve-01~e.17)) :ARG1-of (s2 / simple-02~e.14)))))) # ::id pmid_2352_4590.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the remainder of the review , we describe some of the various MEK inhibitors currently being investigated and their future role in cancer therapy . # ::alignments 2-1.3 3-1.3.1.r 5-1.3.1 7-1.1 8-1 9-1.2.1.2.2 12-1.2.1.2.1.2 13-1.2.1.1.1.1.1 14-1.2.1 14-1.2.1.1 14-1.2.1.1.r 15-1.2.1.2.1.3.1 17-1.2.1.2.1.3 18-1.2 20-1.2.2.3 23-1.2.2.2.1.2.1 24-1.2.2.2 (d2 / describe-01~e.8 :ARG0 (w / we~e.7) :ARG1 (a / and~e.18 :op1 (m / molecular-physical-entity~e.14 :ARG0-of~e.14 (i / inhibit-01~e.14 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.13))) :ARG1-of (i2 / include-91 :ARG2 (m2 / molecular-physical-entity :ARG0-of i :mod (v / various~e.12) :ARG1-of (i3 / investigate-01~e.17 :time (c / current~e.15))) :ARG3 (s / some~e.9))) :op2 (p / play-08 :ARG0 m :ARG1 (t / therapy~e.24 :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.23))) :time (f / future~e.20))) :medium (r / remainder~e.2 :part-of~e.3 (r2 / review~e.5))) # ::id pmid_2352_4590.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Prototypic MEK inhibitors # ::alignments 2-1.1.1.1.1 3-1 3-1.1 3-1.1.r (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (i / inhibit-01~e.3 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.2))) :mod (p / prototype)) # ::id pmid_2352_4590.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite demonstrating in vitro activity , major in vivo limitations were identified for the early first generation MEK inhibitors , PD098059 @^{37 @} and U0126 . @^{38 @} # ::alignments 0-1.3.r 1-1.3 3-1.3.2.2 4-1.3.2.2 6-1.3.2 8-1.1.2 10-1.1.1 11-1.1.1 13-1.1 15-1 16-1.2.r 18-1.2.2 19-1.2.3.1 19-1.2.3.1.1 19-1.2.3.1.1.r 20-1.2.3 21-1.2.1.1.1.1 22-1.2 22-1.2.1 22-1.2.1.r 24-1.2.4.1.1.1.1 27-1.2.4.1.1.2.1.1.1 30-1.2.4.1 31-1.2.4.1.2.1.1 35-1.2.4.1.2.2.1.1.1 (i2 / identify-01~e.15 :ARG1 (l / limit-01~e.13 :manner (i3 / in-vivo~e.10,11) :ARG1-of (m / major-02~e.8)) :location~e.16 (m2 / molecular-physical-entity~e.22 :ARG0-of~e.22 (i / inhibit-01~e.22 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.21))) :time (e2 / early~e.18) :mod (g / generation~e.20 :ord (o2 / ordinal-entity~e.19 :value~e.19 1~e.19)) :ARG1-of (m3 / mean-01 :ARG2 (a / and~e.30 :op1 (s / small-molecule :name (n2 / name :op1 "PD098059"~e.24) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 37~e.27)))) :op2 (s2 / small-molecule :name (n3 / name :op1 "U0126"~e.31) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 38~e.35))))))) :concession~e.0 (d3 / demonstrate-01~e.1 :ARG0 a :ARG1 (a2 / activity-06~e.6 :ARG0 a :manner (i4 / in-vitro~e.3,4)))) # ::id pmid_2352_4590.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although both compounds were deemed unsuitable for clinical consideration they have proven to be invaluable tools for investigating the Ras @/@ MAPK pathway . # ::alignments 0-1 1-1.2.1.2.1 2-1.2.1.2 4-1.2 5-1.2.1 5-1.2.1.1 5-1.2.1.1.r 6-1.2.1.3.r 7-1.2.1.3.2 8-1.2.1.3 10-1 11-1.1 12-1.1.2.r 13-1.1.2.1.r 15-1.1.2 17-1.1.2.2.2 19-1.1.2.2.2.1.1.1 21-1.1.2.2.2.1.1.1 22-1.1.2.2.2.1 (h / have-concession-91~e.0,10 :ARG1 (p / prove-01~e.11 :ARG0 c :ARG1~e.12 (t / tool~e.15 :domain~e.13 c :ARG1-of (v / value-02 :degree (e / extreme) :purpose (i / investigate-01~e.17 :ARG1 (p2 / pathway~e.22 :name (n / name :op1 "Ras/MAPK"~e.19,21)))))) :ARG2 (d / deem-01~e.4 :ARG1 (s / suitable-04~e.5 :polarity~e.5 -~e.5 :ARG1 (c / compound~e.2 :mod (b / both~e.1)) :ARG2~e.6 (c2 / consider-02~e.8 :ARG1 c :manner (c3 / clinic~e.7))))) # ::id pmid_2352_4590.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok CI @-@ 1040 ( PD184352 ) was the first MEK inhibitor to demonstrate tumour inhibitory activity in vivo @ . @^{39 @} # ::alignments 0-1.3.1.1 2-1.3.1.1 4-1.3.2.1.1.1 6-1.3.r 8-1.2 8-1.2.1 8-1.2.1.r 9-1.1.1.1.1 10-1 10-1.1 10-1.1.r 12-1.4 13-1.4.1.2.2 14-1.4.1.2 15-1.4.1 17-1.4.2 18-1.4.2 23-1.5.1.1.1 (m / molecular-physical-entity~e.10 :ARG0-of~e.10 (i / inhibit-01~e.10 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.9))) :ord (o / ordinal-entity~e.8 :value~e.8 1~e.8) :domain~e.6 (s / small-molecule :name (n2 / name :op1 "CI-1040"~e.0,2) :ARG1-of (m3 / mean-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD184352"~e.4)))) :ARG0-of (d / demonstrate-01~e.12 :ARG1 (a / activity-06~e.15 :ARG0 m :ARG1 (i2 / inhibit-01~e.14 :ARG0 m :ARG1 (t / tumor~e.13))) :manner (i3 / in-vivo~e.17,18)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 39~e.23)))) # ::id pmid_2352_4590.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Encouraging phase I results in advanced cancer patients , where one patient with pancreatic cancer achieved a partial response ( PR ) lasting 12 months , prompted a phase II study of CI @-@ 1040 in patients with advanced solid tumours . @^{40 @} # ::alignments 0-1.1.2 1-1.1.1.1 2-1.1.1.1.1.1 3-1.1 3-1.1.1 3-1.1.1.r 4-1.1.3.r 5-1.1.3.3.3 6-1.1.3.3.2.1 7-1.2.3.1 9-1.2.3.r 10-1.1.1.1.1.1 11-1.1.3.2.1.1 13-1.1.3.2.1.3.2.1 14-1.1.3.2.1.3.2.2 15-1.1.3.2.1.2 17-1.1.3.2.1.2.1.1.1 17-1.1.3.2.1.2.1.1.1.r 18-1.1.3.2.1.2.1 18-1.1.3.2.1.2.1.1 18-1.1.3.2.1.2.1.1.r 22-1.1.1.1.1 22-1.1.3.2.1.2.1.1.2.r 22-1.2.2.1 23-1.1.3.2.1.2.1.1.2.1 24-1.1.3.2.1.2.1.1.2.2 26-1 28-1.2.2 29-1.2.2.1.1 30-1.2 31-1.2.1.r 32-1.2.1.1.1 34-1.2.1.1.1 36-1.1.3.1.1 38-1.2.3.2.1.2 39-1.2.3.2.1.1 40-1.2.3.2.1 44-1.3.1.1.1 (p / prompt-01~e.26 :ARG0 (t2 / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3 :ARG1 (p2 / phase~e.1 :ord (o / ordinal-entity~e.22 :value 1~e.2,10))) :ARG0-of (e / encourage-02~e.0) :topic~e.4 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.36)) :ARG2-of (i / include-91 :ARG1 (p7 / person :ARG0-of h~e.11 :ARG0-of (a2 / achieve-01~e.15 :ARG1 (t4 / thing~e.18 :ARG2-of~e.18 (r2 / respond-01~e.18 :degree~e.17 (p9 / part~e.17) :duration~e.22 (t / temporal-quantity :quant 12~e.23 :unit (m / month~e.24))))) :mod (d3 / disease :wiki "Pancreatic_cancer" :name (n3 / name :op1 "pancreatic"~e.13 :op2 "cancer"~e.14)))) :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.6) :ARG1-of (a / advance-01~e.5)))) :ARG1 (s / study-01~e.30 :ARG1~e.31 (s3 / small-molecule :name (n2 / name :op1 "CI-1040"~e.32,34)) :mod (p5 / phase~e.28 :ord (o2 / ordinal-entity~e.22 :value 2~e.29)) :location~e.9 (p6 / person :ARG0-of h~e.7 :ARG0-of (h2 / have-03 :ARG1 (t3 / tumor~e.40 :ARG1-of (s2 / solid-02~e.39) :ARG1-of a~e.38)))) :ARG1-of (d / describe-01 :ARG0 (p11 / publication :ARG1-of (c3 / cite-01 :ARG2 40~e.44)))) # ::id pmid_2352_4590.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in contrast to the phase I trial , no PR was observed . @^{41 @} # ::alignments 0-1 3-1 3-1.2.3 6-1.1.1 7-1.1.1.1.1 8-1.1 10-1.2.1 10-1.2.1.r 13-1.2 17-1.3.1.1.1 (c3 / contrast-01~e.0,3 :ARG1 (t / trial-06~e.8 :mod (p2 / phase~e.6 :ord (o2 / ordinal-entity :value 1~e.7))) :ARG2 (o / observe-02~e.13 :polarity~e.10 -~e.10 :ARG1 (t2 / thing :ARG2-of (r / respond-01 :degree (p / part))) :ARG1-of (c / contrast-01~e.3)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 41~e.17)))) # ::id pmid_2352_4590.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a result of its weak antitumour activity , development of CI @-@ 1040 was terminated in favour of the more potent PD0325901 . # ::alignments 2-1.3 3-1.3.1.r 4-1.3.1.1 4-1.3.1.1.r 5-1.3.1.2 7-1.3.1 9-1.1 11-1.1.1.1.1 11-1.3.1.3 13-1.1.1.1.1 15-1 16-1.2.r 17-1.2 18-1.2.1.r 20-1.2.1.2.1 21-1.2.1.2 22-1.2.1.1.1 (t / terminate-01~e.15 :ARG1 (d / develop-02~e.9 :ARG1 (s / small-molecule :name (n / name :op1 "CI-1040"~e.11,13))) :purpose~e.16 (f / favor-01~e.17 :ARG1~e.18 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"~e.22) :mod (p / potent~e.21 :degree (m3 / more~e.20)))) :ARG2-of (r / result-01~e.2 :ARG1~e.3 (a / activity-06~e.7 :ARG0~e.4 s~e.4 :ARG1-of (w / weak-02~e.5) :ARG0-of (c2 / counter-01~e.11 :ARG1 (t2 / tumor))))) # ::id pmid_2352_4590.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Compared with CI @-@ 1040 , PD0325901 demonstrates significantly improved potency in cell @-@ based assays ( 100 @-@ fold ) , oral bioavailability and metabolic stability . @^{42 @} # ::alignments 0-1.3.r 2-1.3.1.1 4-1.3.1.1 6-1.1.1.1 7-1 8-1.2.1.1.2 9-1.2.1.1 10-1.2.1 11-1.2.1.2.r 12-1.2.1.2.1.1 14-1.2.1.2.1 15-1.2.1.2 17-1.2.1.1.1.1 19-1.2.1.1.1 22-1.2.2.1 23-1.2.2 24-1.2 26-1.2.3 30-1.4.1.1.1 (d / demonstrate-01~e.7 :ARG0 (s3 / small-molecule :name (n / name :op1 "PD0325901"~e.6)) :ARG1 (a / and~e.24 :op1 (p / potency~e.10 :ARG1-of (i / improve-02~e.9 :ARG2 (p2 / product-of~e.19 :op1 100~e.17) :ARG1-of (s / significant-02~e.8)) :condition~e.11 (a2 / assay-01~e.15 :ARG1-of (b / base-02~e.14 :ARG2 (c / cell~e.12)))) :op2 (b2 / bioavailability~e.23 :mod (o / oral~e.22)) :op3 (s2 / stability~e.26 :mod (m2 / metabolize-01))) :compared-to~e.0 (s4 / small-molecule :name (n2 / name :op1 "CI-1040"~e.2,4)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 42~e.30)))) # ::id pmid_2352_4590.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phase I investigation of PD0325901 was conducted in 66 advanced cancer patients . # ::alignments 0-1.1.2 1-1.1.2.1.1 2-1.1 3-1.1.1.r 4-1.1.1.1.1 6-1 7-1.2.r 8-1.2.1 9-1.2.3.3 10-1.2.3.2.1 11-1.2.2.1 (c / conduct-01~e.6 :ARG1 (i / investigate-01~e.2 :ARG1~e.3 (s / small-molecule :name (n2 / name :op1 "PD0325901"~e.4)) :mod (p / phase~e.0 :ord (o / ordinal-entity :value 1~e.1))) :location~e.7 (p2 / person :quant 66~e.8 :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.11)) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.10) :ARG1-of (a / advance-01~e.9)))) # ::id pmid_2352_4590.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Three of 48 evaluable patients with melanoma achieved PR , while 10 had stable disease ( s.d.) for ≥ 4 months . # ::alignments 0-1.1.1.1 2-1.1.1.3.1.1 4-1.1.1.2.1 6-1.1.1.3.1.4.1.1 7-1.1 10-1 11-1.2.1.1 12-1.2 13-1.2.2.1 14-1.2.2 19-1.2.3.1.1 20-1.2.3.1.2 (c / contrast-01~e.10 :ARG1 (a / achieve-01~e.7 :ARG0 (p / person :quant 3~e.0 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.4)) :ARG1-of (i / include-91 :ARG2 (p3 / person :quant 48~e.2 :ARG0-of h :ARG1-of (e / evaluate-01 :ARG1-of (p6 / possible-01)) :mod (m3 / medical-condition :name (n / name :op1 "melanoma"~e.6))))) :ARG1 (t2 / thing :ARG2-of (r / respond-01 :degree (p4 / part)))) :ARG2 (h2 / have-03~e.12 :ARG0 (p5 / person :quant 10~e.11 :ARG0-of h :ARG1-of i) :ARG1 (d2 / disease~e.14 :ARG1-of (s / stable-03~e.13)) :duration (o / or :op1 (t / temporal-quantity :quant 4~e.19 :unit (m / month~e.20)) :op2 (m2 / more-than :op1 t)))) # ::id pmid_2352_4590.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A subset of these patients developed retinal vein occlusion . @^{43 @} # ::alignments 1-1.1 3-1.1.1.1.2 4-1.1.1.1.1.1 5-1 6-1.2.1.1 7-1.2.1 8-1.2 12-1.3.1.1.1 (d / develop-01~e.5 :ARG1 (s / subset~e.1 :ARG1-of (i / include-91 :ARG2 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.4)) :mod (t / this~e.3)))) :ARG2 (o / occlude-01~e.8 :ARG1 (v / vein~e.7 :mod (r / retina~e.6))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 43~e.12)))) # ::id pmid_2352_4590.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A phase II study of PD0325901 was assessed in 34 advanced non @-@ small cell lung carcinoma patients , but was eventually terminated owing to lack of objective responses and increasing concerns about ocular function and neurotoxicity at therapeutic doses . @^{44 @} # ::alignments 1-1.1.1.2 2-1.1.1.2.1.1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.1 10-1.1.2.3.3 11-1.1.2.3.2.1.1 11-1.1.2.3.2.1.1.r 13-1.1.2.3.2.1 14-1.1.2.3.2 15-1.1.2.3.1 16-1.1.2.3 17-1.1.2.2.1 19-1 21-1.2.2 22-1.2 24-1.2.3 25-1.2.3.1.1 26-1.2.3.1.1.1.r 27-1.2.3.1.1.1.2 28-1.2.3.1.1.1 28-1.2.3.1.1.1.1 28-1.2.3.1.1.1.1.r 29-1.2.3.1 30-1.2.3.1.2.2 31-1.2.3.1.2 32-1.2.3.1.2.1.r 33-1.2.3.1.2.1.1.1 34-1.2.3.1.2.1.1 35-1.2.3.1.2.1 36-1.2.3.1.2.1.2 37-1.2.3.1.2.3.r 38-1.2.3.1.2.3.1 39-1.2.3.1.2.3 43-1.3.1.1.1 (c / contrast-01~e.19 :ARG1 (a / assess-01~e.7 :ARG1 (s / study-01~e.3 :ARG1~e.4 (s3 / small-molecule :name (n / name :op1 "PD0325901"~e.5)) :mod (p / phase~e.1 :ord (o / ordinal-entity :value 2~e.2))) :location~e.8 (p2 / person :quant 34~e.9 :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.17)) :mod (c2 / carcinoma~e.16 :mod (l / lung~e.15) :mod (c3 / cell~e.14 :mod (s2 / small~e.13 :polarity~e.11 -~e.11)) :ARG1-of (a2 / advance-01~e.10)))) :ARG2 (t / terminate-01~e.22 :ARG1 s :time (e / eventual~e.21) :ARG1-of (c4 / cause-01~e.24 :ARG0 (a3 / and~e.29 :op1 (l2 / lack-01~e.25 :ARG1~e.26 (t2 / thing~e.28 :ARG2-of~e.28 (r / respond-01~e.28) :mod (o2 / objective~e.27))) :op2 (c5 / concern-01~e.31 :ARG0~e.32 (a4 / and~e.35 :op1 (f / function-01~e.34 :ARG0 (e2 / eye~e.33)) :op2 (n2 / neurotoxicity~e.36)) :ARG1-of (i / increase-01~e.30) :condition~e.37 (d / dose-01~e.39 :mod (t3 / therapy~e.38)))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 44~e.43)))) # ::id pmid_2352_4590.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Investigation of these treatment @-@ related toxicities was conducted in animal models , where PD0325901 was found to cause retinal vein occlusion in rabbits . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1.2.1 5-1.1.1.2 6-1.1.1 8-1 9-1.2.r 10-1.2.1 11-1.2 13-1.2.2.r 14-1.2.2.1.1.1.1 16-1.2.2 19-1.2.2.1.2.1 20-1.2.2.1.2 21-1.2.2.1 22-1.2.2.1.3.r 23-1.2.2.1.3 (c / conduct-01~e.8 :ARG1 (i / investigate-01~e.0 :ARG1~e.1 (t / toxicity~e.6 :mod (t2 / this~e.2) :ARG1-of (r / relate-01~e.5 :ARG2 (t3 / treat-04~e.3)))) :location~e.9 (m / model~e.11 :mod (a / animal~e.10) :location-of~e.13 (f / find-01~e.16 :ARG1 (o / occlude-01~e.21 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"~e.14)) :ARG1 (v / vein~e.20 :mod (r2 / retina~e.19)) :location~e.22 (r3 / rabbit~e.23))))) # ::id pmid_2352_4590.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This adverse effect was attributed to the abrogation of phosphorylated @-@ ERK ( p @-@ ERK ) within the brain . @^{45 @} # ::alignments 0-1.1.2 1-1.1.1 2-1.1 4-1 5-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.2 11-1.2.1.1.1 13-1.2.1.2 15-1.2.1.1.1 19-1.2.2 23-1.3.1.1.1 (a / attribute-01~e.4 :ARG1 (a2 / affect-01~e.2 :mod (a3 / adverse~e.1) :mod (t / this~e.0)) :ARG2~e.5 (a4 / abrogate-01~e.7 :ARG1~e.8 (e / enzyme :name (n / name :op1 "ERK"~e.11,15) :ARG3-of (p / phosphorylate-01~e.9,13)) :location (b / brain~e.19)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 45~e.23)))) # ::id pmid_2352_4590.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In light of these observations , development of PD0325901 has been suspended . # ::alignments 3-1.2.1.1 4-1.2.1 4-1.2.1.2 4-1.2.1.2.r 6-1.1 7-1.1.1.r 8-1.1.1.1.1 11-1 (s / suspend-01~e.11 :ARG1 (d / develop-02~e.6 :ARG1~e.7 (s2 / small-molecule :name (n / name :op1 "PD0325901"~e.8))) :ARG1-of (c / cause-01 :ARG0 (t / thing~e.4 :mod (t2 / this~e.3) :ARG1-of~e.4 (o / observe-01~e.4)))) # ::id pmid_2352_4590.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK inhibitors in development # ::alignments 1-1.1.1.1.1.1 2-1.1 2-1.1.1 2-1.1.1.r 4-1 (d / develop-02~e.4 :ARG1 (m / molecular-physical-entity~e.2 :ARG0-of~e.2 (i / inhibit-01~e.2 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.1))))) # ::id pmid_2352_4590.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD6244 @/@ ARRY @-@ 142886 ( selumetinib ) is a potent MEK inhibitor that has demonstrated significant tumour suppressive activity in a number of preclinical solid tumour models . @^{46 , 47 , 48 @} # ::alignments 0-1.2.1.1 2-1.2.1.1 4-1.2.1.1 6-1.2.2.1.1.1 8-1.2.r 10-1.3 11-1.1.1.1.1 12-1 12-1.1 12-1.1.r 15-1.5 16-1.5.1.3 17-1.5.1.2.2 19-1.5.1 20-1.5.2.r 22-1.5.2 23-1.5.2.1.r 24-1.5.2.1.2 25-1.5.2.1.1.1 26-1.5.2.1.1 27-1.5.2.1 31-1.4.1.1.1.1 35-1.4.1.2.1.1 39-1.4.1.3.1.1 (m / molecular-physical-entity~e.12 :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (p6 / protein-family :name (n / name :op1 "MEK"~e.11))) :domain~e.8 (s5 / small-molecule :name (n2 / name :op1 "AZD6244/ARRY-142886"~e.0,2,4) :ARG1-of (m3 / mean-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib"~e.6)))) :mod (p / potent~e.10) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p3 / publication :ARG1-of (c / cite-01 :ARG2 46~e.31)) :op2 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 47~e.35)) :op3 (p5 / publication :ARG1-of (c3 / cite-01 :ARG2 48~e.39)))) :ARG0-of (d / demonstrate-01~e.15 :ARG1 (a / activity-06~e.19 :ARG0 m :ARG1 (s2 / suppress-01 :ARG0 m :ARG1 (t / tumor~e.17)) :ARG1-of (s3 / significant-02~e.16)) :location~e.20 (n4 / number~e.22 :quant-of~e.23 (m4 / model~e.27 :mod (t2 / tumor~e.26 :ARG1-of (s4 / solid-02~e.25)) :mod (p2 / preclinical~e.24))))) # ::id pmid_2352_4590.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In cell @-@ based enzymatic assays , AZD6244 inhibited purified MEK at an IC @₅₀ of 14.1± 0.79 nM , with no inhibition observed at 10 μℳ against 40 other kinases . # ::alignments 1-1.1.3.2.1 3-1.1.3.2 4-1.1.3.1 5-1.1.3 7-1.1.1.1.1 8-1.1 9-1.1.2.2 10-1.1.2.1.1 13-1.1.1 13-1.1.1.2 13-1.1.1.2.r 13-1.2.4 15-1.1.1.2.1 15-1.2.4.1 19-1.1.1.2.2.1.1.1 19-1.1.1.2.2.1.2.1 20-1.1.1.2.2.2 23-1.2.1 23-1.2.1.r 24-1.2.2 25-1.2 26-1.2.4.2.r 27-1.2.4.2.1 28-1.2.4.2.2 30-1.2.3.1.1 31-1.2.3.1.2 32-1.2.3.1 (a2 / and :op1 (i / inhibit-01~e.8 :ARG0 (s / small-molecule~e.13 :name (n / name :op1 "AZD6244"~e.7) :ARG1-of~e.13 (h / have-percentage-maximal-inhibitory-concentration-01~e.13 :ARG2 50~e.15 :ARG4 (c / concentration-quantity :quant (v / value-interval :op1 (a3 / add-02 :ARG1 0.79~e.19 :ARG2 14.1) :op2 (s2 / subtract-01 :ARG1 0.79~e.19 :ARG2 14.1)) :unit (n3 / nanomolar~e.20)))) :ARG1 (e / enzyme :name (n2 / name :op1 "MEK"~e.10) :ARG1-of (p / purify-01~e.9)) :condition (a / assay-01~e.5 :ARG1 (e2 / enzyme~e.4) :ARG1-of (b / base-02~e.3 :ARG2 (c2 / cell~e.1)))) :op2 (o / observe-02~e.25 :polarity~e.23 -~e.23 :ARG1 (i3 / inhibit-01~e.24) :ARG1-of (c4 / contrast-01 :ARG2 (k / kinase~e.32 :quant 40~e.30 :mod (o3 / other~e.31))) :condition (h2 / have-percentage-maximal-inhibitory-concentration-01~e.13 :ARG2 50~e.15 :ARG4~e.26 (c3 / concentration-quantity :quant 10~e.27 :unit (m / micromolar~e.28))))) # ::id pmid_2352_4590.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell lines harbouring oncogenic B @-@ Raf and N @-@ Ras mutations displayed enhanced sensitivity to AZD6244 , whereas K @-@ Ras mutated tumours showed variable responsiveness . @^{47 @} # ::alignments 0-1.1.1 1-1.1.1 2-1.1.1.1 3-1.1.1.1.1.2 3-1.1.1.1.1.2.1.2.1 4-1.1.1.1.1.1.1.1.1 6-1.1.1.1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1.1.1.1.2.1.1 10-1.1.1.1.1.1.2.1.1 11-1.1.1.1.1 12-1.1 13-1.1.2.3 14-1.1.2 15-1.1.2.2.r 16-1.1.2.2.1.1 18-1 19-1.2.1.1.1.1 21-1.2.1.1.1.1 22-1.2.1.1.2 23-1.2.1 24-1.2 26-1.2.2 30-1.3.1.1.1 (c / contrast-01~e.18 :ARG1 (d / display-01~e.12 :ARG0 (c2 / cell-line~e.0,1 :ARG0-of (h / harbor-01~e.2 :ARG1 (m / mutate-01~e.11 :ARG2 (a / and~e.7 :op1 (e4 / enzyme :name (n5 / name :op1 "B-Raf"~e.4,6)) :op2 (e5 / enzyme :name (n6 / name :op1 "N-Ras"~e.8,10))) :ARG0-of (c3 / cause-01~e.3 :ARG1 (d3 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.3)))))) :ARG1 (s2 / sensitive-03~e.14 :ARG0 c2 :ARG1~e.15 (s / small-molecule :name (n3 / name :op1 "AZD6244"~e.16)) :ARG1-of (e6 / enhance-01~e.13))) :ARG2 (s3 / show-01~e.24 :ARG0 (t / tumor~e.23 :mod (e3 / enzyme :name (n4 / name :op1 "K-Ras"~e.19,21) :ARG2-of (m2 / mutate-01~e.22))) :ARG1 (r / responsiveness~e.26 :ARG1-of (v / vary-01))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 47~e.30)))) # ::id pmid_2352_4590.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In 2004 , a total of 57 patients with advanced cancer were treated in a phase I evaluation of AZD6244 . # ::alignments 1-1.2.1 4-1.1 4-1.1.2 4-1.1.2.r 6-1.1.2.1 7-1.1.1.1 9-1.1.3.1.3 10-1.1.3.1.2.1 12-1 13-1.3.r 15-1.3.2 16-1.3.2.1.1 17-1.3 18-1.3.1.r 19-1.3.1.1.1 (t / treat-03~e.12 :ARG1 (p / person~e.4 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.7)) :ARG1-of~e.4 (t2 / total-01~e.4 :ARG2 57~e.6) :ARG0-of (h2 / have-03 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.10) :ARG1-of (a / advance-01~e.9)))) :time (d / date-entity :year 2004~e.1) :time~e.13 (e / evaluate-01~e.17 :ARG1~e.18 (s / small-molecule :name (n2 / name :op1 "AZD6244"~e.19)) :mod (p3 / phase~e.15 :ord (o / ordinal-entity :value 1~e.16)))) # ::id pmid_2352_4590.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The best clinical response achieved was s.d . ≥ for 5 months in 9 patients , with 2 patients maintaining s.d . for 19 and 22 months . # ::alignments 1-1.2 1-1.2.1 1-1.2.1.r 2-1.3 3-1 3-1.1 3-1.1.r 4-1.4 5-1.5.r 10-1.5.1.1.1 11-1.5.1.1.2 13-1.5.2.1 14-1.5.2.2.1 18-1.5.2.2.1 19-1.5.2.3.1.1.2 19-1.5.2.3.1.2.2 23-1.5.2.3.1.1.3.1 24-1.5.2.3.1 25-1.5.2.3.1.2.2.2.1 26-1.5.1.1.2 26-1.5.2.3.1.1.3.2 26-1.5.2.3.1.2.2.2.2 (t2 / thing~e.3 :ARG2-of~e.3 (r / respond-01~e.3) :ARG1-of (g / good-02~e.1 :degree~e.1 (m2 / most~e.1)) :mod (c / clinic~e.2) :ARG1-of (a / achieve-01~e.4) :domain~e.5 (d / disease :duration (o2 / or :op1 (t3 / temporal-quantity :quant 5~e.10 :unit (m3 / month~e.11,26)) :op2 (m5 / more-than :op1 t3)) :location (p / person :quant 9~e.13 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.14,18)) :ARG2-of (i / include-91 :ARG1 (a2 / and~e.24 :op1 (p3 / person :ARG0-of h :ARG0-of (m6 / maintain-01~e.19 :ARG1 d2) :duration (t4 / temporal-quantity :quant 19~e.23 :unit (m4 / month~e.26))) :op2 (p4 / person :ARG0-of h :ARG0-of (m7 / maintain-01~e.19 :ARG1 (d2 / disease :ARG1-of s) :duration (t5 / temporal-quantity :quant 22~e.25 :unit (m / month~e.26))))))) :ARG1-of (s / stable-03))) # ::id pmid_2352_4590.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to PD0325901 , blurred vision was reported in 7 patients ; however , neurotoxicity was not observed . @^{49 @} # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1.1 4-1.1.1 5-1.1 7-1 8-1.2.r 9-1.2.1 10-1.2.2.1 12-1.5.r 14-1.5.2 16-1.5.1 16-1.5.1.r 17-1.5 21-1.4.1.1.1 (r2 / report-01~e.7 :ARG1 (s2 / see-01~e.5 :ARG1-of (b / blur-01~e.4)) :location~e.8 (p / person :quant 7~e.9 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.10))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (s / small-molecule :name (n2 / name :op1 "PD0325901"~e.2))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 49~e.21))) :concession-of~e.12 (o / observe-01~e.17 :polarity~e.16 -~e.16 :ARG1 (n / neurotoxicity~e.14))) # ::id pmid_2352_4590.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several phase II trials have since examined the effectiveness of AZD6244 in a diverse range of solid tumours . @^{50 , 51 , 52 @} # ::alignments 0-1.1.2 1-1.1.1 2-1.1.1.1.1 3-1.1 5-1.3 6-1 8-1.2 9-1.2.1.r 10-1.2.1.1.1 11-1.2.2.r 13-1.2.2.2 14-1.2.2 15-1.2.2.1.r 16-1.2.2.1.1 17-1.2.2.1 21-1.4.1.1.1.1 25-1.4.1.2.1.1 29-1.4.1.3.1.1 (e / examine-01~e.6 :ARG0 (t2 / trial-06~e.3 :mod (p / phase~e.1 :ord (o / ordinal-entity :value 2~e.2)) :quant (s3 / several~e.0)) :ARG1 (e2 / effective-04~e.8 :ARG0~e.9 (s / small-molecule :name (n / name :op1 "AZD6244"~e.10)) :ARG1~e.11 (r / range-01~e.14 :ARG1~e.15 (t / tumor~e.17 :ARG1-of (s2 / solid-02~e.16)) :mod (d / diverse~e.13))) :time (s4 / since~e.5) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (p2 / publication :ARG1-of (c / cite-01 :ARG2 50~e.21)) :op2 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 51~e.25)) :op3 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 52~e.29))))) # ::id pmid_2352_4590.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In each of these studies , the efficacy and tolerability of AZD6244 was compared with a conventional chemotherapeutic agent . # ::alignments 1-1.3.1 3-1.3.2 4-1.3 8-1.1 11-1.1.1.1.1.1 13-1 14-1.2.r 16-1.2.1 17-1.2.2 18-1.2 (c / compare-01~e.13 :ARG1 (a / and~e.8 :op1 (e / effective-04 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244"~e.11))) :op2 (t / tolerate-01 :ARG1 s :ARG1-of (p / possible-01))) :ARG2~e.14 (a2 / agent~e.18 :mod (c2 / conventional~e.16) :mod (c3 / chemotherapy~e.17)) :manner (s2 / study-01~e.4 :mod (e2 / each~e.1) :mod (t2 / this~e.3))) # ::id pmid_2352_4590.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , even though some objective responses were observed , AZD6244 failed to demonstrate superior clinical responses over established treatment modalities . # ::alignments 0-1.1.3.r 2-1.1.3.r 3-1 3-1.1.3.r 4-1.1.3.1.2 5-1.1.3.1.1 6-1.1.3.1 8-1.1.3 10-1.1.1.1.1 11-1.1 13-1.1.2 14-1.1.2.2.1 15-1.1.2.2.2 16-1.1.2.2 18-1.1.2.2.1.1.2 19-1.1.2.2.1.1.1 20-1.1.2.2.1.1 (h / have-concession-91~e.3 :ARG2 (f / fail-01~e.11 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.10)) :ARG2 (d / demonstrate-01~e.13 :ARG0 s :ARG1 (r / respond-01~e.16 :ARG1-of (s2 / superior-01~e.14 :compared-to (m / modality~e.20 :mod (t / treat-04~e.19) :ARG1-of (e / establish-01~e.18))) :mod (c / clinic~e.15))) :concession~e.0,2,3 (o / observe-01~e.8 :ARG1 (r2 / respond-01~e.6 :mod (o2 / objective~e.5) :quant (s3 / some~e.4))))) # ::id pmid_2352_4590.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a result of these studies there has not been an advocacy for AZD6244 as a monotherapy . # ::alignments 2-1.3 3-1.3.1.r 4-1.3.1.2 5-1.3.1 5-1.3.1.1 5-1.3.1.1.r 8-1.1 8-1.1.r 11-1 12-1.2.r 13-1.2.1.1 16-1.2.2 (a / advocate-01~e.11 :polarity~e.8 -~e.8 :ARG1~e.12 (s / small-molecule :name (n / name :op1 "AZD6244"~e.13) :mod (m / monotherapy~e.16)) :ARG2-of (r / result-01~e.2 :ARG1~e.3 (t / thing~e.5 :ARG1-of~e.5 (s2 / study-01~e.5) :mod (t2 / this~e.4)))) # ::id pmid_2352_4590.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AS703026 @/@ MSC1935369 demonstrates IC @₅₀ values in the subnanomolar range and potently inhibits tumour growth in vivo . @ ^{53 @} Eighty @-@ five advanced cancer patients were recruited for the phase I trial of AS703026 . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1 6-1.1.1.2.1.1 9-1.1.2.4 11-1.1.1.2.2.1 12-1.1.1.2.2 13-1.1 14-1.1.2.3 14-1.1.2.3.r 15-1.1.2 16-1.1.2.2.1 17-1.1.2.2 19-1.1.2.4 20-1.1.2.4 25-1.1.3.1.1.1 31-1.2.1.3.3 32-1.2.1.3.2.1 33-1.2.1.2.1 35-1.2 36-1.2.2.r 38-1.2.2.2 39-1.2.2.2.1.1 40-1.2.2 41-1.2.2.1.r 42-1.2.2.1.1.1 (m / multi-sentence :snt1 (a / and~e.13 :op1 (d / demonstrate-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "AS703026/MSC1935369"~e.0,2)) :ARG1 (c / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01~e.4 :ARG2 50~e.6 :ARG1 s) :ARG1-of (r / range-01~e.12 :ARG2 (s2 / subnanomolar~e.11)))) :op2 (i / inhibit-01~e.15 :ARG0 s :ARG1 (g / grow-01~e.17 :ARG1 (t2 / tumor~e.16)) :manner~e.14 (p / potent~e.14) :manner (i2 / in-vivo~e.9,19,20)) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 53~e.25)))) :snt2 (r2 / recruit-01~e.35 :ARG1 (p2 / person :quant 85 :ARG0-of (h / have-org-role-91 :ARG2 (p4 / patient~e.33)) :mod (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.32) :ARG1-of (a2 / advance-01~e.31))) :purpose~e.36 (t3 / trial-06~e.40 :ARG2~e.41 (s3 / small-molecule :name (n3 / name :op1 "AS703026"~e.42)) :mod (p3 / phase~e.38 :ord (o / ordinal-entity :value 1~e.39))))) # ::id pmid_2352_4590.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Visual disturbances were reported in a subset of patients , including some cases of serous macular detachment . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.1.2.r 6-1.1.2 8-1.1.2.1.1.1.1 10-1.1.2.1 10-1.1.3 11-1.1.3.1.2 12-1.1.3.1 13-1.1.3.1.1.r 14-1.1.3.1.1.1 15-1.1.3.1.1.2 16-1.1.3.1.1 (r / report-01~e.3 :ARG1 (d / disturb-01~e.1 :mod (v / visual~e.0) :location~e.4 (s / subset~e.6 :ARG2-of (i2 / include-91~e.10 :ARG1 (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p2 / patient~e.8))))) :ARG2-of (i / include-01~e.10 :ARG1 (c / case-04~e.12 :ARG1~e.13 (d2 / detach-01~e.16 :mod (s2 / serum~e.14) :mod (m / macular~e.15)) :quant (s3 / some~e.11))))) # ::id pmid_2352_4590.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumour shrinkage was witnessed in four melanoma patients , three of whom ( all bearing B @-@ Raf mutations ) demonstrated PR . @^{54 @} # ::alignments 0-1.1.1 1-1.1 2-1 3-1 4-1.2.r 5-1.2.1 6-1.2.3.1.1 7-1.2.2.1.4.1 9-1.2.2.1.1 13-1.2.2.1.3.2 14-1.2.2.1.3 15-1.2.2.1.3.1.1.1 17-1.2.2.1.3.1.1.1 18-1.2.2.1.3.1 18-1.2.2.1.3.1.2 18-1.2.2.1.3.1.2.r 20-1.2.2.1.2 25-1.3.1.1.1 (w / witness-01~e.2,3 :ARG1 (s / shrink-01~e.1 :ARG1 (t / tumor~e.0)) :location~e.4 (p / person :quant 4~e.5 :ARG2-of (i / include-91 :ARG1 (p2 / person :quant 3~e.9 :ARG0-of (d / demonstrate-01~e.20 :ARG1 (r / respond-01 :degree (p3 / part))) :ARG0-of (b / bear-01~e.14 :ARG1 (e / enzyme~e.18 :name (n / name :op1 "B-Raf"~e.15,17) :ARG2-of~e.18 (m2 / mutate-01~e.18)) :mod (a / all~e.13)) :ARG0-of (h / have-org-role-91 :ARG2 (p5 / patient~e.7)))) :mod (m / medical-condition :name (n2 / name :op1 "melanoma"~e.6))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 54~e.25)))) # ::id pmid_2352_4590.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok XL @-@ 518 @/@ GDC @-@ 0973 is a potent , orally bioavailable inhibitor that blocks MEK1 function with an IC @₅₀@ < 1 nℳ in enzymatic assays measuring ERK phosphorylation . # ::alignments 0-1.2.1.1 2-1.2.1.1 4-1.2.1.1 6-1.2.1.1 7-1.2.r 9-1.3 11-1.4.1 11-1.4.1.r 12-1.4 13-1 13-1.1 13-1.1.r 15-1.5 16-1.5.1.1.1.1 17-1.5.1 18-1.6.r 20-1.6 22-1.6.1 24-1.6.2 25-1.6.2.1.1 26-1.6.2.1.2 27-1.7.r 28-1.7.1 29-1.7 30-1.7.2 31-1.7.2.1.1.1.1 32-1.7.2.1 (m3 / molecular-physical-entity~e.13 :ARG0-of~e.13 (i / inhibit-01~e.13) :domain~e.7 (s / small-molecule :name (n / name :op1 "XL-518/GDC-0973"~e.0,2,4,6)) :mod (p / potent~e.9) :mod (b / bioavailable~e.12 :manner~e.11 (o / oral~e.11)) :ARG0-of (b2 / block-01~e.15 :ARG1 (f / function-01~e.17 :ARG0 (e / enzyme :name (n2 / name :op1 "MEK1"~e.16)))) :ARG1-of~e.18 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.20 :ARG2 50~e.22 :ARG4 (l / less-than~e.24 :op1 (c / concentration-quantity :quant 1~e.25 :unit (n4 / nanomolar~e.26)))) :time~e.27 (a / assay-01~e.29 :ARG1 (e2 / enzyme~e.28) :ARG0-of (m2 / measure-01~e.30 :manner (p2 / phosphorylate-01~e.32 :ARG2 (e3 / enzyme :name (n5 / name :op1 "ERK"~e.31)))))) # ::id pmid_2352_4590.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Pharmacodynamic studies have demonstrated that a single dose of GDC @-@ 0973 inhibits p @-@ ERK in xenograft tumours for up to 48 h . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 6-1.2.1.2 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1.1 11-1.2.1.1.1.1 12-1.2 13-1.2.2.2 15-1.2.2.1.1 16-1.2.3.r 17-1.2.3.1 18-1.2.3 19-1.2.4.r 20-1.2.4 21-1.2.4 22-1.2.4.1.1 23-1.2.4.1.2 (d / demonstrate-01~e.3 :ARG0 (s / study-01~e.1 :mod (p / pharmacodynamic~e.0)) :ARG1~e.4 (i / inhibit-01~e.12 :ARG0 (d2 / dose-01~e.7 :ARG2~e.8 (s3 / small-molecule :name (n / name :op1 "GDC-0973"~e.9,11)) :ARG1-of (s2 / single-02~e.6)) :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.15) :ARG3-of (p2 / phosphorylate-01~e.13)) :location~e.16 (t2 / tumor~e.18 :mod (x / xenograft~e.17)) :duration~e.19 (u / up-to~e.20,21 :op1 (t / temporal-quantity :quant 48~e.22 :unit (h / hour~e.23))))) # ::id pmid_2352_4590.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast to PD0325901 , p @-@ ERK levels in mouse brain tissue were not significantly suppressed following the administration of GDC @-@ 0973 , suggesting reduced potential for adverse CNS events . @^{55 @} # ::alignments 1-1.6 2-1.6.1.r 3-1.6.1.1.1 5-1.2.1.2 7-1.2.1.1.1 8-1.2 9-1.2.2.r 10-1.2.2.1.1 11-1.2.2.1 12-1.2.2 14-1.1 14-1.1.r 15-1.3 16-1 17-1.4 19-1.4.1 20-1.4.1.1.r 21-1.4.1.1.1.1 23-1.4.1.1.1.1 25-1.5 26-1.5.1.1 27-1.5.1 28-1.5.1.2.r 29-1.5.1.2.2 31-1.5.1.2 35-1.7.1.1.1 (s / suppress-01~e.16 :polarity~e.14 -~e.14 :ARG1 (l / level~e.8 :quant-of (e / enzyme :name (n / name :op1 "ERK"~e.7) :ARG3-of (p / phosphorylate-01~e.5)) :location~e.9 (t / tissue~e.12 :mod (b / brain~e.11 :mod (m / mouse~e.10)))) :ARG1-of (s2 / significant-02~e.15) :ARG2-of (f / follow-01~e.17 :ARG1 (a / administer-01~e.19 :ARG1~e.20 (s3 / small-molecule :name (n2 / name :op1 "GDC-0973"~e.21,23)))) :ARG0-of (s4 / suggest-01~e.25 :ARG1 (p2 / potential~e.27 :ARG1-of (r / reduce-01~e.26) :beneficiary~e.28 (e2 / event~e.31 :mod (s6 / system :mod (n4 / nerve) :mod (c / central)) :mod (a2 / adverse~e.29)))) :ARG1-of (c2 / contrast-01~e.1 :ARG2~e.2 (s5 / small-molecule :name (n3 / name :op1 "PD0325901"~e.3))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 55~e.35)))) # ::id pmid_2352_4590.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A phase I study of GDC @-@ 0972 in patients with solid tumour was initiated in 2007 . # ::alignments 1-1.1.2 2-1.1.2.1.1 3-1.1 4-1.1.1.r 5-1.1.1.1.1 7-1.1.1.1.1 8-1.1.3.r 9-1.1.3.2.1 11-1.1.3.1.1.1 12-1.1.3.1.1 14-1 15-1.2.r 16-1.2.1 (i / initiate-01~e.14 :ARG1 (s / study-01~e.3 :ARG1~e.4 (s2 / small-molecule :name (n / name :op1 "GDC-0972"~e.5,7)) :mod (p / phase~e.1 :ord (o / ordinal-entity :value 1~e.2)) :location~e.8 (p2 / person :ARG0-of (h / have-03 :ARG1 (t / tumor~e.12 :ARG1-of (s3 / solid-02~e.11))) :ARG0-of (h2 / have-org-role-91 :ARG2 (p3 / patient~e.9)))) :time~e.15 (d / date-entity :year 2007~e.16)) # ::id pmid_2352_4590.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Confirmed PR were witnessed in three melanoma patients , two of which harboured B @-@ Raf V600E mutations . # ::alignments 0-1.1.1 2-1 3-1 4-1.2.r 5-1.2.1 6-1.2.4.1.1 7-1.2.2.1 7-1.2.3.1 9-1.2.2.1.1 12-1.2.2.1.2 13-1.2.2.1.2.1.2.1.1 15-1.2.2.1.2.1.2.1.1 16-1.2.2.1.2.1.1 17-1.2.2.1.2.1 (w / witness-01~e.2,3 :ARG1 (r / respond-01 :ARG1-of (c / confirm-01~e.0) :degree (p / part)) :location~e.4 (p2 / person :quant 3~e.5 :ARG2-of (i / include-91 :ARG1 (p3 / patient~e.7 :quant 2~e.9 :ARG0-of (h / harbor-01~e.12 :ARG1 (m2 / mutate-01~e.17 :value "V600E"~e.16 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"~e.13,15)))))) :ARG0-of (h2 / have-org-role-91 :ARG2 (p4 / patient~e.7)) :mod (m / medical-condition :name (n2 / name :op1 "melanoma"~e.6)))) # ::id pmid_2352_4590.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Six patients with prolonged s.d . (≥ 5 months ) have been observed to date . @^{56 @} # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.2 7-1.1.2.1.2.1.1.1.1.1 7-1.1.2.1.2.1.1.2.1.1 8-1.1.2.1.2.1.1.1.1.2 10-1.1.2 12-1 13-1.2 14-1.2 18-1.3.1.1.1 (o / observe-01~e.12 :ARG1 (p / patient~e.1 :quant 6~e.0 :ARG0-of~e.2 (h / have-03~e.10 :ARG1 (d / disease :ARG1-of (s / stable-03) :ARG1-of (p2 / prolong-01~e.3 :ARG1-of (m / mean-01 :ARG2 (o2 / or :op1 (e / equal-01 :ARG1 (t2 / temporal-quantity :quant 5~e.7 :unit (m2 / month~e.8))) :op2 (m3 / more-than :op1 (t3 / temporal-quantity :quant 5~e.7 :unit m2)))))))) :time (t / to-date~e.13,14) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 56~e.18)))) # ::id pmid_2352_4590.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MEK inhibitor , BAY869766/RDEA119 , specifically inhibits MEK1 ( IC @₅₀@ = 19 nℳ) and MEK2 ( IC @₅₀@ = 47 nℳ) when compared with 205 other kinases . # ::alignments 1-1.1.1.2.1.1.1 2-1.1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 2-1.1.1.r 4-1.1.1.1.1 4-1.2.1.1.1 6-1.3 7-1.1 7-1.1.1 7-1.1.1.2 7-1.1.1.2.r 7-1.1.1.r 7-1.2 8-1.1.2.1.1 10-1.1.1.3 12-1.1.1.3.1 15-1.1.1.3.2.1 17-1 18-1.2.2.1.1 20-1.2.1 20-1.2.1.2 20-1.2.1.2.r 22-1.2.1.2.1 25-1.2.1.2.2.1 28-1.4 29-1.4.2.r 30-1.4.2.1 31-1.4.2.2 32-1.4.2 (a2 / and~e.17 :op1 (i4 / inhibit-01~e.2,7 :ARG0~e.2,7 (s / small-molecule~e.2,7 :name (n / name :op1 "BAY869766/RDEA119"~e.4) :ARG0-of~e.2,7 (i2 / inhibit-01~e.2,7 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"~e.1))) :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01~e.10 :ARG2 50~e.12 :ARG4 (c2 / concentration-quantity :quant 19~e.15 :unit (n5 / nanomolar)))) :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1"~e.8))) :op2 (i / inhibit-01~e.7 :ARG0 (s3 / small-molecule~e.20 :name (n6 / name :op1 "BAY869766/RDEA119"~e.4) :ARG1-of~e.20 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.20 :ARG2 50~e.22 :ARG4 (c3 / concentration-quantity :quant 47~e.25 :unit (n7 / nanomolar)))) :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK2"~e.18))) :ARG1-of (s2 / specific-02~e.6) :condition (c / compare-01~e.28 :ARG1 s :ARG2~e.29 (k / kinase~e.32 :quant 205~e.30 :mod (o / other~e.31)))) # ::id pmid_2352_4590.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The antitumour effect of BAY8697655 has been established in mouse xenograft models , with potent growth inhibition observed during drug treatment . @^{57 @} # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1.1.1 7-1 8-1.2.r 9-1.2.2 10-1.2.1 11-1.2 14-1.2.3.1.1.1 15-1.2.3.1.1 16-1.2.3.1 17-1.2.3.1.2 18-1.2.3.1.2.1.r 19-1.2.3.1.2.1.1 20-1.2.3.1.2.1 24-1.3.1.1.1 (e / establish-01~e.7 :ARG1 (a / affect-01~e.2 :ARG0~e.3 (s / small-molecule :name (n / name :op1 "BAY8697655"~e.4)) :ARG2 (c2 / counter-01 :ARG1 (t / tumor))) :location~e.8 (m / model~e.11 :mod (x / xenograft~e.10) :mod (m2 / mouse~e.9) :ARG0-of (h / have-03 :ARG1 (i / inhibit-01~e.16 :ARG1 (g / grow-01~e.15 :mod (p / potent~e.14)) :ARG1-of (o2 / observe-01~e.17 :time~e.18 (t2 / treat-03~e.20 :ARG3 (d / drug~e.19)))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 57~e.24)))) # ::id pmid_2352_4590.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Early data from the BAY8679655 phase I trial demonstrates good drug tolerability , with rash being the most prevalent treatment @-@ related adverse effect . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 4-1.1.2.1.1.1 5-1.1.2.2 6-1.1.2.2.1.1 7-1.1.2 8-1 9-1.2.1.2 10-1.2.1.1 13-1.2.r 14-1.2.2 15-1.2.2.1.r 17-1.2.2.1.2.1 18-1.2.2.1.2 19-1.2.2.1.3.1 21-1.2.2.1.3 22-1.2.2.1.1 23-1.2.2.1 (d / demonstrate-01~e.8 :ARG0 (d2 / data~e.1 :time (e / early~e.0) :source~e.2 (t / trial-06~e.7 :ARG2 (s / small-molecule :name (n / name :op1 "BAY8679655"~e.4)) :mod (p / phase~e.5 :ord (o / ordinal-entity :value 1~e.6)))) :ARG1~e.13 (a3 / and :op1 (t2 / tolerate-01 :ARG1 (d3 / drug~e.10) :ARG1-of (g / good-02~e.9) :ARG2-of (e2 / except-01)) :op2 (r / rash~e.14 :domain~e.15 (a / affect-01~e.23 :mod (a2 / adverse~e.22) :ARG1-of (p2 / prevail-02~e.18 :degree (m / most~e.17)) :ARG1-of (r2 / relate-01~e.21 :ARG2 (t3 / treat-03~e.19)))))) # ::id pmid_2352_4590.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Among the 69 advanced cancer patients enroled in the trial , 10 achieved s.d . with a mean duration of 10 months . # ::alignments 0-1.1.3 2-1.1.3.1.1 3-1.1.3.1.4.3 4-1.1.3.1.4.2.1 5-1.1.2.1 9-1.1.3.1.2.1 11-1.1.1 11-1.2.1.1 12-1 15-1.2.r 17-1.2.1.3 20-1.2.1.1 21-1.2.1.2 (a2 / achieve-01~e.12 :ARG0 (p2 / person :quant 10~e.11 :ARG0-of (h / have-org-role-91 :ARG2 (p3 / patient~e.5)) :ARG1-of (i / include-91~e.0 :ARG2 (p / person :quant 69~e.2 :ARG1-of (e / enroll-01 :ARG2 (t / trial-06~e.9)) :ARG0-of h :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.4) :ARG1-of (a / advance-01~e.3))))) :ARG1~e.15 (d / disease :duration (t2 / temporal-quantity :quant 10~e.11,20 :unit (m / month~e.21) :mod (m2 / mean~e.17)) :ARG1-of (s / stable-03))) # ::id pmid_2352_4590.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phase II development of BAY867966 is currently being pursued in light of these findings . @^{58 @} # ::alignments 0-1.1.2 1-1.1.2.1.1 2-1.1 3-1.1.1.r 4-1.1.1.1.1 6-1.2 8-1 12-1.3.1.2 13-1.3.1 13-1.3.1.1 13-1.3.1.1.r 17-1.4.1.1.1 (p / pursue-01~e.8 :ARG1 (d / develop-01~e.2 :ARG2~e.3 (s / small-molecule :name (n / name :op1 "BAY867966"~e.4)) :mod (p2 / phase~e.0 :ord (o / ordinal-entity :value 2~e.1))) :time (c / current~e.6) :ARG1-of (c2 / cause-01 :ARG0 (t / thing~e.13 :ARG1-of~e.13 (f / find-01~e.13) :mod (t2 / this~e.12))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 58~e.17)))) # ::id pmid_2352_4590.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GSK1120212 is a structurally novel allosteric MEK inhibitor with an in vitro IC @₅₀ of 0.4± 00.1 nℳ for MEK1 activation by B @-@ Raf and 10± 2 nℳ for p @-@ MEK1 activity . # ::alignments 0-1.1.1 3-1.4 4-1.3 5-1.2 6-1.5.1.1.1 7-1 7-1.5 7-1.5.r 11-1.7.4 12-1.7.4 14-1.6 14-1.7 16-1.6.1 16-1.7.1 21-1.6.3.2 21-1.7.3.2 23-1.6.2.2.1.1 23-1.7.2.1.1.1 24-1.6.2 25-1.6.2.1.r 26-1.6.2.1.1.1 28-1.6.2.1.1.1 31-1.7.3.1.1.1 31-1.7.3.1.2.1 32-1.7.3.2 33-1.7.2.r 34-1.7.2.1.2 36-1.7.2.1.1.1 37-1.7.2 (s / small-molecule~e.7 :name (n / name :op1 "GSK1120212"~e.0) :mod (a / allosteric~e.5) :mod (n3 / novel~e.4) :mod (s2 / structural~e.3) :ARG0-of~e.7 (i / inhibit-01~e.7 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.6))) :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01~e.14 :ARG2 50~e.16 :ARG3 (a4 / activate-01~e.24 :ARG0~e.25 (e3 / enzyme :name (n5 / name :op1 "B-Raf"~e.26,28)) :ARG1 (e4 / enzyme :name (n6 / name :op1 "MEK1"~e.23))) :ARG4 (c / concentration-quantity :quant (v / value-interval :op1 (s3 / subtract-01 :ARG1 0.001 :ARG2 0.4) :op2 (a3 / add-02 :ARG1 0.001 :ARG2 0.4)) :unit (n9 / nanomolar~e.21)) :manner i2) :ARG1-of (h3 / have-percentage-maximal-inhibitory-concentration-01~e.14 :ARG2 50~e.16 :ARG3~e.33 (a6 / activity-06~e.37 :ARG0 (e6 / enzyme :name (n8 / name :op1 "MEK1"~e.23,36) :ARG3-of (p / phosphorylate-01~e.34))) :ARG4 (c2 / concentration-quantity :quant (v2 / value-interval :op1 (s4 / subtract-01 :ARG1 2~e.31 :ARG2 10) :op2 (a5 / add-02 :ARG1 2~e.31 :ARG2 10)) :unit (n4 / nanomolar~e.21,32)) :manner (i2 / in-vitro~e.11,12))) # ::id pmid_2352_4590.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In cell lines harbouring activating Ras or B @-@ Raf mutations , GSK1120212 inhibited cell proliferation at IC @₅₀ values < 50 nℳ, but demonstrated decreased activity against those cells with wild @-@ type Ras or wild @-@ type @-@ B @-@ Raf . @^{59 @} # ::alignments 1-1.4 2-1.4 3-1.4.1 4-1.4.1.1.1.2 5-1.4.1.1.1.1.1.1 6-1.4.1.1 7-1.4.1.1.2.1.1.1 9-1.4.1.1.2.1.1.1 10-1.4.1.1.1 10-1.4.1.1.2 12-1.1.1.1 13-1 14-1.2.1 14-1.4 15-1.2 17-1.1 17-1.1.2 17-1.1.2.r 19-1.1.2.1 19-1.1.2.2.1.1 22-1.1.2.2 23-1.1.2.1 23-1.1.2.2.1.1 25-1.3 26-1.3.1 27-1.3.1.2.3 28-1.3.1.2 30-1.3.1.2.2.1 31-1.3.1.2.2 33-1.3.1.2.2.2.1.1.2 35-1.3.1.2.2.2.1.1.2 36-1.3.1.2.2.2.1.1.1.1 36-1.4.1.1.1.1.1.1 37-1.4.1.1 38-1.3.1.2.2.2.1.1.2 40-1.3.1.2.2.2.1.1.2 42-1.3.1.2.2.2.1.2.1.1 42-1.4.1.1.2.1.1.1 44-1.3.1.2.2.2.1.2.1.1 44-1.4.1.1.2.1.1.1 48-1.5.1.1.1 (i / inhibit-01~e.13 :ARG0 (s / small-molecule~e.17 :name (n / name :op1 "GSK1120212"~e.12) :ARG1-of~e.17 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.17 :ARG2 50~e.19,23 :ARG4 (l / less-than~e.22 :op1 (c2 / concentration-quantity :quant 50~e.19,23 :unit (n3 / nanomolar))))) :ARG1 (p / proliferate-01~e.15 :ARG0 (c / cell~e.14)) :ARG1-of (c6 / contrast-01~e.25 :ARG2 (d / demonstrate-01~e.26 :ARG0 s :ARG1 (a / activity-06~e.28 :ARG0 s :ARG1 (c3 / cell~e.31 :mod (t2 / that~e.30) :ARG0-of (h3 / have-03 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Ras"~e.36) :mod (w / wild-type~e.33,35,38,40)) :op2 (e3 / enzyme :name (n5 / name :op1 "B-Raf"~e.42,44) :mod w)))) :ARG1-of (d2 / decrease-01~e.27)))) :location (c4 / cell-line~e.1,2,14 :ARG0-of (h4 / harbor-01~e.3 :ARG1 (o / or~e.6,37 :op1 (m / mutate-01~e.10 :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras"~e.5,36)) :ARG0-of (a3 / activate-01~e.4)) :op2 (m2 / mutate-01~e.10 :ARG1 (e5 / enzyme :name (n7 / name :op1 "B-Raf"~e.7,9,42,44)) :ARG0-of a3)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 59~e.48)))) # ::id pmid_2352_4590.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are consistent with other MEK inhibitors , where cells with constitutively active Ras @/@ MAPK signalling demonstrate a reliance on these oncogenic pathways , thereby making them hypersensitive to MEK inhibition . # ::alignments 0-1.2.3.2.1.1 1-1.1 1-1.1.1 1-1.1.1.r 3-1 5-1.2.2 6-1.2.1.1.1.1 7-1.2 7-1.2.1 7-1.2.1.r 7-1.2.3.2.2.1.2.2 9-1.2.3.r 10-1.2.3.1 11-1.2.3.1.1.r 12-1.2.3.1.1.2.1 13-1.2.3.1.1.2 14-1.2.3.1.1.1.1.1 16-1.2.3.1.1.1.1.1 17-1.2.3.1.1 18-1.2.3 20-1.2.3.2 22-1.2.3.2.1.1 23-1.2.3.2.1.2 23-1.2.3.2.1.2.1.2.1 23-1.2.3.2.2 24-1.2.3.2.1 26-1.2.3.1.1.2.1.r 27-1.2.3.2.2.1 29-1.2.3.2.2.1.2 29-1.2.3.2.2.1.2.3 29-1.2.3.2.2.1.2.3.r 30-1.2.3.2.2 31-1.2.1.1.1.1 32-1.2 32-1.2.1 32-1.2.1.r (c / consistent-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG2 (m2 / molecular-physical-entity~e.7,32 :ARG0-of~e.7,32 (i / inhibit-01~e.7,32 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.6,31))) :mod (o / other~e.5) :location-of~e.9 (d / demonstrate-01~e.18 :ARG0 (c2 / cell~e.10 :location-of~e.11 (s / signal-07~e.17 :ARG1 (p2 / pathway :name (n2 / name :op1 "Ras/MAPK"~e.14,16)) :ARG0-of (a / activity-06~e.13 :manner~e.26 (c3 / constitutive~e.12)))) :ARG1 (r2 / rely-01~e.20 :ARG1 (p / pathway~e.24 :mod (t3 / this~e.0,22) :ARG0-of (c5 / cause-01~e.23 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.23)))) :ARG0-of (c4 / cause-01~e.23,30 :ARG1 (m / make-02~e.27 :ARG0 p :ARG1 (s2 / sensitive-03~e.29 :ARG0 p :ARG1 (i2 / inhibit-01~e.7 :ARG1 p3) :degree~e.29 (h / hyper~e.29)))))))) # ::id pmid_2352_4590.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In melanoma xenografted mouse models , GSK1120212 administered orally once daily demonstrated an effective t @_{1 @/@ 2} of 36 h with sustained suppression of p @-@ ERK for > 24 h . @^{60 @} # ::alignments 1-1.2.3.1.1 3-1.2.1 4-1.2 6-1.4.1.1.1 7-1.4 8-1.4.3 8-1.4.3.r 9-1.4.2.1 9-1.4.2.2.1 9-1.4.2.r 10-1.1.1.2 10-1.1.2.4.1 10-1.4.2 10-1.4.2.1 10-1.4.2.1.r 10-1.4.2.2 10-1.4.2.2.1 10-1.4.2.2.1.r 10-1.4.2.2.2 10-1.4.2.2.2.r 10-1.4.2.2.r 11-1 13-1.1.1.3 16-1.4.2.1 21-1.1.1.2.1 22-1.1.1.2.2 23-1.1.r 24-1.1.2.3 25-1.1.2 26-1.1.2.2.r 27-1.1.2.2.2 29-1.1.2.2.1.1 30-1.1.2.4.r 31-1.1.2.4 32-1.1.2.4.1.1 33-1.1.2.4.1.2 37-1.3.1.1.1 (d / demonstrate-01~e.11 :ARG1~e.23 (a2 / and :op1 (h3 / have-half-life-01 :ARG1 s :ARG2 (t3 / temporal-quantity~e.10 :quant 36~e.21 :unit (h / hour~e.22)) :ARG1-of (e / effective-04~e.13)) :op2 (s2 / suppress-01~e.25 :ARG0 s :ARG1~e.26 (e3 / enzyme :name (n3 / name :op1 "ERK"~e.29) :ARG3-of (p / phosphorylate-01~e.27)) :ARG1-of (s3 / sustain-01~e.24) :duration~e.30 (m / more-than~e.31 :op1 (t4 / temporal-quantity~e.10 :quant 24~e.32 :unit h~e.33)))) :location (m2 / model~e.4 :mod (m3 / mouse~e.3) :ARG1-of (x / xenograft-00) :mod (m4 / medical-condition :name (n2 / name :op1 "melanoma"~e.1))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 60~e.37))) :condition (a / administer-01~e.7 :ARG1 (s / small-molecule :name (n / name :op1 "GSK1120212"~e.6)) :frequency~e.9 (r / rate-entity-91~e.10 :ARG1~e.10 1~e.9,10,16 :ARG2~e.10 (t / temporal-quantity~e.10 :quant~e.10 1~e.9,10 :unit~e.10 (d2 / day~e.10))) :manner~e.8 (o / oral~e.8))) # ::id pmid_2352_4590.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , inhibition of p @-@ ERK was not observed within brain samples . # ::alignments 0-1.4 2-1.2 3-1.2.1.r 4-1.2.1.3 6-1.2.1.2.1 8-1.1 8-1.1.r 9-1 11-1.3.1 12-1.3 (o / observe-01~e.9 :polarity~e.8 -~e.8 :ARG1 (i / inhibit-01~e.2 :ARG1~e.3 (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n / name :op1 "ERK"~e.6) :ARG3-of (p / phosphorylate-01~e.4))) :location (s / sample-01~e.12 :ARG1 (b / brain~e.11)) :ARG1-of (n2 / notable-04~e.0)) # ::id pmid_2352_4590.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phase I results of this compound have recently been presented by Gordon et al. @ ^{61 @} For 22 patients with B @-@ Raf mutant melanoma , 1 CR and 9 PR were observed . # ::alignments 0-1.1.2.2 1-1.1.2.2.1.1 2-1.1.2 2-1.1.2.1 2-1.1.2.1.r 3-1.1.2.1.1.r 4-1.1.2.1.1.1 5-1.1.2.1.1 7-1.1.3 9-1.1 11-1.1.1.1.1.1.1 13-1.1.1.1 14-1.1.1.1.2.1 18-1.1.4.1.1.1 22-1.2.2.1 23-1.2.2.3.1 25-1.2.2.2.1.2.1.1 27-1.2.2.2.1.2.1.1 28-1.2.2.2.1.2 28-1.2.2.2.1.2.2 28-1.2.2.2.1.2.2.r 29-1.2.2.2.1.1.1 31-1.2.1.1.1 33-1.2.1 34-1.2.1.2.1 37-1.2 (m / multi-sentence :snt1 (p / present-01~e.9 :ARG0 (p3 / publication-91 :ARG0 (a / and~e.13 :op1 (p4 / person :name (n / name :op1 "Gordon"~e.11)) :op2 (p5 / person :mod (o / other~e.14)))) :ARG1 (t / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2 :ARG1~e.3 (c / compound-01~e.5 :mod (t2 / this~e.4))) :mod (p2 / phase~e.0 :ord (o3 / ordinal-entity :value 1~e.1))) :time (r2 / recent~e.7) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 61~e.18)))) :snt2 (o2 / observe-01~e.37 :ARG1 (a2 / and~e.33 :op1 (r3 / respond-01 :quant 1~e.31 :ARG1-of (c3 / complete-01)) :op2 (r4 / respond-01 :quant 9~e.34 :degree (p9 / part))) :location (p7 / person :quant 22~e.22 :ARG0-of (h / have-03 :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma"~e.29) :mod (e / enzyme~e.28 :name (n2 / name :op1 "B-Raf"~e.25,27) :ARG2-of~e.28 (m3 / mutate-01~e.28)))) :ARG0-of (h2 / have-org-role-91 :ARG2 (p8 / patient~e.23))))) # ::id pmid_2352_4590.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For 22 patients with pancreatic cancer , 1 PR and 9 s.d . were reported . # ::alignments 1-1.2.1 2-1.2 4-1.2.2.1.2.1 5-1.2.2.1.2.2 7-1.1.1.1 9-1.1 10-1.1.2.1 14-1 (r / report-01~e.14 :ARG1 (a / and~e.9 :op1 (r2 / respond-01 :quant 1~e.7 :degree (p / part)) :op2 (d / disease :quant 9~e.10 :ARG1-of (s / stable-03))) :location (p2 / patient~e.2 :quant 22~e.1 :ARG0-of (h / have-03 :ARG1 (d2 / disease :wiki "Pancreatic_cancer" :name (n / name :op1 "pancreatic"~e.4 :op2 "cancer"~e.5))))) # ::id pmid_2352_4590.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Early data from a phase I/II trial examining GSK1120212 in patients with relapsed @/@ refractory myeloid malignancies harbouring Ras mutations has also recently been reported . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 4-1.1.2.1.1 4-1.1.2.1.2 6-1.1.2 7-1.1.2.2 8-1.1.2.2.1.1.1 9-1.1.2.2.2.r 10-1.1.2.2.2.2.1 12-1.1.2.2.2.1.1.1.2 13-1.1.2.1 13-1.1.2.2.2.1.1 14-1.1.2.2.2.1.1.2.1 15-1.1.2.2.2.1.1.1.1 16-1.1.2.2.2.1.1.1 16-1.1.2.2.2.1.1.2 17-1.1.2.2.2.1.1.3 18-1.1.2.2.2.1.1.3.1.1.1 19-1.1.2.2.2.1.1.3.1 19-1.1.2.2.2.1.1.3.1.2 19-1.1.2.2.2.1.1.3.1.2.r 20-1.1.2.2.2 20-1.1.2.2.2.1 20-1.1.2.2.2.1.r 20-1.1.2.2.2.2 20-1.1.2.2.2.2.r 21-1.3 22-1.2 24-1 (r / report-01~e.24 :ARG1 (d / data~e.1 :time (e / early~e.0) :source~e.2 (t / trial-06~e.6 :mod (s / slash~e.13 :op1 (p / phase~e.4 :ord (o / ordinal-entity :value 1)) :op2 (p2 / phase~e.4 :ord (o2 / ordinal-entity :value 2))) :ARG0-of (e2 / examine-01~e.7 :ARG1 (s2 / small-molecule :name (n / name :op1 "GSK1120212"~e.8)) :location~e.9 (p3 / person~e.20 :ARG0-of~e.20 (h / have-03~e.20 :ARG1 (s3 / slash~e.13 :op1 (m / malignancy~e.16 :mod (m2 / myeloid~e.15) :ARG1-of (r2 / relapse-01~e.12)) :op2 (m3 / malignancy~e.16 :mod (r3 / refractory~e.14) :mod m2) :ARG0-of (h2 / harbor-01~e.17 :ARG1 (e3 / enzyme~e.19 :name (n2 / name :op1 "Ras"~e.18) :ARG2-of~e.19 (m4 / mutate-01~e.19))))) :ARG0-of~e.20 (h3 / have-org-role-91~e.20 :ARG2 (p4 / patient~e.10)))))) :time (r4 / recent~e.22) :mod (a / also~e.21)) # ::id pmid_2352_4590.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients were prospectively screened for K @- and N @-@ Ras mutations before receiving daily treatment with GSK1120212 . # ::alignments 0-1.1.1.1 2-1.4 2-1.4.r 3-1 4-1.2.r 5-1.2.1.1.1.1 7-1.2 8-1.2.2.1.1.1 10-1.2.1.1.1.1 10-1.2.2.1.1.1 11-1.2.1 11-1.2.2 12-1.3 13-1.3.1 14-1.3.1.3 15-1.3.1.2 16-1.3.1.2.1.r 17-1.3.1.2.1.1.1 (s / screen-01~e.3 :ARG1 (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p3 / patient~e.0))) :ARG2~e.4 (a / and~e.7 :op1 (m / mutate-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.5,10))) :op2 (m2 / mutate-01~e.11 :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras"~e.8,10)))) :time (b / before~e.12 :op1 (r / receive-01~e.13 :ARG0 p :ARG1 (t / treat-03~e.15 :ARG3~e.16 (s2 / small-molecule :name (n3 / name :op1 "GSK1120212"~e.17))) :frequency (d / day~e.14))) :manner~e.2 (p2 / prospective~e.2)) # ::id pmid_2352_4590.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Encouraging signs of clinical activity with manageable adverse effects have been observed . @^{62 @} # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2.2 7-1.1.1.2.1 8-1.1.1.2 11-1 15-1.2.1.1.1 (o / observe-01~e.11 :ARG1 (s / signal-07~e.1 :ARG1~e.2 (a / activity-06~e.4 :mod (c / clinic~e.3) :ARG0-of~e.5 (a2 / affect-01~e.8 :mod (a3 / adverse~e.7) :ARG1-of (m / manage-01~e.6 :ARG1-of (p / possible-01)))) :ARG0-of (e / encourage-01~e.0)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 62~e.15)))) # ::id pmid_2352_4590.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Enhancing effectiveness with combination therapies # ::alignments 1-1 2-1.1 3-1.2.r 4-1.2 5-1.2.1 (e / enhance-01~e.1 :ARG1 (e2 / effective-04~e.2) :ARG2~e.3 (c / combine-01~e.4 :ARG1 (t / therapy~e.5))) # ::id pmid_2352_4590.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite improvements in clinical potency and pharmacokinetics , MEK inhibitors have generally shown limited effectiveness as monotherapeutic agents . # ::alignments 0-1 1-1.2 2-1.2.1.r 3-1.2.1.1.1 4-1.2.1.1 5-1.2.1 6-1.2.1.2 8-1.1.1.1.1.1.1 9-1.1.1 9-1.1.1.1 9-1.1.1.1.r 11-1.1.3 12-1.1 13-1.1.2.2 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1 17-1.1.2.1 (h / have-concession-91~e.0 :ARG1 (s / show-01~e.12 :ARG0 (m2 / molecular-physical-entity~e.9 :ARG0-of~e.9 (i / inhibit-01~e.9 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.8)))) :ARG1 (e2 / effective-04~e.14 :ARG1~e.15 (a / agent~e.17 :mod (m / monotherapeutic~e.16)) :ARG1-of (l / limit-01~e.13)) :ARG1-of (g / general-02~e.11)) :ARG2 (i2 / improve-01~e.1 :ARG1~e.2 (a2 / and~e.5 :op2 (p / potency~e.4 :mod (c / clinic~e.3)) :op2 (p2 / pharmacokinetics~e.6)))) # ::id pmid_2352_4590.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several reasons may account for this observation . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 3-1.1 4-1.1.2.r 5-1.1.2.1 6-1.1.2 (p / possible-01~e.2 :ARG1 (a / account-01~e.3 :ARG0 (r / reason~e.1 :quant (s / several~e.0)) :ARG1~e.4 (o / observe-01~e.6 :mod (t / this~e.5)))) # ::id pmid_2352_4590.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Abrogation of Ras @/@ MAPK signalling appears to be mainly cytostatic , and suggests that an additional therapeutic modality is required to maximise the antitumour effectiveness of MEK inhibitors . # ::alignments 0-1.1.1.2 1-1.1.1.2.1.r 2-1.1.1.2.1.1.1.1 4-1.1.1.2.1.1.1.1 5-1.1.1.2.1 6-1.1 8-1.1.1.2.r 9-1.1.1.1 10-1.1.1 12-1 13-1.2 17-1.2.2.2.1 18-1.2.2.2 20-1.2.2 25-1.2.2.1.1 26-1.2.2.1.1.1.r 27-1.2.2.1.1.1.1.1.1.1 28-1.2.2.1.1.1 28-1.2.2.1.1.1.1 28-1.2.2.1.1.1.1.r (a / and~e.12 :op1 (a2 / appear-02~e.6 :ARG1 (c / cytostatic~e.10 :mod (m / main~e.9) :domain~e.8 (a3 / abrogate-01~e.0 :ARG1~e.1 (s2 / signal-07~e.5 :ARG0 (p / pathway :name (n / name :op1 "Ras/MAPK"~e.2,4)))))) :op2 (s / suggest-01~e.13 :ARG0 a3 :ARG1 (r / require-01~e.20 :ARG0 (m3 / maximize-01 :ARG1 (e / effective-04~e.25 :ARG0~e.26 (m4 / molecular-physical-entity~e.28 :ARG0-of~e.28 (i / inhibit-01~e.28 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.27)))) :ARG1 (o / oppose-01 :ARG0 i :ARG1 (t3 / tumor)))) :ARG1 (m2 / modality~e.18 :mod (t / therapy~e.17) :ARG1-of (a4 / add-02))))) # ::id pmid_2352_4590.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In hepatocellular carcinoma xenograft models , AZD6244 in conjunction with doxorubicin demonstrated enhanced growth suppression ( 76 %± 7 ) , compared with AZD6244 ( 52± 15 %) and doxorubicin ( 12± 9 %) alone . # ::alignments 1-1.3.2 2-1.3.3.1.1 3-1.3.1 4-1.3 6-1.1.1.1.1 10-1.1.2.1.1 11-1 12-1.2.2 13-1.2.1 14-1.2 16-1.2.3.1.1 18-1.2.3.1.2.1.1 21-1.2.2.1.r 23-1.2.2.1.1.1.1 26-1.2.2.1.1.2.2.1.1 28-1.2.2.1 29-1.2.2.1.2.1.1 32-1.2.2.1.2.2.2.1.1 34-1.2.2.1.3 (d / demonstrate-01~e.11 :ARG0 (a / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.6)) :op2 (s2 / small-molecule :name (n2 / name :op1 "doxorubicin"~e.10))) :ARG1 (s3 / suppress-01~e.14 :ARG1 (g / grow-01~e.13) :ARG1-of (e / enhance-01~e.12 :compared-to~e.21 (a3 / and~e.28 :op1 (s5 / small-molecule :name (n3 / name :op1 "AZD6244"~e.23) :quant (p3 / percentage-entity :value 52 :ARG2-of (a4 / add-02 :ARG1 (p4 / percentage-entity :value 15~e.26)) :ARG2-of (s7 / subtract-01 :ARG1 p4))) :op2 (s6 / small-molecule :name (n4 / name :op1 "doxorubicin"~e.29) :quant (p5 / percentage-entity :value 12 :ARG2-of (a5 / add-02 :ARG1 (p6 / percentage-entity :value 9~e.32)) :ARG2-of (s8 / subtract-01 :ARG1 p6))) :mod (a6 / alone~e.34))) :ARG1-of (m / mean-01 :ARG2 (p / percentage-entity :value 76~e.16 :ARG2-of (a2 / add-02 :ARG1 (p2 / percentage-entity :value 7~e.18)) :ARG2-of (s4 / subtract-01 :ARG1 p2)))) :location (m2 / model~e.4 :mod (x / xenograft~e.3) :mod (h / hepatocellular~e.1) :mod (m3 / medical-condition :name (n5 / name :op1 "carcinoma"~e.2)))) # ::id pmid_2352_4590.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This synergy was associated with increased apoptosis . @^{63 @} # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.1 6-1.2 10-1.3.1.1.1 (a / associate-01~e.3 :ARG1 (s / synergize-01~e.1 :mod (t / this~e.0)) :ARG2~e.4 (a2 / apoptosis~e.6 :ARG1-of (i / increase-01~e.5)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 63~e.10)))) # ::id pmid_2352_4590.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar effects have been observed with AZD6244 and docetaxel in malignant melanoma , ^{64 @} and AZD6244 and cytarabine in acute myelogenous leukaemia . @^{65 @} # ::alignments 0-1.1.1.4 1-1.1.1 1-1.1.2 4-1 5-1.1.1.1.r 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.2.1.1 9-1.1.1.2.r 10-1.1.1.2 10-1.1.1.2.2 10-1.1.1.2.2.r 11-1.1.1.2.1.1 15-1.1.1.3.1.1.1 19-1.1.2.1.1 20-1.1 21-1.1.2.1.2.1.1 22-1.1.2.2.r 23-1.1.2.2.3 24-1.1.2.2.2 25-1.1.2.2.1.1 29-1.1.2.3.1.1.1 (o / observe-01~e.4 :ARG1 (a / and~e.20 :op1 (a2 / affect-01~e.1 :ARG0~e.5 (a3 / and~e.7 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.6)) :op2 (s2 / small-molecule :name (n2 / name :op1 "docetaxel"~e.8))) :ARG1~e.9 (m4 / medical-condition~e.10 :name (n5 / name :op1 "melanoma"~e.11) :ARG2-of~e.10 (m2 / malignant-02~e.10)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 64~e.15))) :ARG1-of (r / resemble-01~e.0)) :op2 (a4 / affect-01~e.1 :ARG0 (a5 / and :op1 s~e.19 :op2 (s3 / small-molecule :name (n3 / name :op1 "cytarabine"~e.21))) :ARG1~e.22 (d3 / disease :name (n4 / name :op1 "leukaemia"~e.25) :mod (m3 / myelogenous~e.24) :mod (a6 / acute~e.23)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 65~e.29))) :mod r))) # ::id pmid_2352_4590.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The mechanism by which these agents cooperate is not entirely clear , but the available evidence suggests that many of these drugs can activate the Ras @/@ MAPK pathway through diverse processes , thereby increasing the effectiveness of MEK inhibitors . @^{66 @} # ::alignments 1-1.1.2 4-1.1.2.1.1.1 5-1.1.2.1.1 6-1.1.2.1 8-1.1.1 8-1.1.1.r 9-1.1.3 10-1.1 12-1 14-1.2.1.1 15-1.2.1 16-1.2 17-1.2.2.r 18-1.2.2.1.1.2 19-1.2.2.1.1.2.r 20-1.2.2.1.1.1 21-1.2.2.1.1 22-1.2.2 23-1.2.2.1 25-1.2.2.1.2.1.1 27-1.2.2.1.2.1.1 28-1.2.2.1.2 30-1.2.2.1.3.1 31-1.2.2.1.3 34-1.2.2.1.4.1 36-1.2.2.1.4.1.1 37-1.2.2.1.4.1.1.1.r 38-1.2.2.1.4.1.1.1.1.1.1.1 39-1.2.2.1.4.1.1.1 39-1.2.2.1.4.1.1.1.1 39-1.2.2.1.4.1.1.1.1.r 43-1.3.1.1.1 (h / have-concession-91~e.12 :ARG1 (c / clear-06~e.10 :polarity~e.8 -~e.8 :ARG1 (m / mechanism~e.1 :instrument-of (c2 / cooperate-01~e.6 :ARG0 (a / agent~e.5 :mod (t / this~e.4)))) :mod (e / entire~e.9)) :ARG2 (s / suggest-01~e.16 :ARG0 (e2 / evidence~e.15 :ARG2-of (a2 / available-02~e.14)) :ARG1~e.17 (p / possible-01~e.22 :ARG1 (a4 / activate-01~e.23 :ARG0 (d / drug~e.21 :mod t~e.20 :quant~e.19 (m2 / many~e.18)) :ARG1 (p2 / pathway~e.28 :name (n / name :op1 "Ras/MAPK"~e.25,27)) :instrument (p3 / process-02~e.31 :mod (d2 / diverse~e.30)) :ARG0-of (c3 / cause-01 :ARG1 (i / increase-01~e.34 :ARG1 (e3 / effective-04~e.36 :ARG0~e.37 (m3 / molecular-physical-entity~e.39 :ARG0-of~e.39 (i2 / inhibit-01~e.39 :ARG1 (p5 / protein-family :name (n2 / name :op1 "MEK"~e.38)))))))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 66~e.43)))) # ::id pmid_2352_4590.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the inhibitory effects of MEK on cell cycle progression may potentially reduce the effectiveness of many standard chemotherapeutic agents in combination therapy , due to the reliance of these agents on killing malignant cells that are rapidly dividing . # ::alignments 0-1 3-1.1.1.1.3 4-1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1 7-1.1.1.1.2.r 8-1.1.1.1.2.1.1 9-1.1.1.1.2.1 10-1.1.1.1.2 11-1.1 12-1.1.1.3 12-1.1.1.3.r 13-1.1.1 15-1.1.1.2 16-1.1.1.2.1.r 17-1.1.1.2.1.3 18-1.1.1.2.1.2 19-1.1.1.2.1.1 20-1.1.1.2.1 21-1.1.1.2.2.r 22-1.1.1.2.2.1 23-1.1.1.2.2 25-1.1.1.4 26-1.1.1.4 28-1.1.1.4.1 31-1.1.1.4.1.1 32-1.1.1.4.1.2.r 33-1.1.1.4.1.2 34-1.1.1.4.1.2.1.1 35-1.1.1.4.1.2.1 38-1.1.1.4.1.2.1.2.1 38-1.1.1.4.1.2.1.2.1.r 39-1.1.1.4.1.2.1.2 (h / have-concession-91~e.0 :ARG2 (p / possible-01~e.11 :ARG1 (r / reduce-01~e.13 :ARG0 (a / affect-01~e.4 :ARG0~e.5 (e / enzyme :name (n / name :op1 "MEK"~e.6)) :ARG1~e.7 (p2 / progress-01~e.10 :ARG1 (c / cycle-02~e.9 :ARG1 (c2 / cell~e.8))) :ARG2 (i / inhibit-01~e.3)) :ARG1 (e2 / effective-04~e.15 :ARG0~e.16 (a2 / agent~e.20 :mod (c3 / chemotherapy~e.19) :ARG1-of (s / standard-02~e.18) :quant (m / many~e.17)) :ARG1~e.21 (t / therapy~e.23 :ARG1-of (c4 / combine-01~e.22))) :manner~e.12 (p3 / potential~e.12) :ARG1-of (c5 / cause-01~e.25,26 :ARG0 (r2 / rely-01~e.28 :ARG0 a2~e.31 :ARG1~e.32 (k / kill-01~e.33 :ARG1 (c6 / cell~e.35 :ARG1-of (m2 / malignant-02~e.34) :ARG1-of (d / divide-02~e.39 :manner~e.38 (r3 / rapid~e.38))))))))) # ::id pmid_2352_4590.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , drug scheduling may have a critical role in the optimal utilisation of MEK inhibitors when combined with traditional chemotherapeutic drugs . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1.1 4-1.1 5-1.1.1 7-1.1.1.2.1 8-1.1.1.2 11-1.1.1.2.1.1.2 14-1.1.1.2.1.1.1.1.1.1.1 15-1.1.1.2.1.1.1 15-1.1.1.2.1.1.1.1 15-1.1.1.2.1.1.1.1.r 17-1.1.1.2.1.2 18-1.1.1.2.1.2.2.r 19-1.1.1.2.1.2.2.1 20-1.1.1.2.1.2.2.2 21-1.1.1.2.1.2.2 (c / cause-01~e.0 :ARG1 (p / possible-01~e.4 :ARG1 (h / have-03~e.5 :ARG0 (s / schedule-01~e.3 :ARG1 (d / drug~e.2)) :ARG1 (r / role~e.8 :ARG1-of (c2 / critical-02~e.7 :ARG2 (u / utilize-01 :ARG1 (m / molecular-physical-entity~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.14)))) :mod (o / optimal~e.11)) :condition (c3 / combine-01~e.17 :ARG1 m :ARG2~e.18 (d2 / drug~e.21 :mod (t2 / traditional~e.19) :mod (c4 / chemotherapy~e.20)))))))) # ::id pmid_2352_4590.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this regard , Yu et al. @ ^{67 @} have demonstrated that incubating leukaemic cells with paclitaxel before PD98059 exposure significantly increased cell death . # ::alignments 1-1.3 4-1.1.1.1.1 6-1.1 7-1.1.2.1 11-1.4.1.1.1 15-1 16-1.2.r 17-1.2.1 18-1.2.1.1.1 19-1.2.1.1 20-1.2.1.2.r 21-1.2.1.2.1.1 22-1.2.1.3 23-1.2.1.3.1.2.1.1 24-1.2.1.3.1 25-1.2.3 26-1.2 27-1.2.2.1 28-1.2.2 (d / demonstrate-01~e.15 :ARG0 (a / and~e.6 :op1 (p / person :name (n / name :op1 "Yu"~e.4)) :op2 (p2 / person :mod (o / other~e.7))) :ARG1~e.16 (i / increase-01~e.26 :ARG0 (i2 / incubate-01~e.17 :ARG1 (c2 / cell~e.19 :mod (l / leukaemic~e.18)) :ARG2~e.20 (s2 / small-molecule :name (n2 / name :op1 "paclitaxel"~e.21)) :time (b / before~e.22 :op1 (e / expose-01~e.24 :ARG1 c2 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PD98059"~e.23))))) :ARG1 (d2 / die-01~e.28 :ARG1 (c3 / cell~e.27)) :ARG2 (s / significant-02~e.25)) :purpose (t / this~e.1) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 67~e.11)))) # ::id pmid_2352_4590.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , pretreatment with the MEK inhibitor reduced the susceptibility of cells to paclitaxel @-@ induced apoptosis . # ::alignments 1-1 3-1.1.1 4-1.1.1.1.r 6-1.1.1.1.1.1.1.1 7-1.1.1.1 7-1.1.1.1.1 7-1.1.1.1.1.r 8-1.1 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1 13-1.1.2.2.r 14-1.1.2.2.1.1.1.1 16-1.1.2.2.1 17-1.1.2.2 (c / contrast-01~e.1 :ARG2 (r / reduce-01~e.8 :ARG0 (p / pretreat-01~e.3 :ARG3~e.4 (m / molecular-physical-entity~e.7 :ARG0-of~e.7 (i / inhibit-01~e.7 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.6))))) :ARG1 (s / susceptibility~e.10 :poss~e.11 (c2 / cell~e.12) :prep-to~e.13 (a / apoptosis~e.17 :ARG2-of (i2 / induce-01~e.16 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "paclitaxel"~e.14))))))) # ::id pmid_2352_4590.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activating mutations within the Ras @/@ MAPK network also contribute to the mechanisms of resistance to MEK inhibitors . # ::alignments 0-1.1.1 1-1.1 4-1.1.1.1.1.1 6-1.1.1.1.1.1 8-1.3 9-1 10-1.2.r 12-1.2 13-1.2.1.r 14-1.2.1 15-1.2.1.1.r 16-1.2.1.1.1.1.1.1 17-1.2.1.1 17-1.2.1.1.1 17-1.2.1.1.1.r (c / contribute-01~e.9 :ARG0 (m / mutate-01~e.1 :ARG0-of (a / activate-01~e.0 :location (p / pathway :name (n2 / name :op1 "Ras/MAPK"~e.4,6)))) :ARG1~e.10 (m2 / mechanism~e.12 :mod~e.13 (r / resist-01~e.14 :ARG1~e.15 (m3 / molecular-physical-entity~e.17 :ARG0-of~e.17 (i / inhibit-01~e.17 :ARG1 (p2 / protein-family :name (n3 / name :op1 "MEK"~e.16)))))) :mod (a2 / also~e.8)) # ::id pmid_2352_4590.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A number of studies have demonstrated that oncogenic amplification of K @-@ Ras and B @-@ Raf confers decreased susceptibility to AZD6244 . @^{68 , 69 @} # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 3-1.1.1.1 3-1.1.1.1.r 5-1 6-1.2.r 7-1.2.1.2 7-1.2.1.2.1.2.1 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.1.1.1 12-1.2.1.1.1.1.1 13-1.2.1.1 14-1.2.1.1.2.1.1 16-1.2.1.1.2.1.1 17-1.2 18-1.2.2.1 19-1.2.2 20-1.2.2.2.r 21-1.2.2.2.1.1 25-1.3.1.1.1.1 29-1.3.1.1.1.2 (d / demonstrate-01~e.5 :ARG0 (n / number~e.1 :quant-of~e.2 (t / thing~e.3 :ARG1-of~e.3 (s / study-01~e.3))) :ARG1~e.6 (c / confer-01~e.17 :ARG0 (a / amplify-01~e.8 :ARG1~e.9 (a2 / and~e.13 :op1 (e / enzyme :name (n2 / name :op1 "K-Ras"~e.10,12)) :op2 (e2 / enzyme :name (n3 / name :op1 "B-Raf"~e.14,16))) :ARG0-of (c3 / cause-01~e.7 :ARG1 (d4 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.7)))) :ARG1 (s2 / susceptibility~e.19 :ARG1-of (d2 / decrease-01~e.18) :prep-to~e.20 (s3 / small-molecule :name (n4 / name :op1 "AZD6244"~e.21)))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG0 (a3 / and :op1 68~e.25 :op2 69~e.29))))) # ::id pmid_2352_4590.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Point mutations within MEK1 may also significantly attenuate the ability of MEK inhibitors to block ERK signalling in B @-@ Raf V600E mutated tumours . @^{70 @} # ::alignments 0-1.1.1.2 1-1.1.1 3-1.1.1.1.1.1 4-1 5-1.3 6-1.1.3 7-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1.1 12-1.1.2.1 12-1.1.2.1.1 12-1.1.2.1.1.r 14-1.1.2.2 15-1.1.2.2.2.1.1.1 16-1.1.2.2.2 17-1.1.2.2.3.r 18-1.1.2.2.3.1.1.1 20-1.1.2.2.3.1.1.1 21-1.1.2.2.3.1.2.1 22-1.1.2.2.3.1.2 23-1.1.2.2.3 27-1.2.1.1.1 (p2 / possible-01~e.4 :ARG1 (a / attenuate-01~e.7 :ARG0 (m / mutate-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "MEK1"~e.3)) :mod (p / point~e.0)) :ARG1 (c / capable-01~e.9 :ARG1~e.10 (m3 / molecular-physical-entity~e.12 :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"~e.11)))) :ARG2 (b / block-01~e.14 :ARG0 m3 :ARG1 (s2 / signal-07~e.16 :ARG0 (e3 / enzyme :name (n3 / name :op1 "ERK"~e.15))) :ARG2~e.17 (t / tumor~e.23 :mod (e4 / enzyme :name (n4 / name :op1 "B-Raf"~e.18,20) :ARG2-of (m2 / mutate-01~e.22 :value "V600E"~e.21))))) :ARG1-of (s / significant-02~e.6)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 70~e.27))) :mod (a2 / also~e.5)) # ::id pmid_2352_4590.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These oncogenic events result in constitutive ERK pathway activation . # ::alignments 0-1.1.2 1-1.1.1 1-1.1.1.1.2.1 2-1.1 3-1 4-1.2.r 5-1.2.2 6-1.2.1.1.1 7-1.2.1 8-1.2 (r / result-01~e.3 :ARG1 (e / event~e.2 :ARG0-of (c / cause-01~e.1 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.1))) :mod (t / this~e.0)) :ARG2~e.4 (a / activate-01~e.8 :ARG1 (p / pathway~e.7 :name (n / name :op1 "ERK"~e.6)) :mod (c3 / constitutive~e.5))) # ::id pmid_2352_4590.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the absence of oncogenic Ras and Raf mutations , other oncogenic events that engage the Ras @/@ MAPK pathway are also likely to stimulate normal feedback mechanisms that may increase the activity of various intermediaries in the Ras @/@ MAPK signalling module , thereby promoting the ongoing activation of ERK kinase signalling . @^{71 @} # ::alignments 2-1.2 3-1.2.1.r 4-1.2.1.3 5-1.2.1.1.1.1.1 6-1.2.1 7-1.2.1.2.1.1.1 8-1.2.1.1 8-1.2.1.2 10-1.1.1.2 11-1.1.1.1 11-1.1.1.1.1.2.1 12-1.1.1 14-1.1.1.3 16-1.1.1.3.1.1.1 18-1.1.1.3.1.1.1 19-1.1.1.3.1 21-1.5 22-1 23-1.1.1.1 24-1.1 25-1.1.2.2 26-1.1.2.1 27-1.1.2 29-1.1.2.3.2 30-1.1.2.3 32-1.1.2.3.1 33-1.1.2.3.1.1.r 34-1.1.2.3.1.1.1 35-1.1.2.3.1.1 36-1.1.2.3.1.2.r 38-1.1.2.3.1.2.1.1 39-1.1.2.3.1.2.1.1 40-1.1.2.3.1.2.1.1 41-1.1.2.3.1.2.1 42-1.1.2.3.1.2 45-1.3 47-1.3.1.2 48-1.3.1 49-1.3.1.1.r 50-1.3.1.1.1.1.1 52-1.3.1.1 56-1.4.1.1.1 (l / likely-01~e.22 :ARG1 (s / stimulate-01~e.24 :ARG0 (e / event~e.12 :ARG0-of (c / cause-01~e.11,23 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.11))) :mod (o / other~e.10) :ARG0-of (e2 / engage-01~e.14 :ARG1 (p / pathway~e.19 :name (n2 / name :op1 "Ras/MAPK"~e.16,18)))) :ARG1 (m / mechanism~e.27 :mod (f / feedback~e.26) :ARG1-of (n / normal-02~e.25) :ARG0-of (i / increase-01~e.30 :ARG1 (a / activity-06~e.32 :ARG0~e.33 (i2 / intermediary~e.35 :mod (v / various~e.34)) :ARG1~e.36 (m2 / module~e.42 :ARG0-of (s2 / signal-07~e.41 :ARG1 p~e.38,39,40))) :ARG1-of (p2 / possible-01~e.29)))) :condition (a2 / absent-01~e.2 :ARG1~e.3 (a3 / and~e.6 :op1 (m3 / mutate-01~e.8 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Ras"~e.5))) :op2 (m4 / mutate-01~e.8 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Raf"~e.7))) :ARG0-of c~e.4)) :ARG0-of (p3 / promote-01~e.45 :ARG1 (a4 / activate-01~e.48 :ARG1~e.49 (s3 / signal-07~e.52 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK"~e.50))) :ARG1-of (g / go-on-15~e.47))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 71~e.56))) :mod (a5 / also~e.21)) # ::id pmid_2352_4590.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For either scenario , the activity of ERK and its target substrates may be maintained at levels that are sufficient to drive key cellular functions even in the presence of a MEK inhibitor . # ::alignments 1-1.2.1 2-1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2.2 9-1.1.1.1.2.2.r 10-1.1.1.1.2.1 11-1.1.1.1.2 12-1 14-1.1 15-1.1.2.r 16-1.1.2 19-1.1.2.1 21-1.1.2.1.1 22-1.1.2.1.1.2.2 23-1.1.2.1.1.2.1 24-1.1.2.1.1.2 26-1.1.2.1.1.3.r 28-1.1.2.1.1.3 29-1.1.2.1.1.3.1.r 31-1.1.2.1.1.3.1.1.1.1.1 32-1.1.2.1.1.3.1 32-1.1.2.1.1.3.1.1 32-1.1.2.1.1.3.1.1.r (p / possible-01~e.12 :ARG1 (m / maintain-01~e.14 :ARG1 (a / activity-06~e.5 :ARG0~e.6 (a2 / and~e.8 :op1 (e3 / enzyme :name (n3 / name :op1 "ERK"~e.7)) :op2 (s / substrate~e.11 :ARG1-of (t2 / target-01~e.10) :poss~e.9 e3~e.9))) :ARG2~e.15 (l / level~e.16 :ARG0-of (s2 / suffice-01~e.19 :ARG1 (d2 / drive-02~e.21 :ARG0 l :ARG1 (f / function-01~e.24 :ARG0 (c / cell~e.23) :ARG1-of (k / key-02~e.22)) :concession~e.26 (p2 / present-02~e.28 :ARG1~e.29 (s4 / small-molecule~e.32 :ARG0-of~e.32 (i2 / inhibit-01~e.32 :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK"~e.31))))))))) :topic (s3 / scenario~e.2 :mod (e / either~e.1))) # ::id pmid_2352_4590.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These observations suggest that targeting multiple nodes within the Ras @/@ MAPK network may be a more efficacious clinical strategy than single target therapy . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.4 5-1.2.1.4.1.1 6-1.2.1.4.1 7-1.2.1.4.1.1.r 9-1.2.1.4.2.1.1 11-1.2.1.4.2.1.1 13-1.2 14-1.2.1.4.r 16-1.2.1.2.1 17-1.2.1.2 18-1.2.1.1 19-1.2.1 20-1.2.1.3.r 21-1.2.1.3.1.1 22-1.2.1.3.1 23-1.2.1.3 (s / suggest-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1~e.3 (p / possible-01~e.13 :ARG1 (s2 / strategy~e.19 :mod (c / clinic~e.18) :mod (e / efficacious~e.17 :degree (m2 / more~e.16)) :compared-to~e.20 (t3 / therapy~e.23 :mod (t4 / target~e.22 :ARG1-of (s3 / single-02~e.21))) :domain~e.14 (t2 / target-01~e.4 :ARG1 (n / node~e.6 :quant~e.7 (m / multiple~e.5)) :location (p2 / pathway :name (n2 / name :op1 "Ras/MAPK"~e.9,11)))))) # ::id pmid_2352_4590.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The contribution of multiple signalling networks to tumorigenesis also accounts for the limited responses seen with MEK inhibitors alone . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 4-1.1.1.1 5-1.1.1 6-1.1.2.r 7-1.1.2 7-1.1.2.1 7-1.1.2.1.r 8-1.3 9-1 10-1.2.r 12-1.2.1 13-1.2 14-1.2.2 15-1.2.2.1.r 16-1.2.2.1.1.1.1.1 17-1.2.2.1 17-1.2.2.1.1 17-1.2.2.1.1.r 18-1.2.2.1.2 (a / account-01~e.9 :ARG0 (c / contribute-01~e.1 :ARG0~e.2 (n2 / network~e.5 :ARG0-of (s / signal-07~e.4) :quant (m / multiple~e.3)) :ARG2~e.6 (c2 / create-01~e.7 :ARG1~e.7 (t2 / tumor~e.7))) :ARG1~e.10 (r / respond-01~e.13 :ARG1-of (l / limit-01~e.12) :ARG1-of (s2 / see-01~e.14 :condition~e.15 (s3 / small-molecule~e.17 :ARG0-of~e.17 (i2 / inhibit-01~e.17 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"~e.16))) :mod (a3 / alone~e.18)))) :mod (a2 / also~e.8)) # ::id pmid_2352_4590.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , the phosphatidylinositol 3 @-@ kinase ( PI3K/Akt/mTOR ) and MAPK pathways share Ras as a common upstream effector . @^{72 @} # ::alignments 0-1.4 1-1.4 4-1.1.1.1.1 5-1.1.1.1.2 7-1.1.1.1.2 9-1.1.1.2.1.1.1 11-1.1 12-1.1.2.1.1 13-1.1.1.2.1 13-1.1.2 14-1 15-1.2.1.1 18-1 19-1.2.2.1.1 20-1.2.2.1 24-1.3.1.1.1 (s / share-01~e.14,18 :ARG0 (a / and~e.11 :op1 (e3 / enzyme :name (n3 / name :op1 "phosphatidylinositol"~e.4 :op2 "3-kinase"~e.5,7) :ARG1-of (m / mean-01 :ARG2 (p2 / pathway~e.13 :name (n4 / name :op1 "PI3K/Akt/mTOR"~e.9)))) :op2 (p3 / pathway~e.13 :name (n5 / name :op1 "MAPK"~e.12))) :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras"~e.15) :ARG1-of (m2 / mean-01 :ARG2 (e5 / effector~e.20 :direction (u / upstream~e.19)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 72~e.24))) :ARG0-of (e / exemplify-01~e.0,1)) # ::id pmid_2352_4590.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consequently , activation of Ras , despite the downregulation of ERK activity by MKPs and SPRYs , could lead to compensatory signalling through this parallel network . # ::alignments 0-1 2-1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1.1.2.r 8-1.1.1.1.2 9-1.1.1.1.2.1.r 10-1.1.1.1.2.1.1.1.1 11-1.1.1.1.2.1 14-1.1.1.1.2.2 17-1.1 18-1.1.1 21-1.1.1.2 23-1.1.1.2.2.2 24-1.1.1.2.2.1 25-1.1.1.2.2 (c2 / cause-01~e.0 :ARG1 (p2 / possible-01~e.17 :ARG1 (l / lead-03~e.18 :ARG0 (a / activate-01~e.2 :ARG1~e.3 (e3 / enzyme :name (n3 / name :op1 "Ras"~e.4)) :concession~e.6 (d / downregulate-01~e.8 :ARG1~e.9 (a2 / activity-06~e.11 :ARG0 (e4 / enzyme :name (n5 / name :op1 "ERK"~e.10))) :ARG2 (a3 / and~e.14 :op1 (e5 / enzyme :name (n6 / name :op1 "MKP")) :op2 (p4 / protein :name (n7 / name :op1 "SPRY"))))) :ARG2 (s / signal-07~e.21 :ARG0-of (c / compensate-01) :instrument (n4 / network~e.25 :mod (p3 / parallel~e.24) :mod (t / this~e.23)))))) # ::id pmid_2352_4590.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Alternatively , oncogenic mutations within the PI3K @/@ Akt axis may enhance MEK @/@ ERK signal transduction . # ::alignments 0-1.2 0-1.2.r 2-1.1.1.1 2-1.1.1.1.1.2.1 3-1.1.1 6-1.1.1.2.1.1.1 8-1.1.1.2.1.1.1 9-1.1.1.2 10-1 11-1.1 12-1.1.2.1.1.1.1 14-1.1.2.1.1.1.1 15-1.1.2.1 16-1.1.2 (p2 / possible-01~e.10 :ARG1 (e / enhance-01~e.11 :ARG0 (m / mutate-01~e.3 :ARG0-of (c / cause-01~e.2 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.2))) :location (a2 / axis~e.9 :mod (p / pathway :name (n / name :op1 "PI3K/Akt"~e.6,8)))) :ARG1 (t / transduce-01~e.16 :ARG1 (s / signal-07~e.15 :ARG0 (p3 / pathway :name (n2 / name :op1 "MEK/ERK"~e.12,14))))) :manner~e.0 (a / alternative~e.0)) # ::id pmid_2352_4590.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , dysregulation of the PI3K @/@ Akt pathway has been shown to correlate with the decreased sensitivity to MEK inhibition . @^{73 @} # ::alignments 0-1.2 2-1.1.1 3-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1.1 11-1 13-1.1 14-1.1.2.r 16-1.1.2.2 17-1.1.2 18-1.1.2.1.r 19-1.1.2.1.1.1.1 20-1.1.2.1 24-1.3.1.1.1 (s / show-01~e.11 :ARG1 (c / correlate-01~e.13 :ARG1 (d / dysregulate-01~e.2 :ARG1~e.3 (p2 / pathway~e.8 :name (n3 / name :op1 "PI3K/Akt"~e.5,7))) :ARG2~e.14 (s2 / sensitive-03~e.17 :ARG1~e.18 (i / inhibit-01~e.20 :ARG1 (e2 / enzyme :name (n4 / name :op1 "MEK"~e.19))) :ARG1-of (d2 / decrease-01~e.16))) :mod (i2 / indeed~e.0) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 73~e.24)))) # ::id pmid_2352_4590.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Predictably targeting both pathways simultaneously has proven effective in several studies . # ::alignments 1-1.1.1 2-1.1.1.1.1 3-1.1.1.1 4-1.1.1.2 4-1.1.1.2.r 6-1 7-1.1 8-1.2.r 9-1.2.2 10-1.2 10-1.2.1 10-1.2.1.r (p / prove-01~e.6 :ARG1 (e / effective-04~e.7 :ARG0 (t / target-01~e.1 :ARG1 (p2 / pathway~e.3 :mod (b / both~e.2)) :manner~e.4 (s / simultaneous~e.4))) :medium~e.8 (t2 / thing~e.10 :ARG1-of~e.10 (s2 / study-01~e.10) :quant (s3 / several~e.9)) :ARG1-of (p3 / predict-01 :ARG1-of (p4 / possible-01))) # ::id pmid_2352_4590.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In AZD6244 @-@ resistant gastric cancer cell lines , activation of Akt through the EGFR/PI3K/Akt pathway was still observed following MEK inhibition . # ::alignments 1-1.4.1.1.1.1 3-1.4.1 4-1.4.2.2.1 5-1.4.2.2.2 6-1.4 7-1.4 9-1.1 10-1.1.1.r 11-1.1.1.1.1 14-1.1.2.1.1 15-1.1.2 17-1.2 18-1 19-1.3 20-1.3.1.1.1.1 21-1.3.1 (o / observe-01~e.18 :ARG1 (a / activate-01~e.9 :ARG1~e.10 (e2 / enzyme :name (n3 / name :op1 "Akt"~e.11)) :instrument (p / pathway~e.15 :name (n4 / name :op1 "EGFR/PI3K/Akt"~e.14))) :mod (s / still~e.17) :ARG1-of (f / follow-01~e.19 :ARG2 (i / inhibit-01~e.21 :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEK"~e.20)))) :location (c / cell-line~e.6,7 :ARG0-of (r / resist-01~e.3 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "AZD6244"~e.1))) :source (d / disease :wiki "Stomach_cancer" :name (n / name :op1 "stomach"~e.4 :op2 "cancer"~e.5)))) # ::id pmid_2352_4590.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Blockade of this pathway using the EGFR inhibitor , gefitinib , synergistically enhanced tumour apoptosis in vitro and in vivo @ . @^{74 @} # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1 6-1.1.2.1.1.1.1 7-1.1.2 7-1.1.2.1 7-1.1.2.1.r 9-1.1.2.2.1.1.1 11-1.3 12-1 13-1.2.1 14-1.2 16-1.4.1 17-1.4.1 19-1.4 21-1.4.1 21-1.4.2 22-1.4.2 27-1.5.1.1.1 (e2 / enhance-01~e.12 :ARG0 (b / blockade-01~e.0 :ARG1~e.1 (p / pathway~e.3 :mod (t2 / this~e.2)) :ARG2 (s3 / small-molecule~e.7 :ARG0-of~e.7 (i2 / inhibit-01~e.7 :ARG1 (e3 / enzyme :name (n2 / name :op1 "EGFR"~e.6))) :ARG1-of (m2 / mean-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "gefitinib"~e.9))))) :ARG1 (a / apoptosis~e.14 :poss (t / tumor~e.13)) :manner (s2 / synergize-01~e.11) :manner (a2 / and~e.19 :op1 (i3 / in-vitro~e.16,17,21) :op2 (i4 / in-vivo~e.21,22)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 74~e.27)))) # ::id pmid_2352_4590.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment of mutant murine lung cancers with the dual PI3K @/@ mTOR inhibitor , NVP @-@ BEZ235 and AZD6244 produced similar results . @^{75 @} # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1 2-1.1.1.4 2-1.1.1.4.r 3-1.1.1.3.1.1 4-1.1.1.2.1 5-1.1.1.2.2 6-1.1.2.r 8-1.1.2.3 9-1.1.2.1.1.1.1 11-1.1.2.1.1.1.1 12-1.1.2 12-1.1.2.1 12-1.1.2.1.r 14-1.1.2.2.1.1.1.1 16-1.1.2.2.1.1.1.1 17-1.1.2.2.1 18-1.1.2.2.1.2.1.1 19-1 20-1.2.2 21-1.2 21-1.2.1 21-1.2.1.r 25-1.3.1.1.1 (p / produce-01~e.19 :ARG0 (t3 / treat-04~e.0 :ARG1~e.1 (d3 / disease~e.2 :wiki "Lung_cancer" :name (n / name :op1 "lung"~e.4 :op2 "cancer"~e.5) :mod (o / organism :name (n5 / name :op1 "Muridae"~e.3)) :ARG2-of~e.2 (m2 / mutate-01~e.2)) :ARG2~e.6 (s2 / small-molecule~e.12 :ARG0-of~e.12 (i2 / inhibit-01~e.12 :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3K/mTOR"~e.9,11))) :ARG1-of (m / mean-01 :ARG2 (a / and~e.17 :op1 (s3 / small-molecule :name (n3 / name :op1 "NVP-BEZ235"~e.14,16)) :op2 (s4 / small-molecule :name (n4 / name :op1 "AZD6244"~e.18)))) :mod (d2 / dual~e.8))) :ARG1 (t2 / thing~e.21 :ARG2-of~e.21 (r2 / result-01~e.21) :ARG1-of (r3 / resemble-01~e.20)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 75~e.25)))) # ::id pmid_2352_4590.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recently , preliminary results from a phase I trial evaluating the combined activity of GDC @-@ 0973 @/@ XL @-@ 518 and the Akt inhibitor , GDC @-@ 0941 , found that in a cohort of 27 advanced solid tumour patients , three patients achieved prolonged s.d . ≥ 6 months when treated with both agents . @^{76 @} # ::alignments 0-1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1.1.1.1.r 6-1.1.1.1.1 7-1.1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.2 11-1.1.1.1.2.1.2 12-1.1.1.1.2.1 13-1.1.1.1.2.1.1.r 14-1.1.1.1.2.1.1.1.1.1 16-1.1.1.1.2.1.1.1.1.1 18-1.1.1.1.2.1.1.1.1.1 20-1.1.1.1.2.1.1.1.1.1 21-1.1.1.1.2.1.1 23-1.1.1.1.2.1.1.2.1.1.1.1 24-1.1.1.1.2.1.1.2 24-1.1.1.1.2.1.1.2.1 24-1.1.1.1.2.1.1.2.1.r 26-1.1.1.1.2.1.1.2.2.1.1.1 28-1.1.1.1.2.1.1.2.2.1.1.1 30-1 32-1.2.r 34-1.2.1.2 35-1.2.1.2.1.r 36-1.2.1.2.1.1 37-1.2.1.2.1.2.2 38-1.2.1.2.1.2.1 39-1.2.1.2.1.2 40-1.2.1.2.1.3 42-1.2.1.1 43-1.2.1.3.1 44-1.2 45-1.2.2.1 49-1.2.2.3.1.1 50-1.2.2.3.1.2 51-1.3.r 52-1.2.3 53-1.2.3.2.r 54-1.2.3.2.1 55-1.2.3.2 59-1.4.1.1.1 (f / find-01~e.30 :ARG0 (t3 / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3 :ARG1~e.4 (t4 / trial-06~e.8 :mod (p2 / phase~e.6 :ord (o / ordinal-entity :value 1~e.7)) :ARG0-of (e / evaluate-01~e.9 :ARG1 (a / activity-06~e.12 :ARG0~e.13 (a2 / and~e.21 :op1 (s / small-molecule :name (n / name :op1 "GDC-0973/XL-518"~e.14,16,18,20)) :op2 (s2 / small-molecule~e.24 :ARG0-of~e.24 (i2 / inhibit-01~e.24 :ARG1 (p6 / protein-family :name (n3 / name :op1 "Akt"~e.23))) :ARG1-of (m2 / mean-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "GDC-0941"~e.26,28))))) :ARG3-of (c3 / combine-01~e.11))))) :mod (p / preliminary~e.2)) :ARG1~e.32 (a3 / achieve-01~e.44 :ARG0 (p3 / person :quant 3~e.42 :part-of (c / cohort~e.34 :consist-of~e.35 (p7 / person :quant 27~e.36 :mod (t / tumor~e.39 :ARG1-of (s5 / solid-02~e.38) :ARG1-of (a5 / advance-01~e.37)) :ARG0-of h~e.40)) :ARG0-of (h / have-rel-role-91 :ARG2 (p5 / patient~e.43))) :ARG1 (d2 / disease :ARG1-of (p4 / prolong-01~e.45) :ARG1-of (s4 / stable-03) :duration (o2 / or :op1 (t2 / temporal-quantity :quant 6~e.49 :unit (m / month~e.50)) :op2 (m3 / more-than :op1 t2))) :condition (t6 / treat-03~e.52 :ARG1 p3 :ARG3~e.53 (a4 / agent~e.55 :mod (b / both~e.54)))) :time~e.51 (r2 / recent~e.0) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 76~e.59)))) # ::id pmid_2352_4590.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Promising clinical activity has also been observed in the phase I trial of GSK1120212 in conjunction with the Akt inhibitor , GSK2141795 . @^{77 @} # ::alignments 0-1.1.2 1-1.1.1 2-1.1 4-1.3 6-1 7-1.2.r 9-1.2.2 10-1.2.2.1.1 11-1.2 12-1.2.1.r 13-1.2.1.1.1.1 14-1.2.3.r 15-1.2.3 18-1.2.1.2.1.1.1.1 19-1.2.1.2 19-1.2.1.2.1 19-1.2.1.2.1.r 21-1.2.1.2.2.1.1.1 25-1.4.1.1.1 (o / observe-01~e.6 :ARG1 (a / activity-06~e.2 :mod (c / clinic~e.1) :ARG2-of (p / promise-01~e.0)) :location~e.7 (t / trial-06~e.11 :ARG2~e.12 (a3 / and :op1 (s / small-molecule :name (n / name :op1 "GSK1120212"~e.13)) :op2 (s2 / small-molecule~e.19 :ARG0-of~e.19 (i / inhibit-01~e.19 :ARG1 (p4 / protein-family :name (n2 / name :op1 "Akt"~e.18))) :ARG1-of (m / mean-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GSK2141795"~e.21))))) :mod (p2 / phase~e.9 :ord (o2 / ordinal-entity :value 1~e.10)) :manner~e.14 (c2 / conjunction~e.15)) :mod (a2 / also~e.4) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 77~e.25)))) # ::id pmid_2352_4590.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The number of preclinical and clinical studies investigating dual Ras @/@ MAPK and PI3K @/@ Akt inhibition indicates a growing trend to using these combinations to maximise antitumour response . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.1 5-1.1.1.2.1 6-1.1.1.1 6-1.1.1.2 7-1.1.1.3 8-1.1.1.3.1.2 9-1.1.1.3.1.1.1.1.1 11-1.1.1.3.1.1.1.1.1 12-1.1.1.3.1.1 13-1.1.1.3.1.1.2.1.1 15-1.1.1.3.1.1.2.1.1 16-1.1.1.3.1 17-1 19-1.2.2 20-1.2 21-1.2.1.r 22-1.2.1 23-1.2.1.1.1 24-1.2.1.1 28-1.2.1.2.1 (i / indicate-01~e.17 :ARG0 (n2 / number~e.1 :quant-of~e.2 (a3 / and~e.4 :op1 (s / study-01~e.6 :mod (p2 / preclinical~e.3)) :op2 (s2 / study-01~e.6 :mod (c / clinical~e.5)) :ARG0-of (i2 / investigate-01~e.7 :ARG1 (i3 / inhibit-01~e.16 :ARG1 (a2 / and~e.12 :op1 (p3 / pathway :name (n3 / name :op1 "Ras/MAPK"~e.9,11)) :op2 (p4 / pathway :name (n4 / name :op1 "PI3K/Akt"~e.13,15))) :mod (d / dual~e.8))))) :ARG1 (t2 / trend-01~e.20 :ARG2~e.21 (u / use-01~e.22 :ARG1 (c2 / combine-01~e.24 :mod (t3 / this~e.23)) :ARG2 (m / maximize-01 :ARG1 (r / respond-01~e.28 :ARG2 (c3 / counter-01 :ARG1 (t4 / tumor))))) :ARG1-of (g / grow-01~e.19))) # ::id pmid_2352_4590.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Aberrant signalling through additional kinase pathways may also contribute to MEK inhibitor resistance . # ::alignments 0-1.1.1.2 1-1.1.1 3-1.1.1.1.2 4-1.1.1.1.1 5-1.1.1.1 6-1 7-1.1.3 8-1.1 9-1.1.2.r 10-1.1.2.1.1.1.1.1 11-1.1.2.1 11-1.1.2.1.1 11-1.1.2.1.1.r 12-1.1.2 (p / possible-01~e.6 :ARG1 (c / contribute-01~e.8 :ARG0 (s / signal-07~e.1 :manner (p2 / pathway~e.5 :mod (k / kinase~e.4) :mod (a2 / additional~e.3)) :manner (a / aberrant~e.0)) :ARG2~e.9 (r / resist-01~e.12 :ARG1 (s2 / small-molecule~e.11 :ARG0-of~e.11 (i2 / inhibit-01~e.11 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"~e.10))))) :mod (a3 / also~e.7))) # ::id pmid_2352_4590.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , although non @-@ small cell lung carcinomas carry both K @-@ Ras and PTEN mutations , resistance of these cell lines to AZD6244 coincides with activation of the Janus kinase @/@ signal transducer and activator of transcription pathway ( JAK/STAT ) following MEK inhibition . @^{78 @} # ::alignments 0-1.3 1-1.3 3-1.4.r 4-1.4.1.2.1 4-1.4.1.2.1.r 6-1.4.1.2.2 7-1.4.1.2 8-1.4.1.1 9-1.4.1 10-1.4 12-1.4.2.1.1.1.1 14-1.4.2.1.1.1.1 15-1.4.2 16-1.4.2.2.1.1.1 17-1.4.2.1 17-1.4.2.2 19-1.1 20-1.1.1.r 21-1.1.1.1 22-1.1.1 23-1.1.1 24-1.1.2.r 25-1.1.2.1.1 26-1 27-1.2.r 28-1.2 29-1.2.1.1.6 31-1.2.1.1.1 32-1.2.1.1.2 34-1.2.1.1.2 35-1.2.1.1.3 36-1.2.1.1.4 37-1.2.1.1.5 38-1.2.1.1.6 39-1.2.1.1.7 40-1.2.1 44-1.2.2 45-1.2.2.1.1.1.1 46-1.2.2.1 50-1.5.1.1.1 (c / coincide-01~e.26 :ARG1 (r / resist-01~e.19 :ARG0~e.20 (c2 / cell-line~e.22,23 :mod (t2 / this~e.21)) :ARG1~e.24 (s2 / small-molecule :name (n4 / name :op1 "AZD6244"~e.25))) :ARG2~e.27 (a2 / activate-01~e.28 :ARG1 (p / pathway~e.40 :name (n5 / name :op1 "Janus"~e.31 :op2 "kinase/signal"~e.32,34 :op3 "transducer"~e.35 :op4 "and"~e.36 :op5 "activator"~e.37 :op6 "of"~e.29,38 :op7 "transcription"~e.39)) :ARG1-of (f / follow-01~e.44 :ARG2 (i / inhibit-01~e.46 :ARG1 (e5 / enzyme :name (n6 / name :op1 "MEK"~e.45))))) :ARG0-of (e4 / exemplify-01~e.0,1) :concession~e.3 (c3 / carry-01~e.10 :ARG0 (c4 / carcinoma~e.9 :mod (l / lung~e.8) :mod (c6 / cell~e.7 :polarity~e.4 -~e.4 :mod (s / small~e.6))) :ARG1 (a3 / and~e.15 :op1 (m / mutate-01~e.17 :ARG1 (e6 / enzyme :name (n7 / name :op1 "K-Ras"~e.12,14))) :op2 (m2 / mutate-01~e.17 :ARG1 (p3 / protein :name (n8 / name :op1 "PTEN"~e.16))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 78~e.50)))) # ::id pmid_2352_4590.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD6244 combined with STAT3 inhibition synergistically induced apoptosis in these cells . # ::alignments 0-1.1.1.1 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1.1.1.1 4-1.1.2.1 5-1.3 6-1 7-1.2 8-1.2.1.r 9-1.2.1.1 10-1.2.1 (i / induce-01~e.6 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"~e.0) :ARG1-of (c / combine-01~e.1 :ARG2~e.2 (i2 / inhibit-01~e.4 :ARG1 (p / protein :name (n3 / name :op1 "STAT3"~e.3))))) :ARG2 (a2 / apoptosis~e.7 :location~e.8 (c2 / cell~e.10 :mod (t / this~e.9))) :manner (s / synergize-01~e.5)) # ::id pmid_2352_4590.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This effect can be explained by STAT3 suppressing the proapoptotic protein Bim through upregulation of miRNA @-@ 17 , which antagonises the Bim expression induced by AZD6244 . @^{79 @} # ::alignments 0-1.1.2.1 1-1.1.2 2-1 4-1.1 5-1.1.1.r 6-1.1.1.2.1 7-1.1.1.3 10-1.1.1 10-1.1.1.3.1 11-1.1.1.3.1.2.1 13-1.1.1.3.2 14-1.1.1.3.2.1.r 15-1.1.1.3.2.1.2.1 17-1.1.1.3.2.1.2.1 22-1.1.1.3.2.2.1.1 23-1.1.1.3.2.2.1 24-1.1.1.3.2.2.1.2 25-1.1.1.3.2.2.1.2.1.r 26-1.1.1.3.2.2.1.2.1.2.1 30-1.2.1.1.1 (p / possible-01~e.2 :ARG1 (e / explain-01~e.4 :ARG0~e.5 (p2 / protein~e.10 :wiki "STAT3" :name (n / name :op1 "STAT3"~e.6) :ARG0-of (s / suppress-01~e.7 :ARG1 (p3 / protein~e.10 :wiki "BCL2L11" :name (n2 / name :op1 "Bim"~e.11) :ARG0-of (f / favor-01 :ARG1 (a2 / apoptosis))) :instrument (u / upregulate-01~e.13 :ARG1~e.14 (n5 / nucleic-acid :wiki "Mir-17_microRNA_precursor_family" :name (n3 / name :op1 "miRNA-17"~e.15,17)) :ARG1-of (a3 / antagonize-02 :ARG2 (e2 / express-03~e.23 :ARG2 p3~e.22 :ARG2-of (i / induce-01~e.24 :ARG0~e.25 (s2 / small-molecule :wiki "Selumetinib" :name (n4 / name :op1 "AZD6244"~e.26)))))))) :ARG1 (a / affect-01~e.1 :mod (t / this~e.0))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 79~e.30)))) # ::id pmid_2352_4590.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Collectively , these results provide a rationale for combining inhibitors of the JAK @/@ STAT pathway and MEK inhibitors to reduce the potential impact of drug resistance . # ::alignments 0-1.4 0-1.4.r 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 6-1.2 7-1.3.r 8-1.3 9-1.3.1 9-1.3.1.1 9-1.3.1.1.r 9-1.3.2 9-1.3.2.1 9-1.3.2.1.r 12-1.3.1.1.1.1.1 14-1.3.1.1.1.1.1 15-1.3.1.1.1 17-1.3.2.1.1.1.1 18-1.3.1 18-1.3.1.1 18-1.3.1.1.r 18-1.3.2 18-1.3.2.1 18-1.3.2.1.r 20-1.3.3 22-1.3.3.1.2 23-1.3.3.1 24-1.3.3.1.1.r 25-1.3.3.1.1.1 26-1.3.3.1.1 (p / provide-01~e.4 :ARG0 (t2 / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :mod (t / this~e.2)) :ARG1 (r2 / rationale~e.6) :ARG2~e.7 (c2 / combine-01~e.8 :ARG1 (s / small-molecule~e.9,18 :ARG0-of~e.9,18 (i2 / inhibit-01~e.9,18 :ARG1 (p2 / pathway~e.15 :name (n2 / name :op1 "JAK/STAT"~e.12,14)))) :ARG2 (s2 / small-molecule~e.9,18 :ARG0-of~e.9,18 (i3 / inhibit-01~e.9,18 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK"~e.17)))) :purpose (r3 / reduce-01~e.20 :ARG1 (i4 / impact-01~e.23 :ARG0~e.24 (r4 / resist-01~e.26 :ARG1 (d / drug~e.25)) :mod (p3 / potential~e.22)))) :manner~e.0 (c / collective~e.0)) # ::id pmid_2352_4590.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Information about the use of MEK inhibitors and other kinase pathway inhibitors is unknown . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1 4-1.2.1.1.r 5-1.2.1.1.1.1.1.1.1 6-1.2.1.1.1 6-1.2.1.1.1.1 6-1.2.1.1.1.1.r 6-1.2.1.1.2 6-1.2.1.1.2.1 6-1.2.1.1.2.1.r 7-1.2.1.1 8-1.2.1.1.2.1.1.2 9-1.2.1.1.2.1.1.1 10-1.2.1.1.2.1.1 11-1.2.1.1.1 11-1.2.1.1.1.1 11-1.2.1.1.1.1.r 11-1.2.1.1.2 11-1.2.1.1.2.1 11-1.2.1.1.2.1.r 13-1 13-1.1 13-1.1.r (k / know-01~e.13 :polarity~e.13 -~e.13 :ARG1 (i2 / information~e.0 :topic~e.1 (u / use-01~e.3 :ARG1~e.4 (a / and~e.7 :op1 (s / small-molecule~e.6,11 :ARG0-of~e.6,11 (i3 / inhibit-01~e.6,11 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.5)))) :op2 (s2 / small-molecule~e.6,11 :ARG0-of~e.6,11 (i4 / inhibit-01~e.6,11 :ARG1 (p / pathway~e.10 :mod (k2 / kinase~e.9) :mod (o / other~e.8)))))))) # ::id pmid_2352_4590.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The role of MEK inhibitors in MM # ::alignments 2-1 3-1.1.r 4-1.1.1.1.1.1 5-1.1 5-1.1.1 5-1.1.1.r 6-1.2.r 7-1.2.1.1 7-1.2.1.2 (r / role~e.2 :poss~e.3 (s / small-molecule~e.5 :ARG0-of~e.5 (i2 / inhibit-01~e.5 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"~e.4)))) :topic~e.6 (d / disease :name (n / name :op1 "multiple"~e.7 :op2 "myeloma"~e.7))) # ::id pmid_2352_4590.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The advent of novel anti @-@ MM agents has improved the management and prognosis of MM . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 4-1.1.1.1 6-1.1.1.1.1.1.1 6-1.1.1.1.1.1.2 7-1.1.1 9-1 11-1.2.1 12-1.2 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1 (i / improve-01~e.9 :ARG0 (a / advent~e.1 :mod~e.2 (a2 / agent~e.7 :ARG0-of (c / counter-01~e.4 :ARG1 (d / disease :name (n2 / name :op1 "multiple"~e.6 :op2 "myeloma"~e.6))) :mod (n / novel~e.3))) :ARG1 (a3 / and~e.12 :op1 (m2 / manage-01~e.11 :ARG1 d) :op2 (p / prognosis~e.13 :topic~e.14 d~e.15))) # ::id pmid_2352_4590.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok With the immunomodulatory drugs , thalidomide and lenalidomide , and the proteasome inhibitor , bortezomib , able to abrogate the survival advantage created by the BMME , current research has focussed on combining these novel therapies to improve patient outcomes . @^{80 @} # ::alignments 3-1.4.1.1 5-1.4.1.1.1.1.1.1.1 6-1.4.1.1.1.1 7-1.4.1.1.1.1.2.1.1 9-1.4.1 9-1.4.1.1.1.1 11-1.4.1.2.1.1.1.1 12-1.4.1.2 12-1.4.1.2.1 12-1.4.1.2.1.r 14-1.4.1.2.2.1.1.1 16-1.4.1.3 18-1.4.1.3.1 20-1.4.1.3.1.1.1 21-1.4.1.3.1.1 22-1.4.1.3.1.1.2 27-1.1.1 28-1.1 30-1 31-1.2.r 32-1.2 33-1.2.1.2 34-1.2.1.1 35-1.2.1 36-1.4 37-1.5 38-1.5.2.1.1.1 39-1.5.2 43-1.3.1.1.1 (f / focus-01~e.30 :ARG0 (r / research-01~e.28 :mod (c / current~e.27)) :ARG2~e.31 (c2 / combine-01~e.32 :ARG1 (t2 / therapy~e.35 :mod (n / novel~e.34) :mod (t / this~e.33))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 80~e.43))) :ARG1-of (c6 / cause-01~e.36 :ARG0 (a / and~e.9 :op1 (d / drug~e.3 :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.6,9 :op1 (s3 / small-molecule :name (n3 / name :op1 "thalidomide"~e.5)) :op2 (s4 / small-molecule :name (n4 / name :op1 "lenalidomide"~e.7)))) :ARG0-of (i / immunomodulate-00)) :op2 (s / small-molecule~e.12 :ARG0-of~e.12 (i4 / inhibit-01~e.12 :ARG1 (m3 / macro-molecular-complex :name (n2 / name :op1 "proteasome"~e.11))) :ARG1-of (m4 / mean-01 :ARG2 (s5 / small-molecule :name (n5 / name :op1 "bortezomib"~e.14)))) :ARG1-of (c3 / capable-01~e.16 :ARG2 (a3 / abrogate-01~e.18 :ARG1 (a4 / advantage~e.21 :mod (s2 / survive-01~e.20) :ARG1-of (c4 / create-01~e.22 :ARG0 (m / microenvironment :mod (m5 / marrow :part-of (b / bone))))))))) :purpose (i2 / improve-01~e.37 :ARG0 r :ARG1 (o / outcome~e.39 :poss (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.38)))))) # ::id pmid_2352_4590.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To date , promising results have been obtained in several clinical trials . @^{81 , 82 @} # ::alignments 0-1.3 1-1.3 3-1.1.2 4-1.1 4-1.1.1 4-1.1.1.r 7-1 8-1.2.r 9-1.2.2 10-1.2.1 11-1.2 15-1.4.1.1.1.1 19-1.4.1.1.1.2 (o / obtain-01~e.7 :ARG1 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :ARG2-of (p / promise-01~e.3)) :ARG2~e.8 (t2 / trial-06~e.11 :mod (c / clinic~e.10) :quant (s / several~e.9)) :time (t3 / to-date~e.0,1) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 81~e.15 :op2 82~e.19))))) # ::id pmid_2352_4590.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , despite the clinical success of thalidomide , lenalidomide and bortezomib , a subset of patients do not initially respond to or ultimately become refractory to these agents . @^{83 @} # ::alignments 0-1 2-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1.1.1 9-1.2.1.2.1.1 10-1.2.1 11-1.2.1.3.1.1 14-1.1.1.2.1.1 16-1.1.1.2.2.1 18-1.1.1.1 18-1.1.1.1.r 19-1.1.1.4 20-1.1.1 22-1.1 23-1.1.2.3 23-1.1.2.3.r 24-1.1.2 25-1.1.2.2 26-1.1.2.2.1.r 27-1.1.2.2.1.1 28-1.1.2.2.1 32-1.3.1.1.1 (h / have-concession-91~e.0,2 :ARG1 (o / or~e.22 :op1 (r / respond-01~e.20 :polarity~e.18 -~e.18 :ARG0 (p / person :ARG1-of (i2 / include-91 :ARG2 (s / subset~e.14)) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient~e.16))) :ARG1 a :time (i / initial~e.19)) :op2 (b / become-01~e.24 :ARG1 p :ARG2 (r2 / refractory~e.25 :prep-to~e.26 (a / agent~e.28 :mod (t / this~e.27) :ARG1-of (m / mean-01 :ARG2 a2))) :manner~e.23 (u / ultimate~e.23))) :ARG2 (s2 / succeed-01~e.5 :ARG0~e.6 (a2 / and~e.10 :op1 (s3 / small-molecule :name (n / name :op1 "thalidomide"~e.7)) :op2 (s4 / small-molecule :name (n2 / name :op1 "lenalidomide"~e.9)) :op3 (s5 / small-molecule :name (n3 / name :op1 "bortezomib"~e.11))) :mod (c / clinic~e.4)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 83~e.32)))) # ::id pmid_2352_4590.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This emphasises the need for innovative anti @-@ MM therapies . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1 6-1.2.1.2 8-1.2.1.2.1.1.1 8-1.2.1.2.1.1.2 9-1.2.1 (e / emphasize-01~e.1 :ARG0 (t / this~e.0) :ARG1 (n / need-01~e.3 :ARG1~e.4 (t2 / therapy~e.9 :ARG1-of (i / innovate-01~e.5) :ARG0-of (c / counter-01~e.6 :ARG1 (d / disease :name (n2 / name :op1 "multiple"~e.8 :op2 "myeloma"~e.8)))))) # ::id pmid_2352_4590.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The impact of AZD6244 has been investigated in MM cells within the BMME . @^{84 @} # ::alignments 1-1.1 3-1.1.1.1.1 4-1.1 6-1 7-1.2.r 8-1.2.2.1.1 8-1.2.2.1.2 9-1.2 16-1.3.1.1.1 (i / investigate-01~e.6 :ARG1 (i2 / impact-01~e.1,4 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"~e.3))) :location~e.7 (c / cell~e.9 :part-of (m / microenvironment :mod (m2 / marrow :part-of (b / bone))) :source (d2 / disease :name (n / name :op1 "multiple"~e.8 :op2 "myeloma"~e.8))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 84~e.16)))) # ::id pmid_2352_4590.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This compound specifically abrogated constitutive and cytokine @-@ stimulated ERK phosphorylation and induced cytotoxicity in a panel of human myeloma cell lines ( HMCL ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1.3 3-1.1 4-1.1.2.1.2 5-1.1.2 6-1.1.2.2.2.1 8-1.1.2.2.2 9-1.1.2.1.1.1.1 10-1.1.2.1 10-1.1.2.2 11-1 11-1.1.2 12-1.2 13-1.2.2 16-1.3 17-1.3.1.r 18-1.3.1.1.2 19-1.3.1.1.1.1 20-1.3.1 21-1.3.1 (a / and~e.11 :op1 (a2 / abrogate-01~e.3 :ARG0 (c3 / compound~e.1 :mod (t / this~e.0)) :ARG1 (a3 / and~e.5,11 :op1 (p2 / phosphorylate-01~e.10 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"~e.9)) :mod (c / constitutive~e.4)) :op2 (p3 / phosphorylate-01~e.10 :ARG1 e2 :ARG1-of (s / stimulate-01~e.8 :ARG0 (c5 / cytokine~e.6)))) :ARG1-of (s2 / specific-02~e.2)) :op2 (i / induce-01~e.12 :ARG0 c3 :ARG2 (c2 / cytotoxicity~e.13)) :location (p5 / panel~e.16 :consist-of~e.17 (c4 / cell-line~e.20,21 :mod (d / disease :name (n / name :op1 "myeloma"~e.19) :mod (h / human~e.18))))) # ::id pmid_2352_4590.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Responses to AZD6244 were also witnessed in tumour cells derived from MM patients with advanced disease . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1 4-1.2 5-1 6-1.3.r 7-1.3.1 8-1.3 9-1.3.2 10-1.3.2.1.r 11-1.3.2.1.1.1.1 11-1.3.2.1.1.1.2 12-1.3.2.1 14-1.3.2.1.1.2 15-1.3.2.1.1 (w / witness-01~e.3,5 :ARG1 (t / thing~e.0 :ARG2-of~e.0 (r / respond-01~e.0 :ARG1~e.1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"~e.2)))) :mod (a / also~e.4) :location~e.6 (c / cell~e.8 :mod (t2 / tumor~e.7) :ARG1-of (d / derive-01~e.9 :ARG2~e.10 (p / patient~e.12 :mod (d3 / disease~e.15 :name (n / name :op1 "multiple"~e.11 :op2 "myeloma"~e.11) :ARG1-of (a2 / advance-01~e.14)))))) # ::id pmid_2352_4590.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that AZD6244 is effective at advanced stages of disease , where MM cells are less reliant on the growth factors produced by the BMME . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1 6-1.2 7-1.2.2.r 8-1.2.2.2 9-1.2.2 10-1.2.2.1.r 11-1.2.2.1 14-1.2.2.3.1.1.1.1 14-1.2.2.3.1.1.1.2 15-1.2.2.3.1 17-1.2.2.3.3 18-1.2.2.3 19-1.2.2.3.2.r 21-1.2.2.3.2 22-1.2.2.3.2 23-1.2.2.3.2.1 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (e / effective-04~e.6 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD6244"~e.4)) :time~e.7 (s3 / stage-02~e.9 :ARG1~e.10 (d / disease~e.11) :ARG1-of (a / advance-01~e.8) :time-of (r2 / rely-01~e.18 :ARG0 (c / cell~e.15 :mod (d2 / disease :name (n4 / name :op1 "multiple"~e.14 :op2 "myeloma"~e.14))) :ARG2~e.19 (g / growth-factor~e.21,22 :ARG1-of (p / produce-01~e.23 :ARG0 (m / microenvironment :mod (m2 / marrow :mod (b / bone))))) :degree (l / less~e.17))))) # ::id pmid_2352_4590.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , culturing of HMCL and patient @-@ derived samples in the presence of exogenous interleukin @-@ 6 or bone marrow stromal cells did not protect against AZD6244 @-@ induced apoptosis . # ::alignments 0-1.1.2.1 2-1.1.2 5-1.1.2.1 6-1.1.2.1.2.1.1.1.1 8-1.1.2.1.2.1 9-1.1.2.1.2 9-1.1.2.1.2.2 9-1.1.2.1.2.2.r 10-1.1.2.2.r 12-1.1.2.2 13-1.1.2.2.1.r 14-1.1.2.2.1.1.2 15-1.1.2.2.1.1.1.1 17-1.1.2.2.1.1.1.1 18-1.1.2.2.1 19-1.1.2.2.1.2.1.1.1 20-1.1.2.2.1.2.1.1 22-1.1.2.1.1 22-1.1.2.2.1.2 24-1.1.1 24-1.1.1.r 25-1.1 26-1.1.3.r 27-1.1.3.1.1.1.1 29-1.1.3.1 30-1.1.3 (a / and :op2 (p / protect-01~e.25 :polarity~e.24 -~e.24 :ARG0 (c / culture-01~e.2 :ARG1 (a2 / and~e.0,5 :op1 (c2 / cell-line~e.22 :mod (d3 / disease :name (n4 / name :op1 "myeloma") :mod (h / human))) :op2 (t / thing~e.9 :ARG1-of (d2 / derive-01~e.8 :ARG2 (p2 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient~e.6)))) :ARG1-of~e.9 (s / sample-01~e.9))) :condition~e.10 (p5 / present-02~e.12 :ARG1~e.13 (o / or~e.18 :op1 (p6 / protein :name (n / name :op1 "interleukin-6"~e.15,17) :mod (e / exogenous~e.14)) :op2 (c3 / cell~e.22 :mod (s2 / stroma :mod (m / marrow~e.20 :mod (b / bone~e.19))))))) :ARG2~e.26 (a3 / apoptosis~e.30 :ARG2-of (i / induce-01~e.29 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "AZD6244"~e.27)))))) # ::id pmid_2352_4590.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Synergistically enhanced cell death was noted in combinations of AZD6244 with conventional ( dexamethasone ) and novel ( bortezomib , lenalidomide , perifisone ) anti @-@ MM agents . # ::alignments 0-1.1.2.1 1-1.1.2 2-1.1.1 3-1.1 5-1 6-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.1.1 10-1.2.2.r 11-1.2.2.1.2 13-1.2.2.1.3.1 15-1.2.2 16-1.2.2.2.2 18-1.2.2.2.3.1.1.1.1 20-1.2.2.2.3.1.2.1.1 22-1.2.2.2.3.1.3.1.1 24-1.2.2.1.1 26-1.2.2.1.1.1.1.1 26-1.2.2.1.1.1.1.2 27-1.2.2.1 27-1.2.2.2 (n / note-01~e.5 :ARG1 (d / die-01~e.3 :ARG1 (c / cell~e.2) :ARG1-of (e / enhance-01~e.1 :manner (s / synergize-01~e.0))) :location~e.6 (c2 / combine-01~e.7 :ARG1~e.8 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"~e.9)) :ARG2~e.10 (a / and~e.15 :op1 (a2 / agent~e.27 :ARG0-of (c3 / counter-01~e.24 :ARG1 (d2 / disease :name (n3 / name :op1 "multiple"~e.26 :op2 "myeloma"~e.26))) :mod (c4 / conventional~e.11) :ARG2-of (i / include-91 :ARG1 (d3 / dexamethasone~e.13))) :op2 (a3 / agent~e.27 :ARG0-of c3 :mod (n4 / novel~e.16) :ARG2-of (i2 / include-91 :ARG1 (a4 / and :op1 (s3 / small-molecule :name (n5 / name :op1 "bortezomib"~e.18)) :op2 (s4 / small-molecule :name (n6 / name :op1 "lenalidomide"~e.20)) :op3 (s5 / small-molecule :name (n7 / name :op1 "perifisone"~e.22)))))))) # ::id pmid_2352_4590.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD6244 as a single agent was also examined in an in vivo human plasmocytoma xenograft model and demonstrated prolonged survival when compared with control animals . # ::alignments 0-1.1.1.1.1 3-1.1.2.1 4-1.1.2 6-1.1.3 7-1.1 8-1.1.4.1 11-1.1.4.1 12-1.1.4.1 14-1.1.4.4 15-1.1.4.3 16-1.1.4 17-1.1.4.2 18-1 19-1.2 20-1.2.2.1 21-1.2.2 23-1.2.2.2.r 25-1.2.2.2.1 26-1.2.2.2 (a / and~e.18 :op1 (e / examine-01~e.7 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.0)) :manner (a2 / agent~e.4 :ARG1-of (s2 / single-02~e.3)) :mod (a3 / also~e.6) :location (x2 / xenograft~e.16 :manner (i / in-vivo~e.8,11,12) :mod (m / model~e.17) :mod (p2 / plasmocytoma~e.15) :mod (h / human~e.14))) :op2 (d / demonstrate-01~e.19 :ARG0 s :ARG1 (s3 / survive-01~e.21 :ARG1-of (p / prolong-01~e.20) :compared-to~e.23 (a4 / animal~e.26 :mod (c / control~e.25))))) # ::id pmid_2352_4590.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Breitkreutz et al. @ ^{85 @} have also investigated the consequences of AZD6244 administration on osteoclast differentiation , function and cytokine secretion in MM . # ::alignments 0-1.1.1.1.1.1 2-1.1.1 3-1.1.1.2.1 7-1.1.2.1.1.1 11-1.3 12-1 14-1.2 15-1.2.1.r 16-1.2.1.1.1.1 17-1.2.1 18-1.2.2.r 19-1.2.2.1.1 20-1.2.2.1 22-1.2.2.2 23-1.2.2 24-1.2.2.3.1.1.1 25-1.2.2.3 26-1.2.3.r 27-1.2.3 27-1.2.3.1.1 (i / investigate-01~e.12 :ARG0 (p / publication-91 :ARG0 (a / and~e.2 :op1 (p2 / person :name (n / name :op1 "Breitkreutz"~e.0)) :op2 (p3 / person :mod (o / other~e.3))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 85~e.7)))) :ARG1 (c2 / consequence~e.14 :poss~e.15 (a3 / administer-01~e.17 :ARG1 (s / small-molecule :name (n2 / name :op1 "AZD6244"~e.16))) :prep-on~e.18 (a4 / and~e.23 :op1 (d / differentiate-01~e.20 :mod (o2 / osteoclast~e.19)) :op2 (f / function-01~e.22 :mod o2) :op3 (s2 / secrete-01~e.25 :ARG1 (p4 / protein :name (n3 / name :op1 "cytokine"~e.24)) :mod o2)) :location~e.26 (m / multiple~e.27 :name (n4 / name :op1 "myeloma"~e.27))) :mod (a2 / also~e.11)) # ::id pmid_2352_4590.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD6244 blocked osteoclast differentiation and bone reabsorption in a dose @-@ dependent manner . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1 3-1.2.1 4-1.2 5-1.2.2.1 9-1.3.1 11-1.3 12-1.3.r (b / block-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244"~e.0)) :ARG1 (a / and~e.4 :op1 (d / differentiate-01~e.3 :ARG1 (o / osteoclast~e.2)) :op2 (r / reabsorb-00 :ARG1 (b2 / bone~e.5))) :manner~e.12 (d2 / depend-01~e.11 :ARG1 (d3 / dose~e.9))) # ::id pmid_2352_4590.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , critical MM growth factors produced by the BMME , including interleukin @-@ 6 , BAFF , APRIL and MIP @-@ 1α were all significantly reduced following AZD6244 treatment . # ::alignments 0-1.1.1.5.1 2-1.1.1.2 3-1.1.1.1.1.1 3-1.1.1.1.1.2 4-1.1.1 5-1.1.1 6-1.1.1.3 11-1.1.1.5 12-1.1.1.5.1.1.1.1 14-1.1.1.5.1.1.1.1 16-1.1.1.5.1.2.1.1 18-1.1.1.5.1.3.1.1 19-1.1.1.5.1 20-1.1.1.5.1.4.1.1 22-1.1.1.5.1.4.1.1 24-1.1.1.4 25-1.1.2 26-1.1 27-1.1.3 28-1.1.3.1.2.1.1 29-1.1.3.1 (a / and :op2 (r / reduce-01~e.26 :ARG1 (g / growth-factor~e.4,5 :mod (d / disease :name (n9 / name :op1 "multiple"~e.3 :op2 "myeloma"~e.3)) :ARG1-of (c / critical-02~e.2) :ARG1-of (p / produce-01~e.6 :ARG0 (m / microenvironment :mod (m2 / marrow :mod (b / bone)))) :mod (a3 / all~e.24) :ARG2-of (i / include-91~e.11 :ARG1 (a2 / and~e.0,19 :op1 (p2 / pritein :name (n / name :op1 "interleukin-6"~e.12,14)) :op2 (p3 / protein :name (n4 / name :op1 "BAFF"~e.16)) :op3 (p4 / protein :name (n5 / name :op1 "APRIL"~e.18)) :op4 (p5 / protein :name (n6 / name :op1 "MIP-1α"~e.20,22))))) :ARG2 (s2 / significant-02~e.25) :time (a4 / after~e.27 :op1 (t / treat-04~e.29 :ARG1 g :ARG2 (s3 / small-molecule :name (n7 / name :op1 "AZD6244"~e.28)))))) # ::id pmid_2352_4590.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these results indicate that AZD6244 is able to abrogate paracrine signal dependent MM cell survival within the bone marrow niche . # ::alignments 0-1.1.3 1-1.1.3.1 3-1.1.2 4-1.1 4-1.1.1 4-1.1.1.r 5-1 6-1.2.r 7-1.2.1.2.1.1 9-1.2 11-1.2.1 12-1.2.1.1.2.1.1 13-1.2.1.1.2.1 14-1.2.1.1.2 15-1.2.1.1.1.1.1.1 15-1.2.1.1.1.1.1.2 16-1.2.1.1.1 17-1.2.1.1 20-1.2.1.3.1.1 21-1.2.1.3.1 22-1.2.1.3 (i2 / indicate-01~e.5 :ARG0 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :mod (t2 / this~e.3) :ARG1-of (t3 / take-01~e.0 :manner (t4 / together~e.1))) :ARG1~e.6 (p / possible-01~e.9 :ARG1 (a / abrogate-01~e.11 :ARG1 (s2 / survive-01~e.17 :ARG0 (c / cell~e.16 :mod (d / disease :name (n2 / name :op1 "multiple"~e.15 :op2 "myeloma"~e.15))) :ARG0-of (d2 / depend-01~e.14 :ARG1 (s3 / signal-07~e.13 :ARG0 (p2 / paracrine~e.12)))) :ARG2 (s / small-molecule :name (n / name :op1 "AZD6244"~e.7)) :location (n3 / niche~e.22 :mod (m / marrow~e.21 :mod (b / bone~e.20)))))) # ::id pmid_2352_4590.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both these studies provide a preclinical rationale for the further evaluation of AZD6244 . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 3-1 5-1.2.1 6-1.2 7-1.2.2.r 9-1.2.2.2 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.1.1 (p / provide-01~e.3 :ARG0 (s / study-01~e.2 :mod (t / this~e.1) :mod (b / both~e.0)) :ARG1 (r / rationale~e.6 :mod (p2 / preclinical~e.5) :purpose~e.7 (e / evaluate-01~e.10 :ARG1~e.11 (s2 / small-molecule :name (n / name :op1 "AZD6244"~e.12)) :degree (f / further~e.9)))) # ::id pmid_2352_4590.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A phase II trial examining the compound in MM is presently ongoing . # ::alignments 1-1.1.2 2-1.1.2.1.1 3-1.1 4-1.1.1 6-1.1.1.1 7-1.1.1.2.r 8-1.1.1.2.1.1 8-1.1.1.2.1.2 10-1.2 11-1 (g / go-on-15~e.11 :ARG1 (t / trial-06~e.3 :ARG2 (e / examine-01~e.4 :ARG1 (c / compound~e.6) :location~e.7 (d / disease :name (n / name :op1 "multiple"~e.8 :op2 "myeloma"~e.8))) :mod (p / phase~e.1 :ord (o / ordinal-entity :value 2~e.2))) :time (p2 / present~e.10)) # ::id pmid_2352_4590.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with AS703026 has also been explored in MM . @^{86 @} # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 4-1.3 6-1 7-1.4.r 8-1.4.1.1 8-1.4.1.2 12-1.2.1.1.1 (e / explore-01~e.6 :ARG1 (t / treat-04~e.0 :ARG2~e.1 (s / small-molecule :name (n / name :op1 "AS703026"~e.2))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 86~e.12))) :mod (a / also~e.4) :location~e.7 (d / disease :name (n2 / name :op1 "multiple"~e.8 :op2 "myeloma"~e.8))) # ::id pmid_2352_4590.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AS703026 inhibits HMCL and cytokine @-@ induced osteoclast differentiation more potently ( 9 @- to 10 @-@ fold ) than AZD6244 , with an IC @₅₀ ranging from 0.005 @–@ 2 μℳ. # ::alignments 0-1.1.1.1 1-1 3-1.2 3-1.4 4-1.2.2.2.1.1.1 6-1.2.2.2 7-1.2.2.1 8-1.2.2 9-1.3.1 10-1.3 10-1.3.r 12-1.4.1.1 15-1.4.2.1 17-1.4.1 17-1.4.2 20-1.5.1.1.1 24-1.1 24-1.1.2 24-1.1.2.r 26-1.1.2.1 29-1.1.2.2.r 30-1.1.2.2.1.1 32-1.1.2.2.2.1 (i / inhibit-01~e.1 :ARG0 (s2 / small-molecule~e.24 :name (n / name :op1 "AS703026"~e.0) :ARG1-of~e.24 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.24 :ARG2 50~e.26 :ARG4~e.29 (v / value-interval :op1 (c2 / concentration-quantity :quant 0.005~e.30 :unit (n5 / nanomolar)) :op2 (c4 / concentration-quantity :quant 2~e.32 :unit (n6 / nanomolar))))) :ARG1 (a / and~e.3 :op1 (c / cell-line :mod (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma") :mod (h / human))) :op2 (d2 / differentiate-01~e.8 :ARG1 (o / osteoclast~e.7) :ARG2-of (i2 / induce-01~e.6 :ARG0 (p / protein :name (n3 / name :op1 "cytokine"~e.4))))) :manner~e.10 (p2 / potent~e.10 :degree (m2 / more~e.9)) :quant (b / between~e.3 :op1 (p3 / product-of~e.17 :op1 9~e.12) :op2 (p4 / product-of~e.17 :op1 10~e.15)) :ARG1-of (c3 / compare-01 :ARG2 (s / small-molecule :name (n4 / name :op1 "AZD6244"~e.20)))) # ::id pmid_2352_4590.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No discernable relationship between Ras or Raf mutational status and the sensitivity of HMCL to AS703026 was observed . # ::alignments 0-1.1 0-1.1.r 2-1.2 4-1.2.1.1.1.1.1.1 5-1.2.1 6-1.2.1.2.1.1.1.1 7-1.2.1.1.1 7-1.2.1.2.1 8-1.2.1.1 8-1.2.1.2 11-1.2.2 14-1.2.2.2.r 15-1.2.2.2.1.1 17-1 (o / observe-01~e.17 :polarity~e.0 -~e.0 :ARG1 (r / relation-03~e.2 :ARG0 (o2 / or~e.5 :op1 (s / status~e.8 :mod (m / mutate-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.4)))) :op2 (s2 / status~e.8 :mod (m2 / mutate-01~e.7 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf"~e.6))))) :ARG2 (s3 / sensitive-03~e.11 :ARG0 (c / cell-line :mod (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma") :mod (h / human))) :ARG1~e.14 (s4 / small-molecule :name (n4 / name :op1 "AS703026"~e.15))) :ARG1-of (d / discern-01 :ARG1-of (p2 / possible-01)))) # ::id pmid_2352_4590.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This compound also induced apoptosis in HMCL cultured in the presence of bone marrow stromal cells . # ::alignments 0-1.1.1 1-1.1 2-1.3 3-1 4-1.2 7-1.4.1.1 10-1.4 12-1.4.1.1.1.1.1.1 13-1.4.1.1.1.1.1 15-1.4.1 15-1.4.1.1.1 (i / induce-01~e.3 :ARG0 (c / compound~e.1 :mod (t / this~e.0)) :ARG2 (a / apoptosis~e.4) :mod (a2 / also~e.2) :condition (p / present-02~e.10 :ARG1 (c2 / cell-line~e.15 :ARG1-of (c4 / culture-01~e.7 :condition (c3 / cell~e.15 :mod (s / stroma :mod (m / marrow~e.13 :mod (b / bone~e.12))))) :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma") :mod (h / human))))) # ::id pmid_2352_4590.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further evaluation of AS703026 in conjunction with conventional ( dexamethasone , melphalan ) and novel ( lenalidomide , bortezomib , perifisone , rapamycin ) anti @-@ MM therapies revealed synergistic cytotoxicity against HMCL and patient samples . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 7-1.1.3.1.1.2 9-1.1.3.1.1.3.1.1.1.1 11-1.1.3.1.1.3.1.2.1.1 13-1.1.3.1 13-1.1.3.1.1.3.1 14-1.1.3.1.2.2 16-1.1.3.1.2.3.1.1.1.1 18-1.1.3.1.2.3.1.2.1.1 20-1.1.3.1.2.3.1.3.1.1 22-1.1.3.1.2.3.1.4.1.1 24-1.1.3.1.1.1 26-1.1.3.1.1.1.1.1.1 26-1.1.3.1.1.1.1.1.2 26-1.2.2.1.1.1.1 27-1.1.3.1.1 27-1.1.3.1.2 28-1 29-1.2.1 30-1.2 31-1.2.2.r 33-1.2.2 34-1.2.2.2.1.1.1.1 35-1.2.2.2 35-1.2.2.2.1 35-1.2.2.2.1.r (r / reveal-01~e.28 :ARG0 (e / evaluate-01~e.1 :ARG1~e.2 (s9 / small-molecule :name (n / name :op1 "AS703026"~e.3)) :degree (f / further~e.0) :ARG1-of (a2 / accompany-01 :ARG0 (a3 / and~e.13 :op1 (t / therapy~e.27 :ARG0-of (c3 / counter-01~e.24 :ARG1 (d2 / disease :name (n3 / name :op1 "multiple"~e.26 :op2 "myeloma"~e.26))) :mod (c4 / conventional~e.7) :ARG2-of (i / include-91 :ARG1 (a4 / and~e.13 :op1 (s3 / small-molecule :name (n5 / name :op1 "dexamethasone"~e.9)) :op2 (s4 / small-molecule :name (n6 / name :op1 "melphalan"~e.11))))) :op2 (t2 / therapy~e.27 :ARG0-of c3 :mod (n4 / novel~e.14) :ARG2-of (i2 / include-91 :ARG1 (a5 / and :op1 (s5 / small-molecule :name (n7 / name :op1 "lenalidomide"~e.16)) :op2 (s6 / small-molecule :name (n8 / name :op1 "bortezomib"~e.18)) :op3 (s7 / small-molecule :name (n9 / name :op1 "perifisone"~e.20)) :op4 (s8 / small-molecule :name (n10 / name :op1 "rapamycin"~e.22)))))))) :ARG1 (c / cytotoxicity~e.30 :ARG0-of (s / synergize-01~e.29) :prep-against~e.31 (a / and~e.33 :op1 (c2 / cell-line :mod (d / disease :name (n2 / name :op1 "myeloma"~e.26) :mod (h / human))) :op2 (t3 / thing~e.35 :ARG1-of~e.35 (s2 / sample-01~e.35 :ARG2 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.34)))))))) # ::id pmid_2352_4590.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lastly , for tumour cells isolated from patients with relapsed @/@ refractory MM treated with AS703026 at concentrations below 200 nℳ, dose @-@ dependent cytotoxicity was observed for 15 of 18 patient MM samples . # ::alignments 0-1.3 3-1.2.2 4-1.2 5-1.2.3 6-1.2.1.r 7-1.2.1.2.1 9-1.2.1.3.1.1.2 12-1.2.1.3.1.1.1.1 12-1.2.1.3.1.1.1.2 12-1.2.1.3.1.2.1.1 12-1.2.1.3.1.2.1.2 13-1.2.1.1 14-1.2.1.1.1.r 15-1.2.1.1.1.1.1 17-1.2.1.1.1.2.1 18-1.2.1.1.1.2 19-1.2.1.1.1.2.1.1 21-1.1.1.1 23-1.1.1 24-1.1 26-1 27-1.4.r 28-1.4.2.1 30-1.4.2.3.1.1 31-1.4.2.2.1.1 32-1.4.1.1 32-1.4.1.2 33-1.4 33-1.4.2 33-1.4.2.3.1 33-1.4.2.3.1.2 33-1.4.2.3.1.2.r 33-1.4.2.r (o / observe-01~e.26 :ARG1 (c / cytotoxicity~e.24 :ARG0-of (d / depend-01~e.23 :ARG1 (d2 / dose~e.21))) :condition (c3 / cell~e.4 :source~e.6 (p2 / person :ARG1-of (t2 / treat-03~e.13 :ARG3~e.14 (s2 / small-molecule :name (n2 / name :op1 "AS703026"~e.15) :quant (b / below~e.18 :op1 (c2 / concentration-quantity~e.17 :quant 200~e.19 :unit (n3 / nanomolar))))) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient~e.7)) :ARG0-of (h3 / have-03 :ARG1 (o2 / or :op1 (d5 / disease :name (n6 / name :op1 "multiple"~e.12 :op2 "myeloma"~e.12) :ARG1-of (r / relapse-01~e.9)) :op2 (d4 / disease :name (n4 / name :op1 "multiple"~e.12 :op2 "myeloma"~e.12) :mod (r2 / refract))))) :mod (t / tumor~e.3) :ARG1-of (i2 / isolate-01~e.5)) :time (l / last~e.0) :location~e.27 (d6 / disease~e.33 :name (n5 / name :op1 "multiple"~e.32 :op2 "myeloma"~e.32) :ARG1-of~e.33 (s3 / sample-01~e.33 :quant 15~e.28 :ARG2 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.31))) :ARG1-of (i / include-91 :ARG2 (t3 / thing~e.33 :quant 18~e.30 :ARG1-of~e.33 (s / sample-01~e.33)))))) # ::id pmid_2352_4590.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this cohort of MM patient samples , while six and two of the patient samples harboured K @-@ Ras/N @-@ Ras and B @-@ Raf mutations , respectively , the presence or absence of Ras or B @-@ Raf mutations did not correlate with the sensitivity to MEK inhibition by AS703026 . # ::alignments 1-1.3.1 2-1.3 3-1.3.2.r 4-1.3.2.1.1 4-1.3.2.1.2 5-1.3.2.2.1.1.1 6-1.1.1.1 6-1.1.1.1.2 6-1.1.1.1.2.r 6-1.3.2 6-1.3.2.2 6-1.3.2.2.r 8-1 9-1.1.1.1.1 10-1.1 11-1.1.2.1.1 14-1.3.2.2.1.1.1 15-1.1.1.1 15-1.1.1.1.2 15-1.1.1.1.2.r 15-1.1.2.1 15-1.1.2.1.2 15-1.1.2.1.2.r 15-1.3.2 15-1.3.2.2 15-1.3.2.2.r 16-1.1.1 16-1.1.2 17-1.1.1.2.1.1.1.1 21-1.1.1.2.1.1.1.1 21-1.1.1.2.2.1.1.1 22-1.1 23-1.2.2.1.1.2 24-1.2.2.1.1.2 25-1.2.2.1.1.2 26-1.2.2.1.1.2 31-1.2.2.1 32-1.2.2 32-1.2.2.1.1 33-1.2.2.2 35-1.2.2.1.1.1.1.1.1 36-1.1.1.2 37-1.1.2.2.1.1.1 39-1.1.2.2.1.1.1 40-1.1.1.2.1 40-1.1.1.2.2 40-1.1.2.2 40-1.2.2.1.1.1 42-1.2.1 42-1.2.1.r 43-1.2 44-1.2.3.r 46-1.2.3 47-1.2.3.1.r 48-1.2.3.1.2.1.1 49-1.2.3.1 50-1.2.3.1.1.r 51-1.2.3.1.1.1.1 (c / contrast-01~e.8 :ARG1 (a / and~e.10,22 :op1 (h / harbor-01~e.16 :ARG0 (t3 / thing~e.6,15 :quant 6~e.9 :ARG1-of~e.6,15 (s / sample-01~e.6,15 :ARG2 p2)) :ARG1 (o / or~e.36 :op1 (m / mutate-01~e.40 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.17,21))) :op2 (m2 / mutate-01~e.40 :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras"~e.21))))) :op2 (h2 / harbor-01~e.16 :ARG0 (t2 / thing~e.15 :quant 2~e.11 :ARG1-of~e.15 (s2 / sample-01~e.15)) :ARG1 (m3 / mutate-01~e.40 :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf"~e.37,39))))) :ARG2 (c2 / correlate-01~e.43 :polarity~e.42 -~e.42 :ARG1 (o2 / or~e.32 :op1 (p / present-02~e.31 :ARG1 (o3 / or~e.32 :op1 (m4 / mutate-01~e.40 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Ras"~e.35))) :op2 m3~e.23,24,25,26)) :op2 (a2 / absent-01~e.33 :ARG1 o3)) :ARG2~e.44 (s3 / sensitive-03~e.46 :ARG1~e.47 (i / inhibit-01~e.49 :ARG0~e.50 (s5 / small-molecule :name (n6 / name :op1 "AS703026"~e.51)) :ARG1 (e5 / enzyme :name (n5 / name :op1 "MEK"~e.48))))) :location (c3 / cohort~e.2 :mod (t / this~e.1) :consist-of~e.3 (d / disease~e.6,15 :name (n8 / name :op1 "multiple"~e.4 :op2 "myeloma"~e.4) :ARG1-of~e.6,15 (s4 / sample-01~e.6,15 :ARG2 (p2 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 (p3 / patient~e.5,14))))))) # ::id pmid_2352_4590.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite these encouraging findings , outcomes from solid tumour models suggest that combination regimes are required to maximise the effectiveness of MEK inhibitors in MM . # ::alignments 0-1 1-1.2.2 2-1.2.1 3-1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.1.1 10-1.1 11-1.1.2.r 12-1.1.2.2.1 13-1.1.2.2 15-1.1.2 19-1.1.2.1.1 20-1.1.2.1.1.1.r 21-1.1.2.1.1.1.1.1.1.1 22-1.1.2.1.1.1 22-1.1.2.1.1.1.1 22-1.1.2.1.1.1.1.r 23-1.1.2.1.1.2.r 24-1.1.2.1.1.2.1.1 24-1.1.2.1.1.2.1.2 (h / have-concession-91~e.0 :ARG1 (s / suggest-01~e.10 :ARG0 (o / outcome~e.5 :source~e.6 (t3 / tumor~e.8 :mod (m / model~e.9 :ARG1-of (s2 / solid-02~e.7)))) :ARG1~e.11 (r / require-01~e.15 :ARG0 (m2 / maximize-01 :ARG1 (e2 / effective-04~e.19 :ARG0~e.20 (m3 / molecular-physical-entity~e.22 :ARG0-of~e.22 (i / inhibit-01~e.22 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.21)))) :ARG1~e.23 (d / disease :name (n2 / name :op1 "multiple"~e.24 :op2 "myeloma"~e.24)))) :ARG1 (r2 / regime~e.13 :ARG3-of (c / combine-01~e.12)))) :ARG2 (f / find-01~e.3 :ARG0-of (e / encourage-02~e.2) :mod (t / this~e.1))) # ::id pmid_2352_4590.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD6244 and AS703026 have demonstrated improved potency when used in combination with other anti @-@ MM agents . @^{84 , 85 , 86 @} # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 4-1 5-1.2.1 6-1.2 8-1.3 9-1.3.2.r 10-1.3.2 11-1.3.2.2.r 12-1.3.2.2.2 13-1.3.2.2.1 15-1.3.2.2.1.1.1.1 15-1.3.2.2.1.1.1.2 16-1.3.2.2 20-1.4.1.1.1.1 24-1.4.1.1.1.2 28-1.4.1.1.1.3 (d / demonstrate-01~e.4 :ARG0 (a / and~e.1 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.0)) :op2 (s2 / small-molecule :name (n2 / name :op1 "AS703026"~e.2))) :ARG1 (p3 / potency~e.6 :ARG1-of (i / improve-01~e.5)) :condition (u / use-01~e.8 :ARG0 a :manner~e.9 (c / combine-01~e.10 :ARG1 a :ARG2~e.11 (a2 / agent~e.16 :ARG0-of (c2 / counter-01~e.13 :ARG1 (d2 / disease :name (n3 / name :op1 "multiple"~e.15 :op2 "myeloma"~e.15))) :mod (o / other~e.12)))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 (a3 / and :op1 84~e.20 :op2 85~e.24 :op3 86~e.28))))) # ::id pmid_2352_4590.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The contribution of additional signalling pathways to MM tumorigenesis also offers the opportunity to target MEK in conjunction with the inhibition of these biochemical networks . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 4-1.1.1.1 5-1.1.1 6-1.1.2.r 7-1.1.2.1.1.1.1 7-1.1.2.1.1.1.2 8-1.1.2 8-1.1.2.1 8-1.1.2.1.r 9-1.3 10-1 12-1.2 14-1.2.1 15-1.2.1.1.1.1 20-1.2.1.2.1 21-1.2.1.2.1.1.r 22-1.2.1.2.1.1.2 23-1.2.1.2.1.1.1 24-1.2.1.2.1.1 (o / offer-01~e.10 :ARG0 (c / contribute-01~e.1 :ARG0~e.2 (p / pathway~e.5 :ARG0-of (s / signal-07~e.4) :mod (a / additional~e.3)) :ARG2~e.6 (c2 / create-01~e.8 :ARG1~e.8 (t / tumor~e.8 :mod (d / disease :name (n3 / name :op1 "multiple"~e.7 :op2 "myeloma"~e.7))))) :ARG1 (o2 / opportunity~e.12 :purpose (t2 / target-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.15)) :manner (a2 / accompany-01 :ARG1 (i / inhibit-01~e.20 :ARG0~e.21 (n2 / network~e.24 :mod (b / biochemistry~e.23) :mod (t3 / this~e.22)))))) :mod (a3 / also~e.9)) # ::id pmid_2352_4590.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Chatterjee et al. @ ^{30 @} have determined that the combined disruption of the Ras @/@ MAPK and JAK @/@ STAT pathway is required to induce MM apoptosis in the presence of bone marrow stromal cells . # ::alignments 0-1.1.1.1.1.1 2-1.1.1 3-1.1.1.2.1 7-1.1.2.1.1.1 11-1 12-1.2.r 14-1.2.2.2 15-1.2.2 16-1.2.2.1.r 18-1.2.2.1.1.1.1 20-1.2.2.1.1.1.1 21-1.2.2.1 22-1.2.2.1.2.1.1 24-1.2.2.1.2.1.1 25-1.2.2.1.1 25-1.2.2.1.2 27-1.2 29-1.2.1 30-1.2.1.1.1.1.1 30-1.2.1.1.1.1.2 31-1.2.1.1 32-1.2.3.r 34-1.2.3 35-1.2.3.1.r 36-1.2.3.1.1.1.1 37-1.2.3.1.1.1 39-1.2.3.1 (d / determine-01~e.11 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.2 :op1 (p5 / person :name (n4 / name :op1 "Chatterjee"~e.0)) :op2 (p6 / person :mod (o / other~e.3))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication :ARG1-of (c2 / cite-01 :ARG2 30~e.7)))) :ARG1~e.12 (r / require-01~e.27 :ARG0 (i / induce-01~e.29 :ARG2 (a2 / apoptosis~e.31 :mod (d3 / disease :name (n3 / name :op1 "multiple"~e.30 :op2 "myeloma"~e.30)))) :ARG1 (d2 / disrupt-01~e.15 :ARG1~e.16 (a / and~e.21 :op1 (p / pathway~e.25 :name (n / name :op1 "Ras/MAPK"~e.18,20)) :op2 (p2 / pathway~e.25 :name (n2 / name :op1 "JAK/STAT"~e.22,24))) :ARG1-of (c3 / combine-01~e.14)) :condition~e.32 (p3 / present-02~e.34 :ARG1~e.35 (c / cell~e.39 :mod (s / stroma :mod (m / marrow~e.37 :mod (b / bone~e.36))))))) # ::id pmid_2352_4590.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , the contribution PI3K @/@ Akt and nuclear factor kappa @-@ light @-@ chain @-@ enhancer of activated B cells ( NFκB ) pathway deregulation exerts on MM and drug resistance also makes these pathways attractive targets for co @-@ inhibition with MEK specific agents . @^{5 , 29 @} # ::alignments 0-1.5 3-1.1.2 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 7-1.1.1.1 22-1.1.1.1.2.1.1 24-1.1.1.1.1 24-1.1.1.1.2 25-1.1.1 26-1.1 27-1.1.3.r 28-1.1.3.1.1.1 28-1.1.3.1.1.2 29-1.1.3 30-1.1.3.2.1 31-1.1.3.2 32-1.4 33-1 33-1.1.2 35-1.2.2 36-1.2.3 37-1.2 42-1.2.1.1.r 43-1.2.1.1.1.1.1.1 44-1.2.1.1.1 45-1.2.1.1 49-1.3.1.1.1.1 53-1.3.1.1.1.2 (m / make-02~e.33 :ARG0 (e / exert-01~e.26 :ARG0 (d / deregulate-01~e.25 :ARG1 (a3 / and~e.7 :op1 (p / pathway~e.24 :name (n / name :op1 "PI3K/Akt"~e.4,6)) :op2 (p2 / pathway~e.24 :name (n2 / name :op1 "NFκB"~e.22)))) :ARG1 (c / contribute-01~e.3,33) :ARG2~e.27 (a / and~e.29 :op1 (d2 / disease :name (n3 / name :op1 "multiple"~e.28 :op2 "myeloma"~e.28)) :op2 (r / resist-01~e.31 :ARG1 (d3 / drug~e.30)))) :ARG1 (t / target-01~e.37 :ARG0 (c2 / coinhibit-00 :instrument~e.42 (a5 / agent~e.45 :ARG1-of (s / specific-02~e.44 :ARG2 (p3 / protein-family :name (n4 / name :op1 "MEK"~e.43))))) :ARG1 a3~e.35 :ARG0-of (a4 / attract-01~e.36)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 5~e.49 :op2 29~e.53)))) :mod (a7 / also~e.32) :ARG1-of (r2 / resemble-01~e.0)) # ::id pmid_2352_4590.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several other small molecule inhibitors have also recently emerged as promising therapies in MM . # ::alignments 0-1.1.3 1-1.1.2 2-1.1 3-1.1 4-1.1.1 6-1.3 7-1.4 8-1 9-1.2.r 9-1.4.r 10-1.2.1 11-1.2 12-1.2.2.r 13-1.2.2.1.1 13-1.2.2.1.2 (e / emerge-02~e.8 :ARG0 (s3 / small-molecule~e.2,3 :ARG0-of (i / inhibit-01~e.4) :mod (o / other~e.1) :quant (s2 / several~e.0)) :ARG1~e.9 (t / therapy~e.11 :ARG0-of (p / promise-01~e.10) :location~e.12 (d / disease :name (n / name :op1 "multiple"~e.13 :op2 "myeloma"~e.13))) :mod (a / also~e.6) :time~e.9 (r / recent~e.7)) # ::id pmid_2352_4590.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histone deacetylases ( HDAC ) represent a family of enzymes that control transcription by modifying histones . # ::alignments 0-1.1.1.1 5-1 7-1.2 8-1.2.1.r 9-1.2.1 11-1.2.2 12-1.2.2.1 13-1.2.2.2.r 14-1.2.2.2 15-1.1.1.1 15-1.2.2.2.2.1.1 (r / represent-01~e.5 :ARG0 (e2 / enzyme :name (n / name :op1 "histone"~e.0,15 :op2 "deacetylase")) :ARG1 (f / family~e.7 :consist-of~e.8 (e / enzyme~e.9) :ARG0-of (c / control-01~e.11 :ARG1 (t / transcribe-01~e.12) :ARG2~e.13 (m / modify-01~e.14 :ARG0 f :ARG1 (p / protein :name (n2 / name :op1 "histone"~e.15)))))) # ::id pmid_2352_4590.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overexpression of HDAC in MM prevents the transcription of various tumour @-@ suppressor genes , which in turn enhances cellular proliferation and represses cell death . @^{87 @} # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.2.r 3-1.6 4-1.1.2.1.1 4-1.1.2.1.2 5-1 7-1.2 8-1.2.1.r 9-1.2.1.2 10-1.2.1.1.1 12-1.2.1.1 13-1.2.1 16-1.6 17-1.6 18-1.4 19-1.4.1.1 20-1.4.1 22-1.5 23-1.5.1.1 24-1.5.1 28-1.3.1.1.1 (p / prevent-01~e.5 :ARG0 (o / overexpress-01~e.0 :ARG1~e.1 (e / enzyme :name (n / name :op1 "HDAC"~e.2)) :location~e.3 (d / disease :name (n2 / name :op1 "multiple"~e.4 :op2 "myeloma"~e.4))) :ARG1 (t / transcribe-01~e.7 :ARG1~e.8 (g / gene~e.13 :ARG0-of (s / suppress-01~e.12 :ARG1 (t2 / tumor~e.10)) :mod (v / various~e.9))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 87~e.28))) :ARG0-of (e2 / enhance-01~e.18 :ARG1 (p2 / proliferate-01~e.20 :ARG0 (c / cell~e.19))) :ARG0-of (r / repress-01~e.22 :ARG1 (d2 / die-01~e.24 :ARG1 c~e.23)) :manner (i2 / in-turn~e.3,16,17)) # ::id pmid_2352_4590.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibition of HDAC activity reverses these outcomes , culminating in the accumulation of acetylated histones that promote the apoptosis of malignant cells . @^{88 @} # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1 5-1.2.1 6-1.2 8-1.3 9-1.3.1.r 11-1.3.1 12-1.3.1.1.r 13-1.3.1.1.2 14-1.3.1.1.1.1 16-1.3.1.1 16-1.3.1.1.3 16-1.3.1.1.3.r 18-1.3.1.1.3.1 19-1.3.1.1.3.1.1.r 20-1.3.1.1.3.1.1.1 21-1.3.1.1.3.1.1 25-1.4.1.1.1 (r / reverse-01~e.4 :ARG0 (i / inhibit-01~e.0 :ARG1~e.1 (a / activity-06~e.3 :ARG0 (e / enzyme :name (n / name :op1 "HDAC"~e.2)))) :ARG1 (o / outcome~e.6 :mod (t / this~e.5)) :ARG2 (c / culminate-01~e.8 :ARG2~e.9 (a2 / accumulate-01~e.11 :ARG1~e.12 (p3 / protein~e.16 :name (n3 / name :op1 "histone"~e.14) :ARG3-of (a3 / acetylate-01~e.13) :ARG0-of~e.16 (p / promote-01~e.16 :ARG1 (a4 / apoptosis~e.18 :poss~e.19 (c2 / cell~e.21 :ARG1-of (m / malignant-02~e.20))))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 88~e.25)))) # ::id pmid_2352_4590.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Clinical evaluation of the HDAC inhibitors as single agents in relapsed @/@ refractory MM patients has yielded modest response rates . @^{89 , 90 @} # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1 5-1.1.1.1 5-1.1.1.1.r 6-1.1.1.2.r 7-1.1.1.2.1 8-1.1.1.2 10-1.1.3.1.2.1.2 13-1.1.3.1.2.1.1.1 13-1.1.3.1.2.1.1.2 13-1.1.3.2.2.1.1.1 13-1.1.3.2.2.1.1.2 14-1.1.3.1.1.1 14-1.1.3.2.1.1 15-1.1.3.1 15-1.1.3.1.1 15-1.1.3.1.1.r 15-1.1.3.1.2 15-1.1.3.1.2.r 15-1.1.3.2 15-1.1.3.2.1 15-1.1.3.2.1.r 15-1.1.3.2.2 15-1.1.3.2.2.r 16-1 17-1.2.2 18-1.2.1 19-1.2 23-1.3.1.1.1.1 27-1.3.1.1.1.2 (y / yield-01~e.16 :ARG0 (e / evaluate-01~e.1 :ARG1~e.2 (m / molecular-physical-entity~e.5 :ARG0-of~e.5 (i / inhibit-01~e.5 :ARG1 (e2 / enzyme :name (n / name :op1 "HDAC"~e.4))) :manner~e.6 (a / agent~e.8 :ARG2-of (s / single-02~e.7))) :mod (c / clinical~e.0) :location (o / or :op1 (p / person~e.15 :ARG0-of~e.15 (h / have-rel-role-91~e.15 :ARG2 (p4 / patient~e.14)) :ARG0-of~e.15 (h3 / have-03~e.15 :ARG1 (d / disease :name (n4 / name :op1 "multiple"~e.13 :op2 "myeloma"~e.13) :ARG1-of (r / relapse-01~e.10)))) :op2 (p2 / person~e.15 :ARG0-of~e.15 (h2 / have-rel-role-91~e.15 :ARG2 (p5 / patient~e.14)) :ARG0-of~e.15 (h4 / have-03~e.15 :ARG1 (d2 / disease :name (n2 / name :op1 "multiple"~e.13 :op2 "myeloma"~e.13) :mod (r2 / refract)))))) :ARG1 (r3 / rate~e.19 :mod (r4 / respond-01~e.18) :quant (m2 / modest~e.17)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 89~e.23 :op2 90~e.27))))) # ::id pmid_2352_4590.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nevertheless , several studies have reported a significant increase in the anti @-@ MM effect of these agents , when used in conjunction with conventional anti @-@ MM chemotherapeutics , ^{91 @} lenalidomide and bortezomib . @^{92 @} # ::alignments 0-1 2-1.1.1.1 3-1.1.1 5-1.1 7-1.1.2.2 8-1.1.2 9-1.1.2.1.r 11-1.1.2.1.2 13-1.1.2.1.2.1.1.1 13-1.1.2.1.2.1.1.2 14-1.1.2.1 15-1.1.2.1.1.r 16-1.1.2.1.1.1 17-1.1.2.1.1 20-1.1.2.3 24-1.1.2.3.2.1.2 25-1.1.2.3.2.1.1 26-1.1.2.3.2.1.1 27-1.1.2.3.2.1.1 32-1.1.2.3.2.2.1.1.1 35-1.1.2.3.2.1.3.1.1.1.1 36-1.1.2.3.2.1.3.1 37-1.1.2.3.2.1.3.1.2.1.1 41-1.1.2.3.2.1.3.1.3.1.1.1 (h / have-concession-91~e.0 :ARG1 (r / report-01~e.5 :ARG0 (s / study-01~e.3 :quant (s2 / several~e.2)) :ARG1 (i / increase-01~e.8 :ARG1~e.9 (a / affect-01~e.14 :ARG0~e.15 (a2 / agent~e.17 :mod (t / this~e.16)) :ARG2 (c / counter-01~e.11 :ARG1 (d / disease :name (n / name :op1 "multiple"~e.13 :op2 "myeloma"~e.13)))) :ARG2 (s3 / significant-02~e.7) :condition (u / use-01~e.20 :ARG1 a2 :manner (a3 / accompany-01 :ARG0 (c2 / chemotherapy :ARG0-of c~e.25,26,27 :mod (c3 / conventional~e.24) :ARG2-of (i2 / include-91 :ARG1 (a4 / and~e.36 :op1 (s4 / small-molecule :name (n2 / name :op1 "lenalidomide"~e.35)) :op2 (s5 / small-molecule :name (n3 / name :op1 "bortezomib"~e.37)) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 92~e.41)))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c4 / cite-01 :ARG2 91~e.32)))))))) # ::id pmid_2352_4590.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combinations of MEK and HDAC inhibitors have been limited to preclinical studies involving chronic myelogenous leukaemia and non @-@ small cell lung carcinoma cell lines , but preliminary results have been promising . @^{93 , 94 @} # ::alignments 0-1.1.1 2-1.1.1.1.1.1.1.1 4-1.1.1.2.1.1.1.1 5-1.1.1.1 5-1.1.1.1.1 5-1.1.1.1.1.r 5-1.1.1.2 5-1.1.1.2.1 5-1.1.1.2.1.r 8-1.1 9-1.1.2.r 10-1.1.2.1 11-1.1.2 12-1.1.2.2 13-1.1.2.2.1.1.2 14-1.1.2.2.1.1.1.1 15-1.1.2.2.1.1.1.2 16-1.1.2.2.1 17-1.1.2.2.1.2.1.2.1.1 17-1.1.2.2.1.2.1.2.1.1.r 19-1.1.2.2.1.2.1.2.1 20-1.1.2.2.1.2.1.2 21-1.1.2.2.1.2.1.1 22-1.1.2.2.1.2.1 23-1.1.2.2.1.2 24-1.1.2.2.1.2 26-1 27-1.2.1.2 28-1.2.1 28-1.2.1.1 28-1.2.1.1.r 31-1.2 35-1.2.2.1.1.1.1 39-1.2.2.1.1.1.2 (c / contrast-01~e.26 :ARG1 (l / limit-01~e.8 :ARG1 (c2 / combine-01~e.0 :ARG1 (m / molecular-physical-entity~e.5 :ARG0-of~e.5 (i / inhibit-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.2)))) :ARG2 (m2 / molecular-physical-entity~e.5 :ARG0-of~e.5 (i2 / inhibit-01~e.5 :ARG1 (e2 / enzyme :name (n2 / name :op1 "HDAC"~e.4))))) :ARG2~e.9 (s / study-01~e.11 :mod (p / preclinical~e.10) :ARG0-of (i3 / involve-01~e.12 :ARG1 (a / and~e.16 :op1 (d / disease :name (n3 / name :op1 "myelogenous"~e.14 :op2 "leukaemia"~e.15) :mod (c3 / chronic~e.13)) :op2 (c4 / cell-line~e.23,24 :source (c5 / carcinoma~e.22 :mod (l2 / lung~e.21) :mod (c6 / cell~e.20 :mod (s2 / small~e.19 :polarity~e.17 -~e.17)))))))) :ARG2 (p2 / promise-01~e.31 :ARG0 (t / thing~e.28 :ARG2-of~e.28 (r / result-01~e.28) :mod (p3 / preliminary~e.27)) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c7 / cite-01 :ARG2 (a2 / and :op1 93~e.35 :op2 94~e.39)))))) # ::id pmid_2352_4590.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Heat shock protein 90 ( HSP90 ) is a molecular chaperone that regulates many of the proteins involved in Ras/MAPK , PI3K/Akt , JAK @/@ STAT and NFκB signalling , as well other biochemical pathways that control apoptosis and cell cycle progression . @^{95 @} # ::alignments 0-1.4.2.1 1-1.4.2.2 2-1.4.2.3 3-1.4.1 7-1.4.r 9-1.2 10-1 12-1.3 13-1.3.1.1 14-1.3.1.1.r 16-1.3.1 16-1.3.1.2.1 17-1.3.1.2.1.1 18-1.3.1.2.1.1.1.r 19-1.3.1.2.1.1.1.1.1.1.1.1 21-1.3.1.2.1.1.1.1.2.1.1.1 23-1.3.1.2.1.1.1.1.3.1.1.1 25-1.3.1.2.1.1.1.1.3.1.1.1 26-1.3.1.2.1.1.1.1 27-1.3.1.2.1.1.1.1.4.1.1.1 28-1.3.1.2.1.1.1.1.1 28-1.3.1.2.1.1.1.1.2 28-1.3.1.2.1.1.1.1.3 28-1.3.1.2.1.1.1.1.4 32-1.3.1.2.1.1.1.2.3 33-1.3.1.2.1.1.1.2.2 34-1.3.1.2.1.1.1.2 36-1.3.1.2.1.1.1.2.1 37-1.3.1.2.1.1.1.2.1.1.1 38-1.3.1.2.1.1.1.2.1.1 39-1.3.1.2.1.1.1.2.1.1.2.1.1 40-1.3.1.2.1.1.1.2.1.1.2.1 41-1.3.1.2.1.1.1.2.1.1.2 45-1.1.1.1.1 (c6 / chaperone~e.10 :ARG1-of (d / describe-01 :ARG0 (p10 / publication :ARG1-of (c5 / cite-01 :ARG2 95~e.45))) :mod (m / molecule~e.9) :ARG0-of (r / regulate-01~e.12 :ARG1 (p2 / protein~e.16 :quant~e.14 (m2 / many~e.13) :ARG1-of (i / include-91 :ARG2 (p3 / protein~e.16 :ARG1-of (i2 / involve-01~e.17 :ARG2~e.18 (a / and :op1 (a2 / and~e.26 :op1 (s / signal-07~e.28 :ARG0 (p4 / pathway :name (n2 / name :op1 "Ras/MAPK"~e.19))) :op2 (s2 / signal-07~e.28 :ARG0 (p5 / pathway :name (n3 / name :op1 "PI3K/Akt"~e.21))) :op3 (s3 / signal-07~e.28 :ARG0 (p6 / pathway :name (n4 / name :op1 "JAK/STAT"~e.23,25))) :op4 (s4 / signal-07~e.28 :ARG0 (p7 / pathway :name (n5 / name :op1 "NFκB"~e.27)))) :op2 (p8 / pathway~e.34 :ARG0-of (c2 / control-01~e.36 :ARG1 (a3 / and~e.38 :op1 (a4 / apoptosis~e.37) :op2 (p9 / progress-01~e.41 :ARG1 (c / cycle-02~e.40 :ARG1 (c4 / cell~e.39))))) :mod (b / biochemistry~e.33) :mod (o / other~e.32)))))))) :domain~e.7 (p / protein :mod 90~e.3 :name (n / name :op1 "Heat"~e.0 :op2 "shock"~e.1 :op3 "protein"~e.2))) # ::id pmid_2352_4590.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with these properties , inhibition of HSP90 has been shown to disrupt multiple pathways crucial to MM survival . @^{96 , 97 @} # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1 3-1.2.1 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 10-1 12-1.1 13-1.1.2.1 14-1.1.2 15-1.1.2.2 16-1.1.2.2.1.r 17-1.1.2.2.1.1.1.1 17-1.1.2.2.1.1.1.2 18-1.1.2.2.1 22-1.3.1.1.1.1 26-1.3.1.1.1.2 (s / show-01~e.10 :ARG1 (d4 / disrupt-01~e.12 :ARG0 (i / inhibit-01~e.5 :ARG1~e.6 (p / protein :name (n / name :op1 "HSP90"~e.7))) :ARG1 (p2 / pathway~e.14 :quant (m / multiple~e.13) :mod (c / crucial~e.15 :purpose~e.16 (s2 / survive-01~e.18 :ARG0 (d2 / disease :name (n2 / name :op1 "multiple"~e.17 :op2 "myeloma"~e.17)))))) :ARG1-of (c2 / consistent-01~e.0 :ARG2~e.1 (p3 / property~e.3 :mod (t / this~e.2))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a / and :op1 96~e.22 :op2 97~e.26))))) # ::id pmid_2352_4590.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While co @-@ treatment of MM cells with a MEK and HSP90 inhibitors might serve as a means of attenuating the feedback mechanisms that promote resistance to MEK inhibitors , the clinical efficacy of these approaches is dependent upon how selective and active these combination regimes are in vivo @ . # ::alignments 0-1 3-1.2.1.1 4-1.2.1.1.1.r 5-1.2.1.1.1.1.1.1 5-1.2.1.1.1.1.1.2 6-1.2.1.1.1 9-1.2.1.1.2.1.1.1.1.1 10-1.2.1.1.2.1.1 11-1.2.1.1.2.1.1.2.1.1 12-1.2.1.1.2 12-1.2.1.1.2.1 12-1.2.1.1.2.1.r 13-1.2 14-1.2.1 15-1.2.1.2.r 17-1.2.1.2 18-1.2.1.2.1.r 19-1.2.1.2.1 21-1.2.1.2.1.1.1 22-1.2.1.2.1.1 24-1.2.1.2.1.1.2 25-1.2.1.2.1.1.2.1 27-1.2.1.1.2.1.1.1.1.1 28-1.2.1.1.2 28-1.2.1.1.2.1 28-1.2.1.1.2.1.r 28-1.2.1.2.1.1.2.1.1 28-1.2.1.2.1.1.2.1.1.1 28-1.2.1.2.1.1.2.1.1.1.r 31-1.1.1.2 34-1.1.1.1.1 35-1.1.1.1 37-1.1 39-1.1.2.4.r 40-1.1.2.1.1 41-1.1.2 42-1.1.2.2.1 43-1.1.1.1.1 44-1.1.2.3.1 45-1.1.2.3 46-1.1.2.3.r 48-1.1.2.4 49-1.1.2.4 (c5 / contrast-01~e.0 :ARG1 (d2 / depend-01~e.37 :ARG0 (e2 / efficient-01 :ARG1 (a3 / approach-02~e.35 :mod (t / this~e.34,43)) :mod (c4 / clinic~e.31)) :ARG1 (a4 / and~e.41 :op1 (t2 / thing :degree-of (s2 / selective~e.40)) :op2 (t3 / thing :degree-of (a5 / activity-06~e.42)) :domain~e.46 (r2 / regime~e.45 :ARG3-of (c3 / combine-01~e.44)) :manner~e.39 (i3 / in-vivo~e.48,49))) :ARG2 (p / possible-01~e.13 :ARG1 (s / serve-01~e.14 :ARG0 (t4 / treat-04~e.3 :ARG1~e.4 (c2 / cell~e.6 :mod (d / disease :name (n / name :op1 "multiple"~e.5 :op2 "myeloma"~e.5))) :ARG2 (m / molecular-physical-entity~e.12,28 :ARG0-of~e.12,28 (i / inhibit-01~e.12,28 :ARG1 (a / and~e.10 :op1 (e / enzyme :name (n2 / name :op1 "MEK"~e.9,27)) :op2 (p2 / protein :name (n3 / name :op1 "HSP90"~e.11)))))) :ARG1~e.15 (m2 / mean~e.17 :ARG0-of~e.18 (a2 / attenuate-01~e.19 :ARG1 (m3 / mechanism~e.22 :mod (f / feedback~e.21) :ARG0-of (p3 / promote-01~e.24 :ARG1 (r / resist-01~e.25 :ARG1 (m4 / molecular-physical-entity~e.28 :ARG0-of~e.28 (i2 / inhibit-01~e.28 :ARG1 e)))))))))) # ::id pmid_2352_4590.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In particular , the potential interrupting multiple kinase networks has for increasing the likelihood of adverse effects and drug toxicity is likely to be an important factor in determining the optimal use of these agents . # ::alignments 1-1.2 4-1.1.1.2.1 5-1.1.1 6-1.1.1.1.2 7-1.1.1.1.1 8-1.1.1.1 9-1.1.1.2 10-1.1.1.2.2.r 11-1.1.1.2.2 15-1.1.1.2.2.1.1.1.1 16-1.1.1.2.2.1.1.1 17-1.1.1.2.2.1.1 18-1.1.1.2.2.1.1.2.1 19-1.1.1.2.2.1.1.2 20-1.1.1.r 21-1 21-1.1.1.2.2.1 23-1.1.1.r 25-1.1.3 26-1.1 27-1.1.2.r 28-1.1.2 30-1.1.2.1.2 31-1.1.2.1 32-1.1.2.1.1.r 33-1.1.2.1.1.1 34-1.1.2.1.1 (l / likely-01~e.21 :ARG1 (f / factor~e.26 :domain~e.20,23 (i / interrupt-01~e.5 :ARG1 (n / network-01~e.8 :ARG1 (k / kinase~e.7) :quant (m / multiple~e.6)) :ARG0-of (h / have-03~e.9 :ARG1 (p / potential~e.4) :purpose~e.10 (i2 / increase-01~e.11 :ARG1 (l2 / likely-01~e.21 :ARG1 (a / and~e.17 :op1 (a2 / affect-01~e.16 :mod (a3 / adverse~e.15)) :op2 (t / toxicity~e.19 :mod (d / drug~e.18))))))) :purpose~e.27 (d2 / determine-01~e.28 :ARG1 (u / use-01~e.31 :ARG1~e.32 (a4 / agent~e.34 :mod (t2 / this~e.33)) :mod (o / optimal~e.30))) :mod (i3 / important~e.25)) :mod (p2 / particular~e.1)) # ::id pmid_2352_4590.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Predicting patient responses to MEK inhibitors : identification of relevant biomarkers # ::alignments 1-1 2-1.1.1.1.1.1 3-1.1 3-1.1.1 3-1.1.1.r 4-1.1.1.2.r 5-1.1.1.2.1.1.1.1 6-1.1.1.2 6-1.1.1.2.1 6-1.1.1.2.1.r 8-1.2.1 10-1.2.1.1.1 (p / predict-01~e.1 :ARG1 (t / thing~e.3 :ARG2-of~e.3 (r / respond-01~e.3 :ARG0 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.2))) :ARG1~e.4 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6 :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"~e.5)))))) :ARG1-of (m2 / mean-01 :ARG2 (i2 / identify-01~e.8 :ARG1 (b / biomarker :ARG1-of (r2 / relevant-01~e.10))))) # ::id pmid_2352_4590.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As all MEK inhibitors tested to date demonstrate potent and selective activity against MEK1 @/@ 2 , toxicity profiles and drug exposure are likely to be the key criteria that refine these drugs for therapeutic use . # ::alignments 0-1.2.1.1.2.1.r 1-1.2.1.1.3 2-1.2.1.1.1.1.1.1 3-1.2.1.1 3-1.2.1.1.1 3-1.2.1.1.1.r 4-1.2.1.1.2 5-1.2.1.1.2.1 6-1.2.1.1.2.1 7-1.2.1 8-1.2.1.2.3 10-1.2.1.2.4 11-1.2.1.2 12-1.2.1.2.2 13-1.2.1.2.2.1.1.1 15-1.2.1.2.2.1.1.1 17-1.1.1.1.1 18-1.1.1.1 19-1.1.1 20-1.1.1.2.1 21-1.1.1.2 23-1 24-1.2 27-1.1.1.3.1 28-1.1.1.3 30-1.1 31-1.1.2.1 32-1.1.2 33-1.1.3.r 34-1.1.3.1 35-1.1.3 (l / likely-01~e.23 :ARG1 (r / refine-01~e.30 :ARG0 (a / and~e.19 :op1 (p / profile-01~e.18 :ARG1 (t / toxicity~e.17)) :op2 (e / expose-01~e.21 :ARG2 (d / drug~e.20)) :mod (c / criteria~e.28 :ARG1-of (k / key-02~e.27))) :ARG1 (d2 / drug~e.32 :mod (t2 / this~e.31)) :purpose~e.33 (u / use-01~e.35 :mod (t3 / therapy~e.34))) :ARG1-of (c2 / cause-01~e.24 :ARG0 (d3 / demonstrate-01~e.7 :ARG0 (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (i / inhibit-01~e.3 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.2))) :ARG1-of (t4 / test-01~e.4 :time~e.0 (t5 / to-date~e.5,6)) :mod (a2 / all~e.1)) :ARG1 (a3 / activity-06~e.11 :ARG0 m :ARG0-of (c3 / counter-01~e.12 :ARG1 (e3 / enzyme :name (n2 / name :op1 "MEK1/2"~e.13,15))) :mod (p2 / potent~e.8) :mod (s / selective~e.10))))) # ::id pmid_2352_4590.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , it has become clear that certain genetic sub @-@ types in solid tumours are associated with increased susceptibility or resistance to MEK inhibitors . # ::alignments 0-1 4-1.1 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.2 8-1.1.1.1.1.1 13-1.1.1.1.1.3.1 14-1.1.1.1.1.3 15-1.1.1.1.2.1.2.r 16-1.1.1.1 17-1.1.1.1.2.r 18-1.1.1.1.2.1.1 20-1.1.1.1.2 21-1.1.1.1.2.2 23-1.1.1.1.2.1.3.1.1.1.1 24-1.1.1.1.2.1.3 24-1.1.1.1.2.1.3.1 24-1.1.1.1.2.1.3.1.r (a / and~e.0 :op2 (b / become-01~e.4 :ARG2 (c / clear-06~e.5 :ARG1~e.6 (a2 / associate-01~e.16 :ARG1 (s / subtype :mod (g / genetics~e.8) :mod (c2 / certain~e.7) :location (t / tumor~e.14 :ARG1-of (s2 / solid-02~e.13))) :ARG2~e.17 (o / or~e.20 :op1 (s3 / susceptible :ARG1-of (i / increase-01~e.18) :domain~e.15 s :topic (m / molecular-physical-entity~e.24 :ARG0-of~e.24 (i2 / inhibit-01~e.24 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.23))))) :op2 (r / resist-01~e.21 :ARG0 s :ARG1 m)))))) # ::id pmid_2352_4590.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This observation highlights the need for a reliable marker of responsiveness to MEK inhibitors , allowing tailoring of individualised therapies and reducing the occurrence of adverse events . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.1.r 7-1.2.1 7-1.2.1.2 7-1.2.1.2.1 7-1.2.1.2.1.r 7-1.2.1.2.r 12-1.2.1.1.1.1.1.1.1.1 13-1.2.1.1.1.1 13-1.2.1.1.1.1.1 13-1.2.1.1.1.1.1.r 15-1.3 16-1.3.1.1 19-1.3.1.1.1 20-1.3.1 21-1.3.1.2 24-1.3.1.2.1.r 25-1.3.1.2.1.1 26-1.3.1.2.1 (h / highlight-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1 (n / need-01~e.4 :ARG1~e.5 (m3 / molecular-physical-entity~e.7 :ARG0-of (m / mark-01 :ARG1 (r / responsive-02 :ARG1 (m2 / molecular-physical-entity~e.13 :ARG0-of~e.13 (i / inhibit-01~e.13 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.12)))))) :ARG1-of~e.7 (r2 / rely-01~e.7 :ARG1-of~e.7 (p / possible-01~e.7)))) :ARG0-of (a / allow-01~e.15 :ARG1 (a2 / and~e.20 :op1 (t2 / tailor-01~e.16 :ARG1 (t3 / therapy~e.19 :ARG1-of (i2 / individualize-02))) :op2 (r3 / reduce-01~e.21 :ARG1~e.24 (e2 / event~e.26 :mod (a3 / adverse~e.25)))))) # ::id pmid_2352_4590.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Currently it remains difficult to determine which patients will benefit most from MEK inhibitor treatment . # ::alignments 0-1.2 2-1 3-1.1 5-1.1.1 6-1.1.1.1.2.2 7-1.1.1.1.2.1.1 9-1.1.1.1 10-1.1.1.1.3 11-1.1.1.1.1.r 12-1.1.1.1.1.1.1.1.1.1 13-1.1.1.1.1.1 13-1.1.1.1.1.1.1 13-1.1.1.1.1.1.1.r 14-1.1.1.1.1 (r / remain-01~e.2 :ARG1 (d / difficult~e.3 :domain (d2 / determine-01~e.5 :ARG1 (b / benefit-01~e.9 :ARG0~e.11 (t / treat-04~e.14 :ARG2 (m / molecular-physical-entity~e.13 :ARG0-of~e.13 (i / inhibit-01~e.13 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.12))))) :ARG1 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.7)) :mod (a / amr-unknown~e.6)) :degree (m2 / most~e.10)))) :time (c / current~e.0)) # ::id pmid_2352_4590.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whilst activating B @-@ Raf mutations are associated with exquisite sensitivity against these agents , other biochemical markers demonstrate less predictability . # ::alignments 1-1.1.1.2 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1 7-1.1 8-1.1.2.r 9-1.1.2.3 10-1.1.2 12-1.1.2.2.1 13-1.1.2.2 15-1.2.1.2 16-1.2.1.1 17-1.2.1 18-1.2 19-1.2.2.2 (c / contrast-01 :ARG1 (a / associate-01~e.7 :ARG1 (m / mutate-01~e.5 :ARG2 (e / enzyme :name (n / name :op1 "B-Raf"~e.2,4)) :ARG0-of (a2 / activate-01~e.1)) :ARG2~e.8 (s / sensitive-03~e.10 :ARG0 m :ARG1 (a3 / agent~e.13 :mod (t / this~e.12)) :degree (e2 / exquisite~e.9))) :ARG2 (d / demonstrate-01~e.18 :ARG0 (m2 / marker~e.17 :mod (b / biochemistry~e.16) :mod (o / other~e.15)) :ARG1 (p / possible-01 :ARG1 (p2 / predict-01) :quant (l / less~e.19)))) # ::id pmid_2352_4590.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , the poor correlation between MEK inhibitor susceptibility Ras genotypes and p @-@ ERK expression is well documented . @^{12 , 41 , 46 , 47 , 48 , 60 @} # ::alignments 0-1 1-1 4-1.1.1.3 5-1.1.1 7-1.1.1.1.2.1.1.1.1 8-1.1.1.1.2 8-1.1.1.1.2.1 8-1.1.1.1.2.1.r 10-1.1.1.1.1.1.1.1 11-1.1.1.1.1 13-1.1.1.2.1.2 15-1.1.1.2.1.1.1 16-1.1.1.2 17-1.1.1.1.1.r 18-1.1.2 19-1.1 23-1.2.1.1.1.1 27-1.2.1.1.1.2 31-1.2.1.1.1.3 35-1.2.1.1.1.4 39-1.2.1.1.1.5 43-1.2.1.1.1.6 (e / exemplify-01~e.0,1 :ARG0 (d / document-01~e.19 :ARG1 (c / correlate-01~e.5 :ARG1 (s / susceptible :domain~e.17 (g / genotype~e.11 :mod (e2 / enzyme :name (n / name :op1 "Ras"~e.10))) :mod (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (i / inhibit-01~e.8 :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK"~e.7))))) :ARG2 (e4 / express-03~e.16 :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK"~e.15) :ARG3-of (p / phosphorylate-01~e.13))) :degree (p2 / poor~e.4)) :ARG1-of (w / well-09~e.18)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (a / and :op1 12~e.23 :op2 41~e.27 :op3 46~e.31 :op4 47~e.35 :op5 48~e.39 :op6 60~e.43))))) # ::id pmid_2352_4590.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In one study , analysis of transcriptional pathway signatures in various solid tumours , identified a panel of 18 genes , the expression of which correlated with responsiveness to AZD6244 . @^{98 @} # ::alignments 1-1.3.1 2-1.3 4-1.1 5-1.1.1.r 6-1.1.1.1.1 7-1.1.1.1 8-1.1.1 9-1.1.2.r 10-1.1.2.2 11-1.1.2.1 12-1.1.2 14-1 16-1.2 17-1.2.1.r 18-1.2.1.1 19-1.2.1 22-1.2.1.2 25-1.2.1.2.1 29-1.2.1.2.1.1.1.1.1 33-1.4.1.1.1 (i / identify-01~e.14 :ARG0 (a / analyze-01~e.4 :ARG1~e.5 (s / signature~e.8 :mod (p / pathway~e.7 :ARG1-of (t / transcribe-01~e.6))) :location~e.9 (t2 / tumor~e.12 :ARG1-of (s2 / solid-02~e.11) :mod (v / various~e.10))) :ARG1 (p2 / panel~e.16 :consist-of~e.17 (g / gene~e.19 :quant 18~e.18 :ARG1-of (e / express-03~e.22 :ARG1-of (c / correlate-01~e.25 :ARG2 (r / responsive-02 :ARG1 (s3 / small-molecule :name (n / name :op1 "AZD6244"~e.29))))))) :medium (s4 / study~e.2 :quant 1~e.1) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 98~e.33)))) # ::id pmid_2352_4590.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This signature contained transcriptional targets of ERK involved in negative @-@ feedback regulation ( DUSP4 @/@ 6 and SPRY2 ) , members of the Ets family of transcription factors ( ETV4 , ETV5 and ELF1 ) and other genes associated with MAPK signalling , cell cycle progression and tumour prognosis . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1.3.2 4-1.2.1.3 5-1.2.1.3.1.r 6-1.2.1.3.1.1.1 7-1.2.1.3.3 8-1.2.1.3.3.1.r 9-1.2.1.3.3.1.1.1 11-1.2.1.3.3.1.1 12-1.2.1.3.3.1 14-1.2.1.1.1.1 16-1.2.1.1.1.1 17-1.2.1 18-1.2.1.2.1.1 21-1.2.2 24-1.2.2.1.1.1.1 25-1.2.2.1.1 27-1.2.1.3.2 30-1.2.2.2.1.1.1.1 32-1.2.2.2.1.2.1.1 33-1.2.2.2.1 34-1.2.2.2.1.3.1.1 36-1.2 36-1.2.2.2.1 37-1.2.3.2 38-1.2.3 39-1.2.3.1 40-1.2.3.1.1.r 41-1.2.3.1.1.1.1.1.1 42-1.2.3.1.1.1 44-1.2.3.1.1.2.1.1 45-1.2.3.1.1.2.1 46-1.2.3.1.1.2 47-1.2.3.1.1 48-1.2.3.1.1.3.1 49-1.2.3.1.1.3 (c / contain-01~e.2 :ARG0 (s / signature~e.1 :mod (t / this~e.0)) :ARG1 (a / and~e.36 :op1 (a2 / and~e.17 :op1 (p8 / protein :name (n / name :op1 "DUSP4/6"~e.14,16)) :op2 (p9 / protein :name (n2 / name :op1 "SPRY2"~e.18)) :ARG1-of (t2 / target-01~e.4 :ARG0~e.5 (e / enzyme :name (n3 / name :op1 "ERK"~e.6)) :ARG1-of (t3 / transcribe-01~e.3,27) :ARG1-of (i / involve-01~e.7 :ARG2~e.8 (r / regulate-01~e.12 :ARG1 (f / feedback~e.11 :ARG0-of (n4 / negative-03~e.9)))))) :op2 (m / member~e.21 :ARG1-of (i2 / include-91 :ARG2 (p / protein-family~e.25 :name (n5 / name :op1 "Ets"~e.24))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and~e.33,36 :op1 (p5 / protein :name (n6 / name :op1 "ETV4"~e.30)) :op2 (p6 / protein :name (n7 / name :op1 "ETV5"~e.32)) :op3 (p7 / protein :name (n8 / name :op1 "ELF1"~e.34))))) :op3 (g6 / gene~e.38 :ARG1-of (a4 / associate-01~e.39 :ARG2~e.40 (a5 / and~e.47 :op1 (s2 / signal-07~e.42 :ARG0 (p2 / pathway :name (n9 / name :op1 "MAPK"~e.41))) :op2 (p3 / progress-01~e.46 :ARG1 (c2 / cycle-02~e.45 :ARG1 (c3 / cell~e.44))) :op3 (p4 / prognosis~e.49 :mod (t4 / tumor~e.48)))) :mod (o / other~e.37)))) # ::id pmid_2352_4590.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A 13 @-@ gene signature was also identified that was predictive of resistance to AZD6244 . # ::alignments 1-1.1.1.1 3-1.1.1 4-1.1 6-1.2 7-1 10-1.3 11-1.3.1.r 12-1.3.1 13-1.3.1.1.r 14-1.3.1.1.1.1 (i / identify-01~e.7 :ARG1 (s / signature~e.4 :mod (g / gene~e.3 :quant 13~e.1)) :mod (a / also~e.6) :ARG0-of (p / predict-01~e.10 :ARG1~e.11 (r / resist-01~e.12 :ARG1~e.13 (s2 / small-molecule :name (n / name :op1 "AZD6244"~e.14))))) # ::id pmid_2352_4590.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This diverse set of genes shared common links with transforming growth factor-β ( TGF-β) , tumour necrosis factor-α and NFκB signalling . # ::alignments 0-1.1.3 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1 5-1 6-1 6-1.2.1 7-1.2 8-1.3.r 9-1.3.1.1.1.1 10-1.3.1.1.1.2 11-1.3.1.1.1.3 15-1.3.1.2.1.1 16-1.3.1.2.1.2 17-1.3.1.2.1.3 18-1.3.1 19-1.3.1.3.1.1 20-1.3 (s / share-01~e.5,6 :ARG0 (s2 / set~e.2 :consist-of~e.3 (g / gene~e.4) :mod (d / diverse~e.1) :mod (t / this~e.0)) :ARG1 (l / link-01~e.7 :mod (c / common~e.6)) :ARG2~e.8 (s3 / signal-07~e.20 :ARG0 (a / and~e.18 :op1 (p / protein :name (n / name :op1 "transforming"~e.9 :op2 "growth"~e.10 :op3 "factor-β"~e.11)) :op2 (p2 / protein :name (n2 / name :op1 "tumour"~e.15 :op2 "necrosis"~e.16 :op3 "factor-α"~e.17)) :op3 (p3 / protein :name (n3 / name :op1 "NFκB"~e.19))))) # ::id pmid_2352_4590.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The role of these genes in MM and their potential predictive value for MEK inhibitor responsiveness has not been appraised . # ::alignments 1-1.2.1 2-1.2.1.1.r 3-1.2.1.1.1 4-1.2.1.1 5-1.2.1.2.r 6-1.2.1.2.1.1 6-1.2.1.2.1.2 7-1.2 8-1.2.2.3 8-1.2.2.3.r 9-1.2.2.2 10-1.2.2.1 11-1.2.2 13-1.2.2.1.2.1.1.1.1.1 14-1.2.2.1.2.1 14-1.2.2.1.2.1.1 14-1.2.2.1.2.1.1.r 17-1.1 17-1.1.r 19-1 (a / appraise-02~e.19 :polarity~e.17 -~e.17 :ARG1 (a2 / and~e.7 :op1 (r / role~e.1 :poss~e.2 (g / gene~e.4 :mod (t / this~e.3)) :topic~e.5 (d / disease :name (n / name :op1 "multiple"~e.6 :op2 "myeloma"~e.6))) :op2 (v / value~e.11 :mod (p / predict-01~e.10 :ARG0 g :ARG1 (r2 / responsive-02 :ARG1 (m / molecular-physical-entity~e.14 :ARG0-of~e.14 (i / inhibit-01~e.14 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"~e.13)))))) :mod (p2 / potential~e.9) :poss~e.8 g~e.8))) # ::id pmid_2352_4590.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recent data published by Annuziata et al. @ ^{99 @} has reported the use of the musculoaponeurotic fibrosarcoma ( MAF ) oncogene as a potential biomarker for MEK inhibitor responses in MM . # ::alignments 0-1.1.1 1-1.1 2-1.1.2 2-1.1.2.1 2-1.1.2.1.r 4-1.1.2.1.1.1.1.1 6-1.1.2.1.1 7-1.1.2.1.1.2.1 11-1.1.2.1.2.1 15-1 17-1.2 18-1.2.1.r 20-1.2.1.1.1 21-1.2.1.1.2 26-1.1.1.r 26-1.2.2.r 28-1.2.2.1 29-1.2.2 30-1.2.2.2.r 31-1.2.2.2.1.1.1.1.1.1 32-1.2.2.2.1.1 32-1.2.2.2.1.1.1 32-1.2.2.2.1.1.1.r 33-1.2.2.2 33-1.2.2.2.1 33-1.2.2.2.1.r 34-1.2.2.2.1.2.r 35-1.2.2.2.1.2.1.1 35-1.2.2.2.1.2.1.2 (r / report-01~e.15 :ARG0 (d / data~e.1 :time~e.26 (r2 / recent~e.0) :ARG1-of (p / publish-01~e.2 :ARG0~e.2 (p2 / publication-91~e.2 :ARG0 (a / and~e.6 :op1 (p3 / person :name (n / name :op1 "Annuziata"~e.4)) :op2 (p4 / person :mod (o / other~e.7))) :ARG1-of (c / cite-01 :ARG2 99~e.11)))) :ARG1 (u / use-01~e.17 :ARG0~e.18 (g / gene :name (n5 / name :op1 "musculoaponeurotic"~e.20 :op2 "fibrosarcoma"~e.21) :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))) :ARG2~e.26 (b / biomarker~e.29 :mod (p5 / potential~e.28) :purpose~e.30 (t / thing~e.33 :ARG2-of~e.33 (r3 / respond-01~e.33 :ARG0 (m / molecular-physical-entity~e.32 :ARG0-of~e.32 (i / inhibit-01~e.32 :ARG1 (p6 / protein-family :name (n3 / name :op1 "MEK"~e.31)))) :location~e.34 (d2 / disease :name (n4 / name :op1 "multiple"~e.35 :op2 "myeloma"~e.35))))))) # ::id pmid_2352_4590.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In approximately 10 % of cases , aberrant MAF expression is due to a ( 14;16 ) translocation . # ::alignments 1-1.3.2.2 2-1.3.2.1 3-1.3.2 5-1.3.1 7-1.2.2 8-1.2.1.1.1 9-1.2 11-1 12-1 17-1.1 (c / cause-01~e.11,12 :ARG0 (t / translocate-01~e.17 :ARG1 (a / and :op1 (c2 / chromosome :mod 14) :op2 (c3 / chromosome :mod 16))) :ARG1 (e / express-03~e.9 :ARG2 (p / protein :name (n3 / name :op1 "MAF"~e.8)) :mod (a2 / aberrant~e.7)) :ARG1-of (i / include-91 :ARG2 (c4 / case-04~e.5) :ARG3 (p2 / percentage-entity~e.3 :value 10~e.2 :ARG1-of (a3 / approximate-01~e.1)))) # ::id pmid_2352_4590.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High levels of MAF were also observed in patient samples with t( 4;14 ) translocations . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.3 6-1 7-1.2.r 8-1.2.1.1.1 9-1.2 14-1.2.2 (o / observe-01~e.6 :ARG1 (l / level~e.1 :quant-of~e.2 (p / protein :name (n / name :op1 "MAF"~e.3)) :ARG1-of (h / high-02~e.0)) :location~e.7 (s / sample-01~e.9 :ARG2 (p2 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient~e.8))) :location-of (t / translocate-01~e.14 :ARG1 (a / and :op1 (c / chromosome :mod 4) :op2 (c2 / chromosome :mod 14)))) :mod (a2 / also~e.5)) # ::id pmid_2352_4590.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both t( 4 @:@ 16 ) and t( 4;14 ) translocations correlate with disease progression and worse overall survival . # ::alignments 2-1.1.1.1.1.1 4-1.1.1.1.2.1 6-1.1 6-1.1.1.1 6-1.1.2.1 10-1.1.1 10-1.1.2 11-1 12-1.2.r 13-1.2.1.1 14-1.2.1 15-1.2 16-1.2.2.2 16-1.2.2.2.1 16-1.2.2.2.1.r 17-1.2.2.1 18-1.2.2 (c / correlate-01~e.11 :ARG1 (a / and~e.6 :op1 (t / translocate-01~e.10 :ARG1 (a2 / and~e.6 :op1 (c2 / chromosome :mod 4~e.2) :op2 (c3 / chromosome :mod 16~e.4))) :op2 (t2 / translocate-01~e.10 :ARG1 (a3 / and~e.6 :op1 c2 :op2 (c4 / chromosome :mod 14)))) :ARG2~e.12 (a4 / and~e.15 :op1 (p / progress-01~e.14 :ARG1 (d / disease~e.13)) :op2 (s / survive-01~e.18 :mod (o / overall~e.17) :ARG1-of (b / bad-07~e.16 :degree~e.16 (m / more~e.16))))) # ::id pmid_2352_4590.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MEK @/@ ERK pathway was found to regulate transcription of the MAF proto @-@ oncogene through ERK activation of FOS , a finding consistent with MAF protein and mRNA levels being downregulated following MEK inhibition . # ::alignments 1-1.2.1.2.1.1.1.1 3-1.1.3.1.1.1 4-1.1.1 6-1 8-1.1 9-1.1.2 10-1.1.2.1.r 12-1.1.2.1.1 13-1.1.2.1 15-1.1.2.1 17-1.1.3.1.1.1 18-1.1.3 19-1.1.3.2.r 20-1.1.3.2.1.1 23-1 24-1.2 26-1.2.1.1.1.1.1.1 27-1.2.1.1.1.1 28-1.2.1.1 29-1.2.1.1.2.1.1.1 30-1.2.1.1.1 30-1.2.1.1.2 32-1.2.1 33-1.2.1.2 34-1.2.1.2.1.1.1.1 35-1.2.1.2.1 (f / find-01~e.6,23 :ARG1 (r / regulate-01~e.8 :ARG0 (p / pathway~e.4 :name (n / name :op1 "MEK/ERK")) :ARG1 (t / transcribe-01~e.9 :ARG1~e.10 (p2 / proto-oncogene~e.13,15 :mod p3~e.12)) :manner (a / activate-01~e.18 :ARG0 (e / enzyme :name (n3 / name :op1 "ERK"~e.3,17)) :ARG1~e.19 (e3 / enzyme :name (n4 / name :op1 "FOS"~e.20)))) :ARG1-of (c / consistent-01~e.24 :ARG2 (d / downregulate-01~e.32 :ARG1 (a2 / and~e.28 :op1 (l / level~e.30 :quant-of (p3 / protein~e.27 :name (n5 / name :op1 "MAF"~e.26))) :op2 (l2 / level~e.30 :quant-of (n8 / nucleic-acid :name (n6 / name :op1 "mRNA"~e.29)))) :ARG1-of (f2 / follow-01~e.33 :ARG2 (i / inhibit-01~e.35 :ARG1 (e2 / enzyme :name (n7 / name :op1 "MEK"~e.1,34))))))) # ::id pmid_2352_4590.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the dependence of MM cells on MEK @/@ ERK signalling , U0126 was administered to 16 HMCL that represented the heterogeneous onco @-@ genetics of the disease . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1.1 5-1.3.1.1.1.1.2 6-1.3.1.1 7-1.3.1.2.r 8-1.3.1.2.1.1.1 10-1.3.1.2.1.1.1 11-1.3.1.2 13-1.1.1.1 15-1 16-1.2.r 17-1.2.1 18-1.2.2.1 20-1.2.3 22-1.2.3.1.1 28-1.2.3.1.2 (a / administer-01~e.15 :ARG1 (s / small-molecule :name (n / name :op1 "U0126"~e.13)) :ARG2~e.16 (c / cell-line :quant 16~e.17 :name (n2 / name :op1 "HMCL"~e.18) :ARG0-of (r / represent-01~e.20 :ARG1 (o / oncogenetics :mod (h / heterogeneity~e.22) :poss (d / disease~e.28)))) :purpose (e / examine-01~e.1 :ARG1 (d2 / depend-01~e.3 :ARG0~e.4 (c2 / cell~e.6 :mod (d4 / disease :name (n3 / name :op1 "multiple"~e.5 :op2 "myeloma"~e.5))) :ARG1~e.7 (s2 / signal-07~e.11 :ARG0 (p / pathway :name (n5 / name :op1 "MEK/ERK"~e.8,10)))))) # ::id pmid_2352_4590.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the 10 HMCL killed by this MEK inhibitor in a dose @-@ dependent manner , 9 cell lines exhibited a t( 4;16 ) or t( 4;14 ) translocation and over expressed MAF . # ::alignments 2-1.3.1.1 4-1.3.1.2 5-1.3.1.2.1.r 6-1.3.1.2.1.2 7-1.3.1.2.1.1.1.1.1 8-1.3.1.2.1 8-1.3.1.2.1.1 8-1.3.1.2.1.1.r 9-1.3.1.2.2.r 11-1.3.1.2.2.1 13-1.3.1.2.2 16-1.1.1.1 17-1.1.1 17-1.3.1 18-1.1.1 19-1.1 24-1.1.2 28-1.1.2.1 28-1.1.2.2 29-1 29-1.1.2.1.1 29-1.1.2.2.1 32-1.2.1.1.1 (a / and~e.29 :op1 (e / exhibit-01~e.19 :ARG0 (c / cell-line~e.17,18 :quant 9~e.16) :ARG1 (o / or~e.24 :op1 (t / translocate-01~e.28 :value (a2 / and~e.29 :op1 4 :op2 16)) :op2 (t2 / translocate-01~e.28 :value (a3 / and~e.29 :op1 4 :op2 14)))) :op2 (o2 / overexpress-01 :ARG1 (p2 / protein :name (n / name :op1 "MAF"~e.32)) :location c) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.17 :quant 10~e.2 :ARG1-of (k / kill-01~e.4 :ARG0~e.5 (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (i2 / inhibit-01~e.8 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"~e.7))) :mod (t3 / this~e.6)) :ARG0-of~e.9 (d / depend-01~e.13 :ARG1 (d2 / dose-01~e.11))) :mod (d3 / disease :name (n2 / name :op1 "myeloma") :mod (h / human))))) # ::id pmid_2352_4590.226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , the cytotoxic effect of U0126 was not neutralised by the presence of bone marrow stromal cells and remarkably , the impact of MEK inhibition on MM viability could be rescued by exogenous MAF expression . # ::alignments 0-1 0-1.1 0-1.1.r 4-1.1.1.3 5-1.1.1.3.1.r 6-1.1.1.3.1.1.1 8-1.1.1.1 8-1.1.1.1.r 12-1.1.1.2 13-1.1.1.2.1.r 14-1.1.1.2.1.2.1 15-1.1.1.2.1.2 16-1.1.1.2.1.1 17-1.1.1.2.1 18-1.1 19-1.1.2.2 22-1.1.2.1.2 23-1.1.2.1.2.1.r 24-1.1.2.1.2.1.1.1.1 25-1.1.2.1.2.1 26-1.1.2.1.2.2.r 27-1.1.2.1.2.2.1.1.1 27-1.1.2.1.2.2.1.1.2 28-1.1.2.1.2.2 29-1.1.2 31-1.1.2.1 32-1.1.2.1.1.r 33-1.1.2.1.1.2 34-1.1.2.1.1.1.1.1 35-1.1.2.1.1 (a / and~e.0 :op2~e.0 (a2 / and~e.0,18 :op1 (n / neutralize-01 :polarity~e.8 -~e.8 :ARG0 (p / present-02~e.12 :ARG1~e.13 (c / cell~e.17 :mod (s / stromal~e.16) :part-of (m / marrow~e.15 :mod (b / bone~e.14)))) :ARG1 (a3 / affect-01~e.4 :ARG0~e.5 (s2 / small-molecule :name (n2 / name :op1 "U0126"~e.6)) :ARG2 (c2 / cytotoxicity))) :op2 (p2 / possible-01~e.29 :ARG1 (r / rescue-01~e.31 :ARG0~e.32 (e / express-03~e.35 :ARG2 (p3 / protein :name (n3 / name :op1 "MAF"~e.34)) :mod (e2 / exogenous~e.33)) :ARG1 (i / impact-01~e.22 :ARG0~e.23 (i2 / inhibit-01~e.25 :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK"~e.24))) :ARG1~e.26 (v / viability~e.28 :mod (d2 / disease :name (n6 / name :op1 "multiple"~e.27 :op2 "myeloma"~e.27))))) :ARG1-of (r2 / remarkable-02~e.19)))) # ::id pmid_2352_4590.227 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , this study provides a mechanistic rationale for using MEK inhibitor therapy in MM patients that overexpress c @-@ MAF . # ::alignments 0-1.4 2-1.1.1 3-1.1 4-1 6-1.2.1 7-1.2 8-1.3.r 9-1.3 10-1.3.1.1.1.1.1.1 11-1.3.1.1 11-1.3.1.1.1 11-1.3.1.1.1.r 12-1.3.1 13-1.3.2.r 14-1.3.2.3.1.1 14-1.3.2.3.1.2 15-1.3.2.1.1 17-1.3.2.2 18-1.3.2.2.1.1.1 20-1.3.2.2.1.1.1 (p / provide-01~e.4 :ARG0 (s / study-01~e.3 :mod (t / this~e.2)) :ARG1 (r / rationale~e.7 :mod (m / mechanism~e.6)) :ARG2~e.8 (u / use-01~e.9 :ARG1 (t2 / therapy~e.12 :mod (m2 / molecular-physical-entity~e.11 :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1 (p5 / protein-family :name (n / name :op1 "MEK"~e.10))))) :location~e.13 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.15)) :location-of (o / overexpress-01~e.17 :ARG1 (p4 / protein :name (n3 / name :op1 "c-MAF"~e.18,20))) :mod (d2 / disease :name (n4 / name :op1 "multiple"~e.14 :op2 "myeloma"~e.14)))) :mod (i2 / important~e.0)) # ::id pmid_2352_4590.228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings emphasise the potential benefit of genetic profiling to identify patients with MAF @-@ expressing MM who may benefit from this class of agents . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.1 8-1.2.1 10-1.2.1.2 11-1.2.1.2.1.1.1 13-1.2.1.2.1.2.1.1.1.1.1 15-1.2.1.2.1.2.1.1 16-1.2.1.2.1.2.1.2.1.1 16-1.2.1.2.1.2.1.2.1.2 18-1.2.1.2.1.3.2 19-1.2.1.2.1.3 20-1.2.1.2.1.3.1.r 21-1.2.1.2.1.3.1.2 22-1.2.1.2.1.3.1 23-1.2.1.2.1.3.1.1.r 24-1.2.1.2.1.3.1.1 (e / emphasize-01 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :mod (t2 / this~e.0)) :ARG1 (b / benefit-01~e.5 :ARG0~e.6 (p / profile-01~e.8 :mod (g / genetics~e.7) :ARG0-of (i / identify-01~e.10 :ARG1 (p3 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p4 / patient~e.11)) :ARG0-of (h2 / have-03 :ARG1 (c / cell :ARG3-of (e2 / express-03~e.15 :ARG2 (p5 / protein :name (n2 / name :op1 "MAF"~e.13))) :mod (d2 / disease :name (n3 / name :op1 "multiple"~e.16 :op2 "myeloma"~e.16)))) :ARG1-of (b2 / benefit-01~e.19 :ARG0~e.20 (c2 / class~e.22 :mod~e.23 (a / agent~e.24) :mod (t3 / this~e.21)) :ARG1-of (p6 / possible-01~e.18))))) :mod (p2 / potential~e.4))) # ::id pmid_2352_4590.229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As part of the phase II trial of AZD6244 in relapsed @/@ refractory MM , extensive molecular profiling of a subset of patients was conducted to correlate the genetic characteristics of MM with clinical outcomes . # ::alignments 1-1.3.r 4-1.3.2 5-1.3.2.1 6-1.3 7-1.3.1.r 8-1.3.1.1.1 9-1.3.3.r 10-1.3.3.1.2 11-1.3.3 12-1.3.3.2.2 13-1.3.3.2.1.1 13-1.3.3.2.1.2 15-1.1.3 16-1.1.2 17-1.1 18-1.1.1.r 20-1.1.1 21-1.1.1.1.r 22-1.1.1.1.1.1 24-1 26-1.2 28-1.2.1.2 29-1.2.1 31-1.2.1.1.1.1 31-1.2.1.1.1.2 31-1.3.3.1.1.1 31-1.3.3.1.1.2 32-1.2.2.r 33-1.2.2.1 34-1.2.2 (c / conduct-01~e.24 :ARG1 (p / profile-01~e.17 :ARG1~e.18 (s / subset~e.20 :consist-of~e.21 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.22)))) :mod (m / molecule~e.16) :ARG1-of (e / extensive-03~e.15)) :purpose (c2 / correlate-01~e.26 :ARG1 (c3 / characteristic-02~e.29 :ARG1 (d4 / disease :name (n5 / name :op1 "multiple"~e.31 :op2 "myeloma"~e.31)) :ARG2 (g / genetics~e.28)) :ARG2~e.32 (o / outcome~e.34 :mod (c4 / clinic~e.33))) :part-of~e.1 (t / trial-06~e.6 :ARG2~e.7 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"~e.8)) :mod (p4 / phase~e.4 :value 2~e.5) :condition~e.9 (s3 / slash~e.11 :op1 (d / disease :name (n / name :op1 "multiple"~e.31 :op2 "myeloma"~e.31) :ARG1-of (r2 / relapse-01~e.10)) :op2 (d2 / disease :name (n3 / name :op1 "multiple"~e.13 :op2 "myeloma"~e.13) :mod (r / refractory~e.12))))) # ::id pmid_2352_4590.230 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To date , detailed clinical data from eight patients has been analysed , four of whom overexpress c @-@ MAF or MAF @-@ B . # ::alignments 0-1.2 1-1.2 3-1.1.2 4-1.1.1 5-1.1 6-1.1.3.r 7-1.1.3.1 8-1.1.3.2.1 9-1.1.3.2 11-1 13-1.1.3.3.1.1 16-1.1.3.3.1.3 17-1.1.3.3.1.3.1.1.1.1 19-1.1.3.3.1.3.1.1.1.1 19-1.1.3.3.1.3.1.2.1.1 20-1.1.3.3.1.3.1 21-1.1.3.3.1.3.1.1.1.1 21-1.1.3.3.1.3.1.2.1.1 23-1.1.3.3.1.3.1.2.1.1 (a / analyze-01~e.11 :ARG1 (d / data~e.5 :mod (c / clinic~e.4) :ARG1-of (d2 / detail-01~e.3) :source~e.6 (p / person :quant 8~e.7 :ARG0-of (h / have-rel-role-91~e.9 :ARG2 (p2 / patient~e.8)) :ARG2-of (i / include-91 :ARG1 (p3 / person :quant 4~e.13 :ARG0-of h :location-of (o / overexpress-01~e.16 :ARG1 (o2 / or~e.20 :op1 (p4 / protein :name (n / name :op1 "c-MAF"~e.17,19,21)) :op2 (p5 / protein :name (n2 / name :op1 "MAF-B"~e.19,21,23)))))))) :time (t / to-date~e.0,1)) # ::id pmid_2352_4590.231 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One patient ( fibroblast growth factor receptor 3 ) had a very good PR lasting 8 months . # ::alignments 0-1.1.1 1-1.1.2.1 3-1.1.3.1.1 4-1.1.3.1.2 5-1.1.3.1.3 6-1.1.3.1.4 7-1.1.3.1.4 9-1 11-1.2.2.1 12-1.2 12-1.2.2 12-1.2.2.r 14-1.2.3.r 15-1.2.3.1 16-1.2.3.2 (h / have-03~e.9 :ARG0 (p / person :quant 1~e.0 :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.1)) :mod (p3 / protein :name (n / name :op1 "fibroblast"~e.3 :op2 "growth"~e.4 :op3 "factor"~e.5 :op4 "receptor-3"~e.6,7))) :ARG1 (t / thing~e.12 :ARG2-of (r / respond-01 :degree (p4 / part)) :ARG1-of~e.12 (g / good-02~e.12 :degree (v / very~e.11)) :duration~e.14 (t2 / temporal-quantity :quant 8~e.15 :unit (m / month~e.16)))) # ::id pmid_2352_4590.232 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Another patient ( MAF @-@ B ) had a PR of 6 months . # ::alignments 0-1.1.3 1-1.1.1.1 3-1.1.2.1.1 5-1.1.2.1.1 7-1 10-1.2.r 11-1.2.1.1.1 12-1.2.1.1.2 (h / have-03~e.7 :ARG0 (p / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p2 / patient~e.1)) :mod (p3 / protein :name (n / name :op1 "MAF-B"~e.3,5)) :mod (a / another~e.0)) :ARG1~e.10 (t / thing :ARG2-of (r / respond-01 :duration (t2 / temporal-quantity :quant 6~e.11 :unit (m / month~e.12)) :degree (p4 / part)))) # ::id pmid_2352_4590.233 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , two patients ( one MAF @-@ B , one pending results ) demonstrated s.d . of > 5 and 13 months , respectively . @^{100 @} # ::alignments 0-1.4 3-1.1.1.2.1 5-1.1.1.1 6-1.1.1.3.1.1 8-1.1.1.3.1.1 10-1.1.1.1 10-1.2.1.1 11-1.2.1.3.2 12-1.2.1.3 12-1.2.1.3.1 12-1.2.1.3.1.r 14-1.1 14-1.2 17-1.1.2.r 18-1.1.2.1 19-1.1.2.1.1.1 20-1 21-1.2.2.1.1 22-1.2.2.1.2 28-1.3.1.1.1 (a3 / and~e.20 :op1 (d / demonstrate-01~e.14 :ARG0 (p / person :quant 1~e.5,10 :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.3)) :mod (p4 / protein :name (n / name :op1 "MAF-B"~e.6,8))) :ARG1~e.17 (d4 / disease :duration (m2 / more-than~e.18 :op1 (t4 / temporal-quantity :quant 5~e.19 :unit m3)) :ARG1-of (s / stable-03))) :op2 (d3 / demonstrate-01~e.14 :ARG0 (p5 / person :quant 1~e.10 :ARG0-of h :mod (t / thing~e.12 :ARG2-of~e.12 (r / result-01~e.12) :ARG1-of (p6 / pend-01~e.11))) :ARG1 (d5 / disease :duration (t3 / temporal-quantity :quant 13~e.21 :unit (m3 / month~e.22)) :ARG1-of (s2 / stable-03))) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c / cite-01 :ARG2 100~e.28))) :mod (f / final~e.0)) # ::id pmid_2352_4590.234 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additional studies with larger sample sizes are required to support or refute MAF expression as a reliable biomarker for MEK inhibition . # ::alignments 1-1.1.1.1 2-1.1.1.1.2.r 3-1.1.1.1.2 3-1.1.1.1.2.2 3-1.1.1.1.2.2.1 3-1.1.1.1.2.2.1.r 3-1.1.1.1.2.2.r 4-1.1.1.1.2.1 4-1.1.1.1.2.1.1 4-1.1.1.1.2.1.1.r 5-1.1.1.1.2 7-1 9-1.1.1 10-1.1 11-1.1.2 12-1.1.1.2.1.1.1 13-1.1.1.2 14-1.1.1.2.2.r 16-1.1.1.2.2.1 16-1.1.1.2.2.1.1 16-1.1.1.2.2.1.1.r 17-1.1.1.2.2 18-1.1.1.2.2.2.r 19-1.1.1.2.2.2.1.1.1 20-1.1.1.2.2.2 (r / require-01~e.7 :ARG0 (o / or~e.10 :op1 (s / support-01~e.9 :ARG0 (s2 / study-01~e.1 :ARG1-of (a / add-02) :mod~e.2 (s3 / size-01~e.3,5 :ARG1 (t / thing~e.4 :ARG1-of~e.4 (s4 / sample-01~e.4)) :ARG2~e.3 (l / large~e.3 :degree~e.3 (m / more~e.3)))) :ARG1 (e / express-03~e.13 :ARG2 (p / protein :name (n / name :op1 "MAF"~e.12)) :mod~e.14 (b / biomarker~e.17 :ARG1-of (r2 / rely-01~e.16 :ARG1-of~e.16 (p2 / possible-01~e.16)) :purpose~e.18 (i / inhibit-01~e.20 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK"~e.19)))))) :op2 (r3 / refute-01~e.11 :ARG0 s2 :ARG1 e)) :ARG1 s2) # ::id pmid_2352_4590.235 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conclusion # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG1-of~e.1 (c / conclude-01~e.1)) # ::id pmid_2352_4590.236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ras/Raf/MEK/ERK pathway has an established role in the various neoplastic phenotypes observed in many malignancies . # ::alignments 1-1.1.1.1 2-1.1 3-1 5-1.2.2 6-1.2 7-1.2.1.r 9-1.2.1.2 10-1.2.1.1 11-1.2.1 12-1.2.1.3 13-1.2.1.3.1.r 14-1.2.1.3.1.1 15-1.2.1.3.1 (h / have-03~e.3 :ARG0 (p / pathway~e.2 :name (n / name :op1 "Ras/Raf/MEK/ERK"~e.1)) :ARG1 (r / role~e.6 :topic~e.7 (p2 / phenotype~e.11 :mod (n2 / neoplasm~e.10) :mod (v / various~e.9) :ARG1-of (o / observe-01~e.12 :location~e.13 (m / malignancy~e.15 :quant (m2 / many~e.14)))) :ARG1-of (e / establish-01~e.5))) # ::id pmid_2352_4590.237 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Deregulation of this pathway is also a common feature of MM , and contributes to the relapsing and refractory nature of the disease . # ::alignments 0-1.2.1 1-1.2.1 2-1.2.1 3-1.2.1 4-1.2.1 5-1.2.1 6-1.2.1 7-1.2.1 8-1.2.1 9-1.2.1 10-1.2.1 12-1 13-1.2 14-1.2.2.r 16-1.2.2.1 17-1.2.2 18-1.2.2.2 20-1.2.2.2.1.r 22-1.2.2.2.1 (a / and~e.12 :op1 (f / feature :domain (d / deregulate-01 :ARG1 (p / pathway :mod (t / this))) :mod (c / common) :mod (a2 / also) :mod (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :op2 (c2 / contribute-01~e.13 :ARG0 f~e.0,1,2,3,4,5,6,7,8,9,10 :ARG2~e.14 (a3 / and~e.17 :op1 (r / relapse-01~e.16 :ARG1 d3) :op2 (r2 / refractory~e.18 :domain~e.20 d3~e.22)))) # ::id pmid_2352_4590.238 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These observations make this pathway an attractive target for pharmaceutical investigation , with a number of MEK inhibitors having been developed and evaluated clinically . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.2.1 4-1.2.2 6-1.2.3 7-1.2 8-1.2.1.r 9-1.2.1.1 10-1.2.1 12-1.3.r 14-1.3.1.1 15-1.3.1.1.1.r 16-1.3.1.1.1.1.1.1.1 17-1.3.1.1.1 17-1.3.1.1.1.1 17-1.3.1.1.1.1.r 20-1.3.1 21-1.3 22-1.3.2 23-1.3.3 23-1.3.3.r (m / make-02~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1 (t2 / target-01~e.7 :ARG0~e.8 (i / investigate-01~e.10 :mod (p / pharmaceutical~e.9)) :ARG1 (p2 / pathway~e.4 :mod t~e.3) :ARG2-of (a / attract-01~e.6)) :accompanier~e.12 (a2 / and~e.21 :op1 (d / develop-02~e.20 :ARG1 (n / number~e.14 :quant-of~e.15 (m2 / molecular-physical-entity~e.17 :ARG0-of~e.17 (i2 / inhibit-01~e.17 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"~e.16)))))) :op2 (e2 / evaluate-01~e.22 :ARG1 n) :manner~e.23 (c / clinical~e.23))) # ::id pmid_2352_4590.239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although preclinical studies of MEK inhibitors in MM have demonstrated a capacity to induce MM apoptosis by overcoming the prosurvival effects of the BMME , solid tumour studies indicate that the therapeutic benefit of MEK inhibitors alone are likely to be of limited benefit . # ::alignments 0-1 1-1.2.1.2 2-1.2.1 3-1.2.1.1.r 4-1.2.1.1 5-1.2.1.1 6-1.2.1.3.r 7-1.2.1.3.1.1 7-1.2.1.3.1.2 9-1.2 11-1.2.2 13-1.2.2.2 14-1.2.2.2.2.1.1 15-1.2.2.2.2 16-1.2.2.2.3.r 17-1.2.2.2.3 20-1.2.2.2.3.1 25-1.1.1.1.1 26-1.1.1.1 27-1.1.1 28-1.1 29-1.1.2.r 31-1.1.2.1.1.2 32-1.1.2.1.1 33-1.1.2.1.1.1.r 34-1.1.2.1.1.1.1.1.1.1 35-1.1.2.1.1.1 35-1.1.2.1.1.1.1 35-1.1.2.1.1.1.1.r 36-1.1.2.1.1.3 38-1.1.2 42-1.1.2.1.2 43-1.1.2.1 (h / have-concession-91~e.0 :ARG1 (i / indicate-01~e.28 :ARG0 (s / study-01~e.27 :ARG1 (t / tumor~e.26 :ARG1-of (s2 / solid-02~e.25))) :ARG1~e.29 (l / likely-01~e.38 :ARG1 (b / benefit-01~e.43 :ARG0 (b2 / benefit-01~e.32 :ARG0~e.33 (m / molecular-physical-entity~e.35 :ARG0-of~e.35 (i2 / inhibit-01~e.35 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.34)))) :mod (t2 / therapy~e.31) :mod (a / alone~e.36)) :ARG1-of (l2 / limit-01~e.42)))) :ARG2 (d / demonstrate-01~e.9 :ARG0 (s3 / study-01~e.2 :ARG1~e.3 m~e.4,5 :mod (p / preclinical~e.1) :location~e.6 (d3 / disease :name (n4 / name :op1 "multiple"~e.7 :op2 "myeloma"~e.7))) :ARG1 (c / capable-01~e.11 :ARG1 m :ARG2 (i3 / induce-01~e.13 :ARG0 m :ARG2 (a2 / apoptosis~e.15 :mod (c2 / cell :mod d3~e.14)) :manner~e.16 (o / overcome-01~e.17 :ARG1 (a3 / affect-01~e.20 :ARG0 (m2 / microenvironment :mod (m3 / marrow :part-of (b3 / bone))) :ARG2 (f / favor-01 :ARG1 (s4 / survive-01)))))))) # ::id pmid_2352_4590.240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , future clinical approaches require a shift towards using MEK inhibitors in combination with current anti @-@ MM compounds and other novel small molecule inhibitors . # ::alignments 0-1 2-1.1.1.2 3-1.1.1.1 4-1.1.1 5-1.1 7-1.1.2 9-1.1.2.2 10-1.1.2.2.1.1.1.1.1 11-1.1.2.2.1.2.1.2.1 13-1.1.2.2.1.2 14-1.1.2.2.1.2.1.r 15-1.1.2.2.1.2.1.1.2 16-1.1.2.2.1.2.1.1.1 18-1.1.2.2.1.2.1.1.1.1.1.1 18-1.1.2.2.1.2.1.1.1.1.1.2 19-1.1.2.2.1.2.1.1 20-1.1.2.2.1.2.1 21-1.1.2.2.1.2.1.2.3 22-1.1.2.2.1.2.1.2.2 23-1.1.2.2.1.2.1.2 24-1.1.2.2.1 24-1.1.2.2.1.2.1.2 25-1.1.2.2.1.1 (c / cause-01~e.0 :ARG1 (r / require-01~e.5 :ARG0 (a / approach-01~e.4 :mod (c2 / clinic~e.3) :time (f / future~e.2)) :ARG1 (s / shift-01~e.7 :ARG1 a :ARG2 (u / use-01~e.9 :ARG1 (m / molecular-physical-entity~e.24 :ARG0-of (i / inhibit-01~e.25 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.10))) :ARG1-of (c3 / combine-01~e.13 :ARG2~e.14 (a2 / and~e.20 :op1 (c4 / compound~e.19 :ARG0-of (c5 / counter-01~e.16 :ARG1 (d2 / disease :name (n4 / name :op1 "multiple"~e.18 :op2 "myeloma"~e.18))) :mod (c6 / current~e.15)) :op2 (s2 / small-molecule~e.23,24 :ARG0-of (i2 / inhibit-01~e.11) :mod (n3 / novel~e.22) :mod (o / other~e.21))))))))) # ::id pmid_2352_4590.241 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The identification of relevant biomarkers of MEK inhibitor responses remains a high priority that can be used to predict patient sensitivity and to tailor individualised therapies . # ::alignments 1-1.1 3-1.1.1.1 6-1.1.1.2.1.1.1.1.1.1 7-1.1.1.2.1.1 7-1.1.1.2.1.1.1 7-1.1.1.2.1.1.1.r 8-1.1.1.2 8-1.1.1.2.1 8-1.1.1.2.1.r 9-1 11-1.2.1 12-1.2 14-1.2.2.2 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1.1 19-1.2.2.1.1.1.1.1.1 20-1.2.2.1.1.1 21-1.2.2.1 23-1.2.2.1.2 25-1.2.2.1.2.1 (r / remain-01~e.9 :ARG1 (i / identify-01~e.1 :ARG1 (b / biomarker :ARG1-of (r2 / relevant-01~e.3) :mod (t / thing~e.8 :ARG2-of~e.8 (r3 / respond-01~e.8 :ARG0 (m / molecular-physical-entity~e.7 :ARG0-of~e.7 (i2 / inhibit-01~e.7 :ARG1 (p6 / protein-family :name (n / name :op1 "MEK"~e.6)))))))) :ARG3 (p / priority~e.12 :ARG1-of (h / high-02~e.11) :ARG1-of (u / use-01~e.16 :ARG2~e.17 (a / and~e.21 :op1 (p2 / predict-01~e.18 :ARG1 (s / sensitive-03~e.20 :ARG0 (p3 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p4 / patient~e.19))))) :op2 (t2 / tailor-01~e.23 :ARG1 (t3 / therapy~e.25 :ARG1-of (i3 / individualize-02)))) :ARG1-of (p5 / possible-01~e.14)))) # ::id pmid_2354_8132.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High resolution melting analysis of KRAS , BRAF and PIK3CA in KRAS exon 2 wild @-@ type metastatic colorectal cancer ( PMID : 23548132 ) # ::alignments 0-1.2.1.1 1-1.2.1 2-1.2 3-1 6-1.1.1.1.1 10-1.1.2.1.1 12-1.1 14-1.1.3.1.1 18-1.1.1.1.1 20-1.4.5 21-1.4.5.1 22-1.4.4 24-1.4.4 25-1.4.3 26-1.4.2.1 27-1.4.2.2 (a / analyze-01~e.3 :ARG1 (a2 / and~e.12 :op1 (g / gene :name (n / name :op1 "KRAS"~e.6,18)) :op2 (g2 / gene :name (n2 / name :op1 "BRAF"~e.10)) :op3 (g3 / gene :name (n3 / name :op1 "PIK3CA"~e.14))) :manner (m2 / melt-01~e.2 :mod (r / resolution~e.1 :ARG1-of (h / high-02~e.0))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMID23548132")) :location (d4 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colorectal"~e.26 :op2 "cancer"~e.27) :ARG1-of (m / metastasize-101~e.25) :mod (w / wild-type~e.22,24) :mod (e / exon~e.20 :mod 2~e.21 :part-of g))) # ::id pmid_2354_8132.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2354_8132.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One mutation was present in 23.4 % ( 47 @/@ 201 ) of the cases and 3.0 % additional cases ( 6 @/@ 201 ) had two concomitant mutations . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.2.2.1 6-1.1.2.2.2 8-1.1.2.1 10-1.1.2.2.1.1 14-1.1.2 14-1.1.2.2.1 15-1 16-1.2.1.2.2.1 17-1.2.1.2.2 19-1.2.1 21-1.2.1.1 23-1.1.2.2.1.1 25-1.2 26-1.2.2.1 27-1.2.2.2 28-1.2.2 (a / and~e.15 :op1 (p / present-02~e.3 :ARG1 (m / mutate-01~e.1 :quant 1~e.0) :ARG2~e.4 (c / case-04~e.14 :quant 47~e.8 :ARG1-of (i / include-91 :ARG2 (c2 / case-04~e.14 :quant 201~e.10,23) :ARG3 (p2 / percentage-entity~e.6 :value 23.4~e.5)))) :op2 (h / have-03~e.25 :ARG0 (c3 / case-04~e.19 :quant 6~e.21 :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p3 / percentage-entity~e.17 :value 3.0~e.16)) :ARG1-of (a2 / add-02)) :ARG1 (m2 / mutate-01~e.28 :quant 2~e.26 :mod (c4 / concomitant~e.27)))) # ::id pmid_2354_8132.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A total of 53 cases showed 59 mutations , with the following distribution : 44.1 % ( 26 @/@ 59 ) in KRAS ( 13 in exon 3 and 13 in exon 4 ) , 18.6 % ( 11 @/@ 59 ) in BRAF ( two in exon 11 and nine in exon 15 ) and 37.3 % ( 22 @/@ 59 ) in PIK3CA ( 16 in exon 9 and six in exon 20 ) . # ::alignments 1-1.1.2 3-1.1.1 4-1.1 5-1 6-1.2.1 7-1.2 7-1.2.2.1.1 7-1.2.2.1.1.4.1.1 7-1.2.2.1.1.4.1.2 7-1.2.2.1.2 7-1.2.2.1.2.4.1.1 7-1.2.2.1.2.4.1.2 7-1.2.2.1.3 7-1.2.2.1.3.4.1.1 7-1.2.2.1.3.4.1.2 9-1.2.2.r 11-1.2.2.2 12-1.2.2 14-1.2.2.1.1.3.2.1 15-1.2.2.1.1.3.2 17-1.2.2.1.1.1 19-1.2.1 23-1.2.2.1.1.2.1.1 26-1.2.2.1.1.4.1.2.1 27-1.2.2.1.1.4.1.1.2.r 28-1.2.2.1.1.4.1.1.2 29-1.2.2.1.1.4.1.1.2.1 31-1.2.2.1.1.4.1.1.1 32-1.2.2.1.1.4.1.2.2.r 33-1.2.2.1.1.4.1.2.2 34-1.2.2.1.1.4.1.2.2.1 37-1.2.2.1.2.3.2.1 38-1.2.2.1.2.3.2 40-1.2.2.1.2.1 42-1.2.1 46-1.2.2.1.2.2.1.1 49-1.2.2.1.2.4.1.1.1 50-1.2.2.1.2.4.1.1.2.r 51-1.2.2.1.2.4.1.1.2 52-1.2.2.1.2.4.1.1.2.1 54-1.2.2.1.2.4.1.2.1 55-1.2.2.1.2.4.1.2.2.r 56-1.2.2.1.2.4.1.2.2 57-1.2.2.1.2.4.1.2.2.1 59-1.2.2.1 60-1.2.2.1.3.3.2.1 61-1.2.2.1.3.3.2 63-1.2.2.1.3.1 65-1.2.1 69-1.2.2.1.3.2.1.1 72-1.2.2.1.3.4.1.1.1 73-1.2.2.1.3.4.1.1.2.r 74-1.2.2.1.3.4.1.1.2 75-1.2.2.1.3.4.1.1.2.1 77-1.2.2.1.3.4.1.2.1 78-1.2.2.1.3.4.1.2.2.r 79-1.2.2.1.3.4.1.2.2 80-1.2.2.1.3.4.1.2.2.1 (s / show-01~e.5 :ARG0 (c / case-04~e.4 :quant 53~e.3 :ARG1-of (t / total-01~e.1)) :ARG1 (m / mutate-01~e.7 :quant 59~e.6,19,42,65 :ARG1-of~e.9 (d / distribute-01~e.12 :ARG2 (a / and~e.59 :op1 (m2 / mutate-01~e.7 :quant 26~e.17 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.23)) :ARG1-of (i / include-91 :ARG2 m :ARG3 (p / percentage-entity~e.15 :value 44.1~e.14)) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and :op1 (m4 / mutate-01~e.7 :quant 13~e.31 :location~e.27 (e6 / exon~e.28 :mod 3~e.29)) :op2 (m5 / mutate-01~e.7 :quant 13~e.26 :location~e.32 (e5 / exon~e.33 :mod 4~e.34))))) :op2 (m6 / mutate-01~e.7 :quant 11~e.40 :ARG1 (g2 / gene :name (n4 / name :op1 "BRAF"~e.46)) :ARG1-of (i2 / include-91 :ARG2 m :ARG3 (p2 / percentage-entity~e.38 :value 18.6~e.37)) :ARG1-of (m7 / mean-01 :ARG2 (a3 / and :op1 (m8 / mutate-01~e.7 :quant 2~e.49 :location~e.50 (e3 / exon~e.51 :mod 11~e.52)) :op2 (m9 / mutate-01~e.7 :quant 9~e.54 :location~e.55 (e4 / exon~e.56 :mod 15~e.57))))) :op3 (m10 / mutate-01~e.7 :quant 22~e.63 :ARG1 (g3 / gene :name (n7 / name :op1 "PIK3CA"~e.69)) :ARG1-of (i3 / include-91 :ARG2 m :ARG3 (p3 / percentage-entity~e.61 :value 37.3~e.60)) :ARG1-of (m11 / mean-01 :ARG2 (a4 / and :op1 (m12 / mutate-01~e.7 :quant 16~e.72 :location~e.73 (e / exon~e.74 :mod 9~e.75)) :op2 (m13 / mutate-01~e.7 :quant 6~e.77 :location~e.78 (e2 / exon~e.79 :mod 20~e.80)))))) :ARG1-of (f / follow-01~e.11)))) # ::id pmid_2354_8132.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In total , 26.4 % ( 53 @/@ 201 ) of the cases had at least one mutation and the remaining 73.6 % ( 148 @/@ 201 ) were wild @-@ type for all regions studied . # ::alignments 1-1.3 3-1.1.1.2.2.1 4-1.1.1.2.2 6-1.1.1.1 8-1.1.1.2.1.1 12-1.1.1 12-1.1.1.2.1 12-1.2.1 13-1.1 14-1.1.2.1 15-1.1.2.1 16-1.1.2.1.1 17-1.1.2 18-1 20-1.2.1.3 21-1.2.1.2.2.1 22-1.2.1.2.2 24-1.2.1.1 26-1.1.1.2.1.1 28-1.2.1.r 29-1.2 31-1.2 32-1.2.2.r 33-1.2.2.1 34-1.2.2 35-1.2.2.2 (a / and~e.18 :op1 (h / have-03~e.13 :ARG0 (c / case-04~e.12 :quant 53~e.6 :ARG1-of (i / include-91 :ARG2 (c2 / case-04~e.12 :quant 201~e.8,26) :ARG3 (p / percentage-entity~e.4 :value 26.4~e.3))) :ARG1 (m / mutate-01~e.17 :quant (a2 / at-least~e.14,15 :op1 1~e.16))) :op2 (w / wild-type~e.29,31 :domain~e.28 (c3 / case-04~e.12 :quant 148~e.24 :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p2 / percentage-entity~e.22 :value 73.6~e.21)) :ARG1-of (r / remain-01~e.20)) :location~e.32 (r2 / region~e.34 :mod (a3 / all~e.33) :ARG1-of (s / study-01~e.35))) :ARG1-of (t / total-01~e.1)) # ::id pmid_2354_8132.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Five of the mutations we report , four in KRAS and one in BRAF , have not previously been described in CRC . # ::alignments 0-1.2.1 3-1.2 3-1.2.2.1 3-1.2.3.1.1 3-1.2.3.1.2 4-1.2.2.1.1.1 5-1.2.2.1.1 7-1.2.3.1.1.1 10-1.2.3.1.1.2.1.1 12-1.2.3.1 13-1.2.3.1.2.1 16-1.2.3.1.2.2.1.1 20-1.1 20-1.1.r 21-1.3 23-1 24-1.4.r 25-1.4.1.1 (d / describe-01~e.23 :polarity~e.20 -~e.20 :ARG1 (m / mutate-01~e.3 :quant 5~e.0 :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01~e.3 :ARG1-of (r / report-01~e.5 :ARG0 (w / we~e.4)))) :ARG2-of (i2 / include-91 :ARG1 (a / and~e.12 :op1 (m3 / mutate-01~e.3 :quant 4~e.7 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.10))) :op2 (m4 / mutate-01~e.3 :quant 1~e.13 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF"~e.16)))))) :time (p / previous~e.21) :location~e.24 (d2 / disease :name (n3 / name :op1 "CRC"~e.25))) # ::id pmid_2354_8132.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF and PIK3CA mutations were more frequent in the colon than in the sigmoid or rectum : 20.8 % vs. 1.6 % vs. 0.0 % ( P= @ 0.000 ) for BRAF and 23.4 % vs. 12.1 % vs. 5.4 % ( P @ = 0.011 ) for PIK3CA mutations . # ::alignments 1-1.1.1.1.1.1 3-1.1 5-1.1.2.1.1.1 7-1.1.1 7-1.1.2 7-1.5.1.1 7-1.5.1.1.4 7-1.5.1.1.4.r 7-1.5.1.1.5 7-1.5.1.1.5.r 7-1.5.1.2.4 9-1.2 10-1 11-1.3.r 13-1.3 14-1.4.r 17-1.4.1 18-1.4 19-1.4.2 21-1.5.1.1.2.1 22-1.5.1.1.2 24-1.4.r 26-1.5.1.1.4.2.1 27-1.5.1.1.4.2 29-1.4.r 31-1.5.1.1.5.2.1 32-1.5.1.1.5.2 35-1.5.1.1.6 37-1.5.1.1.6.1 41-1.5.1.1.1 43-1.1 44-1.5.1.2.2.1 45-1.5.1.2.2 47-1.5.1.2.4.r 49-1.5.1.2.4.2.1 50-1.5.1.2.4.2 52-1.5.1.2.4.r 54-1.5.1.2.5.2.1 55-1.5.1.2.5.2 58-1.5.1.2.6 61-1.5.1.2.6.1 65-1.5.1.2.1 67-1.5.1.2 67-1.5.1.2.5 67-1.5.1.2.5.r (f / frequent-02~e.10 :ARG1 (a / and~e.3,43 :op1 (m / mutate-01~e.7 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.1))) :op2 (m2 / mutate-01~e.7 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.5)))) :degree (m3 / more~e.9) :location~e.11 (c / colon~e.13) :compared-to~e.14,24,29 (o / or~e.18 :op1 (s / sigmoid~e.17) :op2 (r / rectum~e.19)) :ARG1-of (m4 / mean-01 :ARG2 (a2 / and :op1 (m5 / mutate-01~e.7 :ARG1 g~e.41 :quant (p / percentage-entity~e.22 :value 20.8~e.21) :location c :compared-to~e.7 (m6 / mutate-01~e.7 :ARG1 g :quant (p2 / percentage-entity~e.27 :value 1.6~e.26) :location s) :compared-to~e.7 (m7 / mutate-01~e.7 :ARG1 g :quant (p3 / percentage-entity~e.32 :value 0.0~e.31) :location r) :ARG1-of (s2 / statistical-test-91~e.35 :ARG2 0.000~e.37)) :op2 (m8 / mutate-01~e.67 :ARG1 g2~e.65 :quant (p5 / percentage-entity~e.45 :value 23.4~e.44) :location c :compared-to~e.47,52 (m9 / mutate-01~e.7 :ARG1 g2 :quant (p6 / percentage-entity~e.50 :value 12.1~e.49) :location s) :compared-to~e.67 (m10 / mutate-01~e.67 :ARG1 g2 :quant (p7 / percentage-entity~e.55 :value 5.4~e.54) :location r) :ARG1-of (s3 / statistical-test-91~e.58 :ARG2 0.011~e.61))))) # ::id pmid_2354_8132.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2354_8132.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutation frequencies # ::alignments 1-1.1 2-1 (f / frequent-02~e.2 :ARG1 (m / mutate-01~e.1)) # ::id pmid_2354_8132.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A total of 201 KRAS exon 2 wild @-@ type mCRC samples were screened by HRM for mutations in exons 3 and 4 of KRAS , exons 11 and 15 of BRAF , and exons 9 and 20 of PIK3CA ( Figure 1 ) . # ::alignments 1-1.1.2 3-1.1.2.1 5-1.1.1.3.2.1.1 7-1.1.1.3 7-1.3.1.1.1 7-1.3.1.1.2 7-1.3.2.1.1 7-1.3.2.1.2 7-1.3.3.1.1 7-1.3.3.1.2 8-1.1.1.3.1 9-1.1.1.2 11-1.1.1.2 12-1.1.1.1.1 13-1.1 15-1 16-1.2.r 17-1.2.1.1 18-1.3.r 19-1.3.1 19-1.3.2 19-1.3.3 22-1.3.1.1.1.1 23-1.3.1.1 24-1.3.1.1.2.1 27-1.3.1.1.3 31-1.3.2.1.1.1 33-1.3.2.1.2.1 36-1.3.2.1.3.1.1 39-1.3 41-1.3.3.1.1.1 43-1.3.3.1.2.1 46-1.3.3.1.3.1.1 49-1.4.1 51-1.4.1.1 (s / screen-01~e.15 :ARG1 (s2 / sample-01~e.13 :ARG1 (d / disease :name (n / name :op1 "mCRC"~e.12) :mod (w / wild-type~e.9,11) :mod (e / exon~e.7 :mod 2~e.8 :part-of (g / gene :name (n3 / name :op1 "KRAS"~e.5)))) :ARG1-of (t / total-01~e.1 :ARG2 201~e.3)) :manner~e.16 (t2 / thing :name (n4 / name :op1 "HRM"~e.17)) :purpose~e.18 (a / and~e.39 :op1 (m / mutate-01~e.19 :location (a2 / and~e.23 :op1 (e2 / exon~e.7 :mod 3~e.22) :op2 (e3 / exon~e.7 :mod 4~e.24) :part-of g~e.27)) :op2 (m2 / mutate-01~e.19 :location (a3 / and :op1 (e4 / exon~e.7 :mod 11~e.31) :op2 (e5 / exon~e.7 :mod 15~e.33) :part-of (g2 / gene :name (n9 / name :op1 "BRAF"~e.36)))) :op3 (m3 / mutate-01~e.19 :location (a4 / and :op1 (e6 / exon~e.7 :mod 9~e.41) :op2 (e7 / exon~e.7 :mod 20~e.43) :part-of (g3 / gene :name (n12 / name :op1 "PIK3CA"~e.46))))) :ARG1-of (d9 / describe-01 :ARG0 (f / figure~e.49 :mod 1~e.51))) # ::id pmid_2354_8132.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Subsequent automated sequencing of HRM positive cases confirmed the presence of 59 mutations in 53 cases , with the following distribution : 44.1 % ( 26 @/@ 59 ) in KRAS ( 13 in exon 3 and 13 in exon 4 ) , 18.6 % ( 11 @/@ 59 ) in BRAF ( two in exon 11 and nine in exon 15 ) and 37.3 % ( 22 @/@ 59 ) in PIK3CA ( 16 in exon 9 and six in exon 20 ) . # ::alignments 0-1.1.3 0-1.1.3.r 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.2 6-1.1.1 7-1 9-1.2 10-1.2.1.r 11-1.2.1.1 12-1.2.1 12-1.2.3.1.1 12-1.2.3.1.1.4.1.1 12-1.2.3.1.1.4.1.2 12-1.2.3.1.2 12-1.2.3.1.2.4.1.1 12-1.2.3.1.2.4.1.2 12-1.2.3.1.3 12-1.2.3.1.3.4.1.1 12-1.2.3.1.3.4.1.2 13-1.2.2.r 14-1.2.2.1 15-1.2.2 17-1.2.3.r 19-1.2.3.2 20-1.2.3 22-1.2.3.1.1.3.2.1 23-1.2.3.1.1.3.2 25-1.2.3.1.1.1 27-1.2.1.1 31-1.2.3.1.1.2.1.1 34-1.2.3.1.1.4.1.2.1 35-1.2.3.1.1.4.1.1.2.r 36-1.2.3.1.1.4.1.1.2 37-1.2.3.1.1.4.1.1.2.1 39-1.2.3.1.1.4.1.1.1 40-1.2.3.1.1.4.1.2.2.r 41-1.2.3.1.1.4.1.2.2 42-1.2.3.1.1.4.1.2.2.1 45-1.2.3.1.2.3.2.1 46-1.2.3.1.2.3.2 48-1.2.3.1.2.1 50-1.2.1.1 54-1.2.3.1.2.2.1.1 57-1.2.3.1.2.4.1.1.1 58-1.2.3.1.2.4.1.1.2.r 59-1.2.3.1.2.4.1.1.2 60-1.2.3.1.2.4.1.1.2.1 62-1.2.3.1.2.4.1.2.1 63-1.2.3.1.2.4.1.2.2.r 64-1.2.3.1.2.4.1.2.2 65-1.2.3.1.2.4.1.2.2.1 67-1.2.3.1 68-1.2.3.1.3.3.2.1 69-1.2.3.1.3.3.2 71-1.2.3.1.3.1 73-1.2.1.1 77-1.2.3.1.3.2.1.1 80-1.2.3.1.3.4.1.1.1 81-1.2.3.1.3.4.1.1.2.r 82-1.2.3.1.3.4.1.1.2 83-1.2.3.1.3.4.1.1.2.1 85-1.2.3.1.3.4.1.2.1 86-1.2.3.1.3.4.1.2.2.r 87-1.2.3.1.3.4.1.2.2 88-1.2.3.1.3.4.1.2.2.1 (c / confirm-01~e.7 :ARG0 (s / sequence-01~e.2 :ARG1~e.3 (c2 / case-04~e.6 :ARG1 (t / thing :name (n / name :op1 "HRM"~e.4)) :mod (p / positive~e.5)) :ARG1-of (a / automate-01~e.1) :time~e.0 (s2 / subsequent~e.0)) :ARG1 (p2 / present-02~e.9 :ARG1~e.10 (m / mutate-01~e.12 :quant 59~e.11,27,50,73) :ARG2~e.13 (c3 / case-04~e.15 :quant 53~e.14) :ARG1-of~e.17 (d / distribute-01~e.20 :ARG2 (a2 / and~e.67 :op1 (m2 / mutate-01~e.12 :quant 26~e.25 :ARG1 (g / gene :name (n2 / name :op1 "KRAS"~e.31)) :ARG1-of (i / include-91 :ARG2 m :ARG3 (p3 / percentage-entity~e.23 :value 44.1~e.22)) :ARG1-of (m3 / mean-01 :ARG2 (a3 / and :op1 (m4 / mutate-01~e.12 :quant 13~e.39 :location~e.35 (e / exon~e.36 :mod 3~e.37)) :op2 (m5 / mutate-01~e.12 :quant 13~e.34 :location~e.40 (e2 / exon~e.41 :mod 4~e.42))))) :op2 (m6 / mutate-01~e.12 :quant 11~e.48 :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF"~e.54)) :ARG1-of (i2 / include-91 :ARG2 m :ARG3 (p4 / percentage-entity~e.46 :value 18.6~e.45)) :ARG1-of (m7 / mean-01 :ARG2 (a4 / and :op1 (m8 / mutate-01~e.12 :quant 2~e.57 :location~e.58 (e3 / exon~e.59 :mod 11~e.60)) :op2 (m9 / mutate-01~e.12 :quant 9~e.62 :location~e.63 (e4 / exon~e.64 :mod 15~e.65))))) :op3 (m10 / mutate-01~e.12 :quant 22~e.71 :ARG1 (g3 / gene :name (n8 / name :op1 "PIK3CA"~e.77)) :ARG1-of (i3 / include-91 :ARG2 m :ARG3 (p5 / percentage-entity~e.69 :value 37.3~e.68)) :ARG1-of (m11 / mean-01 :ARG2 (a5 / and :op1 (m12 / mutate-01~e.12 :quant 16~e.80 :location~e.81 (e5 / exon~e.82 :mod 9~e.83)) :op2 (m13 / mutate-01~e.12 :quant 6~e.85 :location~e.86 (e6 / exon~e.87 :mod 20~e.88)))))) :ARG1-of (f / follow-01~e.19)))) # ::id pmid_2354_8132.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One mutation was present in 23.4 % ( 47 @/@ 201 ) of the cases and 3.0 % additional cases ( 6 @/@ 201 ) had two concomitant mutations . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.2.2.1 6-1.1.2.2.2 8-1.1.2.1 10-1.1.2.2.1.1 14-1.1.2 14-1.1.2.2.1 15-1 16-1.2.1.2.2.1 17-1.2.1.2.2 19-1.2.1 21-1.2.1.1 23-1.1.2.2.1.1 25-1.2 26-1.2.2.1 27-1.2.2.2 28-1.2.2 (a / and~e.15 :op1 (p / present-02~e.3 :ARG1 (m / mutate-01~e.1 :quant 1~e.0) :ARG2~e.4 (c / case-04~e.14 :quant 47~e.8 :ARG1-of (i / include-91 :ARG2 (c2 / case-04~e.14 :quant 201~e.10,23) :ARG3 (p2 / percentage-entity~e.6 :value 23.4~e.5)))) :op2 (h / have-03~e.25 :ARG0 (c3 / case-04~e.19 :quant 6~e.21 :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p3 / percentage-entity~e.17 :value 3.0~e.16)) :ARG1-of (a2 / add-02)) :ARG1 (m2 / mutate-01~e.28 :quant 2~e.26 :mod (c4 / concomitant~e.27)))) # ::id pmid_2354_8132.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In total , 26.4 % ( 53 @/@ 201 ) of the cases had at least one mutation and the remaining 73.6 % ( 148 @/@ 201 ) were wild @-@ type for all regions studied . # ::alignments 1-1.3 3-1.1.1.2.2.1 4-1.1.1.2.2 6-1.1.1.1 8-1.1.1.2.1.1 12-1.1.1 12-1.1.1.2.1 12-1.2.1 13-1.1 14-1.1.2.1 15-1.1.2.1 16-1.1.2.1.1 17-1.1.2 18-1 20-1.2.1.3 21-1.2.1.2.2.1 22-1.2.1.2.2 24-1.2.1.1 26-1.1.1.2.1.1 28-1.2.1.r 29-1.2 31-1.2 32-1.2.2.r 33-1.2.2.1 34-1.2.2 35-1.2.2.2 (a / and~e.18 :op1 (h / have-03~e.13 :ARG0 (c / case-04~e.12 :quant 53~e.6 :ARG1-of (i / include-91 :ARG2 (c2 / case-04~e.12 :quant 201~e.8,26) :ARG3 (p / percentage-entity~e.4 :value 26.4~e.3))) :ARG1 (m / mutate-01~e.17 :quant (a2 / at-least~e.14,15 :op1 1~e.16))) :op2 (w / wild-type~e.29,31 :domain~e.28 (c3 / case-04~e.12 :quant 148~e.24 :ARG1-of (i2 / include-91 :ARG2 c2 :ARG3 (p2 / percentage-entity~e.22 :value 73.6~e.21)) :ARG1-of (r / remain-01~e.20)) :location~e.32 (r2 / region~e.34 :mod (a3 / all~e.33) :ARG1-of (s / study-01~e.35))) :ARG1-of (t / total-01~e.1)) # ::id pmid_2354_8132.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All mutations were found in heterozygosity and were confirmed in a second HRM and DNA sequence analysis . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2 6-1 8-1.2 9-1.2.1.r 11-1.2.1.3 11-1.2.1.3.1 11-1.2.1.3.1.r 13-1.2.1 14-1.2.1.2.2 15-1.2.1.2.2 16-1.2.1.1 16-1.2.1.2 (a / and~e.6 :op1 (f / find-01~e.3 :ARG1 (m / mutate-01~e.1 :mod (a2 / all~e.0)) :manner~e.4 (h / heterozygosity~e.5)) :op2 (c / confirm-01~e.8 :ARG0~e.9 (a3 / and~e.13 :op1 (a4 / analyze-01~e.16 :ARG1 m :manner (m2 / melt-01 :mod (r / resolution :ARG1-of (h2 / high-02)))) :op2 (a5 / analyze-01~e.16 :ARG1 m :mod (d / dna-sequence~e.14,15)) :ord (o / ordinal-entity~e.11 :value~e.11 2~e.11)) :ARG1 m)) # ::id pmid_2354_8132.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Samples with single mutations were distributed as follows : 10.0 % ( 20 @/@ 201 ) were KRAS mutated , 5.0 % ( 10 @/@ 201 ) in exon 3 and 5.0 % ( 10 @/@ 201 ) in exon 4 ; 5.0 % ( 10 @/@ 201 ) had one BRAF mutation , 0.5 % ( 1 @/@ 201 ) in exon 11 and 4.5 % ( 9 @/@ 201 ) in exon 15 ; 8.5 % ( 17 @/@ 201 ) were PIK3CA mutated , 7.0 % ( 14 @/@ 201 ) in exon 9 and 1.5 % ( 3 @/@ 201 ) in exon 20 ( Table 1 ) . # ::alignments 0-1.1 0-1.1.1 0-1.1.1.r 0-1.2.1.2.1 0-1.2.1.2.1.2 0-1.2.1.2.1.2.r 2-1.1.2.1.1 3-1.1.2.1 5-1 6-1.3.r 7-1.3 9-1.2.1.2.2.1 10-1.2.1.2.2 12-1.2.1.1 14-1.2.1.2.1.1 18-1.2.1.3.1.1.1 20-1.2.1.2.2.2.1.1.3 20-1.2.1.3 22-1.2.1.2.2.2.1.1.2.2.1 23-1.2.1.2.2.2.1.1.2.2 25-1.2.1.2.2.2.1.1.1 27-1.2.1.2.1.1 29-1.2.1.2.2.2.1.1.3.1.r 30-1.2.1.2.2.2.1.1.3.1 31-1.2.1.2.2.2.1.1.3.1.1 32-1.2.1.2.2.2.1 33-1.2.1.2.2.2.1.1.2.2.1 34-1.2.1.2.2.2.1.1.2.2 36-1.2.1.2.2.2.1.1.1 36-1.2.1.2.2.2.1.2.1 38-1.2.1.2.1.1 41-1.2.1.2.2.2.1.2.3.1 42-1.2.1.2.2.2.1.2.3.1.1 44-1.2.2.2.2.1 45-1.2.2.2.2 47-1.2.1.2.2.2.1.2.1 47-1.2.2.1 49-1.2.1.2.1.1 52-1.2.2.2.2.2.1.1.1 52-1.2.2.3.1.1 54-1.2.2.3.1.2.1.1 56-1.2.2.3.1 58-1.2.2.2.2.2.1.1.2.2.1 59-1.2.2.2.2.2.1.1.2.2 61-1.2.2.2.2.2.1.1.1 61-1.2.2.3.1.1 63-1.2.1.2.1.1 66-1.2.2.2.2.2.1.1.3.1 67-1.2.2.2.2.2.1.1.3.1.1 68-1.2.2.2.2.2.1 69-1.2.2.2.2.2.1.2.2.2.1 70-1.2.2.2.2.2.1.2.2.2 72-1.2.2.2.2.2.1.2.1 74-1.2.1.2.1.1 77-1.2.2.2.2.2.1.2.3.1 78-1.2.2.2.2.2.1.2.3.1.1 80-1.2.3.2.2.1 81-1.2.3.2.2 83-1.2.3.1 85-1.2.1.2.1.1 89-1.2.3.3.1.1.1 91-1.2.1.2.2.2.1.2.3 91-1.2.2.2.2.2.1.1.3 91-1.2.2.2.2.2.1.2.3 91-1.2.3.2.2.2.1.1.3 91-1.2.3.2.2.2.1.2.3 91-1.2.3.3 93-1.2.3.2.2.2.1.1.2.2.1 94-1.2.3.2.2.2.1.1.2.2 96-1.2.3.2.2.2.1.1.1 98-1.2.1.2.1.1 100-1.2.3.2.2.2.1.1.3.1.r 101-1.2.3.2.2.2.1.1.3.1 102-1.2.3.2.2.2.1.1.3.1.1 103-1.2.3.2.2.2.1 104-1.2.3.2.2.2.1.2.2.2.1 105-1.2.3.2.2.2.1.2.2.2 107-1.2.3.2.2.2.1.2.1 109-1.2.1.2.1.1 111-1.2.3.2.2.2.1.2.3.1.r 112-1.2.3.2.2.2.1.2.3.1 113-1.2.1.1 113-1.2.3.2.2.2.1.2.3.1.1 115-1.4.1 117-1.4.1.1 (d / distribute-01~e.5 :ARG1 (t / thing~e.0 :ARG1-of~e.0 (s / sample-01~e.0) :ARG0-of (h / have-03 :ARG1 (m / mutate-01~e.3 :ARG1-of (s2 / single-02~e.2)))) :ARG2 (a / and :op1 (t3 / thing :quant 20~e.12,113 :ARG1-of (i / include-91 :ARG2 (t4 / thing~e.0 :quant 201~e.14,27,38,49,63,74,85,98,109 :ARG1-of~e.0 (s4 / sample-01~e.0)) :ARG3 (p / percentage-entity~e.10 :value 10.0~e.9 :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.32 :op1 (t5 / thing :quant 10~e.25,36 :ARG1-of (i2 / include-91 :ARG2 t4 :ARG3 (p2 / percentage-entity~e.23,34 :value 5.0~e.22,33)) :ARG2-of (m3 / mutate-01~e.20 :location~e.29 (e / exon~e.30 :mod 3~e.31))) :op2 (t6 / thing :quant 10~e.36,47 :ARG1-of i2 :ARG2-of (m4 / mutate-01~e.91 :location (e2 / exon~e.41 :mod 4~e.42))))))) :location-of (m5 / mutate-01~e.20 :ARG1 (g / gene :name (n3 / name :op1 "KRAS"~e.18)))) :op2 (t7 / thing :quant 10~e.47 :ARG1-of (i3 / include-91 :ARG2 t4 :ARG3 (p3 / percentage-entity~e.45 :value 5.0~e.44 :ARG1-of (m6 / mean-01 :ARG2 (a3 / and~e.68 :op1 (t8 / thing :quant 1~e.52,61 :ARG1-of (i4 / include-91 :ARG2 t4 :ARG3 (p4 / percentage-entity~e.59 :value 0.5~e.58)) :ARG2-of (m7 / mutate-01~e.91 :location (e3 / exon~e.66 :mod 11~e.67))) :op2 (t9 / thing :quant 9~e.72 :ARG1-of (i5 / include-91 :ARG2 t4 :ARG3 (p5 / percentage-entity~e.70 :value 4.5~e.69)) :ARG2-of (m8 / mutate-01~e.91 :location (e4 / exon~e.77 :mod 15~e.78))))))) :ARG0-of (h2 / have-03 :ARG1 (m9 / mutate-01~e.56 :quant 1~e.52,61 :ARG1 (g2 / gene :name (n6 / name :op1 "BRAF"~e.54))))) :op3 (t10 / thing :quant 17~e.83 :ARG1-of (i6 / include-91 :ARG2 t4 :ARG3 (p6 / percentage-entity~e.81 :value 8.5~e.80 :ARG1-of (m10 / mean-01 :ARG2 (a4 / and~e.103 :op1 (t11 / thing :quant 14~e.96 :ARG1-of (i7 / include-91 :ARG2 t4 :ARG3 (p7 / percentage-entity~e.94 :value 7.0~e.93)) :ARG2-of (m11 / mutate-01~e.91 :location~e.100 (e5 / exon~e.101 :mod 9~e.102))) :op2 (t12 / thing :quant 3~e.107 :ARG1-of (i8 / include-91 :ARG2 t4 :ARG3 (p8 / percentage-entity~e.105 :value 1.5~e.104)) :ARG2-of (m12 / mutate-01~e.91 :location~e.111 (e6 / exon~e.112 :mod 20~e.113))))))) :location-of (m13 / mutate-01~e.91 :ARG1 (g3 / gene :name (n9 / name :op1 "PIK3CA"~e.89))))) :ARG1-of~e.6 (f / follow-01~e.7) :ARG1-of (d8 / describe-01 :ARG0 (t2 / table~e.115 :mod 1~e.117))) # ::id pmid_2354_8132.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concomitant mutations were found with the following distribution : 2.0 % ( 4 @/@ 201 ) of cases had simultaneous mutations in PIK3CA and KRAS , 0.5 % ( 1 @/@ 201 ) in PIK3CA and BRAF , and 0.5 % ( 1 @/@ 201 ) two mutations in KRAS ( Table 2 ) . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.1.2.r 6-1.1.2.2 7-1.1.2 9-1.1.2.1.1.1.2.2.1 10-1.1.2.1.1.1.2.2 12-1.1.2.1.1.1.1 14-1.1.2.1.1.1.2.1.1 17-1.1.2.1.1.1 17-1.1.2.1.1.1.2.1 17-1.1.2.1.2.1 18-1.1.2.1.1 19-1.1.2.1.1.2.2 20-1.1.2.1.1.2 20-1.1.2.1.2.2 23-1.1.2.1.1.2.1.1.1.1 25-1.1.2.1.1.2.1 27-1.1.2.1.1.2.1.2.1.1 30-1.1.2.1.2.1.2.2.1 31-1.1.2.1.2.1.2.2 33-1.1.2.1.2.1.1 35-1.1.2.1.1.1.2.1.1 39-1.1.2.1.2.2.1.1 41-1.1.2.1 43-1.1.2.1.2.2.1.2.1.1 47-1.1.2.1.2.1.2.2.1 48-1.1.2.1.2.1.2.2 50-1.1.2.1.2.1.1 52-1.1.2.1.1.1.2.1.1 54-1.1.2.1.3.2.1 55-1.1.2.1.3.2 58-1.1.2.1.3.2.2 61-1.2.1 63-1.2.1.1 (f / find-01~e.3 :ARG1 (m / mutate-01~e.1 :mod (c / concomitant~e.0) :ARG1-of~e.4 (d / distribute-01~e.7 :ARG2 (a / and~e.41 :op1 (h / have-03~e.18 :ARG0 (c2 / case-04~e.17 :quant 4~e.12 :ARG1-of (i / include-91 :ARG2 (c3 / case-04~e.17 :quant 201~e.14,35,52) :ARG3 (p / percentage-entity~e.10 :value 2.0~e.9))) :ARG1 (m2 / mutate-01~e.20 :ARG1 (a2 / and~e.25 :op1 (g / gene :name (n / name :op1 "PIK3CA"~e.23)) :op2 (g2 / gene :name (n2 / name :op1 "KRAS"~e.27))) :mod (s / simultaneous~e.19))) :op2 (h2 / have-03 :ARG0 (c4 / case-04~e.17 :quant 1~e.33,50 :ARG1-of (i2 / include-91 :ARG2 c3 :ARG3 (p2 / percentage-entity~e.31,48 :value 0.5~e.30,47))) :ARG1 (m3 / mutate-01~e.20 :ARG1 (a3 / and :op1 g~e.39 :op2 (g3 / gene :name (n3 / name :op1 "BRAF"~e.43))))) :op3 (h3 / have-03 :ARG0 c4 :ARG1 (m4 / mutate-01~e.55 :quant 2~e.54 :ARG1 g2~e.58))) :ARG1-of (f2 / follow-01~e.6))) :ARG1-of (d2 / describe-01 :ARG0 (t / table~e.61 :mod 2~e.63))) # ::id pmid_2354_8132.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of all mutations here reported , five have not been previously described in colorectal cancer [ @ 23 @ - @ 25 @ ] : two duplications , one deletion , and one point mutation in KRAS and one point mutation in BRAF ( Figure 2 ) . # ::alignments 1-1.2.2.1.1 2-1.2 2-1.2.2.1 3-1.2.2.1.2.1 4-1.2.2.1.2 6-1.2.1 8-1.1 8-1.1.r 10-1.3 11-1 11-1.5 11-1.5.r 11-1.6 11-1.6.r 12-1.4.r 13-1.4.1.1 14-1.4.1.2 17-1.5.1.1.1.1 21-1.5.1.1.1.2 25-1.2.3.1.1.1 26-1.2.3.1.1 28-1.2.3.1.2.1 29-1.2.3.1.2 31-1.2.3.1 31-1.2.3.1.3 31-1.2.3.1.3.r 32-1.2.3.1.3.1.2.1 33-1.2.3.1.3.1.2 34-1.2.3.1.3.1 37-1.2.3.1.3.1.1.1.1 40-1.2.3.1.3.1.2.1 41-1.2.3.1.3.1.2 42-1.2.3.1.3.1 42-1.2.3.1.3.2 45-1.2.3.1.3.2.1.1.1 48-1.6.1 50-1.6.1.1 (d / describe-01~e.11 :polarity~e.8 -~e.8 :ARG1 (m / mutate-01~e.2 :quant 5~e.6 :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01~e.2 :mod (a / all~e.1) :ARG1-of (r / report-01~e.4 :location (h / here~e.3)))) :ARG1-of (m3 / mean-01 :ARG2 (a2 / and~e.31 :op1 (d2 / duplicate-01~e.26 :quant 2~e.25) :op2 (d3 / delete-01~e.29 :quant 1~e.28) :op3~e.31 (a3 / and~e.31 :op1 (m4 / mutate-01~e.34,42 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.37)) :degree (p / point~e.33,41 :quant 1~e.32,40)) :op2 (m5 / mutate-01~e.42 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF"~e.45)) :degree p))))) :time (p2 / previous~e.10) :location~e.12 (d4 / disease :name (n3 / name :op1 "colorectal"~e.13 :op2 "cancer"~e.14)) :ARG1-of~e.11 (d5 / describe-01~e.11 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 23~e.17 :op2 25~e.21)))) :ARG1-of~e.11 (d6 / describe-01~e.11 :ARG0 (f / figure~e.48 :mod 2~e.50))) # ::id pmid_2354_8132.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KRAS mutations # ::alignments 1-1.1.1.1 2-1 (m / mutate-01~e.2 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.1))) # ::id pmid_2354_8132.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The eight KRAS codon 61 mutations present in our series result in four different amino acid substitutions ( p.Gln61His , p.Gln61Lys , p.Gln61Leu , and p.Gln61Arg ) , with the p.Gln61Leu being the most frequent codon 61 mutation in this series ( 37.5 % ; 3 @/@ 8 ) . # ::alignments 1-1.1.1 3-1.1.2.1.1 5-1.1.3 6-1.1.3.1 6-1.2.4.1.1.2.1 7-1.1 8-1.1.4 9-1.1.4.1.r 10-1.1.4.1.1 10-1.1.4.1.1.r 11-1.1.4.1 12-1 13-1.2.r 14-1.2.1 15-1.2.3 16-1.2.4.1.1.2 17-1.2.2 18-1.2 18-1.2.4.1.1 18-1.2.4.1.2 18-1.2.4.1.3 18-1.2.4.1.4 26-1.2.4.1 35-1.2.4.1.3.3.1 36-1.2.4.1.3.3 37-1.2.4.1.3.3.3.1.2 38-1.2.4.1.3.3.3.1.2 39-1.2.4.1.3.3.3.1 40-1.2.4.1.3.3.2.r 41-1.2.4.1.3.3.2.1 42-1.2.4.1.3.3.2 44-1.2.4.1.3.3.3.1.3.2.1 45-1.2.4.1.3.3.3.1.3.2 47-1.2.4.1.3.3.3.1.1 49-1.1.1 (r / result-01~e.12 :ARG1 (m / mutate-01~e.7 :quant 8~e.1,49 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.3)) :location (c / codon~e.5 :mod 61~e.6) :ARG1-of (p / present-02~e.8 :ARG2~e.9 (s / series~e.11 :poss~e.10 (w / we~e.10)))) :ARG2~e.13 (s2 / substitute-01~e.18 :quant 4~e.14 :ARG2 (a / amino-acid~e.17) :ARG1-of (d2 / differ-02~e.15) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.26 :op1 (s3 / substitute-01~e.18 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "histidine")) :ARG2 (a4 / amino-acid~e.16 :mod 61~e.6 :name (n4 / name :op1 "glutamine"))) :op2 (s4 / substitute-01~e.18 :ARG1 (a5 / amino-acid :name (n5 / name :op1 "lysine")) :ARG2 a4) :op3 (s5 / substitute-01~e.18 :ARG1 (a6 / amino-acid :name (n6 / name :op1 "leucine")) :ARG2 a4 :ARG1-of (f / frequent-02~e.36 :degree (m3 / most~e.35) :location~e.40 (s6 / series~e.42 :mod (t / this~e.41)) :ARG1-of (m5 / mean-01 :ARG2 (m6 / mutate-01~e.39 :quant 3~e.47 :location c~e.37,38 :ARG1-of (i / include-91 :ARG2 m :ARG3 (p2 / percentage-entity~e.45 :value 37.5~e.44)))))) :op4 (s7 / substitute-01~e.18 :ARG1 (a7 / amino-acid :name (n7 / name :op1 "arginine")) :ARG2 a4))))) # ::id pmid_2354_8132.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutations found in codon 146 were restricted to the p.Ala146Thr substitution . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2 4-1.1.2.1 4-1.2.2.1 6-1 10-1.2 (r / restrict-01~e.6 :ARG1 (f / find-01~e.1 :ARG1 (m / mutate-01~e.0) :location~e.2 (c / codon~e.3 :mod 146~e.4)) :ARG2 (s / substitute-01~e.10 :ARG1 (a / amino-acid :name (n2 / name :op1 "threonine")) :ARG2 (a2 / amino-acid :mod 146~e.4 :name (n3 / name :op1 "alanine")))) # ::id pmid_2354_8132.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Besides those in codons 61 and 146 , other KRAS exon 3 mutations represented 19 % ( 5 @/@ 26 ) of all KRAS changes , including one deletion ( p.Ala59del ) , two point mutations ( p.Glu49Lys and p.Gly60Val ) and two large in frame duplications ( p.Cys51_Ser65dup and p.Thr58_Met72dup ) . # ::alignments 2-1.2.4.1.3.4 3-1.1.1.1.1 3-1.1.1.1.2 4-1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1 8-1.1.2.3 10-1.1.2.1.1.1 12-1.1.2.2 13-1.1.2.2.1 14-1.1.2 15-1 16-1.2.2.2.1 17-1.2.2.2 19-1.2.1 21-1.2.2.1.1 24-1.2.3.1.2 26-1.2.3.1.1 28-1.2 28-1.2.2.1 28-1.2.3.1 30-1.2.2 30-1.2.3 30-1.2.4 31-1.2.4.1.1.1 32-1.2.4.1.1 37-1.2.4.1.2.1 38-1.2.4.1.2.3 39-1.1.1 39-1.2.4.1.2 39-1.2.4.1.2.2.1.1 39-1.2.4.1.2.2.1.2 42-1.2.4.1 42-1.2.4.1.2.2.1 45-1.2.4.1.3.2.1 46-1.2.4.1.3.1 47-1.2.4.1.3.3 48-1.2.4.1.3.4 49-1.2.4.1.3.4 50-1.2.4.1.3 50-1.2.4.1.3.2.1.1 50-1.2.4.1.3.2.1.2 53-1.2.4.1.3.2.1 (r / represent-01~e.15 :ARG0 (a / and :op1 (m / mutate-01~e.39 :location (a2 / and~e.5 :op1 (c4 / codon~e.3 :mod 61~e.4) :op2 (c5 / codon~e.3 :mod 146~e.6))) :op2 (m2 / mutate-01~e.14 :ARG1 (g / gene :name (n3 / name :op1 "KRAS"~e.10)) :location (e / exon~e.12 :mod 3~e.13) :mod (o / other~e.8))) :ARG1 (c / change-01~e.28 :quant 5~e.19 :ARG1-of (i / include-91~e.30 :ARG2 (c2 / change-01~e.28 :quant 26~e.21) :ARG3 (p / percentage-entity~e.17 :value 19~e.16)) :ARG1-of (i2 / include-91~e.30 :ARG2 (c3 / change-01~e.28 :ARG1 g~e.26 :mod (a3 / all~e.24))) :ARG2-of (i3 / include-01~e.30 :ARG1 (a4 / and~e.42 :op1 (d4 / delete-01~e.32 :quant 1~e.31 :ARG1 (a5 / amino-acid :mod 59 :name (n5 / name :op1 "alanine"))) :op2 (m3 / mutate-01~e.39 :quant 2~e.37 :ARG1-of (m4 / mean-01 :ARG2 (a6 / and~e.42 :op1 (m5 / mutate-01~e.39 :ARG2 (a7 / amino-acid :name (n6 / name :op1 "lysine")) :ARG3 (a8 / amino-acid :mod 49 :name (n7 / name :op1 "glutamic" :op2 "acid"))) :op2 (m6 / mutate-01~e.39 :ARG2 (a9 / amino-acid :name (n8 / name :op1 "valine")) :ARG3 (a10 / amino-acid :mod 60 :name (n9 / name :op1 "glycine"))))) :degree (p2 / point~e.38)) :op3 (d5 / duplicate-01~e.50 :quant 2~e.46 :ARG1-of (m7 / mean-01 :ARG2 (a11 / and~e.45,53 :op1 (d6 / duplicate-01~e.50 :ARG0 (a12 / amino-acid :mod 51 :name (n10 / name :op1 "cysteine")) :ARG1 (a13 / amino-acid :mod 65 :name (n11 / name :op1 "serine"))) :op2 (d7 / duplicate-01~e.50 :ARG0 (a14 / amino-acid :mod 58 :name (n12 / name :op1 "threonine")) :ARG1 (a15 / amino-acid :mod 72 :name (n13 / name :op1 "methionine"))))) :mod (l / large~e.47) :mod (i4 / in-frame~e.2,48,49)))))) # ::id pmid_2354_8132.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of these five mutations , only p.Gly60Val has been recently reported in CRC [ @ 26 @ ] , whereas the other four are novel mutations in CRC [ @ 23 @ ] . # ::alignments 1-1.1.1.4.1.2 2-1.1.1.4.1.1 3-1.1.1 3-1.1.1.4.1 5-1.1.1.3 9-1.1.2 10-1.1 11-1.1.3.r 12-1.1.3.1.1 15-1.1.4.1.1.1 19-1 21-1.2.3 22-1.2.1 24-1.2.2 25-1.2 26-1.2.4.r 27-1.2.4 30-1.2.5.1.1.1 (c / contrast-01~e.19 :ARG1 (r / report-01~e.10 :ARG1 (m / mutate-01~e.3 :ARG2 (a / amino-acid :name (n / name :op1 "valine")) :ARG3 (a2 / amino-acid :mod 60 :name (n2 / name :op1 "glycine")) :mod (o / only~e.5) :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01~e.3 :quant 5~e.2 :mod (t / this~e.1)))) :time (r2 / recent~e.9) :location~e.11 (d / disease :name (n3 / name :op1 "CRC"~e.12)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 26~e.15)))) :ARG2 (m3 / mutate-01~e.25 :quant 4~e.22 :mod (n4 / novel~e.24) :mod (o2 / other~e.21) :location~e.26 d~e.27 :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 23~e.30))))) # ::id pmid_2354_8132.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One of the cases carrying a KRAS p.Gln61His mutation had a concomitant PIK3CA p.Glu542Lys substitution . # ::alignments 0-1.1.1 3-1.1 3-1.1.3.1 4-1.1.2 7-1.1.2.1.1.1.1 10-1.1.2.1 11-1 13-1.2.4 15-1.2.3.1.1 18-1.2 (h / have-03~e.11 :ARG0 (c / case-04~e.3 :quant 1~e.0 :ARG0-of (c2 / carry-01~e.4 :ARG1 (m / mutate-01~e.10 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.7)) :ARG2 (a / amino-acid :name (n2 / name :op1 "histidine")) :ARG3 (a2 / amino-acid :mod 61 :name (n3 / name :op1 "glutamine")))) :ARG1-of (i / include-91 :ARG2 (c3 / case-04~e.3 :ARG0-of c2))) :ARG1 (s / substitute-01~e.18 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "lysine")) :ARG2 (a4 / amino-acid :mod 542 :name (n5 / name :op1 "glutamic" :op2 "acid")) :ARG3 (g2 / gene :name (n6 / name :op1 "PIK3CA"~e.15)) :mod (c4 / concomitant~e.13))) # ::id pmid_2354_8132.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The p.Thr58_Met72dup duplication occurred in one tumor carrying a PIK3CA p.His1047Tyr substitution . # ::alignments 2-1 4-1.3.r 5-1.3.1 6-1.3 7-1.3.2 10-1.3.2.1.3.1.1 13-1.3.2.1 (d / duplicate-01~e.2 :ARG0 (a / amino-acid :mod 58 :name (n / name :op1 "threonine")) :ARG1 (a2 / amino-acid :mod 72 :name (n2 / name :op1 "methionine")) :location~e.4 (t / tumor~e.6 :quant 1~e.5 :ARG0-of (c / carry-01~e.7 :ARG1 (s / substitute-01~e.13 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine")) :ARG2 (a4 / amino-acid :mod 1047 :name (n4 / name :op1 "histidine")) :ARG3 (g / gene :name (n5 / name :op1 "PIK3CA"~e.10)))))) # ::id pmid_2354_8132.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two tumors with KRAS Ala146Thr mutations also had a PIK3CA mutation , either p.Glu545Lys or p.His1046Arg . # ::alignments 0-1.1.1 1-1.1 4-1.1.2.1.1.1 7-1.1.2 8-1.3 9-1 12-1.2.1.1.1.1 14-1.2.1 14-1.2.2 16-1.2.3 18-1.2 (h / have-03~e.9 :ARG0 (t / tumor~e.1 :quant 2~e.0 :poss (m / mutate-01~e.7 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.4)) :ARG2 (a / amino-acid :name (n2 / name :op1 "threonine")) :ARG3 (a2 / amino-acid :mod 146 :name (n3 / name :op1 "alanine")))) :ARG1 (o / or~e.18 :op1 (m2 / mutate-01~e.14 :ARG1 (g2 / gene :name (n8 / name :op1 "PIK3CA"~e.12)) :ARG2 (a3 / amino-acid :name (n4 / name :op1 "lysine")) :ARG3 (a4 / amino-acid :mod 545 :name (n5 / name :op1 "glutamic" :op2 "acid"))) :op2 (m3 / mutate-01~e.14 :ARG1 g2 :ARG2 (a5 / amino-acid :name (n6 / name :op1 "arginine")) :ARG3 (a6 / amino-acid :mod 1046 :name (n7 / name :op1 "histidine"))) :mod (e / either~e.16)) :mod (a7 / also~e.8)) # ::id pmid_2354_8132.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , one case harbored two KRAS mutations , namely p.Glu49Lys and p.Ala146Thr . # ::alignments 0-1 1-1 3-1.1.1.1 4-1.1.1 5-1.1 6-1.1.2.1 8-1.1.2.3.1.1 10-1.1.2 10-1.1.2.2.1 10-1.1.2.2.2 12-1.1.2.2.3 14-1.1.2.2 (a / and~e.0,1 :op2 (h / harbor-01~e.5 :ARG0 (c / case-04~e.4 :quant 1~e.3) :ARG1 (m / mutate-01~e.10 :quant 2~e.6 :ARG1 (a2 / and~e.14 :op1 (m2 / mutate-01~e.10 :ARG2 (a3 / amino-acid :name (n2 / name :op1 "lysine")) :ARG3 (a4 / amino-acid :mod 49 :name (n3 / name :op1 "glutamic" :op2 "acid"))) :op2 (m3 / mutate-01~e.10 :ARG2 (a5 / amino-acid :name (n4 / name :op1 "threonine")) :ARG3 (a6 / amino-acid :mod 146 :name (n5 / name :op1 "alanine"))) :mod (n6 / namely~e.12)) :ARG2 (g / gene :name (n / name :op1 "KRAS"~e.8))))) # ::id pmid_2354_8132.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF mutations # ::alignments 1-1.1.1.1 2-1 (m / mutate-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "BRAF"~e.1))) # ::id pmid_2354_8132.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The frequency of BRAF p.Val600Glu mutations found in this series was 4.0 % ( 8 @/@ 201 ) . # ::alignments 1-1 4-1.1.1.1.1 7-1.1 7-1.2.2.1 7-1.2.2.1.5.1 8-1.1.4 9-1.1.4.1.r 10-1.1.4.1.1 11-1.1.4.1 13-1.2.1 14-1.2 16-1.2.2.1.1 18-1.2.2.1.5.1.1 (f / frequent-02~e.1 :ARG1 (m / mutate-01~e.7 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.4)) :ARG2 (a / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid")) :ARG3 (a2 / amino-acid :mod 600 :name (n3 / name :op1 "valine")) :ARG1-of (f2 / find-01~e.8 :location~e.9 (s / series~e.11 :mod (t / this~e.10)))) :quant (p / percentage-entity~e.14 :value 4.0~e.13 :ARG1-of (m2 / mean-01 :ARG2 (m3 / mutate-01~e.7 :quant 8~e.16 :ARG1 g :ARG2 a :ARG3 a2 :ARG1-of (i / include-91 :ARG2 (m4 / mutate-01~e.7 :quant 201~e.18)))))) # ::id pmid_2354_8132.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This mutation represented 89 % ( 8 @/@ 9 ) of exon 15 mutations and 73 % ( 8 @/@ 11 ) of all BRAF mutations . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1.3.2.1 4-1.2.1.3.2 6-1.2.2.1 8-1.2.1.3.1.1 11-1.2.1.4 12-1.2.1.4.1 13-1.2.1 13-1.2.1.3.1 13-1.2.2 14-1.2 15-1.2.2.3.2.1 16-1.2.2.3.2 18-1.2.1.1 18-1.2.2.1 20-1.2.2.3.1.1 23-1.2.2.3.1.3 25-1.2.2.3.1.2.1.1 27-1.2.2.3.1 (r / represent-01~e.2 :ARG0 (m / mutate-01~e.1 :mod (t / this~e.0)) :ARG1 (a / and~e.14 :op1 (m2 / mutate-01~e.13 :quant 8~e.18 :mod t :ARG1-of (i / include-91 :ARG2 (m3 / mutate-01~e.13 :quant 9~e.8) :ARG3 (p / percentage-entity~e.4 :value 89~e.3)) :location (e / exon~e.11 :mod 15~e.12)) :op2 (m4 / mutate-01~e.13 :quant 8~e.6,18 :mod t :ARG1-of (i2 / include-91 :ARG2 (m5 / mutate-01~e.27 :quant 11~e.20 :ARG1 (g / gene :name (n2 / name :op1 "BRAF"~e.25)) :mod (a2 / all~e.23)) :ARG3 (p2 / percentage-entity~e.16 :value 73~e.15))))) # ::id pmid_2354_8132.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also found mutations in codons 601 ( p.Lys601Glu ) , 466 ( p.Gly466Glu ) , and 471 ( p.Val471Ala ) of BRAF , the latter not previously described in mCRC [ @ 23 @ ] . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.2 3-1.2.3 5-1.2.1.4 5-1.2.2.4 5-1.2.3.4 6-1.2.1.3.1 6-1.2.1.4.1 11-1.2.2.3.1 11-1.2.2.4.1 16-1.2 17-1.2.3.3.1 17-1.2.3.4.1 23-1.2.1.1.1.1 28-1.2.3.5.1 28-1.2.3.5.1.r 29-1.2.3.5.3 30-1.2.3.5 30-1.4 31-1.2.3.5.2.r 32-1.2.3.5.2.1.1 35-1.4.1.1.1 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / and~e.16 :op1 (m / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.23)) :ARG2 (a8 / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid")) :ARG3 (a3 / amino-acid :mod 601~e.6 :name (n3 / name :op1 "lysine")) :location (c2 / codon~e.5 :mod 601~e.6)) :op2 (m2 / mutate-01~e.3 :ARG1 g :ARG2 a8 :ARG3 (a4 / amino-acid :mod 466~e.11 :name (n5 / name :op1 "glycine")) :location (c3 / codon~e.5 :mod 466~e.11)) :op3 (m3 / mutate-01~e.3 :ARG1 g :ARG2 (a5 / amino-acid :name (n6 / name :op1 "alanine")) :ARG3 (a6 / amino-acid :mod 471~e.17 :name (n7 / name :op1 "valine")) :location (c4 / codon~e.5 :mod 471~e.17) :ARG1-of (d4 / describe-01~e.30 :polarity~e.28 -~e.28 :ARG0~e.31 (d5 / disease :name (n10 / name :op1 "mCRC"~e.32)) :time (p / previous~e.29)))) :mod (a7 / also~e.1) :ARG1-of (d6 / describe-01~e.30 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 23~e.35)))) # ::id pmid_2354_8132.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One BRAF mutation , p.Val471Ala , occurred in a tumor also carrying a PIK3CA p.His1047Arg mutation . # ::alignments 0-1.1 2-1.2.1.1 4-1 9-1.5.r 11-1.5 12-1.5.1.2 13-1.5.1 16-1.5.1.1.1.1.1 19-1.5.1.1 (m / mutate-01~e.4 :quant 1~e.0 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.2)) :ARG2 (a / amino-acid :name (n2 / name :op1 "alanine")) :ARG3 (a2 / amino-acid :mod 471 :name (n3 / name :op1 "valine")) :location~e.9 (t / tumor~e.11 :ARG0-of (c / carry-01~e.13 :ARG1 (m2 / mutate-01~e.19 :ARG1 (g2 / gene :name (n4 / name :op1 "PIK3CA"~e.16)) :ARG2 (a3 / amino-acid :name (n5 / name :op1 "arginine")) :ARG3 (a4 / amino-acid :mod 1047 :name (n6 / name :op1 "histidine"))) :mod (a5 / also~e.12)))) # ::id pmid_2354_8132.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PIK3CA # ::alignments 1-1.1.1 (g / gene :name (n / name :op1 "PIK3CA"~e.1)) # ::id pmid_2354_8132.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PIK3CA mutations were present in 10.9 % ( 22 @/@ 201 ) of the tumors , unequally distributed between exons 9 and 20 : 73 % ( 16 @/@ 22 ) were helical domain mutants ( p.Glu542Lys , p.Glu545Lys , p.Glu545Asp , and p.Gln546Lys ) and 27 % ( 6 @/@ 22 ) kinase domain mutants ( p.Met1043Ile , p.His1047Arg , p.His1047Leu , and p.His1047Tyr ) . # ::alignments 1-1.1.1.1.1 3-1.1 5-1 6-1.2.r 7-1.2.2.2.1 8-1.2.2.2 10-1.2.1 12-1.2.2.1.1 16-1.2 16-1.2.2.1 18-1.1.2.2 18-1.1.2.2.1 18-1.1.2.2.1.r 19-1.1.2 20-1.1.2.1 22-1.1.2.1.1.1 23-1.1.2.1 24-1.1.2.1.2.1 26-1.1.2.3.1.1.3.2.1 27-1.1.2.3.1.1.3.2 29-1.1.2.3.1.1.1 31-1.1.2.3.1.1.3.1.1 34-1.1.2.3.1.1.2.1 35-1.1.2.3.1.1.2 36-1.1.2.3.1.1 36-1.1.2.3.1.1.4.1.1 36-1.1.2.3.1.1.4.1.2 36-1.1.2.3.1.1.4.1.3 36-1.1.2.3.1.1.4.1.4 44-1.1.2.3.1.1.4.1 47-1.1.2.3.1.1.4.1 48-1.1.2.3.1.2.3.2.1 49-1.1.2.3.1.2.3.2 51-1.1.2.3.1.2.1 53-1.1.2.3.1.1.3.1.1 55-1.1.2.3.1.2.2.1 56-1.1.2.3.1.2.2 57-1.1.2.3.1.1.3.1 57-1.1.2.3.1.2 57-1.1.2.3.1.2.4.1.1 57-1.1.2.3.1.2.4.1.2 57-1.1.2.3.1.2.4.1.3 57-1.1.2.3.1.2.4.1.4 65-1.1.2.3.1.2.4.1 (p / present-02~e.5 :ARG1 (m / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "PIK3CA"~e.1)) :ARG1-of (d / distribute-01~e.19 :ARG2 (b / between~e.20,23 :op1 (e2 / exon :mod 9~e.22) :op2 (e3 / exon :mod 20~e.24)) :manner (e / equal-01~e.18 :polarity~e.18 -~e.18) :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (m3 / mutate-01~e.36 :quant 16~e.29 :ARG1 (d4 / domain~e.35 :mod (h / helical~e.34)) :ARG1-of (i / include-91 :ARG2 (m4 / mutate-01~e.57 :quant 22~e.31,53) :ARG3 (p2 / percentage-entity~e.27 :value 73~e.26)) :ARG1-of (m5 / mean-01 :ARG2 (a2 / and~e.44,47 :op1 (m6 / mutate-01~e.36 :ARG2 (a3 / amino-acid :name (n4 / name :op1 "lysine")) :ARG3 (a4 / amino-acid :mod 542 :name (n5 / name :op1 "glutamic" :op2 "acid"))) :op2 (m7 / mutate-01~e.36 :ARG2 a3 :ARG3 (a5 / amino-acid :mod 545 :name (n6 / name :op1 "glutamic" :op2 "acid"))) :op3 (m8 / mutate-01~e.36 :ARG2 (a6 / amino-acid :name (n7 / name :op1 "aspartic" :op2 "acid")) :ARG3 a5) :op4 (m9 / mutate-01~e.36 :ARG2 a3 :ARG3 (a7 / amino-acid :mod 546 :name (n8 / name :op1 "glutamine")))))) :op2 (m10 / mutate-01~e.57 :quant 6~e.51 :ARG1 (d5 / domain~e.56 :mod (k / kinase~e.55)) :ARG1-of (i2 / include-91 :ARG2 m4 :ARG3 (p3 / percentage-entity~e.49 :value 27~e.48)) :ARG1-of (m11 / mean-01 :ARG2 (a8 / and~e.65 :op1 (m12 / mutate-01~e.57 :ARG2 (a9 / amino-acid :name (n9 / name :op1 "isoleucine")) :ARG3 (a10 / amino-acid :mod 1043 :name (n10 / name :op1 "methionine"))) :op2 (m13 / mutate-01~e.57 :ARG2 (a11 / amino-acid :name (n11 / name :op1 "arginine")) :ARG3 (a12 / amino-acid :mod 1047 :name (n12 / name :op1 "histidine"))) :op3 (m14 / mutate-01~e.57 :ARG2 (a13 / amino-acid :name (n13 / name :op1 "leucine")) :ARG3 a12) :op4 (m15 / mutate-01~e.57 :ARG2 (a14 / amino-acid :name (n14 / name :op1 "tyrosine")) :ARG3 a12)))))))) :ARG2~e.6 (t / tumor~e.16 :quant 22~e.10 :ARG1-of (i3 / include-91 :ARG2 (t2 / tumor~e.16 :quant 201~e.12) :ARG3 (p4 / percentage-entity~e.8 :value 10.9~e.7)))) # ::id pmid_2354_8132.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Five of the PIK3CA mutants also contained another mutation in either KRAS or BRAF @ . # ::alignments 0-1.1.1 4-1.1.2.1.1 6-1.1 6-1.1.3.1 6-1.2 7-1.3 8-1 9-1.2.2 10-1.2 14-1.2.1.1.1.1 16-1.2.1 18-1.2.1.2.1.1 (c / contain-01~e.8 :ARG0 (m / mutate-01~e.6 :quant 5~e.0 :ARG2 (g / gene :name (n / name :op1 "PIK3CA"~e.4)) :ARG1-of (i / include-91 :ARG2 (m2 / mutate-01~e.6 :ARG2 g))) :ARG1 (m3 / mutate-01~e.6,10 :ARG1 (o / or~e.16 :op1 (g2 / gene :name (n2 / name :op1 "KRAS"~e.14)) :op2 (g3 / gene :name (n3 / name :op1 "BRAF"~e.18))) :mod (a / another~e.9)) :mod (a2 / also~e.7)) # ::id pmid_2354_8132.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Clinicopathological associations # ::alignments 1-1.1 2-1 (a / associate-01~e.2 :mod (c / clinicopathological~e.1)) # ::id pmid_2354_8132.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok KRAS mutations were more frequent in patients older than the median age of diagnosis ( 21.5 % vs. 8.2 % ; P @ = 0.034 ) , whereas no statistically significant differences were found for BRAF or PIK3CA mutations regarding this parameter . # ::alignments 1-1.1.1.1.1.1 3-1.1.1 5-1.1.2.2.1 5-1.1.3 6-1.1 7-1.1.2.r 8-1.1.2.1.1 9-1.1.2.2 9-1.1.2.2.1 9-1.1.2.2.1.r 10-1.1.2.2.2.r 12-1.1.2.2.2.2 13-1.1.2.2.2 17-1.1.4.1.1.1 18-1.1.4.1.1 20-1.1.4.1 22-1.1.4.1.2.1 23-1.1.4.1.2 26-1.1.5 29-1.1.5.1 32-1 33-1.2.1 33-1.2.1.r 34-1.2.2.3.1 35-1.2.2.3 36-1.2.2 38-1.2 41-1.2.2.1.1.1.1.1 43-1.2.2.1 45-1.2.2.1.2.1.1.1 47-1.2.2.1.1 47-1.2.2.1.2 48-1.2.3 49-1.2.2.2.1 50-1.2.2.2 (c / contrast-01~e.32 :ARG1 (f / frequent-02~e.6 :ARG1 (m / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.1))) :location~e.7 (p / person :ARG0-of (h / have-rel-role-91 :ARG2 (p2 / patient~e.8)) :mod (o / old~e.9 :degree~e.9 (m2 / more~e.5,9) :compared-to~e.10 (a / age~e.13 :mod (d / diagnose-01) :mod (m3 / median~e.12)))) :degree (m4 / more~e.5) :ARG1-of (m5 / mean-01 :ARG2 (c2 / contrast-01~e.20 :ARG1 (p3 / percentage-entity~e.18 :value 21.5~e.17) :ARG2 (p4 / percentage-entity~e.23 :value 8.2~e.22))) :ARG1-of (s3 / statistical-test-91~e.26 :ARG2 0.034~e.29)) :ARG2 (f2 / find-01~e.38 :polarity~e.33 -~e.33 :ARG1 (d2 / differ-02~e.36 :ARG1 (o2 / or~e.43 :op1 (m6 / mutate-01~e.47 :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF"~e.41))) :op2 (m7 / mutate-01~e.47 :ARG1 (g3 / gene :name (n3 / name :op1 "PIK3CA"~e.45)))) :ARG3 (p6 / parameter~e.50 :mod (t / this~e.49)) :ARG1-of (s / significant-02~e.35 :manner (s2 / statistics~e.34))) :ARG0-of (r / regard-01~e.48))) # ::id pmid_2354_8132.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF and PIK3CA mutations were more frequent in the colon than in the sigmoid or rectum : 20.8 % vs. 1.6 % vs. 0.0 % ( P= @ 0.000 ) for BRAF and 23.4 % vs. 12.1 % vs. 5.4 % ( P @ = 0.011 ) for PIK3CA mutations ( Figure 3 ) . # ::alignments 1-1.1.1.1.1.1 3-1.1 5-1.1.2.1.1.1 7-1.1.1 7-1.1.2 7-1.5.1.1 7-1.5.1.1.4 7-1.5.1.1.4.r 7-1.5.1.1.5 7-1.5.1.1.5.r 7-1.5.1.2.4 9-1.2 10-1 11-1.3.r 13-1.3 14-1.4.r 17-1.4.1 18-1.4 19-1.4.2 21-1.5.1.1.2.1 22-1.5.1.1.2 24-1.4.r 26-1.5.1.1.4.2.1 27-1.5.1.1.4.2 29-1.4.r 31-1.5.1.1.5.2.1 32-1.5.1.1.5.2 35-1.5.1.1.6 37-1.5.1.1.6.1 41-1.5.1.1.1 43-1.1 44-1.5.1.2.2.1 45-1.5.1.2.2 47-1.5.1.2.4.r 49-1.5.1.2.4.2.1 50-1.5.1.2.4.2 52-1.5.1.2.4.r 54-1.5.1.2.5.2.1 55-1.5.1.2.5.2 58-1.5.1.2.6 61-1.5.1.2.6.1 65-1.5.1.2.1 67-1.5.1.2 67-1.5.1.2.5 67-1.5.1.2.5.r 69-1.6.1 71-1.6.1.1 (f / frequent-02~e.10 :ARG1 (a / and~e.3,43 :op1 (m / mutate-01~e.7 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.1))) :op2 (m2 / mutate-01~e.7 :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"~e.5)))) :degree (m3 / more~e.9) :location~e.11 (c / colon~e.13) :compared-to~e.14,24,29 (o / or~e.18 :op1 (s / sigmoid~e.17) :op2 (r / rectum~e.19)) :ARG1-of (m4 / mean-01 :ARG2 (a2 / and :op1 (m5 / mutate-01~e.7 :ARG1 g~e.41 :quant (p / percentage-entity~e.22 :value 20.8~e.21) :location c :compared-to~e.7 (m6 / mutate-01~e.7 :ARG1 g :quant (p2 / percentage-entity~e.27 :value 1.6~e.26) :location s) :compared-to~e.7 (m7 / mutate-01~e.7 :ARG1 g :quant (p3 / percentage-entity~e.32 :value 0.0~e.31) :location r) :ARG1-of (s2 / statistical-test-91~e.35 :ARG2 0.000~e.37)) :op2 (m8 / mutate-01~e.67 :ARG1 g2~e.65 :quant (p5 / percentage-entity~e.45 :value 23.4~e.44) :location c :compared-to~e.47,52 (m9 / mutate-01~e.7 :ARG1 2 :quant (p6 / percentage-entity~e.50 :value 12.1~e.49) :location s) :compared-to~e.67 (m10 / mutate-01~e.67 :ARG1 g2 :quant (p7 / percentage-entity~e.55 :value 5.4~e.54) :location r) :ARG1-of (s3 / statistical-test-91~e.58 :ARG2 0.011~e.61)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.69 :mod 3~e.71))) # ::id pmid_2354_8132.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the frequency of KRAS mutations is higher in sigmoid and rectum , the difference is not statistically significant . # ::alignments 0-1.4.r 2-1.4.1 5-1.4.1.1.1.1.1 7-1.4.1.1 9-1.4 9-1.4.3 9-1.4.3.r 10-1.4.2.r 11-1.4.2.1 12-1.4.2 13-1.4.2.2 16-1.1.r 16-1.2 18-1.1 18-1.1.r 19-1.3 20-1 (s / significant-02~e.20 :polarity~e.16,18 -~e.18 :ARG1 (d / differ-02~e.16) :manner (s2 / statistics~e.19) :concession~e.0 (h / high-02~e.9 :ARG1 (f / frequent-02~e.2 :ARG1 (m / mutate-01~e.7 :ARG1 (g / gene :name (n / name :op1 "KRAS"~e.5)))) :location~e.10 (a / and~e.12 :op1 (s3 / sigmoid~e.11) :op2 (r / rectum~e.13)) :degree~e.9 (m2 / more~e.9))) # ::id pmid_2354_8132.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok No significant differences were found between genders regarding KRAS , BRAF , or PIK3CA mutation frequencies . # ::alignments 0-1.1 0-1.1.r 1-1.2.3 2-1.2 4-1 6-1.2.1 9-1.2.2.1.1.1.1.1 13-1.2.2.1.2.1.1.1 16-1.2.2.1 18-1.2.2.1.3.1.1.1 20-1.2.2.1.1 20-1.2.2.1.2 20-1.2.2.1.3 21-1.2.2 (f / find-01~e.4 :polarity~e.0 -~e.0 :ARG1 (d / differ-02~e.2 :ARG1 (g / gender~e.6) :ARG3 (f2 / frequent-02~e.21 :ARG1 (o / or~e.16 :op1 (m / mutate-01~e.20 :ARG1 (g2 / gene :name (n / name :op1 "KRAS"~e.9))) :op2 (m2 / mutate-01~e.20 :ARG1 (g3 / gene :name (n2 / name :op1 "BRAF"~e.13))) :op3 (m3 / mutate-01~e.20 :ARG1 (g4 / gene :name (n3 / name :op1 "PIK3CA"~e.18))))) :ARG1-of (s / significant-02~e.1))) # ::id pmid_2384_5441.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A Genetic Progression Model of Braf @^V600E@ -@ Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention ( PMID : 23845441 ) # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.r 5-1.1.2.2.1.1.1 7-1.1.2.2.1.2.1 10-1.1.2.2 11-1.1.2.1.1 12-1.1.2 12-1.1.2.1 12-1.1.2.1.r 13-1 14-1.2 15-1.2.1.r 16-1.2.1.1 17-1.2.1 (r / reveal-01~e.13 :ARG0 (m / model~e.3 :mod (p / progress-01~e.2 :mod (g / genetic~e.1)) :topic~e.4 (c / create-01~e.12 :ARG1~e.12 (t3 / tumor~e.12 :mod (i2 / intestine~e.11)) :ARG2-of (i3 / induce-01~e.10 :ARG0 (e / enzyme :name (n / name :op1 "Braf"~e.5) :ARG2-of (m2 / mutate-01 :value "V600E"~e.7))))) :ARG1 (t / target-01~e.14 :purpose~e.15 (i / intervene-01~e.17 :ARG1 (t2 / therapy~e.16))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID23845441"))) # ::id pmid_2384_5441.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2384_5441.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @^V600E Initiates a Serrated Pathway to Intestinal Tumorigenesis # ::alignments 1-1.1.1.1 3-1.1.2.1 5-1 7-1.2.1 8-1.2 9-1.2.2.r 10-1.2.2.1.1 11-1.2.2 11-1.2.2.1 11-1.2.2.1.r (i / initiate-01~e.5 :ARG0 (e / enzyme :name (n / name :op1 "BRAF"~e.1) :ARG2-of (m / mutate-01 :value "V600E"~e.3)) :ARG1 (p / pathway~e.8 :ARG1-of (s / serrate-01~e.7) :destination~e.9 (c / create-01~e.11 :ARG1~e.11 (t / tumor~e.11 :mod (i2 / intestine~e.10))))) # ::id pmid_2384_5441.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the effect of Braf @ ^{V600E @} in the intestine , we created a Braf knockin allele , which can be activated by Cre , leading to the production of the V637E mutant Braf protein . # ::alignments 1-1.3 3-1.3.2 6-1.3.2.1.1.1 10-1.3.2.1.2.1 13-1.2.2 13-1.3.2.2.r 15-1.3.2.2 17-1.1 18-1 21-1.2.1.1.1 24-1.2 27-1.2.3.2 29-1.2.3 30-1.2.3.1.r 31-1.2.3.1.1.1 33-1.2.3.3 34-1.2.3.3.1.r 36-1.2.3.3.1 39-1.2.3.3.1.2.2.1 40-1.2.3.3.1.2 40-1.2.3.3.1.2.2 40-1.2.3.3.1.2.2.r 40-1.3.2.1 40-1.3.2.1.2 40-1.3.2.1.2.r 41-1.2.1.1.1 41-1.2.3.3.1.2.1.1 (c / create-01~e.18 :ARG0 (w / we~e.17) :ARG1 (a / allele~e.24 :mod (g / gene :name (n / name :op1 "Braf"~e.21,41)) :ARG1-of (k / knock-in-00~e.13) :ARG1-of (a2 / activate-01~e.29 :ARG0~e.30 (e3 / enzyme :name (n2 / name :op1 "Cre"~e.31)) :ARG1-of (p / possible-01~e.27) :ARG0-of (l / lead-03~e.33 :ARG2~e.34 (p3 / produce-01~e.36 :ARG0 a2 :ARG1 (e4 / enzyme~e.40 :name (n3 / name :op1 "Braf"~e.41) :ARG2-of~e.40 (m / mutate-01~e.40 :value "V637E"~e.39)))))) :purpose (e / examine-01~e.1 :ARG0 w :ARG1 (a3 / affect-01~e.3 :ARG0 (g2 / gene~e.40 :name (n4 / name :op1 "Braf"~e.6) :ARG2-of~e.40 (m2 / mutate-01~e.40 :value "V600E"~e.10)) :ARG1~e.13 (i / intestine~e.15)))) # ::id pmid_2384_5441.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Braf @ ^{V637E @} in mouse exon 18 is at the orthologous position of the human BRAF @ ^{V600E @} mutation affecting exon 15 . # ::alignments 1-1.1.1.1 5-1.1.2.1 9-1.1.3.2 10-1.1.3 11-1.1.3.1 12-1 13-1 15-1.2.1 16-1.2 17-1.2.2.r 19-1.2.2.3 21-1.2.2.1.1 25-1.2.2.2.1 28-1.1 28-1.1.2 28-1.1.2.r 28-1.2.2 28-1.2.2.2 28-1.2.2.2.r 29-1.2.2.4 30-1.2.2.4.1 31-1.2.2.4.1.1 (b / be-located-at-91~e.12,13 :ARG1 (g / gene~e.28 :name (n / name :op1 "Braf"~e.1) :ARG2-of~e.28 (m / mutate-01~e.28 :value "V637E"~e.5) :location (e / exon~e.10 :mod 18~e.11 :mod (m2 / mouse~e.9))) :ARG2 (p / position~e.16 :mod (o / orthologous~e.15) :compared-to~e.17 (g2 / gene~e.28 :name (n2 / name :op1 "Braf"~e.21) :ARG2-of~e.28 (m3 / mutate-01~e.28 :value "V600E"~e.25) :mod (h / human~e.19) :ARG0-of (a / affect-01~e.29 :ARG1 (e2 / exon~e.30 :mod 15~e.31))))) # ::id pmid_2384_5441.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the absence of Cre , a Lox @-@ Stop @-@ Lox cassette located in intron 17 prevents expression of the mutant allele ( Figures 1 @ A @–@ 1D ) . # ::alignments 2-1.3.1 3-1.3.1.1.r 4-1.3.1.1.1.1 7-1.1.1.1 9-1.1.1.1 11-1.1.1.1 12-1.1 13-1.1.2.r 15-1.1.2 16-1.1.2.1 17-1 18-1.2 19-1.2.1.r 21-1.2.1.1 22-1.2.1 25-1.4.1.1 25-1.4.1.2 30-1.4.1.2.1 (p / prevent-01~e.17 :ARG0 (c3 / cassette~e.12 :name (n / name :op1 "Lox-Stop-Lox"~e.7,9,11) :location~e.13 (i / intron~e.15 :mod 17~e.16)) :ARG1 (e / express-03~e.18 :ARG1~e.19 (a / allele~e.22 :ARG2-of (m / mutate-01~e.21))) :ARG1-of (c2 / cause-01 :ARG0 (a2 / absent-01~e.2 :ARG1~e.3 (e2 / enzyme :name (n2 / name :op1 "Cre"~e.4)))) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.25 :mod "1A") :op2 (f2 / figure~e.25 :mod "1D"~e.30)))) # ::id pmid_2384_5441.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To direct mutant Braf expression to the intestine , we used Villin @-@ Cre ( Vil @-@ Cre ) mice in which Cre is broadly expressed in epithelia of the small and large intestine ( Madison et al. , 2002 ) . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.2 2-1.3.2.1.2.r 3-1.3.2.1.1.1 4-1.3.2 5-1.3.3.r 7-1.3.3 9-1.1 10-1 12-1.2.1.1.1.1 14-1.2.1.2.1.1 20-1.2.1.2.1.1 23-1.2 26-1.2.2.1 28-1.2.2.3 29-1.2.2 34-1.2.2.2.1.1.1 35-1.2.2.2.1 36-1.2.2.2.1.2.1 37-1.2.2.2.1.1 37-1.2.2.2.1.2 40-1.4.1.1.1.1.1 41-1.4.1.1 42-1.4.1.1.2.1 44-1.4.1.1.3.1 (u / use-01~e.10 :ARG0 (w / we~e.9) :ARG1 (m / mouse~e.23 :mod (m3 / macro-molecular-complex :part (p5 / protein :name (n / name :op1 "Villin"~e.12)) :part (e4 / enzyme :name (n5 / name :op1 "Cre"~e.14,20))) :location-of (e / express-03~e.29 :ARG2 e4~e.26 :ARG3 (e2 / epithelium :part-of (a / and~e.35 :op1 (i / intestine~e.37 :mod (s / small~e.34)) :op2 (i2 / intestine~e.37 :mod (l / large~e.36)))) :ARG1-of (b / broad-02~e.28))) :ARG2 (d / direct-01~e.1 :ARG0 w :ARG1 (e3 / express-03~e.4 :ARG2 (e5 / enzyme~e.2 :name (n3 / name :op1 "Braf"~e.3) :ARG2-of~e.2 (m2 / mutate-01~e.2))) :ARG2~e.5 (i3 / intestine~e.7)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.41 :op1 (p3 / person :name (n4 / name :op1 "Madison"~e.40)) :op2 (p4 / person :mod (o / other~e.42)) :time (d3 / date-entity :year 2002~e.44))))) # ::id pmid_2384_5441.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E/+ @} mice the stop cassette at the Braf locus is excised specifically in the intestine but not in other organs ( Figure 1 @ E ) . # ::alignments 4-1.3.1.2.1.1 6-1.3.2.1.1 10-1.3.2.2.1 15-1.3 17-1.1.1.1 18-1.1.1 22-1.1.2.1.1.1 24-1.1.2 26-1.1 26-1.2 27-1.1.4 28-1.1.3.r 30-1.1.3 31-1 32-1.2.1 32-1.2.1.r 33-1.2.4.r 34-1.2.4.1 35-1.2.4 38-1.4.1 (c3 / contrast-01~e.31 :ARG1 (e / excise-01~e.26 :ARG1 (c / cassette~e.18 :ARG2-of (s / stop-01~e.17)) :ARG2 (l / locus~e.24 :mod (g / gene :name (n / name :op1 "Braf"~e.22))) :location~e.28 (i / intestine~e.30) :ARG1-of (s2 / specific-02~e.27)) :ARG2 (e2 / excise-01~e.26 :polarity~e.32 -~e.32 :ARG1 c :ARG2 l :location~e.33 (o / organ~e.35 :mod (o2 / other~e.34))) :location (m / mouse~e.15 :mod (m3 / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "Villin")) :part (e4 / enzyme :name (n4 / name :op1 "Cre"~e.4))) :mod (g2 / gene :name (n3 / name :op1 "Braf"~e.6) :ARG2-of (m2 / mutate-01 :value "LSL-V637E/+"~e.10))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.38 :mod "1E"))) # ::id pmid_2384_5441.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The murine Braf @ ^{LSL @-@ V637E @} allele is a knockin allele and is thus expressed from the endogenous Braf locus at physiologic levels . # ::alignments 1-1.3.1.1 3-1.1.1.1 7-1.1.2.1 9-1.1.2.1 12-1.2 13-1.2.r 16-1 16-1.2 18-1.2.r 19-1.2.2 20-1.2.2.1 21-1.2.2.1.2.r 23-1.2.2.1.2.2 25-1.2.2.1.2.1.1.1 27-1.2.2.1.2 28-1.2.2.1.3.r 29-1.2.2.1.3.1 30-1.2.2.1.3 (a / allele~e.16 :mod (g / gene :name (n / name :op1 "Braf"~e.3) :ARG2-of (m / mutate-01 :value "LSL-V637E"~e.7,9)) :domain~e.13,18 (a2 / allele~e.12,16 :ARG1-of (k / knock-in-00) :ARG0-of (c / cause-01~e.19 :ARG1 (e / express-03~e.20 :ARG1 a :ARG3~e.21 (l / locus~e.27 :mod (g2 / gene :name (n2 / name :op1 "Braf"~e.25)) :mod (e2 / endogenous~e.23)) :location~e.28 (l2 / level~e.30 :mod (p / physiologic~e.29))))) :mod (o / organism :name (n3 / name :op1 "Muridae"~e.1))) # ::id pmid_2384_5441.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} animals developed lifelong persistent generalized crypt hyperplasia affecting nearly every crypt , leading to significantly elongated and thickened small and large intestines ( Figures 1 @ F @–@ 1P ; Figure S1 @ A available online ) . # ::alignments 0-1.1.1 4-1.1.2.2.1.1 6-1.1.3.1.1 10-1.1.3.2.1 12-1.1.3.2.1 16-1.1 17-1 18-1.2.3 19-1.2.6 20-1.2.2 21-1.2.1 22-1.2 23-1.2.4 24-1.2.4.1.1.1 25-1.2.4.1.1 26-1.2.4.1 28-1.2.5 29-1.2.5.1.r 30-1.2.5.1.3 31-1.2.5.1.1 32-1.2.5.1 32-1.2.5.1.1.1 33-1.2.5.1.2 34-1.2.5.1.1.1.1.1 35-1.2.5.1.1.1 36-1.2.5.1.1.1.2.1 37-1.2.5.1.1.1.1 37-1.2.5.1.1.1.2 40-1.3.1.1.1 40-1.3.1.2 45-1.3.1.1.2.1 48-1.3.1.1.1 48-1.3.1.1.2 48-1.3.1.2 52-1.3.1.2.2 53-1.3.1.2.2.1 (d / develop-01~e.17 :ARG1 (a / animal~e.16 :mod (a2 / all~e.0) :mod (m2 / macro-molecular-complex :part (p / protein :name (n / name :op1 "Villin")) :part (e4 / enzyme :name (n4 / name :op1 "Cre"~e.4))) :mod (g / gene :name (n2 / name :op1 "Braf"~e.6) :ARG2-of (m / mutate-01 :value "LSL-V637E/+"~e.10,12))) :ARG2 (h / hyperplasia~e.22 :mod (c / crypt~e.21) :ARG1-of (g2 / generalize-01~e.20) :duration (l / lifelong~e.18) :ARG0-of (a3 / affect-01~e.23 :ARG1 (c2 / crypt~e.26 :mod (e / every~e.25 :mod (n3 / near~e.24)))) :ARG0-of (l2 / lead-03~e.28 :ARG2~e.29 (a4 / and~e.32 :op1 (e2 / elongate-01~e.31 :ARG1 (a5 / and~e.32,35 :op1 (i / intestine~e.37 :mod (s / small~e.34)) :op2 (i2 / intestine~e.37 :mod (l3 / large~e.36)))) :op2 (t / thicken-01~e.33 :ARG1 a5) :ARG1-of (s2 / significant-02~e.30))) :ARG1-of (p2 / persist-01~e.19)) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and :op1 (v / value-interval :op1 (f / figure~e.40,48 :mod "1F") :op2 (f2 / figure~e.48 :mod "1P"~e.45)) :op2 (f3 / figure~e.40,48 :mod "S1A" :ARG2-of (a7 / available-02~e.52 :medium (o / online~e.53)))))) # ::id pmid_2384_5441.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Endoscopically and histologically , villi in the small intestine ( SI ) had a thickened and deformed appearance and were often branched ( Figures 1 @ I @–@ 1L ) . # ::alignments 1-1.1.2.1 7-1.1.1.1.1 8-1.1.1.1 12-1.1 14-1.1.2.1.1 15-1.1.2.1 16-1.1.2.1.2 17-1.1.2 18-1 20-1.2.1 21-1.2 24-1.5.1.1 24-1.5.1.2 29-1.5.1.2.1 (a / and~e.18 :op1 (h / have-03~e.12 :ARG0 (v / villus :part-of (i / intestine~e.8 :mod (s / small~e.7))) :ARG1 (a2 / appear-01~e.17 :ARG1 (a3 / and~e.1,15 :op1 (t / thicken-01~e.14) :op2 (d / deform-01~e.16)))) :op2 (b / branch-01~e.21 :frequency (o / often~e.20)) :mod (e / endoscopic) :mod (h2 / histologic) :ARG1-of (d2 / describe-01 :ARG0 (v2 / value-interval :op1 (f / figure~e.24 :mod "1I") :op2 (f2 / figure~e.24 :mod "1L"~e.29)))) # ::id pmid_2384_5441.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Changes in the large intestine ( LI ) included crypt hyperplasia and mucosal protrusions resembling villous structures that replaced the normal crypt pattern ( Figures 1 @ M @–@ 1P ) . # ::alignments 0-1.2 1-1.2.1.r 3-1.2.1.1 4-1.2.1 8-1 9-1.1.1.1 10-1.1.1 11-1.1 13-1.1.2 14-1.1.2.2 16-1.1.2.2.1 18-1.1.2.2.1.2 20-1.1.2.2.1.2.1.1.1 21-1.1.2.2.1.2.1.1 22-1.1.2.2.1.2.1 25-1.3.1.1 25-1.3.1.2 30-1.3.1.2.1 (i / include-01~e.8 :ARG1 (a / and~e.11 :op1 (h / hyperplasia~e.10 :mod (c2 / crypt~e.9)) :op2 (p / protrude-01~e.13 :ARG2 (m / mucus) :ARG1-of (r / resemble-01~e.14 :ARG2 (s / structure~e.16 :mod (v / villus) :ARG2-of (r2 / replace-01~e.18 :ARG1 (p2 / pattern-01~e.22 :ARG1 (c3 / crypt~e.21 :ARG1-of (n / normal-02~e.20)))))))) :ARG2 (c / change-01~e.0 :ARG1~e.1 (i2 / intestine~e.4 :mod (l / large~e.3))) :ARG1-of (d / describe-01 :ARG0 (v2 / value-interval :op1 (f / figure~e.25 :mod "1M") :op2 (f2 / figure~e.25 :mod "1P"~e.30)))) # ::id pmid_2384_5441.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This generalized hyperplasia was characterized by focal serrated epithelial formations , which had cytomorphologic features of human microvesicular or goblet cell @-@ rich hyperplastic ( serrated ) polyps ( Figures 1 @ Q @–@ 1T and S1 @ B ) . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2.1.1 8-1.2.1 9-1.2 12-1.2.2 13-1.2.2.1.1 14-1.2.2.1 15-1.2.2.1.2.r 16-1.2.2.1.2.1.2 17-1.2.2.1.2.1.1 18-1.2.2.1.2 19-1.2.2.1.2.2.2.1.1.1 20-1.2.2.1.2.2.2.1.1.2 22-1.2.2.1.2.2.2 23-1.2.2.1.2.2.1 25-1.2.1.1 27-1.2.2.1.2.1 27-1.2.2.1.2.2 30-1.3.1.1.1 30-1.3.1.1.2 30-1.3.1.2 35-1.3.1.1.2.1 36-1.3.1 (c / characterize-01~e.4 :ARG1 (h / hyperplasia~e.2 :mod (t / this~e.0) :ARG1-of (g / generalize-01~e.1)) :ARG2~e.5 (f / form-01~e.9 :ARG1 (e / epithelium~e.8 :ARG1-of (s / serrate-01~e.7,25 :ARG2 (f2 / focus~e.6))) :ARG0-of (h2 / have-03~e.12 :ARG1 (f3 / feature~e.14 :mod (c2 / cytomorphologic~e.13) :poss~e.15 (o / or~e.18 :op1 (p / polyp~e.27 :mod (m / microvesicular~e.17) :mod (h3 / human~e.16)) :op2 (p3 / polyp~e.27 :mod (h5 / hyperplastic~e.23) :mod (r / rich~e.22 :mod (c3 / cell :name (n / name :op1 "goblet"~e.19 :op2 "cell"~e.20)))))))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.36 :op1 (v / value-interval :op1 (f4 / figure~e.30 :mod "1Q") :op2 (f5 / figure~e.30 :mod "1T"~e.35)) :op2 (f6 / figure~e.30 :mod "S1B")))) # ::id pmid_2384_5441.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both types were present in the LI , whereas microvesicular hyperplasia was predominant in the SI . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 8-1 9-1.2.1.1 10-1.2.1 (c / contrast-01~e.8 :ARG1 (p / present-02~e.3 :ARG1 (t / type-03~e.1 :mod (b / both~e.0)) :ARG2 (i / intestine :mod (l / large))) :ARG2 (p2 / predominate-01 :ARG1 (h / hyperplasia~e.10 :mod (m / microvesicular~e.9)) :location (i2 / intestine :mod (s / small)))) # ::id pmid_2384_5441.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because of this resemblance to human serrated hyperplasia ( Figure S1 @ B ) , we refer to the histology in the mouse as murine serrated hyperplasia ( mSH ) . # ::alignments 0-1.4 2-1.4.1.2 3-1.4.1 4-1.4.1.1.r 5-1.4.1.1.2 6-1.4.1.1.3 7-1.3.1.1 7-1.4.1.1.1.1 16-1.1 17-1 18-1.2.r 18-1.4 20-1.2 21-1.2.1.r 23-1.2.1 24-1.3.r 25-1.3.3.1.1 26-1.3.2 27-1.3.1.1 27-1.4.1.1.1.1 (r / refer-01~e.17 :ARG0 (w / we~e.16) :ARG1~e.18 (h / histology~e.20 :location~e.21 (m / mouse~e.23)) :ARG2~e.24 (m2 / medical-condition :name (n2 / name :op1 "hyperplasia"~e.7,27) :ARG1-of (s / serrate-01~e.26) :mod (o / organism :name (n / name :op1 "Muridae"~e.25))) :ARG0-of (c / cause-01~e.0,18 :ARG1 (r2 / resemble-01~e.3 :ARG2~e.4 (m3 / medical-condition :name (n3 / name :op1 "hyperplasia"~e.7,27) :mod (h4 / human~e.5) :ARG1-of s~e.6) :mod (t / this~e.2)))) # ::id pmid_2384_5441.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like in human serrated hyperplastic polyps , there was a mild increase in the number of proliferating cells in mSH as compared to wild @-@ type mucosa ( Figures S1 @ C and S1D ) . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.3 3-1.4.1.2 4-1.4.1.1 5-1.4.1 10-1.2 11-1 12-1.1.r 14-1.1 15-1.1.1.r 16-1.1.1.1 17-1.1.1 18-1.1.1.2.r 19-1.1.1.2.1.1 20-1.5.r 21-1.5 22-1.5.1.r 23-1.5.1.1 25-1.5.1.1 26-1.5.1 29-1.3.1.1 29-1.3.1.2 33-1.3.1 34-1.3.1.2.1 (i / increase-01~e.11 :ARG1~e.12 (n / number~e.14 :quant-of~e.15 (c / cell~e.17 :ARG0-of (p / proliferate-01~e.16) :location~e.18 (m4 / medical-condition :name (n2 / name :op1 "mSH"~e.19)))) :degree (m / mild~e.10) :ARG1-of (d / describe-01 :ARG0 (a / and~e.33 :op1 (f / figure~e.29 :mod "S1C") :op2 (f2 / figure~e.29 :mod "S1D"~e.34))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (p2 / polyp~e.5 :mod (h / hyperplastic~e.4) :ARG1-of (s / serrate-01~e.3) :mod (h2 / human~e.2))) :ARG1-of~e.20 (c2 / compare-01~e.21 :ARG2~e.22 (m3 / mucosa~e.26 :mod (w / wild-type~e.23,25)))) # ::id pmid_2384_5441.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ki67 @-@ positive cells were present in the mid and @/@ or upper crypt in Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} intestines but were restricted to the lower crypt in wild @-@ type intestines ( Figure S1 @ C ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.2 3-1.1.1 5-1.1 6-1.1.2.r 8-1.1.2.1.1 9-1.1.2 11-1.1.2 12-1.1.2.2.1 13-1.1.2.1 13-1.1.2.2 18-1.1.2.3.2.2.1.1 20-1.1.2.3.1.1.1 24-1.1.2.3.1.2.1 26-1.1.2.3.1.2.1 30-1.1.2.3 31-1 33-1.2 34-1.2.2.r 36-1.2.2.1 36-1.2.2.1.1 36-1.2.2.1.1.r 37-1.2.2 38-1.2.2.2.r 39-1.2.2.2.1 41-1.2.2.2.1 42-1.2.2.2 45-1.3.1 (c / contrast-01~e.31 :ARG1 (p4 / present-02~e.5 :ARG1 (c2 / cell~e.3 :mod (p / protein :name (n / name :op1 "Ki67"~e.0)) :mod (p2 / positive~e.2)) :ARG2~e.6 (a / and-or~e.9,11 :op1 (c3 / crypt~e.13 :mod (m / mid~e.8)) :op2 (c4 / crypt~e.13 :mod (u / upper~e.12)) :part-of (i / intestine~e.30 :mod (g / gene :name (n3 / name :op1 "Braf"~e.20) :ARG2-of (m2 / mutate-01 :value "LSL-V637E"~e.24,26)) :mod (m4 / macro-molecular-complex :part (p3 / protein :name (n2 / name :op1 "Villin")) :part (e2 / enzyme :name (n4 / name :op1 "Cre"~e.18)))))) :ARG2 (r / restrict-01~e.33 :ARG1 c2 :location~e.34 (c5 / crypt~e.37 :ARG1-of (l / low-04~e.36 :degree~e.36 (m3 / more~e.36)) :part-of~e.38 (i2 / intestine~e.42 :mod (w / wild-type~e.39,41)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.45 :mod "S1C"))) # ::id pmid_2384_5441.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hyperproliferation seems to be the underlying mechanism of the hyperplastic changes because apoptosis was not reduced in Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} intestines as compared to wild @-@ type mucosa ( Figures S1 @ E and S1F ) . # ::alignments 1-1 2-1.1.r 2-1.2 3-1.1.2.r 5-1.1.1 6-1.1 7-1.1.1.1.r 9-1.1.1.1.1 10-1.1.1.1 11-1.2 12-1.2.1.2 14-1.2.1.1 14-1.2.1.1.r 15-1.2.1 20-1.2.1.3.1.2.1.1 22-1.2.1.3.2.1.1 26-1.2.1.3.2.2.1 28-1.2.1.3.2.2.1 32-1.2.1.3 33-1.2.1.4.r 34-1.2.1.4 35-1.2.1.4.1.r 36-1.2.1.4.1.1 38-1.2.1.4.1.1 39-1.2.1.4.1 42-1.3.1.1 42-1.3.1.2 46-1.3.1 47-1.3.1.2.1 (s / seem-01~e.1 :ARG1~e.2 (m / mechanism~e.6 :ARG0-of (u / underlie-01~e.5 :ARG1~e.7 (c / change-01~e.10 :mod (h2 / hyperplastic~e.9))) :domain~e.3 (h / hyperproliferate-01)) :ARG1-of (c2 / cause-01~e.2,11 :ARG0 (r / reduce-01~e.15 :polarity~e.14 -~e.14 :ARG1 (a / apoptosis~e.12) :location (i / intestine~e.32 :mod (m4 / macro-molecular-complex :part (p / protein :name (n / name :op1 "Villin")) :part (e2 / enzyme :name (n3 / name :op1 "Cre"~e.20))) :mod (g / gene :name (n2 / name :op1 "Braf"~e.22) :ARG2-of (m2 / mutate-01 :value "LSL-V637E"~e.26,28))) :ARG1-of~e.33 (c3 / compare-01~e.34 :ARG2~e.35 (m3 / mucosa~e.39 :mod (w / wild-type~e.36,38))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.46 :op1 (f / figure~e.42 :mod "S1E") :op2 (f2 / figure~e.42 :mod "S1F"~e.47)))) # ::id pmid_2384_5441.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also intercrossed LSL @-@ Braf @ ^{V600E @} mice with Lgr5 @-@ EGFP @-@ IRES @-@ CreERT2 knockin mice . # ::alignments 0-1.1 1-1.4 4-1.2.1.1.1 6-1.2.2.1.1 10-1.2.2.2.1 13-1.2 13-1.3 16-1.3.2.1.1 18-1.3.2.1.1 20-1.3.2.1.1 22-1.3.2.1.1 25-1.2 25-1.3 (i / intercross-00 :ARG0 (w / we~e.0) :ARG1 (m / mouse~e.13,25 :mod (m5 / molecular-physical-entity :name (n / name :op1 "LSL"~e.4)) :mod (g / gene :name (n2 / name :op1 "Braf"~e.6) :ARG2-of (m2 / mutate-01 :value "V600E"~e.10))) :ARG2 (m3 / mouse~e.13,25 :ARG1-of (k / knock-in-00) :mod (m4 / molecular-physical-entity :name (n3 / name :op1 "Lgr5-EGFP-IRES-CreERT2"~e.16,18,20,22))) :mod (a / also~e.1)) # ::id pmid_2384_5441.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tamoxifen @-@ inducible Lgr5 @-@ Cre allowed stochastic activation of mutant Braf in a part of the intestinal stem cells , thereby inducing hyperplastic polyps in nonhyperplastic surrounding mucosa ( Figure S1 @ G ) . # ::alignments 0-1.1.3.1.1.1 2-1.1 2-1.1.3 2-1.1.3.r 3-1.1.1.1.1 5-1.1.2.1.1 6-1 7-1.2.2 8-1.2 9-1.2.1.r 10-1.2.1 10-1.2.1.2 10-1.2.1.2.r 11-1.2.1.1.1 14-1.1.2.r 14-1.3 15-1.3.1.r 17-1.3.1.2 18-1.3.1.1 19-1.3.1 22-1.4.1 23-1.4.1.1.1 23-1.4.1.2.2 24-1.4.1.1 27-1.4.1.2.1 28-1.4.1.2 31-1.5.1 (a / allow-01~e.6 :ARG0 (m / macro-molecular-complex~e.2 :part (p / protein :name (n / name :op1 "Lgr5"~e.3)) :part~e.14 (e2 / enzyme :name (n2 / name :op1 "Cre"~e.5)) :ARG2-of~e.2 (i / induce-01~e.2 :ARG0 (s / small-molecule :name (n3 / name :op1 "tamoxifen"~e.0)) :ARG1-of (p3 / possible-01))) :ARG1 (a2 / activate-01~e.8 :ARG1~e.9 (e / enzyme~e.10 :name (n4 / name :op1 "Braf"~e.11) :ARG1-of~e.10 (m2 / mutate-01~e.10)) :mod (s2 / stochastic~e.7)) :location (p4 / part~e.14 :part-of~e.15 (c / cell~e.19 :mod (s3 / stem~e.18) :source (i2 / intestine~e.17))) :ARG0-of (c2 / cause-01 :ARG1 (i3 / induce-01~e.22 :ARG2 (p5 / polyp~e.24 :mod (h / hyperplastic~e.23)) :location (m3 / mucosa~e.28 :ARG1-of (s4 / surround-01~e.27) :mod (h2 / hyperplastic~e.23 :polarity -)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "S1G"))) # ::id pmid_2384_5441.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF mutations have been observed in human serrated polyps occurring sporadically or in serrated polyposis syndrome and we show here that BRAF @^V600E is indeed the underlying initiating event that is sufficient to induce lifelong sustained hyperplasia . # ::alignments 1-1.1.1.1.1.1 3-1.1.1 3-1.2.2.3 3-1.2.2.3.2 3-1.2.2.3.2.r 6-1.1 7-1.1.2.r 8-1.1.2.1.1 9-1.1.2.1.2 10-1.1.2.1 12-1.1.2.1.3 13-1.1.2 15-1.1.2.2.1.1 16-1.1.2.2.1 17-1.1.2.2 18-1 19-1.2.1 20-1.2 21-1.2.3 22-1.2.2.r 23-1.2.2.3.1.1 25-1.2.2.3.2.1 27-1.2.2.3.r 28-1.2.2.5 30-1.2.2.2 31-1.2.2.1 32-1.2.2 34-1.2.2.3.r 35-1.2.2.4 37-1.2.2.4.1 38-1.2.2.4.1.1.1 39-1.2.2.4.1.1.2 40-1.2.2.4.1.1 (a / and~e.18 :op1 (o / observe-01~e.6 :ARG1 (m / mutate-01~e.3 :ARG1 (g / gene :name (n / name :op1 "BRAF"~e.1))) :location~e.7 (o2 / or~e.13 :op1 (p / polyp~e.10 :mod (h / human~e.8) :ARG1-of (s / serrate-01~e.9) :frequency (s2 / sporadic~e.12)) :op2 (s3 / syndrome~e.17 :mod (p2 / polyposis~e.16 :ARG1-of s~e.15)))) :op2 (s4 / show-01~e.20 :ARG0 (w / we~e.19) :ARG1~e.22 (e / event~e.32 :ARG0-of (i / initiate-01~e.31) :ARG0-of (u / underlie-01~e.30) :domain~e.27,34 (e2 / enzyme~e.3 :name (n2 / name :op1 "BRAF"~e.23) :ARG2-of~e.3 (m2 / mutate-01~e.3 :value "V600E"~e.25)) :ARG0-of (s5 / suffice-01~e.35 :ARG1 (i2 / induce-01~e.37 :ARG2 (h2 / hyperplasia~e.40 :duration (l / lifelong~e.38) :ARG1-of (s6 / sustain-01~e.39)))) :mod (i3 / indeed~e.28)) :location (h3 / here~e.21))) # ::id pmid_2384_5441.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BRAF @^V600E Induced Serrated Tumorigenesis Progresses through a Hyperplasia/Adenoma/Carcinoma Sequence # ::alignments 1-1.1.3.1.1.1 3-1.1.3.1.2.1 5-1.1.3 6-1.1.2 7-1.1 7-1.1.1 7-1.1.1.r 8-1 12-1.2.1 12-1.2.2 12-1.2.3 (p / progress-01~e.8 :ARG1 (c2 / create-01~e.7 :ARG1~e.7 (t / tumor~e.7) :ARG1-of (s / serrate-01~e.6) :ARG2-of (i / induce-01~e.5 :ARG0 (e / enzyme :name (n / name :op1 "BRAF"~e.1) :ARG2-of (m / mutate-01 :value "V600E"~e.3)))) :instrument (s2 / slash :op1 (s3 / sequence~e.12 :mod (m3 / medical-condition :name (n3 / name :op1 "hyperplasia"))) :op2 (s4 / sequence~e.12 :mod (m2 / medical-condition :name (n2 / name :op1 "adenoma"))) :op3 (s5 / sequence~e.12 :mod (c / carcinoma)))) # ::id pmid_2384_5441.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate whether mSH progresses to dysplasia , we aged Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ mice up to 18 months and sacrificed them at various time points . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 3-1.3.2.2.1.1 4-1.3.2 5-1.3.2.3.r 6-1.3.2.3.1.1 8-1.1.1 9-1.1 13-1.1.2.1.2.1.1 15-1.1.2.2.1.1 19-1.1.2.2.2.1 21-1.1.2.2.2.1 25-1.1.2 26-1.1.3 27-1.1.3 28-1.1.3.1.1 29-1.1.3.1.2 30-1 31-1.2 34-1.2.3.2 35-1.1.3.1 35-1.1.3.r 35-1.2.3.1 35-1.2.3.r 36-1.2.3 36-1.3.r (a / and~e.30 :op1 (a2 / age-01~e.9 :ARG0 (w / we~e.8) :ARG1 (m / mice~e.25 :mod (m2 / macro-molecular-complex :part (p / protein :name (n / name :op1 "Villin")) :part (e2 / enzyme :name (n2 / name :op1 "Cre"~e.13))) :mod (g / gene :name (n3 / name :op1 "Braf"~e.15) :ARG2-of (m3 / mutate-01 :value "LSL-V637E"~e.19,21))) :time~e.35 (u / up-to~e.26,27 :op1 (t / temporal-quantity~e.35 :quant 18~e.28 :unit (m4 / month~e.29)))) :op2 (s / sacrifice-01~e.31 :ARG0 w :ARG1 m :time~e.35 (p3 / point~e.36 :mod (t2 / time~e.35) :mod (v / various~e.34))) :purpose~e.36 (i / investigate-01~e.1 :ARG0 w :ARG1 (p4 / progress-01~e.4 :mode~e.2 interrogative~e.2 :ARG1 (m6 / medical-condition :name (n4 / name :op1 "mSH"~e.3)) :ARG4~e.5 (m7 / medical-condition :name (n5 / name :op1 "dysplasia"~e.6))))) # ::id pmid_2384_5441.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hyperplasia to dysplasia progression was often observed at a young age ( 2 @–@ 3 months ) , at which time some animals already developed macroscopic tumors (> 2 mm ) with dysplasia . # ::alignments 0-1.1.1 2-1.1.2 3-1.1 5-1.3 6-1 7-1.2.r 9-1.2.1 10-1.2 12-1.2.2.1.1.1 14-1.2.2.1.1.2 15-1.2.2.1.2 20-1.2.2.1 20-1.2.3.r 21-1.2.3.1.1 22-1.2.3.1 23-1.2.3.3 24-1.2.3 25-1.2.3.2.1 26-1.2.3.2 28-1.2.3.2.2.1.1 29-1.2.3.2.2.1.2 31-1.2.3.2.3.r 32-1.2.3.2.3 (o / observe-01~e.6 :ARG1 (p / progress-01~e.3 :ARG3 (h / hyperplasia~e.0) :ARG4 (d / dysplasia~e.2)) :time~e.7 (a / age-01~e.10 :ARG2 (y / young~e.9) :ARG1-of (m / mean-01 :ARG2 (t / temporal-quantity~e.20 :quant (v / value-interval :op1 2~e.12 :op2 3~e.14) :unit (m2 / month~e.15))) :time-of~e.20 (d2 / develop-01~e.24 :ARG1 (a2 / animal~e.22 :mod (s / some~e.21)) :ARG2 (t2 / tumor~e.26 :mod (m3 / macroscopic~e.25) :quant (m4 / more-than :op1 (a3 / area-quantity :quant 2~e.28 :unit (m5 / millimeter~e.29))) :accompanier~e.31 d~e.32) :time (a4 / already~e.23))) :frequency (o2 / often~e.5)) # ::id pmid_2384_5441.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At 10 months , virtually all mice had such dysplastic lesions , often large numbers ( Figure 2 @ A ) . # ::alignments 1-1.3.1 2-1.3.2 4-1.1.2 5-1.1.1 6-1.1 7-1 8-1.2.4 9-1.2.1 10-1.2 12-1.2.3 13-1.2.2.1 14-1.2.2 17-1.4.1 (h / have-03~e.7 :ARG0 (m / mouse~e.6 :mod (a / all~e.5) :mod (v / virtual~e.4)) :ARG1 (l / lesion~e.10 :mod (d / dysplastic~e.9) :quant (n / number~e.14 :mod (l2 / large~e.13)) :frequency (o / often~e.12) :mod (s / such~e.8)) :age (t / temporal-quantity :quant 10~e.1 :unit (m2 / month~e.2)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.17 :mod "2A"))) # ::id pmid_2384_5441.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histologically , Braf @^V637E@ -@ induced dysplastic lesions had features of human traditional serrated adenomas ( TSAs ) , including crypt elongation and a serrated eosinophilic adenomatous epithelium ( Figures 2 @ B @–@ 2E and S1 @ B ) . # ::alignments 2-1.1.2.1.1.1 4-1.1.2.1.2.1 7-1.1.2 8-1.1.1 9-1.1 10-1 11-1.2 12-1.2.2.r 13-1.2.2.4 14-1.2.2.3 15-1.2.2.2 16-1.2.1.1.2.3.1.1 16-1.2.2.1.1 21-1.2.1 22-1.2.1.1.1.1 23-1.2.1.1.1 24-1.2.1.1 26-1.2.1.1.2.2 27-1.2.1.1.2.1 29-1.2.1.1.2 32-1.4.1.1.1 32-1.4.1.1.2 32-1.4.1.2 37-1.4.1.1.2.1 38-1.4.1 (h / have-03~e.10 :ARG0 (l / lesion~e.9 :mod (d / dysplastic~e.8) :ARG2-of (i / induce-01~e.7 :ARG0 (e4 / enzyme :name (n / name :op1 "Braf"~e.2) :ARG2-of (m / mutate-01 :value "V637E"~e.4)))) :ARG1 (f / feature~e.11 :ARG2-of (i2 / include-91~e.21 :ARG1 (a2 / and~e.24 :op1 (e / elongate-01~e.23 :ARG1 (c / crypt~e.22)) :op2 (e2 / epithelium~e.29 :mod (e3 / eosinophilic~e.27) :ARG1-of s~e.26 :mod (m2 / medical-condition :name (n2 / name :op1 "adenoma"~e.16))))) :poss~e.12 (m3 / medical-condition :name (n3 / name :op1 "adenoma"~e.16) :ARG1-of (s / serrate-01~e.15) :mod (t / traditional~e.14) :mod (h2 / human~e.13))) :manner (h3 / histologic) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.38 :op1 (v / value-interval :op1 (f2 / figure~e.32 :mod "2B") :op2 (f3 / figure~e.32 :mod "2E"~e.37)) :op2 (f4 / figure~e.32 :mod "S1B")))) # ::id pmid_2384_5441.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although both TSAs and SSAs are associated with mutant BRAF in humans , we did not observe SSA in our model . # ::alignments 0-1 3-1.2.1 6-1.2 7-1.2.2.r 8-1.2.2 8-1.2.2.2 8-1.2.2.2.r 10-1.2.2.1.1 12-1.2.3.r 13-1.2.3 15-1.1.2 17-1.1.1 17-1.1.1.r 18-1.1 20-1.1.4.r 21-1.1.4.1 21-1.1.4.1.r 22-1.1.4 (h / have-concession-91~e.0 :ARG1 (o / observe-01~e.18 :polarity~e.17 -~e.17 :ARG0 (w / we~e.15) :ARG1 (m4 / medical-condition :name (n3 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma")) :location~e.20 (m / model~e.22 :poss~e.21 w~e.21)) :ARG2 (a / associate-01~e.6 :ARG1 (a2 / and~e.3 :op1 (m3 / medical-condition :name (n2 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma")) :op2 m4) :ARG2~e.7 (g / gene~e.8 :name (n4 / name :op1 "BRAF"~e.10) :ARG1-of~e.8 (m2 / mutate-01~e.8)) :location~e.12 (h2 / human~e.13))) # ::id pmid_2384_5441.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A possible reason is that mouse tumors were predominantly in the SI ( only five of 95 tumors were in the large intestine ) , where the specific morphologic features of human colonic SSAs might not develop . # ::alignments 1-1.2 2-1 3-1.1 5-1.1.1.1 6-1.1.1 7-1.1 8-1.1.3 13-1.1.4.1.1.3 14-1.1.4.1.1.1 16-1.1.4.1.1.2.1.1 17-1.1.4.1.1 17-1.1.4.1.1.2.1 18-1.1.4.1 21-1.1.4.1.2.1 22-1.1.2 22-1.1.4.1.2 27-1.1.2.2.2.1 28-1.1.2.2.2.2 29-1.1.2.2.2 30-1.1.2.2.2.3.r 31-1.1.2.2.2.3.2 32-1.1.2.2.2.3.3 34-1.1.2.2.3 35-1.1.2.2.1 35-1.1.2.2.1.r 36-1.1.2.2 (c / cause-01~e.2 :ARG0 (b / be-located-at-91~e.3,7 :ARG1 (t / tumor~e.6 :mod (m / mouse~e.5)) :ARG2 (i / intestine~e.22 :mod (s / small) :ARG1-of (d / develop-01~e.36 :polarity~e.35 -~e.35 :ARG2 (f / feature~e.29 :ARG1-of (s2 / specific-02~e.27) :mod (m3 / morphologic~e.28) :poss~e.30 (m4 / medical-condition :name (n2 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma") :mod (h / human~e.31) :mod (c2 / colon~e.32))) :ARG1-of (p3 / possible-01~e.34))) :ARG1-of (p2 / predominate-01~e.8) :ARG1-of (m2 / mean-01 :ARG2 (b2 / be-located-at-91~e.18 :ARG1 (t2 / tumor~e.17 :quant 5~e.14 :ARG1-of (i3 / include-91 :ARG2 (t3 / tumor~e.17 :quant 95~e.16)) :mod (o / only~e.13)) :ARG2 (i2 / intestine~e.22 :mod (l / large~e.21))))) :ARG1-of (p / possible-01~e.1)) # ::id pmid_2384_5441.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To avoid misleading nomenclature by drawing inadequate morphologic parallels between murine SI lesions and human LI tumors , we refer to dysplastic lesions as “ murine serrated adenoma with dysplasia ” ( mSA ) or more specifically as mSA with low @-@ grade dysplasia ( mSA @-@ LGD ) or high @-@ grade dysplasia ( mSA @-@ HGD ) . # ::alignments 1-1.4 2-1.4.2.1 3-1.4.2 4-1.4.3.r 5-1.4.3 6-1.4.3.1.3 6-1.4.3.1.3.1 6-1.4.3.1.3.1.r 7-1.4.3.1.2 8-1.4.3.1 10-1.4.3.1.1.1.2 12-1.4.3.1.1.1 13-1.4.3.1.1 14-1.4.3.1.3.2.1 16-1.4.3.1.3.2 18-1.1 19-1 21-1.2.1 21-1.3.1.4 22-1.2 25-1.3.1.3.1.1 26-1.3.1.2 27-1.3.1.1.1 27-1.3.2.1.1.1 27-1.3.2.2.1.1 28-1.3.1.4.r 29-1.3.1.4 34-1.3 34-1.3.2 35-1.3.2.2.3.1 36-1.3.2.2 36-1.3.2.2.3 36-1.3.2.2.3.r 39-1.3.1.4.r 39-1.3.2.r 40-1.3.2.1.2.1.1.1 42-1.3.2.1.2.1.1 43-1.3.2.1.2.1 49-1.3.2 50-1.3.2.2.2.1.1.1 52-1.3.2.2.2.1.1 53-1.3.1.4 53-1.3.2.2.2.1 (r / refer-01~e.19 :ARG0 (w / we~e.18) :ARG1 (l / lesion~e.22 :mod (d / dysplastic~e.21)) :ARG2 (o / or~e.34 :op1 (m / medical-condition :name (n3 / name :op1 "adenoma"~e.27) :ARG1-of (s / serrate-01~e.26) :mod (o3 / organism :name (n2 / name :op1 "Muridae"~e.25)) :prep-with~e.28,39 (d2 / dysplasia~e.21,29,53)) :op2~e.39 (o2 / or~e.34,49 :op1 (m2 / medical-condition :name (n4 / name :op1 "adenoma"~e.27) :ARG0-of (h4 / have-03 :ARG1 (d3 / dysplasia~e.43 :degree (g / grade~e.42 :ARG1-of (l2 / low-04~e.40))))) :op2 (m3 / medical-condition~e.36 :name (n5 / name :op1 "adenoma"~e.27) :ARG0-of (h3 / have-03 :ARG1 (d4 / dysplasia~e.53 :degree (g2 / grade~e.52 :ARG1-of (h / high-02~e.50)))) :ARG1-of~e.36 (s3 / specific-02~e.36 :degree (m8 / more~e.35))))) :purpose (a2 / avoid-01~e.1 :ARG0 w :ARG1 (n / nomenclature~e.3 :ARG0-of (m7 / mislead-02~e.2)) :manner~e.4 (d5 / draw-01~e.5 :ARG1 (p / parallel-01~e.8 :ARG1 (a4 / and~e.13 :op1 (l3 / lesion~e.12 :mod (i / intestine :mod (s2 / small)) :mod o3~e.10)) :mod (m6 / morphologic~e.7) :mod (a3 / adequate~e.6 :polarity~e.6 -~e.6 :op2 (t / tumor~e.16 :mod (h2 / human~e.14) :mod (i2 / intestine :mod (l4 / large)))))))) # ::id pmid_2384_5441.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Macroscopically , Braf @^{V6 @ 37 @ E}@ -@ induced neoplasia resembled human BRAF mutant colonic tumors , which frequently show a nonpolypoid sessile growth pattern ( Figure S2 @ A ) . # ::alignments 0-1.3 2-1.1.1.1.1.1 2-1.2.2.1.1 11-1.1.1 12-1.1 13-1 14-1.2.1 16-1.2.2.1.1 18-1.1.1.1 18-1.1.1.1.2 18-1.1.1.1.2.r 18-1.2.2 18-1.2.2.2 18-1.2.2.2.r 19-1.2.3 20-1.2 23-1.2.4.2 24-1.2.4 27-1.2.4.1.1.1 28-1.2.4.1.1 29-1.2.4.1 32-1.4.1 (r / resemble-01~e.13 :ARG1 (n4 / neoplasia~e.12 :ARG2-of (i / induce-01~e.11 :ARG0 (e2 / enzyme~e.18 :name (n / name :op1 "Braf"~e.2) :ARG2-of~e.18 (m / mutate-01~e.18 :value "V637E")))) :ARG2 (t2 / tumor~e.20 :mod (h / human~e.14) :mod (g / gene~e.18 :name (n2 / name :op1 "BRAF"~e.2,16) :ARG1-of~e.18 (m2 / mutate-01~e.18)) :mod (c / colon~e.19) :ARG0-of (s / show-01~e.24 :ARG1 (p / pattern~e.29 :mod (g3 / grow-01~e.28 :ARG1 (s2 / sessile~e.27 :mod (p2 / polypoid :polarity -)))) :ARG1-of (f2 / frequent-02~e.23))) :manner (m3 / macroscopic~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "S2A"))) # ::id pmid_2384_5441.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Proliferation rates were increased on average 2.4 @-@ fold in mSA @-@ LGD and 9.1 @-@ fold in mSA @-@ HGD as compared to hyperplasia ( Figures S2 @ B @–@ 2D ) . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.3 6-1.2.1.1 8-1.2.1 9-1.2.1.2.r 10-1.2.1.2.1.1 12-1.2.1.2.1.1 13-1.2 14-1.2.2.1 16-1.2.2 17-1.2.2.2.r 18-1.2.2.2.1.1 20-1.2.2.2.1.1 21-1.4.r 22-1.4 23-1.4.1.r 24-1.4.1 27-1.3.1.1 27-1.3.1.2 32-1.3.1.2.1 (i / increase-01~e.3 :ARG1 (r / rate~e.1 :degree-of (p / proliferate-01~e.0)) :ARG2~e.4 (a / and~e.13 :op1 (p2 / product-of~e.8 :op1 2.4~e.6 :location~e.9 (d2 / disease :name (n / name :op1 "mSA-LGD"~e.10,12))) :op1 (p3 / product-of~e.16 :op1 9.1~e.14 :location~e.17 (d3 / disease :name (n2 / name :op1 "mSA-HGD"~e.18,20))) :ARG2-of (a2 / average-01~e.5)) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.27 :mod "S2B") :op2 (f2 / figure~e.27 :mod "2D"~e.32))) :ARG1-of~e.21 (c / compare-01~e.22 :ARG2~e.23 (h / hyperplasia~e.24))) # ::id pmid_2384_5441.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like human BRAF mutant tumors , mouse mSAs frequently showed abundant mucin production and stained positive for Alcian blue ( Figure S2 @ E ) . # ::alignments 0-1.3 1-1.3.1.2 3-1.3.1.1.1.1 5-1.3.1.1 5-1.3.1.1.2 5-1.3.1.1.2.r 6-1.3.1 8-1.1.1.2 9-1.1.1.1.1 10-1.1.3 11-1.1 12-1.1.2.2 13-1.1.2.1 14-1.1.2 15-1 16-1.2 17-1.2.3 18-1.2.2.r 19-1.2.2.1.1 20-1.2.2.1.2 23-1.4.1 (a / and~e.15 :op1 (s / show-01~e.11 :ARG0 (d2 / disease :name (n3 / name :op1 "mSA"~e.9) :mod (m3 / mouse~e.8)) :ARG1 (p / produce-01~e.14 :ARG1 (m2 / mucin~e.13) :mod (a2 / abundant~e.12)) :ARG1-of (f2 / frequent-02~e.10)) :op2 (s2 / stain-01~e.16 :ARG1 d2 :ARG2~e.18 (s3 / small-molecule :name (n / name :op1 "Alcian"~e.19 :op2 "blue"~e.20)) :mod (p2 / positive~e.17)) :ARG1-of (r / resemble-01~e.0 :ARG2 (t / tumor~e.6 :mod (g / gene~e.5 :name (n2 / name :op1 "BRAF"~e.3) :ARG2-of~e.5 (m4 / mutate-01~e.5)) :mod (h / human~e.1))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "S2E"))) # ::id pmid_2384_5441.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a subset of mice ( n = 5 ) dysplasia progressed to invasive carcinomas : 8.3 % ( 1 @/@ 12 ) of Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} mice younger than 10 months and 13.8 % ( 4 @/@ 29 ) of mice older 10 months had cancers ( Figure 2 @ A ) . # ::alignments 2-1.3 4-1.3.1.1 4-1.4.1.1.1 8-1.3.2.1 10-1.1 11-1 12-1.2.r 13-1.2.1 14-1.2 16-1.4.1.1.1.2.2.1 17-1.4.1.1.1.2.2 19-1.4.1.1.1.1 21-1.4.1.1.1.2.1.1 27-1.4.1.1.1.2.1.4.2.1.1 29-1.4.1.1.1.2.1.2.1.1 33-1.4.1.1.1.2.1.2.2.1 35-1.4.1.1.1.2.1.2.2.1 39-1.4.1.1.1.2.1 40-1.4.1.1.1.2.1.3 40-1.4.1.1.1.2.1.3.1 40-1.4.1.1.1.2.1.3.1.r 41-1.4.1.1.1.2.1.3.2.r 42-1.4.1.1.1.2.1.3.2.1 43-1.4.1.1.1.2.1.3.2.2 44-1.4.1.1 45-1.4.1.1.2.2.2.1 46-1.4.1.1.2.2.2 48-1.4.1.1.2.1 50-1.4.1.1.2.2.1.1 53-1.4.1.1.2 53-1.4.1.1.2.2.1 54-1.4.1.1.2.2.1.3 55-1.4.1.1.2.2.1.3.2 56-1.4.1.1.2.2.1.3.2 57-1.4.1 58-1.4.1.2.2.1 61-1.5.1 (p / progress-01~e.11 :ARG1 (d / dysplasia~e.10) :ARG4~e.12 (c / carcinoma~e.14 :ARG0-of (i / invade-01~e.13)) :location (s / subset~e.2 :ARG1-of (i2 / include-91 :ARG2 (m / mouse~e.4)) :ord (o / ordinal-entity :value 5~e.8)) :ARG1-of (m2 / mean-01 :ARG2 (h / have-03~e.57 :ARG0 (a / and~e.44 :op1 (m3 / mouse~e.4 :quant 1~e.19 :ARG1-of (i3 / include-91 :ARG2 (m4 / mouse~e.39 :quant 12~e.21 :mod (g / gene :name (n3 / name :op1 "Braf"~e.29) :ARG2-of (m6 / mutate-01 :value "LSL-V637E"~e.33,35)) :mod (y / young~e.40 :degree~e.40 (m7 / more~e.40) :compared-to~e.41 (t / temporal-quantity :quant 10~e.42 :unit (m9 / month~e.43))) :mod (m11 / macro-molecular-complex :part (p3 / protein :name (n / name :op1 "Villin")) :part (e2 / enzyme :name (n2 / name :op1 "Cre"~e.27)))) :ARG3 (p2 / percentage-entity~e.17 :value 8.3~e.16))) :op2 (m8 / mouse~e.53 :quant 4~e.48 :ARG1-of (i4 / include-91 :ARG2 (m10 / mouse~e.53 :quant 29~e.50 :mod g :mod (o2 / old~e.54 :degree m7 :compared-to t~e.55,56) :mod m11) :ARG3 (p5 / percentage-entity~e.46 :value 13.8~e.45)))) :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.58)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.61 :mod "2A"))) # ::id pmid_2384_5441.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Two of these cancers were low @-@ grade tumors ( well and moderately differentiated ) , and three were high @-@ grade cancers ( poorly or undifferentiated ; glandular structures in less than 50 % of the tumor ) . # ::alignments 0-1.1.3.1 2-1.1.3.5 3-1.1.3.3.1 3-1.1.3.4.1.2.1 4-1.1.3.r 5-1.1.1.1 7-1.1.1 8-1.1 10-1.1.2.1.1.2 11-1.1.2.1 12-1.1.2.1.2.2 13-1.1.2.1.1 13-1.1.2.1.2 13-1.2.5.1.1 13-1.2.5.1.2 16-1.1.2.1 17-1.2.3.1 18-1.2.3.r 19-1.2.4.1 21-1.2.4 22-1.2.2.1 22-1.2.3.3.1 24-1.2.5.1.1.2 24-1.2.5.1.1.2.r 25-1.2.5.1 28-1.2.5.1.2.3.1.1 29-1.2.5.1.2.3.1 30-1.2.5.1.2.3.1.2.r 31-1.2.5.1.2.3.1.2.1 32-1.2.5.1.2.3.1.2.1 33-1.2.5.1.2.3.1.2.1.1.1 34-1.2.5.1.2.3.1.2.1.1 35-1.2.5.1.2.3.1.2.1.r 37-1.2.5.1.2.3.1.2 37-1.2.5.1.2.3.1.2.2.1 (a / and :op1 (t / tumor~e.8 :mod (g / grade~e.7 :ARG1-of (l / low-04~e.5)) :ARG1-of (m / mean-01 :ARG2 (a2 / and~e.11,16 :op1 (d / differentiate-01~e.13 :ARG1 t :ARG1-of (g2 / good-02~e.10)) :op2 (d2 / differentiate-01~e.13 :ARG1 t :ARG1-of (m2 / moderate-03~e.12)))) :domain~e.4 (d5 / disease :quant 2~e.0 :wiki "Cancer" :name (n / name :op1 "cancer"~e.3) :ARG1-of (i / include-91 :ARG2 (d6 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.3))) :mod (t4 / this~e.2))) :op2 (d7 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.22) :domain~e.18 (d8 / disease :quant 3~e.17 :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.22) :ARG1-of i) :mod (g3 / grade~e.21 :ARG1-of (h / high-02~e.19)) :ARG1-of (m3 / mean-01 :ARG2 (o / or~e.25 :op1 (d3 / differentiate-01~e.13 :ARG1 d7 :manner~e.24 (p / poor~e.24)) :op2 (d4 / differentiate-01~e.13 :polarity - :ARG1 d7 :ARG1-of (m4 / mean-01 :ARG2 (s / structure~e.29 :mod (g4 / gland~e.28) :poss~e.30 (t2 / tumor~e.37 :quant~e.35 (l2 / less-than~e.31,32 :op1 (p2 / percentage-entity~e.34 :value 50~e.33)) :ARG1-of (i2 / include-91 :ARG2 (t3 / tumor~e.37)))))))))) # ::id pmid_2384_5441.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Examples are shown in Figures 2 @ F @–@ 2I . # ::alignments 0-1.1 2-1 5-1.2.1 5-1.2.2 10-1.2.2.1 (s / show-01~e.2 :ARG1 (e / exemplify-01~e.0) :location (v / value-interval :op1 (f / figure~e.5 :mod "2F") :op2 (f2 / figure~e.5 :mod "2I"~e.10))) # ::id pmid_2384_5441.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Across a larger set of Braf @^V637E@ -@ induced cancers in p53 or p16 mutant backgrounds ( Table S1 and detailed below ) , we found that 30 % of tumors were high grade . # ::alignments 0-1.3 2-1.3.1.1 2-1.3.1.1.1 2-1.3.1.1.1.r 3-1.3.1 5-1.3.1.2.1.3.1.1.1 7-1.3.1.2.1.3.1.2.1 10-1.3.1.2.1.3 11-1.3.1.2.1.2.1 14-1.3.1.2.1.4.1.1.1.1 18-1.3.1.2.1.4.2.1.1.1 20-1.3.1.2.1.3.1 20-1.3.1.2.1.3.1.2 20-1.3.1.2.1.3.1.2.r 20-1.3.1.2.1.4.1.1 20-1.3.1.2.1.4.1.1.2 20-1.3.1.2.1.4.1.1.2.r 21-1.3.1.2.1.4.1 21-1.3.1.2.1.4.2 24-1.3.2.1 25-1.3.2.1.1 27-1.3.1.2.1.4 28-1.3.3 29-1.3.3.1 32-1.1 33-1 34-1.2.r 35-1.2.2.2.1 36-1.2.2.2 38-1.2 38-1.2.2.1 40-1.2.1.1 41-1.2.1 (f / find-01~e.33 :ARG0 (w / we~e.32) :ARG1~e.34 (t / tumor~e.38 :mod (g / grade~e.41 :ARG1-of (h / high-02~e.40)) :ARG1-of (i / include-91 :ARG2 (t2 / tumor~e.38) :ARG3 (p / percentage-entity~e.36 :value 30~e.35))) :location (a / across~e.0 :op1 (s / set~e.3 :mod (l / large~e.2 :degree~e.2 (m / more~e.2)) :ARG2-of (i2 / include-91 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.11) :ARG2-of (i3 / induce-01~e.10 :ARG0 (e / enzyme~e.20 :name (n / name :op1 "Braf"~e.5) :ARG2-of~e.20 (m2 / mutate-01~e.20 :value "V637E"~e.7))) :location (a2 / and~e.27 :op1 (b / background~e.21 :mod (g3 / gene~e.20 :name (n2 / name :op1 "p53"~e.14) :ARG2-of~e.20 (m3 / mutate-01~e.20))) :op2 (b2 / background~e.21 :mod (g2 / gene :name (n3 / name :op1 "p16"~e.18) :ARG2-of m3)))))) :ARG1-of (d / describe-01 :ARG0 (t3 / table~e.24 :mod "S1"~e.25)) :ARG1-of (d2 / detail-01~e.28 :location (b3 / below~e.29)))) # ::id pmid_2384_5441.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Collectively these results describe a mouse model of serrated intestinal cancer , which provides functional evidence for the key role of mutant Braf in tumor initiation . # ::alignments 0-1.4 0-1.4.r 1-1.1.2 2-1.1 2-1.1.1 2-1.1.1.r 3-1 5-1.2.1 6-1.2 7-1.2.2.r 8-1.2.2.4 9-1.2.2.3 10-1.2.2.2.1 13-1.3 14-1.3.1.2 15-1.3.1 16-1.3.1.1.r 18-1.3.1.1.1 19-1.3.1.1 20-1.3.1.1.2.r 21-1.3.1.1.2 21-1.3.1.1.2.2 21-1.3.1.1.2.2.r 23-1.3.1.1.2.1.1 25-1.3.1.1.3.r 26-1.3.1.1.3.2 27-1.3.1.1.3 (d / describe-01~e.3 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2) :mod (t3 / this~e.1)) :ARG1 (m / model~e.6 :mod (m2 / mouse~e.5) :mod~e.7 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.10) :mod (i / intestine~e.9) :ARG1-of (s / serrate-01~e.8))) :ARG0-of (p / provide-01~e.13 :ARG1 (e / evidence-01~e.15 :ARG1~e.16 (r2 / role~e.19 :ARG1-of (k / key-01~e.18) :poss~e.20 (g / gene~e.21 :name (n / name :op1 "Braf"~e.23) :ARG2-of~e.21 (m3 / mutate-01~e.21)) :topic~e.25 (i2 / initiate-01~e.27 :ARG0 g :ARG1 (t2 / tumor~e.26))) :ARG0-of (f / function-01~e.14))) :manner~e.0 (c2 / collective~e.0)) # ::id pmid_2384_5441.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Braf @^V637E@ -@ Induced Murine Intestinal Tumors Are Frequently Microsatellite @-@ Unstable # ::alignments 1-1.2.2.1.1.1 3-1.2.2.1.2.1 6-1.2.2 7-1.2.3.1.1 8-1.2.1 9-1.2 11-1.3 12-1.4 14-1 14-1.1 14-1.1.r (s / stable-03~e.14 :polarity~e.14 -~e.14 :ARG1 (t / tumor~e.9 :mod (i / intestine~e.8) :ARG2-of (i2 / induce-01~e.6 :ARG0 (e / enzyme :name (n / name :op1 "Braf"~e.1) :ARG2-of (m2 / mutate-01 :value "V637E"~e.3))) :mod (o / organism :name (n2 / name :op1 "Muridae"~e.7))) :ARG1-of (f / frequent-02~e.11) :mod (m3 / microsatellite~e.12)) # ::id pmid_2384_5441.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok High level microsatellite instability ( MSI @-@ H ) occurs in 50 % of human BRAF mutant cancers ( Rajagopalan et al. , 2002 ) . # ::alignments 0-1.1.2.1 1-1.1.2 2-1.1.3 3-1.1 3-1.1.1 3-1.1.1.r 11-1.2.5.2.1 12-1.2.5.2 14-1.2.3 16-1.2.4.1.1 18-1.2.4 18-1.2.4.2 18-1.2.4.2.r 19-1.2.2.1 19-1.2.5.1.2.1 22-1.3.1.1.1.1.1 23-1.3.1.1 24-1.3.1.1.2.1 26-1.3.1.2.1 (b / be-located-at-91 :ARG1 (s / stable-03~e.3 :polarity~e.3 -~e.3 :degree (l / level~e.1 :ARG1-of (h2 / high-02~e.0)) :mod (m2 / microsatellite~e.2)) :ARG2 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.19) :mod (h / human~e.14) :mod (g / gene~e.18 :name (n2 / name :op1 "Braf"~e.16) :ARG2-of~e.18 (m / mutate-01~e.18)) :ARG1-of (i / include-91 :ARG2 (d3 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.19) :mod h :mod g) :ARG3 (p / percentage-entity~e.12 :value 50~e.11))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and~e.23 :op1 (p3 / person :name (n3 / name :op1 "Rajagopalan"~e.22)) :op2 (p4 / person :mod (o2 / other~e.24))) :time (d2 / date-entity :year 2002~e.26)))) # ::id pmid_2384_5441.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is however not understood at which stage MSI develops and whether BRAF mutations are cause or consequence of MSI . # ::alignments 2-1 3-1.1.1 3-1.1.1.r 3-1.1.2.1.1.1.1 4-1.1 7-1.1.2.1 9-1.1.2.1.1 10-1.1.2 11-1.1.2.2.1 11-1.1.2.2.1.r 13-1.1.2.2.2.1.1.1.1 15-1.1.2.2.2.1 17-1.1.2.2.2 17-1.1.2.2.3 18-1.1.2.2 19-1.1.2.2.2 (c / contrast-01~e.2 :ARG2 (u / understand-01~e.4 :polarity~e.3 -~e.3 :ARG1 (a / and~e.10 :op1 (s / stage~e.7 :time-of (d / develop-01~e.9 :ARG1 (s2 / stable-03 :polarity -~e.3 :mod (m2 / microsatellite)))) :op2 (o / or~e.18 :mode~e.11 interrogative~e.11 :op1 (c2 / cause-01~e.17,19 :ARG0 (m / mutate-01~e.15 :ARG2 (g / gene :name (n2 / name :op1 "Braf"~e.13))) :ARG1 s2) :op2 (c3 / cause-01~e.17 :ARG0 s2 :ARG1 m))))) # ::id pmid_2384_5441.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To address this question , we assessed the MSI status in Braf @^{V6 @ 37 @ E}@ -@ induced serrated hyperplasia and neoplasia as well as in Msh2 @ ^{− @ / @ −} and Apc @ ^{min @} control tumors . # ::alignments 1-1.3 2-1.3.2.1 3-1.3.2 3-1.3.2.2 3-1.3.2.2.r 5-1.1 6-1 9-1.2 10-1.2.2.r 11-1.2.2.1.3.1.1.1 20-1.2.2.1.3 21-1.2.2.1.2 22-1.2.2.1.1.1 23-1.2.2 24-1.2.2.2.1.1 25-1.2.2 26-1.2.2 27-1.2.2 30-1.2.2.3.2.1.1 39-1.2.2 41-1.2.2.4.2.1.1 45-1.2.2.4.2.2.2 48-1.2.2.3.1 49-1.2.2.3 49-1.2.2.4 (a / assess-01~e.6 :ARG0 (w / we~e.5) :ARG1 (s / status~e.9 :ARG1-of (s3 / stable-03 :polarity - :mod (m5 / microsatellite)) :location~e.10 (a2 / and~e.23,25,26,27,39 :op1 (m6 / medical-condition :name (n / name :op1 "hyperplasia"~e.22) :ARG1-of (s2 / serrate-01~e.21) :ARG2-of (i / induce-01~e.20 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf"~e.11) :ARG2-of (m / mutate-01 :value "V637E")))) :op2 (m7 / medical-condition :name (n6 / name :op1 "neoplasia"~e.24) :ARG1-of s2 :ARG1-of i) :op3 (t2 / tumor~e.49 :mod (c / control~e.48) :mod (p / protein :name (n4 / name :op1 "Msh2"~e.30) :ARG2-of (m2 / mutate-01 :mod "-/-"))) :op4 (t3 / tumor~e.49 :mod c :mod (p2 / protein :name (n5 / name :op1 "Apc"~e.41) :ARG2-of (m3 / mutate-01 :mod "-/+" :mod (m4 / min~e.45)))))) :purpose (a3 / address-02~e.1 :ARG0 w :ARG1 (t / thing~e.3 :mod (t4 / this~e.2) :ARG1-of~e.3 (q / question-01~e.3)))) # ::id pmid_2384_5441.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A panel of eight microsatellite repeats was used for MSI typing ( Figure 2 @ J ; Supplemental Experimental Procedures ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1 4-1.1.1.3 4-1.2.1.2 5-1.1.1 5-1.1.1.2 5-1.1.1.2.r 7-1 10-1.2 13-1.3.1.1 19-1.3.1.2.2 20-1.3.1.2.1 21-1.3.1.2 (u / use-01~e.7 :ARG1 (p / panel~e.1 :consist-of~e.2 (m3 / molecular-physical-entity~e.5 :quant 8~e.3 :ARG1-of~e.5 (r2 / repeat-01~e.5) :part-of (m / microsatellite~e.4))) :ARG2 (t / type-03~e.10 :ARG1 (s2 / stable-03 :polarity - :mod (m2 / microsatellite~e.4))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.13 :mod "2J") :op2 (p2 / procedure~e.21 :mod (e / experiment-01~e.20) :ARG2-of (s / supplement-01~e.19))))) # ::id pmid_2384_5441.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that all Braf @^{V6 @ 37 @ E}@ -@ induced hyperplastic polyps ( 13 @/@ 13 ) were microsatellite stable ( MSS ) or MSI @-@ low ( MSI @-@ L ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.4 4-1.2.1.3.1.1.1 13-1.2.1.3 14-1.2.1.2 15-1.2.1 15-1.2.1.5.1 17-1.2.1.1 19-1.2.1.1 22-1.2.2 23-1.2 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (s / stable-03~e.23 :ARG1 (p / polyp~e.15 :quant 13~e.17,19 :mod (h / hyperplastic~e.14) :ARG2-of (i / induce-01~e.13 :ARG0 (e / enzyme :name (n / name :op1 "Braf"~e.4) :ARG2-of (m2 / mutate-01 :value "V637E"))) :mod (a2 / all~e.3) :ARG1-of (i2 / include-91 :ARG2 (p2 / polyp~e.15))) :mod (m / microsatellite~e.22))) # ::id pmid_2384_5441.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Contrarily , 39.4 % ( 13 @/@ 33 ) of Braf @^{V6 @ 37 @ E}@ -@ induced mSAs and carcinomas were MSI @-@ H and only 6 % ( 2 @/@ 32 ) were MSS ( Figure 2 @ J ) . # ::alignments 0-1 2-1.1.1.1.4.2.1 3-1.1.1.1.4.2 5-1.1.1.1.1 7-1.1.1.1.4.1.1 10-1.1.1.1.4.1.4.1.1.1 19-1.1.1.1.4.1.4 21-1.1.1.1 21-1.1.1.1.4.1 22-1.1.1.1.3.1.1 27-1.1.2.1 28-1.1.2.1.4.2.2 29-1.1.2.1.4.2.1 30-1.1.2.1.4.2 32-1.1.2.1.1 34-1.1.2.1.4.1.1 40-1.2.1 41-1.1.2.1.1 (c / contrast-01~e.0 :ARG2 (a / and :op1 (h / high-02 :ARG1 (a2 / and~e.21 :quant 13~e.5 :op1 (m / medical-condition :name (n3 / name :op1 "adenoma") :ARG1-of (s2 / serrate-01) :mod (o2 / organism :name (n / name :op1 "Muridae"))) :op2 (m5 / medical-condition :name (n5 / name :op1 "carcinoma"~e.22)) :ARG1-of (i2 / include-91 :ARG2 (a4 / and~e.21 :quant 33~e.7 :op1 (m4 / medical-condition :name (n4 / name :op1 "adenoma")) :op2 m5 :ARG2-of (i / induce-01~e.19 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf"~e.10) :ARG2-of (m2 / mutate-01 :value "V637E")))) :ARG3 (p / percentage-entity~e.3 :value 39.4~e.2))) :ARG2 (s / stable-03 :polarity - :mod (m3 / microsatellite))) :op2 (s3 / stable-03 :ARG1 (a3 / and~e.27 :quant 2~e.32,41 :op1 m4 :op2 m5 :ARG1-of (i4 / include-91 :ARG2 (a5 / and :quant 32~e.34 :op1 m4 :op2 m5 :ARG2-of i) :ARG3 (p2 / percentage-entity~e.30 :value 6~e.29 :mod (o / only~e.28)))) :mod m3)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "2J"))) # ::id pmid_2384_5441.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MSI @-@ H was observed at similar frequencies in mSAs ( 10 @/@ 25 ; 40 %) and carcinomas ( 3 @/@ 8 ; 37.5 %) . # ::alignments 4-1 6-1.1.2.1 7-1.1.2 11-1.2.1.1 13-1.2.1.3.1.1 15-1.2.1.3.2.1 17-1.2 18-1.2.2 18-1.2.2.2.1.2.1 20-1.2.2.1 22-1.2.2.2.1.1 24-1.2.2.2.2.1 (o / observe-01~e.4 :ARG1 (h / high-02 :ARG2 (s / stable-03 :polarity - :mod (m3 / microsatellite)) :frequency (f / frequency~e.7 :ARG1-of (r / resemble-01~e.6))) :location (a / and~e.17 :op1 (m / medical-condition :quant 10~e.11 :name (n2 / name :op1 "adenoma") :ARG1-of (i / include-91 :ARG2 (m2 / medical-condition :quant 25~e.13 :name (n3 / name :op1 "adenoma")) :ARG3 (p / percentage-entity :value 40~e.15)) :ARG1-of (s2 / serrate-01) :mod (o2 / organism :name (n / name :op1 "Muridae"))) :op2 (c / carcinoma~e.18 :quant 3~e.20 :ARG1-of (i2 / include-91 :ARG2 (m4 / medical-condition :quant 8~e.22 :name (n4 / name :op1 "carcinoma"~e.18)) :ARG3 (p2 / percentage-entity :value 37.5~e.24))))) # ::id pmid_2384_5441.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Apc @ ^{min @}@ -@ induced adenomas were all ( 9 @/@ 9 ; 100 %) MSS or MSI @-@ L . # ::alignments 1-1.1.3.1.1.1 5-1.1.3.1.2.2 9-1.1.3 10-1.1.2.1 10-1.1.5.1.2.1 12-1.1.4 14-1.1.1 14-1.1.5.1.1 16-1.1.1 16-1.1.5.1.1 18-1.1.5.2.1 (s / stable-03 :ARG1 (m3 / medical-condition :quant 9~e.14,16 :name (n / name :op1 "adenoma"~e.10) :ARG2-of (i / induce-01~e.9 :ARG0 (g / gene :name (n3 / name :op1 "Apc"~e.1) :ARG2-of (m / mutate-01 :mod "-/+" :value (m2 / min~e.5)))) :mod (a3 / all~e.12) :ARG1-of (i2 / include-91 :ARG2 (m4 / medical-condition :quant 9~e.14,16 :name (n2 / name :op1 "adenoma"~e.10)) :ARG3 (p / percentage-entity :value 100~e.18))) :mod (m5 / microsatellite)) # ::id pmid_2384_5441.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lack of MSI @-@ H in mSH , but its presence in all subsequent stages of tumorigenesis ( mSA @-@ LGD , mSA @-@ HGD and carcinoma ) suggests its early development during Braf @^{V6 @ 37 @ E}@ -@ initiated transformation . # ::alignments 1-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1 9-1.1 10-1.1.2.1 10-1.1.2.1.r 14-1.1.2.2.1.3 14-1.1.2.2.1.3.r 15-1.1.2.2 15-1.1.2.2.1 15-1.1.2.2.1.r 16-1.1.2.2.1.1.r 17-1.1.2.2.1.1 17-1.1.2.2.1.1.1 17-1.1.2.2.1.1.1.r 19-1.1.2.2.1.2.1.1.1.1 19-1.1.2.2.1.2.1.2.1.1 21-1.1.2.2.1.2.1.1.1.1 23-1.1.2.2.1.2.1.1.1.1 23-1.1.2.2.1.2.1.2.1.1 25-1.1.2.2.1.2.1.2.1.1 26-1.1.2.2.1.2.1 27-1.1.2.2.1.2.1.3.1.1 29-1 30-1.2.1 30-1.2.1.r 31-1.2.2 32-1.2 33-1.2.2.r 33-1.2.3.r 34-1.2.3.1.1.1.1 43-1.2.3.1 44-1.2.3 (s / suggest-01~e.29 :ARG0 (c / contrast-01~e.9 :ARG1 (l / lack-01~e.1 :ARG0~e.6 (m3 / medical-condition :name (n / name :op1 "mSH"~e.7)) :ARG1 (s4 / stable-03 :polarity - :mod (m5 / microsatellite) :ARG2-of (h / high-02))) :ARG2 (b / be-temporally-at-91 :ARG1~e.10 s4~e.10 :ARG2 (t2 / thing~e.15 :ARG2-of~e.15 (s2 / stage-02~e.15 :ARG1~e.16 (c2 / create-01~e.17 :ARG1~e.17 (t / tumor~e.17)) :ARG1-of (m / mean-01 :ARG2 (a / and~e.26 :op1 (m6 / medical-condition :name (n2 / name :op1 "mSA-LGD"~e.19,21,23)) :op2 (m7 / medical-condition :name (n4 / name :op1 "mSA-HGD"~e.19,23,25)) :op3 (m2 / medical-condition :name (n5 / name :op1 "carcinoma"~e.27)))) :time~e.14 (s3 / subsequent~e.14))))) :ARG1 (d / develop-01~e.32 :ARG2~e.30 s4~e.30 :time~e.33 (e / early~e.31) :time~e.33 (t4 / transform-01~e.44 :ARG1-of (i / initiate-01~e.43 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Braf"~e.34) :ARG2-of (m4 / mutate-01 :value "V637E")))))) # ::id pmid_2384_5441.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok P53 Tumor Suppression Inhibits Invasion and Metastasis but Does Not Affect Tumor Initiation in Braf @^{V637E @}@ -@ Induced Tumorigenesis # ::alignments 1-1.1.1.1.1.1 2-1.1.1.2 3-1.1.1 4-1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.2 8-1 10-1.2.1 10-1.2.1.r 11-1.2 12-1.2.2 13-1.2.3 14-1.2.3.1.r 15-1.2.3.1.2.1.1.1 18-1.2.3.1.2.1.2.1 22-1.2.3.1.2 23-1.2.3.1 23-1.2.3.1.1 23-1.2.3.1.1.r (h / have-concession-91~e.8 :ARG1 (i / inhibit-01~e.4 :ARG0 (s / suppress-01~e.3 :ARG0 (p / protein :name (n / name :op1 "p53"~e.1)) :ARG1 (t / tumor~e.2)) :ARG1 (a2 / and~e.6 :op2 (i2 / invade-01~e.5) :op2 (m / metastasize-101~e.7))) :ARG2 (a / affect-01~e.11 :polarity~e.10 -~e.10 :ARG0 s~e.12 :ARG2 (i3 / initiate-01~e.13 :ARG1~e.14 (c / create-01~e.23 :ARG1~e.23 (t2 / tumor~e.23) :ARG2-of (i4 / induce-01~e.22 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf"~e.15) :ARG2-of (m2 / mutate-01 :value "V637E"~e.18))))))) # ::id pmid_2384_5441.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The long latency and low penetrance of cancer development might be explained by the ability of constitutive MAPK signaling to activate anti @-@ oncogenic programs , most notably the p16 @ ^{INK4a @}@ /Rb and p19 @ ^{ARF @}@ /p53 pathways ( Palmero et al. , 1998 ; Lin et al. , 1998 ) . # ::alignments 1-1.1.2.2.1 2-1.1.2.2 4-1.1.2.3.1 7-1.1.2.1.2.1 8-1.1.2 9-1 11-1.1 12-1.1.1.r 14-1.1.1 16-1.1.1.1.3 17-1.1.1.1.1.1 18-1.1.1.1.2 20-1.1.1.2 21-1.1.1.2.2.1 24-1.1.1.2.2 26-1.1.1.2.2.2.2.1 27-1.1.1.2.2.2.2 38-1.1.1.2.2.2.1 48-1.1.1.1 48-1.1.1.2.2.2.1.1 48-1.1.1.2.2.2.1.2 51-1.2.1.1.1.1.1.1 52-1.2.1.1.1 53-1.2.1.1.1.2.1 55-1.2.1.2.2 57-1.2.1.2.1.1.1.1 58-1.2.1 58-1.2.1.1.1 58-1.2.1.2.1 59-1.2.1.1.1.2.1 61-1.2.1.1.2.1 (p / possible-01~e.9 :ARG1 (e / explain-01~e.11 :ARG0~e.12 (c / capable-01~e.14 :ARG1 (p3 / pathway~e.48 :name (n2 / name :op1 "MAPK"~e.17) :ARG0-of (s / signal-07~e.18) :mod (c2 / constitutive~e.16)) :ARG2 (a / activate-01~e.20 :ARG0 p3 :ARG1 (p4 / program~e.24 :ARG0-of (o / oppose-01~e.21 :ARG1 (o2 / oncogene)) :ARG2-of (i / include-91 :ARG1 (a2 / and~e.38 :op1 (p5 / pathway~e.48 :name (n3 / name :op1 "p16INK4a/Rb")) :op2 (p6 / pathway~e.48 :name (n4 / name :op1 "p19ARF/p53"))) :ARG1-of (n5 / notable-04~e.27 :degree (m / most~e.26)))))) :ARG1 (d / develop-01~e.8 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.7)) :mod (l / latent~e.2 :ARG1-of (l2 / long-03~e.1)) :ARG1-of (p2 / penetrate-01 :ARG1-of (l3 / low-04~e.4)))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.58 :op1 (p7 / publication-91 :ARG0 (a4 / and~e.52,58 :op1 (p8 / person :name (n6 / name :op1 "Palmero"~e.51)) :op2 (p9 / person :mod (o3 / other~e.53,59))) :time (d4 / date-entity :year 1998~e.61)) :op1 (p10 / publication-91 :ARG0 (a5 / and~e.58 :op1 (p11 / person :name (n7 / name :op1 "Lin"~e.57)) :op2 p9) :time d4~e.55)))) # ::id pmid_2384_5441.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the role of p53 in Braf @^{V6 @ 37 @ E}@ -@ induced intestinal tumorigenesis , we used p53 @ ^{LSL @-@ R172H/+ @} knockin mice , expressing the equivalent of the dominant @-@ negative human TP53 @ ^{R175H @} conditionally ( Olive et al. , 2004 ) . # ::alignments 1-1.3 3-1.3.2 6-1.3.2.1.1.1 8-1.2.1 8-1.3.2.2.r 9-1.3.2.2.2.1.1.1 18-1.3.2.2.2 19-1.3.2.2.1.1 20-1.3.2.2 20-1.3.2.2.1 20-1.3.2.2.1.r 22-1.1 23-1 25-1.2.1.1.1.1 25-1.3.2.1.1.1 29-1.2.1.1.2.1 35-1.2 37-1.2.2 39-1.2.2.1 40-1.2.2.1.1.r 42-1.2.2.1.1 42-1.2.2.1.1.4 42-1.2.2.1.1.4.r 45-1.2.2.1.1.3 47-1.2.2.1.1.1.1 51-1.2.2.1.1.2.1 54-1.2.2.2 54-1.2.2.2.r 57-1.4.1.1.1.1.1 58-1.4.1.1 59-1.4.1.1.2.1 61-1.4.1.2.1 (u / use-01~e.23 :ARG0 (w / we~e.22) :ARG1 (m / mouse~e.35 :location-of (k / knock-in-00~e.8 :ARG1 (p / protein :name (n / name :op1 "p53"~e.25) :ARG2-of (m2 / mutate-01 :value "LSL-R172H"~e.29))) :ARG3-of (e / express-03~e.37 :ARG2 (e2 / equal-01~e.39 :ARG1~e.40 (g / gene~e.42 :name (n4 / name :op1 "TP53"~e.47) :ARG2-of (m3 / mutate-01 :value "R175H"~e.51 :mod "-/-") :mod (h / human~e.45) :ARG0-of~e.42 (d3 / dominate-01~e.42))) :manner~e.54 (c / conditional~e.54))) :ARG2 (i / investigate-01~e.1 :ARG0 w :ARG1 (r / role~e.3 :poss (p3 / protein :name (n3 / name :op1 "p53"~e.6,25)) :topic~e.8 (c2 / create-01~e.20 :ARG1~e.20 (t / tumor~e.20 :mod (i2 / intestine~e.19)) :ARG2-of (i3 / induce-01~e.18 :ARG0 (e3 / enzyme :name (n5 / name :op1 "Braf"~e.9) :ARG2-of (m4 / mutate-01 :value "V637E")))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a / and~e.58 :op1 (p5 / person :name (n6 / name :op1 "Olive"~e.57)) :op2 (p6 / person :mod (o / other~e.59))) :time (d2 / date-entity :year 2004~e.61)))) # ::id pmid_2384_5441.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We intercrossed them with Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} mice , aged the different double @- and triple @-@ transgenic cohorts , and monitored mice for tumor development ( Figure 3 @ A ) . # ::alignments 0-1.1.1 2-1.1.2.1 7-1.1.2.2.2.1.1 9-1.1.2.2.1.1.1 13-1.1.2.2.1.2.1 15-1.1.2.2.1.2.1 19-1.1.2.2 21-1.2 23-1.2.2.3 26-1.2.2 30-1.2.2.1 30-1.2.2.2 32-1 32-1.1.2 32-1.2.2 33-1.3 34-1.3.2 35-1.3.3.r 36-1.3.3.1 37-1.3.3 40-1.4.1 41-1.2.2.2.1.1 (a / and~e.32 :op1 (i / intercross-00 :ARG0 (w / we~e.0) :ARG1 (a2 / and~e.32 :op1 (t / they~e.2) :op2 (m / mouse~e.19 :mod (e / enzyme :name (n / name :op1 "Braf"~e.9) :ARG2-of (m2 / mutate-01 :value "LSL-V637E"~e.13,15)) :mod (e2 / enzyme :name (n2 / name :op1 "Cre"~e.7) :ARG2-of (e3 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "Villin"))))))) :op2 (a3 / age-01~e.21 :ARG0 w :ARG1 (a4 / and~e.26,32 :op1 (c / cohort~e.30 :mod (p / product-of :op1 2 :op2 (t2 / transgenesis))) :op2 (c2 / cohort~e.30 :mod (p2 / product-of :op1 3~e.41 :op2 t2)) :ARG1-of (d / differ-02~e.23))) :op2 (m3 / monitor-01~e.33 :ARG0 w :ARG1 a2~e.34 :ARG2~e.35 (d2 / develop-02~e.37 :ARG1 (t3 / tumor~e.36))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.40 :mod "3A"))) # ::id pmid_2384_5441.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that the average number of mSAs per mouse was similar in Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} and Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p53 @ ^{LSL @-@ R172H/+ @} animals ( 2.3 and 1.8 , respectively ; Figure 3 @ B ; Table S2 ) . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.1.1.3 5-1.2.1.1 5-1.2.2.1 6-1.2.1.1.2.r 7-1.2.1.1.2.1.1 8-1.2.1 8-1.2.2 9-1.2.1.2 11-1.2 16-1.2.1.3.2.1.1 18-1.2.1.3.1.1.1 22-1.2.1.3.1.2.1 24-1.2.1.3.1.2.1 32-1.2.1.3.2.1.1 34-1.2.1.3.1.1.1 38-1.2.1.3.1.2.1 40-1.2.1.3.1.2.1 46-1.2.2.3.3.1.1 50-1.2.1.3.1.2.1 50-1.2.2.3.3.2.1 55-1.2.1.3 55-1.2.2.3 57-1.2.1.1.1 59-1.2.2.1.1 64-1.3.1.1 70-1.3.1.2 71-1.3.1.2.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (r / resemble-01~e.11 :ARG1 (r2 / rate-entity-91~e.8 :ARG1 (n / number-01~e.5 :ARG2 2.3~e.57 :ARG1~e.6 (d / disease :name (n2 / name :op1 "mSA"~e.7)) :ARG1-of (a / average-01~e.4)) :ARG2 (m / mouse~e.9) :location (a2 / animal~e.55 :mod (e / enzyme :name (n3 / name :op1 "Braf"~e.18,34) :ARG2-of (m2 / mutate-01 :value "LSL-V637E"~e.22,24,38,40,50)) :mod (e2 / enzyme :name (n4 / name :op1 "Cre"~e.16,32) :ARG2-of (e3 / express-03 :ARG1 (g / gene :name (n5 / name :op1 "Villin")))))) :ARG2 (r3 / rate-entity-91~e.8 :ARG1 (n6 / number-01~e.5 :ARG2 1.8~e.59 :ARG1 d :ARG1-of a) :ARG2 m :location (a3 / animal~e.55 :mod e2 :mod e :mod (p / protein :name (n7 / name :op1 "p53"~e.46) :ARG2-of (m3 / mutate-01 :value "LSL-R172H"~e.50))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f2 / figure~e.64 :mod "3B") :op2 (t / table~e.70 :mod "S2"~e.71)))) # ::id pmid_2384_5441.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , the proportion of mice developing mSAs did not differ between groups ( 82.9 % and 82.8 % , respectively , Table S2 ) , suggesting that the p53 pathway does not restrain dysplasia initiation . # ::alignments 3-1.2 4-1.2.1.r 5-1.2.1 6-1.2.1.1 7-1.2.1.1.1.1.1 9-1.1 9-1.1.r 10-1 12-1.7 14-1.3.1.1 15-1.3.1 15-1.3.2 16-1.3 17-1.3.2.1 18-1.3.2 23-1.4.1 24-1.4.1.1 28-1.5 29-1.5.1.r 31-1.5.1.2.1.1 32-1.5.1.2 34-1.5.1.1 34-1.5.1.1.r 35-1.5.1 36-1.5.1.3.1 37-1.5.1.3 (d / differ-02~e.10 :polarity~e.9 -~e.9 :ARG1 (p / proportion-01~e.3 :ARG1~e.4 (m / mouse~e.5 :ARG1-of (d2 / develop-01~e.6 :ARG2 (d3 / disease :name (n / name :op1 "mSA"~e.7))))) :quant (a / and~e.16 :op1 (p2 / percentage-entity~e.15 :value 82.9~e.14) :op2 (p3 / percentage-entity~e.15,18 :value 82.8~e.17)) :ARG1-of (d4 / describe-01 :ARG0 (t / table~e.23 :mod "S2"~e.24)) :ARG0-of (s / suggest-01~e.28 :ARG1~e.29 (r / restrain-01~e.35 :polarity~e.34 -~e.34 :ARG0 (p4 / pathway~e.32 :name (n2 / name :op1 "p53"~e.31)) :ARG1 (i / initiate-01~e.37 :ARG1 (d5 / dysplasia~e.36)))) :ARG1-of (r2 / resemble-01) :location (g / group~e.12)) # ::id pmid_2384_5441.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In sharp contrast , invasive cancers were found considerably more frequently in Vil @-@ Cre ; Braf @ ^{V637E @ /+}@ ; p53 @ ^{LSL @-@ R172H/+ @} mice ( Figure 3 @ B ; Table S3 ) . # ::alignments 1-1.2 2-1 4-1.1.1 4-1.1.1.3 4-1.1.1.3.r 5-1.1.1.2.1 7-1.1 8-1.1.3.1.1 9-1.1.3.1 10-1.1.3 15-1.1.2.1.1.1 17-1.1.2.2.1.1 21-1.1.2.2.2.1 27-1.1.2.3.1.1 31-1.1.2.3.2.1 36-1.1.2 39-1.3.1.1 45-1.3.1.2 46-1.3.1.2.1 (c / contrast-01~e.2 :ARG2 (f / find-01~e.7 :ARG1 (d / disease~e.4 :wiki "Cancer" :name (n / name :op1 "cancer"~e.5) :ARG0-of~e.4 (i / invade-01~e.4)) :location (m / mouse~e.36 :mod (e / enzyme :name (n2 / name :op1 "Cre"~e.15) :ARG2-of (e2 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "Villin")))) :mod (e3 / enzyme :name (n4 / name :op1 "Braf"~e.17) :ARG2-of (m2 / mutate-01 :value "V637E"~e.21)) :mod (p / protein :name (n5 / name :op1 "p53"~e.27) :ARG2-of (m3 / mutate-01 :value "LSL-R172H"~e.31))) :ARG1-of (f2 / frequent-02~e.10 :degree (m4 / more~e.9 :degree (c2 / considerable~e.8)))) :degree (s / sharp~e.1) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f3 / figure~e.39 :mod "3B") :op2 (t / table~e.45 :mod "S3"~e.46)))) # ::id pmid_2384_5441.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fifty @-@ six percent of Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p53 @ ^{LSL @-@ R172H/+ @} animals at an age of 10 @–@ 20 months had carcinomas , as compared to 13.8 % of mice in the Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} cohort ( p = 0.002 , χ @² test ) . # ::alignments 3-1.1.4.2 8-1.1.1.1.1 10-1.1.2.1.1 14-1.1.2.2.1 16-1.1.2.2.1 22-1.1.3.1.1 26-1.1.2.2.1 26-1.1.3.2.1 31-1.1 31-1.1.4.1 34-1.1.5.r 36-1.1.5.1.1 38-1.1.5.1.2 39-1.1.5.2 40-1 40-1.3 41-1.2 44-1.3.r 45-1.3.1.r 46-1.3.1.2.2.1 47-1.3.1.2.2 49-1.3.1 49-1.3.1.2.1 55-1.1.1.1.1 57-1.1.2.1.1 61-1.1.2.2.1 63-1.1.2.2.1 67-1.3.1.1 69-1.4 71-1.4.1 77-1.4 77-1.4.2 77-1.4.2.r (h / have-03~e.40 :ARG0 (a / animal~e.31 :mod (e / enzyme :name (n / name :op1 "Cre"~e.8,55) :ARG2-of (e2 / express-03 :ARG1 (g / gene :name (n2 / name :op1 "Villin")))) :mod (e3 / enzyme :name (n3 / name :op1 "Braf"~e.10,57) :ARG2-of (m / mutate-01 :value "LSL-V637E"~e.14,16,26,61,63)) :mod (p / protein :name (n4 / name :op1 "p53"~e.22) :ARG2-of (m2 / mutate-01 :value "LSL-R172H"~e.26)) :ARG1-of (i / include-91 :ARG2 (a2 / animal~e.31 :mod e :mod e3 :mod p) :ARG3 (p2 / percentage-entity~e.3 :value 56)) :age~e.34 (t / temporal-quantity :quant (v / value-interval :op1 10~e.36 :op2 20~e.38) :unit (m3 / month~e.39))) :ARG1 (c / carcinoma~e.41) :compared-to~e.44 (h2 / have-03~e.40 :ARG0~e.45 (m4 / mouse~e.49 :location (c2 / cohort~e.67 :mod e :mod e3) :ARG1-of (i2 / include-91 :ARG2 (m5 / mouse~e.49 :location c2) :ARG3 (p3 / percentage-entity~e.47 :value 13.8~e.46))) :ARG1 c) :ARG1-of (s / statistical-test-91~e.69,77 :ARG2 0.002~e.71 :ARG4~e.77 (t2 / test~e.77 :name (n5 / name :op1 "χ2")))) # ::id pmid_2384_5441.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The average number of cancers was 5.2 times higher in the Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p53 @ ^{LSL @-@ R172H/+ @} cohort ( p = 0.007 ; Mann @-@ Whitney rank sum test ) . # ::alignments 1-1.2 2-1 3-1.1.r 3-1.3.2 4-1.1.2.1 6-1.3.2.1 7-1.3.2 8-1.3 8-1.3.1 8-1.3.1.r 14-1.4.1.1.1 16-1.4.2.1.1 20-1.4.2.2.1 20-1.4.3.2.1 28-1.4.3.1.1 32-1.4.2.2.1 32-1.4.3.2.1 37-1.4 39-1.5 41-1.5.1 43-1.5.2.1.1 45-1.5.2.1.1 46-1.5.2.1.2 47-1.5.2.1.3 48-1.5 48-1.5.2 48-1.5.2.1.4 48-1.5.2.r (n / number-01~e.2 :ARG1~e.3 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.4)) :ARG1-of (a / average-01~e.1) :ARG1-of (h / high-02~e.8 :degree~e.8 (m / more~e.8) :degree (p / product-of~e.3,7 :op1 5.2~e.6)) :location (c / cohort~e.37 :mod (e / enzyme :name (n3 / name :op1 "Cre"~e.14) :ARG2-of (e2 / express-03 :ARG1 (g / gene :name (n4 / name :op1 "Villin")))) :mod (e3 / enzyme :name (n5 / name :op1 "Braf"~e.16) :ARG2-of (m2 / mutate-01 :value "LSL-V637"~e.20,32)) :mod (p2 / protein :name (n6 / name :op1 "p53"~e.28) :ARG2-of (m3 / mutate-01 :value "LSL-R172H"~e.20,32))) :ARG1-of (s / statistical-test-91~e.39,48 :ARG2 0.007~e.41 :ARG4~e.48 (t / test~e.48 :name (n7 / name :op1 "Mann-Whitney"~e.43,45 :op2 "rank"~e.46 :op3 "sum"~e.47 :op4 "test"~e.48)))) # ::id pmid_2384_5441.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Some animals had more than one synchronous cancer and 25 % ( 3 @/@ 12 ) of mice with cancer had metastases to local lymph nodes , pancreas , or lungs ( Figures 3 @ C and 3D ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.4 4-1.1.2.4 5-1.1.2.4.1 6-1.1.2.3 7-1.1.2.2.1 8-1 9-1.2.1.2.2.1 10-1.2.1.2.2 12-1.2.1.1 14-1.2.1.2.1.1 17-1.2.1 17-1.2.1.2.1 19-1.2.2.1 20-1.2 20-1.2.1.3 21-1.2.2 22-1.2.2.2.r 23-1.2.2.2.1.2 24-1.2.2.2.1.1 25-1.2.2.2.1 27-1.2.2.2.2 29-1.2.2.2 30-1.2.2.2.3 33-1.3.1.1 33-1.3.1.2 34-1.2.1.1 37-1.3.1 38-1.2.1.1.r 38-1.3.1.2.1 (a / and~e.8 :op1 (h / have-03~e.2 :ARG0 (a2 / animal~e.1 :quant (s / some~e.0)) :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.7) :mod (s2 / synchrony~e.6) :quant (m / more-than~e.3,4 :op1 1~e.5))) :op2 (h2 / have-03~e.20 :ARG0 (m2 / mouse~e.17 :quant~e.38 3~e.12,34 :ARG1-of (i / include-91 :ARG2 (m3 / mouse~e.17 :quant 12~e.14) :ARG3 (p / percentage-entity~e.10 :value 25~e.9)) :ARG0-of (h3 / have-03~e.20 :ARG1 d)) :ARG1 (m4 / metastasize-101~e.21 :ARG1 d~e.19 :ARG2~e.22 (o / or~e.29 :op1 (n2 / node~e.25 :mod (l / lymph~e.24) :ARG1-of (l2 / local-02~e.23)) :op2 (p2 / pancreas~e.27) :op3 (l3 / lung~e.30)))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.37 :op1 (f / figure~e.33 :mod "3C") :op2 (f2 / figure~e.33 :mod "3D"~e.38)))) # ::id pmid_2384_5441.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All together , these data show that p53 does not affect early stages of Braf @^{V6 @ 37 @ E}@ -@ induced tumorigenesis but plays an important role in invasiveness control . # ::alignments 3-1.1.1 4-1.1 5-1 6-1.2.r 7-1.2.1.2.1.1 9-1.2.1.1 9-1.2.1.1.r 10-1.2.1 11-1.2.1.3.1.2 12-1.2.1.3 12-1.2.1.3.1 12-1.2.1.3.1.r 13-1.2.1.3.1.1.r 14-1.2.1.3.1.1.2.1.1.1 23-1.2.1.3.1.1.2 24-1.2.1.3.1.1 24-1.2.1.3.1.1.1 24-1.2.1.3.1.1.1.r 25-1.2 26-1.2.2 28-1.2.2.2.2 32-1.2.2.2 (s / show-01~e.5 :ARG0 (d / data~e.4 :mod (t / this~e.3)) :ARG1~e.6 (c / contrast-01~e.25 :ARG1 (a / affect-01~e.10 :polarity~e.9 -~e.9 :ARG0 (p / protein :name (n / name :op1 "p53"~e.7)) :ARG1 (t3 / thing~e.12 :ARG2-of~e.12 (s2 / stage-02~e.12 :ARG1~e.13 (c3 / create-01~e.24 :ARG1~e.24 (t2 / tumor~e.24) :ARG2-of (i / induce-01~e.23 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf"~e.14) :ARG2-of (m / mutate-01 :value "V637E")))) :time (e2 / early~e.11)))) :ARG2 (p2 / play-02~e.26 :ARG0 p :ARG1 (c2 / control-01~e.32 :ARG1 (i2 / invade-01) :mod (i3 / important~e.28)))) :ARG2-of (s3 / sum-up-01)) # ::id pmid_2384_5441.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of p53 Tumor Suppression during Advanced , but Not Early Tumorigenesis # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1 6-1.2.2.2.r 6-1.2.r 7-1.2.1.2 9-1.2 10-1.2.2.2.1 10-1.2.2.2.1.r 11-1.2.2.2 12-1.2.1 12-1.2.1.1 12-1.2.1.1.r 12-1.2.2 12-1.2.2.1 12-1.2.2.1.r (a / activate-01~e.1 :ARG1~e.2 (s / suppress-01~e.5 :ARG1 (t / tumor~e.4 :mod (p / protein :name (n / name :op1 "p53"~e.3)))) :time~e.6 (c / contrast-01~e.9 :ARG1 (c2 / create-01~e.12 :ARG1~e.12 (t2 / tumor~e.12) :ARG1-of (a2 / advance-01~e.7)) :ARG2 (c3 / create-01~e.12 :ARG1~e.12 (t3 / tumor~e.12) :time~e.6 (e / early~e.11 :polarity~e.10 -~e.10)))) # ::id pmid_2384_5441.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next examined at which stage of tumorigenesis the p53 pathway becomes activated ( Figures 3 @ E @–@ 3N ) . # ::alignments 0-1.1 1-1.3 2-1 5-1.2 5-1.2.1 5-1.2.1.r 6-1.2.1.1.r 7-1.2.1.1 7-1.2.1.1.1 7-1.2.1.1.1.r 9-1.2.2.1.1.1 10-1.2.2.1 11-1.2.2 12-1.2.2.2 15-1.4.1.1 15-1.4.1.2 20-1.4.1.2.1 (e / examine-01~e.2 :ARG0 (w / we~e.0) :ARG1 (t2 / thing~e.5 :ARG2-of~e.5 (s / stage-02~e.5 :ARG1~e.6 (c / create-01~e.7 :ARG1~e.7 (t / tumor~e.7))) :time-of (b / become-01~e.11 :ARG1 (p / pathway~e.10 :name (n / name :op1 "p53"~e.9)) :ARG2 (a / activate-01~e.12 :ARG1 p))) :time (n2 / next~e.1) :ARG1-of (d / describe-01 :ARG0 (v / value-interval :op1 (f / figure~e.15 :mod "3E") :op2 (f2 / figure~e.15 :mod "3N"~e.20)))) # ::id pmid_2384_5441.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We performed immunohistochemistry for p53 and its target gene p21 in wild @-@ type as well as Braf mutant hyperplasia and neoplasia . # ::alignments 0-1.1 1-1 2-1.2 3-1.3.r 4-1.3.1.1.1 5-1.3 6-1.3.2.3 6-1.3.2.3.r 7-1.3.2.2 8-1.3.2 8-1.4.2.1.1 9-1.3.2.1.1 10-1.4.r 11-1.4.1.1 13-1.4.1.1 14-1.4 15-1.4 16-1.4 18-1.4.2.1.1.1.1 20-1.4.2.1 21-1.4.1 21-1.4.2 22-1.4 23-1.4.3 23-1.4.4 (p / perform-01~e.1 :ARG0 (w / we~e.0) :ARG1 (i / immunohistochemistry~e.2) :beneficiary~e.3 (a / and~e.5 :op1 (p2 / protein :name (n / name :op1 "p53"~e.4)) :op2 (g / gene~e.8 :name (n2 / name :op1 "p21"~e.9) :ARG1-of (t / target-01~e.7) :poss~e.6 p2~e.6)) :location~e.10 (a2 / and~e.14,15,16,22 :op1 (h / hyperplasia~e.21 :mod (w2 / wild-type~e.11,13)) :op2 (h2 / hyperplasia~e.21 :ARG2-of (m / mutate-01~e.20 :ARG0 (g2 / gene~e.8 :name (n3 / name :op1 "Braf"~e.18)))) :op3 (n4 / neoplasia~e.23 :mod w2) :op4 (n5 / neoplasia~e.23 :ARG2-of m))) # ::id pmid_2384_5441.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoreactivity for p53 was negative in all wild @-@ type intestines ( n = 21 ) , all Braf @^V637E@ -@ induced mSHs ( n = 43 ) , and most mSAs @-@ LGD ( Figures 3 @ F @–@ 3H and 3N ) . # ::alignments 2-1.2.1.1.1 4-1 5-1.1.r 6-1.1.1.2 7-1.1.1.1 9-1.1.1.1 10-1.1.1 14-1.1.1.3.1 17-1.1.1.2 18-1.1.2.2.1.1.1 20-1.1.2.2.1.2.1 23-1.1.2.2 28-1.1.2.3.1 31-1.1 32-1.1.3.2 33-1.1.3.1.1 35-1.1.3.1.1 38-1.3.1.1.1 38-1.3.1.1.2 38-1.3.1.2 43-1.3.1.1.2.1 44-1.3.1 45-1.3.1.2.1 (n / negative-01~e.4 :ARG1~e.5 (a / and~e.31 :op1 (i2 / intestine~e.10 :mod (w / wild-type~e.7,9) :mod (a2 / all~e.6,17) :ARG1-of (n3 / number-01 :ARG2 21~e.14)) :op2 (m / medical-condition :name (n4 / name :op1 "mSH") :ARG2-of (i3 / induce-01~e.23 :ARG0 (e / enzyme :name (n5 / name :op1 "Braf"~e.18) :ARG2-of (m2 / mutate-01 :value "V637E"~e.20))) :ARG1-of (n6 / number-01 :ARG2 43~e.28) :mod a2) :op3 (d2 / disease :name (n7 / name :op1 "mSA-LGD"~e.33,35) :quant (m4 / most~e.32))) :ARG2 (i / immunoreact-00 :ARG1 (p / protein :name (n2 / name :op1 "p53"~e.2))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and~e.44 :op1 (v / value-interval :op1 (f / figure~e.38 :mod "3F") :op2 (f2 / figure~e.38 :mod "3H"~e.43)) :op2 (f3 / figure~e.38 :mod "3N"~e.45)))) # ::id pmid_2384_5441.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only 5 @/@ 37 mSAs @-@ LGD were p53 @-@ positive ( example in Figure 3 @ I ) . # ::alignments 0-1.3 1-1.2.1 3-1.2.3.1.1 4-1.2.2.1 4-1.2.3.1.2.1 6-1.2.2.1 6-1.2.3.1.2.1 7-1.2.r 8-1.1.1.1 10-1 12-1.4 15-1.4.1 (p / positive~e.10 :topic (p2 / protein :name (n / name :op1 "p53"~e.8)) :domain~e.7 (d / disease :quant 5~e.1 :name (n2 / name :op1 "mSA-LGD"~e.4,6) :ARG1-of (i / include-91 :ARG2 (d2 / disease :quant 37~e.3 :name (n3 / name :op1 "mSA-LGD"~e.4,6)))) :mod (o / only~e.0) :ARG0-of (e / exemplify-01~e.12 :location (f / figure~e.15 :mod "3I"))) # ::id pmid_2384_5441.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We detected however marked p53 expression in 97 % ( 28 @/@ 29 ) of mSAs @-@ HGD ( Figures 3 @ L and 3N ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.1.2.2 4-1.1.2.1.1.1 5-1.1.2 6-1.1.3.r 7-1.1.3.3.2.1 8-1.1.3.3.2 10-1.1.3.1 12-1.1.3.3.1.1 15-1.1.3.2.1 15-1.1.3.3.1.2.1 17-1.1.3.2.1 17-1.1.3.3.1.2.1 20-1.2.1.1 20-1.2.1.2 24-1.2.1 25-1.2.1.2.1 (h / have-concession-91~e.2 :ARG2 (d / detect-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.5 :ARG2 (p / protein :name (n / name :op1 "p53"~e.4)) :degree (m / mark-01~e.3)) :location~e.6 (d2 / disease :quant 28~e.10 :name (n2 / name :op1 "mSA-HGD"~e.15,17) :ARG1-of (i / include-91 :ARG2 (d3 / disease :quant 29~e.12 :name (n3 / name :op1 "mSA-HGD"~e.15,17)) :ARG3 (p2 / percentage-entity~e.8 :value 97~e.7)))) :ARG1-of (d4 / describe-01 :ARG0 (a / and~e.24 :op1 (f / figure~e.20 :mod "3L") :op2 (f2 / figure~e.20 :mod "3N"~e.25)))) # ::id pmid_2384_5441.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There was a strong concordance of p53 and p21 immunoreactivity in all samples . # ::alignments 3-1.4 6-1.1.1.1.1 8-1.2.1.1.1 11-1.3.1 12-1.3 12-1.3.2 12-1.3.2.r (r / resemble-01 :ARG1 (i / immunoreact-00 :ARG1 (p / protein :name (n / name :op1 "p53"~e.6))) :ARG2 (i2 / immunoreact-00 :ARG1 (p2 / protein :name (n2 / name :op1 "p21"~e.8))) :location (t / thing~e.12 :mod (a / all~e.11) :ARG1-of~e.12 (s / sample-01~e.12)) :degree (s2 / strong~e.3)) # ::id pmid_2384_5441.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to p53 , p21 IHC was negative in all wild @-@ type intestines ( n = 21 ) , all Braf @^V637E@ -@ induced mSHs ( n = 15 ) , and most ( 10 @/@ 11 ) mSAs @-@ LGD but was present in the majority ( 8 @/@ 9 ; 89 %) of mSAs @-@ HGD ( Figures 3 @ G , 3J , 3M , and 3N ) . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1.1 4-1.1.2.1.1.1 7-1.1 8-1.1.1.r 9-1.1.1.1.2 10-1.1.1.1.1 12-1.1.1.1.1 13-1.1.1.1 17-1.1.1.1.3.1 20-1.1.1.1.2 21-1.1.1.2.2.1.1.1 23-1.1.1.2.2.1.2.1 26-1.1.1.2.2 31-1.1.1.2.3.1 34-1.1.1 35-1.1.1.3.3.2 37-1.1.1.3.1 39-1.1.1.3.3.1.1 41-1.1.1.3.2.1 41-1.1.1.3.3.1.2.1 43-1.1.1.3.2.1 43-1.1.1.3.3.1.2.1 44-1 46-1.2 47-1.2.2.r 49-1.2.2.3.2.1 51-1.2.2.1 53-1.2.2.3.1.1 55-1.2.2.3.2.2.1 58-1.2.2.2.1 60-1.2.2.2.1 60-1.2.2.3.1.2.1 63-1.4.1.1 63-1.4.1.2 63-1.4.1.3 63-1.4.1.4 68-1.4.1.2.1 70-1.4.1.3.1 72-1.4.1 73-1.4.1.4.1 (c / contrast-01~e.44 :ARG1 (n / negative-01~e.7 :ARG1~e.8 (a / and~e.34 :op1 (i2 / intestine~e.13 :mod (w / wild-type~e.10,12) :mod (a2 / all~e.9,20) :ARG1-of (n3 / number-01 :ARG2 21~e.17)) :op2 (d / disease :name (n4 / name :op1 "mSH") :ARG2-of (i3 / induce-01~e.26 :ARG0 (e / enzyme :name (n5 / name :op1 "Braf"~e.21) :ARG2-of (m / mutate-01 :value "V637E"~e.23))) :ARG1-of (n6 / number-01 :ARG2 15~e.31) :mod a2) :op3 (m4 / medical-condition :quant 10~e.37 :name (n7 / name :op1 "mSA-LGD"~e.41,43) :ARG1-of (i4 / include-91 :ARG2 (m5 / medical-condition :quant 11~e.39 :name (n8 / name :op1 "mSA-LGD"~e.41,43)) :ARG3 (m2 / most~e.35)))) :ARG2 (i / immunohistochemistry :mod (p / protein :name (n2 / name :op1 "p21"~e.4)))) :ARG2 (p4 / present-02~e.46 :ARG1 i :ARG2~e.47 (m6 / medical-condition :quant 8~e.51 :name (n9 / name :op1 "mSA-HGD"~e.58,60) :ARG1-of (i5 / include-91 :ARG2 (m7 / medical-condition :quant 9~e.53 :name (n10 / name :op1 "mSA-HGD"~e.60)) :ARG3 (a3 / and :op1 (m3 / majority~e.49) :op2 (p2 / percentage-entity :value 89~e.55))))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (p3 / protein :name (n11 / name :op1 "p53"~e.2))) :ARG1-of (d6 / describe-01 :ARG0 (a4 / and~e.72 :op1 (f / figure~e.63 :mod "3G") :op2 (f2 / figure~e.63 :mod "3J"~e.68) :op3 (f3 / figure~e.63 :mod "3M"~e.70) :op4 (f4 / figure~e.63 :mod "3N"~e.73)))) # ::id pmid_2384_5441.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest selective activation of p53 tumor suppression during advanced but not early stages of tumor evolution . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1.1 7-1.2.1.1 8-1.2.1 9-1.2.3.2.1.2.r 9-1.2.3.r 10-1.2.3.1.1.2 11-1.2.3 12-1.2.3.2.1.2.1 12-1.2.3.2.1.2.1.r 13-1.2.3.2.1.2 14-1.2.3.1 14-1.2.3.1.1 14-1.2.3.1.1.r 14-1.2.3.2 14-1.2.3.2.1 14-1.2.3.2.1.r 15-1.2.3.1.1.1.r 16-1.2.3.1.1.1.1 17-1.2.3.1.1.1 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1 (a / activate-01~e.4 :ARG1~e.5 (s2 / suppress-01~e.8 :ARG1 (t2 / tumor~e.7 :mod (p / protein :name (n / name :op1 "p53"~e.6)))) :ARG0-of (s3 / select-01) :time~e.9 (c / contrast-01~e.11 :ARG1 (t3 / thing~e.14 :ARG2-of~e.14 (s4 / stage-02~e.14 :ARG1~e.15 (e / evolve-01~e.17 :ARG1 t2~e.16) :ARG1-of (a2 / advance-01~e.10))) :ARG2 (t4 / thing~e.14 :ARG2-of~e.14 (s5 / stage-02~e.14 :ARG1 e :time~e.9 (e2 / early~e.13 :polarity~e.12 -~e.12)))))) # ::id pmid_2384_5441.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the mechanism of p53 activation , we first stained for the DNA damage marker γH2AX . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.1.r 5-1.4.2.1.1.1.1 6-1.4.2.1 8-1.1 9-1.3 10-1 11-1.2.r 13-1.2.2.1.1.1 14-1.2.2 15-1.2 16-1.2.1.1 (s / stain-01~e.10 :ARG0 (w / we~e.8) :purpose~e.11 (m / marker~e.15 :name (n / name :op1 "γH2AX"~e.16) :mod (d / damage-01~e.14 :ARG1 (n2 / nucleic-acid :name (n4 / name :op1 "DNA"~e.13)))) :time (f / first~e.9) :purpose (i / investigate-01~e.1 :ARG0 w :ARG1 (m2 / mechanism~e.3 :poss~e.4 (a / activate-01~e.6 :ARG1 (p / protein :name (n3 / name :op1 "p53"~e.5)))))) # ::id pmid_2384_5441.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogene @-@ induced DNA damage can activate p53 via ARF @-@ independent pathways ( Sherr and McCormick , 2002 ) . # ::alignments 0-1.1.1.2.1 2-1.1.1.2 3-1.1.1.1.1.1 4-1.1.1 5-1 6-1.1 7-1.1.2.1.1 9-1.1.3.1.2.1.1 11-1.1.3.1 11-1.1.3.1.1 11-1.1.3.1.1.r 12-1.1.3 15-1.2.1.1.1.1.1 16-1.2.1.1 17-1.2.1.1.2.1.1 19-1.2.1.2.1 (p / possible-01~e.5 :ARG1 (a / activate-01~e.6 :ARG0 (d / damage-01~e.4 :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "DNA"~e.3)) :ARG2-of (i / induce-01~e.2 :ARG0 (o / oncogene~e.0))) :ARG1 (p2 / protein :name (n / name :op1 "p53"~e.7)) :instrument (p3 / pathway~e.12 :ARG0-of (d3 / depend-01~e.11 :polarity~e.11 -~e.11 :ARG1 (p4 / protein :name (n2 / name :op1 "ARF"~e.9))))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and~e.16 :op1 (p6 / person :name (n3 / name :op1 "Sherr"~e.15)) :op2 (p7 / person :name (n4 / name :op1 "McCormick"~e.17))) :time (d5 / date-entity :year 2002~e.19)))) # ::id pmid_2384_5441.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All mSHs ( n = 20 ) or mSAs @-@ LGD ( n = 12 ) were γH2AX @-@ negative ( Figure 3 @ K ) , and only three of 17 mSAs @-@ HGD ( all p53 @/@ p21 @-@ positive ) showed evidence for activation of the DNA damage response . # ::alignments 0-1.1.1.3 5-1.1.1.1.2.1 7-1.1.1 8-1.1.1.2.1.1 10-1.1.1.2.1.1 14-1.1.1.2.2.1 17-1.1.2.1.1 19-1.1 22-1.1.3.1 23-1.2.1.1 29-1.2.1.4 30-1.2.1.1 32-1.2.1.3.1.1 33-1.2.1.2.1 33-1.2.1.3.1.2.1 35-1.2.1.2.1 35-1.2.1.3.1.2.1 37-1.2.1.3.1.4 38-1.2.1.3.1.3.1.1.1.1 39-1.2.1.3.1.3.1 40-1.2.1.3.1.3.1.2.1.1 42-1.2.1.3.1.3 44-1.2 45-1.2.2 46-1.2.2.1.r 47-1.2.2.1 48-1.2.2.1.1.r 50-1.2.2.1.1.1.1.1.1 51-1.2.2.1.1.1 52-1.2.2.1.1 (a / and :op1 (n / negative-01~e.19 :ARG1 (o / or~e.7 :op1 (m / medical-condition :name (n3 / name :op1 "mSH") :ARG1-of (n4 / number-01 :ARG2 20~e.5)) :op2 (m4 / medical-condition :name (n5 / name :op1 "mSA-LGD"~e.8,10) :ARG1-of (n6 / number-01 :ARG2 12~e.14)) :mod (a2 / all~e.0)) :ARG2 (p4 / protein :name (n2 / name :op1 "γH2AX"~e.17)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.22 :mod "3K"))) :op2 (s / show-01~e.44 :ARG0 (m3 / medical-condition :quant 3~e.23,30 :name (n7 / name :op1 "mSA-HGD"~e.33,35) :ARG1-of (i / include-91 :ARG2 (m2 / medical-condition :quant 17~e.32 :name (n8 / name :op1 "mSA-HGD"~e.33,35) :mod (p / positive~e.42 :topic (s2 / slash~e.39 :op1 (p2 / protein :name (n9 / name :op1 "p53"~e.38)) :op2 (p3 / protein :name (n10 / name :op1 "p21"~e.40)))) :mod a2~e.37)) :mod (o2 / only~e.29)) :ARG1 (e / evidence-01~e.45 :ARG1~e.46 (a3 / activate-01~e.47 :ARG1~e.48 (r / respond-01~e.52 :ARG2 (d6 / damage-01~e.51 :ARG1 (n11 / nucleic-acid :name (n12 / name :op1 "DNA"~e.50)))))))) # ::id pmid_2384_5441.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , p19 @^Arf expression increased substantially during tumor progression : average normalized p19 @^Arf mRNA levels were similar in Braf @^{V6 @ 37 @ E}@ -@ induced mSHs ( 0.7 ) and wild @-@ type mucosa ( 1.0 ) , but were increased 9.9-, 32.3-, and 39.4 @-@ fold in mSAs @-@ LGD , mSAs @-@ HGD , and carcinomas , respectively ( Figure 3 @ E ) . # ::alignments 1-1 7-1.1.1 8-1.1 9-1.1.2 10-1.1.3.r 11-1.1.3.1 12-1.1.3 14-1.1.4.1.1.1.4 15-1.1.4.1.1.1.3 20-1.1.4.1.1.1.1.1.1 21-1.1.4.1.1.1 23-1.1.4.1.1 24-1.1.4.1.1.2.r 25-1.1.4.1.1.2.1.3.1.1.1 34-1.1.4.1.1.2.1.3 37-1.1.4.1.1.2.1.1 39-1.1.4.1.1.2 40-1.1.4.1.1.2.2.2 42-1.1.4.1.1.2.2.2 43-1.1.4.1.1.2.2 45-1.1.4.1.1.2.2.1 48-1.1.4.1 50-1.1.4.1.2.1 50-1.1.4.1.2.2 50-1.1.4.1.2.3 53-1.1.4.1.2 54-1.1.4.1.2.3.2.1 56-1.1.4.1.2.1.2 56-1.1.4.1.2.2.2 56-1.1.4.1.2.3.2 58-1.1.4.1.2.1.3.1.1 58-1.1.4.1.2.2.3.1.1 60-1.1.4.1.2.1.3.1.1 62-1.1.4.1.2.1.3.1.1 62-1.1.4.1.2.2.3.1.1 64-1.1.4.1.2.2.3.1.1 66-1.1.4.1.2 67-1.1.4.1.2.3.3 72-1.2.1 (c / contrast-01~e.1 :ARG2 (i / increase-01~e.8 :ARG1 (e / express-03~e.7 :ARG2 (p / protein :name (n / name :op1 "p19Arf"))) :degree (s / substantial~e.9) :time~e.10 (p2 / progress-01~e.12 :ARG1 (t / tumor~e.11)) :ARG1-of (m / mean-01 :ARG2 (c2 / contrast-01~e.48 :ARG1 (r / resemble-01~e.23 :ARG1 (l / level~e.21 :quant-of (n8 / nucleic-acid :name (n2 / name :op1 "mRNA"~e.20)) :mod p :ARG1-of (n3 / normalize-01~e.15) :ARG1-of (a / average-04~e.14)) :location~e.24 (a2 / and~e.39 :op1 (m6 / medical-condition :quant 0.7~e.37 :name (n4 / name :op1 "mSH") :ARG2-of (i2 / induce-01~e.34 :ARG0 (e2 / enzyme :name (n5 / name :op1 "Braf"~e.25) :ARG2-of (m2 / mutate-01 :value "V637E")))) :op2 (m3 / mucosa~e.43 :quant 1.0~e.45 :mod (w / wild-type~e.40,42)))) :ARG2 (a3 / and~e.53,66 :op1 (i3 / increase-01~e.50 :ARG1 l :ARG2 (p3 / product-of~e.56 :op1 9.9) :location (m4 / medical-condition :name (n6 / name :op1 "mSA-LGD"~e.58,60,62))) :op2 (i4 / increase-01~e.50 :ARG1 l :ARG2 (p4 / product-of~e.56 :op1 32.3) :location (m5 / medical-condition :name (n7 / name :op1 "mSA-HGD"~e.58,62,64))) :op3 (i5 / increase-01~e.50 :ARG1 l :ARG2 (p5 / product-of~e.56 :op1 39.4~e.54) :location (c3 / carcinoma~e.67)))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.72 :mod "3E"))) # ::id pmid_2384_5441.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We conclude that p53 is activated mainly via p19 @^Arf in advanced Braf @^V637E@ -@ iduced tumorigenesis , explaining its late stage specific function . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.2.1.1 5-1.2 6-1.2.3 12-1.2.4.r 13-1.2.4.3 14-1.2.4.2.1.1.1 16-1.2.4.2.1.2.1 20-1.2.4 20-1.2.4.1 20-1.2.4.1.r 22-1.2.5 23-1.2.5.1.1 23-1.2.5.1.1.r 24-1.2.5.1.3 25-1.2.5.1.2.1 25-1.2.5.1.2.1.1 25-1.2.5.1.2.1.1.r 26-1.2.5.1.2 27-1.2.5.1 (c / conclude-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (a / activate-01~e.5 :ARG0 (p / protein :name (n / name :op1 "p19Arf")) :ARG1 (p2 / protein :name (n3 / name :op1 "p53"~e.3)) :mod (m / main~e.6) :time~e.12 (c2 / create-01~e.20 :ARG1~e.20 (t / tumor~e.20) :ARG2-of (i / induce-01 :ARG0 (e / enzyme :name (n4 / name :op1 "Braf"~e.14) :ARG2-of (m2 / mutate-01 :value "V637E"~e.16))) :ARG1-of (a2 / advance-01~e.13)) :ARG0-of (e2 / explain-01~e.22 :ARG1 (f / function-01~e.27 :ARG0~e.23 p2~e.23 :ARG1-of (s / specific-02~e.26 :ARG2 (t2 / thing~e.25 :ARG2-of~e.25 (s2 / stage-02~e.25 :ARG1 c2))) :time (l / late~e.24))))) # ::id pmid_2384_5441.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Selective Pressure for p53 Inactivation Develops at Advanced Stages of Tumor Evolution # ::alignments 2-1.1 3-1.1.1.r 4-1.1.1.2.1.1 5-1.1.1 5-1.1.1.1 5-1.1.1.1.r 6-1 7-1.2.r 8-1.2.2 9-1.2 10-1.2.1.r 11-1.2.1.1 12-1.2.1 (d / develop-01~e.6 :ARG2 (p / pressure-01~e.2 :ARG1~e.3 (a / activate-01~e.5 :polarity~e.5 -~e.5 :ARG1 (p2 / protein :name (n / name :op1 "p53"~e.4))) :ARG0-of (s / select-01)) :time~e.7 (s2 / stage~e.9 :subevent-of~e.10 (e / evolve-01~e.12 :ARG1 (t / tumor~e.11)) :ARG1-of (a2 / advance-01~e.8))) # ::id pmid_2384_5441.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine whether p53 mutations occur spontaneously during Braf @^V637E@ -@ induced intestinal tumorigenesis , we next sequenced p53 in Braf mutant tumors . # ::alignments 1-1.5 2-1.5.2.1 2-1.5.2.1.r 4-1.5.2.2 6-1.5.2 6-1.5.2.4.2.1 6-1.5.2.4.2.1.2 6-1.5.2.4.2.1.2.r 8-1.5.2.3 8-1.5.2.3.r 9-1.5.2.4.r 10-1.5.2.4.2.1.1.1 12-1.5.2.4.2.1.2.1 15-1.5.2.4.2 16-1.5.2.4.1.1 17-1.5.2.4 17-1.5.2.4.1 17-1.5.2.4.1.r 19-1.1 20-1.4 21-1 23-1.2.1.1 27-1.3.1.1.1.1 29-1.3.1 30-1.3 (s / sequence-01~e.21 :ARG0 (w / we~e.19) :ARG1 (p / protein :name (n / name :op1 "p53"~e.23)) :location (t / tumor~e.30 :ARG0-of (m / mutate-01~e.29 :ARG2 (e / enzyme :name (n2 / name :op1 "Braf"~e.27)))) :time (n3 / next~e.20) :purpose (e2 / examine-01~e.1 :ARG0 w :ARG1 (m2 / mutate-01~e.6 :mode~e.2 interrogative~e.2 :ARG1 p~e.4 :manner~e.8 (s2 / spontaneous~e.8) :time~e.9 (c / create-01~e.17 :ARG1~e.17 (t2 / tumor~e.17 :mod (i / intestine~e.16)) :ARG2-of (i2 / induce-01~e.15 :ARG0 (e3 / enzyme~e.6 :name (n4 / name :op1 "Braf"~e.10) :ARG2-of~e.6 (m3 / mutate-01~e.6 :value "V637E"~e.12))))))) # ::id pmid_2384_5441.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whereas mSAs ( n = 17 ) did not have p53 mutations , we identified a missense mutation ( S152R ; equivalent of human T155A ) in one of the two carcinomas . # ::alignments 0-1.4 1-1.4.1.2.1.1 5-1.4.1.2.2.1 8-1.4.1.1 8-1.4.1.1.r 9-1.4.1 11-1.4.1.3.1.1.1 13-1.2 13-1.4.1.3 15-1.1 16-1 18-1.2.2 19-1.2 19-1.2.3.1 21-1.2.1 23-1.2.3 24-1.2.3.1.2.r 25-1.2.3.1.2 26-1.2.3.1.1 28-1.3.r 29-1.3.1 32-1.3.2.1.1 33-1.3 33-1.3.2.1 (i / identify-01~e.16 :ARG0 (w / we~e.15) :ARG1 (m / mutate-01~e.13,19 :value "S152R"~e.21 :mod (m2 / missense~e.18) :ARG1-of (e / equal-01~e.23 :ARG2 (m3 / mutate-01~e.19 :value "T155A"~e.26 :mod~e.24 (h / human~e.25)))) :location~e.28 (c / carcinoma~e.33 :quant 1~e.29 :ARG1-of (i2 / include-91 :ARG2 (c2 / carcinoma~e.33 :quant 2~e.32))) :ARG1-of (c3 / contrast-01~e.0 :ARG2 (h2 / have-03~e.9 :polarity~e.8 -~e.8 :ARG0 (d / disease :name (n / name :op1 "mSA"~e.1) :ARG1-of (n2 / number-01 :ARG2 17~e.5)) :ARG1 (m4 / mutate-01~e.13 :ARG1 (p / protein :name (n3 / name :op1 "p53"~e.11)))))) # ::id pmid_2384_5441.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok S152R leads to stabilization of nonfunctional p53 , as evidenced by loss of p21 expression in cancer cells ( Figures 3 @ O @–@ 3Q ) . # ::alignments 0-1.1.1 1-1 2-1.2.r 3-1.2 4-1.2.1.r 5-1.2.1 5-1.2.1.2 5-1.2.1.2.1 5-1.2.1.2.1.r 5-1.2.1.2.r 6-1.2.1.1.1 8-1.3.r 9-1.3 10-1.3.1.r 11-1.3.1 12-1.3.1.1.r 13-1.3.1.1.1.1.1 14-1.3.1.1 15-1.3.1.1.2.r 16-1.3.1.1.2.1.2.1 17-1.3.1.1.2 20-1.4.1.1 20-1.4.1.2 25-1.4.1.2.1 (l / lead-03~e.1 :ARG0 (m / mutate-01 :value "S152R"~e.0) :ARG2~e.2 (s / stabilize-01~e.3 :ARG1~e.4 (p / protein~e.5 :name (n / name :op1 "p53"~e.6) :ARG0-of~e.5 (f / function-01~e.5 :polarity~e.5 -~e.5))) :ARG1-of~e.8 (e / evidence-01~e.9 :ARG0~e.10 (l2 / lose-02~e.11 :ARG1~e.12 (e2 / express-03~e.14 :ARG2 (p2 / protein :name (n2 / name :op1 "p21"~e.13)) :ARG3~e.15 (c / cell~e.17 :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.16)))))) :ARG1-of (d2 / describe-01 :ARG0 (v / value-interval :op1 (f2 / figure~e.20 :mod "3O") :op2 (f3 / figure~e.20 :mod "3Q"~e.25)))) # ::id pmid_2384_5441.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the second cancer , p53 expression was lost whereas the surrounding dysplasia , which gave rise to the cancer , was p53 @-@ positive ( Figures 3 @ R and 3S ) . # ::alignments 2-1.3.3 2-1.3.3.1 2-1.3.3.1.r 3-1.3.2.1 5-1.1.1.1.1.1 6-1.1.1 8-1.1 9-1 11-1.2.2.1 12-1.2.2 15-1.2.2.2 19-1.2.2.2.1.1.2.1 21-1.2.2.r 22-1.2.1 24-1.2 27-1.4.1.1 27-1.4.1.2 31-1.4.1 32-1.4.1.2.1 (c / contrast-01~e.9 :ARG1 (l / lose-02~e.8 :ARG1 (e / express-03~e.6 :ARG2 (p / protein :name (n / name :op1 "p53"~e.5)))) :ARG2 (p2 / positive~e.24 :topic p~e.22 :domain~e.21 (d / dysplasia~e.12 :ARG1-of (s / surround-01~e.11) :ARG0-of (g / give-01~e.15 :ARG1 (a / arise-02 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.19)))))) :location (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.3) :ord (o / ordinal-entity~e.2 :value~e.2 2~e.2)) :ARG1-of (d4 / describe-01 :ARG0 (a2 / and~e.31 :op1 (f / figure~e.27 :mod "3R") :op2 (f2 / figure~e.27 :mod "3S"~e.32)))) # ::id pmid_2384_5441.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest late stage specific selective pressure to inactivate p53 , further supporting the importance of p53 for invasiveness control . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.4.1 4-1.2.4 5-1.2.3 7-1.2 9-1.2.1.1 10-1.2.1.2.1.1 12-1.3.2 13-1.3 15-1.3.1 16-1.3.1.1.r 17-1.3.1.1 20-1.3.1.2 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1 (p / pressure-01~e.7 :ARG2 (a / activate-01 :polarity -~e.9 :ARG1 (p2 / protein :name (n / name :op1 "p53"~e.10))) :ARG0-of (s2 / select-01) :ARG1-of (s3 / specific-02~e.5) :time (s4 / stage~e.4 :mod (l / late~e.3))) :ARG0-of (s5 / support-01~e.13 :ARG1 (i / important~e.15 :domain~e.16 p2~e.17 :purpose (c / control-01~e.20 :ARG1 (i2 / invade-01))) :mod (f / further~e.12))) # ::id pmid_2384_5441.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inactivation of p16 Promotes Advanced Phases of Braf @^V637E@ -@ Induced Intestinal Tumorigenesis # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1.1.2.r 3-1.1.2.1.1 4-1 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.2.1.1.1 10-1.2.1.2.1.2.1 13-1.2.1.2 14-1.2.1.1.1 15-1.2.1 15-1.2.1.1 15-1.2.1.1.r (p / promote-01~e.4 :ARG0 (a / activate-01~e.1 :polarity~e.1 -~e.1 :ARG1~e.2 (p2 / protein :name (n / name :op1 "p16"~e.3))) :ARG1 (p3 / phase~e.6 :subevent-of~e.7 (c / create-01~e.15 :ARG1~e.15 (t / tumor~e.15 :mod (i / intestine~e.14)) :ARG2-of (i2 / induce-01~e.13 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf"~e.8) :ARG2-of (m / mutate-01 :value "V637E"~e.10)))) :ARG1-of (a2 / advance-01~e.5))) # ::id pmid_2384_5441.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the role of p16 @ ^{Ink4a @} , we first analyzed p16 @ ^{Ink4a @} expression in Braf mutant healthy and neoplastic intestines ( Figure 4 @ A ) . # ::alignments 1-1.4 3-1.4.2 14-1.1 15-1.3 16-1 25-1.2 28-1.2.2.3.1.1.1 30-1.2.2.3 31-1.2.2.2.1 32-1.2.2 33-1.2.2.1.1 34-1.2.2.1 34-1.2.2.2 37-1.5.1 (a / analyze-01~e.16 :ARG0 (w / we~e.14) :ARG1 (e / express-03~e.25 :ARG2 (g / gene :name (n / name :op1 "p16Ink4a")) :ARG3 (a2 / and~e.32 :op1 (i / intestine~e.34 :mod (n2 / neoplasm~e.33)) :op2 (i2 / intestine~e.34 :mod (h / health~e.31)) :ARG0-of (m / mutate-01~e.30 :ARG2 (g2 / gene :name (n3 / name :op1 "Braf"~e.28))))) :time (f / first~e.15) :purpose (e3 / examine-01~e.1 :ARG0 w :ARG1 (r / role~e.3 :poss g)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.37 :mod "4A"))) # ::id pmid_2384_5441.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whereas p16 @ ^{Ink4a @} expression was similar in Braf mutant mSH and WT mucosa , there was a marked upregulation of p16 @ ^{Ink4a @} expression in Braf mutant neoplasia . # ::alignments 0-1.4 9-1.4.1.1 11-1.4.1 14-1.4.1.2.1.2 15-1.4.1.2.1.2 16-1.4.1.2.1.2 17-1.4.1.2.1.1.1 18-1.4.1.2 19-1.4.1.2.2.1 20-1.4.1.2.2 25-1.3 26-1 36-1.1 39-1.2.1.1.1.1 41-1.2.1 42-1.2 (u / upregulate-01~e.26 :ARG1 (e / express-03~e.36 :ARG2 (g / gene :name (n / name :op1 "p16Ink4a"))) :location (n2 / neoplasia~e.42 :ARG0-of (m / mutate-01~e.41 :ARG2 (g2 / gene :name (n3 / name :op1 "Braf"~e.39)))) :degree (m2 / marked~e.25) :ARG1-of (c / contrast-01~e.0 :ARG2 (r / resemble-01~e.11 :ARG1 e~e.9 :location (a / and~e.18 :op1 (m4 / medical-condition :name (n4 / name :op1 "mSH"~e.17) :ARG0-of m~e.14,15,16) :op2 (m3 / mucosa~e.20 :mod (w / wild-type~e.19)))))) # ::id pmid_2384_5441.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This effect was less pronounced in mSAs @-@ LGD than in mSAs @-@ HGD , in which p16 @ ^{Ink4a @} was induced on average 100 @-@ fold ( Figure 4 @ A ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 3-1.3 4-1 4-1.4.2 5-1.2.r 6-1.2.1.1 8-1.2.1.1 9-1.4.r 11-1.4.1.1 13-1.4.1.1 26-1.4.3 27-1.4.3.2.r 28-1.4.3.2.2 29-1.4.3.2.1 31-1.4.3.2 34-1.5.1 (p / pronounced-02~e.4 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (a / affect-01~e.1) :mod (t2 / this~e.0)) :location~e.5 (d / disease :name (n / name :op1 "mSA-LGD"~e.6,8)) :degree (l / less~e.3) :compared-to~e.9 (d2 / disease :name (n2 / name :op1 "mSA-HGD"~e.11,13) :location-of (p2 / pronounced-02~e.4 :ARG1 t) :location-of (i / induce-01~e.26 :ARG2 (g / gene :name (n3 / name :op1 "p16Ink4a")) :quant~e.27 (p4 / product-of~e.31 :op1 100~e.29 :ARG1-of (a2 / average-01~e.28)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.34 :mod "4A"))) # ::id pmid_2384_5441.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , similarly to Braf @^{V6 @ 37 @ E}@ -@ induced Arf @/@ p53 activation , substantial p16 @^Ink4a activation is only triggered at advanced stages of tumorigenesis . # ::alignments 2-1.1.3 4-1.1.3.1.2.1.1.1 13-1.1.3.1.2 14-1.1.3.1.1.1.1 16-1.1.3.1.1.1.1 17-1.1.1 17-1.1.3.1 19-1.1.1.2 24-1.1.1 26-1.1.2 27-1.1 28-1.1.4.r 29-1.1.4.1.2 30-1.1.4 30-1.1.4.1 30-1.1.4.1.r 31-1.1.4.1.1.r 32-1.1.4.1.1 32-1.1.4.1.1.1 32-1.1.4.1.1.1.r (i / infer-01 :ARG1 (t / trigger-01~e.27 :ARG1 (a / activate-01~e.17,24 :ARG1 (p / protein :name (n / name :op1 "p16Ink4a")) :mod (s / substantial~e.19)) :mod (o / only~e.26) :ARG1-of (r / resemble-01~e.2 :ARG2 (a3 / activate-01~e.17 :ARG1 (p2 / pathway :name (n2 / name :op1 "Arf/p53"~e.14,16)) :ARG2-of (i2 / induce-01~e.13 :ARG0 (e / enzyme :name (n3 / name :op1 "Braf"~e.4) :ARG2-of (m / mutate-01 :value "V637E"))))) :time~e.28 (t3 / thing~e.30 :ARG2-of~e.30 (s2 / stage-02~e.30 :ARG1~e.31 (c / create-01~e.32 :ARG1~e.32 (t2 / tumor~e.32)) :ARG1-of (a2 / advance-01~e.29))))) # ::id pmid_2384_5441.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is consistent with observations in humans , where p16 was upregulated in BRAF mutant premalignant lesions ( SSAs and TSAs ) but not in hyperplasia ( Kriegl et al. , 2011 ) . # ::alignments 0-1.1 2-1 3-1.2.r 4-1.2 5-1.2.1.r 6-1.2.1 8-1.2.1.1.r 10-1.2.1.1.1.1.1.1 13-1.2.1.1.1 13-1.2.1.1.2 16-1.2.1.1.1.2.2.1.1 18-1.2.1.1.1.2.2 18-1.2.1.1.1.2.2.2 18-1.2.1.1.1.2.2.2.r 19-1.2.1.1.1.2.1 20-1.2.1.1.1.2 23-1.2.1.1.1.2.3.1 26-1.2.1.1 27-1.2.1.1.2.1 27-1.2.1.1.2.1.r 28-1.2.1.1.2.3.r 29-1.2.1.1.2.3 32-1.3.1.1.1.1.1 33-1.3.1.1 34-1.3.1.1.2.1 36-1.3.1.2.1 (c / consistent-01~e.2 :ARG1 (t / this~e.0) :ARG2~e.3 (o / observe-01~e.4 :location~e.5 (h / human~e.6 :location-of~e.8 (c2 / contrast-01~e.26 :ARG1 (u / upregulate-01~e.13 :ARG1 (g / gene :name (n / name :op1 "p16"~e.10)) :condition (l / lesion~e.20 :mod (p / premalignant~e.19) :mod (g2 / gene~e.18 :name (n2 / name :op1 "BRAF"~e.16) :ARG2-of~e.18 (m / mutate-01~e.18)) :ARG1-of (m2 / mean-01 :ARG2 (a / and~e.23 :op1 (m4 / medical-condition :name (n4 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma")) :op2 (m3 / medical-condition :name (n5 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma")))))) :ARG2 (u2 / upregulate-01~e.13 :polarity~e.27 -~e.27 :ARG1 g :condition~e.28 (h2 / hyperplasia~e.29))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.33 :op1 (p3 / person :name (n3 / name :op1 "Kriegl"~e.32)) :op2 (p4 / person :mod (o2 / other~e.34))) :time (d / date-entity :year 2011~e.36)))) # ::id pmid_2384_5441.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate whether p16 @ ^{Ink4a @} inactivation occurs spontaneously in Braf @^{V6 @ 37 @ E}@ -@ induced tumors , we performed comparative genomic hybridization , sequencing , and methylation analysis of the cdkn2a locus . # ::alignments 1-1.3 2-1.3.2.2 2-1.3.2.2.r 11-1.3.2 11-1.3.2.1 11-1.3.2.1.r 13-1.3.2.4 14-1.3.2.5.r 15-1.3.2.5.1.1.1.1 24-1.3.2.5.1 25-1.3.2.5 27-1.1 28-1 29-1.2.1.3 30-1.2.1.2 31-1.2.1 33-1.2.2 35-1.2 36-1.2.3.2 37-1.2.3 41-1.2.1.1.1.1.1.1 43-1.2.1.1 (p / perform-01~e.28 :ARG0 (w / we~e.27) :ARG1 (a / and~e.35 :op1 (h / hybridize-01~e.31 :ARG1 (l / locus~e.43 :ARG0-of (c2 / contain-01 :ARG1 (g2 / gene :name (n / name :op1 "CDKN2A"~e.41)))) :mod (g / genome~e.30) :ARG0-of (c / compare-01~e.29)) :op2 (s / sequence~e.33 :mod g2) :op3 (a2 / analyze-01~e.37 :ARG1 g2 :mod (m / methylate-01~e.36))) :purpose (i / investigate-01~e.1 :ARG0 w :ARG1 (a3 / activate-01~e.11 :polarity~e.11 -~e.11 :mode~e.2 interrogative~e.2 :ARG1 (g4 / gene :name (n2 / name :op1 "p16Ink4a")) :mod (s2 / spontaneous~e.13) :location~e.14 (t / tumor~e.25 :ARG2-of (i2 / induce-01~e.24 :ARG0 (e / enzyme :name (n3 / name :op1 "Braf"~e.15) :ARG2-of (m2 / mutate-01 :value "V637E"))))))) # ::id pmid_2384_5441.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We did not identify Cdkn2a mutations or copy number alterations in any of the 12 TSAs and eight carcinomas analyzed ( data not shown ) . # ::alignments 0-1.2 2-1.1 2-1.1.r 3-1 5-1.3.1.1.1.1 7-1.3.1 8-1.3 9-1.3.2.1.1 9-1.3.2.1.1.1 9-1.3.2.1.1.1.r 10-1.3.2.1 11-1.3.2 12-1.4.r 13-1.4.3 18-1.4 19-1.4.2.1 20-1.4.2 21-1.4.4 23-1.5.1 24-1.5.1.1.1 24-1.5.1.1.1.r 25-1.5.1.1 (i / identify-01~e.3 :polarity~e.2 -~e.2 :ARG0 (w / we~e.0) :ARG1 (o / or~e.8 :op1 (m / mutate-01~e.7 :ARG2 (g / gene :name (n / name :op1 "Cdkn2a"~e.5))) :op2 (a / alter-01~e.11 :ARG1 (n2 / number~e.10 :quant-of (t2 / thing~e.9 :ARG2-of~e.9 (c / copy-01~e.9))))) :location~e.12 (a2 / and~e.18 :op1 (m2 / medical-condition :name (n3 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma")) :op2 (c2 / carcinoma~e.20 :quant 8~e.19) :mod (a3 / any~e.13) :ARG1-of (a4 / analyze-01~e.21)) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.23 :ARG1-of (s / show-01~e.25 :polarity~e.24 -~e.24)))) # ::id pmid_2384_5441.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a subset of Braf @^V637E@ -@ induced mSAs @-@ HGD and carcinomas , however , we found partial CpG island methylation in the p16 @ ^{Ink4a @} ( but not p19 @ ^{Arf @} ) promoter ( Figure S3 ) , similar to observations in humans ( Kriegl et al. , 2011 ) . # ::alignments 2-1.1.4 4-1.1.4.1.1.3.1.1.1 6-1.1.4.1.1.3.1.2.1 9-1.1.4.1.1.3 10-1.1.4.1.1.1.1.1 12-1.1.4.1.1.1.1.1 13-1.1.4.1.1 14-1.1.4.1.1.2 16-1.1 18-1.1.1.1 19-1.1.1 19-1.1.2 20-1.1.1.2.2 20-1.1.1.2.2.r 20-1.1.2.3.2.r 21-1.1.1.2.1.1.1 21-1.1.2.3.1.1.1 22-1.1.1.2.1.1.2 22-1.1.2.3.1.1.2 23-1.1.1.2 23-1.1.2.3 35-1 35-1.1 35-1.1.r 36-1.1.2.1 36-1.1.2.1.r 46-1.1.1.2.1.2 46-1.1.1.2.1.2.1 46-1.1.1.2.1.2.1.r 46-1.1.2.3.1.2 46-1.1.2.3.1.2.1 46-1.1.2.3.1.2.1.r 49-1.1.3.1 50-1.1.3.1.1 54-1.1.5 55-1.1.5.1.r 56-1.1.5.1 57-1.1.5.1.1.r 58-1.1.5.1.1 61-1.2.1.1.1.1.1 62-1.2.1.1 63-1.2.1.1.2.1 65-1.2.1.2.1 (h / have-concession-91~e.35 :ARG1~e.35 (c2 / contrast-01~e.16,35 :ARG1 (f / find-01~e.19 :ARG0 (w / we~e.18) :ARG1 (m / methylate-01~e.23 :ARG1 (d2 / dna-sequence :name (n / name :op1 "CpG"~e.21 :op2 "island"~e.22) :part-of (m2 / molecular-physical-entity~e.46 :ARG0-of~e.46 (p2 / promote-01~e.46 :ARG1 (g2 / gene :name (n2 / name :op1 "p16Ink4a"))))) :degree~e.20 (p / part~e.20))) :ARG2 (f2 / find-01~e.19 :polarity~e.36 -~e.36 :ARG0 w :ARG1 (m4 / methylate-01~e.23 :ARG1 (d3 / dna-sequence :name (n4 / name :op1 "CpG"~e.21 :op2 "island"~e.22) :part-of (m3 / molecular-physical-entity~e.46 :ARG0-of~e.46 (p4 / promote-01~e.46 :ARG1 (g3 / gene :name (n3 / name :op1 "p19Arf"))))) :degree~e.20 p)) :ARG1-of (d4 / describe-01 :ARG0 (f3 / figure~e.49 :mod "S3"~e.50)) :location (s / subset~e.2 :ARG1-of (i2 / include-91 :ARG2 (a / and~e.13 :op1 (d6 / disease :name (n7 / name :op1 "mSA-HGD"~e.10,12)) :op2 (c3 / carcinoma~e.14) :ARG2-of (i / induce-01~e.9 :ARG0 (e / enzyme :name (n5 / name :op1 "Braf"~e.4) :ARG2-of (m6 / mutate-01 :value "V637E"~e.6)))))) :ARG2-of (r2 / resemble-01~e.54 :ARG1~e.55 (o / observe-01~e.56 :location~e.57 (h2 / human~e.58)))) :ARG1-of (d5 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a2 / and~e.62 :op1 (p7 / person :name (n6 / name :op1 "Kriegl"~e.61)) :op2 (p8 / person :mod (o2 / other~e.63))) :time (d / date-entity :year 2011~e.65)))) # ::id pmid_2384_5441.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To study the effect of p16 @ ^{Ink4a @} inactivation in vivo , we used p16 @ ^{Ink4a @^∗@ @} mice , which have a point mutation that is silent in the p19 @ ^{Arf @} reading frame but introduces a stop codon in p16 @ ^{Ink4a @} ( Krimpenfort et al. , 2001 ) . # ::alignments 1-1.3 3-1.3.2 13-1.3.2.1 13-1.3.2.1.1 13-1.3.2.1.1.r 14-1.3.2.2 15-1.3.2.2 17-1.1 18-1 30-1.2 35-1.2.2.1 36-1.2.2 39-1.2.2.2 40-1.3.2.2 50-1.2.2.3.1 51-1.2.2.3 52-1.2.2.4 53-1.2.2.4.1 55-1.2.2.4.1.2.1 56-1.2.2.4.1.2 57-1.3.2.2 68-1.4.1.1.1.1.1 69-1.4.1.1 70-1.4.1.1.2.1 72-1.4.1.2.1 (u2 / use-01~e.18 :ARG0 (w / we~e.17) :ARG1 (m / mouse~e.30 :mod (g / gene :name (n / name :op1 "p16Ink4a*")) :location-of (m2 / mutate-01~e.36 :mod (p / point~e.35) :mod (s / silent~e.39) :location (f / frame~e.51 :topic (r / read-01~e.50) :mod (g3 / gene :name (n2 / name :op1 "p19Arf"))) :ARG1-of (c / contrast-01~e.52 :ARG2 (i / introduce-02~e.53 :ARG0 m2 :ARG1 (c2 / codon~e.56 :mod (s2 / stop~e.55)) :ARG2 g2)))) :ARG2 (s3 / study-01~e.1 :ARG0 w :ARG1 (a / affect-01~e.3 :ARG0 (a2 / activate-01~e.13 :polarity~e.13 -~e.13 :ARG1 (g2 / gene :name (n5 / name :op1 "p16Ink4a"))) :manner (i2 / in-vivo~e.14,15,40,57))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.69 :op1 (p4 / person :name (n4 / name :op1 "Krimpenfort"~e.68)) :op2 (p5 / person :mod (o / other~e.70))) :time (d / date-entity :year 2001~e.72)))) # ::id pmid_2384_5441.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} mice with heterozygous or homozygous mutation of p16 @ ^{Ink4a @}@ ( Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p16 @ ^{Ink4a @^∗@ @}@ ) were aged and sacrificed at different time points to assess tumor incidence and latency ( Figure 4 @ B ) . # ::alignments 1-1.1.1.4.2.1.1.1 3-1.1.1.4.1.1 5-1.1.1.2.1.1 9-1.1.1.2.2.1 11-1.1.1.2.2.1 15-1.1.1 15-1.1.1.3.1 16-1.1.1.1.r 17-1.1.1.1.1.2 18-1.1.1.1 19-1.1.1.1.2.2 20-1.1.1.1.1 20-1.1.1.1.2 20-1.1.1.2 20-1.1.1.2.2 20-1.1.1.2.2.r 20-1.1.1.3.1.2 20-1.1.1.3.1.2.2 20-1.1.1.3.1.2.2.r 32-1.1.1.4.2.1.1.1 34-1.1.1.4.1.1 36-1.1.1.2.1.1 40-1.1.1.2.2.1 42-1.1.1.2.2.1 62-1.1 63-1 64-1.2 66-1.2.2.1 67-1.2.2.r 68-1.2.2 68-1.2.3.r 70-1.2.3 71-1.2.3.1.3 72-1.2.3.1.1 73-1.2.3.1 74-1.2.3.1.2 77-1.3.1 (a / and~e.63 :op1 (a2 / age-01~e.62 :ARG1 (m / mouse~e.15 :location-of~e.16 (o / or~e.18 :op1 (m2 / mutate-01~e.20 :ARG2 (g2 / gene :name (n / name :op1 "p16Ink4a")) :mod (h / heterozygous~e.17)) :op2 (m3 / mutate-01~e.20 :ARG2 g2 :mod (h2 / homozygous~e.19))) :mod (g / gene~e.20 :name (n2 / name :op1 "Braf"~e.5,36) :ARG2-of~e.20 (m4 / mutate-01~e.20 :value "LSL-V637E/+"~e.9,11,40,42)) :ARG1-of (d3 / describe-01 :ARG2 (m5 / mouse~e.15 :mod g :mod (g3 / gene~e.20 :name (n4 / name :op1 "p16Ink4a") :ARG2-of~e.20 (m6 / mutate-01~e.20)) :mod e)) :mod (e / enzyme :name (n3 / name :op1 "Cre"~e.3,34) :ARG2-of (e2 / express-03 :ARG1 (g4 / gene :name (n5 / name :op1 "Vil"~e.1,32)))))) :op2 (s / sacrifice-01~e.64 :ARG1 m :time~e.67 (p2 / point~e.68 :ARG1-of (d / differ-02~e.66)) :purpose~e.68 (a3 / assess-01~e.70 :ARG1 (a4 / and~e.73 :op1 (i / incidence~e.72) :op2 (l / latency~e.74) :mod (t / tumor~e.71)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.77 :mod "4B"))) # ::id pmid_2384_5441.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We observed 1.3 @-@ fold increased numbers of mSAs in Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p16 @ ^{Ink4a @^∗@ @} animals as compared to Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} mice , but this was statistically not significant ( Figure 4 @ C ; Table S4 ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.2.1.1 4-1.1.2.2.1 5-1.1.2.2 6-1.1.2 7-1.1.2.1.r 7-1.1.2.2.1 8-1.1.2.1.1.1 11-1.1.2.2.3.2 12-1.1.2.2.3.2 13-1.1.2.2.3.2 15-1.1.2.2.3.1.1.1 19-1.1.2.2.3.1.2.1 21-1.1.2.2.3.1.2.1 37-1.1.2.2.2 39-1.1.2.2.3.r 42-1.1.2.2.2.3.2.1.1.1 44-1.1.2.2.2.3.1.1 46-1.1.2.2.3.1.1.1 50-1.1.2.2.3.1.2.1 52-1.1.2.2.3.1.2.1 56-1.1.2.2.3 58-1 62-1.2.1 62-1.2.1.r 63-1.2 66-1.3.1.2 72-1.3.1.1 73-1.3.1.1.1 (c / contrast-01~e.58 :ARG1 (o / observe-01~e.1 :ARG0 (w / we~e.0) :ARG1 (n / number~e.6 :quant-of~e.7 (d2 / disease :name (n6 / name :op1 "mSA"~e.8)) :ARG1-of (i / increase-01~e.5 :ARG2 (p / product-of~e.4,7 :op1 1.3~e.2) :location (a / animal~e.37 :mod g :mod (g2 / gene :name (n4 / name :op1 "p16Ink4a") :ARG2-of (m4 / mutate-01)) :mod (e / enzyme :name (n3 / name :op1 "Cre"~e.44) :ARG2-of (e2 / express-03 :ARG1 (g3 / gene :name (n5 / name :op1 "Vil"~e.42))))) :compared-to~e.39 (m2 / mouse~e.56 :mod (g / gene :name (n2 / name :op1 "Braf"~e.15,46) :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+"~e.19,21,50,52)) :mod e~e.11,12,13)))) :ARG2 (s / significant-02~e.63 :polarity~e.62 -~e.62 :ARG1 n :manner (s2 / statistic)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (t / table~e.72 :mod "S4"~e.73) :op2 (f / figure~e.66 :mod "4C")))) # ::id pmid_2384_5441.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , carcinoma development was significantly increased in Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p16 @ ^{Ink4 @^∗@ @} mice , which had on average 6.4 times as many cancers as Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p16 @ ^{Ink4a+/+ @} mice ( p < 0.001 ; Figure 4 @ C ; Table S5 ) . # ::alignments 1-1 3-1.1.1.1 4-1.1.1 6-1.1.2 7-1.1 10-1.1.3.4.2.1.1.1 12-1.1.3.4.1.1 14-1.1.3.1.1.1 18-1.1.3.1.2.1 20-1.1.3.1.2.1 36-1.1.3 39-1.1.3.2 40-1.1.3.2.1.r 41-1.1.3.2.1.3.2 42-1.1.3.2.1.3.1 43-1.1.3.2.1.3 46-1.1.3.2.1.2.1 49-1.1.3.4.2.1.1.1 51-1.1.3.4.1.1 53-1.1.3.1.1.1 57-1.1.3.1.2.1 59-1.1.3.1.2.1 72-1.1.3 72-1.1.3.2.1.4 74-1.1.4 75-1.1.4.1 76-1.1.4.1.1 79-1.2.1.2 85-1.2.1.1 86-1.2.1.1.1 (c / contrast-01~e.1 :ARG2 (i / increase-01~e.7 :ARG1 (d / develop-01~e.4 :ARG2 (c2 / carcinoma~e.3)) :ARG2 (s / significant-02~e.6) :location (m / mouse~e.36,72 :mod (g / gene :name (n / name :op1 "Braf"~e.14,53) :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+"~e.18,20,57,59)) :ARG0-of (h / have-03~e.39 :ARG1~e.40 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.46) :quant (p / product-of~e.43 :op1 6.4~e.42 :ARG1-of (a / average-01~e.41)) :compared-to (m2 / mouse~e.72 :mod g :mod (g2 / gene :name (n3 / name :op1 "p16Ink4a") :mod (w / wild-type)) :mod e))) :mod (g3 / gene :name (n4 / name :op1 "p16Ink4a") :ARG2-of (m5 / mutate-01)) :mod (e / enzyme :name (n2 / name :op1 "Cre"~e.12,51) :ARG2-of (e2 / express-03 :ARG1 (g4 / gene :name (n5 / name :op1 "Vil"~e.10,49))))) :ARG1-of (s2 / statistical-test-91~e.74 :ARG2 (l / less-than~e.75 :op1 0.001~e.76))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (t / table~e.85 :mod "S5"~e.86) :op2 (f / figure~e.79 :mod "4C")))) # ::id pmid_2384_5441.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Many of the mice developed multiple synchronous carcinomas and , in some animals ( 3 @/@ 24 ) , these tumors were metastatic . # ::alignments 0-1.1.1.1 1-1.1.1.1.r 3-1.1.1 4-1.1 5-1.1.2.1 6-1.1.2.2 7-1.1.2 8-1 11-1.2.2.1 12-1.2.2 12-1.2.2.1.1.1 12-1.2.2.1.1.1.2.1 14-1.2.2.1.1.1.1 16-1.2.2.1.1.1.2.1.1 19-1.2.1.1 20-1.2.1 22-1.2 (a / and~e.8 :op1 (d / develop-01~e.4 :ARG1 (m / mouse~e.3 :quant~e.1 (m2 / many~e.0)) :ARG2 (c / carcinoma~e.7 :quant (m3 / multiple~e.5) :ARG1-of (s / synchronous-02~e.6))) :op2 (m4 / metastasize-101~e.22 :ARG1 (t / tumor~e.20 :mod (t2 / this~e.19)) :location (a2 / animal~e.12 :quant (s2 / some~e.11 :ARG1-of (m5 / mean-01 :ARG2 (a3 / animal~e.12 :quant 3~e.14 :ARG1-of (i / include-91 :ARG2 (a4 / animal~e.12 :quant 24~e.16)))))))) # ::id pmid_2384_5441.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All together , these results show that Arf @/@ p53 and p16 exert independent critical tumor @-@ suppressive effects , which are mainly operative at advanced stages of Braf @^V637E@ -@ induced intestinal tumorigenesis . # ::alignments 0-1.3.1 1-1.3 3-1.1.2 4-1.1 4-1.1.1 4-1.1.1.r 5-1 6-1.2.r 7-1.2.1.1.1.1 9-1.2.1.1.1.1 10-1.2.1 11-1.2.1.2.1.1 12-1.2 13-1.2.2.4 13-1.2.2.4.1 13-1.2.2.4.1.r 14-1.2.2.3 15-1.2.2.2.1 18-1.2.2 22-1.2.2.5.1 22-1.2.2.5.1.r 25-1.2.2.5.2.1.2 26-1.2.2.5.2 26-1.2.2.5.2.1 26-1.2.2.5.2.1.r 28-1.2.2.5.2.1.1.2.1.1.1 30-1.2.2.5.2.1.1.2.1.2.1 33-1.2.2.5.2.1.1.2 34-1.2.2.5.2.1.1.1.1 35-1.2.2.2.1 35-1.2.2.5.2.1.1 35-1.2.2.5.2.1.1.1 35-1.2.2.5.2.1.1.1.r (s / show-01~e.5 :ARG0 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :mod (t2 / this~e.3)) :ARG1~e.6 (e / exert-01~e.12 :ARG0 (a / and~e.10 :op1 (p / pathway :name (n / name :op1 "Arf/p53"~e.7,9)) :op2 (p2 / protein :name (n2 / name :op1 "p16"~e.11))) :ARG1 (a2 / affect-01~e.18 :ARG0 a :ARG2 (s2 / suppress-01 :ARG1 (t3 / tumor~e.15,35)) :ARG1-of (c / critical-02~e.14) :ARG0-of (d / depend-01~e.13 :polarity~e.13 -~e.13) :ARG0-of (o / operate-01 :manner~e.22 (m / main~e.22) :time (t5 / thing~e.26 :ARG2-of~e.26 (s3 / stage-02~e.26 :ARG1 (c2 / create-01~e.35 :ARG1~e.35 (t4 / tumor~e.35 :mod (i / intestine~e.34)) :ARG2-of (i2 / induce-01~e.33 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Braf"~e.28) :ARG2-of (m2 / mutate-01 :value "V637E"~e.30)))) :ARG1-of (a3 / advance-01~e.25)))))) :manner (t6 / together~e.1 :mod (a4 / all~e.0))) # ::id pmid_2384_5441.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Intensification of Map Kinase Signaling during Dysplasia Progression # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1 4-1.1.1.1.2 5-1.1 6-1.2.r 7-1.2.1.1.1 8-1.2 (i / intensify-01~e.1 :ARG1~e.2 (s / signal-07~e.5 :ARG0 (p2 / pathway :name (n / name :op1 "Map"~e.3 :op2 "Kinase"~e.4))) :time~e.6 (p / progress-01~e.8 :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia"~e.7)))) # ::id pmid_2384_5441.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because Braf @-@ induced Mapk signaling does not seem to engage intrinsic tumor suppression in early tumorigenesis , we next assessed the MAPK pathway activity at different stages of tumor evolution . # ::alignments 0-1.4 1-1.4.1.2.1.2.1.1.1 3-1.4.1.2.1.2 4-1.4.1.2.1.1 5-1.4.1.2.1 7-1.4.1.1 7-1.4.1.1.r 8-1.4.1 10-1.4.1.2 11-1.4.1.2.2.2 12-1.4.1.2.2.1 13-1.4.1.2.2 14-1.4.1.2.3.r 15-1.4.1.2.3.2 16-1.4.1.2.3 18-1.1 19-1.3 20-1 22-1.2.1.1.1 23-1.2.1 24-1.2 25-1.5.r 26-1.5.1.2 27-1.5 27-1.5.1 27-1.5.1.r 28-1.5.1.1.r 29-1.5.1.1.1 30-1.5.1.1 (a / assess-01~e.20 :ARG0 (w / we~e.18) :ARG1 (a2 / activity-06~e.24 :ARG0 (p2 / pathway~e.23 :name (n3 / name :op1 "Mapk"~e.22))) :time (n2 / next~e.19) :ARG1-of (c / cause-01~e.0 :ARG0 (s2 / seem-01~e.8 :polarity~e.7 -~e.7 :ARG1 (e2 / engage-01~e.10 :ARG0 (s3 / signal-07~e.5 :ARG0 p2~e.4 :ARG2-of (i / induce-01~e.3 :ARG0 (e4 / enzyme :name (n / name :op1 "Braf"~e.1)))) :ARG1 (s4 / suppress-01~e.13 :ARG1 t~e.12 :mod (i2 / intrinsic~e.11)) :ARG2~e.14 (c2 / create-01~e.16 :ARG1 t :time (e3 / early~e.15))))) :time~e.25 (t2 / thing~e.27 :ARG2-of~e.27 (s / stage-02~e.27 :ARG1~e.28 (e / evolve-01~e.30 :ARG1 (t / tumor~e.29)) :ARG1-of (d / differ-02~e.26)))) # ::id pmid_2384_5441.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Unexpectedly , phospho @-@ p42 @/@ p44 MAPK ( pErk ) protein levels were only slightly increased in Braf @^{V6 @ 37 @ E}@ -@ induced mSH as compared to wild @-@ type mucosa but were highly induced in mSAs and carcinomas ( Figure 5 @ A ) . # ::alignments 0-1.3.1 2-1.1.1.1.2 4-1.1.1.1.1.1 6-1.1.1.1.1.1 7-1.1.1.1.1.2 12-1.1.1 14-1.1.2.1 15-1.1.2 16-1.1 17-1.1.3.r 18-1.1.3.2.1.1.1 27-1.1.3.2 28-1.1.3.1.1 30-1.1.4.r 32-1.1.4.1 34-1.1.4.1 35-1.1.4 36-1 38-1.2.2 39-1.2 40-1.2.3.r 41-1.2.3.1.1.1 42-1.2.3 43-1.2.3.2 46-1.4.1 (c / contrast-01~e.36 :ARG1 (i / increase-01~e.16 :ARG1 (l / level~e.12 :quant-of (e3 / enzyme :name (n2 / name :op1 "p42/p44"~e.4,6 :op2 "MAPK"~e.7) :ARG3-of (p3 / phosphorylate-01~e.2) :ARG1-of (m5 / mean-01 :ARG2 (e4 / enzyme :name (n3 / name :op1 "Erk") :ARG3-of p3)))) :ARG2 (s / slight~e.15 :mod (o / only~e.14)) :location~e.17 (d2 / disease :name (n4 / name :op1 "mSH"~e.28) :ARG2-of (i2 / induce-01~e.27 :ARG0 (e2 / enzyme :name (n / name :op1 "Braf"~e.18) :ARG2-of (m2 / mutate-01 :value "V637E")))) :compared-to~e.30 (m3 / mucosa~e.35 :mod (w / wild-type~e.32,34))) :ARG2 (i3 / induce-01~e.39 :ARG2 l :ARG1-of (h / high-02~e.38) :location~e.40 (a / and~e.42 :op1 (m / medical-condition :name (n5 / name :op1 "mSA"~e.41)) :op2 (c2 / carcinoma~e.43))) :ARG1-of (e / expect-01 :polarity -~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.46 :mod "5A"))) # ::id pmid_2384_5441.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunohistochemistry revealed that in wild @-@ type mucosa and Braf @^{V6 @ 37 @ E}@ -@ induced mSH , pErk reactivity was mostly confined to the lower parts of the crypts ( Figures 5 @ B and 5C ) . # ::alignments 0-1.1 1-1 3-1.2.r 4-1.2.4.1.1 6-1.2.4.1.1 7-1.2.4.1 8-1.2.4 9-1.2.4.2.2.1.1.1 18-1.2.4.2.2 19-1.2.4.2.1.1 24-1.2.3 25-1.2 26-1.2.2.r 28-1.2.2.1 28-1.2.2.1.2 28-1.2.2.1.2.r 29-1.2.2 30-1.2.2.1.1.r 32-1.2.2.1.1 35-1.3.1.1 35-1.3.1.2 39-1.3.1 40-1.3.1.2.1 (r2 / reveal-01~e.1 :ARG0 (i / immunohistochemistry~e.0) :ARG1~e.3 (c / confine-01~e.25 :ARG1 (r / react-01 :ARG0 (e / enzyme :name (n / name :op1 "Erk") :ARG3-of (p2 / phosphorylate-01))) :ARG2~e.26 (p3 / part~e.29 :ARG1-of (l / low-04~e.28 :ARG2~e.30 (c2 / crypt~e.32) :degree~e.28 (m / more~e.28))) :degree (m2 / most~e.24) :location (a / and~e.8 :op1 (m3 / mucosa~e.7 :mod (w / wild-type~e.4,6)) :op2 (m4 / medical-condition :name (n3 / name :op1 "mSH"~e.19) :ARG2-of (i2 / induce-01~e.18 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf"~e.9) :ARG2-of (m5 / mutate-01 :value "V637E")))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.39 :op1 (f / figure~e.35 :mod "5B") :op2 (f2 / figure~e.35 :mod "5C"~e.40)))) # ::id pmid_2384_5441.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In mSAs @-@ LGD , few scattered pERK @-@ positive cells were occasionally additionally detected in dysplastic areas ( Figure 5 @ D ) . # ::alignments 1-1.6.1.1 3-1.6.1.1 5-1.1.1 6-1.1.2 7-1.1.3.1.1.1 7-1.1.3.1.2 9-1.1.3 10-1.1 12-1.2 13-1.3 13-1.3.r 14-1 15-1.4.r 16-1.4.1.1.1 17-1.4 20-1.5.1 (d / detect-01~e.14 :ARG1 (c / cell~e.10 :quant (f / few~e.5) :ARG1-of (s / scatter-01~e.6) :mod (p / positive~e.9 :topic (e / enzyme :name (n / name :op1 "ERK"~e.7) :ARG3-of (p3 / phosphorylate-01~e.7)))) :time (o / occasional~e.12) :manner~e.13 (a / additional~e.13) :location~e.15 (a2 / area~e.17 :mod (m2 / medical-condition :name (n2 / name :op1 "dysplasia"~e.16))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.20 :mod "5D")) :condition (m3 / medical-condition :name (n3 / name :op1 "mSAs-LGD"~e.1,3))) # ::id pmid_2384_5441.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok mSAs @-@ HGD and carcinomas , however , stained uniformly positive for pErk ( Figures 5 @ E @–@ 5G ) . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 6-1 8-1.1 9-1.1.2.1 10-1.1.2 15-1.2.1.1 15-1.2.1.2 15-1.2.1.3 20-1.2.1.3.1 (h / have-concession-91~e.6 :ARG1 (s / stain-01~e.8 :ARG1 (a / and~e.3 :op1 (d2 / disease :name (n2 / name :op1 "mSA-HGD"~e.0,2)) :op2 (m / medical-condition :name (n3 / name :op1 "carcinoma"~e.4))) :manner (p / positive~e.10 :ARG1-of (u / uniform-02~e.9) :topic (e / enzyme :name (n / name :op1 "Erk") :ARG3-of (p3 / phosphorylate-01)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.15 :mod "5E") :op2 (f2 / figure~e.15 :mod "5F") :op3 (f3 / figure~e.15 :mod "5G"~e.20)))) # ::id pmid_2384_5441.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Compared to wild @-@ type mucosa , the number of pERK @-@ positive cells per gland was increased 1.4-, 2.4-, and 6.6 @-@ fold in mSH , mSAs @-@ LGD , and mSAs @-@ HGD , respectively ( Figure S4 @ A ) . # ::alignments 0-1.4.r 2-1.4.1 4-1.4.1 5-1.4 8-1.1.1.1 9-1.1.1.1.1.r 10-1.1.1.1.1.1.1.1.1 10-1.1.1.1.1.1.1.2 12-1.1.1.1.1.1 13-1.1.1.1.1 14-1.1.1 15-1.1.1.2 17-1.1 17-1.2 17-1.3 20-1 21-1.3.2.1 23-1.1.2 23-1.2.2 23-1.3.2 24-1.1.3.r 25-1.1.3.1.1 27-1.2.3.1.1 27-1.3.3.1.1 29-1.2.3.1.1 31-1 32-1.2.3.1.1 32-1.3.3.1.1 34-1.3.3.1.1 36-1.6 36-1.6.r 39-1.5.1 (a3 / and~e.20,31 :op1 (i / increase-01~e.17 :ARG1 (r / rate-entity-91~e.14 :ARG1 (n / number~e.8 :quant-of~e.9 (c / cell~e.13 :mod (p / positive~e.12 :topic (e / enzyme :name (n2 / name :op1 "ERK"~e.10) :ARG3-of (p3 / phosphorylate-01~e.10))))) :ARG2 (g / gland~e.15)) :ARG2 (p4 / product-of~e.23 :op1 1.4) :location~e.24 (m2 / medical-condition :name (n3 / name :op1 "mSH"~e.25))) :op2 (i2 / increase-01~e.17 :ARG1 r :ARG2 (p5 / product-of~e.23 :op1 2.4) :location (m / medical-condition :name (n4 / name :op1 "mSAs-LGD"~e.27,29,32))) :op3 (i3 / increase-01~e.17 :ARG1 r :ARG2 (p6 / product-of~e.23 :op1 6.6~e.21) :location (m3 / medical-condition :name (n5 / name :op1 "mSAs-HGD"~e.27,32,34))) :compared-to~e.0 (m4 / mucosa~e.5 :mod (w / wild-type~e.2,4)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod "S4A")) :manner~e.36 (r2 / respective~e.36)) # ::id pmid_2384_5441.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the functional relevance of these observations , we examined expression of a panel of 15 Erk target genes ( Pratilas et al. , 2009 ) using qRT @-@ PCR ( Figure 5 @ H ) or immunohistochemistry ( Figure S4 ) . # ::alignments 1-1.4 3-1.4.2.1 4-1.4.2 5-1.4.2.2.r 6-1.4.2.2.1 7-1.4.2.2 9-1.1 10-1 11-1.2 12-1.2.1.r 14-1.2.1 15-1.2.1.1.r 16-1.2.1.1.1 17-1.2.1.1.2.1.1.1 18-1.2.1.1.2 19-1.2.1.1 22-1.2.1.2.1.1.1.1.1 23-1.2.1.2.1.1 24-1.2.1.2.1.1.2.1 26-1.2.1.2.1.2.1 29-1.3 29-1.4.r 32-1.3.1.1 32-1.3.1.1.1 32-1.3.1.1.1.r 35-1.3.1.1.2.1 40-1.3.1 41-1.3.1.2 44-1.3.1.2.1.1 45-1.3.1.2.1.1.1 (e2 / examine-01~e.10 :ARG0 (w / we~e.9) :ARG1 (e3 / express-03~e.11 :ARG1~e.12 (p / panel~e.14 :consist-of~e.15 (g / gene~e.19 :quant 15~e.16 :ARG1-of (t / target-01~e.18 :ARG0 (p6 / protein-family :name (n / name :op1 "Erk"~e.17)))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and~e.23 :op1 (p3 / person :name (n2 / name :op1 "Pratilas"~e.22)) :op2 (p4 / person :mod (o / other~e.24))) :time (d / date-entity :year 2009~e.26))))) :manner (u / use-01~e.29 :ARG1 (o2 / or~e.40 :op1 (r2 / react-01~e.32 :ARG0~e.32 (p5 / polymerase~e.32) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.35 :mod "5H")) :mod (c / chain) :mod (r3 / real-time) :mod (q / quantitative) :subevent (t3 / transcribe-01 :ARG1-of (r4 / reverse-01))) :op2 (i / immunohistochemistry~e.41 :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure~e.44 :mod "S4"~e.45))))) :purpose~e.29 (a2 / assess-01~e.1 :ARG0 w :ARG1 (r / relevance~e.4 :mod (f3 / function~e.3) :poss~e.5 (o3 / observe-01~e.7 :mod (t2 / this~e.6))))) # ::id pmid_2384_5441.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The panel of markers includes a number of effectors of Ras @/@ Raf @-@ induced transformation , such as the ETS family members Etv4 and Etv5 or cMyc and Ccnd1 , and genes involved in the feedback regulation of Mek @/@ Erk signaling , such as Dusp4 , Dusp6 , Spry2 , and Spry4 @ . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1 4-1 4-1.1.1.1.2.1.3.1 6-1.1.1 7-1.1.1.1.r 8-1.1.1.1 9-1.1.1.1.1.r 10-1.1.1.1.1.1.1.1.1.1 11-1.1.1.1.1.1.1 12-1.1.1.1.1.1.1.2.1.1 14-1.1.1.1.1.1 15-1.1.1.1.1 17-1.1.1.1.2.r 18-1.1.1.1.2.r 20-1.1.1.1.2.1.3.1.1.1.1 21-1.1.1.1.2.1.3.1.1 22-1.1.1.1.2.1.3 24-1.1.1.1.2.1.1.1.1 26-1.1.1.1.2.1 28-1.1.1.1.2.1.2.1.1 30-1.1.1.1.2 32-1.1.1.1.2.2.1.1 36-1.1.1.1.2.3.1.1 39-1.1 40-1.1.2 41-1.1.2.1 42-1.1.2.1.1.r 44-1.1.2.1.1.2 45-1.1.2.1.1 46-1.1.2.1.1.1.r 47-1.1.2.1.1.1.1.1.1 48-1.1.1.1.1.1.1 49-1.1.2.1.1.1.1.1.1 50-1.1.2.1.1.1 52-1.1.2.2.r 53-1.1.2.2.r 55-1.1.2.2.1.1.1 59-1.1.2.2.2.1.1 63-1.1.2.2.3.1.1 66-1.1.2.2 68-1.1.2.2.4.1.1 (i / include-91~e.4 :ARG1 (a / and~e.39 :op1 (n2 / number~e.6 :quant-of~e.7 (e / effector~e.8 :ARG0-of~e.9 (t / transform-01~e.15 :ARG2-of (i2 / induce-01~e.14 :ARG0 (s / slash~e.11,48 :op1 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.10)) :op2 (e3 / enzyme :name (n4 / name :op1 "Raf"~e.12))))) :example~e.17,18 (o / or~e.30 :op1 (a2 / and~e.26 :op1 (g8 / gene :name (n5 / name :op1 "Etv4"~e.24)) :op2 (g9 / gene :name (n6 / name :op1 "Etv5"~e.28)) :mod (m2 / member~e.22 :ARG1-of (i4 / include-91~e.4 :ARG2 (p3 / protein-family~e.21 :name (n9 / name :op1 "ETS"~e.20))))) :op2 (g / gene :name (n7 / name :op1 "cMyc"~e.32)) :op3 (g2 / gene :name (n8 / name :op1 "Ccnd1"~e.36))))) :op2 (g3 / gene~e.40 :ARG1-of (i3 / involve-01~e.41 :ARG2~e.42 (r / regulate-01~e.45 :ARG1~e.46 (s2 / signal-07~e.50 :ARG0 (p / pathway :name (n / name :op1 "Mek/Erk"~e.47,49))) :mod (f2 / feedback~e.44))) :example~e.52,53 (a3 / and~e.66 :op1 (g4 / gene :name (n10 / name :op1 "Dusp4"~e.55)) :op2 (g5 / gene :name (n11 / name :op1 "Dusp6"~e.59)) :op3 (g6 / gene :name (n12 / name :op1 "Spry2"~e.63)) :op4 (g7 / gene :name (n13 / name :op1 "Spry4"~e.68))))) :ARG2 (p2 / panel~e.1 :consist-of~e.2 (m / marker~e.3))) # ::id pmid_2384_5441.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that the transcriptional output of the Erk pathway was only slightly induced in Braf @^{V6 @ 37 @ E}@ -@ dependent mSH and mSAs @-@ LGD ( average fold @-@ change across target genes : 1.1 and 3.4 , respectively ) but was strongly upregulated in mSAs @-@ HGD and carcinomas ( average fold @-@ change across target genes : 13.0 and 12.6 , respectively ) . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.1.1.1 5-1.2.1.1 6-1.2.1.1.1.1.r 8-1.2.1.1.1.1.1.1 9-1.2.1.1.1.1 11-1.2.1.2.1 12-1.2.1.2 13-1.2.1 14-1.2.1.3.r 15-1.2.1.3.3.1.1.1 24-1.2.1.3.3 25-1.2.1.3.1.1.1 26-1.2.1.3 27-1.2.1.3.2.1.1 29-1.2.1.3.2.1.1 31-1.2.1.2.2.1.2 32-1.2.1.2.2.1.3 34-1.2.1.2.2.1 36-1.2.1.2.2.1.1.1 37-1.2.1.2.2.1.1 39-1.2.1.2.2.1.4.1.1 40-1.2.1.2.2.1.4 41-1.2.1.2.2.1.4.2.1 43-1.2.1.2.2.1.4.3 45-1.2 47-1.2.2.2 48-1.2.2 49-1.2.2.3.r 50-1.2.2.3.1.1.1 52-1.2.2.3.1.1.1 53-1.2.2.3 54-1.2.2.3.2.1.1 56-1.2.1.2.2.1.2 57-1.2.1.2.2.1.3 57-1.2.1.2.2.1.4.1 57-1.2.1.2.2.1.4.2 57-1.2.2.2.1.1.4.1 57-1.2.2.2.1.1.4.2 59-1.2.1.2.2.1 59-1.2.2.2.1.1 61-1.2.2.2.1.1.1 62-1.2.2.2.1.1.1 64-1.2.2.2.1.1.4.1.1 65-1.2.2.2.1.1.4 66-1.2.2.2.1.1.4.2.1 68-1.2.2.2.1.1.4.3 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (c / contrast-01~e.45 :ARG1 (i / induce-01~e.13 :ARG2 (o2 / output~e.5 :ARG1-of (t / transcribe-01~e.4 :ARG0~e.6 (p / pathway~e.9 :name (n / name :op1 "Erk"~e.8)))) :degree (s / slight~e.12 :mod (o / only~e.11) :ARG1-of (m5 / mean-01 :ARG2 (c3 / change-01~e.34,59 :ARG1 (g2 / gene~e.37 :ARG1-of (t2 / target-01~e.36)) :ARG1-of (a3 / average-04~e.31,56) :mod (f2 / fold~e.32,57) :quant (a4 / and~e.40 :op1 (p2 / product-of~e.57 :op1 1.1~e.39) :op2 (p4 / product-of~e.57 :op1 3.4~e.41) :mod (r / respective~e.43))))) :location~e.14 (a / and~e.26 :op1 (m7 / medical-condition :name (n3 / name :op1 "mSH"~e.25)) :op2 (m / medical-condition :name (n4 / name :op1 "mSAs-LGD"~e.27,29)) :ARG0-of (d / depend-01~e.24 :ARG1 (e / enzyme :name (n2 / name :op1 "Braf"~e.15) :ARG2-of (m3 / mutate-01 :value "V637E"))))) :ARG2 (u / upregulate-01~e.48 :ARG1 o2 :degree (s2 / strong~e.47 :ARG1-of (m6 / mean-01 :ARG2 (c4 / change-01~e.59 :ARG1 g2~e.61,62 :ARG1-of a3 :mod f2 :quant (a5 / and~e.65 :op1 (p3 / product-of~e.57 :op1 13.0~e.64) :op2 (p5 / product-of~e.57 :op1 12.6~e.66) :mod r~e.68)))) :location~e.49 (a2 / and~e.53 :op1 (m2 / medical-condition :name (n5 / name :op1 "mSAs-HGD"~e.50,52)) :op2 (m8 / medical-condition :name (n6 / name :op1 "carcinoma"~e.54)))))) # ::id pmid_2384_5441.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The extent of induction varied between markers and was highest for Fosl1 ( 60 @-@ fold induction in Braf @^{V6 @ 37 @ E}@ -@ induced mSAs @-@ HGD ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1 4-1.1 6-1.1.2.1 7-1 9-1.2 9-1.2.2 9-1.2.2.r 10-1.2.3.r 11-1.2.3.1.1 13-1.2.4.1.1.1 15-1.2.4.1.1 16-1.2.4.1 16-1.2.4.1.2.2 17-1.2.4.1.2.r 18-1.2.4.1.2.2.1.1.1 27-1.2.4.1.2.2 28-1.2.4.1.2.1.1 30-1.2.4.1.2.1.1 (a / and~e.7 :op1 (v / vary-01~e.4 :ARG1 (e / extent~e.1 :extent-of~e.2 (i / induce-01~e.3)) :ARG0-of (d / depend-01 :ARG1 (m2 / marker~e.6))) :op2 (h / high-02~e.9 :ARG1 e :degree~e.9 (m / most~e.9) :condition~e.10 (p / protein :name (n / name :op1 "Fosl1"~e.11)) :ARG1-of (m3 / mean-01 :ARG2 (i2 / induce-01~e.16 :degree (p2 / product-of~e.15 :op1 60~e.13) :location~e.17 (m6 / medical-condition :name (n3 / name :op1 "mSAs-HGD"~e.28,30) :ARG2-of (i3 / induce-01~e.16,27 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf"~e.18) :ARG2-of (m5 / mutate-01 :value "V637E")))))))) # ::id pmid_2384_5441.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Wnt Pathway Activation during Dysplasia Progression # ::alignments 1-1.1.1.1 2-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2 (a / activate-01~e.3 :ARG1 (p / pathway~e.2 :name (n / name :op1 "Wnt"~e.1)) :time~e.4 (p2 / progress-01~e.6 :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia"~e.5)))) # ::id pmid_2384_5441.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the role of the Wnt pathway in Braf @^{V6 @ 37 @ E}@ -@ induced tumorigenesis , we first analyzed the expression of ten different Wnt target genes in a total of 78 samples ( Figures 6 @ A and S5 ) . # ::alignments 1-1.4 6-1.4.2.1 7-1.4.2.1 9-1.4.2.2.2.1.1.1 18-1.4.2.2.2 19-1.4.2.2 19-1.4.2.2.1 19-1.4.2.2.1.r 21-1.1 22-1.3 23-1 25-1.2 26-1.2.1.r 27-1.2.1.1 28-1.2.1.2 29-1.2.1.3.1.1.1 30-1.2.1.3 31-1.2.1 32-1.2.2.r 34-1.2.2.2 36-1.2.2.2.1 37-1.2.2 37-1.2.2.1 37-1.2.2.1.r 40-1.5.1.1 40-1.5.1.2 44-1.5.1 46-1.5.1.2.1 (a / analyze-01~e.23 :ARG0 (w / we~e.21) :ARG1 (e / express-03~e.25 :ARG1~e.26 (g / gene~e.31 :quant 10~e.27 :ARG1-of (d / differ-02~e.28) :ARG0-of (t / target-01~e.30 :ARG1 (p / pathway :name (n / name :op1 "Wnt"~e.29)))) :ARG3~e.32 (t4 / thing~e.37 :ARG1-of~e.37 (s / sample-01~e.37) :ARG1-of (t2 / total-01~e.34 :ARG2 78~e.36))) :time (f / first~e.22) :purpose (e2 / examine-01~e.1 :ARG0 w :ARG1 (p2 / play-08 :ARG0 p~e.6,7 :ARG1 (c / create-01~e.19 :ARG1~e.19 (t3 / tumor~e.19) :ARG2-of (i / induce-01~e.18 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Braf"~e.9) :ARG2-of (m / mutate-01 :value "V637E")))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.44 :op1 (f2 / figure~e.40 :mod "6A") :op2 (f3 / figure~e.40 :mod "S5"~e.46)))) # ::id pmid_2384_5441.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that Wnt target gene expression was similar in wild @-@ type mucosa and Braf @^{V6 @ 37 @ E}@ -@ induced mSH but was upregulated in a large number of Braf @^{V6 @ 37 @ E}@ -@ induced mSAs @-@ HGD ( and occasionally in mSAs @-@ LGD ) to similar levels as in Apc @ ^{min @}@ -@ induced tumors . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1.1.1.1.1 4-1.2.1.1.1.1 5-1.2.1.1.1 6-1.2.1.1 6-1.2.1.2 8-1.2.1 9-1.2.1.1.2.r 10-1.2.1.1.2.1 12-1.2.1.1.2.1 13-1.2.1.1.2 15-1.2.1.2.2.2.1.1.1 24-1.2.1.2.2.2 25-1.2.1.2.2.1.1 26-1.2 28-1.2.2 29-1.2.2.2.r 31-1.2.2.2.1.1 32-1.2.2.2.1 33-1.2.2.2.1.2.r 34-1.2.2.2.1.2.2 35-1.2.2.2.1.2.2 36-1.2.2.2.1.2.2 37-1.2.2.2.1.2.2 38-1.2.2.2.1.2.2 39-1.2.2.2.1.2.2 40-1.2.2.2.1.2.2 41-1.2.2.2.1.2.2 42-1.2.2.2.1.2.2 43-1.2.2.2.1.2.2 44-1.2.2.2.1.2.1.1 46-1.2.2.2.1.2.1.1 48-1.2.2.2 49-1.2.2.2.2.2 49-1.2.2.2.2.2.r 51-1.2.2.2.2.1.1 53-1.2.2.2.2.1.1 55-1.2.2.3.r 56-1.2.2.3.1 57-1.2.2.3 57-1.2.2.3.1.1 69-1.2.2.3.1.1.1.1 70-1.2.2.3.1.1.1 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (c / contrast-01~e.26 :ARG1 (r2 / resemble-01~e.8 :ARG1 (e / express-03~e.6 :ARG1 (g / gene~e.5 :ARG0-of (t / target-01~e.4 :ARG1 (p / protein :name (n2 / name :op1 "Wnt"~e.3)))) :ARG3~e.9 (m / mucosa~e.13 :mod (w2 / wild-type~e.10,12))) :ARG2 (e2 / express-03~e.6 :ARG1 g :ARG3 (m6 / medical-condition :name (n5 / name :op1 "mSH"~e.25) :ARG2-of (i / induce-01~e.24 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Braf"~e.15) :ARG2-of (m3 / mutate-01 :value "V637E")))))) :ARG2 (u / upregulate-01~e.28 :ARG1 e :location~e.29 (a / and~e.48 :op1 (n / number~e.32 :mod (l / large~e.31) :quant-of~e.33 (m2 / medical-condition :name (n6 / name :op1 "mSAs-HGD"~e.44,46) :ARG2-of i~e.34,35,36,37,38,39,40,41,42,43)) :op2 (m4 / medical-condition :name (n7 / name :op1 "mSAs-LGD"~e.51,53) :manner~e.49 (o / occasional~e.49))) :degree~e.55 (l2 / level~e.57 :ARG1-of (r3 / resemble-01~e.56 :ARG2 (l3 / level~e.57 :location (t2 / tumor~e.70 :ARG2-of (i2 / induce-01~e.69 :ARG0 (g3 / gene :name (n4 / name :op1 "Apcmin")))))))))) # ::id pmid_2384_5441.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunohistochemical staining of beta @-@ catenin ( Ctnnb1 ) , a key effector of Wnt pathway activation , was performed to further confirm these observations . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 8-1.1.1.2.1.1.1 13-1.1.1.3.1 14-1.1.1.3 15-1.1.1.3.2.r 16-1.1.1.3.2.1.1.1 17-1.1.1.3.2.1 18-1.1.1.3.2 21-1 23-1.2.2 24-1.2 25-1.2.1.1 26-1.2.1 (p / perform-01~e.21 :ARG1 (s / stain-01~e.1 :ARG1~e.2 (p2 / protein :name (n / name :op1 "beta-catenin"~e.3,5) :ARG1-of (e2 / encode-01 :ARG0 (g / gene :name (n3 / name :op1 "Ctnnb1"~e.8))) :mod (e / effector~e.14 :ARG1-of (k / key-02~e.13) :ARG0-of~e.15 (a / activate-01~e.18 :ARG1 (p3 / pathway~e.17 :name (n2 / name :op1 "Wnt"~e.16))))) :mod (i / immunohistochemistry)) :purpose (c2 / confirm-01~e.24 :ARG1 (o / observe-01~e.26 :mod (t / this~e.25)) :degree (f / further~e.23))) # ::id pmid_2384_5441.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As in wild @-@ type mucosa , there was no evidence for nuclear β-catenin accumulation in mSHs ( n = 42 ) and the majority of mSAs @-@ LGD ( 14 @/@ 15 ) . # ::alignments 2-1.4.1.1 4-1.4.1.1 5-1.4.1 9-1.1 9-1.1.r 10-1 11-1.2.r 12-1.2.1 13-1.2.2.1.1 14-1.2 20-1.3.1.2.1.1 22-1.3 24-1.3.2.2 26-1.3.2.2.1.1.2.1 28-1.3.2.1.1 28-1.3.2.2.1.1.2.1 28-1.3.2.2.1.1.3.1.2.1 30-1.3.2.2.1.1.1 32-1.3.2.2.1.1.3.1.1 (e3 / evidence-01~e.10 :polarity~e.9 -~e.9 :ARG1~e.11 (a / accumulate-01~e.14 :ARG0 (n2 / nucleus~e.12) :ARG1 (p / protein :name (n / name :op1 "β-catenin"~e.13))) :location (a2 / and~e.22 :op1 (m9 / medical-condition :name (n3 / name :op1 "mSH") :ARG1-of (m7 / mean-01 :ARG2 (e2 / equal-01 :ARG2 42~e.20 :ARG1 m9))) :op2 (m / medical-condition :name (n4 / name :op1 "mSAs-LGD"~e.28) :quant (m2 / majority~e.24 :ARG1-of (m4 / mean-01 :ARG2 (m3 / medical-condition :quant 14~e.30 :name (n5 / name :op1 "mSAs-LGD"~e.26,28) :ARG1-of (i / include-91 :ARG2 (m5 / medical-condition :quant 15~e.32 :name (n6 / name :op1 "mSAs-LGD"~e.28)))))))) :ARG1-of (s2 / same-01 :ARG2 (m6 / mucosa~e.5 :mod (w / wild-type~e.2,4)))) # ::id pmid_2384_5441.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , there was diffuse or focal nuclear β-catenin accumulation in a substantial part of mSAs @-@ HGD ( 8 @/@ 14 ) and carcinomas ( 2 @/@ 4 ) ( Figures 6 @ B @–@ 6F ) . # ::alignments 1-1 5-1.1.3.1 6-1.1.3 7-1.1.3.2 8-1.1.1 9-1.1.2.1.1 10-1.1 11-1.1.4.r 13-1.1.4.3 14-1.1.4.1 14-1.1.4.2 16-1.1.4.1.1.1.2.1 16-1.1.4.1.2.1.1 18-1.1.4.1.1.1.2.1 18-1.1.4.1.1.1.3.1.2.1 18-1.1.4.1.2.1.1 20-1.1.4.1.1.1.1 22-1.1.4.1.1.1.3.1.1 24-1.1.4 25-1.1.4.2.1 25-1.1.4.2.2.1 25-1.1.4.2.2.1.2.1 27-1.1.4.2.2.1.1 29-1.1.4.2.2.1.2.1.1 33-1.2.1.1 33-1.2.1.2 33-1.2.1.3 33-1.2.1.4 33-1.2.1.5 38-1.2.1.5.1 (c / contrast-01~e.1 :ARG2 (a / accumulate-01~e.10 :ARG0 (n / nucleus~e.8) :ARG1 (p / protein :name (n2 / name :op1 "β-catenin"~e.9)) :mod (o / or~e.6 :op1 (d / diffuse-01~e.5) :op2 (f / focus~e.7)) :location~e.11 (a2 / and~e.24 :op1 (p2 / part~e.14 :ARG1-of (m2 / mean-01 :ARG2 (m / medical-condition :quant 8~e.20 :name (n4 / name :op1 "mSAs-HGD"~e.16,18) :ARG1-of (i / include-91 :ARG2 (m3 / medical-condition :quant 14~e.22 :name (n5 / name :op1 "mSAs-HGD"~e.18))))) :quant-of (m6 / medical-condition :name (n3 / name :op1 "mSAs-HGD"~e.16,18))) :op2 (p3 / part~e.14 :quant-of (c2 / carcinoma~e.25) :ARG1-of (m5 / mean-01 :ARG2 (c3 / carcinoma~e.25 :quant 2~e.27 :ARG1-of (i2 / include-91 :ARG2 (c4 / carcinoma~e.25 :quant 4~e.29))))) :mod (s / substantial~e.13))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure~e.33 :mod "6B") :op2 (f3 / figure~e.33 :mod "6C") :op3 (f4 / figure~e.33 :mod "6D") :op4 (f5 / figure~e.33 :mod "6E") :op5 (f6 / figure~e.33 :mod "6F"~e.38)))) # ::id pmid_2384_5441.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To analyze the mechanisms of Wnt pathway activation , we performed whole @-@ exome sequencing of 20 Braf mutant tumors . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.1.r 5-1.4.2.1.1.1.1 6-1.4.2.1.1 7-1.4.2.1 9-1.1 10-1 11-1.2.1.1 13-1.2.1 14-1.2 15-1.3.r 16-1.3.1 18-1.3.2.1.1 20-1.3.2 20-1.3.2.2 20-1.3.2.2.r 21-1.3 (p / perform-01~e.10 :ARG0 (w / we~e.9) :ARG1 (s / sequence~e.14 :mod (e / exome~e.13 :mod (w2 / whole~e.11))) :location~e.15 (t / tumor~e.21 :quant 20~e.16 :mod (g / gene~e.20 :name (n / name :op1 "Braf"~e.18) :ARG2-of~e.20 (m / mutate-01~e.20))) :purpose (a / analyze-01~e.1 :ARG0 w :ARG1 (m2 / mechanism~e.3 :ARG0-of~e.4 (a2 / activate-01~e.7 :ARG1 (p2 / pathway~e.6 :name (n2 / name :op1 "Wnt"~e.5)))))) # ::id pmid_2384_5441.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We identified a number of mutations in known Wnt pathway genes ( Table S6 ) , including intracellular components of the Wnt pathway ( e.g . , Apc , Ctnnb1 , Gsk3b , and Axin2 ) , Wnt receptors ( e.g . , Lrp8 and Fzd9 ) , or negative regulators of Wnt signaling ( e.g . , Lrp1b and Lrp4 ) . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1 6-1.2.1.1.r 7-1.2.1.1.1 8-1.2.1.1.2.1.1 9-1.2.1.1.2 10-1.2.1.1 10-1.2.1.1.4.1.3 13-1.2.1.1.3.1 14-1.2.1.1.3.1.1 18-1.2.1.1.4 19-1.2.1.1.4.1.1.1 20-1.2.1.1.4.1.1 21-1.2.1.1.4.1.1.2.r 23-1.2.1.1.4.1.1.2 24-1.2.1.1.4.1.1.2 30-1.2.1.1.4.1.1.3.1.1.1 34-1.2.1.1.4.1.1.3.2.1.1 38-1.2.1.1.4.1.1.3.3.1.1 41-1.2.1.1.4.1.1.3 43-1.2.1.1.4.1.1.3.4.1.1 47-1.2.1.1.2.1.1 48-1.2.1.1.4.1.2 54-1.2.1.1.4.1.2.2.1.1.1 56-1.2.1.1.4.1.2.2 58-1.2.1.1.4.1.2.2.2.1.1 62-1.2.1.1.4.1 63-1.2.1.1.4.1.3.2 64-1.2.1.1.4.1.3.2 65-1.2.1.1.4.1.3.2.1.r 66-1.2.1.1.4.1.3.2.1.1 67-1.2.1.1.4.1.3.2.1 73-1.2.1.1.4.1.3.1.1.1.1 77-1.2.1.1.4.1.3.1.2.1.1 (i / identify-01~e.1 :ARG0 (w / we~e.0) :ARG1 (n / number~e.3 :quant-of~e.4 (m / mutate-01~e.5 :ARG1~e.6 (g / gene~e.10 :ARG1-of (k / know-01~e.7) :mod (p / pathway~e.9 :name (n2 / name :op1 "Wnt"~e.8,47)) :ARG1-of (d / describe-01 :ARG0 (t / table~e.13 :mod "S6"~e.14)) :ARG2-of (i2 / include-01~e.18 :ARG1 (o2 / or~e.62 :op1 (c / component~e.20 :mod (i3 / intracellular~e.19) :part-of~e.21 p~e.23,24 :example (a2 / and~e.41 :op1 (p2 / protein :name (n3 / name :op1 "Apc"~e.30)) :op2 (p3 / protein :name (n4 / name :op1 "Ctnnb1"~e.34)) :op3 (e / enzyme :name (n5 / name :op1 "Gsk3b"~e.38)) :op4 (p4 / protein :name (n6 / name :op1 "Axin2"~e.43)))) :op2 (r2 / receptor~e.48 :mod p :example (a3 / and~e.56 :op1 (p5 / protein :name (n7 / name :op1 "Lrp8"~e.54)) :op2 (p6 / protein :name (n8 / name :op1 "Fzd9"~e.58)))) :op3 (g10 / gene~e.10 :example (a / and :op1 (p7 / protein :name (n10 / name :op1 "Lrp1b"~e.73)) :op2 (p8 / protein :name (n11 / name :op1 "Lrp4"~e.77))) :ARG2-of (d2 / downregulate-01~e.63,64 :ARG1~e.65 (s / signal-07~e.67 :ARG0 p~e.66))))))))) # ::id pmid_2384_5441.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We then further analyzed the most frequently altered genes ( Apc , Ctnnb1 , and Lrp1b ) in another 46 tumors and found mutations in these three genes in 21 @/@ 66 samples : Apc ( n = 6 ) , Ctnnb1 ( n = 9 ) , and Lrp1b ( n = 6 ) . # ::alignments 0-1.1.1 1-1.1.3 2-1.1.4 3-1.1 5-1.1.2.1.1.1 6-1.1.2.1.1 7-1.1.2.1 8-1.1.2 11-1.1.2.2.1.1.1.1 13-1.1.2.2.1.2.1.1 18-1.1.2.2.1.3.1.1 21-1.1.5.r 22-1.1.5.2 23-1.1.5.1 24-1.1.5 25-1 25-1.1.2.2.1 26-1.2 27-1.2.2 31-1.1.2.2.1.1 31-1.1.2.2.1.2 31-1.1.2.2.1.3 32-1.2.2.1.r 33-1.2.2.1.4.1 35-1.2.2.1.4.2.1.1 36-1.2.2.1.4 36-1.2.2.1.4.2.1 36-1.2.2.1.4.2.1.2 36-1.2.2.1.4.2.1.2.r 36-1.2.2.1.4.3.1.1 36-1.2.2.1.4.3.1.2 36-1.2.2.1.4.3.1.3 39-1.1.2.2.1.1.1.1 44-1.2.2.1.4.3.1.1.1 44-1.2.2.1.4.3.1.3.1 48-1.2.2.1.4.3.1.2.2 53-1.2.2.1.4.3.1.2.1 56-1.2.2.1 58-1.1.2.2.1.3.1.1 63-1.2.2.1.4.3.1.1.1 (a / and~e.25 :op1 (a2 / analyze-01~e.3 :ARG0 (w / we~e.0) :ARG1 (g / gene~e.8 :ARG1-of (a3 / alter-01~e.7 :ARG1-of (f3 / frequent-02~e.6 :degree (m / most~e.5))) :ARG1-of (m2 / mean-01 :ARG2 (a4 / and~e.25 :op1 (g2 / gene~e.31 :name (n / name :op1 "Apc"~e.11,39)) :op2 (g3 / gene~e.31 :name (n2 / name :op1 "Ctnnb1"~e.13)) :op3 (g4 / gene~e.31 :name (n3 / name :op1 "Lrp1b"~e.18,58))))) :time (t / then~e.1) :degree (f / further~e.2) :location~e.21 (t2 / tumor~e.24 :quant 46~e.23 :mod (a5 / another~e.22))) :op2 (f2 / find-01~e.26 :ARG0 w :ARG1 (m3 / mutate-01~e.27 :ARG1~e.32 (a7 / and~e.56 :op1 g2 :op2 g3 :op3 g4 :ARG1-of (s / sample-01~e.36 :quant 21~e.33 :ARG1-of (i / include-91 :ARG2 (t3 / thing~e.36 :quant 66~e.35 :ARG1-of~e.36 (s2 / sample-01~e.36))) :ARG1-of (m4 / mean-01 :ARG2 (a6 / and :op1 (s3 / sample-01~e.36 :quant 6~e.44,63 :ARG1 g2) :op2 (s4 / sample-01~e.36 :quant 9~e.53 :ARG1 g3~e.48) :op3 (s5 / sample-01~e.36 :quant 6~e.44 :ARG1 g4)))))))) # ::id pmid_2384_5441.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Wnt pathway mutations frequently occurred in high @-@ grade dysplasia , suggesting an early requirement during tumorigenesis . # ::alignments 0-1.1.1.1.1 1-1.1.1 2-1.1 3-1 5-1.2.r 6-1.2.2.1 8-1.2.2 9-1.2.1.1 11-1.3 13-1.3.1.2 14-1.3.1 15-1.3.1.2.r 15-1.3.1.3.r 16-1.3.1.3 16-1.3.1.3.1 16-1.3.1.3.1.r (f / frequent-02~e.3 :ARG1 (m / mutate-01~e.2 :ARG1 (p / pathway~e.1 :name (n / name :op1 "Wnt"~e.0))) :location~e.5 (m2 / medical-condition :name (n2 / name :op1 "dysplasia"~e.9) :mod (g / grade~e.8 :ARG1-of (h / high-02~e.6))) :ARG0-of (s / suggest-01~e.11 :ARG1 (r / require-01~e.14 :ARG1 m :time~e.15 (e / early~e.13) :time~e.15 (c / create-01~e.16 :ARG1~e.16 (t / tumor~e.16))))) # ::id pmid_2384_5441.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only missense , nonsense , essential splice site mutations or frameshift @-@ causing indels were observed ( no silent mutations ) , suggesting a strong enrichment for functionally relevant events . # ::alignments 0-1.2 1-1.1.1.1 3-1.1.2.1 5-1.1.3.2 6-1.1.3.1 7-1.1.3.1.1 8-1.1.1 8-1.1.2 8-1.1.3 9-1.1 10-1.1.4.1.1 12-1.1.4.1 15-1 17-1.1.5.1.1 17-1.1.5.1.1.r 18-1.1.5.1.2 19-1.1.5.1 22-1.3 24-1.3.1.2 25-1.3.1 26-1.3.1.1.r 27-1.3.1.1.1.1 27-1.3.1.1.1.1.r 28-1.3.1.1.1 29-1.3.1.1 (o / observe-01~e.15 :ARG1 (o2 / or~e.9 :op1 (m / mutate-01~e.8 :mod (m2 / missense~e.1)) :op2 (m3 / mutate-01~e.8 :mod (n / nonsense~e.3)) :op3 (m4 / mutate-01~e.8 :ARG0-of (s / splice-01~e.6 :ARG1 (s2 / site~e.7)) :mod (e / essential~e.5)) :op4 (i / indel :ARG0-of (c / cause-01~e.12 :ARG1 (f / frameshift~e.10))) :ARG1-of (m5 / mean-01 :ARG2 (m6 / mutate-01~e.19 :polarity~e.17 -~e.17 :mod (s3 / silent~e.18)))) :mod (o3 / only~e.0) :ARG0-of (s4 / suggest-01~e.22 :ARG1 (e2 / enrich-01~e.25 :ARG1~e.26 (e3 / event~e.29 :ARG1-of (r / relevant-01~e.28 :manner~e.27 (f2 / functional~e.27))) :ARG1-of (s5 / strong-02~e.24)))) # ::id pmid_2384_5441.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , Apc mutations were mostly nonsense or frameshift mutations , whereas Ctnnb1 mutations were recurrent activating mutations at specific positions that have also been described in humans ( e.g . , T141I ) . # ::alignments 1-1.3 4-1.1.4.1.1.1 6-1.2 6-1.2.3 7-1.1.4.r 7-1.2.3.r 8-1.1.3 9-1.1.1.1 10-1.1 11-1.1.2.1 12-1.1.1 12-1.1.2 12-1.1.4 12-1.2 12-1.2.3 14-1 16-1.2.3.1.1.1 18-1.2.3 19-1.2.3.r 20-1.2.2.1 21-1.2.2 22-1.2 22-1.2.3 22-1.2.4 22-1.2.4.r 23-1.2.1.r 24-1.2.1.1 25-1.2.1 28-1.2.5.1 30-1.2.5 31-1.2.5.2.r 32-1.2.5.2 37-1.2.4.1 (c / contrast-01~e.14 :ARG1 (o / or~e.10 :op1 (m / mutate-01~e.12 :mod (n / nonsense~e.9)) :op2 (m2 / mutate-01~e.12 :mod (f / frameshift~e.11)) :quant (m3 / most~e.8) :domain~e.7 (m4 / mutate-01~e.12 :ARG1 (g / gene :name (n2 / name :op1 "Apc"~e.4)))) :ARG2 (m6 / mutate-01~e.6,12,22 :location~e.23 (p / position~e.25 :ARG1-of (s / specific-02~e.24)) :ARG0-of (a / activate-01~e.21 :frequency (r / recurrent~e.20)) :domain~e.7,19 (m5 / mutate-01~e.6,12,18,22 :ARG1 (g2 / gene :name (n3 / name :op1 "Ctnnb1"~e.16))) :example~e.22 (m7 / mutate-01~e.22 :value "T141I"~e.37) :ARG1-of (d / describe-01~e.30 :mod (a2 / also~e.28) :condition~e.31 (h / human~e.32))) :ARG0-of (e / exemplify-01~e.1)) # ::id pmid_2384_5441.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Missense mutations in Lrp1b , a negative regulator of Wnt signaling , have been found earlier in Braf mutant human melanoma ( Nikolaev et al. , 2012 ) . # ::alignments 0-1.1.2 1-1.1 4-1.1.1.1.1 8-1.1.1 8-1.1.1.2 8-1.1.1.2.r 9-1.1.1 9-1.1.1.2 9-1.1.1.2.r 10-1.1.1.2.1.r 11-1.1.1.2.1.1.1.1 12-1.1.1.2.1 16-1 17-1.2 17-1.2.1 17-1.2.1.r 20-1.4.3.1.1 22-1.4.3 22-1.4.3.2 22-1.4.3.2.r 23-1.4.2 24-1.4.1.1 27-1.3.1.1.1.1.1 28-1.3.1.1 29-1.3.1.1.2.1 31-1.3.1.2.1 (f / find-01~e.16 :ARG1 (m2 / mutate-01~e.1 :ARG1 (g / gene~e.8,9 :name (n / name :op1 "Lrp1b"~e.4) :ARG2-of~e.8,9 (d2 / downregulate-01~e.8,9 :ARG1~e.10 (s / signal-07~e.12 :ARG0 (p / pathway :name (n2 / name :op1 "Wnt"~e.11))))) :mod (m3 / missense~e.0)) :time (e / early~e.17 :degree~e.17 (m / more~e.17)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a / and~e.28 :op1 (p2 / person :name (n4 / name :op1 "Nikolaev"~e.27)) :op2 (p3 / person :mod (o / other~e.29))) :time (d / date-entity :year 2012~e.31))) :location (m6 / medical-condition :name (n5 / name :op1 "melanoma"~e.24) :mod (h / human~e.23) :mod (g2 / gene~e.22 :name (n3 / name :op1 "Braf"~e.20) :ARG2-of~e.22 (m5 / mutate-01~e.22)))) # ::id pmid_2384_5441.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All together , these results provide strong evidence for an important role of Wnt pathway activation during early dysplasia progression . # ::alignments 0-1.3.1 1-1.3 3-1.1.1 4-1.1 4-1.1.2 4-1.1.2.r 5-1 6-1.2.2 7-1.2 8-1.2.1.r 10-1.2.1.2 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1.1.1 14-1.2.1.1.1 15-1.2.1.1 16-1.2.1.3.2.r 16-1.2.1.3.r 17-1.2.1.3.2 18-1.2.1.3.1.1.1 19-1.2.1.3 (p / provide-01~e.5 :ARG0 (t / thing~e.4 :mod (t2 / this~e.3) :ARG2-of~e.4 (r / result-01~e.4)) :ARG1 (e / evidence-01~e.7 :ARG1~e.8 (r2 / role~e.11 :poss~e.12 (a / activate-01~e.15 :ARG1 (p2 / pathway~e.14 :name (n / name :op1 "Wnt"~e.13))) :mod (i / important~e.10) :time~e.16 (p3 / progress-01~e.19 :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia"~e.18)) :time~e.16 (e2 / early~e.17))) :ARG1-of (s / strong-02~e.6)) :manner (t3 / together~e.1 :mod (a2 / all~e.0))) # ::id pmid_2384_5441.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is worth noting that in some tumors with strong Wnt target gene expression , no mutations in Wnt pathway genes were found , suggesting additional unidentified mechanisms . # ::alignments 2-1 3-1.1 5-1.1.1.r 6-1.1.1.3.1 7-1.1.1.3 8-1.1.1.3.2.r 9-1.1.1.3.2.2 10-1.1.1.3.2.1.1.1.1.1 11-1.1.1.3.2.1.1 12-1.1.1.3.2.1 13-1.1.1.3.2 15-1.1.1.1.r 16-1.1.1.2 17-1.1.1.2.1.r 18-1.1.1.2.1 19-1.1.1.2.1 20-1.1.1.2.1 22-1.1.1 24-1.1.1.4 25-1.1.1.4.1.1 26-1.1.1.1 26-1.1.1.4.1.2 26-1.1.1.4.1.2.1 26-1.1.1.4.1.2.1.r 27-1.1.1.4.1 (w / worth-02~e.2 :ARG2 (n2 / note-01~e.3 :ARG1~e.5 (f / find-01~e.22 :polarity~e.15 -~e.26 :ARG1 (m / mutate-01~e.16 :ARG2~e.17 g~e.18,19,20) :location (t / tumor~e.7 :quant (s / some~e.6) :mod~e.8 (e / express-03~e.13 :ARG1 (g / gene~e.12 :ARG0-of (t2 / target-01~e.11 :ARG1 (p / pathway :name (n / name :op1 "Wnt"~e.10)))) :ARG1-of (s2 / strong-02~e.9))) :ARG0-of (s3 / suggest-01~e.24 :ARG1 (m2 / mechanism~e.27 :mod (a / additional~e.25) :ARG1-of (i / identify-01~e.26 :polarity~e.26 -~e.26)))))) # ::id pmid_2384_5441.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Large @-@ Scale Drug Screening Identifies Targetable Nodes in Braf @-@ Induced Tumorigenesis # ::alignments 1-1.1.2.1 3-1.1.2 4-1.1.1 5-1.1 6-1 8-1.2 9-1.3.r 10-1.3.2.1.1.1 12-1.3.2 13-1.3 13-1.3.1 13-1.3.1.r (i / identify-01~e.6 :ARG0 (s / screen-01~e.5 :ARG1 (d / drug~e.4) :mod (s2 / scale~e.3 :mod (l / large~e.1))) :ARG1 (n / node~e.8 :ARG1-of (t / target-01 :ARG1-of (p / possible-01))) :location~e.9 (c / create-01~e.13 :ARG1~e.13 (t2 / tumor~e.13) :ARG2-of (i2 / induce-01~e.12 :ARG0 (e / enzyme :name (n2 / name :op1 "Braf"~e.10))))) # ::id pmid_2384_5441.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test the sensitivity of Braf @ ^{LSL @-@ V637E @ /+}@ -@ induced intestinal cancer cell lines to Braf inhibition we performed short @-@ term proliferation assays . # ::alignments 1-1.3 3-1.3.2 6-1.3.2.2.1.1 10-1.3.2.2.2.1 12-1.3.2.2.2.1 17-1.3.2.1.1 18-1.3.2.1.2.3 19-1.3.2.1.2.2.1 20-1.3.2.1 21-1.3.2.1 22-1.3.2.1.1.1.r 23-1.3.2.1.1.1.1.1.1 24-1.3.2.1.1.1 25-1.1 26-1 26-1.3 26-1.3.r 27-1.2.1.1 30-1.2.1 31-1.2 (p / perform-01~e.26 :ARG0 (w / we~e.25) :ARG1 (a / assay-01~e.31 :ARG1 (p2 / proliferate-01~e.30 :ARG1-of (s3 / short-07~e.27))) :purpose~e.26 (t / test-01~e.1,26 :ARG0 w :ARG1 (s2 / sensitive-03~e.3 :ARG0 (c / cell-line~e.20,21 :ARG2-of (i / induce-01~e.17 :ARG0~e.22 (i3 / inhibit-01~e.24 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Braf"~e.23)))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "Cancer"~e.19) :mod (i2 / intestine~e.18))) :ARG1 (g / gene :name (n2 / name :op1 "Braf"~e.6) :ARG2-of (m / mutate-01 :value "LSL-V637E/+"~e.10,12))))) # ::id pmid_2384_5441.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overall , only minor growth inhibition was observed for Braf mutant mouse and human colorectal cancer cell lines treated with 5 μM PLX4720 , a selective inhibitor of mutant Braf ( Figures 7 @ A and 7B ) . # ::alignments 0-1.2 2-1.1.2 3-1.1.4 4-1.1.1 5-1.1 7-1 10-1.1.3.1.1.1.1 12-1.1.3.1.1 12-1.1.3.1.1.2 12-1.1.3.1.1.2.r 13-1.1.3.1 14-1.1.3 15-1.1.3.2.1 16-1.1.3.2.3.2.1 17-1.1.3.2.3.2.2 18-1.1.3.2 19-1.1.3.2 20-1.1.3.2.2 21-1.1.3.2.2.1.r 22-1.1.3.2.2.1.2.1 23-1.1.3.2.2.1.2.2 24-1.1.3.2.2.1.1.1 27-1.1.3.2.2.1.3.2 28-1.1.3.2.2.1 28-1.1.3.2.2.1.3 28-1.1.3.2.2.1.3.r 29-1.1.3.2.2.1.3.1.r 30-1.1.3.2.2.1.3.1 31-1.1.3.2.2.1.3.1 34-1.3.1.1 34-1.3.1.2 38-1.3.1 39-1.3.1.2.1 (o / observe-01~e.7 :ARG1 (i2 / inhibit-01~e.5 :ARG1 (g / grow-01~e.4) :mod (o2 / only~e.2) :beneficiary (a / and~e.14 :op1 (m2 / mouse~e.13 :mod (e / enzyme~e.12 :name (n2 / name :op1 "Braf"~e.10) :ARG2-of~e.12 (m3 / mutate-01~e.12))) :op2 (c / cell-line~e.18,19 :mod (h / human~e.15) :ARG1-of (t2 / treat-04~e.20 :ARG2~e.21 (s / small-molecule~e.28 :name (n3 / name :op1 "PLX4720"~e.24) :quant (c4 / concentration-quantity :quant 5~e.22 :unit (m4 / micromolar~e.23)) :ARG0-of~e.28 (i3 / inhibit-01~e.28 :ARG1~e.29 e~e.30,31 :mod (s2 / selective~e.27)))) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal"~e.16 :op2 "cancer"~e.17)))) :ARG1-of (m / minor-01~e.3)) :mod (o3 / overall~e.0) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.38 :op1 (f / figure~e.34 :mod "7A") :op2 (f2 / figure~e.34 :mod "7B"~e.39)))) # ::id pmid_2384_5441.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Braf inhibition was proposed to cause feedback activation of the epidermal growth factor receptor ( EGFR ) in human BRAF mutant CRCs ( Prahallad et al. , 2012 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1 4-1.1 4-1.1.2.2.r 5-1.1 6-1.1.2.2 7-1.1.2 8-1.1.2.1.r 10-1.1.2.1.1.1 11-1.1.2.1.1.2 12-1.1.2.1.1.3 13-1.1.2.1.1.4 17-1.1.2.3.r 18-1.1.2.3.2 20-1.1.2.3.3.1.1 22-1.1.2.3.3 22-1.1.2.3.3.2 22-1.1.2.3.3.2.r 26-1.2.1.1.1.1.1 27-1.2.1.1 28-1.2.1.1.2.1 30-1.2.1.2.1 (p / propose-01~e.3 :ARG1 (c / cause-01~e.4,5 :ARG0 (i / inhibit-01~e.1 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Braf"~e.0))) :ARG1 (a / activate-01~e.7 :ARG1~e.8 (e3 / enzyme :name (n4 / name :op1 "epidermal"~e.10 :op2 "growth"~e.11 :op3 "factor"~e.12 :op4 "receptor"~e.13)) :destination-of~e.4 (f / feedback~e.6) :location~e.17 (d / disease :name (n / name :op1 "colorectal" :op2 "cancer") :mod (h / human~e.18) :mod (g / gene~e.22 :name (n6 / name :op1 "BRAF"~e.20) :ARG2-of~e.22 (m / mutate-01~e.22))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.27 :op1 (p3 / person :name (n7 / name :op1 "Prahallad"~e.26)) :op2 (p4 / person :mod (o / other~e.28))) :time (d3 / date-entity :year 2012~e.30)))) # ::id pmid_2384_5441.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore treated mouse and human BRAF mutant cell lines with the EGFR small molecule kinase inhibitor , Gefitinib , alone or in combination with PLX4720 . # ::alignments 0-1.1 1-1.4 2-1 3-1.2.1.1 4-1.2 5-1.2.2.1 7-1.2.1.2.1.1 9-1.2.1.2 9-1.2.1.2.2 9-1.2.1.2.2.r 10-1.2.1 10-1.2.2 11-1.2.2 12-1.3.r 14-1.3.1.2.1.1.1 15-1.3.1 16-1.3.1 16-1.3.2.2 17-1.3.1.2.1 18-1.3.1.2 20-1.3.1.1.1 22-1.3.1.3 25-1.3.2 27-1.3.2.2.1.1 (t2 / treat-04~e.2 :ARG0 (w / we~e.0) :ARG1 (a / and~e.4 :op1 (c / cell-line~e.10 :mod (m / mouse~e.3) :mod (g / gene~e.9 :name (n2 / name :op1 "BRAF"~e.7) :ARG2-of~e.9 (m2 / mutate-01~e.9))) :op2 (c2 / cell-line~e.10,11 :mod (h / human~e.5) :mod g)) :ARG2~e.12 (a2 / and :op1 (s / small-molecule~e.15,16 :name (n3 / name :op1 "Gefitinib"~e.20) :ARG0-of (i2 / inhibit-01~e.18 :ARG1 (k / kinase~e.17 :name (n6 / name :op1 "EGFR"~e.14))) :mod (a4 / alone~e.22)) :op2 (c3 / combine-01~e.25 :ARG1 s :ARG2 (s2 / small-molecule~e.16 :name (n4 / name :op1 "PLX4720"~e.27)))) :ARG1-of (c4 / cause-01~e.1)) # ::id pmid_2384_5441.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , Gefitinib and PLX4720 synergized in @-@ growth inhibition ( Figures 7 @ A and 7B ) . # ::alignments 1-1.3 3-1.1.1.1.1 4-1.1 5-1.1.2.1.1 7-1.2.1 9-1.2.1 10-1.2 13-1.4.1.1 13-1.4.1.2 17-1.4.1 18-1.4.1.2.1 (s / synergize-01 :ARG0 (a / and~e.4 :op1 (s2 / small-molecule :name (n / name :op1 "Gefitinib"~e.3)) :op2 (s3 / small-molecule :name (n2 / name :op1 "PLX4720"~e.5))) :ARG2 (i / inhibit-01~e.10 :ARG1 (g / grow-in-00~e.7,9)) :ARG1-of (e / expect-01~e.1) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.17 :op1 (f / figure~e.13 :mod "7A") :op2 (f2 / figure~e.13 :mod "7B"~e.18)))) # ::id pmid_2384_5441.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The murine intestinal cancer cell line MouseT1 ( from a Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+}@ ; p53 @ ^{LSL @-@ R172H/+ @} mouse ) , had similar sensitivity to combinatorial PLX4720 @/@ Gefitinib treatment as HT @-@ 29 ( WiDr ) , one of the three human cell lines tested by Prahallad and colleagues ( Figures 7 @ A and 7B ; inhibition of proliferation by 60 % @–@ 70 %) . # ::alignments 1-1.1.3.2.1 2-1.1.5.3 3-1.1.5.2.1 4-1.1 5-1.1 6-1.1.2.1 8-1.1.4.r 11-1.1.4.1.1.2.1 13-1.1.4.1.2.2.1 15-1.1.4.2.2.1 19-1.1.4.2.3.1 21-1.1.4.2.3.1 27-1.1.4.3.2.1 31-1.1.4.2.3.1 31-1.1.4.3.3.1 36-1.1.4 39-1 40-1.2.3 41-1.2 44-1.2.2.1.1.2.1 46-1.2.2.1.2.2.1 47-1.2.2 48-1.2.3.1.r 49-1.2.3.1.2.1 51-1.2.3.1.2.1 53-1.2.3.1.3.1.2.1 59-1.2.3.1.4.1.1 60-1.2.3.1.4.1.2 61-1.2.3.1.4.1 62-1.2.3.1.4.1 63-1.2.3.1.4.1.3 64-1.2.3.1.4.1.3.1.r 65-1.2.3.1.4.1.3.1.1.2.1 66-1.2.3.1.4.1.3.1 67-1.2.3.1.4.1.3.1.2 70-1.3.1.1 70-1.3.1.2 74-1.3.1 75-1.3.1.2.1 77-1.3.1.3 78-1.3.1.3.1.r 79-1.3.1.3.1 81-1.3.2.1.1 82-1.3.2.1 82-1.3.2.2 84-1.3.2.2.1 (h / have-03~e.39 :ARG0 (c / cell-line~e.4,5 :wiki - :name (n2 / name :op1 "MouseT1"~e.6) :mod (o / organism :wiki "Muridae" :name (n / name :op1 "Muridae"~e.1)) :source~e.8 (m / mouse~e.36 :mod (m2 / macro-molecular-complex :part (p3 / protein :wiki "Villin" :name (n3 / name :op1 "Vil"~e.11)) :part (e2 / enzyme :wiki "Cre_recombinase" :name (n4 / name :op1 "Cre"~e.13))) :mod (e / enzyme :wiki - :name (n5 / name :op1 "Braf"~e.15) :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+"~e.19,21,31)) :mod (p5 / protein :wiki "P53" :name (n6 / name :op1 "p53"~e.27) :ARG2-of (m4 / mutate-01 :value "LSL-R172H/+"~e.31))) :mod (d / disease :wiki "Cancer" :name (n12 / name :op1 "cancer"~e.3) :mod (i / intestine~e.2))) :ARG1 (s / sensitive-03~e.41 :ARG0 c :ARG1 (t / treat-04~e.47 :ARG2 (c3 / combine-01 :ARG1 (s2 / small-molecule :wiki - :name (n7 / name :op1 "PLX4720"~e.44)) :ARG2 (s3 / small-molecule :wiki "Gefitinib" :name (n8 / name :op1 "Gefitinib"~e.46)))) :ARG1-of (r2 / resemble-01~e.40 :ARG2~e.48 (c4 / cell-line :wiki - :name (n9 / name :op1 "HT-29"~e.49,51) :ARG2-of (i4 / include-91 :ARG1 (c7 / cell-line :wiki - :name (n11 / name :op1 "WiDr"~e.53))) :ARG1-of (i2 / include-91 :ARG2 (c5 / cell-line~e.61,62 :quant 3~e.59 :mod (h2 / human~e.60) :ARG1-of (t2 / test-01~e.63 :ARG0~e.64 (a2 / and~e.66 :op1 (p6 / person :wiki - :name (n10 / name :op1 "Prahallad"~e.65)) :op2 (c6 / colleague~e.67)))))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.74 :op1 (f / figure~e.70 :mod "7A") :op2 (f2 / figure~e.70 :mod "7B"~e.75) :op3 (i3 / inhibit-01~e.77 :ARG1~e.78 (p7 / proliferate-01~e.79))) :ARG2 (v / value-interval :op1 (p / percentage-entity~e.82 :value 60~e.81) :op2 (p2 / percentage-entity~e.82 :value 70~e.84)))) # ::id pmid_2384_5441.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It seems , however , that the effectiveness of PLX4720 @/@ Gefitinib varies considerably among human cancers : in three of five tested human cell lines the effects were rather modest ( growth inhibition by 25 % @–@ 40 % ; Figure 7 @ A and data not shown ) . # ::alignments 1-1.1 3-1 5-1.1.1.r 7-1.1.1.1 8-1.1.1.1.1.r 9-1.1.1.1.1.1.1.1 11-1.1.1.1.1.2.1.1 12-1.1.1 13-1.1.1.2 13-1.1.1.2.r 14-1.1.1.3.1.2.2 15-1.1.1.4.3 16-1.1.1.4.2.1 19-1.1.1.3.1.2.1 21-1.1.1.3.1.2.2.1.1 22-1.1.1.3.1.2.2.1.2 23-1.1.1.3.1.2.2.1.3 24-1.1.1.3.1.2 24-1.1.1.3.1.2.2.1 25-1.1.1.3.1.2.2.1 27-1.1.1.3.1.1 28-1.1.1.3.1.1.r 29-1.1.1.3.1.3 30-1.1.1.3.1 32-1.2.1.1.1 33-1.2.1.1 35-1.2.2.1.1 36-1.2.2.1 38-1.2.2.2.1 39-1.2.2.2 42-1.2.1.2 46-1.2.1 47-1.2.1.3 48-1.2.1.3.1.1 48-1.2.1.3.1.1.r 49-1.2.1.3.1 (h / have-concession-91~e.3 :ARG1 (s3 / seem-01~e.1 :ARG1~e.5 (v / vary-01~e.12 :ARG1 (e / effective-04~e.7 :ARG0~e.8 (a / and :op1 (s / small-molecule :name (n / name :op1 "PLX4720"~e.9)) :op2 (s2 / small-molecule :name (n2 / name :op1 "Gefitinib"~e.11)))) :manner~e.13 (c / considerable~e.13) :ARG1-of (m2 / mean-01 :ARG2 (m / modest~e.30 :domain~e.28 (a3 / affect-01~e.27) :location (c3 / cell-line~e.24 :quant 3~e.19 :ARG1-of (i2 / include-91~e.14 :ARG2 (c4 / cell-line~e.24,25 :quant 5~e.21 :ARG1-of (t2 / test-01~e.22) :mod (h2 / human~e.23)))) :degree (r / rather~e.29))) :location (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.16) :mod h2~e.15))) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.46 :op1 (i3 / inhibit-01~e.33 :ARG1 (g / grow-01~e.32)) :op2 (f / figure~e.42 :mod "7A") :op3 (d2 / data~e.47 :ARG1-of (s4 / show-01~e.49 :polarity~e.48 -~e.48))) :ARG2 (v2 / value-interval :op1 (p / percentage-entity~e.36 :value 25~e.35) :op2 (p2 / percentage-entity~e.39 :value 40~e.38)))) # ::id pmid_2384_5441.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next performed long @-@ term ( 14 days ) clonogenic assays and again found that although PLX4720 and Gefitinib synergized in @-@ growth inhibition , most of the treated cell lines retained variable levels of colony @-@ forming capacity ( Figure 7 @ C ) . # ::alignments 0-1.1.1 1-1.1.3 2-1.1 3-1.1.2.2 3-1.1.2.2.r 5-1.1.2.2.r 7-1.1.2.2.1.1.1 8-1.1.2.2.1.1.2 10-1.1.2.1 11-1.1.2 12-1 13-1.2.3 14-1.2 16-1.2.2 17-1.2.2.2.1.1.1.1 18-1.2.2.2.1 19-1.2.2.2.1.2.1.1 21-1.2.2.2.2.1 23-1.2.2.2.2.1 24-1.2.2.2.2 26-1.2.2.1.1.1 27-1.2.2.1.1.1.r 29-1.2.2.1.1.2.1.1 30-1.2.2.1.1.2.1 31-1.2.2.1.1 32-1.2.2.1 34-1.2.2.1.2 35-1.2.2.1.2.2.r 36-1.2.2.1.2.2.2.1 38-1.2.2.1.2.2.2 39-1.2.2.1.2.2 42-1.3.1 (a / and~e.12 :op1 (p / perform-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a2 / assay-01~e.11 :ARG1 (c / clonogenic~e.10) :duration~e.3,5 (l / long-03~e.3 :ARG1-of (m2 / mean-01 :ARG2 (t / temporal-quantity :quant 14~e.7 :unit (d / day~e.8))))) :time (n / next~e.1)) :op2 (f / find-01~e.14 :ARG0 w :ARG1 (h / have-concession-91~e.16 :ARG1 (r / retain-01~e.32 :ARG0 (c2 / cell-line~e.31 :quant~e.27 (m / most~e.26) :ARG1-of (i3 / include-91 :ARG2 (c3 / cell-line~e.30 :ARG1-of (t2 / treat-04~e.29)))) :ARG1 (l2 / level~e.34 :ARG1-of (v / vary-01) :degree-of~e.35 (c4 / capable-01~e.39 :ARG1 c2 :ARG2 (f2 / form-01~e.38 :ARG1 (c5 / colony~e.36))))) :ARG2 (s / synergize-01 :ARG0 (a4 / and~e.18 :op1 (s2 / small-molecule :name (n2 / name :op1 "PLX4720"~e.17)) :op2 (s3 / small-molecule :name (n3 / name :op1 "Gefitinib"~e.19))) :ARG2 (i / inhibit-01~e.24 :ARG1 (g / grow-in-00~e.21,23)))) :mod (a3 / again~e.13)) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.42 :mod "7C"))) # ::id pmid_2384_5441.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To identify alternative drugs with effectiveness across cell lines , we performed high @-@ throughput drug screening . # ::alignments 1-1.3 2-1.3.2.1 3-1.3.2 4-1.3.2.2.r 5-1.3.2.2 6-1.3.2.2.1 7-1.3.2.2.1.1 8-1.3.2.2.1.1 10-1.1 11-1 12-1.2.2.1 14-1.2.2 15-1.2.1 16-1.2 (p / perform-01~e.11 :ARG0 (w / we~e.10) :ARG1 (s / screen-01~e.16 :ARG1 (d / drug~e.15) :manner (t / throughput~e.14 :ARG1-of (h / high-02~e.12))) :purpose (i / identify-01~e.1 :ARG0 w :ARG1 (d2 / drug~e.3 :mod (a / alternative~e.2) :ARG0-of~e.4 (e / effective-04~e.5 :ARG1 (a2 / across~e.6 :op1 (c / cell-line~e.7,8)))))) # ::id pmid_2384_5441.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We tested a large set of compounds inhibiting a broad range of molecules , pathways , and biologic processes ( Figure 7 @ B ; Table S7 ) . # ::alignments 0-1.1 1-1 3-1.2.1 4-1.2 5-1.2.2.r 6-1.2.2 7-1.2.3 9-1.2.3.1.4.1 10-1.2.3.1.4 11-1.2.3.1.r 12-1.2.3.1.1 14-1.2.3.1.2 16-1.2.3.1 18-1.2.3.1.3 21-1.3.1.1 27-1.3.1.2 28-1.3.1.2.1 (t / test-01~e.1 :ARG0 (w / we~e.0) :ARG1 (s / set~e.4 :mod (l / large~e.3) :consist-of~e.5 (c / compound~e.6) :ARG0-of (i / inhibit-01~e.7 :ARG1~e.11 (a / and~e.16 :op1 (m / molecule~e.12) :op2 (p / pathway~e.14) :op3 (p2 / process-01~e.18 :ARG1 (b2 / biology)) :ARG1-of (r / range-01~e.10 :ARG1-of (b / broad-02~e.9))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.21 :mod "7B") :op2 (t2 / table~e.27 :mod "S7"~e.28)))) # ::id pmid_2384_5441.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All compounds were tested alone or in combination with PLX4720 and for each cell line we performed 100 different short @-@ term ( 6 day ) sensitivity assays . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 6-1.1.2.r 7-1.1.2.2 8-1.1.2.2.2.r 9-1.1.2.2.2.1.1 10-1 12-1.2.3.1 13-1.2.3 14-1.2.3 15-1.2.1 16-1.2 17-1.2.2.1 18-1.2.2.3 19-1.2.2.4 23-1.2.2.4.1.1.1 24-1.2.2.4.1.1.2 26-1.2.2.2 27-1.2.2 (a / and~e.10 :op1 (t2 / test-01~e.3 :ARG1 (c / compound~e.1 :mod (a2 / all~e.0)) :manner~e.6 (o / or~e.5 :op1 (a3 / alone~e.4) :op2 (c2 / combine-01~e.7 :ARG1 c :ARG2~e.8 (s / small-molecule :name (n / name :op1 "PLX4720"~e.9))))) :op2 (p / perform-01~e.16 :ARG0 (w / we~e.15) :ARG1 (a4 / assay-01~e.27 :quant 100~e.17 :ARG1 (s2 / sensitive-03~e.26) :ARG1-of (d2 / differ-02~e.18) :ARG1-of (s4 / short-07~e.19 :ARG1-of (m / mean-01 :ARG2 (t / temporal-quantity :quant 6~e.23 :unit (d / day~e.24))))) :beneficiary (c3 / cell-line~e.13,14 :mod (e / each~e.12)))) # ::id pmid_2384_5441.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These screens revealed several treatment approaches that were highly effective ( Figure 7 @ B ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.2 4-1.2.1 5-1.2 8-1.2.3.1 9-1.2.3 12-1.3.1 (r / reveal-01~e.2 :ARG0 (s / screen-01~e.1 :mod (t / this~e.0)) :ARG1 (a / approach-02~e.5 :ARG2 (t2 / treat-04~e.4) :quant (s2 / several~e.3) :ARG1-of (e / effective-04~e.9 :ARG1-of (h / high-02~e.8))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.12 :mod "7B"))) # ::id pmid_2384_5441.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PD0325901 , a Mek inhibitor , was the most effective single compound across cell lines in the short @-@ term assays ( Figure 7 @ B ) . # ::alignments 0-1.4.1.1 3-1.4.2.1.1.1 4-1.4 4-1.4.2 4-1.4.2.r 6-1.4.r 8-1.3.1 9-1.3 10-1.2 11-1 12-1.3.3 13-1.3.3.1 14-1.3.3.1 15-1.3.2.r 17-1.3.2.1 20-1.3.2 23-1.1.1 (c / compound~e.11 :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "7B")) :ARG1-of (s4 / single-02~e.10) :ARG1-of (e2 / effective-04~e.9 :mod (m / most~e.8) :time~e.15 (a / assay-01~e.20 :ARG1-of (s2 / short-07~e.17)) :location (a2 / across~e.12 :op1 (c2 / cell-line~e.13,14))) :domain~e.6 (s / small-molecule~e.4 :name (n2 / name :op1 "PD0325901"~e.0) :ARG0-of~e.4 (i2 / inhibit-01~e.4 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.3))))) # ::id pmid_2384_5441.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the long @-@ term clonogenic assay , it induced complete inhibition of colony @-@ forming capacity in five of six cell lines and partial inhibition in the remaining line RKO ( Figure 7 @ C ) . # ::alignments 2-1.4.2 2-1.4.2.r 4-1.4.2.r 5-1.4.1 6-1.4 8-1.1 9-1 10-1.2.1.2 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1.1 15-1.2.1.1.1 16-1.2.1.1 17-1.2.1.3.r 18-1.2.1.3.1 20-1.2.1.3.2.1.1 21-1.2.1.3 21-1.2.1.3.2.1 22-1.2.1.3.2.1 23-1.2 24-1.2.2.2 24-1.2.2.2.r 25-1.2.2 26-1.2.2.1.r 28-1.2.2.1.2 29-1.2.2.1 30-1.2.2.1.1.1 33-1.3.1 (i / induce-01~e.9 :ARG0 (i3 / it~e.8) :ARG2 (a / and~e.23 :op1 (i2 / inhibit-01~e.11 :ARG1~e.12 (c / capable-01~e.16 :ARG2 (f / form-01~e.15 :ARG1 (c2 / colony~e.13))) :ARG1-of (c3 / complete-01~e.10) :location~e.17 (c4 / cell-line~e.21 :quant 5~e.18 :ARG1-of (i4 / include-91 :ARG2 (c5 / cell-line~e.21,22 :quant 6~e.20)))) :op2 (i5 / inhibit-01~e.25 :location~e.26 (c6 / cell-line~e.29 :name (n / name :op1 "RKO"~e.30) :ARG1-of (r / remain-01~e.28)) :degree~e.24 (p / part~e.24))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.33 :mod "7C")) :time (a2 / assay-01~e.6 :ARG1 (c7 / clonogenic~e.5) :duration~e.2,4 (l / long-03~e.2))) # ::id pmid_2384_5441.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PI3K inhibitor GDC0941 was not effective as a single agent , but induced potent inhibition in combination with PLX4720 across cell lines ( Figures 7 @ B and 7C ) . # ::alignments 1-1.1.2.2.1.1.1 2-1.1.2 2-1.1.2.2 2-1.1.2.2.r 3-1.1.2.1.1 5-1.1.1 5-1.1.1.r 6-1.1 7-1.1.3.r 9-1.1.3.1 10-1.1.3 12-1 13-1.2 14-1.2.2.1 15-1.2.2 16-1.2.3.r 17-1.2.3 18-1.2.3.2.r 19-1.2.3.2.1.1 20-1.2.4 21-1.2.4.1 22-1.2.4.1 25-1.3.1.1 25-1.3.1.2 29-1.3.1 30-1.3.1.2.1 (c / contrast-01~e.12 :ARG1 (e / effective-04~e.6 :polarity~e.5 -~e.5 :ARG0 (s / small-molecule~e.2 :name (n / name :op1 "GDC0941"~e.3) :ARG0-of~e.2 (i2 / inhibit-01~e.2 :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"~e.1)))) :manner~e.7 (a / agent~e.10 :ARG1-of (s2 / single-02~e.9))) :ARG2 (i3 / induce-01~e.13 :ARG0 s :ARG2 (i4 / inhibit-01~e.15 :mod (p / potent~e.14)) :manner~e.16 (c2 / combine-01~e.17 :ARG1 s :ARG2~e.18 (s3 / small-molecule :name (n3 / name :op1 "PLX4720"~e.19))) :location (a2 / across~e.20 :op1 (c3 / cell-line~e.21,22))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.29 :op1 (f / figure~e.25 :mod "7B") :op2 (f2 / figure~e.25 :mod "7C"~e.30)))) # ::id pmid_2384_5441.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Some other drug combinations strongly inhibited selected cell lines , although they were not broadly effective across tumors . # ::alignments 0-1.1.1.2 1-1.1.1.3 2-1.1.1.1 3-1.1.1 4-1.1.3 5-1.1 6-1.1.2.1 7-1.1.2 8-1.1.2 10-1 11-1.2.2 13-1.2.1 13-1.2.1.r 14-1.2.4 15-1.2 16-1.2.3 17-1.2.3.1 (h / have-concession-91~e.10 :ARG1 (i / inhibit-01~e.5 :ARG0 (c / combine-01~e.3 :ARG1 (d / drug~e.2) :mod (s / some~e.0) :mod (o / other~e.1)) :ARG1 (c2 / cell-line~e.7,8 :ARG1-of (s3 / select-01~e.6)) :ARG1-of (s2 / strong-02~e.4)) :ARG2 (e / effective-04~e.15 :polarity~e.13 -~e.13 :ARG0 c~e.11 :ARG1 (a / across~e.16 :op1 (t / tumor~e.17)) :ARG1-of (b / broad-02~e.14))) # ::id pmid_2384_5441.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , the combination of PLX4720 plus the kinase inhibitor VX @-@ 680 was the most potent drug combination for the treatment of RKO , a highly resistant cell line to most other drugs . # ::alignments 0-1.4 1-1.4 4-1 5-1.1.r 6-1.1.1.1 9-1.2.2.1 10-1.2 10-1.2.2 10-1.2.2.r 11-1.2.1.1 13-1.2.1.1 14-1.3.r 16-1.3.2.1 17-1.3.2 18-1.3.1 19-1.3 20-1.3.3.r 22-1.3.3 23-1.3.3.1.r 24-1.3.3.1.1.1 27-1.3.3.1.2.2 28-1.3.3.1.2 29-1.3.3.1 30-1.3.3.1 31-1.3.3.1.2.1.r 32-1.3.3.1.2.1.2 33-1.3.3.1.2.1.1 34-1.3.3.1.2.1 (c2 / combine-01~e.4 :ARG1~e.5 (s / small-molecule :name (n / name :op1 "PLX4720"~e.6)) :ARG2 (s2 / small-molecule~e.10 :name (n2 / name :op1 "VX-680"~e.11,13) :ARG0-of~e.10 (i / inhibit-01~e.10 :ARG1 (k / kinase~e.9))) :domain~e.14 (c / combine-01~e.19 :mod (d / drug~e.18) :mod (p / potent~e.17 :degree (m / most~e.16)) :ARG2-of~e.20 (t2 / treat-04~e.22 :ARG1~e.23 (c3 / cell-line~e.29,30 :name (n3 / name :op1 "RKO"~e.24) :ARG0-of (r / resist-01~e.28 :ARG1~e.31 (d2 / drug~e.34 :mod (o / other~e.33) :mod m~e.32) :ARG1-of (h / high-02~e.27))))) :ARG1-of (e / exemplify-01~e.0,1)) # ::id pmid_2384_5441.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This shows the power of systematic drug screening to identify patient @-@ specific treatment approaches even for highly resistant tumors . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1.1 6-1.2.1.1 7-1.2.1 9-1.2.1.2 10-1.2.1.2.1.1.1.1 12-1.2.1.2.1.1 13-1.2.1.2.1.1.1 14-1.2.1.2.1 15-1.2.1.2.2.2 17-1.2.1.2.2.1.1 18-1.2.1.2.2.1 19-1.2.1.2.2 (s / show-01~e.1 :ARG0 (t / this~e.0) :ARG1 (p / power~e.3 :poss~e.4 (s3 / screen-01~e.7 :ARG1 (d / drug~e.6 :mod (s2 / systematic~e.5)) :ARG2 (i / identify-01~e.9 :ARG1 (a / approach-02~e.14 :ARG1-of (s4 / specific-02~e.12 :ARG2 (t2 / treat-04~e.13 :ARG1 (p2 / patient~e.10)))) :beneficiary (t3 / tumor~e.19 :ARG0-of (r / resist-01~e.18 :ARG1-of (h / high-02~e.17)) :mod (e / even~e.15)))))) # ::id pmid_2384_5441.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Another example is the combination of the Chk1 @/@ 2 inhibitor AZD @-@ 7762 plus PLX4720 , which was very effective in MouseT1 , HT @-@ 29 , LS411N , and COLO @-@ 205 and could potentially be a broadly effective alternative first @-@ line or second @-@ line combination . # ::alignments 0-1.1.3.1 1-1.1.3 4-1.1 5-1.1.1.r 7-1.1.1.2.1.1.1 9-1.1.1.2.1.1.1 10-1.1.1 10-1.1.1.2 10-1.1.1.2.r 11-1.1.1.1.1 13-1.1.1.1.1 14-1.1.4.1 15-1.1.2.1.1 19-1.1.4.2 20-1.1.4 21-1.1.4.1.r 22-1.1.4.1.1.1.1 24-1.1.4.1.2.1.1 26-1.1.4.1.2.1.1 28-1.1.4.1.3.1.1 31-1.1.4.1.4.1.1 33-1.1.4.1.4.1.1 34-1 34-1.1.4.1 35-1.2 36-1.2.2 37-1.2.1.4.r 39-1.2.1.3.1 40-1.2.1.3 41-1.2.1.1.1 42-1.2.1.1.2.1 42-1.2.1.1.2.1.1 42-1.2.1.1.2.1.1.r 44-1.2.1.1.2 45-1.2.1 46-1.2.1.2.2.1 46-1.2.1.2.2.1.1 46-1.2.1.2.2.1.1.r 48-1.2.1.1.2 48-1.2.1.2.2 49-1.2.1.1 49-1.2.1.2 (a / and~e.34 :op1 (c / combine-01~e.4 :ARG1~e.5 (s / small-molecule~e.10 :name (n / name :op1 "AZD-7762"~e.11,13) :ARG0-of~e.10 (i2 / inhibit-01~e.10 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Chk1/2"~e.7,9)))) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PLX4720"~e.15)) :ARG1-of (e3 / exemplify-01~e.1 :mod (a2 / another~e.0)) :ARG0-of (e / effective-04~e.20 :ARG1~e.21 (a3 / and~e.14,34 :op1 (c2 / cell-line :name (n4 / name :op1 "MouseT1"~e.22)) :op2 (c3 / cell-line :name (n5 / name :op1 "HT-29"~e.24,26)) :op3 (c4 / cell-line :name (n6 / name :op1 "LS411N"~e.28)) :op4 (c5 / cell-line :name (n7 / name :op1 "COLO-205"~e.31,33))) :degree (v / very~e.19))) :op2 (p2 / possible-01~e.35 :ARG1 (o / or~e.45 :op1 (c6 / combine-01~e.49 :mod (a4 / alternative~e.41) :mod (l / line~e.44,48 :ord (o2 / ordinal-entity~e.42 :value~e.42 1~e.42))) :op2 (c7 / combine-01~e.49 :mod a4 :mod (l2 / line~e.48 :ord (o3 / ordinal-entity~e.46 :value~e.46 2~e.46))) :ARG1-of (e4 / effective-04~e.40 :ARG1-of (b / broad-02~e.39)) :domain~e.37 c) :mod (p3 / potential~e.36))) # ::id pmid_2384_5441.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In Vivo Validation of Mek and Combinatorial Braf @/@ PI3K Inhibition # ::alignments 1-1.1.2 2-1.1.2 3-1.1 4-1.1.1.r 5-1.1.1.1.1 6-1 8-1.2.1.1.1.1 10-1.2.1.2.1.1 11-1.2 (a / and~e.6 :op1 (v / validate-01~e.3 :ARG1~e.4 (e / enzyme :name (n / name :op1 "MEK"~e.5)) :manner (i / in-vivo~e.1,2)) :op2 (i4 / inhibit-01~e.11 :ARG1 (c / combine-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Braf"~e.8)) :ARG2 (e3 / enzyme :name (n3 / name :op1 "PI3K"~e.10))))) # ::id pmid_2384_5441.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To study the effectiveness of broadly effective drug combinations in vivo , we first transplanted mouse and human cell lines subcutaneously ( s.c.) into immunodeficient Nod Scid IL12R @-@ gamma null ( NSG ) mice and assessed their response to PD0325901 . # ::alignments 1-1.3 3-1.3.2 4-1.3.2.1.r 5-1.3.2.1.3.1 6-1.3.2.1.3 7-1.3.2.1.1 8-1.3.2.1 9-1.3.2.1.2 10-1.3.2.1.2 12-1.1.1 13-1.1.4 14-1.1 15-1.1.2.1.1 16-1.1.2 17-1.1.2.2.1 18-1.1.2.1 18-1.1.2.2 19-1.1.2.2 20-1.1.5 20-1.1.5.r 23-1.1.3.r 24-1.1.3.2 32-1.1.3.1.1 34-1.1.2.1.1 34-1.1.3.1.2 35-1 36-1.2 38-1.2.2 39-1.2.2.2.r 40-1.2.2.2.1.1 (a / and~e.35 :op1 (t / transplant-01~e.14 :ARG0 (w / we~e.12) :ARG1 (a2 / and~e.16 :op1 (c / cell-line~e.18 :mod (m / mouse~e.15,34)) :op2 (c2 / cell-line~e.18,19 :mod (h / human~e.17))) :ARG2~e.23 (o / organism :name (n / name :op1 "NSG"~e.32 :op2 "mouse"~e.34) :mod (i / immunodeficient~e.24)) :time (f / first~e.13) :manner~e.20 (s / subcutaneous~e.20)) :op2 (a3 / assess-01~e.36 :ARG0 w :ARG1 (r / respond-01~e.38 :ARG0 a2 :ARG1~e.39 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"~e.40)))) :purpose (s3 / study-01~e.1 :ARG0 w :ARG1 (e / effective-04~e.3 :ARG0~e.4 (c3 / combine-01~e.8 :mod (d / drug~e.7) :manner (i2 / in-vivo~e.9,10) :ARG0-of (e2 / effective-04~e.6 :ARG1-of (b / broad-02~e.5)))))) # ::id pmid_2384_5441.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment was started 7 @–@ 14 days after s.c . injection of cells as soon as tumors were palpable . # ::alignments 0-1.1 2-1 3-1.2.2.1.1 5-1.2.2.2.1 6-1.2.2.1.2 6-1.2.2.2.2 7-1.2 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1 13-1.2.1.3 13-1.2.1.3.r 14-1.2.1.3 15-1.2.1.3 15-1.2.1.3.r 16-1.2.1.3.1.1 17-1.2.1.3.1.1.r 18-1.2.1.3.1 (s / start-01~e.2 :ARG1 (t2 / treat-04~e.0) :time (a / after~e.7 :op1 (i / inject-01~e.10 :ARG1~e.11 (c / cell~e.12) :manner (s2 / subcutaneous) :time~e.13,15 (a2 / as-soon-as~e.13,14,15 :op1 (p / palpable~e.18 :domain~e.17 (t4 / tumor~e.16)))) :quant (v / value-interval :op1 (t3 / temporal-quantity :quant 7~e.3 :unit (d2 / day~e.6)) :op2 (t / temporal-quantity :quant 14~e.5 :unit (d / day~e.6))))) # ::id pmid_2384_5441.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Animals were given PD0325901 or vehicle by oral gavage for 13 @–@ 15 days . # ::alignments 0-1.2 2-1 3-1.1.1.1.1 4-1.1 5-1.1.2 6-1.3.r 7-1.3.1 8-1.3 9-1.4.r 10-1.4.1.1 12-1.4.2.1 13-1.4.1.2 13-1.4.2.2 (g / give-01~e.2 :ARG1 (o / or~e.4 :op1 (s / small-molecule :name (n / name :op1 "PD0325901"~e.3)) :op2 (v / vehicle~e.5)) :ARG2 (a / animal~e.0) :manner~e.6 (g2 / gavage~e.8 :mod (o2 / oral~e.7)) :duration~e.9 (v2 / value-interval :op1 (t2 / temporal-quantity :quant 13~e.10 :unit (d2 / day~e.13)) :op2 (t / temporal-quantity :quant 15~e.12 :unit (d / day~e.13)))) # ::id pmid_2384_5441.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PD0325901 was highly effective , causing regression of tumors from all tested cell lines ( Figure 7 @ D ) . # ::alignments 0-1.1.1.1 2-1.2 3-1 5-1.3 8-1.3.1.1 9-1.3.1.1.1.r 10-1.3.1.1.1.2 11-1.3.1.1.1.1 12-1.3.1.1.1 13-1.3.1.1.1 16-1.4.1 (e / effective-04~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"~e.0)) :ARG1-of (h / high-02~e.2) :ARG0-of (c / cause-01~e.5 :ARG1 (r / regress-01 :ARG1 (t / tumor~e.8 :source~e.9 (c2 / cell-line~e.12,13 :ARG1-of (t2 / test-01~e.11) :mod (a / all~e.10))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "7D"))) # ::id pmid_2384_5441.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figures S6 @ A and S6B show that after 13 @–@ 15 days of PD0325901 treatment there was complete inhibition of ERK phosphorylation in surviving tumor cells and that only very few scattered Ki67 @-@ positive cancer cells could still be observed in the necrotic tumor mass. # ::alignments 1-1.1.1 1-1.1.2 5-1.1 6-1.1.2.1 7-1 8-1.2.r 9-1.2.1.3 10-1.2.1.3.2.1.1 12-1.2.1.3.2.2.1 13-1.2.1.3.2.1.2 13-1.2.1.3.2.2.2 14-1.2.1.3.1.r 15-1.2.1.3.1.1.1.1 16-1.2.1.3.1 19-1.2.1.2 20-1.2.1 21-1.2.1.1.r 22-1.2.1.1.1.1.1 23-1.2.1.1 24-1.2.1.4.r 25-1.2.1.4.2 26-1.2.1.4.1 27-1.2.1.4 28-1.2 29-1.2.r 30-1.2.2.1.1.3.1 32-1.2.2.1.1.3 33-1.2.2.1.1.2 34-1.2.2.1.1.1.1.1 36-1.2.2.1.1.1.2 37-1.2.2.1.1.4.2.1 38-1.2.2.1.1 39-1.2.2 40-1.2.2.1.3 42-1.2.2.1 45-1.2.2.1.2.2 46-1.2.1.4.1 46-1.2.2.1.2.1 (s / show-01~e.7 :ARG0 (a / and~e.5 :op1 (f / figure~e.1 :mod "S6A") :op2 (f2 / figure~e.1 :mod "S6B"~e.6)) :ARG1~e.8,29 (a2 / and~e.28 :op1 (i / inhibit-01~e.20 :ARG1~e.21 (p / phosphorylate-01~e.23 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.22))) :ARG1-of (c / complete-01~e.19) :time (a3 / after~e.9 :op1~e.14 (t2 / treat-04~e.16 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD0325901"~e.15))) :quant (v / value-interval :op1 (t3 / temporal-quantity :quant 13~e.10 :unit (d3 / day~e.13)) :op2 (t / temporal-quantity :quant 15~e.12 :unit (d / day~e.13)))) :location~e.24 (c2 / cell~e.27 :mod (t4 / tumor~e.26,46) :ARG0-of (s3 / survive-01~e.25))) :op2 (p3 / possible-01~e.39 :ARG1 (o / observe-01~e.42 :ARG1 (c3 / cell~e.38 :mod (p4 / protein :name (n4 / name :op1 "Ki67"~e.34) :mod (p2 / positive~e.36)) :ARG1-of (s4 / scatter-01~e.33) :quant (f3 / few~e.32 :mod (o2 / only~e.30)) :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.37))) :location (m / mass-01 :ARG0 (t5 / tumor~e.46) :mod (n5 / necrosis~e.45)) :mod (s5 / still~e.40))))) # ::id pmid_2384_5441.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next performed orthotopic transplantation of mouse and human Braf mutant cancer cell lines into the cecum of NSG mice . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.4 4-1.2 5-1.2.3.r 6-1.2.3.1.1.2 7-1.2.2 8-1.2.2.2.2 10-1.2.2.1.1.1.1 12-1.2.2.1.1 12-1.2.2.1.1.2 12-1.2.2.1.1.2.r 13-1.2.2.1.3.2.1 14-1.2.2.2 15-1.2.2.1 18-1.2.3 20-1.2.3.1.1.1 21-1.2.2.1.2 21-1.2.3.1.1.2 (p / perform-01~e.2 :ARG0 (w / we~e.0) :ARG1 (t / transplant-01~e.4 :ARG0 w :ARG1 (a / and~e.7 :op1 (c / cell-line~e.15 :mod (g / gene~e.12 :name (n4 / name :op1 "Braf"~e.10) :ARG2-of~e.12 (m / mutate-01~e.12)) :mod (m2 / mouse~e.21) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.13))) :op2 (c3 / cell-line~e.14 :mod g :mod (h / human~e.8) :mod d)) :ARG2~e.5 (c4 / cecum~e.18 :part-of (o / organism :name (n2 / name :op1 "NSG"~e.20 :op2 "mouse"~e.6,21))) :mod (o2 / orthotopic~e.3)) :time (n3 / next~e.1)) # ::id pmid_2384_5441.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fourteen days later , treatment was started with either vehicle or PD0325901 . # ::alignments 0-1.2.1.1.1 1-1.2.1.1.2 2-1.2 2-1.2.1 2-1.2.1.r 4-1.1 6-1 9-1.1.1.1 10-1.1.1 11-1.1.1.2.1.1 (s / start-01~e.6 :ARG1 (t2 / treat-04~e.4 :ARG2 (o / or~e.10 :op1 (v / vehicle~e.9) :op2 (s2 / small-molecule :name (n / name :op1 "PD0325901"~e.11)))) :time (l3 / late~e.2 :degree~e.2 (m3 / more~e.2 :quant (t / temporal-quantity :quant 14~e.0 :unit (d / day~e.1))))) # ::id pmid_2384_5441.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mice were sacrificed after 17 days of treatment . # ::alignments 0-1.1 2-1 3-1.2 4-1.2.2.1 5-1.2.2.2 6-1.2.1.r 7-1.2.1 (s / sacrifice-01~e.2 :ARG1 (m / mouse~e.0) :time (a / after~e.3 :op1~e.6 (t2 / treat-01~e.7) :quant (t / temporal-quantity :quant 17~e.4 :unit (d / day~e.5)))) # ::id pmid_2384_5441.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figures S6 @ C @–@ S6E show that vehicle @-@ treated mice developed large tumors , which metastasized to local lymph nodes and the peritoneum , causing hemorrhagic ascites . # ::alignments 1-1.1.1 1-1.1.2 6-1.1.2.1 7-1 8-1.2.r 9-1.2.1.1.1 11-1.2.1.1 12-1.2.1 13-1.2 14-1.2.2.1 15-1.2.2 18-1.2.2.2 19-1.2.2.2.1.r 19-1.2.2.2.2 20-1.2.2.2.1.1.2 21-1.2.2.2.1.1.1 22-1.2.2.2.1.1 23-1.2.2.2.1 25-1.2.2.2.1.2 27-1.2.2.2.2 28-1.2.2.2.2.1.1 (s / show-01~e.7 :ARG0 (v / value-interval :op1 (f / figure~e.1 :mod "S6C") :op2 (f2 / figure~e.1 :mod "S6E"~e.6)) :ARG1~e.8 (d / develop-01~e.13 :ARG1 (m / mouse~e.12 :ARG1-of (t / treat-04~e.11 :ARG2 (v2 / vehicle~e.9))) :ARG2 (t2 / tumor~e.15 :mod (l / large~e.14) :ARG1-of (m2 / metastasize-101~e.18 :ARG2~e.19 (a / and~e.23 :op1 (n / node~e.22 :mod (l2 / lymph~e.21) :ARG1-of (l3 / local-02~e.20)) :op2 (p / peritoneum~e.25)) :ARG0-of (c / cause-01~e.19,27 :ARG1 (a2 / ascite :mod (h / hemorrhagic~e.28))))))) # ::id pmid_2384_5441.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , in the PD0325901 @-@ treated group , tumors were either not detectable or small ( maximum 0.01 cm @³ ) . # ::alignments 1-1 3-1.1.r 5-1.1.3.1.1.1.1 7-1.1.3.1 8-1.1.3 10-1.1.1.1 10-1.1.2.1 11-1.1.2.1.r 13-1.1.1.2.1 13-1.1.1.2.1.r 14-1.1.1 15-1.1 16-1.1.2 18-1.1.2.1.1.1 19-1.1.2.1.1.1.1.1 20-1.1.2.1.1.1.1.2 (c / contrast-01~e.1 :ARG2~e.3 (o / or~e.15 :op1 (d / detect-01~e.14 :ARG1 (t / tumor~e.10) :ARG1-of (p / possible-01 :polarity~e.13 -~e.13)) :op2 (s / small~e.16 :domain~e.11 (t2 / tumor~e.10 :ARG1-of (m / mean-01 :ARG2 (m2 / maximum~e.18 :op1 (v / volume-quantity :quant 0.01~e.19 :unit (c2 / cubic-centimeter~e.20)))))) :location (g / group~e.8 :ARG1-of (t3 / treat-04~e.7 :ARG2 (s2 / small-molecule :name (n / name :op1 "PD0325901"~e.5)))))) # ::id pmid_2384_5441.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the effect of PD0325901 on proliferation in endogenous Braf @^V637E@ -@ induced tumors , we performed short @-@ term treatments ( 5 days ) of Vil @-@ Cre ; Braf @ ^{LSL @-@ V637E @ /+} mice . # ::alignments 1-1.3 3-1.3.2 4-1.3.2.1.r 5-1.3.2.1.1.1 6-1.3.2.2.r 7-1.3.2.2 8-1.3.2.2.1.r 9-1.3.2.2.1.2 10-1.3.2.2.1.1.1.1.1 12-1.3.2.2.1.1.1.2.1 15-1.3.2.2.1.1 16-1.3.2.2.1 18-1.1 19-1 20-1.2.2 23-1.2 25-1.2.2.1.1.1 26-1.2.2.1.1.2 30-1.2.1.1.1.1.1 32-1.2.1.1.2.1.1 34-1.2.1.2.1.1 38-1.2.1.2.2.1 40-1.2.1.2.2.1 44-1.2.1 (p / perform-01~e.19 :ARG0 (w / we~e.18) :ARG1 (t2 / treat-04~e.23 :ARG1 (m7 / mouse~e.44 :mod (m / macro-molecular-complex :part (p2 / protein :name (n / name :op1 "Vil"~e.30)) :part (e4 / enzyme :name (n2 / name :op1 "Cre"~e.32))) :mod (e / enzyme :name (n3 / name :op1 "Braf"~e.34) :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+"~e.38,40))) :ARG1-of (s3 / short-07~e.20 :ARG1-of (m2 / mean-01 :ARG2 (t / temporal-quantity :quant 5~e.25 :unit (d / day~e.26))))) :purpose (e2 / examine-01~e.1 :ARG0 w :ARG1 (a2 / affect-01~e.3 :ARG0~e.4 (s2 / small-molecule :name (n4 / name :op1 "PD0325901"~e.5)) :ARG1~e.6 (p4 / proliferate-01~e.7 :ARG0~e.8 (t3 / tumor~e.16 :ARG2-of (i / induce-01~e.15 :ARG0 (e3 / enzyme :name (n5 / name :op1 "Braf"~e.10) :ARG2-of (m4 / mutate-01 :value "V637E"~e.12))) :mod (m5 / monocot~e.9)))))) # ::id pmid_2384_5441.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We used animals that were more than 1 year of age and were expected to have tumors . # ::alignments 0-1.1 1-1 2-1.2.1 5-1.2.1.1 6-1.2.1.1 7-1.2.1.1.1.1 8-1.2.1.1.1.2 10-1.2.1.1.r 11-1.2 13-1.2.2 15-1.2.2.1 16-1.2.2.1.2 (u / use-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a3 / and~e.11 :op1 (a / animal~e.2 :age~e.10 (m2 / more-than~e.5,6 :op1 (t / temporal-quantity :quant 1~e.7 :unit (y / year~e.8)))) :op2 (e / expect-01~e.13 :ARG1 (h / have-03~e.15 :ARG0 a :ARG1 (t2 / tumor~e.16))))) # ::id pmid_2384_5441.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figures S6 @ F and S6G show that Ki67 immunoreactivity was weak in the majority of dysplastic cells in PD0325901 @-@ treated mice but was strong in tumors of vehicle @-@ treated animals . # ::alignments 1-1.1.1 1-1.1.2 6-1.1.2.1 7-1 8-1.2.r 9-1.2.1.1.1.1.1 12-1.2.1 13-1.2.1.3.r 15-1.2.1.3.1 16-1.2.1.3.1.r 17-1.2.1.3.2 18-1.2.1.3 19-1.2.1.2.r 20-1.2.1.2.1.1.1.1 22-1.2.1.2.1 23-1.2.1.2 24-1.2 26-1.2.2 29-1.2.2.2.r 30-1.2.2.2.1.1 32-1.2.2.2.1 33-1.2.2.2 (s / show-01~e.7 :ARG0 (v / value-interval :op1 (f / figure~e.1 :mod "S6F") :op2 (f2 / figure~e.1 :mod "S6G"~e.6)) :ARG1~e.8 (c / contrast-01~e.24 :ARG1 (w / weak-02~e.12 :ARG1 (i / immunoreact-00 :ARG1 (p / protein :name (n / name :op1 "Ki67"~e.9))) :location~e.19 (m2 / mouse~e.23 :ARG1-of (t / treat-04~e.22 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"~e.20)))) :location~e.13 (c2 / cell~e.18 :quant~e.16 (m / majority~e.15) :mod (d / dysplastic~e.17))) :ARG2 (s3 / strong-02~e.26 :ARG1 i :location~e.29 (a / animal~e.33 :ARG1-of (t2 / treat-01~e.32 :ARG2 (v2 / vehicle~e.30)))))) # ::id pmid_2384_5441.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All together , these data show that Mek inhibition is effective in the treatment of Braf @-@ induced intestinal tumors in vivo . # ::alignments 0-1.3.1 1-1.3 3-1.1.1 4-1.1 5-1 6-1.2.r 7-1.2.1.1.1.1 8-1.2.1 10-1.2 11-1.2.2.2 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.2.1.1.1 17-1.2.2.1.2 18-1.2.2.1.1 19-1.2.2.1 20-1.2.2.2 21-1.2.2.2 (s / show-01~e.5 :ARG0 (d / data~e.4 :mod (t / this~e.3)) :ARG1~e.6 (e2 / effective-04~e.10 :ARG0 (i / inhibit-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.7))) :ARG1 (t2 / treat-04~e.13 :ARG1~e.14 (t3 / tumor~e.19 :mod (i2 / intestine~e.18) :ARG2-of (i3 / induce-01~e.17 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Braf"~e.15)))) :manner (i4 / in-vivo~e.11,20,21))) :mod (t4 / together~e.1 :mod (a / all~e.0))) # ::id pmid_2384_5441.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To examine the effectiveness of combinatorial Braf @/@ PI3K inhibition in vivo we treated s.c . transplanted murine and human cell lines with a combination of PLX4720 and GDC0941 or vehicle . # ::alignments 1-1.4 3-1.4.2 6-1.4.2.1.1.1.1.1 8-1.4.2.1.1.2.1.1 9-1.4.2.1 10-1.4.2.1.2 11-1.4.2.1.2 12-1.1 13-1 16-1.2.1.1 17-1.2.1.2.1.1 18-1.2 19-1.2.2.1 20-1.2.1 20-1.2.2 21-1.2.2 24-1.3 24-1.4.2.1.1 25-1.3.1.r 26-1.3.1.1.1 28-1.3.2.1.1.1 29-1.3.2 30-1.3.2.2 (t / treat-04~e.13 :ARG0 (w / we~e.12) :ARG1 (a / and~e.18 :op1 (c / cell-line~e.20 :ARG1-of (t2 / transplant-01~e.16 :manner (s / subcutaneous)) :mod (o2 / organism :name (n5 / name :op1 "Muridae"~e.17))) :op2 (c2 / cell-line~e.20,21 :mod (h / human~e.19) :ARG1-of t2)) :ARG2 (c3 / combine-01~e.24 :ARG1~e.25 (s2 / small-molecule :name (n / name :op1 "PLX4720"~e.26)) :ARG2 (o / or~e.29 :op1 (s3 / small-molecule :name (n2 / name :op1 "GDC0941"~e.28)) :op2 (v / vehicle~e.30))) :purpose (e / examine-01~e.1 :ARG0 w :ARG1 (e2 / effective-04~e.3 :ARG0 (i / inhibit-01~e.9 :ARG1 (c4 / combine-01~e.24 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Braf"~e.6)) :ARG2 (e4 / enzyme :name (n4 / name :op1 "PI3K"~e.8))) :manner (i2 / in-vivo~e.10,11))))) # ::id pmid_2384_5441.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figures 7 @ E , S6 @ H , and S6I show that combined Braf @/@ PI3K inhibition elicited potent growth inhibition in both models . # ::alignments 1-1.1.1 1-1.1.2 1-1.1.3 11-1.1 12-1.1.3.1 13-1 14-1.2.r 15-1.2.1.1 16-1.2.1.1.1.1.1 18-1.2.1.1.2.1.1 19-1.2.1 19-1.2.2 20-1.2 21-1.2.2.2 22-1.2.2.1 23-1.2.2 24-1.2.3.r 25-1.2.3.1 26-1.2.3 (s / show-01~e.13 :ARG0 (a / and~e.11 :op1 (f / figure~e.1 :mod "7E") :op2 (f2 / figure~e.1 :mod "S6H") :op3 (f3 / figure~e.1 :mod "S6I"~e.12)) :ARG1~e.14 (e / elicit-01~e.20 :ARG0 (i / inhibit-01~e.19 :ARG1 (c / combine-01~e.15 :ARG1 (e2 / enzyme :name (n / name :op1 "Braf"~e.16)) :ARG2 (e3 / enzyme :name (n2 / name :op1 "PI3K"~e.18)))) :ARG1 (i2 / inhibit-01~e.19,23 :ARG1 (g / grow-01~e.22) :mod (p / potent~e.21)) :location~e.24 (m / model~e.26 :mod (b / both~e.25)))) # ::id pmid_2384_5441.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunohistochemical staining revealed that proliferation was substantially inhibited in the PLX4720 @/@ GDC0941 @-@ treated group , with only few Ki67 @-@ positive cells being detectable in regressed tumor masses ( Figure S6 @ I ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1 6-1.2.1.2 7-1.2.1 8-1.2.1.3.r 10-1.2.1.3.1.1.1.1.1 12-1.2.1.3.1.1.2.1.1 14-1.2.1.3.1 15-1.2.1.3 18-1.2.2.1.1.1.1 19-1.2.2.1.1.1 20-1.2.2.1.1.2.1.1 22-1.2.2.1.1.2.2 23-1.2.2.1.1 25-1.2.2.1 26-1.2.2.1.2.r 27-1.2.2.1.2.2 28-1.2.2.1.2.1 29-1.2.2.1.2 32-1.3.1 (r / reveal-01~e.2 :ARG0 (s / stain-01~e.1 :mod (i / immunohistochemical~e.0)) :ARG1~e.3 (a2 / and :op1 (i2 / inhibit-01~e.7 :ARG1 (p / proliferate-01~e.4) :degree (s2 / substantial~e.6) :location~e.8 (g / group~e.15 :ARG1-of (t / treat-04~e.14 :ARG2 (a / and :op1 (s3 / small-molecule :name (n / name :op1 "PLX4720"~e.10)) :op2 (s4 / small-molecule :name (n2 / name :op1 "GDC0941"~e.12)))))) :op2 (p2 / possible-01 :ARG1 (d / detect-01~e.25 :ARG1 (c2 / cell~e.23 :quant (f2 / few~e.19 :mod (o / only~e.18)) :mod (p4 / protein :name (n3 / name :op1 "Ki67"~e.20) :mod (p3 / positive~e.22))) :location~e.26 (m / mass-01~e.29 :ARG0 (t2 / tumor~e.28) :ARG1-of (r2 / regress-01~e.27))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.32 :mod "S6I"))) # ::id pmid_2384_5441.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data mirror the in vitro effectiveness of these treatments in vivo . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.2 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.2 9-1.2.1 10-1.2.1.1 11-1.2.1.1 (m / mirror-01~e.2 :ARG1 (d / data~e.1 :mod (t / this~e.0)) :ARG2 (e / effective-04~e.6 :ARG0~e.7 (t2 / treat-04~e.9 :manner (i2 / in-vivo~e.10,11) :mod t~e.8) :manner (i / in-vitro~e.4,5))) # ::id pmid_2423_8212.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mek inhibition results in marked antitumor activity against metastatic melanoma patient @-@ derived melanospheres and in melanosphere @-@ generated xenografts ( PMID : 24238212 ) # ::alignments 0-1.1.1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1 5-1.2.1.3 5-1.2.1.3.1 5-1.2.1.3.1.r 6-1.2.1 7-1.2.1.2 7-1.2.1.3 8-1.2.1.2.1.2.2 9-1.2.1.2.1.2.1.1 10-1.2.1.2.1.1.1.1.1 12-1.2.1.2.1.1 13-1.2.1.2.1 14-1.2 16-1.2.2.1.1 18-1.2.2.1 19-1.2.2 (r / result-01~e.2 :ARG1 (i / inhibit-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "Mek"~e.0))) :ARG2~e.3 (a3 / and~e.14 :op1 (a / activity-06~e.6 :ARG1-of (m / mark-01~e.4) :ARG0-of (o / oppose-01~e.7 :ARG1 (m4 / melanosphere~e.13 :ARG1-of (d / derive-01~e.12 :ARG2 (p / person :ARG1-of (h / have-org-role-91 :ARG2 (p2 / patient~e.10)))) :mod (m6 / medical-condition :name (n2 / name :op1 "melanoma"~e.9) :ARG1-of (m3 / metastasize-101~e.8)))) :ARG0-of (c / counter-01~e.5,7 :ARG1~e.5 (t / tumor~e.5))) :op2 (x / xenograft~e.19 :ARG1-of (g / generate-01~e.18 :ARG0 (m5 / melanosphere~e.16)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID24238212"))) # ::id pmid_2423_8212.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2423_8212.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Melanospheres isolated from metastatic melanoma tumors possess stem cell properties , are highly tumorigenic in vivo and recapitulate the patient tumor # ::alignments 1-1.1.1 2-1.1.1.1 3-1.1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.1.1.2.1.1 6-1.1.1.1.1 7-1.1 8-1.1.2.1.1 9-1.1.2.1 10-1.1.2 13-1.2.3 14-1.2.2 15-1.2.4 16-1.2.4 17-1 18-1.3 20-1.3.2.1.1.1 21-1.2.2 21-1.3.2 (a / and~e.17 :op1 (p / possess-01~e.7 :ARG0 (m3 / melanosphere~e.1 :ARG1-of (i / isolate-01~e.2 :ARG2~e.3 (t / tumor~e.6 :ARG1-of (m2 / metastasize-101~e.4) :mod (m / medical-condition :name (n / name :op1 "melanoma"~e.5))))) :ARG1 (p2 / property~e.10 :mod (c2 / cell~e.9 :mod (s / stem~e.8)))) :op2 (c3 / cause-01 :ARG0 m3 :ARG1 (t2 / tumor~e.14,21) :degree (h / high~e.13) :manner (i2 / in-vivo~e.15,16)) :op3 (r / recapitulate-01~e.18 :ARG0 m3 :ARG1 (t3 / tumor~e.21 :mod (p3 / person :ARG1-of (h2 / have-org-role-91 :ARG2 (p4 / patient~e.20)))))) # ::id pmid_2423_8212.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ten patient @-@ derived metastatic melanoma specimens were enzymatically dissociated and tumor cells were cultured in selective conditions for CSC ( tumor spheres ) , as previously described [ @ 41 @ - @ 44 @ ] . # ::alignments 0-1.1.1.1 1-1.1.1.3.1.1.1 3-1.1.1.3 4-1.1.1.2 5-1.1.1.4.1.1 6-1.1.1 9-1.1 10-1 11-1.2.1.1 12-1.2.1 12-1.2.3 14-1.2 17-1.2.2 21-1.2.3.2.1.1 22-1.2.3.2.1 25-1.3.1.r 26-1.3.1 27-1.3 27-1.4 30-1.4.1.1.1.1 34-1.4.1.1.1.2 (a / and~e.10 :op1 (d / dissociate-01~e.9 :ARG1 (s / specimen~e.6 :quant 10~e.0 :ARG1-of (m2 / metastasize-101~e.4) :ARG1-of (d2 / derive-01~e.3 :ARG2 (p / person :ARG1-of (h / have-org-role-91 :ARG2 (p2 / patient~e.1)))) :mod (m4 / medical-condition :name (n2 / name :op1 "melanoma"~e.5))) :manner (e / enzyme)) :op2 (c / culture-01~e.14 :ARG1 (c2 / cell~e.12 :mod (t / tumor~e.11)) :manner (c3 / condition~e.17 :ARG0-of (s2 / select-01)) :purpose (c4 / cell~e.12 :mod (s3 / stem) :ARG1-of (m3 / mean-01 :ARG2 (s4 / sphere~e.22 :mod t~e.21)) :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))) :ARG1-of (d3 / describe-01~e.27 :time~e.25 (p3 / previous~e.26)) :ARG1-of (d4 / describe-01~e.27 :ARG0 (p4 / publication :ARG1-of (c6 / cite-01 :ARG2 (v / value-interval :op1 41~e.30 :op2 44~e.34))))) # ::id pmid_2423_8212.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following prolonged culture , we obtained exponentially growing “ melanospheres ” with efficiency of 80 % ( Figure 1 @ A left ) . # ::alignments 0-1.3 1-1.3.1.1 2-1.3.1 4-1.1 5-1 6-1.2.1.1 6-1.2.1.1.r 7-1.2.1 9-1.2 11-1.2.2.r 12-1.2.2 13-1.2.2.1.r 14-1.2.2.1.1 15-1.2.2.1 17-1.4.1 22-1.4.1.2 (o / obtain-01~e.5 :ARG0 (w / we~e.4) :ARG1 (m / melanosphere~e.9 :ARG1-of (g / grow-01~e.7 :manner~e.6 (e / exponential~e.6)) :ARG1-of~e.11 (e2 / efficient-01~e.12 :degree~e.13 (p / percentage-entity~e.15 :value 80~e.14))) :ARG1-of (f / follow-01~e.0 :ARG2 (c2 / culture-01~e.2 :ARG1-of (p2 / prolong-01~e.1))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.17 :mod "1A" :ARG1-of (l / left-20~e.22)))) # ::id pmid_2423_8212.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The same cells cultured in conditions specific for the growth of melanocytes generated monolayers of tumor cells whose morphology resembled differentiated cells , suggesting the capacity of melanospheres to differentiate in vitro ( Figure 1 @ A right ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1 4-1.1.1.1.r 4-1.3.1.2.1 5-1.1.1.1 6-1.1.1.1.1 7-1.1.1.1.1.1.r 9-1.1.1.1.1.1 10-1.1.1.1.1.1.1.r 11-1.1.1.1.1.1.1 12-1 15-1.2.1.2 16-1.2.1 18-1.2.1.1.1 19-1.2.1.1.1.1 20-1.2.1.1.1.1.1.1 21-1.2.1.1.1.1.1 23-1.3 25-1.3.1 26-1.3.1.1.r 27-1.3.1.1 29-1.3.1.2 31-1.3.1.2.1 32-1.3.1.2.1 35-1.4.1 40-1.4.1.2 (g / generate-01~e.12 :ARG0 (c / cell~e.2 :ARG1-of (c2 / culture-01~e.3 :manner~e.4 (c3 / condition~e.5 :ARG1-of (s2 / specific-02~e.6 :ARG2~e.7 (g2 / grow-01~e.9 :ARG1~e.10 (m4 / melanocyte~e.11))))) :ARG1-of (s4 / same-01~e.1)) :ARG1 (m / monolayer :consist-of (c5 / cell~e.16 :ARG0-of (h / have-03 :ARG1 (m2 / morphology~e.18 :ARG1-of (r / resemble-01~e.19 :ARG2 (c6 / cell~e.21 :ARG1-of (d / differentiate-101~e.20))))) :mod (t / tumor~e.15))) :ARG0-of (s3 / suggest-01~e.23 :ARG1 (c7 / capable-01~e.25 :ARG1~e.26 (m3 / melanosphere~e.27) :ARG2 (d2 / differentiate-101~e.29 :manner (i / in-vitro~e.4,31,32)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.35 :mod "1A" :ARG1-of (r2 / right-04~e.40)))) # ::id pmid_2423_8212.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next investigated the expression of antigens that have been previously associated with MIC . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 6-1.2.1 10-1.2.1.1.2 11-1.2.1.1 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.4 :ARG2~e.5 (a / antigen~e.6 :ARG1-of (a2 / associate-01~e.11 :ARG2 (c / cell :ARG0-of (i2 / initiate-01 :ARG1 (m / medical-condition :name (n2 / name :op1 "melanoma")))) :time (p / previous~e.10)))) :time (n / next~e.1)) # ::id pmid_2423_8212.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Melanospheres did not express CD133 , CD20 , CD24 , ABCB5 or CD271 ( Additional file 1 @ : Figure S1A @-@ B ) , while p @-@ glycoprotein was detectable at low levels . # ::alignments 0-1.1.3 2-1.1.1 2-1.1.1.r 3-1.1 4-1.1.2.1.1.1 6-1.1.2.2.1.1 8-1.1.2.3.1.1 10-1.1.2.4.1.1 11-1.1.2 12-1.1.2.5.1.1 15-1.1.4.1 17-1.1.4.1.1 20-1.1.4.1.3.1.1 20-1.1.4.1.3.1.2 21-1.1.4.1.3.1.1.1 26-1 27-1.2.1.1 29-1.2.1 31-1.2 32-1.2.1.2.r 33-1.2.1.2.1 34-1.2.1.2 (c / contrast-01~e.26 :ARG1 (e / express-03~e.3 :polarity~e.2 -~e.2 :ARG2 (o / or~e.11 :op1 (p / protein :name (n / name :op1 "CD133"~e.4)) :op2 (p2 / protein :name (n2 / name :op1 "CD20"~e.6)) :op3 (p3 / protein :name (n3 / name :op1 "CD24"~e.8)) :op4 (p4 / protein :name (n4 / name :op1 "ABCB5"~e.10)) :op5 (p5 / protein :name (n5 / name :op1 "CD271"~e.12))) :ARG3 (m / melanosphere~e.0) :ARG1-of (d / describe-01 :ARG0 (f / file~e.15 :mod 1~e.17 :ARG1-of (a / add-02) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (f2 / figure~e.20 :mod "S1A"~e.21) :op2 (f3 / figure~e.20 :mod "S1B")))))) :ARG2 (d2 / detect-01~e.31 :ARG1 (g / glycoprotein~e.29 :ARG3-of (p8 / phosphorylate-01~e.27) :quant~e.32 (l / level~e.34 :ARG1-of (l2 / low-04~e.33))) :ARG1-of (p6 / possible-01))) # ::id pmid_2423_8212.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok They expressed stem cell @-@ related markers as c @-@ Kit , Cripto , CD146 , CD44 and CD166 ( Additional file 1 @ : Figure S1A ) in agreement with previous reports on cell line @-@ derived melanospheres [ @ 38 @ ] . # ::alignments 0-1.2 1-1 2-1.1.1.1.1 3-1.1.1.1 5-1.1.1 6-1.1 7-1.3.1.1.r 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 12-1.1.2.1.2.1.1 14-1.1.2.1.3.1.1 16-1.1.2.1.4.1.1 17-1.1.2.1 18-1.1.2.1.5.1.1 21-1.1.2.2.1 23-1.1.2.2.1.1 26-1.1.2.2.1.3.1 27-1.1.2.2.1.3.1.1 30-1.3 32-1.3.1.1 33-1.3.1 33-1.3.1.2 33-1.3.1.2.r 34-1.3.1.2.1.r 35-1.3.1.2.1.1.1 36-1.3.1.2.1.1.1 38-1.3.1.2.1.1 39-1.3.1.2.1 42-1.4.1.1.1 (e / express-03~e.1 :ARG2 (m / marker~e.6 :ARG1-of (r / relate-01~e.5 :ARG2 (c / cell~e.3 :mod (s / stem~e.2))) :ARG1-of (e2 / exemplify-01 :ARG0 (a / and~e.17 :op1 (e3 / enzyme :name (n / name :op1 "c-Kit"~e.8,10)) :op2 (p2 / protein :name (n2 / name :op1 "Cripto"~e.12)) :op3 (p3 / protein :name (n3 / name :op1 "CD146"~e.14)) :op4 (p4 / protein :name (n4 / name :op1 "CD44"~e.16)) :op5 (p5 / protein :name (n5 / name :op1 "CD166"~e.18))) :ARG1-of (d3 / describe-01 :ARG0 (f / file~e.21 :mod 1~e.23 :ARG1-of (a3 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (f2 / figure~e.26 :mod "S1A"~e.27)))))) :ARG3 (t / they~e.0) :ARG0-of (a2 / agree-01~e.30 :ARG2 (t2 / thing~e.33 :time~e.7 (p6 / previous~e.32) :ARG1-of~e.33 (r2 / report-01~e.33 :topic~e.34 (m3 / melanosphere~e.39 :ARG1-of (d / derive-01~e.38 :ARG2 (c3 / cell-line~e.35,36)))))) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c4 / cite-01 :ARG2 38~e.42)))) # ::id pmid_2423_8212.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , embryonic stem cell markers Nanog and Oct @-@ 4 were detected at the RNA level in all samples analyzed ( Additional file 1 @ : Figure S1C ) . # ::alignments 0-1.5 2-1.1.1.4 3-1.1.1.3.1 4-1.1.1.3 5-1.1.1 5-1.1.2 6-1.1.1.2.1 7-1.1 8-1.1.2.2.1 10-1.1.2.2.1 12-1 13-1.3.r 15-1.3.1.2.1 16-1.3 17-1.2.r 18-1.2.1 19-1.2 19-1.2.3 19-1.2.3.r 20-1.2.2 23-1.4.1 25-1.4.1.1 28-1.4.1.3.1 29-1.4.1.3.1.1 (d / detect-01~e.12 :ARG1 (a / and~e.7 :op1 (m / marker~e.5 :wiki "Homeobox_protein_NANOG" :name (n / name :op1 "Nanog"~e.6) :mod (c / cell~e.4 :mod (s / stem~e.3)) :mod (e / embryo~e.2)) :op2 (m2 / marker~e.5 :wiki "Oct-4" :name (n2 / name :op1 "Oct-4"~e.8,10) :mod c :mod e)) :location~e.17 (t / thing~e.19 :mod (a2 / all~e.18) :ARG1-of (a3 / analyze-01~e.20) :ARG1-of~e.19 (s2 / sample-01~e.19)) :location~e.13 (l / level~e.16 :mod (n3 / nucleic-acid :wiki "RNA" :name (n4 / name :op1 "RNA"~e.15))) :ARG1-of (d2 / describe-01 :ARG0 (f / file~e.23 :mod 1~e.25 :ARG1-of (a4 / add-02) :ARG1-of (m3 / mean-01 :ARG2 (f2 / figure~e.28 :mod "S1C"~e.29)))) :time (f3 / final~e.0)) # ::id pmid_2423_8212.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The CD44 isoform V6 was specifically restricted to melanospheres , being not expressed in differentiated cells , nor in tumor cells freshly isolated from melanosphere @-@ derived xenografts nor in melanocytes ( Additional file 1 @ : Figure S1D ) . # ::alignments 1-1.1.2.1.1 2-1.1 3-1.1.1.1 5-1.3 6-1 7-1.2.r 8-1.2 11-1.1.3.1 11-1.1.3.1.r 12-1.1.3 13-1.1.3.2.r 14-1.1.3.2.1.1 15-1.1.3.2.1 17-1.1.3.2 19-1.1.3.2.2.1 20-1.1.3.2.2 21-1.1.3.2.2.2.2 22-1.1.3.2.2.2 23-1.1.3.2.2.2.1.r 24-1.1.3.2.2.2.1.1.1 26-1.1.3.2.2.2.1.1 27-1.1.3.2.2.2.1 28-1.1.3.2 30-1.1.3.2.3 33-1.4.1 35-1.4.1.1 38-1.4.1.3.1 39-1.4.1.3.1.1 (r / restrict-01~e.6 :ARG1 (i / isoform~e.2 :name (n / name :op1 "V6"~e.3) :mod (p / protein :name (n2 / name :op1 "CD44"~e.1)) :ARG1-of (e / express-03~e.12 :polarity~e.11 -~e.11 :ARG3~e.13 (o / or~e.17,28 :op1 (c2 / cell~e.15 :ARG1-of (d / differentiate-101~e.14)) :op2 (c3 / cell~e.20 :mod (t / tumor~e.19) :ARG1-of (i2 / isolate-01~e.22 :ARG2~e.23 (x / xenograft~e.27 :ARG1-of (d2 / derive-01~e.26 :ARG2 m3~e.24)) :ARG1-of (f / fresh-04~e.21))) :op3 (m2 / melanocyte~e.30)))) :ARG2~e.7 (m3 / melanosphere~e.8) :manner (s / specific-02~e.5) :ARG1-of (d3 / describe-01 :ARG0 (f2 / file~e.33 :mod 1~e.35 :ARG1-of (a / add-02) :ARG1-of (m / mean-01 :ARG2 (f3 / figure~e.38 :mod "S1D"~e.39))))) # ::id pmid_2423_8212.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Melanospheres could be expanded in vitro for several months and their proliferation rate was not lost with time ( Additional file 2 @ : Figure S2A ) . # ::alignments 0-1.1.1.1 1-1.1 3-1.1.1 5-1.1.1.2 6-1.1.1.2 8-1.1.1.3.r 9-1.1.1.3 10-1.1.1.3.1.2 11-1 13-1.2.2.1 14-1.2.2 17-1.2 19-1.1.1.3.1 19-1.2.3 22-1.3.1 24-1.3.1.1 27-1.3.1.3.1 28-1.3.1.3.1.1 (a / and~e.11 :op1 (p2 / possible-01~e.1 :ARG1 (e / expand-01~e.3 :ARG1 (m3 / melanosphere~e.0) :manner (i / in-vitro~e.5,6) :duration~e.8 (s / several~e.9 :op1 (t2 / temporal-quantity~e.19 :quant 1 :unit (m / month~e.10))))) :op2 (l / lose-02~e.17 :ARG0 m3 :ARG1 (r / rate~e.14 :degree-of (p / proliferate-01~e.13 :ARG0 m3)) :condition (t / time~e.19)) :ARG1-of (d / describe-01 :ARG0 (f / file~e.22 :mod 2~e.24 :ARG1-of (a2 / add-02) :ARG1-of (m2 / mean-01 :ARG2 (f2 / figure~e.27 :mod "S2A"~e.28))))) # ::id pmid_2423_8212.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok They were composed by a large ( mean 42 % ± 8 in all examined samples ) fraction of self @-@ renewing sphere @-@ reforming cells ( Additional file 2 @ : Figure S2B upper left ) . # ::alignments 0-1.1 2-1 3-1.2.r 5-1.2.2 7-1.3.1.3 8-1.2.3.1.1.1 8-1.2.3.1.2.1 9-1.2.3.1.1 9-1.2.3.1.1.2.1 9-1.2.3.1.2 11-1.2.3.1.1.2.1.1 13-1.2.3.2.1 14-1.2.3.2.2 15-1.2.3.2 15-1.2.3.2.3 15-1.2.3.2.3.r 17-1.2 21-1.2.1.1 22-1.2.1.2.1 24-1.2.1.2 25-1.2.1 28-1.3.1 30-1.3.1.1 33-1.3.1.3.1 34-1.3.1.3.1.1 35-1.3.1.3.1.2.1 36-1.3.1.3.1.2 (c / compose-01~e.2 :ARG1 (t / they~e.0) :ARG2~e.3 (f / fraction-01~e.17 :ARG1 (c2 / cell~e.25 :ARG0-of (r / renew-01~e.21 :ARG1 c2) :ARG0-of (r2 / reform-01~e.24 :ARG2 (s / sphere~e.22))) :mod (l / large~e.5) :ARG1-of (a2 / average-01 :ARG2 (o / or :op1 (p / percentage-entity~e.9 :value 42~e.8 :ARG2-of (a3 / add-02 :ARG1 (p2 / percentage-entity~e.9 :value 8~e.11))) :op2 (p3 / percentage-entity~e.9 :value 42~e.8 :ARG2-of (s2 / subtract-01 :ARG1 p2))) :location (t2 / thing~e.15 :mod (a4 / all~e.13) :ARG1-of (e / examine-01~e.14) :ARG1-of~e.15 (s3 / sample-01~e.15)))) :ARG1-of (d / describe-01 :ARG0 (f2 / file~e.28 :mod 2~e.30 :ARG1-of (a / add-02) :ARG1-of (m / mean-01~e.7 :ARG2 (f3 / figure~e.33 :mod "S2B"~e.34 :ARG1-of (l2 / left-20~e.36 :mod (u / upper~e.35))))))) # ::id pmid_2423_8212.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , secondary and tertiary spheres were formed with a similar frequency and tertiary spheres were able to proliferate indefinitely , indicating that the fraction of self @-@ renewing cells did not decrease with passages ( Additional file 2 @ : Figure S2B upper right panel ) . # ::alignments 0-1.4 2-1.1.1.1.1 3-1.1.1 4-1.1.1.2.1 5-1.1.1.1 5-1.1.1.2 7-1.1 8-1.1.2.r 10-1.1.2.1 11-1.1.2 12-1.1.1 13-1.1.1.2.1 14-1.1.1.2 16-1.2 18-1.2.1 19-1.2.1.2 19-1.2.1.2.1 19-1.2.1.2.1.r 21-1.3 22-1.3.1.r 24-1.3.1.2 28-1.3.1.2.1.1 29-1.3.1.2.1 31-1.3.1.1 31-1.3.1.1.r 32-1.3.1 33-1.3.1.3.r 34-1.3.1.3 37-1.5.1 39-1.5.1.1 42-1.5.1.3.1 43-1.5.1.3.1.1 44-1.5.1.3.1.2.1.1 45-1.5.1.3.1.2.1 46-1.5.1.3.1.2 (a2 / and :op1 (f / form-01~e.7 :ARG1 (a / and~e.3,12 :op1 (s / sphere~e.5 :mod (s2 / secondary~e.2)) :op2 (s3 / sphere~e.5,14 :mod (t / tertiary~e.4,13))) :manner~e.8 (f2 / frequency~e.11 :ARG1-of (r / resemble-01~e.10))) :op2 (p / possible-01~e.16 :ARG1 (p2 / proliferate-01~e.18 :ARG0 s3 :duration (d / definite~e.19 :polarity~e.19 -~e.19))) :ARG0-of (i / indicate-01~e.21 :ARG1~e.22 (d2 / decrease-01~e.32 :polarity~e.31 -~e.31 :ARG0 (f3 / fraction-01~e.24 :ARG1 (c / cell~e.29 :ARG0-of (r2 / renew-01~e.28 :ARG1 c))) :condition~e.33 (p3 / pass-08~e.34))) :time (f4 / final~e.0) :ARG1-of (d3 / describe-01 :ARG0 (f5 / file~e.37 :mod 2~e.39 :ARG1-of (a3 / add-02) :ARG1-of (m / mean-01 :ARG2 (f6 / figure~e.42 :mod "S2B"~e.43 :part (p4 / panel~e.46 :ARG1-of (r3 / right-04~e.45 :mod (u / upper~e.44)))))))) # ::id pmid_2423_8212.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The clonogenic activity was higher in melanospheres than in their differentiated counterpart ( Additional file 2 @ : Figure S2B lower panels ) . # ::alignments 1-1.1.2 2-1.1 4-1 4-1.4 4-1.4.r 5-1.1.1.r 6-1.1.1 7-1.2.r 9-1.2.2 9-1.2.2.r 10-1.2.1 11-1.2 14-1.3.1 16-1.3.1.1 19-1.3.1.3.1 20-1.3.1.3.1.1 21-1.3.1.3.1.2.1 22-1.3.1.3.1.2 (h / high-02~e.4 :ARG1 (a / activity-06~e.2 :ARG0~e.5 (m2 / melanosphere~e.6) :mod (c / clonogenic~e.1)) :compared-to~e.7 (c3 / counterpart~e.11 :ARG1-of (d / differentiate-101~e.10) :poss~e.9 m2~e.9) :ARG1-of (d2 / describe-01 :ARG0 (f / file~e.14 :mod 2~e.16 :ARG1-of (a2 / add-02) :ARG1-of (m / mean-01 :ARG2 (f2 / figure~e.19 :mod "S2B"~e.20 :part (p / panel~e.22 :ARG1-of (l / low-04~e.21)))))) :degree~e.4 (m3 / more~e.4)) # ::id pmid_2423_8212.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Under appropriate conditions , melanospheres generated a progeny of cells with morphology and phenotype of melanocytic , adipogenic or osteogenic cells , demonstrating multiple differentiation ability and recapitulating the plasticity of neural crest cells ( Additional file 2 @ :Figure S2C ) . # ::alignments 1-1.6.1 2-1.6 2-1.6.r 4-1.1 5-1 7-1.2 8-1.2.1.r 9-1.2.1 11-1.2.1.1.1.1 12-1.2.1.1.1 13-1.2.1.1.1.2 18-1.2.1.1.1.3 20-1.2.1.1.1.3.1 20-1.2.1.1.1.3.2 20-1.2.1.1.1.3.3 22-1.3 23-1.3.1.2.1 24-1.3.1.2 25-1.3.1 26-1.2.1.1.1 27-1.4 29-1.4.1 30-1.4.1.1.r 31-1.4.1.1.2 32-1.4.1.1.1 33-1.4.1.1 36-1.5.1 38-1.5.1.1 41-1.5.1.3.1.1 (g / generate-01~e.5 :ARG0 (m5 / melanosphere~e.4) :ARG1 (p / progeny~e.7 :poss~e.8 (c2 / cell~e.9 :ARG0-of (h / have-03 :ARG1 (a / and~e.12,26 :op1 (m / morphology~e.11) :op2 (p2 / phenotype~e.13) :poss (o / or~e.18 :op1 (c3 / cell~e.20 :mod (m2 / melanocyte)) :op2 (c4 / cell~e.20 :mod (a2 / adipogenesis)) :op3 (c5 / cell~e.20 :mod (o2 / osteogenesis))))))) :ARG0-of (d / demonstrate-01~e.22 :ARG1 (c6 / capable-01~e.25 :ARG1 m5 :ARG2 (d2 / differentiate-101~e.24 :mod (m3 / multiple~e.23)))) :ARG0-of (r / recapitulate-01~e.27 :ARG1 (p3 / plasticity~e.29 :poss~e.30 (c7 / cell~e.33 :mod (c8 / crest~e.32) :mod (n2 / neural~e.31)))) :ARG1-of (d3 / describe-01 :ARG0 (f / file~e.36 :mod 2~e.38 :ARG1-of (a3 / add-02) :ARG1-of (m4 / mean-01 :ARG2 (f2 / figure :mod "S2C"~e.41)))) :condition~e.2 (c9 / condition~e.2 :ARG1-of (a4 / appropriate-02~e.1))) # ::id pmid_2423_8212.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Melanospheres were highly tumorigenic when injected subcutaneously in NOD Scid or Nude mice and all samples displayed tumor take of 100 % down to 25000 cells . # ::alignments 0-1.1.1 2-1.1.3 3-1.1.2 5-1.1.4 6-1.1.4.3 6-1.1.4.3.r 7-1.1.4.2.r 8-1.1.4.2.1.1.1 9-1.1.4.2.1.1.1 10-1.1.4.2 11-1.1.4.2.2.1 12-1.1.4.2.1 12-1.1.4.2.2 13-1 14-1.2.1.2 15-1.2.1 15-1.2.1.1 15-1.2.1.1.r 16-1.2 17-1.1.2 18-1.2.2 19-1.2.2.2.r 20-1.2.2.2.1 21-1.2.2.2 22-1.2.2.2.2.1.1 23-1.2.2.2.2.1.1 24-1.2.2.2.2.1.1.1 25-1.2.2.2.2.1 (a / and~e.13 :op1 (c / cause-01 :ARG0 (m4 / melanosphere~e.0) :ARG1 (t / tumor~e.3,17) :degree (h / high~e.2) :condition (i / inject-01~e.5 :ARG1 m4 :ARG2~e.7 (o / or~e.10 :op1 (m5 / mouse~e.12 :name (n / name :op1 "NOD-Scid"~e.8,9)) :op2 (m2 / mouse~e.12 :mod (n3 / nude~e.11))) :manner~e.6 (s / subcutaneous~e.6))) :op2 (d / display-01~e.16 :ARG0 (t2 / thing~e.15 :ARG1-of~e.15 (s2 / sample-01~e.15) :mod (a2 / all~e.14)) :ARG1 (t3 / take-01~e.18 :ARG1 t :quant~e.19 (p / percentage-entity~e.21 :value 100~e.20 :ARG1-of (m3 / mean-01 :ARG2 (c4 / cell~e.25 :quant (d2 / down-to~e.22,23 :quant 25000~e.24)))) :mod t))) # ::id pmid_2423_8212.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For one sample we performed a limiting dilution experiment and even as low as 5 cells readily generated a tumor within 8 weeks ( Figure 1 @ B and C ) . # ::alignments 1-1.1.2.2.1 2-1.1.2.2 2-1.1.2.2.2 2-1.1.2.2.2.r 3-1.1.1 4-1.1 6-1.1.2.3.1 7-1.1.2.3 8-1.1.2 9-1 10-1.2.1.2 11-1.2.4.r 12-1.2.1.1 13-1.2.4.r 14-1.2.1.1.1 15-1.2.1 16-1.2.3 16-1.2.3.r 17-1.2 19-1.2.2 20-1.2.4 20-1.2.4.1.1.r 21-1.2.4.1.1 22-1.2.4.1.2 24-1.3.1.1 24-1.3.1.2 26-1.1.2.2.1 29-1.3.1 (a / and~e.9 :op1 (p / perform-02~e.4 :ARG0 (w / we~e.3) :ARG1 (e / experiment-01~e.8 :ARG0 w :ARG1 (t3 / thing~e.2 :quant 1~e.1,26 :ARG1-of~e.2 (s / sample-01~e.2)) :ARG2 (d / dilute-01~e.7 :ARG0-of (l / limit-01~e.6)))) :op2 (g / generate-01~e.17 :ARG0 (c / cell~e.15 :ARG1-of (l2 / low-04~e.12 :ARG3 5~e.14) :mod (e2 / even~e.10)) :ARG1 (t / tumor~e.19) :manner~e.16 (r / ready~e.16) :time~e.11,13 (u / up-to~e.20 :op1 (t2 / temporal-quantity :quant~e.20 8~e.21 :unit (w2 / week~e.22)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.29 :op1 (f / figure~e.24 :mod "1B") :op2 (f2 / figure~e.24 :mod "1C")))) # ::id pmid_2423_8212.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , melanosphere @-@ derived differentiated cells displayed a decreased and delayed tumor growth in vivo , and as many as 5x10 @⁴ differentiated cells generated a slowly growing tumor with a 10 @-@ week delay post @-@ injection ( Figure 1 @ B ) . # ::alignments 0-1.1.1.3 1-1 3-1.1.1.1.2.1 5-1.1.1.1.2 6-1.1.1.1.1 7-1.1.1.1 8-1.1.1 10-1.1.1.2.2 12-1.1.1.2.3 13-1.1.1.2.1 14-1.1.1.2 16-1.1.1.3 17-1.1.1.3 20-1.1 21-1.1.2.1.2 22-1.1.2.1.2 23-1.1.2.1.2 28-1.1.2.1.1 29-1.1.2.1 30-1.1.2 32-1.1.2.2.1.1 33-1.1.2.2.1 34-1.1.2.2 37-1.1.2.3.1.1.1 39-1.1.2.3.1.1.2 40-1.1.2.3.1 41-1.1.2.3.1.2 43-1.1.2.3.1.2.1 45-1.1.3.1 (c / contrast-01~e.1 :ARG2 (a / and~e.20 :op1 (d / display-01~e.8 :ARG0 (c3 / cell~e.7 :ARG1-of (d4 / differentiate-101~e.6) :ARG1-of (d5 / derive-01~e.5 :ARG2 (m / melanosphere~e.3))) :ARG1 (g / grow-01~e.14 :ARG1 (t / tumor~e.13) :ARG1-of (d2 / decrease-01~e.10) :ARG1-of (d3 / delay-01~e.12)) :manner (i / in-vivo~e.0,16,17)) :op2 (g2 / generate-01~e.30 :ARG0 (c2 / cell~e.29 :ARG1-of d4~e.28 :quant (a3 / as-many-as~e.21,22,23 :op1 50000)) :ARG1 (t2 / tumor~e.34 :ARG1-of (g3 / grow-01~e.33 :ARG1-of (s / slow-05~e.32))) :ARG0-of (h / have-03 :ARG1 (d6 / delay-01~e.40 :ARG2 (t3 / temporal-quantity :quant 10~e.37 :unit (w / week~e.39)) :time (a2 / after~e.41 :op1 (i2 / inject-01~e.43))))) :ARG1-of (d7 / describe-01 :ARG0 (f / figure~e.45 :mod "1B")))) # ::id pmid_2423_8212.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunohistochemical analysis of melanosphere @-@ derived xenografts , performed for all samples , revealed a high similarity between the xenograft and the original patient tumor in terms of morphology and expression of the melanoma @-@ associated diagnostic antigens MART1 and S100 ( Figure 1 @ D is a representative image ) . # ::alignments 0-1.1.4 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1 6-1.1.1 8-1.1.2 9-1.1.3.r 10-1.1.3.2 11-1.1.3 11-1.1.3.1 11-1.1.3.1.r 13-1 15-1.2.3 16-1.2 19-1.2.1 20-1.2.4 22-1.2.2.1 23-1.2.2.2.1.1 24-1.2.2 27-1.2.4.r 28-1.2.4.1 29-1.2.4 30-1.2.4.2 31-1.2.4.2.1.r 33-1.2.4.2.1.1.2.1.1.1 35-1.2.4.2.1.1.2 37-1.2.4.2.1.1 37-1.2.4.2.1.2 38-1.2.4.2.1.1.1.1 39-1.2.4.2.1 40-1.2.4.2.1.2.1.1 42-1.3.1 49-1.3.1.2 50-1.3.1.2.1 (r / reveal-01~e.13 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (x / xenograft~e.6 :ARG1-of (d / derive-01~e.5 :ARG2 (m3 / melanosphere~e.3))) :ARG1-of (p / perform-02~e.8) :beneficiary~e.9 (t / thing~e.11 :ARG1-of~e.11 (s / sample-01~e.11) :mod (a2 / all~e.10)) :mod (i / immunohistochemical~e.0)) :ARG1 (r2 / resemble-01~e.16 :ARG1 x~e.19 :ARG2 (t2 / tumor~e.24 :mod (o / original~e.22) :mod (p2 / person :ARG0-of (h2 / have-org-role-91 :ARG2 (p3 / patient~e.23)))) :ARG1-of (h / high-02~e.15) :topic~e.27 (a3 / and~e.20,29 :op1 (m / morphology~e.28) :op2 (e / express-03~e.30 :ARG2~e.31 (a4 / and~e.39 :op1 (a5 / antigen~e.37 :name (n2 / name :op1 "MART1"~e.38) :ARG1-of (a7 / associate-01~e.35 :ARG2 (m2 / medical-condition :name (n / name :op1 "melanoma"~e.33))) :mod (d2 / diagnose-01)) :op2 (a6 / antigen~e.37 :name (n3 / name :op1 "S100"~e.40) :ARG1-of a7 :mod d2))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.42 :mod "1D" :ARG1-of (r3 / represent-01~e.49 :ARG0 (i2 / image~e.50))))) # ::id pmid_2423_8212.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following xenograft dissociation and re @-@ injection we easily obtained secondary and tertiary tumors , suggesting that tumorigenic potential was not lost with passages in mice , in fact these results proved the ability of tumorigenic cells to self @-@ renew in vivo ( results not shown ) . # ::alignments 0-1.1.5 1-1.1.5.1.1.1 2-1.1.5.1.1 3-1.1.5.1 7-1.1.1 8-1.1.3 9-1.1 10-1.1.2.1.1 11-1.1.2 12-1.1.2.2.1 13-1.1.2.1 13-1.1.2.2 15-1.1.4 17-1.1.2.2 20-1.1.4.1.1 20-1.1.4.1.1.r 21-1.1.4.1 22-1.1.4.1.3.r 23-1.1.4.1.3 24-1.1.4.1.3.1.r 24-1.2.3 25-1.1.4.1.3.1 27-1.2.3 28-1.2.3 29-1.2.1.3 30-1.2.1 30-1.2.1.1 30-1.2.1.1.r 31-1.2 33-1.1.4.1.2 33-1.2.2 35-1.1.4.1.2.1.1 35-1.2.2.1.1.1 36-1.2.2.1 37-1.2.2.1.1 40-1.2.2.2 42-1.2.2.2.3 43-1.2.2.2.3 46-1.2.1 46-1.2.1.1 46-1.2.1.1.r 47-1.2.1.2.1 47-1.2.1.2.1.r 48-1.2.1.2 (m2 / multi-sentence :snt1 (o / obtain-01~e.9 :ARG0 (w / we~e.7) :ARG1 (a / and~e.11 :op1 (t / tumor~e.13 :mod (s / secondary~e.10)) :op2 (t2 / tumor~e.13,17 :mod (t3 / tertiary~e.12))) :ARG1-of (e / easy-05~e.8) :ARG0-of (s2 / suggest-01~e.15 :ARG1 (l / lose-02~e.21 :polarity~e.20 -~e.20 :ARG1 (c / capable-01~e.33 :ARG1 (c2 / cause-01 :ARG1 (t4 / tumor~e.35))) :condition~e.22 (p / pass-03~e.23 :location~e.24 (m / mouse~e.25)))) :ARG1-of (f / follow-01~e.0 :ARG2 (a2 / and~e.3 :op1 (d / dissociate-01~e.2 :ARG1 (x / xenograft~e.1)) :op2 (r / reinject-00 :ARG1 x)))) :snt2 (p2 / prove-01~e.31 :ARG0 (t5 / thing~e.30,46 :ARG2-of~e.30,46 (r2 / result-01~e.30,46) :ARG1-of (s3 / show-01~e.48 :polarity~e.47 -~e.47) :mod (t6 / this~e.29)) :ARG1 (c3 / capable-01~e.33 :ARG1 (c4 / cell~e.36 :ARG0-of (c5 / cause-01~e.37 :ARG1 (t7 / tumor~e.35))) :ARG2 (r3 / renew-01~e.40 :ARG0 c4 :ARG1 c4 :manner (i / in-vivo~e.42,43))) :mod (i2 / in-fact~e.24,27,28))) # ::id pmid_2423_8212.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Based on these in vitro and in vivo results , we considered melanospheres as surrogate of melanoma @-@ initiating cells ( MIC ) exploitable for pre @-@ clinical experimentation . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.4 4-1.4.1.2 4-1.4.1.3 5-1.4.1.3 9-1.4.1.2 9-1.4.1.3 10-1.4.1.2 12-1.4.1 12-1.4.1.1 12-1.4.1.1.r 14-1.1 15-1 16-1.2 17-1.3.1.2.1.1.r 18-1.3 20-1.3.1.1.1.1.1 22-1.3.1.1 23-1.3.1 31-1.3.1.2.1.1.1 32-1.3.1.2.1 (c / consider-02~e.15 :ARG0 (w / we~e.14) :ARG1 (m2 / melanosphere~e.16) :ARG2 (s / surrogate~e.18 :poss (c3 / cell~e.23 :ARG0-of (i / initiate-01~e.22 :ARG1 (m / medical-condition :name (n / name :op1 "melanoma"~e.20))) :ARG1-of (e / exploit-01 :ARG2 (e2 / experiment-01~e.32 :time~e.17 (b / before :op1 (c4 / clinic~e.31))) :ARG1-of (p / possible-01)))) :ARG2-of (b2 / base-02~e.0 :ARG1~e.1 (t / thing~e.12 :ARG2-of~e.12 (r / result-01~e.12) :manner (i2 / in-vivo~e.4,9,10) :manner (i3 / in-vitro~e.4,5,9) :mod (t2 / this~e.2)))) # ::id pmid_2423_8212.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Melanospheres are resistant to chemotherapeutic drugs and to most pathway inhibitors # ::alignments 1-1.1 3-1 4-1.2.r 5-1.2.1.1 6-1.2.1 7-1.2 9-1.2.2.2 10-1.2.2.1.1 11-1.2.2 11-1.2.2.1 11-1.2.2.1.r (r / resist-01~e.3 :ARG0 (m3 / melanosphere~e.1) :ARG1~e.4 (a / and~e.7 :op1 (d / drug~e.6 :mod (c2 / chemotherapy~e.5)) :op2 (m / molecular-physical-entity~e.11 :ARG0-of~e.11 (i / inhibit-01~e.11 :ARG1 (p / pathway~e.10)) :quant (m2 / most~e.9)))) # ::id pmid_2423_8212.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We investigated the response of melaospheres to chemotherapeutic agents currently used in the treatment of melanoma patients . # ::alignments 0-1.1 1-1 3-1.2 6-1.2.2.r 7-1.2.2.1 8-1.2.2 9-1.2.2.2.2 10-1.2.2.2 11-1.2.2.2.1.r 13-1.2.2.2.1 14-1.2.2.2.1.2.r 15-1.2.2.2.1.2.1.1 16-1.2.2.2.1.1.1.1 (i / investigate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (r / respond-01~e.3 :ARG0 (m2 / melanosphere) :ARG1~e.6 (a / agent~e.8 :mod (c2 / chemotherapy~e.7) :ARG1-of (u / use-01~e.10 :ARG2~e.11 (t / treat-03~e.13 :ARG1 (p / person :ARG0-of (h / have-org-role-91 :ARG2 (p2 / patient~e.16))) :ARG2~e.14 (m / medical-condition :name (n / name :op1 "melanoma"~e.15))) :time (c3 / current~e.9))))) # ::id pmid_2423_8212.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Melanospheres were exposed to cisplatin , temozolomide , dacarbazine and paclitaxel for 48 hours and cell viability was assessed by MTT assay . # ::alignments 0-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.1.1 6-1.1.2.2.1.1 8-1.1.2.3.1.1 9-1.1.2 10-1.1.2.4.1.1 11-1.1.3.r 12-1.1.3.1 13-1.1.3.2 14-1 15-1.2.2.1 16-1.2.2 18-1.2 19-1.2.1.r 20-1.2.1.1.1.1 21-1.2.1 (a / and~e.14 :op1 (e / expose-01~e.2 :ARG1 (m / melanosphere~e.0) :ARG2~e.3 (a2 / and~e.9 :op1 (s / small-molecule :name (n2 / name :op1 "cisplatin"~e.4)) :op2 (s2 / small-molecule :name (n3 / name :op1 "temozolomide"~e.6)) :op3 (s3 / small-molecule :name (n4 / name :op1 "dacarbazine"~e.8)) :op4 (s4 / small-molecule :name (n5 / name :op1 "paclitaxel"~e.10))) :duration~e.11 (t / temporal-quantity :quant 48~e.12 :unit (h / hour~e.13))) :op1 (a3 / assess-01~e.18 :ARG0~e.19 (a4 / assay-01~e.21 :instrument (s5 / small-molecule :name (n / name :op1 "MTT"~e.20))) :ARG1 (v / viability~e.16 :mod (c2 / cell~e.15)))) # ::id pmid_2423_8212.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overall a weak cytotoxic effect (< 40 % in all samples and with all drugs ) was observed with no therapeutic window as compared to normal melanocytes ( Figure 2 @ A ) . # ::alignments 0-1.3 2-1.1.3 3-1.1.4 4-1.1 6-1.1.6.1.1 7-1.1.6.1 8-1.1.1.r 9-1.1.1.2 10-1.1.1 10-1.1.1.1 10-1.1.1.1.r 13-1.1.1.2 14-1.1.2 17-1 19-1.1.5.1 19-1.1.5.1.r 20-1.1.5.2.1 21-1.1.5.2 23-1.2.r 25-1.2.1 26-1.2 28-1.4.1 (o / observe-01~e.17 :ARG1 (a / affect-01~e.4 :ARG1~e.8 (t2 / thing~e.10 :ARG1-of~e.10 (s / sample-01~e.10) :mod (a2 / all~e.9,13)) :ARG2 (d2 / drug~e.14 :mod a2) :ARG1-of (w / weak-02~e.2) :mod (c / cytotoxic~e.3) :ARG0-of (h / have-03 :polarity~e.19 -~e.19 :ARG1 (w2 / window~e.21 :mod (t / therapy~e.20))) :degree (l / less-than :op1 (p / percentage-entity~e.7 :value 40~e.6))) :compared-to~e.23 (m / melanocyte~e.26 :ARG1-of (n2 / normal-02~e.25)) :mod (o2 / overall~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.28 :mod "2A"))) # ::id pmid_2423_8212.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Conversely , differentiated cells were extremely sensitive to cisplatin , in 3 out of 3 samples assessed ( Figure 2 @ B is a representative sample ) . # ::alignments 0-1.6 0-1.6.r 2-1.1.1 3-1.1 5-1.3 6-1 7-1.2.r 8-1.2.1.1 10-1.4.r 11-1.4.1 11-1.4.4.1.1 14-1.4.1 14-1.4.4.1.1 15-1.4 15-1.4.3 15-1.4.3.r 16-1.4.2 18-1.5.1 25-1.5.1.2 26-1.5.1.2.1.1 (s / sensitive-03~e.6 :ARG0 (c / cell~e.3 :ARG1-of (d / differentiate-101~e.2)) :ARG1~e.7 (s2 / small-molecule :name (n / name :op1 "cisplatin"~e.8)) :degree (e / extreme~e.5) :location~e.10 (t / thing~e.15 :quant 3~e.11,14 :ARG1-of (a / assess-01~e.16) :ARG1-of~e.15 (s3 / sample-01~e.15) :ARG1-of (i / include-91 :ARG2 (t2 / thing :quant 3~e.11,14 :ARG1-of s3))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.18 :mod "2B" :ARG0-of (r / represent-01~e.25 :ARG1 (t3 / thing :ARG1-of s3~e.26)))) :manner~e.0 (c2 / converse~e.0)) # ::id pmid_2423_8212.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next investigated the cytotoxic potential of a panel of 80 signaling pathway inhibitors on melanospheres derived from patient #1 and #2 and #3 encompassing inhibitors of RAS/RAF/MEK and PI3K @/@ AKT pathways as well as tyrosine kinase receptors . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.2 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.1 11-1.2.1.1.2.1.1 12-1.2.1.1.2.1 13-1.2.1.1 13-1.2.1.1.2 13-1.2.1.1.2.r 15-1.2.3 16-1.2.3.1 17-1.2.3.1.1.r 18-1.2.3.1.1.1.1.1 20-1.2.3.1.1 22-1.2.1.2.1 24-1.2.1.2 25-1.2.1.2.1.1 25-1.2.1.2.1.1.1 25-1.2.1.2.1.1.1.r 26-1.2.1.2.1.1.1.1.r 27-1.2.1.2.1.1.1.1.1.1.1 28-1.2.1.2.1.1.1.1 29-1.2.1.2.1.1.1.1.2.1.1 31-1.2.1.2.1.1.1.1.2.1.1 32-1.2.1.2.1.1.1.1.1 32-1.2.1.2.1.1.1.1.2 33-1.2.1.2.1.1.1.1 34-1.2.1.2.1.1.1.1 35-1.2.1.2.1.1.1.1 35-1.2.1.2.1.r 36-1.2.1.2.1.2.1.1 37-1.2.1.2.1.2.1.2 38-1.2.1.2.1.2.1.3 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (c / capable-01 :ARG1 (p / panel~e.8 :consist-of~e.9 (m / molecular-physical-entity~e.13 :quant 80~e.10 :ARG0-of~e.13 (i2 / inhibit-01~e.13 :ARG1 (p2 / pathway~e.12 :ARG0-of (s / signal-07~e.11)))) :ARG0-of (e / encompass-01~e.24 :ARG1~e.35 (a3 / and~e.22 :op1 (m3 / molecular-physical-entity~e.25 :ARG0-of~e.25 (i3 / inhibit-01~e.25 :ARG1~e.26 (a2 / and~e.28,33,34,35 :op1 (p7 / pathway~e.32 :name (n2 / name :op1 "RAS/RAF/MEK"~e.27)) :op2 (p8 / pathway~e.32 :name (n3 / name :op1 "PI3K/AKT"~e.29,31))))) :op2 (p9 / protein :name (n4 / name :op1 "tyrosine"~e.36 :op2 "kinase"~e.37 :op3 "receptor"~e.38))))) :ARG2 (c2 / cytotoxic~e.4) :beneficiary (m2 / melanosphere~e.15 :ARG1-of (d / derive-01~e.16 :ARG2~e.17 (a / and~e.20 :op1 (p3 / person :ARG1-of (h / have-org-role-91 :ARG2 (p4 / patient~e.18)) :ord (o / ordinal-entity :value 1)) :op2 (p5 / person :ARG1-of h :ord (o2 / ordinal-entity :value 2)) :op3 (p6 / person :ARG1-of h :ord (o3 / ordinal-entity :value 3)))))) :time (n / next~e.1)) # ::id pmid_2423_8212.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only inhibitors of the RAS/RAF/MEK pathway ( including the MEK inhibitors PD098059 and U0126 and the Erk2 inhibitor 5 @-@ iodotubercidin ) showed promising antitumor activity in terms of reduced cell viability , as measured by MTT assay . # ::alignments 0-1.1.3 1-1.1 1-1.1.1 1-1.1.1.r 2-1.1.1.1.r 4-1.1.1.1.1.1 5-1.1.1.1 7-1.1.2 9-1.1.2.1.1.2.1.1.1 10-1.1.2.1.1 10-1.1.2.1.1.2 10-1.1.2.1.1.2.r 11-1.1.2.1.1.1.1 12-1.1.2.1 13-1.1.2.1.2.1.1 14-1.1.2.1 16-1.1.2.1.3.2.1.1.1 17-1.1.2.1.3 17-1.1.2.1.3.2 17-1.1.2.1.3.2.r 18-1.1.2.1.3.1.1 20-1.1.2.1.3.1.1 22-1 23-1.2.2 24-1.2.1.1 25-1.2 28-1.2.3.r 29-1.2.3.2 30-1.2.3.1 31-1.2.3 33-1.2.3.3.r 34-1.2.3.3 35-1.2.3.3.1.r 36-1.2.3.3.1.1.1.1 37-1.2.3.3.1 (s / show-01~e.22 :ARG0 (m / molecular-physical-entity~e.1 :ARG0-of~e.1 (i / inhibit-01~e.1 :ARG1~e.2 (p / pathway~e.5 :name (n / name :op1 "RAS/RAF/MEK"~e.4))) :ARG2-of (i2 / include-01~e.7 :ARG1 (a / and~e.12,14 :op1 (s2 / small-molecule~e.10 :name (n2 / name :op1 "PD098059"~e.11) :ARG0-of~e.10 (i3 / inhibit-01~e.10 :ARG1 (p3 / protein-family :name (n5 / name :op1 "MEK"~e.9)))) :op2 (s3 / small-molecule :name (n3 / name :op1 "U0126"~e.13) :ARG0-of i3) :op3 (s4 / small-molecule~e.17 :name (n4 / name :op1 "5-iodotubercidin"~e.18,20) :ARG0-of~e.17 (i4 / inhibit-01~e.17 :ARG1 (e / enzyme :name (n6 / name :op1 "Erk2"~e.16)))))) :mod (o / only~e.0)) :ARG1 (a2 / activity-06~e.25 :ARG1 (o2 / oppose-01 :ARG1 (t / tumor~e.24)) :ARG0-of (p2 / promise-01~e.23) :topic~e.28 (v / viability~e.31 :mod (c / cell~e.30) :ARG0-of (r / reduce-01~e.29) :ARG1-of~e.33 (m2 / measure-01~e.34 :ARG0~e.35 (a3 / assay-01~e.37 :instrument (s5 / small-molecule :name (n7 / name :op1 "MTT"~e.36))))))) # ::id pmid_2423_8212.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The other drugs , except for the broadly toxic compound staurosporin used as positive control , were nearly unable to reduce cell viability/proliferation , although all compounds were used at doses higher than the described IC @₅₀ in order to enhance their activity . # ::alignments 1-1.2.1.1 2-1.2.1 4-1.2.1.2 5-1.2.1.2.1.r 7-1.2.1.2.1.2.1 8-1.2.1.2.1.2 9-1.2.1.2.1 10-1.2.1.2.1.1.1 11-1.2.1.2.1.3 12-1.2.1.2.1.3.1.r 13-1.2.1.2.1.3.1.1 14-1.2.1.2.1.3.1 17-1.4 18-1 18-1.1 18-1.1.r 20-1.2 21-1.2.2.1.1 24-1.3.r 25-1.3.1.1 26-1.3.1 28-1.3 29-1.3.1.2.r 30-1.3.1.2 31-1.3.1.2.1 31-1.3.1.2.1.1 31-1.3.1.2.1.1.r 32-1.3.1.2.1.2.r 34-1.3.1.2.1.2.2 42-1.3.2 43-1.3.2.1.1 43-1.3.2.1.1.r 44-1.3.2.1 (p / possible-01~e.18 :polarity~e.18 -~e.18 :ARG1 (r / reduce-01~e.20 :ARG0 (d / drug~e.2 :mod (o / other~e.1) :ARG2-of (e / except-01~e.4 :ARG1~e.5 (c / compound~e.9 :name (n / name :op1 "staurosporin"~e.10) :mod (t / toxic~e.8 :ARG1-of (b / broad-02~e.7)) :ARG1-of (u / use-01~e.11 :ARG2~e.12 (c2 / control~e.14 :mod (p2 / positive~e.13)))))) :ARG1 (s / slash :op1 (v / viability :mod (c3 / cell~e.21)) :op2 (p3 / proliferate-01 :ARG0 c3))) :concession~e.24 (u2 / use-01~e.28 :ARG1 (c4 / compound~e.26 :mod (a / all~e.25) :ARG2-of~e.29 (d2 / dose-01~e.30 :ARG1-of (h2 / high-02~e.31 :degree~e.31 (m / more~e.31) :compared-to~e.32 (t2 / thing :name (n2 / name :op1 "IC50") :ARG1-of (d3 / describe-01~e.34))))) :ARG2 (e2 / enhance-01~e.42 :ARG1 (a2 / activity-06~e.44 :ARG0~e.43 c4~e.43))) :mod (n3 / near~e.17)) # ::id pmid_2423_8212.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A similar drug response was observed for the different samples ( Figure 2 @ C shows a representative one ) . # ::alignments 1-1.1.2 2-1.1.1 3-1.1 5-1 8-1.2.2 9-1.2 9-1.2.1 9-1.2.1.r 9-1.3.1.2.1 9-1.3.1.2.1.1 9-1.3.1.2.1.1.r 11-1.3.1 16-1.3.1.2 18-1.3.1.2.1.1.1 (o / observe-01~e.5 :ARG1 (r / respond-01~e.3 :ARG0 (d / drug~e.2) :ARG1-of (r2 / resemble-01~e.1)) :location (t / thing~e.9 :ARG1-of~e.9 (s / sample-01~e.9) :ARG1-of (d2 / differ-02~e.8)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.11 :mod "2C" :ARG0-of (s2 / show-01~e.16 :ARG1 (t2 / thing~e.9 :ARG1-of~e.9 (s3 / sample-01~e.9 :ARG0-of (r3 / represent-01~e.18))))))) # ::id pmid_2423_8212.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In line with the melanosphere sensitivity to compounds targeting the MAPK pathways , we observed the activation of this signaling pathway with high levels of phosphorylation of Erk and downstream S6 ( Figure 2 @ D ) . # ::alignments 4-1.3.1.1.1.1 5-1.3.1 6-1.3.1.2.r 7-1.3.1.2 8-1.3.1.2.1 10-1.3.1.2.1.1.1.1 11-1.3.1.2.1.1 13-1.1 14-1 16-1.2 17-1.2.1.r 18-1.2.1.2 19-1.2.1.1 20-1.2.1 21-1.2.2.r 22-1.2.2.1 23-1.2.2 24-1.2.2.1.1.r 25-1.2.2.1.1 26-1.2.2.1.1.1.r 27-1.2.2.1.1.1.1.1.1 28-1.2.2.1.1.1 29-1.2.2.1.1.1.2.2 30-1.2.2.1.1.1.2.1.1 32-1.4.1 (o / observe-01~e.14 :ARG0 (w / we~e.13) :ARG1 (a / activate-01~e.16 :ARG1~e.17 (p / pathway~e.20 :ARG0-of (s / signal-07~e.19) :mod (t / this~e.18)) :mod~e.21 (l / level~e.23 :ARG1-of (h / high-02~e.22 :ARG2~e.24 (p2 / phosphorylate-01~e.25 :ARG1~e.26 (a2 / and~e.28 :op1 (e / enzyme :name (n / name :op1 "Erk"~e.27)) :op2 (p4 / protein :name (n2 / name :op1 "S6"~e.30) :location (d / downstream~e.29))))))) :ARG1-of (a3 / align-01 :ARG2 (s2 / sensitive-03~e.5 :ARG0 (c / cell :name (n3 / name :op1 "melanosphere"~e.4)) :ARG1~e.6 (c2 / compound~e.7 :ARG0-of (t2 / target-01~e.8 :ARG1 (p5 / pathway~e.11 :name (n4 / name :op1 "MAPK"~e.10)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.32 :mod "2D"))) # ::id pmid_2423_8212.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also found high levels of Cyclin @-@ D and undetectable p16 ( Figure 2 @ D ) . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 4-1.2 5-1.2.1.1.r 6-1.2.1.1.1.1.1 8-1.2.1.1.1.1.1 9-1.2.1.1 10-1.2.1.1.2 10-1.2.1.1.2.2 10-1.2.1.1.2.2.1.1 10-1.2.1.1.2.2.r 11-1.2.1.1.2.1.1 13-1.4.1 17-1.2.1.1.1.1.1 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1 (l / level~e.4 :ARG1-of (h / high-02~e.3 :ARG2~e.5 (a2 / and~e.9 :op1 (p / protein :name (n / name :op1 "Cyclin-D"~e.6,8,17)) :op2 (p2 / protein~e.10 :name (n2 / name :op1 "p16"~e.11) :ARG1-of~e.10 (d / detect-01~e.10 :ARG1-of (p3 / possible-01 :polarity -~e.10)))))) :mod (a / also~e.1) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.13 :mod "2D"))) # ::id pmid_2423_8212.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results are in agreement with the frequent alteration of the RAS/RAF/MEK pathway and cell cycle deregulation found in melanomas . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 4-1 5-1.2.r 7-1.2.1.2 8-1.2.1 9-1.2.1.1.r 11-1.2.1.1.1.1 12-1.2.1.1 13-1.2 14-1.2.2.1.1 15-1.2.2.1 16-1.2.2 17-1.2.3 18-1.2.3.1.r 19-1.2.3.1.1.1 (a / agree-01~e.4 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG2~e.5 (a3 / and~e.13 :op1 (a2 / alter-01~e.8 :ARG1~e.9 (p / pathway~e.12 :name (n / name :op1 "RAS/RAF/MEK"~e.11)) :ARG1-of (f2 / frequent-02~e.7)) :op1 (d / deregulate-01~e.16 :ARG1 (c / cycle~e.15 :mod (c2 / cell~e.14))) :ARG1-of (f / find-01~e.17 :location~e.18 (m / medical-condition :name (n2 / name :op1 "melanoma"~e.19))))) # ::id pmid_2423_8212.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Next , we analyzed DNA sequences of genes whose alterations may contribute to the abnormal pathway activation . # ::alignments 0-1.3 2-1.1 3-1 4-1.2 5-1.2 6-1.2.1.r 7-1.2.1 9-1.2.1.1 10-1.2.1.1.1.2 11-1.2.1.1.1 12-1.2.1.1.1.1.r 14-1.2.1.1.1.1.2 14-1.2.1.1.1.1.2.1 14-1.2.1.1.1.1.2.1.r 15-1.2.1.1.1.1.1 16-1.2.1.1.1.1 (a / analyze-01~e.3 :ARG0 (w / we~e.2) :ARG1 (d / dna-sequence~e.4,5 :part-of~e.6 (g / gene~e.7 :poss-of (a2 / alter-01~e.9 :ARG0-of (c / contribute-01~e.11 :ARG2~e.12 (a3 / activate-01~e.16 :ARG1 (p2 / pathway~e.15) :ARG1-of (n / normal-02~e.14 :polarity~e.14 -~e.14)) :ARG1-of (p3 / possible-01~e.10))))) :time (n2 / next~e.0)) # ::id pmid_2423_8212.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As reported in the Additional file 3 @ : Table S1 , NRAS was never mutated in the analyzed samples . # ::alignments 0-1.5.r 1-1.4 2-1.4.1.r 4-1.4.1.2.2 5-1.4.1.2 7-1.4.1.2.1 10-1.4.1 11-1.4.1.1 13-1.2.1.1 15-1.1 15-1.1.r 15-1.5 16-1 17-1.3.r 19-1.3.1 20-1.3 20-1.3.2 20-1.3.2.r (m / mutate-01~e.16 :polarity~e.15 -~e.15 :ARG1 (e / enzyme :name (n / name :op1 "NRAS"~e.13)) :location~e.17 (t2 / thing~e.20 :ARG1-of (a / analyze-01~e.19) :ARG1-of~e.20 (s / sample-01~e.20)) :ARG1-of (r / report-01~e.1 :medium~e.2 (t / table~e.10 :mod "S1"~e.11 :part-of (f / file~e.5 :mod 3~e.7 :mod (a2 / additional~e.4)))) :time~e.0 (e2 / ever~e.15)) # ::id pmid_2423_8212.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Instead , despite the ubiquitous Erk phosphorylation found in melanospheres , the BRAF @-@ V600E mutation was detected in samples 1 , 2 and 4 , BRAF @-@ V600K mutation was found in samples 5 and 8 , while samples 3 , 6 and 7 displayed wild type BRAF . # ::alignments 0-1.3 2-1 4-1.2.2 5-1.2.1.1.1 6-1.2 7-1.2.3 8-1.2.3.1.r 9-1.2.3.1.1.1 12-1.1.1.1.2.1.1 14-1.1.1.1.1 15-1.1.1.1 17-1.1.1 18-1.1.1.2.r 19-1.1.1.2.1 19-1.1.1.2.1.2 19-1.1.1.2.1.2.r 20-1.1.1.2.1.1 22-1.1.1.2.2.1 23-1.1.1.2 24-1.1.1.2.3.1 26-1.1.2.1.2 28-1.1.2.1.1 29-1.1.2.1 31-1.1.2 32-1.1.2.2.r 33-1.1.2.2.1.2 34-1.1.2.2.1.1 35-1.1.2.2 36-1.1.2.2.2.1 39-1.1.1.2.1 39-1.1.1.2.1.2 39-1.1.1.2.1.2.r 40-1.1.3.1.1.1 42-1.1.3.1.2.1 43-1.1.3.1 44-1.1.3.1.3.1 45-1.1.3 46-1.1.3.2.2 47-1.1.3.2.2 48-1.1.3.2.1.1 (h / have-concession-91~e.2 :ARG1 (a / and :op1 (d / detect-01~e.17 :ARG1 (m / mutate-01~e.15 :value "V600E"~e.14 :ARG2 (e / enzyme :name (n3 / name :op1 "BRAF"~e.12))) :location~e.18 (a2 / and~e.23 :op1 (t / thing~e.19,39 :mod 1~e.20 :ARG1-of~e.19,39 (s / sample-01~e.19,39)) :op2 (t2 / thing :mod 2~e.22 :ARG1-of s) :op3 (t3 / thing :mod 4~e.24 :ARG1-of s))) :op2 (f2 / find-01~e.31 :ARG1 (m2 / mutate-01~e.29 :value "V600K"~e.28 :ARG1 e~e.26) :location~e.32 (a3 / and~e.35 :op1 (t4 / thing :mod 5~e.34 :ARG1-of s~e.33) :op2 (t5 / thing :mod 8~e.36 :ARG1-of s))) :op3 (d2 / display-01~e.45 :ARG0 (a4 / and~e.43 :op1 (t6 / thing :mod 3~e.40 :ARG1-of s) :op2 (t7 / thing :mod 6~e.42 :ARG1-of s) :op3 (t8 / thing :mod 7~e.44 :ARG1-of s)) :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF"~e.48) :mod (w / wild-type~e.46,47)))) :ARG2 (p / phosphorylate-01~e.6 :ARG1 (e3 / enzyme :name (n / name :op1 "Erk"~e.5)) :mod (u / ubiquity~e.4) :ARG1-of (f / find-01~e.7 :location~e.8 (c / cell :name (n2 / name :op1 "melanosphere"~e.9)))) :ARG1-of (i / instead-of-91~e.0)) # ::id pmid_2423_8212.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All samples displayed wild type PTEN . # ::alignments 0-1.1.1 1-1.1 1-1.1.2 1-1.1.2.r 2-1 3-1.2.2 4-1.2.2 5-1.2.1.1 (d / display-01~e.2 :ARG0 (t / thing~e.1 :mod (a / all~e.0) :ARG1-of~e.1 (s / sample-01~e.1)) :ARG1 (p / protein :name (n / name :op1 "PTEN"~e.5) :mod (w / wild-type~e.3,4))) # ::id pmid_2423_8212.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , sequence analysis of the exon 4 and 5 of GNAQ gene , whose mutations have been associated with wild type BRAF and NRAS melanomas , revealed wild type status in all samples ( Additional file 3 @ : Table S1 and Additional file 4 ) [ @ 45 @ ] . # ::alignments 0-1.4 2-1.1.2 3-1.1 6-1.1.1.1 6-1.1.1.2 7-1.1.1.1.1 8-1.1.1 9-1.1.1.2.1 10-1.1.1.r 11-1.1.1.3.1.1 12-1.1.1.3 15-1.1.1.3.2 18-1.1.1.3.2.1 19-1.1.1.3.2.1.1.r 20-1.1.1.3.2.1.1.1.2.2 21-1.1.1.3.2.1.1.1.2.2 22-1.1.1.3.2.1.1.1.2.1.1 23-1.1.1.3.2.1.1 24-1.1.1.3.2.1.1.2.2.1.1 25-1.1.1.3.2.1.1.1.1.1 25-1.1.1.3.2.1.1.2.1.1 27-1 28-1.2.2 29-1.2.2 30-1.2 31-1.2.1.r 32-1.2.1.1 33-1.2.1 33-1.2.1.2 33-1.2.1.2.r 35-1.3.1.1.2.2 36-1.3.1.1.2 38-1.3.1.1.2.1 41-1.3.1.1 42-1.3.1.1.1 43-1.3.1 44-1.3.1.2.2 45-1.3.1.2 47-1.3.1.2.1 52-1.3.1.3.1.1 (r / reveal-01~e.27 :ARG0 (a / analyze-01~e.3 :ARG1~e.10 (a2 / and~e.8 :op1 (e / exon~e.6 :mod 4~e.7) :op2 (e2 / exon~e.6 :mod 5~e.9) :part-of (g / gene~e.12 :name (n / name :op1 "GNAQ"~e.11) :poss-of (m / mutate-01~e.15 :ARG1-of (a3 / associate-01~e.18 :ARG2~e.19 (a4 / and~e.23 :op1 (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.25) :mod (e3 / enzyme :name (n3 / name :op1 "BRAF"~e.22) :mod (w / wild-type~e.20,21))) :op2 (m3 / medical-condition :name (n4 / name :op1 "melanoma"~e.25) :mod (e4 / enzyme :name (n5 / name :op1 "NRAS"~e.24) :mod w))))))) :mod (s / sequence~e.2)) :ARG1 (s2 / status~e.30 :location~e.31 (t2 / thing~e.33 :mod (a5 / all~e.32) :ARG1-of~e.33 (s3 / sample-01~e.33)) :mod w~e.28,29) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and~e.43 :op1 (t / table~e.41 :mod "S1"~e.42 :part-of (f / file~e.36 :mod 3~e.38 :mod (a7 / additional~e.35))) :op2 (f2 / file~e.45 :mod 4~e.47 :mod (a8 / additional~e.44)) :op3 (p / publication :ARG1-of (c / cite-01 :ARG2 45~e.52)))) :time (f3 / final~e.0)) # ::id pmid_2423_8212.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with MEK inhibitor PD0325901 results in strong antitumor activity against melanospheres # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2.1.1.1 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 5-1.1.1.1.1 6-1 7-1.2.r 8-1.2.3 9-1.2.1 9-1.2.2 9-1.2.2.1 9-1.2.2.1.r 10-1.2 11-1.2.1 11-1.2.2 12-1.2.1.1.1.1 (r / result-01~e.6 :ARG1 (t / treat-04~e.1 :ARG2~e.2 (s / small-molecule~e.4 :name (n / name :op1 "PD0325901"~e.5) :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"~e.3))))) :ARG2~e.7 (a / activity-06~e.10 :ARG1 (c2 / counter-01~e.9,11 :ARG1 (c3 / cell :name (n3 / name :op1 "melanosphere"~e.12))) :ARG0-of (c / counter-01~e.9,11 :ARG1~e.9 (t2 / tumor~e.9)) :ARG1-of (s2 / strong-02~e.8))) # ::id pmid_2423_8212.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The encouraging activity of the MEK inhibitors used in the pathway inhibitor screening ( see above ) prompted us to study the antitumor effect of the MEK inhibitor PD0325901 on the melanospheres , based on its antitumor activity described in clinical studies [ @ 16 @ ] . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 5-1.1.1.1.1.1.1 6-1.1.1 6-1.1.1.1 6-1.1.1.1.r 7-1.1.1.2 8-1.1.1.2.1.r 10-1.1.1.2.1.1.1.1 11-1.1.1.2.1.1 11-1.1.1.2.1.1.1 11-1.1.1.2.1.1.1.r 12-1.1.1.2.1 15-1.1.3.1 17-1 18-1.2.1 20-1.2 22-1.2.2.3 22-1.2.2.3.1 22-1.2.2.3.1.r 23-1.2.2 26-1.1.1.1.1.1.1 27-1.1.1 27-1.1.1.1 27-1.1.1.1.r 27-1.2.2.1 27-1.2.2.1.2 27-1.2.2.1.2.r 28-1.2.2.1.1.1 29-1.2.2.2.r 31-1.2.2.2.1.1 33-1.2.3 36-1.2.3.1.2 37-1.2.3.1 38-1.1.3 38-1.2.3.1.3 38-1.2.3.1.3.1.2 39-1.2.3.1.3.1.r 40-1.2.3.1.3.1.1 41-1.2.3.1.3.1 44-1.2.3.1.3.1.2.1.1.1 (p / prompt-01~e.17 :ARG0 (a / activity-06~e.2 :ARG0~e.3 (s / small-molecule~e.6,27 :ARG0-of~e.6,27 (i / inhibit-01~e.6,27 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.5,26))) :ARG1-of (u / use-01~e.7 :ARG2~e.8 (s2 / screen-01~e.12 :ARG1 (s3 / small-molecule~e.11 :ARG0-of~e.11 (i2 / inhibit-01~e.11 :ARG1 (p3 / pathway~e.10)))))) :ARG0-of (e / encourage-01~e.1) :ARG1-of (d / describe-01~e.38 :location (a2 / above~e.15))) :ARG1 (s4 / study-01~e.20 :ARG0 (w / we~e.18) :ARG1 (a3 / affect-01~e.23 :ARG0 (s5 / small-molecule~e.27 :name (n2 / name :op1 "PD0325901"~e.28) :ARG0-of~e.27 (i3 / inhibit-01~e.27 :ARG1 p2)) :ARG1~e.29 (c / cell :name (n3 / name :op1 "melanosphere"~e.31)) :ARG2 (c2 / counter-01~e.22 :ARG1~e.22 (t / tumor~e.22))) :ARG1-of (b / base-02~e.33 :ARG2 (a4 / activity-06~e.37 :ARG0 s5 :ARG1 c2~e.36 :ARG1-of (d2 / describe-01~e.38 :medium~e.39 (s6 / study-01~e.41 :mod (c3 / clinic~e.40) :ARG1-of (d3 / describe-01~e.38 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 16~e.44))))))))) # ::id pmid_2423_8212.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Following 3 day @-@ exposure to PD0325901 , at doses comparable with those achieved in vivo , both wild type and mutated @-@ BRAF cells displayed decreased proliferation/viability , with mutated @-@ BRAF samples being more sensitive to the drug ( Figure 3 @ A ) . # ::alignments 0-1.3 1-1.3.1.3.1 2-1.3.1.3.2 4-1.3.1 5-1.3.1.2.r 6-1.3.1.2.1.1 9-1.3.1.2 9-1.3.1.2.2 9-1.3.1.2.2.1.1 9-1.3.1.2.2.r 9-1.3.1.2.3 9-1.3.1.2.3.r 10-1.3.1.2.2.1 13-1.3.1.2.2.1.1.1 15-1.3.1.2.2.1.1.1.1 16-1.3.1.2.2.1.1.1.1 20-1.1.1.1.2 21-1.1.1.1.2 22-1.1 23-1.1.2.1.2 25-1.1.1.1.1.1 25-1.1.2.1.1.1 26-1.1.1 26-1.1.2 27-1 28-1.2.1.3 32-1.1.2.1.2 34-1.1.1.1.1.1 34-1.1.2.1.1.1 35-1.2.2.1 37-1.2.2.3 38-1.2.2 43-1.4.1 45-1.3.1.3.1 (d / display-01~e.27 :ARG0 (a / and~e.22 :op1 (c / cell~e.26 :mod (e2 / enzyme :name (n / name :op1 "BRAF"~e.25,34) :mod (w / wild-type~e.20,21))) :op2 (c2 / cell~e.26 :mod (e3 / enzyme :name (n2 / name :op1 "BRAF"~e.25,34) :ARG2-of (m / mutate-01~e.23,32)))) :ARG1 (a4 / and :op1 (o / or :op1 (p / proliferate-01) :op2 (v / viability) :ARG1-of (d2 / decrease-01~e.28)) :op2 (s2 / sensitive-03~e.38 :ARG0 (s3 / sample-01~e.35 :mod e3) :ARG1 s :degree (m2 / more~e.37))) :time (a2 / after~e.0 :op1 (e / expose-01~e.4 :ARG1 a :ARG2~e.5 (s / small-molecule~e.9 :name (n3 / name :op1 "PD0325901"~e.6) :quant~e.9 (d4 / dose~e.9 :ARG1-of (c3 / comparable-03~e.10 :ARG2 (d5 / dose~e.9 :ARG1-of (a3 / achieve-01~e.13 :manner (i / in-vivo~e.15,16))))) :ARG2-of~e.9 (d8 / dose-01~e.9)) :duration (t / temporal-quantity :quant 3~e.1,45 :unit (d3 / day~e.2)))) :ARG1-of (d7 / describe-01 :ARG0 (f / figure~e.43 :mod "3A"))) # ::id pmid_2423_8212.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to distinguish the cytostatic from the cytotoxic effect and to unravel the molecular mechanisms of PD0325901 antitumor activity against malenospheres , we first performed cell cycle analysis of control and treated samples . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3.1 9-1.3.1.2 9-1.3.1.3 10-1.3 12-1.3.2 14-1.3.2.2.1 15-1.3.2.2 16-1.3.2.2.2.r 17-1.3.2.2.2.1.1.1 18-1.3.2.2.2.2 18-1.3.2.2.2.2.1 18-1.3.2.2.2.2.1.r 19-1.3.2.2.2 20-1.3.2.2.2.2 20-1.3.2.2.2.3 23-1.1 24-1.4 25-1 26-1.2.2.1 27-1.2.2 28-1.2 29-1.2.1.r 30-1.2.1.1.1 31-1.2.1 32-1.2.1.2.1 33-1.2.1.1 33-1.2.1.1.2 33-1.2.1.1.2.r (p / perform-02~e.25 :ARG0 (w / we~e.23) :ARG1 (a / analyze-01~e.28 :ARG1~e.29 (a2 / and~e.31 :op1 (t3 / thing~e.33 :mod (c3 / control~e.30) :ARG1-of~e.33 (s2 / sample-01~e.33)) :op2 (t4 / thing :ARG1-of (t / treat-04~e.32) :ARG1-of s2)) :mod (c / cycle~e.27 :mod (c2 / cell~e.26))) :purpose~e.0,1,2 (a3 / and~e.10 :op1 (d / distinguish-01~e.3 :ARG0 w :ARG1 (a4 / affect-01~e.9 :ARG2 (c4 / cytostasis)) :ARG2 (a5 / affect-01~e.9 :ARG2 (c5 / cytotoxicity))) :op2 (u / unravel-01~e.12 :ARG0 w :ARG1 (m / mechanism~e.15 :mod (m2 / molecule~e.14) :poss~e.16 (a6 / activity-06~e.19 :ARG0 (s3 / small-molecule :name (n / name :op1 "PD0325901"~e.17)) :ARG1 (c6 / counter-01~e.18,20 :ARG1~e.18 (t2 / tumor~e.18)) :ARG0-of (c7 / counter-01~e.20 :ARG1 (c8 / cell :name (n2 / name :op1 "melanosphere"))))))) :time (f / first~e.24)) # ::id pmid_2423_8212.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok After short exposure ( 2 days ) , PD0325901 greatly affected cell cycle progression by determining accumulation of cells in the G1 phase , both in the wild type and mutated @-@ BRAF samples ( Figure 3 @ B ) . # ::alignments 0-1.6 1-1.6.1.1 2-1.6.1 4-1.6.2.1 5-1.6.2.2 8-1.1.1.1 9-1.4 9-1.4.r 10-1 11-1.2.1.1 12-1.2.1 13-1.2 14-1.3.r 15-1.3 16-1.3.2 17-1.3.2.1.r 18-1.3.2.1 19-1.3.2.2.r 21-1.3.2.2.1.1 22-1.3.2.2.1.2 25-1.3.3.r 27-1.3.3.1.1.2 28-1.3.3.1.1.2 29-1.3.3 30-1.3.3.2.1.2 32-1.3.3.1.1.1.1 32-1.3.3.2.1.1.1 33-1.3.3.1 33-1.3.3.1.2 33-1.3.3.1.2.r 35-1.5.1 (a / affect-01~e.10 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"~e.8)) :ARG1 (p / progress-01~e.13 :ARG1 (c / cycle~e.12 :mod (c2 / cell~e.11))) :ARG2~e.14 (d / determine-01~e.15 :ARG0 s :ARG1 (a2 / accumulate-01~e.16 :ARG1~e.17 (c3 / cell~e.18) :time~e.19 (e2 / event :name (n4 / name :op1 "G1"~e.21 :op2 "phase"~e.22))) :location~e.25 (a3 / and~e.29 :op1 (t2 / thing~e.33 :mod (e3 / enzyme :name (n2 / name :op1 "BRAF"~e.32) :mod (w / wild-type~e.27,28)) :ARG1-of~e.33 (s2 / sample-01~e.33)) :op2 (t3 / thing :mod (e4 / enzyme :name (n3 / name :op1 "BRAF"~e.32) :ARG2-of (m / mutate-01~e.30)) :ARG1-of s2))) :manner~e.9 (g / great~e.9) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.35 :mod "3B")) :time (a4 / after~e.0 :op1 (e / expose-01~e.2 :ARG1-of (s4 / short-07~e.1)) :duration (t / temporal-quantity :quant 2~e.4 :unit (d3 / day~e.5)))) # ::id pmid_2423_8212.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At the molecular level , together with a striking decrease in Cyclin D levels which is in line with the observed cell cycle arrest , treated samples displayed a decline in Erk and S6 phosphorylation , thus , proving MEK signaling inhibition by PD0325901 ( Figure 3 @ C ) . # ::alignments 2-1.4.1 3-1.4 8-1.2.2.2 9-1.2.2 10-1.2.2.1.r 11-1.2.2.1.1.1.1 12-1.2.2.1.1.1.2 13-1.2.2.1 20-1.2.2.3.1.2 21-1.2.2.3.1.1.1 22-1.2.2.3.1.1 23-1.2.2.3.1 25-1.1.1 26-1.1 26-1.1.2 26-1.1.2.r 27-1 29-1.2.1 30-1.2.1.1.r 31-1.2.1.1.1.1.1.1 32-1.2.1.1.1 33-1.2.1.1.1.2.1.1 34-1.2.1.1 36-1.3 38-1.3.1 39-1.3.1.1.2.1.1.1 40-1.3.1.1.2 41-1.3.1.1 42-1.3.1.1.1.r 43-1.3.1.1.1.1.1 45-1.5.1 (d / display-01~e.27 :ARG0 (t2 / thing~e.26 :ARG1-of (t / treat-04~e.25) :ARG1-of~e.26 (s / sample-01~e.26)) :ARG1 (a5 / and :op1 (d2 / decline-01~e.29 :ARG1~e.30 (p / phosphorylate-01~e.34 :ARG1 (a / and~e.32 :op1 (e / enzyme :name (n / name :op1 "Erk"~e.31)) :op2 (p3 / protein :name (n2 / name :op1 "S6"~e.33))))) :op2 (d3 / decrease-01~e.9 :ARG1~e.10 (l2 / level~e.13 :quant-of (p6 / protein :name (n5 / name :op1 "Cyclin"~e.11 :op2 "D"~e.12))) :ARG1-of (s4 / strike-04~e.8) :ARG1-of (a3 / align-01 :ARG2 (a4 / arrest-02~e.23 :ARG1 (c2 / cycle~e.22 :mod (c3 / cell~e.21)) :ARG1-of (o / observe-01~e.20))))) :ARG0-of (c / cause-01~e.36 :ARG1 (p4 / prove-01~e.38 :ARG1 (i / inhibit-01~e.41 :ARG0~e.42 (s2 / small-molecule :name (n3 / name :op1 "PD0325901"~e.43)) :ARG1 (s3 / signal-07~e.40 :ARG0 (p5 / pathway :name (n4 / name :op1 "MEK"~e.39)))))) :location (l / level~e.3 :mod (m / molecule~e.2)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.45 :mod "3C"))) # ::id pmid_2423_8212.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given that PD0325901 may induce apoptosis in melanoma cell lines , we investigated whether a similar mechanism could account for the reduced number of viable cells in PD0325901 @-@ treated melanosphere samples [ @ 17 @ ] . # ::alignments 2-1.2.2.2.3.2.1.1.1 3-1.3.1 4-1.3.1.1 5-1.3.1.1.2 6-1.3.1.1.3.r 7-1.3.1.1.3.1.1.1 8-1.3.1.1.3 9-1.3.1.1.3 11-1.1 12-1 13-1.2.1 13-1.2.1.r 15-1.2.2.1.1 16-1.2.2.1 17-1.2 18-1.2.2 21-1.2.2.2.2 22-1.2.2.2 23-1.2.2.2.1.r 24-1.2.2.2.1.1 25-1.2.2.2.1 27-1.2.2.2.3.2.1.1.1 29-1.2.2.2.3.2 30-1.2.2.2.3.1.1.1 31-1.2.2.2.3 34-1.4.1.1.1 (i / investigate-01~e.12 :ARG0 (w / we~e.11) :ARG1 (p3 / possible-01~e.17 :mode~e.13 interrogative~e.13 :ARG1 (a / account-01~e.18 :ARG0 (m / mechanism~e.16 :ARG1-of (r / resemble-01~e.15)) :ARG1 (n / number-01~e.22 :ARG1~e.23 (c / cell~e.25 :mod (v / viable~e.24)) :ARG1-of (r2 / reduce-01~e.21) :location (s / sample-01~e.31 :ARG1 (c2 / cell :name (n2 / name :op1 "melanosphere"~e.30)) :ARG1-of (t / treat-04~e.29 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD0325901"~e.2,27))))))) :ARG1-of (c3 / cause-01 :ARG0 (p / possible-01~e.3 :ARG1 (i2 / induce-01~e.4 :ARG0 s2 :ARG2 (a2 / apoptosis~e.5) :location~e.6 (c4 / cell-line~e.8,9 :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma"~e.7)))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 17~e.34)))) # ::id pmid_2423_8212.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , PD0325901 @-@ treated mutant @-@ BRAF melanospheres contained a high fraction of apoptotic annexin V @-@ positive cells compared to control samples . # ::alignments 0-1.3 4-1.1.3 5-1.1.2 5-1.1.2.2 5-1.1.2.2.r 7-1.1.2.1.1 8-1.1.1.1 9-1 11-1.2.1 12-1.2 13-1.2.2.r 14-1.2.2.2 15-1.2.2.1.1.1.1 16-1.2.2.1.1.1.2 18-1.2.2.1 19-1.2.2 20-1.2.3.r 22-1.2.3.1 23-1.2.3 23-1.2.3.2 23-1.2.3.2.r (c / contain-01~e.9 :ARG0 (c2 / cell :name (n / name :op1 "melanosphere"~e.8) :mod (e / enzyme~e.5 :name (n2 / name :op1 "BRAF"~e.7) :ARG2-of~e.5 (m / mutate-01~e.5)) :ARG1-of (t / treat-04~e.4 :ARG2 (s / small-molecule :name (n3 / name :op1 "PD0335901")))) :ARG1 (f / fraction~e.12 :ARG1-of (h / high-02~e.11) :quant-of~e.13 (c3 / cell~e.19 :mod (p / positive~e.18 :mod (p2 / protein :name (n4 / name :op1 "annexin"~e.15 :op2 "V"~e.16))) :mod (a / apoptosis~e.14)) :compared-to~e.20 (t2 / thing~e.23 :mod (c4 / control~e.22) :ARG1-of~e.23 (s2 / sample-01~e.23))) :mod (i / indeed~e.0)) # ::id pmid_2423_8212.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , PD0325901 treated wild type @-@ BRAF melanospheres did not show such a dramatic increase ( Figure 3 @ D ) . # ::alignments 1-1 3-1.1.2.2.1.1.1 4-1.1.2.2 5-1.1.2.3.2 6-1.1.2.3.2 8-1.1.2.3.1.1 9-1.1.2.1.1 11-1.1.1 11-1.1.1.r 12-1.1 15-1.1.3.1 16-1.1.3 18-1.2.1 (c3 / contrast-01~e.1 :ARG2 (s / show-01~e.12 :polarity~e.11 -~e.11 :ARG0 (c / cell :name (n / name :op1 "melanosphere"~e.9) :ARG1-of (t / treat-04~e.4 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"~e.3))) :mod (e / enzyme :name (n3 / name :op1 "BRAF"~e.8) :mod (w / wild-type~e.5,6))) :ARG1 (i / increase-01~e.16 :ARG2 (d / dramatic~e.15))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.18 :mod "3D"))) # ::id pmid_2423_8212.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , we found that both wild type and mutated @-@ BRAF melanoma differentiated cells , were exquisitely sensitive to the drug , as indicated by the high fraction of sub @-@ diploid cells detected in treated samples stained with Propidium Iodide ( Figure 3 @ E ) . # ::alignments 0-1.3 2-1.1 3-1 6-1.2.1.2.3 7-1.2.1.2.3 8-1.2.1 9-1.2.1.1.3.2 11-1.2.1.1.3.1.1 12-1.2.1.1.2.1.1 13-1.2.1.1.1 14-1.2.1.1 14-1.2.1.2 17-1.2.3 17-1.2.3.r 18-1.2 19-1.2.2.r 21-1.2.2 23-1.2.4.r 24-1.2.4 25-1.2.4.1.r 27-1.2.4.1.1 28-1.2.4.1 29-1.2.4.1.2.r 30-1.2.4.1.2.1 32-1.2.4.1.2.1 33-1.2.4.1.2 34-1.2.4.1.2.2 35-1.2.4.1.2.2.1.r 36-1.2.4.1.2.2.1.1 37-1.2.4.1.2.2.1 37-1.2.4.1.2.2.1.3 37-1.2.4.1.2.2.1.3.r 38-1.2.4.1.2.2.1.2 39-1.2.4.1.2.2.1.2.1.r 40-1.2.4.1.2.2.1.2.1.1.1 41-1.2.4.1.2.2.1.2.1.1.2 43-1.4.1 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1 (s / sensitive-03~e.18 :ARG0 (a / and~e.8 :op1 (c / cell~e.14 :ARG1-of (d / differentiate-01~e.13) :mod (m2 / medical-condition :name (n / name :op1 "melanoma"~e.12)) :mod (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.11) :ARG2-of (m / mutate-01~e.9))) :op2 (c2 / cell~e.14 :ARG1-of d :mod m2 :mod (w2 / wild-type~e.6,7))) :ARG1~e.19 (d3 / drug~e.21) :manner~e.17 (e / exquisite~e.17) :ARG1-of~e.23 (i / indicate-01~e.24 :ARG0~e.25 (f2 / fraction~e.28 :ARG1-of (h / high-02~e.27) :quant-of~e.29 (c3 / cell~e.33 :mod (s2 / sub-diploid~e.30,32) :ARG1-of (d4 / detect-01~e.34 :location~e.35 (t2 / thing~e.37 :ARG1-of (t / treat-04~e.36) :ARG1-of (s4 / stain-01~e.38 :ARG2~e.39 (s5 / small-molecule :name (n3 / name :op1 "Propidium"~e.40 :op2 "Iodide"~e.41))) :ARG1-of~e.37 (s3 / sample-01~e.37))))))) :mod (i2 / important~e.0) :ARG1-of (d5 / describe-01 :ARG0 (f3 / figure~e.43 :mod "3E"))) # ::id pmid_2423_8212.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This additional apoptosis assay confirmed that , at the level of melanospheres , only mutated @-@ BRAF cells rapidly underwent PD0325901 @-@ induced apoptosis , while apoptotic hypodiploid DNA @-@ cells were almost absent in the treated wild type @-@ BRAF cells ( Figure 3 @ E ) . # ::alignments 0-1.1.3 1-1.1.2 2-1.1.1 3-1.1 4-1 7-1.2.r 9-1.2.3 10-1.2.3.1.r 11-1.2.3.1.1.1 13-1.2.1.1.2 14-1.2.1.1.1.2 16-1.2.1.1.1.1.1 17-1.2.1.1 18-1.2.1.3 18-1.2.1.3.r 19-1.2.1 20-1.2.1.2.1.1.1.1 22-1.2.1.2.1 23-1.2.1.2 25-1.2 26-1.2.1.2 26-1.2.2.1.2 27-1.2.2.1.1 28-1.2.2.1.3.1.1 30-1.2.2.1 30-1.2.2.2 32-1.2.2.3 33-1.2.2 36-1.2.2.2.2 37-1.2.2.2.1.2 38-1.2.2.2.1.2 40-1.2.2.2.1.1.1 41-1.2.2.2 43-1.3.1 (c / confirm-01~e.4 :ARG0 (a / assay-01~e.3 :ARG1 (a2 / apoptosis~e.2) :mod (a3 / additional~e.1) :mod (t / this~e.0)) :ARG1~e.7 (c3 / contrast-01~e.25 :ARG1 (u / undergo-28~e.19 :ARG1 (c2 / cell~e.17 :mod (e2 / enzyme :name (n / name :op1 "BRAF"~e.16) :ARG2-of (m / mutate-01~e.14)) :mod (o / only~e.13)) :ARG2 (a4 / apoptosis~e.23,26 :ARG2-of (i / induce-01~e.22 :ARG0 (s / small-molecule :name (n2 / name :op1 "PD0325901"~e.20)))) :manner~e.18 (r / rapid~e.18)) :ARG2 (a5 / absent-01~e.33 :ARG1 (c4 / cell~e.30 :mod (h / hypodiploid~e.27) :mod (a6 / apoptosis~e.26) :mod (n5 / nucleic-acid :name (n6 / name :op1 "DNA"~e.28))) :ARG2 (c5 / cell~e.30,41 :mod (e / enzyme :name (n3 / name :op1 "BRAF"~e.40) :mod (w / wild-type~e.37,38)) :ARG1-of (t2 / treat-04~e.36)) :degree (a7 / almost~e.32)) :location (l / level~e.9 :mod~e.10 (c6 / cell :name (n4 / name :op1 "melanosphere"~e.11)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.43 :mod "3E"))) # ::id pmid_2423_8212.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that PD0325901 exerted strong cytotoxic activity against mutant @-@ BRAF melanospheres , and a strong cytostatic activity against wild type @-@ BRAF melanospheres , where cytotoxicity played a minor role . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2 6-1.2.2.1.2 8-1.2.2.1 9-1.2.2.1.3 10-1.2.2.1.3.1.2 10-1.2.2.1.3.1.2.2 10-1.2.2.1.3.1.2.2.r 12-1.2.2.1.3.1.2.1.1 13-1.2.2.1.3.1.1.1 17-1.2.2.1.2 19-1.2.2.1 19-1.2.2.2 20-1.2.2.2.2 21-1.2.2.2.2.1.2.2 22-1.2.2.2.2.1.2.2 24-1.2.2.2.2.1.2.1.1 25-1.2.2.2.2.1.1.1 27-1.2.2.2.2.1.3.r 28-1.2.2.1.1 28-1.2.2.2.2.1.3.1 29-1.2.2.2.2.1.3 31-1.2.2.2.2.1.3.2.1 32-1.2.2.2.2.1.3.2 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (e / exert-01~e.5 :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"~e.4)) :ARG1 (a / and :op1 (a2 / activity-06~e.8,19 :ARG1 (c / cytotoxicity~e.28) :ARG1-of (s2 / strong-02~e.6,17) :ARG0-of (c3 / counter-01~e.9 :ARG1 (c2 / cell :name (n2 / name :op1 "melanosphere"~e.13) :mod (e2 / enzyme~e.10 :name (n3 / name :op1 "BRAF"~e.12) :ARG2-of~e.10 (m / mutate-01~e.10))))) :op2 (a3 / activity-06~e.19 :ARG1 (c4 / cytostasis) :ARG0-of (c5 / counter-01~e.20 :ARG1 (c6 / cell :name (n4 / name :op1 "melanosphere"~e.25) :mod (e3 / enzyme :name (n5 / name :op1 "BRAF"~e.24) :mod (w / wild-type~e.21,22)) :location-of~e.27 (p / play-02~e.29 :ARG0 (c7 / cytotoxicity~e.28) :ARG1 (r2 / role~e.32 :ARG1-of (m2 / minor-01~e.31))))) :ARG1-of s2)))) # ::id pmid_2423_8212.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , differentiated melanoma cells were efficiently killed by PD0325901 , regardless BRAF status ( Figure 3 @ E ) . # ::alignments 1-1 3-1.1.2.1 4-1.1.2.2.1.1 5-1.1.2 7-1.1.3 8-1.1 9-1.1.1.r 10-1.1.1.1.1 12-1.1.4.r 13-1.1.4.1.1.1 14-1.1.4 16-1.2.1 (c3 / contrast-01~e.1 :ARG2 (k / kill-01~e.8 :ARG0~e.9 (s / small-molecule :name (n2 / name :op1 "PD0325901"~e.10)) :ARG1 (c / cell~e.5 :ARG1-of (d / differentiate-01~e.3) :mod (m / medical-condition :name (n / name :op1 "melanoma"~e.4))) :ARG2-of (e / efficient-01~e.7) :concession~e.12 (s2 / status~e.14 :mod (e2 / enzyme :name (n3 / name :op1 "BRAF"~e.13)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.16 :mod "3E"))) # ::id pmid_2423_8212.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with MEK inhibitor PD0325901 results in strong antitumor activity in melanosphere @-@ derived xenografts # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2.1.1.1 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 5-1.1.1.1.1 6-1 7-1.2.r 8-1.2.2 9-1.2.1 9-1.2.1.1 9-1.2.1.1.r 10-1.2 11-1.2.3.r 12-1.2.3.1.1.1.1 14-1.2.3.1 15-1.2.3 (r / result-01~e.6 :ARG1 (t / treat-04~e.1 :ARG2~e.2 (s / small-molecule~e.4 :name (n / name :op1 "PD0325901"~e.5) :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"~e.3))))) :ARG2~e.7 (a / activity-06~e.10 :ARG1 (c / counter-01~e.9 :ARG1~e.9 (t2 / tumor~e.9)) :ARG1-of (s2 / strong-02~e.8) :location~e.11 (x / xenograft~e.15 :ARG1-of (d / derive-01~e.14 :ARG2 (c2 / cell :name (n3 / name :op1 "melanosphere"~e.12)))))) # ::id pmid_2423_8212.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We investigated the activity of PD0325901 against melanosphere @-@ generated subcutaneous xenografts . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1.1 6-1.2.2 7-1.2.2.1.2.1.1.1 9-1.2.2.1.2 10-1.2.2.1.1 11-1.2.2.1 (i / investigate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / activity-06~e.3 :ARG0~e.4 (s / small-molecule :name (n / name :op1 "PD0325901"~e.5)) :ARG0-of (c / counter-01~e.6 :ARG1 (x / xenograft~e.11 :mod (s2 / subcutaneous~e.10) :ARG1-of (g / generate-01~e.9 :ARG2 (c2 / cell :name (n2 / name :op1 "melanosphere"~e.7))))))) # ::id pmid_2423_8212.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Doses of 25 or 12.5 mg @/@ Kg were investigated in order to define a well tolerated dose with reduced toxicity and maximum antitumor activity , as the optimal doses and schedules for antitumor activity in the absence of toxicity was not previously determined in cancer patients . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1.1.1.1 4-1.1.1.1.2 5-1.1.1.2 9-1 10-1.2.r 11-1.2.r 12-1.2.r 13-1.2 15-1.2.1.1.1 16-1.2.1.1 17-1.2.1 19-1.2.1.2.1.1.1 20-1.2.1.2.1.1 21-1.2.1.2.1 22-1.2.1.2.1.2.2 23-1.2.1.2.1.2.1 23-1.2.1.2.1.2.1.1 23-1.2.1.2.1.2.1.1.r 24-1.2.1.2.1.2 26-1.3.1.3.r 28-1.3.1.2.1.1 29-1.3.1.2.1 30-1.3.1.2 31-1.3.1.2.2 33-1.3.1.2.3.1 34-1.3.1.2.3 37-1.3.1.4 38-1.3.1.4.1.r 39-1.3.1.4.1 41-1.3.1.1 41-1.3.1.1.r 42-1.3.1.3 43-1.3.1 44-1.3.1.5.r 45-1.3.1.5.2 46-1.3.1.5.1.1 (i / investigate-01~e.9 :ARG1 (d / dose~e.0 :quant~e.1 (c / concentration-quantity :quant (o / or~e.3 :op1 25~e.2 :op2 12.5~e.4) :unit (m / milligram-per-kilogram~e.5))) :purpose~e.10,11,12 (d2 / define-01~e.13 :ARG1 (d3 / dose~e.17 :ARG1-of (t / tolerate-01~e.16 :ARG1-of (w / well-09~e.15)) :ARG0-of (h2 / have-03 :ARG1 (a5 / and~e.21 :op1 (t2 / toxicity~e.20 :ARG1-of (r / reduce-01~e.19)) :op2 (a / activity-06~e.24 :ARG1 (c2 / counter-01~e.23 :ARG1~e.23 (t3 / tumor~e.23)) :degree (m2 / maximum~e.22)))))) :ARG1-of (c3 / cause-01 :ARG0 (d4 / determine-01~e.43 :polarity~e.41 -~e.41 :ARG1 (a2 / and~e.30 :op1 (d5 / dose~e.29 :mod (o2 / optimal~e.28)) :op2 (s / schedule~e.31 :mod o2) :beneficiary (a3 / activity-06~e.34 :ARG1 c2~e.33)) :time~e.26 (p / previous~e.42) :condition (a4 / absent-01~e.37 :ARG1~e.38 (t5 / toxicity~e.39)) :location~e.44 (p2 / person :ARG0-of (h / have-rel-role-91 :ARG2 (p3 / patient~e.46)) :mod (c5 / cancer~e.45))))) # ::id pmid_2423_8212.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We chose the bi @-@ weekly treatment schedule for drug administration based on previously published results showing high systemic toxicity occurring during daily drug administration [ @ 46 @ ] and as we previously experienced similar results in mice ( results not shown ) . # ::alignments 0-1.1 1-1 5-1.2.4 5-1.2.4.1 5-1.2.4.1.r 5-1.2.4.2.2 6-1.2.2 7-1.2 8-1.2.3.r 9-1.2.3.1 10-1.2.3 11-1.3 12-1.3.1.r 13-1.3.1.1.2.1 14-1.3.1.1.2 14-1.3.1.1.5.1 15-1.3.1.1 15-1.3.1.1.1 15-1.3.1.1.1.r 16-1.3.1.1.3 17-1.3.1.1.4 18-1.3.1.1.3.1.1 19-1.3.1.1.3.1 21-1.3.1.1.3.1.2.r 22-1.2.4 22-1.2.4.1 22-1.2.4.1.r 22-1.2.4.2 22-1.2.4.2.r 22-1.3.1.1.3.1.2.2 22-1.3.1.1.3.1.2.2.1 22-1.3.1.1.3.1.2.2.1.1 22-1.3.1.1.3.1.2.2.1.1.r 22-1.3.1.1.3.1.2.2.1.2 22-1.3.1.1.3.1.2.2.1.2.r 22-1.3.1.1.3.1.2.2.1.r 23-1.3.1.1.3.1.2.1 24-1.3.1.1.3.1.2 27-1.3.1.1.5.1.1.1 30-1.3.1 31-1.3.1.1.2.1.r 31-1.3.1.2.3.r 32-1.1 33-1.3.1.2.3 34-1.3.1.2 35-1.3.1.2.2.2 36-1.3.1.2.2 36-1.3.1.2.2.1 36-1.3.1.2.2.1.r 38-1.3.1.2.2.3 40-1.3.1.2.2 40-1.3.1.2.2.1 40-1.3.1.2.2.1.r 41-1.3.1.2.2.4.1 41-1.3.1.2.2.4.1.r 42-1.3.1.2.2.4 (c / choose-01~e.1 :ARG0 (w / we~e.0,32) :ARG1 (s / schedule-01~e.7 :ARG0 w :ARG1 (t / treat-04~e.6) :ARG2~e.8 (a / administer-01~e.10 :ARG1 (d / drug~e.9)) :ARG3 (r / rate-entity-91~e.5,22 :ARG1~e.5,22 1~e.5,22 :ARG2~e.22 (t2 / temporal-quantity~e.22 :quant 2 :unit (w2 / week~e.5)))) :ARG1-of (b / base-02~e.11 :ARG2~e.12 (a3 / and~e.30 :op1 (t3 / thing~e.15 :ARG2-of~e.15 (r2 / result-01~e.15) :ARG1-of (p4 / publish-01~e.14 :time~e.31 (p / previous~e.13)) :ARG0-of (s2 / show-01~e.16 :ARG1 (t4 / toxicity~e.19 :mod (s3 / systemic~e.18) :time~e.21 (a2 / administer-01~e.24 :ARG1 d~e.23 :frequency (r3 / rate-entity-91~e.22 :ARG3~e.22 (t5 / temporal-quantity~e.22 :quant~e.22 1~e.22 :unit~e.22 (d2 / day~e.22)))))) :ARG1-of (h / high-02~e.17) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication~e.14 :ARG1-of (c2 / cite-01 :ARG2 46~e.27)))) :op2 (e2 / experience-01~e.34 :ARG0 w :ARG1 (t6 / thing~e.36,40 :ARG2-of~e.36,40 (r4 / result-01~e.36,40) :ARG1-of (r5 / resemble-01~e.35) :location (m / mouse~e.38) :ARG1-of (s4 / show-01~e.42 :polarity~e.41 -~e.41)) :time~e.31 p~e.33)))) # ::id pmid_2423_8212.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PD0325901 administration , by oral gavage , caused a striking reduction in tumor growth at both drug doses , displaying stronger activity for the higher dose ( Figure 4 @ A and Additional file 5 @ : Figure S3A ) . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2.r 4-1.1.2 7-1 9-1.2.2 10-1.2 11-1.2.1.r 12-1.2.1.1 13-1.2.1 14-1.2.1.2.r 15-1.2.1.2.2 16-1.2.1.2.1 17-1.2.1.2 19-1.1.3 20-1.1.3.1.2 20-1.1.3.1.2.1 20-1.1.3.1.2.1.r 21-1.1.3.1 22-1.1.3.1.1.r 24-1.1.3.1.1.1 25-1.1.3.1.1 27-1.3.1.1 27-1.3.1.2 32-1.3.1 33-1.3.1.2.2.2 34-1.3.1.2.2 36-1.3.1.2.2.1 39-1.3.1.2 40-1.3.1.2.1 (c / cause-01~e.7 :ARG0 (a / administer-01~e.1 :ARG1 (s / small-molecule :name (n / name :op1 "PD0325901"~e.0)) :medium~e.3 (m / mouth~e.4) :ARG0-of (d3 / display-01~e.19 :ARG1 (a2 / activity-06~e.21 :ARG0~e.22 (d4 / dose~e.25 :ARG1-of (h / high-02~e.24 :degree m2)) :ARG1-of (s3 / strong-02~e.20 :degree~e.20 (m2 / more~e.20))))) :ARG1 (r / reduce-01~e.10 :ARG1~e.11 (g / grow-01~e.13 :ARG1 (t / tumor~e.12) :condition~e.14 (d / dose-01~e.17 :ARG1 (d2 / drug~e.16) :mod (b / both~e.15))) :ARG1-of (s2 / strike-04~e.9)) :ARG1-of (d5 / describe-01 :ARG0 (a3 / and~e.32 :op1 (f / figure~e.27 :mod "4A") :op2 (f2 / figure~e.27,39 :mod "S3A"~e.40 :part-of (f3 / file~e.34 :mod 5~e.36 :mod (a4 / additional~e.33)))))) # ::id pmid_2423_8212.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , treated mice did not exhibit signs of toxicity under this treatment schedule . # ::alignments 0-1.5 2-1.2.1 3-1.2 5-1.1 5-1.1.r 6-1 7-1.3 8-1.3.1.r 9-1.3.1 11-1.4.2 12-1.4.1 13-1.4 (e / exhibit-01~e.6 :polarity~e.5 -~e.5 :ARG0 (m / mouse~e.3 :ARG1-of (t / treat-04~e.2)) :ARG1 (s / signal-07~e.7 :ARG1~e.8 (t2 / toxicity~e.9)) :condition (s2 / schedule-01~e.13 :ARG1 (t3 / treat-04~e.12) :mod (t4 / this~e.11)) :mod (i / important~e.0)) # ::id pmid_2423_8212.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblot analysis of xenografts displayed markedly reduced levels of Erk and downstream S6 phosphorylation in treated tumors , indicating that PD0325901 levels reached in vivo were sufficient to achieve almost complete Erk inactivation and that the effects observed on tumors were caused by specific PD0325901 activity ( Additional file 5 @ : Figure S3B ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1 4-1 5-1.2.2.1 6-1.2.2 7-1.2 8-1.2.1.r 9-1.2.1.1.1.1.1 10-1.2.1.1 11-1.2.1.1.2.2 12-1.2.1.1.2.1.1 13-1.2.1 14-1.2.3.r 14-1.3.1.1.1.2.1 15-1.2.3.1 16-1.2.3 18-1.3 20-1.3.1.1.1.1.1.1 21-1.3.1.1.1 22-1.3.1.1.1.2 24-1.3.1.1.1.2.1 25-1.3.1.1.1.2.1 28-1.3.1.1 30-1.3.1.1.2 31-1.3.1.1.2.2.3.1 32-1.3.1.1.2.2.3 33-1.3.1.1.2.2.2 34-1.3.1.1.2.2 34-1.3.1.1.2.2.1 34-1.3.1.1.2.2.1.r 35-1.3.1 36-1.3.1.r 38-1.3.1.2.2 39-1.3.1.2.2.1 40-1.3.1.2.2.1.1.r 41-1.3.1.2.2.1.1 43-1.3.1.2 44-1.3.1.2.1.r 45-1.3.1.2.1.2 46-1.3.1.2.1.1 47-1.3.1.2.1 49-1.4.1.2.2 50-1.4.1.2 52-1.4.1.2.1 55-1.4.1 56-1.4.1.1 (d / display-01~e.4 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (x / xenograft~e.3) :mod (i / immunoblot-01~e.0)) :ARG1 (l / level~e.7 :degree-of~e.8 (p2 / phosphorylate-01~e.13 :ARG1 (a3 / and~e.10 :op1 (e / enzyme :name (n / name :op1 "Erk"~e.9)) :op2 (p3 / protein :name (n2 / name :op1 "S6"~e.12) :location (d2 / downstream~e.11)))) :ARG1-of (r / reduce-01~e.6 :ARG2 (m / marked~e.5)) :location~e.14 (t / tumor~e.16 :ARG1-of (t2 / treat-04~e.15))) :ARG0-of (i2 / indicate-01~e.18 :ARG1~e.36 (a6 / and~e.35 :op1 (s2 / suffice-01~e.28 :ARG0 (l2 / level~e.21 :quant-of (s / small-molecule :name (n3 / name :op1 "PD0325901"~e.20)) :ARG1-of (r2 / reach-01~e.22 :manner (i3 / in-vivo~e.14,24,25))) :ARG1 (a2 / achieve-01~e.30 :ARG0 l2 :ARG1 (a4 / activate-01~e.34 :polarity~e.34 -~e.34 :ARG1 e~e.33 :ARG1-of (c / complete-02~e.32 :degree (a5 / almost~e.31))))) :op2 (c2 / cause-01~e.43 :ARG0~e.44 (a8 / activity-06~e.47 :ARG0 s~e.46 :ARG1-of (s3 / specific-02~e.45)) :ARG1 (a7 / affect-01~e.38 :ARG1-of (o / observe-01~e.39 :location~e.40 (t3 / tumor~e.41)))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.55 :mod "S3B"~e.56 :part-of (f2 / file~e.50 :mod 5~e.52 :mod (a9 / additional~e.49))))) # ::id pmid_2423_8212.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunohistochemistry analysis of xenografts revealed decreased proliferation rates for treated tumors ( lower Ki @-@ 67 expression in comparison with control tumors ) and reduced activation of the Mek @/@ Erk pathway ( lower Erk phosphorylation ) ( Figure 4 @ B ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1 4-1 5-1.2.1.2 6-1.2.1.1 7-1.2.1 8-1.2.1.1.1.r 9-1.2.1.1.1.1 10-1.2.1.1.1 12-1.2.1.3.1.2 12-1.2.1.3.1.2.1 12-1.2.1.3.1.2.1.r 13-1.2.1.3.1.1.1.1 15-1.2.1.3.1.1.1.1 16-1.2.1.3.1 17-1.2.1.3.1.2.2.r 18-1.2.1.3.1.2.2 19-1.2.1.3.1.2.2.1.r 20-1.2.1.3.1.2.2.1.1 21-1.2.1.3.1.2.2.1 23-1.2 24-1.2.2.2 25-1.2.2 26-1.2.2.1.r 28-1.2.2.1.1.1 30-1.2.2.1.1.1 31-1.2.2.1 33-1.2.2.3.1.2 34-1.2.2.3.1.1.1.1 35-1.2.2.3.1 38-1.3.1 (r / reveal-01~e.4 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (x / xenograft~e.3) :mod (i / immunohistochemistry~e.0)) :ARG1 (a2 / and~e.23 :op1 (r2 / rate~e.7 :degree-of (p / proliferate-01~e.6 :ARG0~e.8 (t / tumor~e.10 :ARG1-of (t2 / treat-04~e.9))) :ARG1-of (d / decrease-01~e.5) :ARG1-of (m2 / mean-01 :ARG2 (e / express-03~e.16 :ARG2 (p2 / protein :name (n / name :op1 "Ki-67"~e.13,15)) :ARG1-of (l / low-04~e.12 :degree~e.12 (m / more~e.12) :ARG1-of~e.17 (c / compare-01~e.18 :ARG2~e.19 (t3 / tumor~e.21 :mod (c2 / control~e.20))))))) :op2 (a3 / activate-01~e.25 :ARG1~e.26 (p3 / pathway~e.31 :name (n2 / name :op1 "Mek/Erk"~e.28,30)) :ARG1-of (r3 / reduce-01~e.24) :ARG1-of (m3 / mean-01 :ARG2 (p4 / phosphorylate-01~e.35 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk"~e.34)) :ARG1-of (l2 / low-04~e.33 :degree m))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.38 :mod "4B"))) # ::id pmid_2423_8212.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , staining with murine CD34 antibody demonstrated a strong inhibitory effect of PD0325901 on tumor vascularization , as control tumors contained large vessels , while treated tumors displayed drastically compromised vasculature composed by minuscule vessels ( Figure 4 @ B ) . # ::alignments 0-1 1-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.2.1.1 6-1.1.1.1.1.1.1.1 7-1.1.1.1 8-1.1 10-1.1.2.4 11-1.1.2.3 12-1.1.2 13-1.1.2.1.r 14-1.1.2.1.1.1 16-1.1.2.2.1 16-1.1.2.5.1.1.1 20-1.1.2.5.1.1.1.1 21-1.1.2.5.1.1.1 22-1.1.2.5.1.1 23-1.1.2.5.1.1.2.1 24-1.1.2.5.1.1.2 26-1.1.2.5.1 27-1.1.2.5.1.2.1.1 28-1.1.2.5.1.2.1 29-1.1.2.5.1.2 30-1.1.2.5.1.2.2.1.1 31-1.1.2.5.1.2.2.1 32-1.1.2.5.1.2.2 33-1.1.2.5.1.2.2.2 34-1.1.2.5.1.2.2.2.1.r 35-1.1.2.5.1.2.2.2.1.1 36-1.1.2.5.1.2.2.2.1 38-1.2.1 (a2 / and~e.0,1 :op2 (d / demonstrate-01~e.8 :ARG0 (s / stain-01~e.3 :ARG2~e.4 (a3 / antibody~e.7 :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "CD34"~e.6) :mod (o / organism :name (n3 / name :op1 "Muridae"~e.5)))))) :ARG1 (a / affect-01~e.12 :ARG0~e.13 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"~e.14)) :ARG1 (v / vascularize-01 :ARG1 (t / tumor~e.16)) :ARG2 (i / inhibit-01~e.11) :ARG1-of (s3 / strong-02~e.10) :ARG1-of (c / cause-01 :ARG0 (c7 / contrast-01~e.26 :ARG1 (c3 / contain-01~e.22 :ARG0 (t2 / tumor~e.16,21 :mod (c4 / control~e.20)) :ARG1 (v2 / vessel~e.24 :mod (l / large~e.23))) :ARG2 (d2 / display-01~e.29 :ARG0 (t3 / tumor~e.28 :ARG1-of (t4 / treat-04~e.27)) :ARG1 (v3 / vasculature~e.32 :ARG1-of (c5 / compromise-02~e.31 :manner (d3 / drastic~e.30)) :ARG1-of (c6 / compose-01~e.33 :ARG2~e.34 (v4 / vessel~e.36 :mod (m / minuscule~e.35))))))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.38 :mod "4B"))) # ::id pmid_2423_8212.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A decrease of tumor vascularization appeared also by macroscopic observation of the tumors ( Additional file 5 @ : Figure S3A ) . # ::alignments 1-1.1 3-1.1.1.1 5-1 6-1.2 9-1.3 10-1.3.1.r 12-1.3.1 14-1.4.1.2.2 15-1.4.1.2 17-1.4.1.2.1 20-1.4.1 21-1.4.1.1 (a / appear-01~e.5 :ARG1 (d / decrease-01~e.1 :ARG1 (v / vascularize-01 :ARG1 (t / tumor~e.3))) :mod (a2 / also~e.6) :manner (o / observe-01~e.9 :ARG1~e.10 t~e.12 :mod (m / macroscopy)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.20 :mod "S3A"~e.21 :part-of (f2 / file~e.15 :mod 5~e.17 :mod (a3 / additional~e.14))))) # ::id pmid_2423_8212.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , similar results were obtained when xenografts were generated by wild type @-@ BRAF melanospheres indicating that this strategy might constitute a potentially exploitable therapeutic approach both for mutated @-@ BRAF and wild type @-@ BRAF melanoma patients ( Figure 4 @ C and D ) . # ::alignments 0-1.4 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 5-1 6-1.2.r 7-1.2.2 9-1.2 10-1.2.1.r 11-1.2.1.3.3 12-1.2.1.3.3 14-1.2.1.3.2.1 15-1.2.1.2.1 16-1.3 17-1.3.1.r 18-1.3.1.1.1.1 19-1.3.1.1.1 20-1.3.1 20-1.3.1.1.2.1.1 21-1.3.1.1 23-1.3.1.1.2.1.2 23-1.3.1.1.2.1.2.r 25-1.3.1.1.2.2 26-1.3.1.1.2 28-1.3.1.1.2.3.r 29-1.3.1.1.2.3.1.2.3.3 31-1.2.1.3.2.1 31-1.3.1.1.2.3.1.2.3.2.1 32-1.3.1.1.2.3 32-1.5.1 33-1.2.1.3.3 34-1.2.1.3.3 36-1.2.1.3.2.1 36-1.3.1.1.2.3.1.2.3.2.1 37-1.3.1.1.2.3.1.2.2.1 37-1.3.1.1.2.3.2.2.2.1 38-1.3.1.1.2.3.1.1.1 40-1.5.1.1 40-1.5.1.2 45-1.5.1 (o / obtain-01~e.5 :ARG1 (t / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :ARG1-of (r2 / resemble-01~e.2)) :time~e.6 (g / generate-01~e.9 :ARG0~e.10 (c / cell :wiki - :name (n / name :op1 "melanosphere"~e.15) :mod (e3 / enzyme :wiki - :name (n2 / name :op1 "BRAF"~e.14,31,36) :mod (w / wild-type~e.11,12,33,34))) :ARG1 (x / xenograft~e.7)) :ARG0-of (i / indicate-01~e.16 :ARG1~e.17 (p / possible-01~e.20 :ARG1 (c2 / constitute-01~e.21 :ARG0 (s / strategy~e.19 :mod (t2 / this~e.18)) :ARG1 (a / approach-02~e.26 :ARG1-of (e / exploit-01 :ARG1-of (p2 / possible-01~e.20) :manner~e.23 (p5 / potential~e.23)) :mod (t3 / therapy~e.25) :beneficiary~e.28 (a4 / and~e.32 :op1 (p3 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (p6 / patient~e.38)) :mod (m2 / medical-condition :wiki "Melanoma" :name (n3 / name :op1 "melanoma"~e.37) :mod (e2 / enzyme :wiki - :name (n4 / name :op1 "BRAF"~e.31,36) :ARG2-of (m / mutate-01~e.29)))) :op2 (p4 / person :ARG0-of (h3 / have-rel-role-91 :ARG2 p6) :mod (m3 / medical-condition :wiki "Melanoma" :name (n5 / name :op1 "melanoma"~e.37) :mod e3))))))) :mod (i2 / important~e.0) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.32,45 :op1 (f2 / figure~e.40 :mod "4C") :op2 (f3 / figure~e.40 :mod "4D")))) # ::id pmid_2423_8212.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblot analysis showed that VEGF levels were lower in treated @-@ melanospheres ( Figure 4 @ E ) and immunohistochemistry analysis showed that PD0325901 @-@ treated xenografts expressed reduced levels of VEGF in comparison with control tumors ( Figure 4 @ F ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2.r 4-1.1.2.1.1.1 5-1.1.2 7-1.1.2.2 7-1.1.2.2.1 7-1.1.2.2.1.r 8-1.1.2.3.r 9-1.1.2.3.2 11-1.1.2.3.1.1 13-1.1.2.4.1 19-1 20-1.2.1.1 21-1.2.1 22-1.2 23-1.2.2.r 24-1.2.2.2.1.1.1.1 26-1.2.2.2.1 27-1.2.2.2 28-1.2.2 29-1.2.2.1.2 30-1.2.2.1 31-1.2.2.1.1.r 32-1.2.2.1.1 33-1.2.2.1.3.r 34-1.2.2.1.3 35-1.2.2.1.3.1.r 36-1.2.2.1.3.1.1 37-1.2.2.1.3.1 39-1.1.2.4.1 39-1.2.2.3.1 (a / and~e.19 :op1 (s / show-01~e.2 :ARG0 (a2 / analyze-01~e.1 :mod (i / immunoblot-01~e.0)) :ARG1~e.3 (l / level~e.5 :quant-of (p / protein :name (n / name :op1 "VEGF"~e.4)) :ARG1-of (l2 / low-04~e.7 :degree~e.7 (m / more~e.7)) :location~e.8 (c / cell :name (n2 / name :op1 "melanosphere"~e.11) :ARG1-of (t / treat-04~e.9)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13,39 :mod "4E")))) :op2 (s2 / show-01~e.22 :ARG0 (a3 / analyze-01~e.21 :mod (i2 / immunohistochemistry~e.20)) :ARG1~e.23 (e / express-03~e.28 :ARG2 (l3 / level~e.30 :quant-of~e.31 p~e.32 :ARG1-of (r / reduce-01~e.29) :ARG1-of~e.33 (c2 / compare-01~e.34 :ARG2~e.35 (t3 / tumor~e.37 :mod (c3 / control~e.36)))) :ARG3 (x / xenograft~e.27 :ARG1-of (t2 / treat-04~e.26 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PD0325901"~e.24)))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.39 :mod "4F"))))) # ::id pmid_2423_8212.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results were obtained both for mutated BRAF and wild type BRAF melanospheres and xenografts and suggest that Mek inhibition might determine , together with a direct cytotoxic @/@ cytostatic effect on tumor cells , a reduction of the tumor cell @-@ dependent pro @-@ angiogenic activity in vivo . # ::alignments 0-1.1.1.2 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 3-1.1 6-1.1.2.1.1.2.2 7-1.1.2.1.1.2.1.1 7-1.1.2.1.2.2.1.1 9-1.1.2.1.2.2.2 10-1.1.2.1.2.2.2 11-1.1.2.1.1.2.1.1 11-1.1.2.1.2.2.1.1 12-1.1.2.1.1.1.1 12-1.1.2.1.2.1.1 13-1.1.2 14-1.1.2.2 15-1 15-1.1.2 16-1.2 17-1.2.2.r 18-1.2.2.1.1.1.1.1 19-1.2.2.1.1 20-1.2.2 21-1.2.2.1 26-1.2.2.1.1.2.1.3 30-1.2.2.1.1.2.1 31-1.2.2.1.1.2.1.1.r 32-1.2.2.1.1.2.1.1.1 33-1.2.2.1.1.2.1.1 36-1.2.2.1.2 37-1.2.2.1.2.1.r 39-1.2.2.1.2.1.1.1 40-1.2.2.1.2.1.1.1 42-1.2.2.1.2.1.1 43-1.2.2.1.2.1.3 46-1.2.2.1.2.1 48-1.2.2.1.2.1.2 49-1.2.2.1.2.1.2 (a / and~e.15 :op1 (o / obtain-01~e.3 :ARG1 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :beneficiary (a2 / and~e.13,15 :op1 (a3 / and :op1 (c / cell :name (n / name :op1 "melanosphere"~e.12) :mod (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.7,11) :ARG2-of (m / mutate-01~e.6))) :op2 (c2 / cell :name (n3 / name :op1 "melanosphere"~e.12) :mod (e / enzyme :name (n4 / name :op1 "BRAF"~e.7,11) :mod (w / wild-type~e.9,10)))) :op2 (x / xenograft~e.14))) :op2 (s / suggest-01~e.16 :ARG0 t :ARG1~e.17 (p / possible-01~e.20 :ARG1 (d / determine-01~e.21 :ARG0 (i / inhibit-01~e.19 :ARG1 (e3 / enzyme :name (n5 / name :op1 "Mek"~e.18)) :ARG1-of (a4 / accompany-01 :ARG0 (a5 / affect-01~e.30 :ARG1~e.31 (c5 / cell~e.33 :mod (t3 / tumor~e.32)) :ARG2 (o2 / or :op1 (c3 / cytotoxicity) :op2 (c4 / cytostasis)) :ARG1-of (d2 / direct-02~e.26)))) :ARG1 (r2 / reduce-01~e.36 :ARG1~e.37 (a6 / activity-06~e.46 :ARG0-of (d3 / depend-01~e.42 :ARG1 c5~e.39,40) :manner (i2 / in-vivo~e.48,49) :ARG0-of (f / favor-01~e.43 :ARG1 (a7 / angiogenesis)))))))) # ::id pmid_2456_8222.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Targeting the prohibitin scaffold @-@ CRAF kinase interaction in RAS @-@ ERK @-@ driven pancreatic ductal adenocarcinoma ( PMID : 24568222 ) # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1.2 5-1.1.2.1.1 6-1.1.2 7-1.1 8-1.1.3.r 9-1.1.3.1.1.1.1 11-1.1.3.1.1.1.1 13-1.1.3.1 14-1.1.3.2.1 16-1.1.3 (t / target-01~e.0 :ARG1 (i / interact-01~e.7 :ARG0 (p5 / protein :name (n3 / name :op1 "prohibitin"~e.2) :mod (s / scaffold~e.3)) :ARG1 (k / kinase~e.6 :name (n / name :op1 "CRAF"~e.5)) :location~e.8 (a / adenocarcinoma~e.16 :ARG1-of (d2 / drive-02~e.13 :ARG0 (p / pathway :name (n4 / name :op1 "RAS-ERK"~e.9,11))) :mod (d4 / duct :part-of (p2 / pancreas~e.14)))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID24568222"))) # ::id pmid_2456_8222.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2456_8222.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The level of PHB expression was crucial for maintenance of oncogenic ERK @-@ driven pancreatic tumorigenesis . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1.r 6-1 7-1.2.r 8-1.2 9-1.2.1.r 10-1.2.1.2.1 10-1.2.1.2.1.2 10-1.2.1.2.1.2.1 10-1.2.1.2.1.2.1.r 10-1.2.1.2.1.2.r 11-1.2.1.2.1.1.1 13-1.2.1.2 14-1.2.1.1.1 15-1.2.1 15-1.2.1.1 15-1.2.1.1.r (c / crucial~e.6 :domain~e.5 (l / level~e.1 :mod~e.2 (e / express-03~e.4 :ARG2 (p2 / protein :name (n / name :op1 "PHB"~e.3)))) :purpose~e.7 (m / maintain-01~e.8 :ARG1~e.9 (c4 / create-01~e.15 :ARG1~e.15 (t / tumor~e.15 :mod (p / pancreas~e.14)) :ARG1-of (d / drive-02~e.13 :ARG0 (e2 / enzyme~e.10 :name (n2 / name :op1 "ERK"~e.11) :ARG0-of~e.10 (c2 / cause-01~e.10 :ARG1~e.10 (c3 / cancer~e.10))))))) # ::id pmid_2456_8222.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , rocaglamide ( RocA ) , a small molecular inhibitor , selectively bound to PHB with nanomolar affinity to disrupt the PHB @-@ CRAF interaction by altering its localization to the plasma membrane . # ::alignments 0-1 2-1.1.1.1.1 8-1.1.1.2.1 9-1.1.1.2.1 10-1.1.1.2.1.1 12-1.1.3 13-1.1 14-1.1.2.r 15-1.1.2.1.1 16-1.1.4.r 17-1.1.4.2 18-1.1.4 19-1.1.4.1.r 20-1.1.4.1 22-1.1.4.1.2.1 24-1.1.4.1.2.2.1.1 25-1.1.4.1.2 26-1.1.4.1.3.r 27-1.1.4.1.3 29-1.1.4.1.3.2 32-1.1.4.1.3.2.2.1 33-1.1.4.1.3.2.2 (a / and~e.0 :op2 (b / bind-01~e.13 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "rocaglamide"~e.2) :ARG1-of (m2 / mean-01 :ARG2 (s4 / small-molecule~e.8,9 :ARG0-of (i / inhibit-01~e.10)))) :ARG2~e.14 (p2 / protein :name (n / name :op1 "PHB"~e.15)) :mod (s / selective~e.12) :manner~e.16 (a2 / affinity~e.18 :prep-to~e.19 (d / disrupt-01~e.20 :ARG0 (r / rocaglamide) :ARG1 (i2 / interact-01~e.25 :ARG0 p2~e.22 :ARG1 (e / enzyme :name (n4 / name :op1 "CRAF"~e.24))) :manner~e.26 (a3 / alter-01~e.27 :ARG0 s3 :ARG1 (b2 / be-located-at-91~e.29 :ARG1 i2 :ARG2 (m3 / membrane~e.33 :mod (p / plasma~e.32))))) :mod (n3 / nanomolar~e.17)))) # ::id pmid_2456_8222.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consequently , there was an impairment of oncogenic RAS @-@ ERK signaling , thereby blocking in vitro and in vivo growth and metastasis of pancreatic cancer cells that were addicted to RAS @-@ ERK signaling . # ::alignments 0-1 5-1.1 6-1.1.1.r 7-1.1.1.1 7-1.1.1.1.2 7-1.1.1.1.2.1 7-1.1.1.1.2.1.r 7-1.1.1.1.2.r 8-1.1.1.1.1.1 10-1.1.1.1.1.1 11-1.1.1 13-1.1.1.2.1.1.1.2.r 14-1.1.1.2.1 16-1.1.1.2.1.1.1.2.1 17-1.1.1.2.1.1.1.2.1 19-1.1.1.2.1.1.1.2 21-1.1.1.2.1.1.1.2.1 21-1.1.1.2.1.1.1.2.2 22-1.1.1.2.1.1.1.2.2 24-1.1.1.2.1.1.1 25-1.1.1.2.1.1 25-1.1.1.2.1.1.1.2 26-1.1.1.2.1.1.2 27-1.1.1.2.1.1.1.1.r 28-1.1.1.2.1.1.1.1.2 29-1.1.1.2.1.1.1.1.1 30-1.1.1.2.1.1.1.1 33-1.1.1.2.1.1.1.1.3 34-1.1.1.2 35-1.1.1.1.1.1 37-1.1.1.1.1.1 38-1.1.1 (c / cause-01~e.0 :ARG1 (i / impair-01~e.5 :ARG1~e.6 (s / signal-07~e.11,38 :ARG0 (p2 / pathway~e.7 :name (n / name :op1 "RAS-ERK"~e.8,10,35,37) :ARG0-of~e.7 (c2 / cause-01~e.7 :ARG1~e.7 (c3 / cancer~e.7))) :ARG0-of (c4 / cause-01~e.34 :ARG1 (b / block-01~e.14 :ARG1 (a / and~e.25 :op1 (g / grow-01~e.24 :ARG1~e.27 (c5 / cell~e.30 :mod (c6 / cancer~e.29) :mod (p / pancreas~e.28) :ARG1-of (a3 / addict-01~e.33 :ARG2 s)) :manner~e.13 (a2 / and~e.19,25 :op1 (i2 / in-vitro~e.16,17,21) :op2 (i3 / in-vivo~e.21,22))) :op2 (m / metastasize-101~e.26 :ARG1 c5))))))) # ::id pmid_2456_8222.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More importantly , RocA treatment resulted in a significant increase of the lifespan of tumor @-@ bearing mice without any detectable toxicity . # ::alignments 0-1.3.1 1-1.3 4-1.1 5-1 6-1.2.r 8-1.2.2 9-1.2 10-1.2.1.r 12-1.2.1 14-1.2.1.1.1.1.1 16-1.2.1.1.1.1 17-1.2.1.1.1 18-1.4.1 18-1.4.1.r 20-1.4.2 21-1.4 (r / result-01~e.5 :ARG1 (t / treat-04~e.4 :ARG2 (s2 / small-molecule :name (n / name :op1 "rocaglamide"))) :ARG2~e.6 (i / increase-01~e.9 :ARG1~e.10 (l / lifespan~e.12 :duration-of (l3 / live-01 :ARG0 (m / mouse~e.17 :ARG0-of (b / bear-01~e.16 :ARG1 (t3 / tumor~e.14))))) :ARG1-of (s / significant-02~e.8)) :mod (i2 / important~e.1 :degree (m2 / more~e.0)) :manner (t2 / toxicity~e.21 :polarity~e.18 -~e.18 :ARG1-of (d3 / detect-01~e.20 :ARG1-of (p / possible-01)))) # ::id pmid_2456_8222.39 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2456_8222.40 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Expression and localization of PHB in pancreatic cancer cells and tissue # ::alignments 1-1.1 2-1 3-1.2 4-1.1.1.r 5-1.1.1.1.1 7-1.2.2.1.1 8-1.2.2.1.2 9-1.2.2.1 10-1.2.2 11-1.2.2.2 (a / and~e.2 :op1 (e / express-03~e.1 :ARG2~e.4 (p2 / protein :name (n / name :op1 "PHB"~e.5))) :op2 (b / be-located-at-91~e.3 :ARG1 p2 :ARG2 (a2 / and~e.10 :op1 (c / cell~e.9 :mod (p / pancreas~e.7) :mod (c2 / cancer~e.8)) :op2 (t / tissue~e.11 :mod p :mod c2)))) # ::id pmid_2456_8222.41 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the role of PHB in pancreatic cancer cells , we first chose two human pancreatic cancer cell lines , AsPC @-@ 1 ( high malignancy ) and Capan @-@ 2 ( low malignancy ) . # ::alignments 1-1.3 3-1.3.2 4-1.3.2.1.r 5-1.3.2.1.1.1 7-1.3.2.2.1 8-1.3.2.2.2 9-1.2 9-1.3.2.2 11-1.1 12-1.4 12-1.4.1 12-1.4.1.r 13-1 14-1.2.1 15-1.2.5 16-1.2.3 17-1.2.2 18-1.2 19-1.2 21-1.2.4.1.1.1.1 23-1.2.4.1.1.1.1 25-1.2.4.1.1.2.1.1 26-1.2.4.1.1.2.1 28-1.2.4.1 29-1.2.4.1.2.1.1 31-1.2.4.1.2.1.1 33-1.2.4.1.2.2.1.1 34-1.2.4.1.2.2.1 (c / choose-01~e.13 :ARG0 (w / we~e.11) :ARG1 (c2 / cell-line~e.9,18,19 :quant 2~e.14 :mod (c3 / cancer~e.17) :mod (p / pancreas~e.16) :ARG1-of (m / mean-01 :ARG2 (a / and~e.28 :op1 (c4 / cell-line :name (n / name :op1 "AsPC-1"~e.21,23) :ARG0-of (h3 / have-03 :ARG1 (m2 / malignancy~e.26 :ARG1-of (h2 / high-02~e.25)))) :op1 (c5 / cell-line :name (n2 / name :op1 "Capan-2"~e.29,31) :ARG0-of (h4 / have-03 :ARG1 (m3 / malignancy~e.34 :ARG1-of (l / low-04~e.33)))))) :part-of (h / human~e.15)) :purpose (i / investigate-01~e.1 :ARG0 w :ARG1 (r / role~e.3 :poss~e.4 (p2 / protein :name (n3 / name :op1 "PHB"~e.5)) :location (c6 / cell~e.9 :mod (p3 / pancreas~e.7) :mod (c7 / cancer~e.8)))) :ord (o2 / ordinal-entity~e.12 :value~e.12 1~e.12)) # ::id pmid_2456_8222.42 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , AsPC @-@ 1 cells grew as single cells ( Figure 1 @ A , left ) , whereas Capan @-@ 2 cells exhibited tiny islands of densely packed cells ( Figure 1 @ A , right ) . # ::alignments 0-1.3 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1.2 6-1.1 8-1.1.2.1 9-1.1.2 11-1.1.3.1 13-1.1.1.1.1 17-1.1.3.1.2 20-1 21-1.2.1.1.1 23-1.2.1.1.1 24-1.2.1 25-1.2 26-1.2.2.1 27-1.2.2 28-1.2.2.2.r 29-1.2.2.2.1.1 29-1.2.2.2.1.1.r 30-1.2.2.2.1 31-1.2.2.2 33-1.2.3.1 35-1.1.1.1.1 39-1.2.3.1.2 (c / contrast-01~e.20 :ARG1 (g / grow-01~e.6 :ARG1 (c2 / cell-line :name (n / name :op1 "AsPC-1"~e.2,4,13,35)) :ARG4 (c3 / cell~e.5,9 :ARG1-of (s / single-02~e.8)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "1A" :ARG1-of (l / left-20~e.17)))) :ARG2 (e / exhibit-01~e.25 :ARG0 (c4 / cell-line~e.24 :name (n2 / name :op1 "Capan-2"~e.21,23)) :ARG1 (i / island~e.27 :mod (t / tiny~e.26) :consist-of~e.28 (c6 / cell~e.31 :ARG2-of (p / pack-01~e.30 :manner~e.29 (d2 / dense~e.29)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure~e.33 :mod "1A" :ARG1-of (r / right-04~e.39)))) :ARG2-of (i2 / interest-01~e.0)) # ::id pmid_2456_8222.43 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , AsPC @-@ 1 cells exhibited much higher growth and migration capacities than those of Capan @-@ 2 cells ( Additional file 1 @ : Figure S1A , B ) . # ::alignments 0-1.1.2 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1.1 5-1.1.3 6-1.1 7-1.1.2.1.1.1.1 8-1.1.2.1.1 8-1.1.2.1.1.1 8-1.1.2.1.1.1.r 8-1.1.2.2.2 9-1.1.2.1 10-1.1.2 11-1.1.2.2.1 12-1.1.2.2 13-1.1.3.r 16-1.1.3.1.1 18-1.1.3.1.1 19-1.1.1 21-1.2.1.2 22-1.2.1 24-1.2.1.1 27-1.2.1.3.1 27-1.2.1.3.2 28-1.2.1.3.1.1 (a / and :op2 (e / exhibit-01~e.6 :ARG0 (c / cell-line~e.5,19 :name (n / name :op1 "AsPC-1"~e.2,4)) :ARG1 (a2 / and~e.0,10 :op1 (g / grow-01~e.9 :ARG1-of (h / high-02~e.8 :degree~e.8 (m / more~e.8 :quant (m2 / much~e.7)))) :op2 (c2 / capable-01~e.12 :ARG2 (m3 / migrate-01~e.11) :ARG1-of (h2 / high-02~e.8))) :compared-to~e.13 (c3 / cell-line~e.5 :name (n2 / name :op1 "Capan-2"~e.16,18))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.22 :mod 1~e.24 :mod (a3 / additional~e.21) :part (a4 / and :op1 (f2 / figure~e.27 :mod "S1A"~e.28) :op2 (f3 / figure~e.27 :mod "S1B"))))) # ::id pmid_2456_8222.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RT @-@ PCR showed a difference in PHB mRNA expression levels , revealing higher expression in AsPC @-@ 1 cells than that in Capan @-@ 2 cells ( Figure 1 @ B and Additional file 1 @ : Figure S2A ) . # ::alignments 0-1.1.1.1 2-1.1.1.1 3-1 5-1.2 6-1.2.1.r 7-1.2.1.1.1.2.1.1.1 9-1.2.1.1 10-1.2.1 12-1.3 13-1.3.1.2 13-1.3.1.2.1 13-1.3.1.2.1.r 14-1.3.1 14-1.3.1.2.2 15-1.3.1.1.r 16-1.3.1.1.1.1 18-1.3.1.1.1.1 19-1.3.1.1 19-1.3.1.2.2.1 20-1.3.1.2.2.r 23-1.3.1.2.2.1.1.1 25-1.3.1.2.2.1.1.1 26-1.3.1.1 28-1.4.1.1 30-1.3.1.1.1.1 33-1.4.1 34-1.4.1.2.1 35-1.4.1.2 37-1.3.1.1.1.1 40-1.4.1.2.2 41-1.4.1.2.2.1 (s / show-01~e.3 :ARG0 (t / thing :name (n / name :op1 "RT-PCR"~e.0,2)) :ARG1 (d / differ-02~e.5 :ARG1~e.6 (l / level~e.10 :degree-of (e / express-03~e.9 :ARG2 (n4 / nucleic-acid :name (n6 / name :op1 "RNA") :ARG0-of (e4 / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "PHB"~e.7))))))) :ARG0-of (r2 / reveal-01~e.12 :ARG1 (e2 / express-03~e.14 :ARG3~e.15 (c / cell-line~e.19,26 :name (n3 / name :op1 "AsPC-1"~e.16,18,30,37)) :ARG1-of (h / high-02~e.13 :degree~e.13 (m2 / more~e.13) :compared-to~e.20 (e3 / express-03~e.14 :ARG3 (c2 / cell-line~e.19 :name (n5 / name :op1 "Capan-2"~e.23,25)))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.33 :op1 (f / figure~e.28 :mod "1B") :op2 (f2 / file~e.35 :mod (a2 / additional~e.34) :part (f3 / figure~e.40 :mod "S2A"~e.41))))) # ::id pmid_2456_8222.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In agreement with RT @-@ PCR data , immunoblot analysis also demonstrated high expression of PHB protein in AsPC @-@ 1 cells , but little expression in Capan @-@ 2 cells ( Figure 1 @ C and Additional file 1 @ : Figure S2B ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1.1.1.1 5-1.4.1.1.1.1 6-1.4.1 8-1.1.1 9-1.1 10-1.3 11-1 12-1.2.1.3 13-1.2.1 14-1.2.1.1.r 15-1.2.1.1.1.1 16-1.2.1.1 17-1.2.1.2.r 18-1.2.1.2.1.1 20-1.2.1.2.1.1 21-1.2.1.2 23-1.2 24-1.2.2.2 25-1.2.2 26-1.2.2.1.r 27-1.2.2.1.1.1 29-1.2.2.1.1.1 30-1.2.2.1 32-1.5.1.1 34-1.2.1.2.1.1 37-1.5.1 38-1.5.1.2.1 39-1.5.1.2 41-1.2.1.2.1.1 44-1.5.1.2.2 45-1.5.1.2.2.1 (d / demonstrate-01~e.11 :ARG0 (a / analyze-01~e.9 :mod (i / immunoblot-01~e.8)) :ARG1 (c2 / contrast-01~e.23 :ARG1 (e / express-03~e.13 :ARG2~e.14 (p / protein~e.16 :name (n / name :op1 "PHB"~e.15)) :ARG3~e.17 (c / cell-line~e.21 :name (n2 / name :op1 "AsPC-1"~e.18,20,34,41)) :ARG1-of (h / high-02~e.12)) :ARG2 (e2 / express-03~e.25 :ARG3~e.26 (c3 / cell-line~e.30 :name (n3 / name :op1 "Capan-2"~e.27,29)) :mod (l / little~e.24))) :mod (a2 / also~e.10) :ARG1-of (a3 / agree-01~e.1 :ARG2~e.2 (d2 / data~e.6 :mod (t / thing :name (n4 / name :op1 "RT-PCR"~e.3,5)))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and~e.37 :op1 (f / figure~e.32 :mod "1C") :op2 (f2 / file~e.39 :mod (a5 / additional~e.38) :part (f3 / figure~e.44 :mod "S2B"~e.45))))) # ::id pmid_2456_8222.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Intriguingly , localization of PHB in AsPC @-@ 1 cells was mainly in the plasma membrane and cytosol , whereas its localization was in Capan @-@ 2 cells ( Figure 1 @ D , E ) . # ::alignments 0-1.1.4 2-1.1 4-1.2.1.1.1 6-1.1.2.3.1.1 8-1.1.2.3.1.1 9-1.1.2.3 10-1.1 11-1.1.3 14-1.1.2.1.1 15-1.1.2.1 16-1.1.2 17-1.1.2.2 19-1 21-1.1 22-1.2 24-1.2.2.1.1 26-1.2.2.1.1 27-1.2.2 29-1.1.5.1.1 29-1.1.5.1.2 31-1.1.2.3.1.1 (c2 / contrast-01~e.19 :ARG1 (b / be-located-at-91~e.2,10,21 :ARG1 p2 :ARG2 (a / and~e.16 :op1 (m / membrane~e.15 :mod (p / plasma~e.14)) :op2 (c / cytosol~e.17) :part-of (c3 / cell-line~e.9 :name (n2 / name :op1 "AsPC-1"~e.6,8,31))) :mod (m2 / main~e.11) :ARG0-of (i / intrigue-01~e.0) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.29 :mod "1D") :op2 (f2 / figure~e.29 :mod "1E")))) :ARG2 (b3 / be-located-at-91~e.22 :ARG1 (p2 / protein :name (n / name :op1 "PHB"~e.4)) :ARG2 (c4 / cell-line~e.27 :name (n3 / name :op1 "Capan-2"~e.24,26)))) # ::id pmid_2456_8222.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This result indicated that the observed phenotypes may correlate with the expression and localization of PHB protein . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1.1.1 6-1.2.1.1 7-1.2 8-1.2.1 9-1.2.1.2.r 11-1.2.1.2.1 12-1.2.1.2 13-1.2.1.2.2 14-1.2.1.2.1.1.r 15-1.2.1.2.1.1.1.1 16-1.2.1.2.1.1 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (p / possible-01~e.7 :ARG1 (c / correlate-01~e.8 :ARG1 (p2 / phenotype~e.6 :ARG1-of (o / observe-01~e.5)) :ARG2~e.9 (a / and~e.12 :op1 (e / express-03~e.11 :ARG2~e.14 (p3 / protein~e.16 :name (n / name :op1 "PHB"~e.15))) :op2 (b / be-located-at-91~e.13 :ARG1 p3))))) # ::id pmid_2456_8222.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , AsPC @-@ 1 cells were chosen to investigate the biological properties of PHB in pancreatic cancer both in vitro and in vivo @ . # ::alignments 0-1 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1.1 7-1.1 9-1.1.2 11-1.1.2.1.1 12-1.1.2.1 13-1.1.2.1.2.r 14-1.1.2.1.2.1.1 15-1.1.2.2.1 16-1.1.2.1.2.2.1 17-1.1.2.1.2.2 18-1.1.2.2.3 20-1.1.2.2.1 21-1.1.2.2.1 23-1.1.2.2 25-1.1.2.2.1 25-1.1.2.2.2 26-1.1.2.2.2 (c / cause-01~e.0 :ARG1 (c2 / choose-01~e.7 :ARG1 (c3 / cell-line~e.5 :name (n / name :op1 "AsPC-1"~e.2,4)) :purpose (i / investigate-01~e.9 :ARG1 (p / property~e.12 :mod (b / biological~e.11) :poss~e.13 (p2 / protein :name (n2 / name :op1 "PHB"~e.14) :topic (c4 / cancer~e.17 :mod (p3 / pancreas~e.16)))) :manner (a / and~e.23 :op1 (i2 / in-vitro~e.15,20,21,25) :op2 (i3 / in-vivo~e.25,26) :mod (b2 / both~e.18))))) # ::id pmid_2456_8222.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next assessed PHB expression in pancreatic tissue . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1.1.1 4-1.2 5-1.2.2.r 6-1.2.2.1 7-1.2.2 (a / assess-01~e.2 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.4 :ARG2 (p / protein :name (n2 / name :op1 "PHB"~e.3)) :ARG3~e.5 (t / tissue~e.7 :mod (p2 / pancreas~e.6))) :time (n / next~e.1)) # ::id pmid_2456_8222.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PHB protein was weakly expressed in 63.6 % of normal pancreas samples ( n = 11 ) ( Figure 1 @ F , G ) . # ::alignments 0-1.1.1.1 1-1.1 3-1.3 4-1 5-1.2.r 6-1.2.1.2.1 7-1.2.1.2 9-1.2.1.1.3 10-1.2.1.1.2 11-1.2 11-1.2.1.1 15-1.2.1.1.1 18-1.4.1 (e / express-03~e.4 :ARG2 (p2 / protein~e.1 :name (n / name :op1 "PHB"~e.0)) :ARG3~e.5 (s / sample~e.11 :ARG1-of (i / include-91 :ARG2 (s2 / sample~e.11 :quant 11~e.15 :mod (p3 / pancreas~e.10) :ARG1-of (n2 / normal-02~e.9)) :ARG3 (p / percentage-entity~e.7 :value 63.6~e.6))) :degree (w / weak-02~e.3) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "1F" :mod "1G"))) # ::id pmid_2456_8222.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , PHB protein was strongly expressed in 58.7 % of PDAC samples ( n = 46 ) ( Figure 1 @ F , G and Additional file 1 @ : Figure S3 ) . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1 5-1.1.3 6-1.1 7-1.1.2.r 8-1.1.2.1.2.1 9-1.1.2.1.2 12-1.1.2 12-1.1.2.1.1 16-1.1.2.1.1.1 19-1.2.1.1 21-1.2.1.2.1 27-1.2.1.2.2 28-1.2.1.2 30-1.2.1.2.1 33-1.2.1.2.3 34-1.2.1.2.3.1 (c / contrast-01~e.0 :ARG2 (e / express-03~e.6 :ARG2 (p2 / protein~e.3 :name (n / name :op1 "PHB"~e.2)) :ARG3~e.7 (s2 / sample~e.12 :ARG1-of (i / include-91 :ARG2 (s3 / sample~e.12 :quant 46~e.16 :mod (a / adenocarcinoma :mod (d3 / duct :part-of (p3 / pancreas)))) :ARG3 (p / percentage-entity~e.9 :value 58.7~e.8))) :ARG1-of (s / strong-02~e.5)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.19 :mod "1F" :mod "1G") :op2 (f2 / file~e.28 :mod 1~e.21,30 :mod (a3 / additional~e.27) :part (f3 / figure~e.33 :mod "S3"~e.34))))) # ::id pmid_2456_8222.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , these results show that PHB , which becomes more pronounced with pancreatic cancer malignancy , may serve as a therapeutic target in pancreatic cancer . # ::alignments 0-1.1.2 1-1.1.2.1 3-1.1.3 4-1.1 4-1.1.1 4-1.1.1.r 5-1 6-1.2.r 7-1.2.1.1.1.1 10-1.2.1.1 10-1.2.1.1.2 10-1.2.1.1.2.r 11-1.2.1.1.2.1.1 12-1.2.1.1.2.1 13-1.2.1.1.2.1.2.r 14-1.2.1.1.2.1.2.1 15-1.2.1.1.2.1.2.2 16-1.2.1.1.2.1.2 18-1.2 19-1.2.1 20-1.2.1.2.r 22-1.2.1.2.2 23-1.2.1.2 24-1.2.1.2.3.r 25-1.2.1.2.3.1 26-1.2.1.2.3 (s / show-01~e.5 :ARG0 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :ARG1-of (t2 / take-04~e.0 :mod (t3 / together~e.1)) :mod (t6 / this~e.3)) :ARG1~e.6 (p / possible-01~e.18 :ARG1 (s2 / serve-01~e.19 :ARG0 (p2 / protein~e.10 :name (n2 / name :op1 "PHB"~e.7) :ARG1-of~e.10 (b / become-01~e.10 :ARG2 (p4 / pronounced-02~e.12 :degree (m2 / more~e.11) :condition~e.13 (m3 / malignant-02~e.16 :ARG1 (p5 / pancreas~e.14) :ARG2 (c2 / cancer~e.15))))) :ARG2~e.20 (t4 / target-01~e.23 :ARG1 p2 :mod (t5 / therapy~e.22) :condition~e.24 (c / cancer~e.26 :mod (p3 / pancreas~e.25)))))) # ::id pmid_2456_8222.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PHB is indispensable for EGF @-@ induced ERK activation in pancreatic cancer cells # ::alignments 1-1.1.1.1 3-1 4-1.2.r 5-1.2.1.2.1.1.1 7-1.2.1.2 8-1.2.1.1.1 9-1.2 10-1.2.2.r 11-1.2.2.1.1 12-1.2.2.1 13-1.2.2 (i / indispensable-01~e.3 :ARG1 (p2 / protein :name (n3 / name :op1 "PHB"~e.1)) :ARG2~e.4 (a / activate-01~e.9 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.8) :ARG2-of (i2 / induce-01~e.7 :ARG0 (p4 / protein :name (n4 / name :op1 "EGF"~e.5)))) :location~e.10 (c / cell~e.13 :mod (c2 / cancer~e.12 :mod (p3 / pancreas~e.11))))) # ::id pmid_2456_8222.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The duration of ERK activity is a crucial factor in diverse biological processes that determine cell fate decisions [ @ 18 @ ] . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1.1.1 4-1.2.1 5-1.2.r 7-1.1 8-1 9-1.3.r 10-1.3.2 11-1.3.1 12-1.3 14-1.3.3 15-1.3.3.1.1.1 16-1.3.3.1.1 17-1.3.3.1 20-1.4.1.1.1 (f / factor~e.8 :mod (c / crucial~e.7) :domain~e.5 (d / duration~e.1 :duration-of~e.2 (a / activity-06~e.4 :ARG0 (e / enzyme :name (n / name :op1 "ERK"~e.3)))) :topic~e.9 (p2 / process-01~e.12 :mod (b / biological~e.11) :mod (d2 / diverse~e.10) :ARG0-of (d3 / determine-01~e.14 :ARG1 (d4 / decide-01~e.17 :ARG1 (f2 / fate-01~e.16 :ARG1 (c2 / cell~e.15))))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 18~e.20)))) # ::id pmid_2456_8222.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK is phosphorylated and activated by MEK in response to growth factor stimulation , and then activated ERK phosphorylates and activates nuclear targets to up @-@ regulate immediate @-@ early genes [ @ 19 @ ] . # ::alignments 0-1.1.1.1.1.1 2-1.1.1 3-1.1 4-1.1.2 5-1.1.1.2.r 6-1.1.1.2.1.1 8-1.1.3 9-1.1.3.1.r 10-1.1.3.1.1.1.1 11-1.1.3.1.1.1.1 12-1.1.3.1 14-1.2 15-1.2.4 16-1.2.1.2.2 16-1.2.2 17-1.2.1.2.1.1 18-1.2.1 19-1.2 20-1.2.1.2.2 20-1.2.2 21-1.2.1.1.2 22-1.2.1.1 22-1.2.1.1.1 22-1.2.1.1.1.r 27-1.2.3.1.1.1 29-1.2.3.1.1 30-1.2.3.1 33-1.3.1.1.1 (a6 / and :op1 (a / and~e.3 :op1 (p3 / phosphorylate-01~e.2 :ARG1 (e3 / enzyme :name (n / name :op1 "ERK"~e.0)) :ARG2~e.5 (e / enzyme :name (n4 / name :op1 "MEK"~e.6))) :op2 (a2 / activate-01~e.4 :ARG0 e :ARG1 e3) :ARG2-of (r / respond-01~e.8 :ARG1~e.9 (s / stimulate-01~e.12 :ARG0 (p / protein :name (n5 / name :op1 "growth-factor"~e.10,11))))) :op2 (a4 / and~e.14,19 :op1 (p2 / phosphorylate-01~e.18 :ARG1 (m / molecular-physical-entity~e.22 :ARG1-of~e.22 (t / target-01~e.22) :mod (n3 / nucleus~e.21)) :ARG2 (e4 / enzyme :name (n2 / name :op1 "ERK"~e.17) :ARG1-of (a3 / activate-01~e.16,20))) :op2 (a5 / activate-01~e.16,20 :ARG0 e4 :ARG1 m) :purpose (u2 / upregulate-01 :ARG1 (g2 / gene~e.30 :mod (e2 / early~e.29 :mod (i / immediate~e.27))) :ARG2 e4) :time (t2 / then~e.15)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 19~e.33)))) # ::id pmid_2456_8222.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we determined the expression levels of p @-@ ERK1 @/@ 2 in AsPC @-@ 1 and Capan @-@ 2 cells . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.1.1.r 8-1.1.2.1.1.2 10-1.1.2.1.1.1.1 12-1.1.2.1.1.1.1 13-1.1.2.1.2.r 14-1.1.2.1.2.1.1.1 16-1.1.2.1.2.1.1.1 17-1.1.2.1.2 18-1.1.2.1.2.2.1.1 20-1.1.2.1.2.2.1.1 21-1.1.2.1.2.1 21-1.1.2.1.2.2 (c / cause-01~e.0 :ARG1 (d / determine-01~e.3 :ARG0 (w / we~e.2) :ARG1 (l / level~e.6 :degree-of (e / express-03~e.5 :ARG2~e.7 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"~e.10,12) :ARG3-of (p2 / phosphorylate-01~e.8)) :ARG3~e.13 (a / and~e.17 :op1 (c2 / cell-line~e.21 :name (n2 / name :op1 "AsPC-1"~e.14,16)) :op2 (c3 / cell-line~e.21 :name (n3 / name :op1 "Capan-2"~e.18,20))))))) # ::id pmid_2456_8222.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Intriguingly , the phosphorylation status of ERK2 was much higher than that of ERK1 in AsPC @-@ 1 cells , and this phenomenon was completely converse in Capan @-@ 2 cells ( Figure 2 @ A ) . # ::alignments 0-1.4 3-1.1.1.1 3-1.1.3.2 4-1.1.1 4-1.1.3 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1 8-1.1.2.1 9-1.1 9-1.1.2 9-1.1.2.r 10-1.1.3.r 12-1.1.3.2.1.r 13-1.1.3.2.1.1.1 14-1.1.3.1.r 15-1.1.3.1.1.1 17-1.1.3.1.1.1 18-1.1.3.1 20-1 21-1.2.1.1 22-1.2.1 23-1.2.1.r 24-1.2.2 25-1.2 26-1.2.3.r 27-1.2.3.1.1 29-1.2.3.1.1 30-1.2.3 32-1.3.1 34-1.2.3.1.1 (a / and~e.20 :op1 (h / high-02~e.9 :ARG1 (s / status~e.4 :mod (p / phosphorylate-01~e.3 :ARG1~e.5 (e / enzyme :name (n5 / name :op1 "ERK2"~e.6)))) :degree~e.9 (m / more~e.9 :quant (m2 / much~e.8)) :compared-to~e.10 (s2 / status~e.4 :location~e.14 (c / cell-line~e.18 :name (n3 / name :op1 "AsPC-1"~e.15,17)) :mod (p2 / phosphorylate-01~e.3 :ARG1~e.12 (e2 / enzyme :name (n / name :op1 "ERK1"~e.13))))) :op2 (c5 / converse~e.25 :domain~e.23 (p3 / phenomenon~e.22 :mod (t / this~e.21)) :ARG1-of (c3 / complete-02~e.24) :location~e.26 (c4 / cell-line~e.30 :name (n4 / name :op1 "Capan-2"~e.27,29,34))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "2A")) :ARG0-of (i / intrigue-01~e.0)) # ::id pmid_2456_8222.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This observation suggests distinct roles of ERK1 and ERK2 in the regulation of cell behavior in AsPC @-@ 1 and Capan @-@ 2 cells . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1 4-1.2 5-1.2.3.r 6-1.2.3.1.1.1 7-1.2.3 8-1.2.3.2.1.1 9-1.2.2.r 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1 14-1.2.2.1 15-1.2.2.1.2.r 16-1.2.2.1.2.1.1.1 18-1.2.2.1.2.1.1.1 19-1.2.2.1.2 20-1.2.2.1.2.2.1.1 22-1.2.2.1.2.2.1.1 23-1.2.2.1.2.1 23-1.2.2.1.2.2 (s / suggest-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1 (r / roles~e.4 :mod (d / distinct~e.3) :topic~e.9 (r2 / regulate-01~e.11 :ARG1~e.12 (b / behave-01~e.14 :ARG0 (c / cell~e.13) :location~e.15 (a2 / and~e.19 :op1 (c2 / cell-line~e.23 :name (n3 / name :op1 "AsPC-1"~e.16,18)) :op2 (c3 / cell-line~e.23 :name (n4 / name :op1 "Capan-2"~e.20,22))))) :poss~e.5 (a / and~e.7 :op1 (e / enzyme :name (n / name :op1 "ERK1"~e.6)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"~e.8))))) # ::id pmid_2456_8222.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test whether PHB is required for the ERK pathway , we validated a siRNA against PHB ( siPHB ) in AsPC @-@ 1 and Panc @-@ 1 cells by quantitative real @-@ time PCR . # ::alignments 1-1.5 2-1.5.2.1 2-1.5.2.1.r 3-1.5.2.3.1.1 5-1.5.2 6-1.5.2.2.r 8-1.5.2.2.1.1 9-1.5.2.2 11-1.1 12-1 14-1.2.1.1 15-1.2 15-1.2.2 15-1.2.2.r 16-1.2.2.1 20-1.3.r 21-1.3.1.1.1 23-1.3.1.1.1 23-1.3.2.1.1 24-1.3 25-1.3.2.1.1 27-1.3.1.1.1 27-1.3.2.1.1 28-1.3.1 28-1.3.2 29-1.4.r 30-1.4.2 31-1.4.3 33-1.4.3 34-1.4 34-1.4.1 34-1.4.1.r 34-1.4.4 34-1.4.4.r (v / validate-01~e.12 :ARG0 (w / we~e.11) :ARG1 (n3 / nucleic-acid~e.15 :name (n2 / name :op1 "siRNA"~e.14) :ARG0-of~e.15 (o / oppose-01~e.15 :ARG1 p~e.16)) :location~e.20 (a / and~e.24 :op1 (c / cell-line~e.28 :name (n4 / name :op1 "AsPC-1"~e.21,23,27)) :op2 (c2 / cell-line~e.28 :name (n5 / name :op1 "Panc-1"~e.23,25,27))) :manner~e.29 (r / react-01~e.34 :ARG0~e.34 (p2 / polymerase~e.34) :mod (q / quantitative~e.30) :mod (r2 / real-time~e.31,33) :ARG1-of~e.34 (c3 / chain-01~e.34)) :purpose (t2 / test-01~e.1 :ARG0 w :ARG1 (r3 / require-01~e.5 :mode~e.2 interrogative~e.2 :ARG0~e.6 (p3 / pathway~e.9 :name (n7 / name :op1 "ERK"~e.8)) :ARG1 (p / protein :name (n / name :op1 "PHB"~e.3))))) # ::id pmid_2456_8222.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed that siPHB reduced the PHB mRNA level by about 80 % compared with that using control siRNA ( siCon ) ( Additional file 1 @ : Figure S4A , B ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 5-1.2 7-1.2.2.1.2.1.1 8-1.2.2.1.1.1 9-1.2.2 9-1.2.3.1.2 10-1.2.3.r 11-1.2.3 12-1.2.3.1.1 13-1.2.3.1 14-1.2.3.1.2.r 17-1.2.3.1.2.1 18-1.2.3.1.2.1.1 18-1.2.3.1.2.1.1.2 18-1.2.3.1.2.1.1.2.r 19-1.2.1.1.1 19-1.2.3.1.2.1.1.1.1 24-1.3.1.1 25-1.3.1 30-1.3.1.2 31-1.3.1.2.1 (s / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1 (r2 / reduce-01~e.5 :ARG0 (n4 / nucleic-acid :name (n6 / name :op1 "siRNA"~e.19) :mod p2) :ARG1 (l / level~e.9 :quant-of (n2 / nucleic-acid :name (n5 / name :op1 "mRNA"~e.8) :mod (p2 / protein :name (n / name :op1 "PHB"~e.7)))) :ARG2~e.10 (a / about~e.11 :quant (p / percentage-entity~e.13 :value 80~e.12 :compared-to~e.14 (l2 / level~e.9 :condition (u / use-01~e.17 :ARG1 (n7 / nucleic-acid~e.18 :name (n3 / name :op1 "siRNA"~e.19) :ARG0-of~e.18 (c / control-01~e.18))))))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.25 :mod (a2 / additional~e.24) :part (f2 / figure~e.30 :mod "S4A"~e.31 :mod "S4B")))) # ::id pmid_2456_8222.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , we checked the phosphorylation status of ERK1 @/@ 2 in siPHB @-@ transfected AsPC @-@ 1 and Panc @-@ 1 cells . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2.1 6-1.1.2 7-1.1.2.1.1.r 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 14-1.1.2.1.2.1.2 15-1.1.2.1.2.1.1.1 17-1.1.2.1.2.1.1.1 17-1.1.2.1.2.2.1.1 18-1.1.2.1.2 19-1.1.2.1.2.2.1.1 21-1.1.2.1.2.1.1.1 21-1.1.2.1.2.2.1.1 22-1.1.2.1.2.1 22-1.1.2.1.2.2 (a2 / and~e.0 :op2 (c / check-01~e.3 :ARG0 (w / we~e.2) :ARG1 (s / status~e.6 :mod (p / phosphorylate-01~e.5 :ARG1~e.7 (e / enzyme :name (n / name :op1 "ERK1/2"~e.8,10)) :location (a / and~e.18 :op1 (c2 / cell-line~e.22 :name (n2 / name :op1 "AsPC-1"~e.15,17,21) :ARG1-of (t / transfect-01~e.14 :ARG2 (n5 / nucleic-acid :name (n6 / name :op1 "siRNA") :mod (p3 / protein :name (n4 / name :op1 "PHB"))))) :op2 (c3 / cell-line~e.22 :name (n3 / name :op1 "Panc-1"~e.17,19,21) :ARG1-of t)))))) # ::id pmid_2456_8222.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , stimulation of AsPC @-@ 1 cells with epidermal growth factor ( EGF ) caused an increase of ERK1 @/@ 2 phosphorylation ( Figure 2 @ B , C ) , whereas silencing of PHB expression strongly suppressed the EGF @-@ induced phosphorylation of ERK ( Figure 2 @ B , C ) . # ::alignments 1-1.3 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1.1 9-1.1.1.2.r 10-1.1.1.2.1.1 11-1.1.1.2.1.2 12-1.1.1.2.1.3 16-1.1 18-1.1.2 19-1.1.2.1.r 20-1.1.2.1.1.1.1 22-1.1.2.1.1.1.1 23-1.1.2.1 25-1.1.3.1 27-1.1.2.1.1.1.1 34-1 35-1.2.1 36-1.2.1.1.r 37-1.2.1.1.1.1.1 38-1.2.1.1 39-1.2.4 40-1.2 44-1.2.2.2 45-1.2.2 46-1.2.2.1.r 47-1.2.2.1.1.1 49-1.1.3.1 49-1.2.3.1 51-1.1.2.1.1.1.1 (c3 / contrast-01~e.34 :ARG1 (c / cause-01~e.16 :ARG0 (s / stimulate-01~e.3 :ARG1~e.4 (c2 / cell-line~e.8 :name (n / name :op1 "AsPC-1"~e.5,7)) :ARG2~e.9 (p / protein :name (n2 / name :op1 "epidermal"~e.10 :op2 "growth"~e.11 :op3 "factor"~e.12))) :ARG1 (i / increase-01~e.18 :ARG1~e.19 (p2 / phosphorylate-01~e.23 :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2"~e.20,22,27,51)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.25,49 :mod "2B" :mod "2C"))) :ARG2 (s2 / suppress-01~e.40 :ARG0 (s3 / silence-01~e.35 :ARG1~e.36 (e / express-03~e.38 :ARG2 (p4 / protein :name (n4 / name :op1 "PHB"~e.37)))) :ARG1 (p5 / phosphorylate-01~e.45 :ARG1~e.46 (e4 / enzyme :name (n5 / name :op1 "ERK"~e.47)) :ARG2-of (i2 / induce-01~e.44 :ARG0 p)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.49 :mod "2B" :mod "2C")) :ARG1-of (s4 / strong-02~e.39)) :ARG1-of (e2 / expect-01~e.1)) # ::id pmid_2456_8222.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This finding suggested specific involvement of PHB in the RAS @-@ RAF @-@ ERK pathway . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.3 4-1.2 5-1.2.1.r 6-1.2.1.1.1 7-1.2.2.r 9-1.2.2.1.1 11-1.2.2.1.1 13-1.2.2.1.1 14-1.2.2 (s / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :mod (t2 / this~e.0)) :ARG1 (i / involve-01~e.4 :ARG1~e.5 (p / protein :name (n / name :op1 "PHB"~e.6)) :ARG2~e.7 (p2 / pathway~e.14 :name (n2 / name :op1 "RAS-RAF-ERK"~e.9,11,13)) :ARG1-of (s2 / specific-02~e.3))) # ::id pmid_2456_8222.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , a similar result was obtained in Panc @-@ 1 cells ( Figure 2 @ B ) , indicating general inhibition of ERK activation by PHB depletion . # ::alignments 0-1 3-1.1.1.2 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 6-1.1 7-1.1.2.r 8-1.1.2.1.1 10-1.1.2.1.1 11-1.1.2 13-1.1.3.1 20-1.1.4 21-1.1.4.1.3 22-1.1.4.1 23-1.1.4.1.2.r 24-1.1.4.1.2.1.1.1 25-1.1.4.1.2 26-1.1.4.1.1.r 27-1.1.4.1.1.1.1.1 28-1.1.4.1.1 (a / and~e.0 :op2 (o / obtain-01~e.6 :ARG1 (t / thing~e.4 :ARG2-of~e.4 (r / result-01~e.4) :ARG1-of (r2 / resemble-01~e.3)) :location~e.7 (c / cell-line~e.11 :name (n / name :op1 "Panc-1"~e.8,10)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13 :mod "2B")) :ARG0-of (i / indicate-01~e.20 :ARG1 (i2 / inhibit-01~e.22 :ARG0~e.26 (d2 / deplete-01~e.28 :ARG2 (p2 / protein :name (n3 / name :op1 "PHB"~e.27))) :ARG1~e.23 (a2 / activate-01~e.25 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"~e.24))) :ARG1-of (g / general-02~e.21))))) # ::id pmid_2456_8222.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , these results clearly indicate that PHB is required for EGF @-@ induced ERK1 @/@ 2 activation in pancreatic cancer cells . # ::alignments 0-1 2-1.1.1.2 3-1.1.1 3-1.1.1.1 3-1.1.1.1.r 4-1.1.3 5-1.1 6-1.1.2.r 7-1.1.2.2.1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.2.1.1.1 13-1.1.2.1.1.2 14-1.1.2.1.1.1.1 16-1.1.2.1.1.1.1 17-1.1.2.1 18-1.1.2.1.2.r 19-1.1.2.1.2.1.1 20-1.1.2.1.2.1 21-1.1.2.1.2 (c / cause-01~e.0 :ARG1 (i / indicate-01~e.5 :ARG0 (t / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :mod (t2 / this~e.2)) :ARG1~e.6 (r2 / require-01~e.9 :ARG0~e.10 (a / activate-01~e.17 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"~e.14,16) :ARG2-of (i2 / induce-01~e.13 :ARG0 (p2 / protein :name (n3 / name :op1 "EGF"~e.11)))) :location~e.18 (c2 / cell~e.21 :mod (c4 / cancer~e.20 :mod (p3 / pancreas~e.19)))) :ARG1 (p / protein :name (n / name :op1 "PHB"~e.7))) :ARG1-of (c3 / clear-06~e.4))) # ::id pmid_2456_8222.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RocA disrupts the ERK pathway by targeting the CRAF @-@ PHB interaction in AsPC @-@ 1 cells # ::alignments 1-1.1.1.1 2-1 4-1.2.1.1 5-1.2 6-1.3.r 7-1.3 9-1.3.2.1.1.1 11-1.3.2.2.1.1 12-1.3.2 13-1.3.2.3.r 14-1.3.2.3.1.1 16-1.3.2.3.1.1 17-1.3.2.3 (d / disrupt-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "RocA"~e.1)) :ARG1 (p / pathway~e.5 :name (n2 / name :op1 "ERK"~e.4)) :manner~e.6 (t / target-01~e.7 :ARG0 s :ARG1 (i / interact-01~e.12 :ARG0 (e / enzyme :name (n3 / name :op1 "CRAF"~e.9)) :ARG1 (p2 / protein :name (n4 / name :op1 "PHB"~e.11)) :location~e.13 (c / cell-line~e.17 :name (n5 / name :op1 "AsPC-1"~e.14,16))))) # ::id pmid_2456_8222.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The oncogenic RAS @-@ ERK pathway is a key node for cellular proliferation signals and has been the focus of substantial drug discovery efforts in many cancers [ @ 20 @ - @ 23 @ ] . # ::alignments 1-1.1.1.1.2 1-1.1.1.1.2.1 1-1.1.1.1.2.1.r 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.r 8-1.1 9-1.1.1 10-1.1.2.r 11-1.1.2.1.1 12-1.1.2.1 13-1.1.2 18-1.2 19-1.2.1.r 20-1.2.1.2 21-1.2.1.1.1 22-1.2.1.1 23-1.2.1 24-1.2.3.r 25-1.2.3.1 26-1.2.3 29-1.3.1.1.1.1 33-1.3.1.1.1.2 (a / and :op1 (k / key-02~e.8 :ARG1 (n / node~e.9 :domain~e.6 (p / pathway~e.5 :name (n2 / name :op1 "RAS-ERK"~e.2,4) :ARG0-of (c / cause-01~e.1 :ARG1~e.1 (c2 / cancer~e.1)))) :ARG2~e.10 (s / signal-07~e.13 :ARG1 (p2 / proliferate-01~e.12 :ARG0 (c3 / cell~e.11)))) :op2 (f / focus-01~e.18 :ARG1~e.19 (e / effort-01~e.23 :ARG1 (d / discover-01~e.22 :ARG1 (d2 / drug~e.21)) :degree (s2 / substantial~e.20)) :ARG2 p :location~e.24 (c4 / cancer~e.26 :quant (m / many~e.25))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 (v / value-interval :op1 20~e.29 :op2 23~e.33))))) # ::id pmid_2456_8222.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A previous study has indicated that RocA suppresses the ERK pathway in leukemic cells [ @ 24 @ ] . # ::alignments 1-1.1.1 2-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2 9-1.2.2.1.1 10-1.2.2 13-1.2.3 16-1.3.1.1.1 (i / indicate-01~e.4 :ARG0 (s / study-01~e.2 :time (p2 / previous~e.1)) :ARG1~e.5 (s2 / suppress-01~e.7 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "RocA"~e.6)) :ARG1 (p3 / pathway~e.10 :name (n3 / name :op1 "ERK"~e.9)) :location (c / cell~e.13 :mod (l / leukemia))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 24~e.16)))) # ::id pmid_2456_8222.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm that the anti @-@ tumor effect of RocA is indeed caused by suppression of the ERK pathway , we examined the effect of RocA on ERK activity in AsPC @-@ 1 cells ( Figure 3 @ E ) . # ::alignments 0-1.3.2 1-1.3 4-1.3.2.2.2.1 6-1.3.2.2.2 7-1.3.2.2 8-1.3.2.2.1.r 9-1.3.2.2.1 11-1.3.2.3 12-1.3.2 13-1.3.2.1.r 14-1.3.2.1 15-1.3.2.1.1.r 17-1.3.2.1.1.1.1 18-1.3.2.1.1 20-1.1 21-1 23-1.2 24-1.2.1.r 25-1.2.1.1.1 26-1.2.2.r 27-1.2.2.1.1.1 28-1.2.2 29-1.2.3.r 30-1.2.3.1.1 32-1.2.3.1.1 33-1.2.3 35-1.4.1 (e / examine-01~e.21 :ARG0 (w / we~e.20) :ARG1 (a / affect-01~e.23 :ARG0~e.24 (s2 / small-molecule :name (n2 / name :op1 "RocA"~e.25)) :ARG1~e.26 (a2 / activity-06~e.28 :ARG0 (e2 / enzyme :name (n / name :op1 "ERK"~e.27))) :location~e.29 (c / cell-line~e.33 :name (n3 / name :op1 "AsPC-1"~e.30,32))) :purpose (c2 / confirm-01~e.1 :ARG0 w :ARG1 (c3 / cause-01~e.0,12 :ARG0~e.13 (s / suppress-01~e.14 :ARG1~e.15 (p2 / pathway~e.18 :name (n4 / name :op1 "ERK"~e.17))) :ARG1 (a3 / affect-01~e.7 :ARG0~e.8 s2~e.9 :ARG2 (t / tumor~e.6 :ARG1-of (c4 / counter-01~e.4 :ARG0 s2))) :mod (i / indeed~e.11))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.35 :mod "3E"))) # ::id pmid_2456_8222.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed significant dose @-@ dependent inhibition of the phosphorylation status of ERK1 @/@ 2 ( Figure 3 @ B ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.3 4-1.2.2.1 6-1.2.2 7-1.2 8-1.2.1.r 10-1.2.1.1 11-1.2.1 12-1.2.1.1.1.r 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1 17-1.3.1 (s / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1 (i / inhibit-01~e.7 :ARG1~e.8 (s3 / status~e.11 :mod (p / phosphorylate-01~e.10 :ARG1~e.12 (e / enzyme :name (n / name :op1 "ERK1/2"~e.13,15)))) :ARG0-of (d / depend-01~e.6 :ARG1 (d2 / dose-01~e.4)) :ARG1-of (s2 / significant-02~e.3)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.17 :mod "3B"))) # ::id pmid_2456_8222.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , RocA showed very strong time @-@ dependent suppression of ERK1 @/@ 2 activities ( Figure 3 @ B ) . # ::alignments 0-1.3 2-1.1.1.1 3-1 4-1.2.3.1 5-1.2.3 6-1.2.2.1 8-1.2.2 9-1.2 10-1.2.1.r 11-1.2.1.1.1.1 13-1.2.1.1.1.1 14-1.2.1 16-1.4.1 (s / show-01~e.3 :ARG0 (s4 / small-molecule :name (n / name :op1 "RocA"~e.2)) :ARG1 (s2 / suppress-01~e.9 :ARG1~e.10 (a / activity-06~e.14 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"~e.11,13))) :ARG0-of (d / depend-01~e.8 :ARG1 (t / time~e.6)) :ARG1-of (s3 / strong-02~e.5 :degree (v / very~e.4))) :mod (i / important~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.16 :mod "3B"))) # ::id pmid_2456_8222.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PHB was previously shown to be required for membrane association and activation of CRAF [ @ 15 @ ] . # ::alignments 0-1.1.1.1 2-1.3 3-1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1 9-1.1.2.1.1 10-1.1.2.1 11-1.1.2.1.2 12-1.1.2.1.2.1.r 13-1.1.2.1.2.1.1.1 16-1.2.1.1.1 (s / show-01~e.3 :ARG1 (p / protein :name (n / name :op1 "PHB"~e.0) :ARG1-of (r / require-01~e.6 :ARG0~e.7 (a / and~e.10 :op1 (a2 / associate-01~e.9 :ARG1 (m / membrane~e.8)) :op2 (a3 / activate-01~e.11 :ARG1~e.12 (e / enzyme :name (n2 / name :op1 "CRAF"~e.13)))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 15~e.16))) :time (p3 / previous~e.2)) # ::id pmid_2456_8222.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , we examined whether RocA affects PHB @-@ CRAF membrane association in AsPC @-@ 1 cells . # ::alignments 0-1 2-1.1.1 3-1.1 4-1.1.2.1 4-1.1.2.1.r 5-1.1.2.2.1.1 6-1.1.2 7-1.1.2.3.2.1.1.1 9-1.1.2.3.2.2.1.1 10-1.1.2.3.1 11-1.1.2.3 12-1.1.2.3.3.r 13-1.1.2.3.3.1.1 15-1.1.2.3.3.1.1 16-1.1.2.3.3 (c / cause-01~e.0 :ARG1 (e / examine-01~e.3 :ARG0 (w / we~e.2) :ARG1 (a / affect-01~e.6 :mode~e.4 interrogative~e.4 :ARG0 (s / small-molecule :name (n / name :op1 "RocA"~e.5)) :ARG1 (a2 / associate-01~e.11 :ARG1 (m2 / membrane~e.10) :ARG2 (m3 / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "PHB"~e.7)) :part (e2 / enzyme :name (n3 / name :op1 "CRAF"~e.9))) :location~e.12 (c2 / cell-line~e.16 :name (n4 / name :op1 "AsPC-1"~e.13,15)))))) # ::id pmid_2456_8222.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To this end , cell membrane and cytosol fractions were prepared from AsPC @-@ 1 cells treated with Roc @-@ A or DMSO to analyze the localization of PHB and CRAF . # ::alignments 1-1.4 4-1.1.1.1 5-1.1.1 6-1.1 7-1.1.2.1 8-1.1.2 10-1 11-1.2.r 12-1.2.1.1 14-1.2.1.1 15-1.2 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1.1.1.1 20-1.2.2.1.1.1.1 21-1.2.2.1 22-1.2.2.1.2.1.1 24-1.3 26-1.3.1 28-1.3.1.1.1.1.1 29-1.3.1.1 30-1.3.1.1.2.1.1 (p / prepare-01~e.10 :ARG1 (a / and~e.6 :op1 (m / membrane~e.5 :mod (c / cell~e.4)) :op2 (f / fraction-01~e.8 :location (c2 / cytosol~e.7))) :ARG2~e.11 (c3 / cell-line~e.15 :name (n / name :op1 "AsPC-1"~e.12,14) :ARG1-of (t / treat-04~e.16 :ARG2~e.17 (o / or~e.21 :op1 (s / small-molecule :name (n2 / name :op1 "Roc-A"~e.18,20)) :op2 (s2 / small-molecule :name (n3 / name :op1 "DMSO"~e.22))))) :purpose (a2 / analyze-01~e.24 :ARG1 (b / be-located-at-91~e.26 :ARG1 (a3 / and~e.29 :op1 (p2 / protein :name (n4 / name :op1 "PHB"~e.28)) :op2 (e / enzyme :name (n5 / name :op1 "CRAF"~e.30))))) :purpose (t2 / this~e.1)) # ::id pmid_2456_8222.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Immunoblot analysis showed significant reduction of CRAF , particularly phosphorylated CRAF ( pSer338 ) , in the membrane fraction after RocA treatment ( Figure 3 @ C ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.2 4-1.2 5-1.2.1.r 6-1.2.1.1.1 8-1.2.1.2.1.4 9-1.2.1.2.1.3 10-1.2.1.1.1 15-1.2.3.r 17-1.2.3.1 18-1.2.3 19-1.3 20-1.3.1.1.1.1 21-1.3.1 23-1.4.1 (s / show-01~e.2 :ARG0 (a / analyze-01~e.1 :ARG1 (i / immunoblot-01~e.0)) :ARG1 (r / reduce-01~e.4 :ARG1~e.5 (e / enzyme :name (n / name :op1 "CRAF"~e.6,10) :ARG2-of (i2 / include-01 :ARG1 (a2 / amino-acid :mod 338 :name (n2 / name :op1 "serine") :ARG3-of (p / phosphorylate-01~e.9) :mod (p2 / particular~e.8) :part-of e))) :ARG1-of (s2 / significant-02~e.3) :location~e.15 (f / fraction-01~e.18 :ARG1 (m / membrane~e.17))) :time (a3 / after~e.19 :op1 (t / treat-04~e.21 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "RocA"~e.20)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.23 :mod "3C"))) # ::id pmid_2456_8222.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , RocA also significantly reduced the levels of PHB in the membrane fraction , indicating that binding of RocA to PHB may also interfere with PHB membrane association . # ::alignments 0-1.7 2-1.1.1.1 3-1.3 4-1.4 5-1 7-1.2 8-1.2.1.r 9-1.2.1.1.1 10-1.5.r 12-1.5.1 13-1.5 15-1.6 16-1.6.1.r 17-1.6.1.1.1 18-1.6.1.1.1.1.r 19-1.6.1.1.1.1 21-1.2.1.1.1 22-1.6.1 23-1.6.1.1.3 24-1.6.1.1 25-1.6.1.1.2.r 26-1.6.1.1.2.2 27-1.6.1.1.2.1 28-1.6.1.1.2 (r / reduce-01~e.5 :ARG0 (s / small-molecule :name (n / name :op1 "RocA"~e.2)) :ARG1 (l / level~e.7 :quant-of~e.8 (p / protein :name (n2 / name :op1 "PHB"~e.9,21))) :mod (a / also~e.3) :ARG1-of (s2 / significant-02~e.4) :location~e.10 (f / fraction-01~e.13 :ARG1 (m / membrane~e.12)) :ARG0-of (i / indicate-01~e.15 :ARG1~e.16 (p2 / possible-01~e.22 :ARG1 (i2 / interfere-01~e.24 :ARG0 (b / bind-01~e.17 :ARG1~e.18 s~e.19 :ARG2 p) :ARG1~e.25 (a2 / associate-01~e.28 :ARG1 (m2 / membrane~e.27) :ARG2 p~e.26) :mod a~e.23))) :ARG1-of (n3 / notable-04~e.0)) # ::id pmid_2456_8222.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , RocA did not influence membrane localization of RAS ( Figure 3 @ C ) . # ::alignments 0-1 2-1.1.2.1.1 4-1.1.1 4-1.1.1.r 5-1.1 6-1.1.3.2 7-1.1.3 9-1.1.3.1.1.1 11-1.2.1 (c / contrast-01~e.0 :ARG2 (i / influence-01~e.5 :polarity~e.4 -~e.4 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"~e.2)) :ARG1 (b / be-located-at-91~e.7 :ARG1 (p2 / protein-family :name (n3 / name :op1 "RAS"~e.9)) :ARG2 (m / membrane~e.6))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "3C"))) # ::id pmid_2456_8222.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , immunoprecipitation analysis suggested that RocA substantially decreased the amounts of total CRAF bound to PHB in AsPC @-@ 1 cells ( Figure 3 @ D ) . # ::alignments 0-1.3 2-1.1.1 3-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2.3 7-1.2.3.r 8-1.2 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.2 13-1.2.2.1.1.1 14-1.2.2.1 14-1.2.2.1.3 14-1.2.2.1.3.r 15-1.2.2.1.3.1.r 16-1.2.2.1.3.1.1.1 17-1.2.2.1.3.2.r 18-1.2.2.1.3.2.1.1 20-1.2.2.1.3.2.1.1 21-1.2.2.1.3.2 23-1.4.1 (s / suggest-01~e.4 :ARG0 (a / analyze-01~e.3 :ARG1 (i / immunoprecipitate-01~e.2)) :ARG1~e.5 (d / decrease-01~e.8 :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA"~e.6)) :ARG1 (a2 / amount-01~e.10 :ARG1~e.11 (e / enzyme~e.14 :name (n2 / name :op1 "CRAF"~e.13) :mod (t / total~e.12) :ARG1-of~e.14 (b / bind-01~e.14 :ARG2~e.15 (p / protein :name (n3 / name :op1 "PHB"~e.16)) :location~e.17 (c / cell-line~e.21 :name (n4 / name :op1 "AsPC-1"~e.18,20))))) :manner~e.7 (s3 / substantial~e.7)) :mod (i2 / indeed~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.23 :mod "3D"))) # ::id pmid_2456_8222.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , confocal microscopic analysis showed that treatment of AsPC @-@ 1 cells with 100 nM RocA for 4 h led to a loss of plasma membrane localization and random redistribution of PHB ( Figure 3 @ E ) . # ::alignments 0-1.3 2-1.1.1.1 3-1.1.1 4-1.1 5-1 6-1.2.r 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1.1 11-1.2.1.1.1.1 12-1.2.1.1 13-1.2.1.2.r 14-1.2.1.2.2.1 15-1.2.1.2.2.2 16-1.2.1.2.1.1 17-1.2.1.3.r 18-1.2.1.3.1 19-1.2.1.3.2 20-1.2 21-1.2.2.r 23-1.2.2.1 25-1.2.2.1.1.2.1 26-1.2.2.1.1.2 27-1.2.2.1.1 28-1.2.2 29-1.2.2.2.2 30-1.2.2.2 31-1.2.2.2.1.r 32-1.2.2.2.1.1.1 34-1.4.1 (s / show-01~e.5 :ARG0 (a / analyze-01~e.4 :mod (m / microscopy~e.3 :mod (c / confocal~e.2))) :ARG1~e.6 (l / lead-03~e.20 :ARG0 (t / treat-04~e.7 :ARG1~e.8 (c2 / cell-line~e.12 :name (n / name :op1 "AsPC-1"~e.9,11)) :ARG2~e.13 (s2 / small-molecule :name (n2 / name :op1 "RocA"~e.16) :quant (c3 / concentration-quantity :quant 100~e.14 :unit (n3 / nanomolar~e.15))) :duration~e.17 (t2 / temporal-quantity :quant 4~e.18 :unit (h / hour~e.19))) :ARG1~e.21 (a2 / and~e.28 :op1 (l2 / lose-02~e.23 :ARG1 (b / be-located-at-91~e.27 :ARG1 p2 :ARG2 (m2 / membrane~e.26 :mod (p / plasma~e.25)))) :op2 (r / redistribute-01~e.30 :ARG1~e.31 (p2 / protein :name (n4 / name :op1 "PHB"~e.32)) :manner (r2 / random~e.29)))) :ARG1-of (n5 / notable-04~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "3E"))) # ::id pmid_2456_8222.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This observation indicates that inhibition of the PHB @-@ CRAF interaction by RocA leads to the loss of spatial organization of PHB in AsPC @-@ 1 cells . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1 5-1.2.1.2.r 7-1.2.1.2.1.1.1 9-1.2.1.2.2.1.1 10-1.2.1.2 11-1.2.1.1.r 12-1.2.1.1.1.1 13-1.2 14-1.2.2.r 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1.2 19-1.2.2.1 20-1.2.2.1.1.r 21-1.2.2.1.1 22-1.2.2.1.3.r 23-1.2.2.1.3.1.1 25-1.2.2.1.3.1.1 26-1.2.2.1.3 (i / indicate-01~e.2 :ARG0 (o / observe-01~e.1 :mod (t / this~e.0)) :ARG1~e.3 (l / lead-03~e.13 :ARG0 (i2 / inhibit-01~e.4 :ARG0~e.11 (s / small-molecule :name (n3 / name :op1 "RocA"~e.12)) :ARG1~e.5 (i3 / interact-01~e.10 :ARG0 (p / protein :name (n / name :op1 "PHB"~e.7)) :ARG1 (e / enzyme :name (n2 / name :op1 "CRAF"~e.9)))) :ARG1~e.14 (l2 / lose-02~e.16 :ARG1~e.17 (o2 / organize-01~e.19 :ARG1~e.20 p~e.21 :mod (s2 / space~e.18) :location~e.22 (c / cell-line~e.26 :name (n4 / name :op1 "AsPC-1"~e.23,25)))))) # ::id pmid_2456_8222.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Collectively , these results further demonstrate that RocA blocks the RAS @-@ CRAF @-@ ERK signaling pathway by disruption of the PHB @-@ CRAF interaction in pancreatic cancer . # ::alignments 0-1.4 2-1.1.1 3-1.1 4-1.3 5-1 6-1.2.r 7-1.2.1.1.1 8-1.2 10-1.2.2.1.1 12-1.2.2.1.1 14-1.2.2.1.1 15-1.2.2.2 16-1.2.2 17-1.2.3.r 18-1.2.3 19-1.2.3.2.r 21-1.2.3.2.1.1.1 23-1.2.3.2.2.1.1 24-1.2.3.2 25-1.2.3.3.r 26-1.2.3.3.1 27-1.2.3.3 (d2 / demonstrate-01~e.5 :ARG0 (r / result-01~e.3 :mod (t / this~e.2)) :ARG1~e.6 (b / block-01~e.8 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"~e.7)) :ARG1 (p / pathway~e.16 :name (n3 / name :op1 "RAS-CRAF-ERK"~e.10,12,14) :ARG0-of (s2 / signal-07~e.15)) :manner~e.17 (d3 / disrupt-01~e.18 :ARG0 s :ARG1~e.19 (i / interact-01~e.24 :ARG0 (p2 / protein :name (n4 / name :op1 "PHB"~e.21)) :ARG1 (e / enzyme :name (n5 / name :op1 "CRAF"~e.23))) :location~e.25 (c / cancer~e.27 :mod (p3 / pancreas~e.26)))) :degree (f / further~e.4) :mod (c2 / collective~e.0)) # ::id pmid_2456_8222.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RocA mimics the effect of PHB knockdown on epithelial @-@ mesenchymal transition ( EMT ) markers and reverses the EMT phenotype in AsPC @-@ 1 cells # ::alignments 1-1.1.1.1.1 2-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1.1 7-1.1.2.1 8-1.1.2.2.r 9-1.1.2.2.1.2.1 11-1.1.2.2.1.1.1 12-1.1.2.2.1 14-1.1.2.2.1 16-1.1.2.2 17-1 18-1.2 20-1.2.2.1 21-1.2.2 22-1.2.3.r 23-1.2.3.1.1 25-1.2.3.1.1 26-1.1.2.2.1.1 26-1.1.2.2.1.2 (a / and~e.17 :op1 (m / mimic-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "RocA"~e.1)) :ARG1 (a2 / affect-01~e.4 :ARG0~e.5 (k / knock-down-02~e.7 :ARG1 (p / protein :name (n2 / name :op1 "PHB"~e.6))) :ARG1~e.8 (m2 / marker~e.16 :mod (t / transition-01~e.12,14 :ARG2 (c / cell~e.26 :mod (m3 / mesenchyme~e.11)) :ARG3 (c3 / cell~e.26 :mod (e / epithelium~e.9)))))) :op1 (r / reverse-01~e.18 :ARG0 s :ARG1 (p2 / phenotype~e.21 :mod t~e.20) :location~e.22 (c2 / cell-line :name (n4 / name :op1 "AsPC-1"~e.23,25)))) # ::id pmid_2456_8222.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The oncogenic RAS @-@ RAF @-@ ERK pathway confers epithelial cells with critical motile and invasive capacities during carcinoma progression , often by promotion of EMT [ @ 25 , 26 @ ] . # ::alignments 1-1.1.2 1-1.1.2.1 1-1.1.2.1.r 4-1.1.1.1 6-1.1.1.1 7-1.1 8-1 9-1.3.1 9-1.5.1.2.1 10-1.3 10-1.5.1.1 10-1.5.1.2 11-1.2.r 12-1.2.1.2.1 13-1.2.1.2 14-1.2 15-1.2.2.2 16-1.2.1 16-1.2.2 17-1.4.r 18-1.4.1 19-1.4 21-1.5.2 23-1.5 24-1.5.1.r 25-1.5.1 28-1.6.1.1.1.1 32-1.6.1.1.1.2 (c / confer-02~e.8 :ARG0 (p / pathway~e.7 :name (n / name :op1 "PAS-RAF-ERK"~e.4,6) :ARG0-of (c2 / cause-01~e.1 :ARG1~e.1 (c3 / cancer~e.1))) :ARG1~e.11 (a / and~e.14 :op1 (c8 / capable-01~e.16 :ARG1 c4 :ARG2 (m / motile~e.13 :ARG1-of (c5 / critical-02~e.12))) :op1 (c10 / capable-01~e.16 :ARG1 c4 :ARG2 (i / invade-01~e.15 :ARG0 c4))) :ARG2 (c4 / cell~e.10 :mod (e / epithelium~e.9)) :time~e.17 (p2 / progress-01~e.19 :ARG1 (c7 / carcinoma~e.18)) :manner (p3 / promote-01~e.23 :ARG1~e.24 (t / transition-01~e.25 :ARG2 (c6 / cell~e.10 :mod (m2 / mesenchyme)) :ARG3 (c11 / cell~e.10 :mod (e2 / epithelium~e.9))) :frequency (o / often~e.21)) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c9 / cite-01 :ARG2 (a2 / and :op1 25~e.28 :op2 26~e.32))))) # ::id pmid_2456_8222.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further investigate the role of PHB in EMT , the effects of PHB siRNA and RocA on EMT markers were assayed in AsPC @-@ 1 cells . # ::alignments 1-1.3.2 2-1.3 4-1.3.1 5-1.3.1.2.r 6-1.3.1.2 8-1.1.2.1 11-1.1 12-1.1.1.r 13-1.1.1.1.2.1.1.1 14-1.1.1.1.1.1 15-1.1.1 16-1.1.1.2.1.1 18-1.1.2.1 19-1.1.2 21-1 22-1.2.r 23-1.2.1.1 25-1.2.1.1 26-1.1.2.1.1 26-1.1.2.1.2 (a / assay-01~e.21 :ARG1 (a3 / affect-01~e.11 :ARG0~e.12 (a4 / and~e.15 :op1 (n4 / nucleic-acid :name (n / name :op1 "siRNA"~e.14) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "PHB"~e.13)))) :op2 (s / small-molecule :name (n3 / name :op1 "RocA"~e.16))) :ARG1 (m / marker~e.19 :mod (t / transition-01~e.8,18 :ARG2 (c / cell~e.26 :mod (m2 / mesenchyme)) :ARG3 (c2 / cell~e.26 :mod (e2 / epithelium))))) :location~e.22 (c3 / cell-line :name (n5 / name :op1 "AsPC-1"~e.23,25)) :purpose (i / investigate-01~e.2 :ARG1 (r2 / role~e.4 :topic t :poss~e.5 p~e.6) :degree (f / further~e.1))) # ::id pmid_2456_8222.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok First , we detected EMT markers in AsPC @-@ 1 and Capan @-@ 2 cells ( Figure 4 @ A ) . # ::alignments 0-1.3.1.1.1 0-1.4 2-1.1 3-1 4-1.2.1 5-1.2 6-1.3.r 7-1.3.1.1.1 9-1.3.1.1.1 10-1.3 11-1.3.2.1.1 13-1.3.2.1.1 14-1.2.1.1 14-1.2.1.2 16-1.5.1 (d / detect-01~e.3 :ARG0 (w / we~e.2) :ARG1 (m / marker~e.5 :mod (t / transition-01~e.4 :ARG2 (c / cell~e.14 :mod (m2 / mesenchyme)) :ARG3 (c2 / cell~e.14 :mod (e / epithelium)))) :location~e.6 (a / and~e.10 :op1 (c3 / cell-line :name (n2 / name :op1 "AsPC-1"~e.0,7,9)) :op2 (c4 / cell-line :name (n3 / name :op1 "Capan-2"~e.11,13))) :time (f / first~e.0) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.16 :mod "4A"))) # ::id pmid_2456_8222.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Knockdown of PHB in AsPC @-@ 1 cells by siRNA resulted in upregulation of E @-@ cadherin and β-catenin and downregulation of vimentin ( Figure 4 @ B ) . # ::alignments 0-1.1 1-1.1.2.r 2-1.1.2.1.1 3-1.1.3.r 4-1.1.3.1.1 6-1.1.3.1.1 7-1.1.3 8-1.1.1.r 9-1.1.1.1.1 10-1 11-1.2.r 12-1.2.1 13-1.2.1.1.r 14-1.2.1.1.1.1.1 16-1.2.1.1.1.1.1 17-1.2.1.1 18-1.2.1.1.2.1.1 19-1.2 20-1.2.2 21-1.2.2.1.r 22-1.2.2.1.1.1 24-1.3.1 (r / result-01~e.10 :ARG1 (k / knock-down-02~e.0 :ARG0~e.8 (n7 / nucleic-acid :name (n / name :op1 "siRNA"~e.9)) :ARG1~e.1 (p / protein :name (n2 / name :op1 "PHB"~e.2)) :location~e.3 (c / cell-line~e.7 :name (n3 / name :op1 "AsPC-1"~e.4,6))) :ARG2~e.11 (a / and~e.19 :op1 (u / upregulate-01~e.12 :ARG1~e.13 (a2 / and~e.17 :op1 (p2 / protein :name (n4 / name :op1 "E-cadherin"~e.14,16)) :op2 (p3 / protein :name (n5 / name :op1 "β-catenin"~e.18)))) :op2 (d / downregulate-01~e.20 :ARG1~e.21 (p4 / protein :name (n6 / name :op1 "vimentin"~e.22)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "4B"))) # ::id pmid_2456_8222.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to the effect of PHB knockdown , treatment of AsPC @-@ 1 cells with RocA showed the same results ( Figure 4 @ C ) . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1.1 6-1.3.1.1 8-1.1 9-1.1.1.r 10-1.1.1.1.1 12-1.1.1.1.1 13-1.1.1 14-1.1.2.r 15-1.1.2.1.1 16-1 18-1.2.1 19-1.2 21-1.4.1 (s / show-01~e.16 :ARG0 (t / treat-04~e.8 :ARG1~e.9 (c / cell-line~e.13 :name (n / name :op1 "AsPC-1"~e.10,12)) :ARG2~e.14 (s2 / small-molecule :name (n2 / name :op1 "RocA"~e.15))) :ARG1 (r2 / result-01~e.19 :ARG1-of (s3 / same-01~e.18)) :ARG1-of (r3 / resemble-01~e.0 :ARG2~e.1 (a / affect-01~e.3 :ARG0~e.4 (k / knock-down-02~e.6 :ARG1 (p / protein :name (n3 / name :op1 "PHB"~e.5))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "4C"))) # ::id pmid_2456_8222.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activated ERK2 directly phosphorylates Snail , leading to nuclear accumulation , reduced ubiquitylation , and an increased protein half @-@ life of Snail , and then promotion of breast cancer cell invasion and migration in vitro and metastasis in vivo @ [ @ 27 @ ] . # ::alignments 0-1.2.2 1-1.2.1.1 2-1.5 3-1 4-1.1.1.1 6-1.3 7-1.3.1.r 8-1.3.1.1.1 9-1.3.1.1 11-1.3.1.2.2 14-1.3.1 16-1.3.1.3.3 17-1.1 17-1.3.1.2 17-1.3.1.3 18-1.3.1.3.2.1 20-1.3.1.3.2 22-1.3.1.3.1.1 24-1.3.1 25-1.3.1.4.2 26-1.3.1.4 27-1.3.1.4.1.r 28-1.3.1.4.1.1.1.1.1.1 29-1.3.1.4.1.1.1.1.1 30-1.3.1.4.1.1.1.1 31-1.3.1.4.1.1.1 32-1.3.1.4.1.1 33-1.3.1.4.1.1.2 35-1.3.1.4.1.1.3 36-1.3.1.4.1.1.3 38-1.3.1.4.1 39-1.3.1.4.1.2 41-1.3.1.4.1.2.1 42-1.3.1.4.1.2.1 46-1.4.1.1.1 (p / phosphorylate-01~e.3 :ARG1 (p2 / protein~e.17 :name (n3 / name :op1 "Snail"~e.4)) :ARG2 (e / enzyme :name (n2 / name :op1 "ERK2"~e.1) :ARG1-of (a / activate-01~e.0)) :ARG0-of (l / lead-03~e.6 :ARG2~e.7 (a2 / and~e.14,24 :op1 (a3 / accumulate-01~e.9 :mod (n4 / nucleus~e.8)) :op2 (p3 / protein~e.17 :name (n5 / name :op1 "Ubiquitin") :ARG1-of (r / reduce-01~e.11)) :op3 (p4 / protein~e.17 :name (n6 / name :op1 "Snail"~e.22) :ARG0-of (l2 / live-01~e.20 :degree (h / half~e.18)) :ARG1-of (i / increase-01~e.16)) :op4 (p5 / promote-01~e.26 :ARG1~e.27 (a4 / and~e.38 :op1 (a5 / and~e.32 :op1 (i2 / invade-01~e.31 :ARG0 (c / cell~e.30 :mod (c2 / cancer~e.29 :mod (b / breast~e.28)))) :op2 (m / migrate-01~e.33) :manner (i3 / in-vitro~e.35,36)) :op2 (m2 / metastasize-101~e.39 :manner (i4 / in-vivo~e.41,42))) :time (t / then~e.25)))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 27~e.46))) :ARG1-of (d / direct-02~e.2)) # ::id pmid_2456_8222.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Another study has shown clear increases of ZEB1 and ZEB2 protein levels by ERK2 but not ERK1 [ @ 28 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.1.3 5-1.2.1 5-1.2.2 6-1.2.1.2.r 7-1.2.1.2.1.1.1.1 8-1.2.1.2 9-1.2.1.2.2.1.1.1 10-1.2.1.2.1.1 10-1.2.1.2.2.1 11-1.2.1.2.1 11-1.2.1.2.2 12-1.2.1.1.r 13-1.2.1.1.1.1 14-1.2 15-1.2.2.1 15-1.2.2.1.r 16-1.2.2.2.1.1 19-1.3.1.1.1 (s / show-01~e.3 :ARG0 (s2 / study-01~e.1 :mod (a / another~e.0)) :ARG1 (c / contrast-01~e.14 :ARG1 (i / increase-01~e.5 :ARG0~e.12 (e / enzyme :name (n3 / name :op1 "ERK2"~e.13)) :ARG1~e.6 (a2 / and~e.8 :op1 (l / level~e.11 :quant-of (p / protein~e.10 :name (n / name :op1 "ZEB1"~e.7))) :op2 (l2 / level~e.11 :quant-of (p2 / protein~e.10 :name (n2 / name :op1 "ZEB2"~e.9)))) :ARG1-of (c2 / clear-06~e.4)) :ARG2 (i2 / increase-01~e.5 :polarity~e.15 -~e.15 :ARG0 (e2 / enzyme :name (n4 / name :op1 "ERK1"~e.16)) :ARG1 a2)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 28~e.19)))) # ::id pmid_2456_8222.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further investigate the molecular basis of ERK @-@ regulated EMT , we detected the levels of Snail1 , ZEB1 , and transcription factors known to regulate EMT which act downstream of ERK1 @/@ 2 . # ::alignments 1-1.3.3 2-1.3 4-1.3.2.2 5-1.3.2 6-1.3.2.1.r 7-1.3.2.1.3.1.1.1 9-1.3.2.1.3 10-1.3.2.1 12-1.1 13-1 15-1.2.1 15-1.2.2 15-1.2.3 19-1.2.2.1.1.1 21-1.2 22-1.2.3.1.1 23-1.2.3.1 24-1.2.3.1.2.2 26-1.2.3.1.2 27-1.2.3.1.2.1 29-1.2.3.1.3 30-1.2.3.1.3.1.2 32-1.2.3.1.3.1.1.1.1 34-1.2.3.1.3.1.1.1.1 (d / detect-01~e.13 :ARG0 (w / we~e.12) :ARG1 (a / and~e.21 :op1 (l / level~e.15 :quant-of (p / protein :name (n / name :op1 "Snail"))) :op2 (l2 / level~e.15 :quant-of (p2 / protein :name (n2 / name :op1 "ZEB1"~e.19))) :op3 (l3 / level~e.15 :quant-of (f / factor~e.23 :ARG0-of (t / transcribe-01~e.22 :ARG2 (c / cell :mod (m2 / mesenchyme)) :ARG3 (c2 / cell :mod (e / epithelium))) :ARG0-of (r / regulate-01~e.26 :ARG1 (t2 / transition-01~e.27) :ARG1-of (k / know-01~e.24)) :ARG0-of (a2 / act-02~e.29 :location (r2 / relative-position :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"~e.32,34)) :direction (d2 / downstream~e.30)))))) :purpose (i / investigate-01~e.2 :ARG0 w :ARG1 (b2 / base-02~e.5 :ARG1~e.6 (t3 / transition-01~e.10 :ARG2 c :ARG3 c2 :ARG1-of (r3 / regulate-01~e.9 :ARG0 (p3 / protein-family :name (n6 / name :op1 "ERK"~e.7)))) :ARG2 (m / molecule~e.4)) :degree (f2 / further~e.1))) # ::id pmid_2456_8222.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , we observed similar results in PHB @-@ silenced and RocA @-@ treated AsPC @-@ 1 cells ( Figure 4 @ B , C ) . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.2 5-1.2 6-1.2.1.r 7-1.2.1.3.1.1 9-1.2.1.3.2 11-1.2.1.2.1.1.1 13-1.2.1.2 16-1.2.1.1.1 17-1.2.1 19-1.4.1.1 19-1.4.1.2 (o / observe-01~e.3 :ARG0 (w / we~e.2) :ARG1 (r / result-01~e.5 :ARG2~e.6 (c / cell-line~e.17 :name (n2 / name :op1 "ASPC-1"~e.16) :ARG1-of (t / treat-04~e.13 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "RocA"~e.11))) :location-of (p / protein :name (n / name :op1 "PHB"~e.7) :ARG1-of (s / silence-01~e.9))) :ARG1-of (r3 / resemble-01~e.4)) :ARG2-of (i / interest-01~e.0) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.19 :mod "4B") :op2 (f2 / figure~e.19 :mod "4C")))) # ::id pmid_2456_8222.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AsPC @-@ 1 cells lacking PHB expression showed defective migration ( Figure 4 @ D ) , indicating that the formation of clusters is the consequence of reduced motility of cells that lack high levels of PHB . # ::alignments 2-1.1.1.1 3-1.1 4-1.1.2 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1 8-1.2.1 9-1.2 11-1.3.1 18-1.4 19-1.4.1.r 21-1.4.1.2 22-1.4.1.2.1.r 23-1.4.1.2.1 26-1.4.1 27-1.4.1.1.r 28-1.4.1.1.1 29-1.4.1.1 30-1.4.1.1.2.r 31-1.4.1.1.2 33-1.4.1.1.3 34-1.4.1.1.3.1.1 35-1.4.1.1.3.1 36-1.4.1.1.3.1.2.r 37-1.4.1.1.3.1.2 (s / show-01~e.7 :ARG0 (c / cell-line~e.3 :name (n / name :op1 "ASPC-1"~e.2) :ARG0-of (l / lack-01~e.4 :ARG1 (e / express-03~e.6 :ARG2 (p / protein :name (n2 / name :op1 "PHB"~e.5))))) :ARG1 (m / migrate-01~e.9 :mod (d / defective~e.8)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.11 :mod "4D")) :ARG0-of (i / indicate-01~e.18 :ARG1~e.19 (c3 / cause-01~e.26 :ARG0~e.27 (m2 / motility~e.29 :ARG1-of (r / reduce-01~e.28) :mod~e.30 (c2 / cell~e.31) :ARG0-of (l2 / lack-01~e.33 :ARG1 (l3 / level~e.35 :ARG1-of (h / high-02~e.34) :quant-of~e.36 p~e.37))) :ARG1 (f2 / form-01~e.21 :ARG1~e.22 (c4 / cluster~e.23))))) # ::id pmid_2456_8222.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , AsPC @-@ 1 cells treated with RocA formed cell clusters similar to those formed by cells with reduced PHB expression ( Figure 4 @ D ) . # ::alignments 0-1.3 2-1.1.2.1 4-1.1.2.1 5-1.1 6-1.1.3 7-1.1.3.1.r 8-1.1.3.1.2.1 9-1 9-1.2.1.1.1 10-1.2.1.1.1.1 10-1.2.2 11-1.2 11-1.2.1.1 12-1.2.1 15-1 17-1.1 18-1.2.1.1.1.1.1.r 19-1.2.1.1.1.1.1.2 20-1.2.1.1.1.1.1.1.2.1 21-1.2.1.1.1.1.1 23-1.4.1 (f / form-01~e.9,15 :ARG0 (c / cell-line~e.5,17 :wiki - :name (n / name :op1 "AsPC-1"~e.2,4) :ARG1-of (t / treat-04~e.6 :ARG2~e.7 (s / small-molecule :wiki - :name (n2 / name :op1 "RocA"~e.8)))) :ARG1 (c2 / cluster~e.11 :ARG1-of (r2 / resemble-01~e.12 :ARG2 (c5 / cluster~e.11 :ARG1-of (f2 / form-01~e.9 :ARG0 (c4 / cell~e.10 :ARG3-of~e.18 (e / express-03~e.21 :ARG2 (p / protein :wiki "Prohibitin" :name (n3 / name :op1 "PHB"~e.20)) :ARG1-of (r3 / reduce-01~e.19)))))) :consist-of (c3 / cell~e.10)) :ARG1-of (n4 / notable-04~e.0) :ARG1-of (d / describe-01 :ARG0 (f3 / figure~e.23 :mod "4D"))) # ::id pmid_2456_8222.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , RocA mimics the effect of PHB knockdown on EMT marker expression and reverses the EMT phenotype in AsPC @-@ 1 cells . # ::alignments 0-1.3 1-1.3.1 3-1.1.1.1.1 4-1.1 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2.2.r 11-1.1.2.2.1.1 12-1.1.2.2.1 13-1.1.2.2 14-1 15-1.2 17-1.2.2.1 18-1.2.2 19-1.2.3.r 20-1.2.3.1.1 22-1.2.3.1.1 23-1.1.2.2.1.1.1 23-1.1.2.2.1.1.2 (a2 / and~e.14 :op1 (m / mimic-01~e.4 :ARG0 (s / small-molecule :name (n / name :op1 "RocA"~e.3)) :ARG1 (a / affect-01~e.6 :ARG0~e.7 (k / knock-down-02~e.9 :ARG1 (p / protein :name (n2 / name :op1 "PHB"~e.8))) :ARG1~e.10 (e2 / express-03~e.13 :ARG2 (m2 / marker~e.12 :mod (t / transition-01~e.11 :ARG2 (c / cell~e.23 :mod (m3 / mesenchyme)) :ARG3 (c2 / cell~e.23 :mod (e / epithelium))))))) :op2 (r / reverse-01~e.15 :ARG0 s :ARG1 (p2 / phenotype~e.18 :mod t~e.17) :location~e.19 (c3 / cell-line :name (n4 / name :op1 "AsPC-1"~e.20,22))) :ARG1-of (t2 / take-01~e.0 :manner (t3 / together~e.1))) # ::id pmid_2456_8222.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RocA selectively diminishes the viability of PHB @-@ dependent pancreatic cancer cells in vitro and inhibits their migration in vitro and in vivo @ # ::alignments 1-1.1.1.1.1 2-1.1.3 2-1.1.3.r 3-1.1 7-1.1.2.1.2.1.1.1 9-1.1.2.1.2 10-1.1.2.1.1.1 11-1.1.2.1.1 12-1.1.2.1 14-1.1.2.1.3 15-1.1.2.1.3 17-1 18-1.2 19-1.2.1 19-1.2.1.r 20-1.2.2.1 20-1.2.2.2 22-1.2.2.1.2 22-1.2.2.2.2 23-1.2.2.1.2 27-1.2.2.1.2 28-1.2.2.2.2 (a / and~e.17 :op1 (d2 / diminish-01~e.3 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"~e.1)) :ARG1 (v / viable :domain (c / cell~e.12 :mod (c2 / cancer~e.11 :mod (p / pancreas~e.10)) :ARG0-of (d3 / depend-01~e.9 :ARG1 (p2 / protein :name (n3 / name :op1 "PHB"~e.7))) :mod (i / in-vitro~e.14,15))) :manner~e.2 (s2 / selective~e.2)) :op2 (i2 / inhibit-01~e.18 :ARG0~e.19 s~e.19 :ARG1 (a2 / and :op1 (m / migrate-01~e.20 :ARG0 c :mod (i3 / in-vitro~e.22,23,27)) :op2 (m2 / migrate-01~e.20 :ARG0 c :mod (i4 / in-vivo~e.22,28))))) # ::id pmid_2456_8222.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To characterize the action of RocA on pancreatic cancer cell growth , AsPC @-@ 1 and Panc @-@ 1 cells were treated with RocA ( 100 nM ) or DMSO for 16 h and then applied to CCK @-@ 8 assays . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1 6-1.3.1.2.r 7-1.3.1.2.1.1.1 8-1.3.1.2.1.1 9-1.3.1.2.1 10-1.3.1.2 12-1.1.1.1.1.1 14-1.1.1.1.1.1 14-1.1.1.2.1.1 15-1.1.1 16-1.1.1.2.1.1 18-1.1.1.1.1.1 18-1.1.1.2.1.1 19-1.1.1.1 19-1.1.1.2 21-1.1 22-1.1.2.r 23-1.1.2.1.1.1 25-1.1.2.1.2.1 26-1.1.2.1.2.2 28-1.1.2 29-1.1.2.2.1.1 30-1.1.3.r 31-1.1.3.1 32-1.1.3.2 33-1 34-1.2.3 35-1.2 36-1.2.2.r 37-1.2.2.1.1.1 39-1.2.2.1.1.1 40-1.2.2 (a / and~e.33 :op1 (t / treat-04~e.21 :ARG1 (a2 / and~e.15 :op1 (c / cell-line~e.19 :name (n2 / name :op1 "AsPC-1"~e.12,14,18)) :op2 (c2 / cell-line~e.19 :name (n3 / name :op1 "Panc-1"~e.14,16,18))) :ARG2~e.22 (o / or~e.28 :op1 (s / small-molecule :name (n4 / name :op1 "RocA"~e.23) :quant (c3 / concentration-quantity :quant 100~e.25 :unit (n6 / nanomolar~e.26))) :op2 (s2 / small-molecule :name (n5 / name :op1 "DMSO"~e.29))) :duration~e.30 (t2 / temporal-quantity :quant 16~e.31 :unit (h / hour~e.32))) :op2 (a3 / apply-02~e.35 :ARG1 a2 :ARG2~e.36 (a4 / assay-01~e.40 :mod (t4 / thing :name (n7 / name :op1 "CCK-8"~e.37,39))) :time (t3 / then~e.34)) :purpose (c4 / characterize-01~e.1 :ARG1 (a5 / act-02~e.3 :ARG0~e.4 (s3 / small-molecule :name (n8 / name :op1 "RocA"~e.5)) :ARG1~e.6 (g / grow-01~e.10 :ARG1 (c5 / cell~e.9 :mod (c6 / cancer~e.8 :mod (p / pancreas~e.7))))))) # ::id pmid_2456_8222.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RocA markedly impaired the growth of AsPC @-@ 1 and Panc @-@ 1 cells without affecting Hs 578Bst or L02 cells as controls ( Figure 5 @ A , B ) . # ::alignments 0-1.1.1.1 1-1.3 1-1.3.r 2-1 4-1.2 8-1.2.1.1.1.1 8-1.2.1.2.1.1 9-1.2.1 10-1.2.1.2.1.1 12-1.2.1.1.1.1 12-1.2.1.2.1.1 13-1.2.1.1 13-1.2.1.2 14-1.4.1 14-1.4.1.r 15-1.4 16-1.4.2.1.1.1 17-1.4.2.1.1.2 18-1.4.2 19-1.4.2.2.1.1 20-1.4.2.1 20-1.4.2.2 21-1.4.3.r 22-1.4.3 24-1.5.1.1 24-1.5.1.2 (i / impair-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "RocA"~e.0)) :ARG1 (g / grow-01~e.4 :ARG1 (a / and~e.9 :op1 (c / cell-line~e.13 :name (n2 / name :op1 "ASPC-1"~e.8,12)) :op2 (c2 / cell-line~e.13 :name (n3 / name :op1 "Panc-1"~e.8,10,12)))) :manner~e.1 (m / marked~e.1) :ARG0-of (a2 / affect-01~e.15 :polarity~e.14 -~e.14 :ARG1 (o / or~e.18 :op1 (c3 / cell-line~e.20 :name (n4 / name :op1 "Hs"~e.16 :op2 "578Bst"~e.17)) :op2 (c4 / cell-line~e.20 :name (n5 / name :op1 "L02"~e.19))) :ARG0-of~e.21 (c5 / control-01~e.22)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.24 :mod "5A") :op2 (f2 / figure~e.24 :mod "5B")))) # ::id pmid_2456_8222.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , Capan @-@ 2 cells did not show any detectable toxicity in the presence of RocA ( Additional file 1 @ : Figure S5 ) , suggesting deficient expression of PHB in Capan @-@ 2 cells may rescue the effects of RocA . # ::alignments 0-1.7 2-1.2.1.1 4-1.2.1.1 5-1.2 7-1.1 7-1.1.r 8-1 9-1.3.2 10-1.3.1 11-1.3 12-1.4.r 14-1.4 15-1.4.1.r 16-1.4.1.1.1 19-1.5.1.2 21-1.5.1.2.1 24-1.5.1 25-1.5.1.1 28-1.6 29-1.6.1.1.1.3 30-1.6.1.1.1 31-1.6.1.1.1.1.r 32-1.6.1.1.1.1.1.1 33-1.6.1.1.1.2.r 34-1.6.1.1.1.2 35-1.6.1.1.1.2 36-1.6.1.1.1.2 37-1.6.1.1.1.2 38-1.3.1.1 38-1.6.1 39-1.6.1.1 41-1.6.1.1.2 42-1.6.1.1.2.1.r 43-1.6.1.1.2.1 (s / show-01~e.8 :polarity~e.7 -~e.7 :ARG0 (c / cell-line~e.5 :name (n / name :op1 "Capan-2"~e.2,4)) :ARG1 (t / toxicity~e.11 :ARG1-of (d2 / detect-01~e.10 :ARG1-of (p / possible-01~e.38)) :mod (a3 / any~e.9)) :condition~e.12 (p2 / present-02~e.14 :ARG1~e.15 (s2 / small-molecule :name (n2 / name :op1 "RocA"~e.16))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.24 :mod "S5"~e.25 :location (f2 / file~e.19 :mod 1~e.21 :ARG1-of (a / add-02)))) :ARG0-of (s3 / suggest-01~e.28 :ARG1 (p3 / possible-01~e.38 :ARG1 (r / rescue-01~e.39 :ARG0 (e / express-03~e.30 :ARG2~e.31 (p4 / protein :name (n3 / name :op1 "PHB"~e.32)) :ARG3~e.33 c~e.34,35,36,37 :mod (d / deficient~e.29)) :ARG1 (a2 / affect-01~e.41 :ARG0~e.42 s2~e.43)))) :ARG2-of (i / interest-01~e.0)) # ::id pmid_2456_8222.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Additionally , RocA impaired the migration of AsPC @-@ 1 and Panc @-@ 1 cells ( Figure 5 @ C ) . # ::alignments 0-1.2.1 2-1.1.1.1 3-1 5-1.2 7-1.2.1.1.1.1 9-1.2.1.1.1.1 9-1.2.1.2.1.1 10-1.2.1 11-1.2.1.2.1.1 13-1.2.1.1.1.1 13-1.2.1.2.1.1 14-1.2.1.1 14-1.2.1.2 16-1.4.1 (i / impair-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "RocA"~e.2)) :ARG1 (m / migrate-01~e.5 :ARG0 (a / and~e.0,10 :op1 (c / cell-line~e.14 :name (n2 / name :op1 "AsPC-1"~e.7,9,13)) :op2 (c2 / cell-line~e.14 :name (n3 / name :op1 "Panc-1"~e.9,11,13)))) :ARG1-of (a2 / add-02) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "5C"))) # ::id pmid_2456_8222.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To investigate the effect of RocA on metastasis , we established an orthotopic xenograft model in mice using AsPC @-@ 1 cells . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.1.r 5-1.4.2.1.1.1 6-1.4.2.2.r 7-1.4.2.2 9-1.1 10-1 12-1.2.2 13-1.2.1 14-1.2 15-1.2.3.r 16-1.2.3 17-1.4.r 18-1.3.1.1 20-1.3.1.1 21-1.3 (e / establish-01~e.10 :ARG0 (w / we~e.9) :ARG1 (m / model~e.14 :mod (x / xenograft~e.13) :mod (o / orthotopic~e.12) :location~e.15 (m2 / mouse~e.16)) :instrument (c / cell-line~e.21 :name (n / name :op1 "AsPC-1"~e.18,20)) :purpose~e.17 (i / investigate-01~e.1 :ARG0 w :ARG1 (a / affect-01~e.3 :ARG0~e.4 (s / small-molecule :name (n2 / name :op1 "RocA"~e.5)) :ARG1~e.6 (m3 / metastasize-101~e.7)))) # ::id pmid_2456_8222.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At 1 week after orthotopic implantation of AsPC @-@ 1 cells into severe combined immunodeficient ( SCID ) mice , RocA ( 5 mg @/@ kg body weight ) was administrated via intraperitoneal injection daily for 3 weeks . # ::alignments 1-1.2.1 2-1.3.2 3-1.4 4-1.4.1.3 5-1.4.1 6-1.4.1.1.r 7-1.4.1.1.1.1 9-1.4.1.1.1.1 10-1.4.1.1 11-1.4.1.2.r 12-1.4.1.2.2.1 13-1.4.1.2.2 14-1.4.1.2.1 18-1.4.1.2 20-1.1.1.1 22-1.1.2.1 23-1.1.2.2 25-1.1.2.2 26-1.5.2 27-1.5.2.1 30-1 32-1.5.3 33-1.5 34-1.2 34-1.2.1 34-1.2.1.r 34-1.2.2 34-1.2.2.r 34-1.3 34-1.4.2 34-1.4.2.1 34-1.4.2.1.r 36-1.3.1 37-1.4.2.2 (a / administrate-01~e.30 :ARG1 (s / small-molecule :name (n / name :op1 "RocA"~e.20) :quant (c3 / concentration-quantity :quant 5~e.22 :unit (m2 / milligram-per-kilogram~e.23,25))) :frequency (t3 / temporal-quantity~e.34 :quant~e.34 1~e.1,34 :unit~e.34 (d / day~e.34)) :duration (t2 / temporal-quantity~e.34 :quant 3~e.36 :unit (w2 / week~e.2)) :time (a2 / after~e.3 :op1 (i3 / implant-01~e.5 :ARG1~e.6 (c / cell-line~e.10 :name (n2 / name :op1 "AsPC-1"~e.7,9)) :ARG2~e.11 (m3 / mouse~e.18 :mod (i4 / immunodeficient~e.14) :ARG1-of (c2 / combine-01~e.13 :degree (s2 / severe~e.12))) :mod (o / orthotopic~e.4)) :quant (t / temporal-quantity~e.34 :quant~e.34 1~e.34 :unit (w / week~e.37))) :manner (i / inject-01~e.33 :ARG1 s :ARG2 (b / body~e.26 :ARG1-of (w3 / weight-01~e.27)) :mod (i2 / intraperitoneal~e.32))) # ::id pmid_2456_8222.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a result , treatment with RocA significantly suppressed cancer metastasis to the lung and liver in mice ( Figure 5 @ D ) . # ::alignments 2-1.5 4-1.1 5-1.1.1.r 6-1.1.1.1.1 7-1.3 8-1 9-1.2.1 10-1.2 11-1.2.2.r 13-1.2.2.1 14-1.2.2 15-1.2.2.2 16-1.4.r 17-1.4 19-1.6.1 (s / suppress-01~e.8 :ARG0 (t / treat-04~e.4 :ARG2~e.5 (s2 / small-molecule :name (n2 / name :op1 "RocA"~e.6))) :ARG1 (m / metastasize-101~e.10 :ARG1 (c / cancer~e.9) :ARG2~e.11 (a / and~e.14 :op1 (l / lung~e.13) :op2 (l2 / liver~e.15))) :ARG1-of (s3 / significant-02~e.7) :location~e.16 (m2 / mouse~e.17) :ARG2-of (r / result-01~e.2) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.19 :mod "5D"))) # ::id pmid_2456_8222.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Histological analysis of the lung and liver revealed that dissemination of cancer cells was absent in tissue sections from RocA @-@ treated mice , but an abundance of cancer cells were observed in vehicle @-@ treated mice ( Figure 5 @ D ) . # ::alignments 1-1.1.1 2-1.1.1.1.r 4-1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2 7-1.1 8-1.1.2.r 9-1.1.2.1 10-1.1.2.1.1.r 11-1.1.2.1.1.1 12-1.1.2.1.1 14-1.1.2 15-1.1.2.2.r 16-1.1.2.2.1 17-1.1.2.2 18-1.1.2.2.2.r 19-1.1.2.2.2.1.1.1.1 21-1.1.2.2.2.1 22-1.1.2.2.2 24-1 26-1.2.1 27-1.2.1.1.r 28-1.2.1.1 29-1.2.1.1 31-1.2 32-1.2.2.r 33-1.2.2.1.1 35-1.2.2.1 36-1.2.2 38-1.3.1 (c3 / contrast-01~e.24 :ARG1 (r / reveal-01~e.7 :ARG0 (a / analyze-01~e.1 :ARG1~e.2 (a2 / and~e.5 :op1 (l / lung~e.4) :op2 (l2 / liver~e.6)) :mod (h / histologic)) :ARG1~e.8 (a3 / absent-01~e.14 :ARG1 (d2 / disseminate-01~e.9 :ARG1~e.10 (c / cell~e.12 :mod (c2 / cancer~e.11))) :ARG2~e.15 (s / section-01~e.17 :ARG1 (t / tissue~e.16) :ARG3~e.18 (m / mouse~e.22 :ARG1-of (t2 / treat-04~e.21 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA"~e.19))))))) :ARG2 (o / observe-01~e.31 :ARG1 (a4 / abound-01~e.26 :ARG1~e.27 c~e.28,29) :location~e.32 (m2 / mouse~e.36 :ARG1-of (t3 / treat-04~e.35 :ARG2 (v / vehicle~e.33)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.38 :mod "5D"))) # ::id pmid_2456_8222.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Comparison of the survival curve of RocA @-@ treated mice with that of vehicle @-@ treated mice showed that RocA treatment significantly prolonged the survival of tumor @-@ bearing mice ( Additional file 1 @ : Figure S6A , B ) . # ::alignments 0-1.1 3-1.1.1.1 3-1.1.2.1 4-1.1.1 4-1.1.2 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1.1.1 8-1.1.2.1.1.1 9-1.1.2.1.1 12-1.1.2.1.1.1.1.r 13-1.1.2.1.1.1.1 15-1.1.1.1.1.1 16-1.1.1.1.1 17-1 18-1.2.r 19-1.2.1 20-1.2.1 21-1.2.3 22-1.2 24-1.2.2 25-1.2.2.1.r 26-1.2.2.1.1.1 28-1.2.2.1.1 29-1.2.2.1 32-1.3.1.3 34-1.3.1.3.1 37-1.3.1.1 37-1.3.1.2 38-1.3.1.1.1 (s / show-01~e.17 :ARG0 (c / compare-01~e.0 :ARG1 (c2 / curve~e.4 :mod (s2 / survive-01~e.3 :ARG0~e.5 (m / mouse~e.16 :ARG1-of (t / treat-04~e.15 :ARG2 (s3 / small-molecule :name (n / name :op1 "RocA"~e.6)))))) :ARG2 (c3 / curve~e.4 :mod (s6 / survive-01~e.3 :ARG0 (m2 / mouse~e.9 :ARG1-of (t3 / treat-04~e.8 :ARG2~e.12 (v / vehicle~e.13)))))) :ARG1~e.18 (p / prolong-01~e.22 :ARG0 t~e.19,20 :ARG1 (s5 / survive-01~e.24 :ARG0~e.25 (m3 / mouse~e.29 :ARG0-of (b / bear-01~e.28 :ARG1 (t4 / tumor~e.26)))) :ARG1-of (s4 / significant-02~e.21)) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.37 :mod "S6A"~e.38) :op2 (f2 / figure~e.37 :mod "S6B") :location (f3 / file~e.32 :mod 1~e.34 :ARG1-of (a2 / add-02))))) # ::id pmid_2456_8222.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Taken together , RocA impairs the migration of pancreatic cancer cells in vitro and in vivo @ . # ::alignments 0-1.3 1-1.3.1 3-1.1.1.1 4-1 6-1.2.1 6-1.2.2 7-1.2.1.1.r 8-1.2.1.1.1.1 9-1.2.1.1.1 10-1.2.1.1 12-1.2.1.2 13-1.2.1.2 17-1.2.1.2 17-1.2.2.2.r 18-1.2.2.2 (i / impair-01~e.4 :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"~e.3)) :ARG1 (a / and :op1 (m / migrate-01~e.6 :ARG0~e.7 (c / cell~e.10 :mod (c2 / cancer~e.9 :mod (p / pancreas~e.8))) :manner (i2 / in-vitro~e.12,13,17)) :op2 (m2 / migrate-01~e.6 :ARG0 c :manner~e.17 (i3 / in-vivo~e.18))) :ARG1-of (t / take-01~e.0 :manner (t2 / together~e.1))) # ::id pmid_2456_8222.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RocA suppresses in vivo growth of tumor xenografts # ::alignments 1-1.1.1.1 2-1 4-1.3 5-1.3 7-1.2 8-1.2.1.r 9-1.2.1.1 10-1.2.1 (s / suppress-01~e.2 :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA"~e.1)) :ARG1 (g / grow-01~e.7 :ARG1~e.8 (x / xenograft~e.10 :mod (t / tumor~e.9))) :manner (i / in-vivo~e.4,5)) # ::id pmid_2456_8222.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To further evaluate the anti @-@ tumor activity of RocA , we administered RocA to SCID mice bearing subcutaneous AsPC @-@ 1 tumor cell xenografts and monitored the tumor growth rate . # ::alignments 1-1.3.3 2-1.3 4-1.3.2.2 6-1.3.2.2.1 7-1.3.2 8-1.3.2.1.r 9-1.3.2.1 11-1.1.1 12-1.1 13-1.1.2.1.1 16-1.1.3 17-1.1.3.3 18-1.1.3.3.1.2 19-1.1.3.3.1.1.1.1 21-1.1.3.3.1.1.1.1 22-1.1.3.3.1.1.2 23-1.1.3.3.1.1 24-1.1.3.3.1 25-1 26-1.2 28-1.2.2.1.1 29-1.2.2.1 30-1.2.2 (a2 / and~e.25 :op1 (a / administer-01~e.12 :ARG0 (w / we~e.11) :ARG1 (s / small-molecule :name (n / name :op1 "RocA"~e.13)) :ARG2 (m / mouse~e.16 :mod (i / immunodeficient) :ARG1-of (c / combine-01 :degree (s3 / severe)) :ARG0-of (b / bear-01~e.17 :ARG1 (x / xenograft~e.24 :mod (c2 / cell-line~e.23 :name (n2 / name :op1 "AsPC-1"~e.19,21) :mod (t / tumor~e.22)) :mod (s2 / subcutaneous~e.18))))) :op2 (m2 / monitor-01~e.26 :ARG0 w :ARG1 (r / rate~e.30 :mod (g2 / grow-01~e.29 :ARG1 t~e.28))) :purpose (e / evaluate-01~e.2 :ARG0 w :ARG1 (a3 / activity-06~e.7 :ARG0~e.8 s~e.9 :ARG0-of (c3 / counter-01~e.4 :ARG1 t~e.6)) :degree (f / further~e.1))) # ::id pmid_2456_8222.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RocA was administrated by intraperitoneal injection once per day . # ::alignments 0-1.1.1.1 2-1 3-1.3.r 4-1.3.2 5-1.3 6-1.2.1 6-1.2.2.1 6-1.2.r 7-1.2 8-1.2.2.2 (a / administrate-01~e.2 :ARG1 (s / small-molecule :name (n / name :op1 "RocA"~e.0)) :frequency~e.6 (r / rate-entity-91~e.7 :ARG1 1~e.6 :ARG2 (t / temporal-quantity :quant 1~e.6 :unit (d / day~e.8))) :manner~e.3 (i / inject-01~e.5 :ARG1 s :mod (i2 / intraperitoneal~e.4))) # ::id pmid_2456_8222.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a result , RocA significantly suppressed tumor growth compared with that in the control group . # ::alignments 2-1.4 4-1.1.1.1 5-1.3 6-1 7-1.2.1 8-1.2 8-1.5 9-1.5.r 12-1.5.2.r 14-1.5.2.1 15-1.5.2 (s / suppress-01~e.6 :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA"~e.4)) :ARG1 (g / grow-01~e.8 :ARG1 (t / tumor~e.7)) :ARG1-of (s3 / significant-02~e.5) :ARG2-of (r / result-01~e.2) :compared-to~e.9 (g3 / grow-01~e.8 :ARG1 t :location~e.12 (g2 / group~e.15 :mod (c / control~e.14)))) # ::id pmid_2456_8222.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumor volumes in the RocA @-@ treated group were 37 ± 8 % of those in the control group ( Figure 6 @ A , B ) . # ::alignments 0-1.1.1 1-1.1 1-1.2.1.2 2-1.1.2.r 4-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1.2 9-1.2.1.1.1 9-1.2.2.1.1 11-1.2.1.1.2.1.1 12-1.2.1.1 12-1.2.1.1.2.1 12-1.2.2.1 13-1.2.1 15-1.2.1.2.1.r 17-1.2.1.2.1.1 18-1.2.1.2.1 20-1.3.1.1 20-1.3.1.2 (e / equal-01 :ARG1 (v / volume~e.1 :quant-of (t / tumor~e.0) :location~e.2 (g / group~e.7 :ARG1-of (t2 / treat-04~e.6 :ARG2 (s / small-molecule :name (n / name :op1 "RocA"~e.4))))) :ARG2 (v3 / value-interval :op1 (p4 / product-of~e.13 :op1 (p2 / percentage-entity~e.12 :value 37~e.9 :ARG2-of (s2 / subtract-01 :ARG1 (p / percentage-entity~e.12 :value 8~e.11))) :op2 (v2 / volume~e.1 :location~e.15 (g2 / group~e.18 :mod (c / control~e.17)) :quant-of t)) :op2 (p5 / product-of :op1 (p3 / percentage-entity~e.12 :value 37~e.9 :ARG2-of (a / add-02 :ARG1 p)) :op2 v2)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.20 :mod "6A") :op2 (f2 / figure~e.20 :mod "6B")))) # ::id pmid_2456_8222.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Intriguingly , RocA treatment neither caused any loss of body weight nor exhibited apparent signs of toxicity in mice during the treatments ( Figure 6 @ C ) , suggesting that RocA is generally well tolerated in vivo @ . # ::alignments 0-1.6 2-1.1.2.1.1.1 3-1.1.2 4-1.1.1 4-1.1.1.r 5-1.1 6-1.1.3.2 7-1.1.3 8-1.1.3.1.r 9-1.1.3.1.1 10-1.1.3.1 11-1.2.1 11-1.2.1.r 12-1.2 13-1.2.3.2 14-1.2.3 15-1.2.3.1.r 16-1.2.3.1 17-1.2.4.r 17-1.5.1.3 18-1.2.4 19-1.3.r 21-1.1.2 21-1.3 23-1.4.1 30-1.5 32-1.1.2.1.1.1 34-1.5.1.2.1 35-1.5.1.2 36-1.5.1 38-1.5.1.3 39-1.5.1.3 (a / and :op1 (c / cause-01~e.5 :polarity~e.4 -~e.4 :ARG0 (t / treat-04~e.3,21 :ARG2 (s / small-molecule :name (n / name :op1 "RocA"~e.2,32))) :ARG1 (l / lose-02~e.7 :ARG1~e.8 (w / weight-01~e.10 :ARG1 (b / body~e.9)) :mod (a2 / any~e.6))) :op2 (e / exhibit-01~e.12 :polarity~e.11 -~e.11 :ARG0 t :ARG1 (s2 / signal-07~e.14 :ARG1~e.15 (t2 / toxicity~e.16) :ARG1-of (a3 / appear-02~e.13)) :location~e.17 (m / mouse~e.18)) :time~e.19 (t3 / treat-04~e.21) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "6C")) :ARG0-of (s3 / suggest-01~e.30 :ARG1 (t4 / tolerate-01~e.36 :ARG1 s :ARG1-of (w2 / well-09~e.35 :ARG1-of (g / general-02~e.34)) :manner (i / in-vivo~e.17,38,39))) :ARG0-of (i2 / intrigue-01~e.0)) # ::id pmid_2456_8222.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , although RocA @-@ treated mice eventually died from the pancreatic tumors , treatment with RocA significantly extended their lifespan compared with that of vehicle treatment ( Figure 6 @ D , E ) . # ::alignments 0-1 0-1.2.1 2-1.1 3-1.1.2.1.1.1.1.1 5-1.1.2.1.1 6-1.1.1.4.1 6-1.1.2.1 7-1.1.2.2 8-1.1.2 9-1.1.2.3 11-1.1.2.3.1.1 12-1.1.2.3.1 14-1.1.1.4.1.1 16-1.1.2.1.1.1.1.1 17-1.1.1.3 18-1.1.1 20-1.1.1.2 20-1.1.1.4 21-1.1.1.4.r 25-1.1.1.4.1.1.1 26-1.1.1.4.1.1 28-1.2.1.1 28-1.2.1.2 (a / and~e.0 :op2 (h / have-concession-91~e.2 :ARG1 (e2 / extend-01~e.18 :ARG0 t :ARG1 (l / lifespan~e.20 :poss m) :ARG1-of (s2 / significant-02~e.17) :compared-to~e.21 (l2 / lifespan~e.20 :poss (m2 / mouse~e.6 :ARG1-of (t4 / treat-04~e.14,26 :ARG2 (v / vehicle~e.25))))) :ARG2 (d / die-01~e.8 :ARG1 (m / mouse~e.6 :ARG1-of (t / treat-04~e.5 :ARG2 (s / small-molecule :name (n / name :op1 "RocA"~e.3,16)))) :time (e / eventual~e.7) :ARG1-of (c / cause-01~e.9 :ARG0 (t2 / tumor~e.12 :mod (p / pancreas~e.11))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.0 :op1 (f / figure~e.28 :mod "6D") :op2 (f2 / figure~e.28 :mod "6E")))) # ::id pmid_2456_8222.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Next , we investigated the effect of RocA on cell proliferation in vivo by hematoxylin and eosin ( H&E ) staining and examining Ki @-@ 67 and cyclin D1 expression in tumor tissues harvested from vehicle @- and RocA @-@ treated mice . # ::alignments 0-1.4 2-1.1 3-1 5-1.2 6-1.2.1.r 7-1.2.1.1.1 8-1.2.2.r 9-1.2.2.1 10-1.2.2 12-1.2.2.2 13-1.2.2.2 15-1.3.r 16-1.3.1.2.1.1.1 18-1.3.1.2.2.1.1 22-1.3.1 23-1.3 24-1.3.2 25-1.3.2.2.1.1.1.1 27-1.3.2.2.1.1.1.1 28-1.3.2.2 29-1.3.2.2.2.1.1.1 30-1.3.2.2.2.1.1.2 31-1.3.2.2.1 31-1.3.2.2.2 32-1.2.2.2 32-1.3.2.2.1.2.r 33-1.3.2.2.1.2.1 34-1.3.2.2.1.2 35-1.3.2.2.1.2.2 36-1.3.2.2.1.2.2.1.r 37-1.3.2.2.1.2.2.1.2.1.1 39-1.3.2.2.1.2.2.1 40-1.2.1.1.1 42-1.3.2.2.1.2.2.1.1.1 42-1.3.2.2.1.2.2.1.2.1 43-1.3.2.2.1.2.2.1.1 43-1.3.2.2.1.2.2.1.2 (i3 / investigate-01~e.3 :ARG0 (w / we~e.2) :ARG1 (a / affect-01~e.5 :ARG0~e.6 (s / small-molecule :name (n / name :op1 "RocA"~e.7,40)) :ARG1~e.8 (p / proliferate-01~e.10 :ARG0 (c / cell~e.9) :manner (i2 / in-vivo~e.12,13,32))) :manner~e.15 (a6 / and~e.23 :op1 (s2 / stain-01~e.22 :ARG0 w :ARG2 (a2 / and :op1 (s3 / small-molecule :name (n2 / name :op1 "hematoxylin"~e.16)) :op2 (s4 / small-molecule :name (n3 / name :op1 "eosin"~e.18)))) :op2 (e2 / examine-01~e.24 :ARG0 w :ARG1 (a4 / and~e.28 :op1 (e / express-03~e.31 :ARG2 (p2 / protein :name (n4 / name :op1 "Ki-67"~e.25,27)) :ARG3~e.32 (t / tissue~e.34 :mod (t2 / tumor~e.33) :ARG1-of (h / harvest-01~e.35 :source~e.36 (a5 / and~e.39 :op1 (m3 / mouse~e.43 :ARG1-of (t3 / treat-04~e.42 :ARG2 s)) :op2 (m4 / mouse~e.43 :ARG1-of (t4 / treat-04~e.42 :ARG2 (v / vehicle~e.37))))))) :op2 (e3 / express-03~e.31 :ARG2 (p3 / protein :name (n5 / name :op1 "cyclin"~e.29 :op2 "D1"~e.30)) :ARG3 t)))) :time (n6 / next~e.0)) # ::id pmid_2456_8222.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok H&E staining showed a compact mass of epithelial cells in vehicle @-@ treated mice , whereas RocA @-@ treated tumors exhibited loose epithelial cell aggregates with a higher number of interspersed mesenchymal cells ( Figure 6 @ F , left ) . # ::alignments 1-1.1.1 2-1.1 4-1.1.2.3 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.1 8-1.1.2.1 9-1.1.2.2.r 10-1.1.2.2.1.1 12-1.1.2.2.1 13-1.1.2.2 15-1 16-1.2.1.1.1.1.1 18-1.2.1.1 19-1.2.1 20-1.2 21-1.2.2.2 22-1.2.2.4 23-1.1.2.1 23-1.2.2.1 24-1.2.2 27-1.2.2.3.1.1 27-1.2.2.3.1.1.1 27-1.2.2.3.1.1.1.r 28-1.2.2.3.1 29-1.2.2.3.1.2.r 30-1.2.2.3.1.2.2 31-1.2.2.3.1.2.1 32-1.2.2.3.1.2 34-1.3.1 40-1.3.1.2 (c3 / contrast-01~e.15 :ARG1 (s / show-01~e.2 :ARG0 (s2 / stain-01~e.1 :ARG2 (a / and :op1 (s4 / small-molecule :name (n / name :op1 "hematoxylin")) :op2 (s5 / small-molecule :name (n2 / name :op1 "eosin")))) :ARG1 (m4 / mass-01~e.5 :ARG0~e.6 (c2 / cell~e.8,23 :mod (e / epithelium~e.7)) :location~e.9 (m5 / mouse~e.13 :ARG1-of (t / treat-04~e.12 :ARG2 (v / vehicle~e.10))) :ARG1-of (c / compact-01~e.4))) :ARG2 (e2 / exhibit-01~e.20 :ARG0 (t2 / tumor~e.19 :ARG1-of (t3 / treat-04~e.18 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "RocA"~e.16)))) :ARG1 (a2 / aggregate-01~e.24 :ARG1 (c4 / cell~e.23) :ARG1-of (l / loose-04~e.21) :ARG0-of (h2 / have-03 :ARG1 (n4 / number~e.28 :ARG1-of (h / high-02~e.27 :degree~e.27 (m / more~e.27)) :quant-of~e.29 (c5 / cell~e.32 :mod (m6 / mesenchymal~e.31) :ARG1-of (i / intersperse-01~e.30)))) :mod e~e.22)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "6F" :ARG1-of (l2 / left-20~e.40)))) # ::id pmid_2456_8222.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , RocA treatment resulted in a 3.2 @-@ fold decrease of Ki @-@ 67 @-@ positive cells in tumor sections from RocA @-@ treated mice compared with that in vehicle @-@ treated mice ( Figure 6 @ F , middle and 6 @ G , upper ) . # ::alignments 0-1 1-1 3-1.1.1.1.1.1 4-1.1.1 5-1.1 6-1.1.2.r 8-1.1.2.2.1 10-1.1.2.2 11-1.1.2 11-1.1.2.4 12-1.1.2.1.r 12-1.1.2.2 13-1.1.2.1.1.1.1.1 15-1.1.2.1.1.1.1.1 17-1.1.2.1.1 18-1.1.2.1 19-1.1.2.3.r 20-1.1.2.3.1 21-1.1.2.3 23-1.1.1.1.1.1 25-1.1.1 25-1.1.2.4.1.1 26-1.1.2.3.2 26-1.1.2.4.1 27-1.1.2.4.r 30-1.1.2.4.1.1.1.r 31-1.1.2.4.1.1.1 33-1.1.2.3.2.1 34-1.1.2.3.2 36-1.1.3.1.1 36-1.1.3.1.2 42-1.1.3.1.1.2 43-1.1.3.1 49-1.1.3.1.2.2 (a2 / and~e.0,1 :op2 (r / result-01~e.5 :ARG1 (t / treat-04~e.4,25 :ARG2 (s / small-molecule :name (n / name :op1 "RocA"~e.3,23))) :ARG2~e.6 (d / decrease-01~e.11 :ARG1~e.12 (c / cell~e.18 :mod (p2 / positive~e.17 :mod (p3 / protein :name (n2 / name :op1 "Ki-67"~e.13,15)))) :ARG2 (p / product-of~e.10,12 :op1 3.2~e.8) :location~e.19 (s2 / section-01~e.21 :ARG1 (t2 / tumor~e.20) :ARG3 (m / mouse~e.26,34 :ARG1-of t~e.33)) :compared-to~e.27 (d3 / decrease-01~e.11 :location (m2 / mouse~e.26 :ARG1-of (t4 / treat-04~e.25 :ARG2~e.30 (v / vehicle~e.31))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.43 :op1 (f / figure~e.36 :mod "6F" :direction (m3 / middle~e.42)) :op2 (f2 / figure~e.36 :mod "6G" :direction (u / upper~e.49)))))) # ::id pmid_2456_8222.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , we found a 4.1 @-@ fold decrease of cyclin D1 @-@ positive cells in tumor sections from RocA @-@ treated mice relative to that in vehicle @-@ treated mice ( Figure 6 @ F , right and 6G , lower ) . # ::alignments 0-1 2-1.1.1 3-1.1 5-1.1.2.2.1 7-1.1.2.2 8-1.1.2 8-1.1.2.4.1 9-1.1.2.1.r 9-1.1.2.2 10-1.1.2.1.1.1.1.1 11-1.1.2.1.1.1.1.2 13-1.1.2.1.1 14-1.1.2.1 15-1.1.2.3.r 16-1.1.2.3.1 17-1.1.2.3 18-1.1.2.3.2.r 19-1.1.2.3.2.1.1.1.1 21-1.1.2.3.2.1 21-1.1.2.4.1.1.1 22-1.1.2.3.2 22-1.1.2.4.1.1 23-1.1.2.4 26-1.1.2.4.1.1.1.1.r 27-1.1.2.4.1.1.1.1 29-1.1.2.3.2.1 30-1.1.2.3.2 32-1.2.1.1 32-1.2.1.2 38-1.2.1.1.2 39-1.2.1 40-1.2.1.2.1 42-1.2.1.2.2 42-1.2.1.2.2.1 42-1.2.1.2.2.1.r (a / and~e.0 :op2 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1 (d / decrease-01~e.8 :ARG1~e.9 (c / cell~e.14 :mod (p2 / positive~e.13 :mod (p3 / protein :name (n / name :op1 "cyclin"~e.10 :op2 "D1"~e.11)))) :ARG2 (p / product-of~e.7,9 :op1 4.1~e.5) :location~e.15 (s / section-01~e.17 :ARG1 (t / tumor~e.16) :ARG3~e.18 (m2 / mouse~e.22,30 :ARG1-of (t2 / treat-04~e.21,29 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA"~e.19))))) :ARG1-of (r / relative-05~e.23 :ARG3 (d3 / decrease-01~e.8 :location (m3 / mouse~e.22 :ARG1-of (t4 / treat-04~e.21 :ARG2~e.26 (v / vehicle~e.27))))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.39 :op1 (f2 / figure~e.32 :mod "6F" :ARG1-of (r2 / right-04~e.38)) :op2 (f3 / figure~e.32 :mod "6G"~e.40 :ARG1-of (l / low-04~e.42 :degree~e.42 (m / more~e.42)))))) # ::id pmid_2456_8222.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , RocA is a potent small molecule that suppresses the growth of AsPC @-@ 1 cell @-@ derived tumors in vivo @ . # ::alignments 0-1 2-1.1.3.1.1 3-1.1.3.r 5-1.1.2 6-1.1.1 7-1.1 9-1.1.4 11-1.1.4.1 12-1.1.4.1.1.r 13-1.1.4.1.1.2.1.1.1 15-1.1.4.1.1.2.1.1.1 16-1.1.4.1.1.2.1 18-1.1.4.1.1.2 19-1.1.4.1.1 21-1.1.4.1.1.1 22-1.1.4.1.1.1 (c / cause-01~e.0 :ARG1 (m / molecule~e.7 :mod (s / small~e.6) :mod (p / potent~e.5) :domain~e.3 (s2 / small-molecule :name (n / name :op1 "RocA"~e.2)) :ARG0-of (s3 / suppress-01~e.9 :ARG1 (g / grow-01~e.11 :ARG1~e.12 (t / tumor~e.19 :mod (i / in-vivo~e.21,22) :ARG1-of (d / derive-01~e.18 :ARG2 (c2 / cell-line~e.16 :name (n2 / name :op1 "AsPC-1"~e.13,15)))))))) # ::id pmid_2464_2271.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS @/@ ERK to PI3K @/@ AKT regulation ( PMID : 24642271 ) # ::alignments 0-1.1.2.2.1 1-1.1.2.2.2 2-1.1.1.1.1 3-1.1 4-1 6-1.2.1.2 7-1.2.1.2.1 8-1.2.1.1 9-1.2.1 10-1.2 12-1.4.1.1.1 14-1.4.1.1.1 16-1.3.1.1.1 18-1.3.1.1.1 19-1.3 19-1.4 (s / switch-01~e.4 :ARG0 (r / rearrange-01~e.3 :ARG1 (p7 / protein-family :name (n2 / name :op1 "ETS"~e.2)) :mod (d3 / disease :wiki "Prostate_cancer" :name (n5 / name :op1 "prostate"~e.0 :op2 "cancer"~e.1))) :ARG1 (p2 / program~e.10 :mod (e / express-03~e.9 :ARG1 (g2 / gene~e.8) :ARG3 (c / cell~e.6 :ARG0-of (m / migrate-01~e.7)))) :ARG2 (r3 / regulate-01~e.19 :ARG1 (p4 / pathway :name (n4 / name :op1 "PI3K/AKT"~e.16,18))) :ARG3 (r2 / regulate-01~e.19 :ARG1 (p3 / pathway :name (n3 / name :op1 "RAS/ERK"~e.12,14))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG8 "PMID24642271"))) # ::id pmid_2464_2271.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2464_2271.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We find that oncogenic ETS expression negatively correlates with RAS and RAF mutations in prostate tumors . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1 3-1.2.1.1.2 3-1.2.1.1.2.1.2.1 3-1.2.1.1.2.r 4-1.2.1.1.1.1 5-1.2.1 6-1.2.3 7-1.2 10-1.2.2.1.1.1.1 12-1.2.2.1 14-1.2.2.1.2.1.1 16-1.2.2 17-1.2.4.r 18-1.2.4.1 19-1.2.4 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (c / correlate-01~e.7 :ARG1 (e / express-03~e.5 :ARG2 (p2 / protein~e.3 :name (n / name :op1 "ETS"~e.4) :ARG0-of~e.3 (c2 / cause-01~e.3 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.3))))) :ARG2 (m / mutate-01~e.16 :ARG1 (a / and~e.12 :op1 (g / gene :name (n3 / name :op1 "RAS"~e.10)) :op2 (g2 / gene :name (n4 / name :op1 "RAF"~e.14)))) :ARG2-of (n5 / negative-01~e.6) :location~e.17 (t / tumor~e.19 :mod (p / prostate~e.18)))) # ::id pmid_2464_2271.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , the oncogenic ETS transcription factors only increased cell migration in the absence of RAS @/@ ERK activation . # ::alignments 0-1 3-1.1.1 3-1.1.1.2 3-1.1.1.2.1.2.1 3-1.1.1.2.r 4-1.1.1.1.1 5-1.1.1.1.2 6-1.1.1.1.3 7-1.1.3 8-1.1 9-1.1.2.1 10-1.1.2 11-1.1.4.r 13-1.1.4 14-1.1.4.1.r 15-1.1.4.1.1.1.1 17-1.1.4.1.1.1.1 18-1.1.4.1 (a / and~e.0 :op2 (i / increase-01~e.8 :ARG0 (p / protein-family~e.3 :name (n / name :op1 "ETS"~e.4 :op2 "transcription"~e.5 :op3 "factor"~e.6) :ARG0-of~e.3 (c2 / cause-01~e.3 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.3)))) :ARG1 (m / migrate-01~e.10 :ARG0 (c / cell~e.9)) :mod (o / only~e.7) :condition~e.11 (a2 / absent-01~e.13 :ARG1~e.14 (a3 / activate-01~e.18 :ARG1 (p2 / pathway :name (n2 / name :op1 "RAS/ERK"~e.15,17)))))) # ::id pmid_2464_2271.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast to RAS/ERK , it has been reported that oncogenic ETS expression positively correlates with PI3K @/@ AKT activation . # ::alignments 1-1 2-1.2.r 3-1.2.1.1 8-1.1 9-1.1.1.r 10-1.1.1.1.1 10-1.1.1.1.1.2 10-1.1.1.1.1.2.1.2.1 10-1.1.1.1.1.2.r 11-1.1.1.1.1.1.1 12-1.1.1.1 13-1.1.1.3 13-1.1.1.3.r 14-1.1.1 15-1.1.1.2.r 16-1.1.1.2.1.1.1 18-1.1.1.2.1.1.1 19-1.1.1.2 (c / contrast-01~e.1 :ARG1 (r / report-01~e.8 :ARG1~e.9 (c2 / correlate-01~e.14 :ARG1 (e / express-03~e.12 :ARG2 (p4 / protein~e.10 :name (n2 / name :op1 "ETS"~e.11) :ARG0-of~e.10 (c3 / cause-01~e.10 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.10))))) :ARG2~e.15 (a / activate-01~e.19 :ARG1 (p / pathway :name (n / name :op1 "PI3K/AKT"~e.16,18))) :manner~e.13 (p2 / positive~e.13))) :ARG2~e.2 (p3 / pathway :name (n3 / name :op1 "RAS/ERK"~e.3))) # ::id pmid_2464_2271.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS @/@ AP @-@ 1 binding sequences . # ::alignments 0-1.1 1-1 3-1.2.2 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1 7-1.2.1.2 7-1.2.1.2.r 8-1.3.r 9-1.3 10-1.3.2.r 11-1.3.2.1.1.2 11-1.3.2.1.1.2.1.2.1 12-1.3.2.1.1.1.1 13-1.3.2.1.1 13-1.3.2.1.3 14-1.3.2 15-1.3.2.2.1.1.1 16-1.3.2.2 17-1.3.2.1.1.2 18-1.3.2.1 20-1.3.2.1.2.1.2 21-1.3.2.1.2.1.2.1 22-1.3.2.1.2.1.1 23-1.3.2.1.2.1 24-1.3.2.1.2 26-1.3.2.1.1.1.1 28-1.3.2.1.3.1.1 30-1.3.2.1.3.1.1 31-1.3.2.1.3.2 (i / identify-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / explain-01~e.4 :ARG1~e.5 (t / thing~e.7 :mod (t2 / this~e.6) :ARG1-of~e.7 (f / find-01~e.7)) :mod (m2 / mechanistic~e.3)) :manner~e.8 (s / show-01~e.9 :ARG0 w :ARG1~e.10 (r / require-01~e.14 :ARG0 (a / activate-01~e.18 :ARG0 (p / protein~e.13 :name (n / name :op1 "ETS"~e.12,26) :ARG0-of (c / cause-01~e.11,17 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.11)))) :ARG1 (p2 / program~e.24 :mod (e2 / express-03~e.23 :ARG1 (g / gene~e.22) :ARG3 (c2 / cell~e.20 :ARG0-of (m / migrate-01~e.21)))) :instrument (p4 / protein-segment~e.13 :name (n3 / name :op1 "ETS/AP-1"~e.28,30) :ARG2-of (b / bind-01~e.31))) :ARG1 (s2 / signal-07~e.16 :ARG0 (p3 / pathway :name (n4 / name :op1 "AKT"~e.15)))))) # ::id pmid_2464_2271.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration , but this process did not require mTORC1 . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 2-1.1.1.2 3-1 4-1.2.r 6-1.2 7-1.2.1.r 8-1.2.1.2 8-1.2.1.2.1.2.1 9-1.2.1.1.1 10-1.2.1 11-1.2.1.2 12-1.2.2 13-1.2.2.2.1 14-1.2.2.2 16-1.3 17-1.3.1.2.1 18-1.3.1.2 20-1.3.1.1 20-1.3.1.1.r 21-1.3.1 22-1.3.1.3.1.1 (c / correlate-01~e.3 :ARG1 (l / level~e.0 :quant-of~e.1 (e / enzyme :name (n / name :op1 "AKT"~e.2) :ARG3-of (p / phosphorylate-01~e.2))) :ARG2~e.4 (c2 / capable-01~e.6 :ARG1~e.7 (p2 / protein~e.10 :name (n2 / name :op1 "ETS"~e.9) :ARG0-of (c3 / cause-01~e.8,11 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.8)))) :ARG2 (i / increase-01~e.12 :ARG0 p2 :ARG1 (m / migrate-01~e.14 :ARG0 (c4 / cell~e.13)))) :ARG1-of (c5 / contrast-01~e.16 :ARG2 (r / require-01~e.21 :polarity~e.20 -~e.20 :ARG0 (p3 / process~e.18 :mod (t / this~e.17)) :ARG1 (m2 / macro-molecular-complex :name (n4 / name :op1 "mTORC1"~e.22))))) # ::id pmid_2464_2271.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2464_2271.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogenic ETS gene rearrangement occurs in tumors lacking RAS @/@ ERK mutations # ::alignments 1-1.1.1 1-1.1.1.1.2.1 2-1.1.2.1.1.1 3-1.1 4-1 6-1.2.r 7-1.2 8-1.2.1 9-1.2.1.1.1.1.1 11-1.2.1.1.1.1.1 12-1.2.1.1 (r / rearrange-01~e.4 :ARG1 (g / gene~e.3 :ARG0-of (c / cause-01~e.1 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.1))) :ARG0-of (e / encode-01 :ARG1 (p2 / protein-family :name (n / name :op1 "ETS"~e.2)))) :location~e.6 (t / tumor~e.7 :ARG0-of (l / lack-01~e.8 :ARG1 (m / mutate-01~e.12 :ARG1 (p / pathway :name (n3 / name :op1 "RAS/ERK"~e.9,11)))))) # ::id pmid_2464_2271.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If oncogenic ETS gene rearrangements replace RAS @/@ ERK activation , we predict that RAS @/@ ERK mutations will occur only in ETS rearrangement negative tumors . # ::alignments 0-1.3.r 1-1.2.2.1.2.2 1-1.2.2.1.2.2.1.2.1 2-1.2.2.1.2.1.1.1.1 3-1.2.2.1.2 4-1.2.2.1 4-1.3.2 5-1.3 6-1.3.1.1 7-1.3.1.1 8-1.3.1.1 9-1.3.1 11-1.1 12-1 14-1.2.1.1.1 16-1.2.1.1.1 17-1.2 20-1.2.2.2 22-1.2.2.1.2.1.1.1.1 23-1.2.2.1 25-1.2.2 (p / predict-01~e.12 :ARG0 (w / we~e.11) :ARG1 (m / mutate-01~e.17 :ARG1 (p2 / pathway :name (n / name :op1 "RAS/ERK"~e.14,16)) :location (t / tumor~e.25 :mod (r / rearrange-01~e.4,23 :polarity - :ARG1 (g / gene~e.3 :ARG0-of (e / encode-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "ETS"~e.2,22))) :ARG0-of (c / cause-01~e.1 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.1))))) :mod (o / only~e.20))) :condition~e.0 (r2 / replace-01~e.5 :ARG1 (a / activate-01~e.9 :ARG1 p2~e.6,7,8) :ARG2 (r3 / rearrange-01~e.4 :ARG1 g))) # ::id pmid_2464_2271.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this hypothesis , we examined the results of three recently published studies [ @ 6 , 22 , 23 @ ] that both sequence exons and identify chromosome rearrangements in prostate tumors ( Table 1 ) . # ::alignments 1-1.3 2-1.3.2.2 3-1.3.2 3-1.3.2.1 3-1.3.2.1.r 5-1.1 6-1 8-1.2.3 9-1.2.3.1.r 10-1.2.3.1.1 11-1.2.3.1.2.1 12-1.2.3.1.2 13-1.2.3.1 16-1.2.3.1.3.1.1 20-1.2.3.1.3.1.2 24-1.2.3.1.3.1.3 27-1.2.r 28-1.2.1.1 29-1.2.1 31-1.2 31-1.2.3.1.3.1 32-1.2.2 33-1.2.2.2.1 34-1.2.2.2 35-1.2.2.2.2.r 36-1.2.2.2.2.1 37-1.2.2.2.2 39-1.4.1 41-1.4.1.1 (e / examine-01~e.6 :ARG0 (w / we~e.5) :ARG1~e.27 (a2 / and~e.31 :op1 (s2 / sequence-01~e.29 :ARG0 (b / both~e.28) :ARG1 (e2 / exon)) :op2 (i / identify-01~e.32 :ARG0 b :ARG1 (r3 / rearrange-01~e.34 :ARG1 (c2 / chromosome~e.33) :location~e.35 (t4 / tumor~e.37 :mod (p2 / prostate~e.36)))) :ARG2-of (r / result-01~e.8 :ARG1~e.9 (s / study-01~e.13 :quant 3~e.10 :ARG1-of (p / publish-01~e.12 :time (r2 / recent~e.11)) :ARG1-of (c / cite-01 :ARG2 (a / and~e.31 :op1 6~e.16 :op2 22~e.20 :op3 23~e.24))))) :purpose (t3 / test-01~e.1 :ARG0 w :ARG1 (t / thing~e.3 :ARG1-of~e.3 (h / hypothesize-01~e.3) :mod (t6 / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (t5 / table~e.39 :mod 1~e.41))) # ::id pmid_2464_2271.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together these studies examine 266 prostate tumors . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 3-1 4-1.2.1 5-1.2.2 6-1.2 (e / examine-01~e.3 :ARG0 (s / study-01~e.2 :mod (t / this~e.1) :mod (t3 / together~e.0)) :ARG1 (t2 / tumor~e.6 :quant 266~e.4 :mod (p / prostate~e.5))) # ::id pmid_2464_2271.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok One @-@ half ( 133 ) have ERG or ETV1 chromosome rearrangements . # ::alignments 0-1.1.2.1 2-1.1.2.1 4-1.1.1 6-1 7-1.2.1.1.1.1.1 8-1.2.1 9-1.2.1.2.1.1.1 10-1.2.1.1 10-1.2.1.2 11-1.2 (h / have-03~e.6 :ARG0 (t / thing :quant 133~e.4 :ARG1-of (i / include-91 :ARG3 "1/2"~e.0,2 :ARG2 (t2 / thing))) :ARG1 (r / rearrange-01~e.11 :ARG1 (o / or~e.8 :op1 (c / chromosome~e.10 :mod (g / gene :name (n / name :op1 "ERG"~e.7))) :op2 (c2 / chromosome~e.10 :mod (g2 / gene :name (n2 / name :op1 "ETV1"~e.9)))))) # ::id pmid_2464_2271.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We searched for either gene fusions , or point mutations in canonical RAS @/@ ERK pathway genes ( RAS , RAF , MEK , and ERK encoding genes ) . # ::alignments 0-1.1 1-1 4-1.2.1.1 5-1.2.1 7-1.2 8-1.2.2.2 9-1.2.2 10-1.2.2.1.r 11-1.2.2.1 12-1.2.2.1 13-1.2.2.1 14-1.2.2.1 15-1.2.2.1 16-1.2.2.1 17-1.2.2.1 18-1.2.2.1 19-1.2.2.1 20-1.2.2.1 21-1.2.2.1 22-1.2.2.1 23-1.2.2.1 24-1.2.2.1 25-1.2.2.1 26-1.2.2.1 27-1.2.2.1 (s / search-01~e.1 :ARG0 (w / we~e.0) :ARG2 (o / or~e.7 :op1 (f / fuse-01~e.5 :ARG1 (g / gene~e.4 :mod (p2 / pathway :name (n5 / name :op1 "RAS/ERK") :mod (c / canonical)) :ARG1-of (m2 / mean-01 :ARG2 (g2 / gene :ARG0-of (e5 / encode-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "RAS")) :op2 (e2 / enzyme :name (n2 / name :op1 "RAF")) :op3 (e3 / enzyme :name (n3 / name :op1 "MEK")) :op4 (e4 / enzyme :name (n4 / name :op1 "ERK")))))))) :op2 (m / mutate-01~e.9 :ARG1~e.10 g~e.11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27 :mod (p / point~e.8)))) # ::id pmid_2464_2271.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Eight tumors had such aberrations , and all eight were negative for oncogenic ETS rearrangements . # ::alignments 0-1.1.1.1 1-1.1.1 1-1.2.1 2-1.1 3-1.1.2.1 4-1.1.2 6-1 7-1.2.1.1.2 8-1.2.1.1.1 10-1.2 11-1.2.2.r 12-1.2.2.1 12-1.2.2.1.2 12-1.2.2.1.2.1.2.1 12-1.2.2.1.2.r 13-1.2.2.1.1.1 14-1.2.2 (a / and~e.6 :op1 (h / have-03~e.2 :ARG0 (t / tumor~e.1 :quant 8~e.0) :ARG1 (a2 / aberration~e.4 :mod (s / such~e.3))) :op2 (n / negative-01~e.10 :ARG1 (t2 / tumor~e.1 :ARG1-of (i / include-91 :ARG2 t~e.8 :ARG3 (a3 / all~e.7))) :ARG2~e.11 (r / rearrange-01~e.14 :ARG1 (g / gene~e.12 :name (n2 / name :op1 "ETS"~e.13) :ARG0-of~e.12 (c / cause-01~e.12 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.12))))))) # ::id pmid_2464_2271.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This indicates that , while genomic alterations in RAS @/@ ERK pathway components are rare in prostate cancer , there is a statistically significant ( P = 0.007 ; Fisher ’s exact test ) mutual exclusivity of these alterations and ETS rearrangements . # ::alignments 0-1.1 1-1 5-1.2.3.1.2 6-1.2.3.1 7-1.2.3.1.1.r 8-1.2.3.1.1.1.1.1 10-1.2.3.1.1.1.1.1 11-1.2.3.1.1.1 12-1.2.3.1.1 14-1.2.3 15-1.2.3.2.r 16-1.2.3.2.2.1 17-1.2.3.2.2.2 22-1.2.2 22-1.2.4 23-1.2 25-1.2.4 27-1.2.4.1 31-1.2.4.2.1.2 32-1.2.4 32-1.2.4.2.1.3 34-1.2.1.3 35-1.2.1 37-1.1 38-1.2.1.1 40-1.2.1.2.1.1.1 41-1.2.1.2 (i / indicate-01~e.1 :ARG0 (t / this~e.0,37) :ARG1 (s / significant-02~e.23 :ARG1 (e / exclusive-02~e.35 :ARG0 a3~e.38 :ARG2 (r / rearrange-01~e.41 :ARG1 (g / gene :name (n2 / name :op1 "ETS"~e.40))) :manner (m / mutual~e.34)) :mod (s2 / statistics~e.22) :concession (r2 / rare-02~e.14 :ARG1 (a3 / alter-01~e.6 :ARG1~e.7 (c / component~e.12 :mod (p2 / pathway~e.11 :name (n3 / name :op1 "RAS/ERK"~e.8,10))) :mod (g2 / genome~e.5)) :location~e.15 (d2 / disease :wiki "Prostate_cancer" :name (n5 / name :op1 "prostate"~e.16 :op2 "cancer"~e.17))) :ARG1-of (s3 / statistical-test-91~e.22,25,32 :ARG2 0.007~e.27 :ARG4 (t2 / thing :name (n / name :op1 "Fisher’s" :op2 "exact"~e.31 :op3 "test"~e.32))))) # ::id pmid_2464_2271.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It has been previously reported that PI3K @/@ AKT activation via PTEN deletion positively correlates with ETS gene rearrangements [ @ 16 , 20 @ ] . # ::alignments 3-1.2 4-1 5-1.1.r 6-1.1.1.1.1.1 8-1.1.1.1.1.1 9-1.1.1 11-1.1.1.2.1.1.1 12-1.1.1.2 13-1.1.3 13-1.1.3.r 14-1.1 15-1.1.2.r 16-1.1.2.1.1.1.1.1 17-1.1.2.1 18-1.1.2 21-1.3.1.1.1.1 25-1.3.1.1.1.2 (r / report-01~e.4 :ARG1~e.5 (c / correlate-01~e.14 :ARG1 (a / activate-01~e.9 :ARG1 (p3 / pathway :name (n / name :op1 "PI3K/AKT"~e.6,8)) :manner (d / delete-01~e.12 :ARG1 (p4 / protein :name (n2 / name :op1 "PTEN"~e.11)))) :ARG2~e.15 (r2 / rearrange-01~e.18 :ARG1 (g / gene~e.17 :ARG0-of (e / encode-01 :ARG1 (p6 / protein-family :name (n3 / name :op1 "ETS"~e.16))))) :manner~e.13 (p2 / positive~e.13)) :time (p / previous~e.3) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 16~e.21 :op2 20~e.25))))) # ::id pmid_2464_2271.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A search for PTEN loss in these 266 tumors ( Table 1 ) confirms these findings and indicates that PTEN loss is more than twice as likely in tumors with ETS gene rearrangements than in those without ( P = 0.0008 ; Fisher ’s exact test ) . # ::alignments 1-1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1.1 4-1.1.1.2 5-1.1.1.1.r 6-1.1.1.1.2 7-1.1.1.1.1 8-1.1.1.1 10-1.1.1.3.1 12-1.1.1.3.1.1 15-1.1 16-1.1.2.1 17-1.1.2 17-1.1.2.2 17-1.1.2.2.r 18-1 19-1.2 20-1.2.2.r 21-1.2.2.1.1 22-1.2.2.1 24-1.2.2.2 25-1.2.2.2 26-1.2.2.2.1.1 28-1.2.2 30-1.2.2.1.2 30-1.2.2.2.1.2 32-1.2.2.1.2.1.1.1.1.1.1 33-1.2.2.1.2.1.1 34-1.2.2.1.2.1 34-1.2.2.2.1.2.1 35-1.2.2.2 38-1.2.2.2.1.2.1.1 38-1.2.2.2.1.2.1.1.r 40-1.2.2.3 42-1.2.2.3.1 46-1.2.2.3.2.1.2 47-1.2.2.3 47-1.2.2.3.2.1.3 (a / and~e.18 :op1 (c / confirm-01~e.15 :ARG0 (s / search-01~e.1 :ARG1~e.5 (t / tumor~e.8 :quant 266~e.7 :mod (t2 / this~e.6)) :ARG2~e.2 (l / lose-02~e.4 :ARG1 (p / protein :name (n / name :op1 "PTEN"~e.3))) :ARG1-of (d / describe-01 :ARG0 (t3 / table~e.10 :mod 1~e.12))) :ARG1 (t4 / thing~e.17 :mod t2~e.16 :ARG1-of~e.17 (f / find-01~e.17))) :op2 (i / indicate-01~e.19 :ARG0 s :ARG1~e.20 (l2 / likely-01~e.28 :ARG1 (l3 / lose-02~e.22 :ARG1 p~e.21 :location (t5 / tumor~e.30 :mod (r / rearrange-01~e.34 :ARG1 (g / gene~e.33 :ARG0-of (e / encode-01 :ARG1 (p4 / protein-family :name (n2 / name :op1 "ETS"~e.32))))))) :degree (m / more-than~e.24,25,35 :op1 (p2 / product-of :op1 2~e.26 :op2 (t6 / tumor~e.30 :mod (r2 / rearrange-01~e.34 :polarity~e.38 -~e.38 :ARG1 g)))) :ARG1-of (s2 / statistical-test-91~e.40,47 :ARG2 0.0008~e.42 :ARG4 (t7 / thing :name (n3 / name :op1 "Fisher’s" :op2 "exact"~e.46 :op3 "test"~e.47)))))) # ::id pmid_2464_2271.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In conclusion , ERG and ETV1 gene rearrangements positively correlate with PTEN loss and negatively correlate with RAS @/@ ERK mutations in tumors . # ::alignments 1-1 4-1.1.1.1.1.1.1.1 6-1.1.1.1.1 8-1.1.1.1.1.2.1.1 10-1.1.1.1.1.1 10-1.1.1.1.1.2 11-1.1.1.1 12-1.1.1.3 12-1.1.1.3.r 13-1.1.1 14-1.1.1.2.r 15-1.1.1.2.1.1.1 16-1.1.1.2 17-1.1 18-1.1.2.3 19-1.1.2 20-1.1.2.2.r 21-1.1.2.2.1.1.1 23-1.1.2.2.1.1.1 24-1.1.2.2 25-1.1.r 26-1.1.3 (c / conclude-01~e.1 :ARG1~e.25 (a / and~e.17 :op1 (c2 / correlate-01~e.13 :ARG1 (r / rearrange-01~e.11 :ARG1 (a2 / and~e.6 :op1 (g / gene~e.10 :name (n / name :op1 "ERG"~e.4)) :op2 (g2 / gene~e.10 :name (n2 / name :op1 "ETV1"~e.8)))) :ARG2~e.14 (l / lose-02~e.16 :ARG1 (p2 / protein :name (n4 / name :op1 "PTEN"~e.15))) :manner~e.12 (p / positive~e.12)) :op2 (c3 / correlate-01~e.19 :ARG1 r :ARG2~e.20 (m / mutate-01~e.24 :ARG1 (p3 / pathway :name (n5 / name :op1 "RAS/ERK"~e.21,23))) :ARG2-of (n3 / negative-01~e.18)) :location (t / tumor~e.26))) # ::id pmid_2464_2271.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Prostate cancer cell lines as models of oncogenic ETS function # ::alignments 1-1.2.1.2.1 2-1.2.1.2.2 3-1.2 4-1.2 6-1 7-1.1.r 8-1.1.1 8-1.1.1.2 8-1.1.1.2.1.2.1 8-1.1.1.2.r 9-1.1.1.1.1 10-1.1 (m / model-01~e.6 :ARG1~e.7 (f / function-01~e.10 :ARG0 (p / protein~e.8 :name (n / name :op1 "ETS"~e.9) :ARG0-of~e.8 (c / cause-01~e.8 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.8))))) :location (c2 / cell-line~e.3,4 :mod (d2 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate"~e.1 :op2 "cancer"~e.2)))) # ::id pmid_2464_2271.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test the effect of RAS @/@ ERK signaling and PI3K @/@ AKT signaling on oncogenic ETS function in prostate cell lines , we must first determine which cell lines have these characteristics . # ::alignments 0-1 1-1.3 3-1.3.2 4-1.3.2.1.r 5-1.3.2.1.1.1.1.1 7-1.3.2.1.1.1.1.1 8-1.3.2.1.1 8-1.3.2.1.2 9-1.3.2.1 10-1.3.2.1.2.1.1.1 12-1.3.2.1.2.1.1.1 13-1.3.2.1.1 14-1.3.2.2.r 15-1.3.2.2.1 15-1.3.2.2.1.2 15-1.3.2.2.1.2.1.2.1 15-1.3.2.2.1.2.r 16-1.3.2.2.1.1.1 17-1.3.2.2 18-1.3.2.2.2.r 19-1.3.2.2.2.1 20-1.3.2.2.2 21-1.3.2.2.2 23-1.1 24-1 25-1.2.3 25-1.2.3.1 25-1.2.3.1.r 26-1.2 27-1.2.2.1 28-1.2.2 29-1.2.2 30-1.2.2.2 31-1.2.2.2.1.1 32-1.2.2.2.1 32-1.2.2.2.1.2 32-1.2.2.2.1.2.r (o / obligate-01~e.0,24 :ARG1 (w / we~e.23) :ARG2 (d / determine-01~e.26 :ARG0 w :ARG1 (c4 / cell-line~e.28,29 :mod (a3 / amr-unknown~e.27) :ARG0-of (h / have-03~e.30 :ARG1 (t2 / thing~e.32 :mod (t3 / this~e.31) :ARG2-of~e.32 (c3 / characteristic-02~e.32)))) :ord (o2 / ordinal-entity~e.25 :value~e.25 1~e.25)) :purpose (t / test-01~e.1 :ARG0 w :ARG1 (a / affect-01~e.3 :ARG0~e.4 (a2 / and~e.9 :op1 (s / signal-07~e.8,13 :ARG0 (p / pathway :name (n / name :op1 "RAS/ERK"~e.5,7))) :op2 (s2 / signal-07~e.8 :ARG0 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT"~e.10,12)))) :ARG1~e.14 (f / function-01~e.17 :ARG0 (g / gene~e.15 :name (n3 / name :op1 "ETS"~e.16) :ARG0-of~e.15 (c / cause-01~e.15 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.15)))) :location~e.18 (c2 / cell-line~e.20,21 :source (p3 / prostate~e.19)))))) # ::id pmid_2464_2271.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although some prostate cancer cell lines , such as VCaP ( ERG ) and LNCaP ( ETV1 ) are reported to have oncogenic ETS gene rearrangements [ @ 11 , 14 @ ] , the full extent of oncogenic ETS protein expression , including fusion @-@ independent expression , in commonly used prostate cancer cell lines has not been determined . # ::alignments 0-1.3.r 1-1.3.1.1.1 2-1.3.1.1.3.2.1 3-1.3.1.1.3.2.2 4-1.3.1.1 5-1.3.1.1 7-1.3.1.1.2.r 8-1.3.1.1.2.r 9-1.3.1.1.2.1.1.1 12-1.3.1.1.2.1.2.1.1 15-1.3.1.1.2 16-1.3.1.1.2.2.1.1 19-1.3.1.1.2.2.2.1.1 23-1.3 25-1.3.1 27-1.3.1.2.1.2.1.1.1 28-1.3.1.2.1 29-1.3.1.2 32-1.3.2.1.1.1.1 36-1.3.2.1.1.1.2 41-1.2.2 42-1.2 43-1.2.1.r 44-1.2.1.1.2 44-1.2.1.1.2.1.2.1 45-1.2.1.1.1.1 46-1.2.1.1 46-1.3.1.2.1.2.1 47-1.2.1 49-1.2.1.3 50-1.2.1.3.1.1.2 52-1.2.1.3.1.1 52-1.2.1.3.1.1.1 52-1.2.1.3.1.1.1.r 53-1.2.1.3.1 56-1.2.1.2.2.1 57-1.2.1.2.2 58-1.3.1.1.3.2.1 59-1.3.1.1.3.2.2 60-1.2.1.2 60-1.3.1.1 61-1.3.1.1 62-1.3.1 63-1.1 63-1.1.r 65-1 (d / determine-01~e.65 :polarity~e.63 -~e.63 :ARG1 (e / extent~e.42 :degree-of~e.43 (e2 / express-03~e.47 :ARG2 (p / protein~e.46 :name (n / name :op1 "ETS"~e.45) :ARG0-of (c / cause-01~e.44 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.44)))) :ARG3 (c2 / cell-line~e.60 :mod d2 :ARG1-of (u / use-01~e.57 :mod (c3 / common~e.56))) :ARG2-of (i / include-91~e.49 :ARG1 (e3 / express-03~e.53 :ARG0-of (d3 / depend-01~e.52 :polarity~e.52 -~e.52 :ARG1 (f2 / fuse-01~e.50))))) :ARG1-of (f / full-09~e.41)) :concession~e.0 (r / report-01~e.23 :ARG1 (h / have-03~e.25,62 :ARG0 (c4 / cell-line~e.4,5,60,61 :mod (s / some~e.1) :example~e.7,8 (a / and~e.15 :op1 (c5 / cell-line :name (n4 / name :op1 "VCaP"~e.9) :mod (g / gene :name (n6 / name :op1 "ERG"~e.12))) :op2 (c6 / cell-line :name (n5 / name :op1 "LNCaP"~e.16) :mod (g2 / gene :name (n7 / name :op1 "ETV1"~e.19)))) :mod (d4 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate"~e.2,58 :op2 "cancer"~e.3,59))) :ARG1 (r2 / rearrange-01~e.29 :ARG1 (g3 / gene~e.28 :ARG0-of c :ARG0-of (e4 / encode-01 :ARG1 (p4 / protein-family~e.46 :name (n8 / name :op1 "ETS"~e.27)))))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 (a2 / and :op1 11~e.32 :op2 14~e.36)))))) # ::id pmid_2464_2271.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To identify the expression level of the four oncogenic ETS proteins , we first tested available antibodies using purified recombinant proteins ( Figure 1 @ A ) . # ::alignments 1-1.5 3-1.5.2.1 4-1.5.2 5-1.5.2.1.1.r 7-1.5.2.1.1.1 8-1.5.2.1.1.3 8-1.5.2.1.1.3.1.2.1 9-1.5.2.1.1.2.1 10-1.5.2.1.1 12-1.1 13-1.3 13-1.3.1 13-1.3.1.r 14-1 15-1.2.1 16-1.2 17-1.4 17-1.5.r 18-1.4.2.1 19-1.4.2.2 20-1.4.2 22-1.6.1 24-1.3.1 (t / test-01~e.14 :ARG0 (w / we~e.12) :ARG1 (a / antibody~e.16 :ARG2-of (a2 / available-02~e.15)) :ord (o / ordinal-entity~e.13 :value~e.13 1~e.13,24) :manner (u / use-01~e.17 :ARG0 w :ARG1 (p / protein~e.20 :ARG1-of (p2 / purify-01~e.18) :ARG3-of (r / recombine-01~e.19))) :purpose~e.17 (i / identify-01~e.1 :ARG0 w :ARG1 (l / level~e.4 :degree-of (e / express-03~e.3 :ARG2~e.5 (p3 / protein~e.10 :quant 4~e.7 :name (n / name :op1 "ETS"~e.9) :ARG0-of (c / cause-01~e.8 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.8))))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.22 :mod "1A"))) # ::id pmid_2464_2271.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We identified antibodies to ERG , ETV1 , ETV4 , and ETV5 that could detect each protein at femtomolar levels . # ::alignments 0-1.1 1-1 2-1.2 4-1.2.1.1.1.1.1 6-1.2.1.1.2.1.1 8-1.2.1.1.3.1.1 10-1.2.1.1 11-1.2.1.1.4.1.1 13-1.2.2.2 14-1.2.2 15-1.2.2.1.1 16-1.2.2.1 17-1.2.2.1.2.r 18-1.2.2.1.2.1 19-1.2.2.1.2 (i / identify-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / antibody~e.2 :ARG0-of (c / counter-01 :ARG1 (a2 / and~e.10 :op1 (p / protein :name (n / name :op1 "ERG"~e.4)) :op2 (p2 / protein :name (n2 / name :op1 "ETV1"~e.6)) :op3 (p3 / protein :name (n3 / name :op1 "ETV4"~e.8)) :op4 (p4 / protein :name (n4 / name :op1 "ETV5"~e.11)))) :ARG0-of (d / detect-01~e.14 :ARG1 (p6 / protein~e.16 :mod (e / each~e.15) :quant~e.17 (l / level~e.19 :mod (f / femtomolar~e.18))) :ARG1-of (p5 / possible-01~e.13)))) # ::id pmid_2464_2271.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because ETV1 , ETV4 , and ETV5 are homologous proteins , the sensitivity and specificity of these antibodies were compared . # ::alignments 0-1.2 1-1.2.1.2.1.1.1 3-1.2.1.2.2.1.1 5-1.2.1.2 6-1.2.1.2.3.1.1 7-1.2.1.2.r 8-1.2.1.1 9-1.2.1 12-1.1.1 15-1.1.1.1.r 16-1.1.1.1.1 17-1.1.1.1 19-1 (c / compare-01~e.19 :ARG1 (a / and :op1 (s / sensitive-03~e.12 :ARG0~e.15 (a2 / antibody~e.17 :mod (t / this~e.16))) :op2 (s2 / specific-02 :ARG1 a2)) :ARG1-of (c2 / cause-01~e.0 :ARG0 (p / protein~e.9 :mod (h / homologous~e.8) :domain~e.7 (a3 / and~e.5 :op1 (p2 / protein :name (n / name :op1 "ETV1"~e.1)) :op2 (p3 / protein :name (n2 / name :op1 "ETV4"~e.3)) :op3 (p4 / protein :name (n3 / name :op1 "ETV5"~e.6)))))) # ::id pmid_2464_2271.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ETV1 and ETV4 antibodies were specific , but the ETV5 antibody recognized ETV4 and ETV5 equally . # ::alignments 0-1.1.1.1.1.1.1.1 1-1.1.1 2-1.1.1.2.1.1.1.1 3-1.1.1.1 3-1.1.1.2 5-1.1 7-1 9-1.2.1.1.1.1.1 10-1.2.1 11-1.2 12-1.1.1.2.1.1.1.1 13-1.2.2 14-1.2.1.1.1.1.1 15-1.2.3 (c / contrast-01~e.7 :ARG1 (s / specific-02~e.5 :ARG1 (a / and~e.1 :op1 (a2 / antibody~e.3 :ARG0-of (c2 / counter-01 :ARG1 (p / protein :name (n / name :op1 "ETV1"~e.0)))) :op2 (a3 / antibody~e.3 :ARG0-of (c3 / counter-01 :ARG1 (p2 / protein :name (n2 / name :op1 "ETV4"~e.2,12)))))) :ARG2 (r / recognize-02~e.11 :ARG0 (a4 / antibody~e.10 :ARG0-of (c4 / counter-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ETV5"~e.9,14)))) :ARG1 (a5 / and~e.13 :op1 p2 :op2 p3) :manner (e / equal-01~e.15))) # ::id pmid_2464_2271.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We then examined oncogenic ETS protein levels , along with phosphorylated ERK ( pERK : RAS @/@ ERK pathway ) and phosphorylated AKT ( pAKT : PI3K @/@ AKT pathway ) levels in six prostate cancer cell lines ( Figure 1 @ B and Additional file 1 @ : Figure S1A ) . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1.1.2 3-1.2.1.1.2.1.2.1 4-1.2.1.1.1.1 5-1.2.1.1 6-1.2.1 10-1.2.2.1.2 11-1.2.2.1.1.1 13-1.2.2.1.2 13-1.2.2.1.3.1.1.1 15-1.2.2.1.3.1.1.1 17-1.2.2.1.1.1 18-1.2.2.1 18-1.2.2.1.3.1 21-1.2.2.1.2 22-1.2.3.1.1.1 24-1.2.3.1.3.1.1.1 26-1.2.3.1.3.1.1.1 28-1.2.3.1.1.1 29-1.2.2.1 29-1.2.3.1 29-1.2.3.1.3.1 31-1.2.2 31-1.2.3 32-1.2.r 33-1.2.4.1 34-1.2.4.2.2.1 35-1.2.4.2.2.2 36-1.2.4 37-1.2.4 39-1.4.1.1 39-1.4.1.2 41-1.4.1.2.2.1 46-1.4.1.2.2 48-1.4.1.2.2.1 51-1.4.1.2 52-1.4.1.2.1 (e2 / examine-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.32 (a / and :op1 (l / level~e.6 :quant-of (p / protein~e.5 :name (n4 / name :op1 "ETS"~e.4) :ARG0-of (c2 / cause-01~e.3 :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.3))))) :op2 (l2 / level~e.31 :quant-of (p3 / pathway~e.18,29 :name (n5 / name :op1 "ERK"~e.11,17) :ARG3-of (p4 / phosphorylate-01~e.10,13,21) :ARG1-of (m / mean-01 :ARG2 (p5 / pathway~e.18 :name (n6 / name :op1 "RAS/ERK"~e.13,15))))) :op3 (l3 / level~e.31 :quant-of (p6 / pathway~e.29 :name (n7 / name :op1 "AKT"~e.22,28) :ARG3-of p4 :ARG1-of (m2 / mean-01 :ARG2 (p7 / pathway~e.29 :name (n8 / name :op1 "PI3K/AKT"~e.24,26))))) :location (c / cell-line~e.36,37 :quant 6~e.33 :mod (d / disease :wiki "Prostate_cancer" :name (n / name :op1 "prostate"~e.34 :op2 "cancer"~e.35)))) :time (t / then~e.1) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.39 :mod "1B") :op2 (f2 / figure~e.39,51 :mod "S1A"~e.52 :location (f3 / file~e.46 :mod 1~e.41,48 :ARG1-of (a3 / add-02)))))) # ::id pmid_2464_2271.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok DU145 cells , which have a KRAS gene rearrangement [ @ 24 @ ] , did not have high levels of any oncogenic ETS protein , or pAKT , but did have pERK , consistent with the small fraction of prostate cancers with RAS @/@ ERK pathway mutations ( Table 1 ) . # ::alignments 0-1.1.2.1.1 1-1.1.2 4-1.1.2.2 6-1.1.2.2.1.1.1.1 7-1.1.2.2.1.1 8-1.1.2.2.1 11-1.1.2.2.2.1.1.1 16-1.1.1 16-1.1.1.r 17-1.1 18-1.1.3.3 19-1.1.3.1 19-1.1.3.2 20-1.1.3.1.1.r 21-1.1.3.1.1.2 22-1.1.3.1.1.3 22-1.1.3.1.1.3.1.2.1 23-1.1.3.1.1.1.1 24-1.1.3.1.1 26-1.1.3 27-1.1.3.2.1.1.1 27-1.1.3.2.1.2 29-1 31-1.2 32-1.2.2.1.1 34-1.2.3 35-1.2.3.1.r 37-1.2.3.1.1 38-1.2.3.1 39-1.2.3.1.2.r 40-1.2.3.1.2.2.1 41-1.2.3.1.2.2.2 43-1.2.3.1.2.3.1.1.1.1 45-1.2.3.1.2.3.1.1.1.1 46-1.2.3.1.2.3.1.1 47-1.2.3.1.2.3.1 49-1.3.1 51-1.3.1.1 (c / contrast-01~e.29 :ARG1 (h / have-03~e.17 :polarity~e.16 -~e.16 :ARG0 (c2 / cell-line~e.1 :name (n2 / name :op1 "DU145"~e.0) :ARG0-of (h3 / have-03~e.4 :ARG1 (r / rearrange-01~e.8 :ARG1 (g / gene~e.7 :name (n5 / name :op1 "KRAS"~e.6))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 24~e.11))))) :ARG1 (o / or~e.26 :op1 (l / level~e.19 :quant-of~e.20 (p / protein~e.24 :name (n / name :op1 "ETS"~e.23) :mod (a / any~e.21) :ARG0-of (c3 / cause-01~e.22 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.22))))) :op2 (l2 / level~e.19 :quant-of (e / enzyme :name (n4 / name :op1 "AKT"~e.27) :ARG3-of (p2 / phosphorylate-01~e.27))) :ARG1-of (h2 / high-02~e.18))) :ARG2 (h4 / have-03~e.31 :ARG0 c2 :ARG1 (e2 / enzyme :name (n6 / name :op1 "ERK"~e.32) :ARG3-of p2) :ARG1-of (c5 / consistent-01~e.34 :ARG2~e.35 (f / fraction~e.38 :mod (s / small~e.37) :quant-of~e.39 (d5 / disease :wiki "Prostate_cancer" :name (n9 / name :op1 "prostate"~e.40 :op2 "cancer"~e.41) :ARG0-of (h5 / have-03 :ARG1 (m / mutate-01~e.47 :ARG1 (p5 / pathway~e.46 :name (n8 / name :op1 "RAS/ERK"~e.43,45)))))))) :ARG1-of (d4 / describe-01 :ARG0 (t / table~e.49 :mod 1~e.51))) # ::id pmid_2464_2271.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the remaining five prostate cancer cell lines , four had high expression of a single oncogenic protein . # ::alignments 2-1.2.2.1.2 3-1.2.2.1.1 4-1.2.2.1.3.2.1 5-1.2.2.1.3.2.2 6-1.2.2.1 7-1.2 9-1.2.1 11-1.3 12-1 13-1.1.r 15-1.1.1 16-1.1.2 16-1.1.2.1.2.1 17-1.1 (e / express-03~e.12 :ARG2~e.13 (p2 / protein~e.17 :ARG1-of (s / single-02~e.15) :ARG0-of (c3 / cause-01~e.16 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.16)))) :ARG3 (c / cell-line~e.7 :quant 4~e.9 :ARG1-of (i / include-91 :ARG2 (c2 / cell-line~e.6 :quant 5~e.3 :ARG1-of (r / remain-01~e.2) :mod (d3 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate"~e.4 :op2 "cancer"~e.5))))) :ARG1-of (h / high-02~e.11)) # ::id pmid_2464_2271.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These included ERG in VCaP , consistent with a TMRPSS2 @/@ ERG rearrangement [ @ 11 @ ] , ETV1 in MDA @-@ PCa @-@ 2B , consistent with an ETV1 gene rearrangement [ @ 14 @ ] , and ETV4 in PC3 , consistent with high ETV4 mRNA [ @ 25 @ ] . # ::alignments 0-1.2 1-1 2-1.1.1.1.1 4-1.1.1.2.1.1 6-1.1.1 6-1.1.1.3 6-1.1.1.3.r 10-1.1.1.3.1.1.1.1 12-1.1.1.3.1.1.1.1 14-1.1.1.3.1 17-1.1.1.3.2.1.1.1 21-1.1.2.1.1 21-1.1.2.3.1.1.1.1 23-1.1.2.2.1.1 25-1.1.2.2.1.1 27-1.1.2.2.1.1 29-1.1.2 29-1.1.2.3 29-1.1.2.3.r 33-1.1.2.1.1 33-1.1.2.3.1.1.1.1 35-1.1.1.3.1.1 35-1.1.2.3.1.1 36-1.1.2.3.1 39-1.1.2.3.2.1.1.1 43-1.1 44-1.1.3.1.1 44-1.1.3.3.1.2.1.1.1 46-1.1.3.2.1.1 48-1.1.3 48-1.1.3.3 48-1.1.3.3.r 49-1.1.3.3.1.r 50-1.1.3.3.1 50-1.1.3.3.1.3 50-1.1.3.3.1.3.r 52-1.1.3.3.1.2.1.1.1 54-1.1.3.3.1.1.1 57-1.1.3.3.2.1.1.1 (i / include-91~e.1 :ARG1 (a / and~e.43 :op1 (p / protein~e.6 :name (n / name :op1 "ERG"~e.2) :location (c / cell-line :name (n4 / name :op1 "VCaP"~e.4)) :ARG1-of~e.6 (c4 / consistent-01~e.6 :ARG2 (r / rearrange-01~e.14 :ARG1 (g / gene~e.35 :name (n7 / name :op1 "TMRPSS2/ERG"~e.10,12))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 11~e.17))))) :op2 (p2 / protein~e.29 :name (n2 / name :op1 "ETV1"~e.21,33) :location (c2 / cell-line :name (n5 / name :op1 "MDA-PCa-2B"~e.23,25,27)) :ARG1-of~e.29 (c6 / consistent-01~e.29 :ARG2 (r2 / rearrange-01~e.36 :ARG1 (g2 / gene~e.35 :name (n8 / name :op1 "ETV1"~e.21,33))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c7 / cite-01 :ARG2 14~e.39))))) :op3 (p3 / protein~e.48 :name (n3 / name :op1 "ETV4"~e.44) :location (c3 / cell-line :name (n6 / name :op1 "PC3"~e.46)) :ARG1-of~e.48 (c8 / consistent-01~e.48 :ARG2~e.49 (n11 / nucleic-acid~e.50 :name (n9 / name :op1 "mRNA"~e.54) :ARG0-of (e / encode-01 :ARG1 (p7 / protein :name (n10 / name :op1 "ETV4"~e.44,52))) :ARG1-of~e.50 (h / high-02~e.50)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c9 / cite-01 :ARG2 25~e.57)))))) :ARG2 (t / this~e.0)) # ::id pmid_2464_2271.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ETV4 protein was also present at high levels in CWR22Rv1 . # ::alignments 0-1.1.1.1 1-1.1 3-1.3 4-1 5-1.1.2.r 6-1.1.2.1 7-1.1.2 8-1.2.r 9-1.2.1.1 (p / present-02~e.4 :ARG1 (p2 / protein~e.1 :name (n / name :op1 "ETV4"~e.0) :quant~e.5 (l / level~e.7 :ARG1-of (h / high-02~e.6))) :ARG2~e.8 (c / cell-line :name (n2 / name :op1 "CWR22Rv1"~e.9)) :mod (a / also~e.3)) # ::id pmid_2464_2271.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the four lines with high oncogenic ETS protein expression , all had high levels of pAKT , but only one ( CWR22Rv1 ) had high levels of pERK , consistent with the analysis of prostate tumors in Table 1 @ . # ::alignments 2-1.1.1.1.1.1 3-1.1.1 3-1.1.1.1.1 3-1.2.1 4-1.1.1.1.1.2.r 5-1.1.1.1.1.2.2 6-1.1.1.1.1.2.1.2 6-1.1.1.1.1.2.1.2.1.2.1 7-1.1.1.1.1.2.1.1.1 8-1.1.1.1.1.2.1 9-1.1.1.1.1.2 11-1.1.1.1.2 13-1.1.1.1.1.2.2 14-1.1.2 14-1.2.2 16-1.1.2.1.1.1 16-1.1.2.1.2 18-1 19-1.2.1.2 20-1.2.1.1 22-1.2.1.3.1.1.1 24-1.1 25-1.1.2.2 26-1.1.2 27-1.2.2.2.r 28-1.2.2.2.1.1 30-1.3 31-1.3.1.r 33-1.3.1 34-1.3.1.1.r 35-1.3.1.1.1 36-1.3.1.1 37-1.3.1.2.r 38-1.3.1.2 40-1.3.1.2.1 (c / contrast-01~e.18 :ARG1 (h / have-03~e.24 :ARG0 (c2 / cell-line~e.3 :ARG1-of (i / include-91 :ARG2 (c3 / cell-line~e.3 :quant 4~e.2 :ARG3-of~e.4 (e / express-03~e.9 :ARG2 (p / protein~e.8 :name (n / name :op1 "ETS"~e.7) :ARG0-of (c4 / cause-01~e.6 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.6)))) :ARG1-of (h2 / high-02~e.5,13))) :ARG3 (a / all~e.11))) :ARG1 (l / level~e.14,26 :quant-of (e2 / enzyme :name (n3 / name :op1 "AKT"~e.16) :ARG3-of (p2 / phosphorylate-01~e.16)) :ARG1-of h2~e.25)) :ARG2 (h3 / have-03 :ARG0 (c5 / cell-line~e.3 :quant 1~e.20 :mod (o / only~e.19) :ARG1-of (m / mean-01 :ARG2 (c6 / cell-line :name (n4 / name :op1 "CWR22Rv1"~e.22))) :ARG1-of (i2 / include-91 :ARG2 c3)) :ARG1 (l2 / level~e.14 :ARG1-of h2 :quant-of~e.27 (e3 / enzyme :name (n5 / name :op1 "ERK"~e.28) :ARG3-of p2))) :ARG1-of (c7 / consistent-01~e.30 :ARG2~e.31 (a2 / analyze-01~e.33 :ARG1~e.34 (t / tumor~e.36 :mod (p3 / prostate~e.35)) :location~e.37 (t2 / table~e.38 :mod 1~e.40)))) # ::id pmid_2464_2271.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Surprisingly , despite an ETV1 gene rearrangement [ @ 14 @ ] , and high ETV1 mRNA levels [ @ 25 @ ] , ETV1 protein was not observed in LNCaP cells . # ::alignments 0-1.5 2-1.4.r 4-1.4.1.1.1.1 5-1.4.1.1 6-1.4.1 9-1.4.1.2.1.1.1 13-1.4 14-1.4.2.1 15-1.4.1.1.1.1 16-1.4.2.2.1.1 17-1.4.2 20-1.4.2.3.1.1.1 24-1.2.1.1 25-1.2 27-1.1 27-1.1.r 28-1 29-1.3.r 30-1.3.1.1 31-1.3 (o / observe-01~e.28 :polarity~e.27 -~e.27 :ARG1 (p / protein~e.25 :name (n / name :op1 "ETV1"~e.24)) :location~e.29 (c / cell-line~e.31 :name (n2 / name :op1 "LNCaP"~e.30)) :concession~e.2 (a / and~e.13 :op1 (r / rearrange-01~e.6 :ARG1 (g / gene~e.5 :name (n3 / name :op1 "ETV1"~e.4,15)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 14~e.9)))) :op2 (l / level~e.17 :ARG1-of (h / high-02~e.14) :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"~e.16) :ARG0-of (e / encode-01 :ARG1 g)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 25~e.20))))) :ARG0-of (s / surprise-01~e.0)) # ::id pmid_2464_2271.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , this is consistent with results from Vitari et al. who showed low ETV1 protein levels in LNCaP cells due to proteasomal targeting by the COP1 E3 ubiquitin ligase [ @ 26 @ ] . # ::alignments 0-1 2-1.1.1 4-1.1 5-1.1.2.r 6-1.1.2 6-1.1.2.1 6-1.1.2.1.r 8-1.1.2.1.1.1.1.1.1 10-1.1.2.1.1.1 11-1.1.2.1.1.1.2.1 14-1.1.2.1.1.1.3 15-1.1.2.1.1.1.3.1.1 16-1.1.2.1.1.1.3.1.2.1.1 17-1.1.2.1.1.1.3.1.2 18-1.1.2.1.1.1.3.1 19-1.1.2.1.1.1.3.1.3.r 20-1.1.2.1.1.1.3.1.3.1.1 21-1.1.2.1.1.1.3.1.3 22-1.1.2.1.1.1.3.1.1.1 23-1.1.2.1.1.1.3.1.1.1 25-1.1.2.1.1.1.3.1.1.1.1 26-1.1.2.1.1.1.3.1.1.1.1.1.r 28-1.1.2.1.1.1.3.1.1.1.1.1.1.1 29-1.1.2.1.1.1.3.1.1.1.1.1.1.2 30-1.1.2.1.1.1.3.1.1.1.1.1.1.3 31-1.1.2.1.1.1.3.1.1.1.1.1.1.4 34-1.2.1.1.1 (c / contrast-01~e.0 :ARG2 (c2 / consistent-01~e.4 :ARG1 (t / this~e.2) :ARG2~e.5 (t2 / thing~e.6 :ARG2-of~e.6 (r / result-01~e.6 :ARG1 (p / publication-91 :ARG0 (a / and~e.10 :op1 (p2 / person :name (n / name :op1 "Vitari"~e.8)) :op2 (p3 / person :mod (o / other~e.11)) :ARG0-of (s / show-01~e.14 :ARG1 (l / level~e.18 :ARG1-of (l2 / low-04~e.15 :ARG1-of (c4 / cause-01~e.22,23 :ARG0 (t3 / target-01~e.25 :ARG0~e.26 (e / enzyme :name (n4 / name :op1 "COP1"~e.28 :op2 "E3"~e.29 :op3 "ubiquitin"~e.30 :op4 "ligase"~e.31)) :ARG1 (m / macro-molecular-complex :name (n5 / name :op1 "proteasome"))))) :quant-of (p4 / protein~e.17 :name (n2 / name :op1 "ETV1"~e.16)) :location~e.19 (c3 / cell-line~e.21 :name (n3 / name :op1 "LNCaP"~e.20))))))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 26~e.34)))) # ::id pmid_2464_2271.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Long exposures could identify pERK , pAKT , and some ETS proteins at low levels in immunoblots from most cell lines . # ::alignments 0-1.1.1.1 1-1.1.1 2-1 3-1.1 4-1.1.2.1.1.1 4-1.1.2.1.2 6-1.1.2.1.2 6-1.1.2.2.1.1 8-1.1.2 9-1.1.2.3.2 10-1.1.2.3.1.1 11-1.1.2.3 12-1.1.2.r 13-1.1.2.4.1 14-1.1.2.4 18-1.1.3.1.1 19-1.1.3.1 20-1.1.3.1 (p / possible-01~e.2 :ARG1 (i / identify-01~e.3 :ARG0 (e3 / expose-01~e.1 :ARG1-of (l3 / long-03~e.0)) :ARG1~e.12 (a / and~e.8 :op1 (e / enzyme :name (n / name :op1 "ERK"~e.4) :ARG3-of (p3 / phosphorylate-01~e.4,6)) :op2 (e2 / enzyme :name (n2 / name :op1 "AKT"~e.6) :ARG3-of p3) :op3 (p2 / protein~e.11 :name (n3 / name :op1 "ETS"~e.10) :mod (s / some~e.9)) :quant (l / level~e.14 :ARG1-of (l2 / low-04~e.13))) :location (i2 / immunoblot-01 :ARG2 (c / cell-line~e.19,20 :quant (m / most~e.18))))) # ::id pmid_2464_2271.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To more quantitatively establish the “ high @-@ level ” threshold shown in Figure 1 @ B , ETS proteins in cell extracts were compared with purified standards ( Additional file 1 @ : Figure S1B ) . # ::alignments 1-1.3.2.1 2-1.3.2 2-1.3.2.r 3-1.3 6-1.3.1.1.1 8-1.3.1.1 10-1.3.1 11-1.3.1.2 12-1.3.1.2.1.r 13-1.3.1.2.1 15-1.4.1.1 19-1.1.1.1 20-1.1 21-1.1.2.r 22-1.1.2.1 23-1.1.2 25-1 26-1.2.r 27-1.2.1 28-1.2 31-1.4.1 33-1.4.1.1 36-1.4.1.3 37-1.4.1.3.1 (c / compare-01~e.25 :ARG1 (p / protein-family~e.20 :name (n / name :op1 "ETS"~e.19) :location~e.21 (e / extract-01~e.23 :ARG1 (c2 / cell~e.22))) :ARG2~e.26 (s / standard-02~e.28 :ARG1-of (p2 / purify-01~e.27)) :purpose (e2 / establish-01~e.3 :ARG1 (t / threshold~e.10 :mod (l / level~e.8 :ARG1-of (h / high-02~e.6)) :ARG1-of (s2 / show-01~e.11 :ARG0~e.12 (f / figure~e.13 :mod "1B"))) :manner~e.2 (q / quantitative~e.2 :degree (m / more~e.1))) :ARG1-of (d / describe-01 :ARG0 (f2 / file~e.31 :mod 1~e.15,33 :ARG1-of (a / add-02) :part (f3 / figure~e.36 :mod "S1B"~e.37)))) # ::id pmid_2464_2271.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All “ high @-@ level ” expression for ETS proteins exceeded 50,000 proteins per cell , and was highest at 330,000 proteins per cell for ERG in VCaP . # ::alignments 0-1.1.1.3 2-1.1.1.2.1 4-1.1.1.2 6-1.1.1 6-1.2.1 7-1.1.1.1.r 8-1.1.1.1.1.1 9-1.1.2.1 10-1.1 11-1.1.2.1.1 12-1.1.2.1 13-1.1.2 14-1.1.2.2 16-1 18-1.2 18-1.2.3 18-1.2.3.r 20-1.2.2.1.1 21-1.2.2.1 22-1.2.2 23-1.1.2.2 24-1.2.1.1.r 25-1.2.1.1.1.1 26-1.2.1.3.r 27-1.2.1.3.1.1 (a / and~e.16 :op1 (e / exceed-01~e.10 :ARG0 (e2 / express-03~e.6 :ARG2~e.7 (p / protein-family :name (n / name :op1 "ETS"~e.8)) :mod (l / level~e.4 :ARG1-of (h / high-02~e.2)) :mod (a2 / all~e.0)) :ARG1 (r / rate-entity-91~e.13 :ARG1 (p2 / protein~e.9,12 :quant 50000~e.11) :ARG2 (c / cell~e.14,23))) :op2 (h2 / high-02~e.18 :ARG1 (e3 / express-03~e.6 :ARG1~e.24 (g / gene :name (n2 / name :op1 "ERG"~e.25)) :ARG2 p :ARG3~e.26 (c2 / cell-line :name (n3 / name :op1 "VCaP"~e.27))) :ARG2 (r2 / rate-entity-91~e.22 :ARG1 (p3 / protein~e.21 :quant 330000~e.20) :ARG2 c) :degree~e.18 (m / most~e.18))) # ::id pmid_2464_2271.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Low @-@ level ETS expression was 10,000 proteins per cell ( ETV4 in DU145 ) or less ( Additional file 1 @ : Figure S1B and data not shown ) . # ::alignments 0-1.2.1 2-1.2 3-1.1.1.1 4-1 4-1.4.1 6-1.3.1.1.1 7-1.3.1.1 8-1.3.1 9-1.3.1.2 11-1.4.1.1.1.1 12-1.4.1.2.r 13-1.4.1.2.1.1 15-1.3 16-1.3.2 19-1.5.1.1 21-1.5.1.1.1 24-1.5.1.1.3 25-1.5.1.1.3.1 26-1.5.1 27-1.5.1.2 28-1.5.1.2.1.1 28-1.5.1.2.1.1.r 29-1.5.1.2.1 (e / express-03~e.4 :ARG2 (p / protein-family :name (n / name :op1 "ETS"~e.3)) :mod (l / level~e.2 :ARG1-of (l2 / low-04~e.0)) :quant (o / or~e.15 :op1 (r / rate-entity-91~e.8 :ARG1 (p2 / protein~e.7 :quant 10000~e.6) :ARG2 (c / cell~e.9)) :op2 (l3 / less-than~e.16 :op1 r)) :ARG1-of (m / mean-01 :ARG2 (e2 / express-03~e.4 :ARG1 (p3 / protein :name (n2 / name :op1 "ETV4"~e.11)) :ARG3~e.12 (c2 / cell-line :name (n3 / name :op1 "DU145"~e.13)))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.26 :op1 (f / file~e.19 :mod 1~e.21 :ARG1-of (a2 / add-02) :part (f2 / figure~e.24 :mod "S1B"~e.25)) :op1 (d2 / data~e.27 :ARG1-of (s / show-01~e.29 :polarity~e.28 -~e.28))))) # ::id pmid_2464_2271.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is possible that oncogenic ETS expression and signaling pathway activation could influence each other . # ::alignments 2-1 2-1.1 3-1.1.r 4-1.1.1.1.1.1 4-1.1.1.1.1.1.2 4-1.1.1.1.1.1.2.1.2.1 4-1.1.1.1.1.1.2.r 5-1.1.1.1.1.1.1.1 6-1.1.1.1.1 8-1.1.1.1.2.1.1 9-1.1.1.1.2.1 10-1.1.1.1.2 11-1.1 12-1.1.1.1 12-1.1.1.2 (p / possible-01~e.2 :ARG1~e.3 (p2 / possible-01~e.2,11 :ARG1 (a / and :op1 (i / influence-01~e.12 :ARG0 (e / express-03~e.6 :ARG2 (p3 / protein~e.4 :name (n / name :op1 "ETS"~e.5) :ARG0-of~e.4 (c / cause-01~e.4 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.4))))) :ARG1 (a2 / activate-01~e.10 :ARG1 (p4 / pathway~e.9 :ARG0-of (s / signal-07~e.8)))) :op2 (i2 / influence-01~e.12 :ARG0 a2 :ARG1 e)))) # ::id pmid_2464_2271.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this , RWPE @-@ 1 ( RWPE ) cells derived from normal prostate [ @ 27 @ ] or variations of this line that express either Ki @-@ RAS ( RWPE @-@ KRAS , also known as RWPE @-@ 2 ) or ERG ( RWPE @-@ ERG ) were compared . # ::alignments 1-1.3 2-1.3.1 4-1.1.1.1 6-1.1.1.1 8-1.1.1.1 10-1.1 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1 14-1.1.2.1 17-1.1.3.1.1.1 20-1.2 21-1.2.1 21-1.2.2 23-1.3.1 24-1.1 24-1.2.1.3.1 26-1.2.1.2 26-1.2.2.2 27-1.2.3 28-1.2.1.2.1.1.1 30-1.2.1.2.1.1.1 32-1.2.1.3.1.1.1 36-1.2.1.3.2 37-1.2.1.2.1.1.r 37-1.2.1.3 37-1.2.1.3.1.1.r 38-1.2.1.2.1.1.r 39-1.2.1.3.1.1.1 41-1.2.1.3.1.1.1 43-1.2 44-1.2.2.2.1.1.1 46-1.2.1.3.1.1.1 48-1.2.2.2.1.1.1 51-1 (c / compare-01~e.51 :ARG1 (c2 / cell-line~e.10,24 :name (n / name :op1 "RWPE-1"~e.4,6,8) :ARG1-of (d / derive-01~e.11 :ARG2~e.12 (p / prostate~e.14 :ARG1-of (n2 / normal-02~e.13))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 27~e.17)))) :ARG2 (o / or~e.20,43 :op1 (v / vary-01~e.21 :ARG1 c2 :ARG3-of (e / express-03~e.26 :ARG2 (e4 / enzyme :name~e.37,38 (n4 / name :op1 "Ki-RAS"~e.28,30))) :ARG1-of (k / know-02~e.37 :ARG2 (c4 / cell-line~e.24 :name~e.37 (n5 / name :op1 "RWPE-2"~e.32,39,41,46)) :mod (a / also~e.36))) :op2 (v2 / vary-01~e.21 :ARG1 c2 :ARG3-of (e2 / express-03~e.26 :ARG2 (p4 / protein :name (n3 / name :op1 "ERG"~e.44,48)))) :mod (e3 / either~e.27)) :purpose (t / test-01~e.1 :ARG1 (t2 / this~e.2,23))) # ::id pmid_2464_2271.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERG levels in RWPE @-@ ERG cells were similar to VCaP cells ( Additional file 1 @ : Figure S1C ) . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.2 2-1.1.2.r 3-1.1.2.1.1 5-1.1.1.1.1 6-1.1.2 6-1.2.2 8-1 10-1.2.2.1.1 11-1.1.2 14-1.3.1 16-1.3.1.1 19-1.3.1.3 20-1.3.1.3.1 (r / resemble-01~e.8 :ARG1 (l / level~e.1 :quant-of (p / protein :name (n / name :op1 "ERG"~e.0,5)) :location~e.2 (c / cell-line~e.6,11 :name (n2 / name :op1 "RWPE-ERG"~e.3))) :ARG2 (l2 / level~e.1 :quant-of p :location (c2 / cell-line~e.6 :name (n3 / name :op1 "VCaP"~e.10))) :ARG1-of (d / describe-01 :ARG0 (f / file~e.14 :mod 1~e.16 :ARG1-of (a / add-02) :part (f2 / figure~e.19 :mod "S1C"~e.20)))) # ::id pmid_2464_2271.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok None of the oncogenic ETS were expressed at high levels in RWPE or RWPE @-@ KRAS cells , and only ERG was expressed in RWPE @-@ ERG cells ( Figure 1 @ B ) . # ::alignments 0-1.1.1.1 3-1.1.1.2 3-1.1.1.2.2 3-1.1.1.2.2.1.2.1 3-1.1.1.2.2.r 4-1.1.1.2.1.1 6-1.1 7-1.1.3.r 8-1.1.3.1 9-1.1.3 10-1.1.2.r 11-1.1.2.1.1.1 12-1.1.2 13-1.1.2.1.1.1 15-1.1.2.2.1.1 16-1.1.2.1 16-1.1.2.2 18-1 19-1.2.3 20-1.2.1.1.1 22-1.2 23-1.2.2.r 24-1.2.2.1.1 26-1.2.1.1.1 27-1.2.2 29-1.3.1 (a / and~e.18 :op1 (e / express-03~e.6 :ARG2 (i / include-91 :ARG1 (n / none~e.0) :ARG2 (p / protein~e.3 :name (n2 / name :op1 "ETS"~e.4) :ARG0-of~e.3 (c / cause-01~e.3 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.3))))) :ARG3~e.10 (o2 / or~e.12 :op1 (c2 / cell-line~e.16 :name (n4 / name :op1 "RWPE"~e.11,13)) :op2 (c3 / cell-line~e.16 :name (n6 / name :op1 "RWPE-KRAS"~e.15))) :quant~e.7 (l / level~e.9 :ARG1-of (h / high-02~e.8))) :op2 (e2 / express-03~e.22 :ARG2 (p2 / protein :name (n5 / name :op1 "ERG"~e.20,26)) :ARG3~e.23 (c4 / cell-line~e.27 :name (n7 / name :op1 "RWPE-ERG"~e.24)) :mod (o3 / only~e.19)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "1B"))) # ::id pmid_2464_2271.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected , KRAS increased both pERK and pAKT levels ( Figure 1 @ B ) . # ::alignments 1-1.3 3-1.1.1.1 4-1 6-1.2.1.1.1.1 6-1.2.1.1.2 7-1.2 8-1.2.1.1.2 8-1.2.2.1.1.1 9-1.2.1 9-1.2.2 11-1.4.1 (i / increase-01~e.4 :ARG0 (e / enzyme :name (n / name :op1 "KRAS"~e.3)) :ARG1 (a / and~e.7 :op1 (l / level~e.9 :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK"~e.6) :ARG3-of (p / phosphorylate-01~e.6,8))) :op2 (l2 / level~e.9 :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT"~e.8) :ARG3-of p))) :ARG1-of (e4 / expect-01~e.1) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.11 :mod "1B"))) # ::id pmid_2464_2271.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , over @-@ expression of ERG also resulted in activation of AKT and a small increase in pERK ( Figure 1 @ B ) . # ::alignments 0-1.4 6-1.1.1.1.1 7-1.3 8-1 9-1.2.r 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.1 13-1.2 15-1.2.2.2 16-1.2.2 17-1.2.2.1.r 18-1.2.2.1.1.1 18-1.2.2.1.2 20-1.5.1 (r / result-01~e.8 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "ERG"~e.6))) :ARG2~e.9 (a / and~e.13 :op1 (a2 / activate-01~e.10 :ARG1~e.11 (e / enzyme :name (n2 / name :op1 "AKT"~e.12))) :op2 (i / increase-01~e.16 :ARG1~e.17 (e2 / enzyme :name (n3 / name :op1 "ERK"~e.18) :ARG3-of (p2 / phosphorylate-01~e.18)) :degree (s / small~e.15))) :mod (a3 / also~e.7) :ARG2-of (i2 / interest-01~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "1B"))) # ::id pmid_2464_2271.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In other cell types , the RAS @/@ ERK pathway activates ETV1 , ETV4 , and ETV5 expression [ @ 28 @ ] . # ::alignments 1-1.3.2 2-1.3.1 3-1.3 6-1.1.1.1 8-1.1.1.1 9-1.1 10-1 11-1.2.1.1.1.1 13-1.2.1.2.1.1 15-1.2.1 16-1.2.1.3.1.1 17-1.2 20-1.4.1.1.1 (a / activate-01~e.10 :ARG0 (p / pathway~e.9 :name (n / name :op1 "RAS/ERK"~e.6,8)) :ARG1 (e / express-03~e.17 :ARG2 (a2 / and~e.15 :op1 (p2 / protein :name (n2 / name :op1 "ETV1"~e.11)) :op2 (p3 / protein :name (n3 / name :op1 "ETV4"~e.13)) :op3 (p4 / protein :name (n4 / name :op1 "ETV5"~e.16)))) :location (t / type~e.3 :mod (c / cell~e.2) :mod (o / other~e.1)) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 28~e.20)))) # ::id pmid_2464_2271.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , high ETV4 expression in CWR22Rv1 cells could be the result of ERK activation . # ::alignments 0-1 2-1.1.1.2.3 3-1.1.1.2.1.1.1 4-1.1.1.2 5-1.1.1.2.2.r 6-1.1.1.2.2.1.1 7-1.1.1.2.2 8-1.1 11-1.1.1 12-1.1.1.1.r 13-1.1.1.1.1.1.1 14-1.1.1.1 (c / cause-01~e.0 :ARG1 (p / possible-01~e.8 :ARG1 (r / result-01~e.11 :ARG1~e.12 (a / activate-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "ERK"~e.13))) :ARG2 (e2 / express-03~e.4 :ARG2 (p2 / protein :name (n2 / name :op1 "ETV4"~e.3)) :ARG3~e.5 (c2 / cell-line~e.7 :name (n3 / name :op1 "CWR22Rv1"~e.6)) :ARG1-of (h / high-02~e.2))))) # ::id pmid_2464_2271.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test this , CWR22Rv1 and DU145 cells were treated with the MEK inhibitor U0126 for 24 hours . # ::alignments 1-1.4 2-1.4.1 4-1.1.1.1.1 5-1.1 6-1.1.2.1.1 7-1.1.1 7-1.1.2 9-1 10-1.2.r 12-1.2.2.1.1.1 13-1.2 13-1.2.2 13-1.2.2.r 14-1.2.1.1 15-1.3.r 16-1.3.1 17-1.3.2 (t / treat-04~e.9 :ARG1 (a / and~e.5 :op1 (c / cell-line~e.7 :name (n / name :op1 "CWR22Rv1"~e.4)) :op2 (c2 / cell-line~e.7 :name (n2 / name :op1 "DU145"~e.6))) :ARG2~e.10 (s / small-molecule~e.13 :name (n3 / name :op1 "U0126"~e.14) :ARG0-of~e.13 (i / inhibit-01~e.13 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"~e.12)))) :duration~e.15 (t2 / temporal-quantity :quant 24~e.16 :unit (h / hour~e.17)) :purpose (t3 / test-01~e.1 :ARG1 (t4 / this~e.2))) # ::id pmid_2464_2271.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In both cell lines , U0126 decreased pERK levels , but did not alter levels of ETV4 ( Figure 1 @ C ) . # ::alignments 1-1.3.1 2-1.3 3-1.3 5-1.1.1.1.1 6-1.1 7-1.1.2.1.1.1 7-1.1.2.1.2 8-1.1.2 10-1 12-1.2.1 12-1.2.1.r 13-1.2 14-1.2.3 15-1.2.3.1.r 16-1.2.3.1.1.1 18-1.4.1 (c / contrast-01~e.10 :ARG1 (d / decrease-01~e.6 :ARG0 (s / small-molecule :name (n / name :op1 "U0126"~e.5)) :ARG1 (l / level~e.8 :quant-of (e / enzyme :name (n2 / name :op1 "ERK"~e.7) :ARG3-of (p / phosphorylate-01~e.7)))) :ARG2 (a / alter-01~e.13 :polarity~e.12 -~e.12 :ARG0 s :ARG1 (l2 / level~e.14 :quant-of~e.15 (p2 / protein :name (n3 / name :op1 "ETV4"~e.16)))) :location (c2 / cell-line~e.2,3 :mod (b / both~e.1)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.18 :mod "1C"))) # ::id pmid_2464_2271.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , RAS @/@ ERK activation does not drive oncogenic ETS expression in prostate cancer cell lines , however in at least one context ( ERG in RWPE ) an oncogenic ETS could induce the phosphorylation of both AKT and , to a lesser degree , ERK . # ::alignments 0-1 2-1.1.1.2.1.1.1 4-1.1.1.2.1.1.1 5-1.1.1.2 7-1.1.1.1 7-1.1.1.1.r 8-1.1.1 9-1.1.1.3.1 9-1.1.1.3.1.2 9-1.1.1.3.1.2.1.2.1 9-1.1.1.3.1.2.r 10-1.1.1.3.1.1.1 11-1.1.1.3 11-1.1.2.2.2.1 12-1.1.1.3.2.r 13-1.1.1.3.2.1.2.1 14-1.1.1.3.2.1.2.2 15-1.1.1.3.2 16-1.1.1.3.2 18-1.1 20-1.1.2.2.1 21-1.1.2.2.1 22-1.1.2.1.1.1 22-1.1.2.2.1.1 23-1.1.2.2 25-1.1.2.2.2.1.1.1.1 26-1.1.2.2.2.1.2.r 27-1.1.2.2.2.1.2.1.1 30-1.1.1.3.1 30-1.1.1.3.1.2 30-1.1.1.3.1.2.1.2.1 30-1.1.1.3.1.2.r 31-1.1.1.3.1.1.1 31-1.1.2.1.1.2.1 32-1.1.2 33-1.1.2.1 35-1.1.2.1.2.1 35-1.1.2.1.2.2 38-1.1.2.1.2.1.1.1.1 39-1.1.2.1.2 41-1.1.2.1.2.2.2.r 43-1.1.2.1.2.2.2 43-1.1.2.1.2.2.2.1 43-1.1.2.1.2.2.2.1.r 44-1.1.2.1.2.2.2.1.r 46-1.1.2.1.2.2.1.1.1 (c / cause-01~e.0 :ARG1 (h / have-concession-91~e.18 :ARG1 (d / drive-02~e.8 :polarity~e.7 -~e.7 :ARG0 (a / activate-01~e.5 :ARG0 (p / pathway :name (n / name :op1 "RAS/ERK"~e.2,4))) :ARG1 (e / express-03~e.11 :ARG2 (p2 / protein~e.9,30 :name (n2 / name :op1 "ETS"~e.10,31) :ARG0-of~e.9,30 (c2 / cause-01~e.9,30 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.9,30)))) :ARG3~e.12 (c3 / cell-line~e.15,16 :mod (d3 / disease :wiki "Prostate_cancer" :name (n4 / name :op1 "prostate"~e.13 :op2 "cancer"~e.14))))) :ARG2 (p4 / possible-01~e.32 :ARG1 (i / induce-01~e.33 :ARG0 (p5 / protein :quant 1~e.22 :name (n5 / name :op1 "ETS"~e.31) :ARG0-of c2) :ARG2 (a2 / and~e.39 :op1 (p6 / phosphorylate-01~e.35 :ARG1 (e2 / enzyme :name (n6 / name :op1 "AKT"~e.38))) :op2 (p7 / phosphorylate-01~e.35 :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK"~e.46)) :degree~e.41 (l / less~e.43 :degree~e.43,44 (m / more~e.43))))) :location (c4 / context~e.23 :quant (a3 / at-least~e.20,21 :op1 1~e.22) :ARG1-of (m2 / mean-01 :ARG2 (e4 / express-03~e.11 :ARG2 (p8 / protein :name (n8 / name :op1 "ERG"~e.25)) :ARG3~e.26 (c5 / cell-line :name (n9 / name :op1 "RWPE"~e.27)))))))) # ::id pmid_2464_2271.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogenic ETS proteins and KRAS drive prostate cell migration , but not synergistically # ::alignments 1-1.1.1.1.2 1-1.1.1.1.2.1.2.1 2-1.1.1.1.1.1 3-1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1.1 6-1.2 7-1.1.2.1.1 8-1.1.2.1 9-1.1.2 11-1 12-1.2.1 12-1.2.1.r (c / contrast-01~e.11 :ARG1 (d / drive-02~e.6 :ARG0 (a / and~e.4 :op1 (p / protein~e.3 :name (n / name :op1 "ETS"~e.2) :ARG0-of (c2 / cause-01~e.1 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.1)))) :op2 (e / enzyme :name (n3 / name :op1 "KRAS"~e.5) :ARG0-of c2)) :ARG1 (m / migrate-01~e.9 :ARG0 (c3 / cell~e.8 :mod (p2 / prostate~e.7)))) :ARG2 (d3 / drive-02~e.6 :polarity~e.12 -~e.12 :ARG0 a :ARG1 m :manner (s / synergistical))) # ::id pmid_2464_2271.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next tested the role of signaling pathways in the ability of oncogenic ETS proteins to drive cell migration . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1 7-1.2.1 8-1.2.2.r 10-1.2.2 11-1.2.2.1.r 12-1.2.2.1.2 12-1.2.2.1.2.1.2.1 13-1.2.2.1.1.1 14-1.2.2.1 15-1.2.2.1.2 16-1.2.2.2 17-1.2.2.2.2.1 18-1.2.2.2.2 (t / test-01~e.2 :ARG0 (w / we~e.0) :ARG1 (r / role~e.4 :poss~e.5 (p / pathway~e.7 :ARG0-of (s / signal-07~e.6)) :topic~e.8 (c / capable-01~e.10 :ARG1~e.11 (p2 / protein~e.14 :name (n / name :op1 "ETS"~e.13) :ARG0-of (c2 / cause-01~e.12,15 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.12)))) :ARG2 (d2 / drive-02~e.16 :ARG0 p2 :ARG1 (m / migrate-01~e.18 :ARG0 (c3 / cell~e.17))))) :time (n3 / next~e.1)) # ::id pmid_2464_2271.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because cancer derived cell lines have many mutations and copy number alterations that affect cellular phenotypes , we used the RWPE @-@ ERG and RWPE @-@ KRAS cell lines to compare the ability of oncogenic ETS and RAS signaling to promote cell migration in the same cellular background . # ::alignments 0-1 1-1.1.1.1.1.2.1 2-1.1.1.1 3-1.1.1 4-1.1.1 5-1.1 6-1.1.2.1.2 7-1.1.2.1 8-1.1.2 9-1.1.2.2.1.1 10-1.1.2.2.1 11-1.1.2.2 12-1.1.2.r 13-1.1.2.3 14-1.1.2.3.1.1 15-1.1.2.3.1 17-1.2.1 18-1.2 20-1.2.2.1.1.1 20-1.2.2.2.1.1 22-1.2.2.1.1.1 23-1.2.2 24-1.2.2.1.1.1 24-1.2.2.2.1.1 26-1.2.2.2.1.1 27-1.2.2.1 27-1.2.2.2 28-1.2.2.1 30-1.2.3 32-1.2.3.2 33-1.2.3.2.1.r 34-1.2.3.2.1.1.1 34-1.2.3.2.1.1.1.2 34-1.2.3.2.1.1.1.2.r 35-1.2.3.2.1.1.1.1.1 36-1.2.3.2.1.1 37-1.2.3.2.1.1.2.1.1 38-1.2.3.2.1 40-1.2.3.2.2 41-1.2.3.2.2.2.1 42-1.2.3.2.2.2 43-1.2.4.r 45-1.2.4.2 46-1.2.4.1 47-1.2.4 (c / cause-01~e.0 :ARG0 (h / have-03~e.5 :ARG0 (c2 / cell-line~e.3,4 :ARG1-of (d / derive-01~e.2 :ARG2 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.1)))) :ARG1~e.12 (a / and~e.8 :op1 (m / mutate-01~e.7 :ARG2 c2 :quant (m2 / many~e.6)) :op2 (a2 / alter-01~e.11 :ARG1 (n2 / number-01~e.10 :ARG1 (c3 / copy-01~e.9 :ARG1 c2))) :ARG0-of (a3 / affect-01~e.13 :ARG1 (p / phenotype~e.15 :mod (c4 / cell~e.14))))) :ARG1 (u / use-01~e.18 :ARG0 (w / we~e.17) :ARG1 (a4 / and~e.23 :op1 (c5 / cell-line~e.27,28 :name (n3 / name :op1 "RWPE-ERG"~e.20,22,24)) :op2 (c6 / cell-line~e.27 :name (n4 / name :op1 "RWPE-KRAS"~e.20,24,26))) :ARG2 (c7 / compare-01~e.30 :ARG0 w :ARG1 (c8 / capable-01~e.32 :ARG1~e.33 (s / signal-07~e.38 :ARG0 (a5 / and~e.36 :op1 (p2 / protein~e.34 :name (n5 / name :op1 "ETS"~e.35) :ARG0-of~e.34 (c9 / cause-01~e.34 :ARG1 d2)) :op2 (e / enzyme :name (n6 / name :op1 "RAS"~e.37)))) :ARG2 (p3 / promote-01~e.40 :ARG0 a5 :ARG1 (m3 / migrate-01~e.42 :ARG0 (c10 / cell~e.41))))) :location~e.43 (b / background~e.47 :mod (c11 / cell~e.46) :ARG1-of (s2 / same-01~e.45)))) # ::id pmid_2464_2271.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok RWPE @-@ ERG and RWPE @-@ KRAS cells migrated 5 @- and 10 @-@ fold more than RWPE cells ( Figure 2 @ A and Additional file 2 @ : Figure S2 ) , indicating that both ERG and KRAS induce cell migration . # ::alignments 0-1.1.1.1.1 0-1.1.2.1.1 2-1.1.1.1.1 3-1.1 4-1.1.1.1.1 4-1.1.2.1.1 6-1.1.2.1.1 7-1.4.1.2.1 8-1 9-1.2.1.1.1 11-1.2.1 12-1.2.1.2.1 14-1.2.1.1 14-1.2.1.2 15-1.2 16-1.2.1.3.r 17-1.2.1.3.1.1 18-1.2.1.3 20-1.3.1.1 22-1.3.1.2.1 27-1.3.1.2 29-1.3.1.2.1 32-1.3.1.2.3 33-1.3.1.2.3.1 36-1.4 39-1.4.1.1.1.1.1 40-1.4.1.1 41-1.4.1.1.2.1.1 42-1.4.1 43-1.4.1.2.1 44-1.4.1.2 (m / migrate-01~e.8 :ARG0 (a / and~e.3 :op1 (c / cell-line :name (n / name :op1 "RWPE-ERG"~e.0,2,4)) :op2 (c2 / cell-line :name (n2 / name :op1 "RWPE-KRAS"~e.0,4,6))) :degree (m2 / more-than~e.15 :op1 (a2 / and~e.11 :op1 (p / product-of~e.14 :op1 5~e.9) :op2 (p2 / product-of~e.14 :op1 10~e.12) :compared-to~e.16 (c3 / cell-line~e.18 :name (n3 / name :op1 "RWPE"~e.17)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.20 :mod "2A") :op2 (f2 / file~e.27 :mod 2~e.22,29 :ARG1-of (a4 / add-02) :part (f3 / figure~e.32 :mod "S2"~e.33)))) :ARG0-of (i / indicate-01~e.36 :ARG1 (i2 / induce-01~e.42 :ARG0 (a5 / and~e.40 :op1 (p3 / protein :name (n4 / name :op1 "ERG"~e.39)) :op2 (e / enzyme :name (n5 / name :op1 "KRAS"~e.41))) :ARG2 (m3 / migrate-01~e.44 :ARG0 (c4 / cell~e.7,43))))) # ::id pmid_2464_2271.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to our previous findings [ @ 15 @ ] , overexpression of oncogenic ETS proteins ETV1 , ETV5 , and ERG , but not other ETS proteins ( FLI1 and SPDEF ) , promoted RWPE cell migration ( Figure 2 @ B and Additional file 2 @ : Figure S2 ) . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.1.1 2-1.3.1.1.1.r 3-1.3.1.2 4-1.3.1 4-1.3.1.1 4-1.3.1.1.r 7-1.3.1.3.1.1.1 11-1.1 11-1.1.2.1 12-1.1.1.r 13-1.1.1.2 13-1.1.1.2.1.2.1 14-1.1.1.1.1 15-1.1.1 16-1.1.1.3.1.1.1.1 18-1.1.1.3.1.2.1.1 20-1.1.1.3.1 21-1.1.1.3.1.3.1.1 23-1.1.2 25-1.1.2.1.1.3 26-1.1.2.1.1.1.1 27-1.1.1.3.1.1 27-1.1.1.3.1.2 27-1.1.1.3.1.3 27-1.1.2.1.1 27-1.1.2.1.1.2.1.1 27-1.1.2.1.1.2.1.2 29-1.1.2.1.1.2.1.1.1.1 30-1.1.2.1.1.2.1 31-1.1.2.1.1.2.1.2.1.1 34-1 35-1.2.1.1.1 36-1.2.1 37-1.2 39-1.4.1.1 41-1.4.1.2.1 46-1.4.1.2 48-1.4.1.2.1 51-1.4.1.2.3 52-1.4.1.2.3.1 (p / promote-01~e.34 :ARG0 (o / overexpress-01~e.11 :ARG1~e.12 (p2 / protein~e.15 :name (n / name :op1 "ETS"~e.14) :ARG0-of (c / cause-01~e.13 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.13))) :ARG1-of (m / mean-01 :ARG2 (a / and~e.20 :op1 (p3 / protein~e.27 :name (n3 / name :op1 "ETV1"~e.16)) :op2 (p4 / protein~e.27 :name (n4 / name :op1 "ETV5"~e.18)) :op3 (p5 / protein~e.27 :name (n5 / name :op1 "ERG"~e.21))))) :ARG1-of (c2 / contrast-01~e.23 :ARG2 (o2 / overexpress-01~e.11 :ARG1 (p6 / protein~e.27 :name (n6 / name :op1 "ETS"~e.26) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.30 :op1 (p7 / protein~e.27 :name (n7 / name :op1 "FLI1"~e.29)) :op2 (p8 / protein~e.27 :name (n8 / name :op1 "SPDEF"~e.31)))) :mod (o3 / other~e.25))))) :ARG1 (m3 / migrate-01~e.37 :ARG0 (c3 / cell-line~e.36 :name (n9 / name :op1 "RWPE"~e.35))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (t / thing~e.4 :ARG1-of~e.4 (f / find-01~e.4 :ARG0~e.2 (w / we~e.2)) :time (p9 / previous~e.3) :ARG1-of (d2 / describe-01 :ARG0 (p10 / publication :ARG1-of (c4 / cite-01 :ARG2 15~e.7))))) :ARG1-of (d3 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure~e.39 :mod "2B") :op2 (f3 / file~e.46 :mod 2~e.41,48 :ARG1-of (a4 / add-02) :part (f4 / figure~e.51 :mod "S2"~e.52))))) # ::id pmid_2464_2271.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , when the same ETS proteins were over @-@ expressed in RWPE @-@ KRAS cells , none of the oncogenic ETS proteins induced additional cell migration ( Figure 2 @ C and Additional file 2 @ : Figure S2 ) , suggesting that these ETS proteins and KRAS were functioning to activate the same pathway . # ::alignments 1-1 3-1.1.3.r 5-1.1.3.1.2 6-1.1.3.1.1.1 7-1.1.3.1 13-1.1.3.2.1.1 15-1.1.3.2.1.1 16-1.1.2.1 18-1.1.1.2 21-1.1.1.1.2 21-1.1.1.1.2.1.2.1 22-1.1.1.1.1.1 23-1.1.1.1 24-1.1 26-1.1.2.1 27-1.1.2 29-1.1.4.1.1 31-1.1.4.1.2.1 36-1.1.4.1.2 38-1.1.4.1.2.1 41-1.1.4.1.2.2 42-1.1.4.1.2.2.1 45-1.1.5 48-1.1.1.1.1.1 48-1.1.3.1.1.1 49-1.1.5.1.1.1 50-1.1.5.1.1 51-1.1.5.1.1.2.1.1 53-1.1.5.1 55-1.1.5.1.2 57-1.1.5.1.2.2.1 58-1.1.5.1.2.2 (c / contrast-01~e.1 :ARG2 (i / induce-01~e.24 :ARG0 (i2 / include-91 :ARG2 (p / protein~e.23 :name (n / name :op1 "ETS"~e.22,48) :ARG0-of (c2 / cause-01~e.21 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.21)))) :ARG3 (n3 / none~e.18)) :ARG2 (m / migrate-01~e.27 :ARG0 (c3 / cell~e.16,26) :ARG1-of (a / add-02)) :time~e.3 (o / overexpress-01 :ARG1 (p2 / protein~e.7 :name (n4 / name :op1 "ETS"~e.6,48) :ARG1-of (s / same-01~e.5)) :location (c4 / cell-line :name (n5 / name :op1 "RWPE-KRAS"~e.13,15))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.29 :mod "2C") :op2 (f2 / file~e.36 :mod 2~e.31,38 :part (f3 / figure~e.41 :mod "S2"~e.42)))) :ARG0-of (s2 / suggest-01~e.45 :ARG1 (f4 / function-01~e.53 :ARG0 (a3 / and~e.50 :op1 p2~e.49 :op2 (e / enzyme :name (n6 / name :op1 "KRAS"~e.51))) :ARG1 (a4 / activate-01~e.55 :ARG0 a3 :ARG1 (p3 / pathway~e.58 :ARG1-of s~e.57)))))) # ::id pmid_2464_2271.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings are consistent with our model that oncogenic ETS proteins can mimic RAS activation in cell lines lacking RAS activity , and are distinct from ETS proteins expressed in normal prostate . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1.2.2.2.1.r 3-1 4-1.2.r 5-1.2.1 5-1.2.1.r 6-1.2 7-1.2.2.r 8-1.2.2.1.1.1.2 8-1.2.2.1.1.1.2.1.2.1 9-1.2.2.1.1.1.1.1 10-1.2.2.1.1.1 11-1.2.2.1 12-1.2.2.1.1 13-1.2.2.1.1.2.1.1.1 14-1.2.2.1.1.2 15-1.2.2.1.2.r 16-1.2.2.1.2 17-1.2.2.1.2 18-1.2.2.1.2.1 19-1.2.2.1.2.1.1.1 20-1.2.2.1.2.1.1 22-1.2.2 23-1.2.2.2.1.r 24-1.2.2.2 25-1.2.2.2.2.r 26-1.2.2.2.2.1.1 27-1.2.2.2.2 28-1.2.2.2.2.2 29-1.2.2.2.2.2.1.r 30-1.2.2.2.2.2.1.1 31-1.2.2.2.2.2.1 (c / consistent-01~e.3 :ARG1 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :mod (t2 / this~e.0)) :ARG2~e.4 (m / model-01~e.6 :ARG0~e.5 (w / we~e.5) :ARG1~e.7 (a / and~e.22 :op1 (p / possible-01~e.11 :ARG1 (m2 / mimic-01~e.12 :ARG0 (p2 / protein~e.10 :name (n / name :op1 "ETS"~e.9) :ARG0-of (c2 / cause-01~e.8 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.8)))) :ARG1 (a2 / activate-01~e.14 :ARG1 (e / enzyme :name (n3 / name :op1 "RAS"~e.13)))) :location~e.15 (c3 / cell-line~e.16,17 :ARG0-of (l / lack-01~e.18 :ARG1 (a3 / activity-06~e.20 :ARG0 e~e.19)))) :op2 (d2 / distinct~e.24 :domain~e.2,23 p2 :compared-to~e.25 (p3 / protein~e.27 :name (n4 / name :op1 "ETS"~e.26) :ARG2-of (e2 / express-03~e.28 :ARG3~e.29 (p4 / prostate~e.31 :ARG1-of (n5 / normal-02~e.30)))))))) # ::id pmid_2464_2271.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A role for the PI3K @/@ AKT pathway in oncogenic ETS function # ::alignments 2-1 3-1.1.r 5-1.1.2.1 7-1.1.2.1 8-1.1 9-1.2.r 10-1.2.1 10-1.2.1.3 10-1.2.1.3.1.2.1 10-1.2.1.3.r 11-1.2.1.2.1 12-1.2 (r / role~e.2 :poss~e.3 (p / pathway~e.8 :wiki "Akt/PKB_signaling_pathway" :name (n / name :op1 "PI3K/AKT"~e.5,7)) :topic~e.9 (f / function-01~e.12 :ARG0 (p2 / protein~e.10 :wiki "ETS_transcription_factor_family" :name (n2 / name :op1 "ETS"~e.11) :ARG0-of~e.10 (c / cause-01~e.10 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.10)))))) # ::id pmid_2464_2271.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To identify signaling pathways required for the oncogenic function of ETS factors , a microarray analysis of ETV4 knockdown in PC3 prostate cancer cells [ @ 25 @ ] was compared to the Connectivity Map database [ @ 29 @ ] that contains microarray data of PC3 cells treated with 1309 small molecules , including many signaling pathway inhibitors . # ::alignments 0-1.3.1.2.1.2 1-1.3 2-1.3.1.1 3-1.3.1 4-1.3.1.2 5-1.3.1.2.1.r 7-1.3.1.2.1.2 7-1.3.1.2.1.2.1.2.1 8-1.3.1.2.1 9-1.3.1.2.1.1.r 10-1.3.1.2.1.1.1.1.1 11-1.3.1.2.1.1 14-1.1.2 15-1.1 18-1.1.1.1.1.1 20-1.1.1 21-1.1.1.2.r 22-1.1.1.2.1.1 23-1.1.1.2.2.2.1 24-1.1.1.2.2.2.2 25-1.1.1.2 28-1.1.3.1.1.1 32-1 33-1.2.r 33-1.3.1.2.1.2 35-1.2.1.1 36-1.2.1.2 37-1.2 40-1.2.2.1.1.1 44-1.2.3 45-1.1.2 46-1.2.3.1 47-1.2.3.1.2.r 48-1.2.3.1.2.1.1 49-1.2.3.1.2 50-1.2.3.1.2.2 51-1.2.3.1.2.2.1.r 52-1.2.3.1.2.2.1.1 53-1.2.3.1.2.2.1 54-1.2.3.1.2.2.1 54-1.2.3.1.2.2.1.2.1 56-1.2.3.1.2.2.1.2 57-1.2.3.1.2.2.1.2.1.2 58-1.2.3.1.2.2.1.2.1.1.1.1 59-1.2.3.1.2.2.1.2.1.1.1 60-1.2.3.1.2.2.1.2.1.1 (c / compare-01~e.32 :ARG1 (a / analyze-01~e.15 :ARG1 (k / knock-down-02~e.20 :ARG1 (g / gene :name (n / name :op1 "ETV4"~e.18)) :location~e.21 (c2 / cell-line~e.25 :name (n2 / name :op1 "PC3"~e.22) :mod (d / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate"~e.23 :op2 "cancer"~e.24)))) :mod (m / microarray~e.14,45) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 25~e.28)))) :ARG2~e.33 (d3 / database~e.37 :name (n4 / name :op1 "Connectivity"~e.35 :op2 "Map"~e.36) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 29~e.40))) :ARG0-of (c5 / contain-01~e.44 :ARG1 (d5 / data~e.46 :mod m :topic~e.47 (c6 / cell-line~e.49 :name (n5 / name :op1 "PC3"~e.48) :ARG1-of (t / treat-04~e.50 :ARG2~e.51 (s / small-molecule~e.53,54 :quant 1309~e.52 :ARG2-of (i / include-91~e.56 :ARG1 (m2 / molecular-physical-entity~e.54 :ARG0-of (i2 / inhibit-01~e.60 :ARG1 (p4 / pathway~e.59 :ARG0-of (s2 / signal-07~e.58))) :quant (m3 / many~e.57))))))))) :purpose (i3 / identify-01~e.1 :ARG1 (p5 / pathway~e.3 :ARG0-of s2~e.2 :ARG1-of (r / require-01~e.4 :ARG0~e.5 (f / function-01~e.8 :ARG0~e.9 (f2 / factor~e.11 :mod (p6 / protein :name (n6 / name :op1 "ETS"~e.10))) :ARG0-of (c7 / cause-01~e.0,7,33 :ARG1 (d6 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"~e.7)))))))) # ::id pmid_2464_2271.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarities between the gene expression profile of a signaling pathway inhibitor and ETV4 knockdown would predict a role for that pathway in oncogenic ETS function . # ::alignments 0-1.1 3-1.1.1.1.1 4-1.1.1.1 5-1.1.1 6-1.1.1.2.r 8-1.1.1.2.1.1.1 9-1.1.1.2.1.1 10-1.1.1.2 10-1.1.1.2.1 10-1.1.1.2.1.r 13-1.1.2.1.1.1 15-1.1.2 17-1 19-1.2 22-1.2.1 23-1.2.2.r 24-1.2.2.1 24-1.2.2.1.2 24-1.2.2.1.2.1.2.1 24-1.2.2.1.2.r 25-1.2.2.1.1.1 26-1.2.2 (p / predict-01~e.17 :ARG0 (r / resemble-01~e.0 :ARG1 (p2 / profile-01~e.5 :ARG0 (e / express-03~e.4 :ARG1 (g / gene~e.3)) :ARG1~e.6 (m / molecular-physical-entity~e.10 :ARG0-of~e.10 (i / inhibit-01~e.10 :ARG1 (p3 / pathway~e.9 :ARG0-of (s / signal-07~e.8))))) :ARG2 (k / knock-down-02~e.15 :ARG1 (g2 / gene :name (n / name :op1 "ETV4"~e.13)))) :ARG1 (r2 / role~e.19 :poss p3~e.22 :topic~e.23 (f / function-01~e.26 :ARG0 (p4 / protein~e.24 :name (n2 / name :op1 "ETS"~e.25) :ARG0-of~e.24 (c / cause-01~e.24 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.24))))))) # ::id pmid_2464_2271.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The top two , and three of the top five small molecules that induced gene expression changes most similar to ETV4 knockdown were inhibitors of either PI3K or mTOR , a downstream effector of PI3K ( Table 2 ) . # ::alignments 1-1.1.1.2 2-1.1.1.1 4-1.1 5-1.1.2.1 8-1.1.2.2.1.2 9-1.1.2.2.1.1 10-1.1.1 10-1.1.2 10-1.1.2.2.1 11-1 11-1.1.2.2.1 13-1.1.3 14-1.1.3.1.1.1 15-1.1.3.1.1 16-1.1.3.1 17-1.1.3.1.2.2 18-1.1.3.1.2 21-1.1.3.1.2.1.1.1.1 23-1.1.3.1.2.1 24-1.1.r 25-1.2 26-1.2.1.r 27-1.2.1.3 28-1.2.1.1.1.1 29-1.2.1 30-1.2.1.2.1.1 33-1.2.1.2.2.2 34-1.2.1.2.2 35-1.2.1.2.2.1.r 36-1.2.1.2.2.1 38-1.3.1 40-1.3.1.1 (m / molecular-physical-entity~e.11 :domain~e.24 (a / and~e.4 :op1 (s / small-molecule~e.10 :quant 2~e.2 :ARG0-of (t / top-02~e.1)) :op2 (s2 / small-molecule~e.10 :quant 3~e.5 :ARG1-of (i / include-91 :ARG2 (s3 / small-molecule~e.10,11 :quant 5~e.9 :ARG0-of t~e.8))) :ARG0-of (i2 / induce-01~e.13 :ARG2 (c / change-01~e.16 :ARG1 (e / express-03~e.15 :ARG1 (g / gene~e.14)) :ARG1-of (r / resemble-01~e.18 :ARG2 (k / knock-down-02~e.23 :ARG1 (g2 / gene :name (n / name :op1 "ETV4"~e.21))) :degree (m2 / most~e.17))))) :ARG0-of (i3 / inhibit-01~e.25 :ARG1~e.26 (o / or~e.29 :op1 (p2 / protein-family :name (n2 / name :op1 "PI3K"~e.28)) :op2 (p / protein :name (n3 / name :op1 "mTOR"~e.30) :mod (e3 / effector~e.34 :poss~e.35 p2~e.36 :location (d / downstream~e.33))) :mod (e4 / either~e.27))) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table~e.38 :mod 2~e.40))) # ::id pmid_2464_2271.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data suggest that in PC3 cells , PI3K and ETV4 activate a similar gene expression program . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2.r 5-1.2.3.1.1 6-1.2.3 8-1.2.1.1.1.1 9-1.2.1 10-1.2.1.2.1.1 11-1.2 13-1.2.2.2 14-1.2.2.1.1 15-1.2.2.1 16-1.2.2 (s / suggest-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.4 (a / activate-01~e.11 :ARG0 (a2 / and~e.9 :op1 (e / enzyme :name (n / name :op1 "PI3K"~e.8)) :op2 (p / protein :name (n2 / name :op1 "ETV4"~e.10))) :ARG1 (p2 / program-01~e.16 :ARG1 (e2 / express-03~e.15 :ARG1 (g / gene~e.14)) :ARG1-of (r / resemble-01~e.13)) :location (c / cell-line~e.6 :name (n3 / name :op1 "PC3"~e.5)))) # ::id pmid_2464_2271.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test if the PI3K pathway is required for an oncogenic ETS protein to promote the cell migration phenotype , RWPE @-@ ERG and RWPE @-@ KRAS cells were treated with the PI3K inhibitor , LY294002 . # ::alignments 1-1.3 4-1.3.1.3.1.1 5-1.3.1.3 7-1.3.1 8-1.3.1.2.r 10-1.3.1.2.1.2 10-1.3.1.2.1.2.1.2.1 11-1.3.1.2.1.1.1 12-1.3.1.2.1 13-1.3.1.2.1.2 14-1.3.1.2 16-1.3.1.2.2.1.1 17-1.3.1.2.2.1 18-1.3.1.2.2 20-1.1.1.1.1 20-1.1.2.1.1 22-1.1.1.1.1 23-1.1 24-1.1.1.1.1 24-1.1.2.1.1 26-1.1.2.1.1 27-1.1.1 27-1.1.2 29-1 30-1.2.r 32-1.2.2.1.1.1 33-1.2 33-1.2.2 33-1.2.2.r 35-1.2.1.1 (t / treat-04~e.29 :ARG1 (a / and~e.23 :op1 (c / cell-line~e.27 :name (n / name :op1 "RWPE-ERG"~e.20,22,24)) :op2 (c2 / cell-line~e.27 :name (n2 / name :op1 "RWPE-KRAS"~e.20,24,26))) :ARG2~e.30 (s / small-molecule~e.33 :name (n3 / name :op1 "LY294002"~e.35) :ARG0-of~e.33 (i / inhibit-01~e.33 :ARG1 (e / enzyme :name (n4 / name :op1 "PI3K"~e.32)))) :purpose (t2 / test-01~e.1 :ARG1 (r / require-01~e.7 :mode interrogative :ARG0~e.8 (p / promote-01~e.14 :ARG0 (p2 / protein~e.12 :name (n5 / name :op1 "ETS"~e.11) :ARG0-of (c3 / cause-01~e.10,13 :ARG1 (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.10)))) :ARG1 (p3 / phenotype~e.18 :mod (m / migrate-01~e.17 :ARG0 (c4 / cell~e.16)))) :ARG1 (p4 / pathway~e.5 :name (n7 / name :op1 "PI3K"~e.4))))) # ::id pmid_2464_2271.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok LY294002 reduced AKT phosphorylation in both lines , consistent with PI3K inhibition ( Figure 3 @ A ) . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1.1 3-1.2 4-1.3.r 5-1.3.1 6-1.3 8-1.4 9-1.4.1.r 10-1.4.1.1.1.1 11-1.4.1 13-1.5.1 (r / reduce-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "LY294002"~e.0)) :ARG1 (p / phosphorylate-01~e.3 :ARG2 (e / enzyme :name (n2 / name :op1 "AKT"~e.2))) :location~e.4 (c / cell-line~e.6 :mod (b / both~e.5)) :ARG1-of (c2 / consistent-01~e.8 :ARG2~e.9 (i / inhibit-01~e.11 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PI3K"~e.10)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.13 :mod "3A"))) # ::id pmid_2464_2271.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Strikingly , PI3K inhibition completely abrogated cell migration induced by ERG , but not cell migration induced by KRAS ( Figure 3 @ B and Additional file 2 @ : Figure S2 ) . # ::alignments 0-1.3 2-1.1.1.1.1.1 3-1.1.1 4-1.1.3 5-1.1 5-1.2 6-1.1.2.1 7-1.1.2 7-1.2.3 8-1.1.2.2 8-1.2.3.2 10-1.1.2.2.1.1.1 12-1 13-1.2.1 13-1.2.1.r 14-1.1.2.1 15-1.1.2 16-1.1.2.2 17-1.2.3.2.1.r 18-1.2.3.2.1.1.1 20-1.4.1.1 25-1.4.1 27-1.4.1.2 29-1.4.1.2.1 32-1.4.1.2.3 33-1.4.1.2.3.1 (c / contrast-01~e.12 :ARG1 (a / abrogate-01~e.5 :ARG0 (i / inhibit-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "PI3K"~e.2))) :ARG1 (m / migrate-01~e.7,15 :ARG0 (c2 / cell~e.6,14) :ARG2-of (i2 / induce-01~e.8,16 :ARG0 (p / protein :name (n2 / name :op1 "ERG"~e.10)))) :ARG1-of (c3 / complete-01~e.4)) :ARG2 (a2 / abrogate-01~e.5 :polarity~e.13 -~e.13 :ARG0 i :ARG1 (m2 / migrate-01~e.7 :ARG0 c2 :ARG2-of (i3 / induce-01~e.8 :ARG0~e.17 (e2 / enzyme :name (n3 / name :op1 "KRAS"~e.18))))) :ARG1-of (s / strike-04~e.0) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.25 :op1 (f / figure~e.20 :mod "3B") :op2 (f2 / file~e.27 :mod 2~e.29 :ARG1-of (a4 / add-02) :part (f3 / figure~e.32 :mod "S2"~e.33))))) # ::id pmid_2464_2271.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In fact RWPE @-@ KRAS cells actually migrated more when PI3K was inhibited . # ::alignments 0-1.5 1-1.5 2-1.1.1.1 4-1.1.1.1 5-1.1 6-1.4 7-1 8-1.2 9-1.3.r 10-1.3.1.1.1 12-1.3 (m / migrate-01~e.7 :ARG0 (c / cell-line~e.5 :name (n / name :op1 "RWPE-KRAS"~e.2,4)) :degree (m2 / more~e.8) :time~e.9 (i / inhibit-01~e.12 :ARG1 (e / enzyme :name (n2 / name :op1 "PI3K"~e.10))) :ARG1-of (a / actual-02~e.6) :mod (i2 / in-fact~e.0,1)) # ::id pmid_2464_2271.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This increased migration may be due to relief of RAF inhibition by AKT [ @ 9 @ ] , as RWPE @-@ KRAS cells had higher pMEK levels after treatment by LY294002 ( Figure 3 @ A ) . # ::alignments 0-1.2.1.2.2 1-1.2.1.2.1 2-1.2.1.2 3-1.2 5-1 5-1.2.1 6-1.2.1 7-1.2.1.1 8-1.2.1.1.1.r 9-1.2.1.1.1.2.1.1 10-1.2.1.1.1 11-1.2.1.1.1.1.r 12-1.2.1.1.1.1.1.1 15-1.2.2.1.1.1 19-1.1.3.r 20-1.1.1.1.1 22-1.1.1.1.1 23-1.1.1 24-1.1 25-1.1.2.2 25-1.1.2.2.1 25-1.1.2.2.1.r 27-1.1.2 28-1.1.3 29-1.1.3.1 30-1.1.3.1.1.r 31-1.1.3.1.1.1.1 33-1.3.1 (c / cause-01~e.5 :ARG0 (h / have-03~e.24 :ARG0 (c2 / cell-line~e.23 :name (n / name :op1 "RWPE-KRAS"~e.20,22)) :ARG1 (l / level~e.27 :quant-of (e / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p / phosphorylate-01)) :ARG1-of (h2 / high-02~e.25 :degree~e.25 (m / more~e.25))) :time~e.19 (a / after~e.28 :op1 (t / treat-04~e.29 :ARG2~e.30 (s / small-molecule :name (n3 / name :op1 "LY294002"~e.31))))) :ARG1 (p2 / possible-01~e.3 :ARG1 (c3 / cause-01~e.5,6 :ARG0 (r / relieve-01~e.7 :ARG1~e.8 (i / inhibit-01~e.10 :ARG0~e.11 (e2 / enzyme :name (n4 / name :op1 "AKT"~e.12)) :ARG1 (e3 / enzyme :name (n5 / name :op1 "RAF"~e.9)))) :ARG1 (m2 / migrate-01~e.2 :ARG1-of (i2 / increase-01~e.1) :mod (t2 / this~e.0))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 9~e.15)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.33 :mod "3A"))) # ::id pmid_2464_2271.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To confirm the role of PI3K , a second PI3K inhibitor , ZSTK474 , was also tested ( Figures 3 @ A and 3 @ B ) . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1 8-1.1.2.1.2 8-1.1.2.1.2.1 8-1.1.2.1.2.1.r 9-1.1.2.1.1.1 10-1.1.2.1 10-1.1.2.1.1 10-1.1.2.1.1.r 12-1.1.1.1 15-1.2 16-1 18-1.4.1.1 18-1.4.1.2 23-1.4.1 (t3 / test-01~e.16 :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474"~e.12) :ARG1-of (m / mean-01 :ARG2 (m2 / molecular-physical-entity~e.10 :ARG0-of~e.10 (i2 / inhibit-01~e.10 :ARG1 p~e.9) :ord (o / ordinal-entity~e.8 :value~e.8 2~e.8)))) :mod (a / also~e.15) :purpose (c / confirm-01~e.1 :ARG1 (r / role~e.3 :poss~e.4 (p / pathway :name (n2 / name :op1 "PI3K"~e.5)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.23 :op1 (f / figure~e.18 :mod "3A") :op2 (f2 / figure~e.18 :mod "3B")))) # ::id pmid_2464_2271.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Like LY294002 , ZSTK474 significantly reduced migration of RWPE @-@ ERG cells , but not RWPE @-@ KRAS cells . # ::alignments 0-1.1.3 1-1.1.3.1.1.1 3-1.1.1.1.1 4-1.1.4 5-1.1 5-1.2 6-1.1.2 6-1.2.3 7-1.1.2.1.r 8-1.1.2.1.1.1 10-1.1.2.1.1.1 11-1.1.2.1 11-1.2.3.1 13-1 14-1.2.1 14-1.2.1.r 15-1.2.3.1.1.1 17-1.2.3.1.1.1 18-1.1.2.1 (c / contrast-01~e.13 :ARG1 (r / reduce-01~e.5 :ARG0 (s / small-molecule :name (n2 / name :op1 "ZSTK474"~e.3)) :ARG1 (m / migrate-01~e.6 :ARG0~e.7 (c2 / cell-line~e.11,18 :name (n3 / name :op1 "RWPE-ERG"~e.8,10))) :ARG1-of (r2 / resemble-01~e.0 :ARG2 (s2 / small-molecule :name (n / name :op1 "LY294002"~e.1))) :ARG1-of (s3 / significant-02~e.4)) :ARG2 (r3 / reduce-01~e.5 :polarity~e.14 -~e.14 :ARG0 s :ARG1 (m2 / migrate-01~e.6 :ARG0 (c3 / cell-line~e.11 :name (n4 / name :op1 "RWPE-KRAS"~e.15,17))))) # ::id pmid_2464_2271.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell migration induced by other oncogenic ETS factors , ETV1 , and ETV5 , was also abrogated by PI3K inhibition ( Figure 3 @ C and Additional file 2 @ : Figure S2 ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.2 5-1.1.2.1.4 5-1.1.2.1.4.1.2.1 6-1.1.2.1.1.1.1 7-1.1.2.1 9-1.1.2.1.3.1.1.1.1 11-1.1.2.1.3.1 12-1.1.2.1.3.1.2.1.1 15-1.3 16-1 17-1.2.r 18-1.2.1.1.1 19-1.2 21-1.4.1.1 26-1.4.1 27-1.4.1.2.2 28-1.4.1.2 30-1.4.1.2.1 33-1.4.1.2.3 34-1.4.1.2.3.1 (a / abrogate-01~e.16 :ARG1 (m / migrate-01~e.1 :ARG0 (c2 / cell~e.0) :ARG2-of (i / induce-01~e.2 :ARG0~e.3 (f / factor~e.7 :mod (p4 / protein :name (n / name :op1 "ETS"~e.6)) :mod (o / other~e.4) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.11 :op1 (p2 / protein :name (n3 / name :op1 "ETV1"~e.9)) :op2 (p / protein :name (n2 / name :op1 "ETV5"~e.12)))) :ARG0-of (c3 / cause-01~e.5 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.5)))))) :ARG2~e.17 (i2 / inhibit-01~e.19 :ARG1 (e / enzyme :name (n4 / name :op1 "PI3K"~e.18))) :mod (a3 / also~e.15) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.26 :op1 (f2 / figure~e.21 :mod "3C") :op2 (f3 / file~e.28 :mod 2~e.30 :mod (a5 / additional~e.27) :location-of (f4 / figure~e.33 :mod "S2"~e.34))))) # ::id pmid_2464_2271.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A second cell migration assay , the scratch assay , confirmed that PI3K inhibition reduced migration caused by ERG expression , but not migration caused by KRAS ( Figure 3 @ D and Additional file 3 @ : Figure S3 ) . # ::alignments 1-1.1.3 1-1.1.3.1 1-1.1.3.1.r 2-1.1.1.1 3-1.1.1 4-1.1 7-1.1.2.1.1 8-1.1.2.1 10-1 11-1.2.r 12-1.2.1.1.1.1.1 13-1.2.1.1 14-1.2.1 14-1.2.2 15-1.2.1.2 15-1.2.2.3 16-1.2.1.2.1 16-1.2.2.3.1 18-1.2.1.2.1.1.1.1.1 19-1.2.1.2.1.1 21-1.2 22-1.2.2.1 22-1.2.2.1.r 23-1.2.1.2 24-1.2.1.2.1 25-1.2.2.3.1.1.r 26-1.2.2.3.1.1.1.1 28-1.3.1.1 30-1.3.1.2.1 35-1.3.1.2 37-1.3.1.2.1 40-1.3.1.2.2 41-1.3.1.2.2.1 (c / confirm-01~e.10 :ARG0 (a3 / assay-01~e.4 :ARG1 (m2 / migrate-01~e.3 :ARG0 (c2 / cell~e.2)) :ARG1-of (m3 / mean-01 :ARG2 (a4 / assay-01~e.8 :mod (s / scratch-02~e.7))) :ord (o / ordinal-entity~e.1 :value~e.1 2~e.1)) :ARG1~e.11 (c3 / contrast-01~e.21 :ARG1 (r2 / reduce-01~e.14 :ARG0 (i / inhibit-01~e.13 :ARG1 (e2 / enzyme :name (n / name :op1 "PI3K"~e.12))) :ARG1 (m4 / migrate-01~e.15,23 :ARG1-of (c4 / cause-01~e.16,24 :ARG0 (e / express-03~e.19 :ARG2 (p / protein :name (n2 / name :op1 "ERG"~e.18)))))) :ARG2 (r / reduce-01~e.14 :polarity~e.22 -~e.22 :ARG0 i :ARG1 (m5 / migrate-01~e.15 :ARG1-of (c6 / cause-01~e.16 :ARG0~e.25 (g / gene :name (n3 / name :op1 "KRAS"~e.26)))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure~e.28 :mod "3D") :op2 (f2 / file~e.35 :mod 3~e.30,37 :location-of (f3 / figure~e.40 :mod "S3"~e.41))))) # ::id pmid_2464_2271.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok An AKT inhibitor had a similar effect ( Figure 3 @ D and Additional file 3 @ : Figure S3 ) , indicating that PI3K is functioning via AKT activation . # ::alignments 1-1.1.1.1 2-1.1 2-1.1.1 2-1.1.1.r 5-1.3 6-1 8-1.4.1.1 10-1.4.1.2.1 14-1.4.1.2.2 15-1.4.1.2 17-1.4.1.2.1 20-1.4.1.2.3 21-1.4.1.2.3.1 24-1.2 25-1.2.1.r 26-1.2.1.1.1.1 28-1.2.1 30-1.2.1.2.1.1.1 31-1.2.1.2 (a / affect-02~e.6 :ARG0 (m / molecular-physical-entity~e.2 :ARG0-of~e.2 (i / inhibit-01~e.2 :ARG1 e~e.1)) :ARG0-of (i2 / indicate-01~e.24 :ARG1~e.25 (f / function-01~e.28 :ARG0 (p / pathway :name (n2 / name :op1 "PI3K"~e.26)) :instrument (a2 / activate-01~e.31 :ARG1 (e / enzyme :name (n / name :op1 "AKT"~e.30))))) :ARG1-of (r / resemble-01~e.5) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f2 / figure~e.8 :mod "3D") :op2 (f3 / file~e.15 :mod 3~e.10,17 :mod (a4 / additional~e.14) :part-of (f4 / figure~e.20 :mod "S3"~e.21))))) # ::id pmid_2464_2271.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that overexpression of an oncogenic ETS gene can switch the control of prostate cell migration from the RAS @/@ ERK pathway to the PI3K @/@ AKT pathway . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1 5-1.2.1.1.1.r 7-1.2.1.1.1.2 7-1.2.1.1.1.2.1.2.1 8-1.2.1.1.1.1.1 9-1.2.1.1.1 10-1.2 11-1.2.1 13-1.2.1.2 14-1.2.1.2.1.r 15-1.2.1.2.1.1.1 16-1.2.1.2.1.1 17-1.2.1.2.1 18-1.2.1.2.1.1.1.r 20-1.2.1.4.1.1 22-1.2.1.4.1.1 23-1.2.1.3 23-1.2.1.4 26-1.2.1.3.1.1 28-1.2.1.3.1.1 29-1.2.1.3 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (p2 / possible-01~e.10 :ARG1 (s / switch-01~e.11 :ARG0 (o / overexpress-01~e.4 :ARG1~e.5 (g / gene~e.9 :name (n2 / name :op1 "ETS"~e.8) :ARG0-of (c4 / cause-01~e.7 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.7))))) :ARG1 (c / control-01~e.13 :ARG1~e.14 (m / migrate-01~e.17 :ARG1 (c3 / cell~e.16 :source~e.18 (p3 / prostate~e.15)))) :ARG2 (p5 / pathway~e.23,29 :name (n4 / name :op1 "PI3K/AKT"~e.26,28)) :ARG3 (p4 / pathway~e.23 :name (n3 / name :op1 "RAS/ERK"~e.20,22))))) # ::id pmid_2464_2271.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next tested if the PI3K pathway was regulating the ability of ERG to activate the transcription of RAS @- and ERG @-@ responsive target genes near enhancers that are co @-@ occupied by ETS and AP @-@ 1 proteins . # ::alignments 0-1.1 1-1.3 2-1 5-1.2.2.1.1 6-1.2.2 8-1.2 10-1.2.3 11-1.2.3.2.r 12-1.2.3.2.1 14-1.2.3.2 16-1.2.3.2.2 17-1.2.3.2.2.1.r 18-1.2.3.2.2.1.1.1.1.1.1 20-1.2.3.2.2.1 21-1.2.3.1.1.1 23-1.2.3.2.2.1.1.1 23-1.2.3.2.2.1.2.1 24-1.2.3.2.2.1.3 25-1.2.3.2.2.1.1 25-1.2.3.2.2.1.2 26-1.2.3.2.3 32-1.2.3.2.3.1.2 33-1.2.3.2.3.1.2.1.r 34-1.2.3.2.3.1.2.1.1.1.1 35-1.2.3.2.3.1.2.1 36-1.2.3.2.3.1.2.1.2.1.1 38-1.2.3.2.3.1.2.1.2.1.1 39-1.2.3.1 39-1.2.3.2.3.1.2.1.1 39-1.2.3.2.3.1.2.1.2 (t / test-01~e.2 :ARG0 (w / we~e.0) :ARG1 (r / regulate-01~e.8 :mode interrogative :ARG0 (p / pathway~e.6 :name (n3 / name :op1 "PI3K"~e.5)) :ARG1 (c / capable-01~e.10 :ARG1 (p2 / protein~e.39 :name (n4 / name :op1 "ERG"~e.21)) :ARG2~e.11 (a / activate-01~e.14 :ARG0 p2~e.12 :ARG1 (t2 / transcribe-01~e.16 :ARG1~e.17 (a2 / and~e.20 :op1 (g / gene~e.25 :ARG0-of (r2 / responsive-02~e.23 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.18)))) :op2 (g2 / gene~e.25 :ARG0-of (r3 / responsive-02~e.23 :ARG1 p2)) :ARG1-of (t3 / target-01~e.24))) :ARG1-of (n6 / near-01~e.26 :ARG2 (m / molecular-physical-entity :ARG0-of (e3 / enhance-01) :ARG1-of (o / occupy-01~e.32 :ARG0~e.33 (a3 / and~e.35 :op1 (p3 / protein~e.39 :name (n7 / name :op1 "ETS"~e.34)) :op2 (p4 / protein~e.39 :name (n8 / name :op1 "AP-1"~e.36,38))))))))) :time (n2 / next~e.1)) # ::id pmid_2464_2271.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The expression levels of two such genes , ARHGAP29 , and SMAD3 , were measured by quantitative reverse transcription PCR ( qRT @-@ PCR ) ( Figure 4 @ A and B ) . # ::alignments 1-1.1.1 2-1.1 3-1.1.1.1.r 4-1.1.1.1.1 5-1.1.1.1.4 6-1.1.1.1.2 6-1.1.1.1.3 9-1.1.1.1.2.1.1 12-1.1.1.1 14-1.1.1.1.3.1.1 18-1 20-1.1.1.1.1.r 23-1.2 23-1.2.1 23-1.2.1.r 23-1.2.2 23-1.2.2.r 27-1.2 27-1.2.1 27-1.2.1.r 27-1.2.2 27-1.2.2.r 30-1.3.1.1 30-1.3.1.2 35-1.3.1 (m / measure-01~e.18 :ARG1 (l / level~e.2 :degree-of (e / express-03~e.1 :ARG1~e.3 (a2 / and~e.12 :quant~e.20 2~e.4 :op1 (g / gene~e.6 :name (n2 / name :op1 "ARHGAP29"~e.9)) :op2 (g2 / gene~e.6 :name (n3 / name :op1 "SMAD3"~e.14)) :mod (s / such~e.5)))) :ARG2 (r / react-01~e.23,27 :ARG0~e.23,27 (p / polymerase~e.23,27) :ARG1-of~e.23,27 (c / chain-01~e.23,27)) :ARG1-of (d / describe-01 :ARG0 (a / and~e.35 :op1 (f / figure~e.30 :mod "4A") :op2 (f2 / figure~e.30 :mod "4B")))) # ::id pmid_2464_2271.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both ARHGAP29 and SMAD3 have roles in cell migration and @/@ or cell morphology [ @ 30 , 31 @ ] , are direct targets of oncogenic ETS proteins and AP @-@ 1 by ChIP @-@ seq [ @ 15 @ ] , and are activated by KRAS and oncogenic ETS expression ( Figure 4 @ A and B ) . # ::alignments 2-1.1.1.1.1.1 6-1.1.1.2.1.1 8-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1 12-1.1.2.1.1 15-1.1.2.1 16-1.1.2.1.2.1 17-1.1.2.1.2 20-1.1.3.1.1.1.1 24-1.1.3.1.1.1.2 29-1.2.5 30-1.2 31-1.2.1.r 32-1.2.1.3 32-1.2.1.3.1.2.1 33-1.2.1.1.1.1 34-1.2.1.1 34-1.2.1.2 35-1.2.1 36-1.2.1.2.1.1 38-1.2.1.2.1.1 39-1.2.3.r 40-1.2.3.1.1 42-1.2.3.1.1 45-1.2.4.1.1.1 49-1 51-1.3 52-1.3.1.r 53-1.3.1.1.1.1.1 54-1.2.1 54-1.3.1 54-1.4.1 55-1.2.1.3 55-1.2.1.3.1.2.1 56-1.2.1.1.1.1 56-1.3.1.2.1.1.1 57-1.3.1.1 57-1.3.1.2 59-1.4.1.1 59-1.4.1.2 64-1.4.1 (a / and~e.49 :op1 (h / have-03~e.8 :ARG0 (a4 / and :op1 (g2 / gene :name (n2 / name :op1 "ARHGAP29"~e.2)) :op2 (g / gene :name (n / name :op1 "SMAD3"~e.6))) :ARG1 (r / role~e.9 :topic~e.10 (o / or~e.15 :op1 (m / migrate-01~e.12 :ARG0 (c / cell~e.11)) :op2 (m2 / morphology~e.17 :mod c~e.16))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 (a6 / and :op1 30~e.20 :op2 31~e.24))))) :op2 (t / target-01~e.30 :ARG0~e.31 (a7 / and~e.35,54 :op1 (p2 / protein~e.34 :name (n3 / name :op1 "ETS"~e.33,56)) :op2 (p3 / protein~e.34 :name (n4 / name :op1 "AP-1"~e.36,38)) :ARG0-of (c4 / cause-01~e.32,55 :ARG1 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.32,55)))) :ARG1 a4 :ARG2~e.39 (t2 / thing :name (n5 / name :op1 "ChIP-seq"~e.40,42)) :ARG1-of (d4 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 15~e.45))) :ARG1-of (d3 / direct-02~e.29)) :op3 (a3 / activate-01~e.51 :ARG0~e.52 (a8 / and~e.54 :op1 (e / express-03~e.57 :ARG1 (g3 / gene :name (n7 / name :op1 "KRAS"~e.53))) :op2 (e2 / express-03~e.57 :ARG1 (g4 / gene :name (n6 / name :op1 "ETS"~e.56) :ARG0-of c4))) :ARG1 a4) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.54,64 :op1 (f / figure~e.59 :mod "4A") :op2 (f2 / figure~e.59 :mod "4b")))) # ::id pmid_2464_2271.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar to the cell migration phenotype , the activation of both genes was significantly attenuated by PI3K inhibition in RWPE @-@ ERG cells , but not in RWPE @-@ KRAS cells ( Figure 4 @ A and B ) . # ::alignments 0-1.4 1-1.4.1.r 3-1.4.1.1.1 4-1.4.1.1 5-1.4.1 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.1 11-1.1.2.1 13-1.1.3 14-1.1 14-1.2 15-1.1.1.r 16-1.1.1.1.1.1 17-1.1.1 18-1.1.4.r 19-1.1.4.1.1 21-1.1.4.1.1 22-1.1.4 22-1.2.4 24-1 25-1.2.1 25-1.2.1.r 27-1.2.4.1.1 29-1.2.4.1.1 30-1.1.4 32-1.3.1.1 32-1.3.1.2 37-1.3.1 (c5 / contrast-01~e.24 :ARG1 (a4 / attenuate-01~e.14 :ARG0~e.15 (i / inhibit-01~e.17 :ARG1 (e / enzyme :name (n / name :op1 "PI3K"~e.16))) :ARG1 (a2 / activate-01~e.8 :ARG1~e.9 (g / gene~e.11 :mod (b / both~e.10))) :ARG1-of (s / significant-02~e.13) :location~e.18 (c2 / cell-line~e.22,30 :name (n2 / name :op1 "RWPE-ERG"~e.19,21))) :ARG2 (a5 / attenuate-01~e.14 :polarity~e.25 -~e.25 :ARG0 i :ARG1 a2 :location (c / cell-line~e.22 :name (n3 / name :op1 "RWPE-KRAS"~e.27,29))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.37 :op1 (f / figure~e.32 :mod "4A") :op2 (f2 / figure~e.32 :mod "4B"))) :ARG1-of (r / resemble-01~e.0 :ARG2~e.1 (p2 / phenotype~e.5 :mod (m / migrate-01~e.4 :ARG0 (c4 / cell~e.3))))) # ::id pmid_2464_2271.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore cell migration changes are consistent with changes in the expression of these two oncogenic ETS target genes . # ::alignments 0-1 1-1.1.1.1.1 2-1.1.1.1 3-1.1.1 5-1.1 6-1.1.2.r 7-1.1.2 8-1.1.2.1.r 10-1.1.2.1 11-1.1.2.1.1.r 12-1.1.2.1.1.2 13-1.1.2.1.1.1 14-1.1.2.1.1.3.1 14-1.1.2.1.1.3.1.2 14-1.1.2.1.1.3.1.2.1.2.1 14-1.1.2.1.1.3.1.2.r 15-1.1.2.1.1.3.1.1.1 16-1.1.2.1.1.3 17-1.1.2.1.1 (c6 / cause-01~e.0 :ARG1 (c / consistent-01~e.5 :ARG1 (c2 / change-01~e.3 :ARG1 (m / migrate-01~e.2 :ARG0 (c3 / cell~e.1))) :ARG2~e.6 (c4 / change-01~e.7 :ARG1~e.8 (e / express-03~e.10 :ARG1~e.11 (g / gene~e.17 :quant 2~e.13 :mod (t / this~e.12) :ARG1-of (t2 / target-01~e.16 :ARG0 (p / protein~e.14 :name (n / name :op1 "ETS"~e.15) :ARG0-of~e.14 (c7 / cause-01~e.14 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.14)))))))))) # ::id pmid_2464_2271.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that the PI3K @/@ AKT pathway functions through ERG to regulate expression of cell migration genes . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1.1.1 7-1.2.1.1.1 8-1.2.1 9-1.2 11-1.2.3.1.1 13-1.2.2 14-1.2.2.2 15-1.2.2.2.1.r 16-1.2.2.2.1.1.1 17-1.2.2.2.1.1 18-1.2.2.2.1 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (f / function-01~e.9 :ARG0 (p / pathway~e.8 :name (n / name :op1 "PI3K/AKT"~e.5,7)) :ARG1 (r2 / regulate-01~e.13 :ARG0 p :ARG1 (e / express-03~e.14 :ARG1~e.15 (g / gene~e.18 :mod (m / migrate-01~e.17 :ARG0 (c2 / cell~e.16))))) :instrument (p2 / protein :name (n2 / name :op1 "ERG"~e.11)))) # ::id pmid_2464_2271.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next used a reporter assay to test if these gene expression changes were mediated by the ETS @/@ AP @-@ 1 binding sequences we found in the enhancers of oncogenic ETS target genes . # ::alignments 0-1.1 1-1.4 2-1 4-1.2.1.1 5-1.2 7-1.3 10-1.2.1 11-1.3.2.3.1 12-1.3.2.3 14-1.3.2 15-1.3.2.2.r 17-1.3.2.2.1.1 19-1.3.2.2.1.1 21-1.3.2.2.1.1 22-1.3.2.2.2 24-1.3.2.2.3.1 25-1.3.2.2 25-1.3.2.2.3 25-1.3.2.2.3.r 29-1.3.2.2.3.2.r 30-1.3.2.2.3.2.1.1.1.1 30-1.3.2.2.3.2.1.1.1.1.2 30-1.3.2.2.3.2.1.1.1.1.2.1.2.1 30-1.3.2.2.3.2.1.1.1.1.2.r 31-1.3.2.2.3.2.1.1.1.1.1.1 32-1.3.2.2.3.2.1.1.1 33-1.3.2.2.3.2.1.1 (u / use-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / assay-01~e.5 :ARG1 (g / gene~e.10 :ARG0-of (r / report-01~e.4))) :ARG2 (t / test-01~e.7 :ARG0 w :ARG1 (m / mediate-01~e.14 :mode interrogative :ARG0~e.15 (p / protein-segment~e.25 :name (n2 / name :op1 "ETS/AP-1"~e.17,19,21) :ARG2-of (b2 / bind-01~e.22) :ARG1-of~e.25 (f / find-01~e.25 :ARG0 w~e.24 :location~e.29 (m2 / molecular-physical-entity :ARG0-of (e2 / enhance-01 :ARG1 (g2 / gene~e.33 :ARG1-of (t4 / target-01~e.32 :ARG0 (p4 / protein~e.30 :name (n3 / name :op1 "ETS"~e.31) :ARG0-of~e.30 (c3 / cause-01~e.30 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.30)))))))))) :ARG1 (c / change-01~e.12 :ARG1 (e / express-03~e.11 :ARG1 g2)))) :time (n / next~e.1)) # ::id pmid_2464_2271.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Three copies of an ETS @/@ AP @-@ 1 consensus sequence were cloned upstream of a minimal promoter driving firefly luciferase . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 4-1.1.2.1.1 6-1.1.2.1.1 8-1.1.2.1.1 9-1.1.2.2 12-1 13-1.2 14-1.2.1.r 16-1.2.1.1 17-1.2.1 17-1.2.1.2 17-1.2.1.2.r 18-1.2.1.3 19-1.2.1.3.1.1.1 20-1.2.1.3.1.1.2 (c / clone-01~e.12 :ARG1 (c2 / copy-01~e.1 :quant 3~e.0 :ARG1~e.2 (p2 / protein-segment :name (n / name :op1 "ETS/AP-1"~e.4,6,8) :mod (c3 / consensus~e.9))) :direction (u / upstream~e.13 :op1~e.14 (m2 / molecular-physical-entity~e.17 :ARG1-of (m / minimal-02~e.16) :ARG0-of~e.17 (p / promote-01~e.17) :ARG0-of (d / drive-02~e.18 :ARG1 (e / enzyme :name (n2 / name :op1 "firefly"~e.19 :op2 "luciferase"~e.20)))))) # ::id pmid_2464_2271.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Luciferase expression from this vector was higher when the ERK pathway was active , indicating that this pathway regulates the reporter construct ( Figure 4 @ C ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1 4-1.1.2 6-1 6-1.2 6-1.2.r 7-1.3.r 9-1.3.1.1.1 10-1.3.1 12-1.3 14-1.4 16-1.1.2.1 17-1.4.1.1 18-1.4.1 20-1.4.1.2.1 20-1.4.1.2.1.1 20-1.4.1.2.1.1.r 21-1.4.1.2 23-1.5.1 (h2 / high-02~e.6 :ARG1 (e2 / express-03~e.1 :ARG2 (l / luciferase~e.0) :ARG3~e.2 (v / vector~e.4 :mod (t / this~e.3,16))) :degree~e.6 (m / more~e.6) :time~e.7 (a / activity-06~e.12 :ARG0 (p / pathway~e.10 :name (n / name :op1 "ERK"~e.9))) :ARG0-of (i / indicate-01~e.14 :ARG1 (r / regulate-01~e.18 :ARG0 p~e.17 :ARG1 (c / construct-01~e.21 :ARG0 (g / gene~e.20 :ARG0-of~e.20 (r2 / report-01~e.20))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "4C"))) # ::id pmid_2464_2271.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Point mutations in either the ETS or AP @-@ 1 binding sequences completely eliminated luciferase expression indicating that both binding sites are required for activity ( Figure 4 @ C ) . # ::alignments 0-1.1.2 1-1.1 5-1.1.1.1.1.1.1.1 6-1.1.1 7-1.1.1.2.1.1.1.1 9-1.1.1.2.1.1.1.1 10-1.1.1.1.1 11-1.1.1.1 12-1.4 13-1 14-1.2.1 15-1.2 16-1.5 19-1.5.1.2 20-1.5.1.2 22-1.5.1 23-1.5.1.1.r 24-1.5.1.1 26-1.3.1 (e / eliminate-01~e.13 :ARG0 (m / mutate-01~e.1 :ARG1 (o / or~e.6 :op1 (d2 / dna-sequence~e.11 :ARG2-of (b2 / bind-01~e.10 :ARG1 (p2 / protein :name (n / name :op1 "ETS"~e.5)))) :op2 (p4 / protein-segment :ARG2-of (b / bind-01 :ARG1 (p3 / protein :name (n2 / name :op1 "AP-1"~e.7,9))))) :mod (p / point~e.0)) :ARG1 (e2 / express-03~e.15 :ARG2 (l / luciferase~e.14)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "4C")) :ARG1-of (c / complete-02~e.12) :ARG0-of (i / indicate-01~e.16 :ARG1 (r / require-01~e.22 :ARG0~e.23 (a / activity-06~e.24 :ARG0 o) :ARG1 o~e.19,20))) # ::id pmid_2464_2271.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The PI3K inhibitor , LY294002 , caused a significant decrease in the activity of this reporter in RWPE @-@ ERG cells ( Figure 4 @ D ) , but significantly increased activity in RWPE @-@ KRAS cells ( Figure 4 @ E ) , consistent with the cell migration findings . # ::alignments 1-1.1.1.2.1.1.1 2-1.1.1 2-1.1.1.2 2-1.1.1.2.r 4-1.1.1.1.1 6-1.1 8-1.1.2.2 9-1.1.2 10-1.1.2.1.r 12-1.1.2.1 13-1.1.2.1.1.r 14-1.1.2.1.1.2 15-1.1.2.1.1 15-1.1.2.1.1.1 15-1.1.2.1.1.1.r 16-1.1.2.1.2.r 17-1.1.2.1.2.1.1 19-1.1.2.1.2.1.1 20-1.1.2.1.2 22-1.1.3.1 22-1.2.4.1 29-1 30-1.2.5 31-1.2 32-1.2.2 33-1.2.2.2.r 34-1.2.2.2.1.1 36-1.2.2.2.1.1 37-1.2.2.2 39-1.2.4.1 46-1.2.3 47-1.2.3.1.r 49-1.2.3.1.1.1 50-1.2.3.1.1 51-1.2.3.1 (c / contrast-01~e.29 :ARG1 (c2 / cause-01~e.6 :ARG0 (s3 / small-molecule~e.2 :name (n2 / name :op1 "LY294002"~e.4) :ARG0-of~e.2 (i2 / inhibit-01~e.2 :ARG1 (p / protein-family :name (n / name :op1 "PI3K"~e.1)))) :ARG1 (d / decrease-01~e.9 :ARG1~e.10 (a / activity-06~e.12 :ARG0~e.13 (g / gene~e.15 :ARG0-of~e.15 (r / report-01~e.15) :mod (t / this~e.14)) :location~e.16 (c5 / cell-line~e.20 :name (n3 / name :op1 "RWPE-ERG"~e.17,19))) :ARG1-of (s / significant-02~e.8)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.22 :mod "4D"))) :ARG2 (i / increase-01~e.31 :ARG0 s3 :ARG1 (a2 / activity-06~e.32 :ARG0 g :location~e.33 (c6 / cell-line~e.37 :name (n4 / name :op1 "RWPE-KRAS"~e.34,36))) :ARG1-of (c3 / consistent-01~e.46 :ARG2~e.47 (f / find-01~e.51 :ARG1 (m / migrate-01~e.50 :ARG0 (c4 / cell~e.49)))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure~e.22,39 :mod "4E")) :ARG1-of s~e.30)) # ::id pmid_2464_2271.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , the PI3K pathway can alter the expression of cell migration genes via ETS @/@ AP @-@ 1 sites . # ::alignments 0-1 3-1.1.1.1.1.1 4-1.1.1.1 5-1.1 6-1.1.1 8-1.1.1.2 9-1.1.1.2.1.r 10-1.1.1.2.1.1.1 11-1.1.1.2.1.1 12-1.1.1.2.1 14-1.1.1.3.1.1 16-1.1.1.3.1.1 18-1.1.1.3.1.1 19-1.1.1.3 (c / cause-01~e.0 :ARG1 (p / possible-01~e.5 :ARG1 (a / alter-01~e.6 :ARG0 (p2 / pathway~e.4 :name (n / name :op1 "PI3K"~e.3)) :ARG1 (e / express-03~e.8 :ARG1~e.9 (g / gene~e.12 :mod (m / migrate-01~e.11 :ARG0 (c2 / cell~e.10)))) :instrument (p3 / protein-segment~e.19 :name (n2 / name :op1 "ETS/AP-1"~e.14,16,18))))) # ::id pmid_2464_2271.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The role of AKT in oncogenic ETS function is not via mTORC1 # ::alignments 2-1 3-1.1.r 4-1.1.1.1 5-1.2.r 6-1.2.1 6-1.2.1.2 6-1.2.1.2.1.2.1 6-1.2.1.2.r 7-1.2.1.1.1 8-1.2 10-1.3.1 10-1.3.1.r 12-1.3.2.1 (r / role~e.2 :poss~e.3 (e / enzyme :name (n / name :op1 "AKT"~e.4)) :topic~e.5 (f / function-01~e.8 :ARG0 (g / gene~e.6 :name (n2 / name :op1 "ETS"~e.7) :ARG0-of~e.6 (c2 / cause-01~e.6 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.6))))) :instrument (m2 / macro-molecular-complex :polarity~e.10 -~e.10 :name (n3 / name :op1 "mTORC1"~e.12))) # ::id pmid_2464_2271.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok PI3K @/@ AKT signaling has a number of cellular functions including the activation of the mTOR @-@ containing complexes mTORC1 and mTORC2 [ @ 8 @ ] . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 3-1.1 6-1.5 7-1.5.r 8-1.2 9-1 10-1.4 12-1.4.1 13-1.4.1.2.r 15-1.4.1.2.3.1.1.1 17-1.4.1.2.3 18-1.4.1.2.1 18-1.4.1.2.2 19-1.4.1.2.1.1.1 20-1.4.1.2 21-1.4.1.2.2.1.1 24-1.3.1.1.1 (f2 / function-01~e.9 :ARG0 (s / signal-07~e.3 :ARG0 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT"~e.0,2))) :ARG1 (c / cell~e.8) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 8~e.24))) :ARG1-of (i / include-91~e.10 :ARG2 (a / activate-01~e.12 :ARG0 p2 :ARG1~e.13 (a2 / and~e.20 :op1 (m2 / macro-molecular-complex~e.18 :name (n3 / name :op1 "mTORC1"~e.19)) :op2 (m3 / macro-molecular-complex~e.18 :name (n4 / name :op1 "mTORC2"~e.21)) :ARG0-of (c2 / contain-01~e.17 :ARG1 (p / protein :name (n / name :op1 "mTOR"~e.15)))))) :quant~e.7 (n5 / number~e.6)) # ::id pmid_2464_2271.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok mTORC1 includes the Raptor protein and regulates gene expression via translational control . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2.1.1 4-1.1.2 5-1 6-1.2 7-1.2.2.1 8-1.2.2 10-1.2.3.1 11-1.2.3 (a / and~e.5 :op1 (i2 / include-91~e.1 :ARG1 (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC1"~e.0)) :ARG2 (p2 / protein~e.4 :name (n / name :op1 "Raptor"~e.3))) :op2 (r / regulate-01~e.6 :ARG0 m2 :ARG1 (e / express-03~e.8 :ARG1 (g / gene~e.7)) :instrument (c / control-01~e.11 :ARG1 (t / translate-02~e.10)))) # ::id pmid_2464_2271.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok mTORC2 includes the Rictor protein and provides positive feedback by phosphorylating and activating AKT . # ::alignments 0-1.1.1.1.1 1-1.1 3-1.1.2.1.1 4-1.1.2 5-1 6-1.2 7-1.2.2.1 8-1.2.2 9-1.2.3.r 10-1.2.3.1 11-1.2.3 12-1.2.3.2 13-1.2.3.2.2.1.1 (a / and~e.5 :op1 (i / include-91~e.1 :ARG1 (m2 / macro-molecular-complex :name (n / name :op1 "mTORC2"~e.0)) :ARG2 (p5 / protein~e.4 :name (n2 / name :op1 "Rictor"~e.3))) :op2 (p / provide-01~e.6 :ARG0 m2 :ARG1 (f / feedback~e.8 :mod (p2 / positive~e.7)) :manner~e.9 (a2 / and~e.11 :op1 (p3 / phosphorylate-01~e.10 :ARG1 p4 :ARG2 m2) :op2 (a3 / activate-01~e.12 :ARG0 m2 :ARG1 (p4 / pathway :name (n3 / name :op1 "AKT"~e.13)))))) # ::id pmid_2464_2271.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test the role of mTOR @-@ containing complexes in oncogenic ETS function , shRNAs were used to knockdown mTOR , Raptor , and Rictor , in RWPE @-@ ERG cells ( Figure 5 @ A ) . # ::alignments 1-1.3 3-1.3.1 4-1.3.1.1.r 5-1.3.1.1.1.1.1.1 7-1.3.1.1.1 8-1.3.1.1 9-1.3.1.2.r 10-1.3.1.2.1 10-1.3.1.2.1.2 10-1.3.1.2.1.2.1.2.1 10-1.3.1.2.1.2.r 11-1.3.1.2.1.1.1 12-1.3.1.2 14-1.1.1.1 16-1 16-1.3.r 17-1.2.r 18-1.2 19-1.2.1.1 21-1.2.1.2.1.1 23-1.2.1 24-1.2.1.3.1.1 26-1.2.1.r 27-1.2.1.4.1.1 29-1.2.1.4.1.1 30-1.2.1.4 32-1.4.1 (u / use-01~e.16 :ARG1 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA"~e.14)) :ARG2~e.17 (k / knock-down-02~e.18 :ARG1~e.26 (a / and~e.23 :op1 m~e.19 :op2 (p2 / protein :name (n6 / name :op1 "Raptor"~e.21)) :op3 (p3 / protein :name (n7 / name :op1 "Rictor"~e.24)) :location (c3 / cell-line~e.30 :name (n4 / name :op1 "RWPE-ERG"~e.27,29)))) :purpose~e.16 (t / test-01~e.1 :ARG1 (r / role~e.3 :poss~e.4 (m / macro-molecular-complex~e.8 :ARG0-of (c / contain-01~e.7 :ARG1 (p / protein :name (n / name :op1 "mTOR"~e.5)))) :topic~e.9 (f / function-01~e.12 :ARG0 (g / gene~e.10 :name (n2 / name :op1 "ETS"~e.11) :ARG0-of~e.10 (c4 / cause-01~e.10 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.10))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.32 :mod "5A"))) # ::id pmid_2464_2271.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Loss of Raptor resulted in an increase in cell migration , indicating that mTORC1 is not required for the ability of PI3K @/@ AKT to promote cell migration ( Figure 5 @ B and Additional file 2 @ : Figure S2 ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1 4-1.2.r 6-1.2 7-1.2.1.r 8-1.2.1.1 9-1.2.1 11-1.4 12-1.4.1.r 13-1.4.1.3.1.1 15-1.4.1.1 15-1.4.1.1.r 16-1.4.1 17-1.4.1.2.r 19-1.4.1.2 20-1.4.1.2.1.r 21-1.4.1.2.1.1.1 23-1.4.1.2.1.1.1 25-1.4.1.2.2 26-1.4.1.2.2.2 27-1.4.1.2.2.2 29-1.3.1.1 34-1.3.1 36-1.3.1.2 38-1.3.1.2.1 41-1.3.1.2.2 42-1.3.1.2.2.1 (r / result-01~e.3 :ARG1 (l / lose-02~e.0 :ARG1~e.1 (p2 / protein :name (n2 / name :op1 "Raptor"~e.2))) :ARG2~e.4 (i / increase-01~e.6 :ARG1~e.7 (m / migrate-01~e.9 :ARG0 (c / cell~e.8))) :ARG1-of (d / describe-01 :ARG0 (a / and~e.34 :op1 (f / figure~e.29 :mod "5B") :op2 (f2 / file~e.36 :mod 2~e.38 :part (f3 / figure~e.41 :mod "S2"~e.42)))) :ARG0-of (i2 / indicate-01~e.11 :ARG1~e.12 (r2 / require-01~e.16 :polarity~e.15 -~e.15 :ARG0~e.17 (c3 / capable-01~e.19 :ARG1~e.20 (p5 / pathway :name (n4 / name :op1 "PI3K/AKT"~e.21,23)) :ARG2 (p4 / promote-01~e.25 :ARG0 p5 :ARG1 m~e.26,27)) :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "mTORC1"~e.13))))) # ::id pmid_2464_2271.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Loss of mTOR had little effect on RWPE @-@ ERG migration , while loss of Rictor decreased migration ( Figure 5 @ B and Additional file 2 @ : Figure S2 ) . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.3 5-1.1 6-1.1.2.r 7-1.1.2.1.1.1 9-1.1.2.1.1.1 10-1.1.2 12-1 13-1.2.1 14-1.2.1.1.r 15-1.2.1.1.1.1 16-1.2 17-1.2.2 19-1.3.1.1 24-1.3.1 26-1.3.1.2 28-1.3.1.2.1 31-1.3.1.2.2 32-1.3.1.2.2.1 (c / contrast-01~e.12 :ARG1 (a2 / affect-01~e.5 :ARG0 (l2 / lose-02~e.0 :ARG1~e.1 (p / protein :name (n2 / name :op1 "mTOR"~e.2))) :ARG1~e.6 (m2 / migrate-01~e.10 :ARG0 (c2 / cell-line :name (n / name :op1 "RWPE-ERG"~e.7,9))) :degree (l / little~e.4)) :ARG2 (d2 / decrease-01~e.16 :ARG0 (l3 / lose-02~e.13 :ARG1~e.14 (p2 / protein :name (n3 / name :op1 "Rictor"~e.15))) :ARG1 m2~e.17) :ARG1-of (d / describe-01 :ARG0 (a / and~e.24 :op1 (f / figure~e.19 :mod "5B") :op2 (f2 / file~e.26 :mod 2~e.28 :location-of (f3 / figure~e.31 :mod "S2"~e.32))))) # ::id pmid_2464_2271.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because the major role of the Rictor @-@ containing mTORC2 complex is thought to be the phosphorylation of AKT , we hypothesized that these results were due to changes in AKT phosphorylation . # ::alignments 0-1 2-1.1.1.1 3-1.1.1 4-1.1.1.2.r 6-1.1.1.2.2.1.1.1 8-1.1.1.2.2 9-1.1.1.2.1.1 10-1.1.1.2 11-1.1.1.3.r 12-1.1 14-1.1.1.3.r 16-1.1.1.3 17-1.1.1.3.1.r 18-1.1.1.3.1.1.1 20-1.2.1 21-1.2 22-1.2.2.r 23-1.2.2.2.2 24-1.2.2.2 24-1.2.2.2.1 24-1.2.2.2.1.r 26-1.2.2 27-1.2.2 28-1.2.2.1 29-1.2.2.1.1.r 30-1.2.2.1.1 31-1.2.2.1.1 (c / cause-01~e.0 :ARG0 (t / think-01~e.12 :ARG1 (r / role~e.3 :mod (m / major~e.2) :poss~e.4 (m2 / macro-molecular-complex~e.10 :name (n2 / name :op1 "mTORC2"~e.9) :ARG0-of (c2 / contain-01~e.8 :ARG1 (p2 / protein :name (n3 / name :op1 "Rictor"~e.6)))) :domain~e.11,14 (p / phosphorylate-01~e.16 :ARG1~e.17 (e / enzyme :name (n / name :op1 "AKT"~e.18))))) :ARG1 (h / hypothesize-01~e.21 :ARG0 (w / we~e.20) :ARG1~e.22 (c3 / cause-01~e.26,27 :ARG0 (c4 / change-01~e.28 :ARG1~e.29 p~e.30,31) :ARG1 (t2 / thing~e.24 :ARG2-of~e.24 (r2 / result-01~e.24) :mod (t3 / this~e.23))))) # ::id pmid_2464_2271.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with previous findings [ @ 32 @ - @ 34 @ ] , Raptor knockdown increased AKT phosphorylation , and Rictor knockdown decreased AKT phosphorylation ( Figure 5 @ C ) . # ::alignments 0-1.4 1-1.4.1.r 2-1.4.1.1.1 3-1.4.1 3-1.4.1.1 3-1.4.1.1.r 6-1.4.1.2.1.1.1.1 10-1.4.1.2.1.1.1.2 14-1.1.1.1.1.1 15-1.1.1 16-1.1 17-1.1.2.1.1.1 18-1.1.2 20-1 21-1.2.1.1.1.1 22-1.2.1 23-1.2 24-1.2.2 25-1.2.2 27-1.3.1 (a / and~e.20 :op1 (i / increase-01~e.16 :ARG0 (k / knock-down-02~e.15 :ARG1 (p3 / protein :name (n2 / name :op1 "Raptor"~e.14))) :ARG1 (p / phosphorylate-01~e.18 :ARG1 (e / enzyme :name (n / name :op1 "AKT"~e.17)))) :op2 (d2 / decrease-01~e.23 :ARG0 (k2 / knock-down-02~e.22 :ARG1 (p4 / protein :name (n3 / name :op1 "Rictor"~e.21))) :ARG1 p~e.24,25) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "5C")) :ARG1-of (c / consistent-01~e.0 :ARG2~e.1 (t / thing~e.3 :ARG1-of~e.3 (f2 / find-01~e.3 :time (p2 / previous~e.2)) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 32~e.6 :op2 34~e.10))))))) # ::id pmid_2464_2271.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Therefore , the effect of mTOR containing complexes on RWPE @-@ ERG cell migration can be explained indirectly by changes to pAKT levels , rather than by a direct role . # ::alignments 0-1 3-1.1.1.2 4-1.1.1.2.1.r 5-1.1.1.2.1.1.1.1.1 6-1.1.1.2.1.1 7-1.1.1.2.1 8-1.1.1.2.2.r 9-1.1.1.2.2.1.1.1 11-1.1.1.2.2.1.1.1 12-1.1.1.2.2.1 13-1.1.1.2.2 14-1.1 16-1.1.1 17-1.1.1.3 17-1.1.1.3.1 17-1.1.1.3.1.r 18-1.1.1.1.r 19-1.1.1.1 20-1.1.1.1.1.r 21-1.1.1.1.1.1.1.1 21-1.1.1.1.1.1.2 22-1.1.1.1.1 24-1.1.1.1.2 28-1.1.1.1.2.1.1 29-1.1.1.1.2.1 (c / cause-01~e.0 :ARG1 (p / possible-01~e.14 :ARG1 (e / explain-01~e.16 :ARG0~e.18 (c6 / change-01~e.19 :ARG1~e.20 (l / level~e.22 :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT"~e.21) :ARG3-of (p5 / phosphorylate-01~e.21))) :ARG1-of (i / instead-of-91~e.24 :ARG2 (r / role~e.29 :ARG1-of (d2 / direct-02~e.28)))) :ARG1 (a / affect-01~e.3 :ARG0~e.4 (m3 / macro-molecular-complex~e.7 :ARG0-of (c4 / contain-01~e.6 :ARG1 (p3 / protein :name (n / name :op1 "mTOR"~e.5)))) :ARG1~e.8 (m2 / migrate-01~e.13 :ARG0 (c3 / cell-line~e.12 :name (n2 / name :op1 "RWPE-ERG"~e.9,11)))) :ARG1-of (d / direct-02~e.17 :polarity~e.17 -~e.17)))) # ::id pmid_2465_1010.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Dragging Ras Back in the Ring ( PMID : 24651010 ) # ::alignments 0-1.2 1-1.2.1.1.1 2-1.2.3 3-1.2.2.r 5-1.2.2 (p / publication-91 :ARG8 "PMID24651010" :ARG1 (d / drag-01~e.0 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.1)) :ARG2~e.3 (r / ring~e.5) :direction (b / back~e.2))) # ::id pmid_2465_1010.2 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras proteins play a major role in human cancers but have not yielded to therapeutic attack . # ::alignments 0-1.1.1.1.1 1-1.1.1 2-1.1 4-1.1.3 6-1.1.2.r 7-1.1.2.3 8-1.1.2.2.1 9-1 11-1.2.1 11-1.2.1.r 12-1.2 14-1.2.3.1 15-1.2.3 (c / contrast-01~e.9 :ARG1 (p / play-08~e.2 :ARG0 (p2 / protein-family~e.1 :name (n / name :op1 "Ras"~e.0)) :ARG1~e.6 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.8) :mod (h / human~e.7)) :ARG1-of (m / major-02~e.4)) :ARG2 (y / yield-02~e.12 :polarity~e.11 -~e.11 :ARG0 p2 :ARG2 (a / attack-01~e.15 :ARG0 (t / therapy~e.14) :ARG1 p2))) # ::id pmid_2465_1010.3 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras @-@ driven cancers are among the most difficult to treat and often excluded from therapies . # ::alignments 0-1.1.1.3.1.1.1 2-1.1.1 2-1.1.1.3 2-1.1.1.3.r 3-1.1.1.2.1 3-1.1.2.2.1 5-1.1 7-1.1.2.3.1.1 8-1.1.2.3.1 10-1.1.2 10-1.1.2.3 10-1.1.2.3.r 11-1 12-1.2.3 13-1.2 14-1.2.2.r 15-1.2.2 (a / and~e.11 :op1 (i / include-91~e.5 :ARG1 (d / disease~e.2 :wiki "Cancer" :name (n / name :op1 "cancer"~e.3) :ARG1-of~e.2 (d2 / drive-02~e.2 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"~e.0)))) :ARG2 (d3 / disease~e.10 :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.3) :ARG2-of~e.10 (t / treat-03~e.10 :manner (d4 / difficult~e.8 :degree (m / most~e.7))))) :op2 (e2 / exclude-01~e.13 :ARG1 d :ARG2~e.14 (t2 / therapy~e.15) :frequency (o / often~e.12))) # ::id pmid_2465_1010.4 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ras proteins have been termed “ undruggable , ” based on failures from an era in which understanding of signaling transduction , feedback loops , redundancy , tumor heterogeneity , and Ras ’ oncogenic role was poor . # ::alignments 1-1.1.1.1 5-1 10-1.3 11-1.3.1.r 12-1.3.1 13-1.3.1.1.r 15-1.3.1.1 18-1.3.1.1.1.1 19-1.3.1.1.1.1.1.r 20-1.3.1.1.1.1.1.1.1 21-1.3.1.1.1.1.1.1 23-1.3.1.1.1.1.1.2.1 24-1.3.1.1.1.1.1.2 26-1.3.1.1.1.1.1.3 28-1.3.1.1.1.1.1.4.1 29-1.3.1.1.1.1.1.4 31-1.3.1.1.1.1.1 32-1.3.1.1.1.1.1.5.1 34-1.3.1.1.1.1.1.5 34-1.3.1.1.1.1.1.5.2.2.1 36-1.3.1.1.1.1.r 37-1.3.1.1.1 (t / term-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.1)) :ARG3 (p / possible-01 :polarity - :ARG1 (d / drug-01 :ARG1 e)) :ARG1-of (b / base-02~e.10 :ARG2~e.11 (f / fail-01~e.12 :time~e.13 (e2 / era~e.15 :time-of (p2 / poor~e.37 :domain~e.36 (u / understand-01~e.18 :ARG1~e.19 (a / and~e.31 :op1 (t2 / transduce-01~e.21 :ARG1 (s / signal-07~e.20)) :op2 (l / loop~e.24 :mod (f2 / feedback~e.23)) :op3 (r / redundancy~e.26) :op4 (h / heterogeneous~e.29 :domain (t3 / tumor~e.28)) :op5 (c / cause-01~e.34 :ARG0 e~e.32 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.34)))))))))) # ::id pmid_2465_1010.5 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Structures of Ras oncoproteins bound to their effectors or regulators are unsolved , and it is unknown precisely how Ras proteins activate their downstream targets . # ::alignments 0-1.1.2 1-1.1.2.1.r 2-1.1.2.1.1.1 4-1.1.2.1 4-1.1.2.1.3 4-1.1.2.1.3.r 5-1.1.2.1.3.1.r 6-1.1.2.1.3.1.1.1 6-1.1.2.1.3.1.1.1.r 7-1.1.2.1.3.1.1 8-1.1.2.1.3.1 9-1.1.2.1.3.1.2 9-1.1.2.1.3.1.2.1 9-1.1.2.1.3.1.2.1.r 11-1.1 11-1.1.1 11-1.1.1.r 13-1 16-1.2 16-1.2.1 16-1.2.1.r 17-1.2.3 18-1.2.2.1.r 18-1.2.3.r 19-1.2.2.1.1.1.1 20-1.2.2.1.1 21-1.2.2.1 23-1.2.2.1.2.2 24-1.2.2.1.2 24-1.2.2.1.2.1 24-1.2.2.1.2.1.r (a / and~e.13 :op1 (s / solve-01~e.11 :polarity~e.11 -~e.11 :ARG1 (s2 / structure~e.0 :consist-of~e.1 (e / enzyme~e.4 :name (n / name :op1 "Ras"~e.2) :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :ARG1-of~e.4 (b / bind-01~e.4 :ARG2~e.5 (o2 / or~e.8 :op1 (e2 / effector~e.7 :poss~e.6 e~e.6) :op2 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (r / regulate-01~e.9 :ARG1 e))))))) :op2 (k / know-01~e.16 :polarity~e.16 -~e.16 :ARG1 (t / thing :manner-of~e.18 (a2 / activate-01~e.21 :ARG0 (p2 / protein-family~e.20 :name (n2 / name :op1 "Ras"~e.19)) :ARG1 (m2 / molecular-physical-entity~e.24 :ARG1-of~e.24 (t2 / target-01~e.24 :ARG0 p2) :location (d / downstream~e.23)))) :manner~e.18 (p / precise~e.17))) # ::id pmid_2465_1010.6 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These knowledge gaps have impaired development of therapeutic strategies . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 4-1 5-1.2 6-1.2.1.r 7-1.2.1.1 8-1.2.1 (i / impair-01~e.4 :ARG0 (g / gap~e.2 :mod (t2 / this~e.0) :topic (k / know-03~e.1)) :ARG1 (d / develop-02~e.5 :ARG1~e.6 (s / strategy~e.8 :mod (t / therapy~e.7)))) # ::id pmid_2465_1010.7 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A better understanding of Ras biology and biochemistry , coupled with new ways of targeting undruggable proteins , is likely to lead to new ways of defeating Ras @-@ driven cancers . # ::alignments 1-1.1.1.3 1-1.1.1.3.1 1-1.1.1.3.1.r 2-1.1.1 4-1.1.1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2 9-1.1.1.2 10-1.1.1.2.1.r 11-1.1.1.2.1.1 12-1.1.1.2.1 13-1.1.1.2.1.2.r 14-1.1.1.2.1.2 16-1.1.1.2.1.2.1 19-1 20-1.1.1 21-1.1 22-1.1.1 22-1.1.2.r 23-1.1.2.1 24-1.1.2 25-1.1.2.2.r 26-1.1.2.2 27-1.1.2.2.1.3.1 29-1.1.2.2.1 29-1.1.2.2.1.3 29-1.1.2.2.1.3.r 30-1.1.2.2.1.2.1 (l / likely-01~e.19 :ARG1 (l2 / lead-03~e.21 :ARG0 (u / understand-01~e.2,20,22 :ARG1 (a / and~e.6 :op1 (b / biology~e.5 :mod (p3 / protein-family :name (n / name :op1 "Ras"~e.4))) :op2 (b2 / biochemistry~e.7 :mod p3)) :ARG1-of (c / couple-01~e.9 :ARG2~e.10 (w2 / way~e.12 :ARG1-of (n4 / new-01~e.11) :manner-of~e.13 (t / target-01~e.14 :ARG1 (p / protein~e.16 :ARG1-of (d4 / drug-01 :ARG1-of (p2 / possible-01 :polarity -)))))) :ARG1-of (g / good-02~e.1 :degree~e.1 (m / more~e.1))) :ARG2~e.22 (w / way~e.24 :ARG1-of (n2 / new-01~e.23) :manner-of~e.25 (d / defeat-01~e.26 :ARG1 (d2 / disease~e.29 :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.30) :ARG1-of~e.29 (d3 / drive-02~e.29 :ARG0 p3~e.27)))))) # ::id pmid_2465_1010.8 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Main Text # ::alignments 0-1.1 1-1 (t / text~e.1 :mod (m / main~e.0)) # ::id pmid_2465_1010.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Fifty years have passed since the transforming power of Ras genes was first recognized . # ::alignments 0-1.1.1 1-1.1.2 3-1 4-1.2 6-1.2.1.1.1 8-1.2.1.1.1.1.r 9-1.2.1.1.1.1.2.1 10-1.2.1.1.1.1 12-1.2.1.2 12-1.2.1.2.1 12-1.2.1.2.1.r 13-1.2.1 (p / pass-03~e.3 :ARG1 (t / temporal-quantity :quant 50~e.0 :unit (y / year~e.1)) :time (s / since~e.4 :op1 (r / recognize-02~e.13 :ARG1 (p2 / possible-01 :ARG1 (t2 / transform-01~e.6 :ARG0~e.8 (g / gene~e.10 :wiki - :name (n / name :op1 "Ras"~e.9)))) :ord (o / ordinal-entity~e.12 :value~e.12 1~e.12)))) # ::id pmid_2465_1010.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Harvey sarcoma virus , Kirsten sarcoma virus , and Rasheed sarcoma virus contain Ras genes ( so named for their role in forming ra @ t s @ arcomas ; reviewed in Barbacid , 1987 ; Karnoub and Weinberg , 2008 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.2 2-1.1.1 4-1.1.2.1.1 5-1.1.1.1.2 6-1.1.1 6-1.1.2 6-1.1.3 8-1.1 9-1.1.3.1.1 10-1.1.3.1.2 11-1.1.3.1.3 12-1 13-1.2.1.1 14-1.2 16-1.2.2.1 17-1.2.2 19-1.2.2.1.1.1 19-1.2.2.1.1.1.r 22-1.2.2.1.1.2 32-1.3 35-1.3.1.1.1.1.1 37-1.3.1.1.2.1 39-1.3.1.2.1.1.1.1 40-1.3.1.2.1 41-1.3.1.2.1.2.1.1 43-1.3.1.2.2.1 (c / contain-01~e.12 :ARG0 (a / and~e.8 :op1 (v / virus~e.2,6 :name (n2 / name :op1 "Harvey"~e.0 :op2 "sarcoma"~e.1,5 :op3 "virus")) :op2 (v2 / virus~e.6 :name (n3 / name :op1 "Kirsten"~e.4 :op2 "sarcoma" :op3 "virus")) :op3 (v3 / virus~e.6 :name (n4 / name :op1 "Rasheed"~e.9 :op2 "sarcoma"~e.10 :op3 "virus"~e.11))) :ARG1 (g / gene~e.14 :name (n / name :op1 "Ras"~e.13) :ARG1-of (n5 / name-01~e.17 :ARG1-of (c2 / cause-01~e.16 :ARG0 (p6 / play-08 :ARG0~e.19 g~e.19 :ARG1 (f / form-01~e.22 :ARG1 (s / sarcoma :mod (r / rat))))))) :ARG1-of (r2 / review-02~e.32 :ARG2 (a2 / and :op1 (p / publication-91 :ARG0 (p3 / person :name (n6 / name :op1 "Barbacid"~e.35)) :time (d / date-entity :year 1987~e.37)) :op2 (p2 / publication-91 :ARG0 (a3 / and~e.40 :op1 (p4 / person :name (n7 / name :op1 "Karnoub"~e.39)) :op2 (p5 / person :name (n8 / name :op1 "Weinberg"~e.41))) :time (d2 / date-entity :year 2008~e.43))))) # ::id pmid_2465_1010.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These retroviruses initiated tumors efficiently and , using temperature @-@ sensitive mutants , were shown to be necessary for tumor maintenance ( Shih et al. , 1979 ) . # ::alignments 0-1.1.1.1 2-1.1 3-1.1.2 4-1.1.3 5-1 5-1.3.1.1 7-1.2.2 8-1.2.2.1.2.1 10-1.2.2.1.2 11-1.2.2.1.1 14-1.2 17-1.2.1 18-1.2.1.1.r 19-1.2.1.1.1 20-1.2.1.1 23-1.3.1.1.1.1.1 24-1.3.1.1 25-1.3.1.1.2.1 27-1.3.1.2.1 (a / and~e.5 :op1 (i / initiate-01~e.2 :ARG0 (r / retrovirus :mod (t / this~e.0)) :ARG1 (t2 / tumor~e.3) :ARG2-of (e / efficient-01~e.4 :ARG1 r)) :op2 (s / show-01~e.14 :ARG1 (n / need-01~e.17 :ARG0~e.18 (m / maintain-01~e.20 :ARG1 t2~e.19) :ARG1 r) :manner (u / use-01~e.7 :ARG1 (v / virus :ARG2-of (m2 / mutate-01~e.11) :ARG0-of (s2 / sensitive-03~e.10 :ARG1 (t3 / temperature~e.8))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and~e.5,24 :op1 (p2 / person :name (n2 / name :op1 "Shih"~e.23)) :op2 (p3 / person :mod (o / other~e.25))) :time (d2 / date-entity :year 1979~e.27)))) # ::id pmid_2465_1010.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok They formed part of a fascinating collection of retroviruses that was assembled in the 1970 s , each able to transform cells in culture and in avian and rodent models . # ::alignments 0-1.1 5-1.2.1 6-1.2 11-1.2.3 12-1.2.3.1.r 14-1.2.3.1.1 15-1.2.3.1.1.r 17-1.2.2.2 18-1.2.2.1.2 20-1.2.2.1 21-1.2.2.1.1 22-1.2.2.1.1.1.r 23-1.2.2.1.1.1.1 24-1.2.2.1.1.1 26-1.2.2.1.1.1.2.1 27-1.2.2.1.1.1 28-1.2.2.1.1.1.3.1 29-1.2.2.1.1.1.2 29-1.2.2.1.1.1.3 (i / include-91 :ARG1 (t / they~e.0) :ARG2 (c / collection~e.6 :ARG0-of (f2 / fascinate-01~e.5) :consist-of (r / retrovirus :ARG0-of (t2 / transform-01~e.20 :ARG1 (c2 / cell~e.21 :source~e.22 (a2 / and~e.24,27 :op1 (c3 / culture~e.23) :op2 (m / model~e.29 :mod (b / bird~e.26)) :op3 (m2 / model~e.29 :mod (r2 / rodent~e.28)))) :ARG1-of (p2 / possible-01~e.18)) :mod (e / each~e.17)) :ARG1-of (a / assemble-02~e.11 :time~e.12 (d / date-entity :decade~e.15 1970~e.14)))) # ::id pmid_2465_1010.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These experiments were , essentially , unbiased screens for genes that cause cancer ; the nature of the proteins that the genes encoded was completely unknown . # ::alignments 0-1.1.1.1 1-1.1.1 4-1.1.4 6-1.1.3 6-1.1.3.1 6-1.1.3.1.r 7-1.1 8-1.1.2.r 9-1.1.2 11-1.1.2.1 12-1.1.2.1.1.2.1 15-1.2.2 16-1.2.2.1.r 18-1.2.2.1 21-1.2.2.1.1.1 22-1.2.2.1.1 24-1.2.3 25-1.2 25-1.2.1 25-1.2.1.r (m / multi-sentence :snt1 (s / screen-01~e.7 :ARG0 (e / experiment-01~e.1 :mod (t / this~e.0)) :ARG2~e.8 (g / gene~e.9 :ARG0-of (c / cause-01~e.11 :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.12)))) :ARG1-of (b / bias-01~e.6 :polarity~e.6 -~e.6) :mod (e2 / essential~e.4)) :snt2 (k / know-01~e.25 :polarity~e.25 -~e.25 :ARG1 (n2 / nature~e.15 :mod~e.16 (p / protein~e.18 :ARG1-of (e3 / encode-01~e.22 :ARG0 (g2 / gene~e.21)))) :ARG1-of (c2 / complete-02~e.24))) # ::id pmid_2465_1010.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Remarkably , the majority of these viruses encoded proteins that were later identified as components of the tyrosine kinase @-@ Ras signaling pathway ( Vogt , 2012 ) , even though the biochemical nature of these proteins was unknown , and tyrosine kinase activity had not been discovered ( Eckhart et al. , 1979 ) . # ::alignments 0-1.3 3-1.1.1.2 5-1.1.1.1.1 6-1.1 6-1.1.1.1 7-1 8-1.2 11-1.2.1.2 11-1.2.1.2.1 11-1.2.1.2.1.r 12-1.2.1 13-1.2.1.1.r 13-1.2.1.2.r 14-1.2.1.1 15-1.2.1.1.1.r 17-1.2.1.1.1.1.1 18-1.2.1.1.1.1.2 20-1.2.1.1.1.1.2 21-1.2.1.1.1.2 22-1.2.1.1.1 25-1.4.1.1.1.1.1 27-1.4.1.2.1 31-1.2.1.3 32-1.2.1.3 34-1.2.1.3.1.1.2.1 35-1.2.1.3.1.1.2 37-1.1.1.1.1 38-1.2 40-1.2.1.3.1.1 40-1.2.1.3.1.1.1 40-1.2.1.3.1.1.1.r 42-1.2.1.3.1 43-1.2.1.3.1.2.2.1.1.1 44-1.2.1.3.1.2.2.1.1.2 45-1.2.1.3.1.2.2 47-1.2.1.3.1.2.1 47-1.2.1.3.1.2.1.r 49-1.2.1.3.1.2 52-1.2.1.3.2.1.1.1.1.1 53-1.2.1.3.2.1.1 53-1.4.1.1 54-1.2.1.3.2.1.1.2.1 56-1.2.1.3.2.1.2.1 (e / encode-01~e.7 :ARG0 (v / virus~e.6 :ARG1-of (i / include-91 :ARG2 (v2 / virus~e.6 :mod (t / this~e.5,37)) :ARG3 (m / majority~e.3))) :ARG1 (p / protein~e.8,38 :ARG1-of (i2 / identify-01~e.12 :ARG2~e.13 (c / component~e.14 :part-of~e.15 (p2 / pathway~e.22 :name (n / name :op1 "tyrosine"~e.17 :op2 "kinase-Ras"~e.18,20) :ARG0-of (s / signal-07~e.21))) :time~e.13 (l / late~e.11 :degree~e.11 (m2 / more~e.11)) :ARG1-of (h / have-concession-91~e.31,32 :ARG2 (a / and~e.42 :op1 (k / know-01~e.40 :polarity~e.40 -~e.40 :ARG1 (n2 / nature~e.35 :mod (b / biochemical~e.34) :poss p)) :op2 (d / discover-01~e.49 :polarity~e.47 -~e.47 :ARG1 (a2 / activity-06~e.45 :ARG0 (e2 / enzyme :name (n3 / name :op1 "tyrosine"~e.43 :op2 "kinase"~e.44))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a3 / and~e.53 :op1 (p5 / person :name (n4 / name :op1 "Eckhart"~e.52)) :op2 (p6 / person :mod (o / other~e.54))) :time (d4 / date-entity :year 1979~e.56)))))) :ARG1-of (r / remarkable-02~e.0) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a4 / and~e.53 :op1 (p8 / person :name (n5 / name :op1 "Vogt"~e.25))) :time (d5 / date-entity :year 2012~e.27)))) # ::id pmid_2465_1010.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Of the hundreds of mutant proteins now known to contribute to cancer that could have been identified in these assays , including those involved in DNA repair , cellular metabolism , RNA splicing , and the other hallmarks of cancer ( Hanahan and Weinberg , 2011 ) , those in the tyrosine kinase @-@ Ras pathway stand out as the major drivers and have been the richest source of targets of successful cancer therapies ( Abl , epidermal growth factor receptor [ EGFR ] , Her2/neu , B @-@ Raf , Kit , ALK , etc.) . # ::alignments 2-1.2.1 3-1.2.1 4-1.2.1 5-1.2.1 6-1.2.1 7-1.2.1 8-1.2.1 9-1.2.1 10-1.1.2 11-1.1.1.2.1.3.1 13-1.1.1.2.1.4.2 16-1.1.1.2.1.4 17-1.1.1.2.1.4.1.r 18-1.1.1.2.1.4.1.1 19-1.1.1.2.1.4.1 21-1.1.1.2 21-1.1.1.2.1.5 23-1.1.1.2.1.5.1.1.1 24-1.1.1.2.1.5.1.1.1.1.r 25-1.1.1.2.1.5.1.1.1.1.1.1.2.1 26-1.1.1.2.1.5.1.1.1.1.1 28-1.1.1.2.1.5.1.1.1.1.2.1 29-1.1.1.2.1.5.1.1.1.1.2 31-1.1.1.2.1.5.1.1.1.1.3.1.1.1 32-1.1.1.2.1.5.1.1.1.1.3 34-1.1.1.2.1.5.1.1.1.1 36-1.1.1.2.1.5.1.1.1.1.4.1 37-1.1.1.2.1.5.1.1.1.1.4 38-1.1.1.2.1.5.1.1.1.1.4.2.r 39-1.1.1.2.1.5.1.1.1.1.4.2 42-1.1.1.2.2.1.1.1.1.1 43-1.1.1.2.2.1.1 44-1.1.1.2.2.1.1.2.1.1 46-1.1.1.2.2.1.2.1 53-1.1.1.1.1.1 54-1.1.1.1.1.2 56-1.1.1.1.1.2 57-1.1.1.1 58-1.1 59-1.1 60-1.1.2.1.1 62-1.1.2.1.2 64-1 64-1.2.2.1.2 65-1.2.2.1.1.2 68-1.2.3 68-1.2.3.1 68-1.2.3.1.r 69-1.2 70-1.2.2.r 71-1.2.2 71-1.2.2.1 71-1.2.2.1.r 72-1.2.2.1.1.r 73-1.2.2.1.1.2 74-1.2.2.1.1.1.2.1 75-1.2.2.1.1 77-1.2.2.1.2.1.1.1 79-1.2.2.1.2.2.1.1 80-1.2.2.1.2.2.1.2 81-1.2.2.1.2.2.1.3 82-1.2.2.1.2.2.1.4 87-1.2.2.1.2.3.1.1 89-1.2.2.1.2.4.1.1 91-1.2.2.1.2.4.1.1 93-1.2.2.1.2.5.1.1 95-1.2.2.1.2.6.1.1 (a / and~e.64 :op1 (s / stand-out-06~e.58,59 :ARG1 (p / protein :location (p2 / pathway~e.57 :name (n / name :op1 "tyrosine"~e.53 :op2 "kinase-Ras"~e.54,56)) :ARG1-of (i / include-91~e.21 :ARG2 (p4 / protein :ARG2-of (m2 / mutate-01) :quant (m3 / multiple :op1 100) :ARG0-of (c2 / contribute-01 :ARG2 d2~e.11 :ARG1-of (k / know-01 :time (n9 / now))) :ARG1-of (i2 / identify-01~e.16 :ARG0~e.17 (a3 / assay-01~e.19 :mod (t4 / this~e.18)) :ARG1-of (p5 / possible-01~e.13)) :ARG2-of (i3 / include-91~e.21 :ARG1 (a4 / and :op1 (p6 / protein :ARG1-of (i4 / involve-01~e.23 :ARG2~e.24 (a5 / and~e.34 :op1 (r / repair-01~e.26 :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n13 / name :op1 "DNA"~e.25))) :op2 (m4 / metabolism~e.29 :mod (c3 / cell~e.28)) :op3 (s5 / splice-01~e.32 :ARG1 (n14 / nucleic-acid :name (n15 / name :op1 "RNA"~e.31))) :op4 (h / hallmark~e.37 :mod (o / other~e.36) :mod~e.38 d2~e.39))))))) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a6 / and~e.43 :op1 (p8 / person :name (n10 / name :op1 "Hanahan"~e.42)) :op2 (p9 / person :name (n11 / name :op1 "Weinberg"~e.44))) :time (d5 / date-entity :year 2011~e.46))))) :ARG1-of (c / cause-01~e.10 :ARG0 (d / drive-02 :ARG0 p~e.60 :ARG1-of (m / major-02~e.62)))) :op2 (s2 / source-02~e.69 :ARG0 p~e.2,3,4,5,6,7,8,9 :ARG1~e.70 (t / thing~e.71 :ARG1-of~e.71 (t2 / target-01~e.71 :ARG0~e.72 (t3 / therapy~e.75 :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.74)) :ARG0-of (s3 / succeed-01~e.65,73)) :example (a2 / and~e.64 :op1 (p10 / protein :name (n3 / name :op1 "Abl"~e.77)) :op2 (e / enzyme :name (n4 / name :op1 "epidermal"~e.79 :op2 "growth"~e.80 :op3 "factor"~e.81 :op4 "receptor"~e.82)) :op3 (p3 / protein :name (n5 / name :op1 "Her2/neu"~e.87)) :op4 (e2 / enzyme :name (n6 / name :op1 "B-Raf"~e.89,91)) :op5 (e5 / enzyme :name (n7 / name :op1 "Kit"~e.93)) :op6 (e6 / enzyme :name (n8 / name :op1 "ALK"~e.95)) :op7 (e3 / et-cetera)))) :mod (r3 / rich~e.68 :degree~e.68 (m5 / most~e.68)))) # ::id pmid_2465_1010.16 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These successes can therefore be attributed to the central , dominant role of this pathway in cancer , as well as the fortuitous abundance of druggable targets . # ::alignments 0-1.1.1.1.1 1-1.1.1.1 2-1.1 2-1.1.1.2.2.3.1 3-1 5-1.1.1 6-1.1.1.2.r 8-1.1.1.2.1.4 10-1.1.1.2.1.3 13-1.1.1.2.1.1.1 14-1.1.1.2.1.1 16-1.1.1.2.1.2.2.1 18-1.1.1.2 19-1.1.1.2 20-1.1.1.2 22-1.1.1.2.2.2.1 23-1.1.1.2.2.2 26-1.1.1.2.2 26-1.1.1.2.2.1 26-1.1.1.2.2.1.r (i / infer-01~e.3 :ARG1 (p / possible-01~e.2 :ARG1 (a / attribute-01~e.5 :ARG1 (s / succeed-01~e.1 :mod (t / this~e.0)) :ARG2~e.6 (a2 / and~e.18,19,20 :op1 (p2 / play-08 :ARG0 (p3 / pathway~e.14 :mod t~e.13) :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.16)) :ARG0-of (d2 / dominate-01~e.10) :mod (c / central~e.8)) :op2 (t2 / thing~e.26 :ARG1-of~e.26 (t3 / target-01~e.26) :mod (a3 / abundance~e.23 :mod (f / fortuity~e.22)) :ARG1-of (d3 / drug-01 :ARG1-of (p4 / possible-01~e.2))))))) # ::id pmid_2465_1010.17 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , specific therapies have not been developed for mutant Ras proteins themselves or for the cancers that they drive . # ::alignments 0-1 2-1.1.2.1 3-1.1.2 5-1.1.1 5-1.1.1.r 7-1.1 8-1.1.3.r 9-1.1.3.1 9-1.1.3.1.2 9-1.1.3.1.2.r 10-1.1.3.1.1.1 13-1.1.3 16-1.1.3.2.2.1 18-1.1.3.2.3.1 19-1.1.3.2 19-1.1.3.2.3 19-1.1.3.2.3.r (h / have-concession-91~e.0 :ARG1 (d / develop-02~e.7 :polarity~e.5 -~e.5 :ARG1 (t / therapy~e.3 :ARG1-of (s / specific-02~e.2)) :ARG3~e.8 (o / or~e.13 :op1 (e / enzyme~e.9 :name (n / name :op1 "Ras"~e.10) :ARG2-of~e.9 (m / mutate-01~e.9)) :op2 (d2 / disease~e.19 :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.16) :ARG1-of~e.19 (d3 / drive-02~e.19 :ARG0 e~e.18))))) # ::id pmid_2465_1010.18 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Worse yet , tumors driven by Ras genes are excluded from treatment with other targeted therapies . # ::alignments 0-1 0-1.2 0-1.2.r 1-1.3 3-1.1.1 4-1.1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1 7-1.1.1.1.1 9-1.1 10-1.1.2.r 11-1.1.2 12-1.1.2.2.r 13-1.1.2.2.1 14-1.1.2.2.2 15-1.1.2.2 (b / bad-05~e.0 :ARG1 (e / exclude-01~e.9 :ARG1 (t / tumor~e.3 :ARG1-of (d / drive-02~e.4 :ARG0~e.5 (g / gene~e.7 :name (n / name :op1 "Ras"~e.6)))) :ARG2~e.10 (t2 / treat-03~e.11 :ARG2 t :ARG3~e.12 (t3 / therapy~e.15 :mod (o / other~e.13) :ARG2-of (t4 / target-01~e.14)))) :degree~e.0 (m / more~e.0) :mod (y / yet~e.1)) # ::id pmid_2465_1010.19 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Early efforts to block Ras cancers by preventing Ras farnesylation , once thought to be an essential posttranslational modification for Ras activity , were thwarted by the unexpected presence of a backup system ( geranylgeranyltransferase ) that restored activity of K @-@ Ras and N @-@ Ras after farnesyltransferase treatment . # ::alignments 0-1.2.2 1-1.2 2-1.2.1.1 2-1.2.1.1.3 2-1.2.1.1.3.r 3-1.2.1 4-1.2.1.1.3.1.1.1 5-1.2.1.1.2.1 6-1.2.1.2.r 7-1.2.1.2 8-1.2.1.2.1.1 11-1.2.1.2.1.2.2 12-1.2.1.2.1.2 16-1.2.1.2.1.2.1.3 17-1.2.1.2.1.2.1.2 17-1.2.1.2.1.2.1.2.1 17-1.2.1.2.1.2.1.2.1.r 18-1.2.1.2.1.2.1 19-1.2.1.2.1.2.1.1.r 20-1.2.1.2.1.2.1.1.1 21-1.2.1.2.1.2.1.1 24-1 25-1.1.r 27-1.1.2 27-1.1.2.1 27-1.1.2.1.r 28-1.1 34-1.1.1.1.1 37-1.1.1.3 38-1.1.1.3.1 39-1.1.1.3.1.1.r 40-1.1.1.3.1.1.1.1.1 42-1.1.1.3.1.1.1.1.1 42-1.1.1.3.1.1.2.1.1 43-1.1.1.3.1.1 44-1.1.1.3.1.1.2.1.1 46-1.1.1.3.1.1.2.1.1 47-1.1.1.3.2 48-1.1.1.3.2.1.1.1.1 49-1.1.1.3.2.1 (t / thwart-01~e.24 :ARG0~e.25 (p / present-02~e.28 :ARG1 (e2 / enzyme :name (n / name :op1 "geranylgeranyltransferase"~e.34) :ARG0-of (b / back-up-04) :ARG0-of (r / restore-01~e.37 :ARG1 (a / activity-06~e.38 :ARG0~e.39 (a2 / and~e.43 :op1 (e3 / enzyme :name (n2 / name :op1 "K-Ras"~e.40,42)) :op2 (e4 / enzyme :name (n3 / name :op1 "N-Ras"~e.42,44,46)))) :time (a3 / after~e.47 :op1 (t2 / treat-04~e.49 :ARG1 (e5 / enzyme :name (n4 / name :op1 "farnesyltransferase"~e.48)))))) :ARG1-of (e / expect-01~e.27 :polarity~e.27 -~e.27)) :ARG1 (e6 / effort-01~e.1 :ARG1 (b2 / block-01~e.3 :ARG1 (d / disease~e.2 :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.5) :ARG1-of~e.2 (c / cause-01~e.2 :ARG0 (e8 / enzyme :name (n6 / name :op1 "Ras"~e.4)))) :ARG3~e.6 (p2 / prevent-01~e.7 :ARG1 (f / farnesylate-01 :ARG1 e8~e.8 :ARG1-of (t3 / think-01~e.12 :ARG2 (m / modify-01~e.18 :ARG1~e.19 (a5 / activity-06~e.21 :ARG0 e8~e.20) :time (a4 / after~e.17 :op1~e.17 (t4 / translate-02~e.17)) :mod (e9 / essential~e.16)) :time (o / once~e.11))))) :mod (e7 / early~e.0))) # ::id pmid_2465_1010.20 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , efforts to kill Ras cancers by blocking one of Ras ’ major downstream effectors , Raf kinase ( Figure 1 @ ) , ran into the unexpected discovery that , in Ras @-@ transformed cells , Raf inhibitors activate the pathway rather than inhibit it ( see below and discussion in Holderfield et al. , 2013 and Lito et al. , 2013 ) . # ::alignments 0-1.3 2-1.1 3-1.1.1.1 3-1.1.1.1.3 3-1.1.1.1.3.r 4-1.1.1 5-1.1.1.1.3.1.1.1 6-1.1.1.1.2.1 7-1.1.1.2.r 8-1.1.1.2 9-1.1.1.2.1.3.1.1 11-1.1.1.2.1.2.1.3 13-1.1.1.2.1.2.1.2 14-1.1.1.2.1.2.1.1 15-1.1.1.2.1.2.1 17-1.1.1.2.1.1.1 18-1.1.1.2.1 21-1.1.1.2.1.3.1 22-1.1.1.2.1.3.1.1 27-1 28-1.2.r 30-1.2.2 30-1.2.2.1 30-1.2.2.1.r 31-1.2 34-1.2.1.r 35-1.2.1.4.1.1 37-1.2.1.4.1 38-1.2.1.4 40-1.2.1.1.1.1 41-1.2.1.1 41-1.2.1.1.1 41-1.2.1.1.1.r 42-1.2.1 44-1.2.1.2 45-1.2.1.3 47-1.2.1.3.1 48-1.2.1.3.1.1 50-1.4 51-1.4.1 52-1.5.1 52-1.5.1.1.1 53-1.5 56-1.5.1.1.1.1.1.1 57-1.5.1.1.1 58-1.5.1.1.1.2.1 60-1.5.1.2.2 62-1.5.1 62-1.5.1.1.1 64-1.5.1.2.1.1.1 65-1.5.1 65-1.5.1.1.1 66-1.5.1.1.1.2.1 68-1.5.1.1.2.1 (r / run-07~e.27 :ARG0 (e / effort-01~e.2 :ARG1 (k / kill-01~e.4 :ARG1 (d6 / disease~e.3 :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.6) :ARG1-of~e.3 (c2 / cause-01~e.3 :ARG0 (e2 / enzyme :name (n / name :op1 "Ras"~e.5)))) :ARG2~e.7 (b / block-01~e.8 :ARG1 (k2 / kinase~e.18 :name (n2 / name :op1 "Raf"~e.17) :ARG1-of (i / include-91 :ARG2 (e4 / effector~e.15 :location (d2 / downstream~e.14) :ARG1-of (m / major-02~e.13) :poss e2~e.11)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.21 :mod 1~e.9,22)))))) :ARG1~e.28 (d / discover-01~e.31 :ARG1~e.34 (a / activate-01~e.42 :ARG0 (m2 / molecular-physical-entity~e.41 :ARG0-of~e.41 (i2 / inhibit-01~e.41 :ARG1 k2~e.40)) :ARG1 (p / pathway~e.44) :ARG1-of (i3 / instead-of-91~e.45 :ARG2 (i4 / inhibit-01~e.47 :ARG1 p~e.48)) :location (c3 / cell~e.38 :ARG2-of (t / transform-01~e.37 :ARG0 e2~e.35))) :ARG1-of (e3 / expect-01~e.30 :polarity~e.30 -~e.30)) :manner (l / likewise~e.0) :ARG1-of (s / see-01~e.50 :location (b2 / below~e.51)) :ARG1-of (d4 / discuss-01~e.53 :ARG0 (a2 / and~e.52,62,65 :op1 (p2 / publication-91 :ARG0 (a3 / and~e.52,57,62,65 :op1 (p4 / person :name (n4 / name :op1 "Holderfield"~e.56)) :op2 (p5 / person :mod (o / other~e.58,66))) :time (d5 / date-entity :year 2013~e.68)) :op2 (p3 / publication-91 :ARG0 (p6 / person :name (n5 / name :op1 "Lito"~e.64)) :time d5~e.60)))) # ::id pmid_2465_1010.21 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MAP kinase kinase ( MEK ) inhibitors and phosphatidylinositol 3 @-@ kinase ( PI3K ) inhibitors have not yet shown significant clinical activity in Ras cancers , for reasons relating to feedback loops and poor therapeutic windows , among other issues discussed below . # ::alignments 0-1.2.1.1.1.1.1.1 1-1.2.1.1.1.1.1.2 2-1.2.1.1.1.1.1.3 6-1.2.1.1 6-1.2.1.1.1 6-1.2.1.1.1.r 6-1.2.1.2 6-1.2.1.2.1 6-1.2.1.2.1.r 8-1.2.1.2.1.1.1.1 9-1.2.1.2.1.1.1.2 11-1.2.1.2.1.1.1.2 15-1.2.1.1 15-1.2.1.1.1 15-1.2.1.1.1.r 15-1.2.1.2 15-1.2.1.2.1 15-1.2.1.2.1.r 17-1.1 17-1.1.r 18-1.3 19-1 20-1.2.4 21-1.2.3 22-1.2 23-1.2.2.r 24-1.2.2.3.1.1.1 25-1.2.2.2.1 27-1.4.r 28-1.4 28-1.4.1 28-1.4.1.r 29-1.4.1.1 30-1.4.1.1.1.r 31-1.4.1.1.1.1.1 32-1.4.1.1.1.1 33-1.4.1.1.1 34-1.4.1.1.1.2.2 35-1.4.1.1.1.2.1 36-1.4.1.1.1.2 38-1.4.1.1.1.3 39-1.4.1.1.1.3.1.1 40-1.4.1.1.1.3.1 41-1.4.1.1.1.3.2 42-1.4.1.1.1.3.2.1 (s / show-01~e.19 :polarity~e.17 -~e.17 :ARG1 (a2 / activity-06~e.22 :ARG0 (a / and :op1 (m / molecular-physical-entity~e.6,15 :ARG0-of~e.6,15 (i / inhibit-01~e.6,15 :ARG1 (p3 / protein-family :name (n / name :op1 "MAP"~e.0 :op2 "kinase"~e.1 :op3 "kinase"~e.2)))) :op2 (m2 / molecular-physical-entity~e.6,15 :ARG0-of~e.6,15 (i2 / inhibit-01~e.6,15 :ARG1 (p / protein-family :name (n2 / name :op1 "phosphatidylinositol"~e.8 :op2 "3-kinase"~e.9,11))))) :ARG1~e.23 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.25) :ARG1-of (c3 / cause-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.24)))) :mod (c / clinic~e.21) :ARG1-of (s2 / significant-02~e.20)) :time (y / yet~e.18) :ARG1-of~e.27 (c4 / cause-01~e.28 :ARG0~e.28 (r / reason~e.28 :ARG1-of (r2 / relate-01~e.29 :ARG2~e.30 (a3 / and~e.33 :op1 (l / loop~e.32 :mod (f / feedback~e.31)) :op2 (w / window~e.36 :mod (t / therapy~e.35) :mod (p2 / poor~e.34)) :ARG1-of (i3 / include-91~e.38 :ARG2 (i4 / issue-02~e.40 :mod (o / other~e.39)) :ARG1-of (d / discuss-01~e.41 :location (b / below~e.42)))))))) # ::id pmid_2465_1010.22 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A convergence of urgent unmet clinical needs and advances in drug discovery has energized new efforts to target Ras cancers within academic centers and in the biopharmaceutical industry . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.2 5-1.1.1.3 6-1.1.1 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1.1 11-1.1.2.1 13-1 14-1.2.2 15-1.2 16-1.2.1.1 16-1.2.1.1.3 16-1.2.1.1.3.r 17-1.2.1 18-1.2.1.1.3.1.1.1 19-1.2.1.1.2.1 21-1.2.1.2.1.1 22-1.2.1.2.1 23-1.2.1.2 24-1.2.1.2.r 26-1.2.1.2.2.1 27-1.2.1.2.2 (e / energize-01~e.13 :ARG0 (c / converge-01~e.1 :ARG0~e.2 (n / need-01~e.6 :ARG1-of (m / meet-01 :polarity -) :mod (u / urgent~e.3) :mod (c2 / clinical~e.5)) :ARG1 (a / advance-01~e.8 :ARG1~e.9 (d / discover-01~e.11 :ARG1 (d2 / drug~e.10)))) :ARG1 (e2 / effort-01~e.15 :ARG1 (t / target-01~e.17 :ARG1 (d3 / disease~e.16 :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.19) :ARG1-of~e.16 (c4 / cause-01~e.16 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras"~e.18)))) :location~e.24 (a2 / and~e.23 :op1 (c5 / center~e.22 :mod (a3 / academia~e.21)) :op2 (i / industry~e.27 :mod (b / biopharmaceutical~e.26)))) :ARG1-of (n2 / new-01~e.14))) # ::id pmid_2465_1010.23 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To catalyze these renewed efforts , the National Cancer Institute recently launched a national Ras program at Frederick National Laboratory for Cancer ( see http://webdefence.global.blackspider.com/urlwrap/?q=AXicY2Rn8FrCwHB9AQNDUU6liXmKXnFRmV5uYmZOcn5eSVF-jl5yfi5DiaGJuaeHSY6Bgam5mRFDUlJiSmJRYqlDcQpEPqOkpMBKXz8osdg5FagrMUcvvyidAQIA65QdsA&Z ) , whose goal is to fill critical knowledge gaps that are essential to target Ras cancers effectively and to engage the research community toward solving the Ras problem . # ::alignments 0-1.2.3.1.1.1.2.1 0-1.2.3.1.1.1.2.1.3 0-1.2.3.1.1.1.2.1.3.r 1-1.4 2-1.4.2.2 3-1.4.2.1 4-1.4.2 7-1.1.1.1 8-1.1.1.2 8-1.2.3.1.1.1.2.1.2.1 9-1.1.1.3 10-1.3 11-1 13-1.2.1 14-1.2.2.1.1 15-1.2 16-1.5.r 17-1.5.1.1 18-1.5.1.2 19-1.5.1.3 20-1.5.1.4 21-1.2.3.1.1.1.2.1.2.1 21-1.5.1.5 23-1.6 25-1.6.2.1 32-1.2.3.1.1.1.2.1 32-1.2.3.1.1.1.2.1.3 32-1.2.3.1.1.1.2.1.3.r 33-1.2.3.1 34-1.2.3.1.1.2 35-1.2.3.1.1.1 36-1.2.3.1.1 39-1.2.3.1.1.1.1 40-1.2.3.1.1.1.2.1 40-1.2.3.1.1.1.2.1.3 40-1.2.3.1.1.1.2.1.3.r 41-1.2.3.1.1.1.2 42-1.2.2.1.1 44-1.2.3.1.1.1.2.2 46-1.2.3.1.1.1.2.1 46-1.2.3.1.1.1.2.1.3 46-1.2.3.1.1.1.2.1.3.r 47-1.2.3.2 49-1.2.3.2.1.1 50-1.2.3.2.1 52-1.2.3.2.2 54-1.2.3.2.2.2.1 55-1.2.3.2.2.2 (l / launch-01~e.11 :ARG0 (r / research-institute :name (n / name :op1 "National"~e.7 :op2 "Cancer"~e.8 :op3 "Institute"~e.9)) :ARG1 (p / program~e.15 :mod (n2 / nation~e.13) :topic (e2 / enzyme :name (n3 / name :op1 "Ras"~e.14,42)) :purpose (a / and :op1 (f2 / fill-01~e.33 :ARG1 (g / gap~e.36 :topic (k / know-03~e.35 :mod (e3 / essential~e.39) :purpose (t2 / target-01~e.41 :ARG1 (d / disease~e.0,32,40,46 :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.8,21) :ARG1-of~e.0,32,40,46 (c4 / cause-01~e.0,32,40,46 :ARG0 e2)) :ARG1-of (e4 / effective-04~e.44))) :ARG1-of (c2 / critical-02~e.34))) :op2 (e5 / engage-01~e.47 :ARG1 (c5 / community~e.50 :ARG0-of (r4 / research-01~e.49)) :ARG2 (s / solve-01~e.52 :ARG0 c5 :ARG1 (p2 / problem~e.55 :topic e2~e.54))))) :time (r2 / recent~e.10) :purpose (c / catalyze-01~e.1 :ARG0 r :ARG1 (e / effort-01~e.4 :ARG1-of (r3 / renew-01~e.3) :mod (t / this~e.2))) :location~e.16 (f / facility :name (n4 / name :op1 "Frederick"~e.17 :op2 "National"~e.18 :op3 "Laboratory"~e.19 :op4 "for"~e.20 :op5 "Cancer"~e.21)) :ARG1-of (s2 / see-01~e.23 :ARG0 (y / you) :medium (u / url-entity :value "http://webdefence.global.blackspider.com/urlwrap/?q=AXicY2Rn8FrCwHB9AQNDUU6liXmKXnFRmV5uYmZOcn5eSVF-jl5yfi5DiaGJuaeHSY6Bgam5mRFDUlJiSmJRYqlDcQpEPqOkpMBKXz8osdg5FagrMUcvvyidAQIA65QdsA&Z"~e.25))) # ::id pmid_2465_1010.24 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Here , we will discuss some of these knowledge gaps , as well as recent advances and the challenges that lie ahead . # ::alignments 0-1.3 2-1.1 4-1 5-1.2.1.2 7-1.2.1.1.1.2 8-1.2.1.1.1.1 9-1.2.1 9-1.2.1.1.1 11-1.2 12-1.2 13-1.2.2.1.r 14-1.2.2.1 15-1.2.2 16-1.2 18-1.2.3 20-1.2.3.1 21-1.2.3.1.1 (d / discuss-01~e.4 :ARG0 (w / we~e.2) :ARG1 (a / and~e.11,12,16 :op1 (g / gap~e.9 :ARG1-of (i / include-91 :ARG2 (g2 / gap~e.9 :topic (k / know-03~e.8) :mod (t / this~e.7))) :mod (s / some~e.5)) :op2 (a2 / advance-01~e.15 :time~e.13 (r / recent~e.14)) :op3 (c / challenge-01~e.18 :ARG1-of (l / lie-07~e.20 :ARG2 (a3 / ahead~e.21)))) :medium (h / here~e.0)) # ::id pmid_2465_1010.25 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras Mutations in Cancer # ::alignments 0-1.1.1.1 1-1 2-1.2.r 3-1.2.2.1 (m / mutate-01~e.1 :ARG2 (e / enzyme :name (n / name :op1 "Ras"~e.0)) :location~e.2 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.3))) # ::id pmid_2465_1010.26 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras genes were the first oncogenes identified in human cancer cells . # ::alignments 0-1.3.1.1 1-1.3 2-1.3.r 4-1.2 4-1.2.1 4-1.2.1.r 5-1 6-1.1 7-1.1.1.r 8-1.1.1.1.3 9-1.1.1.1.2.1 10-1.1.1 (o / oncogene~e.5 :ARG1-of (i / identify-01~e.6 :location~e.7 (c / cell~e.10 :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.9) :mod (h / human~e.8)))) :ord (o2 / ordinal-entity~e.4 :value~e.4 1~e.4) :domain~e.2 (g / gene~e.1 :name (n / name :op1 "Ras"~e.0))) # ::id pmid_2465_1010.27 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a series of classic experiments , the groups of Weinberg , Cooper , Barbacid , and Wigler independently identified the transforming genes from T24 @/@ EJ bladder carcinoma cells as H @-@ Ras ( Der et al. , 1982 ; Parada et al. , 1982 ; Santos et al. , 1982 ; Taparowsky et al. , 1982 ) . # ::alignments 2-1.4 3-1.4.1.r 4-1.4.1.1 5-1.4.1 8-1.1.1 8-1.1.2 8-1.1.3 8-1.1.4 10-1.1.1.1.1.1.1 12-1.1.2.1.1.1.1 14-1.1.3.1.1.1.1 16-1.1 17-1.1.4.1.1.1.1 18-1.5.1 19-1 21-1.2.1 22-1.2 23-1.2.2.r 24-1.2.2.1.1 26-1.2.2.1.1 27-1.2.2.2.1 28-1.2.2.2 29-1.2.2 30-1.3.r 30-1.6.1.2.2.r 30-1.6.1.3.2.r 30-1.6.1.4.2.r 31-1.3.1.1 33-1.3.1.1 36-1.6.1.1.1.1.1.1 37-1.6.1.1.1 38-1.6.1.1.1.2.1 40-1.6.1.2.2 42-1.6.1.2.1.1.1.1 43-1.6.1 43-1.6.1.1.1 43-1.6.1.2.1 43-1.6.1.3.1 43-1.6.1.4.1 44-1.6.1.1.1.2.1 46-1.6.1.3.2 48-1.6.1.3.1.1.1.1 49-1.6.1 49-1.6.1.1.1 49-1.6.1.2.1 49-1.6.1.3.1 49-1.6.1.4.1 50-1.6.1.1.1.2.1 52-1.6.1.4.2 54-1.6.1.4.1.1.1.1 55-1.6.1 55-1.6.1.1.1 55-1.6.1.2.1 55-1.6.1.3.1 55-1.6.1.4.1 56-1.6.1.1.1.2.1 58-1.6.1.1.2.1 (i / identify-01~e.19 :ARG0 (a / and~e.16 :op1 (g / group~e.8 :ARG1-of (l / lead-02 :ARG0 (p / person :name (n / name :op1 "Weinberg"~e.10)))) :op2 (g2 / group~e.8 :ARG1-of (l2 / lead-02 :ARG0 (p2 / person :name (n2 / name :op1 "Cooper"~e.12)))) :op3 (g3 / group~e.8 :ARG1-of (l3 / lead-02 :ARG0 (p3 / person :name (n3 / name :op1 "Barbacid"~e.14)))) :op4 (g4 / group~e.8 :ARG1-of (l4 / lead-02 :ARG0 (p4 / person :name (n4 / name :op1 "Wigler"~e.17))))) :ARG1 (g5 / gene~e.22 :ARG0-of (t / transform-01~e.21) :part-of~e.23 (c2 / cell-line~e.29 :name (n5 / name :op1 "T24/EJ"~e.24,26) :mod (c3 / carcinoma~e.28 :mod (b / bladder~e.27)))) :ARG2~e.30 (e2 / enzyme :name (n6 / name :op1 "H-Ras"~e.31,33)) :manner (s / series~e.2 :consist-of~e.3 (e / experiment-01~e.5 :mod (c / classic~e.4))) :ARG0-of (d3 / depend-01 :polarity -~e.18) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.43,49,55 :op1 (p5 / publication-91 :ARG0 (a3 / and~e.37,43,49,55 :op1 (p9 / person :name (n7 / name :op1 "Der"~e.36)) :op2 (p10 / person :mod (o / other~e.38,44,50,56))) :time (d2 / date-entity :year 1982~e.58)) :op2 (p6 / publication-91 :ARG0 (a4 / and~e.43,49,55 :op1 (p11 / person :name (n8 / name :op1 "Parada"~e.42)) :op2 p10) :time~e.30 d2~e.40) :op3 (p7 / publication-91 :ARG0 (a5 / and~e.43,49,55 :op1 (p12 / person :name (n9 / name :op1 "Santos"~e.48)) :op2 p10) :time~e.30 d2~e.46) :op4 (p8 / publication-91 :ARG0 (a6 / and~e.43,49,55 :op1 (p13 / person :name (n10 / name :op1 "Taparowsky"~e.54)) :op2 p10) :time~e.30 d2~e.52)))) # ::id pmid_2465_1010.28 ::amr-annotator SDL-AMR-09 ::preferred # ::tok More than 30 years later , Ras genes are well established as the most frequently mutated oncogenes in human cancer ( Table 1 @ ) , though H @-@ Ras itself is rarely one of them . # ::alignments 0-1.4.1 1-1.4.1 2-1.4.1.1.1 3-1.4.1.1.2 4-1.4 6-1.1.1.1 7-1.1 7-1.5.1 9-1.3 10-1 11-1.2.r 11-1.4.r 13-1.2.1.1.1 14-1.2.1.1 15-1.2.1 16-1.2 17-1.2.2.r 18-1.2.2.3 19-1.2.2.2.1 22-1.6.1 23-1.6.1.1 28-1.5.r 29-1.5.1.1.1 31-1.5.1.1.1 34-1.5.3 35-1.6.1.1 (e3 / establish-01~e.10 :ARG1 (g / gene~e.7 :name (n / name :op1 "Ras"~e.6)) :ARG2~e.11 (o / oncogene~e.16 :ARG1-of (m2 / mutate-01~e.15 :ARG1-of (f / frequent-02~e.14 :degree (m3 / most~e.13))) :location~e.17 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.19) :mod (h / human~e.18))) :mod (w / well~e.9) :time~e.11 (l / late~e.4 :op1 (m / more-than~e.0,1 :op1 (t / temporal-quantity :quant 30~e.2 :unit (y / year~e.3)))) :concession~e.28 (i / include-91 :ARG1 (g2 / gene~e.7 :name (n2 / name :op1 "H-Ras"~e.29,31)) :ARG2 g :ARG1-of (r / rare-02~e.34)) :ARG1-of (d / describe-01 :ARG0 (t2 / table~e.22 :mod 1~e.23,35))) # ::id pmid_2465_1010.29 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although these numbers are , by now , painfully familiar , they underscore major gaps in our knowledge of Ras biology . # ::alignments 0-1.3.r 1-1.1.1 2-1.1 5-1.3.3 6-1.3.3.1 8-1.3.2 9-1.3 11-1.3.1 12-1 13-1.2.1 14-1.2 15-1.2.2.r 16-1.2.2.1 16-1.2.2.1.r 17-1.2.2 18-1.2.2.2.r 19-1.2.2.2.1.1.1 20-1.2.2.2 (u / underscore-01~e.12 :ARG0 (n2 / number~e.2 :mod (t / this~e.1)) :ARG1 (g / gap~e.14 :ARG1-of (m / major-02~e.13) :topic~e.15 (k / know-03~e.17 :ARG0~e.16 (w / we~e.16) :ARG1~e.18 (b / biology~e.20 :mod (e2 / enzyme :name (n3 / name :op1 "Ras"~e.19))))) :concession~e.0 (f / familiarize-01~e.9 :ARG1 n2~e.11 :degree (p / pain-01~e.8) :time (b2 / by~e.5 :op1 (n / now~e.6)))) # ::id pmid_2465_1010.30 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Most obviously , we do not understand why K @-@ Ras mutation is much more frequent in human cancer than N @-@ Ras or H @-@ Ras , even though each of these is a powerful transforming gene in model systems , and all forms are expressed widely in adult tissues and in tumors . # ::alignments 0-1.4.1 1-1.4 3-1.2 5-1.1 5-1.1.r 6-1 7-1.3 7-1.3.1 7-1.3.1.r 8-1.3.1.1.1.1.1.1 10-1.3.1.1.1.1.1.1 11-1.3.1.1.1 11-1.3.1.1.4.1 11-1.3.1.1.4.2 13-1.3.1.1.2.1 14-1.3.1.1.2 15-1.3.1.1 16-1.3.1.1.3.r 17-1.3.1.1.3.3 18-1.3.1.1.3.2.1 19-1.3.1.1.4.r 20-1.3.1.1.4.1.1.1.1 22-1.3.1.1.4.1.1.1.1 22-1.3.1.1.4.2.1.1.1 23-1.3.1.1.4 24-1.3.1.1.4.2.1.1.1 26-1.3.1.1.1.1.1.1 26-1.3.1.1.4.2.1.1.1 28-1.5.r 29-1.5.r 33-1.5.1.1.r 35-1.5.1.4 36-1.5.1.2 37-1.5.1 38-1.5.1.3.r 39-1.5.1.3.1 40-1.5.1.3 42-1.5 42-1.5.1.1 43-1.5.2.1.1 44-1.5.2.1 46-1.5.2 47-1.5.2.3 48-1.5.2.2.r 49-1.5.2.2.1.1 50-1.5.2.2.1 51-1.5.2.2 53-1.5.2.2.2 (u2 / understand-01~e.6 :polarity~e.5 -~e.5 :ARG0 (w / we~e.3) :ARG1 (t / thing~e.7 :ARG0-of~e.7 (c / cause-01~e.7 :ARG1 (f / frequent-02~e.15 :ARG1 (m3 / mutate-01~e.11 :ARG1 (e3 / enzyme :name (n4 / name :op1 "K-Ras"~e.8,10,26))) :degree (m / more~e.14 :quant (m2 / much~e.13)) :location~e.16 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.18) :mod (h / human~e.17)) :compared-to~e.19 (o3 / or~e.23 :op1 (m5 / mutate-01~e.11 :ARG1 (e4 / enzyme :name (n5 / name :op1 "N-Ras"~e.20,22))) :op2 (m7 / mutate-01~e.11 :ARG1 (e5 / enzyme :name (n6 / name :op1 "H-Ras"~e.22,24,26))))))) :ARG1-of (o / obvious-01~e.1 :degree (m4 / most~e.0)) :concession~e.28,29 (a2 / and~e.42 :op1 (g / gene~e.37 :domain~e.33 (a / and~e.42 :op1 e3 :op2 e4 :op3 e5) :ARG0-of (t2 / transform-01~e.36) :location~e.38 (s / system~e.40 :mod (m6 / model~e.39)) :ARG1-of (p / powerful-02~e.35)) :op2 (e / express-03~e.46 :ARG1 (f2 / form~e.44 :mod (a3 / all~e.43)) :ARG3~e.48 (a4 / and~e.51 :op1 (t3 / tissue~e.50 :mod (a5 / adult~e.49)) :op2 (t4 / tumor~e.53)) :ARG1-of (w2 / wide-02~e.47)))) # ::id pmid_2465_1010.31 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A simple explanation for the high frequency of K @-@ Ras mutations , relative to H @-@ Ras and N @-@ Ras , is that the K @-@ Ras protein has unique properties that favor oncogenesis . # ::alignments 1-1.3 2-1 3-1.2.r 5-1.2.2 6-1.2 7-1.1.r 8-1.1.2.1.1 10-1.1.2.1.1 10-1.2.3.1.1.1.1 11-1.2.1 11-1.2.3.1 11-1.2.3.2 14-1.2.3.1.1.r 14-1.2.3.r 15-1.2.3.1.1.1.1 17-1.2.3.1.1.1.1 17-1.2.3.2.1.1.1 18-1.2.3 19-1.2.3.2.1.1.1 21-1.1.2.1.1 21-1.2.3.2.1.1.1 26-1.1.2.1.1 28-1.1.2.1.1 31-1.1.1 32-1.1 34-1.1.3 (e3 / explain-01~e.2 :ARG0~e.7 (p / property~e.32 :mod (u / unique~e.31) :poss (e / enzyme :name (n / name :op1 "K-Ras"~e.8,10,21,26,28)) :ARG0-of (f / favor-01~e.34 :ARG1 (c / create-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))) :ARG1~e.3 (f2 / frequent-02~e.6 :ARG1 (m / mutate-01~e.11 :ARG1 e) :ARG1-of (h / high-02~e.5) :compared-to~e.14 (a2 / and~e.18 :op1 (m2 / mutate-01~e.11 :ARG1~e.14 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.10,15,17))) :op2 (m3 / mutate-01~e.11 :ARG1 (e4 / enzyme :name (n3 / name :op1 "N-Ras"~e.17,19,21))))) :ARG1-of (s / simple-02~e.1)) # ::id pmid_2465_1010.32 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At first sight , this seems unlikely because the Ras proteins are highly conserved , especially in their effector @-@ binding regions where they are actually identical . # ::alignments 1-1.3.1 1-1.3.1.1 1-1.3.1.1.r 4-1.1.2.1 5-1 6-1.1 6-1.1.1 6-1.1.1.r 7-1.2 9-1.2.1.1.1.1 10-1.2.1.3 12-1.2.1.2 13-1.2.1 15-1.2.1.3.4 16-1.2.1.3.2.r 17-1.2.1.3.2 18-1.2.1.3.1.1 20-1.2.1.3.1 22-1.2.1.3.r 25-1.2.1.3.3.1 26-1.2.1.3.3 (s / seem-01~e.5 :ARG1 (l / likely-01~e.6 :polarity~e.6 -~e.6 :ARG1 (t / thing :mod (t2 / this~e.4))) :ARG1-of (c / cause-01~e.7 :ARG0 (c2 / conserve-01~e.13 :ARG1 (p2 / protein-family :name (n2 / name :op1 "Ras"~e.9)) :ARG1-of (h / high-02~e.12) :location~e.22 (p / protein-segment~e.10 :ARG1-of (b / bind-01~e.20 :ARG2 (e / effector~e.18)) :part-of~e.16 p2~e.17 :ARG1-of (i / identical-01~e.26 :ARG1-of (a / actual-02~e.25)) :degree (e4 / especially~e.15)))) :time (s2 / see-01 :ord (o / ordinal-entity~e.1 :value~e.1 1~e.1))) # ::id pmid_2465_1010.33 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , K @-@ Ras , but not N @-@ Ras or H @-@ Ras , confers stem @-@ like properties on certain cell types ( Quinlan and Settleman , 2009 ) . # ::alignments 0-1.1.4 2-1.1.1.1.1 4-1.1.1.1.1 6-1 6-1.1.4 7-1.1.4.1.1 7-1.1.4.1.1.r 8-1.1.4.1.2.1.1.1 10-1.1.4.1.2.1.1.1 10-1.1.4.1.2.2.1.1 11-1.1.4.1.2 12-1.1.4.1.2.2.1.1 14-1.1.1.1.1 14-1.1.4.1.2.2.1.1 16-1.1 16-1.1.4.1 17-1.1.2.1.1.1.1 19-1.1.2.1 20-1.1.2 20-1.1.2.1.1 21-1.1.3.r 22-1.1.3.2 23-1.1.2.1.1.1 23-1.1.3.1 24-1.1.3 27-1.1.5.1.1.1.1.1 28-1.1.5.1.1 29-1.1.5.1.1.2.1.1 31-1.1.5.1.2.1 (c4 / contrast-01~e.6 :ARG2 (c / confer-02~e.16 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras"~e.2,4,14)) :ARG1 (p / property~e.20 :ARG1-of (r / resemble-01~e.19 :ARG2 (p5 / property~e.20 :poss (c5 / cell~e.23 :mod (s / stem~e.17))))) :ARG2~e.21 (t / type-03~e.24 :ARG1 (c2 / cell~e.23) :mod (c3 / certain~e.22)) :ARG1-of (c6 / contrast-01~e.0,6 :ARG0 (c7 / confer-02~e.16 :polarity~e.7 -~e.7 :ARG0 (o / or~e.11 :op1 (e3 / enzyme :name (n3 / name :op1 "N-Ras"~e.8,10)) :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.10,12,14))) :ARG1 p :ARG2 t)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and~e.28 :op1 (p3 / person :name (n4 / name :op1 "Quinlan"~e.27)) :op2 (p4 / person :name (n5 / name :op1 "Settleman"~e.29))) :time (d / date-entity :year 2009~e.31))))) # ::id pmid_2465_1010.34 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras @-@ 4B , the most highly expressed splice variant of K @-@ Ras , binds calmodulin ; H @-@ Ras and N @- Ras do not ( Villalonga et al. , 2001 ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 2-1.1.1.2.2.1.1.1.1 4-1.1.1.1.1 7-1.1.1.2.1.1.1 8-1.1.1.2.1.1 9-1.1.1.2.1 10-1.1.1.2.2.1 11-1.1.1.2 13-1.1.1.1.1 15-1.2.2.1.1.1 17-1.1 17-1.2 18-1.1.2.1.1 18-1.2.3.1.1 20-1.2.2.1.1.1 22-1.2.2.1.1.1 22-1.2.2.2.1.1 23-1.2.2 24-1.2.2.2.1.1 26-1.2.2.2.1.1 28-1.2.1 28-1.2.1.r 31-1.3.1.1.1.1.1 32-1.3.1.1 33-1.3.1.1.2.1 35-1.3.1.2.1 (m / multi-sentence :snt1 (b / bind-01~e.17 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras-4B"~e.0,2,4,13) :mod (v2 / variant~e.11 :ARG1-of (e5 / express-03~e.9 :ARG1-of (h / high-02~e.8 :degree (m2 / most~e.7)) :compared-to r) :ARG2-of (r / result-01 :ARG1 (s / splice-01~e.10 :ARG1 (e4 / enzyme :name (n4 / name :op1 "K-Ras"~e.2)))))) :ARG2 (p / protein :name (n5 / name :op1 "calmodulin"~e.18))) :snt2 (b2 / bind-01~e.17 :polarity~e.28 -~e.28 :ARG1 (a / and~e.23 :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.15,20,22)) :op2 (e3 / enzyme :name (n3 / name :op1 "N-Ras"~e.22,24,26))) :ARG2 (p5 / protein :name (n7 / name :op1 "calmodulin"~e.18))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.32 :op1 (p3 / person :name (n6 / name :op1 "Villalonga"~e.31)) :op2 (p4 / person :mod (o / other~e.33))) :time (d / date-entity :year 2001~e.35)))) # ::id pmid_2465_1010.35 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We believe that this unique property of K @-@ Ras @-@ 4B confers stem @-@ like properties to cells expressing oncogenic K @-@ Ras @-@ 4B proteins ( M . Wang and F.M . , unpublished data ) . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1 4-1.2.1.2 5-1.2.1 6-1.2.1.3.r 7-1.2.1.3.1.1 9-1.2.1.3.1.1 11-1.2.1.3.1.1 12-1.2 13-1.2.2.1.1.1.1 15-1.2.2.1 16-1.2.2 16-1.2.2.1.1 18-1.2.2.1.1.1 18-1.2.3 19-1.2.3.1 20-1.2.3.1.1 20-1.2.3.1.1.2 20-1.2.3.1.1.2.1.2.1 20-1.2.3.1.1.2.r 21-1.2.1.3.1.1 21-1.2.3.1.1.1.1 23-1.2.1.3.1.1 23-1.2.3.1.1.1.1 25-1.2.1.3.1.1 25-1.2.3.1.1.1.1 30-1.3.1.1.2.1.1.2 31-1.3.1.1.2 35-1.3.1.1.1 36-1.3.1 (b / believe-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (c / confer-02~e.12 :ARG0 (p / property~e.5 :mod (t / this~e.3) :mod (u / unique~e.4) :poss~e.6 (e / enzyme :name (n / name :op1 "K-Ras-4B"~e.7,9,11,21,23,25))) :ARG1 (p2 / property~e.16 :ARG1-of (r / resemble-01~e.15 :ARG2 (p6 / property~e.16 :poss (c5 / cell~e.18 :mod (s / stem~e.13))))) :ARG2 (c2 / cell~e.18 :ARG3-of (e2 / express-03~e.19 :ARG2 (e3 / enzyme~e.20 :name (n2 / name :op1 "K-Ras-4B"~e.21,23,25) :ARG0-of~e.20 (c3 / cause-01~e.20 :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.20))))))) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.36 :ARG1-of (p3 / publish-01 :polarity -~e.35 :ARG0 (a / and~e.31 :op1 (p4 / person :name (n3 / name :op1 "M." :op2 "Wang"~e.30)) :op2 (p5 / person :name (n4 / name :op1 "F.M."))))))) # ::id pmid_2465_1010.36 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of human syndromes caused by germline mutations in H @-@ Ras or K @-@ Ras supports the idea that K @-@ Ras is a stronger oncogene . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1 4-1.1.1.2 5-1.1.1.2.1.r 6-1.1.1.2.1.1 7-1.1.1.2.1 8-1.1.1.2.1.2.r 9-1.1.1.2.1.2.1.1.1 11-1.1.1.2.1.2.1.1.1 11-1.1.1.2.1.2.2.1.1 12-1.1.1.2.1.2 13-1.1.1.2.1.2.2.1.1 15-1.1.1.2.1.2.1.1.1 15-1.1.1.2.1.2.2.1.1 16-1 18-1.2 20-1.1.1.2.1.2.2.1.1 22-1.1.1.2.1.2.1.1.1 22-1.1.1.2.1.2.2.1.1 23-1.2.1.1.r 25-1.2.1.3 25-1.2.1.3.1 25-1.2.1.3.1.r 26-1.2.1 (s / support-01~e.16 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (s2 / syndrome~e.3 :mod (h / human~e.2) :ARG1-of (c / cause-01~e.4 :ARG0~e.5 (m / mutate-01~e.7 :ARG1 (g / germline~e.6) :location~e.8 (o / or~e.12 :op1 (e / enzyme :name (n / name :op1 "H-Ras"~e.9,11,15,22)) :op2 (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.11,13,15,20,22))))))) :ARG1 (i / idea~e.18 :mod (o2 / oncogene~e.26 :domain~e.23 e2 :compared-to e :ARG1-of (s3 / strong-02~e.25 :degree~e.25 (m2 / more~e.25))))) # ::id pmid_2465_1010.37 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Unexpectedly , humans can tolerate germline @-@ activating mutations in H @-@ Ras—the same activating mutations that drive somatic mutations . # ::alignments 0-1.2.1 2-1.1.1 3-1 4-1.1 5-1.1.2.1.1 7-1.1.2.1 8-1.1.2 9-1.1.2.2.r 10-1.1.2.2.1.1 13-1.1.2.3 14-1.1.2.3.1.2 15-1.1.2.3.1 17-1.1.2.3.1.1 18-1.1.2.3.1.1.1.1 19-1.1.2.3.1.1.1 (p / possible-01~e.3 :ARG1 (t / tolerate-01~e.4 :ARG0 (h / human~e.2) :ARG1 (m / mutate-01~e.8 :ARG0-of (a / activate-01~e.7 :ARG1 (g / germline~e.5)) :location~e.9 (e / enzyme :name (n / name :op1 "H-Ras"~e.10)) :ARG1-of (s2 / same-01~e.13 :ARG2 (m2 / mutate-01~e.15 :ARG0 (d / drive-02~e.17 :ARG1 (m3 / mutate-01~e.19 :mod (s / somatic~e.18))) :ARG0-of (a2 / activate-01~e.14))))) :ARG1-of (e2 / expect-01 :polarity -~e.0)) # ::id pmid_2465_1010.38 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Costello syndrome , which is characterized by germline H @-@ Ras mutations , is associated with a broad spectrum of developmental abnormalities and a high risk for rhabdomyosarcomas and neuroblastomas ( reviewed in Rauen , 2013 ) . # ::alignments 0-1.1.1.1 1-1.1.1.2 5-1.1.2 6-1.1.2.1.r 7-1.1.2.1.2 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 11-1.1.2.1 14-1 15-1.2.r 17-1.2.1.1.1 18-1.2.1.1 19-1.2.1.1.r 20-1.2.1.2 21-1.2.1 22-1.2 22-1.2.2.1 24-1.2.2.2 25-1.2.2 28-1.2 28-1.2.2.1 31-1.3 34-1.3.1.1.1.1 36-1.3.1.2.1 (a / associate-01~e.14 :ARG1 (d2 / disease :name (n2 / name :op1 "Costello"~e.0 :op2 "syndrome"~e.1) :ARG1-of (c / characterize-01~e.5 :ARG2~e.6 (m / mutate-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "H-Ras"~e.8,10)) :location (g2 / germline~e.7)))) :ARG2~e.15 (a3 / and~e.22,28 :op1 (a2 / abnormality~e.21 :quant~e.19 (s / spectrum~e.18 :ARG1-of (b / broad-02~e.17)) :mod (g / growth~e.20)) :op2 (r / risk-01~e.25 :ARG2 (a4 / and~e.22,28 :op1 (m2 / medical-condition :name (n3 / name :op1 "rhabdomyosarcoma")) :op2 (m3 / medical-condition :name (n4 / name :op1 "neuroblastoma"))) :ARG1-of (h / high-02~e.24))) :ARG1-of (r2 / review-02~e.31 :ARG2 (p2 / publication-91 :ARG0 (p3 / person :name (n5 / name :op1 "Rauen"~e.34)) :time (d / date-entity :year 2013~e.36)))) # ::id pmid_2465_1010.39 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is puzzling that these individuals do not succumb to malignancies associated with sporadic H @-@ Ras mutations ( Table 1 ) . # ::alignments 2-1 4-1.1.2.1 5-1.1.2 7-1.1.1 7-1.1.1.r 8-1.1 9-1.1.3.r 10-1.1.3 11-1.1.3.1 12-1.1.3.1.1.r 13-1.1.3.1.1.2 14-1.1.3.1.1.1.1.1 16-1.1.3.1.1.1.1.1 17-1.1.3.1.1 20-1.2.1 21-1.2.1.1 (p / puzzle-01~e.2 :ARG0 (s / succumb-01~e.8 :polarity~e.7 -~e.7 :ARG0 (i / individual~e.5 :mod (t / this~e.4)) :ARG1~e.9 (m / malignancy~e.10 :ARG1-of (a / associate-01~e.11 :ARG2~e.12 (m2 / mutate-01~e.17 :ARG1 (e / enzyme :name (n / name :op1 "H-Ras"~e.14,16)) :time (s2 / sporadic~e.13))))) :ARG1-of (d / describe-01 :ARG0 (t2 / table~e.20 :mod 1~e.21))) # ::id pmid_2465_1010.40 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although fully activating alleles of H @-@ Ras can be tolerated , fully activated alleles of K @-@ Ras may not . # ::alignments 0-1.3.r 1-1.2.1.1.1 2-1.2.1.1 3-1.2.1 5-1.3.1.1.2.1.1 7-1.2.1.2.1.1 7-1.3.1.1.2.1.1 8-1 8-1.3 10-1.2 10-1.3.1 12-1.2.1.1.1 13-1.2.1.1 13-1.3.1.1.1 14-1.2.1 14-1.3.1.1 15-1.2.1.2.r 16-1.2.1.2.1.1 18-1.2.1.2.1.1 18-1.3.1.1.2.1.1 19-1 20-1.1 20-1.1.r (p / possible-01~e.8,19 :polarity~e.20 -~e.20 :ARG1 (t / tolerate-01~e.10 :ARG1 (a / allele~e.3,14 :ARG1-of (a2 / activate-01~e.2,13 :degree (f / full~e.1,12)) :mod~e.15 (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.7,16,18)))) :concession~e.0 (p2 / possible-01~e.8 :ARG1 (t2 / tolerate-01~e.10 :ARG1 (a3 / allele~e.14 :ARG0-of (a4 / activate-01~e.13 :manner f) :mod (e / enzyme :name (n / name :op1 "H-Ras"~e.5,7,18)))))) # ::id pmid_2465_1010.41 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Variant alleles of K @-@ Ras that account for a small fraction of Noonan ’s syndrome and cardiofaciocutaneous syndrome are weakly activated relative to their sporadic oncogenic counterparts ( Schubbert et al. , 2007 ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1 5-1.1.2.1.1 7-1.1.3 8-1.1.3.1.r 10-1.1.3.1.3.1 11-1.1.3.1.3 15-1.1.3.1.1.1.2 16-1.1.3.1 17-1.1.3.1.2.1.1 18-1.1.3.1.2.1.2 20-1.2 21-1 23-1.3.3 24-1.3.2 24-1.3.2.r 25-1.3.1 26-1.3.3 26-1.3.3.1.2.1 27-1.3 30-1.4.1.1.1.1.1 31-1.4.1.1 32-1.4.1.1.2.1 34-1.4.1.2.1 (a / activate-01~e.21 :ARG1 (a2 / allele~e.1 :mod (v2 / variant~e.0) :mod~e.2 (e / enzyme :name (n / name :op1 "K-Ras"~e.3,5)) :ARG0-of (a3 / account-01~e.7 :ARG1~e.8 (a4 / and~e.16 :op1 (d2 / disease :name (n2 / name :op1 "Noonan’s" :op2 "syndrome"~e.15)) :op2 (d3 / disease :name (n3 / name :op1 "cardiofaciocutaneous"~e.17 :op2 "syndrome"~e.18)) :quant (f / fraction~e.11 :mod (s / small~e.10))))) :ARG1-of (w / weak-02~e.20) :compared-to (c / counterpart~e.27 :mod (s2 / sporadic~e.25) :poss~e.24 v2~e.24 :ARG0-of (c2 / cause-01~e.23,26 :ARG1 (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.26)))) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a5 / and~e.31 :op1 (p2 / person :name (n4 / name :op1 "Schubbert"~e.30)) :op2 (p3 / person :mod (o / other~e.32))) :time (d / date-entity :year 2007~e.34)))) # ::id pmid_2465_1010.42 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further support for the idea that K @-@ Ras has functions distinct from H @-@ Ras and N @-@ Ras comes from analyses of the roles of Ras genes in development . # ::alignments 0-1.3 1-1 2-1.2.r 4-1.2 6-1.2.1.1.1.1 8-1.2.1.1.1.1 10-1.2.1 10-1.2.1.2.1.1 10-1.2.1.2.1.2 11-1.2.1.2 12-1.2.1.2.1.1.1.r 12-1.2.1.2.1.r 13-1.2.1.2.1.1.1.1.1 15-1.2.1.2.1.1.1.1.1 15-1.2.1.2.1.2.1.1.1 16-1.2.1.2.1 17-1.2.1.2.1.2.1.1.1 19-1.2.1.2.1.2.1.1.1 21-1.1.r 22-1.1 23-1.1.1.r 25-1.1.1 26-1.1.1.1.r 27-1.1.1.1.1.1 28-1.1.1.1 29-1.1.2.r 30-1.1.2 (s / support-01~e.1 :ARG0~e.21 (a / analyze-01~e.22 :ARG1~e.23 (r / role~e.25 :mod~e.26 (g / gene~e.28 :name (n3 / name :op1 "Ras"~e.27))) :ARG1-of~e.29 (d / develop-02~e.30)) :ARG1~e.2 (i / idea~e.4 :mod (f2 / function-01~e.10 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras"~e.6,8)) :mod (d2 / distinct~e.11 :compared-to~e.12 (a2 / and~e.16 :op1 (f3 / function-01~e.10 :ARG0~e.12 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.13,15))) :op2 (f4 / function-01~e.10 :ARG0 (e4 / enzyme :name (n4 / name :op1 "N-Ras"~e.15,17,19))))))) :degree (f / further~e.0)) # ::id pmid_2465_1010.43 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mice that lack K @-@ Ras die during embryogenesis , whereas mice lacking H @-@ Ras and @/@ or N @-@ Ras are viable ( Johnson et al. , 1997 ) . # ::alignments 0-1.1.1 2-1.1.1.1 3-1.1.1.1.1.1.1 5-1.1.1.1.1.1.1 6-1.1 7-1.1.2.r 10-1 11-1.2.1 12-1.2.1.1 13-1.2.1.1.1.1.1.1 15-1.2.1.1.1.1.1.1 15-1.2.1.1.1.2.1.1 16-1.2.1.1.1 18-1.2.1.1.1 19-1.2.1.1.1.2.1.1 21-1.2.1.1.1.2.1.1 22-1.2.1.r 23-1.2 26-1.3.1.1.1.1.1 27-1.3.1.1 28-1.3.1.1.2.1 30-1.3.1.2.1 (c2 / contrast-01~e.10 :ARG1 (d2 / die-01~e.6 :ARG1 (m / mouse~e.0 :ARG0-of (l / lack-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.3,5)))) :time~e.7 (c / create-01 :ARG1 (e3 / embryo))) :ARG2 (v / viable~e.23 :domain~e.22 (m2 / mouse~e.11 :ARG0-of (l2 / lack-01~e.12 :ARG1 (a / and-or~e.16,18 :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.13,15)) :op2 (e4 / enzyme :name (n3 / name :op1 "N-Ras"~e.15,19,21)))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and~e.27 :op1 (p2 / person :name (n4 / name :op1 "Johnson"~e.26)) :op2 (p3 / person :mod (o / other~e.28))) :time (d / date-entity :year 1997~e.30)))) # ::id pmid_2465_1010.44 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , replacing K @-@ Ras with H @-@ Ras at the K @-@ Ras genomic locus allows mice to develop , suggesting that differential regulation of K @-@ Ras and H @-@ Ras gene expression determines their relative importance in development rather than the properties of the proteins themselves ( Potenza et al. , 2005 ) . # ::alignments 0-1 2-1.1.1 3-1.1.1.1.1.1 5-1.1.1.1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 9-1.1.1.1.1.1 9-1.1.1.2.1.1 12-1.1.1.1.1.1 14-1.1.1.1.1.1 14-1.1.1.2.1.1 15-1.1.1.3.1 16-1.1.1.3 17-1.1 18-1.1.2.1 20-1.1.2 22-1.1.3 23-1.1.3.1.r 24-1.1.3.1.1.2 25-1.1.3.1.1 26-1.1.3.1.3 27-1.1.1.1.1.1 29-1.1.1.1.1.1 29-1.1.1.2.1.1 31-1.1.1.2.1.1 33-1.1.1.1.1.1 33-1.1.1.2.1.1 34-1.1.1.1 34-1.1.1.2 35-1.1.3.1.1.1 36-1.1.3.1 37-1.1.3.1.2.2 37-1.1.3.1.2.2.r 38-1.1.3.1.2.1 39-1.1.3.1.2 40-1.1.3.1.2.3.r 41-1.1.3.1.2.3 42-1.1.3.1.3 45-1.1.3.1.3.1 46-1.1.3.1.3 52-1.2.1.1.1.1.1 53-1.1.3.1.1.1.1 53-1.2.1.1 54-1.2.1.1.2.1 56-1.2.1.2.1 (h / have-concession-91~e.0 :ARG1 (a / allow-01~e.17 :ARG0 (r / replace-01~e.2 :ARG1 (g2 / gene~e.34 :name (n / name :op1 "K-Ras"~e.3,5,9,12,14,27,29,33)) :ARG2 (g3 / gene~e.34 :name (n2 / name :op1 "H-Ras"~e.5,7,9,14,29,31,33)) :location (l / locus~e.16 :mod (g / genomic~e.15) :ARG0-of (c2 / contain-01 :ARG1 g2))) :ARG1 (d2 / develop-01~e.20 :ARG1 (m / mouse~e.18)) :ARG0-of (s / suggest-01~e.22 :ARG1~e.23 (d3 / determine-01~e.36 :ARG0 (r2 / regulate-01~e.25 :ARG1 (e3 / express-03~e.35 :ARG1 (a2 / and~e.53 :op1 g2 :op2 g3)) :mod (d4 / differential~e.24)) :ARG1 (i / important~e.39 :ARG1-of (r3 / relative-05~e.38) :poss~e.37 a2~e.37 :purpose~e.40 (d5 / develop-01~e.41)) :ARG1-of (i2 / instead-of-91~e.26,42,46 :ARG2 (p2 / property~e.45 :poss a2))))) :ARG1-of (d6 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.53 :op1 (p4 / person :name (n3 / name :op1 "Potenza"~e.52)) :op2 (p / person :mod (o / other~e.54))) :time (d / date-entity :year 2005~e.56)))) # ::id pmid_2465_1010.45 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , Balmain and colleagues discovered that these H @-@ Ras knock @-@ in mice develop tumors in response to carcinogens at normal frequencies , except that they are now driven by H @-@ Ras instead of K @-@ Ras ( To et al. , 2008 ) . # ::alignments 0-1.1.1 0-1.2.1.1 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2 5-1.1 6-1.1.2.r 7-1.1.2.1.2 8-1.1.2.1.1.1.1.1 10-1.1.2.1.1.1.1.1 14-1.1.2.1 15-1.1.2 16-1.1.2.2 17-1.1.2.3.r 18-1.1.2.3 19-1.1.2.3.1.r 20-1.1.2.3.1 21-1.1.2.4.r 22-1.1.2.4 25-1.1.2.5 29-1.1.2.5.1.3 30-1.1.2.5.1 30-1.1.2.5.1.4.1 31-1.1.2.5.1.1.r 32-1.1.2.5.1.1 33-1.1.2.5.1.1 34-1.1.2.5.1.1 35-1.1.2.5.1.4 36-1.1.2.5.1.4 36-1.1.2.5.1.4.1.1.r 37-1.1.2.5.1.4.1.1.1.1 39-1.1.2.1.1.1.1.1 39-1.1.2.5.1.4.1.1.1.1 42-1.2.1.1.1.1.1 43-1.2.1.1 44-1.2.1.1.2.1 46-1.2.1.2.1 (a / and :op2 (d2 / discover-01~e.5 :ARG0 (a2 / and~e.0,3 :op1 (p / person :name (n3 / name :op1 "Balmain"~e.2)) :op2 (c / colleague~e.4 :poss p)) :ARG1~e.6 (d3 / develop-01~e.15 :ARG1 (m / mouse~e.14 :ARG3-of (e4 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "H-Ras"~e.8,10,39))) :mod (t2 / this~e.7)) :ARG2 (t / tumor~e.16) :ARG2-of~e.17 (r / respond-01~e.18 :ARG1~e.19 (c3 / carcinogen~e.20)) :frequency~e.21 (n4 / normal-02~e.22) :ARG1-of (e3 / except-01~e.25 :ARG2 (d4 / drive-02~e.30 :ARG0~e.31 e~e.32,33,34 :ARG1 c3 :time (n5 / now~e.29) :ARG1-of (i / instead-of-91~e.35,36 :ARG2 (d5 / drive-02~e.30 :ARG0~e.36 (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.37,39)) :ARG1 c3)))))) :ARG1-of (d6 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and~e.0,43 :op1 (p3 / person :name (n6 / name :op1 "To"~e.42)) :op2 (p4 / person :mod (o / other~e.44))) :time (d / date-entity :year 2008~e.46)))) # ::id pmid_2465_1010.46 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data argue strongly that the locus is critical and that the specific Ras paralog encoded at that locus does not affect the frequency at which tumors arise . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.3 4-1.2.r 6-1.2.1.1 8-1.2.1 9-1.2 10-1.2.r 12-1.2.2.2.2 13-1.2.2.2.1.1.1 14-1.2.2.2 15-1.2.2.2.3 18-1.2.2.2.3.1 20-1.2.2.1 20-1.2.2.1.r 21-1.2.2 23-1.2.2.3 26-1.2.2.3.1.1 27-1.2.2.3.1 (a / argue-01~e.2 :ARG0 (d / data~e.1 :mod (t / this~e.0)) :ARG1~e.4,10 (a2 / and~e.9 :op1 (c / critical-02~e.8 :ARG1 (l / locus~e.6)) :op2 (a3 / affect-01~e.21 :polarity~e.20 -~e.20 :ARG0 (p / paralog~e.14 :mod (e / enzyme :name (n / name :op1 "Ras"~e.13)) :ARG1-of (s2 / specific-02~e.12) :ARG1-of (e2 / encode-01~e.15 :location l~e.18)) :ARG1 (h / have-frequency-91~e.23 :ARG1 (a4 / arise-02~e.27 :ARG1 (t3 / tumor~e.26))))) :ARG1-of (s / strong-02~e.3)) # ::id pmid_2465_1010.47 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Equally important , they find that K @-@ Ras @-@ 4A , not K @-@ Ras @-@ 4B , is necessary for lung tumor initiation , although K @-@ Ras @-@ 4B is much more highly expressed during progression . # ::alignments 0-1.3.1 1-1.3 3-1.1 4-1 5-1.2.r 6-1.2.1.1.1 8-1.2.1.1.1 10-1.2.1.1.1 12-1.2.4.1.1 12-1.2.4.1.1.r 13-1.2.4.1.2.1.1 15-1.2.4.1.2.1.1 17-1.2.4.1.2.1.1 20-1.2 20-1.2.4.1 21-1.2.2.r 22-1.2.2.1.1 23-1.2.2.1 24-1.2.2 26-1.2.3.r 27-1.2.1.1.1 27-1.2.4.1.2.1.1 29-1.2.1.1.1 29-1.2.4.1.2.1.1 31-1.2.3.1 33-1.2.3.2.1.1 34-1.2.3.2.1 35-1.2.3.2 36-1.2.3 37-1.2.3.3.r 38-1.2.3.3 (f / find-01~e.4 :ARG0 (t / they~e.3) :ARG1~e.5 (n2 / need-01~e.20 :ARG1 (e / enzyme :name (n3 / name :op1 "K-Ras-4A"~e.6,8,10,27,29)) :purpose~e.21 (i2 / initiate-01~e.24 :ARG1 (t2 / tumor~e.23 :mod (l / lung~e.22))) :concession~e.26 (e4 / express-03~e.36 :ARG2 e2~e.31 :ARG1-of (h / high-02~e.35 :degree (m / more~e.34 :quant (m2 / much~e.33))) :time~e.37 (p / progress-01~e.38 :ARG1 t2)) :ARG1-of (c / contrast-01 :ARG2 (n / need-01~e.20 :polarity~e.12 -~e.12 :ARG1 (e2 / enzyme :name (n4 / name :op1 "K-Ras-4B"~e.13,15,17,27,29)) :purpose i2))) :mod (i3 / important~e.1 :degree (e3 / equal~e.0))) # ::id pmid_2465_1010.48 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This supports the idea that K @-@ Ras @-@ 4B is the more important target in established tumors but raises the concern that K @-@ Ras @-@ 4A may have an important role in minor stem @-@ like populations of established tumors . # ::alignments 0-1.1.1.1 1-1.1 3-1.1.2 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 9-1.1.2.1.1.1.1 12-1.1.2.1.2.1 13-1.1.2.1.2 14-1.1.2.1 15-1.1.2.1.2.2.r 16-1.1.2.1.2.2.1 17-1.1.2.1.2.2 18-1 19-1.2 21-1.2.2 23-1.2.2.1.1.1.1.1 25-1.2.2.1.1.1.1.1 27-1.2.2.1.1.1.1.1 28-1.2.2.1 29-1.2.2.1.1.2 31-1.2.2.1.1.2 32-1.2.2.1.1 33-1.2.2.1.1.3.r 34-1.2.2.1.1.3.1 35-1.2.2.1.1.3.2.1.1.1.1 37-1.2.2.1.1.3.2.1 37-1.2.2.1.1.3.2.1.1 37-1.2.2.1.1.3.2.1.1.r 38-1.2.2.1.1.3 39-1.2.2.1.1.3.3.r 40-1.2.2.1.1.3.3 41-1.2.2.1.1.3.3 (c / contrast-01~e.18 :ARG1 (s / support-01~e.1 :ARG0 (t / thing :mod (t2 / this~e.0)) :ARG1 (i / idea~e.3 :mod (t3 / target-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras-4B"~e.5,7,9)) :mod (i2 / important~e.13 :degree (m / more~e.12) :location~e.15 (t4 / tumor~e.17 :ARG1-of (e2 / establish-01~e.16)))))) :ARG2 (r3 / raise-01~e.19 :ARG0 t :ARG1 (c2 / concern-01~e.21 :ARG0 (p / possible-01~e.28 :ARG1 (r2 / role~e.32 :poss (e3 / enzyme :name (n2 / name :op1 "K-Ras-4A"~e.23,25,27)) :mod (i3 / important~e.29,31) :topic~e.33 (p2 / population~e.38 :ARG1-of (m2 / minor-01~e.34) :ARG1-of (c3 / consist-01 :ARG2 (c4 / cell~e.37 :ARG1-of~e.37 (r / resemble-01~e.37 :ARG2 (c5 / cell :mod (s2 / stem~e.35))))) :part-of~e.39 t4~e.40,41)))))) # ::id pmid_2465_1010.49 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These findings point toward an urgent need to validate K @-@ Ras @-@ 4A and K @-@ Ras @-@ 4B as drug targets , a major issue that has not yet been addressed . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 5-1.2.2 6-1.2 8-1.2.1 9-1.2.1.1.1.1.1 9-1.2.1.1.2.1.1 11-1.2.1.1.1.1.1 11-1.2.1.1.2.1.1 13-1.2.1.1.1.1.1 14-1.2.1.1 15-1.2.1.1.1.1.1 15-1.2.1.1.2.1.1 17-1.2.1.1.1.1.1 17-1.2.1.1.2.1.1 19-1.2.1.1.2.1.1 20-1.2.1.1.r 20-1.2.3.2.2.r 21-1.2.1.1.3.1 22-1.2.1.1.3 25-1.2.3.1 26-1.2.3 29-1.2.3.2.1 29-1.2.3.2.1.r 30-1.2.3.2.2 32-1.2.3.2 (p / point-01~e.2 :ARG0 (t / thing~e.1 :ARG1-of~e.1 (f / find-01~e.1) :mod (t2 / this~e.0)) :ARG2 (n / need-01~e.6 :ARG1 (v / validate-01~e.8 :ARG1~e.20 (a / and~e.14 :op1 (e / enzyme :name (n2 / name :op1 "K-Ras-4A"~e.9,11,13,15,17)) :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras-4B"~e.9,11,15,17,19)) :ARG1-of (t3 / target-01~e.22 :ARG0 (d / drug~e.21)))) :mod (u / urgent~e.5) :ARG0-of (i / issue-02~e.26 :ARG1-of (m / major-02~e.25) :ARG1-of (a2 / address-02~e.32 :polarity~e.29 -~e.29 :time~e.20 (y / yet~e.30))))) # ::id pmid_2465_1010.50 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Different frequencies of K @-@ Ras , N @-@ Ras , and H @-@ Ras mutations in human tumors may also reflect differences in gene expression resulting from differential codon usage ; rare codons limit K @-@ Ras expression and thus allow more efficient oncogenesis by preventing oncogene @-@ induced senescence ( Lampson et al. , 2013 ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1 3-1.1.1.1.1.1.1.1.1 5-1.1.1.1.1.1.1.1.1 5-1.1.1.1.1.1.2.1.1 7-1.1.1.1.1.1.2.1.1 9-1.1.1.1.1.1.1.1.1 9-1.1.1.1.1.1.2.1.1 9-1.1.1.1.1.1.3.1.1 11-1.1.1.1.1.1 12-1.1.1.1.1.1.3.1.1 14-1.1.1.1.1.1.1.1.1 14-1.1.1.1.1.1.3.1.1 15-1.1.1.1.1 17-1.1.1.1.3.1 18-1.1.1.1.3 19-1.1 20-1.1.2 21-1.1.1 22-1.1.1.2 23-1.1.1.2.1.r 24-1.1.1.2.1.1 25-1.1.1.2.1 26-1.1.1.2.2 27-1.1.1.2.2.1.r 28-1.1.1.2.2.1.2 29-1.1.1.2.2.1.1 30-1.1.1.2.2.1 32-1.2.1.1 32-1.2.1.1.2 32-1.2.1.1.2.r 33-1.2.1.1.1.1 34-1.2.1 35-1.2.1.2.1.1.1 37-1.2.1.2.1.1.1 38-1.2.1.2 39-1.2 40-1.2.2.3 41-1.2.2 42-1.2.2.2.2 43-1.2.2.2 45-1.2.2.4.r 46-1.2.2.4 47-1.2.2.4.2.1.1 49-1.2.2.4.2.1 50-1.2.2.4.2 53-1.3.1.1.1.1.1 54-1.3.1.1 55-1.3.1.1.2.1 57-1.3.1.2.1 (m / multi-sentence :snt1 (p / possible-01~e.19 :ARG1 (r / reflect-01~e.21 :ARG1 (h / have-frequency-91~e.1 :ARG1 (m2 / mutate-01~e.15 :ARG1 (a / and~e.11 :op1 (e / enzyme :name (n / name :op1 "K-Ras"~e.3,5,9,14)) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"~e.5,7,9)) :op3 (e3 / enzyme :name (n3 / name :op1 "H-Ras"~e.9,12,14)))) :ARG1-of (d3 / differ-02~e.0) :location (t / tumor~e.18 :mod (h2 / human~e.17))) :ARG2 (d4 / differ-02~e.22 :ARG1~e.23 (e4 / express-03~e.25 :ARG1 (g / gene~e.24)) :ARG2-of (r3 / result-01~e.26 :ARG1~e.27 (u / use-01~e.30 :ARG1 (c / codon~e.29) :mod (d5 / differential~e.28))))) :mod (a3 / also~e.20)) :snt2 (a2 / and~e.39 :op1 (l / limit-01~e.34 :ARG0 (d7 / dna-sequence~e.32 :name (n7 / name :op1 "codon"~e.33) :ARG1-of~e.32 (r2 / rare-02~e.32)) :ARG1 (e5 / express-03~e.38 :ARG1 (e7 / enzyme :name (n8 / name :op1 "K-Ras"~e.35,37)))) :op2 (a4 / allow-01~e.41 :ARG0 d7 :ARG1 (e6 / efficient-01~e.43 :ARG2 (o / originate-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :degree (m3 / more~e.42)) :mod (t2 / thus~e.40) :manner~e.45 (p2 / prevent-01~e.46 :ARG0 d7 :ARG1 (s / senescence~e.50 :ARG2-of (i / induce-01~e.49 :ARG0 (o2 / oncogene~e.47)))))) :ARG1-of (d6 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a5 / and~e.54 :op1 (p4 / person :name (n4 / name :op1 "Lampson"~e.53)) :op2 (p5 / person :mod (o3 / other~e.55))) :time (d2 / date-entity :year 2013~e.57)))) # ::id pmid_2465_1010.51 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , different rates of DNA repair have been reported for the K @-@ Ras gene relative to N @-@ Ras and H @-@ Ras ( Feng et al. , 2002 ) . # ::alignments 0-1.2.1.1 1-1 1-1.2.1.1 3-1.1.1 4-1.1.1.3 5-1.1.1.3.1.r 6-1.1.1.3.1.1.2.1 7-1.1.1.3.1 10-1.1 13-1.1.1.1.1.1 15-1.1.1.1.1.1 15-1.1.1.2.2.1.1 16-1.1.1.1 16-1.1.1.2.1 16-1.1.1.2.2 18-1.1.1.2.r 19-1.1.1.2.2.1.1 21-1.1.1.2.1.1.1 21-1.1.1.2.2.1.1 22-1.1.1.2 23-1.1.1.2.1.1.1 25-1.1.1.1.1.1 25-1.1.1.2.1.1.1 28-1.2.1.1.1.1.1 29-1.2.1.1 30-1.2.1.1.2.1 32-1.2.1.2.1 (a / and~e.1 :op2 (r / report-01~e.10 :ARG1 (d2 / differ-02~e.3 :ARG1 (g / gene~e.16 :name (n / name :op1 "K-Ras"~e.13,15,25)) :ARG2~e.18 (a2 / and~e.22 :op1 (g2 / gene~e.16 :name (n2 / name :op1 "H-Ras"~e.21,23,25)) :op2 (g3 / gene~e.16 :name (n3 / name :op1 "N-Ras"~e.15,19,21))) :ARG3 (r2 / rate~e.4 :mod~e.5 (r3 / repair-01~e.7 :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"~e.6)))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and~e.0,1,29 :op1 (p2 / person :name (n4 / name :op1 "Feng"~e.28)) :op2 (p3 / person :mod (o / other~e.30))) :time (d / date-entity :year 2002~e.32)))) # ::id pmid_2465_1010.52 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The underlying reasons for different frequencies of specific activating mutations are not well understood either . # ::alignments 1-1.2.1 2-1.2 4-1.2.1.1.2 5-1.2.1.1 7-1.2.1.1.1.1 8-1.2.1.1.1.2 9-1.2.1.1.1 11-1.1 11-1.1.r 12-1.4 13-1 14-1.3 (u / understand-01~e.13 :polarity~e.11 -~e.11 :ARG1 (r / reason~e.2 :ARG0-of (u2 / underlie-01~e.1 :ARG1 (h2 / have-frequency-91~e.5 :ARG1 (m2 / mutate-01~e.9 :ARG1-of (s / specific-02~e.7) :ARG0-of (a2 / activate-01~e.8)) :ARG1-of (d2 / differ-02~e.4)))) :mod (e / either~e.14) :ARG1-of (w / well-09~e.12)) # ::id pmid_2465_1010.53 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Some of these differences reflect different mutagenic insults to the genome ; the G12C mutation , for example , is a hallmark of exposure to tobacco smoke and , accordingly , is the most common mutation in K @-@ Ras in lung cancer ( reviewed in Prior et al. , 2012 ; Table 2 @ ) . # ::alignments 0-1.2.1.1 2-1.2.1.2.1.1.1 3-1.2.1.2.1 3-1.2.1.2.1.1 3-1.2.1.2.1.1.r 4-1.2 5-1.2.2.2 7-1.2.2 8-1.2.2.1.r 10-1.2.2.1 13-1.1.1.2.1 14-1.1.1.2 14-1.2.2.3.1 16-1 17-1 23-1.1.1.1 25-1.1.1.1.1.1 26-1.1.1.1.1 27-1.1 29-1.1.2.3 33-1.1.2.2.1 34-1.1.2.2 35-1.1.2 36-1.1.1.2.2.r 37-1.1.1.2.2.1.1 39-1.1.1.2.2.1.1 40-1.1.2.4.r 41-1.1.2.4.2.1 42-1.1.2.4.2.2 44-1.3 47-1.3.1.1.1.1.1 48-1.3.1.1 49-1.3.1.1.2.1 51-1.3.1.2.1 55-1.3.1.3 56-1.3.1.3.1 (e / exemplify-01~e.16,17 :ARG0 (a / and~e.27 :op1 (c / characteristic-02 :ARG1 (e2 / expose-01~e.23 :ARG2 (s2 / smoke-02~e.26 :ARG1 (t4 / tobacco~e.25))) :ARG2 (m4 / mutate-01~e.14 :value "G12C"~e.13 :ARG2~e.36 (e3 / enzyme :name (n / name :op1 "K-Ras"~e.37,39)))) :op2 (m3 / mutate-01~e.35 :ARG2 e3 :mod (c2 / common~e.34 :degree (m5 / most~e.33)) :manner (a2 / accordingly~e.29) :location~e.40 (d3 / disease :wiki "Lung_cancer" :name (n5 / name :op1 "lung"~e.41 :op2 "cancer"~e.42)))) :ARG1 (r / reflect-01~e.4 :ARG1 (t / thing :quant (s / some~e.0) :ARG1-of (i / include-91 :ARG2 (t2 / thing~e.3 :ARG1-of~e.3 (d / differ-02~e.3 :mod (t3 / this~e.2))))) :ARG2 (i2 / insult-01~e.7 :ARG1~e.8 (g / genome~e.10) :ARG1-of (d2 / differ-02~e.5) :ARG0-of (g2 / generate-01 :ARG1 (m2 / mutate-01~e.14 :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))))) :ARG1-of (r2 / review-02~e.44 :ARG2 (p / publication-91 :ARG0 (a3 / and~e.48 :op1 (p2 / person :name (n2 / name :op1 "Prior"~e.47)) :op2 (p3 / person :mod (o / other~e.49))) :time (d5 / date-entity :year 2012~e.51) :part (t5 / table~e.55 :mod 2~e.56)))) # ::id pmid_2465_1010.54 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other differences in frequency may reflect different biological properties of mutant proteins . # ::alignments 0-1.1.1.2 1-1.1.1 3-1.1.1.1 4-1 5-1.1 6-1.1.1 6-1.1.2.2 7-1.1.2.3 8-1.1.2 10-1.1.2.1.1.1 11-1.1.2.1.1 (p / possible-01~e.4 :ARG1 (r / reflect-01~e.5 :ARG1 (d2 / differ-02~e.1,6 :ARG3 (f / frequency~e.3) :mod (o / other~e.0)) :ARG2 (p2 / property~e.8 :ARG1-of (h / have-03 :ARG0 (p3 / protein~e.11 :ARG2-of (m / mutate-01~e.10))) :ARG1-of (d / differ-02~e.6) :mod (b / biology~e.7)))) # ::id pmid_2465_1010.55 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , G12C and G12V K @-@ Ras mutations in lung adenocarcinoma preferentially activate the RalGDS pathway , whereas G12D prefers the Raf @/@ mitogen @-@ activated protein kinase ( MAPK ) and PI3K pathways ( Ihle et al. , 2012 ) . # ::alignments 0-1.4.2 1-1.4.2 3-1.1.1.1 4-1.1 5-1.1.2.1 6-1.1.1.2.1.1 8-1.1.1.2.1.1 9-1.1.1 9-1.1.2 9-1.4.1.1 11-1.1.3.1 12-1.1.3 13-1.3 14-1 16-1.2.1.1 17-1.2 19-1.4 20-1.4.1.1.1 21-1.4.1 23-1.4.1.2.1.1.1 27-1 31-1.4.1.2.1.1.1 33-1.4.1.2 34-1.4.1.2.2.1.1 35-1.4.1.2.1 35-1.4.1.2.2 38-1.5.1.1.1.1.1 39-1.5.1.1 40-1.5.1.1.2.1 42-1.5.1.2.1 (a / activate-01~e.14,27 :ARG0 (a2 / and~e.4 :op1 (m / mutate-01~e.9 :value "G12C"~e.3 :ARG2 (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.6,8))) :op2 (m2 / mutate-01~e.9 :value "G12V"~e.5 :ARG2 e2) :location (a4 / adenocarcinoma~e.12 :mod (l2 / lung~e.11))) :ARG1 (p3 / pathway~e.17 :name (n / name :op1 "RalGDS"~e.16)) :ARG1-of (p2 / prefer-01~e.13) :ARG1-of (c / contrast-01~e.19 :ARG2 (p / prefer-01~e.21 :ARG0 (m3 / mutate-01~e.9 :value "G12D"~e.20 :ARG2 e2) :ARG1 (a3 / and~e.33 :op1 (p4 / pathway~e.35 :name (n3 / name :op1 "Raf/MAPK"~e.23,31)) :op2 (p7 / pathway~e.35 :name (n6 / name :op1 "PI3K"~e.34)))) :ARG0-of (e3 / exemplify-01~e.0,1)) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a7 / and~e.39 :op1 (p8 / person :name (n7 / name :op1 "Ihle"~e.38)) :op2 (p9 / person :mod (o / other~e.40))) :time (d2 / date-entity :year 2012~e.42)))) # ::id pmid_2465_1010.56 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , mutations at codon 61 have a more profound effect on intrinsic GTPase when these Ras proteins are bound to Raf kinase . # ::alignments 0-1 1-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1 6-1.1.1.1.1 9-1.1.3.1 10-1.1.3 11-1.1 12-1.1.2.r 13-1.1.2.2 14-1.1.2.1.1 17-1.1.1.1.2.1.1 20-1.1.4 21-1.1.4.2.r 22-1.1.4.2.1.1 23-1.1.4.2 (a / and~e.0,1 :op2 (a2 / affect-01~e.11 :ARG0 (m / mutate-01~e.3 :ARG1~e.4 (c2 / codon~e.5 :mod 61~e.6 :part-of (e3 / enzyme :name (n3 / name :op1 "Ras"~e.17)))) :ARG1~e.12 (e2 / enzyme :name (n2 / name :op1 "GTPase"~e.14) :mod (i / intrinsic~e.13)) :mod (p / profound~e.10 :degree (m2 / more~e.9)) :condition (b / bind-01~e.20 :ARG1 e3 :ARG2~e.21 (k / kinase~e.23 :name (n6 / name :op1 "Raf"~e.22))))) # ::id pmid_2465_1010.57 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This may drive a stronger signal through this effector pathway and account for higher frequency of N @-@ Ras position 61 mutations in melanoma , a disease frequently driven by hyperactivation of Raf kinase through B @-@ Raf mutations ( Buhrman et al. , 2010 ) . # ::alignments 0-1.1.1.1 1-1 2-1.1.1 4-1.1.1.2.2 4-1.1.1.2.2.1 4-1.1.1.2.2.1.r 5-1.1.1.2 7-1.1.1.1 8-1.1.1.2.1.1 9-1.1.1.2.1 10-1.1 11-1.1.2 13-1.1.2.2.2 13-1.1.2.2.2.1 13-1.1.2.2.2.1.r 14-1.1.2.2 16-1.1.2.2.1.2.1.1 18-1.1.2.2.1.2.1.1 20-1.1.2.2.1.1 21-1.1.2.2.1 23-1.1.2.2.1.3.1.1 27-1.1.2.2.1.3.2.2 28-1.1.2.2.1.3 28-1.1.2.2.1.3.2 28-1.1.2.2.1.3.2.r 32-1.1.2.2.1.3.2.1.2.1.1 33-1.1.2.2.1.3.2.1.2 35-1.1.2.2.1.3.2.1.1.1.1.1 37-1.1.2.2.1.3.2.1.2.1.1 38-1.1.2.2.1 38-1.1.2.2.1.3.2.1.1 41-1.2.1.1.1.1.1 42-1.2.1.1 43-1.2.1.1.2.1 45-1.2.1.2.1 (p / possible-01~e.1 :ARG1 (a / and~e.10 :op1 (d3 / drive-02~e.2 :ARG0 (t / this~e.0,7) :ARG1 (s / signal-07~e.5 :ARG0 (p4 / pathway~e.9 :mod (e / effector~e.8)) :ARG1-of (s2 / strong-02~e.4 :degree~e.4 (m / more~e.4)))) :op2 (a3 / account-01~e.11 :ARG0 t :ARG1 (h / have-frequency-91~e.14 :ARG1 (m2 / mutate-01~e.21,38 :value 61~e.20 :ARG2 (e2 / enzyme :name (n / name :op1 "N-Ras"~e.16,18)) :location (m3 / medical-condition~e.28 :name (n5 / name :op1 "melanoma"~e.23) :ARG1-of~e.28 (d5 / drive-02~e.28 :ARG0 (h4 / hyperactivate-00 :ARG0 (m6 / mutate-01~e.38 :ARG2 (e3 / enzyme :name (n6 / name :op1 "B-Raf"~e.35))) :ARG1 (k4 / kinase~e.33 :name (n7 / name :op1 "Raf"~e.32,37))) :ARG1-of (f / frequent-02~e.27)))) :ARG1-of (h2 / high-02~e.13 :degree~e.13 (m5 / more~e.13))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.42 :op1 (p3 / person :name (n2 / name :op1 "Buhrman"~e.41)) :op2 (p5 / person :mod (o / other~e.43))) :time (d2 / date-entity :year 2010~e.45)))) # ::id pmid_2465_1010.58 ::amr-annotator SDL-AMR-09 ::preferred # ::tok From a clinical viewpoint , lung adenocarcinomas driven by K @-@ Ras mutations at G12C and G12V have a worse outcome than G12D , possibly because these mutations engage different downstream effectors as described above ( Figure 1 ; Ihle et al. , 2012 ) . # ::alignments 2-1.5.1 5-1.1.1 6-1.1 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.1.2.1.1 11-1.1.2.1.1.2.1.1 12-1.1.2.1.1 12-1.1.2.1.2 14-1.1.2.1.1.1 15-1.1.2.1 16-1.1.2.1.2.1 17-1 19-1.2.1 19-1.2.1.1 19-1.2.1.1.r 20-1.2 21-1.2.1.2.r 22-1.2.1.2.1 24-1.3.2 25-1.3 27-1.2.1.2 28-1.3.1 29-1.3.1.2.2 30-1.3.1.2.1 31-1.3.1.2 32-1.4.1.2.r 33-1.4 34-1.4.2 37-1.4.1.3 38-1.4.1.3.1 42-1.4.1.1.1.1.1 43-1.4.1.1 44-1.4.1.1.2.1 46-1.4.1.2.1 (h / have-03~e.17 :ARG0 (a / adenocarcinoma~e.6 :mod (l / lung~e.5) :ARG1-of (d4 / drive-02~e.7 :ARG0~e.8 (a2 / and~e.15 :op1 (m2 / mutate-01~e.12 :value "G12C"~e.14 :ARG2 (e / enzyme :name (n / name :op1 "K-Ras"~e.9,11))) :op2 (m3 / mutate-01~e.12 :value "G12V"~e.16 :ARG2 e)))) :ARG1 (o / outcome~e.20 :ARG1-of (b / bad-07~e.19 :degree~e.19 (m / more~e.19) :compared-to~e.21 (m4 / mutate-01~e.27 :value "G12D"~e.22 :ARG2 e))) :ARG1-of (c3 / cause-01~e.25 :ARG0 (e2 / engage-01~e.28 :ARG0 a2 :ARG1 (e3 / effector~e.31 :location (d / downstream~e.30) :ARG1-of (d2 / differ-02~e.29))) :ARG1-of (p / possible-01~e.24)) :ARG1-of (d3 / describe-01~e.33 :ARG0 (p2 / publication-91 :ARG0 (a4 / and~e.43 :op1 (p3 / person :name (n2 / name :op1 "Ihle"~e.42)) :op2 (p4 / person :mod (o2 / other~e.44))) :time~e.32 (d5 / date-entity :year 2012~e.46) :part (f / figure~e.37 :mod 1~e.38)) :medium (a3 / above~e.34)) :ARG1-of (v2 / view-02 :mod (c2 / clinic~e.2))) # ::id pmid_2465_1010.59 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As MEK and PI3K inhibitors are tested in the clinic , it will be important to ask whether Ras alleles respond differently to these treatments . # ::alignments 1-1.2.1.1.1.1.1.1.1 2-1.2.1.1 3-1.2.1.1.2.1.1.1.1 4-1.2.1.1.1 4-1.2.1.1.1.1 4-1.2.1.1.1.1.r 4-1.2.1.1.2 4-1.2.1.1.2.1 4-1.2.1.1.2.1.r 6-1.2.1 7-1.2.1.2.r 9-1.2.1.2 13-1.1.r 14-1 15-1.2 16-1.1 17-1.1.1.1 17-1.1.1.1.r 18-1.1.1.2.1.1 20-1.1.1 21-1.1.1.4 22-1.1.1.3.r 23-1.1.1.3.2 24-1.1.1.3 (i / important~e.14 :domain~e.13 (a / ask-01~e.16 :ARG1 (r / respond-01~e.20 :mode~e.17 interrogative~e.17 :ARG0 (e3 / enzyme :name (n / name :op1 "Ras"~e.18) :ARG2-of (m3 / mutate-01)) :ARG1~e.22 (t / treat-03~e.24 :ARG1 e3 :mod (t2 / this~e.23)) :ARG1-of (d / differ-02~e.21))) :ARG1-of (c / cause-01~e.15 :ARG0 (t3 / test-01~e.6 :ARG1 (a3 / and~e.2 :op1 (m / molecular-physical-entity~e.4 :ARG0-of~e.4 (i2 / inhibit-01~e.4 :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.1)))) :op2 (m2 / molecular-physical-entity~e.4 :ARG0-of~e.4 (i3 / inhibit-01~e.4 :ARG1 (p / protein-family :name (n3 / name :op1 "PI3K"~e.3))))) :location~e.7 (c2 / clinic~e.9)))) # ::id pmid_2465_1010.60 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Patients suffering from cancers driven by any of these Ras mutations are excluded from treatment with cetuximab ( colorectal cancer ) or erlotinib ( lung adenocarcinoma ) because these treatments are ineffective for cancers with these Ras mutations and may even increase rates of progression . # ::alignments 0-1.1 1-1.1.1 3-1.1.1.1.2.1 3-1.3.1.2.1.2.1.1.2.1 4-1.1.1.1 4-1.1.1.1.3 4-1.1.1.1.3.r 6-1.1.1.1.3.1.2 8-1.1.1.1.3.1.3 9-1.1.1.1.3.1.1.1.1 10-1.1.1.1.3.1 12-1 13-1.2.r 14-1.2.1 14-1.2.2 15-1.2.1.2.r 16-1.2.1.2.1.1 18-1.2.1.2.2.2.1 19-1.2.1.2.2.2.2 21-1.2 22-1.2.2.2.1.1 24-1.2.2.2.2.2 25-1.2.2.2.2.1.1 27-1.3 27-1.3.1.1.3 27-1.3.1.1.3.3 27-1.3.1.1.3.3.r 28-1.2.1.1 29-1.3.1.1.2 31-1.3.1.1 31-1.3.1.1.1 31-1.3.1.1.1.r 33-1.1.1.1.2.1 33-1.3.1.1.3.2.1 35-1.1.1.1.3.1.3 36-1.1.1.1.3.1.1.1.1 37-1.1.1.1.3.1 37-1.3.1.1.3.3.1 38-1.3.1 39-1.3.1.2 40-1.3.1.2.1.3 41-1.3.1.2.1 42-1.3.1.2.1.2 43-1.3.1.2.1.2.1.r 44-1.3.1.2.1.2.1 (e / exclude-01~e.12 :ARG1 (p / patient~e.0 :ARG0-of (s / suffer-01~e.1 :ARG1 (d5 / disease~e.4 :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.3,33) :ARG1-of~e.4 (d / drive-02~e.4 :ARG0 (m / mutate-01~e.10,37 :ARG1 (e5 / enzyme :name (n3 / name :op1 "Ras"~e.9,36)) :mod (a6 / any~e.6 :ARG1-of (i3 / include-91)) :mod (t2 / this~e.8,35)))))) :ARG2~e.13 (o / or~e.21 :op1 (t / treat-03~e.14 :ARG1 p~e.28 :ARG3~e.15 (s2 / small-molecule :name (n / name :op1 "cetuximab"~e.16) :condition (d2 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colorectal"~e.18 :op2 "cancer"~e.19)))) :op2 (t5 / treat-03~e.14 :ARG1 p :ARG3 (s3 / small-molecule :name (n2 / name :op1 "erlotinib"~e.22) :condition (m2 / medical-condition :name (n7 / name :op1 "adenocarcinoma"~e.25) :mod (l / lung~e.24))))) :ARG1-of (c5 / cause-01~e.27 :ARG0 (a3 / and~e.38 :op1 (e2 / effective-04~e.31 :polarity~e.31 -~e.31 :ARG0 o~e.29 :condition (d3 / disease~e.27 :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.33) :ARG1-of~e.27 (c6 / cause-01~e.27 :ARG0 (m3 / mutate-01~e.37)))) :op2 (p2 / possible-01~e.39 :ARG1 (i2 / increase-01~e.41 :ARG0 o :ARG1 (r2 / rate~e.42 :degree-of~e.43 (p4 / progress-01~e.44 :ARG1 (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.3)))) :mod (e4 / even~e.40)))))) # ::id pmid_2465_1010.61 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , malignant melanomas with mutant N @-@ Ras are excluded from treatment with vemurafenib . # ::alignments 0-1.3 2-1.1 2-1.1.2 2-1.1.2.r 3-1.1.1.1 5-1.1.3.1 5-1.1.3.1.2 5-1.1.3.1.2.r 6-1.1.3.1.1.1 8-1.1.3.1.1.1 10-1 11-1.2.r 12-1.2 13-1.2.2.r 14-1.2.2.1.1 (e / exclude-01~e.10 :ARG1 (m4 / medical-condition~e.2 :name (n3 / name :op1 "melanoma"~e.3) :ARG2-of~e.2 (m2 / malignant-02~e.2) :ARG0-of (h / have-03 :ARG1 (e2 / enzyme~e.5 :name (n2 / name :op1 "N-Ras"~e.6,8) :ARG2-of~e.5 (m3 / mutate-01~e.5)))) :ARG2~e.11 (t / treat-03~e.12 :ARG1 m4 :ARG3~e.13 (s / small-molecule :name (n / name :op1 "vemurafenib"~e.14))) :manner (l / likewise~e.0)) # ::id pmid_2465_1010.62 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , surprisingly , K @-@ Ras @-@ G13D @-@ bearing colorectal cancers may show clinical benefit when treated with cetuximab . # ::alignments 0-1 2-1.1.2 4-1.1.1.1.3.1.1.1 6-1.1.1.1.3.1.1.1 8-1.1.1.1.3.2.1 10-1.1.1.1.3 11-1.1.1.1.2.1 12-1.1.1.1.2.2 13-1.1 14-1.1.1 15-1.1.1.2.2 16-1.1.1.2 18-1.1.1.2.1 19-1.1.1.2.1.2.r 20-1.1.1.2.1.2.1.1 (c4 / contrast-01~e.0 :ARG2 (p / possible-01~e.13 :ARG1 (s2 / show-01~e.14 :ARG0 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal"~e.11 :op2 "cancer"~e.12) :ARG0-of (b2 / bear-01~e.10 :ARG1 (e / enzyme :name (n2 / name :op1 "K-Ras"~e.4,6)) :ARG2-of (m2 / mutate-01 :value "G13D"~e.8))) :ARG1 (b / benefit-01~e.16 :ARG0 (t / treat-03~e.18 :ARG1 d :ARG3~e.19 (s / small-molecule :name (n / name :op1 "cetuximab"~e.20))) :mod (c2 / clinic~e.15))) :ARG0-of (s3 / surprise-01~e.2))) # ::id pmid_2465_1010.63 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This result challenges our understanding of how these Ras mutations actually function in clinical situations ( De Roock et al. , 2010 ) . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.1 3-1.2.1.r 4-1.2 5-1.2.2.r 6-1.2.2.1.r 7-1.2.2.1.1.2 8-1.2.2.1.1.1.1.1 9-1.2.2.1.1 10-1.2.2.1.2 11-1.2.2.1 12-1.2.2.1.3.r 13-1.2.2.1.3.1 14-1.2.2.1.3 17-1.3.1.1.1.1.1 18-1.3.1.1.1.1.2 19-1.3.1.1 20-1.3.1.1.2.1 22-1.3.1.1.2.2.1 (c / challenge-01~e.2 :ARG0 (t4 / thing~e.1 :ARG2-of~e.1 (r2 / result-01~e.1) :mod (t6 / this~e.0)) :ARG1 (u / understand-01~e.4 :ARG0~e.3 (w / we~e.3) :ARG1~e.5 (t / thing :manner-of~e.6 (f / function-01~e.11 :ARG0 (m2 / mutate-01~e.9 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.8)) :mod (t3 / this~e.7)) :ARG1-of (a / actual-02~e.10) :condition~e.12 (s / situation~e.14 :mod (c2 / clinic~e.13))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and~e.19 :op1 (p2 / person :name (n2 / name :op1 "De"~e.17 :op2 "Roock"~e.18)) :op2 (p3 / person :mod (o / other~e.20) :time (d2 / date-entity :year 2010~e.22)))))) # ::id pmid_2465_1010.64 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Even the prototypic oncogenes of Harvey and Kirsten sarcoma viruses are not fully understood ; each has a codon 12 mutation , but each also carries a mutation of alanine 59 to threonine , which becomes phosphorylated by guanosine triphosphate ( GTP ) . # ::alignments 0-1.1.2.5 2-1.1.2.3 3-1.2.1.1.2 5-1.1.2.1.1.1.1 6-1.1.2 7-1.1.2.2.1.1.1 8-1.1.2.1.1.1.2 8-1.1.2.2.1.1.2 9-1.1.2.1.1 9-1.1.2.1.1.1.3 9-1.1.2.2.1 9-1.1.2.2.1.1.3 11-1.1.1 11-1.1.1.r 12-1.1.3 13-1.1 15-1.2.1.1.2.1 18-1.2.1.1 19-1.2.1.1.1 20-1.2.1 22-1.2 23-1.2.2.1 24-1.2.2.3 25-1.2.2 27-1.2.2.2 28-1.2.2.2.2.r 29-1.2.2.2.2.2.1 30-1.2.2.2.2.1 31-1.2.2.2.1.r 32-1.2.2.2.1.1.1 36-1.2.2.2.1.2 37-1.2.2.2.1.2.1.r 38-1.2.2.2.1.2.1.1.1 39-1.2.2.2.1.2.1.1.2 (m / multi-sentence :snt1 (u / understand-01~e.13 :polarity~e.11 -~e.11 :ARG1 (a / and~e.6 :op1 (g3 / gene :part-of (v / virus~e.9 :name (n / name :op1 "Harvey"~e.5 :op2 "Sarcoma"~e.8 :op3 "Virus"~e.9))) :op2 (g4 / gene :part-of (v2 / virus~e.9 :name (n2 / name :op1 "Kirsten"~e.7 :op2 "Sarcoma"~e.8 :op3 "Virus"~e.9))) :mod (p / prototypic~e.2) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :mod (e / even~e.0)) :degree (f / full~e.12)) :snt2 (c3 / contrast-01~e.22 :ARG1 (m2 / mutate-01~e.20 :ARG1 (c5 / codon~e.18 :mod 12~e.19 :part-of (o / oncogene~e.3 :mod (e2 / each~e.15)))) :ARG2 (c4 / carry-01~e.25 :ARG0 e2~e.23 :ARG1 (m3 / mutate-01~e.27 :ARG2~e.31 (a4 / amino-acid :name (n8 / name :op1 "threonine"~e.32) :ARG1-of (p2 / phosphorylate-01~e.36 :ARG2~e.37 (s4 / small-molecule :name (n4 / name :op1 "guanosine"~e.38 :op2 "triphosphate"~e.39)))) :ARG3~e.28 (a3 / amino-acid :mod 59~e.30 :name (n7 / name :op1 "alanine"~e.29))) :mod (a5 / also~e.24)))) # ::id pmid_2465_1010.65 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This must have helped Scolnick and colleagues ( Shih et al. , 1979 ) identify Ras ’ crucial guanosine diphosphate ( GDP ) / GTP properties ; without covalent phosphorylation , association with these nucleotides would have been very hard to detect . # ::alignments 0-1.1.1.1 1-1.1 3-1.1.1 4-1.1.1.3.1.1.1 5-1.1.1.3 6-1.1.1.3.2 9-1.1.2.1.1.1.1.1 10-1.1.2.1.1 11-1.1.2.1.1.2.1 13-1.1.2.1.2.1 16-1.1.1.2 17-1.1.1.2.2.1.1.1 19-1.1.1.2.2.3 20-1.1.1.2.2.2.1.1.1 21-1.1.1.2.2.2.1.1.2 25-1.1.1.2.2.2 26-1.1.1.2.2.2.2.1.1 29-1.2.3.1 29-1.2.3.1.r 30-1.2.3.3 31-1.2.3 33-1.2.1.1 35-1.1.1.1 36-1.1.1.2.2.2.1 40-1.2.2 41-1.2 43-1.2.1 (a3 / and :op1 (i / infer-01~e.1 :ARG1 (h / help-01~e.3 :ARG0 (t / this~e.0,35) :ARG1 (i2 / identify-01~e.16 :ARG0 a :ARG1 (c3 / characteristic-02 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.17)) :ARG2 (s / slash~e.25 :op1 (n5 / nucleotide~e.36 :name (n3 / name :op1 "guanosine"~e.20 :op2 "diphosphate"~e.21)) :op2 (s2 / small-molecule :name (n4 / name :op1 "GTP"~e.26))) :mod (c4 / crucial~e.19))) :ARG2 (a / and~e.5 :op1 (p2 / person :name (n / name :op1 "Scolnick"~e.4)) :op2 (c / colleague~e.6))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and~e.10 :op1 (p4 / person :name (n7 / name :op1 "Shih"~e.9)) :op2 (p5 / person :mod (o / other~e.11))) :time (d3 / date-entity :year 1979~e.13)))) :op2 (h2 / hard-02~e.41 :ARG1 (d2 / detect-01~e.43 :ARG1 (a2 / associate-01~e.33 :ARG0 e :ARG2 s)) :degree (v / very~e.40) :condition (p3 / phosphorylate-01~e.31 :polarity~e.29 -~e.29 :ARG1 e :mod (c5 / covalent~e.30)))) # ::id pmid_2465_1010.66 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , how phosphorylation at threonine 59 contributes to Ras ’ potent oncogenicity is unclear . # ::alignments 0-1 3-1.1.2.1.1 4-1.1.2.1.1.1.r 5-1.1.2.1.1.1.2.1 6-1.1.2.1.1.1.1 7-1.1.2 7-1.1.2.1 7-1.1.2.1.r 8-1.1.2.1.2 9-1.1.2.1.2.1.1.1 11-1.1.2.1.2.3 14-1.1 14-1.1.1 14-1.1.1.r (h / have-concession-91~e.0 :ARG1 (c / clear-06~e.14 :polarity~e.14 -~e.14 :ARG1 (t / thing~e.7 :ARG1-of~e.7 (c2 / contribute-01~e.7 :ARG0 (p2 / phosphorylate-01~e.3 :ARG1~e.4 (a / amino-acid :mod 59~e.6 :name (n2 / name :op1 "threonine"~e.5) :part-of e)) :ARG2 (c3 / cause-01~e.8 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.9)) :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")) :mod (p3 / potent~e.11)))))) # ::id pmid_2465_1010.67 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This A59T mutation inhibits Ras @-@ Raf interaction ( Shirouzu et al. , 1994 ) and is extremely rare in human cancer . # ::alignments 0-1.1.1.2 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.2.1.1 6-1.1.2.1.1.1 7-1.1.2 10-1.1.3.1.1.1.1.1 11-1.1.3.1.1 12-1.1.3.1.1.2.1 14-1.1.3.1.2.1 17-1 19-1.2.2 20-1.2 21-1.2.3.r 22-1.2.3.3 23-1.2.3.2.1 (a / and~e.17 :op1 (i / inhibit-01~e.3 :ARG0 (m / mutate-01~e.2 :value "A59T"~e.1 :mod (t / this~e.0)) :ARG1 (i2 / interact-01~e.7 :ARG0 (e3 / enzyme :name (n2 / name :op1 "Raf"~e.6)) :ARG1 (e2 / enzyme :name (n / name :op1 "Ras"~e.4))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a2 / and~e.11 :op1 (p2 / person :name (n3 / name :op1 "Shirouzu"~e.10)) :op2 (p3 / person :mod (o / other~e.12))) :time (d2 / date-entity :year 1994~e.14)))) :op2 (r / rare-02~e.20 :ARG1 m :degree (e / extreme~e.19) :location~e.21 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.23) :mod (h / human~e.22)))) # ::id pmid_2465_1010.68 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These anecdotes simply remind us that after 50 years , we still have a lot to learn about the biological and biochemical functions of Ras proteins . # ::alignments 0-1.1.1 1-1.1 2-1.4 3-1 4-1.3 6-1.2.4 7-1.2.4.1.1 8-1.2.4.1.2 10-1.2.1 11-1.2.3 14-1.2.2.3 16-1.2.2 17-1.2.2.2.r 19-1.2.2.2.1.2 20-1.2.2.2 21-1.2.2.2.2.2 22-1.2.2.2.1 22-1.2.2.2.2 23-1.2.2.2.1.1.r 24-1.2.2.2.1.1.1.1 25-1.2.2.2.1.1 (r / remind-01~e.3 :ARG0 (a / anecdote~e.1 :mod (t / this~e.0)) :ARG1 (n / need-01 :ARG0 (w3 / we~e.10) :ARG1 (l / learn-01~e.16 :ARG0 w3 :ARG1~e.17 (a2 / and~e.20 :op1 (f2 / function-01~e.22 :ARG0~e.23 (p / protein-family~e.25 :name (n3 / name :op1 "Ras"~e.24)) :mod (b / biology~e.19)) :op2 (f / function-01~e.22 :ARG0 p :mod (b2 / biochemical~e.21))) :quant (l2 / lot~e.14)) :mod (s2 / still~e.11) :time (a3 / after~e.6 :op1 (t2 / temporal-quantity :quant 50~e.7 :unit (y / year~e.8)))) :ARG2 (w / we~e.4) :ARG1-of (s / simple-02~e.2)) # ::id pmid_2465_1010.69 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although K @-@ Ras has emerged as by far the major Ras gene mutated in human cancer , it is surprising that other activating mutations in other members of the Ras superfamily , such as R @-@ Ras or Rap proteins , occur very rarely . # ::alignments 0-1.2.r 1-1.2.1.1.1 3-1.2.2.1.1 5-1.2 6-1.2.3.r 7-1.2.3 8-1.2.3 10-1.2.2.2 11-1.2.2.1.1 12-1.2.1 12-1.2.2 13-1.2.2.3 14-1.2.2.4.r 15-1.2.2.4.3 16-1.2.2.4.2.1 20-1 22-1.1.4 23-1.1.1 24-1.1 26-1.1.3.1 26-1.1.4 27-1.1.3 30-1.1.3.2.1.1.1 33-1.1.3.3.r 34-1.1.3.3.r 35-1.1.3.3.1.1.1 37-1.1.3.3.1.1.1 38-1.1.3.3 39-1.1.3.3.2.1.1 40-1.1.3.2.1 43-1.1.2.1 44-1.1.2 (s / surprise-01~e.20 :ARG0 (m / mutate-01~e.24 :ARG0-of (a / activate-01~e.23) :ARG1-of (r / rare-02~e.44 :degree (v / very~e.43)) :location (m2 / member~e.27 :mod (o3 / other~e.26) :ARG1-of (i / include-91 :ARG2 (p / protein-family~e.40 :name (n / name :op1 "Ras"~e.30))) :example~e.33,34 (o2 / or~e.38 :op1 (e3 / enzyme :name (n6 / name :op1 "R-Ras"~e.35,37)) :op2 (e4 / enzyme :name (n7 / name :op1 "Rap"~e.39)))) :mod (o / other~e.22,26)) :concession~e.0 (e / emerge-02~e.5 :ARG0 (g2 / gene~e.12 :name (n2 / name :op1 "K-Ras"~e.1)) :ARG1 (g / gene~e.12 :name (n3 / name :op1 "Ras"~e.3,11) :ARG1-of (m3 / major-02~e.10) :ARG1-of (m4 / mutate-01~e.13) :location~e.14 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.16) :mod (h / human~e.15))) :degree~e.6 (b / by-far~e.7,8))) # ::id pmid_2465_1010.70 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This is surprising because these proteins share identical or near @-@ identical effector @-@ binding regions . # ::alignments 0-1.1 2-1 3-1.2 4-1.2.1.1.1 5-1.2.1.1 6-1.2.1 7-1.2.1.2.2.2 8-1.2.1.2 9-1.2.1.2.2.2.1 11-1.2.1.2.1.2 11-1.2.1.2.2.2 12-1.2.1.2.1.1.1 14-1.2.1.2.1.1 15-1.2.1.2.1 15-1.2.1.2.2 (s / surprise-01~e.2 :ARG0 (t / this~e.0) :ARG1-of (c / cause-01~e.3 :ARG0 (s2 / share-01~e.6 :ARG0 (p / protein~e.5 :mod (t2 / this~e.4)) :ARG1 (o / or~e.8 :op1 (r / region~e.15 :ARG0-of (b / bind-01~e.14 :ARG1 (e / effector~e.12)) :ARG1-of (i / identical-01~e.11)) :op1 (r2 / region~e.15 :ARG0-of b :ARG1-of (i2 / identical-01~e.7,11 :degree (n / near~e.9))))))) # ::id pmid_2465_1010.71 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , only H @-@ Ras , N @-@ Ras , and K @-@ Ras are capable of binding and activating Raf kinases , and this unique property may well account for their predominance as human oncogenes . # ::alignments 0-1.1 2-1.1.1.1.1.4 3-1.1.1.1.1.1.1.1 5-1.1.1.1.1.1.1.1 5-1.1.1.1.1.2.1.1 5-1.1.1.1.1.3.1.1 7-1.1.1.1.1.2.1.1 9-1.1.1.1.1.1.1.1 9-1.1.1.1.1.2.1.1 9-1.1.1.1.1.3.1.1 11-1.1.1.1.1 12-1.1.1.1.1.3.1.1 14-1.1.1.1.1.1.1.1 14-1.1.1.1.1.2.1.1 14-1.1.1.1.1.3.1.1 16-1.1.1.1 17-1.1.1.1.2.r 18-1.1.1.1.2.1 19-1.1.1.1.2 20-1.1.1.1.2.2 21-1.1.1.1.2.1.2.1.1 22-1.1.1.1.2.1.2 24-1 25-1.2.1.1.2 26-1.2.1.1.1 27-1.2.1.1 28-1.1.1 28-1.2 29-1.2.1.3 30-1.2.1 32-1.2.1.2.1 32-1.2.1.2.1.r 35-1.2.1.2.2.1 36-1.2.1.2.2 (a / and~e.24 :op1 (h2 / have-concession-91~e.0 :ARG2 (p / possible-01~e.28 :ARG1 (c2 / capable-01~e.16 :ARG1 (a2 / and~e.11 :op1 (e / enzyme :name (n / name :op1 "H-Ras"~e.3,5,9,14)) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"~e.5,7,9,14)) :op3 (e3 / enzyme :name (n3 / name :op1 "K-Ras"~e.5,9,12,14)) :mod (o / only~e.2)) :ARG2~e.17 (a3 / and~e.19 :op1 (b / bind-01~e.18 :ARG0 a2 :ARG1 (k / kinase~e.22 :name (n4 / name :op1 "RAF"~e.21))) :op2 (a4 / activate-01~e.20 :ARG0 a2 :ARG1 k))))) :op2 (p3 / possible-01~e.28 :ARG1 (a5 / account-01~e.30 :ARG0 (p5 / property~e.27 :mod (u / unique~e.26) :mod (t / this~e.25)) :ARG1 (p4 / predominate-01 :ARG1~e.32 a2~e.32 :manner (o2 / oncogene~e.36 :mod (h / human~e.35))) :mod (w / well~e.29)))) # ::id pmid_2465_1010.72 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the closely related R @-@ Ras proteins bind and activate PI3Ks but are rarely mutated in human cancer ( Rodriguez @-@ Viciana et al. , 2004 ) . # ::alignments 1-1 1-1.1 1-1.1.r 4-1.1.1.1.1.2.1 5-1.1.1.1.1.2 6-1.1.1.1.1.1.1 8-1.1.1.1.1.1.1 9-1.1.1.1.2 10-1.1.1.1 11-1.1.1 12-1.1.1.2 14-1.1 16-1.1.2.3 17-1.1.2 18-1.1.2.2.r 19-1.1.2.2.3 20-1.1.2.2.2.1 23-1.2.1.1.1.1.1 25-1.2.1.1.1.1.1 26-1.2.1.1 27-1.2.1.1.2.1 29-1.2.1.2.1 (c / contrast-01~e.1 :ARG2~e.1 (c3 / contrast-01~e.1,14 :ARG1 (a / and~e.11 :op1 (b / bind-01~e.10 :ARG0 (e / enzyme :name (n2 / name :op1 "R-Ras"~e.6,8) :ARG1-of (r / relate-01~e.5 :ARG1-of (c2 / close-10~e.4))) :ARG1 (p4 / protein-family~e.9 :name (n4 / name :op1 "PI3K"))) :op2 (a2 / activate-01~e.12 :ARG0 e :ARG1 p4)) :ARG2 (m / mutate-01~e.17 :ARG1 e :location~e.18 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.20) :mod (h / human~e.19)) :ARG1-of (r2 / rare-02~e.16))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a3 / and~e.26 :op1 (p3 / person :name (n5 / name :op1 "Rodriguez-Viciana"~e.23,25)) :op2 (p2 / person :mod (o / other~e.27))) :time (d / date-entity :year 2004~e.29)))) # ::id pmid_2465_1010.73 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activating mutations in Ras genes , coupled with a long history of Ras biology , implicate these mutant Ras proteins as major drivers in many cancers . # ::alignments 0-1.1 1-1.1.2 3-1.1.2.1.1 4-1.1.2.1 6-1.1.3 7-1.1.3.1.r 9-1.1.3.1.2 10-1.1.3.1 11-1.1.3.1.1.r 12-1.1.3.1.1.1.1.1 13-1.1.3.1.1 15-1 17-1.1.2 18-1.1.3.1.1.1.1.1 19-1.1.3.1.1.1 21-1.2.2 24-1.2.3.3 25-1.2.3.2.1 (i / implicate-01~e.15 :ARG0 (a / activate-01~e.0 :ARG0 (e3 / enzyme) :ARG1 (m2 / mutate-01~e.1,17 :ARG1 (g / gene~e.4 :mod p~e.3)) :ARG1-of (c / couple-01~e.6 :ARG2~e.7 (h / history~e.10 :topic~e.11 (b / biology~e.13 :mod (p / protein-family~e.19 :name (n / name :op1 "Ras"~e.12,18))) :ARG1-of (l / long-03~e.9)))) :ARG2 (d2 / drive-02 :ARG0 m2 :ARG1-of (m3 / major-02~e.21) :location (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.25) :quant (m4 / many~e.24)))) # ::id pmid_2465_1010.74 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Loss of the Ras GTPase @-@ activating protein ( GAP ) neurofibromin inculpates hyperactive wild @-@ type Ras proteins as drivers in many more cancers . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.2.1.1 4-1.1.1.2.1.2 6-1.1.1 7-1.1.1.1 7-1.1.1.2 11-1.1.1.1.1.1 12-1 13-1.2.2.1 14-1.2.2 16-1.2.2 17-1.2.1.1 18-1.1.1.1 22-1.2.3.1.3.1 23-1.2.3.1.3 24-1.2.3.1.2.1 (i / inculpate-00~e.12 :ARG0 (l / lose-02~e.0 :ARG1~e.1 (a / activate-01~e.6 :ARG0 (p2 / protein~e.7,18 :name (n2 / name :op1 "neurofibromin"~e.11)) :ARG1 (p / protein~e.7 :name (n / name :op1 "Ras"~e.3 :op2 "GTPase"~e.4)))) :ARG1 (e / enzyme :name (n3 / name :op1 "Ras"~e.17) :mod (w / wild-type~e.14,16 :mod (h / hyperactive~e.13)) :ARG0-of (d3 / drive-02 :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.24) :mod (m / more~e.23 :mod (m2 / many~e.22)))))) # ::id pmid_2465_1010.75 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Somatic loss of neurofibromin expression by mutation , deletion , or by other means occurs in about 14 % glioblastoma , 13 % @–@ 14 % melanoma , 8 % @–@ 10 % lung adenocarcinoma , and at single @-@ digit frequency in most other cancers ( E.A . Collisson , personal communication ) . # ::alignments 0-1.2 1-1 2-1.1.r 3-1.1.1.1.1 4-1.1 5-1.1.2.r 6-1.1.2.1 8-1.1.2.2 10-1.1.2 12-1.1.2.3.1 13-1.1.2.3 16-1.1.3.r 17-1.1.3.1.2.1 18-1.1.3.1.2 19-1.1.3.1.1.1 21-1.1.3.2.2.1.1 22-1.1.3.1.2 24-1.1.3.1.2.1 24-1.1.3.2.2.1.2 25-1.1.3.1.2 26-1.1.3.2.1.1 28-1.1.3.3.2.1.1 29-1.1.3.1.2 31-1.1.3.3.2.1.2 32-1.1.3.2.2 32-1.1.3.3.2 33-1.1.3.3.3 34-1.1.3.3.1.1 36-1.1.3 38-1.1.3.4.4.1 40-1.1.3.4.4 43-1.1.3.4.3.1 44-1.1.3.4.3 45-1.1.3.4.2.1 49-1.3.1.1.1.2 51-1.3.1.2 52-1.3.1 (l / lose-02~e.1 :ARG1~e.2 (e / express-03~e.4 :ARG2 (p3 / protein :name (n / name :op1 "neurofibromin"~e.3)) :manner~e.5 (o2 / or~e.10 :op1 (m / mutate-01~e.6) :op2 (d / delete-01~e.8) :op3 (m2 / means~e.13 :mod (o / other~e.12))) :location~e.16 (a2 / and~e.36 :op1 (m4 / medical-condition :name (n4 / name :op1 "glioblastoma"~e.19) :mod (p2 / percentage-entity~e.18,22,25,29 :value 14~e.17,24)) :op2 (m6 / medical-condition :name (n2 / name :op1 "melanoma"~e.26) :mod (p5 / percentage-entity~e.32 :value (b / between :op1 13~e.21 :op2 14~e.24))) :op3 (m5 / medical-condition :name (n3 / name :op1 "adenocarcinoma"~e.34) :mod (p6 / percentage-entity~e.32 :value (b2 / between :op1 8~e.28 :op2 10~e.31)) :mod (l2 / lung~e.33)) :op4 (d6 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.45) :mod (o3 / other~e.44 :degree (m3 / most~e.43)) :frequency (d2 / digit~e.40 :ARG1-of (s2 / single-02~e.38))))) :mod (s / somatic~e.0) :ARG1-of (d5 / describe-01 :ARG0 (c2 / communicate-01~e.52 :ARG0 (p / person :name (n5 / name :op1 "E.A." :op2 "Collisson"~e.49)) :ARG1-of (p4 / personal-02~e.51)))) # ::id pmid_2465_1010.76 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neurofibromin must now be considered as a major tumor suppressor , along with p53 and phosphatase and tensin homolog , in human cancers . # ::alignments 0-1.1.1.1.1.1 1-1 2-1.1.2 4-1.1 5-1.1.2.r 7-1.1.1.5.2 8-1.1.1.5.1 9-1.1.1.5 12-1.1.1.r 13-1.1.1.2.1.1 14-1.1.1 15-1.1.1.3.1.1 16-1.1.1 17-1.1.1.4.1.1 18-1.1.1.4.1.2 20-1.1.1.5.3.r 21-1.1.1.5.3.3 22-1.1.1.5.3.2.1 (o2 / obligate-01~e.1 :ARG2 (c / consider-01~e.4 :ARG1~e.12 (a / and~e.14,16 :op1 (p2 / protein :name (n / name :op1 "Neurofibromin"~e.0)) :op2 (p3 / protein :name (n2 / name :op1 "p53"~e.13)) :op3 (e / enzyme :name (n3 / name :op1 "phosphatase"~e.15)) :op4 (p / protein :name (n5 / name :op1 "tensin"~e.17 :op2 "homolog"~e.18)) :ARG0-of (s / suppress-01~e.9 :ARG1 (t / tumor~e.8) :ARG1-of (m / major-02~e.7) :location~e.20 (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.22) :mod (h / human~e.21)))) :time~e.5 (n4 / now~e.2))) # ::id pmid_2465_1010.77 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Loss of neurofibromin is usually mutually exclusive with Ras mutation and receptor tyrosine kinase ( RTK ) activation , suggesting that these genetic events represent different ways of activating similar pathways . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.1.1 4-1.1.4 5-1.1.3 5-1.1.3.r 6-1.1 7-1.1.2.r 8-1.1.2.1.1.1.1 9-1.1.2.1 10-1.1.2 11-1.1.2.2.1.1.1 12-1.1.2.2.1.1.2 13-1.1.2.2.1.1.3 17-1.1.2.2 19-1 20-1.2.r 21-1.2.1.2 23-1.2.1 24-1.2 25-1.2.2.2 26-1.2.2 27-1.2.2.1.r 28-1.2.2.1 29-1.2.2.1.2.1 30-1.2.2.1.2 (s2 / suggest-01~e.19 :ARG0 (e2 / exclusive-02~e.6 :ARG0 (l / lose-02~e.0 :ARG1~e.1 (p / protein :name (n2 / name :op1 "neurofibromin"~e.2))) :ARG2~e.7 (a2 / and~e.10 :op1 (m2 / mutate-01~e.9 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.8))) :op2 (a3 / activate-01~e.17 :ARG1 (e3 / enzyme :name (n3 / name :op1 "receptor"~e.11 :op2 "tyrosine"~e.12 :op3 "kinase"~e.13)))) :manner~e.5 (m / mutual~e.5) :mod (u / usual~e.4)) :ARG1~e.20 (r / represent-01~e.24 :ARG0 (e4 / event~e.23 :mod (g / gene) :mod (t / this~e.21)) :ARG1 (w / way~e.26 :manner-of~e.27 (a / activate-01~e.28 :ARG0 e4 :ARG1 (p3 / pathway~e.30 :ARG1-of (r2 / resemble-01~e.29))) :ARG1-of (d / differ-02~e.25)))) # ::id pmid_2465_1010.78 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the precise consequences of losing neurofibromin are not entirely clear . # ::alignments 0-1 3-1.1.2.1 4-1.1.2 4-1.1.2.2 4-1.1.2.2.r 5-1.1.2.2.1.r 6-1.1.2.2.1 7-1.1.2.2.1.1.1.1 9-1.1.1 9-1.1.1.r 10-1.1.3 11-1.1 (h / have-concession-91~e.0 :ARG2 (c3 / clear-06~e.11 :polarity~e.9 -~e.9 :ARG1 (c / consequence~e.4 :mod (p2 / precise~e.3) :ARG1-of~e.4 (c2 / cause-01~e.4 :ARG0~e.5 (l / lose-02~e.6 :ARG1 (p / protein :name (n / name :op1 "neurofibromin"~e.7))))) :degree (e / entire~e.10))) # ::id pmid_2465_1010.79 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Levels of Ras @-@ GTP are high in cells lacking neurofibromin , but which forms of hyperactive wild @-@ type Ras proteins are most important to the malignant phenotype is a more difficult question . # ::alignments 0-1.1.1 1-1.1.1.1.r 2-1.1.1.1.2 4-1.1.1.1.1.1.1 6-1.1 7-1.1.2.r 8-1.1.2 9-1.1.2.1 10-1.1.2.1.1.2.1 12-1 14-1.2.2 15-1.2.2.1.r 16-1.2.2.1.3 17-1.2.2.1.2 19-1.2.2.1.2 20-1.2.2.1.1.1 21-1.1.2.1.1 22-1.2.2.r 23-1.2.4 23-1.2.6 24-1.2 25-1.2.3.r 27-1.2.3.1 28-1.2.3 29-1.2.2.r 31-1.2.5.1.1 32-1.2.5.1 33-1.2.5 (c / contrast-01~e.12 :ARG1 (h / high-02~e.6 :ARG1 (l / level~e.0 :mod~e.1 (m3 / macro-molecular-complex :part (s / small-molecule :name (n4 / name :op1 "GTP"~e.4)) :part e~e.2)) :location~e.7 (c2 / cell~e.8 :ARG0-of (l2 / lack-01~e.9 :ARG1 (p / protein~e.21 :polarity - :name (n2 / name :op1 "neurofibromin"~e.10))))) :ARG2 (i2 / important~e.24 :mode interrogative :domain~e.22,29 (f / form~e.14 :mod~e.15 (e / enzyme :name (n / name :op1 "Ras"~e.20) :mod (w / wild-type~e.17,19) :mod (h2 / hyperactive~e.16))) :beneficiary~e.25 (p4 / phenotype~e.28 :ARG1-of (m2 / malignant-02~e.27)) :degree (m5 / most~e.23) :ARG1-of (q / question-01~e.33 :mod (d / difficult~e.32 :degree (m / more~e.31))) :degree (m4 / most~e.23))) # ::id pmid_2465_1010.80 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Perhaps elevated H @-@ Ras , N @-@ Ras , K @-@ Ras @-@ 4A , and K @-@ Ras @-@ 4B all contribute to some extent . # ::alignments 0-1 1-1.1.1.5 2-1.1.1.1.1.1 4-1.1.1.1.1.1 4-1.1.1.2.1.1 4-1.1.1.3.1.1 4-1.1.1.4.1.1 6-1.1.1.2.1.1 8-1.1.1.1.1.1 8-1.1.1.2.1.1 8-1.1.1.3.1.1 8-1.1.1.4.1.1 10-1.1.1.3.1.1 10-1.1.1.4.1.1 12-1.1.1.1.1.1 12-1.1.1.2.1.1 12-1.1.1.3.1.1 12-1.1.1.4.1.1 14-1.1.1.3.1.1 16-1.1.1 17-1.1.1.3.1.1 17-1.1.1.4.1.1 19-1.1.1.1.1.1 19-1.1.1.2.1.1 19-1.1.1.3.1.1 19-1.1.1.4.1.1 21-1.1.1.4.1.1 22-1.1.1.6 23-1.1 24-1.1.2.r 25-1.1.2.1 26-1.1.2 (p / possible-01~e.0 :ARG1 (c / contribute-01~e.23 :ARG1 (a / and~e.16 :op1 (e / enzyme :name (n / name :op1 "H-Ras"~e.2,4,8,12,19)) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"~e.4,6,8,12,19)) :op3 (e3 / enzyme :name (n3 / name :op1 "K-Ras-4A"~e.4,8,10,12,14,17,19)) :op4 (e4 / enzyme :name (n4 / name :op1 "K-Ras-4B"~e.4,8,10,12,17,19,21)) :ARG1-of (e5 / elevate-01~e.1) :mod (a2 / all~e.22)) :degree~e.24 (e6 / extent~e.26 :mod (s2 / some~e.25)))) # ::id pmid_2465_1010.81 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , neurofibromin is also a GAP for R @-@ Ras proteins , and hyperactivation of these proteins can also contribute to the malignant phenotype because R @-@ Ras proteins activate p110α, p110γ, and p110δ isoforms of PI3Ks ( Marte et al. , 1997 ; Huang et al. , 2004 ) . # ::alignments 0-1 2-1.1.1.2.1.1 3-1.1.1.2.r 4-1.1.1.4 6-1.1.1.1.1 8-1.1.1.3.1.1 10-1.1.1.3.1.1 11-1.1.1 17-1.1.1 17-1.1.1.2 18-1.1.2 19-1.1.1.2.2 19-1.1.1.4 20-1.1.2.1 21-1.1.2.1.2.r 23-1.1.2.1.2.1 24-1.1.2.1.2 25-1.1.2.2 26-1.1.1.3.1.1 28-1.1.1.3.1.1 29-1.1.1 30-1.1.2.1.1 30-1.1.2.2.1 33-1.1.2.2.1.2.1 34-1.1.2.2.1.2.1.3.1.1 35-1.1.2.2.1.2.1.1 35-1.1.2.2.1.2.1.2 35-1.1.2.2.1.2.1.3 40-1.2.1.1.1.1.1.1 41-1.2.1.1.1 42-1.2.1.1.1.2.1 44-1.2.1.1.2.1 46-1.2.1.2.1.1.1.1 47-1.2.1 47-1.2.1.2.1 48-1.2.1.2.1.2.1 50-1.2.1.2.2.1 (h2 / have-concession-91~e.0 :ARG2 (a / and :op1 (p2 / protein~e.11,17,29 :name (n / name :op1 "GAP"~e.6) :domain~e.3 (p / protein~e.17 :name (n2 / name :op1 "neurofibromin"~e.2) :mod (a2 / also~e.19)) :beneficiary (e2 / enzyme :name (n3 / name :op1 "R-Ras"~e.8,10,26,28)) :mod (a8 / also~e.4,19)) :op2 (p3 / possible-01~e.18 :ARG1 (c2 / contribute-01~e.20 :ARG0 (a3 / activate-01~e.30 :ARG1 a5 :degree (h3 / hyper)) :ARG2~e.21 (p4 / phenotype~e.24 :ARG1-of (m2 / malignant-02~e.23)) :mod a8) :ARG1-of (c3 / cause-01~e.25 :ARG0 (a4 / activate-01~e.30 :ARG0 e2 :ARG1 (i / include-91 :ARG1 (a5 / and~e.33 :op1 (i2 / isoform~e.35 :name (n4 / name :op1 "p110α")) :op2 (i3 / isoform~e.35 :name (n5 / name :op1 "p110γ")) :op3 (i4 / isoform~e.35 :name (n6 / name :op1 "p110δ"~e.34)) :mod (e / enzyme :name (n7 / name :op1 "PI3K")))))))) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and~e.47 :op1 (p6 / publication-91 :ARG0 (a9 / and~e.41 :op1 (p5 / person :name (n9 / name :op1 "Marte"~e.40)) :op2 (p8 / person :mod (o / other~e.42))) :time (d / date-entity :year 1997~e.44)) :op2 (p7 / publication-91 :ARG0 (a7 / and~e.47 :op1 (p9 / person :name (n10 / name :op1 "Huang"~e.46)) :op2 (p10 / person :mod (o2 / other~e.48))) :time (d2 / date-entity :year 2004~e.50))))) # ::id pmid_2465_1010.82 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recently , Legius and colleagues ( Brems et al. , 2007 ) discovered mutations in the Sprouty @-@ related protein , SPRED1 , in a form of neurofibromatosis type I ( NF1 ) in which the neurofibromin gene is wild @-@ type . # ::alignments 0-1.3 2-1.1.1.1.1 3-1.1 3-1.1.3.1.1 4-1.1.2 7-1.1.3.1.1.1.1.1 8-1.1.3.1.1 9-1.1.3.1.1.2.1 11-1.1.3.1.2.1 14-1 15-1.2 16-1.2.1.r 18-1.2.1.2.1.1.1 20-1.2.1.2 21-1.2.1 21-1.2.1.2.1 21-1.2.2.1.2.1.1 23-1.2.1.1.1 25-1.2.2.r 27-1.2.2 28-1.2.2.1.r 29-1.2.2.1.1.1 30-1.2.2.1.1.2 31-1.2.2.1.1.3 38-1.2.2.1.2.1.1.1.1 39-1.2.2.1.2 41-1.2.2.1.2.2 43-1.2.2.1.2.2 (d2 / discover-01~e.14 :ARG0 (a / and~e.3 :op1 (p / person :name (n / name :op1 "Legius"~e.2)) :op2 (c / colleague~e.4) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a2 / and~e.3,8 :op1 (p6 / person :name (n6 / name :op1 "Brems"~e.7)) :op2 (p7 / person :mod (o2 / other~e.9))) :time (d / date-entity :year 2007~e.11)))) :ARG1 (m / mutate-01~e.15 :ARG1~e.16 (p2 / protein~e.21 :name (n2 / name :op1 "SPRED1"~e.23) :ARG1-of (r2 / relate-01~e.20 :ARG2 (p3 / protein~e.21 :name (n3 / name :op1 "Sprouty"~e.18)))) :location~e.25 (f / form~e.27 :mod~e.28 (d4 / disease :name (n4 / name :op1 "neurofibromatosis"~e.29 :op2 "type"~e.30 :op3 "I"~e.31) :location-of (g / gene~e.39 :ARG0-of (e / encode-01 :ARG1 (p4 / protein~e.21 :name (n5 / name :op1 "neurofibromin"~e.38))) :mod (w / wild-type~e.41,43))))) :time (r / recent~e.0)) # ::id pmid_2465_1010.83 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This disease is now called Legius syndrome ( Brems et al. , 2007 ) . # ::alignments 0-1.1.1 1-1.1 3-1.3 4-1 4-1.4.1.1.1.1.r 5-1.2.1 6-1.2.2 9-1.4.1.1.1.1.1 10-1.4.1.1 11-1.4.1.1.2.1 13-1.4.1.2.1 (c / call-01~e.4 :ARG1 (d2 / disease~e.1 :mod (t / this~e.0)) :ARG2 (n / name :op1 "Legius"~e.5 :op2 "syndrome"~e.6) :time (n2 / now~e.3) :ARG1-of (d4 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and~e.10 :op1 (p2 / person :name~e.4 (n3 / name :op1 "Brems"~e.9)) :op2 (p3 / person :mod (o / other~e.11))) :time (d / date-entity :year 2007~e.13)))) # ::id pmid_2465_1010.84 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPRED1 has a well @-@ established pedigree as a negative regulator of the Raf @/@ MAPK pathway , though the mechanism has been unclear . # ::alignments 0-1.1.1.1 1-1 3-1.2.1.1 5-1.2.1 6-1.2 9-1.1 9-1.1.2 9-1.1.2.r 10-1.1 10-1.1.2 10-1.1.2.r 11-1.1.2.1.r 13-1.1.2.1.1.1 15-1.1.2.1.1.1 16-1.1.2.1 18-1.3.r 20-1.3.2 23-1.3 23-1.3.1 23-1.3.1.r (h / have-03~e.1 :ARG0 (p / protein~e.9,10 :name (n / name :op1 "SPRED1"~e.0) :ARG2-of~e.9,10 (d / downregulate-01~e.9,10 :ARG1~e.11 (p3 / pathway~e.16 :name (n2 / name :op1 "Raf/MAPK"~e.13,15)))) :ARG1 (p2 / pedigree~e.6 :ARG1-of (e / establish-01~e.5 :ARG1-of (w / well-09~e.3))) :concession~e.18 (c / clear-06~e.23 :polarity~e.23 -~e.23 :ARG1 (m2 / mechanism~e.20))) # ::id pmid_2465_1010.85 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the fact that loss of neurofibromin is , to a significant extent , phenocopied by loss of SPRED1 , supports the idea that NF1 is a disease of hyperactive Ras and that the major function of neurofibromin is to turn Ras off . # ::alignments 0-1 5-1.1.1.1 5-1.1.1.2 7-1.1.1.2.1.1.1 12-1.1.1.3 17-1.1.1.1 17-1.1.1.2 18-1.1.1.1.1.r 19-1.1.1.1.1.1.1 21-1.1 23-1.1.2 25-1.1.2.1.1.2.1.1 26-1.1.2.1.1.2.r 28-1.1.2.1.1 31-1.1.2.1.1.1.1.1.1 32-1.1.2.1 35-1.1.2.1.2.3 36-1.1.2.1.2 37-1.1.2.1.2.2.r 38-1.1.2.1.2.2.1 39-1.1.2.1.1.2.r 40-1.1.2.1.1.1 41-1.1.2.1.2.2 42-1.1.2.1.2.2.2.1.1 43-1.1.2.1.2.2 (h2 / have-concession-91~e.0 :ARG1 (s / support-01~e.21 :ARG0 (p / phenocopy-00 :ARG0 (l / lose-01~e.5,17 :ARG1~e.18 (p2 / protein :name (n2 / name :op1 "SPRED1"~e.19))) :ARG1 (l2 / lose-02~e.5,17 :ARG1 (p3 / protein :name (n3 / name :op1 "neurofibromin"~e.7))) :ARG1-of (s2 / significant-02~e.12)) :ARG1 (i / idea~e.23 :topic (a / and~e.32 :op1 (d / disease~e.28 :ARG1-of (c2 / cause-01~e.40 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.31) :ARG0-of (a2 / activity-06 :degree (h / hyper)))) :domain~e.26,39 (d2 / disease :name (n4 / name :op1 "NF1"~e.25))) :op1 (f / function-01~e.36 :ARG0 p3 :ARG1~e.37 (t / turn-off-07~e.41,43 :ARG0 p3~e.38 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras"~e.42))) :ARG1-of (m / major-02~e.35)))))) # ::id pmid_2465_1010.86 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The neurofibromin protein itself is over 2,800 amino acids in length , and the GAP domain only accounts for about 300 amino acids , raising the possibility that neurofibromin has other functions that are not directly related to negative regulation of Ras . # ::alignments 1-1.1.1.1.1 2-1.1.1 2-1.2.1 5-1.1.2.1 6-1.1.2.1.1 7-1.1.2 8-1.1.2 10-1.1 12-1 14-1.2.1.1.1 15-1.2.1.1.2 16-1.2.3 17-1.2 18-1.2.2.r 19-1.2.2.1 20-1.2.2.1.1 21-1.2.2 22-1.2.2 24-1.3 26-1.3.1 27-1.3.1.1.r 28-1.3.1.1.1 30-1.3.1.1.2 31-1.3.1.1 34-1.3.1.1.2.1.1 34-1.3.1.1.2.1.1.r 35-1.3.1.1.2.1.3 36-1.3.1.1.2.1 37-1.3.1.1.2.1.2.r 38-1.3.1.1.2.1.2 39-1.3.1.1.2.1.2 40-1.3.1.1.2.1.2.1.r 41-1.3.1.1.2.1.2.1.1.1 (a2 / and~e.12 :op1 (l / long-03~e.10 :ARG1 (p / protein~e.2 :name (n2 / name :op1 "neurofibromin"~e.1)) :ARG2 (a3 / amino-acid~e.7,8 :quant (o / over~e.5 :op1 2800~e.6))) :op2 (a4 / account-01~e.17 :ARG0 (p2 / protein-segment~e.2 :name (n3 / name :op1 "GAP"~e.14 :op2 "domain"~e.15)) :ARG1~e.18 (a5 / amino-acid~e.21,22 :quant (a / about~e.19 :op1 300~e.20)) :mod (o3 / only~e.16)) :ARG0-of (r / raise-01~e.24 :ARG1 (p3 / possible-01~e.26 :ARG1~e.27 (f / function-01~e.31 :ARG0 p~e.28 :ARG1 (o2 / other~e.30 :ARG1-of (r2 / relate-01~e.36 :polarity~e.34 -~e.34 :ARG2~e.37 (d4 / downregulate-01~e.38,39 :ARG1~e.40 (e / enzyme :name (n / name :op1 "Ras"~e.41))) :ARG1-of (d / direct-02~e.35))))))) # ::id pmid_2465_1010.87 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Most attempts to identify additional functions have failed , however , and it seems most likely that neurofibromin senses an unidentified cellular metabolite and downregulates Ras accordingly , just as p120 Ras @-@ GAP senses phosphotyrosine residues , and downregulates Ras when it binds to these residues on activated receptors in the plasma membrane ( reviewed in Bos et al. , 2007 ) . # ::alignments 0-1.1.1.1.2 1-1.1.1.1 3-1.1.1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1.1.1 7-1.1.1 9-1.1 11-1 13-1.2.1 14-1.2.2 15-1.2 16-1.2.1.1.r 17-1.2.1.1.1.1.1.1 18-1.2.1.1.1 20-1.2.1.1.1.2.2 20-1.2.1.1.1.2.2.1 20-1.2.1.1.1.2.2.1.r 21-1.2.1.1.1.2.1 22-1.2.1.1.1.2 23-1.2.1.1 24-1.2.1.1.2 25-1.2.1.1.2.1.1.1 26-1.2.1.1.2.3 28-1.2.1.1.3.2 30-1.2.1.1.3.1.1.1.1.1 31-1.2.1.1.3.1.1.1.1.2 33-1.2.1.1.3.1.1.1.1.2 34-1.2.1.1.3.1.1 36-1.2.1.1.3.1.1.2 38-1.2.1.1.3.1 39-1.2.1.1.3.1.2 40-1.2.1.1.3.1.2.3.1 41-1.2.1.1.3.1.2.3.r 43-1.2.1.1.3.1.2.3 46-1.2.1.1.3.1.2.3.2 47-1.2.1.1.3.1.2.3.3.r 48-1.2.1.1.3.1.2.3.3.1 49-1.2.1.1.3.1.2.3.3 50-1.2.1.1.3.1.2.3.4.r 52-1.2.1.1.3.1.2.3.4.1 53-1.2.1.1.3.1.2.3.4 55-1.3 58-1.3.1.1.1.1.1 59-1.3.1.1 60-1.3.1.1.2.1 62-1.3.1.2.1 (a / and~e.11 :op1 (h / have-concession-91~e.9 :ARG1 (f / fail-01~e.7 :ARG1 (a2 / attempt-01~e.1 :ARG1 (i2 / identify-01~e.3 :ARG1 (f2 / function-01~e.5 :mod (a3 / additional~e.4))) :quant (m2 / most~e.0)))) :op2 (l / likely-01~e.15 :ARG1 (s / seem-01~e.13 :ARG1~e.16 (a4 / and~e.23 :op1 (s2 / sense-01~e.18 :ARG0 (p / protein :name (n2 / name :op1 "neurofibromin"~e.17)) :ARG1 (m4 / metabolite~e.22 :mod (c2 / cell~e.21) :ARG1-of (i / identify-01~e.20 :polarity~e.20 -~e.20))) :op2 (d2 / downregulate-01~e.24 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.25)) :ARG2 p :manner (a5 / accordingly~e.26)) :ARG1-of (r / resemble-01 :ARG2 (a7 / and~e.38 :op1 (s3 / sense-01~e.34 :ARG0 (p2 / protein :name (n3 / name :op1 "p120"~e.30 :op2 "Ras-GAP"~e.31,33)) :ARG1 (r2 / residue~e.36 :mod (a6 / amino-acid :name (n4 / name :op1 "threonine") :ARG3-of (p3 / phosphorylate-01)))) :op2 (d3 / downregulate-01~e.39 :ARG1 e :ARG2 p2 :time~e.41 (b / bind-01~e.43 :ARG1 p2~e.40 :ARG2 r2~e.46 :ARG3~e.47 (r3 / receptor~e.49 :ARG1-of (a8 / activate-01~e.48)) :location~e.50 (m3 / membrane~e.53 :part-of (p4 / plasma~e.52))))) :mod (j / just~e.28)))) :degree (m / most~e.14)) :ARG1-of (r4 / review-02~e.55 :ARG2 (p5 / publication-91 :ARG0 (a9 / and~e.59 :op1 (p6 / person :name (n5 / name :op1 "Bos"~e.58)) :op2 (p7 / person :mod (o / other~e.60))) :time (d / date-entity :year 2007~e.62)))) # ::id pmid_2465_1010.88 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whatever neurofibromin senses ( if this model is correct ) is likely to be conserved between S . cerevisiae and humans because the S . cerevisiae IRA1 and IRA2 proteins look very much like neurofibromin . # ::alignments 1-1.1.1.1.1.1.1 2-1.1.1 2-1.1.1.1 2-1.1.1.1.r 4-1.2.r 5-1.2.1.1 6-1.2.1 8-1.2 11-1 12-1.3 14-1.1 15-1.1.2 19-1.1.2.1.1.2 21-1.1.2 22-1.1.2.2 23-1.3 28-1.3.1.1.1.2 30-1.3.1.1.1.1.1 31-1.3.1.1 32-1.3.1.1.2.1.1 33-1.1.1.1.1 33-1.3.1.1.1 33-1.3.1.1.2 35-1.3.1.3.1 36-1.3.1.3 37-1.3.1 38-1.3.1.2 (l / likely-01~e.11 :ARG1 (c / conserve-01~e.14 :ARG1 (t / thing~e.2 :ARG1-of~e.2 (s / sense-01~e.2 :ARG0 (p / protein~e.33 :name (n / name :op1 "neurofibromin"~e.1)))) :location (b / between~e.15,21 :op1 (o / organism :name (n2 / name :op1 "S." :op2 "cerevisiae"~e.19)) :op2 (h / human~e.22))) :condition~e.4 (c2 / correct-02~e.8 :ARG1 (m2 / model~e.6 :mod (t2 / this~e.5))) :ARG1-of (c3 / cause-01~e.12,23 :ARG0 (r / resemble-01~e.37 :ARG1 (a / and~e.31 :op1 (p2 / protein~e.33 :name (n3 / name :op1 "IRA1"~e.30) :mod o~e.28) :op2 (p3 / protein~e.33 :name (n4 / name :op1 "IRA2"~e.32) :mod o)) :ARG2 p~e.38 :degree (m / much~e.36 :degree (v / very~e.35))))) # ::id pmid_2465_1010.89 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Unfortunately , the complete lack of any recognizable domains or motifs outside the GAP domain and a SEC14 domain has not helped in identifying what these proteins recognize . # ::alignments 0-1.4 0-1.4.1 3-1.2.2 4-1.2 5-1.2.1.r 6-1.2.1.1.1 8-1.2.1.1 9-1.2.1 10-1.2.1.2 11-1.2.3 13-1.2.3.1.1.1.1 14-1.2.3.1.1.1.2 15-1.2.3.1 17-1.2.3.1.2.1.1 18-1.2.3.1.2.1.2 20-1.1 20-1.1.r 20-1.4.1.r 21-1 22-1.3.r 23-1.3 24-1.3.1 25-1.3.1.1.1.1 26-1.3.1.1.1 27-1.2.1.3 27-1.3.1.1 (h / help-01~e.21 :polarity~e.20 -~e.20 :ARG0 (l / lack-01~e.4 :ARG1~e.5 (o / or~e.9 :op1 (d / domain~e.8 :mod (a / any~e.6)) :op2 (m / motif~e.10 :mod a) :ARG1-of (r / recognize-02~e.27 :ARG1-of (p / possible-01))) :ARG1-of (c / complete-02~e.3) :location (o2 / outside~e.11 :op1 (a2 / and~e.15 :op1 (p2 / protein-segment :name (n / name :op1 "GAP"~e.13 :op2 "domain"~e.14)) :op2 (p4 / protein-segment :name (n2 / name :op1 "SEC14"~e.17 :op2 "domain"~e.18))))) :ARG1~e.22 (i / identify-01~e.23 :ARG1 (t / thing~e.24 :ARG1-of (r2 / recognize-02~e.27 :ARG0 (p3 / protein~e.26 :mod (t2 / this~e.25))))) :ARG2-of (f / fortunate-01~e.0 :polarity~e.20 -~e.0)) # ::id pmid_2465_1010.90 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By comparing proteins that bind to wild @-@ type SPRED1 versus mutants from Legius syndrome , we found that neurofibromin binds directly to SPRED proteins , via their EVH1 domains , and that SPRED proteins bring neurofibromin to the plasma membrane ( Stowe et al. , 2012 ) . # ::alignments 1-1.3 2-1.3.1 2-1.3.2 4-1.3.1.1 5-1.3.1.1.1.r 6-1.3.1.1.1.2 8-1.3.1.1.1.2 9-1.3.1.1.1.1.1 11-1.3.2.1 12-1.3.2.2.r 13-1.3.2.2.1.1 14-1.3.2.2.1.2 16-1.1 17-1 18-1.2.r 19-1.2.1.1.1.1 20-1.2.1 21-1.2.1.4 23-1.2.1.2.1.1 24-1.2.1.1 28-1.2.1.3.1.1.1 28-1.2.1.3.2.1.1 29-1.2.1.3.1.1.2 29-1.2.1.3.2.1.2 31-1.2.1.3 33-1.2.1.2.1.1 34-1.2.1.1 34-1.2.1.2 34-1.2.1.3.1 34-1.2.1.3.2 35-1.2.2 36-1.2.2.2 37-1.2.2.3.r 39-1.2.2.3.1 40-1.2.2.3 43-1.4.1.1.1.1.1 44-1.4.1.1 45-1.4.1.1.2.1 47-1.4.1.2.1 (f / find-01~e.17 :ARG0 (w / we~e.16) :ARG1~e.18 (a2 / and :op1 (b / bind-01~e.20 :ARG1 (p / protein~e.24,34 :name (n / name :op1 "neurofibromin"~e.19)) :ARG2 (p2 / protein~e.34 :name (n2 / name :op1 "SPRED"~e.23,33)) :ARG3 (a / and~e.31 :op1 (p10 / protein-segment~e.34 :name (n3 / name :op1 "EVH1"~e.28 :op2 "domain"~e.29) :part-of p) :op1 (p3 / protein-segment~e.34 :name (n7 / name :op1 "EVH1"~e.28 :op2 "domain"~e.29) :part-of p2)) :ARG1-of (d2 / direct-02~e.21)) :op2 (b2 / bring-01~e.35 :ARG0 p2 :ARG1 p~e.36 :ARG2~e.37 (m / membrane~e.40 :part-of (p4 / plasma~e.39)))) :manner (c / compare-01~e.1 :ARG1 (p5 / protein~e.2 :ARG1-of (b3 / bind-01~e.4 :ARG2~e.5 (p6 / protein :name (n4 / name :op1 "SPRED1"~e.9) :mod (w2 / wild-type~e.6,8)))) :ARG2 (p11 / protein~e.2 :ARG2-of (m2 / mutate-01~e.11) :source~e.12 (d5 / disease :name (n5 / name :op1 "Legius"~e.13 :op2 "syndrome"~e.14)))) :ARG1-of (d6 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a3 / and~e.44 :op1 (p8 / person :name (n6 / name :op1 "Stowe"~e.43)) :op2 (p9 / person :mod (o / other~e.45))) :time (d / date-entity :year 2012~e.47)))) # ::id pmid_2465_1010.91 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPRED proteins also bind to c @-@ Kit , and perhaps to other RTKs , suggesting that neurofibromin regulates Ras locally in response to specific receptor signaling , rather than simply suppressing Ras throughout the plasma membrane . # ::alignments 0-1.1.1.1 1-1.1 1-1.4.1.1 2-1.3 3-1 4-1.2.r 5-1.2.1.1.1 7-1.2.1.1.1 9-1.2 10-1.2.2 10-1.2.2.3 10-1.2.2.3.r 11-1.2.2.2.r 12-1.2.2.2 15-1.4 16-1.4.1.r 17-1.4.1.1.1.1 18-1.4.1 19-1.4.1.2.1.1 20-1.4.1.3 21-1.4.1.4.r 22-1.4.1.4 23-1.4.1.4.1.r 24-1.4.1.4.1.1.1 25-1.4.1.4.1.1 26-1.4.1.4.1 28-1.4.1.5 30-1.4.1.5.1.4 31-1.4.1.5.1 32-1.4.1.5.1.2 35-1.4.1.5.1.3.1 36-1.4.1.5.1.3 (b / bind-01~e.3 :ARG1 (p2 / protein~e.1 :name (n2 / name :op1 "SPRED"~e.0)) :ARG2~e.4 (a / and~e.9 :op1 (e2 / enzyme :name (n3 / name :op1 "c-Kit"~e.5,7)) :op2 (e3 / enzyme~e.10 :name (n4 / name :op1 "RTK") :mod~e.11 (o / other~e.12) :ARG1-of~e.10 (p / possible-01~e.10))) :mod (a2 / also~e.2) :ARG0-of (s / suggest-01~e.15 :ARG1~e.16 (r / regulate-01~e.18 :ARG0 (p4 / protein~e.1 :name (n5 / name :op1 "neurofibromin"~e.17)) :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.19)) :ARG1-of (l / local-02~e.20) :ARG2-of~e.21 (r2 / respond-01~e.22 :ARG1~e.23 (s2 / signal-07~e.26 :ARG0 (r3 / receptor~e.25 :ARG1-of (s3 / specific-02~e.24)))) :ARG1-of (i / instead-of-91~e.28 :ARG2 (s4 / suppress-01~e.31 :ARG0 p4 :ARG1 e~e.32 :location (m / membrane~e.36 :part-of (p5 / plasma~e.35)) :ARG1-of (s5 / simple-02~e.30)))))) # ::id pmid_2465_1010.92 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this case , loss of neurofibromin may lead to local activation of Ras that is coupled to specific receptors , suggesting that inhibitors of these receptors might reverse the effects of neurofibromin loss . # ::alignments 0-1.2.r 1-1.2.1 2-1.2 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1 7-1 8-1.1 9-1.1.2.r 10-1.1.2.2 11-1.1.2 12-1.1.2.1.r 13-1.1.2.1.1.1 16-1.1.2.3 17-1.1.2.3.1.r 18-1.1.2.3.1.1 19-1.1.2.3.1 21-1.1.3 22-1.1.3.1.r 23-1.1.3.1.1.1 23-1.1.3.1.1.1.1 23-1.1.3.1.1.1.1.r 25-1.2.1 26-1.1.2.3.1 27-1.1.3.1 28-1.1.3.1.1 30-1.1.3.1.1.2 31-1.1.3.1.1.2.1.r 32-1.1.3.1.1.2.1 33-1.1.3.1.1.2.1 (p / possible-01~e.7 :ARG1 (l / lead-03~e.8 :ARG0 (l2 / lose-02~e.4 :ARG1~e.5 (p2 / protein :name (n2 / name :op1 "neurofibromin"~e.6))) :ARG2~e.9 (a / activate-01~e.11 :ARG1~e.12 (e / enzyme :name (n / name :op1 "Ras"~e.13)) :ARG1-of (l3 / local-02~e.10) :ARG1-of (c / couple-01~e.16 :ARG2~e.17 (r / receptor~e.19,26 :ARG1-of (s / specific-02~e.18)))) :ARG0-of (s2 / suggest-01~e.21 :ARG1~e.22 (p3 / possible-01~e.27 :ARG1 (r2 / reverse-01~e.28 :ARG0 (m / molecular-physical-entity~e.23 :ARG0-of~e.23 (i / inhibit-01~e.23 :ARG1 r)) :ARG1 (a2 / affect-01~e.30 :ARG0~e.31 l2~e.32,33))))) :prep-in~e.0 (c2 / case-04~e.2 :ARG1 (t / this~e.1,25))) # ::id pmid_2465_1010.93 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The recent Cancer Genome Atlas analysis of mutations in lung cancer revealed an intriguing overlap between neurofibromin loss and Met amplification , suggesting a functional connection that merits further investigation ( E.A . Collisson , personal communication ) . # ::alignments 1-1.1.3 2-1.1.1.1.1 3-1.1.1.1.2 4-1.1.1.1.3 5-1.1 6-1.1.2.r 7-1.1.2 8-1.1.2.1.r 9-1.1.2.1.2.1 10-1.1.2.1.2.2 11-1 13-1.2.3 14-1.2 16-1.2.1.1.1.1 17-1.2.1 19-1.2.2.1.1.1 20-1.2.2 22-1.3 24-1.3.1.1 25-1.3.1 27-1.3.1.2 28-1.3.1.2.1.2 29-1.3.1.2.1 31-1.4.1.1.1 33-1.4.1.1.2 35-1.4.2 36-1.4 (r / reveal-01~e.11 :ARG0 (a / analyze-01~e.5 :ARG0 (t / thing :name (n3 / name :op1 "Cancer"~e.2 :op2 "Genome"~e.3 :op3 "Atlas"~e.4)) :ARG1~e.6 (m / mutate-01~e.7 :ARG0~e.8 (d2 / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung"~e.9 :op2 "cancer"~e.10))) :time (r2 / recent~e.1)) :ARG1 (o / overlap-01~e.14 :ARG0 (l / lose-02~e.17 :ARG1 (p2 / protein :name (n4 / name :op1 "neurofibromin"~e.16))) :ARG1 (a2 / amplify-01~e.20 :ARG1 (p3 / protein :name (n5 / name :op1 "Met"~e.19))) :ARG0-of (i2 / intrigue-01~e.13)) :ARG0-of (s / suggest-01~e.22 :ARG1 (c / connect-01~e.25 :ARG0-of (f / function-01~e.24) :ARG0-of (m2 / merit-01~e.27 :ARG1 (i / investigate-01~e.29 :ARG1 c :degree (f2 / further~e.28))))) :ARG1-of (c2 / communicate-01~e.36 :ARG0 (p4 / person :name (n / name :op1 "E.A"~e.31 :op2 "Collisson"~e.33)) :ARG1-of (p / personal-02~e.35))) # ::id pmid_2465_1010.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Validation of Ras as a Target # ::alignments 0-1 1-1.1.r 2-1.1.1.1.1 5-1.1 (v / validate-01~e.0 :ARG1~e.1 (t / target-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.2)))) # ::id pmid_2465_1010.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras oncogenes can certainly initiate cancer in model organisms and probably do so in humans . # ::alignments 0-1.1.1.1.1.1 2-1.1 3-1.1.2 4-1.1.1 4-1.2.1 5-1.1.1.2.2.1 6-1.1.1.3.r 7-1.1.1.3.1 8-1.1.1.3 9-1 10-1.2 12-1.2.1.1 13-1.2.1.3.r 14-1.2.1.3 (a / and~e.9 :op1 (p / possible-01~e.2 :ARG1 (i / initiate-01~e.4 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.0) :ARG0-of (c2 / cause-01 :ARG1 d)) :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.5)) :location~e.6 (o2 / organism~e.8 :mod (m / model~e.7))) :mod (c / certain~e.3)) :op2 (p2 / probable~e.10 :domain (i2 / initiate-01~e.4 :ARG0 e~e.12 :ARG1 d :location~e.13 (h / human~e.14)))) # ::id pmid_2465_1010.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , their role in maintaining tumors is less clear . # ::alignments 0-1 2-1.1.1.1 2-1.1.1.1.r 3-1.1.1 4-1.1.1.2.r 5-1.1.1.2 6-1.1.1.2.1 8-1.1.2 9-1.1 (h / have-concession-91~e.0 :ARG1 (c / clear-06~e.9 :ARG1 (r / role~e.3 :poss~e.2 (t / they~e.2) :topic~e.4 (m / maintain-01~e.5 :ARG1 (t2 / tumor~e.6))) :degree (l / less~e.8))) # ::id pmid_2465_1010.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok There is significant evidence that supports K @-@ Ras as a continued candidate for direct therapeutic targeting , dating back to the classic studies of temperature @-@ sensitive mutants of Ras , by Scolnick , Lowy , and colleagues and including microinjection studies with antibodies that block Ras activity ( Kung et al. , 1986 ) or block specific mutant alleles of Ras ( Feramisco et al. , 1985 ) . # ::alignments 2-1.1 3-1 5-1.2 6-1.2.1.3.1.1 8-1.2.1.3.1.1 11-1.2.1.2 12-1.2.1 13-1.2.1.1.r 14-1.2.1.1.2 15-1.2.1.1.1 16-1.2.1.1 18-1.3 18-1.4.1.2.1.1.2.1.2 18-1.4.1.2.2.1.2.1.2 19-1.3.2 20-1.3.1.r 22-1.3.1.3 23-1.3.1 24-1.3.1.2.r 25-1.3.1.2.3.1 27-1.3.1.2.3 28-1.3.1.2 28-1.3.1.2.2 28-1.3.1.2.2.r 30-1.3.1.2.1.1 32-1.3.1.1.r 33-1.3.1.1.1.1.1 35-1.3.1.1.2.1.1 37-1.3.1.1 38-1.3.1.1.3 39-1.3.1.1 40-1.4 42-1.4.1 43-1.4.1.2.r 44-1.4.1.2.1 44-1.4.1.2.2 46-1.4.1.2.1.1 46-1.4.1.2.2.1 47-1.4.1.2.1.1.1.1.1.1 48-1.4.1.2.1.1.1 51-1.4.1.2.1.1.2.1.1.1.1.1 52-1.4.1.2.1.1.2.1.1 53-1.4.1.2.1.1.2.1.1.2.1 55-1.4.1.2.1.1.2.1.2.1 58-1.4.1.2 59-1.4.1.2.2.1 60-1.4.1.2.2.1.1.3 61-1.4.1.2.2.1.1.2 62-1.4.1.2.2.1.1 63-1.4.1.2.2.1.1.1.r 64-1.4.1.2.2.1.1.1 67-1.4.1.2.2.1.2.1.1.1.1.1 68-1.4.1.2.1.1.2.1.1 68-1.4.1.2.2.1.2.1.1 69-1.4.1.2.1.1.2.1.1.2.1 71-1.4.1.2.2.1.2.1.2.1 (e3 / evidence-01~e.3 :ARG1-of (s / significant-02~e.2) :ARG0-of (s2 / support-01~e.5 :ARG1 (c / candidate~e.12 :purpose~e.13 (t / target-01~e.16 :ARG0 (t2 / therapy~e.15) :ARG1-of (d3 / direct-02~e.14)) :ARG1-of (c2 / continue-01~e.11) :domain (e / enzyme :name (n / name :op1 "K-Ras"~e.6,8)))) :ARG1-of (d4 / date-01~e.18 :ARG2~e.20 (s3 / study-01~e.23 :ARG0~e.32 (a / and~e.37,39 :op1 (p / person :name (n3 / name :op1 "Scolnick"~e.33)) :op2 (p2 / person :name (n4 / name :op1 "Lowy"~e.35)) :op3 (c3 / colleague~e.38)) :ARG1~e.24 (e2 / enzyme~e.28 :name (n2 / name :op1 "Ras"~e.30) :ARG2-of~e.28 (m / mutate-01~e.28) :ARG0-of (s4 / sensitive-03~e.27 :ARG1 (t3 / temperature~e.25))) :mod (c4 / classic~e.22)) :direction (b / back~e.19)) :ARG2-of (i / include-01~e.40 :ARG1 (s5 / study-01~e.42 :ARG1 (i2 / inject-01 :mod (m3 / micro)) :instrument~e.43 (o / or~e.58 :op1 (a2 / antibody~e.44 :ARG0-of (b2 / block-01~e.46 :ARG1 (a3 / activity-06~e.48 :ARG0 (e4 / enzyme :name (n5 / name :op1 "Ras"~e.47))) :ARG1-of (d5 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and~e.52,68 :op1 (p4 / person :name (n6 / name :op1 "Kung"~e.51)) :op2 (p5 / person :mod (o2 / other~e.53,69))) :time (d / date-entity~e.18 :year 1986~e.55))))) :op2 (a5 / antibody~e.44 :ARG0-of (b3 / block-01~e.46,59 :ARG1 (a6 / allele~e.62 :mod~e.63 e4~e.64 :ARG2-of (m2 / mutate-01~e.61) :ARG1-of (s6 / specific-02~e.60)) :ARG1-of (d6 / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a7 / and~e.68 :op1 (p7 / person :name (n7 / name :op1 "Feramisco"~e.67)) :op2 (p8 / person :mod o2)) :time (d2 / date-entity~e.18 :year 1985~e.71))))))))) # ::id pmid_2465_1010.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ablation of K @-@ Ras in mouse models of lung adenocarcinoma ( Fisher et al. , 2001 ) or pancreas cancer ( Ying et al. , 2012 ) led to dramatic tumor regression , just as ablation of H @-@ Ras leads to tumor regression in mouse models of melanoma ( Chin et al. , 1999 ) . # ::alignments 0-1.1 2-1.1.1.1.1 4-1.1.1.1.1 6-1.1.2.1.1 7-1.1.2.1 7-1.1.2.2 8-1.1.2.1.3.r 9-1.1.2.1.3.1.1 10-1.1.2.1.3.1.2 13-1.1.2.1.2.1.1.1.1.1 14-1.1.2.1.2.1.1 15-1.1.2.1.2.1.1.2.1 17-1.1.2.1.2.1.2.1 20-1.1.2 21-1.1.2.2.3.1.1 22-1.1.2.2.3.1.2 25-1.1.2.2.2.1.1.1.1.1 26-1.1.2.1.2.1.1 26-1.1.2.2.2.1.1 27-1.1.2.1.2.1.1.2.1 29-1.1.2.2.2.1.2.1 32-1 34-1.2.2 35-1.2.1 39-1.1.2.1.2.1.2.r 39-1.1.2.2.2.1.2.r 40-1.1 40-1.3.1.1 41-1.3.1.1.1.r 42-1.3.1.1.1.1.1 44-1.3.1.1.1.1.1 45-1.3.1 47-1.3.1.2.1 50-1.3.1.2.2.1 51-1.3.1.2.2 52-1.3.1.2.2.2.r 53-1.3.1.2.2.2.1.1 56-1.3.1.3.1.1.1.1.1 57-1.1.2.1.2.1.1 57-1.3.1.3.1.1 58-1.1.2.1.2.1.1.2.1 60-1.3.1.3.1.2.1 (l / lead-03~e.32 :ARG0 (a / ablate-01~e.0,40 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.2,4)) :location (o / or~e.20 :op1 (m / model~e.7 :mod (m2 / mouse~e.6) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and~e.14,26,57 :op1 (p3 / person :name (n2 / name :op1 "Fisher"~e.13)) :op2 (p4 / person :mod (o2 / other~e.15,27,58))) :time~e.39 (d / date-entity :year 2001~e.17))) :topic~e.8 (m6 / medical-condition :name (n6 / name :op1 "lung"~e.9 :op2 "adenocarcinoma"~e.10))) :op2 (m3 / model~e.7 :mod m2 :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a4 / and~e.26 :op1 (p6 / person :name (n4 / name :op1 "Ying"~e.25)) :op2 (p7 / person :mod o2)) :time~e.39 (d2 / date-entity :year 2012~e.29))) :topic (d9 / disease :name (n7 / name :op1 "pancreas"~e.21 :op2 "cancer"~e.22))))) :ARG2 (r / regress-01 :ARG1 (t / tumor~e.35) :degree (d6 / dramatic~e.34)) :ARG1-of (r2 / resemble-01 :ARG2 (l3 / lead-03~e.45 :ARG0 (a5 / ablate-01~e.40 :ARG1~e.41 (e2 / enzyme :name (n3 / name :op1 "H-Ras"~e.42,44))) :ARG2 (r3 / regress-01 :ARG1 (t2 / tumor~e.47) :location (m4 / model~e.51 :mod (m5 / mouse~e.50) :topic~e.52 (m7 / medical-condition :name (n8 / name :op1 "melanoma"~e.53)))) :ARG1-of (d7 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a6 / and~e.57 :op1 (p9 / person :name (n5 / name :op1 "Chin"~e.56)) :op2 (p10 / person :mod o2)) :time (d3 / date-entity :year 1999~e.60)))))) # ::id pmid_2465_1010.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , K @-@ Ras knockdown in human cell lines resulted in a spectrum of responses , revealing a range of K @-@ Ras dependencies ( Singh et al. , 2009 ) . # ::alignments 2-1.2.1.1.2.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.r 10-1.1.1.2.1 11-1.1.1.2 12-1.1.1.2 13-1.1 14-1.1.2.r 16-1.1.2.2 17-1.1.2.2.r 18-1.1.2 18-1.1.2.1 18-1.1.2.1.r 20-1.1.2.3 22-1.1.2.3.1 23-1.1.2.3.1.1.r 24-1.1.2.3.1.1.1 25-1.1.2.3.1.1.1 26-1.1.2.3.1.1.1 27-1.1.2.3.1.1 30-1.2.1.1.1.1.1 31-1.2.1.1 32-1.2.1.1.2.1 34-1.2.1.2.1 (c / contrast-01 :ARG2 (r / result-01~e.13 :ARG1 (k / knock-down-02~e.8 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.5,7)) :location~e.9 (c2 / cell-line~e.11,12 :mod (h / human~e.10))) :ARG2~e.14 (t / thing~e.18 :ARG2-of~e.18 (r2 / respond-01~e.18) :quant~e.17 (s / spectrum~e.16) :ARG0-of (r3 / reveal-01~e.20 :ARG1 (r4 / range-01~e.22 :ARG1~e.23 (d2 / depend-01~e.27 :ARG1 e~e.24,25,26))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and~e.31 :op1 (p2 / person :name (n2 / name :op1 "Singh"~e.30)) :op2 (p3 / person :mod (o / other~e.2,32))) :time (d / date-entity :year 2009~e.34)))) # ::id pmid_2465_1010.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Assessment of Ras dependency in 3D culture systems suggests that this assay system is a more stringent measure of Ras dependency . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 3-1.1.1 4-1.1.2.r 5-1.1.2.1.1 5-1.1.2.1.1.1 5-1.1.2.1.1.1.r 6-1.1.2.1 7-1.1.2 8-1 9-1.2.r 10-1.2.1.1 11-1.2.1.2 12-1.2.1 15-1.2.3.1 16-1.2.3 17-1.2 18-1.2.2.r 19-1.2.2 20-1.2.2 (s / suggest-01~e.8 :ARG0 (a / assess-01~e.0 :ARG1~e.1 (d / depend-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.2))) :location~e.4 (s2 / system~e.7 :mod (c / culture~e.6 :mod (d2 / dimension~e.5 :quant~e.5 3~e.5)))) :ARG1~e.9 (m / measure-01~e.17 :ARG0 (s3 / system~e.12 :mod (t / this~e.10) :instrument-of (a2 / assay-01~e.11)) :ARG1~e.18 d~e.19,20 :mod (s4 / stringent~e.16 :degree (m2 / more~e.15)))) # ::id pmid_2465_1010.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These studies raise the question of what is the most relevant system to measure this essential parameter and , in general , responses to candidate therapeutics targeting K @-@ Ras . # ::alignments 0-1.1.2 1-1.1.1 2-1 4-1.2 6-1.1 6-1.2.1.1.1.1.2 9-1.2.1.1.2 10-1.2.1.1 11-1.2.1 13-1.2.1.1.1 14-1.2.1.1.1.1.1.2 15-1.2.1.1.1.1.1.1 16-1.2.1.1.1.1.1 17-1.2.1.1.1.1 19-1.2.1.1.1.1.2.1.r 20-1.2.1.1.1.1.2.1.2 22-1.2.1.1.1.1.2.1 23-1.2.1.1.1.1.2.1.1.r 24-1.2.1.1.1.1.2.1.1.1 25-1.2.1.1.1.1.2.1.1 26-1.2.1.1.1.1.2.1.1.2 27-1.2.1.1.1.1.2.1.1.2.1.1.1 29-1.2.1.1.1.1.2.1.1.2.1.1.1 (r / raise-01~e.2 :ARG0 (t / thing~e.6 :ARG1-of (s / study-01~e.1) :mod (t2 / this~e.0)) :ARG1 (q / question-01~e.4 :ARG1 (s2 / system~e.11 :ARG1-of (r2 / relevant-01~e.10 :ARG2 (m2 / measure-01~e.13 :ARG1 (a / and~e.17 :op1 (p / parameter~e.16 :mod (e2 / essential~e.15) :mod t2~e.14) :op2 (t3 / thing~e.6 :ARG2-of~e.19 (r3 / respond-01~e.22 :ARG1~e.23 (t4 / therapeutics~e.25 :mod (c / candidate~e.24) :ARG0-of (t5 / target-01~e.26 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.27,29)))) :ARG1-of (g / general-02~e.20))))) :degree (m / most~e.9))))) # ::id pmid_2465_1010.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , the degree to which Ras genes are knocked down may be critical . # ::alignments 0-1 3-1.1.1.1 3-1.1.1.1.1.r 6-1.1.1.1.1.1.1.1.1.1 7-1.1.1.1.1.1 9-1.1.1.1.1 10-1.1.1.1.1 11-1.1 13-1.1.1 (a / and~e.0 :op2 (p / possible-01~e.11 :ARG1 (c / critical-02~e.13 :ARG1 (d2 / degree~e.3 :degree-of~e.3 (k / knock-down-02~e.9,10 :ARG1 (g / gene~e.7 :ARG0-of (e2 / encode-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.6))))))))) # ::id pmid_2465_1010.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Genetic ablation is obviously different than small interfering RNA @- or small hairpin RNA ( shRNA ) - mediated knockdown . # ::alignments 1-1.1 3-1.3 4-1 6-1.2.1.1.1.1.1 7-1.2.1.1.1.1.2 8-1.2.1.1.1.1.3 10-1.2.1.1 11-1.2.1.1.2.1.1 12-1.2.1.1.2.1.2 13-1.2.1.1.2.1.3 18-1.2.1 19-1.2 (d / differ-02~e.4 :ARG1 (a / ablate-01~e.1 :ARG1 (g / gene)) :ARG2 (k / knock-down-02~e.19 :ARG1-of (m / mediate-01~e.18 :ARG0 (o / or~e.10 :op1 (n3 / nucleic-acid :name (n2 / name :op1 "small"~e.6 :op2 "interfering"~e.7 :op3 "RNA"~e.8)) :op2 (n4 / nucleic-acid :name (n / name :op1 "small"~e.11 :op2 "hairpin"~e.12 :op3 "RNA"~e.13))))) :ARG1-of (o2 / obvious-01~e.3)) # ::id pmid_2465_1010.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is also clear that knocking down activated Ras can lead to hyperactivation of upstream pathways , such as EGFR signaling ( Young et al. , 2013 ) . # ::alignments 2-1.2 3-1 4-1.1.r 5-1.1.1.1 6-1.1.1.1 7-1.1.1.1.1.2 7-1.1.1.2 8-1.1.1.1.1.1.1 9-1.1 10-1.1.1 13-1.1.1.2.2.r 14-1.1.1.2.2.1 15-1.1.1.2.2 17-1.1.1.2.2.2.r 18-1.1.1.2.2.2.r 19-1.1.1.2.2.2.1.1.1 20-1.1.1.2.2.2 23-1.1.1.3.1.1.1.1.1 24-1.1.1.3.1.1 25-1.1.1.3.1.1.2.1 27-1.1.1.3.1.2.1 (c / clear-06~e.3 :ARG1~e.4 (p / possible-01~e.9 :ARG1 (l / lead-03~e.10 :ARG0 (k / knock-down-02~e.5,6 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.8) :ARG1-of (a2 / activate-01~e.7))) :ARG2 (a3 / activate-01~e.7 :ARG0 k :ARG1~e.13 (p2 / pathway~e.15 :location (u / upstream~e.14) :example~e.17,18 (s / signal-07~e.20 :ARG0 (e2 / enzyme :name (n2 / name :op1 "EGFR"~e.19)))) :degree (h / hyper)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and~e.24 :op1 (p4 / person :name (n3 / name :op1 "Young"~e.23)) :op2 (p5 / person :mod (o / other~e.25))) :time (d / date-entity :year 2013~e.27))))) :mod (a / also~e.2)) # ::id pmid_2465_1010.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Presumably , these pathways are suppressed in cells with activated Ras and rebound when the suppressor is removed . # ::alignments 0-1.3 2-1.1.1.1 3-1.1.1 5-1.1 6-1.1.2.r 7-1.1.2 9-1.1.2.1.1.2 10-1.1.2.1.1.1.1 11-1 12-1.2 13-1.2.2.r 15-1.2.2.1.1 17-1.2.2 (a / and~e.11 :op1 (s / suppress-01~e.5 :ARG1 (p / pathway~e.3 :mod (t / this~e.2)) :location~e.6 (c / cell~e.7 :ARG0-of (c2 / contain-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.10) :ARG1-of (a2 / activate-01~e.9))))) :op2 (r / rebound-01~e.12 :ARG1 p :time~e.13 (r2 / remove-01~e.17 :ARG1 (m / molecular-physical-entity :ARG0-of s~e.15))) :ARG1-of (p2 / presume-01~e.0)) # ::id pmid_2465_1010.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although this rebound effect may not be sufficient to sustain a malignant phenotype , it may offset proapoptotic effects associated with oncogene inactivation . # ::alignments 0-1 1-1.2.1.2.2 2-1.2.1.2.1 3-1.2.1.2 4-1.2 5-1.2.1.1 5-1.2.1.1.r 7-1.2.1 9-1.2.1.3 11-1.2.1.3.2.1 12-1.2.1.3.2 14-1.2.1.3.1 15-1.1 16-1.1.1 18-1.1.1.2 19-1.1.1.2.2 20-1.1.1.2.2.1.r 21-1.1.1.2.2.1.2 22-1.1.1.2.2.1 22-1.1.1.2.2.1.1 22-1.1.1.2.2.1.1.r (h / have-concession-91~e.0 :ARG1 (p3 / possible-01~e.15 :ARG1 (o / offset-01~e.16 :ARG0 a :ARG1 (a2 / affect-01~e.18 :ARG2 (f / favor-01 :ARG1 (a5 / apoptosis)) :ARG1-of (a3 / associate-01~e.19 :ARG2~e.20 (a4 / activate-01~e.22 :polarity~e.22 -~e.22 :ARG1 (o2 / oncogene~e.21)))))) :ARG2 (p / possible-01~e.4 :ARG1 (s / suffice-01~e.7 :polarity~e.5 -~e.5 :ARG0 (a / affect-01~e.3 :ARG2 (r / rebound-01~e.2) :mod (t / this~e.1)) :purpose (s2 / sustain-01~e.9 :ARG0 a~e.14 :ARG1 (p2 / phenotype~e.12 :ARG2-of (m / malignant-02~e.11)))))) # ::id pmid_2465_1010.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Do K @-@ Ras Therapies Have to Be Allele Specific ? # ::alignments 1-1.2.1.1.1.1 3-1.2.1.1.1.1 4-1.2.1 8-1.2.2 9-1.2 10-1.1 10-1.1.r (o / obligate-01 :mode~e.10 interrogative~e.10 :ARG2 (s / specific-02~e.9 :ARG1 (t / therapy~e.4 :mod (e / enzyme :name (n / name :op1 "K-Ras"~e.1,3))) :ARG2 (a / allele~e.8))) # ::id pmid_2465_1010.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The most specific way to block oncogenic Ras would be to target the activating substitution itself . # ::alignments 1-1.1.1 2-1.1 3-1 3-1.2.r 4-1.2.1 4-1.2.1.2 4-1.2.1.2.r 5-1.2 6-1.2.1 6-1.2.1.2 6-1.2.1.2.1.2.1 6-1.2.1.2.r 7-1.2.1.1.1 11-1.3 13-1.3.1.1 14-1.3.1 (w / way~e.3 :ARG1-of (s2 / specific-02~e.2 :degree (m / most~e.1)) :manner-of~e.3 (b / block-01~e.5 :ARG1 (e / enzyme~e.4,6 :name (n / name :op1 "Ras"~e.7) :ARG0-of~e.4,6 (c / cause-01~e.4,6 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.6))))) :domain (t / target-01~e.11 :ARG1 (s / substitute-01~e.14 :ARG0-of (a / activate-01~e.13)))) # ::id pmid_2465_1010.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The first example was recently published by Shokat and colleagues , who identified electrophilic compounds that react covalently with cysteine @-@ 12 in G12C mutant K @-@ Ras ( Ostrem et al. , 2013 ) . # ::alignments 1-1.2.1 1-1.2.1.1 1-1.2.1.1.r 2-1.2 4-1.3 5-1 5-1.4.1 6-1.1.r 7-1.1.1.1.1 8-1.1 9-1.1.2 12-1.1.3 14-1.1.3.1 16-1.1.3.1.2 18-1.1.3.1.2.1.r 19-1.1.3.1.2.1.2.1 21-1.1.3.1.2.1.1 22-1.1.3.1.2.3.r 23-1.1.3.1.2.3.2.1 24-1.1.3.1.2.3 24-1.1.3.1.2.3.2 24-1.1.3.1.2.3.2.r 25-1.1.3.1.2.3.1.1 27-1.1.3.1.2.3.1.1 30-1.4.1.1.1.1.1 31-1.1 32-1.4.1.1.2.1 34-1.4.1.2.1 (p / publish-01~e.5 :ARG0~e.6 (a / and~e.8,31 :op1 (p2 / person :name (n / name :op1 "Shokat"~e.7)) :op2 (c / colleague~e.9) :ARG0-of (i / identify-01~e.12 :ARG1 (c2 / compound~e.14 :mod (e2 / electrophile) :ARG0-of (r2 / react-01~e.16 :ARG1~e.18 (a2 / amino-acid :mod 12~e.21 :name (n2 / name :op1 "cysteine"~e.19)) :manner (c3 / covalent) :location~e.22 (e3 / enzyme~e.24 :name (n3 / name :op1 "K-Ras"~e.25,27) :ARG2-of~e.24 (m / mutate-01~e.24 :value "G12C"~e.23)))))) :ARG1 (e / exemplify-01~e.2 :ord (o / ordinal-entity~e.1 :value~e.1 1~e.1)) :time (r / recent~e.4) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91~e.5 :ARG0 (a3 / and :op1 (p4 / person :name (n4 / name :op1 "Ostrem"~e.30)) :op2 (p5 / person :mod (o2 / other~e.32))) :time (d2 / date-entity :year 2013~e.34)))) # ::id pmid_2465_1010.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These compounds interact selectively with the GDP form of K @-@ Ras @-@ G12C protein ( Figure 2 @ ) and bind at a pocket near switch 2 that had not been apparent from analysis of crystal structures . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.3 3-1.1.3.r 4-1.1.2.r 6-1.1.2.2.1.1 9-1.1.2.1.1.1 11-1.1.2.1.1.1 13-1.1.2.1.2.1 17-1.1.4.1 18-1.1.4.1.1 22-1 23-1.2 24-1.2.2.r 26-1.2.2 27-1.2.2.1 28-1.2.2.1.1 29-1.2.2.1.1.1 32-1.2.2.2.1 32-1.2.2.2.1.r 36-1.2.2.2.2 37-1.2.2.2.2.1.r 38-1.2.2.2.2.1.1 39-1.2.2.2.2.1 (a / and~e.22 :op1 (i / interact-01~e.2 :ARG0 (c / compound~e.1 :mod (t / this~e.0)) :ARG1~e.4 (m2 / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "K-Ras"~e.9,11) :ARG2-of (m / mutate-01 :value "G12C"~e.13)) :part (s2 / small-molecule :name (n2 / name :op1 "GDP"~e.6))) :manner~e.3 (s / selective~e.3) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod 2~e.18))) :op2 (b / bind-01~e.23 :ARG1 c :location~e.24 (p / pocket~e.26 :ARG1-of (n3 / near-02~e.27 :ARG2 (s3 / switch~e.28 :mod 2~e.29)) :ARG1-of (a2 / appear-01 :polarity~e.32 -~e.32 :manner (a3 / analyze-01~e.36 :ARG1~e.37 (s4 / structure~e.39 :poss (c2 / crystal~e.38))))))) # ::id pmid_2465_1010.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A similar approach led to the identification of a GDP analog that covalently and specifically binds G12C and renders this oncogenic protein inactive ( Lim et al. , 2014 ) . # ::alignments 1-1.1.1 2-1.1 3-1 4-1.2.r 6-1.2 7-1.2.1.r 9-1.2.1.1.1 10-1.2.1.2 14-1.2.1.3.3 15-1.2.1 15-1.2.1.3 15-1.2.1.3.r 16-1.2.1.3.1.2.1 20-1.2.1.3.1 20-1.2.1.3.1.3 20-1.2.1.3.1.3.1.2.1 20-1.2.1.3.1.3.r 25-1.3.1.1.1.1.1 26-1.3.1.1 27-1.3.1.1.2.1 29-1.3.1.2.1 (l / lead-03~e.3 :ARG0 (a / approach-02~e.2 :ARG1-of (r / resemble-01~e.1)) :ARG1~e.4 (i / identify-01~e.6 :ARG1~e.7 (s / small-molecule~e.15 :name (n / name :op1 "GDP"~e.9) :mod (a2 / analog~e.10) :ARG1-of~e.15 (b / bind-01~e.15 :ARG2 (e / enzyme~e.20 :name (n2 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "G12C"~e.16) :ARG0-of~e.20 (c2 / cause-01~e.20 :ARG1 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.20)))) :manner (c / covalent) :ARG1-of (s2 / specific-02~e.14)) :ARG0-of (d3 / deactivate-01 :ARG1 e))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a4 / and~e.26 :op1 (p / person :name (n3 / name :op1 "Lim"~e.25)) :op2 (p2 / person :mod (o / other~e.27))) :time (d2 / date-entity :year 2014~e.29)))) # ::id pmid_2465_1010.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Perhaps other compounds could be identified that interact specifically with the G12D and G13D mutant forms using similar strategies . # ::alignments 0-1 1-1.1.1.1 2-1.1.1 3-1 5-1.1 7-1.1.1.2 8-1.1.1.2.2 9-1.1.1.2.1.r 11-1.1.1.2.1.1.2.1 12-1.1.1.2.1 13-1.1.1.2.1.2.2.1 14-1.1.1.2.1.1 14-1.1.1.2.1.1.2 14-1.1.1.2.1.1.2.r 14-1.1.1.2.1.2 14-1.1.1.2.1.2.2 14-1.1.1.2.1.2.2.r 16-1.1.2 17-1.1.2.1.1 18-1.1.2.1 (p / possible-01~e.0,3 :ARG1 (i / identify-01~e.5 :ARG1 (c / compound~e.2 :mod (o / other~e.1) :ARG0-of (i2 / interact-01~e.7 :ARG1~e.9 (a / and~e.12 :op1 (e / enzyme~e.14 :name (n / name :op1 "Ras") :ARG1-of~e.14 (m / mutate-01~e.14 :value "G12D"~e.11)) :op2 (e2 / enzyme~e.14 :name (n2 / name :op1 "Ras") :ARG1-of~e.14 (m2 / mutate-01~e.14 :value "G13D"~e.13))) :ARG1-of (s / specific-02~e.8))) :ARG2-of (u / use-01~e.16 :ARG1 (s2 / strategy~e.18 :ARG1-of (r / resemble-01~e.17))))) # ::id pmid_2465_1010.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These brilliant experiments remind us that these proteins are in dynamic and flexible states that might present more opportunities for small molecule attack than was previously realized . # ::alignments 0-1.1.1 1-1.1.2 2-1.1 3-1 4-1.3 5-1.2.r 6-1.2.1.1.3.1 7-1.2.1.1.3 10-1.2.1.1.1 12-1.2.1.1.2 13-1.2.1.1 15-1.2 16-1.2.1 17-1.2.1.2.2 18-1.2.1.2 19-1.2.1.2.1.r 20-1.2.1.2.1.1.1 21-1.2.1.2.1.1 22-1.2.1.2.1 23-1.2.1.2.2 25-1.2.1.2.2.1.1 26-1.2.1.2.2.1 (r / remind-01~e.3 :ARG0 (e / experiment-01~e.2 :mod (t / this~e.0) :ARG1-of (b / brilliant-01~e.1)) :ARG1~e.5 (p / possible-01~e.15 :ARG1 (p2 / present-01~e.16 :ARG0 (s / state~e.13 :mod (d / dynamic~e.10) :ARG1-of (f / flexible-03~e.12) :poss (p3 / protein~e.7 :mod (t2 / this~e.6))) :ARG1 (o / opportunity~e.18 :mod~e.19 (a / attack-01~e.22 :ARG0 (m / molecule~e.21 :mod (s2 / small~e.20))) :quant (m2 / more-than~e.17,23 :op1 (r2 / realize-01~e.26 :time (p4 / previous~e.25)))))) :ARG2 (w / we~e.4)) # ::id pmid_2465_1010.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , it is well established that Ras @-@ GTP exists in two states , only one of which is active and each with distinct binding properties for effectors , GAPs , and nucleotide ( Geyer et al. , 1996 ; Liao et al. , 2008 ) . # ::alignments 0-1.2 4-1.4 5-1 6-1.1.r 7-1.1.1.1.1.1 9-1.1.1.2.1.1 10-1.1 11-1.1.2.r 12-1.1.2.1 13-1.1.2 13-1.1.2.2.1 15-1.1.2.2.1.2 16-1.1.2.2.1.1 20-1.1.2.2.1.3 23-1.1.2.3.r 24-1.1.2.3.2 25-1.1.2.3.1 26-1.1.2.3 27-1.1.2.3.1.1.r 28-1.1.2.3.1.1.1 30-1.1.2.3.1.1.2.1.1 32-1.1.2.3.1.1 33-1.1.2.3.1.1.3 36-1.3.1.1.1.1.1.1 37-1.3.1.1.1 38-1.3.1.1.1.2.1 40-1.3.1.1.2.1 42-1.3.1.2.1.1.1.1 43-1.3.1 43-1.3.1.2.1 44-1.3.1.2.1.2.1 46-1.3.1.2.2.1 (e / establish-01~e.5 :ARG1~e.6 (e2 / exist-01~e.10 :ARG1 (m / macro-molecular-complex :part (e4 / enzyme :name (n3 / name :op1 "Ras"~e.7)) :part (s3 / small-molecule :name (n4 / name :op1 "GTP"~e.9))) :ARG2~e.11 (s / state~e.13 :quant 2~e.12 :ARG2-of (i / include-91 :ARG1 (s2 / state~e.13 :quant 1~e.16 :mod (o / only~e.15) :ARG0-of (a / activity-06~e.20))) :poss-of~e.23 (p / property~e.26 :mod (b / bind-01~e.25 :ARG1~e.27 (a2 / and~e.32 :op1 (e3 / effector~e.28) :op2 (p2 / protein :name (n / name :op1 "GAP"~e.30)) :op3 (n2 / nucleotide~e.33))) :mod (d / distinct~e.24)))) :mod (i2 / indeed~e.0) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.43 :op1 (p3 / publication-91 :ARG0 (a4 / and~e.37 :op1 (p4 / person :name (n5 / name :op1 "Geyer"~e.36)) :op2 (p5 / person :mod (o2 / other~e.38))) :time (d3 / date-entity :year 1996~e.40)) :op2 (p6 / publication-91 :ARG0 (a5 / and~e.43 :op1 (p7 / person :name (n6 / name :op1 "Liao"~e.42)) :op2 (p8 / person :mod (o3 / other~e.44))) :time (d4 / date-entity :year 2008~e.46)))) :degree (w / well~e.4)) # ::id pmid_2465_1010.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The idea of targeting the GDP @-@ bound form of an oncogenic mutant seems counterintuitive because we often think of oncogenic mutants as being locked in their GTP @-@ bound states , signaling persistently downstream . # ::alignments 1-1.1.2 2-1.1.2.1.r 3-1.1.2.1 5-1.1.2.1.1.2.1.1 7-1.2.1.3.1.2.2 7-1.2.1.3.1.2.2.2 7-1.2.1.3.1.2.2.2.r 11-1.1.2.1.1.1.2 11-1.1.2.1.1.1.2.1.2.1 11-1.2 12-1.1.2.1.1.1 12-1.1.2.1.1.1.1 12-1.1.2.1.1.1.1.r 13-1 15-1.1.2.1.1.1.2 15-1.2 16-1.2.1.1 17-1.2.1.4 18-1.2.1 20-1.1.2.1.1.1.2 20-1.1.2.1.1.1.2.1.2.1 20-1.2 21-1.1.2.1.1.1 21-1.1.2.1.1.1.1 21-1.1.2.1.1.1.1.r 23-1.1.2.r 24-1.2.1.3.1 27-1.2.1.3.1.2.2.1.1 29-1.2.1.3.1.2.2 29-1.2.1.3.1.2.2.2 29-1.2.1.3.1.2.2.2.r 32-1.2.1.3.2 33-1.2.1.3.2.3 34-1.2.1.3.2.2 (s / seem-01~e.13 :ARG1 (i3 / intuitive :polarity - :domain~e.23 (i2 / idea~e.1 :mod~e.2 (t / target-01~e.3 :ARG1 (m2 / macro-molecular-complex :part (e / enzyme~e.12,21 :ARG1-of~e.12,21 (m / mutate-01~e.12,21) :ARG0-of (c3 / cause-01~e.11,15,20 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.11,20)))) :part (s2 / small-molecule :name (n / name :op1 "GDP"~e.5)))))) :ARG1-of (c2 / cause-01~e.11,15,20 :ARG0 (t2 / think-01~e.18 :ARG0 (w / we~e.16) :ARG1 e :ARG2 (a / and :op1 (l / lock-01~e.24 :ARG1 e :ARG3 (m3 / macro-molecular-complex :part e :part (s4 / small-molecule~e.7,29 :name (n2 / name :op1 "GTP"~e.27) :ARG2-of~e.7,29 (b2 / bind-01~e.7,29)))) :op2 (s5 / signal-07~e.32 :ARG0 e :location (d / downstream~e.34) :ARG1-of (p / persist-01~e.33))) :frequency (o / often~e.17)))) # ::id pmid_2465_1010.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , codon 12 mutants retain measurable intrinsic GTPase activity , even though they are all refractory to GAP @-@ mediated GTPase stimulation . # ::alignments 0-1 2-1.1.1.1 3-1.1.1.1.1 4-1.1.1.1.2 5-1.1 6-1.1.2.3 7-1.1.2.2 8-1.1.2.1.2.1 9-1.1.2 11-1 12-1 13-1.2.2.2 14-1.2.2.r 15-1.2.2.1 16-1.2 17-1.2.1.r 18-1.2.1.2.1.2.1 20-1.2.1.2 21-1.2.1.1 22-1.2.1 (h / have-concession-91~e.0,11,12 :ARG1 (r / retain-01~e.5 :ARG0 (e2 / enzyme :part (c / codon~e.2 :mod 12~e.3 :ARG2-of (m / mutate-01~e.4))) :ARG1 (a / activity-06~e.9 :ARG0 (e / enzyme :wiki "GTPase" :name (n / name :op1 "GTPase"~e.8)) :mod (i / intrinsic~e.7) :ARG1-of (m2 / measure-01~e.6 :ARG1-of (p / possible-01)))) :ARG2 (r2 / refractory~e.16 :prep-to~e.17 (s / stimulate-01~e.22 :ARG1 e~e.21 :ARG1-of (m3 / mediate-01~e.20 :ARG0 (p2 / protein :wiki "GTPase-activating_protein" :name (n2 / name :op1 "GAP"~e.18)))) :domain~e.14 (e3 / enzyme :mod (a2 / all~e.15) :part c~e.13))) # ::id pmid_2465_1010.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although GTP hydrolysis rates are slow , the GDP off rates are also slow , and indeed , oncogenic mutants often exist with similar levels of GTP and GDP : if intrinsic GTPase and GDP off rates were identical , Ras proteins would be 50 % GTP bound and 50 % GDP bound . # ::alignments 0-1.1.1 1-1.1.1.2.1.1.1.2.1 2-1.1.1.2.1.1 3-1.1.1.1.1 3-1.1.1.2.1 5-1.1.1.1 5-1.1.1.2 8-1.1.1.1.1.1.2.1 10-1.1.1.1.1 12-1.1.1.1.2 13-1.1.1.1 15-1.1 16-1.1.2.4 18-1.1.2.1.1.3.2 18-1.1.2.1.1.3.2.1.2.1 19-1.1.2.1.1.3 19-1.1.2.1.1.3.1 19-1.1.2.1.1.3.1.r 20-1.1.2.3 23-1.1.2 24-1.1.2.1 24-1.1.2.2 26-1.2.1.1.1.1.1.2.1 27-1.1 28-1.1.2.2.1.2.1 30-1.2 31-1.2.2.1.2 32-1.2.2.1.1.2.1 34-1.2.2.2.1.2.1 36-1.2.2.1 36-1.2.2.2 38-1.2.2 40-1.2.1.1.1.3.2.1 41-1.2.1.1.1.3 44-1.2.1.1.1.2.1 45-1.2.1.1.1.2 46-1.1.2.1.1.2.1 46-1.2.1.1.1.1.1.2.1 47-1.2.1.1.1 47-1.2.1.1.1.1 47-1.2.1.1.1.1.r 49-1.2.1.1.1.2.1 50-1.2.1.1.1.2 51-1.2.1.1.2.1.1.2.1 52-1.2.1.1.1 52-1.2.1.1.1.1 52-1.2.1.1.1.1.r 52-1.2.1.1.2 52-1.2.1.1.2.1 52-1.2.1.1.2.1.r (m / multi-sentence :snt1 (a / and~e.15,27 :op1 (h / have-concession-91~e.0 :ARG1 (s / slow-05~e.5,13 :ARG1 (r / rate~e.3,10 :degree-of (s2 / small-molecule :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP"~e.8) :ARG1-of (d / deactivate-01))) :mod (a2 / also~e.12)) :ARG2 (s3 / slow-05~e.5 :ARG1 (r2 / rate~e.3 :degree-of (h2 / hydrolyze-01~e.2 :ARG1 (s4 / small-molecule :wiki "Guanosine_triphosphate" :name (n2 / name :op1 "GTP"~e.1)))))) :op2 (r3 / resemble-01~e.23 :ARG1 (l / level~e.24 :degree-of (s9 / small-molecule :wiki "Guanosine_triphosphate" :name (n11 / name :op1 "GTP"~e.46) :part-of (e2 / enzyme~e.19 :ARG2-of~e.19 (m2 / mutate-01~e.19) :ARG0-of (c / cause-01~e.18 :ARG1 (d3 / disease :wiki "Cancer" :name (n12 / name :op1 "cancer"~e.18)))))) :ARG2 (l2 / level~e.24 :degree-of (s5 / small-molecule :wiki "Guanosine_diphosphate" :name (n3 / name :op1 "GDP"~e.28) :part-of e2)) :frequency (o / often~e.20) :mod (i4 / indeed~e.16))) :snt2 (h3 / have-condition-91~e.30 :ARG1 (i2 / include-91 :ARG1 (a3 / and :op1 (e5 / enzyme~e.47,52 :ARG1-of~e.47,52 (b2 / bind-01~e.47,52 :ARG2 (s7 / small-molecule :wiki "Guanosine_triphosphate" :name (n9 / name :op1 "GTP"~e.26,46))) :quant (p / percentage-entity~e.45,50 :value 50~e.44,49) :mod (p3 / protein-family~e.41 :wiki "Ras_subfamily" :name (n7 / name :op1 "Ras"~e.40))) :op2 (e6 / enzyme~e.52 :ARG1-of~e.52 (b / bind-01~e.52 :ARG2 (s8 / small-molecule :wiki "Guanosine_diphosphate" :name (n10 / name :op1 "GDP"~e.51))) :quant p :mod p3)) :ARG2 (e4 / enzyme :mod p3)) :ARG2 (i / identical-01~e.38 :ARG1 (r4 / rate~e.36 :degree-of (e / enzyme :wiki "GTPase" :name (n4 / name :op1 "GTPase"~e.32)) :mod (i5 / intrinsic~e.31)) :ARG2 (r5 / rate~e.36 :degree-of (s6 / small-molecule :wiki "Guanosine_diphosphate" :name (n5 / name :op1 "GDP"~e.34) :ARG1-of (d2 / deactivate-01)) :mod i5)))) # ::id pmid_2465_1010.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This presents an opportunity for targeting the GDP @-@ bound state and trapping it in the off state and so preventing recharging with GTP . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1 7-1.2.1.1.1.1.1 9-1.2.1.1.1 9-1.2.1.1.1.2 9-1.2.1.1.1.2.r 12-1.2.2 13-1.2.2.1 20-1.2.2.3 21-1.2.2.3.1 22-1.2.2.3.1.1.r 23-1.2.2.3.1.1.1.1 (p / present-01~e.1 :ARG0 (t3 / this~e.0) :ARG1 (o / opportunity~e.3 :mod~e.4 (t / target-01~e.5 :ARG1 (m / macro-molecular-complex :part (s / small-molecule~e.9 :name (n / name :op1 "GDP"~e.7) :ARG1-of~e.9 (b2 / bind-01~e.9)))) :mod (t2 / trap-01~e.12 :ARG1 m~e.13 :ARG2 (d / deactivate-01 :ARG1 m) :purpose (p2 / prevent-01~e.20 :ARG1 (r / recharge-01~e.21 :ARG2~e.22 (s2 / small-molecule :name (n2 / name :op1 "GTP"~e.23))))))) # ::id pmid_2465_1010.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As an alternative to targeting specific Ras mutants , such as G12C , compounds could be developed that target individual Ras isoforms but do not discriminate between wild @-@ type and mutant Ras proteins . # ::alignments 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1 5-1.1.2.1.1.3 6-1.1.1.1.2.1.3.1.1.1 6-1.1.2.1.1.1.1 6-1.1.2.1.1.4.1.1 7-1.1.2.1.1 7-1.1.2.1.1.2 7-1.1.2.1.1.2.r 9-1.1.2.1.1.4.r 10-1.1.2.1.1.4.r 11-1.1.2.1.1.4.2.1 13-1.1.1 14-1 16-1.1 18-1.1.1.1 19-1.1.1.1.1.2 20-1.1.1.1.1.1.1.1 21-1.1.1.1.1 22-1.1.1.1.2 24-1.1.1.1.2.1.1 24-1.1.1.1.2.1.1.r 25-1.1.1.1.2.1 26-1.1.1.1.2.1.3 27-1.1.1.1.2.1.3.1.2 29-1.1.1.1.2.1.3.1.2 30-1.1.1.1.2.1.3 31-1.1.1.1.2.1.3.2 32-1.1.1.1.2.1.3.2 (p / possible-01~e.14 :ARG1 (d / develop-02~e.16 :ARG1 (c / compound~e.13 :ARG0-of (t / target-01~e.18 :ARG1 (i / isoform~e.21 :mod (e / enzyme :name (n / name :op1 "Ras"~e.20)) :mod (i2 / individual~e.19)) :ARG1-of (c2 / contrast-01~e.22 :ARG2 (d2 / discriminate-01~e.25 :polarity~e.24 -~e.24 :ARG0 c :ARG1 (b / between~e.26,30 :op1 (e3 / enzyme :name (n3 / name :op1 "Ras"~e.6) :mod (w / wild-type~e.27,29)) :op2 e2~e.31,32))))) :ARG4 (a / alternative~e.2 :prep-to~e.3 (t2 / target-01~e.4 :ARG1 (e2 / enzyme~e.7 :name (n2 / name :op1 "Ras"~e.6) :ARG2-of~e.7 (m / mutate-01~e.7) :ARG1-of (s / specific-02~e.5) :example~e.9,10 (e6 / enzyme :name (n5 / name :op1 "Ras"~e.6) :ARG2-of (m2 / mutate-01 :value "G12C"~e.11))))))) # ::id pmid_2465_1010.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This could be achieved by targeting specific hypervariable regions at the C terminus where the Ras proteins differ most widely ( Figure 3 @ ) . # ::alignments 0-1.1.1 1-1 3-1.1 4-1.1.2.r 5-1.1.2 6-1.1.2.1.1 8-1.1.2.1 11-1.1.2.1.4.1.1 12-1.1.2.1.4.1.2 13-1.1.2.1.3.r 15-1.1.2.1.3.1.1.1 16-1.1.2.1.3.1 16-1.1.2.1.4 17-1.1.2.1.3 18-1.1.2.1.3.2.1 19-1.1.2.1.3.2 22-1.2.1 23-1.2.1.1 (p / possible-01~e.1 :ARG1 (a / achieve-01~e.3 :ARG1 (t / this~e.0) :manner~e.4 (t2 / target-01~e.5 :ARG1 (r / region~e.8 :ARG1-of (s / specific-02~e.6) :ARG1-of (v / vary-01 :degree (h / hyper)) :location-of~e.13 (d / differ-02~e.17 :ARG1 (p3 / protein-family~e.16 :name (n2 / name :op1 "Ras"~e.15)) :degree (w / wide~e.19 :degree (m / most~e.18))) :part-of (p2 / protein-segment~e.16 :name (n / name :op1 "C"~e.11 :op2 "terminus"~e.12))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.22 :mod 3~e.23))) # ::id pmid_2465_1010.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The C @-@ terminal hypervariable region of K @-@ Ras @-@ 4B is very different from the hypervariable regions of other Ras proteins and is involved in the specific interaction of K @-@ Ras @-@ 4B with calmodulin ( Lopez @-@ Alcalá et al. , 2008 ) . # ::alignments 1-1.1.1.2.1.1 3-1.1.1.2.1.1 4-1.1.1.1 5-1.1.1 7-1.1.1.2.2.1.1 9-1.1.1.2.2.1.1 11-1.1.1.2.2.1.1 13-1.1.3 14-1.1 17-1.1.1.1 18-1.1.1 18-1.1.2 19-1.1.2.2.r 20-1.1.2.2.2 21-1.1.2.2.1.1 22-1.1.1.2 22-1.2.2.2 23-1 23-1.3.1.1 25-1.2 26-1.2.2.r 28-1.2.2.3 29-1.2.2 30-1.2.2.1.r 31-1.2.2.1 32-1.2.2.1 33-1.2.2.1 34-1.2.2.1 35-1.2.2.1 37-1.2.2.2.1.1 40-1.3.1.1.1.1.1 42-1.3.1.1.1.1.1 43-1.3.1.1 44-1.3.1.1.2.1 46-1.3.1.2.1 (a / and~e.23 :op1 (d / differ-02~e.14 :ARG1 (r2 / region~e.5,18 :mod (h / hypervariable~e.4,17) :part-of (p / protein-segment~e.22 :name (n / name :op1 "C-terminus"~e.1,3) :part-of (e / enzyme :name (n2 / name :op1 "K-Ras-4B"~e.7,9,11)))) :ARG2 (r / region~e.18 :mod h :part-of~e.19 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.21) :mod (o / other~e.20))) :degree (v / very~e.13)) :op2 (i / involve-01~e.25 :ARG1 r2 :ARG2~e.26 (i2 / interact-01~e.29 :ARG0~e.30 e~e.31,32,33,34,35 :ARG1 (p5 / protein~e.22 :name (n5 / name :op1 "calmodulin"~e.37)) :ARG1-of (s / specific-02~e.28))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and~e.23,43 :op1 (p3 / person :name (n4 / name :op1 "Lopez-Alcalá"~e.40,42)) :op2 (p4 / person :mod (o2 / other~e.44))) :time (d3 / date-entity :year 2008~e.46)))) # ::id pmid_2465_1010.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Because K @-@ Ras @-@ 4B seems to be the major form of K @-@ Ras in established tumors , these specific biochemical properties may afford unique opportunities for therapeutic attack . # ::alignments 0-1 1-1.1.1.1.1.1 1-1.1.1.3.1.1 3-1.1.1.1.1.1 3-1.1.1.3.1.1 5-1.1.1.3.1.1 6-1.1 8-1.1.1.3.r 10-1.1.1.2 11-1.1.1 13-1.1.1.1.1.1 13-1.1.1.3.1.1 15-1.1.1.1.1.1 15-1.1.1.3.1.1 16-1.1.1.4.r 17-1.1.1.4.1 18-1.1.1.4 20-1.2.1.1.1 21-1.2.1.1.2 22-1.2.1.1.3 23-1.2.1.1 24-1.2 25-1.2.1 26-1.2.1.2.1 27-1.2.1.2 28-1.2.1.2.2.r 29-1.2.1.2.2.1 30-1.2.1.2.2 (c / cause-01~e.0 :ARG0 (s / seem-01~e.6 :ARG1 (f / form~e.11 :mod (e / enzyme :name (n / name :op1 "K-Ras"~e.1,3,13,15)) :ARG1-of (m / major-02~e.10) :domain~e.8 (e2 / enzyme :name (n2 / name :op1 "K-Ras-4B"~e.1,3,5,13,15)) :location~e.16 (t / tumor~e.18 :ARG1-of (e3 / establish-01~e.17)))) :ARG1 (p / possible-01~e.24 :ARG1 (a / afford-02~e.25 :ARG0 (p2 / property~e.23 :mod (t2 / this~e.20) :ARG1-of (s2 / specific-02~e.21) :mod (b / biochemical~e.22)) :ARG1 (o / opportunity~e.27 :mod (u / unique~e.26) :mod~e.28 (a2 / attack-01~e.30 :ARG0 (t3 / therapy~e.29)))))) # ::id pmid_2465_1010.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mouse models suggest that such compounds would be well tolerated because animals lacking any single isoform of Ras are viable ( A . Balmain , personal communication ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.r 4-1.2.1.1 5-1.2.1 8-1.2.2 9-1.2 10-1.3 11-1.3.1.1 12-1.3.1.1.1 13-1.3.1.1.1.1.2 14-1.3.1.1.1.1.1 15-1.3.1.1.1.1 16-1.3.1.1.1.1.3.r 17-1.3.1.1.1.1.3.1.1 18-1.3.1.1.r 19-1.3.1 23-1.4.1.1.2 25-1.4.2 26-1.4 (s / suggest-01~e.2 :ARG0 (m / model~e.1 :mod (m2 / mouse~e.0)) :ARG1~e.3 (t / tolerate-01~e.9 :ARG1 (c / compound~e.5 :mod (s2 / such~e.4)) :manner (w / well-09~e.8)) :ARG1-of (c2 / cause-01~e.10 :ARG0 (v / viable~e.19 :domain~e.18 (a / animal~e.11 :ARG0-of (l / lack-01~e.12 :ARG1 (i / isoform~e.15 :ARG1-of (s3 / single-02~e.14) :mod (a2 / any~e.13) :mod~e.16 (e / enzyme :name (n / name :op1 "Ras"~e.17))))))) :ARG1-of (c3 / communicate-01~e.26 :ARG0 (p / person :name (n2 / name :op1 "A." :op2 "Balmain"~e.23)) :ARG1-of (p2 / personal-02~e.25))) # ::id pmid_2465_1010.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Targeting GDP @/@ GTP Binding and Exchange # ::alignments 0-1 1-1.1.1.1.1.2.1 2-1.1.1.1 3-1.1.1.1.2.2.1 4-1.1.1 5-1.1 6-1.1.2 (t / target-01~e.0 :ARG1 (a / and~e.5 :op1 (b / bind-01~e.4 :ARG2 (s3 / slash~e.2 :op1 (s / small-molecule :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP"~e.1)) :op2 (s2 / small-molecule :wiki "Guanosine_triphosphate" :name (n2 / name :op1 "GTP"~e.3)))) :op2 (e / exchange-01~e.6 :ARG1 s :ARG3 s2))) # ::id pmid_2465_1010.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras proteins bind GDP and GTP with picomolar affinity . # ::alignments 0-1.1.1.1 1-1.1 2-1 3-1.2.1.1.1 4-1.2 5-1.2.2.1.1 7-1.2.1.2.1 8-1.2.1.2 (b / bind-01~e.2 :ARG1 (p2 / protein-family~e.1 :name (n / name :op1 "Ras"~e.0)) :ARG2 (a2 / and~e.4 :op1 (s / small-molecule :name (n2 / name :op1 "GDP"~e.3) :mod (a / affinity~e.8 :mod (p / picomolar~e.7))) :op2 (s2 / small-molecule :name (n3 / name :op1 "GTP"~e.5) :mod a))) # ::id pmid_2465_1010.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It is generally accepted that oncogenic Ras proteins cannot be attacked with nucleotide analogs because high GTP concentrations make competition impossible . # ::alignments 2-1.2 3-1 4-1.1.r 5-1.1.2.2 5-1.1.2.2.2 5-1.1.2.2.2.1.2.1 5-1.1.2.2.2.r 5-1.1.3 6-1.1.2.2.1.1 8-1.1 8-1.1.1 8-1.1.1.r 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1.1 13-1.1.2.1 14-1.1.3 15-1.1.3.1.1.2 16-1.1.3.1.1.1.1.1 17-1.1.3.1.1 18-1.1.3.1 19-1.1.3.1.2.2 20-1.1.3.1.2 20-1.1.3.1.2.1 20-1.1.3.1.2.1.r (a / accept-01~e.3 :ARG1~e.4 (p / possible-01~e.8 :polarity~e.8 -~e.8 :ARG1 (a2 / attack-01~e.10 :ARG0~e.11 (a3 / analog~e.13 :mod (n2 / nucleotide~e.12)) :ARG1 (e / enzyme~e.5 :name (n / name :op1 "Ras"~e.6) :ARG0-of~e.5 (c / cause-01~e.5 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.5))))) :ARG1-of (c3 / cause-01~e.5,14 :ARG0 (m / make-02~e.18 :ARG0 (c4 / concentrate-02~e.17 :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP"~e.16)) :ARG1-of (h / high-02~e.15)) :ARG1 (p2 / possible-01~e.20 :polarity~e.20 -~e.20 :ARG1 (c5 / compete-01~e.19))))) :ARG1-of (g / general-02~e.2)) # ::id pmid_2465_1010.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The high affinity for GTP is also considered a barrier , though it is easy to imagine that analogs could be developed with equally high affinity . # ::alignments 1-1.1.1.1.1 2-1.1.1.1 3-1.1.1.1.2.r 4-1.1.1.1.2.1.1 5-1.1.1.1.r 6-1.1.2 7-1.1 9-1.1.1 11-1 14-1.2 16-1.2.1 17-1.2.1.1.r 18-1.2.1.1.1.1 19-1.2.1.1 21-1.2.1.1.1 22-1.2.1.1.1.1.1.r 23-1.2.1.1.1.1.1.1.1 24-1.2.1.1.1.1.1.1 25-1.2.1.1.1.1.1 (h / have-concession-91~e.11 :ARG1 (c / consider-01~e.7 :ARG1 (b / barrier~e.9 :domain~e.5 (a / affinity~e.2 :ARG1-of (h2 / high-02~e.1) :topic~e.3 (s / small-molecule :name (n / name :op1 "GTP"~e.4)))) :mod (a4 / also~e.6)) :ARG2 (e / easy-05~e.14 :ARG1 (i / imagine-01~e.16 :ARG1~e.17 (p / possible-01~e.19 :ARG1 (d / develop-02~e.21 :ARG1 (a2 / analog~e.18 :poss-of~e.22 (a3 / affinity~e.25 :ARG1-of (h3 / high-02~e.24 :degree (e2 / equal~e.23))))))))) # ::id pmid_2465_1010.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This approach to targeting Ras has therefore been abandoned . # ::alignments 0-1.1.1.2 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1 4-1.1.1.1.1.1.1 6-1 8-1.1 (c / cause-01~e.6 :ARG1 (a / abandon-01~e.8 :ARG1 (a2 / approach-02~e.1 :ARG1~e.2 (t2 / target-01~e.3 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.4))) :mod (t / this~e.0)))) # ::id pmid_2465_1010.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , Ras proteins in their GTP state exist in complexes with effectors ( Raf kinases , RalGDS , PI3K , other Ras @-@ binding proteins ) , as well as regulators ( GAPs and guanine nucleotide exchange factors [ GEFs]) . # ::alignments 0-1 2-1.1.1.1.1.1 3-1.1.1.1 6-1.1.1.1.2.1.1.1 8-1.1.1 8-1.1.2 10-1.1.1.2 10-1.1.2.2 11-1.1.1.2.1.r 12-1.1.1.2.1 14-1.1.1.2.1.1.1.1.1 17-1.1.1.2.1.1.2.1.1 19-1.1.1.2.1.1.3.1.1 21-1.1.1.2.1.1.4.1 22-1.1.1.2.1.1.4.2.1.1.1 24-1.1.1.1.2 24-1.1.1.2.1.1.4.2 25-1.1.1.2.1.1.4 28-1.1 28-1.1.1.2.1.1 28-1.1.2.2.1.2 29-1.1.1.2.1.1 30-1.1.1.2.1.1 30-1.1.2.2.1.r 31-1.1.2.2.1 31-1.1.2.2.1.1 31-1.1.2.2.1.1.r 33-1.1.2.2.1.2.1.1.1 35-1.1.2.2.1.2.2.1.1 36-1.1.2.2.1.2.2.1.2 37-1.1.2.2.1.2.2.1.3 38-1.1.2.2.1.2.2.1.4 (h / have-concession-91~e.0 :ARG1 (a3 / and~e.28 :op1 (e / exist-01~e.8 :ARG1 (p7 / protein-family~e.3 :name (n / name :op1 "Ras"~e.2) :ARG1-of (b / bind-01~e.24 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"~e.6)))) :location (m / macro-molecular-complex~e.10 :part~e.11 (e3 / effector~e.12 :example (a / and~e.28,29,30 :op1 (p6 / protein-family :name (n3 / name :op1 "Raf"~e.14)) :op2 (p4 / protein :name (n5 / name :op1 "RalGDS"~e.17)) :op3 (e5 / enzyme :name (n4 / name :op1 "PI3K"~e.19)) :op4 (p / protein~e.25 :mod (o / other~e.21) :ARG1-of (b2 / bind-01~e.24 :ARG2 (p5 / protein-family :name (n6 / name :op1 "Ras"~e.22)))))))) :op2 (e2 / exist-01~e.8 :ARG1 p7 :location (m3 / macro-molecular-complex~e.10 :part~e.30 (m2 / molecular-physical-entity~e.31 :ARG0-of~e.31 (r / regulate-01~e.31) :example (a2 / and~e.28 :op1 (p2 / protein :name (n7 / name :op1 "GAP"~e.33)) :op2 (p3 / protein :name (n8 / name :op1 "guanine"~e.35 :op2 "nucleotide"~e.36 :op3 "exchange"~e.37 :op4 "factor"~e.38)))))))) # ::id pmid_2465_1010.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The effects of most of these proteins on nucleotide binding have not been measured . # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1.2 5-1.2.1.1.1.1 6-1.2.1 6-1.2.1.1.1 7-1.2.2.r 8-1.2.2.1 9-1.2.2 11-1.1 11-1.1.r 13-1 (m / measure-01~e.13 :polarity~e.11 -~e.11 :ARG1 (e / effect-03~e.1 :ARG0~e.2 (p / protein~e.6 :ARG1-of (i / include-91 :ARG2 (p2 / protein~e.6 :mod (t / this~e.5)) :ARG3 (m2 / most~e.3))) :ARG1~e.7 (b / bind-01~e.9 :ARG1 (n / nucleotide~e.8)))) # ::id pmid_2465_1010.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GEFs , of course , greatly reduce the affinity for nucleotides , allowing GDP to be released rapidly and replaced by GTP . # ::alignments 0-1.1.1.1 2-1.3 3-1.3 5-1.4 6-1 8-1.2 9-1.2.1.r 10-1.2.1 12-1.5 13-1.5.1.1.1.1.1 16-1.5.1.1 17-1.5.1.1.2 17-1.5.1.1.2.r 18-1.5.1 19-1.5.1.2 20-1.5.1.2.2.r 21-1.5.1.2.2.1.1 (r / reduce-01~e.6 :ARG0 (p / protein :name (n / name :op1 "GEF"~e.0)) :ARG1 (a / affinity~e.8 :topic~e.9 (n2 / nucleotide~e.10)) :mod (o / of-course~e.2,3) :degree (g / great~e.5) :ARG0-of (a2 / allow-01~e.12 :ARG1 (a3 / and~e.18 :op1 (r2 / release-01~e.16 :ARG1 (s / small-molecule :name (n3 / name :op1 "GDP"~e.13)) :manner~e.17 (r3 / rapid~e.17)) :op2 (r4 / replace-01~e.19 :ARG1 s :ARG2~e.20 (s2 / small-molecule :name (n4 / name :op1 "GTP"~e.21)))))) # ::id pmid_2465_1010.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although oncogenic mutants do not need GEFs to put them in the active state , they are still sensitive to GEF @-@ mediated exchange and cycle through a complex state in which nucleotide @-@ free Ras protein is bound to the GEF ; this may provide a potential opportunity for a mutant @-@ specific nucleotide analog to bind . # ::alignments 0-1 1-1.2.2 1-1.2.2.1 1-1.2.2.1.1.2.1 1-1.2.2.1.r 2-1.2.2.2 4-1.2.1 4-1.2.1.r 5-1.2 6-1.2.3.1.1.1 7-1.2.2 7-1.2.2.1 7-1.2.2.1.r 9-1.1.1.1 17-1.1.1.3 18-1.1.1 19-1.2.2 19-1.2.2.1 19-1.2.2.1.r 20-1.1.1.2.1.1 22-1.1.1.2.1 23-1.1.1.2 24-1.1 25-1.1.2 26-1.1.2.2.r 28-1.1.2.2 32-1.1.2.2.1.2.1 34-1.1.2.2.1 34-1.1.2.2.1.2 34-1.1.2.2.1.2.r 35-1.1.2.2.1.1.1 36-1.1.2.2.1.3.1 38-1.1.2.2.1.3 39-1.2.2 39-1.2.2.1 39-1.2.2.1.r 41-1.1.2.2.1.3.1 44-1.1.3.2 45-1.1.3 47-1.1.3.1.2 48-1.1.3.1 51-1.1.3.1.1.1.2.1 53-1.1.3.1.1.1.2 54-1.1.3.1.1.1.1 55-1.1.3.1.1.1 57-1.1.2.2.1.3 57-1.1.3.1.1 (h / have-concession-91~e.0 :ARG1 (a2 / and~e.24 :op1 (s / sensitive-03~e.18 :ARG0 e~e.9 :ARG1 (e2 / exchange-01~e.23 :ARG1-of (m2 / mediate-01~e.22 :ARG0 p~e.20)) :mod (s2 / still~e.17)) :op2 (c3 / cycle-02~e.25 :ARG1 e :path~e.26 (m4 / macro-molecular-complex~e.28 :part (e3 / enzyme~e.34 :name (n3 / name :op1 "Ras"~e.35) :ARG1-of~e.34 (f / free-04~e.34 :ARG2 (n4 / nucleotide~e.32)) :ARG1-of (b / bind-01~e.38,57 :ARG2 p~e.36,41)))) :ARG0-of (p2 / provide-01~e.45 :ARG1 (o / opportunity~e.48 :mod (b2 / bind-01~e.57 :ARG1 (a3 / analog~e.55 :mod (n5 / nucleotide~e.54) :ARG1-of (s3 / specific-02~e.53 :ARG2 (m3 / mutate-01~e.51)))) :mod (p4 / potential~e.47)) :ARG1-of (p3 / possible-01~e.44))) :ARG2 (n / need-01~e.5 :polarity~e.4 -~e.4 :ARG0 (e / enzyme~e.1,7,19,39 :ARG0-of~e.1,7,19,39 (c / cause-01~e.1,7,19,39 :ARG1 (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.1))) :ARG2-of (m / mutate-01~e.2)) :ARG1 (a / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "GEF"~e.6)) :ARG1 e))) # ::id pmid_2465_1010.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In support of this , we noted many years ago that antibodies directed against specific codon 12 mutants were effective at reversing transformation in cells , as cited above , yet these antibodies do not bind to nucleotide @-@ loaded Ras ( Clark et al. , 1985 ) . # ::alignments 1-1.4 2-1.4.1.r 3-1.4.1 5-1.1 6-1 7-1.3.2 8-1.3.2.1.2 9-1.3 9-1.3.1 9-1.3.1.r 11-1.2.2.1 12-1.2.2.1.1 13-1.2.2.1.1.1 14-1.2.2.1.1.1.1 14-1.2.2.1.1.1.1.2 14-1.2.2.1.1.1.1.2.r 15-1.2.2.1.1.1.1.1 16-1.2.2.1.1.1.1.1.1 17-1.2.2.1.1.1.1.1.2 19-1.2.2 20-1.2.2.2.r 21-1.2.2.2 22-1.2.2.2.2 23-1.2.2.2.2.1.r 24-1.2.2.2.2.1 26-1.3.r 26-1.5.r 27-1.5 28-1.5.1 31-1.4.1 32-1.2.1.2 34-1.2.1.1 34-1.2.1.1.r 35-1.2.1 36-1.2.1.3.r 37-1.2.1.3.2.1 39-1.2.1.3.2 40-1.2.1.3.1.1 43-1.6.1.1.1.1.1 44-1.6.1.1 45-1.6.1.1.2.1 47-1.6.1.2.1 (n / note-01~e.6 :ARG0 (w / we~e.5) :ARG1 (h / have-concession-91 :ARG1 (b2 / bind-01~e.35 :polarity~e.34 -~e.34 :ARG1 a~e.32 :ARG2~e.36 (e2 / enzyme :name (n3 / name :op1 "Ras"~e.40) :ARG1-of (l / load-01~e.39 :ARG2 (n4 / nucleotide~e.37)))) :ARG2 (e / effective-04~e.19 :ARG0 (a / antibody~e.11 :ARG1-of (d / direct-01~e.12 :ARG2 (a2 / against~e.13 :op1 (e3 / enzyme~e.14 :part (c / codon~e.15 :mod 12~e.16 :ARG2-of (m2 / mutate-01~e.17)) :ARG1-of~e.14 (s / specific-02~e.14))))) :ARG1~e.20 (r / reverse-01~e.21 :ARG0 a :ARG1 (t2 / transform-01~e.22 :ARG1~e.23 (c2 / cell~e.24))))) :time~e.26 (b / before~e.9 :op1~e.9 (n2 / now~e.9) :quant (m / many~e.7 :op1 (t / temporal-quantity :quant 1 :unit (y / year~e.8)))) :ARG0-of (s2 / support-01~e.1 :ARG1~e.2 (t3 / this~e.3,31)) :ARG1-of~e.26 (c3 / cite-01~e.27 :medium (a3 / above~e.28)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and~e.44 :op1 (p2 / person :name (n5 / name :op1 "Clark"~e.43)) :op2 (p3 / person :mod (o / other~e.45))) :time (d3 / date-entity :year 1985~e.47)))) # ::id pmid_2465_1010.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore speculate that oncogenic Ras exists in a nucleotide @-@ free state frequently enough to make it vulnerable to attack . # ::alignments 0-1.1 1-1.2.1 1-1.2.1.2 1-1.2.1.2.r 1-1.3 2-1 3-1.2.r 4-1.2.1 4-1.2.1.2 4-1.2.1.2.1.2.1 4-1.2.1.2.r 5-1.2.1.1.1 6-1.2 7-1.2.2.r 9-1.2.2.1.1 11-1.2.2.1 12-1.2.2 13-1.2.3 14-1.2.3.1 16-1.2.4 16-1.2.4.1.2 18-1.2.1.3 18-1.2.4.1 19-1.2.4.1.2.r 20-1.2.4.1.2 (s / speculate-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (e2 / exist-01~e.6 :ARG1 (e / enzyme~e.1,4 :name (n / name :op1 "Ras"~e.5) :ARG0-of~e.1,4 (c / cause-01~e.1,4 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.4))) :mod (v / vulnerable~e.18)) :ARG2~e.7 (s2 / state~e.12 :ARG1-of (f / free-04~e.11 :ARG2 (n2 / nucleotide~e.9))) :ARG1-of (f2 / frequent-02~e.13 :degree (e3 / enough~e.14)) :ARG0-of (m / make-02~e.16 :ARG1 (v2 / vulnerable~e.18 :domain e :prep-to~e.19 (a / attack-01~e.16,20)))) :ARG1-of (i / infer-01~e.1)) # ::id pmid_2465_1010.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whether oncogenic Ras proteins are regulated at all by Sos and other GEFs has been surprisingly difficult to determine definitively , partly because there are many types of GEFs in mammalian cells . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 1-1.1.1.3 1-1.1.1.3.2 1-1.1.1.3.2.1.2.1 1-1.1.1.3.2.r 2-1.1.1.3.1.1 3-1.1.1.2.1 3-1.1.1.2.2 5-1.1.1 6-1.1.1.4 7-1.1.1.4 9-1.1.1.2.1.1.1 10-1.1.1.2 11-1.1.1.2.2.2 12-1.1.1.2.2.1.1 14-1.1.r 15-1.2 16-1 17-1.1.1.3 17-1.1.1.3.2 17-1.1.1.3.2.r 17-1.3 18-1.1 19-1.1.2 19-1.1.2.r 21-1.1.1.4.r 21-1.3.2 22-1.1.1.3 22-1.1.1.3.2 22-1.1.1.3.2.r 24-1.1.r 25-1.3.1.2 26-1.3.1 27-1.3.1.1.r 28-1.3.1.1 29-1.3.1.3.r 30-1.3.1.3.1 31-1.3.1.3 (d / difficult~e.16 :domain~e.14,24 (d2 / determine-01~e.18 :ARG1 (r / regulate-01~e.5 :mode~e.0 interrogative~e.0 :ARG0 (a3 / and~e.10 :op1 (p / protein~e.3 :name (n2 / name :op1 "Sos"~e.9)) :op2 (p2 / protein~e.3 :name (n3 / name :op1 "GEF"~e.12) :mod (o / other~e.11))) :ARG1 (e / enzyme~e.1,17,22 :name (n / name :op1 "Ras"~e.2) :ARG0-of~e.1,17,22 (c / cause-01~e.1,17,22 :ARG1 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.1)))) :degree~e.21 (a2 / at-all~e.6,7)) :manner~e.19 (d3 / definitive~e.19)) :ARG0-of (s / surprise-01~e.15) :ARG1-of (c3 / cause-01~e.17 :ARG0 (t / type-03~e.26 :ARG1~e.27 p2~e.28 :quant (m / many~e.25) :location~e.29 (c4 / cell~e.31 :mod (m2 / mammal~e.30))) :degree (p3 / part~e.21))) # ::id pmid_2465_1010.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , GEFs such as Sos have allosteric sites for Ras binding as well as sites for GDP @/@ GTP exchange , and it is hard to measure GTP loading on individual Ras isoforms in cells . # ::alignments 0-1 0-1.1 0-1.1.r 2-1.1.1.1.1.1 3-1.1.1.1.2.r 4-1.1.1.1.2.r 5-1.1.1.1.2.1.1 6-1.1.1 7-1.1.1.2.1.1 8-1.1.1.2.1 10-1.1.1.2.1.2.1.1.1 11-1.1.1.2.1.2 12-1.1 13-1.1 14-1.1.1.2 15-1.1.1.2.1 15-1.1.1.2.2 16-1.1.1.2.2.1.r 17-1.1.1.2.2.1.2.1.1 19-1.1.1.2.2.1.1.1.1 20-1.1.1.2.2.1 22-1.1 25-1.1.2 27-1.1.2.1 28-1.1.2.1.1.2 29-1.1.2.1.1 30-1.1.2.1.1.1.r 31-1.1.2.1.1.1.2 32-1.1.2.1.1.1.1 33-1.1.2.1.1.1 34-1.1.2.1.2.r 35-1.1.2.1.2 (a / and~e.0 :op2~e.0 (a2 / and~e.0,12,13,22 :op1 (h / have-03~e.6 :ARG0 (p / protein :name (n3 / name :op1 "GEF"~e.2) :example~e.3,4 (p2 / protein :name (n4 / name :op1 "Sos"~e.5))) :ARG1 (a4 / and~e.14 :op1 (s2 / site~e.8,15 :mod (a3 / allosteric~e.7) :purpose (b / bind-01~e.11 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.10)))) :op2 (s3 / site~e.15 :purpose~e.16 (e2 / exchange-01~e.20 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"~e.19)) :ARG2 (s4 / small-molecule :name (n5 / name :op1 "GDP"~e.17)))))) :op2 (h2 / hard-02~e.25 :ARG1 (m / measure-01~e.27 :ARG1 (l / load-01~e.29 :ARG1~e.30 (i / isoform~e.33 :mod e~e.32 :mod (i2 / individual~e.31)) :ARG2 s~e.28) :location~e.34 (c / cell~e.35))))) # ::id pmid_2465_1010.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , it is clear that mutant Ras proteins are not 100 % GTP bound , and GEFs could increase the fraction of Ras @-@ GTP to some extent . # ::alignments 0-1 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.2 6-1.1.1.1.2.2 6-1.1.1.1.2.2.r 7-1.1.1.1.2.1.1 8-1.1.2.1.1 10-1.1.1.1.1 10-1.1.1.1.1.r 11-1.1.1.1.4.1 12-1.1.1.1.4 13-1.1.1.1.3.1.1 14-1.1.1.1 16-1.1 17-1.1.2.1.1.1.1 18-1.1.2 19-1.1.2.1 21-1.1.2.1.2 22-1.1.2.1.2.1.r 23-1.1.2.1.2.1.1 25-1.1.1.1.3.1.1 26-1.1.2.1.3.r 27-1.1.2.1.3 28-1.1.1.1.4.r (h / have-concession-91~e.0 :ARG1 (a / and~e.16 :op1 (c / clear-06~e.4 :ARG1~e.5 (b / bind-01~e.14 :polarity~e.10 -~e.10 :ARG1 (e / enzyme~e.6 :name (n / name :op1 "Ras"~e.7) :ARG1-of~e.6 (m / mutate-01~e.6)) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"~e.13,25)) :extent~e.28 (p3 / percentage-entity~e.12 :value 100~e.11))) :op2 (p4 / possible-01~e.18 :ARG1 (i / increase-01~e.19 :ARG0 (p5 / protein~e.8 :name (n3 / name :op1 "GEF"~e.17)) :ARG1 (f / fraction~e.21 :mod~e.22 (m2 / macro-molecular-complex :part e~e.23 :part s)) :ARG2~e.26 (s3 / some~e.27))))) # ::id pmid_2465_1010.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , targeting Sos or other GEFs for treating mutant Ras cancers does not appear an attractive proposition . # ::alignments 0-1 2-1.1.2 3-1.1.2.1.1.1.1 4-1.1.2.1 5-1.1.2.1.2.2 6-1.1.2.1.2.1.1 7-1.1.2.2.r 8-1.1.2.2 9-1.1.2.2.1.3 10-1.1.2.2.1.3.1.1.1 11-1.1.2.2.1.2.1 13-1.1.1 13-1.1.1.r 14-1.1 16-1.1.2.3.1 17-1.1.2.3 (h / have-concession-91~e.0 :ARG1 (a / appear-02~e.14 :polarity~e.13 -~e.13 :ARG1 (t / target-01~e.2 :ARG1 (o / or~e.4 :op1 (p / protein :name (n2 / name :op1 "Sos"~e.3)) :op2 (p2 / protein :name (n3 / name :op1 "GEF"~e.6) :mod (o2 / other~e.5))) :purpose~e.7 (t2 / treat-03~e.8 :ARG2 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.11) :location-of (m / mutate-01~e.9 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.10))))) :ARG1-of (p3 / propose-01~e.17 :ARG0-of (a2 / attract-01~e.16))))) # ::id pmid_2465_1010.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogenic mutants may or may not depend on GEFs , to some degree , but wild @-@ type Ras proteins most certainly do . # ::alignments 0-1.1.2.2 1-1.1.2.2 2-1.1.2 3-1.1 4-1.1.1 4-1.1.2 5-1.1.2.1 5-1.1.2.1.r 6-1.1.1.1 6-1.2 7-1.1.1.1.2.r 8-1.1.1.1.2.1.1 11-1.1.3 12-1.1.3.r 14-1 15-1.2.1.2 17-1.2.1.2 18-1.2.1.1.1 19-1.1.1.1.1 20-1.2.3.1 21-1.2.3 (c / contrast-01~e.14 :ARG1 (o / or~e.3 :op1 (p / possible-01~e.4 :ARG1 (d / depend-01~e.6 :ARG0 (p2 / protein~e.19 :ARG2-of (m / mutate-01 :ARG0-of (c2 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))) :ARG1~e.7 (p3 / protein :name (n2 / name :op1 "GEF"~e.8)))) :op2 (p4 / possible-01~e.2,4 :polarity~e.5 -~e.5 :ARG1 d~e.0,1) :degree~e.12 (s / some~e.11)) :ARG2 (d2 / depend-01~e.6 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.18) :mod (w / wild-type~e.15,17)) :ARG1 p3 :mod (c4 / certain~e.21 :degree (m2 / most~e.20)))) # ::id pmid_2465_1010.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For these reasons , recent efforts to target mutant Ras that led to compounds that bind at the Sos @-@ binding site may seem disappointing ( Maurer et al. , 2012 ; Sun et al. , 2012 ) . # ::alignments 1-1.2.1.1 2-1.2 2-1.2.1 2-1.2.1.r 4-1.1.1.1.2 5-1.1.1.1 7-1.1.1.1.1 8-1.1.1.1.1.1 8-1.1.1.1.1.1.2 8-1.1.1.1.1.1.2.r 9-1.1.1.1.1.1.1.1 11-1.1.1.1.1.1.3 12-1.1.1.1.1.1.3.1.r 13-1.1.1.1.1.1.3.1 15-1.1.1.1.1.1.3.1.1 16-1.1.1.1.1.1.3.1.1.1.r 18-1.1.1.1.1.1.3.1.1.1.1.1.1.1 20-1.1.1.1.1.1.3.1.1.1.1 21-1.1.1.1.1.1.3.1.1.1 22-1 23-1.1 24-1.1.1 27-1.3.1.1.1.1.1.1 28-1.3.1 28-1.3.1.1.1 28-1.3.1.2.1 29-1.3.1.1.1.2.1 29-1.3.1.2.1.2.1 31-1.3.1.1.2.1 31-1.3.1.2.2.1 33-1.3.1.2.1.1.1.1 34-1.3.1 34-1.3.1.1.1 34-1.3.1.2.1 35-1.3.1.1.1.2.1 35-1.3.1.2.1.2.1 37-1.3.1.1.2.1 37-1.3.1.2.2.1 (p / possible-01~e.22 :ARG1 (s / seem-01~e.23 :ARG1 (d3 / disappoint-01~e.24 :ARG0 (e2 / effort-01~e.5 :ARG1 (t / target-01~e.7 :ARG1 (e / enzyme~e.8 :name (n / name :op1 "Ras"~e.9) :ARG1-of~e.8 (m / mutate-01~e.8) :ARG0-of (l / lead-03~e.11 :ARG2~e.12 (c / compound~e.13 :ARG0-of (b / bind-01~e.15 :location~e.16 (s2 / site~e.21 :location-of (b2 / bind-01~e.20 :ARG2 (p2 / protein :name (n2 / name :op1 "Sos"~e.18))))))))) :time (r / recent~e.4)))) :ARG1-of (c2 / cause-01~e.2 :ARG0~e.2 (r2 / reason~e.2 :mod (t2 / this~e.1))) :ARG1-of (d4 / describe-01 :ARG0 (a / and~e.28,34 :op1 (p3 / publication-91 :ARG0 (a2 / and~e.28,34 :op1 (p4 / person :name (n3 / name :op1 "Maurer"~e.27)) :op2 (p5 / person :mod (o2 / other~e.29,35))) :time (d2 / date-entity :year 2012~e.31,37)) :op2 (p6 / publication-91 :ARG0 (a3 / and~e.28,34 :op1 (p7 / person :name (n5 / name :op1 "Sun"~e.33)) :op2 (p8 / person :mod (o / other~e.29,35))) :time (d / date-entity :year 2012~e.31,37))))) # ::id pmid_2465_1010.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the compounds that these groups discovered could be excellent starting points toward the discovery of compounds that have selectivity for mutant forms of K @-@ Ras or block effector interactions . # ::alignments 0-1 3-1.1.1.3 5-1.1.1.3.1.1.1 6-1.1.1.3.1.1 7-1.1.1.3.1 8-1.1 9-1.1.1.3.r 10-1.1.1.2 11-1.1.1.1 12-1.1.1 13-1.1.1.4.r 15-1.1.1.4.1 15-1.1.1.4.2 17-1.1.1.4.1.1 17-1.1.1.4.2.1 22-1.1.1.4.1.1.1.1.2 23-1.1.1.4.1.1.1.1 24-1.1.1.4.1.1.1.1.1.r 25-1.1.1.4.1.1.1.1.1.1.1 27-1.1.1.4.1.1.1.1.1.1.1 28-1.1.1.4 29-1.1.1.4.2.1.1 30-1.1.1.4.2.1.1.1.1 31-1.1.1.4.2.1.1.1 (h / have-concession-91~e.0 :ARG1 (p2 / possible-01~e.8 :ARG1 (p3 / point~e.12 :source-of (s / start-01~e.11) :ARG1-of (e2 / excellent-02~e.10) :domain~e.9 (c / compound~e.3 :ARG1-of (d / discover-01~e.7 :ARG0 (g / group~e.6 :mod (t / this~e.5)))) :direction~e.13 (o / or~e.28 :op1 (d2 / discover-01~e.15 :ARG1 (c2 / compound~e.17 :ARG0-of (s2 / select-01 :ARG1 (f / form~e.23 :mod~e.24 (e / enzyme :name (n / name :op1 "K-Ras"~e.25,27)) :ARG2-of (m / mutate-01~e.22))))) :op2 (d3 / discover-01~e.15 :ARG1 (c3 / compound~e.17 :ARG0-of (b / block-01~e.29 :ARG1 (i / interact-01~e.31 :ARG0 (e3 / effector~e.30))))))))) # ::id pmid_2465_1010.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Restoring GTP Hydrolysis # ::alignments 0-1 1-1.1.1.1.1 2-1.1 (r / restore-01~e.0 :ARG1 (h / hydrolyze-01~e.2 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.1)))) # ::id pmid_2465_1010.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mutations at codons 12 , 13 , and 61 inhibit GAP @-@ mediated GTP hydrolysis . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 2-1.1.1.2 2-1.1.1.3 3-1.1.1.1.1 5-1.1.1.2.1 7-1.1.1 8-1.1.1.3.1 9-1 10-1.2.2.1.1.1 12-1.2.2 13-1.2.1.1.1 14-1.2 (i / inhibit-01~e.9 :ARG0 (m / mutate-01~e.0 :location~e.1 (a / and~e.7 :op1 (c / codon~e.2 :mod 12~e.3) :op2 (c2 / codon~e.2 :mod 13~e.5) :op3 (c3 / codon~e.2 :mod 61~e.8))) :ARG1 (h / hydrolyze-01~e.14 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.13)) :ARG1-of (m2 / mediate-01~e.12 :ARG0 (p / protein :name (n5 / name :op1 "GAP"~e.10))))) # ::id pmid_2465_1010.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As a result , mutant Ras proteins accumulate with elevated GTP @-@ bound proportion . # ::alignments 2-1.2 4-1.1.1 4-1.1.1.2 4-1.1.1.2.r 5-1.1.1.1.1 5-1.1.2.2.1.1 7-1 8-1.1.r 9-1.1.2.1 10-1.1.2.2.2.1.1.1 12-1.1.2.2 12-1.1.2.2.2 12-1.1.2.2.2.r 13-1.1.2 (a / accumulate-01~e.7 :ARG1~e.8 (a2 / and :op1 (e / enzyme~e.4 :name (n / name :op1 "Ras"~e.5) :ARG1-of~e.4 (m / mutate-01~e.4)) :op2 (p / proportion~e.13 :ARG1-of (e2 / elevate-01~e.9) :quant-of (e3 / enzyme~e.12 :name (n3 / name :op1 "Ras"~e.5) :ARG1-of~e.12 (b / bind-01~e.12 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"~e.10)))))) :ARG2-of (r / result-01~e.2)) # ::id pmid_2465_1010.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Trahey and McCormick discovered GAP while seeking to explain how relatively small changes in intrinsic GTPase between wild @-@ type and mutant Ras proteins accounted for profound differences in transforming activity ( Trahey and McCormick , 1987 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1 4-1.2.1.1 5-1.3.1.2.r 5-1.4.r 6-1.4 8-1.4.2 10-1.4.2.2.1.2.1 11-1.4.2.2.1.2 12-1.4.2.2.1 13-1.4.2.2.1.1.r 14-1.4.2.2.1.1.2 15-1.4.2.2.1.1.1.1 17-1.4.2.2.1.3.2 19-1.4.2.2.1.3.2 21-1.4.2.2.1.3.3 21-1.4.2.2.1.3.3.2 21-1.4.2.2.1.3.3.2.r 22-1.4.2.2.1.3.1.1 22-1.4.2.2.1.3.3.1.1 23-1.2 24-1.4.2.2 25-1.4.2.2.2.r 26-1.4.2.2.2.3.2 27-1.4.2.2.2 29-1.4.2.2.2.3.1 30-1.4.2.2.2.3 33-1.1.1.1.1 34-1.1 35-1.1.2.1.1 37-1.3.1.2.1 (d2 / discover-01~e.3 :ARG0 (a / and~e.1,34 :op1 (p / person :name (n3 / name :op1 "Trahey"~e.0,33)) :op2 (p2 / person :name (n4 / name :op1 "McCormick"~e.2,35))) :ARG1 (p3 / protein~e.23 :name (n5 / name :op1 "GAP"~e.4)) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 a :time~e.5 (d / date-entity :year 1987~e.37))) :time~e.5 (s / seek-01~e.6 :ARG0 a :ARG1 (e3 / explain-01~e.8 :ARG0 a :ARG1 (a2 / account-01~e.24 :ARG0 (c / change-01~e.12 :ARG1~e.13 (e / enzyme :name (n / name :op1 "GTPase"~e.15) :mod (i / intrinsic~e.14)) :mod (s2 / small~e.11 :ARG2-of (r / relative-05~e.10)) :location (e2 / enzyme :name (n2 / name :op1 "Ras"~e.22) :mod (w / wild-type~e.17,19) :compared-to (e4 / enzyme~e.21 :name (n6 / name :op1 "Ras"~e.22) :ARG1-of~e.21 (m / mutate-01~e.21)))) :ARG1~e.25 (d3 / differ-02~e.27 :ARG1 e2 :ARG2 e4 :ARG3 (a3 / activity-06~e.30 :ARG1 (t / transform-01~e.29) :mod (p4 / profound~e.26))))))) # ::id pmid_2465_1010.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Intrinsic rates of GTP hydrolysis are five orders of magnitude slower than rates catalyzed by GAPs and therefore do not contribute significantly to steady @-@ state levels of Ras @-@ GTP . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1.1 4-1.1.2 6-1.2.1.1 7-1.2.1 8-1.2.1.2.r 9-1.2.1.2 10-1 10-1.2 10-1.2.r 11-1.3.r 12-1.3 13-1.3.1 14-1.3.1.1.r 15-1.3.1.1.1.1 17-1.4 19-1.4.1.1 19-1.4.1.1.r 20-1.4.1 21-1.4.1.4 22-1.4.1.3.r 23-1.4.1.3.1.1 25-1.4.1.3.1 26-1.4.1.3 27-1.4.1.3.2.r 28-1.4.1.3.2.1.1.1 30-1.4.1.3.2.2 (s3 / slow-05~e.10 :ARG1 (r / rate~e.1 :mod (i / intrinsic~e.0) :degree-of~e.2 (h / hydrolyze-01~e.4 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.3)))) :degree~e.10 (m / more~e.10 :degree (o / order~e.7 :quant 5~e.6 :mod~e.8 (m2 / magnitude~e.9))) :compared-to~e.11 (r2 / rate~e.12 :degree-of (c / catalyze-01~e.13 :ARG0~e.14 (p / protein :name (n2 / name :op1 "GAP"~e.15)))) :ARG0-of (c2 / cause-01~e.17 :ARG1 (c3 / contribute-01~e.20 :polarity~e.19 -~e.19 :ARG0 r :ARG2~e.22 (l / level~e.26 :mod (s2 / state~e.25 :ARG1-of (s5 / steady-01~e.23)) :quant-of~e.27 (m3 / macro-molecular-complex :part (e / enzyme :name (n3 / name :op1 "Ras"~e.28)) :part s~e.30)) :ARG1-of (s4 / significant-02~e.21)))) # ::id pmid_2465_1010.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , once Ras proteins bind effectors , GAPs can no longer interact , and intrinsic GTPase may become important in determining how long Ras and its effectors remain engaged . # ::alignments 0-1 3-1.1.3.1.1.1 4-1.1.1.1.2 4-1.1.3.1 5-1.1.3 6-1.1.3.2 8-1.1.1.1.2.1.1 9-1.1.1 10-1.1.1.1.1 10-1.1.1.1.1.r 10-1.1.1.2 11-1.1.1.2 12-1.1.1.1 14-1.1 15-1.1.2.1.1.2 16-1.1.2.1.1.1.1 17-1.1.2 18-1.1.2.1 19-1.1.2.1.2 20-1.1.2.1.2.1.r 21-1.1.2.1.2.1 24-1.1.2.1.2.1.1.1.1.1.1.1 25-1.1.2.1.2.1.1.1.1 26-1.1.2.1.2.1.1.1.1.2.1 26-1.1.2.1.2.1.1.1.1.2.1.r 27-1.1.2.1.2.1.1.1.1.2 28-1.1.2.1.2.1.1.1 29-1.1.2.1.2.1.1.1.2 (h / have-concession-91~e.0 :ARG1 (a / and~e.14 :op1 (p / possible-01~e.9 :ARG1 (i / interact-01~e.12 :polarity~e.10 -~e.10 :ARG0 (p2 / protein~e.4 :name (n4 / name :op1 "GAP"~e.8))) :time (n5 / no-longer~e.10,11)) :op2 (p3 / possible-01~e.17 :ARG1 (b / become-01~e.18 :ARG1 (e2 / enzyme :name (n3 / name :op1 "GTPase"~e.16) :mod (i2 / intrinsic~e.15)) :ARG2 (i3 / important~e.19 :purpose~e.20 (d2 / determine-01~e.21 :ARG1 (t / temporal-quantity :time-of (r / remain-01~e.28 :ARG1 (a2 / and~e.25 :op1 (e / enzyme :name (n / name :op1 "Ras"~e.24)) :op2 (e5 / effector~e.27 :poss~e.26 e~e.26)) :ARG3 (e4 / engage-01~e.29 :ARG1 e5))))))) :time (b2 / bind-01~e.5 :ARG1 (p4 / protein-family~e.4 :name (n2 / name :op1 "ras"~e.3)) :ARG2 (e3 / effector~e.6)))) # ::id pmid_2465_1010.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , effector binding may well affect intrinsic GTPase activity of Ras as it does for heterotrimeric G proteins . # ::alignments 0-1.2 2-1.1.1.1 3-1.1.1 4-1 5-1.1.4 6-1.1 6-1.1.3.1 7-1.1.2.3 8-1.1.2.2.1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1 12-1.1.3.1.1.r 13-1.1.3.1.1 15-1.1.3.1.2.r 16-1.1.3.1.2.2 17-1.1.3.1.2.1.1 18-1.1.3.1.2 (p / possible-01~e.4 :ARG1 (a / affect-01~e.6 :ARG0 (b / bind-01~e.3 :ARG1 (e3 / effector~e.2)) :ARG1 (a2 / activity-06~e.9 :ARG0~e.10 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.11)) :ARG1 (e / enzyme :name (n / name :op1 "GTPase"~e.8)) :mod (i / intrinsic~e.7)) :ARG1-of (s / same-01 :ARG2 (a3 / affect-01~e.6 :ARG0~e.12 b~e.13 :ARG1~e.15 (p2 / protein~e.18 :name (n3 / name :op1 "G"~e.17) :mod (h / heterotrimeric~e.16)))) :degree (w / well~e.5)) :mod (i2 / indeed~e.0)) # ::id pmid_2465_1010.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok If indeed intrinsic GTPase limits signal output , perhaps assays for compounds that stimulate intrinsic GTPase of Ras effector complexes may merit consideration . # ::alignments 0-1.3.r 1-1.3.3 2-1.3.1 3-1.3.1 4-1.3 5-1.3.2.1 6-1.3.2 8-1 8-1.2 8-1.2.r 9-1.1.1 10-1.1.1.1.r 11-1.1.1.1 13-1.1.1.1.1 14-1.1.1.1.1.1.2.2 15-1.1.1.1.1.1.2.1.1 17-1.1.1.1.1.1.1.1.1.1.1 18-1.1.1.1.1.1.1.1 19-1.1.1.1.1.1.1 20-1 21-1.1 22-1.1.2 (p2 / possible-01~e.8,20 :ARG1 (m / merit-01~e.21 :ARG0 (a / assay-01~e.9 :ARG1~e.10 (c2 / compound~e.11 :ARG0-of (s / stimulate-01~e.13 :ARG1 (a2 / act-01 :ARG0 (c3 / complex~e.19 :part (e4 / effector~e.18 :mod (p / protein-family :name (n2 / name :op1 "Ras"~e.17)))) :ARG1 (e / enzyme :name (n / name :op1 "GTPase"~e.15) :mod (i / intrinsic~e.14)))))) :ARG1 (c / consider-01~e.22)) :mod~e.8 (p3 / perhaps~e.8) :condition~e.0 (l / limit-01~e.4 :ARG0 e~e.2,3 :ARG1 (o2 / output~e.6 :mod (s2 / signal~e.5)) :mod (i2 / indeed~e.1))) # ::id pmid_2465_1010.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mattos and colleagues recently showed that the Ras @-@ binding domain of Raf ( the RBD ) has a profound effect on suppressing intrinsic hydrolysis rates of Ras Q61 mutants , but not wild @-@ type Ras or G12V mutants ( Buhrman et al. , 2010 ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2 3-1.3 4-1 5-1.2.r 7-1.2.1.3.1.1.1 9-1.2.1.3 12-1.2.1.2.1.1 15-1.2.1.1.1 19-1.2.3 20-1.2 20-1.2.4.1 22-1.2.2 22-1.2.4.1.3 23-1.2.2.1.2 24-1.2.2.1.1 25-1.2.2.1 26-1.2.2.1.1.1.r 27-1.2.2.1.1.1.1.1 28-1.2.2.1.1.1.2.1 29-1.2.2.1.1.1 29-1.2.2.1.1.1.2 29-1.2.2.1.1.1.2.r 31-1.2.4 32-1.2.4.1.1 32-1.2.4.1.1.r 32-1.2.4.1.3.1 32-1.2.4.1.3.1.r 33-1.2.4.1.3.2.1.2 35-1.2.4.1.3.2.1.2 36-1.2.4.1.3.2.1.1.1 36-1.2.4.1.3.2.2.1.1 37-1.2.4.1.3.2 38-1.2.4.1.3.2.2.2.1 39-1.2.4.1.3.2.2 39-1.2.4.1.3.2.2.2 39-1.2.4.1.3.2.2.2.r 42-1.4.1.1.1.1.1 43-1.4.1.1 44-1.4.1.1.2.1 46-1.4.1.2.1 (s / show-01~e.4 :ARG0 (a / and~e.1 :op1 (p / person :name (n3 / name :op1 "Mattos"~e.0)) :op2 (c / colleague~e.2 :poss p)) :ARG1~e.5 (a2 / affect-01~e.20 :ARG0 (p7 / protein-segment :name (n9 / name :op1 "RBD"~e.15) :part-of (e / enzyme :name (n / name :op1 "Raf"~e.12)) :ARG0-of (b / bind-01~e.9 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.7)))) :ARG1 (s2 / suppress-01~e.22 :ARG1 (r2 / rate~e.25 :degree-of (h / hydrolyze-01~e.24 :ARG1~e.26 (e3 / enzyme~e.29 :name (n4 / name :op1 "Ras"~e.27) :ARG2-of~e.29 (m / mutate-01~e.29 :value "Q61"~e.28))) :mod (i / intrinsic~e.23))) :degree (p2 / profound~e.19) :ARG1-of (c3 / contrast-01~e.31 :ARG2 (a4 / affect-01~e.20 :polarity~e.32 -~e.32 :ARG0 p7 :ARG1 (s3 / suppress-01~e.22 :polarity~e.32 -~e.32 :ARG1 (o / or~e.37 :op1 (e4 / enzyme :name (n5 / name :op1 "Ras"~e.36) :mod (w / wild-type~e.33,35)) :op2 (e5 / enzyme~e.39 :name (n6 / name :op1 "Ras"~e.36) :ARG2-of~e.39 (m2 / mutate-01~e.39 :value "G12V"~e.38)))) :mod p2))) :time (r / recent~e.3) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.43 :op1 (p5 / person :name (n8 / name :op1 "Buhrman"~e.42)) :op2 (p4 / person :mod (o2 / other~e.44))) :time (d / date-entity :year 2010~e.46)))) # ::id pmid_2465_1010.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok They propose that suppression of intrinsic GTPase stabilizes Ras @-@ Raf complexes and increases signal output to the MAPK pathway selectively ; this accounts for the preference of Q61 mutants over G12 mutants in melanoma , a disease that is clearly Raf @-@ MAPK driven ( Buhrman et al. , 2010 ) . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1 4-1.1.2.1.1.1.r 5-1.1.2.1.1.1.2 6-1.1.2.1.1.1.1.1 7-1.1.2.1 8-1.1.2.1.2.1.1.1 10-1.1.2.1.2.2.1.1 11-1.1.2.1.2 12-1.1.2 13-1.1.2.2 14-1.1.2.2.2.1 15-1.1.2.2.2 18-1.1.2.2.2.2.1.1 19-1.1.2.2.2.2 19-1.2.2.3.2.1 22-1.2.1 23-1.2 24-1.2.2.r 26-1.2.2 27-1.2.2.1.r 28-1.2.2.1.1.1 29-1.2.2.1 29-1.2.2.1.1 29-1.2.2.1.1.r 31-1.2.2.2.1.1 32-1.2.2.2 32-1.2.2.2.1 32-1.2.2.2.1.r 33-1.2.2.3.r 34-1.2.2.3.1.1 40-1.2.2.3.2.2 41-1.2.2.3.2.1.1.1 43-1.2.2.3.2.1.1.1 44-1.2.2.3 44-1.2.2.3.2 44-1.2.2.3.2.r 47-1.3.1.1.1.1.1 48-1.3.1.1 49-1.3.1.1.2.1 51-1.3.1.2.1 (m / multi-sentence :snt1 (p2 / propose-01~e.1 :ARG0 (t / they~e.0) :ARG1~e.2 (a / and~e.12 :op1 (s / stabilize-01~e.7 :ARG0 (s2 / suppress-01~e.3 :ARG1~e.4 (e / enzyme :name (n / name :op1 "GTPase"~e.6) :mod (i / intrinsic~e.5))) :ARG1 (m2 / macro-molecular-complex~e.11 :part (e2 / enzyme :name (n3 / name :op1 "Ras"~e.8)) :part (e3 / enzyme :name (n4 / name :op1 "Raf"~e.10)))) :op2 (i2 / increase-01~e.13 :ARG0 s2 :ARG1 (o2 / output~e.15 :mod (s3 / signal~e.14) :direction (p / pathway~e.19 :name (n2 / name :op1 "MAPK"~e.18)))) :manner (s4 / select-01))) :snt2 (a2 / account-01~e.23 :ARG0 (t2 / this~e.22) :ARG1~e.24 (p3 / prefer-01~e.26 :ARG1~e.27 (e4 / enzyme~e.29 :ARG2-of~e.29 (m3 / mutate-01~e.29 :value "Q61"~e.28)) :ARG2 (e5 / enzyme~e.32 :ARG2-of~e.32 (m4 / mutate-01~e.32 :value "G12"~e.31)) :location~e.33 (m5 / medical-condition~e.44 :name (n5 / name :op1 "melanoma"~e.34) :ARG1-of~e.44 (d3 / drive-02~e.44 :ARG0 (p4 / pathway~e.19 :name (n6 / name :op1 "Raf-MAPK"~e.41,43)) :ARG1-of (c / clear-06~e.40))))) :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and~e.48 :op1 (p6 / person :name (n7 / name :op1 "Buhrman"~e.47)) :op2 (p7 / person :mod (o / other~e.49))) :time (d / date-entity :year 2010~e.51)))) # ::id pmid_2465_1010.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the 1980 s , several groups , including those at Cetus and Hoffmann La Roche , screened for compounds that restore GTP hydrolysis to mutant Ras , in the presence or absence of GAP . # ::alignments 2-1.3.1 3-1.3.1.r 5-1.1.1 6-1.1 6-1.1.2.1.1 6-1.1.2.1.2 8-1.1.2 9-1.1.2.1.3 10-1.1.2.1.1.1.r 11-1.1.2.1.1.1.1.1 12-1.1.2.1 13-1.1.2.1.2.1.1.1 14-1.1.2.1.2.1.1.2 15-1.1.2.1.2.1.1.3 17-1 18-1.2.r 19-1.2 20-1.1.2.1.3 21-1.2.1 22-1.2.1.1.1.1.1 23-1.2.1.1 24-1.2.1.1.2.r 25-1.2.1.1.2 25-1.2.1.1.2.2 25-1.2.1.1.2.2.r 26-1.2.1.1.2.1.1 28-1.2.1.2.r 30-1.2.1.2.1 31-1.2.1.2 32-1.2.1.2.2 33-1.2.1.2.1.1.r 34-1.2.1.2.1.1.1.1 (s2 / screen-01~e.17 :ARG0 (g / group~e.6 :quant (s3 / several~e.5) :ARG2-of (i / include-01~e.8 :ARG1 (a2 / and~e.12 :op1 (g2 / group~e.6 :location~e.10 (c / company :name (n3 / name :op1 "Cetus"~e.11))) :op2 (g3 / group~e.6 :location (c2 / company :name (n4 / name :op1 "Hoffmann"~e.13 :op2 "La"~e.14 :op3 "Roche"~e.15))) :mod (t / that~e.9,20)))) :ARG2~e.18 (c3 / compound~e.19 :ARG0-of (r / restore-01~e.21 :ARG1 (h / hydrolyze-01~e.23 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.22)) :ARG2~e.24 (e / enzyme~e.25 :name (n2 / name :op1 "Ras"~e.26) :ARG1-of~e.25 (m / mutate-01~e.25))) :condition~e.28 (o / or~e.31 :op1 (p2 / present-02~e.30 :ARG1~e.33 (p / protein :name (n5 / name :op1 "GAP"~e.34))) :op2 (a / absent-01~e.32 :ARG1 p)))) :time (d / date-entity :decade~e.3 1980~e.2)) # ::id pmid_2465_1010.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These screens failed to find compounds that increased GTPase rates . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.2 7-1.2.2.1 8-1.2.2.1.1.1.1.1 9-1.2.2.1.1 (f / fail-01~e.2 :ARG1 (s / screen-01~e.1 :mod (t / this~e.0)) :ARG2 (f2 / find-01~e.4 :ARG0 s :ARG1 (c / compound~e.5 :ARG0-of (i / increase-01~e.7 :ARG1 (r / rate~e.9 :degree-of (e / enzyme :name (n / name :op1 "GTPase"~e.8))))))) # ::id pmid_2465_1010.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , as structures of Ras proteins emerged , mostly from Wittinghofer ’s group , it became clear that codon 12 substitutions presented a steric block to GAP @-@ mediated GTP hydrolysis that could not be overcome by a small molecule . # ::alignments 0-1 3-1.1.2.1.1 5-1.1.2.1.1.1.1.1 6-1.1.1.1.2.1.2.1 6-1.1.2.1.1.1 7-1.1.2.1 9-1.1.2.1.2.2 10-1.1.2.1.2.r 11-1.1.2.1.2.1.1.1 13-1.1.2.1.2 16-1.1 17-1.1.1 18-1.1.1.1.r 19-1.1.1.1.1.1 20-1.1.1.1.1.1.1 21-1.1.1.1.1 22-1.1.1.1 24-1.1.1.1.2.2 25-1.1.1.1.2 26-1.1.1.1.2.1.r 27-1.1.1.1.2.1.2.1.1.1 29-1.1.1.1.2.1.2 30-1.1.1.1.2.1.1.1.1 31-1.1.1.1.2.1 33-1.1.1.1.2.3.2 34-1.1.1.1.2.3.2.1 34-1.1.1.1.2.3.2.1.r 36-1.1.1.1.2.3 37-1.1.1.1.2.3.1.r 39-1.1.1.1.2.3.1 40-1.1.1.1.2.3.1 (a / and~e.0 :op2 (b / become-01~e.16 :ARG2 (c / clear-06~e.17 :ARG1~e.18 (p2 / present-01~e.22 :ARG0 (s2 / substitute-01~e.21 :ARG2 (c2 / codon~e.19 :mod 12~e.20)) :ARG1 (b2 / block-01~e.25 :ARG1~e.26 (h / hydrolyze-01~e.31 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"~e.30)) :ARG1-of (m / mediate-01~e.29 :ARG0 (p3 / protein~e.6 :name (n3 / name :op1 "GAP"~e.27)))) :manner (s3 / steric~e.24) :ARG1-of (o / overcome-01~e.36 :ARG0~e.37 (s4 / small-molecule~e.39,40) :ARG1-of (p / possible-01~e.33 :polarity~e.34 -~e.34))))) :ARG1-of (c3 / cause-01 :ARG0 (e2 / emerge-02~e.7 :ARG0 (s5 / structure~e.3 :poss (p5 / protein-family~e.6 :name (n / name :op1 "Ras"~e.5))) :source~e.10 (g / group~e.13 :poss (p4 / person :name (n4 / name :op1 "Wittinghofer"~e.11)) :degree (m2 / most~e.9)))))) # ::id pmid_2465_1010.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These studies were mostly based on G12V mutations because these were the most widely used at that time . # ::alignments 0-1.1.1 1-1.1 3-1.3 4-1 5-1.2.r 6-1.2.1 7-1.2 8-1.4 9-1.1.1 12-1.4.1.2.1 13-1.4.1.2 14-1.4.1 16-1.4.1.3 17-1.4.1.3.r (b / base-02~e.4 :ARG1 (s / study-01~e.1 :mod (t / this~e.0,9)) :ARG2~e.5 (m2 / mutate-01~e.7 :value "G12V"~e.6) :degree (m / most~e.3) :ARG1-of (c / cause-01~e.8 :ARG0 (u / use-01~e.14 :ARG1 m2 :ARG1-of (w / wide-02~e.13 :degree (m3 / most~e.12)) :time~e.17 (t2 / that~e.16)))) # ::id pmid_2465_1010.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Whether the same conclusion can be applied to other mutations such as G12D or G13D remains to be seen because structures of these proteins bound to GAP have not been solved . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 2-1.1.1.2.1.1 3-1.1.1.2.1 4-1.1.1 6-1.1.1.2 7-1.1.1.2.2.r 8-1.1.1.2.2.1 9-1.1.1.2.2 9-1.1.1.2.2.2.1 9-1.1.1.2.2.2.2 10-1.1.1.2.2.2.r 11-1.1.1.2.2.2.r 12-1.1.1.2.2.2.1.1 13-1.1.1.2.2.2 14-1.1.1.2.2.2.2.1 15-1 16-1.2 18-1.1 19-1.2 20-1.2.1.2 21-1.2.1.2.1.r 22-1.2.1.2.1.1 23-1.2.1.2.1 24-1.2.1.2.2 25-1.2.1.2.2.1.r 26-1.2.1.2.2.1.1.1 28-1.2.1.1 28-1.2.1.1.r 30-1.2.1 (r / remain-01~e.15 :ARG1 (s2 / see-01~e.18 :ARG1 (p / possible-01~e.4 :mode~e.0 interrogative~e.0 :ARG1 (a / apply-02~e.6 :ARG1 (c / conclude-01~e.3 :ARG1-of (s / same-01~e.2)) :ARG2~e.7 (m / mutate-01~e.9 :mod (o / other~e.8) :example~e.10,11 (o2 / or~e.13 :op1 (m2 / mutate-01~e.9 :value "G12D"~e.12) :op2 (m3 / mutate-01~e.9 :value "G13D"~e.14)))))) :ARG1-of (c2 / cause-01~e.16,19 :ARG0 (s3 / solve-01~e.30 :polarity~e.28 -~e.28 :ARG1 (s4 / structure~e.20 :poss~e.21 (p2 / protein~e.23 :mod (t / this~e.22)) :ARG1-of (b / bind-01~e.24 :ARG2~e.25 (p3 / protein :name (n / name :op1 "GAP"~e.26))))))) # ::id pmid_2465_1010.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The approach of restoring GTP hydrolysis to mutant proteins received a brief infusion of hope when Scheffzek and colleagues showed that G12V H @-@ Ras could indeed hydrolyze a GTP analog diaminobenzophenone @-@ phosphoroamidate @-@ GTP in which the aromatic amino group mimics the catalytic effects of GAP ’s arginine finger ( Ahmadian et al. , 1999 ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1 7-1.1.1.2.1 7-1.3.2.1.2 7-1.3.2.1.2.2 7-1.3.2.1.2.2.r 8-1.1.1.2 9-1 11-1.2.2 12-1.2 13-1.2.1.r 14-1.2.1 15-1.3.r 16-1.3.1.1.1.1 17-1.3.1 18-1.3.1.2 19-1.3 20-1.3.2.r 21-1.3.2.1.2.2.1 22-1.3.2.1.2.1.1 24-1.3.2.1.2.1.1 25-1.3.2 26-1.3.2.2 27-1.3.2.1 29-1.3.2.1.1.1.1 30-1.3.2.1.1.2 31-1.3.2.1.1.1.1 33-1.3.2.1.1.1.1 35-1.3.2.1.1.1.1 39-1.3.2.1.1.3.1.1 40-1.3.2.1.1.3.1.2 41-1.3.2.1.1.3.1 42-1.3.2.1.1.3 44-1.3.2.1.1.3.2.2 45-1.3.2.1.1.3.2 46-1.3.2.1.1.3.2.1.r 47-1.3.2.1.1.3.2.1.1.1.1 49-1.3.2.1.1.3.2.1.2.1.1 50-1.3.2.1.1.3.2.1 53-1.4.1.1.1.1.1 54-1.4.1.1 55-1.4.1.1.2.1 57-1.4.1.2.1 (r / receive-01~e.9 :ARG0 (a / approach-02~e.1 :ARG1~e.2 (r2 / restore-01~e.3 :ARG1 (h / hydrolyze-01~e.5 :ARG1 (s / small-molecule :name (n / name :op1 "GTP"~e.4))) :ARG2 (p2 / protein~e.8 :ARG1-of (m / mutate-01~e.7)))) :ARG1 (i / infuse-01~e.12 :ARG1~e.13 (h2 / hopeful-03~e.14) :duration (b / brief~e.11)) :time~e.15 (s2 / show-01~e.19 :ARG0 (a2 / and~e.17 :op1 (p3 / person :name (n3 / name :op1 "Scheffzek"~e.16)) :op2 (c / colleague~e.18)) :ARG1~e.20 (p / possible-01~e.25 :ARG1 (h3 / hydrolyze-01~e.27 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "diaminobenzophenone-phosphoroamidate-GTP"~e.29,31,33,35) :mod (a3 / analog~e.30 :domain s) :location-of (m3 / mimic-01~e.42 :ARG0 (g / group~e.41 :mod (a4 / aromatic~e.39) :mod (a5 / amine~e.40)) :ARG1 (e2 / effect-03~e.45 :ARG0~e.46 (f / finger~e.50 :part-of (p4 / protein :name (n5 / name :op1 "GAP"~e.47)) :mod (a6 / amino-acid :name (n6 / name :op1 "arginine"~e.49))) :ARG1 (c2 / catalyze-01~e.44)))) :ARG2 (e / enzyme~e.7 :name (n2 / name :op1 "H-Ras"~e.22,24) :ARG2-of~e.7 (m2 / mutate-01~e.7 :value "G12V"~e.21))) :mod (i2 / indeed~e.26))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a7 / and~e.54 :op1 (p6 / person :name (n7 / name :op1 "Ahmadian"~e.53)) :op2 (p7 / person :mod (o / other~e.55))) :time (d / date-entity :year 1999~e.57)))) # ::id pmid_2465_1010.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A small molecule that provided this local charge might therefore trick mutant Ras into GTP hydrolysis . # ::alignments 1-1.1.1 2-1.1.1 4-1.1.1.1 5-1.1.1.1.1.2 6-1.1.1.1.1.1 7-1.1.1.1.1 8-1 9-1.2 10-1.1 11-1.1.2 11-1.1.2.2 11-1.1.2.2.r 12-1.1.2.1.1 13-1.1.3.r 14-1.1.3.1.1.1 15-1.1.3 (p2 / possible-01~e.8 :ARG1 (t / trick-01~e.10 :ARG0 (s2 / small-molecule~e.1,2 :ARG0-of (p3 / provide-01~e.4 :ARG1 (c / charge-03~e.7 :ARG1-of (l / local-02~e.6) :mod (t2 / this~e.5)))) :ARG1 (e / enzyme~e.11 :name (n / name :op1 "Ras"~e.12) :ARG1-of~e.11 (m / mutate-01~e.11)) :ARG2~e.13 (h / hydrolyze-01~e.15 :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"~e.14)))) :ARG1-of (i / infer-01~e.9)) # ::id pmid_2465_1010.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok At first sight , the GTD-/GTP @-@ binding site of Ras does not offer any room for such a molecule to bind . # ::alignments 1-1.2.1 1-1.2.1.1 1-1.2.1.1.r 7-1.1.2 10-1.1.2.1.1.1 12-1.1.1 12-1.1.1.r 13-1.1 14-1.1.3.1 15-1.1.3 19-1.1.2.2.1 19-1.1.2.2.2 21-1.1.2 (s / seem-01 :ARG1 (o2 / offer-01~e.13 :polarity~e.12 -~e.12 :ARG0 (b / bind-01~e.7,21 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.10)) :ARG2 (s2 / slash :op1 (s3 / small-molecule~e.19 :name (n2 / name :op1 "GTD")) :op2 (s4 / small-molecule~e.19 :name (n3 / name :op1 "GTP")))) :ARG1 (r / room~e.15 :mod (a / any~e.14)) :purpose b) :time (s5 / see-01 :ord (o / ordinal-entity~e.1 :value~e.1 1~e.1))) # ::id pmid_2465_1010.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , these issues deserve rethinking—perhaps G12D offers more possibilities for this kind of attack than G12V , for example . # ::alignments 0-1 2-1.1.1.1.1 3-1.1.1.1 4-1.1.1 6-1.1.2.1.1.1 7-1.1.2.1 8-1.1.2.1.2.1 9-1.1.2 9-1.1.2.1.2 10-1.1.2.1.2.2.r 11-1.1.2.1.2.2.1.1 12-1.1.2.1.2.2.1 14-1.1.2.1.2.2 15-1.1.2.1.2.3.r 16-1.1.2.1.2.3.1 18-1.1.2.2.r 19-1.1.2.2.r (c / contrast-01~e.0 :ARG2 (a / and :op1 (d / deserve-01~e.4 :ARG0 (i / issue-02~e.3 :mod (t2 / this~e.2)) :ARG1 (r / rethink-01 :ARG1 i)) :op2 (p / possible-01~e.9 :ARG1 (o / offer-01~e.7 :ARG0 (m / mutate-01 :value "G12D"~e.6) :ARG1 (p2 / possibility~e.9 :mod (m2 / more~e.8) :mod~e.10 (a2 / attack-01~e.14 :mod (k / kind~e.12 :mod (t / this~e.11))) :compared-to~e.15 (m3 / mutate-01 :value "G12V"~e.16))) :example-of~e.18,19 i))) # ::id pmid_2465_1010.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Targeting Ras Posttranslational Modification Pathways # ::alignments 0-1 1-1.1.1.1 2-1.1.1.1.r 2-1.1.2.1 2-1.1.2.1.1 2-1.1.2.1.1.r 3-1.1.2 4-1.1 (t / target-01~e.0 :ARG1 (p / pathway~e.4 :name (n / name :op1~e.2 "Ras"~e.1) :ARG1-of (m / modify-01~e.3 :time (a / after~e.2 :op1~e.2 (t2 / translate-02~e.2))))) # ::id pmid_2465_1010.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras proteins are processed in several steps ( reviewed in Gysin et al. , 2011 ) , including farnesylation , proteolytic cleavage at the C terminus by RCE1 , and carboxymethylation by isoprenylcysteine carboxyl methyltransferase ( ICMT ) . # ::alignments 0-1.1.1.1 1-1.1 1-1.2.3.1.2.2 3-1 4-1.2.r 5-1.2.2 6-1.2 8-1.3 11-1.3.1.1.1.1.1 12-1.3.1.1 13-1.3.1.1.2.1 15-1.3.1.2.1 19-1.2.3 22-1.2.3.1.2.3 23-1.2.3.1.2 26-1.2.3.1.2.2.1.1 27-1.2.3.1.2.2.1.1 28-1.2.3.1.2.1.r 29-1.2.3.1.2.1.1.1 31-1.2.3.1 34-1.2.3.1.3.2.1.1 35-1.2.3.1.3.2.1.2 36-1.2.3.1.3.2.1.3 (p / process-01~e.3 :ARG1 (p7 / protein-family~e.1 :name (n / name :op1 "Ras"~e.0)) :manner~e.4 (s / step-01~e.6 :ARG4 a2 :quant (s2 / several~e.5) :ARG2-of (i / include-91~e.19 :ARG1 (a2 / and~e.31 :op1 (f / farnesylate-01 :ARG1 p7) :op2 (c / cleave-01~e.23 :ARG0~e.28 (e2 / enzyme :name (n3 / name :op1 "RCE1"~e.29)) :ARG1 (p6 / protein-segment~e.1 :name (n4 / name :op1 "C-terminus"~e.26,27) :part-of p7) :mod (p5 / proteolytic~e.22)) :op3 (c2 / carboxymethylate-00 :ARG1 p7 :ARG2 (e3 / enzyme :name (n5 / name :op1 "isoprenylcysteine"~e.34 :op2 "carboxyl"~e.35 :op3 "methyltransferase"~e.36)))))) :ARG1-of (r / review-02~e.8 :ARG2 (p2 / publication-91 :ARG0 (a / and~e.12 :op1 (p3 / person :name (n2 / name :op1 "Gysin"~e.11)) :op2 (p4 / person :mod (o / other~e.13))) :time (d / date-entity :year 2011~e.15)))) # ::id pmid_2465_1010.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras @-@ 4A , H @-@ Ras , and N @-@ Ras are further processed by palmitoylation ( Figure 3 ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 4-1.1.1.1.1 6-1.1.2.1.1 8-1.1.1.1.1 8-1.1.2.1.1 8-1.1.3.1.1 10-1.1 11-1.1.3.1.1 13-1.1.1.1.1 13-1.1.2.1.1 13-1.1.3.1.1 15-1.3 16-1 21-1.4.1 22-1.4.1.1 (p / process-01~e.16 :ARG1 (a / and~e.10 :op1 (e / enzyme :name (n / name :op1 "K-Ras-4A"~e.0,2,4,8,13)) :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras"~e.6,8,13)) :op3 (e3 / enzyme :name (n3 / name :op1 "N-Ras"~e.8,11,13))) :manner (p2 / palmitoylate-01 :ARG1 a) :degree (f / further~e.15) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.21 :mod 3~e.22))) # ::id pmid_2465_1010.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These reactions are not only essential for plasma membrane localization but also for Raf kinase activation . # ::alignments 0-1.2.1 1-1.2 2-1.2.r 5-1 7-1.1.1.1.1 8-1.1.1.1 9-1.1.1 12-1.1.r 13-1.1.2.1.1.1 14-1.1.2.1 15-1.1.2 (e / essential~e.5 :purpose~e.12 (a / and :op1 (b / be-located-at-91~e.9 :ARG2 (m / membrane~e.8 :mod (p / plasma~e.7))) :op2 (a2 / activate-01~e.15 :ARG1 (k / kinase~e.14 :name (n / name :op1 "Raf"~e.13)))) :domain~e.2 (r / react-01~e.1 :mod (t / this~e.0))) # ::id pmid_2465_1010.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The failure of farnesyltransferase inhibitors has been well documented . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 7-1.2 8-1 (d / document-01~e.8 :ARG1 (f / fail-01~e.1 :ARG1~e.2 (m / molecular-physical-entity~e.4 :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "farnesyltransferase"~e.3))))) :ARG1-of (w / well-09~e.7)) # ::id pmid_2465_1010.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By sheer bad luck , the forms of Ras that play the major roles in human cancer , K @-@ Ras and N @-@ Ras , can be geranylgeranylated when farnesyltransferase is inhibited , allowing newly synthesized Ras proteins to be inserted correctly in the membrane and to function normally . # ::alignments 1-1.1.2.1.2 2-1.1.2.1.1 3-1.1.2.1 8-1.1.3.1.1.1.1.1 10-1.1.1.3 12-1.1.1.3.2 14-1.1.1.3.1.r 15-1.1.1.3.1.3 16-1.1.1.3.1.2.1 18-1.1.1.1.1.1 20-1.1.1.1.1.1 20-1.1.1.2.1.1 21-1.1.1 22-1.1.1.2.1.1 24-1.1.1.2.1.1 26-1 30-1.2.1.1.1 32-1.2 34-1.1.3 35-1.1.3.1.1.1.2.1 36-1.1.3.1.1.1.2 37-1.1.3.1.1.1.1.1 41-1.1.3.1.1 42-1.1.3.1.1.3 43-1.1.3.1.1.2.r 45-1.1.3.1.1.2 46-1.1.3.1 48-1.1.3.1.2 49-1.1.3.1.2.2 (p / possible-01~e.26 :ARG1 (g / geranylgeranylate-01 :ARG1 (a / and~e.21 :op1 (e / enzyme :name (n / name :op1 "K-Ras"~e.18,20)) :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"~e.20,22,24)) :ARG0-of (p2 / play-08~e.10 :ARG1~e.14 (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"~e.16) :mod (h / human~e.15)) :ARG1-of (m / major-02~e.12))) :ARG1-of (c2 / cause-01 :ARG0 (l / luck~e.3 :ARG1-of (b / bad-07~e.2) :mod (s / sheer~e.1))) :ARG0-of (a4 / allow-01~e.34 :ARG1 (a3 / and~e.46 :op1 (i2 / insert-01~e.41 :ARG1 (e4 / enzyme :name (n5 / name :op1 "Ras"~e.8,37) :ARG1-of (s2 / synthesize-01~e.36 :ARG1-of (n6 / new-01~e.35))) :ARG2~e.43 (m2 / membrane~e.45) :ARG1-of (c3 / correct-02~e.42)) :op2 (f / function-01~e.48 :ARG0 e4 :ARG1-of (n4 / normal-02~e.49))))) :condition (i / inhibit-01~e.32 :ARG1 (e3 / enzyme :name (n3 / name :op1 "farnesyltransferase"~e.30)))) # ::id pmid_2465_1010.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok H @-@ Ras , on the other hand , is not geranylgeranylated , suggesting that tumors driven by mutant H @-@ Ras , such as bladder cancer or thyroid cancer , might be susceptible to farnesyltransferase inhibition . # ::alignments 0-1.1.2.1.1 2-1.1.2.1.1 10-1.1.1 10-1.1.1.r 13-1.1.3 14-1.1.3.1.r 15-1.1.3.1.1.1 16-1.1.3.1.1.1.1 17-1.1.3.1.1.1.1.1.r 18-1.1.3.1.1.1.1.1 18-1.1.3.1.1.1.1.1.2 18-1.1.3.1.1.1.1.1.2.r 19-1.1.3.1.1.1.1.1.1.1 21-1.1.3.1.1.1.1.1.1.1 23-1.1.3.1.1.1.2.r 24-1.1.3.1.1.1.2.r 25-1.1.3.1.1.1.2.1.3 26-1.1.3.1.1.1.2.1.2.1 27-1.1.3.1.1.1.2 28-1.1.3.1.1.1.2.2.2.1 29-1.1.3.1.1.1.2.1.2.1 29-1.1.3.1.1.1.2.2.2.2 31-1.1.3.1 32-1.1.3.1.1.1.r 33-1.1.3.1.1 34-1.1.3.1.1.2.r 35-1.1.3.1.1.2.1.1.1 36-1.1.3.1.1.2 (c3 / contrast-01 :ARG2 (g / geranylgeranylate-01 :polarity~e.10 -~e.10 :ARG1 (e3 / enzyme :name (n3 / name :op1 "H-Ras"~e.0,2)) :ARG0-of (s2 / suggest-01~e.13 :ARG1~e.14 (p / possible-01~e.31 :ARG1 (s / susceptible~e.33 :domain~e.32 (t / tumor~e.15 :ARG1-of (d / drive-02~e.16 :ARG0~e.17 (e2 / enzyme~e.18 :name (n2 / name :op1 "H-Ras"~e.19,21) :ARG2-of~e.18 (m / mutate-01~e.18))) :example~e.23,24 (o / or~e.27 :op1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.26,29) :mod (b / bladder~e.25)) :op2 (d3 / disease :wiki "Thyroid_cancer" :name (n5 / name :op1 "thyroid"~e.28 :op2 "cancer"~e.29)))) :prep-to~e.34 (i2 / inhibit-01~e.36 :ARG1 (e / enzyme :name (n / name :op1 "farnesyltransferase"~e.35)))))))) # ::id pmid_2465_1010.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Targeting RCE1 or ICMT has also been evaluated , though the consequences of blocking these enzymes are difficult to predict or understand . # ::alignments 0-1.1.1 1-1.1.1.1.1.1.1 2-1.1.1.1 3-1.1.1.1.2.1.1 5-1.1.2 7-1.1 11-1.2.1.1.1 11-1.2.1.1.1.1 11-1.2.1.1.1.1.r 12-1.2.1.1.1.1.1.r 13-1.2.1.1.1.1.1 15-1.2.1.1.1.1.1.1 16-1.2.1.r 17-1.2 18-1.2.1.2 19-1.2.1.1 20-1.2.1 21-1.2.1.2 (c / contrast-01 :ARG1 (e / evaluate-01~e.7 :ARG1 (t / target-01~e.0 :ARG1 (o / or~e.2 :op1 (e2 / enzyme :name (n / name :op1 "RCE1"~e.1)) :op2 (e3 / enzyme :name (n2 / name :op1 "ICMT"~e.3)))) :mod (a / also~e.5)) :ARG2 (d / difficult~e.17 :domain~e.16 (o3 / or~e.20 :op1 (p / predict-01~e.19 :ARG1 (c2 / consequence~e.11 :ARG1-of~e.11 (c3 / cause-01~e.11 :ARG0~e.12 (b / block-01~e.13 :ARG1 o~e.15)))) :op2 (u / understand-01~e.18,21 :ARG1 c2)))) # ::id pmid_2465_1010.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , inhibition of either enzyme can actually lead to increased Ras @-@ mediated tumorigenesis ( Court et al. , 2013 ; Wahlstrom et al. , 2007 ) . # ::alignments 0-1.2 1-1.2 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1 6-1.1.1.1 7-1 8-1.1.3 9-1.1 10-1.1.2.r 11-1.1.2.2 12-1.1.2.3.1.1.1 14-1.1.2.3 15-1.1.2 15-1.1.2.1 15-1.1.2.1.r 18-1.3.1.1.1.1.1.1 19-1.3.1.1.1 20-1.3.1.1.1.2.1 22-1.3.1.1.2.1 24-1.3.1.2.1.1.1.1 25-1.3.1 25-1.3.1.2.1 26-1.3.1.2.1.2.1 28-1.3.1.2.2.1 (p / possible-01~e.7 :ARG1 (l / lead-03~e.9 :ARG0 (i2 / inhibit-01~e.3 :ARG1~e.4 (e2 / enzyme~e.6 :mod (e3 / either~e.5))) :ARG2~e.10 (c / create-01~e.15 :ARG1~e.15 (t / tumor~e.15) :ARG1-of (i / increase-01~e.11) :ARG1-of (m / mediate-01~e.14 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.12)))) :ARG1-of (a / actual-02~e.8)) :ARG0-of (e4 / exemplify-01~e.0,1) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.25 :op1 (p4 / publication-91 :ARG0 (a4 / and~e.19 :op1 (p2 / person :name (n2 / name :op1 "Court"~e.18)) :op2 (p3 / person :mod (o2 / other~e.20))) :time (d2 / date-entity :year 2013~e.22)) :op2 (p5 / publication-91 :ARG0 (a3 / and~e.25 :op1 (p6 / person :name (n3 / name :op1 "Wahlstrom"~e.24)) :op2 (p7 / person :mod (o / other~e.26))) :time (d3 / date-entity :year 2007~e.28))))) # ::id pmid_2465_1010.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Palmitoylation and depalmitoylation of H @-@ Ras , K @-@ Ras @-@ 4A , and N @-@ Ras proteins provide dynamic aspects to membrane localization and may present therapeutic opportunities for these proteins . # ::alignments 1-1 4-1.1.1.1.1.1.1.1 6-1.1.1.1.1.1.1.1 6-1.1.1.1.1.2.1.1 6-1.1.1.1.1.3.1.1 8-1.1.1.1.1.2.1.1 10-1.1.1.1.1.2.1.1 12-1.1.1.1.1.2.1.1 15-1.1.1.1.1.3.1.1 17-1.1.1.1.1.1.1.1 17-1.1.1.1.1.2.1.1 17-1.1.1.1.1.3.1.1 19-1.1 20-1.1.2.1 21-1.1.2 23-1.1.3.2 24-1.1.3 25-1 26-1.2 27-1.2.1 28-1.2.1.2.1 29-1.2.1.2 (a / and~e.1,25 :op1 (p / provide-01~e.19 :ARG0 (a2 / and :op1 (p3 / palmitoylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "H-Ras"~e.4,6,17)) :op2 (e2 / enzyme :name (n2 / name :op1 "K-Ras-4A"~e.6,8,10,12,17)) :op3 (e3 / enzyme :name (n3 / name :op1 "N-Ras"~e.6,15,17)))) :op2 (d / depalmitoylate-01 :ARG1 a3)) :ARG1 (a4 / aspect~e.21 :mod (d2 / dynamic~e.20)) :ARG2 (b / be-located-at-91~e.24 :ARG1 a3 :ARG2 (m / membrane~e.23))) :op2 (p2 / possible-01~e.26 :ARG1 (p4 / present-01~e.27 :ARG0 a2 :ARG1 (o / opportunity~e.29 :mod (t / therapy~e.28)) :ARG2 a3))) # ::id pmid_2465_1010.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recent work demonstrated that acyl protein thioesterase 1 ( APT1 ) , which is responsible for Ras depalmitoylation , could be targeted by palmostatin B to selectively inhibit the growth of N @-@ Ras mutant leukemia cells ( Xu et al. , 2012 ) . # ::alignments 0-1.2.1.1 1-1.2.1 2-1.2 4-1.1.2.1.1 5-1.1.2.1.2 6-1.1.2.1.3 7-1.1.2.1.4 14-1.1.2 14-1.1.2.2 14-1.1.2.2.r 16-1.1.2.2.1.1.1.1 19-1 21-1.1 22-1.1.1.r 23-1.1.1.1.1 24-1.1.1.1.2 26-1.1.3.3 26-1.1.3.3.r 27-1.1.3 29-1.1.3.2 30-1.1.3.2.1.r 31-1.1.3.2.1.2.1.3.1.1 33-1.1.3.2.1.2.1.3.1.1 34-1.1.3.2.1.2.1.3 34-1.1.3.2.1.2.1.3.2 34-1.1.3.2.1.2.1.3.2.r 35-1.1.3.2.1.1 36-1.1.3.2.1 39-1.3.1.1.1.1.1 40-1.3.1.1 41-1.3.1.1.2.1 43-1.3.1.2.1 (p / possible-01~e.19 :ARG1 (t / target-01~e.21 :ARG0~e.22 (s / small-molecule :name (n3 / name :op1 "palmostatin"~e.23 :op2 "B"~e.24)) :ARG1 (e4 / enzyme~e.14 :name (n6 / name :op1 "acyl"~e.4 :op2 "protein"~e.5 :op3 "thioesterase"~e.6 :op4 1~e.7) :ARG0-of~e.14 (r2 / responsible-01~e.14 :ARG1 (d / depalmitoylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.16)) :ARG2 e4))) :purpose (i / inhibit-01~e.27 :ARG0 e4 :ARG1 (g / grow-01~e.29 :ARG1~e.30 (c2 / cell~e.36 :source (l / leukemia~e.35) :ARG1-of (e2 / encode-01 :ARG0 (n / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA") :part (g2 / gene~e.34 :name (n4 / name :op1 "N-Ras"~e.31,33) :ARG0-of~e.34 (m / mutate-01~e.34)))))) :manner~e.26 (s2 / selective~e.26))) :ARG1-of (d2 / demonstrate-01~e.2 :ARG0 (w / work-01~e.1 :time (r / recent~e.0))) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and~e.40 :op1 (p4 / person :name (n5 / name :op1 "Xu"~e.39)) :op2 (p5 / person :mod (o / other~e.41))) :time (d4 / date-entity :year 2012~e.43)))) # ::id pmid_2465_1010.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , K @-@ Ras @-@ 4B localization seemed relatively static and stable : specific localization of K @-@ Ras @-@ 4B to plasma membranes is based on electrostatic interactions between lysine residues in the hypervariable region and phospholipids in the membrane . # ::alignments 1-1.2.2 3-1.1.1.1.1.1 5-1.1.1.1.1.1 7-1.1.1.1.1.1 8-1.1.1 9-1.2 10-1.2.1.1.1 11-1.2.1.1 12-1.2.1 13-1.2.1.2 15-1.1.1.3 16-1.1.1 18-1.1.1.1.1.1 20-1.1.1.1.1.1 22-1.1.1.1.1.1 24-1.1.1.2.1 25-1.1.1.2 25-1.1.2.2.1 26-1.1.1 27-1.1 28-1.1.2.r 29-1.1.2.3 30-1.1.2 32-1.1.2.1.1.1.1 33-1.1.2.1 34-1.1.2.1.2.r 36-1.1.2.1.2.1 37-1.1.2.1.2 42-1.1.1.2 42-1.1.2.2.1 (c2 / cause-01 :ARG0 (b / base-02~e.27 :ARG1 (b3 / be-located-at-91~e.8,16,26 :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras-4B"~e.3,5,7,18,20,22)) :ARG2 (m / membrane~e.25,42 :mod (p / plasma~e.24)) :ARG1-of (s4 / specific-02~e.15)) :ARG2~e.28 (i / interact-01~e.30 :ARG0 (r2 / residue~e.33 :mod (a2 / amino-acid :name (n2 / name :op1 "lysine"~e.32)) :location~e.34 (r3 / region~e.37 :mod (h / hypervariable~e.36))) :ARG1 (p2 / phospholipid :location (m3 / membrane~e.25,42)) :mod (e3 / electrostatic~e.29))) :ARG1 (s / seem-01~e.9 :ARG1 (a / and~e.12 :op1 (s2 / static~e.11 :ARG2-of (r / relative-05~e.10) :domain b3) :op2 (s3 / stable-03~e.13 :ARG1 b3)) :ARG2-of (c3 / contrast-01~e.1))) # ::id pmid_2465_1010.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , another therapeutic opportunity has been presented by the discovery that PDE6δ acts as a solubilizing factor that modulates Ras proteins by sustaining their dynamic distribution in cellular membranes . # ::alignments 0-1 2-1.1.2.2 3-1.1.2.1 4-1.1.2 7-1.1 8-1.1.1.r 10-1.1.1 11-1.1.1.1.r 12-1.1.1.1.1.1.1 13-1.1.1.1 17-1.1.1.1.2 19-1.1.1.1.2.2 20-1.1.1.1.2.2.1.1.1 21-1.1.1.1.1 21-1.1.1.1.2.2.1 22-1.1.1.1.2.2.2.r 23-1.1.1.1.2.2.2 25-1.1.1.1.2.2.2.2.3 26-1.1.1.1.2.2.2.2 27-1.1.1.1.2.2.2.2.2.r 28-1.1.1.1.2.2.2.2.2.1 29-1.1.1.1.2.2.2.2.2 (c / contrast-01~e.0 :ARG2 (p / present-01~e.7 :ARG0~e.8 (d / discover-01~e.10 :ARG1~e.11 (a2 / act-01~e.13 :ARG0 (p2 / protein~e.21 :name (n / name :op1 "PDE6δ"~e.12)) :ARG1 (f / factor~e.17 :ARG0-of (s / solubilize-00 :ARG1 p3) :ARG0-of (m / modulate-01~e.19 :ARG1 (p3 / protein-family~e.21 :name (n2 / name :op1 "Ras"~e.20)) :manner~e.22 (s2 / sustain-01~e.23 :ARG0 f :ARG1 (d2 / distribute-01~e.26 :ARG1 p3 :ARG2~e.27 (m2 / membrane~e.29 :location (c2 / cell~e.28)) :manner (d3 / dynamic~e.25))))))) :ARG1 (o / opportunity~e.4 :mod (t / therapy~e.3) :mod (a / another~e.2)))) # ::id pmid_2465_1010.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A small molecule was identified that prevents association of K @-@ Ras @-@ 4B , and other proteins , with PDEδ and so delocalizes these proteins and inhibits downstream signaling ( Zimmermann et al. , 2013 ) . # ::alignments 1-1.1 2-1.1 4-1 6-1.1.1 7-1.1.1.1 8-1.1.1.1.1.r 9-1.1.1.1.1.1.1.1 11-1.1.1.1.1.1.1.1 13-1.1.1.1.1.1.1.1 15-1.1.1.1.1 16-1.1.1.1.1.2.1 17-1.1.1.1.1.2 19-1.1.1.1.2.r 20-1.1.1.1.2.1.1 21-1.1.1.2 22-1.1.1.2 25-1.1.1.1.1.2 26-1.1.1.1.1 26-1.1.1.2.1 27-1.1.1.2.1.2 28-1.1.1.2.1.2.2.1 29-1.1.1.2.1.2.2 32-1.2.1.1.1.1.1 33-1.2.1.1 34-1.2.1.1.2.1 36-1.2.1.2.1 (i / identify-01~e.4 :ARG1 (s / small-molecule~e.1,2 :ARG0-of (p / prevent-01~e.6 :ARG1 (a / associate-01~e.7 :ARG1~e.8 (a2 / and~e.15,26 :op1 (e / enzyme :name (n / name :op1 "K-Ras-4B"~e.9,11,13)) :op2 (p3 / protein~e.17,25 :mod (o / other~e.16))) :ARG2~e.19 (p4 / protein :name (n2 / name :op1 "PDEδ"~e.20))) :ARG0-of (c2 / cause-01~e.21,22 :ARG1 (a4 / and~e.26 :op1 (d2 / delocalize-01 :ARG0 s :ARG1 a2) :op2 (i2 / inhibit-01~e.27 :ARG0 s :ARG1 (s2 / signal-07~e.29 :source (d / downstream~e.28))))))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a5 / and~e.33 :op1 (p6 / person :name (n3 / name :op1 "Zimmermann"~e.32)) :op2 (p7 / person :mod (o2 / other~e.34))) :time (d4 / date-entity :year 2013~e.36)))) # ::id pmid_2465_1010.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Little is still known about the trafficking of Ras to and from the membrane , and there are likely to be additional factors or chaperones involved in the movement of the proteins that could serve as targets for small molecules . # ::alignments 0-1.1.1 2-1.1.2 3-1.1 4-1.1.1.1.r 6-1.1.1.1.1 6-1.1.1.1.2 7-1.1.1.1.1.1.r 8-1.1.1.1.1.1.1.1 9-1.1.1.1.1.2.r 10-1.1.1.1 11-1.1.1.1.2.2.r 13-1.1.1.1.1.2 13-1.1.1.1.2.2 15-1 18-1.2 21-1.2.1.1.1.1 22-1.2.1.1.1 23-1.2.1.1 24-1.2.1.1.2 25-1.2.1 26-1.2.1.2.r 28-1.2.1.2 29-1.2.1.2.1.r 31-1.2.1.2.1 33-1.2.1.2.1.1.2 34-1.2.1.2.1.1 35-1.2.1.2.1.1.1.r 36-1.2.1.2.1.1.1 37-1.2.1.2.1.1.1.1.r 38-1.2.1.2.1.1.1.1 39-1.2.1.2.1.1.1.1 (a / and~e.15 :op1 (k / know-01~e.3 :ARG1 (l2 / little~e.0 :topic~e.4 (a2 / and~e.10 :op1 (t2 / traffic-01~e.6 :ARG1~e.7 (e / enzyme :name (n / name :op1 "Ras"~e.8)) :destination~e.9 (m / membrane~e.13)) :op2 (t3 / traffic-01~e.6 :ARG1 e :source~e.11 (m2 / membrane~e.13)))) :mod (s / still~e.2)) :op2 (l / likely-01~e.18 :ARG1 (i / involve-01~e.25 :ARG1 (o / or~e.23 :op1 (f / factor~e.22 :mod (a3 / additional~e.21)) :op2 (c / chaperone~e.24)) :ARG2~e.26 (m3 / move-01~e.28 :ARG1~e.29 (p / protein~e.31 :ARG0-of (s2 / serve-01~e.34 :ARG1~e.35 (t / target-01~e.36 :ARG0~e.37 (s3 / small-molecule~e.38,39) :ARG1 p) :ARG1-of (p2 / possible-01~e.33))))))) # ::id pmid_2465_1010.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In a related study , K @-@ Ras @-@ 4B was shown to undergo retrograde trafficking from the plasma membrane to endomembranes . # ::alignments 2-1.2.1 3-1.2 5-1.1.1.1.1 7-1.1.1.1.1 9-1.1.1.1.1 11-1 13-1.1 14-1.1.2.1 15-1.1.2 16-1.1.2.2.r 18-1.1.2.2.1 19-1.1.2.2 (s / show-01~e.11 :ARG1 (u / undergo-28~e.13 :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras-4B"~e.5,7,9)) :ARG2 (t / traffic-01~e.15 :ARG1-of (r2 / retrograde-01~e.14) :source~e.16 (m / membrane~e.19 :mod (p2 / plasma~e.18)) :direction (e / endomembrane))) :medium (s2 / study-01~e.3 :ARG1-of (r / relate-01~e.2))) # ::id pmid_2465_1010.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This may serve as an additional pathway to specifically disrupt for therapeutic benefit ( Bivona et al. , 2006 ) . # ::alignments 0-1.1.1 1-1 2-1.1 3-1.1.2.r 3-1.2.1.2.r 5-1.1.2.1 6-1.1.2 8-1.1.3.2 9-1.1.3 10-1.1.3.3.r 11-1.1.3.3.2 12-1.1.3.3 15-1.2.1.1.1.1.1 16-1.2.1.1 17-1.2.1.1.2.1 19-1.2.1.2.1 (p / possible-01~e.1 :ARG1 (s / serve-01~e.2 :ARG0 (t / this~e.0) :ARG1~e.3 (p2 / pathway~e.6 :mod (a / additional~e.5)) :purpose (d / disrupt-01~e.9 :ARG0 p2 :ARG1-of (s2 / specific-02~e.8) :purpose~e.10 (b / benefit-01~e.12 :ARG0 p2 :mod (t2 / therapy~e.11)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a2 / and~e.16 :op1 (p4 / person :name (n / name :op1 "Bivona"~e.15)) :op2 (p5 / person :mod (o / other~e.17))) :time~e.3 (d3 / date-entity :year 2006~e.19)))) # ::id pmid_2465_1010.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to these processing events , several recent papers have highlighted other posttranslational modifications of K @-@ Ras that could serve as therapeutic targets . # ::alignments 0-1.2 1-1.2 3-1.2.1.1 4-1.2.1.2 5-1.2.1 7-1.1.1 8-1.1.2 9-1.1 11-1 12-1.2.2.2 13-1.2.2.1.1.1.r 13-1.2.2.3 13-1.2.2.3.1 13-1.2.2.3.1.r 14-1.2.2 15-1.2.2.1.r 16-1.2.2.1.1.1 18-1.2.2.1.1.1 20-1.2.2.4.2 21-1.2.2.4 22-1.2.2.3.r 22-1.2.2.4.1.r 23-1.2.2.4.1.1 24-1.2.2.4.1 (h / highlight-01~e.11 :ARG0 (p / paper~e.9 :quant (s / several~e.7) :time (r / recent~e.8)) :ARG1 (a / and~e.0,1 :op1 (e / event~e.5 :mod (t / this~e.3) :topic (p2 / process-01~e.4)) :op2 (m / modify-01~e.14 :ARG1~e.15 (e2 / enzyme :name (n / name :op1~e.13 "K-Ras"~e.16,18)) :mod (o / other~e.12) :time~e.22 (a2 / after~e.13 :op1~e.13 (t2 / translate-02~e.13)) :ARG0-of (s2 / serve-01~e.21 :ARG1~e.22 (t3 / target-01~e.24 :ARG0 (t4 / therapy~e.23) :ARG1 m) :ARG1-of (p3 / possible-01~e.20))))) # ::id pmid_2465_1010.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Mono @-@ ubiquitination at Lys147 has been shown to enhance GTP loading and effector @-@ binding affinity of K @-@ Ras ( Sasaki et al. , 2011 ) , suggesting that targeting of ubiquitin pathway enzymes might have an effect on K @-@ Ras activity . # ::alignments 0-1.1.1.1 0-1.1.1.1.r 2-1.1.1 7-1 9-1.1 10-1.1.2.1.1.1.1 11-1.1.2.1 12-1.1.2 13-1.1.2.2.2.1 15-1.1.2.2.2 16-1.1.2.2 17-1.1.2.2.1.r 18-1.1.2.2.1.1.1 20-1.1.2.2.1.1.1 23-1.2.1.1.1.1.1 24-1.2.1.1 25-1.2.1.1.2.1 27-1.2.1.2.1 31-1.3 32-1.3.1.r 33-1.3.1.1 34-1.3.1.1.1.r 35-1.3.1.1.1.1.1.1 36-1.3.1.1.1.1 37-1.3.1.1.1 38-1.3.1.3 41-1.3.1 42-1.3.1.2.r 43-1.3.1.2.1 44-1.3.1.2.1 45-1.3.1.2.1 46-1.3.1.2 (s / show-01~e.7 :ARG1 (e / enhance-01~e.9 :ARG0 (u / ubiquitinate-01~e.2 :quant~e.0 1~e.0 :ARG1 (a / amino-acid :mod 147 :name (n / name :op1 "lysine"))) :ARG1 (a2 / and~e.12 :op1 (l / load-01~e.11 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP"~e.10))) :op2 (a3 / affinity~e.16 :poss~e.17 (e2 / enzyme :name (n3 / name :op1 "K-Ras"~e.18,20)) :topic (b / bind-01~e.15 :ARG2 (e3 / effector~e.13))))) :ARG1-of (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a4 / and~e.24 :op1 (p2 / person :name (n4 / name :op1 "Sasaki"~e.23)) :op2 (p3 / person :mod (o / other~e.25))) :time (d2 / date-entity :year 2011~e.27))) :ARG0-of (s3 / suggest-01~e.31 :ARG1~e.32 (a5 / affect-01~e.41 :ARG0 (t / target-01~e.33 :ARG1~e.34 (e4 / enzyme~e.37 :part-of (p5 / pathway~e.36 :name (n5 / name :op1 "ubiquitin"~e.35)))) :ARG1~e.42 (a6 / activity-06~e.46 :ARG0 e2~e.43,44,45) :ARG1-of (p4 / possible-01~e.38)))) # ::id pmid_2465_1010.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Acetylation of Lys104 was shown to decrease GEF @-@ induced nucleotide exchange , leading to reduced transformation efficiency in cells , and the deacetylases SIRT2 and HDAC6 were shown to regulate the level of acetylation of K @-@ Ras ( Yang et al. , 2013 ) , suggesting that inhibitors of these enzymes might have an effect on the oncogenic potential of mutant K @-@ Ras tumors . # ::alignments 0-1.1.1.1 4-1.1 6-1.1.1 7-1.1.1.2.2.1.1.1 9-1.1.1.2.2 10-1.1.1.2.1 11-1.1.1.2 13-1.1.1.1.2 14-1.1.1.1.2.1.r 15-1.1.1.1.2.1 16-1.1.1.1.2.1.1.1 17-1.1.1.1.2.1.1 18-1.1.1.1.2.1.1.1.1.r 19-1.1.1.1.2.1.1.1.1 21-1 21-1.3.1.1 24-1.2.1.1.1.1.1 25-1.2.1.1 26-1.2.1.1.2.1.1 28-1.2 30-1.2.1 32-1.2.1.2 33-1.2.1.2.1.r 34-1.2.1.2.1 36-1.2.1.2.1.1.1.1 38-1.2.1.2.1.1.1.1 41-1.3.1.1.1.1.1 42-1.3.1.1 43-1.3.1.1.2.1 45-1.3.1.2.1 49-1.2.2 50-1.2.2.1.r 51-1.2.2.1.1 54-1.1.1.2.2.1 54-1.2.1.1.1 54-1.2.1.1.2 54-1.2.1.2.1.1 55-1.2.2.1.2 55-1.2.2.1.3 58-1.2.2.1 59-1.2.2.1.2.1.r 61-1.2.2.1.2.1 61-1.2.2.1.2.1.2.2.1 63-1.2.2.1.2.1.1.r 64-1.2.2.1.2.1.1.1 65-1.2.2.1.2.1.1.2 66-1.2.2.1.2.1.1.2 67-1.2.2.1.2.1.1.2 68-1.2.2.1.2.1.1 (a / and~e.21 :op1 (s / show-01~e.4 :ARG1 (d / decrease-01~e.6 :ARG0 (a2 / acetylate-01~e.0 :ARG1 (a3 / amino-acid :mod 104 :name (n / name :op1 "lysine")) :ARG0-of (l / lead-03~e.13 :ARG2~e.14 (r / reduce-01~e.15 :ARG1 (e2 / efficient-01~e.17 :ARG2 (t / transform-01~e.16 :ARG1~e.18 (c / cell~e.19)))))) :ARG1 (e / exchange-01~e.11 :ARG1 (n2 / nucleotide~e.10) :ARG2-of (i / induce-01~e.9 :ARG0 (p / protein~e.54 :name (n3 / name :op1 "GEF"~e.7)))))) :op2 (s2 / show-01~e.28 :ARG1 (r2 / regulate-01~e.30 :ARG0 (a4 / and~e.25 :op1 (e4 / enzyme~e.54 :name (n4 / name :op1 "SIRT2"~e.24)) :op2 (e5 / enzyme~e.54 :name (n5 / name :op1 "HDAC6"~e.26)) :ARG2-of (d2 / deacetylate-01 :polarity -)) :ARG1 (l2 / level~e.32 :degree-of~e.33 (a5 / acetylate-01~e.34 :ARG1 (e3 / enzyme~e.54 :name (n8 / name :op1 "K-Ras"~e.36,38))))) :ARG0-of (s3 / suggest-01~e.49 :ARG1~e.50 (a7 / affect-01~e.58 :ARG0 (i2 / inhibit-01~e.51 :ARG1 a4) :ARG1 (p6 / possible-01~e.55 :ARG1~e.59 (c2 / cause-01~e.61 :ARG0~e.63 (t2 / tumor~e.68 :ARG2-of (m / mutate-01~e.64) :mod e3~e.65,66,67) :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.61)))) :ARG1-of (p5 / possible-01~e.55)))) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a6 / and~e.21,42 :op1 (p3 / person :name (n7 / name :op1 "Yang"~e.41)) :op2 (p4 / person :mod (o / other~e.43))) :time (d5 / date-entity :year 2013~e.45)))) # ::id pmid_2465_1010.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , nitrosylation of Cys118 in H @-@ Ras has been shown to activate Ras by enhancing nucleotide dissociation , leading to higher levels of GTP @-@ bound protein . # ::alignments 0-1.1 0-1.1.r 6-1.2.1.2.1.1 8-1.2.2.1.1 11-1 13-1.2 14-1.2.2.1.1 15-1.2.3.r 16-1.2.3 17-1.2.3.2.1 18-1.2.3.2 20-1.2.3.3 21-1.2.3.3.1.r 22-1.2.3.3.1.1 22-1.2.3.3.1.1.1 22-1.2.3.3.1.1.1.r 23-1.2.3.3.1 24-1.2.3.3.1.2.r 25-1.2.3.3.1.2.1.1.1.1 27-1.2.3.3.1.2.1 28-1.2.3.3.1.2 (s / show-01~e.11 :li~e.0 -1~e.0 :ARG1 (a / activate-01~e.13 :ARG0 (n3 / nitrosylate-01 :ARG1 (a2 / amino-acid :mod 118 :name (n6 / name :op1 "cysteine")) :location (e / enzyme :name (n / name :op1 "H-Ras"~e.6))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.8,14)) :manner~e.15 (e3 / enhance-01~e.16 :ARG0 n3 :ARG1 (d / dissociate-01~e.18 :ARG1 (n4 / nucleotide~e.17)) :ARG0-of (l / lead-03~e.20 :ARG2~e.21 (l2 / level~e.23 :ARG1-of (h / high-02~e.22 :degree~e.22 (m / more~e.22)) :degree-of~e.24 (p / protein~e.28 :ARG1-of (b / bind-01~e.27 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "GTP"~e.25))))))))) # ::id pmid_2465_1010.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The eNos protein was identified as a strong enhancer of nitrosylation and therefore could also be a therapeutic target to attack mutant Ras ( Lim et al. , 2008 ) . # ::alignments 1-1.1.1.1.1 2-1.1.1 4-1.1 5-1.3.1.2.r 7-1.1.2.3 11-1.3.1.1 12-1 13-1.2 14-1.2.1.3 17-1.2.1.1 18-1.2.1 20-1.2.1.4 21-1.2.1.4.2 21-1.2.1.4.2.2 21-1.2.1.4.2.2.r 22-1.2.1.4.2.1.1 25-1.3.1.1.1.1.1 26-1.3.1.1 27-1.3.1.1.2.1 29-1.3.1.2.1 (c / cause-01~e.12 :ARG0 (i / identify-01~e.4 :ARG1 (p2 / protein~e.2 :name (n2 / name :op1 "eNos"~e.1)) :ARG2 (e2 / enhance-01 :ARG1 (n3 / nitrosylate-01) :ARG2 p2 :ARG1-of (s / strong-02~e.7))) :ARG1 (p / possible-01~e.13 :ARG1 (t2 / target-01~e.18 :ARG0 (t / therapy~e.17) :ARG1 p2 :mod (a3 / also~e.14) :purpose (a / attack-01~e.20 :ARG0 p2 :ARG1 (e / enzyme~e.21 :name (n / name :op1 "Ras"~e.22) :ARG1-of~e.21 (m / mutate-01~e.21))))) :ARG0-of (d2 / describe-01 :ARG1 (p3 / publication-91 :ARG0 (a2 / and~e.11,26 :op1 (p4 / person :name (n4 / name :op1 "Lim"~e.25)) :op2 (p5 / person :mod (o / other~e.27))) :time~e.5 (d / date-entity :year 2008~e.29)))) # ::id pmid_2465_1010.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Downstream Pathways and Drug Targets # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1 4-1.2 (a / and~e.2 :op1 (p / pathway~e.1 :mod (d / downstream~e.0)) :op2 (t / target-01~e.4 :ARG0 (d2 / drug~e.3))) # ::id pmid_2465_1010.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok When it became clear that targeting mutant Ras proteins directly was technically impossible with the tools available at that time , the search for drugs that block Ras activity moved downstream . # ::alignments 0-1.3.r 3-1.3 4-1.3.1.2.3.1.1.1 5-1.3.1.2 6-1.3.1.2.1 6-1.3.1.2.1.2 6-1.3.1.2.1.2.r 7-1.3.1.2.1.1.1 9-1.3.1.2.2 11-1.3.1.3 12-1.3.1 12-1.3.1.1 12-1.3.1.1.r 13-1.3.1.2.3.r 15-1.3.1.2.3 16-1.3.1.2.3.1 18-1.3.1.2.3.1.1.1 19-1.3.1.2.3.1.1 19-1.3.1.2.3.1.1.r 19-1.3.r 22-1 23-1.1.r 24-1.1 25-1.3.1.2.3.1.1.1 26-1.1.1 27-1.1.1.1.1 28-1.1.1.1 29-1.2 30-1.2.1 (s / search-01~e.22 :ARG2~e.23 (d / drug~e.24 :ARG0-of (b / block-01~e.26 :ARG1 (a / activity-06~e.28 :ARG0 e~e.27))) :ARG0-of (m / move-01~e.29 :ARG2 (d2 / downstream~e.30)) :time~e.0,19 (c / clear-06~e.3 :ARG1 (p / possible-01~e.12 :polarity~e.12 -~e.12 :ARG1 (t / target-01~e.5 :ARG1 (e / enzyme~e.6 :name (n / name :op1 "Ras"~e.7) :ARG1-of~e.6 (m2 / mutate-01~e.6)) :ARG1-of (d3 / direct-02~e.9) :instrument~e.13 (t3 / tool~e.15 :ARG2-of (a2 / available-02~e.16 :time~e.19 (t4 / time~e.19 :mod (t5 / that~e.4,18,25))))) :mod (t2 / technical~e.11)))) # ::id pmid_2465_1010.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the early 1990 s , the MAPK pathway and the PI3K pathway were known to be downstream of Ras ( Figure 1 ) . # ::alignments 2-1.2 3-1.2.1.1 4-1.2.1.1.r 7-1.1.1.1.1.1 8-1.1.1.1 8-1.1.1.2 9-1.1.1 11-1.1.1.2.1.1 12-1.1.1.1 13-1.1 14-1 16-1.1 17-1.1.2.2 19-1.1.2.1.1.1 22-1.3.1 23-1.3.1.1 (k / know-01~e.14 :ARG1 (b / be-located-at-91~e.13,16 :ARG1 (a / and~e.9 :op1 (p / pathway~e.8,12 :name (n / name :op1 "MAPK"~e.7)) :op2 (p2 / pathway~e.8 :name (n3 / name :op1 "PI3K"~e.11))) :ARG2 (r / relative-position :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.19)) :direction (d3 / downstream~e.17))) :time (e / early~e.2 :op1 (d / date-entity :decade~e.4 1990~e.3)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.22 :mod 1~e.23))) # ::id pmid_2465_1010.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In 1993 , four groups showed that Ras binds directly to Raf kinase ( Moodie et al. , 1993 ; Van Aelst et al. , 1993 ; Warne et al. , 1993 ; Zhang et al. , 1993 ) , and later , activation of Raf kinase by Ras was achieved in vitro ( Stokoe and McCormick , 1997 ) . # ::alignments 0-1.2.3.1 1-1.1.3.1 1-1.1.4.1.1.2.1 3-1.1.1.1 4-1.1.1 5-1.1 6-1.1.2.r 7-1.1.2.1.1.1 8-1.1.2 9-1.1.2.3 10-1.1.2.2.r 11-1.1.2.2.1.1 12-1.1.2.2 15-1.1.4.1.1.1.1.1.1 16-1.1.4.1 16-1.1.4.1.1.1 16-1.1.4.1.2.1 16-1.1.4.1.3.1 16-1.1.4.1.4.1 17-1.1.4.1.1.1.2.1 17-1.1.4.1.2.1.2.1 17-1.1.4.1.3.1.2.1 17-1.1.4.1.4.1.2.1 19-1.1.4.1.1.2.1 21-1.1.4.1.2.1.1.1.1 22-1.1.4.1.2.1.1.1.2 23-1.1.4.1 23-1.1.4.1.1.1 23-1.1.4.1.2.1 23-1.1.4.1.3.1 23-1.1.4.1.4.1 24-1.1.4.1.1.1.2.1 24-1.1.4.1.2.1.2.1 24-1.1.4.1.3.1.2.1 24-1.1.4.1.4.1.2.1 26-1.1.4.1.3.2 28-1.1.4.1.3.1.1.1.1 29-1.1.4.1 29-1.1.4.1.1.1 29-1.1.4.1.2.1 29-1.1.4.1.3.1 29-1.1.4.1.4.1 30-1.1.4.1.1.1.2.1 30-1.1.4.1.2.1.2.1 30-1.1.4.1.3.1.2.1 30-1.1.4.1.4.1.2.1 32-1.1.4.1.4.2 34-1.1.4.1.4.1.1.1.1 35-1.1.4.1 35-1.1.4.1.1.1 35-1.1.4.1.2.1 35-1.1.4.1.3.1 35-1.1.4.1.4.1 36-1.1.4.1.1.1.2.1 36-1.1.4.1.2.1.2.1 36-1.1.4.1.3.1.2.1 36-1.1.4.1.4.1.2.1 38-1.1.3.1 42-1 42-1.1.4.1 42-1.2.5.1.1 43-1.2.4 43-1.2.4.1 43-1.2.4.1.r 45-1.2 47-1.1.2.2.1.1 48-1.1.2.2 50-1.1.2.1.1.1 52-1.2.3 53-1.2.3.1 54-1.2.3.1 57-1.2.5.1.1.1.1.1 58-1.2.5.1.1 59-1.2.5.1.1.2.1.1 61-1.2.5.1.2.1 (a / and~e.42 :op1 (s / show-01~e.5 :ARG0 (g / group~e.4 :quant 4~e.3) :ARG1~e.6 (b / bind-01~e.8 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.7,50)) :ARG1~e.10 (k / kinase~e.12,48 :name (n2 / name :op1 "Raf"~e.11,47)) :ARG1-of (d2 / direct-02~e.9)) :time (d / date-entity :year 1993~e.1,38) :ARG1-of (d3 / describe-01 :ARG0 (a5 / and~e.16,23,29,35,42 :op1 (p / publication-91 :ARG0 (a4 / and~e.16,23,29,35 :op1 (p2 / person :name (n3 / name :op1 "Moodie"~e.15)) :op2 (p3 / person :mod (o / other~e.17,24,30,36))) :time (d4 / date-entity :year 1993~e.1,19)) :op2 (p4 / publication-91 :ARG0 (a6 / and~e.16,23,29,35 :op1 (p5 / person :name (n4 / name :op1 "Van"~e.21 :op2 "Aelst"~e.22)) :op2 (p6 / person :mod (o2 / other~e.17,24,30,36))) :time d4) :op3 (p7 / publication-91 :ARG0 (a7 / and~e.16,23,29,35 :op1 (p8 / person :name (n5 / name :op1 "Warne"~e.28)) :op2 (p9 / person :mod (o3 / other~e.17,24,30,36))) :time d4~e.26) :op4 (p10 / publication-91 :ARG0 (a8 / and~e.16,23,29,35 :op1 (p11 / person :name (n6 / name :op1 "Zhang"~e.34)) :op2 (p12 / person :mod (o4 / other~e.17,24,30,36))) :time d4~e.32)))) :op2 (a2 / activate-01~e.45 :ARG0 e :ARG1 k :ARG1-of (a3 / achieve-01~e.52 :manner (i / in-vitro~e.0,53,54)) :time (l / late~e.43 :degree~e.43 (m / more~e.43)) :ARG1-of (d5 / describe-01 :ARG0 (p13 / publication-91 :ARG0 (a9 / and~e.42,58 :op1 (p14 / person :name (n7 / name :op1 "Stokoe"~e.57)) :op2 (p15 / person :name (n8 / name :op1 "McCormick"~e.59))) :time (d6 / date-entity :year 1997~e.61))))) # ::id pmid_2465_1010.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This was unexpectedly difficult ; for one thing , Raf activation by Ras required fully processed Ras in a lipid environment , and direct binding of unprocessed Ras failed to activate the kinase . # ::alignments 0-1.1.1 1-1.1.1.r 2-1.1.2.1 3-1.1 6-1.2.1 9-1.2.2.1.2.1.1 10-1.2.2.1 12-1.2.3.1.1.1.1 13-1.2.2 14-1.2.2.2.2 15-1.2.2.2 16-1.2.2.2.1 17-1.2.2.3.r 19-1.2.2.3.1 20-1.2.2.3 22-1.2 23-1.2.3.1.2 24-1.2.3.1 26-1.2.3.1.1.2 26-1.2.3.1.1.2.1 26-1.2.3.1.1.2.1.r 27-1.2.3.1.1.1.1 28-1.2.3 30-1.2.2.1 30-1.2.3.2 32-1.2.2.1.2 (m / multi-sentence :snt1 (d / difficult~e.3 :domain~e.1 (t / this~e.0) :ARG1-of (e3 / expect-01 :polarity -~e.2)) :snt2 (a3 / and~e.22 :li 1~e.6 :op1 (r / require-01~e.13 :ARG0 (a / activate-01~e.10,30 :ARG0 e2 :ARG1 (k / kinase~e.32 :name (n / name :op1 "Raf"~e.9))) :ARG1 (p / process-01~e.15 :ARG1 e2~e.16 :degree (f / full~e.14)) :location~e.17 (e4 / environment~e.20 :mod (l / lipid~e.19))) :op2 (f2 / fail-01~e.28 :ARG1 (b / bind-01~e.24 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.12,27) :ARG1-of (p2 / process-01~e.26 :polarity~e.26 -~e.26)) :ARG1-of (d2 / direct-02~e.23)) :ARG2 (a2 / activate-01~e.30 :ARG0 b :ARG1 k)))) # ::id pmid_2465_1010.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , autophosphorylation rapidly shut down Raf kinase in vitro ; we had to preincubate processed Ras with Raf in the absence of ATP before measuring Raf kinase activity . # ::alignments 0-1 0-1.1.2.2.2 2-1.1.1.2 3-1.1.1.3 3-1.1.1.3.r 4-1.1.1 5-1.1.1 6-1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.4 9-1.1.1.4 11-1.1.2.1 12-1.1.2 13-1.1.2 14-1.1.2.2 15-1.1.2.2.2.1.2 16-1.1.2.2.2.1.1.1 17-1.1.2.2.2.r 18-1.1.2.2.2.2 19-1.1.1.4 19-1.1.2.2.3.r 21-1.1.2.2.3 22-1.1.2.2.3.1.r 23-1.1.2.2.3.1.1.1 24-1.1.2.2.4 25-1.1.2.2.4.1 26-1.1.2.2.4.1.2.1 27-1.1.2.2.4.1.2.1 28-1.1.2.2.4.1.2 (a4 / and~e.0 :op2 (c / cause-01 :ARG0 (s2 / shut-down-05~e.4,5 :ARG1 (k / kinase~e.7 :name (n3 / name :op1 "Raf"~e.6)) :ARG2 (p / phosphorylate-01~e.2 :ARG1 k :ARG2 k) :manner~e.3 (r / rapid~e.3) :manner (i / in-vitro~e.8,9,19)) :ARG1 (o / obligate-01~e.12,13 :ARG1 (w / we~e.11) :ARG2 (p2 / preincubate-01~e.14 :ARG0 w :ARG1~e.17 (a / and~e.0 :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.16) :ARG1-of (p3 / process-01~e.15)) :op2 k~e.18) :condition~e.19 (a3 / absent-01~e.21 :ARG1~e.22 (s / small-molecule :name (n4 / name :op1 "ATP"~e.23))) :time (b / before~e.24 :op1 (m2 / measure-01~e.25 :ARG0 w :ARG1 (a2 / activity-06~e.28 :ARG0 k~e.26,27))))))) # ::id pmid_2465_1010.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This autophosphorylation accounts , at least in part , for paradoxical activation of Raf kinase by Raf inhibitors , a phenomenon that was discovered 16 years later ( reviewed in Holderfield et al. , 2013 ) . # ::alignments 0-1.1.2 1-1.1 2-1 4-1.3.1 5-1.3.1 6-1.3 7-1.3 11-1.2 12-1.2.2.r 13-1.2.2.1.1 14-1.2.2 16-1.2.2.1.1 17-1.2.1 17-1.2.1.1 17-1.2.1.1.r 23-1.4 24-1.4.1.1.1.1 25-1.4.1.1.1.2 26-1.4.1 26-1.4.1.1 26-1.4.1.1.r 28-1.5 31-1.5.1.1.1.1.1 32-1.5.1.1 33-1.5.1.1.2.1 35-1.5.1.2.1 (a4 / account-01~e.2 :ARG0 (p / phosphorylate-01~e.1 :mod (s / self) :mod (t3 / this~e.0)) :ARG1 (a2 / activate-01~e.11 :ARG0 (m2 / molecular-physical-entity~e.17 :ARG0-of~e.17 (i2 / inhibit-01~e.17 :ARG1 k)) :ARG1~e.12 (k / kinase~e.14 :name (n2 / name :op1 "Raf"~e.13,16)) :manner (p3 / paradox)) :extent (p7 / part~e.6,7 :mod (a / at-least~e.4,5)) :ARG1-of (d2 / discover-01~e.23 :mod (l / late~e.26 :degree~e.26 (m / more~e.26 :quant (t / temporal-quantity :quant 16~e.24 :unit (y / year~e.25))))) :ARG1-of (r / review-02~e.28 :ARG2 (p4 / publication-91 :ARG0 (a3 / and~e.32 :op1 (p5 / person :name (n3 / name :op1 "Holderfield"~e.31)) :op1 (p6 / person :mod (o / other~e.33))) :time (d / date-entity :year 2013~e.35)))) # ::id pmid_2465_1010.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These issues complicate the development of in vitro assays for compounds that prevent Ras @-@ dependent activation of Raf kinase , an obvious system for therapeutic intervention . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.2 5-1.2.1.r 6-1.2.1.2 7-1.2.1.2 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1 12-1.2.1.1.1 13-1.2.1.1.1.1.2.1.1.1 15-1.2.1.1.1.1.2 16-1.2.1.1.1.1 17-1.2.1.1.1.1.1.r 18-1.2.1.1.1.1.1.1.1 19-1.2.1.1.1.1.1 22-1.2.2.1 23-1.2.2 24-1.2.2.2.r 25-1.2.2.2.1 26-1.2.2.2 (c / complicate-01~e.2 :ARG0 (i / issue-02~e.1 :mod (t / this~e.0)) :ARG1 (d / develop-02~e.4 :ARG1~e.5 (a / assay-01~e.8 :ARG1~e.9 (c2 / compound~e.10 :ARG0-of (p / prevent-01~e.12 :ARG1 (a2 / activate-01~e.16 :ARG1~e.17 (k / kinase~e.19 :name (n / name :op1 "Raf"~e.18)) :ARG0-of (d2 / depend-01~e.15 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.13)))))) :manner (i2 / in-vitro~e.6,7)) :mod (s / system~e.23 :ARG1-of (o / obvious-01~e.22) :ARG0-of~e.24 (i3 / intervene-01~e.26 :ARG1 (t2 / therapy~e.25))))) # ::id pmid_2465_1010.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Direct blocking of Ras @-@ Raf binding with small molecules does not appear to be a promising approach because the binding surface ( two antiparallel β strands ) offers no foothold in which a compound could bind . # ::alignments 0-1.2.1.1.3 1-1.2.1.1 2-1.2.1.1.2.r 3-1.2.1.1.2.1.1.1 5-1.2.1.1.2.2.1.1 6-1.2.1.1.2 7-1.2.1.1.1.r 8-1.2.1.1.1 9-1.2.1.1.1 11-1.1 11-1.1.r 12-1 13-1.3 14-1.2.1.1.r 16-1.2 17-1.2.1 18-1.3 20-1.3.1.2 21-1.3.1.2.1 23-1.3.1.3.1.1.2.1.1 24-1.3.1.3.1.1.2.1.3 25-1.3.1.3.1.1.2.1.2.1 26-1.3.1.3.1.1.2.1 28-1.3.1 29-1.3.1.1 29-1.3.1.1.r 30-1.3.1.3 34-1.3.1.3.1.1.1 35-1.3.1.3.1 36-1.3.1.3.1.1 (a / appear-02~e.12 :polarity~e.11 -~e.11 :ARG1 (p2 / promise-01~e.16 :ARG2 (a2 / approach~e.17 :domain~e.14 (b / block-01~e.1 :ARG0~e.7 (s / small-molecule~e.8,9) :ARG1~e.2 (b2 / bind-01~e.6 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.3)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf"~e.5))) :ARG1-of (d / direct-02~e.0)))) :ARG1-of (c / cause-01~e.13,18 :ARG0 (o / offer-01~e.28 :polarity~e.29 -~e.29 :ARG0 (b4 / bind-01~e.20 :ARG3 (s2 / surface~e.21)) :ARG1 (f / foothold~e.30 :location-of (p3 / possible-01~e.35 :ARG1 (b3 / bind-01~e.36 :ARG1 (c3 / compound~e.34) :ARG1-of (m / mean-01 :ARG2 (s3 / strand~e.26 :quant 2~e.23 :name (n3 / name :op1 "β"~e.25) :mod (a3 / antiparallel~e.24))))))))) # ::id pmid_2465_1010.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , for example , preventing binding using peptides or by indirect allosteric approaches has been considered ( see Wu et al. , 2013 ) . # ::alignments 0-1 2-1.1 3-1.1 5-1.1.1.1 6-1.1.1.1.1 7-1.1.1.1.2.1 8-1.1.1.1.2.1.1 9-1.1.1.1.2 10-1.1.1.1.2.r 11-1.1.1.1.2.2.1.1 12-1.1.1.1.2.2.1.2 13-1.1.1.1.2.2 16-1.1.1 18-1.2 20-1.2.1.1.1.1.1 21-1.2.1.1 22-1.2.1.1.2.1 24-1.2.1.2.1 (h2 / have-concession-91~e.0 :ARG1 (e2 / exemplify-01~e.2,3 :ARG0 (c2 / consider-01~e.16 :ARG1 (p / prevent-01~e.5 :ARG1 (b / bind-01~e.6) :manner~e.10 (o3 / or~e.9 :op1 (u / use-01~e.7 :ARG1 (p5 / peptide~e.8)) :op2 (a / approach-02~e.13 :ARG0 (m2 / molecular-physical-entity :mod (i / indirect~e.11) :mod (a3 / allosteric~e.12))))))) :ARG1-of (s / see-01~e.18 :location (p2 / publication-91 :ARG0 (a2 / and~e.21 :op1 (p3 / person :name (n3 / name :op1 "Wu"~e.20)) :op2 (p4 / person :mod (o2 / other~e.22))) :time (d / date-entity :year 2013~e.24)))) # ::id pmid_2465_1010.193 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The drug discovery group at Onyx Pharmaceuticals began screening for Raf kinase inhibitors in 1992 after it was able produce active c @-@ Raf kinase in baculovirus ( by coinfection with v @-@ Src ) and to reconstitute the MAPK pathway in vitro ( Macdonald et al. , 1993 ) . # ::alignments 1-1.1.1.2.1 2-1.1.1.2 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.1.1.2 7-1 8-1.1 9-1.1.2.r 10-1.1.2.1.1.1.1 11-1.1.2.1.1 12-1.1.2 12-1.1.2.1 12-1.1.2.1.r 13-1.1.3.r 13-1.1.4.1.2.2.3 14-1.1.3.1 15-1.1.4 18-1.1.4.1 19-1.1.4.1.2.1 20-1.1.4.1.2.1.2 20-1.1.4.1.2.1.2.2 20-1.1.4.1.2.1.2.2.r 21-1.1.4.1.2.1.2.1.1 23-1.1.2.1.1.1.1 24-1.1.2.1.1 25-1.1.4.1.2.1.4.r 25-1.1.4.1.2.2.3 26-1.1.4.1.2.1.4.1.1 31-1.1.4.1.2.1.3.1.1.1 33-1.1.4.1.2.1.3.1.1.1 35-1.1.4.1.2 37-1.1.4.1.2.2 39-1.1.4.1.2.2.2.1.1 40-1.1.4.1.2.2.2 41-1.1.4.1.2.2.3 42-1.1.4.1.2.2.3 45-1.2.1.1.1.1.1 46-1.2.1.1 47-1.2.1.1.2.1 49-1.2.2.1 (b / begin-01~e.7 :ARG1 (s / screen-01~e.8 :ARG0 (g / group~e.3 :part-of~e.4 (c / company :name (n5 / name :op1 "Onyx"~e.5 :op2 "Pharmaceuticals"~e.6)) :ARG0-of (d3 / discover-01~e.2 :ARG1 (d4 / drug~e.1))) :ARG1~e.9 (m / molecular-physical-entity~e.12 :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (k / kinase~e.11,24 :name (n4 / name :op1 "Raf"~e.10,23)))) :time~e.13 (d / date-entity :year 1992~e.14) :time (a / after~e.15 :op1 (c2 / capable-01~e.18 :ARG1 g :ARG2 (a4 / and~e.35 :op1 (p / produce-01~e.19 :ARG0 g :ARG1 (e2 / enzyme~e.20 :name (n2 / name :op1 "c-Raf"~e.21) :ARG0-of~e.20 (a2 / activity-06~e.20)) :manner (c3 / coinfect-00 :ARG0 (e3 / enzyme :name (n7 / name :op1 "v-Src"~e.31,33))) :location~e.25 (o / organism :name (n3 / name :op1 "baculovirus"~e.26))) :op2 (r / reconstitute-01~e.37 :ARG0 g :ARG1 (p2 / pathway~e.40 :name (n / name :op1 "MAPK"~e.39)) :manner (i3 / in-vitro~e.13,25,41,42)))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and~e.46 :op1 (p4 / person :name (n6 / name :op1 "Macdonald"~e.45)) :op2 (p5 / person :mod (o2 / other~e.47)))) :time (d5 / date-entity :year 1993~e.49))) # ::id pmid_2465_1010.194 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It was then assumed that in cancer cells with mutant Ras , the Raf @/@ MAPK pathway would be hyperactive and that drugs that inhibit Raf would be effective ways of treating Ras mutant cancers . # ::alignments 2-1.3 3-1 6-1.1.2.2.2.1 6-1.2.1.2.1 7-1.2 9-1.1.2.2.3 9-1.2.2.1 10-1.1.2.2.3.1.1.1 13-1.1.1.1.1.1 15-1.1.1.1.1.2 16-1.1.1.1 18-1.1.1.1.r 19-1.1.1 20-1.1 22-1.1.2.1 24-1.1.2.1.1 25-1.1.2.1.1.1.1.1 28-1.1.2.3 31-1.1.2 32-1.1.2.2.3.1.1.1 33-1.1.2.2.3 33-1.2.2.1 (a / assume-02~e.3 :ARG1 (a2 / and~e.20 :op1 (h / hyperactive~e.19 :domain~e.18 (p / pathway~e.16 :name (n4 / name :op1 "Raf"~e.13 :op2 "MAPK"~e.15))) :op2 (t / treat-04~e.31 :ARG0 (d2 / drug~e.22 :ARG0-of (i / inhibit-01~e.24 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Raf"~e.25)))) :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.6) :mod (m / mutate-01~e.9,33 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.10,32))) :ARG0-of (h3 / have-03 :ARG1 m2)) :ARG1-of (e3 / effective-04~e.28))) :location (c / cell~e.7 :mod (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"~e.6)) :ARG0-of (h2 / have-03 :ARG1 (m2 / mutate-01~e.9,33 :ARG1 e))) :time (t2 / then~e.2)) # ::id pmid_2465_1010.195 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It was also assumed that MEK and extracellular signal @-@ regulated kinase ( ERK ) inhibitors would have the same effect . # ::alignments 2-1.2 3-1 5-1.1.1.1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.1.2.1.1.1.1 8-1.1.1.1.2.1.1.1.2 10-1.1.1.1.2.1.1.1.2 11-1.1.1.1.2.1.1.1.3 15-1.1.1.1.1 15-1.1.1.1.1.1 15-1.1.1.1.1.1.r 15-1.1.1.1.2 15-1.1.1.1.2.1 15-1.1.1.1.2.1.r 19-1.1.1.2 20-1.1.1 (a / assume-02~e.3 :ARG1 (p / possible-01 :ARG1 (a2 / affect-01~e.20 :ARG0 (a3 / and~e.6 :op1 (m / molecular-physical-entity~e.15 :ARG0-of~e.15 (i2 / inhibit-01~e.15 :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"~e.5)))) :op2 (m2 / molecular-physical-entity~e.15 :ARG0-of~e.15 (i / inhibit-01~e.15 :ARG1 (p2 / protein-family :name (n2 / name :op1 "extracellular"~e.7 :op2 "signal-regulated"~e.8,10 :op3 "kinase"~e.11))))) :ARG1-of (s / same-01~e.19))) :mod (a4 / also~e.2)) # ::id pmid_2465_1010.196 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In hindsight , most of the assumptions were incorrect : the Raf @/@ MAPK pathway is not often hyperactive in human cancer cells with mutant Ras , as measured by steady @-@ state levels of phospho @-@ MEK or phospho @-@ ERK . # ::alignments 0-1.3.r 1-1.3 3-1.2.1 4-1.2.1.r 6-1.2 7-1.2.2.2.r 8-1 8-1.1 8-1.1.r 11-1.2.2.2.1.1 13-1.2.2.2.1.2 14-1.2.2.2 15-1.2.2.2.r 16-1.2.2.1.1 16-1.2.2.1.1.r 17-1.2.2.1 18-1.2.2 19-1.2.2.3.r 19-1.3.r 20-1.2.2.3.1.3 21-1.2.2.3.1.2.1 22-1.2.2.3 23-1.2.2.3.2.r 24-1.2.2.3.2 24-1.2.2.3.2.2 24-1.2.2.3.2.2.r 25-1.2.2.3.2.1.1 27-1.2.2.4.r 28-1.2.2.4 29-1.2.2.4.1.r 30-1.2.2.4.1.2 32-1.2.2.4.1.2.1 33-1.2.2.4.1 34-1.2.2.4.1.1.r 35-1.2.2.4.1.1.1 37-1.2.2.4.1.1.1.1.1.1 38-1.2.2.4.1.1 39-1.2.2.4.1.1.1 39-1.2.2.4.1.1.2 41-1.2.2.4.1.1.2.1.1.1 (c2 / correct-02~e.8 :polarity~e.8 -~e.8 :ARG1 (a / assume-02~e.6 :quant~e.4 (m / most~e.3) :example (h / hyperactive~e.18 :frequency (o / often~e.17 :polarity~e.16 -~e.16) :domain~e.7,15 (p / pathway~e.14 :name (n3 / name :op1 "Raf"~e.11 :op2 "MAPK"~e.13)) :location~e.19 (c / cell~e.22 :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.21) :mod (h2 / human~e.20)) :prep-with~e.23 (e / enzyme~e.24 :name (n2 / name :op1 "Ras"~e.25) :ARG1-of~e.24 (m3 / mutate-01~e.24))) :ARG1-of~e.27 (m2 / measure-01~e.28 :ARG2~e.29 (l / level~e.33 :degree-of~e.34 (o2 / or~e.38 :op1 (p2 / phosphorylate-01~e.35,39 :ARG2 (e4 / enzyme :name (n4 / name :op1 "MEK"~e.37))) :op2 (p3 / phosphorylate-01~e.39 :ARG2 (e3 / enzyme :name (n5 / name :op1 "ERK"~e.41)))) :ARG1-of (s / steady-01~e.30 :mod (s2 / state~e.32)))))) :prep-in~e.0,19 (h3 / hindsight~e.1)) # ::id pmid_2465_1010.197 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Raf inhibitors lead to paradoxical activation of Raf kinase following exposure to Raf inhibitors , especially in Ras mutant cancers ( reviewed in Lito et al. , 2013 ) . # ::alignments 0-1.1.1.1.1.1 1-1.1 1-1.1.1 1-1.1.1.r 2-1 5-1.2 6-1.2.1.r 7-1.2.1 8-1.2.1 9-1.5 10-1.5.1 11-1.5.1.1.r 12-1.5.1.1 13-1.5.1.1 15-1.3.4 17-1.3.3.1.1.1 18-1.3.3 19-1.3.2.1 21-1.4 24-1.4.1.1.1.1.1 25-1.4.1.1 26-1.4.1.1.2.1 28-1.4.1.2.1 (l / lead-03~e.2 :ARG0 (m2 / molecular-physical-entity~e.1 :ARG0-of~e.1 (i2 / inhibit-01~e.1 :ARG1 (k2 / kinase :name (n6 / name :op1 "Raf"~e.0)))) :ARG2 (a / activate-01~e.5 :ARG1~e.6 k2~e.7,8 :manner (p / paradox)) :location (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.19) :mod (m / mutate-01~e.18 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.17))) :mod (e2 / especially~e.15)) :ARG1-of (r / review-02~e.21 :ARG2 (p3 / publication-91 :ARG0 (a2 / and~e.25 :op1 (p4 / person :name (n5 / name :op1 "Lito"~e.24)) :op2 (p5 / person :mod (o / other~e.26))) :time (d / date-entity :year 2013~e.28))) :time (f / follow-01~e.9 :ARG2 (e3 / expose-01~e.10 :ARG2~e.11 m2~e.12,13))) # ::id pmid_2465_1010.198 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK and ERK inhibitors do not show paradoxical activation but are generally ineffective on their own because they relieve feedback inhibition on upstream kinases , leading to activation of PI3K , among other effects ( Mirzoeva et al. , 2009 ; Corcoran et al. , 2012 ; Turke et al. , 2012 ; Montero @-@ Conde et al. , 2013 ) , and because they lack a clear therapeutic window . # ::alignments 0-1.1.2.1.1.1.1.1 1-1.1.2.1.1 2-1.1.2.1.1.2.1.1 3-1.1.2 3-1.1.2.1 3-1.1.2.1.r 5-1.1.1 5-1.1.1.r 6-1.1 8-1.1.3 9-1 11-1.2.4 12-1.2 12-1.2.1 12-1.2.1.r 13-1.2.3 14-1.2.3 15-1.2.3 16-1.2.5 17-1.2.5.1.1.1 18-1.2.5.1.1 19-1.2.5.1.1.2.1 20-1.2.5.1.1.2 21-1.2.5.1.1.3.r 22-1.2.5.1.1.3.1 23-1.2.5.1.1.3 25-1.2.5.1.1.4 26-1.2.5.1.1.4.1.r 27-1.2.5.1.1.4.1 28-1.2.5.1.1.4.1.1.r 29-1.2.5.1.1.4.1.1.1.1 31-1.2.5.1.1.4.1.2 32-1.2.5.1.1.4.1.2.1.1 33-1.2.5.1.1.4.1.2.1 36-1.2.5.1.1.5.1.1.1.1.1.1 37-1.2.5.1.1.5.1.1.1 38-1.2.5.1.1.5.1.1.1.2.1 40-1.2.5.1.1.5.1.1.2.1 42-1.2.5.1.1.5.1.2.1.1.1.1 43-1.2.5.1.1.5.1 43-1.2.5.1.1.5.1.2.1 43-1.2.5.1.1.5.1.3.1 43-1.2.5.1.1.5.1.4.1 44-1.2.5.1.1.5.1.1.1.2.1 46-1.2.5.1.1.5.1.3.2 48-1.2.5.1.1.5.1.3.1.1.1.1 49-1.2.5.1.1.5.1 49-1.2.5.1.1.5.1.2.1 49-1.2.5.1.1.5.1.3.1 49-1.2.5.1.1.5.1.4.1 50-1.2.5.1.1.5.1.1.1.2.1 52-1.2.5.1.1.5.1.2.2.1 54-1.2.5.1.1.5.1.4.1.1.1.1 56-1.2.5.1.1.5.1.4.1.1.1.1 57-1.2.5.1.1.5.1 57-1.2.5.1.1.5.1.3.1 57-1.2.5.1.1.5.1.4.1 58-1.2.5.1.1.5.1.1.1.2.1 60-1.2.5.1.1.5.1.4.2.1 64-1.2.5.1 64-1.2.5.1.1.5.1 65-1.2.5 66-1.2.5.1.2.1 67-1.2.5.1.2 69-1.2.5.1.2.2.1 70-1.2.5.1.2.2.2 71-1.2.5.1.2.2 (c / contrast-01~e.9 :ARG1 (s / show-01~e.6 :polarity~e.5 -~e.5 :ARG0 (m / molecular-physical-entity~e.3 :ARG0-of~e.3 (i / inhibit-01~e.3 :ARG1 (a2 / and~e.1 :op1 (p11 / protein-family :name (n / name :op1 "MEK"~e.0)) :op2 (p12 / protein-family :name (n2 / name :op1 "ERK"~e.2))))) :ARG1 (a / activate-01~e.8 :mod (p / paradox))) :ARG2 (e / effective-04~e.12 :polarity~e.12 -~e.12 :ARG0 m :mod (b / by-oneself~e.13,14,15) :ARG1-of (g / general-02~e.11) :ARG1-of (c2 / cause-01~e.16,65 :ARG0 (a5 / and~e.64 :op1 (r / relieve-01~e.18 :ARG0 m~e.17 :ARG1 (i2 / inhibit-01~e.20 :subevent-of (f / feedback~e.19)) :ARG2~e.21 (k / kinase~e.23 :location (u / upstream~e.22)) :ARG0-of (l / lead-03~e.25 :ARG2~e.26 (a3 / activate-01~e.27 :ARG1~e.28 (e4 / enzyme :name (n3 / name :op1 "PI3K"~e.29)) :ARG1-of (i3 / include-91~e.31 :ARG2 (a4 / affect-01~e.33 :mod (o / other~e.32))))) :ARG1-of (d2 / describe-01 :ARG0 (a6 / and~e.43,49,57,64 :op1 (p2 / publication-91 :ARG0 (a7 / and~e.37 :op1 (p6 / person :name (n4 / name :op1 "Mirzoeva"~e.36)) :op2 (p7 / person :mod (o2 / other~e.38,44,50,58))) :time (d3 / date-entity :year 2009~e.40)) :op2 (p3 / publication-91 :ARG0 (a8 / and~e.43,49 :op1 (p8 / person :name (n5 / name :op1 "Corcoran"~e.42)) :op2 p7) :time (d4 / date-entity :year 2012~e.52)) :op3 (p4 / publication-91 :ARG0 (a9 / and~e.43,49,57 :op1 (p9 / person :name (n6 / name :op1 "Turke"~e.48)) :op2 p7) :time d4~e.46) :op4 (p5 / publication-91 :ARG0 (a10 / and~e.43,49,57 :op1 (p10 / person :name (n7 / name :op1 "Montero-Conde"~e.54,56)) :op2 p7) :time (d5 / date-entity :year 2013~e.60))))) :op2 (l2 / lack-01~e.67 :ARG0 m~e.66 :ARG1 (w / window~e.71 :ARG1-of (c3 / clear-06~e.69) :mod (t / therapy~e.70))))))) # ::id pmid_2465_1010.199 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK1 @/@ MEK2 isoforms have a high degree of amino acid identity , suggesting redundant roles in signaling . # ::alignments 0-1.1.1.1.1.1 1-1.1 2-1.1.2.1.1.1 3-1.1.1 3-1.1.2 6-1.3 9-1.2 10-1.2 13-1.4 14-1.4.1.3 17-1.4.1.2 (i4 / identical-01 :ARG1 (s / slash~e.1 :op1 (i / isoform~e.3 :mod (e / enzyme :name (n / name :op1 "MEK1"~e.0))) :op2 (i3 / isoform~e.3 :mod (e2 / enzyme :name (n2 / name :op1 "MEK2"~e.2)))) :ARG2 (a / amino-acid~e.9,10) :ARG1-of (h / high-02~e.6) :ARG0-of (s2 / suggest-01~e.13 :ARG1 (p / play-08 :ARG0 s :ARG1 (s3 / signal-07~e.17) :mod (r / redundant~e.14)))) # ::id pmid_2465_1010.200 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The same is true for ERK1/ERK2 . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 3-1 (t / true-01~e.3 :ARG1 (t2 / thing~e.1 :ARG1-of~e.1 (s / same-01~e.1)) :ARG2 (s2 / slash :op1 (e / enzyme :name (n / name :op1 "ERK1")) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2")))) # ::id pmid_2465_1010.201 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , knocking out the gene encoding MEK1 , Map2k1 ( Giroux et al. , 1999 ) , or the gene encoding ERK2 , Mapk1 ( Hatano et al. , 2003 ; Saba @-@ El @-@ Leil et al. , 2003 ; Yao et al. , 2003 ) , is embryonic lethal , indicating a requirement for signaling from a particular isoform , at least in the context of embryogenesis . # ::alignments 0-1 2-1.1.1 3-1.1.1 5-1.1.1.1.1 6-1.1.1.1.1.2 7-1.1.1.1.1.2.1.1.1 10-1.1.1.1.1.1.1 14-1.1.1.1.1.3.1.1.1.1.1 15-1.1.1.1.1.3.1.1 16-1.1.1.1.1.3.1.1.2.1 18-1.1.1.1.1.3.1.2.1 22-1.1.1.1 24-1.1.1.1.1 24-1.1.1.1.2 25-1.1.1.1.1.2 25-1.1.1.1.2.2 26-1.1.1.1.2.2.1.1.1 29-1.1.1.1.2.1.1 33-1.1.1.1.2.3.1.1.1.1.1.1 34-1.1.1.1.1.3.1.1 34-1.1.1.1.2.3.1 34-1.1.1.1.2.3.1.1.1 34-1.1.1.1.2.3.1.2.1 34-1.1.1.1.2.3.1.3.1 35-1.1.1.1.1.3.1.1.2.1 37-1.1.1.1.2.3.1.2.2 39-1.1.1.1.2.3.1.2.1.1.1.1 41-1.1.1.1.2.3.1.2.1.1.1.1 43-1.1.1.1.2.3.1.2.1.1.1.1 44-1.1.1.1.1.3.1.1 44-1.1.1.1.2.3.1 44-1.1.1.1.2.3.1.1.1 44-1.1.1.1.2.3.1.2.1 44-1.1.1.1.2.3.1.3.1 45-1.1.1.1.1.3.1.1.2.1 47-1.1.1.1.2.3.1.3.2 49-1.1.1.1.2.3.1.3.1.1.1.1 50-1.1.1.1.1.3.1.1 50-1.1.1.1.2.3.1 50-1.1.1.1.2.3.1.1.1 50-1.1.1.1.2.3.1.2.1 50-1.1.1.1.2.3.1.3.1 51-1.1.1.1.1.3.1.1.2.1 53-1.1.1.1.2.3.1.1.2.1 58-1.1.2.1 61-1.1.3 63-1.1.3.1 64-1.1.3.1.1.r 65-1.1.3.1.1 66-1.1.3.1.2.r 68-1.1.3.1.2.1 69-1.1.3.1.2 71-1.1.3.1.3.1 72-1.1.3.1.3.1 77-1.1.3.1.3 (c2 / contrast-01~e.0 :ARG2 (c / cause-01 :ARG0 (k / knock-out-03~e.2,3 :ARG1 (o / or~e.22 :op1 (g / gene~e.5,24 :name (n / name :op1 "Map2k1"~e.10) :ARG0-of (e / encode-01~e.6,25 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1"~e.7))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and~e.15,34,44,50 :op1 (p4 / person :name (n5 / name :op1 "Giroux"~e.14)) :op2 (p3 / person :mod (o2 / other~e.16,35,45,51))) :time (d3 / date-entity :year 1999~e.18)))) :op2 (g2 / gene~e.24 :name (n3 / name :op1 "Mapk1"~e.29) :ARG0-of (e3 / encode-01~e.25 :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK2"~e.26))) :ARG1-of (d4 / describe-01 :ARG0 (a3 / and~e.34,44,50 :op1 (p5 / publication-91 :ARG0 (a4 / and~e.34,44,50 :op1 (p8 / person :name (n6 / name :op1 "Hatano"~e.33)) :op2 p3) :time (d5 / date-entity :year 2003~e.53)) :op2 (p6 / publication-91 :ARG0 (a5 / and~e.34,44,50 :op1 (p9 / person :name (n7 / name :op1 "Saba-El-Leil"~e.39,41,43)) :op2 p3) :time d5~e.37) :op3 (p7 / publication-91 :ARG0 (a6 / and~e.34,44,50 :op1 (p10 / person :name (n8 / name :op1 "Yao"~e.49)) :op2 p3) :time d5~e.47)))))) :ARG1 (d / die-01 :ARG1 (e5 / embryo~e.58)) :ARG0-of (i / indicate-01~e.61 :ARG1 (r / require-01~e.63 :ARG1~e.64 (s / signal-07~e.65 :ARG0 i2) :ARG2~e.66 (i2 / isoform~e.69 :mod (p / particular~e.68)) :condition (e6 / embryogenesis~e.77 :mod (a / at-least~e.71,72)))))) # ::id pmid_2465_1010.202 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although Map2k2 @ ^{−/− @} ( MEK2 null ) and Mapk3 @ ^{−/− @} ( ERK1 null ) mice are viable , in vivo ablation of MEK1 in a Map2k2 @ ^{−/− @} background ( Scholl et al. , 2007 ; Blasco et al. , 2011 ) or ERK2 in a Mapk3 @ ^{−/− @} background ( Chan et al. , 2013 ) results in apoptosis and lethality in adult mice . # ::alignments 0-1 10-1.2.1.1.1.2.2.1.1 13-1.2.1 23-1.2.1.2.1.2.2.1.1 26-1.2.1.1 27-1.2.1.r 28-1.2 30-1.1.1.1.2 31-1.1.1.1.2 32-1.1.1.1 32-1.1.1.2 33-1.1.1.1.1.r 34-1.1.1.1.1.1.1 35-1.1.1.1.2 45-1.1.1.1.3 45-1.1.1.2.3 48-1.1.1.1.4.1.1.1.1.1.1 49-1.1.1.1.4.1.1.1 50-1.1.1.1.4.1.1.1.2.1 52-1.1.1.1.4.1.1.2.1 54-1.1.1.1.4.1.2.1.1.1.1 55-1.1.1.1.4.1 55-1.1.1.1.4.1.1.1 55-1.1.1.1.4.1.2.1 56-1.1.1.1.4.1.1.1.2.1 58-1.1.1.1.4.1.2.2.1 61-1.1.1 62-1.1.1.2.1.1.1 63-1.1.1.2.2 73-1.1.1.1.3 76-1.1.1.2.4.1.1.1.1.1 77-1.1.1.1.4.1 77-1.1.1.1.4.1.1.1 77-1.1.1.2.4.1.1 78-1.1.1.1.4.1.1.1.2.1 80-1.1.1.2.4.1.2.1 83-1.1 84-1.1.1.1.2 84-1.1.2.r 85-1.1.2.1 86-1.1.1.1.4.1 86-1.1.1.1.4.1.1.1 86-1.1.2 88-1.1.1.1.2 89-1.1.2.2.1.1 90-1.1.2.2.1 90-1.2.1.2 (h / have-concession-91~e.0 :ARG1 (r / result-01~e.83 :ARG1 (o / or~e.61 :op1 (a2 / ablate-01~e.32 :ARG1~e.33 (e3 / enzyme :name (n7 / name :op1 "MEK1"~e.34)) :manner (i / in-vivo~e.30,31,35,84,88) :location (b / background~e.45,73 :mod g) :ARG1-of (d / describe-01 :ARG0 (a6 / and~e.55,77,86 :op1 (p / publication-91 :ARG0 (a7 / and~e.49,55,77,86 :op1 (p3 / person :name (n9 / name :op1 "Scholl"~e.48)) :op2 (p4 / person :mod (o2 / other~e.50,56,78))) :time (d2 / date-entity :year 2007~e.52)) :op2 (p2 / publication-91 :ARG0 (a8 / and~e.55 :op1 (p5 / person :name (n10 / name :op1 "Blasco"~e.54)) :op2 p4) :time (d3 / date-entity :year 2011~e.58))))) :op2 (a3 / ablate-01~e.32 :ARG1 (e4 / enzyme :name (n8 / name :op1 "ERK2"~e.62)) :manner i~e.63 :location (b2 / background~e.45 :mod g2) :ARG1-of (d4 / describe-01 :ARG0 (p7 / publication-91 :ARG0 (a9 / and~e.77 :op1 (p8 / person :name (n11 / name :op1 "Chan"~e.76)) :op2 p4) :time (d5 / date-entity :year 2013~e.80))))) :ARG2~e.84 (a4 / and~e.86 :op1 (a5 / apoptosis~e.85 :mod m5) :op2 (d6 / die-01 :ARG1 (m5 / mouse~e.90 :mod (a10 / adult~e.89))))) :ARG2 (v / viable~e.28 :domain~e.27 (a / and~e.13 :op1 (m / mouse~e.26 :mod (g / gene :name (n / name :op1 "Map2k2−/−") :ARG1-of (e5 / express-03 :polarity - :ARG2 (e / enzyme :name (n3 / name :op1 "MEK2"~e.10))))) :op2 (m2 / mouse~e.90 :mod (g2 / gene :name (n2 / name :op1 "Mapk3−/−") :ARG1-of (e6 / express-03 :polarity - :ARG2 (e2 / enzyme :name (n5 / name :op1 "ERK1"~e.23)))))))) # ::id pmid_2465_1010.203 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This may suggest a limited therapeutic window for any pan inhibitor of these kinases , and the clinical toxicity of potential drugs in this target class bears this out . # ::alignments 0-1.2.2 1-1.2.2 2-1.2.2 3-1.2.2 4-1.2.2 5-1.2.2 6-1.2.2 7-1.2.2 8-1.2.2 9-1.2.2 10-1.2.2 11-1.2.2 12-1.2.2 13-1.2.2 15-1 17-1.2.1.1 20-1.2.1.2.1 21-1.2.1.2 23-1.1.1.2.3.2.1.1 24-1.2.1.2.2.1.1 25-1.2.1.2.2.1 26-1.2 27-1.2.2 28-1.2 (a / and~e.15 :op1 (p / possible-01 :ARG1 (s / suggest-01 :ARG0 (t / this) :ARG1 (w / window :mod (t2 / therapy) :ARG1-of (l / limit-01) :poss (m / molecular-physical-entity :mod (p2 / pan) :ARG0-of (i / inhibit-01 :ARG1 (k / kinase :mod (t3 / this~e.23))))))) :op2 (b / bear-out-05~e.26,28 :ARG0 (t4 / toxic :mod (c / clinic~e.17) :domain (d / drug~e.21 :mod (p3 / potential~e.20) :ARG1-of (i2 / include-91 :ARG2 (c2 / class~e.25 :ARG1-of (t5 / target-01~e.24))))) :ARG1 p~e.0,1,2,3,4,5,6,7,8,9,10,11,12,13,27)) # ::id pmid_2465_1010.204 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Onyx @/@ Bayer screen for c @-@ Raf inhibitors led to the discovery and development of sorafenib . # ::alignments 1-1.1.1.1.1.1 2-1.1.1 3-1.1.1.2.1.1 4-1.1 8-1.1.2.1.1.1.1 9-1.1.2 9-1.1.2.1 9-1.1.2.1.r 10-1 11-1.2.r 13-1.2.1 14-1.2 15-1.2.2 16-1.2.1.1.r 17-1.2.1.1.1.1 (l / lead-03~e.10 :ARG0 (s / screen-01~e.4 :ARG0 (s2 / slash~e.2 :op1 (c / company :name (n / name :op1 "Onyx"~e.1)) :op2 (c2 / company :name (n2 / name :op1 "Bayer"~e.3))) :ARG2 (m / molecular-physical-entity~e.9 :ARG0-of~e.9 (i / inhibit-01~e.9 :ARG1 (e / enzyme :name (n3 / name :op1 "C-Raf"~e.8))))) :ARG2~e.11 (a / and~e.14 :op1 (d / discover-01~e.13 :ARG1~e.16 (s3 / small-molecule :name (n4 / name :op1 "sorafenib"~e.17))) :op2 (d2 / develop-02~e.15 :ARG1 s3))) # ::id pmid_2465_1010.205 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , it was disappointing when sorafenib failed to show clinical benefit in early clinical trials against Ras mutant cancers , and this lack of response was difficult to understand because sorafenib does indeed inhibit Raf kinase . # ::alignments 0-1 3-1.1.2.1.r 4-1.1.1 5-1.1.1.1.4.2.r 5-1.1.1.1.4.r 6-1.1.1.1.2.2.1 9-1.1.1.1 10-1.1.1.1.3.2 11-1.1.1.1.3 13-1.1.1.1.4.2 14-1.1.1.1.4.1 15-1.1.1.1.4 16-1.1.1.1.4.3 17-1.1.1.1.4.3.1.3.2.1 18-1.1.1.1.4.3.1.3 18-1.1.1.1.4.3.1.3.3 18-1.1.1.1.4.3.1.3.3.r 19-1.1.1.1.4.3.1.2.1 21-1.1 22-1.1.2.1.1.2 23-1.1.2.1.1 24-1.1.2.1.1.1.r 25-1.1.2.1.1.1 26-1.1.2.1.r 27-1.1.2 28-1.1.2.1 28-1.1.2.2 29-1.1.2.1 30-1.1.2.2 31-1.1.2.2.1.1 33-1.1.2.2.1.3 34-1.1.2.2.1 35-1.1.2.2.1.2.2.1 36-1.1.2.2.1.2 (h / have-concession-91~e.0 :ARG1 (a / and~e.21 :op1 (d / disappoint-01~e.4 :ARG0 (s2 / show-01~e.9 :polarity - :ARG0 (s3 / small-molecule :wiki "Sorafenib" :name (n / name :op1 "sorafenib"~e.6)) :ARG1 (b / benefit-01~e.11 :ARG0 s3 :mod (c / clinic~e.10)) :time~e.5 (t / trial-06~e.15 :mod c~e.14 :time~e.5 (e / early~e.13) :purpose (c2 / counter-01~e.16 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.19) :mod (e2 / enzyme~e.18 :wiki "Ras_subfamily" :name (n2 / name :op1 "Ras"~e.17) :ARG2-of~e.18 (m / mutate-01~e.18))))))) :op2 (d2 / difficult~e.27 :domain~e.3,26 (u / understand-01~e.28,29 :ARG1 (l / lack-01~e.23 :ARG1~e.24 (r / respond-01~e.25) :mod (t2 / this~e.22))) :ARG1-of (c3 / cause-01~e.28,30 :ARG0 (i / inhibit-01~e.34 :ARG0 s3~e.31 :ARG1 (k / kinase~e.36 :wiki "RAF_kinase" :name (n3 / name :op1 "Raf"~e.35)) :mod (i2 / indeed~e.33)))))) # ::id pmid_2465_1010.206 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite this , sorafenib and fluoro @-@ sorafenib ( regorafenib ) have since been approved for the treatment of renal cell carcinoma , hepatocellular carcinoma , thyroid cancer , colorectal cancer , and gastrointestinal stromal cancer . # ::alignments 0-1 1-1.2 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 9-1.1.1.2.2.1.1.1 12-1.1.3 14-1.1 15-1.1.2.r 17-1.1.2 18-1.1.2.1.r 19-1.1.2.1.1.1.1 20-1.1.2.1.1.1 21-1.1.2.1.1 23-1.1.2.1.2.1 24-1.1.2.1.2 26-1.1.2.1.3.2.1 27-1.1.2.1.3.2.2 27-1.1.2.1.5.2.1 29-1.1.2.1.4.2.1 30-1.1.2.1.4.2.2 30-1.1.2.1.5.2.1 32-1.1.2.1 33-1.1.2.1.5.3.1 35-1.1.2.1.5.2.1 (h / have-concession-91~e.0 :ARG1 (a / approve-01~e.14 :ARG1 (a2 / and~e.4 :op1 (s2 / small-molecule :name (n / name :op1 "sorafenib"~e.3)) :op2 (s3 / small-molecule :name (n2 / name :op1 "fluoro-sorafenib"~e.5,7) :ARG1-of (m / mean-01 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "regorafenib"~e.9))))) :ARG2~e.15 (t2 / treat-03~e.17 :ARG2~e.18 (a3 / and~e.32 :op1 (c / carcinoma~e.21 :mod (c2 / cell~e.20 :mod (k / kidney~e.19))) :op2 (c3 / carcinoma~e.24 :mod (h2 / hepatocellular~e.23)) :op3 (d / disease :wiki "Thyroid_cancer" :name (n4 / name :op1 "thyroid"~e.26 :op2 "cancer"~e.27)) :op4 (d2 / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal"~e.29 :op2 "cancer"~e.30)) :op5 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"~e.27,30,35) :mod (s5 / stroma :mod (g / gastrointestinal~e.33))))) :time (s / since~e.12)) :ARG2 (t / this~e.1)) # ::id pmid_2465_1010.207 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In hepatocellular carcinoma , biomarker analysis in Phase II clinical trials showed a clear correlation between levels of phospho @-@ ERK and clinical response , suggesting that inhibition of Raf kinase is responsible for part of the clinical benefit ( Abou @-@ Alfa et al. , 2006 ) , but in the other indications , it appears likely that inhibition of vascular endothelial growth factor receptor 2 or other kinases is responsible . # ::alignments 1-1.1.6.1 2-1.1.6 4-1.1.1.1 5-1.1.1 7-1.1.3.2 8-1.1.3.2.1.1 9-1.1.3.1 10-1.1.3 11-1.1 13-1.1.2.3 14-1.1.2 16-1.1.2.1 17-1.1.2.1.1.r 18-1.1.2.1.1.2 20-1.1.2.1.1.1.1 21-1.1.5.1.1 22-1.1.2.2.1 23-1.1.2.2 25-1.1.4 26-1.1.4.1.r 27-1.1.4.1.1 28-1.1.4.1.1.1.r 29-1.1.4.1.1.1.1.1 30-1.1.4.1.1.1 32-1.1.4.1 33-1.1.4.1.2.r 34-1.1.4.1.2.2 37-1.1.4.1.2.1 38-1.1.4.1.2 41-1.1.5.1.1.1.1.1 43-1.1.5.1.1.1.1.1 44-1.1.5.1.1 45-1.1.5.1.1.2.1 47-1.1.5.1.2.1 51-1 52-1.2.r 54-1.2.2.1 55-1.2.2 58-1.2 59-1.2.1 60-1.2.1.1.r 61-1.2.1.1.1 62-1.2.1.1.1.1.r 63-1.2.1.1.1.1.1.1.1 64-1.2.1.1.1.1.1.1.2 65-1.2.1.1.1.1.1.1.3 66-1.2.1.1.1.1.1.1.4 67-1.2.1.1.1.1.1.1.5 68-1.2.1.1.1.1.1.1.6 69-1.2.1.1.1.1 70-1.2.1.1.1.1.2.1 71-1.2.1.1.1.1.2 73-1.2.1.1 (c / contrast-01~e.51 :ARG1 (s / show-01~e.11 :ARG0 (a / analyze-01~e.5 :ARG1 (b / biomarker~e.4)) :ARG1 (c3 / correlate-01~e.14 :ARG1 (l / level~e.16 :degree-of~e.17 (e / enzyme :name (n / name :op1 "ERK"~e.20) :ARG3-of (p2 / phosphorylate-01~e.18))) :ARG2 (r / respond-01~e.23 :mod c2~e.22) :ARG1-of (c4 / clear-06~e.13)) :subevent-of (t / trial-06~e.10 :mod (c2 / clinic~e.9) :mod (p / phase~e.7 :ord (o / ordinal-entity :value 2~e.8))) :ARG0-of (s2 / suggest-01~e.25 :ARG1~e.26 (r2 / responsible-01~e.32 :ARG0 (i / inhibit-01~e.27 :ARG1~e.28 (k / kinase~e.30 :name (n2 / name :op1 "Raf"~e.29))) :ARG1~e.33 (b2 / benefit-01~e.38 :mod (c5 / clinic~e.37) :degree (p3 / part~e.34)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and~e.21,44 :op1 (p5 / person :name (n3 / name :op1 "Abou-Alfa"~e.41,43)) :op2 (p6 / person :mod (o2 / other~e.45))) :time (d2 / date-entity :year 2006~e.47))) :condition (c6 / carcinoma~e.2 :mod (h2 / hepatocellular~e.1))) :ARG2~e.52 (a3 / appear-02~e.58 :ARG1 (l2 / likely-01~e.59 :ARG1~e.60 (r3 / responsible-01~e.73 :ARG0 (i3 / inhibit-01~e.61 :ARG1~e.62 (o4 / or~e.69 :op1 (e3 / enzyme :name (n4 / name :op1 "vascular"~e.63 :op2 "endothelial"~e.64 :op3 "growth"~e.65 :op4 "factor"~e.66 :op5 "receptor"~e.67 :op6 2~e.68)) :op2 (k3 / kinase~e.71 :mod (o5 / other~e.70)))) :ARG1 b2)) :condition (i2 / indicate-101~e.55 :mod (o3 / other~e.54)))) # ::id pmid_2465_1010.208 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Hopefully , a clearer picture will emerge through analysis of exceptional responders or through deciphering mechanisms of drug resistance . # ::alignments 0-1.3 3-1.1.1 3-1.1.1.1 3-1.1.1.1.r 4-1.1 6-1 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.2 12-1.2 14-1.2.2 15-1.2.2.1 16-1.2.2.1.1.r 17-1.2.2.1.1.1 18-1.2.2.1.1 (e / emerge-01~e.6 :ARG0 (p / picture~e.4 :ARG1-of (c / clear-06~e.3 :degree~e.3 (m / more~e.3))) :ARG1 (o / or~e.12 :op1 (a / analyze-01~e.8 :ARG1~e.9 (t / thing :ARG0-of (r / respond-01) :mod (e2 / exceptional~e.10))) :op2 (d / decipher-01~e.14 :ARG1 (m2 / mechanism~e.15 :mod~e.16 (r2 / resist-01~e.18 :ARG1 (d2 / drug~e.17))))) :ARG1-of (h / hopeful-03~e.0)) # ::id pmid_2465_1010.209 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Inhibitors of PI3K pathway have not yet fared much better in the clinic , also because of feedback mechanisms that activate upstream signaling , as well as poor therapeutic index . # ::alignments 0-1.2.2 0-1.2.2.1 0-1.2.2.1.r 1-1.2.2.1.1.r 2-1.2.2.1.1.1.1 3-1.2.2.1.1 5-1.2.1 5-1.2.1.r 6-1.2.5 7-1.2 8-1.2.3.1.1 9-1.2.3 9-1.2.3.1 9-1.2.3.1.r 10-1.2.4.r 12-1.2.4 14-1.1.1.3 15-1 17-1.1.1.1 18-1.1.1 20-1.1.1.2 21-1.1.1.2.1.1 22-1.1.1.2.1 24-1.1 25-1.1 26-1.1 26-1.1.r 27-1.1.2.2 28-1.1.2.1 29-1.1.2 (c / cause-01~e.15 :ARG0~e.26 (a / and~e.24,25,26 :op1 (m4 / mechanism~e.18 :mod (f2 / feedback~e.17) :ARG0-of (a2 / activate-01~e.20 :ARG1 (s / signal-07~e.22 :source (u / upstream~e.21))) :mod (a3 / also~e.14)) :op2 (i2 / index~e.29 :mod (t / therapy~e.28) :mod (p2 / poor~e.27))) :ARG1 (f / fare-01~e.7 :polarity~e.5 -~e.5 :ARG0 (m3 / molecular-physical-entity~e.0 :ARG0-of~e.0 (i / inhibit-01~e.0 :ARG1~e.1 (p / pathway~e.3 :name (n / name :op1 "PI3K"~e.2)))) :ARG1-of (g / good-02~e.9 :degree~e.9 (m / more~e.9 :quant (m2 / much~e.8))) :location~e.10 (c2 / clinic~e.12) :time (y / yet~e.6))) # ::id pmid_2465_1010.210 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , the relative failure of these downstream approaches does not mean that they are not critical to Ras oncogenesis . # ::alignments 0-1 3-1.1.2.2 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1 7-1.1.2.1.2 8-1.1.2.1 10-1.1.1 10-1.1.1.r 11-1.1 13-1.1.3.2 15-1.1.3.1 15-1.1.3.1.r 16-1.1.3 17-1.1.3.3 18-1.1.3.3.1.1.1 (c2 / contrast-01~e.0 :ARG2 (m / mean-01~e.11 :polarity~e.10 -~e.10 :ARG1 (f / fail-01~e.4 :ARG1~e.5 (a / approach-02~e.8 :mod (t / this~e.6) :mod (d / downstream~e.7)) :ARG2-of (r / relative-05~e.3)) :ARG2 (c / critical-02~e.16 :polarity~e.15 -~e.15 :ARG1 a~e.13 :ARG2 (c3 / cause-01~e.17 :ARG0 (e / enzyme :name (n / name :op1 "Ras"~e.18)) :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))) # ::id pmid_2465_1010.211 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Indeed , ablation of c @-@ Raf ( but not B @-@ Raf ) in mice inhibits development and delays progression of Ras @-@ driven tumors in a lung adenocarcinoma model ( Blasco et al. , 2011 ) . # ::alignments 0-1.3 2-1.1.1 2-1.1.1.3.1 6-1.1.1.1.1.1 8-1.1.1.3 9-1.1.1.3.1.1 9-1.1.1.3.1.1.r 10-1.1.1.3.1.2.1.1 12-1.1.1.1.1.1 12-1.1.1.3.1.2.1.1 14-1.1.1.2.r 15-1.1.1.2 16-1.1 17-1.1.2 18-1 18-1.4.1.1 19-1.2 20-1.2.2 21-1.2.2.1.r 22-1.2.2.1.1.1.1.1 24-1.2.2.1.1 25-1.2.2.1 26-1.2.2.2.r 28-1.2.2.2.1.1 29-1.2.2.2.1 30-1.2.2.2 33-1.4.1.1.1.1.1 34-1.4.1.1 35-1.4.1.1.2.1 37-1.4.1.2.1 (a / and~e.18 :op1 (i / inhibit-01~e.16 :ARG0 (a2 / ablate-01~e.2 :ARG1 (e / enzyme :name (n / name :op1 "C-Raf"~e.6,12)) :location~e.14 (m / mouse~e.15) :ARG1-of (c / contrast-01~e.8 :ARG2 (a5 / ablate-01~e.2 :polarity~e.9 -~e.9 :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf"~e.10,12))))) :ARG1 (d2 / develop-01~e.17 :ARG1 m2 :ARG2 t)) :op2 (d / delay-01~e.19 :ARG0 a2 :ARG1 (p / progress-01~e.20 :ARG1~e.21 (t / tumor~e.25 :ARG1-of (d3 / drive-02~e.24 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras"~e.22)))) :location~e.26 (m2 / model~e.30 :topic (a3 / adenocarcinoma~e.29 :mod (l / lung~e.28))))) :mod (i2 / indeed~e.0) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a4 / and~e.18,34 :op1 (p3 / person :name (n4 / name :op1 "Blasco"~e.33)) :op2 (p4 / person :mod (o / other~e.35))) :time (d5 / date-entity :year 2011~e.37)))) # ::id pmid_2465_1010.212 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , in an in vivo pancreatic cancer mouse model , B @-@ Raf was shown to be required for tumor progression ( Sobczak et al. , 2008 ) . # ::alignments 0-1 2-1.1.2.2 4-1.1.2.2 5-1.1.2.2 6-1.1.2.3.2.1 7-1.1.2.3.2.2 8-1.1.2.1 9-1.1.2 11-1.1.1.2.1.1 13-1.1.1.2.1.1 15-1.1 18-1.1.1 19-1.1.1.1.r 20-1.1.1.1.1 21-1.1.1.1 24-1.1.3.1.1.1.1.1 25-1.1.3.1.1 26-1.1.3.1.1.2.1 28-1.1.3.1.2.1 (c2 / contrast-01~e.0 :ARG2 (s / show-01~e.15 :ARG1 (r / require-01~e.18 :ARG0~e.19 (p / progress-01~e.21 :ARG1 (t / tumor~e.20)) :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"~e.11,13))) :condition (m / model~e.9 :mod (m2 / mouse~e.8) :mod (i / in-vivo~e.2,4,5) :topic (d3 / disease :wiki "Pancreatic_cancer" :name (n4 / name :op1 "pancreatic"~e.6 :op2 "cancer"~e.7))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and~e.25 :op1 (p4 / person :name (n2 / name :op1 "Sobczak"~e.24)) :op2 (p5 / person :mod (o / other~e.26))) :time (d2 / date-entity :year 2008~e.28))))) # ::id pmid_2465_1010.213 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This suggests tissue @-@ specific signaling cascades and will require more investigation . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.2.1 4-1.1.2.2 5-1.1.2.1 6-1.1.2 7-1 9-1.2 10-1.2.2.1 11-1.2.2 (a / and~e.7 :op1 (s / suggest-01~e.1 :ARG0 (t / this~e.0) :ARG1 (c / cascade~e.6 :subevent (s2 / signal-07~e.5) :ARG1-of (s3 / specific-02~e.4 :ARG2 (t2 / tissue~e.2)))) :op2 (r / require-01~e.9 :ARG0 t :ARG1 (i / investigate-01~e.11 :degree (m / more~e.10)))) # ::id pmid_2465_1010.214 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Genetic disruption of Ras binding to PI3K-α has a similar effect . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.r 6-1.1.1.2.1.1 9-1.2 10-1 (a / affect-01~e.10 :ARG0 (d / disrupt-01~e.1 :ARG1~e.2 (b / bind-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.3)) :ARG2~e.5 (e2 / enzyme :name (n2 / name :op1 "PI3K-α"~e.6))) :mod (g / genetic~e.0)) :ARG1-of (r / resemble-01~e.9)) # ::id pmid_2465_1010.215 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We can therefore assume that small molecules that can block downstream signaling without triggering feedback and with the correct specificity and biochemical properties may still be effective , but more work needs to be done to develop such compounds effectively . # ::alignments 0-1.2.1.1.1 1-1.2.1 1-1.2.1.1.2 2-1.2 3-1.2.1.1 5-1.2.1.1.2.1.1.1 6-1.2.1.1.2.1.1 8-1.2.1.1.2.1.1.2.3 9-1.2.1.1.2.1.1.2 10-1.2.1.1.2.1.1.2.1.1 11-1.2.1.1.2.1.1.2.1 12-1.2.1.1.2.1.1.2.2.1 12-1.2.1.1.2.1.1.2.2.1.r 13-1.2.1.1.2.1.1.2.2 14-1.2.1.1.2.1.1.2.2.3 15-1.2.1.1.2.1.1.3.1 18-1.2.1.1.2.1.1.3.1.1.1 19-1.2.1.1.2.1.1.3.1.1 20-1.2.1.1.2.1.1.3.1 21-1.2.1.1.2.1.1.3.1.2.1 22-1.2.1.1.2.1.1.3.1.2 23-1.2.1.1.2 24-1.2.1.1.2.1.2 26-1.2.1.1.2.1 28-1 29-1.1.1.1 30-1.1.1 31-1.1 34-1.1.1 36-1.1.1.2 37-1.1.1.2.2.1 38-1.1.1.2.2 39-1.1.1.2.3 (h / have-concession-91~e.28 :ARG1 (n / need-01~e.31 :ARG1 (w2 / work-01~e.30,34 :degree (m2 / more~e.29) :purpose (d2 / develop-02~e.36 :ARG0 w :ARG1 (c2 / compound~e.38 :mod (s5 / such~e.37)) :ARG1-of (e2 / effective-04~e.39)))) :ARG2 (i / infer-01~e.2 :ARG1 (p / possible-01~e.1 :ARG1 (a / assume-02~e.3 :ARG0 (w / we~e.0) :ARG1 (p2 / possible-01~e.1,23 :ARG1 (e / effective-04~e.26 :ARG0 (m / molecule~e.6 :mod (s / small~e.5) :ARG0-of (b / block-01~e.9 :ARG1 (s2 / signal-07~e.11 :source (d / downstream~e.10)) :manner (t / trigger-01~e.13 :polarity~e.12 -~e.12 :ARG0 m :ARG1 (f / feedback~e.14)) :ARG1-of (p4 / possible-01~e.8)) :ARG0-of (h2 / have-03 :ARG1 (a2 / and~e.15,20 :op1 (s3 / specificity~e.19 :ARG1-of (c / correct-02~e.18)) :op2 (p3 / property~e.22 :mod (b2 / biochemical~e.21) :ARG1-of c)))) :mod (s4 / still~e.24))))))) # ::id pmid_2465_1010.216 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The third direct effector arm of Ras signaling that plays a major role in human cancer is the RalGDS ( Ral guanine nucleotide dissociation stimulator ) pathway ( Figure 1 ) . # ::alignments 1-1.3 1-1.3.1 1-1.3.1.r 2-1.1.1 3-1.1 4-1 5-1.2.r 6-1.2.1.1.1 7-1.2 9-1.4 11-1.4.2 13-1.4.1.r 14-1.4.1.3 15-1.4.1.2.1 16-1.5.r 18-1.5.1.1 29-1.6.1 30-1.6.1.1 (a / arm~e.4 :mod (e / effector~e.3 :ARG1-of (d3 / direct-02~e.2)) :poss~e.5 (s / signal-07~e.7 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Ras"~e.6))) :ord (o / ordinal-entity~e.1 :value~e.1 3~e.1) :ARG0-of (p2 / play-08~e.9 :ARG1~e.13 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.15) :mod (h / human~e.14)) :ARG1-of (m / major-02~e.11)) :domain~e.16 (p / protein :name (n / name :op1 "RalGDS"~e.18)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod 1~e.30))) # ::id pmid_2465_1010.217 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Perhaps the best evidence of the importance of this effector pathway comes from demonstration that mice null for RalGDS have reduced skin carcinogen @-@ induced tumor incidence , size , and progression to malignancy compared to wild @-@ type mice ( González @-@ García et al. , 2005 ) . # ::alignments 0-1 2-1.1.3 2-1.1.3.1 2-1.1.3.1.r 3-1.1 4-1.1.2.r 6-1.1.2 7-1.1.2.1.r 8-1.1.2.1.2 9-1.1.2.1.1 10-1.1.2.1 12-1.1.1.r 13-1.1.1 14-1.1.1.1.r 15-1.1.1.1.1 16-1.1.1.1.1.1 17-1.1.1.1.1.1.1.r 18-1.1.1.1.1.1.1.1.1 19-1.1.1.1 20-1.1.1.1.2.4 21-1.1.1.1.2.1.1.2 22-1.1.1.1.2.1.1.1.1 24-1.1.1.1.2.1.1.1 25-1.1.1.1.2.1.1 26-1.1.1.1.2.1 28-1.1.1.1.2.2 30-1.1.1.1.2 31-1.1.1.1.2.3 32-1.1.1.1.2.3.2.r 33-1.1.1.1.2.3.2 34-1.1.1.1.2.4.1 35-1.1.1.1.2.4.1.1.r 36-1.1.1.1.2.4.1.1.1 38-1.1.1.1.2.4.1.1.1 39-1.1.1.1.2.4.1.1 42-1.2.1.1.1.1.1 44-1.2.1.1.1.1.1 45-1.2.1.1 46-1.2.1.1.2.1 48-1.2.1.2.1 (p / possible-01~e.0 :ARG1 (e / evidence-01~e.3 :ARG0~e.12 (d / demonstrate-01~e.13 :ARG1~e.14 (h / have-03~e.19 :ARG0 (m3 / mouse~e.15 :mod (n3 / null~e.16 :mod~e.17 (p7 / protein :name (n / name :op1 "RalGDS"~e.18)))) :ARG1 (a / and~e.30 :op1 (i2 / incidence~e.26 :frequency-of (t / tumor~e.25 :ARG2-of (i3 / induce-01~e.24 :ARG0 (c2 / carcinogen~e.22)) :mod (s / skin~e.21))) :op2 (s2 / size~e.28 :mod t) :op3 (p3 / progress-01~e.31 :ARG1 t :ARG4~e.32 (m2 / malignancy~e.33)) :ARG1-of (r / reduce-01~e.20 :ARG1-of (c3 / compare-01~e.34 :ARG2~e.35 (m4 / mouse~e.39 :mod (w / wild-type~e.36,38))))))) :ARG1~e.4 (i / important~e.6 :domain~e.7 (p2 / pathway~e.10 :mod (e2 / effector~e.9) :mod (t2 / this~e.8))) :ARG1-of (g / good-02~e.2 :degree~e.2 (m / most~e.2))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and~e.45 :op1 (p5 / person :name (n2 / name :op1 "González-García"~e.42,44)) :op2 (p6 / person :mod (o / other~e.46))) :time (d3 / date-entity :year 2005~e.48)))) # ::id pmid_2465_1010.218 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These data , and many others ( Martin et al. , 2011 ; Kashatus , 2013 ) , support a role for RalGDS both in vitro and in vivo as an important effector pathway utilized by oncogenic Ras to drive tumorigenesis that could potentially be exploited for therapeutic intervention , although the absence of somatic mutations in this effector pathway makes its precise role less clear than the Raf @/@ MAPK and PI3K pathways . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.1 3-1.1.3.1 3-1.1.3.1.1.1 4-1.1.2.1 5-1.1.2 5-1.1.3.1.1.1.2.1 8-1.1.3.1.1.1.1.1.1 9-1.1.3.1.1.1 10-1.1.3.1.1.1.2.1 12-1.1.3.1.1.2.1 14-1.1.3.1.2.1.1.1 16-1.1.3.1.2.2.1 20-1 23-1.2.r 24-1.2.1.1.1.1 26-1.2.1.3 27-1.2.1.3 28-1.2 29-1.2.1.3 29-1.2.2.3 30-1.2.2.3 31-1.1.3.1.1.2.r 31-1.1.3.1.2.2.r 33-1.2.1.2.2 34-1.2.1.2.1 35-1.2.1.2 36-1.2.1.2.3 37-1.2.1.2.3.1.r 38-1.2.1.2.3.1 38-1.2.1.2.3.1.2 38-1.2.1.2.3.1.2.1.2.1 38-1.2.1.2.3.1.2.r 39-1.2.1.2.3.1.1.1 40-1.2.1.2.3.1 40-1.2.1.2.3.1.2 40-1.2.1.2.3.1.2.r 41-1.2.1.2.3.2 42-1.2.1.2.3.2.2 42-1.2.1.2.3.2.2.1 42-1.2.1.2.3.2.2.1.r 44-1.2.1.2.3.2.2.2.2 45-1.2.1.2.3.2.2.2.3 47-1.2.1.2.3.2.2.2 48-1.2.1.2.3.2.2.2.1.r 49-1.2.1.2.3.2.2.2.1.1 50-1.2.1.2.3.2.2.2.1 52-1.3.r 54-1.3.1 55-1.3.1.1.r 56-1.3.1.1.1 57-1.3.1.1 58-1.2.1.3 58-1.2.2.3 59-1.1.1.1 60-1.2.1.2.1 61-1.2.1.2 62-1.3 63-1.3.2.1 63-1.3.2.1.r 64-1.3.2.2 66-1.3.2.3.1 67-1.3.2.3 70-1.3.2.3.2.1.1.1.1 72-1.3.2.3.2.1.1.1.1 73-1.3.2.3.2.1 74-1.3.2.3.2.1.2.1.1 75-1.3.2.3.2.1.1 75-1.3.2.3.2.1.2 (s / support-01~e.20 :ARG0 (a / and~e.3 :op2 (d / data~e.1 :mod (t / this~e.0,59)) :op2 (o / other~e.5 :quant (m / many~e.4)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.3 :op1 (p / publication-91 :ARG0 (a3 / and~e.3,9 :op1 (p2 / person :name (n / name :op1 "Martin"~e.8)) :op2 (p3 / person :mod (o2 / other~e.5,10))) :time~e.31 (d3 / date-entity :year 2011~e.12)) :op2 (p4 / publication-91 :ARG0 (p5 / person :name (n2 / name :op1 "Kashatus"~e.14)) :time~e.31 (d4 / date-entity :year 2013~e.16))))) :ARG1~e.23 (a6 / and~e.28 :op1 (p6 / play-02 :ARG0 (p15 / pathway :name (n3 / name :op1 "RalGDS"~e.24)) :ARG1 (p7 / pathway~e.35,61 :mod (e / effector~e.34,60) :mod (i / important~e.33) :ARG1-of (u / utilize-01~e.36 :ARG0~e.37 (e2 / enzyme~e.38,40 :name (n4 / name :op1 "Ras"~e.39) :ARG0-of~e.38,40 (c / cause-01~e.38,40 :ARG1 (d6 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"~e.38)))) :purpose (d5 / drive-02~e.41 :ARG0 e2 :ARG1 (c3 / create-01~e.42 :ARG1~e.42 (t2 / tumor~e.42) :ARG1-of (e3 / exploit-01~e.47 :ARG2~e.48 (i4 / intervene-01~e.50 :mod (t3 / therapy~e.49)) :ARG1-of (p8 / possible-01~e.44) :mod (p9 / potential~e.45)))))) :manner (i2 / in-vitro~e.26,27,29,58)) :op2 (p14 / play-02 :ARG0 p15 :ARG1 p7 :manner (i3 / in-vivo~e.29,30,58))) :concession~e.52 (m2 / make-02~e.62 :ARG0 (a4 / absent-01~e.54 :ARG1~e.55 (m3 / mutate-01~e.57 :mod (s2 / somatic~e.56)) :ARG2 p7) :ARG1 (p10 / play-02 :ARG0~e.63 p15~e.63 :mod (p11 / precise~e.64) :ARG1-of (c4 / clear-06~e.67 :degree (l / less~e.66) :ARG1-of (c5 / compare-01 :ARG2 (a5 / and~e.73 :op1 (p12 / pathway~e.75 :name (n5 / name :op1 "Raf/MAPK"~e.70,72)) :op2 (p13 / pathway~e.75 :name (n6 / name :op1 "PI3K"~e.74)))))))) # ::id pmid_2465_1010.219 ::amr-annotator SDL-AMR-09 ::preferred # ::tok On the other hand , Ral signaling is upstream of NF-κB and TBK1 , both of which have been implicated as essential genes downstream of K @-@ Ras ( Neel et al. , 2011 ; Kashatus , 2013 ) . # ::alignments 2-1.2.1.1.1.2.1 5-1.1.1.1.1.1 6-1.1.1 7-1.1 8-1.1.2.2 10-1.1.2.1.1.1.1 11-1.1.2.1 12-1.1.2.1.2.1.1 19-1.1.2.1.3 20-1.1.2.1.3.2.r 21-1.1.2.1.3.2.1 22-1.1.2.1.3.2 23-1.1.2.1.3.1.2 25-1.1.2.1.3.1.1.1.1 27-1.1.2.1.3.1.1.1.1 30-1.2.1.1.1.1.1.1 31-1.2.1 31-1.2.1.1.1 32-1.2.1.1.1.2.1 34-1.2.1.1.2.1 36-1.2.1.2.1.1.1 38-1.2.1.2.2.1 (c / contrast-01 :ARG2 (b / be-located-at-91~e.7 :ARG1 (s / signal-07~e.6 :ARG0 (p6 / protein :name (n / name :op1 "Ral"~e.5))) :ARG2 (r / relative-position :op1 (a / and~e.11 :op1 (p7 / protein :name (n2 / name :op1 "NF-κB"~e.10)) :op2 (e / enzyme :name (n3 / name :op1 "TBK1"~e.12)) :ARG1-of (i / implicate-01~e.19 :location (r2 / relative-position :op1 (e2 / enzyme :name (n4 / name :op1 "K-Ras"~e.25,27)) :direction (d / downstream~e.23)) :prep-as~e.20 (g3 / gene~e.22 :mod (e3 / essential~e.21)))) :direction (u / upstream~e.8))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.31 :op1 (p / publication-91 :ARG0 (a3 / and~e.31 :op1 (p3 / person :name (n5 / name :op1 "Neel"~e.30)) :op2 (p4 / person :mod (o / other~e.2,32))) :time (d3 / date-entity :year 2011~e.34)) :op2 (p2 / publication-91 :ARG0 (p5 / person :name (n6 / name :op1 "Kashatus"~e.36)) :time (d4 / date-entity :year 2013~e.38))))) # ::id pmid_2465_1010.220 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Other potential Ras effectors that could be important in cancer and therefore a source of potential therapeutic targets include phospholipase CE and Tiam1 , a GEF that stimulates the activation of Rac ( Figure 1 ) . # ::alignments 0-1.2.3 1-1.2.1 2-1.2.2.1.1 3-1.2 5-1.2.4.1 7-1.2.4 8-1.2.4.2.r 9-1.2.4.2.2.1 11-1.2.4.3 13-1.2.4.3.1 14-1.2.4.3.1.2.r 15-1.2.4.3.1.2.3 16-1.2.4.3.1.2.1 17-1.2.4.3.1.2 18-1 19-1.1.1 20-1.1.1.1.1 21-1.1 22-1.1.2.1.1 25-1.1.2.2.1.1.1 27-1.1.2.2.1 27-1.1.2.2.1.2 27-1.1.2.2.1.2.r 29-1.1.2.2.1.2.1 30-1.1.2.2.1.2.1.1.r 31-1.1.2.2.1.2.1.1.1.1 34-1.3.1 35-1.3.1.1 (i / include-01~e.18 :ARG1 (a / and~e.21 :op1 (p4 / phospholipase~e.19 :name (n3 / name :op1 "CE"~e.20)) :op2 (p7 / protein :name (n4 / name :op1 "Tiam1"~e.22) :ARG1-of (m / mean-01 :ARG2 (p5 / protein~e.27 :name (n5 / name :op1 "GEF"~e.25) :ARG0-of~e.27 (s2 / stimulate-01~e.27 :ARG1 (a2 / activate-01~e.29 :ARG1~e.30 (p6 / protein :name (n6 / name :op1 "Rac"~e.31)))))))) :ARG2 (e / effector~e.3 :mod (p / potential~e.1) :mod (p8 / protein-family :name (n / name :op1 "Ras"~e.2)) :mod (o / other~e.0) :mod (i2 / important~e.7 :ARG1-of (p2 / possible-01~e.5) :topic~e.8 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.9)) :ARG0-of (c / cause-01~e.11 :ARG1 (s / source-02~e.13 :ARG0 e :ARG1~e.14 (t / target-01~e.17 :ARG0 (t2 / therapy~e.16) :ARG1 e :mod (p3 / potential~e.15)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.34 :mod 1~e.35))) # ::id pmid_2465_1010.221 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Rac1 is necessary for K @-@ Ras tumor initiation , further implicating the importance of this pathway in K @-@ Ras tumorigenesis , though not yet providing obvious therapeutic targets ( Gysin et al. , 2011 ) . # ::alignments 0-1.2.1.1 1-1.3.1.1.r 2-1 3-1.1.r 4-1.1.1.1.1 6-1.1.1.1.1 7-1.1.2 8-1.1 10-1.3.3 11-1.3 13-1.3.1 16-1.3.1.1 17-1.3.1.2.r 18-1.3.1.2.1 19-1.3.1.2.1 20-1.3.1.2.1 21-1.3.1.2 21-1.3.1.2.2 21-1.3.1.2.2.r 23-1.3.2.r 24-1.3.2.1 24-1.3.2.1.r 25-1.3.2.4 26-1.3.2 27-1.3.2.3.2 28-1.3.2.3.1 29-1.3.2.3 32-1.4.1.1.1.1.1 33-1.4.1.1 34-1.4.1.1.2.1 36-1.4.1.2.1 (n / need-01~e.2 :ARG0~e.3 (i / initiate-01~e.8 :ARG0 (e / enzyme :name (n3 / name :op1 "K-Ras"~e.4,6)) :ARG1 (t / tumor~e.7)) :ARG1 (p / pathway :name (n2 / name :op1 "Rac1"~e.0)) :ARG0-of (i2 / implicate-01~e.11 :ARG1 (i3 / important~e.13 :domain~e.1 p~e.16 :topic~e.17 (c / create-01~e.21 :ARG0 e~e.18,19,20 :ARG1~e.21 (t2 / tumor~e.21))) :concession~e.23 (p2 / provide-01~e.26 :polarity~e.24 -~e.24 :ARG0 p :ARG1 (t3 / target-01~e.29 :ARG0 (t4 / therapy~e.28) :ARG1-of (o / obvious-01~e.27)) :time (y / yet~e.25)) :mod (f / further~e.10)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a / and~e.33 :op1 (p4 / person :name (n4 / name :op1 "Gysin"~e.32)) :op2 (p5 / person :mod (o2 / other~e.34))) :time (d2 / date-entity :year 2011~e.36)))) # ::id pmid_2465_1010.222 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , cyclin D1 , NF-κB , and Myc are necessary for Ras tumorigenesis ; further analysis of the role of these pathways may lead to new therapeutic insights . # ::alignments 0-1.1.3 2-1.1.2.1.1.1 3-1.1.2.1.1.2 5-1.1.2.2.1.1 7-1.1.2 8-1.1.2.3.1.1 12-1.1.1.1.1.1 13-1.1.1 13-1.1.1.2 13-1.1.1.2.r 15-1.2.1.1.2 16-1.2.1.1 17-1.2.1.1.1.r 19-1.2.1.1.1 20-1.2.1.1.1.1.r 21-1.2.1.1.1.1.1 22-1.2.1.1.1.1 23-1.2 24-1.2.1 25-1.2.1.2.r 26-1.2.1.2.2 27-1.2.1.2.1 28-1.2.1.2 (m / multi-sentence :snt1 (r / require-01 :ARG0 (c / create-01~e.13 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"~e.12)) :ARG1~e.13 (t / tumor~e.13)) :ARG1 (a / and~e.7 :op1 (p / protein :name (n / name :op1 "cyclin"~e.2 :op2 "D1"~e.3)) :op2 (p2 / protein :name (n3 / name :op1 "NF-κB"~e.5)) :op3 (p3 / protein :name (n4 / name :op1 "Myc"~e.8))) :mod (l2 / likewise~e.0)) :snt2 (p4 / possible-01~e.23 :ARG1 (l / lead-03~e.24 :ARG0 (a2 / analyze-01~e.16 :ARG1~e.17 (r2 / role~e.19 :topic~e.20 (p5 / pathway~e.22 :mod (t2 / this~e.21))) :degree (f / further~e.15)) :ARG2~e.25 (i / insight~e.28 :mod (t3 / therapy~e.27) :ARG1-of (n5 / new-01~e.26))))) # ::id pmid_2465_1010.223 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , Puyol et al. ( 2010 ) recently demonstrated that germline or conditional deletion of Cdk4 led to senescence in lung cells expressing activated K @-@ Ras . # ::alignments 0-1.3 1-1.3 4-1.1.1.1.1.1 5-1.1.1 6-1.1.1.2.1 8-1.1.2.1 11-1.4 12-1 13-1.2.r 14-1.2.1.1.1 15-1.2.1 16-1.2.1.2.2 17-1.2.1.1 17-1.2.1.2 20-1.2.1.1.2.1.1 22-1.2 23-1.2.2.r 24-1.2.2 25-1.2.3.r 26-1.2.3.2 27-1.2.3 28-1.2.3.1 29-1.2.3.1.1.2 30-1.2.3.1.1.1.1 32-1.2.3.1.1.1.1 (d2 / demonstrate-01~e.12 :ARG0 (p / publication-91 :ARG0 (a / and~e.5 :op1 (p2 / person :name (n2 / name :op1 "Puyol"~e.4)) :op2 (p3 / person :mod (o / other~e.6))) :time (d / date-entity :year 2010~e.8)) :ARG1~e.13 (l / lead-03~e.22 :ARG0 (o2 / or~e.15 :op1 (d3 / delete-01~e.17 :ARG0 (g / germline~e.14) :ARG1 (g2 / gene :name (n4 / name :op1 "Cdk4"~e.20))) :op2 (d4 / delete-01~e.17 :ARG1 g2 :mod (c2 / conditional~e.16))) :ARG2~e.23 (s / senescence~e.24) :location~e.25 (c3 / cell~e.27 :ARG3-of (e4 / express-03~e.28 :ARG2 (e2 / enzyme :name (n / name :op1 "K-Ras"~e.30,32) :ARG1-of (a2 / activate-01~e.29))) :mod (l2 / lung~e.26))) :ARG0-of (e / exemplify-01~e.0,1) :time (r / recent~e.11)) # ::id pmid_2465_1010.224 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , treatment with a Cdk4 inhibitor reduced the growth of K @-@ Ras @-@ driven tumors . # ::alignments 0-1 2-1.1.1 3-1.1.1.1.r 5-1.1.1.1.1.1.1.1 6-1.1.1.1 6-1.1.1.1.1 6-1.1.1.1.1.r 7-1.1 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1.1 13-1.1.2.1.1.1.1.1 15-1.1.2.1.1 16-1.1.2.1 (a / and~e.0 :op2 (r / reduce-01~e.7 :ARG0 (t2 / treat-04~e.2 :ARG2~e.3 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6 :ARG1 (e2 / enzyme :name (n / name :op1 "Cdk4"~e.5))))) :ARG1 (g / grow-01~e.9 :ARG1~e.10 (t3 / tumor~e.16 :ARG1-of (d / drive-02~e.15 :ARG0 (e / enzyme :name (n2 / name :op1 "K-Ras"~e.11,13))))))) # ::id pmid_2465_1010.225 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Finally , unbiased shRNA screens have revealed potential targets for K @-@ Ras cancers . # ::alignments 0-1.1 0-1.1.r 2-1.2.2 2-1.2.2.1 2-1.2.2.1.r 3-1.2.1.1.1 4-1.2 6-1 7-1.3.2 8-1.3 9-1.3.1.r 10-1.3.1.3.1.1 12-1.3.1.3.1.1 13-1.3.1.2.1 (r / reveal-01~e.6 :li~e.0 -1~e.0 :ARG0 (s / screen-01~e.4 :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA"~e.3)) :ARG1-of (b / bias-01~e.2 :polarity~e.2 -~e.2)) :ARG1 (t / target-01~e.8 :ARG1~e.9 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.13) :mod (e / enzyme :name (n / name :op1 "K-Ras"~e.10,12))) :mod (p / potential~e.7))) # ::id pmid_2465_1010.226 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These include STK33 , TBK1 , and GATA @-@ 2 . # ::alignments 0-1.2 1-1 2-1.1.1.1.1 4-1.1.2.1.1 6-1.1 7-1.1.3.1.1 9-1.1.3.1.1 (i / include-01~e.1 :ARG1 (a / and~e.6 :op1 (e2 / enzyme :name (n / name :op1 "STK33"~e.2)) :op2 (e / enzyme :name (n2 / name :op1 "TBK1"~e.4)) :op3 (p3 / protein :name (n3 / name :op1 "GATA-2"~e.7,9))) :ARG2 (t / this~e.0)) # ::id pmid_2465_1010.227 ::amr-annotator SDL-AMR-09 ::preferred # ::tok So far , STK33 inhibition does not appear to be a useful approach to K @-@ Ras cancers ( Weiwer et al. , 2012 ) . # ::alignments 0-1.3 1-1.3 3-1.2.1.1.1.1 4-1.2.1 6-1.1 6-1.1.r 7-1 11-1.2.3 12-1.2 13-1.2.2.r 14-1.2.2.3.1.1 16-1.2.2.3.1.1 17-1.2.2.2.1 20-1.4.1.1.1.1.1 21-1.4.1.1 22-1.4.1.1.2.1 24-1.4.1.2.1 (a / appear-02~e.7 :polarity~e.6 -~e.6 :ARG1 (a2 / approach-02~e.12 :ARG0 (i / inhibit-01~e.4 :ARG1 (p / protein :name (n3 / name :op1 "STK33"~e.3))) :ARG1~e.13 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.17) :mod (e / enzyme :name (n / name :op1 "K-Ras"~e.14,16))) :ARG1-of (u / useful-05~e.11)) :time (s / so-far~e.0,1) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a3 / and~e.21 :op1 (p3 / person :name (n4 / name :op1 "Weiwer"~e.20)) :op2 (p4 / person :mod (o / other~e.22))) :time (d / date-entity :year 2012~e.24)))) # ::id pmid_2465_1010.228 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TBK1 inhibitors are still being investigated : this target is of particular interest because it is part of the well @-@ validated RalGDS pathway . # ::alignments 0-1.1.1.1.1.1.1 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 3-1.1.2 5-1.1 7-1.2.1.2 8-1.2.1 8-1.2.1.1 8-1.2.1.1.r 11-1.2.2 12-1.2 13-1.2.3 14-1.2.3.1.1 19-1.2.3.1.2.2.1 21-1.2.3.1.2.2 22-1.2.3.1.2.1.1 23-1.2.3.1.2 (m / multi-sentence :snt1 (i2 / investigate-01~e.5 :ARG1 (m2 / molecular-physical-entity~e.1 :ARG0-of~e.1 (i / inhibit-01~e.1 :ARG1 (e / enzyme :name (n / name :op1 "TBK1"~e.0)))) :mod (s / still~e.3)) :snt2 (i3 / interest-01~e.12 :ARG2 (t / thing~e.8 :ARG1-of~e.8 (t2 / target-01~e.8) :mod (t3 / this~e.7)) :mod (p2 / particular~e.11) :ARG1-of (c / cause-01~e.13 :ARG0 (i4 / include-91 :ARG1 t~e.14 :ARG2 (p3 / pathway~e.23 :name (n2 / name :op1 "RalGDS"~e.22) :ARG1-of (v / validate-01~e.21 :manner (w / well~e.19))))))) # ::id pmid_2465_1010.229 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GATA2 is also of considerable interest ; genetic ablation leads to tumor regression in mouse models of adenocarcinoma of the lung , and whereas this transcription factor may appear to be the least druggable of targets , its role in regulating the proteasome suggested therapeutic approaches that appear very promising ( Kumar et al. , 2012 ) . # ::alignments 0-1.1.1.1.1 2-1.1.2 4-1.1.3 5-1.1 7-1.2.1.1.1 8-1.2.1.1 9-1.2.1 11-1.2.1.2.1 14-1.2.1.2.2.2 15-1.2.1.2.2 16-1.2.1.2.2.1.r 17-1.2.1.2.2.1.1.1 20-1.2.1.2.2.1.2 22-1.2 24-1.2.2.2.1.1.1.1.2 25-1.2.2.2.1.1.1.1.1 26-1.2.2.2.1.1.1.1 27-1.2.2.2 27-1.2.2.2.1.1 28-1.2.2.2.1 32-1.2.2.2.1.1.1.2 35-1.2.2.2.1.1.1.3 35-1.2.2.2.1.1.1.3.1 35-1.2.2.2.1.1.1.3.1.r 37-1.2.2.1.1.1 37-1.2.2.1.1.1.r 38-1.2.2.1.1 39-1.2.2.1.1.2.r 40-1.2.2.1.1.2 42-1.2.2.1.1.2.2.1.1 43-1.2.2.1 44-1.2.2.1.2.1 45-1.2.2.1.2 47-1.2.2.1.2.2.2 48-1.2.2.1.2.2.1 49-1.2.2.1.2.2 52-1.2.2.3.1.1.1.1.1 53-1.2.2.3.1.1 54-1.2.2.3.1.1.2.1 56-1.2.2.3.1.2.1 (m / multi-sentence :snt1 (i / interest-01~e.5 :ARG2 (p / protein :name (n / name :op1 "GATA2"~e.0)) :mod (a / also~e.2) :degree (c / considerable~e.4)) :snt2 (a2 / and~e.22 :op1 (l / lead-03~e.9 :ARG0 (a3 / ablate-01~e.8 :mod (g / genetic~e.7)) :ARG2 (r / regress-01 :ARG1 (t / tumor~e.11) :location (m2 / model~e.15 :mod~e.16 (m5 / medical-condition :name (n2 / name :op1 "adenocarcinoma"~e.17) :mod (l2 / lung~e.20)) :mod (m3 / mouse~e.14)))) :op2 (h / have-concession-91 :ARG1 (s / suggest-01~e.43 :ARG0 (r2 / role~e.38 :poss~e.37 f~e.37 :topic~e.39 (r3 / regulate-01~e.40 :ARG0 f :ARG1 (m4 / macro-molecular-complex :name (n3 / name :op1 "proteasome"~e.42)))) :ARG1 (a5 / approach-02~e.45 :ARG2 (t6 / therapy~e.44) :ARG0-of (p4 / promise-01~e.49 :degree (v / very~e.48) :ARG1-of (a6 / appear-02~e.47)))) :ARG2 (p2 / possible-01~e.27 :ARG1 (a4 / appear-02~e.28 :ARG1 (p3 / possible-01~e.27 :ARG1 (d4 / drug-01 :ARG2 (f / factor~e.26 :ARG0-of (t2 / transcribe-01~e.25) :mod (t3 / this~e.24)) :degree (l3 / least~e.32) :compared-to (t4 / thing~e.35 :ARG0-of~e.35 (t5 / target-01~e.35)))))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a7 / and~e.53 :op1 (p6 / person :name (n4 / name :op1 "Kumar"~e.52)) :op2 (p7 / person :mod (o / other~e.54))) :time (d / date-entity :year 2012~e.56)))))) # ::id pmid_2465_1010.230 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Future Prospects # ::alignments 0-1.1 1-1 (p / prospect-02~e.1 :time (f / future~e.0)) # ::id pmid_2465_1010.231 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this Review , we have summarized some of the challenges of targeting Ras cancers . # ::alignments 1-1.3.1 2-1.3 4-1.1 6-1 7-1.2.1.2 10-1.2.1.1 10-1.2.1.1.1 10-1.2.1.1.1.r 11-1.2.1.1.1.1.r 12-1.2.1.1.1.1 13-1.2.1.1.1.1.1.3.1.1 14-1.2.1.1.1.1.1.2.1 (s / summarize-01~e.6 :ARG0 (w / we~e.4) :ARG1 (t / thing :ARG1-of (i / include-91 :ARG2 (t2 / thing~e.10 :ARG0-of~e.10 (c / challenge-01~e.10 :ARG1~e.11 (t3 / target-01~e.12 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.14) :mod (e / enzyme :name (n / name :op1 "Ras"~e.13)))))) :ARG3 (s2 / some~e.7))) :medium (r / review~e.2 :mod (t4 / this~e.1))) # ::id pmid_2465_1010.232 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Despite the tremendous progress that has been made , we still have to learn a great deal about these cancers before we can be confident that we can treat them effectively . # ::alignments 0-1 2-1.2.1 3-1.2 7-1.2 9-1.1.1.1 10-1.1.1.5 13-1.1.1 15-1.1.1.3.1 16-1.1.1.3 17-1.1.1.2.r 18-1.1.1.2.3 19-1.1.1.2.2.1 20-1.1.1.4 21-1.1.1.1 22-1.1.1.4.1 24-1.1.1.4.1.1 25-1.1.1.4.1.1.1.r 26-1.1.1.4.1.1.1 27-1.1.1.4.1.1.2 28-1.1.1.4.1.1.2.1 30-1.1.1.4.1.1.2.1.3 (h / have-concession-91~e.0 :ARG1 (o / obligate-01 :ARG2 (l / learn-01~e.13 :ARG0 (w / we~e.9,21) :ARG1~e.17 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.19) :mod (t / this~e.18)) :quant (d / deal~e.16 :mod (g / great~e.15)) :time (b / before~e.20 :op1 (p / possible-01~e.22 :ARG1 (c2 / confident-01~e.24 :ARG1~e.25 w~e.26 :ARG2 (p2 / possible-01~e.27 :ARG1 (t2 / treat-04~e.28 :ARG0 w :ARG1 d2 :ARG1-of (e / effective-04~e.30)))))) :mod (s / still~e.10))) :ARG2 (p3 / progress-01~e.3,7 :degree (t3 / tremendous~e.2))) # ::id pmid_2465_1010.233 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Recent experience in targeting Raf and MEK has underscored how a pathway that appeared simple and linear is extremely complex and poorly understood at the level of detail required to shut it down effectively . # ::alignments 0-1.1.2 1-1.1 3-1.1.1 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1 7-1.1 8-1 9-1.2.1.r 11-1.2.1.1.2 13-1.2.1.1.2.3 14-1.2.1.1.2.1 16-1.2.1.1.2.2 17-1.2.1.1.2.r 18-1.2.1.1.1 19-1.2.1.1 20-1.2.1 21-1.2.1.2.3 22-1.2.1.2 23-1.2.1.2.2.r 25-1.2.1.2.2 26-1.2.1.2.2.1.r 27-1.2.1.2.2.1 28-1.2.1.2.2.1.1 29-1.2.1.2.2.1.1.1.r 30-1.2.1.2.2.1.1.1 31-1.2.1.2.2.1.1.1.1 32-1.2.1.2.2.1.1.1 33-1.2.1.2.2.1.1.1.2 (u / underscore-01~e.8 :ARG0 (e3 / experience-01~e.1,7 :ARG1 (t / target-01~e.3 :ARG1 (a / and~e.5 :op1 (e / enzyme :name (n / name :op1 "Raf"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK"~e.6)))) :time (r / recent~e.0)) :ARG1 (t2 / thing :manner-of~e.9 (a2 / and~e.20 :op1 (c / complex~e.19 :degree (e4 / extreme~e.18) :domain~e.17 (p / pathway~e.11 :ARG1-of (s / simple-02~e.14) :mod (l / linear~e.16) :ARG1-of (a3 / appear-02~e.13))) :op2 (u2 / understand-01~e.22 :ARG1 p :ARG2~e.23 (l2 / level~e.25 :mod~e.26 (d / detail-01~e.27 :ARG1-of (r2 / require-01~e.28 :ARG0~e.29 (s2 / shut-down-05~e.30,32 :ARG1 p~e.31 :ARG1-of (e5 / effective-04~e.33))))) :degree (p2 / poor~e.21))))) # ::id pmid_2465_1010.234 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nobody expected that Raf inhibitors would activate Raf kinase in Ras @-@ transformed cells , for example , or that inhibition of downstream kinases like MEK would lead to activation of upstream signaling . # ::alignments 0-1.1 0-1.1.r 0-1.2 1-1 2-1.3.r 3-1.3.1.1.1.1.1.1 4-1.3.1.1 4-1.3.1.1.1 4-1.3.1.1.1.r 6-1.3.1.1.2 7-1.3.1.1.2.1 8-1.3.1.1.2.1 9-1.3.1.1.2.2.r 10-1.3.1.1.2.2.1.1.1.1 12-1.3.1.1.2.2.1 13-1.3.1.1.2.2 15-1.3.2.1.1.2.r 16-1.3.2.1.1.2.r 18-1.3 20-1.3.2.1 22-1.3.2.1.1.1 23-1.3.2.1.1 24-1.3.1.2 24-1.3.2.1.1.2.r 25-1.3.2.1.1.2.1.1 27-1.3.2 29-1.3.1 29-1.3.2.2 30-1.3.2.2.1.r 31-1.3.2.2.1.1 32-1.3.2.2.1 (e4 / expect-01~e.1 :polarity~e.0 -~e.0 :ARG0 (a / anybody~e.0) :ARG1~e.2 (o / or~e.18 :op1 (a2 / activate-01~e.29 :ARG0 (m / molecular-physical-entity~e.4 :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (k / kinase :name (n / name :op1 "Raf"~e.3))) :ARG0-of (a3 / activate-01~e.6 :ARG1 k~e.7,8 :location~e.9 (c / cell~e.13 :ARG1-of (t2 / transform-01~e.12 :ARG0 (e6 / enzyme :name (n4 / name :op1 "Ras"~e.10)))))) :ARG0-of (e2 / exemplify-01~e.24)) :op2 (l / lead-03~e.27 :ARG0 (i2 / inhibit-01~e.20 :ARG1 (k2 / kinase~e.23 :mod (d / downstream~e.22) :example~e.15,16,24 (e3 / enzyme :name (n2 / name :op1 "MEK"~e.25)))) :ARG2 (a4 / activate-01~e.29 :ARG1~e.30 (s / signal-07~e.32 :direction (u / upstream~e.31)))))) # ::id pmid_2465_1010.235 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We need a much deeper analysis of the molecular mechanisms underlying Ras regulation and effector engagement before we can expect to interfere with these mechanisms effectively . # ::alignments 0-1.1 1-1 3-1.2.2.1.1 4-1.2.2 4-1.2.2.1 4-1.2.2.1.r 5-1.2 6-1.2.1.r 8-1.2.1.1 9-1.2.1 10-1.2.1.2 11-1.2.1.2.1.1.1.1.1 12-1.2.1.2.1.1 13-1.2.1.2.1 14-1.2.1.2.1.2.1 15-1.2.1.2.1.2 16-1.2.3 17-1.1 18-1.2.3.1 19-1.2.3.1.1 21-1.2.3.1.1.2 24-1.2.3.1.1.2.2 25-1.2.3.1.1.2.3 (n3 / need-01~e.1 :ARG0 (w / we~e.0,17) :ARG1 (a / analyze-01~e.5 :ARG1~e.6 (m / mechanism~e.9 :mod (m2 / molecule~e.8) :ARG0-of (u / underlie-01~e.10 :ARG1 (a2 / and~e.13 :op1 (r / regulate-01~e.12 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.11))) :op2 (e2 / engage-01~e.15 :ARG1 (e3 / effector~e.14))))) :ARG1-of (d / deep-02~e.4 :degree~e.4 (m3 / more~e.4 :mod (m4 / much~e.3))) :time (b / before~e.16 :op1 (p / possible-01~e.18 :ARG1 (e4 / expect-01~e.19 :ARG0 w :ARG1 (i / interfere-01~e.21 :ARG0 w :ARG1 m~e.24 :ARG1-of (e5 / effective-04~e.25))))))) # ::id pmid_2465_1010.236 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It seems to us more likely that these deeper insights will lead to productive approaches for intervention than to the conclusion that Ras is indeed undruggable . # ::alignments 1-1 2-1.2.r 3-1.2 4-1.1.1.1.1 4-1.3.1 5-1.3 6-1.1.r 7-1.1.1.2 8-1.1.1.1 8-1.1.1.1.1 8-1.1.1.1.1.r 9-1.1.1 11-1.1 12-1.1.2.r 13-1.1.2.1 14-1.1.2 15-1.1.2.2.r 16-1.1.2.2 20-1.1.2.3.1 22-1.1.2.3.1.1.2.1.1.1 24-1.1.2.3.1.1.3 (s / seem-01~e.1 :ARG1~e.6 (l / lead-03~e.11 :ARG0 (i / insight~e.9 :ARG1-of (d / deep-03~e.8 :degree~e.8 (m / more~e.4,8)) :mod (t / this~e.7)) :ARG1~e.12 (a / approach-02~e.14 :ARG1-of (p / productive-03~e.13) :purpose~e.15 (i2 / intervene-01~e.16) :ARG1-of (i3 / instead-of-91 :ARG2 (c2 / conclude-01~e.20 :ARG1 (p2 / possible-01 :polarity - :ARG1 (d2 / drug-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"~e.22))) :mod (i4 / indeed~e.24)))))) :ARG2~e.2 (w / we~e.3) :ARG1-of (l2 / likely-01~e.5 :degree (m2 / more~e.4))) # ::id pmid_2465_1010.237 ::amr-annotator SDL-AMR-09 ::preferred # ::tok New technologies and insights and fresh eyes are likely to solve this problem . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1.1.2 4-1.1 5-1.1.3.1 6-1.1.3 8-1.3 10-1 11-1.2.1 12-1.2 (s / solve-01~e.10 :ARG0 (a / and~e.2,4 :op1 (t2 / technology~e.1 :ARG1-of (n / new-01~e.0)) :op2 (i / insight~e.3 :ARG1-of n) :op3 (e / eye~e.6 :ARG1-of (f / fresh-04~e.5))) :ARG1 (p / problem~e.12 :mod (t / this~e.11)) :ARG1-of (l / likely-01~e.8)) # ::id pmid_2465_1010.238 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We are also optimistic that completely different approaches to treating cancer will contribute to eliminating Ras cancers , including new ways of knocking down @/@ out genes using RNAi and CRISPR technologies and delivering these payloads to tumors ( Davis et al. , 2010 ) , as well as new ways of deploying the immune system . # ::alignments 0-1.1 1-1.1.r 2-1.2 3-1 5-1.3.1.2.1 6-1.3.1.2 7-1.3.1 8-1.3.1.1.r 9-1.3.1.1 10-1.3.1.1.1.2.1 12-1.3 13-1.3.2.r 14-1.3.2 15-1.3.2.1.3.1.1 16-1.3.2.1.2.1 18-1.3.1.3 19-1.3.1.3.1.1.1 20-1.3.1.3.1.1 22-1.3.1.3.1.1.2.1.1 23-1.3.1.3.1.1.2.1.1 24-1.3.1.3.1.1.2.1 25-1.3.1.3.1.1.2.1.2 26-1.3.1.3.1.1.2.1.1.1 27-1.3.1.3.1.1.2.1.1.2 29-1.3.1.3.1.1.2.1.1.2.1 30-1.3.1.3.1.1.2.1.1.2.1.2.1.1.1 31-1.3.1.3.1.1.2.1.1.2.1.1 31-1.3.1.3.1.1.2.1.1.2.1.2 32-1.3.1.3.1.1.2 32-1.3.1.3.1.1.2.1.1.2.1 33-1.3.1.3.1.1.2.2 34-1.3.1.3.1.1.2.2.1.1 35-1.3.1.3.1.1.2.2.1 36-1.3.1.3.1.1.2.2.2.r 37-1.3.1.3.1.1.2.2.2 40-1.3.1.3.1.1.3.1.1.1.1.1 41-1.3.1.3.1.1.3.1.1 42-1.3.1.3.1.1.3.1.1.2.1 44-1.3.1.3.1.1.3.1.2.1 48-1.3.1.3.1.1.3.1.2.r 49-1.3.1.3.1.1.3.1.1 50-1.3.1.3.1 50-1.3.1.3.1.1.3.1.2.r 51-1.3.1.3.1.1.1 52-1.3.1.3.1.1 52-1.3.1.3.1.2 53-1.3.1.3.1.2.2.r 54-1.3.1.3.1.2.2 56-1.3.1.3.1.2.2.1.1 57-1.3.1.3.1.2.2.1 (o / optimistic~e.3 :domain~e.1 (w / we~e.0) :mod (a / also~e.2) :topic (c / contribute-01~e.12 :ARG0 (a2 / approach-02~e.7 :ARG1~e.8 (t / treat-04~e.9 :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.10))) :ARG1-of (d3 / differ-02~e.6 :ARG1-of (c2 / complete-02~e.5)) :ARG2-of (i / include-01~e.18 :ARG1 (a3 / and~e.50 :op1 (w2 / way~e.20,52 :ARG1-of (n4 / new-01~e.19,51) :manner-of (a5 / and~e.32 :op1 (s / slash~e.24 :op1 (k / knock-down-02~e.22,23 :ARG1 (g / gene~e.26) :ARG5 (u / use-01~e.27 :ARG1 (a4 / and~e.29,32 :op1 (t2 / technology~e.31 :mod (i3 / interfere-01 :ARG0 (n5 / nucleic-acid :name (n8 / name :op1 "RNA")))) :op2 (t3 / technology~e.31 :mod (d8 / dna-sequence :name (n6 / name :op1 "CRISPR"~e.30)))))) :op2 (k2 / knock-out-03~e.25 :ARG1 g :ARG2 u)) :op2 (d5 / deliver-01~e.33 :ARG1 (p / payload~e.35 :mod (t4 / this~e.34)) :ARG2~e.36 (t5 / tumor~e.37))) :ARG1-of (d6 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a6 / and~e.41,49 :op1 (p3 / person :name (n7 / name :op1 "Davis"~e.40)) :op2 (p4 / person :mod (o2 / other~e.42))) :time~e.48,50 (d / date-entity :year 2010~e.44)))) :op2 (w3 / way~e.52 :ARG1-of n4 :manner-of~e.53 (d7 / deploy-01~e.54 :ARG1 (s2 / system~e.57 :ARG1-of (i2 / immune-02~e.56))))))) :ARG2~e.13 (e2 / eliminate-01~e.14 :ARG1 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"~e.16) :mod (e / enzyme :name (n2 / name :op1 "Ras"~e.15)))))) # ::id pmid_2465_1010.239 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In this respect , it is noteworthy that anti @-@ CTLA @-@ 4 therapy appears to be equally effective in treating melanoma driven by N @-@ Ras or B @-@ Raf ; therefore , Ras cancers may not be excluded from these approaches as they have been from others . # ::alignments 0-1.1.2 1-1.1.2.1 2-1.1.2 8-1.1.1.1.1.1.1.1 10-1.1.1.1.1.1.1.1.1.1.1 12-1.1.1.1.1.1.1.1.1.1.1 13-1.1.1.1.1.1 14-1.1.1.1 17-1.1.1.1.1.3 18-1.1.1.1.1 19-1.1.1.1.1.2.r 19-1.1.2 20-1.1.1.1.1.2 21-1.1.1.1.1.2.1.1.1 22-1.1.1.1.1.2.1 22-1.1.1.1.1.2.1.2 22-1.1.1.1.1.2.1.2.r 23-1.1.1.1.1.2.1.2.1.r 24-1.1.1.1.1.2.1.2.1.1.1.1 26-1.1.1.1.1.2.1.2.1.1.1.1 27-1.1.1.1.1.2.1.2.1 28-1.1.1.1.1.2.1.2.1.2.1.1 30-1.1.1.1.1.2.1.2.1.2.1.1 32-1.2 34-1.2.1.2.1.3.1.1 35-1.2.1.2.1.2.1 36-1.2.1 37-1.2.1.1 37-1.2.1.1.r 39-1.2.1.2 39-1.2.1.2.3.1 41-1.2.1.2.2.1 42-1.2.1.2.2 42-1.2.1.2.3.1.2 43-1.2.1.2.3.1.1.r 44-1.2.1.2.3.1.1 47-1.2.1.2.3.1.2.1.r 48-1.2.1.2.3.1.2.1 (m / multi-sentence :snt1 (r / recommend-01 :ARG1 (n4 / note-01 :ARG1 (a / appear-02~e.14 :ARG1 (e / effective-04~e.18 :ARG0 (t / therapy~e.13 :mod (a2 / antibody :ARG0-of (c / counter-01~e.8 :ARG1 (p2 / protein :name (n / name :op1 "CTLA-4"~e.10,12))))) :ARG1~e.19 (t2 / treat-04~e.20 :ARG1 (m2 / medical-condition~e.22 :name (n6 / name :op1 "melanoma"~e.21) :ARG1-of~e.22 (d / drive-02~e.22 :ARG0~e.23 (o / or~e.27 :op1 (e6 / enzyme :name (n7 / name :op1 "N-Ras"~e.24,26)) :op2 (e2 / enzyme :name (n2 / name :op1 "B-Raf"~e.28,30)))))) :degree (e5 / equal~e.17)))) :mod (i3 / in-respect~e.0,2,19 :mod (t4 / this~e.1))) :snt2 (i2 / infer-01~e.32 :ARG1 (p / possible-01~e.36 :polarity~e.37 -~e.37 :ARG1 (e7 / exclude-01~e.39 :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.35) :mod (e3 / enzyme :name (n3 / name :op1 "Ras"~e.34))) :ARG2 (a3 / approach-02~e.42 :mod (t3 / this~e.41)) :ARG1-of (r2 / resemble-01 :ARG2 (e8 / exclude-01~e.39 :ARG1~e.43 d4~e.44 :ARG2 (a4 / approach-02~e.42 :mod~e.47 (o2 / other~e.48)))))))) # ::id pmid_2465_1010.240 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All of these considerations lead us to be optimistic about future prospects of finally delivering the knockout punch . # ::alignments 0-1.1.2 2-1.1.1 3-1.1 4-1 5-1.2 6-1.3.r 7-1.3.1.r 8-1.3 9-1.3.2.r 10-1.3.2.2 11-1.3.2 12-1.3.2.1.r 13-1.3.2.1.2 14-1.3.2.1 16-1.3.2.1.1.1 17-1.3.2.1.1 (l / lead-03~e.4 :ARG0 (c2 / consider-01~e.3 :mod (t / this~e.2) :mod (a / all~e.0)) :ARG1 (w / we~e.5) :ARG2~e.6 (o / optimistic~e.8 :domain~e.7 w :topic~e.9 (p / prospect-02~e.11 :ARG1~e.12 (d / deliver-01~e.14 :ARG1 (p2 / punch-01~e.17 :mod (k / knock-out-03~e.16)) :time (f2 / final~e.13)) :time (f / future~e.10)))) # ::id pmid_2465_1010.241 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 1 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 1~e.1) # ::id pmid_2465_1010.242 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Simplified View of the Ras Pathway # ::alignments 0-1.2 1-1 2-1.1.r 4-1.1.1.1 5-1.1 (v / view-02~e.1 :ARG1~e.2 (p / pathway~e.5 :name (n2 / name :op1 "Ras"~e.4)) :ARG1-of (s / simplify-01~e.0)) # ::id pmid_2465_1010.243 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras proteins are converted from their GDP state to their GTP state by GEFs , in response to upstream signals ( Bos et al. , 2007 ) . # ::alignments 0-1.2.1.1 1-1.1 1-1.2 3-1 5-1.4.2 5-1.4.2.r 6-1.4.1.1.1 7-1.3 7-1.4 8-1.3.r 9-1.3.2 9-1.3.2.r 10-1.3.1.1.1 11-1.3 13-1.1.1.1 15-1.5.r 16-1.5 17-1.5.1.r 18-1.5.1.1 19-1.5.1 22-1.6.1.1.1.1.1 23-1.6.1.1 24-1.6.1.1.2.1 26-1.6.1.2.1 (c / convert-01~e.3 :ARG0 (p2 / protein~e.1 :name (n4 / name :op1 "GEF"~e.13)) :ARG1 (p5 / protein-family~e.1 :name (n / name :op1 "Ras"~e.0)) :ARG2~e.8 (s4 / state~e.7,11 :mod (s2 / small-molecule :name (n3 / name :op1 "GTP"~e.10)) :mod~e.9 p5~e.9) :ARG3 (s3 / state~e.7 :mod (s / small-molecule :name (n2 / name :op1 "GDP"~e.6)) :poss~e.5 p5~e.5) :ARG2-of~e.15 (r / respond-01~e.16 :ARG1~e.17 (s5 / signal-07~e.19 :direction (u / upstream~e.18))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and~e.23 :op1 (p3 / person :name (n5 / name :op1 "Bos"~e.22)) :op2 (p4 / person :mod (o / other~e.24))) :time (d / date-entity :year 2007~e.26)))) # ::id pmid_2465_1010.244 ::amr-annotator SDL-AMR-09 ::preferred # ::tok GAPs convert Ras @-@ GTP back to Ras @-@ GDP . # ::alignments 0-1.1.1.1 1-1 2-1.2.1.1.1 4-1.2.2.1.1 5-1.4 6-1.3.r 7-1.3.1 9-1.3.2.1.1 (c / convert-01~e.1 :ARG0 (p / protein :name (n / name :op1 "GAP"~e.0)) :ARG1 (m / macro-molecular-complex :part (e / enzyme :name (n2 / name :op1 "Ras"~e.2)) :part (s / small-molecule :name (n3 / name :op1 "GTP"~e.4))) :ARG3~e.6 (m2 / macro-molecular-complex :part e~e.7 :part (s2 / small-molecule :name (n4 / name :op1 "GDP"~e.9))) :direction (b / back~e.5)) # ::id pmid_2465_1010.245 ::amr-annotator SDL-AMR-09 ::preferred # ::tok p120 GAP does this when recruited to activated RTKs . # ::alignments 0-1.1.1.1 1-1.1.1.2 2-1 3-1.2 4-1.3.r 5-1.3 6-1.3.2.r 7-1.3.2.2 (d / do-02~e.2 :ARG0 (p / protein :name (n / name :op1 "p120"~e.0 :op2 "GAP"~e.1)) :ARG1 (t / this~e.3) :time~e.4 (r / recruit-01~e.5 :ARG1 p :ARG2~e.6 (e / enzyme :name (n2 / name :op1 "RTK") :ARG1-of (a / activate-01~e.7)))) # ::id pmid_2465_1010.246 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The signal that directs NF1 ( neurofibromin ) / SPRED to inactivate Ras is not known . # ::alignments 1-1.2 3-1.2.1 6-1.2.1.1.1.1.1 8-1.2.1.1 9-1.2.1.1.2.1.1 11-1.2.1.2.1 12-1.2.1.2.3.1.1 14-1.1 14-1.1.r 14-1.2.1.2.1 14-1.2.1.2.1.r 15-1 (k / know-01~e.15 :polarity~e.14 -~e.14 :ARG1 (s / signal-07~e.1 :ARG0-of (d / direct-01~e.3 :ARG1 (s2 / slash~e.8 :op1 (p / protein :name (n2 / name :op1 "neurofibromin"~e.6)) :op2 (p2 / protein :name (n3 / name :op1 "SPRED"~e.9))) :ARG2 (a / activate-01 :polarity~e.14 -~e.11,14 :ARG0 s2 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.12)))))) # ::id pmid_2465_1010.247 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Several other GAPs are capable of downregulating Ras ( Bos et al. , 2007 ) . # ::alignments 0-1.1.2 1-1.1.3 2-1.1.1.1 4-1 5-1.2.r 6-1.2 7-1.2.1.1.1 10-1.3.1.1.1.1.1 11-1.3.1.1 12-1.1.3 14-1.3.1.2.1 (c / capable-01~e.4 :ARG1 (p / protein :name (n2 / name :op1 "GAP"~e.2) :quant (s / several~e.0) :mod (o / other~e.1,12)) :ARG2~e.5 (d2 / downregulate-01~e.6 :ARG1 (e / enzyme :name (n / name :op1 "Ras"~e.7)) :ARG2 p) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a / and~e.11 :op1 (p3 / person :name (n3 / name :op1 "Bos"~e.10)) :op2 (p4 / person :mod o)) :time (d / date-entity :year 2007~e.14)))) # ::id pmid_2465_1010.248 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Ras @-@ GTP binds and activates multiple downstream effectors . # ::alignments 0-1.1.1.1.1.1 2-1.1.1.2.1.1 3-1.1 4-1 5-1.2 6-1.1.2.2 7-1.1.2.1 8-1.1.2 (a / and~e.4 :op1 (b / bind-01~e.3 :ARG0 (m / macro-molecular-complex :part (e / enzyme :name (n / name :op1 "Ras"~e.0)) :part (s / small-molecule :name (n2 / name :op1 "GTP"~e.2))) :ARG1 (e2 / effector~e.8 :mod (d / downstream~e.7) :quant (m2 / multiple~e.6))) :op2 (a2 / activate-01~e.5 :ARG0 m :ARG1 e)) # ::id pmid_2465_1010.249 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The group of proteins shown on the left includes potential effectors whose significance is less well understood relative to RalGDS , Raf kinases , and PI3Ks ( Gysin et al. , 2011 ) . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 4-1.1.2 5-1.1.2.1.r 7-1.1.2.1 8-1 8-1.1.3 9-1.1.3.1.1 10-1.1.3.1 14-1.1.3.1.2.1.1.1 15-1.1.3.1.2.1.1 16-1.1.3.1.2.1 18-1.1.3.1.2.1 18-1.1.3.1.2.1.1.2.r 19-1.1.3.1.2.1.1.2.1.1.1 21-1.1.3.1.2.1.1.2.2.1.1 24-1.1.3.1.2.1.1.2 24-1.2.1.1 28-1.2.1.1.1.1.1 29-1.2.1.1 30-1.2.1.1.2.1 32-1.2.1.2.1 (i / include-01~e.8 :ARG2 (g / group~e.1 :consist-of~e.2 (p / protein~e.3) :ARG1-of (s / show-01~e.4 :location~e.5 (l / left-20~e.7)) :ARG2-of (i2 / include-01~e.8 :ARG1 (e2 / effector~e.10 :mod (p2 / potential~e.9) :ARG0-of (s2 / signify-01 :ARG1-of (u / understand-01~e.16,18 :mod (w / well~e.15 :degree (l2 / less~e.14) :compared-to~e.18 (a / and~e.24 :op1 (p3 / protein :name (n2 / name :op1 "RalGDS"~e.19)) :op2 (p8 / protein-family :name (n3 / name :op1 "Raf"~e.21)) :op3 (p7 / protein-family :name (n / name :op1 "PI3K"))))))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a2 / and~e.24,29 :op1 (p5 / person :name (n4 / name :op1 "Gysin"~e.28)) :op2 (p6 / person :mod (o / other~e.30))) :time (d / date-entity :year 2011~e.32)))) # ::id pmid_2465_1010.250 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein families are represented as single proteins to simplify the schematic ; in addition , feedback loops are not included . # ::alignments 0-1.1.1 1-1.1.2 3-1.1 5-1.1.1.1 6-1.1.1 8-1.1.3 10-1.1.3.2 12-1.2 13-1.2 15-1.2.1.2.1 16-1.2.1.2 18-1.2.1.1 18-1.2.1.1.r 19-1.2.1 (m / multi-sentence :snt1 (r / represent-01~e.3 :ARG0 (p / protein~e.0,6 :ARG1-of (s / single-02~e.5)) :ARG1 (p3 / protein-family~e.1) :purpose (s2 / simplify-01~e.8 :ARG0 r :ARG1 (s3 / schematic~e.10))) :snt2 (a / and~e.12,13 :op2 (i / include-01~e.19 :polarity~e.18 -~e.18 :ARG1 (l / loop-01~e.16 :mod (f2 / feedback~e.15))))) # ::id pmid_2465_1010.251 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 2 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 2~e.1) # ::id pmid_2465_1010.252 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Structure Showing Small Molecule @-@ Directed Electrophilic Attack of K @-@ Ras @-@ G12C # ::alignments 0-1.1 1-1 2-1.2.3.1 3-1.2.3.1 5-1.2.3 7-1.2 8-1.2.1.r 9-1.2.1.1.1 11-1.2.1.1.1 13-1.2.1.2.1 (s / show-01~e.1 :ARG0 (s2 / structure-01~e.0) :ARG1 (a / attack-01~e.7 :ARG1~e.8 (e2 / enzyme :name (n / name :op1 "K-Ras"~e.9,11) :ARG1-of (m / mutate-01 :value "G12C"~e.13)) :mod (e / electrophile) :ARG1-of (d / direct-01~e.5 :ARG0 (s3 / small-molecule~e.2,3)))) # ::id pmid_2465_1010.253 ::amr-annotator SDL-AMR-09 ::preferred # ::tok K @-@ Ras @-@ G12C ( Protein Data Bank 4LUC_A ) is displayed in surface representation . # ::alignments 0-1.1.1.1 2-1.1.1.1 4-1.1.2.1 6-1.1.3.2 7-1.1.3 8-1.1.3 10-1.1.3.1.1 14-1 15-1.2.r 16-1.2.1 17-1.2 (d / display-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"~e.0,2) :ARG1-of (m / mutate-01 :value "G12C"~e.4) :part-of (d2 / data-bank~e.7,8 :name (n2 / name :op1 "4LUC_A"~e.10) :mod (p / protein~e.6))) :ARG2~e.15 (r / represent-01~e.17 :ARG2 (s / surface~e.16))) # ::id pmid_2465_1010.254 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cocrystallized ligands , GDP and N-( 1-[( 2,4 @-@ dichlorophenoxy ) acetyl]piperidin @- 4 @-@ yl ) - 4 @-@ sulfanylbutanamide , are shown in stick mode . # ::alignments 2-1.1 2-1.1.2.1.1 2-1.1.2.1.2 4-1.1.2.1.1.1.1 5-1.1.2.1 14-1.1.2.1.2.1.1 19-1.1.2.1.2.1.1 21-1.1.2.1.2.1.1 24-1 25-1.2.r 26-1.2.1 27-1.2 (s2 / show-01~e.24 :ARG1 (l / ligand~e.2 :ARG1-of (c / cocrystallize-00) :ARG1-of (m / mean-01 :ARG2 (a / and~e.5 :op1 (l2 / ligand~e.2 :name (n2 / name :op1 "GDP"~e.4)) :op1 (l3 / ligand~e.2 :name (n3 / name :op1 "N-(1-[(2,4-dichlorophenoxy)acetyl]piperidin-4-yl)-4-sulfanylbutanamide"~e.14,19,21))))) :manner~e.25 (m2 / mode~e.27 :mod (s / stick~e.26))) # ::id pmid_2465_1010.255 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The location of calcium ion is shown as a green ball . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 6-1 7-1.2.r 9-1.2.1 10-1.2 (s / show-01~e.6 :ARG1 (l / location~e.1 :location-of~e.2 (c / calcium~e.3 :ARG1-of (i2 / ionize-01))) :manner~e.7 (b / ball~e.10 :ARG1-of (g / green-02~e.9))) # ::id pmid_2465_1010.256 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Switch 1 ( 28 @–@ 38 ) and switch 2 ( 57 @–@ 63 ) are highlighted by orange and red colors , respectively . # ::alignments 0-1.1.1 1-1.1.1.1.1 3-1.1.1.2.1 5-1.1.1.2.2 7-1 8-1.1.1 8-1.2.1 9-1.2.1.1.1 11-1.2.1.2.1 13-1.2.1.2.2 16-1.1 16-1.2 17-1.1.2.r 18-1.1.2 19-1 20-1.2.2 (a2 / and~e.7,19 :op1 (h / highlight-01~e.16 :ARG1 (s / switch~e.0,8 :ord (o / ordinal-entity :value 1~e.1) :mod (v / value-interval :op1 28~e.3 :op2 38~e.5)) :manner~e.17 (o2 / orange~e.18)) :op2 (h2 / highlight-01~e.16 :ARG1 (s2 / switch~e.8 :ord (o3 / ordinal-entity :value 2~e.9) :mod (v2 / value-interval :op1 57~e.11 :op2 63~e.13)) :manner (r / red-02~e.20))) # ::id pmid_2465_1010.257 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Key ligand @-@ interacting residue ( C12 , V9 , V7 , F78 , I100 , M72 , Q99 , and R68 ) positions are colored green . # ::alignments 0-1.1.10 1-1.1.9.1 3-1.1.9 4-1.1.1.1 4-1.1.2.1 4-1.1.3.1 4-1.1.4.1 4-1.1.5.1 4-1.1.6.1 4-1.1.7.1 4-1.1.8.1 20-1.1 23-1.1.1 23-1.1.2 23-1.1.3 23-1.1.4 23-1.1.5 23-1.1.6 23-1.1.7 23-1.1.8 25-1 26-1.2 (c / color-01~e.25 :ARG1 (a / and~e.20 :op1 (p / position~e.23 :location-of (r / residue~e.4 :mod (a2 / amino-acid :mod 12 :name (n / name :op1 "cysteine")))) :op2 (p2 / position~e.23 :location-of (r2 / residue~e.4 :mod (a3 / amino-acid :mod 9 :name (n2 / name :op1 "valine")))) :op3 (p3 / position~e.23 :location-of (r3 / residue~e.4 :mod (a4 / amino-acid :mod 7 :name (n3 / name :op1 "valine")))) :op4 (p4 / position~e.23 :location-of (r4 / residue~e.4 :mod 78 :mod (a5 / amino-acid :name (n4 / name :op1 "phenylalanine")))) :op5 (p5 / position~e.23 :location-of (r5 / residue~e.4 :mod 100 :mod (a6 / amino-acid :name (n5 / name :op1 "isoleucine")))) :op6 (p6 / position~e.23 :location-of (r6 / residue~e.4 :mod 72 :mod (a7 / amino-acid :name (n6 / name :op1 "methionine")))) :op7 (p7 / position~e.23 :location-of (r7 / residue~e.4 :mod 99 :mod (a8 / amino-acid :name (n7 / name :op1 "glutamine")))) :op8 (p8 / position~e.23 :location-of (r8 / residue~e.4 :mod 68 :mod (a9 / amino-acid :name (n8 / name :op1 "arginine")))) :ARG0-of (i / interact-01~e.3 :ARG1 (l / ligand~e.1)) :ARG1-of (k / key-02~e.0)) :ARG2 (g / green-02~e.26 :ARG1 a)) # ::id pmid_2465_1010.258 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Position of C12 residue is shown in ball and stick ( green ) . # ::alignments 0-1.1 3-1.1.1 5-1 6-1.2.r 7-1.2.1 8-1.2 9-1.2.2 11-1.2.3 (s / show-01~e.5 :ARG1 (p / position-01~e.0 :ARG1 (r / residue~e.3 :mod (a / amino-acid :mod 12 :wiki "Cysteine" :name (n / name :op1 "cysteine")))) :manner~e.6 (a2 / and~e.8 :op1 (b / ball~e.7) :op2 (s2 / stick~e.9) :ARG1-of (g / green-02~e.11))) # ::id pmid_2465_1010.259 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Note that residues 58 and 60 are part of both switch 2 and the key ligand @-@ interacting group ( shown in blue ) . # ::alignments 0-1 1-1.1.r 2-1.1.1 2-1.1.2 3-1.1.1.1.1 4-1.1 4-1.1.3 5-1.1.2.1.1 7-1.1.3.r 10-1.1.3.1 11-1.1.3.1.1 12-1.1.3 14-1.1.3.2.2 15-1.1.3.2.1.1 17-1.1.3.2.1 18-1.1.3.2 20-1.2 21-1.2.1.r 22-1.2.1 (n / note-01~e.0 :ARG1~e.1 (a / and~e.4 :op1 (r / residue~e.2 :mod (a2 / amino-acid :mod 58~e.3)) :op2 (r2 / residue~e.2 :mod (a3 / amino-acid :mod 60~e.5)) :part-of~e.7 (a4 / and~e.4,12 :op1 (s / switch~e.10 :mod 2~e.11) :op2 (g / group~e.18 :ARG0-of (i / interact-01~e.17 :ARG1 (l / ligand~e.15)) :ARG1-of (k / key-02~e.14)))) :ARG1-of (s2 / show-01~e.20 :manner~e.21 (b / blue~e.22))) # ::id pmid_2465_1010.260 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Figure 3 # ::alignments 0-1 1-1.1 (f / figure~e.0 :mod 3~e.1) # ::id pmid_2465_1010.261 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Schematic Representation of the Ras Isoforms # ::alignments 0-1.2 1-1 2-1.1.r 4-1.1.1.1 5-1.1 (r / representation-02~e.1 :ARG1~e.2 (i / isoform~e.5 :name (n2 / name :op1 "Ras"~e.4)) :ARG2 (s / schematic~e.0)) # ::id pmid_2465_1010.262 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The structures of the G domain of H @-@ Ras , N @-@ Ras , and K @-@ Ras have been solved and are virtually identical , but the structure of processed hypervariable regions has not been solved and is therefore depicted as a linear sequence . # ::alignments 1-1.1.1.1 4-1.1.1.1.1.1.1 4-1.1.1.2.1.1.1 4-1.1.1.3.1.1.1 5-1.1.1.1.1.1.2 5-1.1.1.2.1.1.2 5-1.1.1.3.1.1.2 6-1.1.1.1.1.r 7-1.1.1.1.1.2.1.1 9-1.1.1.1.1.2.1.1 9-1.1.1.2.1.2.1.1 9-1.1.1.3.1.2.1.1 11-1.1.1.2.1.2.1.1 13-1.1.1.1.1.2.1.1 13-1.1.1.2.1.2.1.1 13-1.1.1.3.1.2.1.1 15-1.1.1 16-1.1.1.3.1.2.1.1 18-1.1.1.1.1.2.1.1 18-1.1.1.2.1.2.1.1 18-1.1.1.3.1.2.1.1 21-1.1 22-1 24-1.2.2 25-1.2 27-1.3 29-1.1.1.2 29-1.1.1.3 29-1.3.1.1.2 30-1.3.1.1.2.1.r 30-1.3.1.r 31-1.3.1.1.2.1.2 33-1.3.1.1.2.1 35-1.3.1.1.1 35-1.3.1.1.1.r 37-1.3.1.1 38-1.3.1 41-1.3.1.2 42-1.3.1.2.2.r 44-1.3.1.2.2.1 45-1.3.1.2.2 (a / and~e.22 :op1 (s / solve-01~e.21 :ARG1 (a2 / and~e.15 :op1 (s2 / structure-01~e.1 :ARG1~e.6 (p / protein-segment :name (n3 / name :op1 "G"~e.4 :op2 "domain"~e.5) :part-of (e / enzyme :name (n / name :op1 "H-Ras"~e.7,9,13,18)))) :op2 (s3 / structure-01~e.29 :ARG1 (p2 / protein-segment :name (n4 / name :op1 "G"~e.4 :op2 "domain"~e.5) :part-of (e3 / enzyme :name (n5 / name :op1 "N-Ras"~e.9,11,13,18)))) :op3 (s4 / structure-01~e.29 :ARG1 (p3 / protein-segment :name (n6 / name :op1 "G"~e.4 :op2 "domain"~e.5) :part-of (e2 / enzyme :name (n2 / name :op1 "K-Ras"~e.9,13,16,18)))))) :op2 (i / identical-01~e.25 :ARG1 a2 :mod (v / virtual~e.24)) :ARG1-of (c / contrast-01~e.27 :ARG2~e.30 (a3 / and~e.38 :op1 (s5 / solve-01~e.37 :polarity~e.35 -~e.35 :ARG1 (s6 / structure-01~e.29 :ARG1~e.30 (r / region~e.33 :ARG1-of (v2 / vary-01 :degree (h / hyper)) :ARG1-of (p4 / process-01~e.31)))) :op2 (d / depict-01~e.41 :ARG1 s6 :ARG2~e.42 (s7 / sequence~e.45 :mod (l / linear~e.44)))))) # ::id pmid_2465_1010.263 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Lipid modifications with farnesyl ( purple ) and palmitoyl ( orange ) chains are shown . # ::alignments 0-1.1.1 1-1.1 2-1.1.2.r 3-1.1.2.1.1 5-1.1.2.1.2 7-1.1.2 8-1.1.2.2.1 10-1.1.2.2.1.1.1 12-1.1.2.1 12-1.1.2.2 14-1 (s / show-01~e.14 :ARG1 (m / modify-01~e.1 :ARG1 (l / lipid~e.0) :instrument~e.2 (a / and~e.7 :op1 (c / chain~e.12 :mod (f / farnesyl~e.3) :ARG1-of (p / purple-02~e.5)) :op2 (c2 / chain~e.12 :mod (p2 / palmitoyl~e.8 :ARG1-of (r4 / represent-01 :ARG0 (o / orange~e.10))))))) # ::id pmid_2470_8867.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Met receptor @-@ induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells , albeit they are required for distinct oncogenic functions ( PMID : 24708867 ) # ::alignments 0-1.1.2.1.1.1 1-1.1.2.1 3-1.1.2 4-1.1.1.1.1.1 6-1.1.1.2.1.1 7-1.1 9-1 10-1.2 11-1.2.1.r 12-1.2.1.1.1 13-1.2.1.1 14-1.2.1 17-1.3.2 19-1.3 20-1.3.1.r 21-1.3.1.2 22-1.3.1.1 22-1.3.1.1.1 22-1.3.1.1.1.r 23-1.3.1 (p / promote-02~e.9 :ARG0 (s / signal-07~e.7 :ARG0 (a / and :op1 (p2 / protein :name (n / name :op1 "Grb2"~e.4)) :op2 (p3 / protein :name (n2 / name :op1 "Shc"~e.6))) :ARG2-of (i / induce-01~e.3 :ARG0 (r / receptor~e.1 :name (n3 / name :op1 "Met"~e.0)))) :ARG1 (t / transform-01~e.10 :ARG1~e.11 (c / cell~e.14 :source (e / epithelium~e.13 :part-of (i2 / intestine~e.12)))) :concession (r2 / require-01~e.19 :ARG0~e.20 (f / function-01~e.23 :ARG0-of (c2 / cause-01~e.22 :ARG1~e.22 (c3 / cancer~e.22)) :mod (d / distinct~e.21)) :ARG1 a~e.17) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID24708867"))) # ::id pmid_2470_8867.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2470_8867.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We show , for the first time , that constitutive activation of either Grb2 or Shc signals in IEC @-@ 6 cells , promotes morphological transformation associated with down @-@ regulation of E @-@ cadherin , as well as increased cell growth , loss of growth contact inhibition , anchorage @-@ independent growth , and resistance to serum deprivation and anoikis . # ::alignments 0-1.1 1-1 3-1.3.r 5-1.3 5-1.3.1 5-1.3.1.r 8-1.2.r 9-1.2.1.2 10-1.2.1 13-1.2.1.1.1.1.1.1 14-1.2.1.1.1 15-1.2.1.1.1.2.1.1 16-1.2.1.1 17-1.2.1.3.r 18-1.2.1.3.1.1 20-1.2.1.3.1.1 21-1.2.1.3 23-1.2 24-1.2.2.1.1 25-1.2.2.1 26-1.2.2.1.2 27-1.2.2.1.2.1.r 28-1.2.2.1.2.1 29-1.2.2.1.2.1 30-1.2.2.1.2.1 31-1.2.2.1.2.1.1.r 32-1.2.2.1.2.1.1.1.1 34-1.2.2.1.2.1.1.1.1 36-1.2.2 37-1.2.2 38-1.2.2 38-1.2.2.r 39-1.2.2.2.2 40-1.2.2.2.1 41-1.2.2.2 43-1.2.2.3 44-1.2.2.3.1.r 45-1.2.2.3.1.2 46-1.2.2.3.1.1 47-1.2.2.3.1 49-1.2.2.4.1.2 51-1.2.2.4.1 51-1.2.2.4.1.1 51-1.2.2.4.1.1.r 52-1.2.2.4 54-1.2.2 55-1.2.2.5 56-1.2.2.5.1.r 57-1.2.2.5.1.1.1 58-1.2.2.5.1.1 59-1.2.2.5.1 60-1.2.2.5.1.2 (s / show-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.8 (p / promote-02~e.23 :ARG0 (a / activate-01~e.10 :ARG1 (s2 / signal-07~e.16 :ARG0 (o2 / or~e.14 :op1 (p2 / protein :name (n / name :op1 "Grb2"~e.13)) :op2 (p3 / protein :name (n2 / name :op1 "Shc"~e.15)))) :mod (c / constitutive~e.9) :location~e.17 (c2 / cell-line~e.21 :name (n3 / name :op1 "IEC-6"~e.18,20))) :ARG1~e.38 (a2 / and~e.36,37,38,54 :op1 (t / transform-01~e.25 :mod (m / morphological~e.24) :ARG1-of (a3 / associate-01~e.26 :ARG2~e.27 (d / downregulate-01~e.28,29,30 :ARG1~e.31 (p4 / protein :name (n4 / name :op1 "E-cadherin"~e.32,34))))) :op2 (g / grow-01~e.41 :ARG1 (c3 / cell~e.40) :ARG1-of (i / increase-01~e.39)) :op3 (l / lose-01~e.43 :ARG1~e.44 (i2 / inhibit-01~e.47 :ARG0 (c4 / contact-01~e.46) :ARG1 (g2 / grow-01~e.45))) :op4 (g3 / grow-01~e.52 :ARG0-of (d2 / depend-01~e.51 :polarity~e.51 -~e.51 :ARG1 (a4 / anchorage~e.49))) :op5 (r / resist-01~e.55 :ARG1~e.56 (a5 / and~e.59 :op1 (d3 / deprive-01~e.58 :ARG1 (s3 / serum~e.57)) :op2 (a6 / anoikis~e.60))))) :ord~e.3 (o / ordinal-entity~e.5 :value~e.5 1~e.5)) # ::id pmid_2470_8867.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogenic activation of Met was revealed to induce morphological transformation , E @-@ cadherin down @-@ regulation , and protection against anoikis by mechanisms dependent on Grb2 , while Shc was shown to be partly required for enhanced cell growth . # ::alignments 0-1.1.1.1.2 0-1.1.1.1.2.1 0-1.1.1.1.2.1.r 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1.1.1 5-1.1 7-1.1.1 8-1.1.1.2.1.1 9-1.1.1.2.1 11-1.1.1.2.2.1.1.1 13-1.1.1.2.2.1.1.1 14-1.1.1.2.2 15-1.1.1.2.2 16-1.1.1.2.2 18-1.1.1.2 19-1.1.1.2.3 20-1.1.1.2.3.1.r 21-1.1.1.2.3.1 22-1.1.1.2.3.2.r 23-1.1.1.2.3.2 24-1.1.1.2.3.2.1 25-1.1.1.2.3.2.1.1.r 26-1.1.1.2.3.2.1.1.1.1 28-1 29-1.2.1.2.1.1 31-1.2 34-1.2.1.3 34-1.2.1.3.r 35-1.2.1 36-1.2.1.1.r 37-1.2.1.1.2 38-1.2.1.1.1 39-1.2.1.1 (c / contrast-01~e.28 :ARG1 (r / reveal-01~e.5 :ARG1 (i / induce-01~e.7 :ARG0 (a / activate-01~e.1 :ARG1~e.2 (p5 / protein :name (n / name :op1 "Met"~e.3)) :ARG0-of (c2 / cause-01~e.0 :ARG1~e.0 (c3 / cancer~e.0))) :ARG1 (a2 / and~e.18 :op1 (t / transform-01~e.9 :mod (m / morphological~e.8)) :op2 (d / downregulate-01~e.14,15,16 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin"~e.11,13))) :op3 (p2 / protect-01~e.19 :ARG2~e.20 (a3 / anoikis~e.21) :ARG3~e.22 (m2 / mechanism~e.23 :ARG0-of (d2 / depend-01~e.24 :ARG1~e.25 (p3 / protein :name (n3 / name :op1 "Grb2"~e.26)))))))) :ARG2 (s / show-01~e.31 :ARG1 (r3 / require-01~e.35 :ARG0~e.36 (g / grow-01~e.39 :ARG1 (c4 / cell~e.38) :ARG1-of (e / enhance-01~e.37)) :ARG1 (p4 / protein :name (n4 / name :op1 "Shc"~e.29)) :degree~e.34 (p6 / part~e.34)))) # ::id pmid_2470_8867.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The coupling of activated Met to the Ras/MEK/Erk and PI3K @/@ Akt pathways , and the sustained engagement of Grb2 or Shc in IECs , was shown to trigger negative feedback , limiting the extent of activation of these pathways . # ::alignments 1-1.1.1.1 2-1.1.1.1.1.r 3-1.1.1.1.1.2 4-1.1.1.1.1.1.1 7-1.1.1.1.2.1.1.1 9-1.1.1.1.2.2.1.1 11-1.1.1.1.2.2.1.1 12-1.1.1.1.2.1 12-1.1.1.1.2.2 14-1.1.1 14-1.1.1.1.2 16-1.1.1.2.3 17-1.1.1.2 18-1.1.1.2.1.r 19-1.1.1.2.1.1.1.1 20-1.1.1.2.1 21-1.1.1.2.1.2.1.1 22-1.1.1.2.2.r 23-1.1.1.2.2.1.1 26-1 28-1.1 29-1.1.2.1 30-1.1.2 32-1.1.3 34-1.1.3.1 35-1.1.3.1.1.r 36-1.1.3.1.1 37-1.1.3.1.1.1.r 38-1.1.3.1.1.1.3 39-1.1.3.1.1.1.1 (s / show-01~e.26 :ARG1 (t / trigger-01~e.28 :ARG0 (a / and~e.14 :op1 (c / couple-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "Met"~e.4) :ARG1-of (a3 / activate-01~e.3)) :ARG2 (a2 / and~e.14 :op1 (p2 / pathway~e.12 :name (n2 / name :op1 "Ras/MEK/Erk"~e.7)) :op2 (p3 / pathway~e.12 :name (n3 / name :op1 "PI3K/Akt"~e.9,11)))) :op2 (e / engage-01~e.17 :ARG1~e.18 (o / or~e.20 :op1 (p4 / protein :name (n4 / name :op1 "Grb2"~e.19)) :op2 (p5 / protein :name (n5 / name :op1 "Shc"~e.21))) :ARG2~e.22 (c2 / cell :name (n6 / name :op1 "IEC"~e.23)) :ARG1-of (s2 / sustain-01~e.16))) :ARG1 (f / feedback~e.30 :ARG0-of (n7 / negative-03~e.29)) :ARG0-of (l / limit-01~e.32 :ARG1 (e2 / extent~e.34 :extent-of~e.35 (a5 / activate-01~e.36 :ARG1~e.37 (a6 / and :op1 p2~e.39 :op2 p3 :mod (t2 / this~e.38))))))) # ::id pmid_2470_8867.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nonetheless , morphological alterations and E @-@ cadherin down @-@ regulation induced by the oncogenic Tpr @-@ Met , and by Grb2 or Shc signals , were blocked by MEK , but not PI3K , inhibitors while the enhanced growth and resistance to anoikis induced by Tpr @-@ Met were nearly abolished by co @-@ treatment with both inhibitors . # ::alignments 0-1 2-1.1.1.1.2.1.1 3-1.1.1.1.2.1 4-1.1.1.1.2 5-1.1.1.1.2.2.1.1.1 7-1.1.1.1.2.2.1.1.1 8-1.1.1.1.2.2 9-1.1.1.1.2.2 10-1.1.1.1.2.2 11-1.1.1.1.2.2.2 12-1.1.1.1.2.2.2.1.r 14-1.1.1.1.2.2.2.1.1 14-1.1.1.1.2.2.2.1.1.2 14-1.1.1.1.2.2.2.1.1.2.1 14-1.1.1.1.2.2.2.1.1.2.1.r 14-1.1.1.1.2.2.2.1.1.2.r 15-1.1.1.1.2.2.2.1.1.1.1 17-1.1.1.1.2.2.2.1.1.1.1 19-1.1.1.1.2.2.2.1 21-1.1.1.1.2.2.2.1.2.1.1.1.1 22-1.1.1.1.2.2.2.1.2.1 23-1.1.1.1.2.2.2.1.2.1.2.1.1 24-1.1.1.1.2.2.2.1.2 27-1.1.1.1 27-1.1.1.2 29-1.1.1.1.1.1.1.1.1 31-1.1.1 32-1.1.1.2.1 32-1.1.1.2.1.r 33-1.1.1.2.2.1.1.1.1 35-1.1.1.1.1 35-1.1.1.1.1.1 35-1.1.1.1.1.1.r 35-1.1.1.2.2 35-1.1.1.2.2.1 35-1.1.1.2.2.1.r 36-1.1 38-1.1.2.1.1.1 39-1.1.2.1.1 40-1.1.2.1 41-1.1.2.1.2 42-1.1.2.1.2.1.r 43-1.1.2.1.2.1 44-1.1.2.1.2.1.1 45-1.1.2.1.2.1.1.1.r 46-1.1.2.1.2.1.1.1 47-1.1.2.1.2.1.1.1 48-1.1.2.1.2.1.1.1 50-1.1.2.2 51-1.1.2 55-1.1.2.3 56-1.1.2.3.r 58-1.1.2.3.1.2 (h / have-concession-91~e.0 :ARG1 (c / contrast-01~e.36 :ARG1 (c2 / contrast-01~e.31 :ARG1 (b / block-01~e.27 :ARG0 (m2 / molecular-physical-entity~e.35 :ARG0-of~e.35 (i2 / inhibit-01~e.35 :ARG1 (p6 / protein-family :name (n5 / name :op1 "MEK"~e.29)))) :ARG1 (a / and~e.4 :op1 (a2 / alter-01~e.3 :mod (m / morphological~e.2)) :op2 (d / downregulate-01~e.8,9,10 :ARG1 (p / protein :name (n / name :op1 "E-cadherin"~e.5,7)) :ARG2-of (i / induce-01~e.11 :ARG0~e.12 (a3 / and~e.19 :op1 (p2 / protein~e.14 :name (n2 / name :op1 "Tpr-Met"~e.15,17) :ARG0-of~e.14 (c3 / cause-01~e.14 :ARG1~e.14 (c4 / cancer~e.14))) :op1 (s / signal-07~e.24 :ARG0 (o / or~e.22 :op1 (p3 / protein :name (n3 / name :op1 "Grb2"~e.21)) :op2 (p4 / protein :name (n4 / name :op1 "Shc"~e.23))))))))) :ARG2 (b2 / block-01~e.27 :polarity~e.32 -~e.32 :ARG0 (m3 / molecular-physical-entity~e.35 :ARG0-of~e.35 (i3 / inhibit-01~e.35 :ARG1 (p5 / protein-family :name (n6 / name :op1 "PI3K"~e.33)))) :ARG1 a)) :ARG2 (a4 / abolish-01~e.51 :ARG1 (a5 / and~e.40 :op1 (g / grow-01~e.39 :ARG1-of (e3 / enhance-01~e.38)) :op2 (r / resist-01~e.41 :ARG1~e.42 (a6 / anoikis~e.43 :ARG2-of (i4 / induce-01~e.44 :ARG0~e.45 p2~e.46,47,48)))) :mod (n7 / near~e.50) :instrument~e.56 (t / treat-04~e.55 :ARG2 (a7 / and :op1 m2 :op2 m3~e.58))))) # ::id pmid_2470_8867.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2470_8867.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogenic engagement of Grb2 or Shc signaling promotes morphological transformation in normal IECs and reduces E @-@ cadherin expression # ::alignments 1-1.1.1.2 1-1.1.1.2.1 1-1.1.1.2.1.r 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1.1 5-1.1.1.1.1 6-1.1.1.1.1.2.1.1 7-1.1.1.1 8-1.1 9-1.1.2.2 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1 12-1.1.2.1.2 12-1.1.2.1.2.r 13-1.1.2.1.1.1 14-1 15-1.2 16-1.2.2.1.1.1 18-1.2.2.1.1.1 19-1.2.2 (a / and~e.14 :op1 (p / promote-02~e.8 :ARG0 (e / engage-01~e.2 :ARG1~e.3 (s / signal-07~e.7 :ARG0 (o / or~e.5 :op1 (p2 / protein :name (n / name :op1 "Grb2"~e.4)) :op2 (p3 / protein :name (n2 / name :op1 "Shc"~e.6)))) :ARG0-of (c / cause-01~e.1 :ARG1~e.1 (c2 / cancer~e.1))) :ARG1 (t / transform-01~e.10 :ARG1~e.11 (c3 / cell~e.12 :name (n3 / name :op1 "IEC"~e.13) :ARG1-of~e.12 (n4 / normal-02~e.12)) :mod (m / morphological~e.9))) :op2 (r / reduce-01~e.15 :ARG0 e :ARG1 (e2 / express-03~e.19 :ARG2 (p4 / protein :name (n5 / name :op1 "E-cadherin"~e.16,18))))) # ::id pmid_2470_8867.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast with many other RTKs , the ability of the Met receptor to recruit signaling proteins , and thus its biological activities , is dependent on two phospho @-@ Tyr residues located within its C @-@ terminus ( Y1349/Y1356 in Met ; Y482 @/@ Y489 in Tpr @-@ Met [ @ 28 @ - @ 30 @ ]) . # ::alignments 1-1 2-1.2.r 3-1.2.2 4-1.2.3 8-1.1.1 9-1.1.1.1.r 11-1.1.1.1.1.1 12-1.1.1.1 13-1.1.1.3 14-1.1.1.2 15-1.1.1.2.2.1 16-1.1.1.2.2 19-1.1.1.3 20-1.1.1.3.1.1 20-1.1.1.3.1.1.r 21-1.1.1.3.1.2 22-1.1.1.3.1 25-1.1 28-1.1.2.1.1 30-1.1.2.1.3.1.2.1 30-1.1.2.1.3.2.2.1 30-1.1.2.2.2.1.2.1 30-1.1.2.2.2.2.2.1 31-1.1.2.1 31-1.1.2.2 32-1.1.2.1.2.r 33-1.2.2.r 34-1.1.2.1.2.2 34-1.1.2.1.2.2.r 35-1.1.2.1.2.1.1 37-1.1.2.1.2.1.1 40-1.1.2.1.3.r 41-1.1.2.1.3.3.1.1 44-1.1.2.1.3 44-1.1.2.2.2 46-1.1.2.2.2.3.r 47-1.1.2.2.2.3.1.1 49-1.1.2.1.3.3.1.1 52-1.1.2.3.1.1.1.1 56-1.1.2.3.1.1.1.2 (c / contrast-01~e.1 :ARG1 (d / depend-01~e.25 :ARG0 (c2 / capable-01~e.8 :ARG1~e.9 (r / receptor~e.12 :name (n / name :op1 "Met"~e.11)) :ARG2 (r2 / recruit-01~e.14 :ARG0 r :ARG1 (p / protein~e.16 :ARG0-of (s / signal-07~e.15))) :ARG0-of (c3 / cause-01~e.13,19 :ARG1 (a4 / activity-06~e.22 :ARG0~e.20 r~e.20 :mod (b2 / biology~e.21)))) :ARG1 (a2 / and :op1 (r3 / residue~e.31 :ARG1-of (p2 / phosphorylate-01~e.28) :location~e.32 (p3 / protein-segment :name (n3 / name :op1 "C-terminus"~e.35,37) :part-of~e.34 r~e.34) :mod~e.40 (s2 / slash~e.44 :op1 (a / amino-acid :mod 1349 :name (n5 / name :op1 "tyrosine"~e.30)) :op2 (a3 / amino-acid :mod 1356 :name (n6 / name :op1 "tyrosine"~e.30)) :part-of (p7 / protein :name (n10 / name :op1 "Met"~e.41,49)))) :op2 (r4 / residue~e.31 :ARG1-of p2 :mod (s3 / slash~e.44 :op1 (a5 / amino-acid :mod 482 :name (n4 / name :op1 "tyrosine"~e.30)) :op2 (a6 / amino-acid :mod 489 :name (n9 / name :op1 "tyrosine"~e.30)) :part-of~e.46 (p4 / protein :name (n2 / name :op1 "Tpr-Met"~e.47)))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c4 / cite-01 :ARG2 (v / value-interval :op1 28~e.52 :op2 30~e.56)))))) :ARG2~e.2 (e / enzyme :name (n7 / name :op1 "RTK") :quant~e.33 (m / many~e.3) :mod (o / other~e.4))) # ::id pmid_2470_8867.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This unique characteristic has been exploited to generate Met receptor variants capable of binding exclusively to a single RTK @-@ proximal signaling protein [ @ 8 @ ] . # ::alignments 0-1.1.2 1-1.1.1 2-1.1 2-1.1.3 2-1.1.3.r 5-1 7-1.2 8-1.2.1.1.2.1 9-1.2.1.1 10-1.2.1 11-1.2.1.2 12-1.2.1.2.1.r 13-1.2.1.2.1 14-1.2.1.2.1.3 15-1.2.1.2.1.2.r 17-1.2.1.2.1.2.2 18-1.2.1.2.1.2.1.1.2.1 20-1.2.1.2.1.2.1.2 21-1.2.1.2.1.2.1 22-1.2.1.2.1.2 25-1.3.1.1.1 (e / exploit-01~e.5 :ARG1 (t2 / thing~e.2 :mod (u / unique~e.1) :mod (t / this~e.0) :ARG2-of~e.2 (c / characteristic-02~e.2)) :ARG2 (g / generate-01~e.7 :ARG1 (v / variant~e.10 :mod (r / receptor~e.9 :wiki "C-Met" :name (n / name :op1 "Met"~e.8)) :ARG1-of (c2 / capable-01~e.11 :ARG2~e.12 (b / bind-01~e.13 :ARG1 v :ARG2~e.15 (p / protein~e.22 :ARG0-of (s / signal-07~e.21 :ARG1 (e3 / enzyme :wiki "Receptor_tyrosine_kinase" :name (n2 / name :op1 "RTK"~e.18)) :mod (p2 / proximal~e.20)) :ARG1-of (s2 / single-02~e.17)) :manner (e2 / exclusive-02~e.14))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG0-of (c3 / cite-01 :ARG2 8~e.25)))) # ::id pmid_2470_8867.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These well @-@ characterized docking @-@ specific Met variants consist of the cytosolic oncogenic form of the Met receptor , Tpr @-@ Met , in which the multi @-@ substrate binding region has been replaced with a motif selective for the recruitment of a single signaling protein , found in other RTKs ( Additional file 1 and [ @ 8 @ ]) . # ::alignments 0-1.1.4 1-1.1.3.1 3-1.1.3 4-1.1.2.1 6-1.1.2 7-1.1.1.1.1 8-1.1 9-1 10-1.2.r 12-1.2.2 13-1.2.1 13-1.2.1.1 13-1.2.1.1.r 14-1.2 15-1.2.3.r 17-1.2.3.1.1 18-1.1.1 18-1.2.3 18-1.2.4.1 20-1.2.4.1.1.1 22-1.2.3.1.1 27-1.2.5.2.1 29-1.2.5.2 30-1.2.5.1 31-1.2.5 34-1.2.5.3 35-1.2.5.3.1.r 37-1.2.5.3.1 41-1.2.5.3.1.1.1 42-1.2.5.3.1.1.1.1.r 44-1.2.5.3.1.1.1.1.2 45-1.2.5.3.1.1.1.1.1 46-1.2.5.3.1.1.1.1 48-1.2.5.3.1.1.1.1.3 50-1.1.1.2 50-1.2.5.3.1.1.1.1.3.1.2 53-1.3.1.1.2 54-1.3.1.1 56-1.3.1.1.1 58-1.3.1 61-1.3.1.2.1.1 (c / consist-01~e.9 :ARG1 (v / variant~e.8 :mod (r / receptor~e.18 :name (n / name :op1 "Met"~e.7) :mod (o / other~e.50)) :ARG1-of (s / specific-02~e.6 :ARG2 (d / dock-01~e.4)) :ARG1-of (c2 / characterize-01~e.3 :ARG1-of (w / well-09~e.1)) :mod (t / this~e.0)) :ARG2~e.10 (f / form~e.14 :ARG0-of (c3 / cause-01~e.13 :ARG1~e.13 (c4 / cancer~e.13)) :mod (c5 / cytosol~e.12) :mod~e.15 (r2 / receptor~e.18 :name (n2 / name :op1 "Met"~e.17,22)) :ARG1-of (m / mean-01 :ARG2 (r3 / receptor~e.18 :name (n3 / name :op1 "Tpr-Met"~e.20))) :location-of (r4 / region~e.31 :ARG1-of (b2 / bind-01~e.30) :mod (s5 / substrate~e.29 :quant (m2 / multiple~e.27)) :ARG1-of (r5 / replace-01~e.34 :ARG2~e.35 (m3 / motif~e.37 :ARG0-of (s2 / select-01 :ARG1 (r6 / recruit-01~e.41 :ARG1~e.42 (p / protein~e.46 :ARG0-of (s3 / signal-07~e.45) :ARG1-of (s4 / single-02~e.44) :ARG1-of (f3 / find-01~e.48 :location (e / enzyme :name (n4 / name :op1 "RTK") :mod (o2 / other~e.50)))))))))) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.58 :op1 (f2 / file~e.54 :mod 1~e.56 :mod (a2 / additional~e.53)) :op2 (p2 / publication :ARG0-of (c6 / cite-01 :ARG2 8~e.61))))) # ::id pmid_2470_8867.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To determine whether the selective oncogenic engagement of either the Grb2 or the Shc adaptor protein was sufficient to induce transformation of IECs , we generated populations of IEC @-@ 6 cells [ @ 25 @ ] expressing Tpr @-@ Met variants that specifically bind to either the Grb2 ( TM @-@ Grb2 @-@ IEC @-@ 6 cells ) or Shc ( TM @-@ Shc1 @-@ IEC @-@ 6 and TM @-@ Shc2 @-@ IEC @-@ 6 cells , respectively ) adaptor proteins , through retroviral infection . # ::alignments 1-1.3 2-1.3.2.1 2-1.3.2.1.r 4-1.3.2.2.3 5-1.3.2.2.2 5-1.3.2.2.2.1 5-1.3.2.2.2.1.r 6-1.3.2.2 10-1.2.1.3.1.2.1.1.1.1 10-1.3.2.2.1.1.1.1 11-1.2.1.3.1.2.1 11-1.3.2.2.1 13-1.3.2.2.1.2.1.1 14-1.3.2.2.1.2.2 15-1.2.1.3.1.1 15-1.2.1.3.1.2.1.1 15-1.2.1.3.1.2.1.2 15-1.3.2.2.1.1 15-1.3.2.2.1.2 17-1.3.2 19-1.3.2.3 20-1.3.2.3.2 22-1.2.1.1.1 22-1.2.1.3.1.2.1.1.3.1.1 22-1.3.2.3.2.1.1.1 24-1.1 25-1 26-1.2 27-1.2.1.r 28-1.2.1.1.1 28-1.2.1.3.1.2.1.1.3.1.1 30-1.2.1.1.1 30-1.2.1.3.1.2.1.1.3.1.1 31-1.2.1 31-1.3.2.3.2.1 34-1.2.1.2.1.1 37-1.2.1.3 38-1.2.1.3.1.1.1.1 40-1.2.1.3.1.1.1.1 41-1.2.1.3.1 43-1.2.1.3.1.2.3 44-1.2.1.3.1.2 48-1.2.1.3.1.2.1.1.1.1 50-1.2.1.3.1.2.1.1.3.1.1 52-1.2.1.3.1.2.1.1.1.1 54-1.2.1.3.1.2.1.1.3.1.1 56-1.2.1.3.1.2.1.1.3.1.1 57-1.2.1.3.1.2.1.2.3.1 59-1.2.1.3.1.2.1 60-1.2.1.3.1.2.1.2.1.1 62-1.2.1.3.1.2.1.1.3.1.1 62-1.2.1.3.1.2.1.2.3.1.1.1 62-1.2.1.3.1.2.1.2.3.2.1.1 64-1.2.1.3.1.2.1.2.3.1.1.1 66-1.2.1.3.1.2.1.2.3.1.1.1 66-1.2.1.3.1.2.1.2.3.2.1.1 68-1.2.1.3.1.2.1.2.3.1.1.1 68-1.2.1.3.1.2.1.2.3.2.1.1 69-1.2.1.3.1.2.1.2.3 70-1.2.1.3.1.2.1.2.3.1.1.1 70-1.2.1.3.1.2.1.2.3.2.1.1 72-1.2.1.3.1.2.1.2.3.2.1.1 74-1.2.1.3.1.2.1.1.3.1.1 74-1.2.1.3.1.2.1.2.3.2.1.1 76-1.2.1.3.1.2.1.1.3.1.1 76-1.2.1.3.1.2.1.2.3.2.1.1 77-1.2.1.3.1.2.1.1.3 77-1.2.1.3.1.2.1.2.3.2 81-1.2.1.3.1.2.1.1.2 82-1.2.1.3.1.2.1.1 86-1.2.1.3.1.2.2 (g / generate-01~e.25 :ARG0 (w / we~e.24) :ARG1 (p / population~e.26 :consist-of~e.27 (c / cell-line~e.31 :name (n / name :op1 "IEC-6"~e.22,28,30) :ARG1-of (d / describe-01 :ARG0-of (c2 / cite-01 :ARG2 25~e.34)) :ARG3-of (e / express-03~e.37 :ARG2 (v / variant~e.41 :mod (p2 / protein~e.15 :name (n2 / name :op1 "Tpr-Met"~e.38,40)) :ARG1-of (b / bind-01~e.44 :ARG2 (o / or~e.11,59 :op1 (p3 / protein~e.15,82 :name (n3 / name :op1 "Grb2"~e.10,48,52) :mod (a / adaptor~e.81) :location (c3 / cell-line~e.77 :name (n4 / name :op1 "TM-Grb2-IEC-6"~e.22,28,30,50,54,56,62,74,76))) :op2 (p4 / protein~e.15 :name (n5 / name :op1 "Shc"~e.60) :mod a :location (a3 / and~e.69 :op1 (c4 / cell-line~e.57 :name (n6 / name :op1 "TM-Shc1-IEC-6"~e.62,64,66,68,70)) :op2 (c5 / cell-line~e.77 :name (n7 / name :op1 "TM-Shc2-IEC-6"~e.62,66,68,70,72,74,76))))) :instrument (i / infect-01~e.86 :mod (r / retrovirus)) :manner (s / specific-02~e.43)))))) :purpose (d2 / determine-01~e.1 :ARG0 w :ARG1 (s2 / suffice-01~e.17 :mode~e.2 interrogative~e.2 :ARG0 (e2 / engage-01~e.6 :ARG1 (o2 / or~e.11 :op1 (p5 / protein~e.15 :name (n8 / name :op1 "Grb2"~e.10) :mod a) :op2 (p6 / protein~e.15 :name (n9 / name :op1 "Shc"~e.13) :mod a~e.14)) :ARG0-of (c6 / cause-01~e.5 :ARG1~e.5 (c7 / cancer~e.5)) :mod (s3 / selective~e.4)) :ARG1 (i2 / induce-01~e.19 :ARG0 e2 :ARG2 (t / transform-01~e.20 :ARG2 (c8 / cell~e.31 :name (n10 / name :op1 "IEC"~e.22))))))) # ::id pmid_2470_8867.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For each experiment , these cells were compared with the previously characterized untransformed sham @-@ infected IEC @-@ 6 ( Control @-@ IEC @-@ 6 ) cells or those transformed by unmodified Tpr @-@ Met ( Tpr @-@ Met @-@ IEC @-@ 6 ) [ @ 5 @ ] . # ::alignments 1-1.4.1 2-1.4 4-1.1.1 5-1.1 7-1 8-1.2.r 10-1.2.1.2.1 11-1.2.1.2 13-1.2.1.4.1 15-1.2.1.4 16-1.2.1.1.1 16-1.2.1.5.1.1.1 18-1.2.1.1.1 18-1.2.1.5.1.1.1 20-1.2.1.5.1.1.1 22-1.2.1.1.1 22-1.2.1.5.1.1.1 22-1.2.2.3.1.1.1 24-1.2.1.1.1 24-1.2.1.5.1.1.1 24-1.2.2.3.1.1.1 26-1.2.2 27-1.2 29-1.2.1.3 29-1.2.2.2 31-1.2.1.3.1 31-1.2.2.2.1.2 31-1.2.2.2.1.2.1 31-1.2.2.2.1.2.1.r 32-1.2.2.2.1.1.1 32-1.2.2.3.1.1.1 34-1.2.2.2.1.1.1 34-1.2.2.3.1.1.1 36-1.2.2.2.1.1.1 36-1.2.2.3.1.1.1 38-1.2.2.2.1.1.1 38-1.2.2.3.1.1.1 40-1.2.1.1.1 40-1.2.1.5.1.1.1 40-1.2.2.3.1.1.1 42-1.2.1.1.1 42-1.2.1.5.1.1.1 42-1.2.2.3.1.1.1 46-1.3.1.1.1 (c / compare-01~e.7 :ARG1 (c2 / cell~e.5 :mod (t / this~e.4)) :ARG2~e.8 (o / or~e.27 :op1 (c5 / cell-line :name (n / name :op1 "IEC-6"~e.16,18,22,24,40,42) :ARG1-of (c4 / characterize-01~e.11 :time (p / previous~e.10)) :ARG1-of (t2 / transform-01~e.29 :polarity -~e.31) :ARG1-of (i / infect-01~e.15 :mod (s / sham~e.13)) :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :name (n2 / name :op1 "Control-IEC-6"~e.16,18,20,22,24,40,42)))) :op2 (c6 / cell~e.26 :ARG1-of c4 :ARG1-of (t3 / transform-01~e.29 :ARG0 (p3 / protein :name (n3 / name :op1 "Tpr-Met"~e.32,34,36,38) :ARG1-of (m3 / modify-01~e.31 :polarity~e.31 -~e.31))) :ARG1-of (m2 / mean-01 :ARG2 (c7 / cell-line :name (n4 / name :op1 "Tpr-Met-IEC-6"~e.22,24,32,34,36,38,40,42))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG0-of (c9 / cite-01 :ARG2 5~e.46))) :beneficiary (e / experiment-01~e.2 :mod (e2 / each~e.1))) # ::id pmid_2470_8867.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TM @-@ Grb2 @-@ IEC @-@ 6 , TM @-@ Shc1 @-@ IEC @-@ 6 , and TM @-@ Shc2 @-@ IEC @-@ 6 cells were morphologically transformed to a similar extent relative to Control @-@ IEC @-@ 6 cells , which grew in colonies and displayed typical normal epithelioid morphology ( Figure 1 @ A ) . # ::alignments 0-1.1.1.1.1 0-1.1.2.1.1 0-1.1.3.1.1 2-1.1.1.1.1 4-1.1.1.1.1 4-1.1.2.1.1 4-1.1.3.1.1 6-1.1.1.1.1 6-1.1.2.1.1 6-1.1.3.1.1 8-1.1.1.1.1 8-1.1.2.1.1 8-1.1.3.1.1 10-1.1.2.1.1 12-1.1.1.1.1 12-1.1.2.1.1 12-1.1.3.1.1 14-1.1.1.1.1 14-1.1.2.1.1 14-1.1.3.1.1 16-1.1 17-1.1.1.1.1 17-1.1.2.1.1 17-1.1.3.1.1 19-1.1.3.1.1 21-1.1.3.1.1 23-1.1.3.1.1 24-1.2.2.1 26-1.3 26-1.3.r 27-1 30-1.2.1 30-1.2.2.1.3.1.3 31-1.2 32-1.2.2 34-1.2.2.1.1.1 36-1.2.2.1.1.1 38-1.2.2.1.1.1 39-1.1.1 39-1.1.2 39-1.1.3 39-1.2.2.1 42-1.2.2.1.2 43-1.2.2.1.2.1.r 44-1.2.2.1.2.1 46-1.2.2.1.3 47-1.2.2.1.3.1.1 48-1.2.2.1.3.1.2 50-1.2.2.1.3.1 52-1.4.1 (t / transform-01~e.27 :ARG1 (a / and~e.16 :op1 (c / cell-line~e.39 :name (n / name :op1 "TM-Grb2-IEC-6"~e.0,2,4,6,8,12,14,17)) :op2 (c2 / cell-line~e.39 :name (n2 / name :op1 "TM-Shc1-IEC-6"~e.0,4,6,8,10,12,14,17)) :op3 (c3 / cell-line~e.39 :name (n3 / name :op1 "TM-Shc2-IEC-6"~e.0,4,6,8,12,14,17,19,21,23))) :ARG2 (e / extent~e.31 :ARG1-of (r / resemble-01~e.30) :ARG1-of (r2 / relative-05~e.32 :ARG3 (c4 / cell-line~e.24,39 :name (n4 / name :op1 "Control-IEC-6"~e.34,36,38) :ARG1-of (g / grow-01~e.42 :location~e.43 (c5 / colony~e.44)) :ARG0-of (d / display-01~e.46 :ARG1 (m2 / morphology~e.50 :ARG1-of (t2 / typical-02~e.47) :ARG1-of (n5 / normal-02~e.48) :ARG1-of (r3 / resemble-01~e.30 :ARG2 (e2 / epithelium))))))) :manner~e.26 (m / morphological~e.26) :ARG1-of (d2 / describe-01 :ARG2 (f / figure~e.52 :mod "1A"))) # ::id pmid_2470_8867.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Morphological changes induced in the TM @-@ Grb2 @-@ IEC @-@ 6 , TM @-@ Shc1 @-@ IEC @-@ 6 , and TM @-@ Shc2 @-@ IEC @-@ 6 cells include an apparent breakdown of cell @-@ cell contacts , cell dispersal , the acquisition of a fibroblast @-@ like spindle @-@ shaped morphology , and a more refractile appearance than the Control @-@ IEC @-@ 6 cells . # ::alignments 0-1.2.1 1-1.2 2-1.2.2 3-1.2.2.1.r 5-1.2.2.1.1.1.1 5-1.2.2.1.2.1.1 5-1.2.2.1.3.1.1 7-1.2.2.1.1.1.1 9-1.2.2.1.1.1.1 9-1.2.2.1.2.1.1 9-1.2.2.1.3.1.1 11-1.2.2.1.1.1.1 11-1.2.2.1.2.1.1 11-1.2.2.1.3.1.1 13-1.2.2.1.1.1.1 13-1.2.2.1.2.1.1 13-1.2.2.1.3.1.1 15-1.2.2.1.2.1.1 17-1.2.2.1.1.1.1 17-1.2.2.1.2.1.1 17-1.2.2.1.3.1.1 19-1.2.2.1.1.1.1 19-1.2.2.1.2.1.1 19-1.2.2.1.3.1.1 21-1.2.2.1 22-1.2.2.1.1.1.1 22-1.2.2.1.2.1.1 22-1.2.2.1.3.1.1 24-1.2.2.1.3.1.1 26-1.2.2.1.3.1.1 28-1.2.2.1.3.1.1 29-1.2.2.1.1 29-1.2.2.1.2 29-1.2.2.1.3 30-1 33-1.1.1 34-1.1.1.1.r 35-1.1.1.1.1 37-1.1.1.1.1 37-1.1.1.1.2 38-1.1.1.1 40-1.1.1.1.1 41-1.1.2 44-1.1.3 45-1.1.3.1.r 47-1.1.3.1.1.1 49-1.1.3.1.1 50-1.1.3.1.2.1 52-1.1.3.1.2 53-1.1.3.1 55-1.1 57-1.1.4.1.1 58-1.1.4.1 59-1.1.1.2 59-1.1.4 60-1.1.4.2.r 62-1.1.4.2.1.1 64-1.1.4.2.1.1 66-1.1.4.2.1.1 67-1.1.4.2 (i / include-01~e.30 :ARG1 (a2 / and~e.55 :op1 (b / break-down-12~e.33 :ARG1~e.34 (c5 / contact-01~e.38 :ARG0 (c6 / cell~e.35,37,40) :ARG1 (c7 / cell~e.37)) :ARG1-of (a3 / appear-01~e.59)) :op2 (d / disperse-01~e.41 :ARG1 c6) :op3 (a4 / acquire-01~e.44 :ARG1~e.45 (m2 / morphology~e.53 :ARG1-of (r / resemble-01~e.49 :ARG2 (f / fibroblast~e.47)) :ARG1-of (s / shape-01~e.52 :ARG2 (s2 / spindle~e.50)))) :op4 (a5 / appear-01~e.59 :mod (r2 / refractile~e.58 :degree (m3 / more~e.57)) :compared-to~e.60 (c8 / cell-line~e.67 :name (n4 / name :op1 "Control-IEC-6"~e.62,64,66)))) :ARG2 (c / change-01~e.1 :mod (m / morphology~e.0) :ARG2-of (i2 / induce-01~e.2 :location~e.3 (a / and~e.21 :op1 (c2 / cell-line~e.29 :name (n / name :op1 "TM-Grb2-IEC-6"~e.5,7,9,11,13,17,19,22)) :op2 (c3 / cell-line~e.29 :name (n2 / name :op1 "TM-Shc1-IEC-6"~e.5,9,11,13,15,17,19,22)) :op3 (c4 / cell-line~e.29 :name (n3 / name :op1 "TM-Shc2-IEC-6"~e.5,9,11,13,17,19,22,24,26,28)))))) # ::id pmid_2470_8867.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells expressing the Grb2 and Shc docking @-@ specific oncoproteins also displayed many cell membrane protrusions typical of lamellipodia and invadopodia @-@ like structures . # ::alignments 0-1.1 1-1.1.1 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.1.1 6-1.1.1.1.3.1 8-1.1.1.1.3 10-1.3 11-1 12-1.2.3 13-1.2.1.1 14-1.2.1 15-1.2 16-1.2.2 19-1.2.2.1 22-1.2.2.1.2.1 23-1.2.2.1.1 23-1.2.2.1.2 (d / display-01~e.11 :ARG0 (c / cell~e.0 :ARG3-of (e / express-03~e.1 :ARG2 (a / and~e.4 :op1 (p2 / protein :name (n / name :op1 "Grb2"~e.3) :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer))) :op2 (p / protein :name (n2 / name :op1 "Shc"~e.5) :ARG0-of c2) :ARG1-of (s / specific-02~e.8 :ARG2 (d2 / dock-01~e.6))))) :ARG1 (p3 / protrude-01~e.15 :ARG2 (m / membrane~e.14 :part-of (c4 / cell~e.13)) :ARG1-of (t / typical-02~e.16 :ARG2 (a3 / and~e.19 :op1 (s2 / structure~e.23 :mod (l / lamellipodium)) :op2 (s3 / structure~e.23 :ARG1-of (r / resemble-01~e.22 :ARG2 (i / invadopodium))))) :quant (m2 / many~e.12)) :mod (a2 / also~e.10)) # ::id pmid_2470_8867.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Tpr @-@ Met variants exhibited comparable levels of Tyr phosphorylation in IEC @-@ 6 cells , relative to their expression levels ( Figure 1 @ A ) . # ::alignments 1-1.1.1.1.1 3-1.1.1.1.1 4-1.1 5-1 6-1.2.1 7-1.2 8-1.2.2.r 9-1.2.2.1.1.1 10-1.2.2 11-1.2.2.2.r 12-1.2.2.2.1.1 14-1.2.2.2.1.1 15-1.2.2.2 17-1.2.3 18-1.2.3.1.r 19-1.2.3.1.1.1 19-1.2.3.1.1.1.r 20-1.2.3.1.1 21-1.2.3.1 23-1.3.1 (e / exhibit-01~e.5 :ARG0 (v / variant~e.4 :mod (p / protein :name (n / name :op1 "Tpr-Met"~e.1,3))) :ARG1 (l / level~e.7 :ARG1-of (c / comparable-03~e.6) :degree-of~e.8 (p2 / phosphorylate-01~e.10 :ARG1 (a / amino-acid :name (n3 / name :op1 "tyrosine"~e.9)) :location~e.11 (c2 / cell-line~e.15 :name (n2 / name :op1 "IEC-6"~e.12,14))) :ARG1-of (r / relative-05~e.17 :ARG3~e.18 (l2 / level~e.21 :degree-of (e2 / express-03~e.20 :ARG2~e.19 v~e.19)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "1A"))) # ::id pmid_2470_8867.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok They also demonstrated the predicted binding selectivity [ @ 8 , 9 , 15 , 16 , 20 @ ] ( Additional file 1 ) . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.1 5-1.2.2 9-1.4.1.1.1.1.1 13-1.4.1.1.1.1.2 17-1.4.1.1.1.1.3 21-1.4.1.1.1.1.4 25-1.4.1.1.1.1.5 29-1.4.1.2.2 30-1.4.1.2 32-1.4.1.2.1 (d / demonstrate-01~e.2 :ARG0 (t / they~e.0) :ARG1 (s / select-01 :ARG1-of (p / predict-01~e.4) :mod (b / bind-01~e.5)) :mod (a / also~e.1) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 8~e.9 :op2 9~e.13 :op3 15~e.17 :op4 16~e.21 :op5 20~e.25))) :op2 (f / file~e.30 :mod 1~e.32 :mod (a4 / additional~e.29))))) # ::id pmid_2470_8867.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since such morphological changes in epithelial cells are typically associated with down @-@ regulation of E @-@ cadherin , immunoblot ( IB ) analysis of the E @-@ cadherin protein levels were performed [ @ 31 @ ] . # ::alignments 0-1 1-1.1.1.3 2-1.1.1.2 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1 6-1.1.1.1 8-1.1.3 9-1.1 10-1.1.2.r 11-1.1.2 12-1.1.2 13-1.1.2 14-1.1.2.1.r 15-1.1.2.1.1.1 17-1.1.2.1.1.1 19-1.2.1.2 23-1.2.1 24-1.2.1.1.r 26-1.2.1.1.1 27-1.2.1.1.1 28-1.2.1.1.1 29-1.2.1.1.1 30-1.2.1.1 32-1.2 35-1.3.1.1.1 (c / cause-01~e.0 :ARG0 (a / associate-01~e.9 :ARG1 (c2 / change-01~e.3 :ARG1~e.4 (c3 / cell~e.6 :source (e / epithelium~e.5)) :mod (m / morphological~e.2) :mod (s / such~e.1)) :ARG2~e.10 (d / downregulate-01~e.11,12,13 :ARG1~e.14 (p / protein :name (n / name :op1 "E-cadherin"~e.15,17))) :ARG1-of (t / typical-02~e.8)) :ARG1 (p2 / perform-02~e.32 :ARG2 (a2 / analyze-01~e.23 :ARG1~e.24 (l / level~e.30 :quant-of p~e.26,27,28,29) :mod (i2 / immunoblot-01~e.19))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 31~e.35)))) # ::id pmid_2470_8867.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with the previous characterization of Tpr @-@ Met @-@ IEC @-@ 6 cells [ @ 5 @ ] , also presented herein , oncogenic activation of Grb2 @- and especially Shc @-@ specific signals led to a dramatic decrease in E @-@ cadherin protein levels relative to the Control @-@ IEC @-@ 6 cells ( Figure 1 @ B ) . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1.2 4-1.3.1 5-1.3.1.1.r 6-1.3.1.1.1.1 8-1.3.1.1.1.1 10-1.3.1.1.1.1 12-1.3.1.1.1.1 13-1.3.1.1 16-1.3.2.1.1.1 20-1.3.1.3.1 21-1.3.1.3 22-1.3.1.3.2 24-1.1.2 24-1.1.2.1 24-1.1.2.1.r 25-1.1 26-1.1.1.r 27-1.1.1.1.1.1.1.1 29-1.1.1.1.1 31-1.1.1.1.1.2.1.1 33-1.1.1.1 34-1.1.1 35-1 38-1.2.2 39-1.2 40-1.2.1.r 41-1.2.1.1.1.1 43-1.2.1.1.1.1 44-1.1.1.1.1.1 44-1.1.1.1.1.2 44-1.2.1.1 45-1.2.1 46-1.2.1.2 47-1.2.1.2.1.r 49-1.2.1.2.1.1.1 51-1.2.1.2.1.1.1 53-1.2.1.2.1.1.1 54-1.2.1.2.1 56-1.4.1 (l / lead-03~e.35 :ARG0 (a / activate-01~e.25 :ARG1~e.26 (s / signal-07~e.34 :ARG1-of (s2 / specific-02~e.33 :ARG2 (a2 / and~e.29 :op1 (p / protein~e.44 :name (n / name :op1 "Grb2"~e.27)) :op2 (p2 / protein~e.44 :name (n2 / name :op1 "Shc"~e.31) :ARG1-of (s3 / special-02))))) :ARG0-of (c / cause-01~e.24 :ARG1~e.24 (c2 / cancer~e.24))) :ARG2 (d / decrease-01~e.39 :ARG1~e.40 (l2 / level~e.45 :quant-of (p3 / protein~e.44 :name (n3 / name :op1 "E-cadherin"~e.41,43)) :ARG1-of (r / relative-05~e.46 :ARG2~e.47 (c3 / cell-line~e.54 :name (n4 / name :op1 "Control-IEC-6"~e.49,51,53)))) :manner (d2 / dramatic~e.38)) :ARG1-of (c4 / consistent-01~e.0 :ARG2~e.1 (c5 / characterize-01~e.4 :ARG1~e.5 (c6 / cell-line~e.13 :name (n5 / name :op1 "Tpr-Met-IEC-6"~e.6,8,10,12)) :time (p4 / previous~e.3) :ARG1-of (p6 / present-01~e.21 :mod (a3 / also~e.20) :medium (h / herein~e.22))) :ARG1-of (d3 / describe-01 :ARG0 (p5 / publication :ARG0-of (c7 / cite-01 :ARG2 5~e.16)))) :ARG1-of (d4 / describe-01 :ARG2 (f / figure~e.56 :mod "1B"))) # ::id pmid_2470_8867.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , a marked reduction in E @-@ cadherin ( Cdh1 ) mRNA levels was observed in these cells , as determined by semi @-@ quantitative and quantitative real @-@ time RT @–@ PCR analyses ( Figure 1 @ C and D ) . # ::alignments 0-1.4 3-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1.1.2.1.1.1 8-1.1.1.1.2.1.1.1 11-1.1.1.1.2.1.2.1.1.1 14-1.1.1.1.1.1 15-1.1.1 17-1 18-1.2.r 19-1.2.1 20-1.2 22-1.3.r 23-1.3 25-1.3.1.1.2.1 27-1.3.1.1.2 29-1.3.1.1.2 29-1.3.1.2.1 30-1.3.1.1.3 32-1.3.1.1.3 33-1.3.1.1.1.1.1 35-1.3.1.1.1.1.1 36-1.3.1.1 36-1.3.1.2 38-1.5.1.1 38-1.5.1.2 43-1.5.1 (o / observe-01~e.17 :ARG1 (r / reduce-01~e.4 :ARG1~e.5 (l / level~e.15 :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA"~e.14) :ARG0-of (e / encode-01 :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin"~e.6,8) :ARG1-of (m2 / mean-01 :ARG2 (p2 / protein :name (n3 / name :op1 "Cdh1"~e.11))))))) :ARG1-of (m / mark-01~e.3)) :location~e.18 (c / cell~e.20 :mod (t / this~e.19)) :ARG1-of~e.22 (d / determine-01~e.23 :ARG0 (a / and :op1 (a2 / analyze-01~e.36 :mod (t2 / thing :name (n4 / name :op1 "RT-PCR"~e.33,35)) :mod (q / quantitative~e.27,29 :degree (s / semi~e.25)) :mod (r3 / real-time~e.30,32)) :op2 (a3 / analyze-01~e.36 :mod (q2 / quantitative~e.29) :mod r3 :mod t2))) :manner (l2 / likewise~e.0) :ARG1-of (d2 / describe-01 :ARG2 (a4 / and~e.43 :op1 (f / figure~e.38 :mod "1C") :op2 (f2 / figure~e.38 :mod "1D")))) # ::id pmid_2470_8867.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analysis of the expression profiles of E @-@ cadherin transcriptional repressors in these IECs suggests that a combined up @-@ regulation of Snail2 , Twist1 , or Twist2 , but not of Snail1 or Zeb1 , may partly account for the E @-@ cadherin repression induced by oncogenic Met @-@ dependent signaling , including that one driven by Grb2 and Shc signals ( Additional file 2 ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1 4-1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1.1.1.1 8-1.1.1.1.1.1.1.1.1.1 9-1.1.1.1.1.1.1 10-1.1.1.1.1 10-1.1.1.1.1.1 10-1.1.1.1.1.1.r 11-1.1.2.r 12-1.1.2.2 13-1.1.2.1.1 14-1 15-1.2.r 17-1.2.1.1.1.2 18-1.2.1.1.1 18-1.2.2.2 19-1.2.1.1.1 20-1.2.1.1.1 23-1.2.1.1.1.1.1.1.1 27-1.2.1.1.1.1.2.1.1 30-1.2.1.1.1.1 30-1.2.2.2.1 32-1.2.1.1.1.1.3.1.1 35-1.2 36-1.2.2.1 36-1.2.2.1.r 39-1.2.2.2.1.1.1.1 41-1.2.1.1.1.1 43-1.2.2.2.1.2.1.1 46-1.2.1 47-1.2.1.1.3 47-1.2.1.1.3.r 48-1.2.1.1 48-1.2.2 49-1.2.1.1.2.r 51-1.2.1.1.2.1 52-1.2.1.1.2.1 53-1.2.1.1.2.1 54-1.2.1.1.2 54-1.2.1.1.2.3.1 55-1.2.1.1.2.2 56-1.2.1.1.2.2.1.r 57-1.2.1.1.2.2.1.2 57-1.2.1.1.2.2.1.2.1 57-1.2.1.1.2.2.1.2.1.r 58-1.2.1.1.2.2.1.1.1.1.1 60-1.2.1.1.2.2.1.1 61-1.2.1.1.2.2.1 63-1.2.1.1.2.3 66-1.2.1.1.2.3.1.1 67-1.2.1.1.2.3.1.1.1.r 68-1.2.1.1.2.3.1.1.1.1.1.1.1 69-1.2.1.1.2.3.1.1.1.1 70-1.2.1.1.2.3.1.1.1.1.2.1.1 71-1.2.1.1.2.3.1.1.1 73-1.3.1.2 76-1.3.1.1 (s / suggest-01~e.14 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (p / profile-01~e.4 :ARG1 (e / express-03~e.3 :ARG2~e.5 (m / molecular-physical-entity~e.10 :ARG0-of~e.10 (r / repress-01~e.10 :ARG1 (t / transcribe-01~e.9 :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin"~e.6,8))))))) :location~e.11 (c / cell :name (n2 / name :op1 "IEC"~e.13) :mod (t2 / this~e.12))) :ARG1~e.15 (c2 / contrast-01~e.35 :ARG1 (p3 / possible-01~e.46 :ARG1 (a2 / account-01~e.48 :ARG0 (u / upregulate-01~e.18,19,20 :ARG1 (o / or~e.30,41 :op1 (g / gene :name (n3 / name :op1 "Snail2"~e.23)) :op2 (g2 / gene :name (n4 / name :op1 "Twist1"~e.27)) :op3 (g3 / gene :name (n5 / name :op1 "Twist2"~e.32))) :ARG1-of (c3 / combine-01~e.17)) :ARG1~e.49 (r2 / repress-01~e.54 :ARG1 p2~e.51,52,53 :ARG2-of (i / induce-01~e.55 :ARG0~e.56 (s2 / signal-07~e.61 :ARG0-of (d / depend-01~e.60 :ARG1 (p6 / protein :name (n7 / name :op1 "Met"~e.58))) :ARG0-of (c4 / cause-01~e.57 :ARG1~e.57 (c5 / cancer~e.57)))) :ARG2-of (i2 / include-01~e.63 :ARG1 (r3 / repress-01~e.54 :ARG1-of (d2 / drive-02~e.66 :ARG0~e.67 (s3 / signal-07~e.71 :ARG0 (a3 / and~e.69 :op1 (p7 / protein :name (n8 / name :op1 "Grb2"~e.68)) :op2 (p8 / protein :name (n9 / name :op1 "Shc"~e.70)))))))) :degree~e.47 (p4 / part~e.47))) :ARG2 (a5 / account-01~e.48 :polarity~e.36 -~e.36 :ARG0 (u2 / upregulate-01~e.18 :ARG1 (o2 / or~e.30 :op1 (g4 / gene :name (n10 / name :op1 "Snail1"~e.39)) :op2 (g5 / gene :name (n11 / name :op1 "Zeb1"~e.43))) :ARG1-of c3) :ARG1 r2)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod 2~e.76 :mod (a4 / additional~e.73)))) # ::id pmid_2470_8867.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overall , these results demonstrate that oncogenic activation of Grb2 @- and Shc @-@ dependent signaling pathways , such as those activated by Tpr @-@ Met , is sufficient to induce an epithelial @-@ mesenchymal morphological @-@ like transformation in normal IECs . # ::alignments 0-1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 5-1.2.r 6-1.2.1.2 6-1.2.1.2.1 6-1.2.1.2.1.r 7-1.2.1 8-1.2.1.1.r 9-1.2.1.1.1.1.1.1.1.1 11-1.2.1.1.1.1.1 12-1.2.1.1.1.1.1.2.1.1 14-1.2.1.1.1.1 15-1.2.1.1.1 16-1.2.1.1 16-1.2.1.1.2 18-1.2.1.1.2.r 19-1.2.1.1.2.r 21-1.2.1.1.2.1 22-1.2.1.1.2.1.1.r 23-1.2.1.1.2.1.1.1.1 25-1.2.1.1.2.1.1.1.1 28-1.2 30-1.2.2 32-1.2.2.2.3 34-1.2.2.2.3.1 35-1.2.2.2.2.1 37-1.2.2.2.2 38-1.2.2.2 39-1.2.2.2.1.r 40-1.2.2.2.1 40-1.2.2.2.1.2 40-1.2.2.2.1.2.r 41-1.2.2.2.1.1.1 (d / demonstrate-01~e.4 :ARG0 (t / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :mod (t2 / this~e.2)) :ARG1~e.5 (s / suffice-01~e.28 :ARG0 (a / activate-01~e.7 :ARG1~e.8 (p / pathway~e.16 :ARG0-of (s2 / signal-07~e.15 :ARG0-of (d2 / depend-01~e.14 :ARG1 (a2 / and~e.11 :op1 (p2 / protein :name (n / name :op1 "Grb2"~e.9)) :op2 (p3 / protein :name (n2 / name :op1 "Shc"~e.12))))) :example~e.18,19 (p4 / pathway~e.16 :ARG1-of (a3 / activate-01~e.21 :ARG0~e.22 (p5 / protein :name (n3 / name :op1 "Tpr-Met"~e.23,25))))) :ARG0-of (c / cause-01~e.6 :ARG1~e.6 (c2 / cancer~e.6))) :ARG1 (i / induce-01~e.30 :ARG0 a :ARG2 (t3 / transform-01~e.38 :ARG1~e.39 (c3 / cell~e.40 :name (n4 / name :op1 "IEC"~e.41) :ARG1-of~e.40 (n5 / normal-02~e.40)) :ARG1-of (r2 / resemble-01~e.37 :ARG2 (m / morphology~e.35)) :mod (e2 / epithelium~e.32 :mod (m2 / mesenchyme~e.34))))) :mod (o / overall~e.0)) # ::id pmid_2470_8867.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogenic engagement of Grb2 or Shc signaling enhances cell growth and loss of contact inhibition in IECs # ::alignments 1-1.1.2 1-1.1.2.1 1-1.1.2.1.r 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1 7-1.1.1 8-1 9-1.2.1.1 10-1.2.1 11-1.2 12-1.2.2 13-1.2.2.1.r 14-1.2.2.1.1 15-1.2.2.1 16-1.2.2.2.r 17-1.2.2.2.1.1 (e / enhance-01~e.8 :ARG0 (e2 / engage-01~e.2 :ARG1~e.3 (s / signal-07~e.7 :ARG0 (o / or~e.5 :op1 (p / protein :name (n / name :op1 "Grb2"~e.4)) :op2 (p2 / protein :name (n2 / name :op1 "Shc"~e.6)))) :ARG0-of (c / cause-01~e.1 :ARG1~e.1 (c2 / cancer~e.1))) :ARG1 (a2 / and~e.11 :op1 (g / grow-01~e.10 :ARG1 (c3 / cell~e.9)) :op2 (l / lose-01~e.12 :ARG1~e.13 (i / inhibit-01~e.15 :ARG0 (c4 / contact-01~e.14)) :location~e.16 (c5 / cell :name (n3 / name :op1 "IEC"~e.17))))) # ::id pmid_2470_8867.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next tested the oncogenic growth characteristics of IEC @-@ 6 cells transformed by the Tpr @-@ Met variants . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.3 4-1.2.3.1 4-1.2.3.1.r 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.1.1 10-1.2.1.1.1 11-1.2.1 12-1.2.1.2 13-1.2.1.2.1.r 15-1.2.1.2.1.1.1.1 17-1.2.1.2.1.1.1.1 18-1.2.1.2.1 (t / test-01~e.2 :ARG0 (w / we~e.0) :ARG1 (c / characteristic-02~e.6 :ARG1~e.7 (c4 / cell-line~e.11 :name (n / name :op1 "IEC-6"~e.8,10) :ARG1-of (t2 / transform-01~e.12 :ARG0~e.13 (v / variant~e.18 :mod (p / protein :name (n3 / name :op1 "Tpr-Met"~e.15,17))))) :ARG2 (g / grow-01~e.5 :ARG1 c4) :ARG0-of (c2 / cause-01~e.4 :ARG1~e.4 (c3 / cancer~e.4))) :time (n2 / next~e.1)) # ::id pmid_2470_8867.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok First , cell @-@ counting assays were performed to determine the growth rate of each cell population . # ::alignments 0-1.3 0-1.3.1 0-1.3.1.r 2-1.1.1.1 4-1.1.1 5-1.1 7-1 9-1.2 11-1.2.1.1 12-1.2.1 13-1.2.1.1.1.r 14-1.2.1.1.1.2 15-1.2.1.1.1.1 16-1.2.1.1.1 (p / perform-02~e.7 :ARG1 (a / assay-01~e.5 :ARG1 (c / count-01~e.4 :ARG1 (c2 / cell~e.2))) :purpose (d / determine-01~e.9 :ARG1 (r / rate-01~e.12 :mod (g / grow-01~e.11 :ARG1~e.13 (p2 / population~e.16 :consist-of (c3 / cell~e.15) :mod (e / each~e.14))))) :ord (o / ordinal-entity~e.0 :value~e.0 1~e.0)) # ::id pmid_2470_8867.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The TM @-@ Grb2 @-@ IEC @-@ 6 , TM @-@ Shc1 @-@ IEC @-@ 6 , and TM @-@ Shc2 @-@ IEC @-@ 6 cells displayed more rapid growth than Control @-@ IEC @-@ 6 cells , albeit to a lesser extent than Tpr @-@ Met @-@ IEC @-@ 6 cells ( Figure 2 @ A ) . # ::alignments 1-1.1.1.1.1 1-1.1.2.1.1 1-1.1.3.1.1 3-1.1.1.1.1 5-1.1.1.1.1 5-1.1.2.1.1 5-1.1.3.1.1 7-1.1.1.1.1 7-1.1.2.1.1 7-1.1.3.1.1 9-1.1.1.1.1 9-1.1.2.1.1 9-1.1.3.1.1 11-1.1.2.1.1 13-1.1.1.1.1 13-1.1.2.1.1 13-1.1.3.1.1 15-1.1.1.1.1 15-1.1.2.1.1 15-1.1.3.1.1 17-1.1 18-1.1.1.1.1 18-1.1.2.1.1 18-1.1.3.1.1 20-1.1.3.1.1 22-1.1.3.1.1 24-1.1.3.1.1 25-1.1.1 25-1.1.2 25-1.1.3 25-1.3.2.1.2 26-1 26-1.3 26-1.3.r 27-1.2.1.1 28-1.2.1 28-1.3.2.1 29-1.2 29-1.3.2 30-1.2.1.2.r 31-1.2.1.2.1.1 33-1.2.1.2.1.1 35-1.2.1.2.1.1 36-1.2.1.2 39-1.3.2.1.1.r 41-1.3.2.1.1 43-1.2.1.2.r 44-1.3.2.1.2.1.1 46-1.3.2.1.2.1.1 48-1.1.3.1.1 48-1.2.1.2.1.1 48-1.3.2.1.2.1.1 50-1.1.3.1.1 50-1.2.1.2.1.1 50-1.3.2.1.2.1.1 51-1.2.1.2 53-1.4.1 (d / display-01~e.26 :ARG0 (a / and~e.17 :op1 (c / cell-line~e.25 :name (n / name :op1 "TM-Grb2-IEC-6"~e.1,3,5,7,9,13,15,18)) :op2 (c2 / cell-line~e.25 :name (n2 / name :op1 "TM-Shc1-IEC-6"~e.1,5,7,9,11,13,15,18)) :op3 (c3 / cell-line~e.25 :name (n3 / name :op1 "TM-Shc2-IEC-6"~e.1,5,7,9,13,15,18,20,22,24,48,50))) :ARG1 (g / grow-01~e.29 :mod (r / rapid~e.28 :degree (m / more~e.27) :compared-to~e.30,43 (c4 / cell-line~e.36,51 :name (n4 / name :op1 "Control-IEC-6"~e.31,33,35,48,50)))) :concession~e.26 (d2 / display-01~e.26 :ARG0 a :ARG1 (g2 / grow-01~e.29 :mod (r2 / rapid~e.28 :degree~e.39 (l / less~e.41) :compared-to (c5 / cell-line~e.25 :name (n5 / name :op1 "Tpr-Met-IEC-6"~e.44,46,48,50))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.53 :mod "2A"))) # ::id pmid_2470_8867.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , TM @-@ Shc1 @-@ IEC @-@ 6 cells exhibited accelerated growth relative to TM @-@ Grb2 @-@ IEC @-@ 6 and TM @-@ Shc2 @-@ IEC @-@ 6 cells , between which the doubling time did not differ significantly . # ::alignments 0-1.3 2-1.1.1.1 4-1.1.1.1 6-1.1.1.1 8-1.1.1.1 9-1.1 10-1 11-1.2.1 12-1.2 13-1.2.2 14-1.2.2.1.r 15-1.2.2.1.1.1.1 17-1.2.2.1.1.1.1 19-1.2.2.1.1.1.1 19-1.2.2.1.2.1.1 21-1.2.2.1.1.1.1 21-1.2.2.1.2.1.1 22-1.2.2.1 23-1.2.2.1.1.1.1 23-1.2.2.1.2.1.1 25-1.2.2.1.2.1.1 27-1.2.2.1.1.1.1 27-1.2.2.1.2.1.1 29-1.2.2.1.1.1.1 29-1.2.2.1.2.1.1 30-1.2.2.1.1 30-1.2.2.1.2 35-1.2.2.1.1.2.3.1 36-1.2.2.1.1.2.3 38-1.2.2.1.1.2.1 38-1.2.2.1.1.2.1.r 39-1.2.2.1.1.2 40-1.2.2.1.1.2.4 (e / exhibit-01~e.10 :ARG0 (c / cell-line~e.9 :name (n / name :op1 "TM-Shc1-IEC-6"~e.2,4,6,8)) :ARG1 (g / grow-01~e.12 :ARG1-of (a / accelerate-01~e.11) :ARG1-of (r / relative-05~e.13 :ARG3~e.14 (a2 / and~e.22 :op1 (c3 / cell-line~e.30 :name (n3 / name :op1 "TM-Grb2-IEC-6"~e.15,17,19,21,23,27,29) :ARG1-of (d / differ-02~e.39 :polarity~e.38 -~e.38 :ARG2 c2 :ARG3 (t / time~e.36 :duration-of (d2 / double-01~e.35)) :ARG1-of (s / significant-02~e.40))) :op2 (c2 / cell-line~e.30 :name (n2 / name :op1 "TM-Shc2-IEC-6"~e.19,21,23,25,27,29))))) :ARG1-of (n4 / notable-04~e.0)) # ::id pmid_2470_8867.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The enhanced growth promoting activity of the TM @-@ Shc1 relative to the TM @-@ Shc2 correlates with the affinity of their respective Shc binding sites [ @ 8 @ ] . # ::alignments 1-1.1.2 2-1.1.3.1 3-1.1.3 4-1.1 5-1.1.1.r 7-1.1.1.1.1 9-1.1.1.1.1 10-1.1.4 11-1.1.4.1.r 13-1.1.4.1.1.1 15-1.1.4.1.1.1 16-1 17-1.2.r 19-1.2 23-1.2.1.3.1.1.1 24-1.2.1.3 25-1.2.1.1 25-1.2.1.2 28-1.3.1.1.1 (c / correlate-01~e.16 :ARG1 (a / activity-06~e.4 :ARG0~e.5 (p3 / protein :name (n / name :op1 "TM-Shc1"~e.7,9)) :ARG1-of (e / enhance-01~e.1) :ARG0-of (p / promote-02~e.3 :ARG1 (g / grow-01~e.2)) :ARG1-of (r / relative-05~e.10 :ARG2~e.11 (p2 / protein :name (n2 / name :op1 "TM-Shc2"~e.13,15)))) :ARG2~e.17 (a2 / affinity~e.19 :poss (a3 / and :op1 (p6 / protein-segment~e.25 :part-of p3) :op2 (p7 / protein-segment~e.25 :part-of p2) :ARG2-of (b / bind-01~e.24 :ARG1 (p4 / protein :name (n3 / name :op1 "Shc"~e.23))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 8~e.28)))) # ::id pmid_2470_8867.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Typical of untransformed cells , IEC @-@ 6 cells ceased proliferation upon the establishment of cell @-@ cell contacts [ @ 5 , 25 @ ] . # ::alignments 0-1.3 3-1.3.1 5-1.1.1.1.1 7-1.1.1.1.1 8-1.1.1 9-1 10-1.1 13-1.2 14-1.2.1.r 15-1.2.1.1 17-1.2.1.1 17-1.2.1.2 18-1.2.1 21-1.4.1.1.1.1 25-1.4.1.1.1.2 (c / cease-01~e.9 :ARG1 (p / proliferate-01~e.10 :ARG0 (c2 / cell-line~e.8 :name (n / name :op1 "IEC-6"~e.5,7))) :time (e / establish-01~e.13 :ARG1~e.14 (c3 / contact-01~e.18 :ARG0 (c4 / cell~e.15,17) :ARG1 (c5 / cell~e.17))) :ARG1-of (t / typical-02~e.0 :ARG2 (c6 / cell~e.3 :ARG1-of (t2 / transform-01 :polarity -))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c7 / cite-01 :ARG2 (a / and :op1 5~e.21 :op2 25~e.25))))) # ::id pmid_2470_8867.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As such , Control @-@ IEC @-@ 6 cells formed a monolayer of well @-@ organized epithelial cells upon reaching confluence ( Figure 2 @ B ) . # ::alignments 0-1.3.r 0-1.4.r 1-1.3 3-1.1.1.1 5-1.1.1.1 7-1.1.1.1 8-1.1 9-1 13-1.2.2.2.1 15-1.2.2.2 16-1.2.2.1 17-1.2.2 19-1.4 20-1.4.1 22-1.5.1 (f / form-01~e.9 :ARG0 (c / cell-line~e.8 :name (n / name :op1 "Control-IEC-6"~e.3,5,7)) :ARG1 (l / layer :quant 1 :consist-of (c2 / cell~e.17 :source (e / epithelium~e.16) :ARG1-of (o / organize-01~e.15 :ARG1-of (w / well-09~e.13)))) :prep-as~e.0 (s / such~e.1) :time~e.0 (r / reach-01~e.19 :ARG1 (c3 / confluence~e.20)) :ARG1-of (d / describe-01 :ARG2 (f2 / figure~e.22 :mod "2B"))) # ::id pmid_2470_8867.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In sharp contrast , each of the oncogenic transformed IEC @-@ 6 cell populations appeared highly disorganized and grew in multiple layers at confluence ( Figure 2 @ B ) . # ::alignments 1-1.2 2-1 4-1.1.1.1.2.4 7-1.1.1.1.2.2 7-1.1.1.1.2.2.1 7-1.1.1.1.2.2.1.r 8-1.1.1.1.2.3 9-1.1.1.1.2.1.1.1 11-1.1.1.1.2.1.1.1 12-1.1.1.1.2.1 13-1.1.1.1.2 14-1.1.1 15-1.1.1.1.3 17-1.1 18-1.1.2 19-1.1.2.2.r 20-1.1.2.2.1 21-1.1.2.2 22-1.1.2.3.r 23-1.1.2.3 25-1.3.1 (c / contrast-01~e.2 :ARG2 (a / and~e.17 :op1 (a2 / appear-02~e.14 :ARG1 (o2 / organize-01 :polarity - :ARG1 (p / population~e.13 :consist-of (c2 / cell-line~e.12 :name (n / name :op1 "IEC-6"~e.9,11)) :ARG0-of (c3 / cause-01~e.7 :ARG1~e.7 (c4 / cancer~e.7)) :ARG1-of (t / transform-01~e.8) :mod (e / each~e.4)) :ARG1-of (h / high-02~e.15))) :op2 (g / grow-01~e.18 :ARG1 p :manner~e.19 (l / layer~e.21 :quant (m / multiple~e.20)) :time~e.22 (c5 / confluence~e.23))) :ARG1-of (s / sharp-02~e.1) :ARG1-of (d / describe-01 :ARG2 (f / figure~e.25 :mod "2B"))) # ::id pmid_2470_8867.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , oncogenic specific activation of Grb2 @- or Shc @-@ dependent signals permits IECs to bypass contact inhibition of growth . # ::alignments 0-1.1.1.2 2-1.1.1.2 2-1.1.1.2.1 2-1.1.1.2.1.r 3-1.1.1.3 4-1.1.1 5-1.1.1.1.r 6-1.1.1.1.1.1.1.1.1 9-1.1.1.1.1.1.2.1.1 11-1.1.1.1.1 12-1.1.1.1 13-1.1 14-1.1.3.1.1 16-1.1.2 17-1.1.2.2.1 18-1.1.2.2 19-1.1.2.2.2.r 20-1.1.2.2.2 (i / infer-01 :ARG1 (p / permit-01~e.13 :ARG0 (a / activate-01~e.4 :ARG1~e.5 (s / signal-07~e.12 :ARG0-of (d / depend-01~e.11 :ARG1 (a2 / and :op1 (p2 / protein :name (n / name :op1 "Grb2"~e.6)) :op2 (p3 / protein :name (n2 / name :op1 "Shc"~e.9))))) :ARG0-of (c / cause-01~e.0,2 :ARG1~e.2 (c2 / cancer~e.2)) :ARG1-of (s2 / specific-02~e.3)) :ARG1 (b / bypass-01~e.16 :ARG0 c3 :ARG1 (i2 / inhibit-01~e.18 :ARG0 (c4 / contact-01~e.17) :ARG1~e.19 (g / grow-01~e.20))) :ARG2 (c3 / cell :name (n3 / name :op1 "IEC"~e.14)))) # ::id pmid_2470_8867.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To validate this in a quantitative manner , focus formation assays were performed . # ::alignments 1-1.2 2-1.2.1 5-1.2.2 6-1.2.2.r 8-1.1.1.1 9-1.1.1 10-1.1 12-1 (p / perform-02~e.12 :ARG1 (a / assay-01~e.10 :ARG1 (f / form-01~e.9 :ARG1 (f2 / focus~e.8))) :purpose (v / validate-01~e.1 :ARG1 (t / this~e.2) :manner~e.6 (q / quantitative~e.5))) # ::id pmid_2470_8867.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected [ @ 5 @ ] , Control @-@ IEC @-@ 6 cells failed to form foci , whereas TM @-@ Grb2 @-@ IEC @-@ 6 , TM @-@ Shc1 @-@ IEC @-@ 6 , and TM @-@ Shc2 @-@ IEC @-@ 6 cells displayed strong focus @-@ forming capacities , though less than that of Tpr @-@ Met @-@ IEC @-@ 6 cells ( Figure 2 @ C and D ) . # ::alignments 1-1.4 4-1.4.1.1.1.1 8-1.1.1.1.1 10-1.1.1.1.1 12-1.1.1.1.1 13-1.1.1 14-1.1 16-1.1.2 17-1.1.2.2 19-1 20-1.2.1.1.1.1 20-1.2.1.2.1.1 20-1.2.1.3.1.1 22-1.2.1.1.1.1 24-1.2.1.1.1.1 24-1.2.1.2.1.1 24-1.2.1.3.1.1 26-1.2.1.1.1.1 26-1.2.1.2.1.1 26-1.2.1.3.1.1 28-1.2.1.1.1.1 28-1.2.1.2.1.1 28-1.2.1.3.1.1 30-1.2.1.2.1.1 32-1.2.1.1.1.1 32-1.2.1.2.1.1 32-1.2.1.3.1.1 34-1.2.1.1.1.1 34-1.2.1.2.1.1 34-1.2.1.3.1.1 36-1.2.1 37-1.2.1.1.1.1 37-1.2.1.2.1.1 37-1.2.1.3.1.1 39-1.2.1.3.1.1 41-1.2.1.1.1.1 41-1.2.1.2.1.1 41-1.2.1.3.1.1 43-1.2.1.1.1.1 43-1.2.1.2.1.1 43-1.2.1.3.1.1 44-1.2.1.1 44-1.2.1.2 44-1.2.1.3 44-1.2.3.2.4 45-1.2 45-1.2.3 46-1.2.2.3 47-1.2.2.2.2 49-1.2.2.2 50-1.2.2 50-1.2.3.2 52-1.2.3.r 53-1.2.3.2.3 54-1.2.3.2.4.r 57-1.2.3.2.4.1.1 59-1.2.3.2.4.1.1 61-1.2.1.1.1.1 61-1.2.1.2.1.1 61-1.2.1.3.1.1 61-1.2.3.2.4.1.1 63-1.2.1.1.1.1 63-1.2.1.2.1.1 63-1.2.1.3.1.1 63-1.2.3.2.4.1.1 64-1.2.1.1 66-1.3.1.1 66-1.3.1.2 71-1.3.1 (c / contrast-01~e.19 :ARG1 (f / fail-01~e.14 :ARG1 (c2 / cell-line~e.13 :name (n / name :op1 "Control-IEC-6"~e.8,10,12)) :ARG2 (f2 / form-01~e.16 :ARG0 c2 :ARG1 (f3 / focus~e.17))) :ARG2 (d / display-01~e.45 :ARG0 (a / and~e.36 :op1 (c3 / cell-line~e.44,64 :name (n2 / name :op1 "TM-Grb2-IEC-6"~e.20,22,24,26,28,32,34,37,41,43,61,63)) :op2 (c4 / cell-line~e.44 :name (n3 / name :op1 "TM-Shc1-IEC-6"~e.20,24,26,28,30,32,34,37,41,43,61,63)) :op3 (c5 / cell-line~e.44 :name (n4 / name :op1 "TM-Shc2-IEC-6"~e.20,24,26,28,32,34,37,39,41,43,61,63))) :ARG1 (c6 / capable-01~e.50 :ARG1 a :ARG2 (f4 / form-01~e.49 :ARG0 a :ARG1 (f5 / focus~e.47)) :ARG1-of (s / strong-02~e.46)) :concession~e.52 (d2 / display-01~e.45 :ARG0 a :ARG1 (c7 / capable-01~e.50 :ARG1 a :ARG2 f4 :degree (l / less~e.53) :compared-to~e.54 (c8 / cell-line~e.44 :name (n5 / name :op1 "Tpr-Met-IEC-6"~e.57,59,61,63))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.71 :op1 (f6 / figure~e.66 :mod "2C") :op2 (f7 / figure~e.66 :mod "2D"))) :ARG1-of (e / expect-01~e.1 :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG0-of (c9 / cite-01 :ARG2 5~e.4))))) # ::id pmid_2470_8867.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The number and size of foci formed by the TM @-@ Shc1 @-@ IEC @-@ 6 cells were markedly greater than those of the TM @-@ Grb2 @-@ IEC @-@ 6 or TM @-@ Shc2 @-@ IEC @-@ 6 cells ( Figure 2 @ C and D ) , likely reflecting their accelerated growth rate ( Figure 2 @ A ) . # ::alignments 1-1.1.1 1-1.2.1 2-1.1 2-1.2 3-1.1.2 3-1.2.2 5-1.1.1.1 5-1.2.1.1 6-1.1.1.1.1 6-1.2.1.1.1 7-1.1.1.1.1.1.r 9-1.1.1.1.1.1.1.1 11-1.1.1.1.1.1.1.1 13-1.1.1.1.1.1.1.1 15-1.1.1.1.1.1.1.1 16-1.1.1.1.1.1 17-1.1.r 18-1.1.3 18-1.1.3.r 19-1 19-1.5 19-1.5.r 20-1.2.r 22-1.2.1.1.1.1.r 24-1.2.1.1.1.1.1.1.1 26-1.2.1.1.1.1.1.1.1 28-1.2.1.1.1.1.1.1.1 28-1.2.1.1.1.1.2.1.1 30-1.2.1.1.1.1.1.1.1 30-1.2.1.1.1.1.2.1.1 31-1.2.1.1.1.1 32-1.2.1.1.1.1.1.1.1 32-1.2.1.1.1.1.2.1.1 34-1.2.1.1.1.1.2.1.1 36-1.2.1.1.1.1.1.1.1 36-1.2.1.1.1.1.2.1.1 38-1.2.1.1.1.1.1.1.1 38-1.2.1.1.1.1.2.1.1 39-1.2.1.1.1.1.1 39-1.2.1.1.1.1.2 41-1.3.1.1 41-1.3.1.2 41-1.4.3.1 46-1.3.1 50-1.4.2 51-1.4 53-1.4.1 54-1.4.1.1.1 55-1.4.1.1 57-1.3.1.1 57-1.4.3.1 (g2 / great~e.19 :domain~e.17 (a3 / and~e.2 :op1 (n / number~e.1 :quant-of (f / focus~e.5 :ARG1-of (f2 / form-01~e.6 :ARG0~e.7 (c4 / cell-line~e.16 :name (n8 / name :op1 "TM-Shc1-IEC-6"~e.9,11,13,15))))) :op2 (s / size~e.3 :poss f) :manner~e.18 (m3 / marked~e.18)) :compared-to~e.20 (a2 / and~e.2 :op1 (n4 / number~e.1 :quant-of (f3 / focus~e.5 :ARG1-of (f4 / form-01~e.6 :ARG0~e.22 (o / or~e.31 :op1 (c2 / cell-line~e.39 :name (n2 / name :op1 "TM-Grb2-IEC-6"~e.24,26,28,30,32,36,38)) :op2 (c5 / cell-line~e.39 :name (n3 / name :op1 "TM-Shc2-IEC-6"~e.28,30,32,34,36,38)))))) :op2 (s2 / size~e.3 :poss f3)) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.46 :op1 (f5 / figure~e.41,57 :mod "2C") :op2 (f6 / figure~e.41 :mod "2D"))) :ARG1-of (r2 / reflect-01~e.51 :ARG2 (a5 / accelerate-01~e.53 :ARG1 (r3 / rate~e.55 :mod (g / grow-01~e.54 :ARG1 f))) :ARG1-of (l / likely-01~e.50) :ARG1-of (d2 / describe-01 :ARG0 (f7 / figure~e.41,57 :mod "2A"))) :degree~e.19 (m / more~e.19)) # ::id pmid_2470_8867.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results indicate that the oncogenic engagement of Grb2 @- and Shc @-@ dependent signals is sufficient to relieve contact inhibition of growth in IECs . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 5-1.2.1.2 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.1.1.1.1.1 10-1.2.1.1.1.1 11-1.2.1.1.1.1.2.1.1 13-1.2.1.1.1 14-1.2.1.1 16-1.2 18-1.2.2 19-1.2.2.2.1 20-1.2.2.2 21-1.2.2.2.2.r 22-1.2.2.2.2 23-1.2.2.2.2.1.r 24-1.2.2.2.2.1.1.1 (i / indicate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (s / suffice-01~e.16 :ARG0 (e / engage-01~e.6 :ARG1~e.7 (s2 / signal-07~e.14 :ARG0-of (d / depend-01~e.13 :ARG1 (a / and~e.10 :op1 (p / protein :name (n / name :op1 "Grb2"~e.8)) :op2 (p2 / protein :name (n2 / name :op1 "Shc"~e.11))))) :ARG2 (c / cancer~e.5)) :ARG1 (r2 / relieve-01~e.18 :ARG0 e :ARG1 (i2 / inhibit-01~e.20 :ARG0 (c3 / contact-01~e.19) :ARG1~e.21 (g / grow-01~e.22 :location~e.23 (c2 / cell :name (n3 / name :op1 "IEC"~e.24))))))) # ::id pmid_2470_8867.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Oncogenic engagement of Grb2 and Shc signaling induces anchorage @-@ independent growth and anoikis resistance in IECs # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1 7-1.1.1 8-1 9-1.2.1.1.2 11-1.2.1.1 11-1.2.1.1.1 11-1.2.1.1.1.r 12-1.2.1 13-1.2 14-1.2.2.1 15-1.2.2 16-1.2.r 17-1.2.3.1.1 (i / induce-01~e.8 :ARG0 (e / engage-01~e.2 :ARG1~e.3 (s / signal-07~e.7 :ARG1 (a / and~e.5 :op1 (p / protein :name (n / name :op1 "Grb2"~e.4)) :op2 (p2 / protein :name (n2 / name :op1 "Shc"~e.6)))) :ARG2 (c / cancer~e.1)) :ARG2~e.16 (a2 / and~e.13 :op1 (g / grow-01~e.12 :ARG0-of (d / depend-01~e.11 :polarity~e.11 -~e.11 :ARG1 (a3 / anchorage~e.9))) :op2 (r / resist-01~e.15 :ARG1 (a4 / anoikis~e.14)) :location (c2 / cell :name (n3 / name :op1 "IEC"~e.17)))) # ::id pmid_2470_8867.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next verified whether the oncogenic activation of Grb2 @- or Shc @-@ dependent signals is sufficient to confer to non @-@ transformed IEC @-@ 6 cells the capacity to grow in the absence of anchorage to the extra @-@ cellular matrix ( ECM ) , by performing soft agar growth assays . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.1.r 5-1.2.2.2 5-1.2.2.2.1 5-1.2.2.2.1.r 6-1.2.2 7-1.2.2.1.r 8-1.2.2.1.1.1.1.1.1 10-1.2.2.1.1.1 11-1.2.2.1.1.1.2.1.1 13-1.2.2.1.1 14-1.2.2.1 16-1.2 18-1.2.3 19-1.2.3.2.r 20-1.2.3.2.1.2.1 20-1.2.3.2.1.2.1.r 22-1.2.3.2.1.2 23-1.2.3.2.1.1.1 25-1.2.3.2.1.1.1 26-1.2.3.2.1 28-1.2.3.2 30-1.2.3.2.2 31-1.2.3.2.2.2.r 33-1.2.3.2.2.2 40-1.2.3.2.1 41-1.2.3.2.2.2.1.1 46-1.4.r 47-1.4 48-1.4.2.1.1.1 49-1.4.2.1.1 50-1.4.2.1 51-1.4.2 (v / verify-01~e.2 :ARG0 (w / we~e.0) :ARG1 (s / suffice-01~e.16 :mode~e.3 interrogative~e.3 :ARG0 (a / activate-01~e.6 :ARG1~e.7 (s2 / signal-07~e.14 :ARG0-of (d / depend-01~e.13 :ARG1 (o / or~e.10 :op1 (p / protein :name (n2 / name :op1 "Grb2"~e.8)) :op2 (p2 / protein :name (n3 / name :op1 "Shc"~e.11))))) :ARG0-of (c5 / cause-01~e.5 :ARG1~e.5 (c6 / cancer~e.5))) :ARG1 (c2 / confer-02~e.18 :ARG0 a :ARG1~e.19 (c / capable-01~e.28 :ARG1 (c3 / cell-line~e.26,40 :name (n4 / name :op1 "IEC-6"~e.23,25) :ARG1-of (t / transform-01~e.22 :polarity~e.20 -~e.20)) :ARG2 (g / grow-01~e.30 :ARG1 c3 :condition~e.31 (a2 / absent-01~e.33 :ARG1 (a3 / anchor-01 :location (m / matrix~e.41 :mod (e / extracellular)))))) :ARG2 c3)) :time (n / next~e.1) :manner~e.46 (p3 / perform-01~e.47 :ARG0 w :ARG1 (a4 / assay-01~e.51 :ARG1 (g2 / grow-01~e.50 :condition (a5 / agar~e.49 :ARG1-of (s3 / soft-02~e.48)))))) # ::id pmid_2470_8867.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Consistent with previous findings [ @ 5 @ ] , Control @-@ IEC @-@ 6 cells failed to grow in soft agar whereas Tpr @-@ Met @-@ IEC @-@ 6 cells grew efficiently , forming numerous large colonies ( Figure 3 @ A @–@ C ) . # ::alignments 0-1.3 1-1.3.1.r 2-1.3.1.2 3-1.3.1 3-1.3.1.1 3-1.3.1.1.r 6-1.3.2.1.1.1 10-1.1.1.2 12-1.1.1.1.1 14-1.1.1.1.1 15-1.1.1 16-1.1 18-1.1.2 19-1.1.2.2.r 20-1.1.2.2.1 21-1.1.2.2 22-1 23-1.2.1.1.1 25-1.2.1.1.1 27-1.2.1.1.1 29-1.2.1.1.1 30-1.2.1 31-1.2 32-1.2.2 34-1.2.1.2 35-1.2.1.2.1.2 36-1.2.1.2.1.1 37-1.2.1.2.1 39-1.4.1.1 39-1.4.1.2 39-1.4.1.3 (c / contrast-01~e.22 :ARG1 (f2 / fail-01~e.16 :ARG1 (c8 / cell-line~e.15 :name (n5 / name :op1 "IEC-6"~e.12,14) :ARG0-of (c5 / control-01~e.10)) :ARG2 (g / grow-01~e.18 :ARG1 c8 :location~e.19 (a / agar~e.21 :ARG1-of (s / soft-02~e.20)))) :ARG2 (g2 / grow-01~e.31 :ARG1 (c4 / cell-line~e.30 :name (n / name :op1 "Tpr-Met-IEC-6"~e.23,25,27,29) :ARG2-of (f3 / form-01~e.34 :ARG1 (c6 / colony~e.37 :mod (l / large~e.36) :quant (n4 / numerous~e.35)))) :ARG2-of (e2 / efficient-01~e.32)) :ARG1-of (c2 / consistent-01~e.0 :ARG2~e.1 (t / thing~e.3 :ARG1-of~e.3 (f / find-01~e.3) :time (p / previous~e.2)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c7 / cite-01 :ARG2 5~e.6)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f4 / figure~e.39 :mod "3A") :op2 (f5 / figure~e.39 :mod "3B") :op3 (f6 / figure~e.39 :mod "3C")))) # ::id pmid_2470_8867.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok TM @-@ Grb2 @-@ IEC @-@ 6 , TM @-@ Shc1 @-@ IEC @-@ 6 , and TM @-@ Shc2 @-@ IEC @-@ 6 cells also formed colonies in soft agar , but with lower efficiencies . # ::alignments 0-1.1.1.1.1 0-1.1.2.1.1 0-1.1.3.1.1 2-1.1.1.1.1 4-1.1.1.1.1 4-1.1.2.1.1 4-1.1.3.1.1 6-1.1.1.1.1 6-1.1.2.1.1 6-1.1.3.1.1 8-1.1.1.1.1 8-1.1.2.1.1 8-1.1.3.1.1 10-1.1.2.1.1 12-1.1.1.1.1 12-1.1.2.1.1 12-1.1.3.1.1 14-1.1.1.1.1 14-1.1.2.1.1 14-1.1.3.1.1 16-1.1 17-1.1.1.1.1 17-1.1.2.1.1 17-1.1.3.1.1 19-1.1.3.1.1 21-1.1.1.1.1 21-1.1.2.1.1 21-1.1.3.1.1 23-1.1.1.1.1 23-1.1.2.1.1 23-1.1.3.1.1 24-1.1.1 24-1.1.2 24-1.1.3 25-1.5 26-1 27-1.2 28-1.3.r 29-1.3.1 30-1.3 32-1.4 33-1.4.1.r 34-1.4.1.2 34-1.4.1.2.1 34-1.4.1.2.1.r 35-1.4.1 (f / form-01~e.26 :ARG0 (a / and~e.16 :op1 (c6 / cell-line~e.24 :name (n7 / name :op1 "TM-Grb2-IEC-6"~e.0,2,4,6,8,12,14,17,21,23)) :op2 (c7 / cell-line~e.24 :name (n8 / name :op1 "TM-Shc1-IEC-6"~e.0,4,6,8,10,12,14,17,21,23)) :op3 (c8 / cell-line~e.24 :name (n9 / name :op1 "TM-Shc2-IEC-6"~e.0,4,6,8,12,14,17,19,21,23))) :ARG1 (c4 / colony~e.27) :location~e.28 (a2 / agar~e.30 :ARG1-of (s / soft-02~e.29)) :ARG1-of (c5 / contrast-01~e.32 :ARG2~e.33 (e4 / efficient-01~e.35 :ARG2 f :ARG1-of (l / low-04~e.34 :degree~e.34 (m2 / more~e.34)))) :mod (a3 / also~e.25)) # ::id pmid_2470_8867.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While the three IEC @-@ 6 cell populations expressing docking @-@ specific Tpr @-@ Met variants formed similar numbers of colonies ( Figure 3 @ A ) , those produced by the TM @-@ Shc1 @-@ IEC @-@ 6 cells were larger and displayed a different morphology from those produced by the TM @-@ Shc2 @-@ IEC @-@ 6 and TM @-@ Grb2 @-@ IEC @-@ 6 cells ( Figure 3 @ B and C ) . # ::alignments 0-1 2-1.1.1.1 3-1.1.1.2.1.1 5-1.1.1.2.1.1 6-1.1.1.2 7-1.1.1 8-1.1.1.3 9-1.1.1.3.1.1.2.1 11-1.1.1.3.1.1 11-1.1.1.3.1.1.2 11-1.1.1.3.1.1.2.r 12-1.1.1.3.1.1.1.1 14-1.1.1.3.1.1.1.1 15-1.1.1.3.1 16-1.1 17-1.1.2.2 18-1.1.2 20-1.1.2.1 20-1.2.2 20-1.2.2.2.1.1.1 22-1.1.3.1 24-1.1.1.1 30-1.2 33-1.2.1.1.1 35-1.2.1.1.1 37-1.2.1.1.1 39-1.2.1.1.1 40-1.2.1 40-1.2.2.2.1.1.1.1.1.2 42-1.2.2.1 42-1.2.2.1.1 42-1.2.2.1.1.r 44-1.2.2.2 46-1.2.2.2.1.1 47-1.2.2.2.1 50-1.2.2.2.1.1.1.1 51-1.2.2.2.1.1.1.1.1.r 53-1.2.2.2.1.1.1.1.1.1.1.1 55-1.2.2.2.1.1.1.1.1.1.1.1 57-1.2.2.2.1.1.1.1.1.1.1.1 57-1.2.2.2.1.1.1.1.1.2.1.1 59-1.2.2.2.1.1.1.1.1.1.1.1 59-1.2.2.2.1.1.1.1.1.2.1.1 60-1.2.2.2.1.1.1.1.1 61-1.2.2.2.1.1.1.1.1.1.1.1 61-1.2.2.2.1.1.1.1.1.2.1.1 63-1.2.2.2.1.1.1.1.1.2.1.1 65-1.2.2.2.1.1.1.1.1.1.1.1 65-1.2.2.2.1.1.1.1.1.2.1.1 67-1.2.2.2.1.1.1.1.1.1.1.1 67-1.2.2.2.1.1.1.1.1.2.1.1 68-1.2.2.2.1.1.1.1.1.1 70-1.1.3.1 70-1.2.3.1.1 70-1.2.3.1.2 72-1.1.1.1 75-1.2.3.1 (c / contrast-01~e.0 :ARG1 (f / form-01~e.16 :ARG0 (p / population~e.7 :quant 3~e.2,24,72 :mod (c2 / cell-line~e.6 :name (n / name :op1 "IEC-6"~e.3,5)) :ARG3-of (e / express-03~e.8 :ARG2 (v / variant~e.15 :mod (p2 / protein~e.11 :name (n2 / name :op1 "Tpr-Met"~e.12,14) :ARG1-of~e.11 (s2 / specific-02~e.11 :ARG2 (d / dock-01~e.9)))))) :ARG1 (n3 / number-01~e.18 :ARG1 (c3 / colony~e.20) :ARG1-of (r / resemble-01~e.17)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.22,70 :mod "3A"))) :ARG2 (p3 / produce-01~e.30 :ARG0 (c4 / cell-line~e.40 :name (n4 / name :op1 "TM-Shc1-IEC-6"~e.33,35,37,39)) :ARG1 (c6 / colony~e.20 :mod (l / large~e.42 :degree~e.42 (m / more~e.42)) :ARG0-of (d3 / display-01~e.44 :ARG1 (m2 / morphology~e.47 :ARG1-of (d4 / differ-02~e.46 :ARG2 (c7 / colony~e.20 :ARG1-of (p5 / produce-01~e.50 :ARG0~e.51 (a / and~e.60 :op1 (c5 / cell-line~e.68 :name (n6 / name :op1 "TM-Shc2-IEC-6"~e.53,55,57,59,61,65,67)) :op2 (c8 / cell-line~e.40 :name (n7 / name :op1 "TM-Grb2-IEC-6"~e.57,59,61,63,65,67))))))))) :ARG1-of (d5 / describe-01 :ARG0 (a2 / and~e.75 :op1 (f3 / figure~e.70 :mod "3B") :op2 (f4 / figure~e.70 :mod "3C"))))) # ::id pmid_2470_8867.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Colonies formed by the TM @-@ Shc1 @-@ IEC @-@ 6 cells were composed mainly of loosely associated cells with apparently limited cell @-@ cell contacts , similar to Tpr @-@ Met @-@ IEC @-@ 6 colonies ( Figure 3 @ B ) . # ::alignments 0-1.1 1-1.1.1 2-1.1.1.1.r 4-1.1.1.1.1.1 6-1.1.1.1.1.1 8-1.1.1.1.1.1 10-1.1.1.1.1.1 11-1.2 13-1 14-1.3 16-1.2.1.1 17-1.2.1 18-1.2 20-1.2.2.2 21-1.2.2.1.3 22-1.2.2.1.1 24-1.2.2.1.1 24-1.2.2.1.2 25-1.2.2.1 27-1.4 28-1.4.1.r 29-1.4.1.1.1.1 31-1.4.1.1.1.1 33-1.4.1.1.1.1 35-1.4.1.1.1.1 36-1.4.1 38-1.5.1 (c / compose-01~e.13 :ARG1 (c3 / colony~e.0 :ARG1-of (f / form-01~e.1 :ARG0~e.2 (c2 / cell-line :name (n / name :op1 "TM-Shc1-IEC-6"~e.4,6,8,10)))) :ARG2 (c4 / cell~e.11,18 :ARG1-of (a / associate-01~e.17 :ARG1-of (l / loose-04~e.16)) :ARG0-of (h / have-03 :ARG1 (c5 / contact-01~e.25 :ARG0 (c6 / cell~e.22,24) :ARG1 (c7 / cell~e.24) :ARG1-of (l2 / limit-01~e.21)) :ARG1-of (a2 / appear-02~e.20))) :mod (m / main~e.14) :ARG1-of (r / resemble-01~e.27 :ARG2~e.28 (c9 / colony~e.36 :mod (c10 / cell-line :name (n3 / name :op1 "Tpr-Met-IEC-6"~e.29,31,33,35)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.38 :mod "3B"))) # ::id pmid_2470_8867.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By contrast , colonies produced by the TM @-@ Grb2 @-@ IEC @-@ 6 or TM @-@ Shc2 @-@ IEC @-@ 6 cells were compact and composed of tightly associated cells ( Figure 3 @ B ) . # ::alignments 1-1 3-1.1.2 4-1.1 5-1.1.1.r 7-1.1.1.1.1.1 7-1.1.1.2.1.1 9-1.1.1.1.1.1 11-1.1.1.1.1.1 11-1.1.1.2.1.1 13-1.1.1.1.1.1 13-1.1.1.2.1.1 14-1.1.1 15-1.1.1.1.1.1 15-1.1.1.2.1.1 17-1.1.1.2.1.1 19-1.1.1.1.1.1 19-1.1.1.2.1.1 21-1.1.1.1.1.1 21-1.1.1.2.1.1 22-1.1.1.1 22-1.1.1.2 24-1.1.2.1 26-1.1.2.2 27-1.1.2.2.1.r 28-1.1.2.2.1.1.1 29-1.1.2.2.1.1 30-1.1.2.2.1 32-1.2.1 (c / contrast-01~e.1 :ARG2 (p / produce-01~e.4 :ARG0~e.5 (o / or~e.14 :op1 (c3 / cell-line~e.22 :name (n / name :op1 "TM-Grb2-IEC-6"~e.7,9,11,13,15,19,21)) :op2 (c4 / cell-line~e.22 :name (n2 / name :op1 "TM-Shc2-IEC-6"~e.7,11,13,15,17,19,21))) :ARG2 (c2 / colony~e.3 :ARG1-of (c5 / compact-01~e.24) :ARG1-of (c6 / compose-01~e.26 :ARG2~e.27 (c7 / cell~e.30 :ARG1-of (a / associate-01~e.29 :ARG1-of (t / tight-05~e.28)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "3B"))) # ::id pmid_2470_8867.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Growth in soft agar reflects not only the capacity of cells to proliferate in the absence of ECM attachment , but also to avoid anoikis , a form of apoptosis induced upon loss of matrix attachment [ @ 32 @ ] . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1 3-1.1.1 4-1 8-1.2 9-1.2.1.r 10-1.2.1 12-1.2.2.1 13-1.2.2.1.1.r 15-1.2.2.1.1 18-1.2.2.1.1.1 23-1.2.2.2 24-1.2.2.2.1 27-1.2.2.2.2.1 28-1.2.2.2.2.1.1.r 29-1.2.2.2.2.1.1 30-1.2.2.2.2.1.1.1 32-1.2.2.2.2.1.1.1.1 34-1.2.2.1.1.1.2 34-1.2.2.2.2.1.1.1.1.1.1 35-1.2.2.1.1.1 35-1.2.2.2.2.1.1.1.1.1 38-1.3.1.1.1 (r / reflect-01~e.4 :ARG1 (g / grow-01~e.0 :location~e.1 (a / agar~e.3 :ARG1-of (s / soft-02~e.2))) :ARG2 (c / capable-01~e.8 :ARG1~e.9 (c2 / cell~e.10) :ARG2 (a2 / and :op1 (p / proliferate-01~e.12 :condition~e.13 (a3 / absent-01~e.15 :ARG1 (a4 / attach-01~e.18,35 :ARG1 c2 :ARG2 (m3 / matrix~e.34 :mod (e / extracellular))))) :op2 (a5 / avoid-01~e.23 :ARG1 (a6 / anoikis~e.24) :ARG1-of (m / mean-01 :ARG2 (f / form~e.27 :mod~e.28 (a7 / apoptosis~e.29 :ARG2-of (i / induce-01~e.30 :condition (l / lose-02~e.32 :ARG1 (a8 / attach-01~e.35 :ARG2 (m2 / matrix~e.34)))))))))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 32~e.38)))) # ::id pmid_2470_8867.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Anoikis assays were performed by monitoring the viability of cells seeded in the absence of serum under adherent and suspension conditions . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2 9-1.2.1.1 10-1.2.1.1.1 11-1.2.1.1.1.1.r 13-1.2.1.1.1.1 14-1.2.1.1.1.1.1.r 15-1.2.1.1.1.1.1 18-1.2.1.1.1.1.2 19-1.2.1.1.1.1.2.2 20-1.2.1.1.1.1.2.r (p / perform-01~e.3 :ARG1 (a / assay-01~e.1 :ARG1 (a2 / anoikis~e.0)) :ARG2~e.4 (m / monitor-01~e.5 :ARG1 (v / viable :domain (c / cell~e.9 :ARG2-of (s / seed-02~e.10 :condition~e.11 (a3 / absent-01~e.13 :ARG1~e.14 (s2 / serum~e.15) :condition~e.20 (a4 / and~e.18 :op1 (a5 / adhere-01) :op2 (s3 / suspend-02~e.19)))))))) # ::id pmid_2470_8867.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As expected for normal IECs [ @ 33 , 34 @ ] , Control @-@ IEC @-@ 6 cells displayed anoikis sensitivity under suspension culture conditions ( Figure 3 @ D ) . # ::alignments 1-1.4 3-1.4.1.2 4-1.4.1.1.1 7-1.4.2.1.1.1.1 11-1.4.2.1.1.1.2 15-1.1.2 17-1.1.1.1 19-1.1.1.1 20-1.1 20-1.4.1 21-1 22-1.2.2 23-1.2 25-1.3.1 26-1.3 27-1.3.r 29-1.5.1 (d / display-01~e.21 :ARG0 (c / cell-line~e.20 :name (n / name :op1 "IEC-6"~e.17,19) :ARG0-of (c2 / control-01~e.15)) :ARG1 (s / sensitive-03~e.23 :ARG0 c :ARG1 (a / anoikis~e.22)) :condition~e.27 (c3 / culture~e.26 :ARG1-of (s2 / suspend-02~e.25)) :ARG1-of (e / expect-01~e.1 :topic (c4 / cell~e.20 :name (n2 / name :op1 "IEC"~e.4) :ARG1-of (n3 / normal-02~e.3)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication :ARG1-of (c5 / cite-01 :ARG2 (a2 / and :op1 33~e.7 :op2 34~e.11))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.29 :mod "3D"))) # ::id pmid_2470_8867.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , IEC @-@ 6 cells transformed by either Tpr @-@ Met , or the Grb2 or Shc docking @-@ specific oncoproteins , displayed potent resistance to anoikis , with more than half surviving under non @-@ adherent conditions . # ::alignments 1-1 3-1.1.1.2.1 5-1.1.1.2.1 6-1.1.2.4.1 7-1.1.1.3 8-1.1.1.3.1.r 9-1.1.1.3.1.3 10-1.1.1.3.1.1.2.1 12-1.1.1.3.1.1.2.1 14-1.1.1.3.1 16-1.1.1.3.1.2.1.2.1 17-1.1.1.3.1.2 18-1.1.1.3.1.2.2.2.1 19-1.1.1.3.1.4.1 21-1.1.1.3.1.4 24-1.1 25-1.1.2.3 26-1.1.2 27-1.1.2.2.r 28-1.1.2.2 31-1.1.2.4.1.1.2 32-1.1.2.4.1.1.2 33-1.1.2.4.1.1.2.1 34-1.1.2.4 36-1.1.2.4.2.1.1 36-1.1.2.4.2.1.1.r 39-1.1.2.4.2 (c / contrast-01~e.1 :ARG2 (d / display-01~e.24 :ARG0 (c2 / cell-line :wiki - :name (n / name :op1 "IEC-6"~e.3,5) :ARG1-of (t / transform-01~e.7 :ARG0~e.8 (o / or~e.14 :op1 (p / protein :wiki "Tpr-met_fusion_protein" :name (n2 / name :op1 "Tpr-Met"~e.10,12)) :op2 (o4 / or~e.17 :op1 (p2 / protein :wiki "GRB2" :name (n5 / name :op1 "Grb2"~e.16)) :op2 (p3 / protein :wiki "SHC1" :name (n6 / name :op1 "Shc"~e.18)) :ARG0-of (c5 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :mod (e / either~e.9) :ARG1-of (s / specific-02~e.21 :ARG2 (d2 / dock-01~e.19))))) :ARG1 (r / resist-01~e.26 :ARG0 c2 :ARG1~e.27 (a / anoikis~e.28) :mod (p4 / potent~e.25) :mod (s2 / survive-01~e.34 :ARG0 (c4 / cell~e.6 :ARG1-of (i / include-91 :ARG2 c2 :ARG3 (m2 / more-than~e.31,32 :op1 "1/2"~e.33))) :ARG1 (c3 / condition~e.39 :ARG1-of (a2 / adhere-01 :polarity~e.36 -~e.36)))))) # ::id pmid_2470_8867.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Likewise , the viability of these transformed cells was significantly higher than that of Control @-@ IEC @-@ 6 cells when seeded in the absence of serum and under adherent conditions ( Figure 3 @ E ) . # ::alignments 0-1.3 5-1.1.1.2 6-1.1.1.1 7-1.1.1 8-1.1.1.r 9-1.1.2 10-1 10-1.5 10-1.5.r 11-1.2.r 14-1.2 14-1.2.2 14-1.2.2.r 16-1.2.1.1 18-1.2.1.1 19-1.1.1 21-1.1.1.3 22-1.1.1.3.1.r 24-1.1.1.3.1.1 25-1.1.1.3.1.1.1.r 26-1.1.1.3.1.1.1 27-1.1.1.3.1 30-1.1.1.3.1.2 32-1.4.1 (h / high-02~e.10 :ARG1 (v / viable :domain~e.8 (c2 / cell~e.7,19 :ARG1-of (t / transform-01~e.6) :mod (t2 / this~e.5) :ARG0-of (s / seed-01~e.21 :condition~e.22 (a / and~e.27 :op1 (a2 / absent-01~e.24 :ARG1~e.25 (s2 / serum~e.26)) :op2 (c5 / condition~e.30 :mod (a3 / adhere-01))))) :ARG1-of (s3 / significant-02~e.9)) :compared-to~e.11 (c3 / cell-line~e.14 :name (n / name :op1 "IEC-6"~e.16,18) :ARG0-of~e.14 (c4 / control-01~e.14)) :manner (l / likewise~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.32 :mod "3E")) :degree~e.10 (m / more~e.10)) # ::id pmid_2470_8867.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Overall , these results indicate that the oncogenic engagement of signals downstream of Grb2 or Shc is sufficient to alleviate the anchorage @-@ dependence of growth , and to reduce sensitivity to growth factor deprivation and to anoikis in IECs . # ::alignments 0-1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 5-1.2.r 7-1.2.1.2 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1 11-1.2.1.1.2 12-1.2.1.1.1.r 13-1.2.1.1.1.1.1.1 14-1.2.1.1.1 15-1.2.1.1.1.2.1.1 17-1.2 18-1.2.2.r 19-1.2.2.1 21-1.2.2.1.2.2 23-1.2.2.1.2 24-1.2.2.1.2.1.r 25-1.2.2.1.2.1 27-1.2.2 29-1.2.2.2 30-1.2.2.2.2 31-1.2.2.2.2.1.r 32-1.2.2.2.2.1.1.1 33-1.2.2.2.2.1.1.1 34-1.2.2.2.2.1.1 35-1.2.2.2.2.1 37-1.2.2.2.2.1.2 39-1.2.2.2.2.1.3.1.1 (i / indicate-01~e.4 :ARG0 (t / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :mod (t2 / this~e.2)) :ARG1~e.5 (s / suffice-01~e.17 :ARG0 (e / engage-01~e.8 :ARG1~e.9 (s2 / signal-07~e.10 :ARG1~e.12 (o2 / or~e.14 :op1 (p / protein :name (n / name :op1 "Grb2"~e.13)) :op2 (p2 / protein :name (n2 / name :op1 "Shc"~e.15))) :mod (d / downstream~e.11)) :ARG2 (c / cancer~e.7)) :ARG1~e.18 (a2 / and~e.27 :op1 (a3 / alleviate-01~e.19 :ARG0 e :ARG1 (d2 / depend-01~e.23 :ARG0~e.24 (g / grow-01~e.25) :ARG1 (a4 / anchorage~e.21))) :op2 (r2 / reduce-01~e.29 :ARG0 e :ARG1 (s3 / sensitive-03~e.30 :ARG1~e.31 (a5 / and~e.35 :op1 (d3 / deprive-01~e.34 :ARG1 (g2 / growth-factor~e.32,33)) :op2 (a6 / anoikis~e.37) :location (c2 / cell :name (n3 / name :op1 "IEC"~e.39))))))) :mod (o / overall~e.0)) # ::id pmid_2470_8867.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Silencing of Grb2 impairs Tpr @-@ Met @-@ induced morphological transformation and anoikis resistance in IECs , but reduced expression of Shc decreases cell growth # ::alignments 1-1.1.1 2-1.1.1.1.r 3-1.1.1.1.1.1 4-1.1 5-1.1.2.1.1.1.1.1 7-1.1.2.1.1.1.1.1 9-1.1.2.1.1 10-1.1.2.1.2 11-1.1.2.1 12-1.1.2 13-1.1.2.2.1 14-1.1.2.2 15-1.1.2.r 16-1.1.2.3.1.1 18-1 19-1.2.1.2 20-1.2.1 21-1.2.1.1.r 22-1.2.1.1.1.1 23-1.2 24-1.2.2.1 25-1.2.2 (c / contrast-01~e.18 :ARG1 (i2 / impair-01~e.4 :ARG0 (s / silence-01~e.1 :ARG1~e.2 (p / protein :name (n / name :op1 "Grb2"~e.3))) :ARG1~e.15 (a / and~e.12 :op1 (t / transform-01~e.11 :ARG2-of (i / induce-01~e.9 :ARG0 (p2 / protein :name (n2 / name :op1 "Tpr-Met"~e.5,7))) :mod (m / morphologic~e.10)) :op2 (r / resist-01~e.14 :ARG1 (a2 / anoikis~e.13)) :location (c2 / cell :name (n3 / name :op1 "IEC"~e.16)))) :ARG2 (d / decrease-01~e.23 :ARG0 (e / express-03~e.20 :ARG2~e.21 (p3 / protein :name (n4 / name :op1 "Shc"~e.22)) :ARG1-of (r2 / reduce-01~e.19)) :ARG1 (g / grow-01~e.25 :ARG1 (c3 / cell~e.24)))) # ::id pmid_2470_8867.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The above results with the docking @-@ specific Tpr @-@ Met @-@ derived variants established that the oncogenic activation of either Grb2 or Shc signaling pathways was each sufficient to promote transformation of IECs , conferring upon them aberrant growth characteristics and resistance to anoikis . # ::alignments 1-1.1.2 2-1.1 2-1.1.1 2-1.1.1.r 3-1.1.3.r 5-1.1.3.2.1 7-1.1.3.2 8-1.1.3.1.1.1.1 10-1.1.3.1.1.1.1 12-1.1.3.1 13-1.1.3 14-1 15-1.2.r 17-1.2.1.2 17-1.2.1.2.1 17-1.2.1.2.1.r 18-1.2.1 21-1.2.1.1.1.1.1 22-1.2.1.1 23-1.2.1.1.2.1.1 24-1.2.1.1.3 25-1.2.1.1.1 25-1.2.1.1.2 27-1.2.3 28-1.2 30-1.2.2 31-1.2.2.2 32-1.2.2.2.1.r 33-1.2.2.2.1.1.1 35-1.2.2.2.1.2 37-1.2.2.2.1.2.1.1.1 38-1.2.2.2.1.2.1.1.2.1 39-1.2.2.2.1.2.1.1.2 40-1.2.2.2.1.2.1.1 41-1.2.2.2.1.2.1 42-1.2.2.2.1.2.1.2 43-1.2.2.2.1.2.1.2.2.r 44-1.2.2.2.1.2.1.2.2 (e / establish-01~e.14 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2) :location (a / above~e.1) :accompanier~e.3 (v / variant~e.13 :ARG1-of (d / derive-01~e.12 :ARG2 (p / protein :name (n / name :op1 "Tpr-Met"~e.8,10))) :ARG1-of (s / specific-02~e.7 :ARG2 (d2 / dock-01~e.5)))) :ARG1~e.15 (s2 / suffice-01~e.28 :ARG0 (a2 / activate-01~e.18 :ARG1 (o / or~e.22 :op1 (p6 / pathway~e.25 :name (n5 / name :op1 "Grb2"~e.21)) :op2 (p7 / pathway~e.25 :name (n6 / name :op1 "Shc"~e.23)) :ARG0-of (s4 / signal-07~e.24)) :ARG0-of (c4 / cause-01~e.17 :ARG1~e.17 (c5 / cancer~e.17))) :ARG1 (p5 / promote-01~e.30 :ARG0 a2 :ARG1 (t2 / transform-01~e.31 :ARG1~e.32 (c / cell :name (n4 / name :op1 "IEC"~e.33) :ARG2-of (c2 / confer-02~e.35 :ARG1 (a3 / and~e.41 :op1 (c3 / characteristic-02~e.40 :ARG1 c~e.37 :ARG2 (g / grow-01~e.39 :mod (a4 / aberrant~e.38))) :op2 (r2 / resist-01~e.42 :ARG0 c :ARG1~e.43 (a5 / anoikis~e.44))))))) :mod (e3 / each~e.27))) # ::id pmid_2470_8867.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next sought to determine whether signaling pathways downstream of these adaptor proteins were required for the oncogenic potential of Met in IECs . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.2.1 5-1.2.2.1.r 6-1.2.2.3.1 7-1.2.2.3 8-1.2.2.3.2 9-1.2.2.3.3.r 10-1.2.2.3.3.1 12-1.2.2.3.3 14-1.2.2 15-1.2.2.2.r 17-1.2.2.2.3 17-1.2.2.2.3.1 17-1.2.2.2.3.1.r 18-1.2.2.2 19-1.2.2.2.1.r 20-1.2.2.2.1.1.1 21-1.2.2.2.2.r 22-1.2.2.2.2.1.1 (s / seek-01~e.2 :ARG0 (w / we~e.0) :ARG1 (d / determine-01~e.4 :ARG0 w :ARG1 (r / require-01~e.14 :mode~e.5 interrogative~e.5 :ARG0~e.15 (p3 / potential~e.18 :poss~e.19 (p4 / protein :name (n2 / name :op1 "Met"~e.20)) :location~e.21 (c2 / cell :name (n3 / name :op1 "IEC"~e.22)) :ARG0-of (c3 / cause-01~e.17 :ARG1~e.17 (c4 / cancer~e.17))) :ARG1 (p / pathway~e.7 :ARG0-of (s2 / signal-07~e.6) :mod (d2 / downstream~e.8) :poss~e.9 (p2 / protein~e.12 :mod (t / this~e.10) :ARG0-of (a / adapt-01))))) :time (n / next~e.1)) # ::id pmid_2470_8867.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The impact of silencing the expression of Grb2 or Shc on the features of the Tpr @-@ Met @-@ IEC @-@ 6 cells was evaluated . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 5-1.1.1.1 5-1.1.2.1.2 6-1.1.1.1.1.r 7-1.1.1.1.1.1.1.1 8-1.1.1.1.1 9-1.1.1.1.1.2.1.1 10-1.1.2.r 12-1.1.2 13-1.1.2.1.2.1.r 13-1.1.2.1.r 15-1.1.2.1.2.1.1.1 17-1.1.2.1.2.1.1.1 19-1.1.2.1.1.1 21-1.1.2.1.1.1 22-1.1.2.1 24-1 (e / evaluate-01~e.24 :ARG1 (i / impact-01~e.1 :ARG0~e.2 (s / silence-01~e.3 :ARG1 (e2 / express-03~e.5 :ARG2~e.6 (o / or~e.8 :op1 (p / protein :name (n / name :op1 "Grb2"~e.7)) :op2 (p2 / protein :name (n2 / name :op1 "Shc"~e.9))))) :ARG1~e.10 (f / feature-01~e.12 :ARG1~e.13 (c / cell-line~e.22 :name (n3 / name :op1 "IEC-6"~e.19,21) :ARG3-of (e3 / express-03~e.5 :ARG2~e.13 (p3 / protein :name (n4 / name :op1 "Tpr-Met"~e.15,17))))))) # ::id pmid_2470_8867.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Stable populations of Tpr @-@ Met @-@ IEC @-@ 6 cells displaying marked and selective knockdown of Grb2 ( TM @-@ shGrb2 ) or Shc ( TM @-@ shShc ) were generated using shRNAs . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.1.1 7-1.1.1.1.1 9-1.1.1.1.1 10-1.1.1 10-1.1.1.2.1.1 10-1.1.1.2.1.2 11-1.1.1.2.1.1.2 11-1.1.1.2.1.2.2 12-1.1.1.2.1.1.2.1.2 14-1.1.1.2.1.1.2.1.3 15-1.1.1.2.1.1.2.1 15-1.1.1.2.1.2.2.1 16-1.1.1.2.1.1.2.1.1.r 17-1.1.1.2.1.1.2.1.1.1.1 19-1.1.1.2.1.1.1.1 21-1.1.1.2.1.1.1.1 24-1.1.1.2.1.2.2.1.1.1.1 26-1.1.1.2.1.2.1.1 28-1.1.1.2.1.2.1.1 31-1 32-1.2 33-1.2.1.1.1 (g / generate-01~e.31 :ARG1 (p / population~e.1 :mod~e.2 (c / cell-line~e.10 :name (n2 / name :op1 "Tpr-Met-IEC-6"~e.3,5,7,9) :ARG1-of (m4 / mean-01 :ARG2 (a / and :op1 (c2 / cell-line~e.10 :name (n5 / name :op1 "TM-shGrb2"~e.19,21) :ARG0-of (d / display-01~e.11 :ARG1 (k / knock-down-02~e.15 :ARG1~e.16 (p3 / protein :name (n4 / name :op1 "Grb2"~e.17)) :ARG2-of (m3 / mark-02~e.12) :mod (s2 / selective~e.14)))) :op2 (c3 / cell-line~e.10 :name (n7 / name :op1 "TM-shShc"~e.26,28) :ARG0-of (d2 / display-01~e.11 :ARG1 (k2 / knock-down-02~e.15 :ARG1 (p5 / protein :name (n6 / name :op1 "Shc"~e.24)) :ARG2-of m3 :mod s2)))))) :ARG1-of (s / stable-02~e.0)) :ARG2-of (u / use-01~e.32 :ARG1 (n3 / nucleic-acid :name (n / name :op1 "shRNA"~e.33)))) # ::id pmid_2470_8867.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As demonstrated by IB analyses ( Figure 4 @ A ) , Grb2 and Shc ( all ShcA isoforms ) protein levels were selectively reduced by more than 60 % in TM @-@ shGrb2 and TM @-@ shShc cell populations , respectively , compared to Tpr @-@ Met @-@ IEC @-@ 6 cells expressing a non @-@ targeting shRNA ( TM @-@ shCTRL ) . # ::alignments 1-1.6 4-1.6.1 6-1.6.2.1 13-1.1.1.1.1.1 14-1.1.1 15-1.1.1.2.1.1 17-1.1.1.3.1.2 18-1.1.1.3.1.1.1.1 19-1.1.1.3.1 21-1.1.1.1 21-1.1.1.2 21-1.1.1.3.1.1 22-1.1 24-1.3 25-1 26-1.2.r 27-1.2 28-1.2 29-1.2.1.1 30-1.2.1 31-1.4.r 32-1.4.2.1.1 34-1.4.2.1.1 36-1.4.2.1.1 36-1.4.3.1.1 38-1.4.3.1.1 39-1.4.2 39-1.4.3 40-1.4 42-1.4.1 44-1.5.r 46-1.5.1.1 48-1.5.1.1 50-1.5.1.1 52-1.5.1.1 53-1.5 53-1.5.3.1 54-1.5.2 56-1.5.2.1.2.1 56-1.5.2.1.2.1.r 58-1.5.2.1.2 59-1.5.2.1.1.1 61-1.5.3.1.1.1 63-1.5.3.1.1.1 (r / reduce-01~e.25 :ARG1 (l / level~e.22 :quant-of (a / and~e.14 :op1 (p2 / protein~e.21 :name (n / name :op1 "Grb2"~e.13)) :op2 (p3 / protein~e.21 :name (n2 / name :op1 "Shc"~e.15)) :ARG1-of (m / mean-01 :ARG2 (i / isoform~e.19 :mod (p4 / protein~e.21 :name (n3 / name :op1 "ShcA"~e.18)) :mod (a2 / all~e.17))))) :ARG2~e.26 (m2 / more-than~e.27,28 :op2 (p5 / percentage-entity~e.30 :value 60~e.29)) :mod (s / selective~e.24) :location~e.31 (p / population~e.40 :mod (r2 / respective~e.42) :mod (c3 / cell-line~e.39 :name (n11 / name :op1 "TM-shGrb2"~e.32,34,36)) :mod (c4 / cell-line~e.39 :name (n12 / name :op1 "TM-shShc"~e.36,38))) :compared-to~e.44 (c / cell-line~e.53 :name (n6 / name :op1 "Tpr-Met-IEC-6"~e.46,48,50,52) :ARG3-of (e3 / express-03~e.54 :ARG2 (n4 / nucleic-acid :name (n9 / name :op1 "shRNA"~e.59) :ARG0-of (t / target-01~e.58 :polarity~e.56 -~e.56))) :ARG1-of (m3 / mean-01 :ARG2 (c2 / cell-line~e.53 :name (n8 / name :op1 "TM-shCTRL"~e.61,63)))) :ARG1-of (d / demonstrate-01~e.1 :ARG0 (a3 / analyze-01~e.4 :mod (i2 / immunoblot-01)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.6 :mod "4A")))) # ::id pmid_2470_8867.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Protein levels of Tpr @-@ Met and actin remained equivalent amongst all these cell populations . # ::alignments 0-1.1.1.1 0-1.1.2.1 1-1.1.1 1-1.1.2 3-1.1.1.1.1.1 5-1.1.1.1.1.1 6-1.1 7-1.1.2.1.1.1 8-1 9-1.2 11-1.3.3 12-1.3.2 13-1.3.1 14-1.3 (r / remain-01~e.8 :ARG1 (a / and~e.6 :op1 (l / level~e.1 :quant-of (p5 / protein~e.0 :name (n3 / name :op1 "Tpr-Met"~e.3,5))) :op2 (l2 / level~e.1 :quant-of (p6 / protein~e.0 :name (n4 / name :op1 "actin"~e.7)))) :ARG3 (e / equal-01~e.9) :location (p4 / population~e.14 :mod (c / cell~e.13) :mod (t / this~e.12) :mod (a2 / all~e.11))) # ::id pmid_2470_8867.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phase contrast microscopy revealed that the TM @-@ shGrb2 cells exhibited a partial reversal of the transformed morphology , relative to TM @-@ shCTRL cells , characterized by a decrease in cell refractility and an increase in cell spreading ( Figure 4 @ B ) . # ::alignments 0-1.1.1.1 1-1.1.1 2-1.1 3-1 4-1.2.r 6-1.2.1.1.1 8-1.2.1.1.1 9-1.2.1 10-1.2 12-1.2.2.2 12-1.2.2.2.r 13-1.2.2 14-1.2.2.1.r 16-1.2.2.1 17-1.2.2.1.1 19-1.2.1.2 21-1.2.1.2.1.1.1 23-1.2.1.2.1.1.1 24-1.2.1 24-1.2.1.2.1 26-1.2.2.3 27-1.2.2.3.1.r 29-1.2.2.3.1.1 30-1.2.2.3.1.1.1.r 31-1.2.2.3.1.1.1.1 32-1.2.2.3.1.1.1 33-1.2.2.3.1 35-1.2.2.3.1.2 36-1.2.2.3.1.2.1.r 37-1.2.2.3.1.2.1.1 38-1.2.2.3.1.2.1 40-1.3.1 (r / reveal-01~e.3 :ARG0 (m2 / microscopy~e.2 :mod (c2 / contrast-01~e.1 :ARG1 (p / phase~e.0))) :ARG1~e.4 (e / exhibit-01~e.10 :ARG0 (c6 / cell-line~e.9,24 :name (n4 / name :op1 "TM-shGrb2"~e.6,8) :ARG1-of (r3 / relative-05~e.19 :ARG3 (c / cell-line~e.24 :name (n / name :op1 "TM-shCTRL"~e.21,23)))) :ARG1 (r2 / reverse-01~e.13 :ARG1~e.14 (t / transform-01~e.16 :ARG1 (m / morphology~e.17)) :degree~e.12 (p2 / part~e.12) :ARG1-of (c3 / characterize-01~e.26 :ARG2~e.27 (a / and~e.33 :op1 (d / decrease-01~e.29 :ARG1~e.30 (r4 / refractility~e.32 :mod (c4 / cell~e.31))) :op2 (i / increase-01~e.35 :ARG1~e.36 (s / spread-02~e.38 :ARG1 c4~e.37)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.40 :mod "4B"))) # ::id pmid_2470_8867.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the TM @-@ shShc cells maintained the transformed morphology , and even adopted a slightly more elongated and spindle @-@ shaped appearance than the control TM @-@ shCTRL cells . # ::alignments 1-1 4-1.1.1.1.1.1 6-1.1.1.1.1.1 7-1.1.2.1 8-1.1.1 10-1.1.1.2 11-1.1.1.2.1 13-1.1 14-1.1.2.3 15-1.1.2 17-1.1.2.2.3 18-1.1.2.2.4 19-1.1.2.2.1 21-1.1.2.2.2.1 23-1.1.2.2.2 24-1.1.2.2 25-1.1.2.2.5.r 27-1.1.2.2.5.2 28-1.1.2.2.5.1.1 30-1.1.2.2.5.1.1 31-1.1.2.2.5 (c / contrast-01~e.1 :ARG2 (a / and~e.13 :op1 (m / maintain-01~e.8 :ARG0 (c3 / cell-line :name (n2 / name :op1 "TM-shShc"~e.4,6)) :ARG1 (t / transform-01~e.10 :ARG1 (m2 / morphology~e.11))) :op2 (a2 / adopt-01~e.15 :ARG0 (c2 / cell~e.7) :ARG1 (a3 / appear-02~e.24 :ARG1-of (e3 / elongate-01~e.19) :ARG1-of (s / shape-01~e.23 :mod (s2 / spindle~e.21)) :mod (s3 / slight~e.17) :degree (m3 / more~e.18) :compared-to~e.25 (c5 / cell-line~e.31 :name (n3 / name :op1 "TM-shCTRL"~e.28,30) :ARG0-of (c6 / control-01~e.27))) :mod (e2 / even~e.14)))) # ::id pmid_2470_8867.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concordant with these morphological changes , E @-@ cadherin protein levels were enhanced in TM @-@ shGrb2 cells and reduced in TM @-@ shShc cells , when compared to TM @-@ shCTRL cells ( Figure 4 @ C and D ) . # ::alignments 2-1.3.1.2 3-1.3.1.1 4-1.3.1 6-1.1.1.1.1.1 8-1.1.1.1.1.1 9-1.1.1.1 10-1.1.1 12-1.1 14-1.1.2.1.1 16-1.1.2.1.1 17-1.1.2 17-1.5 18-1 19-1.2 20-1.2.2.r 21-1.2.2.1.1 23-1.2.2.1.1 24-1.2.2 27-1.5.r 29-1.5.1.1 31-1.5.1.1 32-1.2.2 34-1.4.1.1 34-1.4.1.2 39-1.4.1 (a / and~e.18 :op1 (e / enhance-01~e.12 :ARG1 (l / level~e.10 :quant-of (p / protein~e.9 :name (n / name :op1 "E-cadherin"~e.6,8))) :location (c5 / cell-line~e.17 :name (n5 / name :op1 "TM-shGrb2"~e.14,16))) :op2 (r / reduce-01~e.19 :ARG1 l :location~e.20 (c / cell-line~e.24,32 :name (n2 / name :op1 "TM-shShc"~e.21,23))) :ARG1-of (a2 / accord-02 :ARG2 (c4 / change-01~e.4 :ARG1 (m / morphology~e.3) :mod (t / this~e.2))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.39 :op1 (f / figure~e.34 :mod "4C") :op2 (f2 / figure~e.34 :mod "4D"))) :compared-to~e.27 (c2 / cell-line~e.17 :name (n3 / name :op1 "TM-shCTRL"~e.29,31))) # ::id pmid_2470_8867.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Growth and survival characteristics of these cells were then evaluated in cell @-@ count and anoikis assays , respectively . # ::alignments 0-1.1.2.1 1-1.1.2 2-1.1.2.2 3-1.1 4-1.1.1.r 5-1.1.1.1 6-1.1.1 8-1.2 9-1 10-1.3.r 11-1.3.1.1.1 13-1.3.1.1 14-1.3 15-1.3.2.1 16-1.3.1 16-1.3.2 18-1.3.3 (e / evaluate-01~e.9 :ARG1 (c / characteristic-02~e.3 :ARG1~e.4 (c2 / cell~e.6 :mod (t / this~e.5)) :ARG2 (a / and~e.1 :op1 (g / grow-01~e.0 :ARG1 c2) :op2 (s / survive-01~e.2 :ARG0 c2))) :time (t2 / then~e.8) :manner~e.10 (a2 / and~e.14 :op1 (a5 / assay-01~e.16 :ARG1 (c3 / count-02~e.13 :ARG1 (c4 / cell~e.11))) :op2 (a3 / assay-01~e.16 :ARG1 (a4 / anoikis~e.15)) :mod (r / respective~e.18))) # ::id pmid_2470_8867.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While the TM @-@ shGrb2 cells displayed similar growth capacity to TM @-@ shCTRL cells , growth of the TM @-@ shShc cells was observed to decrease in a time @-@ dependent manner , reaching significant inhibition ( 37.67 ± 5.32 %) 3 days after seeding ( Figure 4 @ E ) . # ::alignments 0-1.2.1.3.1.3.1.3.r 2-1.1.1.1.1 2-1.2.1.1.1.1 4-1.1.1.1.1 5-1.1.1 6-1.1 8-1.1.2.1 9-1.1.2 11-1.1.2.2.1.1.1 13-1.1.2.2.1.1.1 14-1.1.2.2.1 14-1.2.1.1 16-1.2.1 19-1.2.1.1.1.1 21-1.2.1.1.1.1 22-1.2.1.1 24-1.2 26-1.2.1.2 29-1.2.1.2.1.1 29-1.2.1.3.1.3.1 31-1.2.1.2.1 32-1.2.1.2.1.r 34-1.2.1.3 35-1.2.1.3.1.1 36-1.2.1.3.1 38-1.2.1.3.1.2.1.1 40-1.2.1.3.1.2.1.2 42-1.2.1.3.1.3.1.1 43-1.2.1.3.1.3.1.2 44-1.2.1.3.1.3 44-1.2.1.3.1.3.1.3 45-1.2.1.3.1.3.1.3.1 47-1.3.1 (h / have-concession-91 :ARG1 (d2 / display-01~e.6 :ARG0 (c6 / cell-line~e.5 :name (n4 / name :op1 "TM-shGrb2"~e.2,4)) :ARG1 (c2 / capacity~e.9 :domain (g / grow-01~e.8) :ARG1-of (c3 / comparable-03 :ARG2 (c / cell-line~e.14 :name (n / name :op1 "TM-shCTRL"~e.11,13))))) :ARG2 (o / observe-01~e.24 :ARG1 (g2 / grow-01~e.16 :ARG1 (c4 / cell-line~e.14,22 :name (n2 / name :op1 "TM-shShc"~e.2,19,21)) :ARG1-of (d3 / decrease-01~e.26 :manner~e.32 (d4 / depend-01~e.31 :ARG1 (t2 / time~e.29))) :ARG0-of (r2 / reach-01~e.34 :ARG1 (i / inhibit-01~e.36 :ARG1-of (s / significant-02~e.35) :mod (p5 / percentage-entity :value (v / value-interval :op1 37.67~e.38 :op2 5.32~e.40)) :time (a2 / after~e.44 :op1 (t3 / temporal-quantity~e.29 :quant 3~e.42 :unit (d5 / day~e.43) :time~e.0 (a / after~e.44 :op1 (s2 / seed-01~e.45)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.47 :mod "4E"))) # ::id pmid_2470_8867.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The TM @-@ shGrb2 cells displayed enhanced anoikis sensitivity when compared to the TM @-@ shCTRL and TM @-@ shShc cells , between which no difference in survival in suspension was observed ( Figure 4 @ F ) . # ::alignments 1-1.1.1.1 3-1.1.1.1 4-1.1 5-1 6-1.2.3 7-1.2.2 8-1.2 9-1.4.r 10-1.4 11-1.4.2.r 13-1.4.2.1.1.1 15-1.4.2.1.1.1 16-1.4.2 17-1.4.2.1.1.1 17-1.4.2.2.1.1 19-1.4.2.2.1.1 20-1.4.2.1 20-1.4.2.2 24-1.4.2.3.1.1 24-1.4.2.3.1.1.r 25-1.4.2.3.1 25-1.4.2.3.1.1 25-1.4.2.3.1.1.r 26-1.4.2.3.1.2.r 27-1.4.2.3.1.2 28-1.4.2.3.1.2.1.r 29-1.4.2.3.1.2.1 31-1.4.2.3 33-1.3.1 (d / display-01~e.5 :ARG0 (c4 / cell-line~e.4 :name (n4 / name :op1 "TM-shGrb2"~e.1,3)) :ARG1 (s / sensitive-03~e.8 :ARG0 c4 :ARG1 (a / anoikis~e.7) :ARG1-of (e2 / enhance-01~e.6)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure~e.33 :mod "4F")) :time~e.9 (c3 / compare-01~e.10 :ARG1 c4 :ARG2~e.11 (a3 / and~e.16 :op1 (c / cell-line~e.20 :name (n / name :op1 "TM-shCTRL"~e.13,15,17)) :op2 (c5 / cell-line~e.20 :name (n5 / name :op1 "TM-shShc"~e.17,19)) :location-of (o / observe-01~e.31 :ARG1 (d2 / differ-02~e.25 :polarity~e.24,25 -~e.24,25 :ARG3~e.26 (s2 / survive-01~e.27 :ARG1~e.28 (s3 / suspend-02~e.29))))))) # ::id pmid_2470_8867.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 4 @ G , no significant difference in cell viability was observed between the TM @-@ shGrb2 , TM @-@ shShc , and TM @-@ shCTRL cells 18 hours following seeding in the absence of serum under adherent conditions ( Figure 4 @ G ) . # ::alignments 1-1.3 3-1.3.1 3-1.4.1 9-1.1.1.r 10-1.1.4 11-1.1 11-1.1.1 11-1.1.1.r 13-1.1.3.1 15-1.1.3.1.r 16-1 19-1.1.2.1.1.1 19-1.1.2.2.1.1 19-1.1.2.3.1.1 21-1.1.2.1.1.1 23-1.1.2.1.1.1 23-1.1.2.2.1.1 23-1.1.2.3.1.1 25-1.1.2.3.1.1 27-1.1.2 28-1.1.2.1.1.1 28-1.1.2.2.1.1 28-1.1.2.3.1.1 30-1.1.2.2.1.1 31-1.1.3.1 32-1.2.1 33-1.2.2 34-1.2.3 35-1.2.3.1 36-1.2.3.1.1.r 38-1.2.3.1.1 39-1.2.3.1.1.1.r 40-1.2.3.1.1.1 43-1.2.3.1.1.2.r 45-1.3.1 45-1.4.1 (o / observe-01~e.16 :ARG1 (d / differ-02~e.11 :polarity~e.9,11 -~e.11 :ARG1 (a3 / and~e.27 :op1 (c5 / cell-line :name (n3 / name :op1 "TM-shGrb2"~e.19,21,23,28)) :op2 (c6 / cell-line :name (n5 / name :op1 "TM-shCTRL"~e.19,23,28,30)) :op3 (c7 / cell-line :name (n6 / name :op1 "TM-shShc"~e.19,23,25,28))) :ARG3 (v / viable :domain~e.15 (c / cell~e.13,31)) :ARG1-of (s / significant-02~e.10)) :duration (t2 / temporal-quantity :quant 18~e.32 :unit (h2 / hour~e.33) :ARG1-of (f / follow-01~e.34 :ARG2 (s2 / seed-02~e.35 :condition~e.36 (a / absent-01~e.38 :ARG1~e.39 (s3 / serum~e.40) :condition~e.43 (a2 / adhere-01))))) :ARG1-of (s4 / show-01~e.1 :location (f2 / figure~e.3,45 :mod "4G")) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.3,45 :mod "4G"))) # ::id pmid_2470_8867.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these results suggest that signals downstream of Grb2 and Shc proteins are required for non @-@ overlapping functions promoted by the oncogenic Met receptor in IECs . # ::alignments 0-1.1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 5-1.2.r 6-1.2.2 7-1.2.2.1.2 9-1.2.2.1.1.1.1.1 10-1.2.2.1.1 11-1.2.2.1.1.2.1.1 12-1.2.2.1.1.1 12-1.2.2.1.1.2 14-1.2 15-1.2.1.r 16-1.2.1.2.1 16-1.2.1.2.1.r 18-1.2.1.2 19-1.2.1 20-1.2.1.1 24-1.2.1.1.1.1.1 25-1.2.1.1.1 26-1.2.1.1.2.r 27-1.2.1.1.2.1.1 (s / suggest-01~e.4 :ARG0 (t / thing~e.3 :ARG2-of~e.3 (r / result-01~e.3) :mod (t2 / this~e.2) :mod (t3 / together~e.0)) :ARG1~e.5 (r2 / require-01~e.14 :ARG0~e.15 (f / function-01~e.19 :ARG1-of (p3 / promote-01~e.20 :ARG0 (r5 / receptor~e.25 :name (n5 / name :op1 "Met"~e.24)) :location~e.26 (c2 / cell :name (n4 / name :op1 "IEC"~e.27))) :ARG0-of (o / overlap-01~e.18 :polarity~e.16 -~e.16)) :ARG1 (s2 / signal-07~e.6 :location (r4 / relative-position :op1 (a / and~e.10 :op1 (p / protein~e.12 :name (n / name :op1 "Grb2"~e.9)) :op2 (p2 / protein~e.12 :name (n2 / name :op1 "Shc"~e.11))) :direction (d / downstream~e.7))))) # ::id pmid_2470_8867.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK , but not PI3K inhibitors reduce IEC transformation promoted by the oncogenic engagement of Met , Grb2 , or Shc signals # ::alignments 1-1.1.1.1.1.1 3-1.1.2 5-1.1.2.1.1.1.1.1 6-1.1 6-1.1.1 6-1.1.1.r 6-1.1.2.1 6-1.1.2.1.1 6-1.1.2.1.1.r 7-1 8-1.2.1.1.1 9-1.2 10-1.2.2 11-1.2.2.1.r 13-1.2.2.1.2 14-1.2.2.1 15-1.2.2.1.1.r 16-1.2.2.1.1.1.1.1.1 18-1.2.2.1.1.1.2.1.1 20-1.2.2.1.1.1 21-1.2.2.1.1.1.3.1.1 22-1.2.2.1.1 (r / reduce-01~e.7 :ARG0 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.1))) :ARG1-of (c / contrast-01~e.3 :ARG2 (m2 / molecular-physical-entity~e.6 :ARG0-of~e.6 (i2 / inhibit-01~e.6 :ARG1 (p6 / protein-family :name (n2 / name :op1 "PI3K"~e.5)))))) :ARG1 (t2 / transform-01~e.9 :ARG1 (c2 / cell :name (n3 / name :op1 "IEC"~e.8)) :ARG1-of (p2 / promote-01~e.10 :ARG0~e.11 (e2 / engage-01~e.14 :ARG1~e.15 (s / signal-07~e.22 :ARG0 (o / or~e.20 :op1 (p3 / protein :name (n4 / name :op1 "Met"~e.16)) :op2 (p4 / protein :name (n5 / name :op1 "Grb2"~e.18)) :op3 (p5 / protein :name (n6 / name :op1 "Shc"~e.21)))) :ARG2 (c3 / cancer~e.13))))) # ::id pmid_2470_8867.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Grb2 and Shc adaptor proteins are known to couple RTKs , such as the Met receptor , to the Ras @/@ MAPK and PI3K @/@ Akt signaling pathways [ @ 28 @ - @ 30 @ ] . # ::alignments 1-1.1.1.1.1 2-1.1 3-1.1.2.1.1 5-1.1.1 5-1.1.2 7-1 9-1.2 12-1.2.2.2.r 13-1.2.2.2.r 15-1.2.2.2.1.1 16-1.2.2.2 18-1.2.3.r 20-1.2.3.1.1.1 22-1.2.3.1.1.1 23-1.2.3 24-1.2.3.2.1.1 26-1.2.3.2.1.1 27-1.2.3.3 28-1.2.3.1 28-1.2.3.2 31-1.3.1.1.1.1 35-1.3.1.1.1.2 (k / know-02~e.7 :ARG1 (a5 / and~e.2 :op1 (p3 / protein~e.5 :name (n2 / name :op1 "Grb2"~e.1)) :op2 (p4 / protein~e.5 :name (n3 / name :op1 "Shc"~e.3)) :ARG0-of (a6 / adapt-01)) :ARG3 (c / couple-01~e.9 :ARG0 a5 :ARG1 (e / enzyme :name (n4 / name :op1 "RTK") :example~e.12,13 (r2 / receptor~e.16 :name (n6 / name :op1 "Met"~e.15))) :ARG2~e.18 (a2 / and~e.23 :op1 (p6 / pathway~e.28 :name (n5 / name :op1 "Ras/MAPK"~e.20,22)) :op2 (p7 / pathway~e.28 :name (n7 / name :op1 "PI3K/Akt"~e.24,26)) :ARG0-of (s2 / signal-07~e.27))) :ARG1-of (d / describe-01 :ARG0 (p8 / publication :ARG1-of (c2 / cite-01 :ARG2 (a4 / and :op1 28~e.31 :op2 30~e.35))))) # ::id pmid_2470_8867.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The Ras @/@ MAPK and PI3K @/@ Akt pathways are important regulators of RTK @-@ mediated epithelial cell transformation , but their actions are cell type @-@ specific [ @ 31 @ ] . # ::alignments 1-1.1.1.1.1.1 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.1 8-1.1.1.1 8-1.1.1.2 10-1.1.3 11-1.1 12-1.1.2.r 13-1.1.2.2.1.1.1 15-1.1.2.2 16-1.1.2.1.1 17-1.1.2.1 18-1.1.2 20-1 21-1.2.1 21-1.2.1.r 22-1.2 24-1.2.2.1.1 25-1.2.2.1 27-1.2.2 30-1.3.1.1.1 (c / contrast-01~e.20 :ARG1 (r2 / regulate-01~e.11 :ARG0 (a / and~e.4 :op1 (p2 / pathway~e.8 :name (n2 / name :op1 "Ras/MAPK"~e.1,3)) :op2 (p3 / pathway~e.8 :name (n3 / name :op1 "PI3K/Akt"~e.5,7))) :ARG1~e.12 (t / transform-01~e.18 :ARG1 (c2 / cell~e.17 :part-of (e / epithelium~e.16)) :ARG1-of (m / mediate-01~e.15 :ARG0 (e2 / enzyme :name (n4 / name :op1 "RTK"~e.13)))) :mod (i / important~e.10)) :ARG2 (a2 / act-02~e.22 :ARG0~e.21 a~e.21 :ARG1-of (s / specific-02~e.27 :ARG2 (t3 / type~e.25 :mod (c3 / cell~e.24)))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 31~e.30)))) # ::id pmid_2470_8867.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To define the role of these signaling pathways in IEC transformation , we first compared their activation status in IEC @-@ 6 cells transformed by the Tpr @-@ Met , TM @-@ Grb2 , TM @-@ Shc1 , and TM @-@ Shc2 oncoproteins , to that one in non @-@ transformed Control @-@ IEC @-@ 6 cells . # ::alignments 0-1.2.2.2.1.5 1-1.5 3-1.5.2 4-1.5.2.1.r 5-1.5.2.1.2 6-1.5.2.1.1 7-1.5.2.1 8-1.5.2.2.r 9-1.5.2.2.1.1.1 10-1.5.2.2 12-1.1 13-1.4 14-1 15-1.2.3 15-1.2.3.r 16-1.2.1 17-1.2 17-1.3 18-1.2.2.r 19-1.2.2.1.1 21-1.2.2.1.1 22-1.2.2 22-1.3.2 22-1.5.2.2.1 23-1.2.2.2 24-1.2.2.2.1.r 26-1.2.2.2.1.1.1.1 28-1.2.2.2.1.1.1.1 30-1.2.2.2.1.2.1.1 30-1.2.2.2.1.3.1.1 30-1.2.2.2.1.4.1.1 32-1.2.2.2.1.2.1.1 34-1.2.2.2.1.2.1.1 34-1.2.2.2.1.3.1.1 34-1.2.2.2.1.4.1.1 36-1.2.2.2.1.3.1.1 38-1.2.2.2.1 39-1.2.2.2.1.2.1.1 39-1.2.2.2.1.3.1.1 39-1.2.2.2.1.4.1.1 41-1.2.2.2.1.4.1.1 44-1.2.2.2.1.5 44-1.3.1.r 45-1.3.1 47-1.3.2.2.r 48-1.3.2.2.1 48-1.3.2.2.1.r 50-1.3.2.2 51-1.3.2.1.1 53-1.5.2.2.1.1.1 55-1.2.2.1.1 55-1.3.2.1.1 56-1.2.2 (c / compare-01~e.14 :ARG0 (w / we~e.12) :ARG1 (s3 / status~e.17 :mod (a3 / activate-01~e.16) :location~e.18 (c3 / cell-line~e.22,56 :name (n2 / name :op1 "IEC-6"~e.19,21,55) :ARG1-of (t4 / transform-01~e.23 :ARG0~e.24 (a2 / and~e.38 :op1 (p2 / protein :name (n3 / name :op1 "Tpr-Met"~e.26,28)) :op2 (p3 / protein :name (n4 / name :op1 "TM-Grb2"~e.30,32,34,39)) :op3 (p4 / protein :name (n5 / name :op1 "TM-Shc1"~e.30,34,36,39)) :op4 (p5 / protein :name (n6 / name :op1 "TM-Shc2"~e.30,34,39,41)) :ARG0-of (c5 / cause-01~e.0,44 :ARG1 (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))) :poss~e.15 p~e.15) :ARG2 (s4 / status~e.17 :mod~e.44 (t3 / that~e.45) :location (c4 / cell-line~e.22 :name (n7 / name :op1 "Control-IEC-6"~e.51,55) :ARG1-of~e.47 (t6 / transform-01~e.50 :polarity~e.48 -~e.48)) :mod a3 :poss p) :time (f / first~e.13) :purpose (d / define-01~e.1 :ARG0 w :ARG1 (r / role~e.3 :poss~e.4 (p / pathway~e.7 :ARG1-of (s / signal-07~e.6) :mod (t / this~e.5)) :purpose~e.8 (t2 / transform-01~e.10 :ARG1 (c2 / cell~e.22 :name (n / name :op1 "IEC"~e.9,53)))))) # ::id pmid_2470_8867.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The phosphorylation @/@ activation levels of the downstream effectors of MEK and PI3K , Erk1 @/@ 2 and Akt , respectively , were assessed by IB analyses of lysates prepared from serum @-@ starved IEC @-@ 6 cells . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1.1.2 4-1.1 7-1.1.1.1.1.5.1 8-1.1.1.1.1.5 9-1.1.1.1.1.r 10-1.1.1.1.1.1.1.1 11-1.1.1.1.1 12-1.1.1.1.1.2.1.1 14-1.1.1.1.1.3.1.1 15-1.1.1 16-1.1.1.1.1.3.1.1 17-1.1.1.1.1 18-1.1.1.1.1.4.1.1 20-1.1.1.1.1.6 23-1 26-1.2 27-1.2.1.r 28-1.2.1 29-1.2.1.1 30-1.2.1.1.1.r 31-1.2.1.1.1.2.1 33-1.2.1.1.1.2 34-1.2.1.1.1.1.1 36-1.2.1.1.1.1.1 37-1.2.1.1.1 (a / assess-01~e.23 :ARG1 (l / level~e.4 :degree-of (s / slash~e.2,15 :op1 (p2 / phosphorylate-01~e.1 :ARG1~e.9 (a3 / and~e.11,17 :op1 (e / enzyme :name (n2 / name :op1 "MEK"~e.10)) :op2 (e3 / enzyme :name (n3 / name :op1 "PI3K"~e.12)) :op3 (e4 / enzyme :name (n4 / name :op1 "Erk1/2"~e.14,16)) :op4 (e5 / enzyme :name (n5 / name :op1 "Akt"~e.18)) :mod (e2 / effector~e.8 :mod (d2 / downstream~e.7)) :mod (r / respective~e.20))) :op2 (a2 / activate-01~e.3 :ARG1 a3))) :manner (a4 / analyze-01~e.26 :ARG1~e.27 (l2 / lysate~e.28 :ARG1-of (p / prepare-01~e.29 :ARG2~e.30 (c / cell-line~e.37 :name (n6 / name :op1 "IEC-6"~e.34,36) :ARG1-of (s2 / starve-01~e.33 :ARG2 (s3 / serum~e.31))))) :mod (i / immunoblot-01))) # ::id pmid_2470_8867.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Phosphorylation levels of neither Erk1 @/@ 2 nor Akt were elevated in Tpr @-@ Met @-@ IEC @-@ 6 , TM @-@ Grb2 @-@ IEC @-@ 6 , TM @-@ Shc1 @-@ IEC @-@ 6 , or TM @-@ Shc2 @-@ IEC @-@ 6 cells , relative to Control @-@ IEC @-@ 6 cells ( Figure 5 @ A ) . # ::alignments 0-1.2.1 1-1.2 3-1.1.r 4-1.2.1.1.1.1.1 6-1.2.1.1.1.1.1 7-1.1 7-1.1.r 8-1.2.1.1.2.1.1 10-1 11-1.2.2.r 12-1.2.2.1.1.1 12-1.2.2.2.1.1 12-1.2.2.3.1.1 12-1.2.2.4.1.1 14-1.2.2.1.1.1 16-1.2.2.1.1.1 16-1.2.2.2.1.1 16-1.2.2.3.1.1 16-1.2.2.4.1.1 18-1.2.2.1.1.1 18-1.2.2.2.1.1 18-1.2.2.3.1.1 18-1.2.2.4.1.1 22-1.2.2.2.1.1 24-1.2.2.1.1.1 24-1.2.2.2.1.1 24-1.2.2.3.1.1 24-1.2.2.4.1.1 26-1.2.2.1.1.1 26-1.2.2.2.1.1 26-1.2.2.3.1.1 26-1.2.2.4.1.1 30-1.2.2.3.1.1 32-1.2.2.1.1.1 32-1.2.2.2.1.1 32-1.2.2.3.1.1 32-1.2.2.4.1.1 34-1.2.2.1.1.1 34-1.2.2.2.1.1 34-1.2.2.3.1.1 34-1.2.2.4.1.1 36-1.2.2 39-1.2.2.4.1.1 41-1.2.2.4.1.1 43-1.2.2.4.1.1 44-1.2.2.1 44-1.2.2.2 44-1.2.2.3 44-1.2.2.4 46-1.3 47-1.3.1.r 48-1.3.1.1.1 50-1.3.1.1.1 52-1.3.1.1.1 53-1.3.1 55-1.4.1 (e / elevate-01~e.10 :polarity~e.3,7 -~e.7 :ARG1 (l / level~e.1 :degree-of (p2 / phosphorylate-01~e.0 :ARG1 (a / and :op1 (e2 / enzyme :name (n / name :op1 "Erk1/2"~e.4,6)) :op2 (e3 / enzyme :name (n2 / name :op1 "Akt"~e.8)))) :location~e.11 (o / or~e.36 :op1 (c3 / cell-line~e.44 :name (n9 / name :op1 "Tpr-Met-IEC-6"~e.12,14,16,18,24,26,32,34)) :op2 (c4 / cell-line~e.44 :name (n10 / name :op1 "Tpr-Grb2-IEC-6"~e.12,16,18,22,24,26,32,34)) :op3 (c5 / cell-line~e.44 :name (n11 / name :op1 "Tpr-Shc1-IEC-6"~e.12,16,18,24,26,30,32,34)) :op4 (c6 / cell-line~e.44 :name (n12 / name :op1 "Tpr-Shc2-IEC-6"~e.12,16,18,24,26,32,34,39,41,43)))) :ARG1-of (r / relative-05~e.46 :ARG3~e.47 (c / cell-line~e.53 :name (n8 / name :op1 "Control-IEC-6"~e.48,50,52))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.55 :mod "5A"))) # ::id pmid_2470_8867.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both Erk2 and Akt protein levels were comparable in all IEC @-@ 6 cell populations . # ::alignments 0-1.3 1-1.1.1.1.1 3-1.2.1.1.1 4-1.1.1 4-1.2.1 5-1.1 5-1.2 7-1 8-1.4.r 9-1.4.2 10-1.4.1.1.1 12-1.4.1.1.1 13-1.4.1 14-1.4 (c / comparable-03~e.7 :ARG1 (l / level~e.5 :quant-of (p2 / protein~e.4 :name (n / name :op1 "Erk2"~e.1))) :ARG2 (l2 / level~e.5 :quant-of (p / protein~e.4 :name (n2 / name :op1 "Akt"~e.3))) :mod (b / both~e.0) :location~e.8 (p3 / population~e.14 :mod (c2 / cell-line~e.13 :name (n3 / name :op1 "IEC-6"~e.10,12)) :mod (a / all~e.9))) # ::id pmid_2470_8867.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A similar trend of Erk1 @/@ 2 and Akt phosphorylation was observed in cells maintained in the presence of serum ( data not shown ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1.1 6-1.1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.2.1.1 9-1.1.1 11-1 12-1.2.r 13-1.2 14-1.2.1 15-1.2.1.1.r 17-1.2.1.1 18-1.2.1.1.1.r 19-1.2.1.1.1 21-1.3.1 22-1.3.1.1.1 22-1.3.1.1.1.r 23-1.3.1.1 (o / observe-01~e.11 :ARG1 (t / trend-01~e.2 :ARG1~e.3 (p3 / phosphorylate-01~e.9 :ARG1 (a2 / and~e.7 :op1 (e / enzyme :name (n / name :op1 "Erk1/2"~e.4,6)) :op2 (e2 / enzyme :name (n2 / name :op1 "Akt"~e.8)))) :ARG1-of (r2 / resemble-01~e.1)) :location~e.12 (c / cell~e.13 :ARG1-of (m / maintain-01~e.14 :condition~e.15 (p2 / present-02~e.17 :ARG1~e.18 (s / serum~e.19)))) :ARG1-of (d2 / describe-01 :ARG0 (d3 / data~e.21 :ARG1-of (s3 / show-01~e.23 :polarity~e.22 -~e.22)))) # ::id pmid_2470_8867.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The lack of evidence for Erk1 @/@ 2 and Akt activation in IEC @-@ 6 cells stably expressing the constitutively activated form of the Met receptor , or the Grb2 and Shc docking @-@ specific oncoproteins , is consistent with both the Ras @/@ MAPK and PI3K @/@ Akt pathways being subject to negative feedback mechanisms [ @ 35 @ ] . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1.1.1 7-1.1.1.1.1.1.1.1 8-1.1.1.1.1 9-1.1.1.1.1.2.1.1 10-1.1.1.1 11-1.1.1.1.2.r 12-1.1.1.1.2.1.1 14-1.1.1.1.2.1.1 15-1.1.1.1.2 16-1.1.1.1.2.2.2 17-1.1.1.1.2.2 19-1.1.1.1.2.2.1.1.2.1 20-1.1.1.1.2.2.1.1.2 24-1.1.1.1.2.2.1.1.1.1 25-1.1.1.1.2.2.1.1 27-1.1.1.1.2.2.1 29-1.1.1.1.2.2.1.2.1.1.1 30-1.1.1.1.2.2.1.2 31-1.1.1.1.2.2.1.2.2.1.1 32-1.1.1.1.2.2.1.2.3.1 34-1.1.1.1.2.2.1.2.3 38-1 39-1.2.r 40-1.2.4 42-1.2.1.1.1 44-1.2.1.1.1 45-1.2 46-1.2.2.1.1 48-1.2.2.1.1 49-1.2.1 49-1.2.2 51-1.2.3 52-1.2.3.1.r 53-1.2.3.1.1.1 54-1.2.3.1.1 55-1.2.3.1 58-1.3.1.1.1 (c / consistent-01~e.38 :ARG1 (l / lack-01~e.1 :ARG1~e.2 (e / evidence-01~e.3 :ARG1~e.4 (a / activate-01~e.10 :ARG1 (a2 / and~e.8 :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1/2"~e.5,7)) :op2 (e3 / enzyme :name (n3 / name :op1 "Akt"~e.9))) :location~e.11 (c2 / cell-line~e.15 :name (n4 / name :op1 "IEC-6"~e.12,14) :ARG3-of (e4 / express-03~e.17 :ARG2 (o2 / or~e.27 :op1 (r / receptor~e.25 :name (n6 / name :op1 "Met"~e.24) :ARG1-of (a6 / activate-01~e.20 :mod (c5 / constitutive~e.19))) :op2 (a4 / and~e.30 :op1 (p4 / protein :name (n / name :op1 "Grb2"~e.29)) :op2 (p5 / protein :name (n5 / name :op1 "Shc"~e.31)) :ARG1-of (s2 / specific-02~e.34 :ARG2 (d / dock-01~e.32)) :ARG0-of (c3 / cause-01 :ARG1 (d3 / disease :wiki "Cancer" :name (n10 / name :op1 "cancer"))))) :ARG1-of (s / stable-02~e.16)))))) :ARG2~e.39 (a5 / and~e.45 :op1 (p / pathway~e.49 :name (n7 / name :op1 "Ras/MAPK"~e.42,44)) :op2 (p2 / pathway~e.49 :name (n8 / name :op1 "PI3K/Akt"~e.46,48)) :ARG1-of (s3 / subject-01~e.51 :ARG2~e.52 (m / mechanism~e.55 :mod (f2 / feedback~e.54 :ARG0-of (n9 / negative-03~e.53)))) :mod (b / both~e.40)) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 35~e.58)))) # ::id pmid_2470_8867.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok It cannot be explained as merely a cell type @–@ specific event , since similarly stable expression of these oncoproteins in fibroblasts failed to promote Erk1 @/@ 2 or Akt activation [ @ 36 @ ] and unpublished observation ] . # ::alignments 0-1.2.1 1-1 1-1.1 1-1.1.r 3-1.2 4-1.2.2.r 5-1.2.2.1.2 7-1.2.2.1.1.1 8-1.2.2.1.1 10-1.2.2.1 11-1.2.2 13-1.3 14-1.3.1.1.3.1 15-1.3.1.1.3 16-1.3.1.1 17-1.3.1.1.1.r 18-1.3.1.1.1.2 20-1.3.1.1.2.r 21-1.3.1.1.2 22-1.3.1 24-1.3.1.2 25-1.3.1.2.2.1.1.1.1.1 26-1.3.1.2.2.1.1 28-1.3.1.2.2.1 29-1.3.1.2.2.1.2.1.1 30-1.3.1.2.2 33-1.4.1.1.1.1 36-1.4.1 37-1.4.1.1 37-1.4.1.2.2 37-1.4.1.2.2.1 37-1.4.1.2.2.1.r 38-1.4.1.2 38-1.4.1.2.1 38-1.4.1.2.1.r (p2 / possible-01~e.1 :polarity~e.1 -~e.1 :ARG1 (e / explain-01~e.3 :ARG1 (i / it~e.0) :manner~e.4 (e2 / event~e.11 :ARG1-of (s / specific-02~e.10 :ARG2 (t / type~e.8 :mod (c / cell~e.7)) :degree (m / mere~e.5)))) :ARG1-of (c2 / cause-01~e.13 :ARG0 (f / fail-01~e.22 :ARG1 (e3 / express-03~e.16 :ARG2~e.17 (p / protein :ARG0-of (c3 / cause-01 :ARG1 (c4 / cancer)) :mod (t2 / this~e.18)) :ARG3~e.20 (f2 / fibroblast~e.21) :ARG1-of (s2 / stable-03~e.15 :ARG1-of (r / resemble-01~e.14))) :ARG2 (p3 / promote-01~e.24 :ARG0 e3 :ARG1 (a / activate-01~e.30 :ARG1 (o / or~e.28 :op1 (s3 / slash~e.26 :op1 (e6 / enzyme :name (n / name :op1 "Erk1"~e.25)) :op2 (e5 / enzyme :name (n2 / name :op1 "Erk2"))) :op2 (e4 / enzyme :name (n3 / name :op1 "Akt"~e.29))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.36 :op1 (p4 / publication~e.37 :ARG1-of (c5 / cite-01 :ARG2 36~e.33)) :op2 (t3 / thing~e.38 :ARG1-of~e.38 (o2 / observe-01~e.38) :ARG1-of (p5 / publish-01~e.37 :polarity~e.37 -~e.37))))) # ::id pmid_2470_8867.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next investigated whether , even at the low levels observed , MEK or PI3K activities were implicated in the induction of transformation features in IEC @-@ 6 cells by the Tpr @-@ Met , TM @-@ Grb2 , TM @-@ Shc1 , or TM @-@ Shc2 oncoproteins . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.1.r 5-1.2.4.3 8-1.2.4.1 9-1.2.4 10-1.2.4.2 12-1.2.2.1.1.1.1 13-1.2.2.1 14-1.2.2.1.2.1.1 15-1.2.2 17-1.2 18-1.2.3.r 20-1.2.3 21-1.2.3.1.r 22-1.2.3.1.1 23-1.2.3.1 24-1.2.3.1.1.2.r 25-1.2.3.1.1.2.1.1 27-1.2.3.1.1.2.1.1 28-1.2.3.1.1.2 29-1.2.3.1.1.1.r 31-1.2.3.1.1.1.1.1.1 33-1.2.3.1.1.1.1.1.1 35-1.2.3.1.1.1.2.1.1 35-1.2.3.1.1.1.3.1.1 35-1.2.3.1.1.1.4.1.1 37-1.2.3.1.1.1.2.1.1 39-1.2.3.1.1.1.2.1.1 39-1.2.3.1.1.1.3.1.1 39-1.2.3.1.1.1.4.1.1 41-1.2.3.1.1.1.3.1.1 43-1.2.3.1.1.1 44-1.2.3.1.1.1.2.1.1 44-1.2.3.1.1.1.3.1.1 44-1.2.3.1.1.1.4.1.1 46-1.2.3.1.1.1.4.1.1 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (i2 / implicate-01~e.17 :mode~e.3 interrogative~e.3 :ARG1 (a / activity-06~e.15 :ARG0 (o / or~e.13 :op1 (e / enzyme :name (n / name :op1 "MEK"~e.12)) :op2 (e2 / enzyme :name (n3 / name :op1 "PI3K"~e.14)))) :ARG2~e.18 (i3 / induce-01~e.20 :ARG2~e.21 (f / feature~e.23 :mod (t / transform-01~e.22 :ARG0~e.29 (o2 / or~e.43 :op1 (p / protein :name (n5 / name :op1 "Tpr-Met"~e.31,33)) :op2 (p2 / protein :name (n6 / name :op1 "TM-Grb2"~e.35,37,39,44)) :op3 (p3 / protein :name (n7 / name :op1 "TM-Shc1"~e.35,39,41,44)) :op4 (p4 / protein :name (n8 / name :op1 "TM-Shc2"~e.35,39,44,46)) :ARG0-of (c2 / cause-01 :ARG1 (c3 / cancer))) :ARG1~e.24 (c / cell-line~e.28 :name (n4 / name :op1 "IEC-6"~e.25,27))))) :condition (l / level~e.9 :ARG1-of (l2 / low-04~e.8) :ARG1-of (o3 / observe-01~e.10) :mod (e3 / even~e.5))) :time (n2 / next~e.1)) # ::id pmid_2470_8867.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cells were treated with vehicle ( DMSO ) , 10 μM U0126 ( a MEK1 @/@ 2 inhibitor ) , 10 μM LY294002 ( a PI3K inhibitor ) , or a combination of both inhibitors , and their morphology was examined by phase contrast microscopy , following 24 ( Additional file 3 ) and 48 hours of treatment ( Figure 5 @ B ) . # ::alignments 0-1.1.1 2-1.1 4-1.1.2.1 6-1.1.2.1.1.1.1 9-1.1.2.2.2.1 10-1.1.2.2.2.2 11-1.1.2.2.1.1 14-1.1.2.2.3.1.1.1.1 15-1.1.2.2.3.1 17-1.1.2.2 17-1.1.2.2.3 17-1.1.2.2.3.r 20-1.1.2.2.2.1 21-1.1.2.2.2.2 22-1.1.2.3.1.1 25-1.1.2.3.3.1.1.1 26-1.1.2.3 26-1.1.2.3.3 26-1.1.2.3.3.r 29-1.1.2 31-1.1.2.4 32-1.1.2.4.3.r 33-1.1.2.4.3 34-1.1.2.4.2 36-1.2.3 37-1.2.1.1 37-1.2.1.1.r 38-1.2.1 40-1.2 41-1.2.2.r 42-1.2.2.1.1 43-1.2.2.1 44-1.2.2 46-1.2.3.1 46-1.2.3.2 47-1.2.3.1.2.1 49-1.2.3.1.3.1.2 50-1.2.3.1.3.1 52-1.2.3.1.3.1.1 56-1.2.3.2.2.1 57-1.2.3.1.2.2 59-1.1 61-1.2.3.2.3.1 (a / and :op1 (t3 / treat-04~e.2,59 :ARG1 (c / cell~e.0) :ARG2 (o / or~e.29 :op1 (v / vehicle~e.4 :mod (s2 / small-molecule :name (n2 / name :op1 "DMSO"~e.6))) :op2 (s / small-molecule~e.17 :name (n / name :op1 "U0126"~e.11) :quant (c2 / concentration-quantity :quant 10~e.9,20 :unit (m / micromolar~e.10,21)) :ARG0-of~e.17 (i2 / inhibit-01~e.17 :ARG1 (s3 / slash~e.15 :op1 (e / enzyme :name (n3 / name :op1 "MEK1"~e.14)) :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2"))))) :op3 (s4 / small-molecule~e.26 :name (n5 / name :op1 "LY294002"~e.22) :quant c2 :ARG0-of~e.26 (i3 / inhibit-01~e.26 :ARG1 (p2 / protein-family :name (n6 / name :op1 "PI3K"~e.25)))) :op4 (c3 / combine-01~e.31 :ARG1 s :ARG2 s4~e.34 :mod~e.32 (b / both~e.33)))) :op2 (e4 / examine-01~e.40 :ARG1 (m2 / morphology~e.38 :poss~e.37 c~e.37) :manner~e.41 (m3 / microscopy~e.44 :mod (c4 / contrast-01~e.43 :ARG1 (p / phase~e.42))) :time (a2 / and~e.36 :op1 (a3 / after~e.46 :op1 t3 :quant (t5 / temporal-quantity :quant 24~e.47 :unit (h / hour~e.57)) :ARG1-of (d / describe-01 :ARG0 (f / file~e.50 :mod 3~e.52 :mod (a5 / additional~e.49)))) :op2 (a4 / after~e.46 :op1 t3 :quant (t / temporal-quantity :quant 48~e.56 :unit h) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.61 :mod "5B")))))) # ::id pmid_2470_8867.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neither individual inhibitor treatment , nor the combination , had an obvious effect on the morphology of the Control @-@ IEC @-@ 6 cells . # ::alignments 0-1.1.r 1-1.2.1.1.2 2-1.2.1.1 2-1.2.1.1.1 2-1.2.1.1.1.r 3-1.2.1 5-1.1 5-1.1.r 7-1.2.2 11-1.4 12-1 13-1.3.r 15-1.3 16-1.3.1.r 18-1.3.1.2 20-1.3.1.1.1 22-1.3.1.1.1 23-1.3.1 (a / affect-01~e.12 :polarity~e.0,5 -~e.5 :ARG0 (a2 / and :op1 (t2 / treat-04~e.3 :ARG2 (m2 / molecular-physical-entity~e.2 :ARG0-of~e.2 (i / inhibit-01~e.2) :mod (i2 / individual~e.1))) :op2 (c / combine-01~e.7)) :ARG1~e.13 (m / morphology~e.15 :poss~e.16 (c2 / cell-line~e.23 :name (n / name :op1 "IEC-6"~e.20,22) :mod (c3 / control~e.18))) :ARG1-of (o / obvious-01~e.11)) # ::id pmid_2470_8867.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the MEK1 @/@ 2 inhibitor , but not the PI3K inhibitor , induced a potent reversion of the transformed morphological features of the Tpr @-@ Met @-@ IEC @-@ 6 , TM @-@ Grb2 @-@ IEC @-@ 6 , TM @-@ Shc1 @-@ IEC @-@ 6 , and TM @-@ Shc2 @-@ IEC @-@ 6 cells , observed within 24 hours of treatment ( Additional file 3 ) and more striking in appearance after 48 hours ( Figure 5 @ B ) . # ::alignments 0-1.3 3-1.1.1.1.1.1.1.1 4-1.1.1.1.1 6-1.1.1 6-1.1.1.1 6-1.1.1.1.r 8-1 9-1.2.1 9-1.2.1.r 11-1.2.2.1.1.1.1 12-1.1.1 12-1.1.1.1 12-1.1.1.1.r 12-1.2.2 12-1.2.2.1 12-1.2.2.1.r 14-1.1 14-1.2 16-1.1.2.2 17-1.1.2 18-1.1.2.1.r 20-1.1.2.1.2 20-1.1.2.1.3.1.2 21-1.1.2.1.1 22-1.1.2.1 23-1.1.2.1.3.1.2.1.r 25-1.1.2.1.3.1.2.1.1.1 27-1.1.2.1.3.1.2.1.1.1 29-1.1.2.1.3.1.1.1 29-1.1.2.1.3.2.1.1 29-1.1.2.1.3.3.1.1 29-1.1.2.1.3.4.1.1 31-1.1.2.1.3.1.1.1 31-1.1.2.1.3.2.1.1 31-1.1.2.1.3.3.1.1 31-1.1.2.1.3.4.1.1 33-1.1.2.1.3.2.2.1.1.1 33-1.1.2.1.3.3.2.1.1.1 33-1.1.2.1.3.4.2.1.1.1 35-1.1.2.1.3.2.2.1.1.1 37-1.1.2.1.3.1.1.1 37-1.1.2.1.3.2.1.1 37-1.1.2.1.3.3.1.1 37-1.1.2.1.3.4.1.1 39-1.1.2.1.3.1.1.1 39-1.1.2.1.3.2.1.1 39-1.1.2.1.3.3.1.1 39-1.1.2.1.3.4.1.1 41-1.1.2.1.3.2.2.1.1.1 41-1.1.2.1.3.3.2.1.1.1 41-1.1.2.1.3.4.2.1.1.1 43-1.1.2.1.3.3.2.1.1.1 45-1.1.2.1.3.1.1.1 45-1.1.2.1.3.2.1.1 45-1.1.2.1.3.3.1.1 45-1.1.2.1.3.4.1.1 47-1.1.2.1.3.1.1.1 47-1.1.2.1.3.2.1.1 47-1.1.2.1.3.3.1.1 47-1.1.2.1.3.4.1.1 49-1.1.2.1.3 50-1.1.2.1.3.2.2.1.1.1 50-1.1.2.1.3.3.2.1.1.1 50-1.1.2.1.3.4.2.1.1.1 52-1.1.2.1.3.4.2.1.1.1 54-1.1.2.1.3.1.1.1 54-1.1.2.1.3.2.1.1 54-1.1.2.1.3.3.1.1 54-1.1.2.1.3.4.1.1 56-1.1.2.1.3.1.1.1 56-1.1.2.1.3.2.1.1 56-1.1.2.1.3.3.1.1 56-1.1.2.1.3.4.1.1 57-1.1.2.1.3.1 57-1.1.2.1.3.2 57-1.1.2.1.3.3 57-1.1.2.1.3.4 59-1.1.2.3 60-1.1.2.3.1 60-1.1.2.3.1.2 60-1.1.2.3.1.2.1.1.r 60-1.1.2.3.1.2.r 61-1.1.2.3.1.2.1.1 62-1.1.2.3.1.2.1.2 63-1.1.2.3.1.1.r 64-1.1.2.3.1.1 66-1.1.2.3.2.1.2 67-1.1.2.3.2.1 69-1.1.2.3.2.1.1 72-1.1.2.1.3 73-1.1.2.4.2 74-1.1.2.4 75-1.1.2.4.1.r 76-1.1.2.4.1 77-1.1.2.4.3 78-1.1.2.4.3.2.1 79-1.1.2.4.3.2.2 81-1.1.2.4.4.1 (c8 / contrast-01~e.8 :ARG1 (i2 / induce-01~e.14 :ARG0 (m3 / molecular-physical-entity~e.6,12 :ARG0-of~e.6,12 (i / inhibit-01~e.6,12 :ARG1 (s2 / slash~e.4 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.3)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"))))) :ARG2 (r / reverse-01~e.17 :ARG1~e.18 (f / feature~e.22 :mod (m / morphology~e.21) :ARG1-of (t4 / transform-01~e.20) :poss (a / and~e.49,72 :op1 (c / cell-line~e.57 :name (n3 / name :op1 "IEC-6"~e.29,31,37,39,45,47,54,56) :ARG1-of (t3 / transform-01~e.20 :ARG0~e.23 (p2 / protein :name (n7 / name :op1 "Tpr-Met"~e.25,27)))) :op2 (c2 / cell-line~e.57 :name (n4 / name :op1 "IEC-6"~e.29,31,37,39,45,47,54,56) :ARG3-of (e4 / express-03 :ARG2 (p3 / protein :name (n8 / name :op1 "TM-Grb2"~e.33,35,41,50)))) :op3 (c3 / cell-line~e.57 :name (n5 / name :op1 "IEC-6"~e.29,31,37,39,45,47,54,56) :ARG3-of (e5 / express-03 :ARG2 (p4 / protein :name (n9 / name :op1 "TM-Shc1"~e.33,41,43,50)))) :op4 (c4 / cell-line~e.57 :name (n6 / name :op1 "IEC-6"~e.29,31,37,39,45,47,54,56) :ARG3-of (e6 / express-03 :ARG2 (p5 / protein :name (n10 / name :op1 "TM-Shc2"~e.33,41,50,52)))))) :mod (p / potent~e.16) :ARG1-of (o / observe-01~e.59 :time (a2 / after~e.60 :op1~e.63 (t5 / treat-04~e.64) :quant~e.60 (u / up-to~e.60 :op1 (t / temporal-quantity :quant~e.60 24~e.61 :unit (h / hour~e.62)))) :ARG1-of (d / describe-01 :ARG0 (f2 / file~e.67 :mod 3~e.69 :mod (a3 / additional~e.66)))) :ARG1-of (s3 / strike-04~e.74 :ARG2~e.75 (a4 / appear-01~e.76) :degree (m2 / more~e.73) :time (a5 / after~e.77 :op1 t5 :quant (t2 / temporal-quantity :quant 48~e.78 :unit (h2 / hour~e.79))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.81 :mod "5B"))))) :ARG2 (i4 / induce-01~e.14 :polarity~e.9 -~e.9 :ARG0 (m4 / molecular-physical-entity~e.12 :ARG0-of~e.12 (i5 / inhibit-01~e.12 :ARG1 (p6 / protein-family :name (n11 / name :op1 "PI3K"~e.11)))) :ARG1 r) :ARG2-of (i3 / interest-01~e.0)) # ::id pmid_2470_8867.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In the presence of U0126 , the MEK1 @/@ 2 inhibitor , either alone or in combination with the PI3K inhibitor , the formerly transformed Tpr @-@ IEC @-@ 6 cells progressively lost their fibroblast @-@ like spindle @-@ shaped morphology , adopted a flatter cobblestone @-@ like appearance , reformed apparent cell @-@ cell contacts and grew again in colonies ; much like the non @-@ transformed Control @-@ IEC @-@ 6 cells . # ::alignments 2-1.5 4-1.5.1.1.1 7-1.5.1.2.1.1.1.1 8-1.5.1.2.1 10-1.5.1 10-1.5.1.2 10-1.5.1.2.r 13-1.5.2.1 14-1.5.2 15-1.5.2.r 16-1.5.2.2 19-1.5.2.2.2.1.1.1.1 20-1.5.1 20-1.5.1.2 20-1.5.1.2.r 20-1.5.2.2.2 20-1.5.2.2.2.1 20-1.5.2.2.2.1.r 23-1.1.1.2.2 24-1.1.1.2 25-1.1.1.2.1.1.1 27-1.1.1.1.1 29-1.1.1.1.1 30-1.1.1 32-1.1 34-1.1.2.1.1 36-1.1.2.1 37-1.1.2.2.1 39-1.1.2.2 40-1.1.2 42-1.2 44-1.2.2.2 44-1.2.2.2.1 44-1.2.2.2.1.r 45-1.2.2.3.1 47-1.2.2.3 48-1.2.2 48-1.3.2.3 50-1.3 52-1.3.1 54-1.3.2.1 54-1.3.2.2 55-1.3.2 56-1 57-1.4 58-1.4.3 59-1.4.2.r 60-1.4.2 62-1.6.2 63-1.6 65-1.6.1.2.1 65-1.6.1.2.1.r 67-1.6.1.2 68-1.6.1.3 70-1.6.1.1.1 72-1.6.1.1.1 73-1.6.1 (a / and~e.56 :op1 (l / lose-02~e.32 :ARG0 (c / cell-line~e.30 :name (n2 / name :op1 "IEC-6"~e.27,29) :ARG1-of (t2 / transform-01~e.24 :ARG0 (p / protein :name (n3 / name :op1 "Tpr"~e.25)) :time (f / former~e.23))) :ARG1 (m / morphology~e.40 :ARG1-of (r / resemble-01~e.36 :ARG2 (f2 / fibroblast~e.34)) :ARG1-of (s2 / shape-01~e.39 :ARG2 (s3 / spindle~e.37))) :manner (p2 / progress-01)) :op2 (a2 / adopt-01~e.42 :ARG0 c :ARG1 (a3 / appear-01~e.48 :ARG1 c :ARG1-of (f3 / flat-06~e.44 :degree~e.44 (m2 / more~e.44)) :ARG1-of (r2 / resemble-01~e.47 :ARG2 (c4 / cobblestone~e.45)))) :op3 (r3 / reform-01~e.50 :ARG0 c~e.52 :ARG1 (c5 / contact-01~e.55 :ARG0 (c6 / cell~e.54) :ARG1 (c7 / cell~e.54) :ARG1-of (a4 / appear-01~e.48))) :op4 (g / grow-02~e.57 :ARG1 c :ARG2~e.59 (c8 / colony~e.60) :mod (a5 / again~e.58)) :condition (p3 / present-02~e.2 :ARG1 (s / small-molecule~e.10,20 :name (n / name :op1 "U0126"~e.4) :ARG0-of~e.10,20 (i / inhibit-01~e.10,20 :ARG1 (s4 / slash~e.8 :op1 (e / enzyme :name (n4 / name :op1 "MEK1"~e.7)) :op2 (e2 / enzyme :name (n5 / name :op1 "MEK2"))))) :manner~e.15 (o / or~e.14 :op1 (a6 / alone~e.13) :op2 (c9 / combine-01~e.16 :ARG1 s :ARG2 (m4 / molecular-physical-entity~e.20 :ARG0-of~e.20 (i2 / inhibit-01~e.20 :ARG1 (p4 / protein-family :name (n6 / name :op1 "PI3K"~e.19))))))) :ARG1-of (r4 / resemble-01~e.63 :ARG2 (c10 / cell~e.73 :name (n7 / name :op1 "IEC-6"~e.70,72) :ARG1-of (t / transform-01~e.67 :polarity~e.65 -~e.65) :mod (c11 / control~e.68)) :degree (m3 / much~e.62))) # ::id pmid_2470_8867.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concordant with this restoration of epithelioid @-@ like morphological features in IEC @-@ 6 cells transformed by the oncogenic Tpr @-@ Met and its derived variants , treatment with U0126 also induced an increase in E @-@ cadherin protein levels ( Figure 5 @ C and D , and Additional file 3 ) . # ::alignments 3-1.4.1 4-1.4.1.1.r 5-1.4.1.1.2.1 7-1.4.1.1.2 8-1.4.1.1.1 9-1.4.1.1 10-1.4.1.1.3.r 11-1.4.1.1.3.1.1 13-1.4.1.1.3.1.1 14-1.4.1.1.3 15-1.4.1.1.3.2 16-1.4.1.1.3.2.1.r 18-1.4.1.1.3.2.1.1.2 18-1.4.1.1.3.2.1.1.2.1 18-1.4.1.1.3.2.1.1.2.1.r 19-1.4.1.1.3.2.1.1.1.1 21-1.4.1.1.3.2.1.1.1.1 22-1.4.1.1.3.2.1 23-1.4.1.1.3.2.1.2.1.1 23-1.4.1.1.3.2.1.2.1.1.r 24-1.4.1.1.3.2.1.2.1 25-1.4.1.1.3.2.1.2 27-1.1 28-1.1.1.r 29-1.1.1.1.1 30-1.3 31-1 33-1.2 34-1.2.1.r 35-1.2.1.1.1.1 37-1.2.1.1.1.1 38-1.2.1.1 38-1.4.1.1.3.2.1.1 39-1.2.1 41-1.5.1.1 41-1.5.1.2 46-1.5.1 49-1.5.1 50-1.5.1.3.2 51-1.5.1.3 53-1.5.1.3.1 (i / induce-01~e.31 :ARG0 (t / treat-04~e.27 :ARG2~e.28 (s / small-molecule :name (n / name :op1 "U0126"~e.29))) :ARG2 (i2 / increase-01~e.33 :ARG1~e.34 (l / level~e.39 :quant-of (p / protein~e.38 :name (n2 / name :op1 "E-cadherin"~e.35,37)))) :mod (a / also~e.30) :ARG0-of (a2 / agree-01 :ARG2 (r / restore-02~e.3 :ARG1~e.4 (f / feature~e.9 :mod (m / morphology~e.8) :ARG1-of (r2 / resemble-01~e.7 :ARG2 (e / epithelioid~e.5)) :poss~e.10 (c / cell-line~e.14 :name (n3 / name :op1 "IEC-6"~e.11,13) :ARG1-of (t2 / transform-01~e.15 :ARG0~e.16 (a3 / and~e.22 :op1 (p2 / protein~e.38 :name (n4 / name :op1 "Tpr-Met"~e.19,21) :ARG0-of (c2 / cause-01~e.18 :ARG1~e.18 (c3 / cancer~e.18))) :op2 (v / variant~e.25 :ARG1-of (d / derive-01~e.24 :ARG0~e.23 p2~e.23)))))))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.46,49 :op1 (f2 / figure~e.41 :mod "5C") :op2 (f3 / figure~e.41 :mod "5D") :op3 (f4 / file~e.51 :mod 3~e.53 :mod (a5 / additional~e.50))))) # ::id pmid_2470_8867.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok By contrast , none of the inhibitor treatments affected E @-@ cadherin protein levels in the Control @-@ IEC @-@ 6 cells ( Figure 5 @ C and D ) . # ::alignments 1-1 4-1.1.r 6-1.1.2.1 6-1.1.2.1.1 6-1.1.2.1.1.r 7-1.1.2 8-1.1 9-1.1.3.1.1.1 11-1.1.3.1.1.1 12-1.1.3.1 13-1.1.3 14-1.1.4.r 16-1.1.4.2 18-1.1.4.1.1 20-1.1.4.1.1 21-1.1.4 23-1.2.1.1 23-1.2.1.2 28-1.2.1 (c / contrast-01~e.1 :ARG2~e.4 (a / affect-01~e.8 :polarity - :ARG0 (t2 / treat-04~e.7 :ARG2 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6))) :ARG1 (l / level~e.13 :quant-of (p / protein~e.12 :name (n / name :op1 "E-cadherin"~e.9,11))) :location~e.14 (c2 / cell-line~e.21 :name (n2 / name :op1 "IEC-6"~e.18,20) :mod (c3 / control~e.16))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.28 :op1 (f / figure~e.23 :mod "5C") :op2 (f2 / figure~e.23 :mod "5D")))) # ::id pmid_2470_8867.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Notably , reversion of the transformed phenotype and E @-@ cadherin up @-@ regulation were also promoted in transformed IEC @-@ 6 cell populations by treatment with 10 μM AZD6244 or PD184352 , two additional pharmacological inhibitors of MEK1 @/@ 2 ( Figure 5 @ B and C , and Additional file 3 ) . # ::alignments 0-1.6 2-1.2.1 3-1.2.1.1.r 5-1.2.1.1.1 6-1.2.1.1 7-1.2 8-1.2.2.1.1.1 10-1.2.2.1.1.1 11-1.2.2 12-1.2.2 13-1.2.2 15-1.3 16-1 17-1.4.r 18-1.4.1.2 19-1.4.1.1.1 21-1.4.1.1.1 22-1.4.1 23-1.4 24-1.1.r 25-1.1 26-1.1.1.r 27-1.1.1.3.1 28-1.1.1.3.2 29-1.1.1.1.1.1 30-1.1.1 31-1.1.1.2.1.1 33-1.1.1.4.1 34-1.1.1.4.2 35-1.1.1.4.4 36-1.1.1.4 36-1.1.1.4.3 36-1.1.1.4.3.r 37-1.1.1.4.3.1.r 38-1.1.1.4.3.1.1.1.1 39-1.1.1.4.3.1 40-1.1.1.4.1 42-1.5.1.1 42-1.5.1.2 47-1.5.1 50-1.5.1 51-1.5.1.3.2 52-1.5.1.3 54-1.5.1.3.1 (p / promote-01~e.16 :ARG0~e.24 (t3 / treat-04~e.25 :ARG2~e.26 (o / or~e.30 :op1 (s2 / small-molecule :name (n4 / name :op1 "AZD6244"~e.29)) :op2 (s3 / small-molecule :name (n5 / name :op1 "PD184352"~e.31)) :quant (c2 / concentration-quantity :quant 10~e.27 :unit (m / micromolar~e.28)) :mod (s / small-molecule~e.36 :quant 2~e.33,40 :mod (a3 / additional~e.34) :ARG0-of~e.36 (i / inhibit-01~e.36 :ARG1~e.37 (s4 / slash~e.39 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.38)) :op2 (e2 / enzyme :name (n6 / name :op1 "MEK2")))) :mod (p5 / pharmacology~e.35)))) :ARG1 (a / and~e.7 :op1 (r / reverse-01~e.2 :ARG1~e.3 (p2 / phenotype~e.6 :ARG1-of (t2 / transform-01~e.5))) :op2 (u / upregulate-01~e.11,12,13 :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin"~e.8,10)))) :mod (a2 / also~e.15) :location~e.17 (p4 / population~e.23 :consist-of (c / cell-line~e.22 :name (n3 / name :op1 "IEC-6"~e.19,21) :ARG1-of t2~e.18)) :ARG1-of (d / describe-01 :ARG0 (a4 / and~e.47,50 :op1 (f / figure~e.42 :mod "5B") :op2 (f2 / figure~e.42 :mod "5C") :op3 (f3 / file~e.52 :mod 3~e.54 :mod a3~e.51))) :ARG1-of (n7 / notable-04~e.0)) # ::id pmid_2470_8867.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , these observations could not be attributed to the cytosolic localization of the Tpr @-@ Met oncoprotein , since both the morphological transformation and the E @-@ cadherin down @-@ regulation induced by a cell surface @-@ localized active chimeric colony stimulating factor 1 ( CSF ) - Met receptor [ @ 37 @ ] , were reverted in a similar manner upon the inhibition of MEK1 @/@ 2 activity , but not of PI3K activity ( Additional file 3 ) . # ::alignments 0-1 2-1.1.2.1.2 3-1.1.2.1 3-1.1.2.1.1 3-1.1.2.1.1.r 4-1.1 5-1.1.1 5-1.1.1.r 6-1.1.2.2 7-1.1.2 10-1.1.2.2.2 11-1.1.2.2 14-1.1.2.2.1.1.1 16-1.1.2.2.1.1.1 19-1.1.2.2.1 19-1.1.2.2.1.2 19-1.1.2.2.1.2.r 19-1.1.3 22-1.1.3.1.1.2.1.1 23-1.1.3.1.1.2.1 24-1.1.3.1.1.2 26-1.1.3.1.1.2.2.1.1.1 28-1.1.3.1.1.2.2.1.1.1 29-1.1.3.1.1.2.2 30-1.1.3.1.1.2.2 31-1.1.3.1.1.2.2 32-1.1.3.1.1.2.3 33-1.1.3.1.1.2.3.1.r 35-1.1.3.1.1.2.3.1.2.1 36-1.1.3.1.1.2.3.1.2 38-1.1.2.2 39-1.1.3.1.1.1.1 41-1.1.3.1.1.2.3.1.1.1 42-1.1.3.1.1.2.3.1.1.2 43-1.1.3.1.1.2.3.1.1.3 44-1.1.3.1.1.2.3.1.1.4 49-1.1.3.1.1.2.3.1.1.5 50-1.1.3.1.1.2.3.1.1.6 53-1.1.3.1.1.2.4.1.1.1 58-1.1.3.1.1 58-1.1.3.1.2 59-1.1.3.1.1.3.r 61-1.1.3.1.1.3.1 62-1.1.3.1.1.3 65-1.1.3.1.1.1 65-1.1.3.1.2.2 67-1.1.3.1.1.1.1.1.1.1.1 68-1.1.3.1.1.1.1.1 70-1.1.3.1.1.1.1 70-1.1.3.1.2.2.1 72-1.1.3.1 73-1.1.3.1.2.1 73-1.1.3.1.2.1.r 74-1.1.3.1.2.2.1.1.r 75-1.1.3.1.2.2.1.1.1.1 76-1.1.3.1.1.1.1 78-1.1.3.1.2.5.1.2 79-1.1.3.1.2.5.1 81-1.1.3.1.2.5.1.1 (a7 / and~e.0 :op2 (p2 / possible-01~e.4 :polarity~e.5 -~e.5 :ARG1 (a / attribute-01~e.7 :ARG1 (t / thing~e.3 :ARG1-of~e.3 (o / observe-01~e.3) :mod (t2 / this~e.2)) :ARG2 (b2 / be-located-at-91~e.6,11,38 :ARG1 (p / protein~e.19 :name (n / name :op1 "Tpr-Met"~e.14,16) :ARG0-of~e.19 (c2 / cause-01~e.19 :ARG1 (c3 / cancer))) :ARG2 (c / cytosol~e.10))) :ARG1-of (c4 / cause-01~e.19 :ARG0 (c8 / contrast-01~e.72 :ARG1 (r2 / revert-01~e.58 :ARG0 (i2 / inhibit-01~e.65 :ARG1 (a4 / activity-06~e.39,70,76 :ARG0 (s2 / slash~e.68 :op1 (e / enzyme :name (n4 / name :op1 "MEK1"~e.67)) :op2 (e2 / enzyme :name (n5 / name :op1 "MEK2"))))) :ARG1 (a2 / and~e.24 :op1 (t3 / transform-01~e.23 :ARG1 (m2 / morphology~e.22)) :op2 (d / downregulate-01~e.29,30,31 :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin"~e.26,28))) :ARG2-of (i / induce-01~e.32 :ARG0~e.33 (p4 / protein :name (n3 / name :op1 "colony"~e.41 :op2 "stimulating"~e.42 :op3 "factor"~e.43 :op4 1~e.44 :op5 "Met"~e.49 :op6 "receptor"~e.50) :location (s / surface~e.36 :part-of (c5 / cell~e.35)) :ARG1-of (a3 / activate-01) :mod (c6 / chimera))) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c7 / cite-01 :ARG2 37~e.53)))) :manner~e.59 (m / manner~e.62 :ARG1-of (r / resemble-01~e.61))) :ARG2 (r3 / revert-01~e.58 :polarity~e.73 -~e.73 :ARG0 (i3 / inhibit-01~e.65 :ARG1 (a5 / activity-06~e.70 :ARG0~e.74 (e3 / enzyme :name (n6 / name :op1 "PI3K"~e.75)))) :ARG1 a2 :manner m :ARG1-of (d3 / describe-01 :ARG0 (f / file~e.79 :mod 3~e.81 :mod (a6 / additional~e.78)))))))) # ::id pmid_2470_8867.173 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since Erk1 @/@ 2 and Akt activities remained at basal levels in transformed IEC @-@ 6 cell populations , the efficacy of these pharmacological inhibitors was evaluated by testing their ability to suppress serum @-@ induced Erk1 @/@ 2 and Akt phosphorylation . # ::alignments 0-1.3 1-1.3.1.1.1 2-1.3.1.1.1 3-1.3.1.1.1 4-1.3.1.1.1 5-1.3.1.1.1 6-1.3.1.1 7-1.3.1 10-1.3.1.2 11-1.3.1.3.r 12-1.3.1.3.1.2 13-1.3.1.3.1.1.1 15-1.3.1.3.1.1.1 16-1.3.1.3.1 17-1.3.1.3 22-1.1.1.2 23-1.1.1.3 24-1.1.1 24-1.1.1.1 24-1.1.1.1.r 26-1 27-1.2.r 28-1.2 30-1.2.1 32-1.2.1.2 33-1.2.1.2.2.2.1 35-1.2.1.2.2.2 36-1.2.1.2.2.1.1.1.1.1 37-1.2.1.2.2.1.1 39-1.2.1.2.2.1 40-1.2.1.2.2.1.2.1.1 41-1.2.1.2.2 (e / evaluate-01~e.26 :ARG1 (e2 / efficient-01 :ARG1 (m / molecular-physical-entity~e.24 :ARG0-of~e.24 (i / inhibit-01~e.24) :mod (t2 / this~e.22) :mod (p2 / pharmacology~e.23))) :manner~e.27 (t3 / test-01~e.28 :ARG1 (c / capable-01~e.30 :ARG1 m :ARG2 (s2 / suppress-01~e.32 :ARG0 m :ARG1 (p / phosphorylate-01~e.41 :ARG1 (a / and~e.39 :op1 (s4 / slash~e.37 :op1 (e3 / enzyme :name (n / name :op1 "Erk1"~e.36)) :op2 (e4 / enzyme :name (n2 / name :op1 "Erk2"))) :op2 (e5 / enzyme :name (n3 / name :op1 "Akt"~e.40))) :ARG2-of (i2 / induce-01~e.35 :ARG0 (s3 / serum~e.33)))))) :ARG1-of (c2 / cause-01~e.0 :ARG0 (r / remain-01~e.7 :ARG1 (a2 / activity-06~e.6 :ARG0 a~e.1,2,3,4,5) :ARG3 (l / level~e.10 :mod (b / base)) :location~e.11 (p3 / population~e.17 :consist-of (c3 / cell-line~e.16 :name (n4 / name :op1 "IEC-6"~e.13,15) :ARG1-of (t / transform-01~e.12)))))) # ::id pmid_2470_8867.174 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Serum @-@ starved Tpr @-@ Met and control IEC @-@ 6 cell populations were treated for 1 hour with DMSO or inhibitors , followed by 5 minutes of stimulation with 10 % serum . # ::alignments 0-1.1.3.1 2-1.1.3 3-1.1.1.1.2.1.1.1 5-1.1.1.1.2.1.1.1 6-1.1 7-1.1.2.2 8-1.1.1.1.1.1 8-1.1.2.1.1.1 10-1.1.1.1.1.1 10-1.1.2.1.1.1 11-1.1.1.1 11-1.1.2.1 12-1.1.1 12-1.1.2 14-1 15-1.3.r 16-1.3.1 17-1.3.2 18-1.2.r 19-1.2.1.1.1 20-1.2 21-1.2.2 21-1.2.2.1 21-1.2.2.1.r 23-1.4 24-1.4.1.r 25-1.4.1.3.1 26-1.4.1.3.2 28-1.4.1 29-1.4.1.2.r 30-1.4.1.2.1.1 31-1.4.1.2.1 32-1.4.1.2 (t4 / treat-04~e.14 :ARG1 (a / and~e.6 :op1 (p4 / population~e.12 :consist-of (c / cell-line~e.11 :name (n4 / name :op1 "IEC-6"~e.8,10) :ARG1-of (t3 / transform-01 :ARG0 (p2 / protein :name (n / name :op1 "Tpr-Met"~e.3,5))))) :op2 (p3 / population~e.12 :consist-of (c2 / cell-line~e.11 :name (n2 / name :op1 "IEC-6"~e.8,10)) :mod (c4 / control~e.7)) :ARG1-of (s / starve-01~e.2 :ARG2 (s2 / serum~e.0))) :ARG2~e.18 (o / or~e.20 :op1 (s3 / small-molecule :name (n3 / name :op1 "DMSO"~e.19)) :op2 (m2 / molecular-physical-entity~e.21 :ARG0-of~e.21 (i / inhibit-01~e.21))) :duration~e.15 (t / temporal-quantity :quant 1~e.16 :unit (h / hour~e.17)) :ARG2-of (f / follow-01~e.23 :ARG1~e.24 (s5 / stimulate-01~e.28 :ARG1 a :ARG2~e.29 (s6 / serum~e.32 :quant (p / percentage-entity~e.31 :value 10~e.30)) :duration (t2 / temporal-quantity :quant 5~e.25 :unit (m / minute~e.26))))) # ::id pmid_2470_8867.175 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A robust phosphorylation of Erk1 @/@ 2 and Akt proteins was seen upon serum stimulation of Control @-@ IEC @-@ 6 cells ( Figure 5 @ E ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1.1.1.1 5-1.1.1.1 7-1.1.1 8-1.1.1.2.1.1 9-1.1.1.2 11-1 13-1.2.2 14-1.2 15-1.2.1.r 16-1.2.1.2 18-1.2.1.1.1 20-1.2.1.1.1 21-1.2.1 23-1.3.1 (s / see-01~e.11 :ARG1 (p / phosphorylate-01~e.2 :ARG1~e.3 (a / and~e.7 :op1 (s2 / slash~e.5 :op1 (e / enzyme :name (n / name :op1 "Erk1"~e.4)) :op2 (e2 / enzyme :name (n2 / name :op1 "Erk2"))) :op2 (p4 / protein-family~e.9 :name (n3 / name :op1 "Akt"~e.8))) :mod (r / robust~e.1)) :time (s3 / stimulate-01~e.14 :ARG1~e.15 (c / cell-line~e.21 :name (n4 / name :op1 "IEC-6"~e.18,20) :mod (c2 / control~e.16)) :ARG2 (s4 / serum~e.13)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "5E"))) # ::id pmid_2470_8867.176 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In sharp contrast , although the levels of Erk2 and Akt proteins were equivalent for each cell population , serum @-@ induced Erk1 @/@ 2 and Akt activation were severely attenuated in the Tpr @-@ Met @-@ IEC @-@ 6 cells ( Figure 5 @ E ) . # ::alignments 1-1.2 2-1 4-1.1.4.r 6-1.1.4.1 6-1.1.4.2 8-1.1.1.1.1.2.1.1 9-1.1.1 10-1.1.1.2.1.1.1 11-1.1.1.2.1 11-1.1.3.2.1 13-1.1.4 14-1.1.4.3.r 15-1.1.4.3.2 16-1.1.4.3.1 17-1.1.4.3 19-1.1.1.3.1 21-1.1.1.3 22-1.1.1.1.1.1.1.1 23-1.1.1.1.1 25-1.1.1 26-1.1.1.2.1.1.1 27-1.1.1.1 27-1.1.1.2 29-1.1.2 30-1.1 31-1.1.3.r 33-1.1.3.2.1.1.1 35-1.1.3.2.1.1.1 37-1.1.3.1.1 39-1.1.3.1.1 40-1.1.3 42-1.3.1 (c / contrast-01~e.2 :ARG2 (a / attenuate-01~e.30 :ARG1 (a4 / and~e.9,25 :op1 (a2 / activate-01~e.27 :ARG1 (s2 / slash~e.23 :op1 (e2 / enzyme :name (n / name :op1 "Erk1"~e.22)) :op2 (e3 / enzyme :name (n2 / name :op1 "Erk2"~e.8)))) :op2 (a5 / activate-01~e.27 :ARG1 (p2 / protein-family~e.11 :name (n3 / name :op1 "Akt"~e.10,26))) :ARG2-of (i / induce-01~e.21 :ARG0 (s3 / serum~e.19))) :degree (s4 / severe~e.29) :location~e.31 (c2 / cell-line~e.40 :name (n4 / name :op1 "IEC-6"~e.37,39) :ARG1-of (t / transform-01 :ARG0 (p / protein~e.11 :name (n5 / name :op1 "Tpr-Met"~e.33,35)))) :concession~e.4 (e5 / equal-01~e.13 :ARG1 (l / level~e.6 :quant-of e3) :ARG2 (l2 / level~e.6 :quant-of p2) :ARG3~e.14 (p5 / population~e.17 :mod (c5 / cell~e.16) :mod (e / each~e.15)))) :ARG1-of (s / sharp-02~e.1) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.42 :mod "5E"))) # ::id pmid_2470_8867.177 ::amr-annotator SDL-AMR-09 ::preferred # ::tok This further substantiates the conclusion that sustained activation of Met signaling pathways , such as those downstream of Grb2 and Shc , can activate negative feedback control of both the Erk1 @/@ 2 and Akt pathways in IECs . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.1.1.1.3.2 6-1.2.1.1.1.2 7-1.2.1.1.1 9-1.2.1.1.1.1.1.1 10-1.2.1.1.1.1.2 11-1.2.1.1.1.1.3 13-1.2.1.1.1.1.3.r 14-1.2.1.1.1.1.3.r 15-1.2.1.1.1.1.3.2 16-1.2.1.1.1.1.3.1.2 18-1.2.1.1.1.1.3.1.1.1.1.1 19-1.2.1.1.1.1.3.1.1 20-1.2.1.1.1.1.3.1.1.2.1.1 22-1.2.1 23-1.2.1.1 24-1.2.1.1.2.2 25-1.2.1.1.2.3 26-1.2.1.1.2 30-1.2.1.1.2.1.1.1.1 32-1.2.1.1.2.1.1.1.1 33-1.2.1.1.2.1 34-1.2.1.1.2.1.2.1.1 35-1.2.1.1.2.1.1 35-1.2.1.1.2.1.2 36-1.2.1.1.3.r 37-1.2.1.1.3.1.1 (s / substantiate-01~e.2 :ARG0 (t / this~e.0) :ARG1 (c / conclude-01~e.4 :ARG1 (p / possible-01~e.22 :ARG1 (a / activate-01~e.23 :ARG0 (a2 / activate-01~e.7 :ARG1 (p2 / pathway :name (n / name :op1 "Met"~e.9) :ARG0-of (s3 / signal-07~e.10) :example~e.13,14 (p3 / pathway~e.11 :location (r / relative-position :op1 (a3 / and~e.19 :op1 (p4 / protein :name (n2 / name :op1 "Grb2"~e.18)) :op2 (p5 / protein :name (n3 / name :op1 "Shc"~e.20))) :direction (d / downstream~e.16)) :mod (t2 / that~e.5,15))) :ARG1-of (s2 / sustain-01~e.6)) :ARG1 (c2 / control-01~e.26 :ARG1 (a4 / and~e.33 :op1 (p6 / pathway~e.35 :name (n5 / name :op1 "Erk1/2"~e.30,32)) :op2 (p7 / pathway~e.35 :name (n6 / name :op1 "Akt"~e.34))) :ARG2-of (n4 / negative-01~e.24) :mod (f2 / feedback~e.25)) :location~e.36 (c3 / cell :name (n7 / name :op1 "IEC"~e.37))))) :degree (f / further~e.1)) # ::id pmid_2470_8867.178 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , the MEK1 @/@ 2 and PI3K inhibitors were confirmed to efficiently suppress serum @-@ induced Erk1 @/@ 2 and Akt phosphorylation , respectively ( Figure 5 @ E ) . # ::alignments 0-1.2 3-1.1.1.1.1.1.1.1.1 4-1.1.1.1.1.1 6-1.1 7-1.1.2.1.1.1.1.1 8-1.1.1.1 8-1.1.1.1.1 8-1.1.1.1.1.r 8-1.1.2.1 8-1.1.2.1.1 8-1.1.2.1.1.r 10-1 12-1.1.1.3 13-1.1.1 13-1.1.2 14-1.1.1.2.2.1 16-1.1.1.2.2 17-1.1.1.2.1.1.1.1 18-1.1.1.2.1 20-1.1 21-1.1.2.2.1.1.1 22-1.1.1.2 22-1.1.2.2 24-1.1.3 24-1.1.3.r 26-1.3.1 (c / confirm-01~e.10 :ARG1 (a / and~e.6,20 :op1 (s / suppress-01~e.13 :ARG0 (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (i / inhibit-01~e.8 :ARG1 (s5 / slash~e.4 :op1 (e2 / enzyme :name (n3 / name :op1 "MEK1"~e.3)) :op2 (e3 / enzyme :name (n4 / name :op1 "MEK2"))))) :ARG1 (p / phosphorylate-01~e.22 :ARG1 (s3 / slash~e.18 :op1 (e5 / enzyme :name (n / name :op1 "Erk1"~e.17)) :op2 (e6 / enzyme :name (n2 / name :op1 "Erk2"))) :ARG2-of (i2 / induce-01~e.16 :ARG0 (s2 / serum~e.14))) :ARG2-of (e / efficient-01~e.12)) :op2 (s6 / suppress-01~e.13 :ARG0 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.8 (i3 / inhibit-01~e.8 :ARG1 (p6 / protein-family :name (n5 / name :op1 "PI3K"~e.7)))) :ARG1 (p4 / phosphorylate-01~e.22 :ARG1 (e4 / enzyme :name (n6 / name :op1 "Akt"~e.21)) :ARG2-of i2) :ARG2-of e) :manner~e.24 (r / respective~e.24)) :mod (i4 / important~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "5E"))) # ::id pmid_2470_8867.179 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although the potential off @-@ target effects of these inhibitors cannot be excluded in these experiments , our results suggest that the morphological transformation induced by the oncogenic Met receptor , and driven by the constitutive activation of Grb2 and Shc signals in IECs , relies , at least in part , on the activation of the Ras @/@ MAPK pathway , but not on PI3K signaling . # ::alignments 0-1.3.r 2-1.3.2.1.2 3-1.3.2.1.3.1 5-1.3.2.1.3 6-1.3.2.1 7-1.3.2.1.1.r 8-1.3.2.1.1.2 9-1.3.2.1.1 9-1.3.2.1.1.1 9-1.3.2.1.1.1.r 10-1.3 10-1.3.1 10-1.3.1.r 12-1.3.2 13-1.3.2.2.r 14-1.3.2.2.1 15-1.3.2.2 17-1.1.2 17-1.1.2.r 18-1.1 18-1.1.1 18-1.1.1.r 19-1 20-1.2.r 22-1.2.1.1.1 23-1.2.1.1 24-1.2.1.1.2 25-1.2.1.1.2.1.r 27-1.2.1.1.2.1.2 27-1.2.1.1.2.1.2.1 27-1.2.1.1.2.1.2.1.r 28-1.2.1.1.2.1.1.1 29-1.2.1.1.2.1 32-1.2.1.1.3 33-1.2.1.1.3.1.r 35-1.2.1.1.3.1.2 36-1.2.1.1.3.1 37-1.2.1.1.3.1.1.r 38-1.2.1.1.3.1.1.1.1.1.1 39-1.2.1.1.3.1.1 40-1.2.1.1.3.1.1.2.1.1.1 41-1.2.1.1.3.1.1.1 41-1.2.1.1.3.1.1.2 42-1.2.1.1.3.1.3.r 43-1.2.1.1.3.1.3.1.1 45-1.2.1 45-1.2.2 47-1.2.1.3.1 48-1.2.1.3.1 49-1.2.1.3 49-1.2.1.3.r 50-1.2.1.3.r 52-1.2.1.2.r 54-1.2.1.2 57-1.2.1.2.1.1.1 59-1.2.1.2.1.1.1 60-1.2.1.2.1 60-1.2.2.3.1 62-1.2 63-1.2.2.1 63-1.2.2.1.r 64-1.2.2.3.r 65-1.2.2.3.1.1.1 66-1.2.2.3 (s / suggest-01~e.19 :ARG0 (t2 / thing~e.18 :ARG2-of~e.18 (r / result-01~e.18) :poss~e.17 (w / we~e.17)) :ARG1~e.20 (c5 / contrast-01~e.62 :ARG1 (r2 / rely-01~e.45 :ARG0 (t3 / transform-01~e.23 :ARG1 (m / morphology~e.22) :ARG2-of (i2 / induce-01~e.24 :ARG0~e.25 (r4 / receptor~e.29 :name (n / name :op1 "Met"~e.28) :ARG0-of (c / cause-01~e.27 :ARG1~e.27 (c2 / cancer~e.27)))) :ARG1-of (d / drive-02~e.32 :ARG0~e.33 (a2 / activate-01~e.36 :ARG1~e.37 (a3 / and~e.39 :op1 (s2 / signal-07~e.41 :ARG0 (p3 / protein :name (n2 / name :op1 "Grb2"~e.38))) :op2 (s3 / signal-07~e.41 :ARG0 (p4 / protein :name (n3 / name :op1 "Shc"~e.40)))) :mod (c3 / constitutive~e.35) :location~e.42 (c4 / cell :name (n4 / name :op1 "IEC"~e.43))))) :ARG1~e.52 (a5 / activate-01~e.54 :ARG1 (p6 / pathway~e.60 :name (n5 / name :op1 "Ras/MAPK"~e.57,59))) :degree~e.49,50 (p5 / part~e.49 :mod (a4 / at-least~e.47,48))) :ARG2 (r3 / rely-01~e.45 :polarity~e.63 -~e.63 :ARG0 t3 :ARG1~e.64 (s4 / signal-07~e.66 :ARG0 (p8 / pathway~e.60 :name (n6 / name :op1 "PI3K"~e.65))))) :concession~e.0 (p / possible-01~e.10 :polarity~e.10 -~e.10 :ARG1 (e2 / exclude-01~e.12 :ARG1 (a6 / affect-01~e.6 :ARG0~e.7 (m2 / molecular-physical-entity~e.9 :ARG0-of~e.9 (i / inhibit-01~e.9) :mod (t / this~e.8)) :mod (p7 / potential~e.2) :mod (t4 / target~e.5 :mod (o / off~e.3))) :ARG2~e.13 (e3 / experiment-01~e.15 :mod t~e.14)))) # ::id pmid_2470_8867.180 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The growth promoting effect of oncogenic Met in IECs is blocked by MEK inhibition , but anoikis sensitivity is restored by concomitant treatment with MEK and PI3K inhibitors # ::alignments 2-1.1.2.3.1 3-1.1.2.3 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1 6-1.1.2.1.2 6-1.1.2.1.2.1 6-1.1.2.1.2.1.r 6-1.1.2.1.2.r 7-1.1.2.1.1.1 8-1.1.2.2.r 9-1.1.2.2.1.1 11-1.1 13-1.1.1.1.1.1 14-1.1.1 16-1 17-1.2.2.1 18-1.2.2 20-1.2 21-1.2.1.r 22-1.2.1.2 23-1.2.1 25-1.1.1.1.1.1 26-1.2.1.1 27-1.2.1.1.2.1.1.1.1 28-1.1.1 28-1.2.1.1.2 28-1.2.1.1.2.1 28-1.2.1.1.2.1.r (c / contrast-01~e.16 :ARG1 (b / block-01~e.11 :ARG0 (i / inhibit-01~e.14,28 :ARG1 (p / protein-family :name (n / name :op1 "MEK"~e.13,25))) :ARG1 (a / affect-01~e.4 :ARG0~e.5 (p3 / protein~e.6 :name (n2 / name :op1 "Met"~e.7) :ARG0-of~e.6 (c2 / cause-01~e.6 :ARG1~e.6 (c3 / cancer~e.6))) :ARG1~e.8 (c4 / cell :name (n3 / name :op1 "IEC"~e.9)) :ARG0-of (p2 / promote-01~e.3 :ARG1 (g / grow-01~e.2)))) :ARG2 (r / restore-02~e.20 :ARG0~e.21 (t / treat-04~e.23 :ARG2 (a3 / and~e.26 :op1 (m / molecular-physical-entity :ARG0-of i) :op2 (m2 / molecular-physical-entity~e.28 :ARG0-of~e.28 (i2 / inhibit-01~e.28 :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K"~e.27))))) :time (c5 / concomitant~e.22)) :ARG1 (s / sensitive-03~e.18 :ARG1 (a2 / anoikis~e.17)))) # ::id pmid_2470_8867.181 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next investigated whether the growth capacity promoted by the oncogenic Met in IECs required MEK or PI3K activity . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.1 3-1.2.1.r 5-1.2.2.2 6-1.2.2 7-1.2.2.3 8-1.2.2.3.1.r 10-1.2.2.3.1 10-1.2.2.3.1.2 10-1.2.2.3.1.2.1 10-1.2.2.3.1.2.1.r 10-1.2.2.3.1.2.r 11-1.2.2.3.1.1.1 12-1.2.2.1.r 13-1.2.2.1.1.1 14-1.2 15-1.2.3.1.1.1.1 16-1.2.3 17-1.2.3.2.1.1.1 18-1.2.3.1 18-1.2.3.2 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (r / require-01~e.14 :mode~e.3 interrogative~e.3 :ARG0 (c / capable-01~e.6 :ARG1~e.12 (c4 / cell :name (n4 / name :op1 "IEC"~e.13)) :ARG2 (g / grow-01~e.5) :ARG1-of (p2 / promote-01~e.7 :ARG0~e.8 (p3 / protein~e.10 :name (n3 / name :op1 "Met"~e.11) :ARG0-of~e.10 (c2 / cause-01~e.10 :ARG1~e.10 (c3 / cancer~e.10))))) :ARG1 (o / or~e.16 :op1 (a / activity-06~e.18 :ARG0 (e / enzyme :name (n / name :op1 "MEK"~e.15))) :op2 (a2 / activity-06~e.18 :ARG0 (e2 / enzyme :name (n5 / name :op1 "PI3K"~e.17))))) :time (n2 / next~e.1)) # ::id pmid_2470_8867.182 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell @-@ count assays were performed with Tpr @-@ Met and Control @-@ IEC @-@ 6 cells that were treated for 24 or 48 hours with vehicle , U0126 or LY294002 inhibitor , or a combination of both inhibitors . # ::alignments 0-1.1.1.1 2-1.1.1 3-1.1 5-1 6-1.2.r 7-1.2.1.3.1.2.1 9-1.2.1.3.1.2.1 10-1.2 11-1.2.2.3 13-1.2.1.2.1 13-1.2.2.2.1 15-1.2.1.2.1 15-1.2.2.2.1 16-1.2.1 16-1.2.2 19-1.2.3 20-1.2.3.2.r 21-1.2.3.2.1.1 22-1.2.3.2 23-1.2.3.2.2.1 24-1.2.3.2.2.2 25-1.2.3.1.r 26-1.2.3.1.1 28-1.2.3.1.2.2.1 29-1.2.3.1 30-1.2.3.1.3.2.1 31-1.2.3.1.3.3 33-1.2.3.1 35-1.2.3.1.4 36-1.2.3.1.4.3.r 37-1.2.3.1.4.3 38-1.2.3.1.4.1 (p / perform-01~e.5 :ARG1 (a / assay-01~e.3 :mod (c / count-01~e.2 :ARG1 (c2 / cell~e.0))) :ARG2~e.6 (a2 / and~e.10 :op1 (c3 / cell-line~e.16 :wiki - :name (n5 / name :op1 "IEC-6"~e.13,15) :ARG1-of (t2 / transform-01 :ARG0 (p2 / protein :wiki "Tpr-met_fusion_protein" :name (n2 / name :op1 "Tpr-Met"~e.7,9)))) :op2 (c4 / cell-line~e.16 :wiki - :name (n3 / name :op1 "IEC-6"~e.13,15) :mod (c6 / control~e.11)) :ARG1-of (t3 / treat-04~e.19 :ARG2~e.25 (o2 / or~e.29,33 :op1 (v / vehicle~e.26) :op2 (s / small-molecule :wiki "U0126" :name (n / name :op1 "U0126"~e.28) :ARG0-of (i / inhibit-01)) :op3 (s2 / small-molecule :wiki "LY294002" :name (n4 / name :op1 "LY294002"~e.30) :ARG0-of i~e.31) :op4 (c7 / combine-01~e.35 :ARG1 s~e.38 :ARG2 s2 :mod~e.36 (b / both~e.37))) :duration~e.20 (o / or~e.22 :op1 (t4 / temporal-quantity :quant 24~e.21 :unit h) :op2 (t / temporal-quantity :quant 48~e.23 :unit (h / hour~e.24)))))) # ::id pmid_2470_8867.183 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As anticipated , treatment with DMSO did not significantly impact cell growth , even after 48 hours . # ::alignments 0-1.5.r 1-1.6 3-1.2 4-1.2.1.r 5-1.2.1.1.1 7-1.1 7-1.1.r 8-1.4 9-1 10-1.3.1 11-1.3 13-1.5.2 14-1.5 15-1.5.1.1 16-1.5.1.2 (i / impact-01~e.9 :polarity~e.7 -~e.7 :ARG0 (t2 / treat-04~e.3 :ARG2~e.4 (s2 / small-molecule :name (n / name :op1 "DMSO"~e.5))) :ARG1 (g / grow-01~e.11 :ARG1 (c / cell~e.10)) :ARG1-of (s / significant-02~e.8) :time~e.0 (a / after~e.14 :quant (t / temporal-quantity :quant 48~e.15 :unit (h / hour~e.16)) :mod (e / even~e.13)) :ARG1-of (a2 / anticipate-01~e.1)) # ::id pmid_2470_8867.184 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with LY294002 exerted similar inhibitory effects upon the growth of both the Tpr @-@ Met @-@ transformed and control IEC @-@ 6 cells , reducing the number of cells by 44 % and 36 % , respectively relative to DMSO @-@ treated cells , after 48 hours ( Figure 6 @ A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1 3-1 4-1.2.1 5-1.2.2 6-1.2 9-1.3.1 9-1.3.2 10-1.3.r 11-1.3.3 13-1.3.1.1.2.1.1.1 15-1.3.1.1.2.1.1.1 17-1.3.1.1.2 18-1.3 19-1.3.2.1.2 20-1.3.2.1.1.1 22-1.3.2.1.1.1 23-1.3.2.1 25-1.4 25-1.5 27-1.4.1 27-1.5.1 29-1.3.1.1 29-1.3.2.1 30-1.4.2.r 31-1.4.2.1 32-1.4.2 33-1.3 34-1.5.2.1 35-1.5.2 38-1.4.2.2 39-1.4.2.2.1.r 40-1.4.2.2.1.1.1.1.1 42-1.4.2.2.1.1 43-1.4.2.2.1 45-1.4.3 46-1.4.3.1.1 47-1.4.3.1.2 49-1.6.1 51-1.3.1.1.1.1 51-1.3.2.1.1.1 (e / exert-01~e.3 :ARG0 (t2 / treat-04~e.0 :ARG2~e.1 (s / small-molecule :name (n / name :op1 "LY294002"~e.2))) :ARG1 (a / affect-01~e.6 :ARG1-of (r / resemble-01~e.4) :ARG0-of (i / inhibit-01~e.5)) :ARG2~e.10 (a2 / and~e.18,33 :op1 (g / grow-01~e.9 :ARG1 (c / cell-line~e.29 :name (n7 / name :op1 "IEC-6"~e.51) :ARG1-of (t3 / transform-01~e.17 :ARG0 (p3 / protein :name (n2 / name :op1 "Tpr-Met"~e.13,15))))) :op2 (g2 / grow-01~e.9 :ARG1 (c2 / cell-line~e.23,29 :name (n3 / name :op1 "IEC-6"~e.20,22,51) :mod (c5 / control~e.19))) :mod (b / both~e.11)) :ARG0-of (r2 / reduce-01~e.25 :ARG1 (n4 / number~e.27 :quant-of c) :ARG2~e.30 (p / percentage-entity~e.32 :value 44~e.31 :ARG1-of (r4 / relative-05~e.38 :ARG3~e.39 (c6 / cell~e.43 :ARG1-of (t4 / treat-04~e.42 :ARG2 (s2 / small-molecule :name (n6 / name :op1 "DMSO"~e.40)))))) :time (a3 / after~e.45 :quant (t / temporal-quantity :quant 48~e.46 :unit (h / hour~e.47)))) :ARG0-of (r3 / reduce-01~e.25 :ARG1 (n5 / number~e.27 :quant-of c2) :ARG2 (p2 / percentage-entity~e.35 :value 36~e.34 :ARG1-of r4) :time a3) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.49 :mod "6A"))) # ::id pmid_2470_8867.185 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , in the presence of U0126 , the growth of Tpr @-@ Met @-@ IEC @-@ 6 cells was significantly attenuated but not that of Control @-@ IEC @-@ 6 cells ( Figure 6 @ A ) . # ::alignments 1-1 1-1.1 1-1.1.r 5-1.1.3 6-1.1.3.1.r 7-1.1.3.1.1.1 10-1.1.1.1 10-1.1.2.2 11-1.1.1.1.1.r 12-1.1.1.1.1.2.1.1.1 14-1.1.1.1.1.2.1.1.1 16-1.1.1.1.1.1.1 18-1.1.1.1.1.1.1 19-1.1.1.1.1 21-1.1.1.2 22-1.1.1 22-1.1.2 23-1.1 24-1.1.2.1 24-1.1.2.1.r 26-1.1.2.2.1.r 27-1.1.2.2.1.2 29-1.1.2.2.1.1.1 31-1.1.2.2.1.1.1 32-1.1.2.2.1 34-1.2.1 36-1.1.2.2.1.1.1 (c / contrast-01~e.1 :ARG2~e.1 (c2 / contrast-01~e.1,23 :ARG1 (a / attenuate-01~e.22 :ARG1 (g / grow-01~e.10 :ARG1~e.11 (c3 / cell-line~e.19 :name (n2 / name :op1 "IEC-6"~e.16,18) :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n3 / name :op1 "Tpr-Met"~e.12,14))))) :ARG1-of (s2 / significant-02~e.21)) :ARG2 (a2 / attenuate-01~e.22 :polarity~e.24 -~e.24 :ARG1 (g2 / grow-01~e.10 :ARG1~e.26 (c4 / cell-line~e.32 :name (n4 / name :op1 "IEC-6"~e.29,31,36) :mod (c7 / control~e.27))) :ARG1-of s2) :condition (p2 / present-02~e.5 :ARG1~e.6 (s / small-molecule :name (n / name :op1 "U0126"~e.7)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.34 :mod "6A"))) # ::id pmid_2470_8867.186 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Furthermore , while co @-@ treatment with U0126 failed to potentiate the growth inhibiting effect of LY294002 in Control @-@ IEC @-@ 6 cells , the growth of Tpr @-@ Met @-@ IEC @-@ 6 cells was further reduced in a time @-@ dependent manner upon exposure to both inhibitors ( Figure 6 @ A ) . # ::alignments 0-1 0-1.1.1.1.2 0-1.1.2.1.1 2-1.1 5-1.1.2.1 6-1.1.2.1.1.r 7-1.1.2.1.1.2.1.1 8-1.1.2 10-1.1.2.2 12-1.1.2.2.1.3.1 13-1.1.1.1.2.3 13-1.1.2.2.1.3 14-1.1.2.2.1 15-1.1.2.2.1.1.r 16-1.1.2.2.1.1.1.1 17-1.1.2.2.1.2.r 18-1.1.2.2.1.2.2 20-1.1.2.2.1.2.1.1 22-1.1.2.2.1.2.1.1 23-1.1.2.2.1.2 26-1.1.1.2 27-1.1.1.2.1.r 28-1.1.1.2.1.2.1.1.1 30-1.1.1.2.1.2.1.1.1 32-1.1.1.2.1.1.1 34-1.1.1.2.1.1.1 35-1.1.1.2.1 37-1.1.1.3 38-1.1.1 41-1.1.1.4.2 43-1.1.1.4 44-1.1.1.4.r 46-1.1.1.1 49-1.1.2.2.1.3 51-1.2.1 53-1.1.2.2.1.2.1.1 (a / and~e.0 :op2 (c / contrast-01~e.2 :ARG1 (r / reduce-01~e.38 :ARG0 (e2 / expose-01~e.46 :ARG1 c3 :ARG2 (a3 / and~e.0 :op1 s :op2 s2 :ARG0-of (i2 / inhibit-01~e.13))) :ARG1 (g2 / grow-01~e.26 :ARG1~e.27 (c3 / cell-line~e.35 :name (n4 / name :op1 "IEC-6"~e.32,34) :ARG1-of (t2 / transform-01 :ARG0 (p2 / protein :name (n5 / name :op1 "Tpr-Met"~e.28,30))))) :degree (f2 / further~e.37) :manner~e.44 (d / depend-01~e.43 :ARG0 r :ARG1 (t / time~e.41))) :ARG2 (f / fail-01~e.8 :ARG1 (t3 / treat-04~e.5 :ARG2~e.6 (a4 / and~e.0 :op1 s2 :op2 (s / small-molecule :name (n / name :op1 "U0126"~e.7)))) :ARG2 (p / potentiate-01~e.10 :ARG1 (a2 / affect-01~e.14 :ARG0~e.15 (s2 / small-molecule :name (n2 / name :op1 "LY294002"~e.16)) :ARG1~e.17 (c2 / cell-line~e.23 :name (n3 / name :op1 "IEC-6"~e.20,22,53) :mod (c4 / control~e.18)) :ARG0-of (i / inhibit-01~e.13,49 :ARG1 (g / grow-01~e.12)))))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure~e.51 :mod "6A"))) # ::id pmid_2470_8867.187 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The impact of inhibiting MEK1 @/@ 2 or PI3K activity on the viability of Tpr @-@ Met @-@ IEC @-@ 6 cells in suspension was also evaluated . # ::alignments 1-1.1 2-1.1.1.r 3-1.1.1 4-1.1.1.1.1.1.1.1.1 5-1.1.1.1.1.1 7-1.1.1.1 8-1.1.1.1.2.1.1.1 9-1.1.1.1.1 9-1.1.1.1.2 10-1.1.2.r 12-1.1.2 13-1.1.2.1.r 14-1.1.2.1.3.1.1.1 16-1.1.2.1.3.1.1.1 18-1.1.2.1.1.1 20-1.1.2.1.1.1 21-1.1.2.1 22-1.1.2.1.2.r 23-1.1.2.1.2 25-1.2 26-1 (e / evaluate-01~e.26 :ARG1 (i / impact-01~e.1 :ARG0~e.2 (i2 / inhibit-01~e.3 :ARG1 (o / or~e.7 :op1 (a2 / activity-06~e.9 :ARG0 (s / slash~e.5 :op1 (e2 / enzyme :name (n / name :op1 "MEK1"~e.4)) :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2")))) :op2 (a3 / activity-06~e.9 :ARG0 (e4 / enzyme :name (n3 / name :op1 "PI3K"~e.8))))) :ARG1~e.10 (v / viability~e.12 :poss~e.13 (c / cell-line~e.21 :name (n4 / name :op1 "IEC-6"~e.18,20) :ARG1-of~e.22 (s2 / suspend-02~e.23) :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n5 / name :op1 "Tpr-Met"~e.14,16)))))) :mod (a / also~e.25)) # ::id pmid_2470_8867.188 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In these anoikis assays , vehicle or the indicated inhibitors were added when cells were seeded and cell viability was measured 24 and 48 hours later . # ::alignments 1-1.3.2 2-1.3.1 3-1.3 5-1.1.1.1 6-1.1.1 8-1.1.1.2.2 9-1.1.1.2 9-1.1.1.2.1 9-1.1.1.2.1.r 11-1.1 12-1.1.2.r 13-1.1.2.1 15-1.1.2 17-1.1.2.1 18-1.2.1 20-1.2 21-1.2.2.1.1.1.1 22-1.2.2 23-1.2.2.2.1.1.1 24-1.2.2.2.1.1.2 25-1.2.2.1 25-1.2.2.1.1 25-1.2.2.1.1.r 25-1.2.2.2 25-1.2.2.2.1 25-1.2.2.2.1.r (a / and :op1 (a2 / add-02~e.11 :ARG1 (o / or~e.6 :op1 (v / vehicle~e.5) :op2 (m3 / molecular-physical-entity~e.9 :ARG0-of~e.9 (i / inhibit-01~e.9) :ARG1-of (i2 / indicate-01~e.8))) :time~e.12 (s / seed-02~e.15 :ARG2 (c / cell~e.13,17))) :op2 (m4 / measure-01~e.20 :ARG1 (v2 / viability~e.18 :mod c) :time (a3 / and~e.22 :op1 (l2 / late~e.25 :degree~e.25 (m2 / more~e.25 :quant (t2 / temporal-quantity :quant 24~e.21 :unit h))) :op2 (l / late~e.25 :degree~e.25 (m / more~e.25 :quant (t / temporal-quantity :quant 48~e.23 :unit (h / hour~e.24)))))) :condition (a4 / assay-01~e.3 :mod (a5 / anoikis~e.2) :mod (t3 / this~e.1))) # ::id pmid_2470_8867.189 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Treatment with the PI3K inhibitor restored anoikis sensitivity to the Tpr @-@ Met @-@ IEC @-@ 6 cells in a time @-@ dependent manner , reducing their viability by close to 45 % relative to DMSO @-@ treated cells after 48 hours ( Figure 6 @ B ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1 4-1.1.1.1 4-1.1.1.1.r 5-1 6-1.2.2 7-1.2 8-1.2.1.r 10-1.2.1.2.1.1.1 12-1.2.1.2.1.1.1 14-1.2.1.1.1 16-1.2.1.1.1 17-1.2.1 20-1.3.2 20-1.4.3.1 22-1.3 23-1.3.r 25-1.4 26-1.4.1.1 26-1.4.1.1.r 27-1.4.1 28-1.4.2.r 29-1.4.2 30-1.4.2.1.r 31-1.4.2.1.1 32-1.4.2.1 33-1.4.2.2 34-1.4.2.2.1.r 35-1.4.2.2.1.1.1.1.1 37-1.4.2.2.1.1 38-1.4.2.2.1 39-1.4.3 40-1.4.3.1.1 41-1.4.3.1.2 43-1.5.1 45-1.2.1.1.1 (r / restore-02~e.5 :ARG0 (t3 / treat-04~e.0 :ARG2~e.1 (m / molecular-physical-entity~e.4 :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (p3 / protein-family :name (n / name :op1 "PI3K"~e.3))))) :ARG1 (s / sensitive-03~e.7 :ARG0~e.8 (c / cell-line~e.17 :name (n2 / name :op1 "IEC-6"~e.14,16,45) :ARG1-of (t5 / transform-01 :ARG0 (p2 / protein :name (n3 / name :op1 "Tpr-Met"~e.10,12)))) :ARG1 (a / anoikis~e.6)) :manner~e.23 (d / depend-01~e.22 :ARG0 r :ARG1 (t2 / time~e.20)) :ARG0-of (r2 / reduce-01~e.25 :ARG1 (v / viability~e.27 :poss~e.26 c~e.26) :ARG2~e.28 (c4 / close-11~e.29 :ARG2~e.30 (p / percentage-entity~e.32 :value 45~e.31) :ARG1-of (r3 / relative-05~e.33 :ARG3~e.34 (c5 / cell~e.38 :ARG1-of (t4 / treat-04~e.37 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "DMSO"~e.35)))))) :time (a2 / after~e.39 :quant (t / temporal-quantity~e.20 :quant 48~e.40 :unit (h / hour~e.41)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.43 :mod "6B"))) # ::id pmid_2470_8867.190 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The MEK1 @/@ 2 inhibitor , on the other hand , did not substantially impact the viability of the Tpr @-@ Met @-@ IEC @-@ 6 cells grown in suspension . # ::alignments 1-1.1.2.1.1.1.1.1 2-1.1.2.1.1 4-1.1.2 4-1.1.2.1 4-1.1.2.1.r 12-1.1.1 12-1.1.1.r 13-1.1.4 13-1.1.4.r 14-1.1 16-1.1.3 17-1.1.3.1.r 19-1.1.3.1.3.1.1.1 21-1.1.3.1.3.1.1.1 23-1.1.3.1.1.1 25-1.1.3.1.1.1 26-1.1.3.1 27-1.1.3.1.2 28-1.1.3.1.2.1.r 29-1.1.3.1.2.1 (c / contrast-01 :ARG2 (i2 / impact-01~e.14 :polarity~e.12 -~e.12 :ARG0 (m / molecular-physical-entity~e.4 :ARG0-of~e.4 (i / inhibit-01~e.4 :ARG1 (s / slash~e.2 :op1 (e / enzyme :name (n / name :op1 "MEK1"~e.1)) :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"))))) :ARG1 (v / viability~e.16 :poss~e.17 (c2 / cell-line~e.26 :name (n3 / name :op1 "IEC-6"~e.23,25) :ARG1-of (g / grow-01~e.27 :manner~e.28 (s3 / suspend-02~e.29)) :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n4 / name :op1 "Tpr-Met"~e.19,21))))) :manner~e.13 (s2 / substantial~e.13))) # ::id pmid_2470_8867.191 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Nonetheless , U0126 treatment did elicit a marked synergistic effect on LY294002 @-@ induced anoikis , reducing Tpr @-@ Met @-@ IEC @-@ 6 cell viability to levels well below those seen upon treatment with the PI3K inhibitor alone ( Figure 6 @ B ) . # ::alignments 0-1 2-1.1.1.1.1.1 3-1.1.1 5-1.1 7-1.1.2.3 8-1.1.2.2 9-1.1.2 10-1.1.2.1.r 11-1.1.2.1.1.1.1.1 13-1.1.2.1.1 14-1.1.2.1 16-1.1.3 17-1.1.3.1.1.2.1.1.1 19-1.1.3.1.1.2.1.1.1 21-1.1.3.1.1.1.1 23-1.1.3.1.1.1.1 24-1.1.3.1.1 25-1.1.3.1 26-1.1.3.2.r 27-1.1.3.2 27-1.1.3.2.1.2 28-1.1.3.2.1.1 29-1.1.3.2.1 30-1.1.3.2.1.2.1 31-1.1.3.2.1.2.2 33-1.1.3.2.1.2.2.1 34-1.1.3.2.1.2.2.1.1.r 36-1.1.3.2.1.2.2.1.1.1.1.1.1 37-1.1.3.2.1.2.2.1.1 37-1.1.3.2.1.2.2.1.1.1 37-1.1.3.2.1.2.2.1.1.1.r 38-1.1.3.2.1.2.2.1.1.2 40-1.2.1 42-1.1.3.1.1.1.1 (h / have-concession-91~e.0 :ARG1 (e / elicit-01~e.5 :ARG0 (t2 / treat-04~e.3 :ARG2 (s / small-molecule :name (n / name :op1 "U0126"~e.2))) :ARG1 (a / affect-01~e.9 :ARG1~e.10 (a2 / anoikis~e.14 :ARG2-of (i2 / induce-01~e.13 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "LY294002"~e.11)))) :ARG2 (s2 / synergize-01~e.8) :mod (m / marked~e.7)) :ARG0-of (r / reduce-01~e.16 :ARG1 (v / viability~e.25 :poss (c / cell-line~e.24 :name (n3 / name :op1 "IEC-6"~e.21,23,42) :ARG1-of (t / transform-01 :ARG0 (p / protein :name (n4 / name :op1 "Tpr-Met"~e.17,19))))) :ARG4~e.26 (l / level~e.27 :mod (b / below~e.29 :degree (w / well~e.28) :compared-to (l2 / level~e.27 :mod (t3 / that~e.30) :ARG1-of (s3 / see-01~e.31 :time (t4 / treat-04~e.33 :ARG2~e.34 (m3 / molecular-physical-entity~e.37 :ARG0-of~e.37 (i / inhibit-01~e.37 :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K"~e.36))) :mod (a3 / alone~e.38))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.40 :mod "6B"))) # ::id pmid_2470_8867.192 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results suggest that Tpr @-@ Met @-@ mediated growth promoting effects observed in IECs implicate MEK @-@ dependent mechanisms , but that the anoikis resistance involves the integration of both MEK @- and PI3K @-@ dependent signaling pathways . # ::alignments 0-1.1.2 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.2.1.1.1 6-1.2.1.1.2.1.1.1 8-1.2.1.1.2 9-1.2.1.1.1.1 10-1.2.1.1.1 11-1.2.1.1 12-1.2.1.1.3 13-1.2.1.1.3.1.r 14-1.2.1.1.3.1.1.1 15-1.2.1 16-1.2.1.2.1.1.1.1 18-1.2.1.2.1 19-1.2.1.2 21-1.2 24-1.2.2.2.1 25-1.2.2.2 26-1.2.2 28-1.2.2.1 31-1.2.1.2.1.1.1.1 33-1.2.2.1.1 34-1.2.2.1.1.2.1.1.1.1 36-1.2.2.1.1.1.1 36-1.2.2.1.1.2.1 37-1.2.2.1.1.3 38-1.2.2.1.1.1 38-1.2.2.1.1.2 (s2 / suggest-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1) :mod (t2 / this~e.0)) :ARG1~e.3 (c / contrast-01~e.21 :ARG1 (i / implicate-01~e.15 :ARG0 (a / affect-01~e.11 :ARG0-of (p2 / promote-01~e.10 :ARG1 (g / grow-01~e.9)) :ARG1-of (m / mediate-01~e.8 :ARG0 (p3 / protein :name (n2 / name :op1 "Tpr-Met"~e.4,6))) :ARG1-of (o / observe-01~e.12 :location~e.13 (c4 / cell :name (n3 / name :op1 "IEC"~e.14)))) :ARG1 (m2 / mechanism~e.19 :ARG0-of (d / depend-01~e.18 :ARG1 (e / enzyme :name (n / name :op1 "MEK"~e.16,31))))) :ARG2 (i2 / involve-01~e.26 :ARG1 (i3 / integrate-01~e.28 :ARG1 (a3 / and~e.33 :op1 (p / pathway~e.38 :ARG0-of (d2 / depend-01~e.36 :ARG1 e)) :op2 (p4 / pathway~e.38 :ARG0-of (d3 / depend-01~e.36 :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K"~e.34)))) :ARG0-of (s / signal-07~e.37))) :ARG2 (r2 / resist-01~e.25 :ARG1 (a2 / anoikis~e.24))))) # ::id pmid_2493_9055.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Antitumor activity of selective MEK1 @/@ 2 inhibitor AZD6244 in combination with PI3K @/@ mTOR inhibitor BEZ235 in gefitinib @-@ resistant NSCLC xenograft models ( PMID : 24939055 ) # ::alignments 0-1.2 0-1.2.1 0-1.2.1.r 1-1 4-1.1.2.1.1.1 6-1.1.2.1.1.1 7-1.1 7-1.1.2 7-1.1.2.r 8-1.1.1.1 9-1.1.3.r 10-1.1.3 11-1.1.3.1.r 12-1.1.3.1.2.1.1.1 14-1.1.3.1.2.1.1.1 15-1.1.3.1 15-1.1.3.1.2 15-1.1.3.1.2.r 16-1.1.3.1.1.1 17-1.3.r 18-1.3.1.2.1.1.1 20-1.3.1.2 21-1.3.1.1.1.1 22-1.3.1 23-1.3 (a / activity-06~e.1 :ARG0 (s / small-molecule~e.7 :name (n2 / name :op1 "AZD6244"~e.8) :ARG0-of~e.7 (i / inhibit-01~e.7 :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2"~e.4,6))) :ARG1-of~e.9 (c2 / combine-01~e.10 :ARG2~e.11 (s2 / small-molecule~e.15 :name (n4 / name :op1 "BEZ235"~e.16) :ARG0-of~e.15 (i2 / inhibit-01~e.15 :ARG1 (p / pathway :name (n3 / name :op1 "PI3K/mTOR"~e.12,14))))) :ARG0-of (s3 / select-01)) :ARG0-of (c / counter-01~e.0 :ARG1~e.0 (t / tumor~e.0)) :location~e.17 (m / model~e.23 :mod (x / xenograft~e.22 :mod (d / disease :name (n5 / name :op1 "NSCLC"~e.21)) :ARG0-of (r / resist-01~e.20 :ARG1 (s4 / small-molecule :name (n6 / name :op1 "gefitinib"~e.18))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG8 "PMID24939055"))) # ::id pmid_2493_9055.9 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2493_9055.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok AZD6244 could inhibit the tumor growth of NCI @-@ H1993 , but slightly inhibit the tumor growth of NCI @-@ 1975 and NCI @-@ H460 . # ::alignments 0-1.1.1.1.1.1 1-1.1 2-1.1.1 4-1.1.1.2.2 5-1.1.1.2 6-1.1.1.2.1.r 7-1.1.1.2.1.1.1 9-1.1.1.2.1.1.1 11-1 12-1.2.2 12-1.2.2.r 13-1.2 15-1.2.1.2 16-1.2.1 17-1.2.1.1.r 18-1.2.1.1.1.1.1 20-1.2.1.1.1.1.1 21-1.2.1.1 22-1.2.1.1.1.1.1 22-1.2.1.1.2.1.1 24-1.2.1.1.2.1.1 (c / contrast-01~e.11 :ARG1 (p2 / possible-01~e.1 :ARG1 (i2 / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244"~e.0)) :ARG1 (g / grow-01~e.5 :ARG0~e.6 (c3 / cell-line :name (n3 / name :op1 "NCI-H1993"~e.7,9)) :ARG1 (t / tumor~e.4)))) :ARG2 (i / inhibit-01~e.13 :ARG1 (g2 / grow-01~e.16 :ARG0~e.17 (a / and~e.21 :op1 (c2 / cell-line :name (n2 / name :op1 "NCI-1975"~e.18,20,22)) :op2 (c4 / cell-line :name (n4 / name :op1 "NCI-H460"~e.22,24))) :ARG1 t~e.15) :manner~e.12 (s2 / slight~e.12))) # ::id pmid_2493_9055.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combining AZD6244 with BEZ235 markedly enhanced their antitumor effects and without any marked adverse events . # ::alignments 0-1.1.1 1-1.1.1.1.1.1 2-1.1.1.2.r 3-1.1.1.2.1.1 4-1.1.3 4-1.1.3.r 5-1.1 5-1.2 7-1.1.2.2 7-1.1.2.2.1 7-1.1.2.2.1.r 8-1.1.2 9-1 9-1.1.2.1 10-1.2.2.1 10-1.2.2.1.r 12-1.2.2.2.2 13-1.2.2.2.1 14-1.2.2.2 (a2 / and~e.9 :op1 (e / enhance-01~e.5 :ARG0 (c / combine-01~e.0 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.1)) :ARG2~e.2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"~e.3))) :ARG1 (a / affect-01~e.8 :ARG0 (a4 / and~e.9 :op1 s :op2 s2) :ARG0-of (c2 / counter-01~e.7 :ARG1~e.7 (t / tumor~e.7))) :manner~e.4 (m / marked~e.4)) :op2 (e2 / enhance-01~e.5 :ARG0 c :ARG0-of (c3 / cause-01 :polarity~e.10 -~e.10 :ARG1 (e3 / event~e.14 :mod (a3 / adverse~e.13) :mod m~e.12)))) # ::id pmid_2493_9055.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis and immunohistochemical staining revealed that AZD6244 alone reduced ERK1 @/@ 2 phosphorylation , angiogenesis , and tumor cell proliferation . # ::alignments 0-1.1.1.1 1-1.1.1.1 2-1.1.1 3-1.1 4-1.1.2.1 5-1.1.2 6-1 7-1.2.r 8-1.2.1.1.1 9-1.2.1.2 10-1.2 11-1.2.2.1.1.1.1 13-1.2.2.1.1.1.1 14-1.2.2.1 16-1.2.2.2 18-1.2.2 19-1.2.2.3.1.1 20-1.2.2.3.1 21-1.2.2.3 (r / reveal-01~e.6 :ARG0 (a / and~e.3 :op1 (a2 / analyze-01~e.2 :mod (i2 / immunoblot-01~e.0,1)) :op2 (s2 / stain-01~e.5 :mod (i / immunohistochemical~e.4))) :ARG1~e.7 (r2 / reduce-01~e.10 :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD6244"~e.8) :mod (a5 / alone~e.9)) :ARG1 (a3 / and~e.18 :op1 (p / phosphorylate-01~e.14 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.11,13))) :op2 (a4 / angiogenesis~e.16) :op3 (p2 / proliferate-01~e.21 :ARG0 (c / cell~e.20 :mod (t / tumor~e.19)))))) # ::id pmid_2493_9055.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , MEK1 @/@ 2 inhibition resulted in decreased AKT phosphorylation in NCI @-@ H1993 tumor model . # ::alignments 0-1 2-1.1.1.1.1.1 4-1.1.1.1.1.1 5-1.1.1 6-1.1 7-1.1.2.r 8-1.1.2.3 9-1.1.2.1.1.1 10-1.1.2 11-1.1.2.2.r 12-1.1.2.2.2.1.1 14-1.1.2.2.2.1.1 15-1.1.2.2.1 16-1.1.2.2 (a / and~e.0 :op2 (r / result-01~e.6 :ARG1 (i / inhibit-01~e.5 :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2"~e.2,4))) :ARG2~e.7 (p / phosphorylate-01~e.10 :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT"~e.9)) :location~e.11 (m / model~e.16 :mod (t / tumor~e.15) :mod (c / cell-line :name (n3 / name :op1 "NCI-H1993"~e.12,14))) :ARG1-of (d / decrease-01~e.8)))) # ::id pmid_2493_9055.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BEZ235 also inhibited AKT phosphorylation as well as their downstream molecules in all three tumor models . # ::alignments 0-1.1.1.1 1-1.3 2-1 3-1.2.1.1.1.1 4-1.2.1 5-1.2 6-1.2 7-1.2 7-1.2.r 8-1.2.2.3 8-1.2.2.3.r 9-1.2.2.1 10-1.2.2 11-1.2.2.2.r 12-1.2.2.2.3 13-1.2.2.2.1 14-1.2.2.2.2 15-1.2.2.2 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "BEZ235"~e.0)) :ARG1~e.7 (a / and~e.5,6,7 :op1 (p / phosphorylate-01~e.4 :ARG1 (e / enzyme :name (n2 / name :op1 "AKT"~e.3))) :op2 (m / molecule~e.10 :direction (d / downstream~e.9) :location~e.11 (m2 / model~e.15 :quant 3~e.13 :mod (t / tumor~e.14) :mod (a2 / all~e.12)) :poss~e.8 s~e.8)) :mod (a3 / also~e.1)) # ::id pmid_2493_9055.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The antiangiogenic effects were substantially enhanced when the agents were combined , which may due to the reduced expression of matrix metallopeptidase @-@ 9 in tumor tissues ( MMP @-@ 9 ) . # ::alignments 2-1.1 4-1.2 5-1 8-1.3.1 10-1.3 13-1.4.2 14-1.4 15-1.4 17-1.4.1.3 18-1.4.1 19-1.4.1.1.r 20-1.4.1.1.1.1 21-1.4.1.1.1.2 23-1.4.1.1.1.2 24-1.4.1.2.r 25-1.4.1.2.1 26-1.4.1.2 30-1.4.1.1.1.2 (e / enhance-01~e.5 :ARG0 (a2 / affect-01~e.2 :ARG0-of (c4 / counter-01 :ARG1 (a3 / angiogenesis))) :degree (s / substantial~e.4) :condition (c3 / combine-01~e.10 :ARG1 (a / agent~e.8)) :ARG1-of (c2 / cause-01~e.14,15 :ARG0 (e2 / express-03~e.18 :ARG2~e.19 (e3 / enzyme :name (n / name :op1 "matrix"~e.20 :op2 "metallopeptidase-9"~e.21,23,30)) :ARG3~e.24 (t / tissue~e.26 :source (t2 / tumor~e.25)) :ARG1-of (r / reduce-01~e.17)) :ARG1-of (p / possible-01~e.13))) # ::id pmid_2493_9055.94 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2493_9055.95 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effect of AZD6244 and BEZ235 on viability of gefitinib @-@ resistant NSCLC in vitro @ # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1 4-1.1 5-1.1.2.1.1 6-1.2.r 7-1.2 8-1.2.1.r 9-1.2.1.2.1.1.1 11-1.2.1 11-1.2.1.2 11-1.2.1.2.r 12-1.2.1.1.1 14-1.2.2 15-1.2.2 (a / affect-01~e.1 :ARG0~e.2 (a2 / and~e.4 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.3)) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"~e.5))) :ARG1~e.6 (v / viability~e.7 :poss~e.8 (d / disease~e.11 :name (n3 / name :op1 "NSCLC"~e.12) :ARG0-of~e.11 (r / resist-01~e.11 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "gefitinib"~e.9)))) :manner (i / in-vitro~e.14,15))) # ::id pmid_2493_9055.96 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Before evaluating the effect of AZD6244 , BEZ235 and AZD6244 plus BEZ235 treatment on gefitinib @-@ resistant NSCLC xenograft models in nude mice , the sensitivity of cell lines to compounds was evaluated in vitro . # ::alignments 0-1.3 1-1.3.1 3-1.3.1.1 4-1.3.1.1.1.r 5-1.3.1.1.1.2.1.1.1 7-1.3.1.1.1.2.2.1.1 8-1.3.1.1.1.2 8-1.3.1.1.1.2.3 8-1.3.1.1.1.2.3.r 9-1.3.1.1.1.2.1.1.1 10-1.3.1.1.1.2 10-1.3.1.1.1.2.3 10-1.3.1.1.1.2.3.r 11-1.3.1.1.1.2.2.1.1 12-1.3.1.1.1 13-1.3.1.1.1.1.r 14-1.3.1.1.1.1.2.1.1.1 16-1.3.1.1.1.1.2 17-1.3.1.1.1.1.1.1.1.1 18-1.3.1.1.1.1.1 19-1.3.1.1.1.1 20-1.2 20-1.3.1.1.1.1.3.r 21-1.3.1.1.1.1.3.1 22-1.3.1.1.1.1.3 25-1.1 26-1.1.1.r 27-1.1.1 28-1.1.1 29-1.1.2.r 30-1.1.2 32-1 34-1.2 35-1.2 (e / evaluate-01~e.32 :ARG1 (s2 / sensitive-03~e.25 :ARG0~e.26 (c2 / cell-line~e.27,28) :ARG1~e.29 (c / compound~e.30)) :manner (i / in-vitro~e.20,34,35) :time (b / before~e.0 :op1 (e2 / evaluate-01~e.1 :ARG1 (a / affect-01~e.3 :ARG0~e.4 (t / treat-04~e.12 :ARG1~e.13 (m / model~e.19 :mod (x / xenograft~e.18 :mod (d / disease :name (n3 / name :op1 "NSCLC"~e.17))) :ARG0-of (r / resist-01~e.16 :ARG1 (s4 / small-molecule :name (n4 / name :op1 "gefitinib"~e.14))) :location~e.20 (m2 / mouse~e.22 :mod (n5 / nude~e.21))) :ARG2 (a2 / and~e.8,10 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.5,9)) :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235"~e.7,11)) :op3~e.8,10 (a3 / and~e.8,10 :op1 s :op2 s3))))))) # ::id pmid_2493_9055.97 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell proliferation was analyzed by MTT assay in cells treated with 0 , 0.01 , 0.1 , 1 , 10 and 100 μM of AZD6244 or BEZ235 for 72 h . # ::alignments 0-1.1.1 1-1.1 3-1 4-1.2.r 5-1.2.1.1.1 6-1.2 7-1.3.r 8-1.3 9-1.3.1 10-1.2.1.r 10-1.3.1.1.r 11-1.3.1.1.1.1 13-1.3.1.1.2.1 15-1.3.1.1.3.1 17-1.3.1.1.4.1 19-1.3.1.1.5.1 20-1.3.1.1 21-1.3.1.1.6.1 22-1.3.1.1.5.2 23-1.3.1.1.7.r 24-1.3.1.1.7.1.1.1 25-1.3.1.1.7 26-1.3.1.1.7.2.1.1 27-1.3.1.2.r 28-1.3.1.2.1 29-1.3.1.2.2 (a / analyze-01~e.3 :ARG1 (p / proliferate-01~e.1 :ARG0 (c / cell~e.0)) :instrument~e.4 (a2 / assay-01~e.6 :instrument~e.10 (s3 / small-molecule :name (n / name :op1 "MTT"~e.5))) :location~e.7 (c2 / cell~e.8 :ARG1-of (t / treat-04~e.9 :ARG2~e.10 (a3 / and~e.20 :op1 (c3 / concentration-quantity :quant 0~e.11 :unit m3) :op2 (c4 / concentration-quantity :quant 0.01~e.13 :unit m3) :op3 (c5 / concentration-quantity :quant 0.1~e.15 :unit m3) :op4 (c6 / concentration-quantity :quant 1~e.17 :unit m3) :op5 (c7 / concentration-quantity :quant 10~e.19 :unit (m3 / micromolar~e.22)) :op6 (c8 / concentration-quantity :quant 100~e.21 :unit m3) :quant-of~e.23 (o / or~e.25 :op1 (s / small-molecule :name (n2 / name :op1 "AZD6244"~e.24)) :op2 (s2 / small-molecule :name (n3 / name :op1 "BEZ235"~e.26)))) :duration~e.27 (t2 / temporal-quantity :quant 72~e.28 :unit (h / hour~e.29))))) # ::id pmid_2493_9055.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed that AZD6244 significantly suppressed the growth of NCI @-@ H1993 with a low micromolar IC50 value of 5.6 μM ( Figure 1 @ A ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.1 5-1.2.3 6-1.2 8-1.2.2 9-1.2.2.1.r 10-1.2.2.1.1.1 12-1.2.2.1.1.1 13-1.2.2.2.r 15-1.2.2.2.3 16-1.2.2.2.2.2 17-1.2.2.2.1.1.1 18-1.2.2.2 20-1.2.2.2.2.1 21-1.2.2.2.2.2 23-1.3.1 (s / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (s2 / suppress-01~e.6 :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD6244"~e.4)) :ARG1 (g / grow-01~e.8 :ARG1~e.9 (c / cell-line :name (n3 / name :op1 "NCI-H1993"~e.10,12)) :ARG2~e.13 (v / value-01~e.18 :ARG1 (t2 / thing :name (n2 / name :op1 "IC50"~e.17)) :ARG2 (c2 / concentration-quantity :quant 5.6~e.20 :unit (m / micromolar~e.16,21)) :ARG1-of (l / low-04~e.15))) :ARG1-of (s4 / significant-02~e.5)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.23 :mod "1A"))) # ::id pmid_2493_9055.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Moreover , AZD6244 alone mildly inhibited cell growth with IC50 values of 37.5 μM and 26.8 μM in NCI @-@ H1975 and NCI @-@ H460 cells , respectively ( Figure 1 @ A ) . # ::alignments 0-1 0-1.1.1 2-1.1.1.1.1.1 2-1.1.1.2.1.1 3-1.1.1.3 4-1.1.3 4-1.1.3.r 5-1.1 6-1.1.2.1 7-1.1.2 8-1.1.1.r 9-1.1.1.1.2.1.1.1 10-1.1.1.1.2 10-1.1.1.2.2 11-1.1.1.1.2.2.r 12-1.1.1.1.2.2.1 13-1.1.1.1.2.2.2 13-1.1.1.2.2.2.2 14-1.1.1 15-1.1.1.2.2.2.1 16-1.1.1.1.2.2.2 16-1.1.1.2.2.2.2 18-1.1.1.1.2.3.1.1 18-1.1.1.2.2.3.1.1 20-1.1.1.1.2.3.1.1 21-1.1.1 22-1.1.1.1.2.3.1.1 22-1.1.1.2.2.3.1.1 24-1.1.1.2.2.3.1.1 25-1.1.1.1.2.3 29-1.2.1 (a / and~e.0 :op2 (i / inhibit-01~e.5 :ARG0~e.8 (a3 / and~e.0,14,21 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.2) :mod (v / value-01~e.10 :ARG1 (t / thing :name (n2 / name :op1 "IC50"~e.9)) :ARG2~e.11 (c3 / concentration-quantity :quant 37.5~e.12 :unit (m2 / micromolar~e.13,16)) :location (c4 / cell-line~e.25 :name (n3 / name :op1 "NCI-H1975"~e.18,20,22)))) :op2 (s2 / small-molecule :name (n5 / name :op1 "AZD6244"~e.2) :mod (v2 / value-01~e.10 :ARG1 t :ARG2 (c2 / concentration-quantity :quant 26.8~e.15 :unit (m3 / micromolar~e.13,16)) :location (c5 / cell-line :name (n4 / name :op1 "NCI-H460"~e.18,22,24)))) :mod (a2 / alone~e.3)) :ARG1 (g / grow-01~e.7 :ARG1 (c / cell~e.6)) :manner~e.4 (m / mild~e.4)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.29 :mod "1A"))) # ::id pmid_2493_9055.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok BEZ235 alone also suppressed the growth of three cell lines with slightly high IC50 values of 23.5 , 67.8 and 16.8 μM in NCI @-@ H1993 , NCI @-@ H1975 and NCI @-@ H460 cells , respectively ( Figure 1 @ B ) . # ::alignments 0-1.1.1.1 1-1.2.1.4 2-1.4 3-1 5-1.2 8-1.2.1.1 9-1.2.1.1 10-1.2.1.1.2.r 11-1.2.1.1.2.3.1 12-1.2.1.1.2.3 13-1.2.1.1.2.1.1.1 14-1.2.1.1.2 14-1.2.1.2.2 14-1.2.1.3.2 15-1.2.1.1.2.2.r 16-1.2.1.1.2.2.1 18-1.2.1.2.2.2.1 19-1.2.1 20-1.2.1.3.2.2.1 21-1.2.1.1.2.2.2 22-1.2.1.1.1.r 23-1.2.1.1.1.1.1 25-1.2.1.1.1.1.1 27-1.2.1.1.1.1.1 27-1.2.1.2.1.1.1 27-1.2.1.3.1.1.1 29-1.2.1.2.1.1.1 30-1.2.1 31-1.2.1.1.1.1.1 31-1.2.1.2.1.1.1 31-1.2.1.3.1.1.1 33-1.2.1.3.1.1.1 34-1.2.1.1 34-1.2.1.2 34-1.2.1.3 38-1.3.1 (s / suppress-01~e.3 :ARG0 (s2 / small-molecule :name (n / name :op1 "BEZ235"~e.0)) :ARG1 (g / grow-01~e.5 :ARG1 (a4 / and~e.19,30 :op1 (c / cell-line~e.8,9,34 :location~e.22 (c3 / cell-line :name (n3 / name :op1 "NCI-H1993"~e.23,25,27,31)) :mod~e.10 (v / value-01~e.14 :ARG1 (t / thing :name (n2 / name :op1 "IC50"~e.13)) :ARG2~e.15 (c2 / concentration-quantity :quant 23.5~e.16 :unit (m / micromolar~e.21)) :ARG1-of (h / high-04~e.12 :degree (s3 / slight~e.11)))) :op2 (c8 / cell-line~e.34 :location (c7 / cell-line :name (n4 / name :op1 "NCI-H1975"~e.27,29,31)) :mod (v2 / value-01~e.14 :ARG1 t :ARG2 (c4 / concentration-quantity :quant 67.8~e.18 :unit m))) :op3 (c9 / cell-line~e.34 :location (c6 / cell-line :name (n5 / name :op1 "NCI-H460"~e.27,31,33)) :mod (v3 / value-01~e.14 :ARG1 t :ARG2 (c5 / concentration-quantity :quant 16.8~e.20 :unit m))) :mod (a3 / alone~e.1))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.38 :mod "1B")) :mod (a / also~e.2)) # ::id pmid_2493_9055.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Concurrent inhibition of MEK and PI3K @/@ mTOR has a synergistic effect on gefitinib @-@ resistant NSCLC cell lines growth in vitro @ # ::alignments 2-1.1 2-1.1.2.1 3-1.1.1.r 4-1.1.1.1.1 6-1.1.2.1.1.1.1 8-1.1.2.1.1.1.1 11-1.3 12-1 13-1.2.r 14-1.2.1.2.1.1.1 16-1.2.1.2 17-1.2.1.1.1.1 18-1.2.1 19-1.2.1 20-1.2 22-1.2.2 23-1.2.2 (a / affect-01~e.12 :ARG0 (i / inhibit-01~e.2 :ARG1~e.3 (e / enzyme :name (n / name :op1 "MEK"~e.4)) :ARG1-of (c2 / concur-01 :ARG0 (i2 / inhibit-01~e.2 :ARG1 (p / pathway :name (n2 / name :op1 "PI3K/mTOR"~e.6,8))))) :ARG1~e.13 (g / grow-01~e.20 :ARG1 (c / cell-line~e.18,19 :mod (d / disease :name (n3 / name :op1 "NSCLC"~e.17)) :ARG0-of (r / resist-01~e.16 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "gefitinib"~e.14)))) :manner (i3 / in-vitro~e.22,23)) :ARG2 (s / synergize-01~e.11)) # ::id pmid_2493_9055.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The anti @-@ proliferative effect of combining a MEK and PI3K @/@ mTOR inhibitor was measured in NCI @-@ H1993 , NCI @-@ H1975 and NCI @-@ H460 cells by calculating the combination index ( CI ) according to the Chou @-@ Talalay method [ @ 21 @ ] using a fixed dose ratio . # ::alignments 1-1.1.2 4-1.1 5-1.1.1.r 6-1.1.1 8-1.1.1.1.1.1.1.1 10-1.1.1.2.1.1.1.1 12-1.1.1.2.1.1.1.1 13-1.1.1.1 13-1.1.1.1.1 13-1.1.1.1.1.r 13-1.1.1.2 13-1.1.1.2.1 13-1.1.1.2.1.r 15-1 16-1.4.r 17-1.4.1.1.1 17-1.4.2.1.1 17-1.4.3.1.1 19-1.4.1.1.1 21-1.4.1.1.1 21-1.4.2.1.1 21-1.4.3.1.1 23-1.4.2.1.1 24-1.4 25-1.4.1.1.1 25-1.4.2.1.1 25-1.4.3.1.1 27-1.4.3.1.1 28-1.4.1 28-1.4.2 28-1.4.3 29-1.2.r 30-1.2 32-1.2.1.1 33-1.2.1 35-1.1.2 37-1.3.2 38-1.3.2 40-1.3.2.1.1.1 42-1.3.2.1.1.1 43-1.3.2.1 46-1.3.3.1.1.1 49-1.3 51-1.3.1.1.1 52-1.3.1.1 53-1.3.1 (m / measure-01~e.15 :ARG1 (a / affect-01~e.4 :ARG0~e.5 (c2 / combine-01~e.6 :ARG1 (m2 / molecular-physical-entity~e.13 :ARG0-of~e.13 (i / inhibit-01~e.13 :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK"~e.8)))) :ARG2 (m3 / molecular-physical-entity~e.13 :ARG0-of~e.13 (i2 / inhibit-01~e.13 :ARG1 (p2 / pathway :name (n / name :op1 "PI3K/mTOR"~e.10,12))))) :ARG0-of (c / counter-01~e.1,35 :ARG1 (p / proliferate-01))) :ARG2~e.29 (c6 / calculate-01~e.30 :ARG1 (i3 / index~e.33 :mod (c7 / combine-01~e.32))) :ARG3 (u / use-01~e.49 :ARG1 (r / ratio~e.53 :mod (d / dose~e.52 :ARG1-of (f / fix-03~e.51))) :ARG1-of (s / say-01~e.37,38 :ARG0 (m4 / method~e.43 :name (n6 / name :op1 "Chou-Talalay"~e.40,42))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG0-of (c8 / cite-01 :ARG1 21~e.46)))) :location~e.16 (a2 / and~e.24 :op1 (c3 / cell-line~e.28 :name (n3 / name :op1 "NCI-H1993"~e.17,19,21,25)) :op2 (c4 / cell-line~e.28 :name (n4 / name :op1 "NCI-H1975"~e.17,21,23,25)) :op3 (c5 / cell-line~e.28 :name (n5 / name :op1 "NCI-H460"~e.17,21,25,27)))) # ::id pmid_2493_9055.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both AZD6244 and BEZ235 were introduced to cell cultures at 0.25×, 0.5×, 1×, 2× and 4× their respective IC50 s in NCI @-@ H1993 , NCI @-@ H1975 and NCI @-@ H460 cell lines for 72 h . # ::alignments 1-1.1.1.1.1 3-1.1.2.1.1 5-1 6-1.2.r 7-1.2.1 8-1.2 14-1.1 14-1.1.4 14-1.1.4.r 17-1.1.4.6 18-1.1.3.1.1 20-1.3.r 21-1.3.1.1.1 21-1.3.2.1.1 21-1.3.3.1.1 23-1.3.1.1.1 25-1.3.1.1.1 25-1.3.2.1.1 25-1.3.3.1.1 27-1.3.2.1.1 28-1.3 29-1.3.1.1.1 29-1.3.2.1.1 29-1.3.3.1.1 31-1.3.3.1.1 32-1.3.1 32-1.3.2 32-1.3.3 33-1.3.1 34-1.4.r 35-1.4.1 36-1.4.2 (i / introduce-01~e.5 :ARG1 (a / and~e.14 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.1)) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"~e.3)) :mod (t / thing :name (n3 / name :op1 "IC50"~e.18)) :quant~e.14 (a3 / and~e.14 :op1 (p / product-of :op1 0.25 :op2 t) :op2 (p2 / product-of :op1 0.5 :op2 t) :op3 (p3 / product-of :op1 1 :op2 t) :op4 (p4 / product-of :op2 2 :op2 t) :op5 (p5 / product-of :op2 4 :op2 t) :mod (r / respective~e.17))) :ARG2~e.6 (c / culture-01~e.8 :ARG1 (c2 / cell~e.7)) :location~e.20 (a2 / and~e.28 :op1 (c3 / cell-line~e.32,33 :name (n4 / name :op1 "NCI-H1993"~e.21,23,25,29)) :op2 (c4 / cell-line~e.32 :name (n5 / name :op1 "NCI-H1975"~e.21,25,27,29)) :op3 (c5 / cell-line~e.32 :name (n6 / name :op1 "NCI-H460"~e.21,25,29,31))) :duration~e.34 (t2 / temporal-quantity :quant 72~e.35 :unit (h / hour~e.36))) # ::id pmid_2493_9055.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Cell growth in all cell lines was markedly decreased following combination treatment at multiple paired concentrations when compared with either single agent alone . # ::alignments 0-1.1.1 0-1.1.2 1-1.1 3-1.1.2.1 4-1.1.2 5-1.1.2 7-1.2 8-1 9-1.3 10-1.3.1.2 11-1.3.1 12-1.3.1.1.r 13-1.3.1.1.2 14-1.3.1.1.1 15-1.3.1.1 17-1.4 18-1.4.1.r 19-1.4.1.2 20-1.4.1.1 21-1.4.1 22-1.4.1.3 (d / decrease-01~e.8 :ARG1 (g / grow-01~e.1 :ARG1 (c / cell~e.0) :location (c2 / cell-line~e.0,4,5 :mod (a / all~e.3))) :ARG2 (m / marked~e.7) :ARG1-of (f / follow-01~e.9 :ARG2 (t / treat-04~e.11 :ARG2~e.12 (c4 / concentrate-01~e.15 :ARG1-of (p / pair-01~e.14) :quant (m2 / multiple~e.13)) :mod (c3 / combine-01~e.10))) :ARG1-of (c5 / compare-01~e.17 :ARG2~e.18 (a2 / agent~e.21 :ARG1-of (s / single-02~e.20) :mod (e / either~e.19) :mod (a3 / alone~e.22)))) # ::id pmid_2493_9055.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The cells viability data were processed to get the CI under the corresponding effective dose ( ED ) in NCI @-@ H1993 , NCI @-@ H1975 and NCI @-@ H460 cell lines ( Figure 2 ) by CalcuSyn software . # ::alignments 1-1.1.1.1 2-1.1.1 3-1.1 5-1 7-1.2 9-1.2.1 9-1.2.1.1 9-1.2.1.1.r 10-1.2.2 12-1.2.2.1.2 13-1.2.2.1.1 14-1.2.2.1.1 18-1.2.2.1.1.1.r 19-1.2.2.1.1.1.1.1.1 19-1.2.2.1.1.1.2.1.1 19-1.2.2.1.1.1.3.1.1 21-1.2.2.1.1.1.1.1.1 23-1.2.2.1.1.1.1.1.1 23-1.2.2.1.1.1.2.1.1 23-1.2.2.1.1.1.3.1.1 25-1.2.2.1.1.1.2.1.1 26-1.2.2.1.1.1 27-1.2.2.1.1.1.1.1.1 27-1.2.2.1.1.1.2.1.1 27-1.2.2.1.1.1.3.1.1 29-1.2.2.1.1.1.3.1.1 30-1.2.2.1.1.1.1 30-1.2.2.1.1.1.2 30-1.2.2.1.1.1.3 31-1.2.2.1.1.1.1 33-1.3.1 35-1.3.1.1 38-1.4.r 39-1.4.1.1 40-1.4 (p / process-01~e.5 :ARG1 (d / data~e.3 :topic (v / viability~e.2 :poss (c / cell~e.1))) :purpose (g / get-03~e.7 :ARG1 (i / interval~e.9 :mod~e.9 (c7 / confidence~e.9)) :ARG2 (u / under~e.10 :op1 (c6 / concentration-quantity :ARG4-of (h2 / have-percentage-maximal-effective-dose-01~e.13,14 :ARG5~e.18 (a2 / and~e.26 :op1 (c3 / cell-line~e.30,31 :name (n4 / name :op1 "NCI-H1993"~e.19,21,23,27)) :op2 (c4 / cell-line~e.30 :name (n3 / name :op1 "NCI-H1975"~e.19,23,25,27)) :op3 (c5 / cell-line~e.30 :name (n2 / name :op1 "NCI-H460"~e.19,23,27,29)))) :ARG1-of (c2 / correspond-01~e.12)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.33 :mod 2~e.35)) :instrument~e.38 (s / software~e.40 :name (n5 / name :op1 "CalcuSyn"~e.39))) # ::id pmid_2493_9055.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For the NCI @-@ H1993 cell line the following CI value was obtained : 0.4101 ( ED50 ) . # ::alignments 2-1.2.1.1 4-1.2.1.1 5-1.2 6-1.2 8-1.1.3 9-1.1.2 9-1.1.2.1 9-1.1.2.1.r 10-1.1 12-1 14-1.1.1 (o / obtain-01~e.12 :ARG1 (v / value-01~e.10 :ARG2 0.4101~e.14 :ARG1 (i / interval~e.9 :mod~e.9 (c / confidence~e.9)) :ARG2-of (f / follow-01~e.8) :ARG1-of (m / mean-01 :ARG2 (h / have-percentage-maximal-effective-dose-01 :ARG2 50))) :purpose (c2 / cell-line~e.5,6 :name (n2 / name :op1 "NCI-H1993"~e.2,4))) # ::id pmid_2493_9055.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For NCI @-@ H1975 and NCI @-@ H460 cell line the CI values were 0.02052 ( ED50 ) , and 0.0440 ( ED50 ) respectively . # ::alignments 1-1.1.3.1.1 1-1.2.3.1.1 3-1.1.3.1.1 4-1 5-1.1.3.1.1 5-1.2.3.1.1 7-1.2.3.1.1 8-1.1.3 9-1.1.3 9-1.2.3 11-1.1.2 11-1.1.2.1 11-1.1.2.1.r 12-1.1 12-1.2 14-1.1.1 19-1 20-1.2.1 (a / and~e.4,19 :op1 (v / value-01~e.12 :ARG2 0.02052~e.14 :ARG1 (i / interval~e.11 :mod~e.11 (c3 / confidence~e.11)) :purpose (c / cell-line~e.8,9 :name (n / name :op1 "NCI-H1975"~e.1,3,5)) :ARG1-of (m / mean-01 :ARG2 (h / have-percentage-maximal-effective-dose-01 :ARG2 50))) :op2 (v2 / value-01~e.12 :ARG2 0.0440~e.20 :ARG1 i :purpose (c2 / cell-line~e.9 :name (n2 / name :op1 "NCI-H460"~e.1,5,7)) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91)) :ARG1-of m)) # ::id pmid_2493_9055.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The CI results suggested that AZD6244 and BEZ235 worked synergistically to produce an anti @-@ proliferative effect in NCI @-@ H1993 , NCI @-@ H1975 and NCI @-@ H460 cell lines ( Figures 2 @ A @-@ C ) . # ::alignments 1-1.2.2.2.1 2-1.1 2-1.1.1 2-1.1.1.r 3-1 5-1.2.1.1.1.1 6-1.2.1 7-1.2.1.2.1.1 8-1.2 11-1.2.2 13-1.2.2.2.1 16-1.2.2.2 18-1.2.2.2.1.1.1.1.1.1 18-1.2.2.2.1.1.1.2.1.1 18-1.2.2.2.1.1.1.3.1.1 20-1.2.2.2.1.1.1.1.1.1 22-1.2.2.2.1.1.1.1.1.1 22-1.2.2.2.1.1.1.2.1.1 22-1.2.2.2.1.1.1.3.1.1 24-1.2.2.2.1.1.1.2.1.1 25-1.2.2.2.1.1.1 26-1.2.2.2.1.1.1.1.1.1 26-1.2.2.2.1.1.1.2.1.1 26-1.2.2.2.1.1.1.3.1.1 28-1.2.2.2.1.1.1.3.1.1 29-1.2.2.2.1.1.1.1 29-1.2.2.2.1.1.1.2 29-1.2.2.2.1.1.1.3 30-1.2.2.2.1.1.1.1 32-1.3.1.1 32-1.3.1.2 32-1.3.1.3 (s / suggest-01~e.3 :ARG0 (t / thing~e.2 :ARG2-of~e.2 (r / result-01~e.2 :ARG1 (i / index :mod (c5 / combine-01)))) :ARG1 (w / work-01~e.8 :ARG0 (a / and~e.6 :op1 (s3 / small-molecule :name (n2 / name :op1 "AZD6244"~e.5)) :op2 (s4 / small-molecule :name (n3 / name :op1 "BEZ235"~e.7))) :ARG1 (p / produce-01~e.11 :ARG0 a :ARG1 (a2 / affect-01~e.16 :ARG0-of (c / counter-01~e.1,13 :ARG1 (p2 / proliferate-01 :location (a3 / and~e.25 :op1 (c2 / cell-line~e.29,30 :name (n4 / name :op1 "NCI-H1993"~e.18,20,22,26)) :op2 (c3 / cell-line~e.29 :name (n5 / name :op1 "NCI-H1975"~e.18,22,24,26)) :op3 (c4 / cell-line~e.29 :name (n6 / name :op1 "NCI-H460"~e.18,22,26,28))))))) :manner (s2 / synergistical)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.32 :mod "2A") :op2 (f2 / figure~e.32 :mod "2B") :op3 (f3 / figure~e.32 :mod "2C")))) # ::id pmid_2493_9055.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Tumor growth inhibition effect of MEK and PI3K @/@ mTOR inhibitors in gefitinib @-@ resistant NSCLC tumor models # ::alignments 1-1.2.1.1 2-1.2.1 3-1.1.1 3-1.1.1.1 3-1.1.1.1.r 3-1.2 4-1 5-1.1.1.1.1.r 5-1.1.r 6-1.1.1.1.1.1.1 7-1.1 8-1.1.2.1.1.1.1 10-1.1.2.1.1.1.1 11-1.1.2 11-1.1.2.1 11-1.1.2.1.r 11-1.2 12-1.3.r 13-1.3.2.1.1.1 15-1.3.2 16-1.3.1.1.1.1 17-1.3.1 18-1.3 (a / affect-01~e.4 :ARG0~e.5 (a2 / and~e.7 :op1 (m2 / molecular-physical-entity~e.3 :ARG0-of~e.3 (i2 / inhibit-01~e.3 :ARG1~e.5 (p2 / protein-family :name (n2 / name :op1 "MEK"~e.6)))) :op2 (m3 / molecular-physical-entity~e.11 :ARG0-of~e.11 (i3 / inhibit-01~e.11 :ARG1 (p / pathway :name (n3 / name :op1 "PI3K/mTOR"~e.8,10))))) :ARG1 (i / inhibit-01~e.3,11 :ARG1 (g / grow-01~e.2 :ARG0 (t / tumor~e.1))) :location~e.12 (m / model~e.18 :mod (t2 / tumor~e.17 :mod (d / disease :name (n / name :op1 "NSCLC"~e.16))) :ARG0-of (r / resist-01~e.15 :ARG1 (s / small-molecule :name (n4 / name :op1 "gefitinib"~e.13))))) # ::id pmid_2493_9055.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to investigate tumor growth inhibition effect of AZD6244 and @/@ or BEZ235 in vivo , we used AZD6244 , BEZ235 , and AZD6244 plus BEZ235 to treat NCI @-@ H1993 , NCI @-@ H1975 and NCI @-@ H460 subcutaneous tumor models respectively for 3 weeks . # ::alignments 0-1.4.r 1-1.4.r 2-1.4.r 3-1.4 4-1.4.2.2.1.1 5-1.4.2.2.1 6-1.4.2.2 7-1.4.2 8-1.4.2.1.r 9-1.4.2.1.1 10-1.2 10-1.2.3 10-1.2.3.r 10-1.4.2.1 12-1.4.2.1 13-1.4.2.1.2 15-1.4.2.3 16-1.4.2.3 19-1.1 20-1 20-1.4.r 21-1.2.1.1.1 23-1.2.2.1.1 25-1.2 25-1.2.3 25-1.2.3.r 26-1.2.1.1.1 27-1.2 27-1.2.3 27-1.2.3.r 28-1.2.2.1.1 30-1.3 31-1.3.2.1.2.1.1 31-1.3.2.2.2.1.1 31-1.3.2.3.2.1.1 33-1.3.2.1.2.1.1 35-1.3.2.1.2.1.1 35-1.3.2.2.2.1.1 35-1.3.2.3.2.1.1 37-1.3.2.2.2.1.1 38-1.3.2 39-1.3.2.1.2.1.1 39-1.3.2.2.2.1.1 39-1.3.2.3.2.1.1 41-1.3.2.3.2.1.1 42-1.3.2.4 43-1.3.2.1.1 44-1.3.2.1 44-1.3.2.2 44-1.3.2.3 45-1.3.4 45-1.3.4.r 46-1.3.3.r 47-1.3.3.1 48-1.3.3.2 (u / use-01~e.20 :ARG0 (w / we~e.19) :ARG1 (a / and~e.10,25,27 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.21,26)) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"~e.23,28)) :op3~e.10,25,27 (a5 / and~e.10,25,27 :op1 s :op2 s2)) :ARG2 (t / treat-04~e.30 :ARG0 w :ARG1 (a2 / and~e.38 :op1 (m / model~e.44 :mod (t3 / tumor~e.43) :mod (c / cell-line :name (n3 / name :op1 "NCI-H1993"~e.31,33,35,39))) :op2 (m2 / model~e.44 :mod t3 :mod (c2 / cell-line :name (n4 / name :op1 "NCI-H1975"~e.31,35,37,39))) :op3 (m3 / model~e.44 :mod t3 :mod (c3 / cell-line :name (n5 / name :op1 "NCI-H460"~e.31,35,39,41))) :mod (s3 / subcutaneous~e.42)) :duration~e.46 (t2 / temporal-quantity :quant 3~e.47 :unit (w2 / week~e.48)) :manner~e.45 (r / respective~e.45)) :purpose~e.0,1,2,20 (i2 / investigate-01~e.3 :ARG0 w :ARG1 (a3 / affect-01~e.7 :ARG0~e.8 (a4 / and-or~e.10,12 :op1 s~e.9 :op2 s2~e.13) :ARG1 (i / inhibit-01~e.6 :ARG1 (g / grow-01~e.5 :ARG1 t3~e.4)) :manner (i3 / in-vivo~e.15,16)))) # ::id pmid_2493_9055.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As shown in Figure 3 @ A @-@ C , treatment with AZD6244 for 3 weeks was able to inhibit tumor growth of NCI @-@ H1993 ( T/C value 40 %) , but slightly inhibit tumor growth in both NCI @-@ H1975 and NCI @-@ H460 subcutaneous tumor models ( T/C values 60 % and 65 %) , whereas BEZ235 treatment caused an approximately 50 % reduction in tumor growth in all three subcutaneous tumor models . # ::alignments 1-1.3 3-1.3.1.1 3-1.3.1.2 3-1.3.1.3 5-1.2.2.3.1 11-1.1.1.1.1 11-1.2.1 12-1.1.1.1.1.1.r 13-1.1.1.1.1.1.1.1 15-1.2.2.3.1 18-1.1.1 20-1.1.1.1 21-1.1.1.1.2.1 22-1.1.1.1.2 23-1.1.1.1.2.2.r 24-1.1.1.1.2.2.1.1 26-1.1.1.1.2.2.1.1 29-1.1.2.4.1.1 30-1.1.1.1.3.1.1.1 33-1.1 34-1.1.2.2 35-1.1.2 36-1.1.2.1.1 37-1.1.2.1 40-1.1.2.3.1.2.1.1 42-1.1.2.3.1.2.1.1 43-1.1.2.3 44-1.1.2.3.1.2.1.1 44-1.1.2.3.2.2.1.1 46-1.1.2.3.2.2.1.1 47-1.1.2.3.3 48-1.1.1.1.2.1 49-1.1.2.3.1 49-1.1.2.3.2 52-1.1.1.1.3.1 52-1.1.2.4.1.1 52-1.1.2.4.1.2 53-1.1.2.4.1.1.1.1 54-1.1.1.1.3.1.1 54-1.1.2.4.1.1.1 54-1.1.2.4.1.2.1 55-1.1.2.4.1 56-1.1.2.4.1.2.1.1 59-1 60-1.2.1.1.1.1 61-1.2.1 62-1.2 64-1.2.2.2 65-1.2.2.2.1.1 66-1.2.2.2.1 67-1.2.2 68-1.2.2.1.r 69-1.2.2.1.1 70-1.2.2.1 72-1.2.2.3.4 73-1.2.2.3.1 74-1.2.2.3.2 75-1.2.2.3.3 76-1.2.2.3 (c7 / contrast-01~e.59 :ARG1 (c3 / contrast-01~e.33 :ARG1 (p6 / possible-01~e.18 :ARG1 (i / inhibit-01~e.20 :ARG0 (t2 / treat-04~e.11 :ARG2~e.12 (s / small-molecule :name (n / name :op1 "AZD6244"~e.13))) :ARG1 (g / grow-01~e.22 :ARG1 (t3 / tumor~e.21,48) :location~e.23 (c2 / cell-line :name (n2 / name :op1 "NCI-H1993"~e.24,26))) :ARG1-of (m / mean-01 :ARG2 (v / value-01~e.52 :ARG2 (p / percentage-entity~e.54 :value 40~e.30))))) :ARG2 (i2 / inhibit-01~e.35 :ARG1 (g2 / grow-01~e.37 :ARG1 t3~e.36) :degree (s3 / slight~e.34) :location (a / and~e.43 :op1 (m2 / model~e.49 :mod t3 :location (c4 / cell-line :name (n3 / name :op1 "NCI-H1975"~e.40,42,44))) :op2 (m3 / model~e.49 :mod t3 :location (c5 / cell-line :name (n4 / name :op1 "NCI-H460"~e.44,46))) :mod (s2 / subcutaneous~e.47)) :ARG1-of (m4 / mean-01 :ARG2 (a2 / and~e.55 :op1 (v2 / value-01~e.29,52 :ARG2 (p2 / percentage-entity~e.54 :value 60~e.53)) :op2 (v3 / value-01~e.52 :ARG2 (p3 / percentage-entity~e.54 :value 65~e.56)))))) :ARG2 (c6 / cause-01~e.62 :ARG0 (t4 / treat-04~e.11,61 :ARG2 (s5 / small-molecule :name (n5 / name :op1 "BEZ235"~e.60))) :ARG1 (r / reduce-01~e.67 :ARG1~e.68 (g3 / grow-01~e.70 :ARG1 t3~e.69) :ARG2 (a3 / approximately~e.64 :op1 (p4 / percentage-entity~e.66 :value 50~e.65)) :location (m5 / model~e.76 :quant 3~e.5,15,73 :mod s2~e.74 :mod t3~e.75 :mod (a4 / all~e.72)))) :ARG1-of (s6 / show-01~e.1 :ARG0 (a5 / and :op1 (f / figure~e.3 :mod "3A") :op2 (f2 / figure~e.3 :mod "3B") :op3 (f3 / figure~e.3 :mod "3C")))) # ::id pmid_2493_9055.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , the combined treatments with the two drugs almost completely inhibited NCI @-@ H1993 , NCI @-@ H1975 and NCI @-@ H460 tumor growth at the end of the 3 weeks of therapy ( Figure 3 @ A @-@ D ) . # ::alignments 1-1 4-1.1.1.1 5-1.1.1 6-1.1.1.1.1.r 8-1.1.1.1.1.1 9-1.1.1.1.1 10-1.1.3.1 11-1.1.3 12-1.1 13-1.1.2.1.1.1.1 13-1.1.2.2.1.1.1 13-1.1.2.3.1.1.1 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 17-1.1.2.2.1.1.1 17-1.1.2.3.1.1.1 19-1.1.2.2.1.1.1 20-1.1.2 21-1.1.2.1.1.1.1 21-1.1.2.2.1.1.1 21-1.1.2.3.1.1.1 23-1.1.2.3.1.1.1 24-1.1.2.1.2 25-1.1.2.1 25-1.1.2.2 25-1.1.2.3 26-1.1.4.r 28-1.1.4 29-1.1.4.1.r 31-1.1.4.1.1.1 32-1.1.4.1.1.2 34-1.1.4.1 36-1.2.1.1 36-1.2.1.2 36-1.2.1.3 36-1.2.1.4 38-1.1.4.1.1.1 (c / contrast-01~e.1 :ARG2 (i / inhibit-01~e.12 :ARG0 (t4 / treat-04~e.5 :ARG1-of (c6 / combine-01~e.4 :ARG2~e.6 (d2 / drug~e.9 :quant 2~e.8))) :ARG1 (a2 / and~e.20 :op1 (g / grow-01~e.25 :ARG0 (c3 / cell-line :name (n / name :op1 "NCI-H1993"~e.13,15,17,21)) :ARG1 (t3 / tumor~e.24)) :op2 (g2 / grow-01~e.25 :ARG0 (c4 / cell-line :name (n2 / name :op1 "NCI-H1975"~e.13,17,19,21)) :ARG1 t3) :op3 (g3 / grow-01~e.25 :ARG0 (c5 / cell-line :name (n3 / name :op1 "NCI-H460"~e.13,17,21,23)) :ARG1 t3)) :ARG1-of (c2 / complete-02~e.11 :degree (a / almost~e.10)) :time~e.26 (e / end-01~e.28 :ARG1~e.29 (t2 / therapy~e.34 :duration (t / temporal-quantity :quant 3~e.31,38 :unit (w / week~e.32))))) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f / figure~e.36 :mod "3A") :op2 (f2 / figure~e.36 :mod "3B") :op3 (f3 / figure~e.36 :mod "3C") :op4 (f4 / figure~e.36 :mod "3D")))) # ::id pmid_2493_9055.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Single agent and combination treatment protocols were well tolerated by mice , with no weight loss or other signs of acute or delayed toxicity ( Figure 4 @ A @-@ C ) . # ::alignments 0-1.2.1.1.1.1 1-1.2.1.1.1 2-1.2 3-1.2.2.1.1 4-1.2.1.1 4-1.2.2.1 5-1.2.1 5-1.2.2 7-1.3 8-1 9-1.1.r 10-1.1 12-1.1.1.r 13-1.1.1.1 13-1.1.1.1.r 14-1.1.1.2 15-1.1.1 16-1.1.2.1 17-1.1.2.2 18-1.1.2 20-1.1.2.1.1.1 21-1.1.2.1 22-1.1.2.1.2.1 23-1.1.2.1.1 23-1.1.2.1.2 25-1.4.1.1 25-1.4.1.2 25-1.4.1.3 (t / tolerate-01~e.8 :ARG0~e.9 (m / mouse~e.10 :ARG0-of~e.12 (l / lose-02~e.15 :polarity~e.13 -~e.13 :ARG1 (w / weight~e.14)) :ARG0-of (s / signal-07~e.18 :ARG1 (o3 / or~e.16,21 :op1 (t2 / toxicity~e.23 :mod (a2 / acute~e.20)) :op2 (t3 / toxicity~e.23 :ARG1-of (d / delay-01~e.22))) :mod (o2 / other~e.17))) :ARG1 (a / and~e.2 :op1 (p / protocol~e.5 :topic (t4 / treat-04~e.4 :ARG2 (a3 / agent~e.1 :ARG1-of (s2 / single-02~e.0)))) :op2 (p2 / protocol~e.5 :topic (t5 / treat-04~e.4 :ARG1-of (c / combine-01~e.3)))) :manner (w2 / well~e.7) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.25 :mod "4A") :op2 (f2 / figure~e.25 :mod "4B") :op3 (f3 / figure~e.25 :mod "4C")))) # ::id pmid_2493_9055.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effect of MEK and PIK3 @/@ mTOR inhibitors on signaling transduction pathways in gefitinib @-@ resistant NSCLC tumor models # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1.1.1 4-1.1 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 8-1.1.1 8-1.1.1.1 8-1.1.1.1.r 8-1.1.2 8-1.1.2.1 8-1.1.2.1.r 9-1.2.r 10-1.2.3 11-1.2.1 12-1.2 13-1.2.2.r 14-1.2.2.2.1.1.1 16-1.2.2.2 17-1.2.2.1.1.1.1 18-1.2.2.1 19-1.2.2 (a / affect-01~e.1 :ARG0~e.2 (a2 / and~e.4 :op1 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.8 (i2 / inhibit-01~e.8 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"~e.3)))) :op2 (m / molecular-physical-entity~e.8 :ARG0-of~e.8 (i / inhibit-01~e.8 :ARG1 (p / pathway :name (n2 / name :op1 "PIK3/mTOR"~e.5,7))))) :ARG1~e.9 (p3 / pathway~e.12 :ARG2-of (t / transduce-01~e.11) :location~e.13 (m4 / model~e.19 :mod (t2 / tumor~e.18 :mod (d / disease :name (n4 / name :op1 "NSCLC"~e.17))) :ARG0-of (r / resist-01~e.16 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "gefitinib"~e.14)))) :ARG0-of (s / signal-07~e.10))) # ::id pmid_2493_9055.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the impact of both compounds on downstream molecules of the MEK and PI3K pathways , we used Western blot analysis to observe phosphorylation status and total protein expression in tumor tissues . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.1.r 5-1.4.2.1.1 6-1.4.2.1 7-1.4.2.2.r 8-1.4.2.2.1 9-1.4.2.2 10-1.4.2.2.2.r 12-1.4.2.2.2.1.1.1 13-1.4.2.2.2 14-1.4.2.2.2.2.1.1 15-1.4.2.2.2.1 15-1.4.2.2.2.2 17-1.1 18-1 18-1.4.r 19-1.2.1 20-1.2.1 21-1.2 23-1.3 24-1.3.2.1.1 25-1.3.2.1 26-1.3.2 27-1.3.2.2.3 28-1.3.2.2.1 29-1.3.2.2 30-1.3.2.2.2.r 31-1.3.2.2.2.1 32-1.3.2.2.2 (u / use-01~e.18 :ARG0 (w / we~e.17) :ARG1 (a / analyze-01~e.21 :mod (i2 / immunoblot-01~e.19,20)) :ARG2 (o / observe-01~e.23 :ARG0 w :ARG1 (a2 / and~e.26 :op1 (s / status~e.25 :mod (p / phosphorylate-01~e.24)) :op2 (e / express-03~e.29 :ARG2 (p2 / protein~e.28) :ARG3~e.30 (t / tissue~e.32 :source (t2 / tumor~e.31)) :ARG1-of (t3 / total-01~e.27)))) :purpose~e.18 (a3 / assess-01~e.1 :ARG0 w :ARG1 (i / impact-01~e.3 :ARG0~e.4 (c / compound~e.6 :mod (b / both~e.5)) :ARG1~e.7 (m / molecule~e.9 :direction (d / downstream~e.8) :source~e.10 (a4 / and~e.13 :op1 (p3 / pathway~e.15 :name (n2 / name :op1 "MEK"~e.12)) :op2 (p4 / pathway~e.15 :name (n3 / name :op1 "PI3K"~e.14))))))) # ::id pmid_2493_9055.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed that p @-@ MEK1 @/@ 2 , p @-@ ERK1 @/@ 2 , p @-@ AKT , p @-@ S6 and p @-@ 4E @-@ BP1 appeared to be inhibited by AZD6244 and BEZ235 combination treatment , whereas the total protein levels of MEK1 @/@ 2 , ERK1 @/@ 2 , AKT , S6 and 4E @-@ BP1 remained unchanged in each tumor model ( Figure 5 ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.1.1.2.1.2 6-1.2.1.1.2.1.1.1 8-1.2.1.1.2.1.1.1 10-1.2.1.1.2.2.2 12-1.2.1.1.2.2.1.1 14-1.2.1.1.2.1.1.1 14-1.2.1.1.2.2.1.1 16-1.2.1.1.2.3.2 18-1.2.1.1.2.3.1.1 20-1.2.1.1.2.4.2 22-1.2.1.1.2.4.1.1 23-1.2.1.1.2 24-1.2.1.1.2.5.2 26-1.2.1.1.2.5.1.1 28-1.2.1.1.2.5.1.1 29-1.2.1 32-1.2.1.1 33-1.2.1.1.1.r 34-1.2.1.1.1.1.1.1.1 36-1.2.1.1.1.1.2.1.1 37-1.2.1.1.1.1 38-1.2.1.1.1 40-1.2 43-1.2.1.1.2.4 43-1.2.1.1.2.5 44-1.2.2.1.1 44-1.2.2.1.2 44-1.2.2.1.3 44-1.2.2.1.4 44-1.2.2.1.5 46-1.2.1.1.2.1.1.1 48-1.2.1.1.2.1.1.1 48-1.2.1.1.2.2.1.1 50-1.2.1.1.2.2.1.1 52-1.2.1.1.2.1.1.1 52-1.2.1.1.2.2.1.1 54-1.2.1.1.2.3.1.1 56-1.2.1.1.2.4.1.1 58-1.2.1.1.2.5.1.1 60-1.2.1.1.2.5.1.1 61-1.2.2 62-1.2.2.3 62-1.2.2.3.1 62-1.2.2.3.1.r 65-1.2.2.2.1 66-1.2.2.2 68-1.3.1 70-1.3.1.1 (s2 / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (c2 / contrast-01~e.40 :ARG1 (a / appear-01~e.29 :ARG1 (i / inhibit-01~e.32 :ARG0~e.33 (t2 / treat-04~e.38 :ARG0-of (c / combine-01~e.37 :ARG1 (s4 / small-molecule :name (n8 / name :op1 "AZD6244"~e.34)) :ARG2 (s3 / small-molecule :name (n7 / name :op1 "BEZ235"~e.36)))) :ARG1 (a2 / and~e.23 :op1 (e / enzyme :name (n2 / name :op1 "MEK1/2"~e.6,8,14,46,48,52) :ARG3-of (p / phosphorylate-01~e.4)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"~e.12,14,48,50,52) :ARG1-of p~e.10) :op3 (e3 / enzyme :name (n4 / name :op1 "AKT"~e.18,54) :ARG1-of p~e.16) :op4 (p3 / protein~e.43 :name (n5 / name :op1 "S6"~e.22,56) :ARG1-of p~e.20) :op5 (p4 / protein~e.43 :name (n6 / name :op1 "4E-BP1"~e.26,28,58,60) :ARG1-of p~e.24)))) :ARG2 (r2 / remain-01~e.61 :ARG1 (a3 / and :op1 (l / level~e.44 :degree-of e) :op2 (l2 / level~e.44 :degree-of e2) :op3 (l3 / level~e.44 :degree-of e3) :op4 (l4 / level~e.44 :degree-of p3) :op5 (l5 / level~e.44 :degree-of p4)) :ARG2 (m / model~e.66 :mod (t3 / tumor~e.65)) :ARG3 (c3 / change-01~e.62 :polarity~e.62 -~e.62))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.68 :mod 5~e.70))) # ::id pmid_2493_9055.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis of downstream signals also showed treatment with AZD6244 or BEZ235 inhibited the phosphorylation of ERK1 @/@ 2 or AKT in all three tumor models respectively . # ::alignments 0-1.1.2 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.1 5-1.1.1 6-1.3 7-1 8-1.2.1 9-1.2.1.1.r 10-1.2.1.1.1.1.1 11-1.2.1.1 12-1.2.1.1.2.1.1 13-1.2 15-1.2.2 16-1.2.2.1.r 17-1.2.2.1.1.1.1 19-1.2.2.1.1.1.1 20-1.2.2.1 21-1.2.2.1.2.1.1 22-1.2.2.2.r 23-1.2.2.2.3 24-1.2.2.2.1 25-1.2.2.2.2 26-1.2.2.2 27-1.2.3 27-1.2.3.r (s / show-01~e.7 :ARG0 (a / analyze-01~e.2 :ARG1~e.3 (s2 / signal-07~e.5 :direction (d / downstream~e.4)) :mod (i2 / immunoblot-01~e.0,1)) :ARG1 (i / inhibit-01~e.13 :ARG0 (t / treat-04~e.8 :ARG2~e.9 (o / or~e.11 :op1 (s3 / small-molecule :name (n2 / name :op1 "AZD6244"~e.10)) :op2 (s4 / small-molecule :name (n3 / name :op1 "BEZ235"~e.12)))) :ARG1 (p / phosphorylate-01~e.15 :ARG1~e.16 (o2 / or~e.20 :op1 (e / enzyme :name (n4 / name :op1 "ERK1/2"~e.17,19)) :op2 (e2 / enzyme :name (n5 / name :op1 "AKT"~e.21))) :location~e.22 (m / model~e.26 :quant 3~e.24 :mod (t2 / tumor~e.25) :mod (a2 / all~e.23))) :manner~e.27 (r / respective~e.27)) :mod (a3 / also~e.6)) # ::id pmid_2493_9055.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , combined treatment with AZD6244 and BEZ235 showed greater inhibition of p @-@ ERK1 @/@ 2 and p @-@ AKT than observed in control group or mice treated with each compound alone in vivo ( Figure 5 ) . # ::alignments 0-1.1.1.1.1 1-1.1.1.1.1 3-1.1.1.1 4-1.1.1 5-1.1.1.1.1.r 6-1.1.1.1.1.1.1.1 8-1.1.1.1.1.2.1.1 9-1.1 10-1.1.2.2 10-1.1.2.2.1 10-1.1.2.2.1.r 11-1.1.2 11-1.1.2.2.2 12-1.1.2.1.r 13-1.1.2.1.1.2 15-1.1.2.1.1.1.1 17-1.1.2.1.1.1.1 19-1.1.2.1.1.2 21-1.1.2.1.2.1.1 22-1.1.2.2.2.r 23-1.1.2.2.2.1 24-1.1.2.2.2.1.1.2.1.2 24-1.1.2.2.2.1.1.r 25-1.1.2.2.2.1.1.1.1 26-1.1.2.2.2.1.1.1 27-1.1.2.2.2.1.1 28-1.1.2.2.2.1.1.2 29-1.1.2.2.2.1.1.2.1 30-1.1.2.2.2.1.1.2.1.1.r 31-1.1.2.2.2.1.1.2.1.1.1 32-1.1.2.2.2.1.1.2.1.1 33-1.1.2.2.2.1.1.2.1.1.2 35-1.1.2.2.2.1.1.2.1.2 36-1.1.2.2.2.1.1.2.1.2 39-1.2.1 41-1.2.1.1 (a / and :op2 (s2 / show-01~e.9 :ARG0 (t / treat-04~e.4 :ARG1-of (c / combine-01~e.3 :ARG2~e.5 (a2 / and~e.0,1 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.6)) :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235"~e.8))))) :ARG1 (i / inhibit-01~e.11 :ARG1~e.12 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1/2"~e.15,17) :ARG3-of (p / phosphorylate-01~e.13,19)) :op2 (e2 / enzyme :name (n4 / name :op1 "AKT"~e.21) :ARG1-of p)) :mod (g / great~e.10 :degree~e.10 (m / more~e.10) :compared-to~e.22 (i2 / inhibit-01~e.11 :ARG1-of (o / observe-01~e.23 :location~e.24 (o2 / or~e.27 :op1 (g2 / group~e.26 :ARG1-of (c3 / control-01~e.25)) :op2 (m2 / mouse~e.28 :ARG1-of (t2 / treat-04~e.29 :ARG2~e.30 (c4 / compound~e.32 :mod (e3 / each~e.31) :mod (a4 / alone~e.33)) :manner (i3 / in-vivo~e.24,35,36))))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.39 :mod 5~e.41))) # ::id pmid_2493_9055.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , the impact from both inhibitors on p @-@ S6 and p @-@ 4E @-@ BP1 levels was , alternatively , tumor model specific . # ::alignments 0-1.3 3-1.1 4-1.1.1.r 5-1.1.1.1 6-1.1.1 6-1.1.1.2 6-1.1.1.2.r 8-1.1.2.1.1.2 10-1.1.2.1.1.1.1 12-1.1.2.1.1.2 14-1.1.2.2.1.1.1 16-1.1.2.2.1.1.1 17-1.1.2.1 17-1.1.2.2 20-1.4 22-1.2.1 23-1.2 24-1 (s2 / specific-02~e.24 :ARG1 (i3 / impact-01~e.3 :ARG0~e.4 (m / molecular-physical-entity~e.6 :mod (b / both~e.5) :ARG0-of~e.6 (i2 / inhibit-01~e.6)) :ARG1 (a / and :op1 (l / level~e.17 :quant-of (p2 / protein :name (n / name :op1 "S6"~e.10) :ARG3-of (p / phosphorylate-01~e.8,12))) :op2 (l2 / level~e.17 :quant-of (p3 / protein :name (n2 / name :op1 "4E-BP1"~e.14,16) :ARG3-of p)))) :ARG2 (m2 / model~e.23 :mod (t / tumor~e.22)) :ARG2-of (i / interest-01~e.0) :mod (a2 / alternative~e.20)) # ::id pmid_2493_9055.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok For example , AZD6244 and BEZ235 alone and in combination markedly inhibited p @-@ S6 and p @-@ 4E @-@ BP1 expression levels in NCI @-@ H1993 tumor models , compared with the minimal suppression observed in NCI @-@ H460 tumor model ( Figure 5 ) . # ::alignments 0-1.3 1-1.3 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 6-1.1.3 7-1.1 7-1.1.1 7-1.1.1.r 9-1.1.2 10-1.4 10-1.4.r 11-1 12-1.2.1.1.1.2 14-1.2.1.1.1.1.1 16-1.2.1.1.1.2 18-1.2.2.1.1.1.1 20-1.2.2.1.1.1.1 21-1.2.1.1 21-1.2.2.1 22-1.2.1 22-1.2.2 23-1.2.2.1.2.r 24-1.2.2.1.2.1.1.1.1 26-1.2.2.1.2.1.1.1.1 27-1.2.2.1.2.1 28-1.2.2.1.2 30-1.5.r 33-1.5.2 34-1.5 35-1.5.1 36-1.5.1.1.r 37-1.5.1.1.2.1.1 39-1.5.1.1.2.1.1 40-1.5.1.1.1 41-1.5.1.1 43-1.6.1 45-1.6.1.1 (i / inhibit-01~e.11 :ARG0 (a / and~e.7 :op1~e.7 (a2 / and~e.4,7 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.3)) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"~e.5))) :op2 (c / combine-01~e.9 :ARG1 s :ARG2 s2) :mod (a4 / alone~e.6)) :ARG1 (a3 / and :op1 (l / level~e.22 :degree-of (e2 / express-03~e.21 :ARG2 (p2 / protein :name (n3 / name :op1 "S6"~e.14) :ARG3-of (p / phosphorylate-01~e.12,16)) :ARG3 m2)) :op2 (l2 / level~e.22 :degree-of (e3 / express-03~e.21 :ARG2 (p3 / protein :name (n4 / name :op1 "4E-BP1"~e.18,20) :ARG1-of p :ARG3-of p) :ARG3~e.23 (m2 / model~e.28 :mod (t / tumor~e.27 :mod (c3 / cell-line :name (n5 / name :op1 "NCI-H1993"~e.24,26))))))) :ARG0-of (e / exemplify-01~e.0,1) :manner~e.10 (m / marked~e.10) :compared-to~e.30 (s3 / suppress-01~e.34 :ARG1-of (o / observe-01~e.35 :location~e.36 (m4 / model~e.41 :mod t~e.40 :mod (c2 / cell-line :name (n6 / name :op1 "NCI-H460"~e.37,39)))) :degree (m3 / minimal~e.33)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.43 :mod 5~e.45))) # ::id pmid_2493_9055.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neither AZD6244 nor BEZ235 alone suppressed p @-@ S6 and p @-@ 4E @-@ BP1 in NCI @-@ H1975 tumor model . # ::alignments 0-1.1.r 1-1.2.1.1.1 2-1.1 2-1.1.r 3-1.2.2.1.1 4-1.2.3 5-1 6-1.3.1.2 8-1.3.1.1.1 10-1.3.1.2 12-1.3.2.1.1 14-1.3.2.1.1 15-1.4.r 16-1.4.2.1.1 18-1.4.2.1.1 19-1.4.1 20-1.4 (s / suppress-01~e.5 :polarity~e.0,2 -~e.2 :ARG0 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"~e.1)) :op2 (s3 / small-molecule :name (n / name :op1 "BEZ235"~e.3)) :mod (a3 / alone~e.4)) :ARG1 (a2 / and :op1 (p2 / protein :name (n4 / name :op1 "S6"~e.8) :ARG3-of (p / phosphorylate-01~e.6,10)) :op2 (p3 / protein :name (n5 / name :op1 "4E-BP1"~e.12,14) :ARG1-of p)) :location~e.15 (m2 / model~e.20 :mod (t / tumor~e.19) :mod (c / cell-line :name (n3 / name :op1 "NCI-H1975"~e.16,18)))) # ::id pmid_2493_9055.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also found that the expression of MMP @-@ 9 was significantly inhibited by AZD6244 and BEZ235 combination treatment , whereas the expression of MMP @-@ 2 was not affected by the treatment . # ::alignments 0-1.1 1-1.3 2-1 3-1.2.r 5-1.2.1.2 6-1.2.1.2.1.r 7-1.2.1.2.1.1.1 9-1.2.1.2.1.1.1 11-1.2.1.3 12-1.2.1 13-1.2.1.1.r 14-1.2.1.1.1.1.1.1 16-1.2.1.1.1.2.1.1 17-1.2.1.1.1 18-1.2.1.1 20-1.2 22-1.2.2.3 23-1.2.2.3.1.r 24-1.2.2.3.1.1.1 26-1.2.2.3.1.1.1 28-1.2.2.1 28-1.2.2.1.r 29-1.2.2 30-1.2.2.2.r 32-1.2.2.2 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1~e.3 (c / contrast-01~e.20 :ARG1 (i / inhibit-01~e.12 :ARG0~e.13 (t2 / treat-04~e.18 :ARG2 (c2 / combine-01~e.17 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "AZD6244"~e.14)) :ARG2 (s3 / small-molecule :name (n4 / name :op1 "BEZ235"~e.16)))) :ARG1 (e3 / express-03~e.5 :ARG2~e.6 (e4 / enzyme :name (n2 / name :op1 "MMP-9"~e.7,9))) :ARG1-of (s / significant-02~e.11)) :ARG2 (a2 / affect-01~e.29 :polarity~e.28 -~e.28 :ARG0~e.30 t2~e.32 :ARG1 (e / express-03~e.22 :ARG2~e.23 (e2 / enzyme :name (n / name :op1 "MMP-2"~e.24,26))))) :mod (a / also~e.1)) # ::id pmid_2493_9055.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Effect of MEK and PIK3 @/@ mTOR inhibitors on the expressions of Ki @-@ 67 and CD31 in gefitinib @-@ resistant NSCLC tumor models # ::alignments 1-1 2-1.1.r 3-1.1.1.1.1.1.1 4-1.1 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 8-1.1.1 8-1.1.1.1 8-1.1.1.1.r 8-1.1.2 8-1.1.2.1 8-1.1.2.1.r 9-1.2.r 11-1.2.1 11-1.2.2 12-1.2.1.1.r 13-1.2.1.1.1.1 15-1.2.1.1.1.1 16-1.2 17-1.2.2.1.1.1 18-1.2.1.2.r 19-1.2.1.2.2.1.1.1 21-1.2.1.2.2 22-1.2.1.2.1.1.1.1 23-1.2.1.2.1 24-1.2.1.2 (a / affect-01~e.1 :ARG0~e.2 (a2 / and~e.4 :op1 (m3 / molecular-physical-entity~e.8 :ARG0-of~e.8 (i / inhibit-01~e.8 :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK"~e.3)))) :op2 (m2 / molecular-physical-entity~e.8 :ARG0-of~e.8 (i2 / inhibit-01~e.8 :ARG1 (p / pathway :name (n3 / name :op1 "PIK3/mTOR"~e.5,7))))) :ARG1~e.9 (a3 / and~e.16 :op1 (e / express-03~e.11 :ARG2~e.12 (p2 / protein :name (n4 / name :op1 "Ki-67"~e.13,15)) :ARG3~e.18 (m / model~e.24 :mod (t / tumor~e.23 :mod (d / disease :name (n / name :op1 "NSCLC"~e.22))) :ARG0-of (r / resist-01~e.21 :ARG1 (s / small-molecule :name (n6 / name :op1 "gefitinib"~e.19))))) :op3 (e2 / express-03~e.11 :ARG1 (p3 / protein :name (n5 / name :op1 "CD31"~e.17)) :ARG3 m))) # ::id pmid_2493_9055.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To characterize the mechanism of tumor growth inhibition observed in our gefitinib @-@ resistant NSCLC tumor models by AZD6244 and BEZ235 , lung tumor tissues were assessed by evaluating Ki @-@ 67 expression using immunohistochemical analyses . # ::alignments 1-1.4 3-1.4.1 4-1.4.1.2.r 5-1.4.1.2.1.1 6-1.4.1.2.1 7-1.4.1.2 8-1.4.1.1 9-1.4.1.1.2.r 10-1.4.1.1.2.3 10-1.4.1.1.2.3.r 11-1.4.1.1.2.1.1.1.1 13-1.4.1.1.2.1 14-1.4.1.1.2.2.1.1.1 15-1.4.1.1.2.2 16-1.4.1.1.2 17-1.4.1.1.1.r 18-1.4.1.1.1.1.1.1 19-1.4.1.1.1 20-1.4.1.1.1.2.1.1 22-1.1.1.1 23-1.1.1 24-1.1 26-1 27-1.2.r 28-1.2 29-1.2.1.1.1.1 31-1.2.1.1.1.1 32-1.2.1 33-1.3 33-1.4.r 34-1.3.1.1 35-1.3.1 (a / assess-01~e.26 :ARG1 (t / tissue~e.24 :source (t2 / tumor~e.23 :part-of (l / lung~e.22))) :manner~e.27 (e / evaluate-01~e.28 :ARG1 (e2 / express-03~e.32 :ARG2 (p / protein :name (n / name :op1 "Ki-67"~e.29,31)))) :manner (u / use-01~e.33 :ARG1 (a2 / analyze-01~e.35 :mod (i / immunohistochemical~e.34))) :purpose~e.33 (c / characterize-01~e.1 :ARG1 (m / mechanism~e.3 :ARG1-of (o / observe-01~e.8 :ARG0~e.17 (a3 / and~e.19 :op1 (s / small-molecule :name (n3 / name :op1 "AZD6244"~e.18)) :op2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235"~e.20))) :location~e.9 (m2 / model~e.16 :ARG0-of (r / resist-01~e.13 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "gefitinib"~e.11))) :mod (t4 / tumor~e.15 :mod (d / disease :name (n5 / name :op1 "NSCLC"~e.14))) :poss~e.10 (w / we~e.10))) :instrument-of~e.4 (i2 / inhibit-01~e.7 :ARG1 (g / grow-01~e.6 :ARG1 (t3 / tumor~e.5)))))) # ::id pmid_2493_9055.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We observed active cell proliferation in NCI @-@ H1993 tumor model , with a 56 % proliferation index ( Figure 6 @ A ) . # ::alignments 0-1.1 1-1 2-1.2.2 3-1.2.1 4-1.2 6-1.2.3.2.1.1 9-1.2.3.1 10-1.2.3 14-1.2.4.1.1 15-1.2.4.1 16-1.2 17-1.2.4 19-1.3.1 (o / observe-01~e.1 :ARG0 (w / we~e.0) :ARG1 (p2 / proliferate-01~e.4,16 :ARG0 (c / cell~e.3) :ARG0-of (a / activity-06~e.2) :location (m / model~e.10 :mod (t / tumor~e.9) :mod (c2 / cell-line :name (n / name :op1 "NCI-H199"~e.6))) :ARG1-of (i / index-01~e.17 :ARG2 (p / percentage-entity~e.15 :value 56~e.14))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "6A"))) # ::id pmid_2493_9055.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Monotherapy with AZD6244 or BEZ235 slightly decreased the percentage of Ki @-@ 67 @-@ positive proliferating tumor tissues , with proliferation indices of 42 % and 39 % , respectively ( Figure 6 @ A ) . # ::alignments 0-1.1 1-1.1.1.r 2-1.1.1.1.1.1 4-1.1.1.2.1.1 5-1.3 6-1 8-1.2 9-1.2.1.r 10-1.2.1.3.1.1 12-1.2.1.3.1.1 14-1.2.1.3.2 15-1.2.1.2 16-1.2.1.1 17-1.2.1 19-1.1.1.r 20-1.2.1.2 21-1.2.1.4.1.1 21-1.2.1.4.1.2 22-1.2.1.4.1.1.2.r 23-1.2.1.4.1.1.2.1 24-1.2.1.4.1.1.2 25-1.2.1.4.1 26-1.2.1.4.1.2.2.1 27-1.2.1.4.1.2.2 31-1.4.1 (d / decrease-01~e.6 :ARG0 (m / monotherapy~e.0 :instrument~e.1,19 (a / and :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.2)) :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235"~e.4)))) :ARG1 (p3 / percentage~e.8 :quant-of~e.9 (t / tissue~e.17 :source (t2 / tumor~e.16) :ARG0-of (p5 / proliferate-01~e.15,20) :mod (p4 / protein :name (n3 / name :op1 "Ki-67"~e.10,12) :mod (p6 / positive~e.14)) :ARG0-of (h / have-03 :ARG1 (a2 / and~e.25 :op1 (i / index~e.21 :mod p5 :mod~e.22 (p / percentage-entity~e.24 :value 42~e.23)) :op2 (i2 / index~e.21 :mod p5 :mod (p2 / percentage-entity~e.27 :value 39~e.26)))))) :degree (s2 / slight~e.5) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "6A"))) # ::id pmid_2493_9055.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Combined treatment with AZD6244 and BEZ235 markedly decreased the percentage of Ki @-@ 67 @-@ positive proliferating tumor tissues to 10 % , consistent with the marked inhibition of ERK1 @/@ 2 and AKT phosphorylation . # ::alignments 0-1.1.1 1-1.1 2-1.1.1.1.r 3-1.1.1.1.1.1.1 4-1.1.1.1 5-1.1.1.1.2.1.1 6-1.3 7-1 9-1.2 10-1.2.1.r 11-1.2.1.3.1.1 13-1.2.1.3.1.1 15-1.2.1.3.2 16-1.2.1.2 17-1.2.1.1 18-1.2.1 19-1.4.r 20-1.4.1 21-1.4 23-1.5 24-1.5.1.r 26-1.5.1.2 27-1.5.1 28-1.5.1.1.r 29-1.5.1.1.1.1.1.1 31-1.5.1.1.1.1.1.1 32-1.5.1.1 33-1.5.1.1.2.1.1.1 34-1.5.1.1.1 34-1.5.1.1.2 (d / decrease-01~e.7 :ARG0 (t / treat-04~e.1 :ARG1-of (c2 / combine-01~e.0 :ARG2~e.2 (a2 / and~e.4 :op1 (s / small-molecule :name (n3 / name :op1 "AZD6244"~e.3)) :op2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235"~e.5))))) :ARG1 (p3 / percentage~e.9 :quant-of~e.10 (t2 / tissue~e.18 :source (t3 / tumor~e.17) :ARG0-of (p4 / proliferate-01~e.16) :mod (p5 / protein :name (n5 / name :op1 "Ki-67"~e.11,13) :mod (p7 / positive~e.15)))) :ARG2 (m / marked~e.6) :ARG4~e.19 (p6 / percentage-entity~e.21 :value 10~e.20) :ARG1-of (c / consistent-01~e.23 :ARG2~e.24 (i / inhibit-01~e.27 :ARG1~e.28 (a / and~e.32 :op1 (p / phosphorylate-01~e.34 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.29,31))) :op2 (p2 / phosphorylate-01~e.34 :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT"~e.33)))) :degree m~e.26))) # ::id pmid_2493_9055.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also found the similar results in NCI @-@ H1975 and NCI @-@ H460 tumor models ( Figure 6 @ A ) .To evaluate the potential antiangiogenic mechanism of AZD6244 and BEZ235 , gefitinib @-@ resistant NSCLC tumor tissues were analyzed by immunostaining for CD31 ( platelet endothelial cell adhesion molecule 1 ) . # ::alignments 0-1.1.1 1-1.1.4 2-1.1 4-1.1.2.2 5-1.1.2 5-1.1.2.1 5-1.1.2.1.r 6-1.1.5.r 7-1.1.5.1.2.1.1 7-1.1.5.2.2.1.1 9-1.1.5.1.2.1.1 10-1.1.5 11-1.1.5.1.2.1.1 11-1.1.5.2.2.1.1 13-1.1.5.2.2.1.1 14-1.1.5.1.1 15-1.1.5.1 15-1.1.5.2 17-1.1.3.1 24-1.2.3 26-1.2.3.1.2.1.1 28-1.2.3.1 29-1.2.3.1.1.r 30-1.2.3.1.1.1.1.1 31-1.2.3.1.1 32-1.2.3.1.1.2.1.1 34-1.2.2.3.1.1.1 36-1.2.2.3 37-1.2.2.2.1.1 38-1.2.2.1 39-1.2.2 41-1.2 42-1.2.1.r 43-1.2.1 44-1.2.1.1.r 45-1.2.1.1.1.1 49-1.1.5.1.2 49-1.1.5.2.2 51-1.2.2.3.1 51-1.2.3.1.1.1 51-1.2.3.1.1.2 (m / multi-sentence :snt1 (f / find-01~e.2 :ARG0 (w / we~e.0) :ARG1 (t / thing~e.5 :ARG2-of~e.5 (r / result-01~e.5) :ARG1-of (r2 / resemble-01~e.4)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure~e.17 :mod "6A")) :mod (a / also~e.1) :location~e.6 (a2 / and~e.10 :op1 (m2 / model~e.15 :mod (t2 / tumor~e.14) :mod (c / cell-line~e.49 :name (n2 / name :op1 "NCI-H1975"~e.7,9,11))) :op2 (m3 / model~e.15 :mod t2 :mod (c2 / cell-line~e.49 :name (n / name :op1 "NCI-H460"~e.7,11,13))))) :snt2 (a3 / analyze-01~e.41 :ARG0~e.42 (i / immunostain-01~e.43 :ARG3~e.44 (p / protein :name (n3 / name :op1 "CD31"~e.45))) :ARG1 (t3 / tissue~e.39 :source (t4 / tumor~e.38) :mod (d2 / disease :name (n4 / name :op1 "NSCLC"~e.37)) :ARG0-of (r3 / resist-01~e.36 :ARG1 (s3 / small-molecule~e.51 :name (n7 / name :op1 "gefitinib"~e.34)))) :purpose (e / evaluate-01~e.24 :ARG1 (m4 / mechanism~e.28 :poss~e.29 (a4 / and~e.31 :op1 (s / small-molecule~e.51 :name (n5 / name :op1 "AZD6244"~e.30)) :op2 (s2 / small-molecule~e.51 :name (n6 / name :op1 "BEZ235"~e.32))) :ARG0-of (c3 / counter-01 :ARG1 (a5 / angiogenesis :mod (p2 / potential~e.26))))))) # ::id pmid_2493_9055.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed BEZ235 significantly decreased the vascular density of all three gefitinib @-@ resistant NSCLC tumors , whereas AZD6244 monotherapy had only a mildly effect upon lung tumor angiogenesis . # ::alignments 1-1.1.1 1-1.1.1.1 1-1.1.1.1.r 2-1.1 3-1.1.2.1.1.1 4-1.1.2.5 5-1.1.2 7-1.1.2.3 8-1.1.2.2 11-1.1.2.4.1 12-1.1.2.4.3.1.1.1 14-1.1.2.4.3 15-1.1.2.4.2.1.1 16-1.1.2.4 18-1 19-1.2.1.1.1.1 20-1.2.1 22-1.2.4 24-1.2.3 24-1.2.3.r 25-1.2 27-1.2.2.1.1 28-1.2.2.1 29-1.2.2 (c / contrast-01~e.18 :ARG1 (s2 / show-01~e.2 :ARG0 (t2 / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1 (d / decrease-01~e.5 :ARG0 (s5 / small-molecule :name (n3 / name :op1 "BEZ235"~e.3)) :ARG1 (d2 / density~e.8) :mod (v / vessel~e.7) :location (t3 / tumor~e.16 :quant 3~e.11 :mod (d3 / disease :name (n / name :op1 "NSCLC"~e.15)) :ARG0-of (r2 / resist-01~e.14 :ARG1 (s / small-molecule :name (n4 / name :op1 "gefitinib"~e.12)))) :ARG1-of (s4 / significant-02~e.4))) :ARG2 (a / affect-01~e.25 :ARG0 (m2 / monotherapy~e.20 :mod (s3 / small-molecule :name (n2 / name :op1 "AZD6244"~e.19))) :ARG1 (a2 / angiogenesis~e.29 :mod (t / tumor~e.28 :source (l / lung~e.27))) :manner~e.24 (m / mild~e.24) :mod (o / only~e.22))) # ::id pmid_2493_9055.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The antiangiogenic effects AZD6244 and BEZ235 were markedly increased when they were combined ( Figure 6 @ B ) . # ::alignments 2-1.1 3-1.1.1.1.1.1 4-1.1.1 5-1.1.1.2.1.1 7-1.2 8-1 10-1.4.1 12-1.4 14-1.3.1 (i / increase-01~e.8 :ARG1 (a / affect-01~e.2 :ARG0 (a2 / and~e.4 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.3)) :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"~e.5))) :ARG0-of (c4 / counter-01 :ARG1 (a3 / angiogenesis))) :ARG2 (m / marked~e.7) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.14 :mod "6B")) :condition (c2 / combine-01~e.12 :ARG1 a2~e.10)) # ::id pmid_2493_9055.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK and PIK3 @/@ mTOR inhibitors had no effect on caspase @-@ 3 , 8 and 9 activities in gefitinib @-@ resistant NSCLC tumor models # ::alignments 1-1.2.1.1.1.1.1 2-1.2 3-1.2.2.1.1.1.1 5-1.2.2.1.1.1.1 6-1.2.1 6-1.2.1.1 6-1.2.1.1.r 6-1.2.2 6-1.2.2.1 6-1.2.2.1.r 8-1.1 8-1.1.r 9-1 11-1.3.1.1.1.1 11-1.3.2.1.1.1 11-1.3.3.1.1.1 13-1.3.1.1.1.2 15-1.3.2.1.1.2 16-1.3 17-1.3.3.1.1.2 18-1.3.1 18-1.3.2 18-1.3.3 19-1.3.r 20-1.3.4.2.1.1.1 22-1.3.4.2 23-1.3.4.1.1.1.1 24-1.3.4.1 25-1.3.4 (a / affect-01~e.9 :polarity~e.8 -~e.8 :ARG0 (a2 / and~e.2 :op1 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (i / inhibit-01~e.6 :ARG1 (p5 / protein-family :name (n / name :op1 "MEK"~e.1)))) :op2 (m2 / molecular-physical-entity~e.6 :ARG0-of~e.6 (i2 / inhibit-01~e.6 :ARG1 (p / pathway :name (n2 / name :op1 "PIK3/mTOR"~e.3,5))))) :ARG1~e.19 (a3 / and~e.16 :op1 (a4 / activity-06~e.18 :ARG0 (p2 / protein :name (n4 / name :op1 "Caspase"~e.11 :op2 3~e.13))) :op2 (a5 / activity-06~e.18 :ARG0 (p3 / protein :name (n5 / name :op1 "Caspase"~e.11 :op2 8~e.15))) :op3 (a6 / activity-06~e.18 :ARG0 (p4 / protein :name (n6 / name :op1 "Caspase"~e.11 :op2 9~e.17))) :location (m3 / model~e.25 :mod (t / tumor~e.24 :mod (d / disease :name (n3 / name :op1 "NSCLC"~e.23))) :ARG0-of (r / resist-01~e.22 :ARG1 (s / small-molecule :name (n7 / name :op1 "gefitinib"~e.20)))))) # ::id pmid_2493_9055.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to investigate whether AZD6244 and @/@ or BEZ235 would induce apoptosis in gefitinib @-@ resistant NSCLC tumor models , activity of caspase @-@ 3 , 8 and 9 were measured by the colorimetric assay . # ::alignments 0-1.3.r 1-1.3.r 2-1.3.r 3-1.3 4-1.3.1.1 4-1.3.1.1.r 5-1.3.1.2.1.1.1 6-1.3.1.2 8-1.3.1.2 9-1.3.1.2.2.1.1 11-1.3.1 12-1.3.1.3 13-1.3.1.4.r 14-1.3.1.4.2.1.1.1 16-1.3.1.4.2 17-1.3.1.4.1.1.1.1 18-1.3.1.4.1 19-1.3.1.4 23-1.2.1.1.1 23-1.2.2.1.1 23-1.2.3.1.1 25-1.2.1.1.2 27-1.2.2.1.2 28-1.2 29-1.2.3.1.2 31-1 32-1.1.r 34-1.1.1 35-1.1 (m / measure-01~e.31 :ARG0~e.32 (a / assay-01~e.35 :mod (c / colorimetric~e.34)) :ARG1 (a2 / and~e.28 :op1 (p / protein :name (n2 / name :op1 "Caspase"~e.23 :op2 3~e.25)) :op2 (p2 / protein :name (n3 / name :op1 "Caspase"~e.23 :op2 8~e.27)) :op3 (p3 / protein :name (n4 / name :op1 "Caspase"~e.23 :op2 9~e.29))) :purpose~e.0,1,2 (i / investigate-01~e.3 :ARG1 (i2 / induce-01~e.11 :mode~e.4 interrogative~e.4 :ARG0 (a3 / and-or~e.6,8 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.5)) :op2 (s2 / small-molecule :name (n5 / name :op1 "BEZ235"~e.9))) :ARG2 (a4 / apoptosis~e.12) :location~e.13 (m5 / model~e.19 :mod (t / tumor~e.18 :mod (d / disease :name (n6 / name :op1 "NSCLC"~e.17))) :ARG0-of (r / resist-01~e.16 :ARG1 (s3 / small-molecule :name (n7 / name :op1 "gefitinib"~e.14))))))) # ::id pmid_2493_9055.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The results showed that AZD6244 and @/@ or BEZ235 had no effect on caspase @-@ 3 , 8 and 9 activities in all three gefitinib @-@ resistant NSCLC tumor models ( Figure 7 ) . # ::alignments 1-1.1 1-1.1.1 1-1.1.1.r 2-1 3-1.2.r 4-1.2.2.1.1.1 7-1.2.2 8-1.2.2.2.1.1 10-1.2.1 10-1.2.1.r 11-1.2 13-1.2.3.1.1.1.1 13-1.2.3.2.1.1.1 13-1.2.3.3.1.1.1 15-1.2.3.1.1.1.2 15-1.2.3.4.1 17-1.2.3.2.1.1.2 18-1.2.3 19-1.2.3.3.1.1.2 20-1.2.3.1 20-1.2.3.2 20-1.2.3.3 21-1.2.3.r 22-1.2.3.4.4 23-1.2.3.4.1 24-1.2.3.4.3.1.1.1 26-1.2.3.4.3 27-1.2.3.4.2.1.1.1 28-1.2.3.4.2 29-1.2.3.4 31-1.3.1 33-1.3.1.1 (s2 / show-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (a / affect-01~e.11 :polarity~e.10 -~e.10 :ARG0 (a2 / and-or~e.7 :op1 (s / small-molecule :name (n / name :op1 "AZD6244"~e.4)) :op2 (s3 / small-molecule :name (n3 / name :op1 "BEZ235"~e.8))) :ARG1~e.21 (a3 / and~e.18 :op1 (a4 / activity-06~e.20 :ARG0 (p / protein :name (n5 / name :op1 "Caspase"~e.13 :op2 3~e.15))) :op2 (a5 / activity-06~e.20 :ARG0 (p3 / protein :name (n4 / name :op1 "Caspase"~e.13 :op2 8~e.17))) :op3 (a6 / activity-06~e.20 :ARG0 (p2 / protein :name (n6 / name :op1 "Caspase"~e.13 :op2 9~e.19))) :location (m / model~e.29 :quant 3~e.15,23 :mod (t2 / tumor~e.28 :mod (d2 / disease :name (n2 / name :op1 "NSCLC"~e.27))) :ARG0-of (r2 / resist-01~e.26 :ARG1 (s4 / small-molecule :name (n7 / name :op1 "gefitinib"~e.24))) :mod (a7 / all~e.22)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod 7~e.33))) # ::id pmid_2540_9876.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86 ( PMID : 25409876 ) # ::alignments 1-1 2-1.2.r 3-1.2.2.1.1.1 4-1.2.2 5-1.2.1 6-1.2 7-1.2.3 8-1.2.3 9-1.1.r 11-1.1.2.1 12-1.1 12-1.1.2 12-1.1.2.r 13-1.1.1.1 (i2 / inhibit-01~e.1 :ARG0~e.9 (s2 / small-molecule~e.12 :name (n2 / name :op1 "SPP86"~e.13) :ARG0-of~e.12 (i / inhibit-01~e.12 :ARG1 (k / kinase~e.11))) :ARG1~e.2 (p / proliferate-01~e.6 :ARG0 (c / cell~e.5) :ARG1-of (m / mediate-01~e.4 :ARG0 (p2 / protein :name (n / name :op1 "RET"~e.3))) :mod (i3 / in-vitro~e.7,8)) :ARG0-of (s / select-01) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMID25409876"))) # ::id pmid_2540_9876.10 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2540_9876.11 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 inhibited MAPK signaling and proliferation in RET @/@ PTC1 expressing TPC1 but not 8505C or C643 cells . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.2 2-1.1.2.1.1.1.1 3-1.1.2.1 4-1.1.2 5-1.1.2.2 7-1.1.3.3.1.1.1 9-1.1.3.3.1.1.1 10-1.1.3.3 11-1.1.3.1.1 12-1 13-1.2.1 13-1.2.1.r 14-1.2.4.1.1.1 15-1.2.4 16-1.2.4.2.1.1 17-1.1.3 17-1.2.4.1 17-1.2.4.2 (c2 / contrast-01~e.12 :ARG1 (i / inhibit-01~e.1 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.0)) :ARG1 (a / and~e.4 :op1 (s2 / signal-07~e.3 :ARG0 (p / pathway :name (n / name :op1 "MAPK"~e.2))) :op2 (p2 / proliferate-01~e.5 :ARG0 p)) :location (c / cell-line~e.17 :name (n3 / name :op1 "TPC1"~e.11) :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")) :ARG3-of (e / express-03~e.10 :ARG2 (p4 / protein :name (n5 / name :op1 "RET/PTC1"~e.7,9))))) :ARG2 (i2 / inhibit-01~e.1 :polarity~e.13 -~e.13 :ARG0 s :ARG1 a :location (o / or~e.15 :op1 (c3 / cell-line~e.17 :name (n6 / name :op1 "8505C"~e.14)) :op2 (c4 / cell-line~e.17 :name (n7 / name :op1 "C643"~e.16))))) # ::id pmid_2540_9876.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In TPC1 cells , the inhibition of RET phosphorylation required co @-@ exposure to SPP86 and the focal adhesion kinase ( FAK ) inhibitor PF573228 . # ::alignments 1-1.3.1.1 2-1.3 5-1.1 6-1.1.1.r 7-1.1.1.1.1.1 8-1.1.1 9-1 12-1.2 13-1.2.1.r 14-1.2.1.1.1.1 15-1.2.1 17-1.2.1.2.2.1.1.1 18-1.2.1.2.2.1.1.1 19-1.2.1.2.2.1.1.1 23-1.2.1.2 23-1.2.1.2.2 23-1.2.1.2.2.r 24-1.2.1.2.1.1 (r / require-01~e.9 :ARG0 (i / inhibit-01~e.5 :ARG1~e.6 (p / phosphorylate-01~e.8 :ARG1 (p2 / protein :name (n / name :op1 "RET"~e.7)))) :ARG1 (e / expose-01~e.12 :ARG2~e.13 (a / and~e.15 :op1 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.14)) :op2 (s2 / small-molecule~e.23 :name (n4 / name :op1 "PF573228"~e.24) :ARG0-of~e.23 (i2 / inhibit-01~e.23 :ARG1 (e2 / enzyme :name (n3 / name :op1 "focal-adhesion-kinase"~e.17,18,19)))))) :location (c / cell-line~e.2 :name (n5 / name :op1 "TPC1"~e.1))) # ::id pmid_2540_9876.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In MCF7 cells , SPP86 inhibited RET @- induced phosphatidylinositide 3 @-@ kinases ( PI3K ) / Akt and MAPK signaling and estrogen receptorα ( ERα) phosphorylation , and inhibited proliferation to a similar degree as tamoxifen . # ::alignments 1-1.3.1.1 2-1.3 4-1.1.1.1.1 5-1.1 6-1.1.2.1.2.1.1.1 8-1.1.2.1.2 9-1.1.2.1.1.1.1.1.1 10-1.1.2.1.1.1.1.1.2 12-1.1.2.1.1.1.1.1.2 16-1.1.2.1.1.1 17-1.1.2.1.1.1.2.1.1 18-1.1.2.1.1 19-1.1.2.1.1.2.1.1 20-1.1.2.1 21-1.1.2 22-1.1.2.2.1.1.1 26-1.1.2.2 28-1 28-1.1.2 29-1.1 29-1.2 30-1.2.2 31-1.2.3.r 33-1.2.3.1 34-1.2.3 35-1.2.3.1.1.r 36-1.2.3.1.1.1.1 (a3 / and~e.28 :op1 (i / inhibit-01~e.5,29 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.4)) :ARG1 (a2 / and~e.21,28 :op1 (s2 / signal-07~e.20 :ARG0 (a / and~e.18 :op1 (s3 / slash~e.16 :op1 (e3 / enzyme :name (n9 / name :op1 "phosphatidylinositide"~e.9 :op2 "3-kinase"~e.10,12)) :op2 (e / enzyme :name (n4 / name :op1 "Akt"~e.17))) :op2 (p / pathway :name (n / name :op1 "MAPK"~e.19))) :ARG2-of (i3 / induce-01~e.8 :ARG0 (p6 / protein :name (n8 / name :op1 "RET"~e.6)))) :op2 (p2 / phosphorylate-01~e.26 :ARG1 (p3 / protein :name (n5 / name :op1 "estrogen-receptor-α"~e.22))))) :op2 (i2 / inhibit-01~e.29 :ARG0 s :ARG1 (p5 / proliferate-01~e.30) :degree~e.31 (d / degree~e.34 :ARG1-of (r / resemble-01~e.33 :ARG2~e.35 (s5 / small-molecule :name (n6 / name :op1 "tamoxifen"~e.36))))) :location (c / cell-line~e.2 :name (n7 / name :op1 "MCF7"~e.1))) # ::id pmid_2540_9876.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , SPP86 and PF573228 inhibited RET @/@ PTC1 and GDNF @- RET induced activation of Akt and MAPK signaling to a similar degree . # ::alignments 0-1.3 2-1.1.1.1.1.1 3-1.1.1 4-1.1.1.2.1.1 5-1.1 6-1.1.2.1.1 8-1.1.2.1.1 9-1 10-1.2.1.1.1 12-1.2.1.1.1 13-1.2 14-1.2.2 15-1.2.2.1.r 16-1.2.2.1.1.1.1.1 17-1.2.2.1.1 18-1.2.2.1.1.2.1.1 19-1.2.2.1 20-1.2.2.2.r 22-1.2.2.2.1 23-1.2.2.2 (a / and~e.9 :op1 (i / inhibit-01~e.5 :ARG0 (a2 / and~e.3 :op1 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.2)) :op2 (s2 / small-molecule :name (n3 / name :op1 "PF573228"~e.4))) :ARG1 (p2 / protein :name (n4 / name :op1 "RET/PTC1"~e.6,8))) :op2 (i2 / induce-01~e.13 :ARG0 (p3 / protein :name (n6 / name :op1 "GDNF-RET"~e.10,12)) :ARG2 (a3 / activate-01~e.14 :ARG1~e.15 (s3 / signal-07~e.19 :ARG0 (a4 / and~e.17 :op1 (p4 / pathway :name (n7 / name :op1 "Akt"~e.16)) :op2 (p / pathway :name (n8 / name :op1 "MAPK"~e.18)))) :degree~e.20 (d2 / degree~e.23 :ARG1-of (r2 / resemble-01~e.22)))) :ARG2-of (i3 / interest-01~e.0)) # ::id pmid_2540_9876.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2540_9876.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We investigated the effect of SPP86 on ERK1 @/@ 2 phosphorylation in thyroid cancer derived cell lines expressing the RET @/@ PTC1 rearrangement ( TPC1 ) , BRAF @^V600E ( 8505C ) or RAS @^G13R ( C643 ) mutations [ @ 47 , 48 @ ] . # ::alignments 0-1.1 1-1 3-1.2 4-1.2.1.r 5-1.2.1.1.1 6-1.2.2.r 7-1.2.2.1.1.1.1 8-1.2.2.1 10-1.2.2 11-1.2.3.r 12-1.2.3.4.1.3 13-1.2.3.4.1.2.1 14-1.2.3.4 15-1.2.3.1 16-1.2.3.1 16-1.2.3.2 16-1.2.3.3 17-1.2.3.1.2 17-1.2.3.2.2 17-1.2.3.3.2 19-1.2.3.1.2.1.1.1.1 20-1.2.2.1 21-1.2.3.1.2.1.1.1.1 22-1.2.3.1.2.1 24-1.2.3.1.1.1 27-1.2.3.2.2.1.1.1 29-1.2.3.2.2.1.2.1 32-1.2.3.2.1.1 34-1.2.3 35-1.2.3.3.2.1.1.1 37-1.2.3.3.2.1.2.1 40-1.2.3.3.1.1 42-1.2.3.2.2.1 42-1.2.3.2.2.1.2 42-1.2.3.2.2.1.2.r 42-1.2.3.3.2.1 42-1.2.3.3.2.1.2 42-1.2.3.3.2.1.2.r 45-1.3.1.1.1.1 49-1.3.1.1.1.2 (i / investigate-01~e.1 :ARG0 (w / we~e.0) :ARG1 (a / affect-01~e.3 :ARG0~e.4 (s / small-molecule :name (n3 / name :op1 "SPP86"~e.5)) :ARG1~e.6 (p / phosphorylate-01~e.10 :ARG1 (s2 / slash~e.8,20 :op1 (e / enzyme :name (n4 / name :op1 "ERK1"~e.7)) :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2")))) :location~e.11 (o2 / or~e.34 :op1 (c5 / cell-line~e.15,16 :name (n12 / name :op1 "TPC1"~e.24) :ARG3-of (e3 / express-03~e.17 :ARG2 (r / rearrange-01~e.22 :ARG1 (p2 / protein :name (n6 / name :op1 "RET/PTC1"~e.19,21))))) :op2 (c4 / cell-line~e.16 :name (n2 / name :op1 "8505C"~e.32) :ARG3-of (e6 / express-03~e.17 :ARG2 (e4 / enzyme~e.42 :name (n9 / name :op1 "BRAF"~e.27) :ARG2-of~e.42 (m2 / mutate-01~e.42 :value "V600E"~e.29)))) :op3 (c2 / cell-line~e.16 :name (n11 / name :op1 "C643"~e.40) :ARG3-of (e7 / express-03~e.17 :ARG2 (e5 / enzyme~e.42 :name (n10 / name :op1 "RAS"~e.35) :ARG2-of~e.42 (m4 / mutate-01~e.42 :value "G13R"~e.37)))) :ARG1-of (d2 / derive-01~e.14 :ARG2 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"~e.13) :mod (t / thyroid~e.12))))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 47~e.45 :op2 48~e.49))))) # ::id pmid_2540_9876.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These mutations have previously been shown to induce constitutive activation of the MAPK signaling pathway in these cell lines [ @ 47 @ – @ 49 @ ] . # ::alignments 0-1.1.1.1 1-1.1.1 3-1.3 5-1 7-1.1 8-1.1.2.2 9-1.1.2 10-1.1.2.1.r 12-1.1.2.1.1.1 13-1.1.2.1.2 14-1.1.2.1 15-1.1.3.r 16-1.1.3.1 17-1.1.3 18-1.1.3 21-1.2.1.1.1.1 25-1.2.1.1.1.2 (s / show-01~e.5 :ARG1 (i / induce-01~e.7 :ARG0 (m / mutate-01~e.1 :mod (t / this~e.0)) :ARG2 (a / activate-01~e.9 :ARG1~e.10 (p2 / pathway~e.14 :name (n2 / name :op1 "MAPK"~e.12) :ARG0-of (s2 / signal-07~e.13)) :mod (c / constitutive~e.8)) :location~e.15 (c2 / cell-line~e.17,18 :mod (t2 / this~e.16))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 47~e.21 :op2 49~e.25)))) :time (p4 / previous~e.3)) # ::id pmid_2540_9876.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since TPC1 but not 8505C and C643 cells depend predominantly on RET @/@ PTC1 signaling for proliferation , we hypothesized that SPP86 should only inhibit the proliferation of the former . # ::alignments 0-1.3 0-1.3.1.1.3.r 1-1.3.1.1.1.1.1 2-1.3.1 3-1.3.1.2.1 3-1.3.1.2.1.r 4-1.3.1.2.2.1.1.1 5-1.3.1.2.2 6-1.3.1.2.2.2.1.1 7-1.3.1.1.1 7-1.3.1.2.2.1 7-1.3.1.2.2.2 8-1.3.1.1 8-1.3.1.2 9-1.3.1.1.4 10-1.3.1.1.2.r 11-1.3.1.1.2.1.1.1 13-1.3.1.1.2.1.1.1 14-1.3.1.1.2 16-1.3.1.1.3 16-1.3.1.2.4 18-1.1 19-1 20-1.2.r 21-1.2.1.1.1.1 22-1.2 23-1.2.1.3 24-1.2.1 26-1.2.1.2 (h / hypothesize-01~e.19 :ARG0 (w / we~e.18) :ARG1~e.20 (r / recommend-01~e.22 :ARG1 (i / inhibit-01~e.24 :ARG0 (s2 / small-molecule :name (n / name :op1 "SPP86"~e.21)) :ARG1 (p2 / proliferate-01~e.26 :ARG0 c3) :mod (o / only~e.23))) :ARG1-of (c / cause-01~e.0 :ARG0 (c2 / contrast-01~e.2 :ARG1 (d / depend-01~e.8 :ARG0 (c3 / cell-line~e.7 :name (n2 / name :op1 "TPC1"~e.1)) :ARG1~e.10 (s / signal-07~e.14 :ARG0 (p3 / protein :name (n3 / name :op1 "RET/PTC1"~e.11,13))) :purpose~e.0 (p4 / proliferate-01~e.16 :ARG0 c3) :ARG1-of (p5 / predominate-01~e.9)) :ARG2 (d2 / depend-01~e.8 :polarity~e.3 -~e.3 :ARG0 (a / and~e.5 :op1 (c4 / cell-line~e.7 :name (n4 / name :op1 "8505C"~e.4)) :op2 (c5 / cell-line~e.7 :name (n5 / name :op1 "C643"~e.6))) :ARG1 s :purpose (p6 / proliferate-01~e.16 :ARG0 (a2 / and :op1 c4 :op2 c5)))))) # ::id pmid_2540_9876.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sorafenib , which inhibits both RET and RAF family kinases , was used as an internal control in these experiments . # ::alignments 0-1.1.1.1 3-1.1 3-1.1.2 3-1.1.2.r 5-1.1.2.1.1.1.1 6-1.1.2.1 7-1.1.2.1.2.1.1 8-1.1.2.1.1 8-1.1.2.1.2 12-1 13-1.2.r 15-1.2.2 16-1.2 17-1.2.3.r 18-1.2.3.1 19-1.2.3 (u / use-01~e.12 :ARG1 (s / small-molecule~e.3 :name (n2 / name :op1 "sorafenib"~e.0) :ARG0-of~e.3 (i2 / inhibit-01~e.3 :ARG1 (a / and~e.6 :op1 (p / protein-family~e.8 :name (n3 / name :op1 "RET"~e.5)) :op2 (p2 / protein-family~e.8 :name (n4 / name :op1 "RAF"~e.7))))) :ARG2~e.13 (c / control-01~e.16 :ARG0 s :ARG1-of (i / internal-02~e.15) :location~e.17 (e3 / experiment-01~e.19 :mod (t / this~e.18)))) # ::id pmid_2540_9876.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 inhibits MAPK pathway activation in RET @/@ PTC1 expressing cell lines # ::alignments 1-1.1.1.1 2-1 3-1.2.1.1.1 4-1.2.1 5-1.2 6-1.3.r 7-1.3.1.1.1.1 9-1.3.1.1.1.1 10-1.3.1 11-1.3 12-1.3 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.1)) :ARG1 (a / activate-01~e.5 :ARG1 (p2 / pathway~e.4 :name (n3 / name :op1 "MAPK"~e.3))) :location~e.6 (c / cell-line~e.11,12 :ARG3-of (e / express-03~e.10 :ARG2 (p3 / protein :name (n4 / name :op1 "RET/PTC1"~e.7,9))))) # ::id pmid_2540_9876.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As previously reported [ @ 45 @ ] , SPP86 effectively inhibits ERK1 @/@ 2 phosphorylation in TPC1 cells expressing the RET @/@ PTC1 rearrangement at a concentration of 1 μM ( Figure 1 @ A ) . # ::alignments 0-1.4.1.r 1-1.4.1 2-1.4 5-1.4.2.1.1.1 9-1.1.1.1 10-1.3 11-1 12-1.2.1.1.1.1 13-1.2.1 15-1.2 16-1.2.2.r 17-1.2.2.1.1 18-1.2.2 19-1.2.2.2 21-1.2.2.2.1.1.1.1 22-1.2.1 23-1.2.2.2.1.1.1.1 24-1.2.2.2.1 25-1.2.2.2.1.2.r 27-1.2.2.2.1.2 29-1.2.2.2.1.2.1 30-1.2.2.2.1.2.2 32-1.5.1 34-1.2.2.2.1.2.1 (i / inhibit-01~e.11 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.9)) :ARG1 (p / phosphorylate-01~e.15 :ARG1 (s2 / slash~e.13,22 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"~e.12)) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2"))) :location~e.16 (c / cell-line~e.18 :name (n4 / name :op1 "TPC1"~e.17) :ARG3-of (e4 / express-03~e.19 :ARG2 (r2 / rearrange-01~e.24 :ARG1 (p2 / protein :name (n5 / name :op1 "RET/PTC1"~e.21,23)) :quant~e.25 (c2 / concentration-quantity~e.27 :quant 1~e.29,34 :unit (m / micromolar~e.30)))))) :ARG1-of (e / effective-04~e.10) :ARG1-of (r / report-01~e.2 :time~e.0 (p3 / previous~e.1) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 45~e.5)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.32 :mod "1A"))) # ::id pmid_2540_9876.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , SPP86 had no effect on ERK1 @/@ 2 phosphorylation in 8505C or C643 cells ( Figure 1 @ B and C ) . # ::alignments 1-1 3-1.1.2.1.1 5-1.1.1 5-1.1.1.r 6-1.1 7-1.1.3.r 8-1.1.3.1.1.1.1 9-1.1.3.1 11-1.1.3 12-1.1.4.r 13-1.1.4.1.1.1 14-1.1.4 15-1.1.4.2.1.1 16-1.1.4.1 16-1.1.4.2 18-1.2.1.1 18-1.2.1.2 23-1.2.1 (c / contrast-01~e.1 :ARG2 (a / affect-01~e.6 :polarity~e.5 -~e.5 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.3)) :ARG1~e.7 (p / phosphorylate-01~e.11 :ARG1 (s2 / slash~e.9 :op1 (e / enzyme :name (n2 / name :op1 "ERK1"~e.8)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2")))) :location~e.12 (o / or~e.14 :op1 (c2 / cell-line~e.16 :name (n4 / name :op1 "8505C"~e.13)) :op2 (c3 / cell-line~e.16 :name (n5 / name :op1 "C643"~e.15)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and~e.23 :op1 (f / figure~e.18 :mod "1B") :op2 (f2 / figure~e.18 :mod "1C")))) # ::id pmid_2540_9876.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sorafenib , which targets both RET and RAF kinases , effectively inhibited ERK1 @/@ 2 phosphorylation in TPC1 cells at a concentration of 0.1 μM ( Figure 1 @ A ) . # ::alignments 0-1.1.1.1 3-1.1 3-1.1.3 3-1.1.3.r 5-1.1.3.1.1.1.1 6-1.1.3.1 7-1.1.3.1.2.1.1 10-1.3 11-1 12-1.2.1.1.1.1 13-1.2.1 15-1.2 16-1.4.r 17-1.4.1.1 18-1.4 19-1.1.2.r 21-1.1.2 23-1.1.2.1 24-1.1.2.2 26-1.5.1 (i / inhibit-01~e.11 :ARG0 (s / small-molecule~e.3 :name (n2 / name :op1 "sorafenib"~e.0) :quant~e.19 (c2 / concentration-quantity~e.21 :quant 0.1~e.23 :unit (m / micromolar~e.24)) :ARG0-of~e.3 (t / target-01~e.3 :ARG1 (a / and~e.6 :op1 (p3 / protein-family :name (n3 / name :op1 "RET"~e.5)) :op2 (p / protein-family :name (n4 / name :op1 "RAF"~e.7))))) :ARG1 (p2 / phosphorylate-01~e.15 :ARG1 (s2 / slash~e.13 :op1 (e2 / enzyme :name (n6 / name :op1 "ERK1"~e.12)) :op2 (e3 / enzyme :name (n7 / name :op1 "ERK2")))) :ARG1-of (e / effective-04~e.10) :location~e.16 (c / cell-line~e.18 :name (n5 / name :op1 "TPC1"~e.17)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "1A"))) # ::id pmid_2540_9876.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Sorafenib ( 10 μM ) also inhibited ERK1 @/@ 2 phosphorylation in 8505C cells , and to a lesser extent in C643 cells consistent with previous reports [ @ 49 @ ] ( Figure 1 @ B and C ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.2.1 3-1.1.1.2.2 5-1.1.4 6-1.1 6-1.2 7-1.1.2.1.1.1.1 8-1.1.2.1 10-1.1.2 12-1.1.3.1.1 13-1.1.3 13-1.2.3 15-1 16-1.2.6.r 18-1.2.6 18-1.2.6.1 18-1.2.6.1.r 21-1.2.3.1.1 22-1.2.7 23-1.2.4 24-1.2.4.1.r 25-1.2.4.1.2 26-1.2.4.1 26-1.2.4.1.1 26-1.2.4.1.1.r 29-1.2.5.1.1.1 33-1.3.1.1 33-1.3.1.2 38-1.3.1 (a2 / and~e.15 :op1 (i / inhibit-01~e.6 :ARG0 (s / small-molecule :name (n / name :op1 "sorafenib"~e.0) :quant (c / concentration-quantity :quant 10~e.2 :unit (m / micromolar~e.3))) :ARG1 (p / phosphorylate-01~e.10 :ARG1 (s2 / slash~e.8 :op1 (e / enzyme :name (n2 / name :op1 "ERK1"~e.7)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2")))) :location (c2 / cell-line~e.13 :name (n4 / name :op1 "8505C"~e.12)) :mod (a3 / also~e.5)) :op2 (i2 / inhibit-01~e.6 :ARG0 s :ARG1 p :location (c3 / cell-line~e.13 :name (n5 / name :op1 "C643"~e.21)) :ARG1-of (c4 / consistent-01~e.23 :ARG2~e.24 (t / thing~e.26 :ARG1-of~e.26 (r / report-01~e.26) :time (p2 / previous~e.25))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 49~e.29))) :degree~e.16 (l / less~e.18 :degree~e.18 (m2 / more~e.18)) :compared-to c2~e.22) :ARG1-of (d3 / describe-01 :ARG0 (a / and~e.38 :op1 (f / figure~e.33 :mod "1B") :op2 (f2 / figure~e.33 :mod "1C")))) # ::id pmid_2540_9876.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The differential sensitivity of 8505C and C643 cells to SPP86 and sorafenib likely results from the latter ’s effect on RAF signaling [ @ 49 @ ] . # ::alignments 1-1.1.2.3 2-1.1.2 3-1.1.2.1.r 4-1.1.2.1.1.1.1 5-1.1.2.1 6-1.1.2.1.2.1.1 7-1.1.2.1.1 7-1.1.2.1.2 8-1.1.2.2.r 9-1.1.2.2.1.1.1 11-1.1.2.2.2.1.1 12-1 13-1.1 18-1.1.1 19-1.1.1.2.r 20-1.1.1.2.1.1.1 21-1.1.1.2 24-1.2.1.1.1 (l / likely-01~e.12 :ARG1 (r / result-01~e.13 :ARG1 (a3 / affect-01~e.18 :ARG0 s3 :ARG1~e.19 (s4 / signal-07~e.21 :ARG0 (e / enzyme :name (n6 / name :op1 "RAF"~e.20)))) :ARG2 (s / sensitive-03~e.2 :ARG0~e.3 (a / and~e.5 :op1 (c / cell-line~e.7 :name (n2 / name :op1 "8505C"~e.4)) :op2 (c2 / cell-line~e.7 :name (n3 / name :op1 "C643"~e.6))) :ARG1~e.8 (a2 / and :op1 (s2 / small-molecule :name (n4 / name :op1 "SPP86"~e.9)) :op2 (s3 / small-molecule :name (n5 / name :op1 "sorafenib"~e.11))) :ARG1-of (d / differ-02~e.1))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 49~e.24)))) # ::id pmid_2540_9876.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , SPP86 induced only modest inhibition of RET @/@ PTC1 phosphorylation Tyr1062 at a concentration of 1 μM ( Figure 1 @ D ) . # ::alignments 0-1.3 2-1.1.1.1 3-1 4-1.2.3 5-1.2.2 6-1.2 7-1.2.1.r 8-1.2.1.1.3.1.1 10-1.2.1.1.3.1.1 11-1.2.1 15-1.1.2 17-1.1.2.1 18-1.1.2.2 20-1.4.1 22-1.1.2.1 (i / induce-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.2) :quant (c / concentration-quantity~e.15 :quant 1~e.17,22 :unit (m2 / micromolar~e.18))) :ARG2 (i3 / inhibit-01~e.6 :ARG1~e.7 (p / phosphorylate-01~e.11 :ARG1 (a / amino-acid :mod 1062 :name (n3 / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "RET/PTC1"~e.8,10)))) :mod (m / modest~e.5) :mod (o / only~e.4)) :ARG2-of (i2 / interest-01~e.0) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.20 :mod "1D"))) # ::id pmid_2540_9876.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Complete inhibition required 10 μM of SPP86 ( Figure 1 @ D ) . # ::alignments 0-1.1.1 1-1.1 2-1 3-1.2.1 4-1.2.2 6-1.2.3.1.1 8-1.3.1 (r / require-01~e.2 :ARG0 (i / inhibit-01~e.1 :ARG1-of (c / complete-02~e.0)) :ARG1 (c2 / concentration-quantity :quant 10~e.3 :unit (m / micromolar~e.4) :quant-of (s / small-molecule :name (n / name :op1 "SPP86"~e.6))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.8 :mod "1D"))) # ::id pmid_2540_9876.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Thus , the ability of SPP86 to abolish ERK1 @/@ 2 phosphorylation at 1 μM does not strictly correlate with its inhibition of RET phosphorylation . # ::alignments 0-1 3-1.1.2 4-1.1.2.2.r 5-1.1.2.2.1 7-1.1.2.2 8-1.1.2.2.2.1.1.1.1 9-1.1.2.2.2.1 11-1.1.2.2.2 13-1.1.2.2.1 14-1.1.2.2.1 16-1.1.1 16-1.1.1.r 17-1.1.4 18-1.1 19-1.1.3.r 20-1.1.3.1 20-1.1.3.1.r 21-1.1.3 22-1.1.3.2.r 23-1.1.3.2.1.1.1 24-1.1.3.2 (c / cause-01~e.0 :ARG1 (c2 / correlate-01~e.18 :polarity~e.16 -~e.16 :ARG1 (c3 / capable-01~e.3 :ARG1 (s / small-molecule :name (n / name :op1 "SPP86") :quant (c4 / concentration-quantity :quant 1 :unit (m / micromolar))) :ARG2~e.4 (a / abolish-01~e.7 :ARG0 s~e.5,13,14 :ARG1 (p / phosphorylate-01~e.11 :ARG1 (s2 / slash~e.9 :op1 (e / enzyme :name (n2 / name :op1 "ERK1"~e.8)) :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2")))))) :ARG2~e.19 (i / inhibit-01~e.21 :ARG0~e.20 s~e.20 :ARG1~e.22 (p2 / phosphorylate-01~e.24 :ARG1 (p3 / protein :name (n4 / name :op1 "RET"~e.23)))) :mod (s3 / strict~e.17))) # ::id pmid_2540_9876.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similar observations have previously been reported with the RET inhibitor RPI @-@ 1 [ @ 28 @ ] . # ::alignments 0-1.1.1 1-1.1 3-1.2 5-1 6-1.3.r 8-1.3.2.1.1 9-1.3 10-1.3.1.1.1 12-1.3.1.1.1 15-1.4.1.1.1 (r2 / report-01~e.5 :ARG1 (o / observe-01~e.1 :ARG1-of (r3 / resemble-01~e.0)) :time (p / previous~e.3) :condition~e.6 (i2 / inhibit-01~e.9 :ARG0 (p2 / protein :name (n / name :op1 "RPI-1"~e.10,12)) :ARG1 (p4 / protein :name (n2 / name :op1 "RET"~e.8))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 28~e.15)))) # ::id pmid_2540_9876.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 also inhibited Akt phosphorylation on Ser473 at a concentration of 1.0 μM ( Figure 1 @ E and F ) . # ::alignments 0-1.1.1.1 1-1.3 2-1 3-1.2.1.3.1.1 4-1.2 9-1.1.2 11-1.1.2.1 12-1.1.2.2 14-1.4.1.1 14-1.4.1.2 19-1.4.1 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.0) :quant (c / concentration-quantity~e.9 :quant 1.0~e.11 :unit (m / micromolar~e.12))) :ARG1 (p / phosphorylate-01~e.4 :ARG1 (a / amino-acid :mod 473 :name (n3 / name :op1 "serine") :part-of (e / enzyme :name (n2 / name :op1 "Akt"~e.3)))) :mod (a2 / also~e.1) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.19 :op1 (f / figure~e.14 :mod "1E") :op2 (f2 / figure~e.14 :mod "1F")))) # ::id pmid_2540_9876.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Prolonged exposure ( 20 h ) to 0.5 @- 1 μM SPP86 was also associated with a decline in cyclin D1 levels in this cell line ( Figure 1 @ E ) . # ::alignments 0-1.1.2 1-1.1 3-1.1.3.1.1 4-1.1.3.1.2 6-1.1.1.r 7-1.1.1.1.1 9-1.1.1.1.2 10-1.1.1.2 11-1.1.1.3.1.1 13-1.4 14-1 15-1.2.r 17-1.2 18-1.2.1.r 19-1.2.1.1.1.1 20-1.2.1.1.1.2 21-1.2.1 22-1.2.2.r 23-1.2.2.1 24-1.2.2 25-1.2.2 27-1.3.1 29-1.1.1.1.2 (a / associate-01~e.14 :ARG1 (e / expose-01~e.1 :ARG2~e.6 (c / concentration-quantity :quant (v / value-interval :op1 0.5~e.7 :op2 1~e.9,29) :unit (m2 / micromolar~e.10) :quant-of (s / small-molecule :name (n / name :op1 "SPP86"~e.11))) :ARG1-of (p / prolong-01~e.0) :ARG1-of (m / mean-01 :ARG2 (t / temporal-quantity :quant 20~e.3 :unit (h / hour~e.4)))) :ARG2~e.15 (d / decline-01~e.17 :ARG1~e.18 (l / level~e.21 :quant-of (p3 / protein :name (n3 / name :op1 "cyclin"~e.19 :op2 "D1"~e.20))) :location~e.22 (c2 / cell-line~e.24,25 :mod (t2 / this~e.23))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.27 :mod "1E")) :mod (a2 / also~e.13)) # ::id pmid_2540_9876.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , prolonged exposure to SPP86 did not affect ERK1 @/@ 2 phosphorylation or cyclin D1 expression in 8505C and C643 cells ( Figure 1 @ G ) . # ::alignments 1-1 3-1.1.2.2 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1 8-1.1.1 8-1.1.1.r 9-1.1 10-1.1.3.1.1.1.1.1 11-1.1.3.1.1 13-1.1.3.1 14-1.1.3 15-1.1.3.2.1.1.1 16-1.1.3.2.1.1.2 17-1.1.3.2 18-1.1.3.2.2.r 19-1.1.3.2.2.1.1.1 20-1.1.3.2.2 21-1.1.3.2.2.2.1.1 22-1.1.3.2.2.1 22-1.1.3.2.2.2 24-1.2.1 (c / contrast-01~e.1 :ARG2 (a / affect-01~e.9 :polarity~e.8 -~e.8 :ARG0 (e / expose-01~e.4 :ARG2~e.5 (s / small-molecule :name (n / name :op1 "SPP86"~e.6)) :ARG1-of (p2 / prolong-01~e.3)) :ARG1 (o / or~e.14 :op1 (p / phosphorylate-01~e.13 :ARG1 (s2 / slash~e.11 :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"~e.10)) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2")))) :op2 (e4 / express-03~e.17 :ARG2 (p4 / protein :name (n7 / name :op1 "cyclin"~e.15 :op2 "D1"~e.16)) :ARG3~e.18 (a2 / and~e.20 :op1 (c2 / cell-line~e.22 :name (n5 / name :op1 "8505C"~e.19)) :op2 (c3 / cell-line~e.22 :name (n6 / name :op1 "C643"~e.21)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.24 :mod "1G"))) # ::id pmid_2540_9876.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We noted however , that prolonged exposure to SPP86 ( 0.5 @- 1.0 μM ) was associated with a decrease in Akt Ser473 phosphorylation in C643 in cells ( Figure 1 @ G ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.1.2.r 5-1.1.2.1.2 6-1.1.2.1 7-1.1.2.1.1.r 8-1.1.2.1.1.1.1 10-1.1.2.1.1.2.2.1 12-1.1.2.1.1.2.2.2 13-1.1.2.1.1.2.1 16-1.1.2 17-1.1.2.2.r 19-1.1.2.2 20-1.1.2.2.1.r 21-1.1.2.2.1.1.3.1.1 23-1.1.2.2.1 24-1.1.2.2.1.2.r 25-1.1.2.2.1.2.1.1 27-1.1.2.2.1.2 29-1.2.1 (c3 / contrast-01~e.2 :ARG2 (n / note-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.4 (a / associate-01~e.16 :ARG1 (e / expose-01~e.6 :ARG2~e.7 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.8) :quant (c / concentration-quantity :unit (m / micromolar~e.13) :quant (v / value-interval :op1 0.5~e.10 :op2 1.0~e.12))) :ARG1-of (p2 / prolong-01~e.5)) :ARG2~e.17 (d / decrease-01~e.19 :ARG1~e.20 (p / phosphorylate-01~e.23 :ARG1 (a2 / amino-acid :mod 473 :name (n3 / name :op1 "serine") :part-of (e2 / enzyme :name (n4 / name :op1 "Akt"~e.21))) :location~e.24 (c2 / cell-line~e.27 :name (n5 / name :op1 "C643"~e.25)))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.29 :mod "1G"))) # ::id pmid_2540_9876.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C643 cells express wild type RET [ @ 47 @ ] . # ::alignments 0-1.2.1.1 1-1.2 2-1 3-1.1.2 4-1.1.2 5-1.1.1.1 8-1.3.1.1.1 (e / express-03~e.2 :ARG2 (p2 / protein :name (n2 / name :op1 "RET"~e.5) :mod (w / wild-type~e.3,4)) :ARG3 (c / cell-line~e.1 :name (n / name :op1 "C643"~e.0)) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c2 / cite-01 :ARG2 47~e.8)))) # ::id pmid_2540_9876.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 may thus inhibit RET @- mediated Akt activation in this cell line . # ::alignments 0-1.1.1.1.1.1 1-1.1 2-1 3-1.1.1 4-1.1.1.2.2.1.1.1 6-1.1.1.2.2 7-1.1.1.2.1.1.1 8-1.1.1.2 9-1.1.1.3.r 10-1.1.1.3.1 11-1.1.1.3 12-1.1.1.3 (c / cause-01~e.2 :ARG1 (p / possible-01~e.1 :ARG1 (i / inhibit-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.0)) :ARG1 (a / activate-01~e.8 :ARG1 (e / enzyme :name (n2 / name :op1 "Akt"~e.7)) :ARG1-of (m / mediate-01~e.6 :ARG0 (p2 / protein :name (n3 / name :op1 "RET"~e.4)))) :location~e.9 (c2 / cell-line~e.11,12 :mod (t / this~e.10))))) # ::id pmid_2540_9876.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results demonstrate that unlike sorafenib , SPP86 appears to selectively inhibit RET @/@ PTC1 @- activated MAPK signaling in these cell lines . # ::alignments 0-1.2.1.4.1 1-1.1 1-1.1.1 1-1.1.1.r 2-1 4-1.2.1.5 4-1.2.1.5.1 4-1.2.1.5.1.r 5-1.2.1.5.2.1.1 7-1.2.1.1.1.1 8-1.2 10-1.2.1.3 10-1.2.1.3.r 11-1.2.1 12-1.2.1.2.2.1.1.1 14-1.2.1.2.2.1.1.1 16-1.2.1.2.2 17-1.2.1.2.1.1.1 18-1.2.1.2 20-1.2.1.4.1 21-1.2.1.4 22-1.2.1.4 (d / demonstrate-01~e.2 :ARG0 (t / thing~e.1 :ARG2-of~e.1 (r2 / result-01~e.1)) :ARG1 (a / appear-01~e.8 :ARG1 (i / inhibit-01~e.11 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.7)) :ARG1 (s3 / signal-07~e.18 :ARG0 (p / pathway :name (n3 / name :op1 "MAPK"~e.17)) :ARG1-of (a2 / activate-01~e.16 :ARG0 (p3 / protein :name (n4 / name :op1 "RET/PTC1"~e.12,14)))) :manner~e.10 (s2 / selective~e.10) :location (c / cell-line~e.21,22 :mod (t2 / this~e.0,20)) :ARG1-of (r / resemble-01~e.4 :polarity~e.4 -~e.4 :ARG2 (s4 / small-molecule :name (n5 / name :op1 "sorafenib"~e.5)))))) # ::id pmid_2540_9876.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next investigated if FAK could maintain RET phosphorylation on Tyr1062 despite the inhibition of RET autophosphorylation by SPP86 [ @ 24 @ ] . # ::alignments 0-1.1 1-1.3 2-1 4-1.2.2.1.1.1 5-1.2 6-1.2.2 7-1.2.2.2.1.3.1.1 8-1.2.2.2 11-1.2.2.3.r 13-1.2.2.3 15-1.2.2.2.1.3.1.1 16-1.2.2.3.2 17-1.2.2.3.1.r 18-1.2.2.3.1.1.1 21-1.4.1.1.1 (i / investigate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (p3 / possible-01~e.5 :mode interrogative :ARG1 (m / maintain-01~e.6 :ARG0 (e / enzyme :name (n2 / name :op1 "FAK"~e.4)) :ARG1 (p2 / phosphorylate-01~e.8 :ARG1 (a2 / amino-acid :mod 1062 :name (n4 / name :op1 "tyrosine") :part-of (p / protein :name (n3 / name :op1 "RET"~e.7,15)))) :concession~e.11 (i2 / inhibit-01~e.13 :ARG0~e.17 (s / small-molecule :name (n5 / name :op1 "SPP86"~e.18)) :ARG1 (p4 / phosphorylate-01~e.16 :ARG1 p :ARG2 p)))) :time (n / next~e.1) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 24~e.21)))) # ::id pmid_2540_9876.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exposure to 2.5 μM of the FAK inhibitor PF573228 [ @ 50 @ ] alone , did not inhibit RET phosphorylation in TPC1 cells ( Figure 2 @ A ) . # ::alignments 0-1.2 1-1.2.1.r 2-1.2.1.1 3-1.2.1.2 6-1.2.1.3.2.1.1.1 7-1.2.1.3 7-1.2.1.3.2 7-1.2.1.3.2.r 8-1.2.1.3.1.1 11-1.2.2.1.1.1 14-1.2.1.3.3 17-1.1 17-1.1.r 18-1 19-1.3.1.1.1 20-1.3 21-1.3.2.r 22-1.3.2.1.1 23-1.3.2 25-1.4.1 (i2 / inhibit-01~e.18 :polarity~e.17 -~e.17 :ARG0 (e / expose-01~e.0 :ARG2~e.1 (c / concentration-quantity :quant 2.5~e.2 :unit (m / micromolar~e.3) :quant-of (s / small-molecule~e.7 :name (n / name :op1 "PF573228"~e.8) :ARG0-of~e.7 (i3 / inhibit-01~e.7 :ARG1 (e2 / enzyme :name (n2 / name :op1 "FAK"~e.6))) :mod (a / alone~e.14))) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 50~e.11)))) :ARG1 (p / phosphorylate-01~e.20 :ARG1 (p3 / protein :name (n3 / name :op1 "RET"~e.19)) :location~e.21 (c3 / cell-line~e.23 :name (n4 / name :op1 "TPC1"~e.22))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.25 :mod "2A"))) # ::id pmid_2540_9876.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , exposure to 2.5 μM of the FAK inhibitor PF573228 in combination with 1 μM SPP86 was sufficient to inhibit RET phosphorylation on Tyr1062 ( Figure 2 @ A ) . # ::alignments 1-1 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1 6-1.1.1.1.2 9-1.1.1.1.3.2.1.1.1 10-1.1.1.1.3 10-1.1.1.1.3.2 10-1.1.1.1.3.2.r 11-1.1.1.1.3.1.1 12-1.1.1.1.3.3.r 13-1.1.1.1.3.3 14-1.1.1.1.3.3.1.r 15-1.1.1.1.3.3.1.1 16-1.1.1.1.3.3.1.3 17-1.1.1.1.3.3.1.2.1.1 19-1.1 21-1.1.2 22-1.1.2.2.1.3.1.1 23-1.1.2.2 27-1.1.3.1 (c / contrast-01~e.1 :ARG2 (s2 / suffice-01~e.19 :ARG0 (e / expose-01~e.3 :ARG2~e.4 (c2 / concentration-quantity :quant 2.5~e.5 :unit (m / micromolar~e.6) :quant-of (s3 / small-molecule~e.10 :name (n2 / name :op1 "PF573228"~e.11) :ARG0-of~e.10 (i / inhibit-01~e.10 :ARG1 (e2 / enzyme :name (n / name :op1 "FAK"~e.9))) :ARG1-of~e.12 (c3 / combine-01~e.13 :ARG2~e.14 (c4 / concentration-quantity :quant 1~e.15 :quant-of (s / small-molecule :name (n3 / name :op1 "SPP86"~e.17)) :unit m~e.16))))) :ARG1 (i2 / inhibit-01~e.21 :ARG0 e :ARG1 (p / phosphorylate-01~e.23 :ARG1 (a2 / amino-acid :mod 1062 :name (n5 / name :op1 "tyrosine") :part-of (p2 / protein :name (n4 / name :op1 "RET"~e.22))))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.27 :mod "2A")))) # ::id pmid_2540_9876.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , PF273228 and SPP86 inhibited Akt and ERK1 @/@ 2 phosphorylation to a similar degree ( Figure 2 @ B and C ) . # ::alignments 0-1.3 2-1.1.1.1.1 3-1.1 4-1.1.2.1.1 5-1 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1.1 9-1.2.1.2 11-1.2 12-1.4.r 14-1.4.1 15-1.4 17-1.5.1.1 17-1.5.1.2 22-1.5.1 (i / inhibit-01~e.5 :ARG0 (a / and~e.3 :op1 (s / small-molecule :name (n / name :op1 "PF273228"~e.2)) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"~e.4))) :ARG1 (p / phosphorylate-01~e.11 :ARG1 (a2 / and~e.7 :op1 (e / enzyme :name (n3 / name :op1 "Akt"~e.6)) :op2 (s3 / slash~e.9 :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1"~e.8)) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK2"))))) :ARG2-of (i2 / interest-01~e.0) :degree~e.12 (d / degree~e.15 :ARG1-of (r / resemble-01~e.14)) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and~e.22 :op1 (f / figure~e.17 :mod "2B") :op2 (f2 / figure~e.17 :mod "2C")))) # ::id pmid_2540_9876.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Exposure to PF573288 but not SPP86 was associated with a reduction of FAK Tyr576 phosphorylation ( Figure 2 @ B ) . # ::alignments 0-1.1.1 0-1.2.2 1-1.1.1.1.r 2-1.1.1.1.1.1 3-1 4-1.2.1 4-1.2.1.r 5-1.2.2.1.1.1 7-1.1 7-1.2 8-1.1.2.r 10-1.1.2 11-1.1.2.1.r 12-1.1.2.1.1.3.1.1 14-1.1.2.1 16-1.3.1 (c / contrast-01~e.3 :ARG1 (a / associate-01~e.7 :ARG1 (e / expose-01~e.0 :ARG2~e.1 (s / small-molecule :name (n / name :op1 "PF573288"~e.2))) :ARG2~e.8 (r / reduce-01~e.10 :ARG1~e.11 (p / phosphorylate-01~e.14 :ARG1 (a2 / amino-acid :mod 576 :name (n2 / name :op1 "tyrosine") :part-of (e2 / enzyme :name (n3 / name :op1 "FAK"~e.12)))))) :ARG2 (a3 / associate-01~e.7 :polarity~e.4 -~e.4 :ARG1 (e3 / expose-01~e.0 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "SPP86"~e.5))) :ARG2 r) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.16 :mod "2B"))) # ::id pmid_2540_9876.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Neither PF273228 nor SPP86 suppressed Src phosphorylation ( Figure 2 @ D ) . # ::alignments 0-1.1.r 1-1.2.1.1.1 2-1.1 2-1.1.r 3-1.2.2.1.1 4-1 5-1.3.1.1.1 6-1.3 8-1.4.1 (s / suppress-01~e.4 :polarity~e.0,2 -~e.2 :ARG0 (a / and :op1 (s2 / small-molecule :name (n / name :op1 "PF273228"~e.1)) :op2 (s3 / small-molecule :name (n2 / name :op1 "SPP86"~e.3))) :ARG1 (p / phosphorylate-01~e.6 :ARG1 (p2 / protein :name (n3 / name :op1 "Src"~e.5))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.8 :mod "2D"))) # ::id pmid_2540_9876.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 inhibited TPC1 cell proliferation more effectively than PF573228 ( 49 % proliferation vs. 77 %) but no additive effect was observed following co @-@ exposure to both drugs ( Figure 2 @ E ) . # ::alignments 0-1.1.1.1.1 1-1.1 1-1.1.3.3 2-1.1.2.1.1.1 3-1.1.2.1 4-1.1.2 4-1.1.3.3.2 5-1.1.3.2 6-1.1.3 7-1.1.3.3.r 8-1.1.3.3.1.1.1 10-1.1.2.2.1 11-1.1.2.2 11-1.1.3.3.2.2 12-1.1.2 14-1.1.3.3.r 16-1.1.3.3.2.2.1 18-1 19-1.2.1 19-1.2.1.r 20-1.2.2.1 21-1.2.2 23-1.2 24-1.2.3 27-1.2.3.1 32-1.3.1 (c2 / contrast-01~e.18 :ARG1 (i / inhibit-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.0)) :ARG1 (p3 / proliferate-01~e.4,12 :ARG0 (c / cell-line~e.3 :name (n2 / name :op1 "TPC1"~e.2)) :degree (p / percentage-entity~e.11 :value 49~e.10)) :ARG1-of (e / effective-04~e.6 :ARG0 s :degree (m / more~e.5) :compared-to~e.7,14 (i2 / inhibit-01~e.1 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "PF573228"~e.8)) :ARG1 (p4 / proliferate-01~e.4 :ARG0 c :degree (p2 / percentage-entity~e.11 :value 77~e.16))))) :ARG2 (o / observe-01~e.23 :polarity~e.19 -~e.19 :ARG1 (a / affect-01~e.21 :ARG2 (a2 / add-02~e.20)) :ARG1-of (f2 / follow-01~e.24 :ARG2 (e2 / expose-01~e.27 :ARG2 (a3 / and :op1 s :op2 s3)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.32 :mod "2E"))) # ::id pmid_2540_9876.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Our observations strongly suggested that SPP86 would selectively inhibit RET @- induced proliferation . # ::alignments 0-1.1.1 0-1.1.1.r 1-1.1 2-1.3 3-1 4-1.2.r 5-1.2.1.1.1 8-1.2 9-1.2.2.1.1.1.1 11-1.2.2.1 12-1.2.2 (s / suggest-01~e.3 :ARG0 (o / observe-01~e.1 :ARG0~e.0 (w / we~e.0)) :ARG1~e.4 (i / inhibit-01~e.8 :ARG0 (s3 / small-molecule :name (n / name :op1 "SPP86"~e.5)) :ARG1 (p / proliferate-01~e.12 :ARG2-of (i2 / induce-01~e.11 :ARG0 (p2 / protein :name (n2 / name :op1 "RET"~e.9)))) :manner (s4 / select-01)) :ARG1-of (s2 / strong-02~e.2)) # ::id pmid_2540_9876.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We thus compared the effect of sorafenib and SPP86 on the proliferation of TPC1 , 8505C and C643 cells in media containing 0.1 % serum ( i.e . low culture conditions ) . # ::alignments 0-1.1.1 1-1 2-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1.1.1.1 7-1.1.2.1 8-1.1.2.1.2.1.1 9-1.1.2.2.r 11-1.1.2.2 12-1.1.2.2.1.r 13-1.1.2.2.1.1.1.1 15-1.1.2.2.1.2.1.1 16-1.1.2.2.1 17-1.1.2.2.1.3.1.1 18-1.1.2.2.1.1 18-1.1.2.2.1.2 18-1.1.2.2.1.3 19-1.1.2.3.r 20-1.1.2.3 21-1.1.2.3.1 22-1.1.2.3.1.1.1 23-1.1.2.3.1.1 24-1.1.2.3.1.1.2 28-1.1.2.3.1.2.1.1 29-1.1.2.3.1.2.1 30-1.1.2.3.1.2 (c / cause-01~e.1 :ARG1 (c2 / compare-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / affect-01~e.4 :ARG0~e.5 (a2 / and~e.7 :op1 (s / small-molecule :name (n / name :op1 "sorafenib"~e.6)) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"~e.8))) :ARG1~e.9 (p2 / proliferate-01~e.11 :ARG0~e.12 (a3 / and~e.16 :op1 (c3 / cell-line~e.18 :name (n3 / name :op1 "TPC1"~e.13)) :op2 (c4 / cell-line~e.18 :name (n4 / name :op1 "8505C"~e.15)) :op3 (c5 / cell-line~e.18 :name (n5 / name :op1 "C643"~e.17)))) :location~e.19 (m / medium~e.20 :ARG0-of (c6 / contain-01~e.21 :ARG1 (p / percentage-entity~e.23 :value 0.1~e.22 :quant-of (s3 / serum~e.24)) :example (c7 / condition~e.30 :mod (c8 / culture~e.29 :ARG1-of (l / low-04~e.28)))))))) # ::id pmid_2540_9876.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Under these conditions , signaling pathway activation is predominantly under the control of the respective oncogenes expressed by these cell lines . # ::alignments 1-1.3 2-1.3.r 4-1.1.1 5-1.1 6-1 8-1.2.2 11-1.2 12-1.2.1.r 14-1.2.1.1 15-1.2.1 16-1.2.1.2 17-1.2.1.2.1.r 18-1.2.1.2.1.1 19-1.2.1.2.1 20-1.2.1.2.1 (a / activate-01~e.6 :ARG1 (p / pathway~e.5 :ARG0-of (s / signal-07~e.4)) :ARG1-of (c / control-01~e.11 :ARG0~e.12 (o / oncogene~e.15 :mod (r / respective~e.14) :ARG1-of (e / express-03~e.16 :ARG3~e.17 (c2 / cell-line~e.19,20 :mod (t / this~e.18)))) :ARG1-of (p2 / predominate-01~e.8)) :condition~e.2 (t2 / this~e.1)) # ::id pmid_2540_9876.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok C643 and TPC1 cells showed marked differential sensitivity to SPP86 ( IC @₅₀ , 61.5 vs 1.5 μM for C643 and TPC1 cells respectively ) ( Figure 3 @ A ) . # ::alignments 0-1.1.1.1.1 1-1.1 2-1.1.2.1.1 3-1.1.1 3-1.1.2 4-1 5-1.2.5 6-1.2.3 7-1.2 8-1.2.2.r 9-1.2.2.1.1 11-1.2.4.1.1 11-1.2.4.1.2 13-1.2.4.1.1.1 13-1.2.4.1.2.1 16-1.2.4.1.1.3.1 18-1.2.4.1.2.3.1 19-1.2.4.1.1.3.2 20-1.2.4.1.1.4.r 21-1.2.4.1.1.4 22-1.2.1 23-1.2.1 24-1.2.1 28-1.3.1 (s / show-01~e.4 :ARG0 (a / and~e.1 :op1 (c / cell-line~e.3 :name (n / name :op1 "C643"~e.0)) :op2 (c2 / cell-line~e.3 :name (n2 / name :op1 "TPC1"~e.2))) :ARG1 (s2 / sensitive-03~e.7 :ARG0 a~e.22,23,24 :ARG1~e.8 (s3 / small-molecule :name (n3 / name :op1 "SPP86"~e.9)) :ARG1-of (d / differ-02~e.6) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (h3 / have-percentage-maximal-inhibitory-concentration-01~e.11 :ARG2 50~e.13 :ARG1 s3 :ARG4 (c3 / concentration-quantity :quant 61.5~e.16 :unit (m2 / micromolar~e.19)) :location~e.20 c~e.21) :op2 (h / have-percentage-maximal-inhibitory-concentration-01~e.11 :ARG2 50~e.13 :ARG1 s3 :ARG4 (c4 / concentration-quantity :quant 1.5~e.18 :unit m2) :location c2))) :ARG1-of (m4 / mark-01~e.5)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.28 :mod "3A"))) # ::id pmid_2540_9876.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , 8505C cells grew poorly under low serum conditions ( data not shown ) , but their proliferation was enhanced when exposed to doses of SPP86 from 1 @–@ 10 μM ( Figure 3 @ A ) . # ::alignments 1-1 1-1.1 1-1.1.r 3-1.1.1.1.1.1 4-1.1.1.1 5-1.1.1 6-1.1.1.2 8-1.1.1.3.1 9-1.1.1.3 10-1.1.1.3.r 12-1.1.1.4.1 13-1.1.1.4.1.1.1 13-1.1.1.4.1.1.1.r 14-1.1.1.4.1.1 17-1.1 18-1.1.2.1.1 18-1.1.2.1.1.r 19-1.1.2.1 21-1.1.2 23-1.1.2.2 24-1.1.2.2.2.r 25-1.1.2.2.2 26-1.1.2.2.2.1.r 27-1.1.2.2.2.1.1.1 29-1.1.2.2.2.1.2.1.1 31-1.1.2.2.2.1.2.1.2 32-1.1.2.2.2.1.2.2 34-1.2.1 (c / contrast-01~e.1 :ARG2~e.1 (c3 / contrast-01~e.1,17 :ARG1 (g / grow-01~e.5 :ARG1 (c2 / cell-line~e.4 :name (n / name :op1 "8505C"~e.3)) :mod (p / poor~e.6) :condition~e.10 (s / serum~e.9 :ARG1-of (l / low-04~e.8)) :ARG1-of (d / describe-01 :ARG0 (d2 / data~e.12 :ARG1-of (s2 / show-01~e.14 :polarity~e.13 -~e.13)))) :ARG2 (e / enhance-01~e.21 :ARG1 (p2 / proliferate-01~e.19 :ARG0~e.18 c2~e.18) :condition (e2 / expose-01~e.23 :ARG1 c2 :ARG2~e.24 (d3 / dose-01~e.25 :ARG1~e.26 (s3 / small-molecule :name (n2 / name :op1 "SPP86"~e.27) :quant (c4 / concentration-quantity :quant (v / value-interval :op1 1~e.29 :op2 10~e.31) :unit (m / micromolar~e.32))))))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure~e.34 :mod "3A"))) # ::id pmid_2540_9876.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Under similar conditions , the IC @₅₀ values for sorafenib were 3.1 μM , 0.28 μM , and 33.3 μM for C643 , TPC1 and 8505C cells respectively ( Figure 3 @ B ) . # ::alignments 1-1.4.1 2-1.4 2-1.4.r 5-1.1 5-1.2 5-1.3 7-1.1.1 7-1.2.1 7-1.3.1 10-1.1.2.r 11-1.1.2.1.1 13-1.1.3.1 14-1.1.3.2 16-1.2.3.1 17-1.1.3.2 19-1 20-1.3.3.1 21-1.3.3.2 23-1.1.4.1.1 25-1.2.4.1.1 26-1 27-1.3.4.1.1 28-1.1.4 28-1.2.4 28-1.3.4 31-1.5.1 (a / and~e.19,26 :op1 (h4 / have-percentage-maximal-inhibitory-concentration-01~e.5 :ARG2 50~e.7 :ARG1~e.10 (s / small-molecule :name (n4 / name :op1 "sorafenib"~e.11)) :ARG4 (c2 / concentration-quantity :quant 3.1~e.13 :unit (m / micromolar~e.14,17)) :location (c / cell-line~e.28 :name (n / name :op1 "C643"~e.23))) :op2 (h / have-percentage-maximal-inhibitory-concentration-01~e.5 :ARG2 50~e.7 :ARG1 s :ARG4 (c4 / concentration-quantity :quant 0.28~e.16 :unit m) :location (c3 / cell-line~e.28 :name (n2 / name :op1 "TPC1"~e.25))) :op3 (h2 / have-percentage-maximal-inhibitory-concentration-01~e.5 :ARG2 50~e.7 :ARG1 s :ARG4 (c6 / concentration-quantity :quant 33.3~e.20 :unit m~e.21) :location (c5 / cell-line~e.28 :name (n3 / name :op1 "8505C"~e.27))) :condition~e.2 (c7 / condition~e.2 :ARG1-of (r / resemble-01~e.1)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.31 :mod "3B"))) # ::id pmid_2540_9876.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In general , low doses of SPP86 do not inhibit the activity of signaling proteins downstream of RET or other kinases that directly interact with it [ @ 45 @ ] . # ::alignments 1-1.4 3-1.2.2 4-1.2 5-1.2.1.r 6-1.2.1.1.1 8-1.1 8-1.1.r 9-1 11-1.3 12-1.3.1.r 13-1.3.1.1.1 14-1.3.1.1 15-1.3.1.1.2.2 17-1.3.1.1.2.1.1.1 18-1.3.1 19-1.3.1.2.1 20-1.3.1.2 22-1.3.1.2.2.2 23-1.3.1.2.2 24-1.3.1.2.2.1.r 25-1.3.1.2.2.1 28-1.5.1.1.1 (i / inhibit-01~e.9 :polarity~e.8 -~e.8 :ARG0 (d / dose-01~e.4 :ARG2~e.5 (s / small-molecule :name (n / name :op1 "SPP86"~e.6)) :ARG1-of (l / low-04~e.3)) :ARG1 (a / activity-06~e.11 :ARG0~e.12 (o2 / or~e.18 :op1 (p / protein~e.14 :ARG0-of (s2 / signal-07~e.13) :location (r / relative-position :op1 (p2 / protein :name (n2 / name :op1 "RET"~e.17)) :direction (d2 / downstream~e.15))) :op2 (k / kinase~e.20 :mod (o / other~e.19) :ARG0-of (i2 / interact-01~e.23 :ARG1~e.24 s~e.25 :ARG1-of (d3 / direct-02~e.22))))) :ARG1-of (g / general-02~e.1) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 45~e.28)))) # ::id pmid_2540_9876.143 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 thus selectively inhibited the proliferation of TPC1 cells dependent on oncogenic RET but not 8505C and C643 cells respectively dependent on oncogenic BRAF and RAS . # ::alignments 0-1.1.1.1.1.1 1-1.1.1.2.1.2.1 1-1.1.1.2.1.2.1.2 1-1.1.1.2.1.2.1.2.r 2-1.1.1.3 2-1.1.1.3.r 3-1.1.1 3-1.1.2 5-1.1.1.2 7-1.1.1.2.1.1.1 8-1.1.1.2.1 9-1.1.1.2.1.2 11-1 11-1.1.1.2.1.2.1 11-1.1.1.2.1.2.1.2 11-1.1.1.2.1.2.1.2.1 11-1.1.1.2.1.2.1.2.1.r 11-1.1.1.2.1.2.1.2.r 12-1.1.1.2.1.2.1.1.1 13-1.1 14-1.1.2.1 14-1.1.2.1.r 15-1.1.2.3.1.1.1 16-1.1.2.3 17-1.1.2.3.2.1.1 18-1.1.2.3.1 18-1.1.2.3.2 19-1.1.2.3.4 20-1.1.1.2.1.2 20-1.1.2.3.3 21-1.1.2.3.3.1.r 22-1.1.2.3.3.1.3 23-1.1.2.3.3.1.1.1.1 24-1.1.2.3.3.1 25-1.1.2.3.3.1.2.1.1 (c / cause-01~e.11 :ARG1 (c5 / contrast-01~e.13 :ARG1 (i / inhibit-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.0)) :ARG1 (p / proliferate-01~e.5 :ARG0 (c2 / cell-line~e.8 :name (n2 / name :op1 "TPC1"~e.7) :ARG0-of (d / depend-01~e.9,20 :ARG1 (p2 / protein~e.1,11 :name (n3 / name :op1 "RET"~e.12) :ARG0-of~e.1,11 (c3 / cause-01~e.1,11 :ARG1~e.11 (c4 / cancer~e.11)))))) :manner~e.2 (s3 / selective~e.2)) :ARG2 (i2 / inhibit-01~e.3 :polarity~e.14 -~e.14 :ARG0 s :ARG1 (a / and~e.16 :op1 (c6 / cell-line~e.18 :name (n4 / name :op1 "8505C"~e.15)) :op2 (c7 / cell-line~e.18 :name (n5 / name :op1 "C643"~e.17)) :ARG0-of (d2 / depend-01~e.20 :ARG1~e.21 (a2 / and~e.24 :op1 (e / enzyme :name (n6 / name :op1 "BRAF"~e.23)) :op2 (e2 / enzyme :name (n7 / name :op1 "RAS"~e.25)) :ARG0-of c3~e.22)) :mod (r / respective~e.19))))) # ::id pmid_2540_9876.144 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 inhibits RET signaling in ERα positive breast cancer cells # ::alignments 1-1.1.1.1 2-1 3-1.2.1.1.1 4-1.2 5-1.3.r 6-1.3.2.1.1 7-1.3.2.2 8-1.3.1.1 9-1.3.1 10-1.3 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.1)) :ARG1 (s2 / signal-07~e.4 :ARG0 (p / protein :name (n2 / name :op1 "RET"~e.3))) :location~e.5 (c / cell~e.10 :mod (c2 / cancer~e.9 :mod (b / breast~e.8)) :mod (p3 / protein :name (n3 / name :op1 "ERα"~e.6) :mod (p2 / positive~e.7)))) # ::id pmid_2540_9876.145 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition to its role in thyroid cancers , RET has been shown to functionally interact with ERα in human breast cancer cell lines [ @ 5 , 6 , 51 , 52 @ ] . # ::alignments 0-1.3.1.1.1 1-1.2 1-1.3.1.1.1 2-1.2.1.r 3-1.2.1.2 3-1.2.1.2.r 4-1.2.1 5-1.2.1.1.r 6-1.2.1.1.1 7-1.2.1.1 9-1.1.1.1.1 12-1 14-1.1.3 15-1.1 16-1.1.2.r 17-1.1.2.1.1 18-1.1.4.r 19-1.1.4.1 20-1.1.4.2.1 21-1.1.4.2 22-1.1.4 23-1.1.4 26-1.3.1.1.1.1 30-1.3.1.1.1.2 34-1.3.1.1.1.3 38-1.3.1.1.1.4 (s / show-01~e.12 :ARG1 (i / interact-01~e.15 :ARG0 (p / protein :name (n / name :op1 "RET"~e.9)) :ARG1~e.16 (p2 / protein :name (n2 / name :op1 "ERα"~e.17)) :ARG1-of (f / function-01~e.14) :location~e.18 (c / cell-line~e.22,23 :mod (h / human~e.19) :mod (c2 / cancer~e.21 :mod (b / breast~e.20)))) :ARG1-of (a / add-02~e.1 :ARG2~e.2 (r / role~e.4 :topic~e.5 (c3 / cancer~e.7 :mod (t / thyroid~e.6)) :poss~e.3 p~e.3)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 (a2 / and~e.0,1 :op1 5~e.26 :op2 6~e.30 :op3 51~e.34 :op4 52~e.38))))) # ::id pmid_2540_9876.146 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We thus evaluated the utility of using SPP86 to interrogate RET signaling in MCF7 breast cancer cells . # ::alignments 0-1.1.1 1-1 2-1.1 4-1.1.2 5-1.1.2.1.r 6-1.1.2.1 7-1.1.2.1.2.1.1 9-1.1.2.1.3 10-1.1.2.1.3.2.1.1.1 11-1.1.2.1.3.2 12-1.1.2.1.3.3.r 13-1.1.2.1.3.3.1.1 14-1.1.2.1.3.3.2.1 15-1.1.2.1.3.3.2 16-1.1.2.1.3.3 (c / cause-01~e.1 :ARG1 (e / evaluate-01~e.2 :ARG0 (w / we~e.0) :ARG1 (u / utility~e.4 :poss~e.5 (u2 / use-01~e.6 :ARG0 w :ARG1 (s / small-molecule :name (n / name :op1 "SPP86"~e.7)) :ARG2 (i / interrogate-01~e.9 :ARG0 w :ARG1 (s2 / signal-07~e.11 :ARG0 (p / protein :name (n2 / name :op1 "RET"~e.10))) :location~e.12 (c2 / cell-line~e.16 :name (n3 / name :op1 "MCF7"~e.13) :mod (c3 / cancer~e.15 :mod (b / breast~e.14)))))))) # ::id pmid_2540_9876.147 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Firstly , we studied the effect of SPP86 on RET @- mediated ERα phosphorylation on serine residue 167 ( Ser167 ) . # ::alignments 2-1.1 3-1 5-1.2 6-1.2.1.r 7-1.2.1.1.1 8-1.2.2.r 9-1.2.2.2.1.1.1 11-1.2.2.2 12-1.2.2.1.2.1.1 13-1.2.2 15-1.2.2.1.1.2.1 16-1.2.2.1 17-1.2.2.1.1.1 (s / study-01~e.3 :ARG0 (w / we~e.2) :ARG1 (a / affect-01~e.5 :ARG0~e.6 (s2 / small-molecule :name (n / name :op1 "SPP86"~e.7)) :ARG1~e.8 (p / phosphorylate-01~e.13 :ARG1 (r / residue~e.16 :mod (a2 / amino-acid :mod 167~e.17 :name (n4 / name :op1 "serine"~e.15)) :part-of (p2 / protein :name (n2 / name :op1 "ERα"~e.12))) :ARG1-of (m / mediate-01~e.11 :ARG0 (p3 / protein :name (n3 / name :op1 "RET"~e.9))))) :time (f / first)) # ::id pmid_2540_9876.148 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Estrogen deprived and serum starved MCF7 cells were exposed to 10 ng @/@ ml GDNF in the absence or presence of increasing does of SPP86 . # ::alignments 0-1.1.2.1.1.1 1-1.1.2 3-1.1.3.1 4-1.1.3 5-1.1.1.1 6-1.1 8-1 9-1.2.r 10-1.2.2.1 11-1.2.2.2 13-1.2.2.2 14-1.2.1.1 15-1.3.r 17-1.3.1 18-1.3 19-1.3.2 21-1.3.1.1.2 24-1.3.1.1.1.1.1 (e / expose-01~e.8 :ARG1 (c / cell-line~e.6 :name (n / name :op1 "MCF7"~e.5) :ARG2-of (d / deprive-01~e.1 :ARG1 (s / small-molecule :name (n2 / name :op1 "estrogen"~e.0))) :ARG1-of (s2 / starve-01~e.4 :ARG2 (s3 / serum~e.3))) :ARG2~e.9 (p / protein :name (n3 / name :op1 "GDNF"~e.14) :quant (c2 / concentration-quantity :quant 10~e.10 :unit (n4 / nanogram-per-milliliter~e.11,13))) :condition~e.15 (o / or~e.18 :op1 (a / absent-01~e.17 :ARG1 (d2 / dose-01 :ARG2 (s4 / small-molecule :name (n5 / name :op1 "SPP86"~e.24)) :ARG1-of (i / increase-01~e.21))) :op2 (p2 / present-02~e.19 :ARG1 d2))) # ::id pmid_2540_9876.149 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In these experiments , SPP86 effectively inhibited GDNF @/@ RET @- induced ERα phosphorylation at a concentration of 0.1 μM ( Figure 4 @ A ) . # ::alignments 1-1.3.1 2-1.3 4-1.1.1.1 5-1.5 6-1 7-1.2.2.1.1.1 9-1.2.2.1.1.1 11-1.2.2 12-1.2.1.1.1 13-1.2 16-1.1.2 18-1.1.2.1 19-1.1.2.2 21-1.4.1 (i / inhibit-01~e.6 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.4) :quant (c / concentration-quantity~e.16 :quant 0.1~e.18 :unit (m / micromolar~e.19))) :ARG1 (p / phosphorylate-01~e.13 :ARG1 (p2 / protein :name (n2 / name :op1 "ERα"~e.12)) :ARG2-of (i2 / induce-01~e.11 :ARG0 (p3 / pathway :name (n3 / name :op1 "GDNF/RET"~e.7,9)))) :location (e / experiment-01~e.2 :mod (t / this~e.1)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "4A")) :ARG1-of (e2 / effective-04~e.5)) # ::id pmid_2540_9876.150 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Higher concentrations of SPP86 , 1 @–@ 10 μM , reduced ERα phosphorylation even below baseline levels . # ::alignments 0-1.1.2 0-1.1.2.1 0-1.1.2.1.r 1-1.1 1-1.1.1.2 2-1.1.1.r 3-1.1.1.1.1 5-1.1.1.2.1.1 7-1.1.1.2.1.2 8-1.1.1.2.2 10-1 11-1.2.1.1.1 12-1.2 13-1.3.2 14-1.3 15-1.3.1.1 16-1.3.1 (r / reduce-01~e.10 :ARG0 (c / concentrate-02~e.1 :ARG1~e.2 (s / small-molecule :name (n / name :op1 "SPP86"~e.3) :quant (c2 / concentration-quantity~e.1 :quant (v / value-interval :op1 1~e.5 :op2 10~e.7) :unit (m2 / micromolar~e.8))) :ARG1-of (h / high-02~e.0 :degree~e.0 (m / more~e.0))) :ARG1 (p / phosphorylate-01~e.12 :ARG1 (p2 / protein :name (n3 / name :op1 "ERα"~e.11))) :ARG2 (b / below~e.14 :op1 (l / level~e.16 :mod (b2 / baseline~e.15)) :mod (e / even~e.13))) # ::id pmid_2540_9876.151 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In addition , exposure of MCF7 cells to SPP86 was associated with a moderate decrease in ERα levels in these experiments ( Figure 4 @ A ) We next investigated the effect of SPP86 on RET @- mediated activation of these pathways in MCF7 cells . # ::alignments 1-1.1.5 3-1.1.1 4-1.1.1.1.r 5-1.1.1.1.1.1 6-1.1.1.1 7-1.1.1.2.r 8-1.1.1.2.1.1 10-1.1 11-1.1.2.r 13-1.1.2.2 14-1.1.2 15-1.1.2.1.r 16-1.1.2.1.1.1.1 17-1.1.2.1 18-1.1.3.r 19-1.1.3.1 20-1.1.3 22-1.1.4.1 28-1.2.1 29-1.2.3 30-1.2 32-1.2.2 33-1.2.2.1.r 34-1.2.2.1.1.1 35-1.2.2.2.r 36-1.2.2.2.2.1.1.1 38-1.2.2.2.2 39-1.2.2.2 40-1.2.2.2.1.r 41-1.2.2.2.1.1 42-1.2.2.2.1 43-1.2.2.2.3.r 44-1.2.2.2.3.1.1 45-1.2.2.2.3 (m / multi-sentence :snt1 (a / associate-01~e.10 :ARG1 (e / expose-01~e.3 :ARG1~e.4 (c / cell-line~e.6 :name (n / name :op1 "MCF7"~e.5)) :ARG2~e.7 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.8))) :ARG2~e.11 (d / decrease-01~e.14 :ARG1~e.15 (l / level~e.17 :quant-of (p / protein :name (n3 / name :op1 "ERα"~e.16))) :ARG2 (m2 / moderate-03~e.13)) :location~e.18 (e2 / experiment-01~e.20 :mod (t / this~e.19)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.22 :mod "4A")) :ARG1-of (a4 / add-02~e.1)) :snt2 (i / investigate-01~e.30 :ARG0 (w / we~e.28) :ARG1 (a2 / affect-01~e.32 :ARG0~e.33 (s2 / small-molecule :name (n4 / name :op1 "SPP86"~e.34)) :ARG1~e.35 (a3 / activate-01~e.39 :ARG1~e.40 (p3 / pathway~e.42 :mod t~e.41) :ARG1-of (m3 / mediate-01~e.38 :ARG0 (p2 / protein :name (n5 / name :op1 "RET"~e.36))) :location~e.43 (c2 / cell-line~e.45 :name (n6 / name :op1 "MCF7"~e.44)))) :time (n7 / next~e.29))) # ::id pmid_2540_9876.152 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 inhibited GDNF/ RET @- induced phosphorylation of Akt and its downstream signaling at concentrations as low as 0.1 μM ( Figure 4 @ B ) . # ::alignments 0-1.1.1.1 1-1 3-1.2.1.2.1.1.1 5-1.2.1.2 6-1.2.1 7-1.2.1.1.r 8-1.2.1.1.1.1 9-1.2 10-1.2.2.1 10-1.2.2.1.r 11-1.2.2.2 12-1.2.2 13-1.4.r 14-1.4 15-1.4.3.r 16-1.4.3 18-1.4.1 19-1.4.2 21-1.3.1 (i / inhibit-01~e.1 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.0)) :ARG1 (a / and~e.9 :op1 (p / phosphorylate-01~e.6 :ARG1~e.7 (e / enzyme :name (n2 / name :op1 "Akt"~e.8)) :ARG2-of (i2 / induce-01~e.5 :ARG0 (p2 / pathway :name (n3 / name :op1 "GDNF/RET"~e.3)))) :op2 (s3 / signal-07~e.12 :ARG0~e.10 e~e.10 :location (d / downstream~e.11))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.21 :mod "4B")) :condition~e.13 (c2 / concentration-quantity~e.14 :quant 0.1~e.18 :unit (m / micromolar~e.19) :ARG1-of~e.15 (l / low-04~e.16))) # ::id pmid_2540_9876.153 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We noted that SPP86 inhibited phosphorylation of Akt more effectively than that of its downstream target p70S6K at this concentration . # ::alignments 0-1.1 1-1 2-1.2.r 3-1.2.1.1.1 4-1.2 5-1.2.2 6-1.2.2.1.r 7-1.2.2.1.1.1 8-1.2.3.1 9-1.2.3 10-1.2.3.2.r 13-1.2.3.2.1 13-1.2.3.2.1.r 14-1.2.3.2.3 15-1.2.3.2 16-1.2.3.2.2.1.1 17-1.2.4.r 18-1.2.4.1 19-1.2.4 (n / note-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (i / inhibit-01~e.4 :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.3)) :ARG1 (p / phosphorylate-01~e.5 :ARG1~e.6 (e / enzyme :name (n3 / name :op1 "Akt"~e.7))) :ARG1-of (e2 / effective-04~e.9 :degree (m / more~e.8) :compared-to~e.10 (t / target-01~e.15 :ARG0~e.13 s~e.13 :ARG1 (e3 / enzyme :name (n4 / name :op1 "p70S6K"~e.16)) :location (d / downstream~e.14))) :condition~e.17 (c / concentration-quantity~e.19 :mod (t2 / this~e.18)))) # ::id pmid_2540_9876.154 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Similarly , SPP86 inhibited Akt phosphorylation at markedly lower concentrations than those required to inhibit MAPK phosphorylation ( 0.1 vs. 1.0 μM ) ( Figure 4 @ B ) . # ::alignments 0-1.4 2-1.1.1.1 3-1 4-1.2.1.1.1 5-1.2 6-1.5.r 7-1.5.3.1.1 8-1.5.3 8-1.5.3.1 8-1.5.3.1.r 9-1.5 9-1.5.3.2 10-1.5.3.2.r 12-1.5.3.2.3 14-1.5.3.2.3.1 15-1.5.3.2.3.1.1.1.1.1 16-1.5.3.2.3.1.1 18-1.5.1 19-1.5.3.2.r 20-1.5.3.2.1 21-1.5.2 24-1.3.1 (i / inhibit-01~e.3 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.2)) :ARG1 (p / phosphorylate-01~e.5 :ARG1 (e / enzyme :name (n2 / name :op1 "Akt"~e.4))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.24 :mod "4B")) :ARG1-of (r2 / resemble-01~e.0) :condition~e.6 (c3 / concentration-quantity~e.9 :quant 0.1~e.18 :unit (m3 / micromolar~e.21) :ARG1-of (l / low-04~e.8 :degree~e.8 (m / more~e.8 :degree (m4 / marked~e.7)) :compared-to~e.10,19 (c4 / concentration-quantity~e.9 :quant 1.0~e.20 :unit m3 :ARG1-of (r / require-01~e.12 :ARG2 (i2 / inhibit-01~e.14 :ARG1 (p2 / phosphorylate-01~e.16 :ARG1 (e2 / enzyme :name (n3 / name :op1 "MAPK"~e.15))))))))) # ::id pmid_2540_9876.155 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 effectively inhibited GDNF @- induced RET phosphorylation Tyr1062 at a concentration of 1.0 μM . # ::alignments 0-1.1.1.1 1-1.3 2-1 3-1.2.2.1.1.1 5-1.2.2 6-1.2.1.3.1.1 7-1.2 11-1.1.2 13-1.1.2.1 14-1.1.2.2 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.0) :quant (c / concentration-quantity~e.11 :quant 1.0~e.13 :unit (m / micromolar~e.14))) :ARG1 (p / phosphorylate-01~e.7 :ARG1 (a / amino-acid :mod 1062 :name (n4 / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "RET"~e.6))) :ARG2-of (i2 / induce-01~e.5 :ARG0 (p3 / protein :name (n3 / name :op1 "GDNF"~e.3)))) :ARG1-of (e / effective-04~e.1)) # ::id pmid_2540_9876.156 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , FAK inhibition with PF573228 only moderately inhibited RET phosphorylation . # ::alignments 1-1 3-1.1.1.2.1.1 4-1.1.1 6-1.1.1.1.1.1 7-1.1.3.1 8-1.1.3 9-1.1 9-1.1.1 9-1.1.1.r 10-1.1.2.1.1.1 11-1.1.2 (c / contrast-01~e.1 :ARG2 (i / inhibit-01~e.9 :ARG0~e.9 (i2 / inhibit-01~e.4,9 :ARG0 (s / small-molecule :name (n / name :op1 "PF573228"~e.6)) :ARG1 (e / enzyme :name (n2 / name :op1 "FAK"~e.3))) :ARG1 (p2 / phosphorylate-01~e.11 :ARG1 (p3 / protein :name (n3 / name :op1 "RET"~e.10))) :ARG1-of (m / moderate-03~e.8 :mod (o / only~e.7)))) # ::id pmid_2540_9876.157 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Co @- exposure to PF573228 and SPP86 however , exerted an additive inhibitory effect on RET phosphorylation ( Figure 4 @ C ) . # ::alignments 4-1.1.1.1.1.1.1 5-1.1.1.1 6-1.1.1.1.2.1.1 7-1 9-1.1 11-1.1.2.4 12-1.1.2.3 13-1.1.2 14-1.1.2.2.r 15-1.1.2.2.1.1.1 16-1.1.2.2 18-1.2.1 (h / have-concession-91~e.7 :ARG1 (e / exert-01~e.9 :ARG0 (c / coexpose-00 :ARG2 (a / and~e.5 :op1 (s / small-molecule :name (n / name :op1 "PF573228"~e.4)) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"~e.6)))) :ARG1 (a2 / affect-01~e.13 :ARG0 c :ARG1~e.14 (p / phosphorylate-01~e.16 :ARG1 (p2 / protein :name (n3 / name :op1 "RET"~e.15))) :ARG2 (i / inhibit-01~e.12) :ARG1-of (a3 / add-02~e.11))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.18 :mod "4C"))) # ::id pmid_2540_9876.158 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both PF573228 and SPP86 inhibited GDNF @- induced ERK1 @/@ 2 and Akt phosphorylation ( Figure 4 @ C and Additional file 1 @ A ) . # ::alignments 1-1.1.1.1.1 2-1.1 3-1.1.2.1.1 4-1 5-1.2.2.1.1.1 7-1.2.2 8-1.2.1.1.1.1 10-1.2.1.1.1.1 11-1.2.1 12-1.2.1.2.1.1 13-1.2 15-1.3.1.1 20-1.3.1 22-1.3.1.2 (i / inhibit-01~e.4 :ARG0 (a / and~e.2 :op1 (s / small-molecule :name (n / name :op1 "PF573228"~e.1)) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"~e.3))) :ARG1 (p / phosphorylate-01~e.13 :ARG1 (a2 / and~e.11 :op1 (e / enzyme :name (n3 / name :op1 "ERK1/2"~e.8,10)) :op2 (e2 / enzyme :name (n4 / name :op1 "Akt"~e.12))) :ARG2-of (i2 / induce-01~e.7 :ARG0 (p2 / protein :name (n5 / name :op1 "GDNF"~e.5)))) :ARG1-of (d / describe-01 :ARG0 (a3 / and~e.20 :op1 (f / figure~e.15 :mod "4C") :op2 (f2 / file~e.22 :mod "1A" :ARG1-of (a4 / add-02))))) # ::id pmid_2540_9876.159 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Prolonged exposure of MCF7 cells to SPP86 also lead to the suppression of cyclin D1 expression ( Figure 4 @ D ) . # ::alignments 0-1.1.3 1-1.1 2-1.1.1.r 3-1.1.1.1.1 4-1.1.1 5-1.1.2.r 6-1.1.2.1.1 7-1.3 8-1 9-1.2.r 11-1.2 12-1.2.2.r 13-1.2.2.1.1.1 14-1.2.2.1.1.2 15-1.2.2 17-1.4.1 (l / lead-03~e.8 :ARG0 (e / expose-01~e.1 :ARG1~e.2 (c / cell-line~e.4 :name (n / name :op1 "MCF7"~e.3)) :ARG2~e.5 (s / small-molecule :name (n2 / name :op1 "SPP86"~e.6)) :ARG1-of (p / prolong-01~e.0)) :ARG2~e.9 (s2 / suppress-01~e.11 :ARG0 e :ARG1~e.12 (e2 / express-03~e.15 :ARG1 (p2 / protein :name (n3 / name :op1 "cyclin"~e.13 :op2 "D1"~e.14)))) :mod (a / also~e.7) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.17 :mod "4D"))) # ::id pmid_2540_9876.160 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next compared the effects of sorafenib and SPP86 on PI3K @/@ Akt and MAPK pathway signaling , with a view to discriminate the direct effects of RET inhibition from those of a combined inhibition of RET and RAF . # ::alignments 0-1.1 1-1.4 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1 9-1.2.2.r 10-1.2.2.1.1.1.1 12-1.2.2.1.1.1.1 13-1.2.2.1 14-1.2.2.1.2.1.1 15-1.2.2.1.1 15-1.2.2.1.2 16-1.2.2 22-1.3 24-1.3.2.1.2 25-1.3.2.1 25-1.3.2.2 27-1.3.2.1.1.1.1.1 28-1.3.2.1.1 28-1.3.2.2.1 33-1.3.2.2.1.2 34-1.3.2.2.1 35-1.3.2.2.1.1.r 36-1.3.2.2.1.1.1 37-1.3.2.2.1.1 38-1.3.2.2.1.1.2.1.1 (c / compare-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / affect-01~e.4 :ARG0~e.5 (a2 / and~e.7 :op1 (s / small-molecule :name (n / name :op1 "sorafenib"~e.6)) :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"~e.8))) :ARG1~e.9 (s3 / signal-07~e.16 :ARG0 (a3 / and~e.13 :op1 (p / pathway~e.15 :name (n3 / name :op1 "PI3K/Akt"~e.10,12)) :op2 (p2 / pathway~e.15 :name (n4 / name :op1 "MAPK"~e.14))))) :purpose (d / discriminate-01~e.22 :ARG0 w :ARG1 (a5 / and :op1 (a4 / affect-01~e.25 :ARG0 (i / inhibit-01~e.28 :ARG1 (p3 / protein :name (n5 / name :op1 "RET"~e.27))) :ARG1-of (d2 / direct-02~e.24)) :op2 (a6 / affect-01~e.25 :ARG0 (i2 / inhibit-01~e.28,34 :ARG1~e.35 (a7 / and~e.37 :op1 p3~e.36 :op2 (p5 / protein-family :name (n7 / name :op1 "RAF"~e.38))) :ARG1-of (c2 / combine-01~e.33))))) :time (n8 / next~e.1)) # ::id pmid_2540_9876.161 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In these experiments , estrogen deprived and serum starved MCF7 cells were exposed to 10 ng @/@ ml GDNF alone or in the presence of either sorafenib or SPP86 . # ::alignments 1-1.4.1 2-1.4 4-1.1.2.1.1.1 5-1.1.2 7-1.1.3.1 8-1.1.3 9-1.1.1.1 10-1.1 12-1 13-1.2.r 14-1.2.2.1 15-1.2.2.2 17-1.2.2.2 18-1.2.1.1 19-1.3.1 20-1.3 20-1.3.2.1 21-1.3.r 23-1.3.2 26-1.3.2.1.1.1.1 27-1.3 28-1.3.2.1.2.1.1 (e / expose-01~e.12 :ARG1 (c / cell-line~e.10 :name (n / name :op1 "MCF7"~e.9) :ARG2-of (d / deprive-01~e.5 :ARG1 (s / small-molecule :name (n2 / name :op1 "estrogen"~e.4))) :ARG1-of (s2 / starve-01~e.8 :ARG2 (s3 / serum~e.7))) :ARG2~e.13 (p / protein :name (n3 / name :op1 "GDNF"~e.18) :quant (c2 / concentration-quantity :quant 10~e.14 :unit (n4 / nanogram-per-milliliter~e.15,17))) :manner~e.21 (o / or~e.20,27 :op1 (a / alone~e.19) :op2 (p2 / present-02~e.23 :ARG1 (o2 / or~e.20 :op1 (s4 / small-molecule :name (n5 / name :op1 "sorafenib"~e.26)) :op2 (s5 / small-molecule :name (n6 / name :op1 "SPP86"~e.28))))) :location (e2 / experiment-01~e.2 :mod (t / this~e.1))) # ::id pmid_2540_9876.162 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Analyses of the relative levels of phosphorylated Akt and ERK1 @/@ 2 demonstrated that both compounds effectively block GDNF @- induced RET signaling at concentrations as low as 1 μM ( Figure 4 @ E ) . # ::alignments 0-1.1 1-1.1.1.r 3-1.1.1.1.2 4-1.1.1.1 4-1.1.1.2 5-1.1.1.1.1.r 6-1.1.1.1.1.2 7-1.1.1.1.1.1.1 8-1.1.1 9-1.1.1.2.1.1.1 11-1.1.1.2.1.1.1 12-1 13-1.2.r 14-1.2.1.1 15-1.2.1 16-1.2.3 17-1.2 18-1.2.2.2.1.1.1 20-1.2.2.2 21-1.2.2.1.1.1 22-1.2.2 23-1.2.1.2.r 24-1.2.1.2 25-1.2.1.2.3.r 26-1.2.1.2.3 28-1.2.1.2.1 29-1.2.1.2.2 31-1.3.1 (d / demonstrate-01~e.12 :ARG0 (a / analyze-01~e.0 :ARG1~e.1 (a2 / and~e.8 :op1 (l / level~e.4 :quant-of~e.5 (e / enzyme :name (n / name :op1 "Akt"~e.7) :ARG3-of (p / phosphorylate-01~e.6)) :ARG1-of (r / relative-05~e.3)) :op2 (l2 / level~e.4 :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.9,11) :ARG3-of p) :ARG1-of r))) :ARG1~e.13 (b / block-01~e.17 :ARG0 (c / compound~e.15 :mod (b2 / both~e.14) :quant~e.23 (c2 / concentration-quantity~e.24 :quant 1~e.28 :unit (m / micromolar~e.29) :ARG1-of~e.25 (l3 / low-04~e.26))) :ARG1 (s / signal-07~e.22 :ARG0 (p2 / protein :name (n3 / name :op1 "RET"~e.21)) :ARG2-of (i / induce-01~e.20 :ARG0 (p3 / protein :name (n4 / name :op1 "GDNF"~e.18)))) :ARG1-of (e3 / effective-04~e.16)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.31 :mod "4E"))) # ::id pmid_2540_9876.163 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We noted however , that sorafenib inhibited Akt and ERK1 @/@ 2 slightly more effectively than SPP86 under these conditions ( Figure 4 @ E ) . # ::alignments 0-1.1.1 1-1.1 2-1 4-1.1.2.r 5-1.1.2.1.1.1 6-1.1.2 7-1.1.2.2.1.1.1 8-1.1.2.2 9-1.1.2.2.2.1.1 11-1.1.2.2.2.1.1 12-1.1.2.3.1.1 13-1.1.2.3.1 14-1.1.2.3 15-1.1.2.3.2.r 16-1.1.2.3.2.1.1 18-1.1.2.4.1 19-1.1.2.4 19-1.1.2.4.r 21-1.2.1 (h / have-concession-91~e.2 :ARG1 (n / note-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.4 (i / inhibit-01~e.6 :ARG0 (s / small-molecule :name (n2 / name :op1 "sorafenib"~e.5)) :ARG1 (a / and~e.8 :op1 (e / enzyme :name (n3 / name :op1 "Akt"~e.7)) :op2 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"~e.9,11))) :ARG1-of (e2 / effective-04~e.14 :degree (m / more~e.13 :degree (s2 / slight~e.12)) :compared-to~e.15 (s3 / small-molecule :name (n4 / name :op1 "SPP86"~e.16))) :condition~e.19 (c / condition~e.19 :mod (t / this~e.18)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "4E"))) # ::id pmid_2540_9876.164 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These differential effects on PI3K @/@ Akt and MAPK signaling may result may stem from the fact that sorafenib and SPP86 target different kinases at low concentrations . # ::alignments 0-1.1.1.3 1-1.1.1.2 2-1.1.1 3-1.1.1.1.r 4-1.1.1.1.1.1.1.1 6-1.1.1.1.1.1.1.1 7-1.1.1.1.1 8-1.1.1.1.1.2.1.1 9-1.1.1.1 10-1 12-1 13-1.1 18-1.1.2.1.1.1.1 19-1.1.2.1 20-1.1.2.1.2.1.1 21-1.1.2 22-1.1.2.2.1 23-1.1.2.2 24-1.1.2.3.r 25-1.1.2.3.1 26-1.1.2.3 (p / possible-01~e.10,12 :ARG1 (s / stem-01~e.13 :ARG1 (a / affect-01~e.2 :ARG1~e.3 (s2 / signal-07~e.9 :ARG0 (a2 / and~e.7 :op1 (p2 / pathway :name (n / name :op1 "PI3K/Akt"~e.4,6)) :op2 (p3 / pathway :name (n2 / name :op1 "MAPK"~e.8)))) :mod (d / differential~e.1) :mod (t / this~e.0)) :ARG2 (t2 / target-01~e.21 :ARG0 (a3 / and~e.19 :op1 (s3 / small-molecule :name (n3 / name :op1 "sorafenib"~e.18)) :op2 (s4 / small-molecule :name (n4 / name :op1 "SPP86"~e.20))) :ARG1 (k / kinase~e.23 :ARG1-of (d2 / differ-02~e.22)) :condition~e.24 (c / concentration-quantity~e.26 :ARG1-of (l / low-04~e.25))))) # ::id pmid_2540_9876.165 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The enhanced inhibition of MAPK signaling observed with sorafenib may also result from the fact that it targets both RET and RAF family kinases [ @ 37 , 45 @ ] . # ::alignments 1-1.1.2.3 2-1.1.2 3-1.1.2.2.r 4-1.1.2.2.1.1.1 5-1.1.2.2 6-1.1.2.4 7-1.1.2.1.r 8-1.1.2.1.1.1 9-1 10-1.3 11-1.1 15-1.1.1.r 16-1.1.1.1 17-1.1.1 19-1.1.1.2.1.1.1 20-1.1.1.2 21-1.1.1.2.2.1.1 22-1.1.1.2.1 22-1.1.1.2.2 26-1.2.1.1.1.1 30-1.2.1.1.1.2 (p / possible-01~e.9 :ARG1 (r / result-01~e.11 :ARG1~e.15 (t / target-01~e.17 :ARG0 s2~e.16 :ARG1 (a / and~e.20 :op1 (p3 / protein-family~e.22 :name (n3 / name :op1 "RET"~e.19)) :op2 (p4 / protein-family~e.22 :name (n4 / name :op1 "RAF"~e.21)))) :ARG2 (i / inhibit-01~e.2 :ARG0~e.7 (s2 / small-molecule :name (n2 / name :op1 "sorafenib"~e.8)) :ARG1~e.3 (s / signal-07~e.5 :ARG0 (p2 / pathway :name (n / name :op1 "MAPK"~e.4))) :ARG1-of (e / enhance-01~e.1) :ARG1-of (o / observe-01~e.6))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op2 37~e.26 :op2 45~e.30)))) :mod (a3 / also~e.10)) # ::id pmid_2540_9876.166 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since these observations suggested that SPP86 disrupts ERα- RET crosstalk , we investigated the effect of SPP86 on the proliferation of MCF7 cells . # ::alignments 0-1.3 1-1.3.1.1.1 2-1.3.1.1 3-1.3.1 4-1.3.1.2.r 5-1.3.1.2.1 6-1.3.1.2 8-1.3.1.2.2.2.1.1 9-1.3.1.2.2 11-1.1 12-1 14-1.2 15-1.2.1.r 16-1.2.1.1.1 17-1.2.2.r 19-1.2.2 20-1.2.2.1.r 21-1.2.2.1.1.1 22-1.2.2.1 (i / investigate-01~e.12 :ARG0 (w / we~e.11) :ARG1 (a / affect-01~e.14 :ARG0~e.15 (s / small-molecule :name (n / name :op1 "SPP86"~e.16)) :ARG1~e.17 (p / proliferate-01~e.19 :ARG0~e.20 (c / cell-line~e.22 :name (n2 / name :op1 "MCF7"~e.21)))) :ARG1-of (c2 / cause-01~e.0 :ARG0 (s2 / suggest-01~e.3 :ARG0 (o / observe-01~e.2 :mod (t / this~e.1)) :ARG1~e.4 (d / disrupt-01~e.6 :ARG0 s~e.5 :ARG1 (c3 / crosstalk-00~e.9 :ARG1 (p2 / protein :name (n3 / name :op1 "ERα")) :ARG2 (p3 / protein :name (n4 / name :op1 "RET"~e.8))))))) # ::id pmid_2540_9876.167 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Estrogen deprived and serum starved cells were cultured in the presence of 1 ng @/@ ml β- estradiol ( E2 ) or 10 ng @/@ ml GDNF alone and in combination in the presence of 1 μM SPP86 for 7 days . # ::alignments 0-1.1.1.1.1.1 1-1.1.1 3-1.1.2.1 4-1.1.2 5-1.1 7-1 8-1.2.r 10-1.2.1 11-1.2.1.1.r 12-1.2.1.1.1.2.1 13-1.2.1.1.1.2.2 15-1.2.1.1.1.2.2 17-1.2.1.1.1.1.1 21-1.2.1.1 22-1.2.1.1.2.2.1 23-1.2.1.1.2.2.2 24-1.2.1.1.2.2.2 25-1.2.1.1.2.2.2 26-1.2.1.1.2.1.1 27-1.2.1.2 28-1.2 30-1.2.2.2 33-1.2.2 34-1.2.2.1.r 35-1.2.2.1.2.1 36-1.2.2.1.2.2 37-1.2.2.1.1.1 38-1.3.r 39-1.3.1 40-1.3.2 (c / culture-01~e.7 :ARG1 (c2 / cell~e.5 :ARG2-of (d / deprive-01~e.1 :ARG1 (s / small-molecule :name (n / name :op1 "estrogen"~e.0))) :ARG1-of (s2 / starve-01~e.4 :ARG2 (s3 / serum~e.3))) :manner~e.8 (a2 / and~e.28 :op1 (p2 / present-02~e.10 :ARG1~e.11 (o / or~e.21 :op1 (s4 / small-molecule :name (n2 / name :op1 "β-estradiol"~e.17) :quant (c3 / concentration-quantity :quant 1~e.12 :unit (n3 / nanogram-per-milliliter~e.13,15))) :op2 (p / protein :name (n4 / name :op1 "GDNF"~e.26) :quant (c4 / concentration-quantity :quant 10~e.22 :unit n3~e.23,24,25))) :mod (a / alone~e.27)) :op2 (p3 / present-02~e.33 :ARG1~e.34 (s5 / small-molecule :name (n5 / name :op1 "SPP86"~e.37) :quant (c5 / concentration-quantity :quant 1~e.35 :unit (m / micromolar~e.36))) :mod (c6 / combine-01~e.30))) :duration~e.38 (t / temporal-quantity :quant 7~e.39 :unit (d2 / day~e.40))) # ::id pmid_2540_9876.168 ::amr-annotator SDL-AMR-09 ::preferred # ::tok SPP86 effectively inhibited E2 and @/@ or GDNF @- induced proliferation ( p < 0.05 ) ( Figure 5 @ A ) . # ::alignments 0-1.1.1.1 1-1.3 2-1 3-1.2.1.1.1.1.1 4-1.2.1.1 6-1.2.1.1 7-1.2.1.1.2.1.1 9-1.2.1 10-1.2 13-1.5 15-1.5.1 16-1.5.1.1 19-1.4.1 (i / inhibit-01~e.2 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.0)) :ARG1 (p2 / proliferate-01~e.10 :ARG2-of (i2 / induce-01~e.9 :ARG0 (a / and-or~e.4,6 :op1 (s2 / small-molecule :name (n2 / name :op1 "E2"~e.3)) :op2 (p / protein :name (n3 / name :op1 "GDNF"~e.7))))) :ARG1-of (e / effective-04~e.1) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.19 :mod "5A")) :ARG1-of (s3 / statistical-test-91~e.13 :ARG2 (l / less-than~e.15 :op1 0.05~e.16))) # ::id pmid_2540_9876.169 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , SPP86 did not inhibit proliferation when MCF7 cells were co @-@ exposed to 1 ng @/@ ml E2 and 5 ng @/@ insulin under similar conditions ( Figure 5 @ B ) . # ::alignments 1-1 3-1.1.2.1.1 5-1.1.1 5-1.1.1.r 6-1.1 7-1.1.3 9-1.1.4.1.1.1 10-1.1.4.1 16-1.1.4.2.1.2.1 17-1.1.4.2.1.2.2 19-1.1.4.2.1.2.2 20-1.1.4.2.1.1.1 21-1.1.4.2 22-1.1.4.2.2.2.1 23-1.1.4.2.1.2.2 25-1.1.4.2.2.1.1 27-1.1.4.3.1 28-1.1.4.3 28-1.1.4.3.r 28-1.1.4.r 30-1.2.1 32-1.1.4.2.2.2.1 (c / contrast-01~e.1 :ARG2 (i / inhibit-01~e.6 :polarity~e.5 -~e.5 :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"~e.3)) :ARG1 (p / proliferate-01~e.7) :condition~e.28 (c2 / coexpose-00 :ARG1 (c3 / cell-line~e.10 :name (n2 / name :op1 "MCF7"~e.9)) :ARG2 (a / and~e.21 :op1 (s2 / small-molecule :name (n3 / name :op1 "E2"~e.20) :quant (c4 / concentration-quantity :quant 1~e.16 :unit (n4 / nanogram-per-milliliter~e.17,19,23))) :op2 (p2 / protein :name (n5 / name :op1 "insulin"~e.25) :quant (c5 / concentration-quantity :quant 5~e.22,32 :unit n4))) :condition~e.28 (c6 / condition~e.28 :ARG1-of (r / resemble-01~e.27)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.30 :mod "5B"))) # ::id pmid_2540_9876.170 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We next compared the effect of SPP86 and tamoxifen on the proliferation of MCF7 cells . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 6-1.2.1.1.1.1 7-1.2.1 8-1.2.1.2.1.1 9-1.2.2.r 11-1.2.2 12-1.2.2.1.r 13-1.2.2.1.1.1 14-1.2.2.1 (c / compare-01~e.2 :ARG0 (w / we~e.0) :ARG1 (a / affect-01~e.4 :ARG0~e.5 (a2 / and~e.7 :op1 (s / small-molecule :name (n / name :op1 "SPP86"~e.6)) :op2 (s2 / small-molecule :name (n2 / name :op1 "tamoxifen"~e.8))) :ARG1~e.9 (p / proliferate-01~e.11 :ARG0~e.12 (c2 / cell-line~e.14 :name (n3 / name :op1 "MCF7"~e.13)))) :time (n4 / next~e.1)) # ::id pmid_2540_9876.171 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Estrogen deprived and serum starved cells were cultured in the presence of 1 ng @/@ ml β- estradiol ( E2 ) and 10 ng @/@ ml GDNF with increasing doses of either SPP86 or tamoxifen , in medium containing 1 ng @/@ ml β- estradiol ( E2 ) and 10 ng @/@ ml GDNF and incubated for 7 days . # ::alignments 0-1.1.1.1.1.1.1 1-1.1.1.1 3-1.1.1.2.1 4-1.1.1.2 5-1.1.1 7-1.1 8-1.1.2.r 10-1.1.2.1 11-1.1.2.1.1.r 12-1.1.2.1.1.1.2.1 13-1.1.2.1.1.1.2.2 15-1.1.2.1.1.1.2.2 17-1.1.2.1.1.1.1.1 22-1.1.2.1.1.2.2.1 23-1.1.2.1.1.1.2.2 25-1.1.2.1.1.1.2.2 26-1.1.2.1.1.2.1.1 28-1.1.2.2.2 29-1.1.2.2 32-1.1.2.2.1.1.1.1 33-1.1.2.2.1 34-1.1.2.2.1.2.1.1 36-1.1.3.r 37-1.1.3 38-1.1.3.1 39-1.1.3.1.1 40-1.1.3.1.1 41-1.1.3.1.1 42-1.1.3.1.1 43-1.1.3.1.1 44-1.1.3.1.1 45-1.1.3.1.1 46-1.1.3.1.1 47-1.1.3.1.1 48-1.1.3.1.1 49-1.1.3.1.1 50-1.1.2.1.1.2.2.2 51-1.1.2.1.1.2.2.2 52-1.1.2.1.1.2.2.2 53-1.1.3.1.1 54-1 55-1.2 56-1.2.2.r 57-1.2.2.1 58-1.2.2.2 (a3 / and~e.54 :op1 (c / culture-01~e.7 :ARG1 (c2 / cell~e.5 :ARG2-of (d / deprive-01~e.1 :ARG1 (s / small-molecule :name (n / name :op1 "estrogen"~e.0))) :ARG1-of (s2 / starve-01~e.4 :ARG2 (s3 / serum~e.3))) :manner~e.8 (a2 / and :op1 (p2 / present-02~e.10 :ARG1~e.11 (a / and :op1 (s4 / small-molecule :name (n2 / name :op1 "β-estradiol"~e.17) :quant (c3 / concentration-quantity :quant 1~e.12 :unit (n3 / nanogram-per-milliliter~e.13,15,23,25))) :op2 (p / protein :name (n4 / name :op1 "GDNF"~e.26) :quant (c4 / concentration-quantity :quant 10~e.22 :unit n3~e.50,51,52)))) :op2 (d2 / dose-01~e.29 :ARG2 (o / or~e.33 :op1 (s5 / small-molecule :name (n5 / name :op1 "SPP86"~e.32)) :op2 (s6 / small-molecule :name (n6 / name :op1 "tamoxifen"~e.34))) :ARG1-of (i / increase-01~e.28))) :location~e.36 (m / medium~e.37 :ARG0-of (c5 / contain-01~e.38 :ARG1 a~e.39,40,41,42,43,44,45,46,47,48,49,53))) :op2 (i2 / incubate-01~e.55 :ARG1 c2 :duration~e.56 (t / temporal-quantity :quant 7~e.57 :unit (d3 / day~e.58)))) # ::id pmid_2540_9876.172 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In these experiments , SPP86 and tamoxifen inhibited proliferation to a similar degree with IC @₅₀ values of 1.0 and 1.4 μM respectively ( Figure 5 @ C ) . # ::alignments 1-1.4.1 2-1.4 4-1.1.1.1.1 5-1.1 6-1.1.2.1.1 7-1 7-1.3.1.1.1.2 8-1.2 9-1.3.r 11-1.3 12-1.3.1.1.1.2.1.r 16-1.3.1.1.1.2.1.1 18-1.3.1.1 18-1.3.1.2 20-1.3.1.1.1.1.1.1 21-1.3.1 22-1.3.1.2.1.1.1.1 23-1.3.1.1.1.1.1.2 24-1.3.1.3 26-1.5.1 (i / inhibit-01~e.7 :ARG0 (a / and~e.5 :op1 (s / small-molecule :name (n / name :op1 "SPP86"~e.4)) :op2 (s2 / small-molecule :name (n2 / name :op1 "tamoxifen"~e.6))) :ARG1 (p / proliferate-01~e.8) :degree~e.9 (r / resemble-01~e.11 :ARG2 (a3 / and~e.21 :op1 (v / value~e.18 :mod (c3 / concentrate-02 :ARG1-of (e / equal-01 :ARG2 (c / concentration-quantity :quant 1.0~e.20 :unit (m / micromolar~e.23))) :mod (i2 / inhibit-01~e.7 :degree~e.12 (p2 / percentage-entity :value 50~e.16)))) :op2 (v2 / value~e.18 :mod (c4 / concentrate-02 :ARG1-of (e3 / equal-01 :ARG2 (c2 / concentration-quantity :quant 1.4~e.22 :unit m)) :mod i2)) :mod (r2 / respective~e.24))) :location (e2 / experiment-01~e.2 :mod (t2 / this~e.1)) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "5C"))) # ::id pmid_2541_3220.1 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses ( PMID : 25413220 ) # ::alignments 0-1.2 1-1 2-1.1.r 4-1.1.1.1 5-1.1 6-1.3.r 7-1.3.1.1.1 8-1.3 9-1.3.2.1 10-1.3.2 12-1.3.3.1 13-1.3.3 15-1.4.1.1 17-1.4.1.1.1 (a / activate-01~e.1 :ARG1~e.2 (p / pathway~e.5 :name (n / name :op1 "ERK"~e.4)) :mod (c / constitutive~e.0) :location~e.6 (a2 / and~e.8 :op1 (m / medical-condition :name (n3 / name :op1 "melanoma"~e.7)) :op2 (m2 / melanocyte~e.10 :mod (s / skin~e.9)) :location (h / horse~e.13 :ARG1-of (g / gray-02~e.12))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG8 (p3 / pmid~e.15 :mod 25413220~e.17)))) # ::id pmid_2541_3220.12 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2541_3220.13 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF , RAS , GNAQ , GNA11 and KIT genes or alterations in the expression of the main components of the pathway . # ::alignments 0-1.1 1-1 2-1.2.r 4-1.2.1.1.1 5-1.2.1 7-1.2.2 7-1.2.2.r 8-1.2 9-1.2.3.r 10-1.2.3.3.1 11-1.2.3.3 12-1.2.3.1.1.1.1 13-1.2.3.1 14-1.2.3 15-1.2.3.2 16-1.2.3.2 17-1.2.4.r 19-1.2.4.1 20-1.2.4.1.1.r 21-1.2.4.1.1.3 22-1.2.4.1.1.2 23-1.2.4.1.1 26-1.2.4.1.1.1.1.1.1 30-1.2.4.1.1.1.2.1.1 34-1.2.4.1.1.1.3.1.1 38-1.2.4.1.1.1.4.1.1 40-1.2.4.1.1.1 42-1.2.4.1.1.1.5.1.1 44-1.2.4.1.1.1.1 44-1.2.4.1.1.1.2 44-1.2.4.1.1.1.3 44-1.2.4.1.1.1.4 44-1.2.4.1.1.1.5 45-1.2.4 46-1.2.4.2 47-1.2.4.2.1.r 49-1.2.4.2.1 50-1.2.4.2.1.1.r 52-1.2.4.2.1.1.1 53-1.2.4.2.1.1 54-1.2.4.2.1.1.2.r 56-1.2.4.2.1.1.2 (f / find-01~e.1 :ARG0 (w / we~e.0) :ARG1~e.2 (a / activate-01~e.8 :ARG1 (p / pathway~e.5 :name (n / name :op1 "ERK"~e.4)) :manner~e.7 (c / constitutive~e.7) :location~e.9 (a2 / and~e.14 :op1 (t / tumor~e.13 :mod (m / medical-condition :name (n8 / name :op1 "melanoma"~e.12))) :op2 (c2 / cell-line~e.15,16) :mod (h / horse~e.11 :ARG1-of (g6 / gray-02~e.10))) :condition~e.17 (o / or~e.45 :op1 (a6 / absent-01~e.19 :ARG1~e.20 (m2 / mutate-01~e.23 :ARG1 (a4 / and~e.40 :op1 (g / gene~e.44 :name (n3 / name :op1 "BRAF"~e.26)) :op2 (g2 / gene~e.44 :name (n4 / name :op1 "RAS"~e.30)) :op3 (g3 / gene~e.44 :name (n5 / name :op1 "GNAQ"~e.34)) :op4 (g4 / gene~e.44 :name (n6 / name :op1 "GNA11"~e.38)) :op5 (g5 / gene~e.44 :name (n7 / name :op1 "KIT"~e.42))) :ARG0-of (a3 / activate-01~e.22) :mod (s / somatic~e.21))) :op2 (a5 / alter-01~e.46 :ARG1~e.47 (e / express-03~e.49 :ARG2~e.50 (c3 / component~e.53 :mod (m3 / main~e.52) :part-of~e.54 p~e.56)))))) # ::id pmid_2541_3220.14 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The pathway is mitogenic and is mediated by BRAF , CRAF and KRAS kinases . # ::alignments 1-1.1.1 2-1.1.1.r 3-1.1 5-1.1.1.r 6-1.2 7-1.2.1.r 8-1.2.1.1.2.1 10-1.2.1.2.2.1 11-1.2.1 12-1.2.1.3.2.1 13-1.2.1.1 13-1.2.1.2 13-1.2.1.3 (a / and :op1 (m / mitogenic~e.3 :domain~e.2,5 (p / pathway~e.1)) :op2 (m2 / mediate-01~e.6 :ARG0~e.7 (a2 / and~e.11 :op1 (k / kinase~e.13 :wiki - :name (n / name :op1 "BRAF"~e.8)) :op2 (k2 / kinase~e.13 :wiki "C-Raf" :name (n2 / name :op1 "CRAF"~e.10)) :op3 (k3 / kinase~e.13 :wiki "KRAS" :name (n3 / name :op1 "KRAS"~e.12))) :ARG1 p)) # ::id pmid_2541_3220.15 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Importantly , we found high activation of the ERK pathway also in epidermal melanocytes , suggesting a general predisposition to melanomagenesis in these horses . # ::alignments 0-1.3 2-1.1 3-1 4-1.2.2 5-1.2 6-1.2.1.r 8-1.2.1.1.1 9-1.2.1 10-1.2.4 13-1.2.3 15-1.4 17-1.4.1.3 18-1.4.1 19-1.4.1.2.r 20-1.4.1.2 21-1.4.1.1.r 22-1.4.1.1.1 23-1.4.1.1 (f / find-01~e.3 :ARG0 (w / we~e.2) :ARG1 (a / activate-01~e.5 :ARG1~e.6 (p / pathway~e.9 :name (n / name :op1 "ERK"~e.8)) :ARG1-of (h / high-02~e.4) :location (m / melanocyte~e.13 :mod (e / epidermis)) :mod (a2 / also~e.10)) :mod (i / important~e.0) :ARG0-of (s / suggest-01~e.15 :ARG1 (p2 / predispose-01~e.18 :ARG1~e.21 (h2 / horse~e.23 :mod (t / this~e.22)) :ARG2~e.19 (m2 / melanomagenesis~e.20) :ARG1-of (g / general-02~e.17)))) # ::id pmid_2541_3220.98 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Results # ::alignments 1-1 1-1.1 1-1.1.r (t / thing~e.1 :ARG2-of~e.1 (r / result-01~e.1)) # ::id pmid_2541_3220.99 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK1 @/@ 2 activation in Grey horse melanomas # ::alignments 1-1.1.1.1 3-1.1.1.1 4-1 5-1.2.r 6-1.2.2.1 7-1.2.2 8-1.2.1.1 (a / activate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.1,3)) :location~e.5 (m / medical-condition :name (n3 / name :op1 "melanoma"~e.8) :mod (h / horse~e.7 :ARG1-of (g / gray-02~e.6)))) # ::id pmid_2541_3220.100 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Given the importance of the MAPK @/@ ERK pathway activation in melanoma development , we examined the levels of the activated ( phosphorylated ) ERK1 @/@ 2 ( P @-@ ERK1 @/@ 2 ) in primary cutaneous melanoma tumours from Grey ( n = 19 ) and non @-@ Grey ( n = 12 ) horses of different breeds from three geographic locations across Europe by indirect immunofluorescence , using an anti @-@ MITF antibody to mark melanocytic lineage [ @ 23 @ ] . # ::alignments 2-1.5.1 3-1.5.1.1.r 5-1.5.1.1.1.1.1 7-1.5.1.1.1.1.1 8-1.5.1.1.1 9-1.5.1.1 10-1.5.1.1.2.r 11-1.5.1.1.2.1 12-1.5.1.1.2 14-1.1 15-1 17-1.2 18-1.2.1.r 20-1.2.1.3 22-1.2.1.2 24-1.2.1.1.1 26-1.2.1.1.1 28-1.2.1.2 30-1.2.1.1.1 32-1.2.1.1.1 34-1.2.2.r 35-1.2.2.1 37-1.2.2.4.1.1 38-1.2.2 39-1.2.2.3.4.r 40-1.2.2.3.2.2 44-1.2.2.3.1.1 46-1.2.2.3 47-1.2.2.3.2.2.1 47-1.2.2.3.2.2.1.r 49-1.2.2.3.1.2 49-1.2.2.3.2.2 53-1.2.2.3.2.1 55-1.2.2.3.1 55-1.2.2.3.2 56-1.2.2.3.r 57-1.2.2.3.3.1 58-1.2.2.3.3 59-1.2.2.3.4.r 60-1.2.2.3.4.1 61-1.2.2.3.4.2 62-1.2.2.3.4 62-1.2.2.3.4.3.r 63-1.2.2.3.4.3 64-1.2.2.3.4.3.1.2.1 65-1.3.r 66-1.3.1 67-1.3 69-1.4 71-1.4.2.1 73-1.4.2.1.1.1.1 74-1.4.2 76-1.4.3 78-1.4.3.2 81-1.4.4.1.1.1 (e / examine-01~e.15 :ARG0 (w / we~e.14) :ARG1 (l / level~e.17 :mod~e.18 (e2 / enzyme :name (n / name :op1 "ERK1/2"~e.24,26,30,32) :ARG3-of (p2 / phosphorylate-01~e.22,28) :ARG1-of (a / activate-01~e.20)) :location~e.34 (t / tumor~e.38 :mod (p4 / primary~e.35) :mod (c / cutis) :location~e.56 (a5 / and~e.46 :op1 (h / horse~e.55 :quant 19~e.44 :ARG1-of (g / gray-02~e.49)) :op2 (h2 / horse~e.55 :quant 12~e.53 :ARG1-of (g3 / gray-02~e.40,49 :polarity~e.47 -~e.47)) :ARG1-of (b / breed-01~e.58 :ARG1-of (d2 / differ-02~e.57)) :source~e.39,59 (l2 / location~e.62 :quant 3~e.60 :mod (g2 / geography~e.61) :location~e.62 (a2 / across~e.63 :op1 (c2 / continent :wiki "Europe" :name (n5 / name :op1 "Europe"~e.64))))) :mod (m / medical-condition :name (n2 / name :op1 "melanoma"~e.37)))) :manner~e.65 (i / immunofluoresce-01~e.67 :mod (i2 / indirect~e.66)) :manner (u / use-01~e.69 :ARG0 w :ARG1 (a3 / antibody~e.74 :ARG0-of (c3 / counter-01~e.71 :ARG1 (p5 / protein :name (n6 / name :op1 "MITF"~e.73)))) :ARG2 (m2 / mark-02~e.76 :ARG0 w :ARG1 (l3 / lineage~e.78 :mod (m3 / melanocyte))) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 23~e.81)))) :ARG1-of (c5 / cause-01 :ARG0 (i3 / importance~e.2 :domain~e.3 (a4 / activate-01~e.9 :ARG1 (p7 / pathway~e.8 :name (n7 / name :op1 "MAPK/ERK"~e.5,7)) :purpose~e.10 (d4 / develop-01~e.12 :ARG2 m~e.11))))) # ::id pmid_2541_3220.101 ::amr-annotator SDL-AMR-09 ::preferred # ::tok All the tumours expressed nuclear and occasionally cytoplasmic P @-@ ERK1 @/@ 2 , however , both signals were by far more abundant in the GHM samples ( 80.2 % ± 8.5 vs @ . 7.6 % ± 21.3 in Grey and non @-@ grey MITF @⁺ cells , respectively ; Figure 1 @ A , B ) . # ::alignments 0-1.2.2.1 2-1.2.2 3-1.2 4-1.2.1.3 6-1.2.1.4.1 8-1.2.1.2 10-1.2.1.1.1 14-1 16-1.1.1.1 17-1.1.1 17-1.1.1.2.3 18-1.1.1.r 19-1.1.2.1 20-1.1.2.1 21-1.1.2 22-1.1 23-1.1.3.r 25-1.1.3.1.1.1 26-1.1.3 28-1.1.1.2.1.1 28-1.1.1.2.2.1 29-1.1.1.2.1 29-1.1.1.2.1.2.1 29-1.1.1.2.2 31-1.1.1.2.1.2.1.1 36-1.1.1.2.3.1.1.1 36-1.1.1.2.3.1.2.1 37-1.1.1.2.3.1.1 37-1.1.1.2.3.1.1.2.1 37-1.1.1.2.3.1.2 39-1.1.1.2.3.1.1.2.1.1 41-1.1.1.2.3.1.3.2 41-1.1.1.2.3.1.3.2.1 41-1.1.1.2.3.1.3.2.1.r 42-1.1.1.2.3.1 43-1.1.1.2.3.1.3.2.1.1 43-1.1.1.2.3.1.3.2.1.1.r 45-1.1.1.2.3.1.3.2 45-1.1.1.2.3.1.3.2.1 45-1.1.1.2.3.1.3.2.1.r 45-1.1.1.2.4.2 45-1.1.1.2.4.2.1 45-1.1.1.2.4.2.1.r 46-1.1.1.2.4.1.1.1 48-1.1.4.1 50-1.1.1.2.3.1.3 50-1.1.1.2.4 54-1.1.4.1.1 54-1.1.4.1.2 54-1.1.4.1.3 56-1.1.4.1.3.1 58-1.1.4.1.1.1 60-1.1.4.1.2.1 (h / have-concession-91~e.14 :ARG1 (a3 / abundant~e.22 :domain~e.18 (s / signal-07~e.17 :mod (b / both~e.16) :quant (b5 / between :op1 (p / percentage-entity~e.29 :value 80.2~e.28 :ARG2-of (a6 / add-02 :ARG1 (p4 / percentage-entity~e.29 :value 8.5~e.31))) :op2 (p5 / percentage-entity~e.29 :value 80.2~e.28 :ARG2-of (s3 / subtract-01 :ARG1 p4)) :compared-to (s4 / signal-07~e.17 :quant (b4 / between~e.42 :op1 (p2 / percentage-entity~e.37 :value 7.6~e.36 :ARG2-of (a7 / add-02 :ARG1 (p6 / percentage-entity~e.37 :value 21.3~e.39))) :op2 (p7 / percentage-entity~e.37 :value 7.6~e.36 :ARG2-of (s5 / subtract-01 :ARG1 p6)) :location (c3 / cell~e.50 :mod p3 :mod (o / organism~e.41,45 :ARG1-of~e.41,45 (g2 / gray-02~e.41,45 :polarity~e.43 -~e.43))))) :location (c2 / cell~e.50 :mod (p3 / protein :name (n4 / name :op1 "MITF"~e.46)) :mod (o3 / organism~e.45 :ARG1-of~e.45 (g / gray-02~e.45))))) :degree (m / more~e.21 :degree (b2 / by-far~e.19,20)) :location~e.23 (s2 / sample-01~e.26 :ARG1 (d / disease :name (n3 / name :op1 "GHM"~e.25))) :ARG1-of (d2 / describe-01 :ARG0 (a5 / and~e.48 :op1 (f / figure~e.54 :mod "A"~e.58) :op2 (f2 / figure~e.54 :mod "B"~e.60) :part-of (f3 / figure~e.54 :mod 1~e.56)))) :ARG2 (e / express-03~e.3 :ARG2 (e2 / enzyme :name (n / name :op1 "ERK1/1"~e.10) :ARG3-of (p9 / phosphorylate-01~e.8) :mod (n9 / nucleus~e.4) :mod (c4 / cytoplasma :frequency (o2 / occasional~e.6))) :ARG3 (t / tumor~e.2 :mod (a / all~e.0)))) # ::id pmid_2541_3220.102 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Although non @-@ grey melanomas were much more heterogeneous for the P @-@ ERK1 @/@ 2 staining than the Grey counterparts , the quantitative difference between the signals reached statistical significance ( P < 0.001 ) . # ::alignments 0-1 1-1.2.4.2.1.1 1-1.2.4.2.1.1.r 3-1.2.3.1.2 3-1.2.3.1.2.1 3-1.2.3.1.2.1.r 3-1.2.4.2 3-1.2.4.2.1 3-1.2.4.2.1.r 4-1.2.3.1.1.1 4-1.2.4.1.1 5-1.2.3.1.r 5-1.2.4.r 6-1.2.1.1 7-1.2.1 8-1.2 8-1.2.3 9-1.2.2.r 11-1.2.2.1.2 13-1.2.2.1.1.1 15-1.2.2.1.1.1 16-1.2.2 17-1.2.3.r 19-1.2.3.1.2 19-1.2.3.1.2.1 19-1.2.3.1.2.1.r 19-1.2.4.2 19-1.2.4.2.1 19-1.2.4.2.1.r 23-1.1.1.2 24-1.1.1 27-1.1.1.1 28-1.1 29-1.1.2.1 30-1.1.2 33-1.2.2.1.2 35-1.1.2.2 36-1.1.2.2.1 (h / have-concession-91~e.0 :ARG1 (r / reach-01~e.28 :ARG0 (d3 / differ-02~e.24 :ARG1 (s2 / signal-07~e.27) :mod (q / quantity~e.23)) :ARG1 (s3 / significance~e.30 :mod (s4 / statistics~e.29) :value (l / less-than~e.35 :op1 0.001~e.36))) :ARG2 (h2 / heterogeneity~e.8 :degree (m / more~e.7 :mod (m2 / much~e.6)) :prep-for~e.9 (s / stain-01~e.16 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2"~e.13,15) :ARG3-of (p / phosphorylate-01~e.11,33))) :compared-to~e.17 (h3 / heterogeneity~e.8 :domain~e.5 (m3 / medical-condition :name (n / name :op1 "melanoma"~e.4) :mod (o / organism~e.3,19 :ARG1-of~e.3,19 (g / gray-02~e.3,19)))) :domain~e.5 (m4 / medical-condition :name (n5 / name :op1 "melanoma"~e.4) :mod (o2 / organism~e.3,19 :ARG1-of~e.3,19 (g2 / gray-02~e.3,19 :polarity~e.1 -~e.1))))) # ::id pmid_2541_3220.103 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The total ERK1 @/@ 2 signal was similarly heterogeneous in both Grey and non @-@ grey samples ( 71.2 ± 17.4 vs @ . 50.5 % ± 13.0 in MITF @⁺ cells of the respective melanoma type ; Figure 1 @ A , B ) . # ::alignments 1-1.1.2 2-1.1.1.1.1 4-1.1.1.1.1 5-1.1 5-1.3.3 6-1.1.r 7-1.2 8-1 11-1.1.3.1.1.1 11-1.1.3.1.1.1.1 11-1.1.3.1.1.1.1.r 11-1.1.3.2.1.1 11-1.1.3.2.1.1.1 11-1.1.3.2.1.1.1.r 12-1.1.3 13-1.1.3.2.1.1.1.1 13-1.1.3.2.1.1.1.1.r 15-1.1.3.1.1.1 15-1.1.3.1.1.1.1 15-1.1.3.1.1.1.1.r 15-1.1.3.2.1.1 15-1.1.3.2.1.1.1 15-1.1.3.2.1.1.1.r 16-1.1.3.1 16-1.1.3.1.1 16-1.1.3.1.1.r 16-1.1.3.2 16-1.1.3.2.1 16-1.1.3.2.1.r 18-1.3.1.1 20-1.3.1.2.1.1 25-1.3.3.1.1.1 26-1.3.1 26-1.3.1.2.1 26-1.3.2 26-1.3.3.1.1 26-1.3.3.1.1.2.1 26-1.3.3.1.2 28-1.3.3.1.1.2.1.1 30-1.3.4.1.1.1 32-1.3.5.1 34-1.3.4 35-1.3.4.2.r 37-1.3.4.2.2.1 38-1.3.4.2.1.1 39-1.3.4.2 39-1.3.4.2.2 39-1.3.4.2.2.r 41-1.3.5.1.1 41-1.3.5.1.2 41-1.3.5.1.3 43-1.3.5.1.3.1 45-1.3.5.1.1.1 47-1.3.5.1.2.1 (h / heterogeneity~e.8 :domain~e.6 (s / signal-07~e.5 :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2"~e.2,4)) :mod (t / total~e.1) :location (a2 / and~e.12 :op1 (t3 / thing~e.16 :ARG1-of~e.16 (s2 / sample-01~e.16 :ARG2 (o / organism~e.11,15 :ARG1-of~e.11,15 (g / gray-02~e.11,15)))) :op2 (t4 / thing~e.16 :ARG1-of~e.16 (s3 / sample-01~e.16 :ARG2 (o2 / organism~e.11,15 :ARG1-of~e.11,15 (g2 / gray-02~e.11,15 :polarity~e.13 -~e.13)))))) :ARG1-of (r / resemble-01~e.7) :quant (b / between :op1 (p3 / percentage-entity~e.26 :value 71.2~e.18 :ARG2-of (a3 / add-02 :ARG1 (p4 / percentage-entity~e.26 :value 17.4~e.20))) :op2 (p5 / percentage-entity~e.26 :ARG2-of (s4 / subtract-01 :ARG1 p4)) :compared-to (s5 / signal-07~e.5 :quant (b2 / between :op1 (p / percentage-entity~e.26 :value 50.5~e.25 :ARG2-of (a4 / add-02 :ARG1 (p6 / percentage-entity~e.26 :value 13.0~e.28))) :op2 (p7 / percentage-entity~e.26 :ARG2-of (s6 / subtract-01 :ARG1 p6)))) :location (c / cell~e.34 :mod (p2 / protein :name (n3 / name :op1 "MITF"~e.30)) :source~e.35 (m / medical-condition~e.39 :name (n5 / name :op1 "melanoma"~e.38) :ARG1-of~e.39 (t2 / type-03~e.39 :mod (r2 / respective~e.37)))) :ARG1-of (d2 / describe-01 :ARG0 (a / and~e.32 :op1 (f / figure~e.41 :mod "A"~e.45) :op2 (f2 / figure~e.41 :mod "B"~e.47) :part-of (f3 / figure~e.41 :mod 1~e.43))))) # ::id pmid_2541_3220.104 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In line with the elevated P @-@ ERK1 @/@ 2 levels in the GHM tissues , high P @-@ ERK1 @/@ 2 levels were detected in two GHM cell lines , HoMel @-@ L1 and HoMel @-@ A1 , established from a primary and metastatic melanoma tumour of a Grey Lipizzaner and Arabian horse , respectively [ @ 24 @ ] . # ::alignments 1-1.2 4-1.1.3.1.1 5-1.1.3.1.3 6-1.1.3.1.3 7-1.1.3.1.3 8-1.1.3.1.3 9-1.1.3.1.3 10-1.1.3.1 11-1.1.3.1.2.r 13-1.1.3.1.2.1.1.1 14-1.1.3.1.2 16-1.1.2 17-1.1.1.2 19-1.1.1.1.1 21-1.1.1.1.1 22-1.1 24-1 26-1.1.1.1.1 26-1.2.1 27-1.2.3 28-1.2 29-1.2 31-1.2.2.1.1.1.1 31-1.2.2.1.2.1.1 33-1.2.2.1.1.1.1 34-1.2.2.1 35-1.2.2.1.1.1.1 35-1.2.2.1.2.1.1 37-1.2.2.1.2.1.1 39-1.2.2.1.3 40-1.2.2.1.3.1.r 42-1.2.2.1.3.1.1.1 43-1.2.2.1.3.1 44-1.2.2.1.3.1.2.1 45-1.2.2.1.3.1.1.2.1.1 46-1.2.2.1.3.1.1 46-1.2.2.1.3.1.2 47-1.2.2.1.3.1.1.3.r 49-1.2.2.1.3.1.1.3.1.1 50-1.2.2.1.3.1.1.3.1.2 51-1.2.2.1.3.1 52-1.2.2.1.3.1.2.3.1.1 53-1.2.2.1.3.1.2.3.1.2 58-1.3.1.1.1 (d / detect-01~e.24 :ARG1 (l / level~e.22 :quant-of (e / enzyme :name (n / name :op1 "ERK1/2"~e.19,21,26) :ARG3-of (p3 / phosphorylate-01~e.17)) :ARG1-of (h / high-02~e.16) :ARG2-of (a4 / align-01 :ARG1 (l2 / level~e.10 :ARG1-of (e3 / elevate-01~e.4) :location~e.11 (t2 / tissue~e.14 :mod (d5 / disease :name (n7 / name :op1 "GHM"~e.13))) :quant-of e~e.5,6,7,8,9))) :location (c / cell-line~e.1,28,29 :quant 2~e.26 :ARG2-of (i / include-91 :ARG1 (a / and~e.34 :op1 (c2 / cell-line :name (n3 / name :op1 "HoMel-L1"~e.31,33,35)) :op2 (c3 / cell-line :name (n4 / name :op1 "HoMel-A1"~e.31,35,37)) :ARG1-of (e2 / establish-01~e.39 :source~e.40 (a3 / and~e.43,51 :op1 (t / tumor~e.46 :mod (p / primary~e.42) :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"~e.45)) :part-of~e.47 (o3 / organism :name (n5 / name :op1 "Grey"~e.49 :op2 "Lipizzaner"~e.50 :op3 "horse"))) :op2 (t3 / tumor~e.46 :mod (m / metastasis~e.44) :mod m2 :part-of (o4 / organism :name (n6 / name :op1 "Arabian"~e.52 :op2 "horse"~e.53))))))) :mod d5~e.27) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 24~e.58)))) # ::id pmid_2541_3220.105 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The P @-@ ERK1 @/@ 2 levels were comparable to those seen in human melanoma cell lines with oncogenic BRAF or NRAS mutations , in contrast to a cell line with wild @-@ type BRAF and NRAS ( Figure 1 @ C , D; Table 1 ) . # ::alignments 1-1.1.1.2 3-1.1.1.1.1 5-1.1.1.1.1 6-1.1 6-1.2 8-1 11-1.2.1 12-1.2.1.1.r 13-1.2.1.1.1 14-1.2.1.1.4.1.1 15-1.2.1.1 16-1.2.1.1 18-1.2.1.1.2.1.1 18-1.2.1.1.2.1.1.2 18-1.2.1.1.2.1.1.2.1.2.1 18-1.2.1.1.2.1.1.2.r 19-1.2.1.1.2.1.1.1.1 20-1.2.1.1.2 21-1.2.1.1.2.2.1.1.1 22-1.2.1.1.2.1 22-1.2.1.1.2.2 25-1.2.1.1.3 28-1.2.1.1 28-1.2.1.1.3.1 29-1.2.1.1 30-1.2.1.1.3.1.1.r 31-1.2.1.1.3.1.1.2 33-1.2.1.1.3.1.1.2 34-1.2.1.1.3.1.1.1.1 36-1.2.1.1.2.2.1.1.1 36-1.2.1.1.3.1.2.1.1 38-1.3.1.1.1 38-1.3.1.1.2 38-1.3.1.1.3 40-1.3.1.1.3.1 42-1.3.1.1.1.1 45-1.3.1.2 47-1.3.1.2.1 (c4 / comparable-03~e.8 :ARG1 (l / level~e.6 :quant-of (e / enzyme :name (n / name :op1 "ERK1/2"~e.3,5) :ARG3-of (p / phosphorylate-01~e.1))) :ARG2 (l2 / level~e.6 :ARG1-of (s / see-01~e.11 :location~e.12 (c / cell-line~e.15,16,28,29 :mod (h / human~e.13) :mod (o / or~e.20 :op1 (m2 / mutate-01~e.22 :ARG1 (e5 / enzyme~e.18 :name (n3 / name :op1 "BRAF"~e.19) :ARG0-of~e.18 (c5 / cause-01~e.18 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.18))))) :op2 (m3 / mutate-01~e.22 :ARG1 (e4 / enzyme :name (n4 / name :op1 "NRAS"~e.21,36) :ARG0-of c5))) :ARG1-of (c2 / contrast-01~e.25 :ARG2 (c3 / cell-line~e.28 :mod~e.30 (e3 / enzyme :name (n5 / name :op1 "BRAF"~e.34) :mod (w / wild-type~e.31,33)) :mod (e2 / enzyme :name (n6 / name :op1 "NRAS"~e.36) :mod w))) :mod (m / medical-condition :name (n7 / name :op1 "melanoma"~e.14))))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (a3 / and :op1 (f / figure~e.38 :mod "C"~e.42) :op2 (f2 / figure~e.38 :mod "D") :part-of (f3 / figure~e.38 :mod 1~e.40)) :op2 (t / table~e.45 :mod 1~e.47)))) # ::id pmid_2541_3220.106 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK1 @/@ 2 was activated even in the absence of serum and serum addition had a minimal stimulatory effect on the P @-@ ERK1 @/@ 2 levels ( Additional file 2 @ : Figure S1A , B ) . # ::alignments 0-1.1.1.1.1 2-1.1.1.1.1 2-1.3.1.3.2.1 4-1.1 6-1.1.2.r 8-1.1.2 9-1.1.2.1.r 10-1.1.2.1 12-1.1.2.1 13-1.2.1 16-1.2.3.1 18-1.2 19-1.2.2.r 21-1.2.2.1.2 23-1.2.2.1.1.1 25-1.2.2.1.1.1 26-1.2.2 28-1.3.1.3.2.2 29-1.3.1.3.2 31-1.3.1.3.2.1 34-1.3.1.1 34-1.3.1.2 34-1.3.1.3 37-1.3.1.2.1 (a / and :op1 (a2 / activate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.0,2)) :concession~e.6 (a7 / absent-01~e.8 :ARG1~e.9 (s / serum~e.10,12))) :op2 (a3 / affect-01~e.18 :ARG0 (a4 / add-02~e.13 :ARG1 s) :ARG1~e.19 (l2 / level~e.26 :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.23,25) :ARG3-of (p / phosphorylate-01~e.21))) :ARG2 (s2 / stimulate-01 :ARG1-of (m / minimal-02~e.16))) :ARG1-of (d / describe-01 :ARG0 (a5 / and :op1 (f / figure~e.34 :mod "A") :op2 (f2 / figure~e.34 :mod "B"~e.37) :part-of (f3 / figure~e.34 :mod "S1" :part-of (f4 / file~e.29 :mod 2~e.2,31 :mod (a6 / additional~e.28)))))) # ::id pmid_2541_3220.107 ::amr-annotator SDL-AMR-09 ::preferred # ::tok MEK @/@ ERK module is required for growth of Grey horse melanoma cells # ::alignments 1-1.2.1.1.1 3-1.2.1.1.1 4-1.2 6-1 7-1.1.r 8-1.1 9-1.1.1.r 10-1.1.1.1.2.1 11-1.1.1.1.2 12-1.1.1.1.1.1 13-1.1.1 (r / require-01~e.6 :ARG0~e.7 (g / grow-01~e.8 :ARG1~e.9 (c / cell~e.13 :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma"~e.12) :mod (h / horse~e.11 :ARG1-of (g2 / gray-02~e.10))))) :ARG1 (m / module~e.4 :mod (p / pathway :name (n / name :op1 "MEK/ERK"~e.1,3)))) # ::id pmid_2541_3220.108 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To assess the involvement of the ERK pathway in proliferation of the GHM cells , we treated the HoMel @-@ L1 and HoMel @-@ A1 cell lines with U0126 , a specific inhibitor of MEK1 @/@ 2 and therefore ERK phosphorylation . # ::alignments 1-1.4 3-1.4.2 4-1.4.2.1.r 6-1.4.2.1.1.1 7-1.4.2.1 8-1.4.2.2.r 9-1.4.2.2 10-1.4.2.2.1.r 12-1.4.2.2.1.1.1.1 13-1.4.2.2.1 15-1.1 16-1 18-1.2.1.1.1 18-1.2.2.1.1 20-1.2.1.1.1 21-1.2 22-1.2.1.1.1 22-1.2.2.1.1 24-1.2.2.1.1 25-1.2.1 25-1.2.2 26-1.2.1 27-1.3.r 28-1.3.1.1 31-1.3.2.1.2 32-1.3.2.1 32-1.3.2.1.1 32-1.3.2.1.1.2.1 32-1.3.2.1.1.r 33-1.3.2.1.1.1.r 34-1.3.2.1.1.1.1.1 36-1.3.2.1.1.1.1.1 38-1.3.2.1.1.2 39-1.3.2.1.1.2.1.1.1 40-1.3.2.1.1.2.1.1 (t / treat-04~e.16 :ARG0 (w / we~e.15) :ARG1 (a / and~e.21 :op1 (c / cell-line~e.25,26 :name (n / name :op1 "HoMel-L1"~e.18,20,22)) :op2 (c2 / cell-line~e.25 :name (n2 / name :op1 "HoMel-A1"~e.18,22,24))) :ARG2~e.27 (s / small-molecule :name (n3 / name :op1 "U0126"~e.28) :ARG1-of (m2 / mean-01 :ARG2 (m / molecular-physical-entity~e.32 :ARG0-of~e.32 (i / inhibit-01~e.32 :ARG1~e.33 (e / enzyme :name (n4 / name :op1 "MEK1/2"~e.34,36)) :ARG0-of (c4 / cause-01~e.38 :ARG1 (i3 / inhibit-01~e.32 :ARG1 (p / phosphorylate-01~e.40 :ARG1 p2~e.39)))) :ARG1-of (s2 / specific-02~e.31)))) :purpose (a3 / assess-01~e.1 :ARG0 w :ARG1 (i2 / involve-01~e.3 :ARG1~e.4 (p2 / pathway~e.7 :name (n6 / name :op1 "ERK"~e.6)) :ARG2~e.8 (p3 / proliferate-01~e.9 :ARG0~e.10 (c3 / cell~e.13 :mod (d / disease :name (n7 / name :op1 "GHM"~e.12))))))) # ::id pmid_2541_3220.109 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Western blot analysis showed an expected decrease in P @-@ ERK1 @/@ 2 in both cell lines upon the treatment ( Figure 2 @ A ) . # ::alignments 0-1.1.1 1-1.1.1 2-1.1 3-1 5-1.2.4 6-1.2 7-1.2.1.r 8-1.2.1.2 10-1.2.1.1.1 12-1.2.1.1.1 13-1.2.2.r 14-1.2.2.1 15-1.2.2 16-1.2.2 19-1.2.3 21-1.3.1 23-1.2.1.1.1 (s / show-01~e.3 :ARG0 (a / analyze-01~e.2 :manner (i / immunoblot-01~e.0,1)) :ARG1 (d / decrease-01~e.6 :ARG1~e.7 (e2 / enzyme :name (n / name :op1 "ERK1/2"~e.10,12,23) :ARG3-of (p / phosphorylate-01~e.8)) :location~e.13 (c / cell-line~e.15,16 :mod (b2 / both~e.14)) :condition (t / treat-04~e.19 :ARG1 c) :ARG1-of (e / expect-01~e.5)) :ARG1-of (d2 / describe-01 :ARG0 (f / figure~e.21 :mod "2A"))) # ::id pmid_2541_3220.110 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The treatment also largely reduced cell viability in both cell lines ( Figure 2 @ B ) . # ::alignments 1-1.1 2-1.5 3-1.3 4-1 5-1.2.1 5-1.2.2 6-1.2 7-1.2.2.r 8-1.2.2.1 9-1.2.2 10-1.2.2 12-1.4.1 (r / reduce-01~e.4 :ARG0 (t / treat-04~e.1) :ARG1 (v / viability~e.6 :mod (c / cell~e.5) :location~e.7 (c2 / cell-line~e.5,9,10 :mod (b / both~e.8))) :ARG2 (l / large~e.3) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.12 :mod "2B")) :mod (a / also~e.2)) # ::id pmid_2541_3220.111 ::amr-annotator SDL-AMR-09 ::preferred # ::tok As judged from the calculated IC @₅₀ values , HoMel @-@ L1 appeared more sensitive to the MEK1 @/@ 2 inhibition than HoMel @-@ A1 ( P < 0.05 ) and at least as sensitive as the human ^Q61R@ NRAS line BL ( Figure 2 @ C ) . # ::alignments 1-1.2 2-1.2.1.r 4-1.2.1.2 5-1.2.1.1 7-1.2.1.1.1 11-1.1.1.1.1.1 11-1.1.1.4.1.1 13-1.1.1.1.1.1 14-1 15-1.1.1.3 16-1.1.1 17-1.1.1.2.r 19-1.1.1.2.1.1.1 21-1.1.1.2.1.1.1 22-1.1.1.2 23-1.1.1.4.r 24-1.1.1.1.1.1 24-1.1.1.4.1.1 26-1.1.1.4.1.1 28-1.4 29-1.4.1 30-1.4.1.1 32-1.1 33-1.1.2.2 34-1.1.2.2 36-1.1.2 41-1.1.2.4.2.2.1 43-1.1.2.4.2.1.1 44-1.1.1.1 44-1.1.1.4 44-1.1.2.4 45-1.1.2.4.1.1 47-1.3.1 49-1.1.1.2.1.1.1 (a / appear-02~e.14 :ARG1 (a2 / and~e.32 :op1 (s / sensitive-03~e.16 :ARG0 (c / cell-line~e.44 :name (n / name :op1 "HoMel-L1"~e.11,13,24)) :ARG1~e.17 (i / inhibit-01~e.22 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK1/2"~e.19,21,49))) :degree (m / more~e.15) :compared-to~e.23 (c3 / cell-line~e.44 :name (n3 / name :op1 "HoMel-A1"~e.11,24,26))) :op2 (s2 / sensitive-03~e.36 :ARG0 c :mod (a3 / at-least~e.33,34) :ARG1-of (e2 / equal-01) :compared-to (c5 / cell-line~e.44 :name (n4 / name :op1 "BL"~e.45) :mod (e3 / enzyme :name (n5 / name :op1 "NRAS"~e.43) :ARG2-of (m2 / mutate-01 :value "Q61R"~e.41))))) :ARG2-of (j / judge-01~e.1 :ARG3~e.2 (c4 / concentration-quantity :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01~e.5 :ARG2 50~e.7) :ARG1-of (c2 / calculate-01~e.4))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.47 :mod "2C")) :ARG1-of (s3 / statistical-test-91~e.28 :ARG2 (l / less-than~e.29 :op1 0.05~e.30))) # ::id pmid_2541_3220.112 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Both GHM cell lines were less sensitive to the U0126 treatment than the human ^V600E@ BRAF line Mel @-@ Ho , although , this did not reach statistical significance for HoMel @-@ L1 . # ::alignments 0-1.1.1.2 1-1.1.1.1.1.1 2-1.1.1 3-1.1.1 5-1.1.3 6-1.1 7-1.1.2.r 9-1.1.2.1.1.1 10-1.1.2 11-1.1.4.r 13-1.1.4.2.2 15-1.1.4.2.3.1 17-1.1.4.2.1.1 18-1.1.1 19-1.1.4.1.1 21-1.1.4.1.1 23-1 27-1.2.1 27-1.2.1.r 28-1.2 29-1.2.3.1 31-1.2.4.r 32-1.2.4.1.1 34-1.2.4.1.1 (h / have-concession-91~e.23 :ARG1 (s / sensitive-03~e.6 :ARG0 (c / cell-line~e.2,3,18 :mod (d / disease :name (n / name :op1 "GHM"~e.1)) :mod (b / both~e.0)) :ARG1~e.7 (t / treat-04~e.10 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "U0126"~e.9))) :degree (l / less~e.5) :compared-to~e.11 (c2 / cell-line :name (n3 / name :op1 "Mel-Ho"~e.19,21) :mod (e / enzyme :name (n4 / name :op1 "BRAF"~e.17) :mod (h2 / human~e.13) :ARG2-of (m / mutate-01 :value "V600E"~e.15)))) :ARG2 (r / reach-01~e.28 :polarity~e.27 -~e.27 :ARG0 s :ARG1 (s3 / signify-01 :mod (s4 / statistics~e.29)) :prep-for~e.31 (c3 / cell-line :name (n5 / name :op1 "HoMel-L1"~e.32,34)))) # ::id pmid_2541_3220.113 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In contrast , cell viability of the human ^WT@ BRAF ^WT@ RAS line M5 was only weakly inhibited by the treatment ( Figure 2 @ B ) . # ::alignments 1-1 3-1.1.2.1 4-1.1.2 9-1.1.2.2.2.2 9-1.1.2.2.3.2 11-1.1.2.2.2.1.1 13-1.1.2.2.2.2 13-1.1.2.2.3.2 15-1.1.2.2.3.1.1 16-1.1.2.2 17-1.1.2.2.1.1 19-1.1.3.1 20-1.1.3 21-1.1 22-1.1.1.r 24-1.1.1 26-1.2.1 (c / contrast-01~e.1 :ARG2 (i / inhibit-01~e.21 :ARG0~e.22 (t / treat-04~e.24) :ARG1 (v / viability~e.4 :mod (c2 / cell~e.3) :poss (c3 / cell-line~e.16 :name (n / name :op1 "M5"~e.17) :mod (e / enzyme :name (n2 / name :op1 "BRAF"~e.11) :mod (w2 / wild-type~e.9,13)) :mod (e2 / enzyme :name (n3 / name :op1 "RAS"~e.15) :mod (w3 / wild-type~e.9,13)))) :degree (w / weak-02~e.20 :mod (o / only~e.19))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.26 :mod "2B"))) # ::id pmid_2541_3220.114 ::amr-annotator SDL-AMR-09 ::preferred # ::tok These results demonstrate that ERK signaling is an important component for GHM cell growth ; however the incomplete inhibition by U0126 suggests that additional ERK @-@ independent mechanisms are involved . # ::alignments 0-1.1.1.1 1-1.1.1 1-1.1.1.2 1-1.1.1.2.r 2-1.1 3-1.1.2.r 4-1.1.2.2.1.1.1 5-1.1.2.2 6-1.1.2.2.r 8-1.1.2.1 9-1.1.2 10-1.1.2.3.r 11-1.1.2.3.1.1.1.1 12-1.1.2.3.1 13-1.1.2.3 15-1 17-1.2.1.2 17-1.2.1.2.1 17-1.2.1.2.1.r 18-1.2.1 19-1.2.1.1.r 20-1.2.1.1.1.1 21-1.2 22-1.2.2.r 23-1.2.2.1.2 24-1.2.2.1.1.2 26-1.2.2.1.1 26-1.2.2.1.1.1 26-1.2.2.1.1.1.r 27-1.2.2.1 29-1.2.2 (c4 / contrast-01~e.15 :ARG1 (d / demonstrate-01~e.2 :ARG0 (t2 / thing~e.1 :mod (t / this~e.0) :ARG2-of~e.1 (r / result-01~e.1)) :ARG1~e.3 (c / component~e.9 :mod (i / important~e.8) :domain~e.6 (s / signal-07~e.5 :ARG0 (e / enzyme :name (n / name :op1 "ERK"~e.4))) :purpose~e.10 (g / grow-01~e.13 :ARG1 (c2 / cell~e.12 :mod (d2 / disease :name (n2 / name :op1 "GHM"~e.11)))))) :ARG2 (s2 / suggest-01~e.21 :ARG0 (i2 / inhibit-01~e.18 :ARG0~e.19 (s3 / small-molecule :name (n3 / name :op1 "U0126"~e.20)) :ARG1-of (c3 / complete-01~e.17 :polarity~e.17 -~e.17)) :ARG1~e.22 (i4 / involve-01~e.29 :ARG1 (m / mechanism~e.27 :ARG0-of (d3 / depend-01~e.26 :polarity~e.26 -~e.26 :ARG1 e~e.24) :mod (a / additional~e.23))))) # ::id pmid_2541_3220.115 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Activation of ERK pathway in Grey horse melanoma cells is not linked to common oncogenic alterations # ::alignments 1-1.2 2-1.2.1.r 3-1.2.1.1.1 4-1.2.1 5-1.2.2.r 6-1.2.2.1.2.1 7-1.2.2.1.2 8-1.2.2.1.1.1 9-1.2.2 11-1.1 11-1.1.r 12-1 13-1.3.2 14-1.3.1 15-1.3.2 15-1.3.2.1.2.1 16-1.3 (l / link-01~e.12 :polarity~e.11 -~e.11 :ARG1 (a / activate-01~e.1 :ARG1~e.2 (p / pathway~e.4 :name (n / name :op1 "ERK"~e.3)) :location~e.5 (c / cell~e.9 :mod (m / medical-condition :name (n3 / name :op1 "melanoma"~e.8) :mod (h / horse~e.7 :ARG1-of (g / gray-02~e.6))))) :ARG2 (a2 / alter-01~e.16 :mod (c2 / common~e.14) :ARG0-of (c3 / cause-01~e.13,15 :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.15))))) # ::id pmid_2541_3220.116 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To test whether the constitutive ERK1 @/@ 2 activation was due to the presence of oncogenic mutations commonly associated with ERK1 @/@ 2 activation in melanocytic neoplasms , we screened the horse cell lines and seven additional GHM tumours for mutations in exons 11 and 15 of BRAF , the full coding regions of N @ -, K @ - and HRAS , exon 4 and 5 of GNAQ and GNA11 , and exons 9 @–@ 21 of KIT @ . # ::alignments 0-1.4.2 1-1.4 2-1.4.2.1 2-1.4.2.1.r 4-1.4.2.3.2 5-1.4.2.3.1.1.1 7-1.4.2.3.1.1.1 8-1.4.2.3 10-1.4.2 11-1.4.2 13-1.4.2.2 14-1.4.2.2.1.r 15-1.4.2.2.1.2 15-1.4.2.2.1.2.1.2.1 16-1.4.2.2.1 17-1.4.2.2.1.1.2 18-1.4.2.2.1.1 19-1.4.2.2.1.1.1.r 20-1.4.2.2.1.1.1.1 21-1.4.2.2.1.1.1.1 22-1.4.2.2.1.1.1.1 23-1.4.2.2.1.1.1 26-1.4.2.2.1.1.1.2 28-1.1 29-1 31-1.2.1.1 32-1.2.1 33-1.2.1 34-1.2 35-1.2.2.1 36-1.2.2.3 37-1.2.2.2.1.1 38-1.2.2 39-1.3.r 40-1.3 43-1.3.1.1.1.1.2 44-1.3.1.1 45-1.3.1.1.2.1.2 48-1.3.1.1.3.1.1 52-1.3.1.2.1 53-1.3.1.2.2 54-1.3.1.2 64-1.3.1.2.3 66-1.3.1.2.3.3.1.1 69-1.3.1.3.1.1.1 69-1.3.1.4.1.1 70-1.3.1.3.1.1.2 71-1.3.1.3 71-1.3.1.3.3 71-1.3.1.3.3.r 72-1.3.1.3.2.1.2 75-1.3.1.3.3.1.1.1 77-1.3.1.3.3 79-1.3.1.3.3.2.1.1 82-1.3.1 82-1.3.1.1 82-1.3.1.1.r 82-1.3.1.3 82-1.3.1.3.3 82-1.3.1.3.3.r 82-1.3.1.3.r 82-1.3.1.4.2 84-1.3.1.4.2.1 86-1.3.1.4.2.2 89-1.3.1.4.3.1.1 (s / screen-01~e.29 :ARG0 (w / we~e.28) :ARG1 (a / and~e.34 :op1 (c / cell-line~e.32,33 :mod (h / horse~e.31)) :op2 (t / tumor~e.38 :quant 7~e.35 :mod (d / disease :name (n / name :op1 "GHM"~e.37)) :mod (a2 / additional~e.36))) :ARG2~e.39 (m / mutate-01~e.40 :ARG1 (a3 / and~e.82 :op1~e.82 (a4 / and~e.44,82 :op1 (p7 / protein-segment :name (n15 / name :op1 "exon" :op2 11~e.43)) :op2 (p2 / protein-segment :name (n2 / name :op1 "exon" :op2 15~e.45)) :part-of (g / gene :name (n4 / name :op1 "BRAF"~e.48))) :op2 (r / region~e.54 :ARG1-of (f / full-09~e.52) :ARG0-of (c2 / code-01~e.53) :part-of (a5 / and~e.64 :op1 (g2 / gene :name (n5 / name :op1 "NRAS")) :op2 (g3 / gene :name (n6 / name :op1 "KRAS")) :op3 (g4 / gene :name (n7 / name :op1 "HRAS"~e.66)))) :op3~e.82 (a6 / and~e.71,82 :op1 (p3 / protein-segment :name (n3 / name :op1 "exon"~e.69 :op2 4~e.70)) :op2 (p8 / protein-segment :name (n17 / name :op1 "exon" :op2 5~e.72)) :part-of~e.71,82 (a7 / and~e.71,77,82 :op1 (g5 / gene :name (n10 / name :op1 "GNAQ"~e.75)) :op2 (g6 / gene :name (n11 / name :op1 "GNA11"~e.79)))) :op4 (p4 / protein-segment :name (n8 / name :op1 "exon"~e.69) :value (b / between~e.82 :op1 9~e.84 :op2 21~e.86) :part-of (g7 / gene :name (n13 / name :op1 "KIT"~e.89))))) :purpose (t2 / test-01~e.1 :ARG0 w :ARG1 (c3 / cause-01~e.0,10,11 :mode~e.2 interrogative~e.2 :ARG0 (p / present-02~e.13 :ARG1~e.14 (m2 / mutate-01~e.16 :ARG1-of (a9 / associate-01~e.18 :ARG2~e.19 (a10 / activate-01~e.23 :ARG1 e6~e.20,21,22 :location (n16 / neoplasm~e.26 :mod (m3 / melanocyte))) :mod (c7 / common~e.17)) :ARG0-of (c5 / cause-01~e.15 :ARG1 (d2 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer"~e.15))))) :ARG1 (a8 / activate-01~e.8 :ARG1 (e6 / enzyme :name (n14 / name :op1 "ERK1/2"~e.5,7)) :mod (c4 / constitutive~e.4))))) # ::id pmid_2541_3220.117 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In all the genes except KIT , no mutations were found , indicating the wild @-@ type status of the genes in this melanoma type . # ::alignments 1-1.1.2.1.1 3-1.1.2.1 4-1.1.2.1.2 6-1.1.2.1.2.1.1.1 9-1.1.1 9-1.1.1.r 10-1.1.2 12-1.1 14-1 16-1.2.1 18-1.2.1 18-1.2.3 18-1.2.3.2 18-1.2.3.2.r 19-1.2 20-1.2.2.r 22-1.2.2 25-1.2.3.1.1 26-1.2.1 26-1.2.3 26-1.2.3.2 26-1.2.3.2.r (i / indicate-01~e.14 :ARG0 (f / find-01~e.12 :polarity~e.9 -~e.9 :ARG1 (m / mutate-01~e.10 :ARG1 (g / gene~e.3 :mod (a / all~e.1) :ARG2-of (e / except-01~e.4 :ARG1 (g2 / gene :name (n / name :op1 "KIT"~e.6)))))) :ARG1 (s / status~e.19 :mod (w / wild-type~e.16,18,26) :poss~e.20 g~e.22 :location (m2 / medical-condition~e.18,26 :name (n3 / name :op1 "melanoma"~e.25) :ARG1-of~e.18,26 (t3 / type-03~e.18,26)))) # ::id pmid_2541_3220.118 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In KIT , four single nucleotide polymorphisms ( SNPs ) were found in exon 14 , 15 , 19 and 20 ( 11 % each ) in each of 4 different tumours ( Table @ 2 ) . # ::alignments 2-1.2.7.1.1 5-1.1.1 5-1.2.6.1.1.1 6-1.1.2.1 7-1.1.2.2 8-1.1.2.3 13-1 14-1.2.r 15-1.2.1.1.1 16-1.2.1.1.2 18-1.2.2.1.2 20-1.2.3.1.2 21-1.2 22-1.2.4.1.2 24-1.2.5.1 25-1.2.5 26-1.2.5.2 26-1.2.6 29-1.2.5.2 31-1.2.6.1.1.1 32-1.2.6.1.1.2 33-1.2.6.1.1 37-1.3.1.1 (f / find-01~e.13 :ARG1 (t4 / thing :quant 4~e.5 :name (n / name :op1 "single"~e.6 :op2 "nucleotide"~e.7 :op3 "polymorphism"~e.8)) :location~e.14 (a / and~e.21 :op1 (p6 / protein-segment :name (n2 / name :op1 "exon"~e.15 :op2 14~e.16)) :op2 (p / protein-segment :name (n3 / name :op1 "exon" :op2 15~e.18)) :op3 (p3 / protein-segment :name (n4 / name :op1 "exon" :op2 19~e.20)) :op4 (p4 / protein-segment :name (n5 / name :op1 "exon" :op2 20~e.22)) :value (p2 / percentage-entity~e.25 :value 11~e.24 :mod (e5 / each~e.26,29)) :location (e6 / each~e.26 :ARG1-of (i / include-91 :ARG2 (t / tumor~e.33 :quant 4~e.5,31 :ARG1-of (d5 / differ-02~e.32)))) :part-of (g2 / gene :name (n8 / name :op1 "KIT"~e.2))) :ARG1-of (d6 / describe-01 :ARG0 (t2 / table :mod 2~e.37))) # ::id pmid_2541_3220.119 ::amr-annotator SDL-AMR-09 ::preferred # ::tok However , these SNPs were silent on the protein level and present in the constitutional DNA from both Grey and non @-@ Grey horses of different breeds ( Table @ 2 ) , and therefore were considered as common germline polymorphisms with no link to the Grey phenotype . # ::alignments 0-1 2-1.1.1.1.2 4-1.1.1.1.r 5-1.1.1 6-1.1.1.2.r 8-1.1.1.2.1 9-1.1.1.2 10-1.1 11-1.1.2 15-1.1.2.2.1.1 16-1.1.2.2.3.r 18-1.1.2.2.3.2.1 20-1.1.2.2.3.2.1.1 20-1.1.2.2.3.2.1.1.r 22-1.1.2.2.3.1.1 22-1.1.2.2.3.2.1 23-1.1.2.2.3.1 23-1.1.2.2.3.2 25-1.1.2.2.3.3.1 26-1.1.2.2.3.3 30-1.1.3.1.1 34-1.1 35-1.1.4 36-1.1.4.1.1.4.r 37-1.1.4.1 38-1.1.4.1.1.r 39-1.1.4.1.1.1 40-1.1.4.1.1.2.1.1 41-1.1.4.1.1 42-1.1.4.1.1.3.r 43-1.1.4.1.1.3.1 43-1.1.4.1.1.3.1.r 44-1.1.4.1.1.3 45-1.1.4 47-1.1.2.2.3.2.1 48-1.1.4.1.1.3.2 (c / contrast-01~e.0 :ARG2 (a / and~e.10,34 :op1 (s / silent~e.5 :domain~e.4 (d / dna-sequence :name (n / name :op1 "SNP") :mod (t2 / this~e.2)) :location~e.6 (l / level~e.9 :mod (p2 / protein~e.8))) :op2 (p / present-02~e.11 :ARG1 d :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "DNA"~e.15) :ARG1-of (c2 / constitute-01) :source~e.16 (a2 / and :op1 (h / horse~e.23 :ARG1-of (g / gray-02~e.22)) :op2 (h2 / horse~e.23 :ARG1-of (g2 / gray-02~e.18,22,47 :polarity~e.20 -~e.20)) :part-of (b / breed~e.26 :ARG1-of (d3 / differ-02~e.25))))) :ARG1-of (d4 / describe-01 :ARG0 (t / table :mod 2~e.30)) :ARG0-of (c3 / cause-01~e.35,45 :ARG1 (c4 / consider-01~e.37 :ARG1~e.38 (p3 / polymorphism~e.41 :mod (c5 / common~e.39) :part-of (c6 / cell-line :name (n2 / name :op1 "germline"~e.40)) :ARG1-of~e.42 (l2 / link-01~e.44 :polarity~e.43 -~e.43 :ARG2 (p4 / phenotype~e.48 :mod h)) :domain~e.36 d))))) # ::id pmid_2541_3220.120 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Another possible mechanism for a constitutive activation of the ERK pathway may involve overexpression of a component of the pathway or underexpression of its negative regulator . # ::alignments 0-1.1.1.3 1-1.1.1.1 2-1.1.1 3-1.1.1.2.r 5-1.1.1.2.2 6-1.1.1.2 7-1.1.1.2.1.r 9-1.1.1.2.1.1.1 10-1.1.1.2.1 11-1 12-1.1 13-1.1.2.1 14-1.1.2.1.1.r 16-1.1.2.1.1 17-1.1.2.1.1.1.r 19-1.1.2.1.1.1 20-1.1.2 23-1.1.2.2.1.1 23-1.1.2.2.1.1.r 24-1.1.2.2.1 24-1.1.2.2.1.2 24-1.1.2.2.1.2.r 25-1.1.2.2.1 25-1.1.2.2.1.2 25-1.1.2.2.1.2.r (p / possible-01~e.11 :ARG1 (i / involve-01~e.12 :ARG0 (m / mechanism~e.2 :ARG1-of (p2 / possible-01~e.1) :instrument-of~e.3 (a2 / activate-01~e.6 :ARG1~e.7 (p3 / pathway~e.10 :name (n / name :op1 "ERK"~e.9)) :mod (c / constitutive~e.5)) :mod (a / another~e.0)) :ARG1 (o / or~e.20 :op1 (o2 / overexpress-01~e.13 :ARG1~e.14 (c2 / component~e.16 :part-of~e.17 p3~e.19)) :op2 (u / underexpress-00 :ARG1 (m2 / molecular-physical-entity~e.24,25 :part-of~e.23 p3~e.23 :ARG2-of~e.24,25 (d / downregulate-01~e.24,25)))))) # ::id pmid_2541_3220.121 ::amr-annotator SDL-AMR-09 ::preferred # ::tok To address this possibility we compared expression levels of the key kinases and two major negative regulators of the pathway , SPROUTY2 and RKIP , in the GHM vs @ . human melanoma cell lines with activated ERK1 @/@ 2 due to oncogenic BRAF or NRAS mutations . # ::alignments 1-1.4 2-1.4.2.1 3-1.4.2 4-1.1 5-1 6-1.2.1 7-1.2 7-1.2.2 7-1.2.2.r 8-1.2.1.1.r 10-1.2.1.1.1.1 11-1.2.1.1.1 12-1.2.1.1 13-1.2.1.1.2.1 14-1.2.1.1.2.3 15-1.2.1.1.2 15-1.2.1.1.2.2 15-1.2.1.1.2.2.r 16-1.2.1.1.2 16-1.2.1.1.2.2 16-1.2.1.1.2.2.r 17-1.2.1.1.2.2.1.r 19-1.2.1.1.2.2.1 21-1.2.1.1.2.4.1.1.1.1 22-1.2.1.1.2.4.1 23-1.2.1.1.2.4.1.2.1.1 27-1.2.3.1.1.1 33-1.2.2.2.1.1.1 34-1.2.2.2 34-1.2.3 36-1.3.r 37-1.3.2 38-1.3.1.1 40-1.3.1.1 41-1.3.2.1 41-1.3.2.1.1.1.1 41-1.3.2.1.1.1.1.2 41-1.3.2.1.1.1.1.2.r 42-1.3.2.1 42-1.3.2.1.1.1.1 42-1.3.2.1.1.1.1.2 42-1.3.2.1.1.1.1.2.r 43-1.3.2.1 43-1.3.2.1.1.1.1 43-1.3.2.1.1.1.1.2 43-1.3.2.1.1.1.1.2.1.2.1 43-1.3.2.1.1.1.1.2.r 44-1.3.2.1.1.1.1.1.1 45-1.3.2.1.1.1 46-1.3.2.1.1.1.2.1.1 47-1.3.2.1.1 (c / compare-01~e.5 :ARG0 (w / we~e.4) :ARG1 (l / level~e.7 :degree-of (e / express-03~e.6 :ARG1~e.8 (a / and~e.12 :op1 (k / kinase~e.11 :ARG1-of (k2 / key-02~e.10)) :op2 (m4 / molecular-physical-entity~e.15,16 :quant 2~e.13 :ARG2-of~e.15,16 (d / downregulate-01~e.15,16 :ARG1~e.17 (p / pathway~e.19)) :ARG1-of (m / major-02~e.14) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and~e.22 :op1 (e2 / enzyme :name (n / name :op1 "SPROUTY2"~e.21)) :op2 (p3 / protein :name (n2 / name :op1 "RKIP"~e.23))))))) :compared-to~e.7 (l2 / level~e.7 :degree-of e :location (c3 / cell~e.34 :mod (m5 / medical-condition :name (n4 / name :op1 "melanoma"~e.33)))) :location (c2 / cell~e.34 :mod (d2 / disease :name (n3 / name :op1 "GHM"~e.27)))) :ARG2~e.36 (e4 / enzyme :name (n5 / name :op1 "ERK1/2"~e.38,40) :ARG1-of (a3 / activate-01~e.37 :ARG1-of (c5 / cause-01~e.41,42,43 :ARG0 (m3 / mutate-01~e.47 :ARG1 (o / or~e.45 :op1 (e5 / enzyme~e.41,42,43 :name (n6 / name :op1 "BRAF"~e.44) :ARG0-of~e.41,42,43 (c6 / cause-01~e.41,42,43 :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"~e.43)))) :op2 (e6 / enzyme :name (n7 / name :op1 "NRAS"~e.46) :ARG0-of c6)))))) :purpose (a4 / address-02~e.1 :ARG0 w :ARG1 (p2 / possible-01~e.3 :mod (t / this~e.2)))) # ::id pmid_2541_3220.122 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We found no substantial differences in the levels of ERK1 @/@ 2 ( Figure 1 @ C ) , MEK1 @/@ 2 , BRAF , NRAS ( Figure 3 @ A and Additional file 3 @ : Figure S2A ) between the horse and human melanoma cells . # ::alignments 0-1.2 1-1 2-1.1 2-1.1.r 3-1.3.3 4-1.3 7-1.3.1.1 7-1.3.1.2 7-1.3.1.3 7-1.3.1.4 8-1.3.1.1.1.r 9-1.3.1.1.1.1.1 11-1.3.1.1.1.1.1 11-1.3.1.2.1.1.1 13-1.3.1.1.1.2.1 20-1.3.1.2.1.1.1 22-1.3.1.1.1.1.1 22-1.3.1.2.1.1.1 24-1.3.1.3.1.1.1 26-1.3.1.4.1.1.1 28-1.3.1.4.1.2.1.1 33-1.3.1.4.1.2.1 35-1.3.1.4.1.2.1.2 40-1.3.1.4.1.2.1.2.1.1 41-1.3.1.4.1.2.1.2.1.1.1 45-1.3.1.5.1.2 46-1.3.1 46-1.3.2 47-1.3.2.5.1.2 48-1.3.1.5.1.1.1 48-1.3.2.5.1.1.1 49-1.3.1.5 49-1.3.2.5 (f / find-01~e.1 :polarity~e.2 -~e.2 :ARG0 (w / we~e.0) :ARG1 (d / differ-02~e.4 :ARG1 (a4 / and~e.46 :op1 (l / level~e.7 :quant-of~e.8 (e / enzyme :name (n / name :op1 "ERK1/2"~e.9,11,22) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure~e.13 :mod "1C")))) :op2 (l2 / level~e.7 :quant-of (e2 / enzyme :name (n2 / name :op1 "MEK1/2"~e.11,20,22))) :op3 (l3 / level~e.7 :quant-of (e3 / enzyme :name (n3 / name :op1 "BRAF"~e.24))) :op4 (l4 / level~e.7 :quant-of (e4 / enzyme :name (n4 / name :op1 "NRAS"~e.26) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and~e.33 :op1 (f3 / figure~e.28 :mod "3A") :op2 (f4 / file~e.35 :ARG1-of (m / mean-01 :ARG2 (f5 / figure~e.40 :mod "S2A"~e.41)) :ARG1-of (a3 / add-02)))))) :location (c / cell~e.49 :source (m4 / medical-condition :name (n5 / name :op1 "melanoma"~e.48) :mod (h / horse~e.45)))) :ARG2 (a / and~e.46 :op1 l :op2 l2 :op3 l3 :op4 l4 :location (c2 / cell~e.49 :source (m2 / medical-condition :name (n6 / name :op1 "melanoma"~e.48) :mod (h2 / human~e.47)))) :degree (s / substantial~e.3))) # ::id pmid_2541_3220.123 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The levels of SPROUTY2 and RKIP in the horse lines were not lower than those in the human lines ( Figure 3 @ A and Additional file 3 @ : Figure S2A ) . # ::alignments 1-1.2.1 1-1.2.2 2-1.2.1.1.r 3-1.2.1.1.1.1 4-1.2 5-1.2.2.1.1.1 8-1.2.3.1 9-1.2.3 11-1.1 11-1.1.r 12-1 12-1.3 12-1.3.r 13-1.4.r 17-1.4.3.1 18-1.4.3 20-1.5.1.1 25-1.5.1 27-1.5.1.2 32-1.5.1.2.1.1 33-1.5.1.2.1.1.1 (l / low-04~e.12 :polarity~e.11 -~e.11 :ARG1 (a / and~e.4 :op1 (l2 / level~e.1 :quant-of~e.2 (e / enzyme :name (n / name :op1 "SPROUTY2"~e.3))) :op2 (l3 / level~e.1 :quant-of (p / protein :name (n2 / name :op1 "RKIP"~e.5))) :location (l4 / line~e.9 :mod (h / horse~e.8))) :degree~e.12 (m / more~e.12) :compared-to~e.13 (a4 / and :op1 l2 :op2 l3 :location (l6 / line~e.18 :mod (h2 / human~e.17))) :ARG1-of (d / describe-01 :ARG0 (a2 / and~e.25 :op1 (f / figure~e.20 :mod "3A") :op2 (f2 / file~e.27 :ARG1-of (m2 / mean-01 :ARG0 (f3 / figure~e.32 :mod "S2A"~e.33)) :ARG1-of (a3 / add-02))))) # ::id pmid_2541_3220.124 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Together , these results suggest that neither oncogenic mutations in the components of the ERK pathway nor alteration in their expression or of that of the pathway ’s major negative regulators is likely to be responsible for the constitutive activation of ERK1 @/@ 2 in GHM cells . # ::alignments 0-1.3 2-1.1.2 3-1.1 3-1.1.1 3-1.1.1.r 4-1 5-1.2.r 6-1.2.1.r 7-1.2.2.1.1.2 7-1.2.2.1.1.2.1.2.1 8-1.2.2.1.1 9-1.2.2.1.1.1.r 11-1.2.2.1.1.1 12-1.2.2.1.1.1.1.r 14-1.2.2.1.1.1.1.1.1 15-1.2.2.1.1.1.1 16-1.2.1 16-1.2.2.1 17-1.2.2.1.2 20-1.2.2.1.2.1 21-1.2.2.1.2.1.1 24-1.2.2.1.2.1.1.r 26-1.2.2.1.2.1.1.1 28-1.2.2.1.2.1.1.2 28-1.2.2.1.2.1.1.2.1 28-1.2.2.1.2.1.1.2.1.r 32-1.2 35-1.2.2 36-1.2.2.2.r 38-1.2.2.2.3 39-1.2.2.2 40-1.2.2.2.1.r 41-1.2.2.2.1.1.1 43-1.2.2.2.1.1.1 44-1.2.2.2.2.r 45-1.2.2.2.2.1.1.1 46-1.2.2.2.2 (s / suggest-01~e.4 :ARG0 (t / thing~e.3 :ARG1-of~e.3 (r / result-01~e.3) :mod (t2 / this~e.2)) :ARG1~e.5 (l / likely-01~e.32 :polarity~e.6 -~e.16 :ARG1 (r2 / responsible-01~e.35 :ARG0 (o / or~e.16 :op1 (m / mutate-01~e.8 :ARG1~e.9 (c3 / component~e.11 :part-of~e.12 (p / pathway~e.15 :name (n / name :op1 "ERK"~e.14))) :ARG0-of (c / cause-01~e.7 :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"~e.7)))) :op2 (a / alter-01~e.17 :ARG1 (e / express-03~e.20 :ARG2~e.24 (o2 / or~e.21 :op1 c3~e.26 :op2 (m3 / molecular-physical-entity~e.28 :ARG1-of~e.28 (m2 / major-02~e.28) :ARG0-of (d / deregulate-01 :ARG1 p)))))) :ARG1~e.36 (a2 / activate-01~e.39 :ARG1~e.40 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.41,43)) :location~e.44 (c4 / cell~e.46 :mod (d2 / disease :name (n3 / name :op1 "GHM"~e.45))) :mod (c5 / constitutive~e.38)))) :mod (t3 / together~e.0)) # ::id pmid_2541_3220.125 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK1 @/@ 2 activation is BRAF , CRAF and KRAS @-@ dependent in Grey horse melanoma cells # ::alignments 1-1.1.1.1.1 3-1.1.1.1.1 4-1.1 6-1.2.1.1.1 8-1.2.2.1.1 9-1.2 10-1.2.3.1.1 12-1 13-1.3.r 14-1.3.1.2.1 15-1.3.1.2 16-1.3.1.1.1 17-1.3 (d / depend-01~e.12 :ARG0 (a / activate-01~e.4 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.1,3))) :ARG1 (a2 / and~e.9 :op1 (e2 / enzyme :name (n2 / name :op1 "BRAF"~e.6)) :op2 (e3 / enzyme :name (n3 / name :op1 "CRAF"~e.8)) :op3 (e4 / enzyme :name (n4 / name :op1 "KRAS"~e.10))) :location~e.13 (c / cell~e.17 :source (m / medical-condition :name (n5 / name :op1 "melanoma"~e.16) :mod (h / horse~e.15 :ARG1-of (g / gray-02~e.14))))) # ::id pmid_2541_3220.126 ::amr-annotator SDL-AMR-09 ::preferred # ::tok In order to identify upstream signaling components involved in the constitutive ERK1 @/@ 2 activation in GHM cells we used specific inhibitors against RAF ( L779450 ) , RAS ( farnesyl thiosalicylic acid , FTS ) and PI3K @/@ AKT ( LY294002 ) proteins . # ::alignments 3-1.3 4-1.3.2.1.1 5-1.3.2.1 6-1.3.2 7-1.3.2.2 8-1.3.2.2.1.r 10-1.3.2.2.1.3 11-1.3.2.2.1.1.1.1 13-1.3.2.2.1.1.1.1 14-1.3.2.2.1 15-1.3.2.2.1.2.r 16-1.3.2.2.1.2.1.1.1 17-1.3.2.2.1.2 18-1.1 19-1 20-1.2.4 21-1.2.1 21-1.2.1.1 21-1.2.1.1.r 21-1.2.2 21-1.2.2.1 21-1.2.2.1.r 21-1.2.3 21-1.2.3.1 21-1.2.3.1.r 23-1.2.1.1.1.1.1 25-1.2.1.2.1.1.1 28-1.2.2.1.1.1.1 30-1.2.2.2.1.1.1 31-1.2.2.2.1.1.2 32-1.2.2.2.1.1.3 36-1.2 37-1.2.3.1.1.1.1 39-1.2.3.1.1.1.1 41-1.2.3.2.1.1.1 43-1.2.1.1.1 43-1.2.2.1.1 (u / use-01~e.19 :ARG0 (w / we~e.18) :ARG1 (a4 / and~e.36 :op1 (m / molecular-physical-entity~e.21 :ARG0-of~e.21 (i4 / inhibit-01~e.21 :ARG1 (p / protein-family~e.43 :name (n4 / name :op1 "RAF"~e.23))) :ARG1-of (m2 / mean-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "L779450"~e.25)))) :op2 (m3 / molecular-physical-entity~e.21 :ARG0-of~e.21 (i5 / inhibit-01~e.21 :ARG1 (p3 / protein-family~e.43 :name (n5 / name :op1 "RAS"~e.28))) :ARG1-of (m4 / mean-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "farnesyl"~e.30 :op2 "thiosalicylic"~e.31 :op3 "acid"~e.32)))) :op3 (m5 / molecular-physical-entity~e.21 :ARG0-of~e.21 (i6 / inhibit-01~e.21 :ARG1 (p2 / pathway :name (n6 / name :op1 "PI3K/AKT"~e.37,39))) :ARG1-of (m6 / mean-01 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "LY294002"~e.41)))) :ARG1-of (s / specific-02~e.20)) :ARG2 (i2 / identify-01~e.3 :ARG0 w :ARG1 (c / component~e.6 :ARG0-of (s5 / signal-07~e.5 :direction (u2 / upstream~e.4)) :ARG1-of (i3 / involve-01~e.7 :ARG2~e.8 (a3 / activate-01~e.14 :ARG1 (e4 / enzyme :name (n7 / name :op1 "ERK1/2"~e.11,13)) :location~e.15 (c2 / cell~e.17 :mod (d / disease :name (n8 / name :op1 "GHM"~e.16))) :mod (c3 / constitutive~e.10)))))) # ::id pmid_2541_3220.127 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Only the L779450 treatment was able to reduce P @-@ ERK1 @/@ 2 levels , suggesting involvement of RAF kinases in the control of ERK activation ( Figure 3 @ B and Additional file 3 @ : Figure S2B ; FTS treatment not shown ) . # ::alignments 0-1.1.1.2 2-1.1.1.1.1.1 3-1.1.1 5-1 7-1.1 8-1.1.2.1.2 10-1.1.2.1.1.1 12-1.1.2.1.1.1 13-1.1.2 15-1.1.3 16-1.1.3.1 17-1.1.3.1.1.r 18-1.1.3.1.1.1.1 20-1.1.3.1.2.r 22-1.1.3.1.2 23-1.1.3.1.2.1.r 24-1.1.3.1.2.1.1.1.1 25-1.1.3.1.2.1 27-1.2.1.1 29-1.2.1.2.1 34-1.2.1.2 36-1.2.1.2.1 39-1.2.1.2.3.1 40-1.2.1.2.3.1.1 42-1.2.1.3.1.1.1 43-1.2.1.3 44-1.2.1.3.2.1 44-1.2.1.3.2.1.r 45-1.2.1.3.2 (p2 / possible-01~e.5 :ARG1 (r / reduce-01~e.7 :ARG0 (t / treat-04~e.3 :ARG2 (s / small-molecule :name (n3 / name :op1 "L779450"~e.2)) :mod (o / only~e.0)) :ARG1 (l / level~e.13 :quant-of (e / enzyme :name (n / name :op1 "ERK1/2"~e.10,12) :ARG3-of (p / phosphorylate-01~e.8))) :ARG0-of (s2 / suggest-01~e.15 :ARG1 (i / involve-01~e.16 :ARG1~e.17 (p4 / protein-family :name (n2 / name :op1 "RAF"~e.18)) :ARG2~e.20 (c / control-01~e.22 :ARG1~e.23 (a / activate-01~e.25 :ARG1 (p3 / protein-family :name (n4 / name :op1 "ERK"~e.24))))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.27 :mod "3B") :op2 (f2 / file~e.34 :mod 3~e.29,36 :ARG1-of (a4 / add-02) :ARG1-of (m / mean-01 :ARG2 (f3 / figure~e.39 :mod "S2B"~e.40))) :op3 (t2 / treat-04~e.43 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "FTS"~e.42)) :ARG1-of (s4 / show-01~e.45 :polarity~e.44 -~e.44))))) # ::id pmid_2541_3220.128 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The treatment attenuated cell growth in both cell lines ( Figure 3 @ C , D ) to the levels comparable to those attained by the U0126 treatment , supporting a role of RAF kinases in GHM cell growth through ERK1 @/@ 2 activation . # ::alignments 1-1.1 2-1 3-1.2.1 3-1.3 4-1.2 6-1.3.1 7-1.3 8-1.3 10-1.1.1.1.1 10-1.1.1.1.2 18-1.4.r 20-1.4 20-1.4.1.1 21-1.4.1 24-1.4.1.1.1 27-1.4.1.1.1.1.1.1.1 28-1.1 28-1.4.1.1.1.1 30-1.1.2 32-1.1.2.1 33-1.1.2.1.1.r 34-1.1.2.1.1.1.1 36-1.1.2.1.2.r 37-1.1.2.1.2.1.1.1.1 38-1.1.2.1.2.1 39-1.1.2.1.2 41-1.1.2.2.1.1.1 43-1.1.2.2.1.1.1 44-1.1.2.2 (a / attenuate-01~e.2 :ARG0 (t / treat-04~e.1,28 :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.10 :mod "3C") :op2 (f2 / figure~e.10 :mod "3D"))) :ARG0-of (s2 / support-01~e.30 :ARG1 (r / role~e.32 :poss~e.33 (p / protein-family :name (n2 / name :op1 "RAF"~e.34)) :beneficiary~e.36 (g2 / grow-01~e.39 :ARG1 (c4 / cell~e.38 :mod (d2 / disease :name (n3 / name :op1 "GHM"~e.37))))) :manner (a4 / activate-01~e.44 :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2"~e.41,43))))) :ARG1 (g / grow-01~e.4 :ARG1 (c / cell~e.3)) :location (c2 / cell-line~e.3,7,8 :mod (b / both~e.6)) :destination~e.18 (l / level~e.20 :ARG1-of (c3 / comparable-03~e.21 :ARG2 (l2 / level~e.20 :ARG1-of (a3 / attain-01~e.24 :ARG0 (t2 / treat-04~e.28 :ARG2 (s / small-molecule :name (n / name :op1 "U0126"~e.27)))))))) # ::id pmid_2541_3220.129 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We also examined the contribution of individual RAF isoforms on ERK1 @/@ 2 activation by RNA silencing ( siRNA ) . # ::alignments 0-1.1 1-1.3 2-1 4-1.2 5-1.2.1.r 6-1.2.1.2 7-1.2.1.1.1.1 8-1.2.1 9-1.2.2.r 10-1.2.2.1.1.1 12-1.2.2.1.1.1 13-1.2.2 14-1.2.3.r 15-1.2.3.1 16-1.2.3 18-1.2.3.1.1.1 (e2 / examine-01~e.2 :ARG0 (w / we~e.0) :ARG1 (c / contribute-01~e.4 :ARG0~e.5 (i / isoform~e.8 :mod (e / enzyme :name (n / name :op1 "RAF"~e.7)) :mod (i2 / individual~e.6)) :ARG2~e.9 (a / activate-01~e.13 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"~e.10,12))) :manner~e.14 (s / silence-01~e.16 :ARG1 (n4 / nucleic-acid~e.15 :name (n3 / name :op1 "siRNA"~e.18)))) :mod (a2 / also~e.1)) # ::id pmid_2541_3220.130 ::amr-annotator SDL-AMR-09 ::preferred # ::tok While no considerable reduction in ERK1 @/@ 2 activation was achieved by ARAF depletion , BRAF and CRAF silencing each reduced the level of ERK1 @/@ 2 phosphorylation ( Figure 4 @ A @-@ E ) . # ::alignments 0-1 1-1.1.1 1-1.1.1.r 2-1.1.2.2 3-1.1.2 4-1.1.2.1.r 5-1.1.2.1.1.1.1 7-1.1.2.1.1.1.1 8-1.1.2.1 10-1.1 11-1.1.3.r 12-1.1.3.1.1.1 13-1.1.3 15-1.2.1.1.1.1.1 16-1.2.1 17-1.2.1.2.1.1.1 18-1.2.1.1 18-1.2.1.2 20-1.2 22-1.2.2 23-1.2.2.1.r 24-1.2.2.1.1 25-1.2.2.1.1 26-1.2.2.1.1 27-1.2.2.1 29-1.3.1.1 29-1.3.1.2 29-1.3.1.3 29-1.3.1.4 29-1.3.1.5 (c / contrast-01~e.0 :ARG1 (a / achieve-01~e.10 :polarity~e.1 -~e.1 :ARG1 (r / reduce-01~e.3 :ARG1~e.4 (a2 / activate-01~e.8 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.5,7))) :mod (c2 / considerable~e.2)) :manner~e.11 (d / deplete-01~e.13 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ARAF"~e.12)))) :ARG2 (r2 / reduce-01~e.20 :ARG0 (a3 / and~e.16 :op1 (s / silence-01~e.18 :ARG1 (e3 / enzyme :name (n3 / name :op1 "BRAF"~e.15))) :op2 (s2 / silence-01~e.18 :ARG1 (e4 / enzyme :name (n4 / name :op1 "CRAF"~e.17)))) :ARG1 (l / level~e.22 :quant-of~e.23 (p / phosphorylate-01~e.27 :ARG1 e~e.24,25,26))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.29 :mod "4A") :op2 (f2 / figure~e.29 :mod "4B") :op3 (f3 / figure~e.29 :mod "4C") :op4 (f4 / figure~e.29 :mod "4D") :op5 (f5 / figure~e.29 :mod "4E")))) # ::id pmid_2541_3220.131 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Since RAS kinases are known upstream activators of wild @-@ type RAF kinases , the failure of the FTS treatment to affect the P @-@ ERK1 @/@ 2 levels was somewhat unexpected . # ::alignments 0-1 1-1.1.2.1.1 2-1.1.2 3-1.1.2.r 4-1.1.3 5-1.1.1.2 6-1.1 6-1.1.1 6-1.1.1.r 7-1.1.1.1.r 8-1.1.1.1.2 10-1.1.1.1.2 11-1.1.1.1.1.1 12-1.1.2 15-1.2.2 16-1.2.2.1.r 18-1.2.2.1.1.1.1 19-1.2.2.1 21-1.2.2.2 23-1.2.2.2.2.1.2 25-1.2.2.2.2.1.1.1 27-1.2.2.2.2.1.1.1 28-1.2.2.2.2 30-1.2.3 31-1.2 31-1.2.1 31-1.2.1.r (c / cause-01~e.0 :ARG0 (m / molecular-physical-entity~e.6 :ARG0-of~e.6 (a2 / activate-01~e.6 :ARG1~e.7 (p2 / protein-family :name (n4 / name :op1 "RAF"~e.11) :mod (w / wild-type~e.8,10)) :direction (u / upstream~e.5)) :domain~e.3 (k2 / kinase~e.2,12 :name (n3 / name :op1 "RAS"~e.1)) :ARG1-of (k / know-01~e.4)) :ARG1 (e3 / expect-01~e.31 :polarity~e.31 -~e.31 :ARG1 (f / fail-01~e.15 :ARG1~e.16 (t3 / treat-04~e.19 :ARG2 (s2 / small-molecule :name (n5 / name :op1 "FTS"~e.18))) :ARG2 (a3 / affect-01~e.21 :ARG0 t3 :ARG1 (l / level~e.28 :quant-of (e4 / enzyme :name (n6 / name :op1 "ERK1/2"~e.25,27) :ARG3-of (p / phosphorylate-01~e.23))))) :degree (s / somewhat~e.30))) # ::id pmid_2541_3220.132 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We therefore decided to directly manipulate the levels of RAS kinases by siRNA @-@ based approach to address their potential contribution to the ERK1 @/@ 2 pathway in GHM cells . # ::alignments 0-1.1.1 1-1 2-1.1 4-1.1.2.5 5-1.1.2 7-1.1.2.2 8-1.1.2.2.1.r 9-1.1.2.2.1.1.1 11-1.1.2.3.r 12-1.1.2.3.1.1.1.1 14-1.1.2.3.1 15-1.1.2.3 17-1.1.2.4 19-1.1.2.4.2.3 20-1.1.2.4.2 21-1.1.2.4.2.2.r 23-1.1.2.4.2.2.1.1 25-1.1.2.4.2.2.1.1 26-1.1.2.4.2.2 27-1.1.2.4.2.2.2.r 28-1.1.2.4.2.2.2.1.1.1 29-1.1.2.4.2.2.2 (c / cause-01~e.1 :ARG1 (d / decide-01~e.2 :ARG0 (w / we~e.0) :ARG1 (m / manipulate-01~e.5 :ARG0 w :ARG1 (l / level~e.7 :quant-of~e.8 (p3 / protein-family :name (n2 / name :op1 "RAS"~e.9))) :manner~e.11 (a / approach-02~e.15 :ARG1-of (b / base-02~e.14 :ARG2 (n5 / nucleic-acid :name (n / name :op1 "siRNA"~e.12)))) :purpose (a2 / address-02~e.17 :ARG0 w :ARG1 (c2 / contribute-01~e.20 :ARG0 l :ARG2~e.21 (p2 / pathway~e.26 :name (n3 / name :op1 "ERK1/2"~e.23,25) :location~e.27 (c3 / cell~e.29 :mod (d3 / disease :name (n4 / name :op1 "GHM"~e.28)))) :mod (p / potential~e.19))) :ARG1-of (d2 / direct-02~e.4)))) # ::id pmid_2541_3220.133 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The initial experiment with combined depletion of NRAS , HRAS and KRAS indicated their involvement in the signaling ( Figure 5 @ B , C left panels ) . # ::alignments 1-1.1.2 2-1.1 3-1.1.1.r 4-1.1.1.2 5-1.1.1 6-1.1.1.1.r 7-1.1.1.1.1.1.1 9-1.1.1.1.2.1.1 10-1.1.1.1 11-1.1.1.1.3.1.1 12-1 13-1.2.1 13-1.2.1.r 14-1.2 15-1.2.2.r 17-1.2.2 19-1.3.1.1 19-1.3.1.2 26-1.3.1.3.1 27-1.3.1.3 (i / indicate-01~e.12 :ARG0 (e / experiment-01~e.2 :ARG1~e.3 (d / deplete-01~e.5 :ARG1~e.6 (a / and~e.10 :op1 (e2 / enzyme :name (n / name :op1 "NRAS"~e.7)) :op2 (e3 / enzyme :name (n2 / name :op1 "HRAS"~e.9)) :op3 (e4 / enzyme :name (n3 / name :op1 "KRAS"~e.11))) :ARG3-of (c / combine-01~e.4)) :mod (i2 / initial~e.1)) :ARG1 (i3 / involve-01~e.14 :ARG1~e.13 a~e.13 :ARG2~e.15 (s / signal-07~e.17)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure~e.19 :mod "5B") :op2 (f2 / figure~e.19 :mod "5C") :location (p / panel~e.27 :ARG1-of (l / left-20~e.26))))) # ::id pmid_2541_3220.134 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Further investigation of individual contribution of the RAS isoforms indicated KRAS as major RAS activator of the ERK signaling in these cells ( Figure 5 @ B @-@ E ) . # ::alignments 0-1.1.2 1-1.1 2-1.1.1.r 3-1.1.1.2 4-1.1.1 5-1.1.1.1.r 7-1.1.1.1.1.1.1 8-1.1.1.1 9-1 10-1.2.1.1 12-1.2.2.3 13-1.2.2.2 14-1.2 14-1.2.2 14-1.2.2.r 15-1.2.2.1.r 17-1.2.2.1.1.1.1 18-1.2.2.1 19-1.2.2.1.2.r 20-1.2.2.1.2.1 21-1.2.2.1.2 23-1.3.1.1 23-1.3.1.2 23-1.3.1.3 23-1.3.1.4 (i / indicate-01~e.9 :ARG0 (i2 / investigate-01~e.1 :ARG2~e.2 (c / contribute-01~e.4 :ARG0~e.5 (i4 / isoform~e.8 :mod (e3 / enzyme :name (n3 / name :op1 "RAS"~e.7))) :mod (i3 / individual~e.3)) :degree (f / further~e.0)) :ARG1 (e4 / enzyme~e.14 :name (n4 / name :op1 "KRAS"~e.10) :ARG0-of~e.14 (a2 / activate-01~e.14 :ARG1~e.15 (s / signal-07~e.18 :ARG0 (p / protein-family :name (n / name :op1 "ERK"~e.17)) :location~e.19 (c2 / cell~e.21 :mod (t / this~e.20))) :topic e3~e.13 :ARG1-of (m / major-02~e.12))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure~e.23 :mod "5B") :op2 (f3 / figure~e.23 :mod "5C") :op3 (f4 / figure~e.23 :mod "5D") :op4 (f5 / figure~e.23 :mod "5E")))) # ::id pmid_2541_3220.135 ::amr-annotator SDL-AMR-09 ::preferred # ::tok ERK pathway is activated already in skin melanocytes of Grey horses # ::alignments 1-1.1.1.1 2-1.1 4-1 5-1.2 6-1.3.r 7-1.3.1 8-1.3 9-1.3.2.r 10-1.3.2.1 11-1.3.2 (a / activate-01~e.4 :ARG1 (p / pathway~e.2 :name (n2 / name :op1 "ERK"~e.1)) :time (a2 / already~e.5) :location~e.6 (m / melanocyte~e.8 :part-of (s / skin~e.7) :poss~e.9 (h / horse~e.11 :ARG1-of (g / gray-02~e.10)))) # ::id pmid_2541_3220.136 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The absence of the oncogenic mutations commonly linked to the activation of the ERK pathway in melanomas , the strong association of the Grey mutation with the melanoma predisposition [ @ 17 @ ] and the notion that the Grey mutation has an effect throughout melanocyte development [ @ 18 @ ] , prompted us to test if the ERK pathway was already activated at the level of normal skin melanocytes in Grey horses . # ::alignments 1-1.1.1 2-1.1.1.1.r 4-1.1.1.1.1 4-1.1.1.1.1.1.2.1 5-1.1.1.1 6-1.1.1.1.2.2 7-1.1.1.1.2 8-1.1.1.1.2.1.r 10-1.1.1.1.2.1 11-1.1.1.1.2.1.1.r 13-1.1.1.1.2.1.1.2.1 14-1.1.1.1.2.1.1 15-1.1.1.1.2.1.2.r 16-1.1.1.1.2.1.2.2.1 19-1.1.2.3 20-1.1.2 24-1.1.2.1.1 24-1.1.2.1.1.1 24-1.1.2.1.1.1.r 26-1.1.2.1 27-1.1.2.2.r 29-1.1.2.2.1 30-1.1.2.2 33-1.1.2.4.1.1.1 36-1.1 38-1.1.3 42-1.1.3.1.1 43-1.1.3.1.1 44-1.1.3.1.1 47-1.1.3.1 49-1.1.3.1.2.1 50-1.1.3.1.2 53-1.1.3.1.3.1.1.1 57-1 58-1.2 59-1.1.1.1.1 60-1.3 63-1.3.2.2 64-1.3.2.2 66-1.3.2.3 67-1.3.2 71-1.3.2.4.r 72-1.3.2.4.1.1 73-1.3.2.4.1 74-1.3.2.4 75-1.3.2.4.2.r 76-1.3.2.4.2.1 77-1.3.2.4.2 (p / prompt-02~e.57 :ARG0 (a / and~e.36 :op1 (a2 / absent-01~e.1 :ARG1~e.2 (m / mutate-01~e.5 :ARG0-of (c2 / cause-01~e.4,59 :ARG1 (d5 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"~e.4))) :ARG1-of (l / link-01~e.7 :ARG2~e.8 (a3 / activate-01~e.10 :ARG1~e.11 (p2 / pathway~e.14 :wiki "MAPK/ERK_pathway" :name (n3 / name :op1 "ERK"~e.13)) :location~e.15 (m5 / medical-condition :wiki "Melanoma" :name (n7 / name :op1 "melanoma"~e.16))) :degree (c6 / common~e.6)))) :op2 (a4 / associate-01~e.20 :ARG1 (m3 / mutate-01~e.26 :mod (o / organism~e.24 :ARG1-of~e.24 (g / gray-02~e.24))) :ARG2~e.27 (p3 / predispose-01~e.30 :ARG2 m5~e.29) :ARG1-of (s / strong-02~e.19) :ARG1-of (d / describe-01 :ARG0 (p4 / publication-91 :ARG1-of (c / cite-01 :ARG2 17~e.33)))) :op3 (n / notion~e.38 :topic (a5 / affect-01~e.47 :ARG0 m3~e.42,43,44 :time (d2 / develop-02~e.50 :ARG1 (m2 / melanocyte~e.49)) :ARG1-of (d4 / describe-01 :ARG0 (p6 / publication-91 :ARG1-of (c7 / cite-01 :ARG2 18~e.53)))))) :ARG1 (w / we~e.58) :ARG2 (t / test-01~e.60 :ARG0 w :ARG2 (a6 / activate-01~e.67 :mode interrogative :ARG1 p2~e.63,64 :time (a7 / already~e.66) :location~e.71 (m4 / melanocyte~e.74 :part-of (s2 / skin~e.73 :ARG1-of (n6 / normal-02~e.72)) :location~e.75 (h / horse~e.77 :ARG1-of g~e.76))))) # ::id pmid_2541_3220.137 ::amr-annotator SDL-AMR-09 ::preferred # ::tok We analyzed expression of both phosphorylated and total ERK1 @/@ 2 in skin samples from Grey ( n = 9 ) vs @ . non @-@ grey horses ( n = 12 ) of different breeds from the same and different geographic locations , as was done for the melanoma samples . # ::alignments 0-1.1 1-1 2-1.2 5-1.2.1.1.2 6-1.2.1 7-1.2.1.2.2 8-1.2.1.1.1.1 8-1.2.1.2.1.1 10-1.2.1.1.1.1 10-1.2.1.2.1.1 11-1.2.2.r 12-1.2.2.1 13-1.2.2 14-1.2.2.2.3.2.r 14-1.2.2.2.r 15-1.2.2.2.2.2 21-1.2.2.2.1.1 27-1.2.2.2.2.2.1 27-1.2.2.2.2.2.1.r 29-1.2.2.2.1.2 29-1.2.2.2.2.2 30-1.2.2.2.1 30-1.2.2.2.2 36-1.2.2.2.2.1 39-1.2.2.2.3.1 40-1.2.2.2.3 41-1.2.2.2.3.2.r 43-1.2.2.2.3.2.1.1.1 44-1.2.2.2.3.2 45-1.2.2.2.3.1 45-1.3 46-1.2.2.2.3.2.1.1 46-1.2.2.2.3.2.2.1 47-1.2.2.2.3.2.1 47-1.2.2.2.3.2.2 51-1.3.1 52-1.3.1.1.r 54-1.3.1.1.1.1.1 55-1.3.1.1 (a / analyze-01~e.1 :ARG0 (w / we~e.0) :ARG1 (e / express-03~e.2 :ARG1 (a2 / and~e.6 :op1 (e2 / enzyme :name (n / name :op1 "ERK1/2"~e.8,10) :ARG3-of (p / phosphorylate-01~e.5)) :op2 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"~e.8,10) :mod (t / total~e.7))) :location~e.11 (s / sample-01~e.13 :ARG1 (s2 / skin~e.12) :ARG2~e.14 (a3 / and :op1 (h / horse~e.30 :quant 9~e.21 :ARG1-of (g / gray-02~e.29)) :op2 (h2 / horse~e.30 :quant 12~e.36 :ARG1-of (g2 / gray-02~e.15,29 :polarity~e.27 -~e.27)) :mod (b / breed~e.40 :ARG1-of (d / differ-02~e.39,45) :source~e.14,41 (a4 / and~e.44 :op1 (l / location~e.47 :mod (g3 / geographic~e.46 :ARG1-of (s3 / same-01~e.43))) :op2 (l2 / location~e.47 :mod (g4 / geographic~e.46 :ARG1-of d))))))) :ARG2-of (r / resemble-01~e.45 :ARG1 (d3 / do-02~e.51 :ARG2~e.52 (s4 / sample-01~e.55 :ARG1 (m / medical-condition :name (n3 / name :op1 "melanoma"~e.54)))))) # ::id pmid_2541_3220.138 ::amr-annotator SDL-AMR-09 ::preferred # ::tok A high percentage of MITF @⁺ epidermal melanocytes positive for the P @-@ ERK1 @/@ 2 was detected in all Grey horse skins ( 75.8 % ± 10.0 ) in sharp contrast to non @-@ grey horse skins , where the phosphorylated ERK was absent ( Figure 6 @ A , B ) . # ::alignments 1-1.1.1 2-1.1 6-1.4.1 9-1.1.2 10-1.1.2.3 11-1.1.2.3.1.r 13-1.1.2.3.1.2 15-1.1.2.3.1.1.1 17-1.1.2.3.1.1.1 19-1 20-1.2.r 21-1.2.2 22-1.2.1.1 23-1.2.1 24-1.2 26-1.1.3.1.1 27-1.1.3.1 27-1.1.3.1.2.1 27-1.1.3.1.3.1 29-1.1.3.1.2.1.1 29-1.1.3.1.3.1.1 31-1.3.r 32-1.3.2 33-1.3 34-1.3.1.r 35-1.3.1.1.1.1 35-1.3.1.1.1.1.r 37-1.3.1.1.1 38-1.3.1.1 39-1.3.1 41-1.3.1.2.r 43-1.3.1.2.3 44-1.3.1.2.1.1 46-1.3.1.2 46-1.3.1.2.2 46-1.3.1.2.2.r 48-1.4.1.1 48-1.4.1.2 (d / detect-01~e.19 :ARG1 (p / percentage~e.2 :ARG1-of (h / high-02~e.1) :quant-of (m2 / melanocyte~e.9 :part-of (e / epidermis) :mod (p2 / protein :name (n2 / name :op1 "MITF+")) :mod (p3 / positive~e.10 :mod~e.11 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"~e.15,17) :ARG3-of (p4 / phosphorylate-01~e.13)))) :ARG1-of (m / mean-01 :quant (p5 / percentage-entity~e.27 :value 75.8~e.26 :ARG2-of (a2 / add-02 :ARG1 (p6 / percentage-entity~e.27 :value 10.0~e.29)) :ARG2-of (s2 / subtract-01 :ARG1 (p7 / percentage-entity~e.27 :value 10.0~e.29))))) :location~e.20 (s / skin~e.24 :part-of (h2 / horse~e.23 :ARG1-of (g / gray-02~e.22)) :mod (a / all~e.21)) :ARG1-of~e.31 (c2 / contrast-01~e.33 :ARG2~e.34 (s4 / skin~e.39 :part-of (h3 / horse~e.38 :ARG1-of (g2 / gray-02~e.37 :polarity~e.35 -~e.35)) :location-of~e.41 (e3 / enzyme~e.46 :name (n4 / name :op1 "ERK"~e.44) :ARG1-of~e.46 (a3 / absent-01~e.46) :ARG3-of p4~e.43)) :ARG1-of (s3 / sharp-02~e.32)) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and~e.6 :op1 (f / figure~e.48 :mod "6A") :op2 (f2 / figure~e.48 :mod "6B")))) # ::id pmid_2541_3220.139 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The activated ERK1 @/@ 2 was detected both in the cytoplasm and the nucleus in Grey melanocytes . # ::alignments 1-1.1.2 2-1.1.1.1 4-1.1.1.1 6-1 8-1.2.r 10-1.2.1 11-1.2 13-1.2.2 15-1.2.3.1 15-1.2.3.1.1 15-1.2.3.1.1.r 16-1.2.3 (d / detect-01~e.6 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.2,4) :ARG1-of (a / activate-01~e.1)) :location~e.8 (a2 / and~e.11 :op1 (c / cytoplasm~e.10) :op2 (n2 / nucleus~e.13) :part-of (m / melanocyte~e.16 :mod (o / organism~e.15 :ARG1-of~e.15 (g / gray-02~e.15))))) # ::id pmid_2541_3220.140 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Percentage of the total ERK1 @/@ 2 positive cells was 99.5 % ± 0.5 in Grey and 77.1 % ± 11.3 in non @-@ grey skins ( Figure 6 @ A , B ) . # ::alignments 0-1.3 1-1.3.1.r 3-1.3.1.1.1.2 4-1.3.1.1.1.1.1 6-1.3.1.1.1.1.1 7-1.3.1.1 8-1.3.1 9-1.3.r 10-1.1.1 11-1.1 11-1.1.2.1 11-1.1.3.1 13-1.1.2.1.1 13-1.1.3.1.1 15-1.2.4.1 17-1.2.1 18-1.2 18-1.2.2.1 18-1.2.3.1 20-1.2.2.1.1 20-1.2.3.1.1 22-1.2.4.1.1 22-1.2.4.1.1.r 24-1.1.4.1 24-1.2.4.1 25-1.1.4 25-1.2.4 27-1.4.1.1 27-1.4.1.2 (a / and :op1 (p3 / percentage-entity~e.11 :value 99.5~e.10 :ARG2-of (a2 / add-02 :ARG1 (p4 / percentage-entity~e.11 :value 0.5~e.13)) :ARG2-of (s / subtract-01 :ARG1 (p5 / percentage-entity~e.11 :value 0.5~e.13)) :location (s2 / skin~e.25 :ARG1-of (g / gray-02~e.24))) :op2 (p6 / percentage-entity~e.18 :value 77.1~e.17 :ARG2-of (a3 / add-02 :ARG1 (p7 / percentage-entity~e.18 :value 11.3~e.20)) :ARG2-of (s3 / subtract-01 :ARG1 (p8 / percentage-entity~e.18 :value 11.3~e.20)) :location (s4 / skin~e.25 :ARG1-of (g2 / gray-02~e.15,24 :polarity~e.22 -~e.22))) :domain~e.9 (p9 / percentage~e.0 :quant-of~e.1 (c / cell~e.8 :mod (p10 / positive~e.7 :mod (e / enzyme :name (n / name :op1 "ERK1/2"~e.4,6) :mod (t / total~e.3))))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure~e.27 :mod "6A") :op2 (f2 / figure~e.27 :mod "6B")))) # ::id pmid_2541_3220.141 ::amr-annotator SDL-AMR-09 ::preferred # ::tok Interestingly , keratinocytes from Grey but not non @-@ grey horses were also positive for P @-@ ERK1 @/@ 2 ( Figure 6 @ A ) . # ::alignments 0-1.4 2-1.1.2 2-1.2.3 3-1.1.2.1.r 3-1.2.3.1.r 4-1.2.3.1.1 5-1 6-1.2.3.1.1.1 6-1.2.3.1.1.1.r 7-1.2.1 7-1.2.1.r 7-1.2.3.1.1.1 7-1.2.3.1.1.1.r 9-1.1.2.1.1 10-1.1.2.1 10-1.2.3.1 11-1.1.2.r 12-1.1.3 13-1.1 13-1.2 14-1.1.1.r 15-1.1.1.2 17-1.1.1.1.1 19-1.1.1.1.1 21-1.3.1 (c / contrast-01~e.5 :ARG1 (p / positive~e.13 :mod~e.14 (e / enzyme :name (n / name :op1 "ERK1/2"~e.17,19) :ARG3-of (p2 / phosphorylate-01~e.15)) :domain~e.11 (k2 / keratinocyte~e.2 :source~e.3 (h / horse~e.10 :ARG1-of (g / gray-02~e.9))) :mod (a / also~e.12)) :ARG2 (p3 / positive~e.13 :polarity~e.7 -~e.7 :mod e :domain (k / keratinocyte~e.2 :source~e.3 (h2 / horse~e.10 :ARG1-of (g2 / gray-02~e.4 :polarity~e.6,7 -~e.6,7)))) :ARG1-of (d / describe-01 :ARG0 (f / figure~e.21 :mod "6A")) :ARG0-of (i / interest-01~e.0)) # ::id pmid_2541_3220.142 ::amr-annotator SDL-AMR-09 ::preferred # ::tok The staining pattern of both P @-@ ERK1 @/@ 2 and ERK1 @/@ 2 was highly reproducible in samples coming from different studs and prepared in different laboratories . # ::alignments 1-1.1.1 2-1.1 5-1.1.1.1.1.2 7-1.1.1.1.1.1.1 7-1.1.1.1.2.1.1 9-1.1.1.1.1.1.1 9-1.1.1.1.2.1.1 10-1.1.1.1 11-1.1.1.1.1.1.1 11-1.1.1.1.2.1.1 13-1.1.1.1.1.1.1 13-1.1.1.1.2.1.1 15-1.3 18-1.4 18-1.4.2 18-1.4.2.r 20-1.4.2.1.r 21-1.4.2.1.1 22-1.4.2.1 24-1.4.1 25-1.4.1.1.r 26-1.4.1.1.1 27-1.4.1.1 (r / reproduce-01 :ARG1 (p2 / pattern~e.2 :topic (s / stain-01~e.1 :ARG1 (a / and~e.10 :op1 (e / enzyme :name (n / name :op1 "ERK1/2"~e.7,9,11,13) :ARG3-of (p3 / phosphorylate-01~e.5)) :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"~e.7,9,11,13))))) :ARG1-of (p / possible-01) :ARG1-of (h / high-02~e.15) :location (t / thing~e.18 :ARG1-of (p4 / prepare-01~e.24 :location~e.25 (l / laboratory~e.27 :ARG1-of d~e.26)) :ARG1-of~e.18 (s2 / sample-01~e.18 :ARG2~e.20 (s3 / stud~e.22 :ARG1-of (d / differ-02~e.21)))))